Diverse structural assemblies of U-shaped hydrazinyl-sulfonamides: experimental and theoretical analysis of non-covalent interactions stabilizing solid state conformations

Article abstract of DOI:10.1039/C8CE01917G

The present study describes the synthesis of five new hydrazinyl-sulfonamide derivatives incorporating linear and branched alkyl chains. An efficient and straightforward synthetic approach was used to achieve these sulfonamide compounds in good yields. Th

Full text of DOI:10.1039/C8CE01917G

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Diverse structural assemblies of U-shaped hydrazinyl-sulfonamides:
experimental and theoretical analysis of non-covalent interactions stabilizing
the solid state conformations
Hina Andleeb,a Imtiaz Khan,a,b Antonio Franconetti,c Muhammad Nawaz Tahir,d Jim Simpson,e
Shahid Hameed,a,* Antonio Fronterac,*
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
bSchool of Chemistry & Manchester Institute of Biotechnology, The University of Manchester,
131 Princess Street, Manchester M1 7DN, United Kingdom
cDepartament de Química, Universitat de les Illes Balears, Crta de Valldemossa km 7.5, 07122
Palma de Mallorca (Baleares), Spain
dDepartment of Physics, University of Sargodha, Sargodha, Pakistan
eDepartment of Chemistry, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand
*Corresponding authors. E-mail: shameed@qau.edu.pk (S. Hameed); Tel.: +92-51-9064-2133;
Fax: +92-51-9064-2241; E-mail: toni.frontera@uib.es (A. Frontera); Tel: +34 971 259576; Fax:
+34 971 17 27 63

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Abstract
The present study unfolds the synthesis of five new hydrazinyl-sulfonamide derivatives
incorporating linear and branched alkyl chains. An efficient and straightforward synthetic
approach was realized to achieve these sulfonamide compounds in good yields. The synthesized
compounds were fully characterized by spectroscopic methods and single crystal X-ray diffraction
analysis. Structural analysis of U-shaped hydrazinyl-sulfonamides reveals the presence of
remarkable similarities in their crystal packing. Supramolecular architectures of these molecules
were stabilized by the classical hydrogen bonds and C—H···O interactions. Furthermore, the U-
shaped conformation observed in the solid state of all compounds has been analyzed using DFT
calculations, AIM analysis and the NCIplot index. It reveals the existence of two intramolecular
interactions, which are NH···π and unconventional π–π interactions involving the hydrazido π-
system.
Introduction
Sulfonamides are the diverse structural pharmacophores prevalent in nearly 200 drugs in the
market which have been developed as anti-migraine, diuretics, acetylcholinesterase and
cyclooxygenase-II (COX-2)-specific anti-inflammatory medicines.1‒3 Sulfonamides have also
been investigated as one of the topmost inhibitors of the metallo-enzyme carbonic anhydrase with
many clinical applications as antiglaucoma agents in the form of acetazolamide (AZA) and
methazolamide (MZA).4‒9 Sulfonamide drugs are widely used as HIV protease,10,11 antitumor,12
anticholestrolacyl transferase,13 and glycogen phosphorylase inhibitors.14,15
In addition, sulfonamide derivatives find several clinical applications as anticonvulsant,16
antibacterial, antibiotic,17‒20 and also for the therapy of other diseases.21,22 Moreover, sulfonamides
have displayed inhibitory effects against dihydropteroate synthase (DHPS),23 preventing the

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synthesis of folic acid (vitamin B9), serine protease,24 and matrix metalloproteinase.25 This
widespread pharmacophoric potential value of sulfonamides has led to the discovery of various
other therapeutic applications such as in cancer chemotherapy and hypoglycemia.15,26
Non-covalent interactions are heavily involved in crystal engineering and molecular recognition,27
showing their diverse utility as a powerful tool for the construction of supramolecular
architectures.28 Among them, nonconventional C–H/X (X = O, N, S and π electrons) hydrogen
bonding29‒33 has garnered immense attention due to its involvement in supramolecular
structures,34‒39 biological structures,40‒44 and anion receptors.45‒49 Inter- and intra-molecular
hydrogen bonding has extensively been employed in the generation of complex organized systems
due to the reversibility, specificity, directionality and cooperativity of such interactions.50 Among
the weak hydrogen bonds, C–H⋯π interactions are of imperative significance holding several
unique features including chiral recognition, polymer chemistry, coordination chemistry,
biochemistry, and the structures of DNA and proteins.51 In view of these significant applications,
it is of much interest to explore the role of non-covalent interactions in new classes of compounds
forming supramolecular architectures.
In this manuscript, we report the synthesis and X-ray characterization of five new hydrazinyl-
sulfonamides and a detailed description of their crystal packing and supramolecular forces
responsible of their crystal growth. Moreover, we have analyzed using DFT methods and several
computational tools the U-shape conformation that these molecules present in the solid state. It is
governed by the formation of two simultaneous intramolecular π-interactions, which occur at the
same face of the aromatic ring where the whole hydrazinyl group is involved.
Experimental
Chemicals and instrumentation

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Unless otherwise noted, all commercially available reagents were used as received. All reactions
were carried out using oven-dried glassware. All the reactions were monitored using pre-coated
silica gel (60F254 0.2 mm) TLC plates from Merck (Germany). Product spots were visualized under
UV light at 254 nm. Melting points were recorded on a Gallenkamp melting point apparatus (MP-
D) in open capillaries and are uncorrected. Infra-red (IR) spectra were recorded on Schimadzu
Fourier Transform Infra-Red Spectrophotometer model 270 using ATR (Attenuated total
reflectance) facility. NMR spectra were recorded on Bruker DQX400 and AV300 spectrometers
1
13
at room temperature. H and C NMR spectra were referenced to external tetramethylsilane via
the residual protonated solvent (1H) or the solvent itself (13C). Chemical shifts () are quoted in
1
parts per million (ppm). For DMSO-d6, the shifts are referenced to 2.50 ppm for H NMR
spectroscopy and 39.52 ppm for 13C NMR spectroscopy. Coupling constant (J) values are reported
to the nearest 0.5 Hz. The elemental analysis was performed on Leco CHNS-932 Elemental
Analyzer, Leco Corporation (USA).
Synthesis
Preparation of N-arylsulfonylated amino acids (3a–e)
The corresponding amino acid (1.00 mmol) was dissolved in an aqueous solution of sodium
carbonate (2.5 mmol in water (5 mL)) and a solution of arylsulfonyl chloride (1.20 mmol) in
toluene (7 mL) was added. The reaction mixture was stirred vigorously at room temperature and
monitored by TLC. After the completion of reaction (24 h), the organic layer was separated, and
the aqueous layer was acidified with dilute hydrochloric acid. The precipitated solid was filtered
and recrystallized from 80% EtOH/H2O. The spectro-analytical data was consistent with those
observed in literature.52

