FlowCAT - continuous flow reactor system for hydrogenation

screening and small scale production

Dr Jasbir Singh
(Jsingh@helgroup.com)
HEL Ltd, England

2nd Symposium on Continuous Flow Reactor Technology for

Industrial Applications,
3-4 October, 2010
Paris

HEL Limited HEL Inc HEL China HEL Italia HEL India
London, England NJ, USA Beijing Milan Mumbai
 Terminology in catalytic reactions

Homogeneous catalysis

Heterogeneous catalysis

Fixed bed or Plug Flow (continuous) and stirred/Batch reactors

Fixed Bed is special case of continuous flow type.

better chemistry - faster

 Terminology in catalytic reactions

Homogeneous catalysis

Heterogeneous catalysis

Fixed bed or Plug Flow (continuous) and stirred/Batch reactors

Fixed Bed is special case of continuous flow type.

better chemistry - faster

 Crude Mathematical equivalence of flow and batch reactors

Batch 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.

better chemistry - faster

 Closer Mathematical equivalence of Reactors

Co-Current feeds
Many CSTRs in series

PFR (plug flow)

Vertical orientation (top-to-bottom)

better chemistry - faster

 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.

better chemistry - faster

 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

Trialled at length by Pfizer for

hydrogenation applications.
Some results to follow.

better chemistry - faster

 flowCAT Feed Section

Manual valve
Tr
Filter
N2

MFC Catalyst / glass packing

H2

HPLC
Pump

Tj
P

Heater

Filter

Reactor

better chemistry - faster

 flowCAT Product Sampling and Collection

Pressure
control Needle
valve
GAS
VENT

Liquid
Seperation
Sample product
vessel

better chemistry - faster

 FlowCAT Typical Specification

Standard lengths: 15cm (6)

Two standard int. diameters: (12mm) or (6mm)
Volumes : 2.8ml, 12ml (in hot zone, approx).
Standard ovens: heated lengths 10 cm
100bar/300C standard (higher temperature/pressure
options)
One liquid and one gas feed standard, other combinations
possible.

Not limited to hydrogenations

Not limited to heterogeneous catalytic reactions

better chemistry - faster

 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
Conversion
Ease of scale up

Flows rates widely selected to favour that trickle bed mode.

better chemistry - faster

 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

flow regime
prediction

flowCAT
typical
 flowCAT performance Testing
C6H5NO2 + 3H2 C6H5NH2 + 2H2O
Hydrogenation of (4%) nitrobenzene to aniline

Hydrogen plus
Nitrobenzene/solvent
G/L vol. ratio 20 (100max, gas at NTP)
Hydrogen excess typically 1.83 x stoich.

0.25 internal dia.

Temperature 30 deg C
1% Pd/C mixed with glass beads
4ml packed volume (30% voids)
Catalyst mass 0.1g (0.2 and 0.4g alternates)

Product (Aniline), analysed

by GC

better chemistry - faster

 Trickle Bed Flow Lab Reactors
Diagram below shows likely position of bench scale flow reactors

flowCAT
range

Reported
data range

better chemistry - faster

 Hydrogen consumption with pressure
Hydrogenation of nitrotoluene to aniline

0.35

0.3

0.25
Gas consumption (mmol/min)

0.2

0.15

0.1

0.05 H2 Saturation

0.5 ml/min Liquid

flow
0
0 10 20 30 40 50 60 70 80 90 100
Pressure (bar)

Hydrogen 1.83 x stoichiometric

( = 20 n ml/min)
Catalyst loading 0.1g
Bed volume 4ml (30% void)
Hydrogen consumption with at different substrate flows
Hydrogenation of nitrotoluene to aniline

0.6

0.5
Gas consumption (mmol/min)

0.4

0.3

0.2

H2 Saturation
0.1
0.5 ml/min

1 ml/min
0
0 20 40 60 80 2 ml/min
100
Pressure (bar)

Hydrogen 1.83 x stoichiometric

(= 20 to 80 n ml/min)
Catalyst loading 0.1g
Bed volume 4ml (30% void)
 Fractional conversion with pressure
Hydrogenation of nitrotoluene to aniline

0.7

0.6

0.5
Fractional Conversion

0.4

0.3

0.2

0.5 ml/min
0.1

0
0 10 20 30 40 50 60 70 80 90
Pressure (bar)

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)
 Conversion at different gas flows
Hydrogenation of nitrotoluene to aniline

0.5

0.45

0.4

0.35
Fractional conversion

Hydrogen flow as
0.3
fraction of
0.25 stoichiometric

0.2 0.92

0.15 1.83

0.1 4.58

0.05

0
0 10 20 30 40 50 60 70 80 90
Pressure (bar)

Liquid flow 1ml/minute

Catalyst loading 0.1g
Bed volume 4ml (30% void)
 Comparison with Stirred Reactor Data

HP Chemscan
Auto-MATE AUTOLAB
8 x 16ml reactors 1000ml HP glass reactor
4 x 100-300ml HP reactors

better chemistry - faster

 HYDROGENATION 100ml stirred HP auto-
auto-MATE

Catalyst loading approx 1/100th of flow reactor

1.4

1.2

1.0 10 bara
Uptake (l)

0.8 3.4 bara

0.6

0.4 50ml 4% nitrobenzene in decanol,

0.35g Pd/C catalyst parallel
0.2 hydrogenations at 40C, 1500 rpm

0.0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Time (mins)
100 Psi 50 Psi 75 Psi 125 Psi 150 Psi
Typical residence time
in flow tests
 Time to 100% conversion in stirred reactors (5 to 500ml)

200 60 C 40 C
180
Data from three sizes
160 of stirred reactors
Reaction time (mins)

140
120
100
80
60
40 4% nitrobenzene Pd/C catalyst, 6.9 bar

20
0
0 2 4 6 8 10 12 14
Residence time in flow tests Catalyst concentration (g/l)

Catalyst conc in flow tests

 Hydrogenation Screening?

