Acid dissociation constant

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Acetic acid, CH3COOH, is composed of a methyl group, CH3, bound chemically to a carboxylate group, COOH. The carboxylate group can lose a proton and donate it to a water molecule, H20, leaving behind an acetate anion CH3COO- and creating a hydronium cation H3O . This is an equilibrium reaction, so the reverse process can also take place.
Acetic acid, a weak acid, donates a proton (hydrogen ion, highlighted in green) to water in an equilibrium reaction to give the acetate ion and the hydronium ion. Red: oxygen, black: carbon, white: hydrogen.

An acid dissociation constant, Ka, (also known as acidity constant, or acid-ionization constant) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions. The larger the Ka value, the more dissociation of the molecules in solution and thus the stronger the acid.

The equilibrium of acid dissociation can be written symbolically as:

\mathrm{HA \rightleftharpoons A^- + H^+}

where HA is a generic acid that dissociates by splitting into A, known as the conjugate base of the acid, and the hydrogen ion or proton, H+, which, in the case of aqueous solutions, exists as the hydronium ion—in other words, a solvated proton. In the example shown in the figure, HA represents acetic acid, and A represents the acetate ion, the conjugate base. The chemical species HA, A and H+ are said to be in equilibrium when their concentrations do not change with the passing of time. The dissociation constant is usually written as a quotient of the equilibrium concentrations (in mol/L), denoted by [HA], [A] and [H+]:

K_a equals the equilibrium concentration of the deprotonated form A-, times the equilibrium concentration of H+, all divided by the equilibrium concentration of the acid AH.

Due to the many orders of magnitude spanned by Ka values, a logarithmic measure of the acid dissociation constant is more commonly used in practice. The logarithmic constant, pKa, which is equal to −log10 Ka, is sometimes also (but incorrectly) referred to as an acid dissociation constant:

\ \mathrm{p}K_{\mathrm a} = - \log_{10}K_{\mathrm a}

The larger the value of pKa, the smaller the extent of dissociation at any given pH (see Henderson–Hasselbalch equation)—that is, the weaker the acid. A weak acid has a pKa value in the approximate range −2 to 12 in water. Acids with a pKa value of less than about −2 are said to be strong acids; a strong acid is almost completely dissociated in aqueous solution, to the extent that the concentration of the undissociated acid becomes undetectable. pKa values for strong acids can, however, be estimated by theoretical means or by extrapolating from measurements in non-aqueous solvents in which the dissociation constant is smaller, such as acetonitrile and dimethylsulfoxide.

Theoretical background[edit]

The acid dissociation constant for an acid is a direct consequence of the underlying thermodynamics of the dissociation reaction; the pKa value is directly proportional to the standard Gibbs energy change for the reaction. The value of the pKa changes with temperature and can be understood qualitatively based on Le Chatelier's principle: when the reaction is endothermic, the pKa decreases with increasing temperature; the opposite is true for exothermic reactions.

The value of pKa also depends on molecular structure in many ways. For example, Pauling proposed two rules: one for successive pKa of polyprotic acids (see Polyprotic acids below), and one to estimate the pKa of oxyacids based on the number of =O and −OH groups (see Factors that affect pKa values below). Other structural factors that influence the magnitude of the acid dissociation constant include inductive effects, mesomeric effects, and hydrogen bonding.

The quantitative behaviour of acids and bases in solution can be understood only if their pKa values are known. In particular, the pH of a solution can be predicted when the analytical concentration and pKa values of all acids and bases are known; conversely, it is possible to calculate the equilibrium concentration of the acids and bases in solution when the pH is known. These calculations find application in many different areas of chemistry, biology, medicine, and geology. For example, many compounds used for medication are weak acids or bases, and a knowledge of the pKa values, together with the water–octanol partition coefficient, can be used for estimating the extent to which the compound enters the blood stream. Acid dissociation constants are also essential in aquatic chemistry and chemical oceanography, where the acidity of water plays a fundamental role. In living organisms, acid-base homeostasis and enzyme kinetics are dependent on the pKa values of the many acids and bases present in the cell and in the body. In chemistry, a knowledge of pKa values is necessary for the preparation of buffer solutions and is also a prerequisite for a quantitative understanding of the interaction between acids or bases and metal ions to form complexes. Experimentally, pKa values can be determined by potentiometric (pH) titration, but for values of pKa less than about 2 or more than about 11, spectrophotometric or NMR measurements may be required due to practical difficulties with pH measurements.

Definitions[edit]

According to Arrhenius's original definition, an acid is a substance that dissociates in aqueous solution, releasing the hydrogen ion H+ (a proton):[1]

HA is in equilibrium with A + H+.

The equilibrium constant for this dissociation reaction is known as a dissociation constant. The liberated proton combines with a water molecule to give a hydronium (or oxonium) ion H3O+ (naked protons do not exist in solution), and so Arrhenius later proposed that the dissociation should be written as an acid–base reaction:

HA + H2O is in equilibrium with A + H3O+.

Brønsted and Lowry generalised this further to a proton exchange reaction:[2][3][4]

acid + base is in equilibrium with conjugate base + conjugate acid.

The acid loses a proton, leaving a conjugate base; the proton is transferred to the base, creating a conjugate acid. For aqueous solutions of an acid HA, the base is water; the conjugate base is A and the conjugate acid is the hydronium ion. The Brønsted–Lowry definition applies to other solvents, such as dimethyl sulfoxide: the solvent S acts as a base, accepting a proton and forming the conjugate acid SH+.

HA + S is in equilibrium with A + SH+.

In solution chemistry, it is common to use H+ as an abbreviation for the solvated hydrogen ion, regardless of the solvent. In aqueous solution H+ denotes a solvated hydronium ion rather than a proton.[5][6]

The designation of an acid or base as "conjugate" depends on the context. The conjugate acid BH+ of a base B dissociates according to

BH+ + OH is in equilibrium with B + H2O

which is the reverse of the equilibrium

H2O (acid) + B (base) is in equilibrium with OH (conjugate base) + BH+ (conjugate acid).

