CHM 222: Organic Chemistry II

STEREOCHEMISTRY

- Stereoisomers
- Geometric isomers
- Optical isomers
- Chirality
- Relative and absolute configuration
STEREOCHEMISTRY
Stereochemistry refers to chemistry in three
dimensions (stereo – three-dimension).

C C
C
 ISOMERS
[Different compounds with
Same molecular formula]

Constitutional isomers Stereoisomers

[Isomers whose atoms have a [Isomers that have the same connect-
different connectivity] ivity but that differ in the arrangement
of atoms in space]

Enantiomers Diastereomers Geometric isomers

[Stereoisomers that are nonsuper- [Stereisomers that are not [Isomers that differ only in the
imposable mirror image of mirror images of each other] spatial orientation of groups
each other plane or direction]
 Constitutional isomers
Molecular formula
CH3
C4H10
CH3CH2CH2CH3 and CH3CHCH3
Butane
2-methylpropane

C3H7Cl CH3CH2CH2Cl Cl
and
1-chloropropane
CH3CHCH3
2-chloropropane

C2H6O CH3CH2OH and CH3OCH3

 Geometric isomers
• Geometric isomers (or cis–trans isomers) differ only
in the spatial orientation of groups about a plane or
direction.
• Two geometric isomers have the same molecular
formula, the same functional groups, the same base
chain or ring, and the same order of attachment of
atoms; they differ in orientation either (1) around a
double bond or (2) across the ring in a cyclic
compound.
• If the larger groups are on opposite sides of the ring
or the double bond, the designation trans appears in
the name; if they are on the same side, the
designation is cis.
 CH2CH3
H3C CH2CH3 H
C C
C C
H3C H
H H
cis-2-pentene trans-2-pentene

H Br

H H H
Br

Cl
Cl trans-1-bromo-3-chlorocyclobutane
cis-1-bromo-3-chlorocyclobutane

H CH 3
H H

H 3C CH 3 H 3C H

cis-1,4-dimethylcyclohexane trans-1,4-dimethylcyclohexane
 MOLECULAR CHIRALITY

x Br

w C y F C Cl

z H

Chirality centre (or chiral carbon or asymetrical

carbon/centre) is a tetrahedra atom bonded to four
different groups.
Identify the chirality centre (if any) in the
following compounds:
1. 2-Butanol

2. 2-Propanol

3. 2-Bromopentane

4. 3-Bromopentane
Identify the chirality centre (if any) in the cyclic
compounds below:
1. OH 2. OH
H H
1
1
5 2 5 2 5 2
3 4
4 3 3
4
2-Cyclopentenol 3-Cyclopentenol

3. 1,1,2-Trimethylcyclobutane

4. 1,1,3-trimetylycyclobutane.
Isomers with one Chiral carbon

C H 3 C* H C H 2 C H 3

Br
2 -b r o m o b u ta n e

Br Br

C C
H H C H 2C H 3
C H 3C H 2 CH3
CH3

Enantiomers
To draw the stereorepresentation for enantiomers;

CH3
OH
CH3CH2CHCH2OH
CH3CH2CHCH3
(b)
(a)
 Step 1: OH
Locate the chiral carbon/centre;
CH3CH2CHCH3
*
Step 2:
Draw the four groups attached to the chiral carbon/centre;

CH3

C
C

H CH2CH3
OH
Step 3:
Draw its mirror image

CH3 CH3

C C
H CH2CH3 H
OH CH3CH2
OH

Mirror

Exercise:
Draw the stereopresentation for compound (b) above
Molecules with Two or more Chiral Carbon

(A) Enantiomers and Diastereoisomers.

Compounds that contain two or more chiral carbons can
exist in more than two optical isomers.
The maximum number of optical isomers is 2n (n =
number of chiral carbons). E.g.

