Non-aqueous acid base titrimetry

Non- aqueous titrations are those in which the

titrations of too weakly acidic or basic
substances are carried out using non-aqueous
solvents so as to get sharp end point.

Such titrations can also be used for the titration

of the substances not soluble in water.

The speed, precision and accuracy of the non-

aqueous method are close to those of classical
acidimetric and alkalimetric titrations.
Non-aqueous titrimetry
First reported successful quantitative
titration of organic acid and base in non-
aqueous solvent: 1910.
To an understanding of non-aqueous acid
base titrimetry the theories of acid and base is
very important. The theories are:
- Arrhenius acids and bases
- Bronsted-Lowry acids and bases
- Lewis acids and bases
Arrhenius acids and bases

Acids are hydrogen containing compounds

that dissociates to yield hydrogen ions (H+)
when dissolved in water.

Bases are compounds that dissociates to

yield hydroxide/hydroxyl ions (OH-) when
dissolved in water.
Arrhenius acids and bases
It has two major limitations.
First, it was limited to water, or aqueous,
solutions.
Second, it practically limited acids and bases to
ionic compounds that contained the H+ ion or
the OH- ion.

Drawbacks:
- Acids or bases must be dissociated or ionized
- Didn’t explain, why CH4 contains H but not an
acid?
- Na2CO3 is basic but unable to donate OH-
Bronsted-Lowry theory
The Bronsted-Lowry theory of acid and
base can be applied to reactions occurring
during acid base titrations in non-aqueous
solvents.

Acid: any substance, charged or uncharged

which can donate proton.

Base: any substance, charged or uncharged

which can accept a proton.
 Acid: HA  H+ + A-

An acid ‘HA’ dissociates to give a proton H+ and

its conjugate base A-.

Base: B + H+  BH+

A base ‘B’ unite with a proton to produce its

conjugate acid BH+.

Every base has its conjugate acid, just as an

acid has its conjugate base.
According to this theory, an acid may be an
electrically neutral molecule (HCl), a positively
charged cation (C5H5NH+), or a negatively

charged anion (H2PO4-).

A base may be an electrically neutral molecule

(C5H5N) or an anion (Cl-).
Lewis acids and bases
The third theory of acids and bases was
proposed by Gilbert Lewis.

Lewis focused on the donation or

acceptance of a pair of electrons during a
reaction.

This concept is more general than either

the Arrhenius theory or the Bronsted-Lowry
theory.
 A Lewis acid is a substance that can accept
a pair of electrons to form a covalent bond.
A Lewis base is a substance that can
donate a pair of electrons to form a covalent
bond.
A hydrogen ion (Bronsted-Lowry acid) can
accept a pair of electrons in forming a bond. A
hydrogen ion, therefore, is also a Lewis acid.
A Bronsted-Lowry base, or a substance
that accepts a hydrogen ion, must have a pair
of electrons available and is also a Lewis base.
Strength of acids and bases
An acid can only exhibit its acidic
properties in the presence of base; conversely a
base can only function as such in the presence
of an acid.
The relative strengths of acids and bases
are measured by the tendencies of these
substances to give up or take on protons.
HCl is strong acid in water because it gives
up its proton readily, where as acetic acid is
weak acid since it relinquishes its proton to a
small extent only.
 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.

Compare this reaction with what happens

when acetic acid is dissolved in the more acidic
solvent like pure sulfuric acid.
 The strength of an acid or base varies with
the solvent or environment.

HCl behaves as a weak acid in glacial

acetic acid whereas acetic acid is a strong acid
in liquid ammonia.

Consequently, the strength of an acid

depends not only on its own ability to release a
proton, but also on the ability of the solvent to
take up proton from acid.
Solvents
The ability of substances to act as acids &
bases will depend very much upon the nature of
the solvent system which is employed.

