Non Aqueous titration
Content
• Theory of non-aqueous titration
• Different types of solvent used
Aprotic solvents
Protophilic
solvents
Protogenic
solvents
Amphiprotic
solvents
• Advantages and disadvantages of solvents
• Indicators used in non-aqueous titration
• Classification of non-aqueous titration
• Preparation and standardisation of 0.1M perchloric acid
• Application of non-aqueous titration
• Advantages and disadvantages of non-aqueous titration
Learning
Objectives
At the end of this
lecture, the student will be able to
• Explain the theory of non-aqueous titration
• Discuss about the solvents used in non-aqueous titrations
• Define and classify the different types non aqueous
titration
• Preparation and standardisation of 0.1M perchloric acid
• Outline the applications of non-aqueous titration
Introduction
Some compounds posed two vital problems of quality control,
both in pure and dosage forms by virtue of their inherent characteristics,
namely:
• Poor solubility, and
• Weak reactivity in aqueous medium
Such compounds were estimated with great difficulty
• Example 1: Amine
salts—It is first changed to the water-soluble free base, extracted with an
appropriate-organic solvent and treated with an excess volume of standard acid;
subsequently, the solvent was evaporated, and the remaining acid determined
with a standard base.
• Example 2: Sodium
salts—It is first acidified to release the water- insoluble organic acid,
extracted with a suitable organic solvent, the solvent was removed and the
residue was subsequently dried and weighed.
• Example 3: Nitrogen
containing compounds—They are estimated by micro Kjeldahl’s Method.
Nevertheless, such specific quantitative methods gave rise
to certain serious anomalies and drawbacks
In order to overcome these shortcomings the non-aqueous
titrations were introduced
• Non-aqueous titrations have the following advantages,
namely:
Elimination of poor solubility of substances
Enhancement of weak reactivity of substances
Selective titration by using suitable solvent and titrant
of acidic/basic components of physiologically active moiety of a salt
• Maintenance of speed, precision, accuracy and simplicity
at par with classical methods of analysis
• Weak bases which have Kb values less than 10–6
can be titrated satisfactorily by non-aqueous titrations
• The reason being that in aqueous medium and at higher Kb
values (> 10–6) the solvent water competes progressively with the
basic species in solution for the proton of the solvent
Theory of
Non Aqueous Titration
The theory of non-aqueous titration is based on Lowry-Bronsted theory
According to this theory:
• An acid is a proton donor and
• A base is a proton acceptor
Therefore,
• When an acid HA undergoes dissociation it gives rise to a
proton and the conjugate base A of the acid:
HA ó H+
+ A–
Acid Proton Base
• In other words, the liberated base A shall unite with a
proton to give the corresponding conjugate acid HA of the base A because every
base has its conjugate acid and vice versa
• Hence, from the above definitions it may be implied that:
(a) An acid:
could be either an electrically neutral molecule: e.g., HNO3; or a negatively
charged anion e.g., HSO4–; or a positively charged cation e.g.,
C6H5NH +, H3O+;
(b) A base: could
be either an electrically neutral molecule e.g., C6H5NH2; or an anion e.g., Cl–,
NO3–
Note: Substances which are potentially acidic can function
as acids only in the presence of a base to which they can donate proton
Solvents
Used in Non-Aqueous Titration
Different types of solvents used in non-aqueous titration
are classified as:
• Aprotic solvents
• Protophilic solvents
• Protogenic solvents
• Amphiprotic solvents
Aprotic
solvents:
– Neutral
– Chemically inert
– Low dielectric
constant
– Do not react with acids
or bases. So do not favor ionization
Examples: Toluene
and chloroform
Protophilic
solvents:
• Basic in character and reacts with acids to form solvated
protons
HB + Sol ó Sol.H+ + B-
Acid basic
Solvent Solvated
proton conjugate base
2 Differentiation –
levelling effect (Kd ~ 10-12 − can be measured)
a) Differentiation
effect:
In water: HClO4 ≈ HCl ≈ HNO3
In CH3COOH: HClO4 >
HCl > HNO3
In HF: medium >
weak > base
acid
Conclusion:
Strong acids (in water) can separetely be measured in acidic
solvents
Strong bases can separately be measured in basic solvents
b) Levelling effect:
In Water: HCl > CH3COOH >
benzoic acid
In pyridine: HCl ≈ CH3COOH ≈
benzoic acid
Conclusions:
Weak acid (in water) can be measure in basic solvents
Weak bases can separately be measure in acidic solvents
Protogenic
solvents
• Are acidic substances
• They exert a leveling effect on bases
Examples: Sulfuric acid
Amphiprotic
solvents
• Have both
– Protophilic and
– Protogenic
properties
Examples: Water,
Glacial acetic acid, Alcohols
Explanation: How
glacial acetic acid act as amphiprotic solvents?
