Utilizing sulfoxide???iodine halogen bonding for cocrystallization

Article abstract of DOI:10.1021/cg300189v

The propensity of a range of different sulfoxides and sulfones to cocrystallize with either 1,2- or 1,4-diiodotetrafluorobenzene, via I???O=S halogen bonding, was investigated. Cocrystallization occurred exclusively with 1,4-diiodotetrafluorobenzene in ei

Full text of DOI:10.1021/cg300189v

Article
pubs.acs.org/crystal
Utilizing Sulfoxide···Iodine Halogen Bonding for Cocrystallization
Kevin S. Eccles,† Robin E. Morrison,† Stephen P. Stokes,† Graham E. O’Mahony,† John A. Hayes,†
Dawn M. Kelly,† Noel M. O’Boyle,† Laszlo Fabian,‡ Humphrey A. Moynihan,† Anita R. Maguire,§
́
́
́
́
and Simon E. Lawrence*,†
†Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
‡School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, U.K.
§Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork,
Cork, Ireland
S
* Supporting Information
ABSTRACT: The propensity of a range of different sulfoxides and sulfones to
cocrystallize with either 1,2- or 1,4-diiodotetrafluorobenzene, via I···O=S
halogen bonding, was investigated. Cocrystallization occurred exclusively with
1,4-diiodotetrafluorobenzene in either a 1:1 or 1:2 stoichiometry of the
organohalide and the sulfoxide, respectively, depending on the sulfoxide used.
It was found that the stoichiometry observed was not necessarily related to
whether the oxygen acts as a single halogen bond acceptor or if it is bifurcated; with I···π interactions observed in two of the
cocrystals synthesized. Only those cocrystals with a 1:2 stoichiometry exhibit C−H···O hydrogen bonding in addition to I···O=S
halogen bonding. Examination of the Cambridge Structural Database shows that (i) the I···O=S interaction is similar to other
I···O interactions, and (ii) the I···π interaction is significant, with the distances in the two cocrystals among the shortest known.
the Cambridge Structural Database (CSD)14 for halogen
bonding between iodine atoms and the sulfinyl or sulfonyl
INTRODUCTION
Cocrystals have attracted significant interest as novel crystalline
■
materials, particularly within the pharmaceutical industry1 due
functional groups, within organic molecules, yielded 142 hits.
Multicomponent systems account for 58 of these: 47 are salts
to their potential to alter and optimize the physical properties
and 11 are DMSO solvates, including a disordered 1:1 DMSO
of an active pharmaceutical ingredient. The use of strong
solvate with 1,4-diiodotetrafluorobenzene.15
hydrogen bonding involving reliable supramolecular synthons
has recently attracted attention,2 and the utilization of weaker,
noncovalent, interactions is also a developing area.3 In addition,
screening methodologies have been developed to accommodate
this demand, with neat grinding,4 liquid assisted grinding,5 and
sonication6 commonly used.
We were interested in whether the I···O=S synthon could be
utilized for cocrystallization, as outlined in Scheme 1, and if so,
Scheme 1. Hypothesis under Investigation
Halogen atoms are known to form strong, specific, and
directional interactions, termed halogen bonds, which have
been exploited in the development of new solid materials.7 The
strength of a halogen bond is dependent on the halogen atom
involved, although there is some debate about the extent to
which fluorocarbons can participate in halogen bonding.8 The
nature of halogen bonding is greatly influenced by the
electronic features of the functional group with which the
halogen atom is associated.9 For example, the halogen bond
interaction is strengthened upon fluorination of the aryl ring,
which is reflected in a shortening of the halogen bond
distance.10
The use of sulfur functional groups as coformers in
cocrystallization is relatively understudied, although recent
work has shown that the potent hydrogen bond acceptor ability
of the sulfoxide group can be used to form cocrystals with a
range of nitrogen functional groups via N−H···O=S hydrogen
bonds.11 However, there are few reports of cocrystallization
involving organoiodine interactions with sulfur functional
groups specifically as a cocrystal former,12,13 and a search of
what stoichiometry of the coformers would be most frequently
observed? How many iodine atoms, or lone pairs on the oxygen
atom, would be utilized in cocrystal formation, and would these
influence the stoichiometry observed?
EXPERIMENTAL SECTION
Chemicals. The sulfide precursors for compounds ( )-d, ( )-e,
and h (Figure 1) were synthesized according to the literature.16,17
Compounds ( )-d, ( )-e, and l were synthesized using oxone
■
Received: February 8, 2012
Revised: May 8, 2012
Published: May 17, 2012
© 2012 American Chemical Society
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Crystal Growth & Design
Article
oxidation.18 The literature procedure for the synthesis of (R)-d19 was
used. Compounds f and h were synthesized as described below. All
other compounds were purchased from Sigma-Aldrich and used
without further purification, including m-CPBA, which was >77%
purity grade.
1,4-Diiodotetrafluorobenzene/( )-Phenyl 2-Methoxyphenyl
Sulfoxide 1:1 Cocrystal (( )-1e). Solid 1 (0.120 g, 0.30 mmol) and
solid ( )-e (0.070 g, 0.30 mmol) were used. Needle crystals were
obtained in quantitative yield, mp 81−84 °C. IR (KBr) νmax/cm−1:
1017 (S=O).
1,4-Diiodotetrafluorobenzene/Thianthrene 5-Oxide 1:2 Coc-
rystal (1f). Solid 1 (0.120 g, 0.30 mmol) and solid f (0.139 g, 0.600
mmol) were used. Crystalline rods were obtained in quantitative yield,
mp 122−124 °C. Anal. Calcd for C30H16F4I2O2S4: C, 41.58; H, 1.86.
