Advantages & considerations for synthesis using segmented flow chemistry
Andrew Mansfield , flow chemistry lead , CCO , at Syrris discuss the key considerations when designing a segmented flow chemistry workflow and the benefits of this methodology
Flow chemistry is growing in popularity for drug discovery , with many demonstrated advantages over traditional synthetic methods . It allows safer and more efficient synthesis of compounds from milligram scale for exploratory projects right through to manufacturing-scale API production . Alternatively , the technique can be used to optimise reaction conditions and translate traditional batch reactions to continuous production .
The development of modern , automated flow chemistry systems has also significantly progressed the capabilities of this technique for drug discovery , where it can be used to synthesise compound libraries and automate reaction optimisation . The main benefit of this approach is the ability to use small volumes of reactants for fast sequential library syntheses .
Understanding the different flow chemistry regimes
The term continuous flow – sometimes referred to as plug flow – is used to describe chemical reactions in continuously flowing systems of cylindrical geometry , known as flow reactors . Fluid flowing through the reactor can be considered a series of ‘ plugs ’ ( or slugs ), each with its own composition , that are perfectly mixed in the radial – but not axial – direction . Effectively ,
a
b
/l V
dV dx
■ ■
■ ■
)It ■■
■ ■
■ ■
■ ■
Continuous flow
a series of reactions is flowing through the system .
This behaviour is shown in Figure 1a , where each coherent plug has a given length ( dx ) and volume ( dV ), travelling in the longitudinal direction of the reactor , with no mixing or diffusion in the direction of the flow path . 1 , 2 However , this is not the only consideration when running continuous flow experiments ; the ‘ ideal ’ plug flow model assumes a steady state , no mixing between plugs , a constant density and
.Ll x
- lllf
Reaction phase
� |
Carrier fluid |
Reaction |
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phase |
phase |
Segmented flow
Figure 1 – Continuous ( above ) & segmented ( below ) flow
only one reaction occurring . Some of these assumptions are addressed later .
Segmented flow is defined by alternating segments of liquids or gases ; for most chemistry applications , this is the reaction phase and a carrier fluid phase ( Figure 1b ). In contrast to a plug flow reactor – which represents an infinite number of plugs with infinitesimal volume – segmented flow represents discrete slugs ( Δx ) with defined volumes ( ΔV ). 1
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981