Facile synthesis, single crystal analysis, and computational studies of sulfanilamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2016.08.032

Antibacterial resistance is a worldwide problem. Sulfanilamide is widely used antibacterial. For the first time, we report here a simple method for the derivative synthesis of the title drugs, single crystal XRD and density functional theory (DFT) studies. The optimized molecular structure, natural bond orbital (NBO), frontier molecular orbitals (FMOs) molecular electrostatic potential studies (MEP) and Mulliken population analysis (MPA) have been performed using M06-2X/6-31G(d, p). The FT-IR spectra and thermodynamic parameters were calculated at M06-2X/6-311?+?G(2d,p) and B3LYP/6-31G(d, p) levels respectively, while, the UV–Vis analysis was performed using TD-DFT/B3LYP/6-31G(d, p) method. The experimental FT-IR spectra of both compounds were also carried out to reconfirm [sbnd]H?O[sbnd] hydrogen bonds. The DFT optimized parameters exhibiting good agreement with the experimental data. NBO analysis explored the hyper conjugative interaction and stability of title crystals, especially, reconfirmed the existence of [sbnd]H?O[sbnd] hydrogen bonds between the dimers. The FT-IR, thermodynamic parameters, MEP and MPA also revealed the hydrogen bonding detail is harmonious to XRD data. As a matter of the fact, the hydrogen bonding is a significant parameter for the understanding and design of molecular crystals, subsequently; it can also play a vital role in the supramolecular chemistry. Moreover, the global reactivity descriptors suggest that title compounds might be bioactive.

Full text of DOI:10.1016/j.molstruc.2016.08.032

Accepted Manuscript
Facile synthesis, single crystal analysis, and computational studies of sulfanilamide
derivatives
Muhammad Nawaz Tahir, Muhammad Khalid, Ayesha Islam, Syed Muddassir Ali
Mashhadi, Ataualpa A.C. Braga
PII:
S0022-2860(16)30862-6
10.1016/j.molstruc.2016.08.032
MOLSTR 22858
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 May 2016
Revised Date: 9 August 2016
Accepted Date: 11 August 2016
Please cite this article as: M.N. Tahir, M. Khalid, A. Islam, S.M. Ali Mashhadi, A.A.C. Braga, Facile
synthesis, single crystal analysis, and computational studies of sulfanilamide derivatives, Journal of
Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.08.032.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Facile Synthesis, Single Crystal Analysis, and Computational Studies of
Sulfanilamide Derivatives
Muhammad Nawaz Tahir,a Muhammad Khalid,b* Ayesha Islam,a Syed Muddassir Ali Mashhadi
c, Ataualpa A. C. Bragab
a University of Sargodha, Department of Physics, Sargodha, Pakistan.
bDepartamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av.
Prof. Lineu Prestes, 748, São Paulo, 05508-000, Brazil.
cAllama Iqbal Open University, Department of Chemistry, Islamabad, Pakistan.
*Corresponding author email: khalid@iq.usp.br (Muhammad Khalid)
Abstract
Antibacterial resistance is a worldwide problem. Sulfanilamide is widely used
antibacterial. For the first time, we report here a simple method for the derivative synthesis of
the title drugs, single crystal XRD and density functional theory (DFT) studies. The optimized
molecular structure, natural bond orbital (NBO), frontier molecular orbitals (FMOs) molecular
electrostatic potential studies (MEP) and Mulliken population analysis (MPA) have been
performed using M06-2X/6-31G(d, p). The FT-IR spectra and thermodynamic parameters were
calculated at M06-2X/6-311+G(2d,p) and B3LYP/6-31G(d, p) levels respectively, while, the
UV-Vis analysis was performed using TD-DFT/B3LYP/6-31G(d, p) method. The experimental
FT-IR spectra of both compounds were also carried out to reconfirm -H···O- hydrogen bonds.
The DFT optimized parameters exhibiting good agreement with the experimental data. NBO
analysis explored the hyper conjugative interaction and stability of title crystals, especially,
reconfirmed the existence of -H···O- hydrogen bonds between the dimers. The FT-IR,
thermodynamic parameters, MEP and MPA also revealed the hydrogen bonding detail is
harmonious to XRD data. As a matter of the fact, the hydrogen bonding is a significant
parameter for the understanding and design of molecular crystals, subsequently; it can also play a
vital role in the supramolecular chemistry. Moreover, the global reactivity descriptors suggest
that title compounds might be bioactive.
