Conformationally-controlled electron-transfer reactions as manifested with copper(ll)/(l) macrocyclic ligand complexes

Studies on the electron-transfer kinetics of copper(II)/(I)-macrocyclic polythiaether complexes have included rapid-scan cyclic voltammetry, stopped-flow kinetic measurements on several cross reactions involving both Cu(II) reduction and Cu(1) oxidation, and direct NMR measurements of the Cu(I1)-Cu(1) self-exchange electron-transfer rate constants. The results demonstrate that the reaction mechanism for these systems conforms to a dual-pathway "square" scheme in which, under appropriate conditions, conformational changes become rate-limiting in one direction, resulting in the condition known as "gated" behavior. The current studies represent the first thorough documentation of gated electron-transfer in Cu(II)/(I) systems. INTRODUCTION The role of conformational change in controlling electron-transfer reaction rates has been recognized as an issue of major importance in biological systems. More than twenty years ago, Vallee and Williams (ref. 1) proposed that the protein matrix in metalloenzymes imposes a strain upon the bonds at the active metal site such that bond rearrangement is minimized during the chemical reaction. In elucidating this so-called "entatic" (strained) state hypothesis, these authors focused on redox-active iron and copper enzymes, recognizing that the changes in bond lengths and/or angles, which normally accompany a change in the oxidation state of these metal ions, comprise a major contribution to the activation parameters for their electron-transfer reactions. Thus, Vallee and Williams concluded that increasing the rigidity of the coordination sphere would reduce the activation energy and result in more rapid reactions. More recently, knounting evidence has been reported that conformational changes may themselves become the rate-limiting processes in redox-active metalloenzymes. Among the blue copper proteins belonging to the class known as blue electron carriers, limiting first-order kinetics have been observed in the reduction of rusticyanin (ref. 2) and in the oxidation of azurin (refs. 3,4). Both observations have been attributed to conformational changes preceding the electron-transfer step. For each of these proteins, spectral evidence has been obtained for the existence of two conformers of the copper site (refs. 2, 5). Additional evidence for rate-limiting conformational control in redox-active metalloenzymes has been claimed in the case of intraand inter-molecular electron-transfer reactions of heme proteins and cytochrome c oxidase (ref. 6) . Recent theoretical treatises have been presented by Hoffman and Ratner (ref. 7) and by Brunschwig and Sutin (ref. 8) to describe reaction mechanisms in which conformational changes and the electron-transfer step occur sequentially, rather than concertedly. Both sets of authors have incorporated into their theories the existence of intermediate conformers for both the oxidant and reductant resulting in a dual-pathway square scheme (see below). Depending upon the reaction conditions and the conformational constraints of the system, the recently developed theories predict that a variety of kinetic behaviors may be anticipated for such systems (refs. 7, 8), including, under appropriate conditions, "gated" (or "directional") electrontransfer in which the rate of conformational change ultimately limits the rate of the reaction in one ditection. It has been speculated that conformational control of this type is employed in biological systems to impede undesired back reactions resulting in a "molecular switch" (ref. 9). Although this mechanistic behavior would appear to be of major importance, the conditions leading to the various types of theoretically predicted behavior have not heretofore been thoroughly explored or characterized experimentally. Copper(II)/(I) redox couples appear to represent optimal systems for investigating gated electron-transfer behavior as a result of the significant structural differences characteristic of these two oxidation states (ref. 10). In our laboratories, we have found that complexation of the copper ion by macrocyclic polythiaether ligands results in two favorable properties for such studies: (i) thiaether sulfur donor atoms promote high