“Process Intensification of the Kolbe-Schmitt- Synthesis ... · Kolbe-Schmitt reaction zDeveloped by A.W. Hermann Kolbe in 1860 for the synthesis of salicylic acid zImproved by

“Process Intensification of the Kolbe-Schmitt-Synthesis by Using Novel Process Windows”

Dipl.-Ing. Ulrich Krtschil, Volker Hessel, Patrick Löb, Dorothee Reinhard

IMM/ Dept. Mixing and Fine Chemistry

Dr. Annegret Stark , Dr. Dana Kralisch, Sabine Hübschmann Friedrich Schiller University of Jena,

Technical Chemistry and Environmental Chemistry

“Novel Process Windows in Chemical Engineering”

- Workshop -

December 10, 2009

Osnabrück, Germany

© IMM, 2009 IMM Presentation 2

Outlook

1. History, motivation, project approach and experimentation

2. Aqueous synthesis using oil bath heating

3. Oil bath heated synthesis using reactive ionic liquids

4. Aqueous synthesis using microwave heating

5. Tailor-made microstructured reactors for microwave heating and direct electrical heating

6. Ecological impact

7. Summary and outlook


History

Kolbe-Schmitt reactionDeveloped by A.W. Hermann Kolbe in 1860 for the synthesis of salicylic acid

Improved by Rudolf Schmitt in 1885

First industrial application in 1874 in Dresden/Radebeul“start-up company” founded by Friedrich von Heyden

(assistant of R. Schmitt)

Cradle of the modern API manufacturing A.W. Hermann Kolbe(source: Wikipedia)

”Salicylsäurefabrik Dr. F. von Heyden” in Radebeul

HO

O O H

salicylic acid


Motivation

Kolbe-Schmitt reaction:

Used as standard method for the fabrication of e.g.

- aromatic hydroxy carboxylic acids (e.g. acetylsalicylic acid = Aspirin®)- p-aminosalicylic acid (PAS)- alkyl p-hydroxybenzoate (paraben)

Products used as

- pharmaceuticals- antimicrobials - fine chemicals

Kolbe-Schmitt synthesis is normally carried out batch wiselong reaction times

Process Intensification of the industrial relevant Kolbe-Schmitt synthesis

- continuously processed- use of Novel Process Windows, e.g. high-p,T, increased concentrations

Stirred tank (before 1950)


Target reaction

Mechanism

Side and consecutive reactions

p=10-40 bar T=140-200 oCτ=10-320 s

“Combining flow chemistry with alternative solvents, new reagentsand advanced reactor engineering”

Project approach

higher temperatures and longer residence times promote side reaction and decomposition

Heating method

Solvent

HCO3- donating ionic liquids

Ionic Liquids

Near-critical CO2

Aqueous solution

conventionally CH-IL-KS CH-A-CO2-KS CH-A-KS

microwave M-IL-KS — M-A-KS


Experimental set-ups

1/8 inch



1/8 inch1/16 inch



1/8 inch1/16 inch


Analytics

HPLC (Shimadzu VP series)

UV detection at 220 and 260 nm

Reported data received when using 220 nm better detection of resorcinol

Acidic eluent to avoid deprotonation of the acidic sites

Eluent is a mixture of acetonitrile, water and potassium dihydrogenphosphate as buffer










0

5

10

15

20

25

30

35

40

45

50

0,000 0,005 0,010 0,015 0,020 0,025 0,030 0,035 0,040 0,045 0,050 0,055 0,060 0,065 0,070 0,075 0,080 0,085 0,090 0,095 0,100

Residence time [s] (reciprocal)

Yiel

d 2,

4-D

HB

A [

%]

160°C and 35 bar, 1/16 inch




1100

11100

100 50 33 25 20 17200 67 13 11

15800

9800

STY[kg/(m³

CH-A-KS: Dependency of yield and STY on the capillary dimension

Higher yield and STY for the 1/16 inch (O.D.) capillary

at short residence times

Higher yield and STY for the 1/16 inch (O.D.) capillary

at short residence times


CH-A-KS: Selectivity improvements for short residence times

0

5

10

15

20

25

30

35

40

45

0,0000 0,0100 0,0200 0,0300 0,0400 0,0500 0,0600 0,0700 0,0800 0,0900 0,1000


Yiel

d 2,

4-D

HB

A a

nd 2

,6-D

HB

A [

%] (

(

2,4-DHBA, 160°C and 35 bar, 1/8 inch






130385 33 25 20 17 1113

1

65

at high temperatures and for shorter residence times:

minor variation in yield

at high temperatures and for shorter residence times:

minor variation in yield

substantial increasein selectivitysubstantial increasein selectivity


Decomposition of the product 2,4-DHBA]

0

10

20

30

40

50

60

70

80

90

100

0,0000 0,0100 0,0200 0,0300 0,0400 0,0500 0,0600 0,0700 0,0800 0,0900 0,1000

Residence time (reciprocal) [s]

