Acceptorless Amine Dehydrogenation and Transamination Using Pd-Doped Hydrotalcites

The acceptorless dehydrogenation of acyclic secondary amines is a highly desirable but still elusive catalytic process. Here we report the synthesis, characterization, and activity of Pd-doped hydrotalcites (Pd-HTs) for acceptorless dehydrogenation of both primary and secondary amines (cyclic and acyclic). These multifunctional catalysts comprise Brønsted basic and Lewis acidic surface sites that stabilize Pd in 0, 2 + , and 4 + oxidation states. Pd speciation and corresponding catalytic performance is a strong function of metal loading. High activity is observed for the dehydrogenation of secondary aliphatic amines to imines, and N-heterocycles, such as indoline, 1,2,3,4-tetrahydroquinoline, and piperidine, to aromatic compounds. Oxidative transamination of primary amines is achieved using low Pd loading (0.5 mol %), without the need for oxidants. The relative yields of secondary imines afforded are consistent with trends for calculated free energy of reaction, while yields for transamination products correspond to the electrophilicity of primary imine intermediates. Reversible amine dehydrogenation and imine hydrogenation determine the relative selectivity for secondary imine/amine products. Poisoning tests evidence that Pd-HTs operate heterogeneously, with negligible metal leaching. Catalysts retain over 90% of activity over six reuse cycles, but do suffer some selectivity loss, attributed to changes of Pd phases

Electronic Effects of Support Doping on Hydrotalcite-Supported Iridium N-Heterocyclic Carbene Complexes

The electronic effects of supports on immobilized organometallic complexes impact their activity and lifetime, yet remain poorly understood. Here we describe a systematic study of the support effects experienced by an organometallic complex immobilized on doped hydrotalcite-like materials. To that end, we describe the synthesis and characterization of the first organometallic species immobilized on a palette of doped hydrotalcites via sulfonate linkers. The organometallic species consists of iridium N-heterocyclic carbene (NHC) carbonyl complex ([Na][Ir-(NHC-Ph-SO3)2(CO)2]), a highly active molecular catalyst for transfer hydrogenation of glycerol. The hydrotalcite supports are composed of Al, Mg, and a compatible transition-metal dopant (Fe, Cu, Ni, Zn). The materials were characterized extensively by STEM, XPS, TGA, PXRD, FT-IR, N2 desorption, ICP-AES, TPD, and microcalorimetry to probe the morphology and electronic properties of the support and elucidate structure–property relationships

A Quantum-Mechanical Approach to Predicting Carcinogenic Potency of N-nitrosamine Impurities in Pharmaceuticals

N-nitrosamine contaminants in medicinal products are of concern due to their high carcinogenic potency; however, not all nitrosamines are created equal, and some are relatively benign chemicals. Understanding the structure-activity relationships (SARs) that drive hazard in one molecule versus another is key to both protecting human health and alleviating costly and sometimes inaccurate animal testing. Here, we report on an extension of the CADRE (Computer-Aided Discovery and REdesign) platform, used broadly by the pharmaceutical and personal care industries to assess environmental and human health endpoints, to predict carcinogenic potency of N-nitrosamines. The model distinguishes compounds in three potency categories with 78% accuracy in external testing, which surpasses reproducibility of rodent cancer bioassays and constraints imposed by limited (quality) data. Robustness of predictions for more complex pharmaceutical nitrosamines is maximized by capturing key SARs using quantum mechanics., i.e., by hinging the model on the underlying chemistry vs. chemicals in the training set. To this end, the present approach can be leveraged in a quantitative hazard assessment and to offer qualitative guidance using electronic-structure comparison between well-studied analogs and unknown contaminants

CADRE-SS, an <i>in Silico</i> Tool for Predicting Skin Sensitization Potential Based on Modeling of Molecular Interactions

Using computer models to accurately predict toxicity outcomes is considered to be a major challenge. However, state-of-the-art computational chemistry techniques can now be incorporated in predictive models, supported by advances in mechanistic toxicology and the exponential growth of computing resources witnessed over the past decade. The CADRE (Computer-Aided Discovery and REdesign) platform relies on quantum-mechanical modeling of molecular interactions that represent key biochemical triggers in toxicity pathways. Here, we present an external validation exercise for CADRE-SS, a variant developed to predict the skin sensitization potential of commercial chemicals. CADRE-SS is a hybrid model that evaluates skin permeability using Monte Carlo simulations, assigns reactive centers in a molecule and possible biotransformations via expert rules, and determines reactivity with skin proteins via quantum-mechanical modeling. The results were promising with an overall very good concordance of 93% between experimental and predicted values. Comparison to performance metrics yielded by other tools available for this endpoint suggests that CADRE-SS offers distinct advantages for first-round screenings of chemicals and could be used as an <i>in silico</i> alternative to animal tests where permissible by legislative programs

