Microfluidique et procédés continus : les outils du chimiste de demain par Jean-Christophe MONBALIU | LIEGE CREATIVE, 06.02.06

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Microfluidique et procédés continus : les outils du chimiste de demain Jean-Christophe MONBALIU, ULg – CiTOS

Avec le soutien de :

Microfluidics*and*Con.nuous*Processes!*

Jean%Christophe.M..Monbaliu!CiTOS!

Department!of!Chemistry!University!of!Liège!

[email protected]|www.citos.ulg.ac.be!

Liège*créa.ve*

Feb*6,*2014*

The Future of Organic Chemistry

Outline!

1.  *Current*status*of*organic*chemistry*2. !What!is!conDnuous!flow!chemistry/conDnuous!manufacturing?!3. !Pros!and!Cons!!4. !Flow!chemistry!at!CiTOS!5. !Conclusions!!

!

2!

Current*status*of*organic*chemistry*!

3!

NIMBY*syndrome*Organic!chemistry!has!gained!a!bad!reputaDon!in!modern!society!•  2000J2014:*85!(US)!/!111!(EU)!serious!chemical!incidents!in!organic!chemistryS

related!industry!•  2000J2013:!120!(US)!serious!incidents!in!organic!chemistrySrelated!academic!

labs!!!!!

hUp://www.csb.gov/!

Current*status*of*organic*chemistry*!

4!

NIMBY*syndrome*Organic!chemistry!has!gained!a!bad!reputaDon!in!modern!society!The!E(nvironmental)Sfactor!!!!

Up to 85% = solvent!

product

waste

kgkg

=E

Green!Chem!2007,!9,!1273!

S  Rethink!processes?!!S  Smaller!producDon!faciliDes,!yet!capable!of!largeSscale!producDon!

A*future*for*organic*chemistry?*!

5!

**

KEY!*FEATURES!

Batch*reactors* Con.nuousJFlow*micro/mesoreactors*

3D!internal!structure!>>!104!µm!(typ.!mL!<!internal!volume!<!kL)!ScaleSdependent!processes!Low!S/V!raDo!

3D!internal!structures!<!1000!µm!(typ.!µL!<!internal!volume!<!mL)!ScaleSindependent!processes!!High!S/V!raDo!

Outline!

1. !Current!status!of!organic!chemistry!2.  *What*is*con.nuous*flow*chemistry/con.nuous*manufacturing?*3. !Pros!and!Cons!!4. !Flow!chemistry!at!CiTOS!5. !Conclusions!!

!

6!

What*is*con.nuous*flow*chemistry?*!

7!2!m!

15!cm!

5!cm!

Channel!Ø:!<!1!mm!Vint:!>!1!mL!

Channel!Ø:!typ.!100!µm!Vint:!up!to!250!µL!

Channel!Ø:!up!to!800!µm!Vint:!µL!S!mL!

microreactors*(typ.*250*µL*Vint)*S !Explore!and!develop!chemistry!S !OpDmize!reacDon!(R&D) !!

mesoreactors*(typ.*10*mL*Vint)*S!Pilot!and!ProducDon!

Con.nuous**micro*/*mesofluidic*(MF)*reactors*

What*is*con.nuous*flow*chemistry?*!

8!

Flow*chemistry*is!a!term!widely!used!to!describe!the!performance!of!a!reacDon!in!a!conDnuous!manner,!in!a!MF!device.!

Tetrahedron Lett. 2010, 51, 5830-5833.

µR1R1

R2P

Con.nuous* manufacturing* is! a! term! widely! used! to! describe! the!performance!of!a!process! in!a! fully!conDnuous!manner,! in!a!single!uninterrupted!MF!reactor!network.!

Glass,!Ceramic,!Si,!SiC,!Polymer,!SS,!etc.!

µL!to!!mL!

9!

What*is*con.nuous*manufacturing?*

Modern*driving*concepts*for*industry*Sustainability!and!Green!Chemistry!• ! GCI! established! in! 2007! that! con.nuous* manufacturing*was! a! research* top*priority*

!!!**!

10!Org!Proc!Res!Dev!2011,!15,!900;!Green!Chem!2012,!14,!38!

Con.nuous*manufacturing!

Modern*driving*concepts*for*industry*Sustainability!–!principles!for!Green!Chemistry!!!!!**!

11!

Preven.on*of*waste*Atom!economy!

Less*hazardous*syntheses*Safer!chemicals!Safer!solvents!

Energy*efficiency*

Renewable!feedstocks!Reduce!derivaDves!

Catalysis!Design!for!degradaDon!RealJ.me*analysis*

Inherently*safer*processes**

12*Principles*for*Green*Chemistry:*

Org!Proc!Res!Dev!2011,!15,!900;!Green!Chem!2012,!14,!38!

