1-4-Methoxybenzyl carbocations

The Hammett reaction constants p = 2.7138 and 3.0157 were determined for addition of water to meta-substituted l-(4-methoxyphenyl)ethyl carbocations (80-X, Scheme 44A) and 1-4-methoxybenzyl carbocations (p-Me-1 +-X), respectively. The value of p = 2.7 for addition of water to 80-X is 36% that of the value of = 7.6, the slope of Hammett-type plots equilibrium constants for addition of water to 80-X to form the alcohol.138 This shows that the addition of water proceeds through a transition state where partial bond formation to the nucleophile results in a 36% change in the interaction between the m-substituent and the cationic benzylic carbon, compared with the complete loss of this interaction at the water adduct. Scheme 44A therefore proceed through a transition state in which there is a 36% change in the interaction between the m-substituent and positive charge at the benzylic carbon due to partial bond formation to the water nucleophile. 

Richard, J. P. Amyes, T. L. Bei, L. Stubblefield, V. The effect of beta-fluorine substituents on the rate and equilibrium-constants for the reactions of alpha-substituted 4-methoxybenzyl carbocations and on the reactivity of a simple quinone methide. J. Am. Chem. Soc. 1990, 112, 9513-9519. 

Table 3 The effects of a-carbonyl and a-thiocarbonyl substituents on the rate and equilibrium constants for the formation and reaction of a-methyl 4-methoxybenzyl carbocations R-[14+] (Scheme 1 l)a... 

Substituent effects on ks. The replacement of an a-methyl group at the 4-methoxycumyl carbocation CH3-[14+] by an a-ester or a-amide group destabilizes the parent carbocation by 7 kcalmol-1 relative to the neutral azide ion adduct (Scheme 11 and Table 3) and results in 5-fold and 80-fold decreases, respectively, in ks for nucleophilic addition of a solvent 50/50 (v/v) methanol/water.33 These results follow the trend that strongly electron-withdrawing substituents, which destabilize a-substituted 4-methoxybenzyl carbocations relative to neutral adducts to nucleophiles, do not lead to the expected large increases in the rate constants for addition of solvent.28,33,92-95... 

T. L. Amyes and J. P. Richard, Concurrent Stepwise and Concerted Substitution Reactions of 4-Methoxybenzyl Derivatives and the Lifetime of the 4-Methoxybenzyl Carbocation, J. 

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. 

Lewis acid-mediated cleavage of p-methoxybenzyl ethers is much easier than benzyl ethers because of the additional resonance stabilisation afforded by the methoxy group in the p-methoxybenzyl carbocation. Consequently, p-methoxybenzyl ethers can be removed from sensitive substrates as in the final step of a synthesis of the anti-HIV-1 sulfolipid 186.2 [Scheme 4.186] wherein three p-methoxybenzyl ethers were expelled on treatment with excess iodotrimethyl-silane.342 Similarly, a synthesis of 1,2-diacylglycerols 187.2 [Scheme 4.187]343... 

Scavengers are usually added to arrest the p-methoxybenzyl carbocation before it can do any collateral damage. Typical combinations of Lewis acid and scavenger are trifluoroborane and triethylsilane tin(IV) chloride and benzene-thiol - catalytic amounts of tin(II) chloride dihydrate and ethanelhiol - catalytic amounts of trichloroalane and ethanethiol magnesium bromide etherate and dimethyl sulfide and trichloroborane and dimethyl sulfide [Scheme 4.188]. Cerium(III) chloride heptahydrate together with sodium iodide cleaves p-methoxybenzyl ethers in refluxing acetonitrile- as does iodine in refluxing methanol but in the latter case, isopropylidene acetals do not survive. ... 

There are less data related to carbocation lifetimes as compared to radical lifetimes. Yet, some extensive studies by Mayr, Richards, and others have provided much insight into substituent effects on their lifetimes. In general, the lifetimes are extremely short in water. For example, Toteva found that the f-butyl carbocation has a lifetime of only lO" s in water. Hence, although we consider tertiary carbocations stable, they are clearly not persistent in this medium. Secondary carbocations are even more reactive toward addition of water, and many secondary derivatives undergo concerted hydrolysis in water that avoids formation of the carbocation reactive intermediate. The primary 4-methoxybenzyl carbocation inter-... 

