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 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 malonic acid will decarboxylate when heated. 5. Product is a carboxylic acid derived from acetic acid.

Malonate synthesis of 2-methylpentanoic acid Start with diethyl malonate and methyl bromide and n-propyl bromide.

Acetoacetate synthesis of ketones. 1.Ethyl acetoacetate has acidic alpha-hydrogens. 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.

Acetoacetate synthesis of 3-methyl-2-hexanone Start with ethyl acetoacetate and methyl bromide and n- propyl bromide.

Biological Synthesis of “Fatty” Acids. Enzyme = ‘fatty acid synthase” (multifunctional enzyme) Condensing Enzyme (CE) Acyl Carrier Protein (ACP)

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. step 5) malonyl CoA transfers malonate to the carrier enzyme. 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

2-oxazoline synthesis of butyric acid from acetic acid

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

organoborane synthesis of 4-methylpentanoic acid

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.

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

enamine synthesis of 2-allylcyclohexanone

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

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

enamine synthesis of aldehydes/ketones