Hrvoj Vančik (Auth.) - Basic Organic Chemistry For The Life Sciences-Springer International Publishing (2014) PDF

Hrvoj Vanik
Basic Organic
Chemistry
for the Life
Sciences
Basic Organic Chemistry for the Life Sciences
Hrvoj Vanik
Basic Organic Chemistry

for the Life Sciences
Hrvoj Vanik
Department of Chemistry
University of Zagreb
Zagreb, Croatia
ISBN 978-3-319-07604-1 ISBN 978-3-319-07605-8 (eBook)

DOI 10.1007/978-3-319-07605-8
Springer Cham Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014941923
Springer International Publishing Switzerland 2014

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This work is the result of my collaboration
with plenty of my colleagues and students
during more than twenty years of my
lecturing of organic chemistry. The
manuscript in this form would not be
possible without the insightful comments of
reviewers Mladen Mintas, Miroslav Baji,
Sranka Tomi-Pisarovi (University of
Zagreb, Croatia) and Igor Novak (Charles
Sturt University, Sydney, Australia), to whom
I owe a debt of gratitude.
Preface
This textbook appears as a result of the experience in more than 20 years of lecturing
organic chemistry to students of biology, molecular biology, and ecology within the
Faculty of Science and Mathematics of the University of Zagreb. Since the great
books of organic chemistry for chemists appear to be too advanced for students
whose study is only partially related to chemistry, I have decided to prepare the text
that is more oriented to the essence of organic chemistry.
Open problems in writing the basic organic chemistry textbook include the selec-
tion of concepts for the representation of the material, but also the level of the expla-
nation of the complex phenomena such as reaction mechanisms or the electron
structure. Here I propose the compromises. First compromise is related to the mode
of the systematization of the contents, which can traditionally be based either on the
classes of compounds, or on the classes of reactions. Here, the main chapter titles
contain the reaction types, but the subtitles involve the compound classes. The elec-
tronic effects as well as the nature of the chemical bond is described by using the
quasi-classical approach starting with the wave nature of the electron, and building
the molecular orbitals from the linear combination of the atomic orbitals on the
principle of the qualitative MO model. Hybridization is avoided because all the
phenomena on this level can be simply explained by non-hybridized molecular
orbitals.
The text is divided in two parts. First chapters deal with fundamental aspects of
the structural theory, reaction dynamics of organic reactions, electronic structure,
and some basic spectroscopy. Last, the largest chapter represents the introduction to
the organic chemistry of natural products. Comparison of the reactions in the labo-
ratory with the analogous molecular transformations in living cells will help the
students to understand the basic principles of biochemistry. The most interesting
property of organic chemical systems, the formation of the high diversity of struc-
tures, is pointed out almost in all chapters. This approach is designed to help the
students to provide deeper insight into the phenomena of the chemical evolution as
a base for the biological evolution.
vii
viii Preface
I intend this book for students of biology, molecular biology, ecology, medicine,
agriculture, forestry, and other professions where the knowledge of organic chemis-
try plays the important role. I also hope that the work could also be of interest to
non-professionals, as well as to the high school teachers.
Zagreb, Croatia Hrvoj Vanik

2014
Contents
1 Alkanes, Composition, Constitution and Configuration ..................... 1

1.1 On the Nomenclature of Organic Compounds............................... 5
1.2 Configurations and Shapes of Molecules....................................... 7
1.3 Molecular Dynamics and Conformations ...................................... 10
1.4 Cycloalkanes .................................................................................. 12
1.4.1 Cyclohexane..................................................................... 13
1.4.2 Cyclopentane ................................................................... 14
1.4.3 Cyclobutane and Cyclopropane ....................................... 15
1.5 Polycyclic Hydrocarbons ............................................................... 15
2 Functional Groups .................................................................................. 17
3 Electronic Structure of Organic Molecules .......................................... 21
3.1 The Covalent Bond ........................................................................ 21
3.2 Molecular Orbitals ......................................................................... 24
3.3 Distribution of Electron Density, and the Shape of Molecules ...... 29
3.4 Bond Lengths, Bond Energy, and Molecular Vibrations ............... 30
3.5 Deducing Molecular Structure by Nuclear Magnetic
Resonance Spectroscopy ................................................................ 34
4 Alkenes and Alkynes ............................................................................... 39
4.1 Constitution and Nomenclature ..................................................... 39
4.2 Configuration of Alkenes ............................................................... 40
4.3 Electronic Structure and Reactions of Alkenes .............................. 43
4.4 Addition Reactions of Alkenes, and the Concept
of Reaction Mechanism ................................................................. 46
4.5 Additions of Hydrogen Halides ..................................................... 47
4.6 Oxidations and Polymerizations of Alkenes .................................. 51
4.7 Aromatic Hydrocarbons ................................................................. 53
4.8 Hydrocarbons in Biology ............................................................... 56
ix
x Contents
5 Substitutions on Saturated Carbon Atoms ........................................... 59

5.1 Radical Substitutions ..................................................................... 60
5.1.1 Alkyl Halides ................................................................... 60
5.1.2 Bond Polarity and the Dipole Moment ............................ 63
5.2 Reactions of Nucleophilic Substitutions and Eliminations............ 65
5.2.1 Reaction Mechanisms of Nucleophilic Substitutions ...... 66
5.2.2 Alcohols ........................................................................... 70
5.2.3 Ethers ............................................................................... 76
5.2.4 Thiols and Sulfides .......................................................... 80
5.2.5 Amines ............................................................................. 80
6 Nucleophilic Additions ............................................................................ 85
6.1 Aldehydes and Ketones.................................................................. 86
6.1.1 Carbon as a Nucleophile .................................................. 91
6.1.2 Condensations with Amines ............................................ 94
6.1.3 Reductions of Aldehydes and Ketones ............................ 94
6.2 Carboxylic Acids............................................................................ 95
7 Stereochemistry, Symmetry and Molecular Chirality ......................... 103
8 Derivatives of Carboxylic Acids ............................................................. 111
8.1 Anhydrides ..................................................................................... 111
8.2 Esters, Nucleophilic Substitution
on the Unsaturated Carbon Atom................................................... 112
8.3 Acyl Halides................................................................................... 115
8.4 Amides ........................................................................................... 116
9 Electrophilic Substitutions ..................................................................... 119
9.1 Substituent Effects in Electrophilic Aromatic Substitution ........... 121
10 Cycloadditions ......................................................................................... 129
11 Organic Natural Products ...................................................................... 131
11.1 Amino Acids and Peptides ............................................................. 132
11.2 Carbohydrates ................................................................................ 143
11.2.1 Cyclic Structures of Monosaccharides ............................ 148
11.2.2 Disaccharides and Polysaccharides ................................. 151
11.3 Glycosides and Nucleotides ........................................................... 154
11.4 Lipids ............................................................................................. 158
11.4.1 Waxes ............................................................................... 158
11.4.2 Fats ................................................................................... 158
11.4.3 Phospholipids ................................................................... 160
11.4.4 Terpenes and Steroids ...................................................... 161
11.5 Alkaloids ........................................................................................ 165
11.6 Organic and Bioorganic Reactions................................................. 166
Index ................................................................................................................. 171
Introduction
The historic moment when organic chemistry appeared as part of chemistry, where
organic chemistry deals with compounds originating from living organisms, is difficult
to establish. More than 200 years ago, in 1784, T. Bergman used the term organic
chemistry for the first time. Perhaps, two historic events in the development of
chemistry could be regarded as crucial for the development of this branch of science.
In the first place one should mention Jn Jacob Berzelius, who, at the beginning
of the nineteenth century, developed the method for the systematic elemental analysis
of organic substances. Berzelius observed that all organic substances produce
carbon dioxide and water upon combustion. By accurately measuring the masses of
these products he calculated the percentages of carbon, hydrogen and oxygen in
organic compounds. The most important conclusion was that all organic compounds
consist of carbon and hydrogen. Accordingly, organic chemistry could also be called
the chemistry of carbon compounds.
Secondly, perhaps the most important event in the development of organic chemistry
has been the discovery that an organic compound could be prepared from inorganic
starting material. In 1828, Friedrich Whler successfully prepared urea, the organic
compound, by heating the inorganic salt ammonium cyanate. Before this discovery,
organic substances were thought to be exclusively derived from living organisms.
One of the fundamental and general questions about the nature of organic com-
pounds is the special nature of carbon as the basic element from which all the
organic substances and all the known substances of Life are built. Could silicon, for
instance, the element which is in the same group of the periodic table as carbon, be
the basic element for the development of some alternative life?
To answer this question it is necessary to look at the special properties of the element
carbon, the properties which are responsible for the emergence and evolution of
complex organic molecules. The most important prebiotic condition for the beginning
of biological evolution is the appearance of a complex mixture of molecules with a
high diversity of structures. Stuart Kauffman calculated that such critical diversity
should comprise at least 200,000 molecules with different structures. Basic properties
of carbon are such that compounds of this element can form an enormous number
of structures. More than ten million organic compounds are known at present.
xi
xii Introduction
In the second half of the nineteenth century, August Kekul, Archibald Couper
and independently Aleksandr Butlerov discovered the most important property of
carbon: the mutual binding of carbon atoms into chains, branched chains and ring
structures. This discovery has been extended with the knowledge that carbon atoms
can be connected by stable single, double and triple bonds. For comparison, silicon
atoms can also be connected by single and double bonds, but in contrast to carbon-
carbon bonds, silicon-silicon bonds are weaker, unstable and sensitive to light. Hence,
silaorganic compounds would not be able to survive under the natural conditions
which were present on Earth at the time when biological evolution started. However,
silicon atoms do form strong bonds with oxygen atoms and form a high diversity of
structures in which silicon-oxygen-silicon structural motifs are present. Such struc-
tures are characteristics of the terrestrial mineral world.
Later in this book, we will introduce a series of other special properties which
make carbon a unique biogenic element.
Structures of organic molecules can be drawn from the structures in which car-
bon appears as an element i.e. from the structures of its allotropic modifications.
Until the last quarter of the twentieth century only two allotropic modifications of
carbon were known, graphite and diamond. From the viewpoint of structural
organic chemistry, structures of graphite and diamond represent basic structural pat-
terns by which carbon atoms can be interconnected.
In graphite, every carbon is surrounded by three neighboring carbon atoms in

such a way that all four atoms lie in the same plane. In contrast, the carbon
atoms in diamond are arranged in the three-dimensional array where every atom
Introduction xiii
is surrounded by four neighbors, which are configured in tetrahedral geometry.

These two motifs, tetrahedral and planar trigonal, respectively, represent basic
structural patterns of organic molecules. Linear binding of atoms is also possi-
ble for organic molecules, but allotropic modification of carbon with such struc-
ture has not been observed yet.
In the intergalactic space there are stars which are in the last phase of their
development and which produce a lot of elemental carbon by eruptions. Harold
Kroto and his collaborators Richard Smalley and Robert Curl have investigated
in detail the nature of such intergalactic carbon. The result of their research has
been the discovery of a new allotropic modification of carbon in which atoms form
structures resembling a ball. By measuring the relative molecular masses of such
ball-molecules and simulating the interstellar conditions in the laboratory, Kroto,
Smalley and Curl have found that these molecules mostly consist of 60 carbon
atom clusters distributed as pentagonal and hexagonal structures. There are 12 pen-
tagons surrounded by hexagons. Since the proposed structure resembles some
works of art, especially the architecture constructed by the architect Richard
Buckminster Fuller, this C60 molecule has been named fullerene. In subsequent
research a series of similar ball-like structures was discovered, some of which also
have tubular structures of carbon atoms. These molecules have dimensions on the
nanometer scale and have intriguing properties which are interesting for use in the
sophisticated technology of novel materials and electronics. The discovery of
fullerenes represents the beginning of the new era of nanotechnology.
Chapter 1
Alkanes, Composition, Constitution
and Configuration
In principle, the organic molecules may be considered as consisting of a hydrocar-

bon skeleton to which functional groups are attached. While the hydrocarbon skel-
eton determines molecular shape and flexibility, the chemical reactivity depends
mostly on the functional groups present. For a better understanding of the basic
properties and structure of the molecular skeleton, let us start with hydrocarbons,
which represent organic compounds without any functional groups.
As compounds which consist of carbon and hydrogen atoms only, the hydrocarbons
can be divided in two main categories, saturated, which comprises alkanes and cycloal-
kanes, and unsaturated, which comprises of alkenes, alkynes, and aromatics. The term
saturated indicates the impossibility of adding more hydrogens to the molecule.
In the following scheme, ethene as an unsaturated compound can be transformed
to the saturated ethane compound via the process of binding a hydrogen molecule.
Since all valencies of the carbon atoms in ethane are occupied there is no place to
add any more hydrogen atoms.
Nature abounds in hydrocarbons especially in crude oil and natural gas. The mix-
ture of hydrocarbons present in oil can be separated into groups of compounds with
different boiling points through the industrial process of fractional distillation. By
analysis of compounds from different fractions it is possible to elucidate their ele-
mental composition from which in turn, their chemical formulas can be calculated, for
instance C2H6 for ethane. The determination of composition is based on the property
of hydrocarbons to combust into water and carbon dioxide. At the beginning of the
H. Vanik, Basic Organic Chemistry for the Life Sciences, 1

DOI 10.1007/978-3-319-07605-8_1, Springer International Publishing Switzerland 2014
2 1 Alkanes, Composition, Constitution and Configuration
nineteenth century, Jn Jacob Berzelius calculated formulas for a series of organic

compounds from the measured masses of water and carbon dioxide.
Although knowledge of the composition is very important for the classification of
organic compounds, for the description of organic molecules in more detail it was
nonetheless insufficient. Difficulties arose because many different organic compounds
have the same composition. Atomic theory that could help resolve these contradictions
was still in the early stages of development at the time. John Dalton had published his
discovery of atoms only in 1808 in his book The New System of Chemical Philosophy.
An additional layer of controversy appeared during this time. It was believed that inor-
ganic and organic compounds have different natural origins. Hence it was thought impos-
sible that organic compounds could be prepared from any inorganic source. They, so it
was thought, could be obtained exclusively from living organisms. This vitalistic point of
view was disproved by a student of Berzelius, Friedrich Whler, who succeeded in
preparing an organic compound from an inorganic precursor. Whlers organic com-
pound urea, was obtained by heating the inorganic salt ammonium cyanate:
Whlers experiment is important not only because of its finding that there is
only one chemistry, independent of the origin of the substances, inorganic or bio-
logical, but because it demonstrated that two very different substances can have the
same composition, in this case CH4N2O. The idea of structure as a higher level of
organizing principle of matter has emerged. Charles-Frdric Gerhardt, August von
Hofmann and Alexander Williamson have around 1850 developed this idea into
the concept of constitution, which describes the way in which atoms are intercon-
nected in the molecule. In Whlers experiment different constitutions of ammo-
nium cyanate and urea can be described by different structural formulas:
Compounds such as urea and ammonium cyanate, which have the same compo-
sition but different constitution are called isomers. After this first example it has
been found that there is an enormous number of isomers of organic compounds,
especially hydrocarbons, in nature. Before clarifying these concepts in more detail
1 Alkanes, Composition, Constitution and Configuration 3
let us describe the composition, constitution and names of some of the most important
saturated hydrocarbons, alkanes. As can be seen from the following Table, all the given
chemical formulas can be reduced to the general formula CnH2n + 2, where n is an integer.
Such alkanes are called n-alkanes and belong to a homologous series of compounds.
Different isomers are possible if the alkane molecule contains more than three
carbon atoms. In the case of butane, which has the composition defined by the
formula C4H10, the carbon atoms can be interconnected in two different ways form-
ing two constitutional isomers. While the compound with the linear carbon chain is
usually called n-butane its branched isomer is called iso-butane.
Structures shown in the following scheme are two different isomers which really
represent two different compounds. To convert one isomer into another it is necessary to
break and reform chemical bonds by a chemical reaction. The isomers are repre-
sented in two ways, by connectivity structural formula in which all the interatomic
bonds and atomic symbols are shown and also by the condensed formula where the
chains between the CH3 and CH2 groups are drawn. Such more practical formulas are
mostly used in organic chemistry. The particular groups in the chain have special
names such as methylene group for CH2 and methyl group for CH3.
Let us consider the number of isomers of alkanes for different numbers of carbon
atoms. For instance, pentane can form three isomers and hexane has five isomers:
In following table, the number of isomers is given for the alkanes with up to 10
C-atoms. The table shows that the number of isomers increases exponentially
with the number of carbon atoms in the alkane molecule. The saturated hydrocarbon
with 20 carbon atoms with the brutto formula C20H42 can have 366,319 isomers!
Number of possible constitutional

Number of C-atoms in alkanes isomers
1 1
2 1
3 1
4 2
5 3
6 5
7 9
8 18
9 35
10 75
Such a large number of isomers of simple alkanes explains why carbon as an element
is unique and why it serves as a basis for the vast diversity of structures necessary for
Life. This propensity for generating great diversity of organic molecules starting
from simple structures will be exemplified further in later parts of this book.
Regarding isomers, it must be noted that depending on the way the atoms are
interconnected, C-atoms can bind to each other in several different ways. Some
carbons are bound to only one neighboring C-atom, some to two, three or four.
Based on this criterion the carbon atoms are named primary, secondary, tertiary
and quaternary, respectively:
1.1 On the Nomenclature of Organic Compounds 5
1.1 On the Nomenclature of Organic Compounds
When discussing chemistry as a discipline we must be aware of three different

categories which are present in the methodology of chemical science and practice.
Chemistry can be recognized by its content, writing and language. The most important
is the content; these are the substances with which we have immediate experience
either in laboratory or in everyday life. Chemical writing and language are human
inventions; they are a kind of models which serve for more or less unambiguous
communication between chemists about substances, chemical concepts and theories.
While chemical writing comprises formulas which we have already mentioned, by
chemical language we describe constitutions and configurations of molecules.
The chemical language is designed to be sufficiently precise so that from the name
of a compound only one structural formula can be deduced. The names of compounds
are based on the linguistic rules called nomenclature. Today, the chemical nomencla-
ture is universal, standardized and governed by international conventions promulgated
by the International Union for Pure and Applied Chemistry (IUPAC). According to
IUPAC convention the name of a compound derives from the root of the word to
which the prefixes and suffixes can be added, depending on the class and structure of
the molecule. The root of the name is based on the number of C-atoms in the longest
carbon chain and is derived from the names of simple hydrocarbons.
The suffix labels the functional group whose presence places the molecule into
the appropriate class of chemical compounds. In this scheme the saturated hydro-
carbons, the alkanes have the suffix -ane. For naming isomers, the system is more
complicated and includes additional rules. Since the molecules of isomers are
branched, the root name must correspond to the longest chain. The sidechains are
treated as additional groups called substituents. In the final name of the structure,
the substituents are introduced as prefixes to the root. The names of substituents are
formed following the same rules as in the case of simple alkanes, i.e. the number of
C-atoms followed by the suffix -yl.
Number Name
of C-atoms Formula Root Suffix of compound Substituent Suffix Name
1 CH4 met- -ane methane -CH3 -yl methyl
2 C2H6 et- -ane ethane -C2H5 -yl ethyl
3 C3H8 prop- -ane propane -C3H7 -yl propyl
4 C4H10 but- -ane butane -C4H9 -yl butyl
5 C5H12 pent- -ane pentane -C5H11 -yl pentyl
(continued)
(continued)
Number Name
of C-atoms Formula Root Suffix of compound Substituent Suffix Name
6 C6H14 hex- -ane hexane -C6H13 -yl hexyl
7 C7H16 hept- -ane heptane -C7H15 -yl heptyl
8 C8H18 oct- -ane octane -C8H17 -yl octyl
9 C9H20 non- -ane nonane -C9H19 -yl nonyl
10 C10H22 dec- -ane decane -C10H21 -yl decyl
The position of the substituent on the longest chain is labeled by a number. Number
1 must be assigned to the terminal carbon of the chain so that all other substituents
can be labelled by the smallest possible numbers. If on the same basic chain two or
more identical substituents are attached, the suffix is expanded by adding labels
di-, tri-, etc. For instance, in the name 2,2-dimethylpropane (shown in the schemes
below), the numbering 2,2- means that two methyl groups are bound to carbon 2.
1.2 Configurations and Shapes of Molecules 7
1.2 Configurations and Shapes of Molecules
The basic idea that molecules are real particles which have particular shape originated
from three chemists, one of them was organic, the other inorganic and the third one
was a physical chemist. By studying the symmetry of crystals of the organic salt
ammonium-sodium tartarate, which had been isolated from the reaction mixture in
alcoholic fermentation, Charles LeBel who worked with Louis Pasteur proposed
in 1874 that the atoms bound to the central carbon atom in substituted alkanes
are distributed in space so as to form a tetrahedron. Such tetrahedral spatial configu-
ration resembles the distribution of C-atoms in diamond. Details of this discovery
by LeBel will be discussed later in this book. The same idea about the tetrahedral
structure of the alkane-like molecules has been independently proposed by physical
chemist Jacobus vant Hoff, who studied isomers of substituted alkanes. The
concept of spatial structure of inorganic compounds in which the atoms surrounding
the central metal atom form an octahedron, was proposed by the inorganic chemist
Alfred Werner.
The methane molecule CH4, has the shape of a tetrahedron in which the carbon
atom is at the center. Spatial three dimensional distribution of atoms in a molecule
is called configuration and we can say that the methane molecule has a tetrahedral
configuration. For pictoral representation of such spatial distribution there is a
convention such that chemical bonds which lie in the plane of the drawing are
labeled with a full line, the bonds located above the plane of the drawing by a wedge
(bold elongated triangle) and the bonds below the plane with a dashed line (dashed
elongated triangle). The angle between two C-H bonds 10928, is known as the
tetrahedral angle.
The fact that the molecule has such a distinct geometric form can be explained
by the branch of physics known as quantum mechanics. In other words, the tetrahe-
dral configuration of C-H bonds is the consequence of the repulsion of electron
pairs which tend to be as far apart as possible from each other. This method of pre-
diction of the molecular shape by considering the optimal distribution of bonds
(bonding electron pairs) in which the electron repulsion is minimal, is called
VSEPR (valence shell electron pair repulsion). Although this method is widely
used, in practice we must point out that this procedure is a simplified approach that
can afford only an approximate picture of the molecule.
Let us use the knowledge about the tetrahedral shape to build structures of
other simple alkane molecules. We observe that the consequence of tetrahedral
structure is the zig-zag form of the alkane chains. Chemical formulas in the following
scheme are called wedge-dash formulas.
H H
H H H
H H H
H H H H C C
H H C H C C H
H H H H
H H C C H
C C C C C C H H
H C C H
H H H H H H
H H
H H
H
Bearing this shape in mind, it is possible to write the structural formula in an

even simpler form. The figure below shows the structures of alkanes, their simplified
structural formulas as well as their condensed structural formulas.
H H
H H H
H H H C C
H
H C H H C C H
H H H H
H H C C H
C C C C H
C C H
H H H
H H H H
H H
H
CH3CH2CH3 CH3CH2CH2CH3 CH3CH2CH2CH2CH3
Although simplified, this geometry model explains molecular shapes satis-

factorily enough to afford an approximate picture of molecules. More detailed
insights into the molecular shapes is possible by using special microscopy techniques
called scanning tunneling microscopy (STM) or by complicated and sophisticated
quantum mechanical calculations.
It is interesting to mention that there is a correlation between the molecular
structures of alkanes and some of their physical properties. By correlating the
number of carbon atoms in simple alkanes with the melting points of the same com-
pounds we observe that the molecules with odd numbers of C-atoms and those with
even numbers of C-atoms exhibit different correlation curves.
1.2 Configurations and Shapes of Molecules 9
Looking at the structures of alkanes in the figure we can see that while the
molecules with an odd number of carbon atoms appear symmetrical (both termi-
nal carbon-carbon bonds being oriented upwards - black lines), where the struc-
tures with an even number are asymmetrical in the sense that the terminal
carbon-carbon bonds are oriented upwards on the left end of the chain, but down-
wards on the right end (blue lines). Although the correct explanation is not simple,
this example demonstrates how macroscopic properties correlate with micro-
scopic structures. We can assume that odd molecules in the condensed state
shall be packed differently from even molecules.
1.3 Molecular Dynamics and Conformations
The consideration of long-chained alkane molecules leads to the question of whether

