Org Chem

Acids and Bases 1 Daniel Palleros
Acids and Bases

1. Brønsted-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

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
that’s 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
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. Brønsted-Lowry Theory
According to Brønsted-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 oxygen’s electron pairs.
+
H Cl + H2O Cl- + H 3O
acid base conjugate base conjugate acid
According to the Brønsted-Lowry theory, each acid has its conjugate base, which is the
same compound minus a proton, and each base has its conjugate acid, which is the same
compound 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 + H 2O NH4+ + HO
base acid conjugate acid 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 NH3 + CH3O- Na+

Alcohols can also act as proton acceptors in the presence of acids such as sulfuric acid,
H2SO4:
H2SO4 + CH3OH HSO4- + CH3OH2
acid base 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:
Keq
HA + H2O A- + H3O+
The equilibrium constant, Keq, is defined by the following equation:

K eq =
[ A ] # [H O ]
"
3
+
(1)
[HA] # [ H 2O]
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
! of the acid (the solute) and, thus, it can be considered constant. Multiplying
concentration
both sides of eq. 1 by [H2O], eq. 2 is obtained.
K eq " [ H 2O] =
[ A ] " [H O ]
#
3
+
(2)
[ HA]
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
+
(3)
[HA]
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
! known. Organic acids, on the other hand, are usually weaker than
strongest acids
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-

To measure the strength of bases such as methylamine, let’s 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 " [ H O] =
[BH ] " [HO ] = K
+ #
(5)
2 b
[ B]
The acidity constant, Ka, of the conjugate acid of B, BH+, is defined using the following
reaction:
!
Ka
BH+ + H2 O H3 O + + B
Thus,
[B] " [H 3O+ ]

Ka = (6)
[BH ] +
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
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 A- + BH+
pKa1 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:
!
[ A ] # [H O ]
"
3
+
[ B] " [ H 3O+ ]
K a1 = (3) Ka2 = (6)
[ HA] [BH ]+
Dividing eq. 3 by eq. 6, Keq is obtained:

! !
K a1 [A" ] # [BH + ]
= = K eq
Ka2 [HA] # [B]
K a1
= K eq
Ka2
!
!
By taking –log on both sides of the above equation, eq. 8 is obtained.
Let’s 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 + CH3NH2 CH3COO + CH3NH3
pKa1 4.76 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 PhONa + H2CO3
pKa 10.0 pKa 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.
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 + H2O H3O+ + HO- (9)
Let’s 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 it’s the solvent of the reaction.
!
K a = K eq " [ H O] =
[H O ] " [HO ]
3
+ #
(10)
2
[ H 2O]
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
! constant, Keq, represents the dissociation of water both as an acid
the same equilibrium
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)
The fact that the pKa and the pKb of water are identical could easily be misinterpreted and
lead to confusion. Didn’t we learn that the sum of pKa and pKb must 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, let’s calculate the pKa of the conjugate acid of water, H3O+.
Ka
H3O+ + H2O H2O + H3O+
acid base
[H 2O] " [H 3O+ ]

Ka = = [ H 2O]
[H O ]
3
+
pKa = -log 55.3 = -1.74

!
Now, let’s calculate the pKb of the conjugate base of water, HO-.
Kb
HO- + H2O H2O + HO-
base acid
Kb =
[H O ] # [HO ] = [H O]
2
" "
2
[HO ] "
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

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. Let’s consider the
dissociation of a generic acid HA.
Ka
HA + H2O 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 ΔGo 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.
ΔGo = -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
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 NH OH H F
Example: alkanes Example: amines Example: alcohols Hydrofluoric acid

pKa : 50-60 pKa : 35-40 pKa : 16-18 pKa : 3.2
acid strength
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.
size
HF HCl HBr HI
pKa : 3.2 pKa : -7 pKa : -9 pKa : -10
acid strength
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 sp2 sp
25% s 33% s 50% s
R - CH2 - R R - CH CH- R R-C CH
pKa: 50-60 pKa: 40-45 pKa: 25-27
acidity
stability
R - CH - R R - CH C- R R-C C
7.3 Inductive effect

Fact: Electronegative elements near the hydrogen increase its acidity.
Why?
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 ClCH2COOH
pKa: 4.76 pKa: 2.85
acidity
!" !+ O O
Cl CH2-C more satble than: H CH2-C
O 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 Br CH2COOH Cl CH2COOH F CH2COOH

pKa: 3.12 pKa: 2.89 pKa: 2.85 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 CF3COOH
pKa: 2.59 pKa: 0.59
acidity
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 O Cl O O
OH OH OH OH
Cl Cl
pKa: 4.82 pKa: 4.50 pKa: 4.05 pKa: 2.86
acidity
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 electron-
donating (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 Cl OH
pKa 4.20 pKa 4.27 pKa 3.83 pKa 4.08
-CH3: e-donor -Cl: e-WD -OH: e-WD

less acidic than more acidic more acidic
benzoic acid than benzoic acid than benzoic acid
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 pKa: 10.0
acidity
O O O O O
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.

N N
H
pyrrole pyridine
Pyrrole is nonbasic despite the lone electron pair on the nitrogen. That electron pair forms
part of the aromatic π cloud and is not available for protonation. The resonance forms
shown below illustrate this point.
N N N N N
H H H H 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
sp2 orbital
basic 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.
OH OH OH OH
NO2
NO2
pKa: 10.0 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 N(CH3)2
pKa: 4.20 pKa : 4.08 pKa: 4.41
methoxy group dimethylamino group
from meta: from meta:
e-WD (inductive) e-D (resonance) predominates over
predominates over e-D (resonance) e-WD (inductive)
More acidic than benzoic acid 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.
COOH COOH COOH COOH

Cl
Cl
Cl
pKa 4.20 pKa 2.88 pKa 3.83 pKa 3.99
inductive e-WD effect stronger than resonance e-D effect.

