Kinetics and mechanism of izomerization of N-alkoxycarbonyl-5-aroxytetrazoles

Article abstract of DOI:10.1023/A:1013947228772

The kinetics and mechanism of the N²-N¹-isomerization of 2-methoxycarbonyl-5-(p-X-phenoxy)-tetrazoles (X = H, CH₃, NHCOCH₃, Cl, Br, NO₂) were studied by ¹H NMR spectroscopy in a DMSO-d₆-CDCl₃ mixture (25: 75). The rate of isomerization of the N²-isomer into N¹-isomer fit the first-order equation (after three half-conversion periods). The isomerization is accompanied by hydrolysis and decarboxylation. The Hammett plot of In(k_Xlk_H) for the isomerization showed a good correlation with σ^- values (p^- = 1.33, r = 0.965). A poor correlation with σ values was obtained. The kinetic data, the effect of solvent polarity, the substituent effects, and the results of AM1 quantum-chemical calculations suggest an ionic mechanism of the isomerization in polar solvents and a concerted mechanism in nonpolar solvents.

Full text of DOI:10.1023/A:1013947228772

Russian Journal of Organic Chemistry, Vol. 37, No. 12, 2001, pp. 1771 1781. From Zhurnal Organicheskoi Khimii, Vol. 37, No. 12, 2001,
pp. 1852 1862.
Original English Text Copyright
2001 by Dabbagh, Mansoori.
Kinetics and Mechanism of Izomerization
of N-Alkoxycarbonyl-5-aroxytetrazoles*
H. A. Dabbagh and Ya. Mansoori
College of Chemistry, Isfahan University of Technology, Isfahan, 8415 Iran
Received January 25, 2001
Abstract The kinetics and mechanism of the N2 N1-isomerization of 2-methoxycarbonyl-5-(p-X-phenoxy)-
1
tetrazoles (X = H, CH3, NHCOCH3, Cl, Br, NO2) were studied by H NMR spectroscopy in a DMSO-d6
CDCl3 mixture (25: 75). The rate of isomerization of the N2-isomer into N1-isomer fit the first-order equation
(after three half-conversion periods). The isomerization is accompanied by hydrolysis and decarboxylation.
The Hammett plot of ln(kX/kH) for the isomerization showed a good correlation with
values ( = 1.33,
r = 0.965). A poor correlation with values was obtained. The kinetic data, the effect of solvent polarity,
the substituent effects, and the results of AM1 quantum-chemical calculations suggest an ionic mechanism
of the isomerization in polar solvents and a concerted mechanism in nonpolar solvents.
Tetrazoles constitute a class of compounds which
are very important for medical chemistry. Substituted
tetrazoles were found to exhibit a wide spectrum of
neurological activity which, depending on the sub-
stitution pattern, ranges from strong stimulation of
the nervous system to depressive action. Tetrazole-
carboxylic acids are widely used as pharmacophores
in drug design, specifically, for creation of anticancer,
antimicrobial, antihypertensive, and antiallergic
agents. Tetrazole derivatives have recently attracted
increasing attention due to their industrial applica-
tions. It is quite probable that pharmacological activity
of tetrazoles is related to their physicochemical pro-
perties, so that thorough investigations in the field
of tetrazole derivatives were initiated many years ago
[1 5]. Every year numerous publications appear on
the chemical behavior of tetrazoles, in particular on
their prototropic tautomerism [6 15] and izomeriza-
tions [16]. Analogous ready isomerizations have been
reported for a few other azoles having a substituent on
the nitrogen, e.g., for benzotriazole [10], benzimid-
azole [17], and pyrazole derivatives [18].
example, some 1,5-disubstituted tetrazoles exhibit
a strong stimulating activity on the central nervous
system while 2,5-disubstituted analogs do not [19].
On the other hand, most azides (which are important
precursors of such compounds as amines, aziridines,
isoureas, oxadiazoles, and many others) are carcino-
genic [14, 15, 20]. Therefore, the major and the most
important task is to control the isomerization process.
It is also important to find conditions ensuring dis-
placement of the equilibrium between isomers toward
the desired species. These goals could be achieved
through understanding of the isomerization mecha-
nism.
Katritzky et al. studied the kinetics of interconver-
sions of N-( -aminoalkyl)benzotriazoles and found
that the reaction follows a dissociation recombination
pattern. The same authors also found that tetrazoles
undergo fast isomerization involving N1 N2-migration
of the substituent [10] due to activation of the C N
bond toward cleavage. This tendency was advantage-
ously utilized in many synthetic transformations,
including reactions with nucleophiles [21 26].
The main difficulty in the studies of tetrazole com-
pounds is that 1-tetrazole, 2-tetrazole, and the corre-
sponding open-chain form of 1-tetrazole in solution
can form an equilibrium mixture whose composition
depends on the substitution pattern, solvent polarity,
and other factors. Generally, each isomer has its own
specific chemical and pharmacological properties. For
Dabbagh and Lwowski (see [16] and references
therein) studied the equilibria of 5-substituted 1- and
2-tetrazoles, the substituent at C5 remaining nearly
unchanged, and showed that 1- and 2-alkoxycarbonyl-
tetrazoles and, in some cases, imidoyl azides occur in
equilibrium. However, in the srystalline state only one
isomer always prevails, depending on the substituent
*
The original article was submitted in English.
