improved chemical synthesisimproved chemical synthesis

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Improved Chemical SynthesisImproved Chemical SynthesisImproved Chemical Synthesis Improved Chemical Synthesis Using Automated Using Automated MicrofluidicMicrofluidicPlatformsPlatforms

Jonathan McMullen & Jonathan McMullen & KlavsKlavs F. JensenF. Jensen

Department of Chemical EngineeringDepartment of Chemical EngineeringMassachusetts Institute of TechnologyMassachusetts Institute of TechnologyCambridge, MA 02139Cambridge, MA 02139617 253 4589 [email protected] 617 253 4589 [email protected] web.mit.edu/web.mit.edu/jensenlabjensenlab

Chemistry classic science Chemistry classic science traditionally performed traditionally performed batchwisebatchwise

~1900

~1750~2000

22

2

Continuous flow Continuous flow microsystemsmicrosystems reduce cost reduce cost of information per experiment and enable of information per experiment and enable new operating conditionsnew operating conditions

Reactor 2

Separator

Integrated continuous, microreactors, separation and detection Integrated continuous, microreactors, separation and detection units in chemically compatible materialsunits in chemically compatible materials

Reactor 1

Separator

y py pHigh throughput, automated, and optimized synthesis High throughput, automated, and optimized synthesis Integrates analytics and workflowIntegrates analytics and workflowLess waste and better use of resourcesLess waste and better use of resourcesPlatform for exploring new reaction chemistry and conditions not Platform for exploring new reaction chemistry and conditions not easily accessed in batcheasily accessed in batch

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MicroreactorMicroreactor technology advantages technology advantages Controlling mixingControlling mixing

Desired features:Desired features:–– chemical compatibilitychemical compatibilitychemical compatibility chemical compatibility

(e.g., glass surfaces)(e.g., glass surfaces)–– controlled mixingcontrolled mixing

activatoracceptordonor

D. Ratner, K.F. Jensen, P. Seeberger et al., Chem Comm 2005, 24, 578 44

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MicroreactorMicroreactor technology advantages technology advantages Controlling mixingControlling mixing

Desired features:Desired features:–– chemical compatibilitychemical compatibilitychemical compatibility chemical compatibility

(e.g., glass surfaces)(e.g., glass surfaces)–– controlled mixingcontrolled mixing

activatoracceptordonor

D. Ratner, K.F. Jensen, P. Seeberger et al., Chem Comm 2005, 24, 578 Using gas to mixUsing gas to mix-- Black ink into water (Black ink into water (S. Khan)S. Khan)55

MicroreactorMicroreactor technology advantagestechnology advantagesControlling residence time and temperatureControlling residence time and temperature

Desired features:Desired features:–– chemical compatibilitychemical compatibility–– controlled mixingcontrolled mixing–– well defined reaction time well defined reaction time

(residence time)(residence time)–– ability to quench reactionability to quench reaction–– temperature control (bath temperature control (bath

or TE element)or TE element)–– connections to fluidconnections to fluid

40 mm

TE heater/cooler

Heat sink fluid chamber

connections to fluid connections to fluid handlinghandling

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MicroreactorsMicroreactors can be fabricated for a can be fabricated for a variety of reactionsvariety of reactions

Chips customized forChips customized forChips customized forChips customized for–– Gas Gas –– liquid reactionliquid reaction–– Gas Gas –– liquid liquid –– solid solid

reactionreaction–– Immobilized catalystImmobilized catalyst

Reactors integrated withReactors integrated withgg–– HeatersHeaters–– MixersMixers–– SeparatorsSeparators–– Temperature measurementTemperature measurement–– SpectroscopySpectroscopy

77

Discovery Laboratory Plant

Continuous flow systems could revolutionize Continuous flow systems could revolutionize the development and production chain for the development and production chain for fine chemicals and pharmaceuticals fine chemicals and pharmaceuticals

Biologists Chemists Chemists Engineers

`

Different discovery, development and production platforms are slow and complicate scale-upIntegrated and automated continuous process platforms span across length scales and accelerate translation of discoveries into development and production88

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Combining continuous flow Combining continuous flow microreactors with liquid handling microreactors with liquid handling yields a reaction screening platform yields a reaction screening platform

•• Set reaction temperature Set reaction temperature and and residence residence timetime

