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Kausar Ahmad Kulliyyah of Pharmacy, IIUM http://staff.iium.edu.my/akausar PHM1153 2011/12 1 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 PHM1153 2011/12 2 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. PHM1153 2011/12 3 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 PHM1153 2011/12 4 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. PHM1153 2011/12 5 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? PHM1153 2011/12 6 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. PHM1153 2011/12 7 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. PHM1153 2011/12 8 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. PHM1153 2011/12 9 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. PHM1153 2011/12 10 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 PHM1153 2011/12 11 [CuCl2 ] [Ag(NH3)2 [AuCl2 PHM1153 2011/12 + ] ] 12 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. PHM1153 2011/12 13 PHM1153 2011/12 14 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. PHM1153 2011/12 15 PHM1153 2011/12 16 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. PHM1153 2011/12 17 The platinum, the two chlorines, and the two nitrogens are all in the same plane. PHM1153 2011/12 18 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: PHM1153 2011/12 19 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 PHM1153 2011/12 End of lecture 1/3 20 A substance, chelating agent, containing Two (2) or more donor groups combine with a metal to form a complex known as a chelate. PHM1153 2011/12 21 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 PHM1153 2011/12 22 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 PHM1153 2011/12 23 In the ethanedioate ion, there are lots more lone pairs than the two shown, but these are the only ones important. PHM1153 2011/12 24 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. PHM1153 2011/12 25 PHM1153 2011/12 26 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. PHM1153 2011/12 27 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. PHM1153 2011/12 28 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. PHM1153 2011/12 29 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. PHM1153 2011/12 30 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. PHM1153 2011/12 31 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. PHM1153 2011/12 32 PHM1153 2011/12 33 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. PHM1153 2011/12 34 Organic coordination compounds are held together by weak valence forces. • Dipole-dipole, London forces, hydrogen bonding… Formation possible if there is no steric hindrance PHM1153 2011/12 35 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 PHM1153 2011/12 36 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 PHM1153 2011/12 37 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!!! PHM1153 2011/12 38 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 PHM1153 2011/12 39 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. PHM1153 2011/12 40 Channel lattice type Layer type Monomolecular inclusion compound PHM1153 2011/12 Clathrates or ‘cage type’ Macromolecular inclusion compound 41 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? PHM1153 2011/12 42 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 PHM1153 2011/12 a) 43 PHM1153 2011/12 44 The crystals are arranged to form layers Other molecules can fit into these layers Examples • Montmorrillonite clay to trap HCs • Graphite PHM1153 2011/12 45 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 PHM1153 2011/12 46 one host molecule. A single guest molecule is entrapped in the cavity of PHM1153 2011/12 47 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. PHM1153 2011/12 48 PHM1153 2011/12 49 A.k.a molecular sieves Atoms are arranged in three dimensions to produce cages and channels Examples • Zeolites (different pore size), dextrins, silica gels PHM1153 2011/12 50 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 PHM1153 2011/12 51 Complexation to enhance the physicochemical properties of pharmaceutical compounds. based on the types of interactions and species involved e.g. metal complexes molecular complexes PHM1153 2011/12 inclusion complexes 52 Iodine/-CD (gargle solution) Chloramphenicol/Me- -CD (eye drop) Cephalosporin ME 1207/-CD (tablet) Dexamethasone/ -CD (ointment) From Encyclopedia of Pharmaceutical Technology 2nd. Ed. PHM1153 2011/12 53 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 PHM1153 2011/12 54 The extent of stabilization observed is related to • • • • the concentration of CAPTISOL the strength of the complex pH storage conditions PHM1153 2011/12 55 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%. PHM1153 2011/12 56 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 PHM1153 2011/12 57