Dev. of heterogeneous catalytic processes-Transferring ... - HEL Group

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Alternately (eg Liu et. al*.) has reported hydrogenation of phenol at pressure and ... solvent, 10 mol% AlCl3, 5 mol% Pd
Development of heterogeneous catalytic processes Transferring batch to continuous flow and including use of scCO2 as solvent

Dr Jasbir Singh

([email protected]) HEL Ltd, England

HEL Limited London, England

HEL Inc NJ, USA

HEL China Beijing

HEL Italia Milan

HEL India Mumbai

HEL Products by Research Area Screening

Low Pressure

High Pressure

Process Dev/Optimization

Low Pressure

High Pressure

Scale up/Pilot

Low Pressure

High Pressure

Process Intensification and Clean Synthesis Intensification -

Increased pressure, especially for gas/liquid chemistry

-

Reduce inventory .. minimise hazard (of pressure/inventory)

Clean Synthesis -

Water contamination, pollution, toxicity

-

Potentially use of scCO2

-

Ideal in conjunction with intensification (ie reduced inventory)

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Intensification is obvious if switching is possible

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Production of Cyclohexanone

Oxidation

Typically at high Temperature, low conversion and selectivity.

Hydrogenation Alternately (eg Liu et. al*.) has reported hydrogenation of phenol at pressure and low temperature, with good results. Batch process. *H. Liu, T. Jiang, B. Han, S. Liang, Y Zhou, Science 326, 1250 (2009).

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Hydrogenation of phenol

First step competes with further hydrogenation to produce the alcohol, reducing selectivity. Liu* looked at batch synthesis (1ml scale) using Lewis acid in DCM with good results * H. Liu, T. Jiang, B. Han, S. Liang, Y Zhou, Science 326, 1250 (2009).

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HEL Objectives

- Scale up Liu’s (1ml) synthesis to stirred reactors - Optimise conditions for production of cyclohexanone and cyclohexanol (ability to select product)

-

Transfer synthesis to fixed bed, “trickle flow” synthesis

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Optimisation in 8 parallel pressure -reactor platform Temperature (ºC)

40

60

80

100

R1

R2

R3

R4

R5

R6

R7

R8

Pressure (bar)

30

40

Figure 1: Diagram illustrating temperature and pressure variation on the HPChemSCAN (using DCM as

Tests in 8 stirred reactors (HP Chemscan)

solvent, 10 mol% AlCl3, 5 mol% Pd/C)

HP Chemscan reactor

10mole % AlCl3 and 5mole % Pd/C in DCM solvent

Phenol Conversion in HP Chemscan at 30 and 40bar

Phenol conversion versus Temperature 102

Phenol Conversion (%)

100 98 96 94 92 Pressure (30 bar) 90 Pressure (40 bar) 88

Literature value at 30 bar 86 30

40

50

60

70

80

Temperature (ºC)

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90

100

110

Product Selectivity Cyclohexanone selectivity Cyclohexanone Selectivity ( %)

120 100 80 60

Pressure (30 bar)

40

Pressure (40 bar)

20

Literature value at 30 bar

0 40

50

60 70 80 Temperature (ºC)

90

100

110 Cyclohexanol Selectivity / %

30

Cyclohexanol Selectivity 70

50

Pressure (40 bar)

40 Literature Value at 30 bar

30 20 10

0 -10

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Pressure (30 bar)

60

30

40

50

60

70

80

Temperature (ºC)

90

100

110

Summary of Conversion/selectivity Liu et al.

HEL Ltd.

HEL Ltd.

(30 bar)

(30 bar)

(40 bar)

Phenol conversion

>99.9%

99.4%

99.6%

Max Cyclohexanone select

95.1%

95.4%

94.1%

Max Cyclohexanol select

4.9%

94.6%

95.9%

Values reported with 0.1 equiv. AlCl3 and 0.0.05 equiv. Pd/C, for 120 minutes. Results at different temperatures that gave maximum selectivity/conversion

Stirred Reactors allows choice between ketone and alcohol

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Transfer to min- flow reactor (flowCAT reactor system)

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Reactor packing suggestion Active catalyst

Feed

Glass (or metal) beads (400 micron dia)

Preheat zone

Catalyst typically 1/5th to 1/10th dia. of reactor (say 100 micron +)

Reaction zone

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Transfer DCM Process to Continuous flow - problematic

Phenol hydrogenation using Lewis Acid and DCM solvent proved to be very difficult: -

-

Pump feed was erratic Sample valve became blocked periodically Back-pressure regulator became blocked periodically

Process not ideal for flow operation

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Physical properties give clue to difficulties Melting Point (ºC)

Boiling Point (ºC)

DCM

-96.7

39.6

THF

-108

66

Phenol

40.5

181.7

Cyclohexanone

-16.4

155.6

Cyclohexanol

25.9

160.8

Problems caused by volatility of feeds/products plus … solubility in DCM

Switch solvent to THF (without Lewis Acid) (Liu reported no conversion with this combination)

