Supramolecular complexes of sulfadiazine and pyridines: Reconfigurable exteriors and chameleon-like behavior of tautomers at the co-crystal-salt boundary

Article abstract of DOI:10.1021/cg301745x

We apply crystal engineering principles to prepare organic co-crystals and salts of sulfadiazine and pyridines. Pyridines are molecular building blocks utilized in crystal engineering that can disrupt the hydrogen bonded (amidine) N-H...N (pyrimidine) dimer within the parent sulfa drug (SD) crystals, while providing access to both co-crystals and salts. We have synthesized four co-crystals and three salts of sulfadiazine involving N,N-dimethyl-4- aminopyridine, 4-aminopyridine, 4-picoline, 4,4′-bipyridine, (E)-1,2-bis(4-pyridyl)ethylene, 1,2-bis(4-pyridyl)acetylene, and 4-(pyridin-4-yl)piperazine. Single-crystal X-ray analyses reveal three hydrogen-bond motifs, namely, dyads, rings, and chains based involving either (amidine/aniline) N-H...N (pyridine/pyrimidine), (pyridinium) ⁺N-H...N^-(amidide), (aniline/piperazine) N-H...O₂S (sulfoxide) interactions, or a combination thereof. The hydrogen-bond motifs are assigned as D1₁(2), R2₂(8), R2₂(20), C2₂(17), and C2₂(13) graph sets. An analysis of the Cambridge Structural Database (CSD) reveals that the S-N bond length is generally shorter in complexes based on an anionic SD, which is consistent with the sulfonamide possessing greater S=N character. From an analysis of SD-based structures involving our work and the CSD, we present a heretofore not discussed role of tautomers at the co-crystal-salt boundary. Specifically, the ability of tautomeric forms of SDs to display reconfigurable exteriors, and thereby act as chameleons, enables SDs to accommodate different co-formers by assuming different geometries and adopting different regions along the co-crystal-salt boundary.

Full text of DOI:10.1021/cg301745x

Article
pubs.acs.org/crystal
Supramolecular Complexes of Sulfadiazine and Pyridines:
Reconfigurable Exteriors and Chameleon-like Behavior of Tautomers
at the Co-Crystal−Salt Boundary
Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju
Elizabeth Elacqua,† Dejan-Kresimir Bucar,† Rodger F. Henry,‡ Geoff G. Z. Zhang,*,§
̌
̌
and Leonard R. MacGillivray*,†
†Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
‡Structural Chemistry, Global Pharmaceutical R&D, Abbott Laboratories, North Chicago, Illinois 60046, United States
§Materials Science, Global Pharmaceutical R&D, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60046, United
States
S
* Supporting Information
ABSTRACT: We apply crystal engineering principles to prepare organic co-
crystals and salts of sulfadiazine and pyridines. Pyridines are molecular building
blocks utilized in crystal engineering that can disrupt the hydrogen bonded
(amidine) N−H···N (pyrimidine) dimer within the parent sulfa drug (SD)
crystals, while providing access to both co-crystals and salts. We have synthesized
four co-crystals and three salts of sulfadiazine involving N,N-dimethyl-4-
aminopyridine, 4-aminopyridine, 4-picoline, 4,4′-bipyridine, (E)-1,2-bis(4-
pyridyl)ethylene, 1,2-bis(4-pyridyl)acetylene, and 4-(pyridin-4-yl)piperazine.
Single-crystal X-ray analyses reveal three hydrogen-bond motifs, namely, dyads,
rings, and chains based involving either (amidine/aniline) N−H···N (pyridine/
pyrimidine), (pyridinium) +N−H···N− (amidide), (aniline/piperazine) N−
H···O2S (sulfoxide) interactions, or a combination thereof. The hydrogen-bond
motifs are assigned as D11(2), R22(8), R22(20), C22(17), and C22(13) graph sets. An
analysis of the Cambridge Structural Database (CSD) reveals that the S−N bond
length is generally shorter in complexes based on an anionic SD, which is consistent with the sulfonamide possessing greater S
N character. From an analysis of SD-based structures involving our work and the CSD, we present a heretofore not discussed role
of tautomers at the co-crystal−salt boundary. Specifically, the ability of tautomeric forms of SDs to display reconfigurable
exteriors, and thereby act as chameleons, enables SDs to accommodate different co-formers by assuming different geometries and
adopting different regions along the co-crystal−salt boundary.
