# Crystallographic and Computational Study of Purine: Caffeine Derivative

Authors: Ahmed F. Mabied; Elsayed M. Shalaby; Hamdia A. Zayed; Ibrahim S. A. Farag
Journal: Journal of Crystallography
 (2014)

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## Abstract

The crystal structure of substituted purine derivative, 8-(3-butyl-4-phenyl-2,3-dihydrothiazol-2-ylidene)hydrazino-3,7-dihydro-1,3,7-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.


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## Body

## 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 mechanicsin 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.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-dihydro-1,3,7-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 onF² 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 Table1. The crystallographic supplementary data of C21H26BrN7O2S can be obtained 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.Table 1
Crystal data of the title compound.
Crystal data
Chemical formula,M
r
C21H26BrN7O2S, 536.519
Crystal system, space group
Monoclinic, P21/c
a, b, c (Å)
15.2634(9), 13.4692(9), 11.9761(7)
β (°)
108.825(3)
V (Å
3), D
x (Mg m−3), Z
2330.4(2), 1.529, 4
μ (mm−1), temperature (K)
1.97, 298
θ (°), F(000)
2.9–27.5, 1072
Refinement
Limits of Miller indices
-
19
≤
h
≤
19, -
15
≤
k
≤
17, -
15
≤
ℓ
≤
15
R
[
F
2
>
3
σ
(
F
2
)
], w
R
(
F
2
)
0.058, 0.106
Number of reflections, parameters, and restraints
2675, 292, 0


### 2.3. Molecular Mechanics Computations

Molecular mechanicsin 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 by Steepest Descents Method. The conformational energy of the molecule was calculated.


## 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.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-dihydro-1,3,7-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 onF² 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 Table1. The crystallographic supplementary data of C21H26BrN7O2S can be obtained 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.Table 1
Crystal data of the title compound.
Crystal data
Chemical formula,M
r
C21H26BrN7O2S, 536.519
Crystal system, space group
Monoclinic, P21/c
a, b, c (Å)
15.2634(9), 13.4692(9), 11.9761(7)
β (°)
108.825(3)
V (Å
3), D
x (Mg m−3), Z
2330.4(2), 1.529, 4
μ (mm−1), temperature (K)
1.97, 298
θ (°), F(000)
2.9–27.5, 1072
Refinement
Limits of Miller indices
-
19
≤
h
≤
19, -
15
≤
k
≤
17, -
15
≤
ℓ
≤
15
R
[
F
2
>
3
σ
(
F
2
)
], w
R
(
F
2
)
0.058, 0.106
Number of reflections, parameters, and restraints
2675, 292, 0


## 2.3. Molecular Mechanics Computations

Molecular mechanicsin 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 by Steepest Descents Method. The conformational energy of the molecule was calculated.


## 3. Results and Discussions

### 3.1. Crystal Structure Description

An ORTEP diagram with 50% probability displacement ellipsoids of the molecular structure is shown in Figure1. 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.Figure 1
The 50% probability displacement ellipsoids representation of the present compound.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.Table 2
Hydrogen-bonding geometry for the structure; cg is the center of gravity of C12–C17 ring.
Bond length (Å)
Bond angle (°)
D–H
H⋯A
D⋯A
D–H⋯A
N3–H3⋯Bri
0.960(4)
2.53(5)
3.334(4)
141(5)
C13–H13⋯Cgi
0.960(3)
2.64(2)
3.439(7)
141(3)
i
1
-
X, 1
/
2
+
Y, and 1
/
2
-
Z.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.


### 3.2. Molecular Mechanics

Figure3 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.Figure 3
Molecular graphics of the title compound as obtained by M.M.Figure 4
The X-ray crystal structure (green) and the structure of the one obtained by M.M. (red) of the target compound.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 higher-energy 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 Table3 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, 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.Table 3
Selected geometrical values of the experimentally and molecular mechanics obtained structures of the compound.
Angles (°)
Exp.
M.M.
Bond length (Å)
Exp.
M.M.
C9–S1–C10
89.47(13)
89.43
S1–C9
1.715(3)
1.810
C6–N7–C8
104.6(2)
103.15
N7–C6
1.410(3)
1.436
C1–N4–C8
102.1(2)
102.82
O1–C3
1.216(3)
1.212
C1–N5–C2
119.4(2)
118.81
N1–C18
1.493(3)
1.489
C9–N1–C11
112.1(2)
111.37
S1–C10
1.723(3)
1.809
N1–C18–C19
111.6(2)
115.07
C6–C3
1.415(4)
1.355
C10–C11–C12–C13
62.4(6)
5.38
N3–N2
1.396(3)
1.354
N5–C1–C6–N7
179.2(7)
179.03
C17–C12
1.394(4)
1.349
C10–C11–N1–C18
170.1(7)
104.36
C2–O2
1.230(3)
1.210
C11–C12–C13–C14
179.0(8)
179.76
N6–C5
1.458(4)
1.452
C11–C12–C17–C16
179.6(9)
179.74
C19–C20
1.531(4)
1.538This 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 (Figure2) is in agreement with what have been found in similar studies [5–7].


## 3.1. Crystal Structure Description

An ORTEP diagram with 50% probability displacement ellipsoids of the molecular structure is shown in Figure1. 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.Figure 1
The 50% probability displacement ellipsoids representation of the present compound.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.Table 2
Hydrogen-bonding geometry for the structure; cg is the center of gravity of C12–C17 ring.
Bond length (Å)
Bond angle (°)
D–H
H⋯A
D⋯A
D–H⋯A
N3–H3⋯Bri
0.960(4)
2.53(5)
3.334(4)
141(5)
C13–H13⋯Cgi
0.960(3)
2.64(2)
3.439(7)
141(3)
i
1
-
X, 1
/
2
+
Y, and 1
/
2
-
Z.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.


## 3.2. Molecular Mechanics

Figure3 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.Figure 3
Molecular graphics of the title compound as obtained by M.M.Figure 4
The X-ray crystal structure (green) and the structure of the one obtained by M.M. (red) of the target compound.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 higher-energy 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 Table3 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, 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.Table 3
Selected geometrical values of the experimentally and molecular mechanics obtained structures of the compound.
Angles (°)
Exp.
M.M.
Bond length (Å)
Exp.
M.M.
C9–S1–C10
89.47(13)
89.43
S1–C9
1.715(3)
1.810
C6–N7–C8
104.6(2)
103.15
N7–C6
1.410(3)
1.436
C1–N4–C8
102.1(2)
102.82
O1–C3
1.216(3)
1.212
C1–N5–C2
119.4(2)
118.81
N1–C18
1.493(3)
1.489
C9–N1–C11
112.1(2)
111.37
S1–C10
1.723(3)
1.809
N1–C18–C19
111.6(2)
115.07
C6–C3
1.415(4)
1.355
C10–C11–C12–C13
62.4(6)
5.38
N3–N2
1.396(3)
1.354
N5–C1–C6–N7
179.2(7)
179.03
C17–C12
1.394(4)
1.349
C10–C11–N1–C18
170.1(7)
104.36
C2–O2
1.230(3)
1.210
C11–C12–C13–C14
179.0(8)
179.76
N6–C5
1.458(4)
1.452
C11–C12–C17–C16
179.6(9)
179.74
C19–C20
1.531(4)
1.538This 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 (Figure2) 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.



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*Source: 179671-2014-03-30.xml*