C-H hydroxylation

Selective C-H hydroxylation on arenes to give the corresponding phenols displays an attractive tool for the chemical industry and organic synthesis. Unfortunately, the desired phenolic product is more electron rich than the substrate and therefore... 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Kinetic isotope effects for C-H hydroxylation of /V,/V-dimethylaniline by cytochrome P450 enzymes indicate that a low-spin mechanism applies.292... 

DFT calculations have shown that in C-H hydroxylation of cyclohexane, the nonhaem oxidant (N4Py)FeIV=02+ is more reactive than P450 Cpd I and is predicted to involve multi-state reactivity with a strong solvent effect and a temperature-dependent stereoselectivity reflecting spin crossover effects.58... 

S. Shaik, S. Cohen, S. P. de Visser, P. K. Sharma, D. Kumar, S. Kozuch, F. Ogliaro, D. Danovich, Eur. J. Inorg. Chem. 207 (2004). The Rebound Controversy An Overview and Theoretical Modeling of the Robound Step in C—H Hydroxylation by Cytochrome P450. 

Schoneboom JC, S Cohen, H Lin, S Shaik, W Thiel (2004) Quantum mechanical/molecular mechanical investigation of the mechanism of C-H hydroxylation of camphor by cytochrome P450(cam) Theory supports a two-state rebound mechanism. J. Am. Chem. Soc. 126 (12) 4017-4034... 

The main side reactions are the decomposition of hydrogen peroxide and, to a lesser extent, the oxidation of alcohol solvent Their competition with C—H hydroxylation increases with increasing buLkiness of the paraffin, becoming predominant with those having a cross-section close to or larger than the size of the pores. 

Scheme 18.18 Generation ofTi—O active species and C—H hydroxylation.

C-H Hydroxylation Using Metallo-Porphyrin and -Salen Complexes as Catalysts its Mechanism and Stereochemistry... 

On the other hand, Newcomb et al. proposed a cationic pathway for P-450 catalyzed C-H hydroxylation, based on experiments using various radical probes [6]. The results suggest that no intermediate is formed during the reactions. Recently Collman et al. proposed that alkane makes a complex with oxo species and oxygen transfer occurs in a stereospecific manner [7],... 

C-H Hydroxylation Using Metallo-Porphyrin 117 Table 1. Asymmetric benzylic oxidation using complexes 3 as the catalysts... 

Recent development of asymmetric C-H hydroxylation was discussed in this chapter. Although the discussions were limited to C-H hydroxylation at active methylene via a radical intermediate, it was demonstrated that efficient differentiation of enantiotopic hydrogen atoms could be achieved by using a well-crafted molecular catalyst as discussed in Section 2.2.2. This may open a gateway to enantioselective C-H hydroxylation at non-activated methylene. On the other hand, studies of asymmetric Kharasch-Sosnovsky reaction proved that transform of a topos-selective issue to the face-selective one by generating an allyl radical intermediate is another useful approach to asymmetric C-H hydroxylation. 

Figure 1.4. Norcarane as a molecular probe of radical intermediates during C-H hydroxylation by cytochrome P450 BM3.

The polarity of the pocket and hydrogenbonding machinery were found to increase the dominance of the LS reactivity in arene hydroxylation and the HS reactivity in sulfoxidation. Similarly, these factors will have a strong impact on the appearance of cationic intermediates during hydroxylation and epoxidation. More intriguing is the result that these properties of the protein pocket have a major impact on the regioselectivity of C-H hydroxylation versus C=C epoxidation as well as on the stereospecificity of both processes. Time will show whether these are generalities or isolated findings. 

Analysis of the results described here as well as those published in the literature for monooxygenases and their chemical analogues shows that, besides the traditional radical mechanism of C-H hydroxylation in the presence of metal complexes, another, five-coordinate, carbon mechanism exists which involves addition of an oxygen atom to a C-H bond, followed by insertion into the C-H bond to form an alcohol. However, the exact nature of the latter mechanism remains to be elucidated and may be somewhat different for different systems. 

H. lin, S. Shaik, W. Thiel, Quantum Mechanical/Molecular Mechanical Investigation of the Mechanism of C-H Hydroxylation of Camphor by Cytochrome P450cam Theory Supports a Twostate Rebound Mechanism, /. Am. Chem. Soc., 2004, 126, 4017-4034. 

---