2,6-Disubstituted 4-azidopyrimidines: synthesis, kinetic and thermodynamic studies of azide-tetrazole rearrangement by NMR spectroscopy

Article abstract of DOI:10.1007/s11172-017-1986-2

Thermodynamic and kinetic parameters of the tautomeric tetrazole-azide rearrangement for a series of 2,6-disubstituted 4-azidopyrimidines are determined by NOESY/EXSY and DNMR: ΔH = 15—28 kJ mol^–1; ΔS = 47—65 J mol^–1 К–1; Е_a = 93—117 kJ mol^–1; lgA = 15.1—18.9. They are dependent on electronic properties of the substituents and the polarity of solvent.

Full text of DOI:10.1007/s11172-017-1986-2

Russian Chemical Bulletin, International Edition, Vol. 66, No.11, pp. 2095—2102, November, 2017
2095
2,6ꢀDisubstituted 4ꢀazidopyrimidines: synthesis, kinetic and
thermodynamic studies of azideꢀtetrazole rearrangement by NMR spectroscopy
N. V. Pleshkova,a E. B. Nikolaenkova,a V. P. Krivopalov,a and V. I. Mamatyuka,b
aN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch, Russian Academy of Sciences,
9 prosp. Lavrentieva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: Nadia789@nioch.nsc.ru
bNovosibirsk State University (National Research University),
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation
Thermodynamic and kinetic parameters of the tautomeric tetrazoleꢀazide rearrangement
for a series of 2,6ꢀdisubstituted 4ꢀazidopyrimidines are determined by NOESY/EXSY and
DNMR: ΔH = 15—28 kJ mol–1; ΔS = 47—65 J mol–1
К ;
–1; Еа = 93—117 kJ mol–1
lgA = 15.1—18.9. They are dependent on electronic properties of the substituents and the
polarity of solvent.
Key words: 4ꢀazidopyrimidine, tetrazolo[c]pyrimidines, azideꢀtetrazole equilibrium,
NMR, NOESY/EXSY, DNMR, entropy, enthalpy, rate constant, Arrhenius equation.
For synthetic chemists heteroaromatic azides are of
temperature establishment times. On the other hand,
measurement by means of dynamic nuclear magnetic
resonance (DNMR) of the line shape for equilibrium raꢀ
tios requires sometimes relatively high temperatures, not
capable with several solvents and compounds. Thus, exꢀ
perimental measurement of the kinetic properties of the
azideꢀtetrazole equilibrium is a quite complicated but inꢀ
teresting challenge.
In the current work we studied substituted 4ꢀazidoꢀ
pyrimidines 1—5, for which twoꢀcomponent equilibrium
is possible (Scheme 2). It is worth of note, that recently
biologically active compounds have been synthesized basꢀ
ing on the 4ꢀazidopyrimidines.15,19 Hence, it would be
useful to complement the present knowledge on the azideꢀ
tetrazole tautomerism with kinetic data.
special interest due to their diverse chemical and photoꢀ
chemical properties, as well as vast practical applications
as photoaffinity labels.1—3
A possibility of the azideꢀtetrazole equilibrium is the
key feature of the azaaromatic compounds bearing azido
group in αꢀposition to nitrogen atom (Scheme 1). This
transformation is controlled by both stuctrural and exterꢀ
nal factors.4—6
Scheme 1
Scheme 2
The first notes about this tautomeric equilibrium date
from the middle of the XX century,7—9 but this reaction
remains still actively investigated experimentally,10—15 as
well as theoretically.16,17 Structure of the tautomers9—11,14
and thermodynamics of the process7,8 were usually under
focus, meanwhile kinetic aspects of the above mentioned
tautomeric equilibrium remain virtually unknown.9,18
Measurement of the kinetic parameters of such tautoꢀ
meric processes is a rather complicated task. Thus, a conꢀ
trol of the process by measurement of the signal intensiꢀ
ties difference in NMR spectra requires nonequilibrium
initial concentrations of the corresponding forms in soluꢀ
tion, which is hard to achieve due to a short lifeꢀtime of
these species which is comparable to a dissolution and
Comꢀ
pound
1
2
3
R
R´
Comꢀ
pound
4
R
R´
Ph
Ph
H
Me
CF3
CF3 Me0
Ph
5
Ph 4ꢀMeOC6H4
Ph =
, 4ꢀMeOC6H4 =
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2095—2102, November, 2017.
