Journal of Molecular Structure (Theochem) 680 (2004) 107–115

www.elsevier.com/locate/theochem

DFT studies on tautomerism of C5-substituted 1,2,4-triazoles

Wojciech P. Ozimińskia,*, Jan Cz. Dobrowolskia,b, Aleksander P. Mazureka
a
Laboratory of Theoretical Methods, Calculations and IT, National Institute of Public Health, 30/34 Chełmska Street, 00-725 Warsaw, Poland
b
Industrial Chemistry Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland
Received 9 March 2004; revised 6 May 2004; accepted 6 May 2004

Abstract
DFT (B3LYP/6-311þ þG**, B3PW91/6-311þþG**) Gibbs free energy and single point CCSD(T)/6-311þþ G**//DFT total energy
calculations were performed to investigate stability and tautomerism of C5-substituted 1,2,4-triazoles. Three different tautomers are possible
for the substituted 1,2,4-triazoles: N1– H, N2– H, and N4– H. Unlike for the 1,2,3-triazoles, where the most stable is the N2 – H tautomer
regardless of substituent applied, for the 1,2,4-triazoles, the electron donating substituents ( – OH, – F, –CN, – NH2, and – Cl) and the
C5-cation stablize the N2– H tautomer, whereas the electron withdrawing substituents ( – CONH2, – COOH, – CHO, – BH2, and – CFO) and
the C5-anion stablize the N1 – H tautomer. Except for the C5-anion and C5-cation, the N4– H form is the least stable tautomer. The relative
stability of the C5-substituted 1,2,4-triazole tautomers is strongly influenced by attractive and/or repulsive intramolecular interactions
between substituent and electron donor or electron acceptor centres of the triazole ring.
q 2004 Elsevier B.V. All rights reserved.
Keywords: 1,2,4-Triazole; DFT; Tautomerism; Gibbs free energy; Substituent effect; CCSD(T)

1. Introduction INDO/S-SOS method) and three hypothetical tautomers of

The 1,2,4-triazole ring is a moiety present in many drug
structures (e.g. anastrozole [1,2], estazolam [3,4], ribavirin
[5 – 7], triazolam [8,9], etc.). The C5-substituted 1,2,4-
triazole molecule may exhibit tautomerism: the H(N)
hydrogen atom can be attached either to the N1, or N2, or
N4 atom (Scheme 1).
The 1,2,4-triazole tautomerism was a subject of previous
computational studies [10,11], which showed that the N1 – H
1,2,4-triazole form is more stable than the N4 – H tautomer by
28.22 kJ/mol ([10], HF/6-31G*//HF/6-31G) or 29.78 kJ/mol
(B3P86/6-311G**) [11]. Inclusion of the zero point
vibrational energy correction shifts the energy difference to
22.31 kJ/mol [11]. The computational results are in harmony
with experimental studies for both gas-phase [12,13], crystal
state [14 –16], and dissolved state studied by 15N MMR
[17,18]: the N1 – H tautomer is the only tautomer observed.
Tautomerism of substituted triazoles was also a topic
of several experimental and theoretical papers [19 – 21].
From among three possible tautomers of 5-methylmercapto-
1,2,4-triazoles [19] (considered semiempirically by
* Corresponding author. Tel.: þ 48-2285-14371; fax: þ 48-2284-10652.
E-mail address: wojozim@il.waw.pl (W.P. Ozimiński).
5-methoxy-1,2,4-triazoles [20], the N2 –H form was the
only form observed by 15N MMR method in DMSO solution.
Tautomerism of five-membered heterocycles of import-
ance for pharmacy (substituted azoles) was a subject of
several theoretical and experimental papers published by
our lab [21 – 28] and such systems are in the field of current
interest of many research groups [29 –35]. The aim of this
study is systematic theoretical investigation of substituent
influence on tautomerism of the C5-substituted 1,2,
4-triazoles.
2. Calculation methods
The quantum chemical calculations were carried out with
GAUSSIAN 98 suite of programs [36]. Full geometry
optimizations were carried out using the DFT calculations
with the hybrid exchange-correlation B3LYP and B3PW91
functionals [37 – 42], which differ only by the correlation
EcY term in the functional definitions
Exc ¼ ax0 ExLDA þ ð1 2 ax0 ÞExHF þ ax1 DExB
þ ð1 2 ac ÞEcLDA þ ac EcY ;

