- Email: [email protected]
Facile synthesis, single crystal analysis, and computational studies of sulfanilamide derivatives
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
DOI:
10.1016/j.molstruc.2016.08.032
Reference:
MOLSTR 22858
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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Graphical Abstract
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Facile Synthesis, Single Crystal Analysis, and Computational Studies of Sulfanilamide Derivatives c
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Muhammad Nawaz Tahir,a Muhammad Khalid,b* Ayesha Islam,a Syed Muddassir Ali Mashhadi , Ataualpa A. C. Bragab
a
University of Sargodha, Department of Physics, Sargodha, Pakistan.
b
Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av.
c
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Prof. Lineu Prestes, 748, São Paulo, 05508-000, Brazil.
Allama Iqbal Open University, Department of Chemistry, Islamabad, Pakistan.
*Corresponding author email: [email protected] (Muhammad Khalid)
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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
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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
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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,
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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 Menace of bacterial resistance1 for antibiotics poses a great hurdle 2 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
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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
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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
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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
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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] but2-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
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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
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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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2. Experimental and calculations 2.1. Experimental section
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Scheme 1: Schematic representation of the synthesis of reported derivatives.
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
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(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.
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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
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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
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Gaussian 09 suite of programs.29 The dimer of (E)-4-oxo-4-[(4-sulfamoylphenyl)amino]but-2enoic 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
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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
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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;
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(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
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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
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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 Hatoms 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) =
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1.5Ueq(O).
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(a) The ORTEP diagram
(b) Molecular packing
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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 R (14) and another ring motif involving heterosynthon is formed by the hydrogen bonding having a graph set R (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
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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).
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(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
Table 1: Single crystal XRD data of 1 and 2
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circles of arbitrary radii, (b) Molecular packing of compound 2 showing H.B.
1
2
Chemical formula
C10H10N2O5S
C10H12N2O5S
Mr
270.26
272.28
Crystal system, space group
Monoclinic, Cc
Triclinic, P¯ 1
Temperature (K)
296
296
a, b, c (Å)
24.529 (3), 5.1692 (7), 9.4722 (12)
5.1309 (4), 11.3811 (11), 11.7458 (10)
α, β, γ (°)
90.0, 106.858(7), 90.0
62.623 (4), 85.940 (4), 77.247 (4)
V (Å3)
1149.4 (3)
593.68 (9)
Z
4
2
Radiation type
Mo Kα
Mo Kα
µ (mm )
0.30
0.29
Crystal size (mm)
0.40 × 0.20 × 0.16
0.34 × 0.26 × 0.22
Bruker Kappa APEXII CCD
Bruker Kappa APEXII CCD
Multi-scan (SADABS; Bruker, 2005)
Multi-scan (SADABS; Bruker, 2005)
0.892, 0.956
0.911, 0.943
No. of measured, independent and observed [I> 2σ(I)] reflections
4664, 2019, 1689
7816, 2323, 2021
Rint
0.043
0.024
0.639
0.617
R[F2> 2σ(F2)], wR(F2), S
0.048, 0.114, 1.05
0.034, 0.095, 1.05
No. of reflections
2019
2323
No. of parameters
172
170
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Compounds
-1
Data collection
Absorption correction
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Tmin, Tmax
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Diffractometer
(sin θ/λ)max (Å ) -1
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Refinement
No. of restraints
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 Compounds D—H···A
D—H (Å) H···A (Å)
D···A (Å)
D—H···A (°)
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N1—H1A···O2i
2.05
2.850 (6)
154.2
0.72 (8)
2.31 (8)
3.022 (8)
170 (8)
iii
0.89 (7)
2.42 (7)
3.035 (7)
127 (5)
0.93
2.68
3.494 (7)
146.1
C10—H10···O3
0.93
2.25
2.853 (7)
121.9
C10—H10···O3
0.93
2.26
2.860 (2)
121.6
i
0.86
2.05
2.9110 (19)
176.2
ii
0.843 (9)
2.074 (10) 2.909 (2)
171 (2)
iii
0.842 (9)
2.196 (10) 3.025 (2)
168 (2)
0.82
1.92
159.8
N2—H2A···O4
1
N2—H2B···O5 C3—H3···N2
iv
N1—H1A···O2
2
N2—H2C···O3
N2—H2D···O1 O1—H1···O5
iv
iv
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0.86
ii
2.7003 (18)
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O1—H1···S1 0.82 2.84 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
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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
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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
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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).
