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  • πάντα ῥεῖ Continuous Flow Organometallic CatalysisContinuous-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

  • known reactions known processes

    known reactions new processing windows

    new reactions new control mechanismsknown processes

    flexibleflexible new processing windows

    integratedintegrated new control mechanisms

    adaptivadaptiv

    PRODUCTIONPRODUCTION

    DEVELOPMENT DEVELOPMENT

    PRODUCTION PRODUCTION

    MESOMESO SCALESCALE

    MACROMACRO SCALESCALE

    SYNTHESIS SYNTHESIS

    MOLECULAR MOLECULAR SCALE SCALE

    H J Federsel

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

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

  • Astra Zeneca API JAK2 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)

  • 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)

  • scCOscCO2 substrates

    UpstreamUpstream

    scCO2 product(s)

    UpstreamUpstream separationseparation

    product(s)

    Downstream Downstream separationseparation

    Catalyst integrated 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.

  • Gas-like:

    miscibility e

    p supersuper--

    y mass transfer

    pr es

    su re

    solid liquid

    critical point

    criticalcritical Liquid-like: solvent power heat capacityp

    gaseous

    Tc = 31.0 °C pc = 73.75 bar

    heat capacity

    U i

    temperature T

    gaseous Unique: tunability reactivityp 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.

  • Extraction Purification

    Catalysis

    Gas-like:

    miscibility

    Purification

    e p supersuper--

    y mass transfer

    F t Th S Ltd /

    pr es

    su re

    solid liquid

    critical point

    criticalcritical Liquid-like: solvent power heat capacityFoto: Degussa

    Foto: Natex/Prof. Weidner, Ruhr Uni Bochum

    Foto: Thomas Swan Ltd / Prof. Poliakoff, Nottingham

    p

    gaseous

    Tc = 31.0 °C pc = 73.75 bar

    heat capacity

    U i

    Foto: Degussa

    Particle Formation

    Chromatography Analytics

    temperature T

    gaseous Unique: tunability reactivityp 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

  • Downstream Separation

    H3C(H2C)10 O

    O (CH2)10CH3O

    OOH

    + + OH

    IL / scCO2 CAL 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

    CO2 O

    OH

    + substrates O (CH2)11H

    O

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

    ee > 97 % sel. > 99.5 %

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

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

  • V-12V-14

    V-15 V-16

    I-1

    V-17

    E-7

    PIRA+ I-4

    V-18E-8 V-20

    Compressed air

    CO /H t t

    TIRC I-8

    Gas-liquid

    vent

    S PscCO2

    Multiphase Catalysis

    E-1 V-1

    V-2 V-3

    V-4

    V-9

    E-3V-10

    V-11

    E-5

    V-13

    PIRA+ I-2

    PIA+ I-3

    WIR I-6

    CO2 PIRCA+

    I-7 V-19

    E-9

    CO2/H2 to vent

    E-10

    TIRC I-9

    Substrate

    separator

    Dry ice ethanol

    E-12

    HPLC

    vent

    vent

    FCR+ I-11

    Back pressure Regulator BPR

    V-21

    P-33

    S P

    Ionic Liquid

    scCO2

    E-2

    H2

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

    V-9

    E-4

    TIRCA+ I-5

    Liq. Product

    el.

    Fraction collector

    Window reactor

    I-10

    I 11

    MFCchiral catalyst

    )( )( 2

    , ILc COcK

    i

    i iN 

    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.

  • CO2

    ( 6 )C

    Ionic Liquid

    [Ru(6-benzene)Cl2]2

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

  • 25000 90

    100

    ee: 90%

    TOF: 122 h-1 15000

    20000

    60 70 80

    % ]

    STY = 0.15 kg/L·h 10000

    15000

    40 50 60

    TO N

    C v,

    e e

    [%

    productivity: 30 kg / g (Ru) 5000

    10 20 30

    conv. ee TON

    00 10

    0 50 100 150 200 t [h]

    TON

    [ ]

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

  • Processing profile for 100 kg of product

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

  • acid co-catalyst solubility: 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

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

  • 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.

  • Comparison of Immobilization Strategies: Modular Set-Up

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

  • 90000100

    70000 80000 90000

    70 80 90

    100

    40000 50000 60000

    50 60 70

    TO N

    v, e

    e [%

    ]

    10000 20000 30000 40000

    20 30 40 TC

    v

    conv. ee

    0 10000

    0 10

    0 50 100 150 200 250 t [h]

    TON

    t [h]

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

  • Cole-Hamilton

    SS t dWasserscheid SSupported IIonic LLiquid

    Wasserscheid, Ferhmann/Rijsager,

    Hölderich,…..

    For gas phase C4-hydroformylation see:

    PPhase

    g p y y S. 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

  • scCO2 scCO2

    H2H2

    water scavenger

    SILP catalyst

    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.

  • PumpMFC (CO2) MFC (H2) Reactor AnalyticsSampling Analytics

    labscale upscaled

    0.04 mL/min 2.12 mL/min

    80 mLN/min 4 LN/min

    20 mLN/min 1 LN/min

    10 mL 170 mL

    offline online

    manual automated

    offline online

    SYNFLOW Demonstrator Unit: An Adaptive Reactor System

  • Possible interactions of catalyst complex and IL matrix

    Ion Pairing -

    Ligand Conformation

    +

    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.

  • ee = 69 % (S)

    racemic catalyst

    chiral ionic liquid

    rac-BINAP

    454647484950515253545556 ppm

    (R)-BINAP