Kinetics and mechanism of cyclization of substituted 2-(benzoylamino)alkanamides in strongly basic medium

Article abstract of DOI:10.1135/cccc19980394

The cyclization reaction of substituted 2-(benzoylamino)alkanamides 1a-1i giving the corresponding substituted 2-phenylimidazol-4(5H)-ones 2a-2i has been studied. The equilibrium constants of reactions of compounds 1d-1f and 2-[(4-nitrobenzoyl)amino]-2,3-dimethylbutanenitrile (3) with methoxide have been determined in methanol-dimethyl sulfoxide media. For compound 1d and N-methyl derivatives 1a-1c, the cyclization rate constants have been measured in dependence on methoxide concentration in media of varying contents of dimethyl sulfoxide. The cyclization reaction mechanism involves formation of anion in a rapid pre-equilibrium and subsequent rate-limiting step: either formation of a cyclic intermediate or splitting off of OH^- ion from this intermediate. The product formed in the given medium is immediately transformed into its conjugate base. A change in reaction medium affects the reactions of all the compounds in the same way. The ratio of concentration of substrate to that of its anion at low methoxide concentrations is affected by the solvent composition (MeOH-DMSO). At higher methoxide and DMSO concentrations the reaction rate distinctly decreases, which can be interpreted by the transformation of reactive anion into non-reactive dianion. The corresponding N-methylbenzoylamino compounds are cyclized faster by a factor of 400 as compared with compounds having no methyl group at the benzamide group.