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Preparation of N-arylsulfonylated amino esters (4a‒e)
To a stirred solution of corresponding carboxylic acid 3a‒c (0.02 mol) in ethanol (30 mL) was
added concentrated sulfuric acid (0.5 mL), and the reaction mixture was heated to reflux. The
reaction progress was monitored by TLC at regular intervals. After completion of the reaction (4
h), the mixture was concentrated in vacuo. The crude solid was dissolved in ethyl acetate and
washed with a 10% aqueous sodium bicarbonate (2 × 25 mL). The organic layer was dried
(Na2SO4), filtered and concentrated in vacuo. The product obtained was recrystallized from 80%
EtOH/H2O.53,54 The spectro-analytical data for 4a‒d was consistent with those observed in
literature.55
Ethyl ((4-chlorophenyl)sulfonyl)valinate (4e)
White crystalline solid (75%): m.p 157‒158 °C; Rf : 0.85 (30% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3298 (NH), 1730 (C=O), 1371, 1149 (O=S=O); H NMR (400 MHz, DMSO-d6): δ 7.94
(1H, s, NHSO2), 7.77‒7.70 (2H, m, ArH), 7.64‒6.59 (2H, m, ArH), 4.53 (2H, q, J = 6.9 Hz, CH2),
3.36 (1H, s, CHC=O), 1.94‒1.71 (1H, m, CH), 1.27 (3H, t, J = 6.9 Hz, CH3), 0.78 (3H, d, J = 6.7
13
Hz, CH3), 0.75 (3H, d, J = 6.7 Hz, CH3); C NMR (100.6 MHz, DMSO-d6): δ 180.11 (C=O),
166.73 (C), 140.92 (C), 128.90 (2 × CH), 128.39 (2 × CH), 60.73 (CH), 42.96 (CH2), 30.67 (CH),
18.94 (CH3), 18.64 (CH3), 21.40 (CH3); Anal. calcd. for C13H18ClNO4S (319.06): C, 48.83; H,
5.67; N, 4.38; S, 10.03%. found: C, 48.64; H, 5.55; N, 4.23; S, 9.91%.
Preparation of hydrazinyl-sulfonamides (5a‒e)
To a stirred solution of corresponding ester 4a‒e (0.01 mol) in methanol (30 mL) was added
hydrazine hydrate (80%, 0.04 mol). The resulting mixture was heated at reflux and progress was
monitored by TLC at regular intervals. After completion of the reaction (6 h), the mixture was

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concentrated in vacuo. The crude solid was washed with cold water, filtered, and recrystallized
from 80% EtOH/H2O.53,54 Compound 5d was reported in literature,54d however, partial
spectroscopic data have been provided.
N-(1-hydrazinyl-3-methyl-1-oxobutan-2-yl)-4-methylbenzene-sulfonamide (5a)
White crystalline solid (84%): m.p 186‒187 °C; Rf : 0.35 (40% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3335, 3329 (NH2), 3277 (NH), 1685 (C=O), 1326, 1156 (O=S=O); H NMR (400 MHz,
DMSO-d6): δ 8.98 (1H, s, NHC=O), 7.75 (1H, d, J = 8.3 Hz, NHSO2), 7.62 (2H, d, J = 8.2 Hz,
ArH), 7.34 (2H, d, J = 8.2 Hz, ArH), 3.93 (2H, br s, NH2), 3.38-3.31 (1H, m, CHC=O), 2.36 (3H,
s, ArCH3), 1.81‒1.67 (1H, m, CH(CH3)2), 0.77 (3H, d, J = 6.6 Hz, CH3), 0.67 (3H, d, J = 6.6 Hz,
13
CH3); C NMR (100.6 MHz, DMSO-d6): δ 169.43 (C=O), 142.24 (C), 138.51 (C), 129.15 (2 ×
CH), 126.51 (2 × CH), 60.64 (CH), 30.68 (CH3), 20.99 (CH), 18.94 (CH3), 18.58 (CH3); Anal.
calcd. for C13H21N3O3S (299.13): C, 52.15; H, 7.07; N, 14.04; S, 10.71%. found: C, 52.01; H, 6.90;
N, 13.82; S, 10.56%.
N-(1-hydrazinyl-4-methyl-1-oxopentan-2-yl)-4-methylbenzene-sulfonamide (5b)
White crystalline solid (81%): m.p 143‒145 °C; Rf : 0.39 (40% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3350, 3322 (NH2), 3044 (NH), 1687 (C=O), 1329, 1152 (O=S=O); H NMR (400 MHz,
DMSO-d6): δ 9.11 (1H, s, NHC=O), 7.84 (1H, br s, NHSO2), 7.64 (2H, d, J = 8.0 Hz, ArH), 7.34
(2H, d, J = 8.0 Hz, ArH), 3.96 (2H, br s, NH2), 3.61 (1H, t, J = 6.9 Hz, CHC=O), 2.36 (3H, s,
ArCH3), 1.48‒1.33 (1H, m, CH(CH3)2), 1.32‒1.16 (2H, m, CH2CHNH), 0.75 (3H, d, J = 6.6 Hz,
CH3), 0.65 (3H, d, J = 6.6 Hz, CH3); 13C NMR (100.6 MHz, DMSO-d6): δ 170.16 (C=O), 142.35
(C), 138.40 (C), 129.21 (2 × CH), 126.54 (2 × CH), 53.25 (CH), 41.65 (CH2), 23.78 (CH), 22.52
(CH3), 21.72 (CH3), 21.00 (CH3); Anal. calcd. for C12H19N3O3S (285.11): C, 50.51; H, 6.71; N,
14.73; S, 11.23%. found: C, 50.34; H, 6.52; N, 14.57; S, 11.02%.

