Chemistry of aryl n -(2-pyridyi) thionocarbamates in basic media

Article abstract of DOI:10.1002/poc.1458

Three aryl A/-pyridylthionocarbamates were synthesized by thioacylation of 2-aminopyridine and 2-methylaminopyridine with the respective chlorothionoformates. Their hydrolysis mechanism was studied in aqueous basic media. The aryl A/-(2-pyridyl)thionocarb

Full text of DOI:10.1002/poc.1458

Research Article
Received: 31 May 2008,
Revised: 11 August 2008,
Accepted: 15 September 2008,
Published online in Wiley InterScience: 11 December 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1458
Chemistry of aryl N-(2-pyridyl)
thionocarbamates in basic mediay
a
a,b
a
c
*
´
´
Daniel Silva , Fatima Norberto , Susana Santos and Pablo Herves
Three aryl N-pyridylthionocarbamates were synthesized by thioacylation of 2-aminopyridine and 2-methylaminopyridine
with the respective chlorothionoformates. Their hydrolysis mechanism was studied in aqueous basic media. The aryl
N-(2-pyridyl)thionocarbamates are considerably less reactive than their oxo analogues, the aryl N-(2-pyridyl)
carbamates, especially the N-monosubstituted ones (1a-b). Absence of significant buffer catalysis, isolation of the
product resulting from trapping of the unsaturated intermediate with piperidine and the entropy of activation
observed for the hydrolysis of compound 1b clearly indicate an E1cB mechanism for the N-monosubstituted aryl
N-(2-pyridyl)thionocarbamates. The experimental data suggest that the N,N-disubstituted substrate (2) undergoes
basic hydrolysis by a general base catalysed BAC2 mechanism. Copyright ß 2008 John Wiley & Sons, Ltd.
Keywords: thionocarbamates; heterocycles; pyridyl group; kinetics; reaction mechanisms
very few attempts made to compare the effect of substitution of
INTRODUCTION
the carbonyl by a thiocarbonyl on the reactivity of this type of
compounds.[8–11] With this purpose it was decided to study the
reactivity of secondary aryl N-(2-pyridyl)thionocarbamates in
order to compare them with their oxo analogues, the aryl
N-(2-pyridyl)carbamates previously investigated in the identical
reaction media.[16] This paper presents the synthesis of
thionocarbamates, whose bioactivity against non-tuberculous
mycobacteria was already published,[17] as well as unreported
kinetic studies and the evaluation of the mechanism of hydrolysis
of aryl N-(2-pyridyl)thionocarbamates (1a-b, 2) over the pH range
12–13.8.
The thionocarbamates are a class of compounds widely used as
herbicides and fungicides of which Tolnaftate and Pyributicarb
are two well-known examples. One important parameter in the
evaluation of new thionocarbamates as biological agents is their
reactivity in aqueous media and therefore the study of their
kinetic behaviour is considerably interesting.
There are several examples of secondary (i.e. N-
monosubstituted) carbamates that hydrolyse in basic media by
an elimination mechanism known as E1cB, depending on
structural properties such as the existence of an acidic a proton
and a reasonable good leaving group.[1–4] A significant number of
thionocarbamates is known to react similarly.[5–13] The E1cB
mechanism is characterized by a pre-equilibrium deprotonation
followed by an unimolecular rate determining step involving the
formation of an unsaturated intermediate, an isocyanate for
carbamates or an isothiocyanate for thionocarbamates. This
intermediate is sometimes too labile to be detected directly but
can be trapped through reaction with an amine.[1–7,13]
The activation parameters, namely the entropy of activation,
are useful criteria to determine whether a compound reacts by a
bimolecular process like the base-catalysed addition–elimination
mechanism known as BAC2 or by an unimolecular mechanism
such as the E1cB. Blocking the E1cB mechanism of carbamates by
introduction of N,N-disubstitutions on the substrate is a also a
definitive argument in this type of discussion, since the
comparison between the pH-rate profiles of both substrates, in
which one is incapable of forming the conjugated anion and is a
model for a BAC2 mechanism, provides a good insight into both
types of mechanistic behaviour.[1–9] Oh et al.[14,15] have studied
the aminolysis of several secondary thionocarbamates in
acetonitrile and concluded that they react by an addition–
elimination mechanistic pathway.
´
Correspondence to: D. Silva, CECF, Faculdade de Farmacia da Universidade de
*
Lisboa, 1600-083 Lisboa, Portugal.
E-mail: dabsilva@ff.ul.pt
a
D. Silva, F. Norberto, S. Santos
CQB and Departamento de Qu´ımica e Bioqu´ımica, Faculdade de Ciencias da
Universidade de Lisboa, 1749-016 Lisboa, Portugal
ˆ
b
F. Norberto
Departamento de Ciencias da Sau´de, Universidade Lusofona, 1749-024
Lisboa, Portugal
ˆ
´
´
c
P. Herves
Departamento de Qu´ımica F´ısica, Facultad de Ciencias, Universidade de Vigo,
Apartado 874, Vigo (Pontevedra), Spain
Although there are many studies concerning the reaction
mechanisms of carbamates in aqueous media, there have been
´
CECF, Faculdade de Farmacia da Universidade de Lisboa, 1600-083 Lisboa,
Portugal.
y
J. Phys. Org. Chem. 2009, 22 221–228
Copyright ß 2008 John Wiley & Sons, Ltd.

