Reactivity of N-pyridylcarbamates in basic media

Article abstract of DOI:10.1039/b200445n

New secondary aryl N-pyridylcarbamates were prepared by reaction of the aminopyridine anion with aryl chloroformates and their hydrolysis was studied over the pH range from 12 to 13.7. The pH-rate profile points to an E1cB mechanism, involving pre-equilibrium deprotonation of the nitrogen atom to form an anion that undergoes rate-limiting decomposition into pyridyl isocyanate and a phenoxide ion. Further reaction of the highly reactive isocyanate with water affords N-pyridylcarbamic acid, which spontaneously decomposes to aminopyridine and carbon dioxide. The absence of significant base catalysis and the isolation of a new product resulting from trapping of the intermediate with the base piperidine are also consistent with an elimination addition mechanism. Finally the observed substituent effect (σ^-) gives ρ 2.45 which is in accordance with a rate-determining departure of the phenoxide group from the anion intermediate formed in a pre-equilibrium step. Blocking the E1cb mechanism of the secondary carbamates by introduction of N,N-disubstitution in the substrate led to a rate-limiting decrease of ca. 10⁶.

Full text of DOI:10.1039/b200445n

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Reactivity of N-pyridylcarbamates in basic media
Fátima Norberto,*a Susana Santos,*a Daniel Silva,a Pablo Hervés,*b Ana Sofia Miguela
and Filipe Vilelaa
2
a Departamento de Química e Bioquímica, CECF, CECUL, Faculdade de Ciências,
Universidade de Lisboa, 1749-016 Lisboa, Portugal. E-mail: fatinor@fc.ul.pt; spina@fc.ul.pt;
Fax: 21 7500088; Tel: 21 7500951
b Departamento de Química Física, Facultad de Ciencias, Universidad de Vigo, Spain.
E-mail: jherves@uvigo.es
Received (in Cambridge, UK) 11th January 2002, Accepted 8th March 2002
First published as an Advance Article on the web 18th April 2002
New secondary aryl N-pyridylcarbamates were prepared by reaction of the aminopyridine anion with aryl chloro-
formates and their hydrolysis was studied over the pH range from 12 to 13.7. The pH–rate profile points to an E1cB
mechanism, involvingpre-equilibriumdeprotonationofthenitrogenatomtoformananionthatundergoesrate-limiting
decompositionintopyridylisocyanateandaphenoxideion. Furtherreactionofthehighlyreactiveisocyanatewithwater
affords N-pyridylcarbamic acid, which spontaneously decomposes to aminopyridine and carbon dioxide. The absence
of significant base catalysis and the isolation of a new product resulting from trapping of the intermediate with the
base piperidine are also consistent with an elimination–addition mechanism. Finally the observed substituent effect
(σϪ) gives ρ 2.45 which is in accordance with a rate-determining departure of the phenoxide group from the anion
intermediate formed in a pre-equilibrium step. Blocking the E1cb mechanism of the secondary carbamates by
introduction of N,N-disubstitution in the substrate led to a rate-limiting decrease of ca. 106.
Introduction
For several years, research in our laboratories has been directed
towards the search for new carbamates, compounds which are
well known for their insecticidal and fungicidal activity.1 The
lability of these compounds in acid or basic aqueous media
is an essential characteristic for evaluating their possible
applications as biological agents.
Carbamates can undergo hydrolysis reactions by a BAC2 or an
E1cB mechanistic pathway depending on their own structural
properties.2–5 Secondary aromatic carbamates, which have
acidic protons in the α-position, are known to react by the E1cB
mechanism, characterized by the pre-equilibrium formation of
an unstable isocyanate This isocyanate intermediate, which
is too labile to be detected directly, may be trapped through
reaction with an amine such as piperidine. High values of ρ are
expected,6,7 and are clearly related to a rate-determining step
that releases phenol following the pre-equilibrium of anion
formation with isocyanate generation. An important criterion
used for mechanistic clarification is blocking of the E1cB
mechanism of secondary carbamates by introduction of N,N-
disubstitution in the substrate. By comparing the pH–rate
profiles of both substrates, one of which is incapable of forming
the conjugated anion and is a model for the BAC2 mechanism
(which is easy to distinguish from nucleophilic catalysis using a
base and its sterically hindered analogue),8 one can get a good
idea of the E1cB and BAC2 mechanistic behaviour9
recorded using a Bruker 400, in CDCl3 with TMS as internal
standard. J values are given in Hz. HRMS were recorded on
a Finnigan FT/MS 2001-DT mass spectrometer. Column
chromatography was carried out with silica gel 60, 0.040–0.063
µm (Merck 9385). Thin layer chromatography (TLC) and
preparative thin layer chromatography (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.
