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 degrees C, mu = 0.1 M) and pyridines (as a function of temperature, mu = 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 then 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 Delta H and Delta S 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 sigma and pi 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 End 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 sigma orbital for primary amines. These observations suggest that both sigma bonding and pi 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.