The nucleofuge in the pyridinolysis of O-(4-nitrophenyl) S-aryl thio and dithiocarbonates

Article abstract of DOI:10.1002/poc.2989

A kinetic investigation is undertaken on the pyridinolysis of S-phenyl O-(4-nitrophenyl) dithiocarbonate (1), S-(4-nitrophenyl) O-(4-nitrophenyl) dithiocarbonate (2) and S-phenyl O-(4-nitrophenyl) thiocarbonate (3) in aqueous ethanol. The Bronsted-type plots (log kN versus pK_a) obtained are linear and are explained by a stepwise mechanism with the existence of a tetrahedral intermediate (T^±) and its breakdown to products as the rate determining step. The high-performance liquid chromatography analysis of the products of these reactions and that for the reaction of S-(4-chlorophenyl) O-(4-nitrophenyl) dithiocarbonate (4) with 4-oxypyridine shows that 4-nitrophenoxide is the principal (or the sole) leaving group in these reactions. From the results obtained in the reaction of compound 2, it can be concluded that 4-nitrophenoxide is a better nucleofuge than 4-nitrobenzenethiolate from the same tetrahedral intermediate, although the former is three pK_a units more basic than the latter. Reasons for this behaviour are given. Copyright

Full text of DOI:10.1002/poc.2989

Research Article
Received: 9 April 2012,
Revised: 22 May 2012,
Accepted: 24 May 2012,
Published online in Wiley Online Library: 2012
(wileyonlinelibrary.com) DOI: 10.1002/poc.2989
The nucleofuge in the pyridinolysis of
O-(4-nitrophenyl) S-aryl thio and
dithiocarbonates
Enrique A. Castroa*, Margarita E. Aliagaa, Marcela Gazitúaa and José G. Santosa*
A kinetic investigation is undertaken on the pyridinolysis of S-phenyl O-(4-nitrophenyl) dithiocarbonate (1),
S-(4-nitrophenyl) O-(4-nitrophenyl) dithiocarbonate (2) and S-phenyl O-(4-nitrophenyl) thiocarbonate (3) in aqueous
ethanol. The Brønsted-type plots (log kN versus pKa) obtained are linear and are explained by a stepwise mechanism
with the existence of a tetrahedral intermediate (Tꢀ) and its breakdown to products as the rate determining step.
The high-performance liquid chromatography analysis of the products of these reactions and that for the reaction of
S-(4-chlorophenyl) O-(4-nitrophenyl) dithiocarbonate (4) with 4-oxypyridine shows that 4-nitrophenoxide is the princi-
pal (or the sole) leaving group in these reactions. From the results obtained in the reaction of compound 2, it can be
concluded that 4-nitrophenoxide is a better nucleofuge than 4-nitrobenzenethiolate from the same tetrahedral
intermediate, although the former is three pKa units more basic than the latter. Reasons for this behaviour are given.
Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
between 4-nitrophenoxide and the corresponding benzenethio-
late as leaving groups in the pyridinolysis of compounds 1, 3
INTRODUCTION
and 4. On the other hand, for the reaction of compound 2,
Several works have appeared in the literature on the kinetics of the
4-nitrobenzenethiolate would be expected to be the nucleofuge.
nucleophilic reactions of O-aryl S-aryl thio and dithiocarbonates.[1–6]
The importance of the present work can be shown by the
Among these studies are the reactions of secondary alicyclic amines
results obtained, which are opposite to the expectations
and pyridines with O-aryl S-(4-nitrophenyl) thiocarbonates,[3]
mentioned previously. We found that in all the reactions studied
and O-aryl S-(4-nitrophenyl) dithiocarbonates,[4,5] where there
in this work, 4-nitrophenoxide is the sole nucleofuge. The
are two possible nucleofuges of different nature (benzenethiolates
situation is remarkable in the case of the pyridinolysis of
versus phenoxides). The question is which of the groups is the
dithiocarbonate 2, where 4-nitrophenoxide is the nucleofuge
nucleofuge. In these cases, the S-(4-nitrophenyl) group was much
despite being 3 pKa units more basic than 4-nitrobenzenethiolate.
