Palladium-catalyzed cross-coupling reactions have transformed the exploration of chemical space in the search for materials, medicines, chemical probes, and other functional molecules. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addition complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of benchtop storage under ambient conditions. We demonstrated the utility of OACs in a variety of experiments including automated nanomole-scale couplings between an OAC derived from rivaroxaban and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.

An undergraduate organic chemistry laboratory experiment has been developed that features a discovery-based microscale Fischer esterification utilizing a microwave reactor. Students individually synthesize a unique ester from known sets of alcohols and carboxylic acids. Each student identifies the best reaction conditions given their particular reagents (either excess alcohol or excess carboxylic acid) as well as the ideal workup procedure for their reaction. Products are analyzed using 1 H NMR spectroscopy, IR spectroscopy, and scent. This modern adaptation of the classic Fischer esterification provides the opportunity for discussion of important chemistry concepts, including acid catalysis, Le Chatelier's principle, and green chemistry.

The utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been limited by the instability of their precursor complexes. Herein, we report the use of Cámpora’s palladacycle as a new, more stable precursor to Pd OACs. Using this palladacycle, a series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared.

Two different protocols were developed and optimized to address the need for (1) high sensitivity or (2) convenient utilization in the determination of the absolute configuration of secondary alcohols. The first protocol uses the competing enantioselective conversion (CEC) method to determine configuration on nanomole scale. Reactions were conducted with 145 nmol of the substrate using a 50 μL microsyringe as the reaction vessel, and the absolute configuration was assigned via qualitative determination of the fast reaction by thin-layer chromatography. This protocol resulted in a 50-fold reduction in material required from previous CEC method studies. The approach was evaluated with benzylic and β-aryl systems. The second protocol was optimized to address the needs of practicing medicinal chemists. A one-use CEC kit was developed, where the fast reaction was identified by (1)H NMR spectroscopy and thin-layer chromatography. The CEC reaction conditions developed for the microsyringe protocol and the one-use kit both displayed data consistent with pseudo-first-order kinetics in substrate. Therefore, the lower limit of sensitivity for the substrate is limited only by the ability to effectively detect the reaction conversions between alcohol substrate and ester product.

An undergraduate organic chemistry experiment has been developed that features asymmetric synthesis of an enantioenriched secondary alcohol, followed by determination of its absolute configuration using the competing enantioselective conversion (CEC) method. Students are given a ketone and an unknown enantiomer of CBS (Corey–Bakshi–Shibata) catalyst. This reaction forms an enantioenriched secondary alcohol of unknown absolute configuration. Students then determine the absolute configuration via the CEC method. The CEC method is a modern application of the Horeau method that runs parallel reactions using both enantiomers of a chiral acyl-transfer catalyst, homobenzotetramisole (HBTM). Reactions are quenched concurrently, and reaction rates are compared using thin-layer chromatography (TLC) and/or 1H nuclear magnetic resonance (NMR) spectroscopy to determine the fast and the slow reactions. By comparing the faster reaction to a previously determined mnemonic, the absolute configuration of the alcohol can be determined. From this information, students can then determine which enantiomer of CBS catalyst they used to form the enantioenriched alcohol. Both parts of this experiment were successfully completed in one 5 h lab section. This experiment provides an opportunity for discussion of important chemistry concepts including asymmetric synthesis, asymmetric catalysis, kinetic resolution, mechanism, transition state theory, and inert-atmosphere techniques.