Isomerism organic chemistry topic ......

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Isomerism
Chapter 3 (Part 1)

Course Learning Outcomes
On completion of this chapter, students will be able to understand:
1. Understand what isomerism is and its significance in chemistry.
2. Identify and represent stereoisomers using methods like wedge-hatched bonds, Fischer
projections, sawhorse projections, and Newman projections.
3. Identify and illustrate different conformations, including eclipse, staggered, gauche, and
anti-conformation, in common organic molecules.
4. Distinguish between configurational and conformational isomers.
5. Understand the conditions and requirements for geometric isomerism

Presentation of Organic Compounds
• Compounds must be presentable
• Various presentation ways, subject to the information, eg. Structure
• Pentane
Molecular
Formula
Empirical
Formula
Line bond
Structures
Condensed
Structures
Skeletal
Structures
• Number of atoms
of each element in
one molecule of a
compound
• C5H12
• Relative ratio’s of
elements preset
• C5 H12
• Show all atoms
and bonds
• Show all atoms,
but only show
bonds when
necessary
• Only C-C bonds
C6H12O6 Vs CH2O

Alkanes and Alkane Isomers
• Alkanes: Compounds with C-C single bonds and C-H bonds only (no functional groups)
• Connecting carbons can lead to large or small molecules
• The formula for an alkane with no rings in it must be CnH2n+2, where the number of C’s is n
• Alkanes are saturated with hydrogen (no more can be added)
• They are also called aliphatic compounds

Isomerism
• Isomers: Compounds that have identical molecular formulas, but different arrangement of
atoms
• Constitutional (Structural) isomers: Same formula, different arrangement
• Stereoisomers: Same formula, same arrangement, different 3D orientation
• E.g. Structural isomers of C2H6O. At room temperature:
i. Ethyl alcohol is a liquid, completely soluble in water
ii. Dimethyl ether is a gas, partially soluble in water

Types of Isomerism

Stereochemistry
• Stereochemistry is also known as three-dimensional (3D) chemistry
because the prefix “stereo-” means “three-dimensionality”
• Stereochemistry: study the arrangement of atoms in space in 3D
structure and its effect on physical, chemical and biological
properties
• In pharmaceuticals, slight differences in 3D spatial arrangement
can make the difference between targeted treatment and
undesired side effects. Why??

•In pharmaceuticals, the 3D spatial arrangement of a molecule, known as its stereochemistry, is crucial
because it determines how the drug interacts with biological targets, such as enzymes or receptors. Here's
why slight differences in 3D structure can make a huge impact:
•Molecular Recognition: Many biological molecules are chiral, meaning they have a specific 3D shape.
Receptors, enzymes, and other biological targets often bind to drugs like a "lock and key," where only the right
3D shape of the drug will fit properly. A different spatial arrangement might not fit as well or at all.
•Enantiomers and Chirality: Some drugs have enantiomers, which are molecules that are mirror images of
each other but not superimposable, like left and right hands. These enantiomers can have very different
effects in the body. For example, one enantiomer may produce the desired therapeutic effect, while the other
might be inactive or even cause harmful side effects.
•Specific Binding: A drug's effectiveness depends on how specifically it can bind to its target in the body. A
slight difference in the 3D structure might prevent the drug from binding to the correct receptor or enzyme, or
it may bind to the wrong target, causing unintended side effects.
•Metabolism and Clearance: The body's enzymes that metabolize drugs are also stereospecific. Different 3D
arrangements can affect how a drug is broken down, its duration of action, and how quickly it is cleared from
the body.
•A famous example is thalidomide, where one enantiomer was effective in treating morning sickness, but its
mirror image caused severe birth defects. This highlights the importance of stereochemistry in drug design
and safety.

Stereochemistry
S isomer is biologically
active
(S)-Ibuprofen is used
primarily for fever
R isomer is biologically
inactive
(R)-Ibuprofen
R isomer is biologically active
(R)-L-dopa is used for
parkinson disease
inactive
(S)-L-dopa
Maleic acid
(Cis-
butenedionic
acid)
Fumaric acid
(Trans-
butenedionic
acid)
R isomer is biologically active
(R)-Salbutamol is
bronchorelaxant
inactive
(S)-Salbutamol is
bronchospasm

Constitutional Isomers
Different IUPAC
names
Same or different
functional groups
Different physical
properties
Different
chemical
properties
• Constitution/structural isomers
have:
Types of
Constitutional
Isomers
Chain Isomers Metamers
Positional
Isomers
Functional
Isomers
Tautomerism
Proton
Tautomerism
Ring Chain
Tautomerism

Stereoisomers
Have identical IUPAC
names (except for a
prefix like cis or trans)
Differ only in the way
the atoms are
oriented in space
Differ in configuration
(its particular three-
dimensional
arrangement)
Always have the same
functional group(s)
 Stereoisomers have:
 There are four main types of representations for
open-chain molecules and are used to show the
three-dimensional structure of chemical
compounds
Stereochemical
representation
Wedge-hatched
bond structure
Fischer projection
Sawhorse
projections
Newman
projection

Wedge-hatched bond structure
 Wedge-hatched is usually done for molecules containing chiral center or chiral carbon
(carbon atom that has four different substituents)
 Wedge (The bond in front of the plane) and Hatched (behind the plane)
 The bonds in the same plane draw in straight line, the bond in front of plane draw wedge
while in behind the plane draw Hatched

Fisher projection
 Fisher projection: is a two-dimensional representation of a three-dimensional
 In Fisher projection: The horizontal line represent bond above the plane (front/wedge) and
vertical lines represent bonds below the plane (back/Hatched)
 Fisher projections were originally proposed for the depiction of carbohydrates
 Two bonds are coming out of the plane. The two remaining bonds are going into the plane
are on a vertical plane

Fisher projection
 Fisher projection is used to differentiate between L- and D-
compounds

Sawhorse projection
 Sawhorse structure is used to show interactions between groups on adjacent carbon
atoms

Sawhorse projection
 Sawhorse structure used for explain Conformational isomerism and explain rotation
around single bonds (alkane)
 Eclipsed form less stable than staggered form due to torsional strain.

Newman projection
 Newman projection is used mainly for determining conformational relationship and to
show interaction leading to steric hindrance between atoms or groups
 Steric hindrance: each atom occupies a certain amount of space when atoms are brought
too close together leads high energy due to overlapping electrons clouds
To write a Newman projection formula :
 We imagine ourselves taking a view from one atom (usually a carbon) directly along a selected bond axis to the next
atom (also usually a carbon atom)
 The front carbon and its bonds are represented as
 The back carbon and its bonds are represented as

Conformational Isomers
Isomers have different spatial orientations of atoms in a molecule that
result from:
 Rotations about single bond (alkanes)
 Ring flipping conformations (cycloalkanes)
 The resulting arrangement referred to eclipsed and staggered conformers
Rotation occur only in
alkane (single bonds)
not occur in alkene
and alkyne

Conformational Isomerism in Alkanes (Ethane)
o Representing 3D conformers in 2D is done with standard types of drawings
o Molecular models are 3D objects that enable us to visualize conformers
o There are two representations:
1) Sawhorse
representation
2) Newman projection

 Dihedral angle or Torsional angle () (in degrees) : angle between the plane formed by the
first three atoms and the plane formed but the last three atoms
 Rotation can be clockwise or anti-clockwise
1) Sawhorse representation
 C-C bonds are at an angle to the
edge of the page
 All C-H bonds are shown
2) Newman projection
 Bonds to front carbon are lines going
to the center
 Bond to rear carbon are lines going to
the edge of the circle

 When one of the carbon atom (front) is kept fixed and other is rotated about C-C bond
an infinite numbers of isomers are possible by rotation about single bonds

3
0
3
0
 Any conformations between eclipsed and staggered are called skew conformations
 Skew conformation of ethane is rapid at room temperature, and is sometimes
described as free rotation
 Eclipsed form (highest energy), skewed form (intermediate energy), staggered (most
stable)

 Potential energy changes that accompany rotation of group about the carbon-carbon
bond of ethane
 The barrier to rotation
between conformations is
small (12 kJ/mol; 2.9 kcal/mol)
 The eclipsed conformers are
12 kJ/mol higher in energy
than the staggered
conformers – energy due to
torsional strain
 Each H-H interaction
contributes 4.0 kJ/mol

Draw Newman projection  Sawhorse projection

Conformational Isomerism in Alkanes (Propane)
 Propane (C3H8) has torsional barrier around the carbon-carbon bonds (14
kJ/mol)
 Eclipsed conformer of C3H8 has two ethane-type H-H interactions and an
interaction between C-H and C-C bond
 The C-H and C-C bond interactions contributes 6.0 kJ/mol (=14 – (2 x 4.0))

 Example: Make a graph of potential energy versus angle of bond rotation for propane, and assign
values to the energy maxima

 Example: Draw Newman projections of the most stable and least stable conformations of 1-
bromopropane

Conformational Isomerism in Alkanes (Butane)
 As the alkane becomes larger, the conformations become more complex
 Butane has eclipsed and staggered conformers with different energy level
around C2-C3:
• Syn(eclipsed)
called fully
eclipsed
• Eclipsed called
partial eclipsed

 Syn-eclipsed is the less stable, high
energy conformers due torsional
angle=0 ° which lead to high
torsional strain and has high steric
hindrance
 Anti-staggered is the most stable,
lowest energy conformers due to
the torsional angle = 180° which
lead to low torsional strain and has
less steric hindrance
Torsional angle Torsional strain Stability

