Computational Evaluation of Potential Molecular Catalysts for Nitrous Oxide Decomposition.

Nitrous oxide (N2O) is a potent greenhouse gas (GHG) with limited use as a mild anesthetic and underdeveloped reactivity. Nitrous oxide splitting (decomposition) is critical to its mitigation as a GHG. Although heterogeneous catalysts for N2O decomposition have been developed, highly efficient, long-lived solid catalysts are still needed, and the details of the catalytic pathways are not well understood. Reported herein is a computational evaluation of three potential molecular (homogeneous) catalysts for N2O splitting, which could aid in the development of more active and robust catalysts and provide deeper mechanistic insights: one Cu(I)-based, [(CF3O)4Al]Cu (A-1), and two Ru(III)-based, Cl(POR)Ru (B-1) and (NTA)Ru (C-1) (POR = porphyrin, NTA = nitrilotriacetate). The structures and energetic viability of potential intermediates and key transition states are evaluated according to a two-stage reaction pathway: (A) deoxygenation (DO), during which a metal-N2O complex undergoes N-O bond cleavage to produce N2 and a metal-oxo species and (B) (di)oxygen evolution (OER), in which the metal-oxo species dimerizes to a dimetal-peroxo complex, followed by conversion to a metal-dioxygen species from which dioxygen dissociates. For the (F-L)Cu(I) activator (A-1), deoxygenation of N2O is facilitated by an O-bound (F-L)Cu-O-N2 or better by a bimetallic N,O-bonded, (F-L)Cu-NNO-Cu(F-L) complex; the resulting copper-oxyl (F-L)Cu-O is converted exergonically to (F-L)Cu-(η2,η2-O2)-Cu(F-L), which leads to dioxygen species (F-L)Cu(η2-O2), that favorably dissociates O2. Key features of the DO/OER process for (POR)ClRu (B-1) include endergonic N2O coordination, facile N2 evolution from LR'u-N2O-RuL to Cl(POR)RuO, moderate barrier coupling of Cl(POR)RuO to peroxo Cl(POR)Ru(O2)Ru(POR)Cl, and eventual O2 dissociation from Cl(POR)Ru(η1-O2), which is nearly thermoneutral. N2O decomposition promoted by (NTA)Ru(III) (C-1) can proceed with exergonic N2O coordination, facile N2 dissociation from (NTA)Ru-ON2 or (NTA)Ru-N2O-Ru(NTA) to form (NTA)Ru-O; dimerization of the (NTA)Ru-oxo species is facile to produce (NTA)Ru-O-O-Ru(NTA), and subsequent OE from the peroxo species is moderately endergonic. Considering the overall energetics, (F-L)Cu and Cl(POR)Ru derivatives are deemed the best candidates for promoting facile N2O decomposition.

Oxo-Rhenium-Catalyzed Radical Addition of Benzylic Alcohols to Olefins.

Although carbon radicals generated from a variety of alcohol derivatives have proven valuable in coupling and addition reactions, the direct use of alcohols as synthetically useful radical sources is less known. In this report, benzylic alcohols are shown to be effective radical precursors for addition reactions to alkenes when treated with triphenylphosphine or piperidine with the catalyst ReIO2(PPh3)2 (I).

Mechanistic Features of the Oxidation-Reductive Coupling of Alcohols Catalyzed by Oxo-Vanadium Complexes.

