Proximity Effects on the Reactivity of a Nonheme Iron (IV) Oxo Complex in C-H Oxidation.

Precise control of substrate positioning and orientation (its proximity to the reactive unit) is often invoked to rationalize the superior enzymatic reaction rates and selectivities when compared to synthetic models. Artificial nonheme iron (IV) oxo (Fe(IV)=O) complexes react with C(sp3)-H bonds via a biomimetic Hydrogen Atom Transfer/Hydroxyl Rebound mechanism, but rates, site-selectivity and even hydroxyl rebound efficiency (ligand rebound versus substrate radical diffusion) are smaller than in oxygenases. Herein, we quantitatively analyze how substrate binding modulates nonheme Fe(IV)=O reactivity by comparing rates and outcomes of C-H oxidation by a pair of Fe(IV)=O complexes that share the same first coordination sphere but only one contains a crown ether receptor that recognizes the substrate. Substrate binding makes the reaction intramolecular, exhibiting Michaelis-Menten kinetics and increased reaction rates. In addition, C-H oxidation occurs with high site selectivity for remote sites. Analysis of Effective Molarity reveals that the system operates at its maximal theoretical capability for the oxidation of these remote sites. Remarkably, substrate positioning also affects Hydroxyl Rebound, whose efficiency only increases on the sites placed in proximity by recognition. Overall, these observations provide evidence that supramolecular control of substrate positioning can effectively modulate the reactivity of oxygenases and its models.

Site-selective methylene C-H oxidation of an alkyl diamine enabled by supramolecular recognition using a bioinspired manganese catalyst.

Site-selective oxidation of aliphatic C-H bonds is a powerful synthetic tool because it enables rapid build-up of product complexity and diversity from simple precursors. Besides the poor reactivity of alkyl C-H bonds, the main challenge in this reaction consists in differentiating between the multiple similar sites present in most organic molecules. Herein, a manganese oxidation catalyst equipped with two 18-benzo-6-crown ether receptors has been employed in the oxidation of the long chain tetradecane-1,14-diamine. 1H-NMR studies evidence simultaneous binding of the two protonated amine moieties to the crown ether receptors. This recognition has been used to pursue site-selective oxidation of a methylenic site, using hydrogen peroxide as oxidant in the presence of carboxylic acids as co-ligands. Excellent site-selectivity towards the central methylenic sites (C6 and C7) is observed, overcoming selectivity parameters derived from polar deactivation by simple amine protonation and selectivity observed in the oxidation of related monoprotonated amines.

Carboxylic Acid Directed γ-Lactonization of Unactivated Primary C-H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification.

Reactions that enable selective functionalization of strong aliphatic C-H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific C-H bond by catalyst control. Herein we describe the catalytic site- and stereoselective γ-lactonization of unactivated primary C-H bonds in carboxylic acid substrates. The system relies on a chiral Mn catalyst that activates aqueous hydrogen peroxide to promote intramolecular lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-selectivity and enables the oxidation of unactivated primary γ-C-H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at α- and ß-carbons. With substrates bearing nonequivalent γ-C-H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, γ-lactonization at methyl groups in gem-dimethyl structural units of rigid cyclic and bicyclic carboxylic acids can be achieved with unprecedented levels of diastereoselectivity. Such control has been successfully exploited in the late-stage lactonization of natural products such as camphoric, camphanic, ketopinic, and isoketopinic acids. DFT analysis points toward a rebound type mechanism initiated by intramolecular 1,7-HAT from a primary γ-C-H bond of the bound substrate to a highly reactive MnIV-oxyl intermediate, to deliver a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuterium isotope effect and 18O labeling experiments provide strong support to this mechanistic picture.

Remote Amino Acid Recognition Enables Effective Hydrogen Peroxide Activation at a Manganese Oxidation Catalyst.

Precise delivery of a proton plays a key role in O2 activation at iron oxygenases, enabling the crucial O-O cleavage step that generates the oxidizing high-valent metal-oxo species. Such a proton is delivered by acidic residues that may either directly bind the iron center or lie in its second coordination sphere. Herein, a supramolecular strategy for enzyme-like H2 O2 activation at a biologically inspired manganese catalyst, with a nearly stoichiometric amount (1-1.5 equiv) of a carboxylic acid is disclosed. Key for this strategy is the incorporation of an α,ω-amino acid in the second coordination sphere of a chiral catalyst via remote ammonium-crown ether recognition. The properly positioned carboxylic acid function enables effective activation of hydrogen peroxide, leading to catalytic asymmetric epoxidation. Modulation of both amino acid and catalyst structure can tune the efficiency and the enantioselectivity of the reaction, and a study on the oxidative degradation pathway of the system is presented.

