This document discusses flow chemistry and its advantages over traditional batch chemistry. Flow chemistry involves performing reactions continuously in a small-scale reactor rather than in batches. It allows for better temperature control, safer handling of hazardous reagents like gases or exothermic reactions, higher selectivity and productivity, and easier scale-up. Areas that benefit greatly from flow chemistry include exothermic reactions, reactions with gases, and scale-up. Miniaturized microreactors in flow systems provide enhanced heat and mass transfer for improved reaction control and safety. Overall, flow chemistry is a useful method for performing chemistry in a safer, more efficient, and reproducible manner compared to batch.

1. Flow chemistry: A useful
method for performing
hazardous chemistry in a
safer manner
László Kocsis
laszlo.kocsis@thalesnano.com

2. What is flow chemistry?
• Performing a reaction continuously, typically on small scale,
through either a coil or fixed bed reactor.
OR
Pump
Reactor
Collection

3. Where is flow chemistry applied best?
Exothermic Reactions
Exothermic Reactions
•Very good temperature control
•Very good temperature control
•Accurate residence time control
•Accurate residence time control
•Efficient mixing
•Efficient mixing
•Less chance for thermal run-away
•Less chance for thermal run-away
•Higher productivity per volume
•Higher productivity per volume
•High selectivity
•High selectivity
Endothermic Reactions
Endothermic Reactions
Reactions with gases
Reactions with gases
Scale up
Scale up
•Accurate gas flow regulation
•Accurate gas flow regulation
•Increased safety
•Increased safety
•Easy catalyst recycling
•Easy catalyst recycling
•High selectivity
•High selectivity
•Higher productivity per volume
•Higher productivity per volume
•Increased safety
•Increased safety
•Higher productivity per volume
•Higher productivity per volume
•Selectivity
•Selectivity
•Reproducibility
•Reproducibility
•Control over T, and residence time
•Control over T, ppand residence time
•High selectivity
•High selectivity
•Accessing new chemistry
•Accessing new chemistry
•Higher productivity per volume
•Higher productivity per volume
•High atom efficiency
•High atom efficiency

4. Miniaturization: Enhanced temperature control
Large surface/volume rate
•
Microreactors have higher surface-to-volume ratio than macroreactors, heat
transfer occurs rapidly in a flow microreactor, enabling precise temperature
control.
Yoshida, Green and Sustainable Chemical Synthesis Using Flow
Microreactors, ChemSusChem, 2010

5. Heating Control
Batch
Flow
- Larger solvent volume.
- Lower temperature control.
- Lower reaction volume.
- Closer and uniform temperature control
Outcome:
Outcome:
-More difficult reaction control.
- Higher possibility of exotherm.
- Safer chemistry.
- Lower possibility of exotherm.

6. Heating Control
Lithium Bromide Exchange
Batch
Flow
• Batch experiment shows temperature increase of 40°C.
• Flow shows little increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems

7. Industry perception
Why move to flow?
Small scale:
 Making processes safer
 Accessing new chemistry
 Speed in synthesis and
analysis
 Automation
Large scale:
 Making processes safer
 Reproducibility-less batch
to batch variation
 Selectivity

8. What is the issue with chemical space?
500
Temperature / °C
400
Unexploited
chemistry space
300
200
100
At ThalesNano
0
100
-100
Region covered in a
conventional
laboratory
pressure / bar 200
300

9. Who we are, what we do?
• ThalesNano makes laboratory reactors that chemists use to
create new drugs, new aromas, new chemicals, or new
processes.
• We push the boundaries of science by giving chemists the
tools to access novel chemistry at high temperatures and
pressures safely and rapidly.
• We also make existing processes safer and more efficient.

10. Strategy
• Strategy: Solve chemical problems using
flow




Dangerous exothermic reactions
High temperature and pressure reactions
Reactions with gases
Highly selective reactions

11. Hydrogenation

12. • Current hydrogenation processes have many
disadvantages:







Need hydrogen cylinder-tough safety regulations
Separate laboratory needed!
Time consuming and difficult to set up
Catalyst addition and filtration is hazardous
Parr has low temperature, low pressure capability
Analytical sample obtained through invasive means.
Mixing of 3 phases inefficient - poor reaction rates

13. Hydrogen generator cell
 Solid Polymer Electrolyte
High-pressure regulating
valves
Water separator, flow
detector, bubble detector

14. Catalyst System-CatCart®
•Benefits
• Safety
• No filtration necessary
• Enhanced phase mixing

15. H-Cube Pro Overview
O2N
H2N
N
H
N
H
H
•
•
•
•
HPLC pumps continuous stream of solvent
Hydrogen generated from water electrolysis
Sample heated and passed through catalyst
Up to 150°C and 100 bar. (1 bar=14.5 psi)

