A facile, catalytic and environmentally benign method for esterification of carboxylic acids and transesterification of carboxylic esters with nearly equimolar amounts of alcohols

Article abstract of DOI:10.1055/s-2006-942456

A practical and green chemical process for the esterification of carboxylic acids with alcohols and transesterification of carboxylic esters in good to excellent yields by using K₅CoW₁₂O₁₄· 3H₂O (0.1 mol%) as catalyst is reported. The catalyst exhibited remarkable reusable activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942456

2392
PAPER
A Facile, Catalytic and Environmentally Benign Method for Esterification of
Carboxylic Acids and Transesterification of Carboxylic Esters with Nearly
Equimolar Amounts of Alcohols
Esterification of
C
.
arboxylic
Ac
S
ids and Transe
u
sterification
b
of Carboxyl
h
ic Esters as Bose,* Apuri Satyender, A. P. Rudra Das, Hari Babu Mereyala
Organic Chemistry Division III, Fine Chemical Laboratory, Indian Institute of Chemical Technology, Habshiguda, Hyderabad – 500 007,
India
Fax +91(40)27160387; E-mail: bose_iict@yahoo.co.in; dsb@iict.res.in
Received 10 February 2006; revised 7 March 2006
necessitated more than equimolar amounts of anhydride
Abstract: A practical and green chemical process for the esterifica-
and silyl dehydrating additives, respectively. The employ-
ment of non-sophisticated and recyclable catalyst un-
doubtedly represents an additional important goal.
tion of carboxylic acids with alcohols and transesterification of car-
boxylic esters in good to excellent yields by using
K5CoW12O14·3H2O (0.1 mol%) as catalyst is reported. The catalyst
exhibited remarkable reusable activity.
In the course of our studies on the use of heterogeneous
catalysis in fine organic chemistry, we developed a meth-
od, which allows the practical route for esterification,
transesterification and simultaneous esterification and
transesterification reactions by using inexpensive and re-
usable K5CoW12O40·3H2O (0.1 mol%) catalyst14 in a high-
ly efficient manner. To our knowledge, however, the
generality and applicability of potassium dodecatangesto-
cobaltate trihydrate (PDTC) to accomplish these reactions
have not appeared so far. We initially investigated the cat-
alytic activity of PDTC, which promotes the esterification
reaction between equimolar amounts of 3-phenylpropion-
ic acid and butan-1-ol in toluene, carried out under azeo-
tropic reflux conditions with removal of water using a
Dean–Stark apparatus for five hours (Table 1, entry 3).
We found that under the best reaction conditions, namely
in the presence of 0.1 mol% of PDTC full conversion into
the ester occurred in five hours. PDTC in excess of five
equivalents did not help to increase the yield to any great-
er extent (Table 1, entry 5). The progress of reaction was
monitored either by TLC or GC. The reaction mixture was
filtered to separate the catalyst, and the filtrate was evap-
orated in vacuo to furnish the product. Moreover, the re-
covered catalyst from the reaction mixture washed with
solvent, and could be reused after thermal activation. The
reactivated catalyst was reused without an appreciable
loss of its catalytic activity (Table 2, entry 1). For exam-
ple, the catalyst was reused for the esterification of phenyl-
acetic acid with butan-1-ol more than three times with
93%, 91%, and 89% yields, respectively.
Key words: esterification, transesterification, alcohols, carboxylic
acids, reusable
Esterifications and transesterifications are widely recog-
nized as one of the most important reactions in organic
synthesis. The ester moiety represents one of the most
ubiquitous functional groups in chemistry, playing a par-
amount role in biology and serving both as key intermedi-
ate and/or protecting group in organic transformations.
