Acids and Bases

Daniel Palleros

Acids and Bases

1. Brnsted-Lowry Theory 2. The Acidity Constant, Ka 3. The Basicity Constant, Kb, and its Relation to Ka 4. Predicting the Direction of Acid-Base Equilibria 5. Two Classes of Acids 6. The Curious Case of Water 7. Strength of Organic Acids
7.1 Element effect 7.2 Hybridization effect 7.3 Inductive effect 7.4 Resonance effect 7.5 Steric effect 7.6 Solvent effect 7.7 H-bond effect

8. Classification of Organic Compounds as Acids and Bases 9. A Hidden Meaning of pKa 10. Degree of Ionization of Organic Acids 11. Polyfunctional Acids 12. Appendix Table 1. pKa of Organic Acids Table 2. pKa of Some Unusual Acids Table 3. Typical pH Values of Tissue Fluids Additional Problems Answers to Additional Problems

Acids and Bases

Daniel Palleros

Acids and Bases

Tropicamide is a pharmaceutical used for eye examination. It dilates the pupil. It is administered as eye drops at an acidic pH (pH 4). The acidic eye drops can sting and thats why some doctors apply a local anesthetic to the eye before using the eye drops. Why is Tropicamide administered in an acidic solution that stings the eye? Why is it not applied at the mild physiological pH of the eye fluid (pH 7.4)?
H O N O N

Tropicamide To answer these and many other questions about the action of pharmaceuticals, we must first take a closer look at acids and bases. The goal of the present discussion is that by the time we finish with acids and bases you should be able to look at a molecule such as Tropicamide and a) identify all the functional groups and determine if they are acidic, basic or neutral b) assign approximate pKa values to those groups c) predict how they would behave as acids or bases at different pH values d) calculate the degree of ionization at different pH values This knowledge will give you some of the tools needed to understand how pharmaceuticals act in the organism.

1. Brnsted-Lowry Theory

According to Brnsted-Lowry, an acid is a substance that donates a proton, H+, and a base is a substance that accepts a proton. For us in organic chemistry, this will be the most important definition of acids and bases. This definition can be supplemented with Lewis theory that states that bases accept the proton donated by acids on a lone electron pair. For example, when HCl is dissolved in water, water acts as a base by accepting a proton on one of the oxygens electron pairs.

H Cl + H2O
acid base

Clconjugate base

H 3O

conjugate acid

Acids and Bases

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According to the Brnsted-Lowry theory, each acid has its conjugate base, which is the acid minus a proton, and each base has its conjugate acid, which is the base plus a proton. Whether a substance acts as acid or base depends on the presence of other compounds. For example, when water is in the presence of strong acids such as HCl or H2SO4, it acts as a base (as shown in the previous reaction) but in the presence of a base such as ammonia, NH3, water acts as an acid by donating a proton:
-

NH3
base

+ H 2O
acid

NH4+ +
conjugate acid

HO

conjugate base

A compound capable of reacting as an acid or a base is called amphoteric. Most organic and many inorganic substances are amphoteric. An example of an amphoteric organic compound is methanol, CH3OH. Alcohols in general and methanol in particular, can act as proton donors in the presence of bases such as sodium amide, NaNH2, as the example below illustrates:

NH2- Na+ + CH3OH

base acid

NH3
conjugate acid

+ CH3O- Na+
conjugate base

Alcohols can also act as proton acceptors in the presence of acids such as sulfuric acid, H2SO4:

H2SO4
acid

+ CH3OH
base

HSO4- + CH3OH2
conjugate base conjugate acid

Not all acids have the same tendency to donate a proton. A strong acid has a great tendency to donate a proton and a strong base a great tendency to accept it. Conversely, weak acids and bases have low tendency to donate and accept protons.

