Lecture 3

Organic Chemistry (CHM102)

Dr. Srinivas Dharavath

Assistant Professor
Department of Chemistry
Indian Institute of Technology, Kanpur
Kanpur- 208016
E-mail: [email protected]
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 L2-Recap:

• Cycloalkanes except cyclopropane, exist in puckered form to reduce their strain

energies
• Chair conformer is more stable than other conformers of cyclohexane as it has no
angle strain or torsional strain (all the hydrogens are staggered)
• Ring flip in cyclohexane occurs readily and equilibrium lies at the more stable
conformers direction. All the eq-hydrogens turn axial and vice versa
• Equatorial conformer is better stabilized than the axial conformer owing to its 1,3-
diaxial strain and/ or gauche butane interaction, the trend is more so with bulky
substituents
• The relative ratio of each conformers can be quantified using equilibrium constant
equation
• Axial or equatorial bonding can influence the property of a molecule significantly as in
the case of starch and cotton
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 Disubstituted Cyclohexane's

• With multiple substituents, solid or dashed wedges are used to show positioning of
the groups or by showing the groups in either axial or equatorial positions
• An “UP” substituent could be axial or equatorial depending on how the ring is flipped

• When naming a disubstituted cycloalkane,

• use the prefix -cis when there are two groups on the same side of the ring
• Use the prefix -trans when two substituents are on opposite sides of a ring

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 Conformations of Disubstituted Cyclohexane's
Pattern 1, 2-(or) 1,4- 1,3- α – below the plane
β – above the plane
a – axial
cis- αα e,a e,e e – equatorial
ββ a,e a,a

trans- αβ e,e e,a

βα a,a a,e

• In disubstituted cyclohexanes, the steric effects of both substituents must be taken

into consideration-cis-1,2-dimethylcyclohexane
• Consider the sum of all interactions in cis-1,2-dimethylcyclohexane
• both conformations are equal in energy

+ =

+ =
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 trans-1,2-Dimethylcyclohexane
• Trans conformation has both methyl groups equatorial and only a gauche butane
interaction between methyls (3.8 kJ/mol) and no 1,3-diaxial interactions
• The ring-flipped conformation has both methyl groups axial with four 1,3- diaxial
interactions

• Steric strain of 4 x 3.8 kJ/mol = 15.2 kJ/mol makes the diaxial conformation 11.4 kJ/mol
less favorable than the diequatorial conformation

• Trans-1,2-dimethylcyclohexane will exist almost exclusively (>99%) in the diequatorial

conformation 5
 Interaction Energies of Substituents on Cyclohexane

Cis-1,2-susbstitution Trans-1,2-susbstitution

• Steric bulk almost and always prefers the equatorial conformation to avoid 1,3-diaxial
interactions
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 Disubstituted Cyclohexane's

1,2-

1,3-

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Relationship Between Substituents in Dimethylcyclohexanes

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 cis-1,3-Dimethylcyclohexane

• Cis-1,3-dimethylcyclohexane can have both methyl groups in axial positions or both

in equatorial positions.
• The conformation with both methyl groups being equatorial is more stable.

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 trans-1,3-Dimethylcyclohexane

• Both conformations have one axial and one equatorial methyl group, so they have the
same energy.

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 Large Interaction Energies can Preclude the Formation of
Chair Conformation
• Both chair conformations
require one of the bulky t-butyl
groups to occupy an axial
position.

• The most stable conformation of cis-

1,4-di-tert-butylcyclohexane is the
twist boat.

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 Why do We Study Conformations?
• Understanding conformations will help us understand stability of a molecule to predict
its reactivity
• Conformations can dictate reactivity.

• Let’s draw the conformations of cyclohexane derivative 1.

most stable conformation

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 Conformations Influence Reactivity

• What about the compound 2?.

• Let’s draw the conformations of cyclohexane derivative 2.

• Both similar in energy so there is no significant preference for one over the other

• No possibility of epoxide formation from either of these conformations! 13

 Conformations Influence Reactivity

• 2-Aminocyclohexanols also exhibit such conformation dependent reactivity.

– trans-2-Aminocyclohexanol affords cyclopentane carboxaldehyde as the

major product

– cis-2-Aminocyclohexanol affords an ~1:1 mixture of cyclopentane

carboxaldehyde and cyclohexanone

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 Conformations Influence Reactivity

• trans-2-Aminocyclohexanol has a preferred major conformation wherein both

substituents are equatorial

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 Conformations Influence Reactivity

• cis-2-Aminocyclohexanols has two conformations both of which have one substituent

in the equatorial position and the other in axial position.

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 Bicyclic systems-Decalins

• Decalins are fused bicyclic compounds (10 carbon atoms) wherein the ring junctions
can be either cis- or trans.
• In cis-decalin hydrogen atoms at the bridgehead carbons are on the same face of the
rings
• In trans-decalin, the bridgehead hydrogens are on opposite faces
• The six-membered rings in cis- and trans-decalin assume chair conformations.

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 cis- and trans-Decalins Are Not Conformers

• cis- and trans-decalin DO NOT interconvert.

• Interactions in cis- and trans- decalin

trans-decalin is lower in energy by 2.7 kcal/mol 18

 Conformational Mobility of cis- and trans-Decalins

• trans-decalin CANNOT undergo a ring flip.

• cis-decalin CAN undergo a ring flip.

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Bicyclic Compounds - Decalin

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 Bicyclic Compounds - Decalin

cis-Decalin can flip as the new structure would also have one axial and one equatorial
bond
1 3 2
2 4 3 4

3
4 1

2
1

1 2
4 4
3 4 3
3
2
2
1
1 21
Polycyclic Ring Systems

Cholesterol is a waxy steroid

found in the cell membranes. It
is an essential component of
mammalian cell membranes.

Corticosteroids: metabolism &

immune function
Anabolic Steroids: muscle &
bone growth

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 Chair Conformations are Ubiquitous In Nature

• Consider glucose, a member of the carbohydrate family of biomolecules.

• Glucose exists almost entirely as its cyclic hemiacetal form.

• The Haworth projection, although widely used, may give the impression of the ring
being flat.
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 Chair Conformations are Ubiquitous In Nature

• Glucose exists in the two forms shown below.

• The only difference in the two molecules is that the stereochemistry at the C1
carbon atom is different.
• Stereoisomeric molecules which differ in the configuration at only one stereogenic
center are called epimers.

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 Epimers

• Epimers are stereoisomers that differ in the configuration at only one stereogenic
center.
• The carbon at which the stereochemistry differs is usually specified.

=>
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 Epimers and Anomers
• Anomers are actually epimers that differ in configuration at the acetal/hemiacetal
carbon.
• This carbon atom is also referred to as the “anomeric carbon”.
• Two anomers of D-glucose are shown below.

• The hydroxyl group on the anomeric (hemiacetal) carbon is down (axial) in the α
anomer and up (equatorial) in the β anomer.

• The β anomer of glucose has all its substituents in equatorial positions.

• The hemiacetal carbon is called the anomeric carbon, easily identified as the only
carbon atom bonded to two oxygens. 26
 Does the a-anomer Exist in Significant Amount?

❑ Despite what we saw for cyclohexane (huge preference for the equatorial
position), the corresponding a-D-glucose is present in significantly higher ratio.

36% 64%

❑ The axial substituent in this case seems to be more stabilized compared to the
corresponding cyclohexanol.

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11% 89%
 Anomeric Effect

• Alkyl substituents in cyclohexane prefer

equatorial position.

• Alkyl substituents in tetrahydropyran

prefer equatorial position.

• The anomeric carbon of the most

abundant natural sugar, D-
glucopyranose, also prefers the –OH
substituent in equatorial orientation.
36% 64%

• Making the substituent

more electronegative
rendered the axial
conformer more stable! 86% 14%
94% 06% 28
 Anomeric Effect
• Orbital Overlap • Polarizability

dipole moment
cancels out

s*C-X s*C-X
dipole moment enhanced
• Overlap between lone pair of
• Overlap NOT possible • Less dipole makes the
oxygen and antibonding
orbital of C-X possible - molecule more stable
Antiperiplanar arrangement is
essential
• As an extreme case, we can imagine complete donation of the lone pairs to give
the following resonance structure

Oxycarbenium
ion
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 Stereoisomerism

• Isomers that have the same connectivity between atoms but different spatial
arrangement of their atoms are called stereoisomers.

• With rings and with C=C double bonds, cis-trans notation is used to distinguish
between stereoisomers
• Cis – Higher priority (CIP notation) groups are positioned on the SAME side of a
ring/double bond
• Trans – Higher priority (CIP notation) groups are positioned on OPPOSITE sides
of a ring/double bond

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 Stereoisomerism

• Optical Isomerism
• Optical isomers, or enantiomers, are mirror images of one another that don’t
superimpose on each other.

• Such entities are said to be chiral.

• Their properties of chiral chemicals differ from each other only when they interact with
other chiral entities (such as plane polarized light).

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 An Interesting Side-Note About Enantiomers

• How can we distinguish the following two enantiomers?

• There are more such enantiomeric pairs!

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An Interesting Side-Note About Enantiomers

analgesic drug antitussive drug

(pain killer) (cough suppressant)

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 Summary

• 1,2 or 1,4-cis: ae; 1,2 or 1,4-trans-aa/ee; 1,3-cis:aa/ee; 1,3-trans: ae

• Axial and equatorial substituents position the orbitals appropriately, which helps in

predicting its reactivity and final product

• Cis-Decalin can flip and trans-decalin is locked cannot flip. Trans-decalin is 2.7

kcal/mol more stable than cis-decalin (gauche-butane interactions)

• In cases like glucopyranose, the axial-substitution is better stabilized due to anomeric

effect, which is accounted by antiperiplanar lone pair hypothesis as well as less dipole

stabilization

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