Synthos 3000 Microwave Assisted Organic Synthesis Meanings & Model Applications - PowerPoint PPT Presentation

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  1. Synthos 3000 Microwave Assisted Organic Synthesis Meanings & Model Applications

  2. Contents • What´s Microwave Assisted Organic Synthesis ? • Why ? - Benefits of MAOS • Instrumentation - Monomode vs. Multimode • Getting Started • Typical Applications • Performance Verification - Model Applications

  3. MAOS Microwave Assisted Organic Synthesis Definition “Preparation of a desired organic compoundfrom available starting materials via some (multi-step) procedure, involving microwave irradiation”

  4. MeOH, 160 °C Power (W) Benefits of MW-Assisted Synthesis • higher temperatures (superheating / sealed vessels) • faster reactions, less byproducts, pure compounds • absolute control over reaction parameters • selective heating / activation of catalysts • energy efficient, rapid energy transfer • easy access to high pressure performance • can do things that can´t be done conventionally

  5. Single Mode Instruments Domestic MW Oven MLS Ethos 1600 Emrys Liberator Initiator Mars-S Multimode Batch Reactors Discover Applicable Microwave Instrumentation


  6. antenna magnetron sample Mode stirrer Wave guide magnetron sample antenna Basic Technical Differences: Multimode vs. Monomode Cavities Multimode Cavity Monomode (Single Mode) Cavity Chaos Standing Wave

  7. Practical Differences: Multimode vs. Monomode Cavities Multimode Cavity Monomode (Single Mode) Cavity • huge cavity • large scale runs (5-1000 mL) • simply applicable for scale-up • high throughput by parallel synthesis • field can be inhomogeneous • lower power density • high output power • small scale experiments troublesome • compact cavity • small scale runs (0.5-50 mL) • scale-up by flow-through technique • throughput by automation • highly homogeneous field • high power density • lower output power • large scale runs time-consuming Choice depends mainly on desired application (combichem, medchem, process chemistry) and the scale, not on the chemistry !

  8. Getting Started Initial Questions • are solvent / reagents suitable for microwave irradiation • what about thermal stability / decomposition • expecting elaboration of pressure • flash heating required • fit limits of chemistry with equipment • consider beneficial influence of selective heating

  9. Getting Started General Hints: • use polar solvents with thermal stability (ROH, MeCN, NMP...) • apply small volumes unless reaction is optimized • starting point 10 min @ 120 °C • max. 30 min hold time • increase temperature rather than time • passive heating elements for improved energy transfer • consider solvents changing their properties at higher temperatures

  10. 80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C 8 h 4 h 2 h 1 h 30 min 15 min 8 min 4 min 2 min –Ea/RT k = A*e Converting Conventional Protocols Arrhenius Equation :  Rule of thumb: 10° temperature increase = 2-fold rate acceleration

  11. 20 °C 30 °C 40 °C 50 °C 60 °C 70 °C 80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C 170 °C 180 °C 190 °C 200 °C 210 °C 220 °C 230 °C 240 °C 250 °C 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 4 2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 8 4 2 1 30 15 8 4 2 56 28 14 7 4 2 53 26 13 7 3 2 1 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 48 24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 1 96 48 24 12 6 3 1.5 45 23 11 6 3 1 42 21 11 5 3 1 40 20 10 5 2 172 86 43 22 11 5 3 1 40 20 10 5 3 1 38 19 9 5 2 1 35 18 9 4 Temp Time - change in color represents change in unit (h/ min / sec) Converting Conventional Protocols works at 2 min at 160°C in the MW e.g. a thermal reaction for 8h at 80°C ©AstraZeneca, Macclesfield, UK

  12. Principle Enhancement of... Major Benefits • every thermal accelerated process • time consuming experiments • sealed vessel reactions • conversion rates / product purity • super heating effect (solvents above their bp) • powerful temperature/pressure conditions • electronic parameter-control / unattended runs • software-supported experiment documentation MW make experimental work more convenient MAOS Applications