1066ꢀ5285/17/6611ꢀ2095 © 2017 Springer Science+Business Media, Inc.

2096
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017
Pleshkova et al.
where K is the equilibrium constant for azideꢀtetrazole rearꢀ
rangement; τ is mixing (exchange) time, s; ITT and IAA are
intensities of the diagonal peaks, Icross = 0.5(ITA + IAT) is halfꢀ
sum of crossꢀpeak intensities.
Experimental
Melting points were determined on the Mettler Toledo
FPꢀ900 instrument. IR spectra for the studied samples were
recorded on Vectorꢀ22 Fourierꢀspectrometer. Elemental analyꢀ
ses were carried out on the Euro EA3000 CHNSꢀanalyser.
NMR spectra were recorded on Bruker AVꢀ600 (600.30,
19F—19F EXSY were registered for the compounds 4 and 5,
for all the rest — 1Н—1Н EXSY. For the studied compounds 1—5
NMR spectra were measured in a range 16—60 °С using CDCl3
as a solvent, or in a range 24—100 °С for DMSOꢀd6. Equilibꢀ
rium constants for transformation of tetrazole into azide were
calculated from signal integral intensity ratios of tautomer A in
1
150.95 and 564.81 MHz for H, 13C and 19F, respectively) and
Bruker DRXꢀ500 (500.13 and 125.75 MHz for 1H and 13C,
respectively) spectrometers in DMSOꢀd6 (дН 2.50, δС 39.50)
and CDCl3 (δН 7.24, дС 76.90). Chemical shifts for 1H and
13C NMR spectra are given according to reference of the solꢀ
vent residual peak (internal standard), for 19F — with reference
1
relation to tautomer T in Н NMR spectra for the compounds
1—3 and in 19F NMR spectra for the compounds 4 and 5 in
CDCl3 and DMSOꢀd6. In the case of the compound 1 mesureꢀ
ment of the protons by numbers 5 and 2 (see Scheme 2) was
carried out, for tetrazole and azide, respectively, and in the
case of the compounds 2 and 3 the measurement was of the
protons of Meꢀgroups.
to trichlorofluoromethane (δ 0, external standard). Reaction
F
convertions were controlled by TLC on Sorbfil plates.
The relevant tautomeric forms and their ratios for comꢀ
pounds 1—5 are attributed according to sygnals in the NMR
Method EXSY allows the most precise measurement of relaꢀ
tively slow reversible processes with rates comparable with rate
of the spinꢀlattice relaxation. For more rapid processes, which
significantly affect the line shape in the NMR spectrum,
DNMR24 method was applied using the standard software
Bruker Top Spin 3.2.
Values of ΔH, ΔS and Еа, lgА and their accuracy were calcuꢀ
lated by the least squares technique.
7ꢀPhenyltetrazolo[1,5ꢀc]pyrimidine (1Т)/4ꢀazidoꢀ6ꢀphenylꢀ
pyrimidine (1А) were prepared according to the previously deꢀ
scribed method.25
5ꢀMethylꢀ7ꢀphenyltetrazolo[1,5ꢀc]pyrimidine (2Т)/4ꢀazidoꢀ
2ꢀmethylꢀ6ꢀphenylpyrimidine (2А). 4ꢀHydrazinoꢀ2ꢀmethylꢀ6ꢀ
phenylpyrimidine (0.6 g, 3 mmol) was dissolved in 70% AcOH
(15 mL). NaNO2 (0.42 g, 6 mmol) solution in water (5 mL) was
added dropwise slowly with cooling with ice cold water. The
stirring was continued at the same temperature for ~1 h. The
1
13
spectra. Tautomer structures are determined basing on Н,
С
NMR and 2D 1Н—13С HSQC/HMBC spectra, with considerꢀ
ation that upfield chemical shift values in the range δ 140—155
are characteristic for carbons С(5), С(7) and С(8а) in tetrazoloꢀ
pyrimidines, and downfield values in the range δ 160—165 —
for the respective atoms in azidopyrimidines.20
Rearrangement rate constants calculations were carried out
with NOESY/EXSY and DNMR methods. In EXSY spectra
along with diagonal peaks crossꢀpeaks appeared, which indiꢀ
cated the signals, which are participate in exchange process.21,22
Example of the typical EXSY spectrum is shown in Fig. 1.
