Quinone methides reactivity

Ramakrishnan, K. Fisher, J. 7-Deoxydaunomycine quinone methide reactivity with thiol nucleophiles. J. Med. Chem. 1986, 29, 1215-1221. 

Bolton, J. L. Turnipseed, S. B. Thompson, J. A. Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins studies utilizing amino acid and peptide models. Chem.-Biol. Interact. 1997, 107, 185-200. 

Modica, E. Zanaletti, R. Freccero, M. Alkylation of amino acids and glutathione in water by o-quinone methide. Reactivity and selectivity. J. Org. Chem. 2001, 66, 41-52. 

Kupfer, R. Dwyer-Nield, L. D. Malkinson, A. M. Thompson, J. A. Lung toxicity and tumor promotion by hydroxylated derivatives of 2,6-di-rm-butyl-4-methylphenol (BHT) and 2-A/7-bu lyl-4-methy 1-6-iso-propyl phenol correlation with quinone methide reactivity. Chem. Res. Toxicol. 2002, 15, 1106-1112. 

Quinone Methides. The reaction between aldehydes and alkylphenols can also be base-cataly2ed. Under mild conditions, 2,6-DTBP reacts with formaldehyde in the presence of a base to produce the methylol derivative (22) which reacts further with base to eliminate a molecule of water and form a reactive intermediate, the quinone methide (23). Quinone methides undergo a broad array of transformations by way of addition reactions. These molecules ate conjugated homologues of vinyl ketones, but are more reactive because of the driving force associated with rearomatization after addition. An example of this type of addition is between the quinone methide and methanol to produce the substituted ben2yl methyl ether (24). 

This addition is general, extending to nitrogen, oxygen, carbon, and sulfur nucleophiles. This reactivity of the quinone methide (23) is appHed in the synthesis of a variety of stabili2ers for plastics. The presence of two tert-huty groups ortho to the hydroxyl group, is the stmctural feature responsible for the antioxidant activity that these molecules exhibit (see Antioxidants). 

The absence of methylol (-CH2OH) groups in all six lower molecular weight resorcinol-formaldehyde condensates which have been isolated [119] reflects the high reactivity of resorcinol under acid or alkaline conditions. It also shows the instability of its para-hydroxybenzyl alcohol groups and their rapid conversion to jpara-hydroxybenzyl carbonium ions or quinone methides. This explains how identical condensation products are obtained under acid or alkaline reaction conditions [119]. In acid reaction conditions methylene ether-linked condensates are also formed, but they are highly unstable and decompose to form stable methylene links in 0.25 to 1 h at ambient temperature [121,122]. 

The ortho-quinone methides are difficult to isolate due to their high reactivity, which leads to rapid Diels-Alder dimerization or trimerization (Fig. 7.26). At 150°C, a partial retro-Diels-Alder reaction of the trimer can occur to form ortho-quinone methide and bis(2-hydroxy-3,5-dimethylphenyl) ethane (dimer).51... 

The mechanisms for model condensation reactions of para-hydroxymethyl-substituted phenol (and therefore para-quinone methide) with reactive ortho positions are described in Fig. 7.29. The phenolate derivatives react with para-quinone... 

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... 

Much attention has been devoted to the development of methods to generate quinone methides photochemically,1,19-20 since this provides temporal and spatial control over their formation (and subsequent reaction). In addition, the ability to photogenerate quinone methides enables their study using time-resolved absorption techniques (such as nanosecond laser flash photolysis (LFP)).21 This chapter covers the most important methods for the photogeneration of ortho-, meta-, and para-quinone methides. In addition, spectral and reactivity data are discussed for quinone methides that are characterized by LFP. 

While ESIPT from a phenolic OH to a carbonyl group is a common and efficient process, the highly reversible nature of the reaction often precludes any further reactivity, except in rare cases. For this reason, this reaction is not commonly used to generate or study quinone methides. 

Chiang, Y. Kresge, A. J. Zhu, Y. Reactive intermediates. Some chemistry of quinone methides. Pure Appl. Chem. 2000, 72, 2299-2308. 

MODELING PROPERTIES AND REACTIVITY OF QUINONE METHIDES BY DFT CALCULATIONS... 

The prototype o-quinone methide (o-QM) and / -quinone methide (p-QM) are reactive intermediates. In fact, they have only been detected spectroscopically at low temperatures (10 K) in an argon matrix,1 or as a transient species by laser flash photolysis.2 Such a reactivity is mainly due to their electrophilic nature, which is remarkable in comparison to that of other neutral electrophiles. In fact, QMs are excellent Michael acceptors, and nucleophiles add very fast under mild conditions at the QM exocyclic methylene group to form benzylic adducts, according to Scheme 2.1.2a 3... 

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