Strengthening N...X halogen bonding via nitrogen substitution in the aromatic framework of halogen-substituted arylpyrazinamides

Article abstract of DOI:10.1039/c3ce41856a

The importance of N...X halogen bonding in a series of N-(5-halo-2-pyridinyl)pyrazine-2-carboxamides has been investigated by different methods. The results show that when nitrogen is substituted for carbon in the aryl backbone of the parent compound, it can affect the electron accepting ability of bromine and iodine substituents. Thus, a stronger halogen bond can be formed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ce41856a

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Strengthening N⋯X halogen bonding via nitrogen
substitution in the aromatic framework of
halogen-substituted arylpyrazinamides†
Cite this: CrystEngComm, 2014, 16,
4546
*
Hamid Reza Khavasi, Mahdieh Hosseini, Alireza Azhdari Tehrani and Soheila Naderi
Received 13th September 2013,
Accepted 11th March 2014
The importance of N⋯X halogen bonding in a series of N-(5-halo-2-pyridinyl)pyrazine-2-carboxamides
has been investigated by different methods. The results show that when nitrogen is substituted for carbon
in the aryl backbone of the parent compound, it can affect the electron accepting ability of bromine and
iodine substituents. Thus, a stronger halogen bond can be formed.
DOI: 10.1039/c3ce41856a
www.rsc.org/crystengcomm
atom to a charged aromatic ring such as pyridinium6a,b and
pyrimidinium moiety6c also has been proposed as an alterna-
Introduction
Weak non-covalent interactions play an important role in the
self-assembly of molecules into supramolecular architectures.
Among the non-covalent interactions, halogen bonding (XB)
has attracted significant attention due to its potential appli-
cations in designing new solids with specific physical and
chemical properties.1 The term halogen bonding describes
any non-covalent interaction involving halogens as electro-
philic species. The interaction can be schematically described
as D⋯X–Y, where X is the electrophilic halogen atom
(XB donor), D is a donor of electron density (XB acceptor), and
Y is a carbon, nitrogen or halogen atom.2 It is well-known that
the electron density is anisotropically distributed around the
covalently bound halogen atom. As a result, a region with a
positive electrostatic potential (the so-called σ-hole) is formed
on the outermost portion of the halogen's surface along the
tive approach to polarize the halogen atom, thereby making it
a better halogen bond donor. As part of our research interest
in the study of weak intermolecular interactions7 and also
halogen bonded systems,8 we became interested in exploring
how the substitution of nitrogen for carbon in the aryl back-
bone of halogen-substituted phenylpyrazinamides could change
the strength of halogen bonding and therefore affect the supra-
molecular structure. Thus, in the following, we present the crys-
tal structures of N-(5-halo-2-pyridinyl)pyrazine-2-carboxamide,
carrying different halogen atoms in the pyridine para-position
to the amide group. Compounds synthesized here can be
schematically shown as X-py, where X represents the halogen
atom (Scheme 1).
direction of the R–X bond, which concomitantly produces a Results and discussion
perpendicular belt of negative electrostatic potential around
the halogen. The positive character of the σ-hole increases
Synthesis
These compounds were prepared by modification of
a
method described previously.8b Crystals suitable for X-ray
analysis were obtained by slow evaporation of methanolic
solution at room temperature. For comparing the halogen
bonding geometrical parameters of X-phen and X-py, crystal
structures of X-phen have been re-determined, at 298 K, here
(Table 1 and Fig. S1).†8b
down the group as the size and polarizability of the halogen
increase, with a corresponding tendency for a halogen bond
to become stronger.3
Many attempts have been made to enhance the electro-
philicity of halogen atoms by substituting electron withdrawing
groups, mostly fluorine4 atoms and rarely a nitro group,5 in
the vicinity of the halogens. The attachment of a halogen
Faculty of Chemistry, Shahid Beheshti University, G. C., Evin, Tehran
1983963113, Iran. E-mail: h-khavasi@sbu.ac.ir; Fax: +98 21 22431663
† Electronic supplementary information (ESI) available: ORTEP diagrams of
X-phen compounds, electrostatic potentials mapped on the electron isodensity
surface of F-phen, Cl-phen, F-py and Cl-py, relative contributions of various
intermolecular contacts to the Hirshfeld surface area in F-phen, F-py, Cl-phen
and Cl-py and full crystallographic data. CCDC 951196–951202 and 877918.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ce41856a
Scheme 1 N-(4-halophenyl)pyrazine-2-carboxamide, X-phen, structures
(a) and N-(5-halo-2-pyridinyl)pyrazine-2-carboxamide, X-py, structures
(b) the halogen bond donor and halogen bond acceptors are shown in
purple and blue circles, respectively.
