Carbanions | — C:

–

| The conjugate bases of weak acids, strong bases, excellent nucleophiles.

1. Alpha-halogenation of ketones

O C C H + X 2 OH or H + O C C X  -haloketone + HX X 2 = Cl 2 , Br 2 , I 2 O H 3 C C CH 3 acetone + Br 2 , NaOH O C H 3 C CH 2 Br  -bromoacetone + NaBr

O + Cl 2 , H + cyclohexanone O Cl + HCl 2-chlorocyclohexanone O C CH 3 + Br 2 , NaOH acetophenone O C CH 2 Br + NaBr  -bromoacetophenone

Alpha-hydrogens: 1 o > 2 o > 3 o

O CH 3 CH 2 CH 2 CCH 3 + Br 2 , NaOH 2-pentanone O CH 3 CH 2 CH 2 CCH 2 Br + NaBr 1-bromo-2-pentanone Hydrogens that are alpha to a carbonyl group are weakly acidic: H 3 C O C CH 3 + OH O H 3 C C CH 2 + H 2 O

Hydrogens that are alpha to a carbonyl are weakly acidic due to resonance stabilization of the carbanion.

R O C CH 2 R O C CH 2 "enolate" anion The enolate anion is a strong base and a good nucleophile

Mechanism for base promoted alpha-bromination of acetone: 1) O H 3 C C CH 3 + OH RDS O H 3 C C CH 2 + H 2 O 2) O H 3 C C CH 2 + Br Br O H 3 C C CH 2 Br + Br Rate = k [acetone] [base]

2) Mechanism for acid catalyzed halogenation of ketones. Enolization.

1) H 3 C O C CH 3 + H + H 3 C OH C CH 3 + :B OH H 3 C C CH 3 OH H 3 C C CH 2 + H:B “enol” 3) H 3 C OH C CH 2 + Br Br OH H 3 C C CH 2 Br + :Br 4) OH H 3 C C CH 2 Br H 3 C O C CH 2 Br + H

Oxidation of "methyl" ketones. Iodoform test.

R O C CH 3

+ (xs) OI

R C O O

+ CHI 3 NaOH + I 2

R O C

CH 2 I

O R C OH

CI 3

good leaving group R O C

CHI 2

R O C

CI 3

+ OH

Carbanions.

The conjugate bases of weak acids; strong bases,

good nucleophiles

.

1. enolate anions 2. organometallic compounds 3. ylides 4. cyanide 5. acetylides

Aldehydes and ketones:

nucleophilic addition

O C + YZ OY C Z Esters and acid chlorides:

nucleophilic acyl substitution

C O W + Z Alkyl halides:

S N 2

C O Z + W R X + Z R Z + X

Carbanions as the nucleophiles in the above reactions.

2. Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones: a) aldol condensation “crossed” aldol condensation b) aldol related reactions (see problem 21.18 on page 811) c) addition of Grignard reagents d) Wittig reaction

Carbanions as the nucleophiles in nucleophilic addition to aldehydes and ketones: c)

addition of Grignard reagents

Grignard reagents are examples of organo metallic carbanions.

O C + RMgX OMgX C R

a) Aldol condensation.

The reaction of an aldehyde or ketone with dilute base or acid to form a

beta

-hydroxycarbonyl product.

CH

3

CH=O acetaldehyde

dil. NaOH

OH CH

3

CHCH

2

CH O 3-hydroxybutanal O CH

3

CCH

3

acetone OH O

dil. NaOH

CH

3

CCH

2

CCH

3

CH

3 4-hydroxy-4-methyl-2-pentanon

e

CH 3 CH=O acetaldehyde dil. NaOH O H CH 3 CH CH 2 CH O 3-hydroxybutanal OH CH 2 CH=O + CH 3 CH O + H 2 O O CH 3 CH CH 2 CH O + H 2 O nucleophilic addition by enolate ion.

O H 3 C C CH 3 OH dil. NaOH O H 3 C C CH 2 O H 3 C C CH 3 + H 2 O H 3 C O C O H CH 3 C H 2 C CH 3 + H 2 O H 3 C O C C H 2 O C CH 3 CH 3

CH

3

CH

2

CH=O + dil. NaOH

OH CH 3 CH 2 CHCH 2 CH 2 CH O CH 3 CHCH O alpha!

CH 3 CH 2 CH O O H CH 3 CH 2 CH CHCH O CH 3

O OH dil. OH O O H O O O + HOH O

O dil. H + O + H 2 O

With dilute acid the final product is the α,β unsaturated carbonyl compound

!

CH 2 CH O dil NaOH phenylacetaldehyde dilute H + O H CH 2 C H CH CH=O CH 2 C H C CH=O + H 2 O note: double bond is conjugated with the carbonyl group!

NB: An aldehyde without alpha-hydrogens undergoes the Cannizzaro reaction with conc. base.

CHO conc. NaOH benzaldehyde COO + CH 2 OH

Crossed aldol condensation:

If you react two aldehydes or ketones together in an aldol condensation, you will get four products. However, if one of the reactants doesn’t have any alpha hydrogens it can be condensed with another compound that does have alpha hydrogens to give only one organic product in a “crossed” aldol.

