Study of the Structure of 1-Hydroxymethylindazole and 1-Hydroxymethylbenzotriazole by X-ray crystallography, Multinuclear NMR in Solution and DFT Calculations

Article abstract of DOI:10.1002/jhet.5570410223

1-Hydroxymethylindazole and 1-hydroxymethylbenzotriazole have been studied in solution by ¹H, ¹³C and ¹⁵N NMR spectroscopy and the X-ray structure of the second compound determined. DFT and GIAO calculations have been used to discuss geometries, energies (comparatively with 2-substituted isomers) and NMR chemical shifts.

Full text of DOI:10.1002/jhet.5570410223

Mar-Apr 2004
285
Study of the Structure of 1-Hydroxymethylindazole and
1-Hydroxymethylbenzotriazole by X-ray crystallography, Multinuclear
NMR in Solution and DFT Calculations
Ibon Alkorta, José Elguero* and Nadine Jagerovic
Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Alain Fruchier
UMR 5076, E.N.S.C.M., 8 rue de l’Ecole Normale, F-34296 Montpellier Cédex 5, France
Glenn P. A. Yap*
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716
Received October 28, 2004
1
1-Hydroxymethylindazole and 1-hydroxymethylbenzotriazole have been studied in solution by H,
13
C
15
and N NMR spectroscopy and the X-ray structure of the second compound determined. DFT and GIAO
calculations have been used to discuss geometries, energies (comparatively with 2-substituted isomers) and
NMR chemical shifts.
J. Heterocyclic Chem., 41, 285 (2004).
The title compounds, 1-hydroxymethylindazole (1) and
Compounds 1 and 2 have had a very different history.
While 1 has been the subject of very few studies [10], the
benzotriazole derivative 2, thanks to Katritzky's chemical
interest, has been reported many times (for a few exam-
ples, see [11-13]). Nevertheless, both have been neglected
as far as structural studies are concerned.
1-hydroxymethylbenzotriazole (2), belong to the class of
aminals, i.e. products of addition of amines to carbonyl
compounds. Due to the aromaticity and good leaving group
character of azoles, these N , N-disubstituted hemiaminals
[1] are only stable when the carbonyl compound is very
reactive, as in the cases of formaldehyde [2] and hexafluo-
roacetone [3,4]. We would like to report in the present work
the structure of the compounds derived from the reaction of
indazole and benzotriazole with formaldehyde.
Crystal Structure of Compound 2.
Crystal data and structure refinement details for com-
pound 2 are reported in Table 4 (see Experimental Part). A
molecular diagram of the crystal structure is presented in
Figure 1. The benzotriazole ring structure is flat, as could
be expected from the aromaticity of the fused benzene ring
and the presence of an N=N double bond in the pentagonal
heterocycle, with the OH of the –CH2OH moiety roughly
Results and Discussion.
Both are known compounds and both are 1-substituted
derivatives 1 and 2 (Scheme 1) [5-8].
The structure of 1 and 2 bears no automatic relationship
with the tautomerism of indazole and benzotriazole (both
1H-tautomers) because the reaction takes place through
the lone pair of the N(2) atom and, besides, the reaction is
under thermodynamic control. That is, 1 and 2 are more
stable than the 2-substituted derivatives, 3 and 4, as in the
parent NH compounds 5 and 6 [9].
Figure 1. Molecular diagram of 2 with 30% probability ellipsoids except
on hydrogen atoms which are depicted as spheres of arbitrary radii.
Selected bond distances (Å), bond angles(º), and torsion angles (º): N(1)-
N(2) 1.3537(19), N(2)-N(3) 1.307(2), N(1)-C(7) 1.462(2); N(2)-N(1)-
C(7) 120.22(13), N(2)-N(1)-C(6) 110.12(13), C(6)-N(1)-C(7)
129.24(14); O-C(7)-N(1)-N(2) –85.63(17), O-C(7)-N(1)-C(6) 86.28(19).

