(154c) Rapid Analysis of Chemoselective Hydrogenation of Multifunctional Nitroarenes with Automated Micropacked Beds

Nitroarenes represent a class of biologically active compounds that are often intermediates to active pharmaceutical ingredients. The direct chemoselective hydrogenation of the nitro group to the corresponding primary amine with hydrogen gas poses an attractive chemistry that circumvents the use of expensive, hazardous and difficult to separate sacrificial reducing agents (LiAlH4, NaBH4, etc.). The reactions can be catalyzed by precious metal catalysts immobilized onto highly porous supports to achieve high catalytic turnover.

Heterogeneous catalysts have been widely utilized in reductions on an industrial scale owing to their high catalytic turnover, ease of recycle, and overall durability. On such scales, packed bed reactor operation becomes complex, however decades of empirical correlations and first principle modeling have been able to characterized the multiphase dynamics within various characteristic flow regimes (trickle, pulsed, bubble flow, etc.). While it is desired to use small particles ( < 100 um) for moderate and large pharmaceutically relevant molecules (MW > 200 amu) to reduce intraparticle diffusion limitations and promote multiphase mixing, incorporation of catalysts at such scales introduces prohibitively high pressure drops in large columns and is widely uncharacterized.

Microreactors offer a strong appeal for the analysis of multiphase heterogeneous reaction systems due to the inherent ability to minimize heat and mass transfer limitations while maintaining a small pressure drop over a short bed. However, the dynamics of the system is greatly complicated by the multiphase flow regimes and several potential rate limiting phenomena (gas/liquid mass transfer, liquid diffusion, intraparticle diffusion, intrinsic kinetics). This work first develops a micropacked bed reactor platform with in line FTIR, pressure and flow measurements, and automated temperature, gas and liquid flow controls. Transport timescales are measured in situ using a surrogate reaction (alphamethyl styrene hydrogenation). Micropacked bed reactors are used with precious metal supported catalysts to assess catalyst performance; reaction rates are extracted under systematic flow conditions across the parameter space to assess reaction kinetics and optimal reactor operating conditions.