CHAPTER THREE

Stereochemistry
3.1.Introduction

 Why can’t you put your right shoe on your left foot?

 Why can’t you put your right glove on your left hand?

 It is because hands, feet, gloves, and shoes have right-handed and left-

handed forms.

 An object with a right-handed and a left-handed form is said to be chiral

(ky-ral).

 “Chiral” comes from the Greek word cheir, which means “hand”.

 A chiral object has a nonsuperimposable mirror image.

 In other words, its mirror image is not the same as itself.

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Chiral and achiral objects

 A hand is chiral because if you look at your left hand in a mirror, you do
not see your left hand; you see your right hand.
 In contrast, a chair is not chiral (achiral)—it looks the same in the
mirror and it has a superimposable mirror image.

Chiral object- not superimposable Achiral object- superimposable

on its mirror image on its mirror image
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Chiral and achiral molecules
 Chiral molecules have an asymmetric center.

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Asymmetric Center versus Stereocenter

 Such carbons are referred to as chirality centers, although other terms such as
stereocenter, asymmetric center, and stereogenic center have also been used.
 Asymmetric center: an atom attached to four different groups while stereocenter
is an atom at which the interchange of two groups produces a stereoisomer.
 Note that chirality is a property of the entire molecule, whereas a chirality center
is the cause of chirality.
 For example, 5-bromodecane is a chiral molecule because four different groups
are bonded to C5, the chirality center.

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Plane of Symmetry
 How can you predict whether a given molecule is or is not chiral?
 A molecule is not chiral if it has a plane of symmetry.
 A plane of symmetry is a plane that cuts through the middle of a molecule (or any
object) in such a way that one half of the molecule or object is a mirror image of
the other half.
 For example, 2,3-dibrombutane has two asymmetric centers.

 A molecule that has a plane of symmetry in any conformation must be identical to

its mirror image and hence must be non chiral, or achiral. 5
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3.2. Enantiomers (optical isomerism, nomenclature of enantiomers)

 Handedness is also important in organic and biological chemistry, where it arises

primarily as a consequence of the tetrahedral stereochemistry of sp3 -hybridized
carbon atoms.

 Many drugs and almost all the molecules in our bodies—amino acids,
carbohydrates, nucleic acids, and many more—have a handedness.

 Stereochemistry is the field of chemistry that deals with the structures of

molecules in three dimensions; it is the arrangement of atoms in space.

 Molecules that are not identical to their mirror images are a kind of stereoisomer
called enantiomers (Greek enantio, meaning “opposite”).

 Enantiomers are related to each other as a right hand is related to a left hand and
result whenever a tetrahedral carbon is bonded to four different substituents.
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 The two isomers of 2-bromobutane are called enantiomers (nonsuperimposable

mirror images molecules) and they are different compounds.
 Enantiomers have the same physical (except optical activity direction) and
chemical properties.
Nomenclature of Enantiomers
 Chemists use the letters R and S to indicate the configuration about an
asymmetric carbon.
 For any pair of enantiomers with one asymmetric carbon, one will have the R
configuration and the other will have the S configuration.
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 The R, S system was devised by Cahn, Ingold, and Prelog, so it is called the Cahn–
Ingold–Prelog rules (CIP system) and these rules the following sequences rules.
Sequence rules for specifying configuration (IUPAC name)
Rule 1
 Look at the four atoms directly attached to the chirality center, and rank
them according to atomic number.

 The atom with the highest atomic number has the highest ranking (first), and the
atom with the lowest atomic number (usually hydrogen) has the lowest ranking
(fourth).

 When different isotopes of the same element are compared, such as tritium (3H)
deuterium ( 2H) and protium (1H), the heavier isotope ranks higher than the lighter
isotope (by atomic mass).

 Thus, atoms commonly found in organic compounds have the following order.
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Rule 2
 If a decision can’t be reached by ranking the first atoms in the substituent (if
there is tie), look at the second, third, or fourth atoms away from the chirality
center until the first difference is found.