D. SILVA ET AL.
RESULTS AND DISCUSSION
The influence of the concentration of hydroxide ion on the
reaction rate was studied ranging between 0.01 and
0.5 molꢀdmꢁ3 for secondary thionocarbamates and between
0.1 and 0.8 molꢀdmꢁ3 for phenyl N-methyl-N-(2-pyridyl)
thionocarbamate, using UV–Vis spectrophotometric techniques
to determine the kinetic pseudo first-order rate constants, kobs
(Table 1). The rate of hydrolysis for compounds 1a and 1b is
linearly proportional to [HOꢁ] being the uncatalysed hydrolysis
reaction negligible as indicated in Eqn (1) (Fig. 1).
ꢁ
ꢁ
kobs ¼ kHO ½HO ꢂ
(1)
The comparison of the basic reactivity of compounds 1a and
1b with the one of secondary aryl N-(2-pyridyl)carbamates
reveals that the thionocarbamates are less reactive to hydrolysis
in basic media (ca. 5 ꢃ 103 times),[16] unlike data reported on
earlier studies in which aryl N-(4-nitrophenyl)thionocarbamates
were ca. 102 times more reactive than their oxo analogues due to
the enhanced acidic character of N–H in thionocarbamates.[10,11]
The secondary aryl N-(2-pyridyl)thionocarbamates do not present
a levelling off region in their pH-rate profiles. This is unlike their
oxo analogues which clearly possess such region as a con-
sequence of a pre-equilibrium deprotonation of the nitrogen
atom with the formation of an anion, typical of an E1cB
mechanism.[16] The absence of such levelling off region in the
pH-rate profile is not necessarily evidence that compounds 1a
and 1b do not react by an E1cB mechanism, but only that
their pKa is higher than 14 and consequently the substrate is
never completely deprotonated in aqueous solution. Although
previous results indicate a considerable increase in the acidity of
secondary thionocarbamates up to 3 U of pKa compared to their
oxo analogues,[10,11] this was not observed since the pKa values of
secondary aryl N-(2-pyridyl)carbamates are around 13.[16] This
Figure 1. Effect of NaOH concentration on the rate of reaction of
compounds 1a and 1b followed by UV–Vis spectroscopy (15% 1,4-
dioxane/water (v/v), m ¼ 0.5 molꢀdmꢁ3 (NaClO4), at a temperature of
27.0 8C)
There is no apparent explanation for the reduced acidic
a
character of the
proton in secondary N-(2-pyridyl)
thionocarbamates, since the pyridine ring and thiocarbonyl
adjacent to the N–H are both two powerful electron-withdrawing
groups and should contribute to promote the substrate acidity.
To confirm the data obtained by UV–Vis spectrophotometric
techniques HPLC kinetic studies were performed with compound
1b because the UV–Vis spectra showed some interference. The
´
result differs considerably from the one obtained by Sartore
et al.[9] for phenyl N-phenylthionocarbamate, whose pKa is 9.04
while the analogous phenyl N-phenylcarbamate studied by
Hegarty et al. presents a value superior to 14 in aqueous media in
similar conditions.[11]
Table 1. Values of kobs for the hydrolysis of compounds 1a-b and 2a
[NaOH] (molꢀdmꢁ3
)
103ꢀkobs (sꢁ1) 1a
103ꢀkobs (sꢁ1) 1b
105ꢀkobs (sꢁ1) 2
0.01
0.04
0.05
0.08
0.1
0.2
0.3
0.4
0.5
—
0.15
—
—
0.93
1.46
2.50
4.33
5.46
6.98
—
—
—
—
—
0.43
0.86
1.40
1.84
2.23
2.63
3.05
3.42
2.19
2.04
2.85
2.67
6.47
7.57
12.0
13.2
—
0.6
0.7
0.8
—
—
—
—
aSolvent 15% 1,4-dioxane/water (v/v), with m ¼ 0.5 molꢀdmꢁ3 (NaClO4) for 1a and 1b, m ¼ 1.0 molꢀdmꢁ3 (NaClO4) for 2, 27.0 8C.
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 221–228

CHEMISTRY OF ARYL N-(2-PYRIDYL)THIONOCARBAMATES
Table 2. Hydrolysis of compound 1a in tert-butylamine
buffer solutions of pH 11.1a
102ꢀ[tert-butylamine]free
(molꢀdmꢁ3
)
104ꢀkobs (sꢁ1
)
6.58
5.26
4.61
3.29
1.17
1.41
0.92
0.81
a Solvent 15% 1,4-dioxane/water (v/v), with m ¼ 0.5 molꢀdmꢁ3
(NaClO4), 27.0 8C.
[(2.56 ꢄ 0.15) ꢃ 10ꢁ2], which suggests that small variations of pH
in the successive dilutions of the buffer may be the probable
cause of the decrease of kobs
.