Despite a widespread presence in drugs and related
pharmaceutical compounds, sulfoxides (−SO2) are less studied
in the context of crystal engineering.7 Moreover, whereas a
search of the Cambridge Structural Database (CSD) reveals
that supramolecular synthons exhibit a tendency to compete in
solid-state materials based on sulfonates,8 less is known about
how sulfa drugs (SDs)9 behave in organic co-crystals and
salts.10 SDs are the original class of PAs with an aniline ring
covalently attached to a sulfonamide (SO2NHR) moiety as a
structural core. SDs were the first compounds used to
systematically treat and prevent bacterial and microbial
infections, while thriving on synergistic effects stemming from
a mixture of at least two PAs (e.g., co-trimoxazole: 1:5 mix of
sulfamethoxazole and trimethoprim).11 Owing to a drive by the
field of pharmaceutics to investigate how intermolecular
INTRODUCTION
■
The ability to design multicomponent pharmaceutical crystal-
line materials is based largely on the use of reliable noncovalent
interactions (e.g., hydrogen bonds, π−π forces) between
constituent components in the form of supramolecular
synthons.1 Synthon hierarchies2 are achieved via extensive co-
crystallization3 studies of model pharmaceutical agents (PAs)
with structurally analogous co-formers that can participate in
specific hydrogen-bonding motifs. Caffeine4 and carbamazepine
(CBZ)5 have been utilized as prototypical PAs to identify
robust supramolecular synthons based on (amide) N−H···O
C (amide), (acid) O−H···OC (amide), (acid) O−H···N
(imidazole), and (phenol) O−H···OC (urea) forces in co-
crystals. Whereas the number of supramolecular synthons
employed in crystal engineering continues to rapidly grow,
there remains a need to continue investigating roles of organic
functionalities that can affect processes of drug discovery and
development.6
Received: November 28, 2012
Published: December 5, 2012
© 2012 American Chemical Society
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Article
interactions between drug molecules dictate therapeutic
efficacy, novel solid forms of SDs merit consideration to
develop pharmaceutical co-crystals.12
To efficiently generate multicomponent pharmaceutical
solids, it is of fundamental importance to analyze a target PA,
evaluate how the molecule interacts with itself in the solid state,
and identify dominant supramolecular synthons. In this context,
the SD sulfadiazine (SDZ) possesses both hydrogen-bond-
donor and -acceptor groups that can be targeted to form
multiple synthons (Scheme 1a). SDZ, in the pure form, self-
upon five of Etter’s graph sets.18 The co-formers that preserve
the amidine−pyrimidine dimer, namely, bpe and bpa, also
afford novel “host−guest” solids, wherein the pyridine only
interrupts the formation of secondary N−H···O2S synthons.
From our efforts to investigate the co-crystal−salt continuum
of complexes involving SDs,17 we demonstrate two salient
observations. First, each solid can be classified as a co-crystal or
salt according to the geometry of the sulfonamide. More
specifically, an analysis of our solids along with reported SD
complexes reveals trends between S−N bond length and nature
of complex formed, with longer and shorter S−N bond lengths
being present in neutral and anionic (i.e., salts) SDs,
respectively. Whereas effects of proton transfer on C−O
bond length have, for example, been well-established in
RCO2H/RCO2− systems,19 an analysis of S−N bond geometry
as related to co-crystals and salts has not been reported.
Second, we reveal how tautomers of SDs can play a heretofore
unaddressed role in supporting the formation of co-crystals as
related to the co-crystal−salt continuum.17 Tautomers are
constitutional isomers that rapidly interconvert by a chemical
reaction between two or more forms.20 A tautomeric form of a
molecule can, in principle, be either neutral or charged (i.e.,
cation or anion), while recent reviews suggest that the majority
of tautomers present in the solid state exist as a neutral form.21
Here, we demonstrate that while those tautomers of SDs
isolated in the solid state to date fall within the co-crystal
regime, the geometries of the higher-energy imidine tautomers
lie effectively at the co-crystal−salt boundary.17 From a crystal
engineering perspective, such an observation is consistent with
a SD being able to assume more “salt-like” behavior in order to
achieve a crystal lattice. Moreover, given that different
tautomers of a molecule can also be expected to form different
supramolecular synthons in solids,20 tautomers can be
considered to exhibit chameleon-like behavior in the solid
state by assuming forms that both promote crystal formation
and conform to geometric demands of different co-former
components. We expect the identification of such a role of
tautomers in supporting the formation of co-crystals to extend
our general understanding of the nature of the co-crystal−salt
continuum.
Materials. SDZ (98%) and pico (98%) were purchased
from Alfa Aesar and used without further purification. dmap
(98%), 4-ap (98%), bipy (97%), and bpe (98%) were
purchased from Aldrich Chemical Co. and used after
recrystallization. 4-pypip (97%) was purchased from Matrix
Scientific and used without further purification. bpa was
synthesized according to a literature procedure.22
Single Crystal Preparation. Single crystals of each solid
were obtained by slow evaporation from solution. In a typical
procedure, SDZ (4 mmol) and pyridine (1.0 mol equiv for
monopyridines, and 0.5 mol equiv for bipyridines) were
dissolved in DMF at 85 °C. Single crystals suitable for X-ray
diffraction were grown upon cooling each solution to ambient
temperature and then allowing the solvent to slowly evaporate.
Single crystals formed within a period of approximately 10 days.