Key words: Sulfanilamide, Antibiotic, XRD, NBO, FMO, FT-IR
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1. Introduction
2
Menace of bacterial resistance1 for antibiotics poses a great hurdle for the treatment of
infections. This situation urges the development of new active compounds. Sulfonamide
functional groups are popular for their wide range pharmaceutical role.3 These well-known
compounds are being administered as antibacterial, antifungal, antiviral, and anti-tumor drugs.4-11
The pharmacological and toxicological properties can be boosted if sulfonamides with amide
moiety are used as drugs. Domagk was the first who discovered sulfonamides as the active
chemotherapeutic ingredient and his work was acknowledged by awarding him the Nobel Prize
in medicine for the year of 1939.12
Sulfanilamide, an aniline derivative of sulfonamide family is a low priced drug having
chemotherapeutic properties popular in developing countries with serious bacterial resistance
problem.13,14 Sulfanilamide was popularized because of its role in reducing infection rates during
2nd world war (WWII).15 Sulfanilamide functions by competing with para amino benzoic acid
(PABA) in folic acid biosynthesis hence suppressing the key growth metabolic factor essential
for bacterial growth.16 In past the structure of sulfanilamide derivatives17-19 and their
characterization have been studied.20-22
However, according to the best of our knowledge, neither experimental technique like
XRD, nor the computational studies regarding the (E)-4-oxo-4-[(4-sulfamoylphenyl) amino] but-
2-enoic acid and 4-oxo-4-[(4-sulfamoylphenyl) amino] butanoic acid employing famous
DFT23,24have been reported so for. Detailed structure-activity studies reveal important
information regarding biological and pharmacological properties to design potential drug
molecules.25 Moreover, hydrogen bond is also a significant parameter for the understanding and
design of molecular crystals and biological activities.26 Therefore, it is very essential and need of
hour to synthesize, exploration of the hydrogen bond details, electronic structures and molecular
features of sulfanilamide derivatives.
To fulfill this research gap regarding the sulfanilamide derivatives, we synthesized two
derivatives by simple reaction of drug with maleic anhydride and with succinic
anhydride.(Scheme 1). Derivatives were characterized using the XRD and computational studies.
The detailed analysis of NBO, FMOs, MEP, MPA, FT-IR, UV-Vis, and thermodynamic
parameters to explore electronic and non-covalent interactions (NCIs) of sulfanilamide
derivatives. They are helpful for a deep understanding of structure-property relation.
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Scheme 1: Schematic representation of the synthesis of reported derivatives.
2. Experimental and calculations
2.1. Experimental section
Analytical grade chemicals were used as received without further purifications. The experimental
FT-IR spectra of both compounds were performed by Perkin Elmer spectrum version 10.4.3.
2.1.1. Sulfanilamide-maleic anhydride derivative (1)
Sulfanilamide (3mmol) and maleic anhydride (3mmol) were dissolved separately in ethyl acetate
(20 mL), after a while, both solutions were mixed together and stirred for 3 hours. The solution
was left for slow evaporation at room temperature. White needle crystals were isolated after 3
days.
2.1.2. Sulfanilamide-succinic anhydride derivative (2)
Sulfanilamide (3mmol) and succinic anhydride (3mmol) were separately mixed in ethyl acetate
(20 mL), thereafter, both solution were combined and stirred together at ambient conditions for 3
hours. White needle crystals were harvested after 2 days under slow evaporation.
2.2. XRD studies
XRD results were collected by using Bruker Kappa APEX II CCD diffract meterat 296 K
equipped with graphite monochromator. Molybdenum Kα X-rays fine focus was used. APEX2
software was used to collect data. For indexing the reflections and determining the unit cell
parameters SAINT27 was employed. SHELXL-97 software solved the structure by direct
methods and was refined by full-matrix least square calculations. PLATON software calculated
the geometric parameters like bond distance, bond angles, Torsion angles and hydrogen bonds.
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Crystal structures, figures and other structural information were inferred by using Mercury 3.7
software.
2.3. Computational studies
All electronic structure calculations were based on density functional theory (DFT)28 with the
Gaussian 09 suite of programs.29 The dimer of (E)-4-oxo-4-[(4-sulfamoylphenyl)amino]but-2-
enoic acid and dimer of 4-oxo-4-[(4-sulfamoylphenyl)amino]butanoic acid are completely
optimized without any symmetry restriction30-32 at M06-2X/6-31G(d, p)33 level of the theory.
Frequency calculations were performed in order to characterize the nature of the optimized
geometry. FT-IR spectra was calculated with same level of theory but a larger basis set such as
6-311+G(2d,p). All the stationary points have only real frequencies. Gauss View,34 Avogadro35
and Chem craft36 programs have been used to visualize the chemical systems.
3. Results and discussion
Synthesized derivatives of sulfanilamide were characterized by single-crystal X-ray diffraction.
Crystallographic information is shown in Table 1 and information regarding hydrogen bonds of
crystals is presented in Table 2. Crystal structures were deposited at the Cambridge
Crystallographic Data Centre. The data have been assigned the following deposition numbers;
(CCDC=1059665) for 1 and (CCDC=1059664) for 2.
