3-[1-(4-Sulfamoylphenyl)-5-p-tolyl-1H-pyrazol-3-yl]propanoic acid and 3-[5-(4-bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl]propanoic acid-dichloromethane-diethyl etherwater (2/0.72/1/1)

Article abstract of DOI:10.1107/S010827010901676X

The structures of two related analogues 3-[1-(4-Sulfamoylphenyl)-5-p-tolyl- 1H-pyrazol-3-yl]propanoic acids and 3-[5-(4-bromophenyl)-1-(4-sulfamoylphenyl)- 1H-pyrazol-3-yl]propanoic acid-dichloromathane-diethyl ether-water has been reported. The compound

Full text of DOI:10.1107/S010827010901676X

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
us to synthesize celecoxib analogues and to investigate their
pharmacological properties. In the process of synthesizing
these analogues, we found that a mixture of regioisomers was
possible, identified as 1 and 2 in the scheme below. Efforts to
identify unambiguously the correct regioisomer by hetero-
nuclear multiple-bond correlation (two-dimensional HMBC)
and one-dimensional nuclear Overhauser effect (one-dimen-
sional NOE) NMR spectroscopy were not successful, leaving
single-crystal X-ray diffraction as the only possible means of
unambiguous identification. We report here the structures of
two related analogues, viz. the title compounds, (I) and (II).
ISSN 0108-2701
3-[1-(4-Sulfamoylphenyl)-5-p-tolyl-
1H-pyrazol-3-yl]propanoic acid and
3-[5-(4-bromophenyl)-1-(4-sulfamoyl-
phenyl)-1H-pyrazol-3-yl]propanoic
acid–dichloromethane–diethyl ether–
water (2/0.72/1/1)
Isuru R. Kumarasinghe, Victor J. Hruby and Gary S.
Nichol*
Department of Chemistry, University of Arizona, 1306 E. University Boulevard,
Tucson, AZ 85721, USA
Correspondence e-mail: gsnichol@email.arizona.edu
Received 10 April 2009
Accepted 4 May 2009
Online 16 May 2009
The asymmetric unit of (I) is shown in Fig. 1. The molecular
dimensions are unexceptional and the compound is unam-
biguously regioisomer 1. A mean plane fitted through the
The syntheses of 3-[1-(4-sulfamoylphenyl)-5-p-tolyl-1H-pyra-
zol-3-yl]propanoic acid, C19H19N3O4S, (I), and 3-[5-(4-bromo
phenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl]propanoic
acid–dichloromethane–diethyl ether–water (2/0.72/1/1),
2C18H16BrN3O4Sꢀ0.72CH2Cl2ꢀC4H10OꢀH2O, (II), are regio-
specific. However, correct identification by spectroscopic
techniques of the regioisomer formed is not trivial and
single-crystal X-ray analysis provided the only means of
unambiguous structure determination. Both structures make
extensive use of hydrogen bonding and while compound (I)
forms a straightforward unsolvated Z0 = 1 structure,
compound (II) crystallizes as an unusual mixed solvate, with
two crystallographically unique molecules of the pyrazole
derivative present in the asymmetric unit. The structure of (II)
also features Brꢀ ꢀ ꢀBr interactions.
˚
central pyrazole ring has an r.m.s. deviation of 0.0036 A,
showing it to be essentially planar. The benzenesulfonamide
ring is rotated by 28.73 (9)ꢁ from the plane of the pyrazole
ring, while the tolyl ring is essentially planar (r.m.s. deviation
˚
of a plane fitted through all seven C atoms = 0.0137 A) and is
rotated by 70.26 (6)ꢁ from the plane of the pyrazole ring. The
propanoic acid group has an extended structure but is not
planar, with the C16—C17—C18—O4 torsion angle being
ꢂ138.85 (16)ꢁ, and the r.m.s. deviation of a mean plane fitted
Comment
Nonsteroidal anti-inflammatory drugs are divided into three
different categories, namely classical cyclooxygenase-1
(COX1) inhibitors, cyclooxygenase-2 (COX2) inhibitors and
dual inhibitors (Charlier & Michaux, 2003). In pharmaco-
logical terms, they possess analgesic, anti-inflammatory and
antipyretic effects (Charlier & Michaux, 2003; Antoniou et al.,
2007). COX1 inhibitors were replaced by COX2 inhibitors due
to problems of severe gastrointestinal irritation and renal
impairment experienced by COX1 patients (Copeland et al.,
1995). In the USA, only the COX2 inhibitor celecoxib is
approved for the treatment of various forms of arthritis and
even then the Food and Drug Administration requires a
warning label highlighting the potential of an increased risk of
cardiovascular events (Antoniou et al., 2007). This prompted
Figure 1
The molecular structure of (I), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii.
