INTERACTIONS OF HYDROXYLAMINES, ALDOXIMES AND NITRIC OXIDE WITH THE GROUP 8 & 9 METALS USING HEME AND NON-HEME MODELS

Abstract

This dissertation investigates the interactions of biologically relevant small molecules, specifically hydroxylamines (RNHOH), aldoximes (RCH=NOH), and nitric oxide (NO), with metalloporphyrins containing iron (Fe), cobalt (Co), and rhodium (Rh) by employing a combination of experimental and computational techniques, including X-ray crystallography, IR and NMR spectroscopy, and density functional theory (DFT) calculations. This work aims to elucidate the structural and electronic factors that govern these interactions and their implications for biochemical processes observed in nature. Chapter 1 provides a brief introduction to the significance of the interactions of hydroxylamines, aldoximes, and nitric oxide with heme-containing enzymes, such as cytochrome P450 and cytochrome P460. These interactions are crucial for essential biological processes, such as drug metabolism, detoxification, and nitrogen cycling. I set the stage for the detailed studies presented in the subsequent chapters, focusing on the fundamental chemistry of these interactions and their implications in bioinorganic chemistry. Chapter 2 examines the role of a previously unrecognized internal H-bond interaction between a hydroxylamine RNHO–H group and porphyrin N-atoms of the (TPP)Fe(AmphNHOH)(AmphNO) and (TPP)Co(AmphNHOH) complexes using DFT calculations. This chapter provides new insights on heme-mediated hydroxylamine activation in the absence of a distal pocket. The DFT calculations show that the conformations with the internal H-bond represent global minima along the potential energy surfaces for both the Fe and Co heme models, confirming that the observed internal H-bond is an intrinsic feature of the complexes and not due to crystal packing effects. The natural bond orbital (NBO) analyses reveal a donor π (porN=C) to acceptor σ* (O-H) interaction of 3.04 kcal/mol for Fe, and 1.36 kcal/mol for Co. These results are consistent with a unique heme-based activation that weakens the hydroxyl O–H bond, thereby facilitating the conversion to its nitroso derivative in the Fe case. In contrast, the Co complex exhibits less π-to-σ* interaction energy, resulting in a lower O–H activation. This difference helps explain the experimentally observed conversion from Fe-AmphNHOH to its nitroso derivative Fe-AmphNO, and the increased stability of the Co–AmphNHOH adduct. Additionally, I extend these computational studies to the parent hydroxylamine (NH2OH). The DFT calculations on ferrous and ferric heme models with NH2OH also reveal the presence of internal H-bonds between hydroxylamine (R/H)NHOH moieties and heme N-atoms, suggesting that this feature might be more common than previously recognized. Chapter 3 centers on the binding and activation of hydroxylamines and aldoximes with Group 9 metals, specifically cobalt and rhodium, using both heme and non-heme models. It examines whether the intramolecular H-bonds observed in alkylhydroxylamine heme derivatives with first-row transition metals (Chapter 2) could also occur in arylhydroxylamine and aldoximes derivatives with second-row transition metals. Additionally, I explore whether this internal hydrogen bonding is a unique characteristic of heme systems or if it could also occur in other nitrogen-containing molecules, such as those in non-heme models. In this chapter, the preparation, crystal structures, spectroscopic characterizations (IR and NMR), and DFT calculations of various cobalt and rhodium complexes with hydroxylamine and aldoxime adducts are presented. The crystal structure of (TPP)Rh(PhNHOH)(C6H4Cl) reveals, in addition to N-binding of PhNHOH to Rh, the presence of an intramolecular H-bond between the hydroxylamine –OH proton and a porphyrin N-atom. In contrast, the crystal structures of (TPP)Co(RCH=NOH)Cl (R = butylaldoxime, benzaldoxime) exhibit two intramolecular H-bonds between the oxime =N-OH and the methine -C(H)=N-OH protons with porphyrin N-atoms; these internal H-bonds were not observed in the Rh derivative (TPP)Rh(CH3(CH2)2CH=NOH)(C6H4Cl-p). While DFT calculations predict the presence of similar intramolecular H-bond interactions in the related aldoxime complexes (TPP)Rh(RCH=NOH)(C6H4Cl) (e.g., R = formaldoxime, butyraldoxime) in their global minima structures, the X-ray crystal structure obtained for the (TPP)Rh(CH3(CH2)2CH=NOH)(C6H4Cl-p) complex is consistent with the local (non-global) minima conformation. Direct comparison of the non-porphyrin cobalt complexes oxime adducts with their porphyrin analogues is also presented. The X-ray crystal structures of (Me2bpbMe2)Co(RCH=NOH)(H2O) (R = butylaldoxime, benzaldoxime) reveal that the NOH protons are not involved in internal H-bonding with the N4-chelate. I show that the π-to-σ* interaction contributes to the overall binding of RCH=NOH to the cobalt centers as evidenced by the experimental H-down conformations in the porphyrin systems but not in the bpb complexes. Chapter 4 explores the reactivity of nitric oxide (NO) with a rhodium porphyrin complex in a solid crystal and in solution. A combination of spectroscopic techniques (e.g., IR, UV-vis, NMR), X-ray crystallography, and computational methods employed, and the results discussed. A notable gap in the existing literature is the lack of comprehensive studies on NO insertion into metal-carbon bonds of metalloporphyrin complexes. Previous work in our laboratory revealed a unique NO insertion in a crystalline rhodium porphyrin complex, but the reproducibility and detailed mechanistic understanding remain elusive. In this chapter, I re-examine the preliminary results where crystals of (TPP)Rh(C6H4Cl) are exposed to NO gas. The X-ray analysis reveals the formation of an NO-inserted product, (TPP)Rh(ONC6H4Cl-o) alongside with the unreacted (TPP)Rh(C6H4Cl-p). This finding suggests a specific reactivity pattern depending on the isomeric form of the chlorophenyl ligand. Advanced 1H NMR spectroscopic techniques (1D TOCSY) show a mixture of para, meta, and ortho Cl-isomers present in the bulk sample (TPP)Rh(C6H4Cl). DFT calculations confirm that the ortho-Cl isomer exhibits a longer Rh-C bond and higher relative energy, making it more susceptible to NO insertion. The freezing string calculation for the NO insertion pathway identifies a transition state with significant elongation of the Rh-C bond that is primed for the formation of a new Rh-N bond. The NPA charge analysis indicates electronic rearrangements favoring the NO-insertion process. Molecular orbital analysis highlights specific σ interactions that stabilize the transition state and product. When (TPP)Rh(C6H4Cl) reacts with NO gas in solution, 1H NMR, IR and UV-vis spectroscopy indicate the formation of various Rh-NO adducts. However, there is no clear evidence of NO insertion; instead, a Rh-C bond cleavage occurs, leading to the formation of new C-N bonds (e.g., O2NC6H4Cl-p). This chapter provides new insights into the reactivity of NO with metalloporphyrin complexes and underscores the importance of reaction medium and crystal morphology in determining reaction pathways and products.