Full text of DOI:10.1135/cccc19980394

3
94
Sedlak, Kavalek, Mitas, Machacek:
KINETICS AND MECHANISM OF CYCLIZATION OF SUBSTITUTED
-(BENZOYLAMINO)ALKANAMIDES IN STRONGLY BASIC MEDIUM
2
1
2
3
Milos SEDLAK , Jaromir KAVALEK , Petr MITAS and Vladimir MACHACEK
Department of Organic Chemistry, University of Pardubice, 532 10 Pardubice, Czech Republic;
e-mail: milos.sedlak@upce.cz, 2 jaromir.kavalek@upce.cz, vladimir.machacek@upce.cz
1
3
Received September 25, 1997
Accepted December 11, 1997
The cyclization reaction of substituted 2-(benzoylamino)alkanamides 1a–1i giving the corresponding
substituted 2-phenylimidazol-4(5H)-ones 2a–2i has been studied. The equilibrium constants of reac-
tions of compounds 1d–1f and 2-[(4-nitrobenzoyl)amino]-2,3-dimethylbutanenitrile (3) with methox-
ide have been determined in methanol–dimethyl sulfoxide media. For compound 1d and N-methyl
derivatives 1a–1c, the cyclization rate constants have been measured in dependence on methoxide
concentration in media of varying contents of dimethyl sulfoxide. The cyclization reaction mechan-
ism involves formation of anion in a rapid pre-equilibrium and subsequent rate-limiting step: either
–
formation of a cyclic intermediate or splitting off of OH ion from this intermediate. The product
formed in the given medium is immediately transformed into its conjugate base. A change in reaction
medium affects the reactions of all the compounds in the same way. The ratio of concentration of
substrate to that of its anion at low methoxide concentrations is affected by the solvent composition
(
MeOH–DMSO). At higher methoxide and DMSO concentrations the reaction rate distinctly de-
creases, which can be interpreted by the transformation of reactive anion into non-reactive dianion.
The corresponding N-methylbenzoylamino compounds are cyclized faster by a factor of 400 as com-
pared with compounds having no methyl group at the benzamide group.
Key words: Reaction kinetics; Mechanism of cyclization; 2-Phenylimidazol-4(5H)-ones; Dissociation
constants; Solvent effect.
1
13
In previous papers we discussed the synthesis as well as H and C NMR spectra of
1
2,3
substituted 2-(benzoylamino)alkanamides and 2-phenylimidazolinones .
The aim of the present work was to study the kinetics and mechanism of cyclization
of substituted 2-(benzoylamino)alkanamides to the corresponding 2-phenylimidazol-
4
(5H)-ones (Scheme 1).
EXPERIMENTAL
Synthesis
1
2
3
The preparation of compounds 1a–1i (ref. ) and 2a, 2b, 2d–2g (ref. ), 2c, 2h and 2i (ref. ) and 3
(
4
ref. ) was described in previous communications.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
Measurement of Dissociation Constants
395
The spectra were measured with a Hewlett–Packard 8453 Diode Array apparatus in a 1 cm cell
placed in thermostatted cell compartment of the apparatus. A saturated methanolic solution of sub-
strate (50 µl) was injected into the respective solution of sodium methoxide (2 ml), and the spectrum
was measured 5 s after mixing. The dissociation constants were measured in solutions of sodium
methoxide in MeOH–DMSO mixtures at 25 °C. After inspecting the spectra of the acid form,
anion, and their mixture, a suitable wavelength was chosen at which the absorbance values were
read. The I values were calculated from the measured absorbances using the relationship I = (A –
ANH)/(A – A), where A AN, and A are the absorbances of the substrate, its conjugate base, and the
N
NH,
solution measured, respectively.
Kinetic Measurements
The measurements were carried out spectrophotometrically using the above-mentioned Hewlett–Packard
8
453 Diode Array apparatus and 1 cm closeable quartz cells kept at 25 °C in the cell compartment
of the apparatus. Before the measurement itself, we measured the electron spectra of the substances
investigated in the given medium in the wavelength range of 200–400 nm. These experiments veri-
fied the presence of isosbestic points and made it possible to select suitable wavelengths for the
kinetic measurements.
The cell was charged with 2 ml of sodium methoxide solution in suitable MeOH–DMSO mixture.
After reaching the said temperature, 20 to 50 µl of methanolic solution of substrate was injected into
–
4
–1
the cell in such a way that the resulting substrate concentration was about 1.5 . 10 mol l . From the
measured time change of absorbance (at 280–300 nm depending on the medium), we calculated the
5
pseudo-first-order rate constants (kobs) using the OPKIN program . The solutions were prepared from
analytical grade methanol (Lachema) and dimethyl sulfoxide (Fluka) dried over molecular sieve Calsit 5
type 5A.
For compounds 1 and 2:
2
3
O
C
R
N
R
C
O
C
1
2
3
1
R
R
R
R
NH2
CH3
a
b
c
d
e
f
H
CH3
CH3
H
CH3
1a-1i
NO2
H
CH3
-
H2O
i-C3H7
i-C3H7
NO2
H
2
3
NO
NO
H
C H
R
2
2
6
5
R
N
H
4-NO -C H
2
6
4
1
CH3
R
g
h
i
NO2
CH3
CH3
H
i-C3H7
N
O
CH3O
CH3O
i-C3H7
i-C3H7
2a-2i
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

