Safe Execution of a Large-Scale Ozonolysis:  Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carboxaldehyde and Its Utility in a Reductive Amination

Abstract

Several routes to bisulfite adduct 2 were explored, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHSO 3 to effect reduction and bisulfite formation in a single pot. The safety and calorimetry of this ozonolysis reaction was studied, and the safe scale-up to 3 kg of olefin is described. The utility of bisulfite adduct 2 as an aldehyde surrogate in a reductive amination reaction is also described.

A New Paradigm in Oxidative Cleavage Reaction: The Use of Continuous Reactors To Enable Safe Scale Up of Ozonolysis

“…During the ozone addition reaction in the RC1 (Figure 5), the observed total heat evolution was -381 kJ/mol with adiabatic temperature rise of 187°C in excellent agreement with previous studies that measured adiabatic temperature (186°C and 170°C) (18,20) for the similar molecules β-pinene 1 and allylic 7 alcohol ozonolysis addition, respectively. Furthermore, the results are also in agreement with the heat predicted by computational modeling carried out by the author (-445 kJ/mol).…”

“…The results are in excellent agreement with calculated energy for the reaction of ethylene with ozone where the heat of reaction to form the secondary ozonide was -427 kJ/mol (25). The latter results from computational chemistry are also in good agreement with the experimental calorimetric results from Pfizer (Scheme 3) where the measured heat of reaction of ozone addition was 535 kJ/mol (18). These predictions are also in good agreement with the calorimetric measurement of β-pinene ozonolysis (Scheme 1) where the heat of ozone addition is 499 kJ/mol (20).…”

“…Then a sample of the ozonized reaction mixture was examined by DSC. An exothermic event occurred at 42°C in good agreement with β-pinene (20) and allylic alcohol (18) ozonides which have onset temperatures of 49°C and 45°C, respectively.…”

“…Finally, during the course of ozonolysis, a stream of oxygen and ozone is fed to the reactor and thus combustion potential poses a serious risk, especially while working with flammable solvents. A common practice to mitigate this hazard is to dilute the oxygen concentration in the reactor headspace by adding a sufficient amount of inert gas to drive the concentration of oxygen below the minimum oxygen concentration (MOC) to prevent the formation of a flammable atmosphere (18). …”

“…Indeed, a safety evaluation (20) of the β-pinene ozonide reaction mixture (Scheme 1) showed a severe and fast self-decomposition with an onset temperature 48°C. In another safety evaluation of the ozonolysis of a terminal alkene substrate similar to β-pinene 1, the DSC of an ozonized reaction mixture of tertiary allylic alcohol 7 to form hydroperoxide 8 by Ragan and co-workers (Scheme 3) showed an exothermic event at 45°C (18). In order to ensure safety well below this relatively low temperature dictates that ozonolysis be conducted at a cryogenic temperature of~-60°C in order to enforce a 100°C safety margin (a common safety practice in the industry) between operating temperature and the onset temperature of a severe exothermic event.…”