Summary

The different spatial arrangments that a molecule can adopt due to rotation about
bonds are called conformations and hence conformational isomers orconformers.
The study of the energy changes that occur during these rotations is called
conformational analysis.
This is important because the structure of a molecule can have a significant influence
on the molecular properties, including dictating the outcome of a reaction. Although the
ideas are developed for the simplest functional groups, the alkanes, the same principles
can be expanded and applied to other functional groups.

Conformational Language

Key terms glossary

Drawing and interpretting Important diagrams (wedge-dash, sawhorse, Newman,

Cyclohexane)

Basics

Energetics

What are conformational isomers ?

Conformational Analysis

Simple alkanes: Methane, Ethane and Propane

Higher alkanes: Butane and beyond

Cycloalkanes : C3 to C5

C6H12, Cyclohexane

Substituted cyclohexanes

Polycyclics

Heterocycles

Interesting Molecules

Sample questions

Crossword

Drill Problems

More practice problems ?

Conformational Language
An alphabetical list of key terms in the language of conformational analysis is provided
below, linked to the more detailed descriptions within the chapter pages

Anti

Description given to two

substitutents attached to
adjacent atoms when their
bonds are at 180o with respect
to each other.

Eclipsed

A high energy conformation

where the bonds on adjacent
atoms are aligned with each
other.

Staggered

A low energy conformation

where the bonds on adjacent
atoms bisect each other,
maximising the separation.

Gauche

Description given to two

substitutents attached to
adjacent atoms when their
bonds are at 60o with respect to
each other.

Syn

Description given to two

substitutents attached to
adjacent atoms when their
bonds are at 0o with respect to
each other.

Conformations

Different spatial arrangments

that a molecule can adopt due
to rotation about sigma bonds.

Conformers

Contracted version of
conformational isomers.

Rotamers

Alternative expression for

conformational isomers.

Conformational
isomers

Structures that can be

interconverted by rotation about
bonds.

Cycloalkane

An ring containing only C-C

bonds.

Heteroatom

A non-carbon atom such as

O,N,S etc.

Heterocycle

A cyclic molecule that includes

a heteratom such as O,N,S etc.
as part of the ring.

Puckered

In general terms, puckered

means "wrinkled, folded or
creased". In conformational
analysis this is used to refer to
the non-planar geometry of a
cyclic structure.

Ring flipping

The process by which a ring

changes it's conformation.

Axial

A position on a cycloalkane in
which the bond to the ring is
perpendicular to the average
plane of the ring (i.e. pointing
towards the poles). Most
commonly encountered in the
chair conformation of
cyclohexane.

Equatorial

A position on a cycloalkane in
which the bond to the ring is
approximately in the average
plane of the ring (i.e. around
the equator). Most commonly
encountered in the chair
conformation of cyclohexane.

Chair

The most stable conformation

for cyclohexane.

Boat

A high energy conformation of

cyclohexane that occurs during
ring flipping.

Strain

Energy associated with a

system due to its geometry.

Angle strain

Destabilisation due to distortion

of a bond angle from its
optimum value caused by the
electrostatic repulsion of the
electrons in the bonds.

Van der Waals

strain

Destabilisation due to the

repulsion between the electron
clouds of atoms or groups. Also
known as Van der Waals
repulsion. This occurs when
atoms or groups are too close
to each other due to the
electrostatic repulsion of the
electrons.

Steric strain

A composite of the other strains

(angle, torsional, Van der
Waals) within a molecule.

Torsional strain

Destabilisation due to the

repulsion between pairs of
bonds caused by the
electrostatic repulsion of the
electrons in the bonds.

Torsional angle

Angle between C-X and C-Y

bonds in a X-C-C-Y system
when viewed along the C-C
bond. Rotation about the C-C
bond will change this torsional
angle. This is also known as a
dihedral angle.

Ring strain

The destabilisation of a cyclic

structure compared to a related
non-cyclic structure, mainly due
to angle and torsional strain.
This extra energy is released
when the ring is broken.