Con

vers

ion

(dec

ompo

sitio

n) o

f 2,4

-DH

BA

[%]

160 °C, 1/16 inch180 °C, 1/16 inch200 °C, 1/16 inch220 °C, 1/16 inch250 °C, 1/16 inch270 °C, 1/16 inch

130 65 32 16 11

T ≥ 220 °C Decomposition

almost independent of residence time

T ≥ 220 °C Decomposition

almost independent of residence time

T < 220 °C Decomposition

increases withresidence times

T < 220 °C Decomposition

increases withresidence times


Comparison of product formation and decomposition

0

10

20

30

40

50

60

70

80

90

0,0000 0,0100 0,0200 0,0300 0,0400 0,0500 0,0600 0,0700 0,0800 0,0900 0,1000


Yiel

d re

sorc

inol

[%] )

0

10

20

30

40

50

60

70

80

90

Yiel

d 2,

4-D

HB

A [%

]160 °C, resorcinol 180 °C, resorcinol 200 °C, resorcinol160 °C, 2,4-DHBA 180 °C, 2,4-DHBA 200 °C, 2,4-DHBA

130 65 32 16 11

Shortening of the residence time promotes product formation

(results for T ≤ 200 °C)

Shortening of the residence time promotes product formation

(results for T ≤ 200 °C)

1/16 inch capillary

oil bath heating









© IMM, 2009

0

10

20

30

40

50

60

0,0000 0,0125 0,0250 0,0375 0,0500 0,0625 0,0750 0,0875 0,1000 0,1125 0,1250 0,1375 0,1500 0,1625 0,1750 0,1875 0,2000 0,2125 0,2250 0,2375 0,2500


Yiel

d 2,

4-D

HB

A [

%]

KHCO3, 180°C and 35 bar, 1/16 in. BMIM-HC, 180 °C and 35 bar, 1/16 in.



KHCO3, 140°C and 35 bar, 1/8 in.

32 16 11 6.5 465130

69900

STY[kg/(m³ h)]

520

8386

44 %

56 %

IMM Presentation 16

CH-IL-KS: Enhancements in yield and space-time yield

19 %

19 %

135 fold increase in STY

386 s 4 s

© IMM, 2009

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

4,5

5,0

0,0000 0,0200 0,0400 0,0600 0,0800 0,1000 0,1200 0,1400 0,1600

Resicence time [s] (reciprocal)

Yiel

d 2,

6-D

HB

A [

%]

EMIM-HC, 220°C KHCO3, 250 °C

EMIM-HC, 200°C KHCO3, 200 °C

EMIM-HC, 180°C KHCO3,180 °C

EMIM-HC, 160°C KHCO3,160 °C

32 16 11 6130 65

IMM Presentation 17

CH-IL-KS: Selectivity improvements compared with KHCO3

By-product formation at all temperatures and residencetimes significantly lower for

ionic liquids

By-product formation at all temperatures and residencetimes significantly lower for

ionic liquids

200

o C

180

o C









© IMM, 2009

0

5

10

15

20

25

30

35

40

45

40 60 80 100 120 140 160 180 200

Outlet Temperature [°C]

Yiel

d 2,

4-D

HB

A [%

] MW 1/4 inch, 130 s Oil bath, 1/8 inch, 130 s

MW 1/4 inch, 65 s Oil bath, 1/8 inch, 65 s




MW 1/16 inch, 5 s "Oil bath, 1/16 inch, 11 s"

32550(MW, 1/16")

2620(MW, 1/4")

15500(Oil, 1/16")

IMM Presentation 19

MW-A-KS: Comparison of yield vs. oil bath heating

Microwave: Synthos 3000 (Anton Paar)Capillary: PEEK, 1/4 inch O.D. (1/16 inch)

Oil bath: CC 405 (Huber) Capillary: Stainless steel, 1/8 inch O.D. (1/16 inch)

Trend for both heating methods andfor short residence times:

increasing yield with Temp. for residence times < 32 s

≥32 s maximum of yield (<200 °C)

significantly higher STY for the 1/16 inch capillary

Trend for both heating methods andfor short residence times:

increasing yield with Temp. for residence times < 32 s

≥32 s maximum of yield (<200 °C)

significantly higher STY for the 1/16 inch capillary

© IMM, 2009

MW-A-KS: Comparison of product decomposition vs. oil bath heating

0

10

20

30

40

50

60

70

80

90

100

0,0000 0,0100 0,0200 0,0300 0,0400 0,0500 0,0600 0,0700 0,0800 0,0900 0,1000


Con

vers

ion

(Dec

ompo

sitio

n) 2

,4-D

HB

A [%

]

Oil bath, 220 °CMW 200 W, 131 °C - 208 °COil bath, 200 °CMW 120 W, 118 °C - 185°COil bath, 180 °CMW 100 W, 123 °C - 165°COil bath, 160 °CMW 80 W, 64 °C - 116 °C

13 65 32 16 11

higher decomposition rate formicrowave heating at comparabletemperatures and residence times

difference becomes more salient forlower temperatures

higher decomposition rate formicrowave heating at comparabletemperatures and residence times

difference becomes more salient forlower temperatures










Modular microstructured reactor for microwave heating - Design

microwavecavity

threadedring

reactorhousing

reactionplate

gasket

coolingplate

threadedring

inlet capillary outlet capillary

fiberopticallytemperature

sensor

attenuator

microwavecavity

threadedring

reactorhousing

reactionplate

gasket

coolingplate

threadedring

inlet capillary outlet capillary

fiberopticallytemperature

sensor

attenuator


Modular microstructured reactor for microwave heating - Concept

Developed for continuous operation and adapted to the cavity of the CEM microwave device „Discover“Designed for pressures up to 40 bar at 150 °CModular construction:

different numbers of reaction plates in series or parallelenables simultaneous release of the reaction heat by a microwave transparent cooling fluid (perfluoropolyether)

Integrated fibre optical temperature measurementHPLC-connectors


Electrical heated microstructured reactor for liquids - Design

part with microstructured channelsgeneral viewexploded view

electricheating cartridge

casing tube

inlet

outlet

cap

tube withmicrostructured

channels


Electrically heated microstructured reactor for liquids - Concept

Comparable cross-sectional area with the 1/16 inch capillaryuse of advantages for small dimensions:

higher yields

better selectivity

40 fold higher productivity due to (internal) equalling-upEnergy savings compared to oil bath heating by reason of

thermally controlled power consumption direct electrical heating

Promising results of pre-tests with an existing gas heaterScale-up to pilot-scale by external numbering-up using a starlike distributor and collector










Cumulative Energy Demand (CED) – Influence of residence time

0

5000

10000

15000

20000

25000

30000

35000

40000

0.02 L

/h0.0

3 L/h

0.07 L

/h0.1

4 L/h

0.2 L/h

0.27 L

/h0.3

4 L/h

0.55 L

/h17

.2 L/h

waste water treatmentelectrical currentsolvent/ILpotassium hydrogen carbonateresorcinol

CED reductionby factor 17

CED reductionby factor 17

4 s

130 s

Electrical currentreduction by

factor >30

Electrical currentreduction by

factor >30

S. Huebschmann, D. Kralisch, V. Hessel, U. Krtschil, V. Kompter, Chem. Eng. Technol. 2009, 32, No. 11, 1757–1765










Progress achieved - Overview

0

10

20

30

40

50

60

0,0000 0,0125 0,0250 0,0375 0,0500 0,0625 0,0750 0,0875 0,1000 0,1125 0,1250 0,1375 0,1500 0,1625 0,1750 0,1875 0,2000 0,2125 0,2250 0,2375 0,2500


Yiel

d 2,

4-D

HB

A [

%]

KHCO3, 180°C, 35 bar, 1/16 in. BMIM-HC, 200 °C, 35 bar, 1/16 in.KHCO3, 140°C, 35 bar, 1/8 in. EMIM-HC, 220 °C, 35 bar, 1/16 in.KHCO3, 220 °C, 35 bar,

32 16 11 8 6,5 465130

69900

STY[kg/(m³ h)]

520

20400

15800Yield

56 %

44 %

58 %

38 %

385

microstructured electrical heater

20300

25 %

10-fold amount of product

U. Krtschil, V. Hessel, D. Reinhard, A. Stark, Chem. Eng. Technol. 2009, 32, No. 11, 1774–1789


SummaryReaction profits from process intensification enabled by Novel Process Windows and micro reaction engineering:

Advantages at higher temperatures and the thereby enabled short residence times:

massive increase in space-time yieldswhereas yields are only moderately decreasedlowering or almost avoidance of by-product formationpredominance of advantages for small dimensions

Best yields and space-time yields if reactive ionic liquids are usedNo increase in yield if additional near-critical CO2 was applied

Improvement for microwave heated capillary reactors compared to oilbath heating with respect to doubling of space-time yieldDedicated microstructured reactor for microwave heating and enabling simultaneous release of the reaction heat by liquid cooling developed and manufacturedElectrically heated microstructured reactor for liquids developed, suited for lab and pilot scale by numbering-up


Outlook

Experimental testing of the microstructured reactor in the microwave and comparison to results gained with the capillary reactorManufacture of the electrically heated microstructured reactorIts application in comparative experiments Erection of a pilot plant and testing of a industrial interesting reaction at industrial site


Acknowledgement

Directorate Micro and Milli ProcessEngineering

Thank you for y

our atte

ntion!

Documents

“Process Intensification of the Kolbe-Schmitt- Synthesis ... · Kolbe-Schmitt reaction zDeveloped by A.W. Hermann Kolbe in 1860 for the synthesis of salicylic acid zImproved by