Stereochemistry

StereochemistryPrepared by Mr. Dharmendrasinh A BariaAssistant professorDepartment of Pharmaceutical ChemistrySmt. S. M. Shah Pharmacy college, Amsaran

IntroductionThe two major classes of isomers are constitutional isomers and stereoisomers.Constitutional/structural isomers have different IUPAC names, the same or different functional groups, different physical properties and different chemical properties.Stereoisomers compounds with the same connectivity, different arrangement in space They have identical IUPAC names (except for a prefix like cis or trans). They always have the same functional group(s).

Configuration the arrangement in space of the four different groups about a chiral center. Stereoisomers differ in configuration.Stereochemistry: The study of the three-dimensional structure of molecules.

Importance of stereochemistryStereochemistry plays an important role in determining the properties and reactions of organic compounds:

Caraway seedSpearmint

The properties of many drugs depends on their stereochemistry:

(S)-Ketamine

(R)-KetamineAnestheticHallucinogen

Enzymes are capable of distinguishing between stereoisomers:

Chirality Although everything has a mirror image, mirror images may or may not be superimposable. Some molecules are like hands. Left and right hands are mirror images, but they are not identical, or superimposable.

Other molecules are like socks. Two socks from a pair are mirror images that are superimposable. A sock and its mirror image are identical.A molecule or object that is superimposable on its mirror image is said to be achiral. A molecule or object that is not superimposable on its mirror image is said to be chiral.

We can now consider several molecules to determine whether or not they are chiral.

In general, a molecule with no stereogenic centers will not be chiral. With one stereogenic center, a molecule will always be chiral.With two or more stereogenic centers, a molecule may or may not be chiral.Achiral molecules usually contain a plane of symmetry but chiral molecules do not.

Stereogenic Centers/Asymmtric carbon/Chiral center/Chiral carbonThe most common feature that leads to chirality in organic compounds is the presence of an asymmetric (or chiral) carbon atom.A point in a molecule where four different groups (or atoms) are attached to carbon is called a chiral center.There are two non-superimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom. If two groups are the same, then there is only one way.A chiral molecule usually has at least one chiral center.

Always omit from consideration all C atoms that cannot be tetrahedral stereogenic centers. These includeCH2 and CH3 groupsAny sp or sp2 hybridized C

In general:no asymmetric Cusually achiral1 asymmetric Calways chiral> 2 asymmetric C may or may not be chiralExample: Identify all asymmetric carbons present in the following compounds.

Internal Plane of SymmetryCis-1,2-dichlorocyclopentane contains two asymmetric carbons but is achiral.Contains an internal mirror plane of symmetry

Any molecule that has an internal mirror plane of symmetry is achiral even if it contains asymmetric carbon atoms.

s

Cis-1,2-dichlorocyclopentane is a meso compound:an achiral compound that contains chiral centersoften contains an internal mirror plane of symmetry

Example: Which of the following compounds contain an internal mirror plane of symmetry?

Optical activityOptical activity the ability to rotate the plane of plane polarized light.Plane polarized light light that has been passed through a nicol prism or other polarizing medium so that all of the vibrations are in the same plane.Polarimeter an instrument used to measure optical activity.Plane-polarized light that passes through solutions of achiral compounds remains in that plane ([] = 0, optically inactive)Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active.

Plane-Polarized Light

Plane-Polarized Light through an Achiral Compound

Plane-Polarized Light through a Chiral Compound

Dextrorotatory when the plane of polarized light is rotated in a clockwise direction when viewed through a polarimeter.(+) or (d) do not confuse with DLevorotatory when the plane of polarized light is rotated in a counter-clockwise direction when viewed through a polarimeter.(-) or (l) do not confuse with LThe angle of rotation of plane polarized light by an optically active substance is proportional to the number of atoms in the path of the light.

Specific rotation the angle of rotation of plane polarized light by a 1.00 gram per cm-3 sample in a 1 dm tube. [ ]D (D = sodium lamp, = 589 m).The more molecules of a chiral sample are present the greater the rotation of the light = concentration dependent.

where = observed rotation l = length (dm) d = concentration (g/cc)

EnantiomersEnantiomers are stereoisomers that are non-superimposable on their mirror images.

Properties of EnantiomersEnantiomers have identical physical properties such as boiling points, melting points, refractive indices, and solubilities in common solvents except optical rotations. Many of these properties are dependent on the magnitude of the intermolecular forces operating between the molecules, and for molecules that are mirror images of each other these forces will be identical.Enantiomers have identical infrared spectra, ultraviolet spectra, and NMR spectra if they are measured in achiral solvents.

