Hydrogen-bonding directed cocrystallization of flexible piperazine with hydroxybenzoic acid derivatives: Structural diversity and synthon prediction

Article abstract of DOI:10.1007/s11426-011-4487-4

Four hydroxybenzoic acid building blocks, m-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, and 5-hydroxyisophthalic acid, have been synthesized as robust cocrystallizing agents and employed in reactions with piperazine, in

Full text of DOI:10.1007/s11426-011-4487-4

SCIENCE CHINA
Chemistry
July 2012 Vol.55 No.7: 1228–1235
doi: 10.1007/s11426-011-4487-4
• ARTICLES •
Hydrogen-bonding directed cocrystallization of flexible piperazine
with hydroxybenzoic acid derivatives: Structural diversity and
synthon prediction
WANG Lei1,2, XUE RuiFeng2, XU LingYan2, LU XiFeng1, CHEN RuiXin2 & TAO XuTang1*
1State Key Laboratory of Crystal Materials; Shandong University, Jinan 250100, China
2Key Laboratory of Eco-chemical Engineering, Ministry of Education; College of Chemistry and Molecular Engineering,
Qingdao University of Science and Technology, Qingdao 266042, China
Received August 21, 2011; accepted November 17, 2011; published online January 7, 2012
Four hydroxybenzoic acid building blocks, m-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid,
and 5-hydroxyisophthalic acid, have been synthesized as robust cocrystallizing agents and employed in reactions with
piperazine, including [(C4H12N2+)·(C7H5O)2] (1), [(C4H12N2+)·(C7H5O)2] (2), [(C4H12N2+)·(C8H5O2)] (3), and
2
3
2
4
2
6
[(C4H12N2+)1/2·(C8H5O)]·2H2O (4). Hydrogen-bonded directed assemblies of four salts were validated by single-crystal X-ray
2
5
diffraction analysis. In compounds 1–4, hydroxybenzoic acids are all deprotonated and piperazine molecules are all protonated
to form piperazine dications and keep the chair conformation. Thermal stability of these compounds has been investigated.
crystal engineering, supramolecular synthons, piperazine, hydroxybenzoic acid
crystal structure and molecular structure owing to its rapidly
1 Introduction
growing discipline. It seeks to understand the role of sol-
id-state materials with wanted physical and chemical prop-
erties. Many efforts toward this goal have focused on or-
ganic molecular solids [9]. In order to simplify the complex-
ity of the link, the concept of the “supramolecular synthon”
as a structural link has been used and defined as a “specific
pattern of intermolecular interactions associated with a spe-
cific type of molecular array in the solid state” [10]. The reli-
able supramolecular synthons, such as the patterns formed by
carboxylic acids-cyclic dimers and open catemer- or by azole
derivatives-cyclic dimmers, trimers, tetramers, and open
catemers-, have been widely investigated [11, 12]. Another
supramolecular synthon that has been commonly employed
in the formation of extended architectures in the solid state
is the carboxylic acid…pyridine heterosynthon (COOH…
The term “crystal engineering” was introduced as a new
concept in crystallography by Pepinsky in 1955 [1], but it
was first employed much later in the context of synthetic
and mechanistic photochemistry by Schmidt in 1971 [2].
Two decades later, in the early 1990s, many achievements
have been accomplished in crystal engineering field, where
an important aspect was focused on the design of organic
compounds with desired structures and properties engi-
neered at the molecular level and derived from molecular
building blocks associated by intermolecular interactions
(e.g., supramolecular synthons) [3–5]. Hydrogen bonding
plays an important role in constructing sophisticated assem-
blies owing to its strength and directionality [6–8].
Crystal engineering is predicted on the link between
pyridine) that consists of the primary O–H…N hydrogen
bond and the auxiliary C–H…O weak interaction [13]. In
the design and synthesis of crystalline solids in crystal en-
*Corresponding author (email: txt@icm.sdu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
1229
gineering, supramolecular synthons are employed as robust
structural units to control the structures of single- and mul-
ti-component solids [14–18].
2 Experimental
2.1 General experimental section
Piperazine (Scheme 1) is often used in crystal engineer-
ing due to its robust geometry and relatively high solubility in
different solvents. The two nitrogen atoms in the piperazine
molecular are always protonated in the crystalline solids and
piperazine molecule often keeps the chair conformation [19].
