Non-aqueous acid base titration and analysis.ppt

Non-aqueous Acid Base Titrimetry

Non-aqueous acid base titrimetry
Titration is carried out in a non-aqueous medium (other
than water).
Advantages:
•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 or degraded by water.
•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.
• It has two major limitations:
 First, limited to water or aqueous solutions.
 Second, practically limited to dissociated or ionic
acids and bases that contained H+
ion or OH-
ion,
respectively. For example, 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.
HA  H+
+ A-
B + H+
 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-
).
Bronsted-Lowry theory

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.

• Lewis acid is a substance that can accept a pair of
electrons to form a covalent bond.
• 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.
Lewis 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.
Strength of acids and bases

• 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
(appeared as
strong acid)
Basic
solvent
Solvated
proton
Conjugated
base of 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
(appeared as strong
base)
From
solvent
Conjugated
acid of 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 solution, actual titrating species is 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.

Solvents used in Non-aqueous titration
Solvents used in Non-aqueous titration
•Glacial acetic acid: It is 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% water.
•Acetonitrile: 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 ethanoate when titrated with perchloric acid.

• Alcohols (isopropyl alcohol, n-butyl alcohol): Salt of organic
acids can be determined in mixtures of glycols and alcohols or
mixtures of glycols and hydrocarbons. The most common
combinations are ethylene glycol with propan-2-ol or butan-1-ol.
• Dimethyl formamide (DMF): It is a protophilic solvent,
employed for the titration of benzoic acid, amides.
• Dioxane: It is often used in place of glacial acetic acid when
mixtures of substances are to be quantified. Unlike acetic acid,
dioxane is not a levelling solvent and produces separate end points,
corresponding to the individual components in the mixtures.
Solvents used in Nonaqueous titration
Solvents used in Nonaqueous titration

Theory of non-aqueous acid base titration
In aqueous titration, water behaves both as a weak acid
and a weak base which 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

• Therefore, 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 do not compete with the analyte for proton
donation and acceptance.

pKa values for some acidic and basic drugs

Terminology and Methodology of Titration
• Preparation of titrant
• Standardization of titrant
• Choice of solvents and indicators
• Final titration

Protophilic solvents are 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
Solvents
Non-aqueous titration of weak acids:

Non-aqueous titration of weak acids:
Titrants:
There are several titrants available for the titration of acids:
- Methoxides of the alkali metals (e.g, CH3ONa) in toluene
- Tetrabutyl ammonium hydroxide in pyridine [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 toluene and methanol.

Preparation of Titrants (0.1 N alkali metal in methanol and toluene

When metal has dissolved, have to add sufficient methanol until clear solution

Then add dry toluene slowly with continuous shaking until the solution appears
cloudy

Repeat the addition of methanol followed by toluene until 1 liter clear solution has
been prepared.
Mixture of 40 ml methanol and 50 ml dry toluene 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)

• Minimum amount of methanol have to use to
ensure clear solution.
• Have to store in sodium free glass.
• Have to protect it from atmospheric O2.
Precaution:
• Titrants are usually standardized by using reference
standard-benzoic acid.
• About 0.5% thymol blue in anhydrous methanol used
as indicator.
• Dimethylformamide used as solvent for the titration.
Standardization:

Standardization Steps of 0.1 N methoxide solution
• Take 10 ml of DMF in a conical flask and add to it 3 to 4
drops of thymol blue.
• Quickly introduce 0.6 g of benzoic acid and titrate
immediately with methoxide in toluene methanol.
Caution:
Caution: Care must be taken to avoid reaction between titrant
and atmospheric carbon dioxide.

Reaction during the standardization of titrant
The titration of benzoic acid in DMF by sodium
methoxide.
C6H5COOH + N(CH3)2CHO  N+
H(CH3)2CHO + C6H5COO-
N+
H(CH3)2CHO+ CH3O-
 CH3OH + N(CH3)2CHO
C6H5COOH + CH3O-
 CH3OH + C6H5COO-
The titration is performed by the direct withdrawal of the
proton from the benzoic acid by the methoxide.

Burettes:
•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.
•The reservoir is flushed out with nitrogen and a
layer of nitrogen is laid over the titrant.
•Teflon stopcocks can be used.
Apparatus
Fig: Apparatus for the titration
of weak acids
Burette

Titration vessel:
• 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
• 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.
• In all instances, an electromagnetic stirring
apparatus is essential.
Apparatus

Assay of Ethosuximide
Assay of Ethosuximide
• Materials:
– Ethosuximide: 0.2 g
– Dimethylformamide: 50 ml
– Indicator [azo-violet (0.1% w/v in DMF): 2 drops]
– Titrant (sodium methoxide 0.1 N) Anticonvulsant
Procedure
•Weigh accurately about 0.2 g of ethosuximide and dissolve in 50 ml of
dimethylformamide.
•Add 2 drops of azo-violet solution and titrate with sodium methoxide to a deep
blue end point
•Take precautions to prevent absorption of atmospheric moisture and carbon
dioxide.
•Each ml of 0.1 N sodium methoxide is equivalent to 0.01412 g of C7H11NO2.
•Determine the potency of ethosuximide

1000 ml 1N sodium methoxide = 141 g ethosuximide
1 ml 0.1 N sodium methoxide = (141/1000)*0.1 = ???

