Expanding the
Boundaries of Organic
Synthesis Through Flow
Chemistry
Ildiko Kovacs, M. Sc
Corporate History
• ComGenex – Largest biotech acquisition in Eastern Europe – Ever
• ThalesNano, Inc. - Founded in 2002
1990s
2000s
High Throughput chemistry
Micro-reactors
Chemistry on chips
Lab on chips
Flow chemistry
 Combinatorial chemistry
 Parallel chemistry
Microwave chemistry started
ThalesNano’s Technology in the World
33 countries
The most comprehensive bench top continuous
process technology and instrument portfolio
H-Cube Pro™
H-Cube Tutor™
X-Cube Flash™
X-Cube™
H-Cube Autosampler™
and CatCart Changer™
H-Cube Midi™
H-Cube Maxi™
H-Cube®
CatCart Packer™
O-Cube ™
P-Cube™
QuantiFlow™
What is flow chemistry?
• Performing a reaction by pumping one or more starting
materials, typically on small scale, through either a coil or
fixed bed reactor.
• Mixing of liquids is typically performed through a T-piece
creating laminar flow.
Batch vs. Flow
Traditional Batch Method
Flow Method
Reactants
Gas inlet
H-Cube®
Better surface interaction
Controlled residence time
Elimination of the products
By-products
By-products
Reactants
Products
Products
Heating Control
Batch
Flow
Lower reaction volume. Closer and
uniform temperature control
Outcome:
Safer chemistry. Lower possibility of
exotherm.
Larger solvent volume. Lower
temperature control.
Outcome:
More difficult reaction control.
Possibility of exotherm.
Batch
Flow
Wider parameter range
500
Goal
Temperature / °C
400
Regions requested
normally by
supercritical fluids
300
200
100
Flow chemistry
Region 2008
(ThalesNano)
At ThalesNano
0
100
-100
Region covered in a
conventional
laboratory
pressure / bar
200
300
Reduced reaction time
1200
1000
600
Flow
Batch
400
200
30
0
Alkylation
SuzukiMiyaura
Azide
synthesis
25
Sonogashira
reaction
20
t / min
t / min
800
15
Flow
Batch
10
5
0
Aldoxime
reduction
Aldehyde
reduction
Where do I start?
Flow Chemistry Database
www.flowreact.com
Number of reaction schemes: 3297
Number of experiments: 5826
The H-Cube® Hydrogenation
Flow Reactor
Disadvantages with batch reactors
Current batch reactor technology has many disadvantages:







Need hydrogen cylinder-tough safety regulations
Separate laboratory needed!
Time consuming and difficult to set up
Catalyst addition and filtration is hazardous
Parr has low temperature, low pressure capability
Analytical sample obtained through invasive means.
Mixing of 3 phases inefficient - poor reaction rates
H-Cube® Overview
O2 N
H2N
N
H
N
H
H
•
•
•
•
HPLC pumps continuous stream of solvent
Hydrogen generated insitu
Sample heated and passed through catalyst
Up to 100°C and 100 bar. (1 bar=14.5 psi)
Example for fast optimization
cis-stilbene
H2 / cat.
+
H2 / cat.
diphenyl-acetylene
1,2-diphenylethane
trans-stilbene
•
Batch reactions gave results after 4 hours!
H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
Optimization of diphenylacetylene reduction
Catalyst: [RuCl2(mTPPMS)2]/Molselect DEAE
80
80
diphenylethane
cis-stilbene
trans-stilbene
conversion
60
% 40
60
%
20
20
0
30
40
50
60
70
0
80
30
0
T ( C)
•
•
•
diphenylethane
cis-stilbene
trans-stilbene
conversion
40
p(H2) = 30 bar, [S] = 0.1 M
Solvent: toluene/ethanol 1/1
24 experiments, total operation time
is one day
40
50
60
70
80
p(H2) (bar)
•
•
•
T = 50 oC, [S] = 0.1 M
Solvent: toluene/ethanol 1/1
26 experiments, total operation
time is one day
H. H., Horváth; G, Papp; Cs., Csajági; F., Joó; Catalysis Communications; 8; 3; 2007; 442-446
How long can a CatCart® be reused?
