Stereochemistry Paderborn, May 2005

Founding Fathers of Stereochemistry Biot: The solutions of many naturally occurring compounds rotate the plane of polarization of polarized light ( ) Biot: The solutions of many naturally occurring compounds rotate the plane of polarization of polarized light ( ) Pasteur recognized in 1850 that this optical activity was caused by an asymmetric arrangement of atoms in a molecule Pasteur recognized in 1850 that this optical activity was caused by an asymmetric arrangement of atoms in a molecule vant Hoff and Le Bel described in 1874 how the atoms of a molecule are actually arranged in space vant Hoff and Le Bel described in 1874 how the atoms of a molecule are actually arranged in space Biot Pasteur Vant Hoff

Subdisciplines of Stereochemistry Static stereochemistry Static stereochemistry Studies the three-dimensional arrangement of the atoms of a molecule in the ground stateStudies the three-dimensional arrangement of the atoms of a molecule in the ground state Dynamic stereochemistry Dynamic stereochemistry Description of the steric relationships in molecules as they change from one state to another, for example during a chemical reactionDescription of the steric relationships in molecules as they change from one state to another, for example during a chemical reaction

Preview Introduction Introduction Conformational analysis Conformational analysis CyclohexaneCyclohexane Bicyclic compounds, steroidsBicyclic compounds, steroids Heterocyclic compoundsHeterocyclic compounds Optical activity and stereoisomerism Optical activity and stereoisomerism Symmetry and chiralitySymmetry and chirality Molecular asymmetryMolecular asymmetry ProchiralityProchirality Chiroptical properties of chiral molecules Chiroptical properties of chiral molecules Optical rotatory dispersionOptical rotatory dispersion

Introduction Structure: Includes both constitution and configuration. Structure: Includes both constitution and configuration. Constitution: Describes the kinds and order of the bonds and atoms or atom groups in a compound. Constitution: Describes the kinds and order of the bonds and atoms or atom groups in a compound. Configuration: Describes the different spatial arrangements of atoms or atom groups of a compound with a given constitution. Configuration: Describes the different spatial arrangements of atoms or atom groups of a compound with a given constitution. StereoisomerismStereoisomerism Enantiomers: Image and mirror image are not identical Enantiomers: Image and mirror image are not identical Diastereomers: Stereoisomers that are not mirror images Diastereomers: Stereoisomers that are not mirror images Conformation:Describes the different spatial arrangements of atoms or groups in a molecule that arise due to rotation (torsion) around single bonds. Conformation:Describes the different spatial arrangements of atoms or groups in a molecule that arise due to rotation (torsion) around single bonds.

Examples Structure and Constitution: Structure and Constitution: Configuration: Configuration:

Examples StereoisomerismStereoisomerism Enantiomers: Image and mirror image are not identical Enantiomers: Image and mirror image are not identical Diastereomers: Stereoisomers that are not mirror images Diastereomers: Stereoisomers that are not mirror images

Conformation: Ethane

Conformational Analysis Cyclohexane Cyclohexane Bicyclic systems and steroids Bicyclic systems and steroids Heterocyclic systems Heterocyclic systems

Optical activity and Stereoisomerism Symmetry und chirality Symmetry und chirality Symmetry axis C nSymmetry axis C n Symmetry plane σSymmetry plane σ Symmetry centre iSymmetry centre i Rotation/reflection axis S nRotation/reflection axis S n Molecular asymmetry Molecular asymmetry Chiral axisChiral axis Chiral planeChiral plane Chiral centreChiral centre Prochirality Prochirality

Symmetry and Chirality n–Fold axis of symmetry C n n–Fold axis of symmetry C n Plane of symmetry σ Plane of symmetry σ

Symmetry and Chirality Centre of symmetry i Centre of symmetry i n-Fold rotation-reflection axis S n n-Fold rotation-reflection axis S n

Symmetry and Chirality Molecules with no reflection symmetry are chiral Molecules with no reflection symmetry are chiral A molecule with only a C n axis is chiral A molecule with only a C n axis is chiral

Molecular Asymmetry Chiral axis Chiral axis Chiral plane Chiral plane Chiral centre Chiral centre