Non-aqueous solvents are classified into

the 4 groups:
- Protophilic solvents
- Protogenic solvents
- Amphiprotic solvents
- Aprotic solvents
Protophilic solvents
Possess high affinity for proton
Weak acids are normally used as solute
Strong protophilic solvents convert weak acid
to strong acid-known as ’leveling effect’
Example: Liquid ammonia, amines, ether
and ketones

HA + S  SH+ + A-

Weak Acid Basic Solvated Conjugated

(appeared as solvent proton base of acid
strong acid)
 Weak acids are normally used in the
presence of strongly protophilic solvents as
their acidic strengths are then enhanced and
then become comparable to these of strong
acids; this is known as the leveling effect.
Protogenic solvents
Acidic in nature
Readily donates protons
Strong protogenic solvents increase the
strength of weak bases
Such solvents exert a leveling effect on all
bases dissolved in them
Example: Anhydrous acid like hydrogen
fluoride & sulfuric acid

B + H+  BH+
Weak Base From Conjugated
(appeared as strong solvent acid of base
base)
Amphiprotic solvents
Combine protogenic and protophilic properties
of solvent
Able to both donate and accept proton
Example: Water, alcohol & weak organic acid
Acetic acid shows acidic property by releasing
proton-
CH3COOH  CH3COO- + H+
In presence of perchloric acid (strong acid)
acetic acid shows basic property by accepting
proton and produce ‘onium’ ion-
CH3COOH + HClO4  CH3COOH2+ + ClO4-
‘onium’ ion
 In such a solution then, the actual titrating
species is the ion CH3COOH2+ which readily
donates its proton to a base.

Aprotic solvents
Chemically neutral substances
Virtually un-reactive
Do not cause ionization of solute
No reactions with acids and bases
Used to dilute reaction mixture
Example: Carbon tetrachloride, benzene,
tolune.
Theory of non-aqueous acid base titration
Water behaves both as a weak acid and a
weak base thus in an aqueous environment it
can compete effectively with very weak acids
and weak bases with regard to proton donation
and acceptance.

H2O + H+  H3O+ Compete with

RNH2 + H+  RNH3+
Base

H2O + B  OH- + BH+ Compete with

ROH + B  RO- + BH+

Acid
 The effect of this is that the inflection in
the titration curves for very weak acids and
very weak bases is small, thus making end-
point detection more difficult.
A general rule is that bases with pKa<7
(morphine, diazepam) or acids with pKa>7
(ascorbic acid, phenytoin) cannot be determine
accurately in aqueous solution.
Various organic solvents may be used to
replace the water since they compete less
effectively with the analyte for proton donation
and acceptance.
Fig. pKa values for some
acidic and basic drugs.
 Phenol (pKa= 9.9, Solubility in water:
8.3g/100ml at 20°C) , for example, cannot be
titrated as an acid in aqueous solution because
water is too acidic and present in too high a
concentration to permit the phenolate ion to be
formed by titration with the hydroxide ion.
Non-aqueous solvents also improve the
solubility of many organic compounds. Many
organic acids will dissolve more readily in
methanol.

 + H+
Titration in non-aqueous solvents: Advantages
1. Weak acids and weak bases give poor
end point during titration in aqueous solutions.
Far more satisfactory end point found when
titrations are carried out in non-aqueous media.
2. Many compounds are insoluble in water
and soluble in organic solvent, thus permit their
titration in non-aqueous media.
Non-aqueous titration of weak acids:
Titrants:
There are several titrant available for the
titration of acids:
- Methoxides of the alkali metals (CH3ONa)
- Potassium hydroxide in methanol (KOH+CH3OH)
- Tetrabutyl ammonium hydroxide [CH3(CH2)3]4NOH

Methoxides of the alkali metals:

- These are most commonly used.
- They are prepared by dissolving the
appropriate amount of alkali metal (Na, K, Li) in
a mixture of benzene and methanol.
Preparation of a 0.1 N solution:
Mixture of 40 ml methanol and 50 ml dry
benzene in Erlenmeyer flask

Add 4 gm of K or 2.3 gm of Na or 0.6 gm of Li
to the flask (the metal should be freshly cut and
have to add slowly)

When metal has dissolved, have to add sufficient methanol until
clear solution

Then add dry benzene slowly with continuous shaking until the
solution appears cloudy

Repeat the addition of methanol followed by benzene until 1 liter
clear solution has been prepared.
Precaution:
1. Minimum amount of methanol have to
use to ensure clear solution.
2. Have to store in sodium free glass.
3.Have to protect it from atmospheric CO2.