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N-(1-hydrazinyl-3-methyl-1-oxobutan-2-yl)-4-methoxybenzene-sulfonamide (5c)
White crystalline solid (79%): m.p 160‒162 °C; Rf : 0.32 (40% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3350, 3301 (NH2), 3019 (NH), 1664 (C=O), 1328, 1149 (O=S=O); H NMR (400 MHz,
DMSO-d6): δ 8.98 (1H, s, NHC=O), 7.73‒7.58 (3H, m, NHSO2 & ArH), 7.07‒7.00 (2H, m, ArH),
3.96 (2H, br s, NH2), 3.81 (3H, s, OCH3), 3.32 (1H, br s, CHC=O), 1.80‒1.65 (1H, m, CH(CH3)2),
0.75 (3H, d, J = 6.8 Hz, CH3), 0.72 (3H, d, J = 6.8 Hz, CH3); 13C NMR (100.6 MHz, DMSO-d6):
δ 169.50 (C=O), 161.90 (C), 133.08 (C), 128.63 (2 × CH), 113.85 (2 × CH), 60.62 (OCH3), 55.60
(CH), 30.67 (CH), 18.96 (CH3), 18.59 (CH3); Anal. calcd. for C12H19N3O4S (301.11): C, 47.83; H,
6.36; N, 13.94; S, 10.64%. found: C, 47.64; H, 6.21; N, 13.76; S, 10.40%.
4-Chloro-N-(1-hydrazinyl-1-oxopropan-2-yl)benzenesulfonamide (5d)
White crystalline solid (81%): m.p 163‒165 °C; Rf : 0.37 (40% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3349, 3338 (NH2), 3049 (NH), 1688 (C=O), 1330, 1152 (O=S=O); H NMR (300 MHz,
DMSO-d6): δ 9.10 (1H, s, NHC=O), 8.16 (1H, s, NHSO2), 7.79‒7.75 (2H, m, ArH), 7.67‒7.63
(2H, m, ArH), 4.08 (2H, br s, NH2), 3.74 (1H, q, J = 6.6 Hz, CHC=O), 1.03 (3H, d, J = 6.9 Hz,
CH3); 13C NMR (75 MHz, DMSO-d6): δ 170.84 (C=O), 140.09 (C), 137.84 (C), 129.56 (2 × CH),
128.87 (2 × CH), 51.00 (CH), 19.25 (CH3); Anal. calcd. for C9H12ClN3O3S (277.03): C, 38.92; H,
4.36; N, 15.13; S, 11.54%. found: C, 38.69; H, 4.19; N, 15.00; S, 11.31%.
4-Chloro-N-(1-hydrazinyl-3-methyl-1-oxobutan-2-yl)benzenesulfonamide (5e)
White crystalline solid (87%): m.p 181‒183 °C; Rf : 0.35 (40% ethyl acetate/n-hexane); IR (ATR,
1
cm‒1): 3367, 3330 (NH2), 3298 (NH), 1687 (C=O), 1373, 1153 (O=S=O); H NMR (400 MHz,
DMSO-d6): δ 9.05 (1H, s, NHC=O), 7.95 (1H, br s, NHSO2), 7.76‒7.69 (2H, m, ArH), 7.65‒6.58
(2H, m, ArH), 3.98 (2H, br s, NH2), 3.37 (1H, br s, CHC=O), 1.82‒1.66 (1H, m, CH(CH3)2, 0.77
13
(3H, d, J = 6.7 Hz, CH3), 0.74 (3H, d, J = 6.7 Hz, CH3); C NMR (100.6 MHz, DMSO-d6): δ

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169.11 (C=O), 140.23 (C), 136.92 (C), 128.90 (2 × CH), 128.39 (2 × CH), 60.73 (CH), 30.67 (CH),
18.94 (CH3), 18.64 (CH3); Anal. calcd. for C11H16ClN3O3S (305.06): C, 43.21; H, 5.27; N, 13.74;
S, 10.48%. found: C, 43.04; H, 5.05; N, 13.53; S, 10.29%.
Crystal growth development
Single crystals of compounds 5a‒e suitable for X-ray diffraction analysis were grown at room
temperature from ethanol solvent.
X-ray structure determination
Crystallographic data for compounds 5a‒e are listed in Table 1. Diffraction data were collected on
a Bruker APEXII CCD diffractometer using graphite-monochromated Mo-K radiation (λ =
0.71073 Å). Data collections were controlled by APEX2 software56 with cell refinement and data
reduction performed using SAINT.56 Multi-scan absorption corrections were applied using
SADABS.56 The structures were all solved with SHELXS57 and refined by full-matrix least-squares
on F2 using SHELXL-2014/7.58 All non-hydrogen atoms were assigned anisotropic displacement
parameters. The H atoms on the three N atoms in each molecule were located in difference Fourier
maps and their coordinates refined with their atomic displacement parameters set to 1.2Ueq(N). All
other H-atoms were positioned geometrically and refined using a riding model with d(C-H) = 0.93
Å for aromatic and 0.98 Å for CH with Uiso = 1.2Ueq(C) and 0.96 Å, Uiso = 1.5Ueq(C) for CH3
atoms. All molecular plots and packing diagrams were drawn using Mercury.59 Other calculations
were performed using PLATON60 and tabular material was produced using WINGX.61
Theoretical Methods
The geometries were fully optimized using the M06-2X/def2-TZVP level of theory by means of
the G09 program package.62 The Bader’s quantum theory of “atoms-in-molecules” analysis
(QTAIM) has been performed at the same level of theory, using the AIMAll program.63 The NCI
plot is a visualization index based on the electron density and its derivatives, and enables

