Design of Inherently Safer Complex Reactive Processes: Application on the N-Oxidation of Alkylpyridines

Alkylpyridine N-oxides are important intermediates in the pharmaceutical industry. The N-oxides are produced via the homogeneously catalyzed N-oxidation of the respective alkylpyridines using hydrogen peroxide as the oxidizing agent and phosphotungstic acid as the catalyst. The N-oxidation is accompanied by the undesired, condition-dependent decomposition of hydrogen peroxide. A runaway of this reaction may result in a rapid generation of oxygen and temperature rise in the alkylpyridine flammable environment, with the additional potential to overpressurize the reaction vessel and/or trigger secondary decompositions of the product. The decomposition of hydrogen peroxide is exacerbated during the N-oxidation of higher order alkylpyridines due to the mass transfer resistance caused by the formation of an organic phase and an aqueous phase. The water-soluble catalyst promotes severe decomposition of hydrogen peroxide, jeopardizing the safety of the process, and reducing its efficiency.

This research focused on the development of a more efficient and inherently safer process for the N-oxidation of alkylpyridines. Isothermal calorimetry, incorporating a factorial design of experiments (DOE), was used to study operating conditions that minimize the decomposition of hydrogen peroxide. Adiabatic calorimetry was used to study the thermal stability of alkylpyridines and their N-oxides. The compounds studied in this work included 3-picoline, 3,5-lutidine, 2,6-lutidine and 2,4,6-collidine, and their corresponding N-oxides. In addition, this research evaluated the use of in-situ FTIR spectroscopy to monitor this reaction system. Thermal stability analyses showed that the alkylpyridines studied are stable up to 400 ?C, while the corresponding N-oxides decompose significantly above 230 ?C. The factorial DOE revealed that the conversion of 3-picoline is most influenced by the interaction between the factors catalyst mass and dosing rate. Conversions of 3-picoline and 3,5-lutidine obtained were as high as 98% and 95%, respectively, using only a stoichiometric amount of hydrogen peroxide. Significant decomposition was observed during the N-oxidation of 2,6-lutidine and 2,4,6-collidine. Knowledge acquired on the N-oxidation of alkylpyridines indicates that reaction efficiency, selectivity and safety can be greatly improved a) by increasing the operating temperature and using a system working under pressure, and b) in the case of the higher order alkylpyridines, by avoiding operating conditions where a heterogeneous mixture is formed.

This work demonstrates the complexity and the multiple studies required for the design of inherently safer reactive processes and it can serve as a model for similar studies on different complex reactions and in the development of inherently safer reactor design.

This research focused on the development of a more efficient and inherently safer process for the N-oxidation of alkylpyridines. Isothermal calorimetry, incorporating a factorial design of experiments (DOE), was used to study operating conditions that minimize the decomposition of hydrogen peroxide. Adiabatic calorimetry was used to study the thermal stability of alkylpyridines and their N-oxides. The compounds studied in this work included 3-picoline, 3,5-lutidine, 2,6-lutidine and 2,4,6-collidine, and their corresponding N-oxides. In addition, this research evaluated the use of in-situ FTIR spectroscopy to monitor this reaction system.

Thermal stability analyses showed that the alkylpyridines studied are stable up to 400 ?C, while the corresponding N-oxides decompose significantly above 230 ?C. The factorial DOE revealed that the conversion of 3-picoline is most influenced by the interaction between the factors catalyst mass and dosing rate. Conversions of 3-picoline and 3,5-lutidine obtained were as high as 98% and 95%, respectively, using only a stoichiometric amount of hydrogen peroxide. Significant decomposition was observed during the N-oxidation of 2,6-lutidine and 2,4,6-collidine. Knowledge acquired on the N-oxidation of alkylpyridines indicates that reaction efficiency, selectivity and safety can be greatly improved a) by increasing the operating temperature and using a system working under pressure, and b) in the case of the higher order alkylpyridines, by avoiding operating conditions where a heterogeneous mixture is formed.

This work demonstrates the complexity and the multiple studies required for the design of inherently safer reactive processes and it can serve as a model for similar studies on different complex reactions and in the development of inherently safer reactor design.