Experimental and computational studies of the mechanism of iron-catalysed C-H activation/functionalisation with allyl electrophiles.

Synthetic methods that utilise iron to facilitate C-H bond activation to yield new C-C and C-heteroatom bonds continue to attract significant interest. However, the development of these systems is still hampered by a limited molecular-level understanding of the key iron intermediates and reaction pathways that enable selective product formation. While recent studies have established the mechanism for iron-catalysed C-H arylation from aryl-nucleophiles, the underlying mechanistic pathway of iron-catalysed C-H activation/functionalisation systems which utilise electrophiles to establish C-C and C-heteroatom bonds has not been determined. The present study focuses on an iron-catalysed C-H allylation system, which utilises allyl chlorides as electrophiles to establish a C-allyl bond. Freeze-trapped inorganic spectroscopic methods (57Fe Mössbauer, EPR, and MCD) are combined with correlated reaction studies and kinetic analyses to reveal a unique and rapid reaction pathway by which the allyl electrophile reacts with a C-H activated iron intermediate. Supporting computational analysis defines this novel reaction coordinate as an inner-sphere radical process which features a partial iron-bisphosphine dissociation. Highlighting the role of the bisphosphine in this reaction pathway, a complementary study performed on the reaction of allyl electrophile with an analogous C-H activated intermediate bearing a more rigid bisphosphine ligand exhibits stifled yield and selectivity towards allylated product. An additional spectroscopic analysis of an iron-catalysed C-H amination system, which incorporates N-chloromorpholine as the C-N bond-forming electrophile, reveals a rapid reaction of electrophile with an analogous C-H activated iron intermediate consistent with the inner-sphere radical process defined for the C-H allylation system, demonstrating the prevalence of this novel reaction coordinate in this sub-class of iron-catalysed C-H functionalisation systems. Overall, these results provide a critical mechanistic foundation for the rational design and development of improved systems that are efficient, selective, and useful across a broad range of C-H functionalisations.

Identification and Reactivity of Cyclometalated Iron(II) Intermediates in Triazole-Directed Iron-Catalyzed C-H Activation.

While iron-catalyzed C-H activation offers an attractive reaction methodology for organic transformations, the lack of molecular-level insight into the in situ formed and reactive iron species impedes continued reaction development. Herein, freeze-trapped 57Fe Mössbauer spectroscopy and single-crystal X-ray crystallography combined with reactivity studies are employed to define the key cyclometalated iron species active in triazole-assisted iron-catalyzed C-H activation. These studies provide the first direct experimental definition of an activated intermediate, which has been identified as the low-spin iron(II) complex [(sub-A)(dppbz)(THF)Fe]2(µ-MgX2), where sub-A is a deprotonated benzamide substrate. Reaction of this activated intermediate with additional diarylzinc leads to the formation of a cyclometalated iron(II)-aryl species, which upon reaction with oxidant, generates C-H arylated product at a catalytically relevant rate. Furthermore, pseudo-single-turnover reactions between catalytically relevant iron intermediates and excess nucleophile identify transmetalation as rate-determining, whereas C-H activation is shown to be facile under the reaction conditions.

Crystal structure of bromido-penta-kis-(tetra-hydro-furan-κO)magnesium bis-[1,2-bis-(di-phenyl-phosphan-yl)benzene-κ2 P,P']cobaltate(-1) tetra-hydro-furan disolvate.

Structural characterization of the ionic title complex, [MgBr(THF)5][Co(dpbz)2]·2THF [THF is tetra-hydro-furan, C4H8O; dpbz is 1,2-bis-(di-phenyl-phosphan-yl)benzene, C30H24P2], revealed a well-separated cation and anion co-crystallized with two THF solvent mol-ecules that inter-act with the cation via weak C-H⋯O contacts. The geometry about the cobalt center is pseudo-tetra-hedral, as is expected for a d 10 metal center, only deviating from an ideal tetra-hedral geometry because of the restrictive bite angles of the bidentate phosphane ligands. Three THF ligands of the cation and one co-crystallized THF solvent mol-ecule are each disordered over two orientations. In the extended structure, the cations and THF solvent mol-ecules are arranged in (100) sheets that alternate with layers of anions, the latter of which show various π-inter-actions, which may explain the particular packing arrangement.

The Effect of ß-Hydrogen Atoms on Iron Speciation in Cross-Couplings with Simple Iron Salts and Alkyl Grignard Reagents.

The effects of ß-hydrogen-containing alkyl Grignard reagents in simple ferric salt cross-couplings have been elucidated. The reaction of FeCl3 with EtMgBr in THF leads to the formation of the cluster species [Fe8 Et12 ]2- , a rare example of a structurally characterized metal complex with bridging ethyl ligands. Analogous reactions in the presence of NMP, a key additive for effective cross-coupling with simple ferric salts and ß-hydrogen-containing alkyl nucleophiles, result in the formation of [FeEt3 ]- . Reactivity studies demonstrate the effectiveness of [FeEt3 ]- in rapidly and selectively forming the cross-coupled product upon reaction with electrophiles. The identification of iron-ate species with EtMgBr analogous to those previously observed with MeMgBr is a critical insight, indicating that analogous iron species can be operative in catalysis for these two classes of alkyl nucleophiles.