Con.nuous*manufacturing!

Outline!

1. !Current!status!of!organic!chemistry!2. !What!is!conDnuous!flow!chemistry/conDnuous!manufacturing?!3.  *Pros*and*Cons**4. !Flow!chemistry!at!CiTOS!5. !Conclusions!!

!

12!

Why*con.nuous*manufacturing?*!

13!

Batch* Flow*

PROS!

CostSefficient.!VersaDle!reactors!(reacDons,!purificaDons,!recristallisaDon,!disDllaDon,!etc.).!Robust,!oldSschool!technology,!common!in!labs!and!industrial!faciliDes.!Wide!tolerance:!gas,!liquid,!solids.!ExisDng!regulaDons!and!longstanding!knowShow.!Product!traceability!(batch!#).!

Reduced!footprint,!flexible,!mobile.!Inherently!safer.!Expansion!of!the!chemical!space!(intensificaDon).!Suitable!for!transient!species!and!unusual!condiDons.!Fast!transfer!from!R&D!to!producDon,!scaleSout!or!numberingSup!strategies.!Telescoping!of!complex!sequences.!High!mixing!and!heat!transfer!efficiencies.!Homogeneous!producDon.!

CONS!

Large!footprint,!dedicated!faciliDes.!High!industrial!risk.!Safety!hazards.!Not!suitable!for!transient!species!or!extreme!condiDons.!ScaleSup!is!Dme!consuming,!and!oqen!requires!reSopDmizaDon.!SequenDal!(step!by!step)!strategies.!Low!mixing!and!heat!transfer!efficiencies.!ProducDon!variability.!

High!starDng!costs.!BatchStoSflow!adaptaDon.!!New!technology:!scarce!knowhow.!Product!traceability!(new!regulaDons!needed).!Difficult!to!process!solids.!

Overview*J*Advantages*|*1*

Transfer*phenomena*S!High!S/V,!high!mixing!efficiency!Safety!S!Small!scale,!no!accumulaDon!of!reacDve/toxic!intermediates!Expansion*of*reac.on*space/feasibility*S!“Forbidden!condiDons”!*Robustness,*stability*S!SteadySstate,!constant!quality!Reac.on*telescoping*S!Fully!conDnuous!mulDple!steps!Scalability!S!20x!scaleSup!is!rouDne!Efficiency!S!Time!and!space!yield,!increase!in!throughput,!reduced!equipment!footprint,!reduced!DmeStoSmarket,!low!OPEX/CAPEX!!!

Chemical*processes*in*MF*reactors:*Pros*

Overview*J*Advantages*|*2*Mass*transfer!

*

SolvaySSeptember!27,!2010!

batch!

flow!

Corollary*1:*strict*stoichiometry! 15!


HOOH

OH

OO

OR

R = H, solketalR = tBu, STBE

X

X = O, CH2

H2O

H2SO4 cat

75-90°C1-17 barg

Corning Advanced-FlowTM reactor90 t/y

16!

A1

A2

B1Feed 1

Feed 2

Feed 1'

Feed 3

HE in

Product

HE out

FM01

FM02 FM03 FM04 FM05 FM06 FM07 FM08 FM09

FM01

Overview*J*Advantages*|*3*Mass*transfer!

*


17!Bioresource)Techn.)2011,!102,!9304;!!Chem.)Today!2010,!28,!8..

Overview*J*Advantages*|*4*Mass*transfer*

*

O

OO

OH

H2O

HOOH

OH OO

O

STEP 1 STEP 2

cat. H+cat. H+

solketal STBE

Batch STEP*1 Corning*AFR10#12%h time 26%s

>%75%°C T 75%°C10#12%eq acetone 4%eqAzeotrope,%etc. additives none

10%wt.#% catalyst 10%wt.#%99%% yield >98%%

Batch STEP*2 Corning*AFR10#12%h time 32%s

60%°C T 90%°C25%bar pressure 17%bar2%eq iBu 1%eq

tBuOH additives none10%wt.#% catalyst 10%wt.#%

95 % yield >95%

41!s!


Overview*J*Advantages*|*5*Heat!transfer!

*

Reactor(type( Surface/volume-(cm²/cm³)-

100-mL-reaction-bulb- 1-1-m³-reactor- 0.06-

µchannel-100-µm- 200-

18!


Overview*J*Advantages*|*6*Heat!transfer!

*

desired!reacDon!A!!!!![B’]!!!!!B!vs.!side!reacDon!A!!!!![C’]!!!!!C!

Corollary*2:*less*side*products,*less*solvents,**higher*yield,*faster*reac.ons*See!also:!exothermic!reacDons! 19!


- selective nitration- less waste- highly exothermic quench- 12 milistructured glass fluidic modules (VT > 150 mL)- 13 kg h-1 total processed material

Naproxcinod

OHR

solvent

HNO3 H2ONaOH

ONO2R

HO

HO O

O

OO2NO

nitration quench

Feed preparation

Chem!Oggi/Chem!Today!2009,!27,!26!20!

Overview*J*Advantages*|*7*Heat!transfer!Exothermic!nitraDon/quench:!!*


Overview*J*Advantages*|*8*Inherent!safety!–!small!volumes,!containment,!onSsite!*

21!

8!mL!internal!volume!1000*L*isobutene/day*

(0.01*mL/s)*

1000*L*internal*volume**

Small*amount**of*processed*material/s*

Large**amount**of*processed*material*

O

O

OH

/ H2SO4

O

O

O

Bioresour!Technol!2011,!102,!9304–7!


Overview*J*Advantages*|*9*Inherent!safety!–!small!volumes,!containment,!onSsite!*

No*stockpiling/transporta.on*issues*

22!


Overview*J*Advantages*|*10*Expansion!of!reacDon!space/feasibility!Flash!chemistry!

S I B

P

k1 k2

quench

k1!=!10!sS1!and!k2/k1!=!0.01!k1!=!10!hS1!and!k2/k1)=!0.01!

Achievable*in*batch* Not*achievable*in*batch*Requires*precise*tR*control*

Manipula.on*of*transient*species,*unstable*intermediates,*etc.!23!


Chem!Eur!J!2010,!14149!

Overview*J*Advantages*|*11*Expansion!of!reacDon!space/feasibility!Revival!of!photochemistry!

24!


!=− #$%↓10 (/(↓0  

Distance from lamp (µm) 0 500 1000 1500 2000

0

0.1

0.2 0.3 0.4

0.5 0.6 0.7

0.9

0.8

1

Ligh

t tra

nsm

issi

on I/

I°

100

•  Uniform! irradiaDon! of! the! whole!reacDon!soluDon!

•  High* concentra.on* soluDons! can!be!irradiated!effecDvely!

•  Precise!control!of!exposure!Dme!

MF*reactors* Batch*reactors*

Overview*J*Advantages*|*12*ReacDon!Telescoping!*

a. Workupb. Purification



A + B C + D + Estep 1 step 2 step 3

reactor 1 reactor 2 reactor 3

A

BC D

E

(a)

(b)

25!




A + B C + D + Estep 1 step 2 step 3

reactor 1 reactor 2 reactor 3

A

BC D

E

(a)

(b)


Overview*J*Advantages*|*14*Scalability!TradiDonal!scaleSup!(batch):!

*

Lab!scale! !!! ! !pilot ! !! !!producDon!

scale*effect*=*reop.miza.on!26!


Overview*J*Advantages*|*15*Scalability!Flow:!numbering!up!or!scaleSout!

*

a!x! A!x!

Same*opera.ng*condi.ons*(Minimal)*reJop.miza.on*

27!

Scale-out:

Numbering up:


28!hUp://corporate.evonik.com!


Overview*J*Advantages*|*18*Reduced!footprint!S!Mobile,!compact,!reconfigurable,!versaDle!

Overview*–*Disadvantages*J*Challenges**•  SolidJcarrying*media*–!accumulaDon,!clogging!•  Adapta.on!–!batchStoSflow,!scarce!knowShow!•  StartJup*costs*–!highly!engineered!equipment!•  Product*traceability*–!new!regulaDons!needed!!*

Chemical*processes*in*MF*reactors:*Cons*

Overview*–*Disadvantages*J*Challenges**!*

Chemical*processes*in*MF*reactors:*Cons*

Decision*Analysis!!

*!

Angew!Chem!Int!Ed!2011,!50,!7502!

ReacDon!

What!is!the!goal!of!the!experiment?!

Is!H!X!important?!

Is!mixing!important?!

Dispersion!effects?!

General** Process*

UnconvenDonal!!condiDons?!

No* Yes*

batch* flow*

Yes*

Yes*

Yes*

No*

batch*

flow*

Decision*roadmap:*batch*or*flow?*

50%*of*reac.ons*currently*in*use*could*benefit*from*con.nuous*flow*chemistry*

Outline!

1. !Current!status!of!organic!chemistry!2. !What!is!conDnuous!flow!chemistry/conDnuous!manufacturing?!3. !Pros!and!Cons!!4. !Flow*chemistry*at*CiTOS*5. !Conclusions!!

!

