Computation Sheds Insight into Iron Porphyrin Carbenes’ Electronic Structure, Formation, and N–H Insertion Reactivity

Abstract

Iron porphyrin carbenes constitute a new frontier of species with considerable synthetic potential. Exquisitely engineered myoglobin and cytochrome P450 enzymes can generate these complexes and facilitate the transformations they mediate. The current work harnesses density functional theoretical methods to provide insight into the electronic structure, formation, and N-H insertion reactivity of an iron porphyrin carbene, [Fe(Por)(SCH3)(CHCO2Et)](-), a model of a complex believed to exist in an experimentally studied artificial metalloenzyme. The ground state electronic structure of the terminal form of this complex is an open-shell singlet, with two antiferromagnetically coupled electrons residing on the iron center and carbene ligand. As we shall reveal, the bonding properties of [Fe(Por)(SCH3)(CHCO2Et)](-) are remarkably analogous to those of ferric heme superoxide complexes. The carbene forms by dinitrogen loss from ethyl diazoacetate. This reaction occurs preferentially through an open-shell singlet transition state: iron donates electron density to weaken the C-N bond undergoing cleavage. Once formed, the iron porphyrin carbene accomplishes N-H insertion via nucleophilic attack. The resulting ylide then rearranges, using an internal carbonyl base, to form an enol that leads to the product. The findings rationalize experimentally observed reactivity trends reported in artificial metalloenzymes employing iron porphyrin carbenes. Furthermore, these results suggest a possible expansion of enzymatic substrate scope, to include aliphatic amines. Thus, this work, among the first several computational explorations of these species, contributes insights and predictions to the surging interest in iron porphyrin carbenes and their synthetic potential.

Catalytic Synthesis of N-Heterocycles via Direct C(sp3)–H Amination Using an Air-Stable Iron(III) Species with a Redox-Active Ligand

“…Similar “nitrene radical” intermediates have recently been spectroscopically characterized for cobalt porphyrins and other systems. 26−28 Formation of the saturated N-heterocycle proceeds via either H atom abstraction followed by radical rebound or direct insertion of the nitrene moiety into the benzylic C–H bond and then forms a pyrrolidine complex. Finally, reaction with Boc 2 O releases the Boc-protected N-heterocycle and regenerates the catalyst (see the Supporting Information for hypothetical scheme based on 1 ).…”

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

“…Using model systems, recent DFT studies have investigated the nature of the putative iron carbenoid intermediate, shedding light on factors governing its formation and reactivity [50–52]. In particular, work by Sharon et al .…”

“…In particular, work by Sharon et al . on carbene N–H insertion [52] indicated that altering the basicity of the enzyme active site may allow access to aliphatic amines, potentially extending the substrate scope from the aromatic amines reported to date [9,17]. This proposal has not yet been tested experimentally.…”

Axial vs. Equatorial Ligand Rivalry in Controlling the Reactivity of Iron(IV)‐Oxo Species: Single‐State vs. Two‐State Reactivity

“…Specifically, carbene‐based organometallic catalysts have been synthesized and characterized . These catalysts have also been found to promote C−H bond activation, epoxidation, and N−H insertion . In this context, efforts have been made to fine‐tune the equatorial ligands, most notably the synthesis and reactivity studies of an iron(IV)‐oxo complex bearing a macrocyclic tetracarbene ligand ([(L NHC )Fe IV (O)(CH 3 CN)] 2+ ( 1 ) where L NHC =3,9,14,20‐tetraaza‐1,6,12,17‐tetraazoniapenta‐cyclohexacosane‐1(23),4,6(26),10,12(25),15,17(24),21‐octaene) .…”