these molecules are flexible? To analyze this flexibility, let us take the ethane mole-
cule as an example. Starting with the tetrahedral configuration, the ethane molecule
could be represented in two different ways:
The form A can be transformed into B simply by rotation of one of the methyl
groups by the torsion angle = 60 around the C-C bond. Such rotations, especially at
room temperature, are very fast and it is possible to imagine that the ethane molecule
could appear in a large number of shapes, depending on the rotation angle . Such dif-
ferent shapes of molecules which follow from internal rotations about single bonds are
called conformations. In the figure above the two most important conformations: stag-
gered and eclipsed are shown using the wedge-dash notation. However, these confor-
mations can also be drawn by rotating the molecule by 90 relative to the plane of
drawing. In that case the carbon atoms appear one behind the other. As shown in the
following figure, the carbon atoms in the front and at the back are separated by a circle.
The representation which is shown in the next scheme is called a Newman formula.
Newman formulas serve to clarify the difference between staggered and eclipsed
conformations. In the staggered conformation, the C-H bonds at the neighboring car-
bon atoms are closer to each other than in the eclipsed conformation. Since the electron
clouds in these covalent bonds are negatively charged they lead to a repulsive interac-
tions so that the eclipsed conformation has a higher potential energy than the staggered
conformation. We can say that the neighboring C-H bonds sterically hinder each
other, which gives the molecule in the eclipsed conformation a higher potential energy.
1.3 Molecular Dynamics and Conformations 11
Starting with the eclipsed conformation, if the torsion angle increases the potential
energy decreases up to the angle of 60, which is characteristic for the staggered
conformation. The dependence of the potential energy on the torsional angle is
shown in the following scheme.
We can observe that the potential energy varies periodically with the angle and that
the staggered conformations always correspond to the energy minima while the eclipsed
conformations always corresponding to the energy maxima. It is for this reason that
ethane molecules assume the staggered rather than the eclipsed conformation.
Stable conformations which correspond to the energy minima are called con-
formers. If the molecule comprises more than one C-C bond the rotation is possible
around all of them and the number of conformers increases. Let us investigate the
conformations and conformers of the butane molecule:
By investigating the conformations of butane and considering only the rotation

around the central C-C bond we can see that three conformers are possible (labeled
B, D and F in the scheme above). The most stable conformer is D because in this
case the bulky methyl groups, which have dense electron clouds, are at the largest
distance from each other, which makes their steric hindrance smallest. Conformer
D has the smallest potential energy and we can say that it corresponds to the global
minimum of the potential energy curve. Less stable conformers B and F corre-
spond to local minima of the potential energy curve. Transformation of one con-
former into another is possible only by passing through the potential energy maxima
A, C, E and G, which belong to eclipsed conformations. As the molecule gets more
complex, the number of conformers (local energy minima), as well as the number
of local maxima (eclipsed conformations) becomes larger. Exploring the shapes and
energies of possible conformers and the energies of eclipsed conformations requires
special calculations called conformational analysis. The simplest and most often
used method is based on the mechanical model in which the atoms are defined as
mass points and the chemical bonds are treated as elastic connectors. Using this
model it is possible to calculate the energy minima and maxima. This method is
called molecular mechanics.
1.4 Cycloalkanes
The idea that carbon atoms can be bound in cyclic structures (besides forming
chains and branched chains) appeared during the second half of nineteenth century.
When these cyclic structures are saturated hydrocarbons we talk about cycloalkanes.
In the nomenclature of this class of compounds the name is formed by adding the
prefix cyclo-.
Configuration of cycloalkanes is based on the combinations of tetrahedrons,

similarly to the case of alkanes. However, in some cases the ring structure requires
that the angles between C-C bonds deviate from the normal tetrahedral values
(10928). Almost ideal tetrahedral angles are present in the molecule of cyclohexane.
For the pictorial representation of three dimensional molecular structures of cyclic
molecules special descriptive projection is used. Let us analyse the structure of
cyclohexane molecule in more detail.
1.4 Cycloalkanes 13
1.4.1 Cyclohexane
As we can see in the following scheme, the hydrogen atoms can be bound to carbons in
two different ways. When C-H bonds (containing green H atoms) are parallel to the
axis perpendicular to the plane of the ring, hydrogens in such bonds are called axial
hydrogens (shown in green). Hydrogens drawn in red lie nearly in the equatorial
plane of the ring and are called equatorial hydrogen atoms. The difference between
these types of hydrogens is better represented by using the Newman formula:
The Newman formula shown in the upper scheme (right) is obtained by looking
along the C3-C4 and C1-C6 bonds. On inspection it becomes clear that the repre-
sented conformation has a staggered form and that these are stable conformers. By
convention they are called chair conformers. Since all the C-C bonds are in the
staggered arrangements the cyclohexane molecule is the most stable cyclic hydro-
carbon. There are no C-H bonds that sterically hinder each other. Conformational
dynamics of the cyclohexane ring involves limited rotation around the C-C bonds:
one chair conformer is transformed into another.
Hydrogen atoms (blue) that are in the axial positions in one conformer appear in
equatorial positions in the product conformer. Such change from axial to the equatorial
position is even more evident in the methyl-substituted cyclohexane.
The methyl group is in the axial position in the first conformer and in equatorial
position in the second conformer. Both conformers can also be represented by
Newman formulas:
In the left conformer (scheme above) the axial methyl group is close to the nearby
axial C-H bond. Since the electron clouds of these two axial groups repel each other,
the molecule posses high energy and becomes less stable. As we have already com-
mented, such unfavorable interaction is called steric hindrance. In the conformer on the
right, the methyl group is in equatorial position, the steric hindrance does not exists and
the conformer is more stable. This is the explanation of the general rule according to
which the conformers of cyclohexane with large substituents in the equatorial positions
are more stable than the conformers with groups in the axial positions.
1.4.2 Cyclopentane
In contrast to cyclohexane the cyclopentane molecule is almost planar. While four

carbon atoms lie in the molecular plane the fifth atom is slightly distorted out of the
plane. Conformational dynamics of the cyclopentane ring is almost negligible and
involves sequential out-of-plane lifting of C-atoms. The molecule in the following
figure is represented in two ways, the accurate description on the left hand side and
a simplified on the right.
Since all the hydrogen atoms are quasi-axial the representation of cyclopentane
molecule by a planar ring is an acceptable description.
1.5 Polycyclic Hydrocarbons 15
1.4.3 Cyclobutane and Cyclopropane
While the angles around carbon atoms in cyclohexane and cyclopentane do not
deviate much from the tetrahedral angle in small ring molecules such as cyclobu-
tane or cyclopropane the geometry requires that the angles between neighboring
C-C bonds deviate significantly from the tetrahedral value. Such forced reduction of
tetrahedral angles requires additional potential energy. Consequently, small cyclic
molecules such as cyclopropane contain an excess potential strain energy called
the Bayer strain. Because of this strain, molecules with three and four membered
rings are chemically active and in chemical reactions the rings tends to cleave and
relieve excess potential energy.
The cyclobutane molecule is not planar and the carbon atoms deviate from the
plane by forming a structure in which four of the hydrogen atoms have an equatorial
position (labeled in red) and the remaining four hydrogens are axial (labeled in green).
In this way the Bayer strain is minimized. In cyclopropane, all the hydrogens are in
quasi-axial positions.
From the detailed studies of the cyclopropane molecule, it has been found that
the C-C bonds are folded i.e. the electron density maxima between bonded carbon
atoms lie off the C-C bond axis.
1.5 Polycyclic Hydrocarbons
Carbon atoms can also be interconnected in structures that have more than one ring.
They are called polycyclic hydrocarbons. One well known polycyclic structure
that appears in a series of natural products is decaline, with two condensed six
membered rings. The term condensed means that rings share one C-C bond. Since
there are two different hydrogen positions on this common C-C bond, the decaline
molecule can appear as two stereoisomers. The neighboring hydrogens can be either
on the same side or on the opposite sides of the shared C-C bond and the stereoiso-
mers are known as cis-decaline and trans-decaline, respectively. As expected, the
isomers have different physical properties. The melting point of cis-decaline is
198 C and the melting point of trans-decaline is 185 C.
In chemical nomenclature, the polycyclic hydrocarbons are named regarding the

size of the bridges. The carbon atoms which belong to two different rings are called
bridgeheads but they do not form part of the bridge. The suffix bicyclo- is used if there
are two rings and the number of C-atoms on the bridges is added in parenthesis.
Let us describe some frequently encountered polycyclic structures. Bicyclo[2.2.1]

heptane, also known as norbornane, is the basic structure of a series of natural
products. The tricyclic compound adamantane (tricyclo[3.3.1.13,7]decane) is in
principle the smallest structural fragment of diamond and its structure appears on
the list of pharmaceutically important products. Adamantane was synthesized for
the first time in 1941 at the University of Zagreb by Vladimir Prelog.
Chapter 2
Functional Groups
As we have seen in the previous chapter, the hydrocarbon skeleton is responsible for
the shape and flexibility of organic molecules. In the case of alkane molecules, the
molecular structure is based on tetrahedral units and the molecular dynamics is the
consequence of relatively free rotations about the carbon-carbon single bonds.
These rotations give rise to different conformations. However, with the exception
of small-ring molecules, the alkanes, as compounds containing only carbon and
hydrogen, are relatively weakly reactive substances.
Most organic molecules which exhibit chemical reactivity have an incorporated
active structural unit called the functional group. In the structural formula the
unspecified group, the substituent, bound to the hydrocarbon skeleton is labeled as
R. To be chemically active, the functional group must possess high energy electrons
which can be either the electrons in the multiple bonds or the non-bonded electrons
on atoms other than carbon or hydrogen. Such atoms (for instance O, N, S, P, Cl, Br,
I etc.) when present in the organic molecules are called heteroatoms. The presence
of the functional group is also the basis for systematization of organic compounds
into specific classes.
The most common functional groups together with their nomenclature are listed
in following tables. The additional functional groups as well as the details of the
nomenclature of specific classes of compounds will be discussed later in this book.

18 2 Functional Groups
Amongst the functional groups which have double and triple bonds we shall
mention those in the following table. All the compounds belong to different types of
hydrocarbons:
The main functional groups and the corresponding organic compounds contain-
ing oxygen are: alcohols, ethers, ketones, aldehydes, carboxylic acids and esters as
listed in the following table:
2 Functional Groups 19
The most important organic compounds with nitrogen are the following:
Some organic compounds possess groups with both elements, oxygen and
nitrogen:
20 2 Functional Groups
Let us also list the classes of compounds with the functional groups containing
sulfur and halogen:
Chapter 3
Electronic Structure of Organic Molecules
3.1 The Covalent Bond
More than a 100 years ago, Joseph John Thomson who in 1897 discovered the
electron, hypothesized that this small negatively charged particle plays crucial
role in the formation of the chemical bond. Thomson argued that atoms in the
chemical bond exchange electrons in such a way that every atom donates one elec-
tron to the common chemical bond. Consequently, the electron pair is responsible
for holding the two atoms together. However, the proposed model was not able
to explain why the bonds in molecules containing the same atoms such as H2 are
different from the bonds in molecules with different atoms, for example HCl or
NaCl. The idea about covalent and ionic bonds appeared in 1916 when Gilbert
Newton Lewis proposed the representation of the chemical bond as the common
electron pair shared by the two bound atoms. The electrons in Lewis pairs do not
have any identity regarding the atoms from which they originate and the covalent
bond can be represented by dots as follows:
Using this model the methane molecule is represented as:
Traditionally used valence lines acquire new meaning: they represent electron
pairs. Within this semantics, the double bond is labeled by two lines which describe
two electron pairs. Commonly, such notation is called the Lewis structure.

22 3 Electronic Structure of Organic Molecules
However, in some molecules such as ammonia, some of the electrons are not
included in the chemical bonds. Out of five valence electrons on the nitrogen
atom, only three take part in covalent bonds with hydrogens, the remaining two are
nonbonding and are called the electron lone pairs.
Molecules with electron lone pairs are very reactive. Since organic chemistry
is based on carbon compounds and carbon atoms only have electron lone pairs
in special cases, the carriers of nonbonding electrons are heteroatoms such as N, O,
S, P or halogens.
The examples of carbon atoms with electron lone pairs are the cyanide ion: CN
or the relatively unstable but reactive carbenes, which are common intermedi-
ates in photochemical reactions.
Although the Lewis model has been accepted as a basic and universal concept
for the description of the constitutions of molecules, this representation appears to
be inadequate for some species. For instance, by using the Lewis model for the
description of the nitrate anion NO3, as shown in the following figure, one of the
oxygen atoms is bound to the nitrogen via a double bond and the two remaining
oxygens via a single bonds. Since it is known that double bonds are shorter than
single bonds (this will be discussed later in the book) the proposed description of
the nitrate ion indicates that one of the nitrogen-oxygen bonds should be shorter
than the two remaining bonds. However, since precise measurements show that all
three nitrogen-oxygen bonds are of equal length, the constitution of the nitrate ion
cannot possibly be explained by a single Lewis formula. At the beginning of the
twentieth century Sir Robert Robinson and Fritz Arndt have proposed that such
molecules can be interpreted with a set of structural formulas, which have differ-
ent electron configurations. This particular electron configuration is called the
resonance structure and we could say that the molecule is better represented by
several resonance structures. In literature we can find the statement that the molecule
is a resonance hybrid of the corresponding canonic resonance structures. In our
example, the nitrate ion is better represented by three canonic resonance structures.
3.1 The Covalent Bond 23
By definition, all resonance structures are descriptions of the same molecule. We use
the notation in which the different resonance structures are connected by double
tipped arrows with all the formulas placed within parentheses.
As shall be demonstrated later in this book, the knowledge of resonance

structures can help with the prediction of important molecular properties such as
charge distribution or the nature of a particular bond. Canonical resonance for-
mulas can be constructed by using special rules:
1. Since the canonic structures are descriptions of the same molecule, the atom
positions in all the resonance formulas must be unchanged.
2. The total charge must also be unchanged. For instance, in the nitrate ion the total
charge in all the structures is 1.
3. Only the electrons and electron pairs can be shifted. In principle, the electron
lone pair in one resonance structure becomes the bonding pair in another structure
and vice versa:
By convention, the shift of electron pairs is indicated by special arrows called the
Robinson arrow, in the honor of Robert Robinson, the chemist who developed the
theory of chemical reaction mechanisms.
One further conclusion can be drawn from the resonance model. The canonical
resonance forms suggest that electrons do not have fixed positions within the
molecule; sometimes they appear as lone pairs, but sometimes they comprise
double bonds. This demonstrates that electrons are distributed throughout the entire
molecule or at least throughout its major part; the electrons are delocalized. It is
important to point out that the delocalization of electrons decreases their energy
so that such delocalized electrons have a lower energy than the electrons which are
localized, for instance in the single bond or on the heteroatom (lone pairs on
nitrogen or oxygen). In this way, by constructing the canonic resonance formulas
we are able to compare the stability of different molecules.
3.2 Molecular Orbitals
Although the Lewis concept together with the resonance model forms the basis
for unambiguous descriptions of structures of molecular classes and for organic
reactions, their use in understanding and explaining the nature of the chemical bond
is insufficient. For a detailed description of the nature of electrons we need the
theory that describes electrons as waves. Such theory is called quantum
mechanics and was created in 1925 by Werner Heissenberg and in 1926 by
Erwin Schrdinger. In quantum mechanics, the electrons are entities which could
behave as either particles or waves, depending on the type of the experiment by
which we observe them. We say that the electrons have a dual nature.
For the study of electrons in atoms and molecules it is more convenient to
consider electrons as waves. Since the electrons are contained within atoms or
molecules, the waves that describe them are standing waves, as are for instance the
waves of water which move within a closed pool. The standing wave also describes
the vibration of a strained wire for example on some musical instrument. Let us use
the analogy of a strained wire to obtain a deeper insight into the behavior of elec-
trons in molecules.
After triggering, the wire vibrates with a certain frequency and we hear the sound
of the corresponding note. If the wire is shorter the note (frequency) is higher and
vice versa, the longer the wire the lower the note (frequency). As we know from
physics, the vibrational frequency is proportional to the energy and consequently,
the shorter wire has higher energy than the longer one. Taking this rule into
account, by connecting two shorter wires to construct one longer wire we shall get
a lower energy. We conclude that the energy is lower if the standing wave moves
over a larger area of space. This is described in the following diagram:
If the wave function is labeled with , than the lower energy wave is obtained by
adding the functions 1 and 2. Imagine that the wires described by 1 and 2
merge into a single wire which has twice the length and that we press the resulting
longer wire in the middle (as we do for instance when playing a string instrument).
The resulting wire will then vibrate with the opposite phases, left and right from the
pressure point. Such a system could be represented as the difference of the functions
1 and 2. The result is two composite waves different in phase but close to each
other in energy. Let us represent them by 1 2. If the smaller wire-waves are both
3.2 Molecular Orbitals 25
electrically charged with the same charge (for instance negative), their common
energy should be higher since the negative charges repel each other.
In principle, the two resulting standing waves can be obtained from wave functions
in two ways: in phase combination (1 + 2) with lower energy and out of phase
combination (1 2) with higher energy. In atoms the standing waves, which
describe electrons, are represented by special functions called atomic orbitals.
Here we will not discuss the details of such mathematical functions. Rather we will
use their graphic representations. Since carbon and hydrogen are the most impor-
tant atoms in organic chemistry, we will represent their atomic orbitals only.
While the electron in the hydrogen atom is present in only one orbital (1s), the
electrons in the carbon atom are distributed in 1s, 2s, 2px, 2py and 2pz orbitals.
From the following figure is clear that the 2px, 2py and 2pz orbitals are of equal
energy, which is however higher than the 2s orbital energy.
The p-orbitals (2px, 2py and 2pz) differ only by their orientation in space along
the coordinate axes x, y and z. The different colors of the two sides of each p-orbital
(gray or white) corresponds to the different wave phases, similar to as was discussed
previously for the wire model.
Next we have to combine the atomic orbitals to construct the molecule in the
same way as we have done with wires representing standing waves. In the simplest
case, the formation of the hydrogen molecule, we have two combinations of atomic
orbitals: the lower energy 1s + 1s combination and the higher energy 1s 1s
combination. These two combinations of atomic orbitals describe electrons in the
molecule and they are called molecular orbitals. In analogy with our standing
wave model, these combinations, i.e. the molecular orbitals, have different phase
relations: (bonding and antibonding). The appearance of electrons in the antibonding
orbital converts the helium molecule back into its corresponding atoms. For this
reason the noble gases do not form molecules.
Bonding between carbon atoms could be described analogously, except that

2px orbitals are used instead of 1s orbitals. Combining 2px orbitals, we get bonding
(2px + 2px) and antibonding (2px 2px) molecular orbitals:
3.2 Molecular Orbitals 27
Since 2p orbitals can have three different spatial orientations along three coordinate
axes, it is necessary to consider the other two combinations: 2py 2py and
2pz 2pz as well. For convenience let us discuss the 2pz 2pz case first.
We obtain two molecular orbitals: bonding 2pz + 2pz and antibonding 2pz 2pz.
The same reasoning would also give pairs of 2px 2px and 2py 2py orbitals.
What is the main difference between (2pz 2pz) or (2py 2py) and (2px 2px)
orbitals. By rotating individual atomic orbitals in the 2px 2px combination around
the bond axis, the properties of the bond remain the same. However, by performing
the same rotation on the 2pz 2pz combination the phases (depicted with gray and
white shading) are exchanged as demonstrated in the next figure.
Using this property, the orbitals can be classified into two types: orbitals which
are symmetric upon the rotation around the bond-axis are called -orbitals and
orbitals which are antisymmetric are called -orbitals.
The same reasoning applies to the antibonding combinations. The antibonding

orbitals are labeled with the symbols * and *.
The extent of the stabilization of bonding orbitals or the destabilization of
antibonding orbitals, depends on the degree of orbital overlap. In -orbitals the
overlap between 2px and 2px atomic orbitals is greater than the overlap between
2pz and 2pz in -orbitals. For this reason the -orbital has lower energy than the
-orbital and the antibonding * has higher energy than the *.
This knowledge can help us in understanding the electron distribution in organic
molecules. The lowest in energy are -orbitals, followed by -orbitals, nonbonding
n-electrons (the electron lone pairs), * orbitals and the highest energy * orbitals.
In the electronic ground states , and n orbitals are occupied by electrons while *
and * orbitals are vacant. The nonbonding n-orbital in principle does not contribute
to the chemical bond. All the molecular orbitals are shown in the following figure.
However, two of them have the additional labels HOMO, and LUMO. These two
orbitals are called frontier orbitals, because they are especially important for
analyzing possible chemical reactions. The HOMO acronym stands for the highest
occupied molecular orbital and LUMO for the lowest unoccupied molecular orbital.
The molecule is in the ground electronic state if all valence electrons occupy
only bonding or n-orbitals. If the molecule absorbs a quantum of visible or ultravio-
let light and if the energy of this quantum corresponds to the energy difference
between the bonding and the antibonding orbitals (for instance between and *)
the electrons can be moved from the bonding to the antibonding orbital and the
molecule shall go to the excited electronic state. Such excitation is the main
characteristic of the reactions induced by light, the photoreactions.
3.3 Distribution of Electron Density, and the Shape of Molecules 29
3.3 Distribution of Electron Density,

and the Shape of Molecules
Description of the electronic structure of molecules by using this molecular orbital

model provides important information about the nature of molecules. One of the
most important pieces of information is the electron density distribution. While in
-bonds the electron density is largest between the atoms i.e. along the line of the
chemical bond in bonds the electron density is concentrated not between the atoms
but above and below the plane which contains the bond line. This is represented
in the next figure. In an ethane molecule, which possess only -bonds, the electron
cloud is situated between the C-atoms. However, in the ethene molecule, with a
-bond, the electron density is highest above and below the plane in which all the
atoms are located. Electron clouds in ethene are not blocked by the atoms and are
situated on the open side of the molecule where other particles can attack it.
Consequently an ethene molecule is much more chemically reactive then ethane.
Although a lot of information about molecular properties can be obtained from

the molecular orbital model, for deeper insight into the electronic structure of
molecules we need a much more sophisticated approach. The methods include
quantum-mechanical (or to use a better term quantum-chemical) calculations based
on fundamental mathematical and physical concepts. Molecular shape, electron
density and charge distribution calculated at such levels provide a much more
realistic picture of the molecules. In the following figure on the left hand side the
methane molecule is presented by using the simple ball-and-stick model, while on
the right hand side the calculated shape of the same molecule is shown. The green
surface represents the surface of the maximum electron density.
3.4 Bond Lengths, Bond Energy, and Molecular Vibrations
The length of the chemical bond depends primarily on the atomic radii of the atoms
included in the bond and on the electron interactions. Since in organic chemistry we
deal mostly with carbon, hydrogen and a few heteroatoms we will focus predomi-
nantly on the bond-lengths between these atoms. As is evident from the table later
in this chapter single, bonds are in principle longer than double bonds, which are in
turn longer than triple bonds. Additionally, multiple bonds are stronger than single
bonds. However, interatomic distances in chemical bonds are not fixed as implied
by the rigid stick-and-ball models. A much better representation would be a mechanical
model in which the balls are interconnected by springs. In such a model the massive
balls are not fixed but are free to vibrate around the equilibrium position. Analogously,
the atoms in the molecule vibrate around the equilibrium point at a certain frequency.
The chemical bond-length is defined as the interatomic distance when the atoms are
in the equilibrium position. Vibrational frequencies of atoms in chemical bonds are
nearly hundred times smaller than the frequencies of electrons-waves. Consequently,
in order to become vibrationally excited, the molecule must absorb electromagnetic
radiation of longer wavelengths than visible light, which is the radiation in the
infrared region.
The simplest molecular vibrations are bond stretchings. Besides stretching, there
are other vibrational modes, for instance vibrations of changing the angle between
bonds. Let us analyze the vibrations of a molecule of water. As shown in the next
scheme, there are two vibrational modes for bond stretching v1 and v2 and one
vibrational mode for the angle change v3.
Vibrations v1 and v2 differ in symmetry. While for v1 we can say that it is symmetric
because both OH bonds stretch simultaneously, v2 is antisymmetric since the H-atoms
move in opposite directions. Hence, the water molecule possesses three vibrational
modes. Generally, if the molecule has N atoms it will have 3 N-6 vibrational modes.
Functional group Wave number in cm1 Mode of vibration