Standardization:
Titrants are usually standardized by using
reference standard- benzoic acid.
0.5% thymol blue in anhydrous methanol
used as indicator.
Dimethylformamide used as solvent for
the titration.
Apparatus:
Burettes:
1. Titrant must be
protected from atmosphere to
obtain highest degree of
precisions. It is preferable to Burette
store the titrant in a burette
with a reservoir sufficiently
large to contain 1 liter.
2. The reservoir is
flushed out with nitrogen and a
layer of nitrogen is laid over
the titrant.
3. Teflon stopcocks can
Fig: Apparatus for the titration
be used. of weak acids
Titration vessel:

1. A three-necked flask
would be ideal, as it provide an
inlet and outlet for the used
inert gas (nitrogen) as well as
A three-necked flask
an opening to admit the burette
tip.
2. An Erlenmeyer flask equipped with a
rubber stopper which has been drilled to permit
passage of the burette tip is satisfactory. A
groove (channel) must be notched in the
stopper to provide an air vent.
3. In all instances, an electromagnetic
stirring apparatus is essential.
Solvents:
The solvents (protophilic solvents) most
commonly employed in the titration of weak
acids are-
Dimethylformamide O=CH-N(CH)3
n-butylamine
Pyridine
Ethylenediamine H2N-CH2-CH2-NH2
Acetone
Morpholine
Practical example:
The titration of benzoic acid in n-butylamine by
sodium methoxide.
+
C6H5COOH + CH3(CH2)3NH2  CH3(CH2)3NH3 + C6H5COO-
+
CH3(CH2)3NH3 + CH3O-  CH3OH + CH3(CH2)3NH2

C6H5COOH + CH3O-  CH3OH + C6H5COO-

The titration is performed by the direct

withdrawal of the proton from the benzoic acid
by the methoxide.
Non-aqueous titration of weak bases
Titrants:
Solutions of perchloric acid (HClO4) in
either glacial acetic acid (CH3COOH) or dioxane
are used almost exclusively for the titration of
bases in non-aqueous titrimetry.

In glacial acetic acid, the titrating species

will be onium ion.

CH3COOH + HClO4  CH3COOH2+ + ClO4-

‘onium’ ion
In dioxane, the titrating species will be mono-
or diprotonated dioxane.

H
+
O O
-
HClO4 + ClO4 +
O O
Dioxane Mono-protonated dioxane

The usual concentration of titrant used is

0.1N to 0.05N. It may be diluted one (0.001N)
Apparatus:
Burettes:
Having teflon stopcock are most suitable.
Necessity of lubricating the teflon stopcock
is eliminated.
Capacity of burette may be from 1ml to
10ml.
Titration vessels:
It is not essential to protect the titration
from environment.
So Erlenmeyer flasks or beakers may be
used.
Solvents:
Glacial acetic acid alone, or
Glacial acetic acid combined with aprotic
solvent is commonly used.
Aprotic solvents commonly used are
chloroform, benzene.
Practical example:
 Titration of ephedrine alkaloid in glacial
acetic acid by acetous perchloric acid.
 Titration of ephedrine alkaloid by the
solutions of perchloric acid (HClO4) in dioxane.
Here aprotic solvents are used as solvent.

See reactions and description

Ref: Pharmaceutical chemistry by Chatten, Volume 1, pp 236-237
OH

H CH3

Ephedrine pKa = 9.6