FlowCAT - continuous flow reactor system for hydrogenation
screening and small scale production
HEL LimitedLondon, England
HEL IncNJ, USA
HEL IndiaMumbai
HEL Italia Milan
HEL China Beijing
Dr Jasbir Singh([email protected])
HEL Ltd, England
2nd Symposium on Continuous Flow Reactor Technology for Industrial Applications,
3-4 October, 2010Paris
Terminology in catalytic reactions
� Homogeneous catalysis
� Heterogeneous catalysis
� Fixed bed or Plug Flow (continuous) and stirred/Batch reactors
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Fixed Bed is special case of continuous flow type.
Terminology in catalytic reactions
� Homogeneous catalysis
� Heterogeneous catalysis
� Fixed bed or Plug Flow (continuous) and stirred/Batch reactors
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Fixed Bed is special case of continuous flow type.
Crude Mathematical equivalence of flow and batch reactors
Batch Time Residence Time = Volume/flow rateBatch Time Residence Time = Volume/flow rate
Equivalence – time in batch reactor equates to position down plug flow.Changing flow rate changes residence time: corresponds to batch time.
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Closer Mathematical equivalence of Reactors
PFR (plug flow)
Many CSTRs in seriesCo-Current feeds
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Vertical orientation (top-to-bottom)
Lab-scale flow Systems – Screening and Prep-scale
Screening •Catalyst in small cartridge, very high catalyst loading• Conversion limited by hydrogen solubility (at high conc.)• Typical throughput 1+ g/day
H-cube (Thales-nono) well established in this field. Limited to
hydrogenations and to screening applications only.
Prep-scale • Traditional “tubular” reactor• “Trickle flow” mode demonstrated• High conversion far exceeding solubility limit• Typical throughput 100+g/day
No fully automated product established up to now.
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FlowCAT Package
•Developed to bridge screening and prep-scale needs•Not limited to hydrogenations• Fully software controlled• Does not require high pressure expert for operation
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Trialled at length by Pfizer for hydrogenation applications. Some results to follow.
flowCAT Feed Section
N2
H2
MFC
HPLC
Pump
Manual valve
Catalyst / glass packing
FilterTr
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P
Reactor
Heater
Tj
Filter
flowCAT Product Sampling and Collection
Pressure
controlNeedle
valve
GAS
VENT
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SampleSeperation
vessel
Liquid
product
FlowCAT Typical Specification
• Standard lengths: 15cm (6”)
• Two standard int. diameters: ½” (12mm) or ¼” (6mm)
• Volumes : 2.8ml, 12ml (in hot zone, approx).
• Standard ovens: heated lengths 10 cm
• 100bar/300C standard (higher temperature/pressureoptions)
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options)
•One liquid and one gas feed standard, other combinationspossible.
Not limited to hydrogenations
Not limited to heterogeneous catalytic reactions
Flow Capacity of Tubular Reactors
Very wide range of flows are possible, subject to pump range and pressure drop across reactor.
Gas and liquid flow rate determines:
• the “pattern” of flow • Gas/liquid mixing and contact with catalyst • Gas/liquid mixing and contact with catalyst • Conversion•Ease of scale up
Flows rates widely selected to favour that “trickle bed” mode.
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Trickle Bed Flow Regime
Most common mode of operation for tubular fixed bed reactors
� Fixed bed of inert and catalyst pellets, former occupying large volume (50% or more)
� Co-current downward flow of gas and liquid
� Leads to gas dispersed, liquid continuous phases around solids
General Plot for
flowCATtypical
General Plot for flow regimeprediction
Hydrogen plusNitrobenzene/solvent
G/L vol. ratio 20 (100max, gas at NTP)Hydrogen excess typically 1.83 x stoich.