Found: C, 42.00; H, 1.92. IR (KBr) νmax/cm−1: 1031 (S=O).
1,4-Diiodotetrafluorobenzene/Di(2-phenyl)ethyl Sulfoxide
1:2 Cocrystal (1h). Solid 1 (0.120 g, 0.30 mmol) and solid h
(0.154 g, 0.600 mmol) were used. Using ethyl acetate as solvent led to
a mixture of 1h with a slight contamination of both starting reagents 1
and h impurities. For all other solvents investigated, block crystals
were obtained in quantitative yield, mp 72−74 °C. Anal. Calcd for
C38H36F4I2O2S2: C, 49.68; H, 3.95. Found: C, 49.95; H, 3.92. IR
(KBr) νmax/cm−1: 1015 (S=O).
Infrared Spectroscopy. Infrared spectra were recorded on a
Perkin-Elmer 1000 spectrometer in the range of 4000−500 cm−1.
Differential Scanning Calorimetry. Thermal analysis was
recorded on a DSC Q1000 instrument. Samples (2−6 mg) were
crimped in nonhermetic aluminum pans and scanned from 30 to 180
°C at a heating rate of 4 °C min−1 under a continuously purged dry
nitrogen atmosphere.
Elemental Analysis. Elemental analysis was performed by the
Microanalysis Laboratory, University College Cork, on a Perkin-Elmer
240 or an Exeter Analytical CE440 elemental analyzer.
Powder Diffraction. PXRD data were collected using a Stoe Stadi
MP diffractometer with Cu Kα1 radiation (λ = 1.5406 Å) at 40 kV and
40 mA using a linear PSD over the 2θ range of 3.5−45° with a step
size equal to 0.5° and step time of 60 s.
Single Crystal Diffraction. Single crystal data for f, h, 1c, α-
( )-1d, β-( )-1d, ( )-1e, and 1f were collected on a Bruker APEX II
DUO diffractometer, as previously described.11b A Bruker SMART
X2S diffractometer21 was used for (R)-d and 1h. All calculations and
refinements were made using the APEX2 software,22,23 and all
diagrams were prepared using Mercury.24
Thianthrene 5-Oxide (f). A solution of m-CPBA (2.72 g, 12.60
mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h to a stirred
solution of thianthrene (2.16 g, 12.00 mmol) in CH2Cl2 (10 mL) at 0
°C. The reaction mixture was stirred for an additional 2 h at 0 °C,
washed with saturated NaOH solution (1.0 M, 3 × 20 mL) and brine
(3 × 20 mL), dried with MgSO4, and concentrated under reduced
pressure to yield the crude product as a white solid. Purification by
column chromatography with hexane/ethyl acetate (80:20) gave f as a
white solid (2.40 g, 86%), mp 142−143 °C, lit. 143 °C.20 Anal. Calcd
for C12H8OS: C, 62.04; H, 3.47. Found: C, 62.39; H, 3.47. IR (KBr)
νmax/cm−1: 1033 (S=O). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.43
(2H, ddd, J = 7.6, J = 7.6, J = 1.4 Hz, 2 × ArH), 7.55 (2H, ddd; J = 7.6,
J = 7.6, J = 1.1 Hz, 2 × ArH), 7.63 (2H, dd, J = 7.6, J = 1.1 Hz, 2 ×
ArH), 7.87 (2H, dd, J = 7.6, J = 1.4 Hz, 2 × ArH).
Di(2-phenyl)ethyl Sulfoxide (h). A solution of m-CPBA (2.17 g,
15.75 mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h to a
stirred solution of di(2-phenyl)ethyl sulfide (3.63 g, 15.00 mmol) in
CH2Cl2 (10 mL) at 0 °C. The reaction mixture was stirred for an
additional 2 h at 0 °C, washed with saturated NaOH solution (1.0 M,
3 × 20 mL) and brine (3 × 20 mL), dried with MgSO4, and
concentrated under reduced pressure to yield the crude product as a
white solid. Purification by column chromatography with hexane/ethyl
acetate (80:20) gave h as a white solid (3.34 g, 83%), mp 54−58 °C.
Anal. Calcd for C14H14OS: C, 74.38; H, 7.02. Found: C, 74.51; H,
6.98. IR (KBr) νmax/cm−1: 1028 (S=O). 1H NMR (CDCl3, 300 MHz)
δ (ppm): 2.82−3.17 (8H, m, 4 × CH2), 7.20−7.35 (10H, m, 10 ×
ArH).
Neat Grinding. Screening involving mechanical grinding was
employed with subsequent crystallization by slow evaporation from
solution in all caseseven where grinding and IR indicated
cocrystallization had not occurred. Screening was performed initially
with a 1:1 ratio (0.2 mmol) of the coformers. For those experiments
involving the sulfoxides, a 1:2 ratio (organohalide/sulfoxide) was also
investigated. Mechanical grinding experiments were conducted in a
Retsch MM400 Mixer mill, equipped with two stainless steel 5 mL
grinding jars and one 2.5 mm stainless steel grinding ball per jar. The
mill was operated at a rate of 30 Hz for 30 min.
The detailed crystallographic data and structure refinement
parameters for these compounds are summarized in Tables 1 and 2.