3.1. Sulfanilamide-maleic anhydride derivative (1)
(E)-4-oxo-4-[(4-sulfamoylphenyl) amino] but-2-enoic acid
Sulfanilamide derivative (1) crystallizes as off white needle-shaped crystal in the monoclinic
space group C c having molecular formula C10H10N2O5S and molar mass 270.26 amu. It is 1:1
adduct with no incorporation of the solvent molecule. Stoichiometry shows a discrete adduct
formation [Figure 1a (ORTEP diagram)] and layer structure (Figure 1b) having hydrogen bond
and extended packing of these discreet adducts. Extensive hydrogen bonding is present between
the sulfonamide groups which lead to layer structure of the drug derivative (Figure 1b). The
oxygen atom of the sulfonamide functional group on one molecule serves as hydrogen bond
acceptor and amino part of sulfonamide group on other molecule act as donor in the formation of
layer structure of derivative (1). Distinct hydrogen bonding is also present between oxygen of
acidic group belonging to one molecule and nitrogen of other molecule to construct the crystal
lattice as shown in Figure 1b. Large ring motifs37 having incorporated benzene rings are formed
to support the layer structure. Hydrogen bonding detail is summarized in Table 2. In compound
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(1) the coordinates of H-atoms of hydroxyl group and the amino group are refined. The other H-
atoms were positioned geometrically (N—H = 0.86, C–H = 0.93 Å) and were included in the
refinement in the riding model approximation, with Uiso(H) = 1.2Ueq(C, N) and Uiso(H) =
1.5Ueq(O).
(a) The ORTEP diagram
(b) Molecular packing
Figure 1: (a) The thermal ellipsoids are drawn at 50 % probability level; the H-atoms are shown as small
circles of arbitrary radii, (b) Molecular packing of compound 1showing H.B.
3.2. Sulfanilamide-succinic anhydride derivative (2)
4-oxo-4-[(4-sulfamoylphenyl) amino] butanoic acid
The derivative (2) crystallizes as white needle crystal having triclinic space group P-1 with
molecular formula C10H12N2O5S and molar mass 272.28 amu. The crystal stoichiometry is a
discrete 1:1 adduct with no incorporated the solvent molecule [Figure 2a (ORTEP diagram)].
The derivative depicts distinct hydrogen bonding between sulfonamide and other functional
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groups and forms layers (Figure 2b). One ring motif resulting the graph set as Rꢀꢀ(14) and another
ring motif involving heterosynthon is formed by the hydrogen bonding having a graph set Rꢁꢁ(18)
(Figure 2b). These graph sets were formed by the incorporation of many molecules of derivative
(2). In this extensive hydrogen bonding sulfonamide group and carboxylic acid groups are
involved. Detail of hydrogen bonding present in crystal is arranged in Table 2. In compound (2)
the coordinates of H-atoms the amino group are refined. The other H-atoms were positioned
geometrically (N—H = 0.86, C–H = 0.93–0.97 Å) and were included in the refinement in the
riding model approximation, with Uiso(H) = 1.2Ueq(C, N) and Uiso(H) = 1.5Ueq(O).
.
(a) The ORTEP diagram
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(b) Molecular packing
Figure 2: (a) The thermal ellipsoids are drawn at 50 % probability level; the H-atoms are shown as small
circles of arbitrary radii, (b) Molecular packing of compound 2 showing H.B.
Table 1: Single crystal XRD data of 1 and 2
Compounds
Chemical formula
Mr
1
2
C10H10N2O5S
270.26
C10H12N2O5S
272.28
Crystal system, space group
Temperature (K)
a, b, c (Å)
Monoclinic, Cc
296
Triclinic, P¯ 1
296
24.529 (3), 5.1692 (7),
9.4722 (12)
5.1309 (4), 11.3811 (11),
11.7458 (10)
62.623 (4), 85.940 (4), 77.247
(4)
α
,
β
,
γ
(°)
90.0, 106.858(7), 90.0
V (Å3)
1149.4 (3)
593.68 (9)
Z
4
2
Radiation type
(mm-1)
Mo Kα
Mo Kα
0.30
0.29
µ
Crystal size (mm)
Data collection
Diffractometer
0.40 × 0.20 × 0.16
0.34 × 0.26 × 0.22
Bruker Kappa APEXII
CCD
Bruker Kappa APEXII CCD
Absorption correction
Multi-scan
Multi-scan
(SADABS; Bruker, 2005)
(SADABS; Bruker, 2005)
Tmin, Tmax
0.892, 0.956
0.911, 0.943
No. of measured, independent and
4664, 2019, 1689
7816, 2323, 2021
observed [I> 2σ(I)] reflections
Rint
0.043
0.639
0.024
0.617
(sin θ/λ)
max (Å-1)
Refinement
R[F2> 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
No. of restraints
0.048, 0.114, 1.05
0.034, 0.095, 1.05
2019
172
2323
170
3
H-atom treatment
H atoms treated by a mixture of independent and
constrained refinement
∆〉max, ∆〉min (e Å-3)
0.31, -0.28
0.27, -0.33
Table 2: Hydrogen bond distances in 1 and 2
D—H···A
D—H (Å) H···A (Å) D···A (Å)
D—H···A (°)
Compounds
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N1—H1A···O2i 0.86
2.05
2.850 (6)
154.2
N2—H2A···O4ii 0.72 (8)
N2—H2B···O5iii 0.89 (7)
2.31 (8)
2.42 (7)
3.022 (8)
3.035 (7)
170 (8)
127 (5)
1
2
C3—H3···N2iv
0.93
2.68
2.25
2.26
2.05
3.494 (7)
2.853 (7)
2.860 (2)
146.1
121.9
121.6
C10—H10···O3 0.93
C10—H10···O3 0.93
N1—H1A···O2i 0.86
2.9110 (19) 176.2
N2—H2C···O3ii 0.843 (9) 2.074 (10) 2.909 (2)
171 (2)
168 (2)
N2—H2D···O1iii 0.842 (9) 2.196 (10) 3.025 (2)
O1—H1···O5iv
O1—H1···S1iv
0.82
0.82
1.92
2.84
2.7003 (18) 159.8
3.4443 (13) 132.1
For 1: Symmetry code(s): (i) x, y+1, z; (ii) x, y-1, z; (iii) x, -y, z+1/2; (iv) x+1/2, -y+1/2, z+1/2.