With a condition of the equal spinꢀspin relaxation of the
examined nuclea the rate constant for tetrazol interconvertion
into azide can be calculated from the integrate intensities of
crossꢀ and diagonal peaks in NOESY/EXSY spectra by the folꢀ
lowing formula:23
resulting precipitate was filtered, washed with Н О and dried
2
(1)
on air. Yield 0.57 g (90%) of the product with m.p. 192—193 °С
(from ethanol). IR (KBr), ν/cm–1: 3074, 1630, 1552, 1502,
1443, 1306, 1232, 1159, 1126, 1084, 991, 887, 874, 779, 762,
772, 702, 690, 652, 644. Found (%): С, 62.73; Н, 4.26; N, 33.31.
Calculated for C11H9N5 (%): C, 62.54; H, 4.29; N, 33.16.
4ꢀAzidoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀphenylpyrimidine (3А)/5ꢀ
(4ꢀmethoxyphenyl)ꢀ7ꢀphenyltetrazolo[1,5ꢀc]pyrimidine (3Т).
A mixture of 2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀchloroꢀ6ꢀphenylpyrimidꢀ
ine (1 g, 3.37 mmol), NaN3 (0.26 g, 4 mmol) NaN3 and anhyꢀ
drous LiCl (0.17 g, 4 mmol) in dry DMF (17 mL) was stirred
upon heating to 40—45 °С for 8 h. After cooling the reaction
A
T
δ
3.88
A
3.90
3.92
3.94
3.96
3.98
mixture was poured into Н О (50 mL), the resulting precipitate
IAA
ITA
2
was filtered, washed with Н О and dried on air. Yield 0.93 g
2
(91%) of the product with m.p. 143—144 °С (from ethanol).
IR (KBr), ν/cm–1: 2164 (N3), 2125 (N3), 1605, 1587, 1566,
1537, 1514, 1495, 1454, 1427, 1392, 1385, 1356, 1302, 1252,
1234, 1221, 1180, 1163, 1124, 1107, 1076, 1026, 924, 847, 771,
731, 688. Found (%): С, 67.35; Н, 4.31; N, 23.06. Calculated
for C17H13N5O (%): C, 67.31; H, 4.32; N, 23.09.
4ꢀAzidoꢀ6ꢀ(trifluoromethyl)ꢀ2ꢀphenylpyrimidine (4А)/7ꢀ
(trifluoromethyl)ꢀ5ꢀphenyltetrazolo[1,5ꢀс]pyrimidine (4Т). NaN3
(0.16 g, 2.4 mmol) and anhydrous LiCl (0.1 g, 2.4 mmol) were
added to a stirred solution of 4ꢀchloroꢀ2ꢀphenylꢀ6ꢀtrifluoroꢀ
methylpyrimidine in dry DMF (10 mL). The reaction mixture
T
ITT
IAT
3.98
3.96
3.94
3.92
3.90
δ
Fig. 1. 1Н—1Н EXSY spectrum fragment for the compound 3 in
DMSOꢀd6 at 45 °С and τmix = 0.3 s.
was stirred for 2 days at ~20 °C and thereafter poured into Н О
2
(50 mL). The resulting precipitate was filtered, washed with

Azideꢀtetrazole rearrangement
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017 2097
H2O and dried on air. Yield 0.5 g (94%) of the product with
m.p. 89—90 °С (from ethanol). IR (KBr), ν/cm–1: 2145 (N3),
2097, 1593, 1576, 1562, 1458, 1408, 1391, 1375, 1310, 1254,
1231, 1204, 1165, 1151, 1121, 1095, 1088, 987, 932, 872, 847,
764, 706, 700. Found (%): C, 49.45; H, 2.41; F, 21.27; N, 26.40.
