MECHANISMS OF COMPETITIVE RING-DIRECTED AND SIDE-CHAIN-DIRECTED METALATIONS IN ORTHO-SUBSTITUTED TOLUENES

Heteroatom-directed metalation reactions of aromatic compounds are com plicated by the presence of an ortho CH3 group or side chain as a seco nd possible metalation site. We have employed ab initio calculations ( Becke3LYP 6-311++G*//HF 6-31G* + Delta ZPE (6-31G*) to study the pref erred site of lithiation of three ortho-substituted toluenes (o-CH3C6H 4OH (13), o-CH3C6H4NH2 (21), and O-CH3C6H4F (28)) with LiH as a model metalation reagent. The results are compared with the ring and side ch ain lithiations of toulene (7). The acidity of the hydrogen which unde rgoes exchange does not explain the regiochemistry. The preferred site for lithiation is governed by the stabilization of the transition sta te, rather than by the initial complexation: electrostatic dipole effe cts and enhanced intramolecular interaction of the metalating reagent with the substituent groups in the transition states are responsible. The complexation energies of lithium hydride with toluene, o-hydroxyto luene, o-aminotoluene, and o-fluorotoluene are -11.8 kcal/mol (8; C6H5 CH3-LiH pi-complex), -14.6 kcal/mol (14, o-CH3C6H4OH-LiH, coordinated to O), -15.6 kcal/mol (15, o-CH3C6H4OH-LiH, coordinated to O with agos tic interaction to -CH3), and -11.9 kcal/mol (16; o-CH3C6H4OH-LiH pi-c omplex). We could only locate one type of sigma complex, both for o-fl uorotoluene and o-aminotoluene (o-toluidine). The binding energies are -15.9 kcal/mol (22; o-CH3C6H4NH2-LiH) and -10.8 kcal/mol (29; o-CH3C6 H4F-LiH), respectively. The related pi complexes are less stable than the a structures with energies of -14.1 kcal/mol (23; o-CH3C6H4NH2-LiH ) and -9.2 kcal/mol (30; o-CH3C6H4F-LiH). The activation barriers for toluene, relative to the separated species, are as follows: for ortho metalation (9), 15.5 kcal/mol; for methyl lithiation (10), 4.4 kcal/mo l. When substituents are present, the activation barriers are reduced significantly: for X = OH, 4.4 kcal/mol (17; TSortho) and 1.3 kcal/mol (18; TSCH3); for X = NH2, 6.6 kcal/mol (24; TSortho), and -1.3 kcal/m ol (25; TSCH3); for X = F, 6.6 kcal/mol (31; TSortho) and 3.4 kcal/mol (32; TSCH,). Benzylic lithiation of toluene is calculated to be -2.0 kcal/mol exothermic (12); however, ortho metalation is 6.8 kcal/mol en dothermic (11). Both ortho and side chain lithiations in substituted t oluenes are exothermic: X = OH, ortho -5.9 kcal/mol (19), -6.7 kcal/mo l (20; CH3); X = NH2, -3.8 kcal/mol (26; ortho), -8.9 kcal/mol (27; CH 3); X = F, -7.5 kcal/mol (33; ortho), -4.1 kcal/mol (34; CH3). Since b enzyl derivatives with different alkali metals have different structur al preferences, substituent interactions vary. The effects of ortho su bstituents X (X = NH2, OH, F) in benzyl and in phenyl alkali-metal com pounds (M = Li, Na, K) were computed with the 6-31G basis set for Li, Na, H, C, N, O, and F and the pseudopotential method (9 VE ECP) for K . Becke3LYP 6-311++G*//6-31G* +Delta ZPE (6-31G*) calculations emphas ize the importance of electrostatic interactions in phenyl alkali-meta l compounds (the stabilization energies follow the electronegativity: N < O < F). The reverse order is calculated for the benzyl series, whe re the intramolecular interactions between the metal and X are most im portant.