2. Stereochemistry

‘Stereochemistry’ is a Greek word in which ‘stereo’ means solid.

Stereochemistry is the ‘chemistry of space’; i.e. stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.

Stereochemistry, a sub-discipline of chemistry, involves the study of the relative spatial arrangement of atoms and groups within molecules.

Stereochemistry

Isomers are different compounds that have the same molecular formula (no. and types of atom present) but different in structural formula.

The compounds that process the same molecular formula but differ from each other in physical and/or chemical properties are called isomers.

This phenomena is termed as isomerism (Greek: isos-equal, meros-part).

Isomers

Isomer

Structural isomer Stereoisomer

Optical isomer Geometric isomer

Enantiomer

Diastereoisomer

Cis-isomer

Trans-isomer

Kinds of isomers

The isomers that have different arrangement of atoms within the molecule, without any reference to space, the phenomenon is termed as constitutional (structural) isomerism and the isomers are called constitutional (structural) isomers.

Constitutional (structural) isomers

Constitutional isomers have (Properties)-

- Different IUPAC (International Union of Pure and Applied Chemistry) names

- Same or different functional groups

- Different physical properties and

- Different chemical properties

Constitutional isomers

Stereoisomers are isomers with the same molecular formula and same connectivity of atoms but different arrangement of atoms in space.

In stereoisomers the atoms and/or groups are attached to the molecule in the same order, but they have a different orientation in space.

Properties:

- Stereoisomers differ only in the way the atoms are oriented in space

- They have identical IUPAC names (except for a prefix like cis or trans and R or S)

- They always have the same functional group

Stereoisomer

Stereoisomers are of two types:

Optical isomers

Geometric isomers

Optical isomers are characterized by compounds having the same structure but different configurations, and because of their molecular asymmetry these compounds can rotate the plane of polarized light.

Optical isomer has similar physical and/or chemical properties. The most marked different between them is there action on polarized light. Example-

a) Optical isomers

(-) Glyceraldehyde (+) Glyceraldehyde

It has been found that only those structures; crystalline or molecular, which are not superimposable on their mirror images are optically active.

CHO

CH2OH

H OH

CHO

CH2OH

OH H

Optical isomer has classified into two groups, there are-

Enantiomer

Diastereoisomer

Enantiomers are optical isomers that rotate the plane of polarized light equal and opposite amounts and differ in structure only in the left and right-handedness of their orientation.

Enantiomers are that isomers, which are, mirror image of each other; i.e. that are not superimposable of mirror images.

Enantiomer

Fig: Enantiomer

//////////////////////////////////////////////

Enantiomers have identical physical and chemical properties (same boiling point, melting point, density, refractive index), except in two important respects-

Properties:

# They rotate the plane of polarized light in opposite direction, though in equal amounts.

The isomer which rotates the plane to the left (counterclockwise) is called the levo isomer and designated as (-), while the one which rotates the plane to the right (clockwise) is called dextro isomer and is designated as (+).

# Though chemically they are identical but their rate of reaction with other optically active compounds (chiral compounds) are usually different. This is the reason that many compounds are biologically active while theirs enantiomers are not.

Enantiomers react at the same rate with achiral compounds. (+) nicotine- less

poisonous

(-) nicotine- more poisonous (+) histidine- sweet

(-) histidine- tasteless

These are the optical isomers rotate the plane of polarization by different amount.

Stereoisomers that are not mirror images of each other are called diastereomers.

Enantiomers are mirror image isomers. All other stereoisomers are called diastereomers. Alternatively, diastereomers are stereoisomers that are not mirror images.

Most diastereomers are either geometric isomers, or compounds with two or more chiral atoms.

Diastereomers

# Diastereomers have different physical properties (like solubility will differ)

# Diastereomers have similar chemical properties

# Diastereomers differ in specific rotation; they may have the same or opposite signs of rotation or some may be inactive

Properties:

For example in 2,3 dichloropentane there are 2-chiral center present, so the no. of isomer will be 4.

CH3 < CH2 < CH < CH < CH3

Cl Cl

* *

CH3

C

C

C2H5

H

H Cl

Cl

CH3

C

C

C2H5

Cl

Cl H

H

I II

Enantiomers

CH3

C

C

C2H5

Cl

H Cl

H

CH3

C

C

C2H5

H

Cl H

Cl

III IV

Enantiomers

Relationship between-

I and II EnantiomersIII and IV EnantiomersI and III/IV DiastereomersII and III/IV DiastereomersIII and I/II DiastereomersIV and I/II Diastereomers

Form of stereoisomerism describing the orientation of functional groups within a molecule

These compounds do not rotate the plane of plane-polarized light.

