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.
Microreactors and Microfluidic Cells in Organic SynthesisMicroreactor Design
Microreactors and Microfluidic Cells in Organic SynthesisMicroreactor Design
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.
Microreactors and Microfluidic Cells in Organic SynthesisMicroreactor Design
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
Microreactors and Microfluidic Cells in Organic SynthesisAdvantages of Microreactors
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.
Microreactors and Microfluidic Cells in Organic SynthesisAdvantages of Microreactors
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.
Microreactors and Microfluidic Cells in Organic SynthesisStoichiometric Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisStoichiometric Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisStoichiometric Reactions
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
Microreactors and Microfluidic Cells in Organic SynthesisCatalytic Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisCatalytic Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisCatalytic Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisHigh-Throughput Synthesis
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
Zhang, X.; Stefanick, S.; Villani, F. J.; Org. Process.Res. Dev. 2004, 8, 455.
Microreactors and Microfluidic Cells in Organic SynthesisHigh-Throughput Synthesis
n Reactive/unstable intermediates can be generated in situ and used in subsequent reactions
Zhang, X.; Stefanick, S.; Villani, F. J.; Org. Process.Res. Dev. 2004, 8, 455.
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.
Microreactors and Microfluidic Cells in Organic SynthesisEnantioselective Reactions
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
Microreactors and Microfluidic Cells in Organic SynthesisEnantioselective Reactions
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
Microreactors and Microfluidic Cells in Organic SynthesisMulti-Step Reactions
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
Microreactors and Microfluidic Cells in Organic SynthesisMulti-Step Reactions
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.
Microreactors and Microfluidic Cells in Organic SynthesisMulti-Step Reactions
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.