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Basic Concepts of Stereochemistry

Isomers are molecules that have the same molecular formula but different arrangements of their constituent atoms. Constitutional isomers (structural isomers) have different bonding arrangements of their atoms (connectivity) and usually show very marked differences in physical and chemical properties. Connectivity differences can involve the carbon skeleton or the nature and position of functional groups.

Stereoisomers are molecules with identical connectivity but different spatial arrangements of their constituent atoms that cannot be interconverted by bond rotation.

The Cahn–Ingold and Prelog Sequence Rules

In order to categorise stereoisomers it is necessary to prioritise different atomic substituents using the Cahn–Ingold and Prelog sequence rules that are applied in order until a distinction is found. Rank substituents in order of decreasing atomic number of the first bound atom. Any higher isotope takes precedence over a lower isotope (H3 > H2 > H1). A lone pair counts as the lowest priority substituent. If no distinction is possible at the first atom, consider atoms at increasing distances until a difference is found. For the purposes of ranking, a multiple–bonded atom is considered equivalent to the same multiple of single–bonded atoms and has higher priority than the corresponding single–bonded substituent.

Chirality (Stereogenicity)

Chirality (cheir, Greek for "hand") refers to objects which are related as non–superimposable mirror images and the term derives from the fact that left and right hands are examples of chiral objects.

sp3–Hybridised carbon atoms possessing four different substituents display this property due to their tetrahedral geometry. Such an asymmetrically substituted carbon atom is a stereogenic centre and is the commonest source of chirality in organic molecules. Unambiguous definition of the spatial arrangement of substituents on a stereogenic centre that distinguishes mirror images gives the absolute configuration. A convention permitting structural distinction between two opposite absolute configurations is based upon the sequence rules. It is independent of the chemical or physical properties of the molecule and is equally applicable to tetrahedral stereocentres other than carbon.

(i) Rank substituents on the stereogenic centre in order of decreasing priority using the sequence rules. (ii) View the stereogenic centre with the lowest priority substituent pointing away. (iii) If the order of priority of the three remaining substituents decreases in a clockwise manner the centre is defined as (R)– (rectus, Latin for "right"). (iii) If the order decreases in an anti-clockwise direction the centre is defined as (S)– (sinister, Latin for "left").

Anti-clockwise direction }(S)–Alanine

Enantiomers

An enantiomer is one of a pair of stereoisomers that are related as non–superimposable mirror images. Enantiomerism commonly results from the presence of one or more stereogenic centres in a molecule but may also occur in orthogonal structures (allenes, hindered biaryls), helical structures (E–cyclic alkenes, helicenes) and extended tetrahedra (differentially substituted adamantanes). Such molecules are chiral and display identical chemical and physical properties in an achiral environment. However, opposite enantiomers will react at different rates with a single enantiomer of a reagent. A solution of a single enantiomer will rotate the plane of plane–polarised light and is referred to as optically active; although this physical property cannot be directly related to absolute configuration of the molecule. An enantiomer is given the prefix (+)– if the rotation is clockwise (dextrorotatory) and (–)– if the rotation is anticlockwise (levorotatory). Examples

An equal mixture of opposite enantiomers is a racemate and solutions of racemic mixtures do not rotate the plane of plane–polarized light. Clearly, unequal mixtures of two enantiomers will have a lower optical rotation than a pure enantiomer and the strength of this rotation will depend upon the enantiomeric excess (e.e.) of the mixture. Mixtures of unequal amounts of enantiomers are referred to as scalemic.

Enantiomeric Excess = (%Enantiomer A –% Enantiomer B)%

Specific Rotation

The specific rotation enables comparison of optical activity between samples by standardising the analysis conditions and permits determination of the enantiomeric excess. For dilute solutions the degree to which a substance rotates plane–polarised light depends upon the number of molecules present in solution and their ability to interact with the light. This is in turn dependent upon the concentration of the solution, the path length of the cell and the wavelength of the light used for analysis. Commonly specific rotation is quoted for light at the wavelength of the D line of the emission spectrum of sodium (589.3nm). The temperature of the sample and the nature of the solvent may also affect the value and these must also be stated when quoting specific rotation. The sign of the rotation must also be quoted. If clockwise it is +ve and if anticlockwise –ve.

