Syntheses of N-alkyl, A,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thioncarbamates: A kinetic study

Article abstract of DOI:10.1007/s00706-011-0596-1

The kinetics of the syntheses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thioncarbamates from sodium ethyl xanthogenacetate, ten alkylamines, and eight substituted anilines were studied at 25, 30, 35, and 40 °C. The reactions were found to follow second-order kinetics. The kinetic (Arrhenius) parameters, such as the activation energy and the frequency factor, as well as the Eyring parameters, such as the standard entropy, the standard Gibbs energy, and the standard enthalpy of activation, were calculated from the second-order rate constants. The mechanism of the reaction was postulated based on the kinetic studies presented and the optimization of the reaction mechanism using the MOPAC PM6 semi-empirical method.

Full text of DOI:10.1007/s00706-011-0596-1

Monatsh Chem (2012) 143:43–49
DOI 10.1007/s00706-011-0596-1
ORIGINAL PAPER
Syntheses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl)
O-ethyl thioncarbamates: a kinetic study
•
Milutin M. Milosavljevic Aleksandar D. Marinkovic
•
´
Vlada B. Veljkovic Dragan D. Milenkovic
´
•
´
´
Received: 26 January 2011 / Accepted: 16 July 2011 / Published online: 11 August 2011
Ó Springer-Verlag 2011
Abstract The kinetics of the syntheses of N-alkyl,
N,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thionc-
arbamates from sodium ethyl xanthogenacetate, ten
alkylamines, and eight substituted anilines were studied at
25, 30, 35, and 40 °C. The reactions were found to follow
second-order kinetics. The kinetic (Arrhenius) parameters,
such as the activation energy and the frequency factor, as
well as the Eyring parameters, such as the standard
entropy, the standard Gibbs energy, and the standard
enthalpy of activation, were calculated from the second-
order rate constants. The mechanism of the reaction was
postulated based on the kinetic studies presented and the
optimization of the reaction mechanism using the MOPAC
PM6 semi-empirical method.
Introduction
Syntheses and properties of thio- and thioncarbamates
have been attractive for many years because of their
structural characteristics, such as the direct connection of
the thiocarbonyl group to nitrogen, which contribute to
their significant biological activity [1–7]. A general
method for their preparation is the reaction of dithiocar-
bonic acid O,S-diesters in aqueous or alcoholic solution
with primary or secondary amines, and the reaction of
monothiocarbonic acid O-ester chloride with the corre-
sponding amines [8]. Thioncarbamates can be prepared by
the reaction of xanthogenates and amines in the presence
of nickel and palladium catalysts [9], thiols and isothio-
cyanate in the presence of catalysts and without the use of
solvent [10], as well as isocyanate and disulfide in the
presence of Zn/AlCl3 [11]. Syntheses of N-alkyl and N,N-
dialkyl O-ethyl thioncarbamates have been performed
from diethyl dixanthogenate and amines using different
oxidants [12].
Keywords Amines ꢀ Kinetics ꢀ Reaction mechanism ꢀ
Synthesis ꢀ Thioncarbamates
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0596-1) contains supplementary
material, which is available to authorized users.
In addition, thioncarbamates can be prepared by reacting
sodium ethyl xanthogenacetate (NaEtXAc) and alkyl- or
dialkylamines [13]. It was found that the reactions follow
second-order kinetics, and the formation of the transition
state is probably the rate-determining step [13]. According
to previous findings [13], the studied reactions were sup-
posed to be thioacyl nucleophile substitutions of NaEtXAc
by amines. The nucleophile, namely amine, ‘‘attacks’’ the
thiocarbonyl carbon of NaEtXAc, forming a tetrahedral
intermediate, as shown in Fig. 1, where R = alkyl, isoalkyl
or cycloalkyl, and R0 = H for monoalkyl amines, R = alkyl
and R0 = alkyl for dialkyl amines, and R = 4-substituted
phenyl and R0 = H for 4-substituted anilines.
