Mechanisms of competitive ring-directed and side-chain-directed metalations in ortho-substituted toluenes

Heteroatom-directed metalation reactions of aromatic compounds are complicated by the presence of an ortho CH3 group or side chain as a second possible metalation site. We have employed ab initio calculations (Becke3LYP 6-311++G**//HF 6-31G* + Delta ZPE (6-31G*) to study the preferred site of lithiation of three ortho-substituted toluenes (o-CH3C6H4OH (13), o-CH3C6H4NH2 (21), and O-CH3C6H4F (28)) with LiH as a model metalation reagent. The results are compared with the ring and side chain lithiations of toulene (7). The acidity of the hydrogen which undergoes exchange does not explain the regiochemistry. The preferred site for lithiation is governed by the stabilization of the transition state, rather than by the initial complexation: electrostatic dipole effects 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-hydroxytoluene, o-aminotoluene, and o-fluorotoluene are -11.8 kcal/mol (8; C6H5CH3-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 agostic interaction to -CH3), and -11.9 kcal/mol (16; o-CH3C6H4OH-LiH pi-complex). We could only locate one type of sigma complex, both for o-fluorotoluene and o-aminotoluene (o-toluidine). The binding energies are -15.9 kcal/mol (22; o-CH3C6H4NH2-LiH) and -10.8 kcal/mol (29; o-CH3C6H4F-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/mol. 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/mol (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 endothermic (11). Both ortho and side chain lithiations in substituted toluenes are exothermic: X = OH, ortho -5.9 kcal/mol (19), -6.7 kcal/mol (20; CH3); X = NH2, -3.8 kcal/mol (26; ortho), -8.9 kcal/mol (27; CH3); X = F, -7.5 kcal/mol (33; ortho), -4.1 kcal/mol (34; CH3). Since benzyl derivatives with different alkali metals have different structural preferences, substituent interactions vary. The effects of ortho substituents X (X = NH2, OH, F) in benzyl and in phenyl alkali-metal compounds (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 emphasize the importance of electrostatic interactions in phenyl alkali-metal compounds (the stabilization energies follow the electronegativity: N < O < F). The reverse order is calculated for the benzyl series, where the intramolecular interactions between the metal and X are most important.