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Table 1 Structural data and refinement parameters for compounds F-py, Cl-py, Br-py, I-py, F-phen, Cl-phen, Br-phen and I-phen
F-py
Cl-py
Br-py
I-py
F-phen
Cl-phen
Br-phen
I-phen
Formula
fw
λ/Å, T/K
C10H7FN4O
218.06
0.71073,
298(2)
C10H7ClN4O C10H7BrN4O C10H7IN4O
C11H8FN3O
217.20
0.71073,
298(2)
C11H8ClN3O C11H8BrN3O C11H8IN3O
234.64
279.09
326.09
0.71073,
298(2)
233.65
0.71073,
298(2)
278.10
0.71073,
298(2)
325.11
0.71073,
298(2)
0.71073,
298(2)
0.71073,
298(2)
Crystal system
Z, space group
Triclinic
4, P21/n
3.7671(5)
15.7465(19) 10.920(5)
16.358(2)
90
Monoclinic
4, P1
7.375(4)
Monoclinic
8, P21/n
7.287(2)
24.367(5)
12.004(3)
90
100.65(2)
90
2094.7(9),
1.770
Monoclinic Monoclinic, P21/n Triclinic
Triclinic
2, P1
Triclinic
2, P1
¯
¯
¯
¯
4, P21/n
5.7717(3)
24.9374(8)
7.5654(3)
90
8, P21/c
6.0141(15)
23.974(5)
13.582(3)
90
2, P1
a/Å
b/Å
c/Å
α/°
β/°
γ/°
5.8988(19)
7.408(3)
13.191(4)
101.56(3)
96.55(2)
110.55(3)
518.0(3),
1.498
5.8743(6)
7.5065(7)
13.3959(9)
101.489(7)
96.656(7)
110.390(8)
531.44(8),
1.738
5.9550(8)
7.7126(11)
12.9998(17)
78.850(11)
85.640(11)
70.594(11)
552.47(13),
1.954
13.606(7)
86.20(4)
83.56(4)
73.19(4)
1041.6(9),
1.496
92.991(11)
90
94.819(4)
90
92.58(2)
90
V/Å3, Dcalc/g cm−3 969.0(2),
1085.5(8),
1.996
1956.2(8),
1.475
1.496
F(000), 2θ/°
R(int), S
448, 52.00
0.0599,
1.002
480, 58.64
0.0657,
1.030
1104, 52.00
0.1256,
0.892
624, 52.00
0.2180,
0.910
896, 58.44
0.1016,
0.864
240, 54.00
0.0998,
1.038
276, 52.00
0.0759,
0.998
312, 58.44
0.0372,
1.091
R1, wR2(I > 2σ(I)) 0.0466,
0.0710,
0.1168
951199
0.0812,
0.1605
951197
0.0787,
0.1239
951202
0.0538
0.0885
951200
0.0715,
0.1410
951198
0.0491,
0.1109
951196
0.0296,
0.0668
877918
0.0773
CCDC no.
951201
Structural analysis of X-py compounds
X-ray crystallographic analyses reveal that F-py, Br-py and I-py
crystallize in the monoclinic P21/n space group, while Cl-py
¯
crystallizes in the centrosymmetric triclinic space group P1.
ORTEP diagrams of compounds X-py drawn with 30% ellip-
soid probability have been shown in Fig. 1. The asymmetric
unit of F-py consists of one crystallographically independent
molecule, Z′ = 1. In F-py, discrete molecules are held together
by head-to-tail Cpyz–H⋯Npy hydrogen bonds for the generation
of a dimeric unit (Fig. 2(a) and Table 2). Adjacent dimeric
units are further linked to each other by Cpy–F⋯H–Cpyz and
Cpy–H⋯OC intermolecular interactions in the bc-plane. As
shown in Fig. 2(b), extensive π–π stacking interactions, in the
a-direction, also occur when the corresponding molecules are
in parallel orientation with respect to one another to form
infinite one-dimensional tape (Table 3). Thus, in F-py, the
overall supramolecular structure is constructed with the coop-
eration of π⋯π stacking, hydrogen bonds and Cpyz–F⋯H–Cpyz
intermolecular interactions.
