Inchemistry,hydroxylation refers to the installation of ahydroxyl group (−OH) into anorganic compound. Hydroxylations generatealcohols and phenols, which are very commonfunctional groups. Hydroxylation confers some degree of water-solubility. Hydroxylation of a hydrocarbon is anoxidation, thus a step in degradation.
Inbiochemistry, hydroxylation reactions are often facilitated byenzymes calledhydroxylases. These enzymes insert an O atom into aC−H bond. Typical stoichiometries for the hydroxylation of a generic hydrocarbon are these:
SinceO2 itself is a slow and unselective hydroxylating agent, catalysts are required to accelerate the pace of the process and to introduce selectivity.[1]
Hydroxylation is often the first step in the degradation of organic compounds in air. Hydroxylation is important indetoxification since it convertslipophilic compounds into water-soluble (hydrophilic) products that are more readily removed by thekidneys orliver andexcreted. Somedrugs (for example,steroids) are activated or deactivated by hydroxylation.[2]
The principal hydroxylation catalyst in nature iscytochrome P-450, hundreds of variations of which are known.[3] Other hydroxylating agents include flavins,alpha-ketoglutarate-dependent hydroxylases (2-oxoglutarate-dependent dioxygenases), and some diiron hydroxylases.[4]
The hydroxylation of proteins occurs as apost-translational modification and is catalyzed by 2-oxoglutarate-dependent dioxygenases.[5] Hydroxylation improves water‐solubility, as well as affecting their structure and function.
The most frequently hydroxylated amino acid residue in humanproteins isproline. This is becausecollagen makes up about 25–35% of the protein in our bodies and contains ahydroxyproline at almost every 3rd residue in its amino acid sequence. Collagen consists of both 3‐hydroxyproline and 4‐hydroxyproline residues.[6] Hydroxylation occurs at the γ-C atom, forminghydroxyproline (Hyp), which stabilizes the secondary structure of collagen due to the strong electronegative effects of oxygen.[7] Proline hydroxylation is also a vital component ofhypoxia response viahypoxia inducible factors. In some cases, proline may be hydroxylated instead on its β-C atom. These three reactions are catalyzed by large, multi-subunit enzymesprolyl 4-hydroxylase,prolyl 3-hydroxylase, andlysyl 5-hydroxylase, respectively. These enzymes require iron (as well as molecular oxygen andα-ketoglutarate). They consume oxygen (the oxidant) andascorbic acid (vitamin C, the reductant). Deprivation of ascorbate leads to deficiencies in proline hydroxylation, which leads to less stable collagen, which can manifest itself as the diseasescurvy. Since citrus fruits are rich in vitamin C, Britishsailors were givenlimes to combat scurvy on long ocean voyages; hence, they were called "limeys".[8]
Several other amino acids aside from proline are susceptible to hydroxylation, especially lysine, asparagine, aspartate and histidine. Lysine may be hydroxylated on its δ-C atom, forminghydroxylysine (Hyl).[9] Several endogenous proteins contain hydroxyphenylalanine and hydroxytyrosine residues. These residues are formed by hydroxylation of phenylalanine and tyrosine, a process in which the hydroxylation converts phenylalanine residues into tyrosine residues.[6] Hydroxylation at C-3 of tyrosine gives 3,4- dihydroxyphenylalanine (DOPA), which is a precursor to hormones and can be converted intodopamine.
Hydroxylations are well explored but only rarely practical in organic synthesis.Peroxytrifluoroacetic acid converts some arenes tophenols. Salts of peroxydisulfate converts phenols to quinols in theElbs persulfate oxidation. Mixtures of ferrous sulfate and hydrogen peroxide, theFenton reagent, behaves similarly.[10]
Installing hydroxyl groups into organic compounds can be effected by biomimetic catalysts, i.e. catalysts whose design is inspired by enzymes such as cytochrome P450.[11]
Whereas many hydroxylations insert O atoms intoC−H bonds, some reactionsadd OH groups to unsaturated substrates. TheSharpless dihydroxylation is such a reaction: it converts alkenes intodiols. The hydroxy groups are provided byhydrogen peroxide, which adds across the double bond ofalkenes.[12]
Methane is one of the most studied substrates for hydroxylation because it is abundant innatural gas. Although methane is welcome as a fuel, it would be more valuable if it could be converted to methanol. Studies on the hydroxylation of methane spans both synthetic and biological approaches. Nature has evolved enzymes calledmethane monooxygenases, which are efficient but impractical for commercial applications. Instead, synthetic catalysts have received much attention, but they too are not yet of practical value.[13]