Influence of bulky and halogen substituents on crystal packing of pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.molstruc.2011.07.018

The crystalline structure of five 3-(R³) and/or 5-(R ⁵)-substituted 7-trichloromethyl-2-methylpyrazolo[1,5-a]pyrimidines [where R³, R⁵ = H, Pr (1); Br, H (2); Br, Me (3); H, H (4); and H, Me (5)] were studied from X-ray diffractometry data. It was found that compounds presented themselves as main intermolecular interactions: Cl?Cl (1), Br?Cl (2,3); and Cl?N-pyrimidine (4,5). In compounds 1-3, other interactions reinforce the stabilization of the crystal structure, such as C-H?N-pyrimidine (1,2) Cl?π-pyrazole (1); C-Br?π-pyrimidine (2); and pyrazole-π?π-pyrimidine, pyrimidine-π?π-pyrimidine (3). This study shows that the Cl?N-pyrimidine interactions present in compounds 4 and 5 are a typical halogen?base Lewis interaction. Geometric information of Cl?Br and Cl?Cl interactions could be explained by the σ-hole concept. In compound 2, the chlorine atom participates with its σ-hole, while in compound 3, the σ-hole of the interaction comes from the bromine atom. The Cl?π-pyrazole and Br?π-pyrimidine interactions have a different nature; while the Br?π-pyrimidine interaction is a strong lone pair?π interaction, the Cl?π-pyrazole is a new interaction: σ-hole?π.

Full text of DOI:10.1016/j.molstruc.2011.07.018

Journal of Molecular Structure 1004 (2011) 45–50
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Influence of bulky and halogen substituents on crystal packing
of pyrazolo[1,5-a]pyrimidines
⇑
Clarissa P. Frizzo , Alexandre R. Meyer, Guilherme S. Caleffi, Letícia V. Rodrigues, Mara R.B. Marzari,
⇑
Patrick T. Campos, Dayse N. Moreira, Helio G. Bonacorso, Nilo Zanatta, Marcos A.P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97.105-900 Santa Maria,
RS, Brazil
a r t i c l e i n f o
a b s t r a c t
The crystalline structure of five 3-(R3) and/or 5-(R5)-substituted 7-trichloromethyl-2-methylpyrazol-
o[1,5-a]pyrimidines [where R3, R5 = H, Pr (1); Br, H (2); Br, Me (3); H, H (4); and H, Me (5)] were studied
from X-ray diffractometry data. It was found that compounds presented themselves as main intermolec-
ular interactions: ClÁ Á ÁCl (1), BrÁ Á ÁCl (2,3); and ClÁ Á ÁN-pyrimidine (4,5). In compounds 1–3, other interac-
Article history:
Received 7 April 2011
Received in revised form 7 July 2011
Accepted 10 July 2011
Available online 4 August 2011
tions reinforce the stabilization of the crystal structure, such as C–HÁ Á ÁN-pyrimidine (1,2) ClÁ Á Á
p
-pyrazole
(1); C–BrÁ Á Á
p
-pyrimidine (2); and pyrazole-
p
Á Á Á
p
-pyrimidine, pyrimidine-
p p-pyrimidine (3). This
Á Á Á
Keywords:
Halogen–halogen interaction
study shows that the ClÁ Á ÁN-pyrimidine interactions present in compounds 4 and 5 are a typical halo-
genÁ Á Ábase Lewis interaction. Geometric information of ClÁ Á ÁBr and ClÁ Á ÁCl interactions could be explained
r
-Hole
by the
3, the
interactions have a different nature; while the BrÁ Á Á
interaction, the ClÁ Á Á -pyrazole is a new interaction:
r
-hole concept. In compound 2, the chlorine atom participates with its
r
-hole, while in compound
-pyrazole and BrÁ Á Á -pyrimidine
-pyrimidine interaction is a strong lone pairÁ Á Á
-holeÁ Á Á
Halogen–nitrogen interaction
Pyrazolo[1,5-a]pyrimidines
X-ray diffractometry
r
-hole of the interaction comes from the bromine atom. The ClÁ Á Á
p
p
p
p
p
r
p.