Single Crystal X-ray Crystallography. Single crystal X-
ray diffraction experiments were performed on a Bruker
SMART system equipped with an APEX2 CCD camera (co-
formers: pico, bipy, bpe, bpa, 4-pypip), or on a Nonius Kappa
CCD diffractometer (co-formers: dmap and 4-ap). Data was
collected at 100 or 293 K with graphite-monochromated MoKα
radiation (λ = 0.71073 Å). The data were collected and
processed using either SaintPlus23 (co-formers: pico, bipy, bpe,
Scheme 1. Schematic of (a) SDZ and (b) Self-Assembly in
the Solid State Involving Primary (Sulfonamide) N−H···N
(Pyrimidine) and Secondary (Aniline) N−H···O2S
(Sulfoxide) Forces
assembles via a complementary (amidine) N−H···N (pyrimi-
dine) synthon, generating dimers that interact via secondary
(aniline) N−H···O2S (sulfoxide) forces (Scheme 1b).13 Such
two-point interactions are well-documented in the field of
molecular recognition (e.g., amide/acid recognition).14 To
date, multicomponent complexes of SDZ have not been
reported, which is likely owing to a marked low solubility in
common organic solvents relative to other SDs. To achieve
multicomponent solids based on SDZ, the use of a co-former
with appreciably strong hydrogen-bond-donors and/or -accept-
ors able to compete with the hydrogen-bond-accepting
pyrimidine functionality would be preferred to help limit
dimer formation.15
Herein, we report the design and construction of multi-
component crystalline solids of SDZ and a series of mono- and
bipyridines. The solids are achieved using our co-crystal
screening technique based on solution-mediated phase trans-
formation (SMPT).16 The pyridines comprise N,N-dimethyl-4-
aminopyridine (dmap), 4-aminopyridine (4-ap), 4-picoline
(pico), 4,4′-bipyridine (bipy), trans-1,2-bis(4-pyridyl)ethylene
(bpe), 1,2-bis(4-pyridyl) acetylene (bpa), and 4-(pyridin-4-
yl)piperazine (4-pypip) (Scheme 2). The resultant solids
involve both co-crystals and salts that, we show, provide
innovative insights into the co-crystal−salt continuum.17 The
co-crystals and salts are sustained by three primary hydrogen-
bond motifs involving heterodimers, rings, and/or chains based
Scheme 2. Pyridine Co-Formers Employed in Solid-State
Complexes Involving SDZ
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Crystal Growth & Design
Article
bpa, 4-pypip), or a combination of Collect24 and HKL
Scalepack/Denzo25 (co-formers: dmap and 4-ap). All structures
were solved using direct methods that generated non-hydrogen
atoms. All hydrogen atoms were located in Fourier-difference
electron density maps. All non-hydrogen atoms were refined
anisotropically. Hydrogen atoms associated with carbon atoms
were refined in geometrically constrained riding positions.
Hydrogen atoms associated with nitrogen atoms were included
in the located positions. Refinement was achieved with the use
of SHELX-97.26
Cambridge Crystallographic Database Search. The
CSD database survey was accomplished using version 5.32
(including update 5, November 2011) with ConQuest37
(version 1.13). The CSD was searched for mono-N-substituted
sulfonamides comprising a sulfanilamide substructure that
satisfies the following criteria: (a) crystallographic R factor <
0.075, (b) not polymer structure,28 (c) not powder structure,
(d) 3D coordinates fully determined, and (e) purely organic
components.29
stacked SDZ molecules in a R22(20) ring. The N−H group
also participates in a weak hydrogen bond with the SO2 group
(dN···O = 3.34 Å), which lies slightly beyond cited cutoff values
for significant hydrogen bonding.8 Additional π···π interactions
between adjacent aniline rings (dπ···π = 3.23 Å) contribute to the
extended packing (Figure 1b).
(2). 2(SDZ)·3(bipy). Co-crystallization of a 2:1 molar ratio
of SDZ and bipy from DMF produces a co-crystal of 2:3
stoichiometry, respectively. The components crystallize in the
triclinic space group P1 with two molecules of SDZ and three
̅
molecules of bipy in the asymmetric unit. SDZ and bipy
interact via intermolecular (amidine) N−H···N (pyridine) and
(aniline) N−H···N (pyridine) hydrogen bonds. The compo-
nents form a 2D polymer sustained by a chain of sulfonamide
and aniline N−H···N hydrogen bonds, as well as (aniline) N−
H···O2S (sulfoxide) forces based on a C(8) graph set (Figure
2). The N−H···O2S interactions link each SDZ in the
Statistical Analysis of Salts and Co-Crystals. The
regions of those parameters (i.e., S−N length, SNC angle)
that support salt or co-crystal formation were analyzed by
calculating the mean (X) and standard deviation (σ) for each
̅
variable. The calculated σ values for S−N length of each
complex type were generally low in comparison to the range of
observed values (S−N range =0.089 Å; σsalt = 0.007 Å (7.9%);
σco‑crystal = 0.018 Å (20.2%)), the σ values for SNC angle were
much larger (SNC range =9.53°; σsalt = 2.55° (26.8%); σco‑crystal
= 1.83° (19.2%)). The SNC angles displayed more variation;
thus, S−N lengths were used to assess salt and co-crystal
regions. The boundaries for each region are depicted such that
each region represented X 2σ.
̅
RESULTS
■
Seven solid forms of SDZ were realized through screening16
with pyridines. The crystal structure of each solid was
determined using single-crystal X-ray diffraction. Four solids
were determined to be co-crystals, while the remaining three
solids were salts, evidenced by proton transfer. In each SDZ
solid, the sulfonamide crystallizes as either an amidine or
amidide for co-crystals and salts, respectively.
Figure 2. View of 2(SDZ)·3(bipy) showing polymer backbone
(green) and hydrogen bonds.
heteromolecular chain to individual (bipy)-(SDZ)-(bipy)
“bridges” that join two parallel chains, wherein each bipy
participates in a single hydrogen bond with a “free” pyridine in
each unit. The free pyridines interact with the main chain
aniline groups via C−H···N forces (dC···N = 3.38 Å). In each
molecule of bipy, the pyridines are twisted ca. 31−33° from
coplanarity and participate in face-to-face π···π interactions
(dπ···π = 3.35, 3.38, and 3.69 Å) with the stacked bipy molecules.
(3). 2(SDZ)·(bpe). 2(SDZ)·(bpe) crystallizes from DMF in
(1). (SDZ)·(pico). (SDZ)·(pico) crystallizes from neat pico
in the triclinic space group P1 . The asymmetric unit consists of
̅
one molecule of SDZ and one molecule of pico (Figure 1a).
