Synthesis, X-ray characterization and computational Studies of N-imidazolyl and N-pyrazolyl pyrimidine derivatives

Article abstract of DOI:10.1016/j.tet.2012.01.023

In this manuscript we report the synthesis and X-ray characterization of neutral 2-(1H-imidazol-1-yl)-pyrimidine (1), 2-(1H-pyrazol-1-yl)-pyrimidine (2) and 1-(2-pyrimidinyl)-1H-benzimidazole (3). We have also obtained crystals of the corresponding hydrochlorides of compounds 1 and 3. Finally, the outer sphere complex of protonated 2-(1H-imidazol-1-yl)-pyrimidine with [CoCl ₄]^2- as counterion is described. In several charged structures interesting anion-π interactions determine the crystal packing. Moreover, in neutral systems some stacking interactions are governed by double lone pair-π interactions. High level ab initio calculations (RI-MP2/def2-TZVP) have been used to evaluate the noncovalent interactions observed in the solid state and the interplay between them.

Full text of DOI:10.1016/j.tet.2012.01.023

Tetrahedron 68 (2012) 2374e2382
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, X-ray characterization and computational Studies of N-imidazolyl and
N-pyrazolyl pyrimidine derivatives
a
a
a
a
,
a
Marta Torres , Pablo Ca n~ ellas , Carolina Estarellas , Angel García-Raso , Juan J. Fiol ,
*
a
a,
b
b
a
*
ꢀ
Francisca M. Albertí , Antonio Frontera , Elies Molins , Ignasi Mata , Pere M. Deya
Departament de Química, Universitat de les Illes Balears, Crta. Valldemossa km 7.5, E-07122 Palma de Mallorca, Baleares, Spain
a
b
Institut de Ci ꢀe ncia dels Materials (CSIC), Campus de la Universitat Aut oꢀ noma, E-0183 Cerdanyola del Vall ꢁe s, Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
In this manuscript we report the synthesis and X-ray characterization of neutral 2-(1H-imidazol-1-yl)-
pyrimidine (1), 2-(1H-pyrazol-1-yl)-pyrimidine (2) and 1-(2-pyrimidinyl)-1H-benzimidazole (3). We
Received 22 November 2011
Received in revised form 3 January 2012
Accepted 11 January 2012
Available online 24 January 2012
have also obtained crystals of the corresponding hydrochlorides of compounds 1 and 3. Finally, the outer
2ꢀ
sphere complex of protonated 2-(1H-imidazol-1-yl)-pyrimidine with [CoCl
scribed. In several charged structures interesting anione
Moreover, in neutral systems some stacking interactions are governed by double lone paire
4
]
as counterion is de-
p
interactions determine the crystal packing.
in-
p
Keywords:
Pyrimidines
Imidazole and benzimidazole
Ab initio calculations
X-ray crystal structures
teractions. High level ab initio calculations (RI-MP2/def2-TZVP) have been used to evaluate the non-
covalent interactions observed in the solid state and the interplay between them.
Ó 2012 Elsevier Ltd. All rights reserved.
Anionep interactions
1. Introduction
chemistry. Matile et al.13 have also published remarkable synthetic
ion channels based on anione
portant role in enzymatic processes has been recently described.
The closely related lone pair (lp)e interactions have been recently
reviewed by Gamez et al., designating the lone paire contacts as
a new supramolecular bond and rigorous analysis of the Cambridge
Structure Database revealed that such contacts are not unusual in
organic compounds, but have been overlooked in the past. Egli et al.
p interactions. In addition, its im-
14
For many years there has been great interest in the chemistry of
pyrazoles, imidazoles, pyrimidines and related N-containing het-
erocyclic derivatives.1 Such systems play a significant role in many
p
,2
15
p
3
biological processes, due to their coordinating ability to metal ions.
The chemistry of transition metals associated with polydentate li-
2
gands with sp hybridised nitrogen atoms has been developed and
very interesting inorganic architectures have been generated using
this approach.4 In particular, ligands designed for this purpose
consist of triazine or pyrimidine moieties attached to one or more
have studied the importance of lone paire
macromolecules (Z-DNA and RNA). Indeed, lone paire in-
teractions have been found to be of great importance for the
stabilization of biological macromolecules, as well as for the bind-
ing of inhibitors in the binding pocket of biochemical receptors.
p
interactions in bio-
16
p
5
pyrazol-1-yl substituents. These architectures are usually gov-
6
17
erned by a variety of noncovalent interactions. These forces in-
7
8
9
clude hydrogen-bonding,
p
p
e
p
stacking, catione
contacts, which are very common and well accepted among
the supramolecular chemists. For around ten years, a new type of
p
and CeH/
We have recently reported that protonated adenines and py-
rimidines are well suited for establishing strong anione
8
b,10
p
in-
ꢀ
ꢀ
ꢀ
2ꢀ
teractions with a variety of anions, including BF
4
, NO
3
, Cl , ZnCl
4
,
11
18
supramolecular interaction, namely anione
p
interaction, has
etc. In this manuscript we report the synthesis of 2-(1H-imidazol-
1-yl)-pyrimidine (imipyr, 1), 2-(1H-pyrazol-1-yl)-pyrimidine (pyr-
apyr, 2) and 1-(2-pyrimidinyl)-1H-benzimidazole (bimipyr, 3).
Their molecular structures in the solid state have been elucidated
by X-ray diffraction analysis. Furthermore, we also report the
synthesis and X-ray characterization of the corresponding hydro-
chlorides of 1 and 3 (compounds 4 and 5, respectively). Moreover,
a multicomponent assembly has been characterized by X-ray
crystallography (compound 6), which consist in a co-crystal of 2
and the nitrate salt of protonated pyrimidin-2-one (see Fig. 1).
