Substituent effects on the relative rates and free energies of ortho-lithiation reactions: families of fluorobenzenes as the substrates

Abstract

2-, 3-and 4-substituted fluorobenzenes and 5-substituted 1,3-difluorobenzenes were metalated with sec-butyllithium (LIS) and with lithium 2,2,6,6-tetramethylpiperidide (LiTMP) under irreversible conditions in order to determine the rates of reaction relative to the unsubstituted parent compounds (fluorobenzene and 1,3-difluorobenzene). In addition, the pairs of resulting aryllithiums were subjected to acid-base equilibration to furnish the thermodynamic stabilities (or: basicities) of these species again relative to the parent compounds. Not surprisingly, the effect diminishes with the distance of a given substituent to the lithiation center (ortho > meta > para) and it reaches its maximum at the ground state equilibration of the organometallic intermediate whereas it fades away at transition states, in particular reactant-like ones. Fluorine, the most powerful activator in the entire series if located at an ortho position, increases the rates of LIS-and LiTMP-promoted metalations by respectively 2 and 3 powers of ten, but by 7 to 8 powers of ten the aryllithium equilibrium stability.

Fluoro- and Chloroferrocene: From 2- to 3-Substituted Derivatives

“…13 These results led us to believe (i) that the ferrocene substrates we used were not acidic enough to ensure the disappearance of LiTMP in the course of the reaction and (ii) that it is necessary to block the free position next to the DG. As a consequence, we chose fluorine and chlorine as efficient short-range acidifying substituents to stabilize the produced ferrocenyllithiums 14 and selected trimethylsilyl (a poor DG) as a protecting group for both the 5-and 4-positions (Figure 1).…”

Synthesis of Polysubstituted Ferrocenesulfoxides

“…Since fluorine is also a group able to direct deprotometalation [ 80 , 81 ], we then studied the reactivity of the fluorinated ferrocenesulfoxide S , R P -1i (see Table 5 ). Inspired by previous studies in fluoroferrocene series [ 52 , 64 ], we chose sec -butyllithium to carry out the reaction in THF at −75 °C ( Method G ).…”

“…( S )- S -(4-Tolyl)ferrocenesulfoxide ( S -FcSO- p -Tol ) [ 46 ], (1 R ,2 S ,5 R )-(−)-menthyl ( S )-4-toluenesulfinate [ 96 ], ( S , R P )- S - tert -butyl-2-iodo-5-(trimethylsilyl)ferrocenesulfoxide ( S , R P -2ba ) [ 46 ] and ZnCl 2 ·TMEDA [ 81 ] were prepared as reported previously.…”

One-Pot Rapid Access to Benzyl Silanes, Germanes, and Stannanes from Toluenes Mediated by a LiN(SiMe3)2/CsCl System

“…Notably, most of the procedures developed by strong bases need a stepwise process under low temperature, which are difficult to access on scale. For example, the chemoselectivity of Schlosser’s superbase ( n -BuLi, t -BuOK) is substrate-dependent, with methoxy-substituted toluenes leading to poor selectivity and with halo-substituted toluenes preferentially metallating aromatic C­(sp) 2 –H bonds near the halogen (Scheme a) . To achieve benzylic metalations, O’Shea and co-workers developed a mixed Li and K metal amide system [ n -BuLi, t -BuOK, and TMP­(H)], which can exclusively control the anion migrations from arene ring to benzylic positions, leading to formal net benzylic deprotonations.…”