H-Cube® conditions: 0.1M, [50:50] EtOAc:EtOH, ~1 bar, 30 oC, 1 mL/min;
Total material processed = 30x 1mmole fractions = 30 mmoles =
4.85 g with 140 mg Pd/C
Product
PRODUCT
STARTING MATERIAL
Starting Material
Optimization of O-CBz group removal
O
OH
10% Pd/C
EtOH/EtOAc (1:1)
H-Cube®
BocHN
COOH
K. Knudsen, J. Holden, S. Ley, M. Ladlow, Adv. Synth. Catal. 2007, 349, 535-538.
BocHN
COOH
Large Scale Hydrogenation
O
OH
10% Pd/C
EtOH/EtOAc (1:1)
60°C, H-Cube®
BocHN
COOH
BocHN
COOH
Single injections 0.2 M
Continuous run 0.2 M
K. Knudsen, J. Holden, S. Ley, M. Ladlow, Adv. Synth. Catal. 2007, 349, 535-538.
Selective aromatic nitroreduction
Catalyst screening
Parameter scanning: effect of residence time to the
conversion and selectivity
Increase and decrease of
residence time on the catalyst
cannot be performed in batch
Flow rate
/ mL/min
Residence
time / sec
Conc. /
mol/dm3
Conv.
/%
Sel.
/%
IrO2
2
9
0.2
52
69
Re2O7
2
9
0.2
53
73
(10%Rh
1% Pd)/C
2
9
0.2
79
60
RuO2
(activated)
2
9
0.2
100
100
1
18
0.2
100
99
0.5
36
0.2
100
98
Ru black
2
9
0.2
100
83
1% Pt/C
doped with
Vanadium
2
9
0.2
100
96
1
18
0.2
100
93
1% Pt/C (V) catalyst at 0,02 concentration of 4-bromo-nitrobenzene
110
105
100
%
Catalyst
95
90
0.5
36
Conditions: 70 bar, EtOH, 25°C
0.2
100
84
Conversion
Selectivity
85
0,4
0,6
0,8
1,0
1,2
1,4
Flow rate / mLmin
1,6
-1
1,8
2,0
2,2
Deuteration in flow
Substrate
Product
Mándity, I.M.; Martinek, T.A.; Darvas, F.; Fülöp, F.; Tetrahedron Letters; 2009, 50, 4372–4374
Deuterium
content(%)
Isolated
yield / %
99
99
97
98
93
97
96
98
96
99
Double bond reduction in H-Cube®
1.) Grubbs-I; CH2Cl2; rt, 60 h, N2
2.) H-Cube® Pd-C, EtOAc; 70°C
(3 cycles; 530 mg of starting material)
32%
265 mg
Grubbs-I
catalyst
Leyden, R.; Velasco-Torrijos, T.; Andre, S.; Gouin, S.; Gabius, H.; Murphy, P.V.;
J. Org. Chem.; 2009; 74, 9010-9026
44%
233 mg
Flow Synthesis of Oxomaritidine
catch, react, release
NMe3N3
HO
HO
(1)
Br
MeCN:THF (1:1), 70 oC
N3
HO
Ph(nBu)2P
(2)
rt to 55 oC
N
MeO
OH
NMe3RuO4
OMe
O
MeO
MeO
OMe
OMe
electrolysis
O
F3C
HO
10% Pd/C, THF
O
O
H2 (g)
H2O
Flow hydrogenation
CF3
HO
80 oC
N
O
MeO
N
H
CF3
OMe
MeO
OMe
O
rt
MeOH / H2O (4:1)
PhI(O2CX3)2
O
NMe3OH
MeO
MeO
H
MeO
N
CF3
O
35 oC
MeO
N
(±)-oxomaritidine
I.R. Baxendale, J. Deeley, C.M. Griffith-Jones, S.V. Ley, S. Saaby, G. Tranmer, J. Chem. Soc., Chem. Commun., 2006, 2566.
