Synthesis, crystal and molecular structure of two biologically active aromatic sulfonamides and their hydrochloride salts

Article abstract of DOI:10.1016/j.molstruc.2010.03.013

4-Sulfamoyl-N-(3-morpholinopropyl) benzamide (P10), N-(3-morpholinopropyl) benzene-1,4-disulfonamide (P20) and their hydrochloride salts (P11 and P22) were prepared. The X-ray molecular structure of these compounds was determined. The gas-phase structure of these drugs was computed using Becke3LYP/6-31G(d) and Becke3LYP/6-311 + G(d,p) model chemistries. The conformational behavior of these systems in water was examined using the solvation CPCM model. In the solid state, gas phase and in solution the conformations of the basic compounds P10 and P20 possess a characteristic L-shaped structure stabilized via an intramolecular hydrogen bonding system of the NH?N type. This hydrogen bond is not present in P11 and P22. A network of intermolecular hydrogen bonds mediated by the Cl atoms and crystal-packing forces in P11 and P22 stabilize a more extended structure in the solid state.

Full text of DOI:10.1016/j.molstruc.2010.03.013

Journal of Molecular Structure 973 (2010) 18–26
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, crystal and molecular structure of two biologically active aromatic
sulfonamides and their hydrochloride salts
b
b
Milan Remko a, , Jozef Kozíšek , Jana Semanová , Fridrich Gregán
ˇ c
*
ˇ
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia
b Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-812 37 Bratislava, Slovakia
c Department of Chemistry, Faculty of Natural Sciences, Matej Bell University, SK-974 01 Banská Bystrica, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Sulfamoyl-N-(3-morpholinopropyl) benzamide (P10), N-(3-morpholinopropyl)benzene-1,4-disulfona-
mide (P20) and their hydrochloride salts (P11 and P22) were prepared. The X-ray molecular structure
of these compounds was determined. The gas-phase structure of these drugs was computed using Beck-
e3LYP/6-31G(d) and Becke3LYP/6-311 + G(d,p) model chemistries. The conformational behavior of these
systems in water was examined using the solvation CPCM model. In the solid state, gas phase and in solu-
tion the conformations of the basic compounds P10 and P20 possess a characteristic L-shaped structure
stabilized via an intramolecular hydrogen bonding system of the NAHꢀ ꢀ ꢀN type. This hydrogen bond is
not present in P11 and P22. A network of intermolecular hydrogen bonds mediated by the Cl atoms
and crystal-packing forces in P11 and P22 stabilize a more extended structure in the solid state.
Ó 2010 Elsevier B.V. All rights reserved.
Received 5 January 2010
Received in revised form 4 March 2010
Accepted 4 March 2010
Available online 10 March 2010
Keywords:
Aromatic sulfonamides
Synthesis
X-ray structure
DFT calculation
Solvent effect
1. Introduction
agent, is to possess modest lipid solubility attributable to its non-
ionized form.
Compounds bearing sulfonamide groups have long been known
to be potent inhibitors of the carbonic anhydrases (CA) [1,2]. In
addition to their established role as diuretics and antiglaucoma
drugs, it has recently emerged that CAIs could have potential as no-
vel anti-obesity, anticancer and anti-infective drugs. Furthermore,
recent studies suggest that CA activation may provide a novel ther-
apy for Alzheimer’s disease [3]. Various substituted aromatic and
heterocyclic sulfonamides have been synthesized and evaluated
for possible therapeutic use as antiglaucoma agents [2,4–7]. Com-
monly used sulfonamide antiglaucomatics include orally adminis-
tered acetazolamide, an ophthalmic suspension of brinzolamide
and an ophthalmic solution of dorzolamide [6,7]. They bind as an-
ions to the Zn2+ ion within the enzyme active site [8–10] with
abnormally high affinities for isozyme CAII [11–13]. Because ther-
apeutically useful antiglaucoma drugs are aromatic and heterocy-
clic sulfonamides, it is evident that for optimal in vivo activity
the balanced hydro- and liposolubility is necessary. It is well
known that a water-soluble sulfonamide, also possessing relatively
balanced lipid solubility, would be an effective antiglaucoma drug
via the topical route [14,15]. One of the conditions [14] needed for
a sulfonamide to act, as an effective intraocular pressure-lowering
In this work we report the synthesis of a novel drug-like
aromatic sulfonamides (4-sulfamoyl-N-(3-morpholinopropyl)
benzamide (P10), and N-(3-morpholinopropyl)benzene-1,4-disulf-
onamide (P20) and their hydrochloride salts) with favorable
biological [16] structural, physicochemical and some pharmacoki-
netic properties comparable to those obtained for the therapeuti-
cally useful acetazolamide, dorzolamide and brinzolamide [17].
The solid-state structure of novel aromatic sulfonamides was
examined by X-ray crystallography. Theoretical quantum chemical
methods were used for structural characterization of these com-
pounds in the gas phase and in water solution.
2. Experimental section
2.1. Chemistry
2.1.1. Synthesis of 4-sulfamoyl-N-(3-morpholinopropyl)benzamide
(P10)
A stirred solution of 125 g (0.865 mol.) 3-morpholinopropyl-
amine in 1.8 l of acetone was added in small aliquots to a solution
of sodium carbonate 91.5 g (0.865 mol.) in 300 ml water at 25 °C.
The solution was cooled to 0 °C. To this stirred solution 190 g
(0.865 mol.) of 4-sulfamoylbenzoylchloride was added in small ali-
quots over 45 min at 10 °C. The reaction mixture was then stirred
for 1 h at 5 °C and 12 h at 25 °C. The solid product was filtered, and
* Corresponding author. Tel.: +421 2 50117225; fax: +421 2 50117100.
