Chapter 6 Reactions of Carbonyl Compounds 羰基化合物的反应 6-1 Nucleophilic Addition...

Chapter 6 Reactions of Carbonyl Compounds

羰基化合物的反应

6-1 Nucleophilic Addition Reacitions 亲核加成反应

6-2 Nucleophilic Addition-Elimination Reactions 亲核加成消除反应

6-3 Condensation Reactions 缩合反应

6-4 The Nucleophilic Substitutions of Carbonyl Acid and Their Derivatives 羧酸及其衍生物的亲核取代

Key Terms Involved in This Chapter

carbonyl ( 羰基 ) aldehyde( 醛 ) ketone ( 酮 )nucleophilic( 亲核的 ) nucleophile ( 亲核试剂 )electrophilic ( 亲电的 ) electrophile( 亲电试剂 )carbanion （碳负离子）diastereomer （非对映体）

IntroductionSeveral functional groups contain the carbonyl group.

Structure of the Carbonyl GroupThe carbonyl carbon is sp2 hybridized and is trigonal planar. All three atoms attached to the carbonyl group lie in one plane.

..:+

-..

::-

+electrophilic at carbon

nucleophilicat oxygen

Nu:

nucleophiles attack here

H+ or E+

electrophiles add here

O

C

O

C

Nu: nucleophile 亲核试剂

The carbonyl group is polarized.There is substantial + charge on the carbon.

6-1 Nucleophilic Addition Reactions （亲核加成反应）

Carbonyl groups can undergo nucleophilic addition.The nucleophile adds to the + carbon.The electrons shift to the oxygen. The carbon becomes sp3 hybridized and therefore tetrahedral.

O

CC

O

Nu

C

O

Nu

C

O

Nu

H

+ :Nuslow

::..

:_

:..

:

+

:..

fast

_

..

H2O

or adding acid

A strong nucleophile attacks the carbonyl carbon, forming an alkoxide ion that is then protonated.

An alkoxide ion

MechanismsMechanisms in Basic or Neutral Solutionsin Basic or Neutral Solutions

An alcohol

Acid Catalyzed MechanismsAcid Catalyzed Mechanisms

Acid catalysis speeds the rate of addition of weak nucleophiles andweak bases (usually uncharged).

more reactive to addition than the un-protonated precursor

ACIDIC SOLUTION

+:Nu

slow:

..

O

C

H

C

O

Nu

H+

O

C

H:O

C+ H

+fast

+:..

..

pH 5-6 stronger acid protonates thenucleophile

Typical Nucleophilies

Nu-: -CN, CC-, RMgX, RLi, RZnBr,Witting Reagents, H-, -OH, RO-, HSO3

-,

Nu: H2O, ROH, RNH2, NH2OH, H2NNHR

+ CN_

R C R

O

R C R

O

CN

R C R

O

CN

+ R C R

O

CN

H

: : : :

: : :

..

..

_

_..

OH2

1. Cyanides act as nucleophiles toward C=O1. Cyanides act as nucleophiles toward C=O

Buffered to pH 6-8

In acid solution there would be little CN-, and HCN (g) would be a problem (poison).

a cyanohydrin

C OCH3

C O C O C OR

C O

H

H> >>>

H

CH3

CH3 CH3 CH3

Ar

(1) Reactivity of Aldehydes and Ketones

Aldehydes are generally more reactive than ketones in nucleophilic additions.

formaldehyde acetaldehyde acetone Methyl ketones

Electronic effects of alkyl groups

HCNK

K=530

CHO

CHO

Br

=210

RC O

H

RC O

H

¦Ä ¦Ä+ +

Nu - Nu -

Electron-donating groupmakes C=O less electrophilicless reactive

Electron-withdrawing group makes C=O more electrophilicmore reactive

(2) Factors affecting the nucleophilic addition

HCN:hydrocyanic acid

HCN

(CH3)3C

C O

C O >CH3

CH3CH2

(CH3)3C

K 1

K<< 1

Steric effect

C OR

R/(H)

Hybridization: sp2 sp3

The bond angle: 120° 109.5°

The crowding in the products is increased by the larger group

Watch out for the possibility of optical isomerism in hydroxynitriles

CN¯ attacks from above

CN¯ attacks from below

(3) Sterochemistry

Enantiomers

CN¯ attacksfrom below

CN¯ attacksfrom above

Enantiomers

Cram’s Rule

How does this center control the

direction of attack at the trigonal carbon?