Scaling up Hydrogenation
Using
H-Cube Pro™ and
H-Cube Midi™
H-Cube Midi™ reactor for scale-up
H-Cube Pro™ and H-Cube Midi™ reactors for
scale-up
ca. 10-25
times
Parameters:
ca. 3-6 times
- p= 1-100 bar
- T=25-100°C
- v=0.1-3 ml/min
- c=0.01-0.1 M
H2 Control: upon constant
bubble/liquid ratio
(saturation)
H-Cube Pro™ Parameters:
- p= 1-100 bar
-T=10-150°C
- v=0.1-3 mL/min
-c=0.01-0.4 M
-H2Control: upon stoichiometry
(production of H2)
H-Cube Midi™ Parameters:
- p= 1-100 bar
- T=25-150°C
- v=5-25 ml/min
- c=0.05-0.25 M
H2Control: upon stoichiometry (production of H2)
Scale-up with H-Cube Pro™
Protocol conversion from Batch to H-Cube Midi™
Batch reactor
H-Cube Midi™
c= 0.2 M
Vsolution=7 L
t= 10 h
Purity: 100 %
Analysed by
LCMS
Reaction parameter
360 mg 5%
Pd/C
catalyst
2.43 g 5% Pd/C
0.05
C (M)
0.15
30 (60 cm3)
T (°C)
70
20
p (bar)
70
Flow rate (mL/min)
10
Conversion (%)
100
Selectivity (%)
100
Yield (%)
89
85
0.03 mol (5.43 g) compound was reduced in
150 min
20 min
Optimization on H-Cube Midi™
Quinoxaline reduction
Catalyst
C (M)
Flow rate (mL/min)
T (°C)
p (bar)
Conversion(%)
Selectivity(%)
Batch in house
H-Cube Midi™
360 mg RaNi
0.05 (60 cm3)
30
20
100
95
15.02 g RaNi
0.2
12.5
30
20
100
95
100
80
60
40
20
0
After 120 min 0.003
mol compound was
reduced
After 1.2 min 0.003
mol compound was
reduced
4
8
12
16
Conversion (%)
Reaction
parameters
C = 0.20 M
c = 0.25 M
c = 0.30 M
c = 0.35 M
c = 0.40 M
20
Analysis by GC-MS
At the same substrate: catalyst ratio 0.125 mol substrate was reduced
After 120 min
After 50 min
Reduction of bromonitrobenzene to bromoaniline
100
Conditions
Conditions
p=70 bar
60
T= 30 °C
80
T= 30 °C
80
Selectivity / %
Selectivity / %
100
Catalyst: 5% Rh/C
40
p=70 bar
60
Catalyst: 5% Rh/C
40
20
20
0
0
5
10
15
20
25
0.05 M
0.10 M
0
30
5
10
Residence time / sec
H-Cube®
35
H-Cube Midi™
100
0.05 M
0.10 M
100
80
80
Selectivity / %
Selectivity / %
15
20
25
30
Residence time / sec
60
40
20
60
40
20
0
0
1
2
3
4
5
Flow rate / mL/min
6
7
8
0
0
5
10
15
20
Flow rate / mL/min
Autoclave: 0%, selectivity: 100%, byproduct (1h, 25°C, 20 bar, 5% Rh/C)
25
The X-CubeTM continuous-flow
heterogeneous catalyst/reagent
reactor
Next generation reactor: X-Cube™
Features:
•Continuous-flow reactions at high T and high
pressure
•Dual pump system
•Temperature up to 200ºC
•Pressures up to 150 bar
•Use of multiple cartridges for different step
•Introduction of gases from an external source
Advantages:
•Easy operation
•Small footprint
•Wide reaction conditions
•Fast optimization
•Multistep reactions
•Tri-phase reactions (CO, H2, CO/H2)
•Scale up reactions
•In-line purification
X-CubeTM overview
touch screen
panel
secondary mixer
system pressure
valve
two heatable
CatCartTM holder
system pressure
sensor
bubble detector
gas inlet valve
gas from an
external source