Among the experiments that have been cited for the viewpoint that borderline behavior results from simultaneous SnI and Sn2 mechanisms is the behavior of 4-methoxybenzyl chloride in 70% aqueous acetone. In this solvent, hydrolysis (i.e., conversion to 4-methoxybenzyl alcohol) occurs by an SnI mechanism. When azide ions are added, the alcohol is still a product, but now 4-methoxybenzyl azide is another product. Addition of azide ions increases the rate of ionization (by the salt effect) but decreases the rate of hydrolysis. If more carbocations are produced but fewer go to the alcohol, then some azide must he formed by reaction with carbocations—an SnI process. However, the rate of ionization is always less than the total rate of reaction, so some azide must also form by an Sn2 mechanism. Thus, the conclusion is that SnI and Sn2 mechanisms operate simultaneously. ... 

Nucleophilic Substitution at Benzyl Derivatives. The sharp break from a stepwise to a concerted mechanism that is observed for nucleophilic substitution of azide ion at X-l-Y (Figs. 2.2 and 2.5) is blurred for nucleophilic substitution at the primary 4-methoxybenzyl derivatives (4-MeO,H)-3-Y. For example, the secondary substrate (4-MeO)-l-Cl reacts exclusively by a stepwise mechanism through the liberated carbocation intermediate (4-MeO)-T, which shows a moderately large selectivity toward azide ion ( az/ s = 100 in 50 50 (v/v) water/ trifluoroethanol). The removal of an a-Me group from (4-MeO)-l-Cl to give (4-MeO,H)-3-Cl increases the barrier to ionization of the substrate in the stepwise reaction relative to that for the concerted bimolecular substitution of azide ion. The result is that both of these mechanisms are observed concurrently for nucleophilic substitution of azide ion at (4-MeO,H)-3-Cl in water/acetone solvents. These concurrent stepwise and concerted nucleophilic substitution reactions of azide ion with (4-MeO,H)-3-Cl show that there is no sharp borderline between mechanisms for substitution at primary benzylic carbon, but instead a region of overlap where both mechanisms are observed. 

DDQ is a potent hydride abstractor with a great tendency to produce oxidations when an intermediate stable carbocation can be formed. That is why DDQ is able to remove p-methoxybenzyl (PMB),106 3,4-dime thoxyben-zyl (DMPM)106 and 2,4-dimethoxybenzyl (DMB)118 protecting groups under very mild conditions. 

However, measurements of pAR in this case lead to a lesser dependence of the equilibrium constant upon carbocation stability than pAR. Guthrie has calculated relative values of pAR and pAR and shown that an unfavorable geminal interaction between Cl and CF3 reduces the difference between ArCH2 and ArCHCF on the pAR scale by about 7 log units compared with pAR. This implies that replacing CH3 by CF3 in the p-methoxybenzyl cation decreases pAR by 14 units. Based on the value of pAR = -8.7 for the -methoxybenzyl cation, pAR for the a-CF3 cation should be close to -23.5. 

The second factor is the dependence of bonding interactions between the nucleophile and carbocation at the transition state upon the distance between the charge centers. The importance of this is suggested by a comparison of rate and equilibrium constants for the reactions of chloride ion and Me2S with the quinone methide 57 and / -methoxybenzyl cation. 

Following previous studies of reactions of carbocations with nucleophiles201 204 discussed in our 1992 chapter,4 Richard s group205,206 reports that electron-withdrawing a-substituents in 4-methoxybenzyl cations, 85, reduce the rate of nucleophilic addition of alcohols and water to... 

An tQ value of 0.50 for the 1-hydroxy-l-methoxybenzyl cation is reasonably attributed to the large stabilization of the positive charge by the hydroxyl and methoxy groups linked directly to the positive carbon centre. Thus, the Tq value seems to decrease in the increasing order of ED ability of the R group(s). This trend is qualitatively consistent with that observed for the ordinary benzylic carbocation system [1C ], PhC (R )R where R and/or R" = H, Me, CF3. 

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