been increasingly reported in the literature, notwithstanding the
preliminary improbability of considering repulsive interactions
12
among the aromatic clouds and electron rich molecules. The de-
sign of highly selective anion receptors and channels represent
important advances in this nascent field of supramolecular
*
Corresponding authors. Fax: þ34 971 173426; e-mail addresses: angel.gar-
cia-raso@uib.es (A. García-Raso), toni.frontera@uib.es (A. Frontera).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.023

M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
2375
4
'
obtained by treatment of EtOH/HCl 2 M, intents to prepare the
similar pyrazole hydrochloride have been unsuccessful, yielding
always different mixtures of compound 2 and products derived
from the CeN bond cleavage. In addition, when the reaction time
5
'
'
H
4
'
3'
2'
4' 3'
3'
2'
N
1'
N
N
6
2
'
5
1
'
5'
1
N
N
N
1
'
7'
N
1'
N
Cl
N
1
2
2
2
was 24 h/
only pyrazole and protonated pyrimidinone. In a single experience
at room temperature, 4 h, using HNO 2 M few crystals of the
D the products detected by H NMR spectroscopy were
3
3
1
3
N
N
N
N
4
N
N
N
4
4
3
6
6
6
5
5
2
5
mixture 6 were obtained. A possible explanation of this particular
reactivity of compound 2 is shown in Scheme 2, where a nucleo-
philic attack of a water molecule on C-2 by means of an addi-
tioneelimination mechanism yields the protonated pyrimidinone.
1
3
4
H
H
N
N
O
N
N
N
N
N
Cl
N
–
2–
HN
NH
NO3
CoCl4
N
N
N
N
2
5
6
7
Scheme 2. Plausible mechanism of the unexpected formation of protonated
Fig. 1. Compounds 1e7 reported in this manuscript and the numbering scheme.
pyrimidinone.
ꢁ
Finally, compound 7 was obtained by slow evaporation at 40 C
2
ꢀ
Finally, an outer sphere complex of protonated 1 with CoCl
reported (compound 7). Latter complex and the hydrochloride salt
of 1 exhibit interesting anione interactions in the solid state,
which are important in the crystal packing. The neutral complexes
e3 present different stacking modes that have been analyzed. The
different noncovalent interactions observed in the solid state have
been studied using high level ab initio calculations. The anione
binding properties of the protonated 2-(1H-imidazol-1-yl)-pyrim-
idine via hydrogen-bonding and anione interactions have been
studied using the Molecular Interaction Potential with polarization
MIPp)19 calculations. The MIPp is a convenient tool for predicting
binding properties. It has been successfully used for rationalizing
molecular interactions, such as hydrogen bonding and ione in-
4
is also
2
of a solution of 1 and CoCl , yielding blue crystals suitable for X-ray
analysis.
p
2.2. Crystal structure description of neutral compounds
1
Although compounds 1e3 were previously synthesized,21 their
X-ray characterization is surprisingly missing in the literature. Ac-
tually, X-ray structures of derivatives of 1 and 3 either complexed to
transition metals or alone are not found in the CSD. The ORTEP
diagrams of compounds 1e3 are shown in Fig. 2. Compound 1
crystallizes in the triclinic crystal system and compounds 2 and 3
crystallize in the monoclinic crystal system. The crystallographic
data collection and refinement parameters are listed in Table 1.
p
p
(
p
2
0
teractions and for predicting molecular reactivity.
2
2
. Results and discussion
.1. Synthesis of the compounds
We have synthesized compounds 1e6 using our own developed
methodology by means of the general procedure shown in Scheme
. Compounds 1e3 are easily prepared, in acceptable yields
40e60%), from 2-chloropyrimidine and the corresponding (benzo)
diazole under refluxing conditions in the presence of a base (K CO
or Et N). Dissolution of compound 1 or 3 in EtOH/HCl 2 M yields the
corresponding salts, 4 and 5, respectively.
1
(
2
3
3
Fig. 2. Top: ORTEP diagrams of 1e3. The thermal ellipsoids are drawn at the 50%
probability level. Bottom: stacking modes observed in compounds 1e3.
Scheme 1. Synthetic route to compounds 1e6.
In solid state, compounds 1e3 basically present CeH/N hy-
drogen bonds and
pep stacking interactions. The geometric pa-
rameters of the hydrogen bonds observed in compounds 1e3 are
As can be seen in Scheme 1, although the corresponding hy-
drochloride derivatives of imidazole compounds have been easily
summarized in Table 2. Stacking interactions are characterized by
an antiparallel orientation of the molecules and
a small

2376
M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
Table 1
Crystal data, data collection and structure solution for crystallographically characterized complexes 1e7
1
2
3
4
5
6
7
Formula
M/g mol
C
7
H
6
N
4
C
7
H
6
N
4
C
11
H
8
N
4
C
7
H
9
ClN
4
O
C
11
H
11ClN
4
O
C
11
H
11
N
7
O
4
C
14 4 8
H14Cl CoN
ꢀ
1
146.16
Triclinic
Pꢀ1
146.16
Monoclinic
P 21/n
6.137(4)
10.237(3)
11.377(3)
90
100.25(5)
90
703.3(5)
4
196.21
Monoclinic
P 21/n
7.4280(10)
17.837(7)
7.546(2)
90
112.620(10)
90
200.63
250.79
Triclinic
Pꢀ1
305.27
Monoclinic
P 21/c
6.373(6)
7.688(5)
27.576(3)
90
93.91(3)
90
495.06
Monoclinic
P 21/c
22.515(9)
7.293(4)
12.458(8)
90
79.76(5)
90
Crystal system
Space group
Monoclinic
P 21/n
9.885(3)
5.115(3)
18.807(8)
90
98.90(3)
90
939.5(7)
4
ꢂ
a/A
5.764(4)
7.069(6)
8.840(7)
81.01(4)
80.36(4)
78.35(3)
345.0(5)
2
7.197(4)
9.637(2)
9.750(2)
ꢂ
b/A
ꢂ
c/A
ꢁ
a
b
g
( )
65.052(17)
78.94(3)
73.17(3)
585.0(4)
2
ꢁ
( )
ꢁ
( )
ꢂ
3
V/A
922.9(5)
4
1.412
1348.0(15)
4
1.504
2011.8(19)
4
1.635
Z
ꢀ
r
c
/g cm 3
1.403
1.380
1.418
1.423
Absorption
ꢀ
1
m
/mm
0.094
Empirical
1.000
0.092
Empirical
0.955
0.091
Gaussian
0.989
0.373
None
d
0.315
Gaussian
0.921
0.119
Gaussian
0.961
1.401
Gaussian
0.829
Correction
Max. T
Min. T
0.751
0.883
0.806
1.057
0.939
0.966
d
0.847
1.065
0.9496
1.055
0.669
1.025
GOF of F2
Final R indices [I>2
1.079
s
(I)]
R
1
0.0821
0.1606
0.0431
0.1107
0.0511
0.1102
0.0391
0.1051
0.0430
0.1246
0.0424
0.0994
0.0468
0.1079
wR
R indices (all data)
2
R
wR
1
0.2074
0.192
0.0591
0.1177
0.0903
0.1222
0.0494
0.1092
0.0537
0.1298
0.0680
0.1124
0.0816
0.1277
2
Table 2
Hydrogen bond data for compounds 1e3
X/Y ( ꢂA )
H/Y ( ꢂA )
XeH/Y ( )
ꢁ
Label
Compound 1
C2eH2/N6
C2eH2/N8
C4eH4/N1
C9eH9/N6
C10eH10/N1
Compound 2
C3eH3/N6
C9eH9/N6
C3eH3/N8
C4eH4/N1
C10eH10/N6
Compound 3
C2eH2/N6
C11eH11/N1
C10eH10/N1
C13eH13/N8
C12eH12/N8
3.370(6)
3.497(6)
3.761(7)
3.603(6)
3.532(6)
2.69
2.75
2.91
2.94
2.61
130(3)
137(3)
154(3)
129(3)
167(4)
3.518(3)
3.531(3)
3.567(3)
3.707(3)
3.599(3)
2.88
2.68
2.79
2.80
2.68
128(2)
152(2)
142(2)
158(2)
171(2)
3.319(3)
3.562(3)
3.538(3)
3.820(3)
3.008(3)
2.51
2.73
2.62
2.91
2.52
143(2)
143(2)
164(2)
162(2)
112(2)
Fig. 3. ORTEP diagrams of 4 and 5. The thermal ellipsoids are drawn at the 50%
probability level.