The N–H bonds can act as hydrogen bond donors to con-
struct the strong N–H…O hydrogen bond interaction, and N
atoms can act as hydrogen bond acceptors to form the
strong O–H…N hydrogen bond interaction. Organic car-
boxylic acids are used as good hydrogen bond acceptors and
donors in crystalline solids. The substitution pattern of the
carboxyl groups introduces structural diversity into the
networks. The hydroxyl group is also a good hydrogen bond
donor and acceptor but is less deprotonated than the car-
boxylic acid. Components that contain both the carboxylic
acid group and the hydroxyl group are thus of interest and
deserve investigation.
All materials were commercially available and used as re-
ceived. The IR spectra were measured using a Nicolet Im-
pact 410 FTIR spectrometer in the range of 400–4000 cm1.
The melting points of all new compounds were recorded on
a WRS-1B digital thermal apparatus without correction. C, H,
and N microanalyses were carried out with a Perkin-Elmer
240 elemental analyzer. Thermogravimetric analysis (TGA)
experiments were carried out on a Perkin-Elmer TGA 7
thermogravimetric analyzer under N2 atmosphere at a heat-
ing rate of 10 °C/min. The co-crystals were prepared as
follows.
2.2 Synthesis and characterization
Synthesis of [(C4H12N22+)·(C7H5O3)2] (1)
m-Hydroxybenzoic acid (0.138 g, 1.0 mmol) and piperazine
hexahydrate (0.097 g, 0.5 mmol) were dissolved in MeOH/
H2O (5:1, 12 mL). The solution was allowed to evaporate at
ambient conditions, resulting in clear, colorless block crys-
tals after 5 days in 80% yield. Anal. Calcd for C18H22N2O6:
C, 59.61; H, 6.07; N, 7.73. Found: C, 59.68; H, 6.15; N,
7.63%. IR (KBr, cm1): 3427m, 3320m, 3249m, 3026m,
2925m, 2853m, 2754m, 2663m, 2605m, 2460m, 2235w,
1647m, 1557s, 1482m, 1447m, 1396m, 1346m, 1309m,
1285m, 1263m, 1237m, 1115w, 1093w, 999w, 939w, 892w,
830w, 816w, 795m, 779m, 743w, 692w, 673w, 606m, 498m,
418m.
In this contribution, we focus on the syntheses and struc-
tural characterization of cocrystallizing piperazine and four
hydroxybenzoic acids: m-hydroxybenzoic acid, 2,4-dihy-
droxybenzoic acid, 2,5-dihydroxyterephthalic acid, and
5-hydroxyisophthalic acid (Scheme 1). Co-crystals of pi-
perazine and various carboxylic acids have emerged as ma-
terials for studying their physical properties, as well as
model components for studying preparation methods and
structural effects associated with pharmaceutical co-crystals
[16]. In this study, we used four kinds of hydroxybenzoic
acids cocrystallizing with piperazine, resulting in four salts,
namely, [(C4H12N22+)·(C7H5O3)2] (1), [(C4H12N22+)·(C7H5-
Synthesis of [(C4H12N22+)·(C7H5O4)2] (2)
O4)2] (2), [(C4H12N22+)·(C8H5O62)] (3), [(C4H12N22+)1/2·
(C8H5O5)]·2H2O (4).
To a solution of 2,4-dihydroxybenzoic acid (0.154 g, 1.0
mmol) in ethanol (7 mL), a solution of piperazine hexahy-
Scheme 1

1230
Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
drate (0.049 g, 0.25 mmol) in methanol (3 mL) was added.
The clear solution was allowed to stand in air for 7 days to
give colorless crystals of 4. Yield 80%. Anal. Calcd for
C18H22N2O8: C, 54.77; H, 5.58; N, 7.10. Found: C, 54.65; H,
5.47; N, 7.15%. IR (KBr, cm1): 3424m, 3116m, 3031m,
2594m, 2349w, 2290w, 1913w, 1640s, 1607s, 1521m,
1481m, 1451m, 1409m, 1363m, 1338m, 1317s, 1217m,
1221m, 1171m, 1156m, 1100m, 1087m, 1073m, 1018w,
976m, 958m, 868w, 839m, 833m, 795m, 756w, 735w,
699m, 628m, 606w, 578m, 532w, 457w.
were first observed in difference electron density maps and
then placed in the calculated sites and included in the final
refinement in the riding model approximation with fixed
thermal factors. Further details for crystallographic data and
structural analysis are listed in Table 1. CCDC No. 831525,
831528, 831529, and 831530 contains the supplementary
crystallographic data for the structures in this paper. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK (Fax: +44-1223-336-033; or E-Mail:
deposit@ccdc.cam.ac.uk, www.ccdc.cam.ac.uk/data_request/
cif).
