C AR BO XY LI C ACIDS a nd the ir Der iv ative s –N ucle op hilic Acyl

su bstitut io n
- Re view t he no me n clatu re fo r t hese co mp ou nd s in you r text b oo k

O O– O–

•• ••
R Z R Z R Z
- the basicity of Z determines the relative stability of carboxylic acid
derivatives; thus, the order of stability is:
O O O O O O
< < ~ <
R Cl R O R R OH R OR R NR'2
anhydrides
carboxylic esters amides (R' = H or alkyl)
acid chloride acids

- the order of reactivity is the reverse (the better the leaving group, the
more reactive RCOZ is in nucleophilic acyl substitution):
O O O O O O
> > ~ >
R Cl R O R R OH R OR R NR'2
anhydrides
carboxylic esters amides (R' = H or alkyl)
acid chloride acids
- based on this order of reactivity, more reactive acyl compounds (acid
chlorides and anhydrides) can be converted to the less reactive ones
(carboxylic acids, esters, and amides) but the reverse is usually not true.
Why?
O For a reaction to
O
occur, Z must be a
R C Z better leaving group
R Z than Nu
Nu
Nu 2 possible leaving groups
-
For mat ion o f Acid C h lo rides
Acid chlorides (or bromides) are extremely reactive. However, they are easily
prepared from carboxylic acids by two common methods:
1) Treatment with thionyl Chloride (SOCl2):

1
- the poor leaving group, OH, is transformed into a better leaving group in this
process- see M echa nis m 22 .5 .

2) Treatment with oxalyl chloride (a much nicer reaction!):

cat. DMF

This reaction is believed to proceed via the mechanism below:

Why make acid chlorides? They are the fastest way to get to any other
carboxylic acid derivative, or to a number of other carbonyl compounds:

2
The mechanism for all of the above reactions (except the last [Friedel-Crafts]) is
pretty much the same – a nucleophile adds to the electrophilic carbonyl group,
creating a tetrahedral intermediate. The electrons on oxygen then pop down,
expelling the good leaving group (Cl-). This type of reaction is frequently called
an addition-elimination reaction:

Acid Anh ydr id es:

O O O O

Ph O Ph Me O Ph

benzoic anhydride acetic benzoic anhydride

Symmetrical anhydrides are typically made by mixing an acid under
dehydrating conditions. For the most part, this is a difficult reaction to perform,
and since the reactivity of anhydrides is so similar to that of acid chlorides,
anhydrides are not commonly used in synthesis.

3
There are two exceptions to this statement. First, acetic anhydride is fairly easy
to prepare in bulk from dirt-cheap acetic acid, and so it is often used in place of
acetyl chloride (MeCOCl).
Second, cyclic anhydrides are fairly easily formed by heating molecules that have
two carboxylic acid functions in close proximity to high temperatures (a
dehydration reaction). A couple of examples are maleic anhydride and phthalic
anhydride:

Cyclic anhydrides have use in organic chemistry; e.g. in Diels-Alder reactions.

Again, the most commonly used anhydride is acetic anhydride. This reagent can
be used to acetylate functional groups such as alcohols and amines. Acetylation
can modify both the chemistry and biological activity of a compound. In the case
of aspirin, for example, acetylation of the relatively acidic phenol alcohol of
salicylic acid leads to a compound that doesn’t dissolve your stomach lining so
easily...

O O H
NH2 N Me
Me O Me
O
HO HO

acetaminophen (active
ingredient in tylenol)
So, remember...anhydrides react just about like acid chlorides.

4
 O R'OH as solvent O
HCl or H2SO4 catalyst + H2O
R OH R OR'
-To drive the reaction to completion, excess alcohol must be used or water must be
removed as it is formed. See Mechanism 22.6.
- esterification of a carboxylic acid occurs in the presence of an acid but not in the
presence of a base (since a carboxylate ion results under basic conditions).

5
performed on an ester rather than an acid. Finally, esters are very common in nature and
thus are often the final goal of synthesis

O O
1. MeMgBr
+ CH4
R OH 2. H2O R OH

MeOH/H2SO4

O OH
1. MeMgBr

R OMe 2. H2O R Me
Me

reverse of Fischer Esterification of carboxylic acids (see mechanism 22.8).

6
7
8
9
10
11