In Cl-py crystal packing, the most noticeable intermolecular
features are CO⋯H–Cpyz
,
Cpyz–H⋯Npy and Cpy–H⋯Cl
hydrogen bonds (Table 2) that are cooperated with π–π stack-
ing interactions between pyridine and pyrazine rings in the
a-direction (Fig. 3 and Table 3). Unlike in Cl-phen, the chlo-
rine atom in Cl-py is not involved in any contacts that can be
categorized as halogen bonds. The crystal structure of Br-py in
the bc-plane is built up mainly by two kinds of N⋯X halo-
gen bonds having different nitrogen atoms as halogen bond
acceptors, (C9–Br1⋯N6 and C19–Br2⋯N1) and N–H⋯Br and
C–H⋯OC hydrogen bonds. A view of the crystal structure
along the crystallographic a-axis reveals that πpy⋯πpyz stack-
ing interactions play an important role in stabilizing the
crystal structure (Fig. 4 and Tables 2 and 3). Based on the
binding energies obtained from DFT calculations with correc-
tion for the basis set superposition error (BSSE), of two
Fig. 1 The ORTEP diagrams of F-py (a), Cl-py (b), Br-py (c) and I-py
(d) compounds. Ellipsoids are drawn at a 30% probability level.
N⋯Br halogen bonds, the stronger halogen bond is formed
when the pyrazine nitrogen atom, anti to the carbonyl, is a
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linked to each other by head-to-tail N⋯X halogen bonds
to generate a wave-like chain (Fig. 5(a)). Extensive πpy⋯πpyz
stacking interactions also stabilize the molecular packing in
the c-direction (Fig. 5(b) and Table 3).
Strengthening N⋯X halogen bonding via nitrogen
substitution in the aromatic framework
A comparison between the significant intermolecular interac-
tions controlling the packing of X-phen and X-py is illustrated
in Scheme 2. A way to understand the strength of XB is con-
sidering and analyzing the crystal packing of isomolecular
structures. This approach enables systematic investigation of
crystal packing changes that arise as a consequence of tuning
the relative strength of XB to the other interactions. Here, we
report the crystallographic study of an isostructural X-py
compound, to provide new insights into the understanding
of the effect of substituting nitrogen for the CH group in the
aromatic backbone of a series of compounds that have been
recently investigated by us.8b This effect has been studied
recently by Blockhuys and his co-workers,9 who have investi-
gated the factors influencing the activation and de-activation
of fluorine synthons, in a different molecular system. The
nitrogen atom is isoelectronic with a CH group; thus aromatic-
ity is maintained when CH group(s) constituting the frame-
work of the phenylpyrazinamide system is (are) replaced by
the nitrogen atom(s) (Scheme 1). The nitrogen atom of the
pyridine ring in the N-(5-halo-2-pyridinyl)pyrazine-2-carboxamide
molecule imports new features into the crystal engineering of
phenylpyrazinamide derivatives. The pyridinic nitrogen atom
Fig. 2 (a) A side view representation of N-(5-fluoro-2-yl)pyrazine-
2-carboxamide, F-py, in the bc-plane, showing the association of the
adjacent molecules through head-to-tail Cpyz–H⋯Npy hydrogen bonds
for the generation of a dimeric unit. Adjacent dimeric units are further
linked to each other by Cpy–F⋯Cpyz and Cpy–H⋯OC intermolecular
interactions in the bc-plane. (b) A side view representation of F-py,
showing how extensive π–π stacking interactions, in the a-direction,
occur when the corresponding molecules are in parallel orientation
with respect to one another to form infinite one-dimensional tape.
halogen bond acceptor, of which the C–Br⋯N angle is farther
from 180° but the C–Br⋯N distance is shorter (Table 4). In the
crystal packing of I-py, dimeric units are formed alternatively
by head-to-tail
C
pyz–H⋯Npy and CO⋯H–Cpy hydrogen
bonds, in the a-direction. Adjacent dimeric units are further
Table 2 Selected hydrogen bond geometries for compounds F-py, Cl-py, Br-py, I-py, F-phen, Cl-phen, Br-phen and I-phen
Compound
D–H⋯A
d(D–H)
d(H⋯A)
d(D⋯A)
<(DHA)
F-py
C10–H10⋯O1–C5a
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
0.93
2.664
2.619
2.483
2.507
2.670
2.687
2.964
2.449
2.625
2.839
2.550
2.640
2.453
2.729
2.497
2.609
2.417
2.770
2.779
2.469
2.764
2.774
2.398
2.841
3.572(2)
3.495(3)
3.148(4)
3.391(4)
3.243(5)
3.594(4)
3.689(4)
3.26(1)
175
157
129
159
121
165
138
145
128
166
128
163
150
153
148
140
143
148
149
139
149
148
145
150
b
C1–H1⋯N4py
Cl-py
C1–H1⋯O2–C15c
C18–H18⋯O1–C5d
C2–H2⋯O2–C15e
f
C10–H10⋯N2pyz
C7–H7⋯Cl2–C19g
C13–H13⋯O1–C5h
C7–H7⋯O2–C15h
N3–H3B⋯Br2–C19a
C8–H8⋯O1–C5i
Br-py
3.28(1)
3.681(8)
3.21(2)
I-py
j
C1–H1⋯N4py
3.54(2)
F-phen
C11–H11⋯O1–C5k
3.293(3)
3.581(3)
3.323(3)
3.373(3)
3.21(1)
l
C13–H13⋯N2pyz
C19–H19⋯F1–C9m
C8–H8⋯F2–C20l
C11–H11⋯O1–C5k
Cl-phen
Br-phen
I-phen
k
C1–H1⋯N2pyz
3.59(1)
3.61(1)
n
C3–H3⋯N1pyz
C11–H11⋯O1–C5n
3.226(7)
3.592(8)
3.597(7)
3.202(4)
3.677(5)
n
C1–H1⋯N2pyz
o
C3–H3⋯N1pyz
C7–H7⋯O1–C5n
n
C1–H1⋯N2pyz
Symmetry codes:a −1/2 + x, 1/2 − y, −1/2 + z. b −x, 1 − y, −z. c 1 − x, 1 − y, 1 − z. d x, y, 1 + z. e 1 − x, 1 − y, 1 − z. f x, −1 + y, z. g x, y, −1 + z. h 1 − x, −y,
i
j
k
l
m
n
o
3 − z. −x, −y, 1 − z. 2 − x, −y, 2 − z. 1 + x, y, z. 1 − x, −1/2 + y, 3/2 − z. 2 − x, 1/2 + y, 1.5 − z. −1 + x, y, z. 1 + x, y, z.
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Table 3 π–π stacking interaction geometries for compounds F-py, Cl-py, Br-py, I-py, F-phen, Cl-phen, Br-phen and I-phen
Complex
Interaction
Type of interaction
C–C (Å)
P–P (°)
P–CC (°)
F-py
Cl-py
Br-py
π–π stacking
π–π stacking
π–π stacking
πpyz–πpyz, πpy–πpy
πpyz–πpy
πpyz–πpy
3.767
0.0
3.62
3.6
25.109, 26.302
29.551, 28.316, 23.228, 26.252
19.831, 23.440, 23.877, 22.066
3.849, 4.028
3.727, 3.739,
3.777, 3.805
3.677, 3.977
3.764, 3.842,
3.874, 3.785
3.865
3.494
3.904
3.534
3.747, 3.992
I-py
F-phen
π–π stacking
π–π stacking
πpyz–πpy
πpyz–πphen
4.34
22.299, 26.418, 29.306, 33.509
25.001, 18.379, 24.577, 18.471
23.454, 21.151, 22.926, 20.572
16.750, 20.125
7.89, 8.37,
8.55, 9.05
11.34
—
11.05
—
Cl-phen
Br-phen
I-phen
π–π stacking
Amide⋯π
πpyz–πphen
Amide⋯π
πpyz–πphen
Amide⋯π
πpyz–πphen
—
π–π stacking
Amide⋯π
19.058, 20.152
—
19.180, 13.065, 27.869, 22.429
π–π stacking
8.15
either could be directly involved in new intermolecular inter-
actions, such as C–H⋯Npy hydrogen bonds, or could indi-
rectly alter the electron distribution of the aromatic ring, to
which the halogen atom is bonded. The dihedral angle
between the planes of pyrazine and pyridine rings lies
between 1.24 and 4.34° for X-py compounds (Table 5). X-py
compounds, compared with X-phen, show better coplanarity
between the aromatic rings, which is the consequence
of intramolecular N–H⋯Npy hydrogen-bond formation. In
addition to intramolecular hydrogen bonding, the pyridinic
nitrogen atom is mainly involved in intermolecular C–H⋯Npy
hydrogen bonds for the formation of dimeric units (Table 2).
