Organic Pharmacy (Pharm 1209)�Chapter 1�Isomerism

Prepared by

SHADIDUZZAMAN

Lecturer

Department of Pharmacy, Northern University

Introduction

• Isomerism is a very common phenomenon in organic chemistry.
• A large number of organic molecules show isomerism. In contrast, inorganic molecules rarely show isomerism (mostly confined to coordination compounds).
• The biomolecules also show isomerism and this isomerism is very important to the living organisms (including humans).

Concept

• In organic molecules, it is frequently possible for a molecular formula to exist as different structures.
• For example, the molecular formula C₄H₁₀O can exist as any of the following structures.

Concept Contd.

• Again, it is possible that two molecules have the same molecular formula and the same structural formula, but the atoms are at different position in space.
• For example, the atoms can occupy space in two ways in the following structure:

Concept Contd.

• Two molecules who have the same molecular formula but different structures will show differences in some physical and chemical properties.
• Similarly, two molecules who have the same molecular formula but different arrangement in space will also show differences in physical and chemical properties.
• Hence two such molecules can’t be considered the same.
• Such molecules are called isomers of each other.

Concept Contd. [Definitions]

• So, when two or molecules have the same molecular formula but have different physical and/or chemical properties due to having different structures or different arrangement of atoms in space, they are called isomers [Isos = same, equal, identical; Meros = part, a share].
• Simply, when two or more different compounds have the same molecular formula, they are called isomers.
• This phenomenon of one molecular formula existing as different compounds is called isomerism.

Types of Isomerism in Organic Molecules

• As we have stated in the previous slides, isomerism can arise from two conditions:
1. The atoms are connected differently to each other.
2. The atoms are connected the same, however occupy different position in space.
• In keeping with that, broadly isomerism is of two types as shown below:

• Isomerism
• Structural isomerism

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• Stereo-isomerism

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• These two types can be further divided into other types.

Types of Isomerism in Organic Molecules Contd.

A more intensive classification is shown below:

• Isomerism
• Structural isomerism
• Chain isomerism

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• Positional isomerism

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• Functional group isomerism

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• Stereo-isomerism
• Geometric isomerism
• cis/trans isomers

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• E/Z isomers

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• Optical isomerism
• D/L isomers

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• R/S isomers

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Structural Isomerism

Definition

• Structural isomerism can be defined as the isomerism that occurs when two or more molecules have the same molecular formula but have different structures.
• In another words, atoms are connected differently in structural isomers.
• Structural isomerism is also referred to as constitutional isomerism.

Types

• Mainly, structural isomerism can be of 3 types –
• Chain isomerism
• Positional isomerism
• Functional group isomerism
• Some refer to ‘metamerism’ and ‘tautomerism’ as types of structural isomerism as well.

Structural Isomerism Contd.

Chain isomerism

• It is also known as nuclear isomerism or skeletal isomerism.
• Chain isomers are those in which the (carbon) chain lengths are different.
• So, we can say that chain isomerism is a phenomenon where two or more molecules have the same molecular formula, but their structures are different due to different chain length.
• We can get one straight-chain and one or more branched-chain isomers due to chain isomerism.

Structural Isomerism Contd.

Examples of chain isomerism:

Structural Isomerism Contd.

Positional isomerism

• It is also known as regioisomerism.
• In case of positional isomers (or position isomers), the chain length doesn’t change rather the position of the functional group changes.
• So in positional isomerism:
• The molecular formula is same.
• The chain length is same.
• The functional group is same.
• But the position of the functional group is different.

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Structural Isomerism Contd.

Examples of positional isomerism:

Structural Isomerism Contd.

Functional group isomerism

• It is also known as functional isomerism.
• In functional group isomerism:
• The molecular formula is the same.
• The functional groups are different.
• So, when two or molecules have the same molecular formula but different functional groups, they are called functional group isomers and the phenomenon is called functional group isomerism.

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Structural Isomerism Contd.

Examples of functional group isomerism:

Structural Isomerism Contd.

Tautomerism

• When two compounds which have different structures and different functional groups but same molecular formula are interconverted between each other, it is called tautomerism.
• Two such compounds are tautomers of each other. These tautomers are at a dynamic equilibrium with each other.
• Tautomerism is also known as desmotropism,
• The most prominent example is the interconversion between ketone and enol.

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• This is a kind of functional group isomerism.

Structural Isomerism Contd.

Metamerism

• If the alkyl groups attached to the functional group differs in two compounds with same molecular formula, this is known as metamerism.
• In another words, if the number of carbons at different side of the functional group differs in two or more compounds, then they are metameric isomers (metamers).
• This is seen when the functional groups are:

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Examples:

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• So, basically it is a type of positional isomerism.

Stereoisomerism

Stereochemistry

• The branch of chemistry which discusses the molecular structure and reactivity of molecules in three dimensions (3D) is called stereochemistry.

Definition of stereoisomerism

• Stereoisomerism can be defined as the isomerism which occurs when two or more molecules have the same molecular formula and structural formula, but there is a difference of properties due to difference in position of the atoms in space.
• In another words, the atoms are positioned differently in stereoisomerism.
• It can also said that the isomerism that results from difference of spatial arrangement of atoms is called stereoisomerism.

Types of stereoisomerism

• Broadly, stereoisomerism can be divided into two types:
• Geometric isomerism
• Optical isomerism

Geometric Isomerism

Definition

• The isomerism which occurs due to difference of the positions of the substituents about a double bond or a ring is called geometric isomerism.
• It is also known as cis-trans isomerism.
• Conditions for geometric isomerism
• There must be a carbon-carbon double bond in the compounds.
• Each of the carbon of the double bond must be attached to two different substituents.
• Now…… Are these compounds below geometric isomers?

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Why does geometric isomerism occur?

• Geometric isomerism occurs because there is no possibility of free rotation about a double bond or a ring.
• As a result, the substituents are fixed in position. They can’t change position without breaking bond.

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• So, the two structures above are separate compounds, and therefore isomers.

Types of geometric isomers

• There are two methods to denote geometric isomers. According to these two methods there are:

Cis or Trans isomers

E or Z isomers

Geometric Isomerism Contd.

Cis/trans isomerism

• This method of denoting geometric isomerism works best when the alkene is disubstituted. In fact, it will always work when the alkene is disubstituted (and other conditions are fulfilled).
• But this method can fail with trisubstituted or tetrasubstituted alkenes.

Cis isomer

• The geometric isomer in which the identical groups on two carbons of the double bond are on the same side of the double bond is called the cis isomer.

Trans isomer

• The geometric isomer in which the identical groups on the two carbons of the double bond are on the opposite sides of the double bond is called the trans isomer.
• In cases of ring compounds, if the groups are on the same side of the ring then it is cis and if on the opposite sides then it is trans.

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Geometric Isomerism Contd.

• For this cis/trans method of denoting to work, there must be at least one identical group on each carbon of the double bond. For example:

Geometric Isomerism Contd.

Geometric Isomerism Contd.

Cis isomer is less stable than trans isomer

• In cis isomer, two large groups on the separate carbons are always on the same side. Thus, these two groups are closer to each other and repel each other. This is called steric strain.
• On the other hand, in trans isomer the two large groups are on the opposite sides. So they are far apart. Hence they don’t repel each other. So, the steric strain is far less.

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• This is why cis isomer is less stable than trans isomer.

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Geometric Isomerism Contd.

E/Z isomerism

• E/Z method of denoting geometric isomers is universal.
• This method will not fail even when cis/trans method has failed.
• While this method can work on all compounds that have geometric isomers, it is used for those compounds where cis/trans method fails.
• According to this method, the groups attached to each carbon of the double bond are analyzed and then given priorities according to Cahn-Ingold-Prelog (CIP) rules.
• If the group of highest priority on both carbon are on the same side, then it is Z (Z = Zusammen = Together) isomer, if they are on opposite sides, then it is E (E = Entgegen = Opposite) isomer.

Geometric Isomerism Contd.

CIP rules for E/Z naming convention

• Substituents on any one of the two double-bonded carbon atom is looked at.
• First, the atom which is directly attached to the double bond carbon is looked at. This is the first atom. The group where first atom has higher atomic number has higher priority.

Geometric Isomerism Contd.

• If, both groups are attached by the same first atom, then the atomic number of the second atom (atom attached to first atom) is looked at.

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• Similarly, if the second atoms are also same, third atoms are looked at.

Geometric Isomerism Contd.

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• If the first atoms of two groups have the same higher atomic number substituents, one with more such substituent is given higher priority.

Geometric Isomerism Contd.

• If there is any double bond or triple bond within the group, it is considered at two or three single bonds respectively. So:

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• Exemplary:

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• If there is a phenyl group attached to first atom, then it is thought that First atom is attached to three carbons.

Geometric Isomerism Contd.

• Example of E and Z isomers:

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• Z isomer is not always cis and E isomer is not always trans

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Optical Isomerism

Definition

• When two molecules only differ by the three-dimensional position of the substituents around one or more atoms, they are called optical isomers and this phenomenon is called optical isomerism.

Optical Isomerism Contd.

Chirality

• The term ‘Chiral’ and therefore the term ‘Chirality’ comes from a Greek word Kheir which means hands.
• An object is called chiral when its mirror image is non-superimposable on the original and this phenomenon is called chirality.
• If the mirror image is superimposable then the object is called achiral.

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Optical Isomerism Contd.

Chiral center

• In chemistry, an atom which is attached to non-identical substituents and the mirror image is non-superimposable is called a chiral center.

Technically, for an atom attached to non-identical substituents, the mirror image should be non-superimposable.

But if the mirror image is not stable enough, then practically that atom will not be considered as a chiral center.

Optical Isomerism Contd.

Tetrahedral center

• In chemistry, an atom which is attached to four substituents is called a tetrahedral center.
• Most commonly, carbons show tetrahedral centers.

Chiral carbon

• A carbon which is attached to four different substituents is called a chiral carbon.

Optical Isomerism Contd.

Elements of symmetry

• Any point, line or plane which divides an object into two equal parts is referred to as an element of symmetry.

Plane of symmetry

• The imaginary plane which divides an object into two equal parts is called a plane of symmetry.
• In chemistry, the plane of symmetry is an imaginary plane which divides a molecule into two parts which are mirror image of each other.

Optical Isomerism Contd.

Conditions for optical isomerism

• Following conditions must be met if a molecule is to have optical isomers:
• The molecule must have at least one chiral carbon.
• There should not be any elements of symmetry (specifically plane of symmetry).
• The mirror image of the molecule must not be suporimposable on the original.
• So, what about the following structures….

Optical Isomerism Contd.

Optical Isomerism Contd.

Meso compounds

• The compounds which have the following criteria are called meso compounds:
• They have one or more chiral carbons.
• There is a plane of symmetry.
• The mirror image of the molecule is superimposable on the original.

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Optical Isomerism Contd.

Wedge and dash representation

• Wedge and dash projection is a method to represent the three-dimensional (3D) structure of a molecule.
• In this method, three types of lines are used to denote bonds:
• Solid lines: Represent atoms/groups in the same plane (the paper).
• Wedged lines: Represent atoms/groups which are coming out of the plane, towards the viewer.
• Dashed lines: Represent atoms/groups which are extending away from the plane, away from the viewer.

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Optical Isomerism Contd.

Fischer projection

• Fischer projection is an attempt to depict three-dimensional molecules in two-dimensional paper.
• According to this method, the groups bonded by horizontal bonds are coming towards the viewer and the grops bonded by vertical bonds are going away from the viewer.

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• In this projection, the longest chain is drawn vertically with C¹ at the top.

Optical Isomerism Contd.

• Types of optical isomerism

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Optical Isomerism Contd.

Enantiomer

• Enantiomers are those optical isomers which are mirror images of each other.
• Since there can only be one mirror image, there will always be two and only two molecules which are enantiomers of each other.
• These two enantiomers differ in one property - optical activity. Based on optical activity, the enantiomers are divided into:
• Dextrorotatory enantiomer: This is the enantiomer which rotates the plane of plane-polarized light to the right.
• Levorotatory enantiomer: This is the enantiomer which rotates the plane of plane-polarized light to the left.

Optical Isomerism Contd.

• These two compounds fullfill the conditions for optical isomerism.
• They are also mirror images of each other.
• Hence they are enantiomers.

• So… What about these two structures?
• Are they optical isomers?
• Are they enantiomers?

• So, can you tell me among the two structures on the left side, which is dextrorotatory and which is levorotatory?
• Can you tell me, which is R isomer and which is S isomer?

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Optical Isomerism Contd.

Diastereomers

• Optical isomers which are not enantiomers are diastereomers.
• Meaning, two optical isomers which are not mirror images of each other are diastereomers.
• For diastereomers to exist, there must be at least two chiral carbons in the structure.
• In diastereomers, the configuration of at least one chiral carbon will be same.
• Diastereomers differ in many physical and chemical properties.
• Two terms ‘erythro’ and ‘threo’ are associated with diastereomers. Another two terms commonly used are ‘syn’ and ‘anti’.

Optical Isomerism Contd.

• These two compounds fullfill the conditions for optical isomerism.
• But they are not mirror images of each other.
• Hence they are not enantiomers, they are diastereomers.

• Erythro: When the identical groups on adjacent chiral carbons are on the same side, the diastereomer is called ERYTHRO.
• Threo: When the identical groups on adjacent chiral carbons are on the opposite sides, the diastereomer is called THREO.

Optical Isomerism Contd.

Racemic mixture

• A racemic mixture is one in which two enantiomers are present in the same amount.
• Since each enantiomer rotates the plane of the plane-polarized light by the same degree but in opposite direction, there is no net rotation in racemic mixture.
• Many optically active compounds exist as racemic mixture. e.g. thalidomide, tartaric acid etcetera.
• Racemic mixtures are denoted by symbols like (±) or dl-. e.g. (± tartaric acid).

Optical Isomerism Contd.

• Physical properties of meso compounds, racemic mixture and enantiomers
• The chemical properties of enantiomers, meso compounds and racemic mixtures do not vary at all. However the physical properties can vary.
• This is shown with tartaric acid below:

Optical Isomerism Contd.

Representation of optical isomerism

• In general optical isomerism is represented based on two criteria:
• Based on optical activity
• d/l method (old).
• (+)/(-) method (modern).
• Based on configuration around chiral carbon.
• D/L method (limited use).
• R/S method (universal).

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Optical Isomerism Contd.

Optical isomers based on optical activity

• Based on the ability to rotate the plane of the plane-polarized light, optical isomers are divided into two types.
• Dextrorotatory: Rotates the plane to the right. It is denoted by d- or (+).
• Levorotatory: Rotates the plane to the left. It is denoted by l- or (-).

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Optical Isomerism Contd.

d/l or (+)/(-) denotation is placed on a compound after its optical rotation is measured with a polarimeter. D/L or R/S denotion has nothing to do with it.

Optical Isomerism Contd.

D/L configuration

• D and L method is used to describe the position of the atoms/groups around the chiral carbon. It doesn’t tell whether the compound is dextrorotatory or levorotatory.
• This method was proposed by Rosanoff in 1906.
• This method uses the two enantiomers of Glyceraldehyde as reference molecules.

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• Any compound which looks like or degrades to D-glyceraldehyde would be denoted by D- and any compound which looks like or degrades to L-glceraldehyde would be denoted by L-.

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Optical Isomerism Contd.

D/L naming method

• It can be applied to compounds which are similar to glyceraldehyde or degrades to glyceraldehyde.
• This method is applied to:
• Carbohydrates
• Derivative of carbohydrates (e.g. some carboxylic acids, aldehydes)
• Amino acids
• For this method, first Fischer projection of the compound must be drawn.
• For carbohydrates and its derivatives, the position of the OH group on the highest numbered chiral carbon is looked at. If the OH group is on the left it is termed L- and if it on the right then it is termed D-.

Optical Isomerism Contd.

Optical Isomerism Contd.

Optical Isomerism Contd.

R/S configuration

• D/L method of expressing chiral carbon configuration works on only a few types of compounds.
• To express the configuration of chiral carbons in other compounds, we need another method.
• This other method is the R/S method. This method is universal, meaning that this method works on any compound.
• In R/S method, the configuration of each chiral carbon of the compound is described.

Optical Isomerism Contd.

R/S naming method

• First, every chiral carbons in the molecule are identified.
• Then the configuration in each chiral carbon is determined.
• To determine the configuration, the groups attached to the chiral carbons are assigned priority 1, 2, 3, and 4 according to Cahn-Ingold-Prelog (CIP) rules.
• The group with priority 4 (lowest priority) is sent to the back. Then it is identified which direction follows if one goes from 1 → 2 → 3.
• If the direction is right (clockwise), the chiral carbon is at R (R = rectus, meaning right) configuration.
• If the direction is left (anticlockwise), the chiral carbon is at S (S = sinister, meaning left) configuration.

Optical Isomerism Contd.

CIP rules with examples

• The group whose first atom (atom connected to the chiral carbon) has highest atomic number is given priority 1 and so on.

Optical Isomerism Contd.

• If first atoms are identical, then second atom will be looked at. If the second atoms are also identical, third atom will be looked at and so on.

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• If the first atoms are identical, second atoms are also identical, then the group with greater number of high atomic number second atoms is given higher priority.

The number of the chiral carbon is written before the configuration is written

Optical Isomerism Contd.

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• If there is any double or triple bond, then it is considered as two single bonds or three single bonds respectively.

Optical Isomerism Contd.

• It is important to note however that Fischer projection is not always reliable, and one should convert the Fischer projection into wedge and dash projection.

Optical Isomerism Contd.

A Simple trick

• If the lowest priority group (priority 4 group) is bonded by vertical bonds, then we can use the Fischer projection to determine R/S configuration directly.
• If the lowest priority group is bonded by horizontal group, then determine the R/S configuration directly. The correct configuration is the opposite of the configuration determined.

Optical Isomerism Contd.

• Find the configuration of following structures

(2R, 3S)-3-Bromo-3-chloro-2-methyl-butane-1,2-diol

(2S)-2-Chloro-propionic acid

(R)-Lactic acid

(2R, 3S, 4R, 5R)-Pentahydroxyhexanal

(2S, 3R, 4S, 5S)-Pentahydroxyhexanal

The stereoisomers of aldohexoses

• Monosaccharides which contain six carbons and a aldehyde group are called aldohexoses.
• Aldohexose contains 4 chiral carbons, so a total of 2⁴=16 stereoisomers are there.

The stereoisomers of aldohexoses Contd.

Epimers & Anomers

Epimers

• Epimers are diastereomers which differ in the configuration of only one chiral carbon.
• The configuration of the remaining chiral carbons are the same.

Anomeric carbon

• Anomeric carbon is the carbon which becomes chiral when cyclization occurs.
• This term is applicable to carbohydrates. The monosaccharide carbohydrates can exist in both open chain form and in cyclic form. When they transform into the cyclic form another carbon becomes chiral (the C¹ carbon). This carbon is the anomeric carbon.

Anomers

• Based on the configuration of the anomeric carbon, two stereoisomers are obtained which are called anomers of each other.
• Anomers are not enantiomers, they are epimers.

Epimers & Anomers Contd.

Importance of studying isomerism

Structural isomerism

• Structural isomers differ in many physical and chemical properties. Hence knowing about them is important.
• Many reactions yields two or more structural isomers, but only one of them is desired.
• Among many structural isomers, only one may be active drug.

Importance of studying isomerism Contd.

Geometric isomerism

• cis and trans isomers can vary in physical and chemical properties.
• Sometimes one isomer is an active drug while other is not. For example, cisplatin is active but not transplatin.
• Again, one isomer may have one function and the other may have another function. e.g. Retinal. 11-cis retinal is normally present in eyes and when light falls on the eye it is converted to all-trans retinal and only then vision occurs.

Importance of studying isomerism Contd.

Optical isomerism

• Biological systems see different optical isomers differently. For example: (R)-carvone smells like spearmint leaves while (S)-carvone smells like caraway seeds.
• Our body prefers certain optical isomers to other optical isomers. For example, all 19 optically active amino acids in our body are L-amino acids.
• Activity of many drugs is affected by optical isomerism. For example, thalidomide. (R)-thalidomide is useful against morning sickness but (S)-thalidomide causes birth defect.

Finished��Thank you