ORGANIC CHEMISTRY. 1. INTRODUCTION.

THE present Report represents a first step towards implementing a new general policy whereby Annual Reports are to revert to being balanced surveys of the main lines of progress during the year they cover. The past fifteen years, during which the Reports on Organic Chemistry were made up of essay articles on special topics, have left a formidable leeway which must to some extent be made good. In the following Report an attempt has been made to deal with some of the more important topics which have not been fully reviewed for some time and we have not tried to present a true Annual Report, except in the section on “ General Methods ”; the topics we have chosen for essay articles, in an attempt to cover some of the more important gaps, comprise “ Long-chain Aliphatic Compounds,” “ Vitamin-A and Related Polyenes,” “ Amino-acids,” “ Alkaloids,” “ Pro- teins,” and certain aspects of “ Theoretical Organic Chemistry,”

The appearance during 1949 of what will surely come to be known as the Penicillin Monograph presented us with a difficult problem. We have regretfully concluded that the space allotted to us is quite insufficient to allow us adequately to summarise this enormous volume of work, out- standingly important though it is; fortunately the subject has been fully reviewed elsewhere and the interested render is referred to the articles by E. Chain2 and A. H. Cook3 and to the summarising chapters in the Monograph itself.

It is hoped to present next year a Report which will deal with the major advances made in 1950, with references to relevant earlier work not pre- viously mentioned in Annual Reports; this will be supplemented by two or three essay articles on special topics. Thereafter it should be possible once more to present true Annual Reports, although it will probably be necessary for several years to come to include a considerable number of references to earlier work which was missed under the previous policy.

A. W. J. H. N. R.

2. THEORETICAL ORGANIC CHEMISTRY.

Various topics bearing on the physical and theoretical aspects of organic chemistry have been reviewed in Annual Reports during the last few years, but an article specifically devoted to this subject has not been included since 1941. The present return to the earlier practice coincides with the

H. T. Clarke, J. R. Johnson, and Sir Robert Robinson (Editors), “ The Chemistry of Penicillin,” Princeton Univ. Press, 1949.

Ann. Reviews Biochem., 1948, 17, 651. Quarterly Reviews, 1948, 2, 203.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online / Journal Homepage / Table of Contents for this issue

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 115

establishment of a section headed I‘ Physical Organic Chemistry ” in the Journal and reflects the intense activity in this field.

The problems of theoretical organic chemistry can still be summarised under the headings : (i) the detailed structure of organic compounds, (ii) the mechanism of organic reactions, and (iii) the correlation between structure and reactivity. These three themes are, of course, closely interwoven, but for this Report the aspect of mechanism has been chosen for special emphasis. Apart from homolytic reactions, which have been fully reviewed recently,l heterolytic substitution has continued to attract the largest amount of attention and it will be necessary? owing to limitations of space, to defer the discussion of other types of heterolytic reactions to a future Report.

Heterolyth Substitution. A. Nucleophilic substitution. 1. Replacement reactions of aZEyZ halides. The well-known work of E. D. Hughes and C. I(. Ingold and their collaborators in this field was reported in 1938 and 1940 and has also been summarised by one of the authorsB2 It will be recalled that methyl halides undergo alkaline hydrolysis in aqueous solvents mainly by a second-order, bimolecular reaction (&2) between the halide molecule and the hydroxyl ion, whereas tert.-butyl and other tertiary halides undergo hydrolysis mainly by a, first-order reaction, the rate of which is almost independent of the alkali concentration. Hydrolyses of substituted primary and of secondary halides exhibit mixed-order kinetics and the contribution of first- and second-order reactions can be determined by studying the effect of alkali concentration, taking into account the accompanying dehydrohalogenation (for a discussion of the elimination reactions, see ref. 3). The first-order (solvolytic) reaction could arise from a one-stage bimolecular reaction between the halide and the solvent, or from a two-stage reaction, the first and rate-determining step of which consists of the ionisation of the carbon-halogen bond. The solvolytic reaction of simple primary and secondary halides is mainly a bimolecular reaction with the solvent, but for tertiary halides, and a-aryl-substituted (e .g . , benzhydryl) halides powerful evidence has been adduced in favour of the two-stage mechanism.* Although it is recognised that electrostatic interaction with solvent molecules plays an essential part in the ionisation and that the concentration of carbonium ions remains immeasurably

D. H. Hey, Ann. Reports, 1940,37,250; 1944,41, 181; 1948,45, 139. H. B. Watson, Ann. Reports, 1938, 35, 210; 1940, 37, 236; E. D. Hughes, Trans..

Faraday Soc., 1941, 37, 603; J . , 1946, 968. E. D. Hughes and C. K. Ingold, Trans. Faraday SOC., 1941, 37, 657; M. L. Dhar,

E. D. Hughes, C. K. Ingold, A. M. M. Mandour, G. A. Maw, and L. I. Woolf, J., 1948, 2093.

4 Cf. L. C. Bateman, M. C. Church, E. D. Hughes, C. K. Ingold, and N. A. Taher, J., 1940, 979; L. C. Bateman, E. D. Hughes, and C. K. Ingold, ibid., p. 1017; G. W. Beste and L. P. Hammett, J . Amer. Chem. SOC., 1940, 62, 2481.

ti C. a. Swain and S. D. Ross, J . Amer. Chem. SOC., 1946,68,658; C . G. Swain, ibid., 1948, 70, 1119; C. G . Swain and R. W. Eddy, ibid., 1948, 70, 2989; of. P. D. Bartlett and R. W. Nebel, ibid., 1940,62, 1345.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

116 ORGANIC CHEMISTRY.

this mechanism has been termed unimolecular (&1) since only one molecule undergoes covalency change in the rate-determining step. The precise nature of the solvation process has been the subject of much discussion; some fresh light has been thrown on this question by the work of C. G. Swain,5 who has shown that the reaction between triphenylmethyl chloride and methanol in benzene exhibits third-order kinetics (second-order with respect to methanol) and has suggested that solvolysis requires a concerted attack by two neutral molecules on the carbon and the halogen atom, respectively. Itl is found that in the a-methylated series, the rate constants (k,) of the second-order reaction in aqueous solvents vary in the sequence Me>Et >Pri>But, while the rate constants (k,) of the first-order reaction vary in the sequence Me-Et-Pr<<But. The decrease in k, with increasing a-substitution is ascribed by Hughes et aL2 to the impedance of the approach of the negatively charged reagent by (i) increasing steric hindrance, and (ii) increasing electron-accession at the reacting carbon atom. The large increase in k, in the tertiary halides is ascribed wholly to the increased electron-accession which facilitates ionisation of the carbon-halogen bond. The reactivities of higher tertiary alkyl halides of the type CMe,R*Hal, where R = Me, Et, Pr, etc., reveal an irregular sequence of inductive effects Me < Et > Pri > Prn, which is also indicated in the primary and secondary halides themselves.’ M. Polanyi and his co-workers * have discussed the experimental results

from the point of view of transition-state theory. In the bimolecular reaction, the entering group X, the carbon atom C at which substitution takes place, and the displaced group Y will be collinearly arranged, and the three atoms attached to C will tend to be in a plane perpendicular to XCY, because this arrangement minimises the repulsion energies. In the case of methyl halides, the activation energy will be practically equal to the energy of stretching of the carbon-halogen bond to the transition state value, which is calculated to be of the order of 25 kcals./mol., and to decrease in the sequence MeCl > MeBr > MeI, in agreement with experiment. When the a-hydrogen atoms are replaced by methyl groups, i t is found that X and Y approach more closely to the p-hydrogen atoms than the sum of the van der Waals radii. The resulting compression is of the order of 0.6 A. and causes a steric hindrance increment to the energy of activation, which increases with the number of a-methyl substituents and amounts to about 2 kcals. in the case of But. Contrary to Hughes, Ingold, and their group,

6 J. Shorter and Sir Cyril Hinshelwood, J., 1949, 2412; H. C. Brown and R. S. Fletcher, J . Amer. Chern. Soc., 1949, 71, 1845.

7 I. Dostrovsky and E. D. Hughes, J., 1946, 157, 161, 164, 166, 169, 171; I. Dostrovsky, E. D. Hughes, and C. K. Ingold, J., 1946, 173; 1948, 1283; cf. Hughes, Quart. Reviews, 1948, 2, 107.

8 E. C. Baughan, M. G. Evans, and M. Polanyi, Trans. Paraday SOC., 1941,37, 377; E. C. Baughan and M. Polanyi, ibid., p. 648; A. G. Evans and M. Polanyi, Nature, 1942, 149, 608, 665; A. G. Evans, ibid., 1946, 157, 438; 158, 586; Trans. Paraday Xoc., 1946, 42, 719; “ The Reactions of Organic Halides in Solution,” Manchester Univ. Press, 1946; A. G. Evans, M. G . Evans, and M. Polanyi, J., 1947, 658.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 117

Polanyi and his co-workers * regard the decrease in the rate of bimolecular substitution in the sequence Me > Et > Pri> But as due entirely to steric hindrance, particularly as the interpretation of the polar effect is ambiguous, since increased electron-accession a t the reaction centre will both repel the negatively charged reagent and help to expel the replaceable group.

Application of transition-state theory to the unimolecular reaction indicates that the activation energy should be practically the same as the endothermicity (&) of the ionisation reaction RHal+ R+ + Hal-, where R+ and Hal- represent solwated ions. According to A. G . Evans,* the calculated values of Q (in kcals./mol.) for aqueous solutions are MeCl 89, EtCl 59, Pr'Cl 37, and BuWl 26, the differences arising mainly from the decreasing ionisation potentials of the alkyl groups. The observed value for the unimolecular solvolysis of BuWl in aqueous ethanol is 23 kcals./mo1.6% The complete change-over in mechanism with the tertiary halides is thus explained by the fact that the energy of activation of the unimolecular reaction here falls below that of the bimolecular reaction.

In a further group of papers by I. Dostrovsky and Hughes the principles previously established are extended in greater detail to the P-methylated series of methyl, ethyl, n-propyl, isobutyl, and neopentyl derivatives. It is known from the work of F. C. Whitmore and his collaborators lo that the neopentyl halides are extraordinarily inert towards the usual nucleophilic reagents. This result is at first sight somewhat surprising, since neopentyl is a primary group. Kinetic measurements show that the reactivity of neopentyl halides is indeed extremely low when the XN2 mechanism is operative (as is the case under the usual preparative conditions), but that the reactivity in solvolytic substitution is very similar to that of other primary halides.

First- or second-order rate constants ( 104k) for substitution reactions of RBr.7

Reagent and

OEt- in EtOH,

I- in Me,CO,

conditions. Mechanism. R = Me Me*CH, Me-CH,*CH, Me,CH*CH, Me,C*CH,

95" ............ S N 2 9650 647 181 26 0.0065

64" ............ S N 2 - 480 - - 0.027 50% H,O-EtOH,

95' ............ S N 2 + S N l 2.86 1.41 0.80 0.011 0.009

95" ............ S,l f s ~ 2 0.017 0.027 0.018 - 0.015 H20 in H*C02H,

The alcoholysis with sodium ethoxide in dry ethanol, and the exchange reaction with sodium iodide in dry acetone, are of the second order for all the primary halides, and the rate constants for the neopentyl derivatives are smaller by factors of 104--105 than those for the ethyl derivatives. In aqueous ethanol, the first four members undergo much slower " neutral "

@ E. D. Hughes, J. , 1935, 255; K. A. Cooper and E. D. Hughes, J., 1937, 1183. lo F. C. Whitmore and C. H. Fleming, J . Amer. Chem. SOC., 1933, 55, 4161; F. C.

Whitmore, E. L. Wittle, and A. H. Popkin, ibid., 1939, 61, 1586; P. D. Bartlett and L. J. Rosen, ibid., 1942, 64, 543.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

118 ORGANIC CHEIXISTRY.

hydrolysis by a bimolecular (though necessarily first-order) reaction with the solvent, whereas neopentyl bromide undergoes somewhat faster hydrolysis which is insensitive to the addition of hydroxide ion but accelerated by increase of the water content and ionising power of the medium. It is concluded that the reaction of the neopentyl derivative is unimolecular under those conditions, and this is supported by the observation that the accom- panying elimination reaction gives rise to tert. -amylene with rearrangement of the carbon skeleton, a phenomenon associated with the (at least partial) liberation of the positive carbonium ion. Finally, solvolysis in slightly aqueous formic acid, a medium of still higher ionising power, is believed to proceed mainly by the X N l mechanism with all the primary halides, and here

the rate of reaction of the neopentyl derivative is no longer abnormal, but quite comparable to that of the other members of the series. A practical out- come of these studies is that, with com- pounds which are sterically hindered in bimolecular substitution, reaction can often be more readily effected by the addition of a suitable solvent (e.g., water) than by the introduction of more power- ful reagents (e.g., hydroxide ion).

Measurements a t different temper- atures show that the low reactivity of the neopentyl halides in bimolecular

FIG. 1. substitution is partly accounted for by !Z'rc~~ition state of n e o p e W l group in a relatively high energy of activation.

bimoleculur substitution. 7 a i s the

gen atoms. d, 0, and f a re the @-carbon given a semi-quantitative interpretation of this result by developing the transition- atoms. The y-hydrogen atoms are .not

shown. state theory due to Polanyi and his

school.8 The transition state (see Fig. 1) is regarded as a resonance hybrid in which X and Y share one unit charge between them, and the distances YC and CX are equated to the sum of the covalent radius of carbon and the mean between the covalent and negative ionic (crystal) radii of X and Y. The orientations of the atoms not directly bonded to C and normally subject to free rotation are assumed to be such that the non-bonded distance which falls furthest below the corresponding van der Waals distance will be a maximum. It is found that two of the p-carbon atoms and four of the y-hydrogen atoms approach X or Y more closely (by about 1 A.) than the " touching " distance and that the compressions are not very dependent on the size of X and Y (because XC and CY increase with the radii of X and Y). Owing to the '' side-ways " approach of the reagent, the compression in the transition state of the neopentyl group is thus considerably larger than in the tert.-butyl group (see above), and, unlike the latter, exceeds the critical value (ca. 0.8 A . ~ ) beyond which atomic repulsion forces inerease

a-carbon atom, b Q& c are the a-hydro- Dostrovs1cy, Hughes, and Ingold ' have

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 119

very rapidly. I n order to translate the geometrical compressions into energy terms, the interaction energy of two atoms is expressed in the form W = WE: + u', + Wr where WE represents the electrostatic energy (arising from induced dipoles), WD the so-called dispersion energy (arising from dipoles set up by molecular vibrations), and WI the interpenetration energy. The first two terms must be positive (attraction) and the last negative (repulsion), but neither the functions connecting the separate terms with the non-bonded atomic distances, nor the constants governing their rela.tive magnitudes are known with any certainty (cf. ref. 11). However, by making reasonable assumptions concerning these quantities and summing W over all the non-bonded atoms concerned, upper limits to the contributions (A.Ew) of steric hindrance to the energy of activation can be calculated. The values thus derived indicate a relatively small steric effect up to the tert.-butyl group, but a strikingly large effect for the neopentyl group.

R = Ma Et Pri Bui But neoPentyl Eexp. fOr RBr + OEt-inEtOH 20.0 21.0 - 22.8 - 26.2 Eerp. for RBr + I- in acetone

or RBr + Br- in ethylene diacetate la ..................... - 19.0 19.8 - 22.6 25

AE, experimental ............... - 1.0 1.8 2.8 4-6 6.2 (7.0) AEw, calculatad .................. - 1.9 1.9 2.3 2.7 12.6

The values of AEw, particularly for the neopentyl group, are almost certainly too large, since the calculation neglects the bending of the XC and CY bonds induced by steric hindrance. Nevertheless, the semi-quantitative treatment does explain how the interpolation of a CH, group in passing from the tert.-butyl to the neopentyl structure results in increased steric hindrance at the reaction centre. This result could hardly have been predicted from classical considerations and provides an excellent illustration of the importance of the transition-state concept in the interpretation of reaction mechanism.

2. Replacement reactions 01 carboxylic esters. Next t o replacement reactions a t carbon-halogen bonds, those a t carbon-oxygen bonds are the most thoroughly investigated type of nucleophilic substitution. The usual mode of alkaline hydrolysis of carboxylic esters involves a bimolecular attack by the hydroxyl ion and acyl-oxygen fission (1). l3 Recent work by J. Kenyon, M. P. Balfe, and their collaborators l4 has led to the recognition of a second mode of hydrolysis which involves alkyl-oxygen fission. It is

l1 F. H. Westheimer, J. Chem. Physics, 1947, 15, 252; D. H. R. Barton, J., 1948,

12 L. J. le ROUX, C. S. Lu, S. Sugden, and R. H. K. Thomson, J., 1945, 586. 340.

H. B. Watson, Ann. Report.9, 1940,37,229; J. N. E. Day and C. K. Ingold, Trans. Paraday SOC., 1941, 37, 686.

14 M. P. Balfe, H. W. J. Hills, J. Kenyon, H. Phillips, and B. C. Platt, J., 1942,556 ; M. P. Balfe, M. A. Doughty, J. Kenyon, and R. Poplett, ibid., p. 605; M. P. Balfe, E. A. W. Downer, A. A. Evans, J. Kenyon, R. Poplett, C. E. Searle, and A. L. Thrnoky, J., 1946, 797; M. P. Balfe, A. Evans, J. Kenyon, and K. N. Nandi, ibid., p. 803; M. P. Balfe, J. Kenyon, and R. Wicks, ibid., p. 807.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

120 ORGANIC CHEMISTRY.

found that the alkaline hydrolysis of esters derived from optically active secondary carbinols R,R,C*H*OH, where R,, or R, and R,, are aryl or alkenyl groups, is accompanied by racemisation, the degree of which depends on R, and R,, and on the alkali concentration. Esters of this type also react with methanol or ethanol to give the methyl or ethyl ethers, and with formic or acetic acid to give the racemic formates or acetates. The gradation of reactivity is illustrated in the table.

XoZvoZytic reactions of esters of R1R,C*H*OH.14 Concen- trated

R1 R* alkali p-Methoxy- Phenyl Racemisa-

phenyl tion Propenyl Methyl Retention

1-Naphthyl Methyl Retention

Phenyl Methyl Retention

Dilute alkali Ethanol

Racemisa- Racemisa- tion tion

Racemisa- Racemisa- tion tion

Partial No re- racemisa- action tion

racemisa- action tion

Slight No re-

Aqueous ethanol

Racemisa-

Racemisa-

Raccmisa-

tion

tion

tion

No ro- action

Formic acid

Racemisa-

Racemisa-

Racemisa-

tion

tion

tion

Racemisa- tion

In strongly alkaline solution, the usual mechanism (1) evidently takes precedence and the configuration at C* is retained, but in dilute alkaline, neutral, or acid solution appreciable or complete racemisation occurs. This suggests the liberation of the positive, optically unstable earbonium ion R,R,CH+, facilitated by the electron-releasing substituents (2). In acid solution, alkyl-oxygen fission will be assisted by the formation of the oxonium ion (cf. ref. 15), which can dissociate without the production of additional charges (3).

I H O R-$-O--C*HR1R2 + OH- - R*E*OH + R1R2C*H.*O- 3

0 slow

0 1 R*E*OH + EIR,C*H*OH + OH- . . (1) 0

I H O R-$-O--C*HR1R2 + OH- - R*E*OH + R1R2C*H.*O- 3

0 slow

0 1 R*E*OH + EIR,C*H*OH + OH- . . (1) 0

R*$-O-C*HR,R, I R*$-O- + R,R,CH+ 3 0 0

R*E*OH + R,R,CH*OH . . (2) 0

H+ 1 1

R*fi-OU*HR Rt R*#--OH*-~CHR,R, + 1 slow I 0 1 2 t 0 I .

R*#*OH + R,R,C€€+ 3 R*G*OH + RlR2CH*OH + H+ . . (3) 0 0

. In esters of allyl alcohols (R, = alkenyl), alkaline hydrolysis by mechanism (2) should result in some rearrangement of the allyl residue,

16 M. F. Carroll, J., 1949, 557, 2188, 2192.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 121

because the intermediate carbonium ion will be rnesomeric (cf. p. 1%). This test was first applied 16a to the acetates of crotyl and l-methylallyl alcohol, with negative results. In 1 : 3-dimethylallyl derivatives (e.g., methylpropenylcarbinyl esters ; see above), application of the test is pre- cluded by the structural symmetry, but 1 -pheny1-3-methylallyl (phenyl- propenylcarbinyl) esters are suitable in this respect, since the tendency towards alkyl-oxygen fission should be even higher and since the allylic equilibrium is known to lie well on the side of the isomeric 3-phenyl-l- methylallyl (styrylmethylcarbinyl) structure (cf. p. 129).27 It was re- ported 16* that dilute alkaline hydrolysis of the hydrogen phthalate, and neutral methanolysis of the p-nitrobenzoate, of phenylpropenylcarbinol give, respectively, styrylmethylcarbinol and its methyl ether and this observation has been cited13 in support of the mechanism involving uni- molecular alkyl-oxygen fission (2). It has recently been established, however,17 that the earlier findings must be ascribed to the incursion of acidic conditions in the course of the reaction or during the isolation of the product's, and that hydrolysis with O.OlM-potassium hydroxide in aqueous dioxan is accompanied by less than 1% of rearrangement. This result can be interpreted in two ways : Either dilute alkaline ( i e . , neutral) hydrolysis with alkyl-oxygen fission is a two-stage process, as shown in ( Z ) , in which case the carbonium ion must be sufficiently free to undergo racemisation, but not sufficiently free to undergo rearrangement ; or neutral hydrolysis with alkyl-oxygen fission involves a bimolecular or termolecular reaction with the solvent ; in this case i t must be concluded that, whereas bimolecular reaction with a negatively charged reagent (e.g. , OH-) generally leads to inversion, multimolecular reaction with a neutral reagent can lead to racemis- ation. Further discussion would be premature, but the latter explanation appears the more likely.

Under acid conditions, the hydrolysis of allylic esters is generally accompanied by some, though not necessarily complete, rearrangement. Reactions of this type are discussed in some detail later (p. 127). It should be mentioned here, however, that their interpretation is to some extent complicated by the fact that the ease of rearrangement of the carbinols, ethers, and esters under such conditions is of the same order and that hydrolysis may be simultaneous with, consecutive to, or independent of, rearrangement. A detailed kinetic study l8 of the acid hydrolysis and rearrangement of the acetate of 1 -eth yn yl-3 -met h ylallylalcohol (propenyl- ethynylcarbinol) in aqueous ethanol and dioxan indicates that in the presence of an electron-attracting substituent (such as the ethynyl group), hydrolysis with acyl-oxygen fission and rearrangement, which must involve alkyl- oxygen fission, can proceed side by side.

In esters of tertiary alcohols, the tendency towards alkyl-oxygen fission l6 (a) C. Prevost, Ann. Chim., 1928, 10, 147; C. K. Ingold and E. H. Ingold, J.,

l7 E. A. Braude and E. S. Waight, unpublished. 1932, 756. ( b ) J. Kenyon, S. M. Partridge, and H. Phillips, J. , 1936, 85; 1937, 226.

E. A. Braude, J., 1948, 794.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

122 ORGANIC CHBMISTRY.

is greatly enhanced ; thus tert.-butyl benzoate reacts with methanol to give methyl butyl ether.lg The fact that tertiary alcohols are difficult t o resolve through their hydrogen phthalates may have the same cause.20

3. Injuence of neighbouring polar substituents in aliphatic substitution. Extensive experimental data concerning the effect of neighbouring groups, other than alkyl, on the mechanism, rate, and stereochemical course of nucleophilic substitution reactions have been assembled by S. Winstein and his co-workers.21 Earlier work 22 had shown that bimolecular substitu- tion at an asymmetric carbon atom is invariably accompanied by inversion of configuration (Walden inversion) as expected from the transition-state model, whereas unimolecular nucleophilic substitution normally leads to extensive (though incomplete) racemisation, since the intermediate positive carbonium ion tends to assume a planar configuration. I n the presence of a negatively charged B-substituent (e.g., in the a-bromopropionate ion), however, SEl reaction is accompanied by retention of configuration, and W. A. Cowdrey et al.22 concluded that, in this case, electrostatic attraction between the two charged centres of the carbonium ion (I) stabilises the pyramidal configuration until the entry of the new group has taken place. Winstein,21 on the other hand, regards the intermediate as a (neutral) or-lactone (11) formed by an intramolecular displacement reaction with inversion of configuration. The intermediate (11) then undergoes bimole- cular reaction with an anion, again accompanied by Walden inversion and resulting in overall retention of configuration.

Me Me Me)d% (11.) (1.1 ‘\&-yo +--- )y*coo- __I,

H’ 0- H Rr H Further evidence for the incursion of cyclic intermediates has been

adduced from a study of the effects of neutral P-substituents.21123 Thus, acetolysis of trans- 1 : 2-dibromocyclohexane (111), trans- 1 -bromo-2-acetoxy- cycbhexane (V), meso-2 : 3-dibromobutane7 and erythro- or threo-3-bromo- 2-acetoxybutane with silver acetate in dry acetic acid or acetic anhydride furnish the corresponding diacetoxy-derivatives with almost complete

1 0 S. G. Cohen and A. Schneider, J . Amer. Chem. SOC., 1941, 63, 3382. 2* C. L. Wilson, Truns. Pu~&y Soc., 1941, 37, 706 ; W. von E. Doering and H. H.

Zeiss, J . Amer. Chem. SOC., 1948, 70, 3966. 21 S. Winstein and H. J. Lucas, J , Amer. Chem. SOC., 1939, 61, 1576, 2845; S. Win-

stein and R. E. Buckles, ibid., 1942,64, 2780, 2787; 1943, 65, 613; s. Winstein, ibid., 1942, 64, 2791, 2792; S. Winstein, H. V. Hess, and R. E. Buckles, ibid., p. 2796; S. Winstein and R. B. Henderson, 1943,65,2196 ; S. Winstein and D. Seymour, ibid., 1946, 68, 119; S. Winstein and E. Grunwald, ibid., F. 536; 1945, 70, 838, 841, 846; S. Win- stein, C. Hanson, and E. Grunwald, ibid., p. 812; s. Winstein, E. Grunwald, R. E. Buckles, and C. Hatxson, ibid., p. 816 ; S. Winstein, E. Grunwald, and L. L. Ingrcaham, ibid., p. 821 ; S. Winstein and R. Adams, ibid., p. 838.

*2 W. A. Cowdrey, E. D. Hughes, C. K. Ingold, S. Mastermann, and A. D. Scott, J. , 1937, 1262.

2o C. Golumbic, J. S. Fruton, and 31. Bergmann, J . Org. Chem., 1946, 11, 518; W. E. Hanby, G. S . Hartley, E. 0. Powell, and H. N. Rydon, J . , 1947, 519; W. C. J. Ross, J . , 1949, 183, 1972, 2589, 2824.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 123

retention of configuration. The replacement of the first bromine atom in the dibromo-derivatives is thought to proceed via the bromonium ion (IV) which has also been postulated as intermediate in the normal trans-addition

\/ C

C I I

A A trans-1 : 2-Dibromo- derivative (111.) /

A c O 8 I C*OAc

of bromine to ~yclohexene.~~ [A more truthful representation of the electron distribution in (IV) is probably achieved in the x-complex formulation proposed by M. J. S. D e ~ a r . ~ 5 ] Thc second replacement of the other bromine atom is thought to proceed via the acetosonium ion (VI).

/\ A Bromonium ion trans-Diacetate

W.1 (VII.)

I I J.

C*OAc C-01 /\ /\

trans-1-Bromo- Acetoxonium 2-acetoxy-

derivative (V.) ion

WI.)

/ Tos*O?C/

I &OAc A

trans-2- Acetoxycyclohexyl toluene-p-sulphonate (XI.)

‘$y Unstable

\ /

A Stable (XII.)

/\ cis- Diacetate

fIX.) .f * c 0 a I

\/ C*OH

-3 A LOAc

cw-Monoacetate (X.1

____I, signifies retention of configuration. signifies inversion of configuration.

In dry acetic acid containing acetate ions, the final product is the trans- diacetate (VII). In slightly aqueous acid, on the other hand, the final product is almost entirely the cis-diacetate (IX); this can be explained by assuming that the acetoxonium ion (VI) reacts with water to give the unstable orthomonoacetate, the ring of which then opens without inversion to give the cis-glycol monoacetate (X). This reacts with acetic acid, again

24 I. Roberts and G. E. Kimball, J . Amer, Chem. SOC., 1937, 59, 947. 26 M. J. S. Dewar, Nature, 1945, 156, 7 8 4 ; J . , 1946, 406, 777; Discussions of tho

Faraday Society, 1947, No. 2, 50; “The Electronic Theory of Organic Chemistry,” Oxford, 1949.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

124 ORGANIC CHEMISTRY.

without inversion, to give the cis-diaceta te (IX). A control experiment showed that (X), prepared independently, is largely converted into (IX) under these conditions. Analogous reactions can be carried out with the toluene-p-sulphonyl derivative (XI), which is converted into the trans- diacetate (VII) by potassium acetate in dry acetic acid. In the absence of acetate ions, however, the product is almost entirely the cis-diacetate (IX), which may be formed by direct reaction of the acetoxonium ion (VI) with acetic acid. In absolute ethanol, the ethyl orthoacetate (XII) is similarly produced. The ortho-ester can be isolated under anhydrous conditions, but is readily hydrolysed to the cis-glycol in the presence of water.

Although it should be emphasised that other interpretations cannot at present be excluded, the hypothesis of cyclic intermediates in reactions of this type is supported by kinetic measurements. Thus, trans-2-acetoxy- cychhexyl toluene-p-sulphonate (XI) undergoes acetolysis only about 3 times more slowly than the parent cyclohexyl toluene-p-sulphonate. Since the acetoxy-group is strongly electron-attracting, a larger difference in reactivity might be expected if a unimolecular ionisation were involved in both cases, but the data are compatible with an internal displacement reaction in the case of the trans-acetoxy-derivative. The corresponding cis-acetoxy- derivative, on the other hand, reacts about 10,000 times more slowly. In this case, the formation of a cyclic intermediate is excluded by steric con- siderations, and the unimolecular ionisation mechanism is thought to operate. The product formed, however, is mainly the trans-diacetate, so that the acetolysis of the cis-2-acetoxy-derivative, unlike that of the trans- derivative, is accompanied by inversion. It appears to the Reporter that this can be explained more satisfactorily by assuming that the cis-2-acetoxy- derivative undergoes solvolysis by a bimolecular reaction with the solvent (AcOH), particularly as there will be no steric hindrance to the approach of the reagent of the trans-side of the carbon-carbon bond.

@-Halogen substituents also have a pronounced effect, the rates of reaction varying in the order I > H > I3r > C1. Since halogen substituents have a strong negative inductive effect, the sequence expected for a uni- molecular ionisation of the sulphonate group is H> I> Br> C1. From this and other considerations it is concluded 21 that the unimolecular ionisation mechanism operates only in the case of a P-chloro-substituent, whereas the iodo- and bromo-substituted derivatives react largely through the cyclic intermediates. Large reactivity effects due to OH, OR, SR,

Acetolysis of 2-substituted cyclohexyt p-bromobenzenesulphonates at 25°.21 R. Relative rate. R. Relative rate.

H ........................... 1 H ............ 1

trans-OAc ............... 0.31 Br ............ 0.072 truns-OMe ............... 0.053 I ............... 1120

c i s - ~ ~ c .................. 1.3 x 1 0 - 4 ci ............ 0.9 x 10-4

and NR, substituents have also been observed in the hydrolysis of p-sub- stituted alkyl chlorides and ethers and there is strong evidence in favour of the participation of the cyclic ethylenesulphonium and ethyleneimonium

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 125

ions in the replacement reactions of “ mustard gas ” and of the “ nitrogen mustards.” 233 26, 27

Three- carbon anionotropy. All molecular rearrangemen-ts can be regarded as special cases of substitution reactions, but a type of rearrangement which is particularly relevant in connection with nucleophilic substitution is three- carbon anionotropy . In ally1 derivatives, nucleophilic replacement reactions are frequently accompanied by rearrangement to give the y-substituted products. Such non-isomeric rearrangement is no different in principle from isomeric rearrangement in which the entering and the displaced anionoid group happen to be identical.

a 1 3 y a B v

A A’

4. Nucleophilic substitution accompanied by allylic rearrungemnt.

(XIII .I RI-YH-CH=CH--R, ---+ R,--CH=CH--CH-Rg (XIV. )

Many new examples of such reactions have been described within recent years and subjected to detailed kinetic study. Spectroscopic methods for following organic reactions have been of great value in this field.28 Aniono- tropy, like ordinary nucleophilic substitution, is greatly facilitated by electron-donating substituents and analogy suggests three possible types of mechanism: (1) A rate-determining separation of A as the anion A- with a, re-distribution of electrons in the resulting carbonium ion, followed by the attachment of A- or A’- a t C’; this represents a two-stage mechanism analogous to XNl substitution; ( 2 ) a bimolecular attack by the reagent at Cy with simultaneous migration of the electron-pair and fission of C-A; this represents a bimolecular substitution at a carbon-carbon double bond (the first displaced group being an electron pair) and is analogous to XN2 substitution ; (3) an intramolecular rearrangement ; this can only apply when A and A’ are identical and is analogous to nucleophilic substitution via a cyclic intermediate (cf. p. 123).

K- AC-CZC =+= A- + [Cz-C--C]+ + A- + C=C-CA’. . (1)

. b. AC-C=C _I, C:<A>:C---t C=C--CA . . . (3)

26 R. C. Fuson, C. C. Price, and D. M. Burness, J. Org. Chem., 1946,11, 475; P. D. Bartlett,, S. D. Ross, and C. G. Swain, J. Arner. Chem. SOC., 1947, 69, 2971; P. D. Bartlett, J. W. Davis, S. D. Ross, and C. G. Swain, ibid., p. 2977; S. D. Ross, ibid., p. 2982; P. D. Bartlett and C. G. Swain, ibid., 1949, 71, 1406; P. D. Bartlett, S. D. Ross, and C. G. Swain, ibid., p. 1415; A. G. Ogston et al., Trans. Paraday Soc., 1948,

27 M. H. Palomaa, Ber., 1941, 74, B, 1866; H. Bohme and K. Sell, ibid., 1948, 81, B, 123.

28 E, A. Braude and E. R. H. Jones, J., 1944, 436; 1946, 122, 128; E. A. Bmude, J., 1944,443 ; 1948, 794 ; E. A. Braude, E. R. H. Jones, and E. S. Stern, J., 1946, 396 ; E. A. Braude and E. S. Stern, J., 1947, 1096; J., 1948, 1982; E. A. Braude and J. S. Fawcett, J., 1950, in the press; cf. Braude, Quart. Reviews, 1950, in the press.

44, 45.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

126 ORGANIC OHEMISTRY.

The range of applicability of these three types of mechanism, all of which have probably been observed, has engendered considerable controversy and i t is no easy task to summarise the evidence adequately within a short space. As in the case of simple substitution, and also for an additional reason which will become apparent, it is convenient to deal separately with anionotropic substitution involving the fission of a C-0 and of a C-Hal bond.

Many of the earlier and some recent discussions32 of the mechanism of anionotropy in alcohols, ethers, and esters are partly invalidated by the demonstration that rearrangement occurs only under acidic conditions and is specifically catalysed by the hydrogen ion."* 18$ 28 It has long been known that anionotropy is subject to acid catalysis ; thus mineral acids are the commonest reagents €or effecting rearrangement and, whereas 1 -alkenyl- and l-aryl-ally1 alcohols can be converted into their own acetates and p- nitrobenzoates by dry acetic anhydride and p-nitrobenzoyl chloride in the presence of pyridine, esterification in the presence of acetic acid or hydrogen chloride gives mainly the corresponding 3-ally1 derivatives. However, acid catalysis has generally been regarded merely as a promoting factor, whereas recent work 18*28 has shown that it is a condition necessary for rearrangement in all the cases so far examined. The evidence is briefly as follows : (i) The speed of rearrangement of ally1 alcohols and esters in dilute acids is directly proportional to the hydrogen-ion concentration, and the plot of the first-order rate constants against [H'] passes through the origin. (ii) In concentrated acid solutions and in the presence of salts, the rate constants are proportional to the acidity function H , which is a measure of the tendency of the medium to donate a proton to a neutral base and which can be determined 29 by colorimetric or spectrometric means, using suitable indicators ; i.e., the ra.te constants are proportional to the fraction of the carbinol converted into its oxonium ion ROH+. (iii) The characteristic dependence of the rate constants on medium composition in organic solvent-water mixtures similarly runs closely parallel to the changes in acidity function, which in turn arise through changes in the solvent " structure " and in the mode of solvation of the hydrogen i0ns.2~ (iv) Ally1 alcohols and esters which are extremely readily isomerised in very dilute acids are completely unchanged on prolonged heating in neutral solvents provided that traces of acids are excluded. (v) The apparent spontaneous rearrangement of certain esters in neutral solvents 166730 can be shown 1 7 ~ 1 ~ to be due to the carboxylic acid produced by elimination or other side reaction ; thus the slow rearrangement of the p-nitrobenzoate of l-phenylallyl alcohol (XIII; R = Ph, R, = H) in boiling chlorobenzene or other neutral solvent is caused by the elimination of a small but isolatable amount of p-nitrobenzoic acid, since the values of the rate constants fall on the straight lines obtained by plotting the rate constants in the presence of added p-nitrobenzoic acid against the acid concentration. Various

29 L. P. Hammstt, Chem. Reviews, 1935, 16, 67; E. A. Braude, J., 1948, 1971; E. A. Braude and E. S. Stern, J., 1948, 1976; Nature, 1948, 161, 169.

50 H. Burton and C. K. Ingold, J., 1928,904; H. Burton, J., 1928, 1650; 1929,455.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 127

contradictory results in the earlier literature can be accounted for by the use of impure reagents and solvents. Others, e.g., the recorded failures 30 of 1 -pheny 'tally1 alcohol and its p-nitrobenzoate to rearrange in the presence of mineral acids, have been found to be e r r o n e o u ~ . ~ ~ ~ ~ ~ The recognition that hydrogen ion is essential for anionotropic rearrangement in alcohols, ethers, and esters in solution necessitates a reformulation of mechanisms (l), (Z), and (3) in these cases; the entities undergoing rearrangement are evidently not the neutral molecules, but their oxonium ions formed bythe reversible addition of a proton to the oxygen atom attached to the a-carbon atom, as shown in (4), (5), and (6). The fission of the C-0 bond no longer involves the separation of two permanent or temporary charges, but the energetically much more favourable separation of an uncharged water or c'arboxylic acid molecule ; furthermore, mechanism (5), the analogue of (Z), involves bimolecular attack a t the y-atom by a neutral molecule (e.g.,

a+ HOB' C---C=C + C-C=C + HOR + [Cz-CzC]+ _I__,

OR - H+

H b 'R c-c-c~c=c-c . . (4) 1

OR' I

I HO+R'

- Rf HOR+CZC---CSC=C-C . . (5 )

1 OR'

I HO'R'

Hf c-c=c * c---c=c --3

- Hf C=C-C +C=C-C. . (6)

bR

I t

H,O, ROH, R*C02H) instead of attack by an anion. These considerations invalidate it good deal of the evidence which has been adduced until quite recently in favour of or against the mechanisms (I), (Z), and (3).

Nechanism (1) was first postulated by H. Burton and C. K. Ing01d,~O who purported to show that anionotropic mobility increases (i) with the anionic stability of the migrating group A in the sequence OH < OAc < OCO*C,H,*N02, and (ii) with increasing dielectric constant of the solvent in the sequence xylene < chlorobenzene < acetic anhydride < benzonitrile. With regard to (i), recent work has shown that under comparable acidic conditions the mobilities of an allylic carbinol and its acetate are very nearly equal,18 while those of the benzoate and p-nitrobenzoate are considerably sma1ler.l' I n the case of 1-phenylallyl derivatives, (i) is superficially true

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

128 ORGANIC CHEMISTRY.

in initially neutral solvents, but the apparent differences in mobility actually arises through the circumstance l7 that the carbinol remains unchanged under these conditions, while the rearrangements of the esters are brought about by small amounts of acetic, benzoic: and nitrobenzoic acid produced by elimination and other side reactions, and that the strengths of the acids increase in that order. With regard to (ii), a comparison of apparent “ uncatalysed ” rates in different neutral solvents has little significance in the light of recent work since the relative rates are again accounted for mainly by the varying amounts of acid produced in side reactions. It has also been found,31 contrary to the earlier results,30 that esters which are re- arranged when heated with acetic anhydride remain unchanged on similar treatment with benzonitrile. Further evidence which has been cited 32

in favour of mechanism (1) is that the rearrangement of optically active derivatives is accompanied by extensive racemisation. However, the same result will be produced by mechanisms ( 2 ) and (5) since the reagent can approach the y-carbon atom on either side of the carbon bond.

