Hindawi Publishing Corporation
Journal of Crystallography
Volume 2014, Article ID 179671, 6 pages
http://dx.doi.org/10.1155/2014/179671
Research Article
Crystallographic and Computational Study of Purine:
Caffeine Derivative
Ahmed F. Mabied,1 Elsayed M. Shalaby,1 Hamdia A. Zayed,2 and Ibrahim S. A. Farag1
1
2
Crystallography Laboratory, Solid State Department, Physics Division, National Research Centre, Dokki, Giza 12622, Egypt
Physics Department, Women’s College, Ain Shams University, Cairo 11757, Egypt
Correspondence should be addressed to Ahmed F. Mabied; [email protected]
Received 30 November 2013; Accepted 12 February 2014; Published 30 March 2014
Academic Editor: Mehmet Akkurt
Copyright © 2014 Ahmed F. Mabied et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
The crystal structure of substituted purine derivative, 8-(3-butyl-4-phenyl-2,3-dihydrothiazol-2-ylidene)hydrazino-3,7-dihydro1,3,7-trimethyl-1H-purine-2,6-diones, caffeine derivative, has been determined. It crystallized in monoclinic system and space
group P21 /c with unit cell parameters a = 15.2634 (9), b = 13.4692 (9), c = 11.9761 (7) Å, and 𝛽 = 108.825 (3)∘ . Although each
constituting moiety of the structure individually is planar, nonplanar configuration for the whole molecule was noticed. Molecular
mechanics computations indicated the same nonplanar feature of the whole molecule. A network of intermolecular hydrogen bonds
contacts and 𝜋 interactions stabilized the structure.
1. Introduction
Caffeine (1,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione) is a well-known purine derivative
and can be biosynthesized naturally in plants from the purine
nucleotides. Caffeine has wide range of pharmacological
applications due to its effects on the central nervous, heart,
and vascular system [1, 2].
Purine ring system is one of the most heterocyclic ring
systems in nature possessing the potential to impact several
areas, such as a better understanding of the biological effect of
DNA damaging agents, enzymes/substrate interactions, and
the development of more potent medicines, such as antineoplastic (anti abnormal tissue growth, tumor), antileukemic
(blood cancer), anti-HIV (anti-human immunodeficiency
virus), and antimicrobial. Moreover, caffeine has been found
to enhance anticancer activity of some chemotherapeutic
agents and ionizing radiation. Previously, it was reported
that methylxanthines may protect cells against the cytotoxic
(poisonous to cells) effects and significantly decrease the
mutagenicity of the anticancer aromatic drugs [2].
Recently, the activity of the present compound has been
studied and it was found to have a great pharmaceutical and
pharmacological interest [2]. Neither the crystal structure nor
the molecular modeling has been reported yet. Therefore, in
the present work, we introduce the X-ray crystallographic
analysis of the molecular structure and discuss the results
with the molecular mechanics computations; such results
should be valuable information in the fields of pharmaceutics
and pharmacology.
In computational terms, molecular mechanics is the least
expensive and fastest method. It is a method to calculate the
structure and energy of molecules for providing excellent
structural parameters in terms of bond distances, angles, and
so forth, for the most stable conformation of the molecules
[3, 4]. Also, many literatures have mentioned successful applications for combining X-ray single crystal structure analysis
with computational studies, such as molecular mechanics in
vacuo calculations (M.M.) [5–7].
2. Materials and Methods
2.1. Synthesis. The target compound was prepared as the reported procedure [2] (Scheme 1), and the IR spectra were
recorded using KBr discs on a Perkin-Elmer 1430 spectrophotometer. Melting point was determined in open-glass
capillaries on a Gallenkamp melting point apparatus and is
uncorrected.
2
Journal of Crystallography
O
CH3
H3 C
O
N
N
O
NH
NH2
1
N
N
NH
N
CH3
H3 C
N
N
CH3
CH3
R1
R1 NCS
4
O
H3 C
O
NH
N
N
O
NH
N
CH3
C
H4
C6
R
-
BR
H2
C
O
R=H
R1 = (CH2 )3 CH3
R
CH3
N
N
S
N
S
NH
NH-R1
Scheme 1: Chemical diagram of synthesis of the target compound.
The starting 8-hydrazinocaffeine (1) was prepared by
the treatment of 8-chlorocaffeine with hydrazine hydrate. A
mixture of 8-(N-butylthiocarbamoylhydrazino)-3,7-dihydro1,3,7-trimethyl-1H-purine-2,6-dione (2 mmole) and phenacyl
bromide (2 mmole) in absolute ethanol (20 mL) was heated
under reflux for 30 minutes. The reaction mixture was then
concentrated and left to cool to room temperature. The
separated crystalline product was filtered, dried, and recrystallized from ethanol.