3
96
Sedlak, Kavalek, Mitas, Machacek:
RESULTS AND DISCUSSION
Mechanism and Kinetics of Cyclization
The course of cyclization for compounds 1d–1f can be expressed by the following
mechanism (Scheme 2). The formation of anion from substrate (HNH) is a fast pre-
equilibrium. The subsequent rate-limiting step can consists in the formation of cyclic
–
intermediate (In ) or splitting of OH ion from the intermediate (In ) formed to give the
1
2
product which is transformed practically completely into its conjugate base in the given
medium.
3
O
C
R
C
O
C
O2N
NH
NH2
+
CH3O
CH3
HNH
K
3
3
O
C
R
C
O
C
O
O
C
_
N
_
R
C
_
NH
_
O2N
NH2
O2N
C
NH
+
3
CH OH
CH3
CH3
N
NH
_
3
O
C
R
O
CH
3
_
N_ H
k1
k
O NH
KT
HO NH CH3
3
3
O2N
NH
C
C
O2N
2
O N
_
R
O
R
O
-
1
HN
CH3
N_
NH
In1
In2
CH3
N
_
N_
CH3
N
k2
3
O2N
3
R
+
H2O
O2N
R
+
HO
O
HN
O
SCHEME 2
The basicity of the medium at a given methoxide concentration increases with the
DMSO content in the mixture whereby the equilibrium is shifted in favour of the anions
of the starting amide. The ratio of “reactive”, cyclizable anion (NH) to that of the other
anion (N) cannot be determined from spectral or kinetic measurements. In a previous
4
communication , we compared a series of pK values of structurally similar 2-(benzoyl-
a
3
amino)alkanamides and found that a combination of sufficiently bulky substituents R
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
397
(
isopropyl, phenyl) with methyl group has a significant steric effect on the values of
dissociation constants and, hence, on the cyclization rate. A very low concentration of
N-anion derived from acetamide moiety (NH) is sufficient for the cyclization to pro-
ceed in sodium methoxide solutions at room temperature.
3
In the case of derivatives with R = H, this steric effect is small and the dissociation
only takes place in the benzamide moiety, and the cyclization does not proceed at all.
The effect of medium on the cyclization (both on the formation of intermediate and
on its decomposition into the starting compound or product) is substantially smaller
than that on the pre-equilibrium because both the anion (NH) and the two transition
states are of considerably similar structures, and it cannot at all be a priori estimated if
the cyclization rate will be lowered or increased by addition of DMSO.
In the case of the cyclization followed as a pseudo-first-order reaction, it is possible
to express the overall rate equation by Eq. (1) on the basis of Scheme 2,
v = kobs c = k [NH] = k ′([N] + [NH]) ,
(1)
s
c
c
where c is total concentration of substrate, [NH] is concentration of reactive anion, and
s
kc is overall rate constant of cyclization of the reactive anion (2).
k = k K k /k
–1
(2)
c
1
T
2
In the methoxide concentration range in the given medium where the ratio I (Eq. (3)) is
about 0.1 to 10, it is possible to express the concentration of both anions by Eq. (4), so
that the observed rate constant can be described by the relationship (5).
I = ([N] + [NH])/[HNH]
(3)
(4)
(5)
cs = [HNH] + [N] + [NH] = [HNH](I/(I + 1))
−1

1

kobs = k ′(I/(I + 1)) = k ′
+ 1

c
c 
−
K[CH O ]
3


K is the equilibrium constant of the acid-base reaction (Scheme 2) valid for the given
medium (methanol, MeOH–DMSO).
At low methoxide concentrations, relation (5) is simplified to Eq. (6).
–
kobs = k ′I = k ′K[CH O ]
(6)
c
c
3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