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identification and visualization of non-covalent interactions efficiently. The isosurfaces
correspond to both favorable and unfavorable interactions, as differentiated by the sign of the
second density Hessian eigenvalue and defined by the isosurface color. NCI analysis allows an
assessment of host–guest complementarity and the extent to which weak interactions stabilize a
complex. The information provided by NCI plots is essentially qualitative, i.e. which molecular
+
regions interact. The color scheme is a red-yellow-green-blue scale with red for ρcut (repulsive)
and blue for ρcut− (attractive). Yellow and green surfaces correspond to weak repulsive and weak
attractive interactions, respectively.64
Table 1 Crystal data and structure refinement of 5a‒e
5a
C12H19N3O3S
285.36
296(2)
0.71073
Monoclinic
P 21
7.6720(11)
9.7977(13)
9.9187(13)
90
90.011(5)
90
5b
C13H21N3O3S
299.39
5c
C12H19N3O4S
301.36
296(2)
0.71073
Monoclinic
P 21
10.4333(7)
6.8279(4)
11.1774(7)
90
113.332(4)
90
5d
C9H12ClN3O3S
277.73
5e
C11H16ClN3O3S
305.78
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
296(2)
296(2)
296(2)
0.71073
Monoclinic
P 21
10.3216(9)
6.6441(5)
12.0540(11)
90
105.426(4)
90
796.86(12)
2
0.71073
Monoclinic
P 21
10.0850(5)
6.6661(3)
18.9899(9)
90
104.813(3)
90
1234.22(10)
4
0.71073
Monoclinic
P 21
10.4296(6)
6.7642(3)
11.2829(6)
90
113.623(3)
90
729.28(7)
2
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (A3)
745.57(18)
2
1.271
731.14(8)
2
1.369
Z
Dcalc (g cm-3)
µ (mm-1)
1.248
0.214
1.495
0.479
1.392
0.412
0.225
0.238
F (000)
304
320
320
576
320
Crystal size (mm)
0.42 × 0.28 × 0.42 × 0.34 ×
0.38 × 0.30 × 0.36 × 0.24 × 0.40 × 0.22 × 0.18
0.25
0.32
0.26
0.20
Theta range for data 2.053 to 27.364
collection
1.753 to 27.120
1.984 to 27.267
1.109 to 27.460
2.249 to 27.862
Reflections collected
independent
observed
6038
6854
6469
10868
6483
3285 [R(int)
0.0220]
3186 [R(int) =
0.0317]
2857
2788 [R(int) = 3061
0.0184]
2608
5580 [R(int)
0.0237]
5007
=
=
2731
2892
Min. and max. transmission 0.948 and 0.912 0.936 and 0.915
0.942 and 0.914 0.911 and 0.848
0.932 and 0.851
3285 / 1 / 186
1.059
Data/restraints/parameters
Goodness-of-fit
3186 / 1 / 189
1.056
2788 / 1 / 196
1.039
3061 / 1 / 196
1.032
5580 / 1 / 333
1.054
Final R indices [I >2σ(I)]
R1
wR2 = 0.0928
R1
wR2 = 0.0965
=
0.0349, R1
wR2 = 0.0801
0.0402, R1
=
0.0309, R1
=
0.0332, R1 = 0.0355, wR2 R1 = 0.0357, wR2
wR2 = 0.0748 = 0.0883 = 0.0947
0.0394, R1 = 0.0410, wR2 R1 = 0.0419, wR2
wR2 = 0.0784 = 0.0920 = 0.1003
R indices (all data)
=
=
0.0339, R1
=
wR2 = 0.0824

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Largest difference peak
and hole (e Å-3)
0.198 and -0.224 0.148 and -0.263 0.189 and
0.198
-
0.167 and -0.274 0.191 and -0.215
CCDC reference number
1826226
1826227
1826228
1826229
1826230
Results and discussion
Synthesis
The N-aryl sulfonamides (5a‒e) were prepared from the corresponding amino acids (1a‒c) in three
steps as depicted in Scheme 1. The amino acids were reacted with sulfonyl chlorides to afford the
corresponding N-sulfonyl-amino acid derivatives (3a‒e)65 which on acid-catalyzed esterification
with ethanol yielded the N-sulfonyl-amino esters (4a‒e).53,54 The hydrazination53,54 of the 4a‒e
using hydrazine hydrate (80%) in methanol furnished the desired hydrazinyl-sulfonamides (5a‒e)
in good yields (79–87%).
R1
O
O
O
O
R1
S
S
Na2CO3(aq)
Cl
N
COOH
H
Toluene, rt, 24 h
H2N
COOH
R2
R2
3a e

1
2
1a
1b
1c
2a
2b
2c
: R = i-Pr
: R = Me
1
2
: R = i-Bu
: R = OMe
EtOH
H2SO4(conc)
reflux, 4 h
1
2
: R = Me
: R = Cl
R1
R1
O
O
O
O
H
N2H4 H2O
S
N
S
N
NH2
N
COOEt
H
MeOH, reflux, 6 h
H
O
R2
R2
5a e

4a e

Compd
R1
R2
3a/4a/5a
3b/4b/5b
3c/4c/5c
3d/4d/5d
3e/4e/5e
i-Pr Me
i-Bu Me
i-Pr
Me
OMe
Cl
Cl
i-Pr
Scheme 1 Synthesis of hydrazinyl-sulfonamides (5a‒e).
X-ray crystallography
Structural background

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A search of the Cambridge structural database (Version 5.37 Nov. 2015 with 2 updates) reveals
the structural novelty of the compounds reported here with no 1-hydrazinylbenzenesulfonamide
reported previously. Indeed, the two reported structures, closest in to those reported here, are (E)-
4-methyl-N-(2-(2-(4-methylbenzylidene)hydrazino)-2-oxoethyl)benzenesulfonamide66 and (E)-
N-(2-(2-(3-chlorobenzylidene)hydrazinyl)-2-oxoethyl)-4-methylbenzenesulfonamide
monohydrate.67 Clearly the scarcity of structures reflects the presence of the hydrazinyl portion of
the molecule as a search for structures containing the C-C(O)-NH-NH2 fragment produced no hits.
In stark contrast, 2194 hits were recorded in a search for the C6H4SO2NHC fragment allowing for
substitution at the 4-position of the benzene ring.
Molecular structures
Single crystals of compounds 5a‒e (Scheme 1) were grown at room temperature from ethanol
solvent and their molecular structures are shown in Fig. 1(a‒e). Bond lengths and angles are given
in Tables S1‒S10 (ESI).

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Fig. 1 The molecular structures of (a) 5a, (b) 5b, (c) 5c and (d) the asymmetric unit of 5d and (e)
5e showing the atom numbering with ellipsoids drawn at the 50% probability level.
The molecular structures of 5a‒c and 5e are sufficiently similar to be discussed together. All four
molecules are U shaped, Fig. 1 (a‒c, e), with sulfonamide N1 atoms at the base of each U and the
i-propyl substituents of 5a and 5c and the i-butyl substituent of 5b on the C7 atoms pointing away
from the us. The benzene rings each carry sulfonamide substituents at C1 bound through the S1
atoms with each ring also substituted in the 4-position with methyl groups for 5a and 5b and a
methoxy substituent in 5d. The planes of the benzene rings are each inclined to the corresponding
hydrazide planes by 17.20(10)° for 5a, 19.28(15)° for 5b and 36.09(9)° for 5c. Compound 5d
crystallizes with two unique molecules, 1 and 2, in the asymmetric unit, Fig 1(d) with both
molecules showing striking similarities to those of 5a‒c. The unique molecules are differentiated

