Stereochemistry of Organic Compounds (PART A) Dr Suban K Sahoo MSc, NET (JRF Qualified), PhD Reference Book: Organic Chemistry by Paula Yurkanis Bruice, 3rd Edition

Isomers Isomers: Isomers are different compounds that have the same molecular formula. Different compounds means that they have different physical properties (melting point, boiling point etc.). They may also have very different chemical properties depending on the type of isomerism present. Differ in the way their atoms are arranged in the space Stereoisomers Conformational Isomers Configurational Isomers Geometrical/cis-trans Isomers Rotation about single bonds Optical Isomers Amine Inversion Structural Isomers (Constitutional Isomerism) Structural (or constitutional) Isomers that differ in the way their atoms are connected.

Exa. of Structural Isomers…. Q1. Draw three constitutional isomers with molecular formula C3H8O? Q2. How many constitutional isomers can you draw for C4H10O?

Conformations of Acyclic Alkanes Conformations are different arrangements of atoms that are interconverted by rotation about single bonds. Conformers can be represented in two different types : Views a C-C bond from front to back Views a C-C bond from an oblique angle

Types of conformers…. We do not observe perfectly free rotation. There is a barrier to rotation, and some conformers are more stable than others; based on this observations, conformers are of (A) Staggered : A low energy conformation where the bonds on adjacent atoms bisect each other (60o dihedral angle), maximizing the separation. (B) Eclipsed : A high energy conformation where the bonds on adjacent atoms are aligned with each other (0o dihedral angle). Example 1….. Ethane Conformers

Torsional strain: resistance to rotation. Note: Rotation about a C-C bond is not completely free because of the energy difference between the staggered and eclipsed conformers. Torsional strain: resistance to rotation. For ethane, only 3.0 kcal/mol

Types of Strain….. Torsional strain: Destabilization due to the repulsion between pairs of bonds caused by the electrostatic repulsion of the electrons in the bonds. Groups are eclipsed. Steric strain (or steric hindrance): Destabilization due to the repulsion between the electron clouds of atoms or groups. Groups try to occupy some common space. Angle strain: Destabilisation due to distortion of a bond angle from it's optimum value caused by the electrostatic repulsion of the electrons in the bonds. e.g. cyclopropane

Example 2…..Propane Conformers Note: slight increase in torsional strain due to the more bulky methyl group.

Example 3….Butane Conformers C2-C3 Highest energy has methyl groups eclipsed due to steric hindrance Dihedral angle = 0 degrees totally eclipsed Methyl groups eclipsed with hydrogens Higher energy than staggered conformer Dihedral angle = 120 degrees eclipsed 9

Gauche, staggered conformer Methyls closer than in anti conformer Example 3….Butane Conformers C2-C3 gauche anti Gauche, staggered conformer Methyls closer than in anti conformer Dihedral angle = 60 degrees gauche Lowest energy has methyl groups anti, staggered conformer. Dihedral angle = 180 degrees anti 10

Example 3….Butane Conformers C2-C3

Conformational Analysis of Higher Alkanes The most stable conformation of unbranched alkanes has anti relationships between carbons

Introduction to Cycloalkanes Besides torsional strain and steric strain, the conformations of cycloalkanes are also affected by angle strain. Angle strain is an increase in energy when bond angles deviate from the optimum tetrahedral angle of 109.5°. The Baeyer strain theory was formulated when it was thought that rings were flat. It states that larger rings would be very highly strained, as their bond angles would be very different from the optimum 109.5°. The bond angles of a regular polygon with n sides are equal to = 1800-(3600/n)

all adjacent CH2 groups are eclipsed Note: It turns out that cycloalkanes with more than three C atoms in the ring are not flat molecules. They are puckered to reduce strain. Cyclopropane: reduced overlap of the sp3-hybridized orbitals Total strain for cyclopropane = angle strain + torsional strain all adjacent CH2 groups are eclipsed

relieves torsional strain Cyclobutane: Not Planar; reduced angle and torsional strain relative to cyclopropane Puckering partially relieves torsional strain Cyclopentane: planar conformation is strain free according to Baeyer; however, there is considerable torsional strain (10 H-H eclipsing interactions) Envelope and half-chair conformations relieve much of the torsional strain 15

Cyclohexane: In reality, cyclohexane adopts a puckered “chair” conformation, which is more stable than any possible other conformation. The chair conformation is so stable because it eliminates angle strain (all C—C—C angles are 109.5°), and torsional strain (all hydrogens on adjacent C atoms are staggered).

