Optimization of the synthesis conditions of products formed in arenesulfonylation of N-alkylated anilines

Article abstract of DOI:10.1134/S1070427214090146

Fundamental kinetic aspects of the arenesulfonylation of N-alkylated anilines in aqueous-organic media, the nonaqueous component of which are alcohols, ethers, and acetonitrile were studied. It was shown that, with increasing fraction of water in the solv

Full text of DOI:10.1134/S1070427214090146

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2014, Vol. 87, No. 9, pp. 1274−1278. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.P. Kustova, E.G. Smirnova, L.B. Kochetova, N.V. Kalinina, 2014, published in Zhurnal Prikladnoi Khimii, 2014, Vol. 87, No. 9,
pp. 1280−1285.
ORGANIC SYNTHESIS AND INDUSTRIAL
ORGANIC CHEMISTRY
Optimization of the Synthesis Conditions of Products Formed
in Arenesulfonylation of N-Alkylated Anilines
T. P. Kustova, E. G. Smirnova, L. B. Kochetova, and N. V. Kalinina
Ivanovo State University, ul. Ermaka 39, Ivanovo, 153025 Russia
e-mail: kustova_t@mail.ru
Received October 15, 2014
Abstract—Fundamental kinetic aspects of the arenesulfonylation of N-alkylated anilines in aqueous-organic
media, the nonaqueous component of which are alcohols, ethers, and acetonitrile were studied. It was shown
that, with increasing fraction of water in the solvent, the reaction rate constant grows and the reactivity of N-alkyl
anilines depends not only on the structure of the alkyl radical, but also on the content of water in the solvent. It
was found that dimethyl sulfoxide has a catalytic effect on these processes. The strategy of choosing the medium
in syntheses of biologically active sulfonyl derivatives of fatty-aromatic amines is discussed. A conclusion about
the applicability of aqueous-organic media in the production technology of N-alkylated anilines is based on a
calculation of the yield of their arenesulfonylation products.
DOI: 10.1134/S1070427214090146
Studies of the fundamental kinetic aspects of how the
sulfonamide bond (–NH–SO2–) is formed in molecules
of organic compounds are topical areas of modern
organic chemistry and chemical technology because these
substances possess quite a number of valuable properties:
they exhibit thermal resistance and hydrolytic stability
in alkaline media [1, 2] and can serve as medicinal
preparations (antibacterial, diuretic, etc.) [3], enzyme
inhibitors [4], etc.
in N-acylation of fatty-aromatic amines and necessity for
finding ways to control their production process, studies
of the fundamental kinetic aspects of these reactions
seems to be topical.
The goal of our study was to optimize the synthesis
conditions of sulfonyl derivatives of N-alkylanilines
by analysis of the fundamental kinetic aspects of the
arenesulfonylation of N-methyl- and N-ethylanilines
with 3-nitrobenzenesulfonic acid chloride (I) in aqueous-
alcoholic, aqueous-etheric solvents and in the water–
acetonitrile system:
Previously, the kinetics of reactions of aliphatic and
aromatic amines, amino acids, and arene carbohydrazides
with aromatic sulfonic acid chlorides in organic and
aqueous-organic solvents has been studied [5–8]. The
kinetics of reactions involving fatty-aromatic amines
has been insufficiently studied [9]. At the same time,
N-alkylated anilines are of indubitable interest due to the
asymmetry of their structure (presence of an aromatic
ring and alkyl moiety in the molecule) and, therefore,
can be readily modified at each of the fragments. Use
of water as a component of binary solvents seems to be
promising because of its accelerating effect on a number
of acylation processes of amino compounds. Thus, in
view of the high practical importance of products formed
II
Ia, Ib
(1)
where R = Me (Ia), Et (Ib).
1274

OPTIMIZATION OF THE SYNTHESIS CONDITIONS OF PRODUCTS
1275
The data in Table 1 demonstrate a monotonic rise in the
acylation rate constant of amines Ia, Ib with increasing
fraction of water in the binary solvent, with the value of
kac possibly increasing by nearly an order of magnitude
(see the data for aqueous 1,4-dioxane) on passing from a
10% aqueous solvent to that with 55% water. Among the
solvents under study, the most technologically promising
solvents are aqueous-alcoholic media because the highest
rate constants, up to 0.1 M–1 s–1, are observed just in
these solvents.
Together with the arenesulfonylation of amines (Ia,
Ib) in aqueous-organic solvents, there occurs a concurrent
process, hydrolysis of sulfonyl chloride(II). Therefore,
provided that the initial concentration of the amine (ca0)
is twice the initial concentration of the acid chloride (c0),
the variation rate of the concentration of the acylating
agent is described by the equation
(2)
It has been found previously [9] that the rate of
arenesulfonylation of secondary fatty-aromatic amines
is strongly affected by the steric factor: the larger and
more branched the alkyl substituent in the amino group,
the lower the acylation rate of the amine. This pattern was
experimentally confirmed for a wide variety of secondary
amines and solvents. In the reactions under study, kac
depends in a complicated manner on the size of the alkyl
radical; in low-polarity media (up to 20 wt % water)
the steric factor noticeably affects the rate constant (for
example, kac for the reaction involving N-methylaniline
in aqueous dioxane is 1.5 times that for the reaction of
N-ethylaniline). With increasing polarity of the medium,
the effect of the steric factor on the rate of the processes
under consideration becomes weaker, with the key role
passing to the electronic effect of the electron-donor alkyl
substituent in the aromatic ring of the amine.
where x is the change in the concentration of sulfonyl
chloride by instant of time τ; ca and c, running concen-
trations of the amine and acid chloride, respectively; kac,
rate constant of the second-order reaction (M–1 s–1); and
kh, rate constant of hydrolysis of the acid chloride (s–1).
To study the kinetics of reaction (1), we used the
conductometric method, with the electrical conductivity
of the working solutions measured with an E7-14
immitance meter equipped with an OK-9023 ring
platinum electrode at a frequency of 1 kHz. The value of
c0–x was calculated by the equation
(3)
where χ0, χ∞, and χτ are the electrical conductivities of
the reaction mixture at the initial instant of time, instant
of time τ, and upon the completion of the reaction,
respectively.
The data in Table 1 suggest that kac only slightly varies
between solvents of the same nature. For example, for
50 wt% water, the value of kac (Ia) in aqueous dioxane
was 0.18 M–1 s–1, whereas for aqueous THF, this value
was 0.196 M–1 s–1.
The rate constant of the hydrolysis of sulfonyl chloride
was determined in an independent kinetic experiment, kh
was calculated on the basis of 80–100 measurements of
the electrical conductivity of the acylating agent solution
by the Guggenheim method
Comparison of the activation parameters of the
reactions under study for the aqueous-organic solvent
compositions under consideration demonstrates the
general tendency toward a decrease in the activation
barrier of the reaction with increasing fraction of water
in the medium. In all probability, this is due to specific
features of the solvation of the amine by molecules of
solvent components. The values of ΔH≠298 vary within
the range 20–30 kJ mol–1. The activated complex of the
ln (χi+1 – χi) = a + khτi,
(4)
where χi and χi+1 are the electrical conductivities of the
solution in the intervals of time τi and τi–1 = τi + Δ, and
a and Δ are constants.
reaction becomes more ordered (reaches a value ΔS≠298
–200 J mol–1 K–1).
=
The errors in determining kac and kh we calculated
with a confidence probability of 0.95.
It should be noted that the rates of the processes under
study in all the aqueous-organic system under study
are rather low, and, therefore, it was of interest to find
a catalyst. Based on the data of [10], the catalytic influence
The rate constants kac obtained for the reactions of
amines Ia, Ib with acid chloride(II) in the aqueous-
organic solvents under study at various contents of water
in the mixture are listed in Table 1.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 87 No. 9 2014

1276
KUSTOVA et al.
Table 1. Rate constants of arenesulfonylation of N-alkylated anilines with 3-nitrobenzene sulfonyl chloride in aqueous-organic
solvents at 298 K
kac × 102, M–1 s–1
ω(Н2О), wt %
X(Н2О), ppm
Iа
Water–ethanol as solvent
–
Ib
X(Н2О), ppm
Ib
Water–2-propanol as solvent
0
0
–
0
5.00 ± 0.01
5
0.12
0.22
0.31
0.39
0.52
0.63
0.72
0.79
16.4 ± 0.1
20.0 ± 0.1
34.1 ± 0.2
37.5 ± 0.2
41.5 ± 0.3
43.5 ± 0.4
53.8 ± 0.6
85.5 ± 0.6
Water–1,4-dioxane as solvent
3.2 ± 0.1
11.4 ± 0.6
15.3 ± 0.2
21.2 ± 0.6
28.1 ± 0.2
41.2 ± 0.8
55.7 ± 0.6
–
0.15
0.27
0.37
0.45
0.59
–
–
10
15
20
30
40
50
60
10.60 ± 0.03
–
16.02 ± 0.01
21.50 ± 0.06
–
–
–
–
–
–
Water–THF as solvent
10
15
20
25
30
35
40
45
50
55
0.36
0.46
0.55
0.62
0.68
0.72
0.77
0.80
0.83
0.86
–
–
–
4.9 ± 0.2
–
–
–
5.3 ± 0.2
3.6 ± 0.2
6.9 ± 0.4
13.2 ± 0.7
18.0 ± 0.9
50.0 ± 2.0
–
–
6.1 ± 0.3
0.57
0.63
0.68
0.72
0.76
0.80
–
4.3 ± 0.2
5.9 ± 0.3
6.3± 0.3
10.0 ± 0.5
12.5 ± 0.6
19.6 ± 0.9
–
8.4 ± 0.4
–
13.9 ± 0.7
14.9 ± 0.7
18.0 ± 0.9
23.8 ± 1.0
100.0 ± 5.0
–
–
Water–acetonitrile as solvent
5
0.11
0.20
0.49
0.60
2.26 ± 0.01
2.89 ± 0.01
3.45 ± 0.02
4.70 ± 0.02
10
30
40
of the reaction of Ia with II in a water–1,4-dioxane binary
solvent. It was impossible to use DMSO as a comonent of
the binary aqueous-organic solvent because, according to
[11], sulfonyl chlorides are unstable in DMSO because of
the occurrence of side reactions in which the acid chloride
is converted to the corresponding sulfonic acid. The
values of kac for the reaction involving Ia, with DMSO
as a catalytic acid, are listed in Table 2.
on the acylation rate of amines is exerted by tertiary
amines, hexamethylenephosphotriamide (HMPTA) and
dimethyl sulfoxide (DMSO), with the latter regarded
in pharmaceutical chemistry as a promising solvent
for medicinal preparations. It is known that numerous
reactions catalyzed by bases are substantially faster in
DMSO, compared with protic solvents. In this context, we
studied for the first time the effect of DMSO on the rate
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 87 No. 9 2014

