•Transition State Affinity Chromatography (TSAC) is evaluated as a new method for catalyst selection HPLC affinity column materials are prepared for the hydrolysis reaction substrate, transition state analog (TSA), and reference species.•The chromatographic affinities of a library of 29 diimine-Zn complexes on the affinity columns are compared to the kinetic parameters, 1/KM and kcat, determined for the hydrolysis of p-nitrophenyl picolinate catalyzed by these complexes.•A moderate linear correlation between the chromatographic retention factors and the kinetic parameters is observed for the set of complexes whose ligands bear a pendant hydroxyalkyl arm.•Chromatographic separation of a subset of 5 Zn-complexes on the affinity columns shows the ability of TSAC to correctly select the most active catalyst.A new method for catalyst selection-optimization is introduced and evaluated, transition state affinity chromatography (TSAC), based on the relative chromatographic affinity of pre-catalysts for a supported-substrate vs. a transition state analog (TSA). The affinities of a library of Zn-imine complexes on three designer HPLC affinity columns that possess either an immobilized substrate, a transition state analog or a non-binding reference compound are compared to their catalytic activities for picolinate ester hydrolysis. For those Zn-complexes whose ligands possess a hydroxyalkyl side chain the retention times on the substrate-affinity column correlate linearly with the catalyst-substrate affinity, 1/KM, derived from the kinetics of the LZn-catalyzed hydrolysis of 4-nitrophenyl picolinate. Additionally, the kinetically determined esterolytic catalytic activities, kcat, for the hydroxyalkyl-bearing complexes also correlate with their relative chromatographic affinity on the TSA- vs Sub-affinity columns. Zinc-complexes that lack the hydroxyalkyl arm, however, show no correlation of their chromatographic behavior with 1/KM and an inverse correlation with kcat. These results are interpreted in terms of differences in the catalytic mechanisms for the two sets of catalysts. TSAC is shown to be viable for selecting the most active esterolytic Zn-catalyst from a mixture of five complexes.Download full-size image

Four oxo-vanadium complexes of the type Z+LVO2– (1–4) have been evaluated for activity as catalysts for the deoxydehydration (DODH) of glycols to olefins with various reductants. Among these, a new complex, [Bu4N](Salhyd)VO2 (4), is found to be uniquely effective for the DODH reaction using the practical reductants: hydrogen and carbon monoxide (CO).Keywords: carbon monoxide; deoxydehydration; glycol; hydrogen; oxo-vanadium

Representative benzylic, allylic and α-keto alcohols are deoxygenated to alkanes and/or reductively coupled to alkane dimers by reaction with PPh3 catalyzed by (PPh3)2ReIO2 (1). The newly discovered catalytic reductive coupling reaction is a rare C–C bond-forming transformation of alcohols.

In this invited Perspective, I provide a personal account highlighting several of my group’s research contributions in metallo–organic chemistry over the past 40 years. Our early work focused primarily in stoichiometric structure/reactivity of transition metal–organic compounds and their use in organic synthesis. More recent efforts have centered on the discovery and development of new metal-catalyzed organic reactions via reactive metal–organic intermediates. The major research findings that are described here include (1) propargyl-cobalt complexes as electrophilic agents for C–C and C–Nu coupling; (2) the activation of carbon dioxide by metal complexes; (3) metal-promoted C–H nitrogenation reactions; (4) oxo–metal catalyzed deoxygenation reactions; and (5) catalyst discovery via dynamic templating with substrate- and transition-state analogues.

Several dihydroaromatic compounds are shown to be effective reducing agents in the oxo-metal-catalyzed deoxydehydration of diols and polyols to produce olefins and the corresponding arenes. NH4ReO4 and MeReO3 are active catalysts for the reactions. The most effective of the hydroaromatic reductants is indoline, which is oxidized to indole. Yields for a variety of diols and polyols range from 35% to 99%. Two hydrogen donors, 1,3-cyclohexadiene and dihydroanthracene, engage in tandem DODH/cycloaddition reactions. Competition experiments show that indoline is more reactive than representative alcohols in H-transfer. Indoline is shown to reduce MeReO3 to MeReO2 via an isolable adduct, MeReO3(indoline) (4), which has been structurally characterized and is suggested to be an intermediate in the catalytic DODH process.

