Stereochemistry, a sub discipline of chemistry, involves the

study of the relative spatial arrangement of atoms within molecules. Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "three-dimensionality". Stereochemistry includes methods for determining and describing these relationships; the effect on the physical or biological properties these relationships impart upon the molecules in question, and the manner in which these relationships influence the reactivity of the molecules in question.

Origin
Louis Pasteur could rightly be described as the first stereochemist. Pasteur resolved (separated) an optically inactive substance (tartaric acid) into two optically active components. Each of the optically active components had properties identical to tartaric acid (density, melting point, solubility, etc.) except that one of the components rotated the polarized light clockwise (+) while the other component rotated the polarized light by the same amount counterclockwise (-). Pasteur made a proposal that still stands as the foundation of stereochemistry: The twin molecules of tartaric acid were mirror images of each other!

Additional research by Pasteur revealed that one component of tartaric acid could be utilized for nutrition by micro-organisms but the other could not. On the basis of these experiments, Pasteur concluded that biological properties of chemical substances depend not only on the nature of the atoms comprising the molecules but also on the manner in which these atoms are arranged in space. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon.

Constitutional Isomers
constitutional isomerism is a form of isomerism in which molecules with the same molecular formula have bonded together in different orders, as opposed to stereoisomerism. Three categories of constitutional isomers are skeletal, positional, and functional isomers.

SKELETAL ISOMERISM
In skeletal isomerism, or chain isomerism, components of the (usually carbon) skeleton are distinctly re-ordered to create different structures. Pentane exists as three isomers: n-pentane (often called simply "pentane"), isopentane (methylbutane) and neopentane (dimethylpropane).

n-Pentane

Isopentane

Neopentane

POSITION ISOMERISM
In position isomerism a functional group or other substituent changes position on a parent structure. In the table below, the hydroxyl group can occupy three different positions on an n-pentane chain forming three different compounds.

1-Pentanol

2-Pentanol

3-Pentanol

FUNCTIONAL GROUP ISOMERISM

Functional isomers are structural isomers that have the same molecular formula (that is, the same number of atoms of the same elements), but the atoms are connected together in different ways so that the groupings are dissimilar. These groups of atoms are called functional groups, functionalities, or moieties. Another way to say this is that two compounds with the same molecular formula, but different functional groups, are functional isomers. For example, cyclohexane and 1-hexene both have the formula C6H12. These two are considered functional group isomers because cyclohexane is a cycloalkane and hex-1-ene is an alkene.

Cyclohexane

1-hexene

Stereo Isomerism
Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms (constitution), but that differ only in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections and/or their order differ(s) between different atoms/groups. In stereoisomers, the order and bond connections of the constituent atoms remain the same, but their orientation in space differ.

They are of two types:

ENANTIOMERS

Enantiomers are two stereoisomers that are related to each other by a reflection: They are mirror images of each other, which are non-super imposable. Human hands are a macroscopic example of stereoisomerism.

DIASTERIOMERS
Stereoisomers that are not mirror images of each other are called Diastereomers. They are not related by a reflection operation

The CHIRAL Centre

A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom.

The term chiral in general is used to describe an object that is nonsuperimposable on its mirror image. Achiral (not chiral) objects are objects that are identical to their mirror image. Human hands are

perhaps the most universally recognized example of chirality: The left hand is a non-superimposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide. A carbon atom to which four different groups are attached is called Chiral Centre or Chiral Carbon. Many molecules that contain a chiral centre are chiral, but not all chiral molecules contain a chiral centre. Chemists have agreed upon diagrams for representation of chiral structures: The horizontal line represents bonds coming towards us out of the paper, whereas the vertical lines represent bonds going away from us behind the plane of the paper. Chirality is the foundation of Stereoisomers

Enantiomers
An Enantiomer is one of two stereoisomers that are mirror images of each other that are "non-superposable" (not identical), much as one's left and right hands are "the same" but opposite. It can be clearly understood if you try to place your hands one over the other without touching the back or palm of the left to the same of the right. You observe that the thumb of one is always over the littlefinger of the other, thus explaining chirality.

Organic compounds that contain a chiral Carbon usually have two non-superimposable structures. These two structures are mirror images of each other and are, thus, commonly called enantiomorphs (enantio = opposite ; morph = form) Hence, optical isomerism is now commonly referred to as enantiomerism Enantiopure compounds refer to samples having, within the limits of detection, molecules of only one chirality.

