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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
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
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
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
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
https://www.ak-loewe.chemie.uni-mainz.de/
Thank You!
https://www.ak-loewe.chemie.uni-mainz.de/
Prof. Dr. Holger Löwe Christoph Deckers Dr. Julian Heinrich