Co-solvents (in water solvent) are defined as kosmotropic (order-making) if they contribute to the stability and structure of water-water interactions. Kosmotropes cause water molecules to favorably interact, which also (in effect) stabilizes intramolecular interactions in macromolecules such as proteins.[1] Chaotropic agents (disorder-makers) have the opposite effect, disrupting water structure, increasing the solubility of nonpolar solvent particles, and destabilizing solute aggregates.[1]

Ionic kosmotropes

Ionic kosmotropes tend to be small or have high charge density. Some ionic kosmotropes are CO2−
, SO2−
, HPO2−
, magnesium(2+), lithium(1+), zinc (2+) and aluminium (+3). Large ions or ions with low charge density (such as bromide, iodide, potassium(1+), caesium(1+)) instead act as chaotropes.[2] Kosmotropic anions are more polarizable and hydrate more strongly than kosmotropic cations of the same charge density.[3]

A scale can be established if one refers to the Hofmeister series or looks up the free energy of hydrogen bonding ( ) of the salts, which quantifies the extent of hydrogen bonding of an ion in water.[4] For example, the kosmotropes CO2−
and OH
have between 0.1 and 0.4 J/mol, whereas the chaotrope SCN
has a between −1.1 and −0.9.[4]

Recent simulation studies have shown that the variation in solvation energy between the ions and the surrounding water molecules underlies the mechanism of the Hofmeister series.[5][6] Thus, ionic kosmotropes are characterized by strong solvation energy leading to an increase of the overall cohesiveness of the solution, which is also reflected by the increase of the viscosity and density of the solution.[6]


Ammonium sulfate is the traditional kosmotropic salt for the salting out of protein from an aqueous solution. Kosmotropes are used to induce protein aggregation in pharmaceutical preparation and at various stages of protein extraction and purification.

Nonionic kosmotropes

Nonionic kosmotropes have no net charge but are very soluble and become very hydrated. Carbohydrates such as trehalose and glucose, as well as proline and tert-butanol, are kosmotropes.

See also


  1. Moelbert S, Normand B, De Los Rios P (2004). "Kosmotropes and chaotropes: modelling preferential exclusion, binding and aggregate stability". Biophysical Chemistry. 112 (1): 45–57. arXiv:cond-mat/0305204. doi:10.1016/j.bpc.2004.06.012. PMID 15501575.
  2. Chaplin, Martin (May 17, 2014). "Kosmotropes and Chaotropes". Water Structure and Science. London South Bank University. Retrieved 2014-09-05.
  3. Yang Z (2009). "Hofmeister effects: an explanation for the impact of ionic liquids on biocatalysis". Journal of Biotechnology. 144 (1): 12–22. doi:10.1016/j.jbiotec.2009.04.011. PMID 19409939.
  4. Marcus Y (2009). "Effect of ions on the structure of water: structure making and breaking". Chemical Reviews. 109 (3): 1346–1370. doi:10.1021/cr8003828. PMID 19236019.
  5. M. Adreev; A. Chremos; J. de Pablo; J. F. Douglas (2017). "Coarse-Grained Model of the Dynamics of Electrolyte Solutions". J. Phys. Chem. B. 121 (34): 8195–8202. doi:10.1021/acs.jpcb.7b04297.
  6. M. Adreev; J. de Pablo; A. Chremos; J. F. Douglas (2018). "Influence of Ion Solvation on the Properties of Electrolyte Solutions". J. Phys. Chem. B. 122 (14): 4029–4034. doi:10.1021/acs.jpcb.8b00518.
  • Polson, C; Sarkar, P; Incledon, B; Raguvaran, V; Grant, R (2003). "Optimization of protein precipitation based upon effectiveness of protein removal and ionization effect in liquid chromatography-tandem mass spectrometry". Journal of Chromatography B. 785 (2): 263–275. doi:10.1016/S1570-0232(02)00914-5. PMID 12554139.
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