Pharmaceutical Analytical Chemistry

PHCM223
Lecture 7
COMPLEX FORMATION REACTIONS (I)

Dr. Nesrine El Gohary

7th lecture
Office: B7.207
Nesrine.elgohary@guc.edu.eg
Learning outcomes

• Define complex formation reaction.

• Differentiate between types of ligands.
• Explain conditions of complexometric titrations.
• Define properties of EDTA titrations.
• Identify metallochromic indicators.
• Identify factors affecting the sharpness of the endpoint.
• Discuss different types of EDTA titrations.

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 Complex Formation Reactions
Complex formation reactions are reactions between metal ions and ligands to form
complexes.
M + Ligand [M Ligand]
Metal ion A molecule or ion that can Complex
donate a pair of electrons (lone
pair). Coordinate bond
Electron deficient species Electron rich species (nucleophile) Coordinate bond: is the
bond formed between
Electron pair acceptor Electron pair donor
electron donating group
(ligand) and an electron
M + :Ligand [M-ligand] acceptor (metal ion).
K= [M-ligand]
[M] [:Ligand]
 The equilibrium constant (Kf) for the reaction between the metal ion and the
ligand is known as a formation constant or stability constant. 3
 Complex Formation Reactions
 Complex formation reactions could be viewed as an acid-base reaction:
-

: :
+

: :
H : O-H O
Lewis base
H H
Lewis acid
Electron pair acceptor Electron pair donor

Cu++ : NH3 [Cu NH3]++

Lewis acid Lewis base
e.g. Ag+ + 2CN- [Ag(CN)2]- n=2 The coordination number (n) :
Cu2+ + 4:NH3 [Cu(NH3)4]2+ n=4 Represents the number of
Fe3+ + 6SCN- [Fe(SCN)6]3- n=6 coordinate bonds around the
Note that: central metal.
[M-ligand] complex could be neutral, positively charged or negatively charged depending
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on
the charges of the metal ion and ligand.
 Types of ligands
Ligands: The molecules or ions that surround the metal in a complex
Must contain at least one unshared pair of valence electrons
 Monodentate ligands:
Ligands which contain only one center of donation e.g.: CN-, F-, :NH3, H2O:

 Bidentate ligands:
Ligands which contain 2 centers of donation e.g. Ethylene diamine

 Multidentate ligands:
Ligands which contain more than 2 centers of donation e.g. Ethylene diamine tetraacetic acid
(EDTA)
Note that:
Multidentate ligands are called Chelating
agents. 5
EDTA is a hexadentate ligand
 Monodentate versus Multidentate ligands
Monodentate ligands react with metals in a stepwise manner
Cu2+ + NH3 [Cu(NH3)]2+ K1= 1.4x104 NH3

:
[Cu(NH3)]2++ NH3 [Cu(NH3)2]2+ K2= 3.1x103
[Cu(NH3)2]2++ NH3 [Cu(NH3)3]2+ K3= 7.8x102 H3N Cu++
: NH3
[Cu(NH3)3]2++ NH3 [Cu(NH3)4]2+ K4= 1.3x102

:
The overall reaction is:
Cu++ + 4NH3 [Cu(NH3)4]2+ K= 4.4x1012
NH3

Multidentate ligands react with metals in one step

Cu++ + EDTA [Cu-EDTA]2- K= 6.3x1018

We conclude that:
Multidentate ligands in one step can form very stable complex
with the metal ion, referring to the stability constant. 6
 Complexometric Titrations
Complexometric titration is a type of titration based on complex formation between the
analyte and titrant. It is usually applied to determine the concentration of metal ions.
Titrant
Ligand Usually Multidentate ligand such as (EDTA)
Stability constants

Sample
Metal ion
Multidentate ligands are preferred as titrants over monodentate ligands since:
• The complex with the metal is formed on one step.
• They form very stable complexes (high stability constants) with metals, which
leads to a clear and sharp endpoint.
 In case of monodentate ligands, the complex with the metal is formed through several
intermediate steps , thus the overall stability constant is divided between these steps.
 The use of monodentate ligands as titrants is only possible, if each intermediate step7
involved in the complex formation had a high stability constant.
 EDTA (ethylenediaminetetraacetic acid) Facts
 EDTA is a tetrabasic acid that has six potential
sites for bonding with a metal ion, four
carboxyl groups and the two amino groups so it
is a Hexadentate ligand.
 EDTA is a chelating agent or sequestering agent as it
binds the metal ion through several coordinate
Mode of chelation: bonds.
 The complex formed is called chelate, it is a cage like
structure that contains cyclic rings in which the metal
ion is effectively surrounded and isolated from the
surrounding media, thus EDTA forms stable complexes
with metal ions.
 EDTA reacts with any metal ion within the ratio of 1:1  EDTA has four COOH (carboxylic groups) so has
regardless of the charge on the cation, thus EDTA is not four Ka (dissociation constants) for the acidic
a selective reagent. groups :
e.g. Ag+ + EDTA [Ag-EDTA]3- K1= 1.02x10-2, K2= 2.14x10-3, K3= 6.92x10-7 and
Al3+ + EDTA [Al-EDTA]- K4 = 5.50x10-11
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 EDTA Facts Cont.
Forms of EDTA H4Y

 EDTA has different forms at different pHs.