less basic than the O-aryl groups and the former was always the
Another aim of the present work was to compare the results in
nucleofuge.
the pyridinolysis reactions of compounds 1–4 and of other
On the other hand, we recently reported the kinetics of
related reactions. This will permit to determine the influence of
aminolysis and phenolysis of a series of S-aryl O-4-nitrophenyl
the nucleophile, electrophile and nonleaving group on the
thiocarbonates, concluding that O-4-nitrophenyl is a better
leaving ability of the possible nucleofuge in these reactions.
nucleofuge than S-aryl, despite being the former 0.7–1.7 pKa
units more basic than the latter.[6]
With the aim to assess the nucleofugality of O-aryl and
S-aryl groups, in the present work we undertake a kinetic in-
vestigation on the pyridinolysis of the compounds S-phenyl
O-(4-nitrophenyl) dithiocarbonate (1), S-(4-nitrophenyl) O-(4-
nitrophenyl) dithiocarbonate (2) and S-phenyl O-(4-nitrophenyl)
thiocarbonate (3). Also, a high-performance liquid chromato-
graphy (HPLC) analysis of the products of these reactions
and that for the reaction of S-(4-chlorophenyl) O-(4-nitrophenyl)
dithiocarbonate (4) with 4-oxypyridine is carried out to evaluate
the nucleofugality of the leaving groups involved in the above
compounds.
The pKa values of the possible nucleofuges in the reactions of
compounds 1, 3 and 4 are similar (see Experimental section).
Nonetheless, for the pyridinolysis of compound 2, the difference
of basicity between the possible nucleofuges is large (pKa values of
4-nitrophenol and 4-nitrobenzenethiol are 7.5 and 4.5, respectively;
see Experimental section). If basicity were the only parameter
affecting nucleofugality, it would be expected a competition
* Correspondence to: Enrique A. Castro and José G. Santos, Facultad de Química,
Pontificia Universidad Católica de Chile, Casilla 306, Santiago 6094411, Chile.
E-mail: ecastro@uc.cl; jgsantos@uc.cl
a E. A. Castro, M. E. Aliaga, M. Gazitúa, J. G. Santos
Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306,
Santiago 6094411, Chile
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

E. A. CASTRO ET AL.
RESULTS AND DISCUSSION
2
0
Under amine excess, pseudo-first-order rate constants (kobsd
)
were found for all the reactions. These were obtained as
described in the Experimental section. The conditions of the
reactions and the values of kobsd are summarized in Tables S1–S15.
The values of kobsd, obtained under pyridine excess, for all the
reactions are in accordance with Eqn (1), where k0 and kN are the
rate coefficients for solvolysis and pyridinolysis of the substrates,
respectively. The values of k0 and kN showed no dependence on
pH within the pH range used. These values were obtained as the
intercept and slope, respectively, of linear plots of kobsd against
free pyridine concentration, at constant pH.
-2
-4
4
6
8
10
pKa
kobsd ¼ k0 þ kN½free pyridineꢁ
(1)
Figure 1. Brønsted-type plots for the reactions of pyridines with (●)
S-phenyl O-(4-nitrophenyl) dithiocarbonate (1), (o) S-(4-nitrophenyl)
O-(4-nitrophenyl) dithiocarbonate (2) and (Δ) S-phenyl O-(4-nitrophenyl)
thiocarbonate (3) in 44 wt% ethanol–water, at 25.0ꢃC, ionic strength
0.2 M (KCl)
For the studied reactions, the k0 values were much smaller
than the kN [free pyridine] term in Eqn (1). The values of kN for
the reactions of compounds 1, 2 and 3 with the series of
pyridines are shown in Table 1.