The oxo-vanadium-catalyzed redox disproportionation of activated alcohols (oxidation-reductive coupling, Ox-RC) produces carbonyl compounds and hydrocarbon dimers. A mechanistic study of this novel reaction is reported herein. Following our initial disclosure, new findings include the following: (1) The [(salimin)VO2]--catalyzed Ox-RC of Ph2CHOH in the presence of fluorene affords the products of H-atom abstraction and all possible hydrocarbon dimers. (2) Electronic substituent effects on the relative rates of Ox-RC with respect to 4-X-BnOH reactants and Bu4N[(Y-salimin)VO2] catalysts (1a-c) reveal (a) a correlation of the oxidation rate of X-BnOH reactants with the radical σ parameter and (b) correlation of the oxidation rate for (Y-salimin)VO2- with the standard Hammett σ parameter. (3) The ease of electrochemical reduction of 1a-c is Y = NO2 > OMe > H. (4) Ambient 1H NMR studies of the interaction of 1 with alcohols suggest only a weak equilibrium association. (5) Density functional theory computational modeling of the Ox-RC reaction supports a ping-pong-type catalytic pathway, beginning with alcohol oxidation by (salimin)VO2-, preferably by stepwise-H-atom transfer from the alcohol to 1, affording the carbonyl product and the reduced (salimin)V(III)(OH)2-. The reduction half-reaction likely begins with condensation of the latter species with R2CHOH to give the alkoxide complex (salimin)V(OR)OH-; homolysis of the R···OV(III)(salimin) bond affords (salimin)V(IV)OH(O)- and the R-radical; the latter dimerizes and the former can disproportionate via H-transfer to reform catalyst (salimin)VO2- (1) and (salimin)V(OH)2-.

A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles.

A straightforward indole synthesis via annulation of C-nitrosoaromatics with conjugated terminal alkynones was realised achieving a simple, highly regioselective, atom- and step economical access to 3-aroylindoles in moderate to good yields. Further functionalizations of indole scaffolds were investigated and an easy way to JWH-018, a synthetic cannabinoid, was achieved.

Determination of Alkyl-Donor Promiscuity of Tyrosine-O-Prenyltransferase SirD from Leptosphaeria maculans.

Natural product prenyltransferases are known to display relaxed acceptor substrate specificity. Although recent studies with a small set of unnatural alkyl donors have revealed that prenyltransferases are flexible with regard to their alkyl donors, the scope of their alkyl donor specificity remains poorly understood. Towards this goal, we report the synthesis of 20 unnatural alkyl pyrophosphate donors and an assessment of the reactions of these synthetic unnatural alkyl pyrophosphate analogues catalyzed by tyrosine O-prenyltransferase SirD. This study demonstrates that SirD can utilize 16 out of 21 alkyl pyrophosphate analogues (including the natural donor) in catalyzing mostly O-alkylation of l-tyrosine. This study reveals the broad alkyl donor specificity of SirD and opens the door for the interrogation of the alkyl donor specificity of other prenyltransferases for potential utility as biocatalysts for differential alkylation applications.

Chemoreactive Natural Products that Afford Resistance Against Disparate Antibiotics and Toxins.

Microorganisms use chemical inactivation strategies to circumvent toxicity caused by many types of antibiotics. Yet in all reported cases, this approach is limited to enzymatically facilitated mechanisms that each target narrow ranges of chemically related scaffolds. The fungus-derived shikimate analogues, pericoxide and pericosine A, were identified as chemoreactive natural products that attenuate the antagonistic effects of several synthetic and naturally derived antifungal agents. Experimental and computational studies suggest that pericoxide and pericosine A readily react via SN 2' mechanisms against a variety of nucleophilic substances under both in vitro aqueous and in situ co-culture conditions. Many of the substitution products from this reaction were highly stable and exhibited diminished toxicities against environmental fungal isolates, including the Tolypocladium sp. strain that produced pericoxide and pericosine A.

A Forty Year Odyssey in Metallo-Organic Chemistry.

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.

Deoxydehydration of polyols.

The development of sustainable chemical processes for the conversion of highly oxygenated biomass feedstocks to chemical products requires efficient and selective processes for partial oxygen removal and refunctionalization. Here we review the development of the deoxydehydration (DODH) reaction, which converts vicinal diols (glycols) to olefins. Uncatalyzed deoxygenative eliminations were first established. The catalyzed DODH reactions have largely employed oxo-rhenium catalysts and a variety of reductants, including PR3, dihydrogen, sulfite, and alcohols. A variety of glycol and biomass-derived polyol substrates undergo the DODH reaction in moderate to good efficiency, regioselectively, and stereoselectively. Observations regarding selectivity, mechanistic probes, and computational studies support the general operation of a catalytic process involving three basic stages: glycol condensation to an M-glycolate, reduction of the oxo-metal, glycol condensation to produce a metal-glycolate, and alkene extrusion from the reduced metal-glycolate. Recent practical developments include the discovery of non-precious V- and Mo-oxo DODH catalysis.

