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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. - PowerPoint PPT Presentation
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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