Given the data in Table 1, the linear Brønsted-type plots of
Figure 1 were obtained. The slopes are 1.2, 1.2 and 1.1 for the
reactions of compounds 1, 2 and 3, respectively. These values
are consistent with a stepwise mechanism, through a tetrahedral
intermediate (Tꢀ), as in Scheme 1, where its breakdown to
products is the rate determining step.[1,2,7,8]
The stepwise nature of the pyridinolysis of compound 3 can be
confirmed by the following analysis: The reactions of compound
3 with secondary alicyclic amines are stepwise.6 Taking into
account that pyridines stabilize a tetrahedral intermediate relative
to that derived from secondary alicyclic amines,[1,2] the pyridinolysis
of compound 3 should also be stepwise. In the same way, the
stepwise pyridinolysis of compound 1 can be confirmed by the fact
that the change of C–Oꢂ by C–Sꢂ in the tetrahedral intermediate
stabilizes the corresponding intermediate.[1,2]
On the other hand, if the pyridinolysis reactions of compounds
1 and 2 are stepwise, the most probable mechanism for the
pyridinolysis of compound 4 is stepwise. This is because 4-
chlorobenzenethiol is of intermediate basicity between benzenethiol
and 4-nitrobenzenethiol, its basicity being very similar to that
of the former (the pKa values for benzenethiol and 4-chloroben-
zenethiol are 7.2 and 7.0, respectively; see Experimental section).
A quantitative HPLC analysis to the reactions of compounds 1,
2 and 3 with 4-oxypyridine shows that 100% of 4-nitrophenol is
formed, suggesting that 4-nitrophenoxide is the principal (or the
sole) leaving group in these reactions. On the other hand, the
same quantitative analysis to these reactions shows that
benzenethiols are not obtained during the time of the kinetic
measurements. 4-Oxypyridine was the amine used for these
analyses because it is one of the most basic pyridines and there-
fore forms the most stable thionocarbamate (or dithiocarbamate)
of pyridinium.
Good first-order kinetics with stable ‘infinity’ absorbance values
during the kinetic studies were obtained in the pyridinolysis of
compounds 1, 2 and 3 with all the pyridines used, in accordance
with the fact that 4-nitrophenoxide ion is the principal nucleofuge.
To confirm that 4-nitrophenoxide found in the reaction of
compound 2 is formed only from the pyridinolysis reaction and
not from the hydrolysis of the hypothetical O-4-nitrophenyl
thionocarbamate of 4-oxypyridinium ion, formed by the pyridi-
nolysis of the substrates, the HPLC analyses were also realized
at longer times. These analyses did not show further increase
of 4-nitrophenoxide.
The kinetic behaviour and the product analysis permit to
propose the reactions model of Scheme 1 as the mechanism of
the studied reactions.
The fact that 4-nitrophenoxide is the nucleofuge in the
reactions of compound 1 is not surprising for two reasons:
(i) the similar basicities of the two possible leaving groups (pKa of
Table 1. Values of pKa for the conjugate acids of pyridines and kN values for the reactions of pyridines with S-phenyl
O-(4-nitrophenyl) dithiocarbonate (1), S-(4-nitrophenyl) O-(4-nitrophenyl) dithiocarbonate (2) and S-phenyl O-(4-nitrophenyl)
thiocarbonate (3)a
102 kN/sꢂ1 Mꢂ1
Pyridine substituent
pKa
1
2
3
3,4-Diamino
4-Dimethylamino
4-Amino
4-Amino-3-bromo
3,4-Dimethyl
None
9.45
9.14
8.98
6.90
5.68
4.63
310 ꢀ 18
268 ꢀ 10
188 ꢀ 6
33200 ꢀ 500
–
1070 ꢀ 40
960 ꢀ 30
600 ꢀ 20
6.2 ꢀ 0.4
0.046 ꢀ 0.006
–
9400 ꢀ 600
0.90 ꢀ 0.04
0.015 ꢀ 0.006
–
78 ꢀ 2
0.80 ꢀ 0.02
0.040 ꢀ 0.002
aBoth pKa and kN values were determined in 44 wt% ethanol–water, at 25.0 ꢃC, ionic strength 0.2 M (KCl).