Geometrical isomerism

They differ in all their physical and in many of their chemical properties.

In general, such isomers contain double bonds, which cannot rotate, but they can also arise from ring structures, where in the rotation of bonds is greatly restricted.

The configurations are differentiated in their names by the prefixes cis- and trans- which indicate that the similar groups lie on the same side (cis-) and when opposite sides (trans-).

Consequently, this type of isomerism is often called as cis-trans isomerism or E-Z isomerism.The cis/trans system for naming isomers is not effective when there are more than two different substituents on a double bond. The E/Z notation should then be used. Z means together and corresponds to the term cis; E means opposite and corresponds to the term trans.

(E)- : the higher priority groups are on opposite sides of the double bond.

(Z)- : the higher priority groups are on the same side of the double bond.

(Z)- isomer (E)- isomer

Light from ordinary electric lamp is composed of waves vibrating in many different planes. When it passed through nicol prisom or polarizing filter, light is found to vibrate in only one plane, and is said to be plane polarized.

Solution of some organic compounds have the ability to rotate the plane of polarized light. These compounds are said to be optically active.

The isomer which rotates the plane to the left (counterclockwise) is called the levo isomer and designated as (-), while the one which rotates the plane to the right (clockwise) is called dextro isomer and is designated as (+).

Plane polarized light

Racemic mixture is a mixture of equal parts of enantiomer. Racemic mixtures are optically inactive since the equal and opposite rotation cancel each other.

Racemic mixture

A mixture of equal parts of enantiomers is called a racemic mixture. A racemic mixture is optically inactive: when enantiomers are mixed together, the rotation caused by a molecule of one isomer is exactly cancelled by an equal and opposite rotation caused by a molecule of its enantiomer.

A mixture is said to be racemic when it contains exactly equal amounts of two enantiomers. Such a mixture is optically inactive (zero rotation of plane polarized light).

For example, (+) Lactic acid [a mixture of (+) Lactic acid and (-) Lactic acid]-

COOH

CH3

H OH

COOH

CH3

OH H

D or (+) Lactic acid

L or (-) Lactic acid

This is demonstrated by the hydrogenation of 2-butanone:

Most chemical reactions which produce chiral molecules produce them in racemic form

There is no energy difference for the attack from the top or bottom face, and there is no energy difference in the (R) or (S) products.

Therefore although chiral products are produced, the products are formed in equal amounts – a racemic mixture.

A carbon atom to which four different groups are attached is a chiral center and is usually denoted with an asterix (*).

Chiral carbon/chiral center

A

DCB

A

D CB

2-butanol

□ If the molecule has no chiral carbon, it is usually

achiral

□ If the molecule has just one chiral carbon, it is

usually chiral

□ If it has 2 or more chiral carbons, it may or may

not be chiral.

Chirality means “handedness”.

Every object has a mirror image, but if a molecule’s mirror image is different from the molecule, it is said to be a chiral molecule.

Chiral objects include: hands, feet, gloves, screws, cork screws

Chirality

Achiral objects have mirror images that are identical to the object.

Any molecule which is not superimposable on its mirror image is said to possess chirality. The term “chirality” means having “handedness” (either left- handed or right- handed).When a molecule is superimposable on its mirror image that molecule does not posses “handedness” and is said to be achiral.

Chirality in organic molecules

If a mirror image of a molecule can be placed on top of the original, and the 3 dimensional arrangement of every atom is the same, then the two molecules are superimposable, and the molecule is achiral.

If a molecule has a non superimposable mirror image, it is chiral.

C ClI

H

SO3H

*C ICl

H

SO3H

*

Not superimposable: Chiral

Superimposable: Achiral

C

H

Cl

CH3CH3

*C

H

Cl

CH3CH3

*

The mirror image of a left hand is a right hand

Left and right hands are not superimposable

Your hands are chiral

Contain chiral carbon but optically inactive.

A meso compounds is one whose molecules are superimposable on their mirror images even through they contain chiral centers.

A meso compound is optically inactive.

Meso structures

Compound C has two chiral centers but it contains a plane of symmetry, and is achiral; C is a meso compound.

» Not optically active

» Superimposable on its mirror image

» Has a plane of symmetry

Sometimes molecules with 2 or more chiral centers will have less than the maximum amount of stereoisomers. e.g.

