Iron Nanocatalysis DOI: 10.1002/anie.201205792 In Situ Generated Iron Oxide Nanocrystals as Efficient and Selective Catalysts for the Reduction of Nitroarenes using a Continuous Flow Method** David Cantillo, Mostafa Baghbanzadeh, and C. Oliver Kappe* Functionalized anilines are industrially important intermedi- ates in the preparation of pharmaceuticals, agrochemicals, dyes, and pigments. The most commonly used method for the synthesis of anilines is the reduction of aromatic nitro compounds. [1] While traditional non-catalytic reduction pro- cesses (that is using Fe/HCl) generate large amounts of undesirable waste; catalytic hydrogenation using heteroge- neous transition-metal catalysts is a well-established tech- nique and often the method of choice for the reduction of nitroarenes to anilines. [2, 3] However, selectivity problems in the presence of other common functional groups can occur, [4] often requiring the use of carefully selected and expensive precious metal catalysts (for example, Pd, Pt, or Ru). [3] Therefore, significant efforts have been made to develop more efficient and sustainable methods to achieve the selective reduction of nitroarenes to anilines. Apart from the use of hydrogen, several other stoichiometric reducing agents such as ammonium salts, [5] silanes, [6] boranes, [7] sodium borohydride, [8] formic acid, [9] and hydrazine, [10] have been used in combination with a number of different metal catalysts. [5–10] Hydrazine, specifically the less hazardous hy- drazine hydrate (N 2 H 4 ·H 2 O), is a particularly good reagent because it generates only N 2 as a side product and is comparatively safe to handle. In the past few years, interest in the use of iron-based catalysts in organic synthesis has increased dramatically. [11] Iron is an abundant, eco-friendly, relatively nontoxic, and inexpensive element, and thus the development of catalysts based on this metal is highly desirable. Several Fe-catalyzed procedures for the hydrazine-mediated reduction of nitro- arenes have been reported. [10a–g] In the general context of nanocatalysis, magnetic nanomaterials, in particular iron oxide nanoparticles, have become very attractive as inex- pensive nanocatalysts that can be easily separated and recovered after the reaction. [12, 13] Nanosized materials feature unique properties as catalysts: the high surface-to-volume ratio of nanoparticles compared to a bulk material generally results in an extremely high catalytic activity and often improved selectivity. [12] Herein, we present a novel method in nanocatalysis applied to the selective reduction of nitroarenes to anilines in a continuous-flow format. In a solution containing the nitroarene, Fe 3 O 4 nanocrystals were generated in situ from an inexpensive Fe precursor using hydrazine hydrate as the reducing agent at elevated temperatures. Upon formation, the highly reactive nanocrystals then selectively catalyze the reduction of the nitro group with hydrazine with unparalleled efficiency. Importantly, the originally colloidal nanocatalyst remains in solution during the time required for nitro group reduction. The Fe 3 O 4 nanocrystals subsequently start to aggregate forming a precipitate that is easily removable using a simple magnet. This unique process combines the benefits of homogeneous and heterogeneous nanocatalysts, and is particularly valuable for continuous manufacturing applications because the initial homogeneous reaction mix- ture can be easily processed in a safe and scalable way using continuous-flow technology. First, we evaluated the generation of iron oxide (that is, magnetite, Fe 3 O 4 ) nanoparticles by treatment of various Fe precursors with hydrazine hydrate, essentially following known procedures. [14] All experiments were performed using small-scale microwave batch heating at elevated temper- atures, thus rapidly generating the desired nanoparticles, ensuring short reaction times for the nitroarene reductions, and a high throughput for use in the continuous-flow method. A typical reaction mixture (see Table 1) consisted of a solution of tris(acetylacenato)iron(III) (Fe(acac) 3 ), nitrobenzene, and hydrazine in methanol at 150 8C in a sealed vessel with microwave irradiation, the formation of solid magnetic particles during the irradiation process could be readily observed after a few minutes with the aid of a built-in camera (see Supporting Information, Figure S1). The magnetic par- ticles could be unambiguously identified as single-phase cubic Fe 3 O 4 by their X-ray powder diffraction (XRD) patterns (Figure S2), while high-resolution transmission electron mi- croscopy (HRTEM) micrographs obtained from a sample of stabilized colloidal Fe 3 O 4 nanocrystals revealed the size of the crystals to be 6 Æ 2 nm (Figure S3). The efficiency of the Fe 3 O 4 nanocrystals generated in situ for the reduction of nitroarenes was first studied using nitrobenzene as model substrate (Figures S4, S5). Experi- [*] Dr. D. Cantillo, Dr. M. Baghbanzadeh, Prof.Dr. C. O. Kappe Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens-University Graz Heinrichstrasse 28, 8010 Graz (Austria) E-mail: oliver.kappe@uni-graz.at Homepage: http://www.maos.net [**] This work was supported by a grant from the Christian Doppler Research Society (CDG). D.C. thanks the Ministerio de Ciencia e Innovación of Spain for a scholarship. We also thank W. Gçssler, W. Haas, and S. Mitsche for ICP-MS, TEM, and XRD analyses, respectively, and B. Gutmann for assistance with the continuous- flow experimentation. Supporting information for this article (experimental details) is available on the WWW under http://dx.doi.org/10.1002/anie. 201205792. A ngewandte Chemi e 1 Angew. Chem. Int. Ed. 2012, 51,1–5  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Ü Ü