Titrants:
Titrants:
• HClO4 in glacial acetic acid or dioxane
• HCl in propylene-glycol /chloroform mixture
Non-aqueous titration of weak bases
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.

Titrants:
•In glacial acetic acid, the titrating species will be onium ion.
•In dioxane, the titrating species will be mono- or diprotonated
dioxane.
•Usual concentration of titrant is 0.1N to 0.05N. It may be diluted to
0.001N.
CH3COOH + HClO4  CH3COOH2
+
+ ClO4
-
‘onium’ ion
O
O
HClO4
+
O
O
ClO4
+
-
H
+
Dioxane Mono-protonated dioxane

Materials:
– Perchloric acid (70.0 to 72.0%)
– Glacial acetic acid
– Acetic anhydride
Q. How can you calculate the molarity of 70% HClO4?
Hint: [(% x d) / MW] x 10 = Molarity]
Density of HClO4= 1.77 g/cm3
Q. How can you calculate the volume required to prepare 0.1 N
1L HClO4 solution?
Preparation of titrant for weak bases

100 ml solution possess 70 g perchoric acid
1000 ml = 1 L ….. 700g perchloric acid* 1.77 g/cm3
=
Molecular weight = 100.46 g/mol

• Gradually mix 8.1 ml of perchloric acid to 900 ml of glacial acetic acid
with vigorous and continuous stirring.
• Add 30 ml acetic anhydride and make up the volume to 1 litre with
glacial acetic acid and allow to stand for 24 hours before use.
• Acetic anhydride reacts with the water (approx. 30%) in perchloric
acid and some traces in glacial acetic acid thereby making the resulting
mixture practically anhydrous.
Procedure of titrant preparation for weak bases

STANDARDIZATION OF 0.1 N PERCHLORIC ACID
Usually potassium hydrogen phthalate (or potassium biphthalate, KHC8H4O4) is
employed as a standardizing agent for acetous perchloric acid.

Procedure
Procedure
•Weigh accurately about 0.5 g of potassium hydrogen phthalate
in a 100 ml conical flask.
•Add 25 ml of glacial acetic acid and attach a reflux condenser
fitted with a silica-gel drying tube.
•Warm until the salt gets dissolved completely
•Cool and titrate with perchloric acid by using any of the two
indicators :
– acetous crystal violet (0.5% w/v) or acetous oracet blue B

CHOICE OF INDICATORS
CHOICE OF INDICATORS
• A number of indicators stated below are commonly used in non-aqueous
titrations.
• It is, however, necessary to mention that same indicator must be used to carry
out the standardization, titration and neutralization of mercuric acetate solution.

Solvents:
•Glacial acetic acid alone
•Combination of glacial acetic acid and aprotic
solvent (chloroform, benzene).

Assay of Methyldopa
Assay of Methyldopa

Materials
Materials
– Methyldopa 0.2 g
– Anhydrous formic acid: 15 ml
– Glacial acetic acid: 30 ml
– Dioxane: 30 ml
– Perchloric acid (0.1 N)
– Crystal violet solution.
Procedure
Procedure
– Dissolve 0.2 g methyldopa in 15 ml anhydrous formic acid, 30 ml of glacial
acetic acid and 30 ml dioxane.
– Add 0.1 ml of crystal violet solution and titrate with 0.1 N perchloric acid.
– Each ml of 0.1 N perchloric acid is equivalent to 0.02112 g of C10H13NO4.
Assay of Methyldopa
Assay of Methyldopa

Titration of Halogen Acid Salts of Bases
Titration of Halogen Acid Salts of Bases
• Halide ions namely, chloride, bromide and iodide are very weakly basic in character,
therefore, they cannot react quantitatively with acetous perchloric acid.
• To overcome this problem, mercuric acetate is usually added to a halide salt thereby
causing the replacement of halide ion by an equivalent amount of acetate ion, which
serves as a strong base in acetic acid as shown below:

Assay of amitriptyline hydrochloride

Materials
Materials
– Amitriptyline hydrochloride: 1.0 g
– Mercuric acetate
– Crystal violet
– Perchloric acid (0.1 N)
– Glacial acetic acid
Procedure
Procedure
•Dissolve about 1.0 g of amitriptyline hydrochloride in 50 ml glacial acetic acid.
•Warming slightly, if necessary, to prepare the solution.
•Cool and add mercuric acetate solution (10 ml)
•Add two drops of crystal violet solution and titrate with 0.1 N perchloric acid to a green end-
point.
•Each ml of 0.1 N perchloric acid is equivalent to 0.03139 g of C20H23N. HCl.

EFFECT OF TEMPERATURE ON ASSAYS
EFFECT OF TEMPERATURE ON ASSAYS

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.

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

Disadvantages of nonaqueous titration
Disadvantages of nonaqueous titration
• Expensive
• Volatile
• Toxic
• Removal of water is necessary.

Non-aqueous acid base titration and analysis.ppt

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