Go With the Flow Microfluidics and Microreactors: An Organic Chemist s New Round-Bottomed Flask

Transcription

1 Go With the Flow Microfluidics and Microreactors: An Organic Chemist s New Round-Bottomed Flask Russell C. Smith Denmark Research Group Meeting 5/13/2008

2 Outline Introduction Design of Microreactors Methods for Introducing Reagents Syringe Pump Electroosmotic Flow (EOM) Advantages Using Microreactors Advances in Organic Synthesis Stoichiometric Catalytic Conclusions

3 Improving Organic Synthesis Organocatalyst Transition Metal RAR DKR Passerini Ugi Improvements in Atom Economy Decreasing the Amount of Waste Generated Chem Rev. 2007, 107, 2300.

4 Scaling-Up Reactions SCALE-UP Academic Laboratory Pilot Plant Problems: Surface to Volume Ratios Thermal Transport Optimization No scale-up Org. Biomol. Chem. 2007, 5, 727.

5 Microreactors: Design Planar objects consisting of small channels ( µm) Microchannel junctions allow for introduction of material Glass, silicon, metal, polymers are used for production Chem Rev. 2007, 107, 2300.

6 Microreactors: Fabrication Lithography (chemical picture) Glass coated with metal and photoresist Channel pattern transferred via a mask Exposed photoresist is removed Metal is cut away Glass is etched (HF/NH 4 F) Top plate is attached (e.g. thermal bonding) TRAC. 2000, 19, 396.

7 Microreactors: Fabrication Injection molding Hot Embossing Elastomeric Stamps Disadvantages: requires specialized equipment in many cases fairly expensive Richard D. Oleschuk, Associate Professor (Queens Univ)

8 Microreactors: Come in all Shapes and Sizes a) Stainless steel b) Glass d) Silicon (right) spiro MFD A number of MR are commercially available Chem Eur. J. 2006, 12, 8434.

9 Microreactors: Micro to Macro Interfaces Similar to HPLC set-up Fluid wells Ferrule-type connections HPLC fittings Luer fittings Standard laboratory equipment is used for microreactors Chem Rev. 2007, 107, 2300.

10 Microreactors: Pumping Techniques Hydrodynamic Flow Syringe Pumps Peristaltic Pumps Most fluids can be introduced Disadvantage: Difficult to control flow throughout system (parabolic flow) Chem Rev. 2007, 107, 2300.

11 Microreactors: Pumping Techniques Electroosmatic Flow (EOF) Requires appropriate ph of solution Electrode placed across reactor Easily control flow by voltage! Dual directionality Disadvantage: Pump performance is linked to the properties of the soln. Org. Biomol. Chem. 2007, 5, 727. Anal. Chem. 1994, 66, 1792.

12 Advantages of Microreactors: Thermal Control Increased temp. causes unwanted by-products Nitration of Aromatic Compounds Batch: 55 % yield; 55 C exotherm (1 L) MR: 75 % (78 % pure); 5 C exotherm MR provide safer and more selective means for reactivity! Org. Process. Res. Dev. 2004, 8, 440. Chem Rev. 2007, 107, 2300.

13 Advantages of Microreactors: Safety Small volumes of toxic / explosive reagents can be used Fluorination (produces HF byproduct) Dangerous gas and liquid products are easily contained Chem Comm. 1999, 883. Singlet Oxygen Rose Bengal Increased yield by 20 % Diazomethane reactions are also possible using MR Chem Rev. 2007, 107, 2300.

14 Advances in Synthesis: C-C bond formation Alkylation using Evan s Chiral auxiliary Batch: 31 % yield, d.r. = 85:15; > 10% by-products MR: 41 % yield, d.r. = 91:9; remaining material recovered SM Increased temperatures led to poor reactivity in both cases Indicates that the resident time for enolate formation was NOT sufficient Lab Chip 2004, 4, 171.

15 Advances in Synthesis: C-C bond formation o-bromophenyllithium reagents Rapidly undergo elimination to benzyne Microsystem for Br-Li exchange J. Am. Chem. Soc. 2007, 129, 3046.

16 Advances in Synthesis: C-C bond formation Monolithiation Addition to CHO was also successful Sequential lithiation J. Am. Chem. Soc. 2007, 129, 3046.

17 Advances in Synthesis: Oxidation Moffat-Swern Oxidation n OH OH n = 8-20 C: 75 % yield; 19 % VII Batch: 11 % yield; 90 % VII -20 C: 88 % yield; 5 % VII Batch: 19 % yield; 70 % VII Recent work by Kemperman utilizes a HPLC pump for continuous flow Org. Proc. Res. Dev. 2008, ASAP. ACIE. 2005, 44, 2413.

18 Advances in Synthesis: Photochemical [2+2] 88 % yield; >25 g/hr [5+2] Simply wrapping the tubing around the light source proved effective J. Org. Chem. 2005, 70, 7558.

19 Palladium Deprotection (Ley) Catalysis in Microreactors Batch: 3 d for complete conversion MR: 3.5 h, 98 % yield Synlett. 2006, 889. C-C bond formation (Haswell) Chem Rev. 2007, 107, Palladium is easily place on supports for MR

20 Kinetic Resolution Catalysis in Microreactors Simple use of HPLC column packed with supported catalyst Reuse of column accomplished by treating column with HOAc/toluene J. Am. Chem. Soc. 1999, 121, 4147.

21 Catalysis in Microreactors!-lactam synthesis Multiple columns required for sequential reactions Chem. Eur. J. 2002, 8, 4114.

22 Flow Chemistry as Tools for Total Synthesis Challenge Devise a racemic synthesis of OXOMARITIDINE BONUS: Develop a Flow Process that does NOT require isolation

23 Chem. Comm. 2006, 2566.

24 Along Came A Spider A significant challenge for scientists is the ability to reproduce spider silk Proc. Nat. Acad. Sci. 2008, 105, 6590.

25 Requirements for Silk Formation MR allowed for the systematic change in both ph and concentration of phosphate Demonstrated the need for controlled flow to polymerize particles towards elongation Proc. Nat. Acad. Sci. 2008, 105, 6590.

26 Journal Dedication 12 issues Started in 2001 Accepts manuscripts from multiple disciplines: biology, engineering, chemistry On or off chip micro/nanoscale "On a personal matter, I want to thank you for the wonderful job done on this paper. Your editorial practices are exceptional. It is an honour to have our work considered by and published in LOC and we hope to send other manuscripts to you in the future" Professor Ralph Nuzzo, University of Illinois, USA

27 Conclusions Microreactors serve as a useful platforms for organic synthesis The number of differing MR has increased significantly in both form and composition The ability to directly analyze reactions provides quick optimization to new reactions Asymmetric Catalysis is still in its infancy Reactions are limited to fast and efficient processes (Click chemistry?) Issues with homogeneity still are troublesome Therefore when are you going to give up your glassware??

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