superposition of the heterocycles when the stacking is projected in
the molecular plane, see Fig. 2. These intermolecular interactions
induce the formation of molecular ribbons or tapes, which are ob-
served in the crystal structures (see Supplementary data for details).
Table 3
Hydrogen bond data in compounds 4 and 5
ꢁ
Label
X/Y ( ꢂA )
H/Y ( ꢂA )
XeH/Y ( )
2
.3. Hydrochloride compounds 4 and 5
Compound 4
C4eH4/N8
3.405(3)
3.045(2)
3.398(3)
2.824(2)
3.132(2)
3.439(3)
3.361(3)
3.575(2)
2.52
2.20
2.57
1.98
2.28
2.52
2.60
2.89
157(2)
162(2)
147(2)
174(3)
172(3)
163(2)
137(2)
131(2)
The ORTEP diagrams of the hydrochloride salts are shown in
N1eH1/Cl1
C2eH2/Cl1
OweHw2/Ow
OweHw1/Cl1
C5eH5/Ow
C9eH9/Ow
C11eH11/Cl1
Compound 5
C11eH11/N6
O1eH1A/Cl1
O1eH1B/Cl1
N1eH1/Cl1
C2eH2/O1
Fig. 3. Compounds 4 and 5 crystallize in the monoclinic and triclinic
crystal system, respectively. Selected bond lengths, angles and su-
pramolecular interactions are listed in Table 3 and crystallographic
data collection and refinement parameters are listed in Table 1.
The hydrated salts 4 and 5 forms ribbons along (010) and (001),
respectively, similar to those observed in 3. In compound 4, each
protonated 2-(1H-imidazol-1-yl)-pyrimidine is connected to two
antiparallel molecules by hydrogen bonding and stacking in-
teractions (see Supplementary data for details). In addition, chlo-
rides are situated over the imidazoles, at the side not involved in
2.523(2)
2.530(4)
2.330(4)
2.181(2)
2.536(2)
2.610(2)
2.925(2)
3.34
3.28
3.26
3.05
3.23
3.31
3.74
145(2)
149(4)
173(3)
173(3)
131(2)
133(2)
148(2)
C10eH10/O1
C14eH14/Cl1
stacking, building an interesting anione
p/pep/peanion assembly
(
see Fig. 4, left), which will be further studied below. Moreover,

M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
2377
Fig. 4. Double hydrogen bonding (left) and anione
observed in compound 4.
p/pep/peanion assembly (right)
Fig. 6. X-ray crystallographic fragment of compound 6 with indication of the anione
p/
ꢂ
pep
assembly. Distances in A.
apart from the CeH/N hydrogen bonds observed in the neutral
compounds a network of hydrogen bonds involving two 2-(1H-
imidazol-1-yl)-pyrimidine molecules and two Cl atoms is ob-
2L
2.5. CoCl
4
complex 7
ꢀ
served (see Fig. 4, left). A similar supramolecular organization has
been recently observed by Domasevitch and collaborators in
bipyrazolium salts, which is originated by strong hydrogen bonding
between multiple NH cationic donors and O, F, Cl, I anionic
acceptors.22
The ORTEP diagram of compound 7, which crystallizes in the
monoclinic crystal system, is shown in Fig. 7. Selected bond lengths,
angles and supramolecular interactions are listed in Table 4 and
crystallographic data collection and refinement parameters are
listed in Table 1.
2
.4. Compound 6
In an effort to obtain the solid state structure of a salt of com-
pound 2, we have tried several strategies, using a variety of acidic
conditions. However, in sharp contrast to compounds 1 and 3, it has
been impossible to obtain the corresponding salt of 2. In one of
these attempts, using nitric acid, we have obtained an unexpected
compound, which is a co-crystal of 2 and the nitrate salt of pyr-
imidin-2-one (see Fig. 5).
Fig. 7. ORTEP diagrams of 7. The thermal ellipsoids are drawn at the 50% probability
level.