´
M. M. Milosavljevic
Economics Institute, Kralja Milana 16, 11000 Belgrade, Serbia
´
A. D. Marinkovic
Faculty of Technology and Metallurgy, University of Belgrade,
Karnegijeva 4, P.O. Box 3503, 11120 Belgrade, Serbia
´
V. B. Veljkovic
ˇ
Faculty of Technology, University of Nis,
16000 Leskovac, Serbia
´
D. D. Milenkovic (&)
ˇ ´
High Chemical Technological School, Kosanciceva 36,
The structure of the amine is the most important factor
affecting the reaction yield, and it was shown that lower
ˇ
37000 Krusevac, Serbia
e-mail: milenkovic_dragan@yahoo.com
123

´
M. M. Milosavljevic et al.
44
cyclopropyl, cyclopentyl, cyclohexyl, as well piperidine
and pyrrolidine] and for aniline and 4-substituted anilines
with various substituents [dimethylamino, methoxy,
methyl, chloro, bromo, acetyl, and nitro groups]. Kinetic
results obtained in this and a previous study [13] are given
in Table 1.
δ+
NHR'R"
:NHR'R"
RO
δ-
RO
S
S
SCH2COONa
NaOOCH2CS
AC
NHR'R"
RO
The order of reaction was confirmed by determining rate
constants for the reactions between NaEtXAc (1.73 9
10-5 mol dm-3) and amines at different initial concentra-
RO
HSCH2COONa
+
S
S
SCH2COONa
R"R'N
I
tions (1.73 9 10-4
, , , and
8.62 9 10-3 1.73 9 10-3
1.73 9 10-2 mol dm-3). The amines with propyl, hexyl,
isopropyl, dipropyl, cyclopentyl, and piperidine groups
were used, as well as aniline and 4-substituted anilines with
methoxy, chloro, and nitro substituents. Plots of the cal-
culated apparent first-order rate constants (kapp) versus
initial amine concentrations gave correlations with slopes
that correspond to the values of the second-order rate
constants given in Table 1 (the relative error is less than
3%). This allowed the second-order rate law of the inves-
tigated reaction to be verified. As the reaction is first order
with respect to both reactants, the proposed reaction
Fig. 1 The most probable reaction pathway (AC activated complex,
I intermediate) [15, 16]
yields were obtained for amines with a bulkier alkyl group
[14].
In the present study, we studied the kinetics of the syn-
theses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl)
O-ethyl thioncarbamates from NaEtXAc and a number
of alkylamines with various alkyl groups [hexyl, sec-butyl
(1-methylpropyl), isopropyl (1-methylethyl), isobutyl
(2-methylpropyl), isopentyl (3-methylbutyl), cyclopropyl,
cyclopentyl, cyclohexyl, as well piperidine and pyrrolidine]
as well as aniline and 4-substituted anilines with various
substituents [dimethylamino, methoxy, methyl, chloro,
bromo, acetyl, and nitro groups]. The main goals of this
study were to determine reaction rate constants and the
reaction order with respect to the reactant, as well to elu-
cidate the reaction mechanism. Based on the kinetics study,
temperature-dependent Arrhenius parameters, such as the
activation energy and frequency factor, and Eyring
parameters, such as the standard entropy, the standard
Gibbs energy, and the standard enthalpy of activation, were
calculated.
Table 1 Second-order reaction rate constants for the reactions of
NaEtXAc with amines
Amine
k2 9 103/dm3 mol-1 s-1
25 °C
30 °C
35 °C
40 °C
Ethyla
Propyla
Butyla
Pentyla
49.61
65.44
69.46
70.56
69.90
6.53
70.20
87.61
93.85
97.50
96.80
9.36
107.41
107.76
128.75
119.14
131.59
13.72
15.64
58.68
77.18
9.85
133.73
140.85
141.20
179.61
165.03
20.09
20.41
90.69
109.54
16.39
9.63
Hexyl
Isopropyl
sec-Butyl
6.08
9.35
Isobutyl
31.47
40.52
6.12
40.50
56.10
8.07
Results and discussion
Isopentyl
Diethyla
Dipropyla
The aminolysis of NaEtXAc with a large excess of amine
in water obeyed the simple kinetic law given by Eqs. 1 and
2. The linear dependence of ln[(A - A?)/(A0 - A?)] on
time indicates that the reactions of NaEtXAc with the
amines were all first order with respect to NaEtXAc. Val-
ues of the apparent rate constant were calculated from the
slope of the linear dependence of ln[(A - A?)/(A0 - A?)]