For 2: Symmetry code(s): (i) -x+3, -y, -z; (ii) -x+1, -y+1, -z; (iii) x-1, y, z+1; (iv) x+2, y, z-1.
3.3. Geometrical structure
The molecular structural parameters of 1 and 2 have been optimized utilizing M06-2X and
B3LYP levels of theory with 6-31G(d, p) basis set as tabulated in Tables S1 and S2
(Supplementary information). They are compared to the XRD determined structural parameters.
The comparative study shows a good agreement among the computational and experimental
parameters. Some few exceptions with small deviations are also collected in Tables S1 and S2
(Supplementary information). These slight variations are not completely unexpected, being it
reported before in analogous systems38 as a result of the various sorts of inter & intra-molecular
interactions in the solid framework.
3.4. Natural bond orbital (NBO) analysis
NBO is considered as a decent method for the investigation of inter and intra-molecular
interactions because of data regarding the interactions by filled and virtual orbitals.39,40
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Figure 3: Optimized dimer (1) and (2) geometries calculated at M06-2X/6-31G(d,p) level of theory.
Distances are in angstroms
.
The data of NBO study regarding both molecules is collected in Table 3 (see also Tables S3 and
S4 in the Supplementary information).
Table 3: Natural bond orbital (NBO) analysis using second-order perturbation theory
E(2)a
[kJ/mol]
9.08
E(j)_E(i)b
[a.u.]
1.42
F(i,j)c
[a.u.]
0.102
0.065
0.142
0.074
0.044
Acceptor
(j)
ꢂꢃꢄꢅ
Compounds Donor(i)
Type
ꢆ∗
ꢆ∗
O6
LP(1)
LP(2)
LP(2)
LP(1)
LP(2)
N38-H39
N38-H39
N36-C46
N21-H23
N21-H23
1
5.31
0.91
O6
ꢆ∗
ꢆ∗
ꢆ∗
28.10
5.43
0.88
O33
1.25
2
O54
O54
2.33
0.96
aEnergy of hyper conjugative interaction (stabilization energy).
b Energy difference between donor and acceptor i and j NBO orbital.
cFock matrix element between i and j NBO orbital.41,42
For numbering of atom refer Figure. 3.
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In this study, the hyper conjugative interactions among LP(1)O6→[N38-H39(σ*)],
LP(2)O6→[N38-H39(σ*)] and LP(1)O33→[N8-H9(σ*)], orbital led to the stabilization energies
are found to be 9.08, 5.31 and 11.34 kJ/mol respectively as seen in Table 3, proved the existence
of inter-hydrogen bonding network; O6···H39-N38 and O33···N8-H9 in dimer (1) see Figure 4.
The dimer (2) also consists of inter-hydrogen bonding network which has been justified by
following hyper conjugative interactions; LP(1)O54→[N21-H23 (σ*)] and LP(2)O54 →[N21-
H23 (σ*)] orbital led to the stabilization energies are observed to be 5.43 and 2.33 kJ/mol
respectively, as seen in Table 3 and Figure 4.
Additionally, the stronger intra-molecular hyper conjugative interactions have been observed due
to intra-molecular charge transfer which affording to the stabilization of the title systems. The
interactions (ꢇ → ꢇ*) play a prominent role to provide proof that both title compounds have
conjugation. The stabilization energies obtained to be 22.35, 24.06, 36.03, 29.84 and 22.41 kJ
mol-1 due to the transitions; ꢇ(C14-C16)→ ꢇ*(O4-C13), ꢇ(C19-C27)→ ꢇ*(C20-C22) and
ꢇ*(C24-C25), ꢇ(C20-C22)→ ꢇ*(C19-C27) and ꢇ*(C24-C25) respectively in dimer (1) as shown
in Table S3 (Supplementary information). The dimer (2) also showed ꢇ(C9-C17)→ ꢇ*(C10-
C12) and ꢇ*(C14-C15), ꢇ(C10-C12)→ ꢇ*(C9-C17) and ꢇ*( C14-C15), ꢇ(C39-C47)→ ꢇ*( C40-
C42) and ꢇ*( C C44-C45) orbitals led to the stabilization energies are found to be 24.66, 37.94,
29.51, 23.32, 24.48 and 37.55 kJ mol-1 respectively as shown in Table S4 (Supplementary
information).