C X* diastereomeric X = C, O, N

Chiralcenter

非对映体

RM

S

L

O

LRNu

OHMS

LNuR

OHMS

Nu:

Less steric

Major product

Nu:

Minor product

OMS

RL More steric

Perspective drawing

2. Grignard reagents act as nucleophiles toward C=O2. Grignard reagents act as nucleophiles toward C=O

Grignard reagents are prepared by the reaction of organic halides with magnesium turnings

Aldehydes and ketones react with Grignard reagents to yield different classes of alcohols depending on the starting carbonyl compound

Esters react with two molar equivalents of a Grignard reagent to yield a tertiary alcohol

The final product contains two identical groups at the alcohol carbon that are both derived from the Grignard reagent.

A ketone is formed by the first molar equivalent of Grignard reagent and this immediately reacts with a second equivalent to produce the alcohol.

Planning a Grignard SynthesisExample : Synthesis of 3-phenyl-3-pentanol

Restrictions on the Use of Grignard Reagents

Grignard reagents are very powerful nucleophiles and bases.They react as if they were carbanions.Grignard reagents cannot be made from halides which contain acidic groups or electrophilic sites elsewhere in the molecule.

The substrate for reaction with the Grignard reagent cannot contain any acidic hydrogen atoms.

Two equivalents of Grignard reagent could be used, so that the first equivalent is consumed by the acid-base reaction , while the second equivalent accomplishes carbon-carbon bond formation.

1 RMgX

2 H2O

+

minor

R major minorCH3 2.5 : 1C6H5 > 4 : 1(CH3)2CH 5 : 1(CH3)3C 49 : 1

R major minorCH3 2.5 : 1C6H5 > 4 : 1(CH3)2CH 5 : 1(CH3)3C 49 : 1

major

H

Ph

C2H5

R

HO H

H

Ph

C2H5

R

H OH

H

Ph

C2H5

H O

H

R

Ph

OH

C2H5H

H R

Ph

OHC2H5H

O

H

C2H5H

Ph

Sterochemistry-Cram’s rule

3. Organolithium act as nucleophiles toward C=OOrganolithium act as nucleophiles toward C=O

Organolithium reagents react with aldehydes and ketOrganolithium reagents react with aldehydes and ketones in the same way that Grignard reagents do.ones in the same way that Grignard reagents do.

4. Sodium alkynidesSodium alkynides act as nucleophiles toward act as nucleophiles toward C=O

NaNH2: sodium amide

propine Sodium alkynide

5. Reformatskii Reactions (Organozinc Addition to C=O )

CH3

+ CH3-CH-CO2C2H5+ Zn H3O+OH

C2H5CHCHO

C4H9(n)

Br

C2H5CHCH

C4H9(n)

-CH-CO2C2H5

C+ Br-C-CO2R(R)H

+ Zn

OZnBr

C-CO2RR

(R)H

H3O+

C

OH

C-CO2RR

(R)H

¦Á-bromoester

¦Â-hydroxyester

C=OR

BrZn-C-CO2R

Organozinc is not as reactive as Grignard reagent,Grignard reagent, so it will not reactive with estersso it will not reactive with esters

YlideYlideA compound or intermediate with both a positive and a negative charge on adjacent atoms.

X Y..- +

Betaine or ZwitterionBetaine or Zwitterion

A compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in different parts of the molecule.

X-

Y+

:

BOND

MOLECULE

内铵盐 两性离子

6. Wittig reaction (Ylides addition to C=O )Synthetic method for preparing alkenes.

(C(C66HH55))33PP CC++

AA

BB

••••––++

++CC CC

RR

R'R'

AA

BB

(C(C66HH55))33PP OO++

••••––••••

••••

CC OO

RR

R'R'

••••

••••

triphenyl phosphine oxide（三苯基氧膦）An alkene

+ (C6H5)3P+

R1 C

R2

X

H

(C6H5)3P C R2

R1

H

X_

(C6H5)3P C

R2

R1

Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide

strong base

:

O-CH3

-

P Ph

Ph

Ph..

Triphenylphosphine( Ph = C6H5 )

:....

( WITTIG REAGENT )

+ ..-

an ylide

benzene

phosphonium salt

ether

SN2 reaction

Substrates: 1°, 2°Alkyl halides

..

INSOLUBLE

very thermodynamicallystable molecule

ylide betaine

+ -

The Wittig ReactionThe Wittig ReactionMECHANISM

synthesis ofan alkene

+

:..

:_ +

C O

R1

R2

(C6H5)3P C

R4

R3

R2 C

R1

O

C R4

R3

P(C6H5)3

+C

R1

R2

C

R4

R3

O P(C6H5)3

:..