2.2. X-Ray Single Crystal Measurements. Crystal was selected
and checked for imperfections such as cracks, bubbles,
twining, or voids and mounted onto thin glass fibers and
glued with epoxy glue. X-ray diffraction data was collected
at room temperature on an Enraf-Nonius 590 Kappa CCD
single crystal diffractometer with graphite monochromated
Mo-K𝛼 (𝜆 = 0.71073 Å) radiation, at the National Research
Center of Egypt [8, 9].
Cell refinement and data reduction were carried using
Denzo and Scalepak programs [10]. The crystal structure was
solved by direct method using SHELXS-97 program [11, 12]
which revealed the positions of all nonhydrogen atoms and
refined by the full matrix least squares refinement based on
F 2 using maXus package [13]. The anisotropic displacement
parameters of all nonhydrogen atoms were refined, and then
the hydrogen atoms were introduced as a riding model
with C–H = 0.96 Å and refined isotropically. The molecular
graphics were prepared using ORTEP [14], Diamond [15], and
Qmol [16] programs.
The crystal data is listed in Table 1. The crystallographic
supplementary data of C21 H26 BrN7 O2 S can be obtained
Table 1: Crystal data of the title compound.
Crystal data
Chemical formula, 𝑀𝑟
Crystal system, space group
𝑎, 𝑏, 𝑐 (Å)
𝛽 (∘ )
3
𝑉 (Å ), 𝐷𝑥 (Mg m−3 ), 𝑍
𝜇 (mm−1 ), temperature (K)
𝜃 (∘ ), 𝐹(000)
Refinement
Limits of Miller indices
𝑅 [𝐹2 > 3𝜎 (𝐹2 )], 𝑤𝑅 (𝐹2 )
Number of reflections,
parameters, and restraints
C21 H26 BrN7 O2 S, 536.519
Monoclinic, P21 /c
15.2634(9), 13.4692(9),
11.9761(7)
108.825(3)
2330.4(2), 1.529, 4
1.97, 298
2.9–27.5, 1072
−19 ≤ ℎ ≤ 19, −15 ≤ 𝑘 ≤ 17,
−15 ≤ ℓ ≤ 15
0.058, 0.106
2675, 292, 0
free of charge using deposit number CCDC 697338, via
http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, Cambridge, UK.
2.3. Molecular Mechanics Computations. Molecular mechanics in vacuo computations were carried out using HyperChem
package [17]. The Molecular Mechanics (MM+) force field
was used as it is developed principally for organic molecules
[4, 18, 19]. The process of energy minimization was carried out
Journal of Crystallography
3
H10
S1
C10
H7c
H7a
O1
H5c
C5
H5a
C3
C11
H3
H7b
N7
H4c
O2
H4b
C16
C18
H18a
H4a
C4
H40
C14
H14
C15
H17
N2
N4
C1
C13
C17
N1
C8
N5
C12
C9
N3
N6
C2
H5b
C6
H13
C7
H16
H19b
H19a
H18b
Br1
H15
C19
C20
H21c
H20b
H20a
H21b
C21
H21a
Figure 1: The 50% probability displacement ellipsoids representation of the present compound.
by Steepest Descents Method. The conformational energy of
the molecule was calculated.
Table 2: Hydrogen-bonding geometry for the structure; cg is the
center of gravity of C12–C17 ring.
3. Results and Discussions
3.1. Crystal Structure Description. An ORTEP diagram with
50% probability displacement ellipsoids of the molecular
structure is shown in Figure 1. The structure consists mainly
of caffeine group linked with thiazole ring through hydrazine
at C8, thiazole ring attached with butane, and phenyl ring.
Each constituting moiety of the compound individually
showed planar configuration; which can be noticed from
the best plane calculations; where the maximum deviations
were corresponding to C11, −0.0251 (5) in thiazole, C16,
0.0099 (6) in phenyl, and C7, 0.0967 (5) Å in caffeine group.
However, nonplanar configuration for the whole molecule
is noted, whereas the dihedral angle between phenyl ring
and thiazole ring is 66.22(3)∘ . Also, the tilting angle between
the thiazole ring and caffeine group is 68.94(4)∘ and butane
plane is 84.98(4)∘ . The nonplanarity feature that has been
observed in this molecule may be attributed to the effect of the
steric hindrance interaction between the different moieties
composing it and the heavy substitution effect of butane
moiety at N1.
The average values of bond lengths and angles are almost
within the expected range and in consent with similar structures [20]. The structure packing was stabilized by a network
of intermolecular hydrogen bonds contacts, N–H⋅ ⋅ ⋅ Br, and 𝜋
interactions between C13–H13 and the center of gravity (cg)
of C12–C17 ring, as shown in Table 2 and Figure 2.