CH2 *CH *CH CHO

OH OH OH
2,3,4 -Trihydroxybutanal
There are 22 = 4 optical isomers
 CHO CHO
CHO CHO
H C OH HO C H HO C H H OH
C
H C OH HO C H H C OH HO C H
CH2OH CH2OH CH2OH CH2OH
(a)
(b) (c) (d)

A pair of enantiomers (Erythrose)

A 2nd pair of enantiomers (Threose)
(a) & (b) ; (c) & (d): enantiomers
(a) & (c) ; (a) & (d) ; (c) & b; (c) & (a) :
diastereoisomer.
Enantiomers are optical isomers that are
nonsuperimposable mirror images of each other.
Diastereoisomer are optical isomers that are not mirror
images of each other.
(B) Meso compounds

CO2H CO2H CO2H CO2H

H C OH HO C H H C OH HO C H
HO C H H C OH H C OH HO C H
CO2H CO2H CO2H CO2H
(a) (b) (c) (d)

A pair of enantiomers A meso compound

The 3 optical isomers of tartaric acid. [(c) and (d) are superimposable]

A structure that contains two or more chiral carbons but is

superimposable on its mirror image is called a meso
compound.
Naming the Enantiomers by the R, S system
[The Cahn-Ingold-Prelog R-S notational system]

According to this nomenclature, one enantiomer in

the pair is designated S, the other R.
[R comes from the Latin rectus for right, and S from
the Latin sinister for left].

The (R) and (S) configurations are assigned on the

basis of the following rules:
 Identify the substituents at the chirality centre and
assigned a priority or ranked them in order of
decreasing/increasing atomic number (a,b,c,d or 1,2,3,4).
If isotopes are involved, the isotope of greatest atomic
mass has the highest priority.
C =O O

H C OH OH CH CH2OH H
(1) (2) (3) (4)

C H 2O H

 If priority cannot be given based on the atoms directly

attached to the stereocenter, the next set of atoms
attached to the unassigned groups is examined. In other
words, priority is assigned at the first point of difference.
E.g. -Cl-H; -CH2-OH; -CH2-NH2; -CH2-CH3; -CH2-H
 A double bond is considered to be bonded to an
equivalent number of similar atoms by single bonds.

O
O
C O H
COH is equivalent to
O

O O

C C H
H is equivalent to
O
 Orient the molecule so that the lowest ranked substituent
points away from you. (this is the imaginary rotation of
the molecule such that the group with lowest priority is
directed away from the observer).

If the order of decreasing precedence of the three highest

ranked substituents appears in a clockwise sense, the
absolute configuration is R. If the order of decreasing
precedence is counterclockwise, the absolute configuration
is S.
Assign absolute configuration as R or S to each of
the following compounds

OH Br H

C C C
H CH2CH3 CH3
CH3CH2 H Br
CH3CH2Br CH3 COOH

RRS
Indicate the configuration of each of the following structures:
A)
Br B) H

C C
CH2CH2CH3 CH2CH2CH2CH3
H Br
CH3 COOH

Cl
D)
C)

OH
Draw the perspective formulas for the following:

a) (S)-2-chlorobutane
b) (S)-1,2-dibromobutane

C
 Absolute And Relative Configuration
The spatial arrangement of substituents at a chirality centre
is its absolute configuration.
Relative configuration compares the arrangement of atoms
in space to some reference.
Absolute configuration is an exact description of the
arrangement of atoms in space.
CO2H
CO2H
C
C
H3C H CH3
H
OH OH
Enantiomers of lactic acid
 Exercise
Assign absolute configuration as R or S to each of the
following compounds
1 O

CH

H C OH

CH2OH
(+)-glyceraldehyde
Solution
1st: Rank the groups attached to the chiral carbon in order
of priority. For (+)-glyceraldehyde, the order is
O

OH CH CH2OH H
(1) (2) (3) (4)

2nd: Turn the molecule in space so that the group of lowest

priority (-H) is away from you and the remaining three
groups face you.