Investigations of intermolecular interactions and crystal
packing of F-py and Cl-py via Hirshfeld surface analysis10
reveal that, upon the replacement of the halogen-substituted
phenyl group of phenylpyrazinamide by a halogen-substituted
pyridine group, the probability of hydrogen bonding increases
while that of π⋯π stacking decreases (Fig. S2).† The differences
in the tendency of aromatic rings to stack via π-bonding
can be elucidated through a comparison of molecular electro-
static potential surfaces of the F-py and Cl-py as shown in
Fig. S3.† The presence of a nitrogen heteroatom within the
ring changes the π-electron distribution throughout the car-
bon backbone, therefore, the aromatic ring in X-py becomes
considerably electron poorer than in X-phen. As a result, the
Cl-py exhibits crystal packing where hydrogen bonding inter-
actions are favored over weak N⋯Cl halogen bonding, a type
of bonding which has been observed in Cl-phen crystal pack-
ing. As expected, the halogen bond strength is enhanced by
using a heavier halogen substituent. Accordingly, the interest-
ing feature in the crystal structures of Br-py and I-py is that
there is a tendency to form a halogen bonding synthon
between halopyridyl and pyrazine rings. For Br-phen, Br-py,
I-phen and I-py, the N⋯X distances of 3.284(5), 3.35(1) and
3.26(1), 3.450(3) and 3.11(1) Å, respectively, between halogen
and nitrogen atoms are 3.4%, 1.4% and 4.1%, 2.2% and
11.9% shorter than the sum of the van der Waals radii,
respectively (Table 4). The θN⋯X–C angle of the halogen
bonded compounds investigated here varies between
154.0(3)° and 175.9(5)° (Table 4). The nearly linear geometry
of N⋯X is in agreement with the n → σ* character of this
Fig.
3 A side view representation of N-(5-chloro-2-yl)pyrazine-
2-carboxamide, Cl-py, in the bc-plane, showing the association of the
adjacent molecules through CO⋯H–Cpyz, Cpyz–H⋯Npy and Cpy–H⋯Cl
hydrogen bonds that are cooperated with π–π stacking interactions
between pyridine and pyrazine rings in the a-direction.
Fig. 4 (a) A side view representation of N-(5-bromo-2-pyridinyl)pyrazine-
2-carboxamide, Br-py, in the bc-plane, showing the formation of a 2D
sheet through N⋯X halogen bonds, and N–H⋯Br and C–H⋯OC
hydrogen bonds. (b) A view of the Br-py crystal structure along the
crystallographic a-axis, and the πpy⋯πpyz stacking interactions are in an
antiparallel fashion. Halogen bonds are highlighted in red.
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Table 4 Halogen bond geometries and calculated XB binding energies for Br-phen, Br-py, I-phen and I-py compounds
Compound X⋯N (Å) C–X⋯N (°) Reduction of the sum of the VDW radii (%) Symmetry code
Calculated XB energy (kJ mol−1
)
X = Br
Br-phen
Br-py
3.284(5)
3.35(1)
3.26(1)
162.8(2)
166.8(4)
154.0(3)
3.4
1.4
4.1
−1 + x, y, −1 + z
1 − x, −y, 2 − z
−14.03
−16.63
1/2 + x, 1/2 − y, 1.5 + z −18.94
X = I
I-phen
I-py
3.450(3)
3.11(1)
166.66(9)
175.9(5)
2.2
11.9
−1 + x, 1 + y, −1 + z
−14.52
1/2 − x, 1/2 + y, 1.5 − z −23.54
Table 5 Dihedral angles between plane A, plane B and the amide
plane in X-phen and X-py compounds (plane A = pyrazine ring, plane
B = phenyl or pyridyl ring)
∠Amide plane ∠Amide plane ∠Plane A
Compound
and plane A (°) and plane B (°) and plane A (°)
F-py
3.45
2.13
1.24
Cl-py
Br-py
I-py
2.62, 6.53
5.60, 2.31
8.15
3.97, 2.93
3.35, 1.70
12.44
3.26, 3.62
3.52, 3.95
4.34
F-phen
Cl-phen
Br-phen
I-phen
4.17, 5.11
0.52
0.96
12.030, 14.16
11.38
12.00
7.89, 9.05
11.34
11.05
3.08
11.00
8.15
Definition of
geometrical
parameters
bonding interaction.1b,c The stronger participation of the
bromine atom in Br-py, compared with Br-phen, suggests that
the pyridinic nitrogen exerts a polarizing effect on the
halogen atom, thereby promoting larger σ-hole (Fig. 6). This
has been manifested in the higher proportion of halogen
bonding interactions in Br-py (6.1%) relative to Br-phen
(4.6%) (Fig. 7). In the case of I-py, the pyridinic nitrogen atom
induces a stronger polarizing effect on the halogen sub-
stituent, due to the higher polarizability of the iodine atom.