on time using the least-squares method; the value of the
linear correlation coefficient for all reactions studied was
higher than 0.98. In a previous study, the reaction was
shown to be first order with respect to six alkylamines:
ethyl, propyl, butyl, pentyl, diethyl, and dipropylamine
[13]. Assuming first-order kinetics with respect to
NaEtXAc, the second-order reaction rate constant was
calculated according to Eq. 3 for the amines used in this
work [hexyl, sec-butyl, isopropyl, isobutyl, isopentyl,
5.48
6.48
7.43
Cyclohexyl
Cyclopentyl
Cyclopropyl
Piperidine
10.67
17.43
27.85
518.4
1036.7
2.28
16.21
26.10
41.92
718.2
1359.8
4.06
21.69
32.72
62.59
869.6
1645.0
6.24
35.92
55.48
86.07
1121.4
2086.0
9.10
Pyrrolidine
4-(Dimethylamino)aniline
4-Methoxyaniline
4-Methylaniline
Aniline
2.05
3.98
6.04
8.56
1.95
3.94
5.97
8.49
1.92
3.92
5.94
8.30
4-Chloroaniline
4-Bromoaniline
4-Aminoacetophenone
4-Nitroaniline
a
1.90
3.90
5.90
8.25
1.89
3.89
5.89
8.23
1.86
3.86
5.86
8.14
1.82
3.80
5.80
8.09
´
From Milosavljevic et al. [13]
123

Syntheses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thioncarbamates
Table 2 Thermodynamic
45
Amine
Ea/kJ mol-1
A/dm3 mol-1 s-1
DS#25/J mol-1 K-1
DG#25/kJ mol-1
parameters of investigated
reactions
Ethyl
52.8 4.1
38.9 1.6
38.0 5.4
46.6 4.5
44.8 2.1
58.2 1.5
64.5 5.0
54.9 5.1
51.1 1.7
48.7 11
28.3 4.4
61.0 4.6
57.4 6.4
58.8 1.8
39.3 3.5
35.8 1.8
71.2 4.3
73.2 7.2
74.1 8.4
74.5 8.9
74.9 9.0
75.1 9.1
75.4 9.4
76.2 9.5
9.10 9 107
4.40 9 105
3.33 9 105
1.01 9 107
5.06 9 106
1.04 9 108
1.21 9 109
1.26 9 108
3.64 9 107
2.03 9 106
4.82 9 102
5.15 9 108
1.93 9 108
5.67 9 109
4.09 9 106
2.02 9 106
2.36 9 108
4.36 9 108
5.72 9 108
6.62 9 108
7.74 9 108
8.35 9 108
8.87 9 108
1.14 9 109
-93.1
-137.5
-139.9
-111.2
-117.2
-91.8
78.2
77.5
77.3
77.3
77.3
83.2
83.4
79.3
78.7
83.4
83.6
82.0
80.8
79.6
72.4
70.6
21.64
21.69
21.73
21.74
21.75
21.76
21.76
21.77
Propyl
Butyl
Pentyl
Hexyl
Isopropyl
sec-Butyl
-71.6
Isobutyl
-89.8
Isopentyl
-100.6
-124.3
-193.8
-78.5
Diethyl
Dipropyl
Cyclohexyl
Cyclopentyl
Cyclopropyl
Piperidine
Pyrrolidine
4-(Dimethylamino)aniline
4-Methoxyaniline
4-Methylaniline
Aniline
-86.7
-77.9
-119.1
-124.8
-72.41
-72.57
-72.67
-72.71
-72.73
-72.74
-72.77
-72.81
4-Chloroaniline
4-Bromoaniline
4-Acetylaniline
4-Nitroaniline
mechanism where the formation of the activated complex
(AC, Fig. 1) is the rate-determining step was also verified.
By analyzing the kinetic data (Table 1), the influence of
structural features of the reacting species on the reaction
rate can be discerned. Considering the stereochemical
aspects of the reacting species involved in creating the AC,
a significant influence of the steric effect of the amine alkyl
group on AC stability (i.e., on the reaction rate) could be
expected. The isoalkylamines that branch at the a carbon
have lower rate constants than those that branch at the b
carbon, which indicates that the steric hindrance of the
bulky group decreases with distance from the reaction
center. A higher value of the rate constant for cyclic amines
was noted compared to isopropyl amine. If we consider the
highly strained cyclopropyl, the less strained cyclopentyl,
and the almost strainless cyclohexyl ring, we can see that
the rate constant decreases with increasing of hindrance of
the amine group. The significantly lower rate constant for
dialkylamines is an indication of the more pronounced
steric repulsion of the groups in the AC. Piperidine and
pyrrolidine show the highest reactivity due to the positive
inductive effect of the two alkyl groups and the signifi-
cantly reduced steric interference of the a-hydrogen atoms.