Table 4
Hydrogen bond data in compound 7
X/Y ( ꢂA )
H/Y ( ꢂA )
XeH/Y ( )
ꢁ
Label
C4BeH4B/N6B
C11BeH11B/N8B
C4AeH4A/N6A
C11AeH11A/N8A
N1AeH1A/Cl3
C2AeH2A/Cl2
N1BeH2B/Cl2
C2BeH2B/Cl3
C10AeH10A/Cl2
C5AeH5A/Cl1
C9BeH9B/Cl1
C10BeH10B/Cl3
3.591(6)
3.594(7)
3.702(7)
3.786(7)
3.312(4)
3.585(5)
3.082(4)
3.699(5)
3.448(5)
3.343(5)
3.452(5)
3.736(5)
2.73
2.71
2.87
3.09
2.54
2.72
2.26
2.86
2.70
2.72
2.80
2.88
155(4)
159(4)
151(4)
133(4)
140(4)
156(4)
166(5)
152(4)
137(4)
126(4)
128(4)
156(4)
Fig. 5. ORTEP diagrams of 6. The thermal ellipsoids are drawn at the 50% probability
level.
4
The asymmetric unit in compound 7 consists of one CoCl anion
In the solid state architecture of compound 6 we have found
an interesting anionep/pep supramolecular assembly, where
the protonated pyrimidin-2-one interacts simultaneously with
nitrate anion at one side of the ring and with the pyrazol ring of 2
and two symmetry independent and protonated 2-(1H-imidazol-1-
yl)-pyrimidine molecules (A and B) in antiparallel conformation. In
the crystal structure, each one of these molecules forms layers
2
ꢀ
intercalated between these
parallel to the (100) plane, being CoCl
layers (Fig. 8). Thus, the succession of layers along (100) consists of
4
at the opposite side (see Fig. 6). The intermolecular distances
ꢂ
2ꢀ
2ꢀ
observed for the anione
p
and
p
ep
are short (3.33 and 3.35 A,
A, CoCl
4
, B, CoCl
4
. Molecule B layers are formed by corrugated
ꢁ
respectively) indicating that the interactions are strong, which is
due to the cationic nature of the protonated pyrimidin-2-one
ring, which reinforces both interactions due to electrostatic
effects.
tapes (angle between molecular planes 46.4 ) along (001), being
the pyrimidine of one molecule connected to the next by two
CeH/N hydrogen bonds. The shorter stacking (3.337 A) is part of
ꢂ
an interesting anionep/pep/peanion assembly involving two

2378
M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
Table 5
Interaction energies without and with the basis set superposition error (E and EBSSE
respectively, in kcal/mol) and distances (R, A) of several dimers at RI-MP2/def2-TZVP
,
ꢂ
level of theory
Dimer
E
E
BSSE
R
1
1
2
3
3
, Short stack.
, Long stack.
ꢀ13.9
ꢀ15.2
ꢀ13.1
ꢀ18.8
ꢀ18.2
ꢀ12.1
ꢀ7.2
ꢀ11.4
ꢀ12.7
ꢀ10.7
ꢀ15.2
ꢀ14.6
ꢀ9.5
3.40
3.55
3.47
3.40
3.53
3.35
3.24
3.24
, Short stack.
, Long stack.
CEWVOQ
TIGLUR
YOLXAZ
ꢀ5.1
ꢀ12.6
ꢀ9.5
Fig. 8. Top: Crystal packing along (100) in compound 7, with indication of the layers
that are perpendicular to the horizontal and parallel to the vertical directions.
2
ꢀ
in different layers, with the Cl atoms over the imidazole
established. We have examined the CSD searching related com-
pounds to learn if this binding mode is also present in other
structures. We have searched fragments consisting in a pyrimidine
molecule with either an imidazo-1-yl or a pyrazo-1-yl substituent
in position 2. Other restrictions have not been imposed. There are
only 37 structures in the database and all of them correspond to 2-
CoCl
4
ꢂ
rings (3.144 A). One of these assemblies (for B molecule) is high-
lighted in Fig. 9. The distances are measured from the ring centroid
to the closest chlorine atom of the anion.
(1H-pyrazol-1-yl)-pyrimidine derivatives. Therefore the X-ray
structures of 2-(1H-imidazol-1-yl)-pyrimidine derivatives reported
herein are unprecedented in the CSD. Most of the 37 structures are
metal complexes and only 13 structures correspond to neutral
molecules. In some of them we have found stacking interactions
that present the double lpep binding mode. Some selected ex-
amples are shown in Fig. 10. We have computed the interaction
2
3
24
25
energies of the dimers of CEWVOQ, TIGLUR and YOLXAZ. We
have used models where the substituents have been replaced by
hydrogen atoms, in order to study the stacking energies free from
other influences. The interaction energies are also included in Table
5. The stacking mode observed for 1 is slightly more favourable
than the observed in CEWVOQ and YOLXAZ. The TIGLUR presents
the least favourable interaction energy.
Fig. 9. Anione
tances in A.
pep
eanion assembly observed in the crystal packing along of 7. Dis-
ꢂ
2
.6. Theoretical ab initio study
We have divided this section into two parts. First we focused our
study in the stacking features of the neutral compounds, including
a comparison with similar compounds found in the CSD. Second,
Fig. 10. On top representation of X-ray structures showing double lpe
p interactions.
we study the energetic characteristics of the anione
p and H-
bonding interactions found in two charged compounds and their
mutual influence.
We have also studied the energetic features of the hydrogen
bonded dimers observed in the solid state in compounds 1 and 3,
where four CeH/N H-bonds are formed using a different combi-
nation of hydrogen bonds (see Fig. 11). The interaction energies of
both dimers are gathered in Table 6. It can be observed that the
interaction energy of compound 3 is 1 kcal/mol more favourable
than compound 1, in agreement with the H-bonding distances. In
fact compound 1 exhibits a very long H-bond distance in one
2.6.1. Neutral compounds. First we have analyzed the energetic
features of the stacked dimers observed in the solid state of com-
pounds 1e3 (see Fig. 3). In Table 5 we summarize the binding en-
ergies and distances of several dimers. It can be observed that
dimer 3 is the most favourable probably because it has a more
ꢂ
extended
very favourable. In 1 (long stacking) there is a very small super-
position of the systems, however it can be observed that the
p-system. Both stacking modes observed in 1 are also
CeH/N bond (2.99 A). We have also computed the distribution of
critical points (CP) using the Bader’s theory of ‘atoms in molecules’.