Drawing and Understanding Diagrams

The ability to draw and interpret the different diagrams that are used to represent the
different conformations is an important skill to acquire. Maximise your artistic talents !
The only person that will be decieved by your poor diagrams is you ! Your instructor will
be able to tell instantly that you are struggling....
These diagrams allow 3D representations of molecules to be drawn on the 2D world
of a piece of paper (or computer screen), in a similar way to which one can look at the
plans for a house.
wedge-dash

sawhorse

Newman

cyclohexane

Wedge-dash diagrams
Usually drawn with two bonds in the plane of the page, one infront, and one behind to
give the molecule perspective. When drawing wedge-dash it is a good idea to visualise
the tetrahedral arrangement of the groups and try to make the diagram "fit" this. As a
suggestion, they seem to be most effective when the "similar" pairs of bonds (2-inplane, 2-out-of-plane) are next to each other, see below:

Sawhorse
Sawhorse diagrams are similar to wedge-dash diagrams, but without trying to use

"shading" to denote the perspective. The representation to the right of propane has
been drawn so that we are looking at the molecule which is below us
and to our left.

Newman Projections
These projections are drawn by looking directly along a particular bond in the system
(here a C-C bond) and arranging the substituents symmetrically around the atoms at
each end of that bond. The protocol requires that the atoms within the central bond are
defined as shown below:

In order to draw a Newman projection from a wedge-dash diagram, it is useful to

imagine putting your "eye" in line with the central bond in order to look along it.
Let's work through an example, consider drawing a Newman projection by looking at the
following wedge-dash diagram of propane from the left hand side.

First draw the dot and circle to represent the front and back C respectively

Since the front carbon atom has an H atom in the plane of the page pointing up we can
add that first

The back carbon atom has an H atom in the plane of the page pointing down

Now add the other bonds to each C so that it is symmetrical

The groups / bonds (blue) that were forward of the plane of the page in the original
wedge-dash diagram are now to our right

Those behind (green) the plane are now to our left

Now you try the same thing, but looking from the right to generate the other Newman
projection.

Drawing Cyclohexanes
Drawing cyclohexane so that it looks like a chair can be the key to appreciating the axial
and equatorial positions. If you are unable to draw good looking structures that clearly
show axial and equatorial positions, then your instructor is probably going to assume
that you don't know.
By not mastering the trick of drawing cyclohexanes the only person that really suffers is
you the student. You deprive yourself of the knowledge and the chance to appreciate it
and what it means. Believe me, it will be needed later.
The first step is drawing the chair itself. Although the chair "looks better" when slightly
angled, it maybe easier to "learn" to draw it with the middle portion horizontal.

Energetics

Fundamentals of electrostatics

Types of strain

The predominant forces involved in chemistry are electrical in origin based on the
physics associated with Coulomb's Law of electrostatics. The basics are reviewed
below:
The force between two charged particles q1 and q2 is inversely
proportional to the distance, r, between them.

If the particles are of opposite polarity, then the force is attractive.

As an example, the attraction of electrons to an atomic nucleus.

If the particles are of the same polarity, then the force is replusive.
As an example, electron pair repulsion used in VSEPR

IMPORTANT IMPLICATIONS : Electron pairs repel each other. As a result, molecules

are most stable when pairs of electrons are as far apart from each other as possible.
When the pairs of electrons are too close together, then the molecule is destabilised
and it is at higher energy. Remember, the most stable states are those of lowest energy.
(You should already know this from General Chemistry and Chapter 1, VSEPR.)
Conformational analysis is essentially an investigation of forces and energies
associated with the interactions of pairs of electrons (these could be pairs of electrons in
bonds or lone pairs). Strain is the term used to for the energy associated with a system
due to its geometry.
There are various types of strain that we need to be familar with. These and associated
terms are described below:

Steric
strain

The overall strain in a molecule due to the nonbonded interactions of atoms or groups of atoms
that are in close proximity so that their electrons
repel each other. It can be broken down into other
types of strain as desecribed below.