The elements zinc, iron, manganese, and carbon are demonstrated to be practical reductants for the oxorhenium catalyzed deoxydehydration (DODH) of biomass model polyols. These reductants and their oxidization products remain heterogeneous throughout the reaction, which aids in their separation. Their effectiveness is shown with the catalysts ammonium perrhenate and trans-[(Py)4Re(O)2]+Z– (1). Stoichiometric experiments with the Re(V) complex indicate a likely rhenium 5↔7 oxidation cycle for the deoxydehydration of polyols reported herein.Keywords: alkene; deoxydehydration; DODH; elemental reductant; oxorhenium; polyol

The thermal (uncatalyzed) and Cu(I)-catalyzed reactions of 2-nitrosopyridine (PyrNO) with the dienes 1,3-pentadiene, E,E-2,4-hexadienol, and 1-phenylbutadiene are investigated experimentally and computationally. The uncatalyzed reactions of the first two dienes occur with low regioselectivity, while the latter proceeds with complete proximal selectivity. Using the M06/6-311+G(d,p)–SDD method, various concerted transition states for the reactions of 2-nitrosopyridine with (E)-1,3-pentadiene and 1-phenylbutadiene were computed. In quantitative agreement with the experimental findings, (a) no energy difference (0.0 kcal/mol) is found between the most stable transition states, endo-prox-anti and endo-dist-anti, in the pentadiene/PyrNO reaction, leading to nearly equal amounts of prox and dist cycloadducts, and (b) the proximal transition state is strongly favored (by 3.7 kcal/mol) over the distal for the highly selective phenylbutadiene/PyrNO reaction. The regioselectivity of the pentadiene/PyrNO reaction is improved markedly (90:10 dist/prox) when catalyzed by Cu(CH3CN)4+; (diimine)2Cu+ catalysts increase selectivity for the proximal product (55–65%). Modest effects of the catalyst nature on regioselectivity are observed in the sorbyl alcohol and 1-phenylbutadiene reactions. The relative affinity of an equilibrating set of (diimine)2Cu+ complexes for the prox and dist cycloadducts, assessed by ESI-MS, is marginally correlated with the prox/dist product regioselectivity produced by the corresponding catalysts. Transition states in the Cu(CH3CN)4+- and Cu(diimine)2+-catalyzed reactions are located that account for the observed regioselectivities. Coordination effects on the regioselectivity are derived from FMO orbital interactions and the extent of electron transfer between the Cu center and the coordinated nitroso and diene units.

[(Neocuproine)Cu]PF6 catalyzes the C–H amidation of unactivated arenes by N-tosyloxytrichloroethylcarbamates. Alkyl benzenes are selectively converted to aromatic amines and substituted arenes display variable regioselectivity.

A survey of several metavandate (VO3−) and chelated dioxovanadium derivatives shows that tetrabutylammonium dioxovanadium(V)dipicolinate most effectively catalyzes the deoxydehydration (DODH) of glycols to olefins in moderate to excellent yields with triphenylphosphine or sodium sulfite as reductants.

