9. Stereochemistry – Advanced Organic Chemistry

9

Stereochemistry

LEARNING OBJECTIVES

By the end of this chapter you should be familiar with

  • Representation of three dimensional molecules in two dimensions.
  • The hybridization of carbon in alkanes, alkenes and alkynes.
  • Chair and boat conformations, ring inversion and 1,3-diaxial interactions in cyclohexanes.
  • Chirality, Fischer, Newman and saw-horse projections, R/S, erythro/threo and syn/anti configuration, meso configuration, enantiomers and diastereoisomers, racemization and resolution.
9.1 INTRODUCTION

Vladimir Prelog performed wide-ranging research on the stereochemistry of alkaloids, antibiotics, enzymes and other natural compounds. In particular, he contributed to the understanding of stereoisomerism, in which two compounds of identical chemical composition have different, mirror-image configurations (like a person’s right and left hands). Cornforth (a British chemist) with Vladimir Prelog, received the 1975 Nobel Prize for Chemistry for his research on the stereochemistry of enzyme-catalyzed reactions. Cornforth investigated enzymes that catalyze change in organic compounds (substrates) by taking the place of hydrogen atoms in a substrate’s chains and rings. In his syntheses and descriptions of the structure of various terpenes, olefins and steroids, he determined specifically which cluster of hydrogen atoms in a substrate is replaced by an enzyme to cause a given change in the substrate. This allowed Cornforth to detail the biosynthesis of cholesterol, an exceptionally complex molecule.

Chemistry, like everyday life, takes place overwhelmingly in three dimensions. Stereochemistry embraces the spatial aspects of chemistry and can be considered in two parts. The first deals with the shapes and properties of mainly three-dimensional molecules and involves knowledge of the terms conformation, configuration and chirality. The second aspect deals with reactivity and includes the preferred or obligatory direction of approach of reagents, and also the consequences for the nature of the products. In respect of reactivity, it can be said that except for spherical reactants, for example, H+ and Cl, there is almost always a preferred direction of approach of one molecule or ion toward another.

Three basic parameters, namely, bond length, bond angle and dihedral angle affect molecular geometry. Bond length can be expressed as the sum of covalent radii of the two atoms forming the bond. The formation of covalent bonds in carbon compounds has been rationalized using the concept of hybridization of bonding orbitals. The different strains and interactions encountered during the discussions are weak attractive van der Walls forces (London forces), nonbonded interactions (van der Waals repulsion), angle and Baeyer strain, coulombic or electrostatic repulsions, torsional strain and interactions due to hydrogen bonds.

The stereochemistry is as old as organic chemistry itself, which refers to chemistry in three dimensions. It is the study of the spatial arrangements of atoms or groups in a molecule and complexes. Isomers of identical constitution but differing in the arrangement of their atoms in space are termed as stereoisomers.

9.2 SIMPLE MOLECULES: HYBRIDIZATION, CONFORMATION AND CONFIGURATION

We consider first the simplest organic molecule methane, CH4, and in particular, its geometry, its representation in two dimensions and its make-up from the component atoms. In methane, all four carbon–hydrogen bonds are equivalent and are directed toward the corners of a regular tetrahedron with carbon at the centre. The HCH bond angles are all 109°28’, a value that is found only in molecules with ‘tetrahedral’ geometry. The normal depiction of methane is given in 1 and the convention, which is applied generally, for representing three-dimensional molecules in two dimensions is now described. The central carbon is taken to lie in the plane of the paper, together with any two hydrogens. Most commonly, these are the upper and left hydrogens and, as shown in 1, lines of ‘normal’ thickness represent bonds between each of these two hydrogens and carbon. The thick ‘wedge’ represents a bond between carbon and the hydrogen in front of the page, and the dashed line indicates a bond between carbon and the hydrogen behind the page.

Note that any three atoms must lie in a plane. One can always draw a plane through three points; in the everyday world, for example, a three-legged stool never rocks. The three atoms that lie in the plane of the paper in 1 are chosen for convenience.

9.2.1 Hybridization: Methane

When a bond is formed between, say, C and H, the electronic distribution in the orbitals is perturbed and two atomic orbitals that normally contain an electron each are said to overlap. In the case of a simple molecule such as in methane, the question arises as to how one can reconcile the equivalence of the four C-H bonds in methane with the outer shell electron configuration, 2s22p2, of carbon in the ground state that suggests bivalency for carbon. Hydrogen contributes its one electron in a 1s orbital, whereas carbon has four atomic orbitals of appropriate energy available for bonding. These four orbitals are one 2s and three 2p orbitals, which are designated 2px, 2py and 2pz, according to their different directions in space; x, y and ζ refer to the directions of a Cartesian coordinate system.

The 2s orbital is spherically symmetrical, and its electron density is highest at the nucleus. Each 2p orbital is cylindrically symmetrical and, in contrast to its 2s counterpart, has zero electron density at the nucleus. If one 2s and three 2p orbitals were used without modification in bonding, then four equivalent bonds would not be found in methane.

A slightly higher energy state of carbon is described by the electron configuration 1s22s12p3. Pauling suggested that the four L-shell orbitals (2s, 2px, 2py, 2pz having one electron each) in excited state be mixed together and then split into a set of four equivalent hybrid orbitals (2), designated as sp3 – a process known as hybridization. These hybrid orbitals, in an ideal condition, are directed towards the four corners of a regular tetrahedron. In the case of carbon in methane and saturated carbon in most other molecules the hybridization is described as sp3. These orbitals have some characteristics of the component atomic orbitals. Accordingly, an sp3 orbital has finite charge density at the nucleus, as does the 2s (but not the 2p) orbital; also, it has directionality in common with the 2p orbitals, with lobes now of unequal size.

Figure 9.1 Four equivalent sp3 orbitals

The observed HCH bond angles in methane are such as to place the hydrogen atoms as far apart as possible. The same angles are observed in, say, CF4, but, in general, the C-C-C bond angles in acyclic saturated molecules are slightly greater, and an example is propane, where the value is ca. 112°.

9.2.2 Hybridization: Ethene and Alkenes

Analysis of the geometry of methane does not explain that of ethene, C2H4, which contains two equivalent carbons. From electron diffraction data, ethene is known to be a flat molecule with all six atoms in a plane and with bond angles of 120°. The bonding of ethene can be rationalized by using the same orbitals, one 2s and three 2p (2px, 2py, 2pz), but with the difference that one of the 2p orbitals does not participate in the hybridization. The net result is that there are three sp2 hybrid orbitals and one pure ρ orbital per carbon. There are a number of significant differences about bonding in ethene compared to that in methane. The sp2 hybrid orbitals in ethene and indeed in all alkenes possess a greater percentage of ‘s’ character, and consequently the electrons reside closer to the carbon nucleus. Additionally, the change of hybridization brings about a change of bond angle. In ethene, and around the sp2 hybrid carbons of alkenes, the bond angles are 120°, which leads to the flat structure. This geometrical arrangement means that the substituents around the alkene carbons are as far away from each other as possible, a feature that is true also of methane. It follows that in cyclohexene, for instance, four of the six carbon atoms (and two hydrogens) are coplanar.

What then of the p orbitals that did not participate in the formation of sp2 hybrid orbitals? These remain as p orbitals, one at each carbon, and each ρ orbital contains one electron. Together they form a bond, termed a π bond, between the carbon atoms. The mode of overlap is ‘sideways on’. This contrasts with the end-on overlap that results in formation of σ bonds, and which in the present context involves C–H bonds in methane and ethene, and the other bond between carbon and carbon in ethene.

The sp2 hybrid orbitals form one carbon-carbon π bond and two carbon-hydrogen π bonds. Ethene may be drawn as in 3a; in 3b ethene is drawn to highlight the overlap of the p orbitals of the two carbons that give rise to the π bond.

The presence of the π bond confers properties on an alkene that mark it out as different from an alkane. In particular, the π bond, by nature of its sideways overlap of the constituent p orbitals, is weaker than a σ bond. Moreover, the electrons of the π bond are relatively exposed, above and below the plane of the alkene. These electrons are the source of reactivity of the alkene toward electrophiles, as in, say, electrophilic addition of bromine. The π bond in ethene (and other alkenes) is, however, sufficiently strong that it prevents rotation around the carbon–carbon σ bond, which is a well-documented property of the carbon-carbon bond in ethane. The bonding between sp2 hybrid carbons of an alkene consists of one σ bond and one π bond; collectively, these are referred to as a double bond.

Double bonds are also formed between carbon and nitrogen to give imines (R2C=NR) and between carbon and oxygen to give aldehydes and ketones. In both these cases also, there is one σ bond and one π bond. In aldehydes, ketones and imines, oxygen, especially, and nitrogen are more electronegative than carbon. Accordingly, the electrons of the π bond in particular are drawn toward the oxygen and the nitrogen, respectively. This has the effect of making oxygen and nitrogen partially negatively charged, and the carbons of these double bonds are correspondingly partially positive.

