Polar, yet greasy

Solvation/desolvation processes have put a spell over chemical reactivity. Indeed, had this not been the case, we would have been able to computationally predict pretty much anything at this point. As it stands, though, failure to accurately account for the balance of entropy and enthalpy during solvation/desolvation is one of the biggest deficiencies of quantum mechanical calculations. Outliers that are found among organic solvents underscore this fact. In this regard, trifluoroethanol (TFE) is one of my favourite solvents. I think my lab uses several liters of this stuff per year, despite the fact that our reactions are typically fairly small in scale. TFE is one of the strangest beasts out there and you might wonder why. The reasons are shown below.


One of the most interesting and useful consequences of this unusual combination of TFE’s relatively high acidity (for an alcohol) and its low dielectric constant is its capacity to encourage “hydrogen bond shielding”. There is a lot of literature on the profound effect exerted by TFE on the peptide secondary structure. Many years ago, Kemp published a definitive paper that explored the mechanism of increased helicity of peptides in the presence of TFE. It appears that TFE raises the energy of the solvent exposed hydrogen bonds. As a result, medium-sized peptides with an intrinsic tendency to assume helical conformations in water show a dramatic increase in helicity upon addition of TFE. I am betting that some of the effects of this solvent on our peptide cyclization reactions are due to globular conformations promoted by TFE. There are many interesting effects of TFE on organic reactions and a lot remain to be discovered.


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