The absence of buffer catalysis is in accordance with a rate
determining unimolecular breakdown of an anionic intermediate
formed in a pre-equilibrium step.[8] The decomposition of the
anion is not dependent upon concentration of the buffer and an
E1cB mechanism exhibits only specific base-catalysis.
Figure 2. Effect of NaOH concentration on the rate of reaction for the
decomposition of compound 1b and the formation of 4-methylphenol
followed by HPLC (15% 1,4-dioxane/water (v/v), m ¼ 0.5 molꢀdmꢁ3
(NaClO4), at a temperature of 27.0 8C)
The temperature effect was studied for the hydrolysis of
compound 1b in sodium hydroxide solutions, with concen-
trations ranging from 0.05 to 0.4 molꢀdmꢁ3 (Table 3) and the
ꢁ
respective values of kHO were calculated with Eqn (1) for each
temperature (Table 4).
hydrolysis products of 1b were identified as being
4-methylphenol and 2-aminopyridine, and it was possible to
verify that for every kinetic experiment the rate of decomposition
of 1b presents the same value as the rate of formation of
4-methylphenol (Fig. 2) confirming the existence of a reactive
intermediate formed throughout the overall reaction.
ꢁ
10ꢁ3 dm3ꢀmolꢁ1ꢀsꢁ1) is slightly lower than the one determined
by UV–Vis spectrophotometry (1.40 ꢃ 10ꢁ3 dm3ꢀmolꢁ1ꢀsꢁ1), due
to experimental conditions, namely the fact that in HPLC studies
the number of experimental points for each kinetic run was
considerably smaller, which contributes for a greater error
associated with each calculated value of kobs in comparison with
the ones obtained by UV–Vis techniques. The HPLC studies were
also quite useful to rule out the possibility of a rearrangement of
1b into the corresponding thiolocarbamate during the hydrolysis
of the substrate in basic media, since it was not observed the
peak corresponding to the formation of 4-methylthiophenol
throughout the kinetic runs; such rearrangement was reported
by Mindl et al.[12] for the hydrolysis of benzidryl N-
phenylthionocarbamate.
The activation parameters for the reactions proceeding via
E1cB mechanism must include also the pre-equilibrium constant
for the formation of the conjugated anion with a negative charge
in the nitrogen (Ka).
The reason of such procedure can be explained by analysing
the kinetic equation for an E1cB mechanism (Eqn 2):[16]
The value obtained for kHO
by HPLC (1.16 ꢃ
k1 ꢃ Ka ꢃ ½HOꢁꢂ
kobs
¼
(2)
Ka ꢃ ½HOꢁꢂ þ KW
Another parameter evaluated was the effect of buffer
concentration on the reaction rate. The hydrolysis of 1a was
studied in several oxygen and nitrogen bases (including
piperidine, n-butylamine, 2,2,2-trifluoroethanol), although due
to spectroscopic problems, it was only possible to obtain reliable
results using tert-butylamine buffer (pH 11.1), for which no
significantly buffer effect was observed (Table 2; Fig. 3). Although
there is a slight variation of kobs values with the free base
concentration, this clearly to small to be ascribed to buffer
catalysis since there is a very poor correlation (R2 ¼ 0.4624) and
the slope presents a considerably low value with quite a large
Figure 3. Hydrolysis of compound 1a in tert-butylamine buffer solutions
of pH 11.1 buffer in 15% 1,4-dioxane/water (v/v), with m ¼ 0.5 molꢀdmꢁ3
(NaClO4), at a temperature of 27.0 8C
error (1.33 ꢄ 1.02) ꢃ 10ꢁ3 compared to the kHO of compound 1a
ꢁ
J. Phys. Org. Chem. 2009, 22 221–228
Copyright ß 2008 John Wiley & Sons, Ltd.
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D. SILVA ET AL.
Table 3. Values of kobs for the hydrolysis of compound 1b at different values of temperaturea (the data for the temperature of
27.0 8C are displayed in Table 1)
[NaOH] (molꢀdmꢁ3
)
103ꢀkobs (sꢁ1) 20.0 8C
103ꢀkobs (sꢁ1) 25.0 8C
103ꢀkobs (sꢁ1) 30.0 8C
103ꢀkobs (sꢁ1) 35.0 8C
0.05
0.08
0.1
0.2
0.3
—
—
0.62
1.29
2.02
2.41
—
—
1.11
2.17
3.49
4.27
—
—
1.74
3.72
5.71
7.02
1.23
2.15
2.93
5.84
—
0.4
—
a Solvent 15% 1,4-dioxane/water (v/v), with m ¼ 0.5 molꢀdmꢁ3 (NaClO4), 27.0 8C.
ꢁ
Table 4. Values of kHO for the hydrolysis of compound 1b at
different values of temperature (with the correspondent
values of R2 for each correlation)
102ꢀkHO (dm3ꢀmolꢁ1ꢀsꢁ1
)
ꢁ
Temperature (8C)
20.0
25.0
27.0
30.0
35.0
0.61 (R2 ¼ 0.9855)
1.08 (R2 ¼ 0.9912)
1.40 (R2 ¼ 0.9964)
1.78 (R2 ¼ 0.9915)
3.06 (R2 ¼ 0.9983)
Being k1 the kinetic constant of the rate determining step, Ka
the thermodynamic acidity constant of the substrate and KW the
auto-protolysis constant for water.
In order to consider both the effect of k1 and Ka in the
calculation of activation parameters it was decided to correlate
ꢁ1
lnðkHO Þ with T instead of ln(kobs) with Tꢁ1.This procedure is
ꢁ
valid and it can be to demonstrated by considering that the Ka of
secondary N-(2-pyridyl)thionocarbamates is smaller than 10ꢁ14
and therefore assuming KW >> Kaꢀ[HOꢁ], so when considering
both Eqns (1) and (2) it is possible to admit without considerable
error that
Figure 4. Eyring plot for compound 1b
the entropy of the system. This situation is not surprising, since
Alborz and Douglas obtained a value for DSz ¼ ꢁ41 Jꢀmolꢁ1ꢀKꢁ1
for an E1cB mechanistic pathway.[19]
k1 ꢃ Ka
Another evidence of an E1cB mechanism comes from the
detection of 2-pyridyl isothiocyanate as a reaction intermediate,
which was trapped during hydrolysis of compound 1b in
piperidine buffer (pH 12.0), forming N-piperidyl-N0-
(2-pyridyl)thiourea (3), whose presence was confirmed by mass
spectrometry. Since the isothiocyanate is originated necessarily
via an elimination mechanism, the presence of its derivative
indicates an E1cB mechanistic pathway. The reason why
piperidine was used as a trapping amine instead of tert-
butylamine (pKa 10.68), for which absence of buffer catalysis was
verified, it is because tert-butylamine is too sterically hindered to
provide an efficient trapping agent for 2-pyridyl isothiocyanate,
while piperidine, a secondary amine with a close pKa (11.12), is
more suitable for that purpose. The possibility of aminolysis of
the substrate by piperidine with formation of N-
piperidyl-N0-(2-pyridyl)thiourea is quite unlikely since the E1cB
mechanism is known to be quite faster than the additio-
n–elimination mechanism and the formation of a thiourea by an
ꢁ
kHO
¼
KW
Data adjustment to Eyring equation (Eqn 3) gives rise to a
satisfactory correlation (Fig. 4) from which were determined the
values for DHz ¼ 77.6 kJꢀmolꢁ1 and for DSz ¼ ꢁ22 Jꢀmolꢁ1ꢀKꢁ1
.
ꢀ
ꢁ
z
z
ꢃ h
kHOꢁ
DH
R
1
T
DS
ln
¼ ꢁ
ꢃ
þ
R
(3)
kB ꢃ T
The value for the entropy of activation obtained is acceptable
for a unimolecular mechanism. The typical values for a BAC2 value
mechanistic pathway usually assume values between ꢁ80 and
ꢁ150 Jꢀmolꢁ1ꢀKꢁ1, while for an E1cB mechanism it is expected a
small and generally positive value for DSz.[18] The negative value
for DSz in this case can easily be explained by the solvent
interactions, due to the presence of a considerable amount of
1,4-dioxane as co-solvent, whose molecules present a rearrange-
ment in solution during the transition state, causing a decrease in
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J. Phys. Org. Chem. 2009, 22 221–228

CHEMISTRY OF ARYL N-(2-PYRIDYL)THIONOCARBAMATES
Hydrolysis of compound 2 in sodium hydroxide solutions gives
rise to phenol and N-methylaminopyridine and showed also a
first order dependence on the concentration of hydroxide ion
(Fig. 5).
ꢁ
(kHO
The
second
order
rate
constant
)
of
4.30 ꢃ 10ꢁ5 dm3ꢀmolꢁ1ꢀsꢁ1 indicates a reactivity difference of
ca. 6 ꢃ 102 compared with the one obtained for the compound
1a. In this case ionization is blocked converting the compound 2
into a good model of a BAC2 mechanism, which is known to occur
with much smaller reaction rates, providing a decisive argument
that a faster E1cB mechanism occurs for compounds 1a and 1b.
Based on these results we propose an E1cB mechanism for the
hydrolysis of secondary aryl N-(2-pyridyl)thionocarbamates
(Scheme 1).
The lower reactivity of secondary aryl N-(2- pyridyl)
thionocarbamates relatively to their oxo analogues can be
interpreted by considering several factors. The most relevant is
the nature of the thiocarbonyl bond, which presents a remarkably
more dipolar character relatively to the carbonyl bond due to the
anti-bonding interactions causing a less efficient 2p–3p p-overlap
in C ¼ S compared to the 2p–2p in C ¼O.[5,7] The more dipolar
character of thiocarbonyl contributes to retard the splitting of the
aryloxide ion in the rate-determining step for an E1cB
mechanism,[12] since the thiocarbonyl is a powerful electro-
n-withdrawing group which can accept electrons in the sulphur
atom and stabilize the anion,[13] but this will also increase the Ka
of a secondary thionocarbamate relatively to its oxo analogue, so
an electron-withdrawing group generally increases the product
Ka ꢃ k1 and accelerates the reaction rate (vide Eqn 2), because the
transition state in the rate-determining step bears a negative
charge. So the overall effect of a thiocarbonyl group on a
substrate undergoing hydrolysis by an E1cB mechanism is of a
rather complex interpretation, since it can cause either an
increase or a decrease in the reactivity of a substrate depending
on how affects the magnitude of both k1 and Ka. Since the aryl
N-(2-pyridyl)thionocarbamates are considerably less acidic than
the corresponding aryl N-(2-pyridyl)carbamates, this means that
k1 and Ka are both smaller for the secondary aryl N-(2-pyridyl)
thionocarbamates compared to their oxo analogues, thus
explaining their reduced reactivity.