Chiral Axis

Chiral Plane 1. Lead atom: atom with highest priority directly linked to the plane 2. Determine the atom sequence in the plane 3. Determine chirality, starting from the lead atom 1 2 3R ab c

Chiral Centre

Prochirality Enantiotopos Enantiotopos Enantiofaces Enantiofaces Diastereotopos Diastereotopos Diastereofaces Diastereofaces

Heterotopy Homotopic Homotopic Heterotopic Heterotopic ConstitutopicConstitutopic StereoheterotopicStereoheterotopic Enantiotopic Enantiotopic Diastereotopic Diastereotopic

Substitution Test Identical molecules Identical molecules Homotopic (equivalent)Homotopic (equivalent) Isomers Isomers HeterotopicHeterotopic Constitutional isomers Constitutional isomers ConstitutopicConstitutopic Stereoisomers Stereoisomers StereoheterotopicStereoheterotopic Enantiomers Enantiomers EnantiotopicEnantiotopic Diastereomers Diastereomers DiastereotopicDiastereotopic

Optical Activity and Stereoisomerism

Chiroptical Properties of Chiral Molecules A linearly polarized wave may be described as the result of a left polarized wave superimposed on a right polarized wave A linearly polarized wave may be described as the result of a left polarized wave superimposed on a right polarized wave Left and right polarized waves are absorbed differently by an optically active compound Left and right polarized waves are absorbed differently by an optically active compound When the two components are recombined after passing through an optically active medium, the result is an elliptically polarized wave with ellipticity θ: When the two components are recombined after passing through an optically active medium, the result is an elliptically polarized wave with ellipticity θ:

Optical Activity Optically active compounds are circularly birefringent – the refractive indices of the left and right polarized waves differ: Optically active compounds are circularly birefringent – the refractive indices of the left and right polarized waves differ: v = c/n, therefore, if v L v R, then n L n Rv = c/n, therefore, if v L v R, then n L n R There is a phase difference, resulting in optical rotation:There is a phase difference, resulting in optical rotation: =.d(n L - n R )/ = 180d(n L - n R )/ =.d(n L - n R )/ = 180d(n L - n R )/ The optical rotation is dependent on the wavelength – Optical rotatory dispersionThe optical rotation is dependent on the wavelength – Optical rotatory dispersion

Anomalous curve

Chiroptical Properties of Chiral Molecules Optical rotatory dispersion Optical rotatory dispersion Plain curvesPlain curves Anomalous curvesAnomalous curves

Chiroptical Properties of Chiral Molecules Optical rotatory dispersion Optical rotatory dispersion Achiral chromophoresAchiral chromophores Chiral chromophoresChiral chromophores

Achiral Chromophores Achiral disturbance Chiral disturbance

Chiral Chromophores

Chiroptical Properties of Chiral Molecules Optical rotatory dispersion Optical rotatory dispersion ConstitutionConstitution ConfigurationConfiguration ConformationConformation

Plain Curves With small amounts of substance, one can measure at shorter wavelengths With small amounts of substance, one can measure at shorter wavelengths To determine whether a substance is really optically active and not racemic To determine whether a substance is really optically active and not racemic

Example

ORD of Steroids: Constitution A B C

Chiroptical Properties of Chiral Molecules Optical rotatory dispersion Optical rotatory dispersion ConstitutionConstitution Configuration and conformationConfiguration and conformation

Cis/trans-Isomerism in Steroids: Configuration

Unsaturated Ketones and Diketones

The Octant Rule for Ketones

Octant Rule

Chiroptical Properties of Chiral Molecules Octant rule:Octant rule: Configuration Configuration Conformation Conformation Absolute configurationAbsolute configuration

Summary Introduction Introduction Conformational analysis Conformational analysis CyclohexaneCyclohexane Bicyclic compounds, steroidsBicyclic compounds, steroids Heterocyclic compoundsHeterocyclic compounds Optical activity and stereoisomerism Optical activity and stereoisomerism Symmetry and chiralitySymmetry and chirality Molecular asymmetryMolecular asymmetry ProchiralityProchirality Chiroptical properties of chiral molecules Chiroptical properties of chiral molecules Optical rotatory dispersionOptical rotatory dispersion

Questions/Remarks ?