E-mail address: remko@fpharm.uniba.sk (M. Remko).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.03.013

M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
19
washed with 100 ml acetone and 100 ml ether. The crude solid
2.2. X-ray crystallographic data
product was mixed three times with 200 ml of a 5% solution of so-
dium chloride in water. The solid was filtered and washed twice in
100 ml cold water and dried (yield 190 g, 67%; m.p. 198–200 °C),
M.r. 327.41. Microanalysis (Elemental Analyser Model 1102, Carlo
Erba) gave the following values (calc for C14H21N3O4S): C 51.20
(51.36), H 6.51 (6.47), N 12.71 (12.83), S 9.88 (9.79). 1H NMR P10
(base) d CH2 (middle) 1.643, 1.666, 1.689, 1.712, 1.736 (2 H), CH2
2.306–2.353 m (6H), CH2 3.272–3.294 m (2 H), (CH2)2 O 3.548,
3.564, 3.580 t (4 H), SO2ANH2 7.477 s (2 H) Har 7.874, 7.880,
7.897, 7.903, 7.971, 7.987, 7.994 m (4 H), COANH 8.644, 8.662,
8.680 t (1 H).
Crystallographic data for compounds P10, P11, P20 and P22
were obtained by GEMINI R [18] diffractometer at room tempera-
ture. A summary of the crystal and collection data is given in Table
1. All crystal structures were solved by direct methods with the
program SHELXS [19] and refined by the full-matrix least-squares
method on F2 with SHELXL [19]. The non-H atoms were refined
anisotropically. All hydrogen atoms were placed geometrically
and refined using a riding model, with Uiso(H) = 1.2 Ueq(C, or N),
CAH distances fixed for CH2 groups at 0.97 Å, for aromatic groups
0
at 0.93 ÅA, and NAH distances for NH2 groups at 0.94 Å and for the
NH group at 0.97 Å. Inspection of the similar crystal structures in
CSD showed that in the case of trivalent nitrogen the interatomic
distances in CAN bonds are in the range of 1.339 Å [20] to
1.478 Å [21] for acyclic bonds and 1.462–1.471 Å for both cyclic
ones [20,21] Our values for P10 and P20 were 1.476 Å, 1.464 Å,
1.464 Å and 1.460 Å, 1.452 Å and 1.454 Å, respectively. On the
other hand in the case of tetravalent nitrogen, the CAN bonds
are in the range of 1.449 Å [22] to 1.508 Å [23] for acyclic bonds
and 1.496 Å and 1.500 Å for both cyclic ones [22], and 1.503 Å
and 1.504 Å [23]. Our values for P11 and P21 were 1.496 Å,
1.477 Å, 1.496 Å and 1.486 Å, 1.493 Å and 1.497 Å, respectively.
2.1.2. Synthesis of 4-sulfamoyl-N-(3-morfolinopropyl)benzamide-
hydrochloride (P11)
A stirred mixture of 168 g (0.513 mol.) 4-sulfamoyl-N-(3-mor-
pholinopropyl)benzamide in 400 ml methanol was added to
480 ml water at 65 °C. Charcoal (20 g) and silica gel (20 g) were
added and the mixture was shaken and filtered. The solution was
cooled and hydrochloride acid (35%) was added in small aliquots
at 25 °C to reach pH = 3. The water was evaporated by distillation
at reduced pressure (20 torr) and traces of moisture were removed
by repeated distillation with toluene. Purification was carried out
by crystallization from ethanol: water (5:1) to give a colorless solid,
yield 110 g, 59%, m.p. 200–202 °C, M.r. 363.86. Microanalysis gave
the following values (calc for C14H22ClN3O4S): C 46.02 (46.21), H
6.13 (6.09), Cl 9.39 (9.74), N 11.38 (11.55), S 9.00 (8.81). 1H NMR
P11 (salt) d CH2 1.963–2.040 m (2 H), CH2 2.991–3.152 m (4 H),
SO2ANH2 7.510 s (2 H) Har 7.892, 7.923, 8.021, 8.053 dd (4 H),
COANH 8.912, 8.933, 8.952 t (1 H), NH+ 10.992 s (1 H).
2.3. Computational details
Ab initio calculations of the 4-sulfamoyl-N-(3-morpholinopro-
pyl) benzamide (P10), and N-(3-morpholinopropyl)benzene-1,4-
disulfonamide (P20) and their hydrochlorides (P11 and P22)
(Fig. 1) were carried out with the Gaussian 03 computer code
[24] at the density functional theory (DFT, Becke3LYP [25]) level
of theory using the 6-31G(d) and 6-311 + G(d,p) basis sets. The
structures of all gas-phase species were fully optimized at the
Becke3LYP level of theory. In order to check the correctness of
the B3LYP calculated geometries using the double-f basis set, we
also performed calculations for the sulfonamide species, using
the larger triple-f basis set 6-311 + G(d,p) implemented in the
Gaussian 03 package of computer codes. The conformational
behavior of these systems in water was examined using the CPCM
solvation method [26,27]. The structures of all condensed-phase
(SCRF) species were fully optimized without any geometric con-
straint at the B3LYP/6-31G(d) level of theory.
2.1.3. Synthesis of N-(3-morpholinopropyl)benzene-1,4-disulfonamide
(P20)
A mixture of 7 g (0.086 mol.) 3-morpholinopropylamine, 24 g
(0.238 mol.) triethylamine and tetrahydrofurane (50 cm3) was ta-
ken up.
A solution of 4-sulfamoylbenzenesulfonylchloride in
50 cm3 tetrahydrofurane was added to this stirred mixture at
5 °C over 30 min. The mixture was stirred for 12 h at room temper-
ature. To this mixture 100 cm3 of hexane was added. The solid was
separated and mixed with cold water (15 cm3) and then filtered,
washed with cold water (5 cm3) and dried. The crude product
was crystallized from water to give a colorless solid, yield 8.7 g,
51%, m.p. 121–123 °C, M.r. 363.46. Microanalysis gave the follow-
ing values (calc for C13H21N3O5S2): C 42.67 (42.96), H 5.91 (5.82),
N 11.39 (11.56), S 17.80 (17.64). 1H NMR P20 (base) d CH2-middle
1.533, 1.564, 1.574 t (3 H), CH2 2.377 m (4 H), CH2AN 2.806, 2.818,
2.829 t (2 H), CH2 3.557 m (6 H), SO2ANH2 7.607 s (2H), SO2ANH
7.865 s (1 H) Har 7.962, 7.975, 8.010, 8.023 dd (4 H).