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
the determination of strengths and directional trends [7]. Hydrogen
and halogen bonds are electrostatically-driven noncovalent interac-
tions. Both, hydrogen and halogens, bonded covalently, can interact
through regions of positive potential surface with a negative poten-
tial surface of other atoms, such as a lone pair of a Lewis base.
In particular, in the bonded halogen atom, the anisotropically-dis-
tributed electron density results in a negative charge concentrated in
theequatorialarea,andinapositivechargealongtheC–Xbond,which
Pyrazolo[1,5-a]pyrimidines are an important class of heterocy-
cles because they are purine analogs and have useful pharmacolog-
ical properties as HMG-CoA reductase inhibitors [1] and COX-2
selective inhibitors [2]. Generally, the pharmacological activity is
closely related to the molecular recognition of the active substance
by the active site. Therefore, a detailed understanding of these
molecular interactions is essential for the development of quanti-
tative approaches toward molecular recognition.
Over the past two decades, our research group has worked to
develop the synthesis of new trihalomethyl substituted heterocy-
cles under conventional methods [3], as well as using ionic liquid
[4], microwave [5], and ultrasound irradiation [6]. The presence
of trihalomethyl groups and, both, donor and acceptor hydrogen
bond groups in heterocycles, together with their aromatic charac-
ter, make them interesting structures for the study of intermolec-
ular interactions such as hydrogen bond, halogen bond, lone
iscalledther-hole[8].Thehalogenbondisnear-linear(anglescloseto
180°), while the hydrogen bond is probably more nonlinear (angles
less than 180°) [9]. The strengths of these two interactions are compa-
rable and they can certainly be competitive [10].
Other intermolecular contacts that have received attention re-
cently are the interactions involving
Á Á Á and lone pair (LP)Á Á Á interactions, that appear to be of great
importance for the stabilization of biological macromolecules [11].
Despite their weak electrostatic nature, LPÁ Á Á interactions have been
reported to be responsible for the Z-DNA stability [12], and the
Á Á Á
p-aromatic systems, such as
p
p
p
p
p
p
pairÁ Á Á
p
, and
p
Á Á Á
p
interactions.
interactions are known as dispersion forces and are auxiliary stabiliz-
ing force in the recognition process of aromatic compounds. They can,
for example, direct the intercalation of drugs into DNA [13].
Weak nonbonding interactions may contribute to the stability,
conformation, and assembly of molecules, generating interest in
In connection with our recent interest in the structure of triha-
lomethyl substituted heterocycles [14], in this work we investigate
the influence of bulky and halogen substituents on the crystal pack-
ing of pyrazolo[1,5-a]pyrimidines by using X-ray diffractometry
⇑
Corresponding authors. Tel./fax: +55 55 3220 8756.
E-mail addresses: clarissa.frizzo@yahoo.com.br (C.P. Frizzo), mmartins@base.
ufsm.br (M.A.P. Martins).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.07.018

46
C.P. Frizzo et al. / Journal of Molecular Structure 1004 (2011) 45–50
and 1,1,1-trichloro-4-methoxy-3-penten-2-one under acetic acid
reflux for 16 h [15]. The products 2 and 3 were obtained from
the cyclocondensation reaction of 3(5)-amino-5(3)-methyl-1H-
pyrazole and 1,1,1-trichloro-4-methoxy-3-penten-2-one under
acetic acid reflux for 16 h, followed by bromination with N-bro-
mosuccinimide in THF under reflux for 20 h [15]. The complete
1H/13C NMR, mass spectra data, and elemental analysis of com-
pounds 1–3 is available in the literature [15]. The crystals used
for the data collection were obtained by recrystallization of com-
pounds from hexane followed by slow evaporation at room
temperature.
1
2
3
2.2. X-ray diffraction data
4
5
The diffraction measurements were carried out by graphite
monochromatized Mo Ka radiation with k = 0.71073 Å on a Bruker
SMART CCD diffractometer [16]. The structures were solved with
direct methods using the SHELXS program [17], and refined on F2
by full-matrix least-squares with the SHELXL [17] package.