2. The Acidity Constant, Ka

Water, the universal solvent, is used to measure the strength of acids and bases. When an acid HA is dissolved in water, an acid-base equilibrium is established:
HA + H2O Keq A- + H3O+

The equilibrium constant, Keq, is defined by the following equation:

Acids and Bases

Daniel Palleros

K eq

[ A ] # [H O ] =
" + 3

[HA] # [ H 2O]

(1)

Under the conditions used to measure the equilibrium, which normally involve very dilute solutions, the concentration of water (the solvent) is very large compared to the ! concentration of the acid (the solute) and, thus, it can be considered constant. Multiplying both sides of eq. 1 by [H2O], eq. 2 is obtained.
K eq " [ H 2O] =

[ A ] " [H O ]
# + 3

[ HA]

(2)

Since Keq is a constant and [H2O] is another constant, their product is also a constant called Ka, or the acidity constant, Ka, eq. 3: !
Ka

[ A ] # [H O ] =
" + 3

[HA]

(3)

The stronger the acid, the larger the acidity constant Ka. For inorganic acids such as HCl and H2SO4, Ka is in the order of 105 -107. These acids represent some of the ! strongest acids known. Organic acids, on the other hand, are usually weaker than inorganic ones; typical Ka values for one of the most important types of organic acids, carboxylic acids (RCOOH), is in the order of 10-4-10-5. This makes carboxylic acids about 109-1012 times less acidic than the strongest inorganic acids. For convenience, acid strength is measured by pKa instead of Ka. By definition, pKa is the negative log of Ka:
pK a = "logK a

(4)

In general, the stronger the acid, the smaller the pKa. A list of pKa values for typical organic acids can be found in Table 1. Organic acids show pKa values in the range 1-60. ! Compounds with pKa values in the range 3-12 are very important from a pharmacological point of view and will be the subject of extensive discussion in this class. Important organic acids include: carboxylic acids (R-COOH), phenols (ArOH) and sulfonic acids (R-SO3H), just to mention a few.

3. The Basicity Constant, Kb, and its Relation to Ka

Amines are important organic bases. The reaction below shows the protonation of methylamine by water. It yields an ammonium salt.

CH3NH2

H2 O

CH3NH3 + HO-

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Daniel Palleros

To measure the strength of bases such as methylamine, lets consider the following general equilibrium where B represents any base:

Keq B + H2O

BH+

HO

The equilibrium constant for this process is given below:

K eq

[BH ] " [HO ] =

+ #

[ B] " [ H 2O]

By similar arguments to those used for acids, a new constant, the basicity constant, Kb, can be defined as follows: !
K eq

[BH ] " [HO ] = K " [ H O] =

+ # 2

[ B]

(5)

The acidity constant, Ka, of the conjugate acid of B, BH+, is defined using the following reaction: !
BH+ + H2 O
Ka

H3 O + +

Thus,

Ka =

[B] " [H 3O+ ]

[BH ]
+

(6)

From eq. 5 and 6, it follows that the product of Ka times Kb is equal to [H3O+]x [HO-], which is the ionic product of water, Kw = 10-14. !
K a " K b = [ H 3O+ ] " [ HO# ] = K w = 10#14

Taking log on both sides of the above equation, the following relation is obtained:
!
pK a + pK b = 14

(7).

Equation 7 holds true for the pKa and pKb values of any pair of acid and its conjugate base or base and its conjugate acid. Typical examples of acid/conjugate base pairs ! include: H2O/HO-, H3O+/H2O, ROH/RO-, R-NH3+/R-NH2, HCl/Cl-, etc. If we know the pKa of an acid, we can calculate, with the help of eq. 7, the pKb of its conjugate base, and vice versa. The pKb of aliphatic amines such as methylamine is in the

Acids and Bases

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range 4-5, thus the pKa of their conjugate acids, the ammonium salts, is in the range 9-10 (Table 1).

4. Predicting the Direction of Acid-Base Equilibria

When an acid HA reacts with a base B, the equilibrium constant for the reaction, and thus the extent of the reaction, can be predicted from the pKa values of the two acids involved, HA and BH+.
Keq

HA + B
pKa1

A- + BH+
pKa2

For this reaction to be shifted to the right, acid HA has to be stronger than BH+, or in other words, the pKa value for HA, pKa1, must be smaller than the pKa value for BH+, pKa2. If BH+ is stronger than HA, then the equilibrium is shifted to the left. It can be easily derived (see below) that for the above reaction: pKeq = pKa1 pKa2 (8)

Keq is the equilibrium constant for the acid-base reaction and measures the extent of the reaction. If pKa1 is smaller than pKa2, the difference pKa1 pKa2 is negative. If pKeq is negative, then Keq > 1, and thus the equilibrium is shifted to the right. The derivation of eq. 8 follows. The equilibrium constant for this acid-base reaction is:
K eq

[ A ] # [BH ] =
" +

[ HA] # [ B]

Eq. 3 and 6 (rewritten below) give the acidity constants for HA and BH+, respectively:
K a1

[ A!] # [H O ] =
" + 3

[ HA]

(3)

Ka2 =

[ B] " [ H 3O+ ]

[BH ]
+

(6)

Dividing eq. 3 by eq. 6, Keq is obtained:

!