E(2)a
E(j)_E(i)b
F(i,j)c
[kJ/mol]
[a.u.]
[a.u.]
∗
9.08
1.42
0.102
N38-H39
∗
5.31
0.91
0.065
LP(2)
N36-C46
∗
28.10
0.88
0.142
O54
LP(1)
N21-H23
∗
5.43
1.25
0.074
O54
LP(2)
N21-H23
∗
2.33
0.96
0.044
Type
Acceptor (j)
O6
LP(1)
N38-H39
O6
LP(2)
O33
Donor(i)
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Compounds
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Table 3: Natural bond orbital (NBO) analysis using second-order perturbation theory
1
2
a
Energy of hyper conjugative interaction (stabilization energy). Energy difference between donor and acceptor i and j NBO orbital. c Fock matrix element between i and j NBO orbital.41,42 For numbering of atom refer Figure. 3. b
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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.
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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 →[N21H23 (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.
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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
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interactions ( → *) 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; (C14-C16)→ *(O4-C13), (C19-C27)→ *(C20-C22) and *(C24-C25), (C20-C22)→ *(C19-C27) and *(C24-C25) respectively in dimer (1) as shown in Table S3 (Supplementary information). The dimer (2) also showed (C9-C17)→ *(C10C12) and *(C14-C15), (C10-C12)→ *(C9-C17) and *( C14-C15), (C39-C47)→ *( C40-
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C42) and *( 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
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(2) and N36LP (1) to the antibonding acceptor [S29-C52 ( ∗ )] [S29-O35 ( ∗ )] and [O33-C46 ( ∗ )], as a result, high stabilization energies are produced to be 18.65, 30.60 and 90.95 kJ/mol
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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( ∗ )], [C44-S60( ∗ )], [C31-O54( ∗ )], [C38O57( ∗ )],[C38-O57) ∗ )] and [C8-O27) ∗ )] 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
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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
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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-
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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.
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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
dimer (1) as can be demonstrated in Figure 5.
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remarkable logical43 for the presence of inter-hydrogen bonding network in the investigated
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)
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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
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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
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findings are in good agreement with experimental FT-IR and single X-ray diffraction obtained
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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
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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 () by using TDDFT/B3LYP/6-31G(d, p) (Tables 4 and 5) (also see Tables S5 and S6 in Supplementary information).
Energy (eV)
Wave length (nm)
Oscillator strength
-0.15014 0.67673
3.6640
338.38
0.0592
0.11962 -0.32966 0.12401 0.45849 0.34891
5.0340
246.30
0.1106
5.1317
241.60
0.2180
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CI coefficient
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Excitation Excited State 1 69→71 70 → 71 Excited State 5 68 →72 69 →72 69 → 73 70 → 72 70 → 73 Excited State 6 68 →71 68 → 72 69 → 72 70 → 72 70→ 73
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Table 4: Calculated parameters for (E)-4-oxo-4-[(4 sulfamoylphenyl) amino] but-2-enoic acid using TDDFT//B3LYP/6-31G (d, p) method.
0.10656 -0.15296 0.24525 0.47286 -0.39159
Table 5: Calculated parameters for 4-oxo-4-[(4 sulfamoylphenyl) amino] butanoic acid using TDDFT/B3LYP/6-31G (d, p) method. Excitation Excited State 2 69 →72 69 →73 71 →72
CI coefficient
Energy (eV)
Wave length (nm)
Oscillator strength
0.12321 0.10826 0.64710
5.0546
245.29
0.5210
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71 →73
-0.19992
Experimental excitation energies, wavelength and oscillator strength () 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.
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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
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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
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(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
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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, -
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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
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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
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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 (µ), 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.