Angle
strain

If the angle between a pair of bonds in an X-C-Y

system is less than the optimal value(e.g. 109.5o
at a tetrahedral center), then there is a
destabilisation due to the electrostatic repulsion of
the electrons in the bonds. Note that the two
bonds share a common atom, here C.

Van der
Waals
strain

If the electron clouds of a pairs of atoms or group

of atoms (such as a methyl group) are too close to
each other, then there is a destabilisation due to
the electrostatic repulsion of the electron clouds.
Note that these groups don't even have to be parts
of the same molecule. This is also known as Van
der Waals repulsion.

Torsional
strain

The electrons in a C-X bond are replled by those

in a C-Y bond within a X-C-C-Y system. When
this pair of bonds are too close to each other, then
there is a destabilisation due to the electrostatic
repulsion of the electrons in the bonds.
(note students often have difficulty with this type of strain
since they confuse it with angle strain)

Torsional
angle

Ring strain

For example, the angle between C-X and C-Y

bonds in a X-C-C-Y system. Also known as a
dihedral angle. Rotation of the single bond C-C
results in a change in the torsional angle.
If we compare the energy of a cyclic structure
compared to a related non-cyclic structure (e.g.
cyclopropane and propane), then typically the
cyclic structure is less stable, mainly due to angle
and torsional strain. This extra energy is released
when the ring is broken and is called ring strain.

What are Conformational Isomers ?

In Chapter 1 we looked at constitutional isomers and we started to grow "an isomer tree". We now
need to grow the next branch in order to start our investigation of conformational isomers. If you
"click" on the named boxes there is a link to a definition and an example.

Isomers are compounds with the same molecular formulae but that are structurally different in some
way. It is important to be able to recognise isomers because they can have different chemical, physical
properties and biological properties.

Constitutional isomers differ in the order in which the atoms are connected so they can contain
different functional groups and / or bonding patterns (e.g. branching)

example: 1-propanol, 2-propanol and ethyl methyl ether (C 3H8O)

Stereoisomers have the same functional groups and connectivities, they differ only in the
arrangement of atoms and bonds in space.

Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers

produced by rotation (twisting) about bonds, and are often rapidly interconverting at room
temperature.

example 1: butane : anti (left) and syn (center). Rotation about the C2-C3 bond is animated
(right). Try rotating the model to look along the C-C to see the two extreme forms.

example 2: cyclohexane : chair (left) and boat (right).These two forms can be interconverted by
twisting the ring structure.

Alkanes
Let's start with simple alkanes so we can prepare ourselves for the more complex world
that lies beyond.....

Methane

Ethane

Propane

Methane: CH4
Although bonds are able to
rotate about the internuclear
axis, the spherical symmetry of
H atoms means that methane
has a single unique

conformation.

Ethane: CH3-CH3
Rotation about the C-C bond in ethane (see the JSMOL
animation to the right) produces different conformations.
Although an infinite number of conformations are possible,
the staggered and eclipsed conformations which
represent the most and least stable respectively are the
two most important.
Try rotating the 3D model of the animation so that you are
looking directly along the C-C bond to see the
interconversion of the two extreme conformations.
The differences between these two conformations are most apparent when viewed directly down
the C-C bond, as in a Newman projection, see below:
STAGGERED
Look at how the each H-C-H bond angle is bisected by a C-H bond on the adjacent C atom. This is
the most stable conformation for ethane since the torsional strain is minimised. The staggered
conformation is 12kJ/mol (2.9 kcal/mol) more stable than the eclipsed conformation (below).
ECLIPSED
Think like an astronomer....each of the C-H bonds is aligned with a C-H bond on the adjacent C
atom so that the H attached to the front C obscures (eclipses) those on the rear C

The animation below shows how the potential energy of the ethane molecule varies for
a full rotation about the central C-C bond.
Use the controls to show the energies of the important conformations.

Propane: CH3-CH2-CH3
Although there are 2 C-C bonds
in propane, they are equivalent
and rotation produces
conformations that are similar to
those of ethane except that the
"extra" methyl group is
interacting with the H atoms.

These can be seen by in the 3D

model of propane to the right.