Calculated for C11H6F3N5 (%): C, 49.82; H, 2.28; F, 21.49;
N, 26.41.
4ꢀAzidoꢀ2ꢀmethylꢀ6ꢀ(trifluoromethyl)pyrimidine (5А)/5ꢀmeꢀ
thylꢀ7ꢀ(trifluoromethyl)tetrazolo[1,5ꢀс]pyrimidine (5Т). A soluꢀ
tion of NaNO2 (0.21 g, 1.5 mmol) in H2O (1.5 mL) was added
dropwise to a cooled with an ice—water bath solution of
4ꢀhydrazinoꢀ2ꢀmethylꢀ6ꢀtrifluoromethylpyrimidine (0.38 g,
Results and Discussion
Compounds 3 and 4 demonstrated tautomeric process
in both CDCl3 and DMSOꢀd6. Compounds 1, 2 and 5
exist in two forms Т and А only in CDCl3, in DMSOꢀd6
only tetrazole tautomer can be detected for these comꢀ
pounds at room temperature (Table 3). In DMSOꢀd6, the
most polar solvent, the most polar tetrazole form Т is
stabilized.7
Temperature dependence of the equilibrium constants
for azideꢀtetrazole tautomerism in CDCl3 are given in
Fig 2. Analogous plots are obtained in DMSOꢀd6.
Thermodinamic parameters of the tetrazoleꢀazide equiꢀ
librium are given in Tables 4 and 5.
2 mmol) in mixture of conc. HCl (1 mL) and Н О (6 mL) upon
2
stirring. The reaction mixture was stirred for 2 h and neutralꢀ
ized with aqueous ammonia. The resulting precipitate was filted,
washed with Н О and dried on air. The precipitates weight
2
was 0.14 g. The filtrate was three times extracted with CHCl3,
the extract was dried with MgSO4. Solvent evaporation yielded
in additional 0.15 g of the product. Combined yield 0.29 g
It was determined that azideꢀtetrazole tautomerism
in a series of 4ꢀazidopyrimidines 1—5 is a slow process up
to temperatures about 50 °С, and notable line broadening
related to exchange process is observed only above 60 °С.
This allowed determination of rate constants for tautomꢀ
erism by two methods. Thus, in a slow exchange range,
while line shape in NMR spectra are almost not vulnerꢀ
able to broadening EXSY method was applied, and within
medium exchange range, which was achieved by signifiꢀ
cant heating up to 100 °C, DNMR method was used. Due
(71%), m.p. 60—61 °С (from hexane). IR (KBr), ν/cm–1
:
1637, 1597, 1566, 1502, 1439, 1412, 1381, 1342, 1331, 1277,
1234, 1200, 1167, 1142, 1092, 1034, 987, 978, 904, 878, 712,
586, 542. Found (%): С, 35.60; H, 2.09; F, 27.66; N, 34.47.
Calculated for C6H4F3N5 (%): C, 35.48; H, 1.98; F, 28.06;
N, 34.48.
13
Spectral data (1Н, С and 19F NMR) for the compounds
1—5 are given in Tables 1 and 2.