PHYSICAL, CHEMICAL and OPTICAL PROPERTIES

PHYSICAL: Physical properties include items like melting point,
boiling point, color, hardness, density,etc. All physical properties of enantiomers are mirror imaged: the property of one enantiomer is the mirror image of the other. In practice, this means that all physical properties of both enantiomers, except for one (optical property), are the same.

CHEMICAL:Enantiomers have identical chemical properties

except towards optically active reagents. Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the body of living beings are enantiomers themselves, there is often a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects (unwanted side-effects).

OPTICAL: Enantiomers rotate light, ie when light passes through

them they rotate the direction in which the waves rise and fall. One enantiomer (of a pair) will rotate the light clockwise and the other will rotate the light counterclockwise by an equal amount. This difference in direction of rotation (one is the mirror image of the other) is the only physical property which is different for the two enantiomers. This ability of enantiomers to rotate light is called optical activity.

Nomenclature Of Enantiomers
There are three naming conventions of Enantiomers

By configuration: R- and SIn organic chemistry, the most common origin of chirality is a tetrahedral (sp3) carbon atom bound to four different groups. A system of nomenclature to distinguish the two groups must somehow describe the three-dimensional arrangement of those four groups about the chiral carbon centre. This can be accomplished by ranking

the four groups in decreasing order of priority, such that group 1 has the highest priority, followed by groups 2, 3 and 4 in decreasing order.

The molecule is turned so that the group with the lowest rank (4) is behind the carbon atom, and the other three ranked groups form a wheel about the carbon. The ranking either forms a clockwise or counter-clockwise circle, tracing a path from 1 to 2 to 3.

If the path is clockwise, then the molecule is the R (rectus, right) enantiomer .

If the path is counter-clockwise, the molecule is the S (sinister, left) enantiomer.

By optical activity: (+)d and ()l

An enantiomer can be named by the direction in which it rotates the plane of polarized light. If it rotates the light clockwise (as seen by a viewer towards whom the light is traveling), that enantiomer is labeled (+). Its mirror-image is labeled (). The (+) and () isomers

have also been termed d- and l-, respectively (for dextrorotatory and levorotatory).

Conformational isomers
Conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted exclusively by rotations about formally single bonds. Such isomers are generally referred to as conformational isomers or conformers and specifically as rotamers when the rotation leading to different conformations is restricted (hindered) rotation, in the sense that there exists a rotational energy barrier that needs to be overcome to convert one conformer to another. Conformational isomers are thus distinct from the other

a class of stereoisomers for which interconversion necessarily involves breaking and reforming of chemical bonds. The rotational barrier, or barrier to rotation, is the activation energy required to interconvert rotamers In ethane (CH3CH3), for example, both carbons are approximately tetrahedral. Thus, there are two limiting structuresstaggered ethane, in which the carbon-hydrogen bonds are as far apart as possible, and eclipsed ethane, in which the bonds are as close as possible. These two structures are certainly not the same. The best view in which to see the difference is a Newman projection. In a Newman projection, the front carbon is located at the intersection of the bonds to the three attached hydrogen atoms, and the back carbon is an exploded circle, with the attached bonds emanating from the circumference of the circle.

The staggered form is lower in energy because in the eclipsed form electrons in carbon-hydrogen bonds on the opposite side of the carbon-carbon bond repel each other. If substitutions are made in the ethane molecule isomeric staggered forms become possible. These staggered forms, called anti and gauche , are different

but are interconverted through rotations around the central carboncarbon bond. Butane has two constitutional isomers, butane and isobutane. Isobutane has no conformational isomers, but butane is closely analogous to 1, 2-dideuterioethane, in that a pair of anti and gauche conformational isomers is possible for that molecule.

Configuration
An absolute configuration in stereochemistry is the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description When the absolute configuration is obtained the assignment of R or S is based on the Cahn-Ingold-Prelog priority rules.