Higher Alkanes
The same basic ideas of conformational analysis developed previously for simple
alkanes also apply, but some new situations are encountered.

Butane: CH3-CH2-CH2-CH3
In butane it is the rotation about the C2-C3 bond that is of most interest since the
relative position of the two methyl groups is important.
This can be seen most easily by rotating the molecule to view it down the C2-C3
bond. Try rotating the 3D model in the animation so that you are looking directly
along the C-C bond to see the interconversion of the two conformations.
The more important conformations are shown below:

ANTI
a staggered conformation with the Me groups at 180 o with respect to each other.
This is the most stable conformation since the Me groups are as far apart as
possible.
GAUCHE
a staggered conformation with the Me groups at 60 o with respect to each other.

SYN
an eclipsed conformation with the Me groups at 0 o with respect to each other.
This is the least stable conformation due to the steric strain caused by the
proximity of the Me groups and the torsional strain of the eclipsed bonds.
GAUCHE
a staggered conformation with the Me groups at 60 o with respect to each other

note: the two gauche conformations are not quite the same, try to convince yourself of this.
How are they related to each other ?
They are non-superimposable mirror iamges (so they are enantiomers)

Question: Hydrocarbons are often drawn as simple "zig-zag" structures an example of

which is given below.
What type of conformation does this represent ?

ANSWER
The zig-zag is an anti conformation - the most stable conformation

Cycloalkanes

Cycloalkanes literally means "cyclic alkanes", which means ring structures

containing only C-C and C-H bonds.

The C atoms in cycloalkanes are predicted to be sp3 hybridised which requires

optimal C-C-C bond angles of 109.5o

These structural units are commonly encountered in natural compounds such as

steroids, with cyclopentanes and cyclohexanes being the most common.

Other than the smallest ring system cyclopropane (which must be planar),
cycloalkanes are "puckered"

Puckering typically reduces ring strain (i.e. makes it more stable) by lowering
torsional strains but this is offset by slightly increased angle strain.

Ring strain : cyclopropane > cyclobutane > cyclopentane > cyclohexane

The most stable conformations of the first three cycloalkanes (the smallest three) are
shown below where they can be contrasted with the planar conformation. In order to be
able to compare the strain in each member of the cycloalkane series, the heat of
combustion per methylene (i.e. -CH2-) is also given (see note below the table). The
smaller this number is the less ring strain there is.
In each case, you should manipulate the 3D-JSMOL images to visualise the deviation
from planarity and the effect this has on the eclipsing interactions of adjacent C-H
bonds and C-C bonds (hint turn the model to "see" the Newman projections).

C3H6
CYCLOPROPANE
Hc / CH2 = -697 kJ/mol
(-166.6 kcal/mol)
ANALYSIS

The 3 C atoms in cyclopropane must be planar (due to the rules of

geometry where 3 points define a plane).

This means the C-C bonds are fully eclipsed (torsional strain).

This means the C-H bonds are fully eclipsed (6 pairs, torsional strain).

By definition, the C-C-C bond angles are 60o (angle strain).

Overall, this means high ring strain.

C4H8
CYCLOBUTANE
Hc / CH2 = -681 kJ/mol
(-162.7 kcal/mol)

ANALYSIS

The 4 membered ring has a little bit of flexibility and can twist to be nonplanar (puckered).

The angle of the fold is of the order of 28 o

This means the C-C bonds are only partially eclipsed (reduces torsional
strain).

This means the C-H bonds are only partially eclipsed (reduces torsional

strain).

The C-C-C bond angles close to 90o (angle strain).

Overall, this means high ring strain.

C5H10

CYCLOPENTANE
Hc / CH2 = -658 kJ/mol
(-157.3 kcal/mol)
ANALYSIS

The 5 membered ring has some flexibility and can twist to be non-planar
(puckered).

The most stable conformation is referred to as the "envelope"

This means the C-C bonds are only partially eclipsed (reduces torsional
strain).

This means the C-H bonds are only partially eclipsed (reduces torsional
strain).

The C-C-C bond angles close to 105o (a little angle strain).