The components interact in a discrete assembly via (amidine)
N−H···N (pyridine) hydrogen bonds that constitute a D11(2)
graph set. The assembly is sustained by intermolecular (aniline)
N−H···N (pyrimidine) interactions between face-to-face
the triclinic space group P1 with one molecule of SDZ and a 1/
̅
2 bpe molecule in the asymmetric unit. SDZ and bpe form a 2D
hydrogen-bonded polymer. The components interact via
intermolecular (aniline) N−H···N (pyridine) hydrogen
bonds, which constitute a D11(2) graph set (Figure 3). The
Figure 1. View of (SDZ)·(pico): (a) primary synthon and (b)
extended structure highlighting (aniline) N−H···N (pyrimidine)
hydrogen bonds and π···π interactions between adjacent aniline rings.
Figure 3. View of 2(SDZ)·(bpe) highlighting: (a) amidine−
pyrimidine dimers and (b) π···π interactions between adjacent
pyrimidine rings and pyridine co-formers.
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sulfonamide -NH group participates in dimer formation with a
second molecule of SDZ that is based on a R22(8) array of
(amidine) N−H···N (pyrimidine) interactions. The NH2 group
of SDZ is involved in an intermolecular N−H···O2S hydrogen
bond. Additional π···π interactions between adjacent pyrimi-
dine rings (dπ···π = 3.63 Å) and stacked pyridines (dπ···π = 3.43
Å) contribute to the extended structure.
(4). 2(SDZ)·(bpa). SDZ and bpa co-crystallize from DMF in
Figure 6. Views of (4-ap+)·(SDZ−): (a) primary interaction and (b)
extended structure.
the triclinic space group P1 with one molecule of SDZ and a 1/
̅
2 bpa molecule in the asymmetric unit. The components form a
2D hydrogen-bonded polymer held together by (aniline) N−
H···N (pyridine) hydrogen bonds. SDZ and bpa assemble
similar to 2(SDZ)·(bpe) wherein adjacent SDZ molecules form
hydrogen-bonded dimers via (amidine) N−H···N (pyrimidine)
forces in a R22(8) ring. The NH2 group of SDZ also participates
in intermolecular N−H···O2S hydrogen bonds (Figure 4).
Additional π···π interactions are present between stacked
pyrimidine (dπ···π = 3.66 Å) and pyridine rings (dπ···π = 3.50 Å).
+
polymer. Intermolecular (pyridinium) N−H···N− (amidide)
and (amine) N−H···O2S (sulfoxide) hydrogen bonds in a
C22(13) chain, as well as (aniline) N−H···O2S (sulfoxide) forces
in a C(8) chain, form a 2D network (Figure 7). The NH2 of
SDZ− is also involved in an array of (aniline) N−H···N
(pyrimidine) hydrogen bonds in a R22(20) graph set.
Figure 4. View of 2(SDZ)·(bpa) highlighting: (a) amidine-pyrimidine
dimers and (b) π···π interactions between adjacent pyrimidine rings
and pyridine co-formers.
(5). (dmap+)·(SDZ−). SDZ and dmap form a salt that
crystallizes in the monoclinic space group P21/n with one
dmap+ cation and one SDZ− anion in the asymmetric unit. The
components form a 2D hydrogen-bonded assembly linked via a
primary intermolecular (pyridinium) +N−H···N− (amidide)
hydrogen bond (Figure 5a). The extended structure is
sustained by intermolecular N−H···O2S interactions, as well
as face-to-face π···π interactions between pyrimidine rings (dπ···π
= 3.29 Å) (Figure 5b).
Figure 7. View of (4-pypip+)·(SDZ−): 2D network of +N−H···N− and
N−H···O2S hydrogen bonds.
DISCUSSION
■
Co-crystallization strategies to disrupt dimer formation and
generate multicomponent solids have been reported with
CBZ.5 The goal was realized using carboxylic acids that act as
stronger hydrogen-bond-donors and compete with CBZ dimer
formation through (acid) O−H···OC (amide) hydrogen
bonds.30 The work involving CBZ suggested to us that a similar
Scheme 3. Approaches to Multicomponent Solids Involving
SDZ and Pyridines: (a) Monopyridyl Co-Formers, (b)
Bipyridyl Co-Formers, and (c) Pyridine Co-Formers with
Hydrogen-Bond-Donor (HD) Groups
Figure 5. Views of (dmap+)·(SDZ−): (a) primary interaction and (b)
extended structure.
(6). (4-ap+)·(SDZ−). SDZ and 4-ap form a salt that
crystallizes from DMF in the monoclinic space group P21/c.
The asymmetric unit consists of one 4-ap+ cation and one
SDZ− anion that assemble via intermolecular (pyridinium)
+N−H···N− (amidide) and (aminopyridine) N−H···O2S
(sulfoxide) hydrogen bonds in a R22(20) ring (Figure 6a).
The components form a 2D polymer with π···π interactions
between pairs of stacked pyrimidine and pyridine rings (dπ···π
=
3.80 Å) (Figure 6b).
(7). (4-pypip+)·(SDZ−). SDZ and 4-pypip form a salt that
crystallizes from DMF in the monoclinic space group P21/n.
The asymmetric unit consists of one 4-pypip+ cation and one
SDZ− anion that self-assemble to form a 3D hydrogen-bonded
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a
Scheme 4. pKa Values of Co-Formers in Relation to SDZ
Figure 9. Co-crystal 3(SDZ)·2(bipy) highlighting: (a) “end-cap” and
(b) “polymer-extending” bipys and secondary interactions with
unbound ends of bipy molecules.
Scheme 7. Schematic of Sulfonamide Geometries in (a)
Anionic and (b) Neutral Forms
a
Red region depicts co-formers that facilitated co-crystal formation
and yellow facilitated proton transfer.