Table 1. Crystallographic Data for the Coformers
Solution Cocrystallization. For cocrystallization from solution,
either a 1:1 or 1:2 ratio of the organohalide/sulfoxide, respectively (0.3
mmol), was mixed together in the solid state, dissolved in acetonitrile,
and allowed to stand at ambient temperature until the solvent had
completely evaporated, between 3−9 days. The resulting crystalline
material was analyzed by PXRD, IR, DSC, and, where appropriate,
single crystal X-ray diffraction. For the cocrystals, 1c, ( )-1d, ( )-1e,
1f, and 1h, the possibility of polymorphism was investigated by varying
the solvent system used.
1,4-Diiodotetrafluorobenzene/Diphenyl Sulfoxide 1:1 Coc-
rystal (1c). Solid 1 (0.120 g, 0.30 mmol) and solid c (0.060 g, 0.30
mmol) were used. In all cases, needle crystals were obtained in
quantitative yield, mp 102−106 °C. Anal. Calcd for C18H10F4I2OS: C,
35.79; H, 1.67. Found: C, 36.22; H, 1.76. IR (KBr) νmax/cm−1: 1026
(S=O).
1,4-Diiodotetrafluorobenzene/( )-Phenyl 4-Tolyl Sulfoxide
1:1 Cocrystal, α Form (α-( )-1d). Solid 1 (0.120 g, 0.30 mmol) and
solid ( )-d (0.064 g, 0.30 mmol) were used. Crystalline needles were
obtained from ethanol in quantitative yield, mp 80−82 °C. Anal. Calcd
for C19H12F4I2OS: C, 36.92; H, 1.96. Found: C, 36.96; H, 2.27. IR
(KBr) νmax/cm−1: 1046 (S=O).
1,4-Diiodotetrafluorobenzene/( )-Phenyl 4-Tolyl Sulfoxide
1:1 Cocrystal, β Form (β-( )-1d). Solid 1 (0.120 g, 0.30 mmol) and
solid ( )-d (0.064 g, 0.30 mmol) were used. In all cases prismatic
crystalline blocks were obtained from solutions of acetone, toluene,
acetonitrile, or ethyl acetate, in quantitative yield, mp 60−62 °C. Anal.
Calcd for C19H12F4I2OS: C, 36.92; H, 1.96. Found: C, 36.85; H, 1.81.
IR (KBr) νmax/cm−1 1027 (S=O).
(R)-d
f
h
formula
MW
C13H12OS
216.29
orthorhombic
P212121, 4
5.6947(10)
8.1334(13)
25.063(5)
90
C12H8OS2
232.32
orthorhombic
Fdd2, 8
16.011(3)
32.093(6)
4.0823(8)
90
C16H18OS
258.38
crystal system
space group, Z
a, Å
triclinic
P1, 2
̅
5.5050(5)
9.1593(9)
13.5985(13)
83.769(2)
86.622(2)
84.422(2)
677.57(11)
1.266
b, Å
c, Å
α, deg
β, deg
90
90
γ, deg
V, Å3
Dc, g·cm−3
μ, mm−1
2θ range, deg
T, K
90
90
1160.8(3)
1.238
2097.7(7)
1.471
0.249
0.473
0.224
2.63−25.46
300(2)
9085
2.54−25.88
293(2)
2741
1.51−28.41
100(2)
total ref
unique ref
obs ref, I > 2σ(I)
no. parameters
R1 [I > 2σ(I)]
wR2
16152
2101
907
3351
1688
826
3161
137
73
163
0.0386
0.1029
1.064
0.0296
0.0685
1.1125
0.25(11)
0.0297
0.0816
S
1.063
Flack
0.00(11)
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Table 2. Crystallographic Data for the Cocrystals
1c (1:1)
α-( )-1d (1:1)
β-( )-1d (1:1)
(
)-1e (1:1)
1f (1:2)
1h (1:2)
formula
MW
C18H10F4I2OS
603.85
C19H12F4 I2OS
618.15
C19H12F4 I2OS
618.15
C19H12F4I2O2 S
634.15
C15H8F2IOS
433.23
monoclinic
P21/c, 4
4.1227(7)
27.533(4)
13.440(2)
90
C19H18F2IOS
459.29
crystal system
space group, Z
a, Å
triclinic
monoclinic
P21/c, 4
9.5808(6)
22.0739(15)
9.5433(6)
90
monoclinic
P21/c, 4
14.198(4)
5.8227(17)
24.354(5)
90
triclinic
triclinic
P1, 2
̅
P1, 2
̅
P1, 2
̅
10.2726(19)
10.3038(19)
11.177(2)
113.093(4)
108.007(5)
100.815(5)
968.3(3)
2.072
8.1472(17)
8.474(2)
15.551(4)
99.470(4)
98.137(8)
94.507(4)
1042.6(4)
2.020
5.5989(10)
12.993(3)
13.328(3)
100.050(7)
95.129(7)
95.360 (7)
945.0(3)
1.614
b, Å
c, Å
α, deg
β, deg
91.1500(10)
90
90.205(5)
90
97.344(3)
90
γ, deg
V, Å3
Dc, g·cm−3
μ, mm−1
2θ range, deg
T, K
2017.9(2)
2.035
2013.3(9)
2.039
1513.1(4)
1.902
3.396
3.262
3.270
3.163
2.407
1.826
2.19−25.79
296(2)
1.85−27.12
296(2)
24478
1.67−27.20
296(2)
24206
1.34−26.49
296(2)
47697
1.70−26.50
296(2)
18003
1.56−24.99
300(2)
9328
total ref
unique ref
obs ref, I > 2σ(I)
no. parameters
R1 [I > 2σ(I)]
wR2
21496
3704
4440
4452
4275
3101
3311
2985
3213
3057
3514
2666
2639
235
245
245
254
190
217
0.0265
0.0388
0.0330
0.0365
0.0572
0.1492
1.198
0.0415
0.0590
0.1025
0.0731
0.0942
0.1312
S
1.066
1.025
1.028
1.032
1.142
Figure 1. The organohalides, 1−2, investigated as coformers with the sulfoxides and sulfones, a−l.
