Model pharmaceutical co-crystallization: Guest-directed assembly of caffeine and aromatic tri-hydroxy and dicarboxylic acids into different heteromolecular hydrogen bonding networks in solid state

Article abstract of DOI:10.1016/j.molstruc.2009.10.015

Three model pharmaceutical caffeine-containing co-crystals of 1,3,5-trihydroxybenzene (phloroglucinol), isophthalic acid and 5-hydroxyisophthalic acid were synthesized and characterized via single-crystal X-ray diffraction. The three crystalline forms reported are an anhydrous co-crystal and other two are co-crystal hydrates. Also their binding properties were studied by UV-vis analysis. In each of these structures, an organised intermolecular hydrogen bonding motif was observed. A comparison of hydrogen bonding motifs in the crystal sheets was presented.

Full text of DOI:10.1016/j.molstruc.2009.10.015

Journal of Molecular Structure 963 (2010) 63–70
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Model pharmaceutical co-crystallization: Guest-directed assembly of caffeine
and aromatic tri-hydroxy and dicarboxylic acids into different heteromolecular
hydrogen bonding networks in solid state
a
Ajit Kumar Mahapatra a, , Prithidipa Sahoo , Shyamaprosad Goswami a,*, Hoong-Kun Fun b,*
*
a Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah – 711103, India
b X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 August 2009
Received in revised form 8 October 2009
Accepted 10 October 2009
Available online 5 November 2009
Three model pharmaceutical caffeine-containing co-crystals of 1,3,5-trihydroxybenzene (phloroglucinol),
isophthalic acid and 5-hydroxyisophthalic acid were synthesized and characterized via single-crystal
X-ray diffraction. The three crystalline forms reported are an anhydrous co-crystal and other two are
co-crystal hydrates. Also their binding properties were studied by UV–vis analysis. In each of these struc-
tures, an organised intermolecular hydrogen bonding motif was observed. A comparison of hydrogen
bonding motifs in the crystal sheets was presented.
Keywords:
Pharmaceutical co-crystals
Caffeine
Ó 2009 Elsevier B.V. All rights reserved.
Phloroglucinol
Isophthalic acid
5-Hydroxyisopthalic acid
Hydrogen bonding
1. Introduction
stoichiometric hydrate [14]. It is a stimulant to central nervous sys-
tem, smooth muscle relaxant and it is commonly employed as a
Caffeine is one of the most widely consumed alkaloid. The tra-
ditional significant sources of caffeine in our daily lives are coffee,
black tea, guarana paste, cola nuts, cocoa beans etc. The alkaloid is
also an ingredient of cola beverages and energy drinks. It is also a
pharmaceutically important alkaloidal drug [1,2]. Co-crystallisa-
tion of pharmaceutically active molecules represents a viable
means of enhancing physical properties. Co-crystals have emerged
as an important tool in the design and construction of solid state
materials with tailor-made properties [3–8]. Co-crystals, one of
the synthetic targets in crystal engineering, are long known class
of compounds [9,10]. The pharmaceutical co-crystals are a subset
of a broader group of multi-component crystals that comes from
supramolecular context. They are related to one another in that
at least two components of the crystal interact by hydrogen bond-
ing and other non-covalent interaction rather than by ion pairing.
Most recently, in the field of pharmaceuticals, co-crystallisation
has been shown to be an effective means of altering a drug’s phys-
ical properties, such as solubility and melting point [11–13].