Absorption correction was performed by the Gaussian method
[18]. Anisotropic displacement parameters for non-hydrogen
atoms were applied. The hydrogen atoms were placed at calculated
positions with 0.96 (methyl CH3), 0.97 (methylene CH2), 0.98
(methyne CH), 0.93 (aromatic CH), and 0.82 Å (OH) using a riding
model. Hydrogen isotropic thermal parameters were kept equal
to Uiso(H) = xUeq (carrier C atom), with x = 1.5 for methyl groups
and x = 1.2 otherwise. The valence angles C–C–H and H–C–H of
methyl groups were set to 109.5°, and H atoms were allowed to ro-
tate around the C–C bond. Molecular graphics were prepared using
ORTEP for Windows [19]. The crystal data and details concerning
data collection and structure refinement are given in Table 1 and
in Supplementary material.
Fig. 1. Structure of pyrazolo[1,5-a]pyrimidines studied in this work.
data. For this purpose we selected the three structures, 7-trichlo-
romethyl-2-methyl-5-propylpyrazolo[1,5-a]pyrimidine (1), 3-bro-
mo-7-trichloromethyl-2-methylpyrazolo[1,5-a]pyrimidine (2), and
3-bromo-7-trichloromethyl-2,5-dimethylpyrazolo[1,5-a]pyrimidine
(3), and compared them with 7-trichloromethyl-2-methylpyrazol-
o[1,5-a]pyrimidine (4) and 7-trichloromethyl-2,5-dimethyl pyraz-
olo[1,5-a]pyrimidine (5), which have been described in our
previous works (Fig. 1) [14].
2. Experimental
2.1. Synthesis and physical measurements
Pyrazolo[1,5-a]pyrimidine 1 was synthesized from the cyclo-
condensation reaction of 3(5)-amino-5(3)-methyl-1H-pyrazole
Table 1
General and crystal data and summary of intensity data collection and structure refinement for compounds 1–3.
Compound
1
2
3
Formula
Mr
C
11H12Cl3N3
C8H5BrCl3N3
329.41
C9H7BrCl3N3
343.44
292.59
CCDC
734997
293(2)
0.71073
Monoclinic
P21/c
734996
293(2)
0.71073
Monoclinic
P21
751834
293(2)
0.71073
Monoclinic
P21
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell parameters
a (Å)
b (Å)
c (Å)
11.2451(8)
5.8697(4)
20.9201(16)
90
104.896(5)
7.4329(2)
6.7756(2)
11.1667(3)
90
90.2760(10)
90
562.37(3)
2
9.6363(3)
6.9353(2)
9.8541(3)
90
111.240(2)
90
613.82(3)
2
a
(°)
b (°)
(°)
V (Å3)
c
90
1334.43(17)
4
1.456
0.667
600
Z
Density (calculated) (g cmÀ3
)
1.945
4.334
320
1.858
3.975
336
Absorption coefficient (mmÀ1
F (0 0 0)
)
Crystal size (mm)
h Range for data collection (°)
h, k, l Range
0.880 Â 0.328 Â 0.158
1.87–28.40
À14 6 h 6 14
À7 6 k 6 7
0.340 Â 0.337 Â 0.162
0.858 Â 0.295 Â 0.166
2.74–28.40
2.22–28.26
À9 6 h 6 8
À12 6 h 6 12
À9 6 k 6 9
À9 6 k 6 8
À27 6 l 6 27
À14 6 l 6 14
5503
À12 6 l 6 13
6092
Reflections collected
13171
Independent reflections
Data/restraints/parameters
Absorption correction
Refinement method
3314 [R(int) = 0.0292]
3314/0/154
Gaussian
2653 [R(int) = 0.0197]
2653/1/136
Gaussian
2998 [R(int) = 0.0199]
2998/1/145
Gaussian
Full-matrix least-squares on F2
R1 = 0.0361, wR2 = 0.1069
R1 = 0.0576, wR2 = 0.1361
1.100
Full-matrix least-squares on F2
R1 = 0.0362, wR2 = 0.0954
R1 = 0.0483, wR2 = 0.1008
1.063
Full-matrix least-squares on F2
R1 = 0.0416, wR2 = 0.1250
R1 = 0.0579, wR2 = 0.1356
1.073
Final R indices [I > 2
R indices (all data)
r(I)]
Goodness of fit on F2
Largest diff. peak and hole (eÅÀ3
)
0.512 and À0.460
0.461 and 0.809
0.510 and À0.792

C.P. Frizzo et al. / Journal of Molecular Structure 1004 (2011) 45–50
47
Table 2
3. Results and discussion
Intramolecular contact geometries for crystals 1–5.
