T. Kremer et al., MECHANISMS OF COMPETITIVE RING-DIRECTED AND SIDE-CHAIN-DIRECTED METALATIONS IN ORTHO-SUBSTITUTED TOLUENES, Organometallics, 15(15), 1996, pp. 3345-3359
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.