Molecules
1
Combinations
A
B
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Table 7: Ionization potential (I), electron affinity(A), electro negativity (X) chemical potential (µ) global hardness (η) global softness (S) and global electrophilicity (ω). 2
C
A
B
C
0.285
0.302
0.311
0.287
0.301
0.3249
Electron affinity (A)
0.056
0.041
0.006
0.019
0.005
0.0005
Electro negativity (X)
0.171
0.172
0.159
0.153
0.153
0.163
Chemical potential (µ)
-0.171
-0.172
-0.159
-0.153
-0.153
-0.163
Global hardness (η).
0.1145
0.1305
0.153
0.134
0.148
0.162
Global softness (S)
4.367
3.831
3.279
3.731
3.378
3.083
Global electrophilicity (ω)
0.127
0.079
0.082
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Ionization potential (I)
0.113
0.082
0.087
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
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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.
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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
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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 (µ) 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. µX
µY
µZ
µT
E(a.u)
Dimer (1)
-13.9918
-4.1754
-4.1754
14.616
-2540.983
Dimer(2)
-11.9510
5.7325
-0.7264
13.2746
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-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
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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
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be attested considering polar molecules.
3.8. Molecular electrostatic potential (MEP)
Usually, MEP is utilized in anticipating electrostatic potential areas, physiochemical features,
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hydrogen bonding network, particularly exhibiting the size and shape of atoms.60
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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( ), heat capacity (, ) and enthalpy ( ) 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.
,
(J/mol.K)a
(J/mol.K)a
(kJ/mol)a
(J/mol.K)b
(J/mol.K)b
(kJ/mol)b
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 80.42 118.04 160.44 206.60 255.75 307.34 360.95
558.01 784.77 981.50 985.06 1169.99 1340.81 1498.02 1642.63 1775.97 1899.37 2014.05
253.44 419.46 573.66 576.40 711.32 819.46 904.22 971.23 1025.25 1069.65 1106.71
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,
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100.00 200.00 298.15 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.0 a monomer, bdimer
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T (K)
15.72 49.38 98.25 99.31 163.92 240.67 327.03 420.92 520.84 625.65 734.53
Table 10: Thermodynamic parameters for 2 with various temperatures. ,
(J/mol.K)a
(J/mol.K)a
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
,
(kJ/mol)a
(J/mol.K)b
(J/mol.K)b
(kJ/mol)b
632.39 870.37 1073.65 1077.33 1268.75 1446.43 1610.67 1762.29 1902.51 2032.60 2153.75
272.08 434.49 592.61 595.46 738.07 854.36 946.49 1019.93 1079.57 1128.90 1170.28
8.89 25.97 50.59 51.13 83.88 123.07 167.42 215.88 267.63 322.09 378.79
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100.00 200.00 298.15 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.0 a monomer, bdimer
17.65 52.91 103.40 104.50 171.38 251.22 341.44 439.90 544.97 655.47 770.49
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T (K)
It is a noteworthy observation that the molar entropy, heat capacity and enthalpy of investigated
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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( ), heat capacity (, ) and enthalpy ( ) between
monomer and dimer for compounds 1 and 2 are determined using the following relationships at 100 K. ∆ (100 K)= (dimer) –2* (monomer) ∆, (100 K)= , (dimer) –2*, (monomer)
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∆ (100 K)= (dimer) –2* (monomer) Consequently, the change in molar entropy(∆ ), heat capacity (∆, ) and enthalpy (∆ )
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
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interactions (NCIs) might be in terms of hydrogen bonding network in dimmers of both ) for 1 is found compounds. Moreover, the negative magnitude of the change molar entropy (∆
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
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compounds. 4. Conclusion
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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
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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-
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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 & intermolecular hydrogen bonding while monomer (1) with intra-molecular hydrogen bonding .The
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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 FTIR 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
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supramolecular chemistry. 5. Acknowledgments
The authors are grateful to Sumaira Khalid for her valuable suggestions and cooperation as well
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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
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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
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•
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.