Enantiomers show different behavior only when they interact with other chiral substances.Enantiomers show different rates of reaction toward other chiral molecules.Enantiomers have identical reaction rates with achiral reagents.

Enantiomers show different solubilities in chiral solvents that consist of a single enantiomer or an excess of a single enantiomer. Enantiomers rotate the plane of plane-polarized light in equal amounts but in opposite directions. Separate enantiomers are said to be optically active compounds.

Reactivity with chiral molecules . e.g., enzymes, receptors, .. drug action/metabolism

Why do chiral molecules react differently with biological molecules?

DiastereomersDiastereomers are stereoisomers that are not mirror images of each other they are stereoisomers that are not enantiomers.

Molecules with 2 or more chiral carbons.

AlkenesCis-trans isomers are not mirror images, so these are diastereomers.

Ring CompoundsCis-trans isomers possible.May also have enantiomers.Example: trans-1,3-dimethylcylohexane

The four stereoisomers of 2,3-dibromopentane

Properties of DiastereomersDiastereomers are similar, but they arent mirror images. Enantiomers have opposite configurations at all chiral centers; Diastereomers are opposite at some, but not all chiral centers.Diastereomers have different physical properties

Epimers are diastereomers different at only 1 chiral center

Diastereomers and constitutional isomers have different physical properties, and therefore can be separated by common physical techniques.

Meso CompoundsA meso compound is one which is superimposable on its mirror image even though it contains stereogenic centres.An achiral compound with chiral centers is called a meso compound it has a plane of symmetry.

As long as any one conformer of a compound has a plane of symmetry, the compound will be achiral.

plane ofsymmetryplane ofsymmetry

Geometrical isomersCistrans isomers (also called geometric isomers) result from restricted rotation.Restricted rotation can be caused either by a double bond or by a cyclic structure. As a result of the restricted rotation about a carboncarbon double bond, an alkene such as 2-pentene can exist as cis and trans isomers. The cis isomer has the hydrogens on the same side of the double bond, whereas the trans isomer has the hydrogens on opposite sides of the double bond.

CISGroups/atoms are on theSAME SIDE of the double bondTRANSGroups/atoms are on OPPOSITE SIDES across the double bond

RESTRICTED ROTATION OF C=C BONDSSingle covalent bonds can easily rotate. What appears to be a different structure in an alkane is not. Due to the way structures are written out, they are the same.

All these structures are the same because c-c bonds have free rotation

C=C bonds have restricted rotation so the groups on either end of the bond are frozen in one position; it isnt easy to flip between the two.RESTRICTED ROTATION OF C=C BONDS

This produces two possibilities. The two structures cannot interchange easily so the atoms in the two molecules occupy different positions in space.

ISOMERISM IN BUTENEThere are 3 structural isomers of C4H8 that are alkenes*. Of these ONLY ONE exhibits geometrical isomerism.

BUT-1-ENE2-METHYLPROPENEtrans BUT-2-ENEcis BUT-2-ENE

Cyclic compounds can also have cis and trans isomers.The cis isomer has the hydrogens on the same side of the ring, whereas the trans isomer has the hydrogens on opposite sides of the ring.

Properties of Geometric Isomers Geometric isomers have similar chemical properties but some different physical properties.Symmetrical alkenes have the same groups or atoms attached to one of the carbon atoms in the C=C bond.

E and Z Based on Priority: Cahn-Ingold-Prelong rules: 1. Atomic Number2. Atomic weight3. Atomic number of the next atom

Higher priority at the opposite side of pi bond (E) Higher priority at the same side of pi bond (Z)

cis or trans?E and Z Based on Priority:

Racemic mixtureA 50:50 mixture of two chiral compounds that are mirror images does not rotate light called a racemic mixture (named for racemic acid that was the double salt of (+) and (-) tartaric acidThe pure compounds need to be separated or resolved from the mixture (called a racemate).A racemic mixture is optically inactive. Because two enantiomers rotate plane-polarized light to an equal extent but in opposite directions, the rotations cancel, and no rotation is observed.

Physical Properties of StereoisomersRacemic Mixtures

Resolution of EnantiomersSeparating enantiomers is called resolution.A pair of enantiomers can be separated in several ways, of which conversion to diastereomers and separation of these by fractional crystallization is the most often used. In this method and in some of the others, both isomers can be recovered, but in some methods it is necessary to destroy one.

