Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis and DFT calculations

Article abstract of DOI:10.1016/j.molstruc.2019.127630

Hydantoin compounds are important heterocyclic scaffolds and a class of well-known bioactive molecules with a broad spectrum of pharmacological properties. Consequently, considerable efforts have been devoted to the design and synthesis of a broad range of hydantoin derivatives. In this context, the compound 3-allyl-5,5-diphenylimidazolidine-2,4-dione, C₁₈H₁₆N₂O₂ (3ADID) was synthesized and its structure was determined by X-ray structure analysis. Further, the molecular structure was examined using Hirshfeld topology analysis and Density Functional Theory (DFT)-B3LYP calculations with the basis set 6–311++G (d,p). In the title molecule, C₁₈H₁₆N₂O₂, the imidazolidine ring is planar with the allyl substituent oriented nearly perpendicular to it. In the crystal, hydrogen bonded chains of molecules are arranged in sets of three about the 3₂ axes by C–H···π (ring) interactions. Hirshfeld surface map and 2D fingerprint plots were used to explore intermolecular interactions. The optimized geometry, global reactivity descriptors, and HOMO-LUMO orbitals of the molecule were computed by DFT and discussed. To evaluate the chemical reactivity and charge distribution on the molecule, molecular electrostatic potential (MEP) and atomic charges, computed by Mulliken population analysis and NBO theory were determined. The local reactivity was examined by determining the Fukui functions and dual descriptor indices. DFT calculations at the same level of theory, with the POP[dbnd]NBO keyword, were used to evaluate charge delocalization and hyperconjugative interactions through Natural Bond orbital analysis.

Full text of DOI:10.1016/j.molstruc.2019.127630

Journal Pre-proof
Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis
and DFT calculations
Walid Guerrab, Hassane Lgaz, Sevgi Kansiz, Joel T. Mague, Necmi Dege, M. Ansar,
Riadh Marzouki, Jamal Taoufik, Ismat H. Ali, Min Chung, Ill, Youssef Ramli
PII:
S0022-2860(19)31739-9
DOI:
https://doi.org/10.1016/j.molstruc.2019.127630
MOLSTR 127630
Reference:
To appear in: Journal of Molecular Structure
Received Date: 19 September 2019
Revised Date: 16 December 2019
Accepted Date: 19 December 2019
Please cite this article as: W. Guerrab, H. Lgaz, S. Kansiz, J.T. Mague, N. Dege, M. Ansar, R. Marzouki,
J. Taoufik, I.H. Ali, M. Chung Ill., Y. Ramli, Synthesis of a novel phenytoin derivative: Crystal structure,
Hirshfeld surface analysis and DFT calculations, Journal of Molecular Structure (2020), doi: https://
doi.org/10.1016/j.molstruc.2019.127630.
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Synthesis of a novel Phenytoin Derivative: Crystal Structure, Hirshfeld Surface
Analysis and DFT calculations
Walid Guerrab1,a, Hassane Lgaz2,a, Sevgi Kansiz3, Joel T. Mague4, Necmi Dege3,
M. Ansar1, Riadh Marzouki5,6,7, Jamal Taoufik1, Ismat H. Ali5, Ill-Min Chung2*,
and Youssef Ramli1*
1Laboratory of Medicinal Chemistry, Drug Sciences Research Center, Faculty of
Medicine and Pharmacy, Mohammed V University, Rabat, Morocco.
2Department of Crop Science, College of Sanghur Life Science, Konkuk University,
Seoul 05029, South Korea.
3Ondokuz Mayıs University, Faculty of Arts and Sciences, Department of Physics,
55139, Kurupelit, Samsun, Turkey.
4Department of Chemistry, Tulane University, New Orleans, LA 70118, USA.
5Chemistry Department, College of Science, King Khalid University, Abha 61413,
Saudi Arabia.
6Laboratory of Materials, Crystal Chemistry and Applied Thermodynamics,
LR15ES01, Faculty of Sciences of Tunis, University of Tunis El Manar, 2092, Tunisia.
7Chemistry Department, Faculty of Sciences of Sfax, University of Sfax, 3038,
Tunisia.
*Corresponding authors:
Youssef Ramli, Email: y.ramli@um5s.net.ma
Ill-Min Chung, Email: imcim@konkuk.ac.kr
aHave equal contribution in this work
Abstract
Hydantoin compounds are important heterocyclic scaffolds and a class of well-known
bioactive molecules with a broad spectrum of pharmacological properties.
Consequently, considerable efforts have been devoted to the design and synthesis of
a broad range of hydantoin derivatives. In this context, the compound 3-allyl-5,5-
diphenylimidazolidine-2,4-dione, C18H16N2O2 (3ADID) was synthesized and its
structure was determined by X-ray structure analysis. Further, the molecular structure
was examined using Hirshfeld topology analysis and Density Functional Theory
1

