8

CARBOXY

A lmost all of the basic types of reactions now have been covered: addition,
elimination, substitution, and rearrangement by polar, radical, and concerted
mechanisms. Indeed, if you have been looking for similarities, you will have
seen that most of the reactions discussed in the preceding three chapters are
variations on basic types we have discussed earlier. Furthermore, most of the
basic structural effects that determine chemical reactivity also have been
covered in previous chapters: bond energies, steric hindrance, electronega-
tivity, electron delocalization, hydrogen bonding, solvation, and conforma-
tional influences.
You might well ask what is left. The answer is, a great deal- but now
we will be concerned mostly with putting concepts together, moving from the
simple to the complex. For example, in this chapter we will be trying to under-

stand the ways that carboxylic acids, which possess the -c' functional
\
group, are similar to and different from alcohols, which have the OH group,
and aldehydes and ketones, which have C=O bonds.
Subsequently we will look at acids that also possess OH or NH, sub-
stituent groups (or both) and develop a rationale for the behavior of these
combinations in terms of effects we already have discussed. Insofar as pos-
sible, you should try to do this yourself whenever you encounter a substance
with a new set of combinations of functional groups on its molecules. You
often will be in error (as many experts will be), because even if you take
Carboxylic Acids and Their Derivatives 789

account of all of the structural effects, as well as the possible reactions or inter-
actions, the overall result of these frequently is very difficult to judge in
advance. In one case, steric hindrance may dominate, in another, electron
delocalization, and so on. Still, trying to assess the effects and possible reac-
tions leads to understanding and recognition of what the alternatives are, even
if the resultant of them is difficult to assess.l Continuing study can be expected
to develop an instinct for what is "good" chemistry and what is not.
We have described previously the acidic properties of several types of
compounds: alkynes, alkenes, and alkanes (Sections 11-8 and 13-5B); halides
(Section 14-7B); alcohols (Section 15-4A); and carbonyl compounds (Section
17-1A). Now we come to compounds that we actually call acids- the car-
boxylic acids, RC0,H. Are these acids different in kind, or only in degree, from
other acidic compounds discussed before? This is not a simple question and
deserves some thought. In the most widely used sense, acids are proton donors
but, as we have seen, their abilities to donate a proton to water vary over an
enormous range: CH, has a K, of < -
whereas HI has a K, of lo9.This
represents a difference in ionization energies of more than 70 kcal mole-l.
The differences in K , are only differences in degree, because examples are
available of acids with K , values in all parts of the range of K , values. An
important difference in kind was mentioned in Section 17-lB, namely, that
acids with the same K , values can differ greatly in the rates at which they give
up a proton to a given base, such as water. Carbon acids, in which the proton
comes from a C-H bond, may react more than 1010 times slower than an
oxygen acid with the same K , in which the proton is given up from an 0 - H
bond.
Tradition reserves the use of the name "acid" for substances that
transfer protons measurably to water. Thus the carboxylic acids stand out
from alkynes, halides, alcohols, and simple aldehydes and ketones in giving
water solutions that are "acidic" to indicator papers or pH meters as the result
of proton transfers from the carboxyl groups:

Even so, carboxylic acids are not very strong acids and, in a 1M water
solution, a typical carboxylic acid is converted to ions to the extent of only
about 0.5%.
The nomenclature of carboxylic acids and their derivatives was dis-
cussed in Section 7-6. Many carboxylic acids have trivial names and often
are referred to as "fatty acids." This term applies best to the naturally occurring
straight-chain saturated and unsaturated aliphatic acids, which, as esters, are
constituents of the fats, waxes, and oils of plants and animals. The most
abundant of these fatty acids are palmitic, stearic, oleic, and linoleic acids.

lThe major problem with assessing the resultant to be expected from opposing factors
in chemical reactions is that relatively small energy differences can cause great differ-
ences in which product is favored. For an equilibrium such as A t-l B at 25"C, a
5.5 kcal mole-I change in AGO (Section 4-4A) can cause the equilibrium to shift from
99% in favor of A to 99% in favor of B.
790 18 Carboxylic Acids and Their Derivatives

They occur as glycerides, which are esters of the trihydric alcohol, 1,2,3-pro-
panetriol (glycerol):
CH3 (CH2)14C02H hexadecanoic (palmitic) acid
cH3 (CH2)16CO2H octadecanoic (stearic) acid
CH3(CH,),CH=CH (CH,),CO,H cis-9-octadecenoic (oleic) acid
CH, (CH,),CH=CHCH,CH=CH (CH,) ,CO,H cis-9-cis-12-octadecadienoic
(linoleic) acid

Fats or glycerides belong to a class of biomolecules known as lipids. The

traditional definition of a lipid is a water-insoluble organic compound that can
be extracted from cells and tissues by nonpolar solvents (chloroform, ether,
benzene). Compounds that meet this definition are substantially hydrocarbon-
like, although they may differ widely in structure. They include not only esters
of long-chain fatty acids but steroids (Section 30-4), terpenes (Section 30-3),
and prostaglandins (Section 30-7). These nonpolar substances serve a variety
of different biological functions, but lipids derived from fatty acids are most
important for energy storage (Sections 18-8F and 20-10) and as components of
membranes. Phosphoglycerides represent an important class of membrane lipids
derived from glycerol. The hydroxyl groups of glycerol are esterified with two
fatty-acid chains and one phosphate-ester residue. One of the phosphate-ester
groups carries a highly polar -N(CH,),@ group, the importance of which is
indicated in Section 18-2F:

0
a typical membrane lipid
( I -palmitoyl-2-oleoylphosphatidylcholine) 0
(CH3),NCH2CH20-P=O
I

Hydrolysis of fats with alkali (e.g., sodium hydroxide) yields salts of the
fatty acids, and those of the alkali metals, such as sodium or potassium, are
useful as soaps:

1 7
CHOCR
LHoH
H@
+ ~ R c o ~ @ N ~---+
@ 3RC02H
soap fatty acid
I CH20H
I ,2,3-propanetriol
(glycerol)
18-1 Physical Properties of Carboxylic Acids 791

The properties of salts of long-chain carboxylic acids that make them useful
as soaps will be discussed in Section 18-2F.
General methods for the preparation of carboxylic acids are summarized
in Table 18-5, at the end of the chapter.

18-1 PHYSICAL PROPERTIES OF CARBOXYLIC ACIDS

18-1A Hydrogen Bonding

Carboxylic acids show a high degree of association through hydrogen bonding.
We have encountered such bonding previously with alcohols; however, acids
form stronger hydrogen bonds than alcohols because their 0 - H bonds are
83 6 0
more strongly polarized as -0-M. Furthermore, carboxylic acids are able
to form hydrogen bonds to the negative oxygen of the carbonyl dipole rather
than just to the oxygen of another hydroxyl group. Carboxylic acids in the solid
and liquid states mostly exist as cyclic dimers, and these dirneric structures
persist to some extent even in the vapor state and in dilute solution in hydro-
carbon solvents:

60
6@P'..H-o
R-C
\so
\ fPR

The physical properties of some representative carboxylic acids are

listed in Table 18-1. The substantially higher melting points and boiling points
of acids relative to alcohols, aldehydes, ketones, and chlorides can be attrib-
uted to the strength and degree of hydrogen bonding. These differences in
volatility are shown more strikingly in Figure 18-1, which is a plot of boiling
point versus n (the total number of carbon atoms) for the homologous series
CH,(CH,),-,X, in which X is -CO,H, -CH,OH, or -CH,Cl.
Hydrogen bonding also is responsible for the high water solubility of
the simple carboxylic acids with less than five carbons; water molecules can
solvate the carbonyl group through hydrogen bonds. Nonetheless, as the chain
length of the hydrocarbon residue R increases, the solubility decreases
markedly, because the proportion of polar to nonpolar groups becomes smaller.

O...H-O...H-0
solvation of a
// \ carboxylic acid
R-C C-R by water through
hydrogen bonding
Table 18-1
Physical Properties of Representative Carboxylic Acids

Solubility, mP, bp, K a (H20)

Acid Structure g/100 g H 2 0 "C "C at 25°C

methanoic (formic) CO

ethanoic (acetic) 00

propanoic (propionic) CO

butanoic (butyric) CO

2-methylpropanoic (isobutyric) 2OZ0

pentanoic (valeric) 3.3'6
hexadecanoic (palmitic) insol.
octadecanoic (stearic) 0.03425
chloroethanoic (chloroacetic) sol.
dichloroethanoic (dichloroacetic) 8.63
trichloroethanoic (trichloroacetic) I2oZ5
trifluoroethanoic (trifluoroacetic) CO

2-chlorobutanoic (a-chlorobutyric)(D,~) sol. hot

3-chlorobutanoic (6-chlorobutyric)(~,~)
4-chlorobutanoic (y-chlorobutyric)
5-chloropentanoic (6chlorovaleric)
methoxyethanoic (methoxyacetic) sol.
cyanoethanoic (cyanoacetic) sol.
3-butenoic (vinylacetic) sol.
benzenecarboxylic (benzoic) 0.2718
phenylethanoic (phenylacetic) 1.6620

"The term "strong" acid implies essentially complete dissociation to RC02@and H30B in aqueous solution.
18-1B Spectra of Carboxylic Acids

3 4 5 6 7 8
n, the total number of carbon atoms

Figure 18-1 Boiling points of acids, CH,(CH,),-,CO,H; alcohols,

CH3(CH,),-,CH,OH; and alkyl chlorides, CH3(CH,),-,CH,CI

18-1 B Spectra of Carboxylic Acids

'
The infrared spectra of carboxylic acids provide clear evidence for the hydro-
gen bonding disoussed in the preceding section. This is illustrated in Figure
18-2, which shows the spectrum of ethanoic acid in carbon tetrachloride solu-
tion, together with those of ethanol and ethanal for comparison.
The spectrum of ethanol has two absorption bands that are character-
istic of the O H bond; one is a sharp band at 3640 cm-l, which corresponds to
free or unassociated hydroxyl groups, and the other is a broad band centered
on 3350 cm-l due to hydrogen-bonded groups. The spectrum of ethanoic acid
shows no absorption from free hydroxyl groups but, like that of ethanol, has a
very broad intense absorption ascribed to associated OH groups. However,
the frequency of absorption, 3000 cm-l, is shifted appreciably from that of
ethanol and reflects stronger hydrogen bonding than in ethanol. The absorp-
tion due to the carbonyl group of ethanoic acid (1740 cm-l) is broad, but is at
about the same position as the carbonyl absorption in ethanal.
The carboxyl function does absorb ultraviolet radiation, but the wave-
lengths at which this occurs are appreciably shorter than for carbonyl com-
pounds such as aldehydes and ketones, and, in fact, are out of the range of
most commercial ultraviolet spectrometers. Some idea of how the hydroxyl
substituent modifies the absorption properties of the carbonyl group in car-
boxylic acids can be seen from Table 18-2, in which are listed the wavelengths
of maximum light absorption (A,) and the extinction coefficients at maximum
absorption (E,,,) of several carboxylic acids, aldehydes, and ketones.
In the nuclear magnetic resonance spectra of carboxylic acids, the car-
boxyl proton is seen to absorb at unusually low magnetic fields, This is illus-
trated in Figure 18-3 by the spectra of phenylethanoic acid (C,H,CH2C02H)
 18 Carboxylic Acids and Their Derivatives

and phenylmethanol (C,H,CH,OH). The chemical shift of the carboxylic

acid proton is here about 9 ppm toward lower magnetic fields than that of the
hydroxyl proton of the alcohol. This behavior parallels that of the en01
hydrogens of 1,3-dicarbonyl compounds and is similarly related to hydrogen-
bond formation (Section 17- 1D).

unassociated OH

trequency, cm-'

Figure 18-2 Infrared spectra of ethanol, ethanoic acid, and ethanal as

10% solutions in carbon tetrachloride
18-1B Spectra of Carboxylic Acids 795

-
Table 18-2
Wavelengths for Maximum Ultraviolet Absorption of Some Carboxylic Acids, Aldehydes,
and Ketones (n n*)

Xmax, Xmax,
Compound nm E, Solvent Compound nm emax Solvent

ethanoic acid 204 40 water 2-propanone 270 16 alcohol

ethanoic acid 197 60 hexane butanoic acid 207 74 water
ethanal 293 12 hexane butanal 290 18 hexane

Figure 18-3 Proton nmr spectra of (a) phenylethanoic acid and (b)
phenylmethanol in carbon tetrachloride solution at 60 MHz relative
to TMS
796 18 Carboxylic Acids and Their Derivatives

Exercise 18-1 Explain why the proton line position of the acidic hydrogen of a car-
boxylic acid, dissolved in a nonpolar solvent such as carbon tetrachloride, changes
much less with concentration than does that of the OH proton of an alcohol under the
same conditions (Section 9-1OE).

18-2 SOME CHEMICAL PROPERTIES OF

CARBOXYLIC ACIDS

Most of the reactions of carboxylic acids belong to one of four principal classes,
depending on the point in the molecule where the reaction occurs.

// Reactions involving the 0 - H bond-these include

a. R-C
\ f acid dissociation and solvolytic reactions.

80 Reactions at the carbonyl carbon-most of which

0
sop involve attack by a nucleophile :Nu on the car-
b. R-C bony1 carbon with subsequent cleavage of a C-0
bond. Examples are esterification, acyl chloride for-
mation, and reduction with hydrides.

i op Decarboxylation- these are reactions in which the

i / / i
c.R--!-c i R-C bond is broken in such a way that CO, is
Ii \ O /t H
lost and R-H is formed.

Substitution on the R group - substitutions for

d. R-C hydrogen or halogen at the 2-carbon are espe-
7 \
OH
cially important.

We will emphasize the way in which the chemistry of carboxylic acids

in each of these categories can be correlated with the principles outlined in
previous chapters.