Dynamic combinatorial libraries of chiral tetradentate bis-imine zinc(II) complexes have been prepared and screened for (1) their discrimination of enantiomeric picolinate esters and pyridyl phosphonate transition state analogs (TSAs) and (2) their catalytic activity and selectivity for enantioselective methanolysis of racemic picolinate esters. The zinc complexes are in equilibrium with their imine ligands as well as with the aldehyde and amine building blocks that form them, enabling the composition of the library to adapt in response to the introduction of coordinating substrates or TSAs. Binary (L)Zn(OTf)(solv)+ complexes are generated either individually or in libraries from chiral tartrate-derived diamines (2,3) and a set of N-heterocyclic aldehydes (4–12) and the distribution of complexes established by ESI-MS analysis. Binding studies of the (diimine)Zn(OTf)2 complex libraries with enantiomeric R- and S-2-pyridyl phosphonate TSA 13 show chiral discrimination via formation of diastereomeric LZn(R/S-13)+ complexes with low to moderate enatioselectivity ratios, kR/kS (α), ranging from 0.5 to 5.0; corresponding templating of selected binary complexes with the enantiomeric substrates, PyrCO2CH(OH)Ph (1), show negligible chiral recognition. The rate constants for methanolysis of the R- and S-esters, PyrCO2CH(OH)Ph (1) catalyzed by several L*Zn(OTf)2 complexes range in value several fold depending on L and with enantioselectivity ratios, kR/kS (α), ranging from 0.76 to 2.8.Keywords: chiral zinc catalysts; dynamic templating; ESI-MS screening; esterolysis; transition state analogs

A copper-mediated bromoamination of aromatic N-heterocycles has been achieved using oxime esters as the N-reagents under mild conditions (ca. 70 °C). The reaction with N-alkyl indoles proceeds regioselectively to produce the 2-amino-3-bromo indole derivatives as confirmed by X-ray crystallographic analysis of the bromoaminated product, 3aa-Br. With N-methylpyrrole both the monobromoaminated and dibromoaminated products were produced by this method.

A series of cyclometalated palladium complexes derived from O-phenylcarbamates has been synthesized by the reaction of the respective carbamates with Pd(OAc)2 in the presence of acids, CF3CO2H, CF3SO3H, and p-TsOH. The palladacycles were observed to coordinate amines and electron rich anilines but not sulfonamides or carboxamides. Analysis of the tBu-NH2 adduct of the palladacycle 2b (2b·tBu-NH2) by NMR spectroscopy (NOE) revealed a cis-coordination of the amine. However, the amine adducts failed to undergo ortho-amination (C–N bond formation) under varied reaction conditions. Notably, the palladacycle 1d was found to react efficiently with N-iodosuccinimide (NIS) to yield the ortho-iodinated carbamate, 1e. More significantly, this reaction can be extended to a palladium-catalyzed ortho C–H bromination of aryl-O-carbamates even at 5 mol % loading of Pd(OAc)2 using N-bromosuccinimide (NBS).

The Cu(OAc)2-catalyzed, O2-mediated amidation of 2-phenylpyridine via C−H bond activation is reported. A variety of nitrogen reagents including sulfonamides, carboxamides, and anilines participate in the reaction in moderate to good yields.

A new series of chiral Zn–Schiff base (imine) complexes has been prepared from mono-N-sulfonyl derivatives of (1R,2R)-diaminocyclohexane, N-heterocyclic aldehydes, and zinc salts. The formation and characterization of the (L)ZnX2 complexes was established by NMR, IR and HRESI-MS. Spectroscopic and kinetic evidence indicates that these ligands may be bidentate or tridentate depending on conditions of the medium. The methanolysis of a chiral, racemic picolinate ester catalyzed by the Zn(II)–Schiff base complexes was studied kinetically. The rate constants were found to vary approximately a hundred-fold and in a complex way depending on the imine ligand and the Zn-counter anion, kobs = 5.0 × 10−6–4.8 × 10−4 M−1 s−1. A Job plot analysis of ternary complex formation of LZnX2 with two phosphonate transition state analogs suggests that two types of (imine)Zn(picolinate)X ternary complexes may be intermediates and that varying rate-limiting steps may be involved in the LZnX2-catalyzed methanolysis of picolinate esters.Graphical abstractA series of chiral Schiff base–zinc complexes derived from N-heterocyclic aldehydes and trans-cyclohexyldiamine N-sulfonamides are effective catalysts for the methanolysis of picolinate esters. Substantial differences in catalytic activity derive from the steric and electronic nature of the N-heterocycle and sulfonyl groups of the imine ligand and the anionic ligand X.Highlights► New zinc–Schiff base complexes of cyclohexyldiamine-sulfonamides are prepared ► Their ester methanolyis activity for depends on the imine, counteranion and sulfonamide units ► The mechanism is probed via ligand deprotonation and TSA binding experiments.