CH 3 CH 2 CH O + H 2 C O NaOH CH O CH 3 CH CH 2 OH

N.B. If the product of the aldol condensation under basic conditions is a “benzyl” alcohol, then it will spontaneously dehydrate to the α,β-unsaturated carbonyl

.

CH=O + CH 3 CH 2 CH 2 CH=O dil OH CH =CCH=O CH 2 CH 3 O H CH CHCH=O CH 2 CH 3 -H 2 O

A crossed aldol can also be done between an aldehyde and a ketone to yield one product. The enolate carbanion from the ketone adds to the more reactive aldehyde.

O C CH 3 acetophenone + CH 3 CH=O acetaldehyde dil OH O C CH 2 O H C H CH 3

b) Aldol related reactions :

of your textbook).

(see problem 21.18 page 811 CH=O + CH 3 NO 2 KOH CH=CHNO 2 + H 2 O CH=O + CH 2 NO 2 CH 2 C N NaOEt CHC N CH=C CN + H 2 O

Perkin condensation CH=O + (CH 3 CO) 2 O CH 3 COONa O H 2 C C O CH 3 C O OH CH CH 2 C O CH 3 C O O CH=CHCOOH + CH 3 COOH hydrolysis of anhydride H C C H CH 3 C O C O O + H 2 O

d) Wittig reaction (synthesis of alkenes)

1975 Nobel Prize in Chemistry to Georg Wittig R C O + Ph 3 P=C R' ylide O C R C R' PPh 3 R C C R' + Ph 3 PO CH 2 CH=CH 2 + Ph 3 PO CH 2 CH=O + Ph 3 P=CH 2 Ph = phenyl

Ph Ph R P Ph C R' ylide O C O C R C R' PPh 3 R C C R' + Ph 3 PO nuclephilic addition by ylide carbanion, followed by loss of Ph 3 PO (triphenylphosphine oxide)

O + Ph 3 PCHCH=CH 2 CHCH CH 2 + Ph 3 PO

3. Carbanions as the nucleophiles in nucleophilic acyl substitution of esters and acid chlorides.

a) Claisen condensation

a reaction of esters that have alpha-hydrogens in basic solution to condense into beta-keto esters

CH

3

COOEt ethyl acetate NaOEt O CH

3

CCH

2

COOEt ethyl acetoacetate + EtOH

Mechanism for the Claisen condensation: CH 3 COOEt NaOEt O CH 3 C CH 2 COOEt + EtOH OEt CH 2 COOEt CH 3 C O OEt CH 3 O C OEt CH 2 COOEt nucleophilic acyl substitution by enolate anion

ethyl propionate CH 3 CH 2 COOEt OEt OEt CH 3 CHCOOEt CH 3 CH 2 C O OEt ethyl 2-methyl-3-oxopentanoate O CH 3 CH 2 C CHCOOEt CH 3 O CH 3 CH 2 C OEt CHCOOEt CH 3

ethyl phenylacetate CH 2 COOEt OEt CHCOOEt NaOEt O CH 2 C OEt O CH 2 C CHCOOEt O CH 2 C OEt CHCOOEt

Crossed Claisen condensation:

COOEt + CH 3 COOEt ethyl benzoate NaOEt HCOOEt + CH 3 CH 2 COOEt ethyl formate OEt O C CH 2 O H C CHCOOEt CH 3 COOEt

COOEt + COOEt ethyl oxalate CH 3 CH 2 COOEt OC 2 H 5 COOEt COOEt + 2 CH 3 CH 2 COOEt NaOC 2 H 5 O C C O CH 3 CHCOOEt OEt O C C O CH 3 CHCOOEt CHCOOEt CH 3

O EtOCOEt ethyl carbonate + COOEt NaOEt CH 2 COOEt ethyl malonate EtO O C COOEt CH COOEt CH 3 CH 2 COOEt ethyl propionate + O NaOEt CH 3 CH 2 O C cyclohexanone enolate from ketone in nucleophilic acyl substitution on ester O

b) Coupling of lithium dialkyl cuprate with acid chloride

O R C Cl

+ R'

2

CuLi nucleophile = R'

R C O

R'

4. Carbanions as nucleophiles in S N 2 reactions with R’X: a) Corey-House synthesis of alkanes R 2 CuLi + R’X



R-R’ b) metal acetylide synthesis of alkynes RC



C M + + R’X



RC



CR’ c) Malonate synthesis of carboxylic acids d) Acetoacetate synthesis of ketones 5. Michael Addition to α,β-unsaturated carbonyl compounds

Carbanions are the conjugate bases of weak acids and are therefore strong bases and excellent nucleophiles that can react with aldehydes/ketones (nucleophilic addition), esters/acid chlorides (nucleophilic acyl substitution), and alkyl halides (S N 2), etc.

Reactions involving carbanions as nucleophiles: 1. Alpha-halogenation of ketones 2. Nucleophilic addition to aldehydes/ketones a) aldol and crossed aldol b) aldol related reactions c) Grignard synthesis of alcohols d) Wittig synthesis of alkenes 3. Nucleophilic acyl substitution with esters and acid chlorides a) Claisen and crossed Claisen b) R 2 CuLi + RCOCl (next slide)

4. S N 2 with alkyl halides a) Corey-House b) metal acetylide c) Malonate synthesis d) Acetoacetate synthesis 5. Michael Addition to α,β-unsaturated carbonyl compounds