Ozonolysis applications in drug synthesis.

Ozonolysis chemistry has been used extensively in academic, research, and industrial environments. A review on ozonolysis by Bailey appeared in Chemical Re Viewsnearly 50 years ago, and a significant amount of research has since been published and reviewed. 1-3 Synthetic chemists have many alternative chemical transformations at their disposal, but the ease with which an ozonolysis reaction can be conducted renders it a clean and effective choice for oxidative cleavage of double bonds. The primary concern with ozonolysis chemistry rests on safety issues because the lowmolecular-weight ozonides and peroxides produced are unstable intermediates. These products could form an explosive hazard upon concentration during the workup if methods to detect and safely quench the peroxides are not employed. Scaling an ozonolysis reaction to an industrial level requires a careful assessment of the energetics of the reaction at hand. The mechanism of an ozonolysis reaction has been thoroughly studied, and the Criegee mechanism has been accepted as shown below. 4-6 Generally, ozone is generated from air or oxygen and passed through a cold solution (from 0 to -78 °C) of solvent and substrate until a blue color is observed, indicating destruction of the double bond. Typical solvents include methanol, ethyl acetate, dichloromethane, ethanol, water, and acetic acid. After sparging with nitrogen to dissipate the free ozone, a reductive or oxidative workup can afford a wide variety of products including alcohols, aldehydes, ketones, acids, and amines. Kula has reported conditions that allow for safely performing ozonolysis reactions up to a 500 g scale. 7 Because the high-energy ozonide (also called normal or secondary ozonide or 1,2,4-trioxolane) is formed in nonparticipating solvents, the use of protic solvents such as alcohols or acids is preferred. The resulting alkoxy and acyloxy hydroperoxides are reduced more efficiently and pose less of a safety risk during scale-up. The temperature at which an ozonolysis reaction is typically carried out is -78 °C; however, Kula recommends temperatures between 0 and-20 °C or higher. His reasoning is based on the idea that at higher temperatures the primary ozonide (1,2,3trioxolane or molozonide) will be more likely to smoothly decompose into the corresponding hydroperoxides and disfavor collapse into the 1,2,4-trioxolane. Running the reaction at higher temperatures in participating solvents will promote the formation of hydroperoxide intermediates that can quickly react with the solvent and provide a safer reaction.