HCLO4 + Pyridine in glacial acetic acid
acid: HClO4 + CH3COOH ó ClO4– + CH3COOH2
base: Py +
CH3COOH ó PyH+ +
CH3COO−
ClO4 − + CH3COOH2+
+ PyH + CH3COO– ó
PyH+…ClO4–
+ 2CH3COOH
Advantages
of Using Non-Aqueous Solvents
• Determination of organic acids and bases which have a
limited solubility in water.
Disadvantages
of Using Non-Aqueous Solvents
• Expensive
• Volatile
• Toxic
• Removal of water is necessary, can take water (humidity)
from the air
Choice of
Solvents in Non-Aqueous Titration
• Pure, nontoxic, miscible with titrant solute
• High dielectric constant
• Depending upon the solubility and nature of sample under
investigation
– For weak acid— basic solvents like DMF, pyrdine are used
– For weak base—- acidic solvent like glacial acetic acid
is used
• No side reactions between the sample and titrant
• The solvent chosen should not affect the sharpness of endpoint
during titration
Examples of
Non-Aqueous Solvents
Glacial Ethanoic
Acid:
• The most frequently used non-aqueous solvent
• Before it is used it is advisable to check the water
content. This may be between 0.1% and 1.0%
Dimethylformamide:
• It is a protophillic solvent, which is frequently employed
for titrations between, for instance, benzoic acid and amides
• Although end points may sometimes be difficult to obtain
Acetonitrile: (methyl
cyanide, cyanomethane)
• It is frequently used with other solvents such as
chloroform and phenol and especially with ethanoic acid
• It enables very sharp end points to be obtained in the
titration of metal ethanoates when titrated with perchloric acid
Dioxane:
• It is another popular solvent, which is often used in place
of glacial ethanoic acid when mixtures of substances are to be quantified
• Unlike ethanoic acid, dioxane is not a levelling solvent
and separate end points are normally possible, corresponding to the individual
components in the mixtures
Alcohol:
• Salts of organic acids, especially of soaps are best
determined in mixtures of glycols and alcohols or mixtures of glycols and
hydrocarbons.
• The most common combinations are ethyleneglycol
(dihydroxyethane) with propan-2-ol or butan-1-ol
• The combinations provide admirable solvents for both the
polar and non-polar ends of the molecules
Indicators
Used in Non-Aqueous Titration
|
Indicator |
Color change |
Color change |
Color change |
|
|
Basic |
Neutral |
Acidic |
|
Crystal violet (0.5 per cent in glacial acetic acid) |
violet
|
blue-green |
yellowish- green |
|
α-Naphtholbenzein (0.2 per cent in glacial acetic acid) |
blue or blue- green |
orange
|
dark-green
|
|
Oracet Blue B (0.5 per cent in glacial acetic acid) |
blue |
purple
|
pink |
|
Quinaldine Red (0.1 per cent in methanol) |
magenta |
|
almost colorless |
Non Aqueous
Titration: Classification
Classification in
general:
• Acidimetry:
Weakly basic substances: alkali salts of organic acids, amines, amine salt,
heterocyclic nitrogen
Titrant: used is
acetous perchloric acid
Solvents: glacial
acetic acid, acetic anhydride
Indicators:
Crystal violet, methyl rosaniline, quinaldine red
• Alkalimetry: Weakly
acidic substances: sodium benzoate, sulfanilamides
Titrant: Sodium
methoxide, lithium methoxide, sodium amino methoxide
Solvents: DMF,
pyridine, ethylenediamine,n-butyl amine, morpholine
Indicators:
Quinaline red, thymol blue Azoviolet, O-nitroaniline
Titration
of Alkali Metal Salts of Organic Acids
Application: Preparation
of 0.1M Perchloric acid
Slowly add 8.5 ml of
72% perchloric acid
â
900 ml of glacial
