principles of flow chemistry. overview what is flow chemistry? flow chemistry vs batch chemistry key...
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Principles of Flow Chemistry
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
Labs in the past!
~1950
~1920
~1750
• 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
What is flow chemistry?
In flow chemistry, reagents are continuously pumped through the reactor and the product is
continuously collected.
A
B
C
Batch and flow
• 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.
Reaction Mixture
>5mm
Reagent A Reagent B
Reagent A
Reaction Mixture
~100µm
Reagent B
Key factors:- Concentration- Mixing- Temperature- Reaction time
Key factors:- Residence time (flow rates)- Mixing- Pressure- Temperature
Key Principles of Flow Chemistry
• Residence Time
• Mixing
• Pressure
• Temperature
Residence time
• 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
Worked example: Residence time
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?
Residence Time = Reactor Volume / Flow Rate
Combined flow rate = 0.25 + 0.25 = 0.5 mL/min
Residence time = 1/0.5 = 2 min
Slow flow rates to 0.0625 mL/min each.
Increase the reactor volume to 4 mL.
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
• 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
Mixing
ReservoirPump
ReservoirPump
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
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
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
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
• 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):
Solids
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%
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
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
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
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
Any questions?