Why would a molecule become more soluble at low temperature?

This is something I wanted to put out there. A colleague of mine reported a situation in which his flexible, complex organic molecule was becoming more soluble in water at low temperature and he was wondering why.

The most straightforward explanation that comes to my mind is this. When the molecule is flexible it naturally exists in several conformations in solution. The lipophilic conformations are going to be higher in energy since they are exposing non-polar groups to aqueous solvent. Conversely, the conformations that are nicely solvated and expose charged or polar groups to solvent are going to be low-energy.

At low temperatures, the higher-energy lipophilic conformations become inaccessible because of less energy in the system, leading to a preponderance of the low-energy polar conformations which are more soluble. Ergo the molecule becomes more soluble.

This can be studied by a couple of different ways, most notably by changing the solvent and altering the conformer population; previous studies have indicated that changes in solvent (say from polar to non-polar) only change populations, and not the conformations themselves.

Any other explanations?


  1. It sounds vaguely analogous to what is believed to occur with micellar systems (formation of the small disc-like structures at low temperature to the formation of the "Swiss cheese" lamellar structures at higher temperature with increased viscosity).

    Combining the above and your suggestion - perhaps as the temperature decreases these flexible, complex organic molecules interact to form aggregates which primarily only expose the polar functional groups to solvent.

    An interesting question to be sure!

  2. Isn't the hydrophobic effect driven primarily by entropy? So, if the hydrophobic effect is driving the formation of insoluble aggregates, then decreasing the temperature of the system would decrease the strength of this effect relative to enthalpic effects that might promote the dissolution of the substance.

  3. Inverse solubility is also seen for salts. It is usually due to the dissolution being exothermic, so that added heat drives the reaction towards the undissolved state (Le Chatelier's principle)

  4. Don't forget about the change in the solvent properties... it seems just as likely that changing the properties of water with temperature could be responsible.

  5. Is the solid state conformation strained? Do the polar groups in the compound make optimal interactions in the solid state? Are there ionisable groups in the molecule and, if so, is the aqueous medium buffered? How different are the solubilities and temperatures?

  6. Thanks for your comments. It's intriguing to consider the conformational shift in lipids that was mentioned. It's also interesting to contemplate the change in the structure of water. I wonder if anyone has investigated the effect of viscosity on conformations. The hydrophobic effect might also contribute, being driven by enthalpy at high T and entropy at low T

  7. One does need to be careful when 'explaining' thermodynamic observations in terms of one of the states. There is a tendency to pick the state with which one is most comfortable. It's also worth remembering that changes in viscosity will affect kinetics and not thermodymanics.


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