The discussion of
acids, introduced the members of the carboxylic acid family;
carboxylic acids, esters, amides, anhydrides, and acyl halides. This
topic looks at the latter four members of this family, with an
emphasis on the formation of esters and amides.
Consider for a moment, the reactions outlined in Equations 1 and
In our discussion of nucleophilic
aliphatic substitution reactions we considered the experimental
evidence that led to the formulation of the
for reaction 1. Figure 1 reiterates that mechanism using iodide ion
as both the nucleophile and the leaving group.
At first glance it seems reasonable to assume that reaction 2
proceeds by this same mechanism. However, the experimental results of
the isotopic labeling study shown in Figure 2 show clearly that this
assumption is false.
If the reaction outlined in Figure 2 involved direct displacement
of a (protonated) OH group by an isotopically labeled water molecule,
then all of the label should end up in the acyl oxygen. Mass spectral
analysis indicates that half of the label ends up in the acyl oxygen,
while the other half is found in the carbonyl oxygen. This 50/50
distribution suggests that a symmetrical intermediate is involved in
this reaction. Scheme 1 indicates how such an intermediate might be
According to this scheme, the benzoic acid is activated toward
nucleophilic attack by protonation of the carbonyl oxygen. This
preliminary equilibrium generates oxonium ion A. In the second step, addition of a labeled
water molecule to the carbonyl carbon produces the tetrahedral intermediate B. A series of proton transfers, steps 3 and
4, scrambles the label between all three oxygen atoms. Note that
intermediates B, C, and D are
identical except for the isotopic label. Loss of a molecule of water,
step 5, produces an intermediate, resonance-stabilized, carbocation,
E, in which the two OH groups are
indistinguishable except for the label. In step 6, loss of a proton
from either OH group, followed by reformation of the C-O double bond
regenerates the benzoic acid. Since the probability of losing
Ha is identical to that of
losing Hb, the 18O
label is evenly distributed between the two oxygen atoms of the
equilibrated benzoic acid.
Exercise 2 How many valid
resonance structures are there for intermediate E?
When methyl benzoate is refluxed with a concentrated solution of
sodium hydroxide, the initially heterogeneous mixture slowly becomes
homogeneous. Work-up of the reaction mixture by acidification with
strong acid yields a white precipitate of benzoic acid in high yield.
Equation 3 illustrates the overall reaction, while Scheme 2 outlines
the sequence of transformations step-by-step.
The reaction begins with addition of a hydroxide ion to the
carbonyl carbon of the ester. This generates tetrahedral intermediate A. Regeneration of
the carbonyl group in Step 2 leads to the expulsion of either the OH
group that bonded to the carbonyl carbon originally (Step 2a) or to expulsion of the methoxy group
(Step 2b). The former event regenerates
the starting materials, while the latter produces a molecule of
benzoic acid, which, in the strongly basic solution is immediately
deprotonated (Step 3). The resulting
sodium benzoate, being ionic, is soluble in the aqueous solution.
However, protonation of the benzoate ion yields benzoic acid which is
much less soluble and which precipitates from the reaction mixture.
The mechanism outlined in Scheme 2 is quite general. Esters,
amides, acid halides, and anhydrides all undergo nucleophilic acyl
substitution reactions by this mechanism. Consider the reactions
shown in Equations 4-6.
In each case, the reaction begins with the addition of hydroxide
ion to the acyl group, which produces a tetrahedral intermediate.
Regeneration of the carbonyl group is accompanied by expulsion of the
leaving group, either chloride ion, amide ion, or benzoate ion. The
relative stabilities of these leaving groups determines the relative
rates at which the starting materials react. The relative stabilities
of the leaving groups is easily assessed by comparing the pKa values
of their conjugate acids, which, in the case of reactions 3-6 are
CH3OH (pKa=16), HCl (pKa = -7), NH3 (pKa = 38),
and C6H5CO2H (pKa = 5). This means
that chloride ion is the best leaving group, while amide ion is the
worst. In other words, acid halides are more reactive than
anhydrides, which are more reactive than esters, which are more
reactive than amides towards nucleophilic aliphatic substitution. We
can push the use of pKa values a bit further and say that acid
chlorides are approximately 1012 times as reactive as
anhydrides; anhydrides are around 1011 times more reactive
than esters; esters are about 1012 times as reactive as
amides. What this means is that running reaction 4 is a risky
proposition; the reaction would be extremely exothermic, perhaps even
causing the reactants to boil out of the flask. On the other hand,
you should expect reaction 5 to require an extended period of heating
before all of the benzamide reacts.