•• Withdraw Withdraw reagents from reagents from sample sample wellwell

•• Inject Inject samples samples into into microfluidic flow systemmicrofluidic flow system

•• Detect reaction segmentDetect reaction segment

•• Collect reaction segmentCollect reaction segment

Flowinlets

Liquid handler

Temp. control

J.R. J.R. GoodellGoodell, J.P. McMullen, K.F. Jensen, J.A. , J.P. McMullen, K.F. Jensen, J.A. PorcoPorco, A.B. Beeler, et al., , A.B. Beeler, et al., J. Org. J. Org. ChemChem (in press)(in press)

• Perform analysis offline

UV/Vis

Fraction collectorTo waste

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Combining continuous flow Combining continuous flow microreactors with liquid handling microreactors with liquid handling yields a reaction screening platform yields a reaction screening platform

O

MeO

O

Ph

HreagentsPhMe

H3

Continuous screening of reactions - building a library

A1+B, A1+C, …A2+B, A2+C, …

Compound libraries can be generated quicklyCompound libraries can be generated quickly

Ex: retro Ex: retro DieckmannDieckmann reactionreactionanalysis by UPLCanalysis by UPLC

1010J.R. J.R. GoodellGoodell, J.P. McMullen, K.F. Jensen, J.A. , J.P. McMullen, K.F. Jensen, J.A. PorcoPorco, A.B. Beeler, et al., , A.B. Beeler, et al., J. Org. J. Org. ChemChem (in press)(in press)

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Integrating microreactors, inIntegrating microreactors, in--line measurements, line measurements, and computer control gives an automated and computer control gives an automated continuous synthesis optimization platformcontinuous synthesis optimization platform

Automatic system for rapid Automatic system for rapid identification of optimal identification of optimal synthesis conditions forsynthesis conditions for

Quench

Reactant 2Residence time / synthesis conditions for synthesis conditions for

complex and multicomplex and multi--step step reactions with minimal use reactions with minimal use of reagentsof reagentsPlatform addresses typical Platform addresses typical process questions:process questions:–– What is the maximum What is the maximum

achievable yield?achievable yield?

Reactant 2

Reactant 1Catalyst Temperature

control

Sample control

concentration control

Analysis byHPLC, IR, …

achievable yield?achievable yield?–– Are there better chemical Are there better chemical

pathways?pathways?–– What are the kinetics?What are the kinetics?–– What are the predicted What are the predicted

costs/benefits based on costs/benefits based on results?results?

Maximize yield by varying reaction time, stoichiometry, catalyst loading, ligand amount

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Also performs all calibrations prior to experiments

Jonathan McMullen

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low [PhCHO] Automated search from 1 initial

Multi Parameter Multi Parameter Automated Optimization Automated Optimization

Maximizebenzaldehyde

0

10

20

30

40

50

60

70

30 35 40 45 50 55 60 65

Res

iden

ce T

ime

[s]

Initial guess

Region of optimality

low [PhCHO]

high [PhCHO]

Yield = 24%

Yield = 27%

Yield = 35%

Yield = 73%

guess to optimal conditions

8

10

12

14

16

18

20

iden

ce T

ime

[s]

Yield = 87%Optimal condition

Yield = 66%

Yield = 65%

Yield = 53%

30 35 40 45 50 55 60 65

Temperature [oC]

0

2

4

6

8

43 44 45 46 47 48 49 50 51 52

Temperature [oC]

Res

i

low [PhCHO]

high [PhCHO]

Yield = 10%

20 experimentsperformed in ~40 minutes

Jonathan McMullen1212

7

80

low [PhCHO]Automated search from 1 initial

t ti l diti

Multi Parameter Multi Parameter Automated Optimization Automated Optimization

Yield = 80%T = 88°C RT= 50s

0

10

20

30

40

50

60

70

30 35 40 45 50 55 60 65

Res

iden

ce T

ime

[s]

Initial guess

Region of optimality

low [PhCHO]

high [PhCHO]

Yield = 24%

Yield = 27%

Yield = 35%

Yield = 73%

guess to optimal conditions

8

10

12

14

16

18

20

iden

ce T

ime

[s]

Yield = 87%Optimal condition

Yield = 66%

Yield = 65%

Yield = 53%

TPhCH2OH] = 8.2 x 10-3 M[CrO3]:[PhCH2OH] = 0.62

30 35 40 45 50 55 60 65

Temperature [oC]

