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?