Maximum number of stereoisomers= 2n

[where n= number of structural units capable of stereochemical variation. Structural units include chirality centers and cis and/or trans double bonds.]

Number is reduced to less than 2n if meso forms are possible

Number of pair of enantiomer= 2n-1

How many stereoisomers?

4 chirality centers 16 stereoisomers 8 enantiomer

O

HOCH2CH—CH—CH—CHCH

OH OH OH OH

* * * *

If the molecule contains at least one of these elements of symmetry, the molecule is symmetric; if none of these elements of symmetry is present the molecule is asymmetric and optically active.

a. A plane of symmetryA plane of symmetry divided a molecule in such a way that the atoms or group of atoms on the one side of the plane form mirror images of those on the other side.

This test may be applied to both solid (tetrahedral) and plane-diagram formula e.g. the plane formula of

the meso-forms of Cabd-Cabd posses a plane of

symmetry; the other two (+) and (-) do not.

Elements of symmetry

b. A center of symmetryA center of symmetry is a point from which lines, when drawn on one side and produce on equal distance on the other side, will meet identical atoms or groups in the molecule.

C C═

H

ClH

Cl

Center of symmetry

This test may be applied only to 3-D formula, particularly those of ring system, e.g. 2,4-dimethyl cyclobutane-1,3 dicarboxylic acid. The form shown possesses a center of symmetry which is the centre of the ring. The form is therefore optically inactive.

A center of symmetry

2,4-dimethyl cyclobutane-1,3 dicarboxylic acid

A molecule possesses an n-fold alternating axis of symmetry if, when rotated through an angle of 360º/n about this axis and then followed by reflection in a plane perpendicular to the axis; the molecule is indistinguishable from the original molecule.

c. Alternating axis of symmetry

Cl

Cl

Cl

Cl

180o rotation

Cis-1,3-dichlorocyclobutane

I II

So when it rotates on angle of 90o about this axis AB which gone through the center of the ring perpendicular to its plane then it gives the molecule II. But the reflection of II in the plane of the ring gives I. The form is therefore optically inactive.

Let us consider 1,2,3,4-tetramethyl cyclobutane. This molecule (I) posses four fold alternating axis of symmetry.

The different arrangement of atoms or groups in the

space due to the free rotation of the groups about a

single bond is called conformation.

Conformation is a three dimensional structural

arrangement.

Conformation

Font carbo

n

Rear carbo

n

Newman projection formulaThis is obtained by viewing the molecule along

the bonding line of the two carbon atoms, with the

carbon atom nearer to the eye being designated by

equally spaced radii and the carbon atom further from

the eye by a circle with three equally spaced radial

extensions.

May differ in energy: The lowest-energy conformer is most prevalent.

Molecules constantly rotate through all the possible conformations.

Conformers of alkanes

Staggered [or transoid] form

The conformation in which the hydrogen atoms

of the two carbon remain at maximum distance when

viewed from one end along the C–C bond axis.

Model

Ethane C2H6 conformers

Staggered conformer has lowest energyDihedral angle = 60 degrees

Eclipsed [or cisoid] formThe conformation in which the hydrogen atoms

of two carbon remain nearer to one another when

viewed from one end along the C–C bond axis.

Eclipsed conformer has highest energy Dihedral angle = 0 degrees

Torsional strain: resistance to rotation. For ethane, only 12.6 kJ/mol

Propane Conformers

Note: slight increase in torsional strain due to the more bulky methyl group.

Butane Conformers C2-C3Highest energy when methyl groups are eclipsed

(cisoid)

Steric hindrance is the major cause

Dihedral angle = 0 degrees

totally eclipsed

Butane Conformers (2)Lowest energy when methyl groups are anti

(staggered)


anti

Butane Conformers (3)Methyl groups eclipsed with hydrogens

Higher energy than staggered conformer


eclipsed

Butane Conformers (4)Gauche, staggered conformer

Methyls closer than in anti conformer


gauche

Conformational analysis

55

Conformations of Butane

The potential energy of ethylene dichloride C2H4Cl2

undergoes changes when one CH2Cl group is rotated

about the C-C bond with the other CH2Cl at rest.

Conformational analysis of ethylene dichloride

There are two positions of minimum energy, one corresponding to staggered (transoid or anti) form and other to the gauche (skew) form, the latter possessing approximately 4.6 kj more than the former.

The fully eclipsed (cisoid) form possesses about 18.83 kj more energy than the staggered form.

Thus staggered form is the preferred form for ethylene dichloride.

What are the internal factors encountered in the stability of a conformation?