1070-4280/01/3712-1771$25.00 2001 MAIK Nauka/ Interperiodica

1772
DABBAGH, MANSOORI
Table 1. Substituent and solvent effects on the position
of the equilibrium between 1,5- and 2,5-disubstituted tetra-
zoles at room temperaturea [16]
(9) Crystallization of the equilibrium mixture of
1- and 2-methoxycarbonyl-5-methoxy(or ethoxy)tetra-
azoles from diethyl ether gives pure 2-substituted
tetrazole.
The aim of this work was to gain a better under-
standing of the mechanism of isomerization of N-sub-
stituted tetrazoles. First, we studied the effect of the
5-substituent (keeping the substitution at the 1- or
2-position constant) and solvent polarity on the rate
of N1 N2-isomerization of N-alkoxycarbonyl-5-aroxy-
tetrazoles (and possibly of the azide isomers) at room
temperature (Scheme 1). The following solvents were
examined: CCl4, CDCl3, C6D5N, CD3COCD3,
CD3OD, CD3CN, D2O, and CDCl3 DMSO-d6 mix-
tures. Second, the rate constants for disappearance of
2-substituted tetrazoles were calculated and correlated
Substituents
Y
Isomer fraction,b
%
Z
2-tetrazole 1-tetrazole
azide
CH3O CO2CH3
CH3Oc CO2CH3
CH3O CO2CH2CCl3
CH3Oc SO2CF3
62
100
46
38
0
37
0
0
0
17
with the Hammett substituent constants and
[27].
0
100
Finally, we performed AM1 quantum-chemical cal-
culations of the molecular geometry of the compounds
under study. We tried to find evidences indicating that
the isomerization of tetrazoles follows an ion pair
mechanism and conditions to control the state of the
equilibrium toward the desired species.
a
In CDCl3 unless otherwise stated.
Calculated from the 1H NMR spectra.
In diethyl ether.
b
c
concentration and solvent polarity. The authors came
to xthe following conclusions:
Scheme 1.
(1) Metoxycarbonyl-5-alkoxy(aroxy)tetrazoles and
related imidoyl azides do exist as an equilibrium
mixture;
(2) The position of the equilibrium depends upon
the electronic nature of the N-substituent, concentra-
tion, and solvent polarity;
(3) In nonpolar solvents weak electron-withdraw-
ing groups (such as CO2CH3) favor acylation of
5-substituted tetrazoles at the 2-position;
I, II, X = CH3, III, IV, X = H; VII, VIII, X =
Cl; IX, X, X = Br; XI, XII, X = NHAc;
XIII, XIV, X = NO2.
(4) Moderate electron-withdrawing groups (such
as CO2CH2CCl3 and CO2CCl3) favor displacement of
the equilibrium toward 1-alkoxycarbonyl isomers;
Initially, we expected to observe a rapid isomeriza-
tion (within hours) of 2-tetrazoles into 1-tetrazoles in
chloroform, as reported previously [16]. However, we
were surprised not to observe isomerization in non-
polar solvents (such as CCl4 and CHCl3) over several
days. This fact prompted us to study the isomerization
eqilibria of N-substituted tetrazoles in more detail.
(5) Strong electron-acceptor groups (CN, SO2CH3,
SO2CF3) favor formation of the azide structure;
(6) The rate of isomerization of both tetrazoles and
open-chain azide isomers increases as their concentra-
tion and solvent polarity rise;
Solvent effect. In a polar solvent, such as DMSO,
the isomerization was very fast (in some cases the rate
could not be measured, and the process was ac-
companied by hydrolysis and decarboxylation. The
best solvent system ensuring a moderate rate of the
isomerization and minimal contribution of side reac-
tions was a mixture of CDCl3 with DMSO-d6 at a
weight ratio of 75: 25. In this solvent system all the
examined 1-methoxycarbonyl-5-aroxytetrazoles were
in equilibrium with the corresponding 2-isomer but
(7) In the solid phase or less polar solvents (e.g.,
in diethyl ether), only one of the three isomers is
formed, depending on the nature of substituent in
position 1 or 2;
(8) The 1H NMR spectra of 1(2)-methoxycarbonyl-
5-methoxytetrazoles, recorded immediately after
addition of a base, indicate that initially 1-substituted
isomer is formed; it then gives rise to an equilibrium
mixture with the 2-isomer and/or imidoyl azide;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

KINETICS AND MECHANISM OF IZOMERIZATION OF N-ALKOXYCARBONYL-.. .
