Stereoisomers

Stereoisomers
As defined in an earlier introductory section, isomers are different compounds that have the same molecular
formula. When the group of atoms that make up the molecules of different isomers are bonded together in
fundamentally different ways, we refer to such compounds as constitutional isomers. For example, in the
case of the C4H8 hydrocarbons, most of the isomers are constitutional. Shorthand structures for four of these
isomers are shown below with their IUPAC names.

Note that the twelve atoms that make up these isomers are connected or bonded in very different ways. As is
true for all constitutional isomers, each different compound has a different IUPAC name. Furthermore, the
molecular formula provides information about some of the structural features that must be present in the
isomers. Since the formula C4H8 has two fewer hydrogens than the four-carbon alkane butane (C4H10), all the
isomers having this composition must incorporate either a ring or a double bond. A fifth possible isomer of
formula C4H8 is CH3CH=CHCH3. This would be named 2-butene according to the IUPAC rules; however, a
close inspection of this molecule indicates it has two possible structures. These isomers may be isolated as
distinct compounds, having characteristic and different properties. They are shown here with the
designations cis and trans.

    The bonding patterns of the atoms in these two isomers are essentially equivalent, the only difference being
the relative orientation or configuration of the two methyl groups (and the two associated hydrogen atoms)
about the double bond. In the cis isomer the methyl groups are on the same side; whereas they are on
opposite sides in the trans isomer. Isomers that differ only in the spatial orientation of their component atoms
are called stereoisomers. Stereoisomers always require that an additional nomenclature prefix be added to
the IUPAC name in order to indicate their spatial orientation, for example, cis (Latin, meaning on this side)
and trans (Latin, meaning across) in the 2-butene case.

Alkene Stereoisomers
Configurational Stereoisomers of Alkenes
The carbon-carbon double bond is formed between two sp2 hybridized carbons, and consists of two
occupied molecular orbitals, a sigma orbital and a pi orbital. Rotation of the end groups of a double bond
relative to each other destroys the p-orbital overlap that creates the pi orbital or bond. Because the pi bond has
a bond energy of roughly 60 kcal/mole, this resistance to rotation stabilizes the planar configuration of this
functional group. As a result, certain disubstituted alkenes may exist as a pair of configurational stereoisomers,
often designated cis and trans. The essential requirement for this stereoisomerism is that each carbon of
the double bond must have two different substituent groups (one may be hydrogen). This is illustrated by
the following general formulas. In the first example, the left-hand double bond carbon has two identical
substituents (A) so stereoisomerism about the double bond is not possible (reversing substituents on the right-
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hand carbon gives the same configuration). In the next two examples, each double bond carbon atom has two
different substituent groups and stereoisomerism exists, regardless of whether the two substituents on one
carbon are the same as those on the other.

Some examples of this configurational stereoisomerism (sometimes called geometric isomerism) are shown
below. Note that cycloalkenes smaller than eight carbons cannot exist in a stable trans configuration due to
ring strain. A similar restriction holds against cycloalkynes smaller than ten carbons. Since alkynes are linear,
there is no stereoisomerism associated with the carbon-carbon triple bond.

Nomenclature of Alkene Stereoisomers

Configurational stereoisomers of the kind shown above need an additional
nomenclature prefix added to the IUPAC name, in order to specify the
spatial orientations of the groups attached to the double bond. Thus far,
the prefixes cis- and trans- have served to distinguish stereoisomers;
however, it is not always clear which isomer should be called cis and
which trans. For example, consider the two compounds on the right. Both
compound A (1-bromo-1-chloropropene) and compound B ( 1-cyclobutyl-
2-ethyl-3-methyl-1-butene) can exist as a pair of configurational
stereoisomers (one is shown). How are we to name these stereoisomers
so that the configuration of each is unambiguously specified? Assignment of a cis or trans prefix to any of
these isomers can only be done in an arbitrary manner, so a more rigorous method is needed. A completely
unambiguous system, based on a set of group priority rules, assigns a Z (German, zusammen for together)
or E (German, entgegen for opposite) to designate the stereoisomers. In the isomers illustrated above, for
which cis-trans notation was adequate, Z is equivalent to cis and E is equivalent to trans.

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 The Sequence Rule for Assignment of Alkene Configurations

    Assign priorities to double bond substituents by looking at the atoms attached directly to the double bond
carbons.

1. The higher the atomic number of the immediate substituent atom, the higher the priority.
For example, H–  <  C–  <  N–  <  O–  <  Cl–. (priority increases left to right)
(Different isotopes of the same element are assigned a priority according to their atomic mass.)
2. If two substituents have the same immediate substituent atom, move to the next atom (away from the double
bond) until a difference is found.
For example, CH3–  <  C2H5–  <  ClCH2–  <  BrCH2–  <  CH3O–.

Once the relative priorities of the two substituents on each of the double bond carbons has been determined, a
cis orientation of the higher priority pair is designated Z, and a trans orientation is termed E. Applying these
rules to the isomers of compounds A and B shown above, we assign the configuration of the 1-bromo-1-
chloropropene isomer as E (Br has higher priority than Cl, and CH3 a higher priority than H). The configuration
of the 1-cyclobutyl-2-ethyl-3-methyl-1-butene isomer is determined to be Z (C4H7 has higher priority than H, and
the isopropyl group has higher priority than an ethyl group). The following example elaborates the priority
determination for a more complex case.

The line formula is expanded to give the structural formula in the center. The root name is heptene (the longest
chain incorporating both carbons of the double bond), and the substituents (in red) are added to give the
IUPAC name. In order to assign a configurational prefix the priority order of substituents at each double bond
carbon must be determined. For carbon #3 the immediate substituent atoms are a chlorine and a carbon. The
chlorine has a higher atomic number and therefore has higher priority (colored green and numbered 1). The
more remote bromine atom does not figure in this choice. For carbon #4 the immediate substituent atoms are
both carbons (colored orange). As a result, we must look at the next higher atomic number atoms in the
substituent chain. These are also carbon, but the isopropyl group has two carbons (also orange) whereas the
propyl group has only one. The priority order is therefore isopropyl (green) > propyl (magenta). Since the two
higher priority groups (#1) are on the same side of the double bond, this configuration is (Z).

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 Cycloalkane Stereoisomers
Configurational Stereoisomers of Cycloalkanes
Stereoisomers are also observed in certain
disubstituted (and higher substituted) cyclic
compounds. Unlike the relatively flat molecules
of alkenes, substituted cycloalkanes must be
viewed as three-dimensional configurations in
order to appreciate the spatial orientations of
the substituents. By agreement, chemists use
heavy, wedge-shaped bonds to indicate a
substituent located above the average plane of
the ring (note that cycloalkanes larger than
three carbons are not planar), and a hatched
line for bonds to atoms or groups located
below the ring. As in the case of the 2-butene
stereoisomers, disubstituted cycloalkane stereoisomers may be designated by nomenclature prefixes such
as cis and trans. The stereoisomeric 1,2-dibromocyclopentanes shown to the right are an example.
In general, if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms)
stereoisomerism is possible. This is similar to the substitution pattern that gives rise to stereoisomers in
alkenes; indeed, one might view a double bond as a two-membered ring. Four other examples of this kind of
stereoisomerism in cyclic compounds are shown below.

If more than two ring carbons have different substituents (not counting other ring atoms) the stereochemical
notation distinguishing the various isomers becomes more complex.

Conformational Isomerism
Conformational Stereoisomers
Structural formulas show the manner in which the atoms of a molecule are bonded together (its constitution),
but do not generally describe the three-dimensional shape of a molecule, unless special bonding notations
(e.g. wedge and hatched lines) are used. The importance of such three-dimensional descriptive formulas
became clear in discussing configurational stereoisomerism, where the relative orientation of atoms in space is
fixed by a molecule's bonding constitution (e.g. double-bonds and rings). Here too it was noted that
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nomenclature prefixes must be used when naming specific stereoisomers. In this section we shall extend our
three-dimensional view of molecular structure to include compounds that normally assume an array of
equilibrating three-dimensional spatial orientations, which together characterize the same isolable compound.
We call these different spatial orientations of the atoms of a molecule that result from rotations or twisting
about single bonds conformations.

In the case of hexane, we have an unbranched chain of six carbons which is often written as a linear formula:
CH3CH2CH2CH2CH2CH3. We know this is not strictly true, since the carbon atoms all have a tetrahedral
configuration. The actual shape of the extended chain is therefore zig-zag in nature. However, there is facile
rotation about the carbon-carbon bonds, and the six-carbon chain easily coils up to assume a rather different
shape. Many conformations of hexane are possible and two are illustrated below.

Extended Chain Coiled Chain

Ethane Conformers
Ethane Conformations
The simple alkane ethane provides a good introduction to conformational analysis. Here there is only one
carbon-carbon bond, and the rotational structures (rotamers) that it may assume fall between two
extremes, staggered and eclipsed. In the following description of these conformers, several structural
notations are used. The first views the ethane molecule from the side, with the carbon-carbon bond being
horizontal to the viewer. The hydrogens are then located in the surrounding space by wedge (in front of the
plane) and hatched (behind the plane) bonds. If this structure is rotated so that carbon #1 is canted down and
brought closer to the viewer, the "sawhorse" projection is presented. Finally, if the viewer looks down the
carbon-carbon bond with carbon #1 in front of #2, the Newman projection is seen.

Extreme Conformations of Ethane Bond Repulsions in

  Ethane

Name of Wedge-Hatched Sawhorse Newman

Conformer Bond Structure Structure Projection

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To see an eclipsed conformer of ethane orient itself as a Newman projection, and then interconvert with the
staggered conformer and intermediate conformers   .

As a result of bond-electron repulsions, illustrated on the right above, the eclipsed conformation is less stable
than the staggered conformation by roughly 3 kcal / mol (eclipsing strain). The most severe repulsions in the
eclipsed conformation are depicted by the red arrows. There are six other less strong repulsions that are not
shown. In the staggered conformation there are six equal bond repulsions, four of which are shown by the blue
arrows, and these are all substantially less severe than the three strongest eclipsed repulsions. Consequently,
the potential energy associated with the various conformations of ethane varies with the dihedral angle of the
bonds, as shown below. Although the conformers of ethane are in rapid equilibrium with each other, the 3
kcal/mol energy difference leads to a substantial preponderance of staggered conformers (> 99.9%) at any
given time.
Although steric and/or bond electron repulsion remain the most popular explanation for the hindered rotation of
ethane, molecular orbital interactions have also been proposed as a significant factor. For a discussion of this
feature.

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 Dihedral Angle
Potential Energy Profile for Ethane Conformers

The above animation illustrates the relationship between ethane's potential energy and its
dihedral angle

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 Butane Conformers
Butane Conformations
The hydrocarbon butane has a larger and more complex set of conformations associated with its constitution
than does ethane. Of particular interest and importance are the conformations produced by rotation about the
central carbon-carbon bond. Among these we shall focus on two staggered conformers (A & C) and two
eclipsed conformers (B & D), shown below in several stereo-representations. As in the case of ethane, the
staggered conformers are more stable than the eclipsed conformers by 2.8 to 4.5 kcal/mol. Since the
staggered conformers represent the chief components of a butane sample they have been given the identifying
prefix designations anti for A and gauche for C.

Four Conformers of Butane

The following diagram illustrates the change in potential energy that occurs with rotation about the C2–C3
bond. The model on the right is shown in conformation D, and by clicking on any of the colored data points on
the potential energy curve, it will change to the conformer corresponding to that point. The full rotation will be
displayed by turning the animation on. This model may be manipulated by click-dragging the mouse for viewing
from any perspective.

 
Potential Energy Profile for Butane Conformers

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  Spacefill Model
  Stick Model

  Animation on/off

It is useful to summarize some important aspects of conformational stereoisomerism at this

time.

(i)   Most conformational interconversions in simple molecules occur rapidly at room temperature.
Consequently, isolation of pure conformers is usually not possible.
(ii)   Specific conformers require special nomenclature terms such
as staggered, eclipsed, gauche and anti when they are designated.
(iii)   Specific conformers may also be designated by dihedral angles. In the butane conformers shown
above, the dihedral angles formed by the two methyl groups about the central double bond
are: A 180º, B 120º, C 60º & D 0º.
(iv)   Staggered conformations about carbon-carbon single bonds are more stable (have a lower
potential energy) than the corresponding eclipsed conformations. The higher energy of eclipsed bonds
is known as eclipsing strain.
(v)   In butane the gauche-conformer is less stable than the anti-conformer by about 0.9 kcal/mol. This
is due to a crowding of the two methyl groups in the gauche structure, and is called steric
strain or steric hindrance.
(vi)   Butane conformers B and C have non-identical mirror image structures in which the clockwise
dihedral angles are 300º & 240º respectively. These pairs are energetically the same, and have not
been distinguished in the potential energy diagram shown here.

Ring Conformers

Ring Conformations
Although the customary line drawings of simple cycloalkanes are geometrical polygons, the actual shape of
these compounds in most cases is very different.

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Cyclopropane is necessarily planar (flat), with the carbon atoms at the corners of an equilateral triangle. The
60º bond angles are much smaller than the optimum 109.5º angles of a normal tetrahedral carbon atom, and
the resulting angle strain dramatically influences the chemical behavior of this cycloalkane. Cyclopropane also
suffers substantial eclipsing strain, since all the carbon-carbon bonds are fully
eclipsed. Cyclobutane reduces some bond-eclipsing strain by folding (the out-of-plane dihedral angle is about
25º), but the total eclipsing and angle strain remains high. Cyclopentane has very little angle strain (the angles
of a pentagon are 108º), but its eclipsing strain would be large (about 10 kcal/mol) if it remained planar.
Consequently, the five-membered ring adopts non-planar puckered conformations whenever possible. Rings
larger than cyclopentane would have angle strain if they were planar. However, this strain, together with the
eclipsing strain inherent in a planar structure, can be relieved by puckering the ring. Cyclohexane is a good
example of a carbocyclic system that virtually eliminates eclipsing and angle strain by adopting non-planar
conformations, such as those shown below. Cycloheptane and cyclooctane have greater strain than
cyclohexane, in large part due to transannular crowding (steric hindrance by groups on opposite sides of the
ring).

Some Conformations of Cyclohexane Rings

A planar structure for cyclohexane is clearly improbable. The bond angles would necessarily be 120º, 10.5º
larger than the ideal tetrahedral angle. Also, every carbon-carbon bond in such a structure would be eclipsed.
The resulting angle and eclipsing strains would severely destabilize this structure. If two carbon atoms on
opposite sides of the six-membered ring are lifted out of the plane of the ring, much of the angle strain can be
eliminated. This boat structure still has two eclipsed bonds (colored magenta in the drawing) and severe steric
crowding of two hydrogen atoms on the "bow" and "stern" of the boat. This steric crowding is often
called steric hindrance. By twisting the boat conformation, the steric hindrance can be partially relieved, but
the twist-boat conformer still retains some of the strains that characterize the boat conformer. Finally, by lifting
one carbon above the ring plane and the other below the plane, a relatively strain-free chair conformer is
formed. This is the predominant structure adopted by molecules of cyclohexane.
An energy diagram for these conformational interconversions is drawn below. The activation energy for the
chair-chair conversion is due chiefly to a high energy twist-chair form (TC), in which significant angle and
eclipsing strain are present. A facile twist-boat (TB)-boat (B) equilibrium intervenes as one chair conformer (C)
changes to the other.

   
Conformational Energy Profile of Cyclohexane
  TC = twist chair

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 B = boat

TB = twist boat

C = chair

These conformations may be examined as interactive models by .

Investigations concerning the conformations of cyclohexane were initiated by H. Sachse (1890) and E. Mohr
(1918), but it was not until 1950 that a full treatment of the manifold consequences of interconverting chair
conformers and the different orientations of pendent bonds was elucidated by D. H. R. Barton (Nobel Prize
1969 together with O. Hassel). The following discussion presents some of the essential features of
this conformational analysis.
On careful examination of a chair conformation of cyclohexane, we find that the twelve hydrogens are not
structurally equivalent. Six of them are located about the periphery of the carbon ring, and are
termed equatorial. The other six are oriented above and below the approximate plane of the ring (three in
each location), and are termed axial because they are aligned parallel to the symmetry axis of the ring. In the
stick model shown on the left below, the equatorial hydrogens are colored blue, and the axial hydrogens are
red. Since there are two equivalent chair conformations of cyclohexane in rapid equilibrium, all twelve
hydrogens have 50% equatorial and 50% axial character.

Because axial bonds are parallel to each other, substituents larger than hydrogen generally suffer greater
steric crowding when they are oriented axial rather than equatorial. Consequently, substituted cyclohexanes
will preferentially adopt conformations in which large substituents assume equatorial orientation. In the two
methylcyclohexane conformers shown above, the methyl carbon is colored blue. When the methyl group
occupies an axial position it suffers steric crowding by the two axial hydrogens located on the same side of the
ring. This crowding or steric hindrance is associated with the red-colored hydrogens in the structure. A careful
examination of the axial conformer shows that this steric hindrance is due to two gauche-like orientations of the
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methyl group with ring carbons #3 and #5. The use of models is particularly helpful in recognizing and
evaluating these relationships.

These conformations may be examined as interactive models by 

To view an animation of the interconversion of cyclohexane chair conformers 

The relative steric hindrance experienced by different substituent groups oriented in an axial versus equatorial
location on cyclohexane may be determined by the conformational equilibrium of the compound. The
corresponding equilibrium constant is related to the energy difference between the conformers, and collecting
such data allows us to evaluate the relative tendency of substituents to exist in an equatorial or axial location.
A table of these free energy values (sometimes referred to as A values) may be examined by .
Clearly the apparent "size" of a substituent is influenced by its width and bond length to cyclohexane, as
evidenced by the fact that an axial vinyl group is less hindered than ethyl, and iodine slightly less than chlorine.

Substituted Cyclohexanes
Substituted Cyclohexane Compounds
Because it is so common among natural and synthetic compounds, and because its conformational features
are rather well understood, we shall focus on the six-membered cyclohexane ring in this discussion. In a
sample of cyclohexane, the two identical chair conformers are present in equal concentration, and the
hydrogens are all equivalent (50% equatorial & 50% axial) due to rapid interconversion of the conformers.
When the cyclohexane ring bears a substituent, the two chair conformers are not the same. In one conformer
the substituent is axial, in the other it is equatorial. Due to steric hindrance in the axial location, substituent
groups prefer to be equatorial and that chair conformer predominates in the equilibrium.
We noted earlier that cycloalkanes having two or more substituents on different ring carbon atoms exist as a
pair (sometimes more) of configurational stereoisomers. Now we must examine the way in which favorable ring
conformations influence the properties of the configurational isomers. Remember, configurational
stereoisomers are stable and do not easily interconvert, whereas, conformational isomers normally interconvert
rapidly. In examining possible structures for substituted cyclohexanes, it is useful to follow two principles.

(i)   Chair conformations are generally more stable than other possibilities.
(ii)   Substituents on chair conformers prefer to occupy equatorial positions due to the increased steric
hindrance of axial locations.

The following equations and formulas illustrate how the presence of two or more substituents on a cyclohexane
ring perturbs the interconversion of the two chair conformers in ways that can be predicted.

Conformational Structures of Disubstituted Cyclohexanes

1,1-dimethylcyclohexane  

1-t-butyl-1-methylcyclohexane  

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 cis-1,2-dimethylcyclohexane  

trans-1,2-dimethylcyclohexane  

cis-1,3-dimethylcyclohexane  

trans-1,3-dimethylcyclohexane  

cis-1,4-dimethylcyclohexane  

trans-1,4-dimethylcyclohexane  

In the case of 1,1-disubstituted cyclohexanes, one of the substituents must necessarily be axial and the other
equatorial, regardless of which chair conformer is considered. Since the substituents are the same in 1,1-
dimethylcyclohexane, the two conformers are identical and present in equal concentration. In 1-t-butyl-1-
methylcyclohexane the t-butyl group is much larger than the methyl, and that chair conformer in which the
larger group is equatorial will be favored in the equilibrium( > 99%). Consequently, the methyl group in this
compound is almost exclusively axial in its orientation.
In the cases of 1,2-, 1,3- and 1,4-disubstituted compounds the analysis is a bit more complex. It is always
possible to have both groups equatorial, but whether this requires a cis-relationship or a trans-relationship
depends on the relative location of the substituents. As we count around the ring from carbon #1 to #6, the
uppermost bond on each carbon changes its orientation from equatorial (or axial) to axial (or equatorial) and
back. It is important to remember that the bonds on a given side of a chair ring-conformation always

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alternate in this fashion. Therefore, it should be clear that for cis-1,2-disubstitution, one of the substituents
must be equatorial and the other axial; in the trans-isomer both may be equatorial. Because of the alternating
nature of equatorial and axial bonds, the opposite relationship is true for 1,3-disubstitution (cis is all equatorial,
trans is equatorial/axial). Finally, 1,4-disubstitution reverts to the 1,2-pattern.

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