General procedure for the preparation of pyridylcarbamates
To a solution of 2-aminopyridine or 2-(N-methylamino)-
pyridine (21 mmol) in DMF were added dropwise sodium
hydride (80% dispersion in oil, 21 mmol) in DMF and the
corresponding phenyl chloroformate (21 mmol). The reaction
was stirred for 3 to 12 hours and worked up by adding water
and dichloromethane; the organic layer was dried with mag-
nesium sulfate and evaporated to dryness. Compounds 1a
and 1e crystallized from the reaction mixture and were further
purified by recrystallization. Column chromatography with
n-hexane–ether (2 : 8), followed by recrystallization with
dichloromethane afforded 1b. Column chromatography
with hexane–ether (4 : 6) and recrystallization with ether
We have studied the chemistry of new phenyl N-benzoyl-,
N-thiobenzoyl-10 and N-arylsulfonyl-carbamates.11 Based on
literature data,12 which indicate further biological interest in
carbamates possessing a pyridine moiety in their structure, we
extended our studies to several new N-pyridylcarbamates, 1a–e
and 2.
Experimental
Melting points are uncorrected. IR spectra were obtained using
1
a Hitachi 270-50 spectrophotometer. H NMR spectra were
1162
J. Chem. Soc., Perkin Trans. 2, 2002, 1162–1165
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b200445n

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afforded compound 1c. Compound 1d was obtained after
column chromatography with petroleum ether–ethyl acetate
(8 : 2) and petroleum ether–ether (6 : 4) and recrystallization
with methanol. Compound 2 was obtained in pure form after
column chromatography with petroleum ether–ether (1 : 1) and
recrystallization with ethanol.
Phenyl N-methyl-N-(2-pyridyl)carbamate 2. 1.4 g, 35%, mp
59–61 ЊC; νmax/cmϪ1(KBr) 1722 (C᎐O), 1590–1443 (C᎐C, C᎐N);
᎐
᎐
᎐
EIMS (probe) 22 eV m/z 183, 135 [C7H7N2O]ϩ, 107 [C7H5O2]ϩ,
[C5H4N]ϩ, 77 [C6H5]ϩ; δH (300 MHz, CDCl3) 8.45 (1 H, d,
J = 4.5, 6-H py), 7.79 (1 H, d, J = 8.4, 3-H py), 7.68 (1 H, ddd,
J = 1.8; 7.5; 8.4, 4-H py), 7.37 (2 H, m, CH aromatic), 7.19 (3 H,
m, CH aromatic), 7.07 (1 H, ddd, J = 7.5; 1.8; 4.5, 5-H py), 3.69
Phenyl N-(2-pyridyl)carbamate 1a. 0.449 g, 13%, mp 155–156
ЊC (EtOH); νmax/cmϪ1 (KBr) 1746 (C᎐O), 1590–1446 (C᎐C,
(3H, s, N-Me); δ (100.4 MHz, CDCl ) 150.9 (C᎐O), 154.5 (C-2
᎐
C 3
py), 150.9 (C-1 Ph), 147.6 (C-6 py), 137.4 (C-4 py), 129.4 (C-3,
C-5 Ph), 125.6 (C-4 Ph), 121.7 (C-2, C-6 Ph), 119.3 (C-5 py),
112.9 (C-3 py). m/z (HRMS) 228.089889 (calc. for C13H12N2O2
228.089878).
᎐
᎐
C᎐N); δ (300 MHz, CDCl ) 11.01 (1 H, s, N-H ), 8.48 (1 H, dd,
᎐
H
3
J = 0.9; 5.0, 6-H py), 8.13 (1 H, d, J = 8.4, 3-H py), 7.74 (1 H,
ddd, J = 2.1; 7.4; 8.4, 4-H py), 7.44 (3 H, m, CH aromatic), 7.27
(2 H, m, CH aromatic), 7.03 (1H, dddd, J = 0.9; 5.0; 7.4, 5-H
Kinetic methods
py); δ (100.4 MHz, CDCl ) 152.2 (C᎐O), 152.0 (C-2 py), 150.5
᎐
C
3
(C-1 Ph), 147.6 (C-6 py), 138.8 (C-4 py), 129.5 (C-3, C-5 Ph),
125.9 (C-4 Ph), 121.8 (C-2, C-6 Ph), 119.0 (C-5 py), 112.9
(C-3 py). m/z (HRMS) 214.075083 (calc. for C12H10N2O2
214.074228).
