Substitution Reactions of Carboxylic Acid
Derivatives
Mechanism
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Substitution at the sp2 hybridized carbonyl group employs a two-step additionelimination sequence as shown above.
Relative to substitution at an sp3 hybridized carbon, the two-step additionelimination 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).
Nature frequently employs carboxylic acid derivatives, since
these bonds are relatively easy to form and to cleave.
Enzymes can catalyze both processes.
Mechanistic Features of Peptide Bond Formation
in the Ribosome
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Mechanistic Features of Peptide Bond Hydrolysis
(in the active site of a peptidase enzyme)
Triglyceride
Acetyl CoA
Carboxylic Acid Derivatives
Acid Chloride + Amine → Amide
Notice the inclusion of the tertiary amine (Et3N) to neutralize the HCl side
product.
Mechanism of
Acid Chloride + Amine → Amide
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).
Notice that the amine nitrogen is a stronger nucleophile than is
the hydroxy group (due to higher basicity and nucleophilicity of
nitrogen).
Notice that the azide functionality (N3) is not nucleophilic.
Notice greater reactivity of acyl chloride (RCOCl) than
that of alkyl halide (RCH2X).
Notice the use of pyridine in the example below as both a mild nucleophile, but
also as a catalyst for the acylation process.
Notice that the secondary amine is the nucleophile, while the tertiary nitrogen
remains unreacted.
4-Dimethylaminopyridine (DMAP), used in the example below, is a particularly
effective catalyst of the acylation process.
Acid Chloride + Alcohol → Ester
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)
Notice the preferential reduction of the (more reactive) acid chloride over the
(unreactive, under these conditions) ester functionalities.
Acid Chloride + (2 eq) Carbanion →
Tertiary Alcohol
Anhydride + Amine → Amide
Formation of an Acid Chloride from a
Carboxylic Acid
Ester To Acid
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.
The hydrolysis of an ester under basic conditions is called
saponification
Notice that the ester is hydrolytically cleaved, but not the (unreactive) ether
linkage.
Notice that the ester linkage is cleaved, but not the (less reactive) cyclic
amide (lactam) linkage.
Notice that the ester linkage is hydrolyzed, but not the amide or the
carbamate (RO-CO-NHR’).
Notice that the one ester linkage is cleaved by hydroxide, but the four ether linkage
are stable toward base.
The hydrolysis of an ester can also occur under acidic
conditions.
Mechanism of Hydrolysis of Esters Under
Acidic Conditions
Enzyme-catalyzed
Ester to Acid
(cleavage of bonds other than the
bonds to the carbonyl carbon)
tert-Butyl esters (and also benzhydryl esters RCO2CHPh2) are cleaved upon
treatment with strong acid, such as trifluoroacetic acid (TFA) shown below.
Mechanism for acid-catalyzed
cleavage of tert-Butyl esters
Notice cleavage of the tert-butyl ester,
but not the benzyl ester
Notice cleavage of the tert-butyl ester,
but not the methyl ester
The selective cleavage of benzyl esters can be
achieved by hydrogenolysis, as shown below.
Notice cleavage of the benzyl ester,
but not the methyl ester
Notice cleavage of the benzyl ester,
but not the tert-butyl esters
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)
Notice the selective cleavage of the allyl ester, but not
the tert-butyl ester, or either of the two carbamates.
Trichloroethyl esters are cleaved by treatment with zinc,
as shown below
Mechanism of cleavage
Notice the selective cleavage of the trichloroethyl
ester by zinc
Ester to Amide
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.
Notice that the amine nitrogen is the most nucleophilic heteroatom.
Some esters, such as the pentafluorophenyl ester shown below, are more activated
toward nucleophiles (due to their more electronegative nature) than are simple
esters.
Another common activated ester is the p-nitrophenyl ester shown below.
This ester has a resonance stablized p-nitrophenolate anion as a leaving
group.
Ester to Ester
The transformation of one ester into another can be catalyzed
by acid or base, as shown in the examples below.
10-CSA = 10-camphorsulfonic acid =
Acid to Ester
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).
The mechanism of acid-catalyzed esterification is
shown below. This is simply the reverse of the acidcatalyzed hydrolysis of esters shown earlier.
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.
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.
Acid to Ester
(Reactions that do not involve attack on the carbonyl
carbon)
Acid to Amide
(including the formation of peptides)
Problems with conversion of the carboxylic acid to an acid
chloride:
1) Requires extra step
2) Other functionality in molecule may not be compatible with
thionyl chloride (SOCl2) reagent
3) 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.
Acid to Amide via Carbodiimide
Coupling Reagents
However, the use of carbodiimides, by themselves, can still lead
to epimerization of the a-carbon, as shown below.
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.
The use of an additive, like hydroxybenzotriazole, can
reduce racemization and still allow efficient coupling.
1-Hydroxy-7-azabenzotriazole (HOAt) has the additional advantage of accelerating the
reaction via an intramolecular assistance through the basic pyridine as shown below.
Byproduct substituted urea can be difficult to remove from
the reaction
The use of the amino-functionalized substituted carbodiimide
shown below can eliminate this problem (however, EDC is much
more costly than DCC)
Other Coupling Reagents
BOP Reagent
(Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate)
or pyBOP
(Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)
HATU
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
Amide to Acid
Enzymatic
Link
Hydride Reduction of Esters
Reaction of Carboxylic Acid
Derivatives with Organometallics
Grignard Reagent + Ester→ Tertiary Alcohol
Acid to Ketone
Use of Weinreb’s Amide Allows
Synthesis of Ketones from
Acids
Biological systems utilize anhydride-like
linkage to store energy