2026 Molecular Stereochemistry Notes (updated)

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 1 Anglo-Chinese Junior College Department of Chemistry Molecular Stereochemistry Prepared by: Mr Marcus Yip No. References 1 2 3 4 5 6 7 Clayden, Greeves, Warren and Wothers; Organic Chemistry L. G. Wade, Jr; Organic Chemistry International Edition; 6th Edition; USA; 2006 David R. Klein; Organic Chemistry as a Second Language (I and II) John E. McMurry; Organic Chemistry Solomons and Fryhle: Organic Chemistry (8th edition) Pharmaceutical Chemistry Notes by MOE K. C. Nicolaou, E. J. Sorensen; Classics in Total Synthesis (547.70459) Learning Outcomes At the end of the lectures, you should be able to: (a) (i) use stereochemical projections including Newman projections, to represent molecules (ii) interpret stereochemical projections of molecules [knowledge of Fischer projection is not required] (b) apply their understanding of the following types of isomerism to explain the stereochemistry of molecules, including saturated ring systems: (i) conformational isomerism, including energy barriers to rotation and interconversion (ii) cis-trans isomerism, including E, Z nomenclature (iii) enantiomerism and diastereomerism: – R, S configuration – optical activity – optical purity as the excess of one enantiomer, including calculation of optical purity by the equation: optical purity = [α]obs [α]pure material ×100% (c) recognise that transition element complexes can also exhibit stereoisomerism: (i) cis-trans isomerism, e.g. square planar complexes such as [Pt(NH3)2Cl2] and octahedral complexes such as [Co(NH3)4(H2O)2]2+ (ii) enantiomerism, e.g. [Ni(H2NCH2CH2NH2)3]2+ and [Ni(H2NCH2CH2NH2)2(H2O)2]2+ [identification of fac-mer isomerism is not required]

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 2 A) Representing molecules in 3D manner • Straight chain compounds a) Wedge-dash diagram (learnt in H2 chemistry) b) Sawhorse diagrams c) Newman projection d) Fischer projection (non-examinable additional reading at the back) • 6-membered ring compounds B) Conformational Isomerism Conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted exclusively by rotations about  bonds (as they are cylindrically symmetrical). Such isomers are generally referred to as conformational isomers or conformers. Conformational isomers are thus distinct from the other classes of stereoisomers where interconversion necessarily involves breaking and reforming of chemical bonds. Strain in molecules A molecule experiences strain when its chemical structure undergoes some stress which raises its internal energy in comparison to a strain-free reference compound. Naturally, molecules will contort and rotate about  bonds to minimise such strain in order to make itself as stable as possible. A study of the Newman projections and chair-boat conformations is essentially a study in the avoidance of such strain. Three types of strain • Angle strain – also known as ‘ring’ strain. Caused by abnormal bond angles. • Steric strain - the electron-electron repulsion of atoms (or groups of atoms) that are too close together • Torsional strain – a type of steric strain that occurs when bonds are stacked on each other. Torsional strain can be relieved by bond rotation whereas steric strain cannot. http://www.chem.illinois.edu/clcwebsite/CLCtutorials_HTML5/104/Newman%20projections_2017/index.html Online ball-and-stick models!

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 3 Newman projections – using ethane as illustration Newman projections of two conformations of ethane: fully eclipsed (II) and staggered or anti (I) In the staggered conformation, the H atoms are as far apart as possible, and the electrostatic repulsion between the C-H bonding electron pairs is at a minimum. In the least stable eclipsed conformation, electron pair repulsion is maximised.  Torsional barrier - energy barrier to the rotation from one staggered conformation to another. The difference in energy between the eclipsed and the staggered conformations is only about 12 kJ mol-1. This is comparable to the thermal energy that molecules have at room temperature, and so molecules experience little hindrance to free rotation around the C-C bond.  Torsional strain - present in the eclipsed conformation due to the electron repulsion between the eclipsed C-H bonding electron pairs The changes in internal (potential) energy which accompany rotation about the C –C bond in ethane are shown. 0 60 120 Potential Energy Rotation ( o ) H H H H H H H H H H H H H H H H HH eclipsed staggered staggered Torsional barrier

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 4 Newman projections – using butane as illustration  Newman projections for the principal conformations of butane are shown: I II III IV (syn) (gauche) (anti)  I, III-- eclipsed conformation -- I is least stable because of additional steric strain due to the close proximity of the 2 bulky methyl groups.  II, IV-- staggered conformations --IV is more stable than II since some steric strain is present in II.  Energy differences for the various conformations are shown below. At room temperature about 70% of butane molecules are anti, which is said to be the preferred conformation.

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 5 The classic example of conformations being important to the pharmacological action of a drug is the nerve transmitter acetylcholine. For example, experimental data suggest that catecholamines such as norepinephrine and dopamine interact with their receptors in the antiperiplanar conformation. Pharmacophoric conformation of catecholamines (norepinephrine).

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 6 Conformations of cycloalkanes  Cyclopropane is relatively unstable because it has both ring strain from shortening of the C-C-C bond angle (109.5o down to 60o) and torsional strain due to eclipsing of the hydrogen atoms.  The folded shape of cyclobutane is a compromise in which a slight increase in ring strain (88o rather than 90 o) allows relief from torsional strain by non -eclipsing of the hydrogen atoms.  Cyclopentane is a flexible molecule with rapidly interchanging conformations. The most stable of these is the 'envelope' in which torsional strain is minimised by having one carbon atom above the plane of the other four. Chair/boat conformations The cyclic compounds that are most commonly found in nature contain 6 -membered rings because such rings can exist in a conformation that is almost completely free from strain. This conformation is called the chair conformation. In the chair conformation of cyclohexane, all the bond angles are 111 0, which is very close to the ideal tetrahedral bond angle of 109.45 0 (hence there is little angle strain) and all the adjacent bonds are staggered (hence there is little torsional strain).

9813/2026 ACJC H3 Chemistry Notes – Molecular Stereochemistry 7 Chair conformations – steps to draw them I. The chair conformation consists of three sets of parallel lines of the same length, slanted upward, drawn in one set at a time. It is important to draw the structure clearly so that the substituents can be placed correctly on the ring. Connect the tops of the lines with a V; the left hand side of the V should be slightly longer than the right hand side. Conne