Transcript Complexation - International Islamic University Malaysia

Kausar Ahmad
Kulliyyah of Pharmacy, IIUM
http://staff.iium.edu.my/akausar
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Lecture 1
• Formation of a complex ion
• Coordination compounds
• Ligands
• Types of bonding
• Shapes
Lecture 2
• Chelates
• Organic molecular complexes
• Inclusion compounds
Lecture 3
• Effect of complexation
• Applications
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the filled ligand orbital overlaps the empty metal ion
orbital.
The ligand (Lewis base) donates the electron pair,
The metal ion accepts it
Form one of the covalent bonds of the complex ion.
Such a bond, in which one atom in the bond
contributes both electrons, is called a coordinate
covalent bond.
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The substances contain at least one complex ion
A species consisting of a central metal cation, either a
transition metal or a main-group metal, that is bonded to
molecules and/or anions (by co-ordinate bonds) called ligands.
In order to maintain charge neutrality in the coordination
compound, the complex ions is typically associated with other
ions, called counter ions
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Simple ligands e.g. water, ammonia and chloride ions.
Have active lone pairs of electrons in the outer energy level.
These are used to form co-ordinate bonds with the metal ion.
All ligands are lone pair donors i.e. function as Lewis bases.
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
What is the bonding in the
complex ion formed when
water molecules attach
themselves to an
aluminum ion to give
Al(H2O)63+?

What is the structure of an
aluminum ion before
bonding?
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Aluminum: electronic structure
1s22s22p63s23px1
When it forms an Al3+ ion it loses the 3-level electrons
1s22s22p6.....3s03px03py03pz03d03d0
all the 3-level orbitals are now empty
The aluminum uses six of these to accept lone pairs from six water molecules
It re-organises (hybridises) the 3s, the three 3p, and two of the 3d orbitals
to produce six new orbitals all with the same energy.
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
Six is the maximum number of water molecules possible to
fit around an aluminum ion (and most other metal ions).

By making the maximum number of bonds, it releases most
energy and so becomes most energetically stable.
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Only one lone pair is shown
on each water molecule.
The other lone pair on O is
pointing away from the
aluminum and so is not
involved in the bonding.
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Because of the movement of electrons towards the centre of the
ion, the 3+ charge is no longer located entirely on the aluminum,
but is now spread over the whole of the ion.
Because the aluminum is forming 6 bonds, the co-ordination
number of the aluminum is said to be 6. The co-ordination
number of a complex ion counts the number of co-ordinate bonds
being formed by the metal ion at its centre.
Some ligands can form more than one co-ordinate bond with the
metal ion.
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For coordination compounds, the geometry of the
complex ion is determined by:
The number and the type of metal-ion hybrid
orbitals occupied by ligand lone pairs
•
•
•
•
Linear
Octahedral
Square planar
Tetrahedral
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[CuCl2
]
[Ag(NH3)2
[AuCl2
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]
]
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central metal ion forms six bonds
• or attached to six simple ligands.
octahedral shape
• Four of the ligands in one plane,
the fifth above the plane,
the sixth below the plane.
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E. g. [CuCl4]2- and [CoCl4]2
The copper(II) and cobalt(II) ions have four
chloride ions bonded to them rather than six,
because the chloride ions are too big to fit
any more around the central metal ion.
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
A 4-co-ordinated complex

E.g. cisplatin which is used as an anti-cancer drug.
Cisplatin is a neutral complex
Pt(NH3)2Cl2
▪ the 2+ charge of the original platinum(II) ion is
exactly cancelled by the two negative charges
supplied by the chloride ions.
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
The platinum, the two chlorines, and the two
nitrogens are all in the same plane.
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

