Evaluation of Alternatives for Safer and More Efficient Reactions: A study of the N-oxidation of Alkylpyridines

The catalytic N-oxidation of alkylpyridines, a reaction which uses hydrogen peroxide as the oxidizing agent and the water soluble phosphotungstic acid as the catalyst, is a reaction employed in the pharmaceutical industry. The safety concerns of this process revolve around the decomposition of hydrogen peroxide and the liquid-liquid phase separation of the reacting mixture. The decomposition of hydrogen peroxide is an undesired reaction parallel to the desired N-oxidation and is responsible for: 1) a high potential for runaway due to the condition sensitivity of the peroxide group, 2) a potential over-pressurization of the reaction vessel during a runaway due to the production of oxygen, and 3) the enrichment with oxygen of the flammable alkylpyridine environment. The presence of an organic phase and an aqueous phase occurs in a wide range of conditions and results in: 1) a dramatic reduction in the reaction selectivity, and consequently in the efficiency, due to the additional mass transfer constrains imposed by the phase separation, and 2) the safety of the process being seriously compromised because most of the catalyst remains in the aqueous phase, excessively promoting the decomposition of hydrogen peroxide over the N-oxidation. With these concerns in mind, this research aimed to determine conditions for an inherently safer and more efficient N-oxidation reaction and focused on three key targets: i) the possibility of reducing the extend of the decomposition of hydrogen peroxide, thus leading to an inherently safer process, ii) the study of phase equilibrium so as to enable the identification of conditions that increase the efficiency of the N-oxidation and reduces the hazards, and iii) the evaluation of safety parameters that will allow for the control of a potential runaway reaction. Two alkylpyridines were considered: 2-methylpyridine which represents the case of a homogeneous reacting mixture and 2,6-dimethylpyridine to study the two-liquid phase separation effects. The methodology employed calorimetric studies to assess the runaway behavior and to determine the conditions that favor the N-oxidation, and for the N-oxidation of 2,6-dimethylpyridine, thermodynamic studies were incorporated to evaluate the conditions for phase separation