Aren-BuLi/TMEDA-Mediated Arene Ortholithiations Directed? Substituent-Dependent Rates, Substituent-Independent Mechanisms

Abstract

Rate studies of the lithiation of benzene and related alkoxy-substituted aromatics by n-BuLi/TMEDA mixtures implicate similar mechanisms in which the proton transfers are rate limiting with transition structures of stoichiometry [(n-BuLi)2(TMEDA)2(Ar−H)]⧧ (Ar−H = benzene, C6H5OCH3, m-C6H4(OCH3)2, C6H5OCH2OCH3, and C6H5OCH2CH2N(CH3)2). Cooperative substituent effects and an apparent importance of inductive effects suggest a mechanism in which alkoxy−lithium interactions are minor or nonexistent in the rate-limiting transition structures. Supported by ab initio calculations, transition structures based upon triple ions of general structure [(n-Bu)2Li]-//+Li(TMEDA)2 are discussed.

Sequential metalation of benzene: electronic, bonding, magnetotropic and spectroscopic properties of coinage metalated benzenes studied by DFT

“…Of immense importance is the lithiation of arenes by means of the so-called directed ortho metalation (DoM) method [2]. Since the pioneering work of Gilman [5], several methodologies have been developed to synthesize aryllithium compounds [6][7][8][9][10][11][12][13][14], namely halogen-lithium exchange [11,15], directed lithiation [16][17][18][19][20][21] and direct deprotonation processes [17,[21][22][23]. It should be noted that the lithiation of unsubstituted arenes is normally a very slow process.…”

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

“…The authors concluded that inductive effects are of great importance and precomplexation between lithium and a substituent is not a factor in this DoM. [58] 2.7. Deprotonative Lithiations: CIPE or "Kinetically Enhanced Metalation"?…”

“…[58] The fact that these reactions follow a common rate law was interpreted to favor a triple-ion model consistent with a lack of oxygenlithium complexation in the transition state for the ratelimiting proton transfer. This hypothesis is consistent with ab initio calculations (see Section 2.6).…”

Configurational stability of chiral lithiated cyclopropylnitriles: A density functional study

“…Pendant amides and carbamates effectively direct lithiation of arenes 32 and alkanes, 1 including cyclopropanes. 33,34 The enhanced acidity of the deprotonated hydrogen in these cases is attributed variously to dipole-stabilization 1,35 and the complexinduced proximity effect. 36 For the sake of computational economy, deprotonation of trans-␤-formylcyclopropylnitrile 5c was examined (Fig.…”