A simple method for the alkaline hydrolysis of esters

Article abstract of DOI:10.1016/j.tetlet.2007.09.074

A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been developed, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alcohols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2007.09.074

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Tetrahedron Letters 48 (2007) 8230–8233
A simple method for the alkaline hydrolysis of esters
a,
a
b
*
Vassiliki Theodorou, Konstantinos Skobridis, Andreas G. Tzakos and
c
Valentine Ragoussis
a
Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
MRC, Laboratory of Molecular Biology, Hills Road, CB2 0QH Cambridge, United Kingdom
Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, GR-157 71 Athens, Greece
b
c
Received 29 June 2007; revised 3 September 2007; accepted 12 September 2007
Available online 18 September 2007
Abstract—A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been devel-
oped, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alco-
hols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is
proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
Synthesis and structure determination, two of the major
concerns of the organic chemist, usually involve the con-
version of functional groups. Among other transforma-
tions, the saponification of esters to carboxylic acids is a
very common organic transformation and one of the
The rate of a saponification reaction is altered by steric
3
4
and electronic effects, as well as by the solvent, due to
specific interactions of solvent molecules with the reac-
tants. Hydroxylic solvents interact strongly with anions
and increase the energy barrier for reactions that involve
the approach of a negative charge to a neutral system. A
1
,2
most extensively studied reactions in chemistry.
ꢀ
direct HO /ester nucleophilic collision in an aqueous
Ester derivatives are widely present in many drugs, nat-
ural products and synthetic compounds. Furthermore,
they are frequently used for the protection of carboxylic
acids and alcohols, which, as synthons, are unmasked
late in the synthesis.
environment must involve a great amount of desolva-
tion energy, since the hydroxide ion is strongly solvated
by water molecules.
5
Changing the traditional protic solvents of saponifica-
tion reactions to other solvents that do not stabilize
the reactants, seems to be a rather good modification,
since in less polar aprotic solvents the reaction goes
faster.
Saponification processes typically involve the use of
aqueous solutions, combining water and other water
miscible organic solvents, such as methanol, ethanol,
tetrahydrofuran, dioxane and dimethoxyethane in order
to dissolve both, esters and hydroxides (KOH, NaOH,
LiOH). The reaction temperature varies from room tem-
perature to the boiling point of the mixture, while the
length of the reaction time varies from 30 min to 24 h,
or more. A relatively large excess of hydroxide is
normally used, with a concentration chosen to be,
usually, between 0.1 N and 2 N.
6
In a recent study on the selective enrichment of the
b-COOH of Ac-Arg(Tos)-Gly-Asp(OBn)-Resin with
oxygen-17, during solid phase peptide synthesis (SPPS),
it has been established that the solvent system dichloro-
methane/methanol, compatible with SPPS, in a ratio of
about 6:1–9:1, was optimal for successful saponification
1
7
of the side chain of the peptide with Na OH. Methanol
was used in order to dissolve sodium hydroxide.
Methanolysis was, also, observed to some extent in the
presence of higher-levels of methanol.
Keywords: Saponification of esters; Mechanism; Non-aqueous condi-
tions; Methanolysis; Selective enrichment of COOH; Carboxylic acids;
Alcohols.
*
Corresponding author. Tel.: +30 26510 98591; fax: +30 26510
8682; e-mail: vtheodor@cc.uoi.gr
This interesting observation encouraged us to study and
develop an efficient and practical saponification process
9
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.074