0

2

4

6

8

43 44 45 46 47 48 49 50 51 52

Temperature [oC]

Res

i

low [PhCHO]

high [PhCHO]

Yield = 10%

20 experimentsperformed in ~40 minutes

Jonathan McMullen1313

Microreactor scaleMicroreactor scale--up by replication up by replication or knowledge based design of larger or knowledge based design of larger flow systems (or both) flow systems (or both)

Scale up by replication

Scale up to larger size by knowledge of chemical and physical rate processes

Number of microreactors to d 1000k /produce 1000kg/year

Volume (mL)

Slow Reaction

Fast Reaction

0.1 10,000 201 1,000 2

10 100 <11414

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Microreactor scaleMicroreactor scale--up up An example of industrial implementation An example of industrial implementation by Corning/ DSMby Corning/ DSM

1,000 tons/year processed

1515

, /y p

Corning/DSM

Chimicaoggi, Chemistry Today, Vol 26 n5, Sept-Oct2008

OCl

N N

Integration of separation techniques Integration of separation techniques enables multistep synthesisenables multistep synthesis

At small length scales surface forces dominate over gravity forces making conventional separation difficult

ON3

NaN3+

VL

Tray

Liq id & Vapor

Traditional columnBo >> 1

<< 1

Scale Capillary

GravityBo =Gravity Interface

p

NaN3 in aqueous phase

Waste aqueousstream

4-Ethylbenzoyl chloride in toluene(Organic phase)

Waste aqueousstream

J.G. Kralj, K.F. Jensen, et al., Lab Chip, 2007, 7, 256 - 263

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Liquid & Vapor

Exploit surface tension forces for continuous extraction

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water organic InletsInletsInletsInlets

OCl

N N

ON3

200μm

MixerMixer

Extraction

ExtractionOutletOutlet

Separator

Separator30 mm

Mixer Channels: 100 μmExtraction Channels: 300 μm

MixerMixer

Extraction

ExtractionOutletOutlet

Separator

Separator30 mm

Mixer Channels: 100 μmExtraction Channels: 300 μm

J.G. Kralj, K.F. Jensen, et al., Lab Chip, 2007, 7, 256 - 263

NaN3+


Waste aqueousstream

Reactor


Waste aqueousstream

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OCl

N N


NCO

ON3

NaN3+

ReactorA. Günther et al., Langmuir, 2005, 21, 1547


Waste aqueousstream

Reactor


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Continuous flow Continuous flow enables synthesis enables synthesis of useful final of useful final products without products without storing reactive, storing reactive, potential harmful potential harmful intermediates.intermediates.

Branch points offer Branch points offer opportunities foropportunities for

H. R. Sahoo et al., Angw. Chem. Int. Ed., 2007, 46, 5704 1919

opportunities for opportunities for synthesis wide synthesis wide range of structures range of structures while safely using while safely using the the reactive reactive intermediates.intermediates.

Solvent exchange or purification by Solvent exchange or purification by distillationdistillation

Separation based on bubbleSeparation based on bubble--point differences enables continuous point differences enables continuous solvent exchange or purification during worksolvent exchange or purification during work--upupg p gg p g pp

μ reactor

DCMAryl triflate

Product+ Toluene

Triflate + toluene

LLE

μ distillation

HCl

T oluene

R. Hartman and K. Jensen, Lab Chip (2009)

Phenol+ DCM Tf 2O + DCM

μ reactor

Aqueous

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Solvent exchange or purification by Solvent exchange or purification by distillation distillation –– integrated deviceintegrated device

R. Hartman and K. Jensen, Lab Chip (2009)

Improved rates and yields at elevated pressures and Improved rates and yields at elevated pressures and temperatures difficult to achieve in batch synthesis: temperatures difficult to achieve in batch synthesis: Emulating microwave conditionsEmulating microwave conditions

15 atm

E.R. Murphy, S. Buchwald, K.F. Jensen, et al., Angw. Chem. Int. Ed., 2007, 46, 1734-173722

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Improved rates and yields at elevated pressures and Improved rates and yields at elevated pressures and temperatures difficult to achieve in batch synthesis: temperatures difficult to achieve in batch synthesis: Emulating microwave conditionsEmulating microwave conditions