As mentioned earlier, acid halides and anhydrides are generally
not synthetic targets. Rather they are used to prepare esters and
amides. Equations 7-10 offer some typical examples.
In this reaction a buffer of acetic acid and sodium acetate keeps
the pH high enough to insure that the 4-aminophenol is not completely
protonated by the acetic acid that is formed as a side product. If
the buffer were omitted, the acetic acid generated in the reaction
could protonate unreacted 4-aminophenol, rendering it
The reaction of the diacid chloride, sebacoyl chloride, with the
diamine, hexmethylenediamine, results in nucleophilic acyl
substitution at both ends of both molecules. The product is the well
known polyamide nylon[6,6], where the symbol [6,6] indicates the
number of carbons in the diacid chloride and the diamine. Nylons with
different repeat units are easily prepared by variations on the
reaction shown in Equation 9.
In this reaction the NaOH acts as an acid
trap, neutralizing the HCl that is formed as a side product.
The product of the reaction, trimetozine, is sometimes used as a sedative.
Note that in all of these reactions the nucleophilic may be
described as ROH, RNH2, or R2NH. Whenever the
nucleophile is electrically neutral, the nucleophilic atom must have
an H attached to it in order for the substitution to be productive.
Ultimately that H ends up combined with the leaving group as HCl or
HOAc, etc. Thus, while ethers, ROR, and tertiary amines,
R3N, both contain nucleophilic atoms, they do not react in
a productive manner.
While it is possible to prepare esters from acid halides or
anhydrides, the more common approach involves the direct, acid
catalysed reaction of carboxylic acids with alcohols. A specific example is the esterification of
salicylic acid with methanol to produce methyl salicylate, one of the
major components in oil of wintergreen, as shown in Equation
Many esters are fragrant compounds. For example, isoamyl acetate,
which may be synthesized by the reaction of acetic acid with isoamyl
alcohol as outlined in Equation 12, smells like bananas. It is also a
component of the alarm pheromone of
An interesting question involving esterification reactions like 11
and 12 involves the identities of the oxygen atoms in the reactants
and products. In other words, does the OH group of the water come
from the alcohol or from the carboxylic acid? The experiment outlined
in Figure 3 provided the answer to this question.
Here the benzoic acid was mixed with isotopically labeled
methanol. If methanol acts as the nucleophile, displacing
(protonated) OH from the carbonyl group the first alternative should
be observed. If the acyl oxygen atom acts as a nucleophile,
displacing (protonated) OH from the methyl group, then the second
outcome should obtain. Analysis of the methyl benzoate and water
formed in the reaction revealed that all of the 18O was
present in the methyl benzoate and none of it was in the water.
Although they involve an acid catalyst, esterification reactions
like 11 and 12 are still nucleophilic acyl
substitution reactions. The mechanism
of acid catalysed esterification is similar to that outlined in
Scheme 2 except that the process begins with protonation of a
carbonyl oxygen atom. Scheme 3 summarizes the steps required to
transform the reactants to products.
Carboxylic acids are not the only kinds of acids that react with
alcohols to produce esters. Phosphoric acid and sulfonic acids behave
similarly to produce phosphate esters
and sulfonate esters. Figure 4 compares
the structures of these three types of acids.
Esterification is not limited to carboxylic acids. Alcohols react
with phosphoric acid to produce phosphate
esters, which are important components of nucleic acids. Adensosine monophospahte (AMP)
is an important phosphate ester in biological systems.
Sulfonate esters are useful intermediates in organic synthesis.
Figure 5 illustrates a key step in one of the first total syntheses
of (-)-taxol, a natural product that is used in the treatment of
ovarian cancer. The reaction involves an intramolecular
nucleophilic substitution in which a primary alcohol displaces a
sulfonate ester of p-toluenesulfonic acid. The tosylate group was
introduced into the molecule by esterification of an alcohol in an
earlier step in the synthesis.