0166-1280/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.theochem.2004.05.005
108 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115
Scheme 1.
where E is functional; a is empirical coefficient, subscripts x
and c denote exchange and correlation; superscripts define
method at which exchange or correlation is described:
LDA: local density approximation which uses Slater
expression for exchange [43] and VWN (Vosko, Wilk
and Nusair) expression for the correlation energy of the
uniform gas [44] parametrized using quantum Monte-
Carlo results [45],
HF: indicate true Hartree – Fock exchange ExHF :
(A functional is called hybrid if a coefficient for the
ExHF term is non-zero.)
B (B88): is Becke gradient-corrected exchange func-
tional [37,38].
Y: is either LYP correlation functional (B3LYP
method) [40] or PW91 correlation functional (B3PW91
method) [39].
For correlation functional EcLDA ; the GAUSSIAN 98
program uses VWN functional 3 instead of VWN functional
5 used by Becke [37]. Originally for the B3LYP method, the
three constants ax0 ; ax1 ; and ac were empirically determined
to be equal to 0.80, 0.72, and 0.81, respectively, and the P86
functional was used as the EcLDA correlation functional [37].
The DFT calculations were followed by the single point
CCSD(T) calculations [46] for frozen DFT geometries. The
Pople’s type 6-311þ þ G** basis set was used for all
calculations. [47 –49]. Geometry optimization was achieved
by using redundant coordinate algorithm [50]. For opti-
mized structures, the harmonic vibrational frequencies were
calculated at the DFT levels. This routine allowed
introducing the thermochemical corrections to DG at
298.15 K. There are two main sources of possible error in
our calculations. The first is treatment of the correlation
energy mainly with single point CCSD(T) calculations, the
second is unsaturation of the basis set. However, a better
representation of the basis set is difficult in the case of
noticeable series of molecules studied.
3. Results and discussion
The calculated total, Gibbs free energy at 298 K, and
relative tautomer energy (referred to the relevant lowest
energy form) are gathered in Tables 1 and 2. The substituents
are listed according to decreasing strength of stabilization of
the N1 –H tautomer, or increasing strength of stabilization
of the N2 – H tautomer (Table 2).
The energies (Tables 1 and 2) were calculated using two
DFT methods usually yielding similar results, B3LYP/
6-311þ þ G** and B3PW91/6-311þ þ G** because they
differ only slightly by the part of correlation functional term
(see Section 2). The B3PW91/6-311þ þ G** method
was applied first to enable data comparison between
5-substituted 1,2,4-triazoles and 1,2,3-triazoles [21]. We
checked, however, that with the most widely utilized
B3LYP method, one can generate lower total DFT energies
and, what is even more important, lower total single point
CCSD(T) energies than those yielded by the B3PW91
method. This mean that in terms of reliable CCSD(T)
method, the EcLYP correlation functional describes electron
correlations better than the EcPW91 functional do.
Based on data gathered in Table 1, comparison of the
relative stabilities of the 5-substituted 1,2,4-triazole tauto-
meric forms can be done using three sets of total energy
values, i.e. DFT total energies, DFT Gibbs free energies at
298.15 K, and single point total CCSD(T) energies taken for
frozen DFT geometries. Moreover, these three sets of data
are generated using the two functionals B3LYP and
B3PW91. Notice, that the relative energies (referred to the
lowest energy tautomer) obtained with the B3LYP func-
tional are consistent with those gathered by using the
B3PW91 functional. On the one hand, Gibbs free energy
includes the zero-point vibrational energy and thermo-
chemical terms, both absent in the total energy of molecule,
on the other hand, the CCSD(T) single point approach
describes electron correlation effects more accurately than
the DFT method does. However, except for energies of the
two limit ions, concordance between the DFT relative
energies and the relative Gibbs free energies, as well as the
DFT relative energies and the single point CCSD(T) relative
energies is fair: they usually fall into ^ 1.5 kJ/mol interval
(Table 2). Thus, the molecule order that results from
comparison of these three energetical parameters, as well as
the two functionals, is practically the same.
Now, let us discuss the substituent effect on relative
stabilities of the N1 – H and N2 – H tautomers, keeping in
mind that the N4 –H tautomer energy is always, but for
anion and cation, the highest energy tautomer because of
destabilizing vicinity of two lone electron pairs at the N1
and N2 atoms (see HOMO orbitals of the N4 –H forms,
Fig. 2). The two stabilization limits are determined by
 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115 109

