Kinetic study of the microflow synthesis of 4-hydroxyquinoline in supercritical ethanol

Highlights

• Supercritical ethanol was used as a green solvent for the thermal cyclization.

• The reaction mechanism and the kinetics were studied with a microreactor.

• The reaction completed in 27 s at 350 °C giving 4-hydroxyquinoline in 97% GC yield.

• The overall kinetics was described by a pseudo-first-order rate constant.

• The corresponding activation energy was determined to be 204 ± 2 kJ mol⁻¹.

Abstract

Supercritical ethanol was used as a solvent for the thermal cyclization of ethyl 3-(phenylimino)-butanoate to 2-methyl-4-hydroxyquinoline; the reaction is of great importance in pharmaceutical and color industries but conventionally needs specific solvents with high boiling points. The mechanism and the kinetics were studied with a microreactor by measuring the yield of the product at various temperatures up to 350 °C. The reaction in ethanol completed in 27 s at 350 °C and 10.0 MPa giving the quinoline in 97% GC yield, although it required higher temperature than that in acetonitrile. The results were explained by the mechanism consisting of the two steps: (i) a reversible elimination of ethanol from the reactant yielding ketene intermediate followed by (ii) an irreversible ring closure into the quinoline. On the basis of the reaction mechanism, the rate constant and the activation energy were determined from the yield-time profiles measured at temperatures of 300–350 °C and a constant ethanol density of 0.11 g cm⁻³. The kinetic analysis revealed that the overall reaction is controlled by a pseudo-first-order rate constant. The activation energy was determined to be 204 ± 2 kJ mol⁻¹, which was close to that calculated by density functional theory (187 kJ mol⁻¹).

Introduction

4-Hydroxyquinolines are important building blocks for the productions of pharmaceuticals and color chemicals, e.g., mefloquine antimalarials and quinacridone pigments [1], [2], [3]. The quinoline ring structure is usually synthesized by the Conrad-Limpach reaction illustrated in Fig. 1 [4]. A condensation of aniline 1 with ethyl acetoacetate 2 provides ethyl 3-(phenylimino)butanoate 3 [5] and the thermal cyclization of 3 gives 4-hydroxyquinoline 4 with an elimination of an equimolar amount of ethanol [6]. However, the thermal cyclization needs very high temperature above 250 °C and thus conventionally requires (i) specific solvents with high boiling points such as diphenyl ether and (ii) long heat-up time to reach the reaction temperature, often leading to undesired side reactions [7]. In the present study, we use supercritical ethanol (T_C = 241 °C, P_C = 6.1 MPa, and ρ_C = 0.276 g cm⁻³) as an alternative solvent for the thermal cyclization and elucidate the reaction mechanism and kinetics using a microreactor.

Microreactor designed for the high-temperature and high-pressure solvent is a powerful tool in controlling the thermal reactions [8], [9], [10], [11], [12], [13]. High-pressure condition allows us to use common solvents above their normal boiling points, thereby extending the choices of solvent and temperature; e.g., sub- and supercritical water [14], [15], [16], [17] and alcohols [18], [19], [20] have been used as environmentally benign alternative solvents for many organic reactions. Microtube reactor enables a rapid heating of the reactant solution to the high reaction temperature and a precise control of the reaction time by changing the reactor length. Recently, Lengyel et al. applied a microreactor to the Conrad-Limpach thermal cyclization and performed the reaction in supercritical tetrahydrofuran (THF; T_C = 267 °C and P_C = 5.1 MPa) [21]. They reported that the reaction in THF completed within 45 s at 360–370 °C and 13.0 MPa giving the target quinoline in 92% isolated yield.

Here we try the thermal cyclization in supercritical ethanol. The use of ethanol as the solvent is apparently inappropriate because the reaction involves an elimination of ethanol from the reactant. The elimination of ethanol may be hindered by the surrounding abundant ethanol. In fact, several papers suggest that ethanol should be removed from the reactor, although it is difficult for the closed-vessel reactions, in order to avoid the equilibrium shift toward the reactant [22], [23], [24]. We show, however, that the reaction can provide a complete conversion within 27 s even in supercritical ethanol at 350 °C and an almost quantitative yield of the target quinoline. The surprising result is explained by the reaction mechanism assuming that the elimination of ethanol is reversible but is followed by an irreversible ring closure. We further demonstrate that the reaction in supercritical ethanol offers a clean and simple reaction system suited not only for easy solvent recycling but also for detailed kinetic analysis and reaction control.

In this paper, the thermal cyclization in ethanol is studied over a wide range of temperature from the subcritical to the supercritical conditions and is compared with that in acetonitrile to clarify the reaction mechanism. The kinetic analysis is also carried out on the basis of the reaction mechanism. The yield-time profile is systematically investigated at various temperatures of 300–350 °C and a fixed ethanol density. We show that the overall reaction kinetics is controlled simply by a pseudo-first-order rate constant with an activation energy. The activation energy experimentally determined is compared with that calculated by density functional theory to support the mechanistic and kinetic analyses.