Intramolecular interaction geometries data for compounds 1–5
are shown in Table 2. Intermolecular interaction geometries for
synthons of compounds 1–5 are listed in Table 3. ORTEP of com-
pounds 1–5 are shown in Fig. 2, and crystal packing of compounds
1–5 are depicted in Fig. 3. The intermolecular interactions
observed for all structures were C–HÁ Á ÁN-pyrimidine (1,2);
C–ClÁ Á ÁCl–C (1); C-ClÁ Á ÁN-pyrimidine (4,5); C–BrÁ Á ÁCl–C (2,3);
Compound
Contact
Cl(2)Á Á ÁN(1)
Distance ClÁ Á ÁN (Å)
3.015(2)
Angle C–ClÁ Á ÁN (°)
69.19(8)
65.33(8)
66.8(2)
67.4(2)
67.43(15)
67.1(2)
1
Cl(3)Á Á ÁN(1)
Cl(2)Á Á ÁN(1)
Cl(3)Á Á ÁN(1)
Cl(1)Á Á ÁN(1)
Cl(2)Á Á ÁN(1)
C(3)Á Á ÁN(1)
Cl(1)Á Á ÁN(1)
3.157(2)
3.106(7)
3.084(7)
3.116(3)
3.097(6)
3.093(6)
3.116(3)
2
3
4
67.3(2)
67.43(15)
5
C–ClÁ Á Á
Á Á Á -pyrimidine, pyrimidine-
All five compounds exhibited intramolecular five-membered
p
-pyrazole (1); C–BrÁ Á Á
p
-pyrimidine (2); and pyrazole-
p
p
pÁ Á Áp-pyrimidine (3).
Table 3
ClÁ Á ÁN contacts. The ClÁ Á ÁN distances (d) are significantly shorter
than the sum of their van der Waals radii (d0 = 3.3 Å), which is also
reflected by the relatively smaller d/d0 value (0.94). This intramo-
lecular contact appears to exist as a consequence of the bulky ef-
fect of the chlorine atom and its fixed geometry in these
compounds.
Compounds 1–3 and 5 relate to the monoclinic space group and
compound 4 relates to the orthorhombic space group. Different
from the intramolecular contacts, which were robust, appearing
in all five compounds, intermolecular contacts were more sensitive
to the presence of the bromine substituent. In compounds 4 and 5,
where there is no bromine substituent in the 3-position, com-
pounds exhibited intermolecular Cl(1)Á Á ÁN(4) contacts, which sta-
bilized the crystal structure, forming a zig-zag infinite chain
along plane ab. Intermolecular contacts change from Cl(1)Á Á ÁN(4)
in compounds 4 and 5, to Cl(1)(2)Á Á ÁBr(31) in compounds 2 and
3, which bear a bromine in the 3-position. This contact stabilizes
the crystal structure forming a zig-zag infinite chain along plane
ac. In compound 1, despite the absence of bromine in the
Intermolecular interaction geometries for synthonsa of compounds 1–5.
Distance (Å)
Angle (°)
Symmetry code
1
2
3
4
5
Cl(1)Á Á ÁCl(2) 3.3406(8) C(71)–Cl(2)Á Á ÁCl(1)
x, 1 + y, z
178.9
Br(31)Á Á ÁCl(1)
3.4778(11)
C(71)–Cl(1)Á Á ÁBr(31)
x, y, 1 + z
176.5
Cl(2)Á Á ÁBr(31)
C(3)–Br(31)Á Á ÁCl(2)
160.7
1 + x, y, 1 + z
x + 1/2, Ày + 1, z
3.540(14)
N(4)Á Á ÁCl(1) 3.115(3)
C(71)–Cl(1)Á Á ÁN(4)
161.6
N(4)Á Á ÁCl(1) 3.174(3)
C(71)–Cl(1)Á Á ÁN(4)
170.6
Àx + 1, y À 1/2,
Àz + 1/2
a
Bold characters indicate the
r-hole atom of interaction.
3-position, the predominant intermolecular contacts were
Cl(1)Á Á ÁCl(2). It is reasonable to suggest that the Cl(2)Á Á ÁCl(1) con-
tacts appear in these compounds due to the bulky effect of the pro-
pyl group attached in the 5-position of pyrazolo[1,5-a]pyrimidine.
Fig. 2. ORTEP of compounds 1–5.

48
C.P. Frizzo et al. / Journal of Molecular Structure 1004 (2011) 45–50
1
2
3
4
5
Fig. 3. Intra- and intermolecular contacts of compounds 1–5.
The presence of this supramolecular bulky alkyl group in the struc-
ture obstructed the N(4)Á Á ÁCl(1) interaction present in compounds
4 and 5, which have no bulky alkyl substituent in their structures.
Regarding the geometric features of these interactions, the
ClÁ Á ÁN distances (d) in compounds 4 and 5 and the ClÁ Á ÁBr distance
(d) in compounds 2 and 3 are close to the sum of their van der
Waals radii (d0 = 3.3 and 3.6 Å, respectively), which is also reflected
by the d/d0 value (0.95 and 0.98 respectively). In addition, the most
important contacts of the compounds studied here involve halogen
atoms. This fact leads us to consider angular requirements of the
interactions. Halogen atoms in covalent bonds are recognized by
their non-spherical charge distribution on the potential surface.
This leads to two favored geometries for contacts involving the hal-
ogen atom (Fig. 4). The first arrangement occurs when h1 = h2,
called type I (where h1 and h2 are the R–X1Á Á ÁX2 and X1Á Á ÁX2–R an-
gles, respectively). The second geometry arises when h1 = 180° and
h2 = 90°; the perpendicular arrangement known as type II (Fig. 4)
[8–10].
We find it important to consider this information thoroughly
because all five compounds discussed here present halogen con-
tacts, and also because a correlation of the geometric data of these
compounds with two preferred geometries allows us to delineate
interesting observations about their behavior. Cl(2)Á Á ÁN(1) contacts
present in compounds 4 and 5 are typical halogenÁ Á Ábase Lewis
interactions (type II), confirmed by the C(71)–Cl(1)Á Á ÁN(4) angle
of 161.6° (4) and 170.6° (5). On the other hand, ClÁ Á ÁBr are consid-
ered typical halogenÁ Á Áhalogen contacts (type II), and due to the
structural similarity between compounds 2 and 3, the angular

C.P. Frizzo et al. / Journal of Molecular Structure 1004 (2011) 45–50
49
Fig. 4. The two geometries for halogen bonds (R = organic group, X = Cl, Br and I).
behavior of the interaction would be expected to be the same in
both compounds. However, there is an angular inversion of this
interaction and, consequently, there is a change in the atom partic-
ipating in the contact with its positive potential surface (r-hole).
