Axial Ligation Impedes Proton-Coupled Electron-Transfer Reactivity of a Synthetic Compound-I Analogue.

The nature of the axial ligand in high-valent iron-oxo heme enzyme intermediates and related synthetic catalysts is a critical structural element for controlling proton-coupled electron-transfer (PCET) reactivity of these species. Herein, we describe the generation and characterization of three new 6-coordinate, iron(IV)-oxo porphyrinoid-π-cation-radical complexes and report their PCET reactivity together with a previously published 5-coordinate analogue, FeIV(O)(TBP8Cz+•) (TBP8Cz = octakis(p-tert-butylphenyl)corrolazinato3-) (2) (Cho, K. A high-valent iron-oxo corrolazine activates C-H bonds via hydrogen-atom transfer. J. Am. Chem. Soc. 2012, 134, 7392-7399). The new complexes FeIV(O)(TBP8Cz+•)(L) (L = 1-methyl imidazole (1-MeIm) (4a), 4-dimethylaminopyridine (DMAP) (4b), cyanide (CN-)(4c)) can be generated from either oxidation of the ferric precursors or by addition of L to the Compound-I (Cpd-I) analogue at low temperatures. These complexes were characterized by UV-vis, electron paramagnetic resonance (EPR), and Mössbauer spectroscopies, and cryospray ionization mass spectrometry (CSI-MS). Kinetic studies using 4-OMe-TEMPOH as a test substrate indicate that coordination of a sixth axial ligand dramatically lowers the PCET reactivity of the Cpd-I analogue (rates up to 7000 times slower). Extensive density functional theory (DFT) calculations together with the experimental data show that the trend in reactivity with the axial ligands does not correlate with the thermodynamic driving force for these reactions or the calculated strengths of the O-H bonds being formed in the FeIV(O-H) products, pointing to non-Bell-Evans-Polanyi behavior. However, the PCET reactivity does follow a trend with the bracketed reduction potential of Cpd-I analogues and calculated electron affinities. The combined data suggest a concerted mechanism (a concerted proton electron transfer (CPET)) and an asynchronous movement of the electron/proton pair in the transition state.

Direct Reduction of NO to N2O by a Mononuclear Nonheme Thiolate Ligated Iron(II) Complex via Formation of a Metastable {FeNO}7 Complex.

Addition of NO to a nonheme dithiolate-ligated iron(II) complex, FeII(Me3TACN)(S2SiMe2) (1), results in the generation of N2O. Low-temperature spectroscopic studies reveal a metastable six-coordinate {FeNO}7 intermediate (S = 3/2) that was trapped at -135 °C and was characterized by low-temperature UV-vis, resonance Raman, EPR, Mössbauer, XAS, and DFT studies. Thermal decay of the {FeNO}7 species leads to the evolution of N2O, providing a rare example of a mononuclear thiolate-ligated {FeNO}7 that mediates NO reduction to N2O without the requirement of any exogenous electron or proton sources.

A Reactive, Photogenerated High-Spin (S = 2) FeIV(O) Complex via O2 Activation.

Addition of dioxygen at low temperature to the non-heme ferrous complex FeII(Me3TACN)((OSiPh2)2O) (1) in 2-MeTHF produces a peroxo-bridged diferric complex Fe2III(µ-O2)(Me3TACN)2((OSiPh2)2O)2 (2), which was characterized by UV-vis, resonance Raman, and variable field Mössbauer spectroscopies. Illumination of a frozen solution of 2 in THF with white light leads to homolytic O-O bond cleavage and generation of a FeIV(O) complex 4 (ν(Fe=O) = 818 cm-1; δ = 0.22 mm s-1, ΔEQ = 0.23 mm s-1). Variable field Mössbauer spectroscopy measurements show that 4 is a rare example of a high-spin S = 2 FeIV(O) complex and the first synthetic example to be generated directly from O2. Complex 4 is highly reactive, as expected for a high-spin ferryl, and decays rapidly in fluid solution at cryogenic temperatures. This decay process in 2-MeTHF involves C-H cleavage of the solvent. However, the controlled photolysis of 2 in situ with visible light and excess phenol substrate leads to competitive phenol oxidation, via the proposed transient generation of 4 as the active oxidant.

A Nonheme Mononuclear {FeNO}7 Complex that Produces N2 O in the Absence of an Exogenous Reductant.