! K a1 [A" ] # [BH + ] = = K eq Ka2 [HA] # [B]

K a1 = K eq Ka2

Acids and Bases

Daniel Palleros

By taking log on both sides of the above equation, eq. 8 is obtained. Lets consider now a couple of examples. When acetic acid (a weak acid; pKa = 4.76) reacts with methylamine (a weak base; pKb = 3.38; pKa (BH+) = 10.62), the reaction is irreversible and shifted to the right.
Keq

CH3COOH
pKa1 4.76

+ CH3NH2

CH3COO

+ CH3NH3
pKa2 10.62

This is confirmed by a negative pKeq (pKeq = 4.76 10.62 = -5.86). When phenol, PhOH, a very weak acid (pKa = 10.0), is in the presence of sodium hydrogen carbonate (NaHCO3, a weak base; pKb = 7.62; pKa H2CO3 = 6.38), no significant reaction takes place. In fact, the reaction takes place in the opposite direction because carbonic acid (carbon dioxide in water) is a stronger acid than phenol.
Keq

PhOH + NaHCO3
pKa1 10.0

PhONa

+ H2CO3
pKa2 6.38

CO2 + H2O

This is reflected by the positive pKeq: pKeq = 10.0 6.38 = 3.62

5. Two Classes of Acids

It is worth observing at this point that there are two classes of acids: Acids without an electrical charge (uncharged acids) that can be represented by HA (examples include water, phenols (ArOH), carboxylic acids (RCOOH), sulfonic acids (RSO3H), etc.), and acids with a positive charge (charged acids) of the form BH+, such as ammonium salts (RNH3+, ArNH3+). The acidity constants for these two types of acids are given by eq. 3 and 6, respectively. It should be noted that in eq. 3, the ionized species, A- (the conjugate base of the acid) appears in the numerator. In eq. 6, on the other hand, the ionized species is the acid itself, BH+, and its concentration appears in the denominator. This small difference in format will have an important impact later when we discuss the degree of ionization of acids (section 10).

6. The Curious Case of Water

Water can act as an acid and also as a base depending on other molecules present in the medium. In addition, water is the universal solvent, the one used to measure pKa values.

Acids and Bases

Daniel Palleros

In an acidic environment, water acts as a base and in a basic environment, as an acid. In a neutral environment one water molecule acts as a base while another acts as an acid: Two water molecules react to form hydroxide anion and hydronium.
Ka H2O base + H2O acid H3O+ conjugate acid + HO(9)

conjugate base

Lets now calculate the pKa of water. The equilibrium constant for the above process is:
K eq

[H O ] " [HO ] =
+ # 3

[H 2O] " [H 2O]

By definition, the acidity constant Ka is the equilibrium constant, Keq, multiplied by the concentration of water, also a constant since its the solvent of the reaction. !

K a = K eq

[H O ] " [HO ] " [ H O] =

+ # 3 2

[ H 2O]

(10)

The product [H3O+] x [HO-] is the ionic product of water, a constant, Kw = 10-14. Thus, the previous equation becomes: !
Kw 10"14 Ka = = [H 2O] [H 2O]

The concentration of pure water at room temperature is 55.3 M, thus:

!

K a = 1.81"10#16

or

pKa = 15.74

Notice that this value also represents the pKb of water. This seems to be a curious finding but it arises because in reaction 9, water acts simultaneously as an acid and as a base, thus ! the same equilibrium constant, Keq, represents the dissociation of water both as an acid and as a base. By definition, Kb is the equilibrium constant Keq multiplied by the concentration of water. This is identical to the definition of Ka, eq. 10. Thus, Kb = Ka.

