Training Graduate Students to Handle Air-Sensitive Compounds

Air-sensitive compounds are essential, e.g., in many organic syntheses. Training students—in particular, new graduate students in organic chemistry labs—in the safe handling of air-sensitive compounds is, thus important. For example, the use of sensitive organometallic reagents to form new C–C bonds is common. Existing teaching approaches often focus on undergraduate students and less sensitive C–C cross-coupling reactions. Reactions such as a more challenging Negishi cross-coupling reaction can be useful model reactions for the training of graduate students.

Michael J. James, Ian J. S. Fairlamb, University of York, UK, and colleagues have developed a teaching experiment to train students in the use of several techniques that are important for handling air-sensitive organometallic reagents, i.e., using Schlenk lines, high-vacuum pumps, liquid nitrogen traps, cannula transfers, and syringe techniques. The team used a specific Negishi cross-coupling reaction as a teaching tool for courses aimed at new Ph.D. or Masters-level students. In the reaction, 4-bromo-6-methyl-2-pyrone is coupled to a 2-pyridyl zinc nucleophile that is generated in situ from 2-bromopyridine, giving a heterobiaryl derivative.

The experiment takes about six hours. It involves the preparation of 2-pyridyllithium via a reaction of 2-bromopyridine with pyrophoric n-butyllithium, followed by transmetalation with dried ZnCl₂ and the reaction with the coupling partner under palladium catalysis. The students learn how to set up and operate a high-vacuum Schlenk line with a liquid nitrogen-cooled trap and work under a nitrogen atmosphere, add reagents using a syringe, and perform a cannula transfer. They also learn about the relevant safety guidelines and the sensitivities of cross-coupling reactions to oxygen and moisture. The crude reaction mixtures are analyzed using NMR spectroscopy or gas chromatography–mass spectrometry (GC-MS) to provide instant feedback to the students.

The experiment is preceded by seminars that introduce the topics of pyrophoric reagents and Schlenk lines and followed by an experimental report. According to the researchers, about 150 graduate students have successfully completed this experiment, with only one instance in which the desired product was not obtained.