32!

www.citos.ulg.ac.be!

Flow*chemistry*at*CiTOS*

Outline!

1. !Current!status!of!organic!chemistry!2. !What!is!conDnuous!flow!chemistry/conDnuous!manufacturing?!3. !Pros!and!Cons!!4. !Flow!chemistry!at!CiTOS!5.  *Conclusions*!

!

34!

35!

Summary!

• !Complex!chemistries!accessible!• !IntegraDon!of!various!unit!operaDons!• !IntensificaDon!• !ManipulaDon!of!highly!unstable!intermediates!• !High!producDviDes!–!small!footprint!• !Greener!processes!• !Mobile!units!

36!

Credits*and*References!General*reviews*on*the*topic:*•  C.!Wiles,!P.!WaUs,!“Con;nuous)process)technology:)a)tool)for)sustainable)produc;on”,)Green)Chem.)2014,!16,!55S62;!•  V.! Hessel,! D.! Kralisch,! N.! Kockmann,! T.! Noël,! Q.! Wang,! “Novel) process) windows) for) enabling,) accelera;ng,) and) upliIing) flow)

chemistry”,!ChemSusChem,!2013,!6,!!746S749.!•  K.!S.!Elvira,!X.!Casadevall!i!Solvas,!R.!C.!R.!WooUon,!A.!J.!deMello,!“The)past,)present)and)poten;al)for)microfluidic)reactor)technology)

in)chemical)synthesis”!Nature)Chemistry,!2013,!5,!905S915.!•  S.!G.!Newman,!K.!F.!Jensen,!“The)role)of)flow)in)green)chemistry)and)engineering”,!Green)Chemistry,!2013,!!15,!1456S1472.!•  L.! N.! Protasova,!M.! Bulut,! D.! Ormerod,! A.! Buekenhoudt,! J.! Berton,! C.! V.! Stevens,! “Latest) highlights) in) liquidPphase) reac;ons) for)

organic)synthesis)in)microreactors”,)Org.)Proc.)Res.)Dev.)2013,*17,!760S769.!•  J.!C.!Pastre,!D.!L.!Browne,!S.!V.!Ley,!“Flow)chemistry)syntheses)of)natural)products”,!Chem.)Soc.)Rev.)2013,!42,!8849S8869.!•  D.! T.!McQuade,! P.! H.! Seeberger,! “Applying) flow) chemistry:)methods,)materials) and)mul;step) synthesis”,) J.) Org.) Chem.)2013,!78,!

6384S6389,!•  C.!Wiles,!P.!WaUs,!“Micro)reactors,)flow)reactors)and)con;nuous)flow)synthesis”,!J.)Chem.)Res.)2012,!181S193.!•  C.!Wiles,!P.!WaUs,!“Con;nuous)flow)reactors:)a)perspec;ve”,!Green)Chem.!2012,!14,)38S54.!•  R.! L.! Hartman,! J.! P.! McMullen,! K.! F.! Jensen,! “Deciding) whether) to) go) with) the) flow:) evalua;ng) the) merits) of) flow) reactors) for)

synthesis”,)Angew.)Chem.)Int.)Ed.)2011,!)50,)7502S7519.!•  D.!Webb,!T.!F.!Jamison,!“Con;nuous)flow)mul;Pstep)organic)synthesis”,!Chem.)Sci.!2010,!1,!675S680.!•  “MicroreacDon!Technology”!SigmaPAldrich)ChemFiles,!2009,!10.!

Books*&*book*chapters*•  Safety)Aspects)related)to)Microreactor)Technology,!J.SC.!Monbaliu,!A.!Cukalovic!and!C.!Stevens,!in!Flow!Chemistry,)Volume!2)(Editors:!

F.!Darvas,!G.!Dormán,!V.!Hessel),)De!Gruyter,)2014.!•  Micro)Reac;on)Technology)in)Organic)Synthesis,!(Editors:!C.!Wiles!and!P.!WaUs)!CRC!Press!Taylor!and!Francis!Group,!Boca!Raton!Fl.,!

2011;*!•  Chemical)Reac;ons)and)Processes)under)Flow)Condi;ons,)RSC)Green)Chemistry)N°5)(Editors:!S.!V.!Luis!and!E.!GarciaSVerdugo),!The!

Royal!Society!of!Chemistry,!Cambridge,!2010.!!*Pictures*•  Slides!5,!7,!9,!16,!18,!20,!21!and!27!contain!pictures!of!Corning®!AdvancedSFlow!ReactorsTM..!*

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Microfluidique et procédés continus : les outils du chimiste de demain par Jean-Christophe MONBALIU | LIEGE CREATIVE, 06.02.06