Optical Activity and Stereoisomers

Optical Activity

Isomers

• Isomers are grouped into two broad classes: constitutional isomers and stereoisomers.
• Constitutional isomers (structural isomers) differ in their bonding sequence; their atoms are connected differently.
• Stereoisomers have the same bonding sequence but differ in the orientation of their atoms in space.
• Stereochemistry is the study of the three-dimensional structure of molecules in space.
• Stereoisomers often have different physical, chemical, and biological properties.

Types of Isomers:

• Constitutional Isomers (Structural Isomers)
• Cis-Trans Isomers (Geometric Isomers)
• Stereoisomers
  • Enantiomers
  • Diastereomers
    • Cis-Trans Isomers
    • Other Diastereomers (two or more chirality centers)

Cis-Trans Isomers

• Cis and trans isomers of butenedioic acid are a special type of stereoisomers called cis-trans isomers (or geometric isomers).
• Both compounds have the formula HOOC-CH=CH-COOH but they differ in how these atoms are arranged in space.
• The cis isomer is maleic acid, which is toxic and irritating to tissues. The trans isomer is fumaric acid, an essential metabolic intermediate in both plants and animals.

Chirality

• Chirality means handedness.
• Objects that have the potential to exist in ‘right-handed’ and ‘left-handed’ forms.
• Every object has a mirror image which can be examined to determine whether or not an object is chiral.
• 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, shoes, screws, cork screws.
• The relationship between two hands or two feet is that they are non-superimposable (non-identical) mirror images of each other.
• Achiral objects have mirror images that are identical to the object.

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, the two molecules are superimposable, and the molecule is achiral.
• If a molecule has a non-superimposable mirror image, it is chiral.
• Many objects are achiral, i.e., the object and its mirror image are identical.
• They can be superimposed on each other – if one object is placed on the other, all parts will coincide.
• All molecules have a mirror image – but for most molecules it is the same molecule.
• For some molecules, the mirror image is a different molecule (the mirror image is non-superimposable).
• A chiral object is one which cannot be superimposed on its mirror image.

Stereoisomers of 1,2-dichlorocyclopentane

• The cis isomer has a superimposable mirror image and is achiral.
• The trans isomer is non-superimposable on its mirror image and is chiral.
• Pairs of non-superimposable mirror images of molecules are called enantiomers.
  • All chiral compounds have enantiomers.
  • Achiral compounds do not have enantiomers; their mirror images are superimposable/same as the original molecule.

Chiral Carbon Atoms

• Rings are not essential for chirality; consider 2-bromobutane.
• 2-Bromobutane cannot be superimposed on its mirror image – it is chiral, and it exists in two enantiomeric forms.
• A chiral molecule has a carbon atom which has four different groups bonded to it.
• This carbon is called the chiral carbon, asymmetric carbon, or stereogenic center.
• A chiral molecule and its mirror image are called a pair of enantiomers.
• Any carbon bound to 4 different groups will be an asymmetric or chiral carbon, which is designated with an asterisk (*).

Rules to determine if a molecule’s mirror is identical to the original molecule:

1. If the molecule has no chiral carbon, it is usually achiral.
2. If the molecule has just one chiral carbon, it is usually chiral.
3. If it has 2 or more chiral carbons, it may or may not be chiral.

Enantiomers of an Asymmetric Carbon Atom

• A carbon atom bonded to just three different types of groups is not chiral.

Mirror Planes of Symmetry

• If a molecule possesses an internal mirror plane of symmetry (\sigma), then it cannot be chiral.
  • The absence of a mirror plane does not imply chirality.
• cis-1,2-dichlorocyclopentane is achiral since its mirror image is identical to the original molecule.
• Any compound with an internal mirror plane of symmetry cannot be chiral even though it may contain asymmetric carbon atoms.
• An asymmetric carbon has a mirror image that is non-superimposable on the original structure; it has no internal mirror plane of symmetry.
• If a carbon atom has only three different kinds of substituents, however, it has an internal mirror plane of symmetry, therefore it cannot contribute to chirality in a molecule.