286
I. Alkorta, J. Elguero, N. Jagerovic, A. Fruchier and G. P. A. Yap
Vol. 41
perpendicular to the ring plane. In the pure crystal (the sit-
uation could be different in a solvate [14]), the hydroxyl
group of one molecule acts as a donor in an intermolecular
hydrogen bonding interaction with a neighboring nitrogen
acceptor in the 3-position with a refined interatomic sepa-
ration, -OH···N=N-N, 2.815(2) Å. This is the expected sit-
uation because N(3) is the most basic nitrogen atom in 1H-
benzotriazoles [15].
B3LYP/6-311++G** levels. The results are reported in
Table 2. The conformations gauche (g), gauche' (g') and
anti correspond to the dihedral angle as defined below (the
other dihedral angle, O-C-N-N is always positive and
close to 90º). These conformations were used as starting
geometries. In some cases a minimum was found close to
them, in others the minimum is identical to that obtained
from another starting point.
Since the pure compound crystallizes in a centrosym-
metric space group, the crystal is racemic and both enan-
tiomers are identically present in the solid state. The R and
S enantiomers refer to the H-O-C7-N1 fragment.
1H, 13C and 15N NMR spectroscopy of compounds 1 and
2.
The results are reported in Table 1.
Table 1
Experimental NMR parameters of 1-Hydroxymethylindazole (1) and 1-Hydroxymethyl-benzotriazole (2) in CDCl and DMSO-d
3
6
Compound 1
Compound 2
CDCl
DMSO-d
CDCl
DMSO-d
6
3
6
3
H(3)
H(4)
H(5)
H(6)
H(7)
8.056
7.774
7.241
7.484
7.628
5.897
5.188
8.104
7.783
7.178
7.421
7.728
5.736
6.709
−
−−−
8.107
7.452
7.586
7.743
6.158
3.6 (vb)
(s)
8.056
7.415
7.566
7.913
6.051
3.9 (vb)
(s)
CH
2
OH
(d, J
= 7.8)
(d, J
= 7.4)
CH OH
2
CH OH
2
J
J
J
J
J
J
J
0.9
8.1
1.0
1.0
7.0
0.9
8.5
1.0
−−−
8.4
1.0
1.0
7.1
1.0
8.3
−−−
8.4
1.0
1.0
6.9
1.0
8.3
H(3),H(7)
H(4),H(5)
H(4),H(6)
H(4),H(7)
H(5),H(6)
H(5),H(7)
H(6),H(7)
8.1
1.0
1.0
6.9
0.9
8.5
C(3)
C(3a)
C(4)
C(5)
C(6)
C(7)
C(7a)
134.49
124.35
121.46
121.20
127.25
109.40
139.35
70.94
134.17
125.03
121.64
121.67
127.00
110.96
139.82
71.61
−
−
c
146.38
119.88
124.95
128.21
111.74
133.14
71.09
a
b
b
c
c
c
c
c
c
a
CH
2
c
c
d
c
c
c
c
c
c
d
N(1)
N(2)
N(3)
−180.83 (−203.8)
−60.47 (−57.6)
−139.78 (−161.5)
d
d
−2.95 (−1.1)
−41.03 (−41.0)
d
−
c
−
e d
J
J
J
7.9 (7.6 )
−−−
−−−
2.2
N(1),H(3)
N(2),H(3)
c
c
e d
13.0 (12.8 )
e d
2.7 (2.0 )
N(2),CH
2
a,b
c
These two values may be reversed; The compound is not enough soluble in CDCl; The values between parentheses belong to the corre-
d
e
sponding N-methyl derivatives [16]; These values are from reference [17].
The first conclusion that can be drawn from Table 2 val-
DFT and GIAO Calculations of Compounds 1-4.
ues is that, using the larger basis set without ZPE correc-
The structure of compounds 1-4 was fully optimized (no
imaginary frequencies) at the B3LYP/6-31G* and
tion, in the case of indazole isomers, 1 is more stable than