Development and Evolution of Mechanistic Understanding in Iron-Catalyzed Cross-Coupling.

Since the pioneering work of Kochi in the 1970s, iron has attracted great interest for cross-coupling catalysis due to its low cost and toxicity as well as its potential for novel reactivity compared to analogous reactions with precious metals like palladium. Today there are numerous iron-based cross-coupling methodologies available, including challenging alkyl-alkyl and enantioselective methods. Furthermore, cross-couplings with simple ferric salts and additives like NMP and TMEDA ( N-methylpyrrolidone and tetramethylethylenediamine) continue to attract interest in pharmaceutical applications. Despite the tremendous advances in iron cross-coupling methodologies, in situ formed and reactive iron species and the underlying mechanisms of catalysis remain poorly understood in many cases, inhibiting mechanism-driven methodology development in this field. This lack of mechanism-driven development has been due, in part, to the challenges of applying traditional characterization methods such as nuclear magnetic resonance (NMR) spectroscopy to iron chemistry due to the multitude of paramagnetic species that can form in situ. The application of a broad array of inorganic spectroscopic methods (e.g., electron paramagnetic resonance, 57Fe Mössbauer, and magnetic circular dichroism) removes this barrier and has revolutionized our ability to evaluate iron speciation. In conjunction with inorganic syntheses of unstable organoiron intermediates and combined inorganic spectroscopy/gas chromatography studies to evaluate in situ iron reactivity, this approach has dramatically evolved our understanding of in situ iron speciation, reactivity, and mechanisms in iron-catalyzed cross-coupling over the past 5 years. This Account focuses on the key advances made in obtaining mechanistic insight in iron-catalyzed carbon-carbon cross-couplings using simple ferric salts, iron-bisphosphines, and iron- N-heterocyclic carbenes (NHCs). Our studies of ferric salt catalysis have resulted in the isolation of an unprecedented iron-methyl cluster, allowing us to identify a novel reaction pathway and solve a decades-old mystery in iron chemistry. NMP has also been identified as a key to accessing more stable intermediates in reactions containing nucleophiles with and without ß-hydrogens. In iron-bisphosphine chemistry, we have identified several series of transmetalated iron(II)-bisphosphine complexes containing mesityl, phenyl, and alkynyl nucleophile-derived ligands, where mesityl systems were found to be unreliable analogues to phenyls. Finally, in iron-NHC cross-coupling, unique chelation effects were observed in cases where nucleophile-derived ligands contained coordinating functional groups. As with the bisphosphine case, high-spin iron(II) complexes were shown to be reactive and selective in cross-coupling. Overall, these studies have demonstrated key aspects of iron cross-coupling and the utility of detailed speciation and mechanistic studies for the rational improvement and development of iron cross-coupling methods.

Multinuclear iron-phenyl species in reactions of simple iron salts with PhMgBr: identification of Fe4(µ-Ph)6(THF)4 as a key reactive species for cross-coupling catalysis.

The first direct syntheses, structural characterizations, and reactivity studies of iron-phenyl species formed upon reaction of Fe(acac)3 and PhMgBr in THF are presented. Reaction of Fe(acac)3 with 4 equiv. PhMgBr in THF leads to the formation of [FePh2(µ-Ph)]2 2- at -80 °C, which can be stabilized through the addition of N-methylpyrrolidone. Alternatively, at -30 °C this reaction leads to the formation of the tetranuclear iron-phenyl cluster, Fe4(µ-Ph)6(THF)4. Further synthetic studies demonstrate that analogous tetranuclear iron clusters can be formed with both 4-F-PhMgBr and p-tolylMgBr, illustrating the generality of this structural motif for reactions of simple ferric salts and aryl Grignard reagents in THF. Additional studies isolate and define key iron species involved in the synthetic pathway leading to the formation of the tetranuclear iron-aryl species. While reaction studies demonstrate that [FePh2(µ-Ph)]2 2- is unreactive towards electrophile, Fe4(µ-Ph)6(THF)4 is found to rapidly react with bromocyclohexane to selectively form phenylcyclohexane. Based on this reactivity, a new catalytic reaction protocol has been developed that enables efficient cross-couplings using Fe4(µ-Ph)6(THF)4, circumventing the current need for additives such as TMEDA or supporting ligands to achieve effective cross-coupling of PhMgBr and a secondary alkyl halide.

Crystal structures of two new six-coordinate iron(III) complexes with 1,2-bis(diphenyl-phosphane) ligands.