3. Results and discussion
3.1. X-ray structure
2.1.4. Synthesis of N-(3-morpholinopropyl)benzene-1,4-disulfonamide
hydrochloride (P22)
The compounds investigated contain a common benzene sul-
fonamide moiety substituted in the para position with a N-(3-mor-
pholinopropyl) amide (P10 and P11) or a N-(3-morpholinopropyl)-
sulfonamide (P20 and P22) substituent. The morpholino nitrogen
atom of the parent P10 and P20 molecules is the principal basic
center with the computed pKa = 7.4, and is partially protonated
(hydrogen bond acceptor site) at the physiological pH = 7.4 [17].
The amide and the sulfonamide NAH groups provide hydrogen
bond donor functionalities. In the solid state the 3D structure of
P10 and P20 is stabilized via an intramolecular hydrogen bonding
system of the N(10)AHꢀ ꢀ ꢀN(4) type (Fig. 1). The prepared com-
plexes of basic aromatic sulfonamides P10 and P20 with HCl form
multicomponent crystals in the solid state. Examination of X-ray
data for the corresponding hydrochloride salts showed the proton
resides on the base, which means that proton transfer had occurred
and that the crystalline complex of P11 and/or P22 is a salt. The
hydrochloride salt of P10 is a monohydrate.
N-(3-Morpholinopropyl)benzene-1,4-disulfonamide 12 g (0.033
mol.) was dissolved in methanol (15 cm3) at 55–60 °C. Charcoal
(5 g) and silica gel (5 g) were added to this solution and after a
short period of stirring the mixture was filtered. A solution of
hydrogen chloride in methanol was added to this stirred solution
at 5 °C to reach pH = 3. After three hours the solid was filtered,
washed with acetone (10 cm3) and dried. The crude product was
crystallized from water: ethanol (1:1) to give a colorless solid, yield
8 g, 60%, m.p. 236–238 °C, M.r. 399.92. Microanalysis gave the fol-
lowing results (calc for C13H22ClN3O5S2): C 39.32 (39.04), H 5.39
(5.54), Cl 8.31 (8.87), N 10.48 (10.51), S 16.32 (16.04). 1H NMR P21
(salt) d CH2 1.813–1.912 m (2 H), CH2 2.823–2.881 m (2 H), CH2
2.953–3.102 m (4 H), CH2 3.322–3.363 m (2 H), CH2 3.731–3.964 m
(4 H), SO2ANH2 7.642 s (2 H) Har 8.002, 8.011, 8.022, 8.032 dd (4
H), SO2ANH 8.053, 8.076, 8.096 t (1 H), NH+ 10.893 s (1 H).

20
M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
Table 1
Crystallographic data for compounds P10, P11, P20 and P22.
Compound
P10
P11
P20
P22
Molecular formula
Molecular weight
Crystal description
Size (mm)
C14 H21 N3 O4
327.40
Colorless
S
C14 H22 Cl N3 O4
363.86
Colorless
S
C13 H21 N3 O5 S2
363.45
Colorless
0.129 ꢁ 0.309 ꢁ 0.493
No. 14 P21/n
11.022(1)
C13 H23 Cl N3 O5 S2
400.91
Colorless
0.361 ꢁ 0.507 ꢁ 0.517
0.051 ꢁ 0.110 ꢁ 0.684
0.219 ꢁ 0.542 ꢁ 0.861
Space group
No. 29 Pca21
No. 14 P21/c
No. 15 C2/c
0
11.014(1)
10.032(2)
14.738(1)
a (AÅ)
0
8.304(1)
18.830(4)
9.839(2)
6.0140(1)
25.163(2)
12.129(1)
21.360(2)
b (AÅ)
0
17.056(2)
c (AÅ)
a
(o)
90.00
90.00
90.00
1559.98(3)
90.00
98.89(3)
90.00
90.00
97.24(2)
90.00
90.00
107.673(2)
90.00
b (o)
c
(o)
0
1836.2(6)
1654.66(7)
3638.1(2)
V (AÅ3)
Z
4
4
4
8
dx (g cmꢂ3
F (000)
)
1.394
696
0.229
1.316
768
0.343
1.470
768
0.353
1.473
1688
0.471
l
(cmꢂ1
)
T (K)
298
29.57
298
26.37
298
29.38
298
29.44
Max h (o)
hkl ranges
ꢂ15 6 h P 15
ꢂ12 6 h P 12
ꢂ14 6 h P 14
ꢂ19 6 h P 210
ꢂ11 6 k P 11
ꢂ23 6 k P 23
ꢂ8 6 k P 8
ꢂ16 6 k P 16
ꢂ21 6 l P 23
ꢂ12 6 l P 12
ꢂ34 6 l P 34
ꢂ29 6 l P 28
No. of reflns. measd.
No. of indep. reflns.
Rint
Refinement type
No. of params. refined
wR2 (all)
R1 (obs.)
No. of obsd. reflns.
Criterion
49504
41069
34897
48593
4138
0.0167
3753
0.0435
4245
0.0296
4742
0.0176
Full-matrix least-squares on F2
Full-matrix least-squares on F2
Full-matrix least-squares on F2
Full-matrix least-squares on F2
206
234
216
232
0.0719
0.0253
3808
0.0517
0.0468
2597
0.1247
0.0403
2919
0.0380
0.0287
3845
Fo > 4
r
(Fo)
Fo > 4
r(Fo)
Fo > 4
r(Fo)
Fo > 4r(Fo)
0
ꢂ0.159
ꢂ0.305
ꢂ0.417
ꢂ0.290
Difference peak/hole (e ÅAꢂ3
)
0.207
0.473
0.317
0.275
Fig. 1. Molecular drawing of compounds studied giving the crystallographic atom-numbering scheme.

