Pharmaceutical ORGANIC CHEMISTRY

 Optical Isomerism  Polarimeter  Chirality  Chiral compounds  Enantiomers and diastereomers  Racemate

 More Than One Chiral Carbon  Enantiomers and Diastereomers  Meso Compounds

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

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

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

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

PolarimeterPolarimeter

 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)

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

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.

Ball-and-stick models and space-filling models are 3D or spatial molecular models.

CHIRALITY AND CHIRAL COMPOUNDS

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

 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.”

chiral carbon  Compounds which contain chiral carbon.  Chiral carbon: It is an sp 3 -hybridized carbon atom with four different groups attached to it. Chiral compound exists in a pair of enantiomers. enantiomers.

 Many pharmaceuticals are chiral.  Often only one enantiomer is clinically active. S-ibuprofen

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

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

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

two important respects:  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 (+).

chiral 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. achiral  They react at the same rates with achiral compounds.

 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

 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.

 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.

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)

 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).

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

S limonene (lemons)R limonene (oranges)

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

Optical isomerism More than one chiral carbon Different chiral carbons CH 3 CH(Br)CH(Br)CH 2 CH 3 CH 3 CH(Br)CH(Br)CH 2 OH CH 3 CH(Br)CH(Cl)OH CH 3 CH(Cl)CH(Br)NH 2 Same chiral carbons CH 3 CH(Br)CH(Br)CH 3 CH 3 CH(OH)CH(OH)CH 3 CO 2 HCH(OH)CH(OH)CO 2 H

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 ………

Stereochemistry Optical isomerism (±)- Ethanolamine CH 3 CH(OH)NH 2 has one chiral carbon, so 2- enantiomers H2NH2NH2NH2N CH 3 H OH H2NH2NH2NH2N OH H Mirror Fischer projection formula

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 CH 3 CH(OH)NH 2 1. Draw Fischer Projection formula H2NH2NH2NH2N CH 3 OH H

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 CH 3 CH(OH)NH 2 2. Rank the substitution according to the priority order H2NH2NH2NH2N CH 3 OH H OH > NH 2 > CH 3 > H 1 2 3

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 H2NH2NH2NH2N CH 3 OH H 1 OH OH H2NH2NH2NH2N H2NH2NH2NH2N H H 2

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 HO H NH 2 CH 3 (R)-ethanolamine (+)- ethanolamine

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

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

Stereochemistry Determination of ( AC ) in enatiomer 1 a. At C1 : H NH 2 C2C2C2C2 C2C2C2C2 H Br Br 2 1 AC at C1 is S Br > NH 2 > C 2 > H

Stereochemistry Optical isomerism Stereochemistry Determination of ( AC ) in enatiomer 1 a. At C2 : H C1C1C1C1 CH 3 Cl H Cl C1C1C1C1 2 1 AC at C2 is S Cl > C 1 > CH 3 > H

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

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

 EXAMPLES: A. 1,2-Dibromo-1-phenylpropane B. 2,3,4-trihydroxybutanal (erthyrose) Cont. More than one chiral carbon

have internal plan of symmetry  In the simplest case, they are compounds which have internal plan of symmetry.  EXAMPLE:  Tartaric acid

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

 Important properties of meso compounds with 2 chiral centers: 1. They are optically inactive. 2. They must be (R,S) configuration. 3. They are diastereomers of the (R,R) and (S,S) isomer. Cont. Meso compounds

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

Stereochemistry Resolution of racemic mixture 1- treat the mixture with microorganism 2- using chiral reagent 2- using chiral reagent ( R) RCOOH ( R) RCOO - (S) R’NH 3 + ( R) RCOOH ( R) RCOO - (S) R’NH ( S) R’NH 2 + ( S) R’NH 2 ( S) RCOOH ( S) RCOO - (S) R’NH 3 + ( S) RCOOH ( S) RCOO - (S) R’NH 3 +

Examine the following structural formulas and select those that are chiral.