catalysts Article Direct Amide Synthesis over Composite Magnetic Catalysts in a Continuous Flow Reactor Yawen Liu 1 and Evgeny V. Rebrov 1,2, *   Citation: Liu, Y.; Rebrov, E.V. Direct Amide Synthesis over Composite Magnetic Catalysts in a Continuous Flow Reactor. Catalysts 2021, 11, 146. https://doi.org/10.3390/catal11020146 Received: 31 December 2020 Accepted: 16 January 2021 Published: 20 January 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 School of Engineering, University of Warwick, Coventry CV4 7AL, UK; liuyw.cn@hotmail.com 2 Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, 5600MB Eindhoven, The Netherlands * Correspondence: E.Rebrov@warwick.ac.uk Abstract: Composite magnetic catalysts containing different amounts of sulfated titania (33–50 wt %) have been prepared by means of high energy ball-milling between TiO 2 and NiFe 2 O 4 . The catalysts have been characterized with N 2 adsorption/desorption isotherms, XRD, temperature programmed oxidation (TPO) and vibrating sample magnetometer (VSM). The catalytic activity was measured in the reaction of aniline and 4-phenylbutyric acid in the continuous mode under conventional and inductive heating. The effect of catalyst loading in the reactor on reaction and deactivation has been studied, indicating the catalyst containing 50 wt % titania gave the highest reaction rate and least deactivation. The operation in a flow reactor under inductive heating increased the amide yield by 25% as compared to conventional heating. The initial reaction rate decreased by 30% after a period of 15 h on stream. The catalyst activity was fully restored after a treatment with an air flow at 400 ◦ C. Keywords: sulfated titania; composite magnetic catalysts; inductive heating; direct amide synthesis 1. Introduction Amide synthesis is considered as one of the most important reactions in the pharma- ceutical industry. At the moment, the reaction is mainly performed utilizing a coupling agent [1], resulting in low atom-economy [2]. Direct amide synthesis over heterogeneous catalysts, using an acid and an amine provides a green and atom efficient way to form the amide bond. In addition, the catalyst can be easily recycled. Many heterogeneous catalysts have been studied to catalyze the direct amide reaction, such as sulfated tungstate [3], CeO 2 [4], SiO 2 [5] and Co based catalysts [6]. Sulfated TiO 2 demonstrated a very high reaction rates and the yield of amides up to 90% at 115 ◦ C in 12 h [7]. A nanostructured sulfated titania catalyst with uniform size was synthesized by the hydrothermal sol–gel method [8]. The amide yields over 75% were reported at a temperature of 110 ◦ C. In our previous work [9], composite magnetic catalyst containing sulfated TiO 2 also showed a better catalytic performance in the direct amidation of 4-phenylbutyric acid and aniline than those containing pure TiO 2 . The reaction is carried out in a batch mode [6,7,10,11]. A continuous process has an advantage of easy scale up compared to a batch process. Comerford et al. [12] developed a continuous reactor packed with mesoporous structured silicas (SBA-15) or activated chromatographic K60 silica catalyst to synthesize N-(phenyl)-phenylacetamide at 150 ◦ C. They used 12 mmol of each reagent (carboxylic acid and aniline) dissolved in toluene at an initial concentration of 0.6 M. The production rate was 0.349 g h −1 under optimized reaction conditions. However, in the case of K60 silica, the loading of the catalyst required was very high to obtain a noticeable amount of product. Britton et al. [13] developed a vortex fluidic device (VFD) for amide synthesis at 60 ◦ C. The reaction between cyclohexylamine and butyrylchloride performed in the VFD provided the target amide in 94% yield in 80 s while the same reaction in the batch mode resulted in 9% yield for the same reaction time. The VFD operated at 6950 rpm enhancing the mixing of reactants on the microscale. While the Catalysts 2021, 11, 146. https://doi.org/10.3390/catal11020146 https://www.mdpi.com/journal/catalysts