Insight into the preferential N-binding versus O-binding of nitrosoarenes to ferrous and ferric heme centers

Abstract

Nitrosoarenes (ArNOs) are toxic metabolic intermediates that bind to heme proteins to inhibit their functions. Although much of their biological functions involve coordination to the Fe centers of hemes, the factors that determine N-binding or O-binding of these ArNOs have not been determined. We utilize X-ray crystallography and density functional theory (DFT) analyses of new representative ferrous and ferric ArNO compounds to provide the first theoretical insight into preferential N-binding versus O-binding of ArNOs to hemes. Our X-ray structural results favored N-binding of ArNO to ferrous heme centers, and O-binding to ferric hemes. Results of the DFT calculations rationalize this preferential binding on the basis of the energies of associated spin-states, and reveal that the dominant stabilization forces in the observed ferrous N-coordination and ferric O-coordination are dπ-pπ* and dσ-pπ*, respectively. Our results provide, for the first time, an explanation why in situ oxidation of the ferrous-ArNO compound to its ferric state results in the observed subsequent dissociation of the ligand.

Figure 1.

Binding modes of monomeric RNO ligands to monometallic centers.

Figure 2.

The nitrosoarenes NODMA and NODEA.

Figure 3.

Oxidation of ferrous heme-RNO compounds.

Figure 4.

Zwitterion contributions to NODMA and NODEA.

Figure 5.

Truncated FTIR spectra of (A) NODMA and (B) NODEA (KBr pellets) and their ¹⁵N-nitroso (broken line trace) and ¹⁸O-nitroso (dotted line trace) isotope-substituted derivatives. The major isotope-sensitive bands in these truncated regions are shown in the respective boxes. See Figures S1–S4 in the SI for additional characterization data.

Figure 6.

The molecular structure of (OEP)Fe(NODEA)(NH₂C₆H₄NEt₂-p) with thermal ellipsoids drawn at 35%. Only the major axially NO/NH₂-disordered (~90%) component is shown (see Figure S7).

Figure 7.

The crystal structures of the cations of (a) [(OEP)Fe(NODEA)]SbF₆, and (b) [(TTP)Fe(NODMA)]SbF₆, with thermal ellipsoids drawn at 35%.

Figure 8.

Optimized structures of the Fe^II-N and Fe^III-O (left panel) and alternate coordination geometries (right panel) of NODMA-coordinated ferrous and ferric porphines (atom colors: N-blue, O-red, C-cyan, H-grey, Fe-black).

Figure 9.

The MOs involving Fe and NO interactions for (a) the ferrous Fe^II-N complex (porphine)Fe(NODMA)₂, (b) the ferric Fe^III-O complex [(porphine)Fe(NODMA)]⁺ with S = 3/2, and (c) the latter ferric Fe^III-O complex with S = 5/2. Contour values =±0.02 au. The MO numbering is for the α spin.