microreactors and microfluidic cells in organic synthesis · microreactors and microfluidic cells...

Microreactors and Microfluidic Cellsin Organic Synthesis

MacMillan Group MeetingDecember 12, 2007

Joe Carpenter

Microreactors and MicrofluidicMicrofluidic Cells in Organic SynthesisPresentation Outline

n Introduction

n Microreactor Design Fabrication and Operation

n Advantages of Microreactors

n Organic Reactions in Microreactors

Lead References:l Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300.

l Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434.

l Watts, P.; Wiles, C. Org. Biomol. Chem. 2007, 5, 727.

l Increased Yields and Selectivity

l Increased Safety

l Increased Efficiency

n Conclusions

l Stoichiometric Reactions

l Catalytic Reactions

Microreactors and Microfluidic Cells in Organic SynthesisIntroduction

Efficient StoichiometricReaction

Multiple ComponentReactions

Catalytic Reactions

Cascade Reactionsor Multi-catalyst Systems

A B

C

Product

Catalytic Biphasic Reaction

Catalytic Packed Bed

Reactor

D

orA+BP

PACat

A+B C

PC+D

BACat 1

PBCat 2

n Why use microreactors instead of more traditional reaction vessels?

Microreactors and Microfluidic Cells in Organic SynthesisIntroduction

Lab-Scale Synthesis Pilot Plant

Large-Scale Production

n Each stage of scale-up usually requires re-optimization of the process.

Scale-up Scale-up

Scale-Out or Number-Up

n The process does not change.

Microreactors and Microfluidic Cells in Organic SynthesisMicroreactor Design

n Simple "home-made" devices can still give good results

n Common materials include: Silicone, glass, stainless steel, and plastics

n Consist of a series of small channels (10–1000µm)

n Usually attatched to auxilary pumps and fluid delivery lines

n Fluids introduced via hydrodynamic pumping or electroosmotic flow

A B C

n Syrringe pumps and peristaltic pumps are the most popular means to provide hydrodynamic flow

n Advantages include: Pumps are relatively inexpensive, they can be used with any solvent and microreactor material, pump does not contact fluid (peristaltic)

n Disadvantages include: Only slow flow rates for small channel reactors, pulsing of flow, and susceptible to parabolic flow profiles.



n Electroosmotic or electrokinetic flow results when a potential bias is applied between the channel inlet and outlet

Bulk Material

AnodeCathode

Negative SurfaceCharge

Double Layer

Bulk Solution

ElectricField

Velocity Profile

n Advantages include: Very precise fluid handling with computerized automation, velocity profile is nearly flat greatly reducing reagent dispersion.

n Disadvantages include: Usually more expensive than hydrodynamic pumping devices, limited to materials that develop surface charge (glass, silicone), limited solvent compatibility.


Reagent 1

Reage

nt 2

Mixing Zone

Reagent 1 Reagent 2

Mixi

ng Z

one

Y-junction T-junctionInterdigitated multilamellar

mixer

n Channel junctions can be simple Y or T-type junctions

n More complex configurations and channel shapes are possible

n Mixing times are usually on the microsecond time-scale

Microreactors and Microfluidic Cells in Organic SynthesisAdvantages of Microreactors

n Microreactors can lead to increased yields and selectivties through rapid mixing and better thermal management.

Typical stirred reactions mix by convection. Inhomogeneities in the fluid and small changes in the reaction vessel can produce convective dead zones that lead to concentration gradients, poor heat transfer "hot spots", and ultimately inefficient chemistry.

Bilgen, B.; Chang-Mateu, I. M.; Barbino, G. A. Biotechnol. Bioeng. 2005, 92, 907.Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300.