Mar-Apr 2004
Study of the Structure of 1-Hydroxymethylindazole and
1-Hydroxymethylbenzotriazole
287
Table
2
–1
Absolute Values (hartree), Relative Values and Zero-point Energy (ZPE) in kcal mol and Dipole Moments (in D) for Different
Conformations of Compounds 1-4
Compd.
Conf.
6-31G*
Erel
ZPE
6-311++G**
Erel
µ
1
g'
g
anti
–494.37006
–494.36665
–494.36389
0.00
2.14
3.87
95.26
95.11
94.79
–494.51099
–494.50770
–494.51099
0.00
2.07
0.00
0.87
3
2
4
g'
g
anti
–494.36218
–494.35798
–494.36218
0.00
2.64
0.00
95.25
95.07
95.25
–494.50332
–494.49922
–494. 50332
0.00
2.57
0.00
1.34
g'
g
anti
–510.39000
–510.39382
–510.38787
2.41
0.00
3.74
87.37
87.55
87.12
–510.53463
–510.53822
–510.53314
2.25
0.00
3.19
2.64
1.53
g'
anti
–510.39395
–510.39395
0.00
0.00
87.91
87.91
–510.53857
–510.53857
0.00
0.00
(or 3H). In
3 by 4.81 kcal mol–1, but in the case of benzotriazole 2 is
less stable than 4, although only by 0.22 kcal mol–1.
These compounds, like azolides [9] and Mannich base
derivatives (N-CH2-NRR) [11] exist in equilibrium in
solution but with transformation rates slow enough to
observe both isomers when they exist. Thus, the experi-
mental finding than only 1 and 2 are present in solution
(and also in the solid state for 2 and almost certainly for 1)
must be related to their intrinsic stability and to phase
effects. In the case of the equilibrium 1/3 the difference of
near 5 kcal mol–1 amply justify the presence of 1. In the
case of benzotriazoles 2/4 the calculations predict that both
isomers should have the same stability, in contradiction
with the experimental result.
the gas phase, the population of the 1H- t a u-
tomer increases with temperature [19,20]. More recent
work confirms these findings [21-24]. In the case of ben-
zotriazole at the 6-311++G** level and without ZPE cor-
rection (this work), 6a –395.97098 and 6b –395.97129
hartree, that is the 2H-tautomer is the most stable by
0.20 kcal mol–1. Thus, the differences in energy of the
monomers in the gas phase are almost independent on
the substituent (H or CH2OH) on the nitrogen atom
(compare 4.81/0.22 with 4.91/0.20). Therefore, we pro-
pose the same explanation for the stability of 2 and 6a in
the condensed phases. Besides, in the solid state, the
OH···N(3) hydrogen bond is a possible source of stabil-
ity of 2 because a OH···N(1) HB in isomer 4 should be
much weaker due to the low basicity of 2-substituted
benzotriazoles [15].
It is interesting to remind the results concerning the tau-
tomerism of indazole 5 and benzotriazole 6.
Although there are differences between both basis set
results (88.4 vs. 92.3 kcal mol–1) for compound 1, select-
ing the larger basis set, in the case of indazoles 1 and 3, the
most stable conformation is the g', the anti is not stable and
reverts to the g', and the g is a minimum but is less stable
than the g'. For benzotriazole 2, the three conformations
are minima, the g being the most stable. Benzotriazole 4
has higher symmetry and, in this case only, the g confor-
mation (identical to the g') is stable. If we compare the X-
ray structure of 2 with the two most stable conformations
(the g and g'), the following HOCN and OCNN dihedral
angles are obtained (not considering that all these com-
pounds exist in two enantiomeric forms that correspond to
a sign inversion of both angles): X-ray 81.0/–85.6º, g
68.3/–99.3º, g' –69.6/–90.8º. Therefore, the experimental
structure presents a conformation close to the calculated
minimum.
1H-Indazole (5 a) is experimentally and theoretically
more stable than 2H-indazole (5 b ) [9,18]; at the
B3YLYP/6-311++G** level and without ZPE correction
(this work), 5a –379.94402 and 5b –379.93619 hartree ,
that is the 1H-tautomer is the most stable by 4.91 kcal
mol–1. The much more controversial case of benzotria-
zole tautomerism is well summarized in the literature
[18] (references till 1998): in the gas phase at 0 K the
most stable tautomer is the 2H, 6 b, but in the solid state
and in solution, the only observed tautomer is the 1H, 6 a
The results of GIAO calculations are reported in Table 3.

288
I. Alkorta, J. Elguero, N. Jagerovic, A. Fruchier and G. P. A. Yap
Vol. 41
Table 3
Fourier electron difference map and refined with a riding model.
All other hydrogen atoms were treated as idealized contributions.
Structure factors are contained in the SHELXTL 6.12 program
library [26]. The CIF is available from the Cambridge
Crystallographic Data Centre under the depository number
CCDC 222190.
NMR Absolute Shieldings (σ ppm) of Compounds 1 and 2
Atom
Compd. 1
Compd. 2
H3
H4
H5
H6
H7
23.91
24.02
24.56
24.40
24.28
----
23.64
24.36
24.27
24.18
Table 4
Crystal data and structure refinement details for compound 2
CH
OH
C3
C3a
C4
C5
C6
C7
C7a
CH
N1
N2
N3
26.01/26.25
25.64/26.18
30.27
2
Formula
Formula weight
T, K
Space group
a/Å
C H N O
7 7 3
30.31
43.16
51.01
57.18
56.83
51.60
69.97
37.18
107.08
30.99
–96.65
----
149.16
150(2)
P2 /c
1
7.408(4)
9.924(4)
9.283(4)
94.56(4)
680.2(5)
4, 1
1.456
1.04
4.37
11.58
----
29.18
56.69
54.76
50.50
70.25
44.55
108.62
–10.07
–162.51
–130.18
b/Å
c/Å
β/ º
V/ Å
3
2
Z, Z’
-3
D / g cm
c
-1
µ(Mo-Kα)/cm
a
R(F),%
2
a
R(wF )/%
The comparison of Tables 1 and 3 lead to the following equations:
2
2
2 2
2 2 1/2
[a] Quantity minimized = R(w F ) = {Σ[w(F –F ) ] /Σ(wF ) }
:
2
o
c
o
2
2
2
-1
R(F) = ΣΔ/Σ(F ), Δ = |(F – F )| : w = [σ (F ) + (aP) + bP] :P = [2F
1
2
o
o
c
o
c
δ H (1+2, CDCl ) = (30.8±0.3) – (0.96±0.01)σ, n = 12, r = 0.999
(1)
3
+ Max(F ,0)]/3
1
2
o
δ H (1+2, DMSO-d ) = (30.9±0.4) – (0.96±0.02)σ, n = 12, r = 0.997 (2)
δ C (1, CDCl ) = (173.3±1.2) – (0.92±0.01)σ, n = 9, r = 0.998 (3)
δ C (1+2, DMSO-d ) = (174.2±0.9) – (0.93±0.01)σ, n = 16, r = 0.998 (4)
6
13
2
3
NMR
13
2
6
15
2
δ N (1+2, DMSO-d ) = –(151±3) – (0.90±0.03)σ, n = 5, r = 0.997
(5)
The NMR spectra were recorded on a BRUKER Avance 250
13
spectrometer working at 62.895 MHz for C and 25.355 MHz
6
15
for N, with digital resolution of 0.09 Hz/pt and 0.12 Hz/pt
respectively. Solutions contained about 100 mg of each com-
In the first four equations, the intercepts are relatively
1
close to the GIAO/B3LYP/6-31G* values of TMS ( H
13
pound in 2.5 ml of DMSO-d for recording C and N spectra
15
6
and they were diluted ten times for H. C chemical shifts are
13
15
1
13
32.18, C 189.69), but for N, the intercept is far from
the calculated value for nitromethane (–117.8 ppm at the
same level) but close to the experimental absolute value (σ
= –143 ppm). We have already discussed this problem
related to the difficulty to calculate nitro groups using
basis of medium quality [25]. In any case, the excellent
correlation coefficients prove the consistency of the
assignments. Solvent effects are negligible [compare eqs.
(1) and (2) and (3) and (4)].
15
expressed in ppm from TMS with δ = 77.00 ppm and
CDCl3
chemical shifts are measured in ppm from external NO Me.
N
2
Computations.
Geometries of the stationary structures 1 and 2 were fully opti-
mized at the Becke 3LYP [27,28] theoretical level, with the 6-
31G* [29] and the 6-311++G** basis set [30] as implemented in
the Gaussian 98 program [31]. Harmonic frequency calculations
[32] verified the nature of the stationary points as minima (all real
frequencies). Absolute shielding have been calculated over the
fully optimized geometry within the GIAO approximation [33] at
the B3LYP/6-311++GG** level.
EXPERIMENTAL
Synthesis.
Crystallographic Structural Determination (Table 4).
1-Hydroxymethylindazole (1).
Compound 2 was crystallized by slow evaporation from a sat-
urated solution in methanol solvent. A suitable crystal was
selected, mounted with Paratone oil on a glass fiber and flash-
cooled to the data collection temperature. Data was collected
using a Bruker AXS SMART APEX diffractometer using Mo kα
radiation (λ = 0.71073 Å). Unit cell parameters were obtained
from 60 data frames, 0.3º ω, from three different sections of the
Ewald sphere. Systematic absences in the diffraction data and
unit cell parameters were uniquely consistent with the reported
Indazole (5 g, 42 mmol) are dissolved in 30 mL of 30%
hydrochloric acid, then 3.85 mL of a 30% aqueous solution of
formaldehyde (42 mmol) was added. After 1 h, 30 mL of water
were added and the mixture was kept at room temperature for 1 h.
The precipitate is collected by filtration to give a white solid, mp
116 ºC, lit. mp 115 ºC [5], 113-114 ºC [6].
Anal. Calcd. for C H N O: C, 64.85; H, 5.44; N, 18.91.Found:
8 8 2
C, 64.68; H, 5.41; N, 19.03.
space group P2 /c. The data-set was treated with SADABS
1
1H-Benzotriazole-1-methanol (2).
absorption corrections based on redundant data [26]. All non-
hydrogen atoms were refined with anisotropic displacement para-
meters. The hydroxyl hydrogen atom, H(1), was located from the
Aldrich, 41,023-3, 98% mp 150-152 ºC. Purified by crystal-
lization in water.

Mar-Apr 2004
Study of the Structure of 1-Hydroxymethylindazole and
1-Hydroxymethylbenzotriazole
289
V. Denisko, Adv. Heterocycl. Chem., 76, 157 (2000).
Anal. Calcd. for C H N O: C, 56.37; H, 4.73; N 28.17. Found:
7 7 3
C, 56.42; H, 4.81; N 28.10.
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