The various EDTA species are often abbreviated as
H4Y, H3Y-, H2Y2-, HY3- and Y4-. H3Y-

• The fully protonated form (H4Y) is only a major

component in very acidic solutions (pH<3).
Note that H4Y exists as a Zwitterion. H2Y2-

• The species H3Y- and H2Y2- are predominant

throughout the pH range of 3 to 10 .
HY3-

• The fully unprotonated form Y4- is dominant only in

very basic solutions (pH>10). Y4-
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 EDTA Facts Cont.
EDTA is slightly soluble in water so its disodium salt (Na2H2Y) is commonly used
instead as a titrant.

 The reaction between metal ion and EDTA is usually written as:

Mn+ + H2Y2- [MY]n-4+ 2H+

• In acidic solutions this reaction will shift to the left while in basic
solutions it will shift to the right towards complex formation.
• It is more easy for EDTA to form stable complexes with metal ions in basic
solutions.
• However, in highly acidic solutions, trivalent and tetravalent metal ions can
form stable complexes with EDTA owing to their high charge.
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 Effect of pH on stability of EDTA complexes
Na2H2Y Na2H2Y Na2H2Y

H+ H + H + H + H + H + H+ H+ H+
H+ Metal ion H+ Metal ion OH-
OH- OH- -
pH is highly acidic (1-3) OH- Metal ion OH
pH is slightly acidic (4-6)
pH is alkaline (10)

[Metal-EDTA] ?? FREE EDTA (H4Y) [Metal-EDTA] ?? FREE EDTA (H3Y-)

Only the trivalent and tetravalent metal ions Some divalent metal ions [Metal-EDTA] ?? FREE EDTA (H2Y2- and HY3-)
2+ 2+ 2+
are able to form a stable complex at this pH such as Pb , Cd and Zn
(log K>20) in the presence of high conc. of H+ are able to form stable Most of the metal ions are able to form
which compete with the metal ion for the complexes with EDTA at this stable complexes with EDTA at this pH
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EDTA. pH
 Effect of pH on stability of EDTA complexes cont.
Na2H2Y

OH -
-
OH-
OH -
OH- OH- OHOH-
OH- Metal ion

pH is highly alkaline (12)

Any metal ion can form a stable complex with EDTA at this pH,
BUT most of the metal ions are precipitated at this pH so will not be available for
reaction with EDTA With the exception of Ca2+ and Ba2+ ions.

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 Effect of pH on stability of EDTA complexes cont.
• The pH values shown in fig. is the
minimum values for effective titration
of the given metal using EDTA.
• Titration at higher pH values is possible
using a suitable indicator.
• The main determining factor in the pH
dependence is the stability of the
formed complex in comparison to the
free EDTA in a given pH, the complexes
should have higher stability constants
so that the titration is possible.

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 Effect of pH on stability of EDTA complexes cont.
The stability of the formed complexes is highly dependent on the pH of the
medium:

Tri and tetravalent valent metal ions such as Bi3+, Fe2+, Cr3+, Th4+, V4+ form
highly stable EDTA complexes having log K>20 . These can be titrated with
EDTA in acid medium pH 1-3 using 0.2N HNO3 to adjust pH.
Some divalent metal ions such as Pb2+, Cd2+, Zn2+ can be titrated in acidic
medium pH 4-6 using hexamine buffer and xylenol orange as indicator.
Ca2 and Ba2+ can be titrated in highly alkaline medium pH 12 using sodium
hydroxide and murexide as indicator.
Ca2+,Mg2+, Ba2+, Pb2+, Zn2+ can also be titrated in alkaline medium pH 10
using ammoniacal buffer and Eriochrome black T as indicator.

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 Which metal ion can be titrated with EDTA at the given
Test yourself: pH?