Database Analysis of Iodine···π-ring Interactions. The radial
distribution plot (Figure 3) was created from a search of the CSD,
version 5.32 (November 2010), with the ConQuest 1.13 program.25
The following general search flags were set: R factor of ≤0.10, “3D
coordinates determined”, not disordered, no ions, no errors, not
polymeric, and only organic. This search yielded all 1-coordinate
iodine atoms interacting with an aromatic ring, which were within 7.0
Å to the centroid of the ring, and it reported the distance to the
centroid r as well as the orthogonal distance between the iodine atom
and the plane of the aromatic ring h. From h and r, the value of the
centroid shift, s (the in-plane distance between the centroid of the
aromatic ring and the iodine atom) was calculated using Pythagoras’
theorem (r2 = h2 + s2). The radial distribution plot was created by
counting hits in bins of size 0.1 Å × 0.1 Å (h versus s) and scaling the
results by 1/4πr2, where r was the distance between the centroid and
an atom at the center of the bin.
Density Functional Theory Calculations. Density functional
theory (DFT) calculations were carried out using Gaussian0926 and
the M062X hybrid meta functional.27 The 6-31G(d,p) basis set was
used for all atoms apart from iodine, for which the LANL2DZdp
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Table 3. Screening Results for Successful Cocrystal Formation, Based on PXRD Data
coformer
grinding
CH2Cl2
acetone
ethyl acetate
ethanol
acetonitrile
toluene
a
a
b
c
b
d
c
1c
1c
( )-1d
1c
( )-1d
1c
1c
( )-1d
1c
1c
( )-1d
e
a,
e
a
,
f
b,
e
c
,
f
b
,
f
d,e
( )-d
( )-1d
( )-1d
( )-1d
a
c
c
d
( )-e
( )-1e
not attempted
a
( )-1e
a
not attempted
( )-1e
c
( )-1e
c
( )-1e
i
g
c
,
h
f
1f
1f
1f
1f
1f
1f
1f
j
a
a
c
,
k
c
c
l
h
1h
1h
1h
1h
1h
1h
1h
a
b
c
d
e
f
Left to stand for 2 days. Left to stand for 5 days. Left to stand for 4 days. Left to stand for 9 days. Exclusively the α-( )-1d polymorph. Mixture
g
h
of α-( )-1d and β-( )-1d polymorphs. Mixture of 1 and f using 1:1 stoichiometry; 1:2 stoichiometry gave exclusively 1f. Mixture of 1f and small
amount of coformers. Left to stand for 8 days. Mixture of 1 and h using 1:1 stoichiometry; 1:2 stoichiometry gave exclusively 1h. Mixture of 1h
and small amount of coformers. Left to stand for 7 days.
i
j
k
l
pseudopotential and basis set was used28 (taken from the EMSL basis
in either a discrete (capping) arrangement with the iodine
set exchange29). After geometry optimization, structures were verified
to be at a minimum by the absence of an imaginary frequency, and all
energies were corrected for zero-point error. The systems containing
both coformers were optimized using the counterpoise correction to
account for basis set superposition error. Wiberg bond orders were
calculated using the NBO program (as part of Gaussian09).30
atoms, or a bifurcated arrangement.31
The initial screening was performed via neat grinding of an
equimolar mixture of the two coformers in the mill for 30 min
at 30 Hz, and the material generated was analyzed using PXRD.
In addition, the individual components were dissolved in a
range of solvents, and solution crystallization, via slow
evaporation, was undertaken. The reasons for this were two-
fold: (i) for comparison with the grinding experiments and (ii)
to obtain crystals suitable for single crystal X-ray diffraction
analysis. The results of the successful grinding experiments and
the solution crystallization experiments, based on PXRD data,
are presented in Table 3. In all cases the results from the
grinding experiments were consistent with those obtained from
solution crystallization, with cocrystallization observed in five
combinations of 1 and the sulfoxide, namely the cocrystals 1c,
( )-1d, ( )-1e, 1f, and 1h. There was no evidence for
cocrystallization involving 2 or any of the sulfones (i−l) in this
study.
