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Some Reflections on Solvent Selection

Valued Contributor III
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Contributed by Dr. Andy Wells, Charnwood Technical Consulting Ltd.

The inspiration for this article came from some work I recently carried out with collaborators in the CHEM 21 consortium, looking at solvent use in the pharmaceutical industry. While there has been a lot of progress and excellent work published in the field of solvent selection, it is clear that this is a journey that is underway, and there is still work to do to influence solvent selection in a global context (Survey of Solvent Usage in Papers Published in Organic Process Research and Development 1997-2012).

So why the concern over solvents? In most cases, solvents are not the most expensive contributor to the cost of a pharmaceutical, but it has become clear that they make a major contribution to the life cycle impact of a product due to the natural resources and energy embedded in to their manufacture/ recycle/disposal (GSK Experiences in Life Cycle Inventory and Assessment). It has also become clear over the past 20 years or so that several solvents have undesirable toxicity towards humans and /or adverse effects in the environment. A further recent related consideration is environmental legislation such as REACH in the European Union, which may seek to restrict or phase out the most hazardous solvents (substances of very high concern) – (REACH - Registration, Evaluation, Authorisation and Restriction of Chemicals).

So, how do you choose a solvent for a reaction? For many chemists, especially those that have not worked in process or manufacturing environments, this is probably via a semi- automatic, instinctive process. You might be reproducing an experiment from a paper, or using a published method using similar reagents/products. You might consult a standard text book or think back to grad school where specific solvent classes were recommended for certain transformations. Of course, practiced chemists will have their ‘favorite’ solvents, and experience of what works well for a particular reaction type.

The selection of an ‘optimum’ solvent for a process is actually quite a complex task, with the solvent needing to full fill a number of tasks:

  • Good mixing (mass transport/phases)
  • Selectivity – acceptable yield and impurity profile
  • Acceptable reaction rate
  • Scalability – solvent presents no  (or manageable) safety issues
  • Enabling process safety – exotherm control through reflux
  • Isolation – high purity product in the desired crystalline form with acceptable levels of residual solvent.

So if the solvent initially chosen, or reported in the literature, does have a poor safety/environmental profile, are you stuck with it? Well, not necessarily, there may be better options available. Take nucleophilic substitution reactions – SNAr and SN2. These reactions are typically run in dipolar aprotic solvents like N,N-dimethylacetamide (DMF). A number of solvents in this class are coming under increasing scrutiny and legislation due to undesirable reprotoxicity effects. However, there could be a number of alternatives to avoid solvents like DMF in SN type reactions.

Choose a member of this solvent class with minimal risks.

Does the reaction have to be run in that solvent class? A number of Sn-type reactions will run in other solvent classes like alcohols or ketones.

If a more beguine solvent works, but suffers from a poor reaction rate, can it be used under pressure to increase the reaction temperature above the boiling point and increase rate?

Can catalysis/additives be used to promote the desired reaction in a more beguine solvent?

Can a more beguine solvent(s) be used with additives like phase transfer catalysts?

Another good reaction class is amide bond formation – often accomplished in solvents like DMF or dichloromethane. There have been several recent publications describing alternative greener solvents for this reaction (Better Solvents for Peptide Synthesis , Evaluation of alternative solvents in common amide coupling reactions: replacement of dichloromethan...)

There is probably no ‘ideal’ solvent – choice is always a number of trade –offs between desired performance of the process and safety/environmental factors, however good solvent selection needs careful choice and consideration driven by data. So, good luck with your reactions, and do give some serious consideration to solvent selection. To conclude, below are some links that lead to useful resources on solvents and solvent selection.

1. Green chemistry tools to influence a medicinal chemistry and research chemistry based organisation

2. Expanding GSK's solvent selection guide – embedding sustainability into solvent selection starting a...

3. Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes

4. ACS GCI Roundtable solvent guide

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