The hydroxide ion OH, a well known base, is here acting as the conjugate base of the acid water. Acids and bases are thus regarded simply as donors and acceptors of protons respectively.

A broader definition of acid dissociation includes hydrolysis, in which protons are produced by the splitting of water molecules. For example, boric acid (B(OH)3) produces H3O+ as if it were a proton donor,[7] but it has been confirmed by Raman spectroscopy that this is due to the hydrolysis equilibrium:[8]

B(OH)3 + 2 H2O is in equilibrium with B(OH)4 + H3O+.

Similarly, metal ion hydrolysis causes ions such as [Al(H2O)6]3+ to behave as weak acids:[9]

[Al(H2O)6]3+ +H2O is in equilibrium with [Al(H2O)5(OH)]2+ + H3O+.

Equilibrium constant[edit]

An acid dissociation constant is a particular example of an equilibrium constant. For the specific equilibrium between a monoprotic acid, HA and its conjugate base A, in water,

HA + H2O is in equilibrium with A + H3O+

the thermodynamic equilibrium constant, KStrikeO.png can be defined by[10]

K standard is a ratio involving the chemical activities of the four species in equilibrium. The numerator of the ratio holds the activity of the deprotonated acid A minus, times that of the hydronium ion H 3 O +. The denominator holds the activity of the acid A H, times that of water, H 2 O.

where {A} is the activity of the chemical species A etc. KStrikeO.png is dimensionless since activity is dimensionless. Activities of the products of dissociation are placed in the numerator, activities of the reactants are placed in the denominator. See activity coefficient for a derivation of this expression.

Illustration of the effect of ionic strength on the p K A of an acid. In this figure, the p K A of acetic acid decreases with increasing ionic strength, dropping from 4.8 in pure water (zero ionic strength) and becoming roughly constant at 4.45 for ionic strengths above 1 molar sodium nitrate, N A N O 3.
Variation of pKa of acetic acid with ionic strength

Since activity is the product of concentration and activity coefficient (γ) the definition could also be written as

K standard can be written equivalently as the product of two ratios. The first ratio involves four chemical concentrations, whereas the second ratio involves four activity coefficients. The numerator of the first ratio holds the concentration of the deprotonated acid A minus, times that of the hydronium ion H 3 O +, whereas its denominator holds the concentration of the acid A H, times that of water, H 2 O. The second ratio has the same form as the first, with activity coefficients in place of concentrations. This second ratio is abbreviated by a capital Gamma.

where [HA] represents the concentration of HA and \Gamma is a quotient of activity coefficients.

To avoid the complications involved in using activities, dissociation constants are determined, where possible, in a medium of high ionic strength, that is, under conditions in which \Gamma can be assumed to be always constant.[10] For example, the medium might be a solution of 0.1 M sodium nitrate or 3 M potassium perchlorate (1 M = 1 mol·dm−3, a unit of molar concentration). Furthermore, in all but the most concentrated solutions it can be assumed that the concentration of water, [H2O], is constant, approximately 55 mol·dm−3. On dividing KStrikeO.png by the constant terms and writing [H+] for the concentration of the hydronium ion the expression

K A equals the equilibrium concentration of the deprotonated acid A minus, times the equilibrium concentration of H +, all divided by the equilibrium concentration of the protonated acid A H.

is obtained. This is the definition in common use.[11] pKa is defined as −log10 Ka. Note, however, that all published dissociation constant values refer to the specific ionic medium used in their determination and that different values are obtained with different conditions, as shown for acetic acid in the illustration above. When published constants refer to an ionic strength other than the one required for a particular application, they may be adjusted by means of specific ion theory (SIT) and other theories.[12]

Although Ka appears to have the dimension of concentration it must in fact be dimensionless or it would not be possible to take its logarithm. The illusion is the result of omitting the constant term [H2O] from the defining expression. Nevertheless it is not unusual, particularly in texts relating to biochemical equilibria, to see a value quoted with a dimension as, for example, "Ka = 300 M".

Monoprotic acids[edit]

This figure plots the relative fractions of the protonated form A H of an acid to its deprotonated form, A minus, as the solution p H is varied about the value of the acid's p K A. When the p H equals the p K a, the amounts of the protonated and deprotonated forms are equal. When the p H is one unit higher than the p K A, the ratio of concentrations of protonated to deprotonated forms is 10 to 1. When the p H is two units higher that ratio is 100 to 1. Conversely, when the p H is one or two unit lower than the p K A, the ratio is 1 to ten or 1 to 100. The exact percentage of each form may be determined from the Henderson-Hasselbalch equation.
Variation of the % formation of a monoprotic acid, AH, and its conjugate base, A, with the difference between the pH and the pKa of the acid

After rearranging the expression defining Ka, and putting pH = −log10[H+], one obtains[13]

p H equals p K A plus the logarithm (base ten) of a ratio of chemical concentrations, namely the concentration of the protonated form A H divided by that of the deprotonated form A minus.

This is a form of the Henderson–Hasselbalch equation, from which the following conclusions can be drawn.

  • At half-neutralization [A]/[HA] = 1; since log(1) =0, the pH at half-neutralization is numerically equal to pKa. Conversely, when pH = pKa, the concentration of HA is equal to the concentration of A.
  • The buffer region extends over the approximate range pKa ± 2, though buffering is weak outside the range pKa ± 1. At pKa ± 1, [A]/[HA] = 10 or 1/10.
  • If the pH is known, the ratio may be calculated. This ratio is independent of the analytical concentration of the acid.

