Lecture 10, Pharmaceutical Organic Chemistry-1, Mansoura National University PDF

Pharmaceutical Organic Chemistry-1 PC102- Lec. 10 Dr Samar Samir Tawfik [email protected] Stereochemistry  Meso compounds A stereoisomer with two or more chiral centers but no optical activity due to an internal plane of symmetry. (which bisects the...

Pharmaceutical Organic Chemistry-1 PC102- Lec. 10 Dr Samar Samir Tawfik [email protected] Stereochemistry  Meso compounds A stereoisomer with two or more chiral centers but no optical activity due to an internal plane of symmetry. (which bisects the molecule in such a way that the top half is the reflection of the bottom half). Zero net rotation of plane polarized light. The number of stereoisomers in tartaric acid is three, one meso compound and one pair of enantiomers.  Chirality in Systems Lacking a Stereogenic Centers: 1. Atropisomerism: (optical isomerism due to restricted rotation) 2. Axial chirality 1. Atropisomers (enantiomeric conformers): are stereoisomers arising because of hindered rotation about a single bond.  ortho substituted biphenyl will exhibit hindered rotation around the single bond connecting the two phenyl groups. (bulky and different substituents) If the two ortho substituents on one ring are bulky and similar, the biphenyl compound will have no optical activity.  Cis–trans isomerism (geometric/ configurational isomerism)  cis indicates that the functional groups (substituents) are on the same side of some plane  trans conveys that they are on opposing (transverse) sides.  Cis–trans isomers are stereoisomers, they have the same formula but functional groups are in different orientations in three-dimensional space.  Cis-trans notation does not always correspond to E–Z isomerism, which is an absolute stereochemical description.  In general, cis–trans stereoisomers contain double bonds that do not rotate.  Stereochemistry of Organic Reactions 1. Substitution reactions: Retention, inversion, or racemization may occur. Inversion of Configuration: The SN2 reaction of R-(+)-2-chlorobutane with OH- in non-polar solvent as acetone, gives S-(-)-2-butanol SN1 is followed by total racemization when it takes place at an asymmetric carbon atom. Chiral synthesis: Starting from well-known absolute configuration followed by inversion through SN2 reaction mechanism. Using a chiral catalyst which gives one stereoisomer as a product.  Biological Significance of Stereochemistry: Optical isomers differ in biological activity. Example: D-Glucose, which is commonly used and L-glucose, which is not used at all. In most of the drugs, only one of the isomers usually shows biological activity. Some stereoisomers (enantiomer) are toxic. Thalidomide disaster: It exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)- enantiomers. The (R)-enantiomer is effective, whereas the (S)-isomer is teratogenic. Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective. Aromaticity Dr. samar samir Aromatic compounds (Arenes) are benzene and compounds that resemble benzene in chemical behavior. Benzene has a single hybrid structure which combines the characteristics of both resonance forms.  Criteria that must be obeyed in an aromatic compound: 1) cyclic. 2) planar: each atom of the ring(s) must have a p-orbital perpendicular to the of the ring) 3) Conjugated system: (SP2) hyperidized (C=C-C=C-). 4) Huckel’s rule must be obeyed: no. of (p) electrons= (4n + 2) where: no. of (p) electrons= no. of double bonds x 2. The π cloud must have (4n+2) π electrons where n is an integer (0, 1, 2, 3, ….)". Aromatic molecules may be neutral or charged. N.B. Lone pair of electrons= double bond Carbon atom with positive charge (C+)= SP2 carbon