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Acids and Bases
Reference: P. Bruice, Organic Chemistry, 6
th
Edition, Chapters 1.16-1.26, 7.9, 16.5.
Definitions
Bases (general definition) - All substances that contain unshared electron pairs are bases.
Examples:
NH
2
H O
..
..
H N
H
H
CH
3
C
O
O
..
..
..
Cl
..
..
CH
3
O
..
..
H O
H
..
..
..
Acids
- Proton or protonic acids - Proton acids (Brønsted acids) are substances that can transfer a
proton to a base. They are proton donors. They are usually substances that have a hydrogen
atom bonded to an electronegative atom.
Examples:
CH
3
C
O
O H
..
..
..
..
..
H O
H
HCl
NH
3
R
- Lewis Acids - According to the concept of G. N. Lewis, acids are not limited to proton
donors, but an acid is any substance that contains an element having a vacant orbital that can
accept a pair of electrons in forming a bond. According to the Lewis concept it is the bare proton
with its vacant s orbital that is the acidic entity in protonic acids. But bare unsolvated protons do
not exist in solution and it is now customary to differentiate between proton acids and Lewis
acids. The term 'Lewis acid' is used to designate substances having a vacant orbital, usually
substances containing an element that is two electrons short of having a complete valence shell.
F
3
B
O
Et
Et
O
Et
Et
F
3
B
Lewis Acid Base Addition Compound
F B N
F
F
H
H
H
B
F
F
F N H
H
H
Lewis Acid Base Addition Compound
Note that the resulting addition
compounds formed from electrically
neutral molecules have a formal negative
charge on the boron (the electron
acceptor) and a formal plus charge on the
electron donor.
Proton Acids and Bases (Conjugate Acid-Base Pairs) - The ionization of a proton acid involves
the transfer of a proton from the acid to a base, or more correctly, the removal of a proton from
the acid by a base. Strong acids are able to transfer their proton to weak bases, but weak acids
may require a very strong base to bring about the proton transfer of ionization. When an acid
ionizes in water, the water molecules, with their unshared pairs of electrons, serve as the base. It
is important to realize that bare unsolvated protons do not exist in solution. Ionization of a
proton acid always requires a base to remove or accept the proton. Often the solvent molecules
serve as the base.
The process can be shown by following general equation, where B represents a base and H–A
represents a proton acid.
H A
B H
A
B
Note that the anion (:A
_
) that results from the removal of the proton from the acid H–A, is itself a
base. It is called the conjugate base of acid H–A. The protonated species B
and it is called the conjugate acid of base B:. The acid-base reaction is therefore a competition
reaction between two bases for a single proton. The reaction is an equilibrium process. The
position of the equilibrium is affected by the relative basicities of the competing bases B: and
:A
_
Scale of Acidity and Basicity - The acidity of an acid refers to the proton donating power of the
acid, to the degree to which the proton is transferred from the acid to a given base. In order to
make a meaningful comparison of the acidity of different acids a common reference base must
be used. The reference base adopted is water.
A H H
2
O H
3
O
A
The protonation of water by an acid is an equilibrium reaction and for most acids the reaction is
extremely fast and the equilibrium is reached almost instantaneously.
The law of mass action allows the concentrations at equilibrium to be related to an equilibrium
constant (K), as shown below, for the ionization of acetic acid.
CH
3
COOH H
2
O CH
3
COO
H
3
O
Since the measurements are made at relatively low concentrations of the acid, the concentration
of the water remains essentially constant and it is usually incorporated in the equilibrium
constant to give the expression:
[H =
2
K' O]
a
[CH
3
COOH]
[H
3
O
[CH ]
3
COO
]
K
a =^ 1.75 x 10
Where Ka is called the acidity constant, the ionization or dissociation constant. The terms in
brackets refer to concentrations in moles per liter after equilibrium is reached. Using A–H to
represent any acid gives the general equilibrium equation:
K
a
[H
3
O
]
[A H]
[A
]
The acidity constant Ka is an equilibrium constant. It allows the calculation of the ratio of the
free acid and its conjugate base, at equilibrium, for a solution of known concentration of the acid
in water.
K'
a
K'
a
[CH
3
COO
][H
3
O
]
[CH
3
COOH][H
2
O]
[H
2
O]
[CH
3
COO
] [H
3
O
]
[CH
3
COOH]
= K =
a
The pK a
- a single scale for reporting and comparing the ionization capacity of acids and bases.
Since every base has its conjugate acid, it is possible to compare all acids and bases on a single
scale. The scale commonly used is the acidity constant of the conjugate acid of any conjugate
pair, expressed in logarithmic units. This is called the pK a
. By definition, the pK a
is the
negative logarithm of K a
value.
pK a
= – log K a
For acetic acid, K a
= 1.75 x 10
= – log (1.75 x 10
- 5 ) = 5 – log 1.75 = 4.76.