Small dimension microreactors can effect mixing in microseconds, classical reactors mix on the order of seconds or longer. Rapid mixing and superior temperature control occur due to high surface-to-volume ratios 30,000 m2m–3 vs. 100 m2m–3.

temp

Batch

MR

Ideal

reaction coordinate

potentialenergy

MR

BatchC'

CB

B'

A

A C' CA C' C

A B' B


n Watt's aldol reaction is one example where the rate increase is dramatic

OSiMe3

H

O

Br

TBAFO OH

Br

Time Needed to Reach 100% ConversionFlow: 20 minutes Batch: 24 hours

n Taghavi-Moghadam obtained excellent Grignard addition selectivity

OMgCl

O HO

A B

Optimized Flow Conditions: 78% Yield, 95:5 A:BBatch Conditions: 49% Yield, 65:35 A:B

Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Lab Chip 2001, 1, 100.Taghavi-Moghadam, S.; Kleemann, A.; Golbig, K. G. Org. Process Res. Dev. 2001, 5, 652.


n Microreactors allow access to exothermic or possible runaway reactions

HNO3

Yield of mononitrate mixure increased from 55% to 75%.Purity increased from 56% to 78%.

n Small volumes also enable the safe use of toxic or explosive reacants

Yield of ascaridole increased:67% batch to 85% in microreactor

Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Org. Process Res. Dev. 2002, 6, 178.

OH OH

NO2

OHNO2

Polymeric byproducts reduced by a factor of 5.

Rose Bengal

O2, hn

OO

N

O

Boc

N2

O

OEt

N

O

OEt

O

Boc

BF3Et2O

89% Yield, 1.8 minute residence time91 g/hour throughput

Ducry, L.; Roberge, D. M. Angew. Chem., Int. Ed. 2005, 44, 7972.

Zhang, X. N.; Stefanick, S.; Villani, F. J. Org. Process Res. Dev. 2004, 8, 455.

Microreactors and Microfluidic Cells in Organic SynthesisStoichiometric Reactions

n A variety of carbon–carbon bond forming reactions have been carried out in flow

ON

O O

Me Ph

1. NaHMDS, THF, –100 ˚C

2. BrON

O O

Me Ph

ON

O O

Me Ph

ONPh

O

Me PhMeMe

PhPh

Flow: 41% Yield, 91:9 d.r., only s.m. presentBatch: 31% ield 85:15 d.r., >10% byproduct

Increased temp in batch gave >50% byproduct

Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Lab Chip 2004, 4, 171.

PPh3Br

NO2

H

O

MeO

O

NaOCH3

CH3OHMeO

O

MeO

O

O2N NO2

Flow: Tunable E:Z ratio from 1:2 to 5:1Batch: 3:1 E:Z

Skelton, V.; Greenway, G. M.; Haswell, S. J.; Styring, P.; Morgan, D. O.; Warrington, B.; Wong, S. Y. F. Analyst 2001, 126, 11.


n Oxidations and reductions in flow often show marked improvement over batch conditions due in part to precise fluid handling capabilities

OH

1. DMSO/TFAA

2. Et3N

OO

S

O CF3

O

At –20 ˚C:Microreactor gives 88% desired product

Batch gives 19% product, 72% side products

n Reinhoudt observed a dramatic rate increase for Fisher esterification at identical conentrations for the flow and batch reactions

OH

O H2SO4, EtOH

50 ˚C

OEt

O For 40 minute reaction time:Microreactor Yield: 83%

Batch Yield: 15%

Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshhida, J. Angew. Chem., Int. Ed. 2005, 44, 2413.

Brivio, M.; Oosterbroek, R. E.; Verboom, W.; Goedbloed, M. H.; van denBerg A,; Reinhoudt, D. N. Chem. Commun. 2003, 1924.


n Watts and Haswell have demonstrated the use of microreactors in peptide synthesis as an alternative to solid-phase synthesis

FmocHN OH

O

Cl

F

FF

F

OHF

EDCl, CH2Cl2FmocHN OPFP

O

Cl

H2N ODmab

O

DMF FmocHN NH

O

Cl

ODmab

O

Multiple syrringe pumps sequentially added the reagent mixtures

Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron 2002, 58, 5427.

Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E.; Styring, P. Chem. Commun. 2001, 990.


n Photochemistry has also found application in flow, including high-throughput synthesis

NH

O

O

Bu

hnCH3CN

NH

O

O

Bu

N

O

ON

O

O

hn

83-88% Yield, >25 g/hour>600 g in 24 hours

80% Yield, >7 g/hour>150 g in 24 hours

Hook, D. B. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-Milburn, K. I. J. Org. Chem. 2005, 70, 7558.

[2+2]Cycloaddition

[5+2]Cycloaddition

Microreactors and Microfluidic Cells in Organic SynthesisCatalytic Reactions

n Catalysts can be introduced as solutions or be immobilized on solid support

B(OH)2 Br CN1.8% Pd/SiO2

75% THFaq200V/25 min

CN

Flow: 68% YieldBatch: 10% Yield

<2 ppb Pd

I PdCl2(PPh3)2 Bu2NH

[bmim][PF6][bmim][PF6]

NN BuMePF6

–

Flow: 93% Yield, 10 minBatch: 95% Yield, 2 h

ICO2Bu

2% Pd cat. (i-Pr)3N

[bmim][PF6]

N NMe Bu

Pd ClPh3PCl

PhCO2Bu

Flow: 98% Yield, 50 min

Haswell, S. J. et. al. Sens. Actuators, B 2000, B63, 153.

Pd cat

Liu, S. F.; Fukuyama, T.; Sato, M.; Ryu, I Org. Process. Res. Dev. 2004, 8, 477.

Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I Org. Lett. 2002, 4, 1691.

Suzuki coupling

Sonogashira coupling

Mizoroki-Heck coupling


n Catalytic oxidations and reductions in microreactors have been studied extensively

CN

O

H Pd/C, MeOH

H2, 25 ˚C CN

HO

72% flow51% batch

Pd/C, MeOH

H2, 90 ˚C

HONH2

71% Yield<2 min.

NCbz HN N

NN Pd/C (10%), H2

EtOAc/AcOH/EtOH NH HN N

NN Flow: 98% conversion in 3.5 hours

Batch: Complete conversion took 3 days

OSc[N(SO2C8F17)2]3

30% H2O2, PhCF3

O O

O O

Flow: 100% Yield, 97:3 ratio of regioisomersBatch: 53% Yield, 67:33 ratio

Yaswathananont, N.; Nitta, K.; Nishiuchi, Y.; Sato, M. Chem. Commun. 2005, 40.

Franckevicius, V.; Knudsen, K. R.; Ladlow, M.; Longbottom, D. A.; Ley, S. V. Synlett 2006, 889.

Mikami, K.; Islam, N.; Yamanaka, M.; Itoh, Y.; Shinoda, M.; Kudo, K. Tetrahedron Lett. 2004, 45, 3681.


n Organocatalytic reactions are also known to take place in microreactors

NCOEt

O

Br

H

O

NNH

CH3CN, 400VBr

NCOEt

O

90% Conversion in 9.5 minutes(Catalyst on silica)

Watts has generated several amine bases suspended on silica to catalyze the Knoevenagel condensation.Wiles, C.; Watts, P.; Haswell, S. J. Tetrahedron 2004, 60, 8421.

O

O

OAc

BnOBnO

BnOO

O

O

OH

O

O

CCl3

NH

O

O

OAc

BnOBnO

BnO

O

O

OO

O

OO

BnOBnO

BnO O

O

O

OO

O

O

TMSOTf

CH2Cl2

For: Temp < –70˚C, rxn. time <1 min favors Bat –40˚C, time ª 4 min exclusively A

A B

Ratner, D. M.; Murphy, E. R.; Jhunjhunwala, M.; Snyder, D. A.; Jensen, K. F.; Seeberger, P. H. Chem. Commun. 2005, 578.


