Caffeine, protonation

The nucleophilicity of the nitrogen atom survives in many different functional groups, although its basicity may be lost. Reactions of non-basic, but nucleophilic urea nitrogens provide, for example, an easy entry to sleeping-pills (barbiturates) as well as to stimulants (caffeine). The nitrogen atoms of imidazoles and indole anions are also nucleophilic and the NH protons can be easily substituted. 

An interesting example of the N(9)-C(8) prototropic tautomerism has been reported for the caffeine radical by pulse radiolysis studies in aqueous solution the transformation of the heteroatom-protonated electron adduct 25 into the carbon-protonated tautomer 26 occurred spontaneously in neutral media [95JCS(F)615]. 

Evidence for the formation of protonated caffeine can be seen in the changed UV spectrum for caffeine at pH 0.14... 

Fig. 11) would likely proceed by different mechanisms. Protonation of the diol (IV, Fig. 12) derived from theobromine would lead to ring opening at the C6— Cs position giving an imidazole isocyanate (XVI, Fig. 12). This could readily form XVII which after hydrolysis and loss of C02 would give dimethyl-allantoin (XVIII). On the other hand, the uric acid diol derived from caffeine (X, Fig. 12) cannot fragment by this mechanism. Accordingly, either or both of the processes could Occur via the form of the diol hydrated at the C6 carbonyl group (XIX, Fig. 12) which could readily lose C02 to give XX followed by rearrangement to trimethylallantoin (XXI).

Many pharmacologically active organic chemicals fonnd in natnre are alkaloids. In general, these componnds contain one or more nitrogen atoms, which in turn impart some basicity to the molecnle. Well-known alkaloid examples are caffeine, cocaine, codeine, ephedrine, morphine, nicotine, qninine, and scopolamine. Heroin is derived from morphine by a chemical modification that increases lipophilicity, making the heroin molecnle inherently more pharmacologically potent than morphine. The exhibition of its basic properties by an alkaloid (Aik) involves (by definition) the acceptance of a proton H+ according to ... 

In Figure 7.2.18, the contour plot of an extraction of 820 mg of roasted coffee is shown [20]. The contour plot is similar to that given above Figure 7.2.11 where the horizontal axis represents the proton chemical shift and the vertical axis represents the pressure. A linear pressure gradient from 85 to 220 bar over 55 min, and a CO2 flow of 1 ml/min at a temperature of 317 K was applied. One can clearly see the caffeine, which is extracted at a pressure of 105 bar, as... 

This can be seen in the behaviour of theophyline, theobromine and caffeine (see Figure 6.38). Whereas the N -nitrogen alkylated xanthines theobromine and caffeine coordinate with the C -carbon atom on the ruthenium [81] or osmium [87] metal, the N H ligand the-ophiline forms the N -metal adduct in the first instance - with possible isomerisation to C coordination upon protonation [81]. 

One way to confirm the identity of an organic compound is to prepcne a derivative of it. Caffeine melts and sublimes at 238°C. It is an organic base and can therefore accept a proton from an acid to form a salt. The salt formed when caffeine combines with hydrochloric acid, like many amine salts, does not have a sharp melting point it simply decomposes when heated. But the salt formed from scilicyclic acid, even though ionic, has a sharp melting point and can thus be used to help characterize caffeine. 

Further studies on caffeine showed that at near-neutral pH in a solution of low ionic strength, the protonated caffeine results from emichment of electrolytically produced protons in the surface layer of the droplets [56], At high pH, protonation of caffeine is due to gas-phase proton transfer from ammonium ions. At neutral and high pH at high ionic strength, protonated caffeine is generated by discharge-induced ionization. It could not be decided whether processes in the gas phase or at the gas-liquid interface were involved. 

Caffeine and theophylline have pharmaceutically important chemical properties. Both arc weak BrOnsted bases. The reported pK values are 0.8 and 0.6 fur caffeine and 0.7 for theophylline. These values represent the basicity of the imino nitrogen at position 9. As acids, caffeine has a pK., above 14. and theophylline, a pK., of 8.8. In theophylline, a proton can be donated from position 7 (i.e.. it can act as a Bronsted acid). Caffeine cannoi donate a proton from position 7 and does not act as a Bretnsted acid at pH values under 14. Caffeine docs have electrophilic sites at positions I. 3. and 7. In addition to its Bronsted acid site at 7. theophylline has electrophilic sites at I and 3. In condensed terms, both compounds arc electron-pair donors, but only theophylline is a proton donor in most pharmaceutical system.s. 

N.m.r. spectra of xanthine, theobromine, theophylline, caffeine, and their conjugate acids have been analysed. The AT-ray crystal structure of (theobromine)2 H2I8 shows it to be a polyiodide salt with alternating cationic (H-bonded protonated theobromines) and anionic (Iti ions) layers. ... 

Andersson T, Holmberg J, Rohss K, Walan A. Pharmacokinetics and effect on caffeine metaboUsm of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol 1998 45 369-375. 

A large number of isobaric compounds, especially those of uric acid, was studied. The spectrum of this compound is distinguished considerably from those of its isobars. Using FI with their instrument, they detected small quantities of caffeine in complex samples (urine). Maquestiau et al. [245] also demonstrated the same compound in tea samples with the same method, but they used Cl conditions to produce protonated molecules. 

Imidazole and Related Donors. Structural models for the co-ordination geometries of a Cu-Cu" redox couple in copper enzymes suggest a mechanism for where both electrons and protons are involved a model has been characterized bis(imidazole) copper(ii) diacetate (102). Dark green crystals of [Cu(caffeine)Cl2,H20] in which copper is tetragonal pyramidal distorted towards trigonal bipyramidal have been characterized Cu—Ni = 1.98 A,Cu—0(H20) = 1.96 A, Cu—Cl = 2.32,2.25 A. Dinitrato-2,6-bis-[l-(phenylimino)ethyl]pyridinecopper(ii) (103) contains a planar... 

Many drugs, including quinine, codeine, caffeine, and amphetamine, are amines. Like other amines, these substances are weak bases the amine nitrogen is readily protonated upon treatment with an acid. The resulting products arc called add salts. If we use A as the abbreviation for an amine, the acid salt formed by reaction with hydrochloric acid can be written AH Cl. It can also be written as A-HCI and referred to as a hydrochloride. Amphetamine hydrochloride, for example, is the acid salt formed by treating amphetamine with HCk... 

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