The most significant interaction energy in the title molecules is electron donating from O34LP
(2) and N36LP (1) to the antibonding acceptor [S29-C52 (ꢆ∗)] [S29-O35 (ꢆ∗)] and [O33-C46
(ꢆ∗)], as a result, high stabilization energies are produced to be 18.65, 30.60 and 90.95 kJ/mol
respectively as shown in Table S3 (Supplementary information). Table S4 (Supplementary
information) also shows highest interactions i.e. O59LP(3), O59LP(2), O56LP(2),N49LP(1) and
N19LP(1) to the anti bonding acceptor [O58-S60(ꢆ∗)], [C44-S60(ꢆ∗)], [C31-O54(ꢆ∗)], [C38-
O57(ꢆ∗)],[C38-O57)ꢇ∗)] and [C8-O27)ꢇ∗)] which led to larger magnitude of energies i.e. 26.90,
21.60, 42.02, 69.79 and 70.99 kJ/mol respectively.
Finally, it can be deduced on the basis of NBO analysis that the strong intra-molecular hyper
conjugation interactions and inter-molecular hydrogen bonding are the main reasons that confer
more stability in these systems.
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Figure 4: HB structures of dimers (1) and (2) are constructed by donor–acceptor interaction.
3.5. Hydrogen bond vibrations
Single X-ray diffraction and NBO examination proposed that both compounds contain stronger
network of non-covalent interactions (NCIs) such as (–H···O-), as displayed in Figures 1, 2 and
4 which may be a reason of extra stability of the title molecules. Experimental FT-IR analysis
also shows that two N-H stretching vibrations of primary amine are found to be 3220 cm-1 and
3426 cm-1 with broad band showing very strong intermolecular hydrogen bond for 1, see Figure
S1 and two N-H stretching vibrations of primary amine are also found to be 3236 cm-1 and 3416
cm-1 with broad peak showing very strong intermolecular hydrogen for 2, see Figure S2.
Therefore, DFT based FT-IR absorption analysis is performed using monomer and dimer of both
compounds with a specific aim to reconfirm the H-bonding network utilizing M06-2X/6-
311G+(2d,p) approach in gas phase. The FT-IR examination allowed us to correlate and affirm
the presence of inter & intra-hydrogen bond in the promised compounds.
3.5.1. Hydrogen bond vibrations for 1
The N-H symmetric and anti-symmetric stretching vibrations of primary amine are obtained to
be 3343 cm-1 with (IIR = 46) and 3455 cm-1 with (IIR = 45) respectively. The N-H stretching band
of secondary amine is obtained at 3154 cm-1 with high intensity (IIR =590) due to intra-molecular
hydrogen bond in monomer (1) as can be seen in Figure 5. On the other hand, the dimer (1)
displayed N-H stretching vibrations of secondary amine are obtained to be 3372 cm-1 with (IIR
=296) and 3163 cm-1 with (IIR = 690) as both are with high intensity due to intra-molecular
hydrogen bond. The N-H stretching vibrations of primary amine are obtained i.e. 3420 cm-1 with
(IIR=139) and 3409 cm-1 with (IIR =155) with very weak H.B and two more N-H stretching
vibrations of primary amine are found to be 3250 cm-1 with high intensity (IIR =367) and 3208
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cm-1 with high intensity (IIR =255) showing very strong intermolecular hydrogen bond, which
were seen using the animation option and hydrogen bond in display types option of Avogadro
software. Of course, the discount in vibrational frequencies and high intensity in dimer is also a
remarkable logical43 for the presence of inter-hydrogen bonding network in the investigated
dimer (1) as can be demonstrated in Figure 5.
3.5.2. Hydrogen bond vibrations for 2
With respect to derivative 2 the N-H anti symmetric and symmetric stretching vibrations of
primary amine are obtained to be 3464 cm-1 with (IIR = 46) and 3352 cm-1 with (IIR = 46)
respectively and N-H stretching band of secondary amine is obtained at 3444 cm-1 with low
intensity (IIR = 36) due to lack of intra-molecular hydrogen bond in monomer (1) as can be seen
in Figure 5, while, in dimer (2), the N-H stretching vibration of primary amine is obtained to be
3314 cm-1 (symmetric) and 3442 cm-1 (antisymmetric) with high intensity (IIR=121) and (IIR=115)
respectively due to the existence of inter-molecular hydrogen bond formation of NH2 to
carbonyl C=O which lowered the NH stretching frequency and increased the intensity as shown
in Figure 5.
On the basis of FT-IR analysis, it can be concluded that the both dimers (1) & (2) containing
strong hydrogen bonding which might play a critical role in the stability of both systems. These
findings are in good agreement with experimental FT-IR and single X-ray diffraction obtained
data as can be seen in Figures 1, 2 and 5 ( also see Figures S1 and S2 ).
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Figure 5: FT-IR absorption spectra for 1 and 2 calculated at M06-2X/6-311G(2d,p) level of theory.
3.6. UV-Visible study
The monomers of (E)-4-oxo-4-[(4 sulfamoylphenyl)amino] but-2-enoic acid and 4-oxo-4-[(4
sulfamoylphenyl)amino] butanoic acid have been computed to determine the parameters
associating the vertical excitation energies, wavelength and oscillator strength (ꢈ) by using TD-
DFT/B3LYP/6-31G(d, p) (Tables 4 and 5) (also see Tables S5 and S6 in Supplementary
information).