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by leading 1 and 2 characters in the atom numbering. As with 5a‒c, both molecules are U shaped,
Fig. 1, with sulfonamide N11 and N21 atoms at the base of each U and the methyl substituents on
C17 and C27 pointing away from the us. The two molecules overlay (Mercury) with an rms
deviation of 0.112 Å with minor differences between the conformations of the C171 and C271
methyl substituents and the O18 and O28 carbonyl O atoms, Fig. 2. This variation is also reflected
in the relative inclinations of the benzene and hydrazide mean planes as the planes of the 4-chloro
substituted benzene rings are inclined to the planes of the hydrazide units by 16.9(2)° and 21.9(2)°
for molecules 1 and 2 respectively. Compound 5e also retains the characteristic U shape again with
a chloro-substituent on the 4-position of the benzene but with an i-propyl group on C7. The
benzene ring is inclined to the hydrazide unit at an angle of 35.01(11)°.
Fig. 2 An overlay (Mercury) of the two unique molecules in the asymmetric unit of 5d.
Crystal packing
Hydrogen bond distances and angles for 5a‒e are given in Table 2. As with the molecular
structures, the similarities in the crystal packing of the five structures, each of which crystallizes
in the monoclinic space group P 21 with Z = 2 for 5a‒c and 5e but with two unique molecules in
the asymmetric unit Z = 4 for 5d, are such that their crystal packing can be discussed together. A
striking commonality in the packing of all five molecules is that the N-H groups of the sulfonamide

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and hydrazinyl groups of the molecules are all involved in classical N-H…N and N-H…O
hydrogen bonds, Table 2. The sulfonamide N1, N11 and N12 atoms invariably act as strong N-
H…N hydrogen bond donors while the N2, N3, N12, N13, N22 and N23 atoms of the hydrazinyl
groups form N—H…O hydrogen bonds for 5a‒c and 5e but a more eclectic mix of N—H…O and
N—H…Cl contacts for 5d.
Another common feature of the packing for all five molecules is the formation of sheets of
molecules parallel to one of the crystallographic axes as shown in Figs. 3-7. For 5a-c these are
generated by N—H…O (N…O distances in the range 2.826(3) to 3.188(3) Å), N—H…N (N…N
distances in the range 2.907(3) to 2.972(4) Å), and much weaker C—H…O hydrogen bonds (C…O
distances in the range 3.216(4) to 3.601(3) Å), Table 2.
Fig. 3 Sheets of molecules of 5a along the b axis.

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Fig. 4. Sheets of molecules of 5b in the ab plane.
Fig. 5 Sheets of molecules of 5c in the ab plane.
In 5d, the presence of chloro-substituents on the benzene rings of the two unique molecules offer
additional hydrogen bonding opportunities. Despite this however, strong similarities are again

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observed with the packing described previously for the analogous systems. Classical N—H···O
(N…O distances in the range 2.997(4) to 3.118(5) Å), and N—H···N hydrogen bonds (N…N
distances 2.905(4) and 2.925(4) Å), are augmented by a single N23—H23···Cl14 hydrogen bond
(N23…Cl14 = 3.859(4) Å, Table 2. The complex packing in this system again results in sheets of
molecules forming in the bc plane, Fig. 6, as a result of additional weak C—H…O contacts (C…O
= 3.504(4) and 3.148(5) Å) and a single C171—H172…Cl14 hydrogen bond (C1712…Cl14 =
3.886(5) Å.
Fig. 6. Sheets formed in the bc plane by the two unique molecules of 5d.
Unlike the situation for 5d, the presence of the chloro-substituent on the aromatic ring of 5e has a
lesser impact on the crystal packing with no N—H···Cl or C—H···Cl contacts observed.
Nonetheless, the ubiquitous formation of sheets of molecules is again found in the N1—H1N···N3
(N1···N3 = 2.893(4) Å), and N—H···O hydrogen bonds (N…O 2.164(3) and 2.868(4) Å) that

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together with a C—H···O contact (C5…O1 = 3.230(4) Å) build sheets of molecules in the ab
plane, Fig. 7. An unusual feature of the packing for 5e is the observation of a weak and unusual
C4—Cl4---Cg1i contacts (Cg1 is the centroid of the C1···C6 benzene ring; i = -X,-1/2+Y,-Z) with
the Cl···Cg1 distance 3.763(2) Å, contacts that link adjacent sheets to generate a three dimensional
network, Fig. 8.
Fig. 7. Sheets of molecules of 5e in the ab plane.

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Fig. 8. Overall packing for 5e viewed along the b axis direction. Representative C—Cl···π
contacts are drawn as green dotted lines with the ring centroids shown as red spheres.
Stacking of the sheets formed by the other structures 5a-d is another common feature of the
packing of these compounds. Fig. 9 shows the stacks formed in the overall packing of 5a as a
representative example with the stacks formed by 5b-d available in the supplementary material
(Figs. S1-3).
Fig. 9 Overall packing for 5a viewed along the a axis direction