inlet pressure
sensor
liquid mixer
six way valve for
manual injection
built in HPLC
pumps
External gas source
gas/liquid mixer
Sample reactions
Suzuki-Miyaura C-C cross coupling:
NO 2
HO
B
OH
X-CubeTM
NO 2
+
Br
CatCartTM 70*4 mm Pd EnCatTM BINAP 30,
2-propanol, TBAF, 80°C, 20 bar, 0.05M, 0.5 ml/min
Conversion: 90-95% (TLC)
Purity: 70% (LC-MS) without work-up
Batch parameters: K3PO4, TBA-Br, Pd(OAc)2, DMF, 2 hours, 130 °C
Reference:
(Zim, Danilo; Monteiro, Adriano L.; Dupont, Jairton; Tetrahedron Lett.; EN; 41; 43; 2000; 81998202)
Reactions involving gases:
Direct aminocarbonylation
Very few literature precedents* for direct formation
Model reaction chosen:
OH
OH
O
+
CO
+
H
N
X-CUBE
O
I
O
N
Rapid, and versatile optimization including
the following parameters
-Catalyst
-Solvent
-Base
-Temperature
-Pressure (CO)
-Flow rate
*F. Karimi, B. Langström, Eur. J. Org. Chem. 2003, 2132-2137 in microautoclave (200 microL) introducing
11C as radioactive tracer for PET
Rapid optimization: catalysts
Catalyst
Conversion
(%)
Pd(TPP)4
83
FiberCat® 1001
25
Pd(TPP)4 Tetrakis(triphenylphosphine)palladium(0)
(polymer supported) (loading: 0.5-0.9 mmol Pd/g,
PS cr. w/ PVB)
FibreCat 1001: Pd(OAc)2/TPP on polymeric fiber
(Pd content: 6 %)
FiberCat® 1007
9
FibreCat 1007: Pd(OAc)2/tri-cyclohexylphosphine
on polymeric fiber (Pd content: 1-10 %)
PdEnCat™ TPP 30
20
Pd EnCat™ TPP 30: microencapsulated Pd(TPP)4
PdEnCat™ 30
2
Pd EnCat™ 30: microencapsulated Pd(OAc)2
(loading: 0.4 mmol Pd/g, crosslinked polyurea
matrix)
*Conversion to 4-(pyrrolidine-1-carbonyl) benzoic acid
Reaction conditions: 0.01 M of 4-iodobenzoic acid in 20
mL of THF, 1.5 eq. of pyrrolidine, 2.0 eq. TEA, 30 bar,
0.5 mL/min flow rate
FiberCat is registered trademark of Johnson Matthey, Inc.
EnCat is trademark of Reaxa, Ltd.
Comparison of continuous process flow, batch and MW conditions
(in house experiments)
OH
OH
O
+
CO
+
H
N
X-CUBE
I
a
O
O
N
Method
Conversiona (%)
Product ratiob
(%)
Comment
Autoclave - CO;
100°C, 30 bar
22
36
Sampling after 30 min.
60
20
Reaction time: 60 min.
Balloon - CO;
68°C (THF bp.); atm.
35
54
Sampling after 30 min.
69
75
Reaction time: 60 min.
Microwave - Mo(CO)6;
100°C, overpressure
72
65
Reaction time: 60 min.
Flow - CO;
100°C, 30 bar
96
83
Reaction time (i.e.
residence time) was
1 minC.
Conversion to all new compounds. b % of desired product (4-(pyrrolidine-1-carbonyl)-benzoic acid).
Details: 4-iodobenzoic acid (1 mmol, 0.248 g), pyrrolidine (1.5 mmol, 124 μL), and triethylamine
(2 mmol, 278 μL) dissolved in 50 mL of THF. Product: 4-(pyrrolidine-1-carbonyl)benzoic acid (0.177 g).
Flow rate: 0.5 mL/min, 0.4 g Pd(TPP)4 catalyst (CatCart®)
c
Csajági, Cs., Borcsek, B., Niesz, K., Kovács, I., Székelyhidi, Zs., Bajkó, Z., Ürge, L., Darvas, F., OL, 2008, 10(8), 1589-1592.
