Two limiting mechanisms, one operating under kinetic and the other thermodynamic control, have been identified for lateral lithiation reactions. The mechanisms of most lateral lithiations fall somewhere between these two limiting mechanisms, and the precise mechanism of a particular lithiation depends on two factors:
* The Lewis acidity of the organolithium reagent (RLi > LiNR)
* The Lewis basicity of the heteroatom substituent (N > O > S)
When both the Lewis acidity of the organolithium compound and the Lewis basicity of the substituent are high, as in lithiations of ortho-(dialkylamino)methyl toluenes with n-butyllithium in a non-coordinating solvent, coordination of the base to the heteroatom substituent takes place. Lithiation then occurs at the most kinetically accessible ortho benzylic position; ortho lithiation is slower in this case.
As either the Lewis acidity of the base or the coordinating ability of the substituent decrease, a mechanism involving purely inductive effects becomes more important. For instance, the lithiation of 1 with lithium di(isopropyl)amide (LDA) affords only the product of benzylic metalation 2; none of the ortho-lithiated product 3 is observed. This result is explained by a mechanism in which the amide substituent affects the acidity of the para benzylic position solely through inductive effects and coordination of the base is not operative. Deprotonation occurs to afford the most thermodynamically stable product.
In most cases, both mechanisms will lead to the same product, as the sites of kinetic and thermodynamic deprotonation will coincide.