Theobromine 3,7-dimethylxanthine

Tea leaf contains 2.5-4.0% caffeine (1,3,7-trimethylxanthine) on a dry weight basis and smaller quantities of the related methylxanthines, theobromine (3,7-dimethylxanthine 0.2-0.4%) and theophylline (1,3-dimethylxanthine ca. 0.02%). Although it is said that var. sinensis is slightly lower in caffeine than var. assamica, black, green and oolong tea beverages all contain about the same levels of caffeine (Cheng and Chen, 1994). 

The methylxanthines of interest are caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine) and they occur in coffee, tea, mate, cocoa products, and cola beverages. This chapter is an introduction to their chemistry, isolation, and biosynthesis. While the class of methylxanthines is large and comprised of more members than these three, this chapter will essentially be limited to caffeine, theobromine, and theophylline. 

Foods derived from cocoa beans have been consumed by humans since at least 460 to 480 AD. The source of cocoa beans, the species Theobroma, contains a variety of biologically active components. These include the purine alkaloids theobromine, caffeine, and theophylline. Structurally, they are methylated xanthines and, thus, are often referred to as methylxanthines. Theobromine (3, 7-dimethylxanthine) is the predominant purine alkaloid in cocoa and chocolate. Caffeine (1, 3, 7-trimethylxanthine), the major purine alkaloid found in coffee and tea, is found in cocoa and chocolate at about one eighth the concentration of theobromine. Only trace amounts of theophylline (1, 3-dimethylxanthine) are detected in cocoa and chocolate products. 

Fig. 11. Mechanism for formation of parabanic acids from the methylated uric acid-4,5-diol derived from theobromine (3,7-dimethylxanthine) and caffeine (1,3,7-trimethylxan-thine). Molar amounts of products are those formed in 1 M HOAc...

A cnp of coffee can contain 50-150 mg of caffeine, and cola drinks can have 35-55 mg. Theophiline,l,3-dimethylxanthine, a principal, characteristic alkaloid of tea, and theobromine, 3,7-dimethylxanthine (23.3.19), a principal alkaloid of cocoa, are among a number of methylxanthines. In small doses, caffeine is a relatively weak psychostimulant and is used for increasing awareness as well as for relieving headaches associated with blood flow disorders of the brain. Caffeine has a stimulatory effect on the respiratory and vasomotor centers, and it stimnlates centers of the vagus nerve. It has a direct stimulatory effect on the myocardium, and in large doses can cause tachycardia and arrhythmia. 

Related xanthines - theobromine (3,7-dimethylxanthin) and theophylline (1,3-dimethylxanthine)... 

Closely related methylxanthines include theophylline (1,3-dimethylxanthine), theobromine (3,7 dimethylxanthine) and paraxanthine (1,7-dimethylxanthine). Theobromine is found primarily in chocolate. These derivatives of caffeine are important because they are pharmacologically active and also are the common metabolites of caffeine. 

The purine nucleus is constructed by a condensation of the pyrimidine and imidazole (glyoxaline) nuclei (Figure 11.12). Xanthine is 2,6-dioxypurine caffeine, 1,3,7-trimethylxanthine theophylline, 1,3-dimethylxanthine and theobromine, 3,7-dimethylxanthine. These alkaloids are found in coffee, tea, cacao, kola, mate, and guarana (Figure 11.13). 

Methyl derivatives of xanthine (2,3-dioxypurine) namely caffeine (1,3,7-trimethyl-xanthine), theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) (Section 1, Appendix) are variously found in plants used for stimulatory drinks such as Ilex paraguayensis (mate) (Aquifoliaceae), Coffea species (coffee) (Rubiaceae), Paullinia cupana (guarana) (Sapindaceae), Cola acuminata (cola) and Theabroma cacao (cocoa) (Sterculiaceae) and Camellia sinensis (tea) (Theaceae). These methylxanthines are variously active as inhibitors of... 

Phenyltheophylline (= 1,3-Dimethyl-8-phenylxanthine)] (methylxanthine) Theobromine (= 3,7-Dimethylxanthine) (methylxanthine)... 