A new nonheme iron(II) complex, FeII (Me3 TACN)((OSiPh2 )2 O) (1), is reported. Reaction of 1 with NO(g) gives a stable mononitrosyl complex Fe(NO)(Me3 TACN)((OSiPh2 )2 O) (2), which was characterized by Mössbauer (δ=0.52 mm s-1 , |ΔEQ |=0.80 mm s-1 ), EPR (S=3/2), resonance Raman (RR) and Fe K-edge X-ray absorption spectroscopies. The data show that 2 is an {FeNO}7 complex with an S=3/2 spin ground state. The RR spectrum (λexc =458 nm) of 2 combined with isotopic labeling (15 N, 18 O) reveals ν(N-O)=1680 cm-1 , which is highly activated, and is a nearly identical match to that seen for the reactive mononitrosyl intermediate in the nonheme iron enzyme FDPnor (ν(NO)=1681 cm-1 ). Complex 2 reacts rapidly with H2 O in THF to produce the N-N coupled product N2 O, providing the first example of a mononuclear nonheme iron complex that is capable of converting NO to N2 O in the absence of an exogenous reductant.

A Mononuclear, Nonheme FeII-Piloty's Acid (PhSO2NHOH) Adduct: An Intermediate in the Production of {FeNO}7/8 Complexes from Piloty's Acid.

Reaction of the mononuclear nonheme complex [FeII(CH3CN)(N3PyS)]BF4 (1) with an HNO donor, Piloty's acid (PhSO2NHOH, P.A.), at low temperature affords a high-spin ( S = 2) FeII-P.A. intermediate (2), characterized by 57Fe Mössbauer and Fe K-edge X-ray absorption (XAS) spectroscopies, with interpretation of both supported by DFT calculations. The combined methods indicate that P.A. anion binds as the N-deprotonated tautomer (PhSO2NOH-) to [FeII(N3PyS)]+, leading to 2. Complex 2 is the first spectroscopically characterized example, to our knowledge, of P.A. anion bound to a redox-active metal center. Warming of 2 above -60 °C yields the stable {FeNO}7 complex [Fe(NO)(N3PyS)]BF4 (4), as evidenced by 1H NMR, ATR-IR, and Mössbauer spectroscopies. Isotope labeling experiments with 15N-labeled P.A. confirm that the nitrosyl ligand in 4 derives from P.A. In contrast, addition of a second equivalent of a strong base leads to S-N cleavage and production of an {FeNO}8 species, the deprotonated analog of an Fe-HNO complex. This work has implications for the targeted delivery of HNO/NO-/NO· to nonheme Fe centers in biological and synthetic applications, and suggests a new role for nonheme FeII complexes in the assisted degradation of HNO donor molecules.

Accessing Remote meta- and para-C(sp2 )-H Bonds with Covalently Attached Directing Groups.

Directing group assisted ortho-C-H activation has been known for the last few decades. In contrast, extending the same approach to achieve activation of the distal meta- and para-C-H bonds in aromatic molecules remained elusive for a long time. The main challenge is the conception of a macrocyclic transition state, which is needed to anchor the metal catalyst close to the target bond. Judicious modification of the chain length, the tether linkage, and the nature of the catalyst-coordinating donor atom has led to a number of successful studies in the last few years. This Review compiles the significant achievements made in this field of both meta- and para-selectivity using covalently attached directing groups, which are systematically classified on the basis of their mode of covalent attachment to the substrate as well as their chemical nature. This Review aims to create a more heuristic approach for recognizing the suitability of the directing groups for use in future organic transformations.

A Nonheme Sulfur-Ligated {FeNO}6 Complex and Comparison with Redox-Interconvertible {FeNO}7 and {FeNO}8 Analogues.

A nonheme {FeNO}6 complex, [Fe(NO)(N3PyS)]2+ , was synthesized by reversible, one-electron oxidation of an {FeNO}7 analogue. This complex completes the first known series of sulfur-ligated {FeNO}6-8 complexes. All three {FeNO}6-8 complexes are readily interconverted by one-electron oxidation/reduction. A comparison of spectroscopic data (UV/Vis, NMR, IR, Mössbauer, X-ray absorption) provides a complete picture of the electronic and structural changes that occur upon {FeNO}6 -{FeNO}8 interconversion. Dissociation of NO from the new {FeNO}6 complex is shown to be controlled by solvent, temperature, and photolysis, which is rare for a sulfur-ligated {FeNO}6 species.

