syntheses and electron density distribution studies in two...

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Syntheses and electron density distribution studies in two new imidazole derivatives

Maharzadi Noureen Shahi, Alia Iqbal, Rashida Bibi, Misbah-ul-Ain Khan, MaqsoodAhmed, Sajida Noureen

PII: S0022-2860(19)31766-1

DOI: https://doi.org/10.1016/j.molstruc.2019.127657

Reference: MOLSTR 127657

To appear in: Journal of Molecular Structure

Received Date: 12 November 2019

Revised Date: 18 December 2019

Accepted Date: 26 December 2019

Please cite this article as: M.N. Shahi, A. Iqbal, R. Bibi, M.-u.-A. Khan, M. Ahmed, S. Noureen,Syntheses and electron density distribution studies in two new imidazole derivatives, Journal ofMolecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2019.127657.

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© 2019 Published by Elsevier B.V.

https://doi.org/10.1016/j.molstruc.2019.127657

https://doi.org/10.1016/j.molstruc.2019.127657

Article [MOLSTR_127657] in Journal of Molecular Structure (Accepted)

Author group with affiliations.

Maharzadi Noureen Shahi1,2, Alia Iqbal2, Rashida Bibi2, Misbah-ul-Ain Khan2, Maqsood Ahmed2 and Sajida Noureen2.

1 Department of Chemistry, University of Okara, Pakistan.

2Materials Chemistry Laboratory, Department of Chemistry, The Islamia University of Bahawalpur, 63100, Pakistan.

Email Addresses:

Maharzadi Noureen Shahi [email protected]

Alia Iqbal [email protected]

Rashida Bibi [email protected]

Misbah-ul-Ain Khan [email protected]

Maqsood Ahmed [email protected]

Sajida Noureen [email protected]


Abstract

Imidazole derivatives find wide scale and diverse applications. In this work two new imidazole based compounds have been synthesized. Their structures were confirmed using NMR, Mass Spectrometry and IR techniques. In addition, three dimensional structures were elucidated using single crystal X-rays diffraction analysis. The structures were refined using the classical independent atom model and the aspherical pseudo-atom model from an electron density database. The electrostatic properties and the topology of covalent bonds and intermolecular interactions of both the molecules were quantified on the basis of transferred electron density parameters. This study encourages the use of transferability principle for routine structure analysis as it gives better refinement statistics and reliable of estimation of chemical reactivity through the study of electrostatic properties.

Introduction:

Ever since the discovery of imidazole in 1858, its various derivatives had been discovered

already in 1840 [1], it is a hot topic for research because of its wide range applications as

pharmaceutical drugs [2], artificial acceptors [3], agrochemicals [4] supramolecular ligands [5]

and biomimetic agent [6] etc. Due to its structural similarity with histidine and presence of 6-π

electrons in the ring [7), this compound can bind easily with proteins, enzymes and receptors in

biological systems by weak interaction like hydrogen bond, ion dipole, π-π stacking, van der

Waal’s interactions and thus exhibit wide range of biological activities [8]. Because of its

exceedingly polar nature with a dipole moment of 3.61D [9] presence of imidazole nucleus in

drugs enhances their bioavailability to a greater extent also improves their metabolic stability and

bioactivity.These characteristics make it an efficient pharmacological agent. Fluconazole, a

triazole drug with antifungal activity has been nominated by World Health Organization(WHO)

as an extraordinary medicinal record against candida infections and has become the number one

choice to cure infections by Candida albicans and Cryptococcus neoformans [10].

Pharmacologically important drugs containing imidazole as their basic structural unit are

antifungal, anthelmintic, anti-HIV, antihistaminic, antiulcer, cardiotonic, antitubercular

antihypertensive, and neuroleptic [11 ]. Their derivatives also exhibit optical properties 12 ].

Lophine (2,4,5-triphenyl)-1H-imidazole, an appealing fluorescent and chemiluminescence

compound, reacts with oxygen in the presence of strong base as a catalyst it gives yellow light

[13]. For certain transition metals like copper, it is used as anticorrosion agent [10]. Thermally

stable polybenzimidazole fused with benzene ring is used as fire retardant [14]. The compounds

used for photography and electronics also contain imidazole [15]. The literature study reveals

that there is need to design and study the different derivatives of it with different functional

group and their effect on antimicrobial activities.