acetic acid with continuous and efficient mixing
â
30 ml of acetic
anhydride
â
Adjust the final
volume to 1000 ml with glacial acetic acid
â
Allow the solution to
stand for 24 h before use
Role of acetic anhydride is to remove the water molecule
• Alkali and alkaline earth salts of organic acids function
as bases in acetic acid solution
RCOOM ó
RCOO- + M+
CH3COOH2 + ó
RCOOH + CH3COOH
Hence potassium hydrogen phthalate is used for standardising
acetous perchloric acid
Standardization of 0.1
M perchloric acid
Dilute up to the mark with glacial acetic acid
Warm until salt has dissolved
Add glacial acetic acid about 25ml
Accurately weigh (0.5g) of potassium hydrogen phthalate into
a 100 ml volumetric flask
Cool and titrate against 0.1M acetous perchloric acid using
2 drops of 0.5%w/V of acetous crystal violet until blue changes to blue green
Reactions Involved in
Standardization of Perchloric acid
HClO4 + CH3COOH ó
CH3COOH2 + + ClO4−
CH3COOH2 + + CH3COO– ó 2 CH3COOH
KHC8H4O4 + HClO4 ó
C8H6O4 + KClO4
Estimation
of Sodium benzoate
HClO4 ó H+ + ClO4–
CH3COOH + H+ ó CH3COOH2+
•Titration
Nonaqueous titration
•Method
Acidimetry
•Indicator
Crystal violet
•End point Violet to emerald green
Titration
of Amines and Amine Salts of Organic Acids
• A wide range of primary, secondary and tertiary amines can
be assayed by acetous per chloric acid
Examples: Adernaline, Chlordiazepoxide, Metronidazole —
etc
Example: Adernaline
Titration
of Primary Amines
Example: Methlyldopa
R.NH2 + HClO4 → [R.NH3] + + ClO4–
• Specific reaction between methyldopa and perchloric acid is
expressed by the following equation
Titration
of Halogen Acid Salts of Bases
• The halide ions chloride, bromide and iodide are too
weakly basic to react quantitatively with acetous perchloric acid
• Addition of mercuric acetate to a halide salt replaces the
halide ion by an equivalent quantity of acetate ion, which is a strong base in
acetic acid
Example: Assay of
ephedrine hydrochloride
Chemical reaction
involved in above method
2R.NH2.HCl ó
2RNH3 + + 2 Cl–
(CH3COO) 2 Hg ( Undissociated) + 2 Cl – →HgCl2
(Undissociated) + 2 CH3COO–
2CH3COOH2 + 2CH3COO- ó 4CH3COOH
Examples: Ephedrine hydrochloride, Chloropromazine
hydrochloride —etc
Example –Ephedrine
hydrochloride
Alkalimetry:
• Weakly acidic substances are determined by non-aqueous
titration using potassium, sodium or lithium methoxide in toluene-methanol
• Or alternatively with tetrabutylammonium hydroxide in
methanol
• Above titrant is used in the assay of cyclic imides
(Ethosuximide), thiazides Hydrochlorthiazide), sulphonamides (Sulphafuruzole)
and phenols (Dichlorophen)
Preparation
of 0.1 N Sodium Methoxide
• Material Required:
Absolute methanol, dry toluene, Potassium metal.
• Procedure:
Add into a dry flask, a mixture of methanol (40 ml) and
dry toluene (50 ml) and cover it loosely
Carefully add freshly cut pieces of sodium metal (2.3 gm)
to the above mixture gradually with constant shaking. After complete
dissolution of potassium metal
Add enough absolute methanol to yield a clear solution
Toluene 50 ml is added with constant shaking until the mixture
turns hazy in appearance
The process is repeated by the alternate addition of
methanol and benzene until 1 litre of solution is obtained, taking care to add
a minimum volume of methanol to give a visible clear solution
Standardization
of 0.1N Sodium Methoxide
• Material Required:
Dimethylformamide (DMF): 10 ml; thymol blue (0.3% in MeOH); 0.1 N lithium methoxide
in toluene methanol; benzoic acid: 0.6 g.