o296 # 2009 International Union of Crystallography
doi:10.1107/S010827010901676X
Acta Cryst. (2009). C65, o296–o299

organic compounds
Compound (II) crystallizes, unusually, with three separate
and chemically different solvent molecules (dichloromethane,
diethyl ether and water) present in the asymmetric unit, along
with two molecules of the pyrazole derivative itself (Fig. 3).
Thus, Z0 = 1, since this represents the empirical chemical
formula. In the following discussion, reference is made to the
molecule containing atoms Br1–C18 (molecule A), with
details for the molecule containing atoms Br51–C68 (molecule
B) given in square brackets. Both molecules A and B are
unambiguously regioisomer 1.
The presence of three separate solvent molecules is rather
unusual. Diethyl ether and dichloromethane were used for
recrystallization and the identity of the remaining solvent
molecule was established by analysis of difference Fourier
maps, which clearly showed the water H atoms; they are also
involved in hydrogen bonding, which is discussed below. The
source of the water is probably due to using bench, rather than
rigourously dried, solvents for recrystallization. The displa-
cement ellipsoids for dichloromethane are rather large, espe-
cially when compared with the remainder of the structure and
considering that the data were measured at 115 K. In this case,
free refinement of the dichloromethane atom occupancies
suggests that it is only ca 0.72 occupied, consistent with the
observation that the crystals lost solvent when removed from
the mother liquor. This model also yields lower refinement
residuals than a fully ordered model. The presence of three
different solvent molecules is not without precedent. The
Cambridge Structural Database (CSD, Version 5.30 plus two
updates; Allen, 2002) has 21 examples of reported structures
containing diethyl ether, dichloromethane and water solvent
molecules, all of them metal complexes.
Figure 2
Hydrogen-bonding interactions (dotted lines) involving O-atom acceptor
sites in (I).
˚
through atoms C16, C17, C18, O3 and O4 is 0.2287 A. This
mean plane is rotated by 48.01 (8)ꢁ from the plane of the
pyrazole ring.
The crystal packing of (I) involves O—Hꢀ ꢀ ꢀO, N—Hꢀ ꢀ ꢀO,
N—Hꢀ ꢀ ꢀN and C—Hꢀ ꢀ ꢀO hydrogen-bond interactions
(Table 1). Fig. 2 shows the interactions involving O-atom
acceptor sites. There are two discrete motifs (Bernstein et al.,
1995): (i) an R22(10) interaction around an inversion centre
formed by symmetry-related C—Hꢀ ꢀ ꢀO interactions, and (ii)
an R33(11) interaction formed by O—Hꢀ ꢀ ꢀO, N—Hꢀ ꢀ ꢀO and
C—Hꢀ ꢀ ꢀO interactions from three adjacent molecules.
N—Hꢀ ꢀ ꢀN interactions form a large discrete motif involving
sites related by inversion symmetry. Hydrogen bonding
overall forms a three-dimensional hydrogen-bonded structure.
Figure 3
The asymmetric unit of (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. C-bound H atoms
have been omitted.
ꢃ
Acta Cryst. (2009). C65, o296–o299
Kumarasinghe et al.
C19H19N3O4S and 2C18H16BrN3O4Sꢀ0.72CH2Cl2ꢀC4H10OꢀH2O o297

organic compounds
Figure 5
Part of the crystal structure of (II), projected along the c axis. The long a
axis has been truncated. Molecules are coloured according to symmetry
equivalence as in Fig. 4. Dashed lines indicate hydrogen bonds. The
dichloromethane solvent has been omitted. (In the electronic version of
the paper, water is indicated in light purple and diethyl ether is shown in
red. Blue dashed lines indicate hydrogen bonds in the direction of the b
axis, while red dashed lines indicate further hydrogen bonding which
propagates the structure in the c-axis direction.)
Figure 4
An overlay of molecules A (lighter shading) and B (black) in (II), formed
˚
by fitting the pyrazole rings, with an r.m.s. deviation of 0.0072 A.
The molecular dimensions of (II) are unexceptional. A
mean plane fitted through the central pyrazole ring has an
˚
˚
r.m.s. deviation of 0.0018 A [0.0038 A], showing it to be
essentially planar. The benzenesulfonamide ring is rotated by
46.79 (10)ꢁ [48.72 (7)ꢁ] from the plane of the pyrazole ring,
while the bromobenzene ring is essentially planar (r.m.s.
deviation of a plane fitted through the one Br and all six C
Brꢀ ꢀ ꢀBr contacts between two Br atoms bonded to benzyl
rings yielded 741 hits, with an average Brꢀ ꢀ ꢀBr distance of
˚
3.576 A. The Brꢀ ꢀ ꢀBr interactions, propagating along the [101]
direction, link the hydrogen-bonded sheets together to form
the overall crystal structure. Molecules of dichloromethane
are also found between the sheets, although there are no
significant interactions between dichloromethane and adja-
cent molecules.
ꢁ
˚
˚
atoms = 0.0303 A [0.0196 A]) and is rotated by 44.85 (8)
[35.11 (9)ꢁ] from the plane of the pyrazole ring. The propanoic
acid group has an extended planar structure (r.m.s. deviation
of a mean plane fitted through atoms C16, C17, C18, O3 and
˚
˚
O4 = 0.0581 A [0.0403 A]) and the group is rotated by
83.07 (10)ꢁ [24.85 (12)ꢁ] from the plane of the pyrazole ring.
Fig. 4 shows an overlay of the two independent molecules,
formed by fitting the two pyrazole rings, and from this the
differences in the relative orientations of the benzyl rings and
the propanoic acid groups can be clearly seen.
Experimental
The title compounds were synthesized by a two-step procedure. 6-(4-
Bromophenyl)-4,6-dioxohexanoic acid and 4,6-dioxo-6-p-tolylhex-
anoic acid were synthesized according to a modified literature
method (Murray et al., 1991), using NaHMDS in place of LiHMDS;
further details are available in the archived CIF.
The crystal structure makes extensive use of hydrogen
bonding (Table 2), forming a thick two-dimensional hydrogen-
bonded structure. Fig. 5 shows a c-axis projection of part of the
structure, showing how two different hydrogen-bonding
motifs, one R33(11) and one R33(13), allow the structure to
propagate along the b axis. The role of water is crucial here
since it acts as both donor (two O—Hꢀ ꢀ ꢀO interactions) and
acceptor (one N—Hꢀ ꢀ ꢀO interaction), allowing both ring
motifs to form. By contrast, the diethyl ether acts as a space-
filling hydrogen-bond acceptor in a D interaction with one
sulfonamide donor site of molecule B. Further D interactions,
one N—Hꢀ ꢀ ꢀO with sulfonamide as both donor and acceptor
and a second N—Hꢀ ꢀ ꢀO with sulfonamide as donor and an
adjacent propanoic acid group as acceptor, allow the two-
dimensional hydrogen-bonded sheet structure to grow.
Several C—Hꢀ ꢀ ꢀO interactions are also found in (II). Atoms
O3 and O51 are of note, both acting as bifurcated acceptors:
O3 is an acceptor from C8 and C59, and O51 acts as a bifur-
cated acceptor from C15 and C51.
For the preparation of (I), a mixture of 4,6-dioxo-6-p-tolylhexanoic
acid (1.639 g, 7 mmol), 4-sulfonamidophenylhydrazine hydrochloride
(1.56 g, 7 mmol) and Et3N (0.97 ml, 7 mmol) were combined in
MeOH (8 ml) and stirred at room temperature for 6 h. The mixture
was then concentrated in vacuo to a residue which was partitioned
between Et2O (40 ml) and 5% aqueous HCl (12.5 ml). The ether
layer was separated, washed with 5% aqueous HCl (2 ꢄ 10 ml) and
brine (10 ml), dried over Na2SO4, filtered, and concentrated to a
residue. The crude residue was flash chromatographed on silica gel
with a hexane–EtOAc–AcOH (6:2:1) eluant, then recrystallized from
methanol, yielding colourless crystals of (I). For C19H19N3O4S:
calculated mass = 385.4 g molꢂ1 and observed mass (LQ-ESI MS) =
386.1 g molꢂ1
.
For the preparation of (II), a mixture of 6-(4-bromophenyl)-4,6-
dioxohexanoic acid (299 mg, 1 mmol), 4-sulfonamidophenylhydra-
zine hydrochloride (224 mg, 1 mmol) and Et3N (0.1 ml, 1 mmol) were
combined in MeOH (8 ml) and stirred at room temperature for 6 h.
The mixture was then concentrated in vacuo to a residue, which was
partitioned between Et2O (40 ml) and 5% aqueous HCl (12.5 ml).
The ether layer was separated, washed with 5% aqueous HCl (2 ꢄ
10 ml) and brine (10 ml), dried over Na2SO4, filtered, and concen-
trated to a residue. The crude residue was flash chromatographed on
silica gel with a 1:1 eluant of hexane and EtOAc, and recrystallized
The third direction is dominated by Brꢀ ꢀ ꢀBr interactions.
˚
The refined Brꢀ ꢀ ꢀBr distance is 3.5787 (9) A. This is consistent
with data derived from the CSD; a search for nonbonded
ꢃ
o298 Kumarasinghe et al.
C19H19N3O4S and 2C18H16BrN3O4Sꢀ0.72CH2Cl2ꢀC4H10OꢀH2O
Acta Cryst. (2009). C65, o296–o299

organic compounds
from diethyl ether and dichloromethane, yielding colourless crystals
of (II). For C18H16BrN3O4S: yield 0.47 g; calculated mass =
Table 1
Hydrogen-bond geometry (A, ) for (I).
ꢁ
˚
450.31 g molꢂ1 and observed mass (LQ-ESI MS) = 452.0 g molꢂ1
.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
O4—H4Oꢀ ꢀ ꢀO1i
N3—H3Aꢀ ꢀ ꢀN1ii
N3—H3Bꢀ ꢀ ꢀO3iii
C8—H8ꢀ ꢀ ꢀO2iv
0.90 (3)
0.82 (3)
0.85 (3)
0.95 (2)
1.83 (3)
2.16 (3)
2.07 (3)
2.44 (2)
2.705 (2)
2.941 (2)
2.910 (2)
3.167 (2)
164 (3)
160 (2)
170 (2)
133 (2)
Compound (I)
Crystal data
C19H19N3O4S
Mr = 385.43
Triclinic, P1
ꢂ = 101.077 (3)ꢁ
3
Symmetry codes: (i) x þ 2; y þ 1; z; (ii) ꢂx; ꢂy þ 1; ꢂz þ 1; (iii) x ꢂ 1; y ꢂ 1; z.
˚
V = 896.5 (4) A
Z = 2
˚
a = 5.8382 (14) A
˚
Mo Kꢀ radiation
ꢃ = 0.21 mmꢂ1
T = 115 K
0.52 ꢄ 0.25 ꢄ 0.15 mm
b = 12.582 (3) A
˚
Table 2
Hydrogen-bond geometry (A, ) for (II).
c = 13.279 (3) A
ꢀ = 106.928 (3)ꢁ
ꢁ = 97.777 (3)ꢁ
ꢁ
˚
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
Data collection
N3—H3Aꢀ ꢀ ꢀO7
0.84 (3)
0.88 (3)
0.816 (10)
0.84 (3)
0.79 (3)
0.814 (10)
0.86 (4)
0.98 (4)
0.95
0.95
0.95
0.95
0.95
1.97 (3)
2.22 (3)
1.910 (13)
2.21 (3)
2.12 (3)
1.924 (12)
2.02 (4)
2.28 (4)
2.39
2.42
2.43
2.47
2.53
2.796 (4)
3.094 (3)
2.708 (3)
3.028 (3)
2.910 (3)
2.726 (3)
2.874 (3)
3.164 (3)
3.327 (3)
3.364 (3)
3.187 (3)
3.395 (3)
3.443 (3)
166 (3)
170 (3)
165 (3)
165 (3)
172 (3)
169 (3)
171 (3)
149 (3)
169
173
137
164
160
N3—H3Bꢀ ꢀ ꢀO3i
O4—H4Oꢀ ꢀ ꢀN51ii
N53—H53Aꢀ ꢀ ꢀO2iii
N53—H53Bꢀ ꢀ ꢀO70iii
O54—H54Oꢀ ꢀ ꢀN1
O7—H7Aꢀ ꢀ ꢀO53
O7—H7Bꢀ ꢀ ꢀO4iv
C8—H8ꢀ ꢀ ꢀO3iii
Bruker SMART 1000 CCD area-
detector diffractometer
Absorption correction: numerical
(SADABS; Sheldrick, 1996)
Tmin = 0.898, Tmax = 0.989
6690 measured reflections
3300 independent reflections
2824 reflections with I > 2ꢄ(I)
Rint = 0.025
Refinement
C9—H9ꢀ ꢀ ꢀO54iii
