Deprotonation kinetic barrier

Fig. 4 Free energy reaction coordinate profiles that illustrate a change in the relative kinetic barriers for partitioning of carbocations between nucleophilic addition of solvent and deprotonation resulting from a change in the curvature of the potential energy surface for the nucleophile addition reaction. This would correspond to an increase in the intrinsic barrier for the thermoneutral carbocation-nucleophile addition reaction.

Although there is a kinetic barrier to the direct deprotonation of tertiary amines, Ahlbrecht and Dollinger showed in 1984 that the Schlosser superbase, i c-BuLi/f-BuOK, can deprotonate A-methylpiperidine selectively on the methyl group (Scheme 3). This superbase probably yields an a-amino-organopotassium species (and f-BuOLi), but treatment with LiBr effects transmetalation to the more nucleophilic, and less basic, a-amino-organolithium species. Electrophilic quench with several aldehydes and ketones gives substitution products in good yields as typified by the example in Scheme 3. Similarly,... 

In 1991, Kessar and coworkers demonstrated that the kinetic barrier could be lowered by complexing the tertiary amine with BF3, snch that i-BuLi is able to deprotonate the ammoninm compound, which can be added to aldehydes and ketones as shown by the example in Scheme 4a. Note the selectivity of deprotonation over vinyl and allyl sites. A limitation of this methodology is that the ylide intermediate does not react well with alkyl hahde electrophiles. To get aronnd this, a seqnence that begins with the stannylation and decomplexation shown in Scheme 4b was developed. The stannane can be isolated in 94% yield (Scheme 4b) and snbseqnently snbjected to tin-lithium exchange to afford an unstabilized lithiomethylpiperidine that is a very good nucleophile. However, isolation of the stannane is not necessary and a procedure was devised in which the amine is activated with BF3, deprotonated, stannylated, decomplexed from BF3 with CsF, transmetalated back to lithium and alkylated, all in one pot (Scheme 4c). ... 

Deprotonation of ethers is another route to the a-alkoxy anions, but this pathway is often precluded by a kinetic barrier. Unless the a-carbon is benzylic [175], surmounting this barrier usually requires conditions that are not favorable to the survival of the anion [164]. Notable exceptions are the hindered aryl esters studied by Beak [176], Figure 3.13a, and the carbamates studied by Hoppe [177], shown in Figure 3.13b. In both cases, ec-butyllithium is required for deprotonation, and the carbonyls which direct the metalation by a complex-induced proximity effect [178] must be shielded from the base by large alkyl groups. Once formed, the organo-lithiums are chelated and stabilized by the heteroatom-induced dipole [179]. 

Unlike lithiated tetrahydroisoquinolines, a-lithio derivatives of saturated heterocycles are configurationally stable [202-204] (review [163]), and they have a considerably higher kinetic barrier to deprotonation. Nevertheless, there have been a number of activating groups developed for the alkylation of a-lithio amines. In 1991, Beak showed that the complex of sparteine and sec-butyllithium enantioselectively deprotonates BOC-pyrrolidine, and that the derived organolithium is a good nucleophile for the reaction with several electrophiles, as shown in... 

In the case of benzene, the large kinetic barrier does not allow the reaction to proceed. The latter is possible, however, in the presenee of TMEDA. The role of this chelate ligand is first to break the hexamerie eluster in hexane by complexation of the Li+ eation, which strongly polarizes the Li-C bond. The addition of benzene or ferrocene then rapidly leads to deprotonation-metallation of the aromatic derivative, because the n-C4H9 anion is rendered more basie onee it is disengaged from the covalent bond with Li. 

---