Brine-mediated efficient benzoylation of primary amines and amino acids

Article abstract of DOI:10.1080/00397910802250929

Benzoylation of primary amines and amino acids is efficiently carried out in a brine solution using a stoichiometric amount of benzoyl chloride followed by trituration with aqueous saturated bicarbonate solution. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802250929

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Brine-Mediated Efficient
Benzoylation of Primary
Amines and Amino Acids
Gautam Chattopadhyay a , Suchandra Chakraborty b
& Chandan Saha b
a Postgraduate Department of Chemistry, Presidency
College, Kolkata, India
b Department of Clinical and Experimental
Pharmacology, School of Tropical Medicine, Kolkata,
India
Published online: 31 Oct 2008.
To cite this article: Gautam Chattopadhyay , Suchandra Chakraborty & Chandan Saha
(2008): Brine-Mediated Efficient Benzoylation of Primary Amines and Amino Acids,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:23, 4068-4075
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Synthetic Communications1, 38: 4068–4075, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802250929
Brine-Mediated Efficient Benzoylation
of Primary Amines and Amino Acids
Gautam Chattopadhyay,1 Suchandra Chakraborty,2 and
Chandan Saha2
1Postgraduate Department of Chemistry, Presidency College,
Kolkata, India
2Department of Clinical and Experimental Pharmacology,
School of Tropical Medicine, Kolkata, India
Abstract: Benzoylation of primary amines and amino acids is efficiently carried
out in a brine solution using a stoichiometric amount of benzoyl chloride
followed by trituration with aqueous saturated bicarbonate solution.
Keyword: Amines, amino acids, benzoylation, brine
Benzoylation provides an efficient and inexpensive means to identify
and characterize amines as well as to protect an amino functionality in
a multistep synthetic process.[1] In addition, benzoylation is used for the
resolution of amino acids.[2] A number of reagents can be used for carry-
ing out this reaction, such as benzoyl chloride,[3] benzoic anhydride,[4]
N-benzoyltetrazole,[5,6] 2-benzoylthio-1-methylpyridinium chloride,[7]
and benzoyl cyanide.[8] Though benzoyl chloride may be a health hazard
because of toxicity, it is widely used because of its ready availability
and low cost. In the well-known Schotten–Baumann method,[9] for the
benzoylation of amines, excess of benzoyl chloride is used in alkali, and
the benzoyl derivative frequently occludes unchanged benzoyl chloride,
which escapes hydrolysis and poses difficulty in isolating the product.
Received April 8, 2008.
Address correspondence to Gautam Chattopadhyay, Postgraduate Depart-
ment of Chemistry, Presidency College, Kolkatta 700073, India. E-mail: g_chatto
padhyay2002@yahoo.co.in
4068

Benzoylation of Amines and Amino Acids
4069
Thus, development of an efficient and convenient methodology is an
important area of research. Considering the importance of benzoylation
and environmental factors, as well as our interest in green chemical
processes, we report here a brine-mediated efficient and convenient ben-
zoylation of primary amines and amino acids using a stoichiometric
amount of benzoyl chloride.
The primary amine or amino acid is dissolved (or suspended) in brine
(scale: 1 g of sodium chloride in 3 ml of water) and then an equivalent
amount of benzoyl chloride in acetone (1:1) is added dropwise with
stirring. The desired product is finally obtained by treating the reaction
mixture with saturated bicarbonate solution.
To gain insight into the role of the brine, it is assumed that the high
concentration of Clꢀ ion in the reaction mixture resists the hydrolysis of
benzoyl chloride and is also responsible for the slow decomposition of the
tetrahedral intermediate formed by the nucleophilic attack of the amino
group toward the benzoyl chloride. The rationale is supported by the fact
that when the reaction is carried out only in water (instead of brine), the
yield is drastically reduced. In the case of o- and p- aminobenzoic acids,
the sodium salt of the benzoyl derivatives are separated because of the
common ion (Naþ) effect. From the sodium salt, the required derivatives
are obtained by usual acid workup followed by washing with hot water to
remove traces of benzoic acid. It is worth mentioning that the usual
Schotten–Baumann method to obtain the benzoyl derivative of alanine
requires longer reaction time coupled with tedious workup.[2] In all the
cases examined, the derivatives are crystallized from methanol=
methanol–water=water and identified by comparing them with authentic
samples. The results are summarized in Table 1.
In conclusion, we have developed a very simple, inexpensive, non-
toxic, and environmentally friendly method for the benzoylation of amines
and amino acids.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
Reagent-grade chemicals were purchased from a commercial source and used
without further purification. IR spectra were recorded in KBr discs on
Schimadzu FTIR-8300, and NMR spectra were recorded on Bruker AV 500.
General Procedure
To a mixture of 25 mmol of primary amine or amino acid (water-
insoluble compounds are taken in 20–30 ml of acetone) and 50 ml of

4070
G. Chattopadhyay, S. Chakraborty, and C. Saha
Table 1. Brine-mediated benzoylation of amines and amino acids
Substrate to sodium
bicarbonate
(eqv. Amt.)
Yield
(%)
Mp=lit. mp of
benzoate (ꢁC)
Entry Substrate (R–NH2)
1
1:2
1:2
56
60
57=57a
2
3
4
148=149
1:2
1:2
72
80
106=105
163=163
5
6
1:2
1:2
62
80
145=144
157=158
7
1:2
82
156=154a
(Continued )