A. G. Catchpole and Hughes 32 searched for mechanism ( 2 ) by carrying out the rearrangement of l-phenylallyl p-nitrobenzoate in acetic anhydride and acetonitrile in the presence of lithium p-nitrobenzoate. Although they appear to have been aware of the formation of nitrobenzoic acid as a by-product, they did not appreciate the essentially acid-catalysed nature of the reaction, and argued that the addition of p-nitrobenzoate ions should have a large accelerating mass-law effect in mechanism (2)’ but only a small salt effect in mechanism (1). Only a smibll effect was observed, and it was concluded that rearrangement occurs by mechanism (1). Catchpole and Hughes’s experimental result is quite compatible with any of the mechanisms (4), (5), or (6) involving acid-catalysis, but the fact that mechanism ( 2 ) cannot be realised in allylic alcohols and esters is shown very clearly by their failure 1 7 9 l8 to undergo anionotropic rearrangement on treatment with alkalis, even in cases where rearrangement takes place with great care under acidic conditions. One of the factors inhibiting nucleophilic attack by anions at the y-carbon atom may be the lateral orientation of the x-orbitals a ccommodating the unsaturation electrons.32 Neutral nucleo- philic reagents will be much less subject to this factor, and mechanism (5) is the one regarded by E. A. Braude and E. R. H. Jones and their colla- borators 1% 28 as predominant in non-isomeric and inter-molecular isomeric anionotropy. The possibility of tthe incursion of mechanism (4) under certain conditions cannot be excluded, but three specific arguments in favour of (5 ) as against (4) are the following : (i) Provided that the necessary corrections are applied, the energies of activation do not vary appreciably with composition of the medium, whereas the energy of liberation of the

91 I. M. Heilbron, E. R. H. Jones, J. T. McCombie, and B. C. L. Weedon, J., 1945, 88.

82 A. G. Catchpole and E. D. Hughes, J., 1948, 1 ,4 ; A. G. Catchpole, E. D. Hughes, rand C, EL. Ingold, ibid,, p. 8; cf, P. B. D. de la Mare, B. D. England, L. Fowden, E. D. Hughes, and C. K. Ingold, J . Chim. physique, 1948,45, 236.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETIUAL ORGANIC CHEMISTRY. 129

free carbonium ion should be very sensitive to ionising properties of the solvent 28 (a similar diEculty, which has received little attention, arises in connection with simple XN1 substitution). (ii) The acetate of propenyl- ethynylcarbinol undergoes hydrolysis with acyl-oxygen fission side by side with rearrangement (which must involve alkyl-oxygen fission) in dilute acid solution; l8 i t is difficult to believe that, if rearrangement involved the liberation of the free carbonium ion, i t would not be accompanied by hydrolysis through the same intermediate. (iii) The rates of rearrange- ment of an allylic alcohol and its methyl ether, acetate, benzoate, and p-nitrobenzoate are all of the same order and the energies of activation differ by less than 2 kcals.; this is consistent with mechanism (5) , whereas rather larger differences would be expected for mechanism (4).17

The intramolecular mechanism (3) was put forward by J. Kenyon and his collaborators 166,33 as a result of the observation that some cases of isomeric anionotropy are accompanied by partial retention of optical activity. For solutions, the intramolecular mechanism must be re- formulated 28 as (6) to take account of the hydrogen-ion catalysis and it is probable that the migration of the positive charge will partly destroy the asymmetry produced by the orientated approach of the migrating group on one side of the y-carbon atom. It seems very probable that the re- arrangements of carbinols and esters in dilute solution in inert solvents such as dioxan, acetone, chlorobenzene, etc., take place entirely by mechanism (6). In aqueous solvents, the inter- and the intra-molecular reactions probably proceed side by side; thus the rearrangement of the acetate of ethynylpropenylcarbinol in dilute aqueous dioxan-hydrochloric acid is slower than the accompanying hydrolysis below 80", but faster than hydrolysis above SO", without any discontinuity in the Arrhenius plots and other characteristics. l8

The conversion of ally lic alcohols into the corresponding chlorides or bromides by hydrochloric or hydrobromic acid, phosphorus halides, and similar acidic reagents generally gives a mixture of the two possible When R, of (XIII) is unsaturated, the equilibrium lies so far on the side of the conjugated isomer that $he other isomer is difficult to detect, and this has led to the erroneous belief that, anionotropic mobility of the halides themselves is necessarily very large. Not only are the isomeric methylallyl chlorides quite stable when p ~ r e , 3 ~ ? 35 but l-phenylallyl chloride, which might be expected to be much more labile, has recently been isolated

S. Winstein and W. G. Young, J. Amer. Chem. SOC., 1936, 58,104; W. G. Young and J. F. Lane, ibid. , 1937,59, 2051 ; 1938,60,847; W. G. Young and K. Nozaki, ibid., 1940, 62, 311 ; J. D. Roberts, W. G. Young, and S. Winstein, ibid., 1942, 64, 2157; W. G. Young and L. J. Andrews, ibid., 1944, 66,421 ; R. E. Kepner, S. Winstein, and W. G. Young, ibid., 1949, 71, 115.

95 M. S. Kharasch, E. T. Margolis, and F. R. Mayo, J. Org. Chem., 1936, 1, 393; M. S. Kharasch, J. Kritchevsky, and F. R. Mayo, ibid., 1937, 2, 489; A. A. Petrov, J. @en. Chem. Russia, 1943, 13, 741; A. J. UltBe, J., 1948, 530; Rec. Trav. chim., 1949, 68, 125.

3s M. P. Baife and J. Kenyon, Trans. Faraday SOC., 1941, 37, 721.

REP.-VOL. XLVI. E

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

130 ORGANIC CHEMISTRY

from the equilibrium mixture obtained by treating 1 -phenylallyl alcohol or cinnamyl alcohol with hydrogen chloride.36 The corresponding bromides are much less easily separated,35 probably owing to homolytic rearrange- n ~ e n t . ~ ~ , 37 The isomeric rearrangement of allylic chlorides, like that of allylic alcohols, is catalysed by hydrochloric acid35 and may involve the formation of " halonium " ions R.CHalH+ analogous to oxonium ions R*COH,+.

Almost all the known examples of anionotropy among allylic halides refer to hydrolysis, alcoholysis, and other replacement reactions in neutral or alkaline conditions, mixtures of rearranged and unrearranged derivatives being generally obtained.32, 3*, 38-42 Replacement without rearrangement must obviously be due to ordinary bimolecular substitution (3$). Replace- ment with rearrangement could be caused by reaction by mechanism (1) (since the intermediate carbonium ion will be mesomeric) or by mechanism (2). In the latter case the reagent attacking the y-carbon atom need not necessarily be an anion as shown, but could be a neutral molecule, as in simple bimolecular solvolysis and in reactions occurring by mechanism (5). The system most thoroughly investigated is that of the 1- and 3-methyl- and -ethyl-ally1 chlorides. Alcoholysis of the primary chlorides is very sensitive to alkali and gives mainly the unrearranged ether. Alcoholysis of the secondary chlorides is less sensitive to alkali and gives a mixture of the two ethers, the proportion of rearranged product decreasing with increas- ing alkali concentration. Catchpole, Hughes, and Ingold 32 have concluded that rearrangement takes place exclusively by mechanism (1) and is the result of unimolecular substitution ( 3 N l ) . The data would appear to indicate, however, that the solvolysis of the secondary as well as of the primary halides is partly bimolecular and that rearrangement occurs partly through an attack by solvent molecules at the y-carbon atom. Bimole- cular solvolysis would also appear to provide the simplest explanation of the fact that, although the equilibria in the phenylallyl and related systems lie almost entirely on the side of the conjugated [e.g. , cinnamyl (XIV; R, = Ph, R, = H)] derivatives, the replacement reactions of cinnamyl and related chlorides give rise to appreciable proportions of deconjugated products (XIII ; R, = Ph, R, = H).38*39 Catchpole, Hughes, and Ingold 32 have maintained that mechanism (1) is nevertheless applicable and that " the mesomerio ion combines with an anion such as acetate or ethoxide in

SIJ H. Martin and N. Q. Trinh, Compt. rend., 1949, 228, 688. 8 7 A. G. Catchpole, Thesis, London, 1942 ; E. A. Braude and E. S. Waight, Nature,

38 E. Charon, Bull. Soc. chim., 1910, 7, 86; J. Dupont and L. Labaume, Chem.

3D J. Meisenheimer and J. Link, Annalen, 1930, 479, 211. ** E. R. H. Jones, R. N. Lacey, and P. Smith, J . , 1946, 940. I1 L. J. Andrews, J . Amer. Chem. SOC., 1946, 68, 2584; 1947, 69, 3062; L. J.

Andrews and S. C. Linden, ibid., 1947, 69, 2091 ; cf. L. F. Hatch, J. J. Russ, and L. B. Gordon, ibid., p. 2614.

1949, 164, 241, and unpublished work.

Zentr., 1910, 11, 734; T. Reichstein and G. Trivelli, Helv. Chim. Acta, 1932, 15, 254.

Ia L. N. Owen and M. U. S. Sultanbawa, J., 1949, 3089.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 131

the a- and the y-positions a t comparable speeds.” This argument does not seem very plausible, because, if the carbonium ion were formed, the positive charge would be expected to remain concentrated on the y-carbon atom. The qualitative results are a t least equally well explained by a bimolecular attack by a neutral nucleophilic molecule, such as water, ethanol, acetic acid, or an amine, a t the a-carbon atom, but a final decision on this point will have to await a kinetic investigation of the reactions involved. Con- clusive evidence for the existence of mechanism (2) has recently been pro- vided by Kepner, Winstein, and Young34 who have shown that the reactions of 1 - and 3-methyl- and -ethyl-ally1 chlorides with diethyl sodio- malonate, which are strictly of the second order and therefore bimolecular, give appreciable proportions of the rearranged products. It thus appears that, with allylic halides, fission of the carbon-halogen bond occurs suffi- ciently readily for y-attack to be successful in neutral or alkaline solution, whereas with allylic alcohols and their derivatives this mode of substitution only takes place in acid solution when the carbon-oxygen bond is sufficiently weakened by the formation of the oxonium ion (cf. p. 130).

B. Electrophilic Substitution. 1. Aromatic nitrut ion.-Nitration is the most common aromatic substitution reaction, and the entire theory of the directive influence of nuclear substituents in aromatic substitution has been built up primarily on qualitative and semi-quantitative observations of the products of nitration. It is perhaps surprising, therefore, that a detailed study of the mechanism of this reaction has been undertaken only within the last few years, partly as a result of the stimulus arising from the increased production of explosives during the late war. Although i t has often been suggested that the actual nitrating agent may be the nitronium ion NO,+, conclusive evidence concerning the nature of the reacting entity has been lacking and most of the recent work has been concerned with this aspect of the problem. Incidentally, this illustrates a general and predictable trend in current investigations on the mechanism of organic reactions in solution, namely an increasing pre-occupa tion with the nature of the reaction medium. I n addition to the classical methods of approach, application of ultra-violet and infra-red absorption spectroscopy and of Raman spectroscopy is proving of much value in this connection.

The proof that the nitronium ion NO,+ is the nitrating agent,under the usual conditions employed in aromatic nitration, was furnished almost simultaneously by independent workers in this country,43, 44 in

43 G. M. Bennett, J. C. D. Brand, and G. Williams, J., 1946, 869, 875; J. C. D. Brand, ibid., p. 880; G. M. Bennett, J. C. D. Brand, D. M. James, T. G. Saunders, and G. Williams, J., 1947, 474; G. M. Bennett, Chem. andInd., 1949, 235.

4 4 E. D. Hughes, C . K. Ingold, and R. I. Reed, h’ature, 1946,158,448; R. J. Gillespie, J. Graham, E. D. Hughes, C. K. Ingold, and E. R. A. Peeling, ibid., p. 480; D. R. Goddard, E. D. Hughes, and C. K. Ingold, ibid., p. 480; C. K. Ingold, D. J. Millen, and H. G. Poole, ibid., p. 480; E. S. Halberstadt, E. D. Hughes, and C . K. Ingold, ibid., p. 514; R. J. Gillespie and D. J. Millen, Quart. Reviews, 1948, 2, 277; R. J . Gillespie. E. D. Hughes, C. K. Ingold, D. J. Millen, and R. I. Reed, Nature, 1949, 163, 599.

4 5 J. ChBdin, Chim. et Ind., 1946, 56, 7.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

132 ORGANIC CHEMISTRY.

and in the United States$$ and no attempt will be made to assess priority. Much of the evidence, including that derived from earlier work, is clearly summarised in a paper by G. M. Bennett, J. C. D. Brand, and G . Williams 43

in which it is shown (i) that nitric acid is present in an altered form when dissolved in an excess of sulphuric acid, (ii) that nitric acid is, in fact, partly present as a cation, (iii) that this cation is NO2', and (iv) that NO2+ is the active nitrating agent in mixed acids.

The freezing point depression of solutions of nitric in sulphuric acid was first measured by Hantzsch47 who deduced a van't Hoff factor, i, of 3, in agreement with the equation

(a) Cryoscopic evidence.

HNO, + 2H2S04 + H,NO,++ + 2HS04- . . . (1)

sulphuric acid acting as a proton donor towards nitric acid. re-evaluation of Hantzsch's results, and re-determinations that i is actually nearer 4 (3.82 & 0.02), in agreement with the equation

However, p8 of i, show

HNO, + 2H2S0, + NO2+ + H,O+ + 2HS04- . . (2) and it would indeed be expected that the nitracidinium ion H,NO,++ (equation 1) would dissociate into a nitronium and a hydroxonium ion (equation 2). Solutions of nitrogen pentoxide in sulphuric acid similarly give rise to a six-fold freezing-point depression, nitronium ions being pro- duced according to the equation 44

(b) Vupour-pressure evidence. Addition of excess of sulphuric acid to nitric acid progressively reduces the partial vapour pressure of the latter until it falls to zero. This and related phenomena were until quite recently ascribed to dehydration of nitric acid to nitrogen pentoxide, but, since nitrogen pentoxide is unstable towards sulphuric acid and, in any case, has a vapour pressure higher than that of nitric acid itself, this explanation is clearly incorrect.43 The effect is to be expected, however, if nitric acid is converted into non-volatile nitronium and hydroxonium ions.

Quantitative evidence for process (2) can be obtained by studying the effect of nitric acid on " oleum ", i.e., sulphuric acid containing an excess of sulphur t r i~xide .~ , The trioxide can be titrated by adding water until fuming ceases, one molecule of SO, reacting with one of H,O to give H,SO,. It is found that the water titre is reduced by 0.5 mol. per mol. of potassium hydrogen sulphate added (probably by the reaction 2850,- + SO, == HS04- + HS207-) whereas it is reduced by 1.5 mols. per mol. of nitric acid added. This is the result to be expected from process (2) in which one mol. of water and one mol. of bisulphate ion are produced from one mol. of nitric acid, but contrary to what would be expected from process (1) or other modes of interaction between nitric and sulphuric acids.

46 F. H. Westheimer and M. S. Kharasch, J . Amer. Chem. Soc., 1946, 68, 1871. 4 7 A. Hantzsch, 2. phyeikul. Chem., 1908, 65, 41. 48 L. P. Kuhn, J . Amer. Chem. Xoc., 1947, 69, 1974.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 133

(c) Conductivity evidence. Solutions of nitric in sulphuric acid have a high conductivity, consistent with the production of ions according to (1) or (2). The fact that the nitric acid is converted into a cation is con- firmed by the demonstration that it migrates towards the cathode during e lec t r~ lys i s .~~ Moreover, solid nitronium salts, (NO,+ )(HS,O,-) and (NO,+ )(C104-), can be isolated,M the constitution of which is confirmed by spectroscopic data (see below).

Aqueous solutions of nitrates and of nitric acid exhibit an ultra-violet absorption band nea.r 3000 A. characteristic of the nitrate ion. In sulphuric acid, this band is gradually replaced by another at 2700 A. as the water content is decreased.49 A change of species is thus clearly indicated, but its nature cannot be deduced with certainty from these results. The nitronium ion can be identified, however, by means of Raman spec t ro~copy.~~~ 45 NO,+ is iso-electronic with CO, and, like the latter, would be expected to have a linear configuration and give rise to a depolarised Raman line near 1400 em.-*. Solutions of nitric acid in con- centrated sulphuric acid exhibit two lines, at 1050 and 1400 cm.-l. The former is absent from solutions in perchloric acid and is due to the nitrate ion, whereas the latter is also present in nitronium perchlorate and is characteristic of the nitronium ion, the concentration of which can be determined by this means.

(e) Kinetic evidence. It has long been known that the speed of nitration in sulphuric acid is proportional to the concentration both of nitric acid and of the aromatic compound, and that i t also depends largely on the com- position of the medium, reaching a maximum in about 90% sulphuric acid. For nitrobenzene at 25", the threshold composition for a measurable speed of nitration is about 80% sulphuric acid (i.e., 20% of H,O) (second-order rate constant, E = 0.0014 rnin.-l mol.-l) and coincides with the limit a t which the NO, ion is spectroscopically detectable. In 90% acid, the speed is increased more than 1080-fold (k = 4.1); at still higher acid concentrations the speed again decreases slowly to about one-tenth of its maximum value (k = 0.4). The decrease in rate a t very high acid concentrations is caused by other factors (see below), but the characteristically rapid increase below 90% should run parallel to the availability of the nitrating agent. Both pro- cesses (1) and (2) depend on the proton-donating properties of the sulphuric acid medium which can be measured by determining colorimetrically the degree of conversion of suitable indicators (proton-acceptors) into their conjugate acids.29, 46 A process analogous to (1) occurs with anthraquinone

(d) Spectroscopic evidence.

(A&) : A& + H,SO, =+ AQH+ + HS04- . . . (4)

while a process analogous to (2) takes place with tri-p-nitrophenylcarbinol

The plot of the logarithm of the ionised fraction of the indicator against the 49 A. Hantzsch, Ber., 1925, 58, 941 ; H. von Halban and J. Eisenbrand, 2. phys&d.

Chern., 1928,132, 433.

Ar3C*OH + 2H,S04 Ar,C+ + H,O+ + ZHS04- . . (5)

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

134 ORGANIC CHEMISTRY.

composition of the solvent is quite different for anthraquinone and for the triarylcarbinol, and the latter gives a plot which nearly coincides with that of log k for nitrobenzene up to the maximum. This is convincing evidence that process (2) rather than (1) is involved in the nitration reaction.

To account for the fact that the speed of nitration is a maximum in about 90% sulphuric acid, Bennett et aE. that nitration is a termolecular reaction (6) which involves a simultaneous attack of the aromatic nucleus by the NO,* ion and the removal of a proton by a proton- acceptor, which may be HSO,-, H,SO,, or HS,O,- (in oleum) :

ArH + NO,+ + HSO,- -3 ArNO, + H,SO, . . (6)

Quantitatively, the theory leads to the expression

where k is the second-order rate constant and El and k, are constants independent of the medium. Equation (7) accurately describes the change of k with change of medium at one temperature and also accounts for the effect of added hisulphate ions, An unpredicted dependence of k on the concentration of the aromatic compound in the case of dinitrotoluene is ascribed43 to simultaneous oxidation, and is not observed with other aromatic compounds which do not undergo side reactions.

The above formulation of the nitration mechanism has been adversely criticised 44 because it involves ternary collisions, and it has been suggested that the decrease in rate a t high acid concentrations is caused by conversion of the aromatic compound itself into its conjugate acid, e.g. , Ph*NO,H+, and a repulsion of the NO,+ ion by the resulting positive charge. Bennett 44

has pointed out, however, that the latter suggestion cannot generally be valid. First, the optimum composition of the medium is the same for different aromatic reactants and the occurrence of the msxirnum must therefore be a property of the medium rather than of the reactant. Secondly, only relatively basic aromatic compounds are appreciably converted into their conjugate acids in sulphuric acid, and in any case even the positive phenyltrimethylammonium ion exhibits a maximum nitration rate in 9076 sulphuric acid. Thirdly, the postulate of ternary collisions is not unreason- able because one of the reactants (HSO,- or H,SO,) constitutes a major proportion of the solvent. Nevertheless, the termolecular mechanism is rendered unlikely by the demonstration 50 that toluene containing a tritium instead of a hydrogen atom in the 2-position, gives, on nitration, 2 : 4-di- nitrotoluene with exactly 50% of the original tritium content. This means that the rates of substitution in the 2-H and 2-T positions are equal, con- trary to what would be expected if the removal of H+ or Tt were part of the rate-determining step. The difficulty is resolved 44 by regarding nitration as a two-stage bimolecular process (8) and ascribing the accelerat-

6o L. Melander, Acta Chem. Scad., 1949, 3, 95; Nature, 1949, 163, 599.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 135

ing influence of small amounts of water in sulphuric acid t o a solvent effect. The intermediate ArHN02+ can be formulated as a x-complex : 24

ArH + NO2+ ArHNO,+ ; ArHNO,+ + B a ArNO, + BH+ (8)

The mechanism of nitration in other media, e.g. , water and organic solvents, has been much less fully studied, but it appears that the nitronium ion is generally the nitrating agent here also. The dynamics of the reaction are, however, not necessarily the same; thus the rate of nitration of relatively unreactive compounds, such as benzene and toluene, in nitra- methane is independent of the concentration and the nature of the aromatic compound, and presumably involves the heterolytic fission of HNO, into NO,+ and H,O as the rate-determining ~ t e p . ~ 4 There is also evidence for the incursion of '' special " mechanisms, e.g. , nitrosation followed by oxid- at ion, under certain conditions.

2. Aromatic Xu2phonation.-Aromatic sulphonation in many respects resembles aromatic nitration, but, as in the latter case, the precise nature of the reagent and the detailed mechanism of the reaction have only recently been elucidated.

Sulphonation in sulphuric acid is strongly retarded by the water pro- duced in the reaction. As the result of a careful investigation of the sulphon- ation of p-nitrotoluene, W. A. Cowdrey and D. S. Davies have now shown 53 that the reaction in 92---1OOoi/, aqueous sulphuric acid (" vitriol ") is a simple first-order process, but that the apparent rate constant ( V ) decreases with increasing water content, and also in the presence of added sodium hydrogen sulphate,according to the equation k' = k/[H,O]([H,O] + [HSO,-]). By applying the appropriate analysis, satisfactory first-order rate constants (k) can be obtained. The Arrhenius equation is obeyed in the temperature range 70-117" and the experimental energy of activation is 27.4 -+ 0.3 kcals./mol. In sulphuric acid containing up to 10% of sulphur trioxide (" oleum "), on the other hand, sulphonation is a simple second-order process, the rate being proportional to the concentration of both p-nitro- toluene and sulphur trioxide. Moreover, sulphonation in oleum is con- siderably faster than in vitriol, and the energy of activation is considerably lower, 18.0 & 0-3 kcals./mol.

Cowdrey and Davies interpret their results on the basis of a termolecular mechanism analogous to that postulated by Bennett et for nitration, namely, the simultaneous attack of the aromatic nucleus by HS03+ or SO, and proton removal by HS04- or H,S04. Since both HSO,+ and SO, will be incorporated in the hydrogen-bonded solvent lattice, it is considered that the distinction between the pairs HSO,*/HSO,- and SO,/H,SO, may lack

51 C. A. Bunton, E. D. Hughes, C. J. Minkoff, and R. I. Reed, Nature, 1946, 158, 514; F. H. Westheimer, E. Segel, and R. Schramm, J. Amer. Chem. Soc., 1947, 69, 773; M. Carmack, M. M. Baizer, G. R. Handrick, L. W. Kissinger, and E. H. Specht, &id., p. 785.

8s J. , 1949, 1871.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

136 ORGANIC CHEMISTRY.

physical significance as it depends only on the assignment of a proton in an 0-H-0 bond to one or other oxygen atom. It is therefore suggested that HS0,- in the form of a " lattice defect " acts as proton-acceptor in vitriol, while in oleum the proton is transferred to a neutral oxygen atom with local disruption of the lattice, and that this accounts for the large difference in rate and energy of activation in the two media. However, in the absence of independent evidence that the ejection of the proton is part of the rate-determining step, it appears to the Reporter that the results can be explained equally well by regarding sulphonation as a two-stage, bi- molecular process, with HSO," and SO, as the effective sulphonating agent in vitriol and oleum, respectively :

ArH + HSO,+ += &S03H2+ ArS0,H + H t . . (1) slow f sst

ArH + SO, ArH*SO,; ArHSO, + B 7 3 slow

ArS0,- + BHf ArS0,H + B . . (2) fast

On this view, the difference in activation energies is caused by the fact that the apparent energy of activation in vitriol includes the temperature coefficient of the equilibria which govern the concentration of HSO,+, whereas in oleum such an effect will not arise, the concentration of SO, being practically temperature- independent.

The conclusion that aromatic sulphonation can be brought about by an uncharged reactant is contrary to what might have been expected by analogy with nitration, but is consistent with the fact that sulphonation can readily be effected by solutions of sulphur trioxide in non-acidic (aprotic) solvents, such as nitrobenzene which is sulphonated only slowly a t low temperat~res.~k Under such conditions, sulphonation is initially of the first order with respect to the aromatic compound and of the second order with respect to sulphur trioxide, but is retarded by the sulphonie acid formed. It may either be assumed that the sulphonating agent is a sulphur trioxide dimer, S,O, :

2SO, a S206; ArH + S206 --+ ArH*S20, --+ ArSO,H*SO, =+ ArS0,H + SO, . . (3)

or that, under these conditions, a second sulphur trioxide molecule is required as a temporary proton-acceptor :

ArH + SO, += ArH-SO, ; ArH*SO, + SO, --+ ArS0,- + SO,H+ + ArS0,H + SO, . . (4)

Sulphonation by 100% sulphuric acid in nitrobenzene has also been studied,5* the reaction being followed by titration with 960/, sulphuric acid until the

64 D. R, Vicary and C. N. Hinshelwood, J. , 1939, 1372; K. D. Wadsworth and C. N. Hinshelwood, J., 1944, 469; E. Dresdel and C. N. Hinshelwood, ibid., p. 649; F. J. Stubbs, C. D. Williams, and C. N. Hinshelwood, J. , 1948, 1065.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 137

mixture becomes turbid. As in the case of sulphonation in sulphuric acid, the reaction is much slower than that with sulphur trioxide and strongly retarded by the water produced. Differences in the rates of sulphonation of substituted benzenes are caused mainly by differences in the energy of activation. For most of the derivatives investigated, the plot of E against the dipole moments is a straight line, indicating that reactivity is directly related to the electron density at the point of attack.

Sulphonution in nitrobenzene at 40°.54 - k *

Benzene ........................... 48 Toluene ........................... - Chlorobenzene .................. 2.4 Bromobenzene .................. 2-1 Nitrobenzene ..................... 7.8 x p-Nitrotoluene .................. 9-5 x IO-' a-Nitronaphthalene ............ 3.3

so3 m E , kcals. [mol.

4-8

7.7 7.8

11.4 11.0 7-9

-

7 106 k * 15-5 79 10.6 9.5 0.24 3.3

26

H*SO, -7

E, kcals./mol. 7.5 6.8 8-9 8.9

11.0 9.8 8.4

* The velocity constants for the two reactions are not directly comparable, since their orders are different.

Aromatic sulphonation is a reversible reaction. In aqueous sulphurjc acid, the rates of both sulphonation and desulphonation become perceptible at acid concentrations of about 50% upwards, but the rate of the forward reaction increases more rapidly with decreasing water content than that of the reverse reaction. It has been suggested 539 55 that desulphonation is brought about by undissociated sulphuric acid, but it is much more probable that desulphonation is the exact reverse of sulphonation as represented by equation (1) and involves the conversion of the sulphonic acid into its conjugate acid. The reaction then becomes analogous to the acid-catslysed decarboxylation of carboxylic acias, and k should be proportional to the proton-donating properties of the medium as measured by Hammett's acidity function.29 Published data indicate that this is, in fact, the case. Reversible desulphonation, rather than direct rearrangement, also accounts for the well-known fact that naphthalene-l-sulphonic acid is converted into naphthalene-2-sulphonic acid at elevated temperature^.^^ The 1 -acid is measurably hydrolysed by sulphuric acid from 70" upwards, whereas the more stable 2-acid is only hydrolysed above 115". The equilibrium constants of the reaction C,,H, + H2S0, C,,H,4303H + H,O are ca. 90, 60, and 40 at 122", 140°, and 163" respectively, and the proportion of 1- to %acid a t 163" is 1 : 7.

3. Aromatic HaZogemtion.-The halogenation of aromatic compounds is even more subject t o the incidence of catalytic effects than is nitration or sulphonation. It has often been assumed that halogenation involves attack by positive halogen ions and that the function of catalysts is to

A. A. Spryskov, J . Qen. Chem. Russia, 1938,8,1858; 1944, 14,833; 1946,16, 1060,2126; 1947,17, 591 ; A. A. Spryskov and N. A. Ovsyankina, ibid., 1946,16,1057.

5 5 Lantz, Bull SOC. chim., 1945, 12, 1004.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

138 ORGANIC CHEMISTRY.

promote the formation of the latter. Recent work, particularly by P. W. Robertson and his collaborator^,^^ however, indicates that ionisation of the halogen-halogen bond occurs during, rather than before, association with the aromatic nucleus. In acetic acid, ch lo r ina t i~n ,~~ and at sufficiently low concentrations (cu. ~11000) b r ~ m i n a t i o n , ~ ~ are simple bimolecular reactions. The rates are very sensitive to the presence of water and are also increased to a lesser extent by other electrolytes, but are retarded by the hydrochloric or hydrobromic acid produced, owing to the formation of HHal,. Substitution under these conditions probably involves a direct attack by the halogen molecule, with simultaneous formation of the C-Hal bond and elimination of Hal-, assisted by solvation :

ArH + Br, ---+ ArHBr+ + Br- --+ ArBr + Hf + Br- . The expulsion of the proton may also be simultaneous with that of the bromine anion, and does not enter into the kinetics; the intermediate ArHBr+ is therefore entirely hypothetical. It serves, however, to emphasise the analogy between aromatic substitution and olefinic addition. The rate- determining steps are very similar, but in ethylenic systems addition of an anion is preferred to loss of proton, because there is not sufficient resonance stabilisation of the unsaturated substitution product in comparison with the saturated addition product.

At higher concentrations (ca. ~ 1 5 0 ) ~ bromination changes from a second- order to a third-order reaction, the kinetics becoming second-order with respect to bromine.57 At the same time, there is a large decrease in the energy of activation (from 11 to 3.3 kcals./mol. in the case of acetanilide). A similar change in kinetics in this concentration range, accompanied by a large decrease in E, is observed in the bromine addition to ethylenic com- pounds (E changing from 9 to 4 kcals./mol. in the case of ally1 acetate). The third-order reaction can be ascribed to the participation of Br, mole- cules which are regarded as fairly loose complexes in which heterolytic fission of the Br-Br bond is facilitated by unsymmetrical polarisation (contributions from Br+Br3-) :

(1)

Brz + Br, =+= Br,; ArH + Br, -3 ArH*Br, --+ ArBr+ H+ +Br3- . . (2)

Alternatively, the second molecule of bromine may act simply by assisting the removal of Br- from an intermediate ArH-Br, :

ArH + Br, ArHeBr,; ArHBr, + Br, + ArBr + H+ + Br3- (3) P. W. Robertson, I?. B. D. de la Mare, and W. T. C. Johnston, J., 1943, 276;

P. B. D. de la Mare and P. W. Robertson, ibid., p. 279; L. J. Lambourne and P. W. Robertson, J., 1947, 1167; P. B. D. de 18 Mare and P. W. Robertson, J., 1948, 100; P. W. Robertson, R. M. Dixon, W. G. M. Goodwin, I. R. McDonald, and J. F. Scaife, J., 1949, 294; P. W. Robertson, J. E. Allan, K. N. Haldane, and M. G. Simmers, ibid.,

A. E. Bradfield and B. Jones, Trans. Far&y SOC., 1941, 37, 726; B. Jones, J., p. 933.

1942,418.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BRAUDE : THEORETICAL ORGANIC CHEMISTRY. 139

Termolecular bromination is thus strongly reminiscent of termolecular sulphonation which involves either the dimer S,O, or the intermediate ArH*SO, (cf. p. 136). It should be possible to distinguish between (2) and (3) by determining whether the concentration range a t which the change from the second-order to the third-order reaction occurs is independent of the aromatic compound.

At still higher concentrations of reactants (ca. M/6), fourth- and fifth- order kinetics are observed, which must be ascribed to polymolecular com- plex formation.57 The strong catalytic effect of iodine which also gives rise to high-order kinetics can be explained in a similar way, and it is of interest in this connection that spectroscopic and other evidence has recently been adduced 59 for the formation of 1 : 1 molecular complexes of iodine and aromatic hydrocarbons. In non-hydroxylic solvents of low ionising and solvating power, and at elevated temperatures, bromination becomes light- sensitive owing to incursion of homolytic chain reactions.5'> 60 Iodination with iodine chloride, which polarises in the sense I+CI-, is kinetically similar to bimolecular b r ~ m i n a t i o n . ~ ~

The well-known work of Bradfield and B. Jones on substituent effects in aromatic chlorination in acetic acid has been further confirmed by B. J0nes.5~ With suitably substituted phenol ethers which can give rise to only one product, the decrease in rate produced by electron-attracting sub- stituents is almost entirely caused by additive increments in the energy of activation, the PZ factor in the equation k = PZe- E/RT remaining essentially constant (2-3 x los). Naphthalene reacts much fa.ster than benzene,57 the approximate values of E being 17 and 7-5 kcals./mol., respectively. The relative rates of chlorination of alkylbenzenes clearly show the operation of the hyperconjugation effect which decreases in the order Me >Et >Pri >But.

Relative rates of chlorination of PhR in 99% acetic mid at H 0 , 5 ?

R ..................... H Me E t Pri But r ..................... 0-29 100 84 51 32

Similar results are obtained in bromination 57* 61 but, since r refers to com- pound rates, part of the apparent decrease in reactivity from PhMe to PhBut may arise from increasing steric hindrance to substitution in the o-position. Halogen substituents give rise to the usual " abnormal " order of reactivities ascribed to a superposition of negative inductive (-1) and positive mesomeric ( + N ) effects.57 A comparison with rela.tive rates of nitration derived from competition experiments reveals that halogeno- benzenes and -naphthalenes are more strongly deactivated in comparison with benzene and naphthalene in halogenation than in nitration, The

59 H. A. Bonesi and J. H. Kildebrand, J. Amer. Chem. Soc., 1948,70,2832; 1949,71, 2703, Nature, 1949, 164, 963.

6o J. P. Wibaut and F. L. J. Sixma, Proc. K . Ned. A k d . Wet., 1948,51,776; F. L. J, Sixma, J. P. Wibaut, J. F. Suyver, G. Bloem, and M. V. Loon, ibid., 1949,52,214.

61 E. Berliner and F. J. Bondhus, J. Amer. Chem. SOC., 1946, 68, 2355; 1948, 70, 854; E. Berliner and F. Berliner, ibid., 1949, 71, 1195.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

140 ORGANIC CHEMISTRY.

differences in reactivity between nitration and halogenation increase in the order ArF<ArCl<ArBr<ArI and it is suggested 57 that this is caused by the additional inductomeric or electromeric polarisability effects evoked by the charged NO,+, but not by the neutral Br, or C1, reagents.

E. A. B. 3. GENERAL METHODS.

Reduction and Hydrogenation.-The usual method of preparation of Raney nickel has been modified to produce more active catalysts: and some correlations between activity and the method of preparation have been made.3 The activity of the catalyst deteriorates on storage and very marked promoting effects can be obtained by the addition of small amounts of platinic chloride or better triethylamine chloroplatinate.* Using the more active Raney nickel catalysts it is possible to hydrogenate esters to alcohols at <loo", and cr-hydroxy- and a-amino-esters even at 25-50",53 although phenyl groups are invariably reduced. The hydrogenation of esters at > 100" is often more conveniently effected with copper chromite catalysts,6 but for small-scale experiments the use of lithium aluminium hydride is tending to replace hydrogenation methods. have described the hydrogenation of malonates, P-keto-esters, and P-hydroxy- esters at 160-180" to 1 : 3-diols, and similarly benzoates at 125-160" to benzyl alcohols using a rather high ratio of copper chromite catalyst to ester. Aromatic ketones are hydrogenated to hydrocarbons in acetic acid solution at 60-70" using palladium-carbon catalysts,* alternative to the Clemmensen and Kishner-Wolff methods. Partly poisoned palladium catalysts have found increasing application in the partial hydrogenation of conjugated enyne systems to p~lyenes .~

Lithium Aluminium Hydride.--It is now possible to give a more general survey of the reductions effected with lithium aluminium hydride, which is available commercially. The quantitative evolution of hydrogen obtained with compounds containing active hydrogen has been developed into a method alternative to the Zerewitinoff procedure for the determination of active hydrogen,l0Y l1 and which has been used in investigations of keto-enol tautomerism. The earlier descriptions of lithium aluminium hydride had

R. Mozingo and K. Folkers

R. Mozingo, Org. Xynth., 1941, 21, 15. H. Adkins et al., J . Amer. Chem. Soc., 1946, 68, 1471 ; 1948, 70, 695. H. A. Smith, W. C. Bedoit, and J. F. Fusek, ibid., 1949, 71, 3769. D. R. Levering and E. Lieber, ibid., p. 1515. H. Adkins and A. A. Pavlic, ibid., 1947, 69, 3039. H. Adkins and H. R. Billica, ibid., 1948, 70, 3121. E. C. Horning and D. B. Reisner, ibk?., 1949, 71, 1036.

7 Ibid., pp. 227, 229.

@ 0. Isler, W. Huber, A. Ronco, M. Kofler et al., Helv. Chim. Acta, 1947, 30, 1911 ; 1949, 32, 489; Emil Barell Jubilee Vol., Hoffmann-La, Roche and Co., Basle, 1946, p. 31; G. W. H. Cheesman, Sir I. M. Heilbron, E. R. H. Jones, F. Sondheimer, and B. C. L. Weedon, J. , 1949, 1516.

lo J. A. Krynitsky, J. E. Johnson, and H. W. Carhart, J . Amer. Chern. Soc., 1948,70, 486.

l1 F. A. Hochstein, ibid., 1949,71, 305.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON GENERAL METHODS. 14 1

established l2 that carbonyl compounds, acids, esters, acid chlorides, and anhydrides were reduced to alcohols, and to this list can now be added epoxides and lactones. Amides and nitriles are reduced to amines, and in most cases halogen atoms are hydrogenolysed and unsaturated carbon- carbon bonds are unaffected. The mechanism of lithium aluminium hydride reductions involves nucleophilic attack on carbon atoms by complex hydride ions as shown by the occurrence of inversion in reactions with bicyclic epoxjdes, by the similarity to sodiomalonic ester in the site of reaction with un- symmetrical epoxides, and by the reactions with organic halides,l3 In- dependent evidence for this mechanism has come from studies of the fission of toluene-p-sulphonyl esters with lithium aluminium hydride.l*

A variety of ketones l5 including steroid ketones l6 have been reduced with this reagent, and it is of interest that enol ethers l7 and thioenol ethers l8

are unaffected. Lithium aluminium hydride is of special value for the reduction of unsaturated carbonyl the double bonds in most cases being unaffected, for sensitive ketones, e.g. , acetylcycZopropane,20 where catalytic hydrogenation causes secondary reactions, and for hindered ketones, e.g. , acetomesitylene 21 and 9-aroylanthracenes,22 where other methods of reduction had been unsuccessful. 1 : &Diketones are reduced normally to the 1 : &dia lcohol~ ,~~ and the reduction of unsaturated 1 : 4-di- ketones has been described.24 Quinones formed quinols by this method. A study of the composition of the lithium aluminium hydride reduction products from 1 : 2-diketones 25 showed that in general, the products were mixtures of the various stereoisomers, although directive effects were en- hanced at low temperatures. There was a close relation between the com- position of the products and those from catalytic hydrogenation, and a sharp contrast appeared with the products from reductions with active metals. cycloHexane- 1 : 2-dione was reduced only to 2-hydroxycydohexan-1 -one.

l2 Ann. Reports, 1948, 45, 122. l3 L. W. Trevoy and W. G. Brown, J. Amer. Chem. Soc., 1949,71, 1675. 14 G. W. Kenner and M. A. Murray, J., 1950, 406. l5 B. Witkop, J. Amer. Chem. SOC., 1948, 70, 3712; F. C. Uhle, ibid., 1949, 71,

761 ; R. Adams, M. Harfenist, and S. Loewe, ibid., p. 1624; J . D. Roberts and C. W. Sauer, ibid., p. 3925.

l6 L. F. Fieser, M. Fieser, and R. N. Chakravarti, &bid., 1949,71,2226; R. H. Levin, G. B. Spero, A. V. McIntosh, and D. E. Rayman, ibid., p. 2958; H . McKennis and G. W. Gaffney, J. Biot. Chem., 1948, 175, 217.

l7 C. Meystre and K. Miescher, Helv. Chim. Acta, 1949, 32, 1758. 0. Rosenkranz, St. Kaufmann, and J. Romo, J. Amer. Chem. SOC., 1949,71, 3689.

l9 H. H. Inhoffen, F. Bohlrnann, and M. Bohlmann, Annalen, 1949, 565, 35; J. F.

2o V. A. Slabey and P. H. Wise, J. Amer. Chem. Soc., 1949,71, 3252; R. V. Volken-

21 R. F. Nystrom and W. G. Brown, ibid., 1947, 69, 1197. 22 P. L. Julian, W. Cole, G. Diemer, and J. G. Schafer, ibid., 1949, 71, 2058. 23 P. Karrer and C. H. Eugster, Helv. Chim. Ada, 1949, 32, 1934. 24 R. E. Lutz and J. S. Gillespie, Abstracts of papers read at the 116th Amer. Chem.

25 R. F. Nystrom and W. G. Brown, J. Amer. Chem. SOC., 1948,70,3738.

h e n s and D. A. van Dorp, Rec. Trav. chim., 1949,6$, 604.

burgh, K. W. Greenlee, J. M. Derfer, and C. E. Boord, ibid., p. 3595.

SOC. meeting, 1949, SM.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

142 ORGANIC CHEMISTRY.

Probably the most widely used of the lithium aluminium hydride reactions so far has been the reduction of esters and acids to alcohols, and many more examples have been provided.26 Benzyl alcohols are readily obtained from benzoic esters 27 and a variety of cc-amino-esters 28 and steroid esters 29

have been reduced to the alcohols. Diesters are reduced to dialcohols, e.g., substituted malonic esters 3* and succinic estersY3l and the selective reduction of the primary carbomethoxy-group * of (I) has been described.32

H2C Me C02Me

H2T flCiC*CH(OH)*CH, / \ I /

\ / \ \ / H2C CH (11.)

