1. Non-Aqueous Titration
BY- SANCHIT DHANKHAR
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2. 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.

3. 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

4. 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.

5. 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-

6. 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.

7. Acid: HA  H+ + A-
Base: B + H+  BH+
An acid ‘HA’ dissociates to give a proton H+ and
its conjugate base A-.
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.

8. 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-).
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9. 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.

10. 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.

11. 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.
Strength of acids and bases

12. 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.

13. 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.

14. 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

15. 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
(appeared as
strong acid)
Basic
solvent
Solvated
proton
Conjugated
base of acid

16. 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.
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17. 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
(appeared as strong
base)
From
solvent
Conjugated
acid of base

18. 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

19. 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.
In such a solution then, the actual titrating
species is the ion CH3COOH2
+ which readily
donates its proton to a base.

20. 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
+
H2O + B  OH- + BH+ Compete with
ROH + B  RO- + BH+
Base
Acid

21. 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.

22. Fig. pKa values for some
acidic and basic drugs.
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23. 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+
+

24. 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.

25. 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.

26. Preparation of a 0.1 N solution:

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.
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)

27. 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.
Precaution:
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.
Standardization:

28. Burettes:
1. Titrant must be protected
from atmosphere to obtain
highest degree of precisions. It
is preferable to 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 be
used.
Apparatus:
Fig: Apparatus for the titration
of weak acids
Burette
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29. 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 an opening
to admit the burette tip. A three-necked flask
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. 29

30. 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
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31. 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.
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32. 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

33. O
O
HClO4
+
O
O
ClO4
+
-
H
+
Dioxane Mono-protonated dioxane
The usual concentration of titrant used is
0.1N to 0.05N. It may be diluted one (0.001N)
In dioxane, the titrating species will be mono-
or diprotonated dioxane.
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34. 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.

35. Solvents:
Glacial acetic acid alone, or
Glacial acetic acid combined with aprotic
solvent is commonly used.
Aprotic solvents commonly used are
chloroform, benzene.

36. 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
N
H CH3
Ephedrine pKa = 9.6
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37. THANKYOU
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