Structural characterization of the ionic complexes [FeCl2(C26H22P2)2][FeCl4]·0.59CH2Cl2 or [(dppen)2FeCl2][FeCl4]·0.59CH2Cl2 (dppen = cis-1,2-bis-(di-phenyl-phosphane)ethyl-ene, P2C26H22) and [FeCl2(C30H24P2)2][FeCl4]·CH2Cl2 or [(dpbz)2FeCl2][FeCl4]·CH2Cl2 (dpbz = 1,2-bis-(di-phenyl-phosphane)benzene, P2C30H24) demonstrates trans coordination of two bidentate phosphane ligands (bis-phosphanes) to a single iron(III) center, resulting in six-coordinate cationic complexes that are balanced in charge by tetra-chlorido-ferrate(III) monoanions. The trans bis-phosphane coordination is consistent will all previously reported mol-ecular structures of six coordinate iron(III) complex cations with a (PP)2X2 (X = halido) donor set. The complex with dppen crystallizes in the centrosymmetric space group C2/c as a partial-occupancy [0.592 (4)] di-chloro-methane solvate, while the dpbz-ligated complex crystallizes in the triclinic space group P1 as a full di-chloro-methane monosolvate. Furthermore, the crystal studied of [(dpbz)2FeCl2][FeCl4]·CH2Cl2 was an inversion twin, whose component mass ratio refined to 0.76 (3):0.24 (3). Beyond a few very weak C-H⋯Cl and C-H⋯π inter-actions, there are no significant supra-molecular features in either structure.

The N-Methylpyrrolidone (NMP) Effect in Iron-Catalyzed Cross-Coupling with Simple Ferric Salts and MeMgBr.

The use of N-methylpyrrolidone (NMP) as a co-solvent in ferric salt catalyzed cross-coupling reactions is crucial for achieving the highly selective, preparative scale formation of cross-coupled product in reactions utilizing alkyl Grignard reagents. Despite the critical importance of NMP, the molecular level effect of NMP on in situ formed and reactive iron species that enables effective catalysis remains undefined. Herein, we report the isolation and characterization of a novel trimethyliron(II) ferrate species, [Mg(NMP)6 ][FeMe3 ]2 (1), which forms as the major iron species in situ in reactions of Fe(acac)3 and MeMgBr under catalytically relevant conditions where NMP is employed as a co-solvent. Importantly, combined GC analysis and 57 Fe Mössbauer spectroscopic studies identified 1 as a highly reactive iron species for the selective formation generating cross-coupled product. These studies demonstrate that NMP does not directly interact with iron as a ligand in catalysis but, alternatively, interacts with the magnesium cations to preferentially stabilize the formation of 1 over [Fe8 Me12 ]- cluster generation, which occurs in the absence of NMP.

Polyoxovanadate-Alkoxide Clusters as a Redox Reservoir for Iron.

Inspired by the multielectron redox chemistry achieved using conventional organic-based redox-active ligands, we have characterized a series of iron-functionalized polyoxovanadate-alkoxide clusters in which the metal oxide scaffold functions as a three-dimensional, electron-deficient metalloligand. Four heterometallic clusters were prepared through sequential reduction, demonstrating that the metal oxide scaffold is capable of storing up to four electrons. These reduced products were characterized by cyclic voltammetry, IR, electronic absorption, and 1H NMR spectroscopies. Moreover, Mössbauer and X-ray absorption spectroscopies suggest that the redox events involve primarily the vanadium ions, while the iron atoms remained in the 3+ oxidation state throughout the redox series. In this sense, the vanadium portion of the cluster mimics a conventional organic-based redox-active ligand bound to an iron(III) ion. Magnetic coupling within the hexanuclear cluster was characterized using SQUID magnetometry. Overall, the results suggest extensive electronic delocalization between the metal centers of the cluster core. These results demonstrate the ability of electronically flexible, reducible metal oxide supports to function as redox-active reservoirs for transition-metal centers.

A Physical-Inorganic Approach for the Elucidation of Active Iron Species and Mechanism in Iron-Catalyzed Cross-Coupling.

Detailed studies of iron speciation and mechanism in iron-catalyzed cross-coupling reactions are critical for providing the necessary fundamental insight to drive new reaction development. However, such insight is challenging to obtain due to the prevalence of mixtures of unstable, paramagnetic organoiron species that can form in this chemistry. A physical-inorganic research approach combining freeze-trapped inorganic spectroscopic studies, organometallic synthesis and GC/kinetic studies provides a powerful method for studying such systems. Mössbauer, EPR and MCD spectroscopy enable the direct investigation of in situ formed iron species and, combined with GC analysis, the direct correlation of reactions of specific iron species to the generation of organic products. This review focuses on a description of the key methods involved in this physical-inorganic approach, as well as examples of its application to investigations of iron-SciOPP catalyzed cross-coupling catalysis.

Facile hydrogen atom transfer to iron(iii) imido radical complexes supported by a dianionic pentadentate ligand.

A dianionic tetrapodal pentadentate diborate ligand is introduced. This ligand forms a high spin neutral iron(ii) complex that reacts with a variety of organoazides to yield transient Fe(iii) imido radicals that are extremely potent hydrogen atom abstractors. The nature of these species is supported by full characterization of the Fe(iii) amido products, kinetic studies, density functional computations and Mössbauer spectroscopy on the -C6H4-p- t Bu substituted derivative.