Table 1
Total energies ðEÞ and Gibbs free energy at 298.15 K ðG298 Þ (hartree) for series of the C-5 substituted 1,2,4-triazoles calculated at three levels of theory, i.e.
B3LYP, B3PW91, and single point CCSD(T) combined with the 6-311þ þG** basis set

Substituent Tautomer E single point E single point E E G298 G298

form CCSD(T)//B3LYP CCSD(T)//B3PW91 B3LYP B3PW91 B3LYP B3PW91

Anion N1 2241.098291 2240.243917 2241.707048 2241.608058 2241.687509 2241.588043

N2 2241.069061 2240.209805 2241.678848 2241.579028 2241.661952 2241.561366
N4 2241.085856 2240.228355 2241.694928 2241.595229 2241.676672 2241.576472
–CONH2 N1 2410.081090 2410.080630 2411.088553 2410.926733 2411.032912 2410.870466
N2 2410.073985 2410.073519 2411.080899 2410.919032 2411.025789 2410.863256
N4 2410.072109 2410.071597 2411.079616 2410.917269 2411.024805 2410.861839
–COOH N1 2429.922525 2429.920264 2430.953442 2430.784981 2430.909773 2430.740402
N2 2429.918599 2429.918308 2430.948779 2430.778597 2430.905592 2430.734786
N4 2429.913092 2429.909965 2430.944038 2430.775814 2430.901131 2430.731948
–CHO N1 2354.807328 2354.806860 2355.677670 2355.535480 2355.638119 2355.495460
N2 2354.802910 2354.802790 2355.672457 2355.530661 2355.633274 2355.490903
N4 2354.798762 2354.798249 2355.669296 2355.526608 2355.630410 2355.487269
–BH2 N1 2267.072254 2267.071923 2267.769579 2267.657427 2267.726932 2267.614492
N2 2267.068736 2267.068420 2267.765306 2267.653061 2267.723067 2267.610517
N4 2267.063495 2267.063110 2267.760844 2267.648217 2267.718999 2267.606085
–CFO N1 2453.906301 2453.905893 2454.965251 2454.786816 2454.934394 2454.755403
N2 2453.904933 2453.904895 2454.963218 2454.784983 2454.932723 2454.753830
N4 2453.897025 2453.896562 2454.956057 2454.777105 2454.925917 2454.746414
–NO2 N1 2445.815115 2445.814455 2446.869871 2446.695955 2446.838519 2446.663909
N2 2445.814849 2445.814186 2446.869007 2446.695199 2446.838386 2446.663768
N4 2445.804838 2445.804087 2446.859762 2446.685288 2446.829162 2446.654014
–CH3 N1 2280.934636 2280.934255 2281.654349 2281.545006 2281.597476 2281.488129
N2 2280.934488 2280.934114 2281.654122 2281.544701 2281.595737 2281.485817
N4 2280.924108 2280.923666 2281.643594 2281.533713 2281.585958 2281.475571
–Br N1 2281.362102 2281.362068 22815.85801 22815.74591 22815.83814 22815.72762
N2 2281.362094 2281.362059 22815.85785 22815.74579 22815.83804 22815.72757
N4 2281.360975 2281.360935 22815.84652 22815.73375 22815.82755 22815.71645
–H N1 2241.712702 2241.712355 2242.320445 2242.225409 2242.286993 2242.191513
N2 2241.712702 2241.712355 2242.320445 2242.225409 2242.286993 2242.191513
N4 2241.701964 2241.701586 2242.309585 2242.213952 2242.276421 2242.180361
–Cl N1 2700.776886 2700.776570 2701.937994 2701.790693 2701.916401 2701.768596
N2 2700.777377 2700.777052 2701.938577 2701.791318 2701.916967 2701.769195
N4 2700.765363 2700.764989 2701.926297 2701.778388 2701.905593 2701.757190
–NH2 N1 2296.958386 2296.958032 2297.701964 2297.586748 2297.653641 2297.537833
N2 2296.959362 2296.959028 2297.703271 2297.588039 2297.654798 2297.538983
N4 2296.946771 2296.946353 2297.689518 2297.573746 2297.641927 2297.525594
–CF3 N1 2578.182033 2578.181763 2579.462635 2579.241247 2579.431632 2579.209652
N2 2578.183618 2578.183354 2579.464041 2579.242637 2579.432880 2579.210882
N4 2578.171338 2578.171026 2579.451731 2579.229773 2579.421788 2579.199358
–CN N1 2333.749798 2333.749412 2334.577808 2334.440398 2334.548724 2334.410847
N2 2333.752078 2333.751712 2334.579298 2334.441872 2334.550133 2334.412233
N4 2333.739891 2333.739452 2334.567743 2334.429814 2334.539461 2334.401074
–F N1 2340.786590 2340.786259 2341.583499 2341.451908 2341.559300 2341.427202
N2 2340.789356 2340.789022 2341.586475 2341.454976 2341.562201 2341.430202
N4 2340.774049 2340.773685 2341.570834 2341.438596 2341.547570 2341.414853
–OH N1 2316.794600 2316.794280 2317.563718 2317.440220 2317.528850 2317.404639
N2 2316.803086 2316.802745 2317.572187 2317.448837 2317.535725 2317.411792
N4 2316.793061 2316.792667 2317.561889 2317.437892 2317.526269 2317.401722
Cation N1 2240.643703 2240.642846 2241.236436 2241.140580 2241.219401 2241.124560
N2 2240.661010 2240.660780 2241.255459 2241.159975 2241.236054 2241.140172
N4 2240.649841 2240.649681 2241.237900 2241.141224 2241.220415 2241.123205
110 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115