(DFT)-B3LYP calculations with the basis set 6-311++G (d,p). In the title molecule,
C18H16N2O2, the imidazolidine ring is planar with the allyl substituent oriented nearly
perpendicular to it. In the crystal, hydrogen bonded chains of molecules are arranged
in sets of three about the 32 axes by C—H···π (ring) interactions. Hirshfeld surface
map and 2D fingerprint plots were used to explore intermolecular interactions. The
optimized geometry, global reactivity descriptors, and HOMO-LUMO orbitals of the
molecule were computed by DFT and discussed. To evaluate the chemical reactivity
and charge distribution on the molecule, molecular electrostatic potential (MEP) and
atomic charges, computed by Mulliken population analysis and NBO theory were
determined. The local reactivity was examined by determining the Fukui functions
and dual descriptor indices. DFT calculations at the same level of theory, with the
POP=NBO keyword, were used to evaluate charge delocalization and
hyperconjugative interactions through Natural Bond orbital analysis.
Keywords: Crystal structure; DFT; XRD; Phenytoin; Fukui function; Hirshfeld
surface.
1. Introduction
Imidazolidine-2,4-diones, known as Hydantoins, are among the privileged chemical
scaffolds utilized in the development of anticonvulsant drugs [1]. It is a popular
scaffold in the design of several pharmaceutical compounds as well as in natural
products and organic synthesis [2,3]. For example, phenytoin is a hydantoin
derivative and it is one of the oldest and well-known non-sedative antiepileptic drugs
[4]. It is the widely used anticonvulsant for treating acute convulsive seizures [5]. It is
also applicable for various diseases, as it has antiarrhythmic, and anti-HIV [6,7], anti-
2

diabetes, and anti-anxiety effects among others [8]. The antiproliferative [9] and
cytotoxic [10] activities of the cycloalkanspiro‐5‐hydantoins have also been reported.
Moreover, chemical modifications of imidazolidine‐2,4‐dione by alkylation allow
researchers to enrich its chemical structure, thus strengthening and extending its
biological activity. Consequently, several recently developed hydantoin derivatives
have a wide spectrum of pharmacological and biological activities, such as isocitrate
dehydrogenase inhibitors [11], anti-inflammatory [12,13], Anti-fibrolytic [14,15],
antibacterial [16], antidiabetic [17], kinesin spindle protein inhibitors [18], antiplatelet
[19], and antimalarials [20] activities. Besides these vast pharmacological and
biological properties, hydantoin derivatives have also shown to be good corrosion
inhibitors [21].
Our research group has more recently reported the synthesis of a novel
thiohydantoin-based compound [22]. In continuation of our efforts toward the
discovery of novel hydantoin-based compounds [23–25], herein, we hereby present
the synthesis of
a
novel phenytoin derivative, namely, 3-allyl-5,5-
diphenylimidazolidine-2,4-dione (3ADID). Characterization of its molecular structure
was carried out by X-ray crystallography, Hirschfeld surfaces analysis and DFT-
B3LYP method with the basis set 6-311++G (d,p). The frontier molecular orbitals
(FMOs) and chemical reactivity descriptors were examined to evaluate the reactivity
of the synthesized compound. Local reactivity (Fukui functions), Molecular
electrostatic potential (MEP) and net charges (NBO&MPA) were also calculated and
discussed. NBO analysis was performed to calculate the net electron transfer from
the donor to acceptor.
2. Experimental section
3

2.1. General information
Mass spectra are recorded in a SYNAPT G2 HDMS (Waters) Spectrometer in
electrospray ionization (ESI). Infrared spectra were recorded on a Perkin Elmer 577,
1
using KBr disks. H NMR and 13C NMR spectra were recorded on Bruker Avance
300NMR Spectrometer in DMSO-ꢀ6. Spectra were internally referenced to TMS.
Peaks are reported in ppm downfield of TMS.
2.2. Synthesis
Synthesis of 5,5-diphenylimidazolidine-2,4-dione: we have adopted the same
procedure described in the literature [11], which first consists in preparing benzyl by
oxidation of benzoin in present of copper sulfate, then the action of urea in ethanol at
reflux with benzyl leads to the phenytoin with a good yield (Scheme 1).
Scheme 1: Synthesis procedure for preparation of 5,5-diphenylimidazolidine-2,4-
dione.
Synthesis of 3-allyl-5,5-diphenylimidazolidine-2,4-dione: Alkylation reaction using
the appropriate bromide allyl was carried out under phase transfer catalysis (PTC) to
prepare the title compound, and added to a solution of 5,5- diphenylhydantoin in
DMF, potassium carbonate and tetra-n-butylammonium bromide (scheme 2). The
4