If you wonder how come the concentration of water happens to be 55.3 M, think that concentration expressed in molarity refers to the number of moles per liter. In one liter of water at room temperature, density 0.997 g/mL, there are 55.3 moles (997 g/18.02 g/mol)

Acids and Bases

Daniel Palleros

The fact that the pKa and the pKb of water are identical could easily be misinterpreted and lead to confusion. Didnt we learn that the sum of pKa and pKb must be equal to 14, eq. 7? pKa + pKb = 14 (7)

So, how could it be that for water both pKa and pKb are equal to 15.74? The answer to this riddle is found in the simple fact that eq. 7 applies to the pKa and pKb values of a conjugate pair. The two water molecules in reaction 9, one acting as base and the other as acid, do not form a conjugate pair. For water acting as an acid, its conjugate base is HO-, and for water acting as a base, its conjugate acid is H3O+. Now, lets calculate the pKa of the conjugate acid of water, H3O+.
Ka H3O+ acid + H2O base H2O + H3O+

Ka =

[H 2O] " [H 3O+ ]

[H O ]
+ 3

= [ H 2O]

pKa = -log 55.3 = -1.74

!
Now, lets calculate the pKb of the conjugate base of water, HO-.
Kb HObase + H2O acid H2O + HO-

Kb

[H O ] # [HO ] = [H O] = [HO ]
" " 2 " 2

pKb = -log 55.3 = -1.74

! We can show now that eq. 7 actually holds. For water acting as an acid, pKa = 15.74; for its conjugate base, HO-, pKb = -1.74
pKa + pKb = 15.74 - 1.74 = 14

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For water acting as a base, pKb = 15.74; for its conjugate acid, H3O+, pKa = -1.74 pKa + pKb = -1.74 + 15.74 = 14. In summary, both the pKa and pKb of water are equal to 15.74 and the pKa of H3O+ is -1.74 and the pKb of HO- is -1.74. And the universe is at peace.

7. Strength of Organic Acids

In this section we will discuss the factors that determine acid strength. Lets consider the dissociation of a generic acid HA.

HA + H2O

Ka

A- + H3O+

Fact: Anything that stabilizes the conjugate base, A-, increases the acidity of the original acid, AH. Why? Because if the product of the reaction, A-, is more stable, the Go is smaller and Ka is larger, eq. 11. In other words, the more stable the product of the reaction (A-), the more shifted the equilibrium to the right. Go = -RT ln Ka (11)

Energy A- + H3O+ (less stable A-) the more stable A-, the smaller !Go, and the larger A- + H3O+ (more stable A-) Ka !Go = - RT ln Ka

HA + H2O

Reaction coordinate

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The most important factors that affect acid strength are: 1. Element effect: electronegativity and size of the atom to which the H is directly attached. 2. Hybridization effect: hybridization of the C atom to which the H is directly attached. 3. Inductive effect: electronegativity of the atoms near the H. 4. Resonance effect: electron delocalization in the conjugate base. 5. Steric effect: steric hindrance of bulky elements and groups near the H. They may affect the solvation of the anion. 6. Solvent effect: polarity of the solvent (dielectric constant of the solvent). 7. H-bond effect: formation of intramolecular H-bonds.

7.1 Element effect

Electronegativity (EN) Fact: The more electronegative the element to which the H is attached, the more acidic the compound. (There are exceptions to this rule as we will discuss at the end of this section.) Why? Because if the element is electronegative, it accepts a negative charge more readily (the conjugate base is more stable). Example:
electronegativity EN: 2.5 EN: 3.0 EN: 3.5 EN: 4.0

CH
Example: alkanes pKa : 50-60

NH
Example: amines pKa : 35-40 acid strength

OH
Example: alcohols pKa : 16-18

H F
Hydrofluoric acid pKa : 3.2

Size Fact: The larger the element to which the H is attached, the more acidic the compound. Why? Because a large atom can spread the negative charge over a larger volume, making the anion (conjugate base) more stable. Example: HI is more acidic than HF. The iodide anion is much larger than the fluoride anion, and thus the negative charge in the iodide anion is delocalized over a larger volume.