Scheme 5. Finite Graph Sets with Pyridine Co-Formers
(Occurrences in Blue)
Scheme 6. Chains with Pyridine Co-Formers (Occurrences
in Blue)
Figure 10. S−N bond length vs SNC angle for SDZ-based solids.
sulfonamide N−H while breaking the dimer. The relative
acidity of SDZ (pKa = 5.69)31 can facilitate proton transfer to a
pyridine N-atom to disrupt dimer formation.
In this context, an investigation of the CSD revealed 35 co-
crystals and 8 salts that comprise a SD.32 The majority of
structures contain either an (amidine) N−H···OC (carbon-
+
yl) (16 hits) or a (pyrimidinium) N−H···N− (amidide) (8
hits) hydrogen bond as a primary interaction between the
components. Most complexes contain secondary interactions in
the form of N−H···O2S hydrogen bonds between two SD
molecules, which suggested that the sulfoxide group can be
integrated into hydrogen-bonded motifs of supramolecular
complexes of pyridines (Scheme 3c). The sulfoxide has very
recently emerged as a group able to sustain synthon formation
in solids.7c
More specifically, SDZ possesses hydrogen-bond-donor and
-acceptor groups that make the molecule an attractive target for
crystal engineering. The -NH2 and -NH groups are donors,
while the pyrimidine N-atoms and -SO2 group are acceptors.
The relative proximity of the sulfonamide -NH group to both
the acceptor sulfoxide and pyrimidine ring also makes the
molecule exploitable for two-point synthons.14 As stated, two-
point synthons based on (amidine) N−H···N (pyrimidine)
forces sustain the hydrogen-bonded dimer of SDZ. Similar two-
Figure 8. Schematic of interactions in pure SDZ and the “host−guest”
co-crystal with bpa.
strategy could be applied in the case of SDZ and pyridines
(Scheme 3a,b). Specifically, pyridine co-formers would provide
a sufficient hydrogen-bond-acceptor to interact with the
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Table 1. Geometric Parameters for Our and Previously Reported SD-Based Complexes
entry
sulfa drug
co-former
θ/°
d1/Å
co-crystal/salt
reference
1
sulfamethoxypyridazine
sulfadiazine
trimethoprim, H2O
ampyr
125.19
122.55
123.47
118.83
119.43
119.63
122.80
118.20
118.30
123.26
122.63
123.69
121.68
121.38
122.81
120.13
124.22
125.55
125.32
126.23
123.58
126.98
121.40
127.73
125.84
124.74
124.05
126.58
125.92
125.78
125.88
126.54
125.94
126.81
122.79
126.92
127.15
125.65
126.23
124.78
125.49
124.62
125.55
126.18
126.20
124.85
126.54
125.56
126.77
124.39
1.571
1.573
1.573
1.576
1.577
1.581
1.584
1.585
1.585
1.585
1.588
1.593
1.598
1.602
1.608
1.618
1.622
1.623
1.624
1.626
1.627
1.628
1.629
1.634
1.635
1.637
1.641
1.641
1.641
1.642
1.642
1.642
1.643
1.643
1.644
1.644
1.644
1.645
1.646
1.647
1.647
1.648
1.648
1.650
1.651
1.652
1.652
1.656
1.658
1.660
salt
salt
salt
salt
salt
salt
41
2
this work
42
3
sulfamethoxazole
sulfametrole
trimethoprim
4
tetroxoprim, MeOH
tetroxoprim, H2O
tetroxoprim, H2O
4-hydroxybenzamide
tetroxoprim, EtOH
trimethoprim
43
5
sulfametrole
43
6
sulfametrole
43
a
7
sulfamethazine
sulfametrole
co-crystal
10b
43
8
salt
salt
9
sulfametrole
44
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
sulfamethazine
sulfadiazine
4-hydroxybenzamide
4-pypip
co-crystal
10b
this work
this work
41
salt
salt
sulfadiazine
dmap
a
sulfamethoxypyridazine
sulfamethazine
sulfamethazine
sulfamethazine
sulfamethazine
sulfamethazine
sulfamethazine
sulfadiazine
trimethoprim
co-crystal
a
picolinamide
co-crystal
10b
10b
45
a
4-hydroxybenzoic acid
theopylline
co-crystal
ab
,
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
co-crystal
trimethoprim, MeOH
indole-2-carboxylic acid
4-aminosalicylic acid
4-pico
46
47
48
this work
49
sulfamethazine
sulfamethazine
sulfamethazine
sulfadiazine
4-aminobenzoic acid
2,4-dihydroxybenzoic acid
3-hydroxy-2-naphthoic acid
bipy
47
a
10b
this work
10b
50
sulfamethazine
sulfamethazine
5-methoxysulfadiazine
sulfamethazine
sulfamethazine
sulfamethazine
5-methoxysulfadiazine
sulfadiazine
fumaric acid, CH3CN
4-chlorobenzoic acid
acetylsalicylic acid
salicylic acid
51
52
2-aminobenzoic acid
theophylline
49
b
45
(18-C-6), CH3CN
bpe
53
this work
48
sulfamethazine
sulfadiazine
acetylsalicylic acid
bpa
this work
54
sulfapyridine
oxalic acid, dibutyl ester
3,4-dichlorobenzoic acid
sorbic acid
sulfamethazine
sulfamethazine
sulfamerazine
10b
10b
53
(18-C-6), CH3CN
dioxane
5-methoxysulfadiazine
sulfamethazine
sulfamethazine
chlorsulfaquinoxaline
5-methoxysulfadiazine
sulfamethazine
sulfamethazine
N-acetylsufanilamide
sulfamethazine
sulfamethazine
sulfamethazine
sulfaproxyline
55
MeOH
56
trimethoprim, H2O
CH3CN
57
58
THF
55
2,4-dinitrobenzoic acid
salicylic acid
47
59
caffeine
60
benzoic acid
61
c
saccharin
salt
62
1-hydroxy-2-naphthoic acid
caffeine
co-crystal
10b
63
co-crystal
a
b
c
Denotes complexes containing the imidine tautomer of the sulfonamide. Entries found in same crystal structure. Denotes salt containing a
cationic SD and anionic co-former (excluded from geometry study).