 A -CH2CH3 substituent and a -CH3 substituent are equivalent by rule 1 because

both have carbon as the first atom.

 By rule 2, however, ethyl ranks higher than methyl because ethyl has a carbon as
its highest second atom, while methyl has only hydrogen as its second atom.

 Look at the following example to see how the rule works:

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Rule 3
 Multiple-bonded atoms are equivalent to the same number of single bonded
atoms.
 For this method, imagine that each pi bond is broken and the atoms at both ends
duplicated.
 Note that when you break a bond, you always add two imaginary atoms.

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 The lowest ranking (4) points directly away from us.

 If a curved arrow drawn from the highest to second-highest to third-highest

ranked substituent (1→2→3) is clockwise, we say that the chirality center has
the R configuration (Latin rectus, meaning “right”).

 If an arrow from 1→2→3 is counterclockwise, the chirality center has the S

configuration (Latin sinister, meaning “left”).

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 First, let’s look at how you can determine the configuration of a compound drawn
as a perspective formula.
 As an example, we will determine which of the enantiomers of 2-bromobutane
has the R configuration and which has the S configuration.

1. Rank the groups (or atoms) that are bonded to the asymmetric carbon in order of
priority.
 In the following pair of enantiomers, bromine has the highest priority (1), the
ethyl group has the second highest priority (2), the methyl group is next (3), and
hydrogen has the lowest priority (4).

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2. If the group (or atom) with the lowest priority is bonded by a hatched wedge, draw
an arrow from the group (or atom) with the highest priority (1) to the group (or
atom) with the second highest priority (2).
 If the arrow points clockwise, the compound has the R configuration, and if it
points counterclockwise, the compound has the S configuration.

3. If the group with the lowest priority (4) is NOT bonded by a hatched wedge, then
interchange two groups so group 4 is bonded by a hatched wedge.
 Then proceed as in step #2 (above): Draw an arrow from the group (or
atom) with the highest priority (1) to the group (or atom) with the second
highest priority (2).
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 So if the arrow points clockwise, the enantiomer (with the interchanged groups)
has the R configuration, which means the original molecule has the S
configuration, if the arrow points counterclockwise, the enantiomer (with the
interchanged groups) has the S configuration, which means the original molecule
has the R configuration.

4. In drawing the arrow from group 1 to group 2, you can draw past the group with
the lowest priority (4), but never draw past the group with the next lowest priority
(3).

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3.3. Optical Activity
 Polarimetry is a common method used to distinguish between enantiomers,
based on their ability to rotate the plane of polarized light in opposite directions.

 Plane polarized light is composed of waves that vibrate in only one plane.

 When polarized light passes through a solution containing a chiral compound, the
chiral compound causes the plane of vibration to rotate.

 Rotation of the plane of polarized light is called optical activity, and substances
that rotate the plane of polarized light are said to be optically active.

 Before the relationship between chirality and optical activity was known,
enantiomers were called optical isomers because they seemed identical except
for their opposite optical activity.

 This ambiguous term has been replaced by the well-defined term enantiomers.
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 Enantiomeric compounds rotate the plane of polarized light by exactly the same
amount but in opposite directions.
 If the (R) enantiomer rotates the plane 30° clockwise, the (S) enantiomer will rotate it
30° counterclockwise.
 Compounds that rotate the plane of polarized light toward the right (clockwise) are
called dextrorotatory, from the Latin word dextro, meaning “toward the right.”
 Compounds that rotate the plane toward the left (counterclockwise) are called
levorotatory, from the Latin word levo, meaning “toward the left.”
 These terms are sometimes abbreviated by a lowercase d or l.
 Using IUPAC notation, the direction of rotation is specified by the (+) or (-) sign of
the rotation:
 We cannot predict which direction (clockwise or counterclockwise), (a particular
enantiomer [either (R) or (S)] will rotate the plane of polarized light.
 R and S are simply names, but the direction and magnitude of rotation are physical
properties that must be measured. 16
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 A polarimeter measures the rotation of polarized light.

