1. Aspects of sustainability in Synthetic Organic Chemistry Exemplos de sustentabilidade em Química Orgânica Sintética Artur M. S. Silva UI Química Orgânica, Produtos Naturais e Agroalimentares (QOPNA) Departamento de Química Universidade de Aveiro artur.silva@ua.pt

2. “Green chemistry, also known as sustainable chemistry, is the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances. Green chemistry applies across the life cycle of a chemical product, including its design, manufacture, and use”. Sustainable Chemistry according to EPA Provide a number of benefits: reduced waste, eliminating costly end-of-the-pipe treatments safer products reduced use of energy and resources improved competitiveness of chemical manufacturers and their customers In a very simply way, one can define Green Chemistry as “preventing pollution at the molecular level.” It follows, that if the pollution is not created in the first place, there is no need for clean-up and remediation technologies.

3. Twelve Principles of Green Chemistry 1.Prevention It is better to prevent waste than to treat or clean up waste after it has been created 2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product 3. Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment 4. Designing Safer Chemicals Chemical products should be designed to effect their desired function while minimizing their toxicity 5. Safer Solvents and Auxiliaries The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used 6. Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure

4. Twelve Principles of Green Chemistry (…) 7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable 8. Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection / deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste 9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment 11. Real-time analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances 12. Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires

5. Synthetic organic chemistry In the past chemists optimized yields rather atom economy Chemical reactions would be designed to maximize incorporation of all materials used in the process in the final product to prevent waste production (atom efficient process) Atom economy is one form to evaluate how green is a chemical process, but are other (energy consumption, pollutants created, etc…) B. M Trost., Angew. Chem. Int. Ed. Engl, 1995, 34, 259 R. Sheldon, Chemtech., 1994, 24, 38

6. Reactions can be done By adsorption and subsequent catalysis on the solid surface of zeolites, clays, silica, alumina and similar substances In solventless and solid-solid conditions Using alternative sources of energy for heating (energy loss)

7. Synthetic organic chemistry Wittig reaction (olefination) Example of an important organic reaction that has poor atom economy The unavoidable by-product Ph 3 P=O, HBr and the base  waste box This do not means that the Wittig reaction is a bad reaction! It is one of the most valuable and powerfull tools to selectively create double bonds from carbonyl groups In large scale we must think about phosphine oxide recycling or to develop alternatives (e.g. alkene methathesis)

8. We have developed an efficient route that gave a diastereomeric mixture of (Z) and (E)-3-styrylchromones Major product (Z) isomer Minor product (E) isomer 3 J H  -H  ~ 12 Hz 3 J H  -H  ~ 16 Hz Silva et al., New J. Chem., 2003, 27, 1592

9. But was a better alternative to the first approach, consisting on the treatment of (E,E)-2’-hydroxycinnamylidene- acetophenones with Tl(NO 3 ) 3 Silva et al., Liebigs Ann./Recueil, 1997, 2065

10. We continue to develop efficient diastereoselective routes for (E)-3-styrylchromones KOC(CH 3 ) 3, dry Py, reflux, 12 to 40 h 48 to 95% KOC(CH 3 ) 3, dry Py, 800W, 180 o C, 1h 54 to 94% Silva et al., Synlett, 2004, 2717 Silva et al., Monatsh. Chem., 2008, 139, 1307 Silva et al., Eur. J. Org. Chem., 2008, 1937 Work also with phenyl malonic acid

11. R = H, Cl, OCH 2 CH 3 1,2,4-trichlorobenzene, reflux, N 2 atm., 36 h < 20 % Diels-Alder reaction = cycloaddition reaction (100% atom economy)

12. We also study the reactivity of (Z)-3-styrylchromones as dienes in Diels-Alder reaction, under microwave irradiation. R = H, Cl, OCH 2 CH 3 > 70 % 4 Equiv of N-methylmaleimide 270 W; 160 o C; 30 min. Silva et al., Synlett, 2003, 1415 Silva et al., Eur. J. Org. Chem., 2005, 2973 “endo” adduct Without solvent and using MW

