Project Summary Deuterium labeled medicines are being used to develop safer alternatives to existing therapeutics and improve the safety of current drug candidates. Despite the tremendous promise that novel deuterated small molecules have in the development of new medicines, methods to incorporate deuterium into molecular scaffolds are primitive. While the synthetic organic chemistry community has grown accustom to highly selective transition metal-catalyzed reactions for the creation of new C–C, C–O and C–N bonds, deuterium installation should also be possible with full stereocontrol and minimal over- and under-deuteration impurities. Not only is highly selective deuteration rare, but spectroscopic techniques to support advances in this field are inadequate. We are launching a holistic research program to not only develop highly selective reactions for deuterium incorporation but pioneer the expansion of analytical techniques required to support the development and use of these reactions among the broader scientific community. Through our established collaboration with leaders in the spectroscopy field, we have started to develop analytical techniques that provide the foundation for accurate characterization and identification of deuterated small molecules. Our preliminary studies indicate that deuterium can be installed precisely into small molecules. In many cases, isotopomer and isotopologue impurities are so minimal that they are nearly undetectable. Our research is now positioned for expansion into broader classes of organic molecules. We will develop new Cu-catalyzed transformations for the selective deuteration and hydrodeuteration of alkenes and alkynes. These transformations will precisely insert deuterium in a small molecule and be compatible with compounds that contain functionality commonly found in small molecule drugs. We anticipate that in the next 5 years, our synthetic strategies and analytical methods will address significant portions of the outlined considerations. This will drastically expand the development of novel deuterated therapeutics to address many of the safety and tolerability problems plaguing modern medicine. Beyond deuterium incorporation, we are proposing to develop new reactions for the regioselective hydrofunctionalization of internal aryl alkynes. Powerful methods for regioselective Cu-catalyzed alkyne hydrofunctionalization exist but are mostly limited to terminal alkynes and symmetrical internal alkynes. Consequently, there exists a major void in the synthesis of a-substituted styrenes. To access these molecules from alkynes, we are proposing to develop a-selective Cu-catalyzed internal aryl alkyne hydrofunctionalization reactions. The research will benefit from deuteration studies performed in our group to develop new Cu-catalyzed alkyne hydrodeuteration reactions. The unprecedented regioselectivities obtained in our ongoing investigations will serve as the starting point for developing the proposed Cu-c...