Synthesis of [(C4H12N22+)·(C8H5O62)] (3)
2,5-Dihydroxyterephthalic acid (0.039 g, 0.25 mmol) was
dissolved in 5 mL DMF, to which a mixture solution (3 mL
ethanol and 2 mL H2O) of piperazine hexahydrate (0.049 g,
0.25 mmol) was added with stirring for 30 min. The result-
ant light yellow solution was filtered and allowed to evapo-
rate in air for 7 days, resulting in brown crystals after a pe-
riod of time. Yield, 75%. Anal. Calcd for C12H16N2O6: C,
50.66; H, 5.63; N, 9.85. Found: C, 50.65; H, 5.45; N, 7.75%.
IR (KBr, cm1): 3440m, 3123m, 2881m, 2713m, 2575m,
2317m, 1827w, 1604m, 1564s, 1529m, 1487m, 1445m,
1373m, 1340s, 1314m, 1295m, 1246s, 1111m, 1091m,
1062m, 1020w, 939m, 925m, 876m, 860m, 817m, 784s,
615w, 583m, 541m, 492m, 455w.
3 Results and discussion
3.1 Preparation of compounds 1–4
m-Hydroxybenzoic acid, 2,4-dihydroxybenzoic acid,
2,5-dihydroxyterephthalic acid, and 5-hydroxyisophthalic
acid have slight solubility in water and good solubility in
some common organic solvents, such as methanol, ethanol,
and ether. All reactions between piperazine and the four
different hydroxybenzoic acids were carried out in a 1:1, 1:2,
or 1:4 molar ratio. For the preparation of 1, hydroxybenzoic
acids and piperazine were mixed directly in methanol and
water solution, which were allowed to evaporate in air to
give the final crystalline products. For compounds 2, 3, and
4, the acid and base were dissolved in different solutions
respectively and then mixed together to form clear solution
for evaporation at ambient conditions. Then the final products
Synthesis of [(C4H12N22+)1/2·(C8H5O5)]·2H2O (4)
A solution of 5-hydroxyisophthalic acid (0.091 g, 0.5 mmol)
in ethanol was added to a solution of piperazine (0.049 g,
0.25 mmol) in water. The clear solution was allowed to
evaporate in air for 5 days. Colorless crystals of 6 were ob-
tained in 70% yield. Anal. Calcd for C10H14NO7: C, 46.11;
H, 5.38; N, 5.38. Found: C, 46.15; H, 5.47; N, 5.35%. IR
(KBr, cm1): 3570m, 3427s, 3247s, 2852m, 2586m, 2026w,
1709m, 1619m, 1552m, 1440m, 1387s, 1289m, 1218s,
1126w, 1087w, 1002w, 978m, 952w, 887w, 866w, 766m,
685m, 599m, 582m, 556m, 462m.
Table 1 Crystallographic data and structural refinement summary for
compounds 1–4
1
2
3
4
Empirical
formula
C18H22N2O6 C18H22N2O8 C12H16N2O6
C10H14NO7
260.22
362.38
394.38
284.27
M
Crystal sys-
tem
monoclinic
monoclinic monoclinic
monoclinic
Space group
P21/c (14)
10.323(3)
8.240(3)
10.708(3)
90
P21/n (14)
8.480(1)
9.757(1)
11.337(2)
90
P21/c (14)
8.239(2)
10.172(2)
7.502(1)
90
P21/c (14)
8.842(1)
16.878(2)
8.058(1)
90
2.3 X-Ray structure determination
a (Å)
b (Å)
c (Å)
 (°)
 (°)
 (°)
Single-crystal X-ray diffraction data for co-crystals 1–4
were collected on a Siemens Smart CCD diffractometer at
293(2) K with MoK radiation ( = 0.71073 Å) by  scan
mode. There was no evidence of crystal decay during data
collection for all compounds. All the measured independent
reflections were used in the structural analysis, and semiem-
pirical absorption corrections were applied using the
SADABS program. The program SAINT was used for inte-
gration of the diffraction profiles [20]. All structures were
solved by direct methods using the SHELXS program of the
SHELXTL package and refined with SHELXL [21]. The
final refinement was performed by full-matrix least-squares
methods with anisotropic thermal parameters for all the
non-hydrogen atoms on F2. Most of the hydrogen atoms
104.348(4)
90
111.96(5)
90
94.20(3)
90
100.107(2)
90
V (Å3)
Z
882.5(5)
2
869.9(2)
627.1 (2)
1183.9(3)
4
1.460
0.130
528
2
2
calcd (g cm3)
 (mm1)
F (000)
1.364
0.131
396
118
0.0234
1.506
0.126
374
1.481
0.133
286

Parameters
Rint
127
91
179
0.0196
0.0190
0.0439,
0.1203
1.049
0.0257
0.0475,
0.1313
1.086
b)
R1a), wR2
0.0489, 0.1242
0.0469, 0.1261
GOF
1.087
1.078
R1a) = ||Fo||Fc||/|Fo|; wR2b) = {[w(Fo2F2c)2]/[w(F2o)]2}1/2
.

Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
1231
were obtained. It should be noted that the assembled reac-
tions were firstly performed under the same C2H5OH/H2O
condition, but the work of obtaining good crystals for suita-
ble single-crystal X-ray diffraction failed. The growth rate
of crystals in different solvents may be a factor that influ-
ences the final crystal structures.
the local structure of cocrystal 1 as shown in Figure 1(a),
the asymmetric unit of 1 contains a m-hydroxybenzoic acid
monoanion and an half piperazine dication (centrosym
metry). The piperazine dications assume the chair confor-
mation. The m-hydroxybenzoic acid monoanions are con-
nected together by strong O3(–OH)–H3…O1(–COO) hy-
drogen bonds to form an zigzag chain along the crystallo-
graphic (010) direction (Figure 1(b)). As shown in Figure
1(c), each –COOH group of a m-hydroxybenzoic acid
monoanion connects the adjacent piperazine dications via
synthon I R21(4) [N1–H1B…O1(–COO) and N1–H1B…
3.2 Molecular and supramolecular structural descrip-
tions
The schematic representations of related hydrogen-bonding
synthons are summarized in Scheme 2. Hydrogen-bond pa-
rameters of 1–4 are listed in Table 2.
O2(–COO)] and N1–H1A…O2(–COO) to form a 2D lay-
er network along the b axis. Then through strong O–H…O
3.2.1 [(C4H12N22+)·(C7H5O3)2] (1)
and N–H…O hydrogen bonds, 1D chain and 2D layer are
joined together to result in a 3D network (Figure 1(d)). Sim-
ilar to 1, the reported co-crystal of p-hydroxybenzoic acid
and piperazine also crystallizes in the monoclinic P21/c
Compound 1 crystallizes in the monoclinic P21/c space
group. In 1, the m-hydroxybenzoic acid molecules are
deprotonated and piperazine molecules are protonated. In
Scheme 2

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Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
Table 2 Hydrogen-bond geometries in the crystal structures of 1–4
D–H
(Å)
H…A D…A D–H…A
Compound
D–H…A (Å)
(Å)
(Å)
(°)
1
O3–H3…O1a)
N1–H1A…O2b)
N1–H1B…O1
N1–H1B…O2
O3–H3…O2
O4–H4…O1m)
N1–H1A…O1n)
N1–H1A…O3
N1–H1B…O2o)
C8–H8B…O2
O3–H3…O2
0.82
0.90
0.90
0.90
0.82
0.82
0.90
0.90
0.90
0.97
0.82
0.90
0.90
0.90
0.97
0.97
0.82
0.82
2.00
1.86
1.85
2.52
1.83
1.94
2.16
2.35
1.89
2.57
1.83
1.78
2.20
2.27
2.51
2.58
1.89
1.88
1.86
1.82
1.54
2.36
2.60
2.59
2.688
2.736
2.730
3.238
2.556
2.670
2.847
2.976
2.743
3.393
2.554
2.672
2.811
2.975
3.089
3.377
2.690
2.592
2.801
2.737
2.393
3.048
3.424
3.263
141
165
165
137
147
147
133
127
157
143
146
170
133
135
118
139
166
145
164
156
141
133
14
2
3
4
N1–H1A…O2
N1–H1B…O1p)
N2–H1B…O1q)
C5–H5B…O3
C6–H6B…O1
O5–H5…O1W
O4–H4…O1b)
O1W–H1WA…O2r) 0.97
O1W–H1WB…O2s)
O2W–H2WA…N1
O2W–H2WB…O2t)
C10–H10B…O3
0.97
0.99
0.91
0.97
0.97
C10–H10B…O4
126
a) x, 1/2+y, z+1/2; b) x+1, 1/2+y, z+1/2; m) x+1/2, y+1/2, 3/2z;
n) 1x, 1y, 1z; o) 1x, y, z; p) 1x, y+1/2, z+1/2; q) x, 3/2y, 1/2+z;
r) x+1, y+3/2, 1/2+z; s) x+1, y, z; t) x+1,y+2, z.