Table 1. Spectral data (1Н, 13С and 19F NMR) for tetrazole forms of the compounds 1—5 in CDCl3
Method
1Т
2Т
3Т
4Т
5Т
1
δ Н
Н(5)
Н(8)
Н(2´)
Н(3´)
Н(4´)
Н(2´´)
Н(3´´)
СН3
9.69 (s, 1 H)
8.24 (s, 1 H)
8.11 (m, 2 H)
7.53—7.57 (m, 3 H)
—
—
—
8.99 (s, 1 H)
8.52 (m, 2 Н)
7.73 (m, 2 Н)
7.79(m, 1 Н)
—
—
8.08—8.10 (m, 3 Н)
8.08—8.10 (m, 3 Н)
7.50—7.53 (m, 3 H) 7.53—7.55 (m, 3 H)
7.50—7.53 (m, 3 H) 7.53—7.55 (m, 3 H)
8.07 (s, 1 Н)
8.13 (m, 2 H)
8.19 (s, 1 H)
—
—
—
—
—
3.23
–72.5
149.1
7.53—7.57(m, 3 H)
—
—
—
—
137.29
154.95
—
—
8.86 (m, 2 H)
7.11 (m, 2 Н)
3.92 (s, 3 H)
—
—
—
–71.1*
149.0
3.20 (s, 3 Н)
—
δ
δ
19F
13C (J/Hz)
СF3
С(5)
С(7)
148.19
154.43
146.37
154.14
142.8 (q,
2JC—F = 36.0)
108.3 (q,
3JC—F = 3.6)
150.9
144.5 (q,
2JC—F = 35.8)
106.9 (q,
3JC—F = 3.7)
С(8)
104.07
101.95
101.11
С(8а)
С(1´)
С(2´)
С(3´)
С(4´)
С(1´´)
С(2´´)
С(3´´)
С(4´´)
СН3
150.33
134.82
127.28
129.21
131.19
—
—
—
—
—
150.65
135.28
127.23
129.04
130.84
—
—
—
—
20.04
—
152.20
135.55
127.26
128.98
130.75
122.32
132.64
114.14
163.42
55.46
151.1
—
—
—
—
—
—
—
—
129.3
130.4
128.8
133.3
—
—
—
—
—
19.9
120.2 (q,
СF3
—
—
120.9 (q,
1JC—F = 274.6) 1JC—F = 273.8)
* In DMSOꢀd6.

2098
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017
Pleshkova et al.
Table 2. Spectral data (1Н, 13С and 19F NMR) for azido forms of the compounds 1—5 in CDCl3
Method
1А
2А
3А
4А
5А
1
δ Н
Н(2)
Н(5)
Н(2´)
Н(3´)
Н(4´)
Н(2´´)
Н(3´´)
СН3
СF3
С(2)
С(4)
С(5)
8.96 (s, 1 H)
7.16 (s, 1 H)
8.02 (m, 2 H)
7.46—7.50 (m, 3 H)
—
—
—
7.49 (s, 1 H)
8.33 (m, 2 Н)
7.55 (m, 2 Н)
7.60 (m, 1 Н)
—
—
7.97—7.99 (m, 3 Н)
7.97—7.99 (m, 3 Н)
7.43—7.46 (m, 3 H) 7.47—7.50 (m, 3 H)
7.43—7.46 (m, 3 H) 7.47—7.50 (m, 3 H)
6.97 (s, 1 Н)
8.17 (m, 2 H)
6.88 (s, 1 H)
—
—
—
—
—
2.71
–74.3
164.2
7.46—7.50 (m, 3 H)
—
—
—
—
—
8.52 (m, 2 H)
6.99 (m, 2 Н)
3.87 (s, 3 H)
—
—
—
–72.3*
164.2
165.5
2.70 (s, 3 Н)
—
δ
δ
19F
13C (J/Hz)
—
158.75
162.97
106.05
165.67
162.72
103.07
164.02
162.83
102.86
169.9
104.0 (q,
3JC—F = 3.1)
156.9 (q,
2JC—F = 35.8)
105.7 (q,
3JC—F = 2.8)
155.9 (q,
2JC—F = 35.4)
134.8
С(6)
165.56
168.60
165.44
С(1´)
С(2´)
С(3´)
С(4´)
С(1´´)
С(2´´)
С(3´´)
С(4´´)
СН3
136.01
127.05
128.90
131.13
—
—
—
—
—
136.29
127.06
128.77
130.77
—
—
—
—
25.85
—
136.66
127.07
128.69
130.81
129.63
130.01
113.66
162.05
55.24
—
—
—
—
—
—
—
—
25.5
127.9
128.9
132.1
—
—
—
—
—
СF3
—
—
120.3 (q,
1JC—F = 275.1) JC—F = 275.2)
120.2 (q,
1
* In DMSOꢀd6.
to low boiling point of CDCl3 (60 °С) it was not possible
to introduce the studied tautomeric systems into medium
exchange state, for this reason rate constants in CDCl3
were determined only by EXSY method.
19F) and methoxyl protons in NMR spectra were simuꢀ
lated. Fragments of the experimental spectra and the reꢀ
spective simulated spectra with calculated rate constant k
are shown at Fig. 3.
