J . Phys. Chem.

1990, 94, 5499-5501 5499

Tautomerism of 1,2,3- and 1,2,4-Triazoie h the Gas Phase and in Aqueous Solution: A
Combined ab Initio Quantum Mechanics and Free Energy Perturbation Study

James R. COX; Stephen Woodcock, Ian H. Hillier,* and Mark A. Vincent

Chemistry Department, University of Manchester, Manchester M13 9PL. U.K. (Received: November 1. 1989;
In Final Form: February 5, 1990)

The energy differences between the tautomers of 1,2,3- and 1,2,4-triazolehave been estimated at the 6-31G**(MP2)//3-21G
level including zero-point effects. The results confirm that only a single tautomer of each isomer is expected to be observed
in the gas phase. In aqueous solution the free energy separation of each pair of tautomers is considerably reduced and has
been estimated by use of the free energy perturbation method. These calculations agree with the experimental findings that
for 1,2,3-triazole both tautomers are observed in a polar solvent, whereas for 1,2,4-triazole the concentration of the rare
tautomer is still extremely low.

Introduction
Due largely to the pioneering work of Pople and collaborators,
it is now possible to carry out accurate a b initio calculations to
predict the electronic structure of quite large molecular systems,
including electron correlation effects. There is now considerable
interest in building into such studies the effect of the environment,
where, of necessity, potentially less rigorous methods may be
involved. As examples, the environment may be a part of the
molecule that takes no direct part in the chemistry being studied,
such as parts of an enzyme distant from the active site, or it may
be the solvent. In this paper we describe a theoretical study of
the latter situation, involving tautomerism in the gas phase and
in aqueous solution utilizing “state-of-the-art” a b initio quantum
N=C N=C
mechanical and free energy perturbation methods.
Accurate a b initio calculations of molecular structure and I \ I \
energetics continue to be of value in many studies of tautomeric
phenomena as shown by recent studies.’ Such studies often have
H/N\CIN N\,/N-H

biological implications as in the Occurrence of the rare tautomers I

of the pyrimidine bases and their role in mutagenesk2 Of
particular interest is the effect of environment, particularly solvent,
on the tautomeric equilibria. Thus, in the case of the well-studied
2-pyridone/2-hydroxypyridineequilibrium, the energy difference
between the two tautomers is very small in the gas phase, while
in the solid state and in polar solvents the 2-pyridone tautomer
is d ~ m i n a n t . ~
The accurate prediction of tautomeric equilibria in solution
requires high-accuracy quantum mechanical calculations of the
structure and energetics of the isolated molecules, where frequently
the structures of only the dominant tautomers are known ex-
perimentally, together with estimates of the solvent-solute in-
teractions.
The review by Elguero et ala4describes many situations where
tautomeric equilibria are poorly understood. For example, they
describe the tautomerism of 1,2,3-triazole as ”... still the most
confused of all the cases of annular tautomerism”. In this paper
we describe theoretical studies of the equilibria involving the 2 H
tautomer (I) and the 1 H tautomer (11) of 1,2,3-triazole and also
that involving the 1 H tautomer (111) and 4 H tautomer (IV) of
1,2,4-triazole.
In the case of 1,2,3-triazole, microwaves and photoelectron’
spectroscopy studies conclude that in the gas phase the 2 H tau-
tomer (I) is the only species observed. However, in solution, both
the 2 H and the 1H tautomer (11) are often observed. Thus, ‘H
NMR studies in CD2C12indicate that both tautomers are present
in solution, their relative proportion depending upon temperature
and concentration.* Two circumstantial but independent argu-
ments have recently been presented that both give the result that
the 2 H tautomer is favored in aqueous solution over the 1 H
tautomer by a factor of about 2.9 For 1,2,4-triazole, microwave
‘Present address: Shell Research Center, Sittingbourne, Kent ME9 8AG,
U.K.
H
IH
UUl IN1
studies have concluded that the 1H tautomer predominates ov-
erwhelmingly in the gas phase.I0 A photoelectron spectroscopic
study has also concluded that the 4 H tautomer is not present at
detectable levels’ in the vapor phase. As far as solution studies
are concerned, a proton NMR study of 1,2,4-triazole indicates
that the relative concentration of the 4H tautomer in tetra-
hydrofuran (THF) is less than 1% at -70 OC.*
In this paper we shall describe calculations of the relative
energetics of the tautomers of both isomers of triazole in the gas
phase and in aqueous solution. First, calculations of the molecular
geometries of the four species will be described followed by
calculations of their energies including both correlation and
zero-point effects. To quantitatively estimate the changes in the
(1) L a , A.; Adamowicz, L.; Bartlett, R. J. J . Phys. Chem. 1989,93,4001.
Kwiatkowski, J. S.; Bartlett, R. J.; Person, W. B. J. Am. Chem. SOC.1988,
110, 2353.
(2) Topal, M. D.; Fresco, J. R. Nature (London) 1976, 263,285; 1976,
263, 289.
(3) Beak, P.; Fry, S.; Lee, J.; Steele, F. J . Am. Chem. Soc. 1976, 98, 171.
Beak, P. Ace. Chem. Res. 1977, IO, 186.
(4) Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. The Tautomerism
of Heterocycles; Academic Press: New York. 1976; p 283.
( 5 ) Nygaard, L. Reported in ref 6.
(6) Palmer, M. H.; Simpson, I.; Findlay, R. H. 2.Naturforsch. 1981,36a,
34.
(7) Palmer, M. H.; Simpson, I.; Wheller, J. R. 2.Naturforsch. 1981,360,
1246.
(8) Lunazzi, L.; Parisi, F.;Macciantclli, D. J . Chem. Soc., Perkin Trans.
2 1984, 1025.
(9) Albert, A.; Taylor, P. J. J . Chem. Soc., Perkin Trans. 2 1989, 1903.
(IO) Bolton, K.; Brown, R. D.; Burden, F. R.; Mishra, A. J . Mol. Srrucr.
1975,27, 261. Bolton, K.; Brown, R. D.; Burden, F. R.; Mishra, A. J . Chem.
Soc., Chem. Commun. 1970, 873.

