Electrophilic quinone methide carbon

The quinone methide carbon of 71 is also the terminal carbon of an extended enol, and therefore reacts as both a nucleophile and electrophile (Scheme 32). This carbon shows a higher relative reactivity with electrophiles compared with nucleophiles than is observed for the corresponding terminal quinone carbon of mitomycins (Scheme 30A).73 Furthermore, the addition of nucleophiles to 71 is readily reversible, but the nucleophile adduct can be trapped by reoxidation to... 

Five novel carbonates/ designed as suicide (mechanism-based) inhibitors of acetylcholinesterase, were synthesized and evaluated against the enzyme in vitro and screened for insecticidal activity. The design strategy of inhibition was based on the isosteric relationship of carbonates to the ester of the natural substrate acetylcholine, and on the release of electrophilic quinone methides or alpha-chloroketones at the active site after enzymatic carbonate hydrolysis. Most coirpounds were inhibitory in vitro, with good specificity for acetylcholinesterase. Some showed modest insecticidal activity. Results of kinetic studies on one analog were consistent with mechanism-based inhibition. 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

These reactions clearly indicate that the exocyclic carbon of the complexed QM in these systems is nucleophilic in character, in contrast to its electrophilic nature in free o-quinone methides. The Cp Ir metal center stabilizes the mesomeric form in which the exocyclic carbon experiences high electron density (Scheme 3.18).29... 

Further examination of the results indicated that by invocation of Pearson s Hard-Soft Acid-Base (HSAB) theory (57), the results are consistent with experimental observation. According to Pearson s theory, which has been generalized to include nucleophiles (bases) and electrophiles (acids), interactions between hard reactants are proposed to be dependent on coulombic attraction. The combination of soft reactants, however, is thought to be due to overlap of the lowest unoccupied molecular orbital (LUMO) of the electrophile and the highest occupied molecular orbital (HOMO) of the nucleophile, the so-called frontier molecular orbitals. It was found that, compared to all other positions in the quinone methide, the alpha carbon had the greatest LUMO electron density. It appears, therefore, that the frontier molecular orbital interactions are overriding the unfavorable coulombic conditions. This interpretation also supports the preferential reaction of the sulfhydryl ion over the hydroxide ion in kraft pulping. In comparison to the hydroxide ion, the sulfhydryl is relatively soft, and in Pearson s theory, soft reactants will bond preferentially to soft reactants, while hard acids will favorably combine with hard bases. Since the alpha position is the softest in the entire molecule, as evidenced by the LUMO density, the softer sulfhydryl ion would be more likely to attack this position than the hydroxide. 

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. 

Most studies point to a nonenzymatic pathway for the polymerization of PAs involving the condensation of the molecules through the electrophilic attack of the carbon C-4 from the pyranic ring C of an extension unit (leucoanthocyanidin) to a nucleophilic carbon C-8 or C-6 of a terminal unit (flavan-3-ol) [76,90,91,108,109]. Polymerization continues with the electrophilic attack of carbon C-4 of a flavan-3,4-diol to the carbon C-8 or C-6 from the dimer previously formed. However, this hypothesis fails in the fact that the majority of extension units in PAs found in planta are 2,3-cis and leucoanthocyanidins are 2,3-trans [86]. Thus, it was proposed that a leucoanthocyanidin derivative must be involved in the polymerization mechanism, such as quinone methides and carbocation products. Another proposal comprises the conversion of the 2/ ,35,4S -leucoanthocyanidins into 2/ ,35-quinone methides that can be directly used as extensirai units. These compounds can also be converted in 2/ ,3/ -quinone methides via flavan-3-en-3-ol that can be further used as extension units [110]. In another pathway, the 2R,3S and 2/ ,3/ -quinone methides can be transformed in the respective carbocations and attack (+)-catechin or (—)-epicatechin, leading to the formation of the diverse PA molecules (Fig. 57.10). 

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