Caffeine is a model pharmaceutical compound that is known to
be unstable to humidity with the formation of a crystalline non-
formulation additive to analgesic remedies (analgesic adjuvant)
[15] due to its weak basic character. The weakly basic imidazole
nitrogen of caffeine results in a pKa of 3.6 [16]. Due to its weak ba-
sicity, caffeine may be particularly suited for co-crystallization in
its neutral form with aromatic carboxylic acids. Several of these
are pharmaceutically acceptable co-crystals, including 1:1 com-
plexes of caffeine with antibiotic sulfa drugs [17]. There have been
a number of studies investigating the complex between caffeine
and dicarboxylic acid which disclose robust supramolecular
network characteristic for caffeine–carboxylic acids assemblies
[18–21]. Further, we noticed that the carbonyl group of caffeine,
in a molecular complex of caffeine with methyl 3,4,5-trihydroxy-
benzoate(methyl gallate) [22], gallocatechin gallate [23], served
as a hydrogen bond acceptor in an O–HÁ Á ÁO bond with the
benzoate component. Several caffeine co-crystals were reported
[24,25,20,26] and a systematic crystal engineering study of poly-
phenolics and aromatic hydroxy dicarboxylic acid is important to
develop model pharmaceutical co-crystals of caffeine and this
has been still attractive.
We have tried to focus on the synthesis and structural
characterizations of co-crystals of caffeine respectively with phlor-
oglucinol (complex-A), isophthalic acid (complex-B) and 5-hydrox-
yisophthalic acid (complex-C) (Scheme 1). In these solids, caffeine
forms molecular complexes in which the carboxyl group interacts
* Corresponding authors. Tel.: +91 03326684561; fax: +91 3326681503 (A.K.
Mahapatra).
E-mail address: mahapatra574@gmail.com (A.K. Mahapatra).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2009.10.015

64
A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
OH
O
OH
N
N
N
HO
OH
OH
HO
OH
HO
O
N
O
O
O
O
(a)
(b)
(c)
(d)
Scheme 1. Chemical structures of (a) caffeine, (b) phloroglucinol, (c) isophthalic acid and (d) 5-hydroxyisophthalic acid in this study.
N
N
O
H
H
H
N
O
O
O
O
N
H
O
H
H
O
H
N
O
(a)
(b)
Scheme 2. (a) Heteromeric synthon showing strong O–HÁ Á ÁN and weaker C–HÁ Á ÁO hydrogen bond interactions. (b) The most common acid–imidazole heterosynthons present
in caffeine–carboxylic acid co-crystals.
with the N atom of the imidazole ring via an O–HÁ Á ÁN hydrogen
bond. The desired supramolecular interaction was the acid–base
heterodimer synthon (Scheme 2a) [27], through strong O–HÁ Á ÁN
and weaker C–HÁ Á ÁO hydrogen bonding [21]. A literature survey
[21] has revealed that caffeine form several co-crystals with
carboxylic acid components and these are held together by one
of the two heterosynthons: (i) an R22(7) heterosynthon and (ii)
an R33(11) network based on R22(7) and R22(6) (Scheme 2b) as well
as caffeine also forms N(imidazole)ÁH–O(phenol) heterosynthons
in the presence of carboxylic groups [24].
two component assemblies of caffeine (imidazole)–carboxylic acid
synthon, our structural analysis of the co-crystal C has revealed a
typical case where a carboxylic acid formed a well-known R22(8)
homo-dimer, though there was the presence of a rationally intro-
duced heterosynthon [24].
2. Experimental
2.1. Preparative methods
Three co-crystals of caffeine with phloroglucinol, isophthalic
acid and 5-hydroxyisophthalic acids are structurally characterized.
Here, it has been shown that in addition to the well-established
All chemicals were purchased from Sigma–Aldrich and used
without further purification. In all preparations equi-millimolar
Table 1
Crystallographic data for co-crystals A, B and C.