0022-3654/90/2094-5499%02.50/00 1990 American Chemical Society

5500 The Journal of Physical Chemistry, Vol. 94, No. 14, 1990 Cox et al.
free energy of solvation between different species, the free energy TABLE I: c h & k t h s to tbe Tocrl EM.rw (in au) of
perturbation method has been shown to be successful. In this work, 1H-l,2,3-Triazde (1H-123) ,
28-1,2,3-Triuole (28-123),
we use this method in molecular dynamics simulations to estimate 1H-1,2,4-Triazole (lH-l24),a d 4H-l,2,4-Triazok (48-124)
the changes in the free energy of solvation between the different ESCF
tautomers of each isomer of triazole. EM"
3-21G//3-21G 6-3IG8*//3-21G' 6-31G1*//3-2IG
Computational Details IH-123 -239.3927 -240.7719 (4.6) -0.7896
The geometric structuresof the four triazole species (I-IV) were 2H-123 -239.3990 -240.7793 (0.5) -0.7881
obtained at the 3-21G basis set level" by using the program 4H-124 -239.4220 -240.7965 (6.0) -0.7786
1H-124 -239.4280 -240.8076 (2.9) -0.7780
G A M E S S . ~ ~ At these optimized geometries large basis set (6-
31G**)l3calculationswere carried out and correlation effects were 'The values in parentheses are the calculated dipole moments (de-
estimated using second-order Maller-Plesset (MP2) perturbation byes).
theory.I4 Zero-point energies were estimated by calculating the
harmonic frequencies at the 3-21G level. These calculations were TABLE II: Relative Stabilities of Triazdes (kJ md-')
carried out by use of the program CADPAC." (2H-123)- (1H-124)-
Subsequent to the quantum mechanical calculations, one tau- (IH-I23) ( ~ 1 2 4 )
tomer was transformed into another in solution by using the free SCF 3-21G//3-21G -16.5 -1 5.7
energy perturbation methodt6 in molecular dynamics simulations SCF 6-31Gi*//3-21G -19.5 -29.2
to obtain the solvation free energy differences (AAG) between SCF DZ//(7s3p/3s)' -15.9 -21.4
the two tautomers, as implemented in the program AMBER." The ZPE 3-2 1GJl3-21G 0.8 1.3
atomic partial charges for the four species studied were obtained MP2 6-31G**//3-21G 3.9 1.6
by using the following strategy proposed by Singh and Kollman.'* total relative stability, -14.8 -26.3
Following geometry optimization at the 3-21G level, single-point SCF(6-3 1G**//3-2 1G)
calculations were carried out using a 6-31G* basis." The 6-31G* + ZPE + MP2
wave functions were then used to calculate the electrostatic po- Reference 7.
tential around the molecules which lead to the determination of
the partial atomic charges. The charges used in the molecular
dynamics simulation were rescaled by a factor of 0.95 to take
account of the overestimation of the molecular dipole moments
given by the SCF wave functions.
The molecular dynamics simulations were carried out at T =
300 K and 1-atm pressure in a water bath that contained 547 or .H
0 9 d H
552 TIP3P water molecules. The initial configurations of water
molecules were taken from a Monte Carlo simulation of TIP3P
water. The walls of the simulated box were chosen to be at least
12 A from the most peripheral solute atoms. In the free energy
perturbation method, the transformation between the two species
involved in the equilibrium is carried out in a number of small
steps involving the coupling parameter A. The molecular me-
.H
chanics energy of the system is expressed in terms of the parameter 122 /H
X as in ref 19. For the tautomeric equilibria studied herein the b @ 1 2 3 1
JYP-6 1141\
transformation involves the simultaneous loss and growth of a \
proton at different nitrogen atoms of the heterocycle. As far as
the molecular mechanics parameters are concerned, the van der
Waals parameters were taken from ref 20, and the intramolecular 11063