In water, measurable pKa values range from about −2 for a strong acid to about 12 for a very weak acid (or strong base). All acids with a pKa value of less than −2 are more than 99% dissociated at pH 0 (1 M acid). This is known as solvent leveling since all such acids are brought to the same level of being strong acids, regardless of their pKa values. Likewise, all bases with a pKa value larger than the upper limit are more than 99% protonated at all attainable pH values and are classified as strong bases.[3]

An example of a strong acid is hydrochloric acid, HCl, which has a pKa value, estimated from thermodynamic quantities, of −9.3 in water.[14] The concentration of undissociated acid in a 1 mol·dm−3 solution will be less than 0.01% of the concentrations of the products of dissociation. Hydrochloric acid is said to be "fully dissociated" in aqueous solution because the amount of undissociated acid is imperceptible. When the pKa and analytical concentration of the acid are known, the extent of dissociation and pH of a solution of a monoprotic acid can be easily calculated using an ICE table.

A buffer solution of a desired pH can be prepared as a mixture of a weak acid and its conjugate base. In practice the mixture can be created by dissolving the acid in water, and adding the requisite amount of strong acid or base. The pKa of the acid must be less than two units different from the target pH.

Polyprotic acids[edit]

Acids with more than one ionizable hydrogen atoms are called polyprotic acids, and have multiple deprotonation states, also called species. This image plots the relative percentages of the different protonation species of phosphoric acid H 3 P O 4 as a function of solution p H. Phosphoric acid has three ionizable hydrogen atoms whose p K A's are roughly 2, 7 and 12. Below p H 2, the triply protonated species H 3 P O 4 predominates; the double protonated species H 2 P O 4 minus predominates near p H 5; the singly protonated species H P O 4 2 minus predominates near p H 9 and the unprotonated species P O 4 3 minus predominates above p H 12.
% species' formation as a function of pH
This image plots the relative percentages of the protonation species of citric acid as a function of p H. Citric acid has three ionizable hydrogen atoms and thus three p K A values. Below the lowest p K A, the triply protonated species prevails; between the lowest and middle p K A, the doubly protonated form prevails; between the middle and highest p K A, the singly protonated form prevails; and above the highest p K A, the unprotonated form of citric acid is predominant.
% species formation calculated with the program HySS for a 10 millimolar solution of citric acid. pKa1=3.13, pKa2 = 4.76, pKa3=6.40.

Polyprotic acids are acids that can lose more than one proton. The constant for dissociation of the first proton may be denoted as Ka1 and the constants for dissociation of successive protons as Ka2, etc. Phosphoric acid, H3PO4, is an example of a polyprotic acid as it can lose three protons.

equilibrium pKa value
H3PO4 is in equilibrium with H2PO4 + H+ pKa1 = 2.15
H2PO4 is in equilibrium with HPO42− + H+ pKa2 = 7.20
HPO42− is in equilibrium with PO43− + H+ pKa3 = 12.37

When the difference between successive pK values is about four or more, as in this example, each species may be considered as an acid in its own right;[15] In fact salts of H2PO4 may be crystallised from solution by adjustment of pH to about 5.5 and salts of HPO42− may be crystallised from solution by adjustment of pH to about 10. The species distribution diagram shows that the concentrations of the two ions are maximum at pH 5.5 and 10.

When the difference between successive pK values is less than about four there is overlap between the pH range of existence of the species in equilibrium. The smaller the difference, the more the overlap. The case of citric acid is shown at the right; solutions of citric acid are buffered over the whole range of pH 2.5 to 7.5.

According to Pauling's first rule, successive pK values of a given acid increase (pKa2 > pKa1).[16] For oxyacids with more than one ionizable hydrogen on the same atom, the pKa values often increase by about 5 units for each proton removed,[17][18] as in the example of phosphoric acid above.

In the case of a diprotic acid, H2A, the two equilibria are

H2A is in equilibrium with HA + H+
HA is in equilibrium with A2− + H+

it can be seen that the second proton is removed from a negatively charged species. Since the proton carries a positive charge extra work is needed to remove it; that is the cause of the trend noted above. Phosphoric acid values (above) illustrate this rule, as do the values for vanadic acid, H3VO4. When an exception to the rule is found it indicates that a major change in structure is occurring. In the case of VO2+ (aq), the vanadium is octahedral, 6-coordinate, whereas vanadic acid is tetrahedral, 4-coordinate. This is the basis for an explanation of why pKa1 > pKa2 for vanadium(V) oxoacids.

equilibrium pKa value
[VO2(H2O)4]+ is in equilibrium with H3VO4 + H+ + 2H2O pKa1 = 4.2
H3VO4 is in equilibrium with H2VO4 + H+ pKa2 = 2.60
H2VO4 is in equilibrium with HVO42− + H+ pKa3 = 7.92
HVO42− is in equilibrium with VO43− + H+ pKa4 = 13.27

Isoelectric point[edit]

Main article: isoelectric point

For substances in solution the isoelectric point (pI) is defined as the pH at which the sum, weighted by charge value, of concentrations of positively charged species is equal to the weighted sum of concentrations of negatively charged species. In the case that there is one species of each type, the isoelectric point can be obtained directly from the pK values. Take the example of glycine, defined as AH. There are two dissociation equilibria to consider.

AH2+ is in equilibrium with AH + H+; [AH][H+] = K1[AH2+]
AH is in equilibrium with A- + H+; [A-][H+] = K2[AH]

Substitute the expression for [AH] into the first equation

[A-][H+]2 = K1K2[AH2+]

At the isoelectric point the concentration of the positively charged species, AH2+, is equal to the concentration of the negatively charged species, A-, so

[H+]2 = K1K2

Therefore, taking cologarithms, the pH is given by

\mathrm{p}I=\frac{\mathrm{p}K_1+\mathrm{p}K_2}{2}

pI values for amino acids are listed at Proteinogenic amino acid#Chemical properties. When more than two charged species are in equilibrium with each other a full speciation calculation may be needed.

Water self-ionization[edit]

Water possesses both acidic and basic properties. It is amphiprotic. The equilibrium constant for the equilibrium

2 H2O is in equilibrium with OH + H3O+

is given by

The acidity constant K A for water equals the concentration of H + times that of O H minus divided by the concentration of water, H 2 O.