R2 C

R1

O

C R4

R3

P(C6H5)3

oxaphosphetane(UNSTABLE)

内磷盐

H

CH3

CH3

CH2CH3 CH3

CH3

O

H

CH2CH3Br

H

H

CH2CH3(C6H5)3P

H

:P(C6H5)3

+

H

CH2CH3(C6H5)3P

:

+

CH3ONa-ylide

CH3

CH3

O

SYNTHESIS OF AN ALKENE - WITTIG REACTIONSYNTHESIS OF AN ALKENE - WITTIG REACTION

ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS

C

H

Br

HO

CH2Br

:P(C6H5)3

C P(C6H5)3

H

HBr-

+

PhLi

..C P(C6H5)3

H

- +

ylide

: ..

+

+-

triphenylphosphineoxide (insoluble)

P(C6H5)3O

O

..

C

H

Georg F. K. Wittig received the Nobel Prize in Chemistry in 1979.Georg F. K. Wittig received the Nobel Prize in Chemistry in 1979.

CH P(C6H5)3+2 O CH CHO

Synthesis of β-Carotene （ β- 胡萝卜素）

Georg Wittig 1/2 of the prize

University of Heidelberg Heidelberg, Federal

Republic of Germany b. 1897d. 1987

German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry.

In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene-triphenylphosphorane, (C6H5)3P=CR2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR2) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D3

German chemist whose method of synthesizing olefins (alkenes) from carbonyl compounds is a reaction often termed the Wittig synthesis. For this achievement he shared the 1979 Nobel Prize for Chemistry.

In the Wittig reaction, he first demonstrated 1954, a carbonyl compound (aldehyde or ketone) reacts with an organic phosphorus compound, an alkylidene-triphenylphosphorane, (C6H5)3P=CR2, where R is a hydrogen atom or an organic radical. The alkylidene group (=CR2) of the reagent reacts with the oxygen atom of the carbonyl group to form a hydrocarbon with a double bond, an olefin (alkene). The reaction is widely used in organic synthesis, for example to make squalene (the synthetic precursor of cholesterol) and vitamin D3

7. Hydride Addition to C=O

Sources of hydride ("H-"), such as NaBH4, LiAlH4, all convert aldehydes and ketones to the corresponding alcohols by nucleophilic addition of hydride to C=O, followed or concurrently with protonation of the oxygen

R

O

H or R'

R

O

H or R'

"H "R

OH

H or R'

H

1)

2) H

LiAlH4, NaBH4, AlH3

"H " HOH orHORNaBH4, NADH (with dehydrogenase)

Ethyl ether

LiAlH4 H2O

+

75% 25%

C C

C2H5H

C6H5 CH3

OHH

C C

C2H5H

C6H5 CH3

OHH

C C

C2H5H

C6H5 CH3

O

20%20%

CHCH33HH33CC

OO

80%80%

OOHH

HH

CHCH33HH33CC

OOHH

HH

CHCH33HH33CCNaBHNaBH44

this methyl group hindersthis methyl group hindersapproach of nucleophileapproach of nucleophilefrom topfrom top

this methyl group hindersthis methyl group hindersapproach of nucleophileapproach of nucleophilefrom topfrom top

HH33B—HB—H––

preferred direction ofapproach is to less hindered(bottom) face of carbonyl group

preferred direction ofapproach is to less hindered(bottom) face of carbonyl group

Steric Hindrance to Approach of Reagent

Biological reductions are highly stereoselective

pyruvic acid S-(+)-lactic acid

OO

CHCH33CCOCCO22HHNADHNADH

HH++

enzyme is lactate dehydrogenaseenzyme is lactate dehydrogenase

COCO22HH

HOHO HH

CHCH33

One face of the One face of the substrate can bind to substrate can bind to the enzyme better the enzyme better than the other.than the other.

Change in geometry from trigonal to tetrahedral is stChange in geometry from trigonal to tetrahedral is stereoselective. Bond formation occurs preferentially ereoselective. Bond formation occurs preferentially from one side rather than the other.from one side rather than the other.

8. Hydration of C=O

hydrates or gem-diols

R

O

H or R' HOHR

OH

H or R'

OH

H or OH(catalyst)

H

O

H HOHH

OH

H

OH

H or OH(catalyst)

H3C

O

H HOH H3C

OH

H

OH

H or OH(catalyst)

(100%)

(58%)

steric hindrance in the product

R

O

H or R' HOHR

OH

H or R'

OH

H or OH(catalyst)

R = CH2X, CHX2, CX3 (X = F, Cl, Br); R = R' = CH2X

Very electrophilic C=O carbon because of nearby highly electronegative atoms

favorable

C=O + H-OH..

COHOH

HHCl3C Cl3C

Knock out drops

O

O

O + H2O

O

O

O

O

H

H

O

HOH

H or OH(catalyst)

OHHO

Hydrate formation relieves some ring strain by decreasing bond angles