Carbanions II Carbanions as nucleophiles in S 2 reactions with alkyl halides.

Transcript Carbanions II Carbanions as nucleophiles in S 2 reactions with alkyl halides.

Carbanions II Carbanions as nucleophiles in S N 2 reactions with alkyl halides.

a) Malonate synthesis of carboxylic acids b) Acetoacetate synthesis of ketones c) 2-oxazoline synthesis of esters/carboxylic acids d) Organoborane synthesis of acids/ketones e) Enamine synthesis of aldehydes/ketones

Malonate synthesis of carboxylic acids.

1. Diethyl malonate has acidic alpha-hydrogens CO 2 CH 2 CH 3 CH 2 CO 2 CH 2 CH 3 2. When reacted with sodium metal, the ester is converted into its conjugate base (an enolate anion) CO 2 CH 2 CH 3 CH 2 CO 2 CH 2 CH 3 Na CO 2 CH 2 CH 3 CH CO 2 CH 2 CH 3 + Na + + H 2

3. The enolate can be used as the nucleophile in an S N 2 reaction with a 1 o or CH 3 alkyl halide.

CO 2 Et CH + R-X CO 2 Et S N 2 R CO 2 Et CH CO 2 Et 4. Upon hydrolysis, the substituted malonic acid will decarboxylate when heated.

R CO 2 Et CH CO 2 Et H 2 O, H + heat R CO 2 H CH CO 2 H - CO 2 heat R CH 2 CO 2 H 5. Product is a carboxylic acid derived from acetic acid.

R O C OEt CH 2 C OEt Na O diethyl malonate O C C C O OEt OEt R'X Na O C CH OEt C O OEt Na RX R O C C C O OEt R' OEt H + ,H 2 O heat R O C CH C O OEt OEt H + ,H 2 O heat R O C O OH CH C OH heat -CO 2 R CH 2 COOH R O C C C O OH R' OH -CO 2 heat R CHCOOH R'

The malonate synthesis makes substituted acetic acids with one or two alkyl groups on the alpha carbon.

R CH 2 COOH R CHCOOH R' for example: synthesis of 4-methylpentanoic acid CH 3 CH 3 CHCH 2 CH 2 COOH start with diethyl malonate and isobutyl bromide

O C OEt CH 2 C OEt Na O diethyl malonate Na O C O OEt CH C OEt CH 3 CH 3 CHCH 2 Br CH 3 CH 3 CHCH 2 O C OEt CH C OEt O H + ,H 2 O heat CH 3 CH 3 CHCH 2 O C OH CH C OH O heat -CO 2 CH 3 CH 3 CHCH 2 CH 2 COOH

Malonate synthesis of 2-methylpentanoic acid CH 3 CH 3 CH 2 CH 2

CHCOOH

Start with diethyl malonate and methyl bromide and

-propyl bromide.

O C OEt CH 2 C OEt Na O diethyl malonate Na O C OEt CH C OEt O CH 3 Br H 3 C O C OEt CH C OEt O Na H 3 C O C OEt C C O OEt CH 3 CH 2 CH 2 Br CH 3 CH 3 CH 2 CH 2 CHCOOH -CO 2 heat H + ,H 2 O heat H 3 C O C C C O OEt CH 2 CH 2 CH 3 OEt

Acetoacetate synthesis of ketones.

1. Ethyl acetoacetate has acidic alpha-hydrogens.

CO 2 CH 2 CH 3 CH 2 COCH 3 O CH 3 CCH 2 CO 2 Et 2. When reacted with sodium metal, the ester is converted into its conjugate base (an enolate anion).

3. The enolate can be used as the nucleophile in an S N 2 reaction with a 1 o or CH 3 alkyl halide.

4. Upon hydrolysis, the substituted acetoacetic acid will decarboxylate when heated.

5. Product is a ketone derived from acetone.

R O C OEt Na CH 2 C CH 3 O ethyl acetoacetate Na O C C OEt C O CH 3 R'X O C CH OEt C O CH 3 Na RX R O C C C O OEt R' CH 3 H + ,H 2 O heat R O C OEt CH C CH 3 O H + ,H heat 2 O R O C CH OH C O CH 3 R O C OH C C O R' CH 3 -CO 2 heat R O heat -CO 2 CH 2 CCH 3 R O CHCCH3 R'

The acetoacetate synthesis makes substituted acetones with one or two alkyl groups on the alpha carbon.