A
B
C
CCDC number
Molecular formula
Molecular weight
Crystal system
Space group
T (K)
706,369
C8H10N4O2, C6H6O3,(H2O)2
356.34
Monoclinic
P21/c
706,370
C8H10N4O2, C8H6O4
360.33
Monoclinic
P21/c
706,371
C8H10N4O2, C8 H6O5, H2
394.34
Triclinic
P-1
O
296
100
296
a (Å)
b (Å)
c (Å)
8.9744(2)
13.9034(3)
13.4743(3)
90.00
105.690(1)
90.00
1618.61(6)
4
1.462
8.6279(5)
14.0198(7)
14.1632(7)
90.00
113.943(1)
90.00
1565.78(14)
4
1.529
9.7443(2)
9.8983(2)
10.5080(3)
81.041(1)
81.740(1)
60.588(1)
869.45(4)
2
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dc (g cmÀ3
F(0 0 0)
l
)
1.506
412
0.123
752
0.119
752
0.119
(Mo K ) (cmÀ1
)
a
Crystal size (mm)
Range of indices
No. of reflections collected
Unique reflections
Rint
0.09 Â 0.21 Â 0.33
À12,12; À19,19; À18,18;
27,018
4845
0.054
0.21 Â 0.31 Â 0.49
À12,10; À20,20; À21,21
22,218
5493
0.048
0.18 Â 0.24 Â 0.54
À13,13; À13,13; À14,14
13,467
5018
0.023
Reflections with I > 2
r(I)
2685
4208
3708
No. of parameters
257
246
268
R(F), F > 2
r
(F)
0.0534
0.1503
0.1082
0.200, À0.195
0.0534
0.1513
0.1933
0.619, À0.381
0.0654
0.1484
0.1348
0.252, À0.380
wR(F2), F > 2
r(F)
wR(F2), all data
Dr (max, min) e ÅÀ3

A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
65
Table 2
tion: SAINT, [37,38] programs used to solve structures: SHELXTL,
molecular graphics: SHELXTL. All non-hydrogen atoms were re-
fined with anisotropic displacement parameters. The –OH hydro-
gen atoms were located in difference Fourier maps and refine
isotropically. The hydrogen atoms bound to carbon atoms were
placed geometrically and were allowed to ride during subsequent
refinement. Further details of crystal and structure refinement
are shown in Table 1.
Carbon–oxygen bond distances of co-crystals A, B and C.
Co-crystal
d(C–O) (Å)
d(C@O) (Å)
A
B
C
1.368(2)
1.3196(16)
1.2199(16)
–
1.3157(19)
1.2144(19)
UV–vis spectra measurements were performed on a JASCO
V530 spectrophotometer. The acidic substrates (b, c and d) and
caffeine were dissolved in dry UV grade chloroform. The corre-
sponding absorbance values during titration were noted and used
for the determination of binding constant values. Binding constant
quantities of the two starting materials were weighed, transferred
to a 50 ml conical flask and 20 ml of solvent added. The mixtures
were stirred and warmed on a water bath until a clear solution
was achieved. Crystals, formed by slow evaporation of the solvent,
were obtained by filtration. The resulted co-crystals were suitable
for single-crystal X-ray diffraction studies.
were determined by the using expression A0/A–A0 = [
eM/(eM–
e
C)](KaÀ1 CgÀ1 + 1), where eM and
eC are molar extinction co-efficient
for receptor and the hydrogen bonding complex respectively at se-
lected wavelength, A0 denotes the absorbance of the free substrate
at the specific wavelength and Cg is the concentration of caffeine.
The measured absorbance A0/A–A0 as a function of the inverse of
the caffeine concentration fits a linear relationship, indicating a
1:1 stoichiometric of the substrate –caffeine complex. The ratio
of the intercepts to the slope was used to determine the binding
constant Ka.
(a) Co-crystal A [caffeine][phloroglucinol][H2O]2: Co-crystals
hydrate were obtained from a 1:1 chloroform–methanol solution.
(b) Co-crystal B [caffeine][isophthalic acid]: Co-crystals were
obtained from a 1:2 chloroform–methanol solution.
(c) Co-crystal C [caffeine][5-hydroxyisophthalic acid][H2O]:
Co-crystals hydrate were obtained from a 1:1 chloroform–metha-
nol solution.