1773
Table 2. Transformations of 2-methoxycarbonyl-5-(p-X-
phenoxy)tetrazoles in CDCl3 DMSO-d6 (75: 25, by
weight) at room temperature
Conversion,a %
Compd. Time,
no.
h
hydrolysis decarboxylation izomerization
II
IV
127.4
123.1
7.8
5.3
10.7
8.1
8.0
20.3
22.1
13.2
20.2
14.7
14.0
16.2
70.1
81.5
69.1
77.2
78.0
63.5
VIII 127.2
126.9
X
XII 122.9
XIV 73.12
Fig. 1. Typical kinetic curves for the isomerization of
(1) 2-methoxycarbonyl-5-(p-nitrophenoxy)tetrazole and
(2) 1-methoxycarbonyl-5-(p-nitrophenoxy)tetrazole in
CDCl3 DMSO-d6 (72: 25, by weight) at room temperature.
a
Calculated from the 1H NMR data.
phenoxy)tetrazole. The contribution of the isomeriza-
tion decreases and the contributions of hydrolysis
and decarboxylation increase with rise in the solvent
polarity.
not with the imidoyl azide. Figure 1 shows a typical
kinetic curve for the isomerization of N-methoxy-
carbonyl-5-(p-nitrophenoxy)tetrazole. Here, hydro-
lysis and decarboxylation of the substrate (minor path-
ways) competed with its isomerization. The degree of
isomerization and the contribution of side reactions
(hydrolysis and decarboxylation) depend on the sub-
stituent nature and solvent polarity (Tables 2, 3). The
data in Table 3 show the effect of solvent polarity on
the isomerization rate and the extent of hydrolysis and
decraboxylation of 2-methoxycarbonyl-5-(p-bromo-
Tetrazole (X) undergoes fast and complete (100%)
hydrolysis on addition of D2O to its solution in
chloroform, prepared in an NMR ampule. The rate of
solvolysis of X in less polar methanol was slow in
favor of the isomerization. This is in good agreement
with the ionic nature of intermediates whose dissocia-
tion is faster in more polar solvents. The rates of
Table 3. Effect of solvent polarity on the isomerization, hydrolysis , and decarboxylation of 2-methoxycarbonyl-5-
(p-bromophenoxy)tetrazole (X) at room temperature
Isomerization,
%
kap 106,b
Hydrolysis,
%
Decarboxyla-
tion, %
Solventa
CDCl3 (120)c
Ratio X: IX
1
s
4.7
12
21
Pyridine-d5 (7.93)
0.13
34.25
206
34.24d
31.5
c
CD3COCD3
CD3OD (8.03)
33
36
78.5
0.15
2.5
55.29
12.5
0
63.3
Fast
32.94
40.5d
100
11.8
15.5
0
CD3CNe
D2Oe, f
DMSO-d6 CDCl3 (w/w)
100: 0 (8.45)
75: 25 (6.25)
50: 50 (6.38)
25: 75 (11.9)
22: 78 (7.83)
49
0.55
0.78
1.0
3.2
3.4
41.1
46.0
64.8
88.7
91.5
221
120
103
5.61
5.58
36.8
34.0
19.0
7.1
22.1
20.0
16.2
4.2
5.1
3.4
a
The numbers in parentheses denote the time (h) after which a sample was withdrawn for analysis.
b
c
d
e
f
Isomerization rate constant [Eq. (1)].
No conversion.
Solvolysis.
Instantaneous reaction.
In chloroform shaken with D2O.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1774
DABBAGH, MANSOORI
1
Fig. 2. Variation of the H NMR spectrum in the course of transformation of 2-methoxycarbonyl-5-(p-chlorophenoxy)tetrazole
VIII into equilibrium mixture of 1- and 2-tetrazoles and hydrolysis and decarboxylation products.
isomerization, hydrolysis, and decarboxylation of X
in pyridine-d5 were nearly the same. In acetonitrile-d3,
the rate of solvolysis was higher than the rates of
the other competing processes. No isomerization was
observed in chloroform and acetone-d6 over several
days (Tables 2, 3).
the 1-isomer is linked to nitrogen and carbon. The
signal at 3.35 ppm belongs to methanol which is
formed along the hydrolysis pathway (side reaction).
Most probably, the hydrolysis is caused by traces of
water absorbed by the solvent during relatively long
period of kinetic measurements. The formation of
methanol (which is also confirmed by IR spectra) in
the equilibrium mixture is responsible for further
solvolysis. The signals at 4.05 and 4.35 ppm belong
to 1-methyl- and 2-methyl-5-(p-chlorophenoxy)tetra-
zoles, respectively, which are formed by thermal
decarboxylation; 2-alkyltetrazoles are always the
major isomers [27]. The decarboxylation is unusual at
room temperature; generally, it requires much higher
temperatures (350 C) [28] (Table 3).
1
Figure 2 shows a typical portion of the H NMR
spectrum illustrating the disappearance of 2-methoxy-
carbonyl-5-(p-chlorophenoxy)tetrazole and appearance
of 1-methoxycarbonyl-5-(p-chlorophenoxy)tetrazole.
Protons of the methyl groups in N2- and N1-substi-
tuted isomers give signals at 4.30 and 3.80 ppm,
respectively, i.e., the signal of the 2-isomer appears
in a weaker field. The reason is that the N2 atom is
linked to two nitrogen atoms, whereas the N1 atom in
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

KINETICS AND MECHANISM OF IZOMERIZATION OF N-ALKOXYCARBONYL-.. .
1775
Fig. 3. Variation of the 1H NMR spectrum in the course of transformation of 2-ethoxycarbonyl-5-mesityloxytetrazole (XX)
into equilibrium mixture of 1- and 2-tetrazoles and hydrolysis products.
The IR spectra of the equilibrium mixture showed
no azide band (methoxycarbonyl group is a relatively
weak electron-withdrawing substituent, whereas only
moderate to strong electron-withdrawing groups favor
the formation of azide isomer; Table 1) [16]. The
occurrence of isomerization is confirmed by the
presence of hydroxy group absorption due to methanol
and by the low-frequency shift of the carbonyl band
electronegativity of the N1 nitrogen atom in the
1-isomer.
The rate of isomerization of 2-ethoxycarbonyl-5-
mesityloxytetrazole (XX) (Fig. 3) is low, k = 4.20
7
1
10 s . In this case the equilibrium does not shift
completely toward the N1-isomer over 674 h (cf. the
data for the other tetrazoles, given in Tables 3 and 4
and Fig. 2).
1
of 2-methoxycarbonyltetrazole by about 50 cm . The
carbonyl absorption frequency shifts due to lower
Isomerization kinetics. The kinetics of the iso-
1
merization were studied by H NMR spectroscopy.
Table 4. Kinetic parameters of the isomerization of 2-methoxycarbonyl-5-(p-X-phenoxy)tetrazoles in CDCl3 DMSO-d6
(75: 25, by weight) at room temperature
5
5
1
Compound no.
N2-to-N1
isomer ratio
[T2]eq 105,
10 ,b
s
10 , s
kap 106,c
s
rd
eq
1/2
Mna
II
IV
VIII
X
XII
XIV
0.69
0.38
0.20
0.14
0.09
0.02
4.56
2.27
0.52
0.45
2.41
0.50
8.81
10.3
4.58
8.65
4.42
7.78
1.55
4.47 (>3
4.05 (>4
5.17 (>3
5.61 (>3
7.41 (>3
26.50 (>4
)
0.990
0.993
0.998
0.994
0.994
0.994
1/2
1/2
1/2
1/2
1/2
1.71
1.34
1.24
0.93
0.26
)
)
)
)
)
1/2
a
b
c
Molal concentration.
Equilibration period; after that time, the tetrazole concentrations in the mixture no longer changed to an appreciable extent.
First-order rate constant for disappearance of the N2-isomer, determined from the 1H NMR data.
Correlation coefficient.
d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1776
DABBAGH, MANSOORI
The rate of disappearance of 2-methoxycarbonyl-5-
(p-XC6H4O)tetrazoles (X = CH3, H, Cl, Br, AcNH,
NO2) was measured in a CDCl3 DMSO-d6 mixture
(75: 25, by weight) (Tables 3, 4). The relative intens-
ity of the methyl proton signal was normalized against
the aromatic proton signals whose intensity did not
change during the process. The rate of disappearance
of the N2-isomer conformed to the first-order kinetics
[after 3 4 half-conversion periods; Scheme 2, Eq. (1)].
In all cases the equilibrium was displaced toward the
more polar N1-isomer (Scheme 2, Tables 2 4, Fig. 1).
Since [H2O] << [T2] or [T1], any change in [H2O]
is negligible.
d[T2]
=
(k + k )[T2] k ([T2]0 [Td] [TH])
1 1
dt
When equilibrium establishes: d[T2]/dt =
0
(k + k )
1
(T2)0 [Td] [TH] =
(T2)e
k
1
d[T2]
=
(k + k )[T2] (k + k )[T2]e
1 1
dt
The geometry of tetrazoles was optimized in terms
of the AM1 semiempirical approximation (Table 5).
The calculation results showed that more polar
N1-tetrazoles are more stable than their N2-isomers
(except for compound XIII). These findings are con-
sistent with the shift of the equilibrium toward the
N1-isomer in CDCl3 DMSO-d6 (75: 25).
d[T2]
=
(k + k )([T2] [T2]e)
1
dt
[T2] [T2]e
[T2]0 [T2]e
ln
= (k + k )t,
1
Substituent effects. Figure 4 shows the Hammett
where (k + k )= kobs
(1)
= 1.33, r =
1
plot of ln(kX/kH) versus substituents constants
[12]
for the N2 N1-isomerization of 2,5-disubstituted tetra-
zoles; a good correlation is observed,
0.965. However, a poor correlation was obtained with
values. These data indicate that a negative charge is
developed in the transition state for the isomerization
pathway (Schemes 3, 4). In other words, electron-
withdrawing groups in the aromatic ring increase the
rate of isomerization and also of decarboxylation and
hydrolysis.
Scheme 2.
Two mechanisms of the N2 N1-isomerization of
tetrazoles can be considered: intermolecular (dissocia-
tion recombination, e.g., an ionic mechanism) and
intramolecular (concerted 1,2-shift). Following the
first of these, 2-alkoxycarbonyl-5-aroxytetrazoles
dissociate completely to form tetrazolide anion and
methoxycarbonyl cation (Scheme 3). Scheme 4 shows
two types of intramolecular concerted mechanism of
the equilibrium N2 N1-isomerization.
