CHAPTER 5

Stereochemistry at
Tetrahedral Centers
Handedness
Right and left hands are not
identical
§ Right and left hands are mirror
images of each other – they are
nonsuperimposable mirror images
§ Almost all the molecules in the
human body are handed
§ Handedness primarily arises from
the tetrahedral stereochemistry of
sp3-hybridized carbon atoms
§ Handedness is crucial to
understanding biological
chemistry
5-1 Enantiomers and the Tetrahedral
Carbon

Molecular handedness
§ Molecules CH3X and
CH2XY are identical to
their mirror images
§ Molecular images can
superimpose on their
mirror images
§ Molecule CHXYZ is not
identical to its mirror
image
§ Molecular image can
not superimpose on its
mirror image
Enantiomers and the Tetrahedral Carbon
Enantiomers

§ From the Greek enantio, meaning “opposite”

§ Stereoisomers in which molecules are not identical to
their mirror images
§ Result whenever a tetrahedral carbon is bonded to four
different substituents CHXYZ (one need not be H)
§ Lactic acid (2-hydroxypropanoic acid) has four different
groups (-H, -OH, -CH3, -CO2H) bonded to the central
carbon atoms and exists as a pair of enantiomers
Enantiomers and the Tetrahedral Carbon

Enantiomers of lactic acid

§ (+)-lactic acid
§ Occurs in muscle tissue
§ Found in sour milk
§ (-)-lactic acid
§ Found in sour milk
Enantiomers and the Tetrahedral Carbon

A molecule of (+)-lactic acid can not superimpose on a

molecule of (-)-lactic acid

Regardless of how the molecules are oriented, they are not

identical
§ When the –H and –OH substituents match up, the –CO2H and
the CH3 substituents do not
§ When –CO2H and the CH3 match up, -H and –OH do not
5-2 The Reason for Handedness in Molecules:
Chirality
Chiral

§ From the Greek cheir meaning “hand”

§ Molecules that are not identical to their mirror images, and
thus exist in two enantiomeric forms
§ A molecule is not chiral (achiral) if it has a plane of
symmetry

Plane of symmetry
§ A plane that cuts through the middle of an object (or
molecule) so that one half of the object is a mirror image of
the other half
The Reason for Handedness in Molecules:
Chirality

a) A markcup has a plane

of symmetry
§ One half of the
markcup is a mirror
image of the other
half
b) A hand does not have
a plane of symmetry
§ One half of the
hand is not a mirror
image of the other
half achiral chiral
The Reason for Handedness in Molecules:
Chirality
Achiral
§ A molecule that has a plane of symmetry in any of its possible conformations
must be identical to its mirror image
§ Propanoic acid, CH3CH2CO2H
§ Has a plane of symmetry and so must be achiral

§ Lactic Acid
§ Has no
plane of
symmetry in
any
conformation
and is chiral
The Reason for Handedness in Molecules:
Chirality
Chirality center (stereocenter)
§ Most common cause of chirality in an organic molecule is
the presence of a tetrahedral carbon atom bonded to four
different atoms or groups
§ The central carbon atom in 5-bromodecane
§ Chirality is a property of the entire molecule
§ Chirality center is the source of chirality
The Reason for Handedness in Molecules:
Chirality
Methylcyclohexane
§ Achiral because there is no carbon atom
in the molecule that is bonded to four
different groups
§ Has a plane of symmetry passing
through the methyl group and through
C1 and C4 of the ring
2-Methylcyclohexanone
§ Chiral because C2 is bonded to four
different groups: a –CH3 group, an –
H atom, a –COCH2– ring
bond (C1) and a –CH2CH2– ring
bond (C3)
§ Has no plane of symmetry
The Reason for Handedness in Molecules:
Chirality
§ Note: Carbons in –CH2, –CH3, C=O, C=C, and C≡C groups
cannot be chirality centers
§ * denotes a chirality center
5.3 Optical Activity
Stereochemistry
§ Study originated in the early 19th century during the
investigations by the French physicist Jean-Baptiste Biot
into the nature of plane-polarized light
§ A beam of ordinary light consists of electromagnetic waves
that oscillate in an infinite number of planes at right angles to
the direction of light travel
§ When a beam of ordinary light passes through a device
called a polarizer only light waves oscillating in a single
plane pass through and the light is plane-polarized
Optically active organic substances
§ Biot observed that when a beam of plane-polarized light
passes through a solution of certain organic molecules,
the plane of polarization is rotated
Optical Activity
Polarimeter
§ Measures the amount (angle) of rotation
§ A solution of optically active organic molecules is placed in a sample tube
§ Plane-polarized light is passed through the tube
§ Rotation of the polarization plane occurs
§ Light goes through a second polarizer called the analyzer
§ The new plane of polarization and degree of rotation can be found by rotating
the analyzer until the light passes through it
§ Angle of rotation is denoted a and is expressed in degrees
Optical Activity
Rotation
§ The amount of rotation observed in a polarimetry experiment
depends on the number of optically active molecules
§ Number of optically active molecules depends on sample
concentration and sample pathlength
§ the pathlength is the length of the sample tube