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size

Daniel Palleros

HF
pKa : 3.2

HCl
pKa : -7

HBr
pKa : -9 acid strength

HI
pKa : -10

Notice that the order of decreasing electronegativity is F > Cl > Br > I. Thus, based solely on EN, we would expect HF to be more acidic than HI, when in fact the opposite is true. Usually, the size effect is more important than the electronegativity effect and overpowers it. Another example of size being more important than electronegativity is the acidity of alcohols, R-OH, vs. thiols, R-SH. Despite oxygen being more electronegative than sulfur, thiols are more acidic than alcohols because the sulfur atom is larger than the oxygen atom and can stabilize better a negative charge.

7.2 Hybridization effect

Fact: As the s character of the hybridized carbon orbital increases (or the p character decreases) the acidity of the attached hydrogen increases. Why? Electrons on an s orbital are closer to the nucleus than on a p orbital. Thus, increasing the s character of a hybridized orbital increases the stability of the conjugate base (carbanion) because the electron pair is pulled closer to the nucleus. This explains why acetylenes (C is sp) are more acidic than alkenes (C is sp2) and alkenes more acidic than alkanes (C is sp3).
s-character sp3 25% s sp2 33% s sp 50% s

R - CH2 - R
pKa: 50-60

R - CH CH- R
pKa: 40-45 acidity

R-C

CH

pKa: 25-27

stability

R - CH - R

R - CH C- R

R-C

7.3 Inductive effect

Fact: Electronegative elements near the hydrogen increase its acidity. Why?

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Because electronegative elements pull electron density away from the anion (conjugate base), stabilizing it. Example: Chloroacetic acid is about two orders of magnitude more acidic than acetic acid. The presence of the electronegative chlorine atom (more electronegative than hydrogen) increases the acidity of carboxylic acids.
CH3COOH
pKa: 4.76 acidity

ClCH2COOH
pKa: 2.85

!"

!+

O
more satble than:

O H CH2-C O

Cl

CH2-C O

In general, electron-withdrawing (e-WD) substituents increase the acidity of carboxylic acids, phenols, alcohols, etc. Three effects are worth mentioning: a) The more electronegative the element, the stronger the effect. This is evident in the following series of halosubstituted acetic acids:
electronegativity EN: 2.7 EN: 2.8 EN: 3.0 EN: 4.0

I CH2COOH
pKa: 3.12

Br CH2COOH
pKa: 2.89

Cl CH2COOH
pKa: 2.85

F CH2COOH
pKa: 2.59

acidity

b) The larger the number of electronegative elements, the larger the effect. Example: Trifluoroacetic acid is two orders of magnitude more acidic than fluoroacetic acid.
F CH2COOH
pKa: 2.59 acidity

CF3COOH
pKa: 0.59

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c) The closer the electronegative element to the hydrogen, the stronger the effect. This is shown below with the isomeric chlorobutanoic acids. As the chlorine atom gets closer to the acidic hydrogen, the acidity increases.
O OH Cl
pKa: 4.82 pKa: 4.50 acidity pKa: 4.05

O OH

Cl

O OH Cl

O OH
pKa: 2.86

The effect is almost negligible when the electronegative element is 5-6 bonds away from the hydrogen. The inductive effect also operates on aromatic rings and affects the acidity of phenols, benzoic acids and aromatic amines. The farther away the substituent from the acidic hydrogen, the weaker the effect. Substituents at the para position have a weaker inductive effect than substituents at the meta and ortho positions. The following substituents have electron-withdrawing (e-WD) inductive effect: -OR; -NR2; -NH-CO-R; -F; -Cl; -Br; -I; -CHO; -CO-R; -CO-OR; -CO-NR2; -NO2; -SO3H; -CN Alkyl groups (-CH3; -CH2CH3, etc.) are the only substituents that have an electrondonating (e-D) inductive effect. The inductive effect on aromatic rings is often masked by resonance effects (discussed in the next section). This is especially true when the substituent is attached to the ortho or para positions. From the meta position, however, the inductive effect is usually the main effect. Examples of the power of the inductive effect are shown below with a series of meta-substituted benzoic acids.
Inductive effect COOH COOH COOH COOH

