Probing the Compound I-like Reactivity of a Bare High-Valent Oxo Iron Porphyrin Complex:  The Oxidation of Tertiary Amines

Abstract

The mechanisms of oxidative N-dealkylation of amines by heme enzymes including peroxidases and cytochromes P450 and by functional models for the active Compound I species have long been studied. A debated issue has concerned in particular the character of the primary step initiating the oxidation sequence, either a hydrogen atom transfer (HAT) or an electron transfer (ET) event, facing problems such as the possible contribution of multiple oxidants and complex environmental effects. In the present study, an oxo iron(IV) porphyrin radical cation intermediate 1, [(TPFPP)*+ Fe(IV)=O]+ (TPFPP = meso-tetrakis (pentafluorophenyl)porphinato dianion), functional model of Compound I, has been produced as a bare species. The gas-phase reaction with amines (A) studied by ESI-FT-ICR mass spectrometry has revealed for the first time the elementary steps and the ionic intermediates involved in the oxidative activation. Ionic products are formed involving ET (A*+, the amine radical cation), formal hydride transfer (HT) from the amine ([A(-H)]+, an iminium ion), and oxygen atom transfer (OAT) to the amine (A(O), likely a carbinolamine product), whereas an ionic product involving a net initial HAT event is never observed. The reaction appears to be initiated by an ET event for the majority of the tested amines which included tertiary aliphatic and aromatic amines as well as a cyclic and a secondary amine. For a series of N,N-dimethylanilines the reaction efficiency for the ET activated pathways was found to correlate with the ionization energy of the amine. A stepwise pathway accounts for the C-H bond activation resulting in the formal HT product, namely a primary ET process forming A*+, which is deprotonated at the alpha-C-H bond forming an N-methyl-N-arylaminomethyl radical, A(-H)*, readily oxidized to the iminium ion, [A(-H)]+. The kinetic isotope effect (KIE) for proton transfer (PT) increases as the acidity of the amine radical cation increases and the PT reaction to the base, the ferryl group of (TPFPP)Fe(IV)=O, approaches thermoneutrality. The ET reaction displayed by 1 with gaseous N,N-dimethylaniline finds a counterpart in the ET reactivity of FeO+, reportedly a potent oxidant in the gas phase, and with the barrierless ET process for a model (P)*+ Fe(IV)=O species (where P is the porphine dianion) as found by theoretical calculations. Finally, the remarkable OAT reactivity of 1 with C6F5N(CH3)2 may hint to a mechanism along a route of diverse spin multiplicity.

Oxygen‐Atom Transfer by a Naked Manganese(V)–Oxo–Porphyrin Complex Reveals Axial Ligand Effect

“…In analogy with previous findings and reasoning about the corresponding iron complex, [12] we ascribe this result to the presence of an isomeric species unfit to release an oxygen atom, most likely a species oxidised on the porphyrin ligand that may be depicted as…”

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…Later, the Yoshizawa group studied the kinetic isotope effect of the C H bond activation of alkane [26,27] and the mechanism of camphor hydroxylation by Cpd I [28]. Since then, P450-catalyzed substrate metabolism has been widely studied using the DFT method, including alkane hydroxylation [28,29], alkene epoxidation [30][31][32][33], aromatic hydroxylation [34][35][36][37][38], S-, N-, O-oxidation and dealkylation [39][40][41][42][43][44], dehalogenation of perhalogenated benzene [45], prostaglandin H 2 isomerization [46], and so on.…”

Multistage Reactive Transmission-Mode Desorption Electrospray Ionization Mass Spectrometry

“…Settings that are different for tandem MS (MS/MS) include: microscans=3, injection time=50, 500, or 1000 ms. -, corresponding to the homolytic catalytic pathway. To our knowledge, these results represent the first direct observation of the Fe-porphyrin homolytic catalytic pathway by MS (previous FT-ICR ESI-MS studies observed the radical cation iron oxo 1a) [42,43].…”

“…-DESI-MS, we studied iron (Fe) porphyrin-catalyzed hydroxylations such as Fe tetra(pentafluorophenyl)-porphyrin (Fe-TPFPP, 1) hydroxylation of substrate propranolol 2 (proposed mechanism shown in Scheme 1 [41]), previously analyzed by ESI Fourier transform ion cyclotron resonance MS [42,43]. Experimental results show that TM 2 -DESI provides the ability to spatially separate reagents and to specify their order of introduction into microdroplet reaction vessels, reducing off-path processes such as oxidant-mediated hydroxylation of 2 (Scheme 1).…”