Proton-triggered chemoselective halogenation of aliphatic C-H bonds with nonheme FeIV-oxo complexes.

Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the formation of an iron(IV)-oxo-chloride species that abstracts the hydrogen atom from the reactive C-H bond to form a carbon-centered radical that selectively reacts with the bound chloride ligand, a process commonly referred to as halide rebound. The factors that determine the halide rebound, as opposed to the reaction with the incipient hydroxide ligand, are not clearly understood and examples of well-defined iron(IV)-oxo-halide compounds competent in C-H halogenation are scarce. In this work we have studied the reactivity of three well-defined iron(IV)-oxo complexes containing variants of the tetradentate 1-(2-pyridylmethyl)-1,4,7-triazacyclononane ligand (Pytacn). Interestingly, these compounds exhibit a change in their chemoselectivity towards the functionalization of C-H bonds under certain conditions: their reaction towards C-H bonds in the presence of a halide anionleads to exclusive oxygenation, while the addition of a superacid results in halogenation. Almost quantitative halogenation of ethylbenzene is observed when using the two systems with more sterically congested ligands and even the chlorination of strong C-H bonds such as those of cyclohexane is performed when a methyl group is present in the sixth position of the pyridine ring of the ligand. Mechanistic studies suggest that both reactions, oxygenation and halogenation, proceed through a common rate determining hydrogen atom transfer step and the presence of the acid dictates the fate of the resulting alkyl radical towards preferential halogenation over oxygenation.

tert-Butyl as a Functional Group: Non-Directed Catalytic Hydroxylation of Sterically Congested Primary C-H Bonds.

The tert-butyl group is a common aliphatic motif extensively employed to implement steric congestion and conformational rigidity in organic and organometallic molecules. Because of the combination of a high bond dissociation energy (~100 kcal mol-1) and limited accessibility, in the absence of directing groups, neither radical nor organometallic approaches are effective for the chemical modification of tert-butyl C-H bonds. Herein we overcome these limits by employing a highly electrophilic manganese catalyst, [Mn(CF3bpeb)(OTf)2], that operates in the strong hydrogen bond donor solvent nonafluoro-tert-butyl alcohol (NFTBA) and catalytically activates hydrogen peroxide to generate a powerful manganese-oxo species that effectively oxidizes tert-butyl C-H bonds. Leveraging on the interplay of steric, electronic, medium and torsional effects, site-selective and product chemoselective hydroxylation of the tert-butyl group is accomplished with broad reaction scope, delivering primary alcohols as largely dominant products in preparative yields. Late-stage hydroxylation at tert-butyl sites is demonstrated on 6 densely functionalized molecules of pharmaceutical interest. This work uncovers a novel disconnection approach, harnessing tert-butyl as a potential functional group in strategic synthetic planning for complex molecular architectures.

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.

Catalyst and Medium Control over Rebound Pathways in Manganese-Catalyzed Methylenic C-H Bond Oxidation.

The C(sp3)-H bond oxygenation of a variety of cyclopropane containing hydrocarbons with hydrogen peroxide catalyzed by manganese complexes containing aminopyridine tetradentate ligands was carried out. Oxidations were performed in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 2,2,2-trifluoroethanol (TFE) using different manganese catalysts and carboxylic acid co-ligands, where steric and electronic properties were systematically modified. Functionalization selectively occurs at the most activated C-H bonds that are α- to cyclopropane, providing access to carboxylate or 2,2,2-trifluoroethanolate transfer products, with no competition, in favorable cases, from the generally dominant hydroxylation reaction. The formation of mixtures of unrearranged and rearranged esters (oxidation in HFIP in the presence of a carboxylic acid) and ethers (oxidation in TFE) with full control over diastereoselectivity was observed, confirming the involvement of delocalized cationic intermediates in these transformations. Despite such a complex mechanistic scenario, by fine-tuning of catalyst and carboxylic acid sterics and electronics and leveraging on the relative contribution of cationic pathways to the reaction mechanism, control over product chemoselectivity could be systematically achieved. Taken together, the results reported herein provide powerful catalytic tools to rationally manipulate ligand transfer pathways in C-H oxidations of cyclopropane containing hydrocarbons, delivering novel products in good yields and, in some cases, outstanding selectivities, expanding the available toolbox for the development of synthetically useful C-H functionalization procedures.