Until 1951 it was not possible to obtain the absolute configuration of chiral compounds. It was at some time decided that (+)glyceraldehyde was the (R)-enantiomer. The configuration of other chiral compounds was then related to that of (+)-glyceraldehyde by sequences of chemical reactions. For example (+)-glyceraldehyde (1) was related to (-)-glyceric acid 2 (oxidation by mercury oxide) which in turn was related to (+)-isoserine 3 (nitric acid oxidation) and bromide 4 and (-)-lactic acid 5 (zinc reduction). Because the chemical transformations did not affect the asymmetric carbon atom, this sequence demonstrated that (-)-lactic acid was also a (R)enantiomer.

In 1951 Bijvoet for the first time used in X-ray crystallography the effect of anomalous dispersion, which is now referred to as resonant scattering, to determine absolute configuration. The compound

investigated was (+)-sodium rubidium tartrate and from its configuration (R,R) it was deduced that the original guess for (+)glyceraldehyde was correct.

Optical Rotation
Optical rotation (optical activity) is the turning of the plane of linearly polarized light about the direction of motion as the light travels through organic compounds. It occurs in solutions of chiral molecules The specific rotation of an enantiomer is defined as the observed angle of optical rotation when plane-polarized light is passed

through the compound. A negative value means levorotatory rotation and a positive value means dextrorotatory rotation. Some examples:

Sucrose +66.47 Lactose +52.3 (S)-bromobutane +23.1 (R)-bromobutane 23.1 (+)-cavicularin +168.2

Optical Purity
Molecules with chirality centers cause the rotation of plane polarised light and are said to be "optical active" (hence the term optical isomers). Enantiomeric molecules rotate the plane in opposite directions but

with the same magnitude. This provides a means of measuring the "optical purity" or "enantiomeric excess (ee)" of a sample of a mixture of enantiomers. The optical purity or the enantiomeric excess (ee%) of a sample can be determined as follows: Optical purity = % enantiomeric excess = % enantiomer1 - % enantiomer2 = 100 [a]mixture / [a]pure sample

ee% = 100 ([R]-[S]) / ([R]+[S]) where [R] = concentration of the R-isomer [S] = concentration of the S-isomer

Diasteromeric substances can have different rotations both in sign and in magnitude.

Racemic Mixture
A racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first

known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid. A racemic mixture is denoted by the prefix ()- or dl-, indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac(or racem-) or the symbols RS and SR are used. If the ratio is not 1:1 (or is not known), the prefix (+)/() or d/l(with a slash) is used instead. A racemate is optically inactive, meaning that there is no net rotation of plane-polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel because they are present in equal amounts. In contrast to the two pure enantiomers, which have identical physical properties except for the direction of rotation of planepolarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible. Racemic mixtures can be separated, or resolved, into their pure enantiomers by three methods:

MECHANICAL SEPERATION

The first method is to mechanically separate the crystals in such a mixture based on differences in their shapes. This was the method first used by Pasteur, and it is mainly of historical interest.

ENZYMES
The second resolution method employs enzymes. Enzymes are stereospecific chiral protein molecules that act as catalysts. Because of their chirality, these molecules react with only one enantiomer in a racemic mixture. The enantiomer that momentarily bonds to an enzyme undergoes reaction, while the enantiomer that does not bond remains unchanged. The unreacted enantiomer can then be removed from the reaction mix by ordinary separation methods, such as distillation or recrystallization.

DIASTEREOMERISATION
The third method involves converting the enantiomers of a racemic mixture into diastereomers and then resolving that mixture with ordinary separation techniques. The separated diastereomers are then treated with appropriate reagents to regenerate the original enantiomers.

In this example, the diastereomer salts are separated by recrystallization, and the original acids are regenerated by the addition of a hydrochloric acid solution.

Meso Compounds
A meso compound or meso isomer is a non-optically active member of a set of stereoisomers, at least two of which are optically active. This means that despite containing two or more stereocenters (chiral centers) it is not chiral. A meso compound is superposable on its mirror image, and it does not produce a "(+)" or "(-)" reading when analyzed with a polarimeter. A meso compound need not even have a chiral center.

For example, there are 3 isomers of tartaric acid (depicted above): There is a meso compound and the optically active pair of dextrotartaric acid (L-(R,R)-(+)-tartaric acid) and levotartaric acid (D-(S,S)-(-)-tartaric acid). In the meso compound an internal plane of symmetry exists, bisecting the molecule which is not present in the non-meso compounds.