Specific Rotation
 A measure of a compound’s ability to rotate the plane of polarized light.
 It is measured in degree and calculated by the following formula.

where α (observed) = rotation observed in the polarimeter

c = concentration in g/mL
l = length of sample cell in (dm)
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Example
 When one of the enantiomers of butan-2-ol is placed in a polarimeter, the
observed rotation is 4.05° counterclockwise. The solution was made by diluting
6.00 g of butan-2-ol to a total of 40.0 mL, and the solution was placed into a
200-mm polarimeter tube for the measurement. Determine the specific rotation
for this enantiomer of butan-2-ol.
Solution
 Since it is levorotatory, this must be (-)-butan-2-ol. The concentration is 6.00 g
per 40.0 mL = 0.150 g/mL and the path length is 200 mm = 2.00 dm.

 The specific rotation (α) is –13.5°.

 “25” means that the measurement was made at 25°C, and the “D” means that the
light used was the D line of the sodium spectrum.
 Without even measuring it, we can predict that the specific rotation (α) of the
other enantiomer of butan-2-ol will be +13.5°.
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Racemic mixtures
 Suppose we had a mixture of equal amounts of (+)-butan-2-ol and (-)-butan-2-ol.
 The (+) isomer would rotate polarized light clockwise with a specific rotation of
+13.5° and the (-) isomer would rotate the polarized light counterclockwise by
exactly the same amount, -13.5°.
 We would observe a rotation of zero, just as though butan-2-ol were achiral, but
butan-2-ol is chiral.
 A solution of equal amounts of two enantiomers, so that the mixture is optically
inactive, is called a racemic mixture.
 Sometimes a racemic mixture is called a racemate, a (±) pair, or a (d, l) pair.
 For example, racemic butan-2-ol would be symbolized by “(±)-butan-2-ol” or
“(d,l)-butan-2-ol.”

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3.4. Fischer projections

 Chemists draw enantiomers using either perspective formulas or Fischer
projections.
 Perspective formulas show two of the bonds to the asymmetric carbon in the
plane of the paper, one bond as a solid wedge protruding out of the paper, and
the fourth bond as a hatched wedge extending behind the paper.
 You can draw the first enantiomer by putting the four groups bonded to the
asymmetric carbon in any order.
 Draw the second enantiomer by drawing the mirror image of the first
enantiomer.

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 A shortcut—called a Fischer projection—for showing the three-dimensional
arrangement of groups bonded to an asymmetric carbon was devised in the late
1800s by Emil Fischer.

 They are most useful for compounds with two or more asymmetric carbon atoms.

 Asymmetric carbons are at the centers of crosses.

 The vertical lines project away from the viewer, the horizontal lines toward the
viewer (like a bow tie ).

 The carbon chain is placed along the vertical, with the IUPAC numbering from
top to bottom.
 In most cases, this places the more oxidized end (the carbon with the most bonds
to O or halogen) at the top (C1).
 The entire projection can be rotated 180° (but not 90°) in the plane of the
paper without changing its stereochemistry.
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 Draw the first enantiomer by arranging the four atoms or groups bonded to the
asymmetric carbon in any order.
 Draw the second enantiomer by interchanging two of the atoms or groups,
interchanging any two groups on an asymmetric carbon (for example, those on
the horizontal line) inverts its stereochemistry.
 Note that interchanging two atoms or groups gives you the enantiomer—whether
you are drawing perspective formulas or Fischer projections.

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Assigning (R) and (S) Configurations from Fischer Projections
 The Cahn–Ingold–Prelog convention, can be applied to structures drawn using
Fischer projections.
 When naming (R) and (S) from Fischer projections with the hydrogen on a
horizontal line (toward you instead of away from you), just apply the normal
rules backward.
 In the Fischer projection, the carbon chain is along the vertical line.
 As an example, consider the Fischer projection formula of one of the
enantiomers of glyceraldehyde.
 If the molecule is turned over so the hydrogen is in back, the arrow is clockwise,
so this is the (R) enantiomer of glyceraldehyde.

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3.5. Multiple Asymmetric Centers
 Many organic compounds have more than one asymmetric carbon.

 If we know how many asymmetric carbons a compound has, we can calculate the
maximum number of stereoisomers for that compound.

 A compound with n asymmetric carbon atoms might have as many as has 2n

stereoisomers.

 This formula is called the 2n rule, where n is the number of chirality centers
(usually asymmetric carbon atoms).

 We may not always find 2n isomers, especially when two of the asymmetric
carbon atoms have identical substituents.

 When compounds have two or more chiral centers they have enantiomers,
diastereomers, or meso isomers.
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Compounds with Two Asymmetric Centers

 The 3-chloro-2-butanol has two asymmetric centers, so it has 22 = 4

stereoisomers.

1 and 2 are enantiomers 3 and 4 are enantiomers

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 In the stereoisomers with two adjacent asymmetric carbons, the enantiomers with
similar groups on the same side of the carbon chain are called the erythro
enantiomers.
 Those with similar groups on opposite sides are called the threo enantiomers.

Fisher projections of the stereoisomers of 3-chloro-2-butanol

perspective formulas of the stereoisomers of 3-chloro-2-butanol

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Diastereomers
 Diastereomers are stereoisomers that are not enantiomers (stereoisomers that are
not mirror images).

1 and 2 are enantiomers 3 and 4 are enantiomers

1 and 3 are diastereomers 2 and 3 are diastereomers
1 and 4 are diastereomers 2 and 4 are diastereomers

 Most diastereomers are either geometric isomers or compounds containing two

or more chirality centers.
 Diastereomers have different physical and chemical properties.
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The cis stereoisomers are The trans stereoisomers are

a pair of enantiomers. a pair of enantiomers.

 There are two asymmetric centers, four stereoisomers.

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Meso Compounds
 Compounds that are achiral even though they have asymmetric carbon atoms
are called meso compounds.

 The term meso (Greek, “middle”) was used to describe an achiral member of a
set of diastereomers, some of which are chiral.

 The optically inactive isomer seemed to be in the “middle” between the

dextrorotatory and levorotatory isomers.

 The definition just given (“an achiral compound with chirality centers”) is
nearly as complete, and more easily applied.

 The (2R,3S) isomer of 2,3-dibromobutane is a meso compound; most meso

compounds have this kind of symmetric structure, with two similar halves of the
molecule having opposite configurations.
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 The 2,3-dibromobutane has fewer than 2n stereoisomers.
 There are only three stereoisomers of 2,3-dibromobutane because two of the four
structures are identical.
 The diastereomer on the right is achiral, having a mirror plane of symmetry.
 The asymmetric carbon atoms have identical substituents, and the one with (R)
configuration reflects into the other having (S) configuration.
 It has two asymmetric carbons (C2 and C3), so the 2n rule predicts a maximum of
four stereoisomers.
 The four permutations of (R) and (S) configurations at C2 and C3 are shown next.

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Naming Stereoisomers of more than one asymmetric centers
 If a molecule has more than one asymmetric centers, the steps used to determine
R and S configurations must be applied separately to each center.
 It is important to remember to place the group with the lowest priority in the
back, this is the case for the carbon on the left.
 So two of the groups are switched placing the group with the lowest priority in
the back.
 The configuration is then determined mentally (here “S”) and switched (back to
“R”) to take into account that the groups were switched to permit the
determination

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Compounds with Three Asymmetric center
 How many isomers does 2,3,4-trichlorohexane
have?
 Since there are three asymmetric centers,
it has 23 = 8 stereoisomers.

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Four asymmetric centers

 In carbohydrate, (+) D-glucose
there four asymmetric centers,
so it has 24 = 16 stereoisomers

Eight asymmetric centers

 Cholesterol has eight chiral centers (stars represent chiral center), so it has
28 = 256 possible stereoisomers, (only one of which is naturally occurring)

*CH3
H
CH H * *
3
* *
* * H *H
HO
H
Cholesterol
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3.6. Prochirality
 A molecule that is achiral but that can become chiral by a single alteration is a
prochiral molecule.

 Attack by hydride from the top “re” face produces (S)-2-butanol.

 Attack by hydride from the top “si” face produces (R)-2-butanol.

 An sp3 carbon with two groups that are the same is a prochirality center

 If the center becomes R the group is pro-R and pro-S if the center becomes S
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3.7. Conformational isomerism
 Carbon–carbon single bonds in alkanes are formed by s overlap of carbon sp3
hybrid orbitals.
 Rotation is possible around s bonds because of their cylindrical symmetry, and
alkanes therefore exist in a large number of rapidly interconverting
conformations.
 The different arrangements of atoms that result from bond rotation are called
conformations, and molecules that have different arrangements are called
conformational isomers, or conformers.
 In ethane for example, the two-carbon alkane, is composed of two methyl groups
with overlapping sp3 hybrid orbitals forming a sigma bond between them.

 The two methyl groups are not fixed in a single position but are relatively free to
rotate about the sigma bond connecting the two carbon atoms.
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 Perspective formulas, sawhorse projections, and Newman projections are
methods chemists commonly use.

 Rotation about a C-C bond results in two extreme conformations that rapidly
interconvert: staggered and eclipsed.

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 The electrons in a C-H bond will repel the electrons in another bond if the bonds
get too close to each other.
 In a perspective formula, solid lines are used for bonds that lie in the plane of
the paper, solid wedges for bonds protruding out from the plane of the paper, and
hatched wedges for bonds extending behind the paper.
 In a sawhorse projection, you are looking at the carbon–carbon bond from an
oblique angle.

 In a Newman projection, you are looking down the length of a particular

carbon–carbon bond.

 The carbon in front is represented by the point at which three bonds intersect, and
the carbon in back is represented by a circle.

 The three lines emanating from each of the carbons represent its other three
bonds.
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 The electrons in a C-H bond will repel the electrons in another C-H bond if the
bonds get too close to each other.
 The staggered conformation, therefore, is the most stable conformation of
ethane because the C-H bonds are as far away from each other as possible.
 There can be two different staggered conformers: anti conformer and gauche
conformer.
 Anti conformation, is the one in which the two methyl groups are as far apart as
possible—180° away from each other (e.g. two methyl groups of butane).
 Gauche conformer where the methyl groups are 60° apart ( e.g. two methyl
groups of butane)
 The anti conformer is more stable than the gauche conformer because of steric
strain.

Newman projection of butane Newman projection of butane

-anti conformation -gauche conformation
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 Cyclohexane rapidly interconverts between two stable chair conformations by

ring flip to form axial bonds and equatorial bonds.
 In axial bonds, the six axial bonds, one on each carbon, are parallel and alternate
up–down and in equatorial bonds, the six equatorial bonds, one on each carbon,
come in three sets of two parallel lines.

Axial bonds Three sets of equatorial bonds

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 Cyclic compounds twist and bend in order to attain a structure that minimizes the
three different kinds of strain that can destabilize a cyclic compound:
1. Angle strain is the strain induced in a molecule when the bond angles are different
from the ideal tetrahedral bond angle of 109.5°.
2. Torsional strain is caused by repulsion between the bonding electrons of one
substituent and the bonding electrons of a nearby substituent.
3. Steric strain is caused by atoms or groups of atoms approaching each other too
closely.
 Five- and six-membered rings are more stable than three- and four-membered
rings because of angle strain.
 Cycloalkanes form chair and boat conformers.
 In the chair conformer of cyclohexane, all the bond angles are 111°, which is very
close to the ideal tetrahedral bond angle of 109.5°, and all the adjacent bonds are
staggered.
 The boat conformer is further destabilized by the close proximity of the flagpole
hydrogens (the hydrogens at the “bow” and “stern” of the boat), which causes
steric strain.
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