N-(2-Pyridyl)carbamates. The measurements were carried
out with an SX.18MV Stopped Flow apparatus equipped with
thermostated cell holders, which were used for the kinetic
studies; the cells were kept at 27.0 0.1 ЊC in the cell com-
partment of the apparatus. The kinetics of hydrolysis of N-(2-
pyridyl)carbamates was studied in 1,4-dioxane–water 15%
(v/v), with the ionic strength kept constant at 0.5 M with
NaClO4 (3 M), by continuously monitoring the increase in
absorbance at 290 nm (compound 1a), 300 nm (compounds 1b,
1c and 1d) and 305 nm (compound 1e) corresponding to the
decomposition of substrate. In all cases, reactions were carried
out under pseudo-first-order conditions, the carbamate con-
centration being much lower than those of the other reagents
(ca. 7 × 10Ϫ5 M, except for 1b which was about half of this
value). The absorbance–time data for all of the kinetic experi-
ments were fitted by first-order integrated equations, and
the values of the pseudo-first-order rate constants (ko) were
reproducible to within 5%.
4-Chlorophenyl N-(2-pyridyl)carbamate 1b. 0.042 g, 1%, mp
189–190 ЊC (DCM); νmax/cmϪ1(KBr) 1749 (C᎐O), 1598–1449
᎐
(C᎐C, C᎐N); δ (300 MHz, CDCl3) 8.33 (1 H, dt, J = 0.9; 4.8,
᎐
᎐
H
6-H py), 7.99 (1 H, d, J = 8.4, 3-H, py), 7.73 (1 H, ddd, J = 0.9;
7.2; 8.4, 4-H py), 7.36 (2 H, d, J = 8.1, 3-H, 5-H Ph), 7.16 (2 H,
d, J = 8.1, 2-H, 4-H Ph), 7.05 (1 H, dd, J = 4.8; 7.2, H-5 py);
δC (100.4 MHz, CDCl3) 147.9 (C-6 py), 138.6 (C-4 py), 129.5
(C-3, C-5 Ph), 119.5 (C-5 py), 123.0 (C-2, C-6 Ph), 112.6
(C-3 py). m/z (HRMS) 248.035376 (calc. for C12H9N2O2Cl
248.035255).
4-Fluorophenyl N-(2-pyridyl)carbamate 1c. 0.585 g, 18%,
mp 176–177 ЊC (MeOH); νmax/cmϪ1(KBr) 1745 (C᎐O), 1591–
᎐
1443 (C᎐C, C᎐N); EIMS (probe), 22 eV m/z 120 [C H N O]ϩ,
᎐
᎐
6
4
2
Hydrolysis of 1a and 2 was accomplished in the presence of
piperidine as buffer, at a concentration of 0.1 M.
112 [C6H5OF]ϩ, 78 [C5H4N]ϩ; δH (300 MHz, CDCl3) 8.37
(1 H, dd, J = 4.5; 1.2, 6-H py), 8.03 (1 H, d, J = 8.4, 3-H py), 7.74
(1 H, ddd, J = 1.2; 7.2; 8.4, 4-H py), 7.09 (2 H, dd, J = 9.1; 8.1,
2-H, 4-H Ph), 7.19 (2 H, dd, J = 4.5; 9.1, 3-H, 5-H Ph), 7.05
(1 H, m 5-H py); δC (100.4 MHz, CDCl3) 161.5 (C-4 Ph),
151.1 (C-2 py), 147.9 (C-6 py), 138.6 (C-4 py), 123.1 (C-2,
C-6 Ph), 119.5 (C-5 py), 116.3, 116.0 (C-3, C-5 Ph), 112.5 (C-3
py). m/z (HRMS) found 232.06398 (calc. for C12H9N2O2F
232.06426).
Isolation of intermediate
Hydrolysis of 1a was carried out in the presence of piperidine
buffer (0.1 M) and compound 3 was isolated. m/z (HRMS)
205.122253 (calc. for C11H15N3O 205.1215).
