Chapter 5 (Stereochemistry)

Stereochemistry: is the three-dimensional structure of a molecule

Stereoisomers are isomers with the same molecular formula and same connectivity
of atoms but different arrangement of atoms in space

Chiral molecule
· A molecule which contains at least a single chiral carbon atom (stereogenic
center). This atom is tetrahedral carbon atom which is bonded to four different
groups. e.g. 2-butanol CH3-CH(OH)-CH2-CH3

Carbon number 2 is chiral carbon atom which is attached to methyl, ethyl,

hydroxyl, and hydrogen atom.
· Chiral molecule does not have a plane of symmetry (an imaginary plane that
bisects a molecule in such a way that the two halves of the molecule are mirror
images of each other)

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While 2-chloropropane is not chiral molecule because it contains plane of symmetry.

To locate a stereogenic center (chiral carbon atom), examine each tetrahedral carbon
atom in a molecule, and look at the four groups—not the four atoms—bonded to it.

Stereogenic centers may also occur at carbon atoms that are part of a ring. To find
stereogenic centers on ring carbons, always draw the rings as flat polygons, and look
for tetrahedral carbons that are bonded to four different groups

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Enantiomers: stereoisomers of chiral molecules which are mirror images to each
other and not superimposable.
The chiral molecule labeled (A) and its mirror image labeled (B) are not
superimposable. No matter how you rotate (A) and (B), all the atoms never align.
Thus, (A) and (B) are different stereoisomers, specifically, they are enantiomers.

Nomenclature of Enantiomers: The R,S System (Cahn-Ingold-Prelog system)

· Locate the stereogenic (chiral) carbon(s) atom

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· Assign priorities (1 – 4) to the four different attached groups; 1 is highest, 4 is
lowest based on atomic numbers of attached atoms
– the higher the atomic number the higher the priority
• E.g. 79Br > 17Cl > 8O > 6C > 1H
– If two identical atoms are attached to the carbon, the next atoms in both
chains are investigated e.g. ethyl (CH3CH2-) > methyl (CH3-).

– Replace multiple bonds with multiple atoms, equivalently bonded

When the group with lowest atomic number (number 4) is pointing away (dash
line). If the rotation 1 ®2 ®3 “motion” is clockwise then it is (R)
If the rotation 1 ® 2 ® 3 “motion” is anticlockwise then it is (S)

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When the group with lowest atomic number (number 4) is NOT pointing away
If the rotation 1 ®2 ®3 “motion” is clockwise then it is (S)
If the rotation 1 ® 2 ® 3 “motion” is anticlockwise then it is (R)

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 Molecules with More than One Stereogenic (Chiral) Center
The maximum number of stereoisomers available will not exceed (2n), where n is
equal to the number of tetrahedral stereogenic centers (chiral carbon atoms) e.g. 2-
bromo-3-iodobutane

This compound contains 2 chiral centers (carbon 2 and carbon 3) so the number of
stereoisomers = 22 = 4 isomers

Compound (A) and compound (B) are Enantiomers (mirror images for each other).
Also Compounds (C) and (D) are Enantiomers (mirror images for each other).
Diastereomers: stereoisomers whose molecules (which contain more than one chiral
center) are not mirror images of each other
Compound (A) and compound (C) are Diastereomers (not mirror images for each
other). Also compounds (A) and (D) [compounds (B) and (C) & compounds (B) and
(D)] are Diastereomers
· Diastereomers have different physical properties (melting and boiling points) and
separated easily
· Enantiomers differ only in reaction with other chiral molecules and the direction
in which polarized light is rotated.
· Enantiomers are difficult to separate.

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Meso Compounds
Achiral compound possessing two or more stereocenters and has plane of symmetry.
E.g. 2,3-dibromobutane

Compound (A) and compound (B) are Enantiomers (mirror images for each other).
While Compounds (C) and (D) are Meso compounds (A chiral molecules).

Stereochemistry of cyclic compounds

Substituted cycloalkanes have different stereoisomers such as Cis- and Trans-
isomers

Cis-isomer is achiral molecule because it has a plane of symmetry while trans-

isomer is chiral molecule as shown in the given examples

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Compound (A) and compound (B) are Enantiomers (mirror images for each other).
While Compounds (C) and (D) are Meso compounds (A chiral molecules).
Compound (A) and compound (C) are Diastereomers (not mirror images for each
other). Also compounds (A) and (D) [compounds (B) and (C) & compounds (B) and
(D)] are Diastereomers

Stereoisomerism in Alkenes
Geometric isomers: stereoisomers with the same molecular formula but different in
the spatial arrangement of the groups.

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Rules for assigning (Z) and (E) System
• Assign priorities for atoms to each side of double bond according to atomic
number E.g. 79Br > 17Cl > 8O > 6C > 1H
• If two identical atoms are attached to the carbon, the next atoms in both chains
are investigated e.g. ethyl (CH3CH2-) > methyl (CH3-). (as previously in R,S
rules)
• Replace multiple bonds with multiple atoms, equivalently bonded (as previously
in R,S rules)
• Choose the group with higher atomic number on both sides of double bond
• If the groups with higher atomic number are in the same direction (Z)
system
• If the groups with higher atomic number are in the opposite direction (E)
system

Question: specify the (E-, Z-) configurations for the following alkenes

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 Chapter 6
Alkyl Halides
Organic compounds which contain at least one carbon-halogen bond (C-X), [X = F,
Cl, Br, I] with general formula (R-X).

Classification of Alkyl halides (R-X)

Alkyl halides are sub-divided as primary (1ry), secondary (2ry), and tertiary halides
(3ry) according as the halogen is attached to a primary, secondary or tertiary carbon
atom.

Other types of Alkyl halides

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Dihalides: Organic compounds which contain two (C-X) bonds which can be
classified into:
Geminal dihalide: in which the two halogen atoms are bonded to the same carbon
Vicinal dihalide: in which the two halogen atoms are bonded to adjacent carbons

Nomenclature of Alkyl halides

In the common system, they are named as halides of the alkyl group present (Alkyl
halide).

· CH2X2 called methylene halide. CH2Cl2 is methylene chloride

· CHX3 is a haloform. CHCl3 is chloroform
· CX4 is carbon tetrahalide. CCl4 is carbon tetrachloride

In the IUPAC system, the name of halogen being prefixed to the name of alkane
involved (Halo alkane).
• Number from end nearest any substituent (alkyl or halogen)
• If two Halides or Alkyl are equally distant from ends of chain begin at the end
nearer the substituent whose name comes first in the alphabet
• If more than one of the same kind of halogen is present, use prefix di, tri,
tetra….etc

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 Preparation of Alkyl halides
1. Halogenation of Alkanes

2- Addition of hydrogen halide (HX) (Hydrohalogenation) into Alkenes

3- Reactions of Alcohols with hydrogen halide (HX)

Alkyl halides (R-X) are prepared by passing HX (HCl, HBr, HI) gas into alcohol in
the presence of ZnCl2 (anhydrous) as catalyst.

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• Reaction of tertiary C-OH with HX is fast and effective
• Primary and secondary alcohols react very slowly

Physical Properties of Alkyl halides

Alkyl halides are weak polar molecules. They exhibit dipole-dipole interactions
because of their polar (C—X)

Reactions of Alkyl halides

1- Grignard Reagents
Reaction of RX [(R is alkyl 1°, 2°, 3°, aryl, alkenyl) and (X = Cl, Br, I)] with Mg in
ether or THF to give an organometallic compound (RMgX).

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2- Nucleophilic Substitution Reaction (SN)

Nucleophile: An electron-rich atom or molecule that donates an electron pair to an

electrophile to form a chemical bond.

The order of reactivity of alkyl halides towards nucleophilic substitution is:

R-I > R-Br > R-Cl > R-F

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 Leaving group: The group that is displaced in a nucleophilic substitution reactions

As the basic character decrease, the leaving group ability will increase (good
leaving group) and vice versa

Good leaving group will accelerate the nucleophilic substitution reaction

Types of Nucleophilic Substitution Reactions
1- Bimolecular Nucleophilic Substitution Reactions (SN2)

Rate = K [CH3-Cl] [HO-] [Second order reaction]

The rate of the reaction depends on both the concentration of alkyl halide and the
nucleophile. i.e. If we double either the concentration of alkyl halide or nucleophile,
the rate of the reaction will also double.
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Mechanism of (SN2)

• Both reactants are involved in the transition state of the rate-determining step
• The nucleophile attacks the reactive center from the side opposite the leaving
group
Stereochemistry of (SN2)
All (SN2) reactions proceed with backside attack of the nucleophile, resulting in
inversion of configuration at a stereogenic center. (R) will inverted into (S) and vice
versa

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Factors affecting on SN2
1- Effect of substrate (Steric effect of alkyl halides R-X)
In SN2 mechanism, the nucleophile must approach the alkyl halide from the side
opposite to the bond of leaving group (back-side attack of C-X bond). If the alkyl
group is methyl (three hydrogen atoms) it will offer little resistance for nucleophilic
attack and the rate of reaction will be fast. On the other hand, if the alkyl group is
bulky (steric hindrance) it will retard the nucleophilic attack and the rate of reaction
will be very slow.

2- Nucleophilicity (Strength of nucleophiles)

Base Nucleophile
Have lone pair of electrons or Have lone pair of electrons or
negative charge or p-bond negative charge or p-bond
Attack proton (H+) Attack other atom (carbon)
Basicity: is a measure of how readily Nucleophilicity: is a measure of how
an atom donates its electron pair to a readily an atom donates its electron
proton pair to other atoms (carbon)
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 · A negatively charged nucleophile (base) is more reactive than a neutral one
(HO – > H2O), (RO – > ROH), (NH2 – > NH3), (RCOO – > RCOOH)
· With the same nucleophilic atom, as the basic character (basicity) increase, the
–
strength of nucleohile (nucleophilicity) will also increase (RO is more
nucleophilic and more basic than RCOO -)
· Within the elements in the same raw of periodic table (N, O, F) as we go from
left to right (N → O → F) the basic character (basicity) and the nucleophilic
strength (nucleophilicity) will decrease (N > O > F) [NH2 – > HO – > F -] [NH3
> H2O]
· Within the elements in the same group of periodic table (F, Cl, Br, I) as we go
down (F → I) the basic character (basicity) will decrease but the nucleophilic
strength (nucleophilicity) will increase
(F - > Cl - > Br – > I -) [order of decrease the basic character]
(F - < Cl - < Br – < I -) [order of increase the strength of nucleophile]
(RO – > RS -), (HO – > HS -) [order of decrease the basic character]
(RO – < RS -), (HO – < HS -) [order of increase the strength of nucleophile]

Strong nucleophiles (bear a negative charge, HO – , RO – , HS - , RS - , NH2- )

present in high concentrations favor SN2 reactions
3- Effect of solvents: There are two types of solvents
Protic solvents: the solvents which contain hydrogen bonded to strongly
electronegative element such as oxygen, nitrogen or sulfur (N-H, O-H, S-H) and form
hydrogen bond with the substrates or their ions e.g. (H2O, CH3OH, C2H5OH, ………)

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Polar protic solvents (N-H, O-H, S-H) will reduce the strength of nucleophile and
will not favor SN2
A Protic solvents: the solvents whose molecules do not have a hydrogen atom that is
attached to strongly electronegative element. These solvent could not form hydrogen
bond with the substrates or their ions

A protic solvents favor SN2 reactions because nucleophiles are not well solvated,
and facilitate its attack into carbon atom.

2- Unimolecular Nucleophilic Substitution Reactions (SN1)

Rate = K [(CH3)3C-Br] [First order reaction]

The rate of the reaction depends on the concentration of alkyl halide only and
independent on the concentration of nucleophile. i.e. If we double the concentration
of alkyl halide the rate of the reaction will also double but if we change the
concentration of nucleophile, the rate of reaction will be constant (doesn’t change).
Mechanism of (SN1)

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Stereochemistry of SN1

The reaction proceeded by formation of achiral carbocation (planer) which was

attacked by nucleophile from both sides (front-side and back-side) to give pair of
enantiomers (R, S) (Racemic mixture). [Racemization takes place whenever the
reaction causes chiral molecules to be converted to an achiral intermediate]

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Factors affecting on SN1
1- Effect of substrate
As the number of alkyl group (or conjugated system) around the carbocation
increase, its stability will increase and will fervor SN1 mechanism

2- Concentration and Strength of nucleophiles

Weak nucleophiles, such as H2O and ROH favor SN1 reactions
Let us compare the substitution products formed when the (2°) alkyl halide (A) is
treated with either the strong nucleophile (HO¯) or the weak nucleophile (H 2O).
Because a (2°) alkyl halide can react by either mechanism, the strength of the
nucleophile determines which mechanism takes place.

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The strong nucleophile favors an SN2 mechanism

The weak nucleophile favors an SN1 mechanism

3- Effect of solvents:
Protic solvents (such as water molecules) will solvate the carbocations and halide
ions (X -) through hydrogen bond so the cleavage of (C-X) bond will be easy and the
rate of SN1 reaction will increase.

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 Summary of SN1 and SN2
Type of alkyl halide SN2 SN1
SN2 is favored SN1 is not favored

SN2 is favored SN1 is not favored

SN2 is favored in SN1 is favored in

Aprotic solvent and Protic solvent (H2O &
strong nucleophile ROH) and weak
(-ve charge) nucleophile (neutral
molecule)
SN2 is not favored SN1 is favored especially
in protic solvent

SN2 is not favored SN1 is favored especially

in protic solvent

Q/ Predict the type of nucleophilic substitution reaction and the stereochemistry

of the products in the following equations?

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3- Elimination Reactions (E)[Dehydrohalogenation]
Removal of halide ion (X-) from one carbon and (H+) from adjacent carbon to give
alkene product.

Base C2H5ONa KOH (CH3)3C-OK

Name Sodium ethoxide Potassium hydroxide Potassium tert-butoxide

Zaitsev’s Rule for Elimination

“The hydrogen atom is removed from the adjacent carbon atom which carries the
least number of hydrogen atoms to give more-substituted alkene as the major product
(more stable)”

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 Types of Elimination Reactions
1- Bimolecular Elimination Reaction (E2)

Rate = K [(CH3)2CH-Br] [Base] [Second order reaction]

The rate of the reaction depends on both the concentration of alkyl halide and the
base. If we double either the concentration of alkyl halide or base, the rate of the
reaction will also double.
Secondary and tertiary alkyl halides favor E2 with strong base and high
temperature.

Mechanism of (E2)

In this mechanism, the halide ion (Br-) and proton (H+) abstraction took place
simultaneously (at the same time) by strong base without formation of intermediate.

2- Unimolecular Elimination Reactions (E1)

Rate = K [(CH3)3C-Br] [First order reaction]

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The rate of the reaction depends on the concentration of alkyl halide only and
independent on the concentration of base.
Tertiary alkyl halide favors E1 with weak base, protic solvent, and high
temperature.

Mechanism of (E1)

In this mechanism, the halide ion (Br-) leaves to form carbocation. Then the base
removes (H+) from adjacent carbon to form alkene.

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