Methyltrioxorhenium and sodium perrhenate catalyze the deoxydehydration of glycols and deoxygenation of epoxides to olefins in moderate yields with sulfite as the reductant.

Several classes of ligands, including α-amino acids, diamines, diphosphines, bis-oxazolines, and diimines, support efficient copper-catalyzed amination of benzylic hydrocarbons by anhydrous chloramine-T. Catalysts derived from homochiral ligands, particularly chiral diimines, effect aminosulfonation with low to moderate enantioselectivity.

The mechanism of hydrocarbon amination by chloramine-T derivatives catalyzed by (diimine)copper complexes has been investigated. The initial synthetic study of the reactions revealed ligand-accelerated catalysis, significant sensitivity to the electronic character of the substrates, and low to moderate enantioselectivities with homochiral ligands. Various mechanistic probes, both experimental and computational, have been focused on the C−H insertion process. A kinetic isotope effect of 4.6 was found in the amination of α-D(H)-cumenes catalyzed by [(diimine)Cu(solv)]Z. Amination of the isomeric substrates cis- and trans-4-tert-butyl-1-phenylcyclohexanes with 4-Me-C6H4SO2NNaCl (chloramine-T) or 4-NO2-C6H4SO2NNaCl (chloramine-N) catalyzed by [(diimine)Cu(CH3CN)]PF6 produced in all cases an approximately 1:1 mixture of the corresponding cis- and trans-4-tert-butyl-1-phenyl-1-sulfonaminocyclohexanes. Amination of the radical-clock substrate 1-phenyl-2-benzylcyclopropane with chloramine-T/(diimine)Cu(CH3CN)]PF6 gave a mixture of ring-opened and cyclopropylmethylamino derivatives. Together, these results are most consistent with a stepwise insertion of an N-Ts(Ns) unit into the C−H bond, via carbon radicals, and a secondary contribution from a concerted insertion pathway. B3LYP and CASSCF computations suggest that the C−H insertion step involves the reaction of the hydrocarbon with a Cu-imido (nitrene) complex, [(diimine)Cu═NSO2R]+. The ground-state triplet of the Cu-imido complex is calculated to be 3−13 kcal/mol more stable that the singlet complex, depending on the method and basis sets employed. The reaction of each complex with toluene is modeled to find that the C−H insertion transition state for the triplet (ΔG‡ = 8.2 kcal/mol) is lower in energy than the singlet. The former reacts by a stepwise H-atom abstraction, while the latter reacts by a concerted C−H insertion. These results and kinetic isotope effect calculations for the singlet (2.9) and triplet (4.8) pathways, respectively, agree with the experimental observations (4.6) and point to a major role for the triplet complex in the stepwise, nonstereoselective insertion pathway.

The ability of the histidine-rich peptides, histatin-5 (Hst-5) and histatin-8 (Hst-8), to support the generation of reactive oxygen species during the Cu-catalyzed oxidation of ascorbate and cysteine has been evaluated. High levels of hydrogen peroxide (70–580 mol/mol Cu/h) are produced by aqueous solutions containing Cu(II), Hst-8 or Hst-5, and a reductant, either ascorbate or cysteine, as determined by the postreaction Amplex Red assay. When the reactions are conducted in the presence of superoxide dismutase, the total hydrogen peroxide produced is decreased, more so in the presence of the peptides (up to 50%), suggesting the intermediacy of superoxide in these reactions. On the other hand, the presence of sodium azide or sodium formate, traps for hydroxyl radicals, has no appreciable effect on the total hydrogen peroxide production for the Cu–Hst systems. EPR spin-trapping studies using 5-(2,2-dimethyl-1,3-propoxy cyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO) in the cysteine–Cu(II) reactions reveal the formation of the CYPMPO–hydroperoxyl and CYPMPO–hydroxyl radical adducts in the presence of Hst-8, whereas only the latter was observed with Cu alone.