Both dimers are characterized by the presence of four bond CPs
connecting the hydrogen atoms with the nitrogen atoms. As
a consequence two ring CPs raise. The values of the charge density
at the ring CPs are also included in Table 6. It can be appreciated
that the value at the ring CP in dimer 3 is greater than 1, in
agreement with the interaction energies.
p
nitrogen atoms are exactly over the carbon atoms and vice versa,
maximizing the electrostatic interactions and giving stability to the
complex. In 1 (short stacking) there is a higher superposition of the
p
systems. As aforementioned, this dimer can be also viewed as
a special stacking arrangement, where two lpe interactions are
p

M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
2379
to the MIPp method and indicates that the position of the anion in
the crystal structure depends on this interaction and probably the
final position over this countour line comes from the other non-
covalent forces. The lowest isocontour line observed in the 2D-
MIPp map reflects a very flat potential surface. This fact agrees with
the experimental results and the Hirshfeld surfaces (see
Supplementary data) that indicate the undirectionality of the
anione
We have also analyzed the influence of the formation of the
hydrogen bonded dimer on the anione interaction. We have first
computed the interaction energy of the anione complex where
only one protonated 2-(1H-imidazol-1-yl)-pyrimidine is present
4A, see Fig. 13). Secondly, we have computed the interaction en-
p interaction in compound 4.
Fig. 11. H-bonded dimers of 1 and 3. Right: bond (red) and ring (yellow) critical points
distribution in 1 and 3.
p
p
Table 6
(
Interaction energies without and with the basis set superposition error (E and EBSSE
,
ꢂ
ergy in complex 4B where the hydrogen bonded dimer interacts
with the chloride anion. The computed interaction energies are
respectively, in kcal/mol) and distances (R, A) of H-bonded dimers 1 and 3 at RI-
MP2/def2-TZVP level of theory. The values of the charge density at the ring critical
points (RCP) are also included in au
gathered in Table 7 (first and second columns). The anione
teraction energy (EBSSE) computed considering that the dimer
interacting with the chloride ions located at the molecular plane)
has been previously formed (4B) is almost 10 kcal/mol more
favourable than the anione interaction considering only the
monomer (4A), indicating that the presence of the double CeH/N
hydrogen bond strengthens the anione interaction. We also in-
p in-
Dimer
E
E
BSSE
R
r
RCP (a)
rRCP (b)
(
1
3
ꢀ8.28
ꢀ9.35
ꢀ7.20
ꢀ8.10
2.65/2.99
2.51/2.73
0.1604
0.2413
0.2438
0.3558
p
2.6.2. Charged compounds. From the X-ray analysis of 4, an in-
p
teresting anione /anione assembly (see Fig. 4, right) has
been observed, that is, very important in determining the solid
state structure of this compound. We have first studied if the po-
p
/
p
e
p
p
clude in Table 7 the energetic results obtained with the MIPp
method for the two systems considered, which are in reasonably
agreement with the E values obtained at the RI-MP2/def2-TZVP
level of theory. Taking advantage of the MIPp method that gives
sition of the anion over the ring is dominated by the anione
p in-
teraction or, on the contrary, it is due to the other interactions
established by the anion. To shed light to this question, we have
computed the Molecular Interaction Potential with polarization
an intuitive partition of the total interaction energy (E
components (see computational details), we have studied the
physical nature of the anione interaction to know, which term is
t
) into three
p
(
MIPp) of a crystal fragment consisting of a H-bonded dimer of the
responsible of the strengthening of the interaction by the presence
of the hydrogen bonds. It can be observed that the polarization and
protonated 2-(1H-imidazol-1-yl)-pyrimidine moiety interacting
with two chloride anions in order to have a neutral system (see
Fig. 12). We have computed the bidimensional (2D) energy map of
van der Waals terms (E
4B. In addition in 4A the total interaction energy is dominated by
the electrostatic (E ) and E terms. In contrast, in 4B the electro-
p
and Evw, respectively) are similar in 4A and
ꢂ
this fragment interacting with chloride at 3.0 A above the molecular
e
p
plane in order to study the spatial regions where the
p
-interaction
static term is very important and clearly dominates the interaction
and it is the responsible of the strengthening of the interaction.
ꢀ
with Cl is more favourable. The 2D-MIPp map computed for the
ꢀ
interaction of a fragment of 4 with Cl is shown in Fig. 12. It can be
observed that there is a wide region where the lowest interaction
potential isocontour line is located (red line). It can be appreciated
the location of the chloride anion in the crystal structure (see Fig. 4
and the on-top representation in the top-left corner of Fig. 12) co-
incides with the lowest isocountour line. This result gives reliability
Fig. 13. Anione
p
complexes 4A and 4B.
Table 7
ꢂ
Interaction energies (kcal/mol) and distances (R, A) of H-bonded dimers 4A and 4B
at RI-MP2/def2-TZVP level of theory. The values of the MIPp terms in kcal/mol are
also included
Complex
E
E
BSSE
E
e
E
p
E
vw
E
t
4
4
A
B
ꢀ22.3
ꢀ33.4
ꢀ20.1
ꢀ29.7
ꢀ11.1
ꢀ24.8
ꢀ9.7
ꢀ1.5
ꢀ1.6
ꢀ22.3
ꢀ37.1
ꢀ10.7
Finally, we have studied computationally the noncovalent in-
teractions observed in compound 7, focussing the analysis in the
influence of the hydrogen bonding interactions upon the anione
interactions. Both interactions are crucial in the crystal packing of 7.
p
2
ꢀ
ꢀ
In fact the CoCl
4
anion is stabilized by two double Cl /HeN and
ꢀ
Cl /HeC hydrogen bonds and two anione
Fig. 14, bottom right). As expected the Cl /HeN hydrogen bonds
are shorter than the Cl /HeC ones. The anione
p interactions (see
ꢀ
ꢀ
p distances are
ꢀ
ꢂ
Fig. 12. 2D-MIPp(Cl ) energy map of 4 at a plane located at 3.0 A above the molecular
slightly different and both are established by means of the five-
membered ring. We have evaluated the interaction energy of the
plane. Isocontour lines are drawn ever 5 kcal/mol apart from the lowest isocontour line
(
red line, ꢀ39 kcal/mol). Positive values of potential are represented by solid lines and
negative values by dashed lines.
anione
p contacts using two equations (see Fig. 14) in order to

2380
M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
analyses were carried out using Carlo-Erba models 1106 and 1108
and Thermo Finigan Flash 1112 microanalysers. Infrared spectra
KBr pellets) were recorded on a Bruker AMX 300 spectrometer.