EDTA EDTA EDTA EDTA

pH=3 pH=5 pH=10 pH=12

Fe3+ Ca2+ Fe3+ Pb2+ Mg2+ Ca2+ Mg2+ Ca2+
ONLY Fe3+ Both Fe3+ and Pb2+ Both Mg2+ and Ca2+ ONLY Ca2+

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 Principle of EDTA titrations
EDTA EDTA
EDTA

Metal ion + Metallochromic indicator

(ligands) At the endpoint:
Near the endpoint: All the metal is complexed
Start point: with EDTA in the form of
EDTA displaces the indicator to form [Metal-EDTA] complex and
Some free metal ion+[Metal- Indicator] [Metal-EDTA] complex and the all the indicator is in its
complex of certain color indicator is released in its free form. free form so a different
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color is observed.
 Metallochromic indicators
They are organic dyes that form a colored complex with metal ions that is
distinguishable from the free indicator color.
Properties of metallochromic indicators:

The free indicator must posses a different color from the metal
indicator complex.
The metal indicator complex must be formed in the same pH of the
metal EDTA complex.
The indicator must be very sensitive towards the metal ion so that
only a small amount of it is necessary for a titration.
The metal indicator complex must be less stable than metal EDTA
so as to dissociate easily in the vicinity of the end point.
The reaction between the indicator and the metal should be
rapidly reversible.
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 Metallochromic indicators cont.
Example of Metallochromic indicators:
Eriochrome black T (EBT )
 This is one of the most widely used metallochromic indicators in EDTA titrations.
 It is the sodium salt of 1-(1-hydroxy-2-naphthylazo)-2-naphthol-6-nitro-4-sulphonic
acid.

It ionizes in three steps:

[Metal-EBT] Free indicator HD2- at pH 10

 The color of [Metal-EBT] complex is wine red.
 The end point is detected from the color of free indictor, so it is most
useful to use EBT in pH range of 8-10 where it will be present in the free
form HD2- which has a blue color, other than this form we will not be able 18
to visually detect the endpoint.
 Factors affecting the sharpness of the endpoint of the titration

2. The number of steps involved in complex

1. The stability of complex formed:
formation:

No. of steps Sharpness of

Sharpness of
Kf the endpoint.
required in the
formation of
the
endpoint.
the complex

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Factors affecting the sharpness of the endpoint of the titration cont.

3. Effect of pH:

Sharpness of
pH the endpoint.

Note that:
pH must be constant by use of a buffer solution. Control of pH is important since the H+
ion plays an important role in chelation:
Mn+ + H2Y2- [MY]n-4+ 2H+
Thus as mentioned before, stability of metal complex is pH dependent. Lower the pH of the
solution, lesser would be the stability of complex (because more H+ ions are available to
compete with the metal ions for ligand). Only metals that form very stable complexes can be
titrated in acidic solution, and metals forming weak complexes can only be effectively titrated
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in alkaline solution.
 Some medial uses of complexes
 Drugs: example Cisplatin, used in cancer treatment.

 Chelation therapy
Chelating agents are given for example in case of metal poisoning, to remove the
toxic metal from the body.
 EDTA is used as an anticoagulant, it chelates Ca2+ in the blood thus preventing
coagulation, mainly used for diagnostic purposes.

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Types of EDTA Titrations

Direct

Back

Displacement

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 Types of EDTA Titrations
Direct

EDTA

Metal ion

 The metal ion is directly titrated with EDTA at a suitable pH with the use of
a suitable indicator.
 This type has a very important application in the determination of
hardness of water.
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 Types of EDTA Titrations
Back
Standard metal ion
e.g (Zn2+)

Metal ion
Known excess EDTA

[Metal-EDTA] + Excess unreacted

complex EDTA
• The excess unreacted EDTA is titrated with a standard metal ion.
It is useful in cases where:
 Metal ion such as (Cr3+ or Co2+) react slowly with EDTA.
 There is no suitable indicator available as in the case of thallium.
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 The metal ion is precipitated at the required pH of the titration.
 Types of EDTA Titrations
Displacement
EDTA

Metal ion + Unmeasured excess of [metal-EDTA] complex

Displacement reaction
[Metal sample-EDTA] complex + free metal ion
Mn+ + MgY2- MYn-4 + Mg2+
• The liberated Mg2+ is titrated with EDTA, and it is exactly equal in amount to the analyte.
Notes:
 The [Metal-EDTA] complex added is usually [Mg-EDTA or Zn-EDTA].
 For this titration to be possible, the analyte must form a more stable complex with
EDTA than Mg or Zn to be able to displace it.
 Hg(II), Pd(II), Ti(II), Mn(II) and V(II) could be determined by this method.
 It is used when there is no suitable indicator or on lacking a sharp endpoint. 25
 References
• D. A. Skoog, D.A. West, F.J. Holler, S.R. Crouch, Analytical Chemistry, an
introduction, 7th Edition, ISBN 0-03-020293-0. (Chapter 15).
• Lecture7 by Prof. Rasha Elnashar, GUC, SS 2015.

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