In the ClÁ Á ÁBr interaction of compound 2, the C(71)–Cl(1)Á Á ÁBr(31)
angle was found to be 176.5°, indicating that the chlorine atom
is the participant in contact with its positive potential surface
(r-hole) and the bromine atom participates in the interaction
through its negative potential surface. On the contrary, in com-
pound 3, the C(71)–Cl(2)Á Á ÁBr(31) angle was found to be 136.9°,
and the C(3)–Br(31)Á Á ÁCl(2) angle was found to be 160.7°, showing
that, here, the bromine atom is the participant in contact with its
r
-hole and the chlorine atom participates in the interaction
through its negative potential surface. Finally, the Cl(2)Á Á ÁCl(1)
contacts, which appear only in compound 1, are also typical halo-
genÁ Á Áhalogen contacts with a strongly directionality, with a
C(71)–Cl(2)Á Á ÁCl(1) angle of 178.9°, where Cl(1) participates in
the interaction through its negative potential surface and Cl(2)
with its
r-hole.
In 1–3, the action of intermolecular contacts, Cl(1)(2)Á Á ÁBr(31),
or Cl(2)Á Á ÁCl(1) is reinforced by interactions such as C–HÁ Á ÁN-
pyrimidine, C–ClÁ Á Á
p
-pyrazole, C–BrÁ Á Á
p
-pyrimidine, or
p p
Á Á Á
between pyrazole and pyrimidine aromatic systems. C–HÁ Á ÁN-
pyrimidine contacts have a very weak electrostatic nature and
appear in compounds 1 and 2. The geometric features of contacts
C–HÁ Á ÁN are given by the C(3)Á Á ÁN(4) distance of 3.563 Å (1 À x,
À1/2 + y, 1/2 À z) in compound 1 and 3.518 Å (1 + x, y, z) in com-
pound 2. The ClÁ Á Á
p interaction arises in compound 1 between
Cl(3) and the pyrazole ring of fused pyrazolo[1,5-a]pyrimi-
dine(1 À x, Ày, 1 À z), and the BrÁ Á Á
p
interaction arises in com-
pound 2 between bromine and the pyrimidine ring (Àx, À1/2 + y,
2 À z). Finally, compound 3 has its crystalline structure reinforced
by
p p interactions between pyrazole and the pyrimidine rings
Á Á Á
(distance between centroids of 4.164 Å, 1 À x, À1/2 + y, 1Àz), and
pÁ Á Áp
interactions between pyrimidine rings (distance between
centroids of 3.702 Å, x, y, z). All contacts that reinforced crystal
stabilization of compounds 1–3 are illustrated in Fig. 5.
We have found further interesting behavior regarding halogen
interactions with contacts with
the literature that halogens rich in electrons (lone pair) are attracted
by electron-deficient -systems; the interaction between the two of
interaction [11,12]. However,
p-systems. It has been reported in
p
Fig. 5. (a) C(71)–Cl(3)Á Á Ápyrazole ring centroid interaction of compound 1; (b) C(3)–
Br(31)Á Á Ápyrimidine ring centroid interaction of compound 2; and (c) pyrimidine-
them is denominated lone pairÁ Á Á
p
pÁ Á Áp-Pyrimidine, pyrazole-pÁ Á Áp-pyrimidine interactions of compound 3.
upon studying the halogen interaction in halomethyl-substituted
pyrazolo[1,5-a]pyrimidines, we found that, in some cases, halogen
atoms can attract p-systems rich in electrons by its r-hole. The role
C(71)–Cl(3)Á Á Ácentroid of pyrazole of 3.631 Å. We consider this to
be a new interaction because it can be described as a
-holeÁ Á Á
interaction. These facts could be expected because the pyrazol-
o[1,5-a]pyrimidine system presented a -deficient pyrimidine ring
and an electron-rich pyrazole ring; where it is expected that the fa-
interac-
r
p
of halogen atoms in this interaction, as in halogenÁ Á Áhalogen con-
tacts, may be determined by geometrical parameters, and, it has
p
been established that a strong lone pairÁ Á Á
p interaction is character-
ized by an angle (lone pair atom-centroid-plane) ranging from 75° to
90°. Therefore, in this study, we adopted as angular criteria the
vored interaction for the pyrimidine ring is a lone pairÁ Á Á
p
tion, and, for the pyrazole ring, a
r
-holeÁ Á Á
p interaction.