The existence of potential energy barriers between the various conformations shows that there are internal forces acting on the molecule.

However, the possible internal forces that prevents the free rotation about a single bond are-

a. Dipole-dipole forcesb. Steric repulsionc. Intermolecular hydrogen bondingd. Repulsion between adjacent pair of electrons

[Dipole moment: when the centers of the electrons and nuclei in a molecule do not coincide, the molecule will posses a permanent electric dipole moment, , the value of which given by = e x d, where e is the electronic charge, and d the distance between the charges (+ve and –ve centers) ]

a. Dipole-dipole forcesAccording to one theory, the hindering of internal

rotation is may be due to dipole-dipole forces.

Calculation of the dipole moment of dichloro ethane on the assumption of free rotation gave a value not similar with the experimental value. Thus the internal rotation in not completely free and there will be preferred conformations.

In the staggered form, the dipole moment is zero but as the molecule absorbs the energy, rotation occurs to produce finally the eclipsed form in which the dipole moment is maximum.[Zero dipole moment: H2, O2, CH4 , CCl4 etc.

Large dipole moment: HF, CH3Cl ]

b. Steric repulsion

Steric repulsion is the repulsion between the non-bonded atoms (of the rotating groups) when they are brought into close proximity.

c. Intermolecular hydrogen bonding

In a molecule such as ethylene chlorohydrins or ethylene glycol, intermolecular hydrogen bonding is possible in the skew form but not the staggered.

This would stabilize the molecule and make the skew form more stable than the staggered form.

Infra red spectroscopy has shown that the skew form predominates.

d. Repulsion between adjacent pair of electronsPauling in 1958 has proposed that the energy

barrier in ethane (and in similar molecules) results form the repulsion between the adjacent bonding pairs of electrons, i.e. the bonding pairs of the C–H bonds on one carbon atom repel those on the other carbon atom.

Thus, the preferred conformation will be the staggered one.

Element of symmetry When a molecule and its mirror image are

superimposable, the molecule is known as symmetric.

But in practice, the following tests are applied to identify any molecule as symmetric-

a. A plane of symmetry

b. A centre of symmetry

c. An alternative axis of symmetry

How can you assign the configuration of a molecule in R & S system ? Or What is the sequence rule for R & S configuration?

Let us consider an asymmetric carbon Cabde and

consider the priority of a,b,d,e is 1,2,3,4 gradually, where a>b>d>e according to priority.

Now by following priority, if eye moves clockwise direction, then the configuration is R-configuration (Latin Rectus,-’right’) and if eye moves anticlockwise direction, then the configuration will be S-configuration (Latin Sinistus,-’left’).

The Cahn Ingold Prelog sequence rulesCahn, Ingold and Prelog introduced this systematic

notation during the period 1951-1956. The sequence rules are- Priority is assigned by considering the decreasing order of the atomic number of the atom by which the group is directly attached to asymmetric carbon. The atom of highest atomic number gets the highest priority (1). e.g.

Group Atomic no Priority

Br 35 1Cl 17 2F 9 3H 1 4

Memorize order of priority: I > Br > Cl > F > O > N > C > H

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 priority 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:

If any substitution is done on groups, then higher substituents containing group will get more priority.

-CHCl2> -CH2Cl> -CH3

CH

CH3

CHCl21

3

CH2Cl

4

2

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 Assigning Priorities

R,S System for isomers with more than one chirality center

(2R,3S)-3-bromo-2-butanol

CH3

CH3

OHH

BrH

2

3

When a compound has more than one stereogenic center, the R and S configuration must be assigned to each of them.

Enantiomers have exactly opposite R,S designations.

Diastereoisomers have the same R,S designation for at least one chiral center and the opposite for at least one of the other chiral center.

Meso compounds have the same R,S designations at every chiral center.

Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers.

In addition they can have stereoisomeric forms that are not mirror images, called diastereomers.

2R,3S 2S,3R2R,3R 2S,3S

2

3

ReceptorReceptor

DrugDrug

The biological importance of chirality

The binding specificity of a chiral receptor site for a chiral molecule is usually only favorable in one way.

Draw the structure without stereochemistry, identify the chiral center and assign priority to the four groups attached to the chiral center. Then draw a tetrahedral carbon and put the group with the lowest priority on the bond pointed away from you. Put the highest priority group on any bond. Then put the group 2 in the position clockwise from the group 1 if it is the (R)-enantiomer or in the position counter clockwise from the group 1 if it is the (S)-enantiomer. Add group 3 on the remaining position.

2. Stereochemistry

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