Mechanisms of 5′-O-benzoyl-2,3′-anhydrothymidine reactions with nucleophiles: IV. Kinetics and thermodynamics of azidation with dimethylammonium azide in DMF-1,4-dioxane

Article abstract of DOI:10.1023/A:1019627509596

The reaction of 5′-O-benzoyl-2,3′-anhydrothymidine with dimethylammonium azide in the system DMF-1,4-dioxane in the temperature range from 80 to 100°C follows the overall second-order kinetics and first-order kinetics with respect to each reactant. The activation parameters in the systems containing 30, 40, and 50 vol % of dioxane are, respectively: ΔH₂₉₈^≠ 99, 85, and 79 kJ/mol; ΔS ₂₉₈^≠ -46, -83, and -101 J mol^-1 K ^-1. A refined model of the transition state for the rate-determining stage was proposed, which takes into account specific interaction with 1,4-dioxane.

Full text of DOI:10.1023/A:1019627509596

Russian Journal of Organic Chemistry, Vol. 38, No. 5, 2002, pp. 735 737. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 5, 2002,
pp. 772 774.
Original Russian Text Copyright
2002 by Korchevskaya, Ostrovskii, Malin, Trukhanovich, Shcherbinin, Ostrovskii.
Mechanisms of 5 -O-Benzoyl-2,3 -anhydrothymidine
Reactions with Nucleophiles:
IV.* Kinetics and Thermodynamics of Azidation
with Dimethylammonium Azide in DMF 1,4-Dioxane**
E. V. Korchevskaya, Yu. V. Ostrovskii, A. A. Malin, M. Z. Trukhanovich,
M. B. Shcherbinin, and V. A. Ostrovskii
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 198013 Russia
e-mail: ostrovskii@mail.convey.ru
Received September 20, 2001
Abstract The reaction of 5 -O-benzoyl-2,3 -anhydrothymidine with dimethylammonium azide in the system
DMF 1,4-dioxane in the temperature range from 80 to 100 C follows the overall second-order kinetics
and first-order kinetics with respect to each reactant. The activation parameters in the systems containing
30, 40, and 50 vol % of dioxane are, respectively: H298 99, 85, and 79 kJ/mol; S298 46, 83, and
1
101 J mol 1 K . A refined model of the transition state for the rate-determining stage was proposed, which
takes into account specific interaction with 1,4-dioxane.
We previously reported [2] on the kinetics of the
reaction of 5 -O-benzoyl-2,3 -anhydrothymidine with
dimethylammonium azide in the system DMF 1,4-di-
oxane at 100 C, which leads to formation of 3 -azido-
5 -O-benzoyl-3 -deoxythymidine (Scheme 1). It
was found that the reaction is described by the overall
second-order kinetic equation, being of first order in
each of the reactants. The order of the reaction does
not depend on the dioxane concentration in the system
(up to 50 vol %). Increase of the fraction of weakly
polar dioxane accelerates the reaction, and the
Addition of large amounts of dioxane increases the
reaction rate to a lesser extent than it might be
expected from the linear Kirkwood dependence. The
observed anomaly was explained in terms of specific
solvation by nucleophilic solvents. However, addi-
tional studies are necessary to get a deeper under-
standing of the process.
The goal of the present work was to determine and
analyze activation parameters of the reaction of
5 -O-benzoyl-2,3 -anhydrothymidine (I) with di-
methylammonium azide (II). For this purpose, the
kinetic measurements were performed in a binary
dependence logk = f[(
1)/(2 + 1)] is nonlinear.
Scheme 1.
____________
*
For communication I, see [1].
**
This study was financially supported by the Russian Foundation for Basic Research (project no. 01-03-32531).
1070-4280/02/3805-0735$27.00 2002 MAIK Nauka/Interperiodica

