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Pharmaceutical ORGANIC CHEMISTRY

Pharmaceutical ORGANIC CHEMISTRY. Pharmaceutical ORGANIC CHEMISTRY. Lecture contents. Optical Isomerism Polarimeter Chirality Chiral compounds Enantiomers and diastereomers Racemate. Lecture contents:. More Than One Chiral Carbon Enantiomers and Diastereomers Meso Compounds.

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Pharmaceutical ORGANIC CHEMISTRY

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  1. Pharmaceutical ORGANIC CHEMISTRY Pharmaceutical ORGANIC CHEMISTRY

  2. Lecture contents • Optical Isomerism • Polarimeter • Chirality • Chiral compounds • Enantiomers and diastereomers • Racemate

  3. Lecture contents: • More Than One Chiral Carbon • Enantiomers and Diastereomers • Meso Compounds

  4. Optical Isomerism

  5. Isomerism (stereoisomerism ) A phenomenon resulting from molecules having the same molecular formula but different arrangement In space

  6. Isomerism • Structural Isomerism 1. Chain isomerism 2. Position isomerism 3. Functional isomerism • Stereoisomerism • Optical active isomers. • Geometrical isomers. • Conformational isomers.

  7. Type of Isomerism 1- Structural – The resulting isomerism are known as Structural isomers 2- Geometrical – The resulting isomerism are known as Diastereoisomers 3- Optical – The resulting isomerism are known as Enantiomers

  8. Stereochemistry Optical isomerism An isomerism resulting from ability of certain molecules to rotate plane of polarized light -- the light is rotated either to the right or left right ( clockwise ) + d ( dexter ) dextro left ( anticlockwise ) - l ( laevous ) levo

  9. Polarimeter

  10. Optical Isomerism: • Any material that rotates the plane of polarized light is said to be optically active. • Optically active compound is nonsuperimposable on its mirror image. • If a molecule is superimposable on its mirror image, the compound does not rotate the plane polarized light; it is optically inactive. • Example: • Alanine (amino acid)

  11. The Two Optical Isomers of Alanine (space-filling models)

  12. For example, most amino acids (and so proteins) are chiral, along with many other molecules. • In nature, only one optical isomer occurs (e.g. all natural amino acids are rotate polarised light to the left). • Many natural molecules are chiral and most natural reactions are affected by optical isomerism.

  13. Ball-and-stick modelsandspace-filling modelsare 3D or spatialmolecular models.

  14. CHIRALITY AND CHIRAL COMPOUNDS

  15. What is chirality? • Chirality (cheir, Greek for hand). • The property of nonsuperimposability of an object on its mirror image is called chirality. • If a molecule is not superimposable on its mirror image, it is chiral. If it is superimposable on its mirror image, it is achiral.

  16. Chirality • Carbons with four different groups attached to them are handed, or chiral. • Optical isomers or stereoisomers • If one stereoisomer is “right-handed,” its enantiomer is “left-handed.”

  17. CHIRAL COMPOUNDS • Compounds which contain chiral carbon. • Chiral carbon: • It is an sp3-hybridized carbon atom with four different groups attached to it. • Chiral compound exists in a pair of enantiomers.

  18. Chirality • Many pharmaceuticals are chiral. • Often only one enantiomer is clinically active. S-ibuprofen

  19. Q: Decide the chiral carbons in the following formulas? a. b. c. d.

  20. SAMPLE EXERCISE PRACTICE EXERCISE How many chiral carbon atoms are there in the open-chain form of fructose Answer: three

  21. Solve: The carbon atoms numbered 2, 3, 4, and 5 each have four different groups attached to them, as indicated here: PRACTICE EXERCISE How many chiral carbon atoms are there in the open-chain form of glucose

  22. Enantiomers have identical physical and chemical properties except in two important respects: • They rotate the plane polarized light in opposite directions, however in equal amounts. • The isomer that rotates the plane to the left (anticlockwise) is called the levo isomer and is designated (-) • While the one that rotates the plane to the right (clockwise) is called the dextro isomer and designated (+).

  23. 2. They react at different rates with other chiral compounds. • This is the reason that many compounds are biologically active while their enantiomers are not. • They react at the same rates with achiral compounds.

  24. A racemic mixture dose not rotate the plane of • polarization of plane-polarized light because the • rotation by each enantiomer is cancelled • by the equal and opposite rotation by the other. • A solution of either a racemic mixture or of • achiral compound said to be optically inactive

  25. Many drugs are optically active, with one enantiomer only having the beneficial effect. • In the case of some drugs, the other enantiomer can even be harmful, e.g. thalidomide.

  26. In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness. • This led to many disabilities in babies and early deaths in many cases.