C–halogenÁ Á Á
p
-system angle. Thus, we found a typical lone pairÁ Á Á
p
interaction, in compound 2, where the angle C(3)–Br(31)Á Á Ápyrimi-
dine centroid is 90.1° and the distance C(3)–Br(31)Á Á Ácentroid of
pyrimidine is 3.427 Å. In compound 1 we found a contact between
4. Conclusion
the chlorine atom and the
p-system of the pyrazole ring, with an
In this work we have described the supramolecular synthons
angle C(71)–Cl(3)Á Á Á -pyrazole of 177.9° and
p
a
distance
present in 7-trichloromethylpyrazolo[1,5-a]pyrimidines by using

50
C.P. Frizzo et al. / Journal of Molecular Structure 1004 (2011) 45–50
X-ray data. Three supramolecular synthons, ClÁ Á ÁCl, ClÁ Á ÁN, and
ClÁ Á ÁBr, involving halogen atoms were described. The synthon
ClÁ Á ÁN was little robust because the addition of a bulky substituent
in the 5-position of 7-trichloromethylpyrazolo[1,5-a]pyrimidines
obstructed this interaction and favored a ClÁ Á ÁCl interaction. The
presence of a bromine atom in the 3-positon of 7-trichloro-
methylpyrazolo[1,5-a]pyrimidines also hindered the ClÁ Á ÁN inter-
actions and led to the ClÁ Á ÁBr interaction. These synthons were
characterized by their robustness and geometric parameters, such
as interatomic distances and angles between interacting groups.
The formation of halogen synthons could be explained by the
734996 for 2, and CCDC 751834 for 3. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road, Cam-
bridge CB21EZ, United Kingdom; Fax: +44 1223 336033 or
deposit@ccdc.cam.ac.uk. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.molstruc.2011.07.018.
References
[1] M. Suzuki, H. Iwasaki, Y. Fujikawa, M. Sakashita, M. Kitahara, R. Sakoda, Bioorg.
Med. Chem. Lett. 11 (2001) 1285.
[2] C. Almansa, M. Merlos, J.G. Rafanell, A.F. Arriba, F.L. Cavalcanti, L.A. Gomez, A.
Miralles, J. Forn, J. Med. Chem. 44 (2001) 350.
[3] M.A.P. Martins, W. Cunico, C.M.P. Pereira, A.F.C. Flores, H.G. Bonacorso, N.
Zanatta, Curr. Org. Synth. 1 (2004) 391.
[4] (a) D.N. Moreira, K. Longhi, C.P. Frizzo, H.G. Bonacorso, N. Zanatta, M.A.P.
Martins, Catal. Commun. 11 (2010) 476;
r
-hole concept. We observed an inversion in the atom that partic-
ipated, through its
-hole, in the ClÁ Á ÁBr interaction, where chlo-
rine was the participant with its -hole in compound 1 and the
bromine atom was the participant with its -hole in the same
r
r
r
(b) C.P. Frizzo, M.R.B. Marzari, L. Buriol, D.N. Moreira, F.A. Rosa, P.S. Vargas, N.
Zanatta, H.G. Bonacorso, M.A.P. Martins, Catal. Commun. 10 (2009) 1967.
[5] (a) L. Buriol, C.P. Frizzo, M.R.B. Marzari, D.N. Moreira, L.D.T. Prolla, N. Zanatta,
H.G. Bonacorso, M.A.P. Martins, J. Braz. Chem. Soc. 21 (2010) 1037;
(b) M.A.P. Martins, P. Beck, D.N. Moreira, L. Buriol, C.P. Frizzo, N. Zanatta, H.G.
Bonacorso, J. Heterocycl. Chem. 47 (2010) 301.
interaction in compound 2. In addition, other contacts that stabi-
lized the crystalline structure of 7-trichloromethylpyrazolo[1,5-
a]pyrimidines were described. A new halogenÁ Á Á
p interaction, also
supported by the -hole concept, was observed, where halogen
r
(Cl) approaches with the
r-hole to attract the p-heterocyclic
[6] (a) P. Machado, G.R. Lima, M. Rotta, H.G. Bonacorso, N. Zanatta, M.A.P. Martins,
Ultrason. Sonochem. 18 (2011) 293;
system (pyrazole).
