Chapter 6 Principles of Stereochemistry Organic Chemistry, 6th ed. Marc Loudon and Jim Parise Chapter 6 Principles of Stereochemistry

Chapter 6 Overview 6.1 – Enantiomers, Chirality, and Symmetry 6.2 – Nomenclature of Enantiomers: The R,S System 6.3 – Physical Properties of Enantiomers: Optical Activity 6.4 – Mixtures of Enantiomers: Enantiomeric excess 6.5 – Stereochemical Correlation 6.6 – Diastereomers 6.7 – Meso Compounds 6.8 – Separation of Enantiomers 6.9 – Rapidly Interconverting Stereoisomers 6.10 – The Postulation of Tetrahedral Carbon

Stereoisomers Stereoisomers are compounds that have the same connectivity, but a different arrangement of atoms in space. An early example of this was E vs Z alkene isomers. Molecular models are essential for this chapter! 6.1 Enantiomers, Chirality, and Symmetry

More about isomers Cis / trans also applies to cyclic compounds And A different introduction to chirality and non-identical mirror images this stresses lack of symmetry rather asymmetric carbons.

Enantiomers and Chirality Mirror images of ethanol: Any molecule (or object) has a mirror image. Congruent molecules – all atoms and bonds in a molecule can be superimposed onto the mirror image. These are achiral cmpds. 6.1 Enantiomers, Chirality, and Symmetry

Enantiomers and Chirality Some molecules such as 2-butanol are not congruent to their mirror image. Molecules that are non-congruent mirror images are enantiomers. 6.1 Enantiomers, Chirality, and Symmetry

Enantiomers and Chirality Molecules that can exist as enantiomers are said to be chiral. Chirality (Greek “hand” or “handedness”) If a mirror image is congruent (i.e., superimposable = identical ) with the original structure that structure is achiral. Some macroscopic chiral objects include hands, screws, baseball gloves 6.1 Enantiomers, Chirality, and Symmetry

Asymmetric Carbon An asymmetric carbon is a carbon to which four different groups are attached. An asterisk is a convention used to denote an asymmetric carbon. Most chiral molecules contain one or more asymmetric carbon atoms, however, the presence of an asymmetric atom is not a necessary or sufficient condition for chirality. 6.1 Enantiomers, Chirality, and Symmetry

Other Asymmetric Atoms Although carbon is the most common asymmetric atom in organic molecules, other atoms can be asymmetric as well. 6.1 Enantiomers, Chirality, and Symmetry

Stereocenters Stereocenter - An atom at which the interchange of two groups gives a stereoisomer. Also known as a stereogenic atom. An asymmetric carbon is a type of stereocenter. Not all carbon stereocenters are asymmetric centers. 6.1 Enantiomers, Chirality, and Symmetry

Chirality and Symmetry Chiral molecules lack certain types of symmetry. Symmetry types include: lines, points, and planes. Examples of objects with a plane of symmetry: 6.1 Enantiomers, Chirality, and Symmetry

Chirality and Symmetry A molecule has a center of symmetry if you can reproduce it by first forming its mirror image and then rotating this mirror image by 180 °about an axis perpendicular to the mirror. Point of symmetry illustrated 6.1 Enantiomers, Chirality, and Symmetry

Nomenclature of Enantiomers Apply the same Cahn-Ingold-Prelog priority rules used to determine E and Z for alkenes. Assign priorities to each of the four groups attached to an asymmetric carbon. View along the asymmetric carbon to the lowest priority group (C* → #4). Assign CW or CCW for #1 → #2 → #3 CW = R (rectus, Latin “proper”) CCW = S (sinister, Latin “left”) 6.2 Nomenclature of Enantiomers: The R,S System

Nomenclature of Enantiomers 6.2 Nomenclature of Enantiomers: The R,S System

Nomenclature of Enantiomers A stereoisomer is named by indicating the configuration of each asymmetric carbon before the systematic name. 6.2 Nomenclature of Enantiomers: The R,S System

Physical Properties of Enantiomers Enantiomers share identical physical properties (m.p., b.p., nD, density, heats of formation, etc.) …except for their interactions with chiral molecules and plane-polarized light. A compound and its enantiomer can be distinguished by their effects on polarized light. 6.3 Physical Properties of Enantiomers: Optical Activity

Plane-Polarized Light (low emphasis) The electric field of ordinary light oscillates in all planes, but it is possible to obtain light with an electric field that oscillates in only one plane. This is called plane-polarized light. 6.3 Physical Properties of Enantiomers: Optical Activity

Optical Activity A substance that rotates the plane of polarized light is said to be optically active. Individual enantiomers of a chiral substance are optically active. If the sample rotates the plane of polarized light CW → dextrorotatory (+). If the sample rotates the plane of polarized light CCW → levorotatory (-). 6.3 Physical Properties of Enantiomers: Optical Activity