2.2. X- Ray crystallography
3. Results and discussion
Single-crystal X-ray diffraction data was collected on a Bruker
3.1. Co-crystal structures
SMART APEX2 CCD area detector diffractometer with Mo K radia-
a
tion (k = 0.71073 Å) equipped with an Oxford Cryosystem Cobra
low-temperature attachment. Cell refinement: APEX2; data reduc-
The crystal structure analysis reveals that an asymmetric unit of
each co-crystal A, B and C contain a minimum one molecule of
Fig. 1. Infrared spectra of the carbonyl stretching region for (a) caffeine, (b) caffeine–phloroglucinol–(H2O)2; (c) caffeine–isophthalic acid and (d) caffeine–5-
hydroxyisophthalic acid–(H2O).
Fig. 2. ORTEP diagram of co-crystal A.

66
A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
Table 3
Hydrogen bond parameters.
D–HÁ Á ÁA
d(D–H) (Å)
d(HÁ Á ÁA) (Å)
d(DÁ Á ÁA) (Å)
h(D–HÁ Á ÁA) (°)
(a) Selected hydrogen bond parameters of co-crystal A
O1W–H1W1Á Á ÁO3
O2W–H1W2Á Á ÁO2ii
O1W–H2W1Á Á ÁO2
O2W–H2W2Á Á ÁO1iii
O3–H1O3Á Á ÁN2iv
O4–H1O4Á Á ÁO2Wv
O5–H1O5Á Á ÁO1W
C2–H2AÁ Á ÁO1Wvi
C6–H6BÁ Á ÁO4vii
0.91(4)
2.11(4)
2.19(4)
1.92(3)
1.89(3)
1.88(3)
1.81(3)
1.80(3)
2.48
2.941(2)
3.010(2)
2.807(2)
2.756(2)
2.846(2)
2.710(2)
2.716(2)
3.392(2)
3.422(3)
2.759(2)
2.715(2)
151(4)
156(3)
167(2)
170(3)
176(2)
170(3)
172(2)
167
0.88(4)
0.91(3)
0.88(3)
0.97(3)
0.91(3)
0.92(3)
0.93
0.96
0.96
0.96
2.60
2.37
2.34
144
104
102
C7–H7AÁ Á ÁO1(intra)
C8–H8AÁ Á ÁO2(intra)
(b) Selected hydrogen bond parameters of co-crystal B
O2–H1O2Á Á ÁN1
0.92(2)
1.79(2)
1.88(2)
2.35
2.38
2.33
2.45
2.30
2.45
2.6762(15)
2.6617(15)
3.2313(16)
3.1332(16)
3.1850(17)
3.3932(17)
2.7513(18)
3.3580(17)
159(2)
155(2)
159
138
148
167
108
159
O4–H1O4Á Á ÁO1i
0.83(2)
0.93
0.93
0.96
0.96
0.96
0.96
C2–H2AÁ Á ÁO5ii
C13–H13AÁ Á ÁO6iii
C14–H14AÁ Á ÁO6iii
C14–H14CÁ Á ÁO5iv(intra)
C15–H15BÁ Á ÁO5(intra)
C16–H16BÁ Á ÁO1
(c) Selected hydrogen bond parameters of co-crystal C
O1W–H2W1Á Á ÁO5i
O3–H1O3Á Á ÁO4ii
O6–H1O6–N1
0.86
2.29
2.753(2)
2.6402(17)
2.662(2)
2.7389(18)
3.416(3)
2.7320(19)
3.291(2)
114
1.06(3)
0.91(3)
0.91(3)
0.96
0.96
0.93
1.59(3)
1.78(3)
1.83(3)
2.56
2.28
2.38
171(3)
162(3)
177(3)
156
108
166
O7–H1O7Á Á ÁO2iii
C6–H6AÁ Á ÁO1W
C7–H7BÁ Á ÁO1(intra)
C10–H10AÁ Á ÁO1iv
C14–H14AÁ Á ÁO6(intra)
0.93
2.41
2.728(2)
100
(a) Symmetry codes: (i) À1Àx, Ày, Àz; (ii) Àx, Ày, 1Àz; (iii) 1Àx, Ày, 1Àz; (iv) Àx, À1/2 + y, 1/2Àz; (v) À1 + x, À1/2Ày, À1/2 + z; (vi) Àx, 1/2 + y, 1/2Àz.