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S0022-2860(16)30862-6
DOI:
10.1016/j.molstruc.2016.08.032
Reference:
MOLSTR 22858
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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Graphical Abstract
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Facile Synthesis, Single Crystal Analysis, and Computational Studies of Sulfanilamide Derivatives c
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Muhammad Nawaz Tahir,a Muhammad Khalid,b* Ayesha Islam,a Syed Muddassir Ali Mashhadi , Ataualpa A. C. Bragab
a
University of Sargodha, Department of Physics, Sargodha, Pakistan.
b
Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av.
c
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Prof. Lineu Prestes, 748, São Paulo, 05508-000, Brazil.
Allama Iqbal Open University, Department of Chemistry, Islamabad, Pakistan.
*Corresponding author email: [email protected] (Muhammad Khalid)
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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
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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
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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,
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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 Menace of bacterial resistance1 for antibiotics poses a great hurdle 2 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
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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
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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
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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
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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] but2-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
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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
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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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2. Experimental and calculations 2.1. Experimental section
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Scheme 1: Schematic representation of the synthesis of reported derivatives.
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
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(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.
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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
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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
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Gaussian 09 suite of programs.29 The dimer of (E)-4-oxo-4-[(4-sulfamoylphenyl)amino]but-2enoic 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
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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
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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;
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(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
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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
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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 Hatoms 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) =
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1.5Ueq(O).
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(a) The ORTEP diagram
(b) Molecular packing
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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 R (14) and another ring motif involving heterosynthon is formed by the hydrogen bonding having a graph set R (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
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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).
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.
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(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
Table 1: Single crystal XRD data of 1 and 2
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circles of arbitrary radii, (b) Molecular packing of compound 2 showing H.B.
1
2
Chemical formula
C10H10N2O5S
C10H12N2O5S
Mr
270.26
272.28
Crystal system, space group
Monoclinic, Cc
Triclinic, P¯ 1
Temperature (K)
296
296
a, b, c (Å)
24.529 (3), 5.1692 (7), 9.4722 (12)
5.1309 (4), 11.3811 (11), 11.7458 (10)
α, β, γ (°)
90.0, 106.858(7), 90.0
62.623 (4), 85.940 (4), 77.247 (4)
V (Å3)
1149.4 (3)
593.68 (9)
Z
4
2
Radiation type
Mo Kα
Mo Kα
µ (mm )
0.30
0.29
Crystal size (mm)
0.40 × 0.20 × 0.16
0.34 × 0.26 × 0.22
Bruker Kappa APEXII CCD
Bruker Kappa APEXII CCD
Multi-scan (SADABS; Bruker, 2005)
Multi-scan (SADABS; Bruker, 2005)
0.892, 0.956
0.911, 0.943
No. of measured, independent and observed [I> 2σ(I)] reflections
4664, 2019, 1689
7816, 2323, 2021
Rint
0.043
0.024
0.639
0.617
R[F2> 2σ(F2)], wR(F2), S
0.048, 0.114, 1.05
0.034, 0.095, 1.05
No. of reflections
2019
2323
No. of parameters
172
170
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Compounds
-1
Data collection
Absorption correction
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Tmin, Tmax
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Diffractometer
(sin θ/λ)max (Å ) -1
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Refinement
No. of restraints
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 Compounds D—H···A
D—H (Å) H···A (Å)
D···A (Å)
D—H···A (°)
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N1—H1A···O2i
2.05
2.850 (6)
154.2
0.72 (8)
2.31 (8)
3.022 (8)
170 (8)
iii
0.89 (7)
2.42 (7)
3.035 (7)
127 (5)
0.93
2.68
3.494 (7)
146.1
C10—H10···O3
0.93
2.25
2.853 (7)
121.9
C10—H10···O3
0.93
2.26
2.860 (2)
121.6
i
0.86
2.05
2.9110 (19)
176.2
ii
0.843 (9)
2.074 (10) 2.909 (2)
171 (2)
iii
0.842 (9)
2.196 (10) 3.025 (2)
168 (2)
0.82
1.92
159.8
N2—H2A···O4
1
N2—H2B···O5 C3—H3···N2
iv
N1—H1A···O2
2
N2—H2C···O3
N2—H2D···O1 O1—H1···O5
iv
iv
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0.86
ii
2.7003 (18)
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O1—H1···S1 0.82 2.84 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
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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
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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
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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).
