Quinone methides reaction pathway

Quinone methides have been shown to be important intermediates in chemical synthesis,1 2 in lignin biosynthesis,3 and in the activity of antitumor and antibiotic agents.4 They react with many biologically relevant nucleophiles including alcohols,1 thiols,5-7 nucleic acids,8-10 proteins,6 11 and phosphodiesters.12 The reaction of nucleophiles with ortho- and /iara-quinone methides is pH dependent and can occur via either acid-catalyzed or uncatalyzed pathways.13-17 The electron transfer chemistry that is typical of the related quinones does not appear to play a role in the nucleophilic reactivity of QMs.18... 

A third reaction pathway for quinone methides generated following ESIPT to aromatic carbon (in addition to H-D exchange and cyclization) was observed following the examination of the photochemistry of 9-(2 -hydroxyphenyl)anthracene... 

SCHEME 2.15 Reaction pathways for the generation of the prototype quinone methide through the oxidation of the 2-methylphenyl radical, investigated by post-HF and DFT methods (data have been taken from Ref. [22]). 

SCHEME 2.16 Additional reaction pathway for the generation of the quinone methide in the gas phase oxidation of 2-methylphenyl radical, investigated by the hybrid functional MPW1K (reproduced from Ref. [23] with permission from American Chemical Society). 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

FIGURE 6.9 Confirmed heterolytic formation pathway for 5a-a-tocopheryl benzoate (11) without involvement of 5a-C-centered radicals and its proof by trapping of ortho-quinone methide 3 with ethyl vinyl ether to pyranochroman 13. Shown are the major products of the reaction of a-tocopherol (1) with dihenzoyl peroxide. 

The oxidation of a-tocopherol (1) to dimers29,50 and trimers15,51 has been reported already in the early days of vitamin E chemistry, including standard procedures for near-quantitative preparation of these compounds. The formation generally proceeds via orf/zo-quinone methide 3 as the key intermediate. The dimerization of 3 into spiro dimer 9 is one of the most frequently occurring reactions in tocopherol chemistry, being almost ubiquitous as side reaction as soon as the o-QM 3 occurs as reaction intermediate. Early accounts proposed numerous incorrect structures,52 which found entry into review articles and thus survived in the literature until today.22 Also several different proposals as to the formation mechanisms of these compounds existed. Only recently, a consistent model of their formation pathways and interconversions as well as a complete NMR assignment of the different diastereomers was achieved.28... 

The combination of neutral non-aromatic and zwitterionic aromatic contributing valence bond structures confers a distinctive chemical reactivity to quinone methides, which has attracted the interest of a tremendous number of chemist and biochemists. This chapter reviews reactions that generate quinone methides, and the results of mechanistic studies of the breakdown of quinone methides in nucleophilic substitution reactions. The following pathways for the formation of quinone methides are discussed (a) photochemical reactions (b) thermal heterolytic bond... 

This chapter will focus on o- and p-quinone methides and will be divided into two parts. The first will present methods for generating quinone methides in photochemical and solvolysis reactions and will emphasize how the structure and stability of quinone methides dictates the pathways for their formation. The second section will discuss the results of experiments to characterize the reactivity of quinone methides with nucleophilic reagents, and the broader implications of these results. The scope of this presentation will reflect our interests, and will focus on studies carried out at Buffalo. We considered briefly writing a comprehensive chapter on quinone methides, but abandoned this idea when we learned of Steven Rokita s plans to edit a 12-chapter text, which presents an extremely comprehensive coverage of the chemistry and biochemistry of quinone methides.9... 

Absorption of a photon in the UV spectral region may lead to generation of electrophilic species by fast heterolytic bond cleavage at the photochemically excited state.10 Quinone methides are readily accessible through reactions of such photochemical excited states.11,12 This section outlines photochemical pathways for the generation of quinone methides. 

There is evidence that quinone methides form as intermediates in the metabolic oxidation of catechol derivatives, a key step in a variety of biosynthetic processes such as melanization and sclerotization of animal cells. Tyrosinase from mushrooms catalyzes the oxidation of a-methyldopa methyl ester 54a. It has been proposed that this reaction observed in vitro is part of a metabolic pathway for the metabolism of 54a. This reaction proceeds by oxidation of ct-methyl dopa methyl ester 54a to give 54b, which cyclizes and is further oxidized to quinone methide 54c (Scheme 26).101 This quinone methide was identified by comparison to authentic 54c, which was prepared by chemical oxidation of 54a to 54c.102... 

An example of this overall approach in elucidating novel bioactivation pathways is highlighted with studies on the potassium channel opener, maxipost (BMS-204352) (Figure 6.2), which undergoes a unique P450-mediated bioactivation reaction in rats, dogs, and humans to yield an electrophilic o-quinone-methide intermediate, which covalently binds to albumin in vivo in animals and human.33-34 Acidic hydrolysis of plasma collected after intravenous administration of [14C]-BMS-204352 to rats and human led to the characterization of a... 

How do reduction reactions that lead to a-CH2-groups affect pulping efficiencies Several typical (P-aryl ether) cleavage pathways would be blocked, which would have a negative effect on efficient delignification. However, because quinone methide formation would be prohibited, undesirable vinyl ether formation and condensation reactions would also be blocked. Bulk-phase fragmentation reactions, involving a... 

The likely pathway of photochemical cleavage is a Norrish type II cleavage reaction (Scheme 17.1). During the photoisomerization, the activated oxygen of the nitro group abstracts a y-hydrogen from the benzylic position to produce a quinone methide-like intermediate, which subsequently rearranges to afford an o-nitrosobenzaldehyde and thereby releases the carboxylic acid product. 

Dimerization of o-fuchsones, generated from o-hydroxybenzyl halides by treatment with either triethylamine or a diethylamino-derivatized polymer, affords dibenzo[i>/][l,5]dioxocin (115) and dinaphtho analogues (116 Ar = Ph, 4-FQH4, 4-MeOC6H4) in unspecified yield (Scheme 34). These reactions are reported to follow a stepwise, ionic pathway rather than radical or concerted [ttSs + r8a] thermal cycloaddition paths <82CCC838>. Curiously, no [4 + 2] dimers are formed in these reactions, although such products are favored for simpler o-quinone methides. 

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