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

NUCLEOFUGE IN THE PYRIDINOLYSIS OF THIO AND DITHIOCARBONATES
X-
O C S
Py+
X
k1
O2N
O C S
Y
O2N
Y
k-1
+
Py
k2
1 X = S, Y = H
2 X = S, Y = NO2
3 X = O, Y = H
X
O2N
O-
+
C S
Py+
Y
Scheme 1. Probable mechanism for the pyridinolysis of 1–3
benzenethiol and 4-nitrophenol are 7.2 (this work) and 7.5,[9]
respectively), and (ii) it is known that phenoxides are better nucleo-
fuges than isobasic benzenethiolates.[10,11] On the other hand, in
the pyridinolysis of compound 3, also 4-nitrophenoxide is the
nucleofuge, showing that, in this case, the change of CO by CS as
the electrophile of the substrate does not change the nucleofuge
from the corresponding tetrahedral intermediate.
As in the pyridinolysis of compound 3 (this study) and in its
aminolysis (secondary alicyclic amines),[6] the nucleofuge is
4-nitrophenoxide ion. Therefore, in these reactions, there is
no effect of the nucleophile on the relative nucleofugality
of benzenethiolate and 4-nitrophenoxide ions.
From the results obtained in the reaction of compound 2, it
can be concluded that 4-nitrophenoxide is a better nucleofuge
than 4-nitrobenzenethiolate from the same tetrahedral interme-
diate (I), although the former is three pKa units more basic than
the latter (the pKa values of 4-nitrophenol and 4-nitrobenze-
nethiolate are 7.5 and 4.5, respectively).[9]
the transition state for decomposition of I to products, the
charge attracted by the 4-nitrobenzenethio group is delocalized
in its sulfur atom, and for the 4-nitrophenoxy group, the negative
charge should be better localized in its O atom. Therefore,
expulsion of 4-nitrophenoxide from I should be favoured relative
to that of 4-nitrobenzenethiolate. In this case, the nonleaving
group (4-nitrobenzenethio) plays an important role and is not a
‘spectator group’.
On the other hand, the nonleaving group in the intermediates
II and III is electron donating. Therefore, the negative charge
impelled by this group toward 4-nitrophenoxy in the transition
state for decomposition of II prevents charge localization on its
O atom. Thus, in the transition states from intermediates II and
III, both nucleofuges are in a similar situation regarding charge
delocalization, and therefore, basicity becomes the important
issue. For this reason, 4-nitrobenzenethiolate should leave faster
from III than 4-nitrophenoxide from II because the former is three
pKa units less basic than the latter.
From the proposed mechanism (Scheme 1) and the Brønsted
plots obtained (Figure 1), it follows that kN = K1k2, where K1 is the
equilibrium constant of the first step for the reactions with the
amine series. From Table 1, it can be observed that kN is more
than 50 times greater in the reaction of compound 2 than that
of compound 1. This result can be explained, in part, by the
greater electron withdrawal of 4-nitrobenzenethiolate in
compound 2 than that of benzenethiolate in compound 1.[13]
Also, by comparing the kN values for the reactions of com-
pounds 1 and 3, it can be concluded that compound 3 is
approximately three times more reactive toward this nucleo-
fuges than compound 1. This is in accordance with the greater
rate of attack of pyridines toward thiolcarbonates relative to
dithiocarbonates.[3,4,14,15]
These results contrast with those obtained by the comparison
between the pyridinolysis of 4-methylphenyl 4-nitrophenyl
thionocarbonate[12] and that of O-(4-methylphenyl) S-(4-nitrophenyl)
dithiocarbonate,[4] which shows that 4-nitrophenoxide is a worse
nucleofuge than 4-nitrobenzenethiolate from the corresponding
tetrahedral intermediates II and III.