M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
21
The sulfonamides studied possess arylsulfonamide functional-
ity, a connecting chain and a basic morpholino substituent. Their
relative molecular orientation is described by twelve dihedral an-
gles. The relevant bond lengths, bond angles and dihedral angles
for X-ray conformations and calculated values of the fully opti-
mized structures are given in Tables 2 and 3, respectively. The
bond lengths and bond angles of the principal RASO2NH2 moiety
in P10, P20 and their hydrochloride salts are very similar. Some
trends are apparent: (i) the CaromAS bond length of about 1.76–
1.78 Å is a single bond length between the sp2 hybridized carbon
atom and sulfur since the sulfonamide group and aromatic rings
lar and intermolecular hydrogen bonds (Table 4). The geometric
parameters show that P10 possesses a typical L-shaped structure
stabilized by means of an intramolecular NAHꢀ ꢀ ꢀN hydrogen bond
with a length of 2.178 Å. The sulfonamide NH2 group is engaged in
two intermolecular hydrogen bonds. One H-bond arises from the
NAHꢀ ꢀ ꢀO interaction with the morpholine oxygen atom of the
neighboring molecule and the second one (also of the NAHꢀ ꢀ ꢀO
type) mediates the oxygen atom of the amide group of another
molecule (Fig. 2). The carbonyl oxygen atom is coordinated with
the sulfonamide group of the neighboring molecule via intermolec-
ular H-bond of the CAOꢀ ꢀ ꢀHAN type. The oxygen atom of the mor-
pholine moiety forms an intermolecular hydrogen bond with the
sulfonamide NH2 group of the other molecule (Fig. 2). Four sur-
rounding molecules form the full coordination sphere of P10
(Fig. 2). In general, these hydrogen bonds generate an overall
three-dimensional framework of hydrogen-bonded molecules of
P10.
are approximately perpendicular (dihedral angles
U[C(17)AC(16)
AS(19)AN(22)] and [C(18)AC(17)AS(20)AN(23)], Tables 2 and
U
3). (ii) The SAN bond length in all of the substituted sulfonamides
investigated is about 1.60 Å, and is much shorter than the SAN sin-
gle bond distance [28] of about 1.75 Å. (iii) The arrangement of
bonds around the sulfur atom creates a distorted tetrahedron, a
structural feature that is found in aromatic and heterocyclic sulfon-
amides [29]. The largest deviation of about 119° is in the OASAO
angle. The other angles are in the range of 105–108°. (iv) The prot-
onization of the morpholine N(4) nitrogen atom (P11 and P22) is
manifested by the lengthening of the neighboring N(4)AC covalent
bonds by about 0.03 Å. (v) The sp3 hybridized nitrogen atoms of the
ASO2NH2 group have a pyramidal character. (vi) The dihedral angles
for individual drugs differ, and no general conclusions about aro-
matic sulfonamide functionality can be deduced (Tables 2 and 3).
3.1.2. P11
The X-ray structure of P11, shown in Fig. 1, displays crystal
packing that is distinct from that of its parent base P10 (Fig. 2).
P10 and HCl form a 1:1:1 complex with water. The chloride anion
in the crystal structure is coordinated with the basic center of the
parent molecule by means of a water molecule. The proton of the
P10-H+ cation residing on the basic N(4) nitrogen is coordinated
with one water molecule via an intermolecular N+AHꢀ ꢀ ꢀOH2 hydro-
gen bond with a N+ꢀ ꢀ ꢀO length of 2.716 Å. One OAH bond of this
water molecule takes part in an intermolecular H-bond with the
anionic Clꢂ atom with an Oꢀ ꢀ ꢀClA length of 3.201 Å. The second
OAH group of the water molecule interacts by means of an H-bond
3.1.1. P10
The solid state conformation of 4-sulfamoyl-N-(3-morpholino-
propyl) benzamide (P10) is stabilized by a system of intramolecu-
Table 2
Experimental and theoretically optimized relevant bond lengths (Å), bond angles (°) and dihedral angles (°) of the P10 and its salt.
