A Facile Optimization of Diazotization and Phase Transfer Catalyzed Azo-Coupling Reactions in Microreactors

Abstract

Herein, we illustrate how microreactor technology can be used as a tool for reaction screening and optimization, in addition to improving the reaction chemistry. We report the in-situ generation of azo compounds by reactive quenching of diazonium intermediates in microreactors. This involves an electrophilic aromatic substitution reaction, namely, an azo-coupling reaction performed in continuous-flow systems in the presence of a phase transfer catalyst with great emphasis on compounds that do not easily couple. Capitalizing on the benefits of a large surface area and the short molecular diffusion distances observed in microreactors, in-situ phase transfer catalyzed azo-coupling reaction of diphenylamine to p-nitroaniline was investigated. A rapid and easy optimization protocol was established which yielded a 99%, 22%, and 33% conversion of diphenylamine, carbazole, and triphenylamine, respectively, in approximately 2.4 min.

Continuous-Flow Synthesis of Pigment Red 146 in a Microreactor System

“…The continuous-flow synthesis of azo dyes in a microreactor system was also studied. The synthesis of the azo dye was the same as that of azo pigments, and as reported in the literature, excellent results, such as a high product yield and selectivity and a short reaction time were obtained by using microreactor technology. − However, to date, there are few reports about the continuous-flow synthesis of C.I. PR 146 in a microreactor system.…”

The continuous flow synthesis of azos

“…In 2016, Akwi and Watts reported the use of continuous flow, microreactors, and phase transfer catalysis (PTC) in the generation azo compounds, Fig. 10 [ 33 ]. Here they utilized a phase transfer catalyst in a liquid– liquid Taylor droplet flow reaction system for the in-situ reactive quench of diazonium salts.…”

Revisiting aromatic diazotization and aryl diazonium salts in continuous flow: highlighted research during 2001–2021

“…To increase the conversion of the coupling reaction, Watts et al predicted and analysed the effect of coupling conditions on reaction conversion and the effect of various parameters on the synthesis of Sudan II azo dye (5) in glass Little Things Factory-MS (LTF-MS) microreactors using the STATISCA 12 -Statsoft program (Scheme 4). 92,93 Of the three parameters of the coupling reaction, temperature, pH, and the flow rate of the coupling reagent, it was found that the pH has the most significant effect on the coupling reaction and that the temperature and flow rate have little effect. This finding is similar to most reports on the effect of temperature and flow rate in the single-step synthesis of azo compounds in continuous flow systems; the effect of temperature is negligible, and the effect of mass transfer is the most significant.…”

“…93 Furthermore, the same group successfully explored surfactants, such as sodium dioctyl sulfosuccinate, as phase transfer catalysts to promote azo coupling reactions in continuous flow systems. 92,94 The addition of a phase transfer catalyst is conducive to the coupling of waterinsoluble coupling agents (e.g., phenol and aniline), which can promote the reduction of the surface tension between the liquid and the liquid phase and stabilize the formation of the liquid-liquid interface. The closer the added amount is to the critical micelle concentration, the more stable the effect of the phase transfer catalyst (Fig.…”