Substitution Reactions of Carboxylic Acid Derivatives

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Substitution Reactions of Carboxylic Acid
Derivatives
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Mechanism
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Substitution at the sp2 hybridized carbonyl group
employs a two-step addition-elimination sequence
as shown above.
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Relative to substitution at an sp3 hybridized
carbon, the two-step addition-elimination scheme
of the carboxylic acid derivatives is more
facile. i.e. it has a lower energy barrier,
due to the placement of the negative charge in
the intermediate on an atom of higher
electronegativity (oxygen).
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Nature frequently employs carboxylic acid
derivatives, since these bonds are relatively
easy to form and to cleave. Enzymes can catalyze
both processes.
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Mechanistic Features of Peptide Bond Formation in
the Ribosome
LINK LINK
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Mechanistic Features of Peptide Bond Hydrolysis
(in the active site of a peptidase enzyme)
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Triglyceride
Acetyl CoA
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Carboxylic Acid Derivatives
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Acid Chloride Amine ? Amide
Notice the inclusion of the tertiary amine (Et3N)
to neutralize the HCl side product.
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Mechanism of Acid Chloride Amine ? Amide
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Notice that the amine nitrogen is functioning as
a nucleophile, while the amide nitrogen is not
(due to the resonance stabilization of the amide
bond).
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Notice that the amine nitrogen is a stronger
nucleophile than is the hydroxy group (due to
higher basicity and nucleophilicity of nitrogen).
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Notice that the azide functionality (N3) is not
nucleophilic.
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Notice greater reactivity of acyl chloride
(RCOCl) than that of alkyl halide (RCH2X).
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Notice the use of pyridine in the example below
as both a mild nucleophile, but also as a
catalyst for the acylation process.
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Notice that the secondary amine is the
nucleophile, while the tertiary nitrogen remains
unreacted.
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4-Dimethylaminopyridine (DMAP), used in the
example below, is a particularly effective
catalyst of the acylation process.
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Acid Chloride Alcohol ? Ester
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Acid Chloride Hydride Source ? Primary Alcohol
Recall that nucleophilic hydride sources are
boron or aluminum-based, while NaH is used almost
exclusively as a base (not as a nucleophile)
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Notice the preferential reduction of the (more
reactive) acid chloride over the (unreactive,
under these conditions) ester functionalities.
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Acid Chloride (2 eq) Carbanion ? Tertiary
Alcohol
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Anhydride Amine ? Amide
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Formation of an Acid Chloride from a Carboxylic
Acid
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Ester To Acid
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Esters can be hydrolyzed by aqueous base
(saponification). The mechanism is shown below.
Note that the process involves formation of a
tetraehedral intermediate and consumes a
stoichiometric amount of base (since the product
carboxylic acid is itself acidic and will thus be
converted to its conjugate base under the basic
reaction conditions.
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The hydrolysis of an ester under basic conditions
is called saponification
Notice that the ester is hydrolytically cleaved,
but not the (unreactive) ether linkage.
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Notice that the ester linkage is cleaved, but not
the (less reactive) cyclic amide (lactam) linkage.
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Notice that the ester linkage is hydrolyzed, but
not the amide or the carbamate (RO-CO-NHR).
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Notice that the one ester linkage is cleaved by
hydroxide, but the four ether linkage are stable
toward base.
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The hydrolysis of an ester can also occur under
acidic conditions.
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Mechanism of Hydrolysis of Esters Under Acidic
Conditions
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Enzyme-catalyzed
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Ester to Acid (cleavage of bonds other than the
bonds to the carbonyl carbon)
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tert-Butyl esters (and also benzhydryl esters
RCO2CHPh2) are cleaved upon treatment with strong
acid, such as trifluoroacetic acid (TFA) shown
below.
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Mechanism for acid-catalyzed cleavage of
tert-Butyl esters
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Notice cleavage of the tert-butyl ester, but not
the benzyl ester
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Notice cleavage of the tert-butyl ester, but not
the methyl ester
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The selective cleavage of benzyl esters can be
achieved by hydrogenolysis, as shown below.