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Back to HP Chemscan – effect of Solvent Change Hydrogen gas uptake in DCM and THF

Liu also reported no conversion in THF !! better chemistry - faster

Reaction Progress tracking by Sampling at intervals (100C, 60bar)

Sample time

R1

R2

R3

R4

45

90

135

180

R5

R6

R7

R8

225

270

315

360

(min):

Sample time

(min):

Stirring and gas feed stopped, cooled, then manually sampled better chemistry - faster

Phenol converted but not to desired product!! Peak at ~4.71

2.40

Peak at ~ 4.86 Peak at ~5.91 (phenol) Peak at ~ 15.29

Peak Area

1.90

Peak at ~ 16.08

P and T too high (60 bar/100C) and leads to very poor selectivity

1.40

0.90

0.40

-0.10 0

45

90

135

180

225

270

Reaction Time (minute)

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315

360

Phenol conversion in stirred reactors (H P Chemscan) (using THF, 5 mol% Pd/C)

Focus switched to lower Pressure/temperature .. Improved selectivity (at expense of lower conversion) 20bar and 100C (@30 minute intervals)

Phenol Conversion (%)

30 25 20 15 10 5 0 0

30

60

90

120

Time (mins)

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150

180

210

240

Product Slate at highest phenol conversion (in THF, 5 mol% Pd/C, sampling at 30 minute intervals). Pressure 20bar (100C) gives highest selectivity

120

Reaction mixture (%)

100

~24% conversion 80 CYCLOHEXANOL 60 CYCLOHEXANONE PHENOL

40

~20% maximum 20

0 0

30

60

90

120

Time (min)

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150

180

210

240

Conclusion – THF and DCM solvent Comparison of results in 16 ml stirred reactors

Max Phenol Conversion (%)  Cyclohexanone select (%)  Cyclohexanol select (%)

DCM 100 88.7 11.3

Max Cyclohexanone Select (%)  Phenol Conversion (%)  Cyclohexanol Select(%)

THF 27.3 75.9 24.1 DCM 94.5 88.2 5.5

THF 94.7 19.9 5.3

DCM

THF

Max Cyclohexanol Select. (%)

62.3

46.2

 Phenol Conversion (%)  Cyclohexanone Select(%)

100 37.7

6.9 53.8

Return to flow reactor with THF solvent

Range of Conditions: -

10% palladium on carbon ~ 3.5 ml catalyst bed (~2.8ml void) mix of catalyst and glass beads (1:4 weight ratio) liquid flow : 0.1 to 4ml/min Corresponding to residence time : 0.7 to 28 min Phenol: hydrogen (molar rate) = 1:9 to 1: 90 (2.5 to 25 excess H2)

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Residence time versus concentration of phenol (5 bar, 20 bar and 60 bar all at temperature, 100 ºC)

Phenol concentration (% of feed)

120

100 5 bar 20 bar

80

60 bar 60

40

20

0 0

5

10

15 Residence time (mins)

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20

25

30

Effect of Temperature on product slate

Concentration (% of phenol feed)

(at 60bar and 0.2ml/minute liquid flow)

100

80 CYCLOHEXANOL

60 CYCLOHEXANONE PHENOL

40

PHENOL CONVERSION

20

0 40

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60

80 Temperature (ºC)

100

20bar

flowCAT Product Range (20 and 60bar , 100C)

80 PHENOL

60

CYCLOHEXANONE CYCLOHEXANOL

40 20 0 0

2

4

6 8 10 12 Residence time (minutes)

14

100 Percentage Product/Reagent (%)

Percentage Product/Reagent (%)

100

16

60bar

80 60

PHENOL CYCLOHEXANONE

40

CYCLOHEXANOL

20 0 0

2

4

6 8 10 12 Residence time (minutes)

14

16

Conclusion – THF solvent without Lewis Acid Comparison of 16ml stirred and trickle bed flow reactors

Max Cyclohexanone Sel (%) Phenol Conversion (%) Catalyst Pd: Phenol ratio Temperature (C) Pressure (bar) Reaction Time (minutes)

Max Cyclohexanol sel (%) Phenol conversion (%) Temperature (C) Pressure (bar) Reaction Time (minutes)

BATCH 94.7 19.9 20% Pd/C type 91 1:20 100 20 120

46.2 6.9 60 40 120

FLOW 95.7 99.8 10% Pd/C type 39 1:2.98 100 20 14

96.8 99.3 100 60 14

Simpler Processes – switching stirred batch to flow Using simpler processes: -

Gives limited success with batch stirred chemistry (100C/20bar gives ~20% conversion to cyclohexanone) Process successfully switched to trickle flow, fixed bed Similar pressure and temperature at both reactor types Conversion to ~80% cyclohexanone achieved Product slate can be “tuned” to give nearly 100% cyclohexanol too, simply by adjusting residence time (feed rate).

Ketone

Select conditions

Alcohol

Not unusual to get this – see Pfizer example better chemistry - faster

Diastereoselectivity and Conversion vs. Pressure 140

100 90

120 80 70 60

80

50 60

40

Increased diastereoselectivity at the higher pressures easily accessible in flow

40

20

0 0

10

20

30

40

50

60

Pressure (bar)

70

80

90

30 20 10 0 100

Conversion (%)

Cis / Trans Ratio

100

Consider scCO2 .... as Solvent  inert

 non-toxic  readily available  relatively low Pc (~ 74 bar) and Tc (~ 31C)

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Supercritical (scCO2) hydrogenation of phenol in HP Chemscan (total pressure 110 bar; pH2 80 bar; 0.05 equiv. Pd/C; 0.1 equiv. AlCl3; reaction time 120 minutes).

Gas uptake versus reaction time for the reaction at 110 bar

50 45

Partial H2 pressure = 63.3 bar Partial H2 pressure = 95.3 bar Partial H2 pressure = 82.1 bar Partial H2 pressure = 52.4 bar

40 Gas Uptake (ml)

Partial H2 pressure = 82.4 bar

35 30

Partial H2 pressure = 64.8 bar Partial H2 pressure = 52.4 bar

25 20 15

0 70

Reaction

5

Cool Down

10

80

90

100 110 120 130 140 150 160 170 180 190 200 Reaction time (minutes)

Uptake control 1.Uptake 1 (ml) Uptake control 4.Uptake 4 (ml) Uptake control 7.Uptake 7 (ml)

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Uptake control 2.Uptake 2 (ml) Uptake control 5.Uptake 5 (ml) Uptake control 8.Uptake 8 (ml)

Uptake control 3.Uptake 3 (ml) Uptake control 6.Uptake 6 (ml)

Supercritical (scCO2) hydrogenation of phenol in HP Chemscan (total pressure 110 bar; pH2 80 bar; 0.05 equiv. Pd/C; 0.1 equiv. AlCl3; reaction time 120 minutes).

100

Phenol Conversion (%)

90 80 70 60 50 40 30 20

10 0 0

20

40

60

80

Temperature ºC

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100

120

140

160

Hydrogenation of phenol in scCO2 : Product Slate (total pressure 110 bar; pH2 80 bar; 0.05 equiv. Pd/C; 0.1 equiv. AlCl3; reaction time 120 minutes).

120

Product slate (%)

100

80 CYCLOHEXANOL

60 CYCLOHEXANONE PHENOL

40

20

0 0

20

40

60

80

100

Temperature ºC

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120

140

160

Conclusion – Stirred 16ml parallel Reactors Performance in THF and scCO2

Highest Phenol Conver (%) Cyclohexanone Select (%) Cyclohexanol Select (%)

THF 27.3 75.9 24.1

Max Cyclohexanone Sel (%) Phenol Conversion (%) Cyclohexanol Select(%)

Max Cyclohexanol Sel(%) Phenol Conversion (%) Cyclohexanone Selectivity (%)

scCO 78.7 15.5 84.5 THF 94.7 19.9 5.3

scCO 94.0 14.0 6.0 THF 46.2 6.9 53.8

scCO 86.0 70.8 14.0

Finally … flow Reactors flexibility and analytical choices?

. Range of applications are possible – including liquid/liquid reactions with long reaction times and low pressure Chemistry . Advanced analytical methods, such as on-line FTIR are available and beneficial – as supplement (even replacement) for GC.

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Liquid-Liquid reaction in flowCAT: Example

Hydrogenation of nitrotoluene (to aniline) using cyclohexene as donor molecule

Transfer hydrogenation of Nitrobenzene by cyclohexene: percentage concentration of aniline as function of residence time at different temperatures 100

Percentage concentration

T=110oC T=100oC

80

T=90oC 60 T=80oC 40

20

0 0

2

4

6 Residence time (mins)

8

10

12

Aniline yield at different conditions Productivity of reactor as function of temperature and residence time 100 Residence=10mins

Conversion (%)

80

60 Residence=5mins Residence=2mins

40

Residence=1min 20

0 70

80

90

100

Temperature (oC)

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110

120

Condensation reaction in PTFE pipe reactor

Benzil + diphenylacetone

Product

Base enhanced reaction 1)Product is an intense purple colour while the starting mixture is very pale green 2) With amount of caustic held constant, several runs were performed at different flows (different reaction times), at 90C

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PTFE Reactor demonstrates reaction progress

Batch samples

Time

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12min

6min

4min

2min

0 min

On-line FTIR for catalyst degradation phenol hydrogenation example

Phenol concentration increasing

Cyclohexanone and cyclohexanol decreasing

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Conclusions  Processes developed for batch reactors are not necessarily practical in flow reactors

 Modifications are generally possible which will overcome the restrictions.  Conversion/selectivity on the same process can often be improved by switching to flow due to the flexibility afforded by flow reactors

 Flow operation can also provide a simple way of tuning the product slate by changing operating conditions (flow, temperature, pressure).  Switching to scCO2 can be quite easily explored with flexible research for both batch and flow chemistry. Improvement in conversion/selectivity is not guaranteed but is possible.

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