space group [22], and analysis of the intermolecular interac-
tions in it reveals that this kind of the co-crystal contains the
similar 1D chains but different 2D layers which are joined
together to result in a 3D supramolecular array. In addition,
the p-hydroxybenzoic acid monoanion and piperazine dication
are held together by two strong N–H…O3(–COO) molecular
interactions [synthon R44(12)] which are not found in 1.
3.2.2 [(C4H12N22+)·(C7H5O4)2] (2)
Figure 1 (a) Molecular structure of 1 with atom labeling of the asymmet-
ric unit; (b) 1D zigzag hydrogen-bonding array in 1 along the (010) direc-
tion; (c) 2D layer network along the b axis; (d) 3D hydrogen-bonding ar-
chitecture along the crystallographic bc plane. O, red; N, blue; C, gray; H,
light gray in this and the subsequent figures.
The centrosymmetric unit of 2 consists of one 2,4-dihy-
droxybenzoic acid monoanion and a half centrosymmetric
piperazine dication in the asymmetric unit (Figure 2(a)). As
shown in Figure 2(b) (top), 2,4-dihydroxybenzoic acid
monoanions are connected together via strong O4–H4…O1
hydrogen-bonding to form a 1D waving chain along the
(010) direction. Furthermore, different from compound 1,
the hydroxyl group of co-crystal 2 is involved in an inter-
molecular O(–OH)–H…O(–COO) hydrogen-bonded with
the carboxylic group to form an S(6) ring [synthon II]. Sim-
ilar to the reported co-crystal of 3,5-dihydroxybenzoic acid
and piperazine [23], 2,4-dihydroxybenzoic acid monoanions
and piperazine dications are interlinked by strong
N1–H1A…O1(–COO) and N1–H1A…O3(–OH) hydrogen
bonds to form a double chain along the ac plane (Figure
2(b), bottom). The double chains are further linked together
via N1–H1B…O2(–COO) hydrogen bonds into a 2D layer
parallel to the bc plane, as shown in Figure 2(c). The 1D
chain and 2D layer are interconnected to form a 3D supra-
molecular network. It is also notable that the weaker non-
covalent interactions C–H…O exist in 2 and further stabi-
lize the 3D network via weak C8–H8…O2(–COO) hydro-
gen-bonding and strong N1–H1B …O2(–COO) hydro-
gen-bonding [synthon III, R12(6)] (Figure 2(d)).
3.2.3 [(C4H12N22+)·(C8H5O62)] (3)
The molecular structure of 3 is depicted in Figure 3(a). The

Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
1233
Figure 3 (a) Molecular structure of 3 with atom labeling of the asymmet-
ric unit; (b) an infinite chain along the (010) direction; (b) (bottom) a dou-
ble chain along the crystallographic ac plane; (c) 3D network joined by
N–H…O hydrogen-bonding along ab plane; (d) 3D supramolecular net-
work of 3.
intermolecular O(–OH)–H…O(–COO) hydrogen-bonded
with the carboxylic group to form an S(6) ring [synthon II].
A 1D chain with 2,5-dihydroxyterephthalic acid dianions
and piperazine dications is formed via strong N1–H1A…O2
(–COO) hydrogen-bonding along the ab plane (Figure 3b).
These 1D motifs are further extended to a 3D supramolecu-
lar network via strong acid-base interactions N1–H1B…O1
(–COO) [H1B…O1(–COO) = 2.195 Å] and N1–H1B…O1
(–COO) [H1B…O1(–COO) = 2.273 Å] hydrogen bonds
Figure 2 (a) Molecular structure of 2 with atom labeling of the asymmet-
ric unit; (b) (top) an infinite chain formed by O–H…O hydrogen-bonding
running along the (010) direction; (b) (bottom) a double chain along the ac
plane; (c) 2D layer network joined by N–H…O hydrogen-bonding along bc
plane; (d) 3D supramolecular network of 2.
[synthon IV, R2 (4)], as depicted in Figure 3(c). In addition,
2
multiple weak C–H…O forces coexist within such 3D non-
covalent networks and consolidate the 3D network via
C6–H6B…O1(–COO) and N1–H1A…O2(–COO) hydro-
gen bonds [synthon V, R22(8)] (Figure 3(d)).
asymmetric unit of it contains a half 2,5-dihydroxytereph-
thalic acid dianion and a half piperazine dication and crys-
tallizes in the space group P21/c. 2,5-Dihydroxyterephthalic
acid dianions and piperazine dications are all centrosym-
metric in this case. Analysis of the structure of 3 suggests
that the hydroxyl group of compound 3, the same as salt 2
and other salicylic acid co-crystals [24], is involved in an
3.2.4 [(C4H12N22+)1/2·(C8H5O5)]·2H2O (4)
The asymmetric unit contains a 5-hydroxyisophthalic acid
monoanion, a half piperazine protonated cation and two
solvent water molecules. The piperazine unit is centrosym-
metric and assumes the chair conformation (Figure 4(a)).
One of the two carboxyls of 5-hydroxyisophthalic acid is

1234
Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
molecule acts as 2-connector; O2W connects a piperazine
dications and a 5-hydroxyisophthalic acid monoanion
through O2W–H2WB…O1(–COO) and O2W–H2WA…
N1 hydrogen bonds. Weak C10–H10B…O3(–COOH) and
C10–H10B …O4(–COOH) forces [synthon VI, R42(8)]
within 3D network connect piperazine dication in the struc-
ture and consolidate the whole supramolecular system (Fig-
ure 4(d)).
3.3 Thermogravimetric analysis
All compounds 1–4 are air stable and can retain their struc-
tural integrity at ambient conditions for a considerable
length of time. To study the stability of compounds 1–4,
thermogravimetric analyses (TGA) were conducted to de-
termine the thermal stability of these compounds. For com-
pound 1, the first weight loss of 75.1% from 180 to 310 °C,
peaking at 262 °C, corresponds to the loss of acid compo-
nent (calculated: 75.7%). The residual base section loses
weight of 23.8% (calcd: 24.3%), subsequently from 310 to
440 °C (peak: 405 °C). The TGA curve of 2 shows two
consecutive weight losses of all samples from 140 to 210 °C
(peaking at 182 and 209 °C, respectively). The network of 3
remains intact until three consecutive mass losses occur in
the region of 240–350 °C with the peaking position of 278,
301 and 333 °C, corresponding to the stepwise removal of
the acid and base subunits continuously. For compound 4,
the TGA curve is more complicated. Four consecutive
weight losses of 4 occur in the 70–900 °C range (peak posi-
tion: 87, 120, 297 and 467 °C).
4 Conclusions
Developing reliable synthetic strategies of predictable and
periodic superstructures is one of the ultimate aims of supra-
molecular chemistry. In this study, four new aromatic build-
ing blocks: m-hydroxybenzoic acid, 2,4-dihydroxybenzoic
acid, 2,5-dihydroxyterephthalic acid, and 5-hydroxyisoph-
thalic acid with robust hydrogen-bonded sites have been
successfully employed to result in four salts. They exhibit
that the polycarboxylic acids have robust hydrogen-bonded
acceptors and piperazine is considered as an excellent su-
pramolecular reagent to fulfill the multiform supramolecular
network structure. It is proved that layers based on pipera-
zine carboxylic co-crystals are useful for the structures of
organic crystal engineering, because they are good supra-
molecular building modules which can produce supramo-
lecular crystals.
Figure 4 (a) Molecular structure of 4 with atom labeling of the asymmet-
ric unit; (b) 1D infinite chain in 4 along the (001) direction; (c) 2D layer
network along the crystallographic ac plane; (d) 3D hydrogen-bonding
architecture of 4.
deprotonated. These acid moieties and water solvents are
linked via strong O1W–H1WB…O2(–COO) and O1W–
H1WA…O2 (–COO) hydrogen bonds to form a 1D chain
along the (001) direction (Figure 4(b)). Such adjacent 1D
chains further join together by O5(–OH)–H5…O1W inter-
actions to form a 2D layer network along the (100) direction
(Figure 4(c)). Within the 2D array, one solvent water mole-
cule that acts as the 3-connector, O1W joins three
5-hydroxyisophthalic acid monoanions via O5(–OH)–H5…
It should be indicated that piperazine plays an important
role in constructing the supramolecular structures of these
organic solids, and its special nature is generally used to
fulfill the diverse and abundant hydrogen-bonded patterns.
