Studies on complex π-π and T-stacking features of imidazole and phenyl/p-halophenyl units in series of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides and their carbonitrile derivatives: Role of halogens in tuning of conformation

Article abstract of DOI:10.1016/j.molstruc.2017.06.124

5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides (N-phenyl AICA) (2a-e) and 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitriles (N-phenyl AICN) (3a-e) had been synthesized. X-ray crystallographic studies of 2a-e and 3a-e had been performed to identify any distinct change in stacking patterns in their crystal lattice. Single crystal X-ray diffraction studies of 2a-e revealed π-π stack formations with both imidazole and phenyl/p-halophenyl units in anti and syn parallel-displaced (PD)-type dispositions. No π-π stacking of imidazole occurred when the halogen substituent is bromo or iodo; π-π stacking in these cases occurred involving phenyl rings only. The presence of an additional T-stacking had been observed in crystal lattices of 3a-e. Vertical π-π stacking distances in anti-parallel PD-type arrangements as well as T-stacking distances had shown stacking distances short enough to impart stabilization whereas syn-parallel stacking arrangements had got much larger π-π stacking distances to belie any syn-parallel stacking stabilization. DFT studies had been pursued for quantifying the π-π stacking and T-stacking stabilization. The plotted curves for anti-parallel and T-stacked moieties had similarities to the ‘Morse potential energy curve for diatomic molecule’. The minima of the curves corresponded to the most stable stacking distances and related energy values indicated stacking stabilization. Similar DFT studies on syn-parallel systems of 2b corresponded to no π-π stacking stabilization at all. Halogen-halogen interactions had also been observed to stabilize the compounds 2d, 2e and 3d. Nano-structural behaviour of the series of compounds 2a-e and 3a-e were thoroughly investigated.

Full text of DOI:10.1016/j.molstruc.2017.06.124

Accepted Manuscript
Studies on complex π-π and T-stacking features of imidazole and phenyl/p-
halophenyl units in series of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-
carboxamides and their carbonitrile derivatives: Role of halogens in tuning of
conformation
Aniruddha Das
PII:
S0022-2860(17)30904-3
10.1016/j.molstruc.2017.06.124
MOLSTR 24010
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 17 May 2017
Revised Date: 25 June 2017
Accepted Date: 27 June 2017
Please cite this article as: A. Das, Studies on complex π-π and T-stacking features of imidazole and
phenyl/p-halophenyl units in series of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides and
their carbonitrile derivatives: Role of halogens in tuning of conformation, Journal of Molecular Structure
(2017), doi: 10.1016/j.molstruc.2017.06.124.
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ACCEPTED MANUSCRIPT
Studies on complex π-π and T-stacking features of imidazole and phenyl/p-halophenyl units in series
of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides and their carbonitrile derivatives:
role of halogens in tuning of conformation
Aniruddha Das*
University College of Science, Technology & Agriculture,University of Calcutta, 92, Acharya Prafulla
Chandra Road, Kolkata-700009
E-mail: aniruddha.1086@rediffmail.com Fax: + 91 033 2351 9755
Graphical Abstract
1

ACCEPTED MANUSCRIPT
Studies on complex π-π and T-stacking features of imidazole and phenyl/p-halophenyl units in series
of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides and their carbonitrile derivatives:
role of halogens in tuning of conformation
Aniruddha Das*
University College of Science, Technology & Agriculture,University of Calcutta, 92, Acharya Prafulla
Chandra Road, Kolkata-700009
E-mail: aniruddha.1086@rediffmail.com
Fax: +91 033 2351 9755
Abstract
5
-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides (N-phenyl AICA) (2a-e) and 5-amino-1-
(phenyl/p-halophenyl)imidazole-4-carbonitriles (N-phenyl AICN) (3a-e) had been synthesized. X-ray
crystallographic studies of 2a-e and 3a-e had been performed to identify any distinct change in stacking
patterns in their crystal lattice. Single crystal X-ray diffraction studies of 2a-e revealed π-π stack
formations with both imidazole and phenyl/p-halophenyl units in anti and syn parallel-displaced (PD)-type
dispositions. No π-π stacking of imidazole occurred when the halogen substituent is bromo or iodo; π-π
stacking in these cases occurred involving phenyl rings only. The presence of an additional T-stacking had
been observed in crystal lattices of 3a-e. Vertical π-π stacking distances in anti-parallel PD-type
arrangements as well as T-stacking distances had shown stacking distances short enough to impart
stabilization whereas syn-parallel stacking arrangements had got much larger π-π stacking distances to
belie any syn-parallel stacking stabilization. DFT studies had been pursued for quantifying the π-π
stacking and T-stacking stabilization. The plotted curves for anti-parallel and T-stacked moieties had
similarities to the ‘Morse potential energy curve for diatomic molecule’. The minima of the curves
corresponded to the most stable stacking distances and related energy values indicated stacking
2

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stabilization. Similar DFT studies on syn-parallel systems of 2b corresponded to no π-π stacking
stabilization at all. Halogen-halogen interactions had also been observed to stabilize the compounds 2d, 2e
and 3d. Nano-structural behaviour of the series of compounds 2a-e and 3a-e were thoroughly investigated.
Keywords
…
N-phenyl AICA; N-phenyl AICN; X-ray crystallography; C-H π-stacking; DFT studies, self-aggregation.
1
. Introduction
Intermolecular interactions are fundamentally important for predicting a gamut of phenomena ranging
from simple acid-base behavior to functional nano-material formation [1-6]. In addition to hydrogen
bonding interactions, π- π interactions [7], non-classical hydrogen bonds [8-10], halogen-halogen soft
…
interactions [11-16] and non-covalent halogen bonds (X N/O, X= halogens) [17-18] have been found to
be instrumental, in various cases, in determining the physical and chemical properties of compounds with
aromatic and heterocyclic rings and halogen substituents. Benzene-dimer serves as the prototypical model
of π- π stacking and two most important structural minima for benzene dimers are the parallel-displaced
…
(
PD) π-stacked and C-H π hydrogen bonded T-stacked structures [19-23]; parameterization of π- π
stacking of benzene dimer have been the subject of many theoretical studies involving various functionals
in the density functional theory (DFT). In case of parallel-stacked substituted benzene dimers, the aspects
of the binding being stronger than the unsubstituted benzene, irrespective of the nature of substituents,
have been reported; important contributions of dispersion, induction and exchange-repulsion items to the
binding energy have also been considered [21,23,24]. Studies on π- π stacking of aromatically substituted
N-heterocyclic molecules have gained momentum [25,26]. Imidazole is an acclaimed heterocyclic nucleus
involved in various biochemical processes and pharmaceutics. AICA riboside (1) (Fig. 1) is the de-nevo
purine precursor in the bio-synthetic pathway of purine nucleotides [27].
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O
H N
2
O
N
HO
HO
H N
2
P
N
O
O
HO
OH
1
Fig. 1. Structure of AICAR (1)
In continuation of earlier work on AICA [28], recently I have reported [29] a systematic study on the π-π
stacking features of a series 5-amino-1-alkylimidazole-4-carboxamides. This reports the fact that the
imidazole units in these 1-alkylimidazole compounds show, in their X-ray crystallographic patterns, the
very important anti-parallel and syn-parallel π-π stackings which were further supported by their DFT
-1
analysis. Since gas-phase benzene-dimer has reportedly got a binding energy of 2-3 Kcal mol [30] I
surmised to take up studies on similar AICA compounds where the imidazole unit holds a phenyl/p-
halophenyl at N-1 instead of alkyl. The aspect of inclusion of an aryl substituent induced possible varieties
of π-π stackings of homo-dimers (imidazole-imidazole and phenyl-phenyl) as well as hetero-dimer
(imidazole-phenyl) types, along with the possible additional intricacies of the presence of anti-parallel and
syn-parallel conformations. The conversion from 5-amino-1-(phenyl/p-halophenyl)imidazole-4-
carboxamides (2a-e) to 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitriles (3a-e) was carried
out to study the change in stack formation in the crystal lattice with the change of the functional group.
DFT studies on these compounds had been pursued for the purpose of quantifying the stabilization in
cases of π-π stacking of imidazole dimers and phenyl/p-halophenyl dimers as well as T-stacking
interactions. In each case, DFT calculated results were in good agreements with the X-ray crystallographic
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results. Recently there has been a surge of studies on π,π stacking-based organic materials to unravel
unique optical and optoelectronic properties [31] being superior to the corresponding bulk counterparts. 1-
D organic nanostructures have been successfully constructed by way of π- π stacking, hydrogen bonding
[31,32] and electrostatic interactions, among others. Compounds 2a-c, 2e and 3a-e had shown to have
generated 1-D nanostructures as well as 2d had shown nano-vesicle morphology.
2
. Experimental
2
.1. Materials and methods
Melting points were recorded on an electrically heated Köfler Block apparatus and are uncorrected. The
solid-state FT-IR measurements were done with a Perkin-Elmer-782 model spectrometer in the form of
1
13
KBr discs of the compounds. H NMR and C NMR spectra were run with DMSO-d solutions at
6
1
13
ambient temperature on a Bruker Avance 300 spectrometer at 300 MHz for H and at 75 MHz for C.
Chemical shifts are reported in δ and coupling constants in Hz. The multiplicity of the carbon atoms was
determined by the DEPT 135º experiment. The DFT calculations had been performed by using the basis
set mpwb95/6-31++g for 2a-d and 3a-d as well as mpwb95/lanl2dz for 2e and 3e in Gaussian 09W [33]
suite of programs. These basis sets included correlation consistent methods which consist of diffusion
correction being advantageous for our targets of π-π stacking calculation considered upto long range.
2
.2. General procedure for the preparation of 5-amino-1-(phenyl/p-halophenyl) imidazole-4-
carboxamides (2a-e)
Syntheses of compounds 2a and 2c were reported [34]. The same protocol was utilized to synthesize
three new compounds 2b, 2d and 2e of the series of 2a-e.
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Scheme 1. Preparation of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamide
compounds (2a-e)
To freshly prepared 2-amino-2-cyanoacetamide (0.02mol) in dry and freshly distilled acetonitrile (15 ml)
triethyl orthoformate (0.02 mol) was added and the mixture was heated under reflux for 40 minutes. To
the reaction mixture at room temperature aniline/ p-haloaniline (0.02 moles) was then added. The reaction
mixture was refluxed for 30 min. when the title compound began to precipitate. The reaction mixture was
allowed to cool. The ice-cooled mixture was filtered and washed with a little of acetonitrile. The crude
product was crystallized from aqueous ethanol.
2
.2.1. 5-Amino-1-phenylimidazole-4-carboxamide (2a)
1
Colourless crystal ( from aq. EtOH), yield 59.4%, m.p. 202 °C: H NMR (300 Mhz, DMSO-d ): δ 7.37
6
H
(
1H, s, 2-H), 5.76 ( 2H, s, O=C-NH ), 6.81 & 6.96 ( 2H, pair of br. s, -NH ), 7.52 (5H, m, o, m and p-
2
2
1
3
protons); C NMR ( 75MHz, DMSO-d
6
): δ
C
128.57 (2-C), 113.48 (4- C), 143.09 (5-C) , 167.21 (O=C-
1
NH
2
), 135.09 (1′-C), 125.00 (2′-C & 6′-C), 130.28 (3′-C & 5′-C), 130.14 (4′-C) ; IR υmax(KBr), cm¯ :
3
750 (amide N-H), 3396 (amino N-H), 3189 (aromatic C-H), 1667 (amide –C=O), 1548 (aromatic C=C).
6

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2
.2.2. 5-Amino-1-(4-fluorophenyl)imidazole-4-carboxamide (2b)
Colourless crystal ( from aq. EtOH), yield 63.63%, m.p. 282-284°C: δ 7.30 (1H, s, 2-H), 5.71 ( 2H, s
H
O=C-NH ), 6.75 & 6.90 ( 2H, pair of br. s, -NH ), 7.36 (2H, t, J 8.7 Hz, 2′-H & 6′-H), 7.50 ( 2H, m, 3′-H
2
2
1
3
&
5′-H),
C NMR ( 75MHz, DMSO-d ): δ 129. 86 (2-C), 112.96 (4-C), 142.88 (5-C) , 166.80 (O=C-
6
C
3
2
NH ), 131.02 (1′-C), 127.28 (dd, J 9.0 Hz , 2 ′-C & 6 ′-C), 116.68 (dd, J 23.25 Hz , 3 ′-C & 5 ′-C),
2
C-F
C-F
1
1
1
61.59 (d, J
244.5 Hz ,4′-C); IR υmax(KBr), cm¯ : 3770 (amide N-H), 3331.5 (amino N-H), 3110
C-F
(
aromatic C-H), 1666 (amide –C=O), 1556 (aromatic C=C).
.2.3. 5-Amino-1-(4-chlorophenyl)imidazole-4-carboxamide (2c)
Colourless crystal ( from aq. EtOH), yield 67.68%, m.p. 258-260°C: H NMR ( 300 Mhz, DMSO-d
.38( 1H, s, 2-H), 5.81 ( 2H, br.s, O=C-NH ), 6.82 and 6.97 ( 2H, pair of br. s., -NH ), 7.54 (2H, d, J 8.7
2
1
6
): δ
H
7
2
2
1
3
Hz, 2′-H & 6′-H), 7.63 (2H,d, J 8.7 Hz, 3′-H & 5′-H), C NMR ( 75MHz, DMSO-d ): δ 130.04
6
C
(
2-C), 113.49 (4-C), 143.08 (5-C) , 167.13 (O=C-NH ), 133.96 (1′-C), 126.95 (2′-C & 6′-C), 130.18 (3′-C
2
1
&
5′-C), 133.08 (4′-C) ; IR υmax(KBr), cm¯ : 3755 (amide N-H), 3322 (amino N-H), 3103 (aromatic C-H),
1
666 (amide –C=O), 1552 (aromatic C=C).
2
.2.4. 5-Amino-1-(4-bromophenyl)imidazole-4-carboxamide (2d)
1
Colourless crystal ( from aq. EtOH), yield 64.05%, m.p. 254-256°C: H NMR ( 300 Mhz, DMSO-d
6 H
): δ
7
.34 (1H, s, 2-H), 5.78 ( 2H, br.s, O=C-NH ), 6.78 & 6.94 ( 2H, pair of br. s ,-NH ), 7.71 (2H, d, J 8.6
2
2
13
Hz, 2′-H & 6′-H), 7.43 (2H, d, J 8.6 Hz, 3′-H & 5′-H), C NMR ( 75MHz, DMSO-d ): δ 129.63 (2-C),
6
C
1
13.11 (4- C), 142.68 (5-C) , 166.76 (O=C-NH ), 134.00 (1′-C), 126.86 (2′-C & 6′-C), 132.77 (3′-C & 5′-
2
1
C), 121.11 (4′-C) ; IR υmax(KBr), cm¯ : 3763 (amide N-H), 3332 (amino N-H), 3169 (aromatic C-H),
1
655 (amide –C=O), 1540 (aromatic C=C).
2
.2.5. 5-Amino-1-(4-iodophenyl)imidazole-4-carboxamide (2e)
7

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1
Colourless crystal ( from aq. EtOH), yield 61.19%, m.p. 270-272°C: H NMR ( 300 Mhz, DMSO-d
6 H
): δ
7
.32( 1H, s, 2-H), 5.76 ( 2H, br.s, O=C-NH ), 6.75 & 6.93 ( 2H, pair of br. s ,-NH ), 7.27 (2H, d, J 8.4
2
2
13
Hz, 2′-H & 6′-H), 7.86 (2H, d, J 8.4 Hz, 3′-H & 5′-H), C NMR ( 75MHz, DMSO-d ): δ 129.73 (2-C),
6
C
1
13.05 (4-C), 142.75 (5-C) , 166.86 (O=C-NH ), 134.45 (1′-C), 126.95 (2′-C & 6′-C), 138.75 (3′-C & 5′-
2
1
C), 94.10 (4′-C) ; IR υmax(KBr), cm¯ : 3763 (amide N-H), 3319 (amino N-H), 3188 (aromatic C-H), 1651
(
amide –C=O), 1529 (aromatic C=C) .
.3. General procedure for the preparation of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrils
3a-e)
Synthesis of compound 3c was reported in literature. Four new compounds 3a-b and 3d-e of the series of
2
(
3
a-e are reported in this paper.
NH2
NC
O
N
NC
N
dry DMF
2% HCl
N
H
N
H N
POCl3
N
2
N
C
H N
2
R
N
R
Me N
R
2
3
3
3
a: R= phenyl, 3b: R= p-fluorophenyl , 3c: R= p-chlorophenyl, 3d: R= p-bromophenyl,
e: R= p-iodophenyl
Scheme 2. Preparation of 5-amino-1-(phenyl/p-halophenyl)imidazole-4-carbonitrile
compounds (3a-e)
5
-amino-1-(phenyl/p-halophenyl)imidazole-4-carboxamides (2) (4mmol) was added in portions to ice-
cold dimethylformamide-phosphorous oxychloride complex, prepared from DMF (6ml) and POCl (1.2
3
ml, 12 mmoles), during 15 min with stirring. After the addition was complete, the mixture was kept in the
ice bath for 30 min. Then the mixture was allowed to warm up to room temperature and kept at room
temperature for a further period of 90 min, stirring being continued all the time. The resulting wine red
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solution was poured into crushed ice. The solution was made strongly ammoniacal. A brown solid was
precipitated. Then it was filtered and the brown mass was warmed on a steam bath with 2% aq.
hydrochloric acid (50 ml) for 1 hour. Afterthat, it was allowed to cool in ice-bath and made strongly
ammoniacal. The solid was precipitated and ice-cooled mixture was then filtered. The crude product was
crystallized from aqueous ethanol.
2
.3.1. 5-Amino-1-phenylimidazole-4-carbonitrile (3a)
1
Colourless crystal ( from aq. EtOH), yield 54.94%, m.p. 182-184 °C: H NMR (300 Mhz, DMSO-d
6
): δ
), 7.45-7.60 (5H, m, o, m and p-protons); C NMR ( 75MHz, DMSO-
C
133.07 (2-C), 91.67 (4-C), 147.70 (5-C) , 117.50 (-CN), 134.38 (1′-C), 125.77 (2′-C & 6′-C),
H
1
3
7
d
1
.41 (1H, s, 2-H), 6.15 (2H, s,-NH
): δ
30.34 (3′-C & 5′-C), 129.17 (4′-C); IR(KBr, cm ): 3317 (amino N-H), 3175 (aromatic C-H), 2211(-
2
6
-1
C≡N), 1578 (aromatic C=C).
.3.2. 5-Amino-1-(4-fluorophenyl)imidazole-4-carbonitrile (3b)
Colourless crystal ( from aq. EtOH), yield 60.10%, m.p. 198-200 °C: H NMR (300 Mhz, DMSO-d ): δ
2
1
6
H
1
3
7
7
1
.45-7.50 (2H, m, 2′-H &6′-H), 7.33-7.38 (3H, m, 2-H, 3′-H & 5′-H), 6.12 (2H, s, -NH ); C NMR (
2
4
5MHz, DMSO-d
6
): δ
C
133.09 (2-C), 91.39 (4-C), 147.96 (5-C), 117.47 (-CN), 130.64 (1′-C, JC-F 3 Hz),
3
2
1
28.5 (2′-C & 6′-C, JC-F 9 Hz), 117.11 (3′-C & 5′-C, JC-F 23.25 Hz), 162.31 (4′-C, JC-F 243.75 Hz).; IR
1
υmax(KBr), cm¯ : 3339.4 (amino N-H), 3191(aromatic C-H), 2368.9, 2217 (-C≡N), 1582 (aromatic C=C).
2
.3.3. 5-Amino-1-(4-chlorophenyl)imidazole-4-carbonitrile (3c)
1
Colourless crystal ( from aq. EtOH), yield 55.55%, m.p. 196-198°C: H NMR (300 Mhz, DMSO-d ): δ
6
H
7
6
1
.35 (1H, s, 2-H), 6.16 (2H, s,-NH ), 7.44 (2H, d, J 2.1 Hz, J 6.6 Hz, 2′-H &6′-H), 7.57 (2H, d, J 2.1 Hz, J
2
1
3
.6 Hz, 3′-H & 5′-H); C NMR ( 75MHz, DMSO-d ): δ 132.67 (2-C), 91.26 (4-C) , 147.52 (5-C) ,
6
C
17.11 (-CN), 133.55 (1′-C), 127.55 (2′-C & 6′-C), 130.00 (3′-C & 5′-C), 132.88 (4′-C); IR υmax(KBr),
1
cm¯ : 3324 (amino N-H), 3175 (aromatic C-H), 2213 (-C≡N), 1577 (aromatic C=C).
9

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2
.3.4. 5-Amino-1-(4-bromophenyl)imidazole-4-carbonitrile (3d)
1
Colourless crystal ( from aq. EtOH), yield 58.82%, m.p. 202-204°C: H NMR (300 Mhz, DMSO-d ): δ
6
H
7
.37 (1H, s, 2-H), 6.19 (2H, s,-NH ), 7.39 (2H, d, J 7.8 Hz, 2′-H &6′-H), 7.71 (2H, d, J 7.8 Hz, 3′-H &5′-
2
1
3
H); C NMR ( 75MHz, DMSO-d ): δ 132.47 (2-C), 91.19 (4-C), 147.36 (5-C) , 117.03 (-CN), 133.26
6
C
1
(
1′-C), 127.68 (2′-C & 6′-C), 132.81 (3′-C & 5′-C), 121.85 (4′-C); IR υmax(KBr), cm¯ : 3317 (amino N-H),
3
183 (aromatic C-H), 2207 (-C≡N), 1568 (aromatic C=C).
.3.5. 5-Amino-1-(4-iodophenyl)imidazole-4-carbonitrile (3e)
2
1
Colourless crystal ( from aq. EtOH), yield 53.19%, m.p. 238-240 °C: H NMR (300 Mhz, DMSO-d
6
): δ
), 7.28 ( 2H, d, J 8.4 Hz, 2′-H & 6′-H), 7.91 (2H, d, J 8.4 Hz, 3′-H &
′-H); C NMR ( 75MHz, DMSO-d ): δ 132.83 (2- C), 91.64 (4-C) , 147.67 (5-C) , 117.42 (-CN),
H
7
5
1
.40 ( 1H, s, 2-H), 6.21 ( 2H, s, -NH
2
1
3
6
C
1
34.11 (1′-C), 128.02 (2′-C & 6′-C), 139.06 (3′-C & 5′-C), 95.28 (4′-C); IR υmax(KBr), cm¯ : 3314 (amino
N-H), 3184 (aromatic C-H), 2205 (-C≡N), 1517.3 (aromatic C=C).
.4. Determination of crystal structure
2
For the purpose of single crystal X-ray diffraction studies, triple distilled ethanol properly diluted with
double distilled water to get aqueous ethanol was used as solvent of crystallization; suitable single crystals
of compounds 2a-e and 3a-e were obtained by recrystallization of the material from this freshly prepared
aqueous ethanol. Diffraction data were collected for 2a-e and 3a-e using the freshly crystallized material
with MoKα radiation at 296 K using a Bruker APEX-II CCD system. The crystals were positioned 50 mm
from the CCD. Frames were measured with a counting time of 10 s. During collection of data none of 2a-e
and 3a-e showed any evidence of crystal decay. Data analyses were carried out with the Bruker APEX2
and Bruker SAINT programs. The structures were solved using direct methods with the SHELXTL 97
program (Sheldrick, 2008).
1
0

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The ORTEP diagram of representative compound 5-amino-1-(4-bromophenyl)imidazole-4-carboxamide
(2e) of the series 2a-e and 5-amino-1-(4-iodophenyl)imidazole-4-carbonitrile (3d) of the series 3a-e are
shown in Fig. 2 and Fig. 3 respectively.
Fig. 2. ORTEP diagram of compound 2e
CCDC no. 1050706
Fig. 3. ORTEP diagram of compound 3d
CCDC no. 1050710
3
. Results and discussion
3
.1. Description of crystal structure
The observations that X-ray crystallographic analyses have been successful in unraveling stacked
arrangements in case of drug molecules and in the aromatic side-chains of proteins [36, 37] have infused
interest in the prediction of the role of stacking interaction on the stabilization of supramolecular
architecture. These findings have generated motivation for knowing its role in quantitative structure-
activity relationships [38]. The self-assembled supramolecular structure formation is intrigued in many
cases by π-π stacking as an important non-covalent force. As early as in 1938, Astbury and Bell [39]
reported a spacing of 3.3-3.4 Å between flat or almost flat nucleotide units existing perpendicular to the
long axis of the molecules. Studies on aromatic stacking interactions using conformationally flexible
1
1

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molecules have been the focus of a no. of relevant experiments [40]. Although there have been some
experimental and DFT studies on the π-π-stacking of several systems containing N-heterocyclic units, a
recent report [29] of studies on π-π stacked imidazole systems have unraveled, for the first time, the role
of π-π stacking of imidazoles in the anti-parallel conformations as the stabilizing factor in the crystal
lattice of a series of 5-amino-1-alkylimidazole-4-carboxamides; corresponding syn-parallel conformation
failed to tender any appreciable stabilization. I describe here in a systematic way the synthesis of series of
compounds 2a-e and 3a-e where the halo moiety embraces all the possible choices out of F, Cl, Br, I. It
was expected that the halogens with the widely varying electronegativities and sizes would sometime offer
drastically different situations. DFT studies had also been taken up in a cue. Parallel-displaced (PD) [41]
π-π stack formations had been observed in the X-ray crystallographic studies for 2a-e, occurring with both
imidazole and phenyl/p-halophenyl units in mutually anti-parallel and syn-parallel arrangements. The
crystal lattices of 3a-e revealed the presence of T-stackings along with the PD-stacked anti-/syn-parallel π-
π stackings of both imidazole-imidazole and phenyl-phenyl/p-halophenyl-p-halophenyl rings of two
correspondingly adjacent AICA derivatives. The crystal lattices of 2a-e did not show any T-stacking. No
hetero-dimer formation was noted in the crystal lattice of 2a-e and 3a-e. In cases of 2d-e and 3a-e some
different behaviours were observed.
Table 1 contains the details of crystal data showing the bond lengths and angles of 2a-e and Table 2
tabulates the similar data of 3a-e.
Table 1
Crystal data of 2a-e
Compound
2a
C H N O C H F N O C H Cl N O C H Br N O C H I N O
1
2b
2c
2d
2e
Formula
10
10
4
1
10
9
1
4
1
10
9
1
4
1
10
9
1
4
1
10 9 1
4
-1
M/g mol
Crystal
system
202.22
triclinic
220.21
triclinic
236.66
triclinic
281.12
monoclinic
328.11
monoclinic
1
2

ACCEPTED MANUSCRIPT
Space group
a (Å)
P-1
P-1
P-1
C12/c1
20.193(5)
10.467(2)
14.481(3)
90.00
C12/c1
13.667(3)
10.732(2)
15.228(3)
90.00
7.6252(7)
7.9439(7)
9.0756(9)
86.642(5)
87.258(4)
62.767(4)
7.6579(12)
7.7666(14)
9.1625(14)
87.927(8)
88.210(8)
63.477(7)
7.723(8)
b (Å)
8.005(8)
c (Å)
9.366(10)
85.799(13)
89.218(13)
63.289(12)
α (° )
β (° )
134.166(11)
90.00
90.462(8)
90.00
γ (° )
3
V (A° )
487.83(8)
2
1.377
487.21(14)
515.7(9)
2
1.524
2195.5(8)
8
1.701
2233.5(8)
8
1.952
Z
2
-3
ρC / g cm
1.501
Absorption
/ mm-1
0.095
0.116
0.353
3.728
2.852
ꢀ
Min. T
0.9720
0.0533
0.9660
0.0405
0.9016
0.0519
0.3553
0.0380
0.4817
0.0341
Final R
indices
[
I>2σ(l)] R
1
wR
R indices (all
2
0.1561
0.0621
0.1209
0.0470
0.1394
0.0915
0.1060
0.0528
0.0826
0.0522
data) R1
wR
2
0.1707
0.1364
0.1743
0.1190
0.0930
Recrys. from
hot aq.
ethanol
hot aq.
ethanol
hot aq.
ethanol
hot aq.
ethanol
hot aq.
Ethanol
CCDC
1050702
1050703
1050704
1050705
1050706
number
Table 2
Crystal data of 3a-e
3
a
3b
3c
3d
Br
263.11
3e
Compound
Formula
C
10
H
8
N
4
C
10
H
7
F
1
N
4
C
10
H
7
Cl
1
N
4
C
10
H
7
1
N
4
10 7 1 4
C H I N
-1
M/g mol
184.20
202.20
218.65
310.10
1
3

ACCEPTED MANUSCRIPT
Crystal system triclinic
Space group P-1
monoclinic monoclinic monoclinic monoclinic
C12/c1
P121/c1
P121/c1
11.1107(7) 10.947(3)
6.4150(4) 6.4268(14)
12.304(3) 12.0976(17) 15.0571(9) 15.673(4)
90.00
90.00 90.00
9.784(2)
105.805(2) 105.432(9)
90.00 90.00 90.00
P121/c1
a (A°)
b (A°)
c (A°)
α (° )
β (° )
6.2970(12) 18.045(5) 18.571(3)
9.248(2)
8.967(2)
18.342(3)
17.470(3)
92.896(10) 90.00
91.266(9)
103.385(3)
9
γ (° )
107.490(10) 90.00
3
V (A° )
968.4(3)
4
1936.9(9) 4060.9(10) 1032.62(11) 1062.9(4)
Z
8
16
4
4
-3
ρC / g cm
1.263
1.387
1.430
1.692
1.938
Absorption
-1
ꢀ
/ mm
0.082
0.103
0.345
3.950
2.983
Correctiontype
Max. T
0
.9919
.9758
0.9898
0.9698
0.6486
0.3646
0.7546
0.4681
0
.9684
0
0.9092
Min. T
Final Rindices 0.0490
I>2σ(l)] R
0.0471
0.0440
0.0364
0.0276
[
1
wR
R indices (all
data)R1
2
0.1562
0.0671
0.1367
0.0893
0.1328
0.0955
0.0952
0.0508
0.0660
0.0398
wR2
0.1843
0.1747
0.1841
0.1055
0.0722
hot aq.
ethanol
hot aq.
ethanol
hot aq.
ethanol
hot aq.
ethanol
hot aq.
ethanol
Recrys.from
CCDC
1050707
1050708
1050709
1050710
1050711
number
The extensive H-bonding patterns of representative compounds 2d of the series 2a-e and 3a of the series
a-e are shown in Fig. 4. The hydrogen bonding patterns are presented in Supplementary data, Fig. S21
3
1
4

ACCEPTED MANUSCRIPT
and Fig. S22 as well as the hydrogen bonding parameters for the compounds 2a-e and 3a-e are presented in
Supplementary data, Table S2 and Table S3.
Fig. 4. a) and b) show hydrogen bonding network of 2d and 3a respectively
The unit cell arrangement of the lattice of representative compound 2c is shown in Fig. 5a. Fig. 5b and Fig.
5
c reveal the features of π-π stacking of imidazole-imidazole and p-chlorophenyl-p-chlorophenyl units
respectively in PD-type anti-parallel arrangements.
1
5

ACCEPTED MANUSCRIPT
Fig. 5. (a) unit cell arrangement viewing along b-direction, (b) π- π stacking of two anti-parallel
imidazoles observed in X-ray crystallographic lattice and (c) π- π stacking of two anti-parallel phenyls
observed in X-ray crystallographic lattice of compound 2c.
Similar anti-parallel PD-stacked imidazole-imidazole and phenyl-phenyl π-π stacking interactions were
observed in the crystal lattices of 2a and 2b (shown in Supplementary data, Fig. S54 and Fig. S55
respectively) where the N1 substituents of AICA were phenyl and p-fluorophenyl groups respectively. It
was further observed from the X-ray studies of 2d and 2e, where the halogen substituents were of larger
size viz. p-bromophenyl- and p-iodophenyl- as the N-1 substituents respectively, the closely-associated
imidazole rings were not oriented in anti-parallel fashion. The closest imidazole rings in the corresponding
crystal lattices displayed dihedral angels of 65.49˚ and 70.41˚ respectively (shown in Fig. 6a. and Fig.
6
b.). These large dihedral angles of closely-associated imidazole rings of 2d and 2e exerted difficulty for
imidazole-imidazole anti-parallel π-π stacking.
1
6

ACCEPTED MANUSCRIPT
Fig. 6. a) and b) show Dihedral angle between the closest pair of imidazoles in the lattice of 2d and 2e
respectively
Table 3 presents the anti-parallel PD π-π stacking distances between imidazole-imidazole of compounds
2
a-c and similar π-π stacking distances between phenyl-phenyl moieties of 2a-c and 2e with their
respective slip angle values. The respective vertical distance values for those compounds are tabulated in
Table 3. Another important parameter termed as “vertical distance” [42] is defined as the shortest distance
between two stacked molecules and is represented by R (Fig. 7). The value of R could be calculated from
2
2
the Equation 1 where R is the distances observed between π-π stacked parallel-displaced imidazoles and θ
1
is designated as slip angle. The slip angle is essentially the angular deviation from the PD-stacked
imidazoles and hypothetical sandwich-stacked imidazoles.
2 1
R =R Cosθ………………………….Equation 1
Fig. 7. The vertical distance (R ), PD-stacked imidazole-imidazole distance (R ) and slip angle (θ)
2
1
1
7