Table 5. Relative stabilities (kcal/mol) and dipole
moments (D) of 1(2)-methoxycarbonyl-5-(p-X-C6H4O)-
tetrazoles, calculated by the AM1 method
d[T2]
Relative stability of the
1-isomer with respect
to the 2-isomera
Dipole moment
= ( kd
+ kn[H2O] + k1)[T2] [T1]
X
dt
1-isomer 2-isomer
[T2]0 = [T2]+ [Td]+ [TH]+ [T1] (Material balance
equation)
CH3
H
Cl
7.50 (I/II)
6.30
3.40
3.40
4.90
1.90
1.70
1.70
5.60
[T1]0 = [T2]0 + [T2]+ [Td]+ [TH]
8.30 (III/IV)
8.10 (VII/VIII)
6.70 (XIII/XIV)
d[T2]
=
k[T2] k ([T2]0 [T2] [Td] [TH]),
NO2
1
dt
a
In parentheses are given the corresponding compound
numbers.
k = kd + kHH2O + k1
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KINETICS AND MECHANISM OF IZOMERIZATION OF N-ALKOXYCARBONYL-.. .
1777
AcNH, Br, Cl, H, CH3) favor an ionic mechanism.
Concerted reactions are generally characterized by
smaller
of type A cannot be ruled out. Mechanism B is ex-
cluded because of the positive value.
values. However, a concerted mechanism
The rate of isomerization and side reactions (hy-
drolysis and decarboxylation) increases in going to
more polar solvents: C6D5N, CD3OD, CD3CN, and
D2O. This was the first indication that the reaction
follows an ion pair mechanism (Table 3). Concerted
mechanisms are less sensitive to the solvent polarity.
In weakly polar solvents (such as CCl4, CDCl3, and
CD3COCD3) the isomerization is very slow. Neither
isomerization no side reactions were observed with
tetrazoles having NO2, AcNH, Br, Cl, H, or CH3
group in the para-position of the 5-phenoxy substit-
uent. The isomerization was not accompanied by side
reactions when the substrates had CH3O, CH3CH2O,
2,4,6-trimethylphenoxy, or 2,6-dimethylphenoxy
groups in position 5 of the heteroring.
Fig. 4. Hammett correlation for the rate of disappearance
of 2-methoxycarbonyl-5-(p-XC6H4O)tetrazoles in CDCl3
DMSO-d6 (75: 25, w/w) at room temperature: y= 1.3334
x + 0.3661; r = 0.9648.
Initially, the concerted mechanisms were consider-
ed (Scheme 4). However, the Hammett plot for the
isomerization ( = 1.33, r = 0.965, for p-XC6H4O
groups at the 5-position of tetrazoles, X = NO2,
Scheme 3.
Ionic intermolecular isomerization mechanism
Scheme 4.
A: Concerted intramolecular isomerization mechanism
with formation of tetrazolide anion
Ar = p-XC6H4; X = NO2, AcNH, Br, Cl, H, CH3.
B: Concerted intramolecular isomerization mechanism with formation of tetrazolium cation
G = CH3S, CH3O, CH3CH2O.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1778
DABBAGH, MANSOORI
Scheme 5.
Intramolecular concerted mechanism of equilibrium isomerization
Scheme 6.
Intramolecular ionic mechanism of equilibrium isomerization
Special experiments were carried out in order to
This eliminates the possibility of intramolecular con-
certed mechanism in CDCl3 DMSO-d6 (75: 25).
verify the proposed mechanisms. A 1: 1 mixture of
2-ethoxycarbonyl-5-(2,4,6-trimethylphenoxy)tetrazole
(XX) and 2-methoxycarbonyl-5-phenoxytetrazole (IV)
was dissolved in CDCl3 DMSO-d6 (75: 25, w/w),
and the rate of disappearance of both substrates was
The rate constants for disappearance of each tetra-
zole in a 1: 1 mixture of XX and IV in solution differ
from those found for solutions of individual tetrazoles
IV and XX (Table 6). Therefore, addition of tetrazole
IV affects the rate of disappearance of tetrazole XX
in solution and vice versa.
1
monitored by H NMR spectroscopy. We expected to
observe four tetrazoles at the equilibrium for the
concerted mechanism (Scheme 5) and eight tetrazoles
for the ionic mechanism (Scheme 6). Unfortunately,
all the signals corresponding to the CO2CH3 group
of N1-tetrazoles appeared at 3.80 0.05 ppm. When
the mixture of tetrazoles IV and XX was injected into
a mass spectrometer, no molecular ion peaks was
observed (due to loss of methoxycarbonyl group).
Neither the mixture of IV and XX nor tetrazole IV
in solution (CDCl3 DMSO-d6, 75: 25) showed the
molecular ion peak even at lower ionization energies
(10 eV). Pure solid tetrazoles or their solution in
chloroform give strong molecular ion peaks; for
example, compound IV showed the molecular ion
peak with m/z 220 (34%) at 70 eV. The loss of
methoxycarbonyl group in solution is a good evidence
for at least partial ionization of substituted tetrazoles.
Table 6. Rate constants of the isomerization of pure
2-methoxycarbonyl-5-aroxytetrazoles and their 1: 1 mix-
tures with 2-ethoxycarbonyl-5-aroxytetrazoles
Compound
no.
kap 106,a
kap 103,b
R
Ar
Ph
Mes
Ph
1
1
s
s
IV
XVIII
VI
Me
Me
Et
3.89
6.22
4.03
0.66
2.0
5.1
5.1
XX
Et
Mes
a
Pure N2-tetrazoles.
b
1: 1 Mixtures of 2-methoxycarbonyl- and 2-ethoxycarbonyl-5-
aroxytetrazoles [Eq. (1)].