When, as is usually the case, the concentration of water can be assumed to be constant, this expression may be replaced by

The ionization constant of water K w equals the concentration of H + times the concentration of O H minus.

The self-ionization constant of water, Kw, is thus just a special case of an acid dissociation constant.

pKw values for pure water at various temperatures[19]
T/°C 0 5 10 15 20 25 30 35 40 45 50
pKw 14.943 14.734 14.535 14.346 14.167 13.997 13.830 13.680 13.535 13.396 13.262

From these data it can be deduced that Kw = 10−14 at 24.87 °C. At that temperature both hydrogen and hydroxide ions have a concentration of 10−7 mol dm−3.

Amphoteric substances[edit]

An amphoteric substance is one that can act as an acid or as a base, depending on pH. Water (above) is amphoteric. Another example of an amphoteric molecule is the bicarbonate ion HCO3 that is the conjugate base of the carbonic acid molecule H2CO3 in the equilibrium

H2CO3 + H2O is in equilibrium with HCO3 + H3O+

but also the conjugate acid of the carbonate ion CO32− in (the reverse of) the equilibrium

HCO3 + OH is in equilibrium with CO32− + H2O.

Carbonic acid equilibria are important for acid-base homeostasis in the human body.

An amino acid is also amphoteric with the added complication that the neutral molecule is subject to an internal acid-base equilibrium in which the basic amino group attracts and binds the proton from the acidic carboxyl group, forming a zwitterion.

NH2CHRCO2H is in equilibrium with NH3+CHRCO2-

At pH less than about 5 both the carboxylate group and the amino group are protonated. As pH increases the acid dissociates according to

NH3+CHRCO2H is in equilibrium with NH3+CHRCO2- + H+

At high pH a second dissociation may take place.

NH3+CHRCO2- is in equilibrium with NH2CHRCO2- + H+

Thus the zwitter ion, NH3+CHRCO2-, is amphoteric because it may either be protonated or deprotonated.

Bases and basicity[edit]

Historically, the equilibrium constant Kb for a base has been defined as the association constant for protonation of the base, B, to form the conjugate acid, HB+.

B + H2O is in equilibrium with HB+ + OH

Using similar reasoning to that used before

The base association constant K b equals the concentration of the protonated form H B +, times the concentration of the hydroxyl anion O H minus, all divided by the concentration of the base B.

Kb is related to Ka for the conjugate acid. In water, the concentration of the hydroxide ion, [OH], is related to the concentration of the hydrogen ion by Kw = [H+] [OH], therefore

The concentration of the hydroxyl anion O H minus equals the ionization constant of water K w divided by the concentration of H +, by the definition of K w.

Substitution of the expression for [OH] into the expression for Kb gives

K b can be written as a ratio of four terms. The numerator holds the concentration of the protonated base H B + times the ionization constant of water K w. The denominator holds the concentration of the base B times that of H +. Using the definition for K A, K b equals K w divided by K A.

When Ka, Kb and Kw are determined under the same conditions of temperature and ionic strength, it follows, taking cologarithms, that pKb or "basicity"= pKw − pKa. In aqueous solutions at 25 °C, pKw is 13.9965,[20] so

pK_{\mathrm b} \approx  14 - pK_{\mathrm a}

with sufficient accuracy for most practical purposes. In effect there is no need to define pKb separately from pKa, but it is done here as often only pKb values can be found in the older literature.

Temperature dependence[edit]

All equilibrium constants vary with temperature according to the van 't Hoff equation[21]

The derivative of the natural logarithm of any equilibrium constant K with respect to the [[kelvin|absolute temperature]] T equals the standard enthalpy change for the reaction divided by the product R times T squared. Here R represents the gas constant, which equals the thermal energy per mole per kelvin. The standard enthalpy is written as Delta H with a superscript plimsol mark represented by the image strikeO. This equation follows from the definition of the Gibbs energy Delta G equals R times T times the natural logarithm of K.

R is the gas constant and T is the absolute temperature . Thus, for exothermic reactions, (the standard enthalpy change, ΔHStrikeO.png, is negative) K decreases with temperature, but for endothermic reactions (ΔHStrikeO.png is positive) K increases with temperature.

Acidity in nonaqueous solutions[edit]

A solvent will be more likely to promote ionization of a dissolved acidic molecule in the following circumstances:[22]

  1. It is a protic solvent, capable of forming hydrogen bonds.
  2. It has a high donor number, making it a strong Lewis base.
  3. It has a high dielectric constant (relative permittivity), making it a good solvent for ionic species.

pKa values of organic compounds are often obtained using the aprotic solvents dimethyl sulfoxide (DMSO)[22] and acetonitrile (ACN).[23]

Solvent properties at 25 °C
Solvent Donor number[22] Dielectric constant[22]
Acetonitrile 14 37
Dimethylsulfoxide 30 47
Water 18 78

DMSO is widely used as an alternative to water because it has a lower dielectric constant than water, and is less polar and so dissolves non-polar, hydrophobic substances more easily. It has a measurable pKa range of about 1 to 30. Acetonitrile is less basic than DMSO, and, so, in general, acids are weaker and bases are stronger in this solvent. Some pKa values at 25 °C for acetonitrile (ACN)[24][25][26] and dimethyl sulfoxide (DMSO)[27] are shown in the following tables. Values for water are included for comparison.

pKa values of acids
HA is in equilibrium with A + H+ ACN DMSO water
p-Toluenesulfonic acid 8.5 0.9 strong
2,4-Dinitrophenol 16.66 5.1 3.9
Benzoic acid 21.51 11.1 4.2
Acetic acid 23.51 12.6 4.756
Phenol 29.14 18.0 9.99
BH+ is in equilibrium with B + H+ ACN DMSO water
Pyrrolidine 19.56 10.8 11.4
Triethylamine 18.82 9.0 10.72
Proton sponge            18.62 7.5 12.1
Pyridine 12.53 3.4 5.2
Aniline 10.62 3.6 4.6

Ionization of acids is less in an acidic solvent than in water. For example, hydrogen chloride is a weak acid when dissolved in acetic acid. This is because acetic acid is a much weaker base than water.

