Insights on Bimetallic Micellar Nanocatalysis for Buchwald- Hartwig Aminations Tharique N. Ansari, †,‡ Armand Taussat, †,‡ Adam H. Clark, ⊥ Maarten Nachtegaal, ⊥ Scott Plummer, ǁ Fab- rice Gallou, # Sachin Handa* † † Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States ⊥ Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen, Switzerland ǁ Novartis Institutes for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, United States # Novartis Pharma AG, Basel, 4056, Switzerland ABSTRACT: A nanocatalyst for micellar Buchwald-Hartwig aminations is developed, thoroughly characterized, and applied on a variety of substrates. The catalyst is stable under ambient conditions for at least six months. The catalyst retained its activity after several cycles, and its structure remained intact as confirmed by NMR spectroscopy. Association of Pd nanoparticles with Cu by a phosphine ligand is revealed by 31 P NMR spectroscopy and their linkage with the activated carbon surface is revealed by XAS anal- ysis. Control NMR experiments revealed the binding of the ligand with both the Cu and Pd, and all phosphine molecules are under the same environment. In addition to NMR and XAS analysis, the catalyst is characterized by SEM, HRTEM, XPS, and TGA. Reac- tions are highly reproducible at variable scales. Environmentally benign, proline-based amphiphile PS-750-M is critical for catalytic activity, which is achieved under mild conditions in water as the reaction medium. The inherent sustainability of these conditions coupled with a low E factor achievable through robust recycling of catalyst and reaction medium demonstrates the significant utility of this technology. KEYWORDS. micellar catalysis, chemistry in water, cross-couplings, heterogeneous catalysis, E factor Introduction. Several Nobel Prizes have been awarded to rec- ognize the remarkable achievements in organometallic cataly- sis. 1-5 However, nano-organometallic catalysis in water is still at its infancy. 6-9 The indispensability and impact of catalysis in organic synthesis 10-12 and material chemistry 12,13 is monumen- tal. Therefore, sustainability in the processes mediated by or- ganometallic catalysts is always highly desirable. 14-16 Related developments in atom-economic reaction pathways, catalysts derived from earth-abundant metals, 17 switchable solvents, 18,19 quasi-homogeneous catalysis, 20,21 and flow chemistry 22-24 have accordingly been adopted by the chemical community to ad- dress future challenges in chemistry. Aiming to replace highly toxic organic solvents, Kobayashi, 25 Lipshutz, 26-29 Uozomi, 30 Krause, 31 and our group 32-36 have very recently developed tech- nologies that use water as a sustainable and recyclable reaction medium. This aqueous chemistry harnesses the hydrophobic ef- fect and is conducted either “on water” 37,38 or inside nanomi- celles. 39 Excellent work following the same approach for C–H activation has very recently been reported by Ackermann and coworkers. 40 Furthermore, leveraging the shielding effect of en- gineered micelles has enabled control over reaction pathway se- lectivity, which is not possible in organic solvents. 34 To further enhance the efficiency of valued reactions, nanopar- ticle (NP) catalysis recently became a topic of interest for the pharmaceutical industry. 41 NP-mediated micellar Suzuki- Miyaura 7,8 and Sonogashira 42 couplings have been very well documented. The NP catalysts in these cases are more efficient and robust than their corresponding organometallic molecular complexes. 39 Despite the high catalytic efficiency, better recy- clability, broader scope, and potential benefit of the hydropho- bic effect in these reactions, the NP-mediated micellar Buch- wald-Hartwig amination reaction 11,12 remains challenging. This challenge may be due to the association of the amine coupling partner with the NP surface, which interferes in the desired cat- alytic cycle and shuts down catalysis. Micelle-enabled amina- tions using a molecular complex as the catalyst have been re- ported. 43-45 These protocols suffer from poor catalyst recyclabil- ity and share a common requirement for (allyl)palladium (Pd). Recently, our group documented the role of allyl species in the catalytic cycle when a molecular organometallic complex was used as a catalyst for convenient sp 2 –sp 3 couplings of nitroal- kanes with aryl bromides. 32 The role of the allyl group was as an ancillary ligand to tune the electronics for achieving the ac- tive catalytic species. 46,47 However, translating the (allyl)Pd Figure 1. Synergy between Cu-Pd-C-micelle in water for sustain- able C–N couplings. This document is the accepted manuscript version of the following article: Ansari, T. N., Taussat, A., Clark, A. H., Nachtegaal, M., Plummer, S., Gallou, F., & Handa, S. (2019). Insights on bimetallic micellar nanocatalysis for Buchwald–Hartwig aminations. ACS Catalysis, 9(11), 10389-10397. https://doi.org/10.1021/acscatal.9b02622