CH3 pKa 4.20 pKa 4.27 -CH3: e-donor less acidic than benzoic acid pKa 3.83

Cl pKa 4.08

OH

-Cl: e-WD more acidic than benzoic acid

-OH: e-WD more acidic than benzoic acid

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7.4 Resonance effect

Fact: The acidity of HA increases when the conjugate base, A-, is stabilized by resonance. Why? Because resonance leads to charge delocalization and charge delocalization lowers the energy, which means more stability. Example: Phenols are more acidic than alcohols because the phenolate anion is resonance stabilized but the alkoxide anion is not.
OH OH

pKa: 16.0 acidity

pKa: 10.0

phenolate anion stabilized by resonance (delocalized charge)

alkoxide anion with localized charge

Another example of the importance of resonance in acid/base properties is offered by amines. Alkylamines are about five order of magnitude more basic than arylamines because in arylamines the lone electron pair is delocalized in the ring and not readily available for protonation. This is shown below with aniline.

NH2

H2N

H2N

H2N

NH2

less basic than alkylamines (R-NH2) because the electron pair is delocalized

Pyrroles and pyridines deserve a special mention.

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N H

pyrrole

pyridine

Pyrrole is nonbasic despite the lone electron pair on the nitrogen. That electron pair forms part of the aromatic cloud and is not available for protonation. The resonance forms shown below illustrate this point.

N H

N H

N H

N H

N H

nonbasic

In pyridine, on the other hand, the lone electron pair is located outside the ring on an sp2 hybrid orbital and does not form part of the aromatic electron cloud. That electron pair is available for protonation and, thus, pyridine is basic.
Pyridine

N
N

basic

sp2 orbital electron pair available for protonation

Pyrroles and pyridines will be discussed in more detail in the chapter on Heterocycles. Resonance effects are particularly important in substituted aromatic compounds such as phenols, benzoic acids and aromatic amines. Resonance affects the pKa values, especially when substituents are located at the ortho and para positions from the acidic hydrogen. Substituents with electron-withdrawing (e-WD) resonance effects are: -CHO; -CO-R; -CO-OR; -CO-NR2; -NO2; -SO3H; -CN These substituents are also electron-withdrawing by inductive effect. Overall, they increase the acidity, regardless of the position, because they stabilize the anion (conjugate base) by delocalizing the charge through resonance and inductive effects. This is illustrated below with para-, meta- and ortho-nitrophenol, all more acidic than phenol. Notice that the effect is stronger from the para and ortho positions than from meta, because the resonance effect is stronger from those positions.

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OH OH OH OH NO2 NO2
pKa: 10.0

Daniel Palleros

NO2
pKa: 7.16

pKa: 8.35

pKa: 7.23

nitro group: e-WD (resonance) e-WD (inductive) more acidic than phenol

Electron-donating (e-D) substituents by resonance include: -OR; -NR2; -F; -Cl; -Br; -I. All these groups have two opposite effects. They donate electron density by resonance but withdraw electron density by inductive effect. For OR and -NR2 the resonance effect from the para position is more important than the inductive effect and therefore, these groups act as electron donors and are expected to decrease the acidity from that position.
OH OH

OCH3
pKa: 10.0 pKa: 10.21 methoxy group from para: e-D (resonance) predominates over e-WD (inductive) Less acidic than phenol

However, when -OR groups operate from the meta position, from which the resonance effect is small, the electron-withdrawing inductive effect dominates and these groups increase the acidity, as we discussed earlier under inductive effect (page 14). Amino groups, -NR2, on the other hand, have such strong resonance effect that they act as weak electron donors even from the meta position and decrease the acidity from that position.
COOH COOH COOH

OCH3
pKa: 4.20 pKa : 4.08 methoxy group from meta: e-WD (inductive) predominates over e-D (resonance) More acidic than benzoic acid

N(CH3)2
pKa: 4.41 dimethylamino group from meta: e-D (resonance) predominates over e-WD (inductive) Less acidic than benzoic acid

Halogens (-F, -Cl, -Br, -I) have a resonance effect that is weaker than the inductive effect regardless of the position and, in general, withdraw electron density from the ring, increasing the acidity. This is illustrated below with chloro-substituted benzoic acids and bromo-substituted phenols.

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COOH

COOH Cl

COOH

COOH

Cl pKa 4.20 pKa 2.88 pKa 3.83

Cl pKa 3.99

inductive e-WD effect stronger than resonance e-D effect. More acidic than benzoic acid

OH

OH Br

OH

OH

Br pKa 10.0 pKa 8.42 pKa 8.87

Br pKa 9.26

inductive e-WD effect stronger than resonance e-D effect. More acidic than phenol

Substituent effects from the ortho position are often obscured by steric factors and other effects, such as the formation of intramolecular H-bonds, and are difficult to predict. It has been observed, however, that most (but certainly not all) substituents at the ortho position increase the strength of the acid regardless of whether the substituent is electron donor or electron withdrawing. For example, 2-methylbenzoic acid and 2-cyanobenzoic acid are both more acidic than benzoic acid, even though the methyl group is an electron donor (inductive) and the cyano group an electron withdrawing group (inductive and resonance).
COOH COOH CH3 COOH CN

pKa 4.20

pKa 3.90

pKa 3.14

There is no simple explanation for this phenomenon.

7.5 Steric effect

Bulky groups, whether they are near or farther away from the acidic hydrogen, may affect its acidity. Bulky groups near the acidic hydrogen decrease the solvation of the ionic species. Farther away from the hydrogen, bulky groups may interfere with resonance forms. These two effects are discussed below. Solvation effect Fact: Bulky groups near the acidic hydrogen destabilize the conjugate base (A-) of the acid, decreasing its acidity.

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Why? When bulky groups are present near the negative charge, they prevent the proper approach of solvent molecules which results in decreased solvation. Less solvated anions are less stable anions. Example: Pentanoic acid is more acidic than its more bulky isomer 2,2dimethylpropanoic acid.
OH O
pKa: 5.04 pKa: 4.76

OH O

acidity

O
less solvated than:

O O

Effects on resonance forms Fact. Bulky substituents may prevent other groups from becoming planar. Planarity is an essential condition for resonance; without planarity no resonance is possible. Since resonance usually stabilizes the anion (conjugate base), a decrease in the resonance of the anion means a decrease in acidity. Example: para-nitrophenol is about three orders of magnitude more acidic than phenol. This is due mainly to the resonance effect of the nitro group and to a lesser degree to its inductive effect (both effects are electron withdrawing). For the nitro group to resonate with the ring, it must be coplanar with the aromatic ring.
OH OH
the nitro group in the para position increases the acidity of the phenol by almost three orders of magnitude pKa: 10.0

NO2
pKa: 7.16

O
one of the resonance forms of p-nitrophenolate anion All atoms are coplanar

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Lets consider now 3,5-dimethyl-4-nitrophenol which is only two orders of magnitude more acidic than 3,5-dimethylphenol. The bulky methyl groups prevent the nitro group from becoming coplanar with the ring. Because of this lack of coplanarity, the nitro group has a decreased electron-withdrawing resonance effect. As a result, there is a lesser increase in acidity.
OH OH
the nitro group cannot be coplanar with the ring and the acidity increases only by two orders of magnitude

H3C
pKa: 10.19

CH3

H3C NO2
pKa: 8.25

CH3

7.6 Solvent effect

The polarity of the solvent has a dramatic effect on the dissociation of acids. Fact: In general, the lower the dielectric constant of the solvent (the lower its polarity), the higher the pKa of an acid of the HA type (the less dissociated the acid). Why? Ionic species such as a conjugate base, A-, are stabilized in polar environments. The lower the dielectric constant of the solvent, the less polar the environment, and the less stabilized the anion. Example: The pKa of methanol in water (dielectric constant: 80) is close to 16, while in the less polar dimethyl sulfoxide, DMSO (dielectric constant: 47) is 29.
CH3OH
pKa (water): 16

CH3OH
pKa (DMSO): 29

This effect has important consequences in the pKa of amino acid residues in proteins. The pKa of the side chain of aspartic acid is 3.65. This value, like most pKa values, was measured in water. However, when aspartic acid is forming part of a protein and its side chain is buried inside the nonpolar core of the protein interior, its pKa value can increase significantly. In some enzymes it can be as high as 8-10.
free aspartic acid aspartic acid residue in a polypeptide chain