Benzylic and allylic hydrocarbons are selectively converted to the corresponding sulfonamides by a ZnBr2–H2O-catalyzed reaction with PhINTs; saturated adamantane is aminosulfonated at the tertiary C–H bond.

In the search for new bis(imidazole)thioether (BIT) copper complexes that accurately mimic the electronic and reactivity features of the CuM site of copper hydroxylase enzymes, a set of tripodal BIT ligands 4a,b−6a,b has been synthesized that vary according to the imidazole C-(Ph or H) and N-(H or Me) substituents, as well as the position (2- or 4-) of the tripodal attachment. Corresponding [(BIT)Cu(L)](PF6) complexes 7a,b′, 8a,b′, and 9a′,b′ [L = CO (a), CH3CN (b)] have been prepared and characterized spectroscopically. The IR spectra of 7a−9a (L = CO), specifically ν(CO), show little variation (2090–2100 cm−1), suggesting a similar electronic character of the Cu centers. In contrast, cyclic voltammetric analysis of these compounds (L = CH3CN) reveals quasi-reversible oxidation waves with significant variation of Epa in the range of + 0.45–0.57 V vs Fc/Fc+, depending on the imidazole substituents. Each of the [(BIT)Cu(CH3CN)]PF6 complexes reacts with dioxygen to form [(BIT)CuII2(μ-OH)2](PF6)2 derivatives, 10−12, but they vary considerably in their relative reactivity, following the same trend as the ease of their electrochemical oxidation, that is, [(2-BITNMe)Cu(CH3CN)]+ (9b′) > [(4-BITPh,NMe)Cu(CH3CN)]+ (8b′) > [(2-BITPh2,NMe)Cu(CH3CN)]+ (1a′) > [(4-BITPh,NH)Cu(CH3CN)]+ (7b′). Thus, N-Me substitution and 4-tethering on the imidazole unit increase oxidation and oxygenation reactivity, while Ph-substitution and 2-tethering decrease reactivity. PM3 and DFT calculations are employed to analyze the relative stability, the electronic features, the Cu−CO vibrtional frequency, and the electrochemical and oxidative reactivity of the complexes.

The preparation, characterization and reactivity of (η5-cyclopentadienyl)iron complexes of nitrosobenzene are investigated as potential intermediates in the [CpFe(CO)2]2 (1)-catalyzed allylic amination of olefins by nitroarenes. The oxidation of 1 by [Cp2Fe]+ in the presence of PhNO produces a novel dinuclear complex {[CpFe-μ-(η2-(N,O)-PhNO)]2-μ-NHPh}BF4 (2) along with [CpFe(CO)3]BF4 and [CpFe(CO)2(NH2Ph)]BF4; 2 has been characterized spectroscopically and by X-ray diffraction. Reaction of CpFe(CO)2I with PhNO and AgSbF6 produces the mononuclear complex [CpFe(CO)2(η2-PhNO)]SbF6 (3) which has also been characterized spectroscopically, crystallographically and by PM3 MO calculations. The reaction of 3 with α-methyl styrene affords [CpFe(CO)2(PhNH2)SbF6] and a trace of N-phenyl-2-phenylallyl amine 4, while the reaction of 3 with 2,3-dimethyl-1,3-butadiene affords the aniline complex and a hetero-Diels-Alder adduct 5, indicative of PhNO dissociation. Together these results preclude the involvement of nitrosoarene complex 3 as an important intermediate in the allylic amination catalyzed by [CpFe(CO)2]2.Two novel CpFe-nitrosobenzene complexes have been prepared and structurally characterized. {[CpFe-μ-(η2-(N,O)-PhNO)]2-μ-NHPh}BF4 (2) features bridging PhNO and PhNH- units, whereas [CpFe(CO)2(η1-PhNO)]SbF6 (3) exhibits η1-N(O)Ph coordination. The possible intermediacy of 3+ in [CpM(CO)2]2-catalyzed allylic amination of alkene by nitroarenes is evaluated via reactions with a representative alkene and diene.