Figure 5. Effect of NaOH concentration on the rate of reaction for
compound 2 (including the point obtained by graphical extrapolation
for hydrolysis in piperidine buffer pH 12.2) in 15% 1,4-dioxane/water (v/v),
with m ¼ 1.0 molꢀdmꢁ3 (NaClO4), at a temperature of 27.0 8C
addition–elimination mechanism would require necessarily
nucleophilic catalysis, which is difficult due to the retarding
effect of thiocarbonyl group in the elimination of the leaving
group (aryloxide ion) as will be later seen for compound 2, so
E1cB mechanism followed by amine trapping of isothiocyanate is
definitely the pathway for the formation of compound 3.
An additional evidence of an E1cB mechanism for secondary
thionocarbamates comes from the comparison of the plot of kobs
versus hydroxide ion concentration of 1a with the one of its
N-methyl analogue 2.
On the other hand, the reactivity of N,N-disubstituted
compound 2 in sodium hydroxide solutions is ca. 10 times
smaller than phenyl N-methyl-N-(2-pyridyl)carbamate.[16] These
Scheme 1. Mechanism of hydrolysis of secondary aryl N-(2-pyridyl)thionocarbamates
J. Phys. Org. Chem. 2009, 22 221–228
Copyright ß 2008 John Wiley & Sons, Ltd.
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D. SILVA ET AL.
results are analogous to the ones obtained for the hydrolysis of
4-nitrophenyl thionobenzoate and its oxo analogue in sodium
hydroxide solutions, being the thionoester eight times less
reactive than its analogous ester.[20] The fact that the thiocarbonyl
carbon is a softer Lewis acid than its carbonylic analogue, while
hydroxide ion is a hard base provides an explanation for this,
since according to Pearson’s Hard Soft Acid Base (HSAB) principle,
a soft acid will react preferentially (thermodynamically and
kinetically) with a soft base, while a hard acid will react
preferentially with a hard base.[18]
The values of kobs for the hydrolysis of compound 2 are linearly
proportional to increasing buffer concentration according to
equation 4, where kBuffer is the second-order rate constant for the
catalytic process in presence of buffers.
ꢁ
ꢁ
kobs ¼ kHO ½HO ꢂ þ kBuffer½xꢂ
(4)
Possibility of buffer catalysis was investigated, using piperidine
as buffer both in H2O and D2O (Table 5; Fig. 6).
The buffer independentꢁrate of hydrolysis for piperidine in
ꢁ
protiated solvent (kHO ½HO ꢂ) was obtained by extrapolation of
the observed rate constant to zero buffer concentration in
protiated solvent and found to correlate with the values of kobs
obtained for the of the plot of kobs versus hydroxide ion
concentration (Fig. 5).
The solvent isotope effect can be quantified by the ratio
kPipðH OÞ=kPipðD OÞ, which measures the catalytic efficiency of the
buffer in protiated and deuterated media. The ratio
Figure 6. Isotope effect for the hydrolysis of compound 2 in piperidine
buffer in 15% 1,4-dioxane/water (v/v), with m ¼ 1.0 molꢀdmꢁ3 (NaClO4), at
a temperature of 27.0 8C
2
2
kPipðH OÞ=kPipðD OÞ ¼ 2:37 indicates a proton transfer process in
2
2
the rate determining step of the reaction, implying a general
base-catalysed process, that is an indirect attack to the substrate
by the base involving the solvent in the rate-determining step.[18]
The other alternative mechanism possible for the basic
hydrolysis of compound 2 would be nucleophilic catalysis, that
is a direct attack to the substrate by the base in the
rate-determining step, which is kinetically distinguishable by
the solvent isotope effect as observed in the hydrolysis of its oxo
analogue, phenyl N-methyl-N-(2-pyridyl)carbamate, for which it
was obtained a ratio for kPipðH OÞ=kPipðD OÞ ¼ 0:88,[21] a value
the value of 14.951 at 25 8C,[22] and these values can be used
without too much error for 27 8C.
ꢁ
The value of kHO
determined this way is 6.18 ꢃ
10ꢁ5 dm3ꢀmolꢁ1ꢀsꢁ1, which is a value quite higher than the
one determined from the plot of kobs versus hydroxide ion
concentration of
2
(4.30 ꢃ 10ꢁ5 dm3ꢀmolꢁ1ꢀsꢁ1), but the
discrepancy is explainable since the associated error is quite
larger for the value obtained by graphical extrapolation. The
ꢁ
2
2
extrapolated value for kDO is 4.31 ꢃ 10ꢁ5 dm3ꢀmolꢁ1ꢀsꢁ1, and so
typical of a mechanism involving nucleophilic catalysis.
