The origin of the Macrocyclic Effect [1] in complexes of cyclam as compared with those of its open-chain analogue 2,3,2- tet is discussed. It is not readily apparent that the presence of four secondary (2°) nitrogens in cyclam, as opposed to two primary (1°) and two 2° in 2,3,2- tet should make much difference, since the pK a's of 2° amines are not much different from those of 1°. Proton basicity in water is a misleading guide to base-strength. for example logK n-(RNH 2 with Ag(I) increases strongly as R changes NiL n L = en pn en 3 dien dien 2 tetren 2,3,2-tet cyclam Δ U 0.61 2.14 0.80 4.04 6.70 11.06 3.33 1.33 −Δ H, calc: 8.99 7.46 28.00 12.06 2.55 18.04 19.27 24.67 −Δ H, obs: 9.0 7.8 28.0 11.9 2.53 18.3 19.2 24.1 in the order R = Me < Et < i-propyl < t-butyl, although the pK a's are almost invariant. This effect is attributable to greater steric hindrance to solvation for the proton. For 1° versus 2° nitrogens, it is found in the gas phase, for example, that (CH 3) 2NH is a much stronger base than CH 3NH 2, although their pK a's in water are identical. This effect is partly attributable to quenching of polarizability effects [2], and also steric hindrace to solvation. The E and C equation of Drago and Wayland [3] is used to show that in the absence of steric effects, the CuN bond in [Cu(H fac) 2NRR′ 2NH. This qualitative suggestion that the MN bond is stronger when N is 2° is supported [4] by empirical force field calculations of the increase in conformational potential energy, U, on complex-formation of Ni(II) with a variety of polyamine complexes. In each case, U has been calculated for each of the species in the reaction below, allowing calculation of Δ U. ▪ It was found that consistency could only be obtained by making the 2° NiN bond 1.7 kcal mol −1 more exothermic than the 1°. If a value of 4.8 kcal mol −1 is accorded to the ideal NiN bond to a nitrogen in the absence of steric strain, summation of the appropriate number of contributions from 1° and 2° nitrogens followed by subtraction of Δ U allows one to calculate −Δ H as shown in the Table. All calculations are for the high-spin complexes. From these results, one may assign the macrocyclic enthalpy to, firstly the presence of more 2° nitrogens in cyclam, followed by a smaller Δ U than is found for 2,3,2-tet. An important point in favour of these ideas which suggests stronger NiN bonds, is that 10 Dq for the Ni(II) cyclam complex is higher than for 2,3,2-tet. Contributions of solvation and entropy effects to the macrocyclic effect are discussed. Results below are an kcal mol −1.