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KINETICS AND MECHANISM OF IZOMERIZATION OF N-ALKOXYCARBONYL-.. .
1779
The following conclusions can be drawn from the
results of our study of the kinetics and mechanism of
isomerization of 2-methoxycarbonyl-5-(p-X-phenoxy)-
Table 7. Synthesis of 1-alkoxycarbonyl-5-aroxytetrazoles
by reaction of 5-aroxytetrazoles with methyl and ethyl
chloroformates
1
tetrazoles. According to the H NMR and IR data,
in polar solvents the equilibrium is displaced toward
the more polar N1-isomer. In the solid phase N2-tetra-
zoles predominate. The isomerization rate increases
with rise in solvent polarity and increase in the elec-
tron-withdrawing power of the substituent in position
5 of the heteroring. A good correlation is observed
Comp.
no.
Yield, mp (decomposi-
X
R
between ln(kX/kH) and Hammett constants
(
=
%
tion point),
C
1.33, r = 0.965). The isomerization follows the inter-
molecular ion pair mechanism in polar solvents. In
less polar solvents, the intramolecular concerted
mechanism of type A is favored. In none of the
systems under study azide tautomer was detected. In
keeping with the calculated (AM1) total energues and
dipole moments, N1-tetrazoles are more stable and
more polar than their N2-isomers. The higher stability
of N1-tetrazoles (except for compound XIII) is
responsible for displacement of the equilibrium
toward the N1-isomer in polar solvents.
II
IV
VI
VIII
X
XII
XIV
XVI
p-CH3
H
H
p-Cl
p-Br
p-NHAc
p-NO2
2,6-(MeO)2
Me
Me
Et
Me
Me
Me
Me
Me
Me
Et
52
55
57
80
94
92
72
68
70
65
72 73 (100)
68 69 (97 98)
54 56 (98)
90 91 (96 97)
77 78 (106)
109 (110 111)
88 (91)
171 173 (125)
104 105 (114)
93 94 (94 95)
XVIII 2,4,6-Me3
XX 2,4,6-Et3
EXPERIMENTAL
Table 8. Spectral parameters of N-methoxycarbonyl-5-
(p-X-phenoxy)tetrazoles
The elemental analysis was determined at the
Tarbiat Modarres University, Iran. The melting points
were determined using a Gallenkamp apparatus and
are uncorrected. All starting compounds and solvents
were purified by standard procedures prior to use. The
1H NMR spectra were recorded in CDCl3 DMSO-d6
(75: 25, by weight). 2-Alkoxycarbonyl-5-(p-X-phen-
oxy)tetrazole, 80 mg, was dissolved in 0.84 g of the
mixed solvent. The solution was placed in an NMR
ampule, and the isomer ratio was measured at
specified time intervals (depending on the substituent
on C5) at room temperature. The AM1 calculations
were performed using HyperChem 5.02 software [27].
1
IR spectrum, , cm
1H NMR spectrum,a, b
, ppm
X
N2-isomerc N1-isomerb N1-isomer N2-isomer
CH3
H
1810 (II) 1750 (I)
3.75 (I)
4.20 (II)
d
1804 (IV)
3.80 (III) 4.25 (IV)
Cl
Br
1797 (VIII) 1750 (VII) 3.80 (VII) 4.25 (VIII)
1797 (X) 1750 (IX) 3.85 (IX) 4.30 (X)
NHAc 1690g, 1750 1690e, 1797 3.80 (XI) 4.30 (XII)
(XII)
(XI)
NO2
1797 (XIV) 1750 (XIII) 3.75 (XIII) 4.30 (XIV)
1H-Tetrazoles were synthesized by the procedures
reported in [16, 29]. The conditions for synthesis of
a
Chemical shifts of CO2CH3; in parentheses are given com-
pound numbers.
In CDCl3 DMSO-d6 (75: 25, w/w) at the equilibrium state.
In KBr.
Not detected.
Amide carbonyl frequency.
2-methoxycarbonyl-5-(p-X-phenoxy)tetrazoles
are
b
c
d
e
given for X = H, CH3, NO2, NHCOCH3, Cl, and Br.
All 1H-tetrazoles reacted with methyl or ethyl chloro-
formate in anhydrous THF in the presence of triethyl-
amine. The results are summarized in Table 7.
2-Alkoxycarbonyl-5-(p-X-phenoxy)tetrazoles
[X= H, CH3, Cl, Br, NHCOCH3, NO2, 2,6-(CH3O)2].
