Editing Acid dissociation constant (section)

=== Mixed solvents ===
[[File:Acetic acid pK dioxane water.png|thumb|alt=The p K A of acetic acid in the mixed solvent dioxane/water. p K A increases as the proportion of dioxane increases, primarily because the dielectric constant of the mixture decreases with increasing doxane content. A lower dielectric constant disfavors the dissociation of the uncharged acid into the charged ions, H + and C H 3 C O O minus, shifting the equilibrium to favor the uncharged protonated form C H 3 C O O H. Since the protonated form is the reactant not the product of the dissociation, this shift decreases the equilibrium constant K A, and increases P K A, its negative logarithm.|p''K''<sub>a</sub> of acetic acid in dioxane/water mixtures. Data at 25&nbsp;°C from Pine ''et al.''<ref>{{cite book
| title = Organic chemistry
| last = Pine
| first = S.H.
| author2 = Hendrickson, J.B.
| author3 = Cram, D.J.
| author4 = Hammond, G.S.
| year = 1980
| publisher = McGraw–Hill
| isbn = 0-07-050115-7
| page = 203
}}</ref>]]

When a compound has limited solubility in water it is common practice (in the pharmaceutical industry, for example) to determine p''K''<sub>a</sub> values in a solvent mixture such as water/[[dioxane]] or water/[[methanol]], in which the compound is more soluble.<ref>{{cite journal
| last = Box
| first = K.J.
| author2 = Völgyi, G.
| author3 = Ruiz, R.
| author4 = Comer, J.E.
| author5 = Takács-Novák, K.
| author6 = Bosch, E.
| author7 = Ràfols, C.
| author8 = Rosés, M.
| year = 2007
| title = Physicochemical Properties of a New Multicomponent Cosolvent System for the pKa Determination of Poorly Soluble Pharmaceutical Compounds
| journal = Helv. Chim. Acta
| volume = 90
| issue = 8
| pages = 1538–1553
| doi = 10.1002/hlca.200790161
}}</ref> In the example shown at the right, the p''K''<sub>a</sub> value rises steeply with increasing percentage of dioxane as the dielectric constant of the mixture is decreasing.

A p''K''<sub>a</sub> value obtained in a mixed solvent cannot be used directly for aqueous solutions. The reason for this is that when the solvent is in its standard state its activity is ''defined'' as one. For example, the standard state of water:dioxane mixture with 9:1 [[mixing ratio]] is precisely that solvent mixture, with no added solutes. To obtain the p''K''<sub>a</sub> value for use with aqueous solutions it has to be extrapolated to zero co-solvent concentration from values obtained from various co-solvent mixtures.

These facts are obscured by the omission of the solvent from the expression that is normally used to define p''K''<sub>a</sub>, but p''K''<sub>a</sub> values obtained in a ''given'' mixed solvent can be compared to each other, giving relative acid strengths. The same is true of p''K''<sub>a</sub> values obtained in a particular non-aqueous solvent such a DMSO.

A universal, solvent-independent, scale for acid dissociation constants has not been developed, since there is no known way to compare the standard states of two different solvents.