Automated test library synthesis
Carbonylation
Iodobenzoic
acid
Amine
I
Yield (%)
Iodobenzoic
acid
O
H
N
81
O
I
Amine
H
N
Yield (%)
80
OH
OH
H
N
63
25
NH2
O
69
OH
H
N
89
I
H2N
H
N
60
88
NH2
NH2
NH2
80
55
71
NH2
30
NH2
53
NH2
X-Cube Flash™
UMPC – Operation System
Back
Pressure
Regulator
Changeable
Heater Block
Outlet Tube
Dual Pump and Injection System
X-Cube Flash™ Schematic
Schematic Diagram
Stainless steel coil
(1000 mm i.d.)
www.thalesnano.com
Razzaq, T.; Glasnov, T. N.; Kappe, C. O. Eur. J. Org. Chem. 2009, doi:10.1002/ejoc.200900077
Microwave and X-Cube Flash Comparison Table
System
X-Cube Flash
Microwave
Solvents
Any solvent apart
from conc.
halogenated acids
180 bar
Only solvents with
a dipole moment
350°C
Typically 250°C
Reaction can be
left to produce
desired amount.
Large scale batch
not possible due to
limited penetration
depth.
Pressure
Temperature
limit
Scale
Typically 20 bar.
Diels Alder reaction
Me
CN
+
toluene (2.0M)
250°C, 60 bar
Me
1
2
Me
CN
Me
3(>99%)
• Diels-Alder reactions usually require long reaction times.
•This reaction time could be reduced to 5 minutes at 250°C
using toluene.
•.Product isolated in near quantitative yield.
•Reaction also possible using lower boiling solvents (MeCN, THF,
DME) with same result using higher pressures (200 bar).
Newmann-Kwart Rearrangement –
MW vs. Flow Experiments
“Easy” Case
Product, DME
HPLC, 215 nm
Conversion, %
Kinetic Analysis (HPLC)
100
90
80
70
60
50
40
30
20
10
0
NMP
DME
100
150
200
250
Temperature, °C
Moseley, J. D. et al. Tetrahedron, 2006, 62, 4685; Moseley, J. D.; Lenden, P. Tetrahedron, 2007, 63, 4120
Newmann-Kwart Rearrangement –
MW vs. Flow Experiments
“Difficult” Case
sc. DME
critical point:
263 °C; 39 bar
Kinetic Analysis (HPLC)
Product, DME
HPLC, 215 nm
Moseley, J. D. et al. Tetrahedron, 2006, 62, 4685; Moseley, J. D.; Lenden, P. Tetrahedron, 2007, 63, 4120
Fluoride-amine exchange
CN
CN
NH3/NMP
F
F
F
NH2
Reaction Conditions: 275°C, 200 bar, c=0.1M, 1 mL/min; 8 mL loop
100% Conversion (GC-MS)
100% Purity (NMR) – containing 10% NMP
95% Yield
Mol Divers. Accepted publication, Lengyel et al.
Fischer-Indole Synthesis: Scale Out
cf. MW reaction: Bagley, M. C.; et al. J. Org. Chem. 2005, 70 , 7003
Continuous Flow Results (4 mL or 16 mL Coil)
In AcOH/2-propanol (3:1) (0.5M)
150 °C, 60 bars,
1.0 mL min-1 (4 min res. time)
88% isolated yield
Scale-up
25 g indole/hour
200 °C, 75 bars,
5.0 mL min-1 (~3 min res. time)
96% isolated yield
Supercritical state
Property
Gas
SCF
Liquid
Density
(g/cm3)
10-3
0,1-0,5
1
Viscosity
(Pa s)
10-5
10-4
10-3
Diffusivity
(cm2/s)
10-1
10-3
10-5-6
Solvent
Propane
Ammonia
Butane
Butane-2-ol
Propane-2-ol
Metanol
Etanol
Water
Tcrit (°C, K)
97°C (369.9 K)
132.4°C (425.1 K)
152°C (647 K)
233°C (512.5 K)
235.5°C (514 K)
239.4°C (506.2 K)
240.9°C (508.6 K)
374°C (405.5 K)
pcrit
42.5 bar
112.8 bar
38.0 bar
39.7 bar
47.6 bar
80.8 bar
61.4 bar
220.6 bar
Claisen Rearrangement
O
OH
toluene (0.1 M)
240°C, 100 bar
1.0 mL/min
(95%)
Results
•Difficult reaction. Requires 1-2 hours reaction times in microwave.