C6H5NO2 + 3H2 C6H5NH2 + 2H2OHydrogenation of (4%) nitrobenzene to aniline
flowCAT performance Testing
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0.25” internal dia.Temperature 30 deg C
1% Pd/C mixed with glass beads4ml packed volume (30% voids)
Catalyst mass 0.1g (0.2 and 0.4g alternates)
Product (Aniline), analysed by GC
Trickle Bed Flow – Lab ReactorsDiagram below shows likely position of bench scale flow reactors
flowCAT
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flowCATrange
Reported data range
0.15
0.2
0.25
0.3
0.35
Gas
co
nsu
mp
tio
n (
mm
ol/m
in)
Hydrogen consumption with pressure Hydrogenation of nitrotoluene to aniline
0
0.05
0.1
0 10 20 30 40 50 60 70 80 90 100
Gas
co
nsu
mp
tio
n (
mm
ol/m
in)
Pressure (bar)
H2 Saturation
0.5 ml/min Liquid flow
Hydrogen 1.83 x stoichiometric( = 20 n ml/min)
Catalyst loading 0.1gBed volume 4ml (30% void)
0.3
0.4
0.5
0.6
Gas
co
nsu
mp
tio
n (
mm
ol/m
in)
Hydrogen consumption with at different substrate flows Hydrogenation of nitrotoluene to aniline
0
0.1
0.2
0 20 40 60 80 100
Gas
co
nsu
mp
tio
n (
mm
ol/m
in)
Pressure (bar)
H2 Saturation
0.5 ml/min
1 ml/min
2 ml/min
Hydrogen 1.83 x stoichiometric(= 20 to 80 n ml/min)Catalyst loading 0.1g
Bed volume 4ml (30% void)
0.4
0.5
0.6
0.7F
ract
ion
al C
on
vers
ion
Fractional conversion with pressure Hydrogenation of nitrotoluene to aniline
0
0.1
0.2
0.3
0 10 20 30 40 50 60 70 80 90
Fra
ctio
nal
Co
nve
rsio
n
Pressure (bar)
0.5 ml/min
Liquid flow = 0.5ml/minuite(residence time approx 2.4 mins)Hydrogen 1.83 x stoichiometric
( = 20 n ml/min)Catalyst loading 0.1g
Bed volume 4ml (30% void)
0.2
0.25
0.3
0.35
0.4
0.45
0.5F
ract
ion
al
con
ve
rsio
n
0.92
Hydrogen flow as
fraction of
stoichiometric
Conversion at different gas flows Hydrogenation of nitrotoluene to aniline
0
0.05
0.1
0.15
0 10 20 30 40 50 60 70 80 90
Fra
ctio
na
l co
nv
ers
ion
Pressure (bar)
1.83
4.58
Liquid flow 1ml/minuteCatalyst loading 0.1g
Bed volume 4ml (30% void)
Comparison with Stirred Reactor Data
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Auto-MATE4 x 100-300ml HP reactors
AUTOLAB 1000ml HP glass reactor
HP Chemscan8 x 16ml reactors
Up
take
(l)
1.4
1.2
1.0
0.8
0.6
HYDROGENATION 100ml stirred HP autoHYDROGENATION 100ml stirred HP auto--MATEMATE
10 bara
3.4 bara
Catalyst loading approx 1/100th of flow reactor
100 Psi 50 Psi 75 Psi 125 Psi 150 PsiTime (mins)
80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0
Up
take
(l)
0.6
0.4
0.2
0.0
50ml 4% nitrobenzene in decanol, 0.35g Pd/C catalyst – parallel hydrogenations at 40°C, 1500 rpm
Typical residence time in flow tests
80
100
120
140
160
180
200
Rea
ctio
n t
ime
(min
s)Time to 100% conversion in stirred reactors (5 to 500ml)
40 °C60 °C
Data from three sizes of stirred reactors
0
20
40
60
80
0 2 4 6 8 10 12 14
Catalyst concentration (g/l)
Rea
ctio
n t
ime
(min
s)
4% nitrobenzene Pd/C catalyst, 6.9 bar
Residence time in flow tests
Catalyst conc in flow tests
Hydrogenation Screening?
H-cube • Hydrogen generation in situ – safety advantage• Low flow only, limited to screening at low conc orsmall scale compound prep (eg med chem)
flowCAT • Needs hydrogen supply – less safe potentially•Low flow version feasible, cartridge designs being tested•Already in use for prep-scale work Can flowCAT be adapted for screening?
.
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Conversion limited by H2 solubility which increases with pressure
Screening with H-cube: Conversion Limited by hydrogen solubility
10% Rh/CPhCHO0.35 M
PhCH2OH
EtOH, 80°C
(courtesy J Hawkins, Pfizer Inc, August 2010)
0.12
0.14
0.16
0.18
0.2
Hyd
rog
en f
low
Hydrogen added
to maintain operating
pressure, no excess H2
Conversion Limited by Solubility - flowCAT Hydrogenation of nitrotoluene to aniline
0
0.02
0.04
0.06
0.08
0.1
0 20 40 60 80 100
Hyd
rog
en f
low
Pressure (bar)
Gas consumption (mmol/min)Gas Solubility
Gas feed on pressureLiquid flow 0.5ml/minute
Catalyst loading 0.1gBed volume 4ml (30% void)
FLOWCATContinuous Flow
Reactor
Sample
flowCAT in commercial R+D
■ Controlled by commercial, well established software/electronics, fully developed
■ Ideal for process development and large enough for prep-scale production
■ Possible to integrate with DOE package and optimise totally automatically.
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Reactor
WinISOHELs Reactor Control
Software
Controls Data
STAVEXDoE Software
Package
Set points Results
GCRaw Data
PAT integration - Real-time monitoring and feed back control
P
GAS VENT (pressure control)
Productfrom flowCAT
In-line sensor (eg FTIR flow cell),almost real-time data
Gas-liquid separation
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Virtually no producthold up (a few ml)
winISO real-time software monitoring
and feed back control
Gas-liquid separation
Integrating Process/Analytical Data
process data schedule
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chromatogram data analyser
Process Development Examples using DOE
■ Samples can be taken at each change of operating condition
■Wide range of conditions can be tested, sequentially, without operator involvement (no need to clean reactor after each change)
■ Integrated with Stavex software
Pressure
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Temp
Pressure
Flow rate
STAVEX software
EXAMPLE 2: Conversion of chloronitrobenzene to chloroaniline
Cl
NO2 NH2
Cl
NH2
H2
Pd/C
H2
Pd/C
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Cl Cl
NO2
H2 Pd/C H2Pd/C
GC Traces: chloronitrobenzene to chloroaniline
Fractions: 55.8% chloronitrobenzene
15.2% chloroaniline 6.1% aniline
Conditions:P=5bar T=22oC
Residence time=0.5min
min2.5 5 7.5 10 12.5 15 17.5 20 22.5
'mV'
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
AIA1,'VWD' of U:\FLOWCAT\ALEXIS\DATA\EXPERI~1\4-GCSA~1\CLORON~1\EXPERI~1\151220~1\S1\TESTRU~1.D\1.CDF (AIA imported)
7.0
20
8.8
86
13.
310
14.
635
Aniline
Chloroaniline
Chloronitrobenzene
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Fractions: 24% chloronitrobenzene
43.4% chloroaniline
24.2% aniline
Conditions:P=10bar T=61oCResidence time=1.96min
min5 7.5 10 12.5 15 17.5 20 22.5
'mV'
0.02
0.04
0.06
0.08
0.1
AIA1,'VWD' of U:\FLOWCAT\ALEXIS\DATA\EXPERI~1\4-GCSA~1\CLORON~1\EXPERI~1\181220~1\S14\TESTRU~1.D\1.CDF (AIA imported)
7.0
14
8.8
89
13.
302 1
3.51
9
14.
481
AnilineChloroaniline
Chloronitrobenzene
chloronitrobenzene to chloroaniline (Pressure-residence time)
Low and high pressures yield the better conversions at medium residence times
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at medium residence times
chloronitrobenzene to chloroaniline (Temp – residence time)
• Conversion favoured bylow temperatures and high
• Chloroaniline reacts to yield aniline at high temperatures
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low temperatures and highresidence times
• Wrong range of conditions selected – go back!
chloronitrobenzene to chloroaniline (Pressure – residence time)
• mid-range residence time favours chloroaniline
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• High or low residence time favours aniline
chloronitrobenzene to chloroaniline (Temp – Residence time)
• Mid-range residence time and low temperature favours high yield chloraniline
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• Aniline favoured by high or low residence time
Sterioselectivity through flowCAT Process Control
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(Example courtesy J. Hawkins, Pfizer Inc, August 2010)
• 100 g hydrogenated with 1 g of catalyst which was still active
Diastereoselectivity and Conversion vs. Pressure
80
100
120
140
Cis
/ T
rans
Rat
io
50
60
70
80
90
100
Conversion (%
)
0
20
40
60
0 10 20 30 40 50 60 70 80 90 100
Pressure (bar)
Cis
/ T
rans
Rat
io
0
10
20
30
40
Conversion (%
)Increased diastereoselectivity at the higher pressures easily accessible in flow
flowCAT - CONCLUSIONS
• Bench-scale flow system, industrially proven development
• Wide range of operating conditions
• Controls all important variables and reports progress in real time.time.
• Full integration of third party sensors for PAT
•Low flow version feasible, cartridge designs being tested
•Already in use for prep-scale work
.
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