Submitted by :Sharath .H .N M . Pharmacy

Seminar on non aqueous titration

INDEX

• Introduction• Classification of solvents• Advantages and Disadvantages of non

aqueous solvents.• Assay by Non aqueous titration.

Non aqueous titration

• Non aqueous titration is the titration of substances dissolved in solvent other than water.

• It is the most common titrimetric procedure used in pharmacopoeial assays and serves a double purpose:

• it is suitable for the titration of very weak acids and very weak bases, and it provides a solvent in which organic compounds are soluble.

. The most commonly used procedure is the titration of organic bases with perchloric acidic anhydrous acetic acid.

These assays sometimes take some perfecting in terms of being able to judge the endpoint precisely.

CLASSIFICATION of SOLVENTS

ACIDIC (protogene): proton donor H2SO4, CH3COOH, HCOOH, acetone

AMPHOTERIC (amphiprotic): alcohols, acetonitrile

BASIC (protophyl) : pyridine, liq. NH3, amins, dioxane proton acceptor

APROTIC: liquid SO2

INERT: CCl4, CHCl3, benzene, carbohydrates

• Aprotic solvents Aprotic solvents are neutral, chemically inert substances such as benzene and chloroform.

They have a low dielectric constant, do not react with either acids or bases and therefore do not favour ionization.

The fact that picric acid gives a colourless solution in benzene which becomes yellow on adding aniline shows that picric acid is not dissociated in benzene solution and also that in the presence of the base aniline it functions as an acid, the development of yellow colour being due to formation of the picrate ion.

Protophilic solvents

• Protophilic solvents are basic in character and react with acids to form solvated protons. HB + Sol . Sol . H++ B−Acid + Basic solvent ⇌ ⇌Solvated proton + Conjugate base of acid A weakly basic solvent has less tendency than a strongly basic one to accept a proton. Similarly a weak acid has less tendency to donate protons than a strong acid

Amphiprotic solvents

• Amphiprotic solvents have both protophilic and protogenic properties. Examples are acetic acid and the alcohols. They are dissociated to a slight extent. The dissociation of acetic acid, which is frequently used as a solvent for titration of basic substances, is shown in the equation below:

• CH3COOH H++ CH3COO−⇌

ADVANTAGES of USING NON-AQUEOUS SOLVENTS

☻ 1. More than 3 acids/bases can be measured in mixture due to the wider pH rangecompared to water

E.g.methyl-ethyl-ketone water0 - 25.7 pH range 0 - 14 pH range5 comp. measurable max. 3 acids (3 x ΔpH(4) = 12)HClO4 - HCl - Salicylic acid - Acetic acid - Phenol(can titrated with TBAH (C4H9)4N+OH−)

☻ 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 > baseacid

Conclusions:Strong acids (in water) can separetely be measured in acidic solventsStrong bases - ″ - in basic solvents

in water: HCl > CH3COOH > benzoic acidb) Levelling effect:

in pyridine: HCl ≈ CH3COOH ≈ benzoic acid

EXPLANATION by the protonaffinity

ADVANTAGES of USING NON-AQUEOUS SOLVENTS

Conclusions:Weak acids (in water) can be measured in basic solventsWeak bases - ″ - in acidic solvents

☻ 3. Determination of organic acids and bases which have a limited solubility in water.☻ 4. Application of new reagents and indicators is possible due to

ADVANTAGES of USING NON-AQUEOUS SOLVENTS

expensive

volatile

toxic

removal of water is necessary, can take water (humidity) from the air

DISADVANTAGES of USING NON-AQUEOUS SOLVENTS

Non-aqueous Titrations

• Theory

• 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 p Ka < 7 and acids with p Ka > 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

REACTIONS in NON-AQUEOUS SOLUTIONS

AUTOPROTOLYSIS EQUILIBRIA determines the ionic product :

2 H2O H3O+ + OH− 10−14 0 - 14 7

☻ neutralization (protolytic solvents) ≈ 90 %☻ complex formation, precipitation, redox ≈ 10 %

solvent K pH scale neutr. point

2 CH3COOH CH3COH2+ + CH3COO− 10−13 0 - 13 6,5

2 NH3 NH4+ + NH2

− 10−32 0 - 32 162 C2H5OH C2H5OH2

+ + C2H5O− 10−19 0 - 19 9,5

− pH scale depends on the value of KHL = [H2L+][L−]