5-(p-X-Phenoxy)tetrazole, 5.91 mmol, and freshly
distilled alkyl chloroformate, 6.5 mmol, were dissolv-
ed in 30 ml of THF dried over metallic sodium. The
solution was cooled to 0 C, and a solution of 0.9 ml
(6.5 mmol) of triethylamine in 10 ml of anhydrous
THF was added dropwise. The mixture was
stirred for 2 h and filtered, and the precipitate was
washed with anhydrous THF (3 10 ml). The filtrate
was evaporated under reduced pressure at 30 C. Dry
diethyl ether was added to the viscous residue until
the solution became cloudy, and the latter was left
overnight in a refriferator. Crystals of 2-alkoxycar-
bonyl-5-(p-X-phenoxy)tetrazole were filtered off and
washed with 10 ml of cold diethyl ether. The 1H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1780
DABBAGH, MANSOORI
Table 9. Elemental analyses of 2-alkoxycarbonyl-5-(p-X-phenoxy)tetrazolesa
Found, %
Calculated, %
H
Compound no.
Formula
C
H
N
C
N
II
51.28
49.09
51.28
42.45
36.14
55.51
4.30
3.66
4.30
2.77
2.36
5.84
23.92
25.45
23.92
22.00
18.73
20.28
C10H10N4O3
C9H8N4O3
C10H10N4O3
C9H7ClN4O3
C9H7BrN4O3
C12H14N4O3
51.80
49.25
51.62
42.44
36.10
56.17
4.34
3.62
4.27
2.75
2.32
5.78
24.49
25.54
24.04
22.34
19.38
20.27
IV
VI
VIII
X
XX
a
Compounds I, III, V, VII, IX, and XI XIX were reported in [29].
Table 10. FT-IR and 1H NMR spectra of 2-alkoxycarbonyl-5-(p-X-phenoxy)tetrazoles
Compd.
1
FT-IR spectrum (KBr), , cm
1H NMR spectrum, , ppm (J, Hz)
no.
II
3046 m, 2966 m, 2950 m, 1810 s, 1549 s, 1360 s, 1193 s, (DMSO, CDCl3): 2.40 s (3H), 4.25 s (3H), 7.20
1078 m, 978 m, 830 s, 749 s 7.50 m (4H)
IV
VI
3181 m, 2910 m, 2890 w, 1804 s, 1549 s, 1193 s, 682 m (DMSO, CDCl3): 4.25 s (3H), 7.20 7.70 m (5H)
3095 w, 2993 m, 2955 w, 1797 s, 1543 s, 1382 s, 1173 s, (DMSO, CDCl3): 1.50 t (3H, 8), 4.70 q (2H, 8),
965 s
7.20 7.70 m (5H)
VIII
X
3113 m, 3100 w, 2959 w, 2955 w, 1797 s, 1549 s, 1488 m, (DMSO, CDCl3): 4.25 s (3H), 7.30 7.70 m (4H)
1367 s, 1233 s, 1078 s, 978 s, 837 m, 750 m
3107 m, 2966 m, 1797 s, 1549 s, 1481 m, 1367 m, 1193 s, (DMSO, CDCl3): 4.30 s (3H), 7.25 7.90 m (4H)
1072 s, 830 s, 749 s
XII
XIV
XVI
3369 m, 3200 w, 3170 w, 3073 w, 1797 s, 1690 s, 1616 m, (DMSO, CDCl3): 2.10 s (3H), 4.20 s (3H), 7.20
1549 s, 1508 s, 1441 s, 1193 s, 978 m, 837 s
3120 m, 1087 m, 1797 s, 1535 s, 1448 s, 1360 s, 1226 s, (DMSO, CDCl3): 4.30 s (3H), 8.50 d (2H, 9),
870 s, 749 s 7.80 d,(2H, 9)
7.50 m (2H), 10.05 s (1H)
3100 w, 3000 m, 2920 m, 2830 m, 1805 s, 1610 s, 1535 s, (DMSO, CDCl3): 2.15 s (6H), 4.30 s (3H), 7.30 d
1480 s, 1440 s, 1365 s, 1310 s, 1230 s, 1110 s, 975 s, 820 s, (2H, 9), 7.70 d (2H, 9)
760 s
XVIII 3045 w, 2995 w, 2919 w, 1797 s, 1549 s, 1367 m, 1193 m, (DMSO, CDCl3): 2.15 s (6H), 2.30 s (3H), 4.25 s
984 m, 749 m (3H), 7.10 s (2H)
3005 m, 2925 m, 1797 s, 1549 s, 1481 m, 1193 s, 857 m, (CDCl3): 1.50 t (3H, 8), 2.15 s (6H), 2.30 s (3H),
XX
756 m
4.70 q (2H, 8), 7.05 s (2H)
1
and FT-IR spectra of the products are given in
Tables 8 and 10, and their elemental analyses are col-
lected in Table 9. The structure of the tetrazoles listed
in Table 7 was established by converting them into
the corresponding N-methyltetrazoles [27].
tion was monitored by measuring H NMR spectra at
room temperature (Fig. 1). The chemical shifts of the
CH3OCO protons of each isomer were preliminarily
found from the H NMR spectra of pure 1- and 2-sub-
1
stituted tetrazoles [16, 27]. The relative concentra-
tions of the reactants and the products were calculated
from the corresponding signal intensities (Figs. 2, 3).