16. Decomposition of High-Energy Materials
OH
O2 N
OH
OH
NO2
9 eqv. H 2
cat
H2N
NO 2
NH2
H2 N
NH2
NH 2
Molecular Weight: 229,10
NH 2
Molecular Weight: 145,20 Molecular Weight: 139,16
Flow rate
(ml/min)
0.5
Pressure
(bar)
100 (∆p: 1)
Temperature
(oC)
100
Catalyst
Result
5% Rh/C
The starting material fully decomposed, the main
product is the desired one. MW is 145g/mol
0.5
100 (∆p: 1)
100
RaNi
The starting material fully decomposed, the main
product is the selective nitro reduced benzene
derivative. MW is 139g/mol
0.5
100 (∆p: 1)
100
10% Pd/C
The starting material fully decomposed, the main
product is the selective nitro reduced benzene
derivative. MW is 139g/mol

17. Reactions with
toxic gases

18. Toxic gases
Carbon monoxide:
4
2
4
Explosive limits: 12.5 – 74.2%
Conc: 1600ppm, death within
2 hours
Ammonia:
1
3
0
IDLH (Immediately Dangerous to Life and Health) is 300 ppm (NIOSH)

19. Carbonylation leading to esters
O
Fibrecat 1001:
Pd content [mmol/g]: 0.47,
Load: mmol/catcart: 0.114.
Void volume: 0.62 ml
O
I
CO, DBU
Fibercat 1001
EtOH
O
Ethanolic solution: DBU: 1.1 eq., 4iodo-anisole: 1.0 ekv,
concentration: 0.1 M - 1.0 M
O
Concentration
Liquid
Temperature Gas flow Pressure Pressure Conversion Selectivity
flow rate
(oC)
rate
(bar)
drop
(%)
(%)
(mL/min)
(ml/min)
(bar)
0.1 M
0.1 M
0.1 M
1M
1M
0.5
0.5
0.5
0.5
1
150
150
150
150
150
10
10
50
100
100
10
30
10
30
30
2
3
3
2
2
>99
>99
>99
>99
98.3
>99
>99
>99
>99
>99
Microwave reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2007, 65):
Concentration: 0.1M, Pressure: 10 bar, Temperature: 125oC, Reaction time: 30 min
Conversion: 90%
Flow reference from Nicholas Leadbeater’s lab (Org.Biomol.Chem. 2011, 6575):
Concentration: 1M, Pressure: 17 bar, Temperature: 120oC Residence time: 120 min
Conversion: 98%

20. Paal-Knorr pyrole synthesis
O
NH3
MeOH
40-110 oC
O
T /oC Conversion (%)
40
100
110
100
N
H
Phoenix with 4 ml loop
60bar, 0.5 ml/min 0.1M hexanedione, 0.5
ml/min NH3 (4 min residence time)
Batch reference (Chem.Ber. 1885, 367):
Temperature: 150oC, Reaction time: 120 min
Flow reference from Steve Ley’s lab (Org.Biomol.Chem. 2012, 5774):
Pressure: 0.1M solution, Pressure: 3.5 bar, Temperature: 0oC for dissolving
ammonia, than 110oC
Residence time: 10 min on 0oC than 110 min on 110oC
Conversion: 100%

21. Low Temperature
Chemistry

22. Set-up of the Ice Cube Modular System
Ozone Module:
generates O3 from O2 100 mL/min, 10 % O3.
Reactor Module:
2 Stage reactor. -70°C-+80°C.
Teflon tubing.
Pump Module – 2 Rotary Piston Pumps.
Excellent chemical compatibility.

23. Versatile: 2 options
A
C
B
-70-+80ºC
Reactor
Pre-cooler/Mixer
C
A
B
D
-70-+80ºC
-30-+80ºC
Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation

24. Exothermic Reactions
Ozonolysis
Diazotization
Nitration
Lithiation
Swern oxidation
?
Halogenation
Azide

25. What is ozonolysis?
• Ozonolysis is a technique that cleaves double and
• triple C-C bonds to form a C-O bond.
R
O
H
R1
R2
R3
R4
O3
R1 O O R2
R3
R
O
R4
Ozonide
O
OH
R
• Market segments:
• Pharmaceutical, Fine chemicals, Agrochemicals
• Any organic chemistry synthesis segment.
OH

26. Ozonolysis in Industry
Synthesis of a Key intermediate for Indolizidine 215F
Biologically active natural product
Oxandrolone, anabolic steroid used to promote weight
gain following extensive surgery, chronic infection
S. Van Ornum et al, Chem. Rev.106, 2990-3001 (2006)

27. Why ozonolysis is neglected?
• Highly exothermic reaction, high risk of explosion
• Normally requires low temperature: -78°C.
• In addition, the batchwise accumulation of ozonide
is associated again with risk of explosion
• There are alternative oxidizing agents/systems:
• Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidation (CrO3, H2SO4)
• Swern oxidation
• Most of the listed agents are toxic, difficult, and/or
expensive to use.