To understand the crystal structure, proper understanding of the molecular planarity,

stereochemistry and interactions is important. The study of these properties is based on the

electron density distribution [16]. In treating the X ray diffraction data, the overall electron

density is divided into the individual atomic densities assuming atoms as neutral and spherical in

shape. Due to the atom to atom interactions like covalent bonding, hydrogen bonding and van

der Waals interactions the atomic electron densities are not spherical any more [17]. The usual

IAM refinement model does not provide complete information of intermolecular contacts, also

can generate serious errors in the refined atomic parameters [18]. The low temperature data

collected for d- spacing less than 0.5Å and sinθ/λ greater than 1 Å¯ provide the conditions to

represent atomic electron density in the deformation electron density map and to quantify it

experimentally by using a non-spherical atomic model [19]. The refinement taking the non-

spherical electron density can describe the thermal motions and the stereochemistry of the

structure. At present for the charge density refinement of small molecules non-spherical models

of electron density are in routine use [16, 17]. Except for improving the structure and dynamic

molecular model, the use of non-spherical atomic model can lead to extract physical properties

like atomic charges and electrostatic potential [20] which in turn is important for understanding

the molecular recognitions, like drug receptor interactions [21] and for evaluating the lattice

energies in the crystals with smaller unit cells [22]. However, as the experimental charge density

analysis requires good quality highly diffracting crystals in a centro-symmetric space group and

low temperature data collection, it is generally a matter of luck to find such high quality crystals.

Usually, the crystals are found to diffract at ordinary resolution of 0.8 Å. This bottleneck can

however, be overcome by using the transferability principle [23]. Several studies have reported

the successful use of transferability principle in studying the chemical properties and binding

affinities in molecules and the results have been found to be comparable with high quality

experimental data refinement as well high level theoretical calculations [17, 24]. Transferability

principle is therefore, a very cost effective and efficient tool in the hands of a chemist to get a

deeper insight into the reactivity and ascertain the further chemical behavior of their synthesized

intermediates and final products.

In this study, we report the synthesis and crystal structure of two new imidazole derivatives I and

II (Scheme I) which according to the survey of the latest Cambridge Structural Database [25]

have never been reported. The structures of both the molecules have been studied by using the

classical spherical atom model and the Hansen & Coppens multipolar atom model by

transferring electron density parameters from the Experimental Library of Multipolar Atom

Model (ELMAM2). The intermolecular interactions are characterized by Hirshfeld surface

calculations and the Bader’s theory of Atom in Molecules. The electrostatic potentials of both

the molecules have been calculated to segregate the electrophilic and nucleophile sites.

Experimental:

Synthesis:

Preparation of Schiff bases: Equimolar mixture of 5-arylfuran-2-carbaldehyde and substituted

anilines was dissolved in 30mL of ethanol in round bottom flask. Few drops of conc. HCl were

added to the mixture and refluxed for 3-4 hours. After completion of reaction the mixture was

cooled at room temperature and poured into ice water. The solid mass was filtered, dried and

recrystallized by ethanol.

General procedure for the preparation of 1, 4, 5-triaryl-2-(5-

arylfuran-2-yl)-1H-imidazoles

Method A: Conventional From pre-synthesized Schiff Bases. An equimolar mixture of

respective schiff base (1.0 equiv) and benzil (1.0 equiv) was taken in 10 mL acetic acid in round

bottom flask. Ammonium acetate (2.0 equiv) was added to this mixture and refluxed for 4-6

hours. Completion of reactions was monitored by TLC. After completion of the reaction, the

mixture was cooled at room temperature and poured into ice water. The resultant precipitates

were filtered dried and recrystallized by chloroform to obtain pure product. Some products were

purified by column chromatography using ethyl acetate and n-Hexane.

Method B: In Microwave oven An equimolar mixture of substituted 5-aryl furan-2-

carbaldehydes and anilines with few drops of acetic acid were taken in beaker and heated for 2

minutes in domestic microwave oven to form Schiff base. Then benzil and ammonium acetate

were added to the reaction mixture and heated for 5 minutes. A pure product was obtained by

above followed procedure. The products from the two Methods A and B were identical in all

respects (TLC; m.p. and spectra).

The chemical reaction for synthesis of two imidazole derivatives I and II (Scheme II).

Yield: method A=23%, method B=36%.

Spectroscopic analysis:

Imidazole derivatives I

M.p: 189°C

FTIR (cm-1):3041.76(C-H), 1502.43(C=N), 1483.59(C=C), 1396.57, 1018.49 (C-Cl)

1H-NMR (400 MHz, CDCl3): δ 7.62(dd,2H), 7.36-7.15(m, 15H), 6.68(d,1H J=3.6), 6.65(d,1H J=3.6),2.43(s,3H, CH3).

MS: m/z (%), 520[M+] (100). Cacd.for (C32H22 Cl2N2O) 520.11.

Yield: method A=28%, method B= 31%

Imidazole derivatives II

M.p:298ᵒC

FTIR (cm-1):1655.80(C=N), 1490.65(C=C), 1096.70(C-Cl).

1H-NMR (400 MHz, CDCl3): δ 7.62(d,2H, J=6.8), 7.41(d,2H, J=8.8), 7.30-7.16(m,14H), 6.73(d,1H, J=3.6), 6.64(d,1H, J=3.6).

Single Crystal X-rays Data collection:

Diffraction data sets of both the molecules were collected on Bruker Kappa APEXII CCD

diffractometer, with graphite monochromated Mo Kα (0.71073Å) as radiation source. For

molecule I data was collected at 213(2) K. Internal consistency factor (Rint) was 0.0132.

Similarly for molecule II data was collected at 133(2) K with (Rint) 0.0223. Total 12392

measured reflections were merged to 6333 independent reflections up to a resolution of

sinθ/λ=0.665Å-1 in Laue class P1� were read by input file while observed [I >2Ϭ (I)] reflections

were 4979. The crystal data, data collection and refinement details are summarized in table 1.

Table 1

Experimental details

Crystal data

I II

Chemical formula C32H22Cl2N2O C31H20Cl2N2O

Mr 521.41 507.39

a, b, c (Å) 9.8877 (4), 10.2814 (4), 14.5127 (6) 9.6094 (7), 10.1229 (7), 14.8450 (1)

α, β, γ (°) 94.508 (1), 102.256 (1), 113.384 (1) 95.167 (1), 105.077 (1), 113.373 (1)

V (Å3) 1301.32 (9) 1249.13 (13)

Z 2 2

µ (mm-1) 0.28 0.29

Crystal size (mm) 0.38 × 0.25 × 0.19 0.32 × 0.14 × 0.10

Temperature (K) 213 (2) 133 (2)

Data collection

Diffractometer Bruker Kappa Apex II CCD detector (Bruker, 2016)

Bruker Kappa Apex II CCD detector (Bruker, 2016)

Absorption correction Multi-scan Multi-scan

Tmin, Tmax 0.903, 0.950 0.903, 0.950

No. of measured, independent and observed reflections

12392, 6198, 6198 [ > 2.0σ(I)] 11502, 5628, 5628 [ > 2.0σ(I)]

(sin θ/λ)max (Å-1) 0.665 0.651

Refinement

I_IAM II_IAM I_ELMAM2 II_ELMAM2

R[F2 > 2σ(F2)], wR(F2), S 0.053, 0.128, 1.22 0.061, 0.144, 1.39 0.038, 0.090, 0.86 0.047, 0.106, 1.01

No. of reflections 6198 5628 6198 5628

No. of parameters 334 325 354 345

∆⟩max, ∆⟩min (e Å-3) 0.40, -0.33 0.41, -0.49 0.40, -0.33 0.27, -0.20

Structure solution and SHELXL refinement:

Structure of both molecules I & II were solved in triclinic space group P1� by Direct methods

using of SIR92 [26]. All the H atoms were visible in the difference Fourier maps. However, they

were placed using a riding model. Initial IAM refinement was done by SHELXL 2013 [27] on

WinGX 2013.3 package [28] using least square refinement techniques on F2. Atoms other than

hydrogen were considered anisotropic and were added using riding models with C–H bond

distance constrained to 1.083Å for aromatic hydrogen and 1.077Å saturated groups (methyl). At

the end of the refinement the highest peak of residual electron density was found to be 0.233

e/Å3 and deepest hole ̶ 0.393 e/Å3. Residual index or R factor value of all data (Rall data) is

5.276% and goodness of fit is 1. 252.The detail of SHELX refinement is given in of

supplementary information.

IAM refinement with MoPro

After initial refinement of I and II with SHELXL, the data was imported to MoPro [17]. An

IAM refinement was carried out separately on both molecules in which scale factor, position and

thermal parameters were successively refined. The C-H bond lengths were contrained to standard

neutron values (Allen, 2010). The same weighting scheme as used in Shelx refinement was used

{W=1/ [σ2(Fº)2 +(ap)2 +bP], while P= Fº

2 +2FC 2/3. For I, the values of a= 0.554 and b = 0.256

whereas for II, the values were 0.596 and 0.17 respectively. Bond lengths of hydrogen atom

were constrained according to standard neutron distances [29]. Refinement was continued till

convergence. For H –atoms anisotropic displacement parameters were constrained by using

SHADE server [30]. The Cl atoms in both the structures were refined enharmonically which

remarkably improved the refinement statistics as given below: For I the R [F2 > 2σ(F2)],

wR(F2), S values before anharmonic refinement 0.041, 0.098, 0.94 and after anharmonic

refinement were reduced to 0.038, 0.090, 0.86 respectively.

For II The R [F2 > 2σ(F2)], wR(F2), S values before anharmonic refinement 0.050, 0.115, 1.10

and after anharmonic refinement were reduced to 0.047, 0.106, 1.01 respectively.

Residual electron density maps after IAM refinement are given in figure 1(a). These maps

indicate that electron density is concentrated around the covalent bonds and there is no notable

residual electron density on the atoms. The final IAM refinement statistics of both molecules are

given in of supplementary information.

ELMAM2 refinement:

The IAM refined models of compounds I and II were subjected to the ELMAM2 refinement.

The multipolar parameters of Hansen and Coppens’ equation available in the ELMAM2 Library

were transferred to the IAM models of both the structures and refined as in IAM refinement

while keeping the multipolar parameters fixed to their original values using charge density least

square refinement program MoPro [17]. After the data base transfer data was neutralized

electrically giving an ELMAM2 model. ELMAM2 refinement brought a clear improvement in

the crystallographic R factor, weighted R factor and goodness of fit. Residual electron density

maps after ELMAM2 refinement are given in figure 1(b). The final ELMAM2 refinement

statistics of both molecules are given in of supplementary information.

Figure 1:The residual electron density maps after IAM and ELMAM refinements.

Molecular crystal structure:

Thermal ellipsoid plots of molecule I and II are shown in Figs 2(a) and (b).

Figure 2:The Thermal ellipsoid plot of molecule I and II drawn at 50% probability level, showing the atom numbering scheme for non-hydrogen atom.

Crystal packing indicates that in each case of I and II, there is one molecule in the asymmetric

unit and two molecules in the unit cell. The two molecules in the unit cell are related to each

other by an inversion center. There are no hydrogen and halogen interaction between these two

molecules in the unit cell. In the crystal molecules are holding to each other by

centrosymmetrically related pairs of molecular interactions. Molecule of 2-(5-(3,4-

dichlorophenyl) furan-2-yl)-4,5-diphenyl-1-(p-tolyl)-1H-imidazole consists of one furan, one

imidazole ring, also have four phenyl rings, one of them contains two chlorine atoms at meta and

para positions and one is carrying methyl group at para position and the molecule II consists of

one furan, one imidazole ring, also have four phenyl rings, two of them contains one chlorine

atom at para positions.

