Continuous anodic oxidation of TEMPO as a mediator for ... · Continuous anodic oxidation of TEMPO...

+

−

Continuous anodic

oxidation of TEMPO as a

mediator for selective

synthesis of aldehydes

from primary alcohols

1 Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-55128 Mainz,

Germany2 Fraunhofer ICT-IMM, Carl-Zeiss-Str. 18-20, 55129 Mainz, Germany

* loewe@uni-mainz.de

Christoph Deckers1, Martin Linden1,

Julian Heinrich1, Holger Löwe1,2*

Outline

• Anelli Oxidation

• One-Phase Approach• Mixing and Residence Time

• Multi-Phase Approach• Mixed Double Emulsions

• Electrooxidation• Voltammetry Experiments → Batch Process → Continuous Process

• Outlook

2

https://www.ak-loewe.chemie.uni-mainz.de/

Anelli Oxidation

3

TEMPO+ TEMPOH

TEMPOTEMPOH TEMPOBr

TEMPO TEMPO+ TEMPOH

1 2

https://www.ak-loewe.chemie.uni-mainz.de/

V.A. Golubev,

E.G. Rozantsev,

M.B. Neimann, Izv.Akad.Nauk

SSSR, 1965, 11, 1927-1936.

P.L. Anelli, C. Biffi,

F. Montanari, S. Quici,

J.Org.Chem., 1987, 52, 2559-

2562.

M. Zhao, J. Li, E. Mano,

et al., J.Org.Chem., 1999, 64,

2564-2566.

Anelli Oxidation

4

Pre-oxidation of TEMPO

• NaOCl in situ causes side products

• Br2 in organic solvents (requires separation)

• electrochemical oxidation in water (several alcohols insoluble, solvent changes, phase separation)

multiphase flow with excess of TEMPO+

Pre-

oxidation

2

TEMPO

+2

TEMPO+ +

TEMPOH

+

TEMPO+

Comproportionation

https://www.ak-loewe.chemie.uni-mainz.de/

Small window for

efficient mixing;

broad residence time

distribution

Mixing controlled;

broad residence time

distribution

Residence time

controlled

Mixing and residence

time controlled

One-Phase Approach

5

Mixer

Segment T-Piece SIMM-V2

Continuous

flow

Segmented

flow

https://www.ak-loewe.chemie.uni-mainz.de/

Constant

mixing

efficiency

Constant

volume flow;

different

capillary length

𝑡R =𝑓(𝑐𝑎𝑝𝑖𝑙𝑙𝑎𝑟𝑦 𝑙𝑒𝑛𝑔𝑡ℎ)

Measurable

Variable

mixing

efficiency

Constant

capillary length;

different

volume flow

𝑡R =𝑓(𝑣𝑜𝑙𝑢𝑚𝑒 𝑓𝑙𝑜𝑤)

Programmable

One-Phase Approach

6

Residence time tR =

Channel length

Volume flow

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One-Phase Approach

Residence time dependency:

• Fixed flow rates

• Observation by GC and by eye (bleaching)

• Full conversion after approx. 3.5 min

• No significant differences between mixer types and flow patterns

• Kinetic limit reached

7

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50.00

0.25

0.50

0.75

1.00

SIMM-V2, heterogeneous

SIMM-V2, homogeneous

T-Jct., heterogeneous

T-Jct., homogeneous

C

tR / min

https://www.ak-loewe.chemie.uni-mainz.de/

One-Phase Approach

8

1 2 3 4 5 6 70.00

0.25

0.50

0.75

1.00

C

tR / min

Flow rate/mixing dependency:

• Fixed reactor volume

• Conversion decreases with increasing residence time

• Decreasing flow rate/mixing efficiency

• Increased reaction time unable to compensate loss in mixing efficiency

https://www.ak-loewe.chemie.uni-mainz.de/

Multi-Phase Approach

9

core

sh

ell

conti

PTFE-capillary

OD = 1/16“, ID = 1,0 mm

PTFE-Capillary

OD = 1/32“,

ID = 0,5 mm

PEEK-Capillary

OD = 360 µm,

ID = 150 µm

water

toluene FC-40TM

outlet

Coaxial double emulsion generator

• 2 T-junctions to insert core and shell capillary into main channel

• Coplanar outlet of inner capillaries

• Core droplet is infused into shell droplet while latter is generated

https://www.ak-loewe.chemie.uni-mainz.de/

V. Misuk, A. Mai, Y. Zhao, J. Heinrich, D. Rauber, K. Giannopoulos, H. Löwe, J. Flow Chem., 2015, 5(2), 101–109.

Video: Link

Multi-Phase Approach

Passive mixing:

• Gravity induced

• Capillary coiled on cylinder

• Double emulsion, core droplet pulled downwards by gravity

• Crosses shell droplet twice every winding

10

Reversal point

Reversal point

Gra

vity

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V. Misuk, A. Mai, Y. Zhao, J. Heinrich, D. Rauber, K. Giannopoulos, H. Löwe, J. Flow Chem., 2015, 5(2), 101–109.

Video: Link

Video: Link

10 20 30 40 50 60 700.00

0.25

0.50

0.75

1.00

excess 1:1

excess 3:1

excess 6:1

excess 10:1

tR / min

C

Multi-Phase Approach

Gravity induced mixing:

• Oxidant and alcohol in different phases

• Interface reaction

• Extended reaction time necessary

• 9-fold excess of TEMPO+ reduces reaction time to 17 min

• Easy recycling of remaining TEMPO+

11

FC-40TM aqueous TEMPO+

1 in toluene

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orbital

shakersample

collection

retention

unitdroplet

generation

camera

Multi-Phase Approach

Active mixing:

• Retention unit mounted on orbital shaker

• Double emulsion, jiggling of core droplet

• Stirring of shell phase with adjustable frequency

12

https://www.ak-loewe.chemie.uni-mainz.de/

V. Misuk, A. Mai, Y. Zhao, J. Heinrich, D. Rauber, K. Giannopoulos, H. Löwe, J. Flow Chem., 2015, 5(2), 101–109.

Video: Link

0.00 0.15 0.30 0.45 0.60 0.75 0.90

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

forbital shaker

/ Hz

Multi-Phase Approach

Stirred double emulsion:

• 1.7 eq of TEMPO+ used

• Conversion 12% in 3 min without mixing

• Increase to approx. 22% conversion between 0.2 Hz and 0.5 Hz

• Maximum expected around 0.35 Hz

• Further Investigation necessary

13

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0 1 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

pH

Electrooxidation

Disproportionation of TEMPO:

• Full conversion to TEMPO+ and TEMPOH at pH = 0

• At pH = 2 TEMPO+ yield is 68%

• Proportion of 33% of TEMPO+, TEMPOand TEMPOH each

• pH ≥ 3 suppresses disproportionation

14

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2 3 4 5 6 7 8 9

0.0

0.2

0.4

0.6

0.8

1.0

pH

Electrooxidation

15

Comproportionation of TEMPO+ and TEMPOH:

• TEMPOH formed in situ by adding 1 to TEMPO+

• Almost total comproportionation at pH = 9

• 80% TEMPO+ left in neutral media

• No comproportionation at pH = 2

Alcohol oxidation with stochiometric amounts of TEMPO+ requires pH < 2

https://www.ak-loewe.chemie.uni-mainz.de/

CV and RDE measurements of TEMPOH:

• No conversion to TEMPO+observed in acidic medium (pH = 2)

• Neutral or alkaline medium required

• Intermediary TEMPO not observed

• Proved by additional CV/RDE measurements of TEMPO

-400EGC/Pt [mV]

-200 0 200 800400 600

I[µ

A]

12

2

0

4

6

8

10

-2

pH=2pH=7pH=9

2,0

1,0

1,5

0

0,5

-0,5

-400

-1

4002000EGC/Pt [mV]

I[µ

A]

600-200

pH=2pH=7pH=9

Electrooxidation

16

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Electrooxidation

Oxidation path:

• Easy oxidation TEMPO → TEMPO+

• No direct oxidation TEMPOH → TEMPO+

• Only in alkaline media

• Preceding deprotonation to TEMPO-

• TEMPO- → TEMPO → TEMPO+

• TEMPO- → TEMPO much slower than TEMPO → TEMPO+

17

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A. M. Janiszewska, M. Grzeszczuk, Electroanalysis, 2004, 16 (20), 1673-1681.

