Continuous-Flow Organometallic CatalysisFlow ... · Continuous-Flow Organometallic CatalysisFlow...

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πάντα εContinuous Flow Organometallic Catalysis Continuous-Flow Organometallic Catalysis Using Advanced Fluids: Towards Adaptive Catalytic Systems for Asymmetric Catalysis Walter Leitner and Giancarlo Franciò Institut für Technische und Makromolekulare Chemie RSC/ACG Conference: Challenges in Catalysis for Pharmaceuticals and Fine Chemicals V London, UK, November 2, 2016

Transcript of Continuous-Flow Organometallic CatalysisFlow ... · Continuous-Flow Organometallic CatalysisFlow...

Page 1: Continuous-Flow Organometallic CatalysisFlow ... · Continuous-Flow Organometallic CatalysisFlow Organometallic Catalysis Using Advanced Fluids: ... Handbook of Green Chemistry Volume

πάντα ῥεῖContinuous Flow Organometallic CatalysisContinuous-Flow Organometallic Catalysis

Using Advanced Fluids:

Towards Adaptive Catalytic Systems for Asymmetric Catalysis

Walter Leitner and Giancarlo Franciò

Institut für Technische undMakromolekulare Chemie

RSC/ACG Conference:Challenges in Catalysis for Pharmaceuticals and Fine Chemicals V

London, UK, November 2, 2016

Page 2: Continuous-Flow Organometallic CatalysisFlow ... · Continuous-Flow Organometallic CatalysisFlow Organometallic Catalysis Using Advanced Fluids: ... Handbook of Green Chemistry Volume

known reactionsknown processes

known reactionsnew processing windows

new reactionsnew control mechanismsknown processes

flexibleflexiblenew processing windows

integratedintegratednew control mechanisms

adaptivadaptiv

PRODUCTIONPRODUCTION

DEVELOPMENT DEVELOPMENT

PRODUCTION PRODUCTION

MESOMESOSCALESCALE

MACROMACROSCALESCALE

SYNTHESIS SYNTHESIS

MOLECULAR MOLECULAR SCALE SCALE

H J Federsel

Continous-flow production is on the top priority listof the Pharmaceutical Industry Round Table of the ACS Green Chemistry Institute!

H. J. Federsel, Green Chemistry 2013, 15, 3105 – 3115.

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Astra Zeneca APIJAK2 kinase inhibitor

Augustine Method

molecular catalyst

Metal oxide

porous support

Electrostatic anchor

(polyoxo-metallate, POM)

material(e.g. silica, alumina)

Z. Amara, M. Poliakoff, R. Duque, D. Geier, G. Franciò, C. M. Gordon, R. E. Meadows, R. Woodward, W. Leitner

Org. Proc. Res. Dev. 2016, 20, 1321-1327 (ACS Editor‘s Choice)

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ccaa 8 8 monthmonth developmentdevelopment time, kg per time, kg per dayday productionproduction, , nono purificationpurification necessarynecessary

Z. Amara, M. Poliakoff, R. Duque, D. Geier, G. Franciò, C. M. Gordon, R. E. Meadows, R. Woodward, W. Leitner

Org. Proc. Res. Dev. 2016, 20, 1321-1327 (ACS Editor‘s Choice)

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scCOscCO2substrates

UpstreamUpstream

scCO2product(s)

UpstreamUpstreamseparationseparation

product(s)

Downstream Downstream separationseparation

Catalystintegrated separation

.

M. Poliakoff, P.Jessop, D. Cole-Hamilton,T. Baker/B. Tumas, T. Ikariya, K. Nozaki, A. Baiker, P. Lodzano, J. Brennecke,….. y

Handbook of Green Chemistry Volume 4: Supercritical Fluids,, Wiley-VCH, 2010.W. Leitner, Acc. Chem. Res. 2002, 35, 746-756.

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Gas-like:

miscibilitye

p supersuper--

ymass transfer

pres

sure

solidliquid

critical point

criticalcritical Liquid-like:

solvent powerheat capacityp

gaseous

Tc = 31.0 °Cpc = 73.75 bar

heat capacity

U i

temperature T

gaseous Unique:

tunabilityreactivityp y

Nontoxic, nonflammable, no ecotoxicity, cheap and abundant!

Handbook of Green Chemistry Volume 4: Supercritical Fluids,, Wiley-VCH, 2010.W. Leitner, Acc. Chem. Res. 2002, 35, 746-756.