Optical Activity Optical activity is measured by a polarimeter. 6.3 Physical Properties of Enantiomers: Optical Activity

Optical Activity Optical rotation (a) is a quantitative measure of optical activity. a = [a]cl [a] = specific rotation; c = concentration; l = path length Specific rotation, [a], is used as a standard measure for optical activity. No calculations using optical rotations in classes taught by Prof. Andersen 6.3 Physical Properties of Enantiomers: Optical Activity

Optical Activity of Enantiomers Enantiomers rotate plane-polarized light in equal, but opposite directions. The sign of optical rotation is unrelated to R and S configuration of a compound. 6.3 Physical Properties of Enantiomers: Optical Activity

Enantiomeric Excess When one enantiomer is uncontaminated by the other enantiomer, it is said to be enantiomerically pure. Mixtures of enantiomers are very common. Enantiomeric Excess (EE) – the difference between the percentages of the two enantiomers in a mixture. No calculation based on this in this class. 6.4 Mixtures of Enantiomers

Racemic Mixtures Racemic Mixture (aka racemate) - A mixture containing equal amounts of two enantiomers. Racemates typically have different physical properties from that of the pure enantiomers. The process of forming a racemate from a pure enantiomer is called racemization. The separation of a pair of enantiomers is called enantiomeric resolution. 6.4 Mixtures of Enantiomers

Absolute Configuration Absolute Configuration – the actual three- dimensional arrangement of atoms on an asymmetric carbon. How does one determine the configuration of a new, enantiomerically pure compound? Recall optical rotation does not reveal R and S. X-ray crystallography (anomalous dispersion) can be used if the compound is crystalline. The most common approach is to use stereochemical correlation. 6.5 Stereochemical Correlation

Stereochemical Correlation Apply reactions that do not break any of the bonds to the asymmetric carbon. Suppose you have obtained an optically active sample of the following alkene: You measure the optical rotation and find the molecule to be the (-) enantiomer. 6.5 Stereochemical Correlation

Stereochemical Correlation You know that you can convert an alkene to a carboxylic acid using ozonolysis. This reaction does not break any of the bonds to the asymmetric carbon. 6.5 Stereochemical Correlation

Stereochemical Correlation You find in the chemical literature that someone who has prepared (+) hydratropic acid has determined it to have the S – absolute configuration. 6.5 Stereochemical Correlation

Stereochemical Correlation You can now deduce the absolute configuration of your alkene, because the corresponding groups in the two compounds must be in the same relative positions. 6.5 Stereochemical Correlation

Diastereomers Additional stereoisomers are possible when a molecule has two or more asymmetric carbons. Stereoisomers that are not enantiomers are called diastereomers. Diastereomers are not mirror images. Diastereomers is a term that also applies to cis/trans-, E/Z- , etc. isomers. Diastereomers differ in all their physical properties. 6.6 Diastereomers

Diastereomers (two chiral centers) For a pair of chiral molecules with more than one asymmetric carbon to be enantiomers, they must have opposite configurations at every asymmetric carbon. 6.6 Diastereomers

Diastereomers and Enantiomers

Physical Properties of Stereoisomers An example 6.6 Diastereomers

Isomerism Summary Isomers have the same molecular formula. Constitutional isomers have different atomic connectivities. Stereoisomers have identical atomic connectivities. Enantiomers are non congruent (non-identical) mirror images. Diastereomers are stereoisomers that are not enantiomers. 6.6 Diastereomers

Isomer Identification Flowchart 6.6 Diastereomers

Asymmetric carbons don’t always result in chirality Meso compounds have two or more asymmetric carbons and are achiral. They are not optically active. Meso compounds possess an internal mirror plane, a plane of symmetry. 6.7 Meso Compounds

Meso Compounds A molecule with n stereocenters, can exist as 2n stereoisomers. Meso compounds have a plane or point of symmetry This number is reduced if a meso compound is present among the possibilities. 2,3-Butanediol possesses two stereocenters = 2n = 22 = 4 possible stereoisomers. 6.7 Meso Compounds

Stereoisomers of 2,3-Butanediol 6.7 Meso Compounds

Stereoisomers of 2,3-Butanediol But two of these “stereoisomers” are the same. Hence, there are only three stereoisomers of 2,3- butanediol. 6.7 Meso Compounds

Stereoisomers of 2,3-Butanediol Relationships among the 2,3-butanediol stereoisomers: 6.7 Meso Compounds

Meso Compounds A meso compound is possible only when a molecule with two or more asymmetric atoms can be divided into halves that have the same connectivity. 6.7 Meso Compounds

Meso Compounds Shortcut If you find any conformation of a molecule with asymmetric carbons that is achiral, the molecule is meso. Meso compounds are particularly easy to spot in the eclipsed conformation. 6.7 Meso Compounds