9.2.3 Hybridization: Ethyne

For completeness, we consider briefly the triple bond in ethyne, 4 (acetylene), though its stereochemical significance is limited. The carbons of ethyne utilize one σ and one π orbital to form two equivalent sp hybrid orbitals. This leaves two unhybridized π orbitals. The sp hybrid orbitals are used to form the σ bonds, one to the other carbon, and one to hydrogen. The p orbitals at each carbon form two separate and independent π bonds that are at right angles to each other, as viewed along the axis of the molecule. Such π bonds are called orthogonal. The two carbon atoms are triply bonded, which causes a further shortening of the bond length and an increase in the bond energy. Bonding in nitriles is similar, with the triple bond again made up of one σ bond and two orthogonal π bonds.

Along the series ethane (carbons sp3, tetrahedral), ethene (sp2, trigonal) and ethyne (sp, linear) there is an increase in the percentage of s character of the carbon hybrid orbitals. This implies a greater electron density at the carbon nucleus as one moves along this series, which is in accord with the progressively shorter carbon-carbon bond lengths observed. Average values of 0.154 nm (ethane), 0.133 nm (ethene) and 0.12 nm (ethyne) have been found. Because of the radial distribution of the electron density, rotation about the triple bond is expected to be free; in any case, it does not alter the shape of the molecule.

9.2.4 Bonding and Anti-bonding Orbitals

A further general point about molecular orbitals is illustrated with the hydrogen molecule. This is composed of two hydrogen atoms, each of which contributes one electron from a 1s orbital to form the molecular orbital. Two electrons in this molecular orbital form the σ bond in the hydrogen molecule. It may appear that two atomic orbitals, which together are capable of containing four electrons, form one molecular orbital that is only capable of containing two electrons. The combination of atomic orbitals is slightly more involved.

When two atomic orbitals combine they produce two molecular orbitals of unequal energy. The lower energy molecular orbital is lower in energy than the component 1s atomic orbitals; it is called a bonding molecular orbital (MO) and contains the two electrons that form the σ bond. Additionally, a second molecular orbital is formed that is higher in energy than the 1s orbitals, and in the ground state hydrogen molecule it is unoccupied. This higher energy orbital is known as an anti-bonding orbital and is given the symbol σ*. Similar behaviour is also shown by π orbitals, which form π and π* molecular orbitals.

9.2.5 Conformation: Ethane

According to the principle of free rotation of classical stereochemistry, rotation around a single bond was considered to be free. Unlike methane, with its fixed geometry, ethane is not rigid and rotation occurs around the carbon-carbon single bond. Conformations of a molecule are three-dimensional arrangements that differ only by rotation around a single bond. Each increment of rotation, however small, produces a change of conformation. In particular, the atoms remain connected in the same order during conformational change, with bonds being neither made nor broken. To explore conformation, it is necessary to define terms and to examine ways of representing molecules, or their key parts, in two dimensions. Molecules containing saturated carbon will be considered here.

Ethane can have a continuous series of conformations as rotation proceeds around the carbon-carbon single bond. In order to analyze this rotation it is appropriate here to present two different conventions for representing ethane and other molecules so that their three-dimensional character can be appreciated. One is the Newman projection 5, in which ethane is viewed along the carbon-carbon bond. The C-H bonds of the ‘front’ methyl group are joined to the centre of the circle, which signifies the carbon-carbon bond axis. The corresponding C-H bonds of the rear CH3 group are differentiated in that they finish at the circumference of the circle. In the eclipsed conformation the dihedral angle is 0°. The dihedral angle is the angle between planes Ha-C(1)-C(2) and C(1)-C(2)Hb. The dihedral angle is sometimes simply known as the torsion angle. The second representation is known as a sawhorse and is shown in 6. Here the molecule is observed from an oblique angle.

As the C–C bond in ethane rotates about its axis, the value of the dihedral angle ϕ increases gradually. When ϕ is 60°, the conformation is termed staggered, and the hydrogens are now as far apart as possible. Accordingly, this conformation corresponds to an energy minimum and is represented by 7 (Newman, M.S. Newman of the Ohio State University) and 8 (sawhorse) projections. Hydrogens Ha and Hb (and also the other pairs) are as close as possible in the eclipsed conformation, which therefore represents an energy maximum.

A clockwise rotation of 120° of the rear methyl group from the eclipsed position in 5 and 6 gives a second eclipsed conformation identical with 5 and 6, and therefore with the same energy. A further 120° clockwise rotation gives a third identical conformation. These are shown in sawhorse projection in 9 and 10, respectively. A still further 120° clockwise rotation completes the revolution, with the original pair of eclipsed hydrogens Ha and Hb now again coincident.

The conformation shown in 11 represents one of a number of skewed conformations in which the rotation around the C-C axis, from the position shown in 5 (or 6), has occurred such that the hydrogens of the rear methyl group have moved in a clockwise direction by 0 < ϕ < 60°. This rotation around the carbon-carbon bond in ethane is rapid at room temperature, and is sometimes described as ‘free rotation’. This is not strictly true, as a small though definite energy barrier is encountered.

It is now clear that eclipsed conformations are of the highest energy, skewed conformations are of intermediate energy and staggered conformations are the most stable. The energy difference between the highest and lowest energy conformations is 12.2 kJ mol−1 at 25 °C, and is referred to as the torsion barrier. In more complicated molecules than ethane, for example, Cabc-Cxyz, the rotational barrier will differ; the peaks and troughs are now all of unequal height and depth and, depending on the substituents, the energy profile may only be repeated once per revolution.

9.2.6 Conformation of Propane and n-butane

Consideration of the Newman projection of propane (12) suggests that the energy profile associated with rotation around the CH3-CH2 bond contains both three identical maxima and three identical minima per revolution. In eclipsed conformations there is now a non-bonded repulsion between a methyl and hydrogen; accordingly, the torsional barrier, at 14.2 kJ mol−1, is a little higher than in ethane.

The case of butane, C(1)H3−C(2)H2−C(3)H2−C(4)H3, is more involved. Three conformations are shown in 13–15, in which the methyl groups are, for convenience, represented by X. In 13 the C(1)-C(2)-C(3)-C(4) dihedral angle ϕ is 0°, and this corresponds to the eclipsed conformation of butane. If one rotates the rear group clockwise, then when ϕ = 60° a staggered conformation 14 is obtained; this is known as a gauche conformation. A further 120° clockwise rotation of the rear group leads, via an eclipsed conformation, to 15, known, as anti, as the dihedral angle ϕ is now 180°. In butane this conformation has a plane of symmetry. A further 120° clockwise rotation yields a gauche conformation 16 that is equal in energy to 14.

In the vast majority of appropriately constructed molecules, for example derivatives of butane, the anti conformation, for example 15, in which the groups X are each flanked by two hydrogens, is the most stable; however, there are a few exceptions. The anti conformation of butane is more stable than the eclipsed by ca. 18.8 kJ mol−1.

The conformations of longer, unbranched hydrocarbons become more complicated the greater the number of carbons. For example, pentane has nine staggered conformations. A series of compounds in which each member differs from the next member by a constant amount is called a homologous series, and the members of the series are called homologs.

9.2.7 Cyclohexane: Chair Conformation

Cyclohexane is a saturated cyclic hydrocarbon, C6H12, in which all the carbons are sp3 hybridized and tetrahedral. Benzene, C6H6, is an unsaturated hydrocarbon with a six-member ring in which all carbon atoms are now sp2 hybridized.

The cyclohexane ring, either alone or as part of a more complex structural unit, occurs in certain natural products and, accordingly, cyclohexane is the most important saturated cyclic hydrocarbon. Unlike 3- to 5-member rings, cyclohexane can adopt a conformation that is free from both angular strain and torsional strain: this is the chair conformation. Two principal conformational isomers exist. The more stable is called the chair conformation 17, and the less stable the boat conformation 18. In both these conformations, the C-C-C bond angles are close to the tetrahedral value of 109°28’; consequently, cyclohexane has little angle strain. Angle strain becomes significant in saturated hydrocarbons if there are meaningful departures from the above value.

The chair conformation of cyclohexane also has minimum torsion strain, as can be confirmed both from a Newman projection and molecular models. The Newman projection 19, derived from 17, in which one looks along the C(1)-C(2) bond of cyclohexane, reveals an almost exact staggered local conformation. This situation is reproduced if one inspects the Newman projections along the other five carbon-carbon bonds in chair cyclohexane. Inspection of 17 indicates that of the 12 hydrogens in a molecule of cyclohexane, six are parallel to a three-fold axis of symmetry (C3 axis) that passes through the molecule as indicated. These six hydrogens are, therefore, termed axial and are further differentiated in that three are above an approximate plane through the molecule and three are below. A molecular model of cyclohexane will accordingly rest on a table by either the three upper or the three lower hydrogens.