Table 4: Calculated parameters for (E)-4-oxo-4-[(4 sulfamoylphenyl) amino] but-2-enoic acid using TD-
DFT//B3LYP/6-31G (d, p) method.
Excitation
CI coefficient
Energy (eV)
Wave length (nm)
Oscillator strength
Excited State 1
69→71
-0.15014
0.67673
3.6640
338.38
0.0592
70 → 71
Excited State 5
68 →72
0.11962
-0.32966
0.12401
0.45849
0.34891
5.0340
5.1317
246.30
241.60
0.1106
0.2180
69 →72
69 → 73
70 → 72
70 → 73
Excited State 6
0.10656
-0.15296
0.24525
0.47286
-0.39159
68 →71
68 → 72
69 → 72
70 → 72
70→ 73
Table 5: Calculated parameters for 4-oxo-4-[(4 sulfamoylphenyl) amino] butanoic acid using TD-
DFT/B3LYP/6-31G (d, p) method.
Excitation
Excited State 2
69 →72
CI coefficient
Energy (eV)
Wave length (nm)
Oscillator strength
0.12321
0.10826
0.64710
5.0546
245.29
0.5210
69 →73
71 →72
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-0.19992
71 →73
Experimental excitation energies, wavelength and oscillator strength (ꢈ) of these compounds
have not been reported in the literature till now, therefore, these computed information regarding
electronic transitions may be proved as assistant for the experimental study.
Three electronic transitions out of six are more intense for compound 1 at 3.6640eV [(338.38nm)
red colored peak], [5.0340eV (246.30nm) pink colored peak] and 5.1317eV [(241.60nm) yellow
colored peak] with oscillator strengths of 0.0592, 0.1106, and 0.2180, respectively as seen in
Figure 6, however, compound 2 showed just one intense peak at 5.0546eV [(245.29nm) red
colored peak] with oscillator strength of 0.5210 as can be seen in Figure 6. Other excitations for
both compounds are observed as a forbidden transitions as shown in Tables S5 and S6
(Supplementary information).
Figure 6: The calculated UV-Vis spectra for 1 & 2.
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3.7. Frontier molecular orbitals (FMOs)
The frontier molecular orbital (FMO) theory has been recognized as an outstanding theory in
elucidating the chemical stability of species.44-47 Specie consisting of a low frontier orbital gap
has more probability to be more polarizable and will show a noteworthy level of intramolecular
charge providing from the electron contributor segment to the electron acceptor segment.
In the current study, the orbital analysis of species (1 & 2) is computed using M06-2X method
with 6-31G (d, p) basis set. Our calculated data in respect to specie (1); the energy of HOMO,
LUMO, HOMO-1, LUMO+1, HOMO-2, LUMO+2 has been figured out to be around -0.285, -
0.056, -0.302, -0.041, -0.311 and -0.006 a.u. respectively, consequently, the energy gap as
concerns to EHOMO–ELUMO, EHOMO-1–ELUMO+1, EHOMO-2–ELUMO+2 are obtained to be 0.229, 0.261
and 0.305 a.u. and regarding to specie (2), the energy of HOMO, LUMO, HOMO-1, LUMO+1,
HOMO-2, LUMO+2 has been obtained to be around -0.287, -0.019, -0.301, -0.005, -0.3249 and
-0.0005 a.u. respectively, thereupon, the energy gap in relation to EHOMO–ELUMO, EHOMO-1
ELUMO+1, EHOMO-2–ELUMO+2 are obtained to be 0.267, 0.296 and 0.3244 a.u. respectively.
–
The transition EH–EL point out an electron density transformation within dimers (1) and (2) as
can be seen from the pictorial representation of FMOs (HOMO & LUMO) (Figures 7 and 8).
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Figure 7: Frontier molecular orbitals of dimer (1). Energy units are in Hartree.
Figure 8: Frontier molecular orbitals of dimer (2). Energy units are in Hartree.
The global reactivity parameters48-52 can reveal the reactivity and stability of specie. Therefore,
the global reactivity descriptors are ascertained with the help of the energies of FMOs presented
in Table 7, such as, electro negativity (X)54 ionization potential (I)55 electron affinity (A), electro
negativity (X), the chemical potential (ꢀ), global hardness (η), global softness (S) and global
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electrophilicity index (ω) are calculated according to the equations given in Supplementary
information.
Table 7: Ionization potential (I), electron affinity(A), electro negativity (X) chemical potential (
hardness ( ) global softness (S) and global electrophilicity ( ).
ꢀ) global
η
ω
Molecules
1
2
Combinations
A
B
C
A
B
C
Ionization potential (I)
Electron affinity (A)
Electro negativity (X)
Chemical potential (ꢀ)
Global hardness (η).