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Table 2 Hydrogen bond distances (Å), angles (°) for 5a–e
Compound D—H···A
D—H
H···A
D···A
‹ D—H···A
N1-H1...N31i
0.79(4)
2.13(4)
2.925(4)
175(3)
5a
N2-H2A...O81ii
N3-H3A...O21iii
C41-H41A...O21iii
0.80(4)
0.83(4)
0.96
2.11(4)
2.31(4)
2.58
2.826(3)
2.894(4)
3.447(5)
150(3)
128(4)
151
N1-H1N...N32i
0.82(3)
0.81(3)
0.91(3)
0.93
2.12(3)
2.22(3)
2.08(3)
2.65
2.907(3)
3.025(3)
2.978(3)
3.216(4)
3.580(3)
163(3)
169(3)
167(3)
120
5b
N2-H2N...O22ii
N3-H3N1...O82iii
C5-H5...O12iv
C7-H7...O12ii
0.98
2.65
159
N1-H1N...N33i
0.80(3)
0.79(3)
0.79(3)
0.98
2.21(3)
2.42(3)
2.39(4)
2.72
2.972(4)
3.188(3)
2.967(4)
3.601(3)
159(3)
166(3)
130(3)
150
5c
N2-H2N...O23ii
N3-H3N2...O83iii
C7-H7...O23ii
N23-H231...O184i
0.95(4)
1.04(4)
0.77(4)
0.79(4)
0.92(5)
0.78(4)
0.83(4)
0.99
2.08(4)
2.86(4)
2.15(5)
2.21(4)
2.51(5)
2.16(4)
2.20(4)
2.68
2.997(4)
3.859(4)
2.905(4)
2.997(4)
3.118(5)
2.925(4)
3.006(4)
3.504(4)
3.886(5)
3.148(5)
162(4)
161(3)
166(4)
169(4)
123(4)
167(4)
165(4)
142
5d
N23-H232...Cl144i
N11-HN11...N134ii
N12-HN12...O124iii
N13-H132...O284iv
N21-HN21...N234v
N22-HN22...O214vi
C17-H17...O114iii
C171-H172...Cl144i
C23-H23...O224ii
0.96
2.94
169
0.93
2.58
119
N1-H1N...N35i
0.74(4)
0.80(4)
0.72(4)
0.93
2.21(4)
2.37(4)
2.36(5)
2.65
2.893(4)
3.164(3)
2.868(4)
3.230(4)
153(4)
169(3)
129(5)
121
5e
N2-H2N...O25ii
N3-H3N1...O85iii
C5-H5...O15iv
Symmetry codes: 1i = 1 -x+1,y+1/2,-z; 1ii = -x+1,y-1/2,-z; 1iii = x+1,y,z; 2i = x,y-1,z; 2ii =-x+1,y+1/2,-z+2; 2iii = -
x+2,y+1/2,-z+2; 2iv = x,y+1,z; 3i = x,y+1,z; 3ii = -x,y-1/2,-z; 3iii = -x+1,y-1/2,-z; 4i = x-1,y,z; 4ii = x,y-1,z; 4iii = -
x+1,y+1/2,-z; 4iv = x+1,y,z; 4v = x,y+1,z; 4vi = -x,y-1/2,-z+1; 5i = x,y+1,z; 5ii = -x+1,y-1/2,-z+1; 5iii = -x,y-1/2,-
z+1; 5iv = x,y-1,z .
Theoretical (DFT) study
As commented above in the structural description of the compounds reported herein, the
supramolecular assemblies observed in their crystal structures are basically dominated by different

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networks of hydrogen bonding interactions. This is basically due to the presence of two functional
moieties that are rich in H-bond donor/acceptor groups, namely the hydrazido and the sulfonamide
moieties. The MEP analysis is almost identical for all the structures in terms of the most
nucleophilic and electrophilic parts of the molecules, and we report the results for 5d as a typical
example. We first computed the MEP surface of the M06-2X/def2-TZVP optimized geometry of
compound 5d in Fig. 10. We also calculated the molecular electrostatic potential (MEP) using this
optimized geometry and plotted it onto the approximate van der Waals surface (isosurface 0.001
a.u.). This type of representation is very useful to distinguish the nucleophilic and electrophilic
parts of a molecule and to rationalize the noncovalent interactions. From an inspection of the MEP
surface shown in Fig. 10 it is evident that the most electron-rich region corresponds to the vicinity
of the O-atoms of the sulfonamide group, which are the best H-bond acceptors. The carbonyl O-
atom and the lone pair at the sp3 hybridized N-atom of the hydrazido group are also good H-bond
acceptors, as is seen in the crystal packing of the compounds. The MEP surface also indicates that
the NH group of the hydrazydo group is the best H-bond donor (205 kJ/mol) followed by the NH
and NH2 groups of the sulfonamide and hydrazido moieties, respectively. The van der Waals
surface also indicates a strong overlap between the hydrazido group and the π-system of the
aromatic ring, which is discussed further below.

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Fig. 10 MEP (two orientations) of compound 5d plotted onto the 0.001 a.u. isodensity surface.
The energies at selected points of the surfaces are given in kJ/mol.
We have used the DFT study to analyze the U-shape conformation adopted for all of the
compounds reported here and to examine the π-interactions of the hydrazido groups with the
benzene rings as anticipated by the examination of the van der Waals surface. Furthermore, we
have also analyzed how the substituent in para position (chloro-, methyl- or methoxy) influences
the intramolecular interactions.
In Fig. 11 we show the optimized theoretical models we have used for this study where R1 is
methyl in all cases and R2 = Cl, Me and OMe, which are denoted as I, II and III, respectively. It
is expected that the substitution of i-Pr or i-Bu by methyl in these theoretical models does not
influence the ability of hydrazinyl-sulfonamides to adopt the U-shaped conformation. In fact, for
R2 = Me we have carried out the calculations for i-Pr or i-Bu obtaining almost identical results.
For each model we have computed two conformations: U-shape (A) and a rotated one (B) where
the hydrazido group is not located over the π-system (Fig. 11). A conformational search (see ESI
for details) performed for R2 = Cl and R1 = Me (compound 5d) indicates that the open
conformation shown in Fig. 11d is the second most stable. The optimized U-shaped conformations
are in all cases more stable than the rotated ones, with energy difference varying from 7.55 to 8.02
kJ/mol. A close examination of the interactions reveals two different contributions, one hand a N-
H···π contact between the -NH2 group and one C atom of the ring and also a pseudo π-stacking
between the π-system of the –NHCO– unit and the aromatic ring. The relevant interatomic
distances are also shown in Figure 11. While these contacts are somewhat longer than those found
in a typical range of such π-interactions the QTAIM analysis discussed below clearly identifies

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these weak contacts through the observation of of critical points and bond paths. Clearly therefore
these contacts play a significant role in the establishment of the lower energy U-conformation of
these molecules. It is also interesting to note that the NH···π interaction distances shorten as the
electron donation ability of the ring substituent increases, as is common in this type of bonding.
All distances are slightly shorter than the experimental ones, likely due to the absence of the
neighboring molecules in the calculations.
Fig. 11 M06-2x/def2-TZVP optimized geometries of models I, II and III, using the U-shaped (a-
c, A series) and open conformations (d-f, B series). Distances in Angstroms. The relative energies
are also indicated.
To further characterize the interactions discussed above that explain the U-shaped conformation
of the compounds, we have used Bader’s quantum theory of atoms-in-molecules (QTAIM). In Fig.

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12 (top) we show the QTAIM distribution of critical points and bond paths. The presence of a bond
critical point (CP) and bond path connecting two atoms is an unambiguous evidence of
interaction.68 The QTAIM analysis reveals the existence of two bond CPs and bond paths. One
connects the H atom of the NH2 group to the C atom of the benzene ring adjacent to the substituent,
thus confirming the existence of the NH···π interactions in all three compounds. Close to each
bond CP we also indicate the value of the density at that CP [ρ(r) in a.u.]. It is well known that the
value of ρ(r) at the bond CP is an indication of the strength of the interaction.69 It is clear that the
value of ρ(r) at the bond CP that characterizes the NH···π interaction increases on going from I to
III, in good agreement with the NH···C distances (Fig. 12). The other CP and bond path connects
the C atom of the carbonyl to one C atom of the ring, also revealing the existence of interaction.
However, neither the O atom or the N atom participate in the distribution of CPs and bond paths.
At this point we have also employed the NCIplot index. The NCI plot enables the visualization
and identification of non-covalent interactions efficiently, because it allows an assessment of host–
guest complementarity and the extent to which such weak interactions stabilize a complex.70
Representations of the NCI plots are shown in Fig. 12 (bottom). It can be seen that in all models a
small green isosurface is present between the –NH2 group and the C atom of the ring thus
characterizing the NH···π interaction. In addition, a more extended isosurface is located between
the π-system of the –NHCO– group and three C atoms of the aromatic ring thus confirming the
existence of this unconventional π-stacking interaction. The extension and shape of the isosurface
is similar in the three complexes.

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Fig. 12 (a-c) Distribution of bond (green spheres) and ring (yellow spheres) critical points in
Compounds IA-IIIA The bond paths are also indicated (dashed lines for noncovalent interactions).
(d-f) NCI plots compounds IA-IIIA. The gradient cut-off is s = 0.35 au, and the color scale is
−0.04 < ρ < 0.04 au.
Finally, we have further analysed the importance of the N–H···π interaction for the formation of
the U-shaped conformation and investigated if the unconventional π-stacking interaction itself is
enough to bend the structure. To do so, we have used a model of 5a (denoted as IV) where we
have changed the hydrazido by an amido group. The results are summarized in Fig. 13. It can be
observed that using this new model the U-shaped conformation is only +3.2 kJ/mol more favored
than the open one (IVB) because the N–H···π is not present. This small difference can be thus
attributed to the contribution of the π-stacking interaction between the π-system of the –NHCO–
group, as confirmed by the existence of a green isosurface in the NCIplot (see Fig 13c) than
embraces the amido group. Moreover the π-stacking distances are comparable to those observed
in model IA (see Fig. 11a)

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Fig. 13 M06-2x/def2-TZVP optimized geometries of model IV, using the open conformation (a)
and U-shaped, distances in Å. (c) NCI plot of compound IVA. The gradient cut-off is s = 0.35 au,
and the color scale is −0.04 < ρ < 0.04 au.
Conclusions
Five new hydrazinyl-sulfonamides (5a‒e) with pendant linear and branched alkyl chains were
efficiently synthesized in good yields. The synthesized compounds were fully characterized by
spectroscopic methods and single crystal X-ray diffraction analysis. Despite the variations in the
substituents on the benzene rings in these molecules and some variation in the aliphatic
substituents adjacent to the sulfonamide units, the crystal packing for all four molecules shows
remarkable similarities. In each case, all three N atoms form classical hydrogen bonds and these
combine with C—H···O contacts to form sheets of atoms. Individual sheets may or may not be
linked but in all cases, molecules are arranged in a head to tail fashion and stacked into columns
along a crystallographic axis. Finally, the U-shaped conformation observed in the solid state of all
compounds has been analyzed using DFT calculations, AIM analysis and the NCIplot index. It
reveals the existence of two intramolecular interactions, which are NH···π and unconventional π–π

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interactions involving the hydrazido π-system. To our knowledge this type on interaction where
has not been previously described in the literature.
Acknowledgements
H.A. is grateful to the Higher Education Commission of Pakistan for financial support under
Indigenous 5000 Ph.D Fellowship program. J.S. thanks the Chemistry Department, University of
Otago for support of his work. AF thanks the MINECO/AEI from Spain for a “Juan de la Cierva”
contract. We thank the MINECO/AEI from Spain for financial support (project number CTQ2017-
85821-R, FEDER funds). We are grateful to the CTI (UIB) for free allocation of computer time.
Supplementary Material
1H and 13C NMR spectra and crystal structures of compounds 5a‒e. CCDC: 1826226 (5a);
1826227 (5b); 1826228 (5c); 1826229 (5d); 1826230 (5e). For ESI and crystallographic data in
CIF or other electronic format see online version of the manuscript.
References
1. H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang and J.-Q. You. J. Am. Chem. Soc., 2011,
133, 7222–7228.
2. H. Göçer, A. Akıncıoğlu, N. Öztaskın, S. Göksu and I. Gülçin, Arch. Pharm., 2013, 346, 783–
792.
3. S. Mutahir, J. Jończyk, M. Bajda, I. U. Khan, M. A. Khan, N. Ullah, M. Ashraf, Qurat-ul-Ain,
S. Riaz, S. Hussain and M. Yar, Bioorg. Chem., 2016, 64, 13–20.
4. C. T. Supuran, Nat. Rev. Drug Discov., 2008, 7, 168‒181.
5. V. Alterio, A. Di Fiore, K. D’Ambrosio, C. T. Supuran and G. De Simone, Chem. Rev., 2012,
112, 4421‒4468.
6. G. De Simone, V. Alterio and C. T. Supuran, Expert Opin. Drug Discov., 2013, 8, 793‒810.

Page 27 of 34
CrystEngComm
View Article Online
DOI: 10.1039/C8CE01917G
7. C. T. Supuran, Bioorg. Med. Chem., 2013, 21, 1377‒1378.
8. C. Capasso and C. T. Supuran, J. Enzyme Inhib. Med. Chem., 2014, 29, 379‒387.
9. C. Congiu, V. Onnis, A. Deplano, G. Balboni, N. Dedeoglu and C. T. Supuran, Bioorg. Med.
Chem. Lett., 2015, 25, 3850–3853.
10. P.-O. Markgrem, W. Schaal, M. Hamalainem, A. Karlen, A. Hallberg and B. Samuelsson, J.
Med. Chem., 2002, 2, 5430–5439.
11. B. R. Stranix, G. Sauvé, A. Bouzide, A. Coté, J. Y. Sévigny and V. Perron, Bioorg. Med. Chem.
Lett., 2004, 14, 3971–3974.
12. R. Crespo, M. G. De Bravo, P. A. Colinas and R. D. Bravo, Bioorg. Med. Chem. Lett., 2010,
20, 6469–6474.
13. K. Takahashi, M. Ohta, Y. Shoji, M. Kassi, K. Kunishiro, T. Miilke, M. Kanada and H.
Shirahase, Chem. Pharma. Bull., 2010, 58, 1057–1065.
14. T. Tite, L. Tomas, T. Docsa, P. Gergely, J. Kovensky, D. Gueyrand and A. Wadouachi,
Tetrahedron. Lett., 2012, 53, 959–961.
15. W. Boufas, N. Dupont, M. Berredjem, K. Berrezag, I. Becheker, H. Berredjem and N.-E. Aouf,
J. Mol. Str., 2014, 1074, 180–185.
16. L. Gavernet and M. Dominguez-Cabrera, Bioorg. Med. Chem., 2007, 15, 1556–1567.
17. A. R. Massah, H. Adibi, R. Khodarahmi, R. Abiri, M. B. Majnooni, S. Shahidi, B. Asadi, M.
Mehrabi and M. A. Zolfigol, Bioorg. Med. Chem., 2008, 16, 5465–5472.
18. M. Adib, E. Sheikhi and G. Sheikhi, Tetrahedron Lett., 2010, 51, 5646–5648.
19. D. Liptrot, L. Alcaraz and B. Robberts, Tetrahedron Lett., 2010, 51, 5341–5343.
20. S. Fu, X. Lian, T. Maa, W. Chen, M. Zheng and W. Zeng, Tetrahedron. Lett., 2010, 51, 5834–
5837.