  13. Solid Phase Synthesis Metal Catalysis • significant rate enhancement (10 min vs. 48 h) • less material strain of solid support • reduction of reagent excess • decreased reaction time (10-30 min vs. > 24 h) • reduced catalyst amount (environmentally friendly) • simplified reaction mixtures • improved purity of products Typical MAOS Applications Eur. J. Org. Chem.2001, 919 Org. Lett.2002, 3541

  14. Focused Library Generation High Pressure Chemistry • shortened optimization sequence (hours vs. days) • automated reaction process, high throughput • evident reduced over-all production time (days vs. weeks) • simplified use of pre-pressurized vessels • reduced reaction times • easy application of gaseous reagents • excess of reagents minimized Typical MAOS Applications J. Comb. Chem. 2001, 624 Org. Process Res. Dev.2003, 707 Org. Biomol. Chem.2004, 154

  15. Metal Catalyzed Carbonylations Reactions in Near Critical Water • ultra-fast chemistry (6-10 sec) • utilizing solid CO-sources (not practicable conventionally) • less catalyst needed • chemistry at extreme conditions (>280°C, >60 bar) • easy approach without toilsome accessories • exact parameter control • comprehensive safety features Remarkable MAOS Applications J. Comb. Chem. 2003, 350 Org. Lett.2003, 4875 Eur. J. Org. Chem.2005, 3672

  16. The Idea of MAOS Changing Meanings of Microwave Instruments: So far... ...and now: • use MW instead of classic methods • remove all other heating sources • replace autoclaves • powerful tool for all chemistries in any scale • develop / investigate / optimize • produce the compounds covering a niche in Organic Chemistry to investigate new pathways supporting the routine labwork representing a valuable laboratory equipment for various applications from R&D to Production

  17. Synthos 3000 Scaling Up Microwave Assisted Organic Synthesis

  18. Method Development Reaction Optimization First Grade Synthesis Batch Synthesis • 0.2 - 5.0 mL volume • 0.1 - 10 mmol scale • 5 - 30 min reaction time • 100 - 200 °C • 20 - 250 mg product • 0.2 - 5.0 mL volume • 0.1 - 5 mmol scale • 1 - 30 min reaction time • 100 - 200 °C • 10 - 100 mg product • > 5.0 mL volume • > 10 mmol scale • minimum reaction time • optimized temperature • 100 - 1000 mg • high throughput approach • > 100 mL volume • > 1 mol scale • optimum time/temperature conditions • > 100 g product Need for proper Scale-Up techniques Typical Operation Range

  19. IR A Versatile and Modular Microwave Platform System • High performance rotors & vessels • Built-in magnetic stirrer • Dual remote temperature sensing • Sophisticated accessories

  20. H2O MeOH EtOH Acetone MeCN Ethylacetate THF Cyclohexane DMF DCM Extended Operation Limits Synthos 3000 Limits Main Experimental Range Average Multimode Limits

  21. Emrys Synthos 3000 4 mmol: 52% 2 mmol: 78% 4 mmol: 92 % 1 mmol: 81 % Biginelli Heck Kindler Negishi 640 mmol: 48% 80 mmol: 79% 40 mmol: 90% 20 mmol: 77 % Performance Verification • Individual Scalability • Protocol for 1 mmol should work for xxx mmol without modifications • Verified for various examples using Synthos 3000 Key publication:A. Stadler, B. Yousefi, D. Dallinger, P. Walla, E. Van der Eycken, N. Kaval, and C. O. Kappe Organic Process Research & Development2003, 707-716

  22. 47.3% 48.1% 47.8% 47.3% 48.5% 47.8% 48.9% 48.1% 48.0 % Vessel 1 Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Vessel 7 Vessel 8 Total 12.1 g 12.3 g 12.2 g 12.1 g 12.4 g 12.2 g 12.5 g 12.3 g98.1 g Performance Verification • Homogeneity • Parallel rotors should provide identical field distribution at any position • Proved by parallel Biginelli synthesis for Synthos 3000

  23. 3-cyano cinnamic acid Performance Verification • Reproducibility Repeating experiments must yield similar results Verified with Heck Couplings in Rotor 8: Exp. 1: 8x 20 mmol, homogeneous catalysis Overall yield: 79% Exp. 2: 8x 20 mmol, 4x homogeneous, 4x heterogeneous catalysis Overall yield: 78% Exp. 3: 8x 20 mmol, parallel synthesis, various substrates Yield of model compound: 79%