C15—H15ꢀ ꢀ ꢀO51v
C52—H52ꢀ ꢀ ꢀO51ii
C59—H59ꢀ ꢀ ꢀO3i
R[F2 > 2ꢄ(F2)] = 0.037
wR(F2) = 0.109
S = 1.06
320 parameters
All H-atom parameters refined
ꢂ3
˚
Áꢅmax = 0.43 e A
ꢂ3
˚
3300 reflections
Áꢅmin = ꢂ0.41 e A
1
3
1
2
1
2
1
2
Symmetry codes: (i) ꢂx þ ; ꢂy þ ; ꢂz þ 1; (ii) x; y ꢂ 1; z; (iii) ꢂx þ ; y þ ; ꢂz þ ;
2
2
(iv) x; y þ 1; z.
Compound (II)
Crystal data
program(s) used to refine structure: SHELXTL; molecular graphics:
ORTEP-3 for Windows (Farrugia, 1997) and Mercury (Version 2.2;
Macrae et al., 2008); software used to prepare material for publica-
tion: SHELXTL and local programs.
2C18H16BrN3O4Sꢀ0.72CH2Cl2ꢀ-
C4H10OꢀH2O
ꢁ = 95.567 (4)ꢁ
3
˚
V = 9283 (5) A
Z = 8
Mr = 1054.11
Monoclinic, C2=c
Mo Kꢀ radiation
ꢃ = 1.98 mmꢂ1
T = 115 K
0.51 ꢄ 0.31 ꢄ 0.05 mm
˚
a = 49.255 (15) A
˚
This work was supported by grants from the United States
Public Health Service and the National Institute on Drug
Abuse. The diffractometer was purchased with funding from
the NSF (grant No. CHE-9610347).
b = 11.702 (3) A
˚
c = 16.181 (5) A
Data collection
Bruker SMART 1000 CCD area-
detector diffractometer
Absorption correction: numerical
(SADABS; Sheldrick, 1996)
Tmin = 0.432, Tmax = 0.908
23405 measured reflections
8605 independent reflections
6781 reflections with I > 2ꢄ(I)
Rint = 0.033
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: FN3023). Services for accessing these data are
described at the back of the journal.
Refinement
References
R[F2 > 2ꢄ(F2)] = 0.037
wR(F2) = 0.105
S = 1.02
8605 reflections
595 parameters
2 restraints
H atoms treated by a mixture of
independent and constrained
refinement
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ꢂ3
˚
Áꢅmax = 0.84 e A
ꢂ3
˚
Áꢅmin = ꢂ0.43 e A
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In (I), all atoms, including H atoms, were freely refined. In (II), O-
and N-bound H atoms were refined with Uiso(H) = 1.2Ueq(O,N), but
without distance restraints. Other H atoms were placed in geome-
trically optimized positions and refined using a riding model with
Uiso(H) = 1.2Ueq(C) or 1.5Ueq(methyl C), and with fixed C—H
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.
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¨
Sheldrick, G. M. (1996). SADABS. Version 2008/1. University of Gottingen,
˚
˚
˚
distances of 0.95 A for aryl, 0.98 A for methyl and 0.99 A for
methylene H atoms. The dichloromethane atom site occupancies
were freely refined to 0.722 (3).
For both compounds, data collection: SMART (Bruker, 2007); cell
refinement: SAINT (Bruker, 2007); data reduction: SAINT;
program(s) used to solve structure: SHELXTL (Sheldrick, 2008);
Germany.
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ꢃ
Acta Cryst. (2009). C65, o296–o299
Kumarasinghe et al.
C19H19N3O4S and 2C18H16BrN3O4Sꢀ0.72CH2Cl2ꢀC4H10OꢀH2O o299