This occurs in planar complexes like the cisplatin.
There are two completely different ways in which the
ammonias and chloride ions could arrange themselves
around the central platinum ion:
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lying within the cancer cell’s DNA double helix
Such that a donor atom on each strand
Replaces a Cl- ligand
And binds the Pt(11) strongly
Preventing DNA replication
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A substance, chelating agent, containing
Two (2) or more donor groups
combine with a metal
to form a complex known as a
chelate.
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If one ligand forms only one bond unidentate.
• It only has one pair of electrons that it can use to
bond to the metal - any other lone pairs are pointing
in the wrong direction.
Some ligands, however, have more than
one lone pair of electrons
• multidentate or polydentate ligands……bidentate,
quadridentate, hexadentate
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Bidentate ligands have two lone pairs, both of which can bond
to the central metal ion. Examples:
• 1,2-diaminoethane
• old name: ethylenediamine - often given the abbreviation
"en"
• ethanedioate ion
• old name: oxalate
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In the ethanedioate ion,
there are lots more
lone pairs than the two
shown,
but these are the only
ones important.
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
You can think of these
bidentate ligands
rather as if they were a pair
of headphones, carrying
lone pairs on each of the
"ear pieces".

These will then fit snuggly
around a metal ion.
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Quadridentate ligand has four lone pairs, all of which can
bond to the central metal ion. E.g. haemoglobin
The functional part of this is an iron(II) ion surrounded by
a complicated molecule called haem (heme).
Haem is a hollow ring of carbon and hydrogen atoms, at
the centre of which are 4 nitrogen atoms with lone pairs
on them.
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Haem is one of a group of similar
compounds called porphyrins.
They all have the same sort of ring
system, but with different groups
attached to the outside of the ring.
Each of the lone pairs on the
nitrogen can form a co-ordinate
bond with the iron(II) ion - holding it
at the centre of the complicated
ring of atoms.
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The iron forms 4 co-ordinate
bonds with the haem, but
still has space to form two
more - one above and one
below the plane of the
ring.
The protein globin attaches
to one of these positions
using a lone pair on one of
the nitrogens in one of its
amino acids.
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complex ion has a co-ordination number of 6
central metal ion forms 6 co-ordinate bonds.
water molecule which is bonded to the bottom position in the
diagram is replaced by an oxygen molecule (again via a lone
pair on one of the oxygens in O2)
• this is how oxygen gets carried around the blood by the
haemoglobin.
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When oxygen gets to where it is needed, it breaks away from
haemoglobin, which returns to the lungs to get some more
oxygen.
• carbon monoxide is poisonous and it reacts with
haemoglobin.
• It bonds to the same site that would otherwise be used by
the oxygen - but it forms a very stable complex.
• The carbon monoxide doesn't break away again, and that
makes the haemoglobin molecule useless for any further
oxygen transfer.
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A hexadentate ligand has 6 lone pairs of electrons
all can form co-ordinate bonds with the same metal ion.
The best example is EDTA.
• EDTA is used as a negative ion - EDTA4-.
• Used as anti-coagulant for blood in laboratory.
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The EDTA ion entirely
wraps up a metal ion using
all 6 of the positions.
The co-ordination number
is again 6 because of the 6
co-ordinate bonds being
formed by the central
metal ion.
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Organic coordination compounds are
held together by weak valence forces.
• Dipole-dipole, London forces, hydrogen bonding…
Formation possible if there is no steric
hindrance
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Whitening agent

A complex of benzoquinone and hydroquinone

Resulted from overlap of pi-framework of electronrich hydroquinone
 Molecules polarise one another - charge transfer
complexes
 May be contributed by hydrogen bonding

E.g. quinhydrone of salicylic acid
 Use as organic electrode
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anaesthetic

antiseptic
Reaction between picric acid and weak bases
 E.g. Butesin2 picrate

Reaction between picric acid and
carcinogenic agents
 Complexation due to carcinogenic activity
Reduces carcinogenicity
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Interaction between caffeine and
sulfonamide
• dipole-dipole force
• or hydrogen bonding between polarized carbonyl
group of caffeine and hydrogen atom of acid
• Secondary non-polar interaction
Reduced solubility of complex is possible!!!
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Xlinked polyvinyl pyrrolidone

Crosspovidone, porous polymer and dipolar, binds with
acetaminophen due to phenolic interaction (drug)