H2? ? (1.1 H2C CH

CH2 CH2*80,Me CH2 Thiol esters are also reduced to alcohols but the method is inferior to Raney nickel desulph~risation.~~ Carbon-carbon double bonds of @-unsaturated esters 34 and polyene esters 35 are mostly unaffected during the reductions but, although the cinnamyl alcohols can be isolated from reductions o f cinnamic esters carried out at -10" or below,36 at room temperature further reduction to the 3-arylpropanols occurs.11, l2 Similarly p-nitrostyrene is reduced to 2-phenylethylamine at room t e m p e r a t ~ r e . ~ ~ The reduction of ally1 alcohol to n-propyl alcohol occurs only at higher temperatures and it has been shown by studies with deuterium that the reduction of carbon-carbon double bonds with lithium aluminium hydride occurs by preliminary addition of the metallic hydride to the double bond. Other cases of the reduction of un- saturated bonds by this method have been given and include the partial reduction of the enyne system of (11) to the corresponding diene,38 and the

26 Inter alia: A. Stoll, A. Hofmann, and W. Schlientz, Helv. Chim. Acta, 1949, 32, 1947; 0. Diirst, 0. Jeger, and L. Ruzicka, ibid., p. 46; M. S. Newman and H. S. White- house, J. Amer. Chem. SOC., 1949, 71, 3664; M. E. Speeter, W. M. Byrd, L. C. Cheney, and S. B. Binkley, ibid., p. 57.

27 R. Adams, M. Harfenist, and S. Loewe, ibid., p. 1624. 28 P. Karrer et al., Helv. Chim. Acta, 1948,31, 1617, 2088; 1949,32,1034, 1156,1934. 29 R. Casanova and T. Reichstein, ibid., 1949, 32, 647 ; C. Meystre and K. Miescher,

30 V. Boekelheide and S. Rothchild, ibid., p. 879. The authors also quote a case

31 C. G. Overberger and C. W. Roberts, ibid., p. 3618. 32 W. E. Bachmann and A. S. Dreiding, ibid., p. 3222. 33 M. S. Newman, M. W. Renoll, and I. Auerbach, ibid., 1948, 70, 1023. 34 C. J. Martin, A. I. Schepartz, and B. F. Daubed, ibid., p. 2601. 35 N. A. Milas and T. M. Harrington, ibid., 1947, 89, 2247; N. L. Wendler, H. L.

Slates, and M. Tishler, ibid., 1949, 71, 3267; 0. Schwarzkopf, H. J. Cahmann, A. D. Lewis, J. Swidinsky, and H. M. Wiiest, Relv. Chim. Acta, 1949, 32, 443; P. Karrer, K. P. Karanth, and J. Benz, ibid., p. 436; H. H. Inhoffen, F. Bohlmann, and M. Bohlmann, Annalen, 1949, 565, 35.

36 F. A. Hochstein and W. G. Brown, J. Amer. Chem. SOC., 1948,70, 3485; C. F. H. Allen and J. R. Byers, ibid., 1949, 71, 2683.

37 K. E. Hamlin and A. W. Weston, ibid., p. 2210. 38 J. D. Chanley and H. Sobotka, ibid., p. 4140.

ibid., p. 1758; R. B. Wagner and J. A. Moore, J. Amer. Chem. SOC., 1949,71,4160.

where the carbethoxy-group is replaced by hydrogen by the action of LiAIH,.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOIFNSON : GENERAL METHODS. 143

conversion of oxindoles and indoles into indolines 39 and of phenanthridine into 5 : 6-dih~drophenanthridine.~~ Reduction of phenanthrene to tetra- hydrophenanthrene and of anthracene to the dihydro-compound has been effected by heating the molten hydrocarbons with the solid reagent a t 220- 230°.41 H. Schmid and P. Karrer 42 have described the reaction of lithium aluminium hydride with aromatic cyclic quaternary salts, e.g. , of quinoline and isoquinoline, and showed that dihydro-derivatives were formed. Similar examples were provided from the alkaloid series, and M. B. Mathews43 has described the reaction with cozymase using sodium borohydride as the reducing agent (p. 146). Sodium dithionite was formerly used for these reductions, e.g. :

CH CH

R R Lactones are reduced smoothly to diols,lli 25, 44 and thus pentane-1 : 4-

diol was obtained from a-valerolactone, and o-hydroxycinnamyl alcohol from coumarin. The reduction of amides with lithium aluminium hydride gives amines and a variety of examples has been provided,ll, 259 45 e.g. :

CH,*CH:CEt*CO*NH, -+ CH,*CH:CEt*CH,*NH,

It will be apparent that N-acylation and subsequent reduction provides an alternative method of N-alkylati~n.~~, 46 This method of reduction of amides has been particularly useful in alkaloid chemistry, e.g., for the reduction of (-)-oxysparteine to (-)-~parteine,4~ and of strychnine to strychnidine,l4,4* and in the synthesis of the structure first proposed for sempervirine.49 P. L. Julian and his co-workers 39, 50 have found that, although N-substi tuted oxindoles were readily reduced to the corresponding

s* P. L. Julian and H. C. Printy, J. d m e r , Chem. Soc., 1948, 70, 3206. 40 W. C. Wooten and R. L. McKee, ibid., p. 2946. 4 1 J. R. Saxnpey and J. M. Cox, ibid., p. 1507. 42 Helv. Chim. Acta, 1949, 32, 960. 44 P. Karrer and P. Banerjea, HeEv. Chim. Acta, 1949,32, 1692 ; R. D. Haworth and

45 A. Uffer and E. Schlittler, Helv. Chim, Acta, 1948, 31, 1397; P. Karrer and

46 J. Ehrlich, J . Amer. Chem. Soc., 1948, 70, 2286; R. H. Wiley, 0. H. Borum, and

47 G . R. Clemo, R. Raper, and W. S. Short, Nature, 1948,162, 296; J. , 1949, 663. ** P. Karrer, C . H. Eugster, and P. Waser, Helv. Chim. Acta, 1949,32,2381.

G . A. Swan, J., 1949, 1720; 0. E. Edwards and L. Marion, J . Amer. Chem. SOC.,

P. L. Julian and A. Magnani, ibid., p. 3207.

43 J . Biol. Chem., 1948, 176, 229.

L. Wilson, J. , 1950, 71.

P. Portxnann, ibid., p. 2088.

L. L. Bennett, ibid., 1949, 71, 2899.

1949,71, 1694.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

144 ORGANIC CHEMISTRY.

indoles, the unsubstituted compounds were very resistant and the reduction could not be effected. Reduction of oxindoles of the type (111) was accom- panied by cyclisation to compounds containing the yohimbine skeleton

(111.)

*. Me GH

CH % I

\.A I I I \/

(X = >CH2, >CO)

Nitriles are reduced to primary amines and no secondary or tertiary amine by-products are formed.ll9 25, 51 Only poor yields of reduction products were obtained from cyanohydrins and dinitriles because of the formation of precipitates during the reaction, although the use of other solvents might circumvent this difficulty. The formation of benzyl alcohol by the lithium aluminium hydride reduction of NN-diethylbenzamide was at first considered to be anomalous, but it has now been shown that, with suitable control of experimental conditions, reduction of amides and nitriles (preferably tert.-amides) can be made to yield aldehydes but experimental conditions have not yet been published.

/o\ Epoxides are smoothly reduced to alcohols 13, 25 -CH*CH- --+

-CH,*CH(OH)-, and the method is thus alternative to the earlier hydrogeno- lyses, Raney nickel dehalogenation of the hydrogen halide adducts, or de- sulphurisation of the thiol ad duct^.^^ From unsymmetrical epoxides, different isomeric alcohols may be formed by the different methods. Thus

the reduction of monosubstituted ethylene oxides, R*CH*CH, with lithium aluminium hydride yields the secondary alcohols, R*CH( OH)*CH3 pre- dominantly,54, 55 whereas hydrogenolysis with Raney nickel in the absence of alkali may yield the primary alcohols. The lithium aluminium hydride reduction of epoxides has been quite widely applied. D. A. Prins 56 has prepared deoxy-sugars from anhydro-sugars, and P1. A. Plattner and his co-workers 57 have used the reaction for the preparation of 5- and 6-hydroxy-

51 R. G. Jones, J . Amer. Chem.Soc., 1949, 71, 383. 52 L. Friedmann, Abstracts of papers read at 116th Amer. Chem. SOC. meeting

53 Ann. Reports, 1948, 45, 203.

A

1949, 5M.

M. S . Newman, G . Underwood, and M. Renoll, J. Amer. Chem. Soc., 1949, 71, 3362.

55 I. Salomon, Belu. Chim. Acta, 1949, 32, 1306. 5 6 J . Amer. Chem. Xoc., 1948, 70, 3955. 57 Helv. Chim. Acta, 1948,31, 1885; 1949, 32, 265, 587, 1070.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : GENERAL METHODS. 145

cholestane and -coprostane derivatives by the reduction of the 4 : 5- and the 5 : 6-oxido-compounds. Similarly 17-hydroxy-groups have been intro- duced into the steroid nucleus by reduction of the 16 : 17-oxido-compounds, e.g., in the partial syntheses of the naturally occurring cortical 17a-hydroxy- steroids J and 0,58 and 20 : 21-oxidouZZopregnanes have been reduced to the 20-hydro~y-compounds.~~

In general, halogen atoms are hydrogenolysed by the action of lithium aluminium h ~ d r i d e . ~ ~ ? 59 Bromo-compounds are reduced more easily than the chloro-analogues, and prima.ry halides are reduced more easily than secondary which in turn are reduced more easily than tertiary halides, which react only very slowly. The reduction of ( - )-phenylmethylcarbinyl chloride, Ph*CHCl*CH,, with lithium aluminium deuteride-lithium deuteride yielded ( - )-a-deuteroethylbenzene which was optically active and was thus the first simple optically active compound of the type RlR,CHD.60 Alicyclic, aromatic, and vinyl-type halides are very unreactive towards lithium aluminium hydride, cis- and trans-1 : 3-dichloropropene giving the corre- sponding 1 -chloropropenes. The halogen atoms of ct-halogeno-acids and their derivatives are not reduced under ordinary conditions, and thus a convenient method for the preparation of a-halogeno-alcohols is available.62 With 1 : 2-dihalogeno-paraffins, the normal displacement reaction is wholly or partly suppressed in favour of olefin formation.13? 59 Like the halides, the toluene-p-sulphonic esters are hydrogenolysed by the action of lithium aluminium hydride 63 but there are two distinct reactions which can occur : (a) with preservation of the hydroxyl grorip and ( b ) with fission of the hydroxyl.

Cases of (a) included the toluene-p-sulphonyl derivatives of (-)-menthol and diisopropylidene D-galactose to ( - )-menthane and d iisopropylidene D-fucose respectively, and ( b ) included diisopropylidene D-glucose and phenol. The results were thus the reverse of those obtained by G. W. Kenner and M. A. Murray who used Raney nickel hydrogenolyses and reported that the aryl toluene-p-sulphonates were converted into aromatic hydrocarbons and the alkyl esters into alcohols. In agreement with L. W.

5 8 PI. A. Plattner, H. Heusser, and M. Feurer, Helv. Chim. Acta, 1948, 31, 2210; P. L. Julian, E. W. Meyer, and I. Ryden, J . Amer. Chem. Soc., 1949, 71, 756.

5s J. E. Johnson, R. H. Blizzard, and H. W. Carhart, ibid., 1948,70,3664. E. E. Eliel, ibid., 1949, 71, 3970; see also E. R. Alexander and A. G. Pinkus, ibid.,

L. F. Hatch and R. H. Perry, ibid., p. 3262. p. 1786.

62 A. L. Henne, R. M. Alm, and M. Smook, ibid., 1948,70,1968; C. E. Sroog, C. M. Chih, F. A. Short, and H. M. Woodburn, ibid., 1949, 71, 1710; R. B. Wagner and J. A. Moore, ibid., p. 4160.

69 H. Schmid and I?. Karrer, Helv. Chim. Acta, 1949, 32, 1371. 64 J., 1949, S 178.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

146 ORGANIC CHEMISTRY.

Trevoy and W. G . these authors l4 regard lithium aluminium hydride as a source of potential hydride ions, and the exceptional sugar reductions were ascribed to steric hindrance.

Miscellaneous reductions effected with lithium aluminium hydride include aromatic nitro- and axoxy-compounds to azo-derivatives,ll> 25 aliphatic nitro- compounds, oximes, and aldimines to amines,ll, 257 37 disulphides to t h i ~ l s , ~ ~ and elimination of methyl groups from methyl quaternary salts : l4

>N + CH,

Other reducing agents of the same type as lithium aluminium hydride have been introduced more recently. Sodium borohydride 66 is normally used in aqueous or methanolic solution and is a milder reagent than lithium aluminium hydride. Carboxylic acids, esters, anhydrides, and nitriles are unaffected although acid chlorides may be reduced to alcohols in non-aqueous media, and the reagent is especially useful for carbonyl compounds. It is also of value for selective reductions, e.g. , m-nitrobenzaldehyde to m-nitro- benzyl alcohol and phenacyl bromide to Z-bromo- 1-phenylethanol. Lithium borohydride 67 is intermediate in action between the other two reagents, and ester reductions take several hours, although the reaction with carboxylic acids is complex. Like lithium aluminium hydride it is used in solution in ether or tetrahydrofuran although i t is relatively insensitive to moisture. The presence of carboxylic acid groups does not interfere seriously with the reduction of nitro- or carbonyl compounds (except p-keto-acids) so that this reagent is also of value for selective reductions.

Dissolving-metal Reductions.-The reduction of organic compounds by dissolving metals has been known for many years but an interesting applic- ation which has been revived recently is the partial reduction of aromatic systems.

B. A. Kazanski 68 described the reduction of several benzenoid hydro- carbons to tetrahydro-derivatives with calcium ammonia, and A. J. Birch G9

has extended these observations using sodium in liquid ammonia as the reducing agent with the addition of an alcohol as a proton source. The latter author has described the isolation of a number of dihydrobenzenoid compounds and has applied the methods to synthetic problems, e.g. , terpenes and partial steroid syntheses. ' 0 The py-unsaturated ketones formed by the reduction and subsequent acid hydrolysis of anisole and related com-

R. C. Arnold, A. P. Lien, and R. M. Alm, Abstracts of papers read at 116th Amer. Chem. SOC. meeting, 1949, 7 ~ .

6 6 S. W. Chaikin and W. G. Brown, J . Amer. Chem. Soc., 1949, 71, 122. 67 R. F. Nystrom, S. W. Chaikin, and W. G. Brown, ibid., p. 3245. 6* Chem. Abstr., 1938, 32, 2090; 1939, 33, 787, 1287, 6256. 6s J., 1944, 430; 1945, 809; 1946, 593; 1947, 102, 1642; Quart. Reviews, in the

press. See also C. B. Wooster, U.S.P., 2,182,242; Chem. Abstr., 1940, 34, 1993; J. P. Wibaut and F. A. Haak, Rec. Frau. chim., 1948, 67, 85.

A. J. Birch and S. M. Mukherji, Nature, 1949, 163, 766; J., 1949, 2531; 1950, 367,

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : GENERAL METHODS. 147

pounds usually rearranged under the hydrolysis conditions to a@-unsaturated ketones :

OMe

The reduction of acetylenic compounds with sodium in liquid ammonia yields the trans-ethylenic analogues.71 Reductions by means of Raney alloy (nickel-aluminium) and sodium hydroxide solution 72 have been applied to partial hydrogenations of the naphthalene nucleus, and in par- ticular 5- and 6-hydroxy-l-tetralones are obtained by reduction of 1 : 5- and 1 : 6-dihydroxynaphthalenes 73 or alternatively by mild hydrogenation in Zoh sodium hydroxide solution in the presence of Raney nickel.?* There has been renewed interest in the partial reduction of naphthalene derivatives to tetralins. G. Stork 75 has reported that hydrogenation of @-naphthol over “ neutral ” Raney nickel at 85-100” gave ar.-p-tetralol but in the presence of alkali the substituted ring was reduced forming ac. - p-tetralol, also formed by hydrogenation over copper chromite.?e

Wolfl-Kishner Reductions.-The scope and mechanism of the Wolff- Kishner reaction has been studied 77 and the intermediate formation of di- imines confirmed by the successful use of mono-substituted but not di- substituted hydrazones in the reaction, RR‘C:N*NNR’‘ + RR’CH*N:NR”

G . Lardelli and 0. Jeger 78 have surveyed the reduction of a@-unsaturated carbonyl compounds by this reaction and have identified the products in a number of cases. In agreement with the earlier work of Kishner the products from the aliphatic unsaturated aldehydes and ketones are either olefins or cyclopropane derivativea, and exocyclic methylene compounds are obtained from alicyclic ctp-un saturated carbonyl compounds such as cyclohexene-l-aldehyde. Thus p-cyclocitral (V) gave l-methylene-2 : 2 : 6- trjmethylcycbhexane (VI) and applications of the method to ap-unsaturated steroid and triterpene carbonyl coppounds were also described.

-+ RR’CHR” + S’,.

CMe, / \

71 K. N. Campbell and L. T. Eby, J . Amer. Chem. SOC., 1941,63,2683 ; A. L. Henne

72 E. Schwenk, D. Papa et al., J. Org. Chem., 1942,7,587; 1944,9,175; 1945,10,232. 73 D. Papa, E. Schwenk, and H. Breiger, ibid., 1949, 14, 366; U.S.P. 2,475,781 ;

7 4 D. Papa, J . Amer. Chem. SOC., 1949,71, 3246. 7 5 Ibid., 1947, 69, 576. 7u H. Adkins et at?., ibid., 1948,70, 412, 4247; H. J. Dauben, B. C. McKusick, and

77 D. Todd, ibid., 1949,71, 1356.

and K. W. Greenlee, ibid., 1943, 65, 2020.

Chem. Abstr., 1949, 43, 7510.

G. P. Mueller, ibid., p. 4179. 7 8 Helv. Chim. Aeta, 1949, 32, 1817.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

148 ORGANIC CHEMISTRY.

The recent Huang-Minlon modification 79 of the Wolff-Kishner reaction has been successfully employed in a variety of syntheses, e.g., hexestrols,W long-chain aliphatic compounds,81 alicyclic derivatives 82 (including steroidss3), and heterocyclic compound^.^^

Reductive Cyc2isations.-Essential features of the methods of synthesis of saturated heterocyclic bases by reductive cyclisations are actual or potential amino-groups (e.g., nitro-, cyano-, or oximiizo-) and ester groups so placed that they will form cyclic amides which undergo subsequent reductions. By hydrogenation over copper chromite catalysts these steps may often be achieved in one operation but with Raney nickel catalysts the amide groups generally resist reduction.85 J. W. Cook and his co- workers *6 have prepared N-alkylpiperidines, N-alkyldecahydroquinolines, and 5-phenylisogranatanine (VII) by the reduction of y-cyano- and oxime- esters, and N. J. Leonard et have obtained pyrrolizidines, e.g., helio- tridine (VIII) by reduction of y-nitropimelic esters. Quinolizidines,88

Ph CH,--C-CH,

I \ I / CH, CH,

/ \

CH,-N-CH,

H,C (VII.)

H,C----CH--CHMe

H,C N CH, I 1 I \ / \ / (VIII.)

CH, CH,

including ( rf i : ) - s ~ a r t e i n e , ~ ~ are formed by reduction of y-2-pyridylbutyric esters. The intermediates for most of these syntheses are formed by Michael additions and in this connection the novel additions to the 2-vinylpyridine system are of interest.88y 90

Addition R,eactions.---Keten and Diketen. A recent review 91 has dealt with the preparation of these Compounds. An important feature of the chemistry of the ketens92 has been the renewed interest in their reactions with carbonyl compounds to give either enol acetates or p- lactone~.~~

7s J . Amer. Chem. Soc., 1946, 68, 2487. Huang-Minlon, ibid., 1948, 70, 2802.

81 K. 1;. Drake and S. Melamed, ibid., p. 364; A. D. Campbell, C. L. Carter, and

82 J. R. Nunn and W. S . Rapson, J., 1949, 1051; A. W. Rytina, R. W. Schiessler,

83 Huang-Minlon, ibid., p. 3301. 84 T. I. Fand and L. F. Lutonski, ibid., p. 2931. 85 C. F. Koelsch, ibid., 1943, 65, 2093, 2458, 2459, 2460. 86 J., 1945, 438; 1948, 2011 ; 1949, 1141. 87 J . Amer. Chem. Soc., 1947, 69, 690; 1948, 70, 2504; 1949, 71, 1758, 1760, 1762,

8 8 V. Boekelheide and S. Rothchild, ibid., 1947, 89, 3149; 1949, 71, 879. N. J. Leonard and R. E. Beyler, ibid., 1948, 70, 2298. W. E. Doering and R. A. N. Weil, ibid., 1947, 69, 2461.

S. N. Slater, J., 1949, 1742.

and F. C. Whitmore, J. Amer. Chem. Soc., 1949, 71, 751.

1876.

s1 W. E. Hanford and J. C. Sauer, Org. Reactions, 1946, 3, 108. 92 0. Nicodemus, “ Preparative Organic Chemistry,” 1948, 1, 205. F.I.A.T.

s3 H. J. Hagemeyer, I d . Eng. Chem., 1949,41, 765. Review of German Science, 1939-46.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : GENERAL METHODS. 149

Diketen itself 94 is now formulated as a p-lactone (IX) or preferably (X) on the basis of its infra-red spectrum 95 and chemical properties 96 including the hydrogenation to @-butyrolactone. The formation of p-lactones is carried

CH3*y=$?H CH,:$+VH, (IX.) 0-0 0-co (X.1

out in the presence of acid catalysts such as boric acid, zinc chloride, boron trifluoride etherate, etc., and the use of a solvent is preferred because of the tendency of the products to polymerise. The availability of the p-lactones, especially P-propiolactone, has prompted a more complete investigation of their properties 97 and the following reactions have been described : polymerisation, either catalytically or on heating, to acidic polyesters, RO,C*[CH,*CH,*CO,*],*CH,*CH~*CO,H ; addition of organic and inorganic salts, alcohols, and phenols, to give p-substituted propionic acids ; and re- actions with dithiocarbamic acid derivatives, thiourea, and Grignard re- agents. ap-Unsaturated carbonyl compounds can react with keten to give a variety of pr0ducts,9~ but in the presence of boron trifluoride, &unsaturated 8-lactones are obtained9* by a Diels-Alder type of addition followed by rearrangement :

CHR CR

// HV’ \7H2 R’*CH CO

FH RH2 R‘*C CO

\\ 0

\ / 0

The reaction of keten with hydrogen cyanide gives mainly a-acetoxyacrylo- nitrile.93 Bifunctional keten derivatives have been used in a novel method of synthesis of rnacrocydic compounds. Dicarboxylic acid chlorides were dehydrohalogenated by tertiary amines to give the ketens which, in very dilute solutions, were converted in moderate yields into cyclic ketones : 99

co*c1 CJXCO CH, co / / / \ / \

\ / \ -+ [C%21n co + [CH,In*, CCH,ln+z [CH,In+, -+ [CHzIn

co \ / CHXO ( 3 3 2

\ COC1

Although the yields from the cyclisation were less than those obtained by the methods of I(. Ziegler or H. Hunsdiecker,, the discrepancy is not

O4 A. B. Boese, Ind. Eng. Chem., 1940, 32, 16. 96 D. H. Whiffen and H. W. Thompson, J., 1946, 1005. O 8 A. T. Blomquist and F. H. Baldwin, J . Amer. Chem. SOC., 1948, 70,29. B7 T. L. Gresham, J. E. Jansen, and F. W. Shaver, ibid., p. 998, 999, 1001, 1003,

08 F. G. Young, ibid., p. 1346. 1004; 1949, 71, 661, 2807.

A. T. Blomquist et d., ibid., 1947, 69, 472; 1948, 70, 30, 34; M. Stoll, Chimia,

Annalen, 1933,504, 94, and later papers. 1948, 2, 217.

* Ber., 1942, 75, 1190, 1197. See also A. T. Blomquist and R. W. Holley, J . Amer. Chem. SOC., 1948,70, 36.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

150 ORGANIC CHEMISTRY.

so great when overall yields are compared. Syntheses of exaltone, civetone, and (&)-muscone (XII) by the new method were described.

The reactions of isocyanates and diisocyanates, which are similar to the ketens in many respects, have been the subject of several recent reviews.3 The formation of the commercially important polyurethanes from the di- isocyanates has also been de~cribed,~ and the reactions of acrylonitrile have been re~iewed.~

Condensations.-AZdoZ Type. P. Karrer and his colleagues have used aldol condensations of dincetyl with the aldehydes R*[CH:CH],*CHO to form polyene a-diketones, R*[CH:C€€], + ,*CO*CO*[CH:CH], + ,OR (R = Ph, n = 2, 3, 4; R = Me, n = 4 ; R = 2-fury1, n = Z ) , which were identified as quinoxaline derivatives. Glyoxal was also used in similar reactions, and condensation with acetoacetic acid gave octa-3 : 5-diene-2 : 7-dione, Me*CO*[CH:CH],*COMe.

The internal aldol condensation of 1 : 4- and 1 : 5-diketones to yield cyclopentenones and eyelohexenones can take either of two courses in the case of unsymmetrical molecules. in a study of the formation of certain bicyclic ketones have shown how ‘steric effects can determine the direction of ring closure :

V. Prelog and his co-workers

/CH2 [CH,In vr=c=yo

/C =?*CH,

/CH2 \CH*CH,*CH,

\C*CH,*CH,*COMe [CH,In 70

T [CH,I\FO p 3 2 C0,Et CH*CH,

Such internal cyclisations have also been used for the preparation of macro- cyclic ketones. Thus the action of the Grignard derivative of N-methyl- aniline on hexadeca-2 : 15-dione in dilute solution yielded the ketone (XI) which on hydrogenation gave (5)-muscone (XII) :

COMe co co / \ / \

\ / \ / ---+ [CH,],, CH -%- [CH,],, CH,

/ ECH 1

CHMe COMe CMe ’”\

(XI.) (xu. 3 J. H. Saunders and R. J. Slocombe, Chem. Reviews, 1948, 43, 203; W. Siefken,

4 0. Bayer, Angew. Chem., 1947, 59, 257; “Preparative Organic Chemistry,”

6 Angew. Chem., 1949, 61, 229; ‘‘ Preparative Organic Chemistry,” 1948, 1, 183.

6 HeEv. Chim. Aeta, 1945, 28, 1181, 1185; 1946, 29, 1836; N. A. SSrensen, E.

7 P. Karrer and C. H. Eugster, Helv. Chim. Acta, 1949, 32, 1013, 1934. * Ibid., 1948,31, 92. * M. Stoll and A. Rouv6, ibid., 1947, 30, 2019 ; see also ibicZ., 1937, 20, 525.

Annalen, 1949, 562, 75; S. Petersen, ibid., p. 205.

1948, 3, 303. F.I.A.T. Review of German Science, 1939-46.

F.I.A.T. Review of German Science, 1939-46.

Samuelsen, and F. Oxaal, Aeta Chem. Seand., 1947,1, 458.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : GENERAL METHODS. 151

The synthesis of p-nitrophenols from the condensation of nitrornalondi- aldehyde with ketones lo has recently been extended to macrocyclic ketones by V. Prelog et aZ.,ll who have studied the reactions of these interesting m-bridged phenols :

Further investigations of the Prins reaction have been reported by J. W. Baker.12 This is a method for the conversion of certain olefins into 1 : 3-glycol diacetates and cyclic formals by reaction with formaldehyde in the presence of a strong acid, such as sulphuric, and acetic acid.13 With propylene a third product, 4-acetoxytetrahydro-4-pyran was also identified : l2

CH,:CHMe 4 CH2-CH, CH2-CH2

0

CH2-CH2

\ /

/ \ / AcO*CH,*CH,*CHMe*OAc + CH,*CH

The activity of the hydrogen atoms depends on their conjugation with the olefinic system and it was shown l4 that, with ethylene where hyperconjuga- tion is impossible and with a-methylstyrene where it might be expected to be diminished, the products were less well-defined than with propylene.

Hannich Reaction.-The most important recent applications of Mannich bases,15 e.g., R.CH,.NEt,, have involved various replacements of the amino-groups, e.g., by nitriles,l6 by other amines,l7 and especially the use of the amines or their quaternary salts as potential unsaturated compounds for Michael-type addition reactions. The last reaction has been applied in numerous syntheses, perhaps the most noteworthy being the formation of intermediates for steroid syntheses.18 In cases where the formation of the methylene intermediate is not possible, e.g., l-diethylaminomethyl-

lo E. C. S. Jones and J. Kenner, J., 1931, 1849, and earlier papers. l1 Hetv. Chim. Acta, 1947, 30, 1465; 1948, 31, 870, 877, 1325. l2 J., 1944, 296. l3 Chem. Weekblad, 1918,16, 1510. l4 J. W. Baker, J., 1948, 89; 1949, 770; see also C. C . Price, F. L. Benton, and

C. J. Schmidle, J . Amer. Chem. Soc., 1949,71, 2860. l5 F. F. Blicke, Org. Reactiom, 1942, 1, 303. See also E. R. Alexander and E. J.

Underhill, J . Amer. Chem. Soc., 1949,71,4014. l6 E. B. Knott, J., 1947, 1190; E. Haggett and S. Archer, J . Amer. Chem. SOC.,

1949, 71, 2255. l7 H. R. Snyder et at., ibid., 1948, 70, 4230, 4233. la Ann. Reports, 1939,36,295; 1943,40, 128; R. H. Martin and (Sir) R. Robinson,

J., 1949, 1866, and earlier papers.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

152 ORGANIC CHEMISTRY.

Z-methoxyi~aphthalene,~~ the amine group is not replaceable by nitriles, amines, or malonic ester, although the necessary activation can be brought about by quaternisation.

Alkaline condensation of the Mannich bases or their quaternary salts with compounds containing active hydrogen atoms and suitably placed potential amino-groups (acylamino-, nitro-, etc.) provides a useful method of synthesis of a-amino-acids.20 There have been further applications and modifications of the Robinson methods of fusing cycbhexenone rings on to suitable ketones by means of Mannich base intermediates?l e.g.

CH, CH, / \ / \

\ / / CH, CH,

/c? NaOMe Hzf! VH2+ CH,*CO*CH,*CH,*NEt,Me __j_ H2? VH CH2 H,C CO v H,C CO CO I \ /

CH2 (XV.1

I SMe h

/ \ H2Y VH2

\ /

/ \ &

"2C CH2

\ / H,C CH, H,C CH,

co (XIII) . (XIV.) co

1 CH, CH, / \ / \

H27 VH (jH2

\ / \ / CH, CH

H,C C CO

C. H. Shunk and A. L. Wilds 22 have found that the use of hydroxymethylene derivatives of the ketones is advantageous in the initial condensations. In the application of these methods to steroid syntheses, H. &I. E. Cardwell 23 has advocated the use of 4-keto-1 : l-dimethylpiperidinium iodide (XIII) or thiacyclohexan-4-one methiodide (XIV) which react with p-keto-esters or malonic esters to give 1 : 5-diketones in which the potentially reactive dimethylamino- or methylthio-group is retained and thus, after reduction, the possibility exists for further ring additions :

C0,Et CH, CH, / \ / \

H2Y FH $332

\ / V

H2C I CH, H,C C0,Et / \ / \ / \ I

VH2

H2Y V CH, H,C-C CO "2V CH +(XIII) H,C----CO /"" Hct_ H,C--CO

CH,*NMe, CH,*NMe,

lD H. R. Snyder and J. H. Brewster, J . Arner. Chern. Soc., 1949, 71, 1058. 2o Inter alia : D. I. Weisblat and D. A. Lyttle, ibid., 1947, 69, 2118; 1949,71, 3079;

H. R. Snyder el al., ibid., 1948, '70, 1703, 1857, 3787, 3855; W. Hem, K. Dittmer, and S. J. Cristol, ibid., p. 504; N. F. Albertson, ibid., p. 669.

21 E. C. Du Feu, F. J. McQuillin, and R. Robinson, J., 1937, 53, and numerous later papers.

2z J . Amer. Chem. SOC., 1949, 71, 3946. 23 J., 1949, 708, 715.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : GENERAL METHODS. 153

Preliminary experiments along these lines have been carried out. An altern- ative method2* of preparing the cyclic ketones such as (XV) for the second condensation has arisen from a study of the reactions of 1 : 3-dichlorobut- 2-ene.25 Condensation with fi-keto-esters gave the unsaturated chlorides (XVI) which, after removal of the carbethoxy-groups, were cyclised by the action of concentrated sulphuric acid, and an obvious limitation of the method is that the intermediates must be sufficiently stable not to be decomposed under these strongly acid conditions. Other examples of its application have been provided by V. Prelog, M. Zimmermann et aZ.26

/ / (XVI.) CH,

CH,

/ \ / CH

Claisen Condensations.-Earlier reviews on these condensations 27

have described how sodiotriphenylmethane is more effective than sodium alkoxides particularly in the case of esters which are difficult to bring into reaction. Since then other condensing agents for metal enolate reactions, such as carbethoxylations and the preparation of p-keto-esters and P-diketones, have been examined, particularly by C. R. Hauser and his co-workers. Thus sodamide 28 (prepared in liquid ammonia solution), po ta~samide ,~~ and lithium amide30 are all much more effective than the sodium alkoxides, although there is a tendency to form amide by-products. Favourable claims have also been made for sodium and lithium hydrides,3l and certain Grignard e.g., diethylamino- and diisopropylamino-magnesium bromides, are effective catalysts for Claisen ester condensations. Comparisons of these various catalysts, as well as boron t r i f l ~ o r i d e , ~ ~ for acylations of a-alkoxy- and a-nryloxy-ketones and esters have been made.34

0. Wichterle, J. Proehitzka, and J. Hofman, Coll. Czech. Chem. Comm., 1948, 13, 300.

25 0. Wichterle et al., ibid., 1947, 12, 101, 129. 2e Helu. Chim. Acta, 1949, 32, 1284, 2360. *? Ann. Reports, 1942, 39, 136; C. R. Hauser and B. E. Hudson, Org. Reactions,

C. R. Hauser et al., J . Amer. Chem. Soc., 1944, 66, 1220, 1768; 1945, 67, 1510; 1942, 1, 266.

1946, 68, 26; 1947,69, 2649; 1949, 71, 2023. 2 O Idem, ibid., 1945, 67, 409; 1947, 69, 2325. ao G. R. Zellars and R. Levine, J . Org. Chem., 1948,13,160. s1 F. W. Swamer and C. R. Hauser, J . Amer. Chem. Soc., 1946, 68, 2647; F. B. La

Forge et al., ibid., 1947, 69, 186, 2677, 2932; 1948, 70, 2287; M. Jackman, M. Klenk, B. Fishburn, B. F. Tullttr, and S. Archer, ibid., 1948, 70, 2884; S. J. Cristol, J. W. Ragsdale, and J. S. Meek, ibid., 1949, 71, 1863.

82 C. R. Hauser et al., ibid., 1943,65,2051; 1947,69, 298; 1948,70,606; 1949,71, 1350; H. D. Zook, W. J. McAleer, and L. Horwin, ibid., 1946,68,2404.

D. S. Breslow and C. R. Hauser, ibid., 1940, 62, 261 1. s4 J. Munch-Petersen and C. R. Hauser, ibid., 1949, 71, 770.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

154 ORGANIC CHEMISTRY.

The condensation of two dissimilar esters can give rise to four different p-keto-esters and possibly the best method in such cases, when only relatively small quantities of the product are required, is to heat the corresponding acylmalonic esters with naphthalene-p-sulphonic a modification of the earlier method of D. S. Breslow, E. Baumgarten, and C. R. Hauser.36

C02Et C02Et / RCOC1 / \ \

EtO*Mg*CH + R*CO*CH -+ R*CO*CH,*CO,Et + C02 + C2H4( 1 )

C02Et C02Et

The ketonic fission of P-keto-esters, CIC,*CO*CRR’*CO,Et, is favoured by a low concentration of alkali, but the yields of the ketonic products vary widely with the nature of R and R’. In difficult cases, e.g., R = n-butyl, R’ = isobutyl, pyrolysis of the tert.-butyl esters is very effective:’ a de- composition related to that of the acylmalonic esters described above. C . R. Hauser, F. W. Swamer, and B. I. Ringler 38 have reported further studies on the alkaline cleavage of unsymmetrical p-diketones (reverse Claisen condensation), including other examples of the ring opening of 2-acylcyclo- hexanones to give o-acylhexoic acids. The alkaline cleavage of nitrosated malonic and acetoacetic esters has been used in the preparation of a-amino- acids.39

The conditions which govern the Dieclrmann cyclisation of unsymmetrical diesters have been discussed by R. B. Woodward and R. H. Eastman in the case of the biotin intermediates, RO2C*CHR’CH,*S*CHR”*CO2R, and a number of related examples have been described, e.g., the formation of unsymmetrical alicyclic ketones 41 and piper id one^.^^

MisceUaneous,-Formation of Halides from Silver Salts of Carboxylic Acids. The reaction of the heavy metal, particularly silver, salts of fatty acids and their substitution products with two equivalents of halogens to give alkyl halides, silver halides, and carbon dioxide has been known for many years and a recent review 43 has summarised the scope of the reaction and the evidence for the intermediate formation of acyl hypohalites containing “positive ” halogen atoms. The mechanism of the reaction has been

?6 B. Riegel and W. M. Lilienfield, J . Amer. Chem, Soc., 1945,67, 1273. 36 Ibid., 1944, 66, 1037, 1286. 37 R..S. Yost and C. R. Hauser, ibid., 1947, 69, 2325; W. R. Renfrow and G. B.

Walker, ibid., 1948, 70, 3957. 38 Ibid., 1948, 70, 4023. 39 C. R. Hauser et al., $bid., 1947, 69, 1264; 1948, 70,4250. 40 Ibid., 1946,68, 2229. 11 H. L. Holmes, H. T. Openshaw, and (Sir) R. Robinson, J. , 1946, 91 1 ; M. W.

Goldberg, F. Hunziker, J. R. Billeter, and H. R. Rosenberg, Helv. Chim. Acta, 1947,30, 200.

S . M. McElvain and J. F. Vozza, J . Amer. Chem. Soc., 1949, 71, 896, and earlier papers.

43 J. Kleinberg, Chem. Reviews, 1947, 40, 381; see also J. W. H. Oldham, J., 1950, 100.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JORNSON : GENERAL METHODS. 155

studied by C. L. Arcus, A. Campbell, and J. Kenyon44 who have shown that optical activity due to asymmetry on the a-carbon atom is largely retained during the reaction. The product from their experiments, (+ )-a-phenylethyl bromide, was found to undergo partial racemisation under the experimental conditions. R. T. Arnold and P. EV40rgan,4~ on the other hand, have reported that the product from a similar reaction with (+)-a-ethyl- hexoic acid wa.s optically inactive but they did not determine whether the product would racemise under the conditions they employed, and thus the free-radical mechanism for the reaction which these authors advance on the basis of their observations is probably incorrect.

From a preparative point of view the reaction has been mainly applied to aliphatic acids and it has been stated that the degradation is unsatisfactory with aromatic acids 46 although isolated successful examples exist in the literature.47 C . P. Huebner and W. A. Jacobs48 have used the method as an indication of the existence or otherwise of a-hydrogen atoms in sub- stituted acetic acids. An important application is the preparation of fatty o-halogeno-acids from the half-esters of ao-dicarboxylic acids:g the products being used for the syntheses of macrocylic lactones and ketones, including ( &)-muscone.2 Although application of this method to the malonic half-esters provides an alternative method of preparation of a-halogeno-e~ters,~~ the method is in general inferior to the direct halogen- ation of the acid chloride^.^^ The decomposition of silver carboxylates with bromine has also been described for the steroid group and for bicycZo[2 : 2 : 2]octane-2-carboxylic acid 53 where an interesting rearrange- ment occurred and 2-bromobicyclo[l : 2 : Sloctane was obtained as the final product. It was shown however that treatment of 2-bromobicyclo- [2 : 3 : 2loctane with silver bromide under the same experimental conditions caused rearrangement and thus the nature of the initial product was not definitely established.

Esteri~cation.-Trifluoroacetic anhydride is an effective catalyst for the preparation of esters directly from carboxy- and hydroxy-compounds. The reactions are rapid and the necessary experimental conditions mild enough to permit the formation of esters from acid labile glycosides. The

See also C. C. Price, “ Mechanism of Re- actions at Carbon-Carbon Double Bonds,” p. 55, New York, 1946; F. Bell and I. F. B. Smyth, J., 1949, 2372.

44 Ndure, 1949, 163, 287; J. , 1949, 1510. 45 J . Amer. Chem. SOC., 1948, 70, 4248.

46 A. Luttringhaus and D. Schade, Ber., 1941, 74,1565. * ? W. Bockemuller and F. W. Hoffmann, Annalen, 1935, 519, 165; E. Schlittler

48 J . Biol. Chem., 1948, 174, 1003. 49 E. Hunsdiecker and C. Hunsdiecker, Ber., 1942, 75, 291. 50 J. R. Dice and J. N. Bowden, J . Amer. Chem. SOC., 1949,71, 3107. 51 P. Bagard, BUZZ. SOC. chim., 1907, 1, 310.

and J. Muller, Helv. Chim. Acta, 1948, 31, 1119.

E. Schwenk and D. Papa, J . Amer. Chem. SOC., 1948, 70, 3626, have described a modification of the method in the case of dicarboxylic acids.