OPTIMIZATION OF THE SYNTHESIS CONDITIONS OF PRODUCTS
1277
Table 2. Rate constants of acylation of (Ia) in a water–1,4-
dioxane solvent in the presence of a catalytic DMSO additive,
ω(H2O) = 35 wt %, 298 K
The data in Table 2 suggest that introduction of the
DMSO catalytic additive leads to an increase in kac,
with the acylation constant the higher, the lower the
DMSO concentration. In all probability, the observed
experimental fact can be accounted for by the occurrence
of side reactions at equimolar ratios between DMSO and
3-nitrobenzene sulfonyl chloride.
kac × 102,
с0
,
kac × 102,
с0DMSO, M
DMSO
M
M–1 s–1
M–1 s–1
0
11.40
170.00
96.30
0.009
0.01
62.10
50.00
0.002
0.006
In aqueous-organic media, a side process, hydrolysis
of 3-nitrobenzene sulfonyl chloride, occurs together
with main reaction of arenesulfonylation of N-alkylated
anilines. Therefore, the system always contains, together
with the target product, an admixture of arenesulfonic
acid. Therefore, it was of interest to determine how the
content of water in the binary solvent affects the yield
αac of the target products 3-nitrobenzenesulfo(N-alkyl)
anilides at various initial concentrations of the reagents.
Using the kinetic data in Table 1 we calculated the yield
αac of the arenesulfonylation product and the fraction
αh of the admixture of 3-nitrobenzene sulfonic acid by
solving the system of differential equations (5) and (6)
by the 4th order Runge–Kutta method:
Table 3. Calculated yield αac of 3-nitrobenzenesulfo(N-methyl)
anilide and fraction αh of 3-NBSA admixture in aqueous-
organic solvents at 298 K
ω(H2O),
wt %
c0,
M
ω(H2O),
wt %
c0,
M
αac
αac
Water–1,4-dioxane
10
15
20
25
30
0.1
0.5
0.968
0.991
40
45
50
55
0.1
0.5
0.916
0.976
0.1
0.5
0.954
0.988
0.1
0.5
0.888
0.967
0.1
0.5
0.929
0.980
0.1
0.5
0.899
0.971
0.1
0.5
0.929
0.980
0.1
0.5
0.912
0.975
(5)
(6)
0.1
0.5
0.933
0.982
Water–THF
The calculated values of αac upon full completion of
reaction (1) involving Ia in aqueous-etheric media are
listed in Table 3.
25
30
35
0.1
0.5
0.897
0.970
40
45
50
0.1
0.5
0.928
0.980
0.1
0.5
0.915
0.976
0.1
0.5
0.932
0.981
In the case of aqueous-alcoholic solvents and
the water–acetonitrile system, the yield of the target
products at the initial reagent concentration of 0.5 M
also exceeded 95%. This suggests that these media can
be recommended for synthesis of arenesulfonylation
products of N-alkylanilines.
0.1
0.5
0.913
0.975
0.1
0.5
0.946
0.986
CONCLUSIONS
Amines Ia, Ib (Aldrich) with 98–99% main substance
were used without additional purification. The acid
chloride(II) of pure grade was recrystallized from a
9 : 1 mixture of hexane and 2-propanol with addition
of activated carbon. 1,4-Dioxane and THF, both of pure
grade, were kept over KOH for seven days and distilled
in a column over metallic sodium. Ethanol of pure grade,
2-propanol of chemically pure grade, and acetonitrile
of pure grade were dried and distilled in a column
under atmospheric pressure. Twice distilled water was
used, with potassium permanganate added in the first
distillation.
(1) The acylation kinetics of N-methyl- and
N-ethylaniline with 3-nitrobenzenesulfonic acid chloride
in five aqueous-organic solvents whose nonaqueous
components are ethanol, 2-propanol, acetonitrile,
1,4-dioxane and terahydrofuran, was studied. It was found
that, with increasing content of water in the solvents, the
rate constants of all the reactions under study grows, with
its maximum value reached in aqueous-alcoholic systems.
(2) It was demonstrated the reactivity of N-alkylanilines
is affected not only by the structure of the alkyl
radical, but also by the solvent composition. In all the
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1278
KUSTOVA et al.
(Synthesis and Properties of Organic Compounds of
Sulfur), Belen’kii, L.I., Ed., Moscow: Khimiya, 1998.
aqueous-organic solvents studied, a higher reactivity
in the arenesulfonylation reaction is demonstrated by
N-methylaniline at low content of water (up to 20 wt %),
and by N-ethylaniline at high content of water.
2. Morgan, P.W., Condensation Polymers: By Interfacial and
Solution Methods, New York: Intersci. Publ., 1965
(3) It was found that dimethyl sulfoxide exerts a
3. Mashkovskii, M.D., Lekarstvennye sredstva (Medicinal
Preparations), Moscow: Novaya Volna, 2006.
catalytic influence on the processes under consideration.
4. Daniela Vullo, Viviana De Luca,Andrea Scozzafava, et al.,
(4) The kinetic data obtained were used to calculate
the yield of arenesulfonylation products of N-alkylated
anilines. For all the solvents under study, the yield
exceeded 95% at an initial reagent concentration of 0.1 M
and more, which suggests that aqueous-organic systems
can be used in the production technology of arenesulfo(N-
alkyl)anilides.
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ACKNOWLEDGMENTS
8. Kalinina, N.V., Kustova, T.P., and Kochetova, L.B., Russ.
Chem. Bull., 2010, vol. 59, no. 5, pp. 922–926.
The authors are grateful to the Ministry of Education
and Science of the Russian Federation for the financial
support of the study.
9. Kustova, T.P. and Sterlikova, I.O., Russ. Chem. Bull., 2006,
vol. 55, no. 6, pp. 973–975.
10. Kustova, T.P. and Kuritsyn, L.V., Russ. J. Gen. Chem.,
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