As expected, the N atoms of piperazine cations act as sig-
nificant hydrogen-bonded donors that crosslink the supra-
O1W, O1W–H1WA…O2(–COO) and O1W–H1WB…O2
(–COO) interactions. Furthermore, the adjacent 2D layer
networks are connected together by N1–H1A…O1 and
O4(–COOH)–H4…O1(–COO) bonds to result in a 3D
network. In the 3D structure of 4, another solvent water

Wang L, et al. Sci China Chem July (2012) Vol.55 No.7
1235
Growth Des, 2010, 10: 4565–4570; (b) Reddy LS, Basnati G, Van-
gala VR, Nangia A. Hydrogen bonding in crystal structures of
N,N′-bis(3-pyridyl)urea. Why is the N–H…O tape synthon absent in
diaryl ureas with electron-withdrawing groups? Cryst Growth Des,
2006, 6: 161–173
molecular structures. Similar 1D chain supramolecular struc-
tures of co-crystal 1–4 are N–H…O or O–H…O. However,
further lattice packing managed by strong or weak interac-
tions leads to the formation of distinct 3D or 2D networks.
Cocrystallization of 5-hydroxyisophthalic acid with pipera-
zine presents 4, which has O–H…N hydrogen-bonding in-
10 Banerjee R, Saha BK, Desiraju GR. Synthon robustness and sol-
id-state architecture in substituted gem-alkynols. Cryst Growth Des,
2006, 6: 999–1009
stead of N–H…O hydrogen-bonding. Further studies on such
flexible building blocks are desirable to deepen understand-
ing of the crystal engineering of hydrogen-bonded solids, and
the related exploration on this perspective is underway.
11 Leiserowitz L. Molecular packing modes: Carboxylic acids. Acta
Cyrstallogr Sect B, 1976, 32: 775–802
12 Foces FC, Alkorta I, Elguero, Supramolecular structure of
1H-pyrazoles in the solid state: A crystallographic and ab initio study.
Acta Crystallogr, Sect B, 2000, 56: 1018–1028
13 (a) Du M, Zhang ZH, Zhao XJ, Cai H. Synthons competi-
tion/prediction in cocrystallization of flexible dicarboxylic acids with
bent dipyridines. Cryst Growth Des, 2006, 6: 114–121; (b) López C,
Claramunt RM, Garcia MA, Pinilla E, Terres MR, Alkorta I, Elguero
J. Cocrystals of 3,5-dimethyl-1H-pyrazole and salicylic acid: Con-
trolled formation of trimers via O–H…N hydrogen bonds. Cryst
Growth Des, 2007, 7: 1176–1184
This work was financially supported by the National Natural Science Foun-
dation of China (20701023, 20971076), and the Natural Science Foundation
of Shandong Province, China (BS2010NJ004, 2009ZRB019KH).
1
2
3
Pepinsky R. Crystal engineering: New concepts in crystallography.
Phys Rev, 1955, 100: 971–971
Schmidt GM. Photodimerization in the solid state. J Pure Appl Chem,
1971, 27: 647–678
14 Desiraju GR, Crystal and co-crystal. CrystEngComm, 2003, 5:
466–467
15 Aakeröy CB, Salmon DJ. Building co-crystals with molecular sense
and supramolecular sensibility. CrystEngComm, 2005, 7: 439–448
16 Du M, Zhang ZH, Guo W, Fu XJ. Multi-component hydrogen-
bonding assembly of a pharmaceutical agent pamoic acid with piper-
azine or 4,4′-bipyridyl: A channel hydrated salt with multiple-helical
motifs vs a bimolecular cocrystal. Cryst Growth Des, 2009, 9: 1655–
1657
17 Du M, Zhang ZH, Wang XG, Wu HF, Wang Q. Flexible building
blocks of N,N′-bis(picolinoyl)hydrazine for hydrogen-bonding directed
cocrystallization: Structural diversity, concomitant polymorphs, and
synthon prediction. Cryst Growth Des, 2006, 6: 1867–1875
18 Du M, Zhang ZH, Zhao XJ. A search for predictable hydrogen-
bonding synthons in cocrystallization of unusual organic acids with a
bent dipyridine. Cryst Growth Des, 2006, 6: 390–396
(a) Braga D. Crystal engineering, Where from? Where to? Chem
Commun, 2003, 2751–2754; (b) Fleischman S, Morales L, Moulton B,
Rodriguez-Hornedo N, Bailey WR, Zaworotko M. Crystal engineer-
ing of the composition of pharmaceutical phases. Chem Commun,
2003, 186–187; (c) Banerjee R, Saha BK, Desiraju GR. Synthon ro-
bustness in saccharinate salts of some substituted pyridines.
