Compounds that have the same molecular formula but different chemical

structures are called isomers.

Depending on what types of differences there are between the structures, it is
possible to classify isomers into various sub-types.
If you "click" on the named boxes there is a link to a definition and an example.

Constitutional (or structural) isomers differ in the order in which the atoms are
connected so they contain different functional groups and / or bonding patterns:

• example: 1-propanol, 2-propanol and ethyl methyl ether (C3H8O)

Stereoisomers contain the same functional groups and differ only in the
arrangement of atoms in space.

Conformational isomers (or conformers or rotamers) are stereoisomers

produced by rotation about sigma bonds, typically rapidly interconverting at room
temperature:

• example 1: butane : staggered (left) and eclipsed (center).The C2-C3

sigma bond rotation is animated (right). Try rotating the model to look
along the C-C to see the two forms.
 • example 2: cyclohexane : chair (left) and boat (right).These two forms can
be interconverted by twisting the ring structure.

Configurational isomers are stereoisomers that do not readily interconvert at

room temperature and can (in principle at least) be separated.

Geometric isomers are configurational isomers that differ in the spatial position
around a bond with restricted rotation (e.g. a double bond):

• (E)-2-butene and (Z)-2-butene

Optical isomers are configurational isomers that differ in the 3D relationship of

the substituents about one or more atoms:

Enantiomers are optical isomers that are non-superimposable mirror images.

• (R)- or (S)-2-chlorobutane. Try moving the images to show that they are
mirror images.

Diastereomers are optical isomers that are not enantiomers.

• (S,R)- or (R,R)-2-bromo-3-chlorobutane

Deriving Possible Isomers

There is no simple way to know how many isomers exist for a given molecular
formula, and therefore, it is important to have a systematic method to derive
them. Important preliminary steps in the process are to determine the IHD to see
what types of structures you should be considering, then list the functional
groups that are possible based on the molecular formula and IHD. Once you
have done that, here are a few suggestions to aid the drawing process.....

• start with the longest continuous chain (or ring) first

• move substituents systematically along the chain
• if you have C=C consider E- and Z- possibilities or cis- and trans- for ring
systems
• decrease the the chain length one step at a time and introduce new alkyl
groups
• watch out that you don't repeat structures
• if chiral centers are present then need to consider R and S stereoisomers,
do this by identifying the chiral centers.

Isomeric molecules that are non-superimposable mirror images are

enantiomers.

(R)-2-chlorobutane (S)-2-chlorobutane

You should be able to draw these molecules, as given below the Chime
images, and indicate how they are mirror images!

Enantiomers are known as chiral molecules (derived from the Greek meaning
hand), therefore, a molecule that is superimposable on its mirror image should be
achiral.

You should be able to draw the two mirror images of an achiral molecule
and then see how if you rotate one of the images the two molecules are
actually the same.
A mixture containing equal quantities of enantiomers is called a racemate or
a racemic mixture.

Enantiomers are characterised by the presence of a stereogenic center.

A stereogenic center is also known as a chiral center. It is characterized by an

atom which has different groups bound to it in such a manner that its mirror
image is non-superimposable. Below are the enantiomers of 2-chlorobutane.

(R)-2-chlorobutane (S)-2-chlorobutane

Note you should be learning to relate the chime images to the drawn
images. More importantly you should be able to reproduce the drawn
images as that is what you will be expected to do on exams or
assignments!

The presence of a single stereogenic center in a molecule results in a chiral

molecule.

Molecules can, however, possess more than one stereogenic center. Such
molecules may or may not be chiral.
Isomers of chiral molecules that possess two or more stereogenic centers, may
be either enantiomers or diastereomers (stereoisomers that are not mirror
images).

(S,R)-2-bromo-3-chlorobutane (R,R)-2-bromo-3-chlorobutane
Diastereomers can have quite different physical and chemical properties from
one another.

Isomers of achiral molecules, that possess two or more stereogenic centers,

are known as meso isomers (stereoisomers that are superimposable). You
should be able to draw a pair of meso isomers and see how one relates to the
other by simple rotation.

Image A above is the mirror image of B, but can be seen to be the same as B
once it has been rotated. A quick way of recognizing whether a molecule is
achiral is to look for a plane of symmetry.

Carbon-based Stereogenic Centers:

The most prevalent stereogenic centers in organic chemistry are carbon atoms,
which have four different groups bound to them.

Stereogenic Centers other than Carbon:

Any atom which has four different groups bound to it is a stereogenic

center. The more common of these atoms, with which an organic chemist should
be familiar, are Si, N and P. They may be tetrahedral molecules (where the four
different groups are atoms) or trigonal pyramidal molecules (where a lone pair is
included as one of the four different groups).

CAUTION: many trigonal pyramidal molecules (especially those of

nitrogen) exhibit rapid pyramidal inversion:

In this case, even though a stereogenic center is present, the molecules are
optically inactive as the optical activity of the two extremes of inversion averages
out.

The larger the atom, though, the slower the pyramidal inversion and as a result
many optically active compounds for P and S have been prepared.

Optical activity is the ability of a chiral molecule to rotate the plane of plane-
polairzed light. It is measured using a polarimeter, which consists of a light
source, polarizing lens, sample tube and analyzing lens.

When light passes through a sample that can rotate plane polarized light, the
light appears to dim to the eye because it no longer passes straight through the
polarizing filters. The amount of rotation is quantified as the number of degrees
that the analyzing lens must be rotated by so that it appears as if no dimming, of
the light has occurred.

Measuring Optical Activity:

When rotation is quantified using a polarimeter it is known as an observed

rotation, because rotation is affected by path length (l, the distance the light
travels through a sample) and concentration (c, how much of the sample is
present that will rotate the light). When these effects are eliminated a standard
for comparison of all molecules is obtained, the specific rotation, [α].
[α] = 100a / cl when concentration is expressed as g sample /100ml solution
Specific rotation is a physical property like the boiling point of a sample and can
be looked up in reference texts.

Enantiomers will rotate the plane of polarization in exactly equal amounts (same
magnitude) but in opposite directions.

Dextrorotary designated as (+), clockwise rotation (to the right)

Levorotary designated as (-), anti-clockwise rotation (to the left)
If only one enantiomer is present a sample is considered to be optically
pure. When a sample consists of a mixture of enantiomers, the effect of each
enantiomer cancels out, molecule for molecule.

For example, a 50:50 mixture of two enantiomers or a racemic mixture will not
rotate plane polarised light and is optically inactive. A mixture that contains one
enantiomer excess, however, will display a net plane of polarisation in the
direction characteristic of the enantiomer that is in excess.

Determining Optical Purity:

The optical purity or the enantiomeric excess (ee%) of a sample can be

determined as follows:

Optical purity = % enantiomeric excess = % enantiomer1 - % enantiomer2

= 100 [α]mixture / [α]pure sample

ee% = 100 ([R]-[S]) / ([R]+[S])

where [R] = concentration of the R-isomer

[S] = concentration of the S-isomer

Diasteromeric substances can have different rotations both in sign and in

magnitude.

Optical Activity in depth:

Consider that (S)-2-bromobutane has a specific rotation of +23.1o and (R)-2-

bromobutane has a specific rotation of -23.1o

Question: Determine the optical purity of a racemic mixture.

Answer: The specific rotation, [α], of the racemate is expected to be 0, since the
effect of one enantiomer cancel's the other out, molecule for molecule.
Optical purity, % = 100 [α]mixture / [α]pure sample
= 100 (0) / +23.1o
= 0%

Question: Determine the enantiomeric excess of the racemic mixture.

Answer: You would expect [R] = [S] = 50%.

ee% = 100 ([R]-[S]) / ([R]+[S])

= 100 (50-50) / (50+50)
= 0%

Let's consider something a bit harder......

Question: Which isomer is dominant and what is the optical purity of a mixture, of
(R)- and (S)-2-bromobutane, whose specific rotation was found to be -9.2o?

Answer: The negative sign tells indicates that the R enantiomer is the dominant
one.

Optical purity, % = 100 [α]mixture / [α]pure sample

= 100 (-9.2) / -23.1o
= 40% this indicates a 40% excess of R over S!

Question: What is the percent composition of the mixture?

Answer: The 60% leftover, which is optically inactive, must be equal amounts of
both (R)- and (S)-bromobutane. The excess 40% is all R so there is a total of
70% (R) and 30% (S).

When the precise arrangement of substituents at a stereogenic center is known

the absolute configuration of the molecule is known. This is usually
accomplished by solving the x-ray crystal structure of a molecule, a method that
is not always readily available.

The arrangement of atoms in an optically active molecule, based on chemical

interconversion from or to a known compound, is a relative
configuration. Relative, because there is no way of knowing just by looking at
a structure whether the assignment of (+) or (-) is correlated to a particular
isomer, R or S.
If the name of a compound includes both the sign of rotation and the
designation R or S then the absolute configuration of that compound is
known.

Let's see how chemists can determine the relative configurations of optically
active compounds by chemically interconverting them.

The reaction of an alcohol with TsCl is known to occur with retention of

configuration, that is the group priority of the stereogenic center has not been
altered. The reaction of the tosylate with nitrile occurs with inversion, as a result
the group priority at the stereogenic centre has been altered. The absolute
configuration of the parent is known while only the relative configurations
of the tosylate and the nitrile are known. The mechanistic aspects behind this
will be discussed in more detail in the next chapter.

The Cahn-Ingold-Prelog R/S rules are used for naming enantiomers.

NB: The term stereogenic has superceded the term chiral.

1. Identify the stereogenic centers (most commonly an sp3 C with 4 different

groups attached)
2. Assign the priority to each group (high = 1, low = 4) based on atomic number
of the atom attached to the stereogenic center
3. Position the lowest priority group away as if you were looking along the C-(4)
sigma bond. If you are using a model, grasp the group in your fist
4. For the other 3 groups, determine the direction of high to low priority (1 to 3)
5. If this is clockwise, then the center is R (Latin: rectus = right)
6. If this is counter clockwise, then it is S (Latin: sinister = left)

Example: chlorofluoroiodomethane

The stereogenic center is easy to spot, and the four attached groups are I
(purple), Cl (green), F(brown) and H (white), listed in priority order, highest to to
lowest. Rotate the CHIME image below so the you are looking along the C-H
bond and the H is away from you, then determine the direction of high to low
priority. It decreases clockwise, so this is the R enantiomer.
Subrules:

• Isotopes: H vs D ? use atomic mass number so D > H

• Same atom attached ? By moving out one unit at a time, locate the first
point of difference and apply rules there.

Can you convey this on a piece of paper?

Fischer Projections are abbreviated structural forms that allow one to convey
valuable stereochemical information to a chemist without them having to draw a
3D structural representation of a molecule. These representations are only used
for molecules that contain stereogenic centers, which are then represented as
simple crosses.

They can be derived by considering the more accurate 3D representation using

wedges and assuming the convention that horizontal lines represent bonds
coming out of the plane of the paper and vertical lines represent bonds going
behind the plane of the paper.

Memory Aid ? A student once told me that she remembered the relative
arrangement of the bonds by the fact that the horizontal bonds were coming out
to hug her !
When relating one Fischer projection to another it may only be manipulated
within the 2D plane in which it is drawn (that is it may not be rotated within 3D
space), and only rotated a total a 180o

A B
o o
Why can't you rotate it 90 ? A 90 rotation is equivalent to breaking bonds and
exchanging two groups, which would result in the formation of the other
enantiomer.

CAUTION Fischer projections are often confused with simpler Lewis

diagrams. Lewis diagrams, however, are not intended to give any
stereochemical information!

Fischer projections a can be used to describe molecules with more than one
stereogenic centre.
If a Fischer projection of this type can be divided into two-halves that are mirror
images than the molecule may be identified as a meso isomer.

Assignment of the configuration at a stereogenic center, in a Fischer projection,

is based on the Cahn-Ingold-Prelog rules.
1. Priorities are assigned to the substituents of a stereogenic center.
2. That of lowest priority is placed on a vertical line, this is equivalent to making
sure the lowest priority group is positioned away from you as if you were looking
along the C-(4) s bond (see figure far right below).
3. The configuration is assigned by moving from the substituent of highest priority
to those of second and third priority.
4. If this is clockwise, then the center is R (Latin: rectus = right)
5. If this is counter clockwise, then it is S (Latin: sinister = left)
Consider the molecules A and B above. What are their configurations ?