That is, on rotating the meso compound by 180 on a plane perpendicular to the screen, the same stereochemistry is obtained, again this is not seen in the non-meso tartaric acid. When we analyze a meso compound with a polarimeter, the indicator will not show (+) or (-). It simply means there is no certain direction of rotation of the polarized light, neither levorotatory (-) and dexorotatory (+).

Fischer Projection
The Fischer projection, devised by Hermann Emil Fischer in 1891, is a two-dimensional representation of a three-dimensional organic molecule by projection.

CONVENTIONS
All bonds are depicted as horizontal or vertical lines. The carbon chain is depicted vertically, with carbon atoms represented by the center of crossing lines.

 The orientation of the carbon chain is so that the C1 carbon is at the top. On a Fischer projection, the penultimate carbon of D sugars are depicted with hydrogen on the left and hydroxide on the right. L sugars will be shown with the hydrogen on the right and the hydroxide on the left.

In a Fischer projection, all horizontal bonds project toward the viewer, while vertical bonds project away from the viewer. Therefore, a Fischer projection cannot be rotated by 90 or 270 in the plane of the page or the screen, as the orientation of bonds relative to one another can change, converting a molecule to its enantiomer.

Since Fischer projections depict the stereochemistry (threedimensional structure) of a molecule, they are very useful for differentiating between enantiomers of chiral molecules.

Conformations Of Substituted Cyclic Systems

MONOSUBSTITUTED
Monosubstituted cyclohexanes always have substituent in equatorial position . Methylcyclohexane, which is obtained by replacing one of the hydrogen atoms of cyclohexane with a methyl group, is a very intriguing compound. The two chair forms of methylcyclohexane are not identical as is the case with cyclohexane itself. The equatorial methyl derivative 1 and the axial methyl derivative 2 form a pair of stereoisomers.

The two chair forms of cyclohexane are identical, but the two chair forms of methylcyclohexane 1 and 2 are stereoisomers.

DISUBSTITUTED
Disubstituted Cyclohexane: 1, 2 dimethylcyclohexane

Cis-isomer
Both methyl groups are on same face of ring Conformations are equal in energy because each has one axial methyl group and one equatorial methyl group

Trans-isomer
Two methyl groups are on opposite faces of the ring Exists almost exclusively in the diequatorial conformation

Conformational analysis can be done for any substituted cyclohexane Glucose and manose (a carbohydrate found in seaweed) In glucose all substituents on the six-membered ring are equatorial In manose one of the OH groups is axial, making manose more strained.

Glucose

Mannose

Biological Significance Of Stereochemistry

Stereochemistry may seem like a trivial subject because differences between stereoisomers are usually subtle. In nature, however, and most importantly, in biological systems such as the human body, these subtle differences have sweeping implications. Most drugs for example, are often composed of a single stereoisomer of a

compound, and while one stereoisomer may have positive effects on the body, another stereoisomer may be toxic. Because of this, a great deal of work done by synthetic organic chemists todayis in devising methods to synthesize compounds that are purely one stereoisomer. Shown below, for example, is the binding of Ibuprofin, a common pain reliever. While one stereoisomer of the compound has the right three-dimensional shape to bind to the protein receptor, the other does not and can not bind, and is therefore ineffective as a pain reliever.

Another example of the significance of stereochemistry was demonstrated by Thalidomide (shown below).Thalidomide was a drug used during the 1950s to suppress morning sickness. The drug, unfortunately, was prescribed as a racemic mixture -- that is, it contained a 50:50 mixture of its mirror images -- and while one stereoisomer of the drug actively worked on controlling morning sickness, the other stereoisomer caused serious birth defects. Ultimately the drug was pulled from the marketplace.

Thalidomide, a drug once used to surpress morning sickness The

importance of stereochemistry in biological systems extends to more than just drugs: our bodies, for example, can only create and digest carbohydrates and amino acids of a certain stereochemistry. Thus, all of our proteins that make up our hair, skin, organs, brain, and tissues, are composed of a single stereoisomer of amino acids. Additionally, our bodies can make and digest starch (found in potatoes and bread) but not cellulose (found in wood and plant fibers), even though both are just polymers of glucose of different stereochemistry. These are just a few of numerous examples of the important role stereochemistry plays in our everyday lives.