Carbanions%20II

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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
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• 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)

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• 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.

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

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Acetoacetate synthesis of 3-methyl-2-hexanone
Start with ethyl acetoacetate and methyl bromide
and n-propyl bromide.
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Biological Synthesis of Fatty Acids. Enzyme
fatty acid synthase (multifunctional
enzyme) Condensing Enzyme (CE) Acyl Carrier
Protein (ACP)
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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 malonateetc.
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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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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.
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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
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2-oxazoline synthesis of acids/esters
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2-oxazoline synthesis of butyric acid from acetic
acid
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Organoborane synthesis of acids/ketones R3B
BrCH2COCH3, base ? RCH2COCH3
bromoacetone alkylacetone R3B
BrCH2CO2Et, base ? RCH2CO2Et ethyl
bromoacetate ethyl alkylacetate
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organoborane synthesis of 4-methylpentanoic acid
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• Enamine synthesis of aldehydes and ketones
• An aldehyde or ketone is reacted with a secondary
  amine to form an enamine.
• The enamine reacts as the nucleophile in an SN2
  reaction with an alkyl halide to form an iminium
  salt.
• The iminium salt is hydrolyzed with H2O, H back
  to the carbonyl compound which has been alkylated
  at the alpha position.

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The secondary amines commonly used to form the
enamine are pyrrolidine or morpholine
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enamine synthesis of 2-allylcyclohexanone
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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.
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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
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2-oxazoline synthesis of acids/esters
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Organoborane synthesis of acids/ketones R3B
BrCH2COCH3, base ? RCH2COCH3
bromoacetone alkylacetone R3B
BrCH2CO2Et, base ? RCH2CO2Et ethyl
bromoacetate ethyl alkylacetate
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enamine synthesis of aldehydes/ketones