736
KORCHEVSKAYA et al.
where D0, D , and D are, respectively, the optical
densities of the reaction solution at 270 nm at the
initial moment, by the end of the process, and at
a moment . The parameters of the linear dependence
were determined by regression analysis under the
constraint that the dispersion of reproducibility is
uniform [5]. The general regression parameters were
calculated using ln(D
or lie at the boundary of confident interval defined
at a significance level of 0.05; Fisher test 0.8;
D ) values which fall into
number of degrees of freedom 16. The D0 values
determined by extrapolation to the initial moment
almost coincided with the optical densities calculated
for the initial concentrations of I. Thus the linearity
of the semilog kinetic plot indicates first order of the
reaction in the substrate, 5 -O-benzoyl-2,3 -anhydro-
thymidine (I). The order of the reaction with respect
to dimethylammonium azide (II) was found from the
dependence of the first-order rate constants on the
concentration of II for all DMF 1,4-dioxane systems.
As an example, Fig. 1 shows concentration depend-
ences of the apparent rate constants in the solvent
system containing 40 vol % of dioxane at 80 100 C.
Fig. 1. Dependences of the apparent rate constants for
azidation of 5 -O-benzoyl-2,3 -anhydrothymidine (I) with
dimethylammonium azide (II) on the concentration of the
latter in the system DMF 1,4-dioxane containing 40 vol %
of dioxane at (1) 80, (2) 85, (3) 90, (4) 95, and (5) 100 C.
Analogous dependences were obtained for all the
examined DMF 1,4-dioxane mixtures. Figure 1 shows
that these dependences are linear throughout the
temperature range under study and that the intercepts
at the y axis are negligible. Taken together, these data
also indicate first order of the reaction in dimethyl-
ammonium azide.
The second-order rate constants were calculated
from the slopes of the above dependences (see table).
These values were used to construct temperature
dependences which are well described by the Arrhe-
nius equation for all the examined DMF dioxane
mixtures (Fig. 2). The activation parameters were
determined from the slopes and intercepts of the
straight lines plotted in Fig. 2, in keeping with the
Arrhenius Eyring theory. Their values are given
Fig. 2. Temperature dependence of the rate of azidation
of 5 -O-benzoyl-2,3 -anhydrothymidine (I) with dimethyl-
ammonium azide (II) in the systems DMF 1,4-dioxane
containing (1) 30, (2) 40, and (3) 50 vol % of dioxane.
system DMF 1,4-dioxane according to the procedure
described in [3]. Dioxane was dried over NaOH and
was distilled over metallic sodium [4]. The reaction
was carried in the temperature range from 80 to 100 C
under conditions of pseudofirst-order with respect to
the substrate (cII >> cI ) in the solvent systems con-
taining 30, 40, and 50 vol % of dioxane. The semilog
kinetic plots remained linear in all the examined
solvent mixtures up to a conversion of 80 85%. It
should also be noted that in all cases the yield of
product III (determined by spectrophotometry) was
nearly quantitative. The pseudofirst-order rate constant
kap was determined from the slope of the semilog
dependence
1
Rate constants (k 105, l mol 1 s ) for azidation of
5 -O-benzoyl-2,3 -anhydrothymidine (I) with dimethyl-
ammonium azide (II) in DMF 1,4-dioxane
Temperature,
C
30 vol %
of dioxane of dioxane of dioxane
40 vol %
50 vol %
80
85
2.0
2.7
2.7
3.9
4.0
5.4
90
5.6
6.0
9.0
95
7.5
9.9
11.4
100
11.9
12.8
17.7
ln(D
D0) = kap
ln(D
D ),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002

MECHANISMS OF 5 -O-BENZOYL-2,3 -ANHYDROTHYMIDINE REACTIONS
737
Scheme 2.
below together with the activation parameters for
azidation of 5 -O-benzoyl-2,3 -anhydrothymidine with
dimethylammonium azide in 100% DMF, which were
determined by us previously [3].
the proton which migrates from the amino nitrogen
atom to the anhydro oxygen. Such specific interaction
increases the degree of ordering of the system, and
the entropy of activation decreases as the fraction of
dioxane rises. An analogous nucleophilic solvent
assistance to stabiliztion of cyclic transition states
was observed previously [7] in the ammonolysis of
carbonyl-containing compounds.
Concentration of
dioxane, vol %
H298
kJ/mol
,
S298,
J mol 1 K
1
0
30
40
50
126
99
85
33
46
83
REFERENCES
79
101
1. Korchevskaya, E.V., Malin, A.A., Shcherbinin, M.B.,
and Ostrovskii, V.A., Russ. J. Org. Chem., 2001,
vol. 37, no. 12, pp. 1767 1770.
These data indicate that addition of dioxane leads
to decrease of both the entropy and the enthalpy of
activation. We tried to interpret the observed pattern
by correcting the transition state model proposed
previously [3]. When the azidation is carried out in
DMF, cyclic complex A (Scheme 2) is formed in the
rate-determining stage. Here, protonation of O2,
nucleophilic azidation at C3 , and loosening of the
2. Korchevskaya, E.V., Malin, A.A., Shcherbinin, M.B.,
and Ostrovskii, V.A., Russ. J. Org. Chem., 2000,
vol. 36, no. 9, pp. 1369 1372.
3. Malin, A.A., Shcherbinin, M.B., Poplavskii, V.S.,
Kononov, A.V., and Ostrovskii, V.A., Russ. J. Org.
Chem., 1997, vol. 33, no. 4, pp. 549 553.
C3 O2 bond occur simultaneously. In going to the
binary DMF 1,4-dioxane system, the transition state
may be stabilized due to reduced polarity of the
medium (as a result of addition of weakly polar
dioxane). Therefore, the enthalpy of activation
decreases and the reaction rate increases as the con-
centration of dioxane in the system rises [2]. Reduc-
tion of the entropy of activation may be explained
using model B which includes 1,4-dioxane molecule.
According to [6], 1,4-dioxane is a more basic solvent
than DMF and it is capable of specifically solvating
4. Gordon, A.J. and Ford, R.A., The Chemist’s Compa-
nion, New York: Wiley, 1972.
5. Spiridonov, V.P. and Lopatkin, A.A., Matemati-
cheskaya obrabotka fiziko-khimicheskikh dannykh
(Mathematical Treatment of Physicochemical Data),
Moscow: Mosk. Gos. Univ., 1970.
6. Pal’m, N. and Pal’m, V., Russ. J. Org. Chem., 2000,
vol. 36, no. 8, pp. 1075 1104.
7. Zelenyuk, A.N., Berlin, P.A., Tiger, R.P., and
Entelis, S.G., Kinet. Katal., 1994, vol. 35, no. 6,
pp. 852 857.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 5 2002