NEUTRALIZATION ANALYSIS in NON-AQUEOUS SOLVENTS

REACTIONS in NON-AQUEOUS MEDIUM

E.g. HClO4 + pyridine (Py) in glacial acetic acidacid: HClO4 + CH3COOH ClO4

− + CH3COOH2+

K = [CH3COOH2+][CH3COO−] = 10−13

base: Py + CH3COOH PyH+ + CH3COO−

ClO4− +

CH3COOH2+

PyH+ + CH3COO−

PyH+ClO4− + 2 CH3COOH

2 CH3COOH

− Brönsted equation can be used− reactions take place through reaction of acids or bases with the solvents

Non-aqueous Titrations• Example, Titration analysis of pyridine (very weak base,

analyte ) dissolved in acetic acid (acidic solvent) titrated with perchloric acid (titrant ) dissolved in acetic acid.

Titrant solution, in buretteAnalyte solution, in Erlenmeyer

Titration

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 pyridine (C6H5N). Therefore, titration of CH3COOH2+ (from titrant solution) with CH3COO- (in analyte solution) will generate sharper end point.

Assay by non aqueous titrationAcidimetry in non aqueous titration—

It can be further divided in to two types, namely ;

1. Titration of primary , secondary, tertiary amines.

2. Titration of halogen acid salts of bases.

Alkalimetry in non aqueous titration---

Titration of acidic substances

Acidimetry in Non aqueous titratione g; primary amines

• methodology: • Preparation of 0.1N Perchloric acid• Standardization of 0.1N perchloric acid• Choice of indicators

Titration of primary amines

• Ex: methyl dopa • RNH2+HCLO4 [RNH2] +CLO4

-

• Specific reaction between methyl dopa and perchloric acid is given .

• Materials required: • methyl dopa 0.2g; anhydrous formic acid;15ml glacial

acetic acid; 30ml dioxane; 30ml perchloric acid and crystal violet solution.

• procedure: • weigh accurately about 0.2g and dissolve in 15ml of

anhydrous formic acid,30ml of glacial acetic acid and 30ml of dioxane . Add 0.1ml of crystal violet solution and titrate with 0.1N perchloric acid. Perform a blank determination and make any necessary correction.

• 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(which is un dissociated in acetic acid solution) to a halide salt replaces the halide ion by an equivalent quantity of acetate ion, which is a strong base in acetic acid.

• 2R.NH2.HCl 2RNH3++2Cl−⇌

• (CH3COO)2Hg(un dissociated) + 2Cl−→ HgCl2(un dissociated)+2CH3COO−2CH3COO+ +2CH3COO− 4CH3COOH⇌

Non-aqueous titration of weak acids

Solvent:

1) alcohol (very weak acids, p Ka 16 – 20, e.g. methanol, ethanol, t-butyl alcohol),

2) amines (weak bases, e.g. ethanediamne, n-butyl amine, pyridine) or

3) Aprotic solvents (N,N- dimethyl formaide (DMF), acetone, methylethaylketon) • which does compete strongly with weak

acid for proton donation

Titrant :

Lithium meth oxide (CH3OLi), Sodium or potassium meth oxide (CH3ONa, CH3OK), tetra butyl 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.

END POINT DETECTION

CHEMICAL:(INDICATORS) − crystal violet (in glacial acetic acid)

INSTRUMENTAL:

− potentiomety : glass electrode in glacial acetic acid− conductometry

− phtaleins (phenolphtalein) (e.g. in pyridine)− azo compounds (methyl red) (e.g. in alcohol)

R + C-R

R ibolya

R + R-H 2+

C-R + H+ C - R R Ribolya zöldeskék

R + R-H 2+ R-H 3+

C-R + H+ C - R + H+ C-R R R R-Hviolet green yellow

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 cloride.

O

ON

Cl2+ Hg(CH3COO)2 HgCl2 + 2CH3COO- +

O

ON

2

2CH3COOH2+ + 2CH3COO- 4CH3COOHFrom 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 the % w/w of thosuximide. HNO

O + CH3ONa CH3OH +

NaNO

ONO

ONa

References:

• Vogel's Text book of Quantitative chemical analysis by J Mendham and R C Denny

• Non aqueous titration Wikipedia• www.Google.co.in

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