HCl + CH3CO2H is in equilibrium with Cl + CH3C(OH)2+
acid + base is in equilibrium with conjugate base + conjugate acid

Compare this reaction with what happens when acetic acid is dissolved in the more acidic solvent pure sulfuric acid[28]

H2SO4 + CH3CO2H is in equilibrium with HSO4 + CH3C(OH)2+

The unlikely geminal diol species CH3C(OH)2+ is stable in these environments. For aqueous solutions the pH scale is the most convenient acidity function.[29] Other acidity functions have been proposed for non-aqueous media, the most notable being the Hammett acidity function, H0, for superacid media and its modified version H for superbasic media.[30]

This image illustrates how two carboxylic acids, C O O H, can associate through mutual hydrogen bonds. The hydroxyl portion O H of each molecule forms a hydrogen bond to the carbonyl portion C O of the other.
Dimerization of a carboxylic acid

In aprotic solvents, oligomers, such as the well-known acetic acid dimer, may be formed by hydrogen bonding. An acid may also form hydrogen bonds to its conjugate base. This process, known as homoconjugation, has the effect of enhancing the acidity of acids, lowering their effective pKa values, by stabilizing the conjugate base. Homoconjugation enhances the proton-donating power of toluenesulfonic acid in acetonitrile solution by a factor of nearly 800.[31] In aqueous solutions, homoconjugation does not occur, because water forms stronger hydrogen bonds to the conjugate base than does the acid.

Mixed solvents[edit]

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.
pKa of acetic acid in dioxane/water mixtures. Data at 25 °C from Pine et al.[32]

When a compound has limited solubility in water it is common practice (in the pharmaceutical industry, for example) to determine pKa values in a solvent mixture such as water/dioxane or water/methanol, in which the compound is more soluble.[33] In the example shown at the right, the pKa value rises steeply with increasing percentage of dioxane as the dielectric constant of the mixture is decreasing.

A pKa 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 9:1 is precisely that solvent mixture, with no added solutes. To obtain the pKa 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 pKa, but pKa values obtained in a given mixed solvent can be compared to each other, giving relative acid strengths. The same is true of pKa values obtained in a particular non-aqueous solvent such a DMSO.

As of 2008, 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.

Factors that affect pKa values[edit]

Pauling's second rule is that the value of the first pKa for acids of the formula XOm(OH)n depends primarily on the number of oxo groups m, and is approximately independent of the number of hydroxy groups n, and also of the central atom X. Approximate values of pKa are 8 for m = 0, 2 for m = 1, −3 for m = 2 and < −10 for m = 3.[16] Alternatively, various numerical formulas have been proposed including pKa = 8 − 5n,[17][34] pKa = 7 − 5n,[18][35] or pKa = 9 − 7n.[17] The dependence on m correlates with the oxidation state of the central atom, X: the higher the oxidation state the stronger the oxyacid. For example, pKa for HClO is 7.2, for HClO2 is 2.0, for HClO3 is −1 and HClO4 is a strong acid (pKa << 0).[3] This rule can help assign molecular structure: for example phosphorous acid (H3PO3) has a pKa near 2 suggested that the structure is HPO(OH)2, as later confirmed by NMR spectroscopy, and not P(OH)3 which would be expected to have a pKa near 8.[35]

Fumaric acid consists of two double-bonded carbon atoms capped on both sides by carboxylic acid groups C O O H; thus, its chemical formula is C O O H C H C H C O O H. The molecule has two ionizable hydrogen atoms and thus two p K As. The central double bond is in the trans configuration, which holds the two carboxylate groups apart. This contrasts with the cis isomer, maleic acid.
Fumaric acid
Maleic acid consists of two double-bonded carbon atoms capped on both sides by carboxylic acid groups C O O H; thus, its chemical formula is C O O H C H C H C O O H. It has two ionizable hydrogen atoms and thus two p K As. The central double bond is in the cis configuration. This holds the two carboxylate groups close enough so that when one group is protonated and the other deprotonated, a strong hydrogen bond can be formed between the two groups. This makes the mono-protonated species much more stable than the corresponding species of the trans isomer, fumaric acid.
Maleic acid
Proton sponge is a derivative of naphthalene with dimethylamino groups in the one and ten positions. This brings the two dimethyl amino groups into close proximity to each other.
proton sponge

With organic acids inductive effects and mesomeric effects affect the pKa values. A simple example is provided by the effect of replacing the hydrogen atoms in acetic acid by the more electronegative chlorine atom. The electron-withdrawing effect of the substituent makes ionisation easier, so successive pKa values decrease in the series 4.7, 2.8, 1.4 and 0.7 when 0,1, 2 or 3 chlorine atoms are present.[36] The Hammett equation, provides a general expression for the effect of substituents.[37]

log Ka = log Ka0 + ρσ.

Ka is the dissociation constant of a substituted compound, Ka0 is the dissociation constant when the substituent is hydrogen, ρ is a property of the unsubstituted compound and σ has a particular value for each substituent. A plot of log Ka against σ is a straight line with intercept log Ka0 and slope ρ. This is an example of a linear free energy relationship as log Ka is proportional to the standard fee energy change. Hammett originally[38] formulated the relationship with data from benzoic acid with different substiuents in the ortho- and para- positions: some numerical values are in Hammett equation. This and other studies allowed substituents to be ordered according to their electron-withdrawing or electron-releasing power, and to distinguish between inductive and mesomeric effects.[39][40]

Alcohols do not normally behave as acids in water, but the presence of a double bond adjacent to the OH group can substantially decrease the pKa by the mechanism of keto-enol tautomerism. Ascorbic acid is an example of this effect. The diketone 2,4-pentanedione (acetylacetone) is also a weak acid because of the keto-enol equilibrium. In aromatic compounds, such as phenol, which have an OH substituent, conjugation with the aromatic ring as a whole greatly increases the stability of the deprotonated form.

