One of the first chemical procedures that an organic chemist learns to perform is the Grignard reaction. I can remember my first time making this tricky compound; it was almost seventeen years ago, and since then, I’ve prepared hundreds of organometallic intermediates. Grignard reagents are very useful, as they can make a carbon-carbon bond. Since carbon skeleton formation is the primary focus of organic chemist, magnesium-based Grignard reagents (and their cousins, the organozincs) have a central place in a synthetic toolbox. However, they can be difficult to prepare. The very property that makes these organometallics so reactive (the electron density on the nucleophilic carbon) makes them sensitive to trace amounts of moisture and even oxygen.
Normally, the only way that these materials can be utilized is to prepare them immediately before use. The solvent (usually a highly flammable ether) has to be rigorously dried so that there are no traces of water left. Normal breathing air is unsuitable, and so the solution has to be “degassed” and then blanketed with a dry, inert gas such as argon. Finally, the solution must be kept at a low temperature (depending on the solvent) so that the metal-carbon complex doesn’t react with the surrounding solvent before it’s coupling partner is even added. All of these drawbacks to the Grignard / organozinc approach can be overcame with the appropriate care and expertise, but there is still danger. Chemical journals were recently abuzz with news of a graduate student assistant who died as a result of an organometallic solution that was spilt, resulting in a fire. The material was so reactive that it heated up and sparked upon hitting moisture in the lab air, which then ignited the organic solvent inside the flask.
It was a horrifying accident, and it wasn’t the first time that I’ve heard of this type of incident. A close friend of mine in graduate school suffered 3rd degree burns after a similar fire. Organometallics are so useful and central to organic synthesis that their use can’t easily be avoided, but there is an obvious need for reagents which maintain their high reactivity while gaining stability. Pyrophoric reagents (those that spontaneously ignite when in contact with moisture) are not only dangerous, they’re difficult to handle. They can be tricky to weigh, which is a problem as most of the time, an excess of the reagent will lead to byproducts. While a glovebox can be used to ensure an inert atmosphere for the weighing, it adds about 20 minutes to each procedure and there’s a temptation to avoid their use in order to hurry things along. What is really needed is an air stable, temperature stable powder that can be dissolved in a wide range of solvents and which maintains the high reactivity.
I was very happy, therefore, to read a recent publication in the German journal Angewandte Chemie that outlines an advance in this area. Researchers from München disclose that by reacting chlorinated (or brominated) starting materials with magnesium in the presence of zinc pivalates, an organozinc complex is prepared. Evaporation of the tetrahydrofuran solvent leads to a powder that is completely stable when stored under argon, and stable under room air for long enough periods to be weighed accurately. These new zinc complexes possess similar reactivity to normal nucleophilic organometallics, in that they can react with electrophiles and also undergo cross-coupling with chlorinated aromatics. The yields of the reactions are high and they don’t require extended reaction times at high temperatures. As someone who has to use these compounds myself and as someone who’s had numerous friends injured in lab fires resulting from organometallic preparation, I’m extremely glad for this published report. Organic chemists have enough hazards in their field as it is. Having access to useful reagents that don’t spontaneously combust is a welcome change.
The source of this article can be found at:
Bernhardt, S., et al. “Preparation of solid salt stabilized functionalized organozinc compounds…”. Angewandte Chemie Int. Ed. Engl. 2011, 50, 9205-9209.