Proton and carbon chemical shifts in dimethyl sulfoxide solution
(
1
(
2
DMSO-d
.50; C NMR
6
) were referenced to DMSO-d
6
itself [ H NMR,
d
(DMSO)¼
13
d
(DMSO)¼39.5 ppm]. Thermogravimetric data in the
ꢁ
temperature range from 30 to 700 C were recorded in a flowing air
ꢁ
ꢀ1
atmosphere (heating rate 5 C min ) on a TA Instruments SDT
2
4
4
960 Simultaneous DSC-TGA thermobalance.
.2. Preparation of the compounds
.2.1. 2-(1H-Imidazol-1-yl)-pyrimidine (1). A suspension of 2-
chloropyrimidine (1.15 g, 9.5 mmol) and 0.65 g of imidazole
(
9.5 mmol) in n-butanol (20 ml) and triethylamine (2 ml) were
ꢁ
heated (vigorous reflux) using an external oil bath at 160 C during
24 h. While the reaction is going on the orange suspension is
transformed into a brown solution. After standing and cooling the
solution, precipitation of triethylammonium hydrochloride may
occur. In this case, the precipitate was filtered off. In any case, the
resulting solution was evaporated to dryness and the resulting solid
washed with cold water and dried (60%). Recrystallisation from
diethyl ether yield white monocrystals. (Found: C: 56.27; H: 4.46;
Fig. 14. Several fragments of the crystal structure of compound 7 and the reactions
ꢂ
used to evaluate the anione
p
interaction. Distances in A.
N: 36.11%. Calcd for C
7
H
6
N
4
$0.33(H
2
O) C: 56.26; H: 4.42; N:
evaluate the influence of the hydrogen bonds. We have first com-
puted the anione interaction energy between a neutral fragment
of the crystal structure and CoCl
energy of this assembly is ꢀ39.5 kcal/mol. This value is probably
overestimated, since the anion is also interacting via hydrogen
bonding to other two protonated 2-(1H-imidazol-1-yl)-pyrimidine
ꢀ1
36.82%). IR (cm ): 1577s, 1570s, 1480s, 1446s, 1333m, 1092w,
p
1
2
ꢀ
(Fig. 14, top). The interaction
1053m, 791m, 751m, 650m, 635m, 618w, 515w, 482m. H NMR,
4
d
(300 MHz; DMSO-d
6
): 8.85d [2H, J¼4.8 Hz; C4-H, C6-H], 8.56s [1H,
0
0
0
C2 -H], 7.93s [1H, C5 -H], 7.43t [1H, J¼4.8 Hz, C5-H], 7.13s [1H, C4 -
1
3
H]. C NMR
d
(75 MHz; DMSO-d
6
): 160.1 [C6, C4], 154.4 [C2], 136.1
0
0
0
[C2 ], 131.0 [C4 ], 120.3 [C5], 117.2 [C5 ] (see Fig. 1 for the numbering
moieties. When the anione
p interaction is evaluated using a sec-
scheme).
ond model where both interacting parts are uncharged (see Fig. 14,
bottom) the binding energy is reduced to ꢀ13.10 kcal/mol. There-
fore the consideration of the ‘naked’ anion in the calculations
overestimates the interaction energy. The intricate combination of
4
(
1
1
.2.2. 2-(1H-Pyrazol-1-yl)-pyrimidine
1.39 g, 10 mmol) was added to a solution of pyrazole (0.68 g,
0.0 mmol) in 15 ml of DMF and stirred at room temperature during
5 min. 2-Chloropyrimidine (1.15 g, 10.0 mmol) was added and the
(2). Anhydrous
2 3
K CO
hydrogen bonding, anionep and pep stacking interactions is re-
sponsible of the unexpected 3D architecture observed in the solid
state of this interesting structure.
suspension refluxed during 24 h. The resulting solids were filtered
off at room temperature to remove the impurities and the mother
solution was evaporated in vacuum to yield a syrup, which is
extracted with diethyl ether (3ꢂ20 ml) and after, newly, evaporated
in vacuum. The resulting oil was, finally, purified by flash chro-
3
. Conclusions
To conclude, we have synthesized and X-ray characterized
several imidazolyl, pyrazolyl and benzimidazolyl derivatives of
pyrimidine that illustrate the importance of anione and
matography (CHCl
evaporation of the solvent. (Found: C: 57.32; H: 4.16; N: 38.20%.
Calcd for C H N C: 57.53; H: 4.14; N: 38.34%). IR (cm ): 1569s,
7 6 4
1523m, 1558s, 1435s, 1400s, 1346m, 1309m, 1261m, 1217m, 1192m,
1146m, 1074w, 1051m, 1035m, 989m, 931s, 910m, 863w, 826m,
3 2
/SiO ). A white solid (0.58 g, 40%) is obtained by
p, pep
ꢀ
1
hydrogen bonding interactions in supramolecular chemistry.
Moreover, we have evaluated the energy of several noncovalent
interactions involved in the crystal structure architecture of the
compounds by using high level ab initio calculations. In addition,
the 2D-MIPp energy maps are in good agreement with the X-ray
structures, since they are able to predict the spatial regions where
the interaction of the anion with the ring is more favourable. Using
MIPp calculation we have also studied the influence of the hydro-
1
791m, 767m, 736m, 650m, 633m, 609m, 541m, 476m. H NMR,
d
(300 MHz; DMSO-d
6
): 8.91d [2H, J¼4.8 Hz; C4-H, C6-H], 8.70d [1H,
0
0
J¼7.8 Hz; C5 -H], 7.91br s [1H, C3 -H], 7,52t [1H, J¼4.8 Hz; C5-H],
0
13
6.65br s [1H, C4 -H] C NMR
d
(75 MHz; DMSO-d
6
): 159.8 [C6, C4],
0
0
0
155.8 [C2], 143.8 [C3 ], 129.9 [C5 ], 120.0 [C5], 109.2 [C4 ].
gen bonded dimers on the anione
Interestingly, the partition of the energy indicates that electrostatic
effects are responsible of the anione enhancement. Finally, in-
depth understanding of weak intermolecular forces that govern
crystal packing potentially allows a rational design of solids with
tailored physical and chemical properties. The results described
above are certainly of importance in this regard and helps to gain
knowledge in this emerging area of supramolecular chemistry.
p interactions in compound 1.