28. Ozonolysis of decene
Batch reference:
-78oC, DCM, NMMO as a quench. Yield: 88-94%
Tetrahedron, 2006, 10747
Ozonolysis in microreactor
Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042

29. Ice-Cube set-up
Quench
Reactant

30. O-Cube™ – H-Cube® - ReactIR™
ozonolysis of decene
Ozonolysis
Quenching with
H-Cube®
React IR™
T = -30 ºC
T = -30 ºC to r.t.
CSM = 0.02 M (in EtOAc) p = 1 bar
Cat: 10 % Pd/C
O3 excess = 30 %
Ozonide eluted into cool vial under N2
ThalesNano lab based
chemistry-unpublished
O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo
International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.

31. O-Cube – Ice Cube comparison
Conversion
(%)
Temperature
(oC)
97
-30
Equipment
Conc. (M)
Decene FR
(ml/min)
Ozone FR
(ml/min)
Quench FR
(ml/min)
O-Cube
0.02
1
20
0.2
Ice-Cube
0.05
Ice-Cube
0.1
Ice-Cube
0.2
81
Ice-Cube
0.5
24
Ice-Cube
0.2
1
Ice-Cube
0.2
1
100
Ice-Cube
0.1
1.5
100
Ice-Cube
0.1
3
58
Ice-Cube
0.1
5
26
100
95
1
100
0,2
100
-40
0
-20

32. Dialdehyde Formation
Reference
T=-78°C
40% conversion, T=-78°C
Org. Proc. Res. Dev. 2003, 7, 155-160
Chem. Rev. 2006, 106, 2990-3001
Our results
OH
O
EtOAc
O3, PPh3
T (°C)
Solvent
O
O
+
O
1
+
2
Vrea
(ml/min)
vQuen
(ml/min)
vO2
(ml/min)
Quench
3
c
(M)
O3
(%)
X (%)
OH
1
(%)
2
(%)
3
(%)
25
EtOAc
1
1
10
PPh3
0.1
16
100
80
6
14
25
EtOAc
0.5
0.5
10
PPh3
0.1
16
100
83
6
11
5
EtOAc
0.5
0.5
10
PPh3
0.1
16
100
83
6
12
25
EtOAc
0.5
0.5
20
PPh3
0.1
16
100
82
8
10

33. Exothermic Reactions
Ozonolysis
Diazotization
Nitration
Lithiation
Swern oxidation
?
Halogenation
Azide

34. Diazonium salts and diazo coupling
• Most aromatic diazonium salts are not stable at temperatures above 5°C
• The synthesis reaction to prepare the diazonium salt is typically exothermic, producing
between 65 and 150 kJ/mole and is usually run industrially at sub-ambient temperatures
• Diazonium salts decompose exothermically, producing between 160 and 180 kJ/mole
• Many diazonium salts are shock-sensitive

35. Azo dyes
• Azo dyes are synthetic colours that contain an azo group, -N=N-, as part of the
structure. Azo groups do not occur naturally.
• Azo dyes account for approximately 60-70% of all dyes used in food and textile
manufacture.
• Azo des used in food: E102: Tartrazine, E107: Yellow 2G, E110: Sunset Yellow,
E122: Azorubine, E123: Amaranth, E124: Ponceau 4R, E129: Allura Red, E151:
Brilliant Black, E154: Brown FK, E155: Brown HT, E180 Lithol Rubine BK
E102 : Tartrazine
E122 : Azorubin
E180 : Lithol Rubine BK

36. Diazotization and azo-coupling
ONH 2
N
OH
NaOH
HCl
Aniline
HCl sol.
N
N N+ Cl-
NaNO2
Pump A
Pump C
NaNO2
sol.
Pump B
Phenol
NaOH sol.
Vflow (ml/min)
T (°C)
τ (1. loop, min)
τ (2. loop, min)
FM79-1
A-B-C
0.4
Isolated Yield
(%)
0
2.12
3.33
91
FM79-2
0.9
0
0.94
1.48
91
FM79-3
0.6
0
1.42
2.22
85
FM79-4
0.9
10
0.94
1.48
85
FM79-5
1.5
10
0.56
0.88
86
FM79-6
1.5
15
0.56
0.88
98
FM79-7
1.2
15
0.71
1.11
84
FM79-8
1.8
15
0.47
0.74
86