synthesized 3ADID has been characterized by single crystal X-ray structure analysis
(Fig. 1).
Scheme 2: Synthesis procedure for preparation of 3-allyl-5,5-diphenylimidazolidine-
2,4-dione (3ADID).
HRMS (ESI) [M+ H]: m/z=293.1
[M+ Na]: m/z=315.3
IR (ν, cm-1) : The IR spectra of imidazolidine-2,4-diones derivative showed bands in
3268 cm-1 region for the NH lactamic functional group 1765-1698 cm-1 for the C=O
functional group, and 3086-3060 cm-1 for the C-H aromatic functional group.
Moreover, IR spectra revel the disappearance of bands for NH in position 3 and the
appearance of new bands 2986-3086cm-1 for aliphatic functional groups C-H.
1
NMR (400 MHz, DMSO) δ (ppm) : The H NMR spectrum of the new synthetized
compound was characterized by the presence of multiple signals at: 5.745-5.837
ppm corresponding for CH=CH2 proton, a double doublet signals corresponding of
CH=CH2 of the aliphatic chains and a quartet signals at 4.020-4.037 ppm was
observed for the methyl protons directly connected to nitrogen atom. Beside the
1
latter three aliphatic signals, the H NMR spectrum of the compound exhibited a
multiple signals for aromatic protons at: 7.402-7.1967 ppm with ten proton integral
5

value which are assigned to protons at C-2,6, C-3,5 and C-4 carbons of phenyls. The
singlet signal at 9.691 ppm is assigned for the NH proton.
13C NMR (on-resonance & DEPT) spectral assignment of the obtained product has
been made. 13C NMR spectra of the studied compound displayed the expected
signals for the 5,5-diphenyl imidazolidine-2,4-diones core at 173.290-155.414 ppm
for C=O, 140.096 ppm for Cq position 5. The aromatic carbons could be readily
distinguished from the other carbons due to their characteristic absorption.13C NMR
at 129.257, 129.079, 128.672. Spectrum showed three signals in the alkene region.
The signal at 132.494 ppm for aliphatic CH, at 128.672 ppm for (CH2=), and a signal
at 116.710 ppm due to N-CH2 group. All spectrums are shown in supplementary
material.
2.3. Single crystal XRD study
Data collection of C18H16N2O2 was performed using a Bruker D8 VENTURE
PHOTON 100 CMOS diffractometer equipped with a mirror monochromatic Cu-Kα
radiation (λ = 1.54178 Å) produced by an Incoatec IꢀS micro focus source. The
structure solution was solved by means of SHELXT [26] and refinements were
carried out on F2 by full-matrix least-squares techniques using SHELXL [26]. The
experimental details including structure refinement and data collection details for
C18H16N2O2 were summarized in Table 1.
Table 1. Crystal data and structure refinement parameters for 3-allyl-5,5-
diphenylimidazolidine-2,4-dione (3ADID).
Chemical formula
C18H16N2O2
1947113
CCDC deposition number
6

Formula weight
Temperature (K)
Crystal system, space group
Unit cell dimensions
a, c (Å)
292.33
150
Trigonal, P32
14.5779 (3), 6.1846 (2)
V (Å3)
1138.24 (6)
Z
3
Cu Kα
Radiation type
µ (mm−1)
0.68
Crystal size (mm)
Data collection
0.26 × 0.12 × 0.11
Diffractometer
Absorption correction
Bruker D8 VENTURE PHOTON 100 CMOS
Multi-scan SADABS [27]
Tmin, Tmax
0.84, 0.93
No. of measured, independent
and observed [I > 2σ(I)]
reflections
5649, 2936, 2858
Rint
0.032
0.618
(sin θ/λ)max (Å−1)
Refinement
R[F2 > 2σ(F2)], wR(F2), S
No. of reflections
0.027, 0.065, 1.05
2936
264
No. of parameters
No. of restraints
1
H-atom treatment
H-atom parameters constrained
∆ρmax, ∆ρmin (e Å−3)
0.12, −0.11
Absolute structure
Flack x determined using 1335 quotients [(I+)-(I-)]/[(I+)+(I-
)[28].
Absolute structure parameter
0.01 (10)
2.4. Hirshfeld surface analysis
7

In order to obtain visualization of intermolecular interactions in 3-allyl-5,5-
diphenylimidazolidine-2,4-dione, Hirshfeld surface analysis was carried out. Both the
Hirshfeld surface [1] and 2D fingerprint [2] plots were generated using
CrystalExplorer17.5 program [3]. The structural input file was obtained in the CIF
format. Hirshfeld surface was represented by de and di, which denote, respectively,
the distance from the nearest atom outside and inside of the surface and both are
used to define the normalized contact distance (dnorm). For the visualization of dnorm, a
red-blue-white (RBW) color scale was selected.
2.5. Quantum chemical calculations
All DFT computations were performed using Gaussian 09W package [29].
GaussView molecular visualization software was used to draw the initial structure
and to visualize the results [30]. The molecular structure of the 3ADID was optimized
using DFT-B3LYB method with the basis set 6-311++G (d,p), default SCF and
geometrical convergence criteria in the gas phase [31–33]. Information about
delocalization of charge in the synthesized compound was provided through NBO
analysis using NBO Ver. 3.1 (Implemented in Gaussian Software) at the same DFT
level with the POP=NBO keyword. Chemical reactivity of the compound was
discussed in view of the global reactivity descriptors and HOMO-LUMO energies.
MEP, natural charges and Mulliken charges were determined to investigate the
charge distribution on the molecule. Electrophilicity and nucleophilicity theoretical
descriptors were investigated by performing Fukui functions calculation using the
GGA functional according to Perdew, Burke and Ernzerhof (PBE) and the DNP basis
set [34] packed in Dmol3 module of Materials Studio (MS) software [35].
8