Structural effects can also be important. The difference between fumaric acid and maleic acid is a classic example. Fumaric acid is (E)-1,4-but-2-enedioic acid, a trans isomer, whereas maleic acid is the corresponding cis isomer, i.e. (Z)-1,4-but-2-enedioic acid (see cis-trans isomerism). Fumaric acid has pKa values of approximately 3.0 and 4.5. By contrast, maleic acid has pKa values of approximately 1.5 and 6.5. The reason for this large difference is that when one proton is removed from the cis- isomer (maleic acid) a strong intramolecular hydrogen bond is formed with the nearby remaining carboxyl group. This favors the formation of the maleate H+, and it opposes the removal of the second proton from that species. In the trans isomer, the two carboxyl groups are always far apart, so hydrogen bonding is not observed.[41]

Proton sponge, 1,8-bis(dimethylamino)naphthalene, has a pKa value of 12.1. It is one of the strongest amine bases known. The high basicity is attributed to the relief of strain upon protonation and strong internal hydrogen bonding.[42][43]

Effects of the solvent and solvation should be mentioned also in this section. It turns out, these influences are more subtle than that of a dielectric medium mentioned above. For example, the expected (by electronic effects of methyl substituents) and observed in gas phase order of basicity of methylamines, Me3N > Me2NH > MeNH2 > NH3, is changed by water to Me2NH > MeNH2 > Me3N > NH3. Neutral methylamine molecules are hydrogen-bonded to water molecules mailnly through one acceptor, N-HOH, interaction and only occasionally just one more donor bond, NH-OH2. Hence, methylamines are stabilized to about the same extent by hydration, regardless of the number of methyl groups. In stark contrast, corresponding methylammonium cations always utilize all the available protons for donor NH-OH2 bonding. Relative stabilization of methylammonium ions thus decreases with the number of methyl groups explaining the order of water basicity of methylamines.[44]

Thermodynamics[edit]

An equilibrium constant is related to the standard Gibbs energy change for the reaction, so for an acid dissociation constant

ΔGStrikeO.png = −RT ln Ka ≈ 2.303 RT pKa.

R is the gas constant and T is the absolute temperature. Note that pKa= −log Ka and 2.303 ≈ ln 10. At 25 °C ΔGStrikeO.png in kJ·mol−1 = 5.708 pKa (1 kJ·mol−1 = 1000 Joules per mole). Free energy is made up of an enthalpy term and an entropy term.[7]

ΔGStrikeO.png = ΔHStrikeO.pngTΔSStrikeO.png

The standard enthalpy change can be determined by calorimetry or by using the van 't Hoff equation, though the calorimetric method is preferable. When both the standard enthalpy change and acid dissociation constant have been determined, the standard entropy change is easily calculated from the equation above. In the following table, the entropy terms are calculated from the experimental values of pKa and ΔHStrikeO.png. The data were critically selected and refer to 25 °C and zero ionic strength, in water.[7]

Acids
Compound Equilibrium pKa ΔGStrikeO.png /kJ·mol−1 ΔHStrikeO.png /kJ·mol−1 TΔSStrikeO.png /kJ·mol−1
HA = Acetic acid HA is in equilibrium with H+ + A 4.756 27.147 −0.41 27.56
H2A+ = GlycineH+ H2A+ is in equilibrium with HA + H+ 2.351 13.420 4.00 9.419
HA is in equilibrium with H+ + A 9.78 55.825 44.20 11.6
H2A = Maleic acid H2A is in equilibrium with HA + H+ 1.92 10.76 1.10 9.85
HA is in equilibrium with H+ + A2− 6.27 35.79 −3.60 39.4
H3A = Citric acid H3A is in equilibrium with H2A + H+ 3.128 17.855 4.07 13.78
H2A is in equilibrium with HA2− + H+ 4.76 27.176 2.23 24.9
HA2− is in equilibrium with A3− + H+ 6.40 36.509 −3.38 39.9
H3A = Boric acid H3A is in equilibrium with H2A + H+ 9.237 52.725 13.80 38.92
H3A = Phosphoric acid H3A is in equilibrium with H2A + H+ 2.148 12.261 −8.00 20.26
H2A is in equilibrium with HA2− + H+ 7.20 41.087 3.60 37.5
HA2− is in equilibrium with A3− + H+ 12.35 80.49 16.00 54.49
HA = Hydrogen sulfate HA is in equilibrium with A2− + H+ 1.99 11.36 −22.40 33.74
H2A = Oxalic acid H2A is in equilibrium with HA + H+ 1.27 7.27 −3.90 11.15
HA is in equilibrium with A2− + H+ 4.266 24.351 7.00 31.35
ΔGStrikeO.png = 2.303RT pKa
Computed here, from ΔH and ΔG values supplied in the citation, using —TΔSStrikeO.png = ΔGStrikeO.png — ΔHStrikeO.png
Conjugate acids of bases
Compound Equilibrium pKa ΔHStrikeO.png /kJ·mol−1 TΔSStrikeO.png /kJ·mol−1
B = Ammonia HB+ is in equilibrium with B + H+ 9.245 51.95 0.8205
B = Methylamine HB+ is in equilibrium with B + H+ 10.645 55.34 5.422
B = Triethylamine HB+ is in equilibrium with B + H+ 10.72 43.13 18.06

The first point to note is that, when pKa is positive, the standard free energy change for the dissociation reaction is also positive. Second, some reactions are exothermic and some are endothermic, but, when ΔHStrikeO.png is negative −TΔSStrikeO.png is the dominant factor, which determines that ΔGStrikeO.png is positive. Last, the entropy contribution is always unfavourable (ΔSStrikeO.png < 0) in these reactions. Ions in aqueous solution tend to orient the surrounding water molecules, which orders the solution and decreases the entropy. The contribution of an ion to the entropy is the partial molar entropy which is often negative, especially for small or highly charged ions.[45] The ionization of a neutral acid involves formation of two ions so that the entropy decreases (ΔSStrikeO.png < 0). On the second ionization of the same acid, there are now three ions and the anion has a charge, so the entropy again decreases.

