Metal ion-biomolecule interactions. Part 22.1 Cr(III)-catalyzed isotopic hydrogen exchange in methylimidazoles

Abstract

The detritiation kinetics of the Cr(III) complexes 1 and 3-6 have been studied in aqueous buffers at 35°C, using the liquid scintillation counting technique. Results for 5 and 6 provide benchmark kinetic data for N-T/N-H exchange under the experimental conditions of the study and have aided in the delineation of N-T/N-H from C-T/C-H exchange in the parallel reactions observed experimentally. Curved first-order plots obtained for 1, 3, and 4 were treated to yield rate constants for two parallel exchange reactions kobsA  and kobsB  for the "fast" and "slow" processes, respectively. The "fast" process has been assigned to C(2)-H exchange in 1, competing N-H and C(2)-H exchange in 3, and N-H exchange in 4. In all cases, the "slow" process is associated with C(4,5)-H exchange. Identification of exchange sites in 1, 3, and 4 was made possible by the consideration of the results of an IR spectroscopic study of hydrogen-deuterium exchange, comparison of the extent of 3H incorporatation in different complexes in the tritiation experiments, and a careful analysis of the exchange kinetic data. Analysis of the rate data indicates that Cr(III) significantly enhances C(2)-H exchange in 1 and 3, while C(4,5)-H exchange, hitherto reported in the literature only under drastic reaction conditions, was observed for 1, 3, and 4 under the mild conditions of the present study. Quantitation of the effect of Cr(III) coordination on 3H exchange in imidazole-type nuclei was achieved fully in 1; giving kM+ values of 6 × 103 and 7 × 102 M-1s-1 for C(2)-H and C(4,5)-H exchange, respectively. Using the literature value for kH+, the second-order rate constant for C(2)-H exchange under H+ catalysis, 2.9 × 102 M-1s-1, it follows that Cr(III) is ca. 20 times better as a catalyst for C(2)-H exchange in 1-methylimidazole than H+, providing the first example of a metal ion being more effective than a proton in these processes. Comparison of the results obtained with 1 with literature results for 2 shows a very large (ca. 3 × 105-fold) difference in the catalytic activities of Cr(III) and Co(III), favouring the former. The dichotomy in the effectiveness of the two metal ions in catalyzing 3H exchange in the imidazole nucleus has been ascribed to differences in (i) extent of Mn+—N bond polarization (and the consequent effect on ligand C-H acidity); (ii) electronic configuration; (iii) crystal field stabilization and activation energies; and (iv) importance of metal-ligand π back-bonding. The study highlights the diversity of factors and complexity of interactions involved in determining the role of metal ions in biological systems, especially where such processes involve complex formation between metal ions and heterocyclic fragments of biomolecules.Key words: metal ion-biomolecule interactions, methylimidazole, isotopic hydrogen exchange, catalysis by chromium.