The three upper axial hydrogens in cyclohexane are termed cis to each other; likewise the three lower axial hydrogens are mutually cis. These cis relationships are at the origin of the phrase ‘cis 1,3-diaxial interaction’ that is used in appropriate 1,3-disubstituted cyclohexanes. It may be helpful to insert an imaginary C(1)-C(3) bond to confirm with the aid of a model that the dihedral angle is 0°. It is noteworthy also that axial hydrogens on adjacent carbons, for example, H1a and H2a in 19 and 20, are said to be trans by virtue of the dihedral angle H1a-C(1)-C(2)-H2a being 180°. These relationships are quite general whether the relevant sites are occupied by hydrogen or by one or more other substituents.

The remaining six C-H bonds of cyclohexane are more or less perpendicular to its C3 axis, and are termed equatorial bonds. Inspection of a model will confirm that they are directed away from the core of the molecule and do not experience significant non-bonded interactions.

9.2.8 Cyclohexane: Boat Conformation

The boat conformation of cyclohexane (18) can be constructed from a molecular model of the chair form by holding the right-hand three carbons C(2), C(3) and C(4) of 17, clamped from the top with the hand and moving the left-hand three carbons upward. A Newman projection of the boat form looking along the C(1)-C(2) bond, and shown in 21, is reminiscent of the highest energy cis conformation of butane.

Further, the boat conformation of cyclohexane is usually thought to possess unfavourable transannular nonbonded interaction between the hydrogens marked H’ in 18; this is known as a ‘1,4-interaction.’ Recently, it has been claimed that the magnitude of the 1,4-interaction in 17 is negligible, but there is a significant 1,4-repulsive interaction between C(1) and C(4) in the boat conformation 18.

On account both of this interaction and the two sets of eclipsed interactions, the boat conformation is less stable than the chair counterpart by 27.5 kJ mol−1. A further conformation of cyclohexane, the twist-boat, is known and is relevant in ring inversion.

9.2.9 Inversion of Cyclohexane

1H Nuclear magnetic resonance (NMR) spectroscopy is a sensitive technique in which the absorption (at higher or lower fields) of different protons in a molecule reflects the different environment of the protons. However, the 1H NMR spectrum of cyclohexane at ambient temperature shows only a single absorption. The reason for this is that cyclohexane is interconverting rapidly between two chair conformers of equal energy, as the energy barrier between these forms is only 42 kJ/mol. Flipping occurs rapidly at room temperature (kc.104s−1). This is shown by the equilibration of 22 and 23 in which only one pair of geminal hydrogens, H1 and H2, is shown. After inversion, axial hydrogen, H1 in 22, has become equatorial in 23 and vice versa. This behaviour is quite general for all hydrogens in cyclohexane.

At room temperature, inversion of cyclohexane is so rapid that its 1H NMR spectrum shows only a single averaged absorption for the 12 protons. At low temperatures, less than 230 K, when the rate of interconversion of 22 and 23 is slow, it is possible to observe separate absorptions for the axial and equatorial protons. If one examines the 1H NMR spectrum of cyclohexane at temperatures in the range in which the changeover takes place from a single average absorption to separate axial and equatorial absorptions, it is possible to estimate the rate constant for the ring inversion of cyclohexane. One can translate this result to room temperature and say that here cyclohexane is undergoing ring inversion more than 100,000 times per second. Ring inversion of cyclohexane occurs by a route that involves twist boat and, possibly, boat conformations.

9.2.10 Monosubstituted Cyclohexanes

The most stable form of a monosubstituted cyclohexane is, like cyclohexane itself, a chair conformation. There are, however, two valid chair conformations and again, like cyclohexane, these are interconvertible by ring inversion. The particular case of methylcyclohexane is shown in 24 and 25.

The substituent in a monosubstituted cyclohexane may be either axial or equatorial. These structures are isomeric that cannot be isolated known as conformational isomers; because the rate of interconversion of the two, through ring flipping, is too rapid and an equilibrium is maintained. It can be seen that in 24 there are two destabilizing cis 1,3-diaxial interactions between H and Me. The molecule responds to these interactions by undergoing ring inversion to produce 25 in which the methyl group is now in the relatively ‘open’ equatorial position. At 25 °C, the rate of 25 to 24 is ca. 18:1, and this corresponds to a free energy difference of ΔG° = −7.1 kJ mol−1.

In 1-methylethylcyclohexane (isopropylcyclohexane), the conformer with the equatorial substituent (shown in 26) is now favoured over its axial counterpart by a factor of ca. 35 because of the larger size of the alkyl substituent, and this ratio corresponds to ΔG° = −8.8 kJ mol−1.

Two more examples merit consideration. In 1,1-dimethylethylcyclohexane (27, t-butylcyclohexane) the very bulky substituent group has an overwhelming preference for the equatorial position on account of its severe cis 1,3-diaxial interactions with two hydrogens when it is axial; this can be verified with spacefilling models. In effect, 27 is locked in the chair conformation with the 1,1-dimethylethyl groups equatorial, incapable of inversion.

By way of contrast, in iodocyclohexane, iodine has little preference as to whether it is axial or equatorial. The reason is that although iodine is a large atom, the C-I bond length of ca. 0.195 nm is much longer than the axial C-H bonds (ca. 0.11 nm), and although the van der Waals’ radius of iodine, ca. 0.22 nm, is large, 1,3-diaxial interactions that involve iodine are not significant.

9.2.11 Disubstituted Cyclohexanes

There are three geometrically different relationships between the substituents, X, in a 1,2-disubstituted cyclohexane of the formula C6H10X2: each substituent may be axial (28), each may be equatorial (29), or one may be axial and the other equatorial (30). None of the structures is immediately superimposable upon its mirror image, and three pairs of enantiomers might be expected. In practice, however, there are fewer stereoisomers as a result of the rapid interconversions of chair conformations. Thus, four structures, 28 and 29, constitute one pair of enantiomers. The remaining pair is superimposable by chair flipping and, therefore, constitutes a (d,l)-pair, which is unresolvable because it interconverts too rapidly. The structures 28 and 29 are described as trans, and the two which constitute the (d,l)-pair 30 are described as cis.

This discussion of the 1,2-disubstituted cyclohexanes can be extended to the 1,3- and 1,4-analogues. The 1,3-compounds exist in three discrete stereoisomeric forms: an enantiomeric trans pair 31 in which one substituent is axial and other equatorial and a cis isomer that has a plane of symmetry (not resolvable) and which consists of interconvertible conformational isomers having both substituents respectively equatorial 32 and axial 33, the former predominating.

The 1,4-compounds exist in only two forms: a trans compound, with both substituent either axial 34 or equatorial 35 and a cis compound, with one axial and one equatorial substituents 36. Both cis and trans compounds possess a plane of symmetry and are optically inactive; the trans isomer is the more stable.

9.3 CHIRAL MOLECULES

9.3.1 Chirality, Enantiomers and Optical Activity

When a sp3 hybridized tetrahedral carbon is attached to four different groups, as in 37, the molecule cannot be superimposed on its mirror image. This is the same property that a right hand, say, placed in front of a plane mirror possesses. Molecules such as 37 are said to be chiral (or handed), from the Greek word ‘cheir’ for hand.

Chirality then is the property of handedness, and the adjective chiral refers to the molecule as a whole, rather than to a particular atom. Molecules such as CCl4 and CH2Cl2 that can be superimposed on their mirror images are said to be achiral.

Molecules such as 37a and 37b are termed enantiomers, from the Greek ‘enantio’ meaning opposite. Enantiomers are defined as a pair of molecules related as non-superimposable mirror images; note that it is essential to include ‘non-superimposable’ in the definition. It can be seen that enantiomers are a particular sub-class of stereoisomers. Each enantiomer of a pair has the same physical properties (for example, m.p., b.p. and solubility), with one exception. This distinguishing feature arises when, in separate experiments, plane-polarized light is passed through a solution of each enantiomer in the same solvent and using the same cell. If the concentration of the two enantiomers is the same, then the plane of polarized light is rotated in opposite directions and by the same amount. This difference in behaviour has important diagnostic value.

As mentioned above, the word chirality comes from the Greek for hand. A hand and a foot are chiral and fulfil the same criteria as chiral molecules. Accordingly, a left hand placed in front of a mirror gives a right hand as its mirror image. These cannot be superimposed, as can readily be demonstrated with one’s own hands. Also, a glove is chiral and a pair of gloves consists of two enantiomeric gloves. Likewise, a shoe or a sandal is chiral. A plain sock is not chiral but it will of course readily adapt to the chirality of the foot.

Another common chiral object is a cylindrical helix, such as a bed-spring. A helix with its mirror image is not superimposable. The thread of a screw ensures that it too is chiral. The body shell of a car as it enters the assembly line is not chiral, and it has a plane of symmetry. When the car leaves the assembly line it has acquired, for example, a steering wheel on one side or another. The finished car is now not superimposable on its mirror image, and it is therefore chiral; it has also lost its plane of symmetry.