Methods of resolutionConversion to Diastereomers.Differential AbsorptionChiral Recognition. Biochemical ProcessesMechanical SeparationKinetic ResolutionDeracemization

Conversion to DiastereomersTo separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent).This gives diastereomers that are separated by their differential solubility.The resolving agent is then removed.Usually, fractional crystallizations must be used and the process is long and tedious.

Fortunately, naturally occurring optically active bases (mostly alkaloids) are readily available. Among the most commonly used are brucine, ephedrine, strychnine, and morphine. Once the two diastereomers have been separated, it is easy to convert the salts back to the free acids and the recovered base can be used again.Most resolution is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted.

However, the principle of conversion to diastereomers is not conned to carboxylic acids, and other functional groups may be coupled to an optically active reagent.Racemic bases can be converted to diastereomeric salts with active acids. Alcohols can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on.

59

Using an Achiral amine doesnt change the relationship of the products Still cant separate the Enantiomeric Salts.

Using a Chiral amine changes the relationship of the productsNow we can separate the Diastereomeric Salts.

Resolution of Enantiomers

Differential Absorption/Chromatographic Resolution of Enantiomers When a racemic mixture is placed on a hromatographic column, if the column consists of chiral substances, then in principle the enantiomers should move along the column at different rates and should be separable without having to be converted to diastereomers.This has been successfully accomplished with paper, column, thin-layer, and gas and liquid chromatography.For example, racemic mandelic acid has been almost completely resolved by column chromatography on starch.

Columns packed with chiral materials are now commercially available and are capable of separating the enantiomers of certain types of compounds.

Chiral RecognitionIn this host forms an inclusion compound with one enantiomer of a racemic guest, but not the other. This is called chiral recognition.One enantiomer ts into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved.An example is use of the chiral crown ether partially to resolve the racemic amine salt.

When an aqueous solution of 59 was mixed with a solution of optically active 58 in chloroform, and the layers separated, the chloroform layer contained about twice as much of the complex between 58 and (R)-59 as of the diastereomeric complex.Many other chiral crown ethers and cryptands have been used, as have been cyclodextrins, cholic acid, and other kinds of hosts.

Biochemical Processes.Biological molcules may react at different rates with the two enantiomers. For example, a certain bacterium may digest one enantiomer, but not the other. Pig liver esterase has been used for the selective cleavage of one enantiomeric ester. This method is limited, since it is necessary to nd the proper organism and since one of the enantiomers is destroyed in the process.

However, when the proper organism is found, the method leads to a high extent of resolution since biological processes are usually very stereoselective.

Mechanical SeparationThis is the method by which Pasteur proved that racemic acid was actually a mixture of (+)- and (-)-tartaric acids.In the case of racemic sodium ammonium tartrate, the enantiomers crystallize separately: all the (+) molecules going into one crystal and all the (-) into another. Since the crystals too are non-superimposable, their appearance is not identical and a trained crystallographer can separate them with tweezers.

However, this is seldom a practical method, since few compounds crystallize in this manner. Even sodium ammonium tartrate does so only when it is crystallized 100. Of course, in this method only one of the enantiomers of the original racemic mixture is obtained, but there are at least two possible ways of getting the other: (1) Use of the other enantiomer of the chiral reagent; (2) Conversion of the product to the starting compound by a reaction that preserves the stereochemistry.

Deracemization. In this type of process, one enantiomer is converted to the other, so that a racemic mixture is converted to a pure enantiomer, or to a mixture enriched in one enantiomer.This is not quite the same as the methods of resolution previously mentioned, although an outside optically active substance is required. To effect the deracemization two conditions are necessary: (1) the enantiomers must complex differently with the optically active substance;

(2) they must interconvert under the conditions of the experiment.When racemic thioesters were placed in solution with a specic optically active amide for 28 days, the solution contained 89% of one enantiomer and 11% of the other.In this case, the presence of a base (EtN) was necessary for the interconversion to take place. Biocatalytic deracemization processes induce deracemization of chiral secondary alcohols.

Enantiotopic Hydrogens, DiastereotopicHydrogens, and Prochiral CarbonsIf a carbon is bonded to two hydrogens and to two different groups, the two hydrogens are called enantiotopic hydrogens. For example, the two hydrogens (Ha and Hb) in the group of ethanol are enantiotopic hydrogens because the other two groups bonded to the carbon ( CH3 and OH) are not identical.Replacing an enantiotopic hydrogen by a deuterium (or any other atom or group other than or OH) forms a chiral molecule.

A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule.

