pubs.acs.org/crystal Published on Web 12/10/2009 r 2009 American Chemical Society DOI: 10.1021/cg9012685 2010, Vol. 10 937–942 Supramolecular Assembly of Protonated Xanthine Alkaloids in Their Perchlorate Salts Kumar Biradha,* ,§ Suman Samai, § Annada C. Maity, # and Shyamaprosad Goswami* ,# § Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, West Bengal, India and # Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103, West Bengal, India Received October 13, 2009; Revised Manuscript Received November 15, 2009 ABSTRACT: Single crystal X-ray structures of new perchlorate salts of a series of four xanthine alkaloids, for example, xanthine (xt), caffeine (cf), theophylline (tp), and theobromine (tb) are reported. The treatment of xanthine derivatives with 70% of HClO 4 afforded their salts Hxt 3 ClO 4 3 2(H 2 O), 1; Htp 3 ClO 4 , 2; Htb 3 ClO 4 , 3; and Hcf 3 ClO 4 3 H 2 O, 4. Xanthine form dimers via N(9)-H 333 O-C(6) hydrogen bond in the crystal structure. Of the two possible resonance structures of the protonated imidazoles, one of the structures was found to be major in xanthine, theobromine, and caffeine salts, while both structures are of equal contribution in theophylline salts. These observations also have been verified by using the structural information available in the Cambridge Structural Database. Interestingly, xanthine 1 is present as a dihydrate and 4 as a monohydrate, whereas 2 and 3 are crystallized without any water. Thus, proton transfer from the strong acid HClO 4 to the weakly basic imidazole ring of xanthines occurs which leads to the build up of H-bonded supramolecular networks. Introduction Caffeine, theophylline, and theobromine are methyl-sub- stituted analogues of xanthine which are commonly used as mild stimulants and bronchodilators for treating the symp- toms of asthma. Xanthine is known as dioxopurine which is a biologically important component of nucleic acids (DNA, RNA) and coenzymes. Caffeine, theobromine, and theo- phylline are key ingredients in coffee, chocolate, and tea leaves, respectively. The crystal structures of caffeine, theo- phylline, and theobromine hydrates and/or anhydrates, their transformations from hydrates to anhydrates, and polymorphism are well studied and still of continuing inter- est. 1 The interest in these studies can be attributed to requirement of crystalline forms of active drug molecules in the pharmaceutical industry. 2-11 The advantages of crystalline forms are their purity, stability, and clear under- standing of their structures. Several cocrystals or salts of caffeine, theophylline, and theobromine with carboxylic acids were reported recently. 12-20 These cocrystals were shown to have better properties than the individual compo- nents. On the other hand, the structures of their inorganic acid salts (HClO 4 , HCl, or H 2 SO 4 ) were not explored to date. Unlike organic acids, inorganic acids are very strong, more selective, and directional, which make them ideal for geometry-based crystal design. 21 In this paper, we would like to present the crystal structures of perchlorate slats of caffeine, theophylline, theobromine, and xanthine. Gene- rally, perchlorates are also used as medicine for treating thyroid gland disorders as they can temporarily and rever- sibly inhibit the ability of the thyroid gland to absorb iodine from the bloodstream; thus, perchlorate is known as goitro- gen. Second, perchlorate salts are more soluble in water, and most of them form good crystalline materials. Some of us recently reported the bridging of hydrogen bonded dimers of lumazine by H 5 O 2 þ in its perchlorate salt. 22 The sp 2 nitrogen of imidazole ring has a higher affinity to react with acids due to its more basic nature in all four struc- tures. The treatment of xanthine derivatives with 70% of HClO 4 resulted in their salts Hxt 3 ClO 4 3 2(H 2 O), 1; Htp 3 ClO 4 , 2; Htb 3 ClO 4 , 3; and Hcf 3 ClO 4 3 H 2 O, 4 (xanthine (xt), caffeine (cf), theophylline (tp), and theobromine (tb)). The crystal structures of these salts were determined (Figure 1) and analyzed in terms of their hydrogen bonding associations. The crystallographic parameters are given in Table 1 and hydrogen bonding para- meters are given in Table 2. We are interested in exploring the following aspects by studying the crystal structures of 1-4. (1) How does the association of the cations differ from their neutral counterparts? (2) What is the role of ClO 4 ions in assembling the cations? (3) In principle, two resonance forms are possible for the protonated xanthine derivatives (Scheme 1). Which of these two forms appears in the crystal structures? Scheme 1 *To whom correspondence should be addressed. (K.B.) Fax:þ91-3222- 282252; tel: þ91-3222-283346; e-mail: kbiradha@chem.iitkgp.ernet.in. (S.G.) Fax: þ91-33-2668-2916; e-mail: spgoswamical@yahoo.com.