1. Principles of Flow Chemistry

2. Overview What is flow chemistry? Flow Chemistry vs Batch Chemistry
Key principles of Flow Chemistry
Residence Time
Mixing
Pressure
Temperature
Types of Flow Chemistry
Summary

3. ~1950 ~1920 ~1750 Labs in the past! New labs – same equipment
Focus has been on new reactions, new chemistries.
New equipment only designed to solve “non-reaction” steps:
Flash chromatography
Evaporation
Reactor automation
~1920
~1750
If you went back to your life in 1750, everything would be completely different. However, if you went into a lab in 1750, you could probably do the same.

4. A C B What is flow chemistry?
In flow chemistry, reagents are continuously pumped through the reactor and the product is continuously collected. A C B

5. Batch and flow Classic way to do chemistry.
Reagent A
Reaction Mixture
~100µm
Reagent B
Reaction Mixture
>5mm
Reagent A
Reagent B
Classic way to do chemistry.
Reagents are loaded into the reactor, mixed and left to react.
The products is collected at the end, after the reaction has been completed and worked-up. .
New technique.
Reagents streams are continuously pumped into the flow reactor.
Reagents mix and react in the flow reactor.
The product leaves the reactor as a continuous stream.
Key factors:
Concentration
Mixing
Temperature
Reaction time
Key factors:
Residence time (flow rates)
Mixing
Pressure
Temperature

6. Key Principles of Flow Chemistry
Residence Time
Mixing
Pressure
Temperature

7. Residence Time = Reactor Volume / Flow Rate
It can be defined as the time that every fraction of the reaction volume spends in the reactor
Residence time is equivalent to reaction time in batch chemistry.
It is calculated as follows:
Two ways of controlling the residence time:
Vary the reactor volume.
Vary the flow rates.
Example: to achieve a longer residence time, it is possible to either pump more slowly and/or use a reactor with a larger volume.
Residence Time = Reactor Volume / Flow Rate

8. Worked example: Residence time
Residence Time = Reactor Volume / Flow Rate
Example: 2 reagents flowing into a 1 mL glass microreactor at 0.25 mL/min flow rate each.
What is the residence time?
To change the residence time to 8 min.
What are the two options?
Combined flow rate = = 0.5 mL/min
Residence time = 1/0.5 = 2 min
Slow flow rates to mL/min each.
Increase the reactor volume to 4 mL.

9. Mixing In batch chemistry, mixing is turbulent
In flow chemistry, the mixing can be turbulent or laminar
Small tube diameter results in laminar flow conditions (Reynolds number Re<2500)
Radial diffusion

10. Mixing
In turbulent flow conditions, static mixers are used to increase mass transfer
In laminar flow conditions, mixing occurs by diffusion
Diffusion time is proportional to distance squared, therefore over short distances, diffusion is rapid
Reservoir
Pump

11. Pressure
In a flow reactor the total pressure at any location is made up of two factors:
Back pressure due to flow
This increases with higher flow rate, narrower channels or more viscous liquid
Back pressure intentionally applied
This is typically applied by a pressure regulator near the exit of the system
Bubbles are best avoided as they can “push out” the reaction, thus lowering the residence time
Flow reactors can be easily pressurised (much easier than a batch reaction)
This can be useful for a variety of reasons:
Reactions with gas
Avoiding cavitation
Superheating

12. Temperature
Due to a higher surface area:volume ratio, flow reactors enable better heat transfer and therefore better temperature control
Reactions cool down or heat up extremely rapidly (faster than a microwave)
By pressurising, flow reactors can operate at temperatures above the typical boiling point of reactions
This enables easy superheating of reactions e.g. 100ºC to 150ºC above reflux temperatures at atmospheric pressure

13. Different types of flow chemistry
Homogeneous flow chemistry:
Monophasic liquid-liquid reactions
Biphasic liquid-liquid reactions (link to video)
Two-phase microfluidic flows, Chemical Engineering Science 66 (2011) 1394
Heterogeneous flow chemistry:
Solid-liquid reactions
Gas-liquid reactions
Gas-solid-liquid reactions

14. Liquid-Liquid Interactions
Batch Flow
Scaling  
Surface Area
Gravity  
Surface Tension
Emulsion
Flow Chemistry is ideal for biphasic liquid reactions
Flow Chemistry is very suitable for aqueous work-up

15. Microfluidic Method of Droplet Production
Hydrophilic coating
Hydrophobic OR Fluorophilic coating + +
Hydrophilic surface
Hydrophobic surface

16. Solids
Solids in flow reactors can in some instances cause problems such as blockages
The ability for flow reactors to tolerate solids varies greatly
Higher ratio between channel diameter and particle size, the lower probability of a blockage
Other factors such as the nature of the particle, reactor design and velocity of the reaction can all influence the likelihood of a blockage
The use of solid reagents is typically easiest by isolating them in a “column” and flowing the reaction in solution through the packed column
Solution to solids issues is often a chemistry solution (and not a technology solution):
Adapt the chemistry
Add co-solvents to increase solubility of products
Reduce concentrations of reaction
Examples of solids produced in Syrris flow chemistry systems (link to Asia Nanoparticle video):

17. What is the potential of flow chemistry?

18. Prof. Steve Ley’s paper 7 flow steps
Mix of homogeneous and heterogeneous reactions including gas phase
Synthesis, evaporation and workup all in flow
Overall yield 40%

19. Examples of Syrris flow Chemistry
Homogeneous catalysis
Suzuki reaction
Heck reaction
Grubbs ring forming
Multicomponent reactions
Passerini 3CR
Biginelli 3CR
Ugi 4CR
Deprotection chemistry
BOC deprotection
MOM deprotection and intra epoxide opening
Ester saponification
Ring formations
Grubbs ring forming
Ugi followed by ring closure to benzimidazole
Diels Alder
1,3,4 Oxadiazole formation
Fischer indole synthesis
1,3 Thiazole formation
Pyrazole formation
Oxidations and reductions
Borohydride reduction
Borane reduction of a heterocycle
Reductive amination
Dess Martin alcohol oxidation
General Synthesis
Aldol reaction
Biphasic Schotten-Baumann
HBTU amide coupling
Elimination of an alcohol to alkene
Esterification of an alcohol
Wittig reaction
Nucleophilic aromatic substitution
SN1 reaction
Mitsunobu reaction
N-Alkylation

20. Residence Time = Reactor Volume / Combined Flow Rate
Summary
Flow chemistry is an exciting new tool for chemists.
Reaction conditions: flow rates ratio, residence time, temperature.
Variable parameters: flow rates, reactor volume, temperature
The technology is growing fast.
Later today you get a chance to see/use the most advanced flow chemistry systems available.
Residence Time = Reactor Volume / Combined Flow Rate

21. Any questions?