Up to 36 reaction Up to 36 reaction samples per daysamples per day44--7 minute residence 7 minute residence time for 100% time for 100% conversionconversionControlled selectivity Controlled selectivity between two productsbetween two productsContinuous flow Continuous flow alternative to alternative to

15 atm

microwave chemistrymicrowave chemistryGasGas--liquid segmented liquid segmented flow with 10flow with 10--fold fold increase in contact increase in contact areaarea

E.R. Murphy, S. Buchwald, K.F. Jensen, et al., Angw. Chem. Int. Ed., 2007, 46, 1734-17372323

Continuous flow simplifies Continuous flow simplifies synthesis removes reactionsynthesis removes reaction

Microreactors enable safe handling of Microreactors enable safe handling of highly energetic reactions: Synthesis highly energetic reactions: Synthesis of energetic materials of energetic materials

synthesis, removes reaction synthesis, removes reaction heat and evolved gas, making heat and evolved gas, making the process safer and efficientthe process safer and efficient~ 90% yield of final product~ 90% yield of final productHighly efficient Si based Highly efficient Si based micromixermicromixer for higher flow for higher flow rates 10rates 10 mLmL/min/min

1 m

5-Nitrotetrazolate (NaNT)

rates 10 rates 10 mLmL/min /min Production of >6 g/h/chain Production of >6 g/h/chain

J.G. Kralj, K.F. Jensen, et al. , 41st AIAA/ASME/ASEE Joint Propulsion Conference, Tucson, AZ (July 2005).

2424 N. Zaborenko

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Size dependent quantum confinement

Continuous micro flow synthesis of Continuous micro flow synthesis of semiconductor semiconductor nanocrystalsnanocrystals --quantum dotsquantum dotsApplications: Applications: –– Optical encoding, QDOptical encoding, QD--

1-10 nm

2 nm 8 nm

optoelectronics; QDoptoelectronics; QD--LEDs, LEDs, QDQD--photodetectorsphotodetectors; Solar cells; ; Solar cells; Floating gate memories; Floating gate memories; NanoNano--patterned templates; Lasers; Biopatterned templates; Lasers; Bio--chemo sensors;…chemo sensors;…

Challenges:Challenges: 1-10 nm

M.G. Bawendi - MIT

Challenges: Challenges: –– Controlled synthesis of rationally Controlled synthesis of rationally

engineered nanoparticles and engineered nanoparticles and nanoparticlenanoparticle heterostructuresheterostructures; ; Understanding basic chemistry and Understanding basic chemistry and kinetics of nucleation and growthkinetics of nucleation and growth

Chan et al., Advanced Materials 2004, 16, 2092-2097.

20 µm

CdSe

Optical Optical properties and average size depend on factors difficult to properties and average size depend on factors difficult to control: injection, local temperature and concentration fluctuations, control: injection, local temperature and concentration fluctuations, mixing and cooling ratesmixing and cooling rates

Batch synthesis Batch synthesis of of quantum dots quantum dots has has numerous challenges and limits numerous challenges and limits realization of novel nanostructuresrealization of novel nanostructures

PrecursorssolventligandsΔ

mixing and cooling ratesmixing and cooling ratesControlled growth of Controlled growth of heterostructuresheterostructures difficult to realize: Core/shells, difficult to realize: Core/shells, graded alloys, rod/rod graded alloys, rod/rod heterostructuresheterostructures, , dumbellsdumbells

Monomers

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Case Study: Continuous synthesis of Case Study: Continuous synthesis of CdSeCdSe QDsQDs

B.K. Yen et al., Angew. Chem. 44, 5447 (2005)

Saif Khan

Narrow emission line widths = Narrow emission line widths = better quantum dotsbetter quantum dotsHigher yield and continuous Higher yield and continuous synthesis enabling optimization of synthesis enabling optimization of reaction conditionsreaction conditions2727

Case Study: Continuous synthesis of Case Study: Continuous synthesis of CdSeCdSe QDsQDsResidence time

180 ° C

12 s 130 s25 s 8.5 min

B.K. Yen et al., Angew. Chem. 44, 5447 (2005)

ure

230 ° C

270 ° C

Saif Khan

Narrow emission line widths = Narrow emission line widths = better quantum dotsbetter quantum dotsHigher yield and continuous Higher yield and continuous synthesis enabling optimization of synthesis enabling optimization of reaction conditionsreaction conditions2828