Negative effect: Tween and salicylic acid

Polyolefin container interaction with drugs depends on
octanol-water partition coefficient
 Liquid form -> loss of active component
Drugs may precipitate, flocculate, ->delayed
biological absorption
End of lecture 2/3
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These complexes are formed when a
“guest” molecule is partially or fully
included inside a “host” molecule .
physicochemical parameters of the guest
molecule are disguised or altered
• improvements in the molecule's solubility, stability,
taste, safety, bioavailability, etc.
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Channel lattice
type
Layer type
Monomolecular
inclusion
compound
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Clathrates or
‘cage type’
Macromolecular
inclusion
compound
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The crystals are arranged to form a channel
Other molecules can fit into these channels
Examples
• Deoxycholic acid with paraffins, organic acids
• Urea & thiourea with unbranched paraffins
• Starch-iodine solution
• Use of urea to separate long chain compounds?
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The TANO radical, C9H16NO2,
forms stable channel-type inclusion
compounds with a large variety of
linear molecules.
The TANO host-matrix contains
parallel channels of 5 angstroms in
diameter in which guest chains are
packed end to end.
b)
Figures:
a) guest in TANO matrix
b) diameter of the channel
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a)
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The crystals are arranged to form layers
Other molecules can fit into these layers
Examples
• Montmorrillonite clay to trap HCs
• Graphite
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The crystals are cage-like
Guest is trapped in this cage
Stability due to strength of cage
Examples
• Hydroquinone – allows specific
size to be entrapped such as
methyl alcohol, HCl, CO2
• Warfarin sodium USP
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one host
molecule.
A single guest
molecule is
entrapped in the
cavity of
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A macromolecule: cyclic oligosaccharides
To increase solubility of poorly soluble drugs
• Hydrophobic interior, hydrophilic entrances
Arrangement of the glucose units allows accommodation of
e.g. mitomycin C, aspirin, morphine.
Activity of drugs depends on orientation in the cavity and
nature of reaction e.g. pH dependency.
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A.k.a molecular sieves
Atoms are arranged in three dimensions to produce cages and
channels
Examples
• Zeolites (different pore size), dextrins, silica gels
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Interaction between poorly soluble drug & soluble material may form
soluble intermolecular complex.
Improved bioavailability e.g.
• Complexation of iodine with 10-15% polyvinylpyrrolidone to
improve aqueous solubility of active agent.
• interaction of salicylates and benzoates with xanthines, such as
theophylline or caffeine.
Enhanced effect
• E.g. stimulant effect of caffeine increases in the presence of
ventolin
Reduced absorption
• Iron absorption is poor when taken with tea due to complexation
of Fe3+ with tenate and phytate
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Complexation to enhance the physicochemical properties of
pharmaceutical compounds.
based on the types of interactions and species involved e.g.
metal complexes
molecular complexes
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inclusion complexes
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Iodine/-CD (gargle solution)
Chloramphenicol/Me- -CD (eye drop)
Cephalosporin ME 1207/-CD (tablet)
Dexamethasone/ -CD (ointment)
From
Encyclopedia of Pharmaceutical Technology 2nd. Ed.
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a polyanionic ß-cyclodextrin derivative with a sodium sulfonate
salt separated from the lipophilic cavity by a butyl ether spacer
group, or sulfobutylether (SBE).
does not exhibit the nephrotoxicity associated with parent
ß-cyclodextrin.
comparable or higher complexation characteristics and superior
water solubility
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The extent of stabilization observed is related to
•
•
•
•
the concentration of CAPTISOL
the strength of the complex
pH
storage conditions
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The shelf life of fosphenytoin, at pH 7.4 and 25°C is increased
from <1 year to >4.5 years
• solubilizes the hydrolytically produced phenytoin and
prevents it from precipitation.
stabilizes some protein and peptide formulations by
minimizing aggregation, preventing adsorption to containers
and aiding in refolding.
The presence of SBE-CDs has been shown to decrease the
aggregation of insulin and nearly doubles subcutaneous
bioavailability to 96%.
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1.
ME Aulton, Pharmaceutics: The Science of Dosage Form
Design, Churchill Livingstone (2002) Chapter 21
2.
MS Silberberg, Chemistry: The Molecular Nature of Matter
and Change 3rd. Ed., McGraw-Hill (2003) Chapter 23
3.
H. Dodziuk (ed.), Cyclodextrins and Their Complexes, WileyVCH: Weinheim (2006)
4.
http://www.cydexinc.com/faq.htm
5.
http://www.ru.ac.za/library/theses/temp/chen/Chapter7d.p
df
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