Besides its utility in the laboratory, this reaction is signif-
icant in various industrial processes, such as the produc-
tion of fatty acids, paints, polyesters, etc. Since
esterification is an equilibrium process, carrying out the
reaction with a large excess of one of the two reactants
usually performs the full conversion into the products. Re-
cently, the growing interest towards green chemistry led
to the development of a new generation of protocols
which aimed at a 1:1 stoichiometry between the acid and
the alcohol under mild and almost neutral conditions. A
number of useful and reliable esterification methods cata-
lyzed by a variety of acids, ion exchange resins, zeolites,
etc., have been reported in the literature.1–11 Environmen-
tal considerations limit the applicability of many, other-
wise useful catalysts commercially. There are not many
reagents available for commercial applications that can
accomplish both esterification and transesterification re-
actions under mild conditions. Transesterifications are
catalyzed by alkali metal hydroxides and alkoxides in ap-
propriate alcohols and also by DMAP, DBU, PTSA, tin,
calcium or titanium compounds.12
To explore the generality and scope of esterification pro-
cess, diverse acids such as saturated, unsaturated, hydroxy
and dicarboxylic acids were esterified with a variety of al-
cohols. The reactions proceeded in high yields at relative-
ly low temperatures (85–100 °C) and the results are
summarized in Table 2. The esterification process worked
well with primary, secondary, tertiary, benzylic and ho-
moallylic alcohols (Table 2, entries 1–20) with the reac-
tivity of the alcohols decreasing in the order of primary >
secondary > tertiary and neither isomerization of the sub-
strate (entries 5 and 9) nor racemization (entry 7) were ob-
From a recent atom-economical standpoint, the use of
nearly equimolar amounts of carboxylic acids (or carbox-
ylic esters) and alcohols is strongly required. Mukaiyama
and Shiina reported13 such direct esterifications mediated
by TiCl2(ClO4)2 and TiCl(OTf)3 reagents; however, they
SYNTHESIS 2006, No. 14, pp 2392–2396
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942456; Art ID: Z03106SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Esterification of Carboxylic Acids and Transesterification of Carboxylic Esters
2393
Table 1 Optimization in the Esterification of 3-Phenylpropionic Acid with Butan-1-ol
catalyst
COOH
COO(CH2)3Me
Me(CH2)3OH
+
Ph
Ph
toluene
Entry
Catalyst (mol%)
Time (h)
Yield (%)
1
2
3
4
5
K5CoW12O40·3H2O (0.01)
K5CoW12O40·3H2O (0.05)
K5CoW12O40·3H2O (0.1)
5
25
70
95
90
86
7
5
K5CoW12O40·3H2O (0.1), molecular sieves
K5CoW12O40·3H2O (0.15)
8
10
Table 2 Esterification of Carboxylic Acids and Alcohols Using K5CoW12O40 Catalysta
O
O
K5CoW12O40⋅3H2O
R1
R1-OH
+
R
OH
R
O
Entry
RCO2H
R1OH
Temp ( °C) Time (h)
Product
Yield (%)b
1
2
3
4
5
6
7
PhCH2CO2H
PhCH2CO2H
PhCH2CO2H
PhCH2CO2H
Me(CH2)3OH
PhCH2OH
85
85
85
85
85
85
85
5
7
PhCH2CO2(CH2)3Me
PhCH2CO2CH2Ph
93, 91, 89c
88
Me(CH2)7OH
TBDMSO(CH2)4OH
CH2=CHCH2OH
CH3(CH2)7OH
OH
5
PhCH2CO2(CH2)7Me
PhCH2CO2(CH2)4OTBDMS
Ph(CH2)2CO2CH2CH=CH2
Ph(CH2)2CO2(CH2)7Me
93
4
92
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
4
90
6
93
25
87, 72
O
OCCH2CH2Ph
i-Pr
i-Pr
8
9
c-C6H11CO2H
MeCH(OH)(CH2)5Me
NO2CH2CH2OH
100
85
85
85
85
85
85
85
85
85
85
85
85
25
6
5
6
5
5
5
8
6
8
9
6
8
c-C6H11CO2CH(Me)(CH2)5Me
65
85
89
85
89
90
91
82
Ph(CH2)2CO2H
Ph(CH2)2CO2H
4-MeC6H4CO2H
PhCH=CHCO2H
Ph(CH2)2CO2CH2CH2NO2
(Z)-Ph(CH2)2CO2(CH2)2CH=CHEt
4-MeC6H4CO2(CH2)2CH(Me)Me
PhCH=CHCO2(CH2)3Me
CH2=CH(CH2)8CO2Et
10
11
12
13
14
15
16
17
18
19
20
(Z)-EtCH=CH(CH2)2OH
MeCH(Me)CH2CH2OH
Me(CH2)3OH
CH2=CH(CH2)8CO2H EtOH
CH2=CH(CH2)8CO2H Me(CH2)8OH
CH2=CH(CH2)8CO2(CH2)8Me
MeO2C(CH2)4CO2Me
HO2C(CH2)4CO2H
HO2C(CH2)4CO2H
PhCH=CHCO2H
HO2C(CH2)8CO2H
2-OHC6H4CO2H
HO2CCH2CO2H
MeOH
Me(CH2)3OH
t-BuOH
t-BuOH
i-PrOH
Me(CH2)3O2C(CH2)4CO2(CH2)3Me 87
PhCH=CHCO2Bu-t
t-BuO2C(CH2)8CO2Bu-t
2-OHC6H4CO2Pr-i
84
80
88
78
i-PrOH
i-PrO2CCH2CO2Pr-i
a Reaction conditions: 1.0 mmol alcohol, 1.0 mmol carboxylic acid, 0.1 mol% catalyst.
b The yields reported refer to isolated products.
c Catalyst was reused at least three times.
Synthesis 2006, No. 14, 2392–2396 © Thieme Stuttgart · New York

2394
D. S. Bose et al.
PAPER
served. The yields of the products also showed a trend in essentially neutral conditions, and the catalyst is recover-
the same order as that of the reactivity.
able and reusable. This protocol can be readily applied to
large-scale processes with high efficiency and selectivity,
making it an economical and environmentally friendly
process especially effective for simultaneous esterifica-
tion and transesterification reactions. Very few catalysts
are known to catalyze esterification and transesterifica-
tion reactions and K5CoW12O40·3H2O is one such catalyst
that accomplishes both.
It is well known that the reactivity of alcohols and carbox-
ylic acids towards esterification primarily depends on the
steric hindrance of both the reactants. We found that acids
bearing at the a position a bulky cyclohexyl (entry 8)
group gave the desired ester, although a higher tempera-
ture or a higher catalyst loading was required to obtain
good yields. Nevertheless, the reactions were carried at
100 °C at the most, since at higher temperatures some de-
composition of the product occurred. Very good results
were obtained in the case of low reactive carboxylic acids
(entries 11 and 12), and wax esters, i.e. esters of long
chain carboxylic acids with long chain alcohols, which are
generally prepared via acyl chlorides, are also easily pre-
pared by this method. Esters of tertiary alcohols that are
otherwise difficult to prepare are obtained in moderate
Potassium Dodecatangestocobaltate Trihydrate
(K5CoW12O40·3H2O)
CoAc2 (1.77 g, 0.01 mol) and Na2WO4·2H2O (39.6 g, 0.12 mol)
were initially treated with AcOH (5 mL) and H2O at pH 6.5 to 7.5
to give sodium tungestocobalt(II)ate. The sodium salt was then con-
verted into the potassium salt by treatment with KCl (26.0 g). Final-
ly, the cobalt(II) complex was oxidized to the cobalt(III) complex
yields (entries 17,18) but required longer reaction times by K2S2O8 (21.0 g) in H2SO4 (2 M, 80 mL). The crystals of
K5CoW12O40·3H2O were dried at 200 °C. After recrystallization
and increased amounts of catalyst since the dehydration
with MeOH, K5CoW12O40·3H2O was obtained; yield: 17.5 g (55%);
process largely prevailed over the condensation.
light-blue solid.