n Reaction details for Seeberger's glycosylation in a microreactor

O

O

OAc

BnOBnO

BnOO

O

O

OH

O

O

CCl3

NH

O

O

OAc

BnOBnO

BnO

O

O

OO

O

OO

BnOBnO

BnO O

O

O

OO

O

O

TMSOTf

CH2Cl2

A B

Ratner, D. M.; Murphy, E. R.; Jhunjhunwala, M.; Snyder, D. A.; Jensen, K. F.; Seeberger, P. H. Chem. Commun. 2005, 578.

n Mixing Zone: 200 mm

n Retention/Reaction Zone: 400 mm

n Retention times from less than 1min to over 1 hour

n In situ Et3N quench/dilution/standard injection for HPLC

product analysis

n 100 mg s.m. enabled analysis of 40 rxn. conditions in <24 hours

Microreactors and Microfluidic Cells in Organic SynthesisHigh-Throughput Synthesis

Zhang, X.; Stefanick, S.; Villani, F. J.; Org. Process.Res. Dev. 2004, 8, 455.

n Researchers at Johnson and Johnson utilized the CYTOS benchtop microreactor to access large quantities of synthetically useful intermediates synthesized through potentially hazardous reaction conditions.


NH2

O

OH

L-tert-leucine

n Highly exothermic reactions that are proplematic in batch-type reactors are easily controlled

Cl

O

OMe

aq. NaOH, THFr.t. –40 ˚C

HN

O

OHOMe

O

91% Yield, 7 min residence time1 kg/12 hours

Me

O Cl

S

MTBEr.t.

HNMe2/THF

Me

O NMe2

S

96% Yield, 1.4 min residence time155 g/hour

n The CYTOS microreactor system can handle temperatures from –65 ˚C to over 200 ˚C

O

S NMe2

NO2 170 ˚C

SOO

S

O NMe2

NO2

100% Yield, 14 min residence time34 g/hour

Newman-Kwartrearrangement



n Reactive/unstable intermediates can be generated in situ and used in subsequent reactions


OMe

Br

Mg, THFor

n-BuLiTHF

OMe

M

O

M = MgBr, Li

OMe

OHBatch –10 ˚C: 32%Yield (M = Li) Batch –65 ˚C: 80% Yield (M = Li)Flow –14 ˚C (17 sec) then –40˚C

87% Yield, 54g/h (M = Li)

N

O

Boc

N2

O

OEt

N

O

OEt

O

Boc

BF3Et2O89% Yield, 1.8 minute residence time

91 g/hour throughput

n Ring expansion with ethyl diazoacetate exhibits an initiation period resulting in a violent exotherm and gas evolution when 60% reagent addition has occured

Microreactors and Microfluidic Cells in Organic SynthesisEnantioselective Reactions

n Reek's asymmetric transfer hydrogenation reaction

O

MeOH [RuCl2(p-cymene)]2

KOt-Bu

NH OH

PhMe

OH

MeO

95% Yield, 90% ee

n Salvadori's glyoxylate–ene reaction with polystyrene–bound bis(oxazoline)

Ph

Me

H

O

CO2Et

cat. box-Cu(OTf)2

CH2Cl2, 0 ˚C Ph

OH

CO2Et

Batch: 99% Yield, 89% ee, 6 hFlow: 78% Yield, 88% ee, <5 min

Reek, J. N. H.; et al. Chem.–Eur. J. 2001, 7, 1202.

O

O

N N

O

Ph Ph

Salvadori, P.; et al. Tetrahedron: Asymmetry. 2004, 15, 3233.


n Dialkyl zinc addition gave good yields and ee's initially but showed erosion over time

O

H

OH

Et

Hodge, P.; Sung, D. W. L.; Stratford, P. W. J. Chem. Soc., Perkin Trans. 1, 1999, 2335.