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ExtractionPurification

Catalysis

Gas-like:

miscibility

Purification

e p supersuper--

ymass transfer

F t Th S Ltd /

pres

sure

solidliquid

critical point

criticalcritical Liquid-like:

solvent powerheat capacityFoto: Degussa

Foto: Natex/Prof. Weidner, Ruhr Uni Bochum

Foto: Thomas Swan Ltd /Prof. Poliakoff, Nottingham

p

gaseous

Tc = 31.0 °Cpc = 73.75 bar

heat capacity

U i

Foto: Degussa

ParticleFormation

ChromatographyAnalytics

temperature T

gaseous Unique:

tunabilityreactivityp y

Nontoxic, nonflammable, no ecotoxicity, cheap and abundant!Foto: Separex

Foto: http://www waters com

Foto: http://www.waters.com

Handbook of Green Chemistry Volume 4: Supercritical Fluids,, Wiley-VCH, 2010.W. Leitner, Acc. Chem. Res. 2002, 35, 746-756.

Foto: http://www.waters.com

Technology Platform for scCO2

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Downstream Separation

H3C(H2C)10 O

O (CH2)10CH3O

OOH

+ + OH

IL / scCO2CAL B

ti ti

SRrac CH3CHO

reaction separation

130 bar 100 bar 200 bar

ee > 97 %sel. > 99.5 %

recovery = 81 %

70 °C 100 °C50 °C

CO2O

OH

+ substrates O (CH2)11H

O

high COhigh CO22--densitydensity low COlow CO22--densitydensity

ee > 97 %sel. > 99.5 %

recovery = 97 %enzyme inionic liquid high COhigh CO22 densitydensity 22 yy

M. T. Reetz, W. Wiesenhöfer, G. Franciò, W. Leitner, Adv. Synth. Catal. 2003, 345, 1221

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V-12V-14

V-15V-16

I-1

V-17

E-7

PIRA+I-4

V-18E-8 V-20

Compressed air

CO /H t t

TIRCI-8

Gas-liquid

vent

S PscCO2

Multiphase Catalysis

E-1V-1

V-2 V-3

V-4

V-9

E-3V-10

V-11

E-5

V-13

PIRA+I-2

PIA+I-3

WIRI-6

CO2

PIRCA+I-7 V-19

E-9

CO2/H2 to vent

E-10

TIRCI-9

Substrate

separator

Dry iceethanol

E-12

HPLC

vent

vent

FCR+I-11

Back pressureRegulator BPR

V-21

P-33

S P

IonicLiquid

scCO2

E-2

H2

V-5V-6 V-7 V-8

V-9

E-4

TIRCA+I-5

Liq. Product

el.

Fraction collector

Windowreactor

I-10

I 11

MFCchiralcatalyst

)()( 2

, ILcCOcK

i

iiN

C. Roosen, J.-L. Muller, M. Kaever, H. Kronenberg, R. Thelen, S. Aey, T. Harwardt, W. Leitner, L. Greiner, J. Supercrit. Fluids 2009, 48, 33-34.

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CO2

( 6 )C

Ionic Liquid

[Ru(6-benzene)Cl2]2

J. Theuerkauf, G. Franciò, W. Leitner, Adv. Synth. Catal., 2013, 355, 209-219.

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2500090

100

ee: 90%

TOF: 122 h-115000

20000

607080

%]

STY = 0.15 kg/L·h10000

15000

405060

TON

Cv,

ee

[%

productivity: 30 kg / g (Ru)5000

102030

conv.eeTON

0010

0 50 100 150 200t [h]

TON

[ ]

J. Theuerkauf, G. Franciò, W. Leitner, Adv. Synth. Catal., 2013, 355, 209-219.

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Processing profile for100 kg of product

Batch Cont. FlowNumber of batches 4 1Reaction unit [L] 50 5,4Reaction solvent [L] 100 2 7Reaction solvent [L] 100 2,7Catalyst [g] 350 25Reaction time [h] 4x6 96Processing time [weeks] 1-2 <1Pressure [bar] 4 250

J. Theuerkauf, G. Francio, W. Leitner, Adv. Synth. Catal., 2013, 355, 209-219.

Temperature [°C] 100 60

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acid co-catalystsolubility: product > substrate

[Ru(6-benzene)Cl2]2

solubility: product < substrate

b t l t

J. Theuerkauf, G. Franciò, W. Leitner, Adv. Synth. Catal., 2013, 355, 209-219.

base co-catalyst

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T. M. Konrad, P. Schmitz, W. Leitner, G. Franciò, Chem. Eur. J. 2013, 19, 13299–13303.

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C. Schmitz, K. Holthusen, W. Leitner, G. Franciò, ACS Catal. 2016, 6, 1584-1589 (ACS Editor‘s choice).