Rowing boats are clearly not chiral, but note that they possess a plane of symmetry. An engine, presumed symmetrical, fitted to this boat will have a propeller, almost certainly with three blades. The propeller itself is chiral and after the engine with propeller is fitted, the boat as a whole has now become chiral by virtue of its propeller, which has also caused the boat to lose its plane of symmetry. Some types of aircraft use one or more propellers that each have four blades; each propeller is again chiral.

Light may be regarded as a wave motion that contains oscillating electric and magnetic fields. The electric field of light oscillates in all planes at right angles to the direction of propagation of the light wave. When a beam of normal light is passed through a device called a polarizer that in effect acts as a filter, only light waves that are oscillating in a single plane are allowed to pass through. The polarizer thus serves to block the passage of light that is oscillating in all other planes. The light that emerges from the polarizer is said to be plane-polarized. In 1815, the French physicist Biot made the important observation that when a beam of plane-polarized light is passed through a solution of certain naturally occurring organic compounds, the plane of polarized light is rotated either to the left or to the right. Molecules that induce this rotation are said to be optically active. The simplest class of optically active molecules has one carbon bonded to four different substituents and, of course, it is necessary for one to be in excess over the other. Measurements of optical activity are carried out with a polarimeter.

Each enantiomer undergoes chemical reactions at the same rate, as long as the other reagent (and the solvent) is not chiral. However, in the case in which the other reagent is chiral, the two enantiomers will react at different rates; this is the basis for enzymic selectivity. A pair of enantiomers represented by 37a and 37b, in which the carbons are called stereogenic centres or less justifiably chiral centres; the term asymmetric carbon is now encountered less frequently.

The opposite configurations of the stereogenic centres in 37a and 37b are indicative of the opposite directions in which they rotate the plane-polarized light. However, it is not possible from inspection of a particular enantiomer to say in which direction the plane is rotated. Enantiomers that rotate the plane to the right, that is, clockwise, are called dextrorotatory and are sometimes given the symbol ‘d’; those that rotate to the left, anti-clockwise, are correspondingly called laevorotatory with the symbol ‘l’. It should be made clear that the terms dextrorotatory and laevorotatory are defined with the observer looking into the propagating beam. These names and their symbols are empirical and have no fundamental significance. Also, those compounds that rotate the plane-polarized light to the right are frequently given the symbol (+), and those that rotate to the left the symbol (−).

Certain dimethylcycloalkanes contain a plane of symmetry. For example, both chair conformers of cis- 1,3-dimethylcycloalkane possess a plane of symmetry, bisecting the molecule through C-2 and C-5. The trans-isomer does not have any element of symmetry and is chiral. One simple test for chirality of substituted cycloalkanes is to represent the ring in planar form.

Some of the examples of ring sizes 3 to 6 are shown below.

Figure 9.2 Chiral and achiral distributed cycloalkanes

In order to characterize the extent of rotation, an index called specific rotation, [α]D, is used. This is given by the equation

‘α’ refers to the observed rotation in degrees, 1 is the length of the polarimeter cell in decimeters, and ‘c’ refers to the concentration of the sample in g 100 cm−3. On the left-hand side of the equation, ‘t’ refers to the temperature in °C at which the measurement takes place, and the subscript ‘D’ indicates that light from the D line of a sodium lamp with a wavelength of 589.6 nm was used. Sometimes the concentration c is expressed as g cm−3.

Enantiomers rotate the plane of polarized light in opposite directions by an amount that is characteristic of the compound. Specific rotation, [α], is a measure of the rotation at unit concentration using a cell (that contains the solution) of unit length.

9.3.2 How to Specify a Configuration

Since stereochemistry is a three-dimensional science that requires two-dimensional representation on paper, a number of conventions for representing structures have been developed. The earliest was Fischer’s projection formula. In order to specify the conformations, three modes of representations are commonly used, namely, saw-horse formula, Newman projection formula and flying wedge formula.

Fischer Projections Emil Fischer (1852–1919) a German chemist became a chemist against the wishes of his father, a successful merchant, who wanted him to enter the family business. In 1902, he received the second Nobel Prize in chemistry for his work on sugars and purine synthesis. Fischer projection represents stereoisomers in two dimensions. Unfortunately, it represents the molecule in its relatively unstable, eclipsed conformation. It is a planar projection formula of a three-dimensional molecular model obtained by drawing the main chain in a vertical arrangement and other groups on either side of that chain such that bonds drawn vertically are considered to be below or behind the projection plane and horizontal bonds above or in front of the plane.

Two conventions are in use to describe the configuration of a stereogenic centre. The older system uses the symbols D and L, and is still employed in two important classes of compound, namely amino acids and sugars; otherwise it has been superseded. The D/L system will be considered first. The use of capital letters here serves to distinguish this convention from d/l, which relates only to the direction in which the plane of polarized light is rotated.

In the early 1900s it was not possible to assign an absolute configuration to a chiral molecule with even a single stereogenic centre, although the need for a system of assignment was appreciated. Accordingly, an arbitrary standard was put in place; this consisted of the molecule glyceraldehyde (38), selected because of its close relationship to sugars. The representation of the three-dimensional structure is addressed as follows:

(+)-Glyceraldehyde was drawn as 38a, using what is known as a Fischer projection. The convention is that a stereo drawing of this molecule is shown as in 38. The vertical bonds are directed behind the page from the stereogenic carbon (which is not shown in a Fischer projection) and the horizontal bonds in 38a resemble a bow tie in 38, projecting out of the page. The decision was taken to assign (+)-glyceraldehyde (38a) the absolute configuration shown, which was termed ‘D’, and the enantiomer (−)-glyceraldehyde was then represented by 38b, and given the symbol ‘L’.

The configuration of (−)-39 is as shown and is accordingly D-glyceric acid. This result shows that there is no correlation between configuration and the sign of rotation.

Except for glycine, the alpha amino acids derived from proteins of higher living organisms have at least one stereogenic centre. Those with a single such centre are represented by Fischer projection formulae 40 (or the corresponding stereo diagram 40a), and all have the L configuration shown at the alpha carbon. In these amino acids, for example, serine, (40, R = CH2OH, assignment of the configuration was achieved by chemical conversions that related it to L-(−)-glyceraldehyde using L-(−)-lactic acid (41) as a relay.

There are further rules for the use of Fischer projections: (a) where relevant, the vertical direction is that of the carbon chain; (b) in the vast majority of cases, the carbon in the highest oxidation state is located at the top of the diagram.

Care must be exercised in testing whether two structures are, or are not, superimposable. Thus, a Fischer projection diagram of a chiral molecule with one stereogenic centre may be rotated only through 180° around the central carbon with preservation of configuration. Rotation of the Fischer projection by 90° inverts the stereogenic centre to give the other enantiomer; exchange of any two groups also produces the other enantiomer.

The representation of compounds containing more than one stereogenic carbon atom through Fischer’s projection is inadequate. There are three conventions that avoid this difficulty. In one, the ‘saw-horse’ representation, the bond between the carbon atoms is drawn diagonally, implying that it runs downwards through the plane of the paper and is slightly elongated for clarity. The substituents on each of the carbons are then projected on to the plane of the paper and can be represented as staggered or eclipsed, for example, for (−)-threose:

In the second, the Newman projection, the molecule is viewed along the bond joining the asymmetric carbon atoms and these atoms are represented as superimposed circles, only one circle being drawn. The remaining bonds and the substituents are then projected into the plane of the paper, the bonds to the nearer carbon being drawn to the centre of the circle and those to the further carbon being drawn only to the perimeter. The Newman projections for (−)-threose, which correspond to the saw-horse representation are:

In the third convention, the longest chain, or backbone of the molecule is drawn as a zig-zag in the plane of the paper; substituents in front and behind the plane are drawn with wedged lines and dashed lines, respectively:

9.3.3 Cahn–Ingold–Prelog R/S Conventions

In the 1950s Cahn, Ingold and Prelog developed a new convention for assignment of configuration at a stereogenic centre (Cahn was editor of the then Journal of the Chemical Society, Ingold from University College, London, initiated and established the study of organic reaction mechanisms and Prelog from ETH Zurich was a distinguished organic chemist who later won the Nobel prize in 1975). Frequently referred to by the initials of its proponents, the CIP convention (also known as the R/S convention) was proposed in 1966. The convention is now in almost universal use and forms part of the IUPAC (International Union of Pure and Applied Chemistry) rules of nomenclature. In a clean break with previous symbolism, the symbols ‘R’ (Latin, ‘rectus’ = right) and ‘S’ (Latin, ‘sinister’ = left) were adopted. Interestingly, the symbol ‘R’ was taken from the Latin word for ‘right’ in the sense of ‘just’ or ‘correct’. The Latin word for right (as in direction) is ‘dexter’, and use of this word would have maintained an undesired continuity with previous nomenclature.

The rules firstly require that the stereogenic centre be specified; next the groups attached to this centre are arranged in a sequence and given numbers 1, 2, 3, 4, corresponding to decreasing atomic number of the atom bonded to the stereogenic carbon. If, in a chiral molecule, two atoms directly bonded to the stereogenic centre are the same, the priority sequence is determined by relative atomic numbers at the first further point along the chains at which a distinction can be made. The convention thus operates in the same manner as when one looks up a name in a telephone directory.

In the case of a simple molecule, for example, butan-2-ol (42), the relevant priorities are assigned as shown. The molecule is then viewed looking toward the atom of lowest priority (H in 42) along a projection of the H–C bond, through a ‘triangle’ constructed of atoms 1, 2 and 3. The sense of decreasing priority 1 ~ 2 ~ 3 is clockwise for 42, which has R configuration. Strictly speaking, the symbol R applies to one carbon, but in molecules with one stereogenic centre this is often not specified.

Assignments of configuration are easier if the atom of lowest priority 4, typically H, is shown behind the plane of the paper. In cases in which the atom with priority 4 is shown in the plane of, or in front of, the paper, extra care is required, and it is beneficial to use a model and re-position the molecule so that it can be re-drawn with the atom of priority 4 behind the plane of the paper.

In a wider context, multiple bonds, such as those in C=O, C=CH2, C6H5 and C=NH, are treated as multiple single bonds and the σ- and π-bonds are given equal status. For two isotopes, which of course have the same atomic number, priority is assigned on the basis of greater atomic mass, that is, for the isotopes of hydrogen the priority is T > D > H. In the case of sulphoxides, for example, the lone pair is a formal substituent and has the lowest priority of all.

9.3.4 Enantiomers and Diastereoisomers

We know that a molecule with one stereocentre gives rise to two enantiomers. A molecule with two stereogenic centres gives rise to a maximum of four stereoisomers; a molecule with three stereogenic centres can have a maximum of eight stereoisomers, and so on. In general, if a molecule contains n stereogenic centres, a maximum of 2" stereoisomers can exist. The molecule 43 has two stereogenic centres and has a different set of substituents at each centre; accordingly, there are four stereoisomers. In designating the stereochemistry of, say, 43, the molecule is first numbered systematically. The configuration at each stereogenic centre is determined in the same way as for molecules with one stereogenic centre.

The symbol R or S is then associated with a particular carbon by its number and the pair of symbols is placed in brackets. Accordingly, for 43, the four stereoisomers can be (1R,2R), (1R,2S), (1S,2S) and (1S,2R).

It can be seen that the stereoisomers with configuration (1R,2R) and (1S,2S) are related as enantiomers, and the (1R,2S) and (1S,2R) stereoisomers are also related as enantiomers. The stereoisomers of 43 with configurations (1R,2S) and (1R,2R) have one stereogenic centre of common, (1R), and the other of opposite, (2S) and (2R), configuration. Clearly these stereoisomers are not enantiomers. Instead, they are related as diastereoisomers and the same can be said for the (1S,2R) and (1S,2S) stereoisomers. The most concise definition, given in the plural, is: ‘diastereoisomers are stereoisomers that are not enantiomers (mirror images)’. Diastereomers can arise when structures have more than one stereogenic centre. With three stereogenic centres, there are 8 (23) ways of arranging the isomers, that is, RRR, RRS, RSR, RSS, SSS, SSR, SRS, SRR.

Diastereomers include all stereoisomers that are not related as an object and its mirror image. For example, 2, 3, 4-trihydroxybutanal has four stereoisomers. The configuration of C-2 and C-3 are indicated. Each of the four structures is stereoisomeric with respect to any of the others. The 2R,3R and 2S,3S isomers are enantiomeric, as are the 2R,3S and 2S,3R pair. The 2R,3S isomer is diastereomeric with the 2S,3S and 2R,3R isomers because they are stereoisomers but not enantiomers.

Figure 9.3 Stereoisomeric relationship in 2,3,4-trihydroxybutanal

Any given structure can have only one enantiomer. All other stereoisomers of that molecule are diastereomeric. The relative configuration of diastereomeric molecules is frequently specified using the terms syn and anti. Diastereomers with substituent on the same side of the extended chain are syn stereoisomers, whereas those with substituents on opposite sides are anti stereoisomers. Sometimes, the terms erythro and threo are also used to specify the relative configuration of two adjacent stereogenic centers. Enantiomerization is a process of conversion of one enantiomer into the other, during the process, both stereogenic centres are inverted, whereas to go from one diastereomer to another (diastereomerization), only one of the two is inverted.

Molecules that are related as diastereoisomers have different melting points, boiling points, chromatographic mobilities and solubilities, and have different rates of reaction. In some cases, these different rates of reaction can lead to a particular product being formed from a reaction of one diastereoisomer but not the other. The specific rotations of diastereomeric molecules differ in both magnitude and sign. Diastereomers can be separated by methods such as crystallization or chromatography.

Enantiomeric excess (ee), enantiomeric ratio A sample that consists of one enantiomer of a chiral compound is said to be enantiomerically pure. This term has mainly replaced ‘optically pure’, which historically was used because the enantiomer content of a sample was determined polarimetrically. Nowadays, other more accurate methods are employed in many instances.

The term ‘enantiomeric excess’, which gives a measure of the enantiomeric makeup of a sample that contains enantiomers A and B, is given by:

An enantiomeric excess of 50% signifies that the sample contains 75% of the enantiomer with, say, R configuration and 25% of S; that is, 50% of a 1:1 mixture and 50% of the R enantiomer. Some other techniques (for example, NMR spectroscopy and gas-liquid chromatography) are used to derive enantiomer proportions under conditions in which each enantiomer gives its own ‘signal’, these are now more rationally expressed as a ratio rather than as an excess.

9.3.5 Racemization

A racemic mixture (or racemate) is defined as a 1:1 ratio of enantiomers. This corresponds to an enantiomeric excess of 0%, or an enantiomeric ratio of 1. Racemization involves the progressive loss of optical activity with time, usually in accord with a well-defined kinetic process. If the starting materials of a reaction are achiral, and the products are chiral, always, a racemic mixture will be formed.

Racemic compounds, or dl pairs, arise from (a) deliberate racemization of enantiomers by interconversion, (b) mixing the enantiomers in a 1:1 molar ratio, and (c) synthesis in the absence of a biasing influence that would cause one enantiomer to predominate.

It should also be noted

  1. that for a molecule with one stereogenic centre, it is not possible to have a single molecule of a racemate; one needs at least both a molecule in which the stereogenic centre has R configuration and a molecule in which it has S (one can alternatively say that one needs a molecule of D configuration and one of L configuration).
  2. a racemic sample of a compound is composed of chiral molecules, just as is the case for a sample of either enantiomer.

A racemate can crystallize in one of three ways: when each enantiomer has a greater affinity for molecules of its own kind than for those of the other, the enantiomer tends to crystallize separately to give a racemic mixture of two types of crystals; when each has a greater affinity for molecules of the other enantiomer, the crystal grows by the laying down of (R)- and (S)-molecules alternatively; to give a racemic compound; when there is little difference between the affinities of one enantiomer for molecules of its own type and for those of the other, the arrangement in the solid is random and a racemic solid solution is obtained.

9.3.6 Meso Configuration

Compounds that contain stereogenic centres, but are themselves achiral are called meso-compounds. In contrast to the general case of 43, we now consider molecules with two stereogenic centres, but which carry an identical set of substituents at each carbon. We then analyse the relative configurations of these substituents and the stereochemical consequences.

As a prototype molecule, tartaric acid (44; 2,3-dihydroxybutanedioic acid), without stereochemical specification, is chosen. Tartaric acid is a compound of considerable historical importance, and derivatives of tartaric acid are still compounds of contemporary research interest. (2R,3R)-(+)-Tartaric acid is shown in sawhorse projection in 45.

The enantiomer of 45 is shown in 46 and is (2S,3S-(−)-tartaric acid. Of course, in principle, any conformation of 45 may be used, with its mirror image, to demonstrate that the compounds in the pair are enantiomers; however, use of the eclipsed forms 45 and 46 are visually easier.

Fischer projections of 45 and 46 are given in 47 and 48, respectively, and the corresponding Newman projections, looking along the C(2)–C(3) bond, are shown in 49 and 50, but now with the rotation of the ‘back’ groups around the C(2)–C(3) bond such that the molecules are shown in staggered and visually less cramped conformations.

We now consider the other configurations of tartaric acid, that is, (2R,3S) 51 and (2S,3R) 52. Here, the presence of identical sets of substituents at C(2) and C(3) brings about a difference from the general case that was shown by 43. Inspection of 51 and 52 reveals that 52 is a mirror image of 51 (and vice versa). However, 51 and 52 are identical and superimposable.

Therefore, and importantly, this molecule is achiral despite containing two stereogenic centres. This can be shown in two ways.

  1. If one focuses on 51, in the conformation shown, there is seen to be a plane of symmetry in this molecule half–way along the C(2)–C(3) bond, such that −CO2H reflects on to −CO2H, −OH on to −OH and H on to −H.
  2. Take a molecular model of 51, and break the C(2)–C(3) bond into half, and then mark the ‘break’ on both sides with tape, or similar, and regard the taped ends as identical substituents. Examination of the resultant taped fragments clearly reveals that C(2) and C(3) are of opposite configuration.

However, 51 is not chiral and one can accordingly amplify the definition given earlier to state: if a molecule possesses a plane of symmetry in any energetically available conformation, it cannot be chiral. This statement holds whatever the complexity of the molecule. However, it should be noted that chiral molecules can possess axes of symmetry.

The achiral nature of 51 is also implicit in the designation of configurations (2R,3S) or (2S,3R), with identical sets of substituents at the stereogenic centres. As regards optical activity, the effects of C(2) and C(3) in 51 are self cancelling because the stereogenic centres have opposite configuration; indeed, in early literature, compounds such as 51 were described as ‘internally compensated’. Nowadays, such compounds are given the prefix meso, and use of the term is general; meso compounds are always achiral (and optically inactive) even though they have two or more stereogenic carbons.

9.3.7 Erythro/Threo and Syn/Anti Configurations

Let us now look at molecules with two stereogenic centres, usually adjacent, which have two common substituents. The names of the two configurations are taken from two carbohydrates, but are now used quite generally. D-Erythrose, shown in Fischer 53 and sawhorse 54 projections in its open-chain forms, is such a compound. In 54, the pairs of like substituents are shown in an eclipsed conformation.

First, one might ask: why is 53 given the configuration D? This assignment is based on the configuration of the stereogenic carbon that is furthest from the carbonyl group [that is, C(3) in 53] with respect to that of D–glyceraldehyde (55). Since they are the same, 53 is given D configuration. This protocol can also be applied to longer chain sugars such as pentoses and hexoses (erythrose and threose are themselves tetroses). If, as in 54, it is possible to eclipse each of the like substituents, H with H, OH with OH, and also the ‘unlike’ substituents, CHO and CH2OH, the configuration is erythro. The nomenclature is quite general; thus erythro–3–phenylbutan–2–ol is shown in 56. Of course, 54 and 56, and indeed all erythro compounds, have enantiomers, but this does not concern us here.

The second configuration is termed threo, and originates from the sugar ‘threose’; D-threose is shown in Fischer 57 and sawhorse 58 projections. With respect to D-erythrose (53), only the configuration at C(2) has changed. Two consequences follow from this: (i) 53 and 57 are related as diastereoisomers and (ii) the stereochemical symbol is D in both 53 and 57.

Use of the terms erythro and threo is quite explicit in the context of two adjacent stereogenic centres, each of which has two sets of substituents in common. However, some confusion has arisen when erythro/threo nomenclature has been applied to systems in which there is only one common substituent on the two adjacent carbons. However, here is the basis of an alternative nomenclature system, which is now becoming more common, introduced by Masamune et al. The main chain is drawn as a zig-zag and lies in the plane of the paper. Substituents that lie on the same side of the plane are termed syn, and those that do not are termed anti.

9.4 HOMOCHIRAL MOLECULES

Kelvin introduced the term homochiral in 1904. Molecules are homochiral if they possess same sense of chirality. For example, the right hands of a group of people are homochiral (or alike). More recently, and unfortunately, homochiral has been used in the sense of enantiomerically pure, that is, one reads of a ‘homochiral compound’, which clearly violates the original definition.

9.5 CAGED COMPOUNDS WITH TWO STEREOGENIC BRIDGEHEAD CARBONS

An example of a compound with two stereogenic carbons in a rigid caged structure is camphor, a naturally occurring bicyclic ketone, which is more abundant in the (+)-form 63. The presence of the carbonyl group in camphor results in two stereogenic centres, at C(1) and C(4). A bicyclic compound, chiral because of stereogenic bridgehead carbons, is restricted to two enantiomers, and no diastereomers.

Accordingly, in 63, C(1) has R configuration, as has C(4). It is not possible to construct a camphor in which C(1) has R configuration and C(4) has S configuration. The (+)-camphor shown in 63 is (1R,4R)-camphor, but on account of the cage structure it is sufficient to specify 63 as (1R)-camphor. The only other possibility is the more expensive enantiomer 64, which is (1S,4S)-camphor, and this enantiomer is often referred as (1,S)-camphor. Camphor and other chiral, caged molecules with stereogenic centres at bridgehead carbons, for example, α-pinene (65), are examples of molecules that possess two stereogenic centres, but which have only two stereoisomers, related as enantiomer of each other. Of course, derivatives of such molecules may contain additional stereogenic centres.

9.6 EPIMERS AND NOMENCLATURE OF BICYCLIC COMPOUNDS

Epimers are diastereoisomers whose configurations differ at only one carbon in a compound that possesses more than one stereocentre. The term epimer originated in sugar chemistry and can be illustrated with the examples of D–lyxose (66) and D–xylose (67). There are three stereogenic centres in each of these molecules; the configuration at C(3) and C(4) are the same in both, whereas the configuration of C(2) differs from that in 67. Two diastereoisomers that differ in configuration at only one stereogenic carbon are called epimers. The term is quite general, though it is rarely applied to molecules with only two stereogenic centres. Consider, for example, reduction of (1R)–camphor (63) with LiAlH4 to give two alcohols, isoborneol (68) and borneol (69). These alcohols fulfil the criteria for being epimers; their configurations are the same at C(1) and C(4), and are opposite at the hydroxyl–bearing carbon, C(2). Although the configurations at C(2) in 68 and 69 can, of course, be specified by the usual R,S convention, there is an alternative and convenient way to describe them. This uses the terms exo and endo, and makes use of the number of ring carbons that constitute the bridges that connect the bridgehead carbons at C(1) and C(4). A substituent on a particular bridge is called exo if it is on the same side as the smaller bridge, that is, the one carbon bridge formed by C(7) [and in which C(7) is bonded to two methyl groups]. On the other hand, the OH group in 69 is described as endo because it is opposite the smaller bridge. In reduction of 63, the preferred approach of LiAlH4 to the carbonyl group is from the less–hindered endo direction with the resultant formation of the exo alcohol 68 as the major product. The designations endo and exo thus serve as internal markers only, that is, in specifying that the OH group is syn (same side) or anti (opposite) to the shorter bridge. These terms do not specify whether the configurations of the OH–bearing carbons in 68 and 69 are R or S.

9.7 SEPARATION OF ENANTIOMERS: RESOLUTION

Resolution can be thought of as the converse of racemization. One starts with a 50:50 mixture of both enantiomers and separates this mixture into the individual enantiomers. As enantiomers have identical properties, including solubility, separation of enantiomers by recrystallization is quite rare. Depending on the requirements, chiral compounds may be partly resolved (partial resolution) or completely resolved (total resolution). It can be made by the following methods.

9.7.1 Mechanical Separation—Crystallization Method

The method of resolution was initiated by Pasteur in 1848. Pasteur’s key observation was that two distinct but related types of crystals were obtained from an aqueous solution of the sodium ammonium salt of racemic tartaric acid. The two types of crystals were related as object and non-superimposable mirror image, and one type was identical to the dextrorotatory crystals of sodium ammonium tartrate obtained from (+)-tartaric acid, itself obtained as a by-product of wine-making. Pasteur separated his crystals manually with the aid of a magnifying glass and tweezers. Moreover, he demonstrated that solutions of the two types of crystals had the same value of specific rotation, though of opposite sign.

9.7.2 Resolution through Formation of Diastereomers

Typically, resolution depends on the conversion of enantiomers, which possess identical physical properties, into diastereoisomers, which do not, and then exploiting the difference in physical properties in order to separate the diastereoisomers. Finally, the diastereoisomers are reconverted to the component, and separated as enantiomers.

Resolution of a carboxylic acid can be achieved directly by formation of diastereomeric salts with an amine. Naturally occurring bases, such as brucine (70) or ephedrine (71), are often used. Resolution of alcohols requires a more ingenious approach in order to acquire suitable diastereomeric salts for resolution by recrystallization. The racemic alcohol, ROH, to be resolved is first converted to its phthalate monoester 72 (phthalic acid is benzene-1,2-dicarboxylic acid). The strategy here is to leave one carboxylic acid group free and available to form diastereoisomeric salts with an amine such as 70 or 71. Once the appropriate ammonium salt of 72 has been resolved, the amine is removed by acidification to give one enantiomer of 72, and this ester is then hydrolyzed with alkali to give one enantiomer of ROH. The more soluble diastereomeric ammonium salt can then, in principle, be processed similarly to yield the other enantiomer.