For two compounds 3 and 4 in DMSOꢀd6 along with
EXSY method DNMR method was applied as well. For
instance, for the compound 3 a notable line broadening
was observed at temperatures above 75 °C, and for the
compound 4 — above 60 °C. For simplification of the
calculation, singlet signals of trifluromethyl groups (in
Comparison of the experimental data obtained with
EXSY and DNMR methods for compounds 3 and 4 in
DMSOꢀd6 is shown in Fig. 4.
RlnK
20
y = 15.237x + 60.825
R
2 = 0.9934
10
0
Table 3. Ratios of tautomers T/A (%) at room
temperature*
y = 15.693x + 55.654
2 = 0.9996
R
y = 27.577x + 65.035
2 = 0.9973
Compound
Ratio T/A
DMSOꢀd6
1
2
3
4
R
CDCl3
–10
–20
y = 22.801x + 59.668
2 = 0.9992
R
1
2
3
4
5
40/60
96/4
20/80
4/96
100/0
100/0
56/44
48/52
100/0
87/13
–3.4 –3.3
–3.2
–3.1 –3.0 –1000/T
* Tautomeric ratio was determined by 1Н and 19
NMR by the integration of characteristic peaks.
F
Fig. 2. Temperature dependence of the equilibrium constants
for the azide into tetrazole rearrangement in CDCl3.

Azideꢀtetrazole rearrangement
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017 2099
a
b
k = 48 s–1
362 K
356 K
k = 36 s–1
k = 21 s–1
352 K
k = 13 s–1
347 K
305 K
4.00
3.95
3.90
3.85
3.80
δ
1
Fig. 3. Н NMR spectrum fragment for the compound 3 at different temperatures (а) and simulated spectra and rate constants k
tetrazole into azide rearrangement (b).
From the Fig. 4 one can observe that temperature
dependence of rate constants, determined by the two
methods, nicely fell along a straight line in coordinates of
the Arrenius Law. As a result an agreement between the
data obtained by EXSY and DNMR methods was shown.
In a Fig. 5 dependences of the rate constants of the
azideꢀtetrazole equilibrium in CDCl3 are depicted. Analoꢀ
gous plots were obtained in DMSOꢀd6. Activation paꢀ
rameters Еа and lgA of the studied rearrangement of the
compounds 1—5 are given in Tables 4 and 5.
Table 4. Termodinamic and kinetic parameters of the tetrazole into azide rearrangement for 4ꢀazidopyrimidines
in CDCl3
Comꢀ
pound
ΔH
ΔS
ΔG298
Еа
lgA
k298•103
/s–1
–1
/kJ mol–1
/J mol–1
К
kJ mol–1
1
2
3
5
15.7 0.2
27.6 0.8
15.2 0.4
22.8 0.4
55.7 0.5
–0.89 0.02
8.2 0.6
–2.9 0.1
4.9 0.2
101
100
96
1
4
1
16.0 0.2
15.2 0.7
16.4 0.2
15.5 0.12
18.5 0.4
4.4 0.4
351 8.0
6.3 0.2
65
61
60
3
1
1
100.8 0.9
Table 5. Termodinamic and kinetic parameters of the tetrazole into azide rearrangement for 4ꢀazidopyrimidines
in DMSOꢀd6
Compound
ΔH
ΔS
ΔG298
Еа
lgA
k298•103
/s–1
–1
/kJ mol–1
/J mol–1
К
kJ mol–1
1
3
4
25.3 0.6
15.2 0.1
59
47.7 0.4
59
2
7.7 0.4
0.98 0.01
–0.58 0.07
111.4 0.8
16.5 0.1
15.1 0.2
18.9 0.3
0.87 0.01
93
1
59
1
17
1
4
117 2
28.8 0.8

2100
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017
Pleshkova et al.
lnk
phenyl groups which lead to azide stabilization as well. In
the case of the compounds 2 and 5 one can observe oppoꢀ
site effect, when strong +I donor (Me group) stabilizes
tetrazole so efficiently in DMSOꢀd6, that tetrazole cycle
cannot open even upon increased temperature (tetrazole
into azide transformation is endothermic). Because of this
reason we could not determine thermodynamic and actiꢀ
vation parameters of the azideꢀtetrazole tautomerism for
the compounds 2 and 5 in DMSOꢀd6. For the comound 1
parameters were obtained, although in DMSOꢀd6 only
tetrazole tautomer is detected at room temperature. Inꢀ
crease of the temperature facilitated in an appearance of
the azido form, the 1Т/1А ratio was 80 : 20 at 90 °C.