Re and Si are used to describe the faces of the prochiral sp2 reactant.

An sp3 carbon with two groups the same is also a prochiral centerThe two identical groups are distinguished by considering either and seeing if it was increased in priority in comparison with the otherIf the center becomes R the group is pro-R and pro-S if the center becomes S

Enantiotopic hydrogens have the same chemical reactivity and cannot be distinguished by achiral agents, but they are not chemically equivalent toward chiral reagents.Diastereotopic hydrogens do not have the same reactivity with achiral reagents

Enantiomeric excess (optical purity) is a measurement of how much one enantiomer is present in excess of the racemic mixture. It is denoted by the symbol ee.Consider the following exampleIf a mixture contains 75% of one enantiomer and 25% of the other, the enantiomeric excess is 75% - 25% = 50%. Thus, there is a 50% excess of one enantiomer over the racemic mixture.

How do we draw a chirality centre?Perspective Formula

Fischer projections

Naming compounds with more than one stereocenter FISCHER PROJECTIONConvention: The carbon chain is drawn along the vertical line of the Fischer projection, usually with the most highly oxidized end carbon atom at the top.Vertical lines: bonds going into the page.Horizontal lines: bonds coming out of the page

Allowed motions for Fischer Projection1. 180 rotation (not 90 or 270):

2. 90 rotation: Rotation of a Fischer projection by 90 inverts its meaning.

3. One group hold steady and the other three can rotate: 4. Differentiate different Fischer projections:

ConfigurationsThe particular arrangement of atoms in space that is characteristic of a given molecule is called its configuration.Configurations are not the same as conformations.Conformations are inter convertible by rotation about single bond(s) whereas bonds must be broken to change one configuration into another.Two types of configurations.Relative configuration (L and D),Absolute configuration (R and S)

Specification of configuration(Cahn - Prelog - Ingold rules) Step 1: assign a priority to the 4 atoms or groups of atoms bonded to the tetrahedral stereogenic centre:If the 4 atoms are all different, priority is determined by atomic number. The atom of higher atomic number has the higher priority.If two atoms on a stereogenic center are the same, assign priority based on the atomic number of the atoms bonded to these atoms. One atom of higher atomic number determines the higher priority.

If two isotopes are bonded to the stereogenic center, assign priorities in order of decreasing mass number. Thus, in comparing the three isotopes of hydrogen, the order of priorities is:

To assign a priority to an atom that is part of a multiple bond, treat a multiply bonded atom as an equivalent number of singly bonded atoms. For example, the C of a C=O is considered to be bonded to two O atoms.

Other common multiple bonds are drawn below:

Examples of assigning priorities to stereogenic centers

Orienting the lowest priority group in back

2,3-Dichloropentane

(2S,3S)(2R,3R)

(2S,3R)(2R,3S)

How many stereoisomers exist?Look at 2,3-dichlorobutane. Are there four different isomeric forms?

There are two tetrahedral stereogenic carbons.......2n?

2,3-dichlorobutane(2S,3S)(2R,3R)(2S,3R)?

Relative configuration compares the arrangement of atoms in space of one compound with those of another. Absolute configuration is the precise arrangement of atoms in space.Sugars and amino acids with same relative configuration as (+)-glyceraldehyde were assigned D and same as (-)-glyceraldehyde were assigned L.

D and L Assignments

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Regioselective reaction: preferential formation of one constitutional isomer

Stereoselective reaction: preferential formation of a stereoisomer

Stereospecific reaction: each stereoisomeric reactant produces a different stereoisomeric product or a different set of products

All stereospecific reactions are stereoselective.Not all stereoselective reactions are stereospecific.

Axial ChiralityThough optical activity due to axial chirality was first reported by Christie and Kenner in 1922.Nonplanar arrangement of four groups about an axis

Atropisomers - stereoisomers resulting from restricted rotation about a single bond

The term Atropisomerism was coined by Richard Kuhn later in 1933.From Greek: a nottropos to turn Atropisomerism is that kind of isomerism, where the conformers (called atropisomers) can be isolated as separate chemical species and which arise from restricted rotation about a single bond.Axis of Chirality: An axis about which a set of atoms/functional groups/ligands is held so that it results in a spatial arrangement that is not superimposable on its mirror image.

Conditions for AtropisomerismTwo necessary preconditions for axial chirality are: a rotationally stable axis Presence of different substituents on both sides of the axisAtropisomers are recognised as physically separable species when, at a given temperature, they have a half life of at least 1000 s.The minimum required free energy barriers at different temperatures are as below.

