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Optical Isomerism

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Content

• History• Enantiomers• Reasons for molecular handedness• Optical activity of enantiomers• Naming Conventions• Diastereomers• Meso Compounds• Resolution of Enantiomers• Importance of Enantiomers

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Isomers

Compounds with thesame molecular formula

ConformationalIsomers

rotation aboutsingle bonds

with chiral centers

Stereoisomers

MesoCompounds

Enantiomers

ConstitutionalIsomers

Cis,Trans (E,Z) Isomers(can be calleddiastereomers)

Conformations

rotation restricted

differentconnectivity

Diastereomers

stereocentersbut no chiral centers

Enantiomers

one chiral centerm ore than

one chiral center

chiralachiral

not mirror images

mirror images

Atropisomers

sameconnectivity

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History

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Discovery of Optical Activity

• In 1850, French Physicist Jean-Baptise Biot observed that solutions of some organic compounds like sugar and camphor have the ability to rotate plane polarized light

• Up till then the basis of this phenomenon was not yet known

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Separation of Enantiomers

• In 1848 French Chemist Louis Pasteur separated a solution of optically inactive tartaric acid into two optically active components. 

• He observed that:– Each of these components had identical physical

properties like density,  melting point, solubility, etc

• But– One of the components rotated plane polarized light

clockwise while the other component rotated the polarized light by the same amount counter clockwise.

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• Pasteur made a proposal that since the crystals of tartaric acid were mirror images of each other, their molecules were also mirror images of each other

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• Additional research done by Pasteur revealed that one component of tartaric acid could be utilized for nutrition by micro-organisms but the other could not.

• Thus 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.

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The tetrahedral Carbon

• In 1874 as a student at University of Utrecht, Jacobus van't Hoff proposed the tetrahedral carbon. His proposal was based upon evidence of isomer number:– Conversion of CH4 into CH3R(1 isomer)

– Conversion of CH3R into CH2RR1(1 isomer)

• van't Hoff realized that the four hydrogens in CH4 had to be equivalent and a geometrical square was ruled out because it would form 2 isomers for CH2RR1. Thus he proposed the tetrahedral carbon centre.

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Explanation of Optical Isomerism

• The tetrahedral carbon not only collaborated the absence of isomers in CH2YZ, but also predicted the existence of mirror image isomers. When carbon makes four single bonds with four different groups such as CHFClBr, non-super-imposable mirror-image molecules exist

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Enantiomers

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Definition

• An enantiomer is one of two stereoisomers that are mirror images of each other and are non-superimposable.

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• As seen here, the two molecules of lactic acid are mirror images of each other, but cannot superimpose.

(S)-Lactic acidor (+)-Lactic acid

(R)-Lactic acidor (-)-Lactic acid

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The Tetrahedral Carbon

• Enantiomers result when two compounds that are mirror-images of each other cannot superimpose

• Eg. when a tetrahedral carbon is bonded to four different substituents(CR1R2R3R4)

• For example, in lactic acid, there are four different groups: -H, -OH, -CH3, -COOH

• Can you name other examples of enantiomers formed this way?– Alanine, Tartaric Acid, Glyceraldehyde

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Reasons for molecular handedness(Chirality)

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Chirality

• A molecule that is not superimposable to its mirror image is said to be chiral

• The most common cause of chirality in organic molecules is the presence of a carbon atom bonded with 4 different groups(eg in lactic acid), this is also known as point chirality.

• These carbon atoms are called chirality centers or chirality centres.

• Can you think of other causes of Chirality? (be creative)

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Identifying Chiral Molecules

• The obvious way: find any carbon with 4 different substituents. If there are any, then the molecule is chiral. Isotopic differences are also considered different substituents.

• Thus, -CH2-, -CH3(methyl), >C=O(carbonyl), >C=C<(alkene) and -C@C-(alkyne) groups cannot be chirality centers as they all have less than 4 substituents.

• Easier way: look for the presence of a plane of symmetry, since a symmetrical molecule is identical to its mirror image and is thus achiral

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Drawing of Enantiomers

• Fischer Projection (do not confuse with Lewis Structure)

• Natta Projection (we all know this)• For cyclic molecules– Haworth Projection– Chair conformation

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1. Fischer Projection 2. Haworth Projection3. Chair Conformation4. Natta Projections

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Optical activity of enantiomers

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• As seen from Biot’s experiment, enantiomers can rotate plane polarised light, since they are optically active

• When a beam of plane polarised light passes through a solution of a non-racemic (scalemic) mixture (ie has enantiomeric excess of one of the enantiomers), rotation of the polarisation plane occurs.

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Polarimeter

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Optical Activity

Observed rotationThe number of degrees, , through

which a compound rotates the plane of polarized light.

Dextrorotatory (+)A compound that rotates the plane of

polarized light to the right.Levorotatory (-)Refers to a compound that rotates the

plane of polarized light to the left.

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Specific RotationSpecific rotation refers to the observed rotation for a sample in a tube 1.0 dm in length and at a concentration of 1.0 g/mL.