Change of Selectivity in C-H Functionalization Promoted by Nonheme Iron(IV)-oxo Complexes by the Effect of the N-hydroxyphthalimide HAT Mediator.

A kinetic analysis of the hydrogen atom transfer (HAT) reactions from a series of organic compounds to the iron(IV)-oxo complex [(N4Py)FeIV(O)]2+ and to the phthalimide N-oxyl radical (PINO) has been carried out. The results indicate that a higher activating effect of α-heteroatoms toward the HAT from C-H bonds is observed with the more electrophilic PINO radical. When the N-hydroxy precursor of PINO, N-hydroxyphthalimide (NHPI), is used as a HAT mediator in the oxidation promoted by [(N4Py)FeIV(O)]2+, significant differences in terms of selectivity have been found. Product studies of the competitive oxidations of primary and secondary aliphatic alcohols (1-decanol, cyclopentanol, and cyclohexanol) with alkylaromatics (ethylbenzene and diphenylmethane) demonstrated that it is possible to modify the selectivity of the oxidations promoted by [(N4Py)FeIV(O)]2+ in the presence of NHPI. In fact, alkylaromatic substrates are more reactive in the absence of the mediator while alcohols are preferably oxidized in the presence of NHPI.

New horizons for catalysis disclosed by supramolecular chemistry.

The adoption of a supramolecular approach in catalysis promises to address a number of unmet challenges, ranging from activity (unlocking of novel reaction pathways) to selectivity (alteration of the innate selectivity of a reaction, e.g. selective functionalization of C-H bonds) and regulation (switch ON/OFF, sequential catalysis, etc.). Supramolecular tools such as reversible association and recognition, pre-organization of reactants and stabilization of transition states upon binding offer a unique chance to achieve the above goals disclosing new horizons whose potential is being increasingly recognized and used, sometimes reaching the degree of ripeness for practical use. This review summarizes the main developments that have opened such new frontiers, with the aim of providing a guide to researchers approaching the field. We focus on artificial supramolecular catalysts of defined stoichiometry which, under homogeneous conditions, unlock outcomes that are highly difficult if not impossible to attain otherwise, namely unnatural reactivity or selectivity and catalysis regulation. The different strategies recently explored in supramolecular catalysis are concisely presented, and, for each one, a single or very few examples is/are described (mainly last 10 years, with only milestone older works discussed). The subject is divided into four sections in light of the key design principle: (i) nanoconfinement of reactants, (ii) recognition-driven catalysis, (iii) catalysis regulation by molecular machines and (iv) processive catalysis.

Predictable Selectivity in Remote C-H Oxidation of Steroids: Analysis of Substrate Binding Mode.

Predictability is a key requirement to encompass late-stage C-H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp3 )-H oxidation, as it requires distinguishing a specific C-H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C-H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host-guest adduct by NMR analysis. These analyses indicate which remote C-H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late-stage C(sp3 )-H oxidation of amino-steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.

Increasing the steric hindrance around the catalytic core of a self-assembled imine-based non-heme iron catalyst for C-H oxidation.

Sterically hindered imine-based non-heme complexes 4 and 5 rapidly self-assemble in acetonitrile at 25 °C, when the corresponding building blocks are added in solution in the proper ratios. Such complexes are investigated as catalysts for the H2O2 oxidation of a series of substrates in order to ascertain the role and the importance of the ligand steric hindrance on the action of the catalytic core 1, previously shown to be an efficient catalyst for aliphatic and aromatic C-H bond oxidation. The study reveals a modest dependence of the output of the oxidation reactions on the presence of bulky substituents in the backbone of the catalyst, both in terms of activity and selectivity. This result supports a previously hypothesized catalytic mechanism, which is based on the hemi-lability of the metal complex. In the active form of the catalyst, one of the pyridine arms temporarily leaves the iron centre, freeing up a lot of room for the access of the substrate.

Enantioselective C-H Lactonization of Unactivated Methylenes Directed by Carboxylic Acids.

The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C-H oxidation a generally unsolved problem for nonenzymatic systems. Discrimination between the two enantiotopic C-H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C-H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ site-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C-H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C-H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]nonane enabled by two key, sequential γ-C-H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.

Coupled X-ray Absorption/UV-vis Monitoring of Fast Oxidation Reactions Involving a Nonheme Iron-Oxo Complex.

Time-resolved X-ray absorption (XAS) and UV-vis spectroscopies with millisecond resolution are used simultaneously to investigate oxidation reactions of organic substrates by nonheme iron activated species. In particular, the oxidation processes of arylsulfides and benzyl alcohols by a nonheme iron-oxo complex have been studied. We show for the first time that the pseudo-first-order rate constants of fast bimolecular processes in solution (milliseconds and above) can be determined by time-resolved XAS technique. By following the Fe K-edge energy shift, it is possible to detect the rate of iron oxidation state evolution that matches that of the bimolecular reaction in solution. The kinetic constant values obtained by XAS are in perfect agreement with those obtained by means of the concomitant UV-vis detection. This combined approach has the potential to provide unique insights into reaction mechanisms in the liquid phase that involve changes of the oxidation state of a metal center, and it is particularly useful in complex chemical systems where possible interferences from species present in solution could make it impossible to use other detection techniques.

Enzyme-like substrate-selectivity in C-H oxidation enabled by recognition.

Substrate-selectivity stemming from recognition is a key feature of enzymes that has been seldom observed in artificial catalysts. Herein, we report a recognition-driven, substrate-selective C-H oxidation that inverts the intrinsic reactivity of the competing C-H bonds. Analysis of this selectivity highlights an unexpectedly high reactivity enhancement imparted by intramolecularity.

Controlling Selectivity in Aliphatic C-H Oxidation through Supramolecular Recognition.

Aliphatic C-H oxidation is the most straightforward approach to functionalize hydrocarbon skeletons. The main challenge of this reaction is the control of site selectivity, given the multiple C-H bonds present in any organic molecule. Natural enzymes elegantly solve this problem through the interplay of different interactions that geometrically orient the substrate to expose a single C-H bond to the active unit, thus overriding intrinsic reactivity patterns. A combination of molecular catalysts and supramolecular receptors can be a promising way to replicate such control. This strategy indeed unlocks hydroxylation of C-H bonds that are not accessible with conventional methodologies, in which the selectivity is dictated by the geometry of the substrate-receptor adduct. Herein, we review the reports of recognition-driven C-H oxidation reactions and highlight the key design principles that inspired these works.

Oxidative functionalization of aliphatic and aromatic amino acid derivatives with H2O2 catalyzed by a nonheme imine based iron complex.

The oxidation of a series of N-acetyl amino acid methyl esters with H2O2 catalyzed by a very simple iminopyridine iron(ii) complex 1 easily obtainable in situ by self-assembly of 2-picolylaldehyde, 2-picolylamine, and Fe(OTf)2 was investigated. Oxidation of protected aliphatic amino acids occurs at the α-C-H bond exclusively (N-AcAlaOMe) or in competition with the side-chain functionalization (N-AcValOMe and N-AcLeuOMe). N-AcProOMe is smoothly and cleanly oxidized with high regioselectivity affording exclusively C-5 oxidation products. Remarkably, complex 1 is also able to catalyze the oxidation of the aromatic N-AcPheOMe. A marked preference for the aromatic ring hydroxylation over Cα-H and benzylic C-H oxidation was observed, leading to the clean formation of tyrosine and its phenolic isomers.

Supramolecular Recognition Allows Remote, Site-Selective C-H Oxidation of Methylenic Sites in Linear Amines.

Site-selective C-H functionalization of aliphatic alkyl chains is a longstanding challenge in oxidation catalysis, given the comparable relative reactivity of the different methylenes. A supramolecular, bioinspired approach is described to address this challenge. A Mn complex able to catalyze C(sp3 )-H hydroxylation with H2 O2 is equipped with 18-benzocrown-6 ether receptors that bind ammonium substrates via hydrogen bonding. Reversible pre-association of protonated primary aliphatic amines with the crown ether selectively exposes remote positions (C8 and C9) to the oxidizing unit, resulting in a site-selective oxidation. Remarkably, such control of selectivity retains its efficiency for a whole series of linear amines, overriding the intrinsic reactivity of C-H bonds, no matter the chain length.

Following a Chemical Reaction on the Millisecond Time Scale by Simultaneous X-ray and UV/Vis Spectroscopy.

An innovative approach aimed at disclosing the mechanism of chemical reactions occurring in solution on the millisecond time scale is presented. Time-resolved energy dispersive X-ray absorption and UV/vis spectroscopies with millisecond resolution are used simultaneously to directly follow the evolution of both the oxidation state and the local structure of the metal center in an iron complex. Two redox reactions are studied, the former involving the transformation of FeII into two subsequent FeIII species and the latter involving the more complex FeII-FeIII-FeIV-FeIII sequence. The structural modifications occurring around the iron center are correlated to the reaction mechanisms. This combined approach has the potential to provide unique insights into reaction mechanisms in the liquid phase and represents a new powerful tool to characterize short-lived intermediates that are silent to common spectroscopic techniques.

Formation of Imidazo[1,5-a]pyridine Derivatives Due to the Action of Fe2+ on Dynamic Libraries of Imines.

An imidazo[1,5-a]pyridine derivative was unexpectedly obtained through the action of Fe2+ on a dynamic library of imines generated in situ via condensation of benzaldehyde and 2-picolylamine. The reaction product was easily isolated as the only nitrogen-containing product eluted from the chromatographic column. A reaction mechanism is proposed, in which combined kinetic and thermodynamic effects exerted by Fe2+ on the various steps of the complex reaction sequence are discussed. The Fe2+ nature of the added metal cation was found to be pivotal for the achievement of the imidazo[1,5-a]pyridine derivative as well as its amount in the reaction mixture. When the electronic effects were evaluated, gratifying yields were obtained only in the presence of moderately electron-releasing or moderately electron-withdrawing groups on the aldehyde reactant. No traces of imidazo[1,5-a]pyridine derivatives were obtained for p-OCH3 and p-NO2 benzaldehyde.

Oxidation of alkane and alkene moieties with biologically inspired nonheme iron catalysts and hydrogen peroxide: from free radicals to stereoselective transformations.

The selective oxidation of hydrocarbons is a challenging reaction for synthetic chemists, but common in nature. Iron oxygenases activate the O-O bond of dioxygen to perform oxidation of alkane and alkenes moieties with outstanding levels of regio-, chemo- and stereoselectivity. Along a bioinspired approach, iron coordination complexes which mimic structural and reactivity aspects of the active sites of nonheme iron oxygenases have been explored as oxidation catalysts. This review describes the evolution of this research field, from the early attempts to reproduce the basic reactivity of nonheme iron oxygenases to the development of effective iron oxidation catalysts. The work covers exclusively nonheme iron complexes which rely on H2O2 or O2 as terminal oxidants. First, it delineates the key steps and the essential catalyst design principles required to activate the peroxide bond at nonheme iron centers without (or at least minimizing) the release of free-diffusing radicals. It follows with a critical description of the mechanistic pathways which govern the reaction between iron complexes and H2O2 to generate the oxidizing species. Eventually, the work presents a state-of-the-art report on the use of these catalysts in aliphatic C-H oxidation, olefin epoxidation and alkene syn-dihydroxylation, under substrate-limiting conditions. A special focus is given on the main strategies elaborated to tune catalyst activity and selectivity by modification of its structure. The work is concluded by a concise discussion on the essential progresses of these oxidation catalysts together with the challenges that remain still to be tackled.

Electron Transfer Mechanism in the Oxidation of Aryl 1-Methyl-1-phenylethyl Sulfides Promoted by Nonheme Iron(IV)-Oxo Complexes: The Rate of the Oxygen Rebound Process.

The oxidation of aryl 1-methyl-1-phenylethyl sulfides promoted by the nonheme iron(IV)-oxo complexes [(N4Py)FeIV═O]2+ and [(Bn-TPEN)FeIV═O]2+ occurs by an electron transfer-oxygen rebound (ET-OT) mechanism leading to aryl 1-methyl-1-phenylethyl sulfoxides accompanied by products derived from Cα-S fragmentation of sulfide radical cations (2-phenyl-2-propanol and diaryl disulfides). For the first time, the rate constants for the oxygen rebound process (kOT), which are in the range of <0.8 × 104 to 3.5 × 104 s-1, were determined from the fragmentation rate constants of the radical cations (kf) and the S oxidation/fragmentation product ratios.

Alcohol oxidation with H2O2 catalyzed by a cheap and promptly available imine based iron complex.

We previously reported that the iminopyridine iron(ii) complex 1, easily and quantitatively obtainable in situ, can activate H2O2 to form a powerful oxidant, capable of aliphatic C-H bond hydroxylation. In the present study we expand the application of this catalyst to the oxidation of a series of alcohols to the corresponding carbonyl compounds. The oxidation of aliphatic alcohols proceeds smoothly, while that of benzylic alcohols is shown to be challenging. Some collected pieces of evidence suggest a preference of the oxidizing species for the aromatic ring instead for the alcoholic moiety. The decrease of the electron density in the aromatic ring shifts the oxidation from the aromatic towards the alcoholic moiety. Quite surprisingly, preferential oxidation of cyclohexanol versus benzylic alcohol was achieved, showing unprecedented selectivity.

Biologically Inspired C-H and C=C Oxidations with Hydrogen Peroxide Catalyzed by Iron Coordination Complexes.

The development of catalysts for the selective oxidation of readily available hydrocarbons or organic precursors into oxygenated products is a long-standing goal in organic synthesis. In the last decade, some iron coordination complexes have shown the potential to fit this role. These catalysts can mimic the O-O activation mode of far more sophisticated iron oxygenase enzymes, generating powerful yet selective oxidants. In this review, we report state-of-the-art C-H and C=C oxidations catalyzed by non-heme iron complexes and H2 O2 as the oxidant. Finally, we briefly describe some novel oxidative reactivity and the perspectives of this chemistry.