  24. Model Reactions 1) Biginelli Multicomponent Reaction • effective multicomponent reaction • optimized conditions tolerable to broad range of building blocks • library generation in multi-gram scale (up to 80 mmol/vessel) • 16 different targets within one run Org. Process Res. Dev.2003, 707-716

  25. Model Reactions 2) Kindler Thioamide Synthesis • efficient synthesis of valuable building blocks for biologically relevant heterocyclic scaffolds (40 mmol/vessel) • significantly reduced reaction times • unproblematic use of large amounts of elemental sulfur • suitable reaction for library generation Org. Process Res. Dev.2003, 707-716

  26. Model Reactions 3) Heck Couplings • most important C-C bond forming reaction • no interference of metal layer with microwaves • parallel synthesis (20 mmol/vessel) with broad range of substrates and varying catalysts • unproblematic use of significant amounts of Pd catalyst (1 mol%) Org. Process Res. Dev.2003, 707-716

  27. Model Reactions 4) Negishi Coupling • short reaction times even at larger scale (20 mmol/vessel) • protection of sensitive reagents by inert gas flush • use of dummy loads did not affect the reaction progress Org. Process Res. Dev.2003, 707-716

  28. Model Reactions 5) Suzuki Cross-Coupling • powerful general Suzuki protocol (4 mmol/vessel) • suitable for parallel synthesis with various substrates • efficient scaffold decoration for valuable building blocks T. N. Glasnov, W. Stadlbauer, C. O. Kappe J. Org. Chem.2005, 3864-3870

  29. Model Reactions 6) Solid Phase Synthesis • efficient batch synthesis utilizing solid supports (5 g per vessel) • non-adhesive PTFE-liners • filtration unit for simplified work-up • drastically enhanced reaction rates • reduced thermal stress due to short reaction times Org. Process Res. Dev.2003, 707-716

  30. Model Reactions 7) Diels-Alder Cycloaddition • simplified employing of gaseous reagents • gas loading in assembled rotor • individual pre-pressurizing • parallel performance of pressurized reactions • considerably reduced reaction times N. Kaval , W. Dehaen , C. O. Kappe, E. Van der Eycken Org. Biomol. Chem. 2004, 2, 154-156 Org. Process Res. Dev.2003, 707-716

  31. Model Reactions 8) Near Critical Water Chemistry • Ester/Amide Hydrolysis • NCWC at temperatures >250°C and pressures >40 bar • easily accessible with Rotor 8 SXQ80 • conditions can be maintained up to 4 hours • enabling development of new reaction pathways • Green Chemistry approach J. M. Kremsner, C. O. Kappe Eur. J. Org. Chem.,2005, 3672-3679

  32. Diels-Alder Cycloaddition (7.6 mmol/vessel) • Fischer Indole Synthesis (10 mmol/vessel) • Pinacol Rearrangement (3 mmol/vessel) Model Reactions 8) Near Critical Water Chemistry J. M. Kremsner, C. O. Kappe Eur. J. Org. Chem.,2005, 3672-3679

  33. Summary • Direct scalability up to 1 L reaction volume • Parallel synthesis up to 48 derivatives in gram-scale • Comprehensive performance verification (scalability, homogeneity, reproducibility) • Simultaneous pressure sensing • Dual remote temperature measurement (IR control & precise immersing temperature probe) • Simplified access to special applications (SPOS, gaseous reagents, sub-critical solvents, pre-pressurizing) • Sophisticated accessories serving extraordinary reaction conditions (quartz vessels, heating elements, gas-loading station, filtration unit, UV lamps)

  34. Kappe, C. Oliver / Stadler, AlexanderMicrowaves in Organic and Medicinal ChemistryMethods and Principles in Medicinal Chemistry (Volume 25) 1. Edition - June 2005420 Pages, >400 References, HardcoverISBN 3-527-31210-2 - Wiley-VCH, Weinheim • Microwave Theory • Equipment Review • Microwave Processing Techniques • Getting started with Microwaves • Comprehensive Literature Survey MAOS – Latest News Comprehensive Review & MAOS Guide: