Organic Chemistry

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Lectures on
Stereochemistry
Nucleophilic Substitution at a
Saturated Carbon
Conformational Analysis
Pericyclic Reactions

Lecture 1
Stereochemistry

Why stereochemistry ?
Biological importance of chirality
Chirality is a phenomenon that pervades the universe
Human body is structurally chiral
Helical seashells are chiral
Most plants show chirality in the way they wind around
supporting structures
Most of the molecules that make up plants and animals
are chiral and usually one form of the chiral molecule
occurs in a given species
All but one of the 20 amino acids are chiral and L-form
Almost all natural sugars are chiral
DNA itself has a helical structure and all naturally occurring
DNA turns to right.
Chiral molecules can show different handeness in
many ways, including the way they affect human beings

H
O
11-cis-retinal
absorbs light when we see

COOH

tretinoin
treatment of skin disease

-carotene
a precursor of Vitamin A, found in carrots, sweet potatoes

Enantiomeric
smell
R- (+)-limonene
smell of orange

S- (-)-limonene
smell of lemons

Perfumery compounds from jasmine

O
S
R
O

CO2Me

strong odour
(+)-Z-methyl epijasmonate
O

Jasmone
CO2Me

odourless
(-)-Z-methyl epijasmonate

Japonilure

pheromone released by Japanese beetles as a means of

communication
larvae of the beetles are serious crop pests
25 g/trap catches thousands of beetles
1% of the other enantiomer destroys the activity

Me
*
COOH

Ibuprofen
500 mg of one tablet contains only half of its as active drug

Me

Me

COOH

S is active

COOH

R is inactive

HO

HO

NH2

NH2
HO

CO2H

L-dopa
marketed as a
single enantiomer

HO

Me

CO2H

D-dopa
toxic

CO2H
MeO

(S)-Naproxen
(only this has anti-inflammatory activity)
Me

Me

NMe2

Me2N

C
C

O
O
O

Darvon
(Pain killer)

Novrad
(anticough agent)

Thalidomide tragedy
O

N
O

N
H

Thalidomide

dexorotatory isomer sedative

levorotatory isomer cause of birth defects

Why is drug chirality an important knowledge for future pharmacists?

The current trend in drug markets is a rapid increase of the sales of chiral drugs at
the expense of the achiral ones.

By the year 2010 chiral drugs, whether enantiomerically pure or sold as a racemic mixture, will dominate
drug markets. It is therefore important to understand how drug chirality affects its interaction with drug
targets and to be able to use proper nomenclature in describing the drugs themselves and the nature of forces
responsible for those interactions.

Chiral An object that has a non-superimposable mirror image is said to be

"chiral" (Greek = "handedness") and one that has a superimposable mirror
image is "achiral".
CHIRALITY is a property of an object which is non-superimposable with
its mirror image. Most objects in the environment are chiral. In chemistry
this term applies to molecules, specific conformations of molecules, as well
as to macros copic objects such as crystals.
Chirality is removed if an object /molecule acquires a plane of
symmetry, or a center of symmetry. The molecule can remain chiral
with a limited combination of symmetry axes.

Enantiomers A pair of molecules that are non-superimposable mirror images of

each other.
The most common type of "chirality" is observed when a carbon atom has four
different groups attached to it (so it must be sp3 hybridised). This carbon atom
is then described as a chirality center.
Older terms are chiral, asymmetric or stereogenic center. This later term can
also be contracted to a stereocenter.

Some examples of structures other than chemical structures which are chiral

Enantiomers and Chirality

O
CN

HO
R

CN
H

How many products are formed ?

O

NC

CN
Approach from front face of the carbonyl
O
HO
R
R
H

OH
H

CN
H

CN
Approach from back face of the carbonyl
NC

HO

OH

CN
A & B are enantiomers

H
A

(Mirror images)

Structures that are not superimposable

on their mirror images, and can thefore
exist as enantiomers, are called chiral

What happens when cyanide is added to acetone

HO
Me

CN
Me

HO
Me

CN
Me

Plane of symmetry runs

through central carbon, OH,
CN

Acetone Cyanohydrine

So, any structure that has no plane of symmetry can exist as two mirror-image forms
(enantiomers)

Stereogenic centres
If a molecule contains one carbon atom carrying four different groups it will not have a plane of
symmetry and must therefore be chiral. A carbon atom carrying four different groups is a
stereogenic or chiral centre
Stereoisomers & Constitutional isomers
OH
R

OH
CN

CN

HO
R

CN

HO
R

Constitutional isomrs

CN
H

Enantiomers
NC

CN

trans / cis isomers

HO
R

CN
H

HO
R

CN
H

two configurations :
going from one enantiomer to
the other requires a bond to be
broken

HO
R

CN
H

NC
R

H
OH

H
R

OH
CN

3 conformations of the same

enantiomer: going from one to
the other requires rotation about a
bond

Racemic mixture
A racemic mixture is a mixture of two enantiomers
in equal proportion
MeMgCl

CHO

Consisting of
50
OH

HO

CHO
OH

Consisting of

HO

OH

50

HO

50

OH

H
O
50

Cahn-Ingold-Prelog rules :
HO

Absolute configuration :
The R & S notation

CH3

CH3
H

OH

CH2

CH2

CH3

CH3

Both are "2-butanol''

1. Assign priority sequence to the four groups attached to a stereogenic

carbon following sequence rule
2. Observe the stereogenic centre from a direction opposite to the group
of lowest priority
3. Trace the path from 1 to 2 to 3.
If clockwise
R (rectus, right)
If anti clockwise
S (sinister, left)

Sequence rules:
1.

Priority is first assigned on the basis of the atomic number of the

atom
3 ?
that is directly attached toCH
the
stereo centre.
(a) HO

H (d)
CH2 ?
CH3

2. When a priority cannot be assigned on the basis of AN, then the

next set of atoms/groups are examined.
(c)
(a)

CH3

HO

H, H, H
H (d)

(b)

CH2

H, H

CH3

3. Rotate the structure so that (d) is directed away from us.

c
CH3

CH3
HO

H
CH2
CH3

OH a
CH2CH3
b

4. Groups containing double or triple bonds are assigned as if both

atoms were duplicated and triplicated.
C

(Y) (C)
(Y) (C)
C

(Y) (C)
CH2CH3

CH CH2

both CH
So move to next carbon
H

(C) (C)

H, H, C

H, C, C

Vinyl > ethyl

Chiroptical properties
Enantiomers have the same chemical and physical properties (melting
points, boiling points, heat of combustion etc.), except for their interaction
with plane polarised light or with other chiral molecules (reagents,
solvents, catalysts etc).
(think about how your feet feel if you put them in the wrong shoes).

Any material which rotates the plane of the polarized light is termed "optically
active." Compounds featuring chiral centers are optically active unless they
possess symmetry plane or a symmetry center (see above). An isomer of
optically active compound can rotate the plane of polarized light to the left
(levorotatory), in which case it will be designated (l, or -), or to the right
(dextrorotatory) in which case it will be termed (d, or +).

Enantiomers cause the plane of polarised light to rotate in opposite

directions, but to the same extent (clockwise = +ve, counterclockwise =
-ve). This can be measured using a polarimeter. An achiral molecule is
optically inactive.

CH2OH

CH2OH

H
Me
Et
(S)-2-methyl-1-butanol
(R)-2-methyl-1-butanol
+5.75 specific rotation []D20-5.75
Me

Et

The specific rotation is the number of degrees of rotation caused by a

solution of 1.0 g of the compound per mL of solution in a sample tube 1.0 dm
long at a specified temperature and wavelength.
T

[] =

lxc

Where [] is the specific rotation; T is temperature in C; is the wavelength of the

incident light (when the sodium D-line is used, is indicated as D); is the observed
rptation; l is the length of the sample tube in decimeters; and c is the concentration of the
sample in grams per mililiter of solution

A 50:50 mixture of a pair of enantiomers is called a racemic mixture. This is optically

inactive since the rotations produced by each of the enantiomers must cancel each other out.
If there is more of one enantiomer than the other, then the optical purity of a sample can be
determined by measuring the rotation and comparing it to that of a pure enantiomer. This
can be used to establish the enantiomeric excess (ee) of the mixture.

observed specific rotation X 100

optical purity
=
(enantiomeric excess; ee) specific rotation of the pure enantiomer

The L/D systems relies on the chemical correlation of the configuration of the chiral center to Dglyceraldehyde. The compounds which can be correlated without inverting the chiral center are
named D (capital D), those correlated to its enantiomer are designated as L (capital L).
The accepted convention for drawing D(+)-glyceraldehyde places the hydrogen atom
at the left and the hydroxyl at the right, with the aldehyde at the top.
CHO
H

CHO
OH

HO

CH2OH

CH2OH

D(+)-glyceraldehyde

L(-)-glyceraldehyde

IMPORTANT NOTE: Although D-glyceraldehyde is dextrorotatory (rotates the plane of

polarized light to the right), the compounds correlated to D-glyceraldehyde do not have to be
dextrorotatory, i.e. could rotate light to the left. Therefore, D-prefix is not correlated with the (+)
or (-) specific rotation, and the D-compound can be l, (or -), and vice versa L-compound can be d
(or +). This nomenclature system is slowly being abandoned in favor of the Cahn-Ingold-Prelog
(CIP) nomenclature, with the exception where the DL-nomenclature has been used traditionally,
and is more useful (D-carbohydrates or L-aminoacids).

THE ANSWER SCRIPTS FOR THE MID SEMESTER

EXAMINATION WILL BE SHOWN TO THE STUDENTS
FROM 12:30-1:30 PM ON TUESDAY MARCH 28, 2006
Section

Room

F 116

SDG

F 127

AR

F 131

SC

F 132

KSG

10

F 142

ST

ANY DISCREPANCIES FOUND ARE TO BE NOTED ON THE TOP

SHEET ONLY FOR REVISION BY THE TEACHERS LATER.

GRAPHICAL REPRESENTATION OF NONPLANAR MOLECULES

Representation of the 3D-structures of molecules as their 2D-projections:
1. Fisher pojection
2.

Wedge projection

Fisher projection:
The tetrahedral atom is viewed
perpendicularly to an edge formed
by connecting two of its ligands.
The convention is that the two
vertical bonds in the projection are
pointing behind the plane of
projection (plane of paper sheet),
and the two horizontal bonds are
pointing towards the viewer.

Wedge projection:
It is obtained by viewing the tetrahedral center perpendicularly to the plane formed by three atoms.
One of the remaining atoms is oriented behind the plane of projection (dashed bond), one towards the viewer (boldface
bond).
Note that, in contrast to Fisher projection, the rotation of the wedge projection about axes perpendicular or coplanar with the
plane of projection does not change anything.
This projection is therefore by far less ambiguous than Fisher projection.
In the case of large linear molecule the molecule backbone has to be drawn in the fully extended conformation.

Sawhorse projection:
The C-C bond is viewed at an angle. The atom shown on the left of the projection is also the one in
the front. This projection is difficult to use with acyclic molecules but is most popular for
representation of cyclic molecules e.g. saturated six-membered rings.

Newman projection:
The molecule with two tetrahedral centers is viewed along the C-C axis. The atom in front
is represented as a three-way branch, the atom in the back as a circle with three outgoing
bonds. This projection is most useful inconsideration of steric relation between ligands
linked to adjacent tetrahedral centers and is most popular

a
d

a
b

Wedge projection

Fisher projection

rotate
a
d
c

tilt
b

a
c

b
d

d
c

a
b
x

c
z

a
x

c
x
y

a
z

Newman projection
c

x
y

Sawhorse projection

Fisher projection

b
z

y
b

z
a

Z/E Geometry of Double Bonds

The same Prelog's precedence rules, as discussed earlier, apply to geometrical
isomers of olefinic compounds and alicyclic compounds. Precedence of
ligands at both nodes of the double bonds is determined pairwise.
If both higher precedence ligands are on the same side of the double bond the
configuration is Z, if on the opposite sides the configuration is E.