Synthesis, Structure and Reactivity of a Mononuclear N,N,O-Bound Fe(II) α-Keto-Acid Complex.

A bulky, tridentate phenolate ligand (ImPh2 NNOtBu ) was used to synthesise the first example of a mononuclear, facial, N,N,O-bound iron(II) benzoylformate complex, [Fe(ImPh2 NNOtBu )(BF)] (2). The X-ray crystal structure of 2 reveals that the iron centre is pentacoordinate (τ=0.5), with a vacant site located cis to the bidentate BF ligand. The Mössbauer parameters of 2 are consistent with high-spin iron(II), and are very close to those reported for α-ketoglutarate-bound non-heme iron enzyme active sites. According to NMR and UV-vis spectroscopies, the structural integrity of 2 is retained in both coordinating and non-coordinating solvents. Cyclic voltammetry studies show that the iron centre has a very low oxidation potential and is more prone to electrochemical oxidation than the redox-active phenolate ligand. Complex 2 reacts with NO to form a S=3 /2 {FeNO}7 adduct in which NO binds directly to the iron centre, according to EPR, UV-vis, IR spectroscopies and DFT analysis. Upon O2 exposure, 2 undergoes oxidative decarboxylation to form a diiron(III) benzoate complex, [Fe2 (ImPh2 NNOtBu )2 (µ2 -OBz)(µ2 -OH)2 ]+ (3). A small amount of hydroxylated ligand was also observed by ESI-MS, hinting at the formation of a high-valent iron(IV)-oxo intermediate. Initial reactivity studies show that 2 is capable of oxygen atom transfer reactivity with O2 , converting methyl(p-tolyl)sulfide to sulfoxide.

Dearomative syn-Dihydroxylation of Naphthalenes with a Biomimetic Iron Catalyst.

Arenes are interesting feedstocks for organic synthesis because of their natural abundance. However, the stability conferred by aromaticity severely limits their reactivity, mostly to reactions where aromaticity is retained. Methods for oxidative dearomatization of unactivated arenes are exceedingly rare but particularly valuable because the introduction of Csp3-O bonds transforms the flat aromatic ring in 3D skeletons and confers the oxygenated molecules with a very rich chemistry suitable for diversification. Mimicking the activity of naphthalene dioxygenase (NDO), a non-heme iron-dependent bacterial enzyme, herein we describe the catalytic syn-dihydroxylation of naphthalenes with hydrogen peroxide, employing a sterically encumbered and exceedingly reactive yet chemoselective iron catalyst. The high electrophilicity of hypervalent iron oxo species is devised as a key to enabling overcoming the aromatically promoted kinetic stability. Interestingly, the first dihydroxylation of the arene renders a reactive olefinic site ready for further dihydroxylation. Sequential bis-dihydroxylation of a broad range of naphthalenes provides valuable tetrahydroxylated products in preparative yields, amenable for rapid diversification.

Highly Selective C(sp3)-H Bond Oxygenation at Remote Methylenic Sites Enabled by Polarity Enhancement.

A detailed study on the C(sp3)-H bond oxygenation reactions with H2O2 catalyzed by the [Mn(OTf)2(TIPSmcp)] complex at methylenic sites of cycloalkyl and 1-alkyl substrates bearing 19 different electron-withdrawing functional groups (EW FGs) was carried out. Oxidations in MeCN were compared to the corresponding ones in the strong hydrogen bond donating (HBD) solvents 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and nonafluoro tert-butyl alcohol (NFTBA). Formation of the products deriving from oxygenation at the most remote methylenic sites was observed, with yields, product ratios (PR) for oxygenation at the most remote over the next methylenic sites, and associated site-selectivities that significantly increased going from MeCN to HFIP and NFTBA. Unprecedented site-selectivities were obtained in the oxidation of cyclohexyl, cycloheptyl, cyclooctyl, 1-pentyl, 1-hexyl, and 1-heptyl substrates, approaching >99%, >99%, 90%, >99%, 93%, and 88% (PR >99, >99, 9.4, >99, 14, and 7.5) with cyclohexyl-2-pyridinecarboxylate, cycloheptyl-2-pyridinecarboxylate, cyclooctyl-4-nitrobenzenesulfonamide, 1-pentyl-3,5-dinitrobenzoate, 1-hexyl-3,5-dinitrobenzoate, and 1-heptyl-3,5-dinitrobenzoate, respectively. The results are rationalized on the basis of a polarity enhancement effect via synergistic electronic deactivation of proximal methylenic sites imparted by the EWG coupled to solvent HB. Compared to previous procedures, polarity enhancement provides the opportunity to tune site-selectivity among multiple methylenes in different substrate classes, extending the strong electronic deactivation determined by native EWGs by two carbon atoms. This study uncovers a simple procedure for predictable, high-yielding, and highly site-selective oxidation at remote methylenes of cycloalkyl and 1-alkyl substrates that occurs under mild conditions, with a large substrate scope, providing an extremely powerful tool to be implemented in synthetically useful procedures.

Highly Enantioselective Catalytic Lactonization at Nonactivated Primary and Secondary γ-C-H Bonds.

Chiral oxygenated aliphatic moieties are recurrent in biological and pharmaceutically relevant molecules and constitute one of the most versatile types of functionalities for further elaboration. Herein we report a protocol for straightforward and general access to chiral γ-lactones via enantioselective oxidation of strong nonactivated primary and secondary C(sp3)-H bonds in readily available carboxylic acids. The key enabling aspect is the use of robust sterically encumbered manganese catalysts that provide outstanding enantioselectivities (up to >99.9%) and yields (up to 96%) employing hydrogen peroxide as the oxidant. The resulting γ-lactones are of immediate interest for the preparation of inter alia natural products and recyclable polymeric materials.

C-H Bonds as Functional Groups: Simultaneous Generation of Multiple Stereocenters by Enantioselective Hydroxylation at Unactivated Tertiary C-H Bonds.

Enantioselective C-H oxidation is a standing chemical challenge foreseen as a powerful tool to transform readily available organic molecules into precious oxygenated building blocks. Here, we describe a catalytic enantioselective hydroxylation of tertiary C-H bonds in cyclohexane scaffolds with H2O2, an evolved manganese catalyst that provides structural complementary to the substrate similarly to the lock-and-key recognition operating in enzymatic active sites. Theoretical calculations unveil that enantioselectivity is governed by the precise fitting of the substrate scaffold into the catalytic site, through a network of complementary weak non-covalent interactions. Stereoretentive C(sp3)-H hydroxylation results in a single-step generation of multiple stereogenic centers (up to 4) that can be orthogonally manipulated by conventional methods providing rapid access, from a single precursor to a variety of chiral scaffolds.

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.

A Common Active Intermediate in the Oxidation of Alkenes, Alcohols and Alkanes with H2O2 and a Mn(II)/Pyridin-2-Carboxylato Catalyst.

The mechanism and the reactive species involved in the oxidation of alkenes, and alcohols with H2O2, catalysed by an in situ prepared mixture of a MnII salt, pyridine-2-carboxylic acid and a ketone is elucidated using substrate competition experiments, kinetic isotope effect (KIE) measurements, and atom tracking with 18O labelling. The data indicate that a single reactive species engages in the oxidation of both alkenes and alcohols. The primary KIE in the oxidation of benzyl alcohols is ca. 3.5 and shows the reactive species to be selective despite a zero order dependence on substrate concentration, and the high turnover frequencies (up to 30 s-1) observed. Selective 18O labelling identifies the origin of the oxygen atoms transferred to the substrate during oxidation, and is consistent with a highly reactive, e. g., [MnV(O)(OH)] or [MnV(O)2], species rather than an alkylperoxy or hydroperoxy species.

An investigation of steric influence on the reactivity of FeV(O)(OH) tautomers in stereospecific C-H hydroxylation.