Data analysis from the Table 4 suggests that introducꢀ
tion of the Meꢀgroup into position 2 of the 4ꢀazidoꢀ6ꢀ
phenylpyrimidine results into decrease of the rate of transꢀ
formation of tetrazole into azide almost 4 times, and on
the other hand introduction of the aryl substituent at the
same position results in 19 times acceleration of the proꢀ
cess. Indeed from the Table 4 k298 for 7ꢀphenyltetrꢀ
2.0
1.5
1.0
0.5
0
3 (DNMR)
3 (EXSY)
4 (DNMR)
4 (EXSY)
–0.165 –0.160 –0.155 –0.150 –0.145 –1000/2.3RT
Fig. 4. Comparison of the kinetic data obtained by EXSY and
DNMR methods for the compounds 3 and 4 in DMSOꢀd6.
azolo[1,5ꢀc]pyrimidine (1) in CDCl3 is 18.5 0.4•10–3 s–1
,
lgk1
1.0
and for 5ꢀmethylꢀ7ꢀphenyltetrazolo[1,5ꢀc]ꢀpyrimidine
(2) and 5ꢀ(4ꢀmethoxyphenyl)ꢀ7ꢀphenyltetrazolo[1,5ꢀc]ꢀ
pyrimidine (3) — 4.4 0.4•10–3 and 351 8•10–3 s–1, reꢀ
spectively. Analogous difference in rate constants was obꢀ
served for compounds 1 and 3 in DMSOꢀd6 solution (see
Table 5). Explanations for decrease and acceleration of
the reaction rate for the conversion of tetrazole into azide
upon introduction of methyl and phenyl substituent into
position 2 of pyrimidine ring are stabilization and destaꢀ
bilization of tetrazole. Thus, nature of the substituent at
the position 2 of the pyrimidine ring is notably influencꢀ
ing the rate of the tetrazoleꢀazide equilibrium. Nature of
the substituent at the position 6 of the pyrimidine ring
almost does not influence the reaction rate. Thus for the
1
2
0.5
3
4
y = 100.81x + 15.55
2 = 0.9998
R
0
–0.5
–1.0
–1.5
–2.0
y = 96.592x + 16.444
2 = 0.9988
R
y = 99.867x + 15.198
R
2 = 0.9966
y = 100.65x + 16.02
2 = 0.9998
R
–0.180
–0.170
–0.160
–1000/2.3RT
compounds 3 and 4 (6ꢀpꢀСН ОС Н ꢀ and 6ꢀCF3ꢀsubꢀ
3
6
4
Fig. 5. Temperature dependence of the rate constants for the
azide into tetrazole rearrangement in CDCl3 in the representaꢀ
tion of the Arrhenius law.
stituted 4ꢀazidoꢀ2ꢀphenylpyrimidines, respectively) rate
constants in DMSOꢀd6 at room temperature are compaꢀ
rable (see Table 5). Analogously, for compounds 5 and 2
(6ꢀCF3ꢀ and 6ꢀPhꢀsubstituted 4ꢀazidoꢀ2ꢀmethylpyrꢀ
imidines, respectively) rate constants in CDCl3 at room
temperature are 6.3 0.2•10–3 and 4.4 0.4•10–3 s–1 reꢀ
spectively (see Table 4). Limited influence of the nature
of the substituent at the position 6 of pyrimidine ring on
the rate of azidoꢀtetrazole equilibrium is due to remote
position of this substituent from nitrogen N(3), on which
annelation of tetrazole ring is performed.