H-cube
Hydrogen generation in situ safety advantage
Low flow only, limited to screening at low conc or
small 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?

better chemistry - faster

 Screening with H-cube: Conversion Limited by hydrogen solubility

PhCHO 10% Rh/C PhCH2OH

0.35 M
EtOH, 80C

(courtesy J Hawkins, Pfizer Inc, August 2010)

Conversion limited by
H2 solubility which
increases with pressure
 Conversion Limited by Solubility - flowCAT
Hydrogenation of nitrotoluene to aniline

0.2

0.18

0.16 Hydrogen added

to maintain operating
0.14 pressure, no excess H2

0.12
Hydrogen flow

0.1

Gas consumption
0.08 (mmol/min)
Gas Solubility
0.06

0.04
Gas feed on pressure
0.02
Liquid flow 0.5ml/minute
Catalyst loading 0.1g
Bed volume 4ml (30% void)
0
0 20 40 60 80 100
Pressure (bar)
 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.

Sample
FLOWCAT
Continuous Flow
Reactor
Controls Data

WinISO
HELs Reactor Control GC
Raw
Software Data

Set points Results

STAVEX
DoE Software
Package

better chemistry - faster

 PAT integration - Real-time monitoring and feed back control

In-line sensor (eg FTIR flow cell),

almost real-time data

GAS VENT
(pressure control)
Product
from flowCAT P

Gas-liquid separation

winISO real-time
software monitoring
Virtually no product and feed back
hold up (a few ml) control

better chemistry - faster

 Integrating Process/Analytical Data

process data schedule

chromatogram data analyser

better chemistry - faster

 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

STAVEX software

Flow rate Temp

better chemistry - faster

 EXAMPLE 2: Conversion of chloronitrobenzene to chloroaniline

NO2 NH2 NH2

H2 H2
Pd/C Pd/C

Cl Cl

H2 Pd/C H2
Pd/C

NO2

better chemistry - faster

 GC Traces: chloronitrobenzene to chloroaniline
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)

14.635
'mV'

0.16

0.14
Chloronitrobenzene Fractions: 55.8% chloronitrobenzene
0.12

Chloroanilin 15.2% chloroaniline 6.1% aniline

0.1

13.310
0.08
Aniline Conditions:P=5bar T=22oC
0.06
7.020

8.886

0.04
Residence time=0.5min
0.02

2.5 5 7.5 10 12.5 15 17.5 20 22.5 min

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)

13.519
'mV'

Fractions: 24% chloronitrobenzene 0.1

Chloroanilin

7.014

13.302
Aniline e
43.4% chloroaniline 0.08

0.06

24.2% aniline
0.04
Chloronitrobenzene
Conditions:P=10bar T=61oC
8.889

14.481
Residence time=1.96min 0.02

5 7.5 10 12.5 15 17.5 20 22.5 min

better chemistry - faster

 chloronitrobenzene to chloroaniline (Pressure-residence time)

Low and high pressures

yield the better conversions
at medium residence times

better chemistry - faster

 chloronitrobenzene to chloroaniline (Temp residence time)

Chloroaniline reacts to yield

aniline at high temperatures

Conversion favoured by
low temperatures and high
residence times

Wrong range of
conditions selected go
back!

better chemistry - faster

 chloronitrobenzene to chloroaniline (Pressure residence time)

mid-range residence time

favours chloroaniline

High or low residence

time favours aniline

better chemistry - faster

 chloronitrobenzene to chloroaniline (Temp Residence time)

Mid-range residence time and

low temperature favours high
yield chloraniline

Aniline favoured by high

or low residence time

better chemistry - faster

 Sterioselectivity through flowCAT Process Control

100 g hydrogenated with 1 g of catalyst which

was still active

(Example courtesy J. Hawkins, Pfizer Inc, August 2010)

better chemistry - faster

 Diastereoselectivity and Conversion vs. Pressure
140 100

90
120
80

100 70
Cis / Trans Ratio

Conversion (%)
60
80
50
60
40
Increased
40 diastereoselectivity 30
at the higher
pressures easily 20
20 accessible in flow
10

0 0
0 10 20 30 40 50 60 70 80 90 100
Pressure (bar)
 flowCAT - CONCLUSIONS

Bench-scale flow system, industrially proven development

Wide range of operating conditions

Controls all important variables and reports progress in real

time.

Full integration of third party sensors for PAT

Low flow version feasible, cartridge designs being tested

Already in use for prep-scale work

better chemistry - faster