Where: a = observed rotation of sample (symbol 176 \f "Symbol" \s 12°) c = concentration of sample (g 100mL–1) l = pathlength of cell (dm) Quoted as: [a]Dt = ± X (c = Y, solvent) • Note the non–standard units for deriving [a] and the fact that, by convention, the figure is always quoted dimensionless. The enantiomeric excess of a scalemic mixture can be deduced from the measured specific rotation:

Diastereoisomers (Diastereomers)

Diastereoisomers are stereoisomers with a different relative configuration and are not related as mirror images. They have different chemical and physical properties. Molecules possessing more than one stereogenic centre also exhibit diastereoisomerism because inverting one or more (but not all) of the centres leads to structures which do not have a mirror image relationship with the original. Inversion of a single stereogenic centre gives an epimer of the original structure. Inversion of all stereogenic centres gives the enantiomer. A molecule possessing n stereogenic centres has a maximum of: 2n stereoisomers, 2n–1 pairs of enantiomers and n epimers Molecular symmetry within the molecule may result in a reduction of the numbers of different isomers due to internal compensation. Example:2,3,4-Trihydroxybutanal

Diastereoisomerism also occurs in alkenes, oximes and imines where interconversion of the double bond substituents is prevented by the energy barrier to rotation about the p–bond. The E–isomer (entgegen, German for "opposite") has the highest priority substituents on the double–bonded atoms pointing away from each other and the Z–isomer (zusammen, German for "together") has the highest priority substituents on the same side. In the case of oximes and imines the lone pair on the nitrogen is counted as the lowest priority substituent of that atom.

Fischer Projections

This convention proposed by Emil Fischer in 1891 attempts to depict molecular structure in a two-dimensional framework of vertical and horizontal bonds. The main carbon chain is drawn as a vertical line and bonds to all substituents are drawn as horizontal lines All vertical lines represent bonds behind the plane of the page All horizontal lines represent bonds in front of the plane of the page

Fischer Projection of (S)-Lactic Acid

Rotating a Fischer projection by 90symbol 176 \f "Symbol" \s 12° or interchanging two substituents results in inversion of the absolute configuration of the stereogenic centre. The absolute configuration may be deduced by ranking the substituents according to the sequence rules, placing the lowest ranking substituent on a vertical axis and determining whether the priority of the remaining substituents descends clockwise (R–) or anti-clockwise (S–).

Fischer Projection of (R)-Lactic Acid

Erythro–, Threo– and Meso–Nomenclature

For many open chain compounds prefixes are employed that are derived from the names of the corresponding sugars and that describe the whole system rather than individual chiral centres separately. Three such prefixes are Erythro–, Threo– that are applied to systems containing two asymmetric carbons when two of the groups are the same and the third is different. Erythro– describes adjacent stereocentres possessing similar or identical substituents on the same side of the vertical axis of the Fischer projection

Erythro-stereocentres

D-Erythrose

Threo– describes adjacent stereocentres possessing similar or identical substituents on the opposite side of the vertical axis of the Fischer projection

Threo-stereocentres

D-Threose

Meso– describes a molecule that is achiral, despite possessing stereogenic centres, due to the presence of an internal mirror plane. Note: For a molecule possessing two stereocentres meso– corresponds to erythro–.

Meso-stereocentres

Meso-Tartaric Acid

L– and D– Nomenclature

Used extensively in carbohydrates, this formalism defines the configuration of the stereocentre furthest from the carbonyl carbon. It is also used for amino acids to define the configuration at the a–centre. When drawn as a Fischer projection with C–1 at the top: the D– configuration possesses the highest priority substituent of the stereocentre in question on the right hand side of the projection:

 

D-Glucose

D -Fructose

D -Valine

the L– isomer< has the higher priority group on the left hand side:

L-Xylose

L -Ribulose

L -Valine