In combination with PXRD, IR and DSC were used to
confirm cocrystal formation, as well as to aid in the
determination of stoichiometric composition. DSC analysis
was undertaken on the material obtained from the grinding
experiments. In addition to the presence of new crystalline
material, melting events due to 1 were observed in the samples
involving f and h that were obtained by grinding, indicating the
formation of cocrystals containing an excess of the sulfoxide
coformer. Table 4 lists the melting points and the changes in
the ν(S=O) stretching frequency for those combinations of
coformers that gave rise to successful cocrystallization. A
decrease in the melting point was observed for all complexes
relative to that of the highest coformer. This is consistent with
the major trend found in the melting point of cocrystals,
whereby the melting point of the cocrystal is between the
melting points of the two coformers.32
In all cocrystals a bathochromic shift in the S=O stretching
frequency relative to that of the sulfoxide starting material was
observed. There is a red shift seen for 1c, α-( )-1d, ( )-1e, 1f,
and 1g relative to that of the starting material, which is due to
halogen bonding interactions between the halogen atom and
the sulfoxide oxygen, leading to a decrease in the sulfoxide
bond order and, hence, a decrease in the sulfoxide stretching
frequency upon complexation. Similar effects have been seen
involving hydrogen bonding to sulfoxides and sulfona-
mides.11,37
To investigate the S=O···I interaction further, gas-phase DFT
calculations were carried out on two coformer pairs, 1 with c,
and 1 with e, using the M062X hybrid functional, as well as on
the individual sulfoxides (Table 5). The calculations indicate a
slight increase in the S=O bond length and a corresponding
RESULTS AND DISCUSSION
Cocrystallization screening investigated 1,4-diiodotetrafluoro-
benzene, 1, with a range of sulfoxides and sulfones, a−l as
■
Table 4. Melting Point, °C, and ν(S=O), cm−1, for Cocrystals
Formed in This Work
a
sulfoxide coformers
cocrystals
ν(S=O),
ν(S=O),
mp, °C
cm−1
mp, °C
cm−1
c
70−7134
103734
1c
102−106
80−84
60−62
81−84
122−124
72−74
1026
1013
1028
1017
1031
1015
( )-d
64−6535
1015
α-( )-1d
β-( )-1d
( )-1e
1f
( )-e
98−9936
142−14320
54−58
103236
1033
f
h
1028
1h
mp of 1 is 108−110 °C.33
a
Table 5. Calculated and Experimental Parameters for Two
Cocrystals, 1c and 1e, and the Corresponding Sulfoxide
Coformers
c
e
calcd
exptl
calcd
exptl
O···I distance, Å
S=O···I angle, deg
2.835
119
2.851(2)
2.820
124
2.815(4)
124.1(2)
122.75(14)
interaction energy, kJ/mol 4.9
30.1
S=O in sulfoxide
S=O in cocrystal
1.506
1.4953(12)38
1.491(3)
1.507
1.518
1.21
unknown
1.483(4)
1.517
1.22
S=O bond order in
sulfoxide
S=O bond order in
cocrystal
1.17
1.17
shown in Figure 1. The 1,2- analogue, 2, was investigated with
the sulfoxides a, c, g, and h. The sulfoxides and sulfones were
specifically chosen to minimize competing intermolecular
interactions and, thereby, maximize the likelihood of the
desired I···O=S synthon prevailing. At the outset, it was
anticipated that cocrystals with either a 1:1 or 1:2 stoichiometry
could be possible because (i) either one or both iodine atoms
are available for halogen bonding and (ii) the lone pairs on each
oxygen atom allow the oxygen atoms to potentially participate
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Table 6. Details of the Intermolecular Interactions Observed in the Cocrystals
a
cocrystal
stoichiometry
1:1
nature of interaction
distance,
Å
angle at I, °
angle at O, °
no. of interactions with O
1
1c
I···O
I···π
2.851(2)
172.46(7)
122.75(14)
b
c
3.38
76.00
α-( )-1d
β-( )-1d
( )-1e
1f
1:1
1:1
1:1
1:2
1:2
I···O
I···O
I···O
I···π
I···O
I···I
I···O
C−H···O
I···O
3.096(4)
2.912(4)
2.850(3)
160.99(16)
178.10(14)
172.05(12)
139.17(19)
103.03(17)
159.79(18)
2
1
1
2
2
b
c
3.46
75.48
2.815(4)
178.50(15)
170.27(16)
175.5(3)
124.1(2)
d
3.8577(9)
2.857(6)
105.80(12)
123.3(4)
e
f
2.51
168
1h
2.985(3)
173.71(11)
119.75(13)
g
f
C−H···O
2.47
154
Note that the sum of the van der Waals radii is 3.50 Å.31 The distance from the I to the plane of the benzene ring. The angle between the C−I
bond and the plane of the benzene ring. The angle at the 2nd I. This is the H···O distance; the C···O distance is 3.421(10) Å. The angle
subtended at the H. This is the H···O distance; the C···O distance is 3.372(4) Å.
a
b
c
d
e
f
g
Figure 2. 2:2 arrangement of coformers found in 1c.
All cocrystals were grown from multiple solvents to
investigate the potential for stoichiometric or polymorphic
cocrystals. In all cases the neat grinding and solution
crystallization matched the theoretical pattern obtained from
single crystal analysis, as detailed in the Supporting
Information. All cocrystals grown from the solution crystal-
lization experiments exhibited a single endotherm in the DSC,
consistent with the data presented in Table 4.
The crystal structures of three coformers, (R)-d, f, and h,
were unknown at the start of this work, and so these were
determined to help with PXRD identification of any possible
cocrystals (see the Supporting Information). There is
significant similarity between the structure of the monosulf-
oxide f and the α form of the related bissulfoxide, cis-
thianthrene-5,10-dioxide, which is in the CSD with no 3D
coordinates (refcode: TANTOX).39 Consideration of the
reduced cell, the microanalysis data, and the melting points20,40
(see the Supporting Information) strongly suggests that the
unit cell of cis-thianthrene 5,10-dioxide in the CSD is actually
that of the monosulfoxide, f, although the possibility that they
are (almost) isostructural cannot be ruled out.
The crystal structure of the cocrystal 1c shows a 1:1
Figure 3. Radial distribution plot of I···π interactions in the CSD. The
y axis shows the height of the iodine atom above the plane of the
phenyl ring, while the x axis indicates the distance between the iodine
atom and the centroid of the phenyl ring, measured in the plane of the
ring. The interactions observed in the structures of 1c and β-( )-1d
are also included and are indicated by the arrows. The total number of
interactions depicted is 6,645, which were obtained from a total of 839
crystal structures.
stoichiometry of the two coformers. As anticipated, halogen
bonding is observed between the iodine and the oxygen of the
sulfoxide group (Table 6). The oxygen atom does not interact
in a bifurcated manner, as may be expected from the 1:1
stoichiometry. Instead, the second iodine atom is involved in
I···π bonding with the phenyl ring of the sulfoxide. Together,
these two halogen interactions combine to form discrete 2:2
molecular complexes (Figure 2).
