Stabilizing solvents nucleophilic methylation

Alkene polymers such as poly(methyl methacrylate) and polyacrylonitrile are easily formed via anionic polymerization because the intermediate anions are resonance stabilized by the additional functional group, the ester or the nitrile. The process is initiated by a suitable anionic species, a nucleophile that can add to the monomer through conjugate addition in Michael fashion. The intermediate resonance-stabilized addition anion can then act as a nucleophile in further conjugate addition processes, eventually giving a polymer. The process will terminate by proton abstraction, probably from solvent. 

In connection with the substituent effects, the kinetic stability of benzyne is suggested to be increased by electron withdrawal (-/) and decreased by electron release (+/).73 However, the inference cannot be extrapolated to selectivity of substituted arynes in general. For example, in additions involving competition between phenyllithium and lithium piperidide, the methyl substituents (+/) on benzyne increase its selectivity, whereas methoxy groups (-/) decrease it (Scheme 6). On the other hand, in reactions of car-banions derived from acetonitrile in alkylamine solvents both +/ and -/ benzyne substituents lower selectivity and cause predominant amination. Thus, the method was found unsuitable for preparation of many substituted benzyl nitriles.74 In symmetrically disubstituted arynes there is partial cancellation of polarization, and in fact acceptable yields of acetonitrile adducts could be obtained from 3,6-dimethoxy-benzyne.75 The selectivity of substituted arynes varies with the set of nucleophiles in the competition and no comprehensive theory or simple generalization is available on this point. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

Lithium and magnesium alkyl catalysts yield metal-polymer bonds with appreciable covalent character and their cations coordinate strongly with nucleophiles. Therefore, these catalysts will initiate simple anionic polymerization only under the most favorable conditions, e. g., in basic solvents and with monomers which produce resonance stabilized polymer anions. As examples of stereoregular anionic polymerization, a-methyl-methacrylate yields syndiotactic polymer with an alkyl lithium catalyst in 1,2-dimethoxyethane at — 60° C. (211, 212) or with a Grignard catalyst at -40° C. (213). 

Base-catalysed hydrolysis using alkali metal hydroxides or carbonates in aqueous methanol or THF remains the commonest method for cleaving simple esters limited mainly by the stability of the substrate to the basic conditions. In more complex substrates, lithium hydroxide in a mixture of THF-methanol-P O (2 2 1) is the base of choice.1-3 In a synthesis of Lepicidin A, Evans and Black4 accomplished the hydrolysis of a methyl ester with lithium hydroxide in aqueous /err-butyl alcohol at 35 °C [Scheme 6.1). Destannylation that accompanied hydrolysis with other solvents was not observed nor was harm inflicted on the TIPS and TES ethers. In a synthesis of cydoisodityrosine derivatives, Boger and co-workers attempted to hydrolyse methyl ester 2 1 [Scheme 6.2] with 1-3 equivalents of lithium hydroxide in a mixture of THF-methanol-HaO (3 1 1) at room temperature, but the desired hydrolysis was accompanied by scission of the tripeptide side chain from the ring system. However, when the reaction was conducted in the presence of the more nucleophilic lithium hydroperoxide, the desired hydrolysis was achieved in 97% yield without racemisation. 

Several possible explanations have been offered. One is that the ground state of the nucleophile is destabilized by repulsion between the adjacent pairs of electrons another is that the transition state is stabilized by the extra pair of electrons a third is that the adjacent electron pair reduces solvation of the nucleophile. Evidence supporting the third explanation is that there was no alpha effect in the reaction of HOj with methyl formate in the gas phase, although HOj shows a strong alpha effect in solution. The a-efifect has been demonstrated to be remarkably dependent on the nature of the solvent. The a-effect is substantial for substitution at a carbonyl or other unsaturated carbon, at some inorganic atoms, and for reactions of a nucleophile with a carbocation, but is generally smaller or absent entirely for substitution at a saturated carbon. ... 

There is no general solvent that is useful for all reactions, and BTF naturally has its limitations. In addition to the limitations posed by the freezing point, boiling point and chemical stability mentioned before, BTF is not very Lewis-basic and therefore is not a good substitute for reactions that require solvents like ethers, DMF, DMSO, etc. Not surprisingly, ions are not readily dissolved in BTF and many types of anionic reactions do not work well in BTF. For example, attempted deprotonations of esters and ketones with LDA in BTF were not successful. Reaction of diethyl malonate with NaH (5 equiv) and reaction with Mel[72] (6 equiv) in BTF was very heterogeneous and yielded 60% of the di-methylated product, compared to 89% in THF. No reaction was observed if the same malonate anion was used as a nucleophile in a Pd-catalyzed allylic substitution reaction in BTF (see 3.7). Wittig reactions also did not work very well in BTF. The ylid of ethyl triphenyl phosphonium bromide [73] was formed only slowly in BTF, and the characteristic deep red color was never obtained. 

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