Almost identical bell-shaped rate-pH curves are produced by [8- H]theophylline (1,3-dimethylxanthine 8), xanthine (77T803) and 1-methylxanthine (79T663) whereas the characteristic curve shown by 9-isopropylpurine is also reproduced by [8- H]caffeine (1,3,7-trimethylxanthine) (77T803), [8- H]-theobromine (3,7-dimethylxanthine), 7-methylxanthine and xanthosine (79T663) in which substituents also occur in the imidazole ring. 3-Methylxanthine (71) on the other hand shows a rate-pH profile which is exceptional. 

Treatment of 7-methylxanthine with phosphoryl chloride and phosphorus pentachloride affords 2,6-dichloro-7-methylpurine (4). The preparation of this compound had previously been reported by Fischer by treatment of theobromine (3,7-dimethylxanthine) with phosphoryl chloride in a sealed tube at 140 °C. 

Theobromine (3,7-dimethylxanthine, 3,7-dihydro-3,7-dimethyl-lW-purine-2,6-dione). C7H,N402, Mr 180.17 formula, see under theophylline. Monoclinic, bitter tasting needles, mp. 357 °C, sublimes at 290-295 °C, soluble in hot water, alkali hydroxides, concentrated acids, moderately soluble in ammonia, poorly soluble in cold water and alcohol. With acids T. forms salts which decompose in water detection by the murexid reaction. T. is the main alkaloid of cocoa (Theobroma cacao, 1.5-3 wt.-%), from which it is obtained - especially from the husks in which it accumulates during fermentation. The typical bitter taste of cocoa is the result of interactions between T. and the pip-erazinediones formed in the roasting process. T. has diuretic, vasodilatory, and stimulating effects on cardiac muscle. The activities are weaker than those of the structurally related caffeine (a methylation product of T.) with which it co-occurs in cola nuts. For further pharmacological properties, see table under theophylline. 

Methylxanthines and methyluric acids are secondary plant metabolites derived from purine nucleotides (Figure 6.59). The most well-known methylxanthines are caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine), which occur in tea (Camellia sinensis. Camellia ptilophylla, and Camellia taliensis) [242,243], coffee (Coffea arabica, Coffea canephora) [244, 245], cacao (Theobroma cacao) [246], and a number of other nonalcoholic beverages of plant origin Ilex paraguariensis, Paullinia cupana. Cola species and Citrus species [247-249]... 

As commented above, the use of a surfactant different from SDS is anecdotal in direct injection MLC procedures. For this reason, the comparison of the determination of a drug such as theophylline (1,3 -dimethylxanthine), using two different surfactants, is interesting. Habel et al. [9] reported a procedure for the direct determination of this drug in human serum by using a p-Bondapak phenyl column, a micellar mobile phase of the zwitterionic surfactant C DAPS (10 M) containing 3% 1-propanol and UV detection at 273 nm. Later, Perez Martinez et al. [29] developed a procedure for theophylline, caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine), in urine, with a Spherisorb Cl8... 

The most well-known purine alkaloid is caffeine (1,3,7-trimethylxanthine) 1 which, along with theobromine (3,7-dimethylxanthine) 2, accumulates in leaves of tea and mate and beans of coffee and cacao, which are popular components of nonalcoholic beverages and/or chocolate products [2]. The pharmacological effects of purine alkaloids in animals, such as stimulation of the central nervous system, have been investigated extensively [3]. Caffeine is also often utilized in cytological studies to induce the formation of binucleate cells and is, therefore, used to measure the duration of the mitotic cycle [4]. 

Theobromine (3,7-dimethylxanthine), which is 1.2% in cocoa, provides a stimulating effect, which is less than that of caffeine in coffee. Therefore, it is of physiological importance. Caffeine is also present, but in much lower amounts (average 0.2%). A cup of cocoa contains 0.1 g of theobromine and 0.01 g of caffeine. Theobromine crystallizes in the form of small rhombic prisms which sublime at 290 °C without decomposition. In cocoa beans theobromine is often weakly bound to tannins and is released by the acetic acid formed during fermentation of the beans. Part of this theobromine then diffuses into the shell. 

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