4.2.3. 2-(1H-Benzimidazol-1-yl)-pyrimidine (3). A suspension of 2-
chloropyrimidine (0.58 g, 5 mmol) and 0.61 g of benzimidazole
(5 mmol) in n-butanol (10 ml) and triethylamine (1 ml) were
p
ꢁ
heated (vigorous reflux) using an external oil bath at 160 C during
24 h. The initial orange suspension is transformed into a brown
solution. After standing and cooling the solution, precipitation of
triethylammonium hydrochloride was obtained, which was filtered
off. The resulting solution was evaporated in vacuum to dryness
and the resulting solid washed with cold water and vacuum dried
4
4
. Experimental section
(
40%). (Found: C: 67.16; H: 4.12; N: 28.63%. Calcd for C11
H
8
N
4
C:
ꢀ
1
.1. Material and measurements
67.34; H: 4.11; N: 28.55%). IR (cm ): 1570s, 1498s, 1464s, 1440s,
1
431s, 1320s, 1299s, 1248s, 1204s, 1003w, 888m, 830s, 793s, 766s,
1
Chemicals and solvents were purchased from commercial
sources (Sigma and Aldrich) and were used as received. Elemental
742s, 640m, 583m, 510m, 424m. H NMR,
9.08s [1H, C2 -H], 8.93d [2H, J¼4.8 Hz; C4-H, C6-H], 8.53d [1H,
d
(300 MHz; DMSO-d
6
):
0

M. Torres et al. / Tetrahedron 68 (2012) 2374e2382
2381
0
0
J¼7.8 Hz; C4 -H], 7.76d [1H, J¼7.8 Hz; C7 -H], 7.48t [1H, J¼4.8 Hz;
contributions of the non-covalent interactions observed in the solid
state. Other possible conformations of the crystal fragments have
not been considered because the ultimate aim of this study is to
analyze the binding properties of the non-covalent interaction in
the geometry that they have in the solid state. This approximation
0
0
C5-H], 7.41t [1H, J¼7.8 Hz, C5 -H], 7.34t [1H, J¼7.8 Hz, C6 -H].
4
(
.2.4. 2-(1H-Imidazol-1-yl)-pyrimidine hydrochloride monohydrate
4). Dissolution of (1) in EtOH/HCl 2 M yields the corresponding
salt as suitable crystals for X-ray difracction. (Found: C: 41.89; H:
.41; N: 27.73%. Calcd for C
2
8
29
has been successfully used by some of us and others to evaluate
non-covalent interactions in the solid state. The partition of the
interaction energies into the individual electrostatic, polarization,
dispersion, and repulsion components has been carried out by
performing Molecular Interaction Potential with polarization
4
2
H
7 7
N
4
Cl$H
2
O C: 41.91; H: 4.52; N:
ꢀ
1
7.53%). IR (cm ): 1630w, 1590s, 1566m, 1530s, 1421s, 1353m,
1
4
8
128w, 1043m, 969w, 833m, 791m, 768s, 737m, 633s, 508w, 482m,
18s, 386w. 1H NMR,
d(300 MHz; DMSO-d ): 9.70s [1H, C2 -H],
0
6
0
0
19
.98d [2H, J¼4.8 Hz; C4-H, C6-H], 8.31s [1H, C5 -H], 7.72s [1H, C4 -
(MIPp), which is an improved generalization of the Molecular
1
3
H], 7.68t [1H, J¼4.8 Hz, C5-H]. C NMR
d
(75 MHz; DMSO-d
6
): 160.4
Electrostatic Potential (MEP) where three terms contribute to the
0
0
0
30
[
C6, C4], 153.0 [C2], 135.5 [C2 ], 122.6 [C5, C5 ], 119.12 [C4 ].
interaction energy, (i) an electrostatic term identical to the MEP,
(
ii) a classical dispersionerepulsion term, and (iii) a polarization
31
4
.2.5. 2-(1H-Benzimidazol-1-yl)-pyrimidine hydrochloride$1.3H
2
O
term derived from perturbation theory. The MIPp calculations
have been performed by means of the MOPETE-98 program. To
analyze the intermolecular interactions, the Atoms-In-Molecules
(AIM) theory was employed. AIM is based upon those critical
points where the gradient of the density, , vanishes. Such points
3
2
(5). A solution of 60 mg of (3) in 12 ml of HCl 2 M in EtOH was
refluxed during 30 min. Evaporation of the final solution at room
temperature yields the corresponding crystals (40%). (Found: C:
3
3
5
1.55; H: 4.29; N: 21.65%. Calcd for C11
H
9
ClN
4
$1.3H
2
O C: 51.59; H:
7
r
ꢀ1
4
.57; N: 21.88%). IR (cm ): 1637w, 1619m, 1528m, 1449s, 1391s,
are classified by the curvature of the electron density, for example,
a bond critical point has one positive curvature (in the internuclear
direction) and two negative ones (perpendicular to the bond). Two
bonded atoms are then connected with a bond path through the
bond critical point. The properties evaluated at such bond critical
points characterize the bonding interactions. They have been
1
272w, 1232m, 1004w, 938w, 800m, 755s, 621m, 601m, 538w,
1
0
416m. H NMR,
d
(300 MHz; DMSO-d
6
): 9.66s [1H, C2 -H], 8.99d [2H,
0
J¼4.8 Hz; C4-H, C6-H], 8.60d [1H, J¼7.8 Hz, C4 -H], 7.84d [1H,
0
0
J¼7.8 Hz; C7 -H], 7.58t [1H, J¼4.8 Hz; C5-H], 7.53t [1H, J¼7.8 Hz, C5 -
0
13
H], 7.49t [1H, J¼7.8 Hz, C6 -H]. C NMR
6
d(75 MHz; DMSO-d ): 160.0
0
0
0
34
[C6, C4]; 155.5 [C2], 142.4 [C2 ], 140.2 [C8 ], 126.1 [C9 ], 120.5 [C5],
widely used to study a great variety of molecular interactions.
0
0
118.7 [C7 ], 116.5 [C4 ].