Pd-Catalyzed C-H arylation of pyridazine-based fused 1,2,4-triazoles: overriding selectivity at the usual position by undermining of preferred chelate formation.

The applicability of C-H functionalization to medicinally important 2-pyridyl-based N-heterocycles suffers from severe challenges owing to the high Lewis basicity of the N-atom. This arrests catalytic activity and yields undesirable positional selectivity due to preferential chelate formation. In this regard, we report a novel palladium(ii)-catalyzed arylation strategy on multiple-N-containing pyridazines by over-riding the functionalization due to a chelated palladacycle. We report a regioselective mono-arylation at the 8-position of diphenyl azolopyridazines without any ortho-C-H activation on the proximal phenyl groups. This methodology presents a broad arylation scope with uncompromised yield and positional selectivity, including the heteroarylation of N-heterocycles, which is an unprecedented feat for these types of molecules.

Palladium-catalyzed benzofuran and indole synthesis by multiple C-H functionalizations.

Heterocyclic compounds are commonly found in the core structures of several pharmaceuticals, natural products, and agrochemicals, thus spurring intensive research for conducting their synthesis in a mild and simpler way. Over the years, a host of different strategies has been introduced in an effort to synthesize these heterocyles. In this context, significant attention has been gained by methodologies that ensure both step as well as atom efficiency. Synthesis of heterocyclic moieties via multiple C-H activations was found to fulfill these expectations besides guaranteeing the use of starting materials that are easily procurable. This review is focused on the current development in the field of benzofuran and indole synthesis using multiple C-H functionalization strategies.

Traceless directing group mediated branched selective alkenylation of unbiased arenes.

Owing to the synthetic importance of branched olefinated products, we report palladium catalyzed formation of branched olefins facilitated by a C-H activation based protocol. This involves selective insertion of olefins and subsequent decarboxylation using a completely unbiased benzene ring as the starting precursor. The significance of the protocol has been further highlighted by exhibition of functionality tolerance along with a late-stage modification of the branched olefinated products leading to the formation of other functionalized molecules.

Reaching the south: metal-catalyzed transformation of the aromatic para-position.

Regioselective functionalization of aromatic arenes has created a rapid insurgence in the modern era of organic chemistry. While the last few years have witnessed significant developments on site-selective ortho- and meta-C-H transformations, there existed very few reports on para-C-H functionalization. Recent advancements on template assisted protocols in para-C-H activation has emerged as a popular and convenient feat in this area. This review highlights the various protocols developed over the years for selective installation of suitable functional groups at the para-position of arenes thereby transforming them into value-added organic cores.

Palladium-Catalyzed Directed para C-H Functionalization of Phenols.

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

Palladium catalysed meta-C-H functionalization reactions.

The directing group assisted site selective C-H functionalization approach is having a continuous impact in the field of natural product synthesis, drug discovery and material sciences. While ortho-selective C-H functionalization has been studied extensively, meta-selective C-H functionalization has been less explored. Recent studies have highlighted the efficacy of palladium as a catalyst in activating the meta-C-H bond of arenes. Notably, the introduction of a novel palladium catalysed directing template based approach to activate the remote meta-position has created a revolutionary impact towards seeking a solution to this long standing challenge. In this review we summarize recent advances in palladium catalysed meta-C-H functionalization that have helped in creating a new outlook towards modern organic synthesis.

Remote para-C-H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly.

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Mechanistic elucidation of C-H oxidation by electron rich non-heme iron(IV)-oxo at room temperature.

Non-heme iron(IV)-oxo species form iron(III) intermediates during hydrogen atom abstraction (HAA) from the C-H bond. While synthesizing a room temperature stable, electron rich, non-heme iron(IV)-oxo compound, we obtained iron(III)-hydroxide, iron(III)-alkoxide and hydroxylated-substrate-bound iron(II) as the detectable intermediates. The present study revealed that a radical rebound pathway was operative for benzylic C-H oxidation of ethylbenzene and cumene. A dissociative pathway for cyclohexane oxidation was established based on UV-vis and radical trap experiments. Interestingly, experimental evidence including O-18 labeling and mechanistic study suggested an electron transfer mechanism to be operative during C-H oxidation of alcohols (e.g. benzyl alcohol and cyclobutanol). The present report, therefore, unveils non-heme iron(IV)-oxo promoted substrate-dependent C-H oxidation pathways which are of synthetic as well as biological significance.