Parameters
P10
P11
X-ray
DFTa,d
DFT-HLb,d
DFT-CPCMc,d
X-ray
DFTa
DFT-HLb
DFT-CPCMc
d[C(16)AS(19)]
d[S(19)AO(20)]
d[S(19)AO(21)]
d[S(19)AN(22)]
d[C(13)AC(11)]
d[C(11)AO(12)]
d[C(11)AN(10)]
d[N(4)AC(7)]
1.777(1)
1.433(1)
1.432(1)
1.601(1)
1.502(2)
1.222(1)
1.336(1)
1.476(2)
1.794
1.466
1.466
1.699
1.509
1.230
1.362
1.476
1.798
1.461
1.461
1.693
1.509
1.226
1.360
1.475
1.791
1.475
1.473
1.678
1.507
1.239
1.351
1.478
1.771(2)
1.433(1)
1.437(1)
1.596(2)
1.500(2)
1.238(2)
1.324(2)
1.496(2)
1.797
1.466
1.465
1.697
1.506
1.230
1.367
1.501
1.801
1.460
1.460
1.691
1.507
1.224
1.365
1.499
1.793
1.473
1.473
1.676
1.506
1.238
1.357
1.511
d[N(4)AC(3)]
1.464(2)
1.472
1.471
1.472
1.496(2)
1.497
1.495
1.507
d[N(4)AC(5)]
1.464(2)
1.472
1.471
1.472
1.477(2)
1.498
1.497
1.509
d[N(4) . . . N(10)]
2.862(1)
2.956
2.991
2.920
4.444(1)
4.590
4.562
4.530
H
H
H
H
H
H
H
[C(17)AC(16)AS(19)]
[C(16)AS(19)AO(20)]
[C(16)AS(19)AO(21)]
[O(20)AS(19)AO(21)]
[C(16)AS(19)AN(22)]
[C(13)AC(11)AO(12)]
[C(13)AC(11)AN(10)]
120.18(8)
105.65(6)
108.78(6)
119.21(7)
107.63(6)
121.34(10)
116.64(9)
ꢂ155.78(10)
75.13(10)
ꢂ40.10(10)
154.69(12)
ꢂ26.40(16)
ꢂ178.83(10)
ꢂ163.05(11)
ꢂ59.86(13)
74.73(14)
ꢂ158.34(11)
80.88(14)
119.18
107.53
107.80
122.40
103.40
120.97
116.43
157.52
23.78
-88.77
158.05
ꢂ21.62
ꢂ175.66
ꢂ172.56
ꢂ61.89
71.75
119.10
107.54
107.72
122.46
103.39
120.71
116.60
157.20
23.41
ꢂ89.26
155.47
ꢂ23.97
ꢂ177.61
ꢂ167.50
ꢂ63.88
71.88
119.49
107.84
109.47
118.21
101.63
120.88
116.06
137.52
7.69
ꢂ111.09
147.48
ꢂ32.42
ꢂ176.69
ꢂ175.43
ꢂ60.50
71.94
120.18(14)
106.47(8)
107.41(9)
119.40(9)
108.48(9)
119.94(19)
118.62(17)
ꢂ143.23(16)
ꢂ14.24(18)
100.90(18)
ꢂ165.24(17)
11.9(3)
119.18
107.48
107.40
122.64
103.32
121.29
116.57
ꢂ154.05
ꢂ20.31
92.83
119.18
107.45
107.39
122.67
103.35
121.19
116.48
ꢂ156.45
ꢂ22.72
90.21
119.22
107.65
107.53
120.06
103.80
120.65
116.91
ꢂ157.59
ꢂ26.91
87.50
U
U
U
U
U
U
U
U
U
U
U
[C(17)AC(16)AS(19)AO(20)]
[C(17)AC(16)AS(19)AO(21)]
[C(17)AC(16)AS(19)AN(22)]
[C(18)AC(13)AC(11)AO(12)]
[C(18)AC(13)AC(11)AN(10)]
[C(13)AC(11)AN(10)AC(9)]
[C(11)AN(10)AC(9)AC(8)]
[N(10)AC(9)AC(8)AC(7)]
[C(9)AC(8)AC(7)AN(4)]
ꢂ156.86
ꢂ153.86
ꢂ152.63
22.82
26.06
27.28
ꢂ177.26(15)
170.81(18)
ꢂ61.8(2)
173.84
91.14
175.11
93.40
176.82
98.70
ꢂ71.19
ꢂ169.09
ꢂ67.54
166.24
2.909
ꢂ69.60
ꢂ170.93
ꢂ66.14
168.13
2.898
ꢂ66.83
ꢂ172.02
ꢂ63.23
172.51
3.018
ꢂ167.85(16)
ꢂ60.5(2)
[C(8)AC(7)AN(4)AC(5)]
[C(8)AC(7)AN(4)AC(3)]
ꢂ158.78
ꢂ158.76
ꢂ157.19
78.43
78.44
80.11
175.42(16)
10.836(1)
d[N(4)ꢀ ꢀ ꢀCl]
a
b
c
B3LYP/6-31 g(d).
B3LYP/6-311 + g(d,p).
B3LYP/6-31 g(d) + CPCM.
Taken from the Ref. [17].
d

22
M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
Table 3
Experimental and theoretically optimized relevant bond lengths (Å), bond angles (°) and dihedral angles (°) of the P20 and its salt.
Parameter
P20
P22
X-ray
DFTa,d
DFT-HLb,d
DFT-CPCMc,d
X-ray
DFTa
DFT-HLb
DFT-CPCMc
d[C(17)AS(20)]
d[S(20)AO(21)]
d[S(20)AO(22)]
d[S(20)AN(23)]
d[C(14)AS(11)]
d[S(11)AO(12)]
d[S(11)AO(13)]
d[S(11)AN(10)]
d[N(4)AC(7)]
1.775(4)
1.425(3)
1.418(5)
1.601(4)
1.777(4)
1.421(5)
1.425(4)
1.597(4)
1.797
1.466
1.465
1.695
1.808
1.464
1.464
1.661
1.802
1.460
1.460
1.689
1.813
1.460
1.460
1.658
1.798
1.471
1.471
1.674
1.802
1.471
1.471
1.665
1.760(9)
1.430(4)
1.422(6)
1.601(9)
1.765(10)
1.429(6)
1.431(3)
1.611(9)
1.486(9)
1.798
1.466
1.465
1.696
1.802