Two new tetradentate N4 ligands (LN4), LN4 = Me2,Me2PyzTACN (1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-4,7-dimethyl-1,4,7-triazacyclononane) and Me2,MeImTACN (1-((1-methyl-1H-imidazol-1-yl)methyl)-4,7-dimethyl-1,4,7-triazacyclononane) have been synthesized and their corresponding Fe(II) complexes [FeII(Me2,Me2PyzTACN)(CF3SO3)2], 1Pz, and [FeII(Me2,MeImTACN)(CF3SO3)2], 1Im, have been prepared and characterized. Complexes 1Pz and 1Im catalyse the hydroxylation of C-H bonds of alkanes with excellent efficiencies, using hydrogen peroxide as oxidant. The high H/D kinetic isotope effect values for C-H hydroxylation, large normalized tertiary/secondary C-H (C3/C2) bond selectivities in adamantane oxidation, and high degrees of stereoretention in the oxidation of cis-1,2-dimethylcyclohexane are indicative of metal-based oxidation processes. The complexes also catalyse the oxidation of cyclooctene to form its corresponding epoxide and syn-diol. For 1Pz the epoxide is the main product, while for the analogous complex 1Im the syn-diol predominates. The active oxidant is proposed to be an [(LN4)FeV(O)(OH)]2+ species (2Pz, LN4 = Me2,Me2PyzTACN and 2Im, LN4 = Me2,MeImTACN) which may exist in two tautomeric forms related by a proton shift between the oxo and hydroxo ligands. Isotope labelling experiments show that the oxygen atom in the hydroxylated products originates from both water and hydrogen peroxide, and labelling experiments involving oxygen atom transfer to sterically bulky substrates provide indirect information on the steric influence exerted by the two ligands in the relative reactivities of the two hypervalent iron tautomers. Based on these labelling studies, the steric influence exerted by each of the ligands towards the relative reactivity of the oxo ligands of the corresponding pair of Fe(V)(O)(OH) tautomers can be derived. Furthermore, this steric influence can be gauged relative to related complexes/ligands.

Characterization of a Ferryl Flip in Electronically Tuned Nonheme Complexes. Consequences in Hydrogen Atom Transfer Reactivity.

Two oxoiron(IV) isomers (R 2a and R 2b) of general formula [FeIV (O)(R PyNMe3 )(CH3 CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4 IO4 . The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R 2a and R 2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R 2a reacts one order of magnitude faster than R 2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R 2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.

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.

Resolving Oxygenation Pathways in Manganese-Catalyzed C(sp3)-H Functionalization via Radical and Cationic Intermediates.

The C(sp3)-H bond oxygenation of the cyclopropane-containing mechanistic probes 6-tert-butylspiro[2.5]octane and spiro[2.5]octane with hydrogen peroxide catalyzed by manganese complexes bearing aminopyridine tetradentate ligands has been studied. Mixtures of unrearranged and rearranged oxygenation products (alcohols, ketones, and esters) are obtained, suggesting the involvement of cationic intermediates and the contribution of different pathways following the initial hydrogen atom transfer-based C-H bond cleavage step. Despite such a complex mechanistic scenario, a judicious choice of the catalyst structure and reaction conditions (solvent, temperature, and carboxylic acid) could be employed to resolve these oxygenation pathways, leading, with the former substrate, to conditions where a single unrearranged or rearranged product is obtained in good isolated yield. Taken together, the work demonstrates an unprecedented ability to precisely direct the chemoselectivity of the C-H oxidation reaction, discriminating among multiple pathways. In addition, these results conclusively demonstrate that stereospecific C(sp3)-H oxidation can take place via a cationic intermediate and that this path can become exclusive in governing product formation, expanding the available toolbox of aliphatic C-H bond oxygenations. The implications of these findings are discussed in the framework of the development of synthetically useful C-H functionalization procedures and the associated mechanistic features.

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.

Site and Enantioselective Aliphatic C-H Oxidation with Bioinspired Chiral Complexes.

Selective oxidation of aliphatic C-H bonds stands as an unsolved problem in organic synthesis, with the potential to offer novel paths for preparing molecules of biological interest. The quest for reagents that can perform this class of reactions finds oxygenases and their mechanisms of action as inspiration motifs. Among the numerous families of synthetic catalysts that have been explored, complexes with linear tetraazadentate ligands combining two aliphatic amines and two aromatic amine heterocycles display a structural versatility proven instrumental in the design of C-H oxidation reactions showing site and enantioselectivities, not accessible by conventional oxidants. This manuscript makes a review of recent advances in the field.