(b) Symmetry codes: (i) 1 + x, À1/2Ày, 1/2 + z; (ii) x, À1 + y, z; (iii) 1 + x, 1/2Ày, 1/2 + z; (iv) 1–x, 1Ày, 1Àz; (iv) 1–x, 1Ày, 1Àz.
(c) Symmetry codes: (i) 1Àx,1Ày, 1Àz; (ii) 2Àx, Ày, 2Àz; (iii) 1Àx, 2Ày, 1Àz; (iv) 1 + x, y, 1 + z.
Fig. 3. Co-crystal A showing in the hydrogen bonding network (a) small groove of R77(31) (b) large groove of R1717(76) (c) head to tail stacked formation (d) highly organised
hydrogen bonding supramolecular network when viewed down crystallographic ‘b’ axis.

A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
67
Fig. 4. ORTEP diagram of co-crystal B.
caffeine and one molecule of acidic substrate. Co-crystals of A and
C form hydrated crystals with two and one molecule(s) of water
respectively in their asymmetric units.
Additionally, analyses of the carbonyl stretching band in the
infrared spectra, which are all above 1600 cmÀ1 (Fig. 1), confirmed
un-ionized carboxylic acids and thus co-crystal formation for these
new phases occur. A typical ionized carboxylic acid salt band
would be expected to occur 1300–1420 cmÀ1, is further indication
of the nonionic character of these complexes.
We have chosen weak acidic groups like carboxyl or hydroxyl
group to see the binding with caffeine where we wanted to prove
the strong acid–base interaction in the co-crystals i.e. between car-
boxyl and imidazole moieties without any proton transfer which
actually happens. All our three complexes are neutral as determined
from X-ray structure analysis. The carbon–oxygen bond distances
were consistent with the formation of a co-crystal in each case (Ta-
ble 2) but not the formation of ionic co-crystal through carboxylate
ion. Salts and co-crystals are multi-component crystals [28] that can
be distinguished by the location of the proton between an acid and a
base. The Fourier difference map suggests that the acidic proton was
located 0.876–0.975 Å from the O atom of the carboxylic acid. We
have also performed the IR spectral analysis [29] of the complexes
which agreed with the simple hydrogen bond formation and that
no proton transferred complexes were formed.
3.3.1. Co-crystal A [caffeine][phloroglucinol][H2O]2
The numbering scheme is shown in Fig. 2. The components of
the co-crystal hydrate A are held together by hydrogen bonding
and crystallizes in the monoclinic P21/c space group where unit cell
contain four molecules (Z = 4). Caffeine and phloroglucinol form a
co-crystal hydrate with two molecules of water. In phloroglucinol
there are three hydrogen bond donor and three acceptor sites. Two
phenolic –OH groups of phloroglucinol makes hydrogen bonds
with two water molecules and remaining –OH group holds caffeine
via imidazole NÁ Á ÁH–O hydrogen bond. In the hydrogen bonding
network, it forms two grooves: one small with 31 membered of
Fig. 5. Co-crystal B showing (a) cactus like polymeric chain (b) space filling model when viewed down to c axis (c) perpendicular stack formation when viewed down
crystallographic b axis in ball and stick model.

68
A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
of caffeine through an intermolecular O1W–H2W1Á Á ÁO2 and O5–
H1O5Á Á ÁO1W hydrogen bonds (Table 3). Another water molecule
interacts with two molecules of caffeine and one molecule of
phloroglucinol making assemblies in opposite directions which
are stacked in a ‘‘head to tail” manner to the other layer. Two
stacked layers interplay by water molecule through intermolecular
hydrogen bonding.