ACCEPTED MANUSCRIPT
Similarly, measurements of slip angle and vertical distances between PD-stacked phenyl/p-halophenyls of
compounds 2a-e were calculated (shown in Supplementary data, Fig.S24- Fig.S42). Table 3 shows
distances between centroids of two imidazoles and centroids of two phenyls in anti-parallel stacking
arrangements were in the range of 4.43-4.53 and 4.01-4.46 Å respectively. These were the experimental
anti-parallel PD π-π stacking distances. In each case of a PD-stacked dimer, the corresponding vertical
distance of anti-parallel imidazole dimer as well as that of the phenyl/p-halophenyl dimer are shown in
Table 3. The vertical distances in the case of phenyl dimers were in the range of 3.83-4.07 Å and those in
the case of imidazole dimers lie in the range of 4.20-4.36 Å (Table 3). Although each of the crystal lattice
of 2a, 2b, 2c and 2e corresponded to anti-parallel conformation of the phenyl/p-halophenyl moieties in
PD-type arrangements[41], compound 2d had got a sensibly sandwich-type anti-parallel stacking of p-
bromophenyl moiety. The π-π stacking distance can very often be considered as a marker of the strength
of stacking interaction. With the results of Ab-initio calculation, Sinnokort et.al. [30] have ascertained a
value of 3.4 Å for vertical separation between the planes of PD π-π stacked benzenes. The earlier report
[29] of the vertical distances of anti-parallel imidazole dimers of 5-amino-1-alkylimidazole-4-
carboxamides, lying in the range 3.70-3.89 Å, can be compared with π-π anti-parallel stacking
stabilization.
Table 3
Anti-parallel PD π-π stacking distances from X-ray crystallographic analysis of 2a-e and the
corresponding vertical π-π stacking distances
Compound
imidazole-imidazole
anti-parallel π-π stacking
Phenyl/p-halophenyl-
phenyl/p-halophenyl
anti-parallel π-π stacking
π-π stacking
distance
slip angle
from
vertical
π-π
π-π stacking
distance from from
slip angle
vertical
π-π
from crystal
lattice
crystal
lattice (º)
distance
(Å)
crystal
lattice(Å)
crystal
lattice(º)
distance
(Å)
(Å)
1
8

ACCEPTED MANUSCRIPT
2
2
2
2
2
a
b
c
4.53
4.43
4.53
-
16.08
18.30
15.63
-
4.35
4.20
4.36
-
4.14
4.46
4.01
4.04
4.20
15.19
30.88
6.49
-
3.99
3.83
3.98
-
#
d
e
-
-
-
14.15
4.07
#
PD π-π stacking distance between p-bromophenyls for 1d is essentially “Sandwich” stacking
A comparison of vertical anti-parallel phenyl-phenyl stacking distances (Table 3) also revealed that
vertical distance for fluoro compound (2b) is the least (3.83 Å) and this value increased steadily in going
from fluoro to iodo in the series of 2b-2e. Among all the halogens, fluorine with the highest
electronegativity value of 4.0, a negative inductive effect value (σ ) of 0.51 and a positive mesomeric
I
effect (σ ) of -0.34 can show strong intramolecular interactions in case of organic fluoro compounds [43].
R
In 2000, Prasanna and Guru Row [44] have published a data base study on the influence of C-F…π
interactions on crystal packing and conformations. Recently S.Terada et.al. [45] have published an
account of polymorphism of different fluoro-substituted aromatic sulfonamides showing dependence on
intermolecular π-π interactions. Sinnokrot et. al. [24] have earlier communicated DFT studies on the effect
of substituent of a substituted-benzene unit on the binding with an unsubstituted benzene where –F and
-CN substituents correspond to much higher binding energies and lower distances between the centroids
of the rings. It had been discussed earlier that the anti-parallel PD π-π stackings between imidazole-
imidazole pairs were not feasible in cases of 2d-e. The phenyl-phenyl stacking for the compound 2d was
actually “Sandwich” (S) in nature which was evidenced from Fig. 8b. Anti-parallel PD-stacked p-
iodophenyl-p-iodophenyl π-π stacking interaction of compound 2e is shown in Supplementary data,
Fig.S56.
1
9

ACCEPTED MANUSCRIPT
Fig. 8. (a) unit cell arrangement viewing along b-direction of 2d, (b) sandwich type π-π stacking of two
anti-parallel p-bromophenyls
Literature survey revealed that PD-type π-π stacking was generally more stabilizing in nature than the S-
type [30]. Overall stabilization of the lattices of 2d and 2e must have come from a balance of other
stabilizing features e.g. halogen-halogen soft interactions etc. Simultaneously, we could take out the closest
syn-parallel dimer in the same fashion to get the π-π stacking distances between the centroids of the two
imidazole units and the centroids of the two phenyl units to have the identical values, irrespective of
slightly different slip angle [42]. They lie in the range of 7.66-11.63 Å. Table 4 shows the syn-parallel π-π
stacking distances between imidazole-imidazole and phenyl-phenyl stacked moieties obtained from X-ray
crystallographic analysis for the compounds 2a-e. Due to variation in the slip angles between the π-π
stacked imidazole-imidazole and phenyl-phenyl moieties, differences in vertical distances for those pairs
were observed.
Table 4
Syn-parallel π-π stacking distances from X-ray crystallographic analysis of 2a-e and the corresponding
vertical π-π stacking distances
Compound
imidazole-imidazole
anti-parallel π-π stacking
Phenyl/p-halophenyl-
phenyl/p-halophenyl
anti-parallel π-π stacking
π-π stacking slip angle vertical
π-π stacking
distance
from crystal
lattice(Å)
slip angle
from crystal
lattice(º)
vertical
π-π
distance
(Å)
distance
from crystal crystal
lattice
lattice (º)
Å)
from
π-π
distance
(Å)
(
2
0

ACCEPTED MANUSCRIPT
2
2
2
2
2
a
b
c
d
e
7.94
7.66
8.25
11.63
8.69
30.91
21.07
55.24
17.62
12.79
6.81
7.14
4.70
11.08
8.47
7.94
7.66
8.25
11.63
8.69
25.45
26.20
54.69
19.31
13.63
7.17
6.87
4.77
10.97
8.44
It was interesting to note that, for compounds 2a-e, the phenyl/p-halophenyl units are attached to respective
N-1 of imidazole units with a free-rotable single bond. The lattices showed that the values of torsion angles
between the imidazole and the respective N1 phenyl/p-halophenyl ring for those AICA derivatives were in
the range of │43.75⁰│ to │52.16⁰ │(please see Supplementary data, Table S4). As a consequence, mixed
imidazole-phenyl stacking was not possible in crystal lattices of 2a-e. Occurrences of preferential
intramolecular π-π stabilizing interactions between two aromatic components of a sufficiently flexible
molecule is documented [46-50]. These molecules are known as foldamers [51]. This phenomenon can be
related to the optimized conformation of a molecule in its crystalline lattices maintaining a balance of size,
electronegativity and electronaffinity of the halogens/substituents (please see Supplementary data, Table
S1). None of the molecules 2a-e exhibited any folding characteristics.
Then the attention was drawn towards the possible mode of π- π stackings in the compounds 3a-e where
the amide groups at C-4 position of imidazole rings of each of the AICA derivatives 2a-e was converted
to cyano groups keeping phenyl/p-halophenyl substituents as N1 of imidazole moiety intact (Scheme 2).
The crystal lattices of 3a-e revealed the presence of T-stackings along with the anti /syn π-π stackings of
both imidazoles and phenyl/p-halophenyl moiety. The unit cells of the lattices of two representative
compounds 3a and 3b, their T-stacking patterns and anti-parallel π-π stackings of imidazole-imidazole
and phenyl-phenyl moieties are shown in Fig. 9 and Fig. 10 respectively.
2
1

