Final Report Summary - BIDECASEOX (Bio-inspired Design of Catalysts for Selective Oxidations of C-H and C=C Bonds) Oxo transfer chemistry mediated by iron lies at the heart of many biological processes and is recognized as a key component in the catalytic oxidation of hard to activate conventional C-H and C=C moieties. Such chemical transformations are fundamental for life in most aerobic living organisms. In addition, because of cost, lack of toxicity and selectivity issues, iron-catalyzed oxidations are a unique emerging tool called to reformulate chemical synthesis technologies. Research in the project has been dedicated to the development of catalysts for the selective oxidation of C-H and C=C bonds. Designed catalysts are based in structural and or functional aspects of non heme iron dependent oxygenases. Fundamental understanding of the catalytic reactions has been also pursued. Major achievements reached so far include; 1) Novel iron based coordination complexes containing highly structured active sites have been prepared and have been found to catalyze the efficient oxidation of alkyl C-H bonds employing H2O2 as terminal oxidant. Steric protection of the active site can be used to limit side degradation paths and to improve the activity of the catalysts. These catalysts are very reactive and can hydroxylate not only relatively weak 3º C-H bonds, but also 2º alkyl sites. The rich structural properties of these catalysts also impart alternative or improved C-H site selectivities that escape from the inherent reactivity of C-H bonds, without the aid of directing groups. Catalysts with bulky active sites have proven to favor oxidation of secondary over tertiary C-H bonds. The former are stronger but sterically less congested than the later, and therefore, size selectivity is obtained. On the other hand, the chiral nature of the catalysts has been used to divert selectivity among multiple C-H bonds in complex organic molecules. These selectivities complement those accomplished with structurally simpler oxidants, including nonheme iron catalysts described up to date. With this toolbox of catalysts in hand, and with the judicious choice of catalyst multiple oxidation products could be prepared from a common substrate in synthetically amenable yields via catalyst-dependent regioselective C-H oxidation. 2) By means of rational manipulation of the electronic properties of iron and manganese based catalysts, highly enantioselective epoxidation of olefins employing H2O2 as oxidant has been discovered. Efficient and fast epoxidation is accomplished for a wide variety of olefins. Highly enantioselective epoxidation of terminal aromatic olefins, inaccessible by other methods, has been described. The first example of highly enantioselective epoxidation of non aromatic substrates has been also discovered. Basic principles for future catalyst design directed towards broadening substrate scope have been stablished. Carboxylic acids have been demonstrated to play key roles in defining enantioselectivity and integration of the catalyst into polypeptidic chains, as a first step in a bottom up approach towards artificial iron oxygenases has been demonstrated. 3) Oxo-iron(IV) and oxo-manganese (IV) compounds in non porphyrinic environments have been prepared and several fundamental aspects of their reactivity have been stablished. That includes hydrogen atom transfer, oxygen atom transfer and water exchange reactions. Elaboration of these compounds into functional and structural models of halogenases has been pursued. Study of the role of spin in defining the oxidation activity of the complexes has been addressed. 4) Highly reactive oxo-iron(V) species are commonly invoked as directly responsible for C-H and C=C oxidation but direct evidence has been lacking. The observation of such species both in enzymes and in chemical synthesis remains a formidable challenge. We have been able to directly observe the first experimental evidence for the identification of a metastable Fe(V) intermediate under catalytic conditions for C-H hydroxylation and C=C cis-dihydroxylation. This unique result has been possible using mass spectrometry to monitor the reaction between a non-heme iron catalyst with H2O2 at -40 ºC. This is a unique example where such an intermediate has been observed and provides unprecedented fundamental knowledge to understanding the nature of the iron-based species responsible in synthetic and enzymatic systems. More recently, we have been also capable of trapping a Fe(V) species in solution under cryogenic conditions and have shown that it hydroxylates C-H bonds and epoxidizes olefinic sites at unprecedentedly fast reaction rates, comparable to those exhibited by CpdI of P450. Reactions are stereospecific and selectivities match those obtained under catalytic conditions. This work constitutes the first example where the species responsible for stereospecific C-H hydroxylation are observed and their oxidation competence is kinetically demonstrated. 5) The oxidation of water in an efficient and sustainable manner is the bottleneck for the development of water-splitting technologies, and research on finding new catalysts for this very challenging transformation is at the forefront of science. Water oxidation catalysts (WOC) based on iron, constitute very attractive technological options, because this metal is abundant, environmentally benign, and inexpensive. Iron based WOC’s affording the highest activities (catalytic cycles) ever reported for any first row transition metal system described to date under homogeneous conditions have been described. The activity of these iron based catalysts approach the most active systems, based on precious metals Ru and Ir. Furthermore, the family of catalysts described is highly available, modular and versatile. This very unique feature has allowed us to identify first-principle structural features to sustain water oxidation. Our study has also provided fundamental knowledge in the nature of the iron-based species responsible for the O-O bond forming event. Catalytic cycles and reaction intermediates have been elucidated, and evidence for the molecular nature of the processes has been provided.