3rd: Draw an arrow from group of highest priority (-OH)

to the group of 2nd-highest priority (-CHO) and then to the
group of 3rd-highest priority (-CH2OH).
For (+)-glyceraldehyde, the arrow turns clockwise,
and therefore the configuration of this enantiomer is
R.
(2)
CHO
CHO
clockwise
turn in clockwise
space
H C OH C H

CH2OH
HO
CH2OH
(1)
(3)
OH

R-(+)-glyceraldehyde
 D and L configuration
Another convention involving the use of letter D and L was
proposed by Emil Fischer to deal with the absolute
configuration of carbohydrates.
CHO CHO

H C OH HO C H

CH2OH CH2OH

D-glyceraldehyde L-glyceraldehyde
The enantiomers of glyceraldehyde
Fischer convention has been modified as follows;
CHO CHO

H OH HO H

CH2OH CH2OH

D-glyceraldehyde L-glyceraldehyde
(R-glyceraldehyde) (S-glyceraldehyde)
To determine the configurationn of a compound
drawn as a Fisher projection
 Rank the groups (or atoms) that are bonded to
the asymmetric centre in order of priority.
 Draw an arrow from the group (or atom) with
the highest priority (1) to the next highest priority
(2). If the arrow points clockwise, the enantiomer
has an R configuration; if it points
counterclockwise, the enantiomers has the S
configuration, provided the group with lowest
priority (4) is on a vertical bond.
 If the group (or atom) with the lowest priority is
on a horizontal bond, the naming will be opposite
the correct answer.
D-glyceraldehyde and L-glyceraldehyde serve as reference
points for the assignment of configuration to all other
aldoses and ketoses.

Those that have the same configuration as D-

glyceraldehyde about the chiral carbon farthest from the
aldehyde or ketone are called D-monosaccharides;

those that have the same configuration as L-glyceraldehyde

about the chiral carbon farthest from the aldehyde are
called L-monosaccharide.
Naming isomers with more than one
chirality centre.

Br
H 3C
C C H
H
CH3
OH

a stereoisomer of 3-bromo-2-butanol
Determine each configuration separately
S 4
H
Br
H3C
3 Br 2 1
H3C C C H
Br
2
C C H H
3 CH3
H OH
4 CH3
OH
1 R

2S,3R-3-bromo-2-butanol
Configuration and conformation
 Changing the configuration of a molecule
always means that bonds are broken.
 A different configuration is a different
molecule
 Changing the conformation of a molecule
means rotating about bonds, but not breaking
them.
 Conformations of a molecule are readily
interconvertible, and are all the same
molecule.
 Absolute And Relative Configuration
The spatial arrangement of substituents at a chirality centre
is its absolute configuration.
Relative configuration compares the arrangement of atoms
in space to some reference.
Absolute configuration is an exact description of the
arrangement of atoms in space.
CO2H
CO2H
C
C
H3C H CH3
H
OH OH
Enantiomers of lactic acid 37
Reactions of compounds with chiral centre
 When a compound containing chiral centre
undergoes a reaction, the effect on the
configuration of the chiral centre depends on
the reaction.
 If the reaction does not break any of the four
bonds to the chiral centre, then the relative
positions of the groups bonded to the chiral
centre will not change. i.e. reactant and
products have the same relative
configurations.
 CH2CH2Cl CH2CH2OH

C HO- C
H H
CH3CH2 CH3CH2
CH3 CH3

(S)-1-chloro-3-methylpentane (S)-3-methyl-1-pentanol
Same relative configurations
CH2=CH2 CH2CH3