point interactions involving pyrimidines are prevalent in the
field of molecular recognition and play a prominent role in
biology.33 The introduction of pyridine co-formers that
compete with dimer formation can also facilitate the formation
of additional intermolecular forces (e.g., (amidine) N−H···O2S
(sulfoxide)). SDZ, thus, represented an attractive model SD for
studies of synthon hierarchies and to generate supramolecular
complexes sustained by different hydrogen-bond patterns.
Co-Crystals and Salts. Given that the pKa of pyridine is
larger than pyrimidine (pKa = −1.3),31 we expected the
pyridine co-formers to interact with the sulfonamide either via
neutral N−H···N interactions or involve proton transfer. Four
of the seven co-formers afforded co-crystals while three
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Crystal Growth & Design
Article
chain, and C22(13) chain (Scheme 5), with the dyads and rings
representative of discrete motifs. The most frequent pattern is a
single interaction between either the amido or amino N−H of
SDZ and the pyridine N-atom, described by the D11(2)
notation. The pattern occurred in four out of seven solids,
with one of three synthons. Specifically, (amidine) N−H···N
(pyridine), (aniline) N−H···N (pyridine), and (pyridinium)
+N−H···N− (amidide) hydrogen bonds comprise the D11(2)
graph set. The R22(8) ring describes the two-point interaction
present between the sulfonamide and pyrimidine ring that
affords the dimer. The two structures that contain the
hydrogen-bonding ring also result in interactions between the
aniline N−H and pyridine N-atom, being classified as D11(2)
notation. The R22(20) ring is present in two different types, each
being promoted by a “bidentate” nature of SDs. Specifically, a
homomolecular ring36 sustained by (amidine) N−H···N
(pyridine) hydrogen bonds is present in (SDZ)·(pico), while
a heteromolecular ring is present in (4-ap+)·(SDZ). The
hydrogen-bond pattern in the salt (4-ap+)·(SDZ−) is based on
Scheme 8. Schematic of Tautomers of SMT
generated salts (Scheme 4). A division of co-crystals and salts
can be assigned using the ΔpKa of the components.17 For the
co-formers, ΔpKa < 0 resulted in co-crystal formation, while
ΔpKa > 0 resulted in proton transfer. Indeed, being able to
recognize combinations of components that exhibit both salt
and co-crystal formation is important when assembling specific
supramolecular architectures, as recently discussed by Aake-
roy.34
̈
Motifs and Graph Sets. There are a wide variety of
commercially available and synthetically accessible pyridines
(pKa pyridine = 5.2)35 that can be used to disrupt dimer
formation of SDZ while supporting the formation of a either a
co-crystal or salt.17 Complexes formed using a wide range of
pyridines would not only provide a means to investigate how
pKa influences co-crystal or salt formation in SD-based solids
but also support different supramolecular synthons in resulting
complexes.
+
an array of (pyridinium) N−H···N− (amidide) and (amine)
N−H···O2S (sulfoxide) forces.
The remaining motif is a heteromolecular chain in
2(SDZ)·3(bipy) (Scheme 6). In the solid, SDZ interacts with
bipy at both hydrogen-bond-donor sites to give a C22(17) chain.
Notably, the salt (4-pypip+)·(SDZ−) demonstrates similar
structural behavior to 2(SDZ)·3(bipy) despite the addition of
a donor site in the form of the piperazine group. Salt formation
results in the 4-pypip+ cation interacting with the strongest two
acceptor sites of SDZ, affording a C22(13) chain. Both structures
also contain homomolecular C(8) chains between aniline N−H
and SO2 groups.9a
While SDZ contains more hydrogen-bond-acceptor than
-donor groups, the use of pyridine co-formers adds to an
imbalance of acceptors and, thus, could be expected to expand
the number and kinds of motifs in the resulting solid-state
complexes.9a In five out of seven solids, the pyridine co-former
interrupted dimer formation. For the co-crystals, the dimer of
SDZ was both disrupted and maintained. Whereas both pico
and bipy disrupted the dimer, solids involving bpe and bpa
maintained the (amidine) N−H···N (pyrimidine) synthon. For
the more basic pyridines (i.e., 4-ap, dmap, 4-pypip), dimer
disruption was accompanied by proton transfer to the pyridine
N-atom.
“Host−Guest” Co-Crystals. In both 2(SDZ)·(bpe) and
2(SDZ)·(bpa), the co-former competed with secondary
hydrogen-bond synthons so as to enable the amidine−
pyrimidine R22(8) ring dimer to be preserved. Both bipyridines,
however, disrupted the formation of N−H···O2S hydrogen
bonds that link pairs of dimers in pure SDZ (Figure 8). Thus,
effectively half of the N−H···O2S interactions were retained in
both solids. Both co-crystals also contain face-to-face π···π
Five different graph sets are ascribed to the solids isolated in
this study, namely, D11(2) dyad, R22(8) ring, R22(20) ring, C22(17)
Figure 11. A plot of S−N bond length vs SNC bond angle for SD-based complexes.