3. Results and discussions
3.1. Description of the crystal structure of 3ADID
The imidazolidene ring is planar with the allyl substituent oriented nearly
perpendicular to it. In the crystal hydrogen bonded chains of molecules are arranged
in sets of three about the 32 axes by C—H···π(ring) interactions.The phenyl rings are
inclined to the mean plane of the imidazolidene ring by approximately equal amounts.
In the crystal, N—H···O and C—H···O form chains extending along the c-axis
direction which are combined into sets of three by helical motifs of C—H···π(ring)
interactions.
The C7···C12 and C13···C18 benzene rings, respectively, are inclined to the mean
plane of the 5-membered ring by 62.08 (7) and 64.55 (7)°. The 5-membered ring is
planar to within 0.0314 (11) Å (rms deviation of the fitted atoms = 0.0036) with C2
showing the largest deviation from the mean plane. The allyl group is oriented nearly
perpendicular to this plane as indicated by the C3—N1—C4—C5 torsion angle of -
83.9 (3)°. In the crystal, the molecules form chain s extending along the c-axis
direction through N2—H2···O1 and C4—H4B···O2 hydrogen bonds (Table 2 and Fig.
2). Sets of three chains surrounding the 32 axes are linked by sets of C16—
H16···Cg3 interactions having a helical motif (Table 2 and Fig. 3).
Table 2. Hydrogen-bond geometry (Å, °)
Cg3 is the centroid of the C13···C18 ring.
D—H···A
D—H
H···A
D···A
D—H···A
N2—H2···O1i
C4—H4B···O2ii
C16—H16···Cg3iii
0.90 (3) 1.94 (3) 2.834 (2) 170 (2)
0.95 (3) 2.52 (3) 3.322 (2) 143 (2)
0.98 (3) 2.98 (4) 3.791 (3) 141 (3)
Symmetry codes: (i) x, y, z+1; (ii) x, y, z−1; (iii) −x+y+1, −x+1, z+1/3.
3.2. Optimized molecular structure by X-Ray crystallography and DFT
9

The geometric structure of 3ADID optimized by using DFT at B3LYP/6-311G++ (d,p)
level is shown in Fig. 4. Based on DFT and XRD studies, selected geometrical
parameters were determined and listed in Table 3. The results of DFT and XRD are
almost identical and a comparison between both results indicates that there are only
minor deviations, which is mainly due to differences in the molecular environment
[36] since the molecular structure of 3ADID was investigated by X-ray crystallography
in the crystalline phase, whereas DFT calculations of isolated molecule were
performed in the gas phase. In X-ray structure, the N1-C2, N1-C3, N2-C1, and N2-C3
bond lengths are 1.352(2), 1.412(2), 1.458(2) and 1.351(2) Å, whereas in DFT-
optimized geometry, the calculated values are 1.36429, 1.41180, 1.45961, and
1.36643 Å, respectively. These values demonstrate a good agreement between
them. Similarly, N1-C4-C5 (112.89(17)/112.85), N2-C1-C7 (112.91(15)/112.88) and
C13-C1-C7 (110.18(15)/110.84) bond angle values computed from the DFT/X-ray
crystallography are in close agreement. The most obvious difference in torsion angle
values occurs at N2-C1-C7-C8 torsion angle, with the difference in the value being of
8.51°. In general, despite differences in the molec ular environment, good correlation
was found between DFT and XR crystallography values.
Table 3. Some selected experimental and theoretical geometric parameters for 3-
allyl-5,5-diphenylimidazolidine-2,4-dione (3ADID) (Å, ˚).
Theoretical
Experimental
Geometric Parameters
[DFT/B3LYB]
[X–ray diffraction]
Bond (Å)
O1-C2
N1-C2
N1-C4
1.221(2)
1.352(2)
1.450(2)
1.21253
1.36429
1.46499
10