  27. S thalidomide (effective drug) The body racemises each enantiomer, so even pure S is dangerous as it converts to R in the body. R thalidomide (dangerous drug)

  28. Thalidomide was banned worldwide when the effects were discovered. • However, it is starting to be used again to treat leprosy and HIV. • Its use is restricted though and patients have to have a pregnancy test first (women!) and use two forms of contraception (if sexually active).

  29. S carvone (caraway seed) R carvone (spearmint) Caraway Seed has a warm, pungent, slightly bitter flavour with aniseed overtones.

  30. S limonene (lemons) R limonene (oranges)

  31. Stereochemistry Optical isomerism Determination of Number of Enantiomers [stereoisomers] 2n where n = number of chiralcarbins n = zero no possible stereoisomers 1 2 enantiomers are possible 2 4 ~ ~ ~ ~ ~ ~ ~ 3 8 ~ ~ ~ ~ ~ ~ 4 16 ~ ~ ~ ~ ~ ~ 5 32 ~ ~ ~ ~ ~ ~

  32. Optical isomerism More than one chiral carbon Different chiral carbons CH3CH(Br)CH(Br)CH2CH3 CH3CH(Br)CH(Br)CH2OH CH3CH(Br)CH(Cl)OH CH3CH(Cl)CH(Br)NH2 Same chiral carbons CH3CH(Br)CH(Br)CH3 CH3CH(OH)CH(OH)CH3 CO2HCH(OH)CH(OH)CO2H

  33. Stereochemistry Optical isomerism Absolute Configuration ( AC ) Is the actual spatial arrangement of atoms or groups around a chiral carbon In 1891 German chemist [ Emil Fisher ] introduce formula showing the spatial arrangement ………

  34. Stereochemistry Optical isomerism (±)- Ethanolamine CH3CH(OH)NH2 has one chiral carbon, so 2- enantiomers H H H2N OH H2N OH CH3 CH3 Mirror Fischer projection formula

  35. Determination of ( AC ) by ( R ) and ( S ) system Groups are assigned a priority ranking using the same set of rules as are used in ( E ) and ( Z ) system CH3CH(OH)NH2 1. Draw Fischer Projection formula H OH H2N CH3

  36. Determination of ( AC ) by ( R ) and ( S ) system Groups are assigned a priority ranking using the same set of rules as are used in ( E ) and ( Z ) system CH3CH(OH)NH2 2. Rank the substitution according to the priority order H OH > NH2 > CH3 > H OH H2N 1 2 3 CH3

  37. Determination of ( AC ) by ( R ) and ( S ) system 3. The group (atom) with lowest priority [H] should be away from the observer , if not do an even number of changes to get H away from the observer H H2N H2N 1 OH H2N H OH CH3 OH 2 CH3 H CH3

  38. Determination of ( AC ) by ( R ) and ( S ) system 4. Draw an arrow from group with highest priority ( OH ) to second highest priority ( NH2 ) . if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S NH2 HO CH3 (R)-ethanolamine (+)- ethanolamine H

  39. Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S

  40. Stereochemistry (±)- CH3CH(Cl)CH(Br)NH2 n = 2 ….. So No. of stereoisomer 4 1,3 and 1,4 2,3 and 2,4 are diastereoisomers

  41. Stereochemistry Determination of ( AC ) in enatiomer 1 a. At C1 : Br > NH2 > C2 > H Br C2 2 Br NH2 C2 H 1 NH2 H AC at C1 is S

  42. Stereochemistry Stereochemistry Optical isomerism Optical isomerism Determination of ( AC ) in enatiomer 1 a. At C2 : Cl > C1 > CH3 > H C1 CH3 2 Cl CH3 Cl H 1 C1 H AC at C2 is S

  43. Stereochemistry Optical isomerism So for overall 1 ( 1S, 2S ) 2 ( 1R, 2R ) similarly: 3 ( 1R, 2S ) 4 ( 1S, 2R )

  44. Enantiomers and diastereomers:EXAMPLE:2-Bromo-3-chlorobutane

  45. Cont.More than one chiral carbon (R) And (S) system for a compound with two chiral carbon atoms: • EXAMPLES: • 1,2-Dibromo-1-phenylpropane • 2,3,4-trihydroxybutanal (erthyrose)

  46. Meso compounds • In the simplest case, they are compounds which have internal plan of symmetry. • EXAMPLE: • Tartaric acid

  47. Stereochemistry Optical isomerism COOHCH(OH)CH(OH)COOH tartaric acid Meso-compound are : - superimposable mirror images - only 3 stereoisomers - optically inactive

  48. Cont. Meso compounds • Important properties of meso compounds with 2 chiral centers: • They are optically inactive. • They must be (R,S) configuration. • They are diastereomers of the (R,R) and (S,S) isomer.

  49. Stereochemistry Optical isomerism Enantiomers • Resolution : process that involves …….. (±) ethanolamine (+)-ehtanolamine (-)-ethanolamine resolution

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