Kinetics of N-Acylation of Glycine and L-Proline with 4-Nitrophenyl 4-Nitrobenzoate in Aqueous-Organic Solutions

Article abstract of DOI:10.1023/A:1025688403234

Kinetic characteristics (rate constants and activation energies and entropies) are determined for N-acylation of glycine and L-proline with 4-nitrophenyl 4-nitrobenzoate in water-acetonitrile, water-2-propanol, and water-2-methyl-2-propanol systems. With

Full text of DOI:10.1023/A:1025688403234

Russian Journal of General Chemistry, Vol. 73, No. 4, 2003, pp. 566 568. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 4, 2003,
pp. 600 602.
Original Russian Text Copyright
2003 by Kuritsyn, Lebedukho, Sadovnikov.
Kinetics of N-Acylation of Glycine and L-Proline
with 4-Nitrophenyl 4-Nitrobenzoate
in Aqueous-Organic Solutions
L. V. Kuritsyn, A. Yu. Lebedukho, and A. I. Sadovnikov
Ivanovo State University, Ivanovo, Russia
Received April 24, 2001
Abstract Kinetic characteristics (rate constants and activation energies and entropies) are determined for
N-acylation of glycine and L-proline with 4-nitrophenyl 4-nitrobenzoate in water acetonitrile, water 2-pro-
panol, and water 2-methyl-2-propanol systems. With increasing water content in the system, the N-acylation
rate constants increase and the activation energy and entropy decrease, which is due to features of solvation
of the reagents and activated complex with aqueous-organic solvents.
Previously we studied the kinetics of N-acylation
of -amino acids and dipeptides with benzoyl chloride
in aqueous 1,4-dioxane [1 4]. Hirata and Nakasato
reported on N-acylation kinetics of -amino acids
with N-acetoxysuccinimide in water [5]. Data on
N-acylation of -amino acids with carboxylic acid
esters are practically lacking. Evidently, this is due to
some experimental difficulties caused by low solubil-
ity of -amino acids in organic solvents, and also by
the occurrence of side reactions in aqueous-organic
solvents at pH >9. In particular, the rate of hydrolysis
of esters is comparable with and sometimes higher
than that of N-acylation of -amino acids. We have
developed a method for studying the kinetics of
N-acylation of -amino acids with esters in aqueous-
organic solvents, allowing these difficulties to be
overcome.
concentrations of the forms of -amino acids are
controlled by the equilibrium constants and solution
pH. They can be estimated by the equations derived in
[9] on the assumption that the concentration of the
neutral form is negligible. We have demonstrated that
hydrolysis of an ester in aqueous-organic media can
be neglected if the anionic and zwitterionic forms are
taken in the ratio of 1/5 and 1/10 for Gly and Pro,
respectively. N-Acylation reactions of Gly and Pro
can be written as follows.
OH
I + Gly
I + Pro
Gly-COC6H4NO2-4 + 4-NO2C6H4O , (1)
Pro-COC6H4NO2-4 + 4-NO2C6H4O . (2)
OH
In studying the kinetics of N-acylation of Gly and
Pro, the amino acids were taken in considerable (102
103) excess relative to the ester. The concentrations
of the anionic forms of the amino acids were (2 4)
In this work we studied the kinetics of N-acylation
of glycine (Gly) and L-proline (Pro) with 4-nitro-
phenyl 4-nitrobenzoate (I) in aqueous-organic solvents
[water acetonitrile (A), water 2-propanol (B), and
water 2-methyl-2-propanol (C)]. It was demonstrated
in a series of works [6 8] that the zwitterionic form
of -amino acids dominates in aqueous and aqueous-
organic solutions. Only anionic and neutral forms can
be N-acylated with carboxylic acid esters. At various
pHs, one or another form of an -amino acid do-
minates; for example, at pH 8 9, the equilibrium
shifts towards the anionic form, but, in this case, the
ester is hydrolyzed more readily. By the essence, the
solution of the zwitterionic and anionic forms of
-amino acids is a buffer solution. Therefore, by
adjusting the ratio between these forms, one can
reduce pH, thus reducing hydrolysis of an ester. The
3
4
10 and (8 9) 10 M for Gly and Pro, respectively.
The first-order rate constants k1 were estimated by
the Guggenheim method, and the second-order
constants k2, by the equation k2 = k1/c, where c is the
concentration of the anionic form of an amino acid.
Kinetic characteristics of Gly and Pro N-acylation with
ester I in aqueous-organic solvents are summarized in
the table. As seen, with increasing water content, the
N-acylation rate constants increase and the activation
energy and entropy decrease, suggesting the occur-
rence of a compensation effect.
The increase in the reaction rate constant with
increasing water content in the aqueous-organic
solvent is caused by formation of activated complexes
1070-3632/03/7304-0566$25.00 2003 MAIK Nauka/Interperiodica