Results and discussion
4-Methylphenyl N-(2-pyridyl)carbamate 1d. 0.126 g, 4%,
N-(2-Pyridyl)carbamates
mp 174 ЊC (decomp.) (MeOH); νmax/cmϪ1 (KBr) 1745 (C᎐O),
᎐
Under the conditions used, the hydrolysis of phenyl N-pyridyl-
carbamate (1a) gave rise to 2-aminopyridine and phenol
in sodium hydroxide solution and to piperidine-derived
N-pyridylurea in the presence of piperidine buffer. The influ-
ence of OHϪ concentration on the reaction rate was studied
by varying the concentration from 0.01 to 0.5 M, using sodium
hydroxide solutions. The rate of hydrolysis is proportional to
the OHϪ concentration until it reaches a plateau region (see
Fig. 1). This plateau comes about because of the possible
pre-equilibrium ionisation of the substrate (K), followed by its
rate-determining decomposition to products (k1), as shown in
Scheme 1, which leads to eqn. (1).
1589–1441 (C᎐C, C᎐N); EIMS (probe), 22 eV m/z 121
᎐
᎐
[C7H8O2]ϩ, 120 [C6H4N2O]ϩ, 108 [C7H8O]ϩ, 78 [C5H4N]ϩ;
δH (300 MHz, CDCl3) 8.41 (1 H, d, J = 4.8, 6-H py), 8.04 (1 H,
d, J = 8.4, 3-H py), 7.72 (1 H, ddd, J = 1.8; 7.5; 8.4, 4-H py), 7.23
(2 H, d, J = 8.4, 2-H, 4-H Ph), 7.04 (1 H, dd, J = 4.8; 7.5, 5-H
py), 7.11 (2 H, d, J = 8.4, 3-H, 5-H Ph), 2.38 (3 H, s, CH3);
δ (100.4 MHz, CDCl ) 151.9 (C᎐O), 151.7 (C-2 py), 148.1 (C-4
᎐
C
3
Ph), 147.8 (C-6 py), 138.6 (C-4 py), 135.6 (C-1 Ph), 129.9 (C-3,
C-5 Ph), 121.4 (C-2, C-6 Ph), 119.1 (C-5 py), 112.6 (C-3 py),
20.8 (CH3). m/z (HRMS) 228.090749 (calc. for C13H12N2O2
228.089878).
4-Methoxyphenyl N-(2-pyridyl)carbamate 1e. 0.873 g, 21%,
mp 173–175 ЊC (MeOH); νmax/cmϪ1(KBr) 1742 (C᎐O), 1594–
᎐
(1)
1445 (C᎐C, C᎐N); EIMS (probe), 22 eC m/z 124 [C H O ]ϩ, 120
᎐
᎐
7
8
2
[C6H4N2O]ϩ, 109 [C6H5O2]ϩ, 78 [C5H4N]ϩ; δH (300 MHz,
CDCl3) 8.30 (1 H, d, J = 4.3, 6-H py), 7.97 (1 H, d, J = 8.4, 3-H
py), 7.69 (1 H, ddd, J = 1.8; 7.8; 8.4, 4-H py), 7.10 (2 H, d,
J = 9.0, 2-H, 4-H Ph), 7.01 (1 H, dd, J = 4.3; 7.8, 5-H py), 6.90
(2 H, d, J = 9.0, 3-H, 5-H Ph), 3.81 (3 H, s, OCH3); δC (100.4
The best fit to the experimental data gives k1 and K = Ka/Kw
for phenyl N-(2-pyridyl)carbamate (1a). Several other aryl pyr-
idylcarbamates (1b–e) were also examined over a wide pH range
in order to determine k1 and the acidity constants of the
carbamates, Ka, the results of which are summarised in Table 1.
Substituents on the aryl carbamate ring give rise to a
Hammett correlation that is somewhat better using a σϪ value
(ρ = 2.45, r2 = 0.9884), rather than a σ value (ρ = 1.98, r2 =
0.9274) for the substituent (Fig. 2). This result is expected on
MHz, CDCl ) 156.7 (C-4 Ph), 152.2 (C᎐O), 151.8 (C-2 py),
᎐
3
147.7 (C-6 py), 143.2 (C-1 Ph), 138.7 (C-4 py), 122.6 (C-2, C-6
Ph), 119.1 (C-5 py), 114.5 (C-3, C-5 Ph), 112.7 (C-3 py), 55.6
(OCH3). m/z (HRMS) 244.083785 (calc. for C13H12N2O3
244.084792).
J. Chem. Soc., Perkin Trans. 2, 2002, 1162–1165
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Fig. 2 Hammett plot for hydrolysis of N-aryl pyridylcarbamates
showing the effect of the substituent on the leaving group.