Note that the standard free energy change for the reaction is for the changes from the reactants in their standard states to the products in their standard states. The free energy change at equilibrium is zero since the chemical potentials of reactants and products are equal at equilibrium.

Experimental determination[edit]

 The image shows the titration curve of oxalic acid, showing the pH of the solution as a function of added base. There is a small inflection point at about pH 3 and then a large jump from pH 5 to pH 11, followed by another region of slowly increasing pH.
A calculated titration curve of oxalic acid titrated with a solution of sodium hydroxide

The experimental determination of pKa values is commonly performed by means of titrations, in a medium of high ionic strength and at constant temperature.[46] A typical procedure would be as follows. A solution of the compound in the medium is acidified with a strong acid to the point where the compound is fully protonated. The solution is then titrated with a strong base until all the protons have been removed. At each point in the titration pH is measured using a glass electrode and a pH meter. The equilibrium constants are found by fitting calculated pH values to the observed values, using the method of least squares.[47]

The total volume of added strong base should be small compared to the initial volume of titrand solution in order to keep the ionic strength nearly constant. This will ensure that pKa remains invariant during the titration.

A calculated titration curve for oxalic acid is shown at the right. Oxalic acid has pKa values of 1.27 and 4.27. Therefore the buffer regions will be centered at about pH 1.3 and pH 4.3. The buffer regions carry the information necessary to get the pKa values as the concentrations of acid and conjugate base change along a buffer region.

Between the two buffer regions there is an end-point, or equivalence point, where the pH rises by about two units. This end-point is not sharp and is typical of a diprotic acid whose buffer regions overlap by a small amount: pKa2 − pKa1 is about three in this example. (If the difference in pK values were about two or less, the end-point would not be noticeable.) The second end-point begins at about pH 6.3 and is sharp. This indicates that all the protons have been removed. When this is so, the solution is not buffered and the pH rises steeply on addition of a small amount of strong base. However, the pH does not continue to rise indefinitely. A new buffer region begins at about pH 11 (pKw − 3), which is where self-ionization of water becomes important.

It is very difficult to measure pH values of less than two in aqueous solution with a glass electrode, because the Nernst equation breaks down at such low pH values. To determine pK values of less than about 2 or more than about 11 spectrophotometric[48] [49] or NMR[11][50] measurements may be used instead of, or combined with, pH measurements.

When the glass electrode cannot be employed, as with non-aqueous solutions, spectrophotometric methods are frequently used.[25] These may involve absorbance or fluorescence measurements. In both cases the measured quantity is assumed to be proportional to the sum of contributions from each photo-active species; with absorbance measurements the Beer-Lambert law is assumed to apply.

Aqueous solutions with normal water cannot be used for 1H NMR measurements but heavy water, D2O, must be used instead. 13C NMR data, however, can be used with normal water and 1H NMR spectra can be used with non-aqueous media. The quantities measured with NMR are time-averaged chemical shifts, as proton exchange is fast on the NMR time-scale. Other chemical shifts, such as those of 31P can be measured.

Micro-constants[edit]

Spermine is a long, symmetrical molecule capped at both ends with amino groups N H 2. It has two N H groups symmetrically placed within the molecule, separated from each other by four methylene groups C H 2, and from the amino ends by three methylene groups. Thus, the full molecular formula is N H 2 C H 2 C H 2 C H 2 N H C H 2 C H 2 C H 2 C H 2 N H C H 2 C H 2 C H 2 N H 2.
spermine

A base such as spermine has a few different sites where protonation can occur. In this example the first proton can go on the terminal -NH2 group, or either of the internal -NH- groups. The pKa values for dissociation of spermine protonated at one or other of the sites are examples of micro-constants. They cannot be determined directly by means of pH, absorbance, fluorescence or NMR measurements. Nevertheless, the site of protonation is very important for biological function, so mathematical methods have been developed for the determination of micro-constants.[51]

Applications and significance[edit]

A knowledge of pKa values is important for the quantitative treatment of systems involving acid–base equilibria in solution. Many applications exist in biochemistry; for example, the pKa values of proteins and amino acid side chains are of major importance for the activity of enzymes and the stability of proteins.[52] Protein pKa values cannot always be measured directly, but may be calculated using theoretical methods. Buffer solutions are used extensively to provide solutions at or near the physiological pH for the study of biochemical reactions;[53] the design of these solutions depends on a knowledge of the pKa values of their components. Important buffer solutions include MOPS, which provides a solution with pH 7.2, and tricine, which is used in gel electrophoresis.[54][55] Buffering is an essential part of acid base physiology including acid-base homeostasis,[56] and is key to understanding disorders such as acid-base imbalance.[57][58][59] The isoelectric point of a given molecule is a function of its pK values, so different molecules have different isoelectric points. This permits a technique called isoelectric focusing,[60] which is used for separation of proteins by 2-D gel polyacrylamide gel electrophoresis.

Buffer solutions also play a key role in analytical chemistry. They are used whenever there is a need to fix the pH of a solution at a particular value. Compared with an aqueous solution, the pH of a buffer solution is relatively insensitive to the addition of a small amount of strong acid or strong base. The buffer capacity[61] of a simple buffer solution is largest when pH = pKa. In acid-base extraction, the efficiency of extraction of a compound into an organic phase, such as an ether, can be optimised by adjusting the pH of the aqueous phase using an appropriate buffer. At the optimum pH, the concentration of the electrically neutral species is maximised; such a species is more soluble in organic solvents having a low dielectric constant than it is in water. This technique is used for the purification of weak acids and bases.[62]

A pH indicator is a weak acid or weak base that changes colour in the transition pH range, which is approximately pKa ± 1. The design of a universal indicator requires a mixture of indicators whose adjacent pKa values differ by about two, so that their transition pH ranges just overlap.