ACCEPTED MANUSCRIPT
Fig. 9. (a) unit cell arrangement viewing along b-direction, (b) T-stacking between the hydrogen attached
with the C-2 position of imidazole and the closest phenyl moiety, (c) T-stacking between the hydrogen
attached with the C-4’ position of phenyl and the closest phenyl moiety and (d) π- π stacking distance of
two anti-parallel imidazole-imidazole of compound 3a
Fig. 10. (a) unit cell arrangement viewing along b-direction, (b) T-stacking distance between the
hydrogen attached with the C-2 position of imidazole and the closest p-fluorophenyl moiety, (c) π- π
stacking distance of two anti-parallel imidazoles and (d) π-π stacking distance of two anti-parallel p-
fluorophenyls of compound 3b.
2
2

ACCEPTED MANUSCRIPT
X-ray crystallographic studies of 3a-e indicated the presence of imidazole-imidazole PD π-π stacking in
anti-parallel fashion (Fig. 9d for compound 3a and Fig. 10c for compound 3b) in their crystal lattices.
Anti-parallel phenyl-phenyl PD π-π stackings were observed in the crystal lattices of 3b-e (Fig. 10d for
compound 3b) whereas similar stacking pattern was not detected in the crystal lattice of 3a. It was
fascinating to note that 3a showed its differences with 3b-e in their T-stacking pattern. The crystal lattice
of 3a had shown dual T-stacking interactions. Each of the molecules belonging to the series 3a-e had
specific T-stacking between C2-H of imidazole ring with the closest π-cloud of phenyl moiety (Fig. 9a and
Fig. 10a). The crystal lattice of 3a disclosed additional T-stacking involving C4'-H of N1-phenyl
substituent with the closest π-cloud of phenyl moiety (Fig. 9b). This type of extra T-stackings were not
identified in the crystal lattices of 3b-e, since in those molecules the C-4' positions of phenyl substituents
at N1 of their imidazole rings were occupied by -F, -Cl, -Br and -I respectively. T-stacking between C2-H
of imidazole ring and closest phenyl/p-halophenyl ring for the compounds 3a-e might originate due to the
acidic nature of C2-H of imidazole ring caused by the electron-withdrawing effect of –CN group at C4
position. T-stacking, anti-parallel PD-stacked imidazole-imidazole and phenyl-phenyl π-π stacking
interactions of compounds 3c-e are presented in Supplementary data, Fig.S57-Fig.S59.
Table 5
Anti-parallel PD π-π stacking distances from X-ray crystallographic analysis of 3a-e and the
corresponding vertical π-π stacking distances
Compound
imidazole-imidazole
phenyl-phenyl
anti-parallel π-π stacking
anti-parallel π-π stacking
π-π stacking
distance
slip angle
from X-ray π-π
vertical
π-π stacking
distance from from X-ray
slip angle
vertical
π-π
from X-ray
crystallogra-
phic
crystallog- distance
X-ray
crystallog-
raphic
crystallogr distance
raphic
(Å)
ap-hic
(Å)
lattice(º)
lattice(º)
lattice(Å)
lattice(Å)
3
3
a
b
4.61
4.09
4.58
5.60
4.59
4.07
-
-
-
4.19
35.18
3.42
2
3

ACCEPTED MANUSCRIPT
3
3
3
.
c
d
e
4.92
4.18
4.03
7.45
36.64
32.07
4.88
3.35
3.41
4.88
4.05
4.16
43.24
7.18
7.71
3.55
4.12
4.12
Table 5 tabulates the distances between the centroids of the two closest imidazoles in anti-parallel stacking
arrangements of 3a-e and also the distances between PD-stacked p-halophenyl–p-halophenyl moieties for
3
b-e. Corresponding vertical distances values for each of the PD-stacked imidazole pairs and p-halophenyl
pairs are reported in Table 5 along with the characteristic slip-angles (shown in Supplementary data,
Fig.S43-Fig.S53). The vertical distances which are important for the measurements of the closeness of two
...
PD-stacked moieties are not applicable in T-stacking interactions which involve C-H π type interactions
instead of PD-stacked π-π type. Simultaneously, the closest syn-parallel dimers from the crystal lattices of
3
a-e were taken out to obtain the π-π stacking distances between the centroids of the two PD-stacked
imidazole units and between the centroids of the two phenyl units. As observed in cases of 2a-e, both types
of PD-stacked arrangements for 3a-e showed identical distance values in respective cases with explicit
differences in slip angles (shown in Table 6). Since the phenyl/p-halophenyl unit is attached to N-1 of
imidazole with a free-rotable single bond, the lattices showed preference for the torsion angles between
imidazole and phenyls to lie in the range of │50.66º│ to │78.36º│ (please see Supplementary data, Table
S5) in cases of 3a-e. Hetero imidazole-phenyl π-π stacking was not possible also in the molecules 3a-e.
Table 6
Syn-parallel π-π stacking distances from X-ray crystallographic analysis of 3a-e and the corresponding
vertical π-π stacking distances
Compound
imidazole-imidazole
phenyl-phenyl
syn-parallel π-π stacking
syn-parallel π-π stacking
π-π stacking slip angle Vertical
π-π stacking
distance
from X-ray
crystallog-
raphic
slip angle
from X-ray
crystallogr-
aphic
Vertical
π-π
dista-
from X-
ray
crystallo-
graphic
lattice(º)
distance
π-π
distance
(Å)
from X-ray
crystallogr-
aphic
nce (Å)
lattice(º)
lattice(Å)
lattice(Å)
2
4

ACCEPTED MANUSCRIPT
3
3
3
3
3
a
b
c
d
e
6.23
6.18
6.08
6.41
6.43
46.50
38.22
38.88
44.03
44.16
4.29
4.85
4.73
4.61
4.61
6.23
6.29
6.29
6.41
6.43
40.93
33.97
30.42
36.33
36.92
4.71
5.22
5.42
5.16
5.14
Table 7 presents T-stacking distances involving C2-H of imidazaole and the closest π-cloud of phenyl/p-
halophenyl moieties in the crysyal lattices of 3a-e. The values were in the range of 2.92-3.16Å and might
afford stability to these systems. Another T-stacking was recognized in the crystal lattice of 3a involving
C4'-H of phenyl substituent and the closest π-cloud of phenyl moiety (Fig. 9c) and presented in Table 7.
Table 7
T- stacking distances from X-ray crystallographic analysis of 3a-e
Compound
T-stacking distance
T-stacking stacking
between C-2 hydrogen
between C-4’hydrogen
of imidazole and the closest
phenyl/p-halophenyl moiety (Å)
of phenyl and the closest
phenyl ring (Å)
3
3
3
3
3
a
b
c
d
e
2.96
3.00, 3.01
2.98
2.92
3.16
3.15
-
-
-
-
T-stacking distances of 3a-e were the shortest stacking distances than the distances corresponding to anti-
parallel imidazole-imidazole and phenyl-phenyl stacked moities whereas the syn parallel PD-stackings for
those molecules recorded the highest values.
3
.2. Computational studies on stacking interactions
At an early date, rotational contour analysis of the electronic spectra of sym-tetrazine has revealed the
…
…
presence of two isomers: a planar C-H N hydrogen bonded dimer and a T-shaped dimer with C-H π
interactions [52]. Using a combination of two-colour resonant two-photon ionization technique and
2
5