The reaction is highly chemoselective. In fact, other func-
tionalities present in the carboxylic acid or in the alcohol,
such as a carbonyl, a cyano and a nitro group, a C–C dou-
ble bond or a bromide were unaffected under the adopted
reaction conditions. The compatibility of some typical
protecting groups with the reaction conditions was also
evaluated. Other functional groups present in the alcohol,
such as, benzyl and o-silyl were almost completely unaf-
Octyl Phenylpropionate; Typical Procedure (Table 2, Entry 3)
To a solution of phenylacetic acid (1.36 g, 10 mmol), octan-1-ol
(1.30 g, 10 mmol), and catalyst K5CoW12O40·3H2O (0.1 mol%, 0.01
mmol, 32 mg) were heated at 85 °C in toluene (5 mL) for 6 h
(Table 2). The progress of the reaction was monitored by TLC. The
mixture was filtered to separate the catalyst and the solid material
was washed with MeCN (5 mL). The solvent removed under re-
duced pressure to afford the crude product, which was purified by
fected (entries 2 and 4). Butyl lactate, a valuable interme- column chromatography to give the desired carboxylic ester; yield:
2.54 g (93%). The filtered catalyst was reactivated by heating in an
oven at 70 °C for 2 h for reuse.
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 7.5 Hz, 3 H), 1.23–1.49
(m, 6 H), 1.57–1.71 (m, 6 H), 3.61 (s, 2 H), 4.08–4.21 (m, 2 H),
7.08–7.10 (m, 3 H), 7.12–7.16 (m, 2 H).
diate for the production of butyl acrylate, is prepared in an
efficient manner by esterification of commercial lactic
acid (88%) with butan-1-ol even in the presence of high
amounts of water (12%) in the lactic acid. It is well known
that esterification reactions are highly sensitive to the
presence of trace amounts of moisture; the reaction cata-
lyzed by K5CoW12O40·3H2O appears to be tolerant to
large amounts of water in the reaction system.
All the products in Table 2 are known compounds and were easily
identified by comparison of their physical properties with those of
authentic samples. Selected analytical data for products are as fol-
lows:
In order to evaluate the possibility of applying our meth-
odology in a large-scale esterification, we carried out the
reaction of octan-1-ol with 3-phenylpropanoic acid start-
ing from 13.0 g (100 mmol) of alcohol. The yield in the
ester (entry 6) was almost the same as that of the small-
scale (1 mmol) reaction.
Butyl Phenylacetate (Table 2, Entry 1)
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 7.5 Hz, 3 H), 1.22–1.48
(m, 2 H), 1.54–1.68 (m, 2 H), 3.58 (s, 2 H), 4.06–4.16 (t, J = 6.0 Hz,
2 H), 7.06–7.10 (m, 3 H), 7.14–7.18 (m, 2 H).
2-Methylheptyl Cyclohexanoate (Table 2, Entry 8)
1H NMR (CDCl3, 200 MHz): d = 0.92 (t, J = 6.8 Hz, 3 H), 1.25 (d,
J = 6.0 Hz, 3 H), 1.27–1.35 (m, 12 H), 1.37–1.46 (m, 1 H), 1.52–
1.60 (m, 1 H), 2.22 (s, 3 H), 2.53 (t, J = 6.5 Hz, 2 H), 2.75 (t, J = 6.5
Hz, 2 H), 4.82–4.95 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 19.7, 22.5, 25.4, 28.2, 29.1,
30.0, 31.8, 36.0, 38.0, 71.5, 172.4, 206.1.
The results obtained in transesterification reactions are il-
lustrated in Table 3. Transformations of esters from low to
higher homologues and vice versa were achieved effi-
ciently using this procedure. Transesterification of a me-
thyl ester to a tert-butyl ester (entries 11 and 14), which is
normally problematic, is achieved with this reagent but
transesterification with benzyl alcohol did not proceed.
