The results of a joint computational and experimental study of the cyclometallation reactions of dimethylbenzylamine (DMBA-H) with [IrCl 2Cp*]2 and a range of chelating bases are presented. With acetate, density functional theory calculations on the key intermediate, [Ir(DMBA-H)(?2-OAc)Cp]+, define a two-step C-H activation process involving initial ?2-?1 displacement of base to give an intermediate that is stabilized by internal H-bonding. Facile C-H bond cleavage then occurs via'ambiphilic metal ligand activation' (AMLA). A similar pattern is computed for other carboxylates and bicarbonate, and in each case the ease of C-H activation is governed by the accessibility of the ?2-?1 base displacement step; thus, more weakly coordinating bases promote C-H activation. For triflate, [Ir(DMBA-H)(?1-CF3SO3)Cp]+ is more stable than its ?2-isomer and C-H activation proceeds with a barrier of only 3.8 kcal mol-1. Experimental studies confirm that a range of carboxylates and triflate can effect cyclometallation; however, reactivity patterns are not consistent with the computed C-H activation barriers. Instead, the role of base in opening the [IrCl2Cp*] 2 dimer and subsequent formation of the [Ir(DMBA-H)(base)Cp*] + intermediates appears crucial. Calculations indicate these processes are far more favourable for acetate than for triflate. © The Royal Society of Chemistry 2009.