399
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Crystal Growth & Design
Article
interactions between adjacent stacks of dimers that are
analogous to those in pure SDZ, as well as additional π···π
interactions between stacked pyridines. Consequently, the co-
formers are akin to guest molecules within host lattices wherein
the bipyridines are inserted into frameworks that do not disturb
primary interactions in pure SDZ. Surprisingly, the “better
donor” (i.e. amidine N−H) does not form a hydrogen bond
with the “better acceptor” (i.e., pyridine N-atom) in each
solid.37 Energy differences between the two different hydrogen-
bond motifs (e.g., ring dimer and expected chain) may be
minimal and overcome by more favorable close packing forces.
Unexpected Stoichiometry. The co-crystal involving SDZ
and bipy is unexpected in terms of stoichiometry. Specifically,
an as-prepared 2:1 ratio of SDZ and bipy co-crystallized as
2(SDZ)·3(bipy) to give a mixed assembly with both the
amidine N−H group and aniline N−H group participating in
hydrogen bonds. Within the co-crystal, there are two distinct
“classes” of bipy molecules. The first type of bipy participates in
two different N−H···N interactions that extend the polymer
framework (Figure 9a, polymer-extending bipy). The second
type comprises the pendant (bipy)-(SDZ)-(bipy) units and
form hydrogen bonds to the strong donor. The pendant bipy
molecules each contain a pyridyl group that does not
participate in a hydrogen bond. The pyridine unit that serves
to effectively end-cap a polymer chain (Figure 9a, end-cap
bipy). The free pyridyl group, instead, participates in C−H···N
forces with an adjacent SDZ molecule (Figure 9b).
A search of the CSD reveals that free 4-pyridyl groups of bipy
molecules and corresponding co-formers similar to SDZ (i.e.,
contains strong hydrogen-bond donors, such as OH or NH)
have been reported.38 A total of 248 solids are observed with
only 16 (6.45%) that possess a bipy molecule with only one 4-
pyridyl group participating in a hydrogen bond.39 Similar to
2(SDZ)·3(bipy), the bipy molecules will often participate in
weak C−H···N or C−H···π forces.38
Geometry of the Sulfonamide: A CSD Study. Although
SDs are gaining interest as building blocks in crystal
engineering,10 less effort has been extended to compare SD-
based co-crystals and salts involving a series of co-formers.
Having generated both co-crystals and salts of SDZ, we
examined the solids with a view to understand geometric
changes associated with the sulfonamide moiety. Proton
transfer from a SD was expected to result in an increase of
the sp2 character of the sulfonamide N-atom and, thus, lead to a
decrease in the S−N bond length and, concomitantly, smaller
SNR bond angle (i.e. higher SN character) (Scheme 7).
Conversely, co-crystals were expected to exhibit longer S−N
bond lengths and larger SNR bond angles. The geometry of
biologically active sulfonamides has been examined in the gas
phase and compared to the anionic form.40 Computational
studies reveal the sulfonamide group to exhibit partial SN
character upon deprotonation.
of multicomponent solids based on SDZ as being either a co-
crystal or salt.
We next turned to the CSD to examine related SD-based
solids. A search of the CSD revealed 42 multicomponent solids
involving 10 SDs, with 34 (81%) being co-crystals and 8 (19%)
being salts. The majority of co-formers were based on N-
heterocyclic amines (10) and carboxylic acids (18), as well as
amides (4) and xanthines (3). One pyridine, namely,
picolinamide, was employed to generate a co-crystal in the
form of (sulfamethazine)·(picolinamide). The components are
sustained by (amidine) N−H···OC (carbonyl) forces and the
pyridine participates in secondary (alkyl) C−H···N (pyridine)
forces. In 24 complexes, the co-former interacts with the
sulfonamide N−H group via either (amidine) N−H···N
(pyrimidine) or (amidine) N−H···OC (carbonyl) forces in
a two-point interaction.
The S−N bond lengths and SNC angles of our pyridine-
based co-crystals and salts generally fall within the ranges of the
reported SD complexes (Table 1). The S−N bond lengths and
sulfonamide SNC angles of the reported complexes range from
1.56 to 1.67 Å and 118 to 127°, respectively. The larger
differences compared to our SDZ-based solids can be attributed
to the larger variety of co-formers and sample size, since
different SDs and co-formers can be expected to accommodate
a wider array of S−N lengths and SNC angles. Indeed, the SDs
differ in electronic character of the R group (R = pyridazine,
pyrimidine, oxazole, thiadiazole, quinoxaline, and acetyl). The
different R groups are expected to affect delocalization
involving the sulfonamide N-atom, and in turn, affect SN
character.
The SD-based solids in the CSD reveal that the salts exhibit
S−N bond lengths of 1.57−1.60 Å, while co-crystals exhibit S−
N bond lengths of 1.58−1.66 Å. In contrast to our pyridine-
based solids, there is slight overlap in S−N bond distances of
the reported salts and co-crystals from 1.58 to 1.60 Å. The
overlap involves five co-crystals and six salts. The SNC angles
ranged from 118 to 125° for salts and 120 to 128° for co-
crystals. There is, thus, also overlap of SNC bond angles from
120 to 125°. The solids in that region comprise 17 co-crystals
and four salts. As discussed by Childs in the context of C−O
bond length and ΔpKa,17 such an overlap is likely representative
of a boundary between co-crystal and salt formation.
