Microwave synthesis
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  • 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. DefinitionPreparation of a desiredcompound from availablestarting materials via some(multi-step) procedure,involving microwaveirradiation. 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) Microwave radiation Electric component Dipolar Ionic polarization conduction 5
  • 6. Dipolar Polarization• Loss Tangent (Energy Dissipation Factor) – a measure of the ability to absorb microwave energy andconvert it into thermal energy (heat)• Derived from Maxwell’s equation tanδ = ε”/ε’• ε” = loss factor• ε’ = dielectric constant• Reaction medium with high tanδ value efficient absorption rapid heating 6
  • 7. Ionic conduction• Due to translational motion of electric charges when anelectric field is applied• Ions cause increased collision rate and convert kinetic energyto heat According to Arrhenius equation: k =A*e-Ea/RT Rule of Thumb: for every 10 C increase in temperature the rate of reaction becomes twice Increasing temperature 80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C 8 hr 4h 2 hr 1 hr 30 min 15 min 8 min 4 min 2 min Decreasing reaction time Tetrahedron 2001, 9225 7
  • 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 (H2O, EtOH, acetone) used• less solvent usage ( 0.5-5mL per reaction)• software-supported experiment documentation 8
  • 9. Thermal effects -Ea/RT• 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
  • 10. Non thermal effects Interaction of Polar reaction electric field with mechanism reaction medium molecules Increase in polarity from ground state Orientation of to transition state molecules Lowering of activation energy Increase in reactivityAngew. Chem. Int. Ed. 2004, 6250-6259 10
  • 11. Applications• Heck reaction• Suzuki reaction• Negishi and Kumada reaction• Multicomponent reactions• Solid phase synthesis• Reactions in the absence of solvents 11
  • 12. Heck reactionMost important C-C bond forming reactionNC Br NC COOH Pd(OAc)2, P(o-tolyl)3 Et 3N, MeCN COOH MW, 180oC, 15 min X XPd(OAc)2, P(o-tolyl)3 can be replaced by Pd/C catalystIonic liquids[bmim]PF6 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 12
  • 13. Suzuki reactionPalladium catalyzed cross coupling of aryl halides with boronic acids X (HO)2 B Pd(OAc)2, TBAB, Na2CO3 H2O MW, 150oC, 5 min R R R R TBAB – phase transfer catalyst Facilitates solubility of organic substrates and activation of boronic acidsJ. Org. Chem. 2005, 3864-3870 13
  • 14. Negishi and Kumada reaction CN CN Br PdCl2 (PPh3) 2, THF H MW, 160oC, 1 min ZnBr H O O Cl PdCl2(PPh3)2, THF BrMg OMe OMe MW, 175oC, 10minOrg. Process Res. Dev. 2003, 707-716 14
  • 15. Multicomponent reactions O O H O dioxane R2 N MW, 180oC, 10 min Ar N H H R1 R2 Ar Me R1 Solid phase synthesis Me Cl N MeNH2, H2O H MW, 150oC, 5 min• significant rate enhancement (10 min vs. 48 h)• less material strain of solid support• reduction of reagent excess 15
  • 16. Conti.. O Cl R-COOH, Cs2CO3, NMP O R MW, 200oC, 15 min O O O R1 O R3 Fmoc H H a, b, c N N N H HO N NH 2 H O R2 O a - deprotection with piperidine at RT b - HATU, iPr2NEt, DMF, MW, 110OC, 20 min c - TFA, RT, 2 hrAngew. Chem. Int. Ed. 2004, 6268-6273 16
  • 17. Reactions in the absence of solvents NH 2 NHR Raney Ni ROH MW, 30min O O COOMe nC 8H 17 KF-Al2O3 HO-nC8H17 MW, 3min O CN CN silica Ph H 2C Ph MW, 150oC, 3 min H CN CNAngew. Chem. Int Ed. 2004, 6250-6252 17
  • 18. Microwave transparent pyrex v/s microwave absorbing SiC O O NC NC Br Pd/C, Et 3N, TBAB OBu MW, 191oC, 30 min OBu Pyrex: 82% SiC: 84% Advantages of SiC: • high melting point • high microwave absorbtivity • thermal conductivity • thermal effusivity • better control over exothermic reactionsAngew. Chem. Int. Ed. 2009, 8321-8324 18
  • 19. • corrosion resistant• differentiates thermal from non – thermal effects Me Me Pyrex or SiC N N BuBr MW, 100o C,10min N N Br Bu Pyrex Temperature temp SiC profile for synthesis of [bmim]Br using pyrex and SiC reaction vials time 19
  • 20. Conclusion• Introduction of this technology in discovery efforts canhelp streamline process improvements in research anddevelopment.• Microwave technology has become easy for medicinalchemists to apply in a beneficial and reproducible manner,providing a green technology that is widely embraced. 20
  • 21. 21