For successful execution, several conditions should be fulfilled, which are as follows:

  1. The substrate and the resolving agent must have suitable functional groups capable of interacting with each other.
  2. It is essential that the configuration of the chiral centres remains unchanged during the formation of the diastereoisomers as well as during the regeneration of the enantiomers.
  3. The resolving agent should be available in enantiomerically pure form.
  4. The choice of solvent is also very important. The most usual solvents are water, alcohols, acetone and ethyl acetate.

9.7.3 Separation of Enantiomers by Chromatography

It is also possible to resolve enantiomers by means of column chromatography. If a column consists of, or contains, a suitable chiral stationary phase, the enantiomers should be eluted that is, washed from the column, at different rates. This is because, although there is no formation of chemical bonds, the enantiomers now experience diastereoisomeric interactions with the chiral stationary phase. The success of chiral column chromatography depends on diastereoisomeric interactions between the chiral stationary phase and the enantiomers; this leads to differential adsorption of enantiomers. Chiral stationary phases can consist of starch, which, for instance, allows almost complete resolution of mandelic acid.

9.7.4 Resolution with Enzymes

Enzymes are compounds of high molar mass, generally contain many amide groups, and catalyze certain reactions in living cells. All enzymes are catalysts; they are themselves chiral and, in their natural aqueous environment, are very stereoselective. Some enzymes are highly selective in the reactions that they catalyze, whereas others are more broadly receptive: in general, enzyme-catalyzed reactions tend to be rapid. A discussion of the characteristics of enzymes and their mode of action is given by Stryer. Furthermore, enzymes have been instrumental in bringing about resolution of enantiomers under laboratory conditions. A quantitative analysis of biochemical kinetic resolutions of enantiomers has been made by Chen et al.

In order to give a flavour of the method, three examples are presented here. As part of a project to synthesize one enantiomer of a chiral insect pheromone, resolution of 75 was required. This was achieved by enantioselective hydrolysis of racemic 75 to produce alcohol 76. The other enantiomer was left untouched by Pseudomonas cepacia lipase (PCL), the enzyme of choice. After reaction is completed, alcohol must be separated from its enantiomeric acetate 77. It is noteworthy that the enzyme functions in a buffered aqueous acetone medium; acetone does not interfere with the action of the enzyme.

Enzymic resolutions involve acceptance by the enzyme, which is a very finely honed chiral system, of one enantiomer of a racemic compound, but not the other. The selective acceptance arises because interactions between the enzyme and the enantiomers are diastereomeric. In its natural environment, the ability of an enzyme to discriminate between enantiomers is virtually absolute. In addition to their stereoselectivity, some enzymes can react at very high rates.

It should be evident that the maximum yield of a particular enantiomer normally available from a racemic mixture is 50%. However, in some enzymic catalyzed kinetic resolutions, it is possible to obtain >50% yield of one enantiomer from a racemate. For this to occur, it is necessary to have the desired chemical reaction; for example, enzyme-catalyzed stereoselective esterification, occurring at the same time as the enantiomers of the racemic starting compound are interconverting under equilibrium conditions. A successful example of this technique is provided by benzaldehyde cyanhydrin (2-hydroxy-2-phenylacetonitrile), the R and S enantiomers, 78 and 79, respectively, of which equilibrate in the presence of a basic anion-exchange resin. In the presence of lipase, (S)-benzaldehyde cyanhydrin acetate 80 was formed in 95% yield and in 84% enantiomeric excess

As an alternative to resolution, one can start with an enantiomerically pure compound that occurs naturally, and the most common examples of these are amino acids, sugars and terpenes. This group of compounds is known collectively as the chiral pool. The procedure then is to transform the compound of choice from the above group into the desired product by chemical synthesis, with care taken to avoid racemization at stereogenic centres.

9.8 SUMMARY

The conventional representation of methane by two dimensions is given, and is applicable to saturated carbon in general. In methane, four equivalent C-H bonds arise from hybridization of one 2s and three 2p carbon orbitals to give four equivalent sp3 hybrid orbitals. The HCH bond angles at carbon in methane are 109° 28’. Both carbons in ethene are sp2 hybridized. The component orbitals that form the hybrid orbitals are one 2s and two 2p. There remains a ρ orbital on each carbon, and these orbitals overlap sideways to form a π bond. Rotation around the axis of the C–C σ bond in ethane means that one set of three hydrogens rotates relative to the other. When this happens the conformation of ethane changes. As hydrogens pass each other (eclipsed conformation) the energy of the ethane molecule rises. At 60° away from this eclipsed conformation comes the most stable conformation, called staggered; intermediate conformations are called skewed. The more involved rotation around the central C-C bond in butane contains a conformation called gauche, in which the dihedral angle between the methyl groups is 60°. When this angle is 180° the conformation is trans.

Cyclohexane, the most important cyclic hydrocarbon, is most stable in the chair conformation, which has very little angle and torsion strain. Hydrogens occupy equatorial and axial positions. At room temperature, cyclohexane inverts conformation rapidly, thus, the equatorial hydrogen becomes axial and, correspondingly, the axial becomes equatorial. 1,2-Diaxial hydrogens are mutually trans and 1,3-diaxial hydrogens are mutually cis. Substituents prefer the more open equatorial position, free from nonbonded interactions, to an extent that is greater, the bulkier the substituent.

Two conventions that are very useful in defining the stereochemistry of molecules are described. The D/L convention is used for sugars and amino acids. Sugars are related to standard, D-(+)-glyceraldehyde, and naturally occurring amino acids are related to L-(−)-glyceraldehyde. The R/S or CIP convention involves assignment of priorities, based on atomic numbers, to the four substituents at a stereogenic carbon or centre. The R/S convention is in almost universal use throughout organic chemistry.

Compounds with n stereogenic centres give rise to a maximum of 2n stereoisomers. A 50:50 mixture of enantiomers is called a racemate; a partially racemized compound is called scalemic. In this latter case, the constitution of a mixture is described numerically by an enantiomeric excess or by an enantiomeric ratio. Cis and trans isomers are geometric isomers also justifiably called diastereoisomers. Caged bicyclic compounds with stereogenic centres only at the bridgehead positions are restricted to two enantiomeric forms. Epimers are usually compounds with three or more stereogenic centres, but which differ in configuration at only one. Resolution is the separation of enantiomers from a racemic mixture.

PROBLEMS
  1. In what stereoisomeric forms would you expect the following compounds to exist?
    1. EtCH(CO2H)Me
    2. MeCH(CO2Et)CO2H
    3. Et(Me)C=C=C(Me)Et
  2. Assign R/S configuration at each stereogenic centre in the following molecules:
  3. What makes molecules chiral? Give three examples of different types of chirality.
  4. Draw sawhorse and Newman projection diagrams of the following structures, which are shown as Fischer projections. Which compound is optically inactive?
  5. Draw two chair forms each for the six possible dimethyl cyclohexane molecules and indicate which is the most stable of each pair. Then arrange the six molecules in order of decreasing stability.
  6. What are the stereochemical relationships between the following pairs of isomers?
  7. What products would you expect from the following reactions?
    1. The dehydration of 1,1,3-triphenyl-3-p-chlorophenylpropan-2-ol.
    2. The treatment of (I) with (i) OH and (ii) HBr.
    3. The elimination of bromine from meso-1,2-dibromo-1,2-diphenylethane by treatment with iodide ion.
    4. The treatment of CH3CHXCH2CH3 with base when (i) X = Cl (ii) X = +NMe3
  8. With reasons, state whether each of the following compounds I to IX is chiral.
  9. Give the product(s) described for each reaction. Specify all aspects of stereochemistry.
    1. Stereospeciflc anti addition of bromine to Z- and E-cinnamic acid.
    2. Solvolysis of (S)-3-bromooctane in methanol with 6% racemization.
    3. Base-induced elimination of HCl from cis- and trans-1-chloro-4-methylcyclohexanone.
    4. Reduction of 4–tert–butylcyclohexanone with (i) LiAlH4/H2O and (ii) EtMgBr/H2O.
  10. Define the following terms:
    1. Racemization
    2. Enantiomerism
    3. Diastereoisomerism
    4. Epimerization
    5. Anomers
    6. Homochiral molecule
    7. Configuration
    8. Conformation
  11. Write out three-dimensional formulae for all the isomers of the following compounds. Indicate the enantiomeric and diastereomeric relationships. Point out all isomers that are optically active.
  12. Consider the isomers of 2-cyano-3-methyl-5,5-dichloro-4-cyclohexanone-1-carboxylic acid.
    1. How many stereoisomers and racemates are possible?
    2. How many chiral carbons must be inverted in a configuration to convert one stereoisomer into its enantiomer?
    3. How many must be inverted to form an epimer?
  13. Draw the structure that satisfies each description below.
    1. A saturated hydrocarbon, C14H26, with more than 50 stereoisomers.
    2. A linear symmetric hydrocarbon with four possible geometric isomers.
    3. A meso hydrocarbon, C9H20.
    4. A meso hydrocarbon, C10H20, which absorbs one mole of hydrogen over platinum.
    5. More stable isomer of 3-methylcyclobutane carboxylic acid.
  14. Draw Fischer projections for all the stereoisomers of (a) 2,3,4-trihydroxypentanoic acid and label each stereogenic carbon R- or S-; (b) 3,5-dimethylcyclohexanol.
  15. For each example given below:
    1. delineate the number and kind of stereoisomers;
    2. draw the most stable conformation of each;
    3. determine the most stable of the stereoisomers.
      1. 3-hydroxy-5-methylcyclohexanecarboxylic acid
      2. 3-hydroxy-3-methylcyclohexane-carboxylic acid
      3. 4-hydroxy-4-methylcyclohexanecarboxylic acid;
      4. 1,3,5-cyclohexanetriol (v) 1,2,3-cyclohexanetriol.
OBJECTIVE TYPE QUESTIONS
  1. Which compound is a D-sugar, giving on oxidation an optically active dibasic acid?
  2. Which compound is a D-sugar, giving on reduction an optically active pentitol?
  3. trans- 1,3-Di-t-butylcyclohexane exists primarily in the
    1. racemic form
    2. staggered form
    3. chair conformation
    4. boat conformation
  4. Which compound is an L-sugar giving on reduction an optically inactive pentitol?
  5. The preferred conformation of trans- 1,2-dibromocyclohexane is:
    1. diaxial
    2. diequatorial
    3. axial/equatorial
    4. neither A, B, nor C
  6. How many stereoisomers of 1,2-dichlorocyclohexane are optically active?
    1. None
    2. One
    3. Two
    4. Four
  7. The compound with the above configuration is called:

    1. (2S,3S)-2-chloro-3-hydroxypentane
    2. (2S,3R)-2-chloro-3-hydroxypentane
    3. (2R,3R)-2-chloro-3-hydroxypentane
    4. (2R,3S)-2-chloro-3-hydroxypentane
  8. How many stereoisomers can exist for the following acid
    1. Two
    2. Four
    3. Eight
    4. Sixteen
  9. Which one of the following statements is true?
    1. Diastereoisomers are a pair of isomers related spatially as object and mirror image.
    2. Diastereoisomers can often be separated by fractional crystallization.
    3. Diastereoisomers rotate the plane of polarization of plane-polarized light to an equal but opposite extent.
    4. Diastereoisomers have identical physical and chemical properties.
  10. The Fischer projection formula shown represents one of the stereoisomers of the drug ephedrine, 1-phenyl-2-methylaminopropan-1-ol. This structure shown is:

    1. (1R,2S)-1-phenyl-2-methylaminopropan-1-ol
    2. (R,R)-1-phenyl-2-methylaminopropan-1-ol
    3. (1S,2R)-1-phenyl-2-methylaminopropan-1-ol
    4. (S,S)-1-phenyl-2-methylaminopropan-1-ol
  11. An optically active carboxylic acid, X, has the molecular formula C6H10O2 and can be shown by chemical and physical tests to contain the group −CH=CH2 and at least one −CH3 group. When X is reduced with hydrogen over platinum, the product formed is optically inactive. Which of the following best represents the structure of X?
    1. CH2=CH-CH(CH3)-CH9-COOH
    2. CH2=CH-CH(CH2.CH3)-COOH
    3. CH2=CH-CH2-CH(CH3)-COOH
    4. CH2=CH-C(CH3)2-COOH
  12. Which of the following completions is incorrect? A pair of enantiomers is identical with each other with respect to their
    1. chemical reactivity
    2. melting point
    3. direction of rotation of plane-polarized light
    4. solubility in a given solvent
    5. density
  13. Which of the following completions is incorrect? Tautomerism is exhibited by
    1. ethyl 3-oxybutanoate
    2. pentan-2,4-dione
    3. dimedone
    4. propan-2-ol
    5. 1-phenylprop-3-en-1-ol
  14. How many stereoisomers of the following molecule are possible?

    HOOC.CH=C=CH.COOH

    1. two optical isomers
    2. two geometrical isomers
    3. two optical and two geometrical isomers
    4. none
  15. Which of the following compounds can exist in enantiomeric (that is, D and L) forms?
  16. Which of the following compounds can exist in two geometrically isomeric forms?
    1. CH3−C ≡ C−CH3
    2. CH3.CH2.CH=CH.CH3
    3. CH3.CH2.CH2.CH=CH2
  17. The structures shown here are related as being:
    1. identical
    2. enantiomorphs
    3. geometrical isomers
    4. diastereoisomers
    5. none of these
  18. Which of the following structures represents R-2,3-dichloro-4-methylhex-3(E)-ene?
  19. How many isomeric structures are possible for 2-methylcyclobutanone oxime?
    1. one only (no isomers)
    2. two
    3. three
    4. four
  20. One of the following completions a to e is incorrect. Choose the letter corresponding to the incorrect completion: Geometrical isomerism is exhibited by
    1. pent-2-ene
    2. 1-chloropropene
    3. 3-chloropropene
    4. 1,2-dibromoethene
    5. 3-bromo-4-methylhex-3-ene
  21. Which of the following molecules is identical with that represented by
  22. Which of the following pairs are isomers?
    1. C5H10 and C10H20
    2. CH3.(CH2)4.CH3 and CH3.(CH2)3.CH3
    3. CH3.CH(CH3).(CH2)2.CH3 and CH3.(CH2)2.CH(CH3)2
    4. (CH3)3.CH and CH3.CH2.CH2.CH3
  23. Which of the following pairs of compounds are identical?
  24. Which compound is an isomer of CH3.CH2.CH2.CH2.OH
    1. CH3.CH2.O.CH3
    2. CH3.CH2.CH2.OH
    3. CH3.CH2.CH2.CH3
    4. CH3.CH(OH).CH2.CH3
    5. CH3.CH2.CH2.CH2.CH2.OH
  25. Which of the following cannot be written in an isomeric form?
    1. CH3-CH(OH)-CH2-CH3
    2. CH3-CHO
    3. CH2=CH-Cl
    4. Cl-CH2-CH2-Cl
    5. CH3-CH2-CH=CH-CH3
  26. Which of the following statements is not an essential feature of an optically active molecule? An optically active molecule will
    1. rotate the plane of polarized light
    2. have a non-superimposable mirror image
    3. have no element of symmetry
    4. have an asymmetric carbon atom
  27. How many pairs of diastereoisomers are possible in the following molecule? Ph.CH(Cl).CH(Ph).CH(Cl).Ph
    1. none
    2. two
    3. four
    4. eight
  28. A compound reacts reversibly with another to give two products that are isomeric. Isomer X is thermodynamically more stable than isomer Y but Y, is formed much faster. What would the reaction product consist of after reaction times which were (1) short and (2) very long? Select from
    1. (1) mainly X (2) mainly X
    2. (1) mainly Y (2) mainly Y
    3. (1) mainly X (2) mainly Y
    4. (1) mainly Y (2) mainly X
  29. Which of the following is capable of exhibiting optical isomerism?
    1. 1,2-Dichloropropane
    2. 1,3-Dichloropropane
    3. 1,1-Dichloropropane
    4. 2,2-Dichloropropane
  30. Which of the following compounds is optically active?
    1. CH3.CH(OH).CH3
    2. CH3.CH(OCH3).CH3
    3. CH3.CH(OH).C6H5
    4. CH3.CO.CH3
    5. CH3.CH2.C6H5
  31. Which of the above formulae represent identical compounds?

    1. I and II
    2. I and IV
    3. II and IV
    4. III and V
  32. Which of the above compounds are enantiomers?

    1. II and III
    2. III and IV
    3. III and V
    4. I and V
  33. Which compounds are both meso forms?

    1. IV and II
    2. I and III
    3. II and V
    4. IV and V
  34. In the following sequence of standard stereochemical formulae, indicate either one or more that may be identical with A.
  35. In the following sequence of standard stereochemical formulae, indicate one or more that are identical with A.
  36. These compounds are

    1. enantiomers [enantiomorphs]
    2. diasteroisomers
    3. conformers
    4. geometrical isomers
    5. identical
  37. The above compounds differ in

    1. configuration
    2. conformation
    3. structure
    4. chirality
    5. molecular weight.
  38. Which species exhibits a plane of symmetry?
  39. Which of the following compounds are optically active?
    1. CH3.CHOH.CH2.CH3
    2. H2C=CH.CH2.CH=CH2
  40. Applying the Sequence Rule, which of the following priority arrangements is correct in determining the R/S configuration of
    1. −C6H5 > −CH=CH2 > −CHO > −COOH
    2. −CH=CH2 > −CHO > −COOH > −C6H5
    3. −COOH > −CH=CH2 > −CHO > −C6H5
    4. −COOH > −CHO > −C6H5 > −CH=CH2
    5. −COOH > −C6H5 > −CHO > −CH=CH2