The monomeric ferric hemepeptide from cytochrome c, N-acetylmicroperoxidase-8 (NAcMP8), retains the proximal His ligand and has a coordinated water molecule in the second axial site. It provides an opportunity for quantitatively studying in aqueous solution the coordination chemistry of an iron porphyrin with a single accessible coordination site. An examination of the dependence of the spectrophotometrically determined equilibrium constants for coordination of imidazole and cyanide as a function of pH provides a procedure for correcting conditional equilibrium constants for the ionization of coordinated H2O in NAcMP8 and protonation of the entering ligand, L. An examination of the coordination by NAcMP8 of L = primary amines and imidazoles (25 °C, μ = 0.1 M) and pyridines (as a function of temperature, μ = 0.1 M) has shown that the process of binding L to NAcMP8 may be complex. With some ligands such as pyridines and some primary amines there is evidence for formation of an outer-sphere complex before displacement of H2O occurs. In some cases, a third process occurs at high concentrations of L which may entail substitution of the proximal His ligand. Pyridines and imidazoles fall into different classes in their basicity−affinity for Fe(III) relationships; primary amines fall into two distinctive classes, with one class having a higher affinity for Fe(III) than expected from basicity alone. It is suggested that neutral or cationic functional groups in the side chain of these ligands provide a second site of attachment to the iron porphyrin by hydrogen bonding. A compensating effect between ΔH and ΔS values for coordination of pyridines to NAcMP8 is demonstrated; hence log K values, rather than the individual thermodynamics parameters, were used to explore the possible influence of the electronic structure of the ligands on the magnitude of their affinity for Fe(III). Log K for coordination of pyridines and imidazoles correlates linearly, and statistically meaningfully, with the energies of the frontier orbitals of σ and π symmetry (determined by ab initio or semiempirical molecular orbital methods at the RHF level of theory using, respectively, the 6-31G* split-valence polarized basis set and the PM3 model), which have large amplitude on the donor N atom. There is only a weak correlation between log K and the energy of the frontier σ orbital for primary amines. These observations suggest that both σ bonding and π bonding between planar aromatic ligands and Fe(III) play a significant role in determining the magnitude of the binding constant of these ligands to a ferric porphyrin.