The Steric Course of S_E2 Reactions of Unstabilized α-Aminoorganolithiums:  Distinguishing between SET and Polar Mechanisms

Abstract

The competing mechanisms that determine the steric course of electrophilic aliphatic substitution reactions (S E 2) of configurationally stable, unstabilized R-aminoorganolithiums are compared. The steric course of the reaction of lithiated pyrrolidines and piperidines with electrophiles is variable, such as when comparisons are made between two electrophiles and a single organolithium, or between two organolithiums and a single electrophile. The possible pathways considered are single electron transfer (SET) and competing polar substitutions (S E 2ret vs S E 2inv). Catalysis of organolithium racemization by the electrophile was eliminated as a possible source of racemic products. When the products are completely racemic, our evidence suggests that SET is the most likely mechanism; when polar pathways are operative, stereoselectivities vary from 75 to 100%, and may be invertive or retentive at the carbanionic carbon, depending on the electrophile.

Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds

“…85 In contrast, 2-lithio- N -methylpyrrolidines, which are homochiral dimers in solution, 85 alkylate with 80% inversion and 20% retention by a polar ( i.e ., nonradical) mechanism. 86 It may be that steric influences are at work here, as suggested by diversion of both lithiopyrrolidines and lithiopiperidines to SET mechanisms when the rings are substituted (see below). 87,88 The alkyl group on nitrogen can affect the steric course.…”

“…Radical probe electrophiles can be used to confirm the presence of radicals on the reaction coordinate. 39,86,88 EPR spectroscopy has been used to detect radicals in additions of α-aminoorganolithiums to benzophenone, 84,86 but the presence of a radical in a reaction mixture does not place it on the reaction coordinate.…”

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li+ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

“…[3][4][5][6] Such an approach fails when the two substituents flanking the ketone or imine are sterically and electronically similar, and in these cases stereospecific construction of the quaternary centre from a pre-existing tertiary centre is an appealing alternative. Carbamate derivatives 1 of benzylic secondary amines [7,8] or alcohols [9,10] may be deprotonated to give configurationally stable lithio derivatives 2, which react with electrophiles either with retention or inversion, [11] allowing the formation of quaternary centres in the products 3 (Scheme 1). [12,13] Aggarwal et al have extended the utility of the lithiated carbamates of secondary benzylic alcohols by showing that they may be transformed into tertiary alcohols and amines 4 through the addition and rearrangement chemistry of boron derivatives.…”

“…However, the rearrangements of ureas and carbamates differ from one another in one very important respect: the aryl migration within the urea proceeds with retention of stereochemistry at the migration terminus, [15] whereas the aryl migration within the carbamate proceeds with inversion of stereochemistry at the migration terminus. [18] Chiral benzyllithium derivatives are known to react with electrophiles with erratic stereospecificity (retentive S E 2ret or invertive S E 2inv), [10][11][12] and while the detailed stereochemical pathways by which such stereospecific electrophilic substitution reactions proceed are yet to be fully clarified, it is generally clear that Lewis base electrophiles capable of coordination to lithium favour retentive over invertive substitution. [12] Scheme 1.…”

Substituted lithiumtrimethylsiloxysilanides LiSiRR′(OSiMe3) – Investigations of their synthesis, stability and reactivity

“…The carbanionic character is favoured by very low temperatures. Exclusively, organolithium compounds with a nitrogen atom at a-position only show carbanionic character [9,14,[16][17][18].…”