Resolution of Enantiomers Enantiomeric Resolution - The separation of a racemate into pure enantiomers. Enantiomers have identical m.p., b.p., and solubility making separation a non-trivial task. The resolution of enantiomers takes advantage of the fact that diastereomers, unlike enantiomers, have different physical properties. Strategy – Convert a mixture of enantiomers temporarily into a mixture of diastereomers. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Resolution of Enantiomers Resolving agent: An enantiomerically pure chiral compound used to form diastereomers from a racemic mixture. Common Methods: Selective Crystallization Diastereomeric Salt Formation Chiral Chromatography 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Selective Crystallization In selective crystallization, a solution of a mixture of enantiomers is cooled to supersaturation and a seed crystal of the desired enantiomer is added. The seed crystal serves as the resolving agent and promotes crystallization of the desired enantiomer. This process is often performed on large scale by the pharmaceutical industry. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Diastereomeric Salts Diastereomeric salt formation is a method used for the enantiomeric resolution of acidic or basic compounds. Acid/Base Reaction: 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Diastereomeric Salts The reaction of (+)-tartaric acid with racemic amine gives a mixture of diastereomeric salts. These salts have different physical properties. The (S,R,R)-diastereomer is less soluble in methanol and can be selectively crystallized. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Diastereomeric Salts Each pure enantiomer may then be recovered by decomposition of the salt with base. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Column Chromatography A mixture of compounds is introduced onto a cylindrical column containing a solid stationary phase. The components of the mixture bind reversibly to the stationary phase. The column is eluted (washed) continually with solvent. Based on the components affinities to the stationary phase, they elute from the column at different times. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Column Chromatography 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Chiral Chromatography In chiral chromatography, the stationary phase consists of tiny glass beads to which an enantiomerically pure chiral compound has been attached. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Chiral Chromatography The chiral stationary phase is the resolving agent. When the two enantiomers of the mixture each bind, diastereomeric complexes result. Diastereomers have different free energies and thus one of the two enantiomers binds more tightly to the resolving agent. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Chiral Chromatography A chromatogram shown the enantiomeric resolution of Nirvanol, a synthetic anti-convulsant. 6.8 Separation of Enantiomers (Enantiomeric Resolution)

Stereoisomers Interconverted by Internal Rotations Conformational enantiomers: Enantiomers that are interconverted by a conformational change. Butane has no stereocenters, but it can exist as a pair of conformational enantiomers. 6.9 Rapidly Interconverting Stereoisomers

Stereoisomers Interconverted by Internal Rotations Conformational diastereomers - Diastereomers that are interconverted by a conformational change. The anti conformation of butane is achiral and is a diastereomer of either one of the gauche butanes. Hence, anti-butane and either one of the gauche-butanes are conformational diastereomers. 6.9 Rapidly Interconverting Stereoisomers

Stereoisomers Interconverted by Internal Rotations Despite the chirality of select conformers of butane, it is not optically active because the two gauche conformations are present in equal amounts. The isolation of an individual chiral conformer is not possible even at very low temperatures. A molecule is achiral if we can find one achiral conformation – even an unstable conformation. 6.9 Rapidly Interconverting Stereoisomers

Asymmetric Nitrogen Ethylmethylamine has four different groups (Et, Me, H, e- pair) arranged around the nitrogen in a tetrahedral fashion. It appears to be chiral. The two enantiomers cannot be separated because they rapidly interconvert by a process called amine inversion. 6.10 Comformational Stereoisomers

Asymmetric Nitrogen Some amines, such as ethylmethylamine, undergo a rapid interconversion of stereoisomers. 6.9 Rapidly Interconverting Stereoisomers

Inversion at Other Atoms Second period elements – rapid inversion Third or greater periods – very slow inversion 6.9 Rapidly Interconverting Stereoisomers

A Brief History of Stereochemistry The first chemical substance in which optical activity was observed was quartz (1815). From 1815-1838, Biot examined several substances and found some to show optical activity while others did not. The first observation of enantiomeric forms of the same compound involved tartaric acid 6.10 The Postulation of Tetrahedral Carbon

A Brief History of Stereochemistry Biot found tartaric acid deposited from fermenting grapes had a positive rotation. He examined a crude tatar sample (racemic) from a “bunch of grapes” and found it to be optically inactive. At the time, the relationship between the two samples remained obscure. 6.10 The Postulation of Tetrahedral Carbon

A Brief History of Stereochemistry Pasteur meticulously separated the “left-” and “right-handed” forms of a tartaric acid double salt via microscope and tweezers (1848). Note: The first resolution occurred by hand! 6.10 The Postulation of Tetrahedral Carbon

A Brief History of Stereochemistry Van’t Hoff suggested that the arrangement of the four groups around carbon is key to the origin of enantiomerism (1874). The model of carbon as tetrahedral was promoted with other possibilities having been ruled out In this arrangement CH2Cl2 would exist at two diastereomers. 6.10 The Postulation of Tetrahedral Carbon