O H3N CH C CH2 C OH
pKa: 3.65 (in water)

O O C H N

O CH C CH2 NH

C OH

pKa depends on the environment. It could be as high as 8-10 ( or even higher) if the side chain is buried in the nonpolar protein interior

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7.7 H-bond effect

Fact: The formation of intramolecular H-bonds in the anion (conjugate base) increases the acidity. Why? Because H-bond formation stabilizes the anion. Example: Maleic acid is fifteen times more acidic than its trans isomer, fumaric acid. The formation of an intramolecular H-bond between the negative oxygen atom and the undissociated OH group stabilizes the anion of maleic acid. Such stabilization is absent in fumaric acid because no internal H-bond can be formed.
Maleic acid O OH OH O O
pKa: 1.91

Fumaric acid O O H H-bond HO O

pKa: 3.10

OH

8. Classification of Organic Compounds as Acids and Bases

Organic chemicals can be classified into three main types according to their acid-base properties: acidic, basic and neutral. Since the acid-base properties of a substance ultimately depend on other chemicals present in the medium (remember from our initial discussion of Brnsted-Lowry theory that methanol, for example, behaves as acid in the presence of bases such as sodium amide, NaNH2, and as base in the presence of acids such as sulfuric acid, H2SO4), any classification of acids and bases must assume a set of experimental conditions. Since we are interested in the fate of pharmaceuticals in the organism where the main substance is water, here we will assume that the compounds are dissolved in water at physiological, or near physiological, pH values (1.5-8.5). Physiological pH values for a number of tissue fluids are listed in Table 3. Only acids with pKa values in the neighborhood of physiological pH can exist in the organism in both the ionized and nonionized forms in any significant amount (the degree of ionization of an acid will be discussed in section 10). If a compound has a pKa which is much larger than the pKa of water (15.74), such compound does not show acidic behavior in water and is considered neutral. These compounds are found in their nonionized form in the organism. On the other hand, compounds with very low pKa values, such as strong inorganic acids, are found totally ionized in the organism. Table 1 shows the pKa values for typical functional groups. Inspect the table and familiarize yourself, once again, with the structure of functional groups and their acidity constants. The table below summarizes the classification of functional groups as acidic, basic and neutral in water.

Acids and Bases

22 Bases
Amines: R-NH2; Ar-NH2 Pyridines:
N

Daniel Palleros

Acids
Sulfonic acids: RSO3H; ArSO3H Carboxylic acids: RCO2H; ArCO2H Phenols: PhOH Sulfonimides: R-CO-NH-SO2 R N-Aryl-sulfonamides: RSO2-NH-Ar Sulfonamides: RSO2NH2 Imides: R-CO-NH-CO-R Thiophenols: ArSH Thiols: RSH 2,3-Diketones: R-CO-CH2-CO-R 3-Ketoesters: R-CO-CH2-COOR 1,3-Diesters: RO-CO-CH2-CO-OR

Neutral
Alcohols: ROH Amides: R-CO-NH2 Aldehydes: R-CO-H Ketones: R-CO-R Esters: R-COOR Acetylenes: R-CCH Alkenes: R-CH=CH-R Alkanes: R-CH2-R Ethers: R-O-R Alkyl and aryl halides: R-X; Ar-X

Imidazole:
N N H

Guanidino:

NH C NH2 R-NH

Those compounds with pKa values larger than 15 are classified as neutral since they do not participate in acid-base reactions in water. Notice that alcohols (ROH, pKa 16-18) are considered neutral in water. In order to unleash alcohols acidic behavior, very strong bases (pKb < -2) must be used. Such bases cannot be obtained in water because when mixed with water they immediately and irreversibly react. An example of such a base is sodium amide, NH2- Na+, which is strong enough to deprotonate alcohols but is decomposed by water:

NH2- Na+ + CH3OH

base acid pKa 16-18

NH3
conjugate acid pKa 35

+ CH3O- Na+
conjugate base

NH2- Na+

H 2O
pKa 15.74

NH3
pKa 35

NaOH

Therefore, the deprotonation of alcohols with sodium amide cannot be carried out in water and must be performed in other solvents in which sodium amide is stable, such as liquid ammonia or ethers.