Free energy changes (Delta G degrees, copper cation basicity) for the reaction L2Cu+ = Cu+ + 2L were obtained in the gas phase for substituted pyridines based on the measurement of ligand-exchange equilibria in a Fourier transform ion cyclotron resonance (FT-ICR) spectrometer. For 3- and 4-substituted pyridines, the relative copper cation basicities (Delta CCB[L2Cu+]) were linearly correlated with the corresponding gas-phase proton basicities (Delta GB) with a slope of 1.01. On the basis of a linear relationship between the calculated copper cation basicities of dimeric and monomeric complexes at MP2/6-311+G(2p,2d)//B3LYP/6-311G*, Delta CCB[L2Cu+](calcd) = 1.54 Delta CCB[LCu+](calcd), the substituent effect on the Delta CCB for the first ligand was estimated to be 0.66 times smaller than the corresponding Delta GB. A comparison with the corresponding results for other Lewis cation basicity of the pyridine system showed that the magnitude of the substituent effect decreases in the order H+ (1.00) > Me3Si+ (0.95) > Cl+ (0.83) > Cu+ (0.66) > Li+ (0.47). This change was associated with the natural charges at the Lewis cation moiety and the natural atomic orbital (NAO) bond order of the M+-N bond of the complex ion, indicating the decrease in covalent character of the M+-N bond in this order. Furthermore, when a variety of neutral bases such as amines, carbonyl compounds, and ethers were included in a comparison between CCB[L2Cu+] and GB, it was found that there is a good linear relationship with significant deviations of small molecules and bulky tributylamine, which is attributed to their different steric environment at the binding sites from others, while there is no simple linear relationship with the lithium cation basicities (LCB). The similarity of the substituent effect between CCB[L2Cu+] and GB reflects the covalent character in the Cu+ interaction. In conclusion, although the ionic (ion-dipole interaction) nature of the Cu+ interaction results in a smaller substituent effect than that for the protonation, the covalent nature also plays an important role in the Cu+ interaction with neutral molecules.