Electrooxidation

18

0.0

0.1

0.2

0.3

0.4

0.5

(a)

TEMPO solution,

5h

(b)

TEMPO solution,

16h

(c)

recycled solution

from (b), 16h

https://www.ak-loewe.chemie.uni-mainz.de/

Batch electrolysis:

• Maximum yield 33%

• Decomposition of water acidifies anolyte

• Disproportionation of TEMPO

0.0

0.1

0.2

0.3

0.4

0.5

(a)

TEMPO solution,

5h

(b)

TEMPO solution,

16h

(c)

recycled solution

from (b), 16h

Electrooxidation

Batch electrolysis:

• Maximum yield 33%

• Decomposition of water acidifies anolyte

• Disproportionation of TEMPO

• TEMPOH associates with TEMPO

• Oxidation is prevented

19

A. M. Janiszewska, M. Grzeszczuk,

Electroanalysis, 2004, 16 (20), 1673-1681.

https://www.ak-loewe.chemie.uni-mainz.de/

Electrooxidation

20

+

Catholyte in

0.1M Na2SO4

Catholyte out

Anolyte in

0.1M Na2SO4

0.1M TEMPOH

pH 8

Anolyte out

Anolyte in

Anolyte out

Catholyte in

Catholyte out−

https://www.ak-loewe.chemie.uni-mainz.de/

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

TEMPO+

TEMPO

(a)

U = 1.5 V;

pH = 8

(b)

U = 2.0 V;

pH = 8

(c)

U = 2.0 V;

pH = 7, buffered

Electrooxidation

Continuous electrolysis:

• Decomposition of water → acidification

• Maximum yield 33%

• Buffering at pH = 7 prevents dimerization, lowers oxidation yield due to protonation of TEMPO-

21

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Outlook

Electrochemical microstructuredreactor:

• Divided cell (NafionTM membrane)

• Ti meshed metal baffle, platinized

• Galvanostatic mode

Challanges:

• pH change required

• Flow rate adjustment

• Continuous phase separation

• Recirculation of mediator

Objective: Fully automated process

22

TEMPOH

oxidans recycling

TEMPO+

circulating FC-40™

continuous phase

pH ≥ 9

pH ≤ 2

substrate

feed

anolyte

cycle

phase

separator

phase

separator

+−

TEMPO

initial feed

product

https://www.ak-loewe.chemie.uni-mainz.de/

J. Heinrich, Automated reaction monitoring and control with microcontrollers on the way to the "Internet of Lab", Ph.D. Thesis, University Mainz, 2018.

Automated reaction monitoring and control with microcontrollers on the way to the "Internet of Lab"

Automated reaction monitoring and control with microcontrollers on the way to the "Internet of Lab"

Automated reaction monitoring and control with microcontrollers on the way to the "Internet of Lab"

Outlook

API synthesis from natural/renewable resources

• Antitumor and –inflammatory properties

• Treatment of leukemia, malaria etc.

23

Betulin

(3β)-Lup-20(29)-en-3,28-diol

Betulin aldehyde Betulinic acid

and derivates

Selective Oxidation

CrO3

Betula pendule

Sorbus americana

Fraxinus americana

https://www.ak-loewe.chemie.uni-mainz.de/

Conclusions

• One-phase process requires much shorter reaction time than multi-phase reaction

• Multi-phase approach simplifies oxidans recycling significantly

• Allows usage of huge excess of oxidans

• Allows mixing in segmented flow

• Disproportionation equilibrium of TEMPO requires pH < 2 for optimal oxidation conditions

• Alkaline medium required for reoxidation of TEMPOH

• Water decomposition and association of TEMPOH and TEMPO major problems in batch and continuous oxidation, maximum yield of TEMPO+ 33%

• Fully integrated continuous process requires pH changes and continuous phase separation

• Applications in API synthesis, focus on betulin and derivates

24

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Thank You!

https://www.ak-loewe.chemie.uni-mainz.de/

Prof. Dr. Holger Löwe Christoph Deckers Dr. Julian Heinrich