Decarbonylative Olefination of Aldehydes to Alkenes

New atom-economical alternatives to Wittig chemistry are needed construct olefins from carbonyl complexes, but none have been developed to-date. Here we report an atom-economical olefination of carbonyls via aldol-decarbonylative coupling of aldehydes using robust and recyclable supported Pd catalysts, producing only CO and H2O as waste. The reaction accommodates homocoupling of aldehydes with an a a-methylene groups, as well as heterocoupling. Computations provide insight into the selectivity of the reaction. The tandem aldol-decarbonylation reaction opens the door to exploration of new carbonyl reactivity to construct olefins

Investigation of Solvent Effects on the Rate and Stereoselectivity of the Henry Reaction

A combined computational and experimental kinetic study on the Henry reaction is reported. The effects of solvation on the transition structures and the rates of reaction between nitromethane and formaldehyde, and between nitropropane and benzaldehyde are elucidated with QM/MM calculations

Acceptorless amine dehydrogenation and transamination using Pd-doped layered double hydroxides

The synthesis, characterization, and activity of Pd-doped layered double hydroxides (Pd-LDHs) for for acceptorless amine dehydrogenation is reported. These multifunctional catalysts comprise Brønsted basic and Lewis acidic surface sites that stabilize Pd species in 0, 2+, and 4+ oxidation states. Pd speciation and corresponding cataytic performance is a strong function of metal loading. Excellent activity is observed for the oxidative transamination of primary amines and acceptorless dehydrogenation of secondary amines to secondary imines using a low Pd loading (0.5 mol%), without the need for oxidants. N-heterocycles, such as indoline, 1,2,3,4-tetrahydroquinoline, and piperidine, are dehydrogenated to the corresponding aromatics with high yields. The relative yields of secondary imines are proportional to the calculated free energy of reaction, while yields for oxidative amination correlate with the electrophilicity of primary imine intermediates. Reversible amine dehydrogenation and imine hydrogenation determine the relative imine:amine selectivity. Poisoning tests evidence that Pd-LDHs operate heterogeneously, with negligible metal leaching; catalysts can be regenerated by acid dissolution and re-precipitation. <br /

Direct Conversion of Alcohols to Long-Chain Hydrocarbons via Tandem Dehydrogenation-Decarbonylative Olefination

Design of active and selective supported catalysts is critical for developing new tandem processes for upgrading biomass-derived alcohols. Hydrogen-free upgrading alcohols to liquid hydrocarbons is desirable for producing drop-in fuel substitutes, but direct and atom-economical processes are yet to be reported. Here we report a novel alcohol upgrading and deoxygenation cascade that meets these criteria. This hydrogen-free cascade is catalyzed by multifunctional Pd catalysts, whose supports feature a range of acid-base properties: primarily basic MgO, acidic Al2O3 and Mg-Al hydrotalcite (HT) with a combination of Lewis acidic and basic sites. The impact of support selection on selectivity offers insights into the design principles for next-generation catalysts for this process and related transformations.</p

A Free Energy Approach to the Prediction of Olefin and Epoxide Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic effects of strong alkylating agents, such as epoxides, have been attributed to their ability to covalently bind DNA in vivo. Most olefins are readily oxidized to reactive epoxides by CytP450. In an effort to develop predictive models for olefin and epoxide mutagenicity, the ring openings of 15 halogen-, alkyl-, alkenyl-, and aryl-substituted epoxides were modeled by quantum-mechanical transition state calculations using MP2/6-31+G­(d,p) in the gas phase and in aqueous solution. Free energies of activation (Δ<i>G</i>^⧧) and free energies of reaction (Δ<i>G</i>_rxn) were computed for each epoxide in the series. This study finds that an aqueous solution Δ<i>G</i>_rxn threshold value of approximately −14.7 kcal/mol can be used to discern mutagenic/carcinogenic epoxides (Δ<i>G</i>_rxn < −14.7 kcal/mol) from nonmutagens/noncarcinogens (Δ<i>G</i>_rxn > −14.7 kcal/mol). The computed reaction thermodynamics are appropriate regardless of ring-opening mechanism in vivo and are thus proposed as an effective in silico screen and design guideline for decreasing potential mutagenicity and carcinogenicity of olefins and their respective epoxides