Research Article Crystallographic and Computational Study ...downloads.hindawi.com/archive/2014/179671.pdfResearch Article Crystallographic and Computational Study of Purine: Caffeine

Research ArticleCrystallographic 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 Crystallography Laboratory, Solid State Department, Physics Division, National Research Centre, Dokki, Giza 12622, Egypt2 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 AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

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 spacegroup P2

1/c with unit cell parameters a = 15.2634 (9), b = 13.4692 (9), c = 11.9761 (7) A, and 𝛽 = 108.825 (3)∘. Although each

constituting moiety of the structure individually is planar, nonplanar configuration for the whole molecule was noticed. Molecularmechanics computations indicated the same nonplanar feature of thewholemolecule. A network of intermolecular hydrogen bondscontacts and 𝜋 interactions stabilized the structure.

1. Introduction

Caffeine(1,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimeth-yl-1H-purine-2,6-dione) is a well-known purine derivativeand can be biosynthesized naturally in plants from the purinenucleotides. Caffeine has wide range of pharmacologicalapplications due to its effects on the central nervous, heart,and vascular system [1, 2].

Purine ring system is one of the most heterocyclic ringsystems in nature possessing the potential to impact severalareas, such as a better understanding of the biological effect ofDNA damaging agents, enzymes/substrate interactions, andthe development of more potent medicines, such as antineo-plastic (anti abnormal tissue growth, tumor), antileukemic(blood cancer), anti-HIV (anti-human immunodeficiencyvirus), and antimicrobial. Moreover, caffeine has been foundto enhance anticancer activity of some chemotherapeuticagents and ionizing radiation. Previously, it was reportedthat methylxanthines may protect cells against the cytotoxic(poisonous to cells) effects and significantly decrease themutagenicity of the anticancer aromatic drugs [2].

Recently, the activity of the present compound has beenstudied and it was found to have a great pharmaceutical andpharmacological interest [2]. Neither the crystal structure nor

the molecular modeling has been reported yet. Therefore, inthe present work, we introduce the X-ray crystallographicanalysis of the molecular structure and discuss the resultswith the molecular mechanics computations; such resultsshould be valuable information in the fields of pharmaceuticsand pharmacology.

In computational terms, molecular mechanics is the leastexpensive and fastest method. It is a method to calculate thestructure and energy of molecules for providing excellentstructural parameters in terms of bond distances, angles, andso forth, for the most stable conformation of the molecules[3, 4]. Also,many literatures havementioned successful appli-cations for combining X-ray single crystal structure analysiswith computational studies, such as molecular mechanics invacuo calculations (M.M.) [5–7].

2. Materials and Methods

2.1. Synthesis. The target compound was prepared as the re-ported procedure [2] (Scheme 1), and the IR spectra wererecorded using KBr discs on a Perkin-Elmer 1430 spectro-photometer. Melting point was determined in open-glasscapillaries on a Gallenkamp melting point apparatus and isuncorrected.

Hindawi Publishing CorporationJournal of CrystallographyVolume 2014, Article ID 179671, 6 pageshttp://dx.doi.org/10.1155/2014/179671

2 Journal of Crystallography

H3C H3C

H3C

O

O

O

1

OO

ON

N

N

N

N

N

NN

N N

NN

N

CH3CH3

CH3

CH3

CH3

CH3

NHNH

NH

NH

NH

NH2

NH-R1

S

S

RR

= HR1

R1

= (CH2)3CH3

R 1NCS

4-RC 6H 4CO

CH2BR

Scheme 1: Chemical diagram of synthesis of the target compound.

The starting 8-hydrazinocaffeine (1) was prepared bythe treatment of 8-chlorocaffeine with hydrazine hydrate. Amixture of 8-(N-butylthiocarbamoylhydrazino)-3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (2mmole) and phenacylbromide (2 mmole) in absolute ethanol (20mL) was heatedunder reflux for 30 minutes. The reaction mixture was thenconcentrated and left to cool to room temperature. Theseparated crystalline product was filtered, dried, and recrys-tallized from ethanol.

2.2. X-Ray Single Crystal Measurements. Crystal was selectedand checked for imperfections such as cracks, bubbles,twining, or voids and mounted onto thin glass fibers andglued with epoxy glue. X-ray diffraction data was collectedat room temperature on an Enraf-Nonius 590 Kappa CCDsingle crystal diffractometer with graphite monochromatedMo-K𝛼 (𝜆 = 0.71073 A) radiation, at the National ResearchCenter of Egypt [8, 9].