Et2Zn

toluene, r.t.PS catalyst

HO

NMe MePS cat =

X X

AldehydeRun # Yield (%) ee (%)

146789

1012141516

X = HX = HX = HX = HX = 4-ClX = 2-OMecyc hex.X = HX = HX = HX = H

9597819776646759506054

9797948692767087848181


n Reetz et al. used integrated microchip electrophoresis to analyze enzymatic reactions

O O

Belder, D.; Ludwig, M.; Wang, L-W. Reetz, M. Angew. Chem., Int. Ed. 2006, 45, 2463.

Epoxide Hydrolase

MethodEnzyme Conv (%) ee (%)Wild type

LW080

LW086

LW144

LW202

chipbenchchipbenchchipbenchchipbenchchipbench

38182223434028374148

49589082848493899595

H2O

OOH

OH

E44

231321203729

101115

substrate

enzyme

buffer

aux.inletoutlet

Microreactors and Microfluidic Cells in Organic SynthesisMulti-Step Reactions

n Schwalbe's synthesis of Ciprofloxacin and analogs is an excellent example of the utility of microreactors.

Cl

O

FF

F

N(CH3)2

OEt

O

NEt3, CHCl3

O

FF

FOEt

O

N(CH3)2

H2N

O

FF

FOEt

O

NH

K2CO3/NMP

O

NF

FOEt

O

HN NH

O

NN

FOEt

O

HN

1. NaOH2. HCl

O

NN

FOH

O

HN

Ciprofloxacin

Schwalbe, T.; Kadzimirsz, D.; Jas, G. QSAR Comb. Sci. 2005, 24, 758.

57% yield>90% purity


n Schwalbe's microreactor schematic for the synthesis of Ciprofloxacin analogs

Solv. Solv.

Pump 1 Pump 2

WasteHeatingCooling

RTUs

CYTOSmicroreactor

Reactant 1:Up to 42 vials

Reactant 2:Up to 42 vials

Product:Up to 84 vials

n Reagent pulses were separated by solvent plugs enabling continuous library synthesis

time

r1r2r3r4

rn: reagent pulseS: solvent plug

SS S

Schwalbe, T.; Kadzimirsz, D.; Jas, G. QSAR Comb. Sci. 2005, 24, 758.

O

NN

FOH

O

R1

R2

R3

Product general structureObtained 22 unique analogs


NMe3N3

n Ley's synthesis of oxomaritidine was accomplished exclusively in flow.HO

Br

OH

OMeMeO

NMe3RuO4

20 equiv., 70 ˚CCH3CN:THF (1:1)

50 mL/min

10 equiv.THF, r.t.

50 mL/min

HO

N3

100% conv.

O

OMeMeO

100% conv.

1)

2)

PhP(n-Bu)2

N

HO

OMeMeO

20 equiv.1) r.t., 2) 55 ˚C

10% Pd/C, THFFlowHydrogenation

NH

HO

OMeMeO

Chip

80 ˚CCH2Cl2

35 mL/min

F3C O CF3

OO

35 mL/minCH2Cl2

N

HO

OMeMeO CF3ON

OCF3O

O

MeO

MeO

PIFA

PIFA = (ditrifluoroacetoxyiodo)benzene

Ley, S. V. et al. Chem. Commun. 2006, 2566.


n Ley's synthesis of oxomaritidine was accomplished exclusively in flow.

NOCF3

O

O

MeO

MeONMe3OH

MeOH/H2O, 4:1

35 ˚C70 mL/min

MeO

MeONH

O

(±)-oxomaritidine

n Product obtained with >90% purity by 1H NMR

n 40% isolated yield overall (phenolic oxidation gave 50% yield)

n Natural product can be obtained in less than 1day

n Only obtained 20 mg of (±)-oxomaritidine

Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006, 2566.

Conclusions

n Microreactor technology is still a relatively new and unexplored tool for organic chemists.

n Microreactors have the potential to increase reaction efficiency and safety while reducing environmental impact.

n Continuous flow reactors can allow access to large quantities of synthetically useful intermediates.

n Asymmetric catalysis is possible but there are few examples in the literature.

n Multiple reactors in tandem can be used to rapidly build molecular complexity.

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