The degree of rotation also depends on the wavelength of the light (the yellow sodium D2 line near 589 nm is commonly used for measurements)

DD

H3CC

OHH

COOH

CH3

C

HO

H

COOH

[]21= -2.6°= +2.6°21

[]

(R)-(-)-Lactic acid(S)-(+)-Lactic acid

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Calculating Specific Rotation (liquids)• The specific rotation of a compound is

given by:

• Where:– [a] is the specific rotation– T is the temperature– l is the wavelength of light used– l is the path length of sample (in decimetres)– d is the density of the sample (in g/cm3 for pure

liquids)– The sign of the rotation (+ or -) is always given

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Calculating Specific Rotation (liquids)• The specific rotation of a compound is

given by:

• Where:– [a] is the specific rotation– T is the temperature– l is the wavelength of light used– l is the path length of sample (in decimetres)– c is the concentration of the sample (in g/cm3)– The sign of the rotation (+ or -) is always given

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Optical Purity• Optical purity: A way of describing the composition of a

mixture of enantiomers.

• Enantiomeric excess: The difference between the percentage of two enantiomers in a mixture.

– optical purity is numerically equal to enantiomeric excess, but is experimentally determined.

x 100[]samplePercent optical purity =

[]pure enantiomer

Enantiomeric excess (ee) = %R - %S

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Naming Conventions

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Types of naming

• R,S designation• +, - designation (explained just now)• D,L Nomenclature

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R-, S- Naming Convention

• This convention labels each chiral center R or S according to a system by which its substituents are each assigned a priority based on atomic number.

• The priority of substituents are assigned based on Cahn–Ingold–Prelog priority rules

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Cahn–Ingold–Prelog priority rules

• Assignment of Priority– Compare the atomic number of the

atoms directly attached to the chirality center. The group with the atom of higher atomic number receives higher priority. (eg –Cl > –OH > –NH2 > –CH3)

– If different isotopes of the same element is attached to the chiral center, the group with the higher mass number recieves higher priority (2H > 1H)

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• If double or triple bonded groups are encountered as substituents, they are treated as an equivalent set of single-bonded atoms.For example, C2H5–  <  CH2=CH–  <  HC≡C– 

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• If there is a tie, consider the atoms at distance 2 from the chirality center—as a list is made for each group of the atoms bonded to the one directly attached to the chirality center. Each list is arranged in order of decreasing atomic number. Then the lists are compared atom by atom; at the earliest difference, the group containing the atom of higher atomic number receives higher priority. (eg. –COOH > –CH3)

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• If there is still a tie, each atom in each of the two lists is replaced with a sub-list of the other atoms bonded to it (at distance 3 from the chirality center), the sub-lists are arranged in decreasing order of atomic number, and the entire structure is again compared atom by atom. This process is repeated, each time with atoms one bond farther from the chirality center, until the tie is broken.

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Identifying the Configuration• After having ranked the four groups

attached to the stereo-center, orientate the molecule such that the lowest ranking group points directly back

• Look at the 3 substituents left facing you: If the priority of the remaining three substituents decreases in clockwise direction, it is labeled R (for Rectus, Latin for right), if it decreases in counterclockwise direction, it is S (for Sinister, Latin for left).

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D,L Nomenclature

• The D/L system names isomers after the spatial configuration of its atoms, by relating the molecule to glyceraldehyde. Glyceraldehyde is chiral itself, and its two isomers are labeled D and L

• This nomenclature is still used in certain organic compounds like saccharides and amino acids

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Identifying the Configuration

• For Monosaccharides:• The absolute configuration of all

monosaccharides is denoted by the configuration at the chirality center furthest from the anomeric centre (the carbonyl carbon in the open chain representation) 

• If, in the Fischer projection, that centre has the hydroxyl group on the right, it is a D-sugar; if on the left, it is an L-sugar. By convention, the "D" and "L" symbols are written in small capitals.

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• Non amino-acids such as Lactic, Ascorbic, Tartaric Acid also follow the same rules as Saccharides.

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Identifying the Configurations

• For Amino Acids• CORN Rule:• The groups: COOH, R, NH2 and H (where

R is a variant carbon chain)are arranged around the chiral center carbon atom. Starting with the hydrogen atom away from the viewer, if these groups are arranged clockwise around the carbon atom, then it is the D-form. If counter-clockwise, it is the L-form.

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Relation to other naming conventions

• The D/L labeling is unrelated to (+)/(−); it does not indicate which enantiomer is dextrorotatory and which is levorotatory.

• Rather, it says that the compound's stereochemistry is related to that of the dextrorotatory or levorotatory enantiomer of glyceraldehyde—the dextrorotatory isomer of glyceraldehyde is, in fact, the D- isomer.

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Diastereomers

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2n Rule

• As a general rule the maximum number of isomers for a compound is 2n, with n being the number of chirality centers.