The I···π interactions observed in the structure of 1c are also
observed in that of β-( )-1d, as detailed in Table 6. Therefore,
a search of the CSD was undertaken and the results analyzed
small decrease in the S=O bond order, upon cocrystallization,
which is consistent with the IR data. The overall interaction
energy is quite low for 1 with c but appreciable for 1 with e.
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Figure 4. I···O=S interactions present in α-( )-1d.
Figure 5. I···O=S and I···π interactions present in β-( )-1d.
Figure 6. I···O=S and I···I interactions present in ( )-1e.
Figure 8. Zigzag C(6) hydrogen-bonded chain present in cocrystal 1f.
interactions are shown as a radial distribution plot (Figure 3)
with the location of the I···π interactions from structures 1c and
β-( )-1d highlighted in relation to those found in the CSD.
Both interactions have among the shortest centroid to iodine
distances found for a particular angular location from the ring
centroid.
The cocrystal ( )-1d forms two polymorphs of 1:1
stoichiometry. Crystals grown from ethanol gave rise to the α
form, α-( )-1d, in which the iodine forms the intended I···O=S
interaction, although in this case the oxygen is bifurcated
between neighboring molecules of 1, resulting in an infinite
zigzag chain (Figure 4). The packing in this crystal structure is
Figure 7. Halogen interactions in cocrystal 1f.
using the method described by Bissantz,41 who had examined
F···π and Cl···π interactions. The results observed for the I···π
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Figure 9. Packing in 1f, viewed along the c-axis.
Figure 10. Halogen bonds bridging the sulfoxides in 1h, left, and the C(4) chain between sulfoxides, right.
The crystal structure of ( )-1e shows a 1:1 stoichiometry of
the two coformer components. The asymmetric unit consists of
one molecule of ( )-e and two crystallographically unique half
molecules of 1, both located over an inversion center.
The iodine of one molecule of 1 forms a halogen bonding
interaction to the oxygen of the sulfoxide, so that the molecule
of 1 is capped by two sulfoxide molecules, forming a linear
three-molecule motif. The other molecule of 1 bridges
neighboring motifs via I···I halogen bonding (Figure 6).
Notably, there is no significant interaction with the oxygen of
the methoxy group.
The 1:2 cocrystal 1f crystallizes with 1 located over the
inversion center. The anticipated halogen bonding between the
iodine and the oxygen of the sulfoxide group is observed (Table
6 and Figure 7). The oxygen acts in a bifurcated fashion, with
additional weak hydrogen bonding to one of the aryl protons,
forming a zigzag C(6) chain along the c-axis (Figure 8). Thus,
the structure consists of chains of sulfoxide molecules linked
together by the halogen-substituted aromatic molecules (Figure
9). The crystal structure of 1f provides further evidence that the
crystal structure of f is correct, as it is highly unlikely that
grinding of the bissulfoxide with 1 would result in a loss of
oxygen in forming 1f. This was investigated by grinding a
sample of f in the absence of 1, which showed no change to the
material, as evident from DSC, microanalysis, and PXRD. Of all
the cocrystals formed in this work, 1f is the only one that
exhibits some instability; in the solid state it decomposes into
the two coformers in approximately 2 weeks in ambient
conditions.
Figure 11. Plot of S=O···I angle versus I···O distance for S=O···I
halogen bonding found in these cocrystals (red) and the crystal
structures deposited in the CSD (blue).
similar to that seen in the cocrystal between 1 and triphenyl
phosphine oxide, of which one form is known.31
Crystals grown from acetonitrile gave rise to the β form, β-
( )-1d, which displays the anticipated I···O=S halogen
bonding (Table 6). Similar to the crystal structure of 1c, it
consists of the oxygen interacting with one iodine atom, as well
as I···π bonding involving the phenyl ring of the sulfoxide
(Figure 5). However, there is a difference in the overall packing,
with the formation of infinite linear chains rather than the
discrete 2:2 complex seen in 1c. The α polymorph is obtained
from solutions of CH2Cl2, ethyl acetate, or toluene. A mixture
of both polymorphs is initially obtained from acetone,
acetonitrile, or ethanol solutions, as evidenced by DSC and
PXRD. The harvested crystals converted to the α polymorph
after standing at room temperature over a period of two
months. It was concluded that the β polymorph is metastable
with respect to the α polymorph.
The crystal structure of 1h is similar to that of 1f, as it too
has a 1:2 stoichiometry. The molecule of 1 lies over the
inversion center, and the sulfoxide acts in a bifurcated manner,
exhibiting both halogen bonding and weak hydrogen bonding
(Figure 10). In 1h the protons α to the sulfoxide are involved in
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weak hydrogen bonding, forming C(4) chains in a similar
manner to that seen in the structure of the parent sulfoxide, h
(see the Supporting Information). Such interactions have been
shown to be structure-directing in sulfoxides.42 The combina-
tion of halogen interactions and weak hydrogen bonds results
in infinite 1D ladders in which the C(4) chains are bridged by
the iodine species.
Examination of the CSD showed that the S=O····I halogen
bonding in these cocrystals is similar to those found in other
crystal structures present in the CSD (Figure 11).