18-2A Dissociation of Carboxylic Acids. The Resonance Effect

Compared with mineral acids such as hydrochloric, perchloric, nitric, and
sulfuric acids, the carboxylic acids, CH, (CH,) .CO,H, are weak. The extent of
18-2 Some Chemical Properties of Carboxylic Acids 997

dissociation in aqueous solution is relatively small, the acidity constants, K,,

being approximately 10-5 (see Table 18-1).

Even though the carboxylic acids are weak acids, they are many orders
of magnitude stronger than the corresponding alcohols, CH,(CH2),,CH20H.
Thus the K , of ethanoic acid, CH,C02H, is 1011 times larger than that of
ethanol, CH3CH20H.
The acidity of the carboxyl group arises, at least in part, from the polar
nature of the carbonyl group, the polarity of which can be ascribed to contribu-

tions of the structure

\o ..o
C - 9 . For a carboxyl group, these structures and an
/
/

additional possibility are shown by 1a , I b, and Ic:

Although the uncharged structure, 1a, is of major importance, structures 1 b

and I c make significant contributions. The stabilization is substantial and
carboxylic acids are more stable than would be expected, from summing up
their bond energies, by fully 18 kcal molem1.
The stabilization energy of the carboxylate anion is substantially greater
than that of the acid, because the anion is a resonance hybrid of two ener-
getically equivalent structures, 2a and 2b, whereas the acid is represented by
a hybrid of nonequivalent structures, I a through I c:

The rules for resonance stress that the greatest stabilization is expected when
the contributing structures are equivalent (Section 6-5B). Therefore we
can conclude that the resonance energy of a carboxylate anion should be
798 18 Carboxylic Acids and Their Derivatives

greater than that of the corresponding acid. Consequently we can say that there
is a "driving force" (a gain in stability) that promotes the dissociation of
carboxylic acids. The fact that alcohols are far weaker acids than carboxylic
acids may be attributed to the lack of stabilization of alkoxide ions compared
to that of carboxylate anions. The difference in energy corresponding to the
dissociation of a carboxylic acid (Equation 18-1) relative to that of an alcohol
(Equation 18-2) actually amounts to about 15 kcal molep1:

Exercise 18-2 Make atomic-orbital models of ethanoic acid and ethanol and of the
ethanoate anion and ethoxide anion. Show how these models can be used to explain
the greater acidity of ethanoic acid relative to ethanol.

Exercise 18-3 The K, for the first ionization of carbonic acid, O=C(OH), 4- H 2 0
f--L O=C(OH)Oe 4- H300, is about 1000 times smaller than K, for ethanoic acid.
Show how this fact can be rationalized by considering the expected relative stabiliza-
tion energies of carbonic acid and the hydrogen carbonate ion compared to those of
ethanoic acid and ethanoate anion.

18-2B The Inductive Effect and Acid Strengths

You may have noticed that there are considerable differences between the
strengths of some of the acids li'sted in Table 18-1. Methanoic acid and almost
all the substituted ethanoic acids are stronger than ethanoic acid. In fact,
trifluoroethanoic acid is similar in strength to hydrochloric acid. The sub-
stituent groups clearly can have a profound effect on acid strength by what
commonly is called the inductive effect, an effect related to the electronega-
tivity of the substituent. The inductive effect is different from resonance
effects discussed in Section 18-2A in that it is associated with substitution on
the saturated carbon atoms of the chain. The inductive effect of the substituent
makes the acid stronger or weaker (relative to the unsubstituted acid), depend-
ing on whether the substituent is electron-attracting or electron-donating
relative to hydrogen.
The electronegativity scale (Section 10-4B) shows chlorine to be more
electron-attracting than hydrogen, and chloroethanoic acid is an 80-times
18-2B The Inductive Effect and Acid Strengths 799

stronger acid than ethanoic acid itself. Substitution by more chlorines enhances
the acidity. Dichloroethanoic acid is 3000 times and trichloroethanoic acid is
5000 times more acidic than ethanoic acid. Moving the position of substitution
along the chain away from the carboxyl group makes the effect smaller, and
4-chlorobutanoic acid is only a two-times stronger acid than butanoic acid
(Table 18-1).
The inductive effect of the substituent can be considered to be trans-
mitted to the carboxyl group in two rather different ways. Most frequently,
the substituent is regarded as causing shifts in the average distributions of
the bonding electrons along the chain of atoms between it and the carboxyl
proton. This produces a succession of electron shifts along the chain, which,
for an electron-attracting substituent, increases the acid strength by making it
more energetically feasible for the -OH hydrogen of the carboxyl group to
leave as a proton:

Many other groups besides halogen exhibit electron-withdrawing acid-

enhancing inductive effects. Among these are nitro (-NO2), methoxy
\
(CH,O-), carbonyl ( C=O, as in aldehydes, ketones, acids, esters, and
/
0
amides), cyano or nitrile (-C=N), and trialkylammonium (R,N-). Alkyl
groups - methyl, ethyl, isopropyl, and so on - are the only substituents listed
in Table 18- 1 that are acid-weakening relative to hydrogen (as can be seen by
comparing the I ( , values of the longer-chain acids with those of methanoic
and ethanoic acids). We may take this to mean that alkyl groups release
electrons to the carboxyl group.

18-2C The Electrostatic Interpretation of Acid Strengths

The other possible mode of transmission of the polar effect of a substituent
group is a purely electrostatic one, sometimes called the "field effect," in which
the dipole of the substituent produces an electrostatic field at the carboxyl
proton, which helps or hinders ionization depending on the way in which the
dipole is oriented with respect to the carboxyl group. It is easiest to visualize
how the electrostatic theory operates by considering a proton midway between
two well-separated carboxylate anions and deciding with which one the proton
can combine more favorably. The more favorable one will correspond to the
more basic carboxylate anion and the weaker carboxylic acid. With CH,C02@
and ClCH2C0,@as examples, and remembering that the Cl-C bond is polar-
60 60
ized as Cl-C, we can write:
 18 Carboxylic Acids and Their Derivatives

The proton will be attracted by both -CO,@groups and the difference in

electrostatic energy of its combination with one or the other of the carboxylate
60 60 60
groups will depend on the influence of the Cl-CH, dipole. The C1 end of the
60
dipole will attract the proton, but the CH, end will repel it. The repulsion effect
60 60
will be more important because the CH, is closer than C1 to the final point of
attachment of the proton to the carboxylate oxygen., Thus, the proton will
go more favorably to CH,COZ0 than to CICH,COzO, which means that
CICH,COzH is a stronger acid than cH,CO,H.
Quantitative application of electrostatic theory to the effect of substituents
on the ionizations of carboxylic acids, such as chloroethanoic acid, is rendered
60 60
difficult by the fact that the polarized Cl-CH, bond and the proton cannot be
treated as if they were point charges in a vacuum. The intervening and surround-
ing matter must be taken into account. This is especially true for water solu-
tions because a molecule of an organic acid in water is a cavity of low dielectric
constant immersed in a medium of high dielectric constant. Therefore, when
ionization occurs the proton goes fronl inside the cavity through the boundary
into the water. At the same time, the riature of the cavity must change because
it then contains an anion, not a neutral molecule.

Exercise 18-4 Which acid in each of the following pairs would you expect to be
the stronger? Give your reasoning.
0
a. (CH3),NCH2C02H or (CH3),NCH2C02H

Exercise 18-5* Simple electrostatic considerations suggest that the acidities of

0
carboxylic acids of the type (CH,),N(CH,),CO,H should decrease much more slowly

T h e electrostatic energy involved in bringing two charges from a distance r, to a

distance I:, apart is given by (e,e,lD)(lI~;- llr,), where e, and e, are the magnitude
of the charges and D is the dielectric constant of the medium (Section 8-7F). If e, and
e, have the same sign, the energy is positive, and with opposite signs the energy is
negative. For calibration, the electrostatic energy resulting from bringing a positive
charge from a large distance (llr; - 0) up to a negative charge at a distance of 1 A in
a vacuum (D = 1) is -335 kcal mole-].
18-2D What Part Does Entropy Play in the Dissociation of Carboxylic Acids?

0 01
with increasing n than the acidities of acids of the type 0-N(CH2),C02H
I
CH3
Explain why this should be so.

Exercise 18-6" The chloro acid 3 is a stronger acid than the acid without the chlorine,
whereas the chloro acid 4 is a weaker acid than the corresponding acid with no
chlorine. Explain why this can be expected from simple electrostatic theory. (Models
may be helpful.)

Exercise 18-7* Fluoroethanoic acid is only about twice as acidic as chloroethanoic

acid, even though fluorine is much more electronegative than chlorine (Section
10-4B). The lengths of aliphatic C-F bonds are about 1.38 A, whereas those of C-CI
bonds are 1.78 A How could this difference in bond lengths tend to compensate for
the differences in electronegativity between chlorine and fluorine and make the
acids similar in strength?

18-2D What Part Does Entropy Play in the Dissociation

of Carboxylic Acids?
We have discussed the influence of substituents on acid strengths of simple
carboxylic acids as though the full electrostatic effect of the substituent were
exerted solely on the AH of ionization. However, careful thermodynamic
analysis of acidities in aqueous solution show that entropy effects (Section
4-4B) are very important. This may seem surprising because entropy effects
ought to be small for relative acid strengths, which can be assessed by the
constants for simple equilibria such as Equation 18-3, in which (1) there are the
same number of molecules on each side of the equation, and (2) the constraints
on the species involved hardly seem different from one side of the equation
to the other:

The entropy effects associated with these equilibria have to do with the
"invisible" participant, water, which is involved in an intimate way, although
 18 Carboxylic Acids and Their Derivatives

by convention we omit it from equations such as 18-3. Solvation of ions puts

constraints on water molecules, and the same electrostatic effects that change
the ease of removing the proton act to change the degree and nature of solva-
tion, thereby requiring consideration of entropy effects on the equilibria.
If solvation entropy effects are important, how can we justify using simple
electrostatic theory to account for changes in acid strengths produced by sub-
stituents? The answer lies in AG; whatever the electrostatic effects are doing to
the balance between AH and AS, it is AG that determines the equilibrium
constant and AG quite consistently follows the predictions of simple electro-
static considerations. Furthermore, the relative acid strengths of a number of
substituted ethanoic acids have been determined in the gas phase by ion-
cyclotron resonance (Section 27-8), under conditions where association and
solvent effects are absent (Section 11-8A). In the gas phase, entropy effects are
small and the relative acidities are in the order expected from the electro-
negativity scale, provided one corrects for the ion-size effect that we en-
countered previously with respect to the gas-phase acidities of alkynes and
alcohols (Section 11-8B and 15-4A). Thus fluoroethanoic acid is weaker than
chloroethanoic acid in the gas phase, whereas the reverse is true in water
solution. The difference may be due simply to the fact that larger ions are in
general more stable than smaller ions in the gas phase.

18-2E Carboxylic Acids as Bases

In addition to their acidic properties, carboxylic acids also can act as weak
bases when the carbonyl oxygen accepts a proton from a strong acid, such as
H2S04, HClO,, or HSbF, in SO, (Equation 18-4). Such protonation is an
important step in acid-catalyzed esterification, as discussed in Section 15-4D:

0 @OH
II II
R-C-OH + H2S04e R-C-OH + HSO,@ ( 18-4)

A proton also can add to the hydroxyl oxygen (Equation 18-5). The
resulting conjugate acid normally is less favorable than its isomer with the
proton on the carbonyl group. Nonetheless, this conjugate acid plays a role in
esterification when the R group is particularly bulky and, in addition, has
electron-donating properties, thereby favoring ionization to an acyl carbo-
cation (as in Equation 18-6; see also Section 18-3A):

0 0
I1 II O
R-C-OH + H2S04e R-C-OH2 + HSO,@
0 0
IIO I1
R-C-OH2 RCO + H20
acyl
carbocation
18-2F Salts of Carboxylic Acids as Soaps. Micelle Formation 803

Exercise 18-8 Explain why the equilibrium of Equation 18-5 is less favorable than
that of Equation 18-4.

18-2F Salts of Carboxylic Acids as Soaps. Micelle Formation

Carboxylic acids have an important practical use in the form of their metal salts
as soaps. We have mentioned how fats, which are 1,2,3-propanetriol (glyceryl)
esters of long-chain acids, can be hydrolyzed with alkali to give the correspond-
ing carboxylate salts. It has been known as far back as Roman times (Pliny)
that such substances have value for cleaning purpose^.^ These salts have a
complicated interaction with water because they are very polar at the salt end
of the molecule and very nonpolar at the long-chain hydrocarbon end of the
molecule. These hydrocarbon ends are not compatible with a polar solvent
such as water.4
When minute amounts of soaps are put into water, instead of forming
simple solutions, the molecules become concentrated at the surface of the
water, with the saltlike ends sticking down into the water and the hydrocarbon
chains forming a layer on the surface. This arrangement greatly reduces the
surface tension of the water and contributes to the startling properties of soap
films and bubbles. At higher concentrations, the solutions become turbid as
the result of micelle formation. Micelles are sizable aggregates of soap mol-
ecules, wherein the hydrocarbon chains form a region of low polarity that is
stabilized by having the polar salt ends of the molecules in contact with the
water (Figure 18-4).
The cleansing action of soap is partly due to the way soap lowers the
surface tension of the water thereby helping it to penetrate into fabrics, and
also to the ability of the micelles to solubilize oils and greases by taking them
into their hydrocarbon regions.
A major disadvantage of the simple carboxylate soaps is that they com-
bine with the calcium and magnesium ions normally present in most tap water
to form insoluble scums, which interfere with the cleansing process. Many so-
called detergents have been developed that do not have this disadvantage- an

3Until the 19th century soaps were made by boiling animal or vegetable fats with wood
ashes, which contain, besides silica, considerable amounts of potassium carbonate. The
resulting mixture of potassium carboxylate salts gives a "soft" soap, and this can be
converted to a "hard" soap by treatment with excess NaC1, which forms the less
soluble sodium carboxylate salts. The KC1 formed goes into the aqueous phase.
4 0 n e might well wonder why soap molecules do not simply crystallize out of water
solution if the hydrocarbon chains are incompatible with water. However, the crystal
packing of the polar salt parts of the molecule is not likely to be very compatible with
the hydrocarbon parts and, furthermore, most soaps are salts of mixtures of aliphatic
acids and this hardly helps crystallization to occur.
 18 Carboxylic Acids and Their Derivatives

Figure 18-4 Schematic diagram of a soap micelle in water solution

example is sodium 4-dodecanylbenzenesu1fonate, whose calcium and magne-

sium salts are water soluble.

