Microwave synthesis

1. Microwave Assisted Synthesis Presented by: Nivedita Singh Medicinal Chemistry IInd Sem

2. Flow of contents Definition Principle Advantages Thermal and non thermal effects Applications Pyrex v/s SiC Conclusion 2

3. Definition Preparation of a desired compound from available starting materials via some (multi-step) procedure, involving microwave irradiation. 3

4. A green chemistry approach Green chemistry is the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products. Out of the 12 principles of green chemistry, the following are taken care through MW synthesis Prevention of waste Less hazardous chemical synthesis Design for energy efficiency Inherently safer chemistry for accident prevention 4

5. Principle Microwave irradiation(0.3-300 GHz) 5

6. 6 Dipolar Polarization • Loss Tangent (Energy Dissipation Factor) – a measure of the ability to absorb microwave energy and convert it into thermal energy (heat) • Derived from Maxwell’s equation tan δ = ε”/ε’ • ε” = loss factor • ε’ = dielectric constant Reaction medium with high tan δ value efficient absorption rapid heating

7. According to Arrhenius equation: k =A*e - E a /RT Rule of Thumb: for every 10°C increase in temperature the rate of reaction becomes twice 80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C 8 hr 4 h 2 hr 1 hr 30 min 15 min 8 min 4 min 2 min Increasing temperature Decreasing reaction time 7 Ionic conduction • Due to translational motion of electric charges when an electric field is applied • Ions cause increased collision rate and convert kinetic energy to heat Tetrahedro n 2001 , 9225

8. Advantages faster reactions less byproducts pure compounds absolute control over reaction parameters selective heating / activation of catalysts low energy input (max=300w, typical reaction ~20w) • green solvents (H 2 O, EtOH, acetone) used • less solvent usage ( 0.5-5mL per reaction) software-supported experiment documentation 8

9. Thermal effects k =A*e Loss tangent factor Superheating effects of solvents at atmospheric pressure Selective heating of microwave absorbing reagents and catalysts Elimination of wall effects 9 -E a /RT

10. 10 Non thermal effects Polar reaction mechanism Interaction of electric field with reaction medium molecules Orientation of molecules Increase in polarity from ground state to transition state Lowering of activation energy Increase in reactivity Angew. Chem. Int. Ed. 2004 , 6250-6259

11. Applications Heck reaction Suzuki reaction Negishi and Kumada reaction Multicomponent reactions Solid phase synthesis Reactions in the absence of solvents 11

12. Heck reaction Most important C-C bond forming reaction 12 Pd( OAc ) 2 , P( o - tolyl ) 3 can be replaced by Pd/C catalyst Ionic liquids[ bmim ]PF 6 can be used as green solvents efficient interaction with microwaves rapid heating less pressure build-up high recyclability Org. Process Res. Dev. 2003 , 707-716

13. Suzuki reaction Palladium catalyzed cross coupling of aryl halides with boronic acids 13 TBAB – phase transfer catalyst Facilitates solubility of organic substrates and activation of boronic acids J. Org. Chem. 2005 , 3864-3870

14. Negishi and Kumada reaction 14 Org. Process Res. Dev. 2003 , 707-716

15. Multicomponent reactions 15 Solid phase synthesis significant rate enhancement (10 min vs. 48 h) less material strain of solid support reduction of reagent excess

16. 16 a - deprotection with piperidine at RT b - HATU, iPr 2 NEt, DMF, MW, 110 O C, 20 min c - TFA, RT, 2 hr Conti.. Angew. Chem. Int. Ed. 2004 , 6268-6273

17. Reactions in the absence of solvents 17 Angew. Chem. Int Ed . 2004 , 6250-6252

18. Microwave transparent pyrex v/s microwave absorbing SiC 18 Angew. Chem. Int. Ed. 2009 , 8321-8324 Advantages of SiC: high melting point high microwave absorbtivity thermal conductivity thermal effusivity better control over exothermic reactions

19. 19 corrosion resistant differentiates thermal from non – thermal effects time temp Pyrex SiC Temperature profile for synthesis of [bmim]Br using pyrex and SiC reaction vials

20. Conclusion 20 Introduction of this technology in discovery efforts can help streamline process improvements in research and development. Microwave technology has become easy for medicinal chemists to apply in a beneficial and reproducible manner, providing a green technology that is widely embraced.

21. 21 THANK YOU