parameters for the tautomers were chosen to obtain a good fit H

H ID) H
to the derived 3-21G geometries. The perturbation calculationsz1 11 062 I
were carried out in a series of 21 "windows" where the values of
A differed by 0.05. For each value of A, 500 steps of equilibration
followed by 500 steps of data collection with a time step of 0.002
ps at constant pressure and temperature (300 K)were performed \ I
using periodic boundary conditions. IN1 H/C-N
We have also investigated the usefulness of the reaction field
continuum model (RFCM)22to estimate the solvation effects in Figure 1. Structuresoptimized at 3-21G level: (I) 2H-I,2,3-triade; (11)
1H-l,2,3-triazole; (111) IH-1,2,4-triazole; (IV) 4H-1,2,4-triazole.

(1 I ) Binkley, J. S.;Pople, J. A.; Hehre, W. J. J . Am. Chem. Soc. 1980,
102, 939.
(12) Guest, M. F.; Kendrick, J. GAMESS User Manual, CCP1/86/1;
Daresbury Laboratory, 1986.
(13) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acro 1973, 28, 213.
(14) Mailer, C.; Plessct, M. S. Phys. Reu. 1934, 46, 618.
( I 5 ) Amos, R. D.; Rice, J. E. CADPAC, The Cambridge Analytic Deriva-
tives Package, Issue 4.0; Cambridge, 1987.
(16) Jorgensen, W. L.; Ravimohan, C. J . Chem. Phys. 1985, 83, 3050.
(17) Singh, U. C.; Weiner, P. K.; Caldwell, J. W.; Kollman, P. A. AMBER
(UCSF), Version 3.0; Department of Pharmaceutical Chemistry, University
of California, San Francisco, 1986.
(18) Singh, U. C.; Kollman, P. A. J . Compur. Chem. 1984, 5 , 129.
(19) S i h , U. C.; Brown, F. K.; Bash, P. A.; Kollman, P. A. J . Am. Chem.
Soc. 1987, 109, 1607.
(20) Weiner, S.J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J. Compur.
Chem. 1986, 7, 230.
(21) Cieplak, P.; Bash, P.; Singh, C.; Kollman, P. A. J . Am. Chem. Soc.
1987, 109,6283.
(22) Rein, R.; Renugopalakrishnan, V.; Nir, S.;Swissler, T. J. In!. J .
Quantum Chem. 1975, S2, 99.
the systems studied herein. In this model the solute molecule is
assumed to be a point dipole located at the center of a cavity within
the solvent which is represented as a dielectric continuum. The
interaction of the dipole with the reaction field induced in the
solvent by the dipole itself gives rise to the stabilization. For a
spherical cavity of radius a, and a solute molecule with dipole p
and polarizability a,the energy is
G=- -fP2
-fa)
where
2(E - 1 )
= (26 + 1)a:
Here E is the dielectric constant of the solvent. For the triazole
systems studied here, the calculated dipole moments are scaled
Tautomerism of 1,2,3- and 1,2,4-Triazole
TABLE III: Cdculrted Free Jhergy Differences (W mot') and
Equilibrium Colet~ntsfor Tautomerimtion for I,%> and
1,2&Trirzoks in H20 at 300 K
N H20
in MD
-
tautomer pair
I 11
simuln
547 I
AAG&
I1 - I1
AAG,
I - LId
1/11
I1-
-8.9
I
-5.6 0.5
111- IV 552 -
+9.6
111 IV IV- 111
-16.5
IV
+17.1
- I11
-9.5 & 0.4
by the factor 0.95, as previously discussed, the polarizabilities are
estimated by the method of Miller and Sa~chik:~and a cavity
radius of 3.2 A was assumed for each species.
Computational Results
Gas-Phase Results. Tables I and I1 summarize the results of
the calculations on the isolated triazole molecules as far as en-
ergetics are concerned. The structures optimized at the 3-21G
level are shown in Figure 1. Comparison with the experimental