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray crystallographic information in CIF format, DSC and
PXRD data, optimized coordinates from DFT calculations, and
additional figures. This material is available free of charge via
the Internet at http://pubs.acs.org. The crystallographic data
for (R)-d, f, h, 1c, α-( )-1d, β-( )-1d, ( )-1e, 1f, and 1h have
been deposited with the Cambridge Crystallographic Data
Centre, CCDC numbers 863887−863895. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
CONCLUDING REMARKS
■
AUTHOR INFORMATION
■
Cocrystallization involving I···O=S halogen bonding was
successful for five of the nine sulfoxides studied, in all cases
with the para-substituted organohalide, 1. This may not be
surprising; there are more reports of 1 being used in halogen
bonding studies than 2. For all cocrystals, the I···O
intermolecular interaction was the dominant interaction in all
cases, with a distance range of 2.82−3.09 Å, indicating strong
halogen bonding. The length and directionality of the halogen
bonds is consistent with the literature.7a In all cases the
organohalide molecule bridges the sulfoxide molecules.
Both 1:1 and 1:2 stoichiometries, of 1 and sulfoxide
respectively, are observed; for the latter case, this was always
seen with a combination of both halogen bonding and weak
hydrogen bonding. Despite the presence of the robust I···O=S
synthon, it was found that it is the weak hydrogen bonding that
is significant in determining the 3D architectures observed in
the solid state. The stoichiometry observed is not necessarily
related to whether the oxygen acts in a discrete fashion or if it is
bifurcated, with I···π interactions observed in two of the
cocrystals examined.
Two of the sulfoxides that did not cocrystallize with 1, a and
b, have melting points just above ambient temperature. A third,
g, is more interesting for two reasons: first, it crystallizes with Z′
= 2,11,43 and compounds with high Z′ have been shown to be
good coformers,44 although this is best used to indicate likely
candidates for cocrystallization, as it is an empirical observation.
Second, the chemical structure of g is closely related to that of c
and h, both of which did form cocrystals. The enantiopure
sulfoxide (R)-d did not form a cocrystal with 1.
Corresponding Author
*E-mail: s.lawrence@ucc.ie. Tel.: +353 21 490 3143. Fax: +353
21 427 4097.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland, under
Grant Nos. 07/SRC/B1158 (K.E., S.S., J.H., D.K.), 05/PICA/
B802 TIDA 09 (L.F.), and 05/PICA/B802/EC07; the Irish
Research Council for Science, Engineering and Technology
(G.O'M.), and a Health Research Board Career Development
Fellowship PD/2009/13 (N.O'B.). We thank the SFI/HEA
Irish Centre for High-End Computing (ICHEC) for the
provision of computational facilities.
REFERENCES
■
(1) (a) Trask, A. V. Mol. Pharmaceutics 2007, 4, 301−309. (b) Shan,
N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440−446.
(2) (a) Aakeroy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439−
̈
448. (b) Stahly, G. P. Cryst. Growth Des. 2009, 9, 4212−4229.
́ ́
(3) Fabian, L. Cryst. Growth Des. 2009, 9, 1436−1443.
(4) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41−70.
(5) (a) Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M.
J. Cryst. Growth Des. 2009, 9, 1106−1123. (b) Trask, A. V.;
Motherwell, W. D. S.; Jones, W. Chem. Commun. 2004, 890−891.
(6) McCausland, L. PCT Int. Appl. WO2007075793, 2007.
(7) (a) Rissanen, K. CrystEngComm 2008, 10, 1107−1113.
(b) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem.
Res. 2005, 38, 386−395. (c) Sarma, J. A. R. P.; Allen, F. H.; Hoy, V. J.;
Howard, J. A. K.; Thaimattam, R.; Biradha, K.; Desiraju, G. R. Chem.
Commun. 1997, 101−102. (d) Thallapally, P. K.; Desiraju, G. R.;
Bagieu-Beucher, M.; Masse, R.; Bourgogne, C.; Nicoud, J.-F. Chem.
Commun. 2002, 1052−1053.
Cocrystallization was not observed with any of the sulfones
studied, which, similar to the results of other studies,11 suggests
that the increased polarity of the sulfoxide functional group, in
comparison with the sulfone functional group, is a significant
contributor to the strength of the intermolecular interactions
that promote cocrystal formation.
(8) (a) Chopra, D. Cryst. Growth Des. 2012, 12, 541−546.
(b) Chopra, D.; Nagarajan, K.; Guru Row, T. N. J. Mol. Struct.
2008, 888, 70−83. (c) Thakur, T. S.; Kirchner, M. T.; Blaser, D.;
̈
In conclusion, cocrystals between 1,4-diiodotetrafluoroben-
zene and sulfoxides show that I···O=S halogen bonding is a
robust supramolecular synthon and merits further attention.
For each of the cocrystals formed in this work, there were two
significant noncovalent interactions present, regardless of the
stoichiometry found in the cocrystals. For the 1:1 cocrystals,
there were three sets of significant intermolecular interactions
observed: (i) two I···O=S halogen bonds, or (ii) one I···O=S
halogen bond, and one I···π interaction, or (iii) one I···O=S
halogen bond and one I···I interaction. For the 1:2 cocrystals,
one I···O=S halogen bond is seen in conjunction with one weak
C−H···O hydrogen bond.
Boese, R.; Desiraju, G. R. CrystEngComm 2010, 2079−2085.
(d) Dikundwar, A. G.; Guru Row, T. N. Cryst. Growth Des. 2012,
12, 1713−1716.
(9) Weiss, R.; Schwab, O.; Hampel, F. Chem.Eur. J. 1999, 5, 968−
974.