In pharmacology ionization of a compound alters its physical behaviour and macro properties such as solubility and lipophilicity (log p). For example ionization of any compound will increase the solubility in water, but decrease the lipophilicity. This is exploited in drug development to increase the concentration of a compound in the blood by adjusting the pKa of an ionizable group.[63]

Knowledge of pKa values is important for the understanding of coordination complexes, which are formed by the interaction of a metal ion, Mm+, acting as a Lewis acid, with a ligand, L, acting as a Lewis base. However, the ligand may also undergo protonation reactions, so the formation of a complex in aqueous solution could be represented symbolically by the reaction

[M(H2O)n]m+ +LH is in equilibrium with [M(H2O)n−1L](m−1)+ + H3O+

To determine the equilibrium constant for this reaction, in which the ligand loses a proton, the pKa of the protonated ligand must be known. In practice, the ligand may be polyprotic; for example EDTA4− can accept four protons; in that case, all pKa values must be known. In addition, the metal ion is subject to hydrolysis, that is, it behaves as a weak acid, so the pK values for the hydrolysis reactions must also be known.[64] Assessing the hazard associated with an acid or base may require a knowledge of pKa values.[65] For example, hydrogen cyanide is a very toxic gas, because the cyanide ion inhibits the iron-containing enzyme cytochrome c oxidase. Hydrogen cyanide is a weak acid in aqueous solution with a pKa of about 9. In strongly alkaline solutions, above pH 11, say, it follows that sodium cyanide is "fully dissociated" so the hazard due to the hydrogen cyanide gas is much reduced. An acidic solution, on the other hand, is very hazardous because all the cyanide is in its acid form. Ingestion of cyanide by mouth is potentially fatal, independently of pH, because of the reaction with cytochrome c oxidase.

In environmental science acid–base equilibria are important for lakes[66] and rivers;[67][68] for example, humic acids are important components of natural waters. Another example occurs in chemical oceanography:[69] in order to quantify the solubility of iron(III) in seawater at various salinities, the pKa values for the formation of the iron(III) hydrolysis products Fe(OH)2+, Fe(OH)2+ and Fe(OH)3 were determined, along with the solubility product of iron hydroxide.[70]

Values for common substances[edit]

There are multiple techniques to determine the pKa of a chemical, leading to some discrepancies between different sources. Well measured values are typically within 0.1 units of each other. Data presented here were taken at 25 °C in water.[3][71] More values can be found in thermodynamics, above.

Chemical Name Equilibrium pKa
BH = Adenine BH is in equilibrium with B- + H+ 4.17
BH2+ is in equilibrium with BH + H+ 9.65
H3A = Arsenic acid H3A is in equilibrium with H2A + H+ 2.22
H2A is in equilibrium with HA2− + H+ 6.98
HA2− is in equilibrium with A3− + H+ 11.53
HA = Benzoic acid HA is in equilibrium with H+ + A 4.204
HA = Butyric acid HA is in equilibrium with H+ + A 4.82
H2A = Chromic acid H2A is in equilibrium with HA + H+ 0.98
HA is in equilibrium with A2− + H+ 6.5
B = Codeine BH+ is in equilibrium with B + H+ 8.17
HA = Cresol HA is in equilibrium with H+ + A 10.29
HA = Formic acid HA is in equilibrium with H+ + A 3.751
HA = Hydrofluoric acid HA is in equilibrium with H+ + A 3.17
HA = Hydrocyanic acid HA is in equilibrium with H+ + A 9.21
HA = Hydrogen selenide HA is in equilibrium with H+ + A 3.89
HA = Hydrogen peroxide (90%) HA is in equilibrium with H+ + A 11.7
HA = Lactic acid HA is in equilibrium with H+ + A 3.86
HA = Propionic acid HA is in equilibrium with H+ + A 4.87
HA = Phenol HA is in equilibrium with H+ + A 9.99
H2A = L-(+)-Ascorbic Acid H2A is in equilibrium with HA + H+ 4.17
HA is in equilibrium with A2− + H+ 11.57

See also[edit]

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Further reading[edit]

  • Albert, A.; Serjeant, E.P. (1971). The Determination of Ionization Constants: A Laboratory Manual. Chapman & Hall. ISBN 0-412-10300-1.  (Previous edition published as Ionization constants of acids and bases. London (UK): Methuen. 1962. )
  • Atkins, P.W.; Jones, L. (2008). Chemical Principles: The Quest for Insight (4th ed.). W.H. Freeman. ISBN 1-4292-0965-8. 
  • Housecroft, C. E.; Sharpe, A. G. (2008). Inorganic Chemistry (3rd ed.). Prentice Hall. ISBN 978-0131755536.  (Non-aqueous solvents)
  • Hulanicki, A. (1987). Reactions of Acids and Bases in Analytical Chemistry. Horwood. ISBN 0-85312-330-6.  (translation editor: Mary R. Masson)
  • Perrin, D.D.; Dempsey, B.; Serjeant, E.P. (1981). pKa Prediction for Organic Acids and Bases. Chapman & Hall. ISBN 0-412-22190-X. 
  • Reichardt, C. (2003). Solvents and Solvent Effects in Organic Chemistry (3rd ed.). Wiley-VCH. ISBN 3-527-30618-8.  Chapter 4: Solvent Effects on the Position of Homogeneous Chemical Equilibria.
  • Skoog, D.A.; West, D.M.; Holler, J.F.; Crouch, S.R. (2004). Fundamentals of Analytical Chemistry (8th ed.). Thomson Brooks/Cole. ISBN 0-03-035523-0. 

External links[edit]