Thus, the participation of iodine in N⋯X halogen bonding is
approximately doubled from I-phen (3.1%) to I-py (6.0%).
Fig. 5 (a) A side view representation of N-(5-iodo-2-pyridinyl)pyrazine-
2-carboxamide, I-py, in the ab-plane, showing the formation of wave-
like 1D chains through head-to-tail N⋯I halogen bonds. (b) Generation
of a dimeric unit in I-py, by head-to-tail Cpyz–H⋯Npy and CO⋯H–Cpy
hydrogen bonds, in the a-direction. Extensive πpy⋯πpyz stacking inter-
actions also stabilize the molecular packing in the c-direction. Head-to-
tail N⋯I halogen bonds are highlighted in red.
Fig.
6 Electrostatic potentials mapped on the electron isodensity
surface of Br-phen (a) Br-py (b) I-phen (c) and I-py (d) at the same
contour value of 0.001 electron per Bohr3. The red color shows the
most negative potential, while the blue color represents the most
positive one. The side view representation of the halogen σ-hole is
shown on the left side of each MEP.
Scheme 2 A comparison between significant intermolecular interactions
controlling the packing of X-phen and X-py.
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Synthesis of N-(5-halophenyl)-2-pyrazinecarboxamides, X-phen
The compounds F-phen, Cl-phen, Br-phen and I-phen
were prepared by simply mixing the same equivalents of
para-haloaniline and pyrazinecarboxylic acid in pyridine in
the presence of triphenyl phosphate, according to what has
been reported previously.8b
Synthesis of N-(5-fluoro-2-yl)pyrazine-2-carboxamide, F-py
Fig. 7 Relative contributions of various intermolecular contacts to the
Hirshfeld surface area in Br-phen, Br-py, I-phen and I-py compounds.
The N-(5-fluoro-2-yl)pyrazine-2-carboxamide compounds were
prepared by the reaction of 2-amino-5-fluoropyridine (5 mmol)
and pyrazine-2-carboxylic acid (5 mmol) in pyridine at boiling
point temperature and under reflux conditions. Specifically,
2-amino-5-fluoropyridine (5 mmol) in 15 ml pyridine was
added to a solution of pyrazine-2-carboxylic acid (5 mmol) in
15 ml pyridine. The resulting solution was stirred at 313 K
for 20 min, then triphenyl phosphite (5 mmol) was added
dropwise, and the reaction mixture was stirred for 5 h at
373 K and for 24 h at ambient temperature. The mixture
was added to 200 ml distilled water. Precipitation of a white
solid resulted in a yield of 60%, which was filtered off and
dried under reduced pressure. Upon slow evaporation of the
filtrate at room temperature, suitable crystals of F-py for X-ray
analysis were obtained after 6 days (melting point = 161 °C).
Anal. calcd for C10H7FN4O: C, 55.05; H, 3.23; N, 25.68. Found:
C, 54.85; H, 3.14; N, 25.48. FT-IR (KBr pellet, cm−1):
3339, 1944, 1844, 1696, 1577, 1543, 1398, 1229, 1102, 1014,
841, 769, 674, 534, 423. 1H NMR (CDCl3, δ from TMS):
10.21 (1H-pyrazine), 9.50 (amidic H), 8.83 (1H-pyrazine), 8.62
(1H-pyrazine), 8.42–8.46 (1H-pyridine), 8.22 (1H-pyridine) and
7.49–7.55 (1H-pyridine).