62 N. G. Brink, D. M. Clark, and E. S. Wallis, J . Biol. Chem., 1946,162,695. W. E. Doering and M. Farber, J . Amer. Chem. Soc., 1949,71, 1514.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

156 ORGANIC CHEMISTRY.

method has been recommended for the acylation of polysaccharides and for the preparation of the poly-ester type of polymers.

Urea Complexes with Linear A liphatic Compounds.-A German observa- tion 55 which should find many commercial applications is that urea forms complexes with a number of various kinds of long-chain aliphatic compounds containing straight chains or branched within certain relatively narrow limits. In general the chain must consist of a t least six carbon atoms and the addition of small amounts of methanol to the reaction mixture is helpful. The complexes are crystalline solids which can be removed by filtration and decomposed by the addition of water, so that the method permits an easy separation of straight-chain from cyclic or branched-chain compounds which do not form similar urea complexes. These observations have been confirmed by other workers 56 who have shown that the urea-n-hexadecane complex contains eleven moles of urea. They also found that complexes could be obtained from long-chain compounds containing one branched methyl group if the chain was of approximately twenty carbon atoms, the exact length depending on the position of the methyl group.

B. Angla 57 has claimed that thiourea forms similar complexes with highly branched aliphatic and alicyclic hydrocarbons. Complexes were also obtained with a variety of halides, alcohols, and carbonyl compounds, but not with the straight-chain aliphatic or simple aromatic hydrocarbons or with terpenes. Analytical applications of these observations were described.

A. W. J.

4. LONG-CHAIN ALIPHATIC COIPOUNDS. This subject was last reviewed in 1940.l The intervening period has

seen a growing interest in this field owing to a number of factors, among which the tuberculosis problem and considerable developments in synthetical methods are prominent, A comprehensive, but condensed, review of the subject has been given by T. A. Lennartz.2

Preparations of pure straight- and branched- chain hydrocarbons by standard methods 1 continue to be reported. A considerable number of branched-chain alkanes containing 26-36 carbon atoms,3 a series of alkyldocosanes,4 1 1 -alkylheneic~sanes,~ 3-ethyldecane

Hydrocarbons.---Parafins.

54 E. J. Bourne, M. Stacey, J. C. Tatlow, and J. M. Tedder, Nature, 1949, 164, 705; J . , 1949, 2976.

5 5 F. Bengen and W. Schlenk, Experientia, 1949, 5, 200. G.P. Appl, O.Z. 124381 1940.

5 6 W. J. Zimmerschied, R. A. Dinnerstein, A. W. Weitkamp, and R. F. Marschner, J. Amer. Chem. SOC., 1949, 71, 2947.

5 7 Bull. SOC. chim., 1949, 16, 12. Ann. Reports, 1940, 37, 211. Angew. Chem., 1947, 59, A , 10.

F. C. Whitmore, L. H. Sutherland, and J. N. Cosby, J . Amer. Chem. SOC., 1942,64,

F. C. Whitmore, J. N. Cosby, and W. S. Sloatman, ibid., p. 1801.

* J. N. Cosby and L. H. Sutherland, Rejher, 1941,20,471.

1360.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAN : LONG-CHAIN ALIPHATIC COMPOUNDS. 157

and 2 : 5-dimethyl~ndecane,~ eicosane and 3-ethylo~tadecane,~ 2-methyl- tetradecane and %methylpentade~ane,~ n-pentatriacontane, hexatriacontane, tetracontane, tristetracontane, 22-methyltristetracontane and 22-n-nonyl- tristetracontane 9 have been synthesised. W. M. Mazee lo has prepared

addition to 2-methyl- and 2 : 2-dimethyl-tricosane, 13-methylpentacosane, and 10-nonylnonadecane.

An optically inactive hydrocarbon, C34H.70, phthiocerane, has been obtained l1 by degradation of phthiocerol (I), the optically active dihydric alcohol found in the waxes of tuberculin residues. This material was not identical with n-tetratriacontane or with 9 : 26-dimethyltetratriacontane obtained by electrolysis of tuberculostearic acid.

(1.) C,,H6,(OH),*kfe CH,*[CH2]2*CHMe*[CH2]28'CH, (11.1

CH,*CHMe*[CH2],*CIIMe.[CH2]~*CHMe.[CH2]3*CHMe*CH3 (111.)

As a preliminary step in the elucidation of the structure of phthiocerane, S. Stallberg-Stenhagen and E. Stenhagen l2 have synthesised a series of alkanes containing 32, 35, and 36 carbon atoms substituted by methyl in positions 2, 3, 4, and 5. A comparison of X-ray data, thermal properties, and infra-red absorption spectra suggests that phthiocerane is a 4-methyl substituted hydrocarbon, probably 4-methyltristriacontane (11). This example serves to emphasise the difficulties encountered in structural determinations in this field. Similar difficulties have attended the formula- tion of pristane, isolated from the unsaponifiable matter of the liver of the basking shark ; l3 it is provisionally regarded as C,,H,, or C20HH42, although its homogeneity is open to doubt and many of its physical properties corre- spond with those of 2 : 6 : 11 : 15-tetramethylhexadecane (111) obtained from tetrahydrogeranyl bromide by the Wurtz reaction. Later st~idies,l* during which all eight isomeric methyloctadecanes were synthesied and shown to differ from pristane, tend to support the allocation of a poly-branched chain to this substance.

OZeJins.-Thermal degradation of alkyl esters of stearict acid to the olefin and stearic acid has been investigated by F. Asinger and H. E. Eckoldt l5 who confirm the predqminantly A l-nature of the olefins obtained from primary alcohols, in distinction from those from secondary alcohols

A. D. Petrov, A. M. Pavlov, and J. A. Makarov, J . Gen. Chem. Russia, 1941,11,

K. W. Sherk, M. V. Augur, and M. D. Soffsr, J . Amer. Chem. Xoc., 1945,67,2239. H. J. Lunshof, J. van Steens, and H. I. Waterman, Rec. Truv. chim., 1947,66,348.

* H. J. Backer and J. Strating (with H. A. Klrtsens, H. J. Winter, J. R. van der Bij,

the c21, c,, c24, c287 c30, c31, c34, c357 c36, c4(), and c43 paraffins in

1104.

J. Vemeer, and J. B. G. Hurenkamp), ibid., 1940, 59, 933. lo Ibid., 1948, 67, 197. l1 L. G. Ginger and R. J. Anderson, J . Bwt. Chem., 1945,157, 203. l2 Ibid., 1948, 173, 383. l5 N. A. Sorensen and J. Mehlum, Acta Chem. Scund., 1948, 2, 140. l4 J. Sorensen and N. A. Sorensen, ibid., p. 166. l6 Ber., 1943, 76, B, 585.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

158 ORGANIC CHEMISTRY.

which are heterogeneous. The standard olefin synthesis involving Grignard reagents such as allylmagnesium bromide has been criticised l6 on the grounds that the magnesium bromide formed in the reaction is capable of isomerising the product. Thus, a sample of dodecene (98% of l-ene, 2% of 2-ene) was converted in refluxing benzene in the presence of anhydrous magnesium bromide (6 hours) into a mixture of olefins consisting of 1-ene 83%, 2-ene loyo, 3-ene 4%, 4-ene and 5-ene 0.4%. It is evident that this cont4ention requires further examination since many of the standard methods of olefin synthesis and of purification through the dibromides involve a final treatment in the presence of magnesium or zinc halide.

It is noteworthy that the syntheses of unsaturated acids described below are of general application and considerably augment the previous methods of olefin synthesis which were few in number and, except for the Boord synthesis, l7 unreliable.

Alcohols and Ketones. AZcohok-A new method of alcohol synthesis has been described.18 Reaction of 1 l-acetoxyundecanoyl chloride * (IV) with octadecylzinc bromide furnished the keto-alcohol (V) which on re- duction yielded nonacosan-1-01 (VI) in good overall yield.

AcO*[CH2],,*COCl + C,,H,,*ZnBr ---+ W.) C,,H,-CO*[CH,],,*OH -+ C,,H,,*OH

(V.1 WI.) Owing to the inaccessibility of most o-acetoxy-acids it is doubtful whether

this route has advantages over the reduction of the appropriate esters by high-pressure hydrogenation or by sodium and alcohol. Preparation of all the primary straight-chain alcohols containing 28-35 carbon atoms,18 2-methyltetradecanoI,19 and docosane-l : 22-diol 2o by the last-mentioned procedure has been recorded. Recent researches 21* 22* 23 have resulted in improvements in Bouveault-Blanc reduction. The method of V. L. Han~ley,~3 in which a mixture of the ester and a carbinol is added to powdered sodium under xylene, is particularly valuable because it gives improved yields and, moreover, permits considerable control of the reaction.

Preparations of eight isomeric hexadecanols 24 and dihexadecylheptadecyl- carbinol 25 by standard Grignard methods have been recorded.

Ketones.-Considerable advances in methods of synthesis of ketones have been made in the last few years. The original Gilman-Nelson26 synthesis

18 F. Asinger, Ber., 1942, 75, B, 1260. 1 7 H. B. Dykstra, J. F. Lewis, and C. E. Boord, J . Amer. Chem. Soc., 1930, 52,

1s R. G. Jones, ibid., 1947, 69, 2350. 1s K. Lindbad and E. Stenhagen, ibid., 1941, 83, 3539. 20 R. Signer and P. Sprecher, Helv. Chim. Acta, 1947, 30, 1001. 21 L. Palfray and P. Anglaret, Cornpt. rend., 1946, 223, 860. 22 Idem, ibid., 1947, 224, 404. 24 F. Asinger and H. E. Eckholdt, Ber., 1943, 76, B, 579. 25 V. V. Korscak, J . Qen. Chem. Russia, 1939, 9, 1470. 26 H. Gilman and J. F. Nelson, Rec. Trav. chim., 1936, 55, 518. * Geneva nomenclature is used in this section of the Report.

3396 et seq.

2s Ind. Eng. Chem., 1947, 39, 35.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAN : LONG-CHATN ALIPHATIC COMPOUNDS. 159

involving reaction of cadmium alkyls with an acid chloride has been im- proved by J. Cason 27 by use of benzene as the reaction medium instead of ether. Unfortunately, the yields from the cadmium di-see.-alkyls are low, but, in spite of this, the method is considered to be one of the most con- venient for the small-scale preparation of ketones .28¶ 29

A new and more general synthesis 30 comprises reaction of an acid chloride with a benzyl sodiomalonate (VII) (obtained by ester interchange, in situ, from the ethyl ester) and subsequent hydrogenolysis and decarboxylation of the intermediate keto-ester (VIII), to give the ketone (IX) :

R-COCl + Na*CR’:( CO,*CH,*C,H,), --+ R*CO*CR’:(CO,*CH,*C,H,), (VII.) (VIII.) 1 H*-Pd, -2 co,

70*CH3 (x.) R.CO*CH*CO,Et

3,

R*CO*CH,R‘ (IX.)

The reaction has been used for the preparation of several long-chain ketones, diketones, keto-alcohols, acyloins, k e t o - a ~ i d s , ~ ~ p-keto-esters, and f~keto-nitriles.~~ Synthesis of many p-keto-esters containing 9-24 carbon atoms by deacylation of the requisite oc-acyl-acetoacetic esters (X) 32 with the aid of sodium methoxide 33 or ammonia 34 has been described.

Carbomlic Acids. Saturated ~traight-chain Monocurboxylic Acids.- Interest in these materials has centred on development of improved methods for their synthesis. The modified dialkylcadmium-ketone synthesis 28

has been used for the preparation of acids containing up to 34 carbon atoms. The general reactions are as follows : CdR, + CI*CO*[CH,],*CO,Et --+ R*CO*[CH,],*CO,H + RfCH,], + ,*CO,H the last step being carried out most conveniently by H. T. Huang-Minlon’s modification 35 of the Wolff-Kishner reduction. Hentriacontanoic 36 and tetratriacontanoic acids 3’ have been thus prepared. The similar use of the zinc alkyls for synthesis of normal fatty acids containing 28-35 carbon atoms has been reported by R. G . Jones.18 It is evident that the development of these methods makes Preparation of acids containing up to 30 carbon atoms, and their derivatives, a comparatively simple matter. Synthesis of acids of greater chain length by such methods is, however, more difficult, owing to the inaccessibility of the .requisite acid chloride esters, but it may be readily accomplished by the debenzylation procedure.30 Thus, the synthesis of hexapentacontanoic acid has been realised by this route.38

27 J . Amer. Chem. SOC., 1946, 68, 2078. 28 M. D. Soffer, N. S. Strauss, M. D. Trail, and K. W. Sherk, ibid., 1947, 69, 1684. 2p J. Cason, Chem. Reviews, 1947,40,15. 31 R. E. Bowman and W. G. Fordham, unpublished. 32 L. Bouveault and A. Bongert, Compt. rend., 1901, 132, 704. 33 S. Stallberg-Stenhagen, Arkiz. Kemi, Min., Geol., 1945, 20, A, Nos. 19, 17. 34 F. L. Breusch and H. Keskin, Rec. Fuc. Sci., Istanbul, 1946, 11, A, 24. 35 J . Amer. Chem. SOC., 1946, 68, 2487. s6 H. A. Schuette, A. 0. Maylott, and D. A. Roth, J . Amer. Oil Chem. SOC., 1948,25,64. 37 N. L. Drake and S. Melamed, J . Amer. Chem. SOC., 1948, 70, 364. 38 R. E. Bowman and R. G. Mason, unpublished.

30 R. E. Bowman, Nature, 1948,162,111.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

160 ORGANIC CHEMISTRY.

A further carboxylic acid synthesis has been developed by L. F. Fiever and J. Szmuszkovicz.39 Condensation of a Grignard reagent with a cyclic ketone (XI; n = 5, 6, or 8) gives the corresponding carbinol (XII) which is smoothly oxidised by chromic acid under anhydrous conditions to give the 4-, 5- , or 7-keto-acid from which the saturated acid may be obtained by reduction in the usual way.

0 R OH R R I 1 + [CH21* +---, 4 pi V --+ ,=o I

--[CH2ln- LrcH21n [ H21n - I*CO,H C0,H (XI.) (XII.)

Finally, preparations of pure stearic acid,#* 4 1 of margaric acid by Arndt- Eistert homologation of palmitic acid:, and of many acid anhydrides from acids up to stearic by treatment with acetic anhydride 43 have been described.

Brunched-chain MonocarboxyZic Acids.-The growing interest in this field is reflected in the increasing number of papers. Besides the acids from wool-fat, which will be discussed later, interest has been focused on the acids isolated by R. J. Anderson and his collaborators from the waxes of the tubercle bacillus,P4 particularly tuberculostearic and phthioic acids.

The evidence for the formulation of tuberculostearic acid as 10-methyl- stearic acid (XIV) and the synthesis of the racemic form of this acid have been described in an earlier Rep0rt.l Further evidence in favour of (XIV) was later obtained by S. F. Velick 45 from X-ray examinations of the amides of both the natural and the racemic acid. In 1948 the whole problem was resolved by the total synthesis, by F. S. Prout, J. Cason, and A. W. Ingersoll,46 of the racemic, dextro-, and Zcevo-forms of 10-methylstearic acid and the com- plete identification of the natural acid as the Zevo-form. The starting materials for this synthesis were the (&I- , the (+)-, and the (-)-decanols (XIII), as follows :

(1) PBr,, (1) Esterification, C,H,,-CHMe*OH (2) malonation, C~H170CHMe*CH20C02H

(XIII.) (3) hydrolysis, (4) -GO,

(1) HBr, C,H,,*CHMe*CH,*CH,*OH 7)- (C,H,,*CHMe*CH2*CH,)2Cd

(3) CdCl, CI-CO*[CH,],*CO,Et

C,H,,-CHMe*CH,*CH2*CO*[CH,],*C0,Et C , H , , ~ C H M e * [ C H , ] , ~ C O , H ~ ~ Cleinmensen

reduction (XIV.)

89 J . Amer. Chem., SOC. 1948, 70, 3352. 40 J. M. Phillipson, M. 5. Heldman, L. L. Lyon, and R. D. Vold, Oil and Soap, 1944,

41 J. Kass and L. $3. Keyser, J . Amer. Chem. SOC., 1940,62, 230. r e M. Prosternik, Arhiv Kemiju, 1946, 18, 1. a8 J. M. Wallace, jun., and J. E. Copenhauer, J . Amer. Chem. SOC., 1941,63,699. 44 R. J. Anderson, Chem. Reviews, 1941, 29, 225. as J . Biol. Chem., 1944, 154, 497.

21, 315.

46 J . Amer. Chem. Soc., 1948, 70, 298.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAX : LONG-CHAIN ALIPHATIC COMPOENDS. 161

The (+)- and the (-)-acid have also been synthesised by S. Stallberg- Stenhagen 47 from methyl hydrogen (+)- and (-)-P-methylglutarate (XV). Again, tuberculostearic acid was found to be identical with the (-)-form and moreover, was assigned the D-configuration as the result of previous work of the same author 4* on the stereochemical relation of the acid-esters (XV) to glyceraldehyde. The synthesis of the isomeric 9-methylstearic acid has also been effected.47

H02C*CH2*CHMe*CH2*C02Me CH3*[CH2],*CHMe*[CH2],*C02H (XV.) (XVI.)

The phthioic acid problem remains 49 The evidence pub- lished to date regarding its structure is as follows. It is a dextrorotatory monobasic carboxylic acid, C2,H5,02, forming monolayers which collapse a t an area of about 38 sq. A,, differing in this respect from those formed by other fatty acids. Oxidation with chromic acid yields a C,, acid pro- visionally regarded as 6-methyldecanoic acid (XVI) ,50* 51 together with azelaic acid,52 whilst C-Me determinations (Kuhn-Roth) reveal the existence of a t least three methyl groups.

Later, by X-ray measurement of multilayers of barium phthioate, Stenhagen and Stiillberg 53 concluded that phthioic acid was a trisubstituted acetic acid, possibly ethyl-n-decyl-n-dodecylacetic acid (XVII). This sug- gestion was, however, disproved by N. Polgar and (Sir) R, Robinson 54 who synthesised this and similar compounds and showed them not to possess any of the relevant properties of phthioic acid. At a later date, these a u t h ~ r s , ~ ~ ? ~ ~ on the basis of the oxidative evidence described above, put forward the alternative formulae (XVIII) or (XIX) for phthioic acid, of which the latter was preferred. Further evidence in support of (XIX) came from

the synthesis of the mixed stereoisomers of 3 : 13 : 19-trimethyltricosanoic acid, which exhibited many of the physical, chemical, and biological properties of phthioic acid, e.g., the formation of monolayers collapsing at 38-39 sq. A. and general similarities between derivati~es.~l More recent evidence,56 however, suggests that phthioic acid is a mixture, probably of two acids.

47 Arkiv Kemi, Min., GeoL., 1948, 26, A , No. 12. 4a Ibid., 25, A , No. 10.

C. V. Wilson, J. Amer. Chem. Soc., 1945, 67, 3161. s1 N. Polgar and (Sir) R. Robinson, J., 1945, 389. s2 T. Wagner-Jauregg, 2. physiol. Chem., 1937, 24'9, 135. s3 J . BioE. Chem., 1941, 139, 345. 54 J., 1943, 615. 6 5 Cf. M. A. Spielman and R. J. Anderson, J. Biol. Chern., 1935,112,759. s6 Ref. 49, p. 297 ; private communication to G . Brownlee.

REP.-VOL. XLVI. B

4g Ann. Reports, 1948, 45, 292.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

162 ORGANIC CHEMISTRY.

(2) hydrolysis,

5 7 S. David, N. Polgar, and (Sir) R. Robinson, J., 1949, 1541. 5 s N. Polgar, (Sir) It. Robinson, and E. Seijo, ibid., p. 1545. 59 J . Arner. Chem. Soc., 1948, 70, 879. 6o S. Velick, J . Biol. Chem., 1944, 152, 533. 61 Idem, ibid., 1944,156, 101. 63 L. G. Ginger and R. J. Anderson, ibid., 1945, 157, 203.

6 5 A. K. Schneider and M. A. Spielman, J . Biol. Chem., 1941,142,345. 6 6 W. Keil, 2. physiol. Chem., 1942, 274, 175. 67 J. Cason and F. S. Prout, J . Amer. Qhem. Soc., 1944,66,46. 68 J. Cason, ibid., 1942, 64, 1106. 69 S. Stallberg-Stenhagen, Arkiv Kemi, Min., Geol., 1945, 19, A , No. 28. 70 J . Amer. Chem. SOC., 1945,67, 447.

62 L. G. Ginger, ibid., p. 443.

E. Stenhagen and B. Tagtstrom, Svensk Kem. Tidskr., 1942, 54, 145.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAN : LONG-CHAIN ALIPHATIC COMPOUNDS. 163

components to fractional distillation, followed by ‘‘ extended distillation ” in hydrocarbon diluents. Three separate series of acids were thus obtained. First, normal acids containing an even number of carbon atoms (XXI; n = 8-24) ; secondly, a series of the iso-acids containing an even number of carbon atoms (XXII ; n = 6-24) ; and thirdly a series of dextrorotatory “ ante-iso-” acids containing an odd number of carbon atoms (XXIII ; n = 6 2 0 ) . S, F. Velick and J. English, j ~ n . , ~ l have since synthesised

CH,*[CH,],*CO,H CHMe,*[CH,],*CO,H CH,*CH,*CHMe*[CH,],*CO,H

(+)-~-14-rnethylpalrnitic acid (XXIII ; n = 12) and shown it to be identical with the similar “ ante-iso-” acid from wool fat, thus confirming the structures previously allocated to these acids and, furthermore, determining their configuration as ( D).

tert.-Carboxylic Acids.-The suggestion that phthioic acid was a tert.-acid (see above) prompted many investigations of methods of preparing these substances. Since the subject is now of less immediate interest, it seems desirable that an outline of the most successful methods should be given, without mention of the considerable number of individual acids thus prepared.

A. Haller and E. Bauer’s 72 method, which consists of stepwise alkylation of acetophenone, followed by fission with sodamide, has been used by several workers.73~ 7*7 75

(XXI.) (XXII.) (XXIII.)

NaNH R\ NaKH R\ CH,*CO*C,H, --G)* R’- C*CO*C,H, -------A R’--C*CO*NH,

(2) R’I ,”/ Rf‘/ (3) R‘I

The product resulting from the addition of a Grignard reagent to an alkylidenecyanoacetic ester may be submitted to hydrolysis and decarboxyl- ation, to give acids substituted in the P-position: 76

R )C:C/CN R”.MgBr R /CN R -+ R”-V*CH, _I, R”-(?*CH,*CO,H R‘ \CO,Et R‘ C0,Et R’

The alkylation of esters with triphenylmethylsodium and an alkyl halide 77 has been shown to give excellent yields of the tert.-acid : 54

Rt Na.C(C,H,), R‘ R’ R-CH*CO,Et - j ” I R-(?H*CO,Et --+ R-\,.H*CO,H

R” R” 71 J . Biol. Chem., 1945,160, 473. 72 Compt. rend., 1909,148, 70, 127. 73 N. P. Buu-Hoi’ and P. Cagniant, 2. physiol. Chem., 1943, 279, 76. 74 A. J. Birch and (Sir) R. Robinson, J. , 1942,490. 7 5 C. L. Carter and S. N. Slater, J. , 1946, 130. 76 W. H. Hook and (Sir) R. Robinson, J., 1944, 152. 7 7 B. E. Hudson, jun., and C. R. Hauser, J . Amer. Chem. Soc., 1940,62,2457.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

164 ORCANIC CHEMISTRY.

Acids branched in the y-position may be readily obtained by cyanoethylation of ketones followed by reduction of the product : 78

R' CH,:CR.CN R' Rt RCOCH/ -- + R*CO*CH*[CH2]2*CN -+ R*CH2*yH*[CH&*CO2H

,It R" \,,I

Unsaturated Acids. Mono-oZeJinic Acids.-The main events of interest in this field are the development of several new methods of synthesis. The first real synthesis of a long-chain, naturally occurring, unsaturated fatty acid was realised in 1934 by C. R. Noller and R. A. Bannerot 79 who prepared oleic acid by application of the Boord olefin synthesis.17 The inaccessibility of the starting materials, vix., w-chloro-aldehydes, however, prevented further use of this method although a later modification due to P. Baudarf *O has, to some extent, removed this difficulty.

A further synthesis by a route developed by L. Ruzicka, P1. A. Plattner, and W. Widmer,81 has been described by the same author.82 A " mixed " acyloin condensation of an unsaturated ester (XXIV) and a saturated ester (XXV) yields the unsaturated acyloin (XXVI) which is submitted to the procedures of Ruzicka et al. (Eoc. c i t . ) , to give the unsaturated acid (XXVIII). A modification in which (XXIV) is replaced by an w-ethoxy-ester is also described, The main advantage of this synthesis is that the two racemic

Na CH2:CH*[CH21z*C02Et R.[CH,]y.CO,Et -+ CH2:CH*[CH,],*CO*CH(OH)~[CH2],,~R

(XXVI .) (XXIV.) (XXV.) Pondorff acetglation,

CH,:CH*[CH,lz*CH(oH).CH(OH).ECH,I,.R -opgyno, -+ (XXVII. ) hydrolysis

HBr-AcOH,

Zn-NaT-COMe, H02C*[CHcJz*CH(OH)*CH(OH)*[CH,f,.R ,->

R*[CH2],*CH:CH[*CH2].*C02H (XXVIII.)

glycols (XXVII) may be separated by fractional crystallisation and submitted separately to the further procedures, to give the individual cis- or trans-acid respectively .

A somewhat siinilar route 83 employs the ap-methoxy-ketones, i.e., the acyloin ethers (XXIX), which may be prepared by the debenzylation ketone synthesis 3O and, to date, this has resulted in the synthesis of erucic and brassidic acids (XXX) :

Pondorff,

c1-13*CcH217 *CH(OW *CO*[CH,I 11*CO2H - E e (XXIX.) CH,*[CH2],~CH:CH*[CH2]11*C02H (XXX.)

Recent improvements in hydrogenation which permit partial reduction of acetylenic bonds have opened the way for the development of important

7 8 A, D. Campbell, C. L. Carter, and S. N. Slater, J., 1948, 1741. 78 J. Amer. Chern. SOC., 1934, 56, 1563.

81 Helu. Chim. Acta, 1942, 25, 604, 1086. 83 R. E. Bowman, 2LTcsture, 1949, 163, 95.

Conapt. rend., 1943, 217, 399; 1945, 220, 404. 82 Bull. Soc. chirn., 1946, 13, 87.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAN : LONG-CHAM A.LrPHBTIC COMPOUNDS. 165

methods for the synthesis of olefins. K. Ahmad and F. M. Strong were the first to apply this method to the synthesis of long-chain unsaturated acids and obtained undec-6-enoic acid 84 and, later, vaccenic acid (XXXI ; R = C6H13, x = 9) 85 according to the following scheme :

the great advantage of this route is the cis-addition of hydrogen to give the pure cis-form of (XXXI). In the last-mentioned synthesis i t wa-s necessary to elaidinise the product (XXXI; R = C,H,,; x = 9) in order to obtain the trans-form which was found to be identical with natural vaccenic acid.

PoZyoZeJinic Acids.-Progress on these materials has been uneventful, but the application, in the last few months, of new synthetical methods promises to revolutionise the whole field. A considerable amount of valuable work has been carried out on the isolation and purification of linoleic 86, 87, 88, SQ and linolenic 88 acids with particular empha.sis on low-temperature fractional crystallisation or regeneration from crystalline polybromides under carefully controlled conditions. The synthesis of linolelaidic acid (XXXIV) has been realised by Baudart so who applied his modification of the Boord synthesis to cca'-dibromoglutardialdehyde tetraethyl diacetal (XXXIII) :

n-CSH,,*MgBr + (EtO),CH-CHBr*CH,*CHBr*CH(OEt), + BrMg*[CH,],*OMe (XXXIII. )

Reaction in Et,O,

treatment with zinc

Br,, HBr, Zn C,H, ,*CH:CH*CH,*CH:CH.[CH,],*O~~e ----+

Malonation,

hydrolysis, -GO, C,H,,*CH:CH*CH2*CH:CH*[CH2],*Br .-+

C,H11*CH:CH*CH2*CH~CH*[CH2]7*COzH (XXXIV.)

An achievement of even greater promise is the total synthesis by R. A. Raphael 91 of linoleic acid, identical with the natural material, from acetylenic precursors.

The vexed problem of the structure of arachidonic acid appears to be settled in favour of (XXXV), originally proposed by I. Smedley-Ma~Lean,~~, 93

an earlier alternative having been withdrawn.94, 95 The isolation of complex 84 K. Ahmad and F. M. Strong, J . Amer. Chem. SOC., 1948, 70, 1699. 8 5 K. Ahmad, F. M. Bumpus, and F. M. Strong, ibid., p. 3391. a6 J. S. Frankel and J. B. Brown, ibid., 1941, 63, 1483. 87 J. S. Frankel, W. S. Stonebwner, and J. B. Brown, ibid., 1943, 65, 259, 415. * 8 R. T. O'Connor, D. C. Heinzelman, M. Caravella, and S. T. Bauer, Oil and Soup,

89 F. A. Kummerow and E. L. Green (with W. G. Schrenk and D. F. Wright), 1946, 23, 5.

J . Amer. Oil Chern. SOC., 1947, 24, 196. Bull. SOC. chim., 1944, [v], 11, 336.

g1 Private communication. 92 D. E. Dolby, L. C. A. Nunn, and I. Smedley-MacLean, Biochem. J. , 1940,34, 1422. 93 C. L. Arcus and I. Smedley-MacLean, ibid., 1943, 37, 1. O4 G. Y. Shinowara and J. B. Brown, J . Biol. CAern., 1940,134, 331.

D. T. Mowry, W. R. Brode, and J. 8. Brown, ibid., 1942,142,671, 679.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

166 OROANIU CHEMISTRY.

unsaturated acids from natural sources continues, e.g., erythrogenic acid (XXXVI a or b) from the oil of Ongokea klaineana, Pierre,96 the ester (XXXVII) from Hutrimria inodora L.,97 eicosa-11 : 14- and docosa-11 : 14- dienoic a~ids ,~8 eicosa-8 : 11 : 14- and docosa-8 : 11 : 14-trienoic acids 99

from the liver oil of Carcharidon carchurias, and isanic acid (XXXVIII) from isano oil.1

CH3*[CH2]4*[CH:CH*CH2]4-CH,*CH2*C0,H (XXXV.)

CH,:CH*[CH,],*C~C*CZEC*[CH~]~*CO~H (XXXVIb.)

(XXXVII.) (XXXVIII. )

CH&CH*CEZC*[CH,]~*C~~~[CH,]~*CO~H (XXXVIa.)

C,H7*~C*C~C*CH:CH*C0,Me CH&CH*[ CH,] ,*CGZC*C%~*[ CH,] *C02H

CH3*CH:CH*CH:CH*[CH2],*CH:CH*CO*NHBui (XXXIX.)

Interest has been aroused in the last few years by the isolation and formulation of three insecticidal principles from natural sources, " affinin " (XXXIX),2 pellitorine and herculin (XL; n = 2 and 4 respectively),3 all of which are N-isobutylamides of unsaturated acids. 17ery recently, the synthesis of geometrical isomers of the last two substances has been announced by v. J. Jac~bson,~ R. A. Raphael and F. Sondheimer,, and L. Crombie and S. H. Harper independently. The route used by Raphael and Sondheimer was as follows :

EtMgBr, H Pd

CO, cts add. C3H7*C=C*[ CH,],*C=CH ---+ C3H7-C~C*[CH2],*C~C*C02H ---++>

(COCI),, C3H7*CH:CH0[ CH2],*CH:CH*C02H --> NH,Bul

C3H7*CH:CH*[CH,],*CH:CH*CO*NHBui (xL.)

Two useful studies have been made of the use of various reagents for the preparation of acid chloride^.^ Oxalyl chloride appears to be the most satisfactory and enables the preparation of linoleyl and linolenyl chlorides to be carried out without appreciable rearrangement .8

*6 A. Castille, Annalen, 1939, 547, 104. $7 N. A. Sorensen and J. Stene, ibid., 1941, 549, 80.

P. Baudart, Bull. Soc. chim., 1942, [v], 9, 922. Idem, ibid., 1943, [v], 10, 440.

F. Acree, jun., M. J. Jacobson, and H. L. Haller, J. Org. Chern., 1941,10, 236;

M. J. Jacobson, J. Arner. Chem. Soc., 1948, 70, 423; 1949, 71, 316. Chem. Eng. News, 1949,27, 2355. Nature, 1949, 164, 707.

2 A. Steger and J. van Loon, Rec. Trav. chim., 1940,59,1156.

1947, 12, 731.

6 ibid., p. 1053. 7 S. T. Bauer, Oil and Soap, 1946,23, 1. * J. R. Wood, F. L. Jackson, A. R. Baldwin, and H. E. Longenecker. J. Amer.

Chem. Soc., 1944, 66, 287.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

BOWMAN : LONG-CHAIN ALIPHATIC COMPOUNDS. 167

Glycerides and Glycer~l Ethers.-Glycerides. Outstanding progress has been made in the synthesis of these materials during the last decade, mainly owing to the work of D. F. Daubert, H. 0. L. Fischer, and P. El. Verkade, and their collaborators. Lack of space prevents more than an outline of the main methods of synthesis being given. Synthesis of mixed glycerides depends on the availability of suitable protecting groups which mag be removed at a later stage. Groups most widely used for this purpose are- the trityl, isopropylidene, Two general examples are given

(jH,*OH R-COCI QH*OH ----+ CH,*O*CPh,

p3,*02CR R”.(33(3’0 vH*O,CR” +---- CH,*O,CR’

CH”>CMe2- CH,*O

7H2*OH RGOCI

(XLI.)

and, to a lesser extent, carbobenzyloxy.

(jH2*02CR R’.COC] 7H2’02CR CH*OH V $?H*O,CR’ CH,*O*CPh, CH,*O*CPh,

Ha-Jl?clB

?H2*O2CR QH,*O,CR vH*OH QH*O,CR’ CH,*OCR’ CH,*OH

QH*O->CMe, + CH*OH CH,*O CH,*OH

(XLII.)

(;1H2*02CR Hydrolysis vH2*02CR

A particularly noteworthy example of the use of the second route is the synthesis of optically active monoglycerides (XLII; R = C,,,) using the D- and the L-forms of (XLI).11

Glycerol Ethers.-The naturally occurring glycerol ethers, chimyl (XLIV ; R = n-C1&&), batyl (XLIV; R = n-CI8H3,), and selachyl (XLV) alcohol, have all been synthesised by H. 0, L. Fischer, E. Baer, and their collaborators. The starting materials for the synthesis of the first two was isopropylidene (-)-L-glycerol (XLI) which was treated, in the form of its sodio-derivative, with n-hexadecyl and octadecyl iodide respectively, to give (XLTII) which on hydrolysis furnished D-chimyf and D-batyl alcohol, identical with the

7H,*OR vH,*OR

CH,*O HO*CH, QHo0->CMe2 YH’OH

(D-) (XLIV.) (XLIII.)

Synthesis of selachyl alcohol (XLV) was not, however, practicable by this

P. E. Verkade, W. D. Cohen, and A. K. Vroege, Rec. Trav. chim., 1940, 59, 1123. lo C. Chen and B. F. Daubert, J. Amer. Chem. Soc,, 1945,67,1256. 11 E. Baer and H. 0. L. Fischer, ibid., p. 2031. l8 Idem, J. Biol. Chem., 1941,140, 397.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

168 ORGANIU CFfEMJSTRY.

route owing to elaidinisation,13 but was finally achieved by the following modification : 14

Lack of space precludes discussion of such other long-chain compounds as the hydroxy-acids, the chaulmoogra acids, the phospholipids and the cerebrosides. R. E. B.

5.VITAMlH A AND RELATED POLYENES.

Isomerism of Vitamin A. Crys tWe Esters and Ethers.-Since the last Report 1 dealing with vitamin A (I), the vitamin has been obtained as a yellow crystalline solid, m. p. 63-64°,2 and the previous sample of crys- talline vitamin A, m. p. 7°,3 shown to contain methanol of crystallis- ation. An isomeric, biologically-active form, neovitamin A, m. p. 59- 60°,4 has also been obtained crystalline. This was shown to occur in various fish-liver oils in amounts of up to 35% of the total vitamin-A content and to be present in a synthetic specimen (the method of synthesis was not given) in comparable amounts, so that vitamin A should be considered physiologically acs a mixture of the two geometrical isomers. Evidence was presented to show that-the two isomers differed only in the spatial configuration of the double bond nearest the hydroxyl group, neovitamin A being tentatively postulated to have the cis-configuration and vitamin A the trans-configuration. The two isomers showed differences in the rates of several chemical reactions, and in particular their different reactivities towards maleic anhydride formed the basis of a method for the estimation of neovitamin A in a mixture of the vitamins.

* Rrg*CH:CH*CMe:CH*CH:CH*CMe:CH*CH2*OH (I.)

* Following the earlier Report,’ Rg will be used to signify the 2 : 6 : 6-trimethyl- cyclohex- 1 -my1 ring.

A variety of crystalline esters of vitamin A has also been described,

13 E. Baer, L. J. Rubin, and H. 0. L. Fischer, J. Biol. Chem., 1944,155,447. 14 Idem, ibid., 1947, 170, 337. 1 E. R. H. Jones, Ann. Reports, 1941, 38, 170. 2 J. G. Baxter and C, D. Robeson, Science, 1940, 92, 203; J . Amer. Chem. Soc.,

3 H. N. Holmes and R. E. Corbett, ibid., 1937, 59, 2042. 4 C. D. Robeson and J. G. Baxter, Nature, 1945, 155, 300; J . Amer. Chem. Soc.,

1947, 69, 136 ; J. D. Cawley, C. D. Robeson, L. Weisler, E. M. Shantz, N. D. Embree, and J. G. Baxter, Science, 1948, 107, 346 ; L. Zechrneister, ‘‘ Vitamins and Hormones,” New York, 1949, 7, 74.

1942, 64, 2411.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JORNSON: VITAMIN A AND RELATED POLYENES. 169

e.g. , 6, palmitate,6* succinate, 6, 2-naphth0ate,~l 7, 8, anthra- quinone-2-carboxylate,4, 77 *, and pphenylazobenzoate,4, * and in the case of neovitamin A, the p-phenylazobenzoate and anthraquinone-2-carb- o ~ y l a t e . ~ Catalytic interconversion of the anthraquinone-2-carboxylates of the two vitamins was accomplished in oitro by the action of iodine in benzene solution.

Crystalline vitamin A methyl ether, which has nearly the same biological activity as vitamin A itself, has been obtained by the action of methyl sulphate on the lithium derivative of the vitamin lo and also synthetically.' The preparation of the pure methyl ether by heating a concentrate of the naturally occurring vitamin-A esters with methanol has been claimed by J. D. Caw1ey.l' Synthetic vitamin-A phenyl ether has also been obtained crystalline.

Syntheses of Vitamin A and its Ethers.-There are now at least four syntheses available for the vitamin and the correlations of biological activity with the chemical structure of several synthetic analogues of vitamin A have already been described. The developments which led to the first syntheses of vitamin A have been surveyed by Sir Ian Heilbron in the 1947 Pedler lecture; l2 other reviews are also a~ai lable .1~~ l4, l5

p- IonylideneacetaEdehyde.-The original synthesis of a biologically active product lG comprised the conversion of p-ionone into P-ionylideneacet- aldehyde (11), condensation of (11) with 3-methylcrotonaldehyde, and finally a Ponndorf reduction of the product.

(11.1 Rfi*CH:CH*CMe:CH*CHO RB*CH:CH*CMe:CH*CO,Et (m.) There have been further unsuccessful attempts 1 7 9 18, l9 to prepare @-ionyl-

ideneacetaldehyde by Kuhn's method and even the structure of the

0. Schwarzkopf, H. J. Cahmann, A. D. Lewis, J. Swidinsky, and H. M. Wiiost, Helv. Chim. Acta, 1949, 32, 443.

J. G. Baxter and C. D. Robeson, J . Amer. Chem. SOC., 1942,64, 2407. 0. Isler, A. Ronco, W. Guex, N. C. Hindloy, W. Huber, K. Dialer, and M. Kofler,

Helv. Chim. Acta, 1949, 32, 489. * 0. Isler, W. Huber, A. Ronco, and M. Kofler, &id., 1947, 30, 1911. * T. H. Mead, Biochem. J. , 1939, 33, 589; S. Hamano, Sci. Papers Inst. Phys.

Chew,. Res., Tokyo, 1935, 28, 69; 1937, 32, 44. lo A. It. Hanze, T. W. Conger, E. C. vtrise, and D. I. Weisblat, J . Amer. Chem. SOC.,

1946, 68, 1389; 1948, 70, 1253. l1 B.P. 579,449 (Chem. Abs., 1947, 41, 1396); U.S.P. 2,430,493 (Chem. Abs., 1948,

42, 1604). 1z J., 1948, 386. l3 N. A. Milas, " Vitamins and Hormones," New York, 1947, 5, 1.

N. T. Gridgemann, Chem. and Ind., 1947, 555 ; A. W. Johnson, Science Progw.ss, 1948, 36, 496.

l5 J. F. k e n s and D. A. van Dorp, Produits Pharm., 1949,4, 249, 397. l6 R. Kuhn and C. J. 0. R. Morris, Ber., 1937,70, 853; U.S.PP. 2,233,375, 2,239,491

l7 I. M. Heilbron, A. W. Johnson, E. R. H. Jones, and A. Spinks, J. , 1942, 727. l8 H. Sobotke, E. Bloch, and D. Glick, J . Amer. Chem. SOC., 1943, 65, 1961. l* N. A. Milas, Science, 1946, 103, 581.

(Chem. Abs., 1941,35, 3774, 4918); G.P. 696,084 (Chem. Abs., 1941, 35, 6394).