(b) G. Sant’Anna, P. Machado, P. Sauzem, F. Rosa, M. Rubin, J. Ferreira, H.G.
Bonacorso, N. Zanatta, M.A.P. Martins, Bioorg. Med. Chem. Lett. 19 (2009) 546.
[7] V.N. Khrustalev, K.A. Krasnov, T.V. Timofeeva, J. Mol. Struct. 878 (2008) 40.
[8] P. Politzer, J.S. Murray, M.C. Concha, J. Mol. Model. 14 (2008) 659.
[9] Z.P. Shields, J.S. Murray, P. Politzer, Int. J. Quant. Chem. 110 (2010) 2823.
[10] G.R. Desiraju, R. Parthasarathy, J. Am. Chem. Soc. 111 (1989) 8725.
[11] (a) J.C. Calabrese, D.B. Jordan, A. Boodhoo, S. Sariaslaniand, T. Vannelli,
Biochemistry 43 (2004) 11403;
We believe that this work provides new detailed understanding
of molecular interactions, which is essential for applications in the
field of synthetic chemistry, material science, and bioorganic
chemistry.
Acknowledgements
(b) E.J. Stollar, J.L. Gelpi, S. Velankar, A. Golovin, M. Orozcoand, B.F. Luisi,
Proteins 57 (2004) 1.
[12] M. Egliand, R.V. Gessner, Proc. Natl. Acad. Sci. USA 92 (1995) 180.
[13] A.H. Wang, G. Ughetto, G.J. Quigley, T. Hakoshima, G.A. Vander Marel, J.H. Van
Boom, A. Rich, Science 225 (1984) 1115.
[14] (a) C.P. Frizzo, M.A.P. Martins, M.R.B. Marzari, P.T. Campos, R.M. Claramunt,
M.A. García, D. Sanz, I. Alkorta, J. Elguero, J. Heterocycl. Chem. 47 (2010) 1259;
(b) C.P. Frizzo, E. Scapin, P.T. Campos, D.N. Moreira, M.A.P. Martins, J. Mol.
Struct. 933 (2009) 142.
[15] (a) M.A.P. Martins, W. Cunico, E. Scapin, D.J. Emmerich, G.F. Fiss, F.A. Rosa, H.G.
Bonacorso, N. Zanatta, A.F.C. Flores, Lett. Org. Chem. 3 (2006) 358;
(b) M.A.P. Martins, E. Scapin, C.P. Frizzo, F.A. Rosa, H.G. Bonacorso, N. Zanatta, J.
Braz. Chem. Soc. 20 (2009) 205.
The authors thank Conselho Nacional de Desenvolvimento Cientí-
fico e Tecnológico – CNPq (Universal/Proc. 485893/2007-0; Univer-
sal/Proc. 471519/2009-0; MAPA/Proc. 578426/2008-0) and
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul – FA-
PERGS (PRONEX/Proc. 10/0037-8) for financial support. The fellow-
ships from CNPq (M.A.P.M., N.Z., H.G.B., P.T.C., M.R.B.M. D.N.M.),
CAPES (C.P.F., PRODOC/Proc. 2684-32/2010), and FAPERGS are also
acknowledged.
[16] Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS (Version 2.0.1.9)
SAINT (Version 7.3A) and SADABS (Version 2004/1) and XPREP (Version 2005/
4), Bruker AXS Inc., Madison, Wisconsin, USA, 2006.
[17] G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112.
[18] P. Coppens, L. Leiserowitz, D. Rabinovich, Acta Crystallogr. 18 (1965) 1035.
[19] L.J. Farrugia, J. Appl. Cryst. 30 (1997) 565.
Appendix A. Supplementary material
Crystallographic data for the structural analysis of the com-
pounds have been deposited at the Cambridge Crystallographic
Data Center with the deposition numbers CCDC 734997 for 1, CCDC