13. Diels-Alder reactions of (Z)-3-styrylchromones with N-phenylmaleimide, under the similar conditions R = H, Cl, OCH 2 CH 3 “endo” adduct > 50 % ~ 20 % 3 Equiv of N-methylmaleimide 270 W; 200 o C; 30 min. Silva et al., Synlett, 2003, 1415 Silva et al., Eur. J. Org. Chem., 2005, 2973 H H H “exo” adduct Thermodynamic control Without solvent and using MW

14. Hypothesis MW Our results indicate that the reaction of (E)-3-styrylchromones selectively afforded the “exo” adduct Thermodynamic control Without solvent and using MW

15. Synthesis of indazoles 68-95% 54-60% Silva et al., Synlett, 2004, 2717 Silva et al., Eur. J. Org. Chem., 2009, 4468 MW Without solvent and using MW

16. Michael addition Silva et al., Synlett, 2010, 1123 Silva et al., Eur. J. Org. Chem., 2010, 3449 Without solvent Entry4R1R1 R2R2 R3R3 Yield 5 (%)ee (%) 14aHHH5a (97)93 24bOHHH5b (33)90 24cNH 2 HH5c (19)87 44dHMeH5d (83)90 54eHOMeH5e (81)93 64fHClH5f (92)94 74gHHNO25g (66)88 84hHHOMe5h (91)>99 Crystallisation ee > 99% Single crystal X-ray Crystallisation ee > 99%

17. Michael addition Entrycatalystyield (%) a ee(%) 11b8592 (S) 21c6491 (R) 31d7476 (R) Crystallisation ee > 99% Single crystal X-ray Without solvent

18. Development of catalytic cascade conversions - one of the important future sustainable organic syntheses (drastically reduce operating time and costs as well as consumption of auxiliary chemicals and use of energy) Tradicionally organic synthesis, involving a recovery step each conversion step Organic synthesis in the cells organisms, involving coupled conversions without intermediate recovery Potential power of cascade conversions to overcome thermodinamic hurdles in multistep syntheses

19. Diastereoselective Synthesis of Pentasubstituted Cyclohexanes Domino Multicomponent Michael-Michael-Aldol Reactions under Phase- Transfer Catalysis Silva et al., Synlett 2010, 115.

20. EntrySolventYield (%)dr 1CH 3 CN63>99 2EtOH52>99 3MeOH33>99 4CHCl 3 23>99 5Toluene26>99 6CH 2 Cl 2 36>99 7THF24>99 Reaction conditions: 0.2 M sol. of 1a 1.1 eq. DBU 0.6 eq. CH 3 NO 2 r.t., 7d Diastereoselective Synthesis of Pentasubstituted Cyclohexanes

21. Entry molar equiv t (h)yield (%)dr Cs 2 CO 3 TBAB 10.500.12059 >99 20.850.2321 >99 30.850.22062 >99 40.850.27454 >99 50.850.32060 >99 60.850.348 >99 71.00.22058 >99 81.00.32079 >99 91.00.32053>99 Reaction conditions: 0.2 M solution of 1a CH 3 NO 2 (0.5 eq.) CH 3 CN (0.43 mL) TBAB, Cs 2 CO 3 TBAB: Tetra-n-butylammonium bromide Reaction conditions: CH 3 NO 2 (0.7 eq.) Diastereoselective Synthesis of Pentasubstituted Cyclohexanes Phase Transfer Catalysis

22. Entry1R1R1 R2R2 R3R3 t (h)2 (%)dr 11bOHHH602b (45)>99 21cHCH 3 H602c (70)>99 31dHOCH 3 H402d (58)>99 41eHBrH402e (97)>99 51fHCNH202f (90)>99 61gHClH602g (81)>99 71hHHOCH 3 202h (81)>99 Diastereoselective Synthesis of Pentasubstituted Cyclohexanes Phase Transfer Catalysis

23. To University of Aveiro, FCT and FEDER for funding projects and the Organic Chemistry Research Unit. Diana Pinto PhD, Staff member Vera L. Silva Post-Doctoral Fellow Raquel Grevy Andreia Almeida Acknowledgements Cristina Oliva Researcher QOPNA Ciência 2007 Diana Resende PhD Students Angela Sandulache