As illustrated in Figure (a), the initial nitrosation reaction between alcohol and nitrous acid to form nitrite ester presents significant challenges in process optimization and reactor design, primarily due to the ambiguous reaction mechanism and formation pathways of gaseous byproducts. In this study, we elucidate a novel nitrosation mechanism mediated by dinitrogen trioxide (N2O3), a highly reactive intermediate generated in situ through the dimerization of nitrous acid, which subsequently undergoes nitrosation with alcohols. This N2O3-mediated mechanism demonstrates a substantially reduced energy barrier compared to conventional acid-catalyzed and nitrosyl cation pathways.
To investigate this complex gas-liquid-liquid reaction system, we developed an advanced microfluidic platform that enables precise characterization of gas holdup dynamics along the reactor length. Our findings reveal that the reaction kinetics and selectivity are predominantly governed by the interfacial mass transfer of N2O3 across the aqueous-organic and gaseous-organic phase boundaries. Leveraging these insights, we implemented a tubular microreactor system to enhance the isopropanol nitrosation process for isopropyl nitrite production, capitalizing on the system's superior interfacial mass transfer characteristics and gas-free operation. Remarkably, this continuous flow system achieves a 95% product yield with a residence time of merely 10 seconds, representing a significant improvement over conventional batch processes that require tens of minutes for reactant addition.
In the subsequent reduction reaction where nitrite ester reacts with hydrazine hydrate to yield sodium azide (NaN3), conventional approaches typically employ nitrites derived from small-chain aliphatic alcohols to enhance aqueous phase solubility. However, these methods are constrained by prolonged reaction durations spanning several hours, coupled with significant safety concerns and volatile organic compound (VOC) emissions due to the inherent volatility of alkyl nitrites. To address these limitations, we introduced benzyl nitrite, synthesized from benzyl alcohol, as an innovative alternative. The aromatic benzyl group confers a stabilizing conjugation effect that facilitates transition state stabilization and substantially lowers the activation energy barrier, thereby dramatically reducing the reaction time from several hours to merely 20 minutes.
Furthermore, the implementation of benzyl nitrite offers multiple advantages: its elevated boiling point effectively mitigates VOC emissions and associated safety risks, while the limited aqueous solubility of benzyl alcohol enables efficient recycling without the need for energy-intensive distillation processes. Through comprehensive characterization of gaseous byproducts and reactive azo intermediates, we have elucidated a detailed reaction mechanism (Figure (b)). Our findings demonstrate that side reactions can be effectively suppressed by optimizing the hydrazine-to-nitrite concentration ratio in the organic phase.
This study not only presents a robust and operationally simple methodology to overcome existing challenges in azide synthesis but also provides fundamental insights into the aminolysis mechanism of nitrite esters, advancing our understanding of this critical chemical transformation.