ACCEPTED MANUSCRIPT
Leonard-Jones potential calculation [53], both syn-parallel and anti-parallel π-stacked and T-stacked
varieties of pyrazine-dimers have been reported [52]. As evident from the order of stability of dimers as
1
,3,5-triazine> pyrazine> pyridine, reported by Sathamurthy et. al.[54], an increase of the number of
nitrogen atoms on the heterocyclic ring leads to an increased π-stacking strength. A comparison of
energetics of benzene-dimer, benzene-pyridine hetero-dimer and pyridine-dimer with the help of
CCSD(T) level of calculation indicates that the introduction of nitrogen to replace the carbon atom of
benzene creates a dipole along with reduction of spatial extent of π cloud and polariziability of hetero-
aromatic moiety comparative to benzene [52,54,26]; the stabilization in the case of pyridine dimer has
-1
shown to be of the order of 1.43 Kcal mol higher than the benzene dimer [26,54] . It is also to note that
the results of ab-initio calculations on the benzene-dimers depend on the selection of basis set to some
extent [42,55]. A detailed understanding of the extent of stabilization offered by different π-π stacking and
T-stacking interactions of compounds 2a-e and 3a-e was correlated with the results of DFT calculations.
For compounds 2a-e, DFT studies were focused on PD-stacked (a) anti/syn-parallel imidazole pairs and
(b) anti/syn-parallel phenyl pairs occurring simultaneously in their crystal lattices. For the consideration of
anti-parallel stackings the studies had focused on the closest pairs of such anti-parallel imidazoles in void
and also such closest pair of anti-parallel phenyls/p-halophenyl in void , in the respective cases, by way of
proper selection out of X-ray crystallographic packing keeping the mode of π-π stacking as well as the slip
angle intact (Table 2 and Table 3). This would afford the optimized form of the respective dimer at once.
In a cue, detailed DFT calculations of the optimized energies of dimers using the basis set mpwb95/6-
3
1++g for 2a-d and mpwb95/lanl2dz [56] for 2e had been pursued by keeping the slip-angle of π-π
stacked dimers unaltered while adopting gradual change of stacking distance parameter.
Subsequently, the -stacking energy corresponding to each set of calculations for a given distance
is computed from the Equation 2.
π-π
π
-
π
π-π
2
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π
-
π
stacking energy= (optimized energy of the dimer) - 2x (optimized energy of the
monomer)…..Equation 2
The optimized energy of the monomer, remaining the same for the anti-parallel conformations of
imidazoles as well as phenyl/p-halophenyl, had been separately calculated by using the same basis sets
mpwb95/6-31++g for 2a-d and mpwb95/lanl2dz for 2e. The crystallographic CIF was used to generate the
initial geometery of the stacked dimer and monomer. Afterthat, single point energy had been calculated
using DFT method. Here ‘optimized geometry’ indicates actually the geometry which had already been
optimized by X-ray crystallographic analysis in the solid state. This calculated π-π stacking energy
corresponded to simple π-π stacking situation only, infact unmixed with other possible interactions like
hydrogen bonding. Here mpwb95/6-31++g and mpwb95/lanl2dz basis sets were used since these
correspond to correlation consistent methods [56,57] and included the features of diffusion correction as
was appropriate for these types of
total data of the calculations have been tabulated in Supplementary data, Table S6-S13). A graph was
drawn by plotting the -stabilization energy data against variable -stacking distance. DFT
calculations on π-π stacking of representative compounds 2c and 2e are shown in Fig. 11 and Fig. 12
DFT calculations on π-π stacking of compounds 2a, 2b and 2d are shown in Supplementary data, Fig.
S60-Fig.S62). Fig. 11b represents -stacking distance of two imidazoles in anti-parallel orientation of
representative compound 2c as appeared in its crystal lattice. Fig. 11c shows DFT-generated curve of
stacking energies vs. variable stacking distances as computed for the compound 2c. Similarly for
corresponding anti-parallel phenyl/p-halophenyl stacking, Fig. 11d and Fig. 12b exhibit -stacking
π-π stacking calculations considered up to a long stacking distance
(
π
-
π
π-π
(
π-π
π-π -
π-π
π-π
distances obtained from the crystal lattices of 2c and 2e respectively and Fig. 11e and Fig. 12c indicate
DFT-generated curve of compound 2c and 2e respectively.
2
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Fig. 11. (a) unit cell arrangement viewing along b-direction, (b) π- π stacking distance of two anti-parallel
imidazoles, (c) the plot of π- π stacking distance of anti-parallel imidazoles, (d) π- π stacking distance of
two anti-parallel p-chlorophenyls and (e) the plot of π- π stacking distance of two anti-parallel p-
chlorophenyls, corresponding to compound 2c
Fig. 12. (a) unit cell arrangement viewing along b-direction, (b) π- π stacking distance of two anti-parallel
p-iodophenyls and (c) the plot of π- π stacking distance of two anti-parallel p-iodophenyls, corresponding
to compound 2e
Thus maximum stacking stabilization energies corresponding to the minimum
known from the curve generated by DFT calculations. Table 8 furnishes an effective comparison of anti-
parallel stacking distances of imidazoles pairs of 2a-c with those deduced from DFT calculations.
π-π -stacking distances are
π-π
2
8

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Table 9 tabulates similar comparisons for anti-parallel
a-e.
π-π stacking distance of phenyls/p-halophenyls of
2
Table 8
Comparison of PD π-π stacking distances for the anti-parallel pairs of imidazoles of 2a-c obtained from
X-ray crystallographic and DFT studies
min. π-π
π-π stacking
distance(Å) from
X-ray
crystallographic
analysis
stacking
energy
(Kcal-mol )
from DFT
stacking
distance(Å)
obtained from
DFT
-1
Compound
calculations
calculations
2
a
4.53
4.43
4.53
4.3
4.2
4.2
-12.80
-11.94
-23.80
2
b
2
c
Table 9
Comparison of PD
π-π stacking distances for the anti-parallel pairs of phenyls of 2a-e obtained from X-
ray crystallographic and DFT studies
min. π-π
π-π stacking
distance(Å) from
X-ray
crystallographic
analysis
stacking
distance(Å)
obtained
from DFT
calculations
stacking energy
-1
(
Kcal-mol )
compound
from DFT
calculations
2
a
4.14
4.46
4.01
4.04
4.2
4.2
4.4
4.1
3.8
4.3
-2.90
-3.84
-1.54
-12.81
-2.31
2b
2
c
2d
2
e
Comparisons of the data, presented in Table 8 and Table 9, reveal that stacking energies for anti-parallel
-1
π- π stackings of imidazole pairs are in the range of 11.94 to 23.80 Kcal mol whereas the anti-parallel π-
-1
π stacking energies of phenyl/p-halophenyl pair are much less viz.1.54-3.84 Kcal mol with the exception
2
9