• Procedure:
Transfer 10 ml of DMF in a conical flask and add to it 3
to 4 drops of thymol blue
And first neutralize the acidic impurities present in DMF
by titrating with 0.1 N lithium methoxide in toluene-methanol
Quickly introduce 0.06g of benzoic acid and titrate
immediately
with methoxide in toluene-methanol
• Caution: Care
must be taken to avoid contamination of neutralized liquid with atmospheric
carbon dioxide
Chemical Equations:
The various equations involved in the above operations are summarized as stated
below:
(i) Na + CH3OH →
CH3ONa + H↑
Precaution: It is
an exothermic reaction and hence, special care must be taken while adding the
metal into the dry solvent in small lots at intervals with adequate cooling so as
to keep the reaction well under control.
(ii) H2O +
CH3ONa → CH3OH
+ NaOH
H2CO3 + 2CH3ONa →
2CH3OH + Na2CO3
Precaution: The
clear solution of sodium methoxide must be kept away from moisture and
atmospheric CO2 as far as possible so as to avoid the above two chemical
reactions that might ultimately result into the formation of turbidity.
Chemical equations:
For Standardization
Step 1: It shows the solution of benzoic acid (primary
standard) in DMF C6H5COOH +
H—CON(CH3)2 ↔ HCON+H(CH3)2+C6 H5 COO-
DMF
Step 2: It depicts ionization of sodium methoxide
CH3ONa ↔ CH3O- + Na+
Step 3: It
illustrates the interaction between the solvated proton and the methylated ion
HCONH+(CH3)2 + CH3O – → HCON(CH3)2 + CH3OH
Summarised whole equation is:
C6H5COOH + CH3ONa →
C6H5COONa + CH3OH
In summing up, the net reaction between the water in the
solvent (DMF) and the titrant is equivalent to the volume of sodium methoxide
consumed by DMF or may be considered as a blank determination.
Advantages
of Non Aqueous Titrations
1) Organic acids and bases that are insoluble in water are
soluble in non- aqueous solvent
2) Organic acid, which is of comparable strength to water,
can be titrated easily in non-aqueous solvent. Bases also follow the same rules
3) A non-aqueous solvent may help two are more acids in
mixture. The individual acid can give separate end point in different solvent
4) By the proper choice of the solvents or indicator, the
biological ingredients of a substance whether acidic or basic can be
selectively titrated
5) Non aqueous titrations are simple and accurate, examples
of non-aqueous titration are: Ephedrine preparations, codeine phosphate in APC,
tetracycline, teramycin, Antihistamines and various piperazine preparations
Applications
of Non Aqueous Titration
Sodium acetate
CH3COONa + HClO4 → CH3COOH + NaClO4
Chemical equation for standardisation:
HClO4 + CH3COOH ó CH3COOH2 + + ClO4−
CH3COOH2 + + CH3COO– ó 2 CH3COOH
KHC8H4O4 + HClO4 ó C8H6O4 + KClO4
Indicator
used in non-aqueous titration
|
Name of Substance |
Indicator Employed |
|
Amantadine hydrochloride |
Crystal violet |
|
Chlorpromazine hydrochloride |
Methyl orange |
|
Clonidine hydrochloride |
α -Naphthol benzein |
|
Cyproheptadiene.HCl |
Crystal violet |
|
Ephedrinehydrochloride |
Crystal violet |
|
Acetazolamide |
Potentiometric determination |
|
Bendrofluazide |
Azo violet |
|
Allopurinol |
Thymol blue |
|
Mercaptopurine |
Thymol blue |
|
Amylobarbitone |
Quinaldine Red |
|
Nalidixic acid |
Thymolphthalein |
Summary:
• Non aqueous titrations: applied for estimation of weak
acidic or basic substances and water insoluble substances
• Theory of non-aqueous titration is based on Bronsted Lowry
concept
• Different types of solvent used are: Aprotic, protophilic,
protogenic and amphiprotic solvents
• Indicators: Crystal violet, α-Naphtholbenzein, Oracet Blue
B, Quinaldine Red
• Types of non-aqueous titration applied for different
compounds:
1. Alkalimetry
2. Acidimetry
3. Titration of alkali metal salts of organic acids
4. Titration of amines and amine salts of organic acids
5. Titration of halogen acid salts of bases
• Perchloric acid can be standardised by using potassium
hydrogen phthalate
• Applications: Sodium benzoate, ephedrine hydrochloride,
Phenobarbitone