The configurational stability of axially chiral biaryl compounds is mainly determined by three following factors:i. The combined steric demand of the substituents in the proximity of the axisii. The existence, length, and rigidity of bridgesiii. Atropsiomerization mechanism different from a merely physical rotation about the axis, e.g. photochemically or chemically induced processes.

Nomenclature of Atropisomers1. Notations used for Atropisomers: aR (axially Rectus) or P (plus)aS (axially Sinister) or M (minus)2. Priority of the substituents are determined by the CIP rule.3. Here it is assumed that priority of A>B and A>B.

Classification of AtropisomersThe following classification is based upon the basic structure of the Biaryl Atropisomers.

Examples of Natural Bridged Atropisomers

Examples of Natural non-bridged Atropisomers

Uses of Atropisomers

Chiral Allenes: General Information

Some Facts About Chiral AllenesThe rotation barrier to stereoisomerization of chiral allenes amounts to 195 kJ/mol for 1,3-dialkylallenes and to > 125 kJ/mol for 1,3diarylallenes, while the threshold for isolation of stereoisomers at 20 C is 83 kJ/mol.Higher cumulenes - pentatetraenes and heptahexaenes - have lower rotation barrier. Thus, only few enantioenriched pentatetraenes and no heptahexaenes are known.Cumulated double bonds in allenes are strained. Upon undergoing any addition reaction it experiences a relief in strain of about 40 kJ/mol.

In allenes, the central carbon is sp bonded. The remaining two p orbitals are perpendicular to each other and each overlaps with the p orbital of one adjacent carbon atom, forcing the two remaining bonds of each carbon into perpendicular planes. Thus allenes fall into the category represented by Fig. 4.2: Like biphenyls, allenes are chiral only if both sides are unsymmetrically substituted.

These cases are completely different from the cistrans isomerism ofcompounds with one double bond (p. 182). In the latter cases, the fourgroups are all in one plane, the isomers are not enantiomers, and neither is chiral, while in allenes the groups are in two perpendicular planes and the isomers are a pair of optically active enantiomers.

When three, ve, or any odd number of cumulative double bonds exist, orbital overlap causes the four groups to occupy one plane and cistrans isomerism is observed. When four, six, or any even number of cumulative double bonds exist, the situation is analogous to that in the allenes and optical activity is possible.

Conformational isomersDifferent arrangements of atoms that can be converted into one another by rotation about single bonds are called conformations. Atoms within a molecule move relative to one another by rotation around single bonds. Such rotation of covalent bonds gives rise to different conformations of a compound. Each structure is called a conformer or conformational isomer.Generally, conformers rapidly interconvert at room temperature. Conformational isomerism can be presented with the simplest example, ethane (C2H6), which can exist as an infinite number of conformers by the rotation of the CC s bond.

Ethane has two sp3-hybridized carbon atoms, and the tetrahedral angle about each is 109.5. The most significant conformers of ethane are the staggered and eclipsed conformers. The staggered conformation is the most stable as it has the lowest energy.

Visualization of conformers There are four conventional methods for visualization of three-dimensional structures on paper. These are the ball and stick method, the sawhorse method, the wedge and broken line method and the Newman projection method. Using these methods, the staggered and eclipsed conformers of ethane can be drawn as follows.

Staggered and eclipsed conformersIn the staggered conformation, the H atoms are as far apart as possible. This reduces repulsive forces between them.

This is why staggered conformers are stable. In the eclipsed conformation, H atoms are closest together. This gives higher repulsive forces between them.

As a result, eclipsed conformers are unstable. At any moment, more molecules will be in staggered form than any other conformation.Torsional energy and torsional strain Torsional energy is the energy required for rotating about the CC s bond. In ethane, this is very low (only 3 kcal). Torsional strain is the strain observed when a conformer rotates away from the most stable conformation (i.e. the staggered form).

Torsional strain is due to the slight repulsion between electron clouds in the CH bonds as they pass close by each other in the eclipsed conformer. In ethane, this is also low.

Conformational isomerism in propane Propane is a three-carbon- (sp3- hybridized) atom-containing linear alkane. All are tetrahedrally arranged. When a hydrogen atom of ethane is replaced by a methyl (CH3) group, we have propane. There is rotation about two CC s bonds.

In the eclipsed conformation of propane, we now have a larger CH3 close to H atom. This results in increased repulsive force or increased steric strain. The energy difference between the eclipsed and staggered forms of propane is greater than that of ethane.