SO3 N a

sodium 4-dodecanyl benzenesulfonate

When carboxylate salts are put into nonpolar solvents, reversed micelles
often are formed, where the polar parts of the molecules are on the inside and
the nonpolar parts are on the outside.
Pronounced differences have been observed for the rates of chemical reactions
in micelles as compared to pure water. For example, the solvolysis of the
I-methylheptyl sulfonate, 5, in dilute water solution proceeds 70 times slower
00
when sufficient sodium dodecanyl sulfate (NaOS03C,,H2,) is added to pro-
vide about twice as many dodecanyl sulfate ions in the micelle state as there
are molecules of 5 present:

HO-CH(CH,),CH~ + CH3CH=CH(CH2),CH3
80% 15% (cis and trans)
18-3 Reactions of the Carbonyl Carbon of Carboxylic Acids

polar heads-

nonpolar talls-

Figure 18-5 Schematic representation of (a) a membrane lipid, (b) a

bilayer structure formed by lipid molecules in polar media; the interior
of the bilayer is nonpolar, and (c) a continuous bilayer structure (lipo-
some) with polar interior and exterior

This slowing of the solvolysis reaction by the alkyl sulfate requires that 5 be
almost completely imprisoned by the micelles, because that part of 5 free in
water would hydrolyze rapidly. An important result is in the stereochemistry of
the reaction, which changes from 100% inversion with optically active 5 in
pure water to only 56% inversion in the micelles. Micelles of the opposite
0 0
polarity, made from hexadecyltrimethylammonium bromide, C,,H3,N (CH,) ,Br,
have no effect on the rate of solvolysis of 5.
Studies of this type have been made on a number of systems and are of great
interest because of the light they may shed on the structure and function of
biological membranes.
There is a close resemblance between fatty-acid salts and phospholipids
(p. 790) in that both possess long hydrocarbon tails and a polar head. Phospho-
lipids also aggregate in a polar medium to form micelles and continuous bilayer
structures such as shown in Figure 18-5. The bilayer lipid structure is very
important to the self-sealing function of membranes and their impermeability
to very polar molecules.

18-3 REACTIONS AT THE CARBONYL CARBON

OF CARBOXYLIC ACIDS

Many important reactions of carboxylic acids involve attack on the carbon of

the carbonyl group by nucleophilic species. These reactions frequently are
catalyzed by acids, because addition of a proton or formation of a hydrogen
$06 18 Carboxylic Acids and Their Derivatives

bond to the carbonyl oxygen makes the carbonyl carbon more vulnerable to
nucleophilic attack. The following equations illustrate how an acid-catalyzed
reaction operates with a neutral nucleophile (H-Nu:):

HNu
0
Subsequent cleavage of a C-O bond and loss of a proton yields a displacement
product:

An important example of this type of reaction is the formation of esters,

which was discussed previously in connection with the reactions of alcohols
in Section 15-4D. Similar addition-elimination mechanisms occur in many
reactions at the carbonyl groups of acid derivatives. A less obvious example
of addition to carboxyl groups involves hydride ion (PI:") and takes place in
lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E
and 18-3C).

(18 kcal mole-I, Section 18-2A) to calculate AH0 for the addition of water to ethanoic
acid to give 1, I ,I-trihydroxyethane. Compare the value you obtain with a calculated
AH0 for the hydration of ethanal in the vapor phase. Would you expect the rate, the
equilibrium constant, or both, for hydration of ethanoic acid in water solution to be
increased in the presence of a strong acid such as sulfuric acid? Explain.

18-3A Esterif ication

Esters, RC02R1,are formed from carboxylic acids and alcohols in the presence
of acid catalysts. The key step in esterification is the nucleophilic attack of a
neutral alcohol molecule, R'OH, at the carbonyl carbon of the conjugate acid
of the carboxylic acid, RC (OH),@, 6:
18-3A Esterification

The intermediate, 7, either can revert to the starting materials or form a second
intermediate, 8, by proton transfer. Loss of water from 8 leads to the conjugate
acid of the ester, 9:

The final step in formation of the ester is proton transfer from 9 to the solvent:

All the steps in ester formation are reversible, but the equilibrium in the C-O
bond-making and -breaking processes are not very favorable, and an excess of
one reactant (usually the alcohol) or removal of one product (most often water)
is required to give a good yield of ester.
The usefulness of direct ester formation from alcohols and acids is
limited to those alcohols or acids that do not undergo extensive side reactions
in the presence of strong acids. Furthermore, if the alcohol is particularly
bulky the reaction usually will not proceed satisfactorily because the inter-
mediates 7 and 8 (as well as the product) are rendered unstable by crowding
of the substituent groups.
Bulky groups in the esterifying acid also hinder the reaction. A classic
example is 2,4,6-trimethylbenzoic (mesitoic) acid, which cannot be esterified
readily under normal conditions because the methyl groups ortho to the
carboxyl group make the transition state for formation of the intermediate 10
less favorable relative to the starting acid than would be the case for less
hindered acids, such as ethanoic acid:

HQ ROH,
very slow CH3
\ --.,OH
CH, )
_*'
/
CH3 \ steric crowding
2,4,6-trimethyl benzoic 10
acid

The important point is the digerence in steric hindrance between the acid and
the intermediate. If you make a scale model you will see that in the acid, the
 18 Carboxylic Acids and Their Derivatives

carboxyl group, being planar, can have reduced hindrance by turning about its
bond to the ring so as to be between the methyl groups. However, no such
relief is possible with 10, in which the -C(OH),OR carbon is tetrahedral.
Esterification of acids with bulky substituents, such as 2,4,6-trimethyl-
benzoic acid, can be achieved through formation of acyl cations. This is done
by simply dissolving the carboxylic acid in strong sulfuric acid, whereby the
acyl cation 11 is formed, and then pouring the solution into an excess of cold
alcohol (see also Equations 18-5 and 18-6). This procedure works because it
avoids the formation of a hindered tetrahedral intermediate similar to 10 and
instead forms the conjugate acid directly:

I/ H@ 1 0
R-C-OH d R-C-OH2

3
0
R-C=O - R'OH 11
R-C-OR'
H
0
-
-H@
RC02R1

Esterification of carboxylic acids with bulky alcohols is unsatisfactory.

However, tertiary alkyl esters often can be prepared by addition of the acid
to the appropriate alkene using an acid catalyst:

-
I/ HCl II
R-C-OH + (CH3)2C=CH2 R-C-OC(CH3)3

The success of such addition reactions depends on formation of a stable

carbocation from the alkene under conditions where the most reactive nucleo-
phile present is the carboxylic acid.

Exercise 18-10 Predict the outcome of an attempted esterification of ethanoic acid

with tert-butyl alcohol in the presence of dry HCI.

Exercise 18-11 What would you expect to happen to the 180 label in a mixture of
ethanoic acid, hydrochloric acid, and H,180? Explain.

Exercise 18-12 Benzoic acid is not esterified by the procedure that is useful for
2,4,6-trimethylbenzoic acid because, when benzoic acid is dissolved in sulfuric acid,
it gives the conjugate acid and no acyl cation. Explain why the acyl cation, 11, of
2,4,6-trimethylbenzoic acid might be more stable, relative to the conjugate acid of
2,4,6-trimethylbenzoic acid, than C,H,COB is, relative to the conjugate acid of benzoic
acid. (Among other factors, consider the geometries of the various species involved.)
18-3B Acyl Chloride Formation

18-3B Acyl Chloride Formation

Carboxylic acids react with phosphorus trichloride, phosphorus pentachloride,
or thionyl chloride with replacement of OH by C1 to form acyl chlorides,
RCOC1:

(CH3)2CHCH2C,
i' SOC, >
(CH3),CHCH2C, + SO2-I- HCI
\
OH
3-methyl butanoic acid 3-methyl butanoyl chloride

Although detailed mechanisms have not been established, the first step
is thought to be formation of an unstable mixed anhydride, which then extrudes
SO, and "collapses" with attack of chloride at the carbonyl carbon. A similar
mechanism occurs in the formation of alkyl chlorides from alcohols and thionyl
chloride (Section 15-5A):

mixed anhydride of carboxylic

and chlorosulfinic acids

Most acyl halides are stable, distillable liquids. However, methanoyl

chloride, HCOC1, decomposes to carbon monoxide and hydrogen chloride
at room temperature.

18-3C Reduction of Carboxylic Acids

Generally, carboxylic acids are difficult to reduce either by catalytic hydroge-
nation or by sodium and alcohol. Nonetheless, reduction to primary alcohols
proceeds smoothly with lithium aluminum hydride, LiAlH,:

CH,=CHCH,CO,H LiA1H4: > CH,=CHCH,CH,OH

3-butenoic acid 3-butenol
(vinylacetic acid)
810 18 Carboxylic Acids and Their Derivatives

The first step in lithium aluminum hydride reduction of carboxylic acids

is formation of a complex aluminum salt of the acid and hydrogen:

R-C + LiAlH, --+ R-C + Hz

\
OH
\OA1H3
o Li
0

Reduction then proceeds by successive transfers of hydride ion, H:@,from

aluminum to carbon. The first such transfer reduces the acid salt to the oxida-
tion level of the aldehyde; reduction does not stop at this point, however, but
continues rapidly to the alcohol. Insufficient information is available to permit
very specific structures to be written for the intermediates in the lithium
aluminum hydride reduction of carboxylic acids. However, the product is a
complex aluminum alkoxide, from which the alcohol is freed by hydrolysis:

Sodium borohydride, NaBH,, is too mild a reducing agent to transfer

hydride to carboxylic acids, and one may suspect that borane, BH,, also would
be ineffective. However, this is not the case and borane in oxacyclopentane
(tetrahydrofuran) reduces carboxylic acids more rapid:y than it adds to alkene
double bonds (see Table 16-5):

The reason for the high reactivity lies in the fact that the acid first converts
the borane to an acyloxyborane, which then undergoes an intramolecular
rearrangement in which the carbonyl group is reduced. Hydrolysis gives
the alcohol:

II II
R-C-OH + BH3 -H2 >
R-C-OBH2

Special methods are required for the direct reduction of R C 0 2 H to

RCHO. Aldehydes can be obtained directly by the slow reduction of car-
boxylic acids with 2,3-dimethyl-2-butylboranein oxacyclopentane solution.
18-3C Reduction of Carboxylic Acids 811

One hydrogen of the borane is wasted through reaction with the acidic hydro-
gen of the carboxyl group to give hydrogen. An example is

The borane is prepared through the addition of B2H6to 2,3-dimethyl-2-butene

and, because of steric hindrance, only the monoalkylborane is formed (Sec-
tion 11-6A):

18-4 DECARBOXYLATION OF CARBOXYLIC ACIDS

The decarboxylation of RC02H to give RH and C 0 2 can be calculated from

bond energies and the stabilization energy of the carboxyl group to have
AN0 = -7 kcal molev1. This does not mean that the reaction goes easily.
Special structural features are required. The simple aliphatic carboxylic acids
do not lose carbon dioxide on heating, but when there are strongly electron-
attracting groups attached to the a carbon, decarboxylation often proceeds
readily at 100- 150". Examples include

NO2 C - C - O H C13C-C02H 02NCH2C02H

0
I1
CH3-C-CH2-C02H NC-CH2-C02H
NO2
3-Butenoic acid also undergoes decarboxylation but has to be heated
to above 200":
842 18 Carboxylic Acids and Their Derivatives

The mechanisms of thermal decarboxylation probably are not the same

for all cases, but when the acid has a double-bonded function such as O=C,
N=C, O=N, or C=C attached to the a carbon then a cyclic elimination
process appears to occur. For propanedioic acid the process is

enol form of
ethanoic acid

Exercise 18-13 Predict the product of decarboxylation of 2-methyl-3-butenoic acid.

Exercise 18-14 Explain why decarboxylation of 2,2-dimethyl-3-oxobutanoic acid,

CH,COC(CH,),CO,H, in the presence of bromine gives 3-methyl-3-bromo-2-butanone,
CH,COC(CH,),Br.

Stepwise decarboxylation also occurs, particularly in reactions in which

the carboxylate radical (RCO,.) is formed. This radical usually decomposes
to a hydrocarbon radical (R.) and CO,. The overall decarboxylation product
is determined by what R. reacts with: If a good hydrogen donor is present,

RCO,. -
RI-I is formed; if a halogen donor such as Br, is present, RBr is formed:

+ CO,
Re

R. + Br, -
Re + R'H ----+ RH + R'.
RBr + Br.

Exercise 18-15 What information would you need to calculate AH0 for the reaction
CH3C0,- ---+ CO, +
.CH3?

Carboxylate radicals can be generated in several ways. One is the

thermal decomposition of diacyl peroxides, which are compounds with rather
weak 0-0 bonds:
18-4 Decarboxylation of Carboxylic Acids

Another method involves electrolysis of sodium or potassium carboxylate

solutions, known as Kolbe electrolysis, in which carboxylate radicals are
formed by transfer of an electron from the carboxylate ion to the anode.
Decarboxylation may occur simultaneously with, or subsequent to, the forma-
tion of carboxylate radicals, leading to hydrocarbon radicals, which subse-
quently dimerize:

eQ
RCO,@

+ H,O
-- +
RCO,. eQ
0
OH #I,
+ anode reaction

cathode reaction

Re + Re

An example is
-
RCO,. --+ Re + CO,
RR

0 -2eQ
2CH302C(CH,) &O2 2 C 0 , > CH302C(CH,) ,,C02CH3 70%

Exercise 18-16 Why does Kolbe electrolysis not give RH by the reaction

-CO H0
RCO,. A R. 4 RH?