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Notice cleavage of the benzyl ester, but not the
methyl ester
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Notice cleavage of the benzyl ester, but not the
tert-butyl esters
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Allyl esters can be cleaved by treatment with a
catalytic amount of Pd0 and an appropriate
nucleophile (to intercept the intermediate
p-allyl palladium complex)
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Notice the selective cleavage of the allyl ester,
but not the tert-butyl ester, or either of the
two carbamates.
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Trichloroethyl esters are cleaved by treatment
with zinc, as shown below
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Mechanism of cleavage
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Notice the selective cleavage of the
trichloroethyl ester by zinc
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Ester to Amide
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Since esters are, in general, less reactive than
more activated carboxylic acid derivatives (like
acid chlorides or anhydrides), the reaction of
esters with amines, for example, requires higher
temperatures and longer reaction times.
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Notice that the amine nitrogen is the most
nucleophilic heteroatom.
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Some esters, such as the pentafluorophenyl ester
shown below, are more activated toward
nucleophiles (due to their more electronegative
nature) than are simple esters.
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Another common activated ester is the
p-nitrophenyl ester shown below. This ester has
a resonance stablized p-nitrophenolate anion as a
leaving group.
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Ester to Ester
The transformation of one ester into another can
be catalyzed by acid or base, as shown in the
examples below.
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10-CSA 10-camphorsulfonic acid
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Acid to Ester
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The esterification of a carboxylic acid using
excess of an alcohol and an acid-catalyst (such
as para-toluenesulfonic acid shown, is called the
Fischer esterification (also known as
Fischer-Speier esterification).
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The mechanism of acid-catalyzed esterification is
shown below. This is simply the reverse of the
acid-catalyzed hydrolysis of esters shown earlier.
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One method for driving the reaction toward
completion (in this equilibrium process) is to
remove the product water by azeotropic
distillation using a Dean-Stark apparatus shown
below.
The solvent is usually benzene or toluene, which
forms an azeotrope with water, which, upon
cooling, re-separates into two layers, water and
solvent, with the water being more dense and
sinking to the bottom of the trap as shown above.
Thus the upper solvent layer is allowed to flow
back into the reaction, while the lower layer of
the distillate is removed via a stopcock.
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Notice that, under the acidic conditions of the
Fischer esterification, that free amino groups
become protonated to their conjugate acids, and
thus do not function as nucleophiles in the
coupling procedure.
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Acid to Ester (Reactions that do not involve
attack on the carbonyl carbon)
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Acid to Amide (including the formation of
peptides)
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• Problems with conversion of the carboxylic acid
  to an acid chloride
• Requires extra step
• Other functionality in molecule may not be
  compatible with thionyl chloride (SOCl2) reagent
• In compounds where the a-carbon is stereogenic,
  this will likely lead to racemization due to
  enhanced formation of the enol form of the
  carbonyl.

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Acid to Amide via Carbodiimide Coupling Reagents
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However, the use of carbodiimides, by themselves,
can still lead to epimerization of the a-carbon,
as shown below.
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Additional Additives Can Reduce
Epimerization 1-Hydroxybenzotriazole (HOBt, 1)
and 1-Hydroxy-7-azabenzotriazole (HOAt, 2) are
common additives to the carbodiimide coupling
reactions. These reagents rapidly react with the
active intermediates, generating new
intermediates that less susceptible to
racemization.
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The use of an additive, like hydroxybenzotriazole,
can reduce racemization and still allow
efficient coupling.
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1-Hydroxy-7-azabenzotriazole (HOAt) has the
additional advantage of accelerating the reaction
via an intramolecular assistance through the
basic pyridine as shown below.
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Byproduct substituted urea can be difficult to
remove from the reaction
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The use of the amino-functionalized substituted
carbodiimide shown below can eliminate this
problem (however, EDC is much more costly than
DCC)
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Other Coupling Reagents
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BOP Reagent (Benzotriazol-1-yloxytris(dimethylami
no)phosphonium hexafluorophosphate) or
pyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphon
ium hexafluorophosphate)
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HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetra
methyluronium hexafluorophosphate
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Amide to Acid
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Enzymatic
Link
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Hydride Reduction of Esters
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Reaction of Carboxylic Acid Derivatives with
Organometallics
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Grignard Reagent Ester? Tertiary Alcohol
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Acid to Ketone
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Use of Weinrebs Amide Allows Synthesis of
Ketones from Acids
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Biological systems utilize anhydride-like linkage
to store energy