KINETICS OF N-ACYLATION OF GLYCINE AND L-PROLINE
567
Kinetic characteristics of Gly and Pro N-acylation with ester I in systems A C
Gly
Pro
H2O
content, wt%
T, K
k2,
l mol 1 s
Ea,
S298
,
k2,
l mol 1 s
Ea,
S298,
J mol 1 K
1
1
1
1
1
1
kJ mol
J mol 1 K
kJ mol
A
40
50
60
70
80
298
308
318
298
308
318
298
308
318
298
308
318
298
308
318
0.19
0.41
0.78
0.22
0.42
0.79
0.29
0.55
0.98
0.37
0.66
1.09
0.38
0.64
1.19
55.1 1.3
51.1 0.5
48.5 1.5
43.1 1.3
39.7 0.5
82.3 4.4
1.12
2.02
3.86
1.24
2.20
4.01
1.29
2.15
3.86
2.02
3.46
5.92
4.33
7.20
11.99
48.9 2.1
45.9 1.4
43.5 2.4
42.3 0.8
40.2 2.5
88.7 6.7
96.6 4.5
95.0 1.7
101.2 5.1
117.1 4.4
134.3 1.7
102.6 7.6
105.7 2.7
108.9 2.5
B
40
50
60
70
80
298
308
318
298
308
318
298
308
318
298
308
318
298
308
318
0.61
1.03
1.64
0.63
1.06
1.73
0.70
1.12
1.85
0.77
1.18
1.93
0.94
1.55
2.26
45.2 1.8
40.4 0.3
38.6 1.4
36.1 1.7
34.4 1.1
124.3 1.6
4.73
7.28
12.12
4.99
7.87
13.37
5.21
8.02
13.60
6.00
9.36
15.19
6.94
37.1 0.6
36.0 1.4
35.0 1.7
34.2 0.8
32.9 0.3
116.1 2.0
119.3 4.6
122.3 5.5
123.9 2.4
127.0 1.0
130.9 1.2
135.4 2.2
142.9 4.0
146.2 3.3
10.61
16.00
C
40
50
60
70
80
298
308
318
298
308
318
298
308
318
298
308
318
298
308
318
0.60
1.16
1.86
0.62
1.09
1.76
0.64
1.03
1.61
0.67
1.03
1.65
0.81
1.25
1.92
44.8 2.7
41.9 1.9
37.9 1.2
36.4 1.4
33.9 0.4
107.3 8.8
4.67
8.06
12.40
4.84
8.08
12.51
5.02
9.50
14.24
5.86
9.94
14.76
6.58
38.3 1.8
36.6 0.6
35.5 1.7
34.9 1.5
32.8 0.6
111.9 5.9
117.3 2.0
119.2 5.7
121.1 5.0
127.8 2.1
116.9 6.3
130.1 3.9
134.9 4.6
141.6 1.2
10.24
15.11
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 4 2003