Exercise 18-17* At higher voltages than normally used in the Kolbe electrolysis,
salts of carboxylic acids in hydroxylic solvents produce (at the anode) alcohols and
esters of the type ROH and RC0,R. Explain how this can occur.

Decarboxylation of the silver salts of carboxylic acids in the presence

of bromine or chlorine, the Wunsdiecker reaction, often is useful for the syn-
thesis of alkyl halides:

C6H5CH2Co2Ag Br, + , .,
> C,H,CH,Br + CO, + AgBr
silver salt of phenylmethyl
phenylethanoic acid bromide

The mechanism of this reaction seems to involve formation of carboxylate

radicals through decomposition of an acyl hypobromite intermediate, 12:

RCO,Ag + Br, -AgBr

> R-C
/P -+ R-C
/O
+ Br.
\ \
OBr 0-

RBr + CO, +- R. + CO, 4- Br.

 18 Carboxylic Acids and Their Derivatives

The Hunsdiecker reaction has certain disadvantages, mainly because it requires

use of the pure dry silver salt, which is often difficult to prepare. With some
acids, however, excellent results can be obtained using the acid itself and an
excess of red mercuric oxide in place of the silver salt,

kco2' +

cyclopropanecarboxyl ic
Br2
Hgo (red) > b
CCl,, 76"
B
cyclopropyl
r + CO, + HBr
acid bromide

or by heating the acid with lead tetraethanoate, Pb(O,CCH,),, and iodine,

A somewhat similar decarboxylation reaction with formation of an alkene

can be achieved by heating a carboxylic acid with lead tetraethanoate,
Pb(O,CCH,),, in the presence of a catalytic amount of Cu(OCH,),. A useful
example is

There is some competing decarboxylation of the ethanoic acid, but the conver-
sions in this kind of reaction are usually good. The key steps in the reaction

-
probably are exchange of carboxylic acid groups on tetravalent lead, cleavage
of the Pb-0 bond to give the carboxylate radical, decarboxylation, oxidation
of the alkyl radical by Cu(11) to give the cation [Re Cu(I1)+ R @ +Cu(I)],
and finally loss of a proton to form the alkene.

Exercise 18-18* Write a sequence of mechanistic steps that embody the sug-
gestions given for conversion of H02C(CH2),C02H to CH2=CH(CH2),C02H with
Pb(02CCH3), and Cu(OCH3), as a catalyst. Complete the steps necessary to give all
of the products and regenerate the catalyst. The role of Cu(ll) in the oxidation of
radicals is discussed briefly in Section 23-106.

18-5 REACTIONS AT THE ALPHA CARBONS

OF CARBOXYLIC ACIDS

18-5A Halogenation
Bromine reacts smoothly with carboxylic acids in the presence of small
18-5 Reactions at the Alpha Carbons of Carboxylic Acids

quantities of phosphorus to form alpha-bromocarboxylic acids (Hell-Volhard-

Zelinsky reaction):

P
CII,CH,COOH + Br, -+ CH,CHBrCOOH + HBr
2-bromopropanoic acid

The reaction is slow in the absence of phosphorus, whose function appears to

be to form phosphorus tribromide, which then reacts with the acid to give the
acyl bromide :

2P + 3Br2-+ 2PBr,
CH,CH,CO,H + PBr, -+ CH,CH,COBr + POBr + HBr
Formation of the acyl bromide speeds up the reaction because acid-catalyzed
enolization of the acyl bromide occurs much more readily than enolization of
the parent acid. Bromine probably reacts with the en01 of the acyl bromide in
the same way as it reacts with the enols of ketones (Section 17-2A).
The final step is the formation of the a-bromo acid by bromine exchange
between the a-bromoacyl bromide and the parent acid; the acyl bromide, which
is necessary for continued reaction, is thus regenerated:

This bromination reaction results exclusively in alpha substitution and there-

fore is limited to carboxylic acids with a hydrogens. Chlorine with a trace of
phosphorus reacts similarily but with less overall specificity, because concurrent
free-radical chlorination can occur at all positions along the chain (as in hydro-
carbon halogenation; see Section 4-6A).

Exercise 18-19 Write the steps in the phosphorus-catalyzed bromination of pro-

panoic acid and explain why propanoyl bromide is expected to undergo acid-
catalyzed bromination more readily than propanoic acid. (Review Section 17-1.)

18-56 Substitution Reactions of a-Haloal kanoic Acids

The halogen of an a-haloalkanoic acid is replaced readily by nucleophilic
reagents such as CN@,OH@,10, and NI-I,. Thus a variety of a-substituted
816 18 Carboxylic Acids and Their Derivatives

carboxylic acids may be prepared by reactions that are analogous to S,2

substitution of alkyl halides:

I I I
I OH
2-iodopropanoic\~@
acid OH{ OH 2-hydroxypropanoic
(lactic acid) acid

\ 1 excess
NH3
00 ~0
CH3CHC02H ----+ CH3CHC02NH, ---+CH3CHC02H
I I I
Br NH,
2-bromopropanoic 2-aminopropanoic
acid acid
(alanine)

CN C02H
2-cyanopropanoic acid methylpropanedioic acid
(methylmalonic acid)

Facile S,2 substitution reactions of halogens are expected from the

electron-attracting characteristics of the neighboring carbonyl function, which
should make the transition state for attack by a nucleophilic reagent more
favorable:

Perhaps it may seem surprising that the carboxyl carbon is not attacked
by the nucleophilic agents, because we have stressed earlier the susceptibility
of carbonyl groups to nucleophilic reagents. No stable product results, how-
ever, from addition to the carbonyl group by the type of reagents considered
here. Thus with cyanide ion the equilibrium constant for addition is unfavor-
able because of the associated loss of stabilization energy of the carboxyl group
(see Exercise 18-9):

0'"' 0
R-C
P I
+ CN@ --' R-C-OH R-C-CEN
I/
+0
OH
18-6 Functional Derivatives of Carboxylic Acids 817

The SN1reactivity of a-haloalkanoic acids is particularly low. This is

reasonable because formation of a cationic center at the a carbon should be
difficult, because of the positive character of the carbonyl carbon. Further-
more, little, if any, help could be expected through electron delocalization
because the corresponding valence-bond structure has a positive, single-
bonded oxygen:

unfavorable

Similar considerations apply to the SN1 and SN2 reactions of a-halo

aldehydes and a-halo ketones (Section 17-2C).

Exercise 18-20* Optically active sodium 2-bromopropanoate is converted to sodium

2-hydroxypropanoate in water solution. The product has the same stereochemical
configuration at C2 as the starting material and the reaction rate is independent of
added OH@at moderate concentrations. At higher concentrations of OH@,the rate
becomes proportional to the OH@concentration and the 2-hydroxypropanoate formed
has the opposite configuration to the starting material. Write appropriate mechanisms
to explain these facts. Give your reasoning. (It may be helpful to review Sections 8-5
and 15-1 1 .)

18-6 FUNCTIONAL DERIVATIVES OF CARBOXYLIC ACIDS

A functional derivative of a carboxylic acid is a substance formed by replace-

ment of the hydroxyl group of the acid by some other group, X, such that it
can be hydrolyzed back to the acid in accord with Equation 18-7:

By this definition, an amide, RCONH,, but not a ketone, RCOCH,, is a func-

tional derivative of a carboxylic acid. Several derivatives of carboxylic acids
are given in Table 18-3, and methods for preparation of these derivatives are
summarized in Tables 18-6 and 18-7 at the end of the chapter.
 18 Carboxylic Acids and Their Derivatives

Table 18-3
Functional Derivatives of Carboxylic Acids

Example

Derivative Structure Structure Name

esters R-C
f CH3-C
/P ethyl ethanoate
\ \ (ethyl acetate)
OR' OC2H5

acyl halides R-C

/P benzenecarbonyl bromide
(benzoyl bromide)
\x
X = F, CI, Br, I

anhydrides ethanoic anhydride

(acetic anhydride)

amides R-C
W benzenecarboxamide
(primary) \ (benzamide)
NH2 NH2

amides
(secondary
and tertiary)
0
II
RCNR'R" H-C
/P
\

R-C
/P
CHzc\
imides I NH
/
I NH butanimide
CH, / (azacyclopenta-2,5-
C
'
dione, succinimide)
\o

acyl azides R-C

/O
CH3-C
/P ethanoyl azide
\ \ (acetyl azide)
N3 N3
18-6 Functional Derivatives of Carboxylic Acids

Table 18-3 (continued)

Functional Derivatives of Carboxylic Acids

Example

Derivative Structure Structure Name

hydrazides R-C
P C2H,-C
/O
diazanylethanonea
\ \NHNH, (propionohydrazide)
NHNH,

hydroxamic R-C
P /O
N-hydroxychloroethanamide
acids \ (chloroacetylhydroxamic acid)
NHOH

/P
lactones
rc\
(CH) 0 oxacyclopentan-2-one
(cyclic esters) 0 (y-butyrolactone)

most stable
with n = 3,4

cc\
P
lactams (CH ) NH
(cyclic amides) \13/
most stable
with n = 3,4

"This is a recommended but not widely used name. Without some thought, few organic chemists
currently could write the proper structure that corresponds to it.

The common structural feature of the compounds listed in Table 18-3

is the acyl group R-C

/P. However, nitriles, R C z N , often are considered
\
to be acid derivatives, even though the acyl group is not present as such, be-
cause hydrolysis of nitriles leads to carboxylic acids:

ethanenitrile ethanoic acid

(aceton itrile) (acetic acid)

The chemistry of nitriles will be discussed in Section 24-5.

820 18 Carboxylic Acids and Their Derivatives

Exercise 18-21 The following substances have boiling points as indicated:

ethyl ethanoate (77") ethanoic acid (1 18")
ethanoic anhydride (140") ethanamide (221")
Account for these differences on the basis of molecular weight and hydrogen bonding.

The two main types of reactions of carboxylic acid derivatives with

which we now shall be concerned are the replacement of X by attack of a
nucleophile :Nu@at the carbonyl carbon with subsequent cleavage of the
C-X bond (Equation 18-8), and substitution at the cw carbon facilitated by the
carbonyl group (Equation 18-9):

18-7 REACTIONS AT THE CARBONYL CARBON

OF ACID DERIVATIVES

18-7A Displacement Reactions

Hydrolysis of most acid derivatives to the parent acids is acid- or base-
catalyzed :

X = halogen, -OR, R-C , -NH,, etc.

\

However, acyl halides and anhydrides usually hydrolyze rapidly without the
aid of an acidic or basic catalyst, when in solution. It is important to recognize
that an insoluble acyl halide or anhydride often reacts slowly with water.
18-7 Reactions at the Carbonyl Carbon of Acid Derivatives

Esters and amides hydrolyze much more slowly, and for useful rates
require a catalyst. The hydrolysis of amides is of exceptional importance in
biochemistry and will be discussed in more detail in Chapters 24 and 25.
Acid-catalyzed hydrolysis of esters is the reverse of acid-catalyzed ester
formation discussed previously. Base-ind~tcedester hydrolysis (saponification)
is an irreversible reaction. The initial step is the attack of hydroxide ion at the
carbonyl carbon:

The intermediate anion, 13, so formed then either loses OH0 and reverts to
the original ester, or it loses C H 3 0 0to form the acid. The overall reaction is
irreversible because once the acid is formed, it immediately is converted to
the carboxylate anion, which is stabilized to such a degree that it is not attacked
by the alcohol and will not reform the starting ester. Consequently, the reaction
goes to completion in the direction of hydrolysis:

Exercise 18-22 Why is a carboxylate anion more resistant to attack by nucleophil ic

agents, such as CH30H or CH30@,than is the corresponding ester?

Ester interchange is closely related to ester hydrolysis. This is a base-

catalyzed reaction that is useful to replace the alcohol group of an ester
with a different alcohol group. The catalyst is alkoxide ion and the equilibrium
constant is close to unity, unless the alcohols differ greatly in size. An
example is

in which ROOis either CH30Gor CH3CH200.

822 18 Carboxylic Acids and Their Derivatives

Exercise 18-23 a. Develop a mechanism for ester interchange between ethanol and
methyl ethanoate catalyzed by alkoxide that is consistent with the mechanism of base-
induced ester hydrolysis.
b. Why doesn't it matter whether one uses methoxide or ethoxide as the catalyst?
c. If one used D-2-butyl ethanoate as the starting ester and methanol as the exchang-
ing alcohol, what would be the configuration of the 2-butanol formed with methoxide
as a catalyst?

Exercise 18-24 Ester interchange also can proceed (but more slowly) with an acidic
instead of a basic catalyst. Write a mechanism for this reaction consistent with acid-
catalyzed ester formation (Section 18-3A).

The formation of esters from acid chlorides and anhydrides according

to the following equation has been discussed:

R-C' + R'OH R-C' -t HX

\ \
X OR'
Amides can be obtained from acyl halides, carboxylic anhydrides, or
esters with amines or ammonia. The mechanisms of these reactions are very
similar to the corresponding reactions of alcohols:

// //
R-C +x@+ R-c + HX

X = C1-, RC02-, R'O-

We will discuss this kind of reaction further in Chapters 24 and 25.

