Substrate-Dependent Oxidation with Alkyl Hydroperoxide Mediated By Iron Porphyrin Coordinated By Thiolate

Alkane and arene hydroxylation by cytochrome P450 is one of the most powerful chemical processes in biological systems.  The highly reactive intermediate in cytochrome P450 catalysis has aroused broad interests and has been the subject for extensive investigations. SR complex successfully created by us is the first synthetic heme thiolate complex that retains its thiolate coordination structure during catalytic oxidation reaction. We have focused on the alkyl hydroperoxide-heme thiolate chemistry. We previously found that SR complex efficiently catalyzed one-electron oxidation of 2,4,6-tri-tert-butylphenol (TBPH) with cumene hydroperoxide (CHPO) or tert-butyl hydroperoxide to afford 2,4,6-tri-tert-butylphenoxyl radical (TBP•). Recently, 2-methyl-1-phenylpropan-2-yl hydroperoxide (MPPH) has been used as a mechanistic probe for O-O bond cleavage mode on catalysis of metal complex.  MPPH is known to give benzyl radical-derived products and acetone via unstable alkoxyl radical in the case of homolytic O-O bond cleavage whereas it simply affords 2-methyl-1-phenyl-2-propanol (MPPOH) in the case of heterolysis. Here we report the substrate oxidation mechanism with CHPO and MPPH catalyzed by SR complex.

    We found that SR complex lost its thiolate coordination after the addition of MPPH (1 equiv. to SR complex) even in the presence of large excess amount of phenol with an electron-withdrawing substituent. On the other hand, the use of TBPH or 2,6-di-tert-butylphenol as a substrate lead to retention of the thiolate coordination.
   Next, equilibrium constant K’ values of THF coordination to SRs were determined by Benesi-Hildebrand plot (inverse of absorption spectral change versus inverse of THF concentration). We plot K’ versus reaction rate since correlation between the two factor was expected. The plot clearly showed that the reaction rate was almost proportionate to K’ value from high linearity of the plot in terms of SR complexes. This result suggests that hydroperoxide coordination step is rate-determining step. Putting together these results, alkyl hydroperoxide-heme-thiolate complex is suggested to be an actual active intermediate.