• *As seen in the next slide

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Definition

• Diastereomers refer to enantiomers that are not mirror images of each other

• They can be chiral or achiral• Eg D-glucose and D-galactose

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Stereochemistry in Sugars

• Aldose• An aldose is a monosaccharide that

contains only one aldehyde group per molecule. The chemical formula takes the form Cn(H2O)n.

• The maximum number of chirality centers for any aldose is 2n-2

• Since the “head”(-CH=O) and “tail”(-CH2OH) carbons cannot be chiral centers

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Examples (Aldotetrose)

• Aldotetroses are Aldoses with 4 carbons

• As such, the maximum number of enantiomers of aldotetroses is 4 (24-2)

• The 4 possible enantiomers of Aldotetroses

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Other examples of diastereomers

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Reasons

• As we can see, although Erythrose and Threose are stereoisomers, they are not enantiomers, since their molecules are not mirror-images of each other. They are thus called diastereomers

Erythrose Threose

They are not mirror images of each other

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• This is because stereoisomers are only enantiomers because all their chirality centers have opposite configurations, but if not all chirality centres have opposite configurations, then they are diastereomers.

Example of D(+)-Glucose and D(+)-Galactose

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Meso Compounds

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Definition

• A meso-compound is a non-optically active member of a set of stereoisomers.– It does not give a (+) or (-) reading on a

polarimeter

• It is non-optically active as it is achiral

• It is achiral since it has a plane of symmetry

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Examples

• Tartaric acid has 3 stereoisomers• D-(2S,3S)-(−)-tartaric acid• L-(2R,3R)-(+)-tartaric acid• (2R,3S)-mesotartaric acid

D-(2S,3S)-(−)-tartaric acid L-(2R,3R)-(+)-tartaric acid (2R,3S)-mesotartaric acid

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Mesotartaric Acid

• Let’s assume the mirror image of mesotartaric acid:

• Flip the molecule:

• And you find that you get the same molecule

Flip this molecule 180 degrees

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Meso Compounds

• Thus, we can say that mesotartaric acid is not an enantiomer, as it is superimposible with its mirror image.

• This is due to the fact that there is a plane of symmetry in the molecule

Rotate this bond 180 degrees

There is a plane of symmetry

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Resolution of Enantiomers

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Resolution of Enantiomers

• In the lab, if we make chiral compounds from achiral starting materials, we are bound to get a racemic mixture.

• The way we separate the mixture is known as resolution

• Resolution is important as most of the time enantiomerically pure compounds are required

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Crystallisation

• One way of resolution would be crystallisation (like what Pasteur did), it’s use is limited to solid compounds (eg Sodium Ammonium Tartrate)

• It does not work for liquid compounds that do not crystallise under ordinary conditions

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• The most common way of resolution would be to use an acid-base reaction between a racemic mixture of chiral carboxylic acid and an amine base to yield an ammonium salt, which can be crystallised.

+

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Resolution of enantiomers

• Another way would be using a chemical reaction to produce a diastereomer.

• This can be done in various ways, by esterification or by forming diastereomeric salt (Adduct).

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Resolution of enantiomers (Esterification)

• One way of resolution of enantiomers would be using an ester

+ TsOHor H2SO4

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Chiral but Racemic

Chiral but enantiomerically pure

Diastereomers

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• Diastereomers have different physical properties (solubility, boiling point etc), and should be quite easy to separate by distillation/crystallisation/chromatography

• When a pure enantiomer (diastereomer) is separated, the original intended products can be obtained

NaOH, H2O

Enantiomerically pure product

+

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Resolution of enantiomers (Forming a diastereomeric salt)

• When a racemic mixture of a carboxylic acid reacts with a single enantiomer of a chiral base, diastereomers are obtained.

• Diastereomers can then be separated just like previously

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• Acidification of the two diastereomeric salts resolved the original racemic mixture.

Racemic MixtureEnantiomerically pure compound

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Importance of Enantiomers

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Chirality in the Biological World

• Enzymes are like hands in a handshake– The substrate fits into a binding site on the enzyme

surface– A left-handed molecule, like hands in gloves, will

only fit into a left-handed binding site and– a right-handed molecule will only fit into a right-

handed binding site.– Because of the differences in their interactions with

other chiral molecules in living systems, enantiomers have different physiological properties.

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Some Examples

• D-Glucose can be used for metabolism for all organisms but not L-glucose

• Almost all of the amino acids in proteins are (S) at the α carbon.

• In most pharmaceutical drugs, only one of the enantiomers are biologically active.– Eg. (S)Ibuprofen is an active analgestic

agent but the (R) enantiomer is biologically inactive

a carbon

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Chirality in the Biological World

– A schematic diagram of an enzyme active site capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde.

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Credits

• Most of these information are taken from online sources[citation needed]

• However due to the fact that the layout was copied from the book, we apologise for the fact that this may be a little boring (for some)

• Done by: Jeff Xu, Luther Mok, Joshua Lay, Wen Song

• Design by Jonathan Yong

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Thank You