Individually all the rings in molecule I are planar but twisted at various angles from the plane of

parent imidazole ring. 17.12º is the dihedral angle between imidazole and chloro substituted

phenyl ring. P-tolyl phenyl ring is twisted from imidazole plane at an angle of 77.03º. Similarly

angle of twist for phenyl ring attached at C3 and C2- position of imidazole is 85.62º,

20.15ºrespectively. Furan ring is held at 8.43º out of the plane of imidazole ring. It is assumed

that all these rings are twisted because their bond pairs with imidazole are repelled by lone pairs

of electrons on two nitrogen of imidazole moiety. In molecule II 86.12º is the dihedral angle

between plane of phenyl ring containing Cl1and imidazole ring and similarly phenyl ring with

Cl2 lies at an angle of 18.9° from the plane of imidazole. In this molecule the two phenyl rings at

position 1 and 5 of imidazole ring are twisted at an angle of 86.12º, 77.72º which is almost

perpendicular to the plane of imidazole. The twist of these two rings is due to the repulsion of

lone pair of electron on nitrogen and bond pair of electron of bond N1–C8 and C3–C20. It is

assumed that these two rings at position 1, 5 of imidazole ring prevent the stacking of molecule

II in zigzag fashion and help to maintain proper intermolecular distances and establish crystal

assembly (Figure 3). A view of molecular packing around asymmetric unit cell of molecule I and

II labelled with symmetric codes and hydrogen bonds can be represented by dashed blue lines in

Figure 3.

Figure 3: A view of molecular packing around asymmetric unit of molecule I and II labelled with symmetry codes which are given in table 2(a) and (b) and hydrogen bonds can be represented by dashed blue lines.

In molecule I the bond distances for Cl2–C30, Cl1–C29 are 1.729Å and 1.728Å, approximately

equal or equal to the average bond distance for chlorinated hydrocarbons. In molecule II the two

chlorine atoms are present on two different phenyl rings at position 11 and 29 [C29–Cl2 and

C11–Cl1] with bond lengths of 1.744Å and 1.740Å. In this case the bond lengths are comparable

for average Cl–C(sp2) bond length of 1.755Å for other chlorinated hydrocarbons [31].

Table 2(a)

Hydrogen-bond geometry (Å, º) for molecule I after ELMAM2 refinement.

D—H···A D—H H···A D···A D—H···A

C17—H17···Cl1i 1.08 2.87 (1) 3.5787 (15) 123 (1)

C20—H20···C21 1.08 2.61 (1) 3.2906 (16) 121 (1)

C22—H22···C2ii 1.08 2.59 (1) 3.5258 (16) 144 (1)

C23—H23···N2ii 1.08 2.69 (1) 3.4637 (17) 128 (1)

C13—H13···C15iii 1.08 2.68 (1) 3.5944 (15) 142 (1)

Symmetry codes: (i) x-1, y-1, z-1; (ii) -x, -y, -z; (iii) -x+1, -y, -z.

Table 2(b)

Hydrogen-bond geometry (Å, º) for molecule II after ELMAM2 refinement.

D—H···A D—H H···A D···A D—H···A

C19—H19···C20 1.08 2.70 (1) 3.387 (2) 121 (1)

C19—H19···C21 1.08 2.59 (1) 3.555 (2) 148 (1)

C21—H21···C5i 1.08 2.68 (1) 3.558 (2) 138 (1)

C30—H30···C18ii 1.08 2.58 (1) 3.546 (2) 149 (1)

Symmetry codes: (i) -x+1, -y, -z; (ii) x+1, y, z+1.

The table 2(a) and (b) lists all intermolecular hydrogen bonding parameters for molecule I and II

respectively, after ELMAM2 refinement with their symmetry codes.

Hirshfeld surface analysis:

The Hirshfeld surface [32] is used to explore the intermolecular interactions of the molecules in a

crystal. Hirshfeld surface analysis was carried out to study the nature of the intermolecular

contacts and to determine their quantitative contributions to the supramolecular assembly of

solvatomorphs. The Hirshfeld surface and fingerprint plots were generated using

CrystalExplorer17 [33].