The intensities of the CH3OCO signal of the reagent
and of the CH3OCO or CH3N signal of the products
were normalized with respect to the aromatic proton
signal whose intensity remained unchanged during
the process. The rate constants were calculated by
Typical procedure for measurement of the rate
of disappearance of 2-alkoxycarbonyl-5-aroxytetra-
1
zoles. A high-precision H NMR ampule was charged
with 80 mmol of 2-methoxycarbonyl-5-aroxytetrazole,
0.84 g of CDCl3 DMSO-d6 (75: 25), and tetramethyl-
silane as internal reference. The progress of the reac-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

KINETICS AND MECHANISM OF IZOMERIZATION OF N-ALKOXYCARBONYL-.. .
1781
Eq. (1), and the molal concentration [X], Mn, by
Eq. (2):
poulou, K., Palenik, G.S., and Zhang, Z.Y., Tetra-
hedron, 1990, vol. 46, p. 633.
11. Gall, J.H. and Purcell, W.L., Inorg. Chem., 1990,
vol. 29, p. 3806.
12. Isaacs, N.S., Physical Organic Chemistry, Harlow,
Essex, Enfland: Longman Scientific & Technical,
1987, p. 129.
mT
[X] = 4/3(SMe/Sarom
)
,
(2)
m
solv MT
where mT, msolv, and MT are, respectively, the weight
of tetrazole (80 mmol), solvent (0.84 g), and mole-
cular weight of tetrazole; SMe and Sarom are the areas
under the signals from methyl and aromatic protons;
the coefficient 3/4 should be replaced by 5/3 in the
case of 5-phenoxytetrazole and by 2/3 in the case of
5-mesityloxytetrazole.
13. Hansch, C. and Leo, A.J., Substituents Constants for
Correlation Analysis in Chemistry and Biology,
New York: Wiley, 1979, p. 3.
14. Dabbagh, H.A. and Lwowski, W., J. Org. Chem.,
1989, vol. 54, p. 3952.
15. Dabbagh, H.A. and Ghaelee, S., J. Org. Chem.,
1996, vol. 61, p. 3439.
16. Dabbagh, H.A. and Lwowski, W., J. Org. Chem.,
2000, vol. 65, p. 7284.
17. Faure, R., Vincent, E.J., and Elguero, J., Hetero-
cycles, 1983, vol. 20, p. 713.
This study was supported by the Graduate Council
of the Isfahan University of Technology.
REFERENCES
18. Gassend, R., Maire, J.C., and Pommier, J.C.,
J. Organomet. Chem., 1977, vol. 132, p. 69.
19. Stone, W.E., Pharmacology, 1970, vol. 3, p. 367.
20. Butller, R.N., Adv. Heterocycl. Chem., 1977, vol. 21,
p. 323.
21. Katritzky, A.R., Rachwal, S., and Rachwal, B.,
J. Chem. Soc., Perkin Trans. 1, 1987, p. 805.
22. Katritzky, A.R., Yannakopoulou, K., Lue, P.,
Rasala, D., and Urogdi, L., J. Chem. Soc., Perkin
Trans. 1, 1989, p. 225.
23. Katritzky, A.R. and Drewniak, M., Tetrahedron
Lett., 1988, vol. 29, p. 1755.
24. Katritzky, A.R., Gallos, J.K., and Yannakopou-
lou, K., Synthesis, 1989, p. 31.
25. Katritzky, A.R., Drewniak, M., and Lue, P., J. Org.
Chem., 1988, vol. 53, p. 5854.
26. Katritzky, A.R., Urogdi, L., and Mayence, A.,
Synthesis, 1989, p. 323.
1. Wehman, T.C. and Popov, I.A., J. Phys. Chem.,
1966, vol. 70, p. 3688.
2. Duncia, J.V., Pierce, M.E., and Santella, J.B., J. Org.
Chem., 1991, vol. 56, p. 2395.
3. El-Ahl, A.-A.S., Elmorsy, S.S., Elbeheery, A.H.,
and Amer, F.A., Tetrahedron Lett., 1997, vol. 38,
p. 1257.
4. Zucchi, F., Trabanelli, G., and Fonsati, M., Corros.
Sci., 1996, vol. 38, p. 2019.
5. Cubreo, E., Orozco, M., and Luque, F.J., J. Am.
Chem. Soc., 1998, vol. 120, p. 4723.
6. Elguero, J., Marzin, C., and Roberts, J.D., J. Org.
Chem., 1974, vol. 39, p. 357.
7. Wofford, D.S., Forkey, D.M., and Russell, J.G.,
J. Org. Chem., 1982, vol. 47, p. 5132.
8. Razynska, A., Tempczyk, A., Malinski, E., Szafra-
nek, J., and Grzonka, Z., J. Chem. Soc., Perkin
Trans. 2, 1983, p. 379.
27. Dabbagh, H.A., Mansoori, Y., Jafari, M., and
Rostami, M., J. Chem. Res., 2000, p. 442 445.
28. Dabbagh, H.A. and Davis, B.H., J. Org. Chem.,
1990, vol. 55, p. 2011.
29. Dabbagh, H.A. and Mohammad Salehi, J., J. Org.
Chem., 1998, vol. 63, p. 7619.
9. Bauer, M., Harris, R.K., Rao, R.C., Apperley, D.C.,
and Rodger, C.A., J. Chem. Soc., Perkin Trans. 2,
1998, p. 475.
10. Katritzky, A.R., Jozwiak, A., Lue, P., Yannako-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001