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

170 ORCANIC CHEMISTRY.

C,,5,-ester (111) has been questioned 18*23 although it is no longer in doubt.e2*

In a series of investigations of new routes to (11) J. F. h e n s and D. A. van Dorp 25 effected Reformatsky reactions with methyl bromothiolacetate but only low yields of the unsaturated thiolesters were obtained, together with by-products. It had been proposed to treat the ap-unsaturated thiolesters with Raney nickel26 in order to obtain the corresponding aldehydes. However another method, which promises to be of general application, was found; 273 28 i t consisted of the Grignard reaction of the ketone with ethoxyacetylene 29 to give an acetylenic ether which was partially hydrogenated to the ethylenic ether. Rearrangement of these en01 ethers with dilute acids gave ap-unsaturated aldehydes and the C,, aldehyde (11) was obtained thus from &ionone : 159 27* 32

RgCH:CH*COMe + EtO*CiC-MgBr RgCH:CH*CMe(OH)*CiC*OEt Rp*CH:CH*CMe(OH)GH:CH*OEt 4 (11)

This aldehyde proved to be identical with that previously described by Kuhn m d Morris l6 and, moreover, on condensation with S-methylcroton- aldehyde a product was obtained which, on fractional crystallisation of the corresponding semicarbazone, yielded crystalline vitamin-A aldehyde semi- carbazone. Ponndorf reduction of the crude aldehyde gave a product with distinct vitamin-A activity. Thus the claim of Kuhn and Morris to the original synthesis of biologically active material must be upheld although their process for the preparation of (11) is not easily reproducible, and their product was undoubtedly very impure. The formation of the C,, alde- hyde (11) by Arens and van Dorp's method has been confirmed by other workers,30~3~ and the same method has been applied to several simpler aldehydes and ketones.27* 315 32 A similar application 27* 33* 34 led to the syntheses of vitamin-A aldehyde and vitamin A itself (p. 173).

In another approach35 to the C,, aldehyde the same authors have

20 P. Karrer and A. Riiegger, Helv. Chim. Acta, 1940, 23, 284. 21 N. S. Vul'fson, Chem. Ah . , 1943, 37, 6657. m W. G. Young and S. L. Linden, J . Amer. Chem. Soc., 1947, 69, 2042. 23 J . Amer. Chem. Soc., 1943, 65, 2061; 1945, 67, 403; Chem. Reviews, 1944, 34,

2' J . Amer. Chem. SOC., 1944, 66, 520, 2130. 26 Rec. Trav. chim., 1947, 66, 407. 26 J. F. W. McOmie, Ann. Reports, 1948, 45, 198. 2' D. A. van Dorp and J. F. Arens, Nature, 1947, 160, 189; Rec. Trav. chim., 1948,

28 Idem, Dutch P. 63,015 (Chem. Abs., 1949, 43, 5418). 29 T. L. Jacobs, R. Cramer et al., J . Amer. Chem, Soc., 1940,62,1849; 1942,64,223. 30 N. A. Preobrazhenskii and I. A. Rubtsov, J . Cen. Chem. Russia, 1948,18,1719. 31 M. N. Schukina and I. A. Rubtsov, ibid., p. 1645. 32 Sir Ian Heilbron, E. R. H. Jones, M. Julia, and B. C. L. Weedon, J., 1949, 1823. 33 J. F. Arens and D. A. van Dorp, Rec. Frau. chim., 1949,68,604. 34 W. Graham, D. A. van Dorp, and J. F. Arens, &id., 1949,68,609. 85 D, A. van Dorp and J. F. b e a s , ibid., 1948,67,469.

435.

67, 973.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : VITAMIN A AND RELATED POLYENES. 171

described the condensation of methyl ketones with hydroxpaleic anhydride in the presence of hydrogen chloride. On heating the keto-dicarboxylic acids so formed with aniline two moles of carbon dioxide were evolved giving the a d s of the a@-unsaturated aldehydes, which were hydrolysed :

HO*C*CO, CO2H PhNH, RB*CH:CH*COMe + 1 1 ,O 4 Rj-yCH:CH-CMe:C/ ___3.

CH*CO \CO*C02H

Rg*CH:CH*CMe:CH*CH:NPh % (11)

The product was identical with that described earlier by and by Kuhn and Morris.16

A recent note by N. L. Wendler, H. L. Slates, and M. Tishler36 has announced yet another synthesis of (TI). 2- p-Ionylidene-ethanol was first described several years ago 37 but a much better method of preparation is the reduction of the corresponding ester (111) with lithium aluminium h ~ d r i d e , ~ ~ > 39 Oxidation of the alcohol with manganese dioxide, according to the method used for a similar oxidation of vitamin A t 0 gave a mixture of two stereoisomeric forms of the C,, aldehyde which were described as nor- and ko-forms, denoting stereochemical relationships to @-carotene. The nor-form was apparently identical with that obtained by earlier workers.l6, 27* 35

The C,, Ketone (IV; R = Me).-In the meantime successful syntheses of vitamin A and the corresponding aldehyde, acid, and esters were elaborated by h e n s and van Dorp, the key intermediate for all of this work being the C,, ketone (IV ; R = Me). This was obtained 4l7 42, 433 459 46 from p-ionone through the C,,,,-ester (IV; R = OEt) and the C,, acid (IV; R = OH) by the method of H. Gilman and P. R. van

R~CH:CH*CMC?CH*CH:CH*COR RgCH:CH*CMe:CH*CH:CH*CMe:CH*CHO (IV.) w.1 Rp*CH:CH*CMe:CH*CH:CH*CMe:CH*CO,Et (IT.)

36 J . Amer. Chent. Xoc., 1949, 71, 3267. These authors (ibid., 1950, 72, 234) have also obtained /3-ionylideneacetaldehyde by oxidation of j3-carotene with hydrogen peroxideosmium tetroxide.

R. G. Gould and A. F. Thompson, ibid., 1935, 57, 340; J . Biol. Chem., 1936, 114, xli.

3 8 N. A. Milas and T. M. Harrington, J. Amer. Chem. SOC., 1947, 69, 2247. 39 H. H. Inhoffen, F. Bohlmann, and M. Bohlmann, Annulen, 1949, 565, 35. 40 S. Ball, T. W. Goodwin, and R. A. Morton, Biochem. J. , 1946,40, lix; 1948,42,516. 41 J. F. Arens and D. A. van Dorp, Nature, 1946,157, 190; Rec. Trau. chim., 1946,

42 Idem, Dutch P. 62,569 (Chem. Abs., 1949, 43, 5418). 43 H. H. Inhoffen, F. Bohlmann, and K. Bartram, Annulen, 1948, 561, 13. 44 J . Amer. Chem. SOC., 1933, 55, 1258. 45 Sir Ian Heilbron, E. R. H. Jones, and D. G. O'Sullivan, Nature, 1946,157,485; J.,

46 P. Karrer, E. Jucker, and E. Schick, Helv. Chim. Acta, 1946, 29, 704.

65, 338.

1946, 866.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

172 ORGANIC CHEMISTRY.

A second C17 acid was later isolated 47 and was formulated as a cis-isomer, isomerism occurring about the bond *. Treatment of this acid with methyl lithium gave a cis-isomer of the CIS ketone. Alternative methods for the preparation of ( IV; R = Me) include the Oppenauer oxidation of 2 4 - ionylidene-ethanol in the presence of acetone,S8 the condensation of the C,, aldehyde (11) with acetone in the presence of aluminium tert.-b~toxide,~~ and the conversion of the C,, aldehyde, p-ionylidenecrotonaldehyde, into the C,, alcohol with methylmagnesium bromide fallowed by oxidation to the ketone.48

Conversion of the CIS Ketone into Vitamin A and the Corresponding AZdehyde, Acid, and Esters.-The CIS ketone (VII ; R = Me) bears the same relation to vitamin-A aldehyde as p-ionone does to the C,, aldehyde (11) and thus application of the ethoxyacetylene reaction to the C,, ketone gave vitamin-A aldehyde or retinene (V) which was reduced to vitamin A (I) by the Ponndorf method 27$ 49 or better with lithium aluminium h ~ d r i d e . ~ ~ The product had 35% of the biological activity of crystalline vitamin A. A similar conversion of the Cis-Cl8 ketone 47 gave the cis-isomer of vitamin-A aldehyde.34

The Reformatsky reaction of (IV; R = Me) with bromoacetic ester gave a hydroxy-ester, which after dehydration yielded the ester of vitamin-A acid (VI). The free acid 41 when dissolved in peanut oil had an activity of about one-tenth that of vitamin A, although an aqueous solution of the sodium salt buffered to pH 10 had equivalent activity when adminis- tered orally or about half of the activity of vitamin A when injected sub- c u t a n e ~ u s l y . ~ ~ The acid was not reduced to vitamin-A alcohol in ~ i v o . ~ l

The preparation of vitamin-A acid has been confirmed by the Heilbron 45

and Karrer 46 schools and later by other workers.5 An entirely different method of synthesis of vitamin-A ester (VI) has

been claimed by Milas,13* 52 but experimental details are not available. Reduction of purified vitamin-A ester with lithium aluminium hydride

gave vitamin A directly in up to 95% yield and thus provided an alternative and easier route to the vitamin from the CIS ketone (IV; R = Me). Such a method had been suggested in earlier papers.12*38 No biological differ- ences between the synthetic a.nd the natural vitamins could be observed 53

and the same authors have announced 54 the preparation of an isomeric vitamin-A acid by the Reformatsky reaction of the CIS ketone with bromo- acetic ester. Mild dehydration (e.g., iodine) of the hydroxy-ester yielded the isomeric C!2,,-ester (VII ; R = C02Et) which, under more vigorous

47 J. F. Arens and D. A. van Dorp, Rec. Trav. chim., 1947,86, 759. 48 Idem, Dutch P. 62,571 (Chem. Abs., 1949, 43, 5418). 49 Idem, Dutch P. 62,735 (Chem. Abs., 1949, 43, 5417).

52 N. A. Milas, U.S.PP. 2,369,168, 2,424,994, 2,432,921 (Chem. Abs., 1945, 39,

53 H. M. Wuest and N. Ereoli, Abstracts of papers read a t the 115th Amer. Chem.

64 0. Schwarzkopf, H. J. Cahnmann, A. D. Lewis, J. Swidinsky, and H. M. Wuest,

Idem, Nature, 1946, 158, 60.

5044; 1947, 41, 6896; 1948, 42, 2278).

SOC. meeting, 1949, 1 2 ~ .

ibid., 1949, 1Zc.

51 Idem, ibid., p. 622.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHIlJSON : VITAMIN A AND RELATED POLYENES. 173

conditions of dehydration, could be re-arranged to the known C,,,,-ester (VI). Reduction of (VII; R = C0,Et) with lithium aluminium hydride gave a new biologically active C,, alcohol, isomeric with vitamin A which was named vitamin A, (VII ; R = CH,*OH). Experimental details of this work are not yet available.

R~.CH:CH*CMe:CH*CH:CH*C (:CH,) *CH,R (nr. )

/o\ (VIII.) Rp*CH,*CH:CMe-CHO RgCH:CH*CMe*CW*CO,R (IX.)

The C,, AZdehyde (VIII).-Since 19-12, much attention has been paid to the use of the C,, aldehyde (VIII) as a starting material for the synthesis of vitamin A, and this approach has also resulted in a complete synthesis of the vitamin. The preparation of (VIII) 55 has been improved consider- ably 56 the modified conditions being applicable to a variety of other ap-unsaturated ketones.57 I. M. Heilbron et aZ.,55 produced good evidence to show that the structure of (VIII) was that of an a@-unsaturated aldehyde, on the basis of the ultra-violet absorption spectrum and by analogy with the product from cc-ionone which is also ap-unsaturated. This conclusion has been challenged by Milas 133 58 who favours a Fy-unsaturated- aldehyde structure. The evidence, including the Raman spectrum,61 for a@-unsaturation in (VIII) has been sumrnarised in a later paper.59 0. Isler and his co-workers have succeeded, by application of a scheme closely related to that formerly envisaged by I. M. Heilbron, A. W. Johnson, E. R. H. Jones et U Z . , ~ ~ ? 61 in preparing crystalline vitamin A 8* 62 as well as a variety of its esters and ethers:7, 63, 64

(VIII) -t HCiC*CMe:CH*CH,=OH

RgCH,*CH:CMe*CH (OH)*CiC-CMe:CH*CH,*OH

RgCH,*CH:CMeGH( OH)*CH:CH*CMe:CH*C33,*OAc

Vitamin A (I)

.1

.1

.1 H, ; partial acetylation

rearrangement ; dehydration ; hydrolysis

6 5 J., 1942, 727. 57 Idem, U.S.P. 2,451,742 (Chem. Abs., 1949, 43, 1800). 5 8 N. A. Milas, S . W. Lee, E. Sakal, H. C. Wohlers, N. S . MacDonald, F. X. Grossi,

5g G. W. H. Cheeseman, Sir Ian Heilbron, E. R. H. Jones, F. Sondheimer, and

6L J. Cymerman, I. M. Heilbron, A. W. Johnson, and E. R. H. Jones, J. , 1944, 141. 62 0. Isler, U.S.P. 2,451,739 (Chem. Abs., 1949,43, 1801) ; Swiss P. 256,699; Chimia,

1949, 3, 156, 63 0. Isler, W. Huber, A. Ronco, and M. Kofler, Experientia, 1946, 2, 31 ; “ Emil

Barell Jubilee vo~ume,” Hoffmann-La Roche and Co., Bade, 1946, p. 31. 64 0. Isler, U.S.PP. 2,451,735-738, 2,451,741 (Chem. A h . , 1949, 43, 1801); B.PP.

605,208, 605 772, and 622,510 (Chern. Abs., 1949, 43, 679, 9083); Swiss PP. 248,801, 250,374, 254,948, 255,253, 256,698, 257,577 ; Chimia, 1948, 2, 259 ; 1949, 3, 156.

66 H. Lindlar, U.S.P. 2,451,740 (Chem. Abs., 1949, 43, 1800).

and H. F. Wright, J . Amer. Chem. SOL, 1948, 70, 1584.

B. C. L. Weedon, J., 1949, 1516.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

174 ORGANIC CHEMISTRY.

The rearrangement and dehydration of the ethylenic acetate were carried out with iodine in boiling ligroin in the presence of (&)-a-tocopherol as a stabiliser, and the product, after hydrolysis, was purified through the anthraquinone-2-carboxylate giving crystalline vitamin A, identical with the natural product.

Before the Swiss publications, an extensive series of patents granted to N. A. Milas 13, 65 was published in which the syntheses of a number of biologically active materials by very similar routes was claimed. Full experimental details of this work are not yet available, and biological data are still lacking for the most highly purified samples of the esters and ethers. A more recent paper by Milas et aZ.66 has described the preparation of rela- tively pure vitamin-A methyl and ethyl ethers and also less pure samples of the isopropyl and tert.-butyl ethers. Vitamin A itself was obtained,l3~ 67

although impure, from the corresponding dimethylamino-compound, through a quaternary ammonium salt, by heating the salt in the presence of an alcohol :

R-NMe, -+ R*NMe3 ---+ R*OH + NMe, + R‘I

(R = RgCH:CH*CMe:CH*CH:CH*CMe:CH*) The product had “ appreciable biological activity ” l3 and the purest speci- men obtained had log hsx. 3240 A. = 4.61 (the crystalline vitamin A of Baxter and Robeson had log cmsX. 3280 A. = 4.70).

Other Synthetic Approaches to Vitamin A and its Ethers.-Aaother route to vitamin A depends on the Reformatsky reaction of propargyl bromide with P-ionone 68s 69 to give the alcohol (X) :

R’OH

w I

RgCH:CH*CMe( OH)*CH,*CiCH (x.)

The further stages of this approach will thus involve condensation with a C4 carbonyl component,70 semi-hydrogenation of the triple bond, and dehydration as in the method based on the C1, aldehyde (VIII) (p. 173). Reformatsky reactions with propargyl bromide have recently been extended to other ap-unsaturated carbonyl c o m p ~ u n d s . ~ ~ ~ 72 Thus the reaction with methyl vinyl ketone gave the tertiary acetylenic alcohol, 3-methylhex-l-en-5-

6 5 N. A. Milas, Science, 1946, 103, 581; U.S.PP. 2,369,156-157, 2,369,169-167; 2,382,085-086, 2,412,465, 2,455,261 (Chem. Abs., 1945, 39, 5043-46; 1946, 40, 681 ; 1947,41, 1240; 1949, 43, 1793).

66 N. A. Milas, E. Sakal, J. T. Plati, J. T. Rivers, J. K. Gladding, F. X. Grossi, 2. Weiss, M. A. Campbell, and H. F. Wright, J . Amer. Chem. Soc., 1948, 70, 1597.

67 N. A. Milas, U.S.P. 2,415,834 (Chem. Abs., 1947, 41, 3483). 6 8 Roche Products Ltd., B.P. 617,482 (Chem. Abs., 1949,43,5798); Swiss P. 258,514. O9 H. H. Inhoffen, H. Pommer, and E. Meth, AnnuZen, 1949,585,45; B. N. Feitelson,

70 K. Zeile and H. Meyer, Ber., 1949, 82, 267. V. Petrow, and 0. Stephenson, J . Pharm. and Pharmacol., 1949,1, 847.

H. B. Henbest, E. R. H. Jones, and I. M. S. Walls, J. , 1949, 2696; Hoffmann- La Roche and Co., Swiss P. 250,658 (Chem. Abs., 1949, 43, 7952).

72 Idem, B.P. 619,898 (Chem. Abs., 1949, 43, 9082); Chimio, 1950, 4, 18, 41.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : VITAMXN A AND RELATED POLYENES. 175

yn-3-01, HCiC*CH,*CMe( OH)*CH:CH,, which by anionotropic rearrangement was converted into the primary alcohol, HC':C*CH,*CMe:CH=CH,*OH or its methyl ether. This methyl ether was used in a further synthesis of vitamin-A methyl ether.72 Reaction of the Grignard derivative with p-ionone gave an acetylenic hydroxy-ether which was semi-hydrogenated and dehydrated to give a product from which a. concentrate of vitamin-A methyl ether of " high biological activity " was isolated after chromatographic purification :

RgCH:CH CMe (OH) *C':C*CH,*CMe:CH*CH,~OMe

RgCH:CH*CMe( OH)*CH:CH*CH,*CMe:CH*CH,*OMe

.1 Rg*CH:CH*CMe:CH*CH:CH*CMe:CH*CH,*OMe

A number of other unconfirmed syntheses of vitamin A and its derivatives has been rep0rted.'~-7~ Details are still lacking of a synthesis of crystalline vitamin A by a method " different from those described in the literature " although a later note has described the isolation of crystalline neovitamin A as well as the ordinary form from the product.

Syntheses of 'Vitamin A Analogues.-The successful syntheses of vitamin A and its ethers stimulated the preparation of analogous com- pounds in order to determine the relation between chemical constitution and biological activity. Several research teams have undertaken this work and a number of synthetic biologically active compounds have been prepared.

Variations of the Side-chain only.-As with the syntheses of vitamin A itself, the starting materials have been p-ionone, the derived C,, aldehyde (VIII), and the CIS ketone (IV; R = Me). These three compounds, as well as the C,,,,-ester (IV; R = OEt) have been reduced by lithium aluminium hydride to give p-ionol and the C,, (XI), C,, (XII; R = H), and CI8 (XI1 ; R = Me) alcohols: 39

Rg*CH,*CH:CMe*CH,*OH R g CH :CH*CMe: CH CH :CH*CHR OH (XI.) (XII.)

The methods of Isler and his co-workers,7> 8, 63 for the conversion of (VIII) into vitamin A and its ethers, have been used 59 for the preparation of the

73 B. C. Cornwall, U.S.P. 2,414,722 (Chem. Abs., 1948, 42, 5174). ?* K. Zeile and H. Neyer, Ber., 1949,82,275; M. Matsui and R. Yamamoto, Jap. P.

76 J . Amer. Chem. Soc., 1945, 67, 1627. 172,549 (Chern. Abs., 1949, 43, 7041).

J. D. Cawley, C. D. Robeson, L. Weisler, E. M. Shantz, N. D. Embree, and J. G. Baxter, Abstracts of papers read at the 112th h e r . Chem. SOC. meeting, 1947,26c.

?* Idem, Science, 1948, 107, 346.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

176 ORGANIC CHEMISTRY.

acetates and methyl ethers of norvitamin A (XIII; R = H) and iso- vitamin A (XIII; R -- Me), i .e. , by substituting pent-2-en-4-yn-1-01 or hex-3-en-5-yn-2-01,~~ and the corresponding methyl ethers for 3-methyl- pent-2-en-4-yn-1-01 and its ethers :

RgCH:CH*CMe:CH*CH:CH*CH:CH*CHR*OH (xm.) Rp*CH:CH*CMe:CH*CH:CH*CMe:CH*CH,*CH,*OEt (XIJT.)

Rp*CH:CH*CMe:CH*CIC*CMe:CH*CH2*CH2*OEt (xv.)

Derivatives of norvitamin A were too unstable for accurate biological assay but the methyl ether had an activity of not less than 1/30 of that of vitamin A. The derivatives of isovitamin A were inactive. By similar methods Milas and his colleagues 13+ 82 have prepared 5-dehydrohomovitamin-A ethyl ether (XV), which possessed activity, and homovitamin-A ethyl ether (XIV) although samples o f the latter, prepared by different methods, had considerably differing absorption spectra.

Following the Reformatsky condensation of p-ionone with y-bromo- crotonic 83 attempts have been made to prepare the C,19,-ester (XVI) by a similar reaction with w-bromosorbic ester, but the activity of this ester was not sufficiently great and the attempts were abandoned.

Rp*CH:CH*CMe:CH*CH:CH*CH:CH*CO,'Et Rp*CH:CH*CO*CH:CH*ONa (XVI.) (XVII.)

In another approach, E. M. Shantz 84 has condensed p-ionone with formic ester to give an unstable product, the sodio-derivative of which (XVII) reacted with Grignard compounds to give secondary alcohols, e.g. , (XVIII ; R = CH,*CMe:CH,) with methallylmagnesium bromide. The ketone (XIX), obtained by dehydration, reacted with methylmagnesium bromide, and the product was hydrolysed and dehydrated to give a C,, hydrocarbon (XX; R = Me, R' = H). Both this and the corresponding C,, hydrocarbon (XX; R = R' = H) were biologically inactive.

R,&H:CH*CO*CH2*CHR*OH (XVIII.)

Rp*CH:CH*CO*C13,*CH:CH*CMe:CH2 (XIX.)

Rp*CH:CH*CMe;:CH*CH:CH*CR:CHR' tXX.1 RgCH:CH*CMe:CH*CH:CMe*CMe:CHMe (XXI.)

More recently a series of hydrocarbons (XX) has been prepared by Karrer and his co-workers by the action of alkyl-lithiums on the c38 ketone (IV; R =Me) and subsequent dehydration of the alcohols so obtained. The

80 Sir Ian Heilbron, E. R. H. Jones et al., J., 1945, 77; 1947, 1583. 81 Sir Ian Heilbron, E. R. H. Jones, P. Smith, and B. C. L. Weedon, J., 1946, 54.

82 N. A. Milas, S. W. Lee, C. Schuerch, R. 0. Edgerton, J. T. Plati, F. X. Grossi, 2. Weiss, and M. A. Campbell, J . Amer. Chem. SOC., 1948, 70, 1591.

83 P. Karrer and R. Schwyzer, Helv. Chirn. Acta, 1946,29, 1191. 84 J . Amer. Chem. SOC., 1946, 68, 2553.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON: VITAMIN A AND RELATED POLYENES. 177

C, hydrocarbon (XX ; R = R' = Me) obtained by use of ethyl-lithium 853 86

was named axerophthene, and similar reactions were described with methyl- lithium and butyl-lithium giving demethylaxerophthene (XX ; R = Me, R' = H), the product previously obtained by Shan t~ ,~4 and lti-ethylaxe- rophthene 88 (XX; R = Me, R' = Pr"), respectively.

Axerophthene was biologically active,8g but demethylaxerophthene and 15-ethylaxerophthene were inactive, as was 12-methylaxerophthene (XXI), the preparation of which has not yet been disclosed.

Variations of the Ring only.-As yet the only compound which has been claimed containing the vitamin-A side-chain and a variant of the ring system is the phenyl analogue but the evidence for its identity is doubtful. It was biologically inactive.

Variations of the Ring and the Side-chain.-A wide variety of polyene compounds related to vitamin A have been prepared containing ring systems other than 2 : 6 : 6-trimethylcycZohex-l-enyl, an obvious early choice being 2 : 6 : 6-trimethylcyclohex-2-enyl as in a-ionone. Thus the Reformatsky reaction of a-ionone with y-bromocrotonic ester gave the CtI7)-ester, and the corresponding acid with methyl-lithium yielded the C,, ketone (XXII) 463 91, 92 as in the p-ionone series.

* R;CH:CH*CMe:CH*CH:CH*COMe R;CH:CH*CMe:CH*CH:CH*CMe:CHR (xx1I.t (XXIII.)

* R, is used to signify-the 2 : 6 : 6-trimethylcycZohex-2-enyI ring as in a-ionone.

The same ketone was also prepared 93 from a-ionylidene-ethanol. Reaction of (XXII) with ethyl-lithium gave isoaxerophthene (XXIII; R = Me) after dehydrati~n?~ and a similar reaction with methyl-lithium yielded demethyl- isoaxerophthene (XXIII; R = H).92

A number of other 4-substituted but-3-en-2-ones, R*CH:CH*COMe, have been prepared containing variants of the p-ionone ring system, 'e.g., R = cyclohe~enyl,~~ 2 - m e t h ~ l - , ~ ~ 4-rneth~l-,9~ and 6 : 6-dimethyl-cyclo- hexenyl,95 ~yclopentenyl,~~ ~ycloheptenyl,~~ 6-methylcyclohexa-1 : 3-dien~1,~4 and phenyl.gO These compounds were prepared by aldol condensations of acetone and the aldehydes RGHO, when the latter were available, or in

85 P. Karrer and J. Benz, Helv. Chim. Acta, 1948, 31, 1048. Idem, ibid., 1949, 32, 232. Idem, ibid., 1948, 31, 1607.

8 8 P. Karrer, D. K. Patel, and J. Benz, ibid., 1949, 32, 1938. 8B H. von Euler and P. Karrer, ibid., 1949, 32, 461. B0 W. H. Linnell and C. C. Shen, J . Pharm. and Pharmacol., 1949,1, 971.

P. Karrer and E. Schick, HeZv. Chim. Acta, 1947, 30, 862. B2 P. Karrer, K. P. Karanth, and J. Benz, ibid., 1949,32, 1036. Oa Idem, ibid., p. 436. 94 Sir Ian Heilbron, E. It. H. Jones, R. W. Richardson, and F. Sondheimer, J. ,

95 Sir Ian Heilbron, E. R. H. Jones, J. B. Toogood, and B. C. L. Weedon, ibid.,

$6 Idem, ibid., p. 1827.

1949, 737.

p. 2028.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

178 ORGANIC CHEMISTRP.

the general case by the route illustrated in the case when R = cycb- hexenyl : cf- 12$ 97

(XXIV.)

Dehydro- p-ionone (XXV) has been prepared by bromination of p-ionone with N-bromosuccinimide and dehydrobromination of the product with diethylaniline.98 The reaction was studied in more detail by G. Biichi, K. Seitz, and 0. Jeger 9Q who showed that under more vigorous conditions of dehydrobromination the product rearranged to a benzenoid derivative (XXVI). P. Karrer and P. Ochsner loo failed to obtain (XXV) but isolated (XXVI) and a hydrocarbon, 3-dehydroionene, from a similar reaction.

Me,,Me Me

The ethynylcycZohexenes, e.g., (XXIV), have been used to prepare struc- tural variants of the vitamin-A molecule.101 Thus the Grignard reaction of crotonylideneacetone with ethynylcyclohexene gave the tertiary alcohol (XXVII) which, by anionotropic rearrangement by the action of dilute acids, was converted into the fully conjugated carbinol. Oppenauer oxid- ation then gave the corresponding ketone (XXVIII), which by Reformatsky condensation with bromoacetic ester and dehydration gave the unsaturated ester (XXIX) :

RGCH + MeC0-I CH:CH],*Me --+ R*CIC*CMe( OH)*[ CH:CH],*Rle I_,

R*CiC*CMe:CH*CH:CH*CHMe*OH + R*CIC*CMe:CH*CH:CH*COMe (XXVII. )

(XXVIII. I Br.CH,.CO,Et ; - R*CIC*CMe:CH*CH:CH*CMe:CH*CO,Et

(XXIX.)

R*CiC*[CH:CH],CMe:CH*CO,H R = cyclohexenyl

Two other methods were developed for the preparation of (XXVIII) and related ketones. In the first, lola the Grignard derivative of ethynyl- cyclohexene was treated with methyl 2-chlorovinyl ketone by E. R. H. Jones and B. C. L. Weedon’s method, lolb and anionotropic rearrangement of the products with subsequent elimination of hydrogen chloride gave an

*7 H. Sobotka and J. D. Chanley, J . Amer. Chem. Soc., 1948, 70, 3912; 1949, ‘71, 4136.

*8 H. B. Henbest, Nature, 1948, 181, 481. e9 Helv. Chim. Ack, 1949, 32, 39. lo1 Sir Ian Heilbron, E. R. H. Jones, and R. W. Richardson, J., 1949, 287. lo1* J. B. Toogood and B. C. L. Weedon, ibid., p. 3123. 101b E. R. H. Jones and B. C. L. Weedon, J., 1946, 937.

loo Ibid., 1948, 31, 2093.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON: VITAMIN A AND RELATED POLYENES. 179

unsaturated aldehyde which, after condensation with acetone, was con- verted into (XXVIII) :

H' R*CIC*MgBr + Me*CO*CH:CHCl+ R*CiC*CMe( OH)*CH:CHCl+

Me,CO R*CiC*CMe:CH*CHO ---+ (XXVIII)

Alternatively (XXVIII) was prepared by the condensation of R*CiC*COMe with y- bromocrotonic ester, and conversion of the unsaturated ester into the methyl ketone. The sodium salt of the acid from (XXIX) had a biological activity of the order of one-thousandth of that of vitamin A.lol Similarly the C,, and the C,, acids containing 2-methylcyclohexenyl, 4- methylcyclohexenyl, and 6 : 6-dimethylcyclohexenyl rings were pre- pared,lOla, lo2 the latter also having about one-thousandth of the activity of vitamin A when administered as the sodium salt and the first two being inactive. In a further variation, the aldehydes Me*[CH:CH],*CHO (n = 0, 1, 2, and 3) were substituted for crotonylideneacetone in the above series of reactions, and a C,, acid (XXX), obtained by using sorbaldehyde (n = 2) and ethynylcyclohexene as starting materials, also had one-thousandth of the activity of vitamin A when administered as the sodium salt. R*CiC*CMe:CH*CH:CH-CMe:CH*CH2*OH Me*CO-CH:CH*CMe:CH*CHCH2

(XXXI. ) (XXXII.)

The preparation of polyene alcohols of the type (XXXI) has been accom- plished lo3 by the reaction of the ethynylcyctoalkene with the triene ketone (XXXII) lo* to yield a tertiary alcohol which gave (XXXI) by anjonotropic rearrangement. The final product, like the corresponding acid (from XXIX), had a biological activity about one-thousandth of that of vitamin A.

No indica.tion has been given so far of the possibility of partially reducing the triple bond in the side chain of these synthetic compounds (e.g., XXIX, XXX, XXXI), but it is of interest in this connection that J. D. Chanley and H. Sobotka lo4a have reduced 4-cyctohex-1 '-enylbut-3-yn-2-01 to the diene alcohol with lithium aluminium hydride :

R = cycbhexenyl

0, Ci C -CH (OH) *Me ~ (),CH:CH*CH(OH)*Me

/ \/ Other groups of workers have used ethynylcyclohexene and its analogues

as starting materials for the preparation of polyenes related to vitamin A. N. A. Milas and his co-workers lo5 used a Grignard reaction with methyl vinyl ketone to synthesise an analogue of the CI8 ketone (IV ; R = Me).

lo2 Sir Ian Heilbron, E. R. H. Jones, D. G . Lewis, and B. C. L. Weedon, J. , 1949,

108 G. W. H. Cheeseman, Sir Ian Heilbron, E. R. H. Jones, and B. C. L. Weedon,

lo* G. W. H. Cheeseman, Sir Ian Heilbron, E. R. H. Jones, F. Sondheimer, and

lobe J . Amer. Chern. Soc., 1949, 71, 4140. zo5 N. A. Milas, F. X. Grossi, S. E. Penner, and S. Kahn, ibid., 1948, 70,1292.

2023.

ibid., p. 3120.

€3. C. L. Weedon, ibid., p. 2031.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

180 ORGAETIC OHEMISTRY.

In a later paper,lo6 Grignard reactions of the ethynylcyclohexenes with chloroacetone, followed by dehydrochlorination with potassium hydroxide, gave epoxides (e .g . , XXXIII), which were shown to react normally with the Grignard or metallic derivatives of ethynyl hydrocarbons. Thus the Grignard reaction of (XXXIII) with l-methoxy-3-methylpent-2-en-4-yne, HCiC*CMe:CH*CH,*OMe, gave a diacetylenic hydroxy-ether, which after conversion into the bromide and dehydrobromination with potassium carbonate yielded the diacetylenic ether (XXXIV).97

R*CiC*CMeCH, '0'

R*CiC*CMe:CH*CiC*CMe:CH*CH,*OMe

(XXXIII.) R = cyclohexenyl (XXXIV.)

Congeners of Vitamin A. Kitol.-This dihydric alcohol, C,0H600,, is found in considerable quan-

tities in whale-, dogfish-, and shark-liver oils, where it occurs as its e ~ t e r s . ~ O ~ ~ lo8 It has little or no biological activity but yields vitamin A in approximately equimolecular quantities together with other products, on being heated above 200". Similarly kitol esters on pyrolysis yield the esters of vitamin A.lo9 The pure crystalline compound has m. p. 88-90' and its absorption spectrum shows the presence of four conjugated double bonds. Altogether there are eight double bonds in the molecule but the detailed structure is not yet known. Kitol is not very stable in the solid state even in sealed ampoules, although solutions in ethanol are said to be relatively stable. It has been suggested no that the physiological function of kitol may be to detoxify excessively high stores of vitamin A. Evidence has also been obtained lo7 for the existence of kitol,, a progenitor of vitamin A, (see below) in the liver oil of a " northern pike."

Vitamin A,.-The early work on vitamin A,, which occurs in the livers of fresh-water fish, was reviewed by I. &I. Heilbron, W. E. Jones, and A. L. Bacharach.ll1 Since that time the most notable achievement has been the isolation of the pure vitamin 112 as an orange-yellow oil from " pike '' livers by a process involving distillation and chromatography.

The structure first proposed for vitamin A, was (XXXV) 113 but this was rejected on the basis of spectral and distillation studies 11* and instead

106 N. A. Milas, N. S. MacDonald, and D. M. Black, J . Amer. Chem. SOC., 1949, 71,

lo' N. D, Embree and E. M. Shantz, ibid., 1943, 65, 910; B.P. 560,077 (Chem. Abs.,

108 R. K. Barua and R. A. Morton, Biochem. J., 1949,45, 308. 109 N. D. Embree and E. M. Shantz, B.P. 668,607 (Chem. Abs., 1947, 41, 4278);

110 K. Hickman, Ann. Rev. Biochem., 1943, 12, 363. 111 " Vitamins and Hormones," New York, 1944, 2, 187. 112 E, M. Shantz, Science, 1948, 108,417. 11s A. E. Gillam, I. M. Heilbron, W. E. Jones, and E. Lederer, Biochem. J. , 1932,

11* E. LeB. Gray and J. D. Cawley, J . €3408. Chem., 1939,131,317; 1940,134, 397.

1829.

1946, 40, 1636).

U.S.P. 2,434,687 (Chem. Abs., 1948, 42, 2404).

32, 405.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON: VITAMIN A AND RELATED POLYENES. 181

i t wits suggested that vitamin A, was a C,, compound containing one double bond more than vitamin A,. On the basis of oxidative studies, P. Karrer, E. Bretscher, and A. Geiger,l15 working, however, with a product which probably contained appreciable amounts of vitamin A1,1l2 advanced the open-chain structure (XXXVI) for vitamin A,, bearing the same relation to vitamin A, that lycopene bears to p-carotene. The biological activity, which is about 40% of that of vitamin A,, was ascribed to the tendency for vitamin A, to cyclise to vitamin Al in ziizio, but Shantz 112 has since demonstrated that there is no evidence for this statement, although vitamin A, can replace vitamin A, in many important body functions in the rat.l16 The structure (XXXVI) has also been challenged 1, on the grounds that lycopene, unlike p-carotene, does not function as a provitamin.

Rp*CH:CH*CMe:CH=CH:CH*CMe:CH*CH:CH*CH2*OH (XXXV.

CH fiH*CH:CH*CMe:CH*CH:CH*CMe:CH*CH,*OH CH, CMe

(XXXVI.)

/\CH:CH*CMe:CH*CH:CH=CMe:CH*CH2*0H

bd, Me, Me

<)be (XXXVII.)

A third formula, incorporating the earlier suggestions of Gray and Cawley,l14 is that vitamin A, is a dehydrovitamin A, 1 1 7 (XXXVII), and this is supported by the identity of a C,, aldehyde, prepared earlier by the Oppenauer oxidation of vitamin A, in the presence of diethyl ketone, and retinene,, the aldehyde of vitamin A,.117 Neither structure (XXXVI) nor (XXXVII) is universally accepted, and any formula for vitamin A, must also explain why the spectra of the anhydro-forms of vitamins A, and A, are almost identical although the spectra of the blue compounds formed with antimony trichloride are totally different.llg5 120

Retinene, and Retinene, ; The Vitamin-A Aldehydes.-The vitamin-A aldehydes or retinenes are concerned with the process of vision and have been the subject of a considerable amount of recent research, particularly

115 Helv. Chim. Acta, 1941, 24, 161~; 1942, 25, 1650; 1943,26, 1758. P. Karrer and P. Schneider (ibid., 1950, 33, 38) have since stated that structure (XXXVI) is probably incorrect for vitamin A,.

116 E. M. Shantz, N. D. Embree, H. C. Hodge, and J. H. Wills, J . Biol. Chem., 1946,163, 455.

R. A. Morton, M. K. Salah, and A. L. Stubbs, Biochem. J., 1946,40, Iix; Nature, 1947, 159, 744.

118 I. M. Heilbron, W. E. Jones et ul., J. , 1939, 125, 1560. 11$ N. D. Embree and E. M. Shantz, J. B i d Chem., 1940,132, 619. 120 E. G. E. Hawkjns and R. F. Hunter, Biochem. J. , 1944, 38, 34.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

182 ORGANIC CHEMISTRY.

from the biochemical point of view. Early work by G. Wald had shown that retinene, (V) could be extracted from retinas which had been exposed to light; dark-adapted retinas on the other hand contained a compound named rhodopsin or visual purple. In fresh-water fish rhodopsin is replaced by porphyropsin or visual violet, and retinene, by retinene, : 121 these retinenes are regarded by Wald as the prosthetic groups of visual purple and visual violet. Hitherto the main cheniical interest in this group of compounds has been in the structures and the reactions of the retinenes. The first suggestion that retinene, might be the aldehyde of vitamin A (VIII) came from R. A. Morton122 and was based on considerations of absorption spectra, and similarly retinene, was considered to be vitamin A, aldehyde. A concentrate showing the spectrographic characteristics of retinene was obtained 123 by shaking light-petroleum solutions of vitamin-A concentrates with aqueous permanganate, followed by chromatographic separation of the products. In a later study of this reaction,124 another product, possibly a retinene epoxide, was obtained from the oxidation, Treatment of vitamin A with aluminium isopropoxide cf. 125 in the presence of acetaldehyde as hydrogen acceptor 126 gave the impure aldehyde, and crystalline retinene,, m. p. 61", has recently been obtainedP4 by oxidation of vitamin A in petroleum solution with manganese dioxide. The oxid- ation method was slightly modified by G . Wald.12' Very small yields of vitamin-A aldehyde have also been obtained from the oxidation of @-carotene with hydrogen peroxide in acetic acid solution under carefully controlled experimental conditi~ns.l~~, 130

The aldehyde of vitamin A,, retinene,, has been obtained 117 by the oxidation of vitamin A, with manganese dioxide. The same aldehyde had been obtained earlier by I. M. Heilbron et ~ Z . 1 1 ~ by the Oppenauer oxidation of vitamin A, in the presence of diethyl ketone, and later experiments 117 showed that i t could be obtained in better yield when retinene, was simi- larly treated with aluminium tert.-butoxide. These experiments led Morton to suggest that vitamin A, was a dehydrovitamin A, (p. 181). It is not possible to discuss here the biochemical relations between rhodopsin, retinene,, and vitamin A, in the process of photoreception in the eyes of vertebrates

121 Nature, 1937, 139, 1017. 122 Ibid., 1944, 153, 69. n3 R. A. Morton and T. W. Goodwin, ibid., 1944,153, 405. 124 P. Meunier and J. Jonanneteau, BUZZ. SOC. Clzim. biol., 1948,30, 185. 1z5 I. M. Heilbron, A. W. Johnson, and W. E. Jones, J., 1939, 1560. 126 E. G. E. Hawkins and R. F. Hunter, J., 1944, 411 ; Nature, 1944, 153,

12' G. Wald, J . Gen. Physiol., 1947-1948, 31, 489; Fed. Proc., 1948, 7 , 129. l a 8 Idem, Science, 1949, 109, 482 ; Biochimica et Biophysica Acta, 1950, 4, 215. 12s R. F. Hunter and N. E. Williams, J., 1945, 554. 130 G. C. L. Goss and W. D. M. McFarlane, Science, 1947, 106, 375.