(10) Aakeroy, C. B.; Schultheiss, N. C.; Rajbanshi, A.; Desper, J.;
̈
Moore, C. Cryst. Growth Des. 2009, 9, 432−441.
(11) (a) Eccles, K. S.; Elcoate, C. J.; Stokes, S. P.; Maguire, A. R.;
Lawrence, S. E. Cryst. Growth Des. 2010, 10, 4243−4245. (b) Eccles, K.
S.; Elcoate, C. J.; Maguire, A. R.; Lawrence, S. E. Cryst. Growth Des.
2011, 11, 4433−4439.
(12) Arman, H. D.; Gieseking, R. L.; Hanks, T. W.; Pennington, W.
T. Chem. Commun. 2010, 46, 1854−1856.
2976
dx.doi.org/10.1021/cg300189v | Cryst. Growth Des. 2012, 12, 2969−2977

Crystal Growth & Design
Article
(13) Cinci
753.
̌
c,
́
D.; Frisc
̌
i
̌
c,
́
T.; Jones, W. Chem.Eur. J. 2008, 14, 747−
(41) Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061−
5084.
(42) Brondel, N.; Moynihan, E. J. A.; Lehane, K. N.; Eccles, K. S.;
Elcoate, C. J.; Coles, S. J.; Lawrence, S. E.; Maguire, A. R.
CrystEngComm 2010, 12, 2910−2927.
(43) (a) Fuller, A. L.; Aitken, R. A.; Ryan, B. M.; Slawin, A. M. Z.;
Woollins, J. D. J. Chem. Crystallogr. 2009, 39, 407−415. (b) Zeng, Y.
X.; Xu, Z. G.; Zhan, Q. G.; Liu, H. Y. Acta Crystallogr. 2011, E67, o177.
(44) Anderson, K. M.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des.
2008, 8, 2517−2524.
(14) Allen, F. H. Acta Crystallogr. 2002, B58, 380−388.
(15) Britton, D. Acta Crystallogr. 2003, E59, o1332−1333.
(16) Xu, H. J.; Zhao, X. Y.; Fu, Y.; Feng, Y. S. Synlett 2008, 19,
3063−3067.
(17) Eccles, K. S.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R.
ARKIVOC 2010, ix, 216−228.
(18) Hirano, M.; Tomaru, J.; Morimoto, T. Bull. Chem. Soc. Jpn.
1991, 64, 3752−3754.
(19) Drabowicz, J.; Bujnicki, B.; Mikołajczyk, M. J. Org. Chem. 1982,
47, 3325−3327.
(20) Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1955, 77,
3387−3389.
(21) Eccles, K. S.; Stokes, S. P.; Daly, C. A.; Barry, N. M.;
McSweeney, S. P.; O’Neill, D. J.; Kelly, D. M.; Jennings, W. J.; Ní
Dhubhghaill, O. M.; Moynihan, H. A.; Maguire, A. R.; Lawrence, S. E.
J. Appl. Crystallogr. 2011, 44, 213−215.
(22) APEX2 v2009.3-0; Bruker AXS: 2009.
(23) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122.
(24) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.;
McCabe, P.; Pidock, E.; Rodriguez-Monge, L.; Taylor, R.; van de
Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470.
(25) Bruno, I. J.; Cole, J. C.; Edgington, P. R.; Kessler, M.; Macrae, C.
F.; McCabe, P.; Pearson, J.; Taylor, R. Acta Crystallogr. 2002, B58,
389−397.
(26) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
̈
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision B.1; Gaussian, Inc.: Wallingford, CT, 2009.
(27) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.
(28) Check, C. E.; Faust, T. O.; Bailey, J. M.; Wright, B. J.; Gilbert, T.
M.; Sunderlin, L. S. J. Phys. Chem. A 2001, 105, 8111−8116.
(29) Schuchardt, K. L.; Didier, B. T.; Elsethagen, T.; Sun, L.;
Gurumoorthi, V.; Chase, J.; Li, J.; Windus, T. L. J. Chem. Inf. Model.
2007, 47, 1045−1052.
(30) NBO Version 3.1. Glendening, E. D.; Reed, A. E.; Carpenter, J.
E.; Weinhold, F.
(31) Cinci
3224−3231.
̌ ́ ̌ ̌ ́
c, D.; Friscic, T.; Jones, W. CrystEngComm 2011, 13,
(32) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950−
2967.
(33) Syssa-Magale,
́
J. L.; Boubekeur, K.; Palvadeau, P.; Meerschaut,
A.; Schollhorn, B CrystEngComm 2005, 7, 302−308.
̈
(34) Oae, S.; Zalut, C. J. Am. Chem. Soc. 1960, 82, 5359−5363.
(35) Noguchi, Y.; Kurogi, K.; Sekioka, M.; Furukawa, M. Bull. Chem.
Soc. Jpn. 1983, 56, 349−350.
(36) Meyers, C. Y. Gazz. Chim. Ital. 1963, 93, 1206−1221.
(37) Goud, N. R.; Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11,
1930−1939.
(38) Casarini, D.; Lunazzi, L.; Mazzanti, A. Angew. Chem., Int. Ed.
2001, 40, 2536−2540.
(39) Hosoya, S.; Wood, R. G. Chem. Ind. (London) 1957, 1042.
(40) Bonchio, M.; Conte, V.; De Conciliis, M. A.; Di Furia, F.;
Ballistreri, F. P.; Tomaselli, G. A.; Toscano, R. M. J. Org. Chem. 1995,
60, 4475−4480.
2977
dx.doi.org/10.1021/cg300189v | Cryst. Growth Des. 2012, 12, 2969−2977