Chemistry of Natural Products

Course code: Phar 2081

Course ECTS: 5

By: Tadesse B. (PhD)

WELCOME
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• METHODS OF DELIVERY (Parallel)
– Teaching and learning Methods:
• Lecture
• Practical sessions
• Seminars, assignments and presentation

METHODS OF ASSESSMENT
– Seminar/Assignments: 15%
– Quizzes: 10%
– Mid-Exam: 35%
– Final Exam: 40%

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 Course Description
• The course covers some selected topics in natural
products chemistry.
• The goal is to acquaint students to the basic
evidences, which are results of observations carried
out over generations that are in use to chemically
characterize natural products of primary and
secondary metabolism.
• It also realizes that the same reactions organic
chemists know so well are apparently only mimics
of what occurs naturally

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 Course Objective
• After completion of this course students will be
able to:
– Describe the chemical structure, chemical reactions,
some chemical classes and related properties of
natural products as well as their applicability

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 Course Contents
• Chapter 1: Stereochemistry
– Introduction
– Isomerism
– Conformation and configuration
– Chirality, enantiomers, optical activity,
– Diastereomers, racemic mixtures, meso-compounds
• Chapter 2: Carbohydrates
– Introduction, classification, reactions and configuration of carbohydrates
– Cyclic structures of monosaccharides, conformation of monosaccharides,
– Chemistry of disaccharides and polysaccharides
• Chapter 3: Lipids
– Definition, occurrence and composition of fats, oils and waxes;
– Reactions of fats and oils;
– Determination of analytical values for fats and oils
• Chapter 4: Amino Acids And Proteins
– Structure, nomenclature, physical and chemical properties of amino acids
– Structure and nomenclature of peptides
– Classification and properties of proteins
– Synthesis of peptides
• Chapter 5: Terpenes
– Introduction, properties and isolation of terpenoids,
– Overview of Isoprene rule
– Classification of terpenoids
– Significance of terpenoids in pharmacy
• Chapter 6: Steroids
• Chapter 7: Purines And Nucleic Acids
• Chapter 8: Heterocyclic Compounds

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 References
• Required readings (Text)
• 1. Sarker SD, Nahar L. Chemistry
for Pharmacy Students. General,
Organic and Natural Product
Chemistry. John Willey and Sons
Ltd, UK, 2007
• 2. Dewick PM. Medicinal Natural
Products: A biosynthetic
Approach, 3rd edition. Jhon Wiley
and Sons, LTD, England 2009.
• 3. David R. Klein, Organic
Chemistry as a Second
Language: First Semester
Topics, Wiley; 5 edition (Sept. 11,
2019)
7 Tadesse B. (PhD)
Chapter 1: Stereochemistry
 Contents of Chapter 1
• Stereochemistry:
– Isomerism
– Conformation and configuration
– Chirality, enantiomers, Diastereomers
– Optical activity

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 Learning Outcomes
After completing this lesson, students should be able to:
• Define stereochemistry
• Classify different types of isomerisms
• Distinguish between conformational isomers and
configurational isomers;
• Explain the terms enantiomers, chirality, optical activity,
diastereomers, meso compounds and racemic mixture
• Designate configuration of enantiomers using D and L
system, and (R) and (S) system;
• Explain geometrical isomerism in alkenes and cyclic
compounds;
• Discuss the significance of stereoisomerism in determining
drug action and toxicity

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 Brainstorming?

• How can we define Natural Products?

• What is the Role of Natural Products?

• Where do Drugs come from?

• How Are New Drugs Developed?

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 Introduction
• Chemistry is the science of composition, structure, properties
and reaction of matter
• Life it self is full of chemistry
• Medicines that we take for treatment of various diseases are
chemicals, either organic or inorganic.
– However, most drugs are organic molecules
• Example: Aspirin, most popular and widely used analgesic is
chemically known as acetyl salicylic acid, an organic molecule.
• The precursor of aspirin is salicin which is found in willow tree bark.
– However, aspirin can be easily found from phenol using the kolbe
reaction

Tadesse B. (PhD) 12
 Introduction…
• An example of the Kolbe‟s reaction (Kolbe Schmitt Reaction) is
given below:

• The bark of white willow contains salicin, which is a chemical

similar to aspirin (acetylsalicylic acid).
• In combination with the herb's powerful anti-inflammatory
plant compounds (called flavonoids), salicin is thought to be
responsible for the pain-relieving and anti-inflammatory
effects of the herb
• Hence, in order to have a proper understanding and
knowledge of such drugs, there is no other alternative but
to learn chemistry
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 Introduction
• Chemistry is involved every where from
o Discovery to development
o Production to storage
o Storage to administration
o Desired action to adverse effect of drugs

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 Introduction…
• Chemistry is involved in all processes of the discovery phase.
– If the drug molecule has to be purified from the natural sources, e.g.
a plant, processes such as extraction, isolation & identification are
used and all this processes involve chemistry.
• In the drug development step the structure and physical properties e.g.
solubility and pH of the drug molecules is exploited.
• In chemistry, particularly physical properties of the drug is important to
determine the storage condition
– For example drugs having an ester functional group such as aspirin could be
quite unstable in the presence of moisture and should be kept in dry and
cool place
• The chemistry of drug molecule dictate the choice of appropriate route
of administration
– Hence, to become a good pharmacist the knowledge of chemistry of drugs is
essential

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 What are Natural Products?
 Natural products are:
 A natural compound or substance produced by a living organism, i.e.,
found in nature
 Any organic compound that is synthesized by a living organism
 Compounds which are isolated from natural sources like plants,
animals, micro-organisms such as fungi, bacteria and lichens
 In the broadest sense, natural products include any substance
produced by life.
 Natural products can also be prepared by chemical synthesis
(both semi-synthesis and total synthesis) and have played a central
role in the development of the field of organic chemistry by
providing challenging synthetic targets
 The term natural product has also been extended for commercial
purposes to refer to cosmetics, dietary supplements, and foods
produced from natural sources without added artificial ingredients

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 What are Natural Products?...
 Natural products can be
• An entire organism (e.g. a plant, an animal or a micro-
organism),
• A part of an organism (e.g. leaves or flowers of a plant, an
isolated animal organ),
• An extract of an organism or part of an organism and an
exudate, or
• Pure compounds (e.g. alkaloids, coumarins, flavonoids,
lignans, steroids and terpenoids) isolated from plants,
animals or micro-organisms.
o However, in practice, such compounds are referred as secondary
metabolites.
 Natural products chemistry is focused on the study of small
organic molecules, especially secondary metabolites,
produced by organisms such as bacteria, fungi and plants
17
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 Where Do We Find Natural Products?
• Natural products may be extracted from the cells, tissues, and secretions
of microorganisms, plants and animals.

• A crude (unfractionated) extract from any one of these sources will

contain a range of structurally diverse and often novel chemical
compounds.
• Chemical diversity in nature is based on biological diversity, so researchers
travel around the world obtaining samples to analyze and evaluate in drug
discovery screens or bioassays.
– This effort to search for natural products is known as bioprospecting

• Natural products have proven to be rich sources of medically- and

industrially-important bioactive molecules.

• A medicinal plant is usually described as “any plant which, in one or more

of its organs, contains substances that can be used for therapeutic
purposes or which are precursors for the synthesis of useful drugs”

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Streptomycin

Fig. Bacteria isolated from soil are prolific producers of antibacterial compounds

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Nature has been a potential source of therapeutic agents
for thousands of years.
The use of natural products, especially plants, for healing
is as ancient and universal as medicine.
Natural products have been an integral part of the
ancient traditional medicine systems, e.g. Chinese,
Ayurvedic and Egyptian.
o Even now, continuous traditions of natural product therapy
exist throughout the third world, where numerous minerals,
animal substances and plants are still in common use.
However, an impressive number of modern drugs have
been derived from natural sources.

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 Over the last century, a number of top selling drugs have been developed from
natural products. Examples:
– Anticancer drugs: Paclitaxel & vinblastine (from Taxus
brevifolia and Catharanthus roseus, respectively),
– Narcotic analgesic: Morphine from Papaver somniferum,
– Antimalarial drug: Artemisinin from Artemisia annua
– Drug used to treat Alzheimer‟s disease: Galantamine (from Galanthus spp.), &
– Antibiotic penicillins from Penicillium sp. are just a few examples.
 Apart from natural product-derived modern medicine, many natural products are
also used directly in the pharmaceutical industry.

Fig. Examples of biologically active metabolites from plants

21
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Fig. Examples of biologically active metabolites from plants
Tadesse B. (PhD) 22
• Several anti-infective medications have been derived from fungi
including the penicillins and the cephalosporins (antibacterial
drugs from Penicillium chrysogenum and Cephalosporium
acremonium, respectively), and griseofulvin (an antifungal drug
from Penicillium griseofulvum).

Fig. Examples of fungal secondary metabolites 23

Tadesse B. (PhD)
• Another medicinally useful fungal metabolite is lovastatin (from
Aspergillus terreus), which became a lead for the statins, a
series of drugs commonly used to lower cholesterol levels

Ergometrine (from Claviceps spp.) acts as a vasoconstrictor, and is used to

prevent bleeding after childbirth

Ergometrine
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Tadesse B. (PhD) 25
Dextropropoxyphene Levopropoxyphene

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 Definitions of Terminologies
 Stereochemistry is a branch of chemistry that studies
properties of stereoisomers
 Stereochemistry: is concerned with the three-dimensional
arrangement of atoms (groups) and molecules in space
 Stereoisomers: are molecules with the same connectivity
but different arrangement of atoms (groups) in space
 Stereochemistry plays a major role in the pharmacological
properties because
o Any change in stereospecificity of the drug will affect its
pharmacological activity
o The isomeric pairs have different physical properties (partition
coefficient, pka, etc.) and thus, differ in pharmacological activity.
 This is an important topic in pharmaceutical chemistry because the
shape of a drug molecule affects both its desired biological activity
and its potential for exhibiting undesired effects.

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 ISOMERISM
• Isomerism (Greek isos, equal; meros, parts)
• Compounds with the same molecular formula but different
structures are called isomers.
– For example, 1-butene and 2-butene have the same
molecular formula, C4H8, but structurally they are different
because of the different position of the double bond.

• There are two types of isomers:

– Constitutional isomers and
– Stereoisomers; which are themselves sub-divided.

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Tadesse B. (PhD) 29
 ISOMERISM…
A. Structural (constitutional) isomerism
a. Chain isomerism,
b. Positional isomerism, and
c. Functional isomerism
B Stereoisomerism
a. Conformational isomerism
b. Configurational isomerism
i. Geometric isomerism
ii. Optical isomerism
a) Diastereomers
b) Enantiomers

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 A) Constitutional Isomers
• When two different compounds have the same molecular
formula but differ in the nature or sequence of bonding,
they are called constitutional isomers.
• Isomers that have the same molecular formula but
their atoms are connected in a different order.
– For example, ethanol & dimethyl ether have same molecular
formula, C2H6O, but they differ in the sequence of bonding.
– Similarly, butane and isobutane are two constitutional isomers

• Constitutional isomers generally have different physical

and chemical properties.

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 A) Constitutional Isomers…
a. Chain isomerism: Arise because of the possibility of
branching in carbon chains. E.g., there are two isomers of
butane, C4H10.

b. Positional isomerism: The basic carbon skeleton remains

unchanged, but important groups are moved around on that
skeleton. E.g.1 , there are two structural isomers with the molecular
formula C3H7Cl.

Tadesse B. (PhD) 32
 A) Constitutional Isomers…
c. Functional isomerism: The isomers contain the
same molecular formula but different functional
groups.
◦ E.g. C3H6O could be either propanal (an aldehyde) or
propanone (a ketone).

Tadesse B. (PhD) 33
 B) Stereoisomers
• A clear understanding of stereochemistry is crucial for the study
of complex molecules that are biologically important, e.g.
proteins, carbohydrates & nucleic acids, & also drug molecules
• One aspect of stereochemistry is stereoisomerism
• Stereoisomers are compounds where the atoms are connected in
the same order but with different geometries, i.e. they differ in
the three-dimensional (3D) arrangements of groups or atoms
in space.
• For example, in -glucose and β-glucose, the atoms are connected
in the same order, but the 3D orientation of the hydroxyl group
at C–1 is different in each case.
• Similarly, cis- and trans-cinnamic acid only differ in the 3D
orientation of the atoms or groups.

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 B) Stereoisomers…
Alpha Glucose Beta Glucose
Alpha glucose is a Beta glucose is a
cyclic hemiacetal cyclic hemiacetal
form of glucose form of glucose
where at anomeric where at anomeric
carbon, the position carbon the position
of hydroxyl group of hydroxyl group
is in downward is in upward
direction. direction.

• Cinnamic acid exists as trans & cis isomers, but the trans form is
the one most often found in nature & is the article of commerce.
• It is obtained from cinnamon bark & balsam resins such as storax

trans- Cinnamic acid cis- Cinnamic acid

Tadesse B. (PhD) 35
 B) Stereoisomers…
• There are two major types of stereoisomer:
– Conformational Isomers and
– Configurational Isomers.

• Configurational Isomers include:

– Geometrical Isomers
• Cis- and
• Trans-
– Optical Isomers
• Enantiomers and
• Diastereomers.

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i) Conformational Isomers

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 i) Conformational Isomers
• Atoms within a molecule move relative to one another by
the rotation around covalent single bonds (σ bonds) and
the 3D tetrahedral shape of the sp3-hybridized centres.
– Such rotation of covalent bonds gives rise to different
conformations of a compound.
• Each structure is called a conformer or conformational
isomer.
– Conformers may also result from restricted rotations in rings.
• The number of different conformers depends on the
number of single bonds and on the number and size of
the flexible rings.
• Generally, conformers rapidly interconvert at room
temperature.

Tadesse B. (PhD) 38
 i) Conformational Isomers…
Conformational Isomers of Alkanes
• Conformational isomerism can be presented with the simplest
example, ethane (C2H6), which can exist as an infinite
number of conformers by the rotation of C─C σ 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 is of the
lowest energy.

Rotation about the C-C bond in ethane

Tadesse B. (PhD) 39
 i) Conformational Isomers…
Visualization of Conformers
• There are four conventional methods for visualization of 3D
structures on paper, that is, the ball and stick method,
sawhorse method, wedge and broken line method and
Newman projection method.
• Using these methods, the staggered and eclipsed conformers of
ethane can be drawn as follows:

Tadesse B. (PhD) 40
 i) Conformational Isomers…
Eclipsed and Staggered Conformers
• In the the H atoms are as far apart as possible.
 This reduce the repulsive force between them.
 That is why staggered conformers are stable
• In the the H atoms are closest together.
 This gives highest repulsive force between them; hence, they are
unstable.
• At any moment, more molecules will be in staggered form than any other
conformations.
• The angles in the eclipsed conformation are 0°, whereas the angles in the
staggered conformation are 60°

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i) Conformational Isomers…

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Tadesse B. (PhD) 43
 i) Conformational Isomers…
Torsional Energy and Torsional Strain
• Torsional energy is the energy required for rotating
about the C─C σ 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, that is, staggered form.
• Torsional strain is due to the slight repulsion between
electron-clouds in the C─H bonds as they pass close
by each other in the eclipsed conformer.
– In ethane, this is also low.

Tadesse B. (PhD) 44
 i) Conformational Isomers…
Conformational Isomerism in Cyclohexane
• Cyclohexane (C6H12) is a six-carbon cyclic alkane that occurs
extensively in nature.
• Many pharmaceutically important compounds possess
cyclohexane rings, for example, steroidal molecules
• If it is consider cyclohexane as a planar and regular hexagon, the
angles are 120° (109.5° for sp3 hybrids)

Cyclohexane as a Most stable chair conformation Boat conformation of

planar molecule of cyclohexane cyclohexane
(bond angle 120°) All neighbouring C-H bonds are
staggered
Tadesse B. (PhD) 45
 i) Conformational Isomers…
• 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 & boat
conformations are most significant.
• At any one moment 99.9% cyclohexane molecules will
have chair conformation
• The chair conformation of cyclohexane is the most
stable conformer as the C–C–C angles can reach the
strain free tetrahedral value (109.5o), and all
neighbouring C–H bonds are staggered
– This conformation does not have any angle strain or torsional strain.

Tadesse B. (PhD) 46
i) Conformational Isomers…

Tadesse B. (PhD) 47
 i) Conformational Isomers…
 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) &
– Equatorial (in the plane of the ring, i.e. around the ring
equator) positions

Tadesse B. (PhD) 48
 i) Conformational Isomers…
• Six hydrogen atoms are in the axial positions and six others in
the equatorial positions.
• Each carbon atom in the cyclohexane chair conformation has
one axial hydrogen and one equatorial hydrogen atom.
• The two chair forms interconvert each other

Tadesse B. (PhD) 49
 i) Conformational Isomers…
• But if there is a substituent other than H, the two
chair forms are not equivalent.
– The equatorial substitution is more stable
• Because it free from 1,3-diaxial interaction

Tadesse B. (PhD) 50
ii) Configurational Isomers

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 Introduction
• Configurational isomers are stereoisomers that
cannot be converted into one another by
rotations about single bonds within the
molecules.
• They differ from each other only in the
arrangement of their atoms in the space
(3D)

Tadesse B. (PhD) 52
 Configurational Isomers
• The two main types of configurational isomers are geometric
isomers & optical isomers
• Example: cis- and trans-2-butene are configurational isomers and
cis- and trans-1,2-dimethylcyclopropane

• The terms cis-trans isomerism or geometric isomerism

commonly are used to describe configurational isomerism in
compounds with double bonds and rings

Tadesse B. (PhD) 53
 Chirality and Chiral Molecules
• Are you right-handed or left-handed?
• When you hold a left hand up to a mirror, the image you see looks like a right
hand
– Hence, our left and right hands are mirror images of each other, and cannot be
superimposed on each other.

• Other chiral objects include shoes, gloves and printed pages.

• Many molecules are also handed, that is, they cannot be superimposed on
their mirror images.
– Such molecules are called chiral molecules.
• Many compounds that occur in living organisms, for example, carbohydrates
and proteins, are chiral.
• Chirality is extremely important in biological systems.
Tadesse B. (PhD) 54
 Chirality and Chiral Molecules…
• The most common feature in chiral molecules is a
tetrahedral, that is, sp3-hybridized, carbon atom with four
different atoms or groups attached.
• Such a carbon atom is called a chiral carbon or an asymmetric
carbon or asymmetric centre.
• Chiral molecules do not have a plane of symmetry.

Chiral carbon Achiral carbon

Four different groups/atoms At least two same groups/atoms
present (Z) present

Tadesse B. (PhD) 55
 Chirality and Chiral Molecules…
• When there are two or more same atoms/groups, the carbon is
called achiral.
• For example, the carbon atom in bromo-chloro-methane has a
bromine, a chlorine, but two hydrogen atoms linked to it as shown
below.
Achiral molecule
Superimposable mirror image

• Thus, the carbon atom in this compound is achiral.

• Achiral molecules have a plane of symmetry.
• A plane of symmetry is an imaginary plane that divides a molecule
into two equal halves that are mirror image of each other.
• With achiral molecules, the compound and its mirror image are
the same, which means that they can be superimposed.
– If you rotate the mirror image through 180°, it is identical to the
original structure

Tadesse B. (PhD) 56
 Chirality and Chiral Molecules: Symmetry and Dissymmetry
• Plane of symmetry: an imaginary plane which passes through atoms and bonds
in a molecule so that it divides it into two equal halves that are mirror image
of each other.
• Centre of symmetry: A point within the molecule such that if a straight line
is drawn from any part of the molecule through it and extended on either
side to an equal distance meets with similar environment.
• Any molecule with a plane of symmetry or a center of symmetry are achiral
• Dissymmetric molecules: Molecule will be a dissymmetric molecule if it has
no plane of symmetry, no center of symmetry & no alternating axis of
symmetry.

Propanoic acid(Achiral) Lactic acid

Tadesse B. (PhD) 57
 Chirality and Chiral Molecules: Asymmetric Carbon
• A molecule containing a carbon with four different groups attached results
in a chiral molecule and the carbon is referred to as a chiral carbon or
asymmetric carbon or stereogenic center
• A molecule with a stereo center will not have a plane of symmetry and
will be optically active
Asymmetric carbon

• Asymmetric molecules: Dissymmetric molecule having at least one

asymmetric carbon is known as asymmetric molecule.
• All asymmetric molecules are also dissymmetric molecules but the
reverse is not necessarily true.
• If all the groups around the central carbon are not different; hence, it is
not a stereo center.
– The molecule has a plane of symmetry

58
Tadesse B. (PhD)
 Chirality and Chiral Molecules: Asymmetric Carbon…
• Enantiomers: are non-superimposable mirror image isomers
• Our hands are not identical; rather, they‟re mirror images.
• When you hold a left hand up to a mirror, the image you see looks like a right
hand

Left Hand Right Hand

Tadesse B. (PhD) 59
 Chirality and Chiral Molecules: Asymmetric Carbon…

• Some compounds may contain multiple asymmetric centers

(More than one chiral center)
– Some molecules have more than one chirality center.
• Enantiomers have opposite configurations at all chirality
centers, whereas diastereomers have the same configuration
in at least one center but opposite configurations at the others.
• A type of stereoisomer that possesses more than one chiral
center is termed as Diastereomers
• Some drugs with more than one chiral center are of high
medicinal values

Tadesse B. (PhD) 60
 Chirality and Chiral Molecules
• Enzyme active sites are capable of chiral discrimination
and can distinguish between enantiomers.
• For example, the enantiomers of S-(+)-carvone,
smells like caraway seeds and R-(-)-carvone smells like
spearmint.
• But not all enantiomers have distinguishable odours

S-(+)-Carvone R-(-)-Carvone
(Smells like caraway seeds) (Smells like spearmint)

Tadesse B. (PhD) 61
 Enantiomers
• Every chiral molecule has enantiomers, but achiral molecules do not have
enantiomers.
• Greek word enantio means „opposite‟.
• A chiral molecule and its mirror image are called enantiomers or enantiomeric
pairs
– They are non-superimposable.
• The actual arrangement or orientation (in space) of atoms or groups attached to the
chiral carbon (asymmetric centre, stereogenic centre, or stereocentre) is called the
configuration of a compound.

The arrangement of W, X, Y and Z is the configuration

They are enantiomers & not superimposable (Enantiomers of 2-butanol)

• Enantiomers share same physical properties, for example, melting points, boiling
points and solubilities.
• They also have same chemical properties.
• However, they differ in their activities with plane polarized light that gives rise to
optical isomerism, and also in their pharmacological actions
Tadesse B. (PhD) 62
 Enantiomers…
How to Designate the Configuration of Enantiomers?
• A (+) or (-) sign indicates optical activity of an enantiomer.
– However, the optical activity does not tell us the actual configuration of
an enantiomer.
– It only gives us the information whether an enantiomer rotates the
plane-polarized light clockwise or anti-clockwise.
• For example of glyceraldehyde, an optically active molecule.
– It can exist as enantiomers, that is, (+) and (-) forms, but the sign does not
describe the exact configuration.

• There are two systems to designate configuration of enantiomers:

o D and L-system, and (R) and (S)-system, also known as Cahn–Ingold–Prelog system.

Tadesse B. (PhD) 63
 Enantiomers…
D and L system
• Emil Fischer used glyceraldehyde as a standard for the D and L
system of designating configuration.
• He arbitrarily took the (+)-glyceraldehyde enantiomer and assigned
the D-glyceraldehyde and the (-)-glyceraldehyde was assigned as L-
glyceraldehyde.
• It can easily identify the only difference between the structures is the
orientation of the hydroxyl group at the chiral centre.
• In the D and L system, structures that are similar to glyceraldehyde (at
chiral carbon) are compared.
– For example: 2,3-dihydroxypropanoic acid

D-2,3-dihydroxypropanoic acid D-2,3-dihydroxypropanoic acid

The -OH on the chiral carbon The -OH on the chiral carbon
(+)-D-Glyceraldehyde (-)-L-Glyceraldehyde (*) is on the right (*) is on the left

Tadesse B. (PhD) 64
 Enantiomers…
• One must remember that there is no correlation between D and L
configurations, and (+) and (-) rotations.

• D-isomer does not have to have a (+) rotation, and similarly, L-isomer does
not have to have a (-) rotation.

• For some compounds, the D-isomer is (+) and for others the L-isomer may
be (+).

• Similarly, for some, we may have L (-) & others may have D (-).

• This D and L system is common in biology/biochemistry, especially with

sugars and amino acids (with amino acids, the ─NH2 configuration is
compared with ─OH of glyceraldehyde).

• This system is particularly used to designate various carbohydrate or sugar

molecules, for example, D-glucose, L-rhamnose and L-alanine.

Tadesse B. (PhD) 65
 Enantiomers…

(+)-ketamine (Esketamine) is the active enantiomer of

ketamine and is more potent than racemic ketamine

Fig. Examples of enantiomers. Atoms constituting centers of chirality are

labeled with asterisks

Tadesse B. (PhD) 66
 Enantiomers…
• Cahn–Ingold–Prelog system: (R) and (S) System
• Three chemists, R. S. Cahn (England), C. K. Ingold (England)
and V. Prelog (Switzerland), devised a system of nomenclature
that can describe the configuration of enantiomers more
precisely.
– This system is called the (R) and (S) system, or the Cahn–Ingold–
Prelog system.
• According to this system, one enantiomer of 2-hexanol should
be designated (R)-2-hexanol and (S)-2-hexanol.
• R and S came from the Latin words rectus and sinister, meaning
right and left, respectively.

Tadesse B. (PhD) 67
 Enantiomers…
• The following rules or steps are applied for designating any
enantiomer to R or S.
• i) Each of the four groups attached to the chiral carbon is
assigned 1–4 (or a–d) in terms of order of priority or
preference, 1 being the highest and 4 being the lowest
priority.
– Priority is first assigned on the basis of the atomic number of
the atom that is directly attached to the chiral carbon.
– Higher atomic number gets higher priority.
• This can be shown by the structure of 2-hexanol.

Tadesse B. (PhD) 68
 Enantiomers…
• ii) When a priority cannot be assigned on the basis of the atomic
numbers of the atoms that are directly attached to the chiral carbon,
the next set of atoms in the unassigned groups is examined.
– This process is continued to the first point of difference.
• In 2-hexanol, there are two carbon atoms directly attached to the
chiral carbon; one is of the methyl group, and the other is of the
propyl group.
• In this case, only on the basis of the atomic number of the carbon
atom, one cannot assign the priority of these two carbon atoms,
and must consider the next set of atoms attached to these carbon
atoms.
– When the methyl group of the enantiomer is examine, it is find that
the next set of atoms consists of three H atoms.
– On the other hand, in the propyl group, the next set of atoms consists
of one C and two H atoms.
– Carbon has a higher atomic number than H, so the CH3CH2CH2─
group gets the priority over CH3.

Tadesse B. (PhD) 69
 Enantiomers…
• iii) Groups containing double or triple bonds (π bonds) are assigned
priorities as if both atoms were duplicated or triplicated.
• For example:

• iv) Having decided on priority of the four groups, one has to arrange (rotate)
the molecule in a way that group 4, that is, the lowest priority, is pointing
away from the viewer.