R O CH 2 CCH 3 R O CHCH 2 CH 3 R' for example: synthesis of 5-methyl-2-hexanone CH 3 O CH 3 CHCH 2 CH 2 CCH 3 start with ethyl acetoacetate and isobutyl bromide

O C OEt CH 2 C CH 3 O Na ethyl acetoacetate Na O C CH OEt C O CH 3 CH 3 CH 3 CHCH 2 Br CH 3 CH 3 CHCH 2 O C CH OEt C O CH 3 H + ,H 2 O heat CH 3 CH 3 CHCH 2 O C CH OH C O CH 3 heat -CO 2 CH 3 O CH 3 CHCH 2 CH 2 CCH 3

Acetoacetate synthesis of 3-methyl-2-hexanone CH 3 CH 3 CH 2 CH 2

CHCCH

O

Start with ethyl acetoacetate and methyl bromide and

propyl bromide.

O C OEt CH 2 C CH 3 O Na Na ethyl acetoacetate O C CH OEt C O CH 3 CH 3 Br H 3 C O C OEt CH C CH 3 O Na H 3 C O C C OEt C O CH 3 CH 3 CH 2 CH 2 Br CH 3 CH 2 CH 2 CH 3 CHCCH 3 O -CO 2 heat H + ,H 2 O heat H 3 C O C C C O OEt CH 2 CH 2 CH 3 CH 3

Synthesis of 2,5-hexanedione O O CH 3 CCH 2 CH 2 CCH 3 O C OEt Na CH 2 C CH 3 O ethyl acetoacetate Na O C OEt CH C CH 3 O O CH 3 CCH 2 Br CH 3 O CCH 2 O C CH C O OEt CH 3 H + ,H heat 2 O O CH 3 CCH 2 O C CH OH C O CH 3 heat -CO 2 O O CH 3 CCH 2 CH 2 CCH 3

Synthesis of 2,4-pentanedione O O CH 3 C CH 2 CCH 3 O C OEt Na CH 2 C CH 3 O ethyl acetoacetate Na O C CH OEt C O CH 3 O H 3 C C Cl CH 3 O C O C CH C O OEt CH 3 H + ,H heat 2 O using the carbanion in a nucleophilic acyl substitution O CH 3 C O C CH OH C O CH 3 heat -CO 2 O O CH 3 C CH 2 CCH 3

Biological Synthesis of “Fatty” Acids.

Enzyme = ‘fatty acid synthase” (multifunctional enzyme) Condensing Enzyme (CE) Acyl Carrier Protein (ACP)

Coenzyme A N HS O O CH 3 CH 2 CH 2 NHCCH 2 CH 2 NHCCHCCH 2 O OH CH 3 O P O O O N P O O O H H O P O O O H H H NH 2 N N

Acetyl CoA CH

O C

Malonyl CoA O O O C CH

C

biological oxidation/reduction O C NH 2 -O -O -O HO P O P O O HO H P O O H H H O O O N H H OH O H N N + N NH 2 N nicotinamide adenine dinucleotide phosphate NADP+ H N H O C NH 2 NADPH NADPH is a biological reducing agent NADP+ is a biological oxidizing agent

ACP = acyl carrier protein CE = condensing enzyme 1 SH SH acetyl CoA malonyl CoA CO 2 2NADPH 2NADP + O S C CH 3 S C O CH 2 C O O 2 SH S O C O CH 2 C CH 3 3 SH S C O CH 2 CH 2 CH 3

CO 2 O S C CH 3 S C O CH 2 C O O ->enolate 2 SH S O C O CH 2 C CH 3 decarboxylation S O C CH 3 S C CH C O O OH nucleo.acyl

substitution SH S C O O HC C CO CH 3 2 H

SH S C O CH 2 CH 2 CH 3 4 O S C CH 2 CH 2 CH 3 SH malonyl CoA CO 2 5 O S C CH 2 CH 2 CH 3 S C O CH 2 C O O 6 -> enolate SH nucleophilic acyl substitution -CO 2 S C O CH 2 C O CH 2 CH 2 CH 3

2NADPH 2NADP + SH S C O CH 2 C O CH 2 CH 2 CH 3 7 malonyl CoA SH S C O CH 2 CH 2 CH 2 CH 2 CH 3 8 O S C CH 2 CH 2 CH 2 CH 2 CH 3 SH 9

Overall: step 1) malonyl CoA and acetyl CoA transfer the acetyl and malonate to the carrier enzyme (CE) and acyl carrier protein (ACP) respectively.

step 2) enolate carbanion from malonate (ACP) nucleophilic acyl substitution on the acetyl (CE) followed by decarboxylation.

step 3) reduction of the ketone to a hydrocarbon.

step 4) transfer of the carboxylate from CE ACP to CE.

enzyme.

step 5) malonyl CoA transfers malonate to the carrier step 6) enolate from malonate…etc.