194.

More recently N. L. Wendler, C. Rosenblum, and M. Tishler ( J . Amer. Chem. SOG., 1950, 72, 234) have re-examined the oxidation of p-carotene with hydrogen peroxide-osmium tetroxide and have described the isolation of vitamin-A aldehyde (yields up to 30%), 8-ionylidene- acetaldehyde (11), and 2 : 7-dimethyloctatrienedial from the reaction products.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : VITAMIN A AND RELATED POLYENES. 183

or the parallel relations of porphyropsin, retinene,, and vitamin A,, but attention is drawn to a number of recent

Vitamin A Epoxide.-The oxidation of vitamin A with perphthalic acid gives an epoxide (XXXVIII) 132p 133 showing an absorption maximum a t 2750 A,, and this compound has proved to be identical with the 574 chromogen of P. Karrer and R. Morf,f34 later designated h e p a ~ a n t h i n . ~ ~ ~ G. V. Troitskii 136 considers that the epoxide is identical with other oxidation products of vitamin A which have been described in the literature,l3? and he claims, although without chemical evidence, that a structure (XXXIX) would be in better accord with the observed absorption spectrum.

128, 131

Me,,Me \ CH:CH*CIMe:CH*CH:CH*CMe:CH*CH~*~H

(XXXVIII.) R~.CH:CH*CMe:CH*CH*CH*CMe:CH*CH,*OH

(XXXIX.)

Xubvitumin A .-A substance, provisionally named subvitamin A, occurs in traces in shark-liver oil and has chemical properties which relate i t to the vitamin-A It has little or no growth-promoting power and is possibly an oxygenated derivative of vitamin

Anhydrovitamin A.-It has been known for many years that vitamin A, on treatment with dilute alcoholic hydrogen chloride is converted into a compound having three bands in its ultra-violet absorption spectrum, and possessing slight biological activity The reaction was a t first thought to be one of cyclisation but a later inves- tigation 140 has shown that a dehydration is involved, and the product is therefore known as anhydrovitamin A, rather than “ cyclised vitamin A.” The name axerophthene which was formerly applied to this hydro- carbon 141, 142 is now reserved for the synthetic C,, hydrocarbon (XX;

131 R. Granit, “ Sensory Mechanisms of the Retina,” Oxford, 1947 ; A. F. Bliss, J . BioE. Chem., 1948, 172, 165 ; S. Ball, R. A. Morton et al., Nature, 1948, 181, 424; Biochem. J. , 1949, 45, 298, 304.

f 60 \/(Me

\O’

138

(0.4% of that of vitamin A).

132 P. Karrer and E. Jucker, Helv. Chim. Acta, 1947, 30, 559. 133 A. Vinet and P. Meunier, Compt. rend., 1947, 222, 1144; Bull. SOC. Chim. biol.,

134 Ibid., 1933, 18, 625; M. van Eekelen, A. Emmerie, H. W. Julius, and L. K.

136 H. von Euler, P. Karrer, and A. Zubris, Helv. Chim. Acta, 1934,17, 24. lae G. V. Troitskii, Biokhimiya, 1948, 13, 7. 137 Idem, ibid., 1941,6,3 ; G . A. LePage and L. B. Pett, J . Biol. Chem., 1941,141, 747. 138 N. D. Embree and E. M. Shantz, J . Amer. Chem. Soc., 1943, 65, 906. 13s J. R. Edisbury, A. E. Gillam, I. M. Heilbron, and R. A. Morton, Biochem. J.,

1932,28, 1164; N. D. Embree, J . Biol. Chem., 1939,128, 187. 140 J . Amer. Chem. Soc., 1943, 85, 901. 141 P. Meunier, R. Dulou, and A. Vinet, Compt. rend., 1943, 216, 907; Bull. SOC.

1947, 29, 25.

Wolff, Nature, 1933, 132, 171.

Chim. biol., 1943, 25, 371. P. Meunier, Compt. r e d . , 1948, 227, 206.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

184 ORGANIC CHEMISTRY.

R = R' = Me).85, 86* 87 Anhydrovitamin A is a crystalline solid, c2oH28,

and the present accepted formula (XL) was suggested both by E. M. Shantz, J. D. Cawley, and N. D. Embree 140 and by P. Meunier et aZ.141

(XLI.)

P. Karrer and R. Schwyzer 143 have also obtained (XL) from other reactions of vitamin A and in one of these a small amount of a carofenoid, possibly @-carotene on the basis of its spectrum and biological properties, was also obtained in solution. Meunier 142 considered this latter compound to be the symmetrical ether of vitamin A,144 but Karrer does not accept this view. lo1

Vitamin A, also forms an anhydro-derivative which can be readily separated from anhydrovitamin A, and thus provides a method for the determination of relative amounts of the two vitamins in mixtures.136 The scope of this type of dehydration reaction has been examined by E. G. E. Hawkins and R. F. Hunter 126 and neither kitol lo' nor vitamin A, 54

forms anhydro-derivatives. Anhydrovitamin A may be converted into compounds of greater biological activity either in vivo in the rat 145 or in vitro by heating with water and an organic acid.146

When vitamin A is allowed to react with alcoholic hydrogen chloride for longer periods: there is formed another compound, isottnhydrovitamin A 140 for which structure (XLI) has been suggested.147

A. W. J.

6. AMINO-ACIDS.

Introduction.-Since the last full Report on this subject several new amino-acids have been encountered in bacteria. Those identified with certainty are aa'-diaminopimelic acid, from Corynebacteriurn diphtherice and Mycobacterium and ay-diamino-n- butyric acid from Bacillus polymyxa ; less certainly identified are a-amino-y-hydroxy- @@-

lP3 Helv. Chim. Acta, 1948, 31, 1055. lP4 P. Meunier and A. Vinet, Compt. rend., 1944, 219, 141 ; Bull. SOC. Chim. biol.

1*5 E. M. Shantz, Abstracts of papers read at the 114th Amer. Chem. SOC. meeting,

346 N. D. Embree and E. M. Shantz, U.S.P. 2,410,575 (Chem. Abs., 1947, 41, 568).

1945, 27, 186.

1948, 16c.

A. Gudrillot, P. Meunier, J. Jonanneteau, and M. Gourevitch, Compt. rend.,

A. H . Cook, Ann. Reports, 1944, 41, 120. J, R. Catch and T. S . G. Jones, Biochem. J. , 1948, 42, lii.

1948, 226, 128. E. Work, Nature, 1950, 165, 74.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

RYDON : AMINO-ACIDS. 185

dimethyl-n-butyric acid from Bacterium w Z ~ , ~ and amino- and amino- hydroxy-adipic acids from Vibrio choler^^!.^ Welcome confirmatory evidence has been provided for the presence of 8-hydroxylysine in gelatin.6 On the debit side is the proof that J. L. W. Thudichum's " glycoleucine " is not norleucine, as has been commonly supposed, but DL-leucine ; there remains no evidence for the occurrence of norleucine in Nature and i t must be removed from the list of natural amino-acids.

A noteworthy contribution to the stereochemistry of the amino-acids is the experimental establishment, by ill. L. Wolfrom and his colleagues,9 of their configurational relationship to the carbohydrates ; this was achieved by conversion of D,-glucosamine (I) into acetyl-L,-alanine (11), identical with the acetyl derivative of natural alanine, as follows :

CH,*OH

Y

(1.) CH,*O Ac CH,*OH (11.) General Synthetic M3thods.-The most striking technical advance

of recent years in the synthesis of amino-acids has undoubtedly been the introduction l1 of acetamidomalonic ester (111) as a general reagent for syntheses from halides :

RHal + NHAc*CH( CO,Et), +Ac*NH*CR(CO,Et),- NH,*CHR*CO,H

or from suitable unsaturated compounds :

NaOEt hydrol.,

(111.)

NuORt yHAc hydrol., N H 2 X*CH:CH, + (111) -+ X*CH,*CH,*C(CO,Et), a X*CH,*CH,*bH*CO,H

Acetamidomalonic ester is readily prepared from malonic ester by nitrosation, reduction, and acety1ation,l0 and is now an article of commerce. Acetamido- cyanoacetic ester, similarly prepared from cyanoacetic ester,12 has been suggested l3 as an alternative to the malonic ester; although i t has advantages in certain cases 14, l5 it has not been widely used. A. GaIat l6

W. W. Ackermann and H. Kirby, J . Biol. Chem., 1948, 175, 483. J. Blass and M. Macheboeuf, HeEv. Chim. Acta, 1946, 29, 1315. J. G. Heathcote, Biochem. J . , 1948, 42, 305. R. Consden, A. H. Gordon, A. J. P. Martin, 0. Rosenheim, and R. L. M. Synge,

ibid., 1945, 39, 251. 8 Ann. Repts. Local Govt. Board, 1881-2,11, 305. * M. L. Wolfrom, R. U. Lemieux, and S. M. O h , J . Amer. Chem. Soc., 1940,71,2870.

lo 13. R. Snyder and C. VV. Smith, ibid., 1944, 66, 500. 11 N. F. Albertson, S. Archer, and C. R I . Suter, ibid., p. 500. l2 W. Wilson, J., 1948, 1159. l3 N. F. Albertson and I3. F. Tullar, J . Amer. Chem. SOC., 1945, 67, 502. 14 N. F. Albertson, ibid., 1946, 68, 450. l5 W. Herz, K. Dittmer, and S. J. Cristol, J . Biol. Chem., 1947, 171, 383. l6 J . Amer. Chem. Soc., 1947, 69, 965.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

186 ORGANIC CHEMISTRY.

introduced the easily prepared formamidomalonic ester and there are indications that this may eventually replace the acetyl compound as a, general purpose synthetic reagent. Attention may be drawn to the use of nitromalonic l7 and nitroacetic l8 esters for similar purposes ; advantage is taken of the presence of a reactive methylene group in the latter compound.

Another advance in general methods is the use of Z-thiothiazolid- &one (IV) in the Erlenmeyer type of synthesis : l9

RR'CO + H2C;I----\10 RRfC--\1--C;I---O zn- RR'CH*HC;I----VO HN \ /s ""\ /s dc*R/

CS cs "bS -+ cs w-1 MeOH-HCI

RR'CH*CH(NH,)*CO,H RR'CH*CH(NH,)CI)*CO,H

which has the advantage of being applicable to aliphatic aldehydes and ketones and of employing very mild reaction conditions. The use of lead acetate as catalyst in the condensation of aliphatic aldehydes with hippuric acid 20 makes the standard Erlenmeyer method practicable for aliphatic amino-acids.

G. Hillman 22 describes a convenient procedure for liberating amino- acid esters from their hydrochlorides by treatment with a cold solution of ammonia in chloroform.

The classical chemica.1 resolution of DL-amino-acids by fractional crystallisation of alkaloidal salts of their N-acyl derivatives is usually tedious, and more rapid biochemical methods have been devised. The papain method of M. Bergmann and H. Fraenkel-Conrat 22 fails in some cases23~24 and three new procedures are therefore very welcome. In the first of these 25 an ester of the DL-amino-acid is hydrolysed asymmetrically with crude chyrnotrypsin to give the L-amino-acid and the D-amino-acid ester ; in the other two methods, the acetyl or chloroacetyl-DL-amino-acid is hydrolysed asymmetrically with an enzyme from hog or rat kidney26 or with crude carb~xypeptidnse,~' respectively, to give the L-amino-acid and the D-acylamino-acid. All three new methods show promise of being fairly general and should find wide application.

Individual Amino-acids.-During the last five years the increased

17 D. I. Weisblat and D. A. Lyttle, J . Amer. Chem. Soc., 1949, 71, 3079. I* Idem, ibid., 1947, 69, 2118. ls J. D. Billimoria and A. H. Cook, J., 1949, 2323. 2o I. L. Finar and D. D. Libman, J., 1949, 2726. 21 Z . Naturforschung, 1946, 1, 682. 23 C. A. Dekker and J. S . Fruton, ibid., 1948, 173, 471.

25 M. Brenner, E. Sailer, and V. Kocher, Helv. Chim. Acta, 1948, 31, 1908; IWE.

26 P. J. Fodor, V. E. Price, and J. P. Greenstein, J . UioZ. Chsm., 1949, 178, 503;

27 Idem, ibid., 1949, 180, 473.

22 J . Biol. Chem., 1937, 119, 707.

H. T. Hanson and E. L. Smith, ibid., 1949, 179, 815.

Brenner and V. Kocher, ibid., 1949, 32, 333.

V. E. Price, J. B. Gilbert, and J. P. Greenstein, ibid., 1949, 1'79, 1169.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

RYDON : AMIXO-ACIDS. 187

nutritional interest in amino-acids has led to the development of many new syntheses, the more significant of which are outlined below, together with references to the more important work of the past five years on the preparation of amino-acid analogues and isotopically marked amino-acids ; information on the earlier preparative methods will be found in R. J. Block's comprehensive review.28

Fatty a-Amino-acids.-Valine 13* 29 and leucine 1 3 9 30 have been synthesised by condensation of the appropriate alkyl halides with acetamido-malonic and -cyanoacetic esters. N. F. Albertson and S. Archer,31 however, prefer to prepare leucine from 2-methylally1 chloride, with subsequent hydro- genation, owing to the possibility of rearrangement in the condensation using isobutyl bromide. Alanine has been prepared in good yield by the Bucherer hydantoin method from a~etaldehyde,~, and valine by a modifica- tion pf the Strecker synthesis from is~butaldehyde.~~ Alanine, valine, and leucine have all been resolved by means of the kidney enzyme,26 Iso- topically marked glycine (13C in the carboxyl group) 34 and alanine (13C in the a-carbon) 35 have been synthesised.

@-Alanine (V) may be prepared in excellent yield by addition of phthalimide to aerylonitrile, followed by hydrolysis : 36

Ph~CI-I,+NMe,)OH C,H,(CO),NH + CH,:CH.CN -___ ---+ c6H4*( CO),N*CH,-CH,*CN

hydrol. -+ H,N*CH,*CH,*CO,H (v.)

A similar procedure, using ammonia as a d d ~ c t , ~ ' is probably more economical in spite of the lower yield.

Amino-hydroxy-acids.-Serine (VI) has been prepared by two new methods, from methyl acrylate 38 and from formaldehyde : 39

HOBr Ph-CH,*NH, YH *CH2Ph CH,:CH*CO,Me ----+ HO*CH,*CHBr*CO,Me -+ HO*CH,*CH*CO,Me

h ydrog., hydrol.

NaOH NHAe hydrol. NHz HCHO + (111) --+ HO*CH,*C(CO,Et), 2 HO*CH,*CH*CO2H

a s Chem. Reviews, 1946, 38, 501. 29 R. 0. Atkinson and P. A. A. Scott, J. Amer. Chem. Soc., 1945, 67, 502. 30 H. R. Snyder, J. F. Shekleton, and C. D. Lewis, ibid., p. 310. *l Ibid., p. 308. 32 R. Gaudry, Canadian J. Res., 1948, 28, B, 773. 3s Idem, ibid., 1946, 24, B, 301. 34 N. Sahami, W. E. Evans, and S. Gurin, J . Amer. Chem. SOC., 1947,69, 1110. 5~~ J. Baddiley, G. Ehresvard, and H. Nilsson, J . Bid . Chem., 1949, 178, 399. 36 A. Galat, J . Amer. Chem. SOG., 1945, 67, 1414. 3 7 S . R. Buc, J. H. Ford, and E. C. Wise, ibid., p. 92; J. H. Ford, S. R. Buc, and

J. W. Greiner, ibid., 1947, 69, 844; J. H. Ford, Org. Synth., 1947, 27, 1 ; S . R. Buc, ibid., p. 3.

(VI.)

A. M. Mattocks and W. H. Hartung, J. Biol. Chem., 1946, 15, 501. J. A. King, J . Amer. Chem. Xoc., 1947, 69, 2738.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

188 ORUANIC CHEMISTRY.

m-Serine has been resolved by means of the kidney enzyme; 26 homoserine (a-amino-y-hydroxy -n-butyric acid) has been synthesised and resolved.40

The synthesis of threonine (XII) offers more diflticulty, owing to the presence in the molecule of a second asymmetric centre. Hydrogenation of acetamidoacetoacetic ester, followed by hydrolysis, yields mainly allo- t h r e ~ n i n e , ~ ~ as does amination of the addition product from hypobromous acid and crotonic acid.42 The key to a successful preparative synthesis was the finding, by D. F. Elliott and his colleague^,^^ that the mixture of diastereoisomeric N - benzoylthreonine esters (VIII), obtained by hydro- genation of benzamidoacetoacetic ester (VII), could be converted into DL-threonine containing only traces of the allo-compound by way of the oxazoline (IX). The final synthesis, which gives a 60% overall yield, is the following :

NH*COPh ABc,o, N-CPh EtOH NH*COPh CH3*C= oH “<,,-A ---+ CH,*CO*CN*CO,Et

m1.1

hydrog. OH PfTH-COPh -+ CH,dH*CH*CO,Et

(VIII.)

Ph*CO*Q VH, NaOH.

. , CPh - CH,dH-CH*CO,Et < NROFI /\

* T -+ SOCI,

VX.1

VH vH*COPh HCI Q” 7H2 CH3*CH*CH*C02H - CH,*CH*CH*CO,H - CH,*CH:CH*CO,H

(X.1 (XI-) (XII.)

in which (VIII) and (IX) are mixtures of, diastereoisomerides, whereas (X), (XI), and (XII) are stereochernically homogeneous ; the remarkable isomerisation of O-benzoylthreonine (X) to the N-benzoyl compound (XI) with dilute alkali is noteworthy. A similar in’ which acetamido- acetoacetic ester45 is used in place o f (VII), gives a product containing 80 o/o of DL-threonine, which is separated from the allothreonine accompany- ing i t by taking advantage of the lower solubility of its sodium salt in ethanol. Elliott 46 has described a procedure for the isolation of threonine from protein hydrolysates by way of the oxazoline (IX).

DL-Threonine has been resolved by way of the brucine salt of its N-p- nitrobenzoyl derivative 47 and by means of the kidney enzyme.26

40 M. D. Armstrong, J. Amer. Chem. SCC., 1948, 70, 1756. 4 1 N. F. Albertson, B. F. Tullar, J. A. King, B. B. Fishburn, and S. Archer, ibid.,

42 H. E. Carter and C. L. Zirkle, J. Biol. Chenz., 1949, 178, 709. 43 J. Attenburrow, D. F. Elliott, and G. F. Penny, J., 1948, 310; D. F. Elliott, J. ,

1949, 589. 44 K. Pfister, C. A. Robinson, A. C. Shabica, and M. Tishler, J. Amer. Chem. SOC.,

1948,70,2297 ; K, Pfister, E. E. Howe, C. A. Robinson, A. C. Shabica, E. W. Pietrusza, and M. Tishler, ibid., 1949, 71, 1096.

45 Alternative preparation : R. H. Wiley and 0. H. Borum, ibid., 1948, 70, 1666. 46 Biochem. J. , 1949, 45, 429. 4 7 A. J. Zambito, W. L. Peretz, and E. E. Howe, J . Amer. Chem. Soc., 1949,71, 2541.

p. 1150.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

RYDON : AMINO-ACXDS. 189

Amino-dicarboxylic Acids.-Aspartic acid has been synthesised in good yield from chloroacetic ester and formamidomalonic ester l6 and resolved by using the kidney enzyme.26

Three useful new methods are available for the synthesis of glutamic acid ; all of them involve an initial Michael addition, followed by hydrolysis and decarboxylation (cf. p. 185), the reactants in the three cases being methyl acrylate and acetamidomalonic ester,30 acrylonitrile and acetamido- maJonic ester,48 and acrylonitrile and formamidomalonic ester.l6 DL- Glutamic acid has been resolved by means of the kidney enzyme26 and, very simply, as the quinine half salt.49

J. S. Fruton 50 has described an elegant synthesis of glutamine (XIV) in which papain is used to hydrolyse specifically the ol-amide group in carbo benzyloxyglutamic diamide (XIII) :

MeO2C*CH2*CH2*bH*CO2&1e papain -+ KIT, CH2Ph*O*CO*vH

-3 H2N*CO*CH2*CH,*CH*CO*NH2 CH,Ph*O*CO*NH

( X I I . ) hydrog. y"2

H2N*CO*CH2.CH,*CH*C02H (XIV.)

-+ CH,Ph*O*CO*NH H2N*CO*CH2*CH2*hH*C02H -.

Sulphur-containing Amino-acids.--The synthesis of cystine (XVI) from cc-acetamidoa2rylic acid (XV), obtained by heating pyruvic acid with a ~ e t a m i d e , ~ ~ ? 54 has been described from three laboratories : 52* 53? 54

CH3*COoCO2H - CH2k*C02H --+ AcS*CH2*CH*C02H GG? AcNH, NHAc ACSH THAc HC~,

(XV.) v 2 (XVI.) [*S*CH2*eH*CO2HI2

Cystine isotopically marked with 35S has been synthes i~ed ,~~, 56 as also has the selenium analog~e .~ '

A new synthesis of methionine from methanethiol and acraldehyde was reported last year.58 Another useful method involves the condensation of P-methylthioethyl chloride with phthalimidomalonic ester,59 acetamido- cyanoacetic ester,13 or acetamidomalonic ester.60 m-Methionine has been

4 8 N. I?. Albertson and S. Archer, J . Amer. Chern. Soc., 1945, 67, 2043. 49 G. Hillmann and A. Hillmann, 2. physiol. Chem., 1948,283, 31. 5O J . Biol. Chem., 1946,165,333 ; for another new synthesis see F. E. King and A. A.

5 1 M. Bergmann and K. Grafe, 2. physiol. Chem., 1930, 187, 187. 52 A. Schoberl and A. Wagner, Naturwiss., 1947, 34, 189. 58 H. Behringer, Chem. Ber., 1948, 81, 326, 54 M. W. Farlow, J . Biol. Chem., 1948, 176, 71. 6 5 J. B. Illelchior, Arch. Biochem., 1947, 12, 301.

ST E. P. Painter, J . Amer. Chem. Soc., 1947,439, 229; L. R. Williams and A. Ravve,

5 8 B. C. Saunders, Ann. Reports, 1948, 45, 130. &9 E. Booth, V. C. E. Burnop, and W. E. Jones, J. , 1944, 666. 60 D. Goldsmith and M. Tishler, J . Amer. Chem. Soc., 1946, 68, 144.

Kidd, J., 1949, 3315.

J. L. Wood and L. van Middlesworth, J . Biol. Chem., 1949, 179, 529.

ibid., 1948, SO, 1244.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

190 ORGANIC CHEMISTRY.

resolved using papain,23 carb~xypeptidase,~~ and the kidney enzyme.26 Isotopically marked methionine with 14C in the 8-methyl and with 35S in the sulphur 56 has been synthesised, its has the selenium analogue.6,

Basic Amino-acids.-Two useful new syntheses of ornithine (XIX) involve condensation of acetamidomalonic ester with acrylonitrile 48 and with acraldehyde : 63

CH,:CH*CHO + (111) ---+ NaOEt

YHAc Ph.NH*NH, NHAc OCH*CH,*CH,*C(CO,Et), Ph*NH*N:CH*CH,*CH,*C(CO,Et),

(XVIII.) 1 + Ha-Raney Ni

(XVII.)

CH2 NHAc Ha-Rnney Ni / \ NHAc

+ g g+O,Et

NH 4 HCI

CH,:CH.CN NatOEt - NC*CH,*CH,*C(CO,Et), --- + (111) \ /

NH R H YH2 H,N.C.OMe I I y 3 2 H,N*C*NH*CH,*CH,*CH,*CH*CO,H -- H&*CH,*CH,*CH,*CH*CO,H

Ornithine is conveniently converted into arginine (XX) by condensing its copper derivative (in which the a-amino-group is protected) with O-methyl- ~ r e a . ~ 4 An improved method for the isolation of arginine from hydrolysed casein has also been described.65

of lysine (XXII) include a considerable improvement in the amination stage by working in the presence

WX.1 (XIX.)

Modifications of the standard synthesis

CH2 / \

---+ Ph*CO*NH*[CH,],~CH,*CO,H VH2 ?Ha HzSOI ~ YE2 YHp Ph.COCI-NaOH

CH, CH, CH, CH, (XXI.)

\ / \ / CO-NH Y Br,

4 NH,

G N*OH

Ph*CO*NH*[ CH,],*CHCl*CO,H Ph*CO*NH*[ CH,],*CHBr*CO,H

yH2 \ HC1 p 2 (XXII.) H,N*CH,*CH,*CH,*CH,*CH*CO,H f- Ph*CO*NH-[CH,],*CH*CO,H

61 D. B. Melville, J. R. Rachele, and E. B. Keller, J . Biol. Chem., 1947, 169, 419. 62 E. P. Painter, J . Amer. Chem. SOC., 1947, 69, 232; H. J. Klostennan and E. P.

63 D. T, Warner and 0. A. Moe, ibid., 1948, YO, 2763, 2765. 64 F, Turba and K. H. Schuster, 2. physiol. Chem., 1948, 283, 27. 6 6 A. H. Schein and C. P. Berg, Arch. Biochem., 1946,11, 215. 86 J. C. Eck and C. S. Marvel, Org. Synth., 1943, Coll. Vol. 11, p. 3'74.

Painter, ibid., p. 2009.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

RYDON : ANINO-ACIDS. 191

of ammonium carbonate and cuprous chloride.67 Variable yields in the original method for the bromination of (XXI) are overcome by using wet bromine 68 or by chlorination with sulphuryl chloride.69 A second method 70

starts from acraldehyde :

(XVII) NC*CH( OH)-CH,*CH,*C(CO,Et), -7 NHAc Ac,O, hydrog.,

NHAc hydrot., Ac*NH*CH,*CH,*CH2-CH2*C( COEt), (XXII)

and a third from dihydropyran (XXIII) which is converted into the chloro- butylhydantoin (XXIV) which is then aminated, directly 71 or with potassium ~hthalimide,~, and hydrolysed :

(XXIII. 1

/NH*co /NH*co H,N*[CH,],*CH I CI*[CH,],*CH 1 (XXIV.)

\CO*NH \CO*NH 1 hydrol.

fiydrol. ,NH*CO

‘CO*NH (XXII) +-- C,H4( CO),N*[ CH,],*CH I

Lyaine isotopically marked with 15N in the c-amino-group 73 and with 14C in the &-carbon 7* has been synthesised.

Aromatic Amino-acids.--Phenylalanine has been synthesised by con- densing benzyl chloride with acetamidomalonic ester,3*, 31 acetamido- cyanoacetic ester, l3 and formamidomalonic ester I6 and has been resolved by means of carb~xypeptidase.~~ Phenylalanine isotopically marked with l4C in the carboxyl group and in C(=) has been ~yn thes i sed .~~ Many phenyl- alanine derivatives and analogues, including various p-substituted phenyl- a l a n i n e ~ , ~ ~ , 77 @-2-furylalanine,15 and p-2-thienylalanine,78 have been prepared for biological study.

67 C. Sayles, with E. F. Degering, J. Amer. Chem. Soc., 1949,71,3161. 68 E. E. Hows and E. W. Pietrusza, ibid., p. 2581. 70 D. T. Warner and 0. A. Moe, ibid., 1948, 70, 3918.

6* A. Galat, ibid., 1947,69,86.

A. 0. Rogers, R. D. Emmick, L. W. Tyran, L. B. Phillips, A. A. Levine, and N. D. Scott, ibid., 1949, 71, 1837.

72 R. Gaudry, Canadian J. Res., 1948, 26, €3, 387. 73 R. M. Fink, T. Enns, C. P. Kimball, H. E. Silberstein, W. I. Bale, S. C. Madden,

and G. H. Whipple, J. Exp. Med., 1944, 80, 455. 74 P. Olynyk, D. B. Camp, A. M. Griffith, S. Woislowski, and R. W. Helmkamp,

J. Org. Chem., 1948,13, 465; H. Borsook, C. L. Deasy, A. J. Haagen-Smit, G. Ksighley, and P. H. Lo-, J. Biol. Chem., 1948, 176, 1383.

75 S. Gurin and A. M. Delluva, ibid., 1947, 170, 545. 76 D. F. Elliott, A. T. Fuller, and C. R. Harington, J., 1948, 85, 7 7 D. F. Elliott and Sir Charles Harington, +%id., 1949, 1374. 7 8 K. Dittmer, W. Hertz, and J. S. Chambers, J. Biol. Chem., 1946, 186, 541;

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

192 ORGANIC CHEMISTRY.

A new method suitable for the synthesis of tyrosine in quantity has been described. 79 DL-Tyrosine has been resolved by asymmetric hydrolysis of its N-chloroacetyl derivative with carboxypeptidase ; 27 it is claimed 80 that D-tyrosine is best prepared by converting L-tyrosine, readily available from protein hydrolysates, into N-acetyl-DL-tyrosine, which is then resolved with brueine. Tyrosine marked with 14C in Ctpt has been synthesised,sl as have a number of analogues.82 Syntheses of the biochemically important 2 : 4- and 3 : 5-dihydroxyphenylalanines 83, 84 have been described.

A new synthesis of DL-thyroxine (XXV) in 14% overall yield from p-hydroxybenzaldehyde, by way of the hydantoin, has been described.85 Making use of the methods so developed, J. R. Chalmers, G . T. Dickson, J. Elks, and B. A. Hems have devised the following very satisfactory

TosO-

I I (XXV.)

E. Campaigne, R. C. Bourgeois, R. Garst, W. C. McCarthy, R. L. Patrick, and H. G. Day, J. Amer. Chem. SOC., 1948, '70, 2611 ; M. F. Berger and V. du Vigneaud, J. BioZ. Chem., 1948, 174, 241 ; R. Garst, E. Campaigne, and H. G . Day, ibid., 1949, 180, 1013; K. Dittmer, R. P. Martin, W. Herz, and S. J. Cristol, J. Amer. Chem. SOC., 1949, 71, 1201 ; K. Dittmer, ibicl., p. 1205.

79 E. T. Borrows, J. C. Clayton, and B. A. Hems, J., 1949, S 185. J. C. Reid, Science, 1947,105,208.

82 C . Niemann and M. M. Rapport, J. Amer. Chem. SOC., 1946,68,1671; W. C. Evans and N. Walker, J., 1947, 1571; M. E. Specter, lowa State CoEl. J . Sci., 1947, 22, 76.

R. H. Barry, A. M. Mattocks, and W. H. Hartung, J . Amer. Chem. Soc., 1948, 'SO, 693.

A Neuberger, Bwchem. J., 1948, 43, 599; J. P. Lambooy, J. Amer. Chern. SOC., 1949, 71, 3758.

R. R. Sealock, J. Biol. Chem., 1946,166, 1.

eli J., 1949, S 199. 86 I'bid., p. 3424,

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

RYDON : AMINO-ACIDS. 193

The overall yield from L-tyrosine is 26% and the product is optically pure; L-thyroxine thus becomes readily available. Two analogues of thyroxine have been ~ynthesised.~'

HeterocycEic Amino-acids.-Two new syntheses of proline (XXVI), from acrylonitrile 88 and from 6-chlorob~tyronitrile,~~ are described :

CH,:CH.CN + CH,(CO,Et), L

1 >

/? CH2 / \

(jH*C02Et H2V VCI*CO,Et

I hydrog. NaoEG J.

NC.CH,*CH,*CH(CO,Et), --+ H2C! HZC, ,,CO =H2C, ,,CO

NH Cl*[ CH,],.CN !El, NaOH, RCI

HCI 1 J. NH, H2vpVH2

\ /cHocOa C1-[CH2],-C02H -pa, C1*[CH2],*CHBr*C02H --+ H,C

NH (XXVI.)

Much work has been directed towards the synthesis of tryptophan The most (XXVIII), and a number of useful methods has been evolved.

fully studied of these is the gramine synthesis :

R CH,*CX*CO,Et

\A. / NH

R /\---- CH,*CX*CO,Et I I I I 1 \A. /

NH In the original method 103 l1 the methiodide of gramine (XXVII) was con- densed with acetamidomalonic ester in the presence of sodium ethoxide. Improvements consist in the condensation of gramine with acetamido- malonic or acetamidocyanoacetic ester,13 in the presence of sodium ethoxide and methyl sulphate (which forms gramine methosulphate in situ), or by means of sodium hydroxide in boiling toluene; 91 in the latter pro- cedure, nitroacetic ester can replace acetamidomalonic ester.18 Nitro- malonic ester is even more reactive and an excellent yield of tryptophan is obtained by refluxing gramine with nitromalonic ester in toluene and reduc- ing and hydrolysing the product.17 A very ingenious method, involving the Fischer cyclisation of the phenylhydrazone (XVIII) of the Michael

C. R. Harington, Riochern. J . , 1948, 43, 434; E. Frieden and R. I. Winzler. J . Amer. Chern. SOC., 1948, 70, 3511.

88 N. F. Albertson and J. L. Fillman, ibid., 1949, 71, 2818. 8* R. Gaudry and L. Berlinguet, Canadian J. Res., 1947, 27, B, 282.

N. F. Albertson, S. Archer, and C. M. Suter, J . Arner. Ghem. Soc., 1945, 67, 36. E. E. Howe, A. J. Zambito, H. R. Snyder, and M. Tishler, ibid., p. 38.

REP.-VOL. XLVI. G

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

194 ORGANIC CHEMISTRY.

addition product from acraldehyde and acetamidomalonic ester, has been described by D. T. Warner and 0. A. Moe 63 and gives excellent results :

DL-Tryptophan has been resolved by using carboxypeptidase 27 and crude ~hymotrypsin,2~ but the simple chemical method of resolving the N-acetyl derivative with brucine is claimed 92 to be the best available. Numerous analogues and substitution products of tryptophan have been prepared for biological investigation, including all the methyltrypt~phans,~~ a number of halogenated tryptophansYg4 the thionaphthen 953 97 and benzfuran 96

analogues, and p-2-indolyl-a-amino-n-butyric acid.97 Tryptophans iso- topically marked with 13C at C(a)98 and with 14C at C t ~ , of the side-chain and a t C(2) of the indole nucleus 99 have also been prepared.

Histidine (XXXI) syntheses have been revolutionised by the develop- ment loo of a simple method for the preparation of 2-hydroxymethylglyoxaline from fructose or sucrose; in one new synthesis31 the derived chloride is condensed with acetamidomalonic ester, and in two others the derived aldehyde is condensed with hydantoin lol and with 2-mercaptothiazol-5- one.lo2 A. C. Davis and A. L. Levy lo2 describe an ingenious synthesis in which the glyoxaline nucleus is formed at a late stage, the starting materials being 2 : 4-dithiohydantoin (XXIX) 1°3 and 2-phenyl-4-ethoxymethylene- oxazolone (XXX) : 104

S$+---7H2 EtO*CH=$+---(lO N E ~ , , S(l---~H-CH=(l---CO,Me KN -+ \

COPh \ /NH

N 0 N a m e HN

CS \ /

HN,,NH + cs (XXIX.) CPh (xxx.)

Raney H(l===(lH-CH2TH--CO$le H~==(l-CH,*CH*CO,H

"\\ PH HN

CH (xxx~.) \ N..% / NH

CH COPh va A. C. Shabica and 111. Tishler, J . Amer. Chem Soc., 1949, 71, 3251. v3 M. E. Jackman and S. Archer, ibid., 1946, 68,2105; H. N. Rydon, J., 1948, 705;

H. R. Snyder and F. J. Pilgrim, J . Amer. Chem. SOC., 1948, 70, 3787; H. R. Snyder and E. L. Eliel, ibid., p. 3855; W. R. Boon, J., 1949, S 231.

w H. R. Snyder, S. M. Pamerter, and L. Katz, J . Amer. Chem. Soc., 1948, 70, 222; 18. N. Rydon and C. A. Long, Nature, 1949,164,575.

v5 S. Avakian, J. Moss, and G. J. Martin, J . Amer. Chem. SOC., 1948, 70, 3075. v 6 H. Erlenmeyer and W. Grubenmann, Helv. Chim. Acta, 1947, 30, 297. *' H. R. Snyder and F. J. Pilgrim, J . Amer. Chem. Xoc., 1948,70, 1962. v * H. W. Bond, J. BioE. Chem., 1948, 1'95, 531.

C. Heidelberger, ibid., 1949, 179, 139. loo J. R. Totter and W. J. Darby, Org. Synth., 1944, 24, 64. lol V. Deulofeu and A. E. A. Mitta, J . Org. Chem., 1949, 14, 915. lo2 A. C. Davis and A. L. Levy, J. , 1949, 2179. loS A. H. Cook, Sir Ian Heilbron, and A. L. Levy, ibid., 1948, 201. lo4 H. J. Barber and R. Slack, " The Chemistry of Penicillin," Princeton Univ.

Press, 1949, p. 803.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALEALOIDS. 195

Peptide Syntheses. Attention is drawn to a review on naturally occurring peptides.lo5 W. J.

Polglase and E. L. Smithlo6 have made the important observation that resolution can accompany peptide synthesis by the carbobenzyloxy-method ; thus, L-leucyl-D-alanine and L-leucyl-L-alanine are obtained by condensing carbobenzyloxy-L-leucine azide with DL-alanine methyl ester, separating the diastereoisomeric carbobenzyloxy-L-leucyl-D- and -L-alanine methyl esters, and hydrogenating and hydrolysing each of them. A new synthesis of glutathione by conventional methods has been de~cribed.1~~

Two new peptide syntheses involve the use of phthalic anhydride lo8 and phenylthiocarbonyl chloride lo9 as protective agents for a-amino-groups. J. L. Baileyl’o has described a new peptide synthesis using N-carboxy- anhydrides under very gentle anhydrous conditions :

TH*CHRTO + H2N*CHR’*C02Et + Et,N --+ co- 0

P;JH.CHR*CO*1UH*CHR’*C02Et H,N*CHR*CO*NH*CHR’*CO,Et CO,(NHEt,

The method seems very versatile, having been used by Bailey for the preparation of a wide variety of di-, tri-, tetra-, and penta-peptides, and much should be heard of it in the future. H. N. R.

7. ALKALOIDS. The fourth edition of T. A. Henry’s authoritative text-book “ The Plant

Alkaloids ” 1 has recently been issued and covers the published literature up to a recent date, later than the last Report on this subject. In the introduction to his book, Henry mentions a number of alkaloidal surveys aimed a t systematising the botanical distribution of alkaloids. He also draws attention to the increasing use of ion exchange resin^,^ as well as applications of partition chromatography,* in the isolation of alkaloids.

of this subject have been compiled and a number of further alkaloid “ syntheses under

Alkaloid Biogenesis.-Several new reviews 1 sii), 5, 6,

loS R. L. M. Synge, Quart. Reviews, 1949, 3, 245. lo6 J . Amer. Chem. SOC., 1949, 71, 3081. lo7 B. Hegedus, HeEv. Chiin. Acta, 1948, 31, 737. lo* J. C. Sheehan and V. S. Frank, J . Amer. Chem. SOC., 1949, 71, 1856; cf. M.

Fling, F. M. Minard, and S. W. Fox, ibid., 1947,69, 2466, and J. H. Billmann and W. F. Harting, ibid., 1948, ‘SO, 1473.

loo G. C. H. Ehrensv&rd, Nature, 1947, 159, 500. 110 J. L. Bailey, ibid., 1949, 164, 889.

H. T. Openshaw, Ann. Reports, 1944,41, 218. N. Applezweig, Ann. New York Acad. Sci., 1948, 49, 300. W. Evans and M. Partridge, Quart. J . Pharm., 1948,21,126 ; J . Pharm. Phamnacol.,

(Sir) R. Robinson, J . Roy. SOC. Arts, 1948, 96, 795. C. Schopf, Chimia, 1948, 2, 206. Idern., “ Preparative Organic Chemistry,” Part 11, 1948, p. 117 ; F.I.A.T. Review

1 J. and A. Churchill, Ltd., London, 1949.

1949,1, 593.

of German Science, 1939-46.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

196 ORGANIC CHEMISTRY.

physiological conditions " has been reported. isoPelletiorine (I) has been prepared in 60 yo yield from 8-aminovaleraldehyde by condensation with acetoacetic acid at pH 11 and N-methylisopelletiorine similarly from 6-methylaminovaleraldehyde at pH 7 .8 The condensation of &amino- valeraldehyde, acetonedicarboxylic acid and formaldehyde has given 8-ketosparteine.*U Following an early claim to have prepared ( -J-)-hygrine by a similar method, E. Anet, G . K. Hughes, and E. Ritchie 10 have obtained cuscohygrine (11) from the condensation of 8-methylaminobutyraldehyde with acetonedicarboxylic ester at pH 7. (-J-)-Anabasine (111) has been

CH2 / \

H2C: 7% \ /

Hz(j-YH2 H2(+-YH2 H2C CH*CH,*COMe H2C CH*CH,*CO*CH,*CH CH,

\ / NMe

\ / NMe NH

(1.1 (11.)

prepared by silver aceta$e dehydrogenation of decahydro-2 : 3-dipyridyl (IV) obtained by the dimerisation of l-piperidein.ll Hydrolysis of the tropane alkaloid, meteloidine, gives the base teloidine (V) which has been synthesised by the condensation of mesotartaric dialdehyde, methyla*mine, and acetonedicarboxylic acid.1, C . Schopf and H. Stener 13 also have synthesised the indole alkaloid, rutmarpine (VI), by condensation of o- amino benzaldeh yde with 4 : 5-dihydro-3 - car boline perchbra te .

CH,

* E. Anet, G. K, Hughes, and E. Ritchie, Nature, 1949,164, 501. ea Idem, ibid., 1950,165, 35.

lo Nature, 1949, 163, 289. 11 C. Schopf, A. Komzak, F. Braun, and E. Jacobi, A n d e n , 1948, 559, 1. 12 C. Schopf and W. Arnold, ibid., 1947, 558, 109. 13 Ibid., 1947, 558, 124.