geometry*' of lH-1,2,4-triazole yields agreement to better than
0.03 A and 2O for bond lengths and angles, respectively. The 2H
tautomer of 1,2,3-triazole and the 1H tautomer of 1,2,4-triazole
are found to be the most stable tautomers, the energy separation
from the less stable tautomer being considerable in both cases.
The use of the larger basis (6-31G**) increases the energy sep-
aration between the tautomers, this effect being particularly
pronounced in the case of 1 ,2,4-triazole0 The energy separations
we obtain at the 3-21G level are similar to the values obtained
from a DZ//(7s3p/3s) cal~ulation.~ The relative stabilities of
the tautomers may be readily understood in terms of the unfa-
vorable lone pair-lone pair repulsion in the less stable tautomers.
Correlation effects estimated at the MP2 level reduce the energy
differences between the tautomers, although this reduction is quite
modest. Such an effect of correlation is not unexpected in view
of the unfavorable electron repulsion effects previously discussed.
Zero-point-energy contributions to the relative stabilities of the
tautomers are smaller than the effects of electron correlation,being
close to 1 kJ mol-' in both systems studied. Our final estimates
- -
of the relative energies of the tautomers in the gas phase (Table
11) allow the equilibrium constants (I 11; 111 IV) involving
the tautomer pairs to be estimated. The values are 2 X for
1,2,3-triazole and 2 X for 1,2,4-triazole,values in line with
the observation that no rare tautomers are detected in the gas
phase.
Solution Studies. In Table I11 we summarize the free energies
and equilibrium constants obtained from the calculationsdescribed
herein. The free energy differences between the tautomers in
solution (AAGtot) were estimated by using the equation
AAGtot = PAC,,, + AEqm+ ASq,,,
Here AAG& is the solvation free energy difference between the
tautomers obtained from the molecular dynamics calculations,
A&,, is the difference in the energy of the isolated tautomers,
including zero-point effects, obtained from ab initio calculations
(Table II), and ASq,,,is the difference in the entropies which could
be calculated by quantum mechanical methods, but which are
generally assumed to be negligible.21We first note that the most
stable tautomer for each system is the same in solution as in the
gas phase. However, the less stable tautomer in the gas phase
(23) Miller, K. J.; Savchik, J. A. J . Am. Chem. Soc. 1979, 101, 7206.
(24) Jeffrey, G. A.: Ruble, J. R.; Yates, J. H. Acta C r p r a h r . 1983,839,
388.
The Journal of Physical Chemistry, Vol. 94, No. 14, 1990 5501
TABLE I V Energy Differems (W mor1)for Tautomers of 1,2,3-
and 1.2.4-Triazoles in H,O Calculated Usinn RFCM
~ ~~~
IV
--
tautomer pair
I1 I
111
AAG&
+21.3
+28.2
AAGtc4
+6.5
+1.9
is preferentially stabilized in aqueous solution on account of its
IO greater dipole moment compared to that of the dominant tautomer
(Table I). Thus for the pair of 1,2,3-triazole tautomers, the energy
III/IV
separation is reduced from 14.8 kJ mol-' in the gas phase to 5.6
kJ mol-' in aqueous solution. For 1,2,4-triazole the reduction is
46
from 26.3 kJ mol-' to 9.5 kJ mol-'. These free energy estimates