Nevertheless, this apparent contradiction evidences the
effect of the nonleaving group on the nucleofuge expulsion
from the tetrahedral intermediate. A possible explanation can
be made, considering that from the tetrahedral intermediate I,
both possible nucleofuges are electron withdrawing. Thus, in
CONCLUSIONS
In the pyridinolysis of compound 2, 4-nitrophenoxide is a better
nucleofuge than 4-nitrobenzenethiolate from the same tetrahedral
intermediate (I), although the former is three pKa units more basic
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

E. A. CASTRO ET AL.
by least squares fitting of the experimental absorbance data to the
single-exponential curve At = A0 exp(ꢂkobsd t) + C, where At and A0 are
the absorbances at time t and 0, respectively. The experimental conditions
of the reactions and the kobsd values are shown in Tables S1–S15.
than the latter. This behaviour is attributed to the fact that in the
transition state for decomposition of I to products, the charge
attracted by the 4-nitrobenzenethio group is delocalized in its
sulfur atom and for the 4-nitrophenoxy group the negative charge
should be better localized in its O atom. In this way, the nonleaving
group plays an important role in the expulsion of 4-nitrophenoxide
and is not a spectator.
Product studies
From the kinetic point of view, compound 3 is approximately
three times more reactive toward pyridines than compound 1,
and the 4-nitrobenzenethio group in compound 2 makes this
compound more than 50 times more reactive against pyridines
than the benzenethiol group in compound 1.
For the reactions of the three substrates studied with all the pyridines
series, 4-nitrophenoxide was identified as one of the reaction products,
by comparison of the UV-visible spectra at the end of the reactions with
that of an authentic sample in the same experimental conditions.
HPLC analyses were performed for the reactions of compounds 1–4
with 4-oxypyridine using the following conditions: mobile phase of
50% CH3CN/acetate buffer (0.01 M, pH 5.0), flow rate of 1.2 mL minꢂ1
and UV-visible detection. The analyses carried out at short times showed
the presence of 4-nitrophenoxide and the absence of the corresponding
benzenethiolates (or their dimers). This was achieved by comparison of
the retention times and UV-visible spectra with those of authentic
samples (for the reaction of compound 2, see Figures S1 and S2).
EXPERIMENTAL
Materials
Pyridines were purified before use. Dithiocarbonate 1 was synthesized by
a modification of Araki’s procedure[16] by carrying out the reaction of
phenyl chlorodithioformate with 4-nitrophenol, in dry acetone, in the
presence of pyridine. This compound was identified by its spectroscopic
properties and melting point. The latter was 100 ꢃC–102 ꢃC (103ꢃC–103.5 ꢃC[16]).
Compound 3 was prepared as in a previous work.[6]
Acknowledgements
This work was supported by Project ICM-P10-003-F, CILIS, granted
by Fondo de Innovación para la Competitividad, del Ministerio de
Economía, Fomento y Turismo, Chile, and FONDECYT of Chile
(Project 1095145).
The synthesis of dithiocarbonate 2 was carried out by the reaction of
4-nitrophenyl chlorothionoformate with 4-nitrobenzenethiolate in
dichloromethane. Compound 2: mp 157–158 ꢃC (170 ꢃC–171 ꢃC[16]).
1H-NMR (400 MHz, CDCl3) d (ppm): 7.43 (d, 2H, J = 9.1 Hz); 7.61 (d, 2H,
J = 8.9 Hz); 8.19 (d, 2H, J = 8.9 Hz); 8.37 (d, 2H, J = 9.1 Hz).13C-NMR (100
MHz, CDCl3) d (ppm): 123.1, 124.5, 125.6, 126.4, 144.1, 146.3, 147.0,
157.2 and 192.1.
REFERENCES
[1] E. A. Castro, Chem. Rev. 1999, 99, 3505–3524.