It was of interest to investigate further, using theoretical
methods, the halogen bonding energy in Br-phen, Br-py,
I-phen and I-py compounds. The binding energies obtained
from DFT calculation with correction for the basis set super-
position error (BSSE) on two relative fragments provide us an
opportunity to evaluate the halogen bonding interaction
energy between two fragments. The selected fragments were
cut out directly from CIF data. The outcomes obtained from
DFT methods are listed in Table 4. From these data, it is
shown that N⋯X (X = Br and I) halogen bonding energies
vary within a range of −14.03 to −23.54 kJ mol−1. The theoreti-
cal results show that the halogen bonding interaction energy
increases from Br-phen to Br-py and from I-phen to I-py
(Table 4). Interestingly enough, in the X-phen (X = Cl, Br, I)
and X-py (X = Br, I) series, the melting points are increased
by increasing the strength of halogen bonding interaction
energies.
Conclusion
In conclusion, replacement of CH groups in Br-phen and
I-phen compounds with nitrogen atoms leads to crystal struc-
tures where the importance of halogen bonding becomes
even more pronounced. Interestingly enough, in the X-phen
(X = Cl, Br, I) and X-py (X = Br, I) series, the melting points
are increased by increasing the strength of halogen bonding
interaction energies. The results of this study should provide
an additional design tool in crystal engineering to tune the
relative strength of the halogen bonding.
Synthesis of N-(5-chloro-2-yl)pyrazine-2-carboxamide, Cl-py
The procedure was similar to the synthesis of F-py
except that 2-amino-5-chloropyridine was used instead of
2-amino-5-fluoropyridine. Precipitation of
a white solid
resulted in a yield of 70%, which was filtered off and dried
under reduced pressure. Upon slow evaporation of the filtrate
at room temperature, suitable crystals of Cl-py for X-ray anal-
ysis were obtained after 7 days (melting point = 165 °C). Anal.
calcd for C10H7ClN4O: C, 51.19; H, 3.01; N, 23.88. Found:
C, 51.15; H, 2.95; N, 23.76. FT-IR (KBr pellet, cm−1): 3352, 1957,
1698, 1572, 1523, 1462, 1380, 1301, 1100, 1016, 842, 736, 680,
Experimental section
Chemicals and instrumentation
1
438, 302. H NMR (CDCl3, δ from TMS): 10.23 (1H-pyrazine),
9.51 (amidic H), 8.84 (1H-pyrazine), 8.63 (1H-pyrazine),
840–8.43 (1H-pyridine), 8.33 (1H-pyridine), 7.74–7.78 (1H-pyridine).
All solvents such as methanol and pyridine and the chemicals
were commercially available (reagent grade) and were pur-
chased from Merck and Aldrich and used without further
purification. Infrared spectra (4000–400 cm−1) of the solid
samples were taken as 1% dispersion in KBr pellets using a
Synthesis of N-(5-bromo-2-yl)pyrazine-2-carboxamide, Br-py
The procedure was similar to the synthesis of F-py
except that 2-amino-5-bromopyridine was used instead of
1
BOMEM-MB102 spectrometer. H NMR spectra were recorded
using a Bruker AC-300 MHz spectrometer at ambient temper-
ature in CD3OD. All chemical shifts are quoted in parts per
million (ppm) relative to tetramethylsilane. The melting point
was obtained using a Bamstead Electrothermal type 9200
melting point apparatus and corrected.
2-amino-5-fluoropyridine. Precipitation of a white solid
resulted in a yield of 55%, which was filtered off and dried
under reduced pressure. Upon slow evaporation of the filtrate
at room temperature, suitable crystals of Br-py for X-ray
analysis were obtained after 8 days (melting point = 166 °C).
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Anal. calcd for C10H7BrN4O: C, 43.03; H, 2.53; N, 20.07.