Figure 4: A view of Hirshfeld surface analysis around asymmetric unit cell of molecule I and II ,showing interactions with neighbouring molecules. Symmetric codes are given in table 2(a) and (b).

Fingerprint plots:

The Hirshfeld surface and fingerprint plots of I were computed by Crystal Explorer [34 ].

Approximately 66% of the surface of this molecule is dominated by H atoms. The other two

significant species are C and Cl with 19.95% and 9.94% of molecular surface. C atoms

participate in molecular interactions only when having less than four covalent bonds in case of

aromatic or unsaturated systems with sp2 type of hybridization. Oxygen and nitrogen are

participating molecular surface by 1.05%, 1.8% respectively.

The structure of a molecular crystal is established by a fine balance of intermolecular interactions

some of them are very fragile and non-directional while others are strong and directional like

halogen interactions [35]. Thus a crystal structure represents how the intermolecular forces are

competing and cooperating to establish an energetically balanced body of a crystal [36 ].

According to Nangia and Desiraju, to understand the crystal structure or to design the crystal

structure it is necessary to understand the complete molecule and all molecular interactions not

only the selective interactions that have been considered vital in holding crystals [37]. Although

Hirshfeld surface provides a formerly invisible picture of intermolecular or intramolecular

interactions in a crystal space, but to extract maximum information about molecular interactions

and to represent it on the page or computer screen a more advanced two dimensional interactive

graphics have been developed that complement the properties like crystal packing etc. These

two dimensional maps providing unique display for all the molecular interactions in a crystal are

distinct for each crystal and polymorph that’s why are named as ̔fingerprint ̓ plots.

These graphs are plotted first by generating Hirshfeld surface [38], de and di are calculated for

each and every point on the surface then data are binned at regular intervals of de and di to

construct fingerprint plot [39]. In case of molecule I and II these plots have been created by

binning the de and di at regular intervals of 0.2Å. These plots are colored as red (a lot of points)

to green and blue (few points). The Hirshfeld surface and its fingerprint plots have the ability of

not only explaining the regions of closest interaction the red spots but also the regions of weakest

interactions or more distant contacts. Hirshfeld surface also contains voids indicating the point of

very weak interactions where electron densities are so small that the space is not occupied by a

single molecule. The Finger Print plots of molecule I and II are shown in Figs 5 (a) and (b)

respectively.

Figure 5: Finger print plots of molecule I and II ,showing various percentage of interactions.

Enrichment ratios.

The enrichment ratio (ER) was calculated using the Jelsch’s method [40 ] In molecule I

enrichment ratios of Cl···H, O···H, H···H interactions are EClH=1.515, EOH=1.515, EHH=1.515

respectively. C···H and N···H have enrichment ratio of ECH=1.515 and ENH=1.516. O···O,

N···N, N···C, N···Cl contacts are totally avoided. While the Cl···Cl, O···C, O···Cl have

enrichment ratio of EClCl =10.60, EOC=5.02, EOCl=10.63, and for C···C and Cl···C this value is

ECC =5.012, EClC =10.739 respectively. From the Hirschfeld surface short contacts between the

C3 and H22, C15 and H13 are clearly represented by large red spots indicating molecular

interaction shorter than the van der Waal’s radii of two interacting atoms. In molecule II Finger

print plots indicate ten different types of interaction including H···H accounts for 40.765%,

Cl···H 12.70, O···H 1.46%, C···H 26.82%, N···H2.49%, Cl···Cl0.99%, O···C0.48% and O···Cl

0.23%. Enrichment ratio indicate that O···C interaction with EOC =2.38are most favorable in

holding crystal assembly. The next favorable interactions are Cl···C and H···H with

EClC=2.2732, EHH=1.515. Enrichment ratios for O···H, N···H, Cl···H are EOH=0.787, ENH=0.783,

EClH=0.783. While for O···Cl, Cl···Cl, C···C enrichment ratios are EOCl=5.026, EClCl=9.6 ECC =

4.76. The enrichment ratio for C···H is ECH =0.7815. The ER factor shorter than 1 signifies that

the particular interaction is less favored statistically.