Assigning direction of rotation

§ Levorotatory molecules
§ Optically active molecules that rotate polarized light to the left
(counterclockwise)
§ Given the symbol (-) as in (-)-morphine
§ Dextrorotatory molecules
§ Optically active a molecules that rotate polarized light to the right
(clockwise)
§ Given the symbol (+) as in (+)-sucrose
Optical Activity
The specific rotation, [a]D

§ Optical rotation expression under standard conditions

§ The observed rotation when light of 589.6 nanometer (nm; 1 nm
= 10-9 m) wavelength is used with a sample pathlength l of 1
decimeter (dm; 1 dm = 10 cm) and a sample concentration C of 1
g/mL
§ Light of 589.6 nm, sodium D line, is the yellow light emitted from
common sodium street lamps
Optical Activity
When optical rotation data are expressed in the standard way the
specific rotation, [a]D , is a physical constant characteristic of a
given optically active compound
§ (+)-lactic acid has [a]D = +3.82
§ (–)-lactic acid has [a]D = –3.82
§ Two enantiomers rotate the plane-polarized light to exactly the
same extent but in opposite directions
Worked Example 5.2
Calculating an Optical Rotation
A 1.20 g sample of cocaine, [a]D = –16, was
dissolved in 7.50 mL of chloroform and placed
in a sample tube having a pathlength of 5.00
cm. What was the observed rotation?

Strategy
a
Since [a]D =
l´c where [a]D = –16, l = 5.00 cm = 0.500 dm
Then a = l ´ c ´ [a]D and C = 1.20 g/7.50 cm3 = 0.160 g/cm3

Solution

a = (0.500) x (0.160) x (-16) = –1.3º

5.4 Pasteur’s Discovery of Enantiomers
Louis Pasteur discovered
enantiomers in 1848 when he
began his study of crystalline
tartaric acid salts derived from
wine
§ He observed that two distinct
kinds of crystals precipitated
from a concentrated solution of
ammonium tartrate
§ The two kinds of crystals
were mirror images
§ Pasteur separated the crystals
into piles of “left-handed”
crystals and “right-handed”
crystals
Pasteur’s Discovery of Enantiomers
Solution of ammonium tartrate
§ The original mixture, a 50 : 50 mixture of right and left, was
optically inactive
§ Solutions of crystals from each of the sorted piles were
optically active
§ Their specific rotations were equal in amount but
opposite in sign

§ Enantiomers, also called optical isomers

§ Have identical physical properties, such as melting and
boiling point
§ Differ in the direction in which their solutions rotate
plane-polarized light
5.5 Sequence Rules for Specifying
Configuration
Configuration
§ The three-dimensional arrangement of substituents at a chirality
center

Cahn-Ingold-Prelog Sequence Rules

§ Used to specify the configuration of a chirality center:
1. Look at the four atoms directly attached to the chirality center and
assign priorities in order of decreasing atomic number
§ The atom with the highest atomic number is ranked first; the
atom with the lowest atomic number (usually hydrogen) is ranked
fourth
§ Heavier isotopes of the same element rank higher than the
lighter isotopes
Sequence Rules for Specifying Configuration
2. If a decision cannot be reached by ranking the first atoms
in the substituents, look at the second, third, or fourth
atoms outward until a difference is found
Sequence Rules for Specifying Configuration
3. Multiple-bonded atoms are equivalent to the same
number of single-bonded atoms
Sequence Rules for Specifying Configuration

Stereochemical configuration around the carbon

§ Once priorities have been assigned to the four groups attached
to the chiral carbon, orient the molecule so that the group of
lowest priority (4) points directly back
§ Look at the three remaining substituents

§ R configuration (Latin rectus, meaning “right”)

§ If a curved arrow drawn from highest to lowest priority (1→2→3)
through substituents is clockwise

§ S configuration (Latin sinister, meaning “left”)

§ If a curved arrow drawn from highest to lowest priority (1→2→3)
through substituents is counterclockwise
Sequence Rules for Specifying Configuration
Sequence Rules for Specifying Configuration
(–)-Lactic acid
Rule 1
§ –OH has priority 1
§ –H has priority 4
Rule 2
§ –CO2H is higher in
priority than –CH3
§ O (the highest
second atom
in –CO2H)
outranks H (the
highest second
atom in –CH3)
Sequence Rules for Specifying Configuration
Both have the S configuration, although one is levorotatory and the other is
dextrorotatory
§ The sign of optical rotation, (+) or (–) is not directly correlated to the R,S
designation
Sequence Rules for Specifying Configuration

Absolute configuration

§ The exact three-dimensional structure of a chiral

molecule
§ They are specified verbally by the Cahn-Ingold-
Prelog R,S convention
§ In 1951, an X-ray spectroscopic method for
determining the absolute spatial arrangement of
atoms in a molecule was found
§ Based on these results, it can be said with a
certainty that the R,S conventions are correct
Worked Example 5.4
Drawing the Three-Dimensional Structure of an Enantiomer
Draw the tetrahedral representation of (R)-2-chlorobutane.
Strategy
§ Begin assigning priorities to the four substituents bonded to the chirality
center:
§ (1) –Cl, (2) –CH2CH3, (3) –CH3, (4) –H
§ To draw a tetrahedral representation of the molecule, orient the lowest-
priority –H group away from you and imagine that the other three groups
are coming out of the page toward you
§ Place the remaining three substituents such that the direction of travel
1→2→3 is clockwise (right turn), and tilt the molecule toward you to
bring the rear hydrogen into view
Solution
5.6 Diastereomers
Molecules with more than one chirality center
§ A molecule with n chirality centers can have up to 2n
stereoisomers (although it may have fewer)

§ Amino acid threonine (2-amino-3-hydroxybutanoic acid)

CH3CH(OH)CH(NH2)COOH
§ Two chirality centers (C2 and C3)
§ Four possible stereoisomers
Diastereomers
The four stereoisomers of 2-amino-3-hydroxybutanoic acid
Diastereomers
The four stereoisomers of 2-amino-3-hydroxybutanoic acid can
be grouped into two pairs of enantiomers
§ The 2R, 3R stereoisomer is the mirror image of 2S, 3S
§ The 2R, 3S stereoisomer is the mirror image of 2S, 3R
Diastereomers
§ Stereoisomers that are not mirror images
§ Enantiomers have opposite configurations at all chirality
centers
§ Diastereomers have opposite configurations at one or more of
the chirality centers but the same configuration at others
§ 2R, 3R stereoisomer and 2R, 3S stereoisomer are
diastereomers because they have the same configuration at
C2 but different configurations at C3.
Diastereomers
§ Of the four stereoisomers of threonine, only the 2S,
3R isomer [a]D = -28.3 occurs naturally in plants and
animals and is an essential human nutrient
§ Most biological molecules are chiral, and usually only
one stereoisomer is found in nature
Diastereomers
Epimers
§ Two diastereomers that differ at only one chirality center but
are the same at all the others
§ Cholestanol and coprostanol are both found in human feces
and both have nine chirality centers
§ Eight of the nine chirality centers are identical, but the one at
C5 is different
§ Cholestanol and coprostanol are epimeric at C5
5.7 Meso Compounds
Tartaric acid
§ An example compound with more than one chirality center
Meso Compounds
§ 2R, 3R and 2S, 3S structures represent a pair of
enantiomers because they are not identical
§ 2R, 3S and 2S, 3R structures are identical
§ The molecule has a plane of symmetry
§ Achiral
Meso Compounds
Meso compounds
§ Compounds that are achiral, yet contain chirality centers
§ Tartaric acid exists as only three stereoisomers: two
enantiomers and one meso form
Meso Compounds
The (+)- and (-)-tartaric acids
§ Have identical melting points, solubilities, and densities
§ Differ in sign of their rotation of plane-polarized light
§ The meso isomer is diastereomeric with the (+) and (-) forms
§ It has no mirror-image relationship to (+)- and (-)-tartaric acids
§ Is a different compound
§ Has different physical properties
Worked Example 5.5
Distinguishing Chiral Compounds from Meso Compounds
Does cis-1,2-dimethylcyclobutane have any chirality centers? Is it chiral?
Strategy
§ To find a chiral center, look for a carbon atom
bonded to four different groups
§ To see whether the molecule is chiral, look for the
presence or absence of a symmetry plane
§ Not all molecules with chirality centers are chiral
overall – meso compounds are an exception
Solution
§ A look at the structure of cis-1,2-
dimethylcyclobutane show that both methyl-bearing
ring carbons (C1 and C2) are chirality centers
§ Overall the compound is achiral because there is a
symmetry plane bisecting the ring between C1 and
C2
§ Cis-1,2-dimethylcyclobutane is a meso
compound
5.8 Racemic Mixtures and the Resolution of
Enantiomers
Racemate or racemic mixture
§ Denoted by either the symbol (±) or the prefix d,l to
indicate an equal mixture of dextrorotatory and
levorotatory forms
§ Show no optical rotation because the (+) rotation form one
enantiomer exactly cancels the (–) rotation from the other
§ Pasteur started with a 50 : 50 mixture of the two chiral
tartaric acid enantiomers
§ He was able to resolve, or separate, the racemic tartaric
acid into its (+) and (–) enantiomers
Racemic Mixtures and the Resolution of
Enantiomers
The most common method of resolution uses an acid-base reaction
between the racemate of a chiral carboxylic acid (RCO2H) and an amine
base (RNH2) to yield an ammonium salt

§ Reaction of the
racemate of a chiral
acid, lactic acid, and
an achiral amine base,
methylamine, CH3NH2
§ The product is an
unresolvable 50 :
50 mixture of
methylammonium
(+)-lactate and
methylammonium
(–)-lactate
Racemic Mixtures and the Resolution of
Enantiomers
Reaction of the racemate of lactic acid and a single enantiomer of a
chiral amine base (R)-1-phenylethylamine
§ (+)- and (–)-lactic acids react with (R)-1-phenylethylamine to give an
R,R ammonium salt and an S,R ammonium salt
§ Ammonium salts are separated as two different diastereomers with
different chemical and physical properties
5.9 A Review of Isomerism
Isomers are compounds that have the same chemical formula
but different structures
A Brief Review of Isomerism
Two fundamental types of
isomers:
1. Constitutional isomers
Compounds whose atoms
are connected differently
Kinds of constitutional
isomers:
Skeletal isomers,
Functional isomers,
Positional isomers
2. Stereoisomers
§ Compounds whose atoms are connected in the same order but with a
different geometry
§ Enantiomers
A Brief Review of Isomerism
§ Diastereomers

§ Cis-trans isomers are non-mirror-image stereoisomers

5.10 Chirality at Nitrogen, Phosphorus, and
Sulfur
The most common cause for chirality is the presence of four different substituents
bonded to a tetrahedral atom
§ The atom does not necessarily have to be a carbon
§ A nonbonding pair can be a substituent
§ Nitrogen, phosphorus and sulfur can all be chiral centers
Trivalent nitrogen compounds
§ Undergo a rapid umbrella-like
inversion that interconverts
enantiomers
§ Except for in special cases,
individual enantiomers cannot be
isolated

Trivalent phosphorus compounds or phosphines

§ The inversion at phosphorus is substantially
slower than inversion at nitrogen
§ Stable chiral phosphines can be isolated
§ (R)- and (S)-methylpropylphenylphosphine
are configurationally stable at 100 ºC
Chirality at Nitrogen, Phosphorus, and Sulfur
Trivalent sulfur compounds called sulfonium salts (R3S+) can be chiral
§ Undergo relatively slow inversions
§ Chiral sulfonium salts are configurationally stable and can be isolated
§ Coenzyme S-adenosylmethionine is involved in many metabolic pathways
as a source of CH3 groups
§ The “S” in S-adenosylmethionine stands for sulfur and means that the
adenosyl group is attached to the sulfur atom of methionine
§ The molecule has (S) stereochemistry at sulfur, its (R) enantiomer is
also known, but has no biological activity
5.11 Prochirality
Prochiral molecule
§ A molecule that can be converted from achiral to chiral in a single chemical step
§ An unsymmetrical ketone, butan-2-one, is prochiral because it can be
converted to the chiral alcohol butan-2-ol by addition of hydrogen

The enantiomer formed depends upon which face of the planar sp2-hybridized
carbonyl group undergoes reaction
§ The stereochemical descriptors Re and Si are used to distinguish possibilities
1. Assign priorities to the three groups attached to the trigonal, sp2-
hybridized carbon
2. Imagine curved arrow from the highest to second-highest to third-highest
priority substituent
Prochirality
§ Re designator is used on the face where the arrows curve
clockwise
§ Addition of hydrogen from the Re faces gives (S)-butan-2-ol
§ Si designator is used to the face where the arrows curve
counterclockwise
§ Addition of hydrogen from the Si faces gives (R)-butan-2-ol
Prochirality
Compounds with tetrahedral, sp3-hybridized atoms can also be
prochiral

Prochirality center
§ An atom in a compound that can be converted into a chirality center
by changing one of its attached substituents
§ An sp3-hybridized atom is a prochirality center if changing one of its
attached groups makes it a chirality center

§ -CH2OH carbon atom

of ethanol
§ Changing one of its
attached –H atoms
converts it into a
chirality center
Prochirality
Distinguishing between two identical atoms (or groups) on a
prochirality center
§ Imagine raising the priority of one atom over the other without affecting
its priority with respect to other attached groups
§ On the –CH2OH carbon of ethanol, imagine replacing one of the 1H
atoms (protium) by 2H (deuterium)
§ The atom whose replacement leads to an R chirality center is
said to be pro-R
§ The atom whose replacement leads to an S chirality center is
said to be pro-S
Prochirality
Many biological reactants involve prochiral compounds
§ One of the steps in the citric cycle is the addition of H2O to
fumarate to give malate
§ Addition of –OH occurs on the Si face of fumarate and gives
(S)-malate as product
Prochirality
§ Alcohol dehydrogenase occurs during the reaction of
ethanol with coenzyme NAD+ catalyzed by yeast
§ Occurs with exclusive removal of the pro-R hydrogen from
ethanol and with addition only to the Re face of NAD+
5.12 Chirality in Nature and Chiral
Environments
Enantiomers of a chiral molecule
§ Have same physical properties
§ Usually have different biological properties
§ (+) enantiomer of limonene has the odor of oranges
§ (–) enantiomer of limonene has the odor of lemons
Chirality in Nature and Chiral Environments
Dramatic examples of how a change in chirality can affect the biological
properties of a molecule are seen in many drugs
§ Fluoxetine, a heavily prescribed medication sold under the trade name
Prozac
§ Racemic
fluoxetine is an
effective
antidepressant but
has no activity
against migraine
§ The pure S
enantiomer works
well in preventing
migraine
Chirality in Nature and Chiral Environments

To have a biological effect, a substance typically must fit into

an appropriate receptor that has an exactly complementary
shape
§ Biological receptors (such as enzymes) are chiral
§ Only one enantiomer of a chiral substrate can fit into the
receptor
§ The mirror-image enantiomer (b) will be a misfit