1.469
1.467
1.651
1.802
1.460
1.460
1.690
1.807
1.464
1.462
1.649
1.798
1.472
1.472
1.674
1.801
1.470
1.469
1.663
1.460(5)
1.473
1.473
1.477
1.517
1.516
1.517
d[N(4)AC(3)]
1.454(3)
1.472
1.472
1.473
1.493(9)
1.506
1.505
1.510
d[N(4)AAC(5)]
d[N(4)ꢀ ꢀ ꢀN(10)]
1.452(4)
2.752(1)
1.470
2.863
1.470
2.895
1.472
2.864
1.497(4)
4.327(1)
1.505
3.135
1.504
3.127
1.507
3.412
H
H
H
H
H
H
H
H
H
[C(18)AC(17)AS(20)]
[C(17)AS(20)AO(21)]
[C(17)AS(20)AO(22)]
[O(21)AS(19)AO(22)]
[C(17)AS(20)AN(23)]
[C(14)AS(11)AO(12)]
[C(14)AS(11)AO(13)]
[O(12)AS(11)AO(13)]
[C(14)AS(11)AN(10)]
119.80(2)
107.55(19)
106.57(20)
119.63(18)
107.73(22)
108.66(22)
106.34(19)
120.70(16)
107.09(21)
ꢂ11.17(16)
118.26(16)
ꢂ127.94(23)
48.66(19)
179.97(15)
ꢂ64.59(26)
ꢂ58.98(23)
ꢂ162.87(16)
ꢂ63.12(30)
58.99(30)
ꢂ166.24(17)
70.70(27)
119.15
107.43
107.39
122.57
103.35
106.64
106.59
122.79
107.00
23.95
157.54
ꢂ89.17
24.75
157.51
ꢂ87.97
ꢂ67.82
ꢂ171.91
ꢂ66.13
61.94
119.08
107.40
107.37
122.59
103.36
106.71
106.52
122.62
107.25
23.98
157.56
ꢂ89.15
26.48
159.02
ꢂ86.54
ꢂ67.93
ꢂ171.99
ꢂ67.28
63.51
119.03
107.39
107.37
120.28
103.51
107.01
107.16
120.27
108.56
25.88
156.54
ꢂ88.67
23.47
153.78
ꢂ90.48
ꢂ66.44
ꢂ179.03
ꢂ66.39
64.36
120.62(29)
107.41(37)
108.55(44)
119.46(27)
106.85(41)
107.29(35)
108.09(33)
119.96(23)
106.96(43)
ꢂ137.86(25)
ꢂ7.39(13)
108.57(31)
ꢂ151.13(18)
ꢂ20.45(17)
94.26(33)
58.75(28)
171.74(11)
ꢂ72.71(30)
171.46(12)
58.96(27)
ꢂ176.66(11)
3.054(1)
119.18
107.35
107.64
122.61
103.16
107.47
107.74
121.40
107.58
ꢂ160.98
ꢂ27.22
85.47
119.10
107.37
107.61
122.62
103.14
107.47
107.00
121.28
107.80
ꢂ159.64
ꢂ25.87
87.01
118.95
107.22
107.86
120.04
103.16
107.54
107.28
120.31
107.85
ꢂ161.60
ꢂ31.03
82.04
U
U
U
U
U
U
U
U
U
U
U
U
[C(18)AC(17)AS(20)AO(21)]
[C(18)AC(17)AS(20)AO(22)]
[C(18)AC(17)AS(20)AN(23)]
[C(19)AC(14)AS(11)AO(12)]
[C(19)AC(14)AS(11)AO(13)]
[C(19)AC(14)AS(11)AN(10)]
[C(14)AS(11)AN(10)AC(9)]
[S(11)AN(10)AC(9)AC(8)]
[N(10)AC(9)AC(8)AC(7)]
[C(9)AC(8)AC(7)AN(4)]
ꢂ172.44
ꢂ40.76
72.52
ꢂ170.78
ꢂ39.23
74.22
ꢂ160.21
ꢂ29.46
84.43
88.77
85.74
64.88
135.78
ꢂ46.25
94.06
139.86
ꢂ45.59
93.13
165.22
ꢂ52.08
106.61
83.11
[C(8)AC(7)AAN(4)AC(5)]
[C(8)AC(7)AN(4)AC(3)]
ꢂ163.42
ꢂ162.39
ꢂ160.55
96.76
97.31
72.80
73.97
76.47
ꢂ137.63
ꢂ137.51
ꢂ161.14
d[N(4)ꢀ ꢀ ꢀCl]
3.018
3.007
3.174
d[N(10))ꢀ ꢀ ꢀCl]
3.210(1)
3.138
3.122
3.260
a
b
c
B3LYP/6-31 g(d).
B3LYP/6-311 + g(d,p).
B3LYP/6-31 g(d) + CPCM.
Taken from the Ref. [17].
d
Table 4
Hydrogen bond geometry of P10 (hydrogen bond lengths in Å).
hydrogen bonds (Table 5). The crystal packing of the molecule
shows a system of four intermolecular hydrogen bonds connecting
a parent P20 with three neighboring molecules (Fig. 2). The hydro-
gen bonding centers are sulfonamide ASO2NH2 group and morpho-
line oxygen atoms, respectively. The central N-substituted
ASO2NHA group is involved in an intramolecular hydrogen bond
only. This NAHꢀ ꢀ ꢀN hydrogen bond with a length of 2.105 Å stabi-
lizes the structure around the flexible connecting chain A(CH2)3A
in the stable L-shaped conformation.
H-bond type
DAHꢀ ꢀ ꢀA
DAH
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
ASO2NH2ꢀ ꢀ ꢀO@C
ASO2NH2ꢀ ꢀ ꢀO<
NAHꢀ ꢀ ꢀOa
NAHꢀ ꢀ ꢀOa
NAHꢀ ꢀ ꢀOb
NAHꢀ ꢀ ꢀOb
0.940
0.755
0.940
0.755
1.948
2.214
1.948
2.214
2.865
2.965
2.865
2.965
ASO2NH2ꢀ ꢀ ꢀO@CANHA
ASO2NH2ꢀ ꢀ ꢀO<
a
Parent molecule as H-bond donor.
Parent molecule as H-bond acceptor.
b
3.1.4. P22
The hydrochloride salt of N-(3-morpholinopropyl)benzene-1,4-
disulfonamide (P22) exists in an extended conformation in the so-
lid state. The reaction of the base P20 with hydrochloric acid re-
sults in the formation of a 1:1 salt. X-ray analysis showed that
the proton is located on the basic nitrogen atom of the morpholine
moiety. A network of intermolecular hydrogen bonds mediated by
the Cl atoms stabilizes the crystal structure. Each Cl atom bridges
three molecules via NAHꢀ ꢀ ꢀCl hydrogen bonds (Fig. 2). The differ-
ent hydrogen bonding network and crystal-packing forces in P20
and its salt P22 are the reason for the large differences in dihedral
angles describing both the sulfonamide functionality and para-
substituted N-(3-morpholinopropyl) sulfonamide moiety (Table
2). The N-(3-morpholinopropyl) sulfonamide moiety in P22 is al-
most in the trans arrangement. The morpholine substituent of
P22 is located, in comparison to that of P20, in the opposite posi-
tion in space (Fig. 3).
with the oxygen atom of the substituted amide group of the neigh-
boring molecule (the OAHꢀ ꢀ ꢀO bond length is about 2.813 Å). The
specific hydrogen bond interactions in the solid forms of P10 and
P11 give rise to their unique overall shape. The orientation of the
sulfonamide moiety in the base P10 and its salt P11 is very differ-
ent (Fig. 3). The difference in dihedral angle
U[C(17)AC(16)A
S(19)AN(22)] can be as large as 140° (Table 1). The morpholinopro-
pyl chain in P10 is in the L-shaped conformation, with C(9)AC(8)
bound cis with respect to C(7)AN(4)
(U[C(9)AC(8)AC(7)A
N(4)] = 74.7°), whereas in P11 it is found to be trans (ꢂ167.6°,
see Table 2).
3.1.3. P20
The X-ray structure of N-(3-morpholinopropyl)benzene-1,4-
disulfonamide (P20) is also stabilized by means of a network of

M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
23
Fig. 2. Details of the three-dimensional hydrogen bonding network of P10, P11, P20 and P22 with atoms participating in the drawn hydrogen bonds represented by dashed
lines.
3.2. Theoretical calculations
an increase in the basis set gives essentially the same results [30–
32]. Thus, for the purpose of determining reasonable geometries of
large systems, B3LYP/6-31G(d) should be considered the method
of choice. Important geometric parameters of the molecules investi-
gated are given in Tables 2 and 3. In the isolated sulfonamide P10 and
P20 species theabsolute minimumis stabilizedby an intramolecular
NAHꢀ ꢀ ꢀN hydrogen bond. The hydrochloride salts were considered
as 1:1 complexes of the bases P10 and P20 with hydrochloric acid.
HCl bridges thebasic N(4)nitrogen atom by means of protontransfer
to the hydrogen bond of the N+AHꢀ ꢀ ꢀClA type.
In order to determine the stable conformations of title com-
pounds in the gas phase and/or in water solution we also carried
out theoretical calculations. The initial conformations for use in
the calculations of the aromatic sulfonamides and their salts were
constructed by means of the Gauss View graphical interface. It is
common in the computational study of drugs to use structural data
obtained from X-ray crystallography or NMR spectroscopy as
guides to the quality of theoretical computations. We took the rel-
ative orientation of the individual functional groups of the sulfon-
amides studied from the X-ray data of the crystal structures
discussed earlier. Examination of the space models of the B3LYP
computed structures using two basis sets of the drugs showed that
3.2.1. Gas phase
The gas-phase geometry of P10 and P20 was comprehensively
discussed in a recent publication [17]. The connecting chain of

24
M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
the Supplementary Information. In both cases the thermodynami-
cally most stable structures are conformers possessing the charac-
teristic L-shaped structure stabilized via an intramolecular
hydrogen bonding system of the NAHꢀ ꢀ ꢀN type. It is also apparent
that this intramolecular hydrogen bond is a prevailing stabilizing
geometric factor in the solid state (Tables 2 and 3). To demonstrate
the changes in the molecular structure of P10 and P20 in the gas-
phase and solid state we used the superposition of these two struc-
tures as presented in Fig. B. It is apparent that a particularly large
change in geometry occurs for the morpholinopropyl and para-sul-
fonamide moieties of these compounds.
A different situation occurs with the hydrochloride salts. In gen-
eral there is, of course, no reason why the minimum-energy con-
formation in the gas phase should also be the minimum-energy
conformation in the solid state. Extensive intermolecular hydrogen
bonding as well as crystal-packing forces may influence which con-
former is actually adopted in the solid state, and the gas-phase
structure can also contain intramolecular hydrogen bonds. In the
absence of the stabilizing effect of intermolecular hydrogen bonds
mediated via chlorine atoms the most stable gas phase conformers
of P11 and P22 correspond to the conformation in which the anio-
nic chlorine atom forms a salt bridge of the N+AHꢀ ꢀ ꢀClA type
(Fig. 4). In P11 the chlorine atom is directly coordinated with the
charged N+AH group of the morpholine part of the molecule. For
P22 the most stable conformer corresponds to the structure in
which the Clꢂ atom is bicoordinated and forms two intramolecular
hydrogen bonds with the proton donor NAH groups of the mole-
cule (Fig. 4).
3.2.2. In water
In order to study the influence of the surrounding medium on
the relative stability of the complexes studied we also investigated
Fig. 3. (A) – molecular superimposition of the X-ray structure of P10 (blue) and its
hydrochloride salt P11 (green). (B)
– molecular superimposition of the X-ray
structure of P20 (blue) and its hydrochloride salt P22 (green). (For interpretation of
the references to colour in this figure legend, the reader is referred to the web
version of this article.)
Table 5
Hydrogen bond geometry of P20 (hydrogen bond lengths in Å).
H-bond type
DAHꢀ ꢀ ꢀA
DAH
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
ASO2NH2ꢀ ꢀ ꢀO@SONH2
ASO2NH2ꢀ ꢀ ꢀO<
NAHꢀ ꢀ ꢀOa
NAHꢀ ꢀ ꢀOa
NAHꢀ ꢀ ꢀOb
NAHꢀ ꢀ ꢀOb
0.810
0.848
0.810
0.848
2.103
2.060
2.103
2.060
2.909
2.894
2.909
2.894
ASO2NH2ꢀ ꢀ ꢀO@SONH2
ASO2NH2ꢀ ꢀ ꢀO<
a
Parent molecule as H-bond donor.
Parent molecule as H-bond acceptor.
b
three carbon atoms imparts some flexibility to the P10 and P20
structures investigated. Thus, although the conformation is stabi-
lized in the solid state by means of an intramolecular hydrogen
bond of the NAHꢀ ꢀ ꢀN type, ‘‘extended” conformations without
hydrogen bonding may also exist. Thus, we also carried out calcu-
lations for two additional ‘‘trans” structures. The relative stability
order of individual conformers computed by two theoretical meth-
ods at the HF and Becke3LYP levels of theory is shown in Fig. A of
Fig. 4. B3LYP/6-311 + G(d,p) optimized structures of P11 and P22.

M. Remko et al. / Journal of Molecular Structure 973 (2010) 18–26
25
Table 6
Theoretically optimized hydrogen bond lengths (Å) and bond angles (°) of P11 and P20.
Parameter
P11
P22
N+(4)AHꢀ ꢀ ꢀClA
N+(4)AHꢀ ꢀ ꢀClA
N(10)AHꢀ ꢀ ꢀClA
DFT
DFT-CPCM
1.060
2.049
3.108
178.9
DFT
DFT-CPCM
1.053
2.123
3.174
171.7
DFT
DFT-CPCM
1.031
2.291
3.260
156.2
RNꢀ ꢀ ꢀH
RClꢀ ꢀ ꢀH
RNꢀ ꢀ ꢀCl
hNAHꢀ ꢀ ꢀCl
1.126
1.784
2.909
179.3
1.082
1.943
3.108
172.2
1.034
2.196
3.138
150.5
the environmental effects. The effect of bulk solvent was assessed
using the CPCM solvation method [27,29] in combination with the
B3LYP/6-31G(d) calculations. Water has a remarkable effect on the
geometry and stability of the individual molecules studied, espe-
cially the ionic complexes (Tables 2 and 3). The solvent effect
causes substantial structural rearrangement of the morpholinopro-
pyl moiety in P11 and P22, and the difference in torsion angles can
be as large as 20° (Tables 2 and 3). The energetic stability of the
three stable solvated conformers of basic sulfonamides (P10 and
P20) is not considerably altered. The most stable conformer in
water solution is also the L-shaped structure with an intramolecu-
lar hydrogen bond of the NAHꢀ ꢀ ꢀN type (Fig. A). The conforma-
tional change in the basic sulfonamides P10 and P20 upon water
solvation is small and related to the morpholinopropyl moiety
(Fig. B).
The calculated hydrogen bond geometries of the ionic com-
plexes in H2O are quite different (Table 6). The difference in Nꢀ ꢀ ꢀCl
bond lengths is about 0.2 Å. A proton is located on the N(4) nitro-
gen atom, indicating that in solution, as in the solid state, the sul-
fonamides P11 and P22 will be salts. The preference for proton
transfer in solution can be deduced from the known pKa values
of the reactants in water. It is generally accepted that reaction of
an acid with a base will form a salt (ionized complex) if the
which means that proton transfer had occurred and that the
crystalline complex of P11 and/or P22 is a salt. The hydrochlo-
ride salt of P10 is a monohydrate.
2. Calculations showed that P10 and P20 exist in their most stable
conformers in the gas phase, possessing a characteristic L-
shaped structure that is stabilized via an intramolecular hydro-
gen bonding system of the NAHꢀ ꢀ ꢀN type. The solvent effect
causes substantial structural rearrangement of the morpholino-
propyl moiety of these compounds, and the difference in torsion
angles can be as large as 20o.
3. In polar solvents like water the computed
DpKa difference
(D
pKa = pKa(base)–pKa(acid)) for P11 and P22, respectively, is
very high and the same (15.4), indicating the existence of these
structures in solution in the form of an ionized complex (salt).
The concentration of the ionized species in both cases is about
15 times greater than the concentration of the non-ionized
(neutral) species.
Acknowledgements
The authors are grateful to the Slovak Grant Agency (to JK Grant
No. 1/0817/08). The authors thank the Structural Funds, Interreg
IIIA for the financial support in purchasing the X-ray
diffractometer.
D
pKa = pKa(base)–pKa(acid) is greater than 2 or 3 [33]. This crite-
rion is frequently used in pharmaceutical research for the selection
of appropriate counterions in a salt selection. We used ACD/Labs
software [34] to compute the theoretical pKa values of the studied
structures in the condensed-phase (water). The calculated pKa val-
ues of the morpholinopropyl moiety in the P10 and P20 are the
same (7.4) and are characterized as weak organic bases [17]. For
hydrochloric acid we used an experimentally determined value
Appendix A. Supplementary material
Crystallographic data for the molecules P10, P11, P20 and P22
have been deposited at the Cambridge Crystallographic Data Cen-
tre with the deposition numbers CCDC 760296–760299. Copies
of the data can be obtained free of charge via External link
http://ccdc.cam.ac.uk/retrieving.html. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.molstruc.2010.03.013.
of pKa = ꢂ8.0 [35]. For P11 and P12 the computed
DpKa difference
is very high and the same (15.4), indicating the existence of these
structures in solution in the form of an ionized complex (salt).
Based on the pKa values of the separation between P11 (P22) and
HCl (15.4) and on mixing equimolar quantities in water the con-
centration of the ionized species is about 3 ꢁ 1015. Therefore the
concentration of the ionized species in both cases is about 15 times
greater than the concentration of the non-ionized (neutral) species.
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tions and study the solvent effect of two aromatic sulfonamides
and their hydrochloride salts for which a relatively small amount
of experimental and theoretical physicochemical data exist, given
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via an intramolecular hydrogen bonding system of the
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matic sulfonamides P10 and P20 with HCl form multicompo-
nent crystals. Examination of X-ray data for corresponding
hydrochloride salts showed that the proton resides on the base,
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