Global softness (S)
Global electrophilicity (ω)
0.285
0.302
0.041
0.172
-0.172
0.1305
3.831
0.113
0.311
0.006
0.159
-0.159
0.153
3.279
0.082
0.287
0.301
0.005
0.153
-0.153
0.148
3.378
0.079
0.3249
0.056
0.171
-0.171
0.1145
4.367
0.127
0.019
0.153
-0.153
0.134
3.731
0.087
0.0005
0.163
-0.163
0.162
3.083
0.082
A= HOMO & LUMO; B= HOMO-1 & LUMO+1; C= HOMO-2 & LUMO+2;
These reactivity parameters have also been recently utilized in understanding the reactivity and
selectivity of molecules.56-59 The species that have positive electron affinity are referred as
electron acceptors and the electron donation strength for any donor compound can be estimated
by its ionization potential, the energy needed to take off an electron from the HOMO. Electro
negativity is considered one of the most significant chemical properties which define the power
of specie to attract electrons towards itself.
Table 7 suggests that the magnitude of hardness is less than magnitude of softness in both cases
which means species are less stable and more reactive and the softness enhanced in the following
manner:
2 [3.731(S)] < 1[4.367(S)]
The value of global electrophilicity is one order of magnitude greater for 1 as compared to 2
which confirms the double bond in compound 1 as shown in Table 7. The obtained negative
values of chemical potential (ꢀ) suggest that the both molecules are stable, so, the global
reactivity descriptors suggest that the title compounds might be bioactive because of their
reactivity. The attained global reactivity observations can become attractive for the researchers in
order to continue an extensive study. These interesting observations can play a significant
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function in the field of experimental research, particularly, for biological activity of title
compounds.
Table 8:The dipole moment in three dimensions, total dipole moment and energy.
Molecules
Dimer (1)
Dimer(2)
µX
µY
µZ
µT
E(a.u)
-13.9918
-11.9510
-4.1754
5.7325
-4.1754
-0.7264
14.616
13.2746
-2540.983
-2543.438
The dipole moment holds a critical worth to depict the electronic features of a particle, in
consequence of atomic charge distribution. It can impact the capacity of specie to associate with
neighboring species. Both compounds [dimers (1) & (2)] by the reason of computed dipole
moments which are found to be 14.7554 Debye of dimer (1) and 13.2746 Debye of dimer (2) can
be attested considering polar molecules.
3.8. Molecular electrostatic potential (MEP)
Usually, MEP is utilized in anticipating electrostatic potential areas, physiochemical features,
hydrogen bonding network, particularly exhibiting the size and shape of atoms.60
Figure 9: Molecular electrostatic potential maps for dimers of 1 & 2.
Figure 9 shows, negative potential which is confined over the oxygen and the nitrogen atoms,
whereas positive region is confined around the hydrogen atoms. As in most cases, H-bond
network exists between the positive and negative parts, therefore, the hydrogen bonding i.e.
O6···H39-N38 and O33···H9-H8 exist in dimer (1) and O54···H23 in dimer (2) which showed
well agreement to experimental, NBO, MPA and FT-IR findings.
3.9. Thermodynamic properties
The molar entropy(ꢉꢊꢋ ), heat capacity (ꢌꢍꢋ,ꢊ) and enthalpy (ꢎꢊꢋ ) of monomers and dimers for
compounds 1 and 2 are determined using vibrational investigation and statistical
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thermodynamics at B3LYP/6-31G(d,p) using scale factor 0.962761 are tabulated in Tables 9 and
10.
Table 9: Thermodynamic parameters for 1 with various temperatures.
ꢒꢑꢓ,ꢐ
ꢒꢑꢓ,ꢐ
(J/mol.K)b
ꢏꢐꢑ
ꢔꢐꢑ
ꢏꢐꢑ
ꢔꢐꢑ
(kJ/mol)b
T (K)
(J/mol.K)a
(kJ/mol)a (J/mol.K)b
(J/mol.K)a
100.00
200.00
298.15
300.00
400.00
500.00
600.00
700.00
800.00
900.00
1000.0
379.02
488.92
584.76
586.50
676.94
760.68
837.86
908.94
974.53
1035.27
1091.74
122.88
203.82
280.09
281.45
348.34
402.06
444.22
477.58
504.50
526.62
545.10
8.17
24.49
48.30
48.82
558.01
784.77
981.50
253.44
419.46
573.66
576.40
711.32
819.46
904.22
971.23
1025.25
1069.65
1106.71
15.72
49.38
98.25
985.06
99.31
80.42
1169.99
1340.81
1498.02
1642.63
1775.97
1899.37
2014.05
163.92
240.67
327.03
420.92
520.84
625.65
734.53
118.04
160.44
206.60
255.75
307.34
360.95
amonomer, bdimer
Table 10: Thermodynamic parameters for 2 with various temperatures.