Exercise 18-25 By analogy with the reaction mechanisms already discussed, pro-
pose a mechanism for each of the following reactions:
+
a. C6H5C02CH3 C2H50H--+
+
b. CH3COCI CH3CH20H
H
- @

C6H,C02C2H, CH30H
CH3C02CH2CH3 HCI
+
+
18-7B Reactions with Organometallic Compounds

---
H0
d. +
CH3CONH2 H300A CH3C02H NH,@ +
e. +
CH3CONH2 OOH CH3C02@+NH,
f. +
CH3COCI 2NH3 CH3CONH2 NH,CI +
g. +
CH3C02CH3 CH3NH2 CH3CONHCH3 CH,OH +
Exercise 18-26 What can you conclude about the mechanism of acid-catalyzed
hydrolysis of oxacyclobutan-2-one (P-propiolactone) from the following equation:

Exercise 18-27 Write a plausible mechanism supported by analogy for the following
reaction:

Exercise 18-28 Explain why the base-induced hydrolysis of methyl 2,4,6-trimethyl-

benzoate is unusually slow. Write a mechanism for the hydrolysis of methyl 2,4,6-tri-
methylbenzoate that occurs when the ester is dissolved in concentrated sulfuric acid
and the solution poured into a mixture of ice and water (see Section 18-3A):

18-78 Reactions with Organometall ic Compounds

The reactions of several carboxylic acid derivatives with organomagnesium
and organolithium compounds were described in Section 14-12. The key step
in these reactions is addition of the organometallic compound, as RmM6@,
to the carbonyl group. For a Grignard reagent,
R Z
\SOSO SOSO I
C=O + Rf:MgX + R-C-OMgX Z = C1, OR, 0 2 C R
/- I
z R'
 18 Carboxylic Acids and Their Derivatives

The reaction normally does not stop at this stage; MgXZ is eliminated
and the resulting ketone rapidly reacts with another molecule of organometallic
compound. On hydrolysis, a tertiary alcohol is formed with at least two
identical alkyl groups on the tertiary carbon:

R R'
\ 1. R'MgX I
R-C~OM~X- C = O + M ~ X Z 2. H20 > R-C-OH + Mg(0H)X
I / I
R' R' R'

Exercise 18-29 Grignard reagents add to N,N-dialkylal kanamides, RCONR,', to

give ketones after hydrolysis. With esters or acyl chlorides, a tertiary alcohol is the
usual product. Explain why, on the basis of the stability of the RRICZ(OMgX) inter-
mediate, the amides may be expected to be less likely than esters or acyl chlorides
to give tertiary alcohols. How could you use an N,N-dialkylalkanamide to prepare an
aldehyde with the aid of a Grignard reagent?

18-7C Reduction of Acid Derivatives

Esters, chlorides, and anhydrides are reduced by lithium aluminum hydride
in the same general way as the parent acids (Section 18-3C), the difference
being that no hydrogen is evolved. The products after hydrolysis are primary
alcohols:

1. LiAlH,
R-C RCH20H
\ 2. H@,H,O'
Z
Z = C1, OR, 0 2 C R

Nitriles can be reduced to amines by lithium aluminum hydride. An

imine salt is an intermediate product; if the reaction is carried out under the
proper conditions, this salt is the major product and provides an aldehyde on
hydrolysis (see Section 16-4C):

RCN
(imine salt)
18-8 Reactions at the Alpha Carbons of Carboxylic Acid Derivatives

Amides are reduced to primary amines, and N-substituted amides to

secondary and tertiary amines:

Borane also will reduce esters, amides, and nitriles to the same products as
does LiAlH,, but with reduced reactivity (Table 16-6).
Although lithium aluminum hydride and boranes are very useful
reagents, they are expensive and impractical to employ on a large scale. Other
methods of reduction then may be necessary. Of these, the most important are
reduction of esters with sodium and ethanol (acids do not react readily),

RC02R1 4Na + + 4C2H50H C2H50H > RCH20H + R'OH + ~ c , H , o @ N ~ @

and high-pressure hydrogenation over a copper chromite catalyst,

RC02R1 2H2 + - 200"

copper
chromite
RCH20H + R'OH

18-8 REACTIONS AT THE ALPHA CARBONS OF

CARBOXYLIC ACID DERIVATIVES

18-8A The Acidic Properties of Esters with a Hydrogens

Many important synthetic reactions in which C-C bonds are formed involve
esters and are brought about by basic reagents. This is possible because the
a hydrogens of an ester, such as RCH2C02C2H5,are weakly acidic, and a
strong base, such as sodium ethoxide, can produce a significant concentration
of the ester anion at equilibrium:

The acidity of a hydrogens is attributed partly to the electron-attracting

inductive effects of the ester oxygens, and partly to resonance stabilization of
the resulting anion (Section 17-1A):
826 18 Carboxylic Acids and Their Derivatives

When the a carbon of the ester carries a second strongly electron-

attracting group, the acidity of a hydrogen is greatly enhanced. Examples of
such compounds follow:

ethyl nitroethanoate diethyl propanedioate

(ethyl nitroacetate) (d iethyl malonate)
pKa = 5.8 pKa= 13.3

ethyl cyanoethanoate ethyl 3-oxobutanoate

(ethyl cyanoacetate) (ethyl acetoacetate)
pK,- 13 pKa = 10.7

The stabilization of the anions of these specially activated esters is

greater than for simple esters because of the electron-withdrawing inductive
effects of the substituents but more importantly because the negative charge
can be distributed over more than two centers. Thus for the anion of ethyl
3-oxobutanoate we can regard all three of the valence-bond structures, 14a
through 14c, as important in contributing to the hybrid, 14:
18-8A The Acidic Properties of Esters with a Hydrogens

Figure 18-6 Proton nmr spectrum of ethyl 3-oxobutanoate (ethyl aceto-

acetate) at 60 MHz; calibrations are relative to tetramethylsilane at 0.00
ppm. Peaks marked a, b, and c are assigned, respectively, to the OH,
alkenyl, and methyl protons of the enol form, whereas peaks d and e are
assigned to the a-CH, and methyl protons, respectively, of the keto form.
The quartet of lines at 4.2 ppm and the triplet at 1.3 ppm result from the
ethyl groups of both keto and enol forms.

The anion, 14, is sufficiently stable relative to the ester that the K , is about
10-XIin water solution (Table 17- 1).
Ethyl 3-oxobutanoate exists at room temperature as an equilibrium
mixture of keto and en01 tautomers in the ratio of 92.5 to 7.5. The presence of
en01 can be shown by rapid titration with bromine, but is more evident from the
proton nmr spectrum (Figure 18-6), which shows absorption of the hydroxyl,
alkenyl, and methyl protons of the en01 form, in addition to absorptions
expected for the keto form:

keto form, 92.5% enol form, 7.5%

Interconversion of the en01 and keto forms of ethyl 3-oxobutanoate is

powerfully catalyzed by bases through the anion, 15, and less so by acids
828 18 Carboxylic Acids and Their Derivatives

through the conjugate acid of the keto form:

c) 0
li 0 il
CH,-C. ,C-OC,H,
-cg
l5 Y@ /H.
0 0 0 '"0
I1 II I I1
,
v@-$$/
CH3-C, C-OC2H5 CH,-C ,C-
CH, \CH
keto form en01 form

@o/H....O
II I1
CH,-C ,COC2H5
'CH,

Nonetheless, if contact with acidic and basic substances is rigidly excluded to

the extent of using quartz equipment in place of glass (glass normally has a
slightly alkaline surface), then interconversion is slow enough that it is possible
to separate the lower-boiling en01 from the keto form by fractional distillation
under reduced pressure. The separated isomers are indefinitely stable when
stored at -80" in quartz vessels.

Exercise 18-30 Explain why 2,4-pentanedione can be expected to contain much

more enol at equilibrium than does ethyl 3-oxobutanoate. How much enol would you
expect to find in diethyl propanedioate? In 3-oxobutanal? Explain.

Exercise 18-31 Arguing from the factors that appear to regulate the ratio of C- to
0-alkylation of enolate anions (Section 17-4), show how you could decide whether
the reaction of the sodium enolate salt of ethyl 3-oxobutanoate with a strong acid
would give, as the initial product, mostly the enol form, mostly the keto form, or the
equilibrium mixture.

Exercise 18-32 When a small amount of sodium ethoxide is added to ethyl 3-0x0-
butanoate, the proton nmr peaks marked a , 6 ,and c in Figure 18-6 disappear. Explain
why this should be so. (You may wish to review Section 9-10E.)
18-8B The Claisen Condensation 829

"1-8B The Claisen Condensation

One of the most useful of the base-induced reactions of esters is illustrated by
the self-condensation of ethyl ethanoate under the influence of sodium ethoxide
to give ethyl 3-oxobutanoate:

This reaction, called the Claisen condensation, is interesting because, from

consideration of bond and stabilization energies, it is expected to be unfavor-
able thermodynamically with AN0 (vapor) equal to 6 kcal molep1.This expecta-
tion is realized in practice, and much effort has been expended to determine
conditions by which practical yields of the condensation product can be
obtained.
The Claisen condensation resembles both the aldol addition (Section
17-3) and carbonyl additions of acid derivatives discussed previously (Sections
16-4 and 18-7). The first step, as shown in Equation 18-10, is the formation of
the anion of ethyl ethanoate which, being a powerful nucleophile, attacks the
carbonyl carbon of a second ester molecule (Equation 18-11). Elimination of
ethoxide ion then leads to the P-keto ester, ethyl 3-oxobutanoate (Equation
18-12):

The sum of these steps represents an unfavorable equilibrium, and satisfactory

yields of the P-keto ester are obtained only if the equilibrium can be shifted
by removal of one of the products.
One simple way of doing this is to remove the ethanol by distillation as
it is formed; however, this may be difficult to carry to completion and, in any
case, is self-defeating if the starting ester is low-boiling. Alternatively, one can
use a large excess of sodium ethoxide. This is helpful because ethanol is a
weaker acid than the ester enol, and excess ethoxide shifts the equilibrium to
830 18 Carboxylic Acids and Their Derivatives

the right through conversion of the P-keto ester to the enolate salt (Equation
18- 13).

Obviously, the condensation product must be recovered from the en01

salt and isolated under conditions that avoid reversion to starting materials.
The best procedure is to quench the reaction mixture by pouring it into an
excess of cold dilute acid.

Exercise 18-33 Possible by-products of the Claisen condensation of ethyl ethanoate

are

Explain how these products may be formed and why they are not formed in signifi-
cant amounts.

Exercise 18-34 Ethanol has a K, of 10-l8 and ethyl 3-oxobutanoate has K, = 10-ll.
Calculate AGO for the reaction of sodium ethoxide with the ester as per Equation
18-13. (See Section 4-4A.)

A limitation on the Claisen condensation is that although the starting

ester need have only one a hydrogen for Reactions 18- 10 through 18- 12 to
occur, two a hydrogens are necessary for a favorable equilibrium utilizing the
ionization reaction of Equation 18-13. As a result, it is not surprising to find
that ethyl 2-methylpropanoate fails to condense with itself in the presence of
sodium ethoxide, because the condensation product has no a hydrogen next
to the ester group:

ethyl 2-methylpropanoate ethyl 2,2,4-trimethyl

3-oxopentanoate
 18-8B The Claisen Condensation $31

However, if an excess of a very much stronger base than sodium

ethoxide is used [such as triphenylmethylsodium, (C6H5)3C@Na@], this same
condensation does take place in reasonable yields. The reason is that the base
is now strong enough to convert the alcohol formed in the reaction to sodium
ethoxide, thus shifting the equilibrium to the right:

CH3 CH3 CH3

\ \ I
/CHC0CCO2C2H5+ C2H50H
d
CHC02C2H5 'unfavorable
/ I
CH3 CH3 CH3
C2H50H +( favzble
~ 6 ~ 5 1 3 ~ ~ '~+ 2 ~ 5 0 ' (C6H5)3CH

The overall reaction then is

2
CH3
\
/
CHC02C2H5+ (c,H,)~c@
CH3
- CH,
\
/
I
CH3
CHCOCCO2C2H5+ c2H50e
CHI3
I
CH3
+ (C6H5)3CH

Claisen condensations can be carried out between two diferent esters

but, because there are four possible products, mixtures often result. Less
difficulty is encountered if one of the esters has no a hydrogen and reacts
readily with a carbanion according to Equations 18-11 and 18-12. The reaction
then has considerable resemblance to the mixed aldol additions discussed in
Section 17-3C. Among the useful esters without a hydrogens, and with the
requisite electrophilic reactivity, are those of benzenecarboxylic, methanoic,
ethanedioic, and carbonic acids. Several practical examples of mixed Claisen
condensations are shown in Equations 18-14 through 18-16 (all of the products
exist to the extent of 10% or so as the en01 forms):
 18 Carboxylic Acids and Their Derivatives

A n important variation on the Claisen condensation is to use a ketone as

the anionic reagent. This often works well because ketones usually are more
acidic than simple esters and the base-induced self-condensation of ketones
(aldol addition) is thermodynamically unfavorable (Section 17-3C). A typical
example is the condensation of cyclohexanone with diethyl ethanedioate
(diethyl oxalate):

a-Keto esters of the type formed according to Equations 18-16 and

18- 17 have synthetic utility in that they lose carbon monoxide when strongly
heated:

A somewhat similar decarbonylation reaction was mentioned previously for

diphenylpropanetrione (Section 17-10).
18-8C Alkylation of Ester Anions 833

Exercise 18-35 Write structures for all of the Claisen condensation products that
reasonably may be expected to be formed from the following ester mixtures and
sodium ethoxide:
a. ethyl ethanoate and ethyl propanoate
b. diethyl carbonate and 2-propanone
c. diethyl ethanedioate and ethyl 2,2-dimethylpropanoate

Exercise 18-36 Show how the following substances may be synthesized by Claisen-
type condensations from the indicated starting materials. Specify the reagents and
reaction conditions as completely as possible.
a. ethyl 2-methyl-3-oxopentanoate from ethyl propanoate
b. ethyl 2,4-dioxopentanoate from 2-propanone
c. diethyl 2-phenylpropanedioate from ethyl phenylethanoate
d. 2,4-pentanedione from 2-propanone
e. 2,2,6,6-tetramethyl-3,5-heptanedione from 3,3-dimethyl-2-butanone
f. ethyl 2,2-dimethyl-3-phenyl-3-oxopropanoate from 2-methylpropanoate.

Exercise 18-37 What advantages and disadvantages may sodium hydride (NaH)
have as the base used in the Claisen condensation?

