Pharmaceutical ORGANIC CHEMISTRY Stereochemistry Pharmaceutical ORGANIC CHEMISTRY

Stereochemistry is the study of molecules on space i.e. how atoms or groups in a molecule arranged in space relative to each other it is that part of the science which deals with structure in three dimensions is the field of chemistry that concerned with isomerism in space ( stereoisomerism )

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

Isomerism Isomerism (stereoisomerism ) A phenomenon resulting from molecules having the same molecular formula but different arrangement In space When two or more organic compounds have the same molecular formula but differ in their physical or chemical properties they are called Isomers and the phenomenon called isomerism.

Stereoisomerism Greek, Stereos=occupying space). The stereoisomers have the same structural formulas but differ in the spatial arrangement of atoms or groups in the molecule. In other words, stereoisomerism is exhibited by such compounds which have identical molecular structure but different configurations.

2- Geometrical – The resulting isomerism are known as Stereochemistry 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

Isomers They are compounds that contain the same atoms bonded together in different ways they include:- 1. Constitutional (Structural) isomers. 2. Stereoisomers. Chain

Isomers Isomerism Constitutional Stereoisomers. (Structural) isomers Chain isomerism Optical isomerism Chain Positional isomerism Geometrical isomerism Functional isomerism

Constitutional Isomers They differ in the way their atom are connected. 1. Chain isomerism 2. Position isomerism 3. Functional isomerism

Chain Isomerism (or Skeletal Isomerism) Chain isomers have the same molecular formula but differ in order in which the carbon atoms are bonded.

Predict C4H10 C5H12

Position Isomerism Position isomers have the same molecular formula but differ in the position of functional group on the carbon chain. Examples are:-

Predict C6H6O2 C3H8O

Functional Isomerism Functional isomers have the same molecular formula but different functional groups. Examples are;

An isomerism resulting from rigidity in molecules Stereochemistry Geometric isomerism An isomerism resulting from rigidity in molecules and accures only in two class of compounds alkenes and cyclic compounds Rigidity ≠ Flexibility σ – bond free rotation ( flexibility )  - bond C = C no free rotation ( rigidity ) σ – bond restricted rotation ( semi-fexable )

Free rotation' of carbon- carbon single bonds  Restricted rotation' of carbon-carbon double bonds 

1- Geometric isomerism in alkenes Stereochemistry 1- Geometric isomerism in alkenes The requirement for this type of isomerism is that each carbon atom involved in the double bond has different substitution D ≠ E A ≠ B On same side cis On differ side trans

1- Geometric isomerism in alkenes Stereochemistry 1- Geometric isomerism in alkenes Diastereoisomers are designed cis or trans according to the priority orders or sequence rules [ atomic number = atomic weight \ 2 ] 126I > 80Br > 35Cl > 32S > 19F > 16O > 14N > 12C > 1H

Sequence Rules or Priority Order Stereochemistry Sequence Rules or Priority Order 1- If the two atoms in question are different, the atom of highest atomic number receives the highest priority I > Br > Cl > ……

Sequence Rules or Priority Order Stereochemistry Sequence Rules or Priority Order 2- If the two atoms are identical, the atomic numbers of next atoms are used, until the priority is determined at the first points of difference along the chain

Sequence Rules or Priority Order Stereochemistry Sequence Rules or Priority Order 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds ) > > > > > > RCH2OH RCN -CH=CR2

Sequence Rules or Priority Order Stereochemistry Sequence Rules or Priority Order 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds )

Sequence Rules or Priority Order Stereochemistry Sequence Rules or Priority Order 3- Atoms attached to double or triple bonds are given single-bond equivalencies, each doubly bonded atom is duplicated ( or triplicated for triple bonds ) Diastereoisomer

Stereochemistry E , Z – system of nomenclature Diastereoisomers can also be designted by : 1- E instead of trans 2- Z instead of cis

Stereochemistry Stereochemistry Compounds which have the same molecular formula but differ in arrangement of atoms or groups in space different configuration Diastereoisomers have different physical and chemical properties, as solubility and boiling points thus: - if are liquids……. Fractional distillation - if are solids …….. Fractional crystallization

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds The most illustrative example is cyclohexane Rotation of group ( atoms ) around sigma bonds, result in different conformations ( conformer )

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds All cyclic compounds except cyclopentane would be strained because ……

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds Conformation is different arrangement …. In ethane Newman projection Ball and stick 3D formula

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds Cyclohexane is not flat …. Axial hydrogen ( Ha ) : H parallel to axis Equatorial hydrogen ( He ) : H in plane upon flipping and reflipping between conformers, axial becomes equatorial and equatorial becomes axial

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds Mono-substituted cyclic compounds, do not exhibit geometrical ……… cis or trans

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds 1,2-disubstituted : same as 1,4-disubstituted Cis both down = e,a both up = a,e Trans up and down = a,a down and up = e,e 1,4-disubistuted cyclohexane as 1,2 In summary : a,e e,a a,a e,e

2- Geometric isomerism in cyclic compounds Stereochemistry 2- Geometric isomerism in cyclic compounds 1,3-disubstituted : both down = e,e both up = a,a up and down = a,e down and up = e,a

Label each of the following disubistiuted rings as cis or trans and as a,a ; e,e ; or a,e