The near thermal conditions of an ion-trap mass spectrometer were used to examine the intrinsic gas-phase reactivity and selectivity of nucleophilic substitution reactions. The well-defined organocuprate anions [CH3CuR]– (R = CH3CH2, CH3CH2CH2, (CH3)2CH, PhCH2CH2, PhCH2, Ph, C3H5, and H) were reacted with CH3I. The rates (reaction efficiencies, ϕ) and selectivities (the product ion branching ratios) were compared with those of [CH3CuCH3]– reacting with CH3I. Alkyl R groups yielded similar efficiencies, with selectivity for C–C bond formation at the coordinated R group. Inclusion of unsaturated R groups curbed the overall reactivity (ϕ = 1 to 2 orders of magnitude lower). With the exception of R = PhCH2CH2, these switched their selectivity to C–C bond formation at the CH3 group. Replacing an organyl ligand with R = H significantly enhanced the reactivity (8-fold), resulting in the selective formation of methane. Unique decomposition and side-reactions observed include: (1) spontaneous β-hydride elimination from [RCuI]– byproducts; and (2) homocoupling of the pre-existing organocuprate ligands in [CH3CuC3H5]–, as shown by deuterium labeling. DFT (B3LYP-D/Def2-QZVP//B3LYP/SDD:6-31+G(d)) predicts that the alkylation mechanism for all species is via oxidative addition/reductive elimination (OA/RE). OA is the rate-limiting step, while RE determines selectivity: the effects of R on each were examined.