Nitrogen chirality center

Inversion barrier 6 kcal/mol

Resolvable ?
N cannot achieve a 1200 bond angle
in a 3-membered ring
The two enantiomers can be separated

C(CH3)3
CH3
P

inversion barrier 32.7 kcal/mol

H3 C

H2C=HCH2C

[]D = 16.80
S-enantiomer

CH3
C(CH3)3

CH3

CH3
Br

H3CH2CH2C

CH2CH3

H3CH2C

Br
CH2CH2CH3

a pair of enantiomers
O

O
P
H3CH2CO

H
OCH3

H3CH2CO

a pair of enantiomers

OCH2CH3

Diastereomers
Diastereomers are stereoisomers that are not mirror images.
Two diastereomers are different compounds and have different
relative stereochemistry.
Diastereomers may be chiral (have no plane of symmetry):
Ar

CO2Me

Ar

CO2Me
O

Diastereomers may be
achiral
OH

OH

plane of symmetry

Relative Configurations in Compounds with Multiple Chiral Centers .

The use of CIP nomenclature requires assignment of R,S descriptors for every
center. The quicker way (older and a more ambiguous one) is by using
threo/erythro nomenclature.
It requires vertical projection of the sugar main chain.
threo-compounds are defined as those that have two ligands of higher precedence
on each carbon atom on the opposite sides of the chain.
erythro on the same side. The ambiguity arises from the question what should be
used as the main chain.
CH3

CH3

H3C

*
CH
Cl

*
CH
OH

3-Chloro-2-butanol

CH3

OH

HO

Cl

Cl

CH3
A

CH3

B
erythro enantiomers

CH3

CH3
H

OH

HO

Cl

H
Cl

CH3

CH3

threo enantiomers

diastereomers

A&C
A&D
B&C
B&D

Tartaric acids
OH
HO2C

OH

HO2C

CO2H

OH

OH

diastereomers

enantiomers
OH
HO2C

HO2C

HO

OH

HO

COOH
meso compound

COOH

COOH
H

CO2H

stereoisomers ?

HO2C

OH

OH

OH
22 = 4

CO2H

OH

COOH

CO2H

OH

HO

COOH

H
OH
COOH

pair of enantiomers

CO2H
S

meso
OH

Chiral compounds with no stereogenic

centres
Me

Me

C
H

C
Me

Me

These mirror images are not superimposable - enantiomers

O
rotation around the single
bond is restricted

PPh2
PPh2

N
H

H
N

N
H

H
N

nonsuperimposable enantiomers

Q. Identical, enantiomeric, or diastereomeric?

O

&

CH2OH

CHO
O

H
HO

NH2
H

&

H
H

CHO

CH2OH
&
S

OH
NH2

O
S

H
Cl

H
Ph

CH3

Cl

H
&

CH3
Ph

Q. Give structures (with R/S specification) of the products

in the following reaction?
cold alkaline

(R)-HOCH2CHOHCH=CH2

A (opt active) + B (opt. inactive)

KMnO4

Q. The following compound racemises in base, why?

O

HO
O
S

HO
H

Q. Moshers Acid
MeO

CF3
COOH

R or S ?

Recommended Books
1. Organic Chemistry (2nd Ed.) by P. Y. Bruice
2. Organic Chemistry by Clayden, Greeves, Warren and
Wothers
3. A Guide Book to mechanism in Organic Chemistry
by P. Sykes

Do the compounds have the same molecular formula ?

NO

Not isomers

Yes
isomers
Do the compounds have the same connectivity ?
Yes

NO

Stereoisomer isomer

Constitutional isomer

Can the compounds be

interconverted by rotation
about single bonds ?
NO

Yes

Configurational iosmers

cis-trans isomers

Confortional iosmers

isomers that contain chirality center/s

Enantiomers

Diastereomers