Overall, this means relatively low ring strain.

Cyclohexane
This is a common and therefore important ring system, what should you know ?

How to draw cyclohexanes so you can convey your knowledge !

The most stable conformation is the chair

There are other less stable conformations such as the boat and the twist boat.

Ring flipping interconverts chair conformations.

There are two types of substituent positions around a chair cyclohexane axial
and equatorial.

C6H12

CYCLOHEXANE
Hc / CH2 = -653 kJ/mol
(-156.1 kcal/mol)

The most stable conformation of cyclohexane is the chair form shown to the right. The
C-C-C bonds are very close to 109.5o, so it is almost free of angle strain. It is also a fully
staggered conformation and so is free of torsional strain.
Rotate the molecule in the JSMOL image to show this just like a Newman projection so
that you can inspect the staggered C-H and C-C bonds.
The chair conformation is the most stable conformation of cyclohexane.
In chair cyclohexane there are two types of positions, axial and equatorial. The axial positions
point perpendicular to the plane of the ring, whereas the equatorial positions are around the
plane of the ring. You should notice that adjacent axial postions point in opposite directions. The
same is true for the equatorial positions. The axial and equatorial positions can be highlighted in
the JSMOL image to the right
A second, much less stable conformer is the boat conformation. This too is almost free of angle
strain, but in contrast has torsional strain associated with eclipsed bonds at the four of the C
atoms that form the side of the boat. Rotate the molecule in the JSMOL image to show this just
like a Newman projection. In addition, a steric interaction of the H atoms inside the "bow" and
the "stern", known as the flagpole interaction also destabilises the boat.
A third conformation is produced by twisting the boat to give the twist or skew-boat
conformation. The twist relieves some of the torsional strain of the boat and moves the flagpole
H further apart reducing the steric strain. Consequently the twist boat is slightly more stable
than the boat.

Conformational rotation of cyclohexane interconverts the conformations. This

proceeds from one chair to twist boat to boat to twist boat to the other chair
conformation. This process is often referred to as "ring flipping".
Watch the JSMOL animation carefully and look for the two chair forms, stop and rotate
the animation if needed. The animation will pause at the chair conformation before
continuing.

An important feature of this process is that the axial and equatorial positions are
interchanged. If you use the colour coding you should be able to see that a position that
was axial in one chair is equatorial in the other and vice versa.
An important feature of this process is that the axial and equatorial positions switch. If you
watch carefully you will see that a position that was axial in one chair is equatorial in the other
and vice versa.

Substituted Cyclohexanes
Cyclohexane substituents can be found in either axial or equatorial positions. However,
in general, equatorial substituents tend to be preferred because they are more stable
because of reduced steric interactions.
Let's consider an example, methycyclohexane.
In the equatorial system, the methyl group has space around it as it is pointed away
from the rest of the ring. The C-C bond that connects the methyl group is anti to the two
C-C bonds in the rest of the ring system which means there is minimal torsional strain.
However, in the axial conformation, the methyl group is closer to the rest of the ring.
There is an unfavourable steric interaction between the methyl group with the two axial
hydrogen atoms on the same face of the ring. This destabilises the axial conformation.
In the JSMOL images below, this 1,3-diaxial interaction can be highlighted and
contrasted with the equatorial conformer. The close proximity of the substituent and the
H atoms is most obvious when looking at the space filling model. In addition, the C-C
bond that connects the methyl group is gauche to the two C-C bonds in the rest of the
ring system which means there is also some torsional strain.
Make sure you can see the steric differences between the axial and equatorial
situations.
The larger the alkyl substituent is, the greater the preference for the equatorial position since the
larger the group the greater the steric interaction with the axial hydrogens.

Polycyclic Systems
Both nature and human kind has created many examples of compounds that contain
more than one ring system. These can be classified depending on how many rings are
present and how the rings are joined together.
If there is a single atom common to two rings, then the system
is said to be "spirocyclic" and the central atom can be

described as the "spirocenter". The simplest example is

spiropentane.