Optical Activity

• Mirror-image molecules have nearly identical physical properties.
• Enantiomers have the same Boiling points, Melting points, Density.
• Differences in enantiomers become apparent in their interactions with other chiral molecules and plane-polarized light.
• Polarimetry is used to distinguish between enantiomers & measure their purity.
• Distinction between enantiomers is based on their ability to rotate the plane of polarized light in opposite directions.
• Unpolarized light vibrates randomly in all directions.
• Plane-polarized light is composed of waves that vibrate in only one plane.
• Unpolarized light passed through a polarizing filter filters randomly vibrating light waves so that most of the light passing through is vibrating in one direction.
  • The direction of vibration is called the axis of the filter.
• When polarized light passes through a solution containing a chiral compound, the chiral compound causes the plane of vibration to rotate.
• Rotation of the plane of polarized light is called optical activity, and substances that rotate the plane of polarized light are said to be optically active.
• Enantiomeric compounds rotate the plane of polarized light in equal but opposite directions.
• Chiral compounds are called optically active compounds.
• If the (R) enantiomer rotates the plane 5° counterclockwise, the (S) enantiomer will rotate it 5° clockwise.
• A polarimeter measures the rotation of polarized light. It has a tubular cell filled with a solution of the optically active material and a system for passing polarized light through the solution and measuring the rotation as the light emerges.
• Monochromatic (one-color) light from the source passes through a polarizing filter, then through the sample cell containing a solution of the optically active compound.
• On leaving the sample cell, the polarized light encounters another polarizing filter.
  • This filter is movable, with a scale allowing the operator to read the angle between the axis of the second (analyzing) filter and the axis of the first (polarizing) filter.
• The observed rotation is symbolized by \\alpha
• Optically active compounds which rotate plane polarized light clockwise are called dextrorotatory are designated (+) or d.
  • dexios is Greek for toward the right.
• Optically active compounds which rotate plane polarized light counterclockwise are levorotatory are designated (-) or l.
  • laevus means toward the left.
• There is no relationship between (R) and (S) and the direction of the rotation of plane polarized light. (R) does not mean d and (+).

Specific Rotation

• Angular rotation of polarized light by a chiral compound is a characteristic physical property of that compound.
• The rotation observed in a polarimeter depends on the concentration of the sample solution and the length of the cell, as well as the optical activity of the compound.
• Specific rotation is the rotation found using a 10 cm (1dm) sample cell and a concentration of 1 g/mL.
• Other cell lengths and concentrations may be used, as long as the observed rotation is divided by the path length of the cell (l) and the concentration (c).

Racemic Mixtures (Racemates)

• A racemic mixture or racemate contains exactly equal amounts of two enantiomers.
• Such a mixture is optically inactive (zero rotation of plane-polarized light).
• A racemic mixture is symbolized by placing (+/-) or (d,l) in front of the name of the compound.
• Racemic mixtures are very common since it is difficult to produce exclusively one enantiomer.
• Any reaction that uses optically inactive reactants and catalysts cannot produce a mixture that is optically active.
• Any chiral products formed will be formed as a racemate.
• This is demonstrated by the hydrogenation of 2-butanone: 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.

Chirality in Biological Systems

• Two enantiomers may have totally different biological properties.
• Enzymes in living systems are chiral, and they are capable of distinguishing between enantiomers.
• Usually, only one enantiomer of a pair fits properly into the chiral active site of an enzyme. Thus active sites of enzymes are capable of chiral discrimination.
• The receptor sites for sense of smell can also distinguish between enantiomers.
• The absolute configuration of a molecule is the detailed stereochemical picture including how the atoms are arranged in space.

Biological Importance of Chirality

• Many naturally occurring molecules exhibit chirality. Amino acids are chiral, hence proteins are also chiral.
• All amino acids rotate plane-polarized light to the right.
• The anti-inflammatory drug, ibuprofen is marketed as a racemate. Only the S-isomer is effective, but the body slowly converts the R-isomer to the S-isomer.
• S limonene (lemons) and R limonene (oranges) have different smells.
• S carvone (caraway seed) and R carvone (spearmint) have different smells.
• S thalidomide (effective drug) and R thalidomide (dangerous drug): The body racemizes each enantiomer, so even pure S is dangerous as it converts to R in the body.

(R) and (S) Nomenclature of Asymmetric Carbon Atoms

• A pair of enantiomers represents the two possible spatial arrangements or what is known as configurations about the asymmetric carbon of the compound.
• The difference between two enantiomers is in the 3D arrangement of the four groups around the asymmetric carbon atom.
• The Cahn-Ingold-Prelog Convention is used to give (R) and (S) designations of each chiral carbon to distinguish between the two enantiomers.
  • Cahn, Ingold, and Prelog devised the R,S System of Nomenclature to indicate the configuration (arrangement) of the atoms or groups about the asymmetric carbon.
• There are two steps to assigning (R) or (S) to an enantiomer in which priorities are assigned to the 4 substituents.
  1. Assignment of “priority” to each group bonded to the asymmetric carbon.
  2. Using the “priority” to decide on (R) or (S).

Assignment of Priority

• Rank the groups/atoms bonded to the asymmetric carbon in order of priority. Only consider the atomic number of the atom directly attached to the asymmetric carbon, not the entire group.
• Atoms with higher atomic numbers receive higher priorities. 1 for highest and 4 for lowest priority.
  • In the case of the same atoms being bound directly to the chiral carbon, the atomic number of the next atom along the chain of each group is used to assign priority.
  • Double and triple bonds are treated as if each bond were to a separate atom.