Cell refinement and data reduction were carried usingDenzo and Scalepak programs [10].The crystal structure wassolved by direct method using SHELXS-97 program [11, 12]which revealed the positions of all nonhydrogen atoms andrefined by the full matrix least squares refinement based onF2 using maXus package [13]. The anisotropic displacementparameters of all nonhydrogen atoms were refined, and thenthe hydrogen atoms were introduced as a riding modelwith C–H = 0.96 A and refined isotropically. The moleculargraphicswere prepared usingORTEP [14],Diamond [15], andQmol [16] programs.

The crystal data is listed in Table 1. The crystallographicsupplementary data of C

21H26BrN7O2S can be obtained

Table 1: Crystal data of the title compound.

Crystal dataChemical formula,𝑀

𝑟C21H26BrN7O2S, 536.519

Crystal system, space group Monoclinic, P21/c

𝑎, 𝑏, 𝑐 (A) 15.2634(9), 13.4692(9),11.9761(7)

𝛽 (∘) 108.825(3)𝑉 (A3),𝐷

𝑥(Mgm−3), 𝑍 2330.4(2), 1.529, 4

𝜇 (mm−1), temperature (K) 1.97, 298𝜃 (∘), 𝐹(000) 2.9–27.5, 1072

Refinement

Limits of Miller indices −19 ≤ ℎ ≤ 19, −15 ≤ 𝑘 ≤ 17,−15 ≤ ℓ ≤ 15

𝑅 [𝐹2 > 3𝜎 (𝐹2)], 𝑤𝑅 (𝐹2) 0.058, 0.106Number of reflections,parameters, and restraints 2675, 292, 0

free of charge using deposit number CCDC 697338, viahttp://www.ccdc.cam.ac.uk/conts/retrieving.html or from theCambridge Crystallographic Data Centre, Cambridge, UK.

2.3. Molecular Mechanics Computations. Molecular mechan-ics in vacuo computationswere carried out usingHyperChempackage [17]. The Molecular Mechanics (MM+) force fieldwas used as it is developed principally for organic molecules[4, 18, 19].Theprocess of energyminimizationwas carried out

Journal of Crystallography 3

C8

N4C1

H4aC4

H4b

H4c

N5C2

O2

N6C5

H5c

H5a

O1

C3 C6 N7

C7

H7b

H7c

H7a

N3

H3

N2

N1

C9

S1 C10

H10

C11C12 C13

H13C14

H14

C15H15

C16

H16

C17

H17

C18

H18aH18b

C19H19a

H19b

H20aH20b

C20

H21b

C21

H21a

H21c

Br1H40

H5b

Figure 1: The 50% probability displacement ellipsoids representation of the present compound.

by Steepest Descents Method. The conformational energy ofthe molecule was calculated.

3. Results and Discussions

3.1. Crystal Structure Description. An ORTEP diagram with50% probability displacement ellipsoids of the molecularstructure is shown in Figure 1. The structure consists mainlyof caffeine group linked with thiazole ring through hydrazineat C8, thiazole ring attached with butane, and phenyl ring.Each constituting moiety of the compound individuallyshowed planar configuration; which can be noticed fromthe best plane calculations; where the maximum deviationswere corresponding to C11, −0.0251 (5) in thiazole, C16,0.0099 (6) in phenyl, and C7, 0.0967 (5) A in caffeine group.However, nonplanar configuration for the whole moleculeis noted, whereas the dihedral angle between phenyl ringand thiazole ring is 66.22(3)∘. Also, the tilting angle betweenthe thiazole ring and caffeine group is 68.94(4)∘ and butaneplane is 84.98(4)∘. The nonplanarity feature that has beenobserved in thismoleculemay be attributed to the effect of thesteric hindrance interaction between the different moietiescomposing it and the heavy substitution effect of butanemoiety at N1.

The average values of bond lengths and angles are almostwithin the expected range and in consent with similar struc-tures [20]. The structure packing was stabilized by a networkof intermolecular hydrogen bonds contacts, N–H⋅ ⋅ ⋅Br, and𝜋interactions 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 thecenter of gravity of C12–C17 ring.

Bond length (A) 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)i1 − 𝑋, 1/2 + 𝑌, and 1/2 − 𝑍.