• Reaction proceeded in high yield after only 4 minutes residence time.
• High temperature control needed:
• <230°C gave incomplete conversion
• >250°C gives numerous side products.
•Reaction optimized “on the fly” for quick results.
O-Cube:
Ozonolysis Reinvented
What is ozonolysis?
Ozonolysis is a technique that cleaves double and
triple C-C bonds to form a C-O bond.
“Typically” Three Main Products Desired
Carboxylic Acid
(oxidative work-up)
Aldehyde/Ketone
(simple quenching)
Alcohol
(reductive work-up)
How to work-up?
Ozone and ozonide detection
• Indigo can detect both ozonide and ozone
Few drops of indigo solution turns colorless if ozone or
ozonide is present
• Isolation – safety
•
•
•
•
Never dry completely the solution
Use low temperature during evaporation of solvents
Be careful with handling and shaking
Ozonide can be detected by MS
Why is ozonolysis neglected?
The reaction is highly exothermic.
Temperature is difficult to control, so is carried out at
-78ºC.
Batchwise accumulation of ozonide dangerous.
Typical batch ozonolysis equipment a collection of
parts.
 Not a purpose built system
 Parameters difficult to monitor and control
Ozonolysis Chemical Substitutes
This has lead chemists to find alternatives
Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)
However:




OsO4 is highly poisonous
OsO4 is very expensive so is not ideal for scale up.
Regeneration is required
Water is required as a solvent for the hydrolysis of the
intermediate osmate ester.
Flow Ozonolysis Setup
Ozonolysis examples
Ar
R1
CH3
R2
Step 1
Step 2
H
MeOH
25°C
NaBH4/MeOH
25°C
90
H
Me2CO
0°C
5% H2O/Me2CO
10°C
91
H
Me2CO
25°C
5% H2O/Me2CO
25°C
84
Me2CO
10°C
5% H2O/Me2CO
15°C
72
H
H
CH3
Product
(%)*
100-215 mg of product within 40 min
*Isolated yield with full conversion (comparable with batch reactions)
Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987
Ozonolysis examples
1.) Me2CO, 25°C, 1 mL/min
2.) 5% H2O/Me2CO, 25°C, 0.7 mL/min
Yield: 70%
1.) CHCl3, 25°C, 1 mL/min
2.) 1.5 M H2O2/CHCl3, 25°C, 0.5 mL/min
Yield: 86%
1.) EtOAc, 25°C, 1 mL/min, 0.05 M, 10% ozone (3 equ.)
2.) 1.5 M H2O2/CHCl3, 25°C, 0.5 mL/min
Yield: 73%
Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987
Work-up (all cases)
evaporation → >95% purity
Optimization of ozonolysis of thioanisole
O3
equ.
Solvent
Step 1.
flow rate
(mL/min)
Step 1.
temperature
(°C)
1
MeOH
1
25
2
Me2CO
0.5
2
Me2CO
2
Quenching
solution
Step 2.
flow rate
(mL/min)
Step 2.
Temperature
(°C)
Conv.
of 1.
(%)
Conv.
of 2.
(%)
Conv.
of 3.
(%)
0.1 M
NaBH4/MeOH
0.7
25
0
99
0
25
0.05 M
NaIO4/H2O
1
25
82
18
0.5
10
1 M H2O2/H2O
1
15
0
57
43
Me2CO
1
5
3 M H2O2/H2O
1
10
0
22
78
2
Me2CO
1
5
5 M H2O2/H2O
1
10
0
12
88
2
MeOH
1
-10
5M
H2O2/MeOH
1
0
32
0
68
2
MeOH
1
-20
5M
H2O2/MeOH
1
-10
14
0
86
-10
0
0
99
5M
0.5
H2O2/MeOH
Irfan, M.; Glasnov, N. T.; Kappe, O. C.; Organic Letters; 2011; 13(5); 984-987
4
MeOH
0.5
-20
0
Thank you for your kind attention!
Ildiko.kovacs@thalesnano.com