3
98
Sedlak, Kavalek, Mitas, Machacek:
In the region of high methoxide concentrations, k ′ need not have a constant value and
c
can change with the change of medium. In order to be able to determine k ′ at such
c
DMSO concentrations when I < 0.1 (where I cannot be determined spectrophotometri-
cally), it was necessary to construct an acidity function for amides in the range from 0
to 85% (v/v) DMSO and, on the basis of the acidity function, to determine the I ratio at
4
low DMSO concentrations or even in methanol alone .
Effect of DMSO and Methoxide Concentrations on Basicity of Medium
and Equilibrium Constants
For compounds 1d–1f, we measured the equilibrium and rate constants of cyclization at
various DMSO concentrations in methanol. Because of the low acidity, it was im-
possible to determine their equilibrium constants in pure methanol, and thus we pre-
pared 2-[(4-nitrobenzoyl)amino]-2,3-dimethylbutanenitrile (3). This nitrile has a
structure similar to compounds 1, in spite of the terminal amide group being replaced
by a nitrile group. This substitution increases the acidity of the NH group, which made
it possible to measure the acidity of compound 3 in neat methanol and at low DMSO
O
C
CH3
O2N
NH
C
CN
CH
H3C
CH3
3
concentrations. The dependences of log I on logarithm of methoxide concentration at
DMSO concentrations of 75 and 50% are given in Figs 1 and 2 for compounds 1d and
1
e, respectively. The dependence of log I on logarithm of methoxide concentration for
–
1
6
methoxide concentrations below 0.1 mol l should be linear with a slope of unity.
1
.0
.5
log I
0
0.0
–0.5
FIG. 1
–
Dependence of log I vs –log [CH O ] in 75% (v/v)
3
0.0
0.5
1.0
1.5
DMSO at 25 °C for compound 1d
–
–
log [CH O ]
3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
399
From Figs 1 through 5, it follows that:
–1
1
. Deviations from the slope of unity appear at methoxide concentrations above 0.2 mol l
–
1
(
Fig. 1) and above 0.6 mol l (Fig. 2).
. The difference between the log I values (∆ log I) for any pair of compounds is
constant (within experimental error) in a given medium, even at methoxide concentra-
2
–
1
tions above 0.1 mol l , i.e., the change in methoxide concentration has a similar effect
on I for all the compounds investigated (∆ log I is constant for a given pair of com-
pounds in solutions of the same DMSO concentration).
3
. The difference in log I at the same methoxide concentration but different DMSO
concentrations is the same in the given media for all the compounds studied, i.e., the
change in DMSO concentration has the same effect on log I for all the compounds, and
∆
log I is the same at the same change in DMSO concentration for all the compounds.
Figure 3 presents the dependence of log K on the molar fraction of DMSO in MeOH
(
xDMSO) for the individual substances. In the cases of 50% dissociation of the substrate
–
1
at a methoxide concentration below 0.1 mol l , the K values were calculated directly
1
from Eq. (7).
–
log I = log K + log [CH O ]
(7)
1
3
In the cases of 50% dissociation of the substrate at methoxide concentrations above 0.1
–
1
–
mol l (the slope of dependence of log I upon –log [CH O ] gradually increasing), we
3
made use of the fact that ∆ log I for any pair of compounds is constant even at higher
0.5
–
0.5
log I
log K
0.0
–1.0
–
–
1.5
2.0
–
0.5
1.0
–
0.0
0.5
1.0
0.2
0.4
0.6
–
x
DMSO
–log [CH O ]
3
FIG. 2
FIG. 3
–
Dependence of log I vs –log [CH O ] in 50% (v/v)
DMSO at 25 °C for compound 1e
Dependence of log K on molar fraction of DMSO
(xDMSO) at 25 °C for compounds 3 (❍), 1f (●),
3
1
e (∆), and 1d (▲)
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

4
00
Sedlak, Kavalek, Mitas, Machacek:
methoxide concentrations. Therefore, it was possible to calculate the equilibrium con-
stant from Eq. (8).
log K = log K – ∆ log I ,
(8)
R
where K is the equilibrium constant of the “reference substance” measured at methoxide
R
–
1
concentrations below 0.1 mol l . The equilibrium constant of compound 3 measured in
methanol was taken as the basis, and from the found equilibrium constants of the sub-
stances at various DMSO concentrations we calculated the equilibrium constants of
these substances in methanol using Eq. (9).
0
log K = log K + Σ ∆ log I
(9)
i
i
0
The quantity K means the equilibrium constant of the i-th compound in methanol, and
i
Σ ∆ log I is the sum of averaged values of ∆ log I (at the same methoxide concentra-
tion) between the individual DMSO concentrations for the compounds measured in
these solutions. In an analogous way, we also calculated the K values in such DMSO
i
concentration regions where it was impossible to determine them experimentally. The
values of ∆ log I are a quantitative measure of the increase in basicity with increasing
DMSO concentration (referenced to compounds of similar structural type, which were
measured, i.e. amides). The log K values are presented in Table I and the dependence
i
–
of log I upon –log [CH O ] is depicted in Fig. 4. The log I values needed for determi-
3
–
1
nation of cyclization rate constants at methoxide concentrations below 0.1 mol l were
calculated from Eq. (7).
The equilibrium constant in the individual solutions can be defined by Eq. (10).
0.5
log I
0.0
–0.5
FIG. 4
–
Dependence of log I vs –log [CH O ] in 60%
3
(
1
v/v) DMSO at 25 °C for compounds 1d (❍) and
e (●)
0.0
0.5
1.0
1.5
–
–
log [CH O ]
3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
401
γNH
I
K =
(10)
i
−
[
CH O ] γ
γ
−
3
HNH CH O
3
–
1
At methoxide concentrations below 0.1 mol l , the activity coefficient of methoxide
ion is practically equal to unity (Eq. (3)). At higher methoxide concentrations, it is
7
necessary to adopt the extended Debye–Hückel equation in the form (11).
TABLE I
Equilibrium constants log K of compounds 3 and 1d–1f (and their standard deviations s) in methanolic
solutions of DMSO
log K (s)
%
(v/v)DMSO
(
xDMSO)
3
1d
–
1e
–
1f
–
0
–0.55
(0.01)
–0.70
(0.05)
–0.96
(0.01)
–1.15
(0.03)
–1.50
(0.05)
–1.85
(0.02)
–2.30
(0.02)
–
(
0)
1
(
0
–
–
–
0.06)
0
2
–
–
–
(
(
(
(
(
(
(
(
(
(
0.125)
3
0
–
–
–0.66
(0.03)
–1.00
(0.04)
–1.35
(0.02)
–1.92
(0.04)
–
0.197)
4
0
–
–
0.276)
5
0
–
–0.36
(0.04)
–0.82
(0.04)
–1.00
(0.02)
–1.30
(0.04)
–1.65
(0.03)
–
0.364)
6
0
–0.17
(0.02)
–0.40
(0.05)
–
0.462)
6
5
0.515)
7
0
–
–
–
–
–
–
–
–
0.572)
7
5
–0.75
(0.05)
–1.00
(0.04)
–1.40
(0.04)
0.632)
8
0
0.695)
8
5
–
0.764)
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

