Adelina M. Voutchkova

Palladium-catalyzed decarboxylative coupling of aromatic acids with aryl halides or unactivated arenes using microwave heating

Microwave heating greatly accelerates Pd-catalyzed decarboxylative coupling of aromatic acids and aryl iodides, and allows the coupling of benzoic acids with unactivated arenes.

Toward a Comprehensive Molecular Design Framework for Reduced Hazard

The history of chemistry has been one of understanding the properties and transformations of matter. Perhaps the most important aspect of this understanding is the properties that have an impact on human and environmental health and the transformations that take place in our bodies and in the biosphere. Only through a mastery of this understanding will chemistry be able to genuinely design molecules that perform their intended function (e.g., therapeutic or industrial) and are safer for humans and the environment. Knowledge about the nature of toxic effects comes from the field of toxicology. Once primarily a descriptive science, relying to a large extent on whole-animal toxicology studies, the field has developed an extensive understanding of many of the mechanisms by which chemicals can exert toxicity.1 Application of this knowledge has made it possible to develop correlations, equations, and models that relate chemical structure and properties to biological responses. This has led to an increasingly sophisticated in silico predictive aspect of toxicology2 and provides the basis for current work being pursued in the development of a comprehensive design strategy for safer chemicals. While there has been significant work in the field of chemistry in designing for various functions ranging from medicines to materials, there has been a lack of a comprehensive framework for designing molecules to have a reduced impact on human health and the environment. A framework for the design of safer chemicals was originally published by the noted medicinal chemist E. J. Ariens in 1980, titled appropriately Domestication of Chemistry by Design of Safer Chemicals3 and later revised in 1985.4 An ACS Symposium Series book published in 1996 on Designing Safer Chemicals5 puts forth a framework that draws on a variety of sources and contains chapters that illustrate how the framework can be applied. In light of the tremendous advances in toxicology and molecular science in the 25 and 14 years since these prior perspectives were written, this review seeks to incorporate the new knowledge and tools available to today’s chemist. In the final measure, the ultimate success of deeply studying a problem is not simply to admire the problem but rather to solve it. This review provides an overview of the excellent research that has been done in the evolution of the * To whom correspondence should be addressed. E-mail: Paul.Anastas@ yale.edu. † Yale University. ‡ Science Strategies LLC. Chem. Rev. 2010, 110, 5845–5882 5845

Towards rational molecular design: derivation of property guidelines for reduced acute aquatic toxicity

One of the most elusive yet significant goals of green chemistry is the routine design of commercially useful chemicals with reduced toxicological hazard. The main objective of this study was to derive property guidelines for the design of chemicals with reduced acute aquatic toxicity to multiple species. The properties explored included chemical solubilities, size, shape and molecular orbital energies. Physicochemical properties were predicted using Schrodingers QikProp, while frontier orbital energies (HOMO, LUMO and HOMO–LUMO gap) were determined based on AM1 and DFT calculations using Gaussian03. Experimental toxicity data included acute toxicity thresholds (LC50) for the fathead minnow (Pimephales promelas; 570 compounds), the Japanese medaka (Oryzias latipes; 285 compounds), a cladoceran (Daphnia magna; 363 compounds) and green algae (Pseudokirchneriella subcapitata, 300 compounds). Mechanistically-driven qualitative and quantitative analyses between the in-silico predicted molecular properties and in vivo toxicity data were explored in order to propose property limits associated with higher probabilities of acutely safe chemicals. The analysis indicates that 70–80% of the compounds that have low or no acute aquatic toxicity concern by EPA guidelines to the four species have a defined range of values for octanol-water partition coefficient (logPo/w) and ΔE (LUMO–HOMO gap). Compounds with logPo/w values less than 2 and ΔE (AM1) greater than 9 eV are significantly more likely to have low acute aquatic toxicity compared to compounds that do not meet these criteria. These results are mechanistically rationalized. Our work proposes design guidelines that can be used to significantly increase the probability that a chemical will have low acute toxicity to the four species studied, and potentially other aquatic species.

Atom economic synthesis of amides via transition metal catalyzed rearrangement of oxaziridines

A mild synthetic route to amides involves imine oxidation to an oxaziridine followed by a transition-metal catalyzed rearrangement to the amide. This route shows potential for a greener pathway to amides. DFT studies showed a possible rearrangement pathway in the case of the Rh catalyst.

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.