Table 2
Relative energies (DE; DG298 ; kJ/mol) referred to the relevant lowest energy tautomer for series of the C-5 substituted 1,2,4-triazoles calculated at three levels
of theory, i.e. B3LYP, B3PW91, and single point CCSD(T) combined with the 6-311þ þG** basis set
NBO
Substituent Tautomer DE single point DE single point DE DE DG298 DG298 DEDA
form CCSD(T)//B3LYP CCSD(T)//B3PW91 B3LYP B3PW91 B3LYP B3PW91 B3LYP

Anion N1 0 0 0 0 0 0
N2 76.781 89.605 74.075 76.256 67.133 70.075 –
N4 32.664 40.878 31.837 33.699 28.466 39.680
–CONH2 N1 0 0 0 0 0 0
N2 18.663 18.681 20.105 20.227 18.711 18.938 248.3
N4 23.591 23.728 23.476 24.857 21.295 22.663
–COOH N1 0 0 0 0 0 0
N2 10.313 5.137 12.248 16.769 10.983 14.752 235.4
N4 24.778 27.050 24.703 24.078 22.701 22.207
–CHO N1 0 0 0 0 0 0
N2 11.607 10.690 13.692 12.659 12.727 11.972 249.1
N4 22.501 22.619 21.996 23.304 20.250 21.491
–BH2 N1 0 0 0 0 0 0
N2 9.241 9.201 11.224 11.470 10.153 10.440 242.1
N4 23.010 23.151 22.945 24.191 20.838 22.081
–CFO N1 0 0 0 0 0 0
N2 3.592 2.622 5.339 4.814 4.389 4.132 276.3
N4 24.366 24.512 24.149 25.510 22.267 23.614
–NO2 N1 0 0 0 0 0 0
N2 0.697 0.706 2.269 1.988 0.349 0.368 27.9
N4 26.994 27.235 26.555 28.021 24.579 25.991
–CH3 N1 0 0 0 0 0 0
N2 0.389 0.370 0.596 0.800 4.568 6.074 2.6
N4 27.655 27.814 28.253 29.662 30.255 32.986
–Br N1 0 0 0 0 0 0
N2 0.021 0.024 0.420 0.328 0.247 0.150 32.3
N4 2.960 29.75 30.182 31.957 27.807 29.362
–H N1 0 0 0 0 0 0
N2 0 0 0 0 0 0 211.0
N4 28.207 28.287 28.526 30.094 27.770 27.913
–Cl N1 1.289 1.267 1.5310 1.641 1.487 1.574
N2 0 0 0 0 0 0 62.3
N4 31.557 31.687 32.258 33.966 29.877 31.534
–NH2 N1 2.564 2.617 3.433 3.391 3.039 3.022
N2 0 0 0 0 0 0 106.2
N4 33.074 33.294 36.126 37.545 33.809 35.171
–CF3 N1 4.163 4.179 3.693 3.651 3.278 3.231
N2 0 0 0 0 0 0 243.4
N4 32.257 32.383 32.336 33.791 29.136 30.271
–CN N1 5.989 6.042 3.913 3.872 3.701 3.642
N2 0 0 0 0 0 0 2107.5
N4 32.013 32.203 30.351 31.676 28.033 29.311
–F N1 7.264 7.257 7.815 8.062 7.620 7.882
N2 0 0 0 0 0 0 109.0
N4 40.207 40.287 41.086 43.028 38.433 40.320
–OH N1 22.291 22.234 22.246 22.634 18.059 18.791
N2 0 0 0 0 0 0 128.7
N4 26.334 26.473 27.051 28.750 24.839 26.452
Cation N1 45.462 70.167 50.006 50.947 43.744 41.009
N2 0 0 0 0 0 0 –
N4 29.339 81.787 46.124 49.255 41.080 44.569
NBO
The values derived from Table 1. 1 Hartree ¼ 2626.7861 kJ/mol DEDA (kJ/mol): difference between donor and acceptor substituent properties according
to second order NBO analysis.
 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115 111

the C5-anion (N1 –H) and C5 –cation (N2 –H), where in the
two cases hydrogen is abstracted from the triazole system
either as Hþ or H2 ion. Based on simple lone electron pairs
scheme it is also possible to guess why the N2 – H form is
the most stable for cation (Tables 1 and 2). For this form, the
positive charge ‘localized’ at the C5 atom is in between two
lone electron pairs at the N1 and N4 atoms, while for the
other two tautomeric cation forms (which are quite close in
energy) the positive charge neighbours to only one electron
pair thus the whole system is less stabilized. Analogously,
one can guess why the N1 – H form is the most stable anion
form (Tables 1 and 2). For it there are only two
neighbouring lone electron pairs at the C5 and N4 atoms,
while the N4 –H and N2 – H forms are more destabilized by
vicinity of three electron pairs. However, it is difficult to say
why the N4 – H anion is much more stable than the N2 – H
form. The substituents other than NO2, CH3, Br, and Cl (for
which there is small energy difference between the N1 – H
and N2 – H tautomeric forms) exhibit either apparent
electron withdrawing (top of Table 2) or electron donating
effect (bottom of Table 2). The following substituents (listed
according to decreasing stabilization of the N1 – H tautomer)
exhibit the electron withdrawing effect and stabilize the Fig. 1. The highest occupied p orbitals in electron-withdrawing (BH2) and
N1 – H tautomer: CONH2, COOH, CHO, BH2, CFO. The electron-donating (F) C5-substituted 1,2,4-triazole system (calculations at
the B3PW91/6-311þ þG** level).
following substituents (listed according to decreasing
stabilization of the N2 – H tautomer) exhibit the electron
donating effect and stabilize the N2 –H tautomer: OH, F,
CN, NH2, CF3.
The most electron withdrawing role of the anion, and the
most donating role of the cation is counterintuitive. One
would expect that in case of anion, the electron pair
remaining at the C5 atom could be incorporated into the ring
electron system, thus could play an electron-donating role.
On the other hand, one would assume that the positively
charged C5 atom, should withdraw electrons from the ring.
Yet, the calculations show quite opposite effect: the anion
favours the N1 – H form while the cation stabilizes the
N2 – H tautomer. Thus, the anion acts like very strong
electron withdrawing, whereas the cation acts like very
strong electron donating substituent.
The substituent effect seems to be observable also by
inspection of molecular orbitals (Figs. 1– 4). Comparison of
the HOMO-p and HOMO-s orbitals in the three tautomers
of the 1,2,4-triazole ring (C5-substituted with the electron
withdrawing BH2 group and the electron donating F
substituent) with those in the unsubstituted triazole (Figs. 1
and 2), should allow to connect the substituent effect with
changes of the shape of molecular orbitals. Indeed, for the
electron withdrawing BH2 group, the HOMO-p state is
deformed toward the substituent (Fig. 1), yet, the HOMO-s
state looks like to be unperturbed by the substituent (Fig. 2).
However, for the evidently electron donating F substituent,
both: the HOMO-p and HOMO-s states, seem to be
perturbed only slightly, if not negligibly (Figs. 1 and 2). For Fig. 2. The highest occupied s orbitals in electron-withdrawing (BH2) and
the other groups the effects are not very clear and often electron-donating (F) C5-substituted 1,2,4-triazole system (calculations at
they are also interfered by intramolecular interactions. the B3PW91/6-311þ þG** level).
112 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115
Fig. 3. The highest occupied p orbitals in positively and negatively charged
C5 atom in 1,2,4-triazole system (calculations at the B3PW91/
6-311þ þG** level).
Nevertheless, by looking at Figs. 3 and 4 showing the
HOMO-p and HOMO-s states in cation and anion,
respectively, one can confirm that the negative charge in
anion simulates a very strong electron withdrawing effect,
Fig. 4. The highest occupied s orbitals in positively and negatively charged
C5 atom in 1,2,4-triazole system (calculations at the B3PW91/
6-311þ þG** level).
whereas the positive charge in cation mimics a strong
electron donating substituent. Indeed, the HOMO-p orbitals
of anions are deformed toward exterior of the C5 atom,
while these of cation are like pushed toward interior of the
triazole ring (Fig. 3). An analogous conclusion can be drawn
for the HOMO-s orbitals of anions and cations (Fig. 4).
Finally, we also looked for a correlation of the Natural
Bond Orbitals (NBO) charges with the substituent effect,
however, we found no such relationship. We followed also
the suggestion of the reviewer of this paper and looked
deeper into the second order NBO analysis which express
perturbative donor –acceptor interactions involving a filled
natural bonding orbital with an unfilled antibonding one
(which unlike the Hartree –Fock virtual MO, generally
exhibits non-zero occupancies, contributes to definite
energy reduction, and changes form of the wave function).
We considered three main donor and three main acceptor
NBOs contributions into the second order perturbative
energy lowering caused by donor – acceptor interactions
between NBOs of substituent and 1,2,4-triazole ring system.
(We assumed that the C5-Y orbital belonged to the
substituent Y.) In result we got two energy values which
can be assigned to each substituent estimating its donor and
acceptor properties according to the NBO scheme. The
NBO
difference of these values (DEDA ) were expected to reflect
more quantitativly the substituent effect (Table 2). Indeed,
NBO
the electron withdrawing substituents have negative DEDA
Fig. 5. Dependence of the B3PW91/6-311þþ G** total energy of 1,2,4-
triazoles on rotation of the COOH substituent, relative energies (kJ/mol) are
referred to the most stable conformer.
 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115 113

