Vendredi 6 Février
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!
Chemical*processes*in*MF*reactors:*Pros*
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!
*
Chemical*processes*in*MF*reactors:*Pros*
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!
Chemical*processes*in*MF*reactors:*Pros*
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!
Chemical*processes*in*MF*reactors:*Pros*
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!
Chemical*processes*in*MF*reactors:*Pros*
- 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:!!*
Chemical*processes*in*MF*reactors:*Pros*
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!
Chemical*processes*in*MF*reactors:*Pros*
Overview*J*Advantages*|*9*Inherent!safety!–!small!volumes,!containment,!onSsite!*
No*stockpiling/transporta.on*issues*
22!
Chemical*processes*in*MF*reactors:*Pros*
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!
Chemical*processes*in*MF*reactors:*Pros*
Chem!Eur!J!2010,!14149!
Overview*J*Advantages*|*11*Expansion!of!reacDon!space/feasibility!Revival!of!photochemistry!
24!
Chemical*processes*in*MF*reactors:*Pros*
!=− #$%↓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. Workupb. Purification
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. Workupb. Purification
a. Workupb. Purification
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)
Chemical*processes*in*MF*reactors:*Pros*
Overview*J*Advantages*|*14*Scalability!TradiDonal!scaleSup!(batch):!
*
Lab!scale! !!! ! !pilot ! !! !!producDon!
scale*effect*=*reop.miza.on!26!
Chemical*processes*in*MF*reactors:*Pros*
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:
Chemical*processes*in*MF*reactors:*Pros*
28!hUp://corporate.evonik.com!
Chemical*processes*in*MF*reactors:*Pros*
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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