(R) and (S) Assignments

• The molecule is drawn in 3D and arranged so the bond between the chiral carbon and the lowest priority group heads back into the paper (away from the viewer).
  • View the molecule with the first, second, and third priority groups radiating toward you.
• Draw an arrow from the highest priority group, through the second, to the third priority group.
  • If the arrow is clockwise, the chiral carbon is assigned (R). (Latin, rectus, “upright”).
  • If the arrow is counterclockwise, the chiral carbon is assigned (S). (Latin, sinister, “left”).
  • To provide the full name for the molecule, R or S is added in parenthesis in front of the name. Thus, this molecule is (R)-2-chlorobutane.
  • NB If the lowest priority group is in front of the plane of molecule, then the assignment is reversed: clockwise is S and counterclockwise is R.

Fischer Projections

• Wedge-dash, Sawhorse, and Newman representations are less convenient for molecules with many chiral carbon atoms, and so Fischer Projections are used instead.
• Fischer projections are drawn like a cross, with the chiral atom at the center of the cross.
  • The horizontal lines represent wedges (bonds coming out of the plane of paper toward the viewer).
  • The vertical lines represent dashed lines (bonds going into the plane of the paper away from viewer).

Fischer Projections Rules

• Fischer projections that differ by a 180° rotation are the same since the vertical lines are still behind, and the horizontal lines are still forward.
• Fischer projections that differ by a 90° rotation are enantiomers of the original molecule.
  • In comparing Fischer projections, they cannot be rotated by 90°, and cannot be flipped over. Either of these operations gives an incorrect representation of the molecule. The Fischer projection must be kept in the plane of the paper, and it may be rotated only by 180°.
• Another rule is that the carbon chain is drawn along the vertical line of the projection, with the most highly oxidized carbon substituent at the top.
• To draw a mirror image of a Fischer projection, simply exchange the left and right positions, whilst keeping the top and bottom unchanged.
  • i.e. Interchanging the groups on the horizontal part of the cross reverses left and right while leaving the other directions unchanged.
• Fischer projections are very useful to determine if a compound is chiral or achiral. (Assuming the Fischer projections are correctly drawn).
• If the mirror image cannot be made to look like the original image by only rotating by 180° in the plane of the paper, then the images are enantiomers, and the original compound is therefore chiral.
• Mirror planes are easy to identify in Fischer projections, and molecules with mirror planes cannot be chiral.

Assigning (R) and (S) in Fischer Projection

• (R) and (S) are determined according to the Cahn-Ingold-Prelog convention and can be applied to Fischer projections.
  • Either by converting Fischer projection to perspective drawing and assigning R/S, or determining R/S directly from Fischer projections without converting.
• In Fischer projections and the lowest priority group is usually H (it will be on the horizontal axis, sticking out of the page) and since the Carbon chain is arranged vertically.

Procedure

1. Ensure the Fischer projection is drawn correctly.
2. Ignore the lowest priority group and label the other three.
3. Draw the arrow from the highest to lowest priority groups (1-2-3).
4. Since the lowest priority bond is now sticking out (opposite to normal), a clockwise arrow means S configuration.
   • If the molecule were turned around so that the hydrogen would be in back [as in the definition of (R) and (S)], the arrow would rotate in the other direction.
   • We can mentally turn the arrow around (or simply applying the rule backward), then assign the configuration.
5. First priority goes to the OH group followed by CHO and CH2OH groups.
6. The hydrogen atom receives the lowest priority.
7. The arrow from group 1 to group 2 to group 3 appears counterclockwise in the Fischer projection.

Diastereomers

• Stereoisomers are molecules that have atoms bonded together in the same order, but differ in how the molecules are directed in space.
  • Enantiomers are mirror image isomers.
• All other stereoisomers are called diastereomers.
  • i.e., diastereomers are stereoisomers that are not mirror images.
• Most diastereomers are either geometric isomers or compounds with two or more chiral atoms.

Diastereomers - Geometric Isomers

• One class of diastereomers are cis-trans isomers or geometric isomers, for example, 2-butene.
• They are not mirror images of each other – not enantiomers.

Diastereomers - Molecules with 2 or More Chiral Atoms

• Most other compounds that are diastereomers have two or more chirality centers, usually asymmetric carbon atoms e.g., 2-bromo-3-chlorobutane which can exist in 4 possible stereoisomers; (2S, 3R), (2R, 3S), (2S, 3S) and (2R, 3R).
• For a molecule with n stereogenic centers, the maximum number of stereoisomers is 2^n.

Diastereomers Physical Properties

• Enantiomers have identical physical properties (b.p., m.p., density, etc.) except for their rotation of plane-polarized light.
• Diastereomers have different physical properties.
• Since diastereomers have different physical properties, they are often easy to separate to by normal techniques; distillation, recrystallization, chromatography etc.
• Enantiomers are much more difficult to separate.

Configuration Exercises

• List the following substituents in order of priority from highest to lowest.
  • (a) -Cl, -OH, SH, —H
  • (b) —CH³, —CH₂Br, —CH₂CI, —CH₂OH
  • (c) –H, –OH, —CHO, —CH₃
  • (d) CH(CH₃)₂, C(CH₃)₃, -H