CH3, CH2, CH, alkanes 2,8302,990 C-H stretch
=CH2, CH alkenes 3,0003,100 C-H stretch
CH3, CH2, CH, alkanes 1,3001,450 HCH bending
(continued)
3.4 Bond Lengths, Bond Energy, and Molecular Vibrations 31
Functional group Wave number in cm1 Mode of vibration

C=C, alkenes 1,6001,660 C=C stretch
CC, alkynes 2,0002,150 CC stretch
C=O, aldehydes, ketones, carboxylic 1,7001,780 C=O stretch
acids, esters
C-O, alcohols, ether 1,1501,280 C-O stretch
C-Cl, alkyl-chlorides 420700 C-Cl stretch
Each vibrational mode has its characteristic frequency and the molecule can
absorb infrared light of frequencies which correspond to the vibrations that are
active in the molecule. This fact is used for structural characterization of molecules.
Frequencies of the absorption maxima in the infrared spectrum allow us to identify
the vibrational modes. Since every functional group possesses characteristic vibrations,
the infrared spectrum can be used to identify the functional groups present in the
molecule. This method is called infrared spectroscopy. In spectroscopy the
vibrational frequencies are represented as wavenumbers which are measured in
units called reciprocal centimeters cm1. The reciprocal centimeter unit is the
number of waves within 1 cm. Some characteristic vibrational wavenumbers for
the most important functional groups are presented in the table above.
In the figure below the infrared spectrum of acetone, CH3COCH3 is shown
100
TRANSMITTANCE
50
0
1000 3000 2000 1500 1000 500
WAVENUMBER cm-1
Signals at 2,966 cm1 are assigned to the CH stretching of the methyl groups, the
sharp maximum at 1,749 cm1 is the characteristic stretching of the CO group and
peaks at 1,363 cm1 correspond to the change of the angle between the CH bonds in
the methyl groups (bending).
Assignment of all the peaks is difficult because the vibrations of the acetone
molecule are complex: the molecule has 10 atoms and by using the formula 3N-6 it
must have 3 10 6 = 24 vibrational modes.
Now, we must return to the simplest vibration, the stretching of the bond in a
diatomic molecule e.g. in HCl. Imagine that the H-Cl bond is stretched continuously
in one direction. From the mechanical point of view the stretching of the spring
increases the potential energy. At some distance the bond will break. Potential
energy increases also by compressing the bond. Relationship between the potential
energy and bond length is represented in the next figure. Such curves are known as
Morse curves. As shown in the following figure at interatomic distances larger than
a certain value, the potential energy becomes constant because the chemical bond is
broken. The distance at which the potential energy has minimum value is associated
with the length of the chemical bond. In reality, the molecule is never at this minimum
because the molecule constantly vibrates and the energy of this vibration must be
larger than this minimum. The difference between the minimum energy and the
vibrational energy level is called zero point energy and it depends on the frequency
of vibration by the formula E = (h). h is Planck constant and is the vibrational
frequency. If the molecule is cooled down to the temperature of absolute zero than
all its vibrations will have energy (h).
In analogy with the energy of electrons, the energy of molecular vibration

cannot have any value, but is distributed amongst the accessible quantum energy
levels. Such energy levels have defined values and the distance between them
diminishes as the potential energy increases. If the energy reaches E the poten-
tial energy becomes continuous (see the previous figure) and the chemical bond is
broken. Hence, the energy E required to break the chemical bond is called the
3.4 Bond Lengths, Bond Energy, and Molecular Vibrations 33
dissociation energy. There is close relation between the dissociation energy and
the bond energy i.e. the energy necessary to break the chemical bond. Strength
and energy of the chemical bond depends on the energy difference between the
zero point energy and the energy of continuum. If a chemical bond is strong, the
potential energy curve is steep and the bond energy (related to E) is larger, so
the position of the energy minimum is at the shorter bond distance. Conversely,
weak bonds have wider potential energy curves, a small E and the positions of
their minima are at large interatomic distances.
Typical values of bond energies and bond distances for the chemical bonds in
organic molecules are listed in the following table. Please note that the values in
the table are averages, based on the measurements for a large number of molecules.
Accurate parameters for individual molecules can be obtained from high level
quantum chemical calculations or by the use of sophisticated instruments.
Covalent bond Bond length in pm Bond energy in kJ/mol

C-H 106 413
C-C 154 347
C=C 134 614
CC 121 811
C-O 113 351
C=O 116 711
C-Cl 163 326
C-Br 191 276
O-H 94 464
N-H 98 389
S-H 132 339
Cl-H 127 431
The important conclusion from this discussion is the rule that the bond
energy and bond length are in an inverse relationship: as the bond gets shorter it
becomes stronger and vice versa, as the bond is weaker its energy is smaller. This is
important information, because from the data about bond lengths it is possible to
predict which bond is weaker and consequently which is more prone to breaking in
a chemical reaction.
In principle, by using values such as those in the table above, it is possible to
predict molecular geometry and from this the possible reactivity of molecules.
Additionally, the sum of all bond energies in the molecule represents approximate
value of the enthalpy of formation of the corresponding compound. For example
in a molecule of ethanol CH3CH2OH we count five C-H bonds, one C-C bond,
one O-H bond and one C-O bond, so the approximate enthalpy of formation, Hf,
is therefore: 5 413 + 347 + 464 + 351 = 3,227 kJ/mol.
3.5 Deducing Molecular Structure by Nuclear Magnetic

Resonance Spectroscopy
Besides infrared spectroscopy the most convenient method for deducing the molecular
structure is nuclear magnetic resonance spectroscopy (nmr). The basic principle of
this method is the detection of changes in the orientation of the atomic nuclear spin of
hydrogen (the spin of a proton) and carbon (the spin of the nucleus of the 13C isotope).
Like an electron, the proton also has an angular momentum (spin) which is
something akin to the rotation around its proper axis. Since the proton is a charged
particle, its rotation induces a magnetic field. Roughly speaking, the proton resem-
bles a small magnet. Let us imagine the model in which we have two such small
magnets with different orientations. If the magnets are distant from each other their
energies are equal, independent of their mutual orientation. However, inside an
external magnetic field the proton whose orientation is favored relative to the exter-
nal field has a lower energy and the proton with the opposite orientation has a higher
energy. This energy difference is shown on the figure below as E.
The higher energy proton can change its orientation from disfavored to favored
by radiating a quantum of energy. This radiation has a corresponding frequency :
3.5 Deducing Molecular Structure by Nuclear Magnetic Resonance Spectroscopy 35
This emitted radiation falls within the radio wave or microwave frequency region.
By using a radio wave receiver which can detect this radiation we can detect this
quantum transition. However, the transition is so fast that at the moment when the
sample is placed into the magnetic field all the protons will reorient themselves so
quickly that is becomes very difficult to register signals. To avoid this difficulty the
instrument, the nmr spectrometer has an oscillator which irradiates the sample with
radio or microwaves by which the spins are constantly reoriented into disfavored ori-
entations. The basic principle of the construction of nmr spectrometer is represented in
the next figure.
The frequency or radiation depends on the energy difference between nuclei HA

and HB (middle of the figure above). However, the protons (nuclei of hydrogen
atoms) exist within molecules and are surrounded by electron clouds of different
densities. Such electron density clouds can reduce the influence of the external
magnetic field on the energy required for the reorientation of proton spins. We can
say that the electrons shield the atomic nucleus. The extent of this shielding
depends on the functional group to which the hydrogen atom belongs. Thus the
hydrogen in a CH3 group is more shielded than the hydrogen in the CH2 group.
Hydrogen in the =CH2 is shielded even less:
Consequently in the nmr spectrum of the molecule which contains all three
groups (CH3, CH2, and =CH2) three signals at 1, 2 and 3, which can be assigned to
the three different H-atoms, will appear. This spectroscopy detects hydrogen atoms
in different environments in the molecule and is called the 1Hnmr spectroscopy.
In most nmr spectra the units which are related to the energies of radiation are not
frequencies themselves but rather they are differences in frequencies with respect to the
corresponding standard substance which has highly shielded protons. This frequency
difference is called the chemical shift. In most cases the standard used for measuring
chemical shifts is tetramethylsilane, (CH3)4Si (TMS). Frequency differences relative
to TMS are small, only millionth parts of the frequencies themselves. Therefore the
chemical shifts are measured in units called ppm (parts per million). Chemical shifts
for the most important groups containing hydrogen are listed in the table below.
The 1Hnmr spectrum of ethanol constructed from the data for chemical shifts in
the table above is represented in the next figure. Since an ethanol molecule consists
of three different groups containing hydrogen (CH3, CH2, and OH) three signals
appear in the spectrum.
3.5 Deducing Molecular Structure by Nuclear Magnetic Resonance Spectroscopy 37
The intensities of these signals depend on the number of hydrogen atoms in the
corresponding group, so the ratio of intensities of signals is 3:2:1 for CH3, CH2 and
OH. It can be seen from the figure, that the spectrum of ethanol is even more complex.
The magnetic moments of hydrogen nuclei are somewhat coupled between each
other, because of the influence of the electron cloud. Such coupling between protons
is detected from the splitting of spectral lines (four lines for the CH2 and three lines
for the CH3 group). The splitting of the signal is called the multiplet; it depends on
the number of hydrogen atoms in the neighboring group. If neighboring group has
n hydrogens the signal is split into n + 1 lines. These multiplets are named according
to the number of lines: two lines form a doublet, three lines a triplet and four lines
a quartet. In the above spectrum of ethanol the CH3 group signal is split into a trip-
let because the neighboring CH2 group has two hydrogens (n = 2), and the CH2
group is split into a quartet because its neighboring CH3 group has three hydrogens
(n = 3). Hydrogen in the OH group exhibits special behavior which will be discussed
later in this book and its coupling with the neighboring groups is not simple.
Chapter 4
Alkenes and Alkynes
The simplest alkene is ethene, the compound which has previously been called
ethylene. Ethene is produced in large quantities because it is one of the most
important substances in the production of a wide variety of organic compounds and
technological materials. The parent alkyne is ethyne which is marketed under the
trade name of acetylene. This substance is also a very important industrial product.
Both ethene and ethyne are flammable; ethyne mixed with oxygen produces a very
hot flame so acetylene is used for gas welding. Ethyne can be easily prepared from
calcium carbide and water:
4.1 Constitution and Nomenclature
In contrast to the relatively unreactive alkanes, alkenes and alkynes are chemically
reactive because they have double and triple carbon-carbon bonds as functional
groups. In the IUPAC nomenclature the names of alkenes end with the suffix -ene
and the position of the double bond is labeled by number of the C-atom on which this
double bond begins. In analogy with alkanes with branched chains, the root of the
word is the name of the longest chain of C-atoms and the atom numbering is arranged

40 4 Alkenes and Alkynes
so that C-atom with the double bond has the smallest possible number. The rules for
naming alkynes are the same as for alkenes with the exception that the suffix is -yne.
If the alkene molecule has two or more double bonds the names are formed in
accordance with their number, for instance dienes, trienes, polyenes etc. If single
and double bonds alternate, such alkenes are named conjugated alkenes. These
structures are responsible for the special properties of conjugated compounds. For
example, alkenes which have four or more conjugated double bonds can be colored
because they absorb light in the visible region. Double bonds in the molecule can
also be located on the neighboring atoms. Such bonds are called cumulated and the
corresponding compounds are cumulenes. The simplest cumulene is allene:
Cumulenes with ten or more cumulated carbon atoms have been detected in the
interstellar space and some theories propose that such molecules played very impor-
tant role in the formation of organic molecules during chemical evolution.
4.2 Configuration of Alkenes
Since carbon atoms in alkenes are interconnected with double bonds, every C-atom has
three neighbors. As we know from previous chapters, the molecule is more stable if
groups surrounding certain central atom are positioned as far as possible from each
other (VSEPR method). If the central atom is carbon as in alkenes, its neighbors must
4.2 Configuration of Alkenes 41
lie in the same plane similarly as the C-atoms in graphite. Such planar structure appears
not only in alkenes but in all organic molecules that have C-atom with a double bond.
In alkynes, the carbon atom has only two neighbors and the alkyne molecule is linear.
A similar linear structure is also characteristic of the structure of cumulene molecules.
The largest electron density in planar molecules like alkenes is not located
between the two carbon atoms but rather above and below the molecular plane.
Such distribution of electron density is rationalized by the molecular orbital model
in which the double bond includes -orbitals as shown in the following figure.
These sterically unhindered -electron densities are a perfect target for the attack
by other particles, atoms or molecules. In the previous discussion about the elec-
tronic structure of organic molecules it has been mentioned that the -orbital is
antisymmetric upon the rotation around the bond axis. The consequence of this
symmetry property (as well as of the electron density distribution) is that torsion
of one CR2 group relative to other CR2 group causes breaking of the -bond. For
example, the structure A* which appears after rotation around the C=C bond in
but-2-ene (figure below) has a high energy and is very unstable.
Subsequently, A* may experience rotation around the C=C bond and return back
to form A or generate a new molecule B:
Transformation A A* B includes the breaking and re-forming of a chemical

bond (in this case a -bond). The process in which a chemical bond is broken or formed
is known as chemical reaction. If A is transformed into B by a chemical reaction then
A and B are isomers. However, these isomers differ only in the spatial arrangement
of functional groups; these isomers have different configurations. Isomers which
differ from each other only in spatial configuration are called stereoisomers.
Stereoisomers must be unequivocally named using appropriate chemical nomen-
clature. According to the traditional nomenclature such stereoisomers are desig-
nated depending on the position of large groups bound to the carbons of the double
bond. If the large groups are present on the same side of the double bond, the isomer
is labeled by the prefix cis and if the groups are situated on opposite sides the prefix
is trans. We can therefore have cis-isomers and trans-isomers, respectively.
This rule for naming stereoisomers is practical, but still equivocal because most
alkene molecules have structures in which it is impossible to decide whether they
belong to the cis, or to the trans configuration. For instance, let us examine the fol-
lowing structure:
What is the criterion for deciding which groups are larger and which smaller, so
as to determine which is cis and which is trans configuration? To solve this problem
Robert Sidney Cahn, Sir Christopher Ingold and Vladimir Prelog have devel-
oped the new system of nomenclature for stereoisomers.
Let us apply the Cahn-Ingold-Prelog (CUP) system to the molecule shown in
the last example via a sequence of steps. In the first step we divide the C-atoms of
the double bond by a red broken line as shown in the next figure.
4.3 Electronic Structure and Reactions of Alkenes 43
The left and right C-atoms of the double bond are connected to different groups
(CH3 and H on the left C-atom, Br and CH2Cl on the right C-atom). These groups
must be classified by using the priority rule. If the groups which have the highest
priority are on the same side of the double bond the isomer is labeled with letter Z
(by the German word zusammen), but if the groups with the highest priority are on
the opposite sides, the isomer is labeled with letter E (by German word entgegen).
The priorities depend on the atomic number of the atom bound to the C-atom of the
double bond. In our example, the left C-atom is bound to atoms C and H. Since the
atomic number of C is greater than the atomic number of H, the CH3 group has priority
over H. The right C-atom is connected to atoms Br and C with Br having higher atomic
number. Hence, Br has priority over the CH2Cl group. While in the left isomer, the groups
with highest priorities (CH3 and Br) are on the same side and the structure is the Z-isomer,
the groups with the highest priority in the right isomers are on the opposite sides making
this the E-isomer. The next example is more complicated because both atoms bound to
the C-atom of the double bond are the same (carbons in CH2OH and CH2Cl).
In this case, the priority of -CH2OH and -CH2Cl groups must be distinguished by
inspecting the atomic numbers of atoms bound to carbons in these two functional
groups. Carbon atom in -CH2OH is bound to H, H and O while carbon in -CH2Cl is
bound to H, H and Cl. Since Cl has larger atomic number than O the -CH2Cl group
has priority over the -CH2OH group and the configurations are:
4.3 Electronic Structure and Reactions of Alkenes
The simplest reaction of alkenes, the Z E isomerization, was already mentioned in

the previous section. The transformation in which one isomer (the reactant) is rear-
ranged to give another isomer (the product) by rotation of 180 requires heating to
temperatures above 200 C in most cases.
However, many cis-trans (Z-E) isomerizations of natural products are known to

occur under mild conditions in living cells. These reactions proceed via different
mechanism, utilizing light rather than heat. The well known example is the reaction
which occurs in the eye retina. This reaction represents a fundamental step in the
process of visual perception.
The molecule of the derivative retinal (see figure below) is an alkene with con-
jugated double bonds. As we have already mentioned the conjugated molecules
have the property to absorb visible light. Upon the absorption of a photon the retinal
molecule is transformed from the Z- to the E-isomer. This change in the molecular
stereochemistry triggers the signal by which the information about the absorption of
a photon is transferred to the nervous system.
Such photoisomerizations are typical of alkenes and can be explained by a shift

of one electron from the bonding to the antibonding * orbital. This process is
shown in following diagram.
4.3 Electronic Structure and Reactions of Alkenes 45
A molecule in which electrons, after absorption of a photon, become shifted to

higher orbitals (for instance into * or * orbital) is said to be in an electronic
excited state. In the example represented in the figure above the excited molecule
is described with the structure A*. Since the * orbital has an antibonding character
as we have already discussed, the double bond in A is broken and in A* only the
single bond remains. Because of the almost free rotation around the single bond
(see chapter about conformations) the molecule can be converted to the new cis
(or Z) configuration in which all atoms lie in the same plane and the -bond can
be reformed.
Conjugated alkenes have the property that the energy gap between and *
orbitals diminishes when the number of conjugated double bonds increases. It is the
reason why the alkenes with a small number of conjugated double bonds absorb
ultraviolet radiation, while the alkene molecules with a large number of double
bonds as for instance retinal, absorb visible light. Molecules absorbing visible
light are colored. Hence, retinal is a good sensor for visible light.
4.4 Addition Reactions of Alkenes, and the Concept

of Reaction Mechanism
Alkenes are also called unsaturated hydrocarbons because their molecules

can be transformed into the saturated hydrocarbons, the alkanes, by binding
molecules of hydrogen. From the formal structural point of view the binding of
hydrogen H2 to the alkene molecule requires several steps. In the first step the H-H
bond is broken, followed by the breaking of one -bond and the formation of two
new C-H bonds. Amongst the bonds mentioned, the H-H bond in the hydrogen
molecules has the highest energy (434 kJ/mol). Breaking of this bond is possible
only under drastic conditions, for instance at high temperature and pressure,
which is not always practical in the laboratory
However, it has been found that a hydrogen molecule can be adsorbed on the
surface of metals such as palladium or platinum. By such adsorption the electron
cloud from the H-H bond is partially redistributed to the metal atoms:
Strong covalent bond

H H
Weakened covalent bond

H H
Pt Pt Pt Pt Pt Pt Pt Pt
Consequently, the covalent bond between the H-atoms becomes weaker and the
hydrogen molecule becomes activated for addition to the double bond. On the
other hand, -electrons in the alkene molecule have the highest electron density
above and bellow the plane in which carbon atoms lie. Thus the electrons in the
alkene molecule are available for the formation of new C-H bonds with activated
hydrogen as shown in the next figure. This class of reactions is called addition and
is typical for unsaturated hydrocarbons. Addition of hydrogen to the unsaturated
compounds is called hydrogenation. The role of the metal is only to activate the
hydrogen molecule so the metal is the catalyst. The reaction can in this case be
called catalytic hydrogenation.
4.5 Additions of Hydrogen Halides 47
The reaction can be represented by the simple equation:
The same reaction is also characteristic for alkynes. The only difference is that
alkynes have triple bond and the saturation requires two molecules of hydrogen:
Let us imagine that in the first step we add one H2 molecule to alkyne and in the
second step another H2 molecule is added to the remaining double bond of alkene as
shown in the next scheme. In organic chemistry the addition of hydrogen is called
reduction while the removing of hydrogen is called oxidation. Oxidation also
occurs upon addition of oxygen or halogen.
4.5 Additions of Hydrogen Halides
Hydrogen halides form alkyl halides by addition to the double bonds of alkenes. For
example, hydrogen bromide HBr, can be readily added to propene in the reaction in
which hydrogen binds to the carbon atom of the CH2 group. The resulting product
is 2-bromopropane. If HBr is added to 2-methylbut-2-ene the hydrogen binds to the
C-atom of the CH group, yielding 2-bromo-2-methylbutane (see the next scheme).

Alternative reactions in which hydrogen binds to the CH group producing
1-bromopropane (propyl bromide) in the first example or to the C=atom yielding
2-bromo-3-methylbutane in the second example are highly unfavored. By carrying
out systematic experiments Russian chemist Vladimir Vasiljevi Markovnikov
found that hydrogen always binds to the alkene carbon which possesses more
hydrogens. This empirical finding is known as the Markovnikov rule.
Explanation of this rule was not possible in Markovnikovs time because the
theory of chemical reactions and electronic structure had not yet been developed.
To gain deeper insight into the details of the observed behavior it is necessary to
introduce a new chemical concept, the reaction mechanisms. The mechanism
of chemical reaction describes successive events along the way from reactants
(the starting substances) to the products. What is the nature of these successive
steps? One example of the reaction mechanism was already discussed: the reaction
of catalytic hydrogenation.
The reaction mechanism theory is connected to the Lewis concept of the elec-
tronic structure of molecules. Starting with the Lewis idea that chemical bonds are
described as electron pairs, Sir Robert Robinson and Sir Christopher Ingold
have proposed that the reaction mechanism can be explained as the transfer of these
electron pairs in such a way that the molecular structure can be rearranged from
reactants into products.
Let as apply this concept to the previous examples of additions of hydrogen
bromide to 2-methylbut-2-ene. Since the reactant HBr molecule easily dissoci-
ates into H+ and Br, the electron deficient H+ will readily react with the
-electron cloud of the alkene molecule. The H+ ion is called the electrophile
because it has affinity for the negatively charged electron clouds. The second
ion Br is negative and is called the nucleophile because it has affinity for the
positively charged regions of the molecule of the second reactant. Nucleophiles
can be easily recognized because their molecules always possess the nonbonded,
electron lone pairs, the n-electrons. Several common nucleophiles and electro-
philes are listed below:
4.5 Additions of Hydrogen Halides 49
H2O OH Br H2S NH3
Nucleophiles
+ + +
H Na H3 O
Electrophiles
Now we are ready to explain the mechanism of addition of HBr to the alkene
molecule. The electrophile H+, takes the electron pair from the double bond and
binds to the carbon atom. In this process the second carbon atom of the double bond
loses one electron and becomes positively charged. Such addition of proton H+ to
the molecule is called the protonation.
From the upper scheme it is clear that the protonation forms new positively
charged molecule which is called carbocation and in which the positive charge is
mostly localized on the carbon atom. Carbocations are relatively unstable mol-
ecules, the reactive intermediates which are present for only a short time dur-
ing some chemical reactions. Since formally either of the alkene carbons could
be protonated two carbocations can possibly form. However, experiments and
high level quantum chemical calculations have shown that they have different
stabilities:
Since only the stable carbocation can survive long enough to react, the Br
nucleophile donates its lone pair to the positively charged carbon atom and
binds to it:
In summary, the reaction mechanism consists of two steps: (i) the protonation of
the double bond resulting in the formation of stable carbocation and (ii) the attack
of the nucleophile (Br) on the positive carbon of the same carbocation.
The stability of carbocation depends on the substituents bound to its positively

charged carbon. Amongst hydrocarbons, the most stable carbocations are molecules
with the positively charged C-atom surrounded by three nonhydrogen neighbors i.e.
the tertiary carbocations. Less stable are secondary carbocations with primary
carbocations being the least stable. The simplest examples of carbocations are
shown in the following scheme.
An important reaction of alkenes is also the addition of water. Since the dissocia-
tion of water does not produce a sufficient concentration of protons required for
protonation during the first step in the addition mechanism, sulfuric acid must be
added for an efficient reaction. After the initial protonation the nucleophilic attack
of the water molecule follows, with the subsequent removal of H+. Addition of water
also occurs in accordance with Markovnikov rule because the preferred reactive
intermediate is a tertiary carbocation (see the following scheme).
Reagents for additions to alkenes and alkynes can also be halogens. The products
of these additions are dihaloalkanes and tetrahaloalkanes, respectively.
4.6 Oxidations and Polymerizations of Alkenes 51
The mechanism of halogen addition is more complex. Since there are no protons
in the first step it is necessary that the halogen molecule becomes polarized when
being attached to the double bond. Polarization means that the electron density is
redistributed between halogen atoms so that one of the halogen atom becomes par-
tially positive while the other becomes partially negatively charged. In other words
the covalent bond becomes polarized. A partially positive halogen atom behaves as
an electrophile and binds to one of the alkene C-atoms. The carbocation which then
appears is a good target for the addition of the remaining halogen which acts as a
nucleophile. In the scheme below the mechanism of addition of chlorine is shown.
From the mechanism of catalytic hydrogenation we notice that hydrogen adds to

the alkene molecule in such a way that both H-atoms are added to the same side of
the molecular plane. The stereochemistry of this reaction is called syn-addition.
Addition of halogen follows quite different stereochemistry: two halogen atoms
approach the alkene molecular plane from the opposite sides. Such stereochemistry
is called anti-addition. The mechanism is confirmed by the analysis of configura-
tions of products of addition of chlorine to cyclopentene.
4.6 Oxidations and Polymerizations of Alkenes
In previous sections we have mentioned that oxidation in organic chemistry includes

the removal of hydrogen or the addition of oxygen. Alkenes can easily be oxidized
in a reactions with ozone, O3. The reaction mechanism involves the formation of a
reactive intermediate, the ozonide, which subsequently decomposes into two
molecules that can be either aldehydes or ketones, depending on the structure of the
starting alkene (see the next scheme).
Alkenes can also be oxidized by other reagents such as KMnO4.
Under high pressure and temperature and in the presence of oxygen or peroxides,
ethene is transformed into a solid elastic substance in which the molecules are
connected in long carbon chains. This product is called polyethylene and the pro-
cess is polymerization. Polymerizations of alkenes are important processes for the
industrial production of different technological materials.
The types and properties of polymeric materials being formed depend on the
starting molecule, the monomer and on the conditions of polymerization. Almost
all industrial polymerizations require the use of an appropriate catalyst. Some
polymers and starting monomers are listed in the following scheme.
4.7 Aromatic Hydrocarbons 53
4.7 Aromatic Hydrocarbons
Although the aromatic hydrocarbons have a six-membered ring and conjugated

double bonds formally characterizing them as unsaturated hydrocarbons, they
exhibit distinct chemical behavior, different from the behavior of alkenes. The
simplest compound with such properties is benzene C6H6, the substance which
was discovered by Michael Faraday 200 years ago. Derivatives of benzene and
other analogous compounds were called aromatic compounds because of their
characteristic odor. At that time, determining the molecular structure of benzene
represented a problem for chemists because it had been difficult to deduce its
constitution by using the structural theory then available. Additions, the most
characteristic reactions of alkenes, were never observed with benzene and the
catalytic hydrogenation of benzene to cyclohexane, C6H12 is possible only under
drastic experimental conditions (high pressure and using specific catalyst). In the
middle of nineteenth century, August Kekul (the chemist who is together with
Couper and Butlerov known for the discovery of the property of carbon to form
chains) proposed that six carbon atoms in the benzene molecule are connected so
as to form a six-membered ring:
Later, chemists isolated other more complex aromatic compounds in which

the benzene rings are condensed (two rings are condensed if they have a
common bond). The most important examples are naphthalene, anthracene and
phenanthrene:
Aromatic structures can also appear as substituents on the hydrocarbon chains.