Electrostatic potential and Dipole moment:

Electrostatic potential (ESP) is an effective tool for the better understanding and determination of

various atomic and molecular properties that depend upon inter and intramolecular interactions.

It is prediction of chemical reactivity or binding ability of molecule because negative ESP is

likely to be sites of nucleophilic attack, while positive ESP may direct towards electrophilic sites.

The electrostatic potential, electric field and electric field gradient was calculated from

description of multipoles obtained from charge density data [41].

The ESP of molecule was calculated by equation

Φ(r)=�()

|� |��

In equation, � is indication of total nuclear and electronic charge,�� represents the position

relative to origin and integration is considered over molecular volume [42 ]. The ESP is

calculated for an electrically neutralized asymmetric unit cell and electron density surface is

colored according to it. The electrostatic potential isosurface in Figure 6 (a) and (b), showing the

extension of highly electropositive and electronegative regions in both molecules I and II

respectively.

Figure 6: A 3D electron density surface colored according to calculated electrostatic potential for molecule I and II.

The negative electrostatic potential is generated around the N1, N2 atoms of imidazole, O1 of

furan ring and two Cl atoms attached to one benzene ring of molecule I. The positive

electrostatic potential is generated around all the C-H groups. The presence of two strong

electron withdrawing groups (CI atoms at meta and para positions) making the carbons C29,

C30 of aromatic ring electrophilic in nature and susceptible to good nucleophile attack. It

generates the possible reactive site of the molecule. Due to lone pair of electrons, Oxygen has

electron donating effect and increased electron density making carbons of ring nucleophilic in

nature and liable to electrophile attack. N1 and N2 both have a lone pair of electron and with

increased electron density act as a nucleophile and susceptible to electrophile attack. But N1 and

N2 make the central carbon atom (C1) more electrophilic in nature, thus favors the nucleophilic

attack. The red regions in map will act as hydrogen bond acceptor sites and blue regions (C-H

group) will provide the donor sites. In molecule II the negative electrostatic potential covers the

N1 and N2 of imidazole ring, O1 of Furan ring and Cl (1) and Cl (2) attached to two different

benzene ring. The positive electrostatic potential covers the carbon and hydrogen atoms. Due to

presence of Cl atom, C29 and C11 are expected to be electrophilic in nature and will be the site

of a nucleophile attack. Due to presence of O1, the furan ring has an accumulation of the

negative charge thus susceptible to an electrophilic attack. The increased in electron density on

N1 and N2 of imidazole ring due to their lone pair of electron and favor the electrophilic attack

but decreased the electron density on C1 due to electronegative effect.

For electrically neutralized asymmetric unit cell, the dipole moment was calculated using

MoProViewer [43]. Due to presence of two electronegative Cl1 and Cl2 atoms attached to one of

the benzene ring in molecule I, charge is more shifted towards them, represented by red color

and positive charge is shifted on C-H group, represented by blue color. As can be noticed, in (a)

the charge is highly concentrated around the region where Chlorine atoms are situated making it

more polar than II, as is evident from the dipole moment values (31.0D) (Figure 7 (a). In

molecule II, positive and negative charge is dispersed due to different in position of two

Chlorine atoms which are attached to two different aromatic rings. This distribution of charge

over the molecular surface in II makes it less polar with a dipole moment of (27.82D) (Figure7

(b).

Figure 7: A view of Dipole moment vector and its direction of asymmetric unit cell of molecule I and II.

Topological study of intermolecular interactions.

The search of critical point for all intermolecular interactions of molecule I and II gave a (3, -1)

type of critical points (Table S3 and S4). The main purpose of topological analysis is quantitative

understanding of intermolecular interactions for designing new compound with desired

properties, its molecular recognition and the binding properties of drug with enzyme [44]. In case

of molecule I the whole crystal assembly is established by wide range of weak interactions such

as C-H···π, C-H···Cl and C-H···N interactions between H23··· N2, H17···Cl1, H23···N2, and

H13···C2 with bond distance of 2.689Å, 2.877Å, 2.689 Å, 2.663Å respectively. Also these

interactions are related centrosymmetrically. The electron density of ρbcp(r) of intermolecular

hydrogen bonds like H17···Cl1i with symmetry code of (i)x, y, z (ii)-1+x, -1+y, -1+z and

H23···N2ii with symmetry code of (i)-x, -y, -z (ii) x, y, z is 0.061 and 0.085eÅ-3, respectively and

their positive value of Laplacian ∇2 ρbcp(r) > 0, ∣V∣/G<1 are indication of the closed shell

interactions [45]. The crystal structure is also stabilized by an important homonuclear Cl1···Cl1

interaction with bond distance 3.576 Å smaller than sum of van der Waals radii. The molecule II

also forms weak intermolecular interactions like H···H, H···C, H···Cl, C···C, C···Cl and H···N

in a molecule which plays an important role in stability of molecule. Similar centrosymmetric

pairs of interaction are found in case of II, such as H17··· Cl1, C18··· C27, H9··· N2, H25··· C3,

H23··· N2with bond distances of 2.905Å, 3.396Å, 2.686Å, 2.686Å, 2.960Å respectively. There

is no Cl···Cl intermolecular contact as present in molecule I. There is also a close contact of

H10···H6 in molecule I with distance of 2.366Å with symmetry code of (i)x, y, z (ii)x, -1+y, z

and a close contact of H16···H28 in molecule II with distance of 2.345Å with symmetry code of

(i)x, y, z (ii)-1+x, -1+y, -1+ z. A cluster of molecules interacting with molecules I and II,

showing the intermolecular interactions bond paths and critical points in Figure 8 (a) and (b)

respectively.

Figure 8: A cluster of molecules around molecule I and II ,showing the intermolecular interactions of bond paths (green) and critical points (small black dots).Symmetry codes are given in table 2(a) and (b).

Topological study of covalent bond.

A critical point search for all types of bonds of molecule I and II was carried out and (3, -1)

types of critical points and confirmation of covalent bond of atoms in molecule was found and

characterized (Table S5 and S6) as shown in figure 9 (a) and (b).In molecule I and II, the highest

value of electron density and its negative value of Laplacian (∇2ρ) was 1.585 eÅ-3 and -4.840

e/Å5, respectively, for N2─C1 bond and 1.296 eÅ-3 and 1.300 e/Å5, respectively, for Cl1─C11

and their critical points were significantly shifted towards electropositive atom. In aromatic ring,

the critical points of carbon – carbon bond lie in the middle of bond with electron density

ranging from 1.296 eÅ-3 to 1.575 eÅ-3 in molecule I and -2.504 eÅ-3 to 1.296 eÅ-3 in molecule

II. The BCPs of C─N bonds are also shifted towards carbon atoms. In hetronuclear atoms, the

distances and electron densities in BCPs of Cl1─C28 and Cl2─C30(I), Cl1─C11 and

Cl2─C29(II) are almost identical, but slight difference in their Laplacian values (3.090 vs. 3.105

e/Å5), (-1.30 vs.-1.299).

Figure 9: Bond critical point (purple color) present in molecule I and II.

Conclusions:

We have successfully synthesized two imidazole derivatives whose structures were confirmed by

NMR and by single crystal X-rays diffraction techniques. For an in depth analysis of chemical

reactivity and intermolecular interactions, we have used multipolar parameters from an electron

density database to assess the charge distribution in the molecule and to find the regions of

possible electrophilic or nucleophilic attacks. The transferred electron density parameters also

allowed us to make a quantitative characterization of covalent and intermolecular bonds using

the Bader’s QTAIM approach. This study strongly encourages the chemists to use the

transferability principle while characterizing the crystal structure as it would lead to better

understanding the chemistry of their target molecules.

Acknowledgement

The authors gratefully acknowledge the Materials Chemistry Laboratory, Department of Chemistry, The

Islamia University of Bahawalpur, Pakistan for the provision of research facilities.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as the

supplementary publication no. 1963838-1963843

Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge

CB2 1EZ, UK (fax: +44-1223-336033;

E-mail: [email protected]

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