The analysis of single-crystal of the complex A reveals the for-
mation of stacked [31] layer hydrogen bonded network among
the phloroglucinol, caffeine and water molecules in a unit cell
which is extended further into an infinite 3D network via H–
OÁ Á ÁH hydrogen bonds. Interestingly complex A was arranged in
a highly organised extended supramolecular hydrogen bonding
network (Fig. 3) in the solid state when viewed perpendicular to
ac-plane.
3.3.2. Co-crystal B [caffeine][isophthalic acid]
The numbering scheme of co-crystal B is shown in Fig. 4. Co-
crystal B crystallizes in the monoclinic P21/c space group where
unit cell contain four molecules (Z = 4). The caffeine and
isophthalic acid form two binary component assemblies involving
an intermolecular O–HÁ Á ÁO and O–HÁ Á ÁN hydrogen bonds. The 1:1
caffeine/diacid co-crystals arranged according to heteromeric syn-
thon with only one of the two carboxyl groups of dicarboxylic acid.
The other carboxyl group formed a hydrogen bond to another car-
boxyl group of second diacid molecule. This implies that in the co-
crystal B the hydrogen bond acceptor ability of the caffeine imidaz-
ole nitrogen did not successfully compete with that of a carboxyl
Fig. 6. ORTEP diagram of co-crystal C.
R77(31) and another large groove with 76 membered of R1717(76).
In both the ring systems, the two caffeine molecules are present
a and b forms [30] and small and large rings are present alter-
natively in the H-bonding network.
In the crystal structure, one water molecule is attached with
one hydroxy group of phloroglucinol and also the carbonyl oxygen
as
Fig. 7. Co-crystal C showing (a) sheets of dimeric hydrogen bonded units (b) viewed down crystallographic a axis; (c) space filling model down to b axis (red: water; blue:
caffeine and green: 5-hydroxyisophthalic acid) (d) 3D stair like supramolecular network. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this paper.)

A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
69
group in dictating the hydrogen bonding preference of the second
carboxyl group of isophthalic acid. It is usual that basic N of imid-
azole part of caffeine makes hydrogen bonds with most acidic
hydrogen of carboxylic acid of isophthalic acid. Selected hydrogen
bond parameters are shown in Table 3. The acid–base pairs interact
parallel via weak van der Waals forces to form stacks. The stacks
are sustained by C16–H16BÁ Á ÁO1 hydrogen bonds (Fig. 5). Co-crys-
tal B forms a cactus like polymeric chain when viewed along a axis.
The other two presentations are also shown in Fig. 5(b and c)
which look like parallel dolls holded together by back hands
Fig. 5(b) and gymnastic display Fig. 5(c), respectively.
are present which makes selectivity in the complex (Fig. 7a)
through hydrogen bond preference, here weakly acidic hydrogen
(phenolic –OH) makes hydrogen bond with less basic carbonyl
oxygen of caffeine, whereas most acidic carboxylic acid hydrogen
makes hydrogen bond with more basic imidazole ring –N of caf-
feine via O–H(carboxy). . .N(imidazole). Whereas, in Bucar’s [31]
case there is no O–H(carboxy). . .N(imidazole part of the caffeine)
hydrogen bond in the proposed co-crystals. The introduction of a
free hydroxyl group in 5-hydrxyisophthalic acid resulted in the for-
mation of an O–HÁ Á ÁO hydrogen bond (Table 3) with caffeine car-
bonyl group in the co-crystal C along with the coexistence of a
carboxylic acid dimer in the presence of such a supramolecular
heterosynthon [32] is rare (Fig. 7a). As carboxylic acid dimer is
more stronger than hetero synthon COOHÁ Á ÁN interaction due to
more number of hydrogen bonds in dimer structures. In co-crystal
C there is no addition of no new hetero synthon co-crystal former
so it yields the well-known hydrogen-bond carboxylic acid dimer.