18-8C Alkylation of Ester Anions

The anions of esters such as ethyl 3-oxobutanoate and diethyl propanedioate
can be alkylated with alkyl halides. These reactions are important for the
synthesis of carboxylic acids and ketones and are similar in character to the
alkylation of ketones discussed previously (Section 17-4A). The ester is con-
verted by a strong base to the enolate anion, Equation 18-18, which then is
alkylated in an SN2reaction with the alkyl halide, Equation 18-19. Usually,
C-alkylation predominates:
0
CH3COCH2C02C2H5 c 2 H 5 0 @ + +
C H ~ C O C H C O ~ C , H ~C2H50H (18-18)

Esters of propanedioic (malonic) acid can be alkylated in a similar

fashion (Equation 18-20):
 18 Carboxylic Acids and Their Derivatives

Unfortunately, monoalkylation seldom occurs cleanly by the above

sequence whenever the monoalkylation product has an a hydrogen located
so as to permit dialkylation to occur. In practice, alkylation reactions, using
one mole of ester, one mole of sodium ethoxide, and one mole of an alkyl
halide (e.g., CH31), give a mixture of the starting ester, its mono- and dialky-
lation products. The situation is more favorable when large alkyl groups are
introduced, because then the physical properties and reactivities of the
starting materials and of mono- and dialkylation produces differ considerably.
Usually dialkylation is inhibited by having a bulky alkyl group in the mono-
alkylation product.
Alkyl-substituted 3-oxobutanoic and propanedioic esters can be
hydrolyzed under acidic conditions to the corresponding acids, and when these
are heated they readily decarboxylate (Section 18-4). Alkyl 3-oxobutanoic
esters thus yield methyl alkyl ketones, whereas alkylpvopanedioic esters
produce carboxylic acids:

CH3 CH3
I 1 heat
CH3COCHC02C2H5 H@' > CH3COCHC02H C 0 2 > CH,COCH2CH3
2- butanone

H@' t
/C02H
CH3CH2CH heat CH3CH2CH,C02H
CH3CH2CH
\ \ -co2 butanoic acid
C02C2H5 C02H

These reactions commonly are known as the acetoacetic-ester ketone and the
malonic-ester acid syntheses, respectively.
Alkyl 3-oxobutanoic esters react with concentrated alkali by a diferent
path to reverse the Claisen condensation:

Exercise 18-38 Why does the following reaction fail to give ethyl.propanoate?

Exercise 18-39 Show a synthesis of 3-ethyl-2-pentanone from ethyl 3-oxobutanoate.

What advantage would this route have over alkylation of 2-pentanone with sodium
amide and ethyl iodide? (Section 17-4A.)
18-8D Acylation of Ester Anions 835

Exercise 18-40 How could you prepare diethyl methylpropanedioate that is free of
diethyl propanedioate and diethyl dimethyl propanedioate? (Review Section 18-8B
to find an alternative synthesis not involving alkylation.)

Exercise 18-41 Show how one could prepare cyclobutanecarboxylic acid from
diethyl propanedioate and a suitable dihalide.

Exercise 18-42 Write a mechanism based on analogy with other reactions in this
chapter that will account for the strong alkali-induced cleavage of ethyl 2-methyl-3-
oxobutanoate in accord with Equation 18-21.

18-8D Acylation of Ester Anions

Enolate anions of esters, such as ethyl 3-oxobutanoate or diethyl propane-
dioate, react with acyl halides or anhydrides to give acylation products. These
reactions are carried out best using sodium hydride instead of sodium ethoxide
for production of the en01 salt, because then no alcohol is liberated to react
with the acyl halide or anhydride:

18-8E Aldol-Type Additions of Ester Anions and the

Reformatsky Reaction
Addition of an ester anion to the carbonyl group of an aldehyde or ketone is a
type of aldol addition (Section 17-3):

There are certain difficulties in achieving this type of aldol reaction. First,
alkali-induced ester hydrolysis would compete with addition. Second, a Claisen
condensation of the ester might intervene, and third, the ester anion is a stronger
base than the enolate anions of either aldehydes or ketones, which means reac-
tion could be defeated by proton transfer of the type
 18 Carboxylic Acids and Their Derivatives

However, a useful synthetic reaction can be achieved in the following way.

First, the ester anion is formed in the absence of water without causing a Claisen
condensation or other carbonyl addition. This can be done with ethyl ethanoate
by treating it with lithium bis(trimethylsily1)amide in oxacyclopentane solution
at -80":
-80"
+
CH,C02C2H5 LiN [Si(CH,),12 ------+ +
LiCH2C02C2H5 H N [Si(CH,),], (18-22)

The advantage of LiN[Si(CH,),], as the base in this reaction is that

0
N[Si(CH,),I, is a reasonably strong base; it is bulky, which inhibits addition
to the carbonyl; and it also forms a weakly basic amine, HN[Si(CH,),],,
which does not interfere in the subsequent reactions.
The solution of ethyl lithioethanoate must be kept cold and treated promptly
with an aldehyde or ketone. Thus, with 2-propanone,

+
proton transfer reaction, LiCH2C02C2H5 CH,COCH, -
For the reaction to be successful, the carbonyl addition has to be faster than the
CH,C02C2H5
LiCH2COCH, and, at -80°, this is the case. This synthesis of P-hydroxy esters
is a beautiful example of how rates of competing reactions can be manipulated
+

to obtain a high yield of a desired addition product that may not be the most
thermodynamically favorable one.
A closely related synthesis of P-hydroxy esters is provided by the Refor-
matsky reaction. This synthesis starts with an aldehyde or ketone, RCOR',
and an a-bromo ester, such as ethyl bromoethanoate. Zinc in a nonhydroxylic
solvent (usually benzene) transforms the bromo ester into an organozinc com-
pound, which then adds to the aldehyde or ketone carbonyl. Hydrolysis pro-
duces the P-hydroxy ester:

OZnBr OH
I
RR1CCH2C02C2H5NH4C1> RR'(!CH2C02C2H5
H20

As do aldols, P-hydroxy esters dehydrate (usually readily) to a$-unsaturated

carbonyl compounds.
18-8F Biological Claisen Condensations and Aldol Additions. Fatty Acid Metabolism

Exercise 18-43* a. In the formation of LiCH2C02C2H, (Equation 18-22), would it be

better to add the ester to the solution of the base in oxacyclopentane, or the reverse?
Give your reasoning.

b. Suppose a solution formed in accord with Equation 18-23 were allowed to stand
(before adding acid and water) until equilibrium is established between the various
possible Claisen, mixed-Claisen, and aldol-addition products described in Sections
18-8B and 17-3C. What products would you then expect to be formed on hydrolysis
with dilute acid and water? Which would be expected to predominate? Give your
reasoning.

c. Show how you could synthesize methyl 2-(I-cyclohexenyl)ethanoate from cyclo-

hexanone by the reactions described in this section.

18-8F Biological Claisen Condensations and Aldol Additions.

Fatty Acid Metabolism
The overall result of a Claisen condensation is the transfer of an acyl group

(R-C,
/P) from one ester molecule to another:

In biological systems, related reactions of acyl transfer occur by way of

0
II
thioestevs, R-C-SR', derived from carboxylic acids and a thiol known as
coenzyme A (HSCoA).The full structure of coenzyme A is shown in Figure
18-7. Although it is large and complex, the reactive part for our discussion here

5Considerable confusion is possible because of the way in which biochemists use

abbreviated names and formulas for the acyl derivatives of coenzyme A. To emphasize
the vital -SH group, coenzyme A is usually written as CoASH. However, the acyl
derivatives most often are called acetyl CoA and the like, not acetyl SCoA, and you
could well get the erroneous impression that the sulfur has somehow disappeared in
forming the acyl derivative. We will include the sulfur in formulas such as CH,COSCoA,
but use the customary names such as acetyl CoA without including the sulfur. To make
clear that CoA does not contain cobalt, CoA is printed in this text in boldface type.
 18 Carboxylic Acids and Their Derivatives

H0 CH, j 0 0 " I

2-aminoethanethiol pantothenic acid

ADP 3'-phosphate

Figure 18-7 The structure of coenzyme A (HSCoA) showing the seg-

ments of which it can be considered to be constructed. The thiol group
at the left end of the molecule reacts to form thioesters of the type
0
1I
R-C-SCoA. The other parts of the coenzyme A molecule provide the
structural elements that permit a high degree of specificity for interactions
with enzymes.

is the thiol (SH) group. The thioester equivalent of the Claisen condensation
of Equation 18-24 is

0 0
II II
SCoA + CH3C-SCoA t=L CH2C-SCOA + HSCoA
The reverse of the above reaction is a key step in the oxidative degradation
of fatty acids. This reverse Claisen condensation (catalyzed by thiolase) in-
volves the cleavage of a carbon-carbon bond of a p-keto ester of coenzyme A
by another molecule of coenzyme A to give a new acyl derivative (RCO-SCoA)
and ethanoyl (acetyl) derivative (CH,CO-SCoA):

0 0 0 0
p 11
R-C-CH2-C-SCoA
thiolase
A
II
R-C-SCoA
II
+ CH3C-SCoA
1'

For further degradation of RCO-SCoA, it first must be oxidized to a p-keto

thioester. The reactions that accomplish this oxidation are shown in Figure 18-8
and involve a sequence of enzymatic transformations of the type
18-8F Biological Claisen Condensations and Aldol Additions. Fatty Acid Metabolism

Figure 18-8 Steps in the metabolic oxidation of a fatty acid. In each

cycle of reactions, one mole of CH,COSCoA is formed and the alkyl group
R is shortened by two carbons.

After formation of the P-keto thioester, it is cleaved by CoASH, and the

resulting thioester goes back into the sequence two carbons shorter than
before. In this way, a fatty acid is degraded from the carboxyl end, two carbons
at a time.

Exercise 18-44* The formation of an acyl coenzyme A, RCO-SCoA, from coenzyme

A and a carboxylic acid is coupled to a cleavage reaction of ATP to give AMP:

RC0,H + ATP + COA-SH RCO-SCOA + AMP + PP

Write the possible steps involved in this esterification reaction. (Review Section 15-5F.)

There are two principle pathways for utilization of the ethanoyl coenzyme A
(CH,CO-SCoA) formed in each turn of the oxidation cycle of Figure 18-8.
Either it is used to synthesize larger molecules such as fatty acids, steroids, and
so on, as will be described in Section 30-5A, or the acyl group is oxidized to
CO, and H,O:

The oxidation of the acyl group of coenzyme A is the net outcome of the
citric acid or Krebs cycle (Section 20-10B). We will be interested here in the
 18 Carboxylic Acids and Their Derivatives

entry point of the cycle whereby ethanoyl coenzyme A is employed in a reac-

tion that builds the C, chain of citric acid (3-carboxy-3-hydroxypentanedioic
acid) from C, and C, pieces:

C02H
I citrate SCoA
C=O synthetase
I f SCoA > HO-C-C02H
CH2 I
I CH2

2-oxobutanedioic acid citryl CoA

(oxaloacetic acid)

This reaction is quite special in that it is an aldol-type addition in which a

thioester is the donor (nucleophile) and a keto acid is the acceptor (electro-
phile). From the discussion in Section 18-8E, you will see that reactions of this
kind involving an ester as the donor and an aldehyde or ketone as the acceptor
can be achieved in the laboratory only under rather special conditions. For the
thioester to function as a nucleophile at the a carbon under the restraints
imposed by having the reaction occur at the physiological pH, the catalyzing
enzyme almost certainly must promote formation of the en01 form of the
thioester. The en01 then could add to the ketone carbonyl with the assistance
of a basic group on the enzyme. This kind of catalysis by enzymes is discussed
in Section 25-9C.

0
II
CH,-C-SCoA
I
HO-C-

18-9 REACTIONS OF UNSATURATED CARBOXYLIC ACIDS

AND THEIR DERIVATIVES

Unsaturated carboxylic acids of the type RCH=CH (CH,) ,COOH usually

exhibit the properties characteristic of isolated double bonds and isolated
carboxyl groups when n is large and the functional groups are far apart. As
18-9 Reactions of Unsaturated Carboxylic Acids and Their Derivatives

expected, exceptional behavior is found most commonly when the groups are
sufficiently close together to interact strongly, as in a,P-unsaturated acids,
P a
RCH=CHCO,H. We shall emphasize those properties that are exceptional
in the following discussion.

18-9A Migration of the Double Bond

In the presence of strong base, a$- and P,y-unsaturated carboxylic acids
tend to interconvert by migration of the double bond:

@ NaOH 0
RCH=CH-CH2C02 W RCH,CH=CHCO,

Ester derivatives, RCH=CH-CH2COORf7 and the corresponding

unsaturated aldehydes and ketones, RCH=CH-CH2CORf, are much more
prone to this type of rearrangement than are the acids.

Exercise 18-45 Write a mechanism for the base-catalyzed equilibration of a,p- and
0,y-unsaturated esters. Which isomer wou Id you expect to predominate? Why does
this type of isomerization proceed less readily for the carboxylate anions than for the
esters? Would y16unsaturated esters rearrange readily to the alp-unsaturated esters?
Why, or why not?