4
02
Sedlak, Kavalek, Mitas, Machacek:
γNH



1
1



−
log
= A √ m
−
+ b[CH O ]
(11)
3
γHNH
γ
−
1 + aNH √ m 1 + a
√ m
CH O
CH O
3
3
The ratio of activity coefficients at concentrations lower than 0.1 mol l–1 is equal to
unity (hence the value of the expression in brackets is practically zero). This means that
at higher concentrations of methoxide anion, log I is expressed by Eq. (12).
–
–
log I = log K + log [CH O ] + b[CH O ]
(12)
i
3
3
–
The dependence of difference Y = log I – log [CH O ] on the methoxide concentration
3
in 60% DMSO is given in Fig. 5 for compounds 1d and 1e.
Kinetics of Cyclization of Compounds 1d–1f
The cyclization kinetics of compound 1d was measured in solutions of sodium methoxide
alone and in solutions of DMSO (20, 40, 50, 60, and 75% (v/v) DMSO) in the sodium
–
1
methoxide concentration range from 0.1 to 1.6 mol l . The dependence of k on
obs
–
[
CH O ] in the individual mixtures is presented in Figs 6 and 7.
3
In the solutions in neat methanol and at low concentrations of DMSO, the slope of
–
dependence kobs vs [CH O ] increases with increasing methoxide concentration at first
3
(
the concentration of anion is much lower than that of the neutral form of substrate).
2
0
.4
.1
3
Y
k
.10
obs
0
1
–0.2
0
.0
0.5
1.0
–
0.0
FIG. 6
0.5
–
1.0
[
CH O ]
[CH O ]
3
3
FIG. 5
–
–1
Dependence of Y = log I – log [CH O ] vs
CH O ], mol l , in 60% (v/v) DMSO at 25 °C
Dependence of observed rate constant (k , s )
obs
3
–
–1
–
–1
[
vs [CH O ], mol l , measured for compound
3
3
for compounds 1e (❍) and 1d (●)
1d in methanol (❍), 20% (v/v) DMSO (●),
4
0% (v/v) DMSO (∆), and 60% (v/v) DMSO
(
▲) at 25 °C
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
403
The reaction rate is defined by the relationship (13).
v = kobs c = k ′ Ic
s
(13)
s
c
The increase in the observed rate constant with increasing methoxide concentration is
similar to the increase in I with methoxide concentration.
Besides the effect on I, an effect of methoxide concentration upon the rate constant
kc′ can also be seen. Therefore, the dependence of I on methoxide concentration was
plotted for compound 3 (which does not cyclize) in neat methanol (Table I). The I
values thus obtained were then plotted against kobs in the same medium for compound
1
d. The dependence is linear within the limits of experimental error and is presented in
Fig. 8; obviously the k ′ constant changes but slightly in the given range.
c
At higher concentrations of DMSO and methoxide, where I ranges from about 0.1 to
1
0.0, we used Eq. (5). In this case it was found for compound 1d that at values I > 10,
the constant decreases more and more rapidly. This decrease is in accordance with that
in the observed rate constant (Fig. 7). From the dependences given it is obvious that at
various DMSO concentrations the decrease in the observed rate constant occurs at various
–
1
–1
methoxide concentrations (from 1.3 mol l in 50% DMSO down to 0.4 mol l in 75%
DMSO).
3
2
4
k
.10
obs
3
k
. 10
obs
2
1
1
0.0
0.5
1.0
1
2
3
–
[
CH O ]
3
I
FIG. 7
FIG. 8
–
1
–1
Dependence of observed rate constant (k , s )
Dependence of observed rate constant (kobs, s )
measured for compound 1d in methanol vs
I ratio determined in methanol (in dependence on
obs
–
–1
vs [CH O ], mol l , measured for compound
3
1
(
d in 50% (v/v) DMSO (❍), 65% (v/v) DMSO
●), and 75% (v/v) DMSO (∆) at 25 °C
–
–1
[CH O ], mol l ) for compound 3 at 25 °C
3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