@ (Sir) R. Robinson, J., 1936, 1081.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JORNSON : ALKALOIDS. 197

In the case of strychnine (XXXVII, p. 207), R. B. Woodward l4 has introduced a novel concept into theories of alkaloid biogenesis. The earlier idea of G. Hahn l5 regarding the formation of the yohimbine alkaloids was that the nucleus (VII) could be built up by a preliminary Mannich-type condensation of tryptamine and 3-hydroxyphenylacetaldehyde or its equivalent, and a subsequent condensation with formaldehyde. If the initial condensation occurred at the p-position of the indole nucleus, then starting from 3 : 4-dihydroxyphenylacetaldehyde (or its equivalent, 3 : 4-dihydroxyphenylalanine) the product would be (VIII) and the 7- membered ether ring could be built up by a fission of the cateohol ring :

-9 OH

sulted

$+d=&- -+ -C-O-C-&&-. The original should be con- OH for the implications of these ideas and the several variants which

C? A--/ I I I It CH2 \/\ /\ A

I II \/

OH (VIII.) (VII.)

were outlined. Sir Robert Robinson has commented favourably on the scheme and has assumed a similar fission of an aromatic nucleus to account

OMe OMe OH O M e L 7 CH, CH, ft$J,OMe

/ / \ / \ / \/\/

\ / \ /

HO/\

) E YHD CH H?’’B I I I I CH,

H,C N CHEtHN2 4CH2 \/‘\ / \/’;)OH

H,C\ AT\ /\//OH f c”fJ 11 ~ _ _ _ _ _ _ _

\d CH2 CH, CH,

m.1 (X.) CH, CH,

for the biogenesis of emetine.17 The condensation of norlaudanosine of the Winterstein-Trier hypothesis with formaldehyde or its equivalent would lead to (IX) which, after oxidative degradation of one of the aromatic rings as shown, condensation with dihydroxyphenylalanine, and subsequent O-methylation, would give the accepted structure of emetine (X) ; the ethyl group is derived by a reduction of the --CH2*CH0 group at some stage. Woodward points out that these possibilities of building up complicated alkaloid molecules from plausible starting materials are so striking that i t is difficult to believe that they lack significance. On the other hand, a recent

l4 Nature, 1948, 162, 155. l5 Ber., 1934, 67, 2031 ; 1938,71, 2192 ; Annalen, 1935, 520, 123. l6 Nature, 1948, 162, 156. 1’ Ibid., p. 524.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

198 ORGANIC CHEMISTRY.

review l8 giving some of the biological background to the subject stresses the need for caution when applying the information gained from syntheses "under physiological conditions " to events in vuivo, although it is very difficult to accept the opinion of this author that such studies " have con- tributed little to a direct understanding of alkaloid biogenesis ."

LeuccmoZ.---'J!his alkaloid, derived from Leucmna gZauea Benthsm of the family Mimosaceze, has the formula C8Hl0O4N2 and appears t o be identical with mimosine 19920 from Mimosa pudiccr; L. The structure (XI) of leuczenol is based on the observations that pyrolysis gave 3 : 4- dihydroxypyridine,21s 22 degradative methylation gave S-methoxy- 1 -methyl- 4-pyrid0ne,2~* 2* and oxidation with bromine gave ap-diaminopropionic acid hydrobr~mide ,~~ thus proving thaf the alanine side chain was attached through the nitrogen atom of the 3-hydroxy-4-pyridone ring and not through the 3-hydroxy group26 or a carbon atom of the nuc1e~s.l~ R. Adams and J. L. Johnson2' have described a simple synthesis of the (&)-alkaloid by the addition of 3-methoxy-4-pyridone to a-acetamido- acrylic acid, followed by hydrolysis of the product with hydrogen iodide. In the course of this work many novel reactions of the pyridones were described .28

Simple Bases.

CH, / \

\ / NH

j;'H2*CH(NH2)*C02H (XI.) (XII.) (XIII.)

Conhydrine and $-Conhydrine.-Syntheses of conhydrine 29 (XII) and $-conhydrine 30, 31 (XIII) have been reported, the resolutions of the (&)- products being carried out with (+)-6 : 6'-dinitrodiphenic acid in every case. The first30 of the two preparations of $-conhydrine was based on 2-chloro-5-nitropyridine and used a malonic-type synthesis, and the second started from a-picoline-5-sulphonic acid.31

Cuscohygrine.-The structure of this compound (XIV) has now been

co CH2 / \

H2Y p 3 2

\ /

HO*HV vH2 / \

H0.G $H H2C CH*CHEt*OH H2C CH*CH,Et

\JCH NH

HC

18 R. F. Dawson, Adv. Enzymology, 1948, 8, 203. 19 D. Kostermans, Rec. Trav. chim., 1946, 65, 319; 1947, 66, 93. 20 J. P. Wibaut, ibid., 1946, 65, 392. 21 R. Adams et al., J . Amer. Chem. Soc., 1945, 67, 89; 1947, 69, 1806, 1810. 22 A. F. Bickel, ibid., 1947, 69, 1805. s3 J. P. Wibaut et al., Rec. Trav. chim., 1946, 65, 6 5 ; 1947, 66, 24. 24 A. F. Bickel, J . Amer. Chem. Soc., 1947,69, 1801. Z 5 Idem, ibid., 1948, 70, 326. 26 R. Adams and V. V. Jones, ibid., 1947, 69, 1803. 28 R. Adams and V. V. Jones, ibid., p. 3826. Zs F. Galinovsky and H. Mulley, Monatsh., 1948, 79,426, 30 W. Gruber and K. Schlogl, ibid., 1949, 80,499. 81 L. Marion and W. F. Cockburn, J . Amner. Chem. SOC., 1949, 71, 3402.

27 Ibid., 1949, 71, 705.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JORNSON : ALKALOIDS. 199

established by two independent syntheses, one of which has been described in the section dealing with syntheses under physiological conditions. Two independent groups of workers 321 33 have prepared cuscohygrine from l-methyl-2-pyrrylacetic acid by pyrolysis of a metallic salt to give 1 : 3- di-( 1 -methyl-2-pyrryl)acetone, and subsequent hydrogenation of the pyrrole rings. An earlier Russian claim 34 to have synthesised this alkaloid has not been confirmed.

Lupinane Group.-Although the structure of sparteine (XV) was estab- lished in 1933 and confirmed by the synthesis of (&)-oxysparteine (10-

CH, CH-CH, CH, H2(7---p32 H2(7--$=2 / 5 \ / \ 17\ P5\

NMe B\ \12/

H2C CH*CH,*CO*CH,*CH CH, H2v4 ‘YH >CH, yl‘ 14(iH3 \ / H2C3 1N \nCH 13CH2 \ /

NMe ‘66 ‘8H,-CH CH, (XIV.) (XV4

ketosparteine) in 1936,35 i t was not until last year that the reduction of the keto-group was successfully accomplished, and then the total synthesis of sparteine was announced from no less than four different laboratories. G. R. Clemo, R. Raper, and W. F. Short 36 synthesised (-)-sparteine by reduction of (- )-oxysparteine with lithium aluminium hydride, and IF. Galinovsky and G. Kainz 37 have described the resolution of (k)-oxy- sparteine. The latter authors used an electrolytic method of reduction to prepare (XV) either from (+)- or (-)-oxysparteine or from (&)-lo : 17- dioxy~parteine,~~ a method which was also used by E’. Sorm and B. Kei1.39 In another approach,40 (&)-sparteine was isolated from the mixed products of the hydrogenation of 4-keto-l-earbethoxy-3-2’-pyridylpyrido~oline (XVI) 35 over a copper chromite catalyst at 250”/350 atmospheres. (&)- Sparteine was resolved by means of (+)-p-camphorsulphonic acid,*l or less satisfactorily by ( -)-2 : 2’-dihydroxy- 1 : 1 ‘-dinaphthyl-3 : 3’-dicarboxylic acicL37

39 E. Spath and H. Tuppy, Monatsh., 1948, 79, 119. 33 H. Rapport and E. Jorgensen, J . Org. Chem., 1949, 13, 664. 34 G. V. Lazur’evskii, Chem. Abs., 1941, 35, 4029. 3B G. R. Clemo, W. MeG. Morgan, and R. Raper, J. , 1936, 1025. 36 J. , 1949, 663; Nature, 1948, 162, 296. 38 G. Galinovsky and G. Kainz, ibid., 1947, 77, 137. 3s Coll. Czechoslov. Chem. Comm., 1948, 13, 544; Chem. Abs. , 1949, 43, 3828. 40 N. J. Leonard and R. E. Beyler, J. Amer. Chem. Soc., 1948, 70,2298. 41 Idem, ibid., 1949, 71, 757.

37 Monatsh., 1949, 80, 112.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

200 ORGANIC CHXMISTRY.

The alkaloid rhombinine, isolated from Thermupsis rhombifoZia 42 and Lupinus mcounii R ~ d b . , 4 ~ has been shown 44 to be identical with anagyrine (XVII) and with m o n o l ~ p i n e . ~ ~ Tetrahydrorhombinine is ( - )-lupanine which often occurs together with rhombinine.

isoQuinoline Group.---Morp>hine. The considerable advances which have been made in synthetic analgesics have been the subject of comprehensive recent reviews,Q6 and only some recent syntheses directed a t the morphine nucleus itself will be mentioned here. R. Grewe and his co-workers 47 have synthesised the base N-methylmorphinan (XVIII; R = R' = H) by the cyclisation of 1 -benzyl-2-methyloctahydroisoquinoline (XIX ; R = R' = H) with phosphoric acid. Moreover by introduction of substituents into the benzyl group, several analogues were prepared>* one of which, S-hydroxy- N-methylmorphinan was also synthesised by 0. Schnider and A. Griissner 49

and found to have considerable analgesic activity. Grewe also showed that the action of concentrated hydrochloric acid on 1 -(3' : 4'-dimethoxybenzy1)- 2-methyloctahydroisoquinoline (XIX ; R = R' = OMe) gave 4-hydroxy- 3-methoxy-N-metbylmorphinan identical with ( -j- )-tetrahydrodeoxycodein (XVIII ; R = OH, R' = OMe). (-)-Tetrahydrodeoxycodein has been obtained from dihydrothebainone and the (+)-form from sinomenin by Clemmensen reduction. 50

/ \ / \ / \ / H2f l'fy H2C 1 C /NMe H,C 1 CH

R,C- -CH2 1 FW-I-CH~ I Hp-I-CN

\ / \ / H2C CH2 H,C CH2

\ / CH CH2

(XIX.) (XX.)

H2 ( 3 3 2 (XVIII.)

M. Gates and W. F. Newhall 51 have obtained an isomer of N-methyl- morphinan, identical with a by-product from the Grewe synthesis. 4- Cyanomethyl-1 : 2-naphthaquinone was treated with butadiene to give (XX) which by a series of reductions was converted into an oxygen-free base and this after methylation gave the N-methylmorphinan isomer.

4a R. H. F. Manske and L. Marion, Canadian J . Res., 1943, 21,B, 144. 43 L. Marion, J . Amer. Chem. SOC., 1946, 68, 759. 44 L. Marion and J. Quellet, ibid., 1948, 'SO, 3076. 45 J. F. Couch, ibid., 1936, 58, 686; 1939, 61, 3327. MI F. Bergel and A. L. Morrison, Quart. Reviews, 1948, 2, 349; R. Grewe, Angew.

67 R. Grewe and A. Mondon, Ber., 1948,71, 279. 4* R. Grewe, A. Mondon, and E. Nolte, Annulen, 1949, 564, 161. 49 Helv. Chim. Acta, 1949, 32, 821; Swiss P. 252,755; B.P. 620,258; Chem. Abs.,

50 H. Kondo and E. Ochiai, Annuten, 1929,470,227; Ber., 1930,63,646. 51 J . Amer. Chem. Soc,, 1948, 70, 2261; Experientia, 1949, 5, 285.

Chem., 1947, A , 59, 194.

1949, 43, 7517.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALKALOIDS. 201

E. Schlittler and his co-workers 52 have reviewed and introduced some modifications into certain of the methods of synthesis of benzylisoquinolines

(XXI.) (XXII.) and aporphines. The same author 53 has re-examined the structure of isothebaine on the basis of the Hofmann degradation and has confirmed that the final product from the reactions is 3 : 4 : 5-trimethoxyphenanthrene, thus supporting the formula (XXI) of Gadamer and Klee.54 These con- clusions are not accepted by other workers.55

Chelerythrine. -Furt her synthetic experiments, aimed at the Chelidonium alkaloids, e.g., chelerythrine (XXII), have been described 56 and in par- ticular A. s. Bailey and Sir R. R~binson,~’ in a method which may well lead to the alkaloids themselves, have synthesised a dihydro- 1 : S-benzphen- anthridone containing the two necessary vicinal substituents in ring A.

Daphnandra Alkuloids.-I. R. C. Bick and A. R. Todd 58 have established that the Duphnundru alkaloids belong to the bisbenzylisoquinoline series and that sterically they are closely related to o~yacan th ine .~~ Thus formula (XXIII) arid (XXIV) represent the group repandine (R = R’ = Me ;

52

53

6 5

66

61

58

CH, . CH2 \/\ 0 A/

l l I I R”l,l II \/ \/ (XXIII.)

RN\ /\$? /\A /NR’

CH2 CH2

VH CH2

VH CH2

H.&/ V N O M e 11 IOR” M e O f y \VH2

0

/\/ 11 lf)Rtir 1-1 11 \/ \/ (XXIV.)

HeEv. Chim. Acta, 1948, 31, 914, 1111; 1949, 32, 1880. Ibid., 1948, 31, 1119. V. V. Kiselev and R. A. Konovalovs, J . Gelz. Chem. Russia, 1949, IS, 148. H. S. Forrest, R. D. Haworth, A. R. Pinder, and T. S . Stevens, J., 1949, 1311. Nature, 1949, 164, 402; see also ibid., 1950,165, 235. J., 1948, 2170; 1949, 2767. 6e E. Sphth and J. Pikl, Ber., 1929,62,2251.

Arch. PhQrm., 1914, 252, 247.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

202 ORGANIC CHEMISTRY.

R” = Me; R”’ = H), aromoline (R = R’ = Me; R” = H ; R”’ = H), daphnandrine (R or R’ = H; R‘ or R =r Me; R” = H; R”‘ = Me), and daphnoline (R or R’ = H ; R’ or R = Me; R” =r H ; R”’ = H). Tri- lohamine 6o is probably identical with daphnoline.

Emetine.-Recent degradative experiments on the ipecacuanha alkaloid emetine 61 have established the structure (X) and a. scheme for its biogenesis has already been outlined l7 (p. 197). Several workers 62p 63 have subjected emetine to Hofmann degradation, and M. Pailer 63 et al. established that with the rest of the molecule as in (X) ring D could be represented as (XXV), (XXVI), or (XXVII), of which (XXVI) was eliminated by their later results 64 and those of H. T. Openshaw et ~ 1 . ~ ~ Pailer isolated 4-methyl- 3-ethylpyridine ( p-collidine) from the dehydrogenation of the hydrogenated dimethine base obtained by Hofmann degradation of N-methylemetine and thus provided direct evidence for the ethyl group in emetine. Exclud- ing the rather remote possibility of ring expansion in these reactions, we thus arrive a t structure (X) for the alkaloid.

b CH, CH, b CH, CH, \ / \ / \ / \ \ / \ / \ / \

C CH CH c CH CH

CH, ‘ N ‘ hHEt AH: 4 = bHMe \ / \ /

CH, CHMe \ / \ /

CH, CH, (XXV.) - (XXVI. )

CH,

A. R. Battersby, H. T. Openshaw, and H. C. S. have proposed the cyanine-like structure (XXVIII) for the anion of the red rubremetinium salts which were found to be obtained from emetine by mercuric acetate oxidation in acid solution. Such a structure seems to offer a better explan-

6o H. Kondo and ,M. Tomita, Arch. Pharm., 1931, 269, 433; 1936, 274, 70; J . Pharm. Xoc. Japan, 1935, 55, 104.

Review : M.-M. Janot, Bull. SOC. chim., 1949, 185. 62 A. Ah1 and T. Reichstein, Hdv . Ohirn. Acta, 1944, 27, 366; A. R. Battersby and

H. T. Openshaw, J. , 1949, S 59. 63 MoWsh., 1948, 78, 348; 1948, 79, 127, 331. 6s Ezperientia, 1949, 5, 114.

Ibid., 1949, 80, 94. The structure (X) has received further support from

later degradative experiments by A. R. Battersby and HI. T. Openshaw, J., 1949, 3207.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALKALOIDS. 203

ation of the properties of these compounds than does that of P. Karrer and his co-workers,66 involving aromatisation of rings B and E.

By similar Hofmann degradakions cephaelin has been shown to have the structure (X) but with the 6-hydroxyl group ~ n m e t h y l a t e d . ~ ~

Indole Group. Quinamine and Cinchonamine.-The interesting observ- ation that quinamine, one of the minor Cinchona alkaloids, produced 2 : 3-dimethylindole on degradation, suggested that i t might contain an indole rather than a quinoline nucleus, in addition to the usual vinyl- quinuclidine group,6s and more recently,69 K. S. Kirby et al. have shown that quinamine is isomerised to the yellow isoquinamine on treatment with alcoholic potassium hydroxide. Raymond-Hamet 7* has reported that cinchonamine and aricine give colour reactions which indicate an indole nucleus. Sir R. Robinson in collaboration with Kirby has taken up the subject of the structure of quinamine and in a preliminary statement 71

they have shown that, on the basis of diazonium coupling reactions, quin- amine is not an aromatic indole; possibly it is a hydroindole but more probably a hydroquinoline compound.

Yohimbine.-The accepted structure for yohimbine (XXIX) is a modific- ation by B. Witkop et aZ.72 of the earlier formula of C. Sch01z.~~ Yohimban, the basic ring system of yohimbine [ i .e . , (XXIX) without -OH and -CO,Me groups], has been prepared from yohimbine 7* and from the diastereoisomer, ~o rynan th ine .~~ The structure of yohimbine was largely established on the nature of its dehydrogenation products, yobyrin, ‘‘ tetrahydroyobyrin,” and “ ketoyobyrin,” which were obtained by J. P. Wibaut et aZ.76 by the action of selenium on the alkaloid. The structures of all three compounds are now known with certainty and have been confirmed by synthesis, and

e 6 Helv. Chim. Acta, 1948, 31, 1219. 87 M. Pailer and K. Porechinski, Monatiph., 1949, 80, 101.

J. , 1945, 524, 528. 70 Compt. red . , 1941, 212, 135; 1945,220, 670; 221, 307. ‘1 Festschrift P. Karrer, 1949, 40.

6s J. , 1949, 735.

A n important communication concerning the structures of cinchonamine and quinamine has since been published (R. Goutard, M.-M. Janot, V. Prelog, and W. I. Taylor, Helv. Chim. Acta, 1950, 33, 150; see also W. I. Taylor, ibid., p. 164), in which degradative experiments are described leading the authors to propose the following structures for the alkaloids. Cinchonamine is obtainable from quinamine by lithium aluminium hydride reduction :

CH2*CH2*OH

+---

Cinchonamine. Quinamine ( 9 ) 72 Annalen, 1943, 554, 83, 127. 7 p J. Jost, ibid., 1949, 32, 1297. 7 5 M.-M. Janot and R. Goutarel, Bull. Soc. chim., 1949, 509, 659. 76 Rec. Trav. chirn., 1929, 48, 191; 1931, 50, 91; 1935, 54, 85.

Helv. Chim. Acta, 1935,18, 923.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

204 ORGANIC CHEMISTRY.

it will be evident that the names, still widely used, applied to the last two of these products, do not represent their true relation to yobyrin.

CH,

(XXIX.) ‘CbOH (XXX.)

A substance having Witkop’s structure (XXX) 72 for yobyrin has been synthesised by G. R. Clemo and G. A. Swan 77 and by P. L. Julian et who also synthesised “ tetrahydroyobyrin ” or 2-(tetrahydro-3-isoquinolyl)- 3-ethylindole (XXXI), the structure of which was established by Sch01z.~~ An outstanding property of ketoyobyrin, the smallest fraction from the dehydrogenation of yohimbine, is the smooth cleavage by arnyl-alcoholic potassium hydroxide to 2 : 3-dimethylbenzoic acid and norharman and on this basis Witkop 72 proposed the structure (XXXII), which however did not explain the neutral properties of the compound and did not correspond with the observed spectral properties 79 which resembled those of rutaecarpine (VI). Moreover, the chemical behaviour of ketoyobyrin did not agree with that of synthetic acylnorharmans.80 Another structure (XXXIII) was advanced by a number of workers 81% and by others 83% 84, who also described the synthesis of this compound. showed how (XXXIII) would be expected to show the properties of ketoyobyrin and described the further dehydrogenation of (XXXIII) over palladium, giving (XXXIII; extra double bond a t C(5-61). It was also pointed out how (XXXIII) removed any ambiguity concerning the position of the C(16)- carbomet hoxy -group of yohim bine.

The syntheses of (XXXIII) followed the general method of Clemo and Swan 77 with modification~.~3~ s5 There were differences in the colour and colour reactions of the ketoyobyrin obtained from yohimbine and the synthetic product unless the latter was heated under reflux in xylene solution with Raney nickel. On the basis of this and the results obtained from the

77 J., 1946, 617. ’* Raymond-Hamet, Compt. rend., 1945, 221, 387.

*l R. B. Woodward and B. Witkop, J . Amer. Chem. Soc., 1948, 70, 2409.

R. B. Woodward and B. Witkop

78 J . Amer. Chem. Soc., 1948, 70, 180.

R. Speitel and E. Schlittler, HeZv. Chim. Actu, 1949, 32, 860.

Raymond-Hamet, Compt. rend., 1948, 226, 1379; M.-M. Janot and R. Goutarel, Ann. pharnz. frang., 1948, 6, 254.

83 G. R. Clemo and G. A. Swan, J., 1949, 487; Nature, 1948,162, 693. P. L. Julian, W. J. Karpel, A. Magnani, and E. W. Meyer, J . Amer. Chem. Soc.,

1948, 70, 2834; E. Schlittler and R. Speitel, Hdv . Chim. Acta, 1948, 31, 1199. so E. Schlittler and T. Allernann, ibid., p. 128.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALKALOIDS. 205

lithium aluminium hydride reduction of ketoyobyrin, Swan 86 believes that ketoyobyrin is a mixture of (XXXIII) and its dehydrogenation product (XXXIII ; extra double bond at c(5-6)).

CH,

(40 Me

(XXXII.)

Witkop has given evidence for the trans junction of rings D and E of yohiznbine and preliminary synthetic experiments aimed at the yohimbine skeleton have been rep~rted.~~g 88

8empervirine.-The important observation of V. Prelog 89 that dehydro- genation of sempervirine, a yellow alkaloid from Gelsemium sempervirens Ait, with selenium a t 300” gave yobyrin (XXX), and with Raney nickel in boiling xylene gave tetrahydroyobyrin (XXXI), led him to propose structure (XXXIV) for the alkaloid. Syntheses of this structure 86~w have shown, however, that it is not that of the alkaloid. In order to account for the colour of sempervirine, the absence of a free >NH group (infra-red spectrum and failure to form an amine oxide):’ its strong basic character, and the formation of (XXXI), i t has since been formulated 92 as an anhydronium base (XXXV+XXXVI), and the metho-salts are held to be (XXXVI; Me group on the indole nitrogen) which accounts for the formation of N - methylyobyrin (synthesis from their selenium dehydrogenation. The structure of the salts was confirmed by an elegant synthesisQ4 from the

86 J., 1949, 1720. 87 J . Amer. Chem. Xoc., 1949, 71, 2559. 88 P. L. Julian, A. Magnani, et al., ibid., 1948, 70, 174; 1949, 71, 3207. 8s Ezperientia, 1948, 4, 24; Helv. Chim. Acta, 1948, 31, 588.

0. E. Edwards and L. Marion, J . Amer. Chem. Soc., 1949, 71, 1694. B. Witkop, ibid., 1948, 70, 1424.

92 R. B. Woodward and B. Witkop, ibid., 1949, 71, 379; R. Bentley and T. S. Stevens, Nature, 1949, 164, 141.

P. L. Julian and H. C. Printy, J . Amer. Chem. Soc., 1949, 72, 3206. O4 R. B. Woodward and W. M. McLamore, ib&€., p. 380.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

206 ORGANIC CIXEMISTRY.

lithium derivative of N-methylharman and Z-isopropoxyrnethylenecycb- hexanone after acid treatment of the reaction mixture.

Aspidospermine ; VuZZesine.-Aspidospermine, from the bark of Aspido- sperm quebracho and from the leaves of VaZZesia glabra, has been shown to be an N-acetyldihydroindole derivative 95 and B. Witkop 96 has obtained 3 : 5-diethylpyridine and an alkylindole by its degradation. Vallesine, also from Vallesia glabru, is apparently N-formyldeacetylaspidospermine 97

(>N*CHO for >N.COMe). Strychnos Albaloids.1 (p. 5541 Strychnine and Brucine.-The involved

arguments which have resulted in the formula (XXXVII) for strychnine can be treated here only in a very abbreviated fashion. The whole field has been surveyed by Sir R. Robinson in a Chemical Society lecture but this has not yet been published.

17 18

\ / \ / CH, O*CH, (XXXVII.)

\ / \ / CH2 O*CH,

(XXXVIII.)

The structure (XXXVII) has received independent confirmation from the detailed X-ray studies of C . Bokhoven, J. C . Schoone, and J. &I. Bijvoet 97*

on certain strychnine salts, particularly the sulphate. An important series of oxidative degradations which were to a large measure responsible for the modification of the earlier Robinson strychnine formula 98 (XXXVIII)

v5 H. T. Openshaw and G. F. Smith, Experientia, 1948, 4, 428 ; Ramond-Hmet,

ss J . Amer. Chem. Soc., 1948, 70, 3712. v7 E. Schlittler and M. Rottenberg, Helv. Chim. Acta, 1948, 31, 446. v7a Proc. Koninkl. Nederland. Akad. Wetenschap., 1947, 50, 967; 1948, 51, 990;

s8 J., 1939, 603.

Conapt. rend., 1948, 226, 2154.

1949,52, 120; Chem. Abs., 1948, 42, 4421 ; 1949, 43,4918, 5254.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALKALOIDS. 207

were described with strychninonic acidQQ and showed that ring D must be a t least 6-membered :

I cn- r; /&H ,&H

\CHO i.e., n>3

\ D / -+ cfl + c, co-co \CO*CO,H

(XXXIX .)

Confirmatory evidence was provided by studies of the lactamisation of cuninecarboxylic acid.1 The alternative Swiss formula (XXXIX) for strychnine could not be accepted 2s 3 for several reasons, principally because it did not provide an explanation of the properties of +strychnine (OH at C,,,,), now conveniently obtained by treatment of strychnine N-oxide with potassium chromate solution a t lOO".* H. T. Openshaw and Sir R. Robin- son % s therefore advanced the present formula (XXXVII) as interpreting '' the whole behaviour of strychnine better than any other " although it did not, a t that time, appear to offer a satisfactory explanation of the formation and properties of certain of the neostrychnine derivatives, e.g. methoxymethylchanodihydrostrychnone (XLI ; p. 210). On the other hand it explained the formation of the most important products from drastic degradations of strychnine, e.g., tryptamine, carbazole, and especially p-collidine. Moreover, it bore a biogenetic relation to the cinchonine molecule which was even more apparent in another strychnine formula,6 later rejected in the light of further experiments on the neo-derivatives, whereupon the authors reverted to the earlier formula (XXXVII). A more recent scheme 14; p. ls7 for the biogenetic synthesis of strychnine has already been outlined (p. 197).

An observation which gave insight into the mode of linkage of N(p) to the indole ring came from a study of the properties of strychnone, an oxidation product of $-strychnine.8 R. B. Woodward, W. J. Brehm, and

** V. Prelog and S. Szpilfogel, H e h . Chim. Acta, 1945, 28, 1669; Experielztia, 1945, 1, 197.

H. L. Holmes, H. T. Openshaw, and (Sir) R. Robinson, J. , 1946, 908. (Sir) R. Robinson, Nature, 1946, 157, 438; Exparientia, 1946, 2, 28. V. Prelog and M. Kocbr, Helv. Chim. Acta, 1947, 30, 359.

L. H. Briggs, H. T. Openshaw, and (S ir ) R. Robinson, J., 1946, 903. * A. S. Bailey and (S i r ) R. Robinson, J. , 1948, 703.

* (Sir) R. Robinson, Nature, 1947, 159, 263. ' R. N. Chakravarti and (Sir) R. Robinson, ibid., 1948,160, 18. * H. Leuchs, E. Tuschen and M. Mengelberg, Ber., 1944, 77, 408.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

208 ORGANIC CHEMISTRY.

A. L. Nelson9 showed that strychnone, on the basis of its absorption spectrum, was not a dihydroindole as had been assumed, but a true indole and formulated the reaction :

CO \

This deduction was accepted by A. S. Bailey and Sir R. Robinson lo who arrived a t similar conclusions from a study of the analogous brucones.

Treatment of methoxymethyldihydroneostrychnine l1 (XL) with dilute acids gave the neostrychninium salts which on pyrolysis yielded neo- strychnine isomeric with strychnine. neostrychnine is now more readily obtained by treating strychnine with Raney nickel in boiling xylene,'. l2 and its structure (XXXVII ; double bond a t C(21-22) moved to C(20-21,) has been deduced from its ready oxidation with bromine to give the aldehydic oxodihydroneostrychnine (renamed oxodihydroallostrychnine) : l3

,CHO -N( @)*CH:C < + -N( @)Cy Perbenzoic oxidation of methoxymethyldihydroneostrychnine (XL) gave methoxymethylchanodihydrostrychnone (XLI) l4 which on Clemmensen reduction yielded methoxymethylchanodihydrostrychnane (XLII) l5 con- taining a C-methyl group. These reactions have been discussed in detail by R. B. Woodward and W. J. Brehm l6 who showed that the degradative evidence could be satisfactorily explained onIy on the basis of formula (XXXVII) for strychnine. These authors devised a scheme whereby the formation of a new C-methyl group in (XLII) did not necessarily indicate a C-aldehydo-group in (XLI), vix., by reductive cleavage of the reactive

* J . Amer. Chem. SOC., 1947, 69, 2250. 11 0. Achmatowicz, G. R. Clemo, W. H. Perkin, and R. Robinson, J. , 1932, 767. l* (Sir) R. Robinson and R. N. Chakravarti, J., 1947, 78.

I* R. Robinson et at., J. , 1934, 590; 1935, 936. l6 T. M. Reynolds and R. Robinson, J., 1934, 592. l6 J . Amer. Chem. Soc., 1948, 70, 2107.

lo Nature, 1948, 161, 433.

R. N. Chakravarti, K. H. Pausacker, and (Sir) R. Robinson, ibid., p. 1554.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

JOHNSON : ALKALOIDS. 209

p-ether grouping as shown, reduction of the crtrbonyl group to an alcohol and formation of a new ether as in (XLII). I n support of their theory, they found that a milder reduction of (XLI) by the action of Raney nickel on the corresponding diethyl mercaptal gave methoxymethyldeoxychano- dihydrostrychnone (XLIII) which contained no C-methyl group.

CH,-CH,*OMe CH,---CH,*OMe ' CH

--(i YH, YMe CH CH CHO

I / \\\ -y-? c CH2D rnle

CH CH CH

\ / CH2

H,--- CII2-- 9 3 2 HO,C 7 CO y"

\ / \

HY 'iH G \ / \ /

7 (7H2 YMe R\--(i (iH2 TMe CH CH CH2 \/\ I I I / C H CH CH, lrrMe / \ / \ / HO N \ / \ / \/\

I 11 N 4 /

\/

I (?H G \ / \ /

OC CH CH OC CH CH ICHMe, CH, O*CH, CH, O*CH,

(XLIV.) (XLVT) (XLVI.)

Vornicine.-The relation between vomicine, strychnine, and brucine has been established lo by the formation of the same C17 acid (XLIV) by chromic acid oxidation of either N-methyl-sec.-$-strychnine,17 N-methyl- sec.-$-brucine, or vomicine, now formulated as (XLV) l8 on the basis of the extensive studies of H. Wieland and his colleague^.^^ The structure

H. Leuchs, Ber., 1937, 70, 2455. K. H. Pausacker and (Sir) R. Robinson, J., 1948, 951.

l9 R. Huisgen, H. Wieland and H. Eder, Annulen, 1949, 561, 193 and earlier papers; R. Huisgen, " Preparative Organic Chemistry," Part 11, 1948, p. 109; F.I.A.T. review of German Science, 1939-46.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

210 ORGANIC CHEMISTRY.

of be of

vomip yrine (XLVI) by strychnine

obtained from a degradation of vomicine has been shown to direct synthesis,20 and the synthesised degradation products now cover the whole carbon-nitrogen skeleton with the

exception of ring F. G. R. Clemo et aL21 have described some new reduction products of

strychnine and have discussed the structures of their products and their bearing on the nature of rings E and F. Support for ring E being 6-membered has come from its conversion into derivatives of 2 - ~ y r i d o n e , ~ , ~ ~ the work of V. Prelog, M. Kocbr, and W. I. Taylor 22 in this connection being part of an investigation 23 of new oxidative degradations of strychnine.

AjmZine.-Further work has been reported 24 on the structure of ajmaline (the rauwolfine of L. van Italie and A. J. Steenhauer) 25 from the roots of RauwoEJia serpentinu Benth. Distillation of the alkaloid from zinc gave carbazole and N-methylharman. Possible structures for the alkaloid were suggested.

Acridine Group.-The bark of Melicope fareanu F. Muell, from the Queensland rain-forest, contains the alkaloids melicopine, melicopidine, melicopicine, and acronycidine, the bark of Acronychia buueri also contains acronycine, and that of Evodia xanthoxyloides evoxanthine. These com- pounds were shown 26 to be derivatives of N-methylacridone, a ring system which had not previously been found in the alkaloids. In a detailed investigation, W. D. Crow and J. R. Price 27 have determined the stmctures of melicopine (XLVII), melicopidine (XLVIII), and rnelicopicine (XLIX) , as well as several of the degradation products.

(XLVII.) (XLVIII.) (XLIX.)

Quinazolone Group.-The roots of the saxifrage, Dichroa febrifuga, Lour., contain alkaloids which are active antimalarials, two of which have been named febrifugine and isofebrifugine C16H,,03N3, and they appear to be 3-substituted 4-q~inazolones.~~ Both yield 4-quinazolone on per- manganate oxidation and are very susceptible to alkaline hydrolysis although they are relatively stable to acids. Febrifugine is apparently dimorphic, and J. B. Koepfli et aZ.28 believe that the three dichroines of T. Q. Chou,

2o (Sir) R. Robinson and A. M. Stephen, Nature, 1948,162, 177. 21 J . , 1946, 891; 1948, 1661; Chem. and Id., 1948, 156. 22 HeEv. Chim. Acta, 1949, 32, 1052. 2* D. Mukherji, (Sir) R. Robinson, and E. Schlittler, Ezperientia, 1949, 5, 216. 25 Arch. Pharm., 1932, 270, 313. e s G. K. Hughes, F. N. Lahey, J. R. Price, and L. J. Webb, Nature, 1948,162,223. 27 Austrdian J. Sci. Res., 1949, 2, 249, 255, 264, 272, 282. 28 J. B. Koepfli, F. B. Mead, and J. A. Brockman, J . Amer. Chem. SOC., 1947, 69,

25 Ibid., 1948, 31, 237, 505.

1837; 1949,71, 1048.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTEINS. 21 1

F. Y. Fu et ~ 1 . ~ 9 correspond to isofebrifugine and the two forms of febri- fugine, although the Chinese workers give Cl,H,lO,N, as the molecular formula. The isolation of these alkaloids has also been described by F. A. Kuehl, C. F. Spencer, and K. Folkers,30 their results being in essential agreement with the other

Discussion of several postponed.

The chemistry of the

American workers. other important alkaloid groups has had to be

A. W. J. 8. PROTEINS.

proteins has not been reviewed in these Reports since 1937.l It is impossible therefore to refer to more than a fraction of the significant advances in our knowledge of this group of compounds that have occurred since then, and this Report will therefore make special refer- ence to a single protein-p-lactoglobulin. This is a typical member of the corpuscular class of proteins which behave in solution as though the ultimate particles have no one dimension more than a few times as great as another. It is still possible to speak of their molecular weight as a property with some meaning, and to estimate i t by chemical and physical methods. The other class of proteins is that of the fibrous polymers in which particle weight in solution is more a reflection of the method of preparation than of any intrinsic property of the compound. Myosin, a soluble, fibrous protein, has been recently the subject of a review in these Reports? tobacco mosaic virus, also soluble, has been reviewed by N. W. P i~- ie ,~ and the insoluble keratin-collagen group by W. T. Astbury.* Many corpuscular proteins are known but only a very few fibrous proteins. This is perhaps indicative of their properties rather than of their distribution in living organisms. Corpuscular proteins are as a rule soluble and easily prepared whilst fibrous proteins tend not to be. The fibrous proteins that have been studied are all obvious subjects either because of their economic importance (keratin of wool, collagen of leather, silk fibroin, fibrous plant viruses) or of their outstanding theoretical importance (myosin of muscle). The distinction made between the two classes is useful but not absolute. Insulin, usually considered as a typical corpuscular protein, is readily and reversibly trans- formed into a fibrous state by extremes of P H , ~ and there is evidence that tobacco mosaic virus in the form usually investigated may be a linear polymer of a corpuscular unit.6

The last Report was written during the heyday of hypotheses regarding the structure of proteins. In a textbook of 1938 ten hypotheses of protein

25 Science, 1946, 103, 59; Nature, 1948, 161, 400; J . Anzer. Chem. Soc., 1948, 70,

30 Ibid., 1948, 70,2091. 1765.

T. W. J. Taylor, Ann. Reports, 1937, 34, 302. 3 Advances in Enzymobgy, 1945, 5, 1. I<. Bailey, ibid., 1946, 43, 280.

Proc. Roy. Xoc., 1947, 33, 134, 303.

F. C. Bawden and N. W. Pirie, Brit. J . Exp. Path., 1945, 26, 294. ti D. F. Waugh, J . Arner. Chenz. Soc., 1948, 70, 1850.

’ ‘‘ The Chemistry of the Amino Acids and Proteins,” edited by C. L. A. Schmidt, Baltimore, 1938.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

212 ORGANIC CHEMISTRY.

structure were discussed of which seven commanded widespread assent. These were : (i) that proteins consist of a chain of amino-acids joined by the peptide link (E. Fischer and F. Hofmeister), (ii) that apparent mathe- matical relations between the frequencies of amino-acid residuei calculated from protein analyses were a reflection of a simple pattern of residues in the polypeptide chain (M. Bergmann and C. Niemann), (iii) that isolated proteins may represent variable fragments of ‘( protein supermolecules ” such as the total serum protein (W. B. Hardy and S. P. L. Sarrensen), (iv) that basic amino-acids are of particular importance in providing the ‘( founda- tion” of protein structure (R. J. Block), (v) that the molecular weights of proteins fall in well-defined groups each a simple multiple of the smallest and that this reflects a principle of protein construction (T. Svedberg), (vi) that polypeptide chains are organised into three-dimensional lattices of a fixed number of residues that supply the basis of Svedberg’s groups (D. M. Wrinch), and (vii) that the a- and the p-patterns found by the X-ray examination of proteins are explicable in terms of two definite structures (Astbury). Of these i t is fair to say that only the first stands unshaken apart from the mild caveat that there may be more than one polypeptide chain in a single molecule, whilst the last, after partial revision, is still the subject of controversy. Little has replaced the missing hypotheses which are now seen to have been based on oversimplification, inadequate or in- accurate evidence, or misinterpretation of the facts. Evidence is now accumulating that many proteins are built of a number of polypeptide chains linked together in a manner not definitely known. The search for underlying regularities that inspired the hypotheses of Bergmann and Niemann, Block, and Svedberg was perhaps foredoomed by being carried out at the organisational level of the total protein rather than at the level of the constituent polypeptide chain. The Sarrensen hypothesis was based in part on the observation that the solubilities of certain proteins believed to be pure did not obey the phase rule-possibly because they were in fact not pure, or because dissociation of a complex organised body of protein into constituent proteins was occurring. It was the acceptance of the latter explanation that led to A. Gronwald’s experiments,* which showed the heterogeneity of p-lactoglobulin, being ignored as evidence until the independent demonstration by C. H. Li four years later.

During the early 1930’s interest in the amino-acid analysis of proteins was slight, perhaps owing to the tedium of pursuing the aim of a complete analysis with methods known to be largely unsatisfactory. Consequently the proteins were examined in the main by physical methods. Great advances were made in the interpretation of titration curves and in techniques of deriving information about the size and shape of molecules in solution by the measurement of rate of sedimentation, sedimentation equilibria, rate of diffusion, viscosity, and electrophoretic and surface-film properties. In the present decade the study of the dielectric properties, electroviscous

Compt. rend. Trav. Lab. Carlsberg, 1942, 24, 185. J . Amer. Chem. Xoc., 1946, 68, 2746.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTEINS. 213

effects, and light scattering of proteins in solution has been added to the methods of investigation available, and repeated attempts to reconcile the often conflicting results for degree of hydration and dissymmetry have been made.