It does seem reasonable that the increased reaction rates of
piperidine and pyrrolidine can be attributed primarily to
lower steric requirements that may favor the reaction. The
polar effect (inductive/field effect) of the alkyl group has a
role to play, too. The lower rate constants in a series of
4-substituted anilines are generally the consequence of
their lower nucleophilicity, while differences in reaction
constants are caused by electronic effects of the substituent.
The activation parameters, such as the activation energy
and the frequency factor, as well as thermodynamic
parameters, the standard entropy, the standard Gibbs
energy and the standard enthalpy of activation, were cal-
culated from the second-order rate constants [15], and the
values are given in Table 2. By analyzing the relation
between the nucleophile structure and the Eyring parame-
ters, it could be possible to obtain information about the
nature of the AC. A high negative value of the standard
entropy of activation indicates that a high degree of
arrangement is needed to create the activated amine–
NaEtXAc complex. Standard entropies of activation for
diethylamine, piperidine, and pyrrolidine were close to the
values for alkylamines, while dipropylamine has a signif-
icantly more negative value, meaning a lower degree of
freedom in the corresponding AC. In the series of cyclo-
alkylamines, values of the standard entropies of activation
123

´
M. M. Milosavljevic et al.
46
are more positive than in the isoalkyl series. There are two
main factors that contribute to these entropy changes: the
lower flexibility of the cycloalkylamine ring enables higher
degrees of freedom for other constituents of the AC. The
standard entropies of activation for 4-substituted anilines
are more positive than those in the alkyl series, and show a
low dependence on steric and electronic effects of the
substituents present on the phenyl ring.
The values of the Eyring parameters DH#25 and DS2#5 are
in line with the proposed mechanism, where the expulsion
of thioacetate anion is enhanced by the hydrogen bonding
in AC, contributing to the highly structured nature of the
AC and leading to the large negative standard entropies of
activation.
series (Table 3). This result indicates the significance of the
steric effects of the amine alkyl groups, as their electronic
effects contribute in only a minor way to the values of the
Eyring parameters. The large negative values of the pro-
portionality constant observed for 4-substituted anilines
(Table 3) indicate that the electronic effect of the sub-
stituent does have a pronounced effect on the kinetics.
Generally, the correlations showed that amines with similar
structures and electronic effects have a similar influence on
the reaction rate.
In order to analyze the influence of the electronic
substituent on the reactivities of N-(substituted phenyl)
O-isobutyl thioncarbamates, a linear free-energy relation-
ship (LFER) in the form of a single-substituent parameter
equation (SSP), s = h ? qr, was applied. The substituent-
dependent value s used in the SSP equation is k2, where q is
the proportionality constant that reflects the sensitivity of
the s value to substituent effects, r is the constant for the
corresponding substituent [16], and h is the intercept (i.e., it
describes the unsubstituted member of the series). Corre-
lation results are presented in Table 4.
Table 3 provides data on four series of amines that were
used in the investigated reaction. All of the series have high
correlation coefficients for the dependence of the standard
enthalpy DH#25 on the standard entropy DS2#5 of activation
(Fig. 2), which indicates that steric effects have a similar
qualitative influence on the reaction rate in all four series.
However, the quantitative influence of the steric effects
varies with the series.
The results for SSP correlations of rate constants with r
at 25 and 30 °C show good precision, and at higher reac-
tion temperatures (35 and 40 °C), the statistical parameters
Positive values of the correlation coefficient were noted
for an alkyl series, a dialkyl series, and a cycloalkylamine
Table 3 Correlation between standard enthalpies and standard entropies of activation for the investigated reaction, considering four series of
amines
Amines
q
h
r
s.d.