Regioselectivity in the Cu(I)-catalyzed [4 + 2]-cycloaddition of 2-nitrosopyridine with unsymmetrical dienes.

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.

Catalytic Activation of Thioglycosides with Copper-Carbenes for Stereoselective 1,2-Cis-Furanosylations.

Thioglycoside activation, crucial for oligosaccharide synthesis, faces challenges with the need for stoichiometric promoters, additives, and cryogenic conditions, particularly in stereoselective 1,2-cis-linkage formation. This study introduces a carbene-based catalytic method using Cu(OTf)2 for thioglycoside activation, enabling efficient 1,2-cis-furanosylation in ribose and arabinose. The method is orthogonal to conventional thioglycoside and alkyne donors, accommodates sterically demanding acceptors, and achieves stereoselectivity independent of the donor anomeric configuration and C2-protecting groups, with copper chelation playing a key role.

Visualization of Electron Density Changes Along Chemical Reaction Pathways.

We propose a simple procedure for visualizing the electron density changes (EDC) during a chemical reaction, which is based on a mapping of rectangular grid points for a stationary structure into (distorted) positions around atoms of another stationary structure. Specifically, during a small step along the minimum energy pathway (MEP), the displacement of each grid point is obtained as a linear combination of the motion of all atoms, with the contribution from each atom scaled by the corresponding Hirshfeld weight. For several reactions (identity SN2, Claisen rearrangement, Diels-Alder reaction, [3+2] cycloaddition, and phenylethyl mercaptan attack on pericosine A), our EDC plots showed an expected reduction of electron densities around severed bonds (or those with the bond-order lowered), with the opposite observed for newly-formed or enhanced chemical bonds. The EDC plots were also shown for copper triflate catalyzed N2O fragmentation, where the N-O bond weakening initially occurred on a singlet surface, but continued on a triplet surface after reaching the minimum-energy crossing point (MECP) between the two potential energy surfaces.

Palladium catalyzed C-H functionalization of O-arylcarbamates: selective ortho-bromination using NBS.

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, CF(3)CO(2)H, CF(3)SO(3)H, and p-TsOH. The palladacycles were observed to coordinate amines and electron rich anilines but not sulfonamides or carboxamides. Analysis of the (t)Bu-NH(2) adduct of the palladacycle 2b (2b·(t)Bu-NH(2)) 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).

Copper-catalyzed amidation of 2-phenylpyridine with oxygen as the terminal oxidant.

The Cu(OAc)(2)-catalyzed, O(2)-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.

Iodine-catalyzed aminosulfonation of hydrocarbons by imidoiodinanes. A synthetic and mechanistic investigation.

The amino-functionalization of a range of benzylic and some aliphatic saturated and unsaturated hydrocarbons by reaction with imido-iodinanes (PhI═NSO2Ar) is catalyzed by I2 under operationally simple and mild conditions. The first examples of 1,2-functionalization of unactivated C-H bonds using imido-iodinanes as aminating agents are reported. Mechanistic investigations, including Hammett analysis, kinetic isotope effects, a cyclopropane clock experiment, and stereoselectivity tests, are indicative of a stepwise pathway in C-N bond formation. Investigation into the nature of the active aminating species has led to the isolation of a novel aminating agent formulated as (ArSO2N)(x)I(y) (x = 1, y = 2; or x = 3, y = 4).

Rhenium-catalyzed deoxydehydration of glycols by sulfite.

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

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones.

We introduced a regioselective and atom-economical procedure for the synthesis of 3-substituted indoles by annulation of nitrosoarenes with ethynyl ketones. The reactions were carried out achieving indoles without any catalyst and with excellent regioselectivity. No traces of 2-aroylindole products were detected. Working with 4-nitronitrosobenzene as starting material, the 3-aroyl-N-hydroxy-5-nitroindole products precipitated from the reaction mixtures and were isolated by filtration without any further purification technique. Differently from the corresponding N-hydroxy-3-aryl indoles that, spontaneously in solution, give dehydrodimerization products, the N-hydroxy-3-aroyl indoles are stable and no dimerization compounds were observed.

On the mechanism of nitrosoarene-alkyne cycloaddition.

The thermal reaction between nitrosoarenes and alkynes produces N-hydroxyindoles as the major products. The mechanism of these novel reactions has been probed using a combination of experimental and computational methods. The reaction of nitrosobenzene (NB) with an excess of phenyl acetylene (PA) is determined to be first order in each reactant in benzene at 75 degrees C. The reaction rates have been determined for reactions between phenyl acetylene with a set of p-substituted nitrosoarenes, 4-X-C(6)H(4)NO, and of 4-O(2)N-C(6)H(4)NO with a set of p-substituted arylalkynes, 4-Y-C(6)H(4)C[triple bond]CH. The former reactions are accelerated by electron-withdrawing X groups (rho = +0.4), while the latter are faster with electron-donating Y groups (rho = -0.9). The kinetic isotope effect for the reaction of C(6)H(5)NO/C(6)D(5)NO with PhC[triple bond]CH is found to be 1.1 (+/-0.1) while that between PhC[triple bond]CH/PhC[triple bond]CD with PhNO is also 1.1 (+/-0.1). The reaction between nitrosobenzene and the radical clock probe cyclopropylacetylene affords 3-cyclopropyl indole in low yield. In addition to 3-carbomethoxy-N-hydroxyindole, the reaction between PA and o-carbomethoxy-nitrosobenzene also affords a tricyclic indole derivative, 3, likely derived from trapping of an intermediate indoline nitrone with PA and subsequent rearrangement. Computational studies of the reaction mechanism were carried out with density functional theory at the (U)B3LYP/6-31+G(d) level. The lowest energy pathway of the reaction of PhNO with alkynes was found to be stepwise; the N-C bond between nitrosoarene and acetylene is formed first, the resulting vinyl diradical undergoes cis-trans isomerization, and then the C-C bond forms. Conjugating substituents Z on the alkyne, Z-C[triple bond]CH, lower the calculated (and observed) activation barrier, Z = -H (19 kcal/mol), -Ph (15.8 kcal/mol), and -C(O)H (13 kcal/mol). The regioselectivity of the reaction, with formation of the 3-substituted indole, was reproduced by the calculations of PhNO + PhC[triple bond]CH; the rate-limiting step for formation of the 2-substituted indole is higher in energy by 11.6 kcal/mol. The effects of -NO(2), -CN, -Cl, -Br, -Me, and -OMe substituents were computed for the reactions of p-X-C(6)H(4)NO with PhC[triple bond]CH and of PhNO and/or p-NO(2)-C(6)H(4)NO with p-Y-C(6)H(4)C[triple bond]CH. The activation energies for the set of p-X-C(6)H(4)NO vary by 4.3 kcal/mol and follow the trend found experimentally, with electron-withdrawing X groups accelerating the reactions. The range of barriers for the p-Y-C(6)H(4)C[triple bond]CH reactions is smaller, about 1.5 and 1.8 kcal/mol in the cases of PhNO and p-NO(2)-PhNO, respectively. In agreement with the experiments, electron-donating Y groups on the alkyne accelerate the reactions with p-NO(2)-C(6)H(4)NO, while both ED and EW groups are predicted to facilitate the reaction. The calculated kinetic isotope effect for the reaction of C(6)H(5)NO/C(6)D(5)NO with PhC[triple bond]CH is negligible (as found experimentally) while that for PhC[triple bond]CH/PhC[triple bond]CD with PhNO (0.7) differs somewhat from the experiment (1.1). Taken together the experimental and computational results point to the operation of a stepwise diradical cycloaddition, with rate-limiting N-C bond formation and rapid C-C connection to form a bicyclic cyclohexadienyl-N-oxyl diradical, followed by fast tautomerization to the N-hydroxyindole product.

In vitro reactive oxygen species production by histatins and copper(I,II).

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.

Hydrous zinc halide-catalyzed aminosulfonation of hydrocarbons.

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