4
04
Sedlak, Kavalek, Mitas, Machacek:
This behaviour is entirely different from what has been found from the dependence
of logarithm of ratio of activity coefficients upon methoxide concentration (Fig. 5, Eq. (10)).
This dependence was linear in the whole range studied although the structure of anion
of compound 1d differs very much from that of solvated methoxide anion, the former
being considerably similar to the structure of negatively charged activated complex.
Therefrom it follows that the considerable and rapidly developing decrease in the re-
gion of predominant occurrence of the starting substance in anionic form has another
reason (Fig. 7). When measuring the equilibrium constants in media with DMSO con-
centrations above 50%, we observed formation of another isosbestic point (the second
degree of dissociation). The second equilibrium constant (dissociation of the acetamide
moiety), however, could not be determined experimentally. The drop in the reaction
rate can be interpreted by the formation of an unreactive dianion.
We also studied the cyclization kinetics of compounds 1e and 1f, where the steric
effect should be comparable with that of isopropyl group; hence the difference in the polar
effects of the phenyl and 4-nitrophenyl groups should be sensible. This is most distinct
in the difference of log K values (Table I) for compounds 1d and 1e (∆ log I = 0.65)
and for compounds 1d and 1f (∆ log K = 1.85). Both substituents also influence the
acidity of benzamide group, which was manifested when the kobs values were deter-
mined at the same DMSO concentrations and low concentrations of methoxide anion.
The kobs values were practically the same with all the substances in a given medium.
On the other hand, a large difference was observed in the maximum rates reached. The
maximum cyclization rates of compounds 1e and 1f were lower by the factors of 7 and 15,
respectively, than that of compound 1d. This is probably due to the fact that the forma-
tion of dianion starts to be more significant with compounds 1f and 1e then with 1d.
In the case of compound 1e, the observed rate constant measured in the whole range
of methoxide concentrations in 50% DMSO (Fig. 9) was recalculated on the basis of
Eq. (5) to give the k ′ constant. As it follows from Table II, the k ′ value is practically
c
c
constant up to I = 8, showing a linear decrease for I values higher than 10.
Kinetics of Cyclization of N-Methylamides 1a–1c
Another part of our work dealt with investigation of cyclization kinetics of N-methyl-
amides 1a–1c. These substrates can undergo dissociation in the acetamide group only,
which means that the cyclization rate constant found should not decrease with increas-
ing basicity of medium. A comparison of rate constants of cyclization of two com-
pounds differing only in the presence of methyl group or hydrogen on the benzamide
nitrogen atom made it possible to determine the effect of the methyl group on the
cyclization rate. The cyclization rate constant of 2,3-dimethyl-2-[N-methyl-N-(4-nitroben-
zoyl)amino]butanamide (1g) was immeasurably high, even at low methoxide concentra-
tions. Therefore, several other derivatives were prepared in which the nitro group was
replaced by hydrogen (compound 1c) or the isopropyl group by methyl group (com-
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Kinetics and Mechanism of Cyclization Reaction
405
pound 1b). At methoxide and DMSO concentrations allowing spectral determination of
the ratio of anion to starting substance, the cyclization rate of all those compounds was
high but still measurable. Therefore, we tried to determine the equilibrium constant of
the starting substrate from the kinetic dependence of the observed rate constant on
methoxide concentration.
However, when following the cyclization kinetics of compounds 1a, 1b, and 1g in
–
1
5
0% DMSO at methoxide concentrations above 1 mol l , we found that the rates of
formation and decomposition of the intermediate were comparable, so that kinetically
the reaction proceeded as a consecutive reaction with two relaxation times τ and τ ,
1
2
which were functions of all the rate constants (k , k , k ); hence no conclusions could
1
–1
2
be made from these experiments. In order to obtain information about the influence of
N-methyl group on the cyclization rate, we measured the cyclization rates of methoxy
derivatives 1h and 1i (differing in methyl group in benzamide moiety) in 50% DMSO
–
1
at the methoxide concentration of 1.5 mol l . For compounds 1h and 1i, we found the
TABLE II
–
–1
–1
Dependence of I values for compound 3 on methoxide concentration [CH O ], mol l , and k ′, s ,
3
c
for compound 1e
–
kc′ . 104
–
kc′ . 104
[
CH O ]
I
[CH O ]
I
3
3
0
0
0
0
0
.05
.2
0.09
0.4
5.1
7.2
5.5
5.6
5.6
0.6
0.7
0.8
0.9
1.1
2.8
6.4
7.58
9.33
5.5
.3
0.78
1.25
1.95
5.16
4.5
.4
20.4
39.8
.5
3.88
4
4
k
.10
obs
3
2
1
FIG. 9
–
1
Dependence of observed rate constant (k , s ) vs
obs
–
–1
[
CH O ], mol l , measured for compound 1e in
3
0.0
0.5
1.0
1.5
–
5
0% (v/v) DMSO at 25 °C
[CH O ]
3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