We then use special prefixes in their nomenclature. For instance, the C6H5 group is
named phenyl and the C6H5CH2 group is called benzyl as is shown in the next
scheme.
The structure of the benzene molecule proposed by Kekul was not accepted
without criticism. The basic concerns appeared related to the study of substituted
derivates of benzene. For example, if the structure includes the alternating double
bonds the dimethylbenzene derivative should exist as four isomers:
The isomers 1,2-dimethylbenzene, 1,3-dimethylbenzene and 1,4-dimethylbenzene

also have traditional names: o-dimethylbenzene, m-dimethylbenzene and
p-dimethylbenzene (ortho-dimethylbenzene, meta-dimethylbenzene, and para-
dimethylbenzene). If the positions of double bonds were localized, as proposed by
Kekul, 1,2-dimethylbenzene and 1,6-dimethylbenzene would be different isomers
because the bond between carbons C1 and C2 is double while the bond between C1
and C6 would be a single bond. However, all the experiments have demonstrated
that only three isomers exist, hence 1,2-dimethylbenzene and 1,6-dimethylbenzene
are identical. Consequently, the classical structure theory which implies that the double
bonds are localized is unable to describe the structures of the benzene molecule and
other aromatic compounds.
The resolution of this conflict between the structure theory and experimental
results was not possible during the Kekuls time, because the electronic structure
of the chemical bond has not been discovered.
It was only during the first decades of twentieth century that Robinson and Arndt
proposed the concept of delocalized electrons. Six electrons in three formal double
bonds are not localized in these bonds but are equally distributed among all six
4.7 Aromatic Hydrocarbons 55
carbon atoms of the benzene ring. This concept was later supported by the discovery
that all carbon-carbon bonds in benzene ring are of equally length (139 pm).
Benzene C-C bond length is intermediate between the values for single and double
bonds (see previous chapter).
Robinson had also proposed two ways to represent the structures with delocalized
electrons. The first representation is the method of resonance structures which we
already discussed in this book. By using this method, the benzene molecule is
represented by two resonance structures. The other representation proposed by
Robinson describes the six delocalized electrons by plotting a circle inside the
six-membered ring.
Here, it is necessary to point out that the circle corresponds to six -electrons and
cannot be used for the descriptions of naphthalene or other aromatics which possess
more than six -electrons. For the representation of the electronic structures of other
aromatic molecules, the method of resonance structures is preferred.
Enumeration of -electrons present in different aromatic molecules reveals a
certain regularity: 6 -electrons in benzene, 10 -electrons in naphthalene and 14
-electrons in anthracene. The numbers 6, 10 and 14 all result from the formula
4N + 2, where N is integer. For 6 -electrons N = 1, for 10 -electrons N = 2 and for
14 -electrons N = 3. Compounds whose molecules possess 4N + 2 delocalized elec-
trons afford greater stability than corresponding conjugated alkenes with planar
chains. This additional stability is called the aromatic effect.
Within the molecular orbital theory presented earlier in this book, aromatic
stabilization is described by -orbitals, constructed by combining six 2pz atomic
orbitals of carbon atoms which are perpendicular to the molecular plane.
Other aromatic molecules have analogous structures described by the combi-

nations of perpendicular 2pz atomic orbitals. In naphthalene the ten 2pz atomic
orbitals of carbon are combined into -orbitals.
The stabilizing aromatic effect explains why the addition reactions characteristic
of alkenes do not occur with aromatics compounds. Addition of chlorine to benzene
requires special conditions. The reaction can proceed only by irradiation of the mix-
ture of benzene and chlorine with ultraviolet light. The result of this reaction is a
mixture of isomers of hexachlorocyclohexane. Some of these isomers known under
the commercial name HCH are used as pesticides.
However, their use is restricted because of negative effects on human health.

Other reactions of aromatic compounds will be discussed later in the section
about the electrophilic substitutions.
4.8 Hydrocarbons in Biology
Many unsaturated hydrocarbons are natural products which have an important role
in the functioning of living organisms and living communities. The relatively high
vapor pressure of simple alkenes is responsible for these compounds being used
as communication carriers between organisms. Transfer of information must be
based on the emission and detection of molecules with a particular structure. This
effect is known as chemotaxy and the molecular carriers of information are called
pheromones. Some compounds that are pollutants can interfere with pheromones
in nature and thus disturb communications between organisms.
4.8 Hydrocarbons in Biology 57
Chapter 5
Substitutions onSaturated Carbon Atoms
Alkyl Halides, Alcohols, Thiols, Ethers, Amines
In the previous chapters we have discussed two types of reactions, isomerizations and
additions. Another major class of organic chemical reactions is a substitution. A sub-
stitution in an organic molecule can occur either at the saturated or at the unsaturated
carbon atom which is called the reactive center. The reaction mechanism of a
substitution includes replacement of the leaving group with the incoming group.
The incoming group can not only be a nucleophile or an electrophile which were
already discussed in this book, but also other molecular species such as radicals,
which are molecules with unpaired electrons. The general layout of a substitution
reaction is shown in the scheme below.

60 5 Substitutions onSaturated Carbon Atoms
5.1 Radical Substitutions
5.1.1 Alkyl Halides
The substitution reactions in which the incoming and leaving groups are radicals
were perhaps the most important processes in early chemical evolution. Because
radicals are molecules with one unpaired electron they are exceedingly reactive. In
a vacuum, the radical can have a long lifetime because the probability of encounter-
ing another particle and undergoing the reaction is very low. This is why cosmic
space and outer layers of planetary atmospheres contain large amounts of radicals.
However, even under laboratory conditions, some radicals can survive long enough
to be detected by spectroscopic methods and be used in practical chemical reac-
tions. Remember that simple inorganic molecules such as NO or NO2 are also radi-
cals. Some organic radicals are listed in the next scheme.
In most cases organic radicals are products of breaking the carbon-carbon single
bond. Since a large amount of energy is required for this process, the reaction in
most cases occurs photochemically after the absorption of a quantum of ultraviolet
light. To produce a chlorine radical (Cl.), a chlorine molecule (Cl2) must be irradiated
with light of the wavelength which corresponds to the Cl-Cl bond energy, which is
243kJ/mol. Bonds between other halogens are weaker and can be broken by irradia-
tion with light of longer wavelengths. The Br-Br bond energy is 193kJ/mol and the
I-I bond energy is as low as 151kJ/mol. This is why halogens are convenient reactants
in radical substitution reactions which are used for the preparation of alkyl halides.
Irradiation of a mixture of methane and chlorine results in the formation of
different chlorides of methane. It has been observed that for this photoreaction to
proceed it is not necessary to irradiate the reaction mixture continuously during the
reaction. It is sufficient to irradiate it for only a short time and the reaction then will
continue in the dark. Since the irradiation is used only for triggering the reaction this
first step is called initiation. As was explained in the previous section this step
5.1 Radical Substitutions 61
serves only to break the Cl-Cl bond, i.e. to generate two chlorine atoms (radicals).
As shown by the equations presented in the next scheme, the chlorine radical
removes one H-atom from the methane molecule which results in the formation of
HCl and the methyl radical CH3.. The methyl radical reacts in the dark with another
chlorine molecule producing methyl chloride and another chlorine radical Cl.. The
last two reactions which occur in the dark, continue spontaneously and this reaction
step is called propagation. The system of reactions ends with the recombination of
the remaining radicals into stable product molecules. This last step is called termi-
nation and the overall reaction system is called a chain reaction.
In this reaction a chlorine radical can also react with methyl chloride:
The final product mixture also contains dichloromethane CH2Cl2, trichlorometh-

ane CHCl3 and tetrachloromethane CCl4.
Except for the methyl chloride which is gaseous under standard conditions, the
chlorides of methane are liquid substances which are used widely in the laboratory,
in industry and also in medicine. Trichloromethane, CHCl3, is also known under the
traditional name of chloroform and can be used as an anesthetic. Tetrachloromethane
or carbon tetrachloride is a very good solvent with practical applications in the labo-
ratory, but it must be handled with care because of its carcinogenic properties.
Compounds with different halogens bound to same carbon atom are known as
freons and they are mostly used as gases in refrigeration systems. Molecules of
freons always contain fluorine and other halogens which are mostly chlorine and
bromine. Wide application of freons is the consequence of their relatively high
vapor pressure and low boiling point. In industry, freons have special nomenclature
that is based on the number of carbon, fluorine, and hydrogen atoms. The first number
designates the number of C-atoms minus 1, the second number is the number of
H-atoms plus 1 and third number gives the number of Cl-atoms. The remaining
atoms in the molecule are F-atoms. Some simple freons and their names are given
in the following scheme.
Under standard atmospheric conditions, freons behave as chemically inert sub-

stances, but they undergo photochemical reactions upon irradiation by ultraviolet
light in the higher layers of the stratosphere (at an altitude of 25km). These photo-
chemical transformations also include reactions with ozone O3, converting it into
the common allotrope of oxygen O2. Since the stratospheric ozone layer protects
Earths surface from dangerous ultraviolet radiation, its depletion by reactions with
freons can have negative ecological effects.
The freon molecule possesses two kinds of chemical bonds, C-F and C-Cl which
differ markedly in bond energies. While the C-F bond is strong with a bond energy
of 485kJ/mol, the C-Cl bond is much weaker with a bond energy of 331kJ/mol.
Consequently, irradiation of a freon molecule like for instance CF3Cl, results in the
breaking of the C-Cl bond and yields the following radicals:
The very reactive chlorine radical reacts readily with ozone by removing one
oxygen atom and forming the ClOradical and a molecule of oxygen:
Besides ozone and molecular oxygen, the stratosphere also contains oxygen in
the atomic form O.Atomic oxygen reacts with the ClOradical regenerating the
chlorine radical and one O2 molecule. The chlorine radical can then react again with
another ozone molecule. The chlorine atom regenerated in this process allows a
single freon molecule to destroy millions of molecules of ozone. The overall pro-
cess is a chain reaction summarized in the following scheme:
5.1 Radical Substitutions 63
This knowledge has curtailed the production and use of freons with small
olecular masses. However, freons with higher molecular masses do not undergo
m
such chemical reactions and can be used safely in technological applications, for
instance in air conditioners.
The undesirable ecological effects have also restricted the applications of
polychlorinated biphenyls (PCBs), the substances which are used in the cooling
of high voltage electrical transformers. The main disadvantage of the use of
PCBs is their slow rate of degradation after use. Dichlorodiphenyltrichloroethane
(DDT) is a very efficient insecticide, but its use is restricted due to its carcino-
genic and neurotoxic effects.
5.1.2 Bond Polarity andtheDipole Moment
In the covalent -bond, the electron density is highest between the two atomic nuclei.
However, if the atoms which form the chemical bond are different, the electron d ensity
maximum is shifted closer to the atom which has a higher electronegativity. The pro
perty of an atom to attract the electron density is called electronegativity. There are
different scales of electronegativity, but the most frequently used are values calculated
by Linus Pauling. In principle, the electronegativity of an element increases on going
from the left to the right within the period and from bottom to top of the group in the
periodic table of elements. For instance, in alkyl halides the halogen atom is more
electronegative than carbon so the C-atom becomes partially positively charged and
the halogen atom partially negatively charged. Partial positive or negative charges are
designated in formulas by + and , respectively. The chemical bond in which the
charge is unequally distributed is called the polar bond. In structural formula, the bond
polarity is indicated by a vector (bond dipole) as shown in the following scheme.
If the molecule has several polar bonds, the average polarity corresponds to the
vector sum of bond dipoles called the dipole moment and labeled by the symbol .
The dipole moment is defined as the product of charges and distance between
centers ofthe same charges. The unit for measuring the dipole moment is debye
(D), in the honor of Peter Debye, the scientist who made the greatest contribution
to research on the polarity of molecules. The molecules with nonzero dipole
moments are called polar molecules.
=Qr
(Q charge in Coulombs, r distance between charges in pm)

For the example, if the proton and electron are separated by 100pm the
dipole moment is 4.80D.This is the limiting value which can be used as a
standard for the chemical bond with 100% ionic character [(1.601029C.m)
(1D/3.3361030C.m)=4.80D]. The C-Cl bond-length is 178pm and the dipole
moment is 1.87D.If we assume that the C-Cl bond is 100% ionic, the expected
dipole moment would be =(178/100) (4.80D)=8.54D.Since the experimen-
tal dipole moment is much smaller, 1.87D, the character of the C-Cl bond is
only 22% ionic (% of ionic character=(1.87/8.54)100=22%). In this way
the polarity can be related to the ionic character of the chemical bond.
Since the dipole moment is the vector sum of the polarities of the chemical
bonds, it depends on the molecular geometry. Consequently, molecules such as CO2
or CCl4, with symmetrically distributed polar bonds, are nonpolar because their
total dipole moment equals zero.
As already mentioned, chlorides of methane are very useful solvents. From the
knowledge about the polarity of molecules, i.e. their dipole moments, we can distin-
guish between polar and nonpolar solvents. The polar solvents are for example
CH2Cl2 and CHCl3, while tetrachloromethane, CCl4, is a nonpolar solvent. Polarity
of solvents is one of the most important properties, not only for practical labora-
tory applications, but also for the theory of reaction mechanisms, reactivity and
selectivity of organic compounds.
5.2 Reactions ofNucleophilic Substitutions andEliminations 65
5.2 Reactions ofNucleophilic Substitutions andEliminations
Nucleophiles are electron rich molecules or ions which may contain for example
the electron lone pair, also called the nonbonding electrons. From the building
principle of the electronic structure of organic molecules we know that non
bonding n-electrons occupy the highest energy level called the HOMO orbital.
Accordingly, these electrons are mostly responsible for the reactivity of organic
molecules.
Collision of a nucleophile with an alkyl halide molecule will result in a chemical
reaction if the nucleophile attaches to the partially positively charged carbon atom.
Since the carbon-bromine bond is polarized, the nucleophile will approach the
C-atom bound to the bromine atom (see following scheme). In the given example
theincoming nucleophile is the OH anion and the leaving group is the bromide
anion. The product of the reaction of 1-bromopropane with a hydroxide anion is
propane-1-ol. One functional group (Br) is replaced by another functional group
(OH) and the product belongs to the new class of organic compounds alcohols.
For simplicity, in the second equation only the nonbonded electrons which are
involved in the reaction mechanism are depicted.
Detailed analysis of this reaction mechanism requires a discussion of the elec-

tronic structure of both reactants in the framework of the molecular orbital model.
We will avoid this approach because it is outside the scope of this book.
The pertinent question is why Br as a nucleophile (because it possesses non-
bonded electrons) does not react with the product (propane-1-ol) reverting back to
1-bromopropane? Such a reversible reaction is not probable because OH and Br
have different nucleophilicities. While OH is a stronger nucleophile, Br is a better
leaving group. On the basis of experimental experience and high level quantum-
mechanical calculations, chemists have quantified nucleophilicity and arranged it
into the nucleophilic order. In principle the stronger nucleophile replaces the poorer
nucleophile. Nucleophilicity as well as the nucleophilic order are not universal
properties because they strongly depend on the reaction environment, especially on
the solvent, but in standard chemical practice the following order applies:
- SH > NH > - OH > I - > Br - > Cl-

3
5.2.1 Reaction Mechanisms ofNucleophilic Substitutions
The systematic measurements of reaction rates of nucleophilic substitutions have

shown that, depending on the structure of reactants, the reaction kinetics can follow
either the first or the second order rate law. The chemical reaction rate can be
expressed by kinetics equations in which the main parameter is the reaction coeffi-
cient (rate constant) k:
While in the first reaction of the scheme above the rate depends only on the con-
centration of single molecular species A, the rate in the second reaction depends on
the concentration of two different molecular species A and B.Therefore, the first
reaction follows the unimolecular mechanism and the second reaction is described
by the bimolecular mechanism.
In most nucleophilic substitutions, the substrate with the leaving group bound
to a tertiary carbon atom follows the unimolecular mechanism and the reactant
with the leaving group on a primary carbon proceeds via the bimolecular reaction
mechanism.
Christopher Ingold and Edward D.Hughes, in the middle of the last century, used
such kinetic properties to devise nomenclature for the mechanisms of organic reactions.
For the nucleophilic substitutions, Ingold and Hughes have proposed labels SN1, and
SN2, where S and N refer to substitution and nucleophilic, respectively. Numbers 1 or
2 are used to designate unimolecular or bimolecular mechanisms, respectively.
The difference in kinetic behavior between the primary and tertiary substrates is
a consequence of different underlying reaction mechanisms. Before discussing the
details of the mechanisms of nucleophilic substitutions, let us mention the basic
principles of the theory of the rates of chemical reaction established by Henry Eyring.
In a simple chemical reaction, the molecule of the reactant is transformed to the
product by passing through a high energy structure which is called the transition state.
Hence, the Eyrings concept is known under the name of transition state theory.
For the rearrangement into the transition structure, the reactant molecule must
absorb a specific amount of energy called the activation energy. The lifetime of the
transition structure is very short, around 1013s; this time is comparable to the period
of one molecular vibration. In the previous chapters we have already discussed the
nature of molecular vibrations and the corresponding spectroscopic techniques.
The reaction rate expressed through the rate constant k strongly depends on tem-
perature and on the activation energy. This dependence is expressed in the equation
given by Svante Arrhenius and Henricus Jacobus vant Hoff:
k = Ae- Ea / KT
where k stands for the reaction rate constant, Ea for activation energy, K is Boltzmann
constant and T is temperature. If the activation energy is low then the transition
structure is more stable, the reaction is fast and consequently the reaction constant
k is large. This is shown in the next scheme.
In the two reactions presented, the first one requires a higher activation energy
than the second one. Consequently, the second reaction is faster. Such a scheme
describes a reactions that follow the SN2 mechanism. After the collision of the sub-
strate molecule with the nucleophile, provided the molecules have sufficient energy
to overcome the activation energy barrier, the transition state is formed. This transi-
tion state could be described as a vibration in which the incoming nucleophile
approaches and the leaving group departs from the reaction center (carbon atom).
The breaking of the existing bond and the formation of a new bond are concerted
processes, so the SN2 mechanism is called the concerted mechanism.
The transition state resembles a trigonal bipyramid in which the incoming and
leaving groups occupy axial positions and the other three substituents are almost
coplanar with the carbon atom. While the central carbon atom holds a partial posi-
tive charge the leaving and incoming groups carry a partial negative charge. The rate
of this bimolecular reaction depends on the concentrations of the two molecular
species, the OH ion and 1-bromopropane as shown below:
Nucleophilic substitutions of tertiary substrates follow more a complicated

mechanism that consists of two steps. The first step is the dissociation of the bond
between the carbon atom and the leaving group. The result of this dissociation is
the formation of short-lived reactive intermediate called carbocation. In this
book we have already discussed the carbocations in the section about addition
reactions. We have mentioned that the most stable are the tertiary carbocations,
in which the positive carbon is bound to three neighboring C-atoms. In substrates
such as 1-bromopropane in the last example, only the C-Br bond can be cleaved to
form a primary carbocation. Since such a primary carbocation is highly unstable,
the reaction proceeds via the concerted SN2 mechanism in which the primary
carbocation does not appear.
Let us discuss the SN1 mechanism in more detail. Dissociation of the C-Cl bond
in 2-chloro-2-methylpropane in the first step yields a tertiary carbocation (in this
case a tert-butyl cation) which as a stable species lives long enough to collide with
the OH nucleophile and to form the product. It must be pointed out that the stability
of the carbocation depends also on the environment. For instance, the cations are
more stable in polar than in nonpolar solvents.
As is shown in the scheme above, the reaction consists of two steps: the second
step being much faster than the first step. In principle, there are two reactions, one
following the other. Such processes are called consecutive reactions. The observed
rate of such a reaction system corresponds to the rate of the slowest step. This step, in
our example the dissociation of the C-Cl bond, is called therate-determining step.
Consequently, the observed rate depends only on the concentration of one molecular
species, in this case on the concentration of the reactant 2-chloro-2-methylpropane:
Unimolecular SN1 processes can be described in the framework of transition

state theory. Since the first, rate-determining step is slower, its activation energy
(Ea1) is higher than the activation energy (Ea2) for the second, faster step. The com-
plete energy diagram is shown in the next scheme.
The reaction mechanisms of SN1 and SN2 nucleophilic substitutions are conve-
nient for describing reactions where the reactive carbon atom is either primary or
tertiary. Reactions of molecules with a secondary reactive carbon atom usually

follow a mechanism that could be described as the combination of these two mecha-
nisms. The presence of an SN1 or SN2 mechanism strongly depends on the reaction
conditions, mostly on the polarity of the solvent. For instance, polar solvents which
stabilize ionic species favor the SN1 mechanism.
5.2.2 Alcohols
In the previous examples we have demonstrated that nucleophilic substitution in

which water and hydroxyl group were used as nucleophiles, yield alcohols as
products. We note that the carbon atom bound to the OH group can be primary,
secondary or tertiary. Accordingly, alcohols can be classified as primary, secondary
or tertiary.
Alcohols are named starting with the name of the longest carbon chain and using
the suffix -ol. Numbering of C-atoms must be such that the carbon on which the OH
group is attached has the smallest possible number.
Alcohols which have two or more OH groups are called diols, triols, etc. In the
following scheme IUPAC names of some alcohols are given together with their
trivial names which are still used, especially in trade or manufacturing.
The simplest primary alcohol is methanol or methyl alcohol, the substance

d iscovered in eighteenthcentury by the Irish chemist Robert Boyle. Methanol is
one of the products of the dry distillation of wood. It is also the product of different
biological processes and appears in some alcoholic drinks, which is illegal because
of the poisonous nature of methanol. Although the molecule of methanol is small
and has a small molecular mass its boiling point, 65C, is relatively high. Such a
high boiling point is the consequence of hydrogen bonds between methanol mole-
cules. In this property methanol is similar to water and consequently methanol and
water can mix in any amount.
99% pure methanol can be obtained by fraction distillation of the methanol/

water mixture. Further distillation does not produce 100% methanol, because the
mixture of methanol and water in a volume ratio of 99/1 has the same composition
in the liquid and gas phase. Such mixtures are known as azeotropes. Therefore
pure or absolute methanol cannot be obtained by distillation. The best methods for
preparation of absolute alcohols must include chemical reactions with metals such
as sodium or magnesium. The products of such reactions are compounds that
readily react with traces of water.
Reactions of alcohols with metals yield special salts called alcoholates or alkox-
ides. For example, methanol reacts with sodium producing sodium methanolate
(sodium methoxide) with the evolution of hydrogen:
Sodium methanolate reacts further with water forming sodium hydroxide and
methanol. Sodium hydroxide is not soluble in alcohol and precipitates out. The
remaining liquid consists only of methanol which can be distilled to get absolute
methanol.
For safety reasons, magnesium is used in the preparation of absolute methanol as

magnesium is a less reactive metal than sodium.
Ethanol, or ethyl alcohol, CH3CH2OH is one of the basic products of fer-
mentation of fruits, especially wine grapes. Such natural reaction is known as
alcoholic fermentation by which the carbohydrate glucose is decomposed into
ethanol and carbon dioxide. The reaction is promoted by special biocatalysts
called enzymes:
The volume of ethanol in wine produced by fermentation cannot exceed

15% because the large amount of alcohol deactivates the fermentation enzymes.
Distillation of ethanol (boiling point 78C) from water yields the azeotrope
with 96% of alcohol. Absolute ethanol can be prepared by adding alkali metals
followed by distillation, similarly to the preparation of methanol. Propanol forms
two isomers, 1-propanol, CH3CH2CH2OH and propane-2-ol, CH3CH(OH)CH3.
These isomers also have the traditional names: n-propanol and isopropanol,
respectively. Isopropanol is a very good organic solvent. Both, ethanol and isopro-
panol are in wide use for disinfection. An excellent liquid for cleaning laboratory
glassware is the solution of 5% of potassium hydroxide in isopropanol.
Ethane-1,2-diol or ethyleneglycol belongs to alcohols with more than one hydroxyl
group. Ethyleneglycol is the main component of antifreeze in car engines. Propane-
1,2,3-triol is known under the name glycerol and is one of the most important alcohols
in living organisms. Glycerol is the main structural component of biologically impor-
tant compounds lipids; this class of compounds also includes fats. Because of its high
viscosity and the relaxing effect on human skin, glycerol has wide use in cosmetics.
The reaction of glycerol with nitric acid yields glycerylnitrate, the explosive liquid
called nitroglycerin. Since pure nitroglycerin is explosive and is so sensitive that can-
not be safely transported and handled, its use was very limited until 1867 when Alfred
Nobel discovered that the sensitivity of nitroglycerin can be controlled by the addition
of some neutral powders. Such powders which adsorb nitroglycerin are used in the
explosive called dynamite. Taking into account the destructive power of dynamite and
its possible military applications, Nobel used the profits from his discovery to establish
the prizes awarded to people in the sciences and the arts whose activities promoted
world peace and the development of the human society.
Many biologically important compounds are alcohols. Because of their c haracteristic

pleasant odor many alcohols, for the instance menthol and citronellol are used in the
preparation of perfumes. An alcohol with a more complex molecular structure is
cholesterol, which is a component of cellular membranes and the starting compound
for the biosynthesis of various hormones.
The similarity of alcohols to water can be recognized from their behavior in

solutions. In the nineteenthcentury Svante Arrhenius discovered that water
molecules in the liquid state dissociate into H+ and OH ions. We know that H+ ions
react with undissociated water molecules and form oxonium ions, H3O+. Analogously,
molecules of alcohols can dissociate into H+ (H3O+) and the corresponding alco-
holate anion.
Since the dissociation of water molecules produce equal number of H+ and OH

ions, the medium is neutral and its pH=7. However, since the dissociation of alco-
hols yields only H+ ions their solution could be expected to be acidic, i.e. pH<7. We
shall discuss the phenomena of acidity and basicity in more detail.
At the end of eighteenthcentury, Antoine Lavoisier argued that acids are
compounds that contain oxygen. In recognition of that Lavoisier named the
chemical element oxygen using the French word oxygene, which means acid.
However, soon after the work of Lavoisier, Scheele prepared an acid which did
not contain the element oxygen, namely hydrochloric acid. After the discovery
of hydrochloric acid the element essential for the property of acidity became
hydrogen. At the beginning of twentiethcentury, Johannes Brnsted and
Thomas M.Lowry defined acids as substances which are proton donors and
bases as proton acceptors.
The equations above showed the behavior of alcohols as acids. In the presence of
strong acids, alcohols can also behave as bases:
H+ ions, which originate from a strong acid, bind to the oxygen atom via one of
its electron lone pairs. We say that strong acid protonates oxygen in the alcohol
molecule forming the oxonium ion. Accordingly, alcohols can behave either as
acids or as bases, depending on the medium.
In general, acidic behavior can be represented by the equation in which the acid
is labeled as AH.Anion A that remains after removing the proton behaves as a
base, because it is in chemical equilibrium and can again accept the proton. Such
base is named the conjugated base.
This equilibrium can be characterized by the equilibrium constant Ka. By con-

vention, the equilibrium constant is defined as the quotient of concentrations of
products and reactants:
Because the range of equilibrium constants spans many orders of magnitude it is

in practice replaced by the logarithmic parameter pKa:
pK a = log K a

When the acid is more dissociated it is stronger and yields more protons. Hence, if
the equilibrium is shifted to right, the constant Ka is larger and the pKa is smaller.
Therefore strong acids are characterized by a small pKa. The ability of the acid molecule
to dissociate depends on the stability of its conjugated base. An alcohol which behaves
as a moderate acid is phenol, the substance also known as carbolic acid. Because of
its acidity, phenol is frequently used as a disinfectant in medicine. Dissociation of the
phenol molecule forms a conjugated base called the phenolate anion:
The stability of the phenolate anion is a consequence of its electron delocalization.

Remember that the electron energy is reduced by electron delocalization, as we
have demonstrated in the case of the benzene molecule. The existence of electron
delocalization in the phenolate ion can be demonstrated using the resonance method.
The resonance structures of the phenolate anion are given below:
As we can see from the above formulas, the negative charge is not localized on
the oxygen atom (as is the case in the methanolate anion CH3O) but rather it is
delocalized over the entire benzene ring.
The behavior of alcohol as a base is evident in the chemical reaction in which
alkenes are formed. In a strong acid medium, alcohol is protonated at the oxygen
atom, forming the oxoniun ion intermediate. The reaction ends with the formation
of an alkene by the removal of the water molecule from this oxonium ion. Such
reactions, in which some atoms or groups depart from the molecule, are called
elimination reactions. In most cases the preparation of alkenes from alcohols
includes a reaction with concentrated sulfuric acid, which is a sufficiently strong
protonating agent.
In the case of tertiary alcohols with different hydrocarbon branches we may

expect three different elimination products as shown in the next scheme. However,
Russian chemist Aleksandr Zajtsev who lived in the nineteenthcentury used
systematic experimental studies to show that, out of the three possible products,
only one appears. Zajtsev proposed the rule according to which the preferred pro
duct is the one in which the carbons of the double bond have the largest number of
alkyl substituents. We say that the reaction obeys Zajtsev rule.
5.2.3 Ethers
Alcoholates (alkoxides), which were already mentioned in the discussion on the

reactions of alcohols with metals, behave as strong bases and are good nucleophiles.
In the middle of nineteenthcentury Alexander William Williamson succeeded in
preparing ethers in the reactions of alkoxides with primary alkyl halides. Later it
was demonstrated that these reactions follow the SN2 mechanism.
However, the reactions with secondary and tertiary alkyl halides yield alkenes,
because the elimination reaction is preferred over a substitution. In contrast to the
previously mentioned elimination of water from alcohol initiated by a strong acid,
the elimination of hydrogen halide requires a strong base (in this case sodium
ethoxide).
The base, as proton acceptor, deprotonates alkyl halide causing the removal
of a halide anion. The reaction proceeds via the transition state in which both
C-H and C-Br bonds break simultaneously. Such reactions are called concerted.
The reaction is bimolecular because its rate depends on the concentrations of two
molecular species, alkyl-bromide and the ethoxy anion. This mechanism is called
the E2 elimination mechanism.
If the leaving group is bound to a tertiary carbon atom, the slow reaction step
involves dissociation of the C-Br bond and the formation of a tertiary carbocation.
In that case the reaction rate depends only on the concentration of one molecular
species, the alkyl bromide in our example. Accordingly, the reaction is unimolecular
and such mechanism is called E1 elimination.
Ethers and alcohols can be regarded as structural analogs of a water molecule.

Whilein alcohols only one of the H-atoms is replaced with alkyl group, in ethers
both hydrogens are replaced with alkyl groups (see the next scheme). In the
nineteenthcentury Williamson used such analogy to derive the concept of chemical
constitution. This first structural theory was known as the type theory in which
alcohols and ethers belonged to the water structural type. This was the beginning of
the structural formulas which are also used today.
While alcohols have high boiling points because of hydrogen bonds, ethers do
not have OH groups and cannot form molecular aggregates. This is why ethers
have low boiling points. Dimethyl-ether is gaseous under the standard conditions
and diethyl-ether is liquid with the boiling point as low as 32C.The similarity and
analogy between ether molecules and water is also evident in their molecular
polarities. Because of their molecular polarity, ethers are good solvents for chemi-
cal reactions that occur through polar reaction intermediates. Ethers are partially
miscible with water. For instance, diethyl-ether can mix with 8% of water. For this
reason ether as a solvent for reactions must be dried by using standard methods for
the removal of water.
Ether molecules with several ether groups are called oligoethers or polyethers. Some
of them have cyclic structures, for instance furan, tetrahydrofuran, pyran or dioxane.
Cyclic ethers with three- and four-membered rings represent a special group of
ethers; the epoxides (oxiranes) and oxetanes, respectively. These compounds are
very reactive and have important uses in industry. The most basic cyclic ether,
oxirane, ethylene-oxide is used for artificial maturation of vegetables.
Other epoxide compounds are used as starting materials in the production of

polymeric materials. The oligomer represented in the following scheme is one of
the components of epoxide resins.
Cyclic ethers with several oxygen atoms in the ring are of special chemical
importance. The simplest, dioxane, is routinely used as a solvent in organic synthe-
sis. Ring containing ethers with five or six oxygen atoms afford special chemical
properties. Inspection of the structure of the molecules represented in the formulas
below shows that oxygen atoms form a cavity which is negatively charged because
of the dense electron clouds of electron lone pairs. Such molecules resemble crowns
and are known as crown-ethers.
These ethers are named on the basis of the number of O-atoms and the size of the
ring. For instance, the molecule in the scheme above is named 18-chown-6 because
the ring has 18 atoms and 6 oxygens. The cavity formed by the O-atoms is large
enough for metal ions such as K+ to enter. Crown ethers with cavities of different
sizes can capture metal ions of different ionic radii. The synthesis of crown ethers
heralded the rise of a new branch of chemistry, supramolecular chemistry, which
investigates complex molecular aggregates.
5.2.4 Thiols andSulfides
Sulfur analogs of alcohols and ethers are thiols or mercaptanes and sulfides,
respectively. According to the nomenclature rules, thiols are named following the
same rules as for alcohols, the only difference being that the suffix -ol is replaced
with -thiol. Most of these substances can be recognized by their unpleasant odor.
Ethanethiol is used as an additive to natural gas since its odor serves as an indicator
of a gas leak in home installations. Pure natural gas is odorless. Some animals such
as skunks release an unpleasant odor which originates from thiols shown in the next
scheme. However, some thiols have a pleasant odor, for instance the components of
the aroma of coffee.
5.2.5 Amines
The molecule of ammonia has an electron lone pair on the nitrogen atom and is a
strong nucleophile. In the reaction with alkyl halides it yields amines. The reaction
mechanism includes removing hydrogen halide as the leaving group.
As alcohols and ethers are analogs of water, amines can be considered as analogs
of ammonia. The basic chemical properties of amines are consistent with this
analogy. Any of the three hydrogen atoms in ammonia can be replaced with an alkyl
group. Depending on the number of hydrogens substituted, three types of amines can
be formed. In the primary amine, only one H-atom is substituted, in the secondary
amine, two hydrogens are substituted and in the tertiary amine, three hydrogen
atoms are replaced with the alkyl group.
Amines with four substituents are known as quaternary ammonium salts and
were discovered by Alexander von Hofmann during his work on the determination
of the structures of natural products. Quaternary ammonium salts can be prepared
by reactions of amines with alkyl iodides, mostly with methyl iodide.
Since primary amines can be obtained from ammonia by nucleophilic substitu-

tion, the secondary amines can be prepared by using a primary amine instead of
ammonia, while tertiary amines are accessible by starting from secondary amines.
In water solution, ammonia behaves as a base because the molecule can accept a
proton at its nitrogen lone pair. All amines behave similarly to ammonia: they are
organic bases because they act as proton-acceptors.
For example, the protonation of ammonia yields the ammonium ion and the
p rotonation of ethyl amine forms the ethylammonium ion. The behavior of bases
can be described by a chemical equilibrium and the corresponding constant Kb,
similarly as for acids. Analogously, the negative logarithm of Kb (pKb) is used as a
measure of basicity. As pKb gets smaller, the base is stronger.
Acids and bases can also be considered from another point of view. In this view
acids are electron acceptors while bases are electron donors. Lewis has used this
definition to extend the concept of acidity and basicity to the compounds which
dont have hydrogen. The molecule of amine is a stronger base if the electron lone
pair on nitrogen is more localized. Localization or delocalization can be estimated
by writing the appropriate resonance structures. Electrons are localized if only one
resonance formula can be drawn. In principle, if the electron pair is delocalized over
a large part of the molecule, the electron energy is lower, the system is more stable
and does not require the addition of a proton.
Let us elaborate this concept in case of the basicity of aniline and pyridine. The
nonbonded electron pair at the nitrogen atom is delocalized over the entire mole-
cule, as is evident from the resonance structures shown below.
In the pyridine molecule the nitrogen electron pair cannot be delocalized

because it occupies the 2px orbital which is perpendicular to the 2pz orbitals of the
aromaticring.
Hence this electron pair remains localized on the nitrogen atom, its electron
energy is higher and its protonation is favored. For this reason pyridine is a stronger
base than aniline.
Chapter 6
Nucleophilic Additions
Compounds with a Carbonyl Group
Organic compounds with a carbonyl group are not only numerous but also represent
excellent substrates for various chemical reactions. This due to the nature of the
carbonyl group and its electronic structure. Since the carbonyl group has oxygen as
the heteroatom bound by double bond to the carbon atom, its electrons are distrib-
uted amongst , and n orbitals.
The C=O group is polar because of the high electron affinity of the oxygen atom.
Consequently, the carbon atom carries partial positive and the oxygen atom partial
negative charge. This polarity is evident in the resonance structures below. The dipole
moment of the carbonyl group is relatively high and varies between 1.7 and 3.6 D.
Nucleophiles can attack the partially positive carbon atom in the carbonyl group
(see following scheme). The formation of the new chemical bond between the
nucleophile and the carbonyl carbon induces an electron shift from the carbon-oxygen

86 6 Nucleophilic Additions
double bond to the oxygen atom. The result is a reaction intermediate with the
negative charge on oxygen. This mechanism is universal and describes all the reac-
tions called nucleophilic additions to the carbonyl group.
6.1 Aldehydes and Ketones
Aldehydes appear as products of oxidation of primary alcohols while ketones are

products of the oxidation of secondary alcohols. Since oxidation is recognized as
the reaction in which hydrogen is removed from the molecule, the removal of a
hydrogen molecule from the primary alcohol yields a compound that has histori-
cally been called alcohol dehydrogenatus. The word aldehyde is derived from the
first few letters of this historic name.
Besides being prepared by oxidation, aldehydes and ketones can also be pre-
pared by reactions in which the first step includes the addition of water to the triple
bond of the alkyne molecule. The first intermediate, the unsaturated alcohol (enol)
is unstable and undergoes isomerization to the stable ketone. This type of reaction
in which one isomer is transformed to another is called rearrangement. The older
name for this molecular rearrangement is tautomerism and this special case is
called the keto-enol tautomerism.
6.1 Aldehydes and Ketones 87
The constitutional difference between aldehydes and ketones lies in the

substituents at the carbonyl carbon atom. While in aldehydes one of the substituents
is always hydrogen in ketones both substituents are alkyl groups. Therefore, the
chemical properties of aldehydes and ketones, especially in nucleophilic addition
reactions are similar. The simplest aldehyde is methanal or formaldehyde and the
parent ketone is propan-2-one or acetone.
In the systematic nomenclature the names of aldehydes are formed with the
suffix -al. In complex molecules the aldehyde group is designated by the suffix
-carbaldehyde. The names of ketones include the suffix -one and the numerical
label of the carbonyl carbon atom. The numbering of carbons must be such that each
one has the smallest possible number. Ketones can also be named by using the pre-
fix oxo- and the numerical label of the carbonyl group. The prefix oxo- is used when
the compound possesses both aldehyde and ketone functional groups. The longest
chain for naming such molecules is defined by the position of the aldehyde, rather
than the keto group.
In the following scheme we list structures and the traditional names of some of
the important and well-known aldehydes and ketones. Most of them are natural
products, which shall be discussed in the subsequent chapters of this book.
In water solution, aldehydes react with water molecules as nucleophiles. The

OH nucleophile attacks the carbonyl carbon forming a new C-O bond and shifting
the electron pair from the double C=O bond to the oxygen atom. In the reactive
intermediate, the former carbonyl oxygen becomes negatively charged, as is shown
in the next scheme. This negative oxygen is easily protonated and converted to a
hydroxyl group. The final product is called a diol, in which both OH groups are
bound to the same carbon atom. Such diols are called geminal diols. The reaction is
reversible and the elimination of a water molecule yields the aldehyde reactants.
In general, the reaction can be represented as:

The position of equilibrium depends on the nature of the substituent R. In some

aldehydes such as chloral, CCl3CHO or formaldehyde HCHO, the equilibrium is
shifted towards the diol. In its diol form chloral is known as chloral hydrate and
serves as a disinfectant. The trade name of formaldehyde is formol which is actu-
ally the water solution of formaldehyde.
Under the standard conditions formaldehyde is gaseous. However, its molecules

can interact with each other by a mechanism similar to nucleophilic attack. The
oxygen of the carbonyl group behaves as the nucleophilic atom (see the next
scheme). The product of such a reaction is a polymer, the white powder called para-
formaldehyde. Hence, formaldehyde can be provided either in the form of the
water solution formol or as paraformaldehyde powder. Pure formaldehyde gas for
use in chemical reactions can be prepared by heating paraformaldehyde under vac-
uum. Similarly, the molecules of acetaldehyde can condense into cyclic trimers giv-
ing the substance known as paraldehyde.
Alcoholate anions in alcohol solutions react with aldehydes and ketones forming
ketals and acetals, or hemiacetals and hemiketals. The rates of nucleophilic addi-
tions on the carbonyl group are enhanced by protonation of the carbonyl oxygen, so
these reactions are acid catalysed.
Acetals and ketals are unstable in acidic solutions and undergo hydrolysis revert-
ing to the original aldehydes and ketones.
The mechanism analogous to acid catalysed nucleophilic addition to the car-

bonyl group applies to the reactions of aldehydes with different nucleophiles like
halide or nitrile ions, yielding halohydrins or cyanohydrins.
The preparation of cyanohydrins is an important reaction in organic synthesis

because it is used to lengthen the hydrocarbon chain by one C-atom: the molecule
of 1-cyanopropanol in the scheme above has one carbon atom more than the starting
propanal. Some cyanohydrins are natural products, especially the derivatives of
benzaldehyde, which are poisonous and used by particular insects for their defense.
The toxic activity of these compounds is based on the hydrolysis of cyanohydrins
into benzaldehyde and highly toxic HCN.
6.1.1 Carbon as a Nucleophile
As we mentioned at the beginning of this book, the large diversity of hydrocarbon

compounds is the foundation of organic and biological evolution. This has been
proposed by considering the large number of possible isomers. Aldehydes and
ketones undergo simple transformations by which high structural diversity can be
obtained, starting with only a few simple compounds. In alkaline medium, carbonyl
compounds can act as acids, i.e. they behave as proton donors (see following
scheme). A stable conjugate base can appear only after removing the proton from
the C-atom which is directly bound to the carbonyl group.
Stability of the conjugated base arises from the electron delocalization that can
be identified by using the resonance structure method. Acids in which the proton is
removed from the carbon atom are called carbon acids and their conjugate base is
called an enolate ion.
The anions which would be generated by removing a proton from the carbon
atoms which are not neighbors of the carbonyl group are unstable because their
electron pair is localized. No resonance structures can be written in such cases (see
the structure below).
Since under basic conditions the aldehyde molecules partially dissociate, their
mixture contains two molecular species, dissociated and undissociated. The dissoci-
ated molecule, the enolate ion can behave as nucleophile because of the electron
pair on its carbon atom. This nucleophile can attack the carbonyl group of the undis-
sociated aldehyde yielding a product with two functional groups, aldehyde and
alcohol. Such compounds are named aldols and the corresponding reaction is called
aldol condensation.
After loosing a molecule of water, aldol is transformed into the corresponding

unsaturated aldehyde.
The example given is the reaction in which a molecule with five C-atoms in the
hydrocarbon chain (pentanal) gets converted to a molecule containing nine atoms in
the longest chain. Let us imagine a mixture of two different aldehydes, A and
B. Since these aldehydes can form two enolate nucleophiles and two undissociated
molecules, the cross reactions must yield four products: A + A, B + B, A + B and
B + A. The number of products of aldol condensation follows the n2 rule where n is
the number of different aldehydes used. For instance, the mixture of ten different
aldehydes will produce a hundred different products. If unsymmetrical ketones with
two different carbons next to the carbonyl group are added to the starting mixture,
the diversity of products in the mixture is further enhanced. This example demon-
strates how a large number of diverse structures can originate from a small number
of starting molecules.
Molecules with carbon as a nucleophilic center also appear in the reactions of
carbonyl compounds with organometallic compounds. Such reactions are very use-
ful in organic synthesis. The best known reagents that include such carbon nucleo-
philes are alkyl- or arylmagnesium halides, are called Grignard reagents, in honor
of Victor Grignard. The reagents can be easily prepared by direct reactions of an
alkyl- or aryl halide with the magnesium metal. Since Grignard reagents are like
many organometallic compounds, unstable and sensitive to moisture, the reaction
must be performed in dry diethyl-ether.
The carbon-magnesium bond is polar with the partial negative charge on the carbon
atom. Consequently, this nucleophilic C-atom attacks the carbon atom of the carbonyl
group while the positive magnesium halide residue bonds to oxygen. The intermediate
produced in the next reaction step is hydrolyzed to the corresponding alcohol. It is
important to observe that the product molecule has one additional methyl group.
Starting with alkyl halides, we can prepare the appropriate Grignard reagents and
in combination with different aldehydes or ketones, synthesize a series of com-
pounds with branched hydrocarbon chains.
6.1.2 Condensations with Amines
Aldehydes and ketones react readily with equimolar amounts of primary amines,
yielding imines and water. Imines (also called Schiff bases) can be considered to
be amines with carbon-nitrogen double bonds.
6.1.3 Reductions of Aldehydes and Ketones
Since aldehydes and ketones are produced by oxidations of primary and secondary
alcohols, it must be possible to achieve the reverse transformation i.e. their reduc-
tion back to alcohols. For this reaction we use special reducing reagents, the metal
hydrides, because the reduction in organic reactions involves the addition of a
hydride ion H. The best known reducing agents are lithium aluminium hydride,
LiAlH4, sodium boron hydride, NaBH4 and sodium hydride, NaH. Molecules of
LiAlH4 and NaBH4 consist of lithium or sodium cations and AlH4 or BH4 anions.
6.2 Carboxylic Acids 95
The hydride anion (H) behaves as a nucleophile in the reduction of a carbonyl

group and binds to the positively charged carbon atom. The remaining AlH3 is a
Lewis acid which, as an electron acceptor, attacks the oxygen. After hydrolysis and
release of aluminum hydroxide, the reaction ends with the formation of an alcohol,
in this case propanol (see the following scheme).
The reduction of a ketone follows the same mechanism. In the following example,
acetone is reduced to propane-2-ol.
6.2 Carboxylic Acids
In organic chemistry, the oxidation process can also imply the addition of oxygen
atoms. In such a way the aldehyde group is oxidized to the carboxyl group by add-
ing an oxygen atom. The compounds with a carboxyl group belong to the carbox-
ylic acids. Oxidative agents for this transformation include sulfuric acid, solutions
of potassium permanganate KMnO4, potassium bichromate K2Cr2O7 or chromium
trioxide CrO3. The following example represents the oxidation of pentanal to the
corresponding carboxylic acid.
Justus von Liebig and Bernhard Tollens have discovered that milder agents
such as silver oxide, Ag2O oxidize aldehydes to carboxylic acids. This reaction,
which is characteristic for aldehydes, serves as a specific qualitative test for this
class of compounds and is known as the Tollens test. Metallic silver being one of
the byproducts, precipitates and forms the characteristic silver mirror that can be
easily observed.
An alternative method for the preparation of carboxylic acids is the reaction of

nitriles with sulfuric acid. This reaction is important in organic synthesis because it
can be used to extend the hydrocarbon chain by one carbon atom. Nitriles can be
obtained from the corresponding alkyl halides in the reaction with HCN by nucleo-
philic substitution. Nitrile can easily be oxidized to carboxylic acid.
Many essential natural products that are ubiquitous in living organisms are
carboxylic acids. The simplest (parent) carboxylic acid is formic acid (acidum for-
micum) which is named methanoic acid in the IUPAC nomenclature. This acid is
the main component of the poison of ants.
Acetic acid (acidum aceticum) with IUPAC name ethanoic acid is used as an
everyday food additive. Citric acid, which is also a natural product, is a polyfunc-
tional compound with three carboxylic and one OH group. A molecule of the simple
oxalic acid consists of only two carboxylic groups. Oxalic acid salts are frequently
present in kidney stones.
Many carboxylic acids such as cholic acid or long-chained fatty acids are com-
plex molecules. In contrast to the saturated fatty acids, molecules of unsaturated
fatty acids always have carbon-carbon double bonds. Interestingly, the molecules of
fatty acids, without exception, have even number of C-atoms. This is an indication
that the natural pathways for biosynthesis of these classes of compounds are the
same. The role of fatty acids and other natural products in living organisms will be
discussed later in this book.
The rules for naming carboxylic acids include principles of organic and inor-
ganic nomenclature. The name of the acid consists of the name of the longest hydro-
carbon chain and the prefix -oic acid. In numbering C-atoms of the hydrocarbon
chain, the smallest number must be assigned to the carboxyl group. If the carboxyl
group is only a substituent, when its carbon atom does not belong to the hydrocar-
bon chain, the name is formed with the suffix carboxylic acid (as cyclohexanecar-
boxylic acid in the following example).
Carboxylic acids are substances with high boiling points: formic acid 101 C,
acetic acid 118 C and propanoic acid 141 C. This is the consequence of dimeriza-
tion and the formation of molecular aggregates via hydrogen bonds. Even in the gas
phase, the molecules can remain in dimeric form.
The strong acidic behavior of carboxylic acids as good proton donors is the
consequence of stabilization of the corresponding conjugated base (carboxylate
anion). As can be seen from the resonance structures presented below the electrons
in the carboxylate anion are delocalized.
The structures show that the negative charge is equally distributed on both oxygen
atoms. The charge distribution in the molecule can be calculated by using quantum-
mechanical methods and molecular modeling. When the carboxylate anion (in our
case ethanoate anion) is modeled by such methods we obtain the diagram shown
below with the regions of the highest electron density (negative charge) shown in red:
We have already mentioned that the acidity of organic compounds can be

expressed by the acidity constant, Ka, or its negative logarithm, pKa. Remember
that stronger acids have lower pKa values. The relationship between molecular
structure and acidity for different carboxylic acids, which is shown in the table
below, can be used to study the structure-activity relationships of organic com-
pounds in general.
Carboxylic acid pKa

CH3COOH 4.7
CH3CH2COOH 4.9
CH2FCOOH 2.6
CH2ClCOOH 2.9
CHCl2COOH 1.3
CCl3COOH 0.9
The first pattern that is evident from these data is the influence of halogens on
acidity. As halogens become more electronegative or when their number increases,
the carboxylic acid becomes stronger (it has lower pKa). Since it is not possible to
write resonance structures which would include electrons from the halogens, the
electron delocalization in such anions must have a different origin. To get a better
insight into this alternative mode of charge delocalization, let us discuss a number
of additional examples.
Acidity amongst the three chlorobutanoic acids decreases as the chlorine atom
moves away from the carboxyl group. The weakest is 4-chlorobutanoic acid with a
pKa of 4,53. It is known that since the electronegative halogens attract electron
density, their neighboring atoms become partially positively charged. Such effect is
most pronounced on the first neighboring C-atom and it gets smaller along the
hydrocarbon chain, as shown in the scheme below.
Negative charge that is concentrated on the Cl-atom induces progressively

weaker positive charges on the rest of the chain. Such electron delocalization is
achieved through -bonds and is called the inductive effect. Since the chlorine
atom in the series of chlorobutanoic acid anions is located at different distances
from the carboxylic group, its inductive stabilizing influence on the anion is also
different: the strongest is in 2-chlorobutanoic acid with a pKa value of 2.89.
In summary, the carboxylic acid is stronger if after the removal of the proton, it
can form a more stable conjugated base, the carboxylate anion. The anion is stabi-
lized by electron delocalization over the largest possible region of the molecule.
The charge delocalization can occur in two ways: through the -electron system
by the resonance effect or through the -electron network by the inductive effect.
The resonance effect has already been explained in the section on alcohols when we
discussed the acidity of phenol (vide infra).
In the analogy with inorganic acids, the carboxylic acids can be neutralized by
bases. The names of the salts which are formed after neutralization follow the
inorganic nomenclature.
Of special interest are sodium and potassium salts of the long-chained fatty
acids, the compounds known under the traditional name of soaps (see the next
scheme). The chemical behavior of these molecules exhibits a dual nature. The long
hydrocarbon chain is typical of the organic component which is insoluble in water.
Because hydrocarbon chains repel water molecules, they are called hydrophobic.
On the other side the carboxylate group and the metal ion are bound by an ionic
bond and such compounds are readily soluble in water. They attract water molecules
and we call them hydrophilic. The molecules of soaps possess a hydrophilic head
and a hydrophobic tail.
Because of their specific structures, the soap molecules exhibit special behavior
in water solutions, they undergo self-organization. The molecules form complex
structures called micelles, in which the hydrophobic tails are oriented towards the
middle of the particle and the hydrophilic heads are pointed towards the water
solvent.
The medium inside micelles is hydrophobic and behaves as a non-polar organic

solvent. Because of their dual nature, the soaps are used for removing fatty impuri-
ties, which cannot be washed away with water. The micelle absorbs the impurity
into its hydrophobic central part, but the whole particle is hydrophilic and can be
easily washed away by water. Similar behavior is shown by detergents, the com-
pounds that differ from soaps by the nature of their hydrophilic head. The most
popular detergents are salts of organic sulfates or quaternary ammonium salts (see
for example SDS, and CTAB in the following scheme). The hydrophilic head in
SDS is an anion so these micelles are called anionic, while the head in CTAB is
cationic and these are named cationic micelles. Substances whose molecules can
form such micellar structures belong to the large class of compounds, the surfac-
tants, which are substances of great practical and industrial significance.
Chapter 7
Stereochemistry, Symmetry
andMolecular Chirality
Joseph Achille LeBel was one of the most important pupils and collaborators of Louis
Pasteur. Both of them were interested in the salts of tartaric acid (contained in wine),
the tartarates. During the isolation of ammonium-sodium-tartarate, Pasteur and LeBel
observed that two kinds of crystals appear (see figure bellow). Although these crystals
are equal in shape they differ in such a way as to be mirror picture of one another.
h h
T T
h h
M M
b b
P P

104 7 Stereochemistry, Symmetry andMolecular Chirality
This is similar to the spatial relationship between the left and the right hand
which cannot be superimposed by any possible reorientation in space. Since LeBels
crystals reveal the same property they have been called chiral i.e. similar to the hand
(Greek word for hand is ). Almost at the same time, Jean Baptist Biot, the
physicist who also collaborated with Pasteur, discovered polarized light. Today we
know that light is an electromagnetic wave described as a vibration of two perpen-
dicular vectors, electric and magnetic. If both vectors vibrate in fixed planes, the
light is linearly or plane polarized. Natural visible light is a mixture of numerous
linearly polarized waves. Some substances like polymers and certain crystals trans-
mit only one plane of the propagating light. They are called polarizers.
By passing through the polarizer, the nonpolarized light becomes linearly polar-
ized. If the polarized light passes through two polarizers in sequence, the extent of
passage will depend on the relative orientation of the two polarizers. When the polar-
izing planes in both polarizers are parallel the light will pass through both of them,
but if the planes are perpendicular the light cannot pass trough the second polarizer.
7 Stereochemistry, Symmetry andMolecular Chirality 105
LeBel discovered that if the solution of only one of the two types of crystals (for
instance one at the left side of the diagram) is placed between the two polarizers the
polarized light passes through both polarizers. However, for this to occur the polar-
izers are not oriented in parallel, but are rotated with respect to each by a certain
angle. The solution of the crystals at the right hand side of the diagram rotates the
polarized light by the same angle but in the opposite direction. Such rotation of the
plane of polarization is known as optical activity. Since the solutions behave as
left and right in the same way as their crystals are left- and right-handed, the
optical activity must have its origin in the structure of molecules. LeBel concluded
that molecules must also be left- and right-handed, i.e. they must be chiral.
Accordingly, the molecules must have spatial structures which are mirror images
of one another. Taking into account this evidence, LeBel discovered that organic
molecules may be chiral only if the carbon atom is located at the center of tetrahe-
dron. This discovery gave birth to the field of stereochemistry. The same idea about
tetrahedral structure and chirality of organic molecules has also been proposed by
vant Hoff, who developed his theory independently and using a quite different
approach.
Besides the tetrahedral structure, the chirality of a molecule requires one addi-
tional condition: all four substituents bound to the central carbon atom must be
different. A carbon atom with four different substituents induces chirality of the
entire molecule and is called a stereogenic, chiral or asymmetric center. If two or
more substituents are identical the molecule and its mirror image can be superim-
posed and the molecule is not chiral. Some chiral and non-chiral molecules are
represented bellow.
Let us examine why only molecules with four different substituents are chiral?
What is the fundamental geometric property which the molecule, crystal or hand
must possess in order to be chiral? These phenomena can be examined within the
theory of symmetry. Symmetry is the property which ensures that the figure or
geometrical body remains unchanged under particular spatial operation, which is
called a symmetry element. We say that the object is symmetric in relation to these
symmetry elements. Some of the symmetry elements were already described in the
chapter on the symmetry of molecular orbitals. Here, let us introduce additional

symmetry elements:
The scheme above represents three symmetry elements: symmetry plane,

s ymmetry axis and the center of symmetry. We can recognize that the water
molecule, methyl-chloride and formaldehyde all have symmetry planes. The water
molecule and formaldehyde also possess one symmetry axis that leaves the mole-
cule unchanged when rotated by 180. The symmetry axis around which the object
can be rotated by 180 angle and remain unchanged is called a second order
symmetry axis or digyre. The methyl chloride molecule has a symmetry axis with
120 rotation. It is called a third order axis or trigyre. In the bottom row of the
diagram above (E)-but-2-ene has a center of symmetry, but (Z)-but-2-ene does not.
A centre of symmetry is the point (labeled with the symbol i) through which each
atom can be reflected into the equivalent atom with both atoms being at the same
distance from i. In this way the H-atom in (E)-but-2-ene is reflected through i into
another H-atom. The same principle is valid for methyl groups. The chiral mole-
cules have special symmetry properties because they do not have any symmetry
planes as for instance the molecule CHClBrF.Clearly, all molecules in which the
carbon atom is bound with the double bond are not chiral and such carbon is not a
center of chirality. We know that each C-atom of the double bond is coplanar with
three of its neighbors and this plane is at the same time the plane of symmetry.
Formaldehyde is a good example. The four different substituents bound to the chiral
carbon need not be the atoms of four different chemical elements. Chirality is pres-
ent if the substituents are different groups or if they have different constitutions.
Every chiral molecule with one stereogenic center can have two isomers called
enantiomers. Enantiomers are related to each other as the object is to its mirror
image. Since enantiomers are isomers they can be transformed into each other only
by a chemical reaction i.e. by the breaking and forming of chemical bonds.
Transformation of one enantiomer into another can involve breaking of any two
chemical bonds to the stereogenic centre, switching the positions of the correspond-
ing substituents and the forming of two new chemical bonds.
If the molecule has more than one stereogenic center, every center can exist in
two enantiomeric forms. For n stereogenic centers, the number of stereoisomers is
2n. Stereoisomers of molecules with more than one asymmetric carbon (stereogenic
centers) are called diastereomers. In constitutional molecular formulas, the stereo-
genic centers are usually labeled with an asterisks. Some examples of molecules
having diastereomers are shown bellow.
In search of chiral C-atoms, it is convenient first to eliminate carbon atoms which

cannot be chiral centers. These are for instance CH2, or CH3 groups as well as all the
C-atoms connected with double or triple bonds.
As already mentioned, the enantiomers rotate the plane of polarized light by a
particular angle. Usually, the label (+) is used for the enantiomer whose solution
rotates the plane to the right and the label () for the one which rotates it to the left.
The mixture in which both enantiomers are in equal concentrations does not exhibit
optical rotation. Such a solution, known as a racemate, does not show rotation of
plane polarized light. This is because as one enantiomer rotates to the right by a
given angle, the other enantiomer rotates to the left by the same angle so that the
rotations cancel each other out. Optical rotation is a characteristic property of a
particular compound and is called specific rotation, []D25. Its value is calculated
from the measured optical rotation angle , the length of the measuring container l
in dm and the concentration of the sample c in g/100cm3. The index D refers to the
type of light used in the measurement. In the instruments used for measuring optical
rotation, called polarimeters, the source of light is a sodium lamp which emits the
specific light called the D-line. Additionally, the superscript 25 indicates that the
measurement is made at the 25C.
100 [ ]
[ ]D
25
=
cl
After LeBel and vant Hoffs discovery that the tetrahedral structure underpins
the spatial distribution of atoms in organic molecules, the new concept of configu-
ration was introduced. Since the enantiomers differ in their configuration, it was
necessary to develop a system of nomenclature by which their configurations can be
labeled unequivocally. Cahn, Ingold and Prelog have invented the system of abso-
lute configuration, a method similar to the procedure which we have already
discussed in the previous chapters. To determine the absolute configuration of a
molecule it is necessary to follow certain steps which are similar to the determina-
tion of Z and E isomers of alkenes.
1 . Determination of the priorities.
The highest priority pertains to the atom with the highest atomic number. In the
examples given below, chlorine with the highest atomic number has the priority (1)
followed by oxygen (2), carbon (3) and the atom with lowest priority hydrogen (4).
2. Molecular orientation
The molecule must be oriented such a way that the chiral carbon atom is in front
and the substituent with the lowest priority (in our example hydrogen) behind
this carbon. Frontal atoms and groups are labeled in blue in the next scheme.
3 . Determination of the direction of rotation

The molecule is rotated around the axis between the chiral center and the sub-
stituent of the lowest priority (see diagram below). The direction of rotation fol-
lows the order of priorities of the three substituents. If the rotation has clockwise
orientation, the molecule has (R) absolute configuration and if the rotation is
anticlockwise, the molecule will have absolute configuration (S).
4. In most organic molecules the atoms directly bound to the chiral carbon are
identical. In that case, the rule must be extended so that we look at the atomic
number of the next atom along the chain. In the following example we distin-
guish between the C-atoms in groups CH3 and CH3CH2. In the CH3 group, the
C-atom bound to the stereogenic center is also bound to three hydrogen atoms.
In the CH3CH2 group the corresponding atom is bound to atoms H, H,
C.Therefore since in the CH3CH2 group the next atom along the chain is C rather
than H, the CH3CH2 group has higher priority than CH3. Hence, the configura-
tion must be (R).
5. If the substituent has an atom with a double bond, its priority is considered to be
equivalent to two such atoms each bound with the single bond. In the example
bellow, the -CHO group has a higher priority than -CH2OH, because the oxygen
in -CHO carries a double bond and its priority is equivalent to two oxygen atoms
(counted as two C-O single bonds).
Chapter 8
Derivatives ofCarboxylic Acids
If the OH-group is removed from the carboxylic group, the remaining group has
the form RCO- which is called an acyl group. By connecting different atoms or
groups to the acyl group we can obtain various structural derivatives of carboxylic
acids, like anhydrides, esters, acyl halides or amides. The substituent R in the fol-
lowing scheme can be carboxylate RCOO-, alkoxide -OR, halide, for instance -Cl,
and amine -NH2, NHR or NR2.
8.1 Anhydrides
Removing a water molecule from an acid yields an anhydride. Inorganic anhydrides

are oxides, so SO3 is the anhydride of sulfuric acid H2SO4. Upon removing water
from the carboxylic acids, the molecules condense, yielding an anhydride. If the

112 8 Derivatives ofCarboxylic Acids
molecule has only one carboxyl group the condensation involves two molecules, as
in the case with acetic acid, where two molecules form acetanhydride. Acids with
two carboxylic groups, such as maleic acid or phthalic acid, after the removal of
water, form the corresponding cyclic structures.
8.2 E
sters, Nucleophilic Substitution ontheUnsaturated
Carbon Atom
An alcohol is a good nucleophile because it has two electron lone pairs on the oxy-
gen atom. In the reaction with a carboxylic acid, the oxygen atom of alcohol attacks
the carbon atom of the carboxylic acid group. The mechanism is analogous to the
previously discussed nucleophilic additions of aldehydes and ketones. The main
difference between the two mechanisms is that the reaction involving carboxylic
acid also involves removing a molecule of water. The final product is an ester.
The mechanism of this reaction which is called esterification is a nucleophilic

substitution on the unsaturated carbon (the carbon atom is unsaturated because
it is bound with the double bond). In summary, esters are formed by the reaction of
a carboxylic acid and an alcohol with the elimination of a water molecule. However,
removing the water molecule is only possible in an acidic medium, so that in the
preparation of esters a few drops of strong acid must be added (see the scheme
8.2 Esters, Nucleophilic Substitution ontheUnsaturated Carbon Atom 113
below). The basic step in this mechanism is the protonation of the oxygen atom of
the carboxylic group by a strong acid. This protonated form is susceptible to the
nucleophilic attack on the C=O group. The reaction intermediate is transformed into
the ester molecule by the removal of a molecule of water:
The nomenclature of esters is relatively simple, because it is similar to the

nomenclature of salts. For instance, the ester obtained from methanol and ethanoic
acid (acetic acid) is called methyl ethanoate (methyl acetate). Esters are com-
pounds that comprise a large number of structures depending on what the alcohol
and acid components are. Esters with a small molecular mass are volatile sub-
stances, in most cases with a pleasant odor. For instance, butyl acetate is responsible
for the odor of apples. In nature, some esters serve as pheromones for insects, for
example isoamyl acetate which attracts butterflies. Other kinds of esters can be
large molecules as for instance waxes and fats where both the alcohol and the acid
components can be long-chained or complicated structures. These natural esters
will be discussed in the chapter on lipids. In industry, esters are used in the fabrica-
tion of polymeric fibers for textile materials and plastic materials for various uses.
The most common material is polyethylene terephthalate (PET), the ester pre-
pared from terephthalic acid and ethylene glycol.
One of the most typical reactions of esters is the saponification or hydrolysis of

esters by strong bases such as NaOH or KOH.Boiling ester with a water solution
of KOH or NaOH yields the salt of a carboxylic acid and the corresponding
alcohol.
Salts can simply be transformed into a carboxylic acid just by reacting with a
strong acid. Remember the principle that strong acids can yield weak acids from
their salts:
Analogously with aldehydes and ketones, esters can be reduced by strong reduc-
ing agents such as LiAlH4. Weaker reducing reagents such as NaBH4 can reduce
only aldehydes and ketones, but are unreactive towards esters. The reaction with
LiAlH4 must be performed in dry ether. The obtained intermediate cannot be i solated
but is immediately hydrolyzed with diluted acid. The products are two alcohols, the
first from the acid component and the second from the alcohol component of the
ester precursor.
8.3 Acyl Halides 115
8.3 Acyl Halides
Replacing the OH group in a carboxylic acid with a halogen generates acyl halides,
the reactive compounds which are important intermediates in the organic synthesis
of various other compounds, especially amides. The most frequently used acyl
halide is acyl chloride, the compound prepared from carboxylic acid and a special
reagent called thionyl chloride SOCl2. This reagent has an unpleasant odor because
it readily reacts with water, yielding HCl and SO2.
SOCL 2 + H 2O SO 2 + 2HCl
Thionyl chloride reacts with carboxylic acids in the way as shown in the scheme
below. In the first step the reaction yields HCl and the intermediate benzoyl
chlorosulfonate:
Benzoyl chlorosulfonate immediately rearranges into the acyl chloride (benzoyl

chloride in our example) and SO2. This reaction is an interesting example of internal
nucleophilic substitution. The internal nucleophile is the chlorine atom (it is
electron-rich) which attacks the carbonyl carbon. The final products are benzoyl
chloride and SO2.
The nomenclature of acyl halides is simple. Their names are deduced from the
name of the constituent acid with the suffix -yl or -oyl and the name of the halide.
Like thionyl chloride, acyl halides are sensitive to moisture and quickly hydrolyze
into the corresponding carboxylic acid and HCl. This is an example of the nucleo-
philic substitution at the unsaturated carbon with H2O as the nucleophile.
Besides OH or water, other nucleophiles can also be involved in this type of

reaction. If a molecule of alcohol is the nucleophile, the products are ethers. The
reaction is faster if HCl is removed immediately from the reaction mixture. In gen-
eral, hydrogen halides can be removed efficiently from the reaction mixtures by the
addition of an amine which, together with hydrogen halide, forms the correspond-
ing ammonium salt (this has already been discussed in previous chapters). In the
following example the amine used is pyridine.
8.4 Amides
Perhaps the most important synthetic use of acyl halides is in the reactions with ammo-
nia or with amines. The products are important natural compounds called amides.
Depending on the structure of the nucleophiles, i.e. whether they are ammonia, primary
or secondary amines, the products are primary, secondary or tertiary amides.
8.4Amides 117
In amides, the amino group is directly bonded to the carbonyl group. Amide
nomenclature includes the simple suffix -amide. In secondary and tertiary amides,
the substituents that are bound to the nitrogen atom are not labeled by the number,
but by the letter N. The representative examples are N-methylmethanamide or
N,N- dimethylmethanamide in the above scheme. Some amides which are deriva-
tives of formic or of acetic acids also bear traditional names as formamide or
acetamide.
Since amides have two different heteroatoms with lone pairs, the electrons can be
delocalized over both N- and O-atoms. Let us discuss the electron delocalization by
using the method of resonance structures:
Two important conclusions can be drawn from the given resonance structures.
First, the electron lone pair is not localized on the nitrogen atom as in saturated
amines. We recall from the previous chapter that amines are less basic if the nitro-
gen lone pair is not localized on the N-atom. This was illustrated by an example
where we compared the basicities of aniline and pyridine and showed that aniline is
a weaker base because its lone pair electrons are delocalized over the entire benzene
ring. For the same reason, amides are neutral rather than basic.
The second very important conclusion is related to the nature of the covalent
bond between the nitrogen and the carbon atom. This bond has a single bond
character in one of the resonance structures and a double bond character in the
other. Hence, the amide bond has a bond order of 1.5, i.e. it has an intermediate
character between a double and a single bond. In the chapter on alkanes we have
mentioned that while the rotation around a single bond is free, the rotation around
a double bond is forbidden. Because the amides bond has a partial double bond
character the rotation around it is hindered. This evidence is important in the
study of the stereochemistry of complex molecules with amide groups, such as
polyamides and polypeptides.
One of the best known polyamides is nylon, the substance which was first pro-
duced in 1935. Nylon can be obtained from hexamethylenediamine and adipic acid
by a procedure called polycondensation.
Many antibiotics and other pharmaceutical products have molecules with amide
groups. A large group of such compounds are antibiotics derived from penicillin
(see the scheme below). These compounds are stable because the amide bond is
difficult to hydrolyze.
Chapter 9
Electrophilic Substitutions
Reactions of Aromatic Compounds
In the chapter about hydrocarbons we have discussed aromatic compounds, their

stability and specific chemical behavior. The electrons in -orbitals are delocalized
around the benzene ring and although there are formal double bonds, aromatic com-
pounds do not undergo standard addition reactions typical for alkenes. The distribu-
tion of -electrons in the ring is such that the highest electron density is above and
below the plane of the aromatic ring. Such -electron distribution is the reason that
the benzene ring behaves like a Lewis base, which can donate electrons or react with
strong Lewis acids. Protons and other positively charged particles are electrophiles
because they tend to bind to species which are electron rich. Consequently, benzene
and other aromatic molecules can be protonated by strong acids such as H2SO4.
The cation which is formed by protonation is stabilized because of the delocal-
ization of electrons, as shown in the next scheme. For simplicity, these resonance
structures can be replaced with a single formula where the region in which the elec-
trons are delocalized is designated with dotted line and the + sign in the middle.

120 9 Electrophilic Substitutions
In general, the electrophile is labeled with E+ and its addition to the benzene
ring is analogous to protonation (see scheme below). If the cationic reaction
intermediate loses a proton, the electrophile remains attached to the ring. The
final product has the structure in which hydrogen is replaced with the incoming
electrophile and such a reaction is called an electrophilic substitution on the
unsaturated carbon atom.
If we wish to replace one hydrogen atom with some functional group or atom,
this group or atom must be transformed into the cationic, electrophilic form. For
instance, for the halogenation of a benzene ring, the halogen atom must appear
in its electrophilic form called a halonium ion. Since such ions are unstable in
solution so they must be prepared in situ (immediately, without isolation) and in
the form of the complex with a larger molecule. Such reactants, with a positive
halogen, appear in the reaction of halogens with metal halides such as FeCl3,
FeBr3, or AlCl3.
Bromonium or chloronium complexes, which are shown in the examples

above, are good electrophiles and react with benzene by replacing the hydrogen
atom with the halogen.
Alkyl or acyl groups can be bound to benzene in an analogous way. These reac-
tions are called Friedel-Crafts alkylations or acylations, respectively, in honor of
their discoverers Charles Friedel and James M. Crafts. The starting compound in
alkylation is an alkyl halide which, together with the corresponding metal halide,
forms a molecular complex that consists of a carbocation and a tetrahalometallic
anion. For instance, ethyl bromide reacts with FeBr3 forming a complex in which
9.1 Substituent Effects in Electrophilic Aromatic Substitution 121
the ethyl group has a cationic character and behaves as an electrophile. This electrophile
reacts with benzene molecule as shown in the following scheme.
In acylation the starting compound is the corresponding acyl-chloride:
Reaction of nitric acid with sulfuric acid yields the nitronium ion (NO2+), which
as an electrophile reacts with benzene and forms nitrobenzene.
9.1 Substituent Effects in Electrophilic Aromatic

Substitution
The chemistry of substituted benzenes belongs to the field of organic synthesis which
was developed during the nineteenth century for the needs of the dye industry.
Aromatic compounds which have several substituents on the benzene ring have
been of special practical interest. The problem of introducing the second substituent
arises because this additional group can bind at different positions along the ring.
From their long experience in synthesis the chemists have discovered that the
first substituent on benzene plays a crucial role in influencing (directing) the
position of the second substituent group. Some functional groups direct the next
substituent into the ortho or para position while others favor a meta substitution.
The groups which direct into the ortho or para position are called activating
substituents while those which direct into the meta position are called deactivat-
ing groups. In principle, the term activating implies the donation of electrons to
the benzene ring and deactivating has the opposite effect, i.e. the withdrawal of
electrons from the ring.
Experience has shown that substituents with electron lone pairs on the atom
directly bound to benzene are activating and they are also ortho or para-directors,
i.e. they guide the second substituent into ortho/para positions. The deactivating
substituents do not have such atoms, but they can have a double bond or an
electronegative atom. The deactivating substituents are meta-directors, i.e. they
display regioselectivity by directing the second substituent into the meta position.
The alkyl groups are a special case, they are activating in spite of their lack of a
heteroatom with an electron lone pair.
These experimental observations have played a crucial role, not only in the
development of the theory of reaction mechanisms, but also in the final solution of
the problem of the electronic structure of benzene. Historically, the explanation of
the laws of substituent direction appeared at two levels. During the first quarter of the
last century, when the theory of resonance was in the early stages of development,
substituent directing was explained by the charge distribution in the reactant mole-
cule. As we can see in the example of the aniline molecule, the activating NH2
group causes the negative charge to appear only in the ortho or para positions. Since
they are negatively charged, these positions are preferred for an electrophilic attack.
Conversely, a deactivating group such as -NO2 in nitrobenzene induces a positive

charge in the ortho and para positions, so the electrophilic attack will not take place
at these positions. Instead, the electrophile will attack the meta position.
These initial ideas were inadequate to explain the orientation effect of all
groups. The problem appeared with the methyl group in toluene, which is activating,
but for which no resonance structures could be constructed. The proper explana-
tion of the regioselectivity (the preference for certain substituent positions) only
came with the development of the theory of reaction mechanisms by Robinson
and Ingold. As we have seen at the beginning of this chapter, the electrophilic
attack causes the formation of a reaction intermediate, the carbocation. Since
we know that the rate of chemical reaction depends mostly on the stability of
the reaction intermediate, let us discuss the structure of the activated and deacti-
vated cations.
In the following example, the activating substituent is the methoxy group. If the
electrophile attacks the ortho position the corresponding cation can be described by
the resonance structures shown in the following scheme.
The electron-donating property of the methoxy group is most evident in the

last resonance structure, describing the oxonium ion, with a positive charge on
the oxygen. The cation is stabilized by electrons transferred from the oxygen lone
pairs. This is why all groups with electron lone pairs on the atom directly bound
to the benzene ring are activating. Analogous resonance structures can also be
written for aniline.
A methyl group, which does not have electron lone pairs, is activating because it
forms inter alia a stable tertiary carbocation (scheme below).
An electrophilic attack on para position leads to the formation of an inter-

mediate the resonance structure of one of these is also stable tertiary carbocation.
In conclusion, the activating substituents direct the next group into both the
ortho and para positions.
The electrophilic attack on meta position would yield a carbocation that cannot
be stabilized by the activating group, so this position is not favored. This can clearly
be seen from the resonance structures in the next scheme. The carbon on which
the activating group is bound always has a double bond and the delocalization of
electrons from the methoxy group into the ring is not possible. The corresponding
carbocation is not stabilized and activating groups do not support the formation of
meta-products.
The deactivating groups withdraw electrons from the ring and the binding of an
electrophile will yield an intermediate in which the resonance structures can be
written as shown in the scheme below. In the ortho or para position, the electrophile
induces the formation of intermediates in which two positive charges are located
next to each other (labeled with dashed circle in the scheme), which is energetically
unfavorable. However, this situation is avoided if the electrophile is bound in the
meta position. Hence the deactivating group is always a meta-director.
The deactivating effect of the CF3 group is the consequence of a strong electron
withdrawing of electron density from the benzene ring via the inductive effect of
three fluorine atoms.
A typical example of the substituent-director effect (regioselectivity) is the

preparation of the well-known explosive trinitrotoluene (TNT) by nitration of
toluene. A methyl group is activating and directs the nitro substituents into the
ortho and para positions.
Chapter 10
Cycloadditions
In the first chapters of this book we have mentioned polycyclic compounds.

Reactions in which polycyclic compounds are formed have been known for more
than a hundred years, but their mechanisms remained puzzling for a long period of
time. These reactions were even called reactions without a mechanism. The best
known of this type of reactions, is the Diels-Alder addition, named in the honor of
Otto Diels and Kurt Alder in which two alkene molecules are condensed so that
two new -bonds are formed. Good examples are reactions in which the norbornene
skeletons are obtained.
The occurrence of these reactions strongly depends on the electronic struc-

tures of the reactants, especially on the number of -electrons. It has been shown
that the reactions are favored if one of the reactants has four -electrons and the
other has two -electrons (4 + 2 addition). These six electrons are rearranged
in the product into two new bonds (labeled in red in the scheme) and one new
bond.

130 10 Cycloadditions
Other combinations of reactants such as two electrons with two electrons or

four electrons with four electrons do not react under thermal conditions, but read-
ily react if they are irradiated with visible or ultraviolet light. These rules of reactivity
in cycloadditions were discovered by Robert B. Woodward and Roald Hoffmann
on the basis of quantum-mechanical analysis and the symmetry properties of molecu-
lar orbitals. These rules are known as the Woodward-Hoffmann rules.
Chapter 11
Organic Natural Products
The knowledge of basic structural and dynamic concepts of organic chemistry

allows us to examine some aspects of the chemistry of living organisms. The branch
of organic chemistry that deals with compounds isolated from the living organisms
is called chemistry of natural products. Basic knowledge of this field of chemistry
is of fundamental importance for the understanding of biochemistry.
In principle, natural products can be divided in two categories, primary and
secondary metabolites. Primary metabolites are compounds that are necessary for
the functioning of the organism and with minor variations they are common to all
living organisms. This group comprises amino acids, carbohydrates, lipids and
nucleotides. Some organic compounds that are characteristic of a specific biological
genus belong to secondary metabolites. Good examples of secondary metabolites
are alkaloids, some terpenes, flavonoids, etc. These classes of compounds are not
common to all organisms. The literature definition states that the chemistry of
natural products has its main interest in secondary metabolites while the science
interested in primary metabolites is called bioorganic chemistry. Bioorganic
chemistry is closely related to biochemistry, which investigates the chemical
systems in living organisms.
Our discussions about the natural products will begin with the primary metabo-
lites. Since the organic compounds in nature always exist in complex mixtures,
chemists developed special laboratory methods for their purification and isolation.
One of the earliest of such methods is extraction, the technique that is based on the
different solubility of substances. Because similar substances dissolve in similar sol-
vents, most organic substances will be soluble in organic solvents: polar substances
in polar solvents, nonpolar substances in nonpolar solvents. In contrast, ionic com-
pounds are well soluble in water. Amongst primary metabolites, the most water
soluble compounds are amino acids and polar carbohydrates. A large group of struc-
turally diverse natural products soluble in nonpolar solvents are lipids which will be
discussed at the end of this chapter.

132 11 Organic Natural Products
11.1 Amino Acids and Peptides
The physiologically most important components of living beings are proteins, the car-
riers of basic physiological and biochemical functions. Their molecules are extraordi-
narily complex and varied but in spite of this complexity their structures are built from
only 20 relatively simple molecules the amino acids. Before investigating these
biologically important amino acids which are the products of hydrolysis of proteins,
we shall describe the structure and properties of this class of compounds in general.
The molecules of amino acids have two functional groups with different proper-
ties, the basic amino group and the acidic carboxyl group. Because the amino group
can be bound to different carbon atoms on the hydrocarbon chain, the names of these
compounds are derived from the position of this functional group. However, for this
class of compounds, the traditional nomenclature in which the C-atoms are labeled
not by numbers, but by letters of the Greek alphabet is still in use. In addition, the
letter does not correspond to the carbon atom labeled with number 1, but to the
atom with the number 2. In this nomenclature there are , , amino acids, etc.
All 20 amino acids obtained from natural proteins belong to the -amino acids
and can be represented by the general formula H2NCHRCOOH. They differ only in
the substituent R.
Amino acids are amphoteric compounds; the carboxylic groups given them acidic
properties and the amino groups give them a basic character. Their amphoteric behav-
ior is shown in the next scheme.
Amino acids are well soluble in water, because they can appear in the form of a
dipolar ion called, by the German word, Zwitterion. This ion can be considered as
the product of self-protonation: the amino group is protonated by the proton that
comes from the carboxyl group.
11.1 Amino Acids and Peptides 133
When the R group is neutral the pH of the solution of such an amino acid would
be approximately 7, i.e. this amino acid is neutral. However, R groups can be neu-
tral, acidic or basic. For instance, in aspartic acid (see following scheme) the group
R has a carboxylic functional group. Consequently, pH of a water solution of aspar-
tic acid must be lower than 7 and it is actually 2.95. On the other hand, in the amino
acid lysine, the R group contains an amino group and the compound behaves as a
base. In water solution, lysine has a pH equal to 9.8. The pH value of the amino acid
in water solution depends on the functional group R and is called the isoelectric
point, which is labeled with the symbol pI.
In the following schemes all 20 amino acids are given and classified into
neutral, basic and acidic forms together with their pI values. Since in biochemis-
try we handle complex protein molecules consisting of thousands of amino acids,
the writing of exact formulas becomes unpractical, so every amino acid is labeled
by three letters. All three-letter labels are listed in the schemes that follow.
The amino acids valine, leucine, isoleucine, methionine, phenylalanine, trypto-

phane, threonine, lysine, arginine and histidine are called essential, because they
are necessary components of the food of mammals. Namely, mammalian organisms
are not able to synthesize amino acids in this group.
In all the listed amino acids, with the exception of glycine, the -carbon is bound
to four different substituents hence it is a stereogenic center. From this it follows
that every amino acid can appear in the form of two enantiomers. In the following
example, both the enantiomers of alanine are represented together with their abso-
lute configurations. However, enantiomers of amino acids can also be represented
by the traditional notation of chiral molecules that is called the relative configura-
tion. This nomenclature for configuration was proposed Emil Fischer in the nine-
teenth century for the representation of the stereochemistry of carbohydrates.
For the determination of the relative configuration, the molecule is oriented so
that the chiral carbon atom is in the center of the cross, the substituents positioned
at the top and bottom arms of the cross lie bellow the plane of drawing and the
groups at the left and right arm are above the plane of the drawing. Substituents H
and NH2 are always either the left or the right arm and the carboxylic group is on the
top arm of the cross. These representations are called Fischer formulas. If the NH2
group is on the left arm of the cross, the configuration is designated as the
L-configuration. Conversely, if NH2 is on the right arm the molecule has the
D-configuration. Relative and absolute configurations of alanine are presented in
the next scheme. It must be pointed out that absolute and relative configurations do
not correlate: (R) is not always D and (S) is not always L.
It is important to mention that all 20 amino acids obtained from living organ-
isms have the same L relative configuration. Although science does not have the
full explanation for this observation, such stereoselectivity supports the notion that
chemical and later biological evolution started from the same enantiomer.
The laboratory synthesis of amino acids is fundamentally different from the way
these compounds are synthesized in the living organisms (biosynthesis). The tradi-
tional synthesis of amino acids is known as Strecker synthesis (in the honor of
Adolph Strecker). This method is based on the nucleophilic attack on the carbonyl
group; a reaction which we already discussed in this book. In this reaction of alde-
hyde with ammonium chloride and sodium cyanide the product is aminonitrile. By
boiling with strong acid, this aminonitrile is transformed into the corresponding
amino acid.
From the chemical equations above it is clear that the laboratory synthesis is not
a clean reaction, because it yields a mixture of the both enantiomers: L-alanine
and D-alanin i.e. a racemate. The appearance of the racemate can be explained from
the knowledge of the reaction mechanism of nucleophilic addition to the carbonyl
group. In the carbonyl group the carbon atom is bound by a double bond and lies
with all three of its substituents in the same molecular plane. The CN group as a
nucleophile can attack the carbonyl carbon with the same probability from either
side of the molecular plane. Consequently above-the-plane attack yields (R) enan-
tiomer and below-the-plane attack gives the (S) enantiomer.
The biosynthesis of amino acids in living organisms is a more complex process

that involves biocatalysts, enzymes. This biocatalytic process is stereoselective,
meaning that it leads to only one enantiomer as a product, the enantiomer having
L-configuration.
One of the known mechanisms of biosynthesis is shown in the next scheme. The
enzyme aminotransferase transfers the amino group from the precursor amino acid
to the -ketoacid, which is rearranged into the product amino acid. In this process,
the precursor amino acid is transformed into the corresponding -ketoacid. It must
be pointed out that besides transferring the amino group, the enzyme aminotransferase
also preserves the stereochemistry: the L-precursor amino acid leads to the forma-
tion of the L-product aminoacid. This mechanism presented below is for the biosyn-
thesis of L-glutamic acid.
The most important property of amino acids is their ability to form dimers, oligo-
mers and polymers that are called peptides and polypeptides. The mechanism of the
formation of peptides and polypeptides is complex and will not be discussed in this
book. Let us only mention that the peptide bond is formed by connecting the amino
group of one amino acid to the carboxyl group of the other amino acid followed by
the elimination of water.
By convention, the peptides are represented by connecting the short labels of

amino acids in such a way that the first amino acid on the left hand side has a free
amino group and the last amino acid on the right hand side ends with the carboxyl
group. By using this convention, the dipeptide cysteyl-serine was represented in the
scheme above. In reality, the peptide bond is the amide group because there is an
amino group directly bonded to the carbonyl group. Large numbers of amino acids
can be connected into polypeptides that are represented in the same way as
dipeptides. The first and the last amino acid in the polypeptide chain are called
terminal amino acids. Accordingly, the left and the right end of the chain are
named the N-terminus, and C-terminus, respectively.
Longer polypeptide chains can be interconnected by the formation of the disul-

fide bond as shown for the two polypeptides in the scheme below.
In the same way the long polypeptide chain can also form a loop as shown below:
We have argued that the peptide bond is essentially related to the amide func-
tional group. The resonance structures of amides, which we have discussed earlier,
can also be used in the representation of the electronic structure of polypeptide
molecules.
Inspection of these structures makes it clear that the chemical bonds between
carbon and nitrogen have a double bond character. Consequently, the rotation
around these bonds is restricted as is the rotation around the double bonds in alkenes.
This restricted rotation makes polypeptide chains rigid. Because of structural rigid-
ity polypeptide chains appear in two forms: the -helix and the -sheet.
Each complete turn of the helix requires 3.6 amino acids (residues) in the chain
which contains N-C-C-N bonds. The helix is additionally stabilized by hydrogen
bonds between the CO group of residue n and the NH group of residue n + 4 i.e.
between spatially close amino acids (see next diagram).
In -sheets the chains are oriented with respect to each other in such a way
that the N-H groups in the backbone of one strand establish hydrogen bonds
with the C=O groups in the backbone of the adjacent strand. The chains can be
interconnected in two ways: antiparallel or parallel. In the antiparallel arrange-
ment, as represented in the scheme below, the successive strands alternate
directions so that the N-terminus of one strand is adjacent to the C-terminus of
the other strand.
In the parallel structure shown below the N-termini in both strands are oriented
in the same direction as are the C-termini.
11.2 Carbohydrates 143
Since the protein molecules consist of polypeptide chains interconnected by

disulfide bonds, their structure can be represented by simple graphical models in
which the -helices and -sheets are depicted as in the figure below.
As we have seen from the overview of chemistry of polypeptides, three levels

of the structure of proteins can be discerned. The first level is the primary
structure of proteins (polypeptides) which is simply the linear order of amino
acids in the chain starting from the N-terminus up to the C-terminus. Formation of
-helices and -sheets is the secondary structure of proteins and it is responsi-
ble for the shape of the polypeptide molecule. Aggregation of these polypeptides
into the final molecule of the protein is its tertiary structure (as shown in the
figure above). The most common way by which polypeptides are interconnected
into the tertiary structure includes the disulfide bonds between the cysteine
residues (amino acids).
11.2 Carbohydrates
Another class of primary metabolites soluble in water are the carbohydrates. To this
class belong the substances which we know as sugars, but also polymers such as
starch and cellulose, compounds that are ubiquitous components of the living organ-
isms. The first discovery in the chemistry of sugars was the observation that some
of them yield other carbohydrates by hydrolysis. In contrast, there are also sugars
that cannot be further hydrolyzed. They are called monosaccharides. The
molecules of monosaccharides can be joined into the larger molecules called

oligosaccharides or even polysaccharides.
The name carbohydrates comes from their composition which is represented by
the general formula Cm(H2O)n which resembles the combination of carbon and water.
This composition implies that a molecule of monosaccharide consists of a hydrocar-
bon chain with attached hydroxyl groups. More detailed analysis shows that most of
the monosaccharide molecules have hydrocarbon chains which are from five to
seven carbon atoms long. From the study of the chemical behavior of different
monosaccharides it follows that some of them exhibit reactions typical for aldehydes
and others show reactions typical for ketones. The monosaccharides can therefore be
classified into two groups: aldoses and ketoses. In their nomenclature, the names of
carbohydrates are formed from the root based on the number of C-atoms, the funda-
mental functional group (ketone or aldehyde) and the suffix -ose. While the aldehyde
group always contains the first carbon atom of the chain, keto-group in all known
carbohydrates appears at the second carbon atom of the chain. Some monosaccha-
rides named in accordance with these rules are represented in the scheme below.
Carbon atoms not situated at the ends of the molecule always have four different
substituents and thus represent stereogenic centers. Such chiral C-atoms are labeled
with an asterisks in the scheme above. Since every chiral carbon atom can have two
configurations, every monosaccharide can have 2n stereoisomers with n being the
number of stereogenic centers. For instance, aldohexose can have 16 stereoisomers.
This is a good example of a large variety of possible structures for organic com-
pounds. As we recall from the chemistry of amino acids, nature is very selective in
the generation of specific isomers. The most common monosaccharide found in
living organisms is the aldohexose traditionally called D-glucose.
The configurations of all chiral C-atoms in the glucose molecule are shown in the
formulas of the scheme below. Here, the structures A and B represent a glucose
molecule using the wedge-dash notation, C is the Fischer projection formula and D
is the shorthand Fischer formula. The horizontal lines label the positions of -OH
groups. Remember that the substituents written on the left and right side of the verti-
cal line are located above the plane of drawing.
Let us give some more examples of monosaccharides. D-mannose belongs to the

aldohexoses, D-ribose and D-arabinose belong to the aldopentoses and D-fructose
is the most important ketohexose. The label D represents the relative configuration
in accordance with the rules which were discussed in the section on amino acids.
Since the monosaccharide molecule possesses several stereogenic C-atoms the
labels D or L are used only for the chiral carbon that is furthest from the aldehyde
or the ketone group. Where all natural amino acids have the L-configuration, all
natural monosaccharides have the D-configuration. This is another example of
selectivity in nature!
The evidence that in natural products, especially in primary metabolites, some

structural patterns are repeated in different structures, implies that most organisms
have common biosynthetic pathways. At the end of the nineteenth century when the
biosynthetic pathways were not known, Heinrich Kiliani and Hermann Emil
Fischer developed a simple model which could explain how stereochemically pure
long-chained monosaccharides can form from simple molecules. The simplest, par-
ent monosaccharide is aldotriose with only one chiral carbon atom. Hence, there
are D- and L-aldotrioses. Since aldotriose is the product of mild oxidation of glyc-
erol it can also be called glyceraldehyde.
To extend a molecule of aldotriose (glyceraldehyde) by an extra carbon atom,

