Spencer E. Taylor

Metal ion-biomolecule interactions. II. Methylmercuration of the deprotonated amino groups in adenine, guanine, and cytosine derivatives, and its relationship to amino group acidity

Proton nmr spectroscopic evidence is presented for methylmercury(II) binding to the deprotonated amino groups in adenosine, 9-methyladenine, guanosine, 1-methylguanosine, and cytidine under basic conditions. Except for the guanosine case, 1H nmr spectra of the products from aqueous or ethanolic 1:1 mixtures of substrate and MeHgOH are consistent with methylmercuration of the deprotonated amino groups. Guanosine undergoes initial binding of MeHg to N1, and a second equivalent of MeHgOH is necessary to effect amino binding. The nmr spectra of the complexed adenine derivatives suggest that different geometrical isomers exist in (CD3)2SO solution, reflecting the partial double bond character of the C6ue5f8N bond in these systems. Using a correlation relating the magnitude of the 199Hg-1H coupling constant (J) for MeHg-ligand complexes with the ligand pKa (J = −3.88 pKa + 248.5, extending over 13 pK units, based on a variety of N and O donor ligands), estimates (± 0.3 pK unit) of the pKas of the amino groups of the above substrates have been made. In this way, pKa values of 15.5 (cytidine), 17.0 (adenosine and 9-methyladenine), 15.1 (guanosine), and 14.9 (1-methylguanosine) are obtained. In the cases where comparisons with literature pKa data can be made, good agreement is found.

Metal ion-biomolecule interactions. III. Versatility of metal ion binding to imidazoles. Synthesis and 1H nmr spectroscopic properties of N- and C-bound mercury(II) complexes

Abstract Methylmercury(II) and mercury(II) complexes of imidazole ( 1 ), 1-methylimidazole ( 2 ), and the 1,3-dimethylimidazolium ion ( 3 ) have been prepared in aqueous or ethanolic solution. Elemental analysis and 1 H nmr spectroscopy have been used to characterize the complexes. The MeHg (Me = methyl) binding sites have been identified as N 1 , N 3 ( 1 ), N 3 , C 2 ( 2 ), and C 2 ( 3 ). Reaction with HgO leads to the formation of Hg-bridged complexes of the type Im-Hg-Im, (Im = imidazole), where bonding occurs through N 1 ( 1 ) and C 2 ( 3 ); the latter is also formed as a result of symmetrization of the C 2 -bound MeHg complex. The formation of the C 2 -bound (carbene) complexes is discussed in terms of the increased acidity of the C 2 proton resulting from coordination of an electrophilic species at N 3 . Based on electrostatic considerations, there appears to be a “minimum degree of activation” required before C 2 bonding can occur, which explains the lack of this coordination mode in 1 . 199 Hg- 1 H spin-spin coupling ( 4 J ) is observed for C-bound mercury, but not for N-bound mercury, which is interpreted in terms of a decreased ligand exchange rate in the former case, due to the greater stability of the Hg-C bond. 2 J coupling constants measured in (CD 3 ) 2 SO for a number of MeHg complexes of heterocyclic ligands (including the imidazoles of the present study) correlate well with the ligand p K a (25°C, aqueous solution), according to 2 J = −3.88 p K a + 248.5. Results in the present work are discussed in relation to our previous work with nucleosides. The significance of the results to biological systems is considered.

Metal ion–C(8) binding in purine nucleosides. Ready formation of carbon-bound inosine and guanosine complexes of methylmercury(II)

The increased lability of purine nucleoside C(8)–H bonds upon co-ordination of a metal ion to the adjacent N(7) position has been used to explain the observed formation of C(8)-bonded inosine and guanosine methylmercurials, these being the first reported carbon bound species formed from the interaction of nucleosides with organomercurials.

Isotopic hydrogen exchange at C8 in purines. Effects of the site of protonation.

An analysis of linear-free-energy data for base-catalysed isotopic hydrogen exchange from the C8 position of protonated purines indicates that N7 is only partially protonated in aqueous solution.

Proton transfer from heterocyclic compounds. Part 6. Detritiation rates of various xanthines

Rates of detritiation from the C-8 position of xanthine, xanthosine, and a series of methylated xanthines (caffeine, theophylline, theobromine, and paraxanthine) have been measured over a pH range at 85°. In all cases the results can be interpreted in terms of rate-determining hydroxide ion attack on one or more of the different ionised species present in solution; the less the degree of methylation the greater the number of ionisable forms and the larger the number of potential mechanisms. In the case of theobromine and paraxanthine three forms (protonated, neutral, and monoanionic) are involved and in the case of xanthosine a further form (dianionic) makes a contribution to the overall rate. The possibility of zwitterionic contributions are also discussed.

Proton transfer from heterocyclic compounds. Part 11. Histidine, histamine, N-acetylhistidine, and histidine-containing peptides

Rates of detritiation from the C-2 position of [2-3H]histidine, histamine, and N-acetylhistidine as well as a number of histidine-containing peptides (glycyl-L-histidine, glycyl-L-histidylglycine, β-alanylhistidine, histidylserine, and histidyltyrosine) have been measured over a pH range at 85°. For both histidine and histamine the rate–pH profiles are indicative of hydroxide ion attack on both the protonated and ‘neutral’ species. The magnitude of the rate constant for the second mechanism indicates that the kinetically equivalent zwitterionic form of the substrate also participates in the reaction. The results for N-acetylhistidine can be represented by a bell-shaped rate–pH profile, consistent with hydroxide ion attack on the N-3 protonated species. The results for the other peptides can, to a first approximation, be represented by the same profile, but this may be an over-simplification, resulting from closely similar pKa values. Electrostatic factors arising from the presence of charged carboxylate and amino-groups close to the C-2 exchanging position are negligible.

Effects of metal ions on rates of detritiation–new probe in the study of metal–substrate interactions

The rate retarding effect of metal ions (Cu2+ > Zn2+≃ Ni2+ > > MeHg+) on isotopic hydrogen exchange from the C(2) position of imidazole can be rationalised in terms of complex formation; the stability constants can be evaluated from the exchange rate constants.

Proton transfer from heterocyclic compounds. Part 10. Adenine mono- and poly-nucleotides

Detritiation rate constants from the C-8 position of adenosine 5′-monophosphate, adenosine 3′-monophosphate, adenosine 3′,5′-cyclic phosphate, and poly(adenosine 5′-monophosphate) have been measured over a pH range at 85°. The rate–pH profiles are of the same form as for adenosine with the important difference that for the first two compoounds an additional plateau region is obtained in the pH range where ionisation of the secondary phosphoric acid function occurs. The reactivity of the species formed (AMPH–) is greater than it would otherwise be because it can also exist as a zwitterion (H+AMP2–). Exchange from the polymer is ca. 30 times slower than for the mononucleotides.

Proton transfer from heterocyclic compounds. Part 7. Methylated guanosine and inosine derivatives and the question of zwitterionic involvement

The rates of detritiation of 1-methyl[8-3H]guanosine, 7-methyl[8-3H]guanosine, and 1-methyl[8-3H]inosine have been measured over a pH range at 85 °C and the results compared with those already available for guanosine and inosine. At low pH where the mechanism involves hydroxide ion attack on the protonated substrate methyl substitution has only a marginal effect on the rate. By contrast the results at high pH show that methyl substitution in the 1-position brings about a large rate retardation (ca. 103) and leads to the conclusion that in the case of both guanosine and inosine the hydroxide ion reacts with both the neutral and zwitterionic forms.

Proton transfer from heterocyclic compounds. Part 9. Effect of transition-metal ion co-ordination on isotopic hydrogen exchange in purines

Rates of detritiation from the C-8 position of 1-methyl[8-3H]guanosine and 1-methyl[8-3H]inosine at 85 °C in the presence of various metal ions are reported. Analysis of the data shows that the metal-complexed species are more reactive than the neutral species by factors of 104–106 but less reactive than the protonated substrates. Detritiation studies on the cis[(1,2-diaminoethane)(guanosine)2]platinum di-iodo-complex are consistent with this viewpoint.