Acknowledgements
4.2.6. Mixture of 2-(1H-pyrazol-1-yl)-pyrimidine and protonated
pyrimidinone nitrate (1:1)(6). A solution of 63 mg (4.3 mmol) of (2)
in 10 ml of HNO 2 M was stirred at room temperature during 4 h.
Slow evaporation at room temperature yield two single crystals,
We thank CONSOLIDER-Ingenio 2010 (CSD2010-0065) and the
MICINN of Spain (project CTQ2008-00841/BQU, FEDER funds) for
financial support. C.E. thanks the MICINN of Spain for a fellowship.
We thank the CESCA for computational facilities.
3
suitable for X-ray diffraction, which correspond to the mixture (6).
1
H NMR,
d
(300 MHz; DMSO-d
6
): 8.91d [2H, J¼4.8 Hz; C4-H, C6-H],
0
8
.71br d [2H, C4-H, C6-H protonated pyrimidone and C5 -H], 7.91br
Supplementary data
0
s [1H, C3 -H], 7.52t [1H, J¼4.8 Hz; C5-H], 6.78t [1H, J¼4.8 Hz; C5-H
0
protonated pyrimidone], 6.65br s [1H, C4 -H].
The supplementary file includes a more detailed description of
the crystal packing characteristics of compounds 1e7 and the cal-
culation of the Hirshfeld surfaces of the compounds. Supplemen-
tary data related to this article can be found online at doi:10.1016/
j.tet.2012.01.023.
4.2.7. 2-(1H,3H-Imidazol-1-yl)-pyrimidine tetrachloridecobaltate (7).
A 0.01 M solution of 2-(1H-imidazol-1-yl)-pyrimidine (5 ml) was
added to 1 ml of 0.1 M solution of CoCl
2
$6H
2
O. The resulting solution
ꢁ
was partially evaporated warming at 40 C during 3 h. Few suitable
crystals for X-ray diffraction were grown after several weeks. IR
ꢀ1
References and notes
(
cm ): 1628s, 1588s, 1566m, 1528s, 1422s, 1355m, 1129m, 1043m,
9
66w, 836w, 791m, 753m, 735w, 635m, 509w, 478w.
.3. X-ray crystallography
1
. (a) Karlin, K. D.; Cruse, R. W.; Gultneh, Y.; Farooq, A.; Hayes, J. C.; Zubieta, J. J.
Am. Chem. Soc. 1987, 109, 2668; (b) Karlin, K. D.; Haka, M. S.; Cruse, R. W.;
Gultneh, Y. J. Am. Chem. Soc. 1985, 107, 5828; (c) Kitajima, N.; Koda, T.; Ha-
shimoto, S.; Kitagawa, T.; Moro-oka, Y. J. Am. Chem. Soc. 1991, 113, 5664; (d)
Kitajima, N.; Fujisawa, K.; Fujimoto, C.; Moro-oka, Y.; Hashimoto, S.; Kitagawa,
T.; Toriumi, K.; Tatsumi, K.; Nakamura, A. J. Am. Chem. Soc. 1992, 114, 1277.
2. (a) Lai, S. W.; Cheung, T. C.; Chan, M. C. W.; Cheung, K. K.; Peng, S. M.; Che, C. M.
Inorg. Chem. 2000, 39, 255; (b) Ghiladi, R. A.; Ju, T. D.; Kretzer, R. M.; Moenne-
Loccoz, P.; Woods, A. S.; Cotter, R. J.; Karlin, K. D. J. Inorg. Biochem. 1999, 74, 140;
4
X-ray diffraction data were collected in an Enraf-Nonius CAD4
diffractometer with graphite monochromated Mo-K
a
radiation
ꢂ
(l
¼0.71073 A). Absorption was corrected either with DIFABS or
Gaussian quadrature. Structure solution and refinement were per-
formed with SIR2004 and SHELXL97 as included in the WinGX
program suite. Non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were located in the Fourier difference maps in all
cases but 4, where H-atoms were introduced in calculated positions
and refined in the riding atom. Details are given in Table 1. The
CCDC reference numbers for compounds 1e7 are 845914e845920.
(
c) Sorrell, T. N.; Garrity, M. L. Inorg. Chem. 1991, 30, 210; (d) Casella, L.; Carugo,
O.; Gullotti, M.; Doldi, S.; Frassoni, M. Inorg. Chem. 1996, 35, 1101.
3
4
5
. (a) Volbeda, A.; Hol, W. G. L. J. Mol. Biol. 1989, 209, 249; (b) Solomon, E. I.;
Baldwin, M. J.; Lowery, M. D. Chem. Rev. 1992, 92, 521; (c) Brudvig, G. M.;
Stevens, T. H.; Chan, S. I. Biochemistry 1980, 19, 5275; (d) Martin, C. T.; Morese,
R. H.; Kanne, R. M.; Gray, H. B.; Mamstr o€ m, B. G.; Chan, S. I. Biochemistry 1981,
2
0, 5147.
. (a) Bassani, D. M.; Lehn, J.-M.; Fromm, K.; Fenske, D. Angew. Chem., Int. Ed. 1998,
7, 2364; (b) Breuning, E.; Ruben, M.; Lehn, J.-M.; Renz, F.; García, Y.; Kseno-
3
fontov, V.; G u€ tlich, Ph.; Weglius, E.; Rissanen, K. Angew. Chem., Int. Ed. 2000, 39,
2504; (c) Funeriu, D. P.; Lehn, J.-M.; Fromm, K. M.; Fenske, D. Chem.dEur. J.
4
.4. Computational details
2
000, 6, 2103.
. (a) Elguero, J.; Guerrero, A.; G oꢁ mez de la Torre, F.; de la Hoz, A.; Jal oꢁ n, F. A.;
Manzano, B. R.; Rodríguez, A. New J. Chem. 2001, 25, 1050; (b) Chirayil, S.;
Hedge, V.; Jahng, Y.; Thummel, R. P. Inorg. Chem. 1991, 30, 2821; (c) Gupta, N.;
Grover, N.; Neyhart, G. A.; Singh, P.; Thorp, H. H. Inorg. Chem 1993, 32, 310;
All calculations were carried out using the TURBOMOLE version
.92 using the RI-MP2/def2-TZVP level of theory. The RI-MP2
6
5
method is considerably faster than MP2 itself and geometries are
almost identical for both methods.27 We have used the crystallo-
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