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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/greenchem Page 1 of 51 Green Chemistry Recyclable organocatalysts based on hybrid silicas M. Ferré, a R. Pleixats, a* M. Wong Chi Man, b and X. Cattoën c* a Department of Chemistry and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universitat Autònoma de Barcelona, 08193- Cerdanyola del Vallès, Barcelona, Spain. Fax: 34 93 5812477; e-mail: [email protected]. b Institut Charles Gerhardt Montpellier, UMR5253 CNRS-UM2-ENSCM-UM1, 8, rue de l’école normale 34296 Montpellier, France. c Inst. Néel, CNRS and Univ Grenoble-Alpes, 38042 Grenoble, France. email: [email protected]. Abstract The quest for efficient and “greener” catalysts for chemical processes has set a precedent for the development of reliable methods for their synthesis. Those methods based on heterogeneous platforms present an excellent opportunity as they allow recyclability and easy work-up and handling. Hybrid organosilica-based materials are of interest particularly as heterogeneous platforms which can operate with a Manuscript synergy between the well-defined properties of the organocatalytic fragments and the structural and mechanical stability as well as the presumed chemical inertness of the silica matrices. This review focuses on the recent advances on the incorporation methods to strongly bound organocatalysts into organosilica scaffolds and their promising applications in supported organocatalysis. Accepted Chemistry Green 1 Green Chemistry Page 2 of 51 Table of contents 1. Introduction .......................................................................................................................................................... 3 2. Design of the organosilica material ...................................................................................................................... 3 2.1. Pure silica materials ...................................................................................................................................... 3 2.2. Organic functionalization ............................................................................................................................... 4 2.2.1. SYNTHESIS OF FUNCTIONAL ORGANOSILANES BEARING ORGANOCATALYSTS ........................................... 5 2.2.2. FUNCTIONALIZATION DURING THE SOL -GEL PROCESS ................................................................................ 5 2.2.3. POST -FUNCTIONALIZATION ......................................................................................................................... 6 2.3. Towards multi-functional materials .............................................................................................................. 6 3. Main classes of catalysts and main reactions............................................................................................................ 7 3.1. Achiral catalytic organosilicas ........................................................................................................................... 7 3.1.1. ACIDIC ORGANOSILICAS .......................................................................................................................... 7 3.1.2. BASIC ORGANOSILICAS . ........................................................................................................................ 10 3.1.3. IONIC ORGANOSILICAS .............................................................................................................................. 14 Manuscript 3.1.4. BIFUNCTIONAL ORGANOSILICAS .......................................................................................................... 16 3.2. Supported chiral amines for enamine activation.............................................................................................. 19 3.2.1. SUPPORTED PROLINES ............................................................................................................................... 19 3.2.2. SUPPORTED PROLINE DERIVATIVES .......................................................................................................... 22 3.3. Supported Cinchona derivatives for the formation of chiral ion-pairs ............................................................ 27 3.4. Supported chiral imidazolidinones for iminium activation ...................................................................... 30 Accepted 4. Main results in asymmetric catalysis ...................................................................................................................... 32 4.1. Direct asymmetric aldol reaction ..................................................................................................................... 32 4.2. Asymmetric Michael reaction and conjugate additions ................................................................................... 36 4.3. Asymmetric multicomponent reactions ..................................................................................................... 38 4.4. Asymmetric Diels-Alder cycloadditions .................................................................................................... 39 4.5. Other asymmetric reactions with organosilicas derived from proline, Cinchona alkaloids or MacMillan imidazolidinones .............................................................................................................................. 40 Chemistry 4.6. Miscellaneous ................................................................................................................................................ 41 4.6.1. ACID AND BASE -CATALYZED DIELS -ALDER CYCLOADDITIONS ...................................................... 41 4.6.2. NUCLEOPHILIC CROSS -CONJUGATE ADDITION ................................................................................... 42 Green 4.6.3. SILICA -SUPPORTED ORGANOCATALYSTS FOR OXIDATION REACTIONS ........................................... 42 4.6.4. SILICA -SUPPORTED THIAZOLIUM SALTS .............................................................................................. 43 5. Conclusions ............................................................................................................................................................ 44 Bio sketches ........................................................................................................................................................ 46 Acknowledgements .................................................................................................................................................... 46 References .................................................................................................................................................................. 46 2 Page 3 of 51 Green Chemistry 1. Introduction Organocatalysis involves the acceleration of a chemical reaction by a substoichiometric amount of a metal-free organic compound. Although this type of catalysis has for long been overlooked, most probably due to the prominence of organometallic catalysis, the recent past decades have witnessed a tremendous growth of this field. 1-3 Moreover, the availability of natural organic molecules in optically active form has enabled the extremely fast development of asymmetric organocatalysis for the synthesis of highly valuable chiral building blocks.4-12 Organocatalysis represents an eco-friendly and cost-effective methodology for fine chemical synthesis, especially when metal traces are of real concern, particularly for pharmaceutical industry. Ideal organocatalysts must be robust, readily available through easy synthesis and are commonly small molecules that can be rapidly degraded in the environment without significant effluent generation. Still then, the usual work-ups (e.g. column chromatography) remain a major drawback with tedious separation of the catalyst from the reaction media. Besides, the reactions often require high catalyst loadings and the reuse of the organocatalyst becomes of economic interest. A straightforward step to ensure low environmental impact and to facilitate an easy recovery and recycling is to tether organocatalysts on solid polymeric supports, in particular hybrid silicas, to benefit from the usual advantages of heterogeneous catalysis. 13-18 In order to achieve more sustainable catalytic processes by improving the yield, productivity and energy efficiency, recent contributions have also been made on immobilized organocatalysts in continuous-flow systems. 19, 20 The formation of