For asymmeric hydroformylation in scCO2 flow, see:K. Nozaki et al., J. Am. Chem. Soc. 2003, 125, 8555-8660.

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Comparison of Immobilization Strategies: Modular Set-Up

Z. Zhang, G. Franciò, W. Leitner, ChemCatChem, 2015, 7, 1961-1965.

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90000100

700008000090000

708090

100

400005000060000

506070

TON

v, e

e [%

]

10000200003000040000

203040 T

Cv

conv.ee

010000

010

0 50 100 150 200 250t [h]

TON

t [h]

Z. Zhang, G. Franciò, W. Leitner, ChemCatChem 2015, 7, 1961-1965.

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Cole-Hamilton

SS t dWasserscheid SSupportedIIonicLLiquid

Wasserscheid,Ferhmann/Rijsager,

Hölderich,…..

For gas phase C4-hydroformylation see:

PPhase

g p y yS. Walter, M. Haumann, P. Wasserscheid, H. Hahn, R. Franke, AIChE J. 2015, 61, 893.

G. Francò, U. Hintermair, W. Leitner, Phil. Trans. R. Soc. A 2015, 373, 20150005

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scCO2 scCO2

H2H2

waterscavenger

SILPcatalyst

ee > 99%

lab scale: > 1 kg / weeklab scale: > 1 kg / week

STY = 0.3 kg/lxh

productivity: > 100 kg / g (Rh)

U. Hintermair, G. Franciò, W. Leitner, Chem. Eur. J. 2013, 19,4538-4547.

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PumpMFC (CO2) MFC (H2) Reactor AnalyticsSampling Analytics

labscaleupscaled

0.04 mL/min2.12 mL/min

80 mLN/min4 LN/min

20 mLN/min1 LN/min

10 mL170 mL

offlineonline

manualautomated

offlineonline

SYNFLOW Demonstrator Unit: An Adaptive Reactor System

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Possible interactions of catalyst complex and IL matrix

Ion Pairing-

LigandConformation

+

Coordination

Conformation

Early Examples for „External“ chirality transfer: Seebach, Anderson, Brown, Faller, Mikami, .….

Angew. Chem Int. Ed. 2006, 45, 3689-3692; Chem. Commun. 2007, 4012-4014;Angew. Chem. Int. Ed. 2008, 47, 7339-7341; ChemCatChem. 2010, 2, 55-57.

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ee = 69 % (S)

racemiccatalyst

chiralionic liquid

rac-BINAP

454647484950515253545556 ppm

(R)-BINAP

D. Chen, M. Schmitkamp, G. Franciò, J. Klankermayer, W. Leitner, Angew. Chem. Int. Ed. 2008, 47, 7339-7341.

31P{1H}-NMR

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Ph2P

RhNH

Ph2P N

H

NTf2-

chiral ILPh2P

RhNH

NTf2-

+diastereomerisationO

Rh

Ph2P

PPh2

Rh HO OMe

NTf2-PPh2

Rh HO OMe CH2Cl2,

50 °C, 20 h

(RaSc)

PPh2

Rh HO OMe

(RaSc)

+O

RhPPh2

(SaSc)

CH2Cl2,-10 °C, 10 min

hi lchiralionic liquid

P. Oczipka, D. Müller, W. Leitner, G. Franciò, Chem. Sci. 2016, 7, 678-683.

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P. Oczipka, D. Müller, W. Leitner, G. Franciò, Chem. Sci. 2016, 7, 678-683.

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scCO2substrates

scCOscCO2product(s)

Catalystin supported liquid phase matrixin supported liquid phase matrix

For Review, see:K. L. Luska, P. Migowski, W. Leitner, Green Chem. 2015, 17; 3195 – 3206.

For Review, see:E. García-Verdugo, B. Altava, M. I. Burguete,

P. Lozano, S. V. Luis, Green Chem. 2015, 17, 2693 – 2713

Review (gold open access):G. Franciò, U. Hintermair, W. Leitner, Phil. Trans. R. Soc. A. 2015, 373, 20150005.

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DFG

Markus Hölscher

Giancarlo Franciò

Jürgen Klankermayer

Walter Leitner

Regina Palkovits

Marcel Liauw

MarcusRose

NilsTheyssen*

Thomas Müller*

* affiliated members

Technical Chemistry @ RWTH Aachen University

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πάντα ῥεῖ

panta rheip

all flows“„all flowsἩἩράκλειτοςράκλειτοςHeraclitusHeraclitus

caca 535 535 -- 475 BC 475 BC