Quinone methides with water

Leary, G. Miller, I. J. Thomas, W. Woolbouse, A. D. The chemistry of reactive lignin intermediates. Part 5. Rates of reactions of quinone methides with water, alcohols, and carboxylic acids. J. Chem. Soc., Perkin Trans. 1977, 2, 1737-1739. 

Table 1 Rate and equilibrium constants determined for the reactions of quinone methides with water in acidic solutions...

The second-order rate constants for the reaction of several substituted hydrazines, hydrazides, hydroxylamines, methylamines, and ammonia with benzhydrylium ions and quinone methides in water and MeCN have been measured and the N and % values [in the log k = %(At + E) equation] of the various nucleophiles determined. The effect of adding methyl or larger group(s) to the a- or -position of the nucleophiles is discussed. Although the amine and hydrazine nucleophiles react much slower in water... 

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). 

Release and Reactivity of tf-o-QMs Although the r 2-o-QM Os complexes 11 are stable when exposed to air or dissolved in water, the quinone methide moiety can be released upon oxidation (Scheme 3.8).16 For example, reaction of the Os-based o-QM 12 with 1.5 equivalents of CAN (ceric ammonium nitrate) in the presence of an excess of 3,4-dihydropyran led to elimination of free o-QM and its immediate trapping as the Diels-Alder product tetrahydropyranochromene, 14. Notably, in the absence of the oxidizing agent, complex 12 is completely unreactive with both electron-rich (dihydropyran) and electron-deficient (A-methylmaleimide) dienes. 

We also wanted to evaluate the disassembly of our dendritic system under physiological conditions. Thus, we synthesized a self-immolative AB6 dendron 32 with water-soluble tryptophan tail units and a phenylacetamide head as a trigger (Fig. 5.26) to evaluate disassembly in aqueous conditions. The phenylacetamide is selectively cleaved by the bacterial enzyme penicillin G amidase (PGA). The trigger was designed to disassemble through azaquinone methide rearrangement and cyclic dimethylurea elimination to release a phenol intermediate that will undergo six quinone methide elimination reactions to release the tryptophan tail units. 

SCHEME 7.23 Mechanism of quinone methide trapping of water with calculated 13C chemical shifts of the five-carbon center of methide enolates. 

Quinone methides are electron-deficient at C7, as readily understood via the resonance forms of QM1 shown in Fig. 12.7. They are therefore susceptible to nucleophilic attack at that position. Although reactions during high-temperature pulping demonstrate that 8-<9-4-aryl ether quinone methides QM1 are rearomatized by attack with hard nucleophiles such as HO- and HS, 81 these reactions do not readily occur at ambient temperatures.41,85 Thus, HO will not add to quinone methide QM1 under any conditions that we have tried (including with cosolvents, and using phase-transfer conditions). Of course water will add to quinone methides under acidic conditions... 

It is pertinent at this point to refer briefly to the sources of quinone methides, though these have been reviewed (B-74M122400). The general approach used in chroman syntheses involves the thermal elimination of HX from an -substituted phenol. Commonly the eliminated molecules are water, methanol or dimethylamine (287 X = OH, OMe, NMe2, respectively). However, these methods are not entirely suitable because the eliminated molecules may promote side reactions. In the case of 1,2-naphthoquinone 1-methide, the thermal dissociation of the spirodimer (288) is a better source than the other methods. Its formation represents another example of dimerization by a [4+2]-cycloaddition, since it is prepared by heating l-dimethylaminomethyl-2-naphthol in dodecane or xylene with careful exclusion of moisture (73JCS(P1)120,81CJC2223). 

In another case, 4-alkylphenols can be transformed with the help of the flavoenzyme vanillyl alcohol oxidase (VAO) to either (R)-l-(4 -hydroxyphenyl) alcohols or to 1 -(4 -hydroxyphenyl)alkenes. Both products pass through a common intermediate, the p-quinone methide, which then either is attacked by water or rearranges. The product spectrum can be controlled by medium engineering in organic solvents such as acetonitrile and toluene, more ris-alkene but not trans-alkene, and less alcohol, are produced (van den Heuvel, 2001). A similar shift in cis/trans-alkene was achieved by the addition of monovalent anions that bind specifically close to the active site. 

Irradiation of 2,2-dimethyl chromene through Pyrex using a 550-W Hanovia lamp initiates a retro 4 + 2 reaction to form the extended quinone methide 4, which reacts with methanol to form a pair of methyl ethers (Scheme 6A).18 Flash photolysis of coniferyl alcohol 5 generates the quinone methide 6 (Scheme 6B) by elimination of hydroxide ion from the excited-state reaction intermediate.19 The kinetics for the thermal reactions of 6 in water were characterized,20 but not the reaction products. These were assumed to be the starting alcohol 5 from 1,8-addition of water to 6 and the benzylic alcohol from 1,6-addition of water (Scheme 6). A second quinone methide has been proposed to form as a central intermediate in the biosynthesis of several neolignans,21a and chemical synthesis of neolignans has been achieved... 

The silyl group is widely used as an oxygen protecting group, because of the ease of its removal by nucleophilic substitution by fluoride anion. The protected phenols 0-(tert-butyldimethylsilyl)-/ -(bromomethyl)phenol (45) and 0-(tert-butyldimethylsilyl)-2,6-bis(bromomethyl)phenol (46) react rapidly with fluoride anion in water to form the corresponding phenols, which then break down to the ortho-quinone methide 41 (Scheme 21A) and the substituted ortho-quinone... 

Quinone methides have been generated by reaction of their transition metal complexes.127 The T)2-methylene-coordinated complex 77 forms stable solutions in water and methanol. NMR spectroscopy showed that 77 and dibenzy-lideneacetone (DBA) in methanol undergo rapid conversion to 79 (Scheme 37). This is consistent with the reaction of DBA with the palladium ligand at 77 to... 

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... 

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