N2-C1
O2-C3
N1-C3
N2-C3
C1-C13
C1-C2
C5-C6
C7-C12
C8-C9
C9-C10
C10-C11
C11-C12
C13-C18
C1-C7
C4-C5
C7-C8
C13-C14
1.458(2)
1.210(2)
1.412(2)
1.351(2)
1.530(3)
1.538(2)
1.307(4)
1.391(3)
1.390(3)
1.392(4)
1.376(4)
1.397(3)
1.398(3)
1.534(3)
1.494(3)
1.392(3)
1.386(3)
1.393(3)
1.375(4)
1.387(3)
1.385(3)
1.45961
1.21025
1.41180
1.36643
1.53721
1.55676
1.33243
1.39824
1.39340
1.39779
1.39432
1.39796
1.40381
1.53633
1.50764
1.40292
1.39944
1.39773
1.39434
1.39721
1.39374
C14-C15
C15-C16
C16-C17
C17-C18
Bond angles (º)
C2-N1-C3
C3-N1-C4
N2-C1-C13
C13-C1-C7
O1-C2-N1
N1-C2-C1
O2-C3-N1
N1-C4-C5
C8-C7-C1
C18-C13-C1
C2-N1-C4
C3-N2-C1
N2-C1-C7
N2-C1-C2
O1-C2-C1
O2-C3-N2
N2-C3-N1
C12-C7-C1
C14-C13-C1
Torsion angles (º)
C3-N2-C1-C13
C4-N1-C2-C1
C4-N1-C3-N2
C1-C7-C12-C11
C3-N1-C2-O1
N2-C1-C2-O1
C13-C1-C2-N1
C1-N2-C3-O2
111.89(14)
122.71(15)
110.64(14)
110.18(15)
126.57(17)
107.44(14)
124.52(16)
112.89(17)
119.31(17)
117.56(16)
125.40(15)
113.39(15)
112.91(15)
100.42(14)
125.97(17)
128.91(17)
106.57(15)
120.89(18)
123.33(17)
112.44977
122.98799
110.26729
110.84643
125.98273
106.98941
125.56565
112.85208
119.02032
118.15902
124.44698
113.21870
112.88016
100.49177
127.02738
128.20371
106.21940
121.75268
122.92036
124.48(16)
-174.99(17)
177.24(17)
-177.36(19)
-176.48(18)
176.55(18)
-123.56(16)
178.92(19)
-121.41418
179.52381
176.54569
179.33481
-176.90189
-178.18573
119.93976
-172.78462
11

C2-N1-C3-O2
N2-C1-C7-C8
C1-C7-C8-C9
C7-C1-C13-C14
C2-C1-C13-C18
C1-C13-C14-C15
177.29(18)
170.54(16)
178.45(19)
129.00(19)
-177.08(16)
176.4(2)
173.93619
-179.05444
-176.11034
129.36833
-176.17660
176.34060
-176.11034
C1-C13-C18-C17
Numbering is according to Fig. 4.
-176.02(19)
3.3. Molecule’s reactivity analysis by global reactivity descriptors
Frontier molecular orbitals (FMOs), i.e. HOMO and LUMO, are the most important
orbitals in a molecule. They are a well-known analysis to investigate the reactive
ability of compounds [37–40]. They determine the ability of a compound to accept (in
the case of LUMO) or donate (in the case of HOMO) an electron [39,41,42]. HOMO
and LUMO orbitals of the title compound were examined and are shown in Fig. 5.
The electronic distribution reflects the donor-acceptor capabilities of the molecular
structure. Accordingly, both HOMO and LUMO orbitals are located over the two
phenyls and the hydantoin moiety. The well-defined electron density map for 3ADID
reflects its good interactive ability.
By using the energies of FMOs, the ionization energy (IP) and electron affinity (EA)
can be determined by the following formulas [43]:
EA=−E
(1)
(2)
LUMO
IP=−EHOMO
χ
η
The chemical potential (ꢀ), absolute electronegativity ( ) and absolute hardness ( )
were calculated from combination of ionization energy and electron affinity values
using the following equations [43]:
IP + EA
(3)
χ
= −µ =
2
12

1
IP − EA
σ =
(4) and
(5) denotes the softness (σ).
η
=
η
2
Recently, Serdaroğlu and Ortiz have reported quantum chemical calculations for
phenytoin [44]. Therefore, in order to investigate the effect of alkylation on the
reactivity and electronic properties of 3ADID, it is instructive to compare their results
with ours. Quantum chemical parameters of phenytoin and 3ADID are reported in
Table 4. A large EHOMO value indicates a higher tendency to donate electrons,
whereas, in contrast, a lower ELUMO value indicates a higher ability to accept
electrons [45,46]. The HOMO-LUMO gap (∆E), on the other hand, is an important
stability index. If its value is higher, it indicates higher stability, and vice versa if its
value is lower [45,47]. Based on results in Table 4, 3ADID compound has a more
tendency to give its electrons while phenytoin tends to accept electrons. In terms of
the gap value, there is a low value for the phenytoin molecule compared to 3ADID.
-1
η
The and σ values of 3ADID are, respectively 2.979 eV and 0.336 eV and those of
phenytoin are, respectively 2.936 eV and 0.340 eV-1. These results indicate that the
phenytoin became harder after its alkylation. It is well known that molecules with
smaller energy gap are in most case softer than those with a large energy gap (which
is the case here).
The electrophilicity index (ω) and its multiplicative inverse i.e. the nucleophilicity index
( ε
) were calculated using the following formulas [48,49]:
µ2
ω=
(6)
2η
1
(7)
ε =
ω
The electrophilicity is a good indicator of the electron-accepting ability, whereas
molecules having a large nucleophilicity are known to have strong ability to accept
13

