substitution reactions of carboxylic acid derivatives
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Substitution Reactions of Carboxylic Acid Derivatives
Mechanism
LINK
R X
O
Nu-
AdditionR C
O-
X
Nu
Tetrahedral Intermediate
R Nu
OElimination
+ X-
Substitution at the sp2 hybridized carbonyl group employs a two-step addition-elimination sequence as shown above.
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).
R Cl
O
R Cl
H H H2O
R OH
H HVery Slow Reaction
R OR'
H H NaOH
R OH
H H+ HOR' No Reaction
Substitution at sp3 hybridized carbon
H2O
R OHFast Reaction
O
R OR'
NaOHR O- Na+
+ HOR'O
Alkyl Chloride
Ether
Acyl Chloride
Ester
Occurs at Room Temperature
O
Substitution at sp2 hybridized C=O
+ HCl
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
LINK
LINK
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.
R1 Cl
O
R2NH2
R1
O-
NH2+
Cl
R2
Tetrahedral Intermediate
R1 N+
O
H
R2
H
NEt3
R1 N
O
R2
H
Et3NH+ Cl-
+
Cl-
Addition Elimination
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
R OEt
O
-OH
R C OEt
O-
OH
Tetrahedral Intermediate
R O
O-OEtH
R O-
O
HOEt+
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.
R OR'
O
+ H2O
cat. H+
R OH
O
+ HOR'
The hydrolysis of an ester can also occur under acidic conditions.
Mechanism of Hydrolysis of Esters Under Acidic Conditions
R OEt
O
H+
R OEt
+OH
R OEt
OH+
OH
H
R OEt
OH
+OH2
R +OEt
OH
OHH
-H+, +H+
R OH
+OH - EtOH
R OH
O - H+
+ H2O
- H2O
+ EtOH+ H+
Enzyme-catalyzed
Ester to Acid
(cleavage of bonds other than the bonds to the carbonyl carbon)
R O
O
Me
MeMe F3C OH
O
Trifluoroacetic Acid(TFA, pKa = 0.3)
R O
O
H +
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
R O
O
Me
MeMe
H+
R O
O+
Me
MeMe
H
R O
O
Me
MeMe
H
+
R O
OH
Me CH2
Me
++
bond cleaved
Relatively stabletertiary carbocation
HE1
elimination
Me
Me
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.
R O
OH2C
Ph R O
O
HH3C
Ph+
H2,
cat. Pd
Notice cleavage of the benzyl ester, but not the methyl ester
Notice cleavage of the benzyl ester, but not the tert-butyl esters
R O
OH2C
R O
O
H +
Nu-H
cat. Pd0
Nu
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.
R O
OH2C
R O
O
H +
Zn
AcOHCl
ClCl
Cl
Cl
+ Zn+2
Trichloroethyl esters are cleaved by treatment with zinc, as shown below
R O
OH2C Cl
ClCl
Zn
O-
O Zn+2 Cl-
Cl
Cl
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).
R OH
O
+ EtOH
cat. p-TsOH
R OEt
O
+ H2O
The mechanism of acid-catalyzed esterification is shown below. This is simply the reverse of the acid-catalyzed hydrolysis of esters shown earlier.
R OH
O
H+
R OH
+OH
R OH
OH+
OH
Et
R OH
OH
+OEt
R OH2
OH
OEt
-H+, +H+
R OEt
+OH - H2O
R OEt
O - H+
+ H2O
H
+
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 step2) Other functionality in molecule may not be compatible with
thionyl chloride (SOCl2) reagent3) 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.
OH
O
R1
R2H
SOCl2Cl
O
R1
R2H
+ HCl + SO2
Cl
OH
R1
R2
Cl
O
R1
R2H
Cl
O
R1
HR2
+
Epimerization of -Carbon
Acid to Amide via Carbodiimide Coupling Reagents
R1 OH
OCyN C NCy
Dicyclohexylcarbodiimide(Cy = cyclohexyl)
+R1 O
O
NCy
NCy
Better Leaving Group
R2NH2
R1 NHR2
O
CyNH NHCy
O
Dicyclohexylurea(Thermodynamically stable byproduct)
+
H
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.
R1 OH
OCyN C NCy
Dicyclohexylcarbodiimide(Cy = cyclohexyl)
+R1 O
O
NCy
NCy
Better Leaving Group
R2NH2
R1 NHR2
O
CyNH NHCy
O
Dicyclohexylurea(Thermodynamically stable byproduct)
+
H
NN
N
OHR1 O
O
N
NN
More stable and less prone to racemization of R1
NN
N
OH
+
Hydroxybenzotriazole(HOBt)
The use of an additive, like hydroxybenzotriazole, can reduce racemization and still allow efficient coupling.
R1 OR2
O
Nu- +R1 Nu
O+ R2O-
Most active carboxylic acid derivativeshave the weakest bases as leaving groups(i.e. lowest pKa of conjugate acid, the alcohol)
EtOH
Alcohol pKa
OH
OHO2N
NN
N
OH
N OH
O
O
15.2
9.86
7.23
7.39
7.81 Increasing Reactivityof Corresponding Ester
1-Hydroxy-7-azabenzotriazole (HOAt) has the additional advantage of accelerating the reaction via an intramolecular assistance through the basic pyridine as shown below.
R1 OH
OCyN C NCy
Dicyclohexylcarbodiimide (DCC)(Cy = cyclohexyl)
+R2NH2
R1 NHR2
O
CyNH NHCy
O
Dicyclohexylurea(Difficult to Remove from Reaction)
+
Byproduct substituted urea can be difficult to remove from the reaction
N C N
Ethyl Dimethylaminopropylcarbodiimide (EDC)(sold has hydrochloride salt)
NMe2 R2NH2
R1 NHR2
O
EtNH NH
O
+NMe2
Aqueous HCl Wash
EtNH NH
O
NMe2
H
Cl-
Water-Soluble Byproduct Urea
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
Me2N P+
NMe2
BtO
NMe2 PF6-
R1 O-
OEt3NH+
R1 O
O
P+
NMe2
NMe2
NMe2
BtO-
R1 OBt
O
O P
NMe2
NMe2
NMe2+
R2NH2
R1 NHR2
O
NN
N
OH
+
BOP Reagent (Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate)
or pyBOP(Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)
HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
Amide to Acid
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
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