[2] E. A. Castro, J. Sulfur Chem. 2007, 28, 401–429.
[3] E. A. Castro, M. Aliaga, J. G. Santos, J. Phys.Org. Chem. 2008, 21,
271–278.
Determination of pKa
The pKa values of benzenethiol and 4-chlorobenzenethiol were determined
spectrophotometrically by the reported method.[17] The experimental
conditions used were the same as those for the kinetic measurements:
44 wt% ethanol–water, 25.0 ꢃCꢀ 0.1 ꢃC and ionic strength 0.2 M (maintained
with KCl). The pKa values obtained for benzenethiol and 4-chlorobenze-
nethiol are 7.2 and 7.0, respectively. The pKa of 4-nitrophenol and 4-nitroben-
zenethiol were determined previously under the same conditions. These
values are 7.5 and 4.5, respectively.[9]
[4] E. A. Castro, M. Gazitua, J. G. Santos, J. Phys. Org. Chem. 2009, 22,
1003–1008.
[5] E. A. Castro, M. Gazitua, J. G. Santos, J. Phys. Org. Chem. 2011, 24,
466–473.
[6] E. A. Castro, M. Aliaga, P. R. Campodónico, M. Cepeda, R. Contreras,
J. G. Santos, J. Org. Chem. 2009, 74, 9173–9179.
[7] M. J. Gresser, W. P. Jencks, J. Am. Chem. Soc. 1977, 99, 6963–6970.
[8] M. J. Gresser, W. P. Jencks, J. Am. Chem. Soc. 1977, 99, 6970–6980.
[9] E. A. Castro, M. Cepeda, P. Pavez, J. G. Santos, J. Phys. Org. Chem.
2009, 22, 455–459.
Kinetic measurements
[10] K. T. Douglas, M. Alborz, J. Chem. Soc. Chem. Commun. 1981,
551–553.
[11] K. T. Douglas, Acc. Chem. Res. 1986, 19, 186–192.
[12] E. A. Castro, P. Garcia, L. Leandro, N. Quesieh, A. Rebolledo, J. G. Santos,
J. Org. Chem. 2000, 65, 9047–9053.
[13] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
[14] E. A. Castro, M. I. Pizarro, J. G. Santos, J. Org. Chem. 1996, 61,
5982–5985.
These were carried out using a diode array spectrophotometer in 44 wt%
ethanol aqueous solution, at 25.0 ꢃC ꢀ 0.1 ꢃC, ionic strength 0.2 M (KCl).
Phosphate and borate buffers were used in some reactions. The
reactions, studied under excess of the pyridine over the substrate, were
started by the injection of a substrate stock solution in acetonitrile (10 mL)
into the pyridine solution (2.5 mL in the spectrophotometric cell). The initial
substrate concentration was approximately 5ꢄ 10–5 M.
As in the reactions of the analogue substrates with tertiary amines,[4,18,19]
in this work a consecutive reactions behaviour was observed: the formation
and later hydrolysis of the cationic pyridinium thio or dithiocarbamate
formed. For the studied reactions, the hydrolysis was more than 10 times
slower than the formation of the thiocarbamates, so that both reactions
can be considered kinetically independent.
[15] E. A. Castro, C. A. Araneda, J. G. Santos, J. Org. Chem. 1997, 62,
126–129.
[16] Y. Araki, Bull. Chem. Soc. Jap. 1970, 43, 252–257.
[17] A. Albert, E. P. Searjeant, The Determination of Ionization Constants,
Chapman and Hall Ltd., London, 1971, 44.
[18] E. A. Castro, M. Gazitua, J. G. Santos, J. Phys. Org. Chem. 2009, 22,
1030–1037.
Pseudo-first-order rate coefficients (kobsd) were found for all reactions.
These were determined through the spectrophotometer kinetic software,
[19] E. A. Castro, M. Cubillos, J. G. Santos, J. Org. Chem. 2004, 69,
4802–4807.
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)