E(2)a
E(j)_E(i)b
F(i,j)c
[kJ/mol]
[a.u.]
[a.u.]
∗
9.08
1.42
0.102
N38-H39
∗
5.31
0.91
0.065
LP(2)
N36-C46
∗
28.10
0.88
0.142
O54
LP(1)
N21-H23
∗
5.43
1.25
0.074
O54
LP(2)
N21-H23
∗
2.33
0.96
0.044
Type
Acceptor (j)
O6
LP(1)
N38-H39
O6
LP(2)
O33
Donor(i)
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Compounds
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Table 3: Natural bond orbital (NBO) analysis using second-order perturbation theory
1
2
a
Energy of hyper conjugative interaction (stabilization energy). Energy difference between donor and acceptor i and j NBO orbital. c Fock matrix element between i and j NBO orbital.41,42 For numbering of atom refer Figure. 3. b
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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.
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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 →[N21H23 (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.
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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
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interactions ( → *) 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; (C14-C16)→ *(O4-C13), (C19-C27)→ *(C20-C22) and *(C24-C25), (C20-C22)→ *(C19-C27) and *(C24-C25) respectively in dimer (1) as shown in Table S3 (Supplementary information). The dimer (2) also showed (C9-C17)→ *(C10C12) and *(C14-C15), (C10-C12)→ *(C9-C17) and *( C14-C15), (C39-C47)→ *( C40-
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C42) and *( 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
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(2) and N36LP (1) to the antibonding acceptor [S29-C52 ( ∗ )] [S29-O35 ( ∗ )] and [O33-C46 ( ∗ )], as a result, high stabilization energies are produced to be 18.65, 30.60 and 90.95 kJ/mol
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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( ∗ )], [C44-S60( ∗ )], [C31-O54( ∗ )], [C38O57( ∗ )],[C38-O57) ∗ )] and [C8-O27) ∗ )] 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
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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
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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-
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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.
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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
dimer (1) as can be demonstrated in Figure 5.
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remarkable logical43 for the presence of inter-hydrogen bonding network in the investigated
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)
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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
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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
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findings are in good agreement with experimental FT-IR and single X-ray diffraction obtained
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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
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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 () by using TDDFT/B3LYP/6-31G(d, p) (Tables 4 and 5) (also see Tables S5 and S6 in Supplementary information).
Energy (eV)
Wave length (nm)
Oscillator strength
-0.15014 0.67673
3.6640
338.38
0.0592
0.11962 -0.32966 0.12401 0.45849 0.34891
5.0340
246.30
0.1106
5.1317
241.60
0.2180
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CI coefficient
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Excitation Excited State 1 69→71 70 → 71 Excited State 5 68 →72 69 →72 69 → 73 70 → 72 70 → 73 Excited State 6 68 →71 68 → 72 69 → 72 70 → 72 70→ 73
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Table 4: Calculated parameters for (E)-4-oxo-4-[(4 sulfamoylphenyl) amino] but-2-enoic acid using TDDFT//B3LYP/6-31G (d, p) method.
0.10656 -0.15296 0.24525 0.47286 -0.39159
Table 5: Calculated parameters for 4-oxo-4-[(4 sulfamoylphenyl) amino] butanoic acid using TDDFT/B3LYP/6-31G (d, p) method. Excitation Excited State 2 69 →72 69 →73 71 →72
CI coefficient
Energy (eV)
Wave length (nm)
Oscillator strength
0.12321 0.10826 0.64710
5.0546
245.29
0.5210
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71 →73
-0.19992
Experimental excitation energies, wavelength and oscillator strength () 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.
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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
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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
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(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
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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, -
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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
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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
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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 (µ), 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.
Molecules
1
Combinations
A
B
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Table 7: Ionization potential (I), electron affinity(A), electro negativity (X) chemical potential (µ) global hardness (η) global softness (S) and global electrophilicity (ω). 2
C
A
B
C
0.285
0.302
0.311
0.287
0.301
0.3249
Electron affinity (A)
0.056
0.041
0.006
0.019
0.005
0.0005
Electro negativity (X)
0.171
0.172
0.159
0.153
0.153
0.163
Chemical potential (µ)
-0.171
-0.172
-0.159
-0.153
-0.153
-0.163
Global hardness (η).