F
n
Alkyl and isoalkyl
0.33 0.01
0.30 0.01
0.52 0.03
81.35 1.30
82.97 0.18
98.72 2.97
0.994
0.999
0.995
0.993
0.56
0.13
1.36
0.19
831
7
4
5
8
Dialkyl and sec-alkyl
44,106
303
Cycloalkyl, piperidine, and pyrrolidine
4-Substituted anilines
-12.12 0.57
-809.18 41.67
447
q Reaction constant, h intercept, r correlation coefficient, s.d. standard deviation, F Fisher test of significance; n number of data included in the
correlation
Fig. 2 Correlations between
the standard enthalpy and the
standard entropy of activation
for reactions between NaEtXAc
and amines
123

Syntheses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thioncarbamates
47
Table 4 Hammett SSP correlations of reaction rates for the synthesis
of N-(4-substituted phenyl) O-ethyl thioncarbamates with substituent
r values
T/°C
q
h
r
s.d.
F
n
25
30
35
-0.16 0.02 1.93 0.01 0.989 0.02
-0.15 0.01 3.93 0.01 0.990 0.01
-0.26 0.03 5.97 0.02 0.967 0.04
-0.37 0.03 5.93 0.02 0.993 0.02
-0.17 0.02 5.92 0.01 0.984 0.02
-0.62 0.08 8.44 0.04 0.950 0.11
277
320
86
148 4a
91 5b
8
8
8
40
56
8
-0.95 0.03 8.31 0.14 0.998 0.02 1,476 4a
-0.28 0.02 8.30 0.01 0.994 0.01
273 5b
a
Electron donor included
b
Electron acceptor included
for separate correlations for electron donor and electron
acceptor substituted compounds are excellent. These
results show that reaction temperature has a significant
influence on the reactivity of 4-substituted anilines that
have substituents with different electronic properties. At
increased temperature, electron donation from electron
donors leads to higher amine nucleophilicity, or it may
enable more effective stabilization/delocalization of the
charges created during the formation of the AC.
Fig. 3 Structure of the activated NaEtXAc–ethylamine complex with
minimum potential energy, as calculated by the MOPAC PM6
method
The hydrogen bonding contributes to the stability of the
AC, resulting in a more negative value of the standard
entropy of activation. The significantly higher value of the
standard entropy of activation for dipropylamine than that
for diethylamine could be a consequence of its longer alkyl
groups, which lead to higher steric repulsion and thereby a
higher degree of AC order. The rigid structures of the
piperidine and pyrrolidine rings can be arranged in a lim-
ited number of ways in the corresponding AC, which
probably contributes to a greater extent than the hydrogen
bonding.
To gain better insight into the mechanism of the reac-
tion, the most probable intermediate structure in the
reaction pathway was modeled by using a semi-empirical
method. A difficulty was encountered during the optimi-
zation process, as the program could not simulate the
charged sites of the reacting species, so part of the mole-
cule (the sodium salt of the carboxylic acid) was fixed. The
reaction pathway involves the out-of-plane nucleophilic
attack of amine on the p orbital of the thiocarbonyl group
(Fig. 3) to give the tetrahedral AC (Fig. 1).
Conclusion
The optimized structure of the AC (Fig. 3) was stabilized
through the formation of a hydrogen bond between the
partially positive hydrogen at the amino group or a-hydro-
gens and hydrogen bond accepting sites on NaEtXAc. A
highly polarizable and dipolar water molecule could
additionally stabilize polarizable sites on the AC through
electrostatic interactions and hetero-intermolecular hydro-
gen bonding. It has been proposed that a hydrogen bond is
created during the formation of a four-center type of AC in
the reaction of aryl thiocarbamates with substituted ben-
zylamines in acetonitrile, and the reaction follows second-
order kinetics [17–19]. Castro et al. [20] reported that the
reactions of pyrrolidine with O-ethyl S-(substituted phenyl)
dithiocarbonates in aqueous ethanol [w(C2H5OH) = 0.44]
at 25 °C occurred via a mechanism involving a tetrahedral
intermediate, the formation of which is the rate-determining
step.
The kinetic study of the syntheses of N-alkyl, N,N-dialkyl,
and N-(4-substituted phenyl) O-ethyl thioncarbamates
indicates that the steric effects of alkylamines as well as the
electronic effects of substituents on aromatic amines exert
significant influences on the reaction rate. The values of the
thermodynamic activation parameters were in accord with
the proposed reaction mechanism and the postulated sec-
ond-order reaction rate law for all of the amines studied.