electron [50]. In our results, phenytoin is found to be strongest electrophile whereas
the synthesized phenytoin derivative (3ADID) is the strongest nucleophile.
Table 4. Quantum chemical parameters of 3-allyl-5,5-diphenylimidazolidine-2,4-dione
obtained by DFT-B3LYB.
Parameter
Value
3ADID
-6.603
-0.644
5.959
6.603
0.644
2.979
3.624
2.203
0.335
0.453
Phenytoin [44]
-7.061
-1.188
5.873
EHOMO, (eV)
ELUMO, (eV)
∆E, (eV)
IP, (eV)
EA, (eV)
Ƞ, (eV)
7.061
1.188
2.936
4.124
2.896
0.340
0.345
χ, (eV)
ω, (eV)
σ, (eV-1)
ε, (eV-1)
3.4. Molecular electrostatic potential analysis
The MEP map is a visual tool to understand the relative polarity and predict reactive
sites of a molecule [38]. It is associated with the electronic cloud and it is an
important descriptor in evaluating the potential electrophilic and nucleophilic regions
in a molecule [51]. In this work, the MEP mapping was calculated by DFT-B3LYB
method as shown in Fig. 6 to visualize the charge distribution on the molecule. The
area with dark red color means potential that is more negative and that area in a
molecule have more preference for electrophilic attacks, while the area with intense
blue color indicates potential that is more positive and it is related to nucleophilic
reactivity [22,38]. Intermediate electrostatic potentials are between red and blue
potentials according to the following order: red < orange < yellow < green < blue.
14

From the MEP plot, it can been seen that negative electrostatic potentials are spread
over the carbonyl oxygen atom, indicating possible sites for electrophilic attack while
electropositive region is mainly localized over the protonated nitrogen atom.
3.5. Mulliken and NBO atomic charges
We have also computed Mulliken and NBO charges and results are listed in Table 5
and Fig. S1. The charge distribution over the atoms was found to be significant in
describing donor and acceptor pairs and to get insights into the overall activity of the
compound [22]. Moreover, it would be very interesting to compare these results with
those of similar compounds, especially to show the effect of substitution of the
hydantoin moiety on the charge distribution. The computed results reveal that only
C4, C6, C7 and C13 (Mulliken charges) and C3, C4 and C6 (NBO charge) exhibit a
positive charge whereas all other atoms exhibit negative charges. The O1 (-
0.427346) and O33 (-0.425187) atoms have the maximum negative Mulliken
charges, while the N31 atom has the highest negative NBO charge, followed by O33
and O1 atoms. This is compatible with results of Nogueira et al. who found that both
oxygen atoms are the most electronegative atoms in 1-methylhydantoin molecule
[52]. The nitrogen atoms N2 and N31 have negative total charges because of their
strong electronegativity as compared to carbon atoms to which they are attached;
and the same results were found by Nogueira et al. for 5 methylhydantoin and 1-
methylhydantoin molecules [52,53]. The results showed, unsurprisingly, that the
maximum positive NBO charges are obtained for C4 and C6 (0.70418 and 0.81564,
respectively) because they are connected to more electronegative atoms, i.e. oxygen
and nitrogen. Overall, these results indicate that the hydantoin moiety plays an
important role in the chemical reactivity of the synthesized compound.
15

Table 5. The Mulliken, natural atomic charge and the total negative charge (TNC) of
3-allyl-5,5-diphenylimidazolidine-2,4-dione obtained by DFT-B3LYB.
Atoms
1 O
2 N
3 C
4 C
5 C
6 C
7 C
8 C
Mulliken charges
-0.427346
-0.332549
-0.092554
0.448394
-0.091602
0.546891
0.151390
-0.094742
-0.066158
-0.059768
-0.069822
-0.098379
0.135369
-0.101869
-0.064409
-0.061554
-0.071285
-0.070790
-0.392727
-0.425187
-0.005825
-0.187605
-2.714171
NBO charges
-0.57466
-0.48537
0.04659
0.70418
-0.30134
0.81564
-0.05175
-0.23213
-0.22885
-0.23372
-0.22625
-0.22496
-0.05649
-0.23295
-0.23227
-0.23571
-0.23011
-0.21634
-0.67262
-0.59577
-0.24241
-0.41587
-5.68957
9 C
10 C
11 C
12 C
13 C
14 C
15 C
16 C
17 C
18 C
31 N
33 O
34 C
36 C
TNC
Numbering is according to Fig. 4.
3.6. Fukui functions
Identifying local reactivity parameters is among the most basic and commonly used
tools to understand the reactivity and selectivity of a molecule [39]. The condensed
Fukui functions, which resulted from a derivative of electron density keeping the
positions of nuclei unchanged are a more practical and convenient way in predicting
favorable sites for electrophilic or nucleophilic attack [22,54,55]. Nucleophilic,
16