In cyclohexane, three C atoms pucker up and three C atoms pucker down, alternating around the ring. Each C in cyclohexane has two different kinds of hydrogens: (1) axial hydrogens are located above and below the ring (along a perpendicular axis); (2) equatorial hydrogens are located in the plane of the ring (around the equator).

Ring-flipping interconverts axial and equatorial hydrogens in cyclohexane An important conformational change in cyclohexane involves “ring-flipping.” Ring-flipping is a two-step process. As a result of a ring flip, the up carbons become down carbons, and the down carbons become up carbons. Axial and equatorial H atoms are also interconverted during a ring-flip. Axial H atoms become equatorial H atoms, and equatorial H atoms become axial H atoms.

Ring-flipping interconverts axial and equatorial hydrogens in cyclohexane The chair forms of cyclohexane are 7 kcal/mol more stable than the boat forms. The boat conformation is destabilized by torsional strain because the hydrogens on the four carbon atoms in the plane are eclipsed. Additionally, there is steric strain because two hydrogens at either end of the boat, the “flag pole” hydrogens, are forced close to each other.

Views of the boat conformation of cyclohexane….. Newman Projection

Chair-Chair Interconversion of Cyclohexane Half-chair (+ 45 KJ/mol) Chair Twist-boat (+23 KJ/mol) Twist-boat (+ 23 KJ/mol) Boat (+ 32 KJ/mol) axial equatorial Half-chair (+ 45 KJ/mol) 22 Chair 22

Energy Profile for the Chair-Chair Interconversion of Cyclohexane Ring-flip Note: All axial bonds become equatorial 23

Conformations of Monosubstituted Cyclohexanes Two possible conformations of cyclohexane are different, so they are not equally stable. Larger axial substituents create destabilizing (and thus unfavorable) 1,3-diaxial interactions. 95% More stable 5%

Equatorial Conformation is Preferred…….Why???? Axial Methyl group is Gauche to C3 in the ring Equatorial Methyl Group is Anti to C3 in the ring

Note: With a very large substituent like tert-butyl [(CH3)3C-], essentially none of the conformation containing an axial tert-butyl group is present at room temperature, so the ring is essentially anchored in a single conformation having an equatorial tert-butyl group.

Conformational Analysis of Disubstituted Cyclohexanes In disubstituted cyclohexanes, the steric effects of both substituents must be taken into account in both conformations There are two isomers of 1,2-dimethylcyclohexane: cis and trans In the cis isomer, both methyl groups are on the same face of the ring, and compound can exist in two chair conformations Consider the sum of all interactions; In cis-1,2, both conformations are equal in energy 3.8 KJ/mol 15.2 KJ/mol

Lets understand… Cis-Trans Isomerism in Cycloalkanes Cycloalkanes are less flexible than open-chain alkanes Much less conformational freedom in cycloalkanes Because of their cyclic structure, cycloalkanes have 2 faces as viewed edge-on: “top” face “bottom” face

1,3-Dimethylcyclohexane

Problems… Q1. Draw the different possible conformation of 1,4-Dimethylcyclohexane Q2. Draw the more stable chair conformer of cis-1-ethyl-2-methylcyclohexane Q3. Draw the more stable conformer of trans-1-ethyl-2-methylcyclohexane Conformation of dimethyl cyclohexanes Compounds Cis-isomer Trans-isomer 1,2-Dimethyl- a,e or e,a e,e, or a,a 1,3-Dimethyl- 1,4-Dimethyl-

Amine Inversion… Second kind of conformational isomer Rapid pyramidal inversion of the amine nitrogen End of (PART A)