Quinone methides, generation studies

The quinone methide can also be generated in situ, at least in aqueous NaOH, directly from the peracetate, as hydrolysis of the phenolic acetate is faster than the benzylic acetate (see an example in Section 12.5.3). This method was used to demonstrate the addition of anthrahydroquinone (AHQ) and anthranol to (actual polymeric) lignin quinone methides in studies elucidating the anthraquinone (AQ)-catalyzed 8-0-4-aryl ether cleavage mechanisms in alkaline pulping.64-66... 

Full details of a careful study of the regio- and stereospecific intramolecular [4 + 2] cycloadditions of o-quinone methides generated by the thermal or acid-catalyzed (CF3CO2H) dehydration of o-hydroxybenzyl alcohols have been described 75 and have found application in the total synthesis of enantiomerically pure (3/ )-26 and (3/ )-27 possessing the ring system and correct absolute configuration of the cannabinol family [Eq. (47)]. 

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, J. Zhu, Y. Flash photolytic generation of ortho-quinone methides in aqueous solution and study of its chemistry in that medium. J. Am. Chem. Soc. 2001,123, 8089-8094. 

The partial combustion of toluene, with the generation of the intermediate 2-methyl-phenyl radical (MP, in Scheme 2.15) leading to the prototype quinone methide, has recently been investigated by high-level post-HF and DFT theoretical studies.22... 

The starting point for much of the work described in this article is the idea that quinone methides (QMs) are the electrophilic species that are generated from ortho-hydro-xybenzyl halides during the relatively selective modification of tryptophan residues in proteins. Therefore, a series of suicide substrates (a subtype of mechanism-based inhibitors) that produce quinone or quinonimine methides (QIMs) have been designed to inhibit enzymes. The concept of mechanism-based inhibitors was very appealing and has been widely applied. The present review will be focused on the inhibition of mammalian serine proteases and bacterial serine (3-lactamases by suicide inhibitors. These very different classes of enzymes have however an analogous step in their catalytic mechanism, the formation of an acyl-enzyme intermediate. Several studies have examined the possible use of quinone or quinonimine methides as the latent... 

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... 

Kresge and coworkers, and McClelland et al.39 have generated o-quinone methide,50,5 -quinone methide,52 and related simple quinone methides as products of photolytic cleavage of 2-hydroxybenzyl and 4-hydroxylbenzyl derivatives.53 58 The results of studies on the mechanism for nucleophile addition to these simple quinone methides are summarized in latter sections of this chapter. 

The tetramethyl quinone methide 38f has been generated by cleavage of the chloride precursor in dichloromethane, and its reactions with amine bases studied.74... 

These questions were addressed in studies of the reactions ofp-1 and / -Me-1 + in aqueous solution. The quinone methide p-1 was generated by photoheterolysis of neutral 4-hydroxybenzyl acetate in water, and ks = 3.3 s 1 determined for addition of water.52 The O-methylated quinone methide / -Me-l+ was generated as an intermediate of solvolysis of neutral precursors in water,128 and ks = 2.5 x 108 s 1 for addition of water was determined by using the diffusion-limited rate of nucleophile addition of azide anion to / -Me-l+ as a clock for the slower addition reaction of solvent.135,138 These data show that methylation ofp-1 causes an enormous 6 x 107-fold increase in the reactivity of the electrophile with solvent water.52... 

The quinone methide 48 was generated by nucleophilic aromatic substitution of water at Me-48+ as shown in Scheme 23,89 and its reaction with solvent and added nucleophiles studied in water and in 50/50 (v/v) H20/trifluoroethanol at 25°C.4,67,89,91 The addition of a pair of strongly electron-deficient q -CF3 groups to the parent unsubstituted pura-quinone methide p-1 should increase the... 

During my early years as an assistant professor at the University of Kentucky, I demonstrated the synthesis of a simple quinone methide as the product of the nucleophilic aromatic substitution reaction of water at a highly destabilized 4-methoxybenzyl carbocation. I was struck by the notion that the distinctive chemical reactivity of quinone methides is related to the striking combination of neutral nonaromatic and zwitterionic aromatic valence bond resonance structures that contribute to their hybrid resonance structures. This served as the starting point for the interpretation of the results of our studies on nucleophile addition to quinone methides. At the same time, many other talented chemists have worked to develop methods for the generation of quinone methides and applications for these compounds in organic syntheses and chemical biology. The chapter coauthored with Maria Toteva presents an overview of this work. 

Studies of the generation and properties of o-quinone methide imines38-42 (Table 9-III) suggest that with continued investigation they will prove to be useful synthetic intermediates comparable to the o-xylylenes43 and o-quinone methides.44 Although a few notable examples of successful efforts to trap the unstable o-quinone methide imines in intermolecular [4 +... 

Solid state excitation of electron donor-acceptor complexes of various diaryl-acetylenes and dichlorobenzoquinone in either the acceptor or the 1 2 complex absorption bands induces [2+2] cycloaddition and produces identical mixtures of the quinone methides. Evidence is presented for the participation of an ion-radical pair as the reactive intermediate in both cases. Irradiation of an appropriately substituted o-hydroxybenzyl alcohol precursor generates the corresponding o-quinone methide which is reported to undergo an efficient [4+2] cycloaddition to form the hexahydrocannabinol system. Time-resolved studies confirm the intermediacy of the o-quinone methide and show its lifetime to be > 2 ms. Laser photolysis of 1,2-bis(phenoxymethyl)benzene, l,2-bis[(phenylthio)-methyl]benzene, and l,2-bis[(phenylseleno)methyl]benzene occurs by a two-photon process to produce o-quinodimethane which will cycloadd to various dienophiles including maleic anhydride, dimethyl maleate, dimethyl fumarate, fumaronitrile and dimethyl acetylenedicarboxylate. ... 

The methods that generate quinone methides were reviewed, along with a detailed analysis of the mechanisms of the reactions of these electrophiles with nucleophiles. " Quinone methide (10), the para isomer and the zwitterionic meta isomer, were obtained by photolysis of 2-phenylphenol derivatives substituted with a hydroxyadamantane. The mechanisms of decomposition of these intermediates were studied by a combination of product analysis and laser flash photolysis. Irradiation of 1-hydroxypyrene results in intramolecular proton transfer from OH to carbon atoms at the 3, 6, and 8 positions resulting in quinone methide intermediates (e.g. the zwitterion (11)). These revert to starting material by proton loss, a process that is monitored by deuterium labelling. 

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