The standard entropy of activation reflected the high
degree of order in the AC, especially for amines that can
create an intermolecular hydrogen bond and dialkylamines.
The rather high values of the activation energies for
4-substituted anilines are a consequence of their low
nucleophilicities, while the similar values of the standard
entropy of activation indicate a high degree of order, but a
very low sensitivity to electronic substituent effects was
also noted.
123

´
M. M. Milosavljevic et al.
48
Experimental
reported in the literature [21–26]. These data can also be
found in the Electronic supplementary material (ESM).
1
The H and 13C NMR spectral measurements were per-
N-Isopentyl O-ethyl thioncarbamate (C8H17NOS)
Yield 90.5% (GC purity 98.5%); b.p.: 124–126 °C
formed on a Bruker AC 250 spectrometer at 250 MHz for
1H NMR and 62.89 MHz for 13C NMR spectra. The
spectra were recorded at room temperature in deuterated
chloroform (CDCl3) in 5 mm tubes. The chemical shifts
are expressed in ppm (d) values referenced to the TMS
1
(2,000 Pa); MS: m/z = 175.12 (M?); H NMR (CDCl3):
d = 0.92 (6H, d, N(CH2)2CH(CH3)2), 1.12 (3H, t,
OCH2CH3), 1.42 (2H, q, NHCH2CH2), 1.68 (1H, m,
CH), 3.28 (2H, t, NCH2), 4.19 (2H, q, OCH2CH3), 6.44
(1H, bs, NH) ppm; 13C NMR (CDCl3): d = 14.6, 22.6,
25.8, 36.7, 38.9, 67.9, 188.8 ppm.
1
(tetramethylsilane) reference signal in H NMR and the
residual solvent signal in 13C NMR spectra.
All mass spectra were recorded on a Thermo Finnigan
Polaris Q ion trap mass spectrometer integrated with a
Trace GC 2000 (ThermoFinnigan, Austin, TX, USA) to
achieve a GC–MS/MS system. The DIP (direct insertion
probe) mode was used to introduce the sample and the EI/
MS/MS technique was employed to acquire the spectra.
Ionization conditions were: ion source temperature 200 °C,
maximum energy of electron excitation 70 eV, corona
current 150 lA.
Gas chromatographic analysis (GC) was performed on a
PerkinElmer 8700 equipped with a FID detector and a
column filled with 5% OV-210 on Gas-Chrom Q [length
2 m, diameter 0.3175 cm (1/800)]. Injector temperature was
250 °C; detector temperature was 270 °C; the column
program was 50 °C (5 min), 10 °C/min, 130 °C (15 min);
carrier gas was nitrogen (purity 99.99%), flow was 1 cm3/
min; air flow was 250 cm3/min (purity 99.99%); and
hydrogen flow was 25 cm3/min (purity 99.99%).
N-Cyclopentyl O-ethyl thioncarbamate (C8H15NOS)
Yield 87.2% (GC purity 98.4%); b.p.: 124–128 °C
1
(2,000 Pa); MS: m/z = 173.06 (M?); H NMR (CDCl3):
d = 1.12 (3H, t, OCH2CH3), 1.52 (4H, m, NCHCH2CH2),
1.75 (4H, m, NCHCH2), 2.68 (1H, q, NCHCH2), 4.31 (2H,
q, OCH2CH3) ppm; 13C NMR (CDCl3): d = 14.4, 22.8,
23.2, 32.6, 32.8, 55.2, 67.8, 188.7 ppm.
N-Cyclopropyl O-ethyl thioncarbamate (C6H11NOS)
Yield 89.4% (GC purity 99.1%); b.p.: 114–117 °C
1
(2,000 Pa); MS: m/z = 145.04 (M?); H NMR (CDCl3):
d = 0.68 (4H, m, NCHCH2), 1.12 (3H, t, OCH2CH3), 1.79
(1H, q, NCHCH2), 4.16 (2H, q, OCH2CH3) ppm; 13C NMR
(CDCl3): d = 7.2, 14.4, 25.8, 67.3, 188.6 ppm.
Syntheses of N-(4-substituted phenyl) O-ethyl
thioncarbamates
Syntheses of N-(4-substituted phenyl) O-ethyl thioncarba-
mates were performed analogously to the method described
above, except that an ethanol solution (0.34 mol of
4-substituted aniline in 50 cm3 of ethanol) was added to the
aqueous solution of ethyl xanthogenacetic acid sodium
salt. After heating the reaction mixture at 60 °C for 3 h,
the ethanol was evaporated away and the crude reac-
tion product was vacuum distilled, except for the nitro-
and acetyl-substituted compounds, and crystallized from
ethanol.
Syntheses of N-alkyl and N,N-dialkyl O-ethyl
thioncarbamates [13]
In a three-necked flask (500 cm3) equipped with a mag-
netic stirrer, dropping funnel, condenser, and thermometer,
13.6 g of sodium hydroxide (0.34 mol) were dissolved in
150 cm3 of water while being cooled in an ice bath, fol-
lowing by the addition of 32.1 g of chloroacetic acid
(0.34 mol), which was added in small portions. Thereafter,
a solution of 54.5 g of potassium ethyl xanthate (0.34 mol)
in 200 cm3 of water was added to the flask at ambient
temperature, and the reaction mixture was gently mixed for
2 h. The prepared solution of sodium ethyl xanthogenac-
etate was then treated with 0.34 mol of the appropriate
amine for 1 h, allowed to stand overnight, before being
acidified with glacial acetic acid. The product was sepa-
rated from the reaction mixture by three extractions with
150 cm3 of ether, and the ether solutions were washed once
with 10% aqueous sodium bicarbonate, twice with distilled
water, and dried over anhydrous magnesium sulfate. Pure
N-alkyl and N,N-dialkyl O-ethyl thioncarbamates were
obtained by vacuum distillation.
The structures were confirmed by comparing their
physical and spectroscopic data with those reported in the
literature [27–32]. These data can also be found in the
ESM.
Study of the reaction kinetics
The reaction kinetics was followed spectrophotometrically
(UV spectrophotometer, Shimadzu 1700) at 280 nm at four
different temperatures (25, 30, 35, and 40 °C). The aque-
ous solutions of NaEtXAc and an amine or ethanol solution
of substituted anilines were thermostated at the appropriate
temperature for 30 min prior to performing measurements.
The initial concentrations of NaEtXAc and the amines
The structures of known compounds were confirmed by
comparing their physical and spectroscopic data with those
123

Syntheses of N-alkyl, N,N-dialkyl, and N-(4-substituted phenyl) O-ethyl thioncarbamates
49
were 1.73 9 10-5 and 4.68 9 10-2 mol dm-3, respec-
References
tively; exceptionally, the initial concentration of
n-hexylamine was 2.34 9 10-2 mol dm-3. The solutions
(5 cm3 of each) were mixed, and part of the mixture was
poured into a measuring cell placed into the UV spectro-
photometer with a thermostat.
1. Glazsrin AB, Denisov AN, Talzi VP, Savin BP (1988) Tiokar-
bamats, Prommiilennostm po proizvodstvu mineralmnih
udobreniy, seriz, Himicheskie sredstva zaoitmi rasteniy. Nau-
chno-isledovalteski institut, Tehniko-ekonomicheskii isledovanii,
Moskva
2. Walter W, Bode KD (1967) Angew Chem 79:285
3. Spallarossa A, Cesarini S, Schenone S, Ranise A (2009) Arch
Pharm 342:344
4. Cichero E, Cesarini S, Fossa P, Spallarossa A, Mosti L (2009)
Eur J Med Chem 44:2059
5. Leonard JT, Roy K (2007) QSAR Comb Sci 26:980
6. Struck RF, Waud WR (2006) Cancer Chemother Pharmacol
57:180
7. Rodis NP, Digenis GA (2001) J Enzyme Inhib 16:95
8. Gotts L (1976) US Patent 3,963,768
Because the amines were in excess in all cases, the
reactions became pseudo first order, corresponding to the
following well-known kinetic equation:
ꢁ lnðcA=cA Þ ¼ kappt;
where cA and cA are the actual and initial NaEtXAc
ð1Þ
0
0
concentrations.
Since cA * (A - A ) and c ꢂ ðA0 ꢁ A Þ, Eq. 1
A0
1
?