Biological synthesis of fatty acids is analogous to the malonate synthesis of carboxylic acids. The enolate carbanion from malonate acts as a nucleophile in a nucleophilic substitution on the acetyl-CE followed by decarboxylation. Each series puts the three carbon malonate on the ACP and then decarboxylates the substitution product resulting in lengthening the carbon chain by two carbons at a time. Naturally occuring fatty acids are even numbered carboxylic acids.

Can we

directly

alkylate carbonyl compounds? Generally speaking, no!

Problems: 1) self-condensation 2) polyalkylation 3) in unsymmetric ketones, both sides or the wrong side!

Approach: place a group on the compound that prevents self condensation, directs the substitution where wanted and then is easily removed.

Three such approaches: 1) 2-oxazoline synthesis of acids/esters A. I. Meyers, Colorado State University 2) organoborane synthesis of acids/ketones H. C. Brown, Purdue University 3) enamine synthesis of aldehydes/ketones G. Stork, Colombia University

2-oxazoline synthesis of acids/esters R CH 2 O C OH + CH 3 H 2 N C CH 3 HO CH 2 2-amino-2-methyl-1-propanol N R CH 2 O 2-oxazoline R O CH C R' OEt EtOH H 2 SO 4 R CH R' N O + 2 H

-BuLi R'X R CH N O 2 O

2-oxazoline synthesis of butyric acid from acetic acid CH 3 C O OH + CH 3 H 2 N C CH 3 HO CH 2 CH 3 CH 2 CH 2 H 2 SO 4 H 2 O N O CH 3 N O + 2 H 2 O

-BuLi CH 3 CH 2 Br CH 2 N O CH 3 CH 2 CH 2 CO 2 H

Organoborane synthesis of acids/ketones R 3 B + BrCH 2 COCH 3 , base  bromoacetone R—CH 2 COCH 3 alkylacetone R 3 B + BrCH 2 CO 2 Et, base  ethyl bromoacetate R—CH 2 CO 2 Et ethyl alkylacetate

Mechanism for organoborane synthesis 1) :base + CH 2 BrCOCH 3 CHBrCOCH 3 + H:base 2) R 3 B + CHBrCOCH 3 R 3 BCHBrCH 2 OCH 3 3) 4) R R B R CHCOCH 3 Br R B R R CHCOCH 3 + Br R R 2 B CHCOCH 3 + H:base R CH 2 COCH 3 + R 2 B:base

R 3 B + RCH=CH B-H 9-borabicyclo[3.3.1]nonane 2 B CH 2 CH 2 R B-alkyl-9-borabicylo[3.3.1]nonane B H + B B O + BrCH 2 CCH 3 , base CH 3 CH 3 CHCH 2 O CH 2 CCH 3

organoborane synthesis of 4-methylpentanoic acid B H + CH 3 CH 3 C CH 2 B CH 3 CH 2 CHCH 3 BrCH 2 CO 2 Et base CH 3 CH 3 CHCH 2 CH 2 CO 2 H H 2 O, H +  CH 3 CH 3 CHCH 2 CH 2 CO 2 Et

Enamine synthesis of aldehydes and ketones 1) An aldehyde or ketone is reacted with a secondary amine to form an enamine.

2) The enamine reacts as the nucleophile in an S N 2 reaction with an alkyl halide to form an iminium salt.

3) The iminium salt is hydrolyzed with H 2 O, H + back to the carbonyl compound which has been alkylated at the alpha position.

C C O H + R' 2 NH C C H R' OH N R' C C N R' R' enamine C C N R' R' R X S N 2 C C N R' R R' X iminium ion H 2 O H + C C O R + R' 2 NH

The secondary amines commonly used to form the enamine are pyrrolidine or morpholine:

N H pyrrolidine O N H morpholine

enamine synthesis of 2-allylcyclohexanone O N H N ClCH 2 CH=CH 2 N Cl O CH 2 CH=CH 2 H 2 O,H +