Two new isomeric bis(trans-fused cyclohexano) substituted 1,4,7,10,13-pentaazacyclopentadecane ligands and their Mn(II) complexes, 3 and 14, have been synthesized, and their activity as superoxide dismutase (SOD) catalysts has been studied. Complex 3 is an excellent SOD catalyst with a second-order rate constant at pH 7.4 of 1.2 x 10(+8) M-1 s(-1). In contrast, the isomeric complex 4 has virtually no detectable catalytic SOD activity, implying the need to understand the effect that the position, number, and stereochemistry of substituents exert on the catalytic rate. The crystal structure of the complex 4 was determined and reveals that the Mn(II) ion is coordinated in a pentagonal bipyramid array of the dye nitrogens of the macrocyclic ligand and capped by two trans-chloro ligands. Crystal data for MnC18H37Cl2N5 are as follows : triclinic at 20 degrees C, space group P-1-C(i)2 (no. 2); a = 9.746(3) Angstrom, b = 12.631(6) Angstrom, c = 11.311(5) Angstrom; alpha = 73.14(4)degrees, beta = 76.39(3)degrees, gamma = 79.98(3)degrees, V = 1287(1) Angstrom(3), and Z = 2 (rho(calc) = 1.279 g/cm(3); mu(2) Mo K-alpha = 6.23 mm(-1)). Mechanistic studies with the complex 3 and the pentamethyl susbstituted complex, 5, including D2O rate studies, are reported and are consistent with the existence of two pathways for the rate-determining electron-transfer from Mn(II) to superoxide : (1) hydrogen atom transfer from a bound water on Mn(IP) to HO2. to yield a Mn(III) hydroxo intermediate and (2) the dissociative pathway in which superoxide anion binds to a vacant coordination site on Mn(II) followed by protonation/oxidation to yield a Mn(III)hydroperoxo species. Subsequent reduction of the intermediate Mn(III) with superoxide anion completes the catalytic cycle. Substituent effects on the rates and relative contribution of the two pathways to the overall rate of SOD activity is ascribed to the propensity of the ligand to fold around Mn(II) forming a pseudo-octahedral complex similar in geometry to the oxidized Mn(III) complex. Folding of the pentaaza macrocyclic ligand is confirmed as a relevant structural motif for this series of Mn(TI) complexes by the X-ray structure determination of the bis(nitrate) derivative of 1, [Mn(C10H25N5)NO3]NO3, which reveals a six-coordinate structure with a folded conformation of the macrocyclic ligand. Crystal data for [Mn(C10H25N5)NO3]NO3 : orthorhombic at -100 degrees C, space group P2(1)2(1)2(1); a = 9.457(2) Angstrom, b = 12.758(2) Angstrom, c = 13.834(2) Angstrom, V = 1669.1(5) Angstrom(3), and Z = 4 (rho(calc) = 1.549 g/cm(3)).