4
06
Sedlak, Kavalek, Mitas, Machacek:
rate constant values kobs = 2.7 . 10–1 and 6.8 . 10–4 s–1, respectively. From the ratio of
the cyclization rate constants of compounds 1h and 1i, we deduced that the introduction
of methyl group instead of hydrogen resulted in the cyclization rate increase by a factor
of 400.
The authors are indebted to Prof. V. Sterba for valuable discussions. This work and the previous work
(
Collect. Czech. Chem. Commun. 1998, 63, 85) were financially supported by the Grant Agency of the
Czech Republic, grant No. 203/97/0545.
REFERENCES
1
. Sedlak M., Halama A., Kavalek J., Machacek V., Sterba V.: Collect. Czech. Chem. Commun.
995, 60, 150.
1
2. Sedlak M., Halama A., Kavalek J., Machacek V., Mitas P., Sterba V.: Collect. Czech. Chem.
Commun. 1996, 61, 910.
3
4
5
6
. Sedlak M., Halama A., Mitas P., Kavalek J., Machacek V.: J. Heterocycl. Chem. 1997, 34, 1227.
. Mitas P., Kavalek J.: Unpublished results.
. Pytela O., Vecera M., Vetesnik P.: Chem. Listy 1979, 73, 754.
. Rochester C. H. in: Acidity Functions; A Series of Monographs Organic Chemistry (A. T.
Blomquist, Ed.), Vol. 17, p. 258. Academic Press, London 1970.
. Sterba V., Panchartek J.: Kinetic Methods in Studies of Reactions of Organic Compounds. SNTL,
Praha 1985.
7
Collect. Czech. Chem. Commun. (Vol. 63) (1998)