Conformational isomerism in butane Butane is a four-carbon- (sp3- hybridized) atom-containing linear alkane. All are tetrahedrally arranged. When a hydrogen atom of propane is replaced by a methyl (CH3) group, we have butane. There is rotation about two CC s bonds, but the rotation about C2C3 is the most important.

Among the conformers, the least stable is the first eclipsed structure, where two CH3 groups are totally eclipsed, and the most stable is the first staggered conformer, where two CH3 groups are staggered, and far apart from each other. When two bulky groups are staggered we get the anti conformation, and when they are at 60 to each other, we have the gauche conformer. In butane, the torsional energy is even higher than in propane. Thus, there is slightly restricted rotation about the C2C3 bond in butane.

The order of stability (from the highest to the lowest) among the following conformers is anti Gauche another eclipsed eclipsed. The most stable conformer has the lowest steric strain and torsional strain.

Conformational isomerism in Cyclopropane.Cyclopropane is the first member of the cycloalkane series, and composed of three carbons and six hydrogen atoms (C3H6). The rotation about CC bonds is quite restricted in cycloalkanes, especially in smaller rings, e.g. cyclopropane.

In cyclopropane, each C atom is still sp3-hybridized, so we should have a bond angle of 109.5, but each C atom is at the corner of an equilateral triangle, which has angles of 60 As a result, there is considerable angle strain. The sp3 hybrids still overlap but only just! This gives a very unstable and weak structure. The angle strain can be defined as the strain induced in a molecule when bond angle deviates from the ideal tetrahedral value. For example, this deviation in cyclopropane is from 109.5 to 60.

Conformational isomerism in cyclobutaneCyclobutane comprises four carbons and eight hydrogen atoms (C4H8). If we consider cyclobutane to have a flat or planar structure, the bond angles will be 90, so the angle strain (cf. 109.5) will be much less than that of cyclopropane. However, cyclobutane in its planar form will give rise to torsional strain, since all H atoms are eclipsed.

Cyclobutane, in fact, is not a planar molecule. To reduce torsional strain, this compound attains the above nonplanar folded conformation. Hydrogen atoms are not eclipsed in this conformation and torsional strain is much less than in the planar structure. However, in this form angles are less than 90, which means a slight increase in angle strain.

Conformational isomerism in cyclopentaneCyclopentane is a five carbon cyclic alkane. If we consider cyclopropane as a planar and regular pentagon, the angles are 108. Therefore, there is very little or almost no angle strain (cf. 109.5 for sp3 hybrids). However, in this form the torsional strain is very large, because most of its hydrogen atoms are eclipsed.

Thus, to reduce torsional strain, cyclopentane twists to adopt a puckered or envelope shaped, nonplanar conformation that strikes a balance between increased angle strain and decreased torsional strain. In this conformation, most of the hydrogen atoms are almost staggered.

Conformational isomerism in cyclohexane Cyclohexane (C6H12) is a six-carbon cyclic alkane that occurs extensively in nature. Many pharmaceutically important compounds possess cyclohexane rings, e.g. steroidal molecules. If we consider cyclohexane as a planar and regular hexagon, the angles are 120 (cf. 109.5 for sp3 hybrids).

Again, in reality, cyclohexane is not a planar molecule. To strike a balance between torsional strain and angle strain, and to achieve more stability, cyclohexane attains various conformations, among which the chair and boat conformations are most significant. At any one moment 99.9 per cent of cyclohexane molecules will have the chair conformation. The chair conformation of cyclohexane is the most stable conformer. In the chair conformation, the CCC angles can reach the strain free tetrahedral value (109.5), and all neighbouring CH bonds are staggered. Therefore, this conformation does not have any angle strain or torsional strain.

Another conformation of cyclohexane is the boat conformation. Here the H atoms on C2C3 and C5C6 are eclipsed, which results in an increased torsional strain. Also, the H atoms on C1 and C4 are close enough to produce steric strain. In the chair conformation of cyclohexane, there are two types of position for the substituents on the ring, axial (perpendicular to the ring, i.e. parallel to the ring axis) and equatorial (in the plane of the ring, i.e. around the ring equator) positions.

Six hydrogen atoms are in the axial positions and six others in the equatorial positions. Each carbon atom in the cyclohexane chair conformation has an axial hydrogen and an equatorial hydrogen atom, and each side of the ring has three axial and three equatorial hydrogen atoms.

CH

3

-CH-CH-CH

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-CH

3

Cl

Cl

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CH

3

-CH-CH-CH

3

Cl

Cl

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