Tem

pera

tu310 ° C

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Access to supercritical conditions produce Access to supercritical conditions produce product with superior performance product with superior performance --CdSeCdSe QDs with narrow size distributionQDs with narrow size distribution

20 nm

Supercritical fluid processing narrows RTD and enhances Supercritical fluid processing narrows RTD and enhances nucleation leading to narrow line width emissionnucleation leading to narrow line width emission

20 nm

Automated Automated microfluidicmicrofluidic platform for platform for biological applicationsbiological applicationsCase: Delivering compounds into cellsCase: Delivering compounds into cellsFundamental biological studies of cell Fundamental biological studies of cell function relevant to disease and curefunction relevant to disease and cureViral vectors for DNA, but challenges Viral vectors for DNA, but challenges in flexibility and transfer of in flexibility and transfer of iRNAiRNA

TTools ools for transfer of proteins and for transfer of proteins and molecular probes across cell molecular probes across cell membranes all have shortcomingsmembranes all have shortcomings–– Chemical Chemical methods: synthetic methods: synthetic

vectors vectors and nanoparticlesand nanoparticlespp–– Biological vectors : virusesBiological vectors : viruses–– ElectroporationElectroporation–– UltrasoundUltrasound–– Gene Gene gungun–– Manual injectionManual injection

gold standardbut slow

3030

16

Pressure

Use pressure to create a small jet that Use pressure to create a small jet that pierces the cell wall injecting known pierces the cell wall injecting known picopico liter volumes of materialliter volumes of material

Automated control unit

Cell suspension

In flow~ 15 μm Out flow

CellMicron sizedNozzle

Pressure chamber with fluid to be

injected

generation unit

Cell detection system

In flow

3131

Use electrical measurements to detect Use electrical measurements to detect presence of cells and flow focusing to control presence of cells and flow focusing to control cell position and avoid adhesioncell position and avoid adhesion

3232

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Use electrical measurements to detect Use electrical measurements to detect presence of cells and flow focusing to control presence of cells and flow focusing to control cell position and avoid adhesioncell position and avoid adhesion

0ptical

Fluorescence

3333

Fluorescence

Injection of high MW fluorescent dextran into Jurkat cells ~1000 cells/h

Summary and OutlookSummary and Outlook

Automated continuous flow microfluidic systems and their scaleAutomated continuous flow microfluidic systems and their scale--up equivalents offer opportunities for revolutionizing traditionally up equivalents offer opportunities for revolutionizing traditionally b t h i t d i lt h i t d h ti l hb t h i t d i lt h i t d h ti l hbatch oriented specialty chemistry and pharmaceutical research batch oriented specialty chemistry and pharmaceutical research and developmentand developmentMicrofluidic systems enable synthesis of Microfluidic systems enable synthesis of novel novel engineered engineered nanostructures with improved yield and controlled size nanostructures with improved yield and controlled size distribution at conditions difficult to achieve be conventional distribution at conditions difficult to achieve be conventional means means Future research and development efforts will increasingly rely Future research and development efforts will increasingly rely on automated, integrated continuous flow systems offering on automated, integrated continuous flow systems offering faster access to process information and speed to market at faster access to process information and speed to market at lower cost and less environmental impactlower cost and less environmental impactIntegration of multiple functions and ease of use remain a Integration of multiple functions and ease of use remain a significant challenges to the wide spread use of chemical and significant challenges to the wide spread use of chemical and biological biological microsystemsmicrosystems, but advances are being made, but advances are being made

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AcknowledgementsAcknowledgements

Microreactors:Ryan Hartman, Jason Kralj, Eddie Murphy, Hemantkumar Sahoo, Nik l Z b kNikolay Zaborenko

Colloids and Quantum dot synthesis:Axel Günther, Saif Kahn, Jane Rempel, Samuel Marre, Soubir BasakJongnam Park, Brian Yen (Bawendi Lab)

Bi l i l i tBiological microsystemsAndrea Adamo and Armon Sharei

Microfabrication:Professor Marty Schmidt and the staff of Microsystems Technology Laboratories3535

Thank You Thank You

QuestionsQuestions??

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improved chemical synthesisimproved chemical synthesis

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