C H2 C
H Pd/C H
CH3CH2CH2 CH3CH2CH2
CH3 CH3

(S)-3-methylhexene (R)-3-methylhexane

Same relative configurations, but different

absolute configurations
 Racemic mixtures
 mixtures containing equal quantities of
enantiomers are called racemic mixtures.
 Racemic mixtures are optically inactive.
 Optical activity is the ability of of a chiral
substance to rotate the plane of plane-
polarized light and is a measured using an
instrument called a polarimeter.
 To be optically active, the sample must
contain a chiral substance and one
enantiomer must be present in excess of the
other.
 All achiral substances are optically inactive.
40
 Rotation of plane of polarized light in the
clocckwise sense is taken as positive (+) and
rotation in the counterclockwise sense is taken as
negative (-) rotation (formerly dextrorotatory &
levorotatory respectively).
 Specific rotation [α]T λ = α
cl
[α] unit = 10-1 deg cm2 g-1
where c is the concentration of the sample in
gram/mL of solution, and l is the length of
polarimeter tube in decimeter. T = Temperature
(oC), λ = wavelength of the incident light.
 Specific rotation [α] = α where c = g/mL
cl
Specific rotation is a physical property (such as
boiling point, melting point, density etc.) and is
usually cited as
[α]25D = +3.8o
Where the temperature (oC) and the wavelength
of light (when sodium D-line is used, λ is
indicated as D) at which the measurement was
made are indicated in the superscripts and
subscripts respectively.
 Exercise
1. Monosodium glutamate (MSG) ia a flavour
enhancer used in many foods. Some people have
allergic reaction to MSG (headache, chest pain,
etc). (S)-(+)-MSG has a specific rotation of +24.
(a) what is the specific rotation of (R)-(-)MSG?
(b) what is the specific rotation of racemic mixture of
MSG?

2. Cholesterol, when isolate from natural sources, is

obtained as a single enantiomer. The observed
rotation α of a 0.3g sample of cholesterol in 15mL
of chloroform solution contained in a 10cm
polarimeter tube is -0.78o Calculate the specific
rotation of cholesterol.
 Separation of enantiomers
 Enantiomers can not be separated by the usual
separation techniques such as fractional distillation,
crystallization etc: because of their identical boiling
points and solubilities.
 Resolution of enantiomers can be done by;
 Manual separation with a pair of tweezers – Louis
Pasteur method (few compounds form asymetrical
compounds).
 Chemically converting enantiomers to diastereomers,
which can be separated because they have different
physical properties. After separation, the individual
diastereomers had to be chemically converted back to
the original enantiomers (tedious and unreliable)
 Chromatography technique: Best method.
 Chromatography method
 The mixture to be separated is dissolved in a solvent
and the solution is passed through a column packed
with a chiral material that tends to adsorb organic
compounds.
 The two enantiomers can be expected to move
through the column at different rates because they will
have different affinities for the chiral material.
 Because of the ease of separation of enantiomers,
many drugs are now being sold as a single
enantiomerss rather than as racemic mixtures.
 The chiral material used in chromatography is an
example of chiral probe, another example is
polarimeter: capable of distinguishing between
enantiomers.
 ENERGY OF ACTIVATION AND FREE RADICAL
SUBSTITUTION REACTION OF ALKANE
• The ultimate source of organic chemicals is petroleum.
Petroleum is a mixture of paraffin-alkane, cyclic and
aromatic hydrocarbons. Alkane undergoes substitution
reaction due to its saturated nature. Alkane has no pie
(Π)-bond, no expanded octet, neither is it nucleophilic
or electrophilic in nature, hence it is less reactive at
room temperature.
• Substitution of an H atom in alkane by a functional
group to give a substituted product, which can be
transformed into other organic compounds by reaction
which occur at the site of the functional groups. For
instance:
Even though the C-H of alkane is not polar
(i.e. alkane does not react with nucleophilic
or electrophilic acids or base), alkane can
still undergo certain chemical reactions
under certain reaction conditions suitable
for the substitution of a H atom by a
functional group.
 CHLORINATION OF ALKANE
This is the oldest known substitution reaction of
alkane. This reaction occur in the presence of
ultra violet (UV) radiation or heat, 300oC; e.g

