Continuous-Flow Synthesis of 4-(2-Nitrophenyl) Morpholine Coiled Tube Microreactor

Abstract

The continuous-flow synthesis of 4-(2-nitrophenyl) morpholine was investigated using a coiled tube microreactor to evaluate the influence of reaction temperature and residence time on product yield and purity. Solutions of 2-fluoronitrobenzene and morpholine in the presence of potassium carbonate were continuously pumped through a 100 mL flow reactor equipped with a back-pressure regulator. Reaction temperatures between 140 and 170 °C and residence times from 20 to 50 min were systematically examined. Increasing the reaction temperature from 140 to 160 °C significantly improved the isolated yield from 69.9% to 94.6%, while a further increase to 170 °C resulted in a slight decline in yield to 93.2%. Similarly, increasing the residence time from 20 to 50 min enhanced the product yield from 72.2% to 95.5%, with only marginal improvement beyond 40 min. The optimized reaction conditions were established at 160 °C with a residence time of 40–50 min, affording the desired product in up to 95.5% isolated yield and 99% purity. Structural confirmation was achieved using 1H NMR, 13C NMR, and mass spectrometry. The study demonstrates that continuous-flow processing provides excellent temperature control, enhanced mass transfer, high product quality, and an efficient, scalable alternative to conventional batch synthesis for aromatic nucleophilic substitution reactions.