Hydroxylation-induced migration

The process observed is reminiscent of the NIH shift , observed previously in iron hydroxylases, in which a reactive iron-oxy species (with an as yet undetermined identity) is an electrophile, attacking an arene substrate. This results in hydroxylation-induced migrations, due to the formation of carbonium ion intermediates and retention of heavier... 

G Guroff, JW Daly, DM Jerina, J Renson, B Witkop, S Udenfriend. Hydroxylation-induced migration the NIH shift. Science 157 1524—1530,1967. 

With the enzyme, phenylalanine hydroxylase, a variety of substrates have been found to undergo hydroxylation-induced migrations. 4-Deu-tero- (i5), 4-tritio- (i4), 4-chloro-, 4-bromo- (i3), or 4-methylphenyl-alanine (7) are hydroxylated to the corresponding 3-substituted tyrosines, while only small amounts of unsubstituted tyrosine are formed (Figure 1). By contrast, hydroxylation of 4-fluorophenylalanine leads to formation of tyrosine with complete loss of the substituent as fluoride ion (20). 

G. GurofF, J.W. Daly, D.M. Jerina, J. Reson, B.Witkop, S. Udenfriend, Hydroxylation-induced migration the NIH shift. Recent experiments reveal an unexpected and general result of enzymatic hydroxylation of aromatic compounds. Science 157 September 29 (1967) 1524-1530. 

This hydroxylation-induced intramolecular migration, known as the NIH shift, was explained by the involvement of arene oxides formed by the attack of electrophilic oxoiron(V) porphyrin on the aromatic ring.753 Intermediate 98 was also suggested to be formed in hydroxylation by the Fenton and related reagents in aprotic media after initial oxidation with an oxoiron(V) complex followed by electron transfer.744 754... 

Scheme 7.16 Photo-Friess rearrangement involvingthe photo-induced migration of the acid component of a phenoiic ester to a position vicinai to the hydroxyl group.

The benzoate ester is one of the more common esters used to protect alcohols. Benzoates are less readily hydrolyzed than acetates, and the tendency for benzoate migration to adjacent hydroxyls, in contrast to that of acetates, is not nearly as strong, but they can be forced to migrate to a thermodynamically more stable position. The p-methoxybenzoate is even less prone to migrate than the benzoate. Migration from a secondary to a primary alcohol has also been induced with AgN03, KF, Pyr, H2O at 100°. ... 

Recently, the mechanism of 6-nitro-BaP ring hydroxylation has been elucidated by using 3-deutero-6-nitro-BaP (144). When incubated with 3-methylcholanthrene-induced rat liver microsomes, this deuterated analogue yielded the same metabolite profile previously observed with 6-nitro-BaP. Spectroscopic analysis of 3-hydroxy-6-nitro-BaP and 6-nitro-BaP-3,9-hydroquinone indicated that 30% of the deuterium label had migrated to carbon 2, presumably via an NIH shift. Therefore, it appears that 6-nitro-BaP-2,3-oxide is a common intermediate for these two metabolites. 

Several chemical oxidants produce the NIH shift in the hydroxylation of 4-anisole-2H.681 Significantly, the system consisting of f-Bu02H-Mo(CO)6 induced deuterium migration the most. This reagent is known to effect many other reactions characteristic of monooxygenases. The yields obtained in these hydroxylations were not reported. 

Two groups of the cathedulin alkaloids, E3, E4, E5, and E6 and Kl, K2, K6, and K15, form subsets which differ within each other only in the acetylated or nonacetylated state of certain hydroxyl groups. In consequence, certain alkaloids could be artifacts caused by deacetylation induced by isolation or chromatography, or acetyl migration might have unexpectedly occurred. This cannot be ruled out with certainty in all cases, but there is evidence which indicates in general... 

---