Wednesday, January 18, 2012

Process Wednesday: non-green solvents

Credit: Laird, T. Org. Process Res. Dev.,
Dunn, P.J. Pharmaceutical Process Development
In a recent editorial, Trevor Laird reiterated Organic Process Research and Development's stance on "undesirable solvents":
...From 2012 the policy on use of organic solvents has been changed to discourage scientists from using  particular solvents and to encourage them to seek alternatives wherever possible; papers containing strongly undesirable solvents (e.g., benzene, carbon tetrachloride, chloroform, HMPA, carbon disulfide, etc.) will only be considered if accompanied by an analysis of alternatives or if a convincing justification for such use is presented.
The editors encourage all authors to consider these issues before submitting their papers to OPRD, and we warn that authors risk having papers rejected unless environmental impact and green chemistry principles are considered. (emphasis Laird's)
He also provides a helpful table. Finally, he throws darts (legitimately!) at ethyl acetate:
The only quibble I have is that I prefer isopropyl acetate to ethyl acetate as an extraction solvent since the relatively high solubility of EtOAc in water (and water in EtOAc) means that the aqueous waste is contaminated with more organic material, thus making it harder to dispose of and also product could be lost in the aqueous layer!
 I'm vaguely surprised to see DMF and NMP on the list -- what's non-green about them?

UPDATE: Chemblogosphere pioneer milkshake has some recommended alternative solvents. 


  1. Looks like birth defects for both, per Wiki mobile.

  2. DMF and NMP and hard to get out of water. Any thing that taints your waste streams is a bad thing. This is why factories are loath to use water as a solvent... the heat capacity is too high, making distillation prohibitive. Hexane is particularly bad because it develops a static charge which chemical plants don't like.

  3. Yeah, the hexane thing I was aware of. Bad day for me to leave my copy of Anderson at home...

  4. other thing about hexane is a moderate chronic neurotoxicity of its metabolites, 2-hexanone and 2,5-hexadione. Pentane and heptane do not have this tox issue. Apparently it was found out in a plant workers extracting vegetable oils for food use, who were breathing hexane vapors at work

  5. Ack -- I've always meant to talk about that. A pyrrole derivative of the 2,5-hexadione, right?

  6. Does anyone else feel a bit distributed by policy for restriction of solvents/mandating requirements for inclusion of EI/Green assessments for acceptance of papers? While I agree, and believe most process chemist know or learn, avoiding certain solvents (plus other hazards) very important in large scale to dictate acceptability criteria in this fashion strikes me as going against Scientific approach. Does this policy apply to Reagents and other chemicals with toxic handling/waste issues, so is focus because of the volume differences (certain metals commonly employed would pose more danger I might think). Frankly often from experience the initial function in Drug Process Development is to do switch outs the solvents as profiled in Table 2 and other nasty chemicals which are inherent in most medchem/academic procedures and as felt it would be nice if the mindset would be adopted earlier in peoples lab training but since it is not one can get blocked into continued use of undesirable things for longer than ideal.

    Another reason to possibly avoid EtOAc is that can under some conditions easily react with acids/Me esters for unwanted by-products that do not occur with iPOAc (which likewise seems to provide more distinct boundary layers in extraction).

  7. I do not believe in "Green Chemistry" it does not exist.


looks like Blogger doesn't work with anonymous comments from Chrome browsers at the moment - works in Microsoft Edge, or from Chrome with a Blogger account - sorry! CJ 3/21/20