Pharmaceutical Organic Chemistry I (CPR 101)

Pharmaceutical Organic Chemistry I

1

Head of Department Prof. Dr. Adel Hamdy Ghiaty

Dr. Nirvana Gohar

Department of Organic Chemistry Faculty of Pharmacy

M.T.I University

2021-2022

Pharmaceutical Organic

Chemistry I

(CPR 101)


2

Course name: Pharmaceutical organic chemistry I

(CPR-101)

Academic year: 2021-2022

Course Specifications A- Basic Information

Program(s) on which the course is given: Clinical Pharm D of Pharmacy

Department responsible for offering the course: Department of Pharmaceutical

Organic Chemistry

Department responsible for teaching the course: Department of Pharmaceutical

Organic Chemistry

Academic year/level/Semester: 2021-2022/ Level I /Fall

Prerequisites and codes: none

Course title and code: Pharmaceutical Organic chemistry I

(CPR-101)

Course credit and contact hours: 3 Credit Hours, 4 Contact hours 2(2)

+1(2)

Number of teaching staff: 2

Name of internal evaluator: Ass. Prof. Dr. Tamer Nasr

Name of external evaluator: Prof. Dr. Ashraf Biomy

Date of specification approval: Sep.2021

Course Coordinator:

Fall term Spring term Summer term Dr. Nirvana Ali Gohar ---------- Dr. Nirvana Ali Gohar

B- Professional Information

1- Overall aims of the course:

At the end of this course the student must be able to: provide students with comprehensive knowledge,

clear understanding and outstanding skills of chemistry of aliphatic organic compounds, knowledge of

basic organic reactions. The structure, conformation and stereochemistry of hydrocarbons, as well as a


3

basic understanding of the fundamental principles of organic chemistry. The synthesis and reactivity of the

most important functional groups in organic compounds will be studied and considered.

2- Intended learning outcomes of course (ILOs):

a- Knowledge and understanding

At the end of this course the student must be able to:

a1- Define the organic compounds using systematic nomenclature methodology.

a2- Describe the appropriate chemical equations for the preparation and reactions of functional groups.

a3- Identify an unknown chemical aliphatic organic compound via its physical and chemical properties.

b- Intellectual skills


b1- Compare the molecules according to their relative physical and chemical properties.

b2- Correlate the principles of chemical reactions and mechanisms to organic functional groups

b3- Cite the chemical structures of carbohydrates, lipids and proteins to their biological and chemical

behavior.

c- Professional and/or Practical skills


c1- Handle chemicals effectively, employ laboratory safety and waste management techniques to preserve

personal and environmental safety.

c2- Appraise the appropriate chemical tests to identify practically an unknown aliphatic organic compound

and distinguish between different functional groups using simple chemical reactions practically.

c3-Reframe data in a suitable format, calculate results where appropriate and draw conclusions.

d- General and transferable skills


d1-Use information technology skills.

d2-Roleplay a greener approach for synthesis and handling a disposal of chemical compounds.

d3- Practice effective time management.


4

3- Contents:

3.1- Theoretical lectures:

Week no. Topic No. of

Lectures/week

Credit and

contact

hours/week

1st Introduction, bonding,

electronegativity, Hybridization, Isomerism

1 2

2nd Saturated hydrocarbons 1 2

3rd Unsaturated hydrocarbons 1 2

4th Organohalogen compounds 1 2

5th Organometallic compounds 1 2

6th Alcohols 1 2

7th Mid – Term Exam --- ---

8th phenols 1 2

9th Ethers 1 2

10th Aldehydes 1 2

11th Ketones 1 2

12th Amines, Carboxylic acids and derivatives

1 2

13th Carbohydrates and proteins 1 2

14th Final Written Exam --- ---

Total 12 24

3.2- Practical:

Week

no. Topic

No. of

Practical/week

Credit and

contact

hours/week

1st Safety in the organic chemistry laboratory

1 2

2nd Identification of the unknown via its physical properties

1 2

3rd Solubility scheme 1 2

4th Chemical characters 1 2

5th Identification of Aliphatic Alcohols 1 2


5

6th Revision 1 2

7th Mid – Term Exam --- ---

8th Identification of aldehydes 1 2

9th Identification of ketones 1 2

10th Identification of Carboxylic acids 1 2

11th Identification of salts of Carboxylic acids 1 2

12th Final Practical Exam --- ---

Total 10 20

4. Teaching and learning methods 4.1- interactive Lectures 4.2- Assignment and presentation 4.3- Laboratory classes

4.4- Case studying

5. Student assessment methods:

Methods of

Assessment

To a

sses

s

Achieved course ILOs Week Marks Weight

Quizes a1, b1

3rd 10 6.66

9th

Assignment d1, d2, d3 3rd – 11th 10 6.66

Mid – term exam a1, a2, b2 7th 25 16.66

Final practical exam a3, b3, c1, c2, c3 12th 40 26.66

Final written exam a1, a2, b1, b2 14th 50 33.33

Oral exam a1, a2 14th 15 10

Total 150 100%


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6. List of references

6.1- Course notes:

ISBN Number Author Date

Theoretical note: Organic Chemistry

I: For 1st Level Pharmacy Students

Prof. Dr. Adel Hamdy Ghiaty Dr. Nirvana Ali Gohar

2021

Laboratory manual: Practical

Organic Chemistry I: Qualitative Organic Analysis

Prof. Dr. Adel Hamdy Ghiaty Dr. Nirvana Ali Gohar

2021

6.2- Essential books (textbooks):

ISBN Number Author Date Title Publisher

9780582462366,0582462363

A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford,

P.W.G. Smith

1996 Title: Vogel's Textbook

on practical organic chemistry

Prentice Hall

6.3-Recommended books:

ISBN Number Author Date Title Publisher

307-310-316-3,763-797-919-9 Carey F.A 2004 Organic chemistry MGH

a) 6.4- Periodicals, Web sites, Etc: http://www.

American Chemical Society website: http://www.acs.org/

The Royal Society of Chemistry website: http://www.rsc.org/

ChemWiki:

http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biolo

gical_Emphasis

7. Facilities required for teaching and learning: a. Class rooms, laboratory facilities.

b. Computers, internet

c. Projectors

http://www/

http://www.acs.org/

http://www.rsc.org/

http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis

http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis


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Course Contribution in the Program ILO's

Course ILOs Achieved program ILO's

Knowledge and understanding A1

Intellectual skills B5

Professional and practical skills C2

General and transferable skills D6, D7 , D9

Course intended learning outcomes (course ILOs) matrix:

Theoretical lectures

Course Content

Course ILOs

Knowledge and

Understanding Intellectual Skills

Professional and

Practical Skills

General and

Transferable

Skills

Introduction, bonding, electronegativity, Hybridization,

Isomerism a2, a3 b1, b3 d2

Saturated hydrocarbons a1,a2,a3 b1,b2,b3 d1,d2 Unsaturated hydrocarbons a1,a2,a3 b1,b2,b3

Organohalogen compounds a1,a2,a3 b1,b2,b3 d1,d2 Organometallic compounds a1,a2,a3 b1,b2,b3 c1,c2,c3 d2,d3

Alcohols a1,a2,a3 b1,b2,b3 c1,c2,c3 d1,d2,d3 Ethers a1,a2,a3 b1,b2,b3 c1,c2,c3 d1,d2,d3

Aldehydes a1,a2,a3 b1,b2,b3 d1,d2,d3 Ketones a1,a2,a3 b1,b2,b3 d1,d2,d3

Carboxylic acids and derivatives a1,a2,a3 b1,b2,b3 d1,d2,d3

Practical Safety in the organic chemistry

laboratory a3 b1 c1 d2,d3

Identification of the unknown via its physical properties a2,a3 b1,b2 c1,c2,c3 d2,d3

Solubility scheme a2,a3 b1,b2,b3 c1,c2,c3 d2,d3 Chemical characters a2,a3 b1,b2,b3 c1,c2,c3 d2,d3

Identification of Aliphatic Alcohols a2,a3 b1,b2,b3 c1,c2,c3 d2,d3 Identification of aldehydes a2,a3 b1,b2,b3 c1,c2,c3 d2,d3

Identification of ketones a2,a3 b1,b2,b3 c1,c2,c3 d2,d3

Identification of Carboxylic acids a2,a3 b1,b2,b3 c1,c2,c3 d2,d3


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Identification of salts of Carboxylic acids

a2,a3 b1,b2,b3 c1,c2,c3 d2,d3

Course Plan

Teaching and learning methods

Course ILOs

Knowledge and

understanding Intellectual Skills

Professional and

Practical Skills

General and

Transferable

Skills

Interactive Lectures a1, a2 b1, b2 d1, d3 Assignments and presentation a1, a3 d2, d3

Case studying b1, b3

Laboratory classes c2, c3

Course Coordinator: Dr. Nirvana Ali Gohar

Head of Department Prof. Dr. Adel Hamdy Ghiaty

Date Sep.2021


9

Chapter 1

Structure and bonding in organic

molecules


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Introduction:

What is organic chemistry? Why should you study it?

The answers to these questions are everywhere. Every living organism is composed

of organic chemicals; the food you eat and most medicines you take are organic

chemicals; the wood, paper, plastics and fibers that make modern life possible are

organic chemicals.

The historical roots of organic chemistry can be traced to the mid-1700s when

alchemists noticed unexplainable differences between compounds derived from

living sources and those derived from minerals. Therefore, chemicals were

classified into organic and inorganic substances, and the term organic chemistry

came to mean the chemistry of compounds from living organisms. To many

chemists of the time, the only explanation of the difference in behavior between

organic and inorganic compounds was that organic compounds contained an

indefinable “vital force” because of their origin in living sources.

However, Friedrich Wohler’s synthesis of urea (organic substance) in 1828 in the

lab from the (inorganic salt) ammonium cyanate, this achievement served as

milestone event contributed to a “demystification of the vital force theory" and

illuminated the entrance to a path which subsequently led to great and countless

achievements in organic synthesis.

The only unifying characteristic of organic compounds is that they all contain the

element carbon. Organic chemistry, then, is the study of compounds of carbon.

Bonding and Molecular structure


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But why is carbon special? What is it that sets carbon apart from all other

elements in the periodic table? This could be attributed to the unique ability of

carbon atoms to bond together, forming rings and long chains. Carbon, alone of

all elements, can form enormous diversity of compounds, from the simple to the

complex, from methane, containing 1 carbon to DNA, which can contain tens of

billions.

Atomic structure

The atom consists of a dense, positively charged nucleus surrounded at a relatively

large distance by negatively charged electrons. The nucleus consists of subatomic

particles called neutrons, which are electrically neutral, and protons, which are

positively charged. The positive charges equal the negative charges, so the atom has

no overall charge; it is electrically neutral. Most of an atom’s mass is in its nucleus;

the mass of the electron is negligible. Although the nucleus is heavy, it is quite small

compared with the overall size of an atom. Electrons orbit the nucleus at

approximately 10-10 m. thus the diameter of atypical atom is about 2 X 10-10 m, often

called 2 angstroms (Å), where 1 Å = 10-10 m.

Schematic view of atom

Table 1: Fundamental particles of the matter

Particle Charge Mass (amu)

Proton +1 1.00728

Neutron 0 1.00867

Electron -1 0.000549

An atom is described by its atomic number, which is the number of protons in

the atom’s nucleus, and its mass number, which is the number of protons and


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neutrons. All the atoms of a given element have the same atomic number 1 for

hydrogen, 6 for carbon, and 7 for nitrogen and so on but they can have different

mass numbers depending on how many neutrons they contain.

Isotopes: although all atoms of an element have the same number of protons, the

atoms may differ in the number of neutrons they have. These differing atoms of

the same element are called isotopes. For example, 35Cl (75.53% of all chlorine

atoms found in nature) has 18 neutrons in its nucleus and its isotope 37Cl (24.47%)

has 20 neutrons, 12C and 13C …etc. the weighted average mass in atomic mass

units (amu) of an element’s isotopes is called the element’s atomic weight: 1.008

for hydrogen, 12.011 for carbon, 35.453 for chlorine, and so on.

Orbitals

How are the electrons distributed in an atom? According to the quantum

mechanical model of the atom, the motion of an electron around the nucleus can

be described mathematically by what is known as a wave equation–the same sort

of expression used to describe the motion of waves in a fluid. The solution to

wave equation is called a wave function or orbital and is denoted by the Greek

letter psi (ψ). A good way of viewing an orbital is to think of it as a mathematical

expression whose square, ψ2, predicts the volume of space around the nucleus

where an electron is most likely be found.

Although we don’t know the exact position of an electron at a given moment, the

orbitals till us where we would be most likely to find it. You might think of an

orbital as looking like a blurry cloud indicating the region of space around the

nucleus where the electron has recently been. This electron cloud doesn’t have

sharp boundary, but for practical purposes we can set the limits by saying that an

orbital represents the space where an electron spends most (90-95%) of its time.


13

What do orbitals look like? There are 4 kinds of orbitals, denoted s, p, d, and f.

of the 4 we’ll be concerned only with s and p orbitals because most of atoms

found in living organisms use only these. The s orbitals have spherical shape with

the nucleus at the center, and the p orbitals have a dumbbell shape as shown in

figure 1:

Figure 1: shapes of atomic orbitals

Note that shell p is subdivided into 3 different p orbitals, oriented in space so that

each is perpendicular to the other two and they are denoted as Px, Py and Pz

depending on which coordinate axis they lie.

The different shells have different numbers and kinds of orbitals. The two

electrons of the first shell occupy a single s orbital, designated 1s. The eight

electrons of the second shell occupy one S orbital (designated 2s) and three p

orbitals (each designated 2p). These electron distributions and their relative

energy levels are indicated in figure 2.

Figure 2: Relative energies of S & P orbitals


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Because electrons are in constant motion around the nucleus, it is not possible to

define their exact locations. It turns out, though, that electrons are not completely

free to move; different electrons are confined to different regions within the atom

according to the amount of energy they have. The farther a shell is from the

nucleus, the more electrons it can hold and the greater the energies of those

electrons. Thus, an atom’s lowest energy electrons occupy the first shell, which

is nearest the nucleus and has the capacity of only two electrons. The second shell

is farther from the nucleus and can hold eight electrons; the third shell is still

farther from the nucleus and can hold eighteen electrons. The number of electrons

could be hold by a shell is given by the following formula: 2(n2) where n =

number of shell.

Table 2: Distribution of electrons into shells

No of shell Electron capacity of shell

First 2

Second 8

Third 18

Fourth 32

Electronic configuration of atoms

The lowest energy arrangement, or ground state electronic configuration, of any

atom is a description of the orbitals that the atom’s electrons occupy. This state

could be determined by the following three rules:

1. The orbitals of lowest energy (those nearest the nucleus) are filled first. (Aufbau principle).

2. Only two electrons can occupy the same orbital and must be of opposite spin. (Pauli

exclusion principle)

3. If two or more empty orbitals of equal energy are available, one electron is placed in each

until all are half-full. (Hund’s rule)

Some examples of how these rules are applied are shown below.

Table 3: Electron configurations in the periodic table


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1A 2A 3A 4A 5A 6A 7A 8A

1

H

1s1

2

He

1s2

3

Li

1s2

2s1

4

Be

1s2

2s2

5

B

1s2

2s22p1

6

C

1s2

2s22p2

7

N

1s2

2s22p3

8

O

1s2

2s22p4

9

F

1s2

2s22p5

10

Ne

1s2

2s22p6

According to the Aufbau principle, the electrons of an atom occupy orbitals

starting from the lowest energy level, and proceeding to the highest, with each

orbital holding a maximum of two paired electrons (opposite spins). The highest

occupied electron shell is called the valence shell, and the electrons occupying

this shell are called valence electrons. The chemical properties of the elements

reflect their electron configurations. For example, helium, neon and argon are

exceptionally stable and unreactive monoatomic gases. Helium is unique since

its valence shell consists of a single s-orbital. The other members of group 8 have

a characteristic valence shell electron octet (ns2 + npx2 + npy

2 + npz2).

Chemical Bonding and Valence

Why do the atoms of many elements interact with each other and with other

elements to give stable molecules? In addressing this question, it is instructive to

begin with a very simple model for the attraction or bonding of atoms to each

other, and then progress to more sophisticated explanations.

Ionic Bonding

When sodium is burned in a chlorine atmosphere, it produces the compound

sodium chloride. This has a high melting point (800 °C) and dissolves in water to

give a conducting solution. Sodium chloride is an ionic compound, and the

crystalline solid has the structure shown above. Transfer of the lone 3s electron

of a sodium atom to the half-filled 3p orbital of a chlorine atom generates a

sodium cation and a chloride anion. Electrostatic attraction results in these

javascript:chse1();


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oppositely charged ions packing together in a lattice. The attractive forces

holding the ions in place can be referred to as ionic bonds.

Covalent Bonding

A different attractive interaction between atoms, called covalent bonding, is

involved in H2 and CO2. Covalent bonding occurs by a sharing of valence

electrons, rather than a complete electron transfer. Similarities in physical

properties (they are all gases) suggest that the diatomic elements H2, N2, O2, and

F2 & Cl2 also have covalent bonds.

Examples of covalent bonding shown below include hydrogen and fluorine.

These illustrations use a simple Bohr notation, with valence electrons designated

by dots. Note that both hydrogen atoms achieve a helium-like pair of 1s-electrons

by sharing.

Figure 4: examples of covalent bonding

Covalent bonding is of two types:

1. Non-polar: Where the distribution of shared electron will be symmetrical i.e.

the two electrons are equally influenced by identical nuclei, e.g. H2, F2, and

Cl2.

2. Polar: Where the distribution of shared electrons will be unsymmetrical, e.g.

HCl and HF. In this case the electrons of the covalent bond will be drifted

toward the more electronegative atom represented in Cl or F in the above

examples.


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Co-ordinate bond

The electrons forming the bond are donated by one atom (electron donor) and the

other atom that accept the electron (electron acceptor) to complete the number of

electrons to achieve stable configuration e.g. ammonia and BF3.

N

H

H

H B

F

F

F O

H3C

H3C

B

F

F

F

These electron sharing diagrams (Lewis formulas) are a useful first step in

understanding covalent bonding, but it is quicker and easier to draw Couper-

Kekulé formulas in which each shared electron pair is represented by a line

between the atom symbols. Non-bonding valence electrons are shown as dots.

These formulas are derived from the graphic notations suggested by A. Couper

and A. Kekulé. Some examples of such structural formulas are given in the

following table.

Table 4: Representation of molecular structure:

Common Name Molecular Formula Lewis Formula Kekulé Formula

Methane CH4

C H

H

H

H

Ammonia NH3

N

H

H

H

N

H

H

H Ethane C2H6

C

H

H

H CH

H

H C

H

H

H

C H

H

H Acetylene C2H2 CH C H

CH C H

Multiple bonding, the sharing of two or more electron pairs, is illustrated by

ethylene (has a double bond), and acetylene (with a triple bond). Boron

compounds such as BH3 and BF3 are exceptional in that conventional covalent

bonding does not expand the valence shell occupancy of boron to an octet.

http://www.chemistry.msu.edu/Portraits/PortraitsHH_Detail.asp?HH_LName=Kekule


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Consequently, these compounds have an affinity for electrons, and they exhibit

exceptional reactivity when compared with the compounds shown above.

Valence

The number of valence shell electrons an atom must gain or lose to achieve a

valence octet is called valence. In covalent compounds the number of bonds

which are characteristically formed by a given atom is equal to that atom's

valence. From the formulas written above, we arrive at the following general

valence assignments:

Atom H C N O F Cl Br I

Valence 1 4 3 2 1 1 1 1

The valences noted here represent the most common form these elements assume

in organic compounds. Many elements, such as chlorine, bromine and iodine, are

known to exist in several valence states in different inorganic compounds.

Atomic and Molecular Orbitals

A more detailed model of covalent bonding requires a consideration of valence

shell atomic orbitals. For second period elements such as carbon, nitrogen and

oxygen, these orbitals have been designated 2s, 2px, 2py & 2pz. The spatial

distribution of electrons occupying each of these orbitals is shown in the diagram

below.

Figure 5: shapes of molecular orbitals


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The valence shell electron configuration of carbon is 2S2, 2px1, 2py

1 & 2pz0. If this

were the configuration used in covalent bonding, carbon would only be able to form

two bonds.

Molecular Orbitals

Just as the valence electrons of atoms occupy atomic orbitals (AO), the shared

electron pairs of covalently bonded atoms may be thought of as occupying

molecular orbitals (MO). It is convenient to approximate molecular orbitals by

combining or mixing two or more atomic orbitals. In general, this mixing of n

atomic orbitals always generates n molecular orbitals. The hydrogen molecule

provides a simple example of MO formation. In the following diagram, two 1s

atomic orbitals combine to give a sigma (σ) bonding (low energy) molecular

orbital and a second higher energy MO referred to as an antibonding orbital. The

bonding MO is occupied by two electrons of opposite spin, the result being a

covalent bond.

Figure 7: overlap of two 1s orbitals gives rise to a σ and σ* orbitals

The notation used for molecular orbitals parallels that used for atomic orbitals.

Thus, s-orbitals have a spherical symmetry surrounding a single nucleus, whereas

σ-orbitals have a cylindrical symmetry and encompass two (or more) nuclei. In

the case of bonds between second period elements, p-orbitals or hybrid atomic

orbitals having p-orbital character are used to form molecular orbitals. For


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example, the sigma molecular orbital that serves to bond two fluorine atoms

together is generated by the head to head overlap of p-orbitals (part A below),

and two sp3 hybrid orbitals of carbon may combine to give a similar sigma orbital.

When these bonding orbitals are occupied by a pair of electrons a covalent bond

(sigma bond) generated. Although we have ignored the remaining p-orbitals, their

inclusion in a molecular orbital treatment does not lead to any additional bonding.

Figure 8: σ orbital formation from 2 p-orbitals (A) and from 2 sp3 orbitals (B):

Another type of MO (the π orbital) may be formed from two p-orbitals by a

lateral overlap, as shown in part A of the following diagram. Since bonds

consisting of occupied π-orbitals (pi-bonds) are weaker than sigma bonds, pi-

bonding between two atoms occurs only when a sigma bond has already been

established. Thus, pi-bonding is generally found only as a component of double

and triple covalent bonds. Since carbon atoms involved in double bonds have

only three bonding partners, they require only three hybrid orbitals to contribute

to three sigma bonds. A mixing of the 2S-orbital with two of the 2p orbitals gives

three sp2 hybrid orbitals, leaving one of the p-orbitals unused. Two sp2 hybridized

carbon atoms are then joined by sigma and pi-bonds (a double bond), as shown

in part B.


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Figure 9: π orbital formation from 2 p-orbitals

Figure 10: π orbital formation from 2 sp2-orbitals

The 1s and 2s atomic orbitals do not provide any overall bonding, since orbital

overlap is minimal, and the resulting sigma bonding and antibonding components

would cancel. In both these cases three 2p atomic orbitals combine to form a

sigma and two pi-molecular orbitals, each as a bonding and antibonding pair. The

overall bonding order depends on the number of antibonding orbitals that are

occupied. The subtle change in the energy of the σ2p bonding orbital, relative to

the two degenerate π-bonding orbitals, is due to s-p hybridization.

Finally, in the case of carbon atoms with only two bonding partners only two hybrid

orbitals are needed for the sigma bonds, and these sp hybrid orbitals are directed

180° from each other. Two p-orbitals remain unused on each sp hybridized atom,

and these overlaps to give two pi-bonds following the formation of a sigma bond (a

triple bond), as shown below.

Figure 11: π orbital formation from 2 sp-orbitals


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Intramolecular forces

The actual structure of a molecule is the net result of a combination of repulsive

and attractive forces, which are related to charge and electron spin.

a) Repulsive forces:

Electrons tend to stay as far apart as possible because they have the same charge and,

if they are unpaired, because they have the same spin (Pauli Exclusion Principle).

The like-charged atomic nuclei, too, repel each other.

b) Attractive forces:

Electrons are attracted by atomic nuclei and atomic nuclei are attracted by electrons,

because of their opposite charges. The bonding electrons, hence, tend to occupy the

region between two nuclei. Opposite spin permits two electrons to occupy the same

region.

Polarity of Bonds

Because of their differing nuclear charges, and because of shielding by inner

electron shells, the different atoms of the periodic table have different affinities

for nearby electrons. The ability of an element to attract or hold onto electrons is

called electronegativity. A rough quantitative scale of electronegativity values

was established by Linus Pauling, and some of these are given in the following

table. A larger number on this scale signifies a greater affinity for electrons.

Fluorine has the greatest electronegativity of all the elements, and the heavier


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alkali metals such as potassium, rubidium and cesium have the lowest

electronegativities. It should be noted that carbon is about in the middle of the

electronegativity range and is slightly more electronegative than hydrogen.

H

2.20

Electronegativity values for some elements

Li

0.98

Be

1.57

B

2.04

C

2.55

N

3.04

O

3.44

F

3.98

Na

0.90

Mg

1.31

Al

1.61

Si

1.90

P

2.19

S

2.58

Cl

3.16

K

0.82

Ca

1.00

Ga

1.81

Ge

2.01

As

2.18

Se

2.55

Br

2.96

When two different atoms are bonded covalently, the shared electrons are

attracted to the more electronegative atom of the bond, resulting in a shift of

electron density toward the more electronegative atom. Such a covalent bond is

polar and will have a dipole (one end is positive and the other end negative). The

degree of polarity and the magnitude of the bond dipole will be proportional to

the difference in electronegativity of the bonded atoms. Thus, an O–H bond is

more polar than a C–H bond, with the hydrogen atom of the former being more

positive than the hydrogen bonded to carbon. Likewise, C–Cl and C–Li bonds

are both polar, but the carbon end is positive in the former and negative in the

latter. The dipolar nature of these bonds is often indicated by a partial charge

notation (δ+/–) or by an arrow pointing to the negative end of the bond.

Although there is a small electronegativity difference between carbon and

hydrogen, the C–H bond is regarded as weakly polar at best, and hydrocarbons

in general are non-polar compounds.


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The shift of electron density in a covalent bond toward the more electronegative

atom or group can be observed in several ways. For bonds to hydrogen, acidity

is one criterion. If the bonding electron pair moves away from the hydrogen

nucleus the proton will be more easily transferred to a base (it will be more

acidic). A comparison of the acidities of methane, water and hydrofluoric acid is

instructive. Methane is essentially non-acidic, since the C–H bond is nearly non-

polar. As noted above, the O–H bond of water is polar, and it is at least 25 powers

of ten (1025) more acidic than methane. H–F is over 12 powers of ten more acidic

than water because of the greater electronegativity difference in its atoms.

Electronegativity differences may be transmitted through connecting covalent

bonds by an inductive effect. Replacing one of the hydrogens of water by a more

electronegative atom increases the acidity of the remaining O–H bond. Thus,

hydrogen peroxide, HO–O–H, is 10,000 times more acidic than water, and

hypochlorous acid, Cl–O–H is one hundred million times more acidic. This

inductive transfer of polarity fades out as the number of transmitting bonds

increases, and the presence of more than one highly electronegative atom has a

cumulative effect. For example, trifluoro ethanol, CF3CH2–O–H is about ten

thousand times more acidic than ethanol, CH3CH2–O–H.

Electronegativity F > O > Cl, N> Br > C, H

Polarity of molecules

Polar molecule constitutes a dipole: two equal and opposite charges separated in

space.

A dipole is often symbolized ( ) where the arrow points from positive to

negative. The molecule possesses a dipole moment () which is equal to the

magnitude of the charge (e) multiplied by the distance (d) between the centers of

charges.


25

= e x d

[Units of is debye (D), e units is (e.s.u) and d units is (Å)]

Importance of Dipole moment:

1) Reveal the character of chemical bond whether ionic, covalent or polar bond

2) Indicate the geometrical structure of the molecules

In CO2 the C-O bond oppose each other and canceled (=Zero)

A zero dipole indicates symmetrical distribution of - about + carbon in CO2 so

the geometry must be linear.

3) Differentiation of identically Disubstituted isomers

For disubstituted benzene the will be zero only for the group which have linear

moment (at Para- position), but ortho- and meta- will be not zero

4) Assigning the configuration of geometrical isomers

Trans isomer have equal and opposite bond moment leaving a zero D while cis

isomer has a magnitude of value, so for assignment of two isomers the values

were measured, and the type of isomer is concluded whether cis or trans.


26

Some values of dipole moments:

H2 0 HF 1.75 CH4 0

O2 0 H2O 1.84 CH3Cl 0.86

N2 0 NH3 1.46 CCl4 0

Cl2 0 NF3 0.24 CO2 0

Br2 0 BF3 0

Molecules like hydrogen, oxygen or chlorine have zero dipole moments that are

non-polar. The two identical atoms of each of these molecules have the same

electronegativity and share electrons equally, i.e. (e) will be zero so () will be

also zero.

A molecule like hydrogen fluoride has a high dipole moment of 1.75 D. although

HF is a small molecule, the very high electronegative fluorine pulls the electrons

strongly; although (d) is small (e) is large and hence the dipole moment is large.

Water has a dipole moment to 1.84D; this is a vector sum, resulting from two

individual moments. Ammonia also has a net dipole (vector sum). The directions

of polarity in molecules have net dipole moments (vector sum) is the direction of

the vector sum.

Dipole moments of molecules, polarity of bonds and molecules

Dipole moments can give valuable information about the structure of molecules.

For example, any structure for CCl4 that would result in a polar molecule can be

ruled out based on dipole moment alone. The evidence of dipole moment thus

supports the tetrahedral structure for CCl4. The physical properties of a

compound depend upon which kind of bonds hold its component atoms together.


27

Inductive effect:

After studying the polarity of bonds, a question may appear; how does a

substituent exert its polar effect? We shall consider electron withdrawal and

electron release to result from the operation of inductive effect (and resonance

effect also). The inductive effect depends upon the intrinsic tendency of a

substituent to release or withdraw electrons (i.e. its electronegativity).

Electronegativity is acting either through molecular chain or through space. Try

to make a thorough look for the following table.

Ka value (Acidity constants) of carboxylic acids.

HCOOH 17.7 X10-5 ClCH2COOH 136 X 10-5 CH3COOH 1.7 X 10-5 CH3CH2CH(Cl)COOH 139 X10-5 CH3CH2CH2COOH 1.5 X 10-5 CH3CH(Cl)CH2COOH 8.9 X10-5 ClCH2CH2CH2COOH 2.7 X10-5

It has been noticed that chlorine withdraws electrons from the attached carbon

and so forth thus increasing the acidity of the acid having a chlorine atom e.g.

acetic and chloroacetic acids. The effect weakens steadily with increasing

distance from the substituent.

Cl←CH2←CH2←CH2←COOH

Most elements likely to be substituted for hydrogen in an organic molecule are

more electronegative than hydrogen, so that most of the substituents exert

electron-withdrawing inductive effects e.g. F, Cl, I, Br, OH, NH2, NO2.

Importance of Inductive and Mesomeric effect

1) They have an influence on the basicity and acidity of the compounds, where

a comparison was made based on releasing and drawing of the electrons.


28

Intermolecular forces

The interionic forces seem to be electrostatic in nature, involving attraction of

positive charge for negative charge. There are two kinds of intermolecular forces:

dipole-dipole interaction and van der Waals forces.

Dipole-dipole interaction

It is the attraction of the positive end of one polar molecule for the negative end

of another polar molecule. In HCl, e.g., the relatively positive hydrogen of one

molecule is attracted to the relatively negative chlorine of another molecule.

Because of this type of interaction polar molecules are generally held to each

other more strongly than are non-polar molecules of comparable molecular

weight.

There must be forces between the molecules of a non-polar compound; Van der

Waals (London) forces. The average distribution of charge about e.g. methane

molecule is symmetrical so that there is no net dipole moment. However, the

electrons move about, so that at any instant of time the electron distribution will

probably be distorted and a small dipole, momentary, will exist. The momentary

dipole will affect the end in a second nearby molecule. The negative end of the

dipole tends to repel electrons on the positive end which tends to attract electrons;

the dipole thus induces an opposite oriented dipole in the neighboring molecules.

Although the momentary dipoles and induced dipoles are constantly changing,

the net result is attraction between the two molecules. The forces acting are only


29

portions of the surfaces of different molecules that are in close contact. The large

the surface area of a non-polar molecule, the higher the Van der Waals forces

between molecules. This applies for only attractive forces between non-polar

molecules.

Hydrogen bonding:

It is described as an attractive force that occurs between certain types of

molecules. When hydrogen is covalently bonded to the more electronegative

elements (e.g. O, N, F) it become somewhat electron-deficient taking on a partial

positive charge (δ+). Thus, the hydrogen atom has an increased affinity for the

non-bonded electrons of other electronegative atoms in neighboring molecules.

This attraction is not usually enough to cause the original covalent bond to break.

The type of interaction between water molecules is an example of this

OH

OH

OH

OH

OH

H H H H H

Hydrogen bonding is responsible for physical and chemical properties of water

and alcohols. Compared to hydrogen sulfide (gas), water has a high boiling point

due to the strong association between the molecules through hydrogen bonding.

This type of association can also occur between unlike molecules e.g. ammonia,

water and aqueous HCl… etc. Hydrogen bonding is also important in interactions

between complex molecules and in proteins. It is also important for binding in

drug-receptor interactions.

There are two types of hydrogen bond:

a) Intermolecular hydrogen bond: That occurs between molecules (of the same

structure or different structure), as in water molecules in the above-mentioned

example.


30

b) Intramolecular hydrogen bond: That occurs within the same molecules

The Intramolecular H. B will affect acidity. Salicylic acid more acidic than benzoic

acid due to the Intramolecular H.B., and it affects the melting and boiling point, e.g.

p- and o-nitro phenol

P-nitro phenol has high boiling and melting point due to association of long chain

of molecules by H.B while o-nitro phenol has no such association will occur due

to steric effect.

Nature of Chemical Reactions

Molecules formation is accompanied by liberation of energy. In contrast, for a

molecule to break into atoms, an equivalent amount of energy must be consumed.

The amount of energy consumed or liberated when a bond is broken is known as

bond dissociation energy.

Types of bond fission (dissociation)

The chemical reaction between two substances involves breaking of already

existing bond/s and formation of a new one. Thus, in the hydrolysis of alkyl

halides (e.g. methyl chloride) to the corresponding alcohols (e.g. methyl alcohol),

the covalent bond (C-Cl) is broken and a new covalent bond (C-OH) is formed.


31

H3C-Cl + NaOH (aqueous) → H3C-OH + NaCl

Breaking of a simple covalent bond can take place in two different ways:

1) Heterolysis (Heterolytic Fission):

In this type of fission, the bond is broken unsymmetrically, i.e. the two electrons are

retained by one atom. Such fission results in the formation of ions.

A: B A+ + B- A: B A- + B+

Reactions in which this type of fission occurs are known as heterolytic or ionic

reactions. Such reactions are said to proceed through an ionic mechanism.

Heterolytic fission is the most common in reactions taking place in solution,

because the energy required to break the bond can be partly derived from the

energy of solvation of the opposite charges produced.

2) Homolysis (Homolytic Fission):

This type involves symmetrical breaking of the shared electron pair, one electron

being retained by each atom.

A: B A. + B.

This type of fission leads to the formation of free radicals each possessing an odd

(unpaired) electron. Reactions in which the fission occurs are classified as

homolytic or free radical reactions. Such reactions are said to proceed through a

free radical mechanism. The homolytic fission is predominant in gaseous phase.

It does, however, also occur in solutions.

Types of Reagents

1. Nucleophiles or nucleophilic reagents (electron donors):


32

A nucleophilic reagent (electron rich) is one which in reaction, donates electrons

to share by its electrons with the center attacked. Attack by such reagents will be

facilitated by low electron density at the center attacked.

N: + R: X N: R + : X

1- Electrophilic reagents

The attack of an electrophilic reagent (electron acceptor, E) on an organic molecule

can be generally represented by: E + R: Y → E: R + Y. The electrophilic

reagent (electron deficient) accepts a share of the electrons of the bonding orbital of

R:Y, the reaction results in the formation of the new E:R bond. The R-Y bond breaks

with the release of Y without the bonding electrons.

Types of organic reactions

Four Reaction Classes

Addition

Elimination

Substitution Rearrangement

Reactive Intermediates:

The products of bond breaking, shown above, are not stable in the usual sense,

and cannot be isolated for prolonged study. Such species are referred to as

reactive intermediates and are believed to be transient intermediates in many

reactions. The general structures and names of four such intermediates are given

below.


33

Functional groups – special groups of reactive atoms that enable carrying out

chemical reactions in many organic compounds. Organic reactions are facilitated and

controlled by the functional groups of the reactants.

Functional groups


34

Chapter 2

Hydrocarbons


35

Hydrocarbons are compounds that only contain carbon and hydrogen

atoms, and they can be classified as follows depending on the bond types

that are present within the molecules.

Alkanes

Hydrocarbons having single bonds are classified as alkanes. The

carbon atoms of the molecule are arranged in chains (alkanes) or in rings

(cycloalkanes).

All alkanes have the general molecular formula CnH2n+2 and are

called saturated hydrocarbons. A group derived from an alkane by

removal of one of its hydrogen atoms is known as an alkyl group, for

example the methyl group (CH3_) from methane (CH4).

The IUPAC nomenclature of alkanes

In general, organic compounds are given systematic names (IUPAC

naming) by using the order prefix–parent–suffix, where:

Prefix indicates how many branching groups are present.

Parent indicates how many carbons are in the longest chain.

Suffix indicates the name of the family.

Hydrocarbons


36

Common names as well as systematic names are used for alkanes

and their derivatives. However, it is advisable to use systematic names or

the IUPAC (International Union of Pure and Applied Chemistry)

nomenclature, which can be derived from a simple set of rules.

Prefix Parent Suffix

What is the primary functioal group?

How manycarbons?

Where and what are the substituents

The IUPAC naming of the alkanes is based on a prefix indicating the

number of carbon atoms in the chain (as shown below) followed by the

suffix -ane. For example, if a chain contains three carbons the parent name

is propane, if four carbons the parent name is butane and so on. The

remaining parts of the structure are treated as substituents on the chain.

Numbers are used to indicate the positions of the substituents on the parent

carbon chain.

Prefix Number of carbon atoms Prefix Number of carbon atoms

Meth- 1 Hept- 7

Eth- 2 Oct- 8

Prop- 3 Non- 9

But- 4 Dec- 10

Pent- 5 Undec- 11

Hex- 6 Dodec- 12

1. First, determine the number of carbons in the longest continuous chain.

2. Number the chain so that the substituent gets the lowest possible

number.

3. Numbers are used only for systematic names, never for common names.

Substituents are listed in alphabetical order. A number and a word are


37

separated by a hyphen; numbers are separated by a comma. di, tri, tetra,

sec, and tert are ignored in alphabetizing. iso, neo, and cyclo are not

ignored in alphabetizing.

4. Only if the same set of numbers is obtained in both directions does the

first group cited get the lower number.

5. In the case of two hydrocarbon chains with the same number of carbons,

choose the one with the most substituents.

Isomerism and physical properties

Compounds that differ from each other in their molecular formulas by the

unit _CH2_ are called members of homologous series.

Compounds that have same molecular formula but different order of

attachment of their atoms are called constitutional isomers. For the

molecular formulas CH4, C2H6 and C3H8, only one order of attachment of

atoms is possible. The molecular formula C4H10 gives rise to two different

structural formulas in which 4 carbon atoms and 10 hydrogen atoms can be

connected to each other in the following ways. These structures also can

be drawn using line drawings, where zigzag lines represent carbon chains.

Isobutane (2-methylpropane) and n-Butane are constitutional isomers.


38

Their structures differ in connectivity, and they are different compounds.

They have different physical properties, e.g. different boiling points.

Alkanes have similar chemical properties, but their physical properties

vary with molecular weight and the shape of the molecule.

Compared with other functional groups, alkanes have low melting and

boiling points, and low solubility in polar solvents, e.g. water, but high

solubility in nonpolar solvents, e.g. hexane. Most cycloalkanes also have

low polarity.

Name Number of carbons

Molecular formula

Condensed structure

b.p (⁰C) mp (⁰C)

Methane 1 CH4 CH4 -160 -183

Ethane 2 C2H6 CH3CH3 -88.6 -183.3 Propane 3 C3H8 CH3CH2CH3 -42.1 -189.7 Butane 4 C4H10 CH3(CH2)2CH3 -0.60 -138.4 Pentane 5 C5H12 CH3(CH2)3CH3 36.1 -129.7 Hexane 6 C6H14 CH3(CH2)4CH3 68.9 -93.5 Heptane 7 C7H16 CH3(CH2)5CH3 98.4 -90.6 Octane 8 C8H18 CH3(CH2)6CH3 125.7 -56.8 Nonane 9 C9H20 CH3(CH2)7CH3 150.8 -51.0 Decane 10 C10H22 CH3(CH2)8CH3 174.1 -29.7

Undecane 11 C11H24 CH3(CH2)9CH3 196 -26.0 Dodecane 12 C12H26 CH3(CH2)10CH3 216 -10.0

The boiling points of alkanes increase steadily with increasing molecular

weights, as shown in the above table. Alkanes from methane to butane are

gases at room temperature.

Structure and conformation of alkanes

Alkanes have only sp3-hybridized carbons. Methane (CH4) is a

nonpolar molecule and has four covalent carbon–hydrogen bonds. In


39

methane, all four C_H bonds have the same length (1.10 Å), and all the

bond angles (109.5⁰) are the same.

Three different ways to represent a methane molecule are shown here.

One of the hydrogen atoms in CH4 is replaced by another atom or

group to give a new derivative, such as alkyl halide or alcohol.

Chloromethane (CH3Cl) is a compound in which one of the hydrogen

atoms in CH4 is substituted by a Cl atom.

H C

H

H

or H C

H

Cl

H

orH3C H3C Cl H3C OHH C

H

OH

H

or

Methyl group(An alkyl group)

Methyl chloride(An alkyl halide)

Methyl alcohol(An alcohol)

Names of some alkyl groups:

Alkyl

group

structure Alkyl

group

structure

Methyl CH3- Isobutyl

Ethyl CH3CH2- Sec-Butyl

H3CH2CHC CH3

Propyl CH3CH2CH2- Isopentyl

Isopropyl

tert-butyl

Butyl CH3CH2 CH2CH2- neopentyl

Classification of carbon substitution

A carbon atom is classified as primary (1⁰), secondary (2⁰), tertiary

(3⁰) and quaternary (4⁰) depending on the number of carbon atoms bonded


40

to it. A carbon atom bonded to only one carbon atom is known as 1⁰; when

bonded to two carbon atoms, it is 2⁰; when bonded to three carbon atoms,

it is 3⁰, and when bonded to four carbon atoms, it is known as 4⁰. Different

types of carbon atoms are shown in the following compound.

Cycloalkanes

Cycloalkanes are alkanes that are cyclic with the general formula CnH2n.

Name Molecular

formula

Structural

formula

Name Molecular

formula

Structural

formula

Cyclopropane C3H6

Cyclopentane C5H10

Cyclobutane C4H8

Cyclohexane C6H12

Nomenclature of cycloalkanes

The nomenclature of cycloalkanes is almost the same as that for alkanes,

with the exception that the prefix cyclo- is to be added to the name of the

alkane. When a substituent is present on the ring, the name of the

substituent is added as a prefix to the name of the cycloalkane. No number

is required for rings with only one substituent.

However, if two or more substituents are present on the ring,

numbering starts from the carbon that has the group of alphabetical


41

priority, and proceeds around the ring to give the second substituent the

lowest number.

When the number of carbons in the ring is greater than or equal to

the number of carbons in the longest chain, the compound is named as a

cycloalkane. However, if an alkyl chain of the cycloalkane has a greater

number of carbons, then the alkyl chain is used as the parent, and the

cycloalkane as a cycloalkyl substituent.

Physical properties of cycloalkanes

Cycloalkenes are nonpolar molecules like alkanes. As a result, they tend to

have low melting and boiling points compared with other functional

groups.

Preparation of alkanes and cycloalkanes

1) Alkanes are prepared simply by catalytic hydrogenation of alkenes

or alkynes

2) From alkyl halides:


42

1. Reduction of alkyl halide:

Lithium aluminum hydride (LiAlH4) and a combination of metal and acid,

usually Zn with acetic acid (AcOH), can be used to reduce alkyl halides

to alkanes.

CH3CH2CH2BrLiAlH4, THF or

Zn, AcOH

CH3CH2CH3

Propyl bromide Propane

2. Reduction of organometallics

H3CH2C BrMg

EtherH3CH2C MgBr

H2OCH3CH3

+ Mg(OH)Br

EthaneEthyl bromide Ethyl magnesiumbromide

H3CH2C Br2Li

EtherH3CH2C Li

H2OCH3CH3

+ LiOH

EthaneEthyl bromide Ethyl lithium

+ LiBr

3. From compounds containing fewer carbon atoms

By Wurtz reaction:

RX + R_X + 2Na R-R- + 2NaX

Preparation of cycloalkanes

Reactions of alkanes and cycloalkanes

Alkanes contain only strong σ bonds, and all the bonds (C_C and C_H)

are nonpolar. As a result, alkanes and cycloalkanes are quite unreactive

towards most reagents. More branched alkanes are more stable and less


43

reactive than linear alkanes. For example, isobutane is more stable than n-

butane.

1. Combustion or oxidation of alkanes

Alkanes undergo combustion reaction with oxygen at high temperatures to

produce carbon dioxide and water. Therefore, alkanes are good fuels.

2. Free radical chain reactions

Radical reactions are often called chain reactions. All chain reactions have

three steps: chain initiation, chain propagation and chain termination. For

example, the halogenation of alkane is a free radical chain reaction.

Chlorine or bromine reacts with alkanes in the presence of light (hν) or

high temperatures to give alkyl halides. Usually, this method gives

mixtures of halogenated compounds containing mono-, di-, tri- and tetra-

halides.

CH4 + Cl2h

CH3Cl + HCl

Cl2CH2Cl2 + HCl

Cl2 CHCl3 + HCl

Cl2 CCl4 + HCl

To maximize the formation of monohalogenated product, a radical

substitution reaction must be carried out in the presence of excess alkane.

When a large excess of cyclopentane is heated with chlorine at 250

°C, the major product is chlorocyclopentane (95%), along with small

amounts of dichlorocyclopentanes.


44

A free radical chain reaction is also called a radical substitution

reaction, because radicals are involved as intermediates, and the result is

the substitution of a halogen atom for one of the hydrogen atoms of alkane.

The free radical chain halogenation involves three steps: initiation,

propagation and termination.

Initiation:

Cl Clh 2 Cl

chlorine chlorine radicals

Propagation:

Termination:

Bromination of alkanes follows the same mechanism as

chlorination. The only difference is the reactivity of the radical; i.e., the

chlorine radical is much more reactive than the bromine radical. Thus, the

chlorine radical is much less selective than the bromine radical, and it is a


45

useful reaction when there is only one kind of hydrogen in the molecule.

For example, radical chlorination of n-butane produces a 71% of 2-

chlorobutane, and bromination of n-butane produces a 98% of 2-

bromobutane.

Relative stabilities of radicals

Carbocations are classified according to the number of alkyl groups

that are bonded to the positively charged carbon. A primary 1⁰carbocation

has one alkyl group, a secondary 2⁰ has two and a tertiary 3⁰ has three alkyl

groups.

Alkyl groups can decrease the concentration of positive charge on

the carbocation by donating electrons inductively, thus increasing the

stability of the carbocation. The greater the number of alkyl groups bonded

to the positively charged carbon, the more stable is the carbocation.

Therefore, a 3⁰ carbocation is more stable than a 2⁰carbocation, and a 2⁰

carbocation is more stable than a 1⁰ carbocation, which in turn is more

stable than a methyl cation.

The relative stabilities of radicals follow the same trend as for

carbocations. Allyl and benzyl radicals are more stable than alkyl radicals,

because their unpaired electrons are delocalized. Electron delocalization


46

increases the stability of a molecule. The more stable a radical, the faster it

can be formed. Therefore, a hydrogen atom, bonded to either an allylic

carbon or a benzylic carbon, is substituted more selectively in the

halogenation reaction. The percentage substitution at allylic and benzylic

carbons is greater in the case of bromination than in the case of

chlorination, because bromine radical is more selective.

3. Reduction of smaller cycloalkanes

Alkenes

Alkenes (olefins) are unsaturated hydrocarbons that contain carbon–

carbon double bonds. A double bond consists of a σ bond and a π bond. A

π bond is weaker than a σ bond, and this makes π bonds more reactive than

σ bonds. Thus, π bond is a functional group. Alkenes form a homologous


47

series with general molecular formula CnH2n. The simplest members of the

series are ethene (C2H4), propene (C3H6), butene (C4H8) and pentene

(C5H10).

Among the cycloalkenes, cyclobutene, cyclopropene and cylcohexene are

most common.

Nomenclature of alkenes

The systematic name of an alkene originates from the name of the

alkane corresponding to the longest continuous chain of carbon atoms that

contains the double bond. When the chain is longer than three carbons, the

atoms are numbered starting from the end nearest to the double bond. The

functional group suffix is -ene.

For branches, each alkyl group is given a number, but the double

bond still gets preference when numbering the chain.

A cyclic alkene is named by a prefix cyclo- to the name of the acyclic

alkene. Double bonded carbons are considered to occupy positions 1 and

2.


48

When a geometric isomer is present, a prefix cis (Z) or trans (E) is

added. Because of the double bonds, alkenes cannot undergo free rotation.

Thus, the rigidity of a π bond gives rise to geometric isomers.

Compounds with two double bonds are called dienes, three double

bonds are trienes and so on. Where geometric isomerism exists, each

double bond is specified with numbers indicating the positions of all the

double bonds.

The sp2 carbon of an alkene is called vinylic carbon, and an sp3

carbon that is adjacent to a vinylic carbon is called an allylic carbon. The

two unsaturated groups are called the vinyl group (CH2=CH_) and the allyl

group (CH2=CHCH2_).

Physical properties of alkenes

As with alkanes, the boiling points and melting points of alkenes

increase with increasing molecular weight but show some variations that


49

depend on the shape of the molecule. Alkenes with the same molecular

formula are isomers of one another if the position and the stereochemistry

of the double bond differ. For example, there are four different acyclic

structures that can be drawn for butene (C4H8). They have different b.p and

m.p as follows.

Preparation of alkenes and cycloalkanes

Alkenes are obtained by the transformation of various functional

groups, e.g. dehydration of alcohols, dehydrohalogenation of alkyl halides

and dehalogenation of alkyl dihalides. These reactions are known as

elimination reactions. An elimination reaction results when a proton and a

leaving group are removed from adjacent carbon atoms, giving rise to a π

bond between the two carbon atoms.

Alkenes are obtained from selective hydrogenation of alkynes.

Elimination reactions: 1,2-elimination or β-elimination

The term elimination can be defined as the electronegative atom or

a leaving group being removed along with a hydrogen atom from adjacent


50

carbons in the presence of strong acids or strong bases and high

temperatures. Alkenes can be prepared from alcohols or alkyl halides by

elimination reactions. The two most important methods for the preparation

of alkenes are dehydration (_H2O) of alcohols, and dehydrohalogenation

(_HX) of alkyl halides.

In 1,2-elimination, e.g. dehydrohalogenation of alkyl halide, the

atoms are removed from adjacent carbons. This is also called β-

elimination, because a proton is removed from a β-carbon. The carbon to

which the functional group is attached is called the α-carbon. A carbon

adjacent to the α-carbon is called a β-carbon. Depending on the relative

timing of the bond breaking and bond formation, different pathways are

possible: E1 reaction or unimolecular elimination and E2 reaction or

bimolecular elimination.

E1 reaction or first order elimination

E1 reaction or first order elimination results from the loss of a

leaving group to form a carbocation intermediate, followed by the removal

of a proton to form the C=C bond. This reaction is most common with good

leaving groups, stable carbocations and weak bases (strong acids). The

reaction is unimolecular, i.e. the rate-determining step involves one


51

molecule, and it is the slow ionization to generate a carbocation. The

second step is the fast removal of a proton by the base (solvent) to form the

C=C bond. In fact, any base in the reaction mixture (ROH, H2O, and HSO4-

) can remove the proton in the elimination reaction. The E1 is not

particularly useful from a synthetic point of view and occurs in competition

with SN1 reaction of tertiary alkyl halides. Primary and secondary alkyl

halides do not usually react with this mechanism.

Mechanism:

E2 reaction or second order elimination

E2 elimination or second order elimination takes place through the

removal of a proton and simultaneous loss of a leaving group to form the

C=C bond. This reaction is most common with high concentration of strong

bases (weak acids), poor leaving groups and less stable carbocations. For

example, 3-chloro-3-methyl pentane reacts with sodium methoxide to give

3-methyl-2-pentene. The bromide and the proton are lost simultaneously to

form the alkene. The E2 reaction is the most effective for the synthesis of

alkenes from primary alkyl halides.


52

Mechanism:

1. Dehydration of alcohols

The dehydration of alcohols is a useful synthetic route to alkenes.

Alcohols typically undergo elimination reactions when heated with strong

acid catalysts, e.g. H2SO4 or phosphoric acid (H3PO4), to generate an

alkene and water. The hydroxyl group is not a good leaving group, but

under acidic conditions it can be protonated. The ionization generates a

molecule of water and a cation, which then easily deprotonates to give

alkene. For example, the dehydration of 2-butanol gives predominately

(E)-2-butene; the reaction is reversible, and the following equilibrium

exists.

Mechanism:


53

The dehydration of 2,3-dimethylbutan-2-ol gives predominantly 2,3-

dimethylbutene via E1 reaction.

Mechanism:

While dehydration of 2⁰ and 3⁰ alcohols is an E1 reaction,

dehydration of 1⁰ alcohols is an E2 reaction. Dehydration of 2o and 3o

alcohols involves the formation of a carbocation intermediate, but

formation of a primary carbocation is rather difficult and unstable. For

example, dehydration of propanol gives propene via E2.


54

Mechanism:

An E2 reaction occurs in one step: first the acid protonates the

oxygen of the alcohol; a proton is removed by a base (HSO4-) and

simultaneously carbon–carbon double bond is formed via the departure of

the water molecule.

Use of concentrated acid and high temperature favors alkene

formation but use of dilute aqueous acid favors alcohol formation. To

prevent the alcohol formation, alkene can be removed by distillation as it

is formed, because it has a much lower boiling point than the alcohol. When

two elimination products are formed, the major product is generally the

more substituted alkene.

2. Dehydrohalogenation of alkyl halides

Alkyl halides typically undergo elimination reactions when heated

with strong bases, typically hydroxides and alkoxides, to generate alkenes.

Removal of a proton and a halide ion is called dehydrohalogenation. Any

base in the reaction mixture (H2O, HSO4-) can remove the proton in the

elimination reaction.

A. E1 elimination of HX: preparation of alkenes

The E1 reaction involves the formation of a planar carbocation

intermediate. Therefore, both syn and anti-elimination can occur. If an

elimination reaction removes two substituents from the same side of the C-

C bond, the reaction is called syn elimination. When the substituents are


55

removed from opposite sides of the C-C bond, the reaction is called anti-

elimination. Thus, depending on the substrates E1 reaction forms a mixture

of cis (Z) and trans (E) products. For example, tert-butyl bromide (3⁰ alkyl

halide) reacts with water to form 2-methylpropene, following an E1

mechanism. The reaction requires a good ionizing solvent and a weak

base. When the carbocation is formed, SN1 and E1 processes compete, and

often mixtures of elimination and substitution products occur. The reaction

of t-butyl bromide and ethanol gives major product via E1 and minor

product via SN1.

Mechanism:

B. E2 elimination of HX: preparation of alkenes

Dehydrohalogenation of 2⁰ and 3⁰ alkyl halides undergo both E1 and

E2 reactions. However, 1⁰ alkyl halides undergo only E2 reactions. They

cannot undergo E1 reaction because of the difficulty of forming primary

carbocations. E2 elimination is stereospecific, and it requires an

antiperiplanar (180⁰) arrangement of the groups being eliminated. Since

only anti elimination can take place, E2 reaction predominantly forms one

product. The elimination reaction may proceed to alkenes that are

constitutional isomers with one formed more than the other, described as

regioselectivity. Similarly, eliminations often favor the more stable trans-


56

product over the cis product, described as stereoselectivity. For example,

bromopropane reacts with sodium ethoxide (EtONa) to give only propene.

Mechanism:

The E2 elimination can be an excellent synthetic method for the

preparation of alkene when 3º alkyl halide and a strong base, e.g. alcoholic

KOH, is used. This method is not suitable for SN2 reaction.

A bulky base (a good base, but poor nucleophile) can further

discourage undesired substitution reactions. The most common bulky

bases are potassium- t-butoxide (t-BuOK), diisopropyl amine and 2,6-

dimethylpyridine.

Cyclohexene can be synthesized from bromocyclohexane in a high yield

using diisopropylamine.


57

Generally, E2 reactions occur with a strong base, which eliminates

a proton quicker than the substrate can ionize. Normally, the SN2 reaction

does not compete with E2 since there is steric hindrance around the C-X

bond, which retards the SN2 process.

The methoxide (CH3O-) is acting as a base rather than a nucleophile.

The reaction takes place in one concerted step, with the C-H and C-Br

bonds breaking as the CH3O-H and C-C bonds are forming. The rate is

related to the concentrations of the substrate and the base, giving a second

order rate equation. The elimination requires a hydrogen atom adjacent to

the leaving group. If there are two or more possibilities of adjacent

hydrogen atoms, mixtures of products are formed as shown in the

following example.

The major product of elimination is the one with the most highly

substituted double bond and follows the following order.

R2C=CR2 > R2C=CRH > RHC=CHR and R2C=CH2 > RCH=CH2.

C. E2 elimination of X2

Preparation of alkenes Dehalogenation of vicinal-dihalides with NaI in

acetone produces alkene via E2 reactions.

3. Selective hydrogenation of alkynes


58

Preparation of cis-alkenes Lindlar’s catalyst, which is also known as

poisoned catalyst, consists of barium sulphate, palladium and quinoline,

and is used in selective and partial hydrogenation of alkynes to produce

cis-alkenes.

Preparation of trans-alkenes the anti-addition (trans-alkenes) is achieved

in the presence of an alkali metal, e.g. sodium or lithium, in ammonia at

_78 ⁰C.

Reactivity and stability of alkenes

The following three factors influence the stability of alkenes.

The degree of substitution: more highly alkylated alkenes are more

stable. Thus, the stability follows the order tetra > tri > di >

monosubstituted.

The stereochemistry: trans > cis due to reduced steric interactions.

The conjugated alkenes are more stable than isolated alkenes.

Reactions of alkenes and cycloalkanes

Alkenes are electron-rich species. The double bond acts as a

nucleophile and attacks the electrophile. Therefore, the most important

reaction of alkenes is electrophilic addition to the double bond.

An outline of the electrophilic addition reactions of alkenes is presented

here.


59

1. Catalytic hydrogenation:

Electrophilic addition to symmetrical and unsymmetrical π bonds

Unsymmetrical means different substituents are at each end of the

double or triple bond. Electrophilic addition of unsymmetrical reagents to

unsymmetrical double or triple bonds follows Markovnikov’s rule.

According to Markovnikov’s rule, addition of unsymmetrical reagents, e.g.

HX, H2O or ROH, to an unsymmetrical alkene proceeds in a way that the

hydrogen atom adds to the carbon that already has the most hydrogen

atoms. The reaction is not stereoselective since it proceeds via a planar

carbocation intermediate.

The modern Markovnikov rule states that, in the ionic addition of an

unsymmetrical reagent to a double bond, the positive portion of the adding

reagent adds to a carbon atom of the double bond to yield the more stable

carbocation as an intermediate.

2. Addition of hydrogen halides to alkenes

Alkenes are converted to alkyl halides by the addition of HX (HCl,

HBr or HI). Addition of HX to unsymmetrical alkenes follows

Markovnikov’s rule. The reaction is regioselective and occurs via the most

stable carbocation intermediate.


60

Mechanism:

Addition of HBr to 2-methylpropene gives mainly tert-butyl

bromide, because the product with the more stable carbocation

intermediate always predominates in this type of reaction.

Mechanism:

3. Free radical addition of HBr to alkenes: peroxide effect.

It is possible to obtain anti-Markovnikov products when HBr is added to

alkenes in the presence of free radical initiators, e.g. hydrogen peroxide

(HOOH) or alkyl peroxide (ROOR).

4. Addition of water to alkenes:


61

Mechanism:

5. Addition of sulphuric acid to alkenes:

Addition of concentrated H2SO4 to alkenes yields acid-soluble alkyl

hydrogen sulphates. The addition follows Markovnikov’s rule. The

sulphate is hydrolyzed to obtain the alcohol.

1. Addition of alcohols to alkenes:

The addition of alcohols in the presence of an acid catalyst, most

commonly aqueous H2SO4, produces ethers. Addition of alcohol to an

unsymmetrical alkene follows Markovnikov’s rule.

2. Addition of halides to alkenes:


62

Addition of X2 (Br2 and Cl2) to alkenes gives vicinal-dihalides. This

reaction is used as a test for unsaturation (π bonds), because the red color

of the bromine reagent disappears when an alkene or alkyne is present.

Mechanism:

When Br2 approaches to the double bond it becomes polarized. The

positive part of the bromine molecule is attacked by the electron rich π

bond and forms a cyclic bromonium ion. The negative part of bromine is

the nucleophile, which attacks the less substituted carbon to open the cyclic

bromonium ion and forms 1,2-dibromoethane (vicinal-dihalide).

When cyclopentene reacts with Br2, the product is a racemic mixture

of trans-1,2-dibromocyclopentane. Addition of Br2 to cycloalkenes gives a

cyclic bromonium ion intermediate instead of the planar carbocation. The

reaction is stereospecific and gives only anti addition of dihalides.

Mechanism:


63

3. Addition of halides and water to alkenes:

When halogenation of alkenes is carried out in aqueous solvent, a

vicinal halohydrin is obtained. The reaction is regioselective and follows

the Markovnikov rule. The halide adds to the less substituted carbon atom

via a bridged halonium ion intermediate, and the hydroxyl adds to the more

substituted carbon atom.

Mechanism:

4. Oxidation:

a) Syn-hydroxylation of alkenes:

Hydroxylation of alkenes is the most important method for the

synthesis of 1,2-diols (also called glycol). Alkenes react with cold,

dilute and basic KMnO4 or osmium tetroxide (OsO4) and hydrogen

peroxide to give cis-1,2- diols. The products are always syn-diols, since

the reaction occurs with syn addition.


64

b) Anti-hydroxylation of alkenes:

Alkenes react with peroxyacids (RCO3H) followed by hydrolysis to give

trans-1,2-diols. The products are always anti-diols, since the reaction

occurs with anti-addition.

d) Oxidation with hot KMnO4 solution:

Reaction of an alkene with hot basic potassium permanganate

(KMnO4) results in cleavage of the double bond, and formation of highly

oxidized carbons. Therefore, unsubstituted carbon atoms become CO2,

monosubstituted carbon atoms become carboxylates, and di-substituted

carbon atoms become ketones. This can be used as a chemical test (known

as the Baeyer test) for alkenes and alkynes, in which the purple color of the

KMnO4 disappears, and a brown MnO2 residue is formed.


65

e) Epoxide formation:

Alkanes react with oxygen in the presence of silver catalyst at 250ºC to

form epoxides.

Alkenes are also oxidized to epoxides by peracid or peroxyacid

(RCO3H), e.g. peroxybenzoic acid (C6H5CO3H). A peroxyacid contains an

extra oxygen atom compared with carboxylic acid, and this extra oxygen

is added to the double bond of an alkene to give an epoxide. For example,

cyclohexene reacts with peroxybenzoic acid to produce cyclohexane oxide.

f) Oxidation with ozone

When ozone is passed through an alkene in an inert solvent, it adds

across the double bond to form an ozonoide, ozonoids are explosive

compounds and are not isolated. The products obtained from an ozonolysis

reaction depend on the reaction conditions. If ozonolysis is followed by the

reductive work-up (Zn/H2O), the products obtained are aldehydes and/or

ketones. Unsubstituted carbon atoms are oxidized to formaldehyde, mono-


66

substituted carbon atoms to aldehydes, and disubstituted carbon atoms to

ketones.

When ozonolysis is followed by the oxidative work-up (H2O2/

NaOH), the products obtained are carboxylic acids and/or ketones.

Unsubstituted carbon atoms are oxidized to formic acids, mono-substituted

carbon atoms to carboxylic acids and di-substituted carbon atoms to

ketones.

Preparation of aldehydes and ketones

Ozonolysis followed by reductive work-up yields aldehydes and ketones.

Preparation of carboxylic acids and ketones

Ozonolysis followed by oxidative work-up yields ketones and carboxylic

acids.

It is the best method of locating the position of a double bond in unknown

alkene suppose an alkene on ozonolysis gives the carbonyl compounds.

Forming the oxygenated carbons (marked by asterisk) by a double bond,

we get the following structure of the unknown alkene.


67

8) Substitution of alkenes by halogen (allylic substitution): when alkene

is treated with Cl2 or Br2 at high temperature, one of their allylic

hydrogens is replaced by a halogen atom. Allylic position is the carbon

adjacent to one of the unsaturated carbon atoms.

Alkynes

Alkynes are hydrocarbons that contain a carbon–carbon triple bond.

A triple bond consists of a σ bond and two π bonds. The general formula

for the alkynes is CnH2n-2. The triple bond possesses two elements of

unsaturation. Alkynes are commonly named as substituted acetylenes.

Compounds with triple bonds at the end of a molecule are called terminal

alkynes. Terminal -CH groups are called acetylenic hydrogens. If the triple

bond has two alkyl groups on both sides, it is called an internal alkyne.

Nomenclature of alkynes

The IUPAC nomenclature of alkynes is like that for alkanes, except

the –ane ending is replaced with –yne. The chain is numbered from the end

closest to the triple bond. When additional functional groups are present,

the suffixes are combined.


68

Acidity of terminal alkynes

Terminal alkynes are acidic, and the end hydrogen can be removed

as a proton by strong bases (e.g. organolithiums, Grignard reagents and

NaNH2) to form metal acetylides and alkynides. They are strong

nucleophiles and bases and are protonated in the presence of water and

acids. Therefore, metal acetylides and alkynides must be protected from

water and acids.

Physical characters

Test for terminal alkynes

The position of the triple bond can alter the reactivity of the alkynes.

Acidic alkynes react with certain heavy metal ions, e.g. Ag and Cu, to form

precipitation. Addition of an alkyne to a solution of AgNO3 in alcohol

forms a precipitate, which is an indication of hydrogen attached to the triple

bonded carbon. Thus, this reaction can be used to differentiate terminal

alkynes from internal alkynes.


69

Preparation of alkynes

Alkynes can be produced by elimination of two moles of HX from a

geminal (halides on the same carbon)-or vicinal (halides on the adjacent

carbons)-dihalide at high temperatures. Stronger bases (KOH or NaNH2)

are used for the formation of alkyne via two consecutive E2

dehydrohalogenations. Under mild conditions, dehydrohalogenation stops

at the vinylic halide stage. For example, 2-butyne is obtained from

geminal- or vicinal-dibromobutane.

Alkynes are produced by reaction of primary alkyl halides or

tosylates with metal acetylides or alkynides [R`C≡CNa or R`C≡CMgX].

The reaction is limited to 1º alkyl halides. Higher alkyl halides tend to react

via elimination.

Mechanism:

Reactions of alkynes

Alkynes are electron-rich reagents. The triple bond acts as a

nucleophile and attacks the electrophile. Therefore, alkynes undergo

electrophilic addition reactions, e.g. hydrogenation, halogenation and


70

hydrohalogenation, in the same way as alkenes, except that two molecules

of reagent are needed for each triple bond for the total addition. It is

possible to stop the reaction at the first stage of addition for the formation

of alkenes. Therefore, two different halide groups can be introduced in each

stage.

Addition of hydrogen halides to alkynes:

Electrophilic addition to terminal alkynes (unsymmetrical) is

regioselective and follows Markovnikov’s rule. Hydrogen halides can be

added to alkynes just like alkenes, to form first the vinyl halide, and then

the geminal alkyl dihalide. The addition of HX to an alkyne can be stopped

after the first addition of HX. A second addition takes place when excess

HX is present. For example, 1-propyne reacts with one equivalent of HCl

to produce 2-chloropropene; a second addition of HCl gives 2,2-

dichloropropane, a geminal-dihalide.

Mechanism:

The vinyl cation is more stable with positive charge on the more

substituted carbon, because a secondary vinylic cation is more stable than

a primary vinylic cation.


71

Addition of hydrogen halides to an internal alkyne is not

regioselective. When the internal alkyne has identical groups attached to

the sp carbons, only one geminal-dihalide is produced.

Free radical addition of HBr to alkynes: peroxide effect.

The peroxide effect is also observed with the addition of HBr to

alkynes. Peroxides (ROOR) generate anti-Markovnikov products, e.g. 1-

butyne reacts with HBr in the presence of peroxide to form 1-bromobutene.

Addition of water to alkynes:

Internal alkynes undergo acid-catalyzed addition of water in the

same way as alkenes, except that the product is an enol. Enols are unstable,

and tautomerize readily to the more stable keto form. Thus, enols are

always in equilibrium with their keto forms. This is an example of keto–

enol tautomerism.

Addition of water to an internal alkyne is not regioselective. When

the internal alkyne has identical groups attached to the sp carbons, only one

ketone is obtained. For example, 2-butyne reacts with water in the presence

of acid catalyst to yield 2-butanone.


72

Terminal alkynes are less reactive than internal alkynes towards the

acid catalyzed addition of water. Therefore, terminal alkynes require Hg

salt (HgSO4) catalyst for the addition of water to yield aldehydes and

ketones. Addition of water to acetylene gives acetaldehyde, and all other

terminal alkynes give ketones. The reaction is regioselective and follows

Markovnikov addition. For example, 1-butyne reacts with water in the

presence of H2SO4 and HgSO4 to yield 2-butanone.

Mechanism:

Addition of HgSO4 generates a cyclic mercurinium ion, which is

attacked by a nucleophilic water molecule on the more substituted carbon.

Oxygen loses a proton to form a mercuric enol, which under work-up

produces enol (vinyl alcohol). The enol is rapidly converted to 2- butanone.

Addition of halides to alkynes:

Halides (Cl2 or Br2) add to alkynes in an analogous fashion as for

alkenes. When one mole of halogen is added, a dihaloalkene is produced,

and a mixture of syn and anti-addition is observed.


73

It is usually hard to control the addition of just one equivalent of

halogen, and it is more common to add two equivalents to generate

tetrahalides.

Acetylene undergoes electrophilic addition reaction with bromine in

the dark. Bromine adds successively to each of the two π bonds of the

alkyne. In the first stage of the reaction, acetylene is converted to an alkene,

1,2-dibromoethene. In the final stage, another molecule of bromine is

added to the π bond of this alkene, and produces 1,1,2,2-tetrabromoethane.

Reactions of acetylides and alkynides

Besides electrophilic addition, terminal alkynes also perform acid–

base type reaction due to acidic nature of the terminal hydrogen. The

formation of acetylides and alkynides (alkynyl Grignard reagent and

alkynyl lithium) are important reactions of terminal alkynes. Acetylides

and alkynides undergo nucleophilic addition with aldehydes and ketones

to produce alcohols.


74

They react with alkyl halides to give internal alkynes via

nucleophilic substitution reactions. This type of reaction also is known as

alkylation. Any terminal alkyne can be converted to acetylide and alkynide,

and then alkylated by the reaction with alkyl halide to produce an internal

alkyne. In these reactions, the triple bonds are available for electrophilic

additions to several other functional groups.

Oxidation of alkynes:

Alkynes are oxidized to diketones by cold, dilute and basic potassium

permanganate.

When the reaction condition is too warm or basic, the oxidation

proceeds further to generate two carboxylate anions, which on acidification

yield two carboxylic acids.

Unsubstituted carbon atoms are oxidized to CO2, and mono-

substituted carbon atoms to carboxylic acids. Therefore, oxidation of 1-

butyne with hot basic potassium permanganate followed by acidification

produces propionic acid and carbon dioxide.

Ozonolysis of alkynes:


75

Ozonolysis of alkynes followed by hydrolysis gives similar products

to those obtained from permanganate oxidation. This reaction does not

require oxidative or reductive work-up. Unsubstituted carbon atoms are

oxidized to CO2, and mono-substituted carbon atoms to carboxylic acids.

For example, ozonolysis of 1-butyene followed by hydrolysis gives

propionic acid and carbon dioxide.


76

Chapter 3

Isomerism & stereochemistry


77

Stereochemistry Introduction

Stereochemistry involves the study of the relative spatial arrangement of

atoms that form the structure of molecules and their manipulation. It is also

known as 3D chemistry because the prefix "stereo-" means "three-

dimensionality. The importance of stereochemistry appears clearly in the

synthesis of drugs. Most drugs for example, are often composed of two

stereoisomers, and while one stereoisomer may have positive effect on the

body, another stereoisomer may be toxic. Because of this, a great deal of work

done by synthetic organic chemists today is in devising methods to synthesize

compounds that are purely one stereoisomer.

http://en.wikipedia.org/wiki/Atom

http://en.wikipedia.org/wiki/Molecule

http://en.wikipedia.org/wiki/Three-dimensional_space


78

Isomerism is a phenomenon exhibited only by organic compounds. Isomers are

compounds with the same molecular formula and have limited difference in

physical and /or chemical properties. Isomers are classified into: Constitutional

(Structural) isomers and Stereoisomers.

Constitutional (Structural) isomers:

They have the same molecular formula but differ in connectivity i.e. their atoms are

attached in different sequences e.g. ethanol and dimethyl ether.

CH3CH2OH and CH3OCH3 Ethanol Dimethyl ether

Types of constitutional (Structural) isomers:

1-Chain or Skeletal isomers: They are different in their carbon skeleton e.g.

isomers of butane C4H10

CH3CH2CH2CH3 and CH3CH(CH3)2

n-butane isobutane

2-Positional isomers:

They are isomers having the same carbon skeleton but differ in the position

occupied by a substituent group/ function group e.g.

pentan-1-ol pentan-2-ol pentan-3-ol

Isomers of pentanol: C5H12O


79

Special type of positional isomers:

Metameric isomers:

A special case of position isomers, they are those isomers which show different

alkyl substituents around certain function groups or atoms (like O, N, S …etc.) e.g.

CH3CH2OCH2CH3 & CH3OCH2CH2CH3

3-Functional group isomers:

They are those isomers which are different in the types of their function groups.

e.g.1 CH3CH2OH & CH3OCH3

Ethanol Dimethyl ether

e.g. 2 CH3COCH3 & CH3CH2CHO Acetone Propanal

Tautomerism:

It is a special case of function group isomerism. It is a phenomenon in which a

single compound can give the reaction characteristic of two different function

groups. This indicates that this compound occurs as two interconvertible forms of

two functional group isomers in dynamic equilibrium with each other.

Types of tautomerism: [One isomer with two tautomeric forms]


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Proton tautomerism

Valence tautomerism

Ring-chain tautomerism

1- Proton tautomerism:

A spontaneous isomerization in which a proton migrates in one direction and a

covalent bond migrate in the opposite direction within the molecule. Tautomeric

structures are classified as diad, triad …etc. depending upon the number of the

atoms intervening between the initial and final positions of the mobile acidic

hydrogen atom.

Diad tautomerism:

The equilibrium is obtained by 1, 2 migration of acidic hydrogen atom e.g.

Triad tautomerism:

The equilibrium is obtained by 1, 3 migration of acidic hydrogen atom with

opposite delocalization of a double bond.

Examples of triad tautomerism:

Keto-enol system:


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Relative ratio of keto and enol forms:

For most simple aldehydes and ketones (e.g. acetaldehyde and acetone), the keto

form predominates by more than 99% at equilibrium. For certain types of

molecules, the enol form predominates in equilibrium. In β- diketones, acetyl

acetone and 1,3-cyclohexadiene, the position of equilibrium shifts in favor of the

enol form. These enol forms are stabilized by:

Resonance of conjugated π- system of C=C and C=O.

Intramolecular H-bonding.

2-Valence tautomerism:

It involves reversible change in electronic distribution with changes in location

of valence bond (σ or π- bond) e.g. cycloocta-1,3,5-triene is present in equilibrium

of mono and bicyclic forms.


82

c- Ring-chain tautomerism:

Tautomers of this type exist as an equilibrium mixture of two tautomers, one is

an open chain system and the other is cyclic system. It occurs when one functional

group of a bifunctional molecule enters reaction with the other one, and thus forms

a ring

Stereoisomers

They have the same bonding sequence, but they differ in the orientation of their

atoms in space. Stereoisomers may be classified according to symmetry or energy.

Classification of stereoisomers according to symmetry into:

Enantiomers: are chiral molecules that are mirror-images and they are non-

superimposed on one another. This means that the molecules cannot be placed

on top of one another. Stereoisomers with one or more stereocenter.

Diastereomers: are stereoisomers that are not mirror images of one another

and are non-superimposable on one another. Stereoisomers with two or more

stereo centers can be diastereomers.


83

Classification of stereoisomers according to energy barrier criterion:

It is concerned with the energy required to convert one stereoisomer into its

isomeric form.

1) Configurational isomers: stereoisomers which are separated by a high energy

barrier and so these two isomers cannot be converted to each other at room

temperature.

2) Conformational isomers: stereoisomers which are separated by a low energy

barrier and so these isomers can be interconverted to each other at room

temperature.

Molecular Representation of Stereoisomers

Representation of stereoisomers could be 3D representation e.g. Sawhorse

and Newman projections or 2D representation e.g. Fischer projection.


84

3 D-Representation of stereoisomers:

Flying-Wedge or Wedge-Dashed representation:

Sawhorse projection:

They are useful for determining enantiomeric or diasteromeric relationships

between two molecules, because the mirror image or superimposibility

relationships are clearer. Sawhorse projection is a view of a molecule down a

particular carbon-carbon bond, and groups connected to both the front and back

carbons are drawn using sticks at 120-degree angles. Sawhorse Projections can also

be drawn so that the groups on the front carbon are staggered or eclipsed with the

groups on the back carbon. Below are two Sawhorse projections of ethane. The

structure on the right is staggered, and the structure on the left is eclipsed. These

are the simplest Sawhorse projections because they have only two carbons, and all

the groups on the front and back carbons are identical.

H

H

H

HH

H

HH

H

HH

H


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Adding more carbons makes Sawhorse projections slightly more complicated.

Sawhorse projections can be made for butane, such that it’s eclipsed, gauche,

and anti-conformations can be seen.

H H

CH3

H H

CH3

CH3

CH3

H H

H H

CH3

H H

H

CH3H

Eclipsed Gauch Staggered

Newman Projection:

Used mainly for determining conformational relationships. Conformations are

the different positions a molecule can bend into. Atoms and bonds remain the same

on the molecule, the only variation is the angles in which certain parts of molecule

are bent or twisted at room temperature. Newman Projections are also useful when

studying a reaction from stereochemistry point of view. In this notation, you are

viewing a molecule by looking down a carbon-carbon bond. The front carbon of

this bond is represented by a dot, and the back carbon is represented by a large

circle. The three remaining bonds are drawn as sticks coming off the dot (or circle),

separated by one another by 120 degrees. A Newman Projection can be drawn

such that the groups on the front carbon are staggered or eclipsed with the groups

on the back carbon.

Below are two Newman Projections of ethane, C2H6. The structure on the left

is staggered, and the structure on the right is eclipsed. These are the simplest

Newman Projections because they have only two carbons, and all the groups on

both carbons are identical.


86

Another example is propane

2D Representation-The Fischer projection formula:

The difficulty of drawing “understandable” three-dimensional formulas

increases as the number of chiral centers increases. An adequate substitute

for a three-dimensional representation of an open-chain molecule is found

in Fischer projections formulas. It is 2D representation of the

stereoisomers. In this representation, the molecule is so oriented that the

chiral carbon atom is in the plane of the projection, and the four different

substitutions are above (horizontal line) and below (vertical line) the plane

of the chiral carbon. Fischer Projections are used often in drawing sugars


87

and hydrocarbons, because the carbon backbone is drawn as a straight

vertical line, making them very easy to draw. When properly laid-

out, Fischer Projections are useful for determining enantiomeric or

diastereomeric relationships between two molecules, because the mirror

image relationship is very clear.

Thus propane-1,2-diol might be projected using Fischer projection as

follows:

The following fundamental rules must be carefully understood when

working with Fischer projection:

Carbon chain is on the vertical line.

Highest oxidized carbon is on the top.

Double interchange of substituents leaves original configuration

unchanged as if the entire formula rotated 180° in the projection plane

without changing the identity of the enantiomer. e.g:

OHH

CHO

CH2OH

OH H

CHO

CH2OH

double

interchange

One interchange of substituents is equivalent to reflecting the molecule in

a mirror (mirror image).


88

Neither the entire formula, nor any part of it may be rotated out of the

projection plane (i.e. the Fischer projection may never be lifted out of the

paper and rotated).

Chirality and Optical Activity

Chirality (Greek word cheir = hand) or handedness means molecular asymmetry,

i.e. mirror images molecules that are not superimposable on each other are said to

be chiral. Chirality is encountered in 3 dimensional objects of all sorts. Human

hands, ears, eyes, legs are chiral objects. Most of the 3 dimensional organic

molecules exhibit chirality and every chiral molecule will be present in nature in

two opposite forms (object and its mirror image which is non superimposable on

each other) e.g. Lactic acid [CH3-*CH(OH)-COOH] is present in nature in two

forms, one extracted from milk and the other is derived from cooked meat. The

chemical and physical properties of both forms are exactly similar except that they

have optical activity with opposite directions of rotation of the plan-polarized light

(PPL) when placed in a polarimeter, (Figure 1). Ordinary light, which vibrates in

all directions, can, with the help of a polarizer, be made to vibrate in one plane.

Such light is called plane-polarized light (PPL). An optically active substance is

one that rotates the polarized light either to the left or to the right (physical

character).

Figure 1. The Polarimeter


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The 3-dimensional representation of the two isomers of lactic acid molecule (A)

&(B), are not superimposed on each other. This means that the molecule of lactic

acid is chiral and so it will be present in nature in two stereoisomeric forms (A&B).

Isomers that are non-superimposable mirror images of one another are called

enantiomers and the phenomenon, enantiomerism. Enantiomers are said to have

opposite configurations.

The chirality present in this molecule is responsible for the optical activity, while

one isomeric form can rotate the plane-polarized light to the left and is called

levorotatory isomer (l); the other isomeric form rotates the polarized light to the

right and is called dextrorotatory (d) isomer.

The contrasting situation of chirality occurs when an object and its mirror image

are superimposable. This can be done, if the object and its mirror image are

identical. The original object is, then, considered Achiral (i.e. lack of chirality).

Achiral molecules are found to be optically inactive i.e. cannot rotate plane

polarized light (PPL) to left or to right [since it is symmetric molecule]. Examples

of achiral molecules and objects are: CH4; (CH3)4C; Meso tartaric acid, 2-

chloropropane, cubes, spheres …etc.

Tetrahedral carbon

Experimentally it was observed that compounds of the general formula CXYZW

(X, Y, Z, W) are four different substitutions around the carbon atom) have TWO

configurations, which are non-superimposable on one another. In fact, Van`t Hoff


90

predicted this as early as 1874. Van`t Hoff`s elegant logic rested upon “his

assumption” that carbon atom has tetrahedral configuration.

Finally, for a tetrahedral configuration, one expects only two forms: A

structure and its mirror image. There are only two forms (isomers) for

substituted methanes on which the carbon atom is surrounded by four

different groups. This is consistent with a tetrahedral configuration of the

carbon atom. For example, there are two forms of 2-butanol: CH3– *CH

(OH)–CH2 –CH3

The second carbon atom (with an asterisk) carries four different groups;

CH3, H, –CH2–CH3 and –OH and thus the molecule of 2-butanol is not

superposable on its mirror image. The two enantiomers may be shown as

follows:

(a) Three-dimensional drawings of the 2-butanol enantiomers I and II. (b) Models of the 2-

butanol enantiomers. (c) An unsuccessful attempt to superpose models of I and II.

Two enantiomers of 2-butanol

In the above convention bonds drawn as ordinary lines indicate bonds in

the plane of the paper while heavy wedges ( ) are bonds directed

above the plane of the molecule (plane of the paper) and those with dotted


91

lines ( ) indicate bonds directed below this plane. At this stage we

should know that any structure, which cannot be superimposed on its

mirror image, has optical activity (rotate PPL). We already know that

substituted methane in which the four substituents are different is non-

superimposable on its mirror image. In fact, carbon atoms were called in

the past asymmetric atoms and now being called chiral atoms or

stereogenic atoms. Therefore, a chiral carbon atom has four different

groups attached to it. Hence, a compound, which contains one chiral

carbon, is expected to have an enantiomer.

But, is the mere presence of chiral carbons enough for enantiomerism? To

answer this, we might rephrase our question by saying: would a molecule,

which possesses more than one chiral carbon atom, be necessarily non-

superimposable on its mirror image? (and hence have an enantiomer?) The

answer is simple: a molecule is non-superimposable on its mirror image

only if it DOES NOT have certain types of elements of symmetry.

Some elements of symmetry:

Plane of symmetry, simple axis of symmetry, center of symmetry or an

alternating axis of symmetry. The most common elements of symmetry

are:

1-Plane of symmetry (ơ):

This divides the molecule into two halves that are mirror images of one

another.


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Tartaric acid, COOH–*CH(OH)–*CH(OH)–COOH, has two chiral carbon

atoms, yet, one form of it, the so called Meso tartaric acid is optically

inactive because it is superimposable on its mirror reflection, just because

of this particular configuration, tartaric acid has a plane of symmetry. Meso

tartaric acid: optically inactive due to internal compensation despite having

two chiral centers.

2-Center of symmetry (i):

It is a point such that, if a line is drawn from any element to this point

and then extended an equal distance beyond the point, another identical

element will be found at the end of the line. We consider the following

cyclobutane which contain several chiral centers yet is optically inactive.

The presence of center of symmetry makes molecule superimposed on its

reflection.

When a molecule is free from all elements of symmetry, then it will be

chiral molecule or asymmetric molecule, that is, it will be present in nature

in two opposite forms, which are mirror image to each other and non-

superimposable called enantiomers and each enantiomer (alone) has

opposite optical rotation.

When the molecule contain an element (or elements) of symmetry, then,

it will be symmetric molecule or achiral molecule (i.e. its mirror image


93

forms are superimposable on each other (i.e.) there is no enantiomers and

hence there is no optical-activity (optically inactive). A mixture of equal

amounts of any two enantiomers is called a racemic mixture which is

optically inactive due to external compensation.

Configuration of stereoisomers

There are three kinds of descriptors that explain the configuration (spatial

arrangement of the substituents around stereocenter) of any stereoisomers.

These descriptors are experimental, relative or absolute configurations.

Experimental

Enantiomers possess identical physical and chemical properties except

direction of rotation of plane polarized light and behavior towards optically

active reagents.

If an optically active compound rotates the plane polarized light to the

right, it is called “dextrorotatory (d)” while its enantiomer, which rotates

the plane polarized light to the left (with the same degrees) is called

“levorotatory (l)”. Naturally, as the number of enantiomers increased, a

method to differentiate two enantiomers (i.e. to label them) was desirable.

The original method of labeling enantiomers was to prefix each one by d

or l according as it was dextrorotatory or levorotatory. More recently the

symbols d and l have been replaced by (+) or (–) signs indicate

dextrorotatory and levorotatory characters respectively.

Relative configuration describing the structure of the stereoisomers:

In order to have a meaning for D and L configurations one needs a standard

relative to which a symbol D or L is given to enantiomer in question. It is

agreed that glyceraldehyde be such a standard. The accepted convention


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for drawing D (+) glyceraldehyde is shown below:

Various ways of representing D (+) Glyceraldehyde

D (+) Glyceraldehyde means that the OH group is at the right side of

Fischer projections. Therefore L (-) glyceraldehyde would be when the OH

group is at the left side of Fischer projections. For amino acids, D and L

descriptors are used to describe the position of the NH2 group rather than

OH group.

L (-) glyceraldehyde

Absolute Configuration:

It turned out, however, that this method of employing a reference of

known (relative) configuration has some shortcomings and therefore

another system of labeling enantiomers, through determining their absolute

configuration was suggested and is now in use. In order to determine the

absolute configuration, we must first study the R and S conventions. There

are two steps involved in labeling an enantiomer as R or S.

Step 1:

A molecule may contain any number of stereocenters and any number

of double bonds, and each gives rise to two possible configurations. The

purpose of the sequence rule (Cahn–Ingold–Prelog priority rules, CIP

system or CIP conventions) is to assign an R or S descriptor to each

stereocenter and an E or Z descriptor to each double bond so that the

configuration of the entire molecule can be specified uniquely by including

the descriptors in its systematic name. Following this rule, we assign a

http://en.wikipedia.org/wiki/Stereocenter

http://en.wikipedia.org/wiki/Covalent_bond#Bond_order

http://en.wikipedia.org/wiki/Chirality_(chemistry)#By_configuration:_R-_and_S-

http://en.wikipedia.org/wiki/Cis-trans_isomerism#E.2FZ_notation


95

sequence of priority to the four atoms or groups of atoms attached to the

asymmetric (chiral) carbon atom.

Step 2:

The molecule is visualized oriented so that the group of the lowest

priority is directed behind the plane of the paper (i.e. directed at the bottom

in the corresponding Fischer projection). The arrangement of other three

groups is then observed. If then, in proceeding from group of highest

priority to group of second priority and then third our eye travels in

clockwise direction, the configuration is specified R (Latin: rectus, right);

if counterclockwise; the configuration is specified S (Latin: Sinster, left).

1

4

2

31

2

3

4

Sequence rules CIP (Cahn–Ingold–Prelog) priority Rules:

Rule 1

If the four atoms attached to the chiral carbon atom are all different,

priority depends on atomic number, with the atom of higher atomic number

getting higher priority e.g. O > N > C >H

Rule 2

If the relative priority of two groups cannot be decided by rule 1, it shall

be determined by similar comparison of the next atoms in the groups (and

so on, if necessary, working outward from chiral carbon). If two atoms


96

attached to the chiral carbon are the same, we compare the atoms attached

to each of these first atoms. e.g., take sec-butyl chloride, in which two of

the atoms attached to the chiral carbon are themselves carbon. In CH3 the

second atoms are H, H, H; in C2H5 they are C, H, H. Since carbon has higher

priority than hydrogen, C2H5 has higher priority. A complete sequence of

priority for sec-butyl chloride is therefore Cl, C2H5, CH3, H.

C

CH3

C2H5Cl

H

1 2

3

4

Rule 3

A double- or triple-bonded atom A is equivalent to two or three A`s. Thus

e.g. in glyceraldehyde the OH has the highest priority of all, and the O,O,H

of CHO takes priority over the O,H,H of CH2OH.The complete sequence

is then –OH, -CHO, CH2OH, -H

In the compound, e.g.

NH2

H

CH

CH3

CH3

The C, C, C of phenyl takes priority over C, C, H of isopropyl but NH2

takes priority over both (c.f. rule 1). So, the sequence would be -NH2, -

C6H5, -C3H7, -H.


97

All these examples are chiral molecules and the two enantiomers will have an

optical activity with opposite direction of rotation towards plane polarized light. A

mixture of equal amounts of any two enantiomers is called a racemic mixture

which is optically inactive due to external compensation.

Racemic modification:

A racemic modification is an equimolar mixture of the R and S

enantiomers. Such a mixture will be optically inactive due to external

compensation. A racemic modification might be produced mechanically or

during the formation of chiral compounds from achiral ones (i.e.

compounds with no chiral centers). The synthesis of lactic acid from

acetaldehyde using the cyanohydrin reaction is an example of such

achiral→ chiral syntheses, the resulting acid being an R-S racemic

modification (sometimes designated as ± form). The steps involved in this

synthesis are outlined below:

When a racemic modification (a+b) is hydrolyzed racemic lactic acid is produced

which means that (a) and (b) are produced in identical amounts (why?).

There are two types of racemization; physical and chemical.

Physical racemization can be divided into:

Autoracemization:

Many optically active substances become more and more inactive with time until

their optical activity completely disappears. This process is known as racemization.

The only property that is lost in racemization is the optical activity, chemical


98

composition; structure and chemical properties are retained. There are various

ways through which racemization might be affected. Certain substances undergo

spontaneous racemization on standing (the so called autoracemization) e.g. (+)-

phenylbromoacetic acid, C6H5C*H(Br)COOH completely loses its optical activity, in

the solid phase, after three years of its storage. In general, optically active

substances that have halogen atom attached to the chiral center display

autoracemization.

Thermal racemization:

Phenyl ethyl chloride, C6H5C*HClCH3 undergoes racemization during distillation.

Chemical racemization:

Several hypotheses have been put forward to account for racemization. One of

the most widespread is the hypothesis of enolization mechanism, which is since

racemization takes place readily if there is a carbonyl group next to the chiral

center. E.g. when menthone undergoes enolization, one of the asymmetric

centers present in this compound disappears and when the enol form reverts to

the keto form, it can do so to produce not only the original keto molecule but also

the keto form in which the configuration of the bottom asymmetric carbon atom

is opposite to that in the original ketone:

Both acids and alkali catalyze the above racemization, i.e. by reagents, which

catalyze enolization itself. Lewis acids also catalyze the process.

Compounds containing two chiral centers:

The general formula for calculating stereoisomer is:


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Number of stereoisomers = 2n, where n is the number of chiral centers.

A couple of things to keep in mind:

1. Stereoisomers are compounds with the same chemical formula but different

spatial arrangement.

2. Chiral centers are carbons that are bonded to 4 different groups. This rule is valid

for compounds with different substitutions around the chiral carbons but for

compounds with similar substitution around the chiral carbons e.g. tartaric acid this

rule is not valid.

How to identify an Enantiomer, Diastereomer, and Meso Compound?

Steps that should be considered:

1. Identify the number of stereocenters.

(0) Stereocenters= Not a stereoisomer and therefore cannot be either an enantiomer,

diastereomer or meso compound.

(1) Stereocenter= possibly an enantiomer but must not be superimposable on its

mirror image.

(2 or more) Stereocenters= All the three possibilities i.e. enantiomers,

diastereomers and meso are possible.

2. Identify the absolute configurations (R or S) of each stereocenter.

3. Is there a mirror plane? And is it superimposable on its mirror image?

4. Accumulate all the information and list out all the absolute configurations.

Example:

Compounds having the general formula C (a b d) C (a b e) possess two different

chiral centers. There are four possible special arrangements:


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The relation among the above four structures are as follows:

I is an enantiomer of II

III is an enantiomer of IV

(I+II) is a racemic modification

(III+IV) is another racemic modification

I is a diastereomer of III

I is a diastereomer of IV

II is a diastereomer of III

II is a diastereomer of IV

Diastereomers:

Diastereomers are stereoisomers, which are not enantiomers i.e. not mirror

images of one another. The cis-trans isomers are also diastereomers, e.g. cis and

trans 2-butenes. Now we recall that enantiomers have identical physical and

chemical properties (except their behavior towards plane polarized light and

optically active reagents). Contrary to this fact, a pair of diastereomers differs from

one another in their physical properties such as melting points, boiling points,

refractive indices, solubility, densities etc. (as we shall learn later, this property

will be made use of in the resolution of racemic modification). Pairs of

diastereomers, however, have similar chemical properties since they are members

of the same family.

Meso structures:

When d = e (in structures I and II above), I become equivalent to II and the

number of stereoisomers become reduced to three:


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b

b

a

a

d

d

b

b

a

a

d

b

b

a

ad

V

d

d

VI VII

meso( )

Compound V is superimposable on its mirror image. (Why?)

It has a plane of symmetry, which bisects it into two identical moieties and

therefore is optically inactive due to internal compensation (contrary to a racemic

modification which is optically inactive due to external compensation).

Configuration such as V is called Meso structure. Meso compounds exist only

when two chiral centers are identical, i.e. in compounds having the general

structure Cabd. Cabd.

R and S Assignments in Compounds with Two or More Stereogenic Centers.

When a compound has more than one stereogenic center, R and S

configurations must be assigned to each of them.

Identical compounds have the same R, S designations at every stereogenic

center.

Enantiomers have opposite R, S designations.

Diastereomers have the same R, S designation for at least one stereogenic

center and the opposite for at least one of the other stereogenic centers.


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Resolution of racemic modifications via the formation of diastereomers

We let (R, S) represents a racemic modification of a certain stereoisomer. The

difficulty in separating them lies in the fact that R and S are enantiomeric

structures and thus have identical physical properties and therefore cannot be

separated, e.g. by fractional crystallization or any of the other conventional

methods of separation. If, however, the racemic modification is allowed to react

with another optically active substance, say R1 a pair of substances results, e.g.,

(RS) + 2R1 → { (R1.R) + (S.R1) }

Compounds (R1R) and (SR1) are no longer mirror reflections of one another; they

are, in fact, diastereomeric and hence might be separated via conventional

methods. The resolving reagent, R1, might then, by some reaction, be removed

from each of the diastereomers to leave pure R and S. The formation of

diastereomers from the racemic modification is possible only if the compound to

be resolved has a chemically active group capable of interacting with a suitable

optically active reagent (resolving reagent). Racemic acids might be resolved using

optically active bases and vice versa. E.g. we consider the resolution of racemic α-

methyl phenyl acetic acid by means of (-) α-phenyl ethylamine as a resolving

agent:

The salt of the (-) acid is less soluble; it separates out and is purified by

recrystallization from water. The diastereomeric salt after separation might be

decomposed by hydrochloric acid. There are other methods of resolution, but they

are of interest only to specialized courses.


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Chirality without a tetrahedral stereo center:

Certain compounds are chiral by virtue of restricted rotation about one or more

carbon-carbon bonds. This restricted rotation will make these molecules free from

all elements of symmetry, as for examples, certain derivatives of allenes, spirans

and tri or tetra ortho-substituted biphenyls. Because rotation is restricted about the

cumulated double bond of allenes, the spiro carbon in spirans and the C-C single

bond in biphenyls, these molecules are chiral, and each molecule exists as a pair

of enantiomers. This class of chirality is referred “Atropisomers” (compounds

containing chiral axis), (A= no, Trophy= rotation).

1-Stereochemistry of allenes:

Optical activity is a result of chirality. Chirality is when one molecule is NOT

superimposable with its mirror image. If you have an allene with four different

substituents, since there is no rotation about the double bonded carbons, the mirror

image of itself is not superimposable, and it’s chiral. With allenes the two end

carbons are in a state of trigonal hybridization and the carbon atom in the center is

in the diagonal state. Thus, the center carbon atom forms two π-bonds, which are

perpendicular to each other. Consequently, substituents at the terminal carbons lie

in two perpendicular planes, thus making the configuration as a whole chiral.

2-Stereochemistry of spirans:

If the two double bonds of allenes are replaced by ring system, the resulting

molecules are spirans (Spiro compounds where the two rings are at two

perpendicular planes due to restriction of rotation e.g., Spiro[5.5]undecane and

Spiro[4.2]heptane.


104

3-Stereochemistry of o-substituted biphenyls:

o-Substituted biphenyl, molecule would exhibit optical activity. This is due to steric

effect which prevents free rotation around C-C single bond joining the two phenyl

rings and so these two rings cannot be coplanar, and they always be perpendicular

to each other e.g. 2-2`-dinitrobiphenyl-6-6`dicarboxylic acid.

(1) (2)

Two conditions are necessary for a biphenyl compound to be nonsuperposable on

its mirror image:

Neither ring must have a plane of symmetry.

The three substituents in the ortho position must have large size otherwise the

molecule will have plane of symmetry e.g. 2-methylbiphenyl-2,6-dicarboxylic

acid is optically inactive.


105

Geometrical (cis-trans) isomerism:

Geometrical isomerism which results from restricted rotation around double bond

e.g. 2-butene CH3CH=CHCH3 exists in two geometrical isomers, cis-form (when

the two methyl groups are on the same side) and trans- form (when the two methyl

groups are on opposite sides).

The restricted rotation about the double bond makes it possible to isolate the two

geometrical (cis-, trans-) isomers.

Geometrical isomerism cannot exist if either carbon atoms carry identical groups

(why?). Thus:

Geometrical isomers are not enantiomers but diastereomers and thus possess

different physical properties.

The E-Z system of labeling alkene diastereomers:

It is difficult to use the cis-trans system for trisubstituted or tetrasubstituted alkenes.

e.g. how would we distinguish?


106

For such compounds, the E-Z system is used: the two groups attached to each

carbon of the double bond are arranged in the order of their priorities according to

sequence rules explained before. We then take the group of higher priority on one

carbon and compare with the group of higher priority on the other carbon. If the

two groups of higher priority are on the same side of the double bond the alkene is

labeled Z (German: Zusammen = together). If the two groups of the higher priority

are on opposite sides of the double bond, the alkene is designated E (German:

Entgegen = opposite).

Conformations (Rotational Isomers)

They are different forms of spatial arrangement of atoms in a molecule of a given

constitution and configuration as a result of either rotation around single bonds

or flipping or inversion of cycles as cyclohexane without affecting the

constitution or the configuration of this compound. These forms (of the same

molecule) are called conformations (or rotomers or conformers). For example, the

molecule of ethane (CH3-CH3) show free rotation around single bond and the

Newman projection for its conformations (eclipsed and staggered) are outlined as

such:


107

These Newman projections are obtained by viewing the molecule along the

bonding line of the two carbon atoms with the carbon atom nearer to the eye being

designated by equal space radii and the carbon atom further from the eye by a circle

with three equal space radial extensions. The rotation around the C-C bond will

change the dihedral angle (Ǿ) [i.e. the

angle between C-X and C-Y bonds in a X-C-C-Y system] and so different

conformers are obtained. Also known as torsional angle.

In the staggered conformation, the hydrogen atoms of ethane are as far apart as

possible (with dihedral angle Φ = 60° or 180°), while in the eclipsed conformation,

the hydrogens are as close together as possible (with dihedral angle Φ= 0°).

The difference between eclipsed and staggered conformers is in the energy barrier

between them. In case of ethane the energy barrier between its conformers is much

too small to the extent that they are readily interconvertible and hence neither can

be isolated.

However, the staggered conformation is the preferred form (i.e.) its ratio is greater

than that of the eclipsed form. It should be noted that molecules in its normal

condition will exist largely in the conformation of the lowest energy content.


108

In case of ethylene glycol or ethanolamine, the most stable conformer is the gauche

(Φ = 60°), due to the high stabilization induced by intramolecular hydrogen bond.

In case of acetylcholine [CH3COO-CH2-CH2-N+(CH3)3] the parasympathetic

mediator, is present mainly in the skew conformation due to dipole-dipole

attraction. This conformation is probable for fitting with receptor sites, and any

change in the structure which destabilizes this skew conformation will abolish its

parasympathetic activity.

Conformations of cyclohexane

All C-C-C bond angles in the hypothetical planer form of cyclohexane are 120°,

a value considerably larger than the tetrahedral angle of 109.5°. So, cyclohexane

can be twisted into a number of nonplanar or puckered conformations (chair and

boat conformations). The most stable of which is the chair conformation in which

all C-C-C bond singles are 109.5°, and C-H bonds on adjacent carbons are

staggered (gauche) with respect to one another.


109

In cyclohexane, three carbon atoms pucker up and three C atoms pucker down,

alternating around the ring.

Each carbon in cyclohexane has two different kinds of hydrogens: axial

hydrogens (a) are located above and below the ring (along a perpendicular

axis) and equatorial hydrogens (e) are in the plane of the ring (around the

equator). That is, there are three axial bonds and three equatorial bonds in each

side of the ring.

An important conformational change in cyclohexane involves “ring-flipping.”

Ring-flipping is a two-step process.


110

As a result of a ring flip, the up carbons become down carbons, and the down

carbons become up carbons.

Axial and equatorial H atoms are also interconverted during a ring-flip. Axial

H atoms become equatorial H atoms, and equatorial H atoms become axial H

atoms.

The chair forms of cyclohexane are 7 kcal/mol more stable than the boat form. This

large difference in the potential energy between chair and boat conformations

means that at room temperature, chair conformation makes up more than 99.99%

of the equilibrium mixture. For cyclohexane, the two equivalent chair

conformations can be interconverted by twisting (flipping) first to a boat and then

to the other chair.

The boat conformation is considerably less stable than the chair conformation

because of two factors;

The boat conformation is destabilized by torsional strain because the hydrogens on

the four carbon atoms in the plane are eclipsed.

One set of “flagpole” interactions between hydrogens on carbon 1 and carbon 4.


111

As mentioned above, the boat form of cyclohexane has very low population

(0.01%) in its equilibrium with the other two chair conformations. This means that

it has no existence, but it may be a transient of flipping process.

1, 3-Diaxial interactions in cyclohexane:

The chair conformation of cyclohexane is very stable, but it suffers from little

steric repulsion (or opposition interactions) induced by the atoms or groups present

in the axial bonds in each side. This numbering do not refer to the relationship

between any two axial bonds in each side of the ring which have the 1, 3-position

i.e. 1,3 & 3,5 & 5,1& 2,4 & 4,6 and 6,2. That is, groups or atoms occupy axial bonds

will suffer from 1,3-diaxial interaction. However, groups or atoms which occupy

equatorial bonds have not any interactions (since they are oriented outside the ring

which means that they are very far

from any steric repulsion).

Indeed, when one chair is

converted to the other (by

flipping or twisting the ring), a change occurs in the relative orientations in

space of the hydrogen atoms attached to each carbon.

A hydrogen atom axial in one chair becomes equatorial in the other and vice

versa. In non-substituted cyclohexane, where the two chairs are readily


112

interconvertible and so they are equal energy; and each hydrogen will be axial

half of the time and equatorial the other half of the time.

Conformations of Monosubstituted Cyclohexane

When a substituent group replaces one hydrogen atom of cyclohexane, the

difference between equatorial and axial positions can become significant. For

example, the methyl group of methylcyclohexane rapidly interconverts between the

equatorial and axial positions but is energetically more favorable in equatorial

position.

Measurements show that, at equilibrium the methyl group is 95 % equatorial

conformation and 5 % axial conformation.

The t-butyl group [C(CH3)3], because of its large size, is far more stable in the e-

than in the a-position. Thus, almost only the e-form is present and consequently this

position is “locked” alternatively, the t-butyl group is referred to as an “anchor”, or

anchoring group and the molecule is said to be conformationally “Biased”.


113

Conformational Structures of Disubstituted Cyclohexane

1,1-Dimethyl Cyclohexane

1-t-butyl-1-methyl cyclohexane

cis-1,2-dimethyl cyclohexane

trans-1,2-dimethyl cyclohexane


trans-1,3-dimethyl

cyclohexane


trans-1,4-dimethyl cyclohexane

In the case of 1,1-disubstituted cyclohexane, one of the substituents must

necessarily be axial and the other equatorial, regardless of which chair

conformer is considered. Since the substituents are the same in 1,1-


114

dimethylcyclohexane, the two conformers are identical and present in

equal concentration. In 1-t-butyl-1-methylcyclohexane the t-butyl group is

much larger than the methyl, and that chair conformer in which the larger

group is equatorial will be favored in the equilibrium (> 99%).

Consequently, the methyl group in this compound is almost exclusively

axial in its orientation.

In the cases of 1,2-, 1,3- and 1,4-disubstituted compounds the analysis

is a bit more complex. It is always possible to have both groups equatorial,

but whether this requires a cis-relationship, or a trans-relationship depends

on the relative location of the substituents. As we count around the ring

from carbon 1 to 6, the uppermost bond on each carbon changes its

orientation from equatorial (or axial) to axial (or equatorial) and back. It is

important to remember that the bonds on a given side of a chair ring-

conformation always alternate in this fashion. Therefore, it should be

clear that for cis-1,2-disubstitution, one of the substituents must be

equatorial and the other axial; in the trans-isomer both may be equatorial.

Because of the alternating nature of equatorial and axial bonds, the

opposite relationship is true for 1,3-disubstitution (cis is all equatorial,

trans is equatorial/axial). Finally, 1,4-disubstitution reverts to the 1,2-

pattern.

Stereoisomerism in Biological System

Biomolecules (sugars, amino acids, DNA, proteins, steroids) are chiral.

Proteins are built from L-amino acids, which implies that enzymes – the

catalysts of nature - are chiral.

Also, receptors, drugs, biopharmaceuticals, are chiral and the natural ligand to

a receptor is often only one specific enantiomer.


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Enantiomers differ in plasma protein or tissue protein binding and in various

transport mechanisms. Only one of the two enantiomers shown in the above

figure (R) can achieve three-point binding with hypothetical binding site.

The enantiomers differ in both pharmacodynamics and pharmacokinetics

(absorption, tissue distribution, plasma protein binding, metabolism and

elimination).

Therefore, enantiomers of compounds can react differently in the body with

greatly helpful or harmful outcomes.

One enantiomer may have beneficial effects while the other has adverse effects: e.g

thalidomide.

Thalidomide tragedy- In 1960s in Europe, the drug was sold as a racemic

mixture to reduce costs. One enantiomer (R) stops morning sickness in

pregnant women. However, it was later discovered that the other

enantiomer (S) causes severe birth defects. Babies were born with missing

or abnormal arms, hands, legs or feet. Thus, important to make sure you

have the right optical isomers in your drugs.


116

One enantiomer may have beneficial activity while the other has antagonistic activity;

e.g salbutamol.

R-Salbutamol is a strong bronchodilator used in treatment of asthma. Its

enantiomer S-salbutamol is not only inactive as bronchodilator, but also

antagonize the bronchodilator activity.

Enantiomers may have entirely different effects; e.g Thyroxin.

Levothyroxine known as L-thyroxine is used to treat thyroid hormone

deficiency. On the other hand, dextrothyroxine was used as a

cholesterol-lowering drug but was withdrawn due to cardiac side

effects.

One enantiomer may have the activity while the other is much less active; e.g

etomidate.

R–Etomidate is a short acting intravenous sedative and anesthetic agent.

R–Etomidate is ten-fold more potent than its S enantiomer.

Each enantiomer is metabolized by a different pathway; e.g. Verapamil.


117

Verapamil is an antihypertensive drug. R- and S-verapamil have unequal

oral bioavailability. Oral tablets and solutions resulted in approximately

75% of the drug in the body the less active R-verapamil and only 25%

being the more active S-verapamil.

Importance of studying chirality and separation of isomers:

Increased selectivity to receptors and increased potency.

Decreased side effects and increased safety.

Decreased dose given to the patients.


118

Chapter 4

Alkyl Halide


119

Alkyl halides

They are classified into primary, secondary and tertiary alkyl halides according to the

carbon to which the halogen is directly attached.

Nomenclature:

1) They are named as substituents of alkanes and not a functional group.

2) Choose the longest continuous chain and give the substituents the lowest number.

Preparation:

I- By direct halogenation of alkanes:

The reaction proceeds by free radical mechanism. It is used for preparation of chloro and

bromoalkanes only, as fluorine is very reactive while iodine is unreactive.

II- By hydrohalogenation of alkenes:

III- From alkynes:

a) To obtain geminal dihaloalkanes:

b) To obtain tetrahalo compounds:


120

IV- From alcohols:

The hydroxyl group is replaced by halogen either:

a) By using hydrogen halides:

R––OH + HX R––X + H2O

The reactivity of HX in halogenation is HI > HBr >HCl>HF while, the reactivity of alcohols

toward this reaction is:

3 alcohols > 2alcohols> 1 alcohol.

The reaction mechanism proceeds through “unimolecular nucleophilic substitution” SN1

i.e. the rate of reaction depends on the concentration of only one reactant. This mechanism

involves formation of carbocation and thus rearrangement may occur to give the most stable

carbocation. Therefore, tertiary alcohols are more reactive than secondary than primary alcohols

toward the reaction.

b) By using halogenating agents:

Example of halogenating agents are; PX5 or PX3 or I2/P “red phosphorus”.

Reactions of alkyl halides:


121

They are very reactive compounds; they react with many reagents to yield a variety of

important compounds. They react by either:

1) Nucleophilic substitution.

2) Elimination reactions.

A) Nucleophilic substitution reactions: “SN”

The halogen atom in these reactions is replaced by another atom or group.

These reactions proceed by either:

1) Unimolecular nucleophilic substitution. “SN1”

2) Bimolecular nucleophilic substitution. “SN2”

I- Unimolecular nucleophilic substitution: “SN1”

The rates of these reactions depend on the concentration of only one substrate. Their

mechanisms involve the formation of carbocation.

e.g. R––X + Nü R–Nu + X

II- Bimolecular nucleophilic substitution: “SN2”

Here the rate of reaction depends on the concentration of both substrates, the alkyl halide

and the nucleophile. The reaction involves the formation of transition state.


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It is a one-step reaction in which a bond is formed, and a bond is broken at the same time.

Stereochemistry of reaction:

a) In case of SN2:

The nucleophile attack from the back of the carbon leading to inversion of

configuration.

In case of SN1:

Since the mechanism involves carbocation formation and the carbocation configuration is

sp2 i.e. planar. Therefore, it will be attacked by the nucleophile from any side giving rise to a

racemic mixture with 50% retention of configuration and 50% inversion of configuration.

Factors affecting substitution reaction mechanism:

These factors control the progress of reaction whether to proceed by SN1 or SN2:

1) Nature of nucleophile.

2) Nature of halogen “leaving group”.

3) Type of alkyl group.

4) Nature of medium “Solvent”.

1. Nature of nucleophile:

If the nucleophile is strong, it will have high affinity towards the carbon attack the carbon

leading to SN2 mechanism while in case of weak nucleophiles, the R–X bond will be broken first

before they attack i.e. proceed by SN1 mechanism.

2. Nature of halogen “leaving group:

The halogen here is the leaving group, so if it gives a stable anion, it is a good leaving group

and thus enhances the reaction to proceed by SN1 mechanism while, if X- is unstable, the

halogen will be a poor leaving group and the reaction will proceed by SN2 mechanism.

3- Type of alkyl group:


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The alkyl groups attached to the halide are classified into:

a) Primary alkyl group.

b) Secondary alkyl group.

c) Tertiary alkyl group.

The alkyl groups have three effects:

a) Steric effect.

b) Electronic effect.

c) Stability of intermediate.

a) Steric effect:

In case of SN2 mechanism the attack occurs from the back of the carbon. Therefore, if it is

sterically crowded, it will hinder SN2 mechanism and enhance SN1

Primary alkyl halides enhance SN2 mechanism while tertiary alkyl halides enhance SN1

mechanism due to steric hindrances. However, secondary alkyl halides proceed by both

mechanisms.

b) Electronic effect:

In case of primary alkyl halides, the δ+ on carbon is more than δ+ on the carbon of tertiary

alkyl halides. Therefore, it is easier to be attacked by nucleophile leading to SN2 mechanism.

However, in case of tertiary alkyl halides the three alkyl groups decrease the δ+ on the

carbon by positive inductive effect thus enhancing SN1 mechanism.

c) Stability of intermediate:

According to the stability of the intermediate the reaction will proceed. If the reaction

proceeds by SN1 mechanism, they will form carbocation in which tertiary carbocation is more

stable than secondary than primary due to positive inductive effect of alkyl groups.

Therefore, the nucleophilic substitution reactions of tertiary alkyl halides proceed by SN1

mechanisms while primary alkyl halides proceed by SN2 mechanism. However, secondary alkyl

halides can proceed either by SN1 or SN2 mechanisms.

d) Nature of medium: “solvent”

The effect of solvent depends on either it is polar or non-polar.

i) Polar solvents:


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Polar solvents as water make a sheath around the ions of the compound; a process called

“solvation”, this occur to decrease the charge on the ions, therefore, stabilizing these ions. e.g.

“Solvation of sodium chloride by water”

In SN1 reactions, polar solvents solvate the carbocation intermediate stabilizes it and thus

enhances the reaction.

While in SN2 reactions, the polar solvents have no effect on the transition state as there is

no definite charge. However, it solvates the nucleophile leading to retardation of attack, thus

slowing the initiation of reaction. In spite that they solvate the leaving group their overall effect,

that they retard SN2 reactions.

“Solvation of carbocation”. “solvation of nucleophile”

ii) Non-polar solvents:

They have no appreciable effect on the rate of reaction, as they do not stabilize the

carbocation in case of SN1 neither the transition state in case of SN2 mechanism.

Generally, the nucleophilic reactions proceed by both mechanisms, but which is predominant?

this depends on the strength of the factors affecting the reaction.

Factors enhancing SN1 mechanism: Factors enhancing SN2 mechanism:

(i) weak nucleophile.

(ii) Good leaving group.

(iii) Tertiary alkyl halide.

(iv) Polar solvent.

(v) Strong nucleophile.

(vi) Poor leaving group.

(vii) Primary alkyl halide.

(viii) Non-polar solvent.


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The reaction of primary, secondary or tertiary alkyl halides with metals as lithium or magnesium

under anhydrous conditions yield the highly reactive organometallic compounds.

However, the rate of formation of organometallic compounds with alkyl iodides is more than

alkyl bromides than chlorides than fluorides.

The Grignard reagent is a powerful nucleophile, which renders it an important intermediate for

preparation of various functional groups.

B) Elimination reactions:

Elimination of one molecule of hydrogen halide or halogen occur either by E1 or E2

mechanisms.

Elimination reactions generally occur at high temperature and by using a strong base.

"E2 mechanism"

The attack by base occur on -hydrogen and from the opposite side to the halogen.

"E1 mechanism"

Factors enhancing elimination reaction:

a. Conditions of reaction:


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i. Temperature e.g. high temperature.

ii. Solvent e.g. alcohol.

b. Tertiary alkyl group:

It enhances elimination reaction since it has many -hydrogens therefore giving high

probability for elimination

c. Strong bases: Strong base as:

II. Aryl Halides

These are compounds in which the halogen is directly attached to the aromatic

ring.

Preparation:

1. Direct halogenations:

a) Chlorination:

The reaction is restricted to monohalogenation due to negative inductive effect of

chlorine.

b) Bromination:

2. Halogenation of monosubstituted benzene derivatives:

It follows the rules of EAS.


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Since amines and phenols are very reactive, they give trihalogenated compounds.

3. Halogen derivatives from diazonium salts:

The halogen gets the same position of the diazonium group.

Chemical reactions of aryl halides:

1. Electrophilic aromatic substitution:

They are o-, p-directing toward electrophiles, the order of reactivity is Ar-F >

Ar–Cl > Ar–Br > Ar–I due to mesomeric effect. But Ar–F is mainly p-directing

since the o-position is subjected to strong negative inductive effect.

2. Reaction with metals:

a) Grignard reagent:


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Aryl halides are less reactive than alkyl halides in forming Grignard reagent

in which Ar- I > Ar-Br > Ar-Cl > Ar-F in reactivity.

mechanism:

b) With sodium:

c) Ullmann reaction:

d) With lithium:

Chloro and bromobenzene react with lithium to give phenyl lithium which

react like Grignard.

3. Nucleophilic aromatic substitution: “SNAr”

They require drastic conditions for their substitution by nucleophile unless

there is another electron withdrawing group which facilitates the reaction.


129

This can be attributed to the strong Ar-X bond due to its partial double bond

character in which the electron delocalization occurs over the ring and the halogen.

In addition, the C–Cl bond is sp2C-Cl which is much stronger than sp3C–Cl of alkyl

halides.

The electron withdrawing group must be in o- or p-position to the halogen to

facilitate the nucleophilic substitution.

Therefore, according to the reactivity of aryl halides toward nucleophilic

substitution, they are classified into:

1. Unreactive aryl halides e.g. Halobenzene or m-nitrohalobenzene.

2. Reactive aryl halides e.g. o- and p-nitro derivatives of halobenzene.


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I- Reactive aryl halides:

They carry out their reactions by SN2 aromatic mechanism which involves a

carbanion intermediate that is called "Meisenheimer intermediate". It is also called

“Addition-Elimination mechanism”.

The intermediate is stabilized by four canonical structures, in one of them the nitro

group contributes in its stabilization.

In this reaction, Ar-F > Ar-Cl > Ar-Br > Ar-I in reactivity; since F is more

electronegative than Cl than Br than I and thus as leaving groups which also

stabilizes the anionic intermediate by negative induction.

II. Unreactive aryl halides:

The reaction of unreactive aryl halides proceeds also through SNAr

mechanism but involving "Benzyne intermediate", it is also called “Elimination-

Addition mechanism”.

mechanism:

They labelled the carbon C–Cl by 14C isotope, they found that addition on

the bond of benzyne intermediate occur at both ends to give two compounds one


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of which the Nu is on C–Cl carbon while the second product the Nu is on the o-

carbon to C-Cl bond.

But in case of substituted aryl halides, the percentage of both ways differ according

to the stability of intermediate.

Other examples of SN aromatic reactions:

Preparation of D.D.T.:


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D.D.T. and other polyhalogenated compounds are used as insecticides and

pesticides. But their use now is restricted due to their serious side effects as they

are non-polar, lipid soluble as well as they are very stable and do not undergo

biochemical degradation, therefore, they enter food chain and they are accumulated

in body tissues.

Preparation of o-chlorotoluene: (pure isomers)

III. Aralkyl Halides

I. Direct halogenations:

They are obtained upon reaction of alkyl benzenes with Cl2/UV. The reaction

product can be controlled to mono- or di- or trichloro products by controlling the

amount of halogen. It occurs by free radical mechanism.

mechanism:


133

Halogenation occur on benzylic carbon due to stabilization of benzyl radical.

if the compound has two side chains both will be halogenated.

II. Chloromethylation:

III. From benzaldehyde:

Properties of aralkyl halides:

They react by nucleophilic substitution, if the halogen is on benzylic carbon,

it becomes more reactive than alkyl halides more reactive than aryl halides due to

the stabilization of the benzyl carbocation by resonance on the ring.


134


135

Chapter 5

Aromatic Compounds


136

Structure of Benzene

Benzene, a volatile liquid hydrocarbon (bp 80 ͦC), was isolated by

Faraday in 1825. It is the parent structure of a large class of naturally

occurring and synthetic substances known as aromatic compounds.

It is quite different from “benzene” used as car fuel (Gasoline) which is

a mixture of aliphatic hydrocarbons.

Benzene presented a puzzle to the chemists of the nineteenth century due

to the following:

1. Molecular formula of benzene is C6H6, that means it is highly unsaturated.

2. Although benzene is unsaturated, it reacts by substitution and not by

addition to give one mono-substitution product. This means that all six

hydrogens in benzene are equivalent.

3. Further reaction of bromobenzene with Br2 give three isomeric

dibromobenzenes.

4. Benzene is remarkably stable; it does not undergo addition and

oxidation reactions characteristic of alkenes.

Based on the above results, in 1865 , Kekulé proposed that benzene

can be formulated as 1,3,5–cyclohexatriene.

Kekulé structure accounts for:

1- The exact molecular formula C6H6.

2- The presence of four unsaturation in benzene.


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3- The formation of single mono substitution product.

It fails to account for

1- Stability of benzene, because it represents benzene as an alkene with

localized double bonds.

2- Benzene reacts by substitution and not by addition.

3- It gives 3 isomeric disubstitution products (i.e. there is no difference

between 1,2 and 1,6 positions).

4- All C–C bonds are equivalent in length (1.4 Å) this value is

intermediate in length between C–C single bond (1.48 Å) and C=C

double bond (1.34 Å)

Orbital Picture of Benzene

There are two types of bonding in benzene:

σ-Bonding: x-ray showed that benzene is a planar symmetrical hexagon

with bond angle 120o and C–C bond length 1.4 Å (i.e. intermediate

between C–C and C=C). Each C is sp2 hybridized and uses 3 sp2 orbitals

to form 3 σ-bonds and all C’s are planar.

π-Bonding: Each carbon has p orbital perpendicular to the plane of

the ring. Each p orbital can overlap equally with each of the two adjacent

p orbitals i.e. C1 can overlap with each of C2 and C6.


138

Overlap of all 6 p orbitals occurs to form delocalized MO containing 6

π electrons. The electron density is greatest above and below the plane of

the benzene ring.

The orbital picture of the π bonding in benzene is empirical, because no 6

π electrons can occupy a single MO.

The quantum theory developed in 1930’s produced two ways of

viewing the bonding in benzene: resonance and molecular orbital (MO)

theories.

Resonance explanation of the structure of benzene

1- According to resonance theory, benzene is a resonance hybrid

of two Kekulé structures I and II which are identical except for

the position of π electrons.

2- The resonance structures I and II are imaginary structures.

Benzene has a single hybrid structure III which combines the

characteristics of I and II.

3- Structures I and II are equivalent and hence will make equal

contribution to the hybrid. Each C-C bond is single in one structure

but double in the other structure. Therefore C-C bond in benzene

is intermediate in length between C-C and C=C bond; i.e. it has

partial π bond.

4- The π electrons delocalization over cyclic conjugated system is

associated with increased stability (lower energy), i.e. benzene is


139

more stable (lower energy) than expected for contributing

structures I and II by an amount of energy called resonance

energy.

Stability of benzene

1- Hydrogenation of alkenes is exothermic reaction. The heat of

hydrogenation (ΔH) of cyclohexene = -28.6 kcal / mole.

2- calcd ∆H for benzene based on the 1,3,5-cyclohexatriene: calcd ∆H =

3 x -28.6 = -85.8Kcal/mol

3- The actual heat of hydrogenation (ΔH found) of benzene is -49.8

Kcal / mole.

This indicates that benzene has lower energy content (i.e. more stable) than

the imaginary 1,3,5–cyclohexatriene by 36 Kcal / mole. The difference

between ΔH calcd and ΔH found is called resonance energy.

Resonance energy = ΔH calculated –ΔH found

= -85.8 – (- 49.8) = -36 Kcal/mole

The high resonance energy of benzene means that more energy is

required for reactions in which aromaticity is lost (addition reactions)

e.g. alkenes are hydrogenated at room temperature while benzene

requires high temperature and pressure.


140

Aromaticity

The term aromaticity (or aromatic characters) is used to describe certain

properties of benzene and benzene–like compounds. These properties are:

1- Increased stability: aromatic compounds are stable and possess large

resonance energy.

2- Special chemical reactivity: aromatic compounds react by

substitution rather than addition.

3- NMR spectroscopy: aromatic ring hydrogens are deshielded i.e., have

resonance signals farther downfield (7 – 9 ppm) than alkene

hydrogens (5 – 6 ppm).

4- C–C bond length: of aromatic rings is intermediate between C–C

single bond and C=C lengths.

Requirements of aromaticity:

The structural requirements for a molecule to be aromatic

are

1. It must be cyclic.

2. It must be fully conjugated, i.e. all ring carbons are sp2 hybridized.

3. It must be planar.

4. Huckel’s rule is applied only when the molecule satisfies

conditions1-3.

a. If the molecule contains 4n+2 π electrons (where n= 0,1,2…), it will

be aromatic (i.e. stabilized relative to a localized polyene structure).

b. If the molecule contains 4n π electrons, it will be antiaromatic (i.e.

destabilized relative to a localized polyene structure).

c. If the molecule does not satisfy conditions 1 – 3, it is nonaromatic.


141

Application of Huckel’s MO method:

To predict aromaticity or antiaromaticity for a molecule, Huckel’s

criteria for aromaticity must be applied. A continuous planar ring of

overlapping p orbitals is required for the rule to apply. Resonance alone

is not enough to predict aromaticity.

Benzene (C6H6)

Monocyclic, conjugated, planar, it has 6 π electrons (4n+2), it is stable

aromatic system.

Cyclobutadiene (C4H4)

Monocyclic, conjugated almost planar has 4 πelectrons (i.e. 4n π system) it

is antiaromatic.

Cyclooctatetraene (C8H8)

It is monocyclic, conjugated contain 8 π electrons (i.e. 4n π system) therefore

it is antiaromatic if planar

Planar C8H8 is destabilized by Huckel’s rule and by angle strain (135˚).

Cyclooctatetraene is more flexible than cyclobutadiene. It exists as non–

planar tub shaped molecule and behaves as non-aromatic cyclic polyene,

e.g. it adds Br2, shows nmr singlet at δ 5.7 ppm and has alternating C–C

and C=C


142

How C8H8 is converted to aromatic molecule:

Cyclooctatetraene contains 8π electrons in a cyclic conjugated system.

Gain of 2 electrons convert it to aromatic 10 π electron system (i.e. 4n+2 π

system).

C8H82-is aromatic because it is cyclic, conjugated planar system containing

10 π electrons (4n+2) because aromatic stabilization is greater than angle

strain. All bonding and nonbonding MO’s are filled. All π electrons are paired.

Although C8H82- is aromatic it shows NMR singlet at δ 5.7 ppm because

shielding effect of excess electrons balances deshielding effect of aromaticity

Application of Huckel’s rule to hydrocarbon ions:

The cyclopropenyl system:

Cyclopropene (C3H4) has CH2 (sp3 carbon) in the ring and therefore

is not aromatic. Removal of H+ or H- convert cyclopropene to fully

conjugated ion and its aromaticity can be predicted.

Cyclopropene (C3H4), Nonaromatic


143

3 Cyclopropenyl anion (C3H3

-) cyclic, conjugated planar contains 4πelectrons

(4n π system), therefore antiaromatic

Cyclopropenyl cation (C3H3+) cyclic, fully conjugated, planar contains

2π electrons (4n + 2), therefore aromatic

Examples of aromatic stabilization of cyclopropenyl cation:

Cyclopropenone is a stable ketone, has large dipole moment (4.4D) and

its NMR spectrum shows singlet at δ 9.0 ppm.

The cyclopentadienyl system:

Cyclopentadiene (C5H6) has sp3 carbon in the ring and therefore is

not aromatic. Removal of H+ or H- converts the sp3 carbon to sp2

and the ring becomes fully conjugated.

Cyclopentadienyl cation (C5H5+),

cyclic, conjugated, almost planar

contains 4 π electrons (4n π

system) therefore antiaromatic

Cyclopentadiene

(C5H6)

Nonaromatic

Cyclopentadienyl anion (C5H5-

): cyclic, conjugated contains 6π

electrons (4n + 2π system)

therefore aromatic


144

The cycloheptatrienyl system:

Cycloheptatriene (C7H8) is not aromatic due to the presence of CH2

group (sp3 carbon). Removal of H+ or H- converts it to the fully

conjugated system.

`

Anion, (C7H7-)

cyclic, conjugated contains 8

π electrons (4n π system)

Therefore, planar C7H7-

is

Antiaromatic

Cycloheptatriene

(C7H8)

Nonaromatic

Cation (C7H7

+

) (tropylium ion)

cyclic, conjugated contains 6 π

electrons

Aromatic


145

Aromaticity in higher Annulenes

Completely conjugated monocyclic hydrocarbons are called annulenes.

Examples,

In [10]-annulene, there is considerable steric interaction between

hydrogens at 1 and 6 positions. Bridging C1 and C6 in [10]-annulene leads

to the compound VII which is reasonably planar and show


146

Electrophilic Aromatic Substitution Reactions

(SE aromatic)

Benzene is a nucleophile just like alkenes because they all have electrons.

Many electrophiles that add to alkenes react with benzene and its derivatives.

Alkenes form addition products whereas most aromatic compounds form

substitution products. Thus, the principal reactions of aromatic compounds are

electrophilic aromatic substitution (SE aromatic).

A list of typical SE aromatic reactions is given below:


147

To understand why aromatic compounds, react with electrophiles by substitution

rather than addition, we must understand mechanism of SE aromatic.

General mechanism of electrophilic aromatic substitution:

The general mechanism of SE aromatic reactions has three steps:

Step 1: generation of electrophile from the reagents used e.g.

Step 2: is generally the rate determining step. It is the addition of electrophile to

benzene to give intermediate carbocation (-complex) in which aromaticity is lost

(i.e. less stable).

It can be pictured as a resonance hybrid of three resonance structures.

Step 3: Deprotonation by anion Z- to regenerate aromaticity and give the

substitution product.

Overall reaction:

This mechanism explains two questions:


148

a) Why benzene is less reactive to addition of electrophiles than alkenes?

Aromaticity makes benzene more stable than alkenes. Addition of E+ to

benzene forms a carbocation that has lost aromaticity. This result in a larger energy

of activation (Eact1) compared with alkenes.

b) Why benzene forms substitution products?

If the intermediate carbocation undergoes addition of the anion, the resulting

product is not aromatic and is less stable than the reactant by 36 kcal/mole, while

loss of a proton restores aromaticity and gives a product more stable than the

reactant.

The potential energy diagram for an electrophilic aromatic substitution reaction. The σ complex is a

true intermediate lying between transition states 1 and 2

Isotope effect:

The isotope effect helps chemists to prove the mechanism of the electrophilic

aromatic substitution reaction. There are three basic steps during the


149

reaction: The E-Z bond is broken, the C-E bond is formed and finally the C-

H bond is broken.

Does the C-H bond break in the rate determining step (2nd step) or in the fast step (3rd

step)???

This question can be answered by looking for the "isotope effect". The

most common isotope of hydrogen is 1H, but 2H is also available; it is called

"deuterium". Deuterium is twice as heavy as the common protium. The

C-H bond vibrates more rapidly and energetically than a C-D bond;

therefore, the C-H bond is more easily broken than the C-D bond.

If we take a sample of ordinary benzene (C6H6) and a sample of deuterated

benzene (C6D6), we can measure how quickly they each undergo a

bromination reaction. Very often, a reaction that involves C-H bond

cleavage will slow down if a C-D bond is involved. However, no

deuterium isotope effect is observed during bromination, or other aromatic

electrophilic substitution reactions (KH/KD. =1). Both reactions involving

the C-H and C-D bonds take place so quickly and easily, by comparison,

that we don't really notice the difference between them.

The absence of an isotope effect usually proves that C-H bond cleavage is

not a rate-determining step. However, it is the final fast step that restores

aromaticity.

a) Nitration of benzene:

Benzene reacts with a mixture of nitric and sulphuric acids to form

nitrobenzene. The electrophile in the nitration reaction is the nitronium ion

NO2+


150

Step 1: Reaction of nitric acid and sulphuric acids to form NO2+

Step 2: addition of NO2 to benzene to form intermediate carbocation.

Step 3: Deprotonation of the intermediate carbocation by the base to regenerate the

benzene

b) Sulphonation of benzene

The sulphonation of benzene is often carried out with fuming H2SO4 (SO3

/ H2SO4). Conc H2SO4 alone can be used, but the reaction is slower.

The electrophile is SO3.

Step 1: with fuming H2SO4, SO3 is already present, but if H2SO4 is used

alone, SO3 is produced as follows:

2 H2SO4 SO3 + H3O+ + HSO4

-

Step 2: Addition of SO3 to benzene


151

Step 3: Deprotonation to regenerate benzene

Step 4: proton transfer

All steps in sulphonation are equilibria and the overall reaction is an

equilibrium as well.

Sulphonation reactions are reversible. The energy barriers on either side of

the complex are of roughly the same height

Sulphonation and Desulphonation:

Q: Sulphonation is a reversible reaction, using the following equation suggest

the conditions that influence the position of the equilibrium of the reaction

c) Halogenation of benzene:

Benzene does not react with Br2 or Cl2 alone unless catalyst is present.

Typical catalysts are Lewis acids such as FeBr3 and FeCl3.


152

Mechanism of bromination of benzene:

Step 1: Reaction of a Lewis acid with Br2 to form Br2–Lewis acid complex

which is stronger electrophile than Br2 molecule.

Step 2: Addition of the electrophile to benzene to form carbocation

intermediate

Step 3: Deprotonation to regenerate the aromatic ring.


153

The function of the catalyst Lewis acid:

The electrons of benzene are tightly held and are not able to polarize

Br–Br (as in alkenes). The Lewis acid polarizes Br–Br bond by forming a

complex. Complex formation makes the halogen more electrophilic.

Highly activated aromatic rings e.g. phenols and anilines react with

molecular halogen without the aid of catalyst.

Chlorination of benzene with Cl2 and FeCl3 proceeds by a mechanism like that of

bromination.

Fluorination of benzene is not used because fluorine is very reactive, and the

reaction is difficult to control.

Iodination is quite slow because I2 is unreactive toward most aromatic rings. It is

useful only with activated rings.

d) (i) Friedel–Crafts alkylation:

Alkyl halides react with benzene in the presence of AlCl3 to give

alkylbenzenes

Mechanism of reaction:

Step 1: formation of the electrophile


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Q: Predict the possible mechanism for alkylation of benzene using 1 ͦ ,2 ͦ ,3 ͦ

alkyl halidesͦ

Limitations of Friedel – Crafts alkylation:

1) Aryl and Vinyl halides are unreactive and do not form carbocations easily.

2) Polyalkylation often occurs because the alkyl group is activating o,p – directing

group e.g.

A practical way to overcome polyalkylation is to use excess aromatic

compound and at low temperature.

3) Rearrangement of the alkyl group to a more stable carbocation

e.g. sec. or ter. carbocations can be formed from primary alkyl halides by

rearrangement under the reaction conditions e.g.

Explanation: In the presence of AlCl3, the primary alkyl halide can

rearrange to more stable isopropyl cation


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The non-rearranged product is formed by reaction of the complex with

benzene The rearranged product: is formed by addition of isopropyl cation

to benzene followed by loss of proton (write steps 2 and 3).

4) Alkyl groups rearrange to different positions in the aromatic ring (isomerization)

because of the reversibility of the Friedel – Crafts reactions e.g.

5) Friedel–Crafts alkylation fails on benzene rings with strong deactivating

group e.g. NO2, SO3H, -CHO, -COOH, CF3…etc. The reaction is

successful only with: benzene, halobenzenes, and benzene substituted with

activating groups such as: R-, -OR, and –NHCOR.

6) Benzenes with NH2, NHR and – NR2 do not undergo Friedel–Crafts

alkylation because these substituents become strong electron withdrawing

by forming a complex with AlCl3.


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(ii) Friedel–Crafts Acylation:

Acyl halides react with benzene in the presence of Lewis acid to give

acylbenzenes (aryl ketones)

Mechanism:

step 1: Formation of the electrophile.

Q: Predict the possible mechanism for preparation of acylbenzene

The ketone–Aluminum chloride complex should be treated with water to regenerate

the free ketone.

Acylation can also be carried out using acid anhydride.

Advantages of Friedel – Crafts acylation:

1- No polyacylation occurs because the acyl group is deactivating.


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2- Acylium ions do not rearrange and the acyl group is transferred unchanged.

3-It can be used for the preparation of unrearranged alkylbenzenes by

acylation followed by reduction.

Why Friedel–Crafts acylation use more than one molar equivalent of AlCl3?

Because the produced ketone binds with AlCl3 as 1:1 complex (Ar – C = O+– Al-

Cl3).

Reactivity and Orientation in Electrophilic Aromatic Substitution

When substituted benzene undergoes electrophilic substitution, the substituent

group already present affects the following:

(a) Rate of the reaction (Reactivity).

(b) Position taken by the incoming substituent (Orientation).

Classification of groups

Substituent groups are classified into the following:

(a) Activating and o, p– directing groups: these groups cause the rate of

electrophilic substitution to be faster than that for benzene and direct the incoming

group mainly to o- and p- positions e.g.

Strong activating groups: -NH2, -NHR, -NR2, -OH, -O-


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Moderate activating groups: -OR, - O-CO-R, -NH-CO-R

Weak activating groups: -R, -Ar

(b) Deactivating and o, p-directing: These groups cause the rate of electrophilic

substitution to be slower than that for benzene and direct the incoming group mainly

to o- and p- positions e.g. halogens (F, Cl, Br, I).

(c) Deactivating and m-directing groups: These groups decrease the rate of

electrophilic substitution relative to that of benzene and direct the incoming group

mainly to m- position. e.g.

Moderate deactivating groups: -CHO, -CO-R, -CO-OH, -CO-OR,

-CO-NH2, -SO3H, -C≡N.

Strong deactivating groups: +NO2, +NH3, -CF3, -CCl3

Theory of reactivity and orientation in electrophilic aromatic

substitution:

The rate determining step in electrophilic aromatic substitution is

addition of E+ to the benzene ring to form intermediate carbocation. This

step is endothermic because aromaticity is lost.


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The relative rate of reaction at o-, m- and p- positions of monosubstituted

benzene is determined by Eact for the intermediate carbocation. The Eact is

determined by the energy (stability) of the intermediate. We can understand the

role of the substituents S by evaluating their inductive (I) and resonance (M) effects

on the stability of the intermediate carbocation formed by reaction at each position.

In general, electron releasing substituents stabilize the intermediate carbocation,

thus decreasing its Eact and the reaction will be faster (activation).

Electron–withdrawing substituents destabilize the intermediate carbocation, thus

increasing its Eact and the reaction will be slower (deactivation).


160

Reactivity and orientation of monosubstituted benzene in electrophilic

substitution reactions can be accounted for by considering the inductive and

resonance effects of substituents on the stability of the intermediate carbocation:

Activating o, p - directing groups - alkyl groups (+I groups):

Alkyl groups are weak activating o, p–directing groups due to:

a)- Electron releasing +I effect of the alkyl group which increases electron

density on ring carbons.

b)- the o- and p- positions are activated more than m- position as shown by

examination of resonance structures for the intermediates formed from o-, m-

and p- attack by E+.


161

The intermediates from o- and p- attack have especially stable structure in which

positive charge is adjacent to the R group (ter. carbocation structure) and are thus

more stable and formed faster than intermediate from m-attack which has no

especially stable structure.

Activating o-, p- directing groups (+M groups):

These groups which have unshared electron pair on the atom attached to

benzene are activating o-, p- directing by their electron donating resonance +M

effect (which is stronger than their –I effects).

e.g. The high reactivity and o, p- orientation in electrophilic substitution of aniline

is explained by writing resonance structures of the intermediates that arise from o-

, m- and p- attack.

NH2

E+E

H

NH2

+

E

H

NH2

+

E

H

NH2

+

ortho attack

E

H

NH+

exceptionally stable

NH2

E+

E

H

NH2

+

E

H

NH2

+E

H

NH2

+

meta attack


162

The intermediates from o- and p- attack have especially stable structure which

is stabilized by the strong electron donating resonance effect (+M effect) of the NH2

group (i.e. donation of electron pair from NH2 to the ring). This +M effect of the

NH2 group does not occur in the intermediate from m-attack. As a result, the NH2

stabilize the intermediate from o- and p- attack more than intermediate from m-

attack.

The activating and o, p–directing effects of other +M groups:

-OR, -OH, -OCOR, -NHR, -NR2, -NHCOR can be explained in a similar manner

to aniline.

Deactivating m- directing groups (-I groups):

These group are strong electron withdrawing by inductive effect only (i.e. have

–I effect). These include –CF3, -NH3, -NR3, CCl3…etc.

e.g. Why -CF3 group is strong deactivating and m- directing?

Reactivity: CF3 group is strong deactivating, it deactivates all positions on benzene

because the intermediate carbocation is destabilized by its strong –I effect.

NH2

E+E H

NH2

+

EH

NH2

+

E H

NH2

+para attack

E H

NH2

+

exceptionally stable


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Orientation: We write resonance structures for the carbocation intermediate

resulting from o-, m- and p- attack.

The intermediate formed by o- and p- attack are particularly unstable because

each is characterized by an unstable resonance structure in which there is a positive

charge on the carbon that bears the electron withdrawing CF3 group. The


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intermediate formed by m- attack has no such unstable structure and is relatively

more stable than intermediates from o- and p- attack.

Therefore, electrophilic substitution of C6H5–CF3 gives the m- isomer.

The deactivating and m- directing effects of other –I groups can be similarly

explained.

Deactivating and m- directing groups (-I, -M groups):

These groups which have multiple bonds are electron withdrawing by inductive(-I)

and resonance (-M) effects e.g.:

e.g. Why NO2 group is deactivating m- directing?

Reactivity: NO2 group is deactivating group through inductive and resonance

effects:

(a) Inductive effect: the NO2 is deactivating because its electron

withdrawing – I effect make the intermediate carbocation less stable

(i.e. destabilized) by increasing Eact leading to its formation.

(b) Resonance effect: Resonance in nitrobenzene stabilizes it, i.e. lower its

potential energy, this raises Eact leading to the formation of the intermediate

carbocation.


165

The electron withdrawing –M effect of the NO2 group decreases electron density

on the benzene ring especially at o- and p- positions.

Orientation

Just like the addition to C6H5–CF3, the intermediates formed by o- and p- attack

are particularly unstable due to the presence of unstable resonance structure. The

intermediate formed by m- attack, which have no such unstable structure is

relatively more stable and is formed in preference to intermediates formed by o-

and p- attack.

Q1: When nitrobenzene is treated with Br2 in presence of FeBr3, the major product is m-

bromonitrobenzene. Explain using resonance structures

The deactivating and m- directing effects of other –I, -M groups can be similarly

explained.

The halogens: Weak deactivating and o, p- directing groups:

Halogens differ from other substituents because they are deactivating groups but

o, p-directing. The halogens, in general have weaker electron donating resonance

effect (+M effect) and stronger electron withdrawing inductive effect (-I effect) i.e.

–I > +M effect.

Why halogens are o- and p- directing groups?

Because intermediates formed from o- and p- attack contain comparatively

stable structure by the +M effect of the halogen. So, aryl halides react faster with

electrophiles at the o- and p- positions.


166

Why halogens are deactivating?

Because in halogens –I effect > +M effect. Halogens (Cl, Br, I) have weaker

electron donating +M effect (less effective than OH or NH2) due to overlapping of

p orbitals (between C and the halogen) of different sizes (2p–3p, 2p–4p and 2p–5p

respectively) which is less effective than 2p–2p overlap (between C and N or O

atoms).

In the same time, halogens are strong electr012onegative elements and

destabilize intermediate by strong –I effect. because –I > +M effect, halogens are

deactivating.

Fluorine atom is deactivating and mainly p-directing:

(a) Fluorine is more reactive than other halogens because its +M effect

result from 2p – 2p overlap.

(b) Fluorine has the greatest –I effect which is strongest at the o- positions

and weakest at the p- position. because –I > +M effect F is deactivating

mainly p- directing.

Orientation in disubstituted benzenes:

When two substituents exist on a benzene ring, the directing effects of both

substituents must be considered:


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(1) Sometimes the two substituents direct the entering group into the same position

i.e. reinforce each other, e.g. a) nitration of p-nitrotoluene, b) sulphonation of m-

xylene and c) chlorination of toluene-p-sulphonic acid.

(2) When the directing effects of the two substituent groups oppose each other, the

more powerful activating group determines the orientation of the incoming group,

e.g.

a) Bromination of p-toluidine. b) Friedel-Crafts alkylation of o-cresol. c) Friedel-

Crafts alkylation of p-methoxytoluene.

(3) Steric effects are important e.g., a) a third group is least likely to enter between

two substituents m-to each other e.g., sulphonation of m-xylene occurs at position

4- only, b) Nitration of 3 butyltoluene occurs at position o-to CH3.

(4) When the two opposing substituents have approximately equal directing ability,

mixture of products is formed, e.g., nitration of o-chlorotoluene gives 4 isomers.

Both the alkyl group and the halogen are weak activating and deactivating

respectively and the difference between them is very smal


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Pharmaceutical Organic Chemistry I (CPR 101)

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