Conformation and

Stereochemistry
Topics
● Conformational Isomerism and Newman Projections
● Rotational Energetics; Torsional and Steric Strain
● Rings Systems and Angle Strain
● Six membered Rings; Axial/Equatorial Positions and Ring Inversions
● Stereoisomerism: Enantiomers and Diastereomers
● Absolute Configuration (R/S, D/L) and Optical Rotation
● Fischer and Haworth Projections
● Stereochemistry in Alkenes: E/Z Absolute Configuration
● Prochiral systems
Chapter Objectives
● Draw Newman projections and identify conformers and their relative energies
● Identify the axial and equatorial positions on cyclohexane rings and how they
interconvert
● Draw and identify enantiomers/diastereomers; identify chiral centers
● Assign R/S configurations to chiral centers using the Cahn-Ingold-Prelog convention
● Use optical rotation to calculate concentration, optical purity
● Draw and interpret Fischer and Haworth projections; assign D/L configurations
● Assign E/Z configuration to double bonds using the Cahn-Ingold-Prelog convention
● Identify prochiral carbons; enantiotopic and diastereotopic groups, re and si sides
of sp2 carbons.
Conformational Isomerism
Rotation about the C-C bond of ethane gives the molecule a different appearance as a
conformational isomer; this is clearly seen by sighting down the C-C bond axis, as
represented by the Newman projections shown:
Conformational Isomerism (contd)
● The two differing Newman projections for ethane are achieved via a 60 o rotation
about the C-C axis; note that additional 60 o rotation generates the original isomer.

● The two possible conformations of ethane are referred to as staggered and

eclipsed.
Energetics of Rotation
As the ethane rotates about the C-C bond from the staggered conformation, the C-H
covalent bonds interfere with each other in the eclipsed conformation, increasing the
energy of the molecule. As it rotates to the next staggered conformation, energy
decreases.
More Conformations: Butane
The C1-C2 Newman projection of butane has one staggered and one eclipsed conformer

However, the C2-C3 Newman projection has two staggered and two eclipsed conformers
Dihedral Angles in Newman Projections
The angle measured between groups on adjacent atoms in the Newman projection is
called the dihedral angle. In butane, we have separate names for the two staggered
conformers: anti and gauche, based on the dihedral angle between the methyls
Rotational Energetics in Butane
The energetics of rotation in butane are more complex than those of ethane. The two
staggered and two eclipsed conformers all have different energies
Rotational Strain in Organic Molecules
There are two types of strain that increase the energy of butane during rotation:
● Torsional strain is the strain associated with the eclipsing of covalent bonds. There
is an MO explanation for this, but for now we can attribute it to electron-electron
repulsion. This contributes to the higher energies of the eclipsed conformers.
● Steric strain is the strain caused when nonbonded atoms begin to approach each
other too closely. Larger atoms and functional groups lead to larger amounts of
steric strain. This contribution to strain increases the energy of the gauche
conformer and the conformer where the methyl groups are eclipsed.
Lowest Energy Alkane Conformers
The “zigzag” line structure typically used for linear alkanes corresponds to the
conformation with the lowest torsional and steric strain:

This conformer is “anti” across the C2-C3, C3-C4 and C4-C5 bonds.
Drawing Ring Systems in Organic Chemistry
Rings systems will have substituents drawn as either “up” (coming out of the page) or
“down” (going into the page). All groups that are up are cis to each other (as are all
groups that are down). Groups that are up are trans to all the down groups.
Angle Strain in Rings
● The bond angles between the carbon atoms in cyclopropane and cyclobutane are
substantially smaller than the 109.5o bond angles in sp3-hybridized atoms.