If two or more atoms are shared between more than one ring
then the system is said to be "polycyclic" in general terms or
as bicyclic, tricyclic, tetracyclic etc. depending on how many
rings systems are present. The simplest polycyclic system is
bicyclobutane.
When there are two common atoms in the rings, then it is a
"fused" system, as in bicyclobutane.

If there are more than two common atoms then the a

"bridged" system is obtained, the simplest example being
bicyclo[1.1.1]pentane.

Heterocycles
Of course atoms other than carbon can occur as part of the cyclic structure. Such
atoms, which are known as heteroatoms, e.g. N, O, S give rise to heterocycles. From
a conformational analysis presepective, these heterocycles are, in general, very similar
to the analogous hydrocarbons, check out the JSMOL images of a few common simple
heterocylces shown below.
Tetrahydrofuran
(THF)
Pyrrolidine

Piperidine

Morpholine

This page contains some examples of interesting polycyclic and / or heterocyclic

molecules used as pharmaceuticals. Look at the JSMOL images to see the types and
shapes of the ring systems that are present.
RANITIDINE : C13H22N4O3S, mol. wt. = 314.41 g/mol
Physical properties: Solid, mp = 69-70oC. US patent is held by Allen and Hanburys.
The hydrochloride of Ranitidine is called Zantac, one of the most prescribed drugs in the
western world. Zantac is an off white solid, mp = 133-134 oC. It is soluble in acetic acid,
water and methanol, sparingly soluble in ethanol, insoluble in chloroform.
Ranitidine is a histamine H2-receptor antagonist which inhibits gastric acid secretion.
Therapeutically it is used as an antiulcerative.
PRONTOSIL : C12H13N5O2S, mol. wt. = 291.33 g/mol
The hydrochloride salt is an orange-red cyrstaline material, mp : 248-250 oC, solubility: 1g
in 400 ml water, much more soluble in hot water, soluble in alcohol, acetone, fats and oils.
Prontosil was original prepared as an "azo-dye" and used for dyeing wool fibres. However,
it was part of an in vivo study for antibacterial activity (found to be active against Grampositive infections) and became a prototype compound that led to the development of the
important sulphonamide antibacterials. Prontosil was first drug introduced to treat bacterial
infections.
Therapeutically it is used as an antibacterial, but it is also used as a specific stain for
carbonic anhydrase in polyacrylamide gels.
PROMAZINE : C17H20N2S, mol. wt. = 284.43 g/mol
Physical properties: an oily liquid, having an "amine" odour. bp(0.3) : 203-210 oC.
Prepared by heating a xylene solution of phenothiazine and 3-dimethylamino-1-chloropropane in the presence of sodamide. US patent for Promazine is held by Rhone-Poulenc.
The hydrochloride salt, Prazine (also known as Talofen or Sparine) is a white/yellow
crystalline material that oxidises in air. One gram is soluble in 3 ml of water. it is also
soluble in alcohols and chloroform, insoluble in diethyl ether and benzene. Aqueous
solutions are slightly acidic to litmus.
Therapeutically it is used as an antipsychotic and an antihistamine in man and as a
tranquilizer for animals.
NOVOCAIN : C13H20N2O2.HCl, mol. wt. = 273.07 g/mol
Novocain is the hydrochloride salt of another pharmaceutical, Procaine. Novocain is a
crystaline material:mp = 153-156 oC. Numbing taste. Air stable. Solubility: 1g dissolvesin
1ml water and 30ml of alcohol, slightly soluble in chloroform, virtuallyinsoluble in diethyl
ether. pH of 0.1M solution is 6.0. Aqueous solutionscan be sterilised by boiling. LD50 (mice
mg/kg) = 660.
Novocain was synthesised to replace cocaine due to the abuse of cocaine.It was designed to
have the same pain-killing properties but not the psychologicalside effects.
Therapeutically used as a local anesthetic for humans and animals.
LIDOCAINE : C14H22N2O, mol. wt. = 234.34 g/mol
Physical properties: crystaline needles (from benzene or alcohol) mp = 68-69oC, bpt (4mm)
= 180-182oC.
Soluble in chloroform, benzene, ether and alcohol. Insoluble in water.
Lidocaine was developed from Procaine (ie Novocain), the structure of which is shown
above. Compare the two structures. Due to the presence of a labile ester bond, Procaine has
only a short lifetime/duration of action. Changing this to a more stable amide linkage as in
Lidocaine provides a material with a longer lifetime and therefore duration. The US patent
is held by Astra.

Also known as Lignocaine and Xylocaine amongst many other names.

Therapeutically it is used as a local anesthetic and a class IB antiarrhythmic.
DIAZEPAM : C16H13ClN2O, mol. wt. = 284.74 g/mol
Physical properties: crystaline plates (from acetone and petroleum ether) mp = 125-126oC.
pKa = 3.4. Soluble in chloroform, dimethyl formamide, benzene, acetone and alcohol.
Slightly soluble in water. LD50 (orally for rats) = 710mg/kg
This is a controlled substance in US code of Federal Regulations. US patent is held by
Hoffmann-La Roche.
Also known as Valium, Novazam amongst many other names.
Therapeutically it is a anxiolytic, a skeletal muscle relaxant.
NORETHINDRONE : C20H26O2, mol. wt. = 298.43 g/mol
Physical properties: crystaline (from ethyl acetate) mp = 203-204oC. Specific rotation =
-31.7 in chloroform.
Prepared from 19-nor-4-androstene-3,17-dione. US patent is held by Syntex.
Also known as Coniudag, Menzol, Micronor, Micronovum, Mini-Pe, Norcuolut, Noriday,
Norluten, Norlutin, Nor-Qd, Primolut N, and, Utovlan.
Norethindrone is a synthetic steroid and was developed since it was known that natural
steroids have potent physiological effects.
Therapeutically it is a progestogen. Norethindorne and its acetate with estrogen is used as
an oral contraceptive. The enanthate is an injectable contraceptive.
MIFEPRISTONE : C29H35NO2, mol. wt. = 429.60 g/mol
Physical properties: mp = 150oC. Specific rotation = +138.5o (c = 0.5 in chloroform).
Mifepristone is a progesterone receptor antagonist with partial agonist activity. When used
with prostaglandins, Mifepristone terminates pregnancy within the first 9 weeks of
gestation. Structurally it is very similar to Norethindrone. The US patent is held by
Rousell-UCLAF. Also known as RU-486 and Mifegyne.
Therapeutically it is used as an abortifacient.

Conformational Analysis Questions

Q
The energy diagram shows the relative energies of the conformations of 2,2,3u
trimethylpentane produced during the rotation about the C3-C4 bond.
1:
Match the structural representations provided to the appropriate points on the energy profile.

Qu 2:

There are four possible stereoisomers of 1-tert-butyl-3-methylcyclohexanes in which the

cyclohexane is in a chair conformation. The calculated heats of formation, Hf, of these four
structures are listed to the right.
Draw the four possible structures.
Match the heats of formation, Hf, values to the appropriate structures
Justify your choice.

Hf (1
Hf (2
Hf (3
Hf (4
Hc (H
Hc (C
R = 1.

Using the available data, calculate :

i) the heat of combustion, Hc, of the most stable structure
ii) the equilibrium constant, K, for the interconversion of the two cis forms at 25oC.

Hf (1
Hf(2)
Hf (3
Hf (4
Hc (H
Hc (C
R = 8.

Cyclopropane is unique among the cycloalkanes in that it can be hydrogenated with H2

Qu 3: and Pt metal, giving propane. Similarly, propene can be hydrogenated to give propane.
(tough)

The heats of formation (Hf) for the hydrocarbons are:

propane = - 24.8 kcal/mol, cyclopropane = + 12.8 kcal/mol , and propene = + 4.9
kacl/mol
You should recall that the Hf for the elements ( e.g. H2) is defined to be zero.
(1.) From this data, calculate the heats of hydrogenation (Hh) of cyclopropane and
propene.
(2.) Show this data on a typical energy diagram in which the enthalpies of propene + H2,
cyclopropane + H2 and propane are given in rough relative positions.
(3.) The bond energy of a C-C single bond is about 83 kcal/mol, a C=C double bond is
about 146 kcal/mol. Using this data, together with the data from part (1), calculate a "ring
strain" for cyclopropane, and compare this with the "ring-strain" value of 28 kcal/mol
found experimentally from combustion data.
Answers ?

Conformational Analysis Answers

Ans 1:

First, as in any question you encounter with a compound name, draw out the compound (hence understa
Using your model kit will also help solving this problem. It is convienient to describe the C3-C4 bond s
methyl groups and a C3-t-butyl.
In general terms, all the energy maxima will be eclipsed conformations, and the minima will be stagger
The highest energy conformation will be with the C3-t-butyl and C4-methyl groups eclipsed, B. Rotatio
of the staggered conformers with the C4-methyl group gauche to both the C3-t-butyl and methyl groups
eclipsed conformer with the C3- and C4- methyls eclipsed, E, then onto the lowest energy conformation
groups at 180o to each other, in the staggered conformation, D. Now to the most favourable eclipsed con
groups eclipsed only by H atoms, AB. The next staggered conformation has the C3-t-butyl group gauch
and finally back to B.

Ans The four structures are shown below along with their respective Hf values. The most stable
2: conformation will have the most exothermic Hf and this will correspond to the situation
with both alkyl groups in the more favourable equatorial position. Equatorial substitutents
are prefered over axial substituents due to the presence of the destabilising 1,3-diaxial
interactions (a steric effect) when the substituent is axial due to its proximity to the other

axial positions on the same face of the cyclohexane. The larger the substituent, the more
destabilising this steric effect is. So the most stable isomer will be the one with both Me and
tBu equatorial, then the one with the larger tBu equatorial and Me axial, then equatorial Me,
axial tBu, and the both axial isomer will be the least stable.

Hf = -46.84

Hf = -44.41

Hf = -40.53

Hf = -38.16

Hf = -195.98
most

Hf = -185.81

Hf = -169.58

Hf = -159.66
least

kcal/mo
l
kJ/mol
stability

The Hc of the most stable

isomer can be calculated using
the Hess's Law relationship for
the balanced reactions shown to
the left. From the diagram we
get the relationship that:
Hc (elements) = Hf (isomer)
+ Hc(isomer)
So, based on the molecular
formula, C11H22, we can insert
the numbers to get :
-1782 = -46.84 + Hc,
therefore Hc = -1735.16
kcal/mol.
To calculate the equilibrium constant, we need to use the equation G = -RT ln K and make
the approximation
that G = H, thus G = -46.84 --38.16 = -8.68 kcal/mol (for the two cis isomers).
Inserting the values, -8680 cal/mol = -(1.987 cal/molK) (298 K) ln K, so K = 2.3 x 106

Ans 3:

Here is a diagram showing the reactions and the data provided in the question:

The heat of a reaction (in this case the heat of hydrogenation) can be calculated from
the heats of formation of the products and starting materials (also see the figure
below):

With this data, we can create the required energy diagram. If a C=C is 146 kcal/mol
and a C-C is 83 kcal/mol, then we can estimate the strength of a bond as 146 - 83 =
63 kcal/mol. This means a bond is 20 kcal/mol stonger than a bond.
We need to compare the reactions of cyclopropane and propene to propane.
The reaction of cyclopropane breaks a bond and that of propene a bond.
Remember that breaking a bond requires an INPUT of energy and therefore, 20
kcal/mol more was required for cyclopropane compared to propene.
But the ring strain of
cyclopropane will be
RELEASED on going to
propane.
If we correct for the
differing bonds, then the
heat of hydrogenation of
cyclopropane becomes
-57.6 kcal/mol. (ie. more
exothermic by 20
kcal/mol)
Now we can get an
estimate of the energy
released due to ring strain
by -57.6 - - 29.7 = -27.9 kcal/mol
This compares very favourably with 28 kcal/mol found by combustion analysis.