ꢒꢑꢓ,ꢐ
ꢒꢑꢓ,ꢐ
ꢏꢐꢑ
ꢔꢐꢑ
ꢏꢐꢑ
ꢔꢐꢑ
(kJ/mol)b
T (K)
(J/mol.K)a
(kJ/mol)a
(J/mol.K)b
(J/mol.K)a
(J/mol.K)b
100.00
200.00
298.15
300.00
400.00
500.00
600.00
700.00
800.00
900.00
1000.0
396.83
512.05
611.16
612.95
706.68
793.89
874.64
949.26
1018.32
1082.43
1142.16
131.35
211.21
289.63
291.05
361.91
419.75
465.60
502.18
531.89
556.48
577.10
8.89
25.97
50.59
51.13
632.39
870.37
272.08
434.49
592.61
595.46
738.07
854.36
946.49
1019.93
1079.57
1128.90
1170.28
17.65
52.91
1073.65
1077.33
1268.75
1446.43
1610.67
1762.29
1902.51
2032.60
2153.75
103.40
104.50
171.38
251.22
341.44
439.90
544.97
655.47
770.49
83.88
123.07
167.42
215.88
267.63
322.09
378.79
amonomer, bdimer
It is a noteworthy observation that the molar entropy, heat capacity and enthalpy of investigated
of monomers and dimmers of both compounds are enhanced with temperature increasing from
100 to 1000 K, due to the atomic vibrational intensities increment with temperature as can be
seen in Tables 9 and 10.
The difference of molar entropy(ꢉꢊꢋ ), heat capacity (ꢌꢍꢋ,ꢊ) and enthalpy (ꢎꢊꢋ ) between
monomer and dimer for compounds 1 and 2 are determined using the following relationships at
100 K.
∆ꢉꢊꢋ (100 K)= ꢉꢊꢋ (dimer) –2*ꢉꢋ
(monomer)
ꢊ
∆ꢌꢍꢋ,ꢊ(100 K)= ꢌꢍꢋ,ꢊ(dimer) –2*ꢌꢍꢋ,ꢊ
(monomer)
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∆ꢎꢊꢋ (100 K)= ꢎꢊꢋ (dimer) –2*ꢎꢊꢋ
(monomer)
Consequently, the change in molar entropy(∆ꢉꢊꢋ ), heat capacity (∆ꢌꢍꢋ,ꢊ) and enthalpy (∆ꢎꢊꢋ )
are obtained to be -200.03, 7.68 and -0.62 respectively for 1 as well as -161.27, 9.38 and -0.13
respectively for 2. The obtained differences indicate that the species having non-covalent
interactions (NCIs) might be in terms of hydrogen bonding network in dimmers of both
ꢋ
(
)
compounds. Moreover, the negative magnitude of the change molar entropy ∆ꢉꢊ for 1 is found
significantly greater as compared to 2 which confer the presence of double in 1.
The obtained data might be fruitful to grant knowledge for the advance work relevant to the title
compounds.
4. Conclusion
In the present study two sulfanilamide derivatives with maleic anhydride and succinic anhydride
have been synthesized using a plain method and characterized by single crystal XRD and
extensively quantum chemical approach (DFT). The X-ray crystal structures of (1) and (2) are
off white needle-shaped having monoclinic space group C c and white needle-shaped having
triclinic space group P -1 respectively. Both crystals displayed the hydrogen bonding network.
This hydrogen bonding motif transformed the compounds into supramolecular structures. The
comparative study in regards to geometry optimization revealed that the DFT optimized
parameters have a good agreement with the experimental data. NBO analysis explored the hyper
conjugative interaction and stability of title crystals, especially, reconfirmed the existence of N-
H···O=C and N-H···OH hydrogen bonds between the dimeric supramolecular structures of both
compounds. The FT-IR analysis also concluded that the dimer (1) exhibiting intra & inter-
molecular hydrogen bonding while monomer (1) with intra-molecular hydrogen bonding .The
dimer (2) just containing inter molecular hydrogen bonding, while, monomer (2) does not have
intra-molecular hydrogen bonding which is an excellent consistency to XRD, experimental FT-
IR and NBO data. The UV-Vis study is described here in detail which was not reported in the
literature previously and maybe a valuable addition to scientific literature. The molecular
electrostatic potential map (MEP) has been utilized for anticipating the electrostatic potential
areas, electrophilic, nucleophilic reactivity and hydrogen bonding network. The FMOs energy
gap and global descriptors illustrate the stability and also indicate the bioactivity of the title
compounds. Moreover, the global reactivity observations can be proved as adequate and efficient
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parameters for the researchers in order to continue an extensive study. The obtained
thermodynamic data also indicate the presence of hydrogen bond framework which is a well
agreement to experimental and DFT i.e. NBO, FT-IR, MPA and MEP studies. These interesting
observations can play a vital role in designing new drugs for different infections and also in the
supramolecular chemistry.
5. Acknowledgments
The authors are grateful to Sumaira Khalid for her valuable suggestions and cooperation as well
as HEC Pakistan. Moreover, Mian Muhammad Muzaffar is gratefully acknowledged for his
careful reading of this article. We also acknowledge Dr. Ana Paula L. Batista for her always
cooperation.
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Highlights
•
•
•
Two sulfanilamide derivatives were synthesized.
Single crystal XRD results were compared with DFT data.
Experimental and DFT based FT-IR analysis were performed to reconfirm hydrogen
bonding.
•
•
•
•
Hyperconjugative interactions and H.B. were also determined by NBO method.
Noncovalent interaction are responsible for the stability of both compounds.
Energies of FMOs were used to calculate the global reactivity parameters
MEP and thermodynamic properties were also calculated.