While esterification of o-toluic acid was not achieved with
this reagent, the transesterification of methyl o-toluate to
butyl o-toluate was accomplished with ease.
(Z)-3-Hexenyl 3-Phenylpropanoate (Table 2, Entry 10)
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 7.5 Hz, 3 H), 2.03–2.08
(m, 2 H), 2.15–2.18 (m, 2 H), 2.65 (t, J = 7.8 Hz, 2 H), 2.96 (t,
J = 7.8 Hz, 2 H), 4.04 (t, J = 6.0 Hz, 2 H), 5.10–5.18 (m, 1 H), 5.22–
5.25 (m, 1 H), 7.08–7.12 (m, 3 H), 7.14–7.18 (m, 2 H).
13C NMR (CDCl3, 50 MHz): d = 15.0, 20.5, 27.0, 30.6, 35.7, 63.8,
123.8, 126.1, 128.0, 128.5, 134.5, 140.5, 173.2.
In conclusion, we have reported herein several notewor-
thy features of a new catalyst for esterification and trans-
esterification reactions. The reaction proceeds under
Synthesis 2006, No. 14, 2392–2396 © Thieme Stuttgart · New York

PAPER
Esterification of Carboxylic Acids and Transesterification of Carboxylic Esters
2395
Table 3 Transesterification of Carboxylic Esters with Alcoholsa
Entry
1
R1CO2R2
R3OH
Product
Time (h) Yield (%)b
PhCH2CO2(CH2)3Me
PhCH2CO2Me
MeOH
PhCH2CO2Me
8
9
91
90
86c
95
95
92
90
89
82
74
91
87
84
80
35
2
PhCH2OH
PhCH2OH
Me(CH2)3OH
PhCH2OH
Me(CH2)7OH
i-PrOH
PhCH2CO2CH2Ph
3
PhCH2CO2Me
PhCH2CO2CH2Ph
9
4
2-HOC6H4CO2(CH2)2CHMe2
2-HOC6H4CO2(CH2)2CHMe2
2-HOC6H4CO2Me
2-HOC6H4CO2Me
4-CH3C6H4CO2Me
PhCH=CHCO2Me
CH2=CH(CH2)8CO2Me
Me(CH2)16CO2Me
Me(CH2)16CO2Me
3-ClC6H4CO2Et
2-HOC6H4CO2(CH2)3Me
2-HOC6H4CO2CH2Ph
2-HOC6H4CO2(CH2)7Me
2-HOC6H4CO2Pr-i
6
5
8
6
7
7
10
8
8
Me2CH(CH2)2OH
Me(CH2)3OH
Me(CH2)3OH
t-BuOH
4-MeC6H4CO2(CH2)2CHMe2
PhCH=CHCO2(CH2)3Me
CH2=CH(CH2)8CO2(CH2)3Me
Me(CH2)16CO2Bu-t
Me(CH2)16CO2CH2Ph
3-ClC6H4CO2Bu-t
9
7
10
11
12
13
14
15
8
12
10
12
8
PhCH2OH
t-BuOH
CH2=CH(CH2)8CO2Me
EtOCH2CO2Et
t-BuOH
CH2=CH(CH2)8CO2Bu-t
EtOCH2CO2CH2CH2NPht
10
O
OH
OH
N
O
O
16
ClCH2CO2Et
ClCH2CO2CH2CH2NPht
15
45
N
O
a Reaction conditions: 1.0 mmol ester, 1.0 mmol alcohol, 10 mol% catalyst, 85 °C.
b Isolated yield, average of two runs.
c Catalyst was reused at least twice.
2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) 2-Ethoxyacetate;
Typical Procedure (Table 3, Entry 15)
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Synthesis 2006, No. 14, 2392–2396 © Thieme Stuttgart · New York