Found: C, 42.97; H, 2.45; N, 19.72. FT-IR (KBr pellet, cm−1):
3339, 1900, 1823, 1700, 1570, 1525, 1356, 1283, 1087, 1035,
Computational details
DFT calculations were performed using the ORCA quantum
chemistry suite.21 The local spin density approximation (LSD)
exchange correlation potential was used with the local
density approximation of the correlation energy.22 Gradient-
corrected geometry optimizations23 were performed by using
the generalized gradient approximation (Perdew–Wang
non-local exchange and correlation corrections-PW91).24 The
selected two fragments were cut out directly from the CIF
data without optimization. Large atom basis sets TZP are
used to ascribe all the atoms here. A frozen core approxima-
tion was used to treat the core electrons: (1s) for C and N,
(4p) for I, (3p) for Br, (2p) for Cl, (1s) for O and F. Scalar rela-
tivistic effects were taken into account by using the zeroth-
order regular approximation (ZORA).25
1
829, 776, 663, 502, 438. H NMR (CDCl3, δ from TMS): 10.22
(1H-pyrazine), 9.51 (amidic H), 8.84 (1H-pyrazine), 8.63
(1H-pyrazine), 8.50–8.53 (1H-pyridine), 8.35–8.42 (1H-pyridine)
and 7.87–7.9 (1H-pyridine).
Synthesis of N-(5-iodo-2-yl)pyrazine-2-carboxamide, I-py
The procedure was similar to the synthesis of F-py
except that 2-amino-5-iodopyridine was used instead of
2-amino-5-fluoropyridine. Precipitation of
a white solid
resulted in a yield of 70%, which was filtered off and dried
under reduced pressure. Upon slow evaporation of the filtrate
at room temperature, suitable crystals of I-py for X-ray
analysis were obtained after 8 days (melting point = 170 °C).
Anal. calcd for C10H7IN4O: C, 36.83; H, 2.16; N, 17.18. Found:
C, 36.80; H, 2.14; N, 17.13. FT-IR (KBr pellet, cm−1): 3352,
1690, 1563, 1530, 1356, 1290, 989, 842, 660, 522, 441, 275.
1H NMR (CDCl3, δ from TMS): 10.18 (1H-pyrazine), 9.49
(amidic H), 8.83 (1H-pyrazine), 8.62 (1H-pyrazine), 8.55
(1H-pyridine), 8.24–8.27 (1H-pyridine) and 8.02–8.05
(1H-pyridine).
Computational details for generating molecular electrostatic
potential surfaces
Electrostatic potential surfaces were generated for F-phen,
F-py, Cl-phen, Cl-py, Br-phen, Br-py, I-phen and I-py from
DFT calculations performed at the B3LYP/6-311G (d,p) basis
set level for all atoms except iodine, and the LANL2DZdp-ECP
(with polarization functions of d symmetry and diffuse
functions of p symmetry) basis set level for iodine. Potential
surfaces were mapped by conventional molecular electron
density (0.001 electron per Bohr3) and color-coding.
Single crystal diffraction studies
For all compounds apart from F-phen, the intensity data were
collected using STOE IPDS-II or STOE-IPDS-2 T diffractometers
with graphite monochromated Mo-Kα radiation, 0.71073 Å.
Data were collected at a temperature of 298(2) K in a series
of ω scans in 1° oscillations and integrated using the Stoe
X-AREA11 software package. A numerical absorption correc-
tion was applied using the X-RED12 and X-SHAPE13 software.
The X-ray data for compound F-phen were collected using a
Bruker SMART APEX-II CCD diffractometer equipped with
fine focus 1.75 kW sealed tube Mo-Kα radiation, 0.71073 (Å).
The total number of images was based on the results from
the program COSMO.14 Cell parameters were retrieved using
the APEX II software15 and refined using SAINT on all
observed reflections. Data reduction was performed using the
SAINT software,16 which corrects for Lorentz and Polarizing
effects. Scaling and absorption corrections were applied
using the SADABS17 multi-scan technique, supplied by
George Sheldrick. All of the structures were solved by direct
methods using SHELXS-97 and refined with full-matrix least-
squares on F2 using the SHELXL-97 program package.18 All
non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were added at ideal positions and constrained to ride
on their parent atoms, with Uiso(H) = 1.2 Ueq. All of the refine-
ments were performed using the X-STEP32 crystallographic
software package.19 Structural illustrations have been drawn
using the MERCURY20 windows. ORTEP diagrams of these
complexes are shown in Fig. 1 and S1.† Crystallographic details
including crystal data and structure refinement parameters
are listed in Table S1.†
Acknowledgements
We would like to thank the Graduate Study Councils of
Shahid Beheshti University, General Campus, and the Iran
National Elite Foundation for financial support.
Notes and references
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