568
KURITSYN et al.
were determined spectrophotometrically from the
variation in the 4-nitrophenolate concentration (
log k2
=
400 nm). In measurements we used a KFK-2UKhL
4.2 photoelectric colorimeter equipped with a thermo-
statically controlled cell holder and a Shch-300 digital
voltmeter. Acetonitrile (analytical grade) was distilled
from P2O5. 2-Propanol (chemically pure grade) was
distilled on a column. 2-Methyl-2-propanol (chemi-
cally pure grade) was purified according to the
procedure described in [12]. Reaction mixtures were
prepared from saturated NaOH (analytical grade), Gly,
and Pro. The apparent rate constants (k1) were
estimated by the Guggenheim method to within 1 2%
(at a 0.95 confidence level).
0
0.1
0.2
0.480
0.483
0.486
0.489
(
1)/(2 + 1)
Rate constant (log k ) of Gly N-acylation with ester I in
2
system B at 298 K vs. Kirkwood function.
REFERENCES
of the -amino acids and ester I with water molecules
through hydrogen bonding, thus decreasing the acti-
vation energy. In its turn, H bonding makes the struc-
ture of the solvated activated complex more regular,
resulting in increased negative activation entropy.
1. Kuritsyn, L.V. and Kalinina, N.V., Zh. Org. Khim.,
1988, vol. 24, no. 19, p. 2065.
2. Kuritsyn, L.V. and Kalinina, N.V., Zh. Org. Khim.,
1994, vol. 30, no. 5, p. 723.
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ONIITEKhim, Cherkassy, 1989, no. 380-khp-89, Ref.
Zh. Khim., 1989, 18E182 Dep.
The table shows that the activation energy is higher
in system A, which can be attributed to the features
of solvation of the reagents with the nonaqueous
component of a binary solvent. It should be pointed
out also that the Pro N-acylation rate constants in all
the solvents are considerably higher as compared to
Gly. This can be explained by higher basicity of Pro
(pKaGly 9.6, pKParo 10.6) [9]. The Gly and Pro N-acyla-
tion rate constants in system A are considerably lower
than those in systems B and C, the latter two being
practically equal. This is probably due to the presence
of hydroxy groups in the alcohol molecules, which
are capable of forming hydrogen bonds with the
reagents, thus enhancing the amino acid reactivity.
4. Kuritsyn, L.V. and Kalinina, N.V., Available from
ONIITEKhim, Cherkassy, 1989, no. 381-khp-89, Ref.
Zh. Khim., 1989, 18E183 Dep.
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Soc. Jpn., 1982, vol. 55, no. 4, p. 3064.
8. Niasi, M.S. and Mollin, J., Bull. Chem. Soc. Jpn.,
The Gly acylation rate constant in system B is
plotted in the figure vs. the Kirkwood function.
Similar dependences were observed in all the solvents
studied. The observed nonlinearity of the log k2 (
1)/(2 + 1) plot ( is the dielectric constant of the
solvent [10]) suggests the effect of other solvent
parameters, such as polarizability, donor acceptor
characteristics, etc., on the rate constant [11].
1987, vol. 60, no. 7, p. 2605.
9. Kuritsyn, L.V. and Kalinina, N.V., Zh. Fiz. Khim.,
1996, vol. 70, no. 12, p. 2168.
10. Akhadov, Ya.Yu., Dielektricheskie svoistva binarnykh
rastvoritelei (Dielectric Properties of Binary Solvents),
Moscow: Nauka, 1977, p. 399.
11. Palm, V.A., Osnovy kolichestvennoi teorii organi-
cheskikh reaktsii (Principles of Quantitative Theory of
Organic Reactions), Leningrad: Khimiya, 1977.
EXPERIMENTAL
In the work we used glycine and L-proline of
12. Maryott, A.A., J. Am. Chem. Soc., 1941, vol. 63, no. 8,
analytical grade. The Gly and Pro N-acylation rates
p. 3079.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 4 2003