This may happen [25] due to 1:1 stoichiometry of caffeine/dia-
cid in co-crystal C. Interestingly complex C was organised in a 3D
3.3.3. Co-crystal C [caffeine][5-hydroxyisophthalic acid][H2O]
The numbering scheme of co-crystal C is shown in Fig. 6. Co-
crystal hydrate C crystallizes in the triclinic P-1 space group where
unit cell contain two molecules (Z = 2). Similar to co-crystal A, an
intermolecular hydrogen bond has formed between caffeine and
5-hydroxyisophthalic acid through a water molecule. In 5-hydrox-
yisophthalic acid there are two different types of acidic hydrogens
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
250
260
270
280
290
300
255
260
265
270
275
280
285
Wave length (nm)
Wave length (nm)
(a)
(b)
8
6
4
2
0
0.65
5-Hydroxy isophthalic acid
Isophthalic acid
Phloroglucinol
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
0
20
40
60
260
280
1/[G] x 103
Wave length (nm)
(c)
(d)
Fig. 8. UV–vis spectra for (a) phloroglucinol (b) isophthalic acid (c) 5-hydroxyisophthalic acid upon addition of caffeine. (d) Binding constant calculation curves.

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A.K. Mahapatra et al. / Journal of Molecular Structure 963 (2010) 63–70
Table 4
Crystallographic Data Centre, respectively (CCDC 706369, CCDC
706370 and CCDC 706371) as supplementary publications. These
data can be obtained free of charge, by request to the Director,
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033;
email: deposit@ccdc.cam.ac.uk).
Binding constants for caffeine by UV–vis spectroscopy method.
Receptors
UV–vis method (Ka MÀ1
)
Phloroglucinol
Isophthalic acid
5-Hydroxyisophthalic acid
2.7 Â 103
4.5 Â 103
5.5 Â 103
Acknowledgements
stair [33] like (Fig. 7d) supramolecular network in the solid state
extended when viewed perpendicular to ac-plane.
We thank UGC (Grant No. 34-340/2008/SR), New Delhi, India
for financial support and we also would like to thank the Malaysian
Government and University Sains Malaysia for the Scientific
Advancement Grant Allocation (SAGA).
3.2. UV–vis studies [34]
To investigate the sensitivity of photo-physical property and
binding interaction behaviors in solution of these acidic substrates,
we carried out UV–vis titration at very low concentration
(ꢀ10À5 M). In solution, the acidic substrates and caffeine both
present in dynamic nature but the intermolecular hydrogen bond-
ing force is playing the major role to associate them. The binding
constant is a measurement of overall interaction of the two binding
components by hydrogen bonding including dipole–dipole forces,
stacking and hydrophobic interactions etc. So we studied the
UV–vis titration of the three acidic substrates with caffeine. The
binding of caffeine to substrates (phloroglucinol, isophthalic acid
and 5-hydroxyisophthalic acid) was evaluated by monitoring the
UV–vis intensity variations occurring as a continuous increase of
absorbance [35,36] (Fig. 8). Phloroglucinol, isophthalic acid and
5-hydroxyisophthalic acid have absorbance maxima in its UV–vis
spectra at kmax = 275, 277 and 275 nm, respectively in chloroform.
Bathochromic shifts are observed for all the receptors as a function
of increasing concentration of caffeine. From the Ka values (Table
4), it is clear that caffeine complexation is influenced by a number
of acid groups present in the receptors. It should be noted that the
binding constant of 5-hydroxyisophthalic acid is to some extent
greater than isophthalic acid which contains one extra phenolic –
OH group with respect to isophthalic acid.
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Supporting information available
The crystallographic data for the structures of these three co-
crystals A, B and C have been deposited with the Cambridge