18-9B Hydration and Hydrogen Bromide Addition

Like alkenes, the double bonds of a,p-unsaturated acids can be brominated,
hydroxylated, hydrated, and hydrobrominated, although the reactions often
are relatively slow. In the addition of unsymmetrical reagents the direction of
addition is opposite to that observed for alkenes (anti-MarkownikofQ.Thus
propenoic (acrylic) acid adds hydrogen bromide and water to form 3-bromo-
and 3-hydroxypropanoic acids:

HBr BrCH,CH,COOH 3-brornopropanoic acid

CH,=CHCOOH
7
propenoic acid
CH2CH2COOH Bhydroxypropanoic acid
H@ I
 18 Carboxylic Acids and Their Derivatives

These additions are analogous to the addition of halogens and halogen acids to
1,3-butadiene (Section 13-2). In the first step, a proton is transferred to the
carbonyl oxygen. The resulting conjugate acid can be regarded as a resonance
hybrid of structures 16a-16d:

In the second step, a nucleophile (such as Br@or a water molecule) attacks an

electron-deficient carbon of the hybrid 16. Attack at the carboxyl carbon may
occur but does not lead to a stable product. Attack of the nucleophile at the
6 carbon, however, produces the en01 form of the 6-substituted acid, which
then is converted rapidly to the normal carboxylic acid:

BrCH2-CH=C
pH
\
OH
-
fast
BrCH2-CH2-C
\
OH

18-9C Lactone Formation

When the double bond of an unsaturated acid is farther down the carbon chain
than between the alpha and beta positions, the so-called "conjugate addition"
is not possible. Nonetheless, the double bond and carboxyl group frequently
interact in the presence of acidic catalysts because the carbocation that results
from addition of a proton to the double bond has a built-in nucleophile (the
18-9C Lactone Formation

carboxyl group), which may attack the cationic center to form a cyclic ester
called a lactone.
Lactone formation only occurs readily by this mechanism when a
five- or six-membered ring can be formed:

3-pentenoic acid

a lactone

Five- or six-membered lactones also are formed by internal esterification when

either y- or 6-hydroxy acids are heated. Under similar conditions, @-hydroxy
acids are dehydrated to a,@-unsaturatedacids, whereas a-hydroxy acids under-
go bimolecular esterification to substances with six-membered dilactone rings
called lactides:

H0CH2CH2CH2C02H
4-hydroxybutanoic 0, /CH2
acid
C
II
0
oxacyclopentan-2-one

CH2C02H -heat
CH3CH=CHC0,H -t- H 2 0
2-butenoic acid

3-hydroxybutanoic
acid

2-hydroxypropanoic a lactide
acid
(lactic acid)

Exercise 18-46 Would you expect 3-butenoic acid to form a lactone with a five-
or a four-membered ring when heated with a catalytic amount of sulfuric acid?
 18 Carboxylic Acids and Their Derivatives

18-9D More on the Michael Addition

The foregoing examples of addition to the double bonds of unsaturated car-
boxylic acids all involve activation by an electrophilic species such as H@.
Conjugate addition also may occur by nucleophilic attack on acid derivatives,
the most important being the base-catalyzed Michael addition (Section 17-5B)
and 1,4-addition of organometallic compounds (Section 14- 12D). In all of these
reactions a nucleophilic agent, usually a carbanion, attacks the double bond
of an a,p-unsaturated acid derivative, or more generally an a,p-unsaturated
carbonyl compound, or an unsaturated compound in which the double bond is
conjugated with, and activated by, a strongly electr~ne~ative unsaturated
group (such as -CN, -NO2, etc.) In the Michael addition, the carbanion
usually is an enolate salt.
The overall reaction is illustrated here by the specific example of the
addition of diethyl propanedioate (diethyl malonate) to ethyl 3-phenylpro-
penoate (ethyl cinnamate):

The mechanism of this kind of transformation, with diethyl propanedioate

as the addend, is outlined in Equations 18-25 and 18-26. The basic catalyst
required for the Michael addition (here symbolized as B:) serves by forming
the corresponding anion:

A variety of nucleophilic agents can be used; propanedinitrile, 3-0x0-

butanoate esters, and cyanoethanoate esters all form relatively stable car-
banions and function well in Michael addition reactions. Obviously, if the
carbanion is too stable, it will have little or no tendency to attack the double
bond of the a,p-unsaturated acid derivative. The utility of the Michael addi-
tion for preparing 1,5-dicarbonyl compounds is illustrated by the examples
in Exercise 18-49.
18-90 More on the Michael Addition

Enamines (Sections 16-4C and 17-4B) are excellent addends i n many Michael-
type reactions. A n example is provided by the addition o f N-(1-cyclohexeny1)-
azacyclopentane to methyl 2-methylpropenoate:

H C O N (CH,),
reflux

Exercise 18-47 Explain why the Michael addition of diethyl propanedioate to 3-

phenylpropenoic acid is unlikely to be successful.

Exercise 18-48* The Michael-addition product that results from ethyl 3-phenyl-
propenoate and diethyl propanedioate, in principle, also can be formed by sodium
ethoxide-catalyzed addition of ethyl ethanoate to ethyl (2-carbethoxy)-3-phenyl-
propenoate. Work out the course of this reaction along the lines of Equations 18-25 and
18-26 and explain why it is less likely to be successful than the addition of diethyl
propanedioate to ethyl 3-phenylpropenoate. It will be helpful to compare the various
possible acid-base equilibria involved in the two possible routes to the same Michael-
addition product.

Exercise 18-49 Show how the following substances can be prepared by syntheses
based on Michael additions. In some cases, additional transformations may be
required.
a. 3-phenylpentanedioic acid from ethyl 3-phenylpropenoate
b. 3,5-diphenyl-5-oxopentanenitrile from 1,3-diphenylpropenone (benzalacetophe-
none)
c. 4,4-(dicarbethoxy)heptanedinitrile from propenenitrile (acrylonitrile)

d. and 3-butene-2-one
0
846 18 Carboxylic Acids and Their Derivatives

Exercise 18-50 Explain how steric hindrance would lead one to expect that the pro-
ton-transfer product in the addition of N-(1-cyclohexenyI)azacyclopentane to methyl
2-methylpropenoate would have the structure shown in Equation 18-27, rather than
the following:

18-10 DICARBOXYLIC ACIDS

Acids in which there are two carboxyl groups separated by a chain of more
than five carbon atoms (n > 5) for the most part have unexceptional properties,
and the carboxyl groups behave more or less independently of one another.

However, when the carboxyl groups are closer together the possibilities for
interaction increase; we shall be interested primarily in such acids. A number
of important dicarboxylic acids are listed in Table 18-4 together with their
physical properties, methods of manufacture, and commercial uses.

18-10A Acidic Properties of Dicarboxylic Acids

The inductive effect of one carboxyl group is expected to enhance the acidity
of the other. In Table 18-4 we see that the acid strength of the dicarboxylic
acids, as measured by the first acid-dissociation constant, K,, is higher than
that of ethanoic acid (K, = 1.5 x and decreases with increasing number
of bonds between the two carboxyl groups. The second acid-dissociation con-
stant, K,, is smaller than K, for ethanoic acid (with the exception of oxalic
acid) because it is more difficult to remove a proton under the electrostatic
attraction of the nearby carboxylate anion (see Section 18-2C).

18-10 8 Thermal Behavior of Dicarboxylic Acids

The reactions that occur when dicarboxylic acids are heated depend critically
upon the chain length separating the carboxyl groups. Cyclization usually is
18-10 Dicarboxylic Acids 847

favored if a strainless five- or six-membered ring can be formed. Thus hex-

anedioic and heptanedioic acids decarboxylate and cyclize to cyclopentanone
and cyclohexanone, respectively:

,CH2
/COOH 300" CH2 \
(CH2),
\
I C=O + CO, + H 2 0
COOH

Butanedioic and pentanedioic acids take a different course. Rather

than form the strained cyclic ketones, cyclopropanone and cyclobutanone,
both acids form cyclic anhydrides that have five- and six-membered rings,
respectively. 1,2-Benzenedicarboxylic (phthalic) and cis-l,4-butenedicar-
boxylic (maleic) acids behave similarly:

/C
/P
P O o H 300" CH2 \
(CH,), -H20' I 0 -H20
'COOH CH2
C' /

/P
/COOH
(CH,),
3 00" /CH2-C \
CH2
HCC02H 2000 H d C \
\ 4 3 2 0 ) \ /" II C 0 2 H -H20
HC ' I' /O
COOH CH2-C
\\ \\
0 0
Because of their short chains, propanedioic and ethanedioic acids
simply decarboxyate when heated (Section 18-4):

0 0
II I/
HO-C-C-OH H20 + CO + C 0 2
850 18 Carboxylic Acids and Their Derivatives

Exercise 18-51 The cis- and trans-butenedioic acids give the same anhydride on
heating, but the trans acid must be heated to much higher temperatures than the cis
acid to achieve anhydride formation. Explain. Write a reasonable mechanism for
both reactions.

18-10C lmides from Dicarboxylic Acids

The cyclic anhydride of butanedioic acid reacts with ammonia, as may be
expected for a typical anhydride; but the product, when strongly heated, forms
a cyclic imide (butanimide):

butanedioic anhydride butanimide

(succinic anhydride) (succinimide)

1,2-Benzenedicarboxylic (phthalic) anhydride behaves similarly, giving 1,2-

benzenedicarboximide (phthalimide):

2. heat

0
1,2-benzenedicarboxylic (phthalic) 1,2-benzenedicarboximide
anhydride (phthal imide)

Unlike amines, imides do not have basic properties in water solution;

the electron pair of nitrogen is partly delocalized over the carbonyl groups,
18-10C lmides from Dicarboxylic Acids 851

as indicated by 17a to 17c. This stabilization is lost if a proton is added to

nitrogen to give the conjugate acid, 18:

Imides are, in fact, quite acidic and readily dissolve in alkali-metal

hydroxide solutions to give salts. Like carboxylic acids and 1,3-dicarbonyl com-
pounds, imides are. acidic primarily because the stabilization of the anion is
greater than that of the acid. This can be seen by comparison of the resonance
structures that may be written for the imide, 17, with those of the anion, 18.
Separation of positive and negative charge, as in Structures 17b and 17c, in-
creases the energy of such structures. There is no charge separation in the
anion; thus 19b and 19c are more important with respect to their hybrid than
are 17b and 17c to their hybrid. (You may wish to review the corresponding
argument for the acidity of carboxylic acids, Section 18-2A.)

The salts of imides are useful in synthesis, as is described in Sec-

tion 23-911).

18-1OD The Dieckmann Condensation

Esters of. most dicarboxylic acids, except propanedioic esters, undergo the
Claisen condensation in much the same way as do esters of monocarboxylic
 18 Carboxylic Acids and Their Derivatives

acids (see Section 18-8B). However, when a strainless five- or six-membered

ring can be formed, an intramolecular Claisen condensation, called the
Dieckmann condensation, may take place which would result in the formation
of a cyclic p-keto ester:

0
/CH~CO~CZ~~ CHC02C2H5
0
'iH2
CH2 OCZH5> :1 \/?
'CH~CO~C,H~ 'CH,C \
OC2H5
diethyl hexanedioate

18-10E The Acyloin Reaction

A useful method of forming carbon-carbon bonds involves reduction of esters
with sodium metal in aprotic solvents such as ether or benzene and is called
the acyloin reaction:

1. Na, ether II I
2CH3 (CH2)3CO2CZH5 CH3(CH2)3C-CH(CH2),CH3
2. H? H20' 65%

This interesting reaction is especially useful for the synthesis of medium- and
large-ring compounds from dicarboxylic esters, and is effective for ring sizes
that cannot be made by the Dieckmann condensation or decarboxylation
(Section 18-10B). Radical anions formed by addition of sodium to the ester
Additional Reading 853

groups appear to be the key intermediates for carbon-carbon bond formation.

Thus, for dimethyl decanedioate,

Additional Reading

J. Hine, Structural Effects on Equilibria in Organic Chemistry, Wiley-lnterscience,

New York, 1975, Chapter 2.
G. V. Calder and T. J. Barton, "Actual Effects Controlling the Acidity of Carboxylic
Acids," J. Chem. Educ. 48, 338 (1971).
K. Hiraoka, R. Y. Yamdagni, and P, Kebarle, "Effects of Halogen Substituents on the
Intrinsic Acidity of Acetic Acids Determined by Measurements of Gas-Phase Ion
Equilibria," J. Amer. Chem. Soc, 95, 6834 (1 973).
P. H. Elworthy, T. Florence, and C. B. MacFarlane, Solubilization by Surface Active
Agents and its Applications in Chemistry and the Biological Sciences Chapman and
Hall, London, 1968.
G. A. Olah and A. M. White, "Carbon-13 Resonance Investigation of Protonated Car-
boxylic Acids (Carboxonium lons) and Oxocarbonium lons (Acyl Cations)," J. Amer.
Chem. Soc. 89, 7072 (1967).
H. 0 . House, Modern Synthetic Reactions, 2nd ed., W. A. Benjamin, Inc., Menlo Park,
Calif., 1972.
R. A. Sheldon and J. K. Kochi, "Oxidative Decarboxylation of Acids by Lead Tetra-
acetate," Organic Reactions 19, 279 (1972).
M. W. Rathke, "The Reformatsky Reaction," Organic Reactions 22, 423 (1975).
J. P. Schaefer and J. J. Bloomfield, "The Dieckmann Condensation," Organic Reac-
tions 15, 1 (1967).
 18 Carboxylic Acids and Their Derivatives

Table 18-5
Methods of Preparation of Carboxylic Acidsa

Reaction Comment

1. Hydrolysis of nitriles Acid or base catalyzed; amide is

formed first, then hydrolyzed to the
RCN H20 ,RCONH, H20 r RC0,H acid; a useful laboratory synthesis if
H@ or OH@ H@ or OH@ the nitrile is accessible as by S,2
reactions of RX (Section 8-7F).

2. Hydrolysis of esters and amides Useful where the starting material can
be prepared by alkylation of 30x0-
RCO,Rr
H@ or OH@
> RC02H + R'OH butanoate or propanedioate esters
and similar reactions.

RCONH, H@ Or OH@ > RC02H + NH,

3. Carbonation of organometallic compounds Usually carried out by pouring solution
of organometallic compound over
RMgX --%
co RC0,MgX ,
H@ RCO,H powdered Dry Ice and stirring effi-

RLi '02 ,RC0,Li

4. Malonic ester synthesis
-
H20, H@
RCO,H
ciently; an important and versatile
reaction (see Section 14-12B).

An important reaction for synthesis of

alkyl and dialkylethanoic acids (RX
RX + CH2(C0,C2H5), Na0C2H5+ RCH(C02C,H5), and R'X are primary or secondary alkyl
halides); dicarboxylic acids (RX =
H201H@
2. heat (-COP)
,RCH,CO,H haloester); unsaturated acids (RX =
an unsaturated halide, best for allylic
halides); p-keto acids (R = acyl
R'X + RCH(C0,C2H5), Na0C2H5,RRtC(CO,C2H5), chloride); (see Sections 18-8C
and 18-8D).
H@ ,RR'CHCO,H
2. heat (-CO,)
5. Acetoacetic ester syntheses No particular advantage.over 4; in fact,
ketones may be formed in competition
RX + CH3COCH2C02C,H5 Na0C2H5 ,CH3COCHC0,C2H5 with acids in acetoacetic-ester
I synthesis (see Section 18-8B).