V. Theodorou et al. / Tetrahedron Letters 48 (2007) 8230–8233
8231
in non-aqueous conditions that would be applied to a
variety of esters (Eq. 1).
to the broad scientific community. In order to establish
a gentle, time and temperature effective methodology,
without large excess of alkali or high concentrations of
reactants, avoiding undesirable by-products, we sought
to perform saponification experiments on several types
of esters using CH Cl as the reaction solvent, contain-
1
2
. NaOH, rt
(
CH Cl / CH OH ~9:1)
2
3
ð1Þ
RCOOR'
RCOOH + R'OH
+
2
. H O
3
2
2
ing methanol in a ratio CH Cl /CH OH ꢁ9:1.
To the best of our knowledge, there are only a few
reports on non-aqueous saponification conditions.
2
2
3
7
A range of several carboxylic esters was saponified
quantitatively in dichloromethane using NaOH (dis-
solved in MeOH) with a final normality of 0.1–0.5 N,
for a short time at rt (Table 1). The aprotic solvents
Among the various approaches, (CH ) COK in DMSO,
3
3
or in dry Et O with the presence of 1 equiv of water, has
2
7
a,b
been reported for the hydrolysis of hindered esters,
while Ba(OH) Æ8H O in methanol has been used to
2
2
7
c
Et O, THF and dioxane demonstrated comparable effi-
deprotect simple alkyl esters, under conditions suitable
for parallel synthesis. Recently, sodium trimethylsilano-
2
ciency, however, CH Cl was the best choice, since the
2
2
7
d
reaction was apparently faster and the work-up easier.
late (TMSONa) has been utilized for the selective re-
moval of methyl esters on the chain of Glu or Asp on
solid support. More recently, the use of hydroxide ion-
exchange resin has been investigated for ester hydroly-
From the results summarized in Table 1, it is obvious
8
that the proposed hydrolysis protocol works efficiently
7
e
in all cases. Minor differentiations could be observed
depending on the substrate structure. As expected, the
reaction rate depends on the concentration and the ratio
of the reactants, as well as on steric and electronic
effects.
sis in various organic solvents, but the proposed proce-
dure was time consuming. A microwave-enhanced
7
f
hydrolysis of esters, using KF–Al O under solvent
2
3
free conditions has also been described.
Procedures allowing simple, efficient and reliable ester
hydrolysis, without racemizations or other undesirable
side reactions would be advantageous and very helpful
The described methodology provides an efficient labora-
tory procedure for ester hydrolysis and the possibility of
Table 1. Reaction conditions for the alkaline hydrolysis of esters to carboxylic acids
0
a
b
Entry
Ester
RCOOR /NaOH
NaOH (N)
Time
RCOOH
2
D
0
Mp (°C)
½aꢂ
c
10b
1
2
Ac–Pro–OMe
1:1.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
50 min
15 min
1 h 20 min
45 min
30 min
15 min
10 min
10 min
116–118 (115–117)
ꢀ167° (ꢀ171),
12a
3
1
:5
c 1 in CHCl
c
e
Boc–Tyr(2,6-di-Cl–Bzl)–OMe
1:1.1
103–104 (105)
+20.2° (+20),
c 2 in EtOH
e
1
1
:2
:4
3
4
Boc–Glu(OAll)–OH
Boc–Asp(OBzl)–OH
1:2
:3
ꢀ14.1° (ꢀ14.5),
e
1
c 1 in MeOH
1:3
ꢀ4.8° (ꢀ5.0),
e
c 1 in MeOH
d
5
6
7
8
9
0
1
2
Fmoc–Asp(OMe)–OH
1:3
0.1
0.5
0.3
0.2
0.2
0.2
0.2
10 min
15 min
15 min
55 min
1 h 20 min
30 min
30 min
—
—
CH
CH
2
@C(CH
CH@CHCOOEt
3
)–COOMe
1:1.5
1:1.5
1:1.5
1:1.5
1:2
e
3
70–72 (70–72)
130–132 (133)
120–122 (122–123)
—
—
e
PhCH@CHCOOEt
PhCOOMe
e
1
1
1
n-C
n-C
4
H
H
9
CH@CHCH
11CH@CHCH
2
COOEt
COOMe
5
2
1:2
RCH(COOEt)
2
e
(
(
(
(
a, R = H)
1:1.1
0.5
35 min
45 min
1 h 50 min
2 h
130–133 (134–135)
128–131 (129–132)
b, R = Me)
c, R = n-Bu)
d, R = Bzl)
1
2c
100–101 (102)
110–114 (117–120)
e
1
2d
13
14
15
16
17
18
19
20
Methyl (3,5-dibenzyloxy)benzoate
Isopropyl myristate
Tripalmitin
CH
CH
Geranyl phenylacetate
Benzyl pivalate
2-Phenylethyl pivalate
1:8
1:2
1:2
1:1.5
1:1.5
1:2
1:2
1:2
0.5
0.2
0.2
0.3
0.2
0.2
0.2
0.2
4 h
208–209 (210-1)
1
2e
ꢁ2 h
55–57 (57–58)
1
2f
ꢁ2.5 h
5 min
15 min
ꢁ4 h
62–64 (65)
3
COOPh
—
—
3
2 3 2
COOCH CH@C(CH )
e
75–77 (77–78)
ꢁ10 h
ꢁ12 h
—
—
a
b
c
Monitored by TLC until the starting material was exhausted.
The literature melting points and specific rotations are given in parentheses.
The methyl esters of these amino acids were prepared from the corresponding protected amino acids with diazomethane.
With simultaneous Fmoc-deprotection.
d
e
These values have been derived from the pure products supplier (Fluka Laboratory Chemicals).