CrystEngComm
Page 28 of 34
View Article Online
DOI: 10.1039/C8CE01917G
21. F. Pacchiano, M. Aggarwal, B. S. Avvaru, A. H. Robbins, A. Scozzafava, R. McKenna and C.
T. Supuran, Chem. Commun., 2010, 46, 8371‒8373.
22. F. Carta, M. Aggarwal, A. Maresca, A. Scozzafava, R. McKenna and C. T. Supuran, Chem.
Commun., 2012, 48, 1868‒1870.
23. G. M. Brown, Adv. Enzymol. Relat. Areas. Mol. Biol., 1971, 35, 35–77.
24. A. Casini, J. Antel, F. Abbate, A. Scozzafava, S. David, H. Waldeck, S. Schäfer and C. T.
Supuran, Bioorg. Med. Chem. Lett., 2003, 13, 841–845.
25. X.-C. Cheng, Q. Wang, H. Fang and W.-F. Xu, Curr. Med. Chem., 2008, 15, 368–373.
26. T. H. Maren, Physiol. Rev., 1967, 47, 595–781.
27. (a) J. W. Steed and J. L. Atwood, Supramolecular Chemistry, John Wiley & Sons, Ltd., UK,
2nd edn, 2009; (b) A Bauzá, S. K. Seth and A Frontera, Coord. Chem. Rev. 2019, 384, 107-
125; (c)
28. (a) T. Shimizu, M. Masuda and H. Minamikawa, Chem. Rev., 2005, 105, 1401-1444; (b) E. R.
Kay, D. A. Leigh and F. Zerbetto, Angew. Chem., Int. Ed., 2007, 46, 72-191; (c) J. D. Fox and
S. J. Rowan, Macromolecules, 2009, 42, 6823–6835.
29. G. R. Desiraju, Chem. Commun., 2005, 2995–3001.
30. G. R. Desiraju, Acc. Chem. Res., 2002, 35, 565–573.
31. S. S. Kuduva, D. C. Craig, A. Nangia and G. R. Desiraju, J. Am. Chem. Soc., 1999, 121, 1936–
1944.
32. G. R. Desiraju and T. Steiner, The Weak Hydrogen Bond in Structural Chemistry and Biology,
Oxford University Press, Oxford, U.K., 1999.
33. T. Steiner, Chem. Commun., 1997, 727–734.

Page 29 of 34
CrystEngComm
View Article Online
DOI: 10.1039/C8CE01917G
34. C. R. Kaiser, K. C. Pais, M. V. N. de Souza, J. L. Wardell, S. M. S. V. Wardell and E. R. T.
Tiekink, CrystEngComm, 2009, 11, 1133–1140.
35. (a) L.-F. Ma, L.-Y. Wang, J.-L. Hu, Y.-Y. Wang, S. R. Batten and J.-G. Wang,
CrystEngComm, 2009, 11, 777–783; (b) R. Bag, Y Sikdar, S. Sahu, D. K. Maiti, A. Frontera,
A. Bauzá, M. G. B. Drew and S. Goswani, Dalton Trans., 2018, 47, 17077-17085; (c) B.
Naskar, A. Bauzá, A. Frontera, D. K. Maiti, C. D. Mukhopadhyay, S. Goswami, Dalton Trans.,
2018, 47, 15907-15916; (d) K. Ghosh, K. Harms, A. Bauzá, A. Frontera, S. Chattopadhyay,
CrystEngComm 2018, 20, 7281-7292; (e) S. Saha, N. Biswas, A. Sasmal, C. J. Gómez-García,
E Garribba, A Bauza, A. Frontera, G. Pilet, G. M. Rosair, S. Mitra, C. R. Choudhury, Dalton
Trans., 2018, 47, 16102-16118
36. (a) H. Zhou, L. Chen, R. Chen, Z.-H. Peng, Y. Song, Z.-Q. Pan, Q.-M. Huang, X.-L. Hu and
Z.-W. Bai, CrystEngComm, 2009, 11, 671–679; (b) S. Dutta, S. Jana, P. Mahapatra, A. Bauzá,
A. Frontera and A. Ghosh, CrystEngComm, 2018, 20, 6490–6501; (c) A. Castiñeiras, I. García-
Santos, J. M. González-Pérez, A. Bauzá, J. K. Zaręba, J. Niclós-Gutiérrez, R. Torres, E.
Vílchez and A. Frontera, Cryst. Growth Des., 2018, 18, 6786–6800; (d) M. N. Piña, P.
Rodríguez, M. S. Gutiérrez, D. Quiñonero, J. Morey and A. Frontera, Chem. Eur. J. 2018, 24,
12820-12826; (e) T. Maity, H. Mandal, A. Bauza, B. C. Samanta, A. Frontera and S. K. Seth,
New J. Chem., 2018, 42, 10202–10213; (f) G. Mahmoudi, S. K. Seth, A. Bauza, F. I. Zubkov,
A. V. Gurbanov, J. White, V. Stilinovic, T. Doert and A. Frontera CrystEngComm, 2018, 20,
2812–2821.
37. (a) Y. R. Zhong, M. L. Cao, H. J. Mo and B. H. Ye, Cryst. Growth Des., 2008, 8, 2282–2290;
(b) A. Gogoi, S. M. Nashre-ul-Islam, A. Frontera and M. K. Bhattacharyya, Inorg. Chim. Acta,
2019, 484, 133-141