I
R'X -I- CH,COCHC0,C2H, ,
Na0C2H5 CH3COCC02C2H,
I I
R R
 Methods of Preparation of Carboxylic Acids

Table 18-5 (continued)

Methods of Preparation of Carboxylic Acidsa

Reaction Comment

6. Arndt-Eistert reaction Useful method of preparing next-higher

homologue of an acid (see Sections
RCOCI + CH,N, --+ RCOCHN,
Ag2O
,RCH,CO,H 16-4A and 24-7C).

d iazomethane d iazoketone

7. Oxidation of primary alcohols and aldehydes Oxidizing agents are KMnO, (H@ or
01-10), CrO,, HNO,, and Ag,O. (Ag,O
RCH,OH RCHO '01 RC0,H only works for aldehydes.)

8. Oxidation of alkenes Oxidizing agents are KMnO, (H@ or

OH@), CrO,, and HNO,; used mainly
for structure determination; further
degradation may occur.

9. Oxidation of methyl ketones (halo form reaction) Hypochlorites may be used in place of

RCOCH, - Br NaOH
[RCOCBr,]
1. NaOH
2. H@ >
Br, and NaOH; limited by possible
substitution of halogen in R radical
(see Section 17-2B).

-
10. Cannizzaro reaction Useful only when aldehyde has no a
hydrogen and cannot then undergo an
NaOH
2RCH0 RCH,OH + RC0,H aldol condensation (see Section 16-4E).

11. Baeyer-Villiger oxidation of ketones with peracids Generally useful method for aliphatic
and aryl ketones without double bonds;
oxidizing agents commonly used are
II
RCOR + R'C-0-0-H ---+ RC0,R + R1C02H peroxybenzoic acid (C,H,CO,H),

1
I
ti@, H 2 0
peroxyethanoic acid (CH,CO,H), and
trifluoroperoxyethanoic acid
(CF,CO,H); the last is prepared from
RC0,H + ROH trifluoroethanoic anhydride and H,O,
and used in the presence of
NaH,PO, as a buffering agent
(Section 16-7).

"Methods specific for the preparation of aromatic acids are discussed in Chapter 26.
 18 Carboxylic Acids and Their Derivatives

Table 18-6
'Methods of Preparation of Carboxylic Esters

Reaction Comment

1 . From carboxylic acids and primary alcohols Generally limited to primary alcohols;
acidic catalysts include H2S04,HCI,
H@
RC0,H + R'OH T----$ RC02Rt + H,O BF,; for details and mechanism see
Sections 15-4D and 18-3A.

2. From acid chlorides and alcohols Versatile reaction; works well with
prim., sec., and tert. alcohols; a base
RCOCl + R'OH -+ RC02Rt + HCI may be necessary to remove HCI,
because tert-aliphatic alcohols may
give a1kenes and tert-butyl chlorides.

3. From anhydrides and alcohols Widely applicable; acid-catalyzed.

(RCO),O + R'OH --H+

@
+
RC02R1 RC0,H

4. Ester interchange Acid- and base-catalyzed; generally

limited to primary alcohols (for dis-
H@ or OH@
+
RCO2R1 R1'OH< +
RCO2RU R'OH cussion, see Section 18-7A).

R'OH + SOCI, -
5. From carboxylate salts, thionyl chloride, and alcohols

R'OSOCI
al kyl chlorosulfite
+ HCI
Limited to primary alcohols; it amounts
to an SN2 displacement of chloro-
sulfite group by carboxylate ion; steric
hindrance in the carboxylate salt
RC0,Na + R'OSOCI ---. RC02Rr+ SO, + NaCl seems unimportant

6. From carboxylate salts and alkyl halides Restricted to primary halides with
high SN2 reactivity.
RC0,Na + R'X ---.RC02R1+ NaX

7. Alcoholysis of nitriles Analogous to hydrolysis of nitriles,

Method I , Table 18-5.
H@ H O
RCN + R'OH +
RC02R1 NH,@

RC0,H + CH,N, -
8. Diazomethane and carboxylic acids

RCO,CH, + N,
High yield, clean reaction, but
diazomethane is a reactive, explosive,
and toxic compound; useful for methyl
esters of rare or acid-sensitive
carboxylic acids.
Methods of Preparation of Acyl Halides, Anhydrides, Amides, and Related Compounds 857

Table 18-7
Methods of Preparation of Acyl Halides, Anhydrides, Amides, and Related Compounds

Reaction Comment

ACYL HALIDES

RC0,H -
1. From thionyl chloride and carboxylic acids

+ SOCI, RCOCl + HCI + SO,

Most acyl chlorides are prepared by
this method; anhydride formation is
sometimes an objectionable side
reaction.

3RC0,H
RC0,H
+ PBr,
+ PCI,
-
2. From phosphorus halides and carboxylic acids

- 3RCOBr + H3P03
RCOCl + POCI, + HCI
Separation difficulties from H3P03
and POCI, sometimes occur.

3. From thionyl chloride and anhydrides Useful only when anhydride is more
accessible than the parent acid.

1,2-benzenedicarboxylic 1,2-benzenedicarbonyl dichloride

anhydride

4. Acyl fluorides, bromides, and iodides from chlorides Sometimes the only route available to
halides other than the chloride.
RCOCl + HX ---+ RCOX + HCI
in which HX = HF, HBr, or HI

RC0,H + COCl
I
COCl
-
5. From ethanedioyl dichloride
RCOCl + CO + CO, + HCI
Usually an excellent method.

ANHYDRIDES

1. From acid halides and carboxylic acids The most frequently used method;
simple or mixed anhydrides can be
RC0,H + R'COCI pyridine ,RCO-O-COR~ + HCI prepared.

RC0,Na -
2. From acid halides and carboxylic salts
+ R'COCI RCO-0-COR' + NaCl
3. From ketene and carboxylic acids Commercial preparation of ethanoic
anhydride (Section 17-6B).
CH,=C=O + RC02H---+ RCO-0-COCH,
858 18 Carboxylic Acids and Their Derivatives

Table 18-7 (continued)

Methods of Preparation of Acyl Halides, Anhydrides, Amides, and Related Compounds

Reaction Comment

1 . From acyl chlorides and ammonia or amines Most amides are prepared by this
00 method; use base to convert
RCOCl + 2NH3 --+ RCONH, + NH,CI RtNH,CI to RNH, (Sections 23-9A
0 0 and 24-3).
RCOCl + 2RtNH2--+RCONHR' + R1NH3CI
2. From carboxylic acids and ammonia or amines Requires relatively high temperatures.
00 heat
+ NH,
-
RC02H --+ RCO,NH, -----+ RCONH, -tH 2 0

RC0,H + R'NH, - 00
RCO,NH,R
heat
RCONHR + H20

(RCO),O + NH, -
3. From anhydrides and ammonia or arnines
00
RC02NH4'r RCONH,
Important method for preparation of
cyclic imides from cyclic anhydrides.

heat
-H20 RCONH,

4. Hydrolysis of nitriles Hydrolysis stops at amide stage if R

is a tert-al kyl group; H202
accelerates the hydrolysis reaction in
RCN + H20, y7 RCONH, alkaline solution (Section 24-3B).
H202,OH@
5. Addition of nitriles to alkenes (Ritter reaction) Gives N-alkylamides; good only for
alkenes (or alcohols) that form
R,C=CH, + R'CN > R2C-CH, relatively stable carbonium ions;
I useful for preparation of amines with
N=C-R' tert-alkyl groups by hydrolysis of
amides (Section 24-3B).

6. Hydrazides

RCOZC2H5 + NH2NH2 --+ RCONHNH, + C2H50H

hydrazine hydrazide
7. Hydroxamic acids (acylazanols)
0 0
RC02C2H, + NH,OH CI --+ RCONHOH t- C,H,OH + HCI
hydroxylammonium
chloride
8. Acyl azides

RCOCI t- NaN,
sodium
- RCON, + NaCI
azide
Supplementary Exercises 859

Supplementary Exercises

18-52 Write equations for a practical laboratory synthesis of each of the following
substances from the indicated starting materials (several steps may be required).
Give reagents and conditions.
a. butanoic acid from I-propanol
b. 2,2-dimethylpropanoic acid from tert-butyl chloride
c. 2-methylpropanoic acid from 2-methylpropene
d. 2-bromo-3,3-dimethyl butanoic acid from tert-butyl chloride
e. cyclobutylmethanol-1-14C, (CH2)3CH14CH20H,from cyclobutanecarboxylic acid
and Ba14C03
f. 4-pentenamide from 3-chloropropene
g. 2,2-dimethylpropyl 2,2-dimethylpropanoate from tert-butyl chloride

18-53 Write reasonable mechanisms for each of the following reactions:

HOBr / \
b. CH2=CHCH2CH2C02H ----+ BrCH2- CH C=O
\n-'

The order of reactivity for CH3C02R is R = CH3-> CH3CH2->> (CH3),CH-.

18-54 4-Bromobicyclo[2.2.2]octane-I-carboxylic acid (A) is a considerably stronger

acid than 5-bromopentanoic acid (B). Explain. (Hint: Consider the possible conforma-
tions and modes of transmission of the electrical effect of the C-Br dipole.)

18-55 tert-Butyl ethanoate is converted to methyl ethanoate by sodium methoxide

in methanol about one tenth as fast as ethyl ethanoate is converted to methyl ethanoate
under the same conditions. With dilute HCI in methanol, tert-butyl ethanoate is rapidly
converted to 2-methoxy-2-methylpropane and ethanoic acid, whereas ethyl ethanoate
goes more slowly to ethanol and methyl ethanoate.
a. Write reasonable mechanisms for each of the reactions and show how the relative-
rate data agree with your mechanisms.
b. How could one use 180as a tracer to substantiate your proposed mechanisms?
860 18 Carboxylic Acids and Their Derivatives

18-56 It has been reported that esters (RCO2Rt)in 180water containing sodium hy-

droxide are converted to R-C' in competition with alkaline hydrolysis. The

\
0 R'
rates of both exchange and hydrolysis reactions are proportional to OH@concentra-
tion. Explain what these facts mean with regard to the mechanism of ester hydrolysis.

18-57 Write equations for a practical laboratory synthesis of each of the following
substances from the indicated starting materials (several steps may be required).
Give reagents and conditions.
a. 2-chloroethyl bromoethanoate from ethanol and/or ethanoic acid
b. 2-methoxy-2-methylpropanamide from 2-methylpropanoic acid
c. 3,5,5-trimethyl-3-hexanol from 2,4,4-trimethyl-1-pentene (commercially available)
d. 3,3-dimethylbutanal from 2,2-dimethylpropanoic acid
e. 2,3,3-trimethyl-2-butanol from 2,3-dimethyl-2-butene

f. the 1,2-ethanediol ketal of cyclopentanone, , from hexanedioic acid

18-58 For each of the following pairs of compounds give a chemical test, preferably
a test-tube reaction, that will distinguish between the two substances. Write an equa-
tion for each reaction.
a. HC02H and H3CC02H
b. CH3C02C2H,and CH30CH2C02H
c. CH2=CHC02H and CH3CH2C02H
d. CH3COBr and BrCH2C02H
e. BrCH2CH2CH2C02CH3 and CH3CH2CHBrC02CH3

FHr7H2
f. (CH3CH2CO),0 and
o=c\ /c=o
0

C02H C02H CO2H H

\ / \ /
and C=C
"
H
?="\H /
H
\
C02H

h. HC-CC02CH3 and CH2=CHC02CH3

i. CH3C02NH, and CH3CONH2
j. CH2=CH-CH2CH2C02H and CH3CH2CH=CHC02H
k. (CH3CO),0 and CH3C02CH2CH3

18-59 Explain how you could distinguish between the pairs of compounds listed in
Exercise 18-58 by spectroscopic means. Be specific about what would be observed.
Supplementary Exercises 86 1

18-60 Suppose you were given four bottles, each containing a different isomer (2-,
3-, 4-, or 5-) of hydroxypentanoic acid. Explain in detail how you could distinguish
the various isomers by chemical reactions.

18-61 Compound A (C4H,03) was optically active, quite soluble in water (giving a
solution acidic to litmus), and, on strong heating, yielded B (C4H602), which was op-
tically inactive, rather water-soluble (acidic to litmus), and reacted much more readily
with KMnO, than did A. When A was oxidiz'ed with dilute chromic acid solution, it was
converted to a volatile liquid C (C3H60),which did not react with KMnO,, and gave a
yellow precipitate with I, and NaOH solution.
Write appropriate structures for the lettered compounds and equations for all
of the reactions mentioned. Is Compound A uniquely defined by the above descrip-
tion? Explain.

18-62 Name each of the following substances by the IUPAC system:

18-63 Write equations for the synthesis of each of the substances in Exercise 18-62
a-l from compounds with fewer carbon atoms, using the type of reactions discussed
in Sections 18-9, 18-10, and 18-1 1. You may wish to review Sections 13-6 to 13-9
before beginning.

18-64 Direct reduction of aldehydes with 2,3-dimethyl-2-butylborane proceeds

rapidly and gives the corresponding alcohol. Nonetheless, reduction of carboxylic
acids with the same borane (Section 18-3C) proceeds slowly and gives high yields of
aldehydes. Explain why the reaction of RC02H with the 2,3-dimethyl-2-butylborane
produces RCHO instead of RCH,OH.