value, majority of electron donor substituents have positive

DEDANBO
; value, and the weekly interacting substituents have
NBO
intermediate and relatively small DEDA value. Also for
NBO
halogen substituent the DEDA changes consistently: it
increases from Br trough middle value for Cl to the largest
for F substituent. However, there are some irregularities in
the trend: the acceptor properties of the CFO group seem to
be twice as large as for example these of the COOH group
and the CF3 and CN groups which stabilize the N2 – H form
seem to act like electron withdrawing substituents (Table 2).
Moreover, these discrepancies remain when donor and
acceptor contributions of all NBOs of the CFO, CF3, and
CN substituens are taken into account. In conclusion, the
second order NBO analysis of the substituent effect on the
triazoles systems seems to be quite promising and deserves
deeper study. However, because of multitude effects
connected to each of the substituent such a study can hardly
be completed within the frame of this paper.
Beside sheer substituent effect, the other intramolecular
effects influence the tautomer equilibria. The electron
withdrawing and electron donating substituents can form
intramolecular H-bond either as acceptors of the N1 –H or
N4 – H proton, or proton donors to the electron lone pair Fig. 7. Dependence of the B3PW91/6-311þþ G** total energy of 1,2,4-
localized either at the N1 or N4-atom (Figs. 5– 8). Electron triazoles on rotation of the CHO substituent, relative energies (kJ/mol) are
repulsion between substituent and ring atoms, as well as referred to the most stable conformer.
hyperconjugation effects, can also contribute to the
tautomer stabilization or destabilization (Figs. 5 – 8).

Fig. 6. Dependence of the B3PW91/6-311þ þG** total energy of 1,2,4- Fig. 8. Dependence of the B3PW91/6-311þþ G** total energy of 1,2,4-
triazoles on rotation of the CONH2 substituent, relative energies (kJ/mol) triazoles on rotation of the CFO substituent, relative energies (kJ/mol) are
are referred to the most stable conformer. referred to the most stable conformer.
114 W.P. Ozimiński et al. / Journal of Molecular Structure (Theochem) 680 (2004) 107–115
Indeed, from among nine carboxy-substituted 1,2,4-tri-
azoles, the most stable is the N1 –H tautomer stabilized by
two intramolecular hydrogen bonds, namely OH· · ·N4 and
N1 – H· · ·OyC (Fig. 5). The N2 –H carboxy-substituted
1,2,4-triazole tautomers, are all destabilized by the electron
repulsion of either CyO· · ·N4 or CyO· · ·N2 moieties
(Fig. 5), while from among the possible N4 – H forms, the
most stable is again the conformer with two intramolecular
hydrogen bonds (Fig. 5). For the amido-substituted 1,2,
4-triazoles (Fig. 6) as well as those substituted by COH
and COF groups (Figs. 7 and 8) similar conclusions can be
drawn.
4. Conclusions
Unlike for C5-substituted 1,2,3-triazoles, for which the
N2 – H form is the only stable form, in the case of
C5-substituted 1,2,4-triazoles the electron withdrawing
substituents and the C5-anion stabilize the N1 –H tautomer,
and the electron donating substituents and the C5-cation
favor the N2 –H tautomer. Except for the C5-anion and
C5-cation of 1,2,4-triazole, the N4 – H form of the
C5-substituted molecule is the least stable tautomer.
Comparison of the HOMO-p and HOMO-s orbitals in the
three tautomers of the 1,2,4-triazole ring C5-substituted
with the electron withdrawing BH2 group and the electron
donating F substituent with those in the unsubstituted
triazole, allowed us to give an evidence for the substituent
effect. However, for less strongly acting substituents the
analogous change in shape of the HOMO-p and HOMO-s
orbitals is not very obvious and often is interfered by
intramolecular interactions. Thanks to inspection of the
HOMO-p and HOMO-s states we show that influence of
the negative and positive charge at the C5 atom of the 1,2,4-
triazole system is like that which could appear in case of
very strongly acting electron withdrawing and electron
donating substituents, respectively. We found no correlation
between the NBO atomic charges and the substituent effect.
The calculations presented in the paper were done by
using two DFT methods usually yielding similar results,
namely B3LYP/6-311þþG** and B3PW91/6-311þþG**.
We have shown that the most widely utilized B3LYP
method, generates total energies and, what is even more
important, total single point CCSD(T) energies lower than
those yielded by the B3PW91 method.
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