Tautomers in the Co-Crystal−Salt Continuum. From
our analysis of the 34 SD-based co-crystals in the CSD, seven
sulfonamides (∼21%), in contrast to our co-crystals, exist as the
imidine tautomer. The tautomer is present in six of the
sulfamethazine (SMT) co-crystals and one co-crystal of
sulfamethoxypyridazine. Both SDs contain an N-heterocyclic
ring atom adjacent to the sulfonamide and can generate two
tautomers (Scheme 8). Relative energies of tautomeric forms
have been investigated in the case of SMT. DFT calculations
reveal the amidine form to be more stable than the imidine
form by 33.2 kJ mol−1.45 The higher energy of the imidine form
has been attributed to less aromatic character of the adjacent
pyrimidine ring.45 It has also been suggested that secondary
interactions between a co-former and a given sulfonamide will
likely influence whether the imidine amidine tautomer forms in
a co-crystalline solid.10b,45
From our work involving pyridines, the S−N bond lengths
and S−N−C (pyrimidine) angles were different for salts and
co-crystals. The salts exhibited shorter S−N bond lengths with
a range of 1.56−1.60 Å, which is consistent with greater SN
character. The co-crystals exhibited longer S−N bonds with a
range of 1.61−1.65 Å. Additionally, the SNC bond angles were
appreciably smaller for salts (122−124°) as compared to co-
crystals (126−128°). Collectively, the geometry of the
sulfonamide moiety enables the co-crystals and salts reported
here to be delineated (Figure 10). We, thus, conclude that both
S−N bond length and SNC angle can guide the identification
From a geometric standpoint, the seven co-crystals involving
the higher-energy imidine tautomer possess S−N bond lengths
and SNC angles of 1.58−1.63 Å and 120−124°, respectively.
The remaining 28 co-crystals in the CSD, along with our co-
crystals, which are all based upon the amidine tautomer, exhibit
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Crystal Growth & Design
Article
S−N bond lengths of 1.62−1.66 Å. The SNC bond angles of
the amidine co-crystals range from 122 to 128°. In comparison,
our salts and salts present in the CSD exhibit S−N lengths of
1.57−1.60 Å and SNC angles of 118−125°.
lies at the co-crystal−salt boundary. Moreover, we anticipate
that the identification of a role of tautomers to support
multicomponent solids outlined here may provide further
insight on understanding and exploiting the co-crystal−salt
continuum, particularly as related to co-crystal formation.
It is clear from the X-ray data that the ranges of S−N length
for salts and amidine co-crystals do not overlap (Figure 11).
Remarkably, however, effectively all of the S−N lengths of the
imidine − or higher energy tautomer − sit in between the S−N
lengths of salts and the amidine tautomer. The observation is
supported by an analysis of S−N bond lengths of the different
ASSOCIATED CONTENT
* Supporting Information
■
S
Crystallographic information and .cif files of (SDZ)·(pico),
2(SDZ)·(bpe), 2(SDZ)·(bpa), 2(SDZ)·3(bipy),
(dmap+)·(SDZ−), (4-ap+)·(SDZ−), and (4-pypip+)·(SDZ−).
This material is available free of charge via the Internet at
http://pubs.acs.org.
types of complexes. Using the mean (X) S−N length and
̅
standard deviation (σ) for co-crystals and salts, we analyzed the
S−N distribution regions represented by X
2σ. From the
̅
data, the salt region covered a range of 1.571−1.593 Å, while
the co-crystal region covered 1.594−1.673 Å. The range for S−
N bond length of amidine co-crystals was 1.622−1.660 Å; thus,
the imidine−amidine boundary is assigned at 1.622 Å (Figure
11, dashed line). To our knowledge, such a structural
relationship of tautomers as related to the salt−co-crystal
boundary has not been reported.
AUTHOR INFORMATION
Corresponding Author
*E-mail: len-macgillivray@uiowa.edu (L.R.M.); geoff.gz.
zhang@abbott.com (G.G.Z.Z.).
Notes
■
The authors declare no competing financial interest.
Tautomers: Implications in Solids. The co-crystals of
SDs described here (i.e., CSD and our results) reveal that the
geometries of the higher-energy imidine tautomers lie between
the salts and those amidine co-crystals. The positioning means
that the imidine tautomers effectively lie at the co-crystal−salt
boundary. We believe that the relative positioning of the
imidine tautomers can be considered significant owing to the
following. First, different tautomers of the same compound will
exhibit different relative energies. The differences in energy will,
de facto, correspond to forms that exhibit different polarities.64
From semiempirical calculations involving SMT,65 for example,
we have determined the imidine tautomer to exhibit a larger
dipole moment (9.8 D vs 4.9 D) than the amidine tautomer.
From a solid-state chemistry perspective, one can envisage that
a higher energy (i.e., higher dipole) form of a tautomer may
promote the formation of a co-crystal by supporting a more
stable crystal lattice20 or a lattice more akin to that of a salt.
Second, molecules that exhibit tautomeric forms may be
particularly useful to promote co-crystal formation since the
ability to interconvert between forms can accommodate
geometric demands of different co-formers. A molecule that
exhibits tautomeric forms, thus, can augment the crystallo-
graphic landscape66 by increasing the number of possible
synthons able to support a multicomponent solid. Moreover,
the ability of tautomers to exhibit such reconfigurable exteriors,
or display chameleon-like behavior,67 may, in effect, be
employed to the advantage of the crystal engineer so as to
increase the probability of obtaining co-crystals of a given target
molecule.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation (L.R.M.,
DMR-1104650) for financial support.
■
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