• Then an arrow from group 1→2 →3 is to be drawn.

• If the direction is clockwise, it is called an (R)-isomer.
• If it is anti-clockwise, it is called an (S)-isomer.
• With enantiomers, one will be the (R)-isomer and the other, the (S)-isomer. Again,
there is no correlation between (R) and (S), and (+) and (−).
70
Tadesse B. (PhD)
 Enantiomers…
•

(R)-2-Hexanol
Priority order 1 to 4 is in clockwise direction

• Then an arrow from group 1→2 →3 is to be drawn.

• If the direction is clockwise, it is called an (R)-isomer.
• If it is anti-clockwise, it is called an (S)-isomer.
• With enantiomers, one will be the (R)-isomer and the other, the
(S)-isomer.
o Again, there is no correlation between (R) and (S), and (+)
and (−).
71
Tadesse B. (PhD)
 Enantiomers…
• Following the Cahn–Ingold–Prelog system, it is now possible to
draw the structures of (R)- and (S)-enantiomers of various
chiral molecules.
• For example: 2,3-dihydroxypropanoic acid where the priorities,
1 = OH, 2 = COOH, 3 = CH2OH, and 4 = H.

(R)-2,3-Dihydroxypropanoic acid
(S)-2,3-Dihydroxypropanoic acid
Priority order 1 to 4 is in clockwise direction
Priority order 1 to 4 is in clockwise direction

Tadesse B. (PhD) 72
 Enantiomers…
• When there are more than one stereocentre (chiral carbon)
present in a molecule, it is possible to have more than two
stereoisomers.
• It is then necessary to designate all these stereoisomers using (R)
and (S) system.
• In 2,3,4-trihydroxybutanal, there are two chiral carbons.
• The chiral centres are at C-2 and C-3. Using the (R) and (S)
system, one can designate these isomers as follows.

Tadesse B. (PhD) 73
Geometric Isomerism (cis-trans isomerisms)
 Occur as a result of restricted rotation about a chemical bond, owing to
double bonds or rigid ring system in the molecule.
 They are not mirror images and have different physicochemical properties
and pharmacological activity.
o Because different distances separate the functional groups of
these isomers.
 They generally do not fit to the same receptor equally well and if these
functional groups are pharmacophores, the isomers will differ in biologic
activity.
o For example, cis-diethylstilbestrol has only 7% of the estrogenic activity
of trans- diethylstilbestrol

Tadesse B. (PhD) 74
Geometric Isomerism cont.

Tadesse B. (PhD) 75
 Optical Isomerism
• A French physicist Jean-Baptiste Biot (in the early 19th century)
observed that when a beam of plane-polarized light passes
through a solution of certain organic molecules, such as sugar
or camphor, the plane of polarization is rotated through an
angle α.

• Not all organic substances exhibit this property, but those that
do are said to be optically active.

• The angle of rotation can be measured with an instrument

called a Polarimeter

Tadesse B. (PhD) 76
 Optical Isomerism
• An optically active molecule rotates the plane of polarization of
polarized light to the right it is considered to be
“dextrorotatory” (clockwise), if it is to the left it is
“levorotatory” (counterclockwise)
• Dextro and levo rotation is also indicated with the sign (+) and
(-) or “d” and “l” letters, respectively.

Plane-polarized light passes through a solution of optically active molecules, which

rotate the plane of polarization
Tadesse B. (PhD) 77
 Optical Isomerism cont.
• Optical isomers are molecules that differ three-dimensionally by the
placement of substituents around one or more atoms in a molecule
• Optical isomers are compounds that contain at least one chiral
carbon atom or are compounds that differ only in their ability to
rotate the polarized light.
• Optical isomers are compounds that are non-superimposable
mirror images of each other, i.e. they do not possess the plane of
symmetry
• The molecules which are non-superimposable mirror image of each
other are called chiral and this property is called chirality

Tadesse B. (PhD) 78