0.1145
0.1305
0.153
0.134
0.148
0.162
Global softness (S)
4.367
3.831
3.279
3.731
3.378
3.083
Global electrophilicity (ω)
0.127
0.079
0.082
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Ionization potential (I)
0.113
0.082
0.087
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
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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.
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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
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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 (µ) 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. µX
µY
µZ
µT
E(a.u)
Dimer (1)
-13.9918
-4.1754
-4.1754
14.616
-2540.983
Dimer(2)
-11.9510
5.7325
-0.7264
13.2746
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Molecules
-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
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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
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be attested considering polar molecules.
3.8. Molecular electrostatic potential (MEP)
Usually, MEP is utilized in anticipating electrostatic potential areas, physiochemical features,
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hydrogen bonding network, particularly exhibiting the size and shape of atoms.60
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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( ), heat capacity (, ) and enthalpy ( ) 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.
,
(J/mol.K)a
(J/mol.K)a
(kJ/mol)a
(J/mol.K)b
(J/mol.K)b
(kJ/mol)b
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 80.42 118.04 160.44 206.60 255.75 307.34 360.95
558.01 784.77 981.50 985.06 1169.99 1340.81 1498.02 1642.63 1775.97 1899.37 2014.05
253.44 419.46 573.66 576.40 711.32 819.46 904.22 971.23 1025.25 1069.65 1106.71
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,
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100.00 200.00 298.15 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.0 a monomer, bdimer
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T (K)
15.72 49.38 98.25 99.31 163.92 240.67 327.03 420.92 520.84 625.65 734.53
Table 10: Thermodynamic parameters for 2 with various temperatures. ,
(J/mol.K)a
(J/mol.K)a
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
,
(kJ/mol)a
(J/mol.K)b
(J/mol.K)b
(kJ/mol)b
632.39 870.37 1073.65 1077.33 1268.75 1446.43 1610.67 1762.29 1902.51 2032.60 2153.75
272.08 434.49 592.61 595.46 738.07 854.36 946.49 1019.93 1079.57 1128.90 1170.28
8.89 25.97 50.59 51.13 83.88 123.07 167.42 215.88 267.63 322.09 378.79
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100.00 200.00 298.15 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.0 a monomer, bdimer
17.65 52.91 103.40 104.50 171.38 251.22 341.44 439.90 544.97 655.47 770.49
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It is a noteworthy observation that the molar entropy, heat capacity and enthalpy of investigated
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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( ), heat capacity (, ) and enthalpy ( ) between
monomer and dimer for compounds 1 and 2 are determined using the following relationships at 100 K. ∆ (100 K)= (dimer) –2* (monomer) ∆, (100 K)= , (dimer) –2*, (monomer)
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∆ (100 K)= (dimer) –2* (monomer) Consequently, the change in molar entropy(∆ ), heat capacity (∆, ) and enthalpy (∆ )
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
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interactions (NCIs) might be in terms of hydrogen bonding network in dimmers of both ) for 1 is found compounds. Moreover, the negative magnitude of the change molar entropy (∆
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
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compounds. 4. Conclusion
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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
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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-
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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 & intermolecular hydrogen bonding while monomer (1) with intra-molecular hydrogen bonding .The
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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 FTIR 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
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supramolecular chemistry. 5. Acknowledgments
The authors are grateful to Sumaira Khalid for her valuable suggestions and cooperation as well
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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
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Highlights Two sulfanilamide derivatives were synthesized.
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Single crystal XRD results were compared with DFT data.
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Experimental and DFT based FT-IR analysis were performed to reconfirm hydrogen
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•
bonding.
Hyperconjugative interactions and H.B. were also determined by NBO method.
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Noncovalent interaction are responsible for the stability of both compounds.
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Energies of FMOs were used to calculate the global reactivity parameters
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MEP and thermodynamic properties were also calculated.
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•