On an example of the compounds 1 and 3 one can
observe significant dependence of rate constant for tetrꢀ
azole azide conversion from the selected solvent. Thus
this value in CDCl3 is significantly higher than in DMSOꢀd6
solution. Because of this, we decided to investigate influꢀ
ence of the solvent nature on the rate of the tautomerism
more in detail. The most suitable for this purpose model
7ꢀphenyltetrazolo[1,5ꢀc]pyrimidine (1), demonstrated
Rearrangement of the tetrazolo[c]pyrimidines into
4ꢀazidopyrimidines is endotermic reaction and the value of
the enthalpy of the interconvertion isabout 15—28 kJ mol–1
(see Tables 4 and 5). Ring opening in each case is characꢀ
terized by a significant ΔS increase, and for the comꢀ
pounds 1 and 3 in chloroform entropy contribution exꢀ
ceeds enthalpy one, which results in predominance of the
azide in the mixture, although azide transformation into
tetrazole is exothermic.7
Appearance of the azido form in DMSOꢀd6 at room
temperature for the compounds 3 and 4 can be attributed
to a weak –Iꢀeffect of the phenyl substituents at the
2 position of pyrimidine ring, and thus a decrease of the
electron density on the nodal N atom, which leads to
azide stabilization, either to sterical hindrance from the

Azideꢀtetrazole rearrangement
Russ. Chem. Bull., Int. Ed., Vol. 66, No. 11, November, 2017 2101
Table 6. Comparison of the the thermodynamic and kinetic parameters of the tetrazole into azide rearrangement 7ꢀphenꢀ
yltetrazolo[1,5ꢀc]pyrimidine (1) in different solvents
Solvent (ε)
T/A
ΔH
ΔS
ΔG298
Еа
lgA
k298•103
/s–1
–1
/kJ mol–1
/J mol–1
К
kJ mol–1
DMSOꢀd6 (46.7)
CD3CN (37.5)
DMFꢀd7 (36.7)
(CD3)2CO (20.7)
CDCl3 (4.8)
100/0
86/14
92/8
81/19
40/60
25.3 0.6
18.8 0.4
23.1 0.4
20.7 0.8
15.7 0.2
59
49
57
58
2
7.7 0.4
4.2 0.2
6.1 0.2
3.2 0.3
–0.89 0.02
111.4 0,8
16.5 0.1
15.1 0.6
15.7 0.3
15.3 0.3
16.0 0.2
0.87 0.01
3.5 0.3
2.8 0.1
5.5 0.2
18.5 0.4
1
1
3
100
104
100
101
4
2
2
1
55.7 0.5
azideꢀtetrazole interconversion in different solvents with
reasonable ratios of tautomers. Thus, a ratio of different
forms the compound 1 in DMSOꢀd6 and CDCl3 differs
for 40% at room temperature.
For 7ꢀphenyltetrazolo[1,5ꢀc]pyrimidine (1) thermoꢀ
dynamic and kinetic parameters of the rearrangement in
different solvents were determined (Table 6).
Upon increase of the polarity of the solvent rate of
conversion of tetrazole into azide is decreased, which is
associated with stabilization of the more polar form
(tetrazole) in more polar solvents (see Table 6). However
for a solvent CD3CN some deviation in thermodynamics
and subsequently in kinetics of the process is observed. In
CD3CN, according to ΔG298 value in a greater degree
azido form is stabilized in comparison to a solvent of the
analogous polarity DMFꢀd7. This leads to a faster transꢀ
formation of the tetrazole into azide in CD3CN media in
comparison to DMFꢀd7. A possible explanation of the
indicated phenomenon could be associated with coordiꢀ
nation of azido group with nitrile group of the solvent
azide rearrangement under equilibrium conditions in a wide
temperature range. Thermodynamic and kinetic paraꢀ
meters for a series of the substituted 4ꢀazidopyrimidines 1—5
are: ΔH = 15—28 kJ mol–1; ΔS = 47—65 J mol–1 K–1
;
Еа = 93—117 kJ mol–1; lgA = 15.1—18.9 for a reaction of
tetrazole into azide conversion.
Authors would like to acknowledge the MultiꢀAccess
Chemical Service Center of the Siberian Branch RAS for
spectral and analytical measurements.
This work was financially supported by the Ministry
of Education and Science of the Russian Federation
(Project 5ꢀ100).
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Received May 4, 2017;
in revised form June 29, 2017