● This deviation from the expected bond angle leads to angle strain in these
cycloalkanes. The ring bonds in these rings will break more readily than in acyclic
systems to relieve this strain.
Ring Systems in Biomolecules
Five and six membered rings are more common in biomolecules. However, some
antibiotic drugs rely on the high reactivity of three and four membered rings.
Six Membered Rings
● Just as the bond angles in three and four membered rings are much less than
109.5o, the angles in a six membered ring are greater at 120 o.
● However, the cyclohexane ring is not a planar hexagon; it is “folded” to allow each
ring atom to have a tetrahedral geometry, as shown in the Newman projection:
Ring Conformers, Substituent Positions
● The “chair” conformer of cyclohexane is the most stable, with one gauche
interaction.
● In this conformation, the hydrogen atoms on the ring are designated as axial or
equatorial.
Cyclohexane Ring Inversions
● Although there is no full rotation about the ring bonds, there is partial rotation
allowing the ring to invert between two conformers.
● All the axial hydrogens become equatorial, and all the equatorial ones become
axial. The circled hydrogen is the same in both conformers.
Substituted Cyclohexane Rings
● Due to the rapid equilibration between the two chair conformers, the axial and
equatorial hydrogen atoms are equivalent to all measurements at room
temperature.
● Adding a methyl group makes the two conformers different, with different
stabilities:
Preference for Equatorial Groups
The methyl group in the axial position has an unfavorable steric interaction with the two
axial hydrogen atoms; this is called a 1,3-diaxial interaction, which increases the energy
of the conformer.
Preference for Equatorial Groups (contd)
The larger the substituent is, the greater the preference for the equatorial position. The
equilibrium constant for equatorial versus axial t-butylcyclohexane is >16,000.
Disubstituted Cyclohexanes
With two (non-H) substituents that can compete for the equatorial position, the
conformer with larger substituent in the equatorial position will be preferred.
Carbohydrate Conformers - Pyranose Forms
The pyranose (6-membered ring) forms of glucose and fructose predominantly assume
the conformer with the majority of substituents in the equatorial positions.
Cyclopentane Ring Conformers
Cyclopentane rings do not have axial and equatorial substituent positions; the ring can
be seen as having five coplanar atoms and one endo atom. The ring atom that is endo
exchanges by a process called pseudorotation.
5-Membered Rings in Biochemistry
The steroid skeleton has one five membered ring; the ribose sugar subunit is a
component of the backbone of RNA and (in deoxygenated form) DNA.
Stereoisomerism
● Constitutional isomers (discussed in Ch 1) have the same molecular formula, but
the atoms are bonded differently
● Stereoisomers have the same bonding between atoms, but the spatial arrangment
of the atoms is different
○ Conformational isomers are one type of stereoisomers; cis/trans alkenes are
another
Chirality
● Chirality leads to another type of stereoisomerism, and is critically important for
many biological processes.
● A chiral molecule has a non-superimposable mirror image molecule; these two
molecules are distinct species, referred to as enantiomers.
How Do You Know They Are Different?
When one molecule is rotated so that two substituents match the other molecule, the
other substituents are “switched”; you cannot make the two molecules look exactly
alike.
How Do Enantiomers Differ?
● In an achiral environment (more on this later), enantiomers have the same melting
points, boiling points, solubilities and chemical reactivities.
● The only physical property that differs is called optical rotation.
○ When light that has been polarized is passed through a chiral substance in
gaseous, liquid or solution state, the plane of polarization of the light will be
rotated in one direction.
○ Passing the same polarized light through the same amount/concentration of
the enantiomer will result in the plane of polarization being rotated to the
same extent in the opposite direction.
● Solid mixtures of enantiomers will have a lowered melting point - Why?
What is the Source of Chirality?
● Looking at the bromochlorofluoromethane example, the chirality of the molecule
arises from the tetrahedral carbon having four different substituents attached.
○ Replacing the fluorine with a bromine removes the chirality
○ Making the carbon trigonal planar removes the chirality
More Than One Source of Chirality
● A tetrahedral carbon with four different attachments is called a chiral center.
● A molecule with more than one carbon can have more than one chiral center.
● However, the groups can be arranged in a way to make a stereoisomer that is not
an enantiomer:
Diastereomers
● Diastereomers are stereoisomers that are not enantiomers
● Generally, there are 2n stereoisomers for a molecule with n chiral centers; these
consist of 2n-1 pairs of enantiomers
Diastereomers (contd)
Based on the definition, cis/trans-isomers are also diastereomers
Chiral Centers in Molecules
● A chiral center is a tetrahedral (sp3-hybridized) atom with four different “things”
attached to it; these things do not have to be different atoms.

● 2-Butanol is chiral, even though the chiral center is bonded to two carbon atoms
○ The “*” is frequently used to show a chiral center in a molecule
Chiral Centers in Molecules (contd)
● Rings can also have chiral centers; the different “things” attached have to be
determined by looking at one atom at a time along the bonds until a difference
occurs.
Drawing Enantiomers and Diastereomers
● Enantiomers can be drawn by switching two bonds on every chiral center:

● Switching some, but not all of the chiral centers generates a diastereomer:
Chiral Centers Other than Carbon
Amines can “technically” be chiral; however, the bonds to the N atom invert around the
nonbonding electron pair. Ammonium cations can be chiral centers:

Other atoms (P for example) can be chiral centers, but these are rarely encountered in
organic and biochemistry.
Labelling Chiral Centers - The CIP System
● As has been shown, switching two groups on a chiral center “reverses” the center;
logically, switching two groups again returns the original center.
● This means that there are only two possible configurations for a chiral center.
● The Cahn-Ingold-Prelog convention is used to assign each chiral center in a
molecule as (R) or (S), the two possible configurations.
● The textbook and the link above provide instructions for assigning R/S
configurations.
Nomenclature and Absolute Configuration
Note that enantiomers and diastereomers have the same IUPAC name. To distinguish
them, we need to specify R/S configurations for each chiral center when naming the
isomer; this is called assigning the absolute configurations of the chiral centers

When there is more than one chiral center, the R/S designations must be numbered.
Achiral Molecules with Chiral Centers
● It is possible for a molecule to have chiral center but to be overall achiral.
● This is due to an internal element of symmetry (such as a mirror plane); these
molecules are called meso compounds
Chiral Molecules Without Chiral Centers
A molecule can be chiral without chiral centers if there is an element of chirality to the
overall structure:

DNA is chiral due to the direction that the double helix is “wound”
Why is Chirality Important?
● It was noted earlier that enantiomers have the same physical* and chemical
properties “in an achiral environment”.
● Most organisms (including us) are not achiral; our enzymes and receptors are chiral
● For example, the carvone enantiomers below taste and smell differently due to our
taste/smell receptors, the binding sites of which are chiral:
Why is Chirality Important? (contd)
● The chiral nature of our enzymes and receptors means that the enantiomers of
drugs will have different interactions. As a general rule, one enantiomer provides
the therapy, the other provides the (generally adverse) side effect.

NY Times thaldomide retrospective

Optical Activity
● The enantiomers of a chiral molecule will rotate plane-polarized light in equal and
opposite directions. If the plane is rotated clockwise, the enantiomer is
dextrorotatory; if rotation is counterclockwise, the enantiomer is levorotatory.
● Dextrorotatory isomers are designated with a d or (+); levorotatory is designated
with l or (-)
Using Optical Rotation as an Assay
● The magnitude of optical rotation is dependent on the temperature, the
wavelength of light, the path length, the concentration and the structure of the
enantiomer.
● Specific rotation is a reference value measured controlling the first four
parameters (25 C, D-spectral line for Na, 1 dm path length, 1 g/ml concentration).
This makes the reference value unique for each enantiomerically pure substance.
● Specific rotation can be used to determine concentration (c) from the observed
rotation in a cell of length l in dm using the following equation:
Using Optical Rotation for Enantiomeric Purity
● If the concentration of the substance is known, the expected rotation for the pure
enantiomer can be determined based on specific rotation and concentration.

● This can then be related to the observed rotation to determine the optical purity of
the substance, determining the amounts of each enantiomer present:
Racemic Mixtures
● Based on the equation for optical purity, if the sample is a mixture with an equal
amount of each enantiomer, the observed rotation will be zero:

● This type of mixture is called a racemic mixture or racemate.

● As a general rule in organic chemistry, if the starting materials in a reaction are
achiral, the products will be either:
○ achiral (if no chiral center is generated in the reaction), or
○ a racemic mixture (if a chiral center is generated in the reaction)
D/L Stereochemistry in Monosaccharides
● The simplest monosaccharide is glyceraldehyde (2,3-dihydroxypropanal); the R-
enantiomer is most commonly encountered in biochemistry:

● Before the development of the Cahn-Ingold-Prelog convention,

carbohydrates were classified using the D/L system for absolute
configuration. In this system, (+)-glyceraldehyde is called D-glyceraldehyde.
D/L Stereochemistry (contd)
● D-glyceraldehyde gets its designation because it is dextrorotatory. Larger
monosaccharides are assigned as D or L based on the absolute configuration of the
chiral carbon furthest away from the aldehyde or ketone group.
○ There is no relation to optical rotation for the larger molecules
Monosaccharides Epimers
Epimers are monosaccharide
diastereomers which differ in the
chirality at only one chiral center,
referred to as the epimeric
carbon.
Epimers in Biochemistry
Epimerases are enzymes that catalyze the conversion of one monosaccharide epimer to
another:
Chirality in Amino Acids
Amino acids are typically* chiral at the carbon atom bearing the NH 2 and CO2H functional
groups. Most of the naturally occurring amino acids have the L-configuration.

Again, the D/L-configuration has no relation to the optical rotation of the molecule.
Fischer Projections
An alternative to drawing 3-D organic structures is often used in biochemistry. This is the
use of Fischer projections. In these drawings, the horizontal groups point towards the
viewer, while the vertical groups point away.
Fischer Projections (contd)
For monosaccharides, it is relatively easy to assign
R/S to Fischer projections. For each chiral center:
1. The high priority group (1) is OH
2. The low priority group (4) is H
3. The priority (2) group is at the top
4. If OH is on the right, the chiral center is R
Note that both examples are D-monosaccharides
Acyclic and Cyclic Monosaccharides
In the slides you have seen several examples of glucose in cyclic and acyclic forms. These
forms interconvert in aqueous solution, with the cyclic (pyranose) form preferred.
Haworth Projections
Haworth projections are frequently used in biochemistry to show cyclic
monosaccharides. These show the stereochemistry, but not the tetrahedral geometry.
Alkene Stereochemistry and Nomenclature
● Alkene diastereomers have been assigned cis and trans stereochemsitry in previous
examples, as shown in the 1,2-dichloroethene isomers on the left.
● However, there are frequent instances where assigning cis or trans stereochemsitry
to alkenes is not straightforward, as is the case for the 1-bromo-2-chloro-1-
fluoroethene diastereomers on the right.
E/Z Nomenclature for Alkenes
Using the Cahn-Ingold-Prelog convention to assign priority to groups attached to the
double bond gives a clear assignment of absolute configuration:
● If the high priority groups are on the same side of the bond, the double bond is “Z”
● If they are on opposite sides, the double bond is “E”
E/Z Nomenclature for Alkenes (contd)
● Numbering for E/Z is needed if there is more than one asymmetrically substituted
double bond in the molecule.
● Double bonds with the same two substituents on one side are symmetrically
substituted; there is not stereochemistry.
Thermodynamic Stabilities of Alkenes
● Trans-alkenes are
generally more stable
than cis-alkenes due
to decreased steric
and torsional strain
E/Z Isomers in Biochemistry
The biosynthesis of terpenes and steroids proceeds through coupling if isoprene units to
generate E-alkenes. Z-linkages do occurs in the biosynthesis of natural rubber.
Prochirality
A prochiral carbon is one that will become chiral if one group is changed:

Many biochemical reactions occur at prochiral positions, altering one substituent in

preference to the other, based on how the molecule fits into the enzyme’s cavity.
Pro-R and Pro-S; Enantiotopic H’s
The Cahn-Ingold-Prelog convention is applied in this case by replacing one hydrogen with
a deuterium, then assigning R/S stereochemistry to the carbon

The two hydrogen atoms are enantiotopic; replacements of each one generates an
enantiomer.
Diastereotopic and Homotopic H’s
● If there is already another chiral center, replacement of each H on the prochiral
carbon gives a mixture of diastereomers; the two hydrogen atoms are
diastereotopic.
● If replacement of the H’s does not make a chiral center, they are homotopic.
Prochiral C with Other Groups
● Non-H groups can be pro-R or pro-S; assigning the group a higher priority than it’s
matching group allows you to make the assignment
● In the Krebs (citric acid) cycle, citrate is isomerized by moving the hydroxyl group to
the pro-R arm of the species.
Prochiral sp2 Carbons: re and si faces
Unsymmetrically substituted trigonal planar sp 2 carbon atoms are also prochiral; if they
are converted to tetrahedral centers by the addition of a new group, they become chiral.
● Cahn-Ingold-Prelog conventions can be applied to assign the re and si faces of the
prochiral carbon
○ Note that re does not necessarily lead to R, and si may not lead to S (Why?)
Biochemical Reduction of Carbonyls
Enzyme-mediated NADH/NAD+ reductions typically take place at one face of a carbonyl
compound.
Prochiral Alkenes
Unsymmetrically substituted alkene carbons can also have re and si faces.
Review Questions
1. _____________ are used to identify conformational isomers (conformer) by sighting down one bond.
2. Two large groups with a dihedral angle of 30o are in the __________ conformation.
3. _______________ strain is maximized when ethane is in the eclipsed conformation.
4. _______________ strain increases when atoms come into close proximity.
5. _______________ strain increases as the bond angle deviates from the expected value.
6. In a cyclohexane ring, an axial up group becomes ___________ when the ring inverts.
7. Larger groups on a cyclohexane ring prefer to be equatorial due to _____________ interactions.
8. Two molecules that are nonsuperimposable mirror images of each other are _______________.
9. A tetrahedral carbon with four different groups attached is a _______________.
10. What is the difference between enantiomers and diastereomers?
11. The __________________ convention is used to assign absolute configurations to chiral centers and
alkenes.
Review Questions (contd)
12. A molecule with chiral centers that is achiral due to symmetry is called a ___________ compound.
13. Why is it important for a drug to have a high optical purity?
14. Monosaccharides that differ at one chiral center are called _____________.
15. In general , trans-alkenes are more stable than cis-alkenes due to __________ and ________ strain.
16. Atoms that can become chiral by adding or changing one attached group are called _____________.
17. If changing one group on an achiral carbon generates a diastereomer, the groups are _____________.
18. Changing a homotopic group results in ________________.
19. The two faces of an unsymmetrically substituted sp2 carbon are the ______ and _______ faces.