It is very important to recognize that the pK a
of bases, such as ammonia or the organic amines, is
a measure of the acidity of the conjugate acid of the base, a measure of the acidity of the salts of
ammonia or amines.
The pK a
of methylamine [CH 3
NH
3
] is given as 10.6. This means that a salt of methylamine,
such as CH 3
NH
3
Cl
, has an acidity constant K a
H
2
O CH
3
NH
2
H
3
O
Cl
CH 3
NH
3
Cl
= 2.51 x 10
[H
3
O
[CH ]
3
NH
2
]
K
a
[CH
3
NH
3
]
pK a
= – log (2.51 x 10
The ionization of water is K w
2 H
2
O H
3
O
+ OH
K
w
= [H
3
O
] [OH
] = 10
pK w
= – log K w
Here again, the constant concentration term of the water is incorporated in the constant K w
. In
pure water the concentration of hydronium and hydroxide ions must of course be equal. At
25 ° C, the concentration of each is 10
[H
3
O
] [OH
]
[H
2
O]
K
a
pK
a
–15.
K
w
Examples of Acids and Acidity Scale
Conjugate Acid pK a
Conjugate Base
Strong Acids
1. H–I ~ – 10 : I :
- H–Cl ~ – 7 : Cl :
3. H
2
SO
4
~ – 3 HSO
4
The above acids cannot exist as such in aqueous solution. In each case the conjugate base is a
weaker base than the water molecule. The proton would be completely transferred to the water
molecules. The standard "strong" acids are completely ionized in water. These are HClO 4
, HI,
HCl and H 2
SO
4
(first proton).
4. F
3
C C
O
OH ~ 0 F
3
C C
O
O
- Cl 3
C C
O
OH ~ 0.8 Cl 3
C C
O
O
6. NH
3
O
2
N
1.0 NH
2
O
2
N
..
- Cl 2
CH C
O
OH 1.3 Cl 2
CH C
O
O
- ClCH 2
C
O
OH 2.8 ClCH 2
C
O
O
OH
C OH
O
OH
C O
O
10. O
2
N C
O
OH 3.4 O
2
N C
O
O
- Cl C OH
O
4.0 Cl C O
O
- (^) Cl NH 3
4.0 (^) Cl NH 2
..
Conjugate Acid pK a
Conjugate Base
13. C
O
OH 4.2 C
O
O
14. CH
3
O C
O
OH 4.5 CH
3
O C
O
O
15. NH
3
4.6 NH
2
..
16. CH
3
C
O
OH 4.76 CH
3
C
O
O
17. NH
3
CH
3
O
5.3 CH
3
O NH
2
..
18. N^ H
5.3 N
19. O
2
N OH 7.2 O
2
N O
20. H
2
N C O
O
CH 2
CH 2
N
H
Et
Et
Procaine
8.9 H
2
N C O
O
CH
2
CH
2
N
Et
Et
..
21. NH
4
9.2 NH
3
22. OH 9.6 O
C
N
C
O
O
H 9.
C
N
C
O
O
C
N
C
O
O
C
N
C
O
O
24. CH
2
CH
CH
3
NH
3
Amphetamine
~ 10 CH
2
CH
CH
3
NH
2
..
25. H
2
N SO
2
NH
2
..
Sulfanilamide
..
H
2
N SO
2
N
H
..
An imide
For acids of intermediate strengths (pKa between 0 and 14) which are soluble in water, the
degree of water protonation will depend on the pKa of the acid. For a 0.1 N solution of acetic
acid most of the acid is in the nonionized form. Taking the pKa as 5 would give:
[AcOH]
[H
3
O
[AcO ]
]
K
a
=
x
2
0.1 - x
AcOH H 2
O AcO
H
3
O
0.1 molar x^ x
Since x is small (compared to 0.1M), it can be neglected in the denominator and x
x = 10 -^3.
The pH of the solution is about 3 and the ratio of ionized to nonionized acetic acid is about
For dilute aqueous solutions of weak acids the approximate pH can be calculated as the negative
log of the square root of the product of the K a
and the molar concentration.
pH =^ −^ log^ Ka^ [molar concentration of acid]
K
a
x
2
[AcOH]
x
K
a
[AcOH] ;^ x=^ K a
[AcOH]
Drugs which are amines (weak bases) are sometimes used as their hydrochloride salts, procaine
hydrochloride for example. Salts of amines are the conjugate acids of amines and are of course
acidic. The pH of a 0.1 N solution of procaine hydrochloride will be about 5.
H 2
H O
2
N C O
O
CH
2
CH
2
N Et
H
Et
H
2
N C O
O
CH
2
CH
2
N Et
Et
..
+ H
3
O
[0.1 molar]
pK a
K
a
= , K
a
[BH
] = x
2 = (
- 9 ) ( - 1 ) = 10 - 10 , x = 10 - 5 , pH = 5.
It is important to remember that pKa values are logarithmic values. A difference of one pKa unit
means that the ionization constant varies by a factor of ten. Compare the acidity of the salts of
aromatic and aliphatic amines.
pH of a 0.1 Molar solution,
K
a
[BH
] = x
2 = (
x = 10
pH of a 0.1 Molar solution,
K
a
[BH
] = x
2 = (
x = 10
The aniline hydrochloride is 10
6 (one million times) more acidic than methylamine
hydrochloride. The aliphatic methylamine is one million times more basic than the aromatic
amine, aniline.
[B : ] [H
3
O
]
[BH
]
NH
3
Cl
, pK a
Cl
, pK a
CH
3
NH
3
By definition, – log [H 3
O
] is pH and – log K a
is pK a
, therefore
pH = pK a
Thus, if the conjugate acid is a non-ionized compound such as a carboxylic acid, then the
conjugate base is the ionized form, the anion; and when dealing with amines, it is the conjugate
acid that is the ionized form (the protonated amine, the cation).
In buffered solutions (solution at constant pH) a conjugate acid - conjugate base pair will adjust
itself to a particular ratio of ionized to non-ionized species that is dependent only on the pKa of
the acid-base pair and the pH of the solution. The same ratio is obtained regardless of whether
the conjugate acid or the conjugate base was used to prepare the solution. If a solution of acetic
acid (pKa 4.8) were injected in the blood stream (pH 7.4), the acetic acid would ionize to the
extent of more than 99%, difference greater than 2 log units. The same result would be obtained
by injecting a solution of sodium acetate.
It is obvious from the Henderson-Hasselbalch equation that the pH and the pKa are numerically
equal when the ratio of conjugate acid and conjugate base is equal to one, when the substance is
50% ionized. An acid or base is 50% ionized at the pH that equals its pKa.
[Conjugate base]
[Conjugate acid]
Clonidine pK a
Naphazoline pKa = 10.
Guanidines substituted with electron withdrawing groups have greatly reduced basicity, e.g.
cimetidine.
N NH
CH
2
S CH
2
CH
2
N
H
C
N
NHCH
3
CN
H
3
C
neutral
(insulin) C NH
O
CH C
CH
2
NH
O
CH COO
CH
2
CH
2
CH
2
H
N C NH
2
NH
CH
2
CH
2
H
N C
NH
NH
2
MW
glargine insulin
Soluble HCl salt administered subcutaneously. It precipitates and the slow rate of subsequent
dissolution and then absorption into the blood stream provides a long duration of effect.
(Two arginines added to the
carboxyl end of the B-chain
of insulin.)
N
H
Cl
Cl
N
N
H
N
H
N
CH
2
B. Amines - Tertiary, Secondary, and Primary
Many drugs are tertiary or secondary aliphatic amines, a few are primary amines. Tertiary
amines usually are metabolized by fewer independent pathways than those with fewer alkyl
groups on nitrogen, i.e. secondary and primary aliphatic amines may be metabolized by different
processes. Most amine drugs are basic (pKa ~ 9). Even though they are highly ionized at
physiological pH, most are readily absorbed after oral administration (rapid equilibrium between
ionized and non-ionized forms to penetrate membranes), and many lipophilic ones reach the
CNS.
Examples
CH OCH
2
CH
2
N
CH
3
CH
3
Diphenhydramine pKa = 9.
F
3
C
O
CH CH
2
CH
2
NHCH
3
Fluoxetine pK a
O
NCH
2
CH
2
C
F
NC
H
3
C
H
3
C
H
2
Citalopram pK a
OCH
2
CH CH
2
NHCH(CH
3
2
OH
Propranolol pK a
Effect of aqueous solubility on oral bioavailability.
L-685,
IC 50
No Oral Bioavailability
O
O
O
OH
NH
HN (^) OH
N
O NH
N
N (^) OH
NH
OH
O
Ionizable
Center
Insoluble
More Soluble
indinavir
IC 50
Oral Bioavailability = 60% Human
C. Phenols, Enols, Imides, Sulfonamides and Related Compounds
Increased acidity (dissociation of acid) is associated with stabilization of resulting structures by
resonance (anions especially), to a greater extent than in the non-dissociated acid.
Resonance rules:
- Only electrons move. The nuclei of the atoms never move.
- Only π electrons or non-bonding electrons contribute.
- Electrons move toward a positive charge or toward a π bond.
- Total number of electrons does not change. The number of paired and unpaired
electrons does not change.
Examples
HO
HO
CH
2
CH
2
NH
2
Dopamine pK a
= 10.6 (phenol)
8.9 (RNH
3
O
H
3
C
H
H H
HO
Estrone pK a
O
OH
CH
3
H
H
3
C
CH
3
H
C
5
H
11
9
cyclohexanol
pKa ~ 15-
phenolate
anion
phenol
pKa ~ 10
O OH
+ H
3
O
OH
+ H
2
O
O
O
O
O