N3–H3⋅ ⋅ ⋅ Bri
C13–H13⋅ ⋅ ⋅ Cgi
i
Bond length (Å)
D–H
H⋅ ⋅ ⋅ A
D⋅ ⋅ ⋅ A
0.960(4) 2.53(5) 3.334(4)
0.960(3) 2.64(2) 3.439(7)
Bond angle (∘ )
D–H⋅ ⋅ ⋅ A
141(5)
141(3)
1 − 𝑋, 1/2 + 𝑌, and 1/2 − 𝑍.
3.2. Molecular Mechanics. Figure 3 represents the obtained
molecular structure of the present compound using molecular mechanics calculations; comparison with that obtained
crystallographically is given in Figure 4. The minimum
energy structure obtained by molecular mechanics of the
investigated compound to some extent matches the crystal
structures obtained experimentally.
The global minimum energy conformation of the molecule has the values 30.3 and 31.46 kcal/mol, for the molecular
structures obtained experimentally (Exp.) and using molecular mechanics (M.M.) respectively. Unexpectedly, the crystal
structure has the lower value, although it was reported that
the crystal structure causes the molecules to adopt higherenergy conformations, which corresponds to local minima
in the molecular potential energy surface. This is may be due
to that the total potential energy in crystal structure of the
present compound is affected by the steric hindrance.
It is noticeable from Table 3 and Figure 3 that the dimensions of the caffeine group, thiazole ring, phenyl ring, and
butane obtained theoretically agree to some extent with those
obtained experimentally with X-ray diffraction. However,
4
Journal of Crystallography
Table 3: Selected geometrical values of the experimentally and molecular mechanics obtained structures of the compound.
Angles (∘ )
C9–S1–C10
C6–N7–C8
C1–N4–C8
C1–N5–C2
C9–N1–C11
N1–C18–C19
C10–C11–C12–C13
N5–C1–C6–N7
C10–C11–N1–C18
C11–C12–C13–C14
C11–C12–C17–C16
Exp.
89.47(13)
104.6(2)
102.1(2)
119.4(2)
112.1(2)
111.6(2)
62.4(6)
179.2(7)
170.1(7)
179.0(8)
179.6(9)
M.M.
89.43
103.15
102.82
118.81
111.37
115.07
5.38
179.03
104.36
179.76
179.74
Bond length (Å)
S1–C9
N7–C6
O1–C3
N1–C18
S1–C10
C6–C3
N3–N2
C17–C12
C2–O2
N6–C5
C19–C20
Exp.
1.715(3)
1.410(3)
1.216(3)
1.493(3)
1.723(3)
1.415(4)
1.396(3)
1.394(4)
1.230(3)
1.458(4)
1.531(4)
M.M.
1.810
1.436
1.212
1.489
1.809
1.355
1.354
1.349
1.210
1.452
1.538
a
b
Br
S
N
C
c
O
H
cg
Figure 2: The molecular packing of the title compound with the intermolecular interactions. The N–H⋅ ⋅ ⋅ Br and C–H⋅ ⋅ ⋅ 𝜋 (cg) interactions
are shown as green and brown dashed lines, respectively.
H7C
H7A
C7
O1
H5C
N2
C6
C8
N6
H5A
N4
N1
N5
C4
H4C
H4B
H4A
H20A
C20
H21B H20B
H10
H13
C11
H18A C18
H19A
C19
O2
C10
C9
N3
H3
C1
C2
S1
N7
C3
H5B
C5
H7B
C12
H17 C17
H18B
C13
C16
H16
H19B
C21
H21C
H21A
Figure 3: Molecular graphics of the title compound as obtained by M.M.
C14
H14
C15
H15
Journal of Crystallography
5
Figure 4: The X-ray crystal structure (green) and the structure of the one obtained by M.M. (red) of the target compound.
the structure obtained theoretically as a whole is not in a
good agreement with the X-ray crystal structure. Moreover,
the values of C10–C11–C12–C13 and C10–C11–N1–C18 torsion
angles have a considerable difference between theoretical and
experimental results, as shown in Figure 4.
This variation may be because of the steric hindrance
effect within the whole molecule, which has been noticed in
the crystal structure. Also, the effect of the above-mentioned
intermolecular contacts (Figure 2) is in agreement with what
have been found in similar studies [5–7].
4. Conclusions
Crystallographic and computational study of purine, caffeine
derivative, 8-(3-butyl-4-phenyl-2,3-dihydrothiazol-2-ylidene)
hydrazino-3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-diones,
was introduced. The study reported the crystal structure,
monoclinic system with P21 /c space group, and showed
nonplanar features of the whole molecule, which may have
come from steric hindrance effect, which also may cause the
molecules to be in a lower-energy conformation.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
Acknowledgments
The authors thank the Pharmaceutical Chemistry Group [2],
Faculty of Pharmacy, Alexandria University, Egypt, for supplying them with the materials. They also would like to offer
thanks to the kind soul of Professor Naima Abdel-Kader
Ahmed (Crystallography Laboratory, NRC, Egypt), who gave
them the idea of the present work.
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