3.2. Molecular Mechanics. Figure 3 represents the obtainedmolecular structure of the present compound using molec-ular mechanics calculations; comparison with that obtainedcrystallographically is given in Figure 4. The minimumenergy structure obtained by molecular mechanics of theinvestigated compound to some extent matches the crystalstructures obtained experimentally.

The global minimum energy conformation of the mol-ecule has the values 30.3 and 31.46 kcal/mol, for themolecularstructures obtained experimentally (Exp.) and using molecu-lar mechanics (M.M.) respectively. Unexpectedly, the crystalstructure has the lower value, although it was reported thatthe crystal structure causes the molecules to adopt higher-energy conformations, which corresponds to local minimain the molecular potential energy surface. This is may be dueto that the total potential energy in crystal structure of thepresent compound is affected by the steric hindrance.

It is noticeable from Table 3 and Figure 3 that the dimen-sions of the caffeine group, thiazole ring, phenyl ring, andbutane obtained theoretically agree to some extent with thoseobtained experimentally with X-ray diffraction. However,


Table 3: Selected geometrical values of the experimentally and molecular mechanics obtained structures of the compound.

Angles (∘) Exp. M.M. Bond length (A) Exp. M.M.C9–S1–C10 89.47(13) 89.43 S1–C9 1.715(3) 1.810C6–N7–C8 104.6(2) 103.15 N7–C6 1.410(3) 1.436C1–N4–C8 102.1(2) 102.82 O1–C3 1.216(3) 1.212C1–N5–C2 119.4(2) 118.81 N1–C18 1.493(3) 1.489C9–N1–C11 112.1(2) 111.37 S1–C10 1.723(3) 1.809N1–C18–C19 111.6(2) 115.07 C6–C3 1.415(4) 1.355C10–C11–C12–C13 62.4(6) 5.38 N3–N2 1.396(3) 1.354N5–C1–C6–N7 179.2(7) 179.03 C17–C12 1.394(4) 1.349C10–C11–N1–C18 170.1(7) 104.36 C2–O2 1.230(3) 1.210C11–C12–C13–C14 179.0(8) 179.76 N6–C5 1.458(4) 1.452C11–C12–C17–C16 179.6(9) 179.74 C19–C20 1.531(4) 1.538

BrSNC

OHcg

b c

a

Figure 2: The molecular packing of the title compound with the intermolecular interactions. The N–H⋅ ⋅ ⋅Br and C–H⋅ ⋅ ⋅ 𝜋 (cg) interactionsare shown as green and brown dashed lines, respectively.

H5CH5B

H5A

O1

C3

N6

C2

C5

O2

C6

C1

N5

C4H4CH4B

H7CH7A H7B

C7

N7

C8

N4

H4A

N2

N3

H3

S1

C9

N1

H18AH18B

H19B

H19AC19

H20AC20

C18

H21BC21

H21C

H20B

H21A

H10

C10

C11

H17

H13

C12

C17

C13

C16

H16

C14

C15

H14

H15

Figure 3: Molecular graphics of the title compound as obtained by M.M.

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 agood agreement with the X-ray crystal structure. Moreover,the values of C10–C11–C12–C13 and C10–C11–N1–C18 torsionangles have a considerable difference between theoretical andexperimental results, as shown in Figure 4.

This variation may be because of the steric hindranceeffect within the whole molecule, which has been noticed inthe crystal structure. Also, the effect of the above-mentionedintermolecular contacts (Figure 2) is in agreement with whathave been found in similar studies [5–7].

4. Conclusions

Crystallographic and computational study of purine, caffeinederivative, 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 P2

1/c space group, and showed

nonplanar features of the whole molecule, which may havecome from steric hindrance effect, which also may cause themolecules to be in a lower-energy conformation.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

The authors thank the Pharmaceutical Chemistry Group [2],Faculty of Pharmacy, Alexandria University, Egypt, for sup-plying them with the materials. They also would like to offerthanks to the kind soul of Professor Naima Abdel-KaderAhmed (Crystallography Laboratory, NRC, Egypt), who gavethem the idea of the present work.

References

[1] H. Ashihara, A. M. Monteiro, F. M. Gillies, and A. Crozier,“Biosynthesis of caffeine in leaves of coffee,” Plant Physiology,vol. 111, no. 3, pp. 747–753, 1996.

[2] S. M. Rida, F. A. Ashour, S. A. M. El-Hawash, M. M. El-Semary,and M. H. Badr, “Synthesis of some novel substituted purinederivatives as potential anticancer, anti-HIV-1 and antimicro-bial agents,” Archiv der Pharmazie, vol. 340, no. 4, pp. 185–194,2007.

[3] A. Leach, Molecular Modelling: Principles and Applications,Prentice Hall, 2nd edition, 2001.

[4] N. L. Allinger, “Conformational analysis. 130. MM2. A hydro-carbon force field utilizing V1 and V2 torsional terms,” Journalof the American Chemical Society, vol. 99, no. 25, pp. 8127–8134,1977.

[5] O. Q. Munro and L. Mariah, “Conformational analysis: crystal-lographic, mole-cular mechanics and quantum chemical stud-ies of C-H...O hydrogen bonding in the flexible bis(nosylate)derivative of catechol,” Acta Crystallographica B: StructuralScience, vol. 60, no. 5, pp. 598–608, 2004.

[6] J. C. Burley, R. Gilmour, T. J. Prior, and G. M. Day, “Structuraldiversity in imidazolidinone organocatalysts: a synchrotronand computational study,” Acta Crystallographica C: CrystalStructure Communications, vol. 64, no. 1, pp. o10–o14, 2007.

[7] H. Novoa De Armas, E. Ruiz Reyes, E. Salfran Solano, M.Suarez Navarro, and N. Blaton, “Methyl [(1E)-(4-methoxy-phen-yl)methyl-eneamino]acetate,” Acta Crystallographica E:Structure Reports Online, vol. 63, no. 3, Article ID fj2002, pp.o1459–o1461, 2007.

[8] X-ray Crystallography Lab., National Research Center of Egypt(NRC), http://www.xrdlab-nrc-eg.org/.

[9] Enraf-Nonius, COLLECT, Nonius BV, Delft, The Netherlands,1998.

[10] Z. Otwinowski and W. Minor, “Processing of X-ray diffractiondata collected in oscillationmode,”Methods in Enzymology, vol.276, pp. 307–326, 1997.

[11] G. M. Sheldrick, “A short history of SHELX,” Acta Crystallo-graphica A: Foundations of Crystallography, vol. 64, no. 1, pp.112–122, 2007.


[12] G. M. Sheldrick, SHELXS-97-A Program For Crystal StructureDetermination, University of Gottingen, Gottingen, Germany,1997.

[13] S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, and K.Shankland, MaXus Computer Program For the Solution andRefinement of Crystal Structures, Japan & the University ofGlasgow, Madison, Wis, USA, 1999.

[14] L. J. Farrugia, “ORTEP-3 for windows—a version of ORTEP-III with a graphical user interface (GUI),” Journal of AppliedCrystallography, vol. 30, no. 5, p. 565, 1997.

[15] K. Brandenburg, DIAMOND Software, Crystal Impact GbR,Bonn, Germany, 2012.

[16] J. D. Gans and D. Shalloway, “Qmol: a program for molecularvisualization on Windows-based PCs,” Journal of MolecularGraphics and Modelling, vol. 19, no. 6, pp. 557–609, 2001.

[17] HyperChem (TM) Professional 7. 51, Hypercube, Inc., 1115 NW4th Street, Gainesville, Florida 32601, USA.

[18] N. L. Allinger and Y. H. Yuh, Quantum Chemistry ProgramExchange, Bloomington, Indiana, Program No. 395, MolecularMechanics, Burkert, U.; Allinger, N.L., Ed., ACS Monograph 177,American Chemical Society, Washington, DC, USA, 1982.

[19] J.-H. Lii and N. L. Allinger, “Molecular Mechanics. The MM3force field for hydrocarbons. 3. The van der Waals’ potentialsand crystal data for aliphatic and aromatic hydrocarbons,”Journal of the American Chemical Society, vol. 111, no. 23, pp.8576–8582, 1989.

[20] A. Chandramohan, D. Gayathri, D. Velmurugan, K. Ravikumar,and M. A. Kandhaswamy, “1,3,7-Trimethylxanthenium 2,4,6-trinitrophenolate,” Acta Crystallographica E: Structure ReportsOnline, vol. 63, no. 5, pp. o2495–o2496, 2007.

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Research Article Crystallographic and Computational Study ...downloads.hindawi.com/archive/2014/179671.pdfResearch Article Crystallographic and Computational Study of Purine: Caffeine