f+ f−
f0
electrophilic and radical attack are, respectively, expressed as ( ), ( ) and ( ).
They are defined as follows [56]:
fk+ =qk(N+1)−qk(N)
(8)
fk- = qk (N)−qk (N −1)
(9)
1
f 0 = q (N+1)−q (N−1)
[
]
(10)
k
k
k
2
th
q
where k is the atomic charge at the k atomic site within a molecule in its neutral (N),
anionic (N+1) or cationic (N-1) state [57].
The propensity toward nucleophilic or electrophilic attacks can be more precisely
predicted by the dual descriptor, which is proposed by Morell et al. [58] and defined
as:
∆f (k) = fk+ − fk−
(11)
In order to characterize the reactivity of an atomic site and to distinguish between
electrophilic and nucleophilic attacks, the sign of the dual descriptor is mostly
considered. The sites for electrophilic attack are marked with a positive sign of the
dual descriptor while its negative sign means nucleophilic attack [51]. In the present
study, condensed Fukui functions indices along with dual descriptor values of
investigated molecule are listed in Table 6. Inspection of results in Table 6 shows that
N1 and C9 atoms of both phenyls have a greater susceptibility to electrophilic attack
(large values of ƒ- and negative ∆f). In the case of the nucleophilic attack, C2, N3,
C4, C5, O6, O7, C8, and C10 atoms have a higher propensity to nucleophilic attack
(large values of ƒ+ and positive ∆f). On the other hand, atoms that are more prone to
radical attack are the C4, O6, O7, and C15. A closer inspection of results revealed
17

that the distribution of electrophilic and nucleophilic sites are in accordance with
HOMO-LUMO orbitals.
Table 6. Condensed Fukui functions and dual descriptor of 3-allyl-5,5-
diphenylimidazolidine-2,4-dione obtained by DFT-GGA.
ꢁꢂ
∆ꢁ
f+
f−
Atom
N ( 1)
C ( 2)
N ( 3)
C ( 4)
C ( 5)
O ( 6)
O ( 7)
C ( 8)
C ( 9)
C ( 10)
C ( 11)
C ( 12)
C ( 13)
C ( 14)
C ( 15)
C ( 16)
C ( 17)
C ( 18)
C ( 19)
C ( 20)
C ( 21)
C ( 22)
2.2
3.4
2.4
6.7
1.3
9.2
5.6
0.9
0.4
1.4
3.7
1.9
3.1
4.8
6.4
3.3
4.3
3.2
2.3
3.9
3.7
1.7
2
2.4
1.2
1.1
1
-0.4
4.3
2.7
11.3
1
11.4
5.8
0.5
-0.4
0.6
-2.9
-2.8
-0.7
-2.9
-3.2
-1
-2.4
-3.6
-1.5
-4.1
-4
5.5
3.8
12.3
1.8
14.9
8.5
1.1
0.2
1.7
2.2
0.5
2.8
3.3
4.8
2.8
3.1
1.4
1.5
1.9
1.7
0.9
0.8
3.5
2.7
0.6
0.6
1.1
5.1
3.3
3.5
6.2
8
3.8
5.5
5
3
6
5.7
2.6
-1.7
Numbering is according to Fig. S2.
3.7. Donor-acceptor interactions by NBO analysis
The NBO analysis was performed to show the interaction between the donor NBO
"filled" and acceptor NBO "virtual" in the molecule [41]. The NBO analysis is a
sensitive tool for examining all possible interactions between filled Lewis-type NBOs
(donors) and unoccupied non-Lewis NBOs (acceptors) and estimating their
stabilization energy by the theory of 2nd order perturbations [39]. It allows
18

interpretation of hyperconjugative interaction or intermolecular delocalization result in
the transfer of charge between vacant (antibonding or Rydgberg) and filled (bonding
or lone pair) orbitals of two subsystems. The stabilization energy E(2), which is
associated with electron delocalization between electron donor orbital i and electron
acceptor orbital j reflects the extent of conjugation of the whole system. Larger E(2)
means a stronger electron donor-acceptor interaction [59,60]. According to NBO
analysis, the stabilization energy (E2) is computed from below formula [61]:
2
F2
i F j
ij
E(2) =−q
=−q
i
(12)
i ∆E
εj −εi
where qi is the donor orbital occupancy, εj, and εi are diagonal elements, Fij is the off-
diagonal NBO Fock matrix constituent.
For the title compound, some of the important donor-acceptor interactions
(stabilization energy E (2) higher than 4 kcal/mol) are reported in Table S1
(Supplementary Material). The stabilization of the molecule is attained by the strong
hyper-conjugative interaction of donors to acceptors. The results of the NBO analysis
reveal that the most relevant donor-acceptor interactions are the interactions
between the lone electron pair (LP) of the nitrogen atoms and the carbonyl bonds π
antibonding orbitals. These are the same reported by Nogueira et al. in their NBO
analysis of 5 methylhydantoin and 1-methylhydantoin molecules [52,53]. Lone pair
around LP (1) N2 is distributed to π* anti-bonding O1-C4 and C6-O33 with
stabilization energy of about 59.64 and 48.87 kcal/mol, respectively. Interestingly,
similar interactions were reported by Nogueira et al. but with smallest stabilization
energy [52,53]. Whereas, lone pair around LP (1) N31 is distributed to π* anti-
bonding C6-O33 with stabilization energy of about 50.28 kcal/mol. Despite
competition between the two interactions involving N2, the interaction energy for LP
19