ꢁ
ꢁ
the ratio kHO =kDO ¼ 1.43. This value is acceptable for a general
base catalysis because in the lyate ion (HOꢁ or DOꢁ) will attack
directly the substrate independently of the type of catalysis,
being the deuteroxide ion (pKa 16.61) a stronger base than
hydroxide (pKa 15.74). On the other hand, there is a significant
error associated with the determination of this ratio, and the
validity of its interpretation is quite reduced.
On the other hand, it is possible also to calculate also the values
ꢁ
ꢁ
of kHO and kDO from graphical extrapolation for hydrolysis in
piperidine buffer in protiated and deuterated media respectively,
and applying Eqn (4) for null buffer concentration. In order to
convert the values of pH and pD into [HOꢁ] and [DOꢁ],
respectively, it is necessary to resort to Eqn (5):
The possibility of formation of a thiourea from the nucleophilic
attack from piperidine to compound 2 is quite unlikely since
whenever nucleophilic catalysis happens it is the predominant
process, being this generally extremely faster than a general base
pL þ pOL ¼ pKw
(5)
Being L ¼ H and D for protiated and deuterated media,
respectively. For H2O the pKw is 13.995 while for D2O it presents
Table 5. Buffer catalysis for compound 2 in piperidine buffer in H2O (pH 12.2) and in D2O (pD 12.4)a
101ꢀ[piperidine]free (molꢀdmꢁ3) (H2O)
106ꢀkobs (sꢁ1
)
102ꢀ[piperidine]free (molꢀdmꢁ3) (D2O)
106ꢀkobs (sꢁ1
)
1.83
1.64
1.46
1.28
6.60
6.05
5.54
4.89
9.53
7.65
5.73
4.77
1.37
1.08
0.89
0.73
a Solvent 15% 1,4-dioxane/water (v/v), m ¼ 1.0 molꢀdmꢁ3 (NaClO4), 27.0 8C.
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 221–228

CHEMISTRY OF ARYL N-(2-PYRIDYL)THIONOCARBAMATES
only diagnostic bands are reported on a cmꢁ1 scale. NMR spectra
were recorded using a Bruker ARX-400 MHz spectrometer, in
chloroform-d as solvent, and chemical shifts are reported in parts
per million (ppm, d), using as reference the signal for TMS.
Coupling constants are reported to the nearest 0.1 Hz. HREIMS
were recorded in a Finnigan FT/MS 2001-DT. Column chroma-
tography used silica-gel 60, 0.040–0.063 mm (Merck 9385). Thin
layer chromatography (TLC) and preparative TLC (PTLC) were
performed on pre-coated silica-gel 60 F254 (respectively Merck
5554 and Merck 5717). All solvents and reagents were obtained
from Merck or Aldrich and used without further purification,
except for acetone, which was dried with potassium carbonate
for 24 h, prior to distillation.
Scheme 2. Mechanism of hydrolysis of phenyl N-methyl-N-(2-pyridyl)
thionocarbamate
catalysis process,[23] so if the experimental data points to general
base catalysed mechanism the nucleophilic catalysis can be
disregarded.
General procedure for the preparation of
pyridylthionocarbamates
Another consistent parameter in favour of a general base
catalysis is the absence of a effect for the hydrolysis of compound
2 in the presence of peroxymonocarbonate ion ([HCOꢁ4 ] ¼
2 ꢃ 10ꢁ2 molꢀdmꢁ3 in carbonate buffer pH 9.0), since there was
not observed any noticeable reaction in those conditions. The
peroxymonocarbonate ion is generated from hydroperoxide
solutions in carbonate buffer.[24,25] The pKa of hydrogen peroxide
is about 11.7 and at pH 9.0 the fraction of HOꢁ2 ion is too low to act
as an effective catalyst. So in the presence of carbonate buffer the
peroxymonocarbonate anion is formed (pKa 10.6) and this
particular species is highly nucleophilic. For a nucleophilic
catalysis process an a nucleophile presents a considerably
enhanced reactivity towards the substrate.[18] Phenyl N-methyl-
N-(2-pyridyl)carbamate displays an increased reactivity in the
presence of HCOꢁ4 , being this effect measured by the ratio of the
catalytic constants of peroxymonocarbonate and hydroxide ions
To a suspension of 2-aminopyridine or 2-methylaminepyridine
and potassium carbonate in dry acetone was added drop wise
the corresponding aryl chlorothionoformate dissolved in
acetone. The reaction was stirred for 30 min, then refluxed for
4 h, and worked up by adding water and dichloromethane; the
organic layer was dried with magnesium sulphate and
evaporated to dryness. The compounds were purified by column
chromatography (n-hexane/ethyl acetate 8:2 for 1a; n-hexane/
dichloromethane 3:7 for 1b; n-hexane/diethyl ether 1:1 for 2)
followed by recrystalization.
Phenyl N-(2-pyridyl)thionocarbamate (1a): (0.042 g; 2%); yellow
crystals; mp 116–118 8C (from dichloromethane/n-hexane); IR
nmax(KBr)/cmꢁ1: 1591–1499, 1260; dH (400 MHz; CDCl3; Me4Si):
8.66 (1 H, dd, J 1.8, 4.5 Hz, H-6 py), 7.89 (1 H, dt, J 1.8, 7.8, H-4 py),
7.62 (1 H, d, J 8.0, H-3 py), 7.45 (2 H, m, C-30, C-50 Ph), 7.32 (2 H, m,
CH aromatic), 7.26 (2 H, m, C-20, C-60 Ph); dC (100.4 MHz,
CDCl3; Me4Si) 189.9 (C ¼ S), 155.7 (C-2 py), 153.8 (C-10Ph), 149.6
(C-6 py), 138.6 (C-4 py), 129.7 (C-30, C-50 Ph), 126.8 (C-40 Ph), 123.7
(C-5 py), 123.5 (C-3 py), 121.8 (C-20, C-60 Ph); EI-MS 230 [Mꢅ]þ, 229,
197, 137, 136, 94, 78, 77; HREIMS: 230.050875 (230.0513885 [Mꢅ]þ
for C12H10N2OS).
4-Methylphenyl N-(2-pyridyl)thionocarbamate (1b): (0.212 g;
8%); yellow crystals; mp 114–115 8C (dichloromethane/
n-hexane); IR nmax(KBr)/cmꢁ1: 1591–1499, 1260; dH (400 MHz,
CDCl3; Me4Si): 8.61 (1 H, d, J 4.8 Hz, H-6 py), 7.85 (1 H, ddd, J 1.8, 7.5,
7.9 Hz, H-4 py), 7.57 (1 H, dd, J 0.6, 7.9 Hz, H-3 py), 7.34 (1 H, dd, J
4.8, 7.5 Hz, H-5 py), 7.21 (2 H, d, J 8.7 Hz, H-30, H-50 Ph), 7.09 (2 H, d, J
8.4 Hz, H-20, H-60 Ph), 2.35 (3 H, s, CH3); dC (100.4 MHz,
CDCl3; Me4Si) 190.2 (C ¼ S), 155.8 (C-2 py), 151.7 (C-10 Ph),
149.6 (C-6 py), 138.5 (C-4 py), 136.5 (C-40 Ph), 130.2 (C-30, C-50 Ph),
123.6 (C-5 py), 123.5 (C-3 py), 121.4 (C-20, C-60 Ph), 21.0 (CH3);
EI-MS: 244 [Mꢅ]þ, 243, 211, 151, 137, 136, 123, 108, 91, 78; HREIMS:
244.067271 (244.067035 [Mꢅ]þ for C13H12N2OS).
Phenyl N-methyl-N-(2-pyridyl)thionocarbamate (2): (3.39 g; 75%);
white crystals; mp 96–97 8C (dichloromethane/n-hexane); IR
nmax(KBr)/cmꢁ1: 1588–1432, 1215; dH (400 MHz, CDCl3; Me4Si):
8.54 (1 H, d, J 4.8 Hz, H-6 py), 7.76 (1 H, dt, J 2.0, 7.8 Hz, H-4 py), 7.49
(1 H, d, J 8.1Hz, H-3 py), 7.38 (2 H, t, J 7.8 Hz, H-30, H-50 Ph), 7.23 (2 H,
m, C-H aromatic), 7.07 (2 H, m, H-20, H-60 Ph), 3.78 (3 H, s, N-CH3). dC
(100.4 MHz, CDCl3; Me4Si) 188.4 (C ¼ S), 155.5 (C-2 py), 153.7 (C-10
Ph), 149.0 (C-6 py), 137.9 (C-4 py), 129.3 (C-30, C-50 Ph, 126.1 (C-40
Ph), 122.4 (C-5 py), 122.6 (C-20, C-60 Ph), 122.0 (C-3 py), 41.5
(N-CH3). EI-MS: 244 [Mꢅ]þ, 151, 136, 135, 78, 77; HREIMS: 244.0674
(244.0670 [Mꢅ]þ for C13H12N2OS).
kHCO =kHO ¼ 243.[21]
ꢁ
ꢁ
4
The kinetic parameters suggest a general base catalysed
hydrolysis for compound 2, in which the base assists the solvent
in its attack on the carbamate carbon (Scheme 2). There are other
examples of thionocarbamates undergoing hydrolysis with
general base catalysis, such as the 1-(aryloxythiocarbonyl)
pyridinium cations studied by Castro et al.[26] An explanation
for the change of basic catalysis with the replacement of carbonyl
by the thiocarbonyl group is that the more electrophilic carbon of
thiocarbonyl group, when attacked by a nucleophile undergoes a
considerably destabilized transition state for the expulsion of
negatively charged phenoxide compared to a non-charged
nucleophile (e.g. piperidine) expulsion. On the other hand, the
stronger electron-withdrawing effect of thiocarbonyl will
decrease the leaving group ability of phenoxide, thus hindering
a nucleophilic attack by the catalyst. As an example, Neuvonen
observed a similar change of base-catalysis for the aminolysis of
4-nitrophenyl acetates and trifluoroacetates, the latter hydro-
lysed via a general-base catalysed mechanistic pathway, since it
possesses a much more electron-withdrawing acyl moiety.[27]
EXPERIMENTAL
Synthesis
Melting points were measured in a Stuart Scientific-melting point
apparatus SMP3 and are uncorrected. IR spectra were obtained
using a Hitachi 270–50 spectrophotometer on KBr pastille and
J. Phys. Org. Chem. 2009, 22 221–228
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

D. SILVA ET AL.
Reactivity
that period of time to avoid the possibility of decomposition of
the thiourea, although thioureas are less reactive than
thiocarbamates in basic aqueous media. The pH of the reaction
mixture was neutralized with HCl 1 molꢀdmꢁ3 and extracted with
dichloromethane and ethyl acetate (2 ꢃ 15 cm3 each), the
combined organic phases were dried with anhydrous sodium
sulphate, filtered off and evaporated to dryness. The presence of
the urea was detected by TLC (n-hexane/diethyl ether 4:6) and
identified by EI-MS. EI-MS: 221 [Mꢅ]þ, 137, 136, 128, 94, 78.
The kinetic studies of the aryl N-(2-pyridyl)thionocarbamates
hydrolysis in sodium hydroxide and buffer solutions were
performed in 1,4-dioxane/water 15% (v/v) with ionic strength
kept constant at 0.5 molꢀdmꢁ3 (compounds 1a and 1b) or at
1.0 molꢀdmꢁ3 (compound 2) with sodium perchlorate. The ionic
strength was increased for compound 2 to allow to study the
reactivity on higher concentrations of sodium hydroxide, since
this compound was much less reactive than its secondary
analogue (1a).
The measurements were carried out either in a UV 1603-Visible
Spectrometer Shimadzu apparatus provided with thermostated
cell holders, being the quartz cells kept at 27.0 ꢄ 0.1 8C in the cell
compartment of the apparatus, or in a chromatographer
equipped with a Merck LichroCART 250-4 RP8 column, manual
injecting system Spectra SYSTEM P2000 with a Reodhyne loop of
20 mL and an UV–Vis detector Spectra SYSTEM UV 1000.
In the UV–Vis spectrophotometric technique, the reactions
were followed by continuously monitoring the increase in
absorbance at 285 nm corresponding to the formation of phenol
(compound 1a), the decrease in absorbance at 304 nm
corresponding to the decomposition of the substrate (compound
1b) and the decrease in absorbance at 260 nm corresponding to
the to the decomposition of the substrate (compound 2), and the
spectra exhibited clear isosbestic points for all studied substrates.
In the HPLC technique, the reactions were followed by
continuously monitoring the peak areas for both the compound
1b and 4-methylphenol at 290 nm, thus allowing to follow
simultaneously the decomposition of 1b and the formation of
4-methylphenol for every HPLC experiment, using as eluent
acetonitrile–water 75–25% (v/v) in isocratic conditions. Aliquots
of 0.5 cm3 were collected from the reaction mixture at
27.0 ꢄ 0.1 8C and their pH adjusted to 7 with HCl 1.0 molꢀdmꢁ3
and cooled in an ice bath prior to be injected into the system.
The temperature effect was studied in a temperature range
between 20.0 and 35.0 8C with an error less than 0.1 8C for each
temperature. Absorbance-time data always fitted the first
Acknowledgements
˜
ˆ
Daniel Silva is grateful to the Fundac¸ao para a Ciencia e Tecnologia
from Ministerio da Ciencia e Ensino Superior of Portugal for his PhD
´
ˆ
Grant (SFRH/BD/4860/2001).
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obs
1
at least 90% completion of the reaction and the values of the
pseudo-first-order constants (kobs) were reproducible within 5%.
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much lower respecting to the concentration of other reagents
(between 2 ꢃ 10ꢁ5 and 3 ꢃ 10ꢁ5 molꢀdmꢁ3). The peroxymono-
carbonate ion solutions used in the study of basic reactivity of
compound 2 were prepared by adding the corresponding
amount of hydrogen peroxide in a carbonate buffer pH 9.0
([Buffer]total ¼ 0.2 molꢀdmꢁ3). The values of pH were measured in
an Orion Research digital ionalyzer 501 potentiometer equipped
with a with a KCl/AgCl electrode. All solvents and reagents were
obtained from Aldrich or Merck and used without further
purification, except for tert-butylamine and piperidine, which
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N-Piperidyl-N0-(2-pyridyl)thiourea (3)
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[27] H. Neuvonen, J. Chem. Soc., Perkin Trans. 2 1987, 159–167.
Compound 1b (0.122 g; 0.5 mmol) was hydrolysed in piperidine
buffer pH 12.0 ([Buffer]total ¼ 1.0 molꢀdmꢁ3
) in the same
conditions of the kinetic assays. The reaction was carried out
for 1 h in spite of the half live of the reaction being superior to
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 221–228