To study the mechanism of the process in more detail, the
effect of the buffer concentration on the reaction rate was
evaluated, and so the reaction was studied in several bases using
piperidine, piperazine and butylamine. No buffer effect was
observed (Table 2), a result which is also in accordance with a
rate-determining breakdown of the carbanion intermediate
formed in the pre-equilibrium step. According to the litera-
ture,14 decomposition of such a species is not dependent upon
concentration of any buffer and the rate-limiting step only
exhibits specific base catalysis.
Fig. 1 Influence of [NaOH] on ko for 1a–e.
Additional support for the proposed mechanism comes from
comparison of the reaction of compound 1a with that of its
N-methyl analogue, 2.
N-Methyl(pyridyl)carbamate
Hydrolysis of 2 in NaOH also gave rise to the corresponding
phenol and N-methylaminopyridine and showed a first-order
dependence on the concentration of OHϪ (see Fig. 3). A second-
Scheme 1 Mechanism of hydrolysis of aryl N-pyridylcarbamates.
Table 1 Values of k1 and Ka for N-(2-pyridyl)carbamates
Fig. 3 pH–Rate profile for phenyl N-methyl(2-pyridyl)carbamate 2.
order rate constant of 6 × 10Ϫ4 MϪ1 s was obtained, which,
when compared with the value obtained for the analogous
secondary carbamate, gives a rate difference of ca. 106. In this
case, ionisation is blocked, and turns the substrate into a good
model for the BAc2 mechanism (Scheme 2), which is known to
occur with much smaller reaction rates.
The possibility of catalysis by general bases was investigated
and piperidine in H2O was used as a buffer. The observed
first-order rate constants ko were found to increase linearly with
increasing buffer concentration (Fig. 4), which suggests the
involvement of the general base according to eqn. (2), where kB
is the second-order rate constant for the catalytic process in the
presence of buffers.
X
k1/sϪ1
1013 Ka/M
H
8.30
3.26
4.71
8.96
35.6
1.4
1.0
0.8
1.8
2.1
CH3O
CH3
F
Cl
the basis of a rate-determining departure of the phenoxide
group from the anion intermediate formed in a pre-equilibrium
step. Another high value, ρ = 2.86, was observed for a typical
E1cB process.7 In fact, this mechanism is very sensitive to
the nature of the leaving group, since the transition state is
reached with almost complete acyl–oxygen bond cleavage. On
the other hand, a BAc2 mechanism would certainly involve little
acyl–oxygen bond cleavage in the transition state as judged
from the low value (e.g. ρ = 1.1) for aryl acetates.13
ko = kOH [OHϪ] ϩ kB [B]
(2)
The buffer-independent rate of hydrolysis for piperidine,
kOH[OH], obtained by extrapolation of the observed rate
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J. Chem. Soc., Perkin Trans. 2, 2002, 1162–1165

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Table 2 Base catalysis for 4-methoxyphenyl N-(2-pyridyl)carbamate (1e)
103 [Piperidine]/M
102 ko/sϪ1
103 [Piperazine]/M
103 ko/sϪ1
103 [Butylamine]/M
103 ko/sϪ1
2.50
2.00
1.50
—
2.61
2.58
2.51
—
4.30
3.44
2.58
2.15
4.0
4.1
3.5
3.6
2.28
1.82
1.37
1.14
4.2
3.5
3.9
4.1
constant to zero buffer concentration, was found to correlate
with the value of ko obtained in the study of the influence of the
NaOH concentration.
Conclusion
The results show the existence of an E1cb mechanism for
the hydrolysis of 1a. The evidence includes the levelling off of
the pH–rate profile, together with the absence of general base
catalysis and the high substituent effect. All these favour
a
mechanism involving a rate-determining step for the
departure of phenoxide, with formation of an isocyanate
that subsequently decomposes to the products (Scheme 1).
Identification of the presence of isocyanate was accomplished
by its trapping with the buffer piperidine, as the corresponding
urea was isolated at the end of the reaction. Further support
that an elimination–addition mechanism, rather than a normal
addition–elimination, is operating in this case, comes from
the relative magnitude of the rate constants of the secondary
carbamate when compared to those of the tertiary one (2),
where substrate ionisation is no longer possible. The kinetic
parameters obtained for hydrolysis of 2 suggest a bimolecular
type of hydrolysis for N-methyl(pyridyl)carbamate.
Scheme 2 Mechanism of hydrolysis of phenyl N-methylpyridylcarb-
amate.
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Fig. 4 Influence of piperidine concentration in H2O upon hydrolysis
of 2.
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