Halogens such as Cl and Br2 substitute H in compounds containing

αsp3-s C—H bonds. These reactions are initiated either thermally
(action of heat) or upon irradiation with UV light. Fluorinations also
occur with alkane but such substitution must be initiated by light at
low temperature. At room temperature or above room
temperature, reactions are explosive. Alkane does not react with I2
to give a substituted product.
• The relative order of reactivities of Halogens is
F2 > Cl2 > Br2 > I2
• Compounds formed when alkane reacts with
halogen are referred to as alkyl halides; RX,
represented by the general formular CnH2n+1X,
where X is the substituted halogen atom.
Thus:
TYPES OF HYDROGEN OR DIFFERENT KINDS OF
HYDROGEN IN ALKANE AND RATE OF
SUBSTITUTION
• It is important to note that substitution
reactions of alkane occur via free radical chain
reaction mechanism, involving three steps:
chain initiation (step 1), chain propagation (step
2) and chain termination (step 3). Free radicals
are species formed via homolytic bond cleavage
of covalent bonds. They are highly reactive and
unstable species. They contain unpaired
electrons.
• Iodination is not feasible under the reaction
conditions above since I—I bond cannot be
splitted into radical at low temperature of the
reaction, due to low electronegativity of iodine.

Since each H is subject to substitution by a

halogen, all possible isomeric products
(monohalides) can be obtained in the halogenations
reaction, e.g.
• The number of isomeric alkyl halides obtained depends on the
type of H on the alkane moiety. There are 3 types of Hydrogen
positions, primary, secondary and tertiary hydrogen.
• Isomeric halides can be separated using fractional distillation.
• However, ratio of isomeric halides does not often correspond to
the number and kind of chemically equivalent hydrogen at each
chemically equivalent position. For example, propane has 2
kinds of hydrogen, CH3*CH2**CH3*, where * represents
primary and ** represent secondary hydrogen. Hence only two
monosubstituted products /halides can be obtained if propane
reacts with halogen, given the necessary conditions. Propane
has 8 eight hydrogen, six equivalent hydrogen are primary while
2 equivalent hydrogen are secondary. Hence, only two
substituted alkyl halide will be produced, assuming the
substitution is statistical.
• Likewise, n-butane has the ratio of primary to secondary
hydrogen as 3:2, by this statistical argument, we would expect
chlorination of butane at 300oC to give 60% 1-chlorobutane
and 40% 2-chlorobutane in a statistical ratio of 3:2.
Chlorination of isobutene at 300oC shows similar result e.g.

CH3 CH3
CH3
Cl2 H2C C H
CH3 C H + H3C C Cl
300oC
CH3 CH3 CH3
o isobutylchloride
9-1 Hydrogen tert-butylchloride
1-3oHydrogen predicted=90% predicted=10%
oserved=67% oserved=33%
RELATIVE REACTIVITIES IN THE HALOGENATION
OF ALKANE

• Halogenation of alkane does not give the

isomeric primary, secondary and tertiary
monohalides in statistical yields. The observed
ratio of product indicates a difference in the
reactivity at primary, secondary and tertiary
positions. The relative reactivity at each position
can then be calculated for each position, e.g.
• CH3CH2CH3 + Cl2 …………. CH3CH2CH3Cl +
CH3CH(Cl)CH3
• Relative reactivity at 2o position over 1o position
is calculated thus:
• (% 2-chloropropane)obs/ (% 2-
chloropropane)pred X 100
• (% 1-chloropropane)obs/ (% 1-
chloropropane)pred
• Key:
• obs= observed yields, pred = predicted yields
• = 50%/25% = 3.0
• 50%/75%
• The relative reactivity of 3.0 indicates that
hydrogen on 2o position is three times more
reactive than hydrogen on 1o position towards
chlorination at 300oC. Similarly, H on a 3o position
is 4.5 times more reactive towards chlorination at
300oC than are H on primary position.
• In summary, the relative order of chemical
reactivity at different hydrogen position follows
the rate and type of radical formed at each stage.
Note that free radical reaction mechanism has
been proposed for the mechanism of
halogenations, it stems clearly that 1o, 2o and 3o
radicals reacts at different rate.
 FREE RADICAL REACTION
• Just like carbonium ions, free radicals have
different reactivity and stability. The order of
stability and relative reactivities of free
radicals is in the order:

