HAT pathway

The O-dealkylation of ethers, while not as frequently encountered as N-dealkylation in drug metabolism studies, is still a common metabolic pathway. Mechanistically it is less controversial than N-dealkylation in that it is generally believed to proceed by the HAT pathway, i.e., a-hydrogen atom abstraction followed by hydroxyl radical rebound, and not a SET pathway (Fig. 4.58). The product of the reaction is unstable, being a hemiacetal or hemiketal depending on the number of hydrogens on the a-carbon, which dissociates to generate an alcohol and an aldehyde or ketone. 

Based on these general relationships, we may now examine separately the ECE-HAT and DISP-HAT pathways. 

SCHEME 7. The hydrogen atom transfer (HAT) pathway of an aminoxyl radical... 

Figure 12 [ Cu (MePY2) 2(02)] (10), which exists as a mixture of both bis-/x-oxo and /u.-ri ri -petoxo complexes in solution, wiU oxidatively N-deaUcylate /lara-substituted dimethylanilines through either a PCET or a HAT pathway...

In an attempt to address the PCET versus HAT issue, Shearer, Karlin, and coworkers investigated the mechanism of dimethylaniline oxidations by [ Cu(MePy2) 2(02)] + (10, Figure 12). Here, the complexes are not pure peroxo or bis-/u.-oxo complexes, but instead are mixtures. The R -para pyridyl ligand donor substituent produces more of the bis-/u.-oxo tautomer as the R group is made more electron donating (7-30% bis-/u.-oxo). Based upon comparisons of both infra- vs intermolecular KIEs and KIE profiles of para-substituted dimethylaniline oxidations (R-DMA, Figure 12), it was determined that both PCET and HAT reactions occur. For the more easily oxidizable R-DMAs, a PCET reaction is preferred, while for the more difficult to oxidize R-DMAs a HAT pathway is favored. Also, it was observed that the more bis-/tr-oxo isomer that is in solution, the more likely it is that a HAT reaction will occur. 

This chapter is intended to focus on the mechanistic borderline between a sequential PCET pathway and a one-step HAT pathway and also the effects of metal ions on HAT reactions as well as overall two-electron and two-proton processes in relation to the borderline between the outer-sphere and inner-sphere ET pathways. 

As demonstrated in this chapter, there have always been the fundamental mechanistic questions in oxidation of C-H bonds whether the rate-determining step is ET, PCET, one-step HAT, or one-step hydride transfer. When the ET step is thermodynamically feasible, ET occurs first, followed by proton transfer for the overall HAT reactions, and the HAT step is followed by subsequent rapid ET for the overall hydride transfer reactions. In such a case, ET products, that is, radical cations of electron donors and radical anions of electron acceptors, can be detected as the intermediates in the overall HAT and hydride transfer reactions. The ET process can be coupled by proton transfer and also by hydrogen bonding or by binding of metal ions to the radical anions produced by ET to control the ET process. The borderline between a sequential PCET pathway and a one-step HAT pathway has been related to the borderline between the outer-sphere and inner-sphere ET pathways. In HAT reactions, the proton is provided by radical cations of electron donors because the acidity is significantly enhanced by the one-electron oxidation of electron donors. An electron and a proton are transferred by a one-step pathway or a sequential pathway depending on the types of electron donors and acceptors. When proton is provided externally, ET from an electron donor that has no proton to be transferred to an electron acceptor (A) is coupled with protonation of A -, when the one-electron reduction and protonation of A occur simultaneously. The mechanistic discussion described in this chapter will provide useful guide to control oxidation of C-H bonds. 

Figure 11 Cu2 (bis-/.t-oxo) complex [ Cu (Bz3-TACN) 2 (0 )2] + (9) will undergo an auto-oxidation resulting in ligand N-dealkylation of a benzyl group, forming benzaldehyde, presumably through a HAT pathway...

Electron transfer from OOH to canolol SET was found to be endergonic as shown by Gibbs s free energy values and hence its possibility was ruled out. In both RAF and HAT, the two possible ways of reaction are H transfer from OH moiety from canolol (site 4a) and OOH addition to site C8. Compared to the other ROS, OOH has low reactivity. Therefore, it is obvious that canolol can work faster and efficiently in all ROS. It was found out that 99% of all reactions between canolol and OOH undergo through HAT pathway in all environments. Thus, it can be expected to predominantly form one product. However, it cannot be ruled out that other mechanisms are less important. Reactivity and structure of the radicals are also equally important in deciding the antioxidation mechanisms (Galano et al., 2009). 

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