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Carbanions II Carbanions as nucleophiles in S N 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

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

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  1. Carbanions II Carbanions as nucleophiles in SN2 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

  2. Malonate synthesis of carboxylic acids. • Diethyl malonate has acidic alpha-hydrogens • 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 SN2 reaction with a 1o or CH3 alkyl halide. • Upon hydrolysis, the substituted malonic acid will decarboxylate when heated. • 5. Product is a carboxylic acid derived from acetic acid.

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

  5. Acetoacetate synthesis of ketones. • Ethyl acetoacetate has acidic alpha-hydrogens. • When reacted with sodium metal, the ester is converted into its conjugate base (an enolate anion). • The enolate can be used as the nucleophile in an SN2 reaction with a 1o or CH3 alkyl halide. • Upon hydrolysis, the substituted acetoacetic acid will decarboxylate when heated. • Product is a ketone derived from acetone.

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

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

  8. 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.

  9. 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.

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