• Methyl radical < ethyl radical(1o) < propyl

radical (2o) < tert-butyl (3o) radical < H2C=CH-
CH2. (vinyl radical) < phenyl radical (C6H5.) <
triphenyl radical (C6H5.)3.
• The relative stability of radical species can be explained
on the basis of the electron-releasing tendency of alkyl
group which stabilize the radical. The more the alkyl
groups, the higher the stability of the radical. The
positive inductive effects of alkyl group accounts for
this tendency.
• Again, the number of canonical structure dictates
relative stability of radical.
• Free radicals unlike free carbonium ions are incapable
of exhibiting optical activity. Free radicals
• Are neither acidic nor basic in the Bronsted-Lowry or
Lewis sense, and do not react with other paramagnetic
substances. However, due to unpaired electron in free
radical, they are paramagnetic and can react with
species (nucleophiles) such asoxygen. They abstract
atoms from covalent molecules and can add on to
unsaturated compounds. The major reactions are
shown thus:
CH3. + A B CH3 A + B. ATOM ABSTRACTION

CH3. + H2C=CH2 CH2CH2CH3. + B. RADICAL ADDITION

n-propyl radical
 BOND DISSOCIATION ENERGY (BDE)
• In homolytic bond cleavage of covalent bond, such as CH3—
H CH3. + H., energy required for the homolytic cleavage
(measured in KJ/mol) is known as the bond dissociation
energy. The lower the BDE, the less the energy required for
homolytic cleavage, e.g. less energy is required to cleave a
Br—Br bond (46 KCal/mol) than a Cl—Cl bond (58
KCal/mol), etc. Various values of BDE for different bonds
are in literature.
• The BDE allows an easy estimation of the reasonableness of
the pathway by which certain reactions occur. It allows us
to predict the covalent bond preferably broken or cleaved
preferentially.
• BDE allows one to predict the probability of a subsequent
process and in the process allows an easy calculation of the
enthalpy (heat) of a reaction (ΔH).
• ΔH = Σ (BDE bond broken – BDE bond formed).
• Calculation based on bond dissociation
energy (BDE)
• Q1 Given the BDE data as C6H5—H =
103kCal/mol, Br—Br = 46kCal/mol, H—Br =
87.5 kCal/mol, C6H5—Br = 1311.5 kCal/mol,
calculate ΔH for the reaction below:
• Solution:
• ΔH = Σ (BDE bond broken – BDE bond formed)
• Bond broken = C6H5—H, Br—Br bonds
• Bond formed = C6H5—Br, H—Br bonds.
•
• ΔH = [(103+ 46)-(1311.5-87.5)] kCal/mol
• = [149-1399.0] kCal/mol
• = -1250 kCal/mol.
• Thus BDE can be used to predict the probability
of a reaction occurring, since ΔH can be used to
predict the feasibility of a reaction.
FREE RADICAL REACTION OF HBr – effect of peroxide
• In the absence of light and peroxides, addition of
HBr to an alkene gives a product in line with
Markovnikov rule, often called Markovnikov
addition, e.g
•
• CH3CH=CH2 + HBr
•
• However, free radical addition in the presence of
light, occur via anti Markovnikov addition.
•
• CH3CH=CH2 + HBr
• Peroxides such as di-tertiary butyl peroxides i.e.
(CH3)3—O –O – (CH3)3 undergoes homolytic
cleavage of the oxygen-oxygen bonds at
temperature below 100oC to give alkoxyl radical,
e.g.

• Alkoxyl radicals produced through homolytic

cleavage of peroxides abstracts H from HBr. The
resulting bromine atom adds to the C—C double
bonds to form the more stable free radical. The
carbon radical subsequently abstracts H from H—
Br to continue the chain reaction process.
 CHAIN INITIATION
.. .. heat or light ..
R O
.. O R 2R O . where R =(CH3)3C
.. ..

2R O. + H Br R O H + Br.
HOMOLYTIC CLEAVAGE OF COVALENT BOND

CHAIN PROPAG ATION

.
Br. + H 2 C=CHCH 3 Br CH 2 CHCH 3
propene
.
BrCH 2 CHCH 3 Br CH 2 CH 2 CH 3 + Br.
+ HBr
Formation of m ore stable free radical