8232
V. Theodorou et al. / Tetrahedron Letters 48 (2007) 8230–8233
path A
O
O
H C O
3
HO
C R
OR'
H C O
HO C R
OR'
CH OH + RCOO + R'OH
3
3
H
H
path B
HO
O
O
O
H O
C R
HO
H
O C R
H2O + H C O C R
3
CH3
H C
3
OR'
OR'
OR'
....
R'OH + HO + R-COOCH3
RCOO + CH OH + R'OH
3
Figure 1. Suggested mechanism for the saponification of esters in CH
2
Cl
2
/MeOH ꢁ9:1 (path A: direct, path B: through methanolysis).
isolating both products,8,9 acids (entries 1–15, 18) and/
or alcohols (entries 16–20).
17
Na OH for the selective enrichment of the COOH
group.
1
0
The saponification of several discrete classes of natural
products, such as, triglycerides, terpenoids and amino
acid derivatives, received more attention and a detailed
monitoring of the optimum conditions of time and
reagents concentration at rt has been performed.
The method appears to be fairly general, allowing quan-
titative hydrolysis of both alkyl and aryl esters. More-
over, it can be applied in cases where aqueous work-
up must be avoided, since the sodium salt RCOONa
9
can be isolated pure, while the alcohol can be extracted.
1
1a
It is well known that triglycerides in olive oil samples,
3
,11b
11c
11d
The hydrolysis conversion was quantitative for all the
compounds studied, as shown in Table 1. The yields of
recovered pure products were ꢁ80–90%, except for en-
tries 1, 3 and 4, where the yields were about 70–75%,
due to the high solubility of products in both water
and organic solvents. For cases 5, 12a, 16 and 17 yields
were not determined, as the reaction products were,
also, very soluble in water and without special interest.
cinnamates,
prolinates,
other amino acids,
1
2b,c
malonates,
etc., are saponified under relatively more
vigorous reaction conditions, compared with these of
the present work.
A plausible mechanistic process, very similar to the
2
widely accepted classical mechanism and consistent
with our results, can be proposed (Fig. 1). The forma-
tion of a tetrahedral intermediate would be achieved
via a nucleophilic attack on the carbonyl carbon by
Importantly, the saponification of the methyl esters of
orthogonally protected amino acids (entries 1 and 2)
was carried out without racemization, as evidenced by
ꢀ
the HO with assistance by a methanol molecule (path
A). Moreover, a parallel process, where nucleophilic
interaction of a methanol molecule, assisted by a
hydroxide ion, could be responsible for the observed
their observed specific rotations [a] . In the case of
D
side-chain ester derivatives of amino acids (entries
6
3
–5), one more equivalent of NaOH was required, due
methyl ester, which is, subsequently saponified (path
to the a-COOH group. It is, also, of interest that the
saponification of b,c-unsaturated esters (entries 10 and
B). In the less polar solvent CH Cl , used in this work,
2
2
ꢀ
the HO /ester nucleophilic attack is favored, and the
reaction accelerated, due to extensive desolvation of
the hydroxide ions.
1
1) was accomplished without any isomerization to the
corresponding a,b-unsaturated acids, as shown by their
1
H NMR spectra, compared with those of authentic
samples. The saponification of diethyl malonates3c to
malonic acids, was found to proceed relatively rapidly,
depending on the substituent R, without any decarbox-
ylation. On the other hand, longer reaction times, or
more harsh reaction conditions were required for the
sterically hindered esters, especially for entries 13 and
In summary, a simple, rapid and gentle saponification
method has been established, which involves the use of
CH Cl as the reaction solvent, containing about one-
tenth its volume of methanol, and low concentrations
of the hydroxide at room temperature. This methodo-
logy constitutes an advantageous alternative protocol,
compared to the existing methods, for the alkaline
hydrolysis of esters.
2
2
1
8–20, while the esters of fatty acids (14 and 15) reacted
at a moderate rate (Table 1).
1
The H NMR data of all the isolated products, without
further purification, were identical to those of the ex-
pected pure compounds.
References and notes
1
. (a) Euranto, E. K. In Chemistry of Carboxylic Acids and
Esters; Patai, S., Ed.; Interscience: New York, 1969; pp
505–588; (b) Beigley, J. R.; Hutton, A. T.; McLean, W. D.
Org. Process Res. Dev. 1999, 3, 224–226; (c) H o¨ ller, U.;
Conversion reactions for entries 1, 2, 9 and 12a were,
also, performed with equivalent amounts of MeONa
17
and H O, instead of NaOH, in order to produce
2

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8
. General experimental procedure for the saponification
reaction: To a solution of the ester (1 equiv), in a
CH
2
Cl
2
/CH
3
OH (ꢁ9:1, v/v) mixture, was added a meth-
anolic solution of NaOH 2–3 N (1–4 equiv), with the final
concentration of the alkali being about 0.1–0.2 N. After
2
–3 min of stirring, the solution became cloudy and the