lead to equilibrium constants of 10 for 1,2,3-triazole and 46 for
1,2,4-triazole in aqueous solution. The arguments of Albert and
Taylor? with an equilibrium constant of -2 for 1,2,3-triazole
would imply a value of AAGtot near 2 kJ mol-'. However, we
would expect uncertainties of -4 kJ mol-' in the solvation con-
tribution to the free energy differences, so that our calculations
agree extremely well with the conclusions of Albert and Taylor.
As far as comparison with NMR data in the solvents CD2C12and
THF is concerned? our calculationswhich model aqueous solution
should be of relevance in view of the similar dipole moments of
all three solvents. Thus the experimental occurrence of both
tautomers of 1,2,3-triazole in CD2C12and less than 1% of 4H
1,2,4-triazole in THF at -70 "C are in line with our calculated
equilibrium constants (Table 111). The considerably simpler
reaction field continuum model (Table IV) predicts the same
trends as the simulation studies although the calculated solvation
energies are considerably larger in magnitude. This results in an
inversion of the populations of the tautomers on going from the
gas phase to aqueous solution, a result in disagreement with the
conclusions of Albert and Taylor for 1,2,3-triazole and unlikely
in view of the NMR data for 1,2,4-triazole.
Discussion
The results of our quantum mechanical calculations confirm
conclusions of previous studies of tautomeric equilibria that use
of a large basis (6-31G**) is needed to obtain accurate energy
differences and that calculations at a lower level (3-21G) are
probably adequate as far as geometry optimization is concerned.'
Indeed, we find that for both isomers the calculated energy sep-
aration between the tautomer pairs at the 6-31G**//3-21G level
(Table 11) is essentially unaltered at the 6-31G**//6-31G level,25
in agreement with a recent report by Catalan et al.26on 1,2,3-
triazole. We find that correlation effects reduce the energy
separation between the tautomers to a small extent and that
zero-point contributions can be essentially neglected. Similar
conclusions were drawn from our previous calculations of the
tautomers of uraciL2'
The molecular dynamics simulations predict a reduced free
energy separation for both tautomeric pairs upon solvation in
water, in line with experiment. Comparison of our calculated
equilibrium constants with the limited amount of experimental
data available confirms the predictive value of these calculations,
shown by previous studies.21 In contrast, the reaction field con-
tinuum model is found to seriously overestimate solvation energy
differences for at least one of the isomers studied.
Acknowledgment. We thank P. J. Taylor and Dr.C. Reynolds
for helpful discussions and the SERC for support of this research.
These calculations were carried out on the CRAY-XMP/48 of
the Rutherford Appleton Laboratory and on the AMDAHL
VPl 100 of the Manchester Computing Center.
R@hy NO. I, 288-35-7; 11,288-36-8,111,288-88-0; IV, 63598-71-0.
(25) Cox, J. R. Ph.D. Thesis, University of Manchester, 1987.
(26) Catalan, J.; Sanchez-Cabezudo, M.; de Paz, J. L. G.; Elguero, J.;
Taft, R. W.; Anvia, F. J . Compur. Chem. 1989, 10, 426.
(27) Gould, I. R.; Hillier, I. H. J. Chem. Soc., Perkin Trans. 2 1990,329.