The effects of catalyst structural variation on the activity and selectivity of titanocene-catalyzed pinacol coupling of cyclohexane carboxaldehyde by Mn/TMSCl have been evaluated. Complexes which have been tested include: Cp2TiCl2 (1), Cp2TiBr2 (2), (C5Me5)2TiCl2 (3), (1,3-t-Bu2C5H3)2TiCl2 (4), (1,3-t-Bu2C5H3)(Cp)TiCl2 (5), ansa-[(η5-tetrahydroindenyl)CH2CH2(η5-tetrahydroindenyl)]TiCl2 (6), and ansa-[(η5-Cp)CH2CH2(η5-fluorenyl)]TiCl2 (7). Cp2TiCl2 (1) is the most active (pre)catalyst for pinacol silylether (8a) formation, but Brintzinger's complex 6 provides the best dl/meso diastereoselectivity (5:1). Complexes 2, 4 and 7 slowly catalyze the predominant formation of the corresponding pinacol acetal 9a as a secondary product. Comparative stoichiometric reactions of benzaldehyde/Me3SiCl with [Cp2TiCl·MnCl2(THF)2·Cp2TiCl] (10) and [Cp2TiCl]2 (11) result in highly diastereoselective pinacol silylether formation with binuclear 11 (29:1), but primarily the production of pinacol acetal (9b) from trimetallic 10, suggesting a dominant role for the binuclear complex (or derived mononuclear species) in the catalytic systems employing Cp2TiCl2/M/TMSCl, contrary to previous suggestions.A series of substituted titanocene dihalides have been evaluated as catalysts for the pinacol coupling of cyclohexane carboxaldehyde by Mn/TMSL; Cp2TiCl2 is the most active for pinacol silylether formation, but Brintzinger's complex provides the best dl/meso diastereoselectivity (5:1). Stoichiometric reaction of benzaldehyde/Me3SiCl with [Cp2TiCl]2 gives the pinacol ether with high diastereoselectivity but [Cp2TiCl·MnCl2(THF)2·Cp2TiCl] produces largely the corresponding pinacol acetal, suggesting a dominant role for the binuclear complex (or derived mononuclear species) in the catalytic systems employing Cp2TiCl2/M/TMSCl.

The reaction of MoO2(dedtc)2 (1, dedtc=N,N-diethyl dithiocarbamate) with hydroxylamine in methanol produces Mo(NO)(dedtc)3 (3) the structure of which has been determined by X-ray diffraction.

[(Neocuproine)Cu]PF6 catalyzes the C–H amidation of unactivated arenes by N-tosyloxytrichloroethylcarbamates. Alkyl benzenes are selectively converted to aromatic amines and substituted arenes display variable regioselectivity.

Benzylic and allylic hydrocarbons are selectively converted to the corresponding sulfonamides by a ZnBr2–H2O-catalyzed reaction with PhINTs; saturated adamantane is aminosulfonated at the tertiary C–H bond.

A survey of several metavandate (VO3−) and chelated dioxovanadium derivatives shows that tetrabutylammonium dioxovanadium(V)dipicolinate most effectively catalyzes the deoxydehydration (DODH) of glycols to olefins in moderate to excellent yields with triphenylphosphine or sodium sulfite as reductants.

Representative benzylic, allylic and α-keto alcohols are deoxygenated to alkanes and/or reductively coupled to alkane dimers by reaction with PPh3 catalyzed by (PPh3)2ReIO2 (1). The newly discovered catalytic reductive coupling reaction is a rare C–C bond-forming transformation of alcohols.