More acidic than benzoic acid
OH OH OH OH
Br
Br
Br
pKa 10.0 pKa 8.42 pKa 8.87 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 COOH

CH3 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.
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 2,2-
dimethylpropanoic acid.
OH OH
O O
pKa: 5.04 pKa: 4.76
acidity
O 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
one of the resonance forms of

p-nitrophenolate anion
All atoms are coplanar
N
O O
Let’s 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 CH3 H3C CH3
pKa: 10.19 NO2
pKa: 8.25
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 CH3OH
pKa (water): 16 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 O O
H
H3N CH C O C N CH C NH
CH2 CH2
C O C O
OH OH
pKa: 3.65 pKa depends on the environment. It could be as

(in water) high as 8-10 ( or even higher) if the side
chain is buried in the nonpolar protein interior
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 Fumaric acid

O
O O
OH H-bond
O OH
OH H
O HO
O
O O
pKa: 1.91 pKa: 3.10
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 Brønsted-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 Bases Neutral

Sulfonic acids: RSO3H; ArSO3H Amines: R-NH2; Ar-NH2 Alcohols: ROH
Carboxylic acids: RCO2H; Pyridines: Amides: R-CO-NH2
ArCO2H Aldehydes: R-CO-H
Phenols: PhOH Ketones: R-CO-R
Sulfonimides: R-CO-NH-SO2 R N Esters: R-COOR
N-Aryl-sulfonamides: Imidazole: Acetylenes: R-CCH
RSO2-NH-Ar N Alkenes: R-CH=CH-R
Sulfonamides: RSO2NH2 Alkanes: R-CH2-R
Imides: R-CO-NH-CO-R N Ethers: R-O-R
H
Thiophenols: ArSH Alkyl and aryl halides: R-X;
Guanidino:
Thiols: RSH Ar-X
NH
2,3-Diketones: R-CO-CH2-CO-R
3-Ketoesters: R-CO-CH2-COOR C
R-NH NH2
1,3-Diesters:
RO-CO-CH2-CO-OR
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 NH3 + CH3O- Na+

pKa 16-18 pKa 35
NH2- Na+ + H 2O NH3 + NaOH

pKa 15.74 pKa 35
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.

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Acids and Bases 1 Daniel Palleros

Acids and Bases

Acids and Bases

A compound capable of reacting as an acid or a base is called amphoteric. Most organic

NH2- Na+ + CH3OH NH3 + CH3O- Na+

H2SO4 + CH3OH HSO4- + CH3OH2

acid base conjugate base conjugate acid

2. The Acidity Constant, Ka

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

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

CH3NH2 + H2 O CH3NH3 + HO-

The equilibrium constant for this process is given below:

[B] " [H 3O+ ]

4. Predicting the Direction of Acid-Base Equilibria

pKeq = pKa1 – pKa2 (8)

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

By taking –log on both sides of the above equation, eq. 8 is obtained.

This is confirmed by a negative pKeq (pKeq = 4.76 – 10.62 = -5.86).

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

5. Two Classes of Acids

6. The Curious Case of Water

In an acidic environment, water acts as a base and in a basic environment, as an acid. In a

base acid conjugate acid conjugate base

Let’s now calculate the pKa of water.

The equilibrium constant for the above process is:

[H 2O] " [H 2O]

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

pKa + pKb = 14 (7)

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

pKa = -log 55.3 = -1.74

pKb = -log 55.3 = -1.74

pKa + pKb = 15.74 - 1.74 = 14

pKa + pKb = -1.74 + 15.74 = 14.

And the universe is at peace.

7. Strength of Organic Acids

ΔGo = -RT ln Ka (11)

The most important factors that affect acid strength are:

7.1 Element effect

EN: 2.5 EN: 3.0 EN: 3.5 EN: 4.0

Example: alkanes Example: amines Example: alcohols Hydrofluoric acid

7.2 Hybridization effect

7.3 Inductive effect

pKa: 4.76 pKa: 2.85

In general, electron-withdrawing (e-WD) substituents increase the acidity of carboxylic

Three effects are worth mentioning:

EN: 2.7 EN: 2.8 EN: 3.0 EN: 4.0

I CH2COOH Br CH2COOH Cl CH2COOH F CH2COOH

pKa: 2.59 pKa: 0.59

pKa: 4.82 pKa: 4.50 pKa: 4.05 pKa: 2.86

COOH COOH COOH COOH

-CH3: e-donor -Cl: e-WD -OH: e-WD

7.4 Resonance effect

pKa: 16.0 pKa: 10.0

phenolate anion stabilized by resonance

alkoxide anion with localized charge

Another example of the importance of resonance in acid/base properties is offered by

NH2 H2N H2N H2N NH2

Pyrroles and pyridines deserve a special mention.

Resonance effects are particularly important in substituted aromatic compounds such

-CHO; -CO-R; -CO-OR; -CO-NR2; -NO2; -SO3H; -CN

These substituents are also electron-withdrawing by inductive effect. Overall, they

COOH COOH COOH COOH

inductive e-WD effect stronger than resonance e-D effect.