CrystEngComm, 2006, 8: 680–685
(a) Liu YL, Kravtsov VC, Larsen R, Eddaoudi M. Molecular building
blocks approach to the assembly of zeolite-like metal–organic
frameworks (ZMOFs) with extra-large cavities. Chem Commun, 2006,
1488–1490; (b) Ferey G, Mellot DC, Serre C, Millange F, Dutour J,
Surble S, Margiolaki I. A chromium terephthalate-based solid with
unusually large pore volumes and surface area. Science, 2005, 309:
2040–2042
4
5
19 (a) Andre V, Braga D, Grepioni F, Duarte MT. Crystal forms of the
antibiotic 4-aminosalicylic acid: Solvates and molecular salts with
dioxane, morpholine, and piperazine. Cryst Growth Des, 2009, 9:
5108–5116; (b) Skovsgaard S, Bond AD. Mechanochemistry and co-
crystals. CrystEngComm, 2009, 11: 444–453
(a) Báthori NB, Lemmerer A, Venter GA, Bourne SA, Caira MR.
Pharmaceutical co-crystals with isonicotinamide-vitamin B3, clofi-
bric acid, and diclofenac- and two isonicotinamide hydrates. Cryst
Growth Des, 2011, 11: 75–87; (b) Ulrich J. Is melt crystallization a
green technology? Cryst Growth Des, 2004, 4: 879–880
20 SAINT Software Reference Manual, Bruker AXS: Madison, WI,
1998
6
7
Begum NS, Girjia CR, Nagendrappa G. The influence of the trime-
thylsilyl group: Helical self-assembly of syn-7-trimethylsilyl-5-nor-
bornene-endo-2,3-dicarboxylic acid. CrystEngComm, 2004, 6: 116–119
Dale SH, Elsegood MRJ, Hemmings M, Wilkinson AL. The
co-crystallisation of pyridine with benzenepolycarboxylic acids: The
interplay of strong and weak hydrogen bonding motifs. CrystEngComm,
2004, 6: 207–214
21 Sheldrick GM. SHELXTL NT Version 5.1. Program for solution and
refinement of crystal structure: University of Gottingen, Germany,
1997
22 Zhao PS, Wang X, Jian FF, Zhang JL, Xiao HL. Crystal engineered
acid–base complexes with 2D and 3D hydrogen bonding systems us-
ing p-hydroxybenzoic acid as the building block. J Serb Chem Soc,
2010, 75: 459–473
8
9
Biradha K, Su CY, Vittal JJ. Recent developments in crystal engi-
neering. Cryst Growth Des, 2011, 11: 875–886; (b) Lemmerer A,
Bourne SA, Fernandes MA. Robust supramolecular heterosynthons
in chiral ammonium carboxylate salts. Cryst Growth Des, 2008, 8:
1106–1109
Rajput L, Jana N, Biradha K. Carboxylic acid and phenolic hydroxyl
interactions in the crystal structures of co-crystals/clathrates of tri-
mesic acid and pyromellitic acid with phenolic derivatives. Cryst
23 Burchell CJ, Ferguson G, Lough AJ, Gregson RM, Glidewell C. Hy-
drated salts of 3,5-dihydroxybenzoic acid with organic diamines: hy-
drogen-bonded supramolecular structures in two and three dimen-
sions. Acta Cyrstallogr, Sect B, 2001, 57: 329–338
24 Skovsgaard S, Bond AD. Co-crystallisation of benzoic acid derivatives
with N-containing bases in solution and by mechanical grinding: Stoi-
chiometric variants, polymorphism and twinning. CrystEngComm,
2009, 11: 444–453