In the late 1930’s the delightfully simple hypotheses of Bergmann and Niemann attracted considerable attention. It was fortunate that the scanty analyses of proteins that were then available lent support to their ideas, for it was to the advantage of both the proponents and opponents of the theory to produce more detailed, and above all, more accurate analyses. During the period under review the problems of determining the quantity and identity of amino-acids present in protein hydrolysates have largely been solved. In 1941 H. B. Vickery 10 reported that satisfactory methods for the determination of only nine amino-acids were known and that many of these depended on quantitative isolation. The classical methods of quantitative isolation were brought to their highest pitch a t this time by A. C. Chibnalf and his co-workers.ll The dicarboxylic acids and basic amino-acids were determined by their methods with an error of only 1-2%. At the time that the classical methods were reaching their peak, however, a number of new methods began to appear, relatively simple in execution and requiring little material. These included partition chromatography,12 adaptable to both qualitative and quantitative requirements, micro- biological methods by which nearly all amino-acids may be determined by measuring the growth response of selected strains of moulds or bacteria to their presence, isotope dilution in which an isotope-containing amino- acid is added to the hydrolysate as a tracer, the isotopic-derivative method, and the use of specific enzymes. With these methods the determination of the amino-acids present in a hydrolysate is now possible. Information has also been accumulated on the destruction of some amino-acids occurring during hydrolysis. Thus an estimate may be made of the composition of the material analysed. Whether or not this information is to be regarded as concerning the composition of a single, pure species of protein molecule is to some extent a matter of taste. The interpretation depends entirely on the weight given to the evidence available as to the purity of the proteins l3

and indeed on the meaning of the word purity when applied to proteins. That the difficulty is real may be seen from the history of @-lactoglobulin. For long thought to be a homogeneous protein as judged on the basis of solubility, and behaviour in the ultracentrifuge and in electrophoresis, it has been shown that although apparently homogeneous in the Tiselius apparatus a t pH 5.3, 5.6,g and 8*3,lP it behaves as a mixture of three com- ponents a t pH 4-8 and 6 ~ 5 . ~ T. L. McMeekin et aL1* recognised two main

lo Ann. New Yo& Acad. Sci., 1941,41, 87. l1 A. C. Chibnall, M. W. Rees, and E. F. Williams, Biochem. J., 1943, 37, 372. l2 Idem, Biochem. SOC. Symposia, 1949, 3. lS N. W. Pirie, BioE. Rev., 1940, 15, 377.

T. L. McMeekin, B. D. Polis, E. S. DellaMonica, and J. H. Custor, J . Amer. Chem. Soc., 1948, 70, 881.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

214 ORGANIC CHEMISTRY.

components at pH 4.8,60% of one and 40% of the other. Moreover, these workers were able to separate the components partially, by recrystallisation from acetate buffer and by fractional precipitation with ethanol. The fractions were shown to differ in solubility in water and O-O~M-N~CI. It is possible that this heterogeneity may be due to no more than the combination of one or two small molecules with charged groups on a portion of the mole- cules. Such a combination would be sufficient to result in electrophoretic inhomogeneity at some pH's and would be difficult to demonstrate by analytical means.15

p-Lactoglobulin. The preparation from whey of a crystalline globulin during an unsuccessful

attempt to obtain crystalline lactalbumin was reported by A. H. Palmer in 1934.16 The protein crystallised in two forms, needles and plates, the former being unstable and changing slowly into the latter. The protein appeared to be pure and was named lactoglobulin.

Elementary Composition.-The total nitrogen content on an ash-free, dry basis was reported by Palmer as 15.3y0; subsequently values varying from 14.35 to 15-62y0 were quoted. The work of A. C. Chibnall, 31. W. Rees, and E. F. Williams l7 on the determination of the total nitrogen of proteins showed that erratic, low results may be obtained if anhydrous proteins are analysed, owing to their great hygroscopicity. Further errors may be ascribed to inadequate digestion times if the Kjeldahl method is used. The use of air-dry proteins of known water content and digestion times known to be adequate gives reproducible results. The value (15.58%) given by these workers agrees well with that of 15.60~0 obtained by the micro-Dumas method.ls Phosphorus and carbohydrates have not been found in p-lactoglobulin : sulphur contents of 1-60y0 1* and 1.680/, l9 have been found by the Pregl procedure. The difficulties of sulphur estimation in proteins with low sulphur contents have been underlined by the recent experiences of C. A. Knight.20 41 analyses by 3 analysts of 13 preparations of cucumber virus 4 gave values for the sulphur content of 0.07-1.26~0, with an average of 0.6y0. One analyst obtained values differing by 50% on the same preparation at different times. E. Brand and his co-workers have reported a total analysis of p-lactoglobulin : C, 53.39% ; H, 7.22% ; N, 15.60%; S, 1.60%; 0, 22.19% (by difference).21

Amino-acid Composition.--In protein chemistry, determination of the proportions of constituent atoms is replaced in importance by determination of functional groups of atoms (amino- and carboxyl groups, etc.) and con-

1 5 T. L. McMeekin, B. D. Polis, E. s. DellaMonica, and J. H. Custer, J , Amer. Chem.

16 J . Biol. Chern., 1934, 104, 359. 18 E. Brand and B. Kassell, J . BioZ. Chem., 1942, 145, 365, l9 D. Bolling and R. J. Block, Arch. Biochem., 1943, 2, 93. 2O J. Amer. Chem. Soc., 1949, '71, 3108. 81 E. Brand, L. J. Saidel, W. H. Goldwater, B. Kassell, and F. J. Ryan, ibid.,

Soc., 1949,7l, 3606. I7 Bwchem. J., 1943, 37, 354.

1945,87, 1524.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRBCEY : PROTEIXS. 216

stituent groups of atoms-the amino-acid residues. Determination of functional p u p s is usually carried out on the intact molecule, and will be considered later. Most amino-acids are determined in a protein hydrolysate though some are determined on the intact protein. An analysis of p-lacto- globulin reported by Brand et aL21 is summarised in Table I. There are two striking points about this analysis, first the very high total of 99.13% of the protein accounted for and secondly that of the 26 estimations included only one is by isolation and no less than 10 rely on biological methods.

TABLE I. The Composition of p-lactoglobulin.

Amino-acid. Method. (a). ( b ) . Found, %.

Glycine bact. 1 4 1.39 Alanine bact. 6.2 7.09 Valine bact. 5.8 6-62 Leucine mould, isotope diln. 15.6 16.5 isoLeucine bact. 8.4 5.86 Proline mould 4.1 5-14 Phenylalanine bac t . 3.5 3.78

Cystine absorp. 2.29 (2.29) Rlethionine iodometric 3-22 (3.22) Tryptophan ultra-violet 1.94 (1.94) Arginine absorp., isolation 2.88 2-91 Histidine absorp. 1.58 1.63 Lysine enz., isotope diln., bact. 11.4 12.58 Aspartic acid bact., isotope diln. 11.4 11.52 Clutamic acid bact. 19.5 19.08 Amide-ammonia microdiffusion 1.31 (1.31)

Threonine periodic acid oxidation 5.8 4.92 Tyrosine absorp . 3.78 3.64

116.33 11 1.49

C ysteine absorp. 1.11 (1.11)

Serine periodic acid oxidation 5-0 3-96

Bact. : assay by growth response of suitable bacterium ; mould : assay by growth response of mutant Neurospora ; absorp. : absorptiometric method ; ultra-violet : ultra-violet absorption of tryptophan-mercury complex ; enz. : isolated bacterial decarbox ylase.

Column (a) are the results given in reference 21 ; the recovery on a residue basis is 99.13%. Column (6) gives the results of chromatographic analysis on starch columns by Stein and Moore 27 ; the figures in parentheses are from column (a) and the total of column ( b ) which includes these corresponds to a residue recovery of 97.7%

The biological methods depend on the measurement of the growth response of a selected strain of bacteria or of a mutant mould to the presence of an amino-acid which is the limiting factor to its growth in the medium used. The amino-acid is added in known amounts at different levels to some cultures and as aliquots of hydrolysate to others. Inaccuracies in this method may arise from differences in response due to other substances

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

216 ORGANIC CHEMISTRY.

added in the hydrolysate which may either enhance or depress the growth response and also from the fact that usually only the L-isomer of amino- acids is utilised. If racemisation has occurred during hydrolysis low results for the total amino-acid will result. The purity of the amino-acid used as standard also requires attention. E. L. Smith and R. D. GreeneB found 807% of isoleucine in P-lactoglubulin which agreed well with the value of 8.4% found by Brand and his co-workers (Table I). Smith and Greene 23 later found however that their standard had contained DL-iSoaZZoleucine and accordingly emended their value for isoleucine to 6.1%. The values for amino-acids determined by the isotope-dilution method by G . L. Foster, which are those quoted by Brand in Table I, only refer to the L-isomer, for after the addition of DL-isomer containing 15N to the hydrolysate, purification was directed towards the isolation of pure isomer.^* On the whole the evidence seems to be that racemisation in acid hydrolysis is not of great importance. A recent method for the analysis of protein hydrolysates uses an isotopic reagent reacting quantitatively with the amino-acid to be determined.25 pIodobenzenesulphony1 chloride containing 1311 was the reagent used, and after completion of its reaction with the amino-acids in the hydrolysate very large quantities of carrier (the p-iodobenzenesulphonyl derivative of the amino-acid to be determined) were added. The derivative was then isolated, if necessary in very low yield, and the isotopic dilution measured. Co-precipitation in the isolation procedure must of course be avoided, but the enormous amounts of carrier that may be used permit rigorous purification. Either L- or D-amino-acids may be estimated, the corresponding carrier being used. The glycine (1.56 %), alanine (7.05 yo) , and proline (4-84y0) values found for a P-lactoglobulin hydrolysate are higher than those obtained by Brand and his colleagues by biological methods. No D-alanine or D-proline was found ; 25 hydroxyproline was also absent.26

Analysis by partition chromatography has also been applied to P-lacto- globulin hydrolysates. W. H. Stein and S. Moore 27 using starch columns and fractional elution report the figures given in column ( b ) of Table I. Values for the sulphur amino-acids are not given as the use of thiodiglycol as an antioxidant for methionine on the column had not been developed and the cysteine + cystine values found were known to be low owing to destruction during hydrolysis. Similarly tryptophan was not found owing to loss on acid hydrolysis. The figures for threonine and serine have been corrected for decomposition on hydrolysis by Rees’s factors.28 Using the values given by Brand et aZ. for the missing amino-acids a 99.6% recovery of protein nitrogen and 97.7% weight recovery was achieved. The hydrolysate from only 25-50 mg. of protein was sufficient for analysis in triplicate. It will

22 J . BioE. Chem., 1947, 167, 833. 24 Ibid., 1945, 159, 431. z5 A. S. Keston, S. Udenfriend, and R. K. Cannan, J . Anzer. Chem. Soc., 1949,

26 Idem, quoted in ref. 27. g8 Biochem. J., 1946,40, 632.

23 Idem, ibid., 1948, 172, 111.

71, 249. 27 J . Bwl. Chem., 1949,178, 79.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTEINS. 217

be seen from Table I that the major differences between the chromato- graphic results and the earlier values are in those for alanine, isoleucine, proline, phenylalanine, lysine, serine, and threonine. It is known that some decomposition of serine, threonine,28 and phenylalanine 24 occurs on acid hydrolysis, the extent varying with the conditions. Stein and Moore’s results for alanine and proline agree with those obtained by the isotope- derivative method whilst Brand’s high isoleucine value may be due to an unsatisfactory standard in the biological assay.23 Stein and Moore’s high lysine value may be due to a low biological value caused by racemisation, or to the presence of an unidentified compound travelling with lysine on the starch column. No components other than those already known to be present were detected by chromatography. The recent work of J. R. Spies and D. C. Chambers on the estimation of tryptophan, in which losses on acid and alkaline hydrolysis were followed, suggests that an upward revision of the value in Table I is necessary. After alkaline hydrolysis 1.75y0 of tryptophan was found in a p-lactoglobulin hydrolysate by a colorimetric method and 1.84y0 by a biological method.29 By applying the colorimetric method to the intact protein a value of 2.57% was obtained.

It will be clear from the previous discussion of some of the results recorded for the composition of p-lactoglobulin, that though complete analyses of proteins with almost theoretical nitrogen and weight recoveries are now possible the values for individual amino-acids are subject to error that in some instances may be considerable. This is especially so for amino-acids that may undergo decomposition on hydrolysis. Corrections may be made on the basis of losses known to occur on treatment of the amino-acids under the conditions of hydrolysis used. Unfortunately these model experiments may be misleading as the rate of destruction of an amino-acid may depend not only on the other amino-acids or other substances present, but also on the state of combination of the amino-acids. If tryptophan is heated in alkaline solution with cystine, cysteine, lanthionine, serine, or threonine significant losses occur.29 Twelve other amino-acids tested had no effect. Moreover, some amino-acids may protect tryptophan from destruction by serine. Nine amino-acids were tested, and protection varied from complete with-histidine and hydroxyproline to none with proline. Some of these effects apparently depended on whether the amino-acids were free or peptide-linked.

lklinhal Molecular Weight.-Minimal molecular weights of proteins may be calculated from the amino-acid composition. Good agreement with results from physical measurements is usually obtained; in the case of p-lactoglobulin the results are approximately equal ; in other proteins such as insulin the molecular weight observed by physical methods is a multiple of that calculated from analysis. The method depends to a great extent upon the accuracy with which the percentage of the least abundant amino-acids has been determined.

Estimation of Reactive Groups.-Further light can be thrown on the AltaZyt. Chem., 1949, 21, 1249.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

218 ORaANIC CHXMISTRY.

chemical composition of proteins by the examination of the reactive groups in the intact protein. R. K. Cannan in 1938 30 briefly reported the presence of 47 carboxyl groups per molecule of p-lactoglobulin (assumed, M 34,500) from an examination of its titration curve, and in a contribution 31 to the discussion of another paper commented that a molecule of p-lactoglobulin (assumed M 39,000) appeared to contain 5 a-amino-groups. He suggested that these represented the free ends of five constituent polypeptide chains. Later results 32 gave an estimate of 57-60 carboxyl groups, 33-35 amino- (of which 29 were assigned to lysine), 6 glyoxaline, and 5-7 guanidino- groups per 40,000 g. of p-lactoglobulin. These results agree well with those later obtained by direct analysis. If the casboxyl ends of the polypeptide chain or chains are free, titration should reveal an excess of carboxyl groups over those accountable for as dicarboxylic acids by analysis. A decision on this point is rendered difficult by the large number of dicarboxylic residues and the masking of some by amide formation. Published figures indicate an excess of 0-3. Figures for free a-amino-groups range from 5 (titration,32 total amino-nitrogen less lysine nitrogen 339 21) to 3 (end-group assay 34).

Chibnall,35 arguing on the basis of similar figures, suggests that a real deficit of carboxyl end groups could be explained by the polypeptide chains being linked by a union of a carboxyl group of one chain with a side group of another. The possibilities include (a) an ester link with serine, threonine, or tyrosine, ( b ) an imide link between C02H and CO*NH2, and ( b ) a thiol ester link.

and R’NH*CO*CH(NH,)*CH,*CH,*CO*NHR’’ involving dicarboxylic acids and leaving a free a-amino-group do not occur in 8-lactoglobulin 36 or other proteins3’ has been provided by the work of F. Haurowitz. He has also advanced evidence for the existence of more than one residue of glutamic acid y-linked without free a-amino-groups in some proteins.3s The thiol ester link is attractive in that it might be expected to be a weak link and to explain the appearance of thiol groups in proteins under conditions in which rupture of the -S-S- bond seems unlikely. The development of a method by which a-carboxyl groups could be determined separately from p- and y-carboxyl groups is obviously of great importance in the future advance of our knowledge of protein structure. The fact that proteins can be shown to have free a-amino-groups does not enable any distinction to be made between a structure of parallel chains held together by cross links (which would have an equal number of free a-carboxyl groups) and

Evidence that imide links of the type R’NH*CO*CH( NH2)*CH,.CH2*CO*NH*COR”

30 Cold Spring Harb. Symp. p a n t . Biol., 1938, 8, 1. 31 Idem, ibid., p. 17. 32 R. K. Cannan, A. H. Palmer, and A. C. Kirbrick, J . Biol. Chern., 1942, 142, 803. 33 S. R. Hoover, E. L. Kokes, and R. F. Peterson, Tezt. Res. J . , 1948, 18, 423. 3 4 R. R. Porter, Biochim. Biophys. Acta, 1948, 2, 105. 35 Proc. Roy . Soc., 1943, B, 131, 136. 36 F. Haurowitz and S. Tekman, Bull. Fac. wed. Istanbul, 1946, 9, 225. 5’ F. Haurowitz and M. Tunca, Biochern. J. , 1946, 39, 443. 38 Haurowitz and F. Bursa, ibid., 1949, 44, 509.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

W C E Y Z PROTEINS. 219

one in which a number of chains are attached by their a-carboxyl groups to a cyclic peptide (which would have no free carboxyl groups). It is possible to demonstrate the absenee of amido-links between lysine amino- groups and carboxyl groups in many proteins.39 Cyclic peptides are known 4o and ovalbumin seems to have no free a-amino-group, which suggests a cyclic structure.

Our knowledge of the chemistry of a protein has only begun when its composition in terms of aminc-acids and reactive groups is known. Many of the properties of a protein must depend not only on its amino-acid com- position but also on the arrangement of the residues within the molecule. The isolation and characterisation of peptides from partial hydrolysates have been carried out sporadically since the work of Fischer in 1902 on silk fibroin.41 This work, much of it inconclusive, has been reviewed by R. L. M. Synge42 up to the advent of partition chromatography which gave it a new impetus. F. Sanger 39 has shown that it is possible to prepare protein derivatives in which free amino-groups have been treated with l-fluoro-2 : 4- dinitrobenzene to form dinitrophenyl derivatives. The substituent is fairly stable to the conditions used in protein hydrolysis and it is possible to separate from the hydrolysate by chromatographic methods the dinitrophenyl- arnino-acids. Amino-acids which are a-substituted must be assumed to have had free a-amino-groups, and therefore if they are monoamino- monocarboxylic acids to have been at the ends of chains. Application of this method has shown the presence of three terminal residues of leucine in p-lactoglobulin per 40,000 g.34 The terminal groups of other proteins determined by this method are given in Table 11. If hydrolysis of dinitro- phenyl proteins is not carried to completion it is possible to isolate dinitro- phenyl peptides, in which the order of amino-acids can be established by further substitution and hydrolysis. Since peptides with an cc-amino- substituent must come from the end of a chain it is possible to work out the order of residues, for a short distance from this point. In horse globin, which has six terminal valyl residues in a molecule of molecular weight about 66,000, the chains are apparently not identical, for 2 : 4-dinitrophenyl- valyl-leucine, 2 : 4-dinitrophenylvalylglutamyl-leucine, and 2 : 4-dinitro- phenylvalylglutaminyl-leucine have been isolated from partial h ydrolysates. Similar methods led to the conclusion that the amino-acid sequences glycyl- isoleucylvalylglutamic acid and phenylalanylvalylaspartylglutamic acid occur in insulin, the glycyl and phenylalanyl residues being terminal.43 Further details of our knowledge of the structure of insulin are given in Sanger’s review.44 His work on the splitting of the molecule into separate chains by oxidation with performic acid is of particular interest in that it provides convincing evidence for the existence of inter-chain -S-S- bonds. This form of linkage has long been suggested, and more recently assumed,

39 I?. Ssnger, Biochem. SOC. Symposia, 1949,3, 21. 40 R. L. M. Synge, Quarterly Reviews, 1949, 3, 245. 41 Chem. Ztg., 3902, 26, 939. 43 Nature, 1948,162, 491.

42 Chem. Reviews, 1943, 32, 135. 44 Ann. Reports, 1940, 45, 203.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

220 ORGANIC CHEMISTRY.

Protein. Insulin

Haemoglobin : Horse Donkey Human cow

Sheep

Goat

Myoglobin : Horse Whale

Edes tin

S-Lac toglobulin Native Denatured

Ovalbumin y-Globulin

Salmine (rabbit native)

TABLE 11. Terminal Residues of Proteins.39

Terminal residue. M ,

assumed. 12,000

66,000 66,000 66,000 66,000

66,000

66,000

17,000 17,000

300,000

40,000 - -

44,000

170,000 6,000

to occur in many proteins.

amino-acid. gl ycine phenylalanine

valine valine valine valine methionine valine methionine valine methionine

glycine valine glyeine leucine

leucine leucine none

alanine proline

NO. ’per mol.

2 2

6 6 5 2 2 2 2 2 2

1 1 6 1

3 3 - 1 7

No. of free No. of lysine amino-groups of lysine.

2 - 40 41 43 47

47

48

- - - 20 19 50 _L

19 32 19

65 0

residues per rnol.

2 I

39 - - - - 45 - I

-

19

48 .__

- 31 31 20

95 0

In fact good evidence for its existence is at present confined to-insulin and wool.- The structure of wool keratin has been investigated by A. J. P. Martin 45 and R. Consden and A. H. Gordon 46

by the isolation of dipeptides from partial hydrolysates. Synthesis of peptides during acid hydrolysis is unlikely and has been shown not to occur in the hydrolysis of tyrocidin. Their results are of considerable theoretical interest in that the number of different amino-acids found to be linked with the two basic am&o-acids indicates a very complex structure in which simple regularities may be hard to detect, and in that glutamylglutamic acid occurred in the greatest amount. Its high proportion in the products isolated may be a result of the methods of isolation used but its existence in appreciable amounts is dficult to reconcile with the Bergmann-Niemann hypothesis and Astbury’s suggested structure for keratin (in which polar and non-polar residues alternate).

Information on the relation of constituent parts of the protein molecule is hard to get but some light is thrown on it by a study of protein denaturation and the steric hindrance to the reaction of large molecules with active groups in some proteins. It has often been observed that the number of detectable thiol groups in proteins is increased by denaturation under conditions in which the rupture of an -S-S- bond is unlikely. The usual interpretation of this phenomenon is that the reagents used in the detection

45 “ Fibrous Proteins,” Bradford SOC. ; Dyers and Colourists, p. 1. 4* Biochem. J. , 1948, 43, x.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTEINS. 221

of thiol groups cannot penetrate the interior of the closely knit structure of the native molecule while the disordering consequent on denaturation would be expected to make groups accessible which were previously inaccessible. K. Linderstrsm-Lang and C. F. Jacobsen 4' have suggested, however, that thiol groups unapparent in native proteins are so, through being involved in a thiazoline link with an adjacent amino-acid. They have

7H2-SH R'NH*CO*CH=NH*C0.CHR2*NH*COR3 --+ p 3 2 - 7

R'NH.C0.CH.N:C*CHR2*NH*COR3 shown that such a ring would be expected to be opened with the appearance of free -SH groups under many of the conditions that lead to denaturation. Porter 34 has shown that some s-amino-groups of lysine in p-lactoglobulin and rabbit y-globulin do not react with l-fluoro-2 : 4-dinitrobenzene when the protein is native though they may after denaturation (Table 11). Keten will, however, react with all the s-amino-groups of p-lactoglobulin. It is suggested that this difference is connected with the difference in size of the two reagent molecules and hence with the ease with which they may be presumed to penetrate the interstices of the structure of the native protein.

Purely chemical evidence leads to the following picture of the structure of P-lactoglobulin. It is composed entirely of amino-acids, eighteen in number (cysteine, cystine, and the amides of aspartic and glutamic acids being counted separately), linked by the peptide link. It is composed of sub-units, each having a terminal leucyl group with free a-amino-group, joined by links probably not involving lysine &-amino- or carboxyl groups in such a way that it is spatially compact and, whilst allowing the penetration of small molecules, not permitting the entry of large molecules. Calculations based on the proportions of amino-acids present suggest a minimal molecular weight of about 40,000, implying the presence of about 350 amino-acid residues per molecule. Much of the evidence leading to the statements in this summary depends on the assumption that p-lactoglobulin is composed of a single molecular species. The only evidence suggesting that it is not is that of solubility and electrophoretic behaviour. It appears from the recent work of McMeekin et aE.15 that the combination of a substance with as few as two of the charged groups of p-lactoglobulin may alter significantly its behaviour in these respects. It appears likely therefore that p-lacto- globulin may be pure by the chemical criteria that can so far be used.

Further evidence regarding the structure of p-lactoglobulin has come from enzymic studies. The digestion of this protein by chymotrypsin and trypsin has been studied by Linderstrsm-Lang and J a c o b ~ e n . ~ ~ The appearance of titratable acid and base was used to estimate the number of peptide links split, and the total volume change of the system was measured a t intervals during the hydrolysis. The splitting of a peptide

47 J . Biol. Chem., 1941, 137, 443. Compt. rend. Trav. Lab. Carisberg, 1941, 24, 1.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

222 ORGANIC CHEMISTRY.

link involves the creation of two new charged groups round which water is more densely packed than in the body of the solution. This electrostriction effect can be measured in the splitting of simple peptides and has a value of about 15 ml./mole. On theoretical grounds the contraction has a maxi- mum value of 25 ml./mole. In the digestion of clupein (a low molecular- weight protein of relatively simple composition) normal values of about 15 ml./mole were found throughout the course of the hydrolysis. In the initial stages of the digestion of native p-lactoglobulin by trypsin or chymo- trypsin abnormally high values were recorded-about 50 ml. /mole for trypsin and 35 ml. /mole for chymotrypsin. When denatured p-lacto- globulin was the substrate the value was initially normal (20 ml./mole) but rose rapidly to a value of 35 ml./mole at a stage corresponding to the breaking of 10 peptide links per molecule and then fell to a normal value again. These results cannot be interpreted on the assumption that only peptide links are being broken during the early stages of hydrolysis : they can be explained on the assumption that the breaking of peptide bonds very early in the course of digestion renders the protein molecule unstable, leading to the spontaneous rupture of other bonds producing charged groups not detected by the methods of titration used. It appears unlikely that ruptured salt bonds would give rise to effects great enough to explain the abnormal contractions observed. Further evidence that reactions other than peptide-link rupture may occur during the hydrolysis of p-lacto- globulin was presented by G. Haugaard and R. N. Roberts who measured heat evolution during its breakdown by pepsin.49 The heat evolved was not proportional to the number of peptide links split, and the evidence pointed to the existence of an exothermic non-hydrolytic process occurring during hydrolysis. Dilatometric measurements were made during the digestion of alkali-denatured p-lactoglobulin by pepsin and, in contrast with the previous results48 with trypsin, there was no change in the value of 24.2 ml./mole during the course of hydrolysis. The increase in dialysable nitrogen and nitrogen not precipitable by trichloroacetic acid (which were found to be equivalent) was also followed. It was’of great interest that the ratio of amino-nitrogen to total nitrogen in the dialysable and undialysable fractions did not change during the course of the enzyme action. It must be concluded that pepsin action on p-lactoglobulin is an “ all-or-none ” process and that its result is the rapid production of a definite number of resistant fragments with no evidence of any intermediate stage. Alkaline denaturation of the protein did not affect the constancy of the amino- nitrogenltotal nitrogen ratios of the dialysable and undialysable fraction. It did however affect their values, for the hydrolysis of native and denatured p-lactoglobulin resulted in different end products. The rate of digestion of the native form is slower than that of the denatured protein but, sur- prisingly, the process is more complete. About 73 peptide links per mole- cule (M 40,000) are split when the native form is the substrate and 47 when this is the denatured form. Evidence for the “all-or-none ” action of

49 J . Amer. Chem. Soc., 1942, 64, 2664.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTZTNS. 223

pepsin on egg albumin was obtained by A. Tiselius and I. B. Ericsson- &uensel,m who followed the course of hydrolysis by electrophoretic, sedi- mentation, and diffusion methods. They found only two components in the digestion system - unaltered acid-denatured albumin and a fraction of average molecular weight of about 1,000 with no fragments of intermediate size. Results of a similar nature have also been obtained by other w~rkers.~Oa, 50b B

J. A. V. Butler, E. C. Dodds, I). M. P. Phillips, and J. M. L. Stephen 519 52 have followed the course of hydrolysis of insulin by pepsin and chymotrypsin. In both there is a rapid reaction resulting in the pro- duction of small fragments of the molecule (when chymotrypsin is used there is also a large fragment, M about 4,000). During the rapid initial phase the relation between amino-nitrogen and non-protein nitrogen is similar to that in the work of Haugaard and Roberts. The spontaneous formation of ‘‘ plastein ” which appears to occur in pepsin hydrolysates of insulin without the mediation of pepsin or the formation of peptide links may be related to the exothermic non-hydrolytic process observed by the former workers. Prolonged action of the enzymes was found to result in the slow breakdown of the fragments rapidly formed initially. Explanations of the results described postulate that the structure of the proteins con- cerned must be such that the breaking of a peptide link results in an inherently unstable residue which then either disrupts spontaneously or is much more readily broken up by the enzyme. There are two difficulties in this view. First it implies subtleties in the chemical structure of the protein for which we have no other evidence, and the nature of which it is diflficult to imagine, and secondly these unknown factors must be unaffected by denaturation of the protein which is itself regarded as a loss of organisation in the structure of the protein. A simple postulate regarding the nature of the enzyme may be advanced that would explain the facts and involve no violence to our ideas of protein structure. It is supposed that action of an enzyme on its substrate is preceded by the attachment of an active area on the surface of the enzyme to the substrate, a t or near the point of attack. Following the completion of the attack the enzyme is then free to repeat the process. If the enzyme is multivalent in respect of its active areas then, when attack- ing a large polymer such as a protein, attachment to the substrate niay occur in more than one site at once. Then after the breaking of the first link that of a second may follow a t once and so on. In effect this would mean that once the enzyme was within striking distance of the protein i t would not be free to leave it until all available and suitable bonds were ruptured. This explanation may be used also to cover the increased digestion of native p-lactoglobulin over the denatured form, since pre- sumably in the former susceptible links would be present in a smaller space

Biochem. J., 1939, 33, 1752. 50e 31. L. Petermann, J . Physica? Clzem., 1942, 46, 183. 50b T. Winnick, J . Biol. Chem., 1944, 152, 465. 61 Biochent. J . , 1948, 42, 116, 52 Idem, ibid., p. 122.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

224 ORGANIU CHEMISTRY.

than in the elongated denatured form. It would also imply that the digestion of proteins would be a more rapid process than that of peptides since there would be less ‘‘ lost time ” between the hydrolysis of successive links by individual enzyme molecules. J. H. Northrop, M. Kunitz, and R. M. Herriott 53 have commented that the rate of hydrolysis of synthetic substrates by pepsin is extremely slow compared to the rate of hydrolysis of proteins. i )

Physical Evidence.-The survey of physical evidence for the structure of p-lactoglobulin will exclude that dealing with molecular shape and hydration in solution which has been summarised by J. L. Oncley.54 X-Ray measurements by D. Crowfoot and D. Riley55 and by I. Fankuchen56 agree in assigning dimensions of 110-111~. x 60a. x 62-63~. to the unit cell of air-dried P-lactoglobulin. The direct determinations of crystal density and hydration by T. L. McMeekin and R. C. Warner 57 indicate that the molecular weight of the air-dried protein is 39,700, or 35,800 for anhydrous protein. Values for the wet crystal unit cell give a molecular weight of 61,000 or on a dry basis 33,000. Measurement of osmotic pressure also gives results uncomplicated by hydration or shape in solution. The measurements of H. B. Bull and B. T. Currie 58 give a value of 35,050 (with a standard deviation of the mean of 144), whilst H. Gutfreund 59 found 38,000 (with a standard error of 900). Some evidence for a slight increase in average molecular weight with ageing of the crystals was found by Bull and Currie who suggest that aggregation of a small number of molecules may occur. They quote in support of their value the results of W. Heller and H. B. Klevens who found 35,000 & 1,OOO from light-scattering data. Study of monolayers of the protein on ammonium sulphate solutions indicated that dissociation into two surface-active fragments with an average molecular weight of 17,000 occurs. I n the presence of Cut+, however, dissociation is suppressed or re-association occurs and the molecular weight becomes 34,300. That re-association occurs is suggested by a greater area of gaseous film per mg. of protein in the presence of Cu++. The measure- ments reported all lead to a molecular weight of about 35,000. Molecular weights calculated from analytical data (about 42,000) 359 21 and from ultra- centrifugal data (38,000--41,500) are considerably higher. Molecular weights from chemical data are unreliable unless the components of p-lactoglobulin are identical in composition and size, and differ only in, for example, the order in which amino-acid residues occur. End-group assays of sufficient accuracy would, if available, give an average molecular weight dependent on the number of molecules such as is given by osmotic pressure, film pressure, and X-ray data. Results from sedimentation

58 I ‘ Crystalline Enzymes,” New York, 1948, p. 73. 54 E. J. Cohn and J. T. Edsall, “Proteins, Amino Acids and Peptides,” New

5 5 Nature, 1938, 141, 521. 67 Ibid., p. 2393. 69 Nature, 1945, 155, 237.

York, 1943, p. 563. 66 J . Amer. Chem. Soc., 1942, 64, 2504. 58 Ibid., 1946, 88, 742.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

!I!RAC!EY : PROTEINS. 225

equilibrium and sedimentation rate in relation to diffusion would be expected to be higher since they are in the first case a weight average and in the second approach the weight average value. Denaturation of p-lacto- globulin in solution at pH 7 by heat has been studied by D. R. Briggs and R. There are two processes involved, the first of which begins a t 65" and results in an approximate quadrupling of particle size with little change in mobility. The second, which occurs only after the first, will proceed a t temperatures below 65" and results in further particle-size increase and increased mobility. Denaturation in the cold by urea (38%) has a negative temperature coefficient,61 being apparently reversed at 37".

Synthetic Polypeptides. The intensive study of polymerisation reactions, stimulated by the

development of new synthetic fibres and films, led in the period under review to a re-awakening of interest in the preparation of synthetic poly- peptides. The H. Leuchs 62 method in which N-carboxyanhydrides of amino-acids are polymerised in a moist atmosphere or in organic solvents containing a trace of water or other catalyst has been widely employed. Y. Go and H. Tani 63 prepared the N-carboxyanhydrides of glycine, alanine, and leucine; on exposure to moist air, or on heating in pyridine a t loo", polymers of high molecular weight were formed with loss of carbon dioxide. A copolymer of glycine and leucine was also prepared. None of the products was attacked by enzymes. R. B. Woodward and C. H. Schramm 64 using the same reaction prepared a copolymer of leucine and phenylalanine by polymerisation in benzene containing a trace of water. They estimated, by viscosity measurements, the molecular weight of the product, which was insoluble in water, to be between 106 and 15 x lo6. C. J. Brown, D. Coleman, and A. C. Farthing 65 prepared the polymer by the same method, and found a molecular weight of about 15,000 for their product by end- group essay. A polylysine, prepared from the N-carboxyanhydride of lysine, in which the c-amino-group was blocked by forming the carbo- benzyloxy-derivative, was one of the first of these polymers to be thoroughly investigated by chemical means (E. Katchalski, I. Grossfeld, and M. Frankel).66 A fraction of average chain length 32, as determined by estimation of free amino-nitrogen of the carbobenzyloxy-derivative, con- tained no free lysine, and gave a quantitative yield of lysine on hydrolysis. By the use of Sanger's l-fluoro-2 : 4-dinitrobenzene method it was shown to have the expected ratio of a- to c-amino-groups. It was readily soluble in water and appears to be the only polymer so far shown to be split by enzymes (glycerol extract of pancreatin, or crystalline trypsin). The

6o J . Amer. Chem. Soc., 1945, 67, 2007. 61 C. F. Jacobson and L. K. Cristensen, Nature, 1948,161, 30. 62 Ber., 1906, 39, 857.

64 J . Amer. Chem. Soc., 1947,69,1551. 6s Nature, 1949,163, 834.

Bull. Chem. SOC. Japan, 1939, 14, 510.

$6 J . Amer. Ckm. Soc., 1947, 89, 2564. REP.-VOL. XLVI. H

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

226 ORGANIC CHEMISTRY.

method has been subsequently used for the preparation of polymerised L-glutamic acid (y-carboxyl group shielded by methylation),67 glycine, sarcosine, DL-alanine, L-alanine, L-valine, m-leucine, L-leucine, D-leucine, DL-isoleucine, L-isoleucine, D -isoleucine, DL-norleucine, DL- a-phenylglycine, DL-phenylalanine, L-phenylalanine, L-tyrosine,68 and L-aspartic acid ( p- carboxyl group shielded by benzylation) .G9 Many copolymers have also been prepared, and difficulty in the application of the reaction to proline has been reported.68 An interesting difference in water solubility of the DL-alanine polymer and the L-alanine polymer, the former being soluble while the latter is insoluble, was noticed by Astbury et aZ.68

Another method of synthesis has been used by Frankeland I ia t~halsk i .~~ , 71

Heating the ethyl or other esters of glycine and alanine ( ‘1 DL) in organic solvents results in polymerisation with the release of the alcohol. Deter- minations of the average chain length indicated that products of 1 2 4 2 units for glycine (110 if the methyl ester was used) and 10-23 units for alanine were attainable. The alanine polymers were soluble in water whilst the glycine polymers were not.

This sudden wealth of synthetic polypeptides, many of which may be prepared in an orientated form, has naturally led to their examination by physical methods in the hope that they will throw light on protein structure. S. E. Darmon and G . B. B. M. Sutherland examined the infra-red spectrum of Woodward and Schramm’s polymer and found it to be very similar to that of denatured keratin in the region 1450 cm.11.72 Differences below this frequency are to be attributed to differences in residue and skeletal frequencies. The infra-red spectrum of polyglutamic acid was found 67

to be very similar to that of the remarkable natural polypeptide found in the capsule of BaciZEus anthracis. This material was shown by G. Ivanovics and V. Bruckner 73 to be largely composed of D-glutamic acid residues. W. E. Hanby and H. N. Rydon succeeded in isolating it in a relatively undegraded condition and concluded that it was composed entirely of a- linked chains of D-glutamic acid which were in turn joined by y-peptide links.74 The presence of these latter unusual links was confirmed by Hauro- witz and Bursa.38 This material therefore provides an, a t present unique, link between synthetic polypeptides and natural products for it seems feasible to construct from a-linked synthetic polyglutamic acid units of suitable chain length a closely analogous material.

A preliminary examination of a number of amino-acid polymers by X-ray and infra-red techniques was published by Astbury et aZ. in 1948 : 68

the majority of the compounds examined gave an X-ray pattern similar 67 W. E. Hanby, S. G . Waley, and J. Watson, Nature, 1948, 161, 132. 6 8 W. T. Astbury, C. E. Dalgliesh, S. E. Darmon, and G. B. B. M. Sutherland,

O9 31. Frankel and A. Berger, ibid., 1949, 163, 213. 70 Ibid., 1939, 144, 330.

72 Ibid., 1947, 69, 2074. 74 Biochem. J. , 1946,40, 297.

ibid., 162, 596.

J . Amer. Cibem. SOC., 1942, 64, 2264, 2268. 73 2. Immunats., 1938, 93, 119.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

TRACEY : PROTEINS. 227

to that of p-keratin ; D-leucine-DL-phenylahnine copolymer, however, gave a pattern resembling that of a-keratin as has been reported by Brown, Coleman, and Farthing.65 There are, however, differences in the pattern that have recently been re-emphasized by A s t b ~ r y . ~ ~ Attempts to convert the a-pattern into a p-pattern were unsuccessful. Infra-red study of the polymers showed that, as the confusion due to end groups normally found on examination of simple peptides was absent, characteristic frequencies could be assigned to individual residues. These enabled residues to be identified in copolymers, and even in a protein (glycine, alanine, and tyrosine in silk fibroin). At higher frequencies evidence for the existence of at least two distinct types of hydrogen bond in some polymers, such as are found in some proteins and in nylon, was secured. Brown, Coleman, and Farthing 65 on the basis of their observations on the leucine-phenylalanine copolymer were led to suggest that the polypeptide chains run across the fibre axis in both the synthetic products examined and the natural a-proteins. This suggestion has been strongly opposed by Astburg 75 on the grounds that their suggested backbone spacing of 5.2 A. is impossible, as it cannot exceed 4-77 9. Examination of the dichroism of frequency bands in the infra-red spectra of a- and p-keratin, myosin, and tropomyosin attributable to imino- groups in which hydrogen bonding occurs led E. J. Ambrose, A. Elliott, and R, B. Temple 76 to suggest an alternative structure for the a-fold in proteins to that proposed by A s t b ~ r y , ~ ~ This alternative structure involves a repeating unit of two residues in place of the three suggested by Astbury. It will be seen that in this structure all the imino-hydrogen bonds are of

R

one type and tend to be oriented in the direction of the chain. This orient- ation is suggested by the dichroism of the frequency bands. A s t b ~ r y , ~ ~ however, points out that such a structure would only give a strong meridional reflection of about 5.1 A., such as is found, if light and heavy side chains always alternated along the chain, a supposition for which there is no evidence. Furthermore, interpretation of the 100 yo extension of keratin and myosin is not easy on this model. Darmon and Sutherland point out that the proposed structure allows for only one type of hydrogen bond whereas there is evidence for the existence of a t least two or three types of NH . . . OC bonds in proteins, and that too great reliance on present inter- pretations of imino-bond dichroism is hazardous. 78 Support for the views

7 5 Nature, 1949, 164, 439. 7 7 Chem. and id., 1941,60,491.

? 8 Ibid., 163, 859. 7 * Nature, 1949, 164, 440.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online

228 ORGANIC CHEMISTRY.

of Ambrose and his co-workers has recently come from S. Mizushima, T. Simanouti, M. Tsuboi, T. Sugita, and E. Kato 79 who had arrived at similar conclusions independently. M. V. T.

R. E. BOWMAN. E. A. BRAUDE. A. W. JOHNSON. H. N. RYDON. M. V. TEACEY.

7O Nature, 1949, 164, 918.

Publ

ishe

d on

01

Janu

ary

1949

. Dow

nloa

ded

by U

nive

rsity

of

Mic

higa

n L

ibra

ry o

n 28

/10/

2014

15:

22:3

8.

View Article Online