Benzoylation of Amines and Amino Acids
4071
Table 1. Continued
Substrate to sodium
bicarbonate
(eqv. Amt.)
Yield
(%)
Mp=lit. mp of
benzoate (ꢁC)
Entry Substrate (R–NH2)
8
1:2
76
99=99
9
1:2
82
194=193
10
11
1:2
1:2
76
78
98=98
157=157
12
1:2
84
199=199
13
1:2
45
160=161
(Continued )

4072
G. Chattopadhyay, S. Chakraborty, and C. Saha
Table 1. Continued
Substrate to sodium
bicarbonate
(eqv. Amt.)
Yield
(%)
Mp=lit. mp of
benzoate (ꢁC)
Entry Substrate (R–NH2)
14
1:2
60
152=—a
15
16
1:3
51
166=166a
1:4
49
178=176a (anhyd.)
17
18
19
1:3
1:3
1:3
80
70
80
183=182
252=248
284=278
20
1:3
60
248=— (dec.)
aProducts were characterized by their spectral data.

Benzoylation of Amines and Amino Acids
4073
brine (10 ml for water-soluble compounds), 25 mmol of benzoyl chloride
in 3 ml of acetone are added in portions with continuous stirring during
15 min. The requisite amount (Table 1) of the saturated solution of
sodium bicarbonate is added, and the reaction mixture is stirred for a
further period of 15 min. The sparingly soluble benzoyl derivative of
primary amine is separated as solid. In the case of amino acids such
as m-aminobenzoic acid, DL-alanine, DL-aspartic acid, and sulfanilic
acid, the sodium salt remains in solution, whereas for the amino acids
such as o-and p-aminobenzoic acids, the sodium salt separates as solid.
From the sodium salt, the corresponding benzoyl derivative is obtained
by usual acid workup (for sulphanilic acid, acidification is accomplished
by conc. H2SO4) followed by washing with hot water to remove
traces of benzoic acid. The benzoyl derivatives are crystallized from
methanol=methanol–water=water. In the cases of DL-alanine and
DL-aspartic acid, the benzoyl derivatives after crystallization were
purified by vacuum sublimation.
Representative Spectral Data of Benzoyl Derivatives
Entry 1
1H NMR (500 MHz, DMSO-d6) d, ppm, 7.85 (d, J ¼ 7.7 Hz, 2H), 7.53–
7.44 (m, 3H), 3.09 (t, 2H), 1.85 (m, 1H), 0.90 (d, J ¼ 7 Hz, 6H);
13C NMR (125 MHz, DMSO-d6) d, ppm, 166.23, 134.76, 130.77,
128.03 (ꢂ2), 127.07 (ꢂ2), 46.64, 28.02, 20.07 (ꢂ2); IR (KBr) n, cmꢀ1
,
3296, 2958, 2916, 2873, 1633.
Entry 7
1H NMR (500 MHz, DMSO-d6) d, ppm, 7.95 (d, J ¼ 7.6 Hz, 2H), 7.68 (d,
J ¼ 8.2 Hz, 2H), 7.58–7.51 (m, 3H), 6.94 (d, J ¼ 8.2 Hz, 2H), 3.75 (s, 3H);
13C NMR (125 MHz, DMSO-d6) d, ppm, 164.90, 155.54, 134.96, 132.13,
131.22, 128.20 (ꢂ2), 127.42 (ꢂ2), 121.88 (ꢂ2), 113.62 (ꢂ2), 55.06; IR
(KBr) n, cmꢀ1, 3330, 2900, 2805, 1647.
Entry 14
1H NMR (500 MHz, DMSO-d6) d, ppm, 8.11 (s, 1H), 8.09 (s, 1H), 7.66–7.29
(m, 5H); 13C NMR (125 MHz, DMSO-d6) d, ppm, 164.97, 158.63, 137.44,
132.38, 132.07, 128.43 (ꢂ2), 128.01 (ꢂ2), 113.71; IR (KBr) n, cmꢀ1, 3109,
2935, 1676.

4074
G. Chattopadhyay, S. Chakraborty, and C. Saha
Entry 15
1H NMR (500 MHz, DMSO-d6) d, ppm, 7.89 (d, J ¼ 7.7 Hz, 2H), 7.56–
7.46 (m, 3H), 4.42 (quintet, 1H), 1.41 (d, 3H); 13C NMR (125 MHz,
DMSO-d6) d, ppm, 174.13, 166.09, 133.89, 131.24, 128.14 (ꢀ2),
127.34 (ꢀ2), 48.08, 16.83; IR (KBr) n, cmꢁ1, 3369, 2981, 2933, 1724,
1705, 1627.
Entry 16
1H NMR (500 MHz, DMSO-d6) d, ppm, 7.85 (d, J ¼ 7.3 Hz, 2H), 7.57–
7.47 (m, 3H), 4.76 (q, 1H), 2.78 (overlapping dd, 2H); 13C NMR
(125 MHz, DMSO-d6) d, ppm, 172.55, 171.82, 166.13, 133.83, 131.45,
128.89 (ꢀ2), 127.80 (ꢀ2), 49.40, 35.85; IR (KBr) n, cmꢁ1, 3319, 3037,
2937, 1706, 1649.
ACKNOWLEDGMENT
We are thankful to D. K. Neogi, director, School of Tropical Medicine,
for his interest in the work. We are also thankful to the Council of Scien-
tific and Industrial Research (CSIR), New Delhi, India, for providing a
junior research fellowship to one of the authors (S. C.).
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