Stability of all conformers of butane
 Syn Eclipsed (Fully Eclipsed)
 Torsional angle zero & Torsional
strain maximum
 Has steric strain
 Staggered (Gauche)
 Torsional angle=60°
 Has steric strain
 More stable than fully eclipsed
 Eclipsed (Partial Eclipsed)
 Torsional strain = 120° &
Torsional strain less than fully
eclipsed
 More stable than fully eclipsed
 Anti-staggered
 Torsional angle = 180 & has
lowest torsional strain
 More stable form

Conformational Isomerism in Alkanes
 Example: For each of the following compounds, predict the energy barrier
to rotation

 Example: For each of the following compounds, predict the energy barrier
to rotation
Answe
r:
6 kJ/mol
6 kJ/mol
6 kJ/mol
Total cost: 18
kJ/mol
4 kJ/mol
6 kJ/mol
6 kJ/mol
Total cost: 16
kJ/mol
4 kJ/mol
4 kJ/mol
4 kJ/mol
Total cost: 12
kJ/mol
3.8
kJ/mol
Total cost: 3.8
kJ/mol

 Example: Consider the following compound:
a) Rotating only the C3-C4 bond, identify the lowest energy conformation
b) Rotating only the C3-C4 bond, identify the highest energy conformation
Answe
r:

Configurational vs. Conformational Isomers

Configurational Isomers
 Configurational isomers are stereoisomers that cannot be converted into one
another rotation around a single bond
Configurational
Isomers
Geometrical
isomers
Optical isomers

Geometrical Isomers
 Geometrical isomers: compounds with the same connectivity, different
arrangement of atoms in space
 Two system used to describing the orientation of substituents within a
molecule (configuration at double bond and configuration of cyclic
compound), known as cis/trans or E/Z system
 Substituents on the same side (cis, latin word) or opposite side (trans) of
double bond or ring
 When two groups are the same to use the cis/trans system of naming, if you
have four different groups on a double bond use E/Z system

Geometrical Isomers
 The chemical properties of geometrical
isomers tend to be similar but their physical
properties are different
 E/Z isomers is used when there are more than
two different substituents on a double bond
 Z (from the German zusammen) means
“together” and corresponds to the term cis
 E (from the German entgegen) means
“opposite” and corresponds to trans

Geometrical Isomers
 Rank the atoms directly attached to double
bond according to their atomic numbers
 High priority is given to the atom with higher
atomic number
 {H-(1) < C-(6) < N-(7) < O-(8) < F-(9) < Cl-(17) <
Br-(35) < I-(53)}
 If isotopes of the same element are present,
the higher priority is given to the isotope with
higher atomic mass (mass number)
 Ordinary hydrogen is written 1H1, deuterium
is 2H1, and tritium is 3H1

Nomenclature of Z/E isomers
 The E-Z nomenclature is proposed by three chemists Canh, Ingold and Prelog.
Therefore rules based on it is called as C.I.P rules
 Rule No 01: Atom directly attached with restricted atom if have higher atomic
number than is has high priority for example

 Rule No 02: If directly attached atoms are same, then go to next atom and
follow the same concept of higher atomic number for example

 Rule No 03: If groups have multiple bond then convert all π bonds into
hypothetical sigma bonds and follow the same concept of higher atomic
number

 Rule No 04: Only in case of isotopes higher atomic mass is given higher
priority

Geometrical Isomers
Exercise: Are these cis or trans?

Geometrical Isomers
Answer: Are these cis or trans?

Geometrical Isomers
Exercise: Name each, using cis-trans prefixes when needed?

Geometrical Isomers
Answer: Name each, using cis-trans prefixes when needed?

Geometrical Isomers
Exercise: Order the following in increasing priority?
a) -H, -Cl, -OH
b) -CH3, -CH2OH, -CH2CH3
c) -C=CH, -CH=CH2, -CH=O
Answer
a) -H, -OH, -Cl
b) -CH3, -CH2CH3, -CH2OH
c) -C=CH, -CH=CH2, -CH=O

Geometrical Isomers
Exercise: Determine if each of the following alkenes has and E or Z configuration?
4,4-dimethylpent-
2-ene
4-ethyl-3-heptane 1-bromo-2-chloro-2-
methylbut-1-ene
Answe
r
Z-1-bromo-2-chloro-2-
methylbut-1-ene
trans-4,4-
dimethylpent-2-
ene
cis-4,4-
dimethylpent-2-
ene
Cis/trans-4-ethyl-3-
heptane

Properties of Geometrical Isomers
 The chemical properties of geometrical isomers tend to be similar but their physical
properties are different

To be
continued

Isomerism organic chemistry topic ......

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