Kiliani and Fischer applied the already known reaction of nucleophilic addition
to the aldehyde group. They used the cyanide ion CN as the nucleophile. After
the addition of cyanide to the aldehyde group, whose carbon atom is achiral, the
carbon atom becomes chiral in the product because of the four different substitu-
ents attached. This change in stereochemistry is shown in blue in the following
scheme. The products are two diastereomers in which the new stereogenic center
(the C-atom bound to the CN group) can have the D- or the L-configuration.
Since the aldehyde carbon is bound to oxygen by the double bond this carbon
is coplanar with all three substituents. The CN nucleophile can then attack this
carbonyl plane from either side with equal probability which leads to the forma-
tion of two products that differ in their relative configurations, D or L (scheme
below).
If the cyanhydrine products are then first oxidized to acids and subsequently
reduced to aldehydes, the final products are two new monosaccharides, the aldotet-
roses D-erithrose and D-threose:
This Kiliani-Fischer synthesis can be continued starting from these new tetroses
(D-erithrose and D-threose) to prepare four new monosaccharides (aldopentoses),
because every tetrose can yield two new pentose diastereomers. By repeating this
series of reactions it is possible to extend the carbon chain further to get hexoses. If
the synthesis starts with D-glyceraldehyde all the product molecules of the corre-
sponding aldoses will have the D-configuration on the C-atom which is furthest
from the aldehyde group. These monosaccharides belong to the D-series. On the
other hand, aldoses prepared from L-glyceraldehyde will have the last C-atom with
the L-configuration. These monosaccharides belong to the L-series. All living
organisms produce only the D-series of carbohydrates!
11.2.1 Cyclic Structures of Monosaccharides
The representation of monosaccharide molecules as open-chain structures is only

partially correct. In solution, the molecules with five- and six carbon atoms can also
appear in cyclic forms which are in equilibrium with the open-chain structures. The
cyclization process represents the intramolecular nucleophilic attack of the hydroxyl
group on the aldehyde or keto group.
The carbon atom, which in the open-chain form was part of the carbonyl group,
becomes chiral after cyclization and is called the anomeric carbon atom. In the
cyclic form the anomeric carbon can have two configurations which are labeled with
the Greek letters and . Stereoisomers that differ in the configuration at this new
chiral center are called anomers. For example, the cyclic form of D-glucose can
have and anomers named -D-glucopyranose, and -D-glucopyranose. The
word pyranose has been taken from the analogous cyclic ether with the six-mem-
bered ring which is known as pyrane. In the first chapter of this book we have
claimed that the substituted cyclohexane ring is most stable when its substituents
are in equatorial positions. The anomeric carbon atom is an exception; the most
stable anomer has the OH group in the axial position which makes it the -anomer.
This is called the anomeric effect.
Anomers also appear in cyclic form as five-membered rings, for instance in the
monosaccharides fructose and ribose. These cyclic molecules are named furanoses
because of their similarities to the cyclic ether furan. Starting from D-fructose and
D-ribose, the cyclization yields anomers - and -D-fructofuranose, as well as -
and -D-ribofuranose, respectively.
In analogy with pyranoses, the furanoses are also in equilibrium with the open-
chain forms. The new functionality which appears in the cyclic forms is hemiacetal,
the structure already mentioned in our discussions on alcohol addition to the
carbonyl group. The hemiacetals can easily undergo hydrolysis yielding the open
chain monosaccharide molecule.
Representation of the cyclic forms could be simplified by using the special short-
hand notation called the Haworth formula (in the honor of Sir Norman Haworth).
Fischer formulas can be easily transformed into Haworth formulas by the rules
given in the following scheme.
Chiral carbon atoms that do not contribute to the formation of the cyclic form
have substituents attached labeled in blue. In D-glucopyranose these atoms are
numbered as 2, 3 and 4 while in D-fructofuranose these atoms are 3 and 4. The rule
for writing Haworth formulas says that the substituents below the plane of the ring
in Haworth projections are equivalent to those on the right-hand side of the
corresponding Fischer projection (shown in blue).
11.2.2 Disaccharides and Polysaccharides
The hydroxyl group on the anomeric carbon of the monosaccharide molecule can
be replaced by another monosaccharide molecule. The resulting dimer is called a
disaccharide. Binding of -D-glucopyranose to -D-fructofuranose gives the
disaccharide -D-glucopyranosyl--D-fructofuranoside, the disaccharide known

under the name sucrose which is commonly used in food preparation (see the
scheme). Analogously, -D-galactopyranose can bind with -D-glucopyranose into
the disaccharide -D-galactopyranosyl--D-glucopyranoside or lactose, the main
sugar component of milk. The chemical bond by which the monosaccharide units
are joined is called the glycosidic bond. In lactose, carbon atom 1 on one monosac-
charide is bonded to carbon 4 of the another monosaccharide and such bond is
known as the 1,4 glycosidic bond. This is the most frequent mode of binding
between monosaccharide units.
In the same way, glucose molecules can be connected by a glycosidic bond into
long polymeric structures of polysaccharides. The structure of the polysaccharide
formed from glucose depends mostly on the starting anomer. Polymerization of
-D-glucopyranose by the (1,4)-glycosidic bond yields amylose, the polysaccha-
ride which is a component of starch.
Polymerization of another anomer, -D-glucopyranose by the (1,4)-glycosidic

bond forms cellulose.
11.3 Glycosides and Nucleotides
Glycosides are compounds in which the substituent is bound to the anomeric carbon.
This group comprises numerous natural products; the primary metabolites. The most
important are nucleosides, the basic structural units from which nucleotides and nucleic
acids are formed. The monosaccharide component of the nucleoside is D-ribose or its
partially reduced form D-deoxyribose. In biochemistry and molecular biology the most
important are the nucleosides in which ribose is bonded to heterocyclic molecules called
nucleic bases. The most common nucleic bases are pyrimidines and purines.
Pyrimidines are derivatives of the cyclic amine pyrimidine while purines are
derived from the bicyclic amine purine.
The glycoside that consists of adenine and D-ribose (in its cyclic form ribofura-
nose) is adenosine.
11.3 Glycosides and Nucleotides 155
In biochemical systems, adenosine appears as a phosphate in three forms, as

adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine
triphosphate (ATP). These phosphate esters of nucleosides are called nucleotides
and they are the basic building blocks of nucleic acids DNA and RNA, the com-
pounds which are carriers of genetic information.
In an enzyme catalyzed reaction, ATP can be hydrolyzed by losing one phosphate

group PO43, with the release of large amount of energy that has been accumulated
in the P-O bond. This reaction serves as the source of energy for the processes in
living cells.
Nucleic acids are polymers made from nucleotides. In living organisms two
main sorts of nucleic acids are present: ribonucleic acid, RNA and the deoxyribo-
nucleic acid, DNA. The building blocks of nucleic acid molecules comprise five
nucleotides bound either to the ribofuranose (as in RNA) or to the deoxyribofu-
ranose (as in DNA) and to the phosphate group. Nucleotides which are phosphates
of adenine, thymine, guanine and cytosine are the components of DNA. In RNA
the thymine unit is replaced with uracil. Polymeric molecules of nucleic acids can
exist as either single-stranded or double-stranded chains. In the single-stranded
chain the ribose molecules are interconnected via the phosphate groups. The struc-
ture of the nucleic acid chain is represented in the scheme below. RNA and DNA
differ in the substituent Z on C2 carbon atom of the monosaccharide unit. If Z is the
OH group, the fragment of the nucleic acid molecule would represent RNA, but if
Z is the hydrogen atom, the structure would represent DNA. Ribose and deoxyribose
differ in this detail only.
The double-stranded DNA consists of two parallel chains folded into an -helix.
The chains are joined by hydrogen bonds that follow the rules of complementar-
ity. In accordance with these rules, adenine is always bound with thymine of the
other chain and guanine is always bound to cytosine (see the following scheme).
The principles of molecular complementarity do not apply only to nucleic acids.
Rather, they represent general rules for the formation of various supramolecular
structures. If nucleotides are labeled by their first letters, the complementary pairs
would be AT and GC, respectively. The structural key for complementarity is the
number of hydrogen bonds. There are two such bonds in the AT pair and three in
11.3 Glycosides and Nucleotides 157
the GC pair. For example, it is impossible for G to be bound to T: the nucleotides

are selective.
Based on the complementarity principle, two DNA chains bind as shown in the
scheme:
In biochemical processes, the DNA molecule can be separated into two single-
stranded molecules. One of such single-stranded intermediates serves as a matrix on
which the complementary chain can be synthesized. This is the main principle of
DNA replication. The mechanism and numerous details of this process are studied
in biochemistry.
11.4 Lipids
At the beginning of this Chapter we have mentioned that one of the oldest methods for
isolation of organic natural products is extraction. Primary metabolites discussed up
to now were mainly ionic or polar compounds soluble in water or in polar solvents.
Organic natural products that belong to different structural classes but which have in
common the solubility in nonpolar solvents are called lipids. Some of the lipids are
esters of long-chained fatty acids and they can be readily hydrolyzed under acidic or
basic conditions. In this group we encounter waxes, fats and phospholipids.
11.4.1 Waxes
Waxes are structurally the simplest lipids, being esters of long-chained carboxylic
acids and long-chained alcohols. The chains can have 12 or more carbon atoms. The
ester represented in the following scheme is the main component of wax produced by
bees. It can be easily saponified into the corresponding long-chained acid and alcohol.
The reaction of saponification has already been discussed in the chapter on

esters. This reaction is the basic procedure for decomposition of ester lipids.
11.4.2 Fats
Fats are esters of long-chained fatty acids and the alcohol glycerol. Since glycerol
has three hydroxyl groups its complete esterification requires three fatty acid
molecules. The chains in the molecules of fatty acids can be saturated or partially
non-saturated. Some examples are given in the following table.
CH3(CH2)10COOH Lauric acid

CH3(CH2)12COOH Myristic acid
CH3(CH2)14COOH Palmitic acid
CH3(CH2)16COOH Stearic acid
CH3(CH2)7CH=CH(CH2)7COOH Oleic acid
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7COOH Linolenic acid
Fats and oils differ according to the structures of their fatty acid. While fats are
made of saturated acids, oils are esters of unsaturated fatty acids. As we know from
11.4 Lipids 159
the chemistry of hydrocarbons, unsaturated compounds such as alkenes or alkynes

can be saturated by addition of hydrogen in a metal-catalysed reaction. Using the
same method, natural oils can be transformed to fats that are frequently called
synthetic fats. The process of hydrogenation which yields the fat tristearin is repre-
sented in the following scheme.
Because of the presence of double bonds, the digestion of oils is easier than the
digestion of saturated fats. A recent nutritional recommendation is to use oils that
consist of -3 fatty acids. Another name for them is n-3 fatty acids. These com-
pounds have hydrocarbon chains consisting of 1822 carbon atoms in which the
first of several double bonds resides on the third C-atom counting from the alkyl
(not carboxyl!) terminus of the molecule. Linoleic acid is a representative example
of -6 fatty acids. In addition, the molecules of unsaturated fatty acids have a
Z-configuration around the carbon-carbon double bonds!
Saponification of fats with KOH or NaOH yields soaps, the sodium or potassium
salts of fatty acids and glycerol. The behavior of soaps in water solutions and the
formation of micelles have already been discussed.
Let us mention the old tradition known from ethnology for the preparation of
soaps by boiling animal fat with the ash that remains after the burning of beech
wood. This ash contains potassium carbonate and hydroxide which serve as bases
for the saponification. Interestingly, in the Arabic language, the word for ash is kali.
The terms alkali or kalium (for the element potassium) were derived from this root.
The arabic culture and tradition strongly influenced European alchemy and its trans-
formation into modern chemistry.
11.4.3 Phospholipids
The property of the glycerol-based lipids to form micelles even without saponifica-
tion is especially pronounced in phospholipids. The basic structural unit of the
phospholipid molecule is phosphatidic acid shown in the scheme below. The sub-
stituents R and R are long-chained alkane or alkene groups. The phosphate group
can be bound in different structures such as choline or serine, molecules which play
important roles in metabolism.
11.4 Lipids 161
Compounds similar to lecithin are components of cellular membranes because

they can form double-layered structures in which the hydrophobic sides are oriented
towards each other. Being hydrophilic, the choline group is oriented towards the
water solvent.
Such membranes prevent the passage of Na+ and K+ ions, the process important
for the transmission of electrical signals between lining cells. Being hydrophilic,
these ions cannot pass through the hydrophobic layer of the membrane. For ion
transport through membranes, the cells have developed special catalytic systems
which require specific groups of enzymes.
11.4.4 Terpenes and Steroids
In contrast to fats and phospholipids, terpenes and steroids cannot be hydrolyzed to

simpler units. However, Otto Wallach in the nineteenth century and Leopold Ruika
(Croatian Nobel laureate) in the first half of twentieth century discovered that these
compounds can be decomposed into simpler structures that consist of five carbon atoms.
These units are structural analogs of the alkene named isoprene (2-methylbuta-1,3-diene).
Isoprene can be regarded as a molecule containing a head and a tail.
Isoprenic units can be interconnected in different ways: head-to-head, tail-to-tail,

head-to-tail or tail-to-head. Oligomers of such isoprene units are called terpenes. A
molecule with two isoprenes is named monoterpene, a molecule with four units is
diterpene. Three isoprene monomers form sesquiterpenes. One of the most impor-
tant terpenes is squalene, a primary metabolite that is present in all living organ-
isms. In contact with the atmospheric oxygen, squalene is oxidized to squalene-oxide.
In the reaction with the corresponding enzyme, squalene-oxide is folded into the
conformation represented in the scheme below.
In the subsequent reaction step, the epoxide ring is protonated to a carbocation

which activates successive cyclizations of four double bonds to give the tetracyclic
structure of lanosterol.
11.4 Lipids 163
Lanosterol is the precursor for the biosyntheses of primary metabolites that have
a common structural motif of three 6-membered rings and one 5-membered ring.
These compounds are known as steroids. In the chemistry of natural products the
rings are labeled by capital letters A, B, C and D.
Some steroids, such as cholic acid, progesterone and testosterone were already
mentioned in the chapters discussing aldehydes, ketones and carboxylic acids. The
most common steroid in humans is cholesterol. Although the compound has been
discovered in the eighteenth century its complete molecular structure was deter-
mined only in the middle of the last century. Cholesterol appears in most of tissues
and it has a special role in the regulation of blood circulation. An imbalance of
cholesterol in the organism can cause serious health problems similar to arthero-
sclerosis. The cholesterol molecule, like other steroids, is formed by a particular
biosynthetic pathway from the terpene precursors, squalene and lanosterol. Since
cholesterol has 27 carbon atoms, 3 atoms less than the triterpene squalene (which
has 30 C-atoms), 3 C-atoms are eliminated during the biosynthetic process.
Under exposure to sunlight the cholesterol in the skin is oxidized to

7-dehydrocholesterol, which is immediately rearranged to vitamin D3.
H 3C CH3 H3C CH3

CH3 CH3
CH3 CH3
CH3 H CH3
OXIDATION
H H ENZYME H H
H - H2
HO HO
H Cholesterol 7-Dehydrocholesterol
LIGHT
H 3C CH3
CH3
CH3
HO
Vitamin D3
Most hormones are also steroids. Besides the already mentioned sexual hor-
mones testosterone and progesterone, there is also estradiol, the female sexual
hormone, which is responsible for the development of the secondary characteristics
of the female anatomy.
11.4.4.1 Terpenes as Secondary Metabolites
We have already mentioned that secondary metabolites are compounds which are
specific to particular biological species. They are not common to all living organ-
isms. Terpenes, which were discussed in the previous section, are primary metabo-
lites. However, many organisms produce secondary metabolites structurally similar
to terpenes, i.e. their molecules can be decomposed into isoprene units. One of
them is the already mentioned camphor but more examples are given below.
11.5 Alkaloids 165
Formulas of terpenes in the scheme above are presented in two rows. In the
bottom row, if the chemical bonds labeled in red are deleted the residues represent
isoprene units. Based on the number of isoprene fragments, menthol is monoter-
pene, -selinene belongs to sesquiterpenes and cembrene as well as vitamin A are
diterpenes. Menthol is the component of peppermint responsible for its refreshing
odor. The aroma of celery originates from -selinene while cembrene can be iso-
lated from pine trees. The derivative of retinal has already been discussed in the
section about the cis-trans isomerism in the biochemical process of vision.
11.5 Alkaloids
The first secondary metabolites that were isolated from natural sources are the
alkaloids, these were also the compounds which were the first group of natural
products studied systematically by chemists. These compounds were named alka-
loids because all of them have nitrogen in their molecules and it is known that
nitrogen causes alkaline behavior. As is typical for all secondary metabolites, the
molecules of alkaloids can have a wide variety of structures. Many alkaloids induce
marked physiological effects, especially on the nervous systems. Some of them like
nicotine or components of opium are drugs or have analgesic properties.
Adrenaline is produced in the brain as a stress activator and it causes increased
psychophysical activity. Compounds isolated from special sorts of poppy have
frequently been used, in the form of impure substances, as tranquilizers and are
known under the name opium. The name is drawn from the Greek word
which means poppy. The first pure substance isolated from opium is heroin, a com-
pound that has also been synthesized for medicinal use.
In everyday use as pain killier, the acetylsalicylic acid can be isolated from the
willow bark (salix). On the market this compound, which is not an alkaloid, is
known under the name aspirin. Many antibiotics are also alkaloids. One of the
alkaloids, quinine is very efficient drug against malaria.
11.6 Organic and Bioorganic Reactions
Most of the reactions mentioned so far are used in laboratory preparations. The dif-
ference between bioorganic and laboratory synthesis has already been mentioned in
the context of the synthesis and biosynthesis of amino acids. The Strecker synthesis
was compared with reactions catalyzed by the enzyme aminotransferase. The most
important difference between the laboratory synthesis and biosynthesis is that
biosynthesis is strongly stereospecific. In living cells the reaction conditions are
fundamentally different from those in the organic laboratory. In the laboratory, the
reactions are performed under drastic conditions of elevated temperature or pres-
sure, frequently by using strong reagents such as metal catalysts and/or strong acids
and bases. Besides, most of the reactions in the laboratory occur in organic solvents
and within a wide range of acidity. In contrast, the living cell is made mostly from
water and is very sensitive to strong inorganic reagents. In most cells the acidity is
nearly constant with the pH maintained close to the value of 7.5.
11.6 Organic and Bioorganic Reactions 167
For the reactions such as nucleophilic substitutions, eliminations or redox

reactions, living systems do not only use special catalysts such as enzymes, but also
specific biologically compatible reagents, leaving groups and nucleophiles.
As we know, nucleophilic substitution can occur via two possible mechanisms,
SN1 or SN2. While the SN2 mechanism depends on the concentration and on the
nature of the nucleophile, the SN1 mechanism depends only on the nature of the
leaving group. The reaction intermediates in SN1 reactions, the carbocations, are the
molecules that can be effectively stabilized by the enzyme catalysts and the reaction
conditions for SN1 processes can be milder. Consequently, most nucleophilic substi-
tutions in living cells occur via the SN1 mechanism. For the interconversion of func-
tional groups by nucleophilic substitution in the laboratory we use alkyl halides as
a starting materials. Since alkyl halides are hydrophobic, they cannot persist in the
aqueous medium of the living cell and halide as a leaving group is not compatible
with bioorganic systems. Leaving groups in cells must be hydrophilic such as
pyrophosphate esters, which are ionic molecules well soluble in water.
Carboxylic acid derivatives are prepared in the laboratory starting from acyl
chlorides. Since acyl chloride reacts vigorously with water, yielding HCl, using it
would kill the cell. Hence, the leaving group in the biosynthesis of derivates of
carboxylic acids, coenzyme A has a special and more complex structure.
Oxidations and reductions can be performed in the laboratory by using metallates

or metal hydrides. Under very mild conditions, living cells use special redox sys-
tems which involve enzymes and the corresponding active reagents with complex
structures.
The most common reagents are nicotinamide adenine dinucleotide NAD+ and
its phosphate derivative NADP+. In reduced form these molecules are transformed
to NADH and NADPH by accepting hydrogen atom.
NAD+ is efficient in reactions which yield functional groups with double bonds
between a carbon atom and the heteroatom. In this way alcohols can be converted to
ketones. In the laboratory we need strong oxidants such as KMnO4 or K2Cr2O7 to
oxidize alcohols.
For the reduction of alkenes or alkynes to alkanes in laboratory we use metal

catalysts such as Pt or Pd and often high pressures. The heating of alkane precursors
with these metal catalysts reoxidizes alkanes to alkenes. In biosynthesis these reac-
tions proceed with special reagents like flavine adenine dinucleotide FAD or its
reduced form FADH2.
11.6 Organic and Bioorganic Reactions 169
An example of reactions mediated by FAD or FADH2 is given in the scheme:
One of the most important redox processes in living organisms includes the
transfer of oxygen in erythrocytes by the protein hemoglobin. The active function-
ality in hemoglobin is an organometallic group called heme. The organic part of this
complex is the porphyrin aromatic heterocyclic molecule (heterocyclic structures
are cyclic molecules with heteroatoms in the ring).
The oxygen molecule binds to the iron atom situated in the molecular plane of
the porphyrin ring. The opposite side of the plane is occupied by the histidine
amino acid that is part of the polypeptide chain of the protein molecule.
The presence of the protein is of high importance because without it the oxygen
atom close to the iron atom would immediately oxidize Fe2+ in heme to Fe3+ and the
oxygen molecule would then not bind to iron. In addition, the iron ion in the complex
with porphyrin, oxygen and histidine forms an octahedral coordination, a sterically
favored structure.
In this comparison between the reactions in the living organisms and those in the
laboratory, we have discussed only the most common examples. We did not men-
tion the most important property of bioorganic reaction systems, their interconnec-
tivity. Biochemical reactions form organized systems that act more or less
autonomously.
Index
A Alcohols, 18, 31, 65, 7078, 80, 81, 86, 90,

Absolute configuration, 108, 136 9295, 100, 112114, 116, 150,
(R) Absolute configuration, 109 158, 168
(S) Absolute configuration, 109 Aldehyde, 18, 31, 51, 52, 8695, 114, 136,
Absolute methanol, 71, 72 144148, 163
Acetal, 90 Alder, K., 129
Acetaldehyde, 87, 89, 137 Aldohexose, 144, 145
Acetamide, 117 Aldol, 92, 93
Acetanhydride, 112 Aldol condensation, 92, 93
Acetic acid (acidum aceticum), 96, 97, 100, Aldopentose, 145, 148
112, 113, 117 Aldose, 144, 148
Acetone, 31, 87, 88, 95 Aldotriose, 146
Acetylene, 39 Alkaloids, 131, 165166
Acid halides, 111 Alkanes, 117, 30, 39, 46, 117,
Acids, 50, 7275, 77, 82, 9092, 95100, 160, 168
103, 111115, 119, 121, 136, 147, Alkenes, 1, 18, 3031, 3957, 75, 77, 108,
158, 166 119, 129, 140, 159161, 168
Acidum aceticum, 96 Alkoxides, 76, 111
Acidum formicum, 96 Alkylation, 120
Acrolein, 88 Alkyl halides, 47, 6063, 65, 76, 77, 80, 94,
Activation (of benzene ring), 122, 124 96, 120, 167
Activation energy, 6769 Alkynes, 1, 18, 31, 3957, 86, 159, 168
Acylation, 120, 121 Allene, 40
Acyl group, 111, 120 Amides, 19, 111, 115118, 138, 139
Adamantane, 16 Amines, 19, 8083, 94, 111, 116, 117, 154
Addition, 4651, 56, 82, 86, 94, 95, 106, 120, Amino acids, 131145, 166, 170
129, 146, 150, 159 -Amino acids, 132
Adenine, 154157 -Amino acids, 132
Adenosine, 154, 155 -Amino acids, 132
Adenosine diphosphate (ADP), 155 Aminotransferase, 137, 138, 166
Adenozine monophosphate (AMP), 155 Ammonia, 22, 8082, 116
Adenozine triphosphate (ATP), 155 Ammonium cyanate, xi, 2
Adipic acid, 117 AMP. See Adenozine monophosphate (AMP)
ADP. See Adenosine diphosphate (ADP) Amylose, 152, 153
Adrenaline, 165 Anhydride, 111112
Alanine, Ala, 135137 Aniline, 82, 83, 117, 122124
Alcoholates, 71, 73, 76, 90 Anionic micelle, 101

DOI 10.1007/978-3-319-07605-8, Springer International Publishing Switzerland 2014
172 Index
-Anomer, 149 Bonding orbital, 27

-Anomer, 149 