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
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.
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)
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)
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.
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.
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
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
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.
CO2
( 6 )C
Ionic Liquid
[Ru(6-benzene)Cl2]2
J. Theuerkauf, G. Franciò, W. Leitner, Adv. Synth. Catal., 2013, 355, 209-219.
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.
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
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
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
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.
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
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.
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
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.
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
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.
P. Oczipka, D. Müller, W. Leitner, G. Franciò, Chem. Sci. 2016, 7, 678-683.
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.
DFG
Markus Hölscher
Giancarlo Franciò
Jürgen Klankermayer
Walter Leitner
Regina Palkovits
Marcel Liauw
MarcusRose
NilsTheyssen*
Thomas Müller*
* affiliated members
Technical Chemistry @ RWTH Aachen University
πάντα ῥεῖ
panta rheip
all flows“„all flowsἩἩράκλειτοςράκλειτοςHeraclitusHeraclitus
caca 535 535 -- 475 BC 475 BC