9. Bolth FA, Crozier RD, Strow LE (1975) US Patent 3,907,854
10. Movassagh B, Soleiman-Beigi M (2008) Monatsh Chem 139:137
11. Movassagh B, Zakinezhad Y (2005) Chem Lett 34:1330
becomes
ln½ðA ꢁ A Þ=ðA0 ꢁ A Þꢃ ¼ ꢁkappt;
ð2Þ
1
1
´
´
12. Milosavljevic M, Sovrlic M, Marinkovic AD, Milenkovic DD
where A0, A, and A? are the absorbances of the reaction
system at the initial time, after some period of time, and
after infinite time, respectively, and kapp is the apparent
first-order reaction rate constant, defined as follows:
(2010) Monatsh Chem 141:749
´
´
ˇ ´
13. Milosavljevic M, Djordjevic S, Rrazic S (2007) Chem Ind Chem
Eng Quart 13:175
´
ˇ ´
14. Milosavljevic MM, Razic S (2005) Vaprosy Himii i Himicheskoi
Tehnologii 3:50
15. Espenson JH (1981) Chemical kinetics and reaction mechanisms.
McGraw-Hill, New York
16. Hansch C, Leo A, Hoekman D (1995) Exploring QSAR (ACS
Prof Ref Book). American Chemical Society, Washington, DC
17. Oh HK, Jin YC, Sung DD, Lee I (2005) Org Biomol Chem
3:1240
kapp ¼ k2cB;0
where k2 is the second-order reaction rate constant and cB,0
;
ð3Þ
is the initial amine concentration.
Determining the order of reaction
18. Oh HK, Lee JY, Lee I (1998) Bull Korean Chem Soc 19:1198
19. Oh HK, Woo SY, Shin CH, Lee I (1998) Int J Chem Kinet 30:849
20. Castro EA, Cubillos M, Munoz G, Santos JG (1994) Int J Chem
Kinet 26:571
21. Linke S, Sitt S (1974) DE Patent 2263296
22. Herrera M, Ruiz VM, Tapia R, Valderrama J, Vega JC (1980) An
Quim C 76:183
The reaction kinetics was followed at 30 °C, the initial
concentration of NaEtXAc was 1.73 9 10-5 mol dm-3
,
and initial amine concentrations were 1.73 9 10-4, 8.62 9
10-3, 1.73 9 10-3, and 1.73 9 10-2 mol dm-3
.
23. Lozynski M, Kubaszewski E (1983) Chem Anal 28:95
24. Tall AB, Sheldon GP (2008) WO Patent 2008019451
25. Sowa FJ (1964) US Patent 3,161,666
Geometry optimization
26. Scully EJ, Ortega T (1989) J Org Chem 54:2978
27. Hanefeldt W (1975) Liebigs Ann Chem 12:2015
28. Burrows AA (1952) J Chem Soc 4118
29. Sayre RE (1952) J Am Chem Soc 74:3647
30. Mull R (1955) J Am Chem Soc 77:581
31. Goeckeritz D (1963) Pharm Zentralhalle Dtschl 102:685
32. Browne DW, Dyson GM (1931) J Chem Soc 3285
33. Burket U, Allinger NL (1982) Molecular mechanics. American
Chemical Society, Washington, DC
34. Gajevski JJ, Gilbert KE, McKelvey J (1990) Adv Mol Model
2:65
The MNDO-PM6 method implemented in MOPAC2009TM
was used to calculate the minimum potential energy of the
AC. The initial structures of the compounds were generated
by PC MODEL version 4.0 using an MMX force field [33,
34], and were saved as MOPAC input files for the MNDO-
PM6 semi-empirical calculations [35, 36]. The geometries
of all molecular species were optimized by the PM6
method to the root-mean-square gradient using eigenvector
following below 0.042 kJ/mol. VEGA ZZ 2.3.2 was used
as the graphical user interface (GUI). Simulation of the
polar medium, with full geometry optimization, was per-
formed using the COSMO facility [37, 38].
35. Klamt A, Schu¨rmann G (1993) J Chem Soc Perkin Trans 2 799
36. Stewart JJP (1989) J Comp Chem 10:209
37. Stewart JJP (1989) J Comp Chem 10:221
38. Cramer CJ, Truhlar DG (1999) Chem Rev 99:2161
Acknowledgments This work was supported by the Ministry of
Science and Technological Development of Serbia (project number
172013).
123