(1) N31 → π* (C6-O33) is smaller than that corresponding to the LP (1) N2 →
π*(O1-C4) orbital interaction, which is in contrast to what has been found by
Nogueira et al. in their two studies [52,53].
Concerning other NBO interactions, the π electron delocalization is greater around
C15-C16 bond and is dispersed to π* anti-bonding of C13-C14 and C17-C18 with
energy 22.37 and 19.56 kcal/mol, respectively. The maximum stabilization energies
22.41 and 20.38 kcal/mol are due to the π electron delocalization about C17-C18 that
is dispersed to π* anti-bonding of C13-C14 and C15-C16. In the case of intra
molecular hydrogen bond, the significant interaction is occurred in σ(C36-H38) → σ*
(C5-C34) (6.09ꢁkcal/mol).
3.8. Hirshfeld surface analysis
Fig. 7 illustrates the Hirshfeld surface and the intermolecular contacts of the title
compound mapped over dnorm. It was established that dnorm values vary from -0.5973
to +1.5340 a.u. The red regions (distances shorter than the sum of the van der Waals
radii) is apparent around the oxygen atom (O2) participating in the C—H···O contacts
and around the hydrogen atom (H2) participating in the N—H···O contacts in Fig. 7.
The fingerprint plots are given in Fig. 8 for the title compound. The largest
contribution to the overall crystal packing in the compound is from H···H interactions
(54.8%). This significant contribution of H···H interactions to the total Hirshfeld
surface was also reported in other studies [62,63]. C···H/H···C contacts are the
second largest contribution to the Hirshfeld surface with 26.7%. The O···H/H···O
contacts appear as a pair of characteristic tips in the fingerprint plots. O···H/H···O
contacts contribute 15.9% to the Hirshfeld surface. Also, the O···H/H···O contacts
20

indicate the presence of intermolecular N—H···O and C—H···O interactions,
respectively.
4. Conclusions
In the present work, a new phenytoin derivative, 3-allyl-5,5-diphenylimidazolidine-2,4-
dione, formulated as C18H16N2O2 was synthesized and its structure was determined
by X-ray crystallography. Further, the molecular structure was examined using
Hirshfeld topology analysis and Density Functional Theory (DFT) at B3LYB/6-
311++G(d,p) level. It was found that the compound crystallizes in the trigonal space
group P 32 with parameters a= 14.5779(3) Å, b= 14.5779(3) Å, c= 6.1846(2) Å, Z=3.
Global and local descriptors of reactivity such as HOMO-LUMO and condensed
Fukui functions along with net charges and MEP were used to evaluate the chemical
reactivity of 3ADID. NBO analysis was performed for understanding the stability,
intramolecular charge transfer and donor-acceptor interactions in the synthesized
compound.
Conflict of interest:
The authors of this manuscript have no conflict of interest to declare.
Acknowledgements
“The authors extend their appreciation to the Deanship of Scientific Research at King
Khalid University for funding this work through research groups program under grant
number R.G.P.2/46/40.”
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25

Figure Captions
Figure 1. The title molecule with labeling scheme and 50% probability ellipsoids.
Figure 2. A portion of one hydrogen bonded chain viewed along the a-axis direction.
N—H···O and C—H···O hydrogen bonds are shown, respectively, by blue and black
dashed lines.
Figure 3. Packing viewed along the c-axis direction with the C—H···π(ring)
interactions shown as green dashed lines.
Figure 4. Optimized molecular structure of 3-allyl-5,5-diphenylimidazolidine-2,4-dione
obtained by DFT.
Figure 5. Frontier molecular orbitals (HOMO-LUMO) of 3-allyl-5,5-
diphenylimidazolidine-2,4-dione.
Figure 6. The molecular electrostatic potential map of 3-allyl-5,5-
diphenylimidazolidine-2,4-dione.
Figure 7. The view of the three-dimensional Hirshfeld surface of 3-allyl-5,5-
diphenylimidazolidine-2,4-dione plotted over dnorm in the range -0.5973 to 1.5340 a.u..
Figure 8. The two-dimensional fingerprint plots for 3-allyl-5,5-diphenylimidazolidine-
2,4-dione, showing (a) all interactions, (b) H···H, (c) C···H/H···C and (d) O···H/H···O
interactions.
26

Fig. 1.
27

Fig. 2
28