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Non-aqueous Acid-Base

Muh. Nur Khoiru Wihadi, S.Pd.,

Non-aqueous Titrations
Non-aqueous titrations is the most titrimetric
procedure used in pharmacopoeial assays and serves
a double purpose, as it suitable for the titration of
weak acids and bases and provides a solvent in which
organic compounds are soluble.
The most commonly used procedure is the titration of
organic bases with perchloric acid in acetic acid
Water behaves as both a weak acid and weak base;
thus in aqueous environment, it can compete
effectively with very weak acids and bases with regard
to proton donation and acceptance.

Non-aqueous Titrations

Non-aqueous Titrations
The effect of this is that the inflection in the titration
curves for weak acids and weak bases is small,
because they approach the pH limits in water of 14
and 0 respectively, thus making end-point detection
more difficult.
A general rule is that bases with pKa < 7 and acids
with pKa > 7 cannot determined accurately in
aqueous solution
Various organic solvents may be used to replace
water since they compete less effectively with the
analyte or proton donation and acceptance.

Non-aqueous Titrations
Advantages of non-aqueous titrations:
1) Provide suitable solvent
2) Increase the basicity or acidity of the analyte.
No water to interfere with titration, which would
give sharper inflection region

Non-aqueous Titrations
Non-aqueous titration of weak bases
Solvent: neutral or acidic
Acetic acid is the most common solvent for weak base
titration because it does not compete effectively with weak
bases for protons.
Only very strong acid (like perchloric acid) will protonate
acetic acid:
onium ion

As the CH3COOH2+ ion can instantly donate its proton to a

base, therefore, a solution of perchloric acid in glacial acetic
acid, behaves as a strongly acidic solution.

Non-aqueous Titrations
Benzene and chloroform (aprotic solvent) can also be
used as neutral solvents
Since dissociation is not an essential preliminary to
neutralization, aprotic solvents are added to ionizing
solvents to depress solvolysis of the neutralization
product and so sharpen the end point
Butanol can be added to enhance the solubility of
insoluble substances.
Titrant: most commonly used titrant is perchloric acid.
The choice of the titrant here is more crucial than in the
case of aqueous titration (How?)
Acetic anhydride, measured but not in excess amount
(why?), is used to remove water from aqueous
perchloric acid (the commercially available form).
Standarized with KHP

Non-aqueous Titrations

Crystal violet (most common one)

When a base is in the form of a chloride or bromide salt,

the counter ion has to be removed prior to titration by
addition of mercuric acetate.
2RNH3+Cl- + Hg(CH3COO)2


HgCl 2 + 2RNH3+ + 2CH3COO-


However, when the base in the form of a salt of a weak

acid (tartrate, acetate, or succinate) removal of an anionic
counter ion prior to titration is not necessary (why?)
Blank Titration : It is usually carried out to account for the
possible reaction of atmospheric moisture with the titrant
perchloric acid

Non-aqueous Titrations
Example, Titration analysis of pyridine (very weak
base, analyte) dissolved in acetic acid (acidic
solvent) titrated with perchloric acid (titrant)
acetic acid.
solution, in
Analyte solution, in

The whole idea of non-aqueous titration is to increase the acidity

and basicity for
both the solvent and analyte by generating more acidic and basic
species, i.e.,
CH3COOH2+ is more acidic than HClO4, and acetate (CH3COO-) is
more basic then pyridin (C6H5N). Therefore, titration of CH3COOH2+

Non-aqueous Titrations
Non-aqueous titration of weak acids
1) alcohol (very weak acids, pKa 16 20, e.g.
methanol, ethanol, t-butyl alcohol),
2) amines (weak bases, e.g. ethanediamne, nbutyl amine, pyridine) or
3) aprotic solvents (N,N-dimethyl formaide (DMF),
aceton, methylethayl keton)
which does compete strongly with weak acid for
proton donation

Non-aqueous Titrations
Lithium methoxide (CH3OLi), Sodium or potassium
methoxide (CH3ONa, CH3OK), tetrabutyl
ammonium hydroxide
Generally, drugs can be titrated directly in a
dosage form
If the dosage form is aqueous, analyte should be
extracted to non-aqueous solvent

Example, Titration analysis of benzoic acid(weak

acid, analyte) dissolved in DMF titrated with
sodium methoxide (titrant) dissolved in methanol.

Analyte solution, in
Titrant solution, in


Non-aqueous Titrations

Practical application
Example 1. 4 g tablet of methacholine cloride (195.69 g /
mol), dried and stored in a vacuum desiccator, dissolved in
50 ml of glacial acetic acid, 10 ml of mercuric acetate
solution and one drop of crystal violet was added and then
titrated with 56 ml of 0.1 M perchloric acid to a blue-green
end point. Blank titration was conducted and 1.7 ml of
perchloloric aid used. Calculate % w/w of methacholine
O cloride.
+ Hg(CH COO)
HgCl + 2CH COO +


2CH 3 COOH2 + + 2CH 3COO From acetous HClO4 From the above rxn


Non-aqueous Titrations

Practical application
Example 2. 0.5 g tablet of Ethosuximide (141.17
g/mol) dissolved in 50 ml of dimethylformamide, 2
drops of azo-violet solution was added and tirated with
12 ml of 0.1 N sodium methoxide to a deep blue end
point. 0.6 ml was needed in blank titration. Calculate
Hthe % w/w of thosuximide.

O + CH3ONa



Example for Kjeldahl method

0.9092-g sample of a wheat flour was analyzed by
the Kjeldahl procedure. The arnmonia formed was
distilled into 50.00 mL of 0.05063 M HCI, and then
back titrated with 7.46-mL of 0.04917 M NaOH.
Calculate the percentage of protein in the flour.
Note. Since most proteins contain approximately the same
percentage of nitrogen, multiplication of this percentage by a
suitable factor (6.25 for meats, 6.38 for dairy products, and
5.70 for cereals) gives the percentage of protein in a sample.
%N = Mass of N/ Sample mass x 100%
% of crude protein = %N x F