37. Diazotization and azo-coupling
O-
NH2
NaNO 2
N
N N + Cl-
HCl
N
NaOH
OH
Vflow (ml/min)
A-B-C
T (°C)
τ (1. loop, min)
τ (2. loop, min)
Isolated
Yield (%)
FM81-1
0.6
0
1.42
2.22
77
FM81-2
1.5
0
0.56
0.88
99
FM81-3
1.5
15
0.56
0.88
99
Advantages of diazotization in flow:
• safe handling of the diazonium salt
• only small amount of diazonium is present at one time, determined by the size of the
first loop (1.7 ml in our case)
• Cooling is very effective, no danger of overheating and explosion
• Diazotization can be driven safely > 5°C, if the residence time in the first loop is short
enough
• pH can be kept constant during the coupling
• Residence time can be as low as 0.5-1 min, with concentrations similar to batch
conditions (0.66M solutions)

38. Exothermic Reactions
Ozonolysis
Diazotization
Nitration
Lithiation
Swern oxidation
?
Halogenation
Azide

39. Nitration
Nitration is a general class of chemical process for the introduction of a nitro
group into an organic chemical compound.
Industrial use of nitro compounds:
• Drugs
• Explosives
• Solvents
• Plastics
• Rocket propellants
Hazards of nitrations:
• Highly exothermic
• Tends to be runaway
• Sideproducts are highly poisoning
• The products are explosives

40. Nitration of Aromatic Alcohols
Pump A
Solution
ccHNO3
1.48g NH4NO3/15ml
ccH2SO4
1.48g NH4NO3/15ml
ccH2SO4
70% ccH2SO4 30%
ccHNO3
70% ccH2SO4 30%
ccHNO3
Flow rate
(ml/min)
0.4
0.7
0.5
0.6
0.6
Pump B
Flow rate
Solution
(ml/min)
1g Ph/15ml
ccH2SO4
0.4
1g Ph/15ml
ccH2SO4
0.5
1g Ph/15ml
ccH2SO4
0.5
1g Ph/15ml
ccH2SO4
0.5
1g Ph/15ml
ccH2SO4
0.5
Temperature Loop size Conversion
(oC)
(ml)
(%)
Selectivity (%)
5 - 10
7
100
0 (different
products)
5 - 10
13
100
100
5 - 10
13
50
80 (20% dinitro)
5 - 10
13 (3 bar)
100
100
80
70 (30% dinitro
and nitro)
5 - 10
13 (1 bar)

41. Selective nitrations of aromatic alcohols
OH
Ice-Cube, 10°C
Temperature
(oC)
+
NO 2
2
1
OH
NO 2
NO2
+
cc. H 2SO 4, 3.3eq HNO3
SM
OH
OH
OH
O2N
NO 2 O2N
+
+
NO 2
3
OH
NO 2
NO 2
5
4
Composition of the product (%)
Residence
time (min)
SM
1
2
3
4
5
10
5
7
80
1
7
5
0
10
1
9
56
24
5
4
0
10
0.5
10
49
28
6
5
0
10
0.25
10
50
29
5
4
0
10
0.1
13
57
19
6
5
0
0
0.5
19
48
22
6
4
0
-10
0.5
22
45
22
7
4
0

42. Exothermic Reactions
Ozonolysis
Diazotization
Nitration
Lithiation
Swern oxidation
?
Halogenation
Azide

43. Swern Oxidation
If the temperature is not kept near -78°C, mixed thioacetals may result:
Cryogenic operating conditions
(< - 60°C), limit its utility for scale up
operations in batch.
Residence
time (tR1) [s]
2.4
Microreactor
0.01
0.01
Method
Flask
Chemistry-A European Journal 2008, 7450
T [oC]
-20
0
20
-20
-70
Selectivity of
cyclohexanone [%]
88
89
88
19
83

44. Swern Oxidation
OH
DMSO, Oxalyl-Chloride
Quench: TEA
O
Ice-Cube Flow Reactor
Temperature (°C)
OAC Solution (ml/min)
Alcohol and DMSO Solution (ml/min)
Conversion (%)
Selectivity (%)
-30
0.96
1.9
100%
100%
-20
0.96
1.9
100%
100%
-10
0.96
1.9
100%
100%
0
0.96
1.9
100%
60%
Using TFAA as a DMSO activator seems to afford even higher temperatures.
No chloromethyl-methyl-sulfide production at higher Temps.

45. Exothermic Reactions
Ozonolysis
Diazotization
Nitration
Lithiation
Swern oxidation
?
Halogenation
Azide

46. Lithiation on Ice-Cube
OH
Br
O
BuLi
O
O
T= 0oC; 1. loop: 1.7 ml; 2. loop: 4.0 ml
Flow Rate (ml/min)
Conversion (%)
Selectivity (%)
0.8
100
60
0.5
98
71
0.3
100
75

47. Conclusions
• Hazardous reactions can be managed in a safer
manner using the flow methodology
• Better temperature control
• Smaller amount of reactants
• More efficient mixing
• Some exothermic reactions were shown as case
studies
•
•
•
•
•
•
Hydrogenation
Carbonylation
Ozonolysis
Diazotization
Nitration
Swen oxidation

48. THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS?