The Valence Bond Way: Reactivity Patterns of Cytochrome P450 Enzymes and Synthetic Analogs

Abstract

The preceding decade has witnessed an immense surge of activity in the bioinorganic chemistry of transition metal enzymes and synthetic analogs that model their operation. The wide range of research covers both experimental and theoretical investigations of structure and reactivity patterns. Theory, and especially density functional theory (DFT), has become a very useful tool, an important partner of experiment in resolving structural and mechanistic issues. This flare of activity has generated a great deal of knowledge on intermediates, transition states, barriers, rate constants, rate-equilibrium relationships, stereoselectivity, and so forth. This abundance of acquired knowledge has created the need for establishing order, namely, the outlining of broad generalizations, as well as the creation of a more-intuitive interface between experimental and theoretical data. The valence bond (VB) diagram model, originally developed for organic reactions, is such a theoretical framework that has the potential to guide the requisite generalizations in the field of bioinorganic chemical reactivity. In this Account, we briefly describe the principles of construction of VB diagrams for bioinorganic reactions, detailing applications in the booming research area of heme enzyme (specifically cytochrome P450) reactivity, and particularly two archetypal reactions of these enzymes, alkane hydroxylation and thioether sulfoxidation. For congruence with the lingua franca of bioinorganic chemistry, the VB model is formulated to create bridges to (i) the molecular orbital (MO) description, (ii) the oxidation state formulation of transition metal complexes, and (iii) widely used concepts such as the Bell-Evans-Polanyi (BEP) principle. The VB diagram model reveals the origins of the barrier, describes the formation of transition states and reaction intermediates, and allows the prediction of barrier heights and structure-reactivity relationships. Thus, from the VB diagram model, we can rationalize the mechanistic selection during alkane hydroxylation compared with thioether sulfoxidation, as well as the different behaviors of the spin states during the reactions with the active species of P450, the high-valent iron oxo species called compound I (Cpd I). Furthermore, the VB model leads to expressions that enable us to estimate barrier heights from easily accessible reactant properties, such as bond energies, ionization potential, and electron affinities. We further show that the model is not limited to these archetypal processes: its applicability is wider and more general. Accordingly, we outline the potential applications of these principles to other reactions of P450 (such as olefin epoxidation and arene hydroxylation) and to similar reactions of nonheme enzymes and synthetic models. The VB diagram model leads to a unified understanding of complex bioinorganic transformations, creates order in the data, and provides an important framework for making useful predictions.

Effect of the Axial Ligand on Substrate Sulfoxidation Mediated by Iron(IV)–Oxo Porphyrin Cation Radical Oxidants

“…[6] Recent computational studies for the reaction of Cpd I(SH) with four parasubstituted thioanisole substrates also gave a correlation between barrier height and substrate IE, which was rationalized by a VB curve-crossing diagram. [7,30] In this work, we found the same correlation between barrier height and substrate IE for the reaction of Cpd I(SH) with substrates. In addition, we show that the barrier height is proportional to the polarizability difference for the reaction and proportional to the barrier height for the reaction of dimethyl sulfide sulfoxidation mediated by metal-oxo oxidants and BDE OH .…”

“…These wave functions are normally the electronic images of the states they correlate with, but here they represent the one-electron excitation energies. [30] Thus, the curve crossing between the reactant-and product-wave functions is located at a certain energy (DE c ), but the actual transition state (DE SO°) for the sulfoxidation is lower in energy by a factor of B. It was further shown that the barrier height is proportional to a fraction (f) of the promotion gap in the reactant state (G H,r ) through…”

Strengths, Weaknesses, Opportunities and Threats: Computational Studies of Mn- and Fe-Catalyzed Epoxidations

“…Sometimes, theoretical findings are able to propose and explore novel reaction paths and intermediates not readily perceived in experimental studies. Such is the case of proposing an oxo-iron-porphyrin intermediate as the active species of cytochrome P450, which DFT and valence bond methods applied by Shaik and co-workers [68,[92][93][94] demonstrated to be more active towards the epoxidation of olefins than the previously proposed iron-hydroperoxide intermediates. This further yielded novel models that better describe the product distribution of iron-porphyrin catalyzed epoxidations.…”

“…Despite this, the models published in the last 20 years gravitate around a common model for both Mn-and Fe-catalyzed epoxidations; namely, the use of oxo-Mn and oxo-Fe species as the active forms of the catalyst [23,32,68,69,[92][93][94]132], the avoidance of a spin-crossing mechanism [42,48,76] and the possible role of a radical intermediate as a putative explanation for the incomplete stereoselectivity of these reactions [76,82]. It should be noted that many of these insights on the reaction mechanism are subtle enough to elude most of the standard kinetic studies.…”

Biomimetic Oxidation of Hydrocarbons with Air over Metalloporphyrins

“…The oxygenation mechanism operating in CP-450 and in synthetic metalloporphyrin models has received much attention in recent decades [21,[88][89][90]. However, the putative character of www.intechopen.com the active oxidants recently remains a controversial matter in the catalytic cycles of reductive oxygen activation and reaction by CP-450 [35,91] (Scheme 16), three different species have been considered as possible active oxidants [2]: one presenting a nucleophilic character, a peroxy species (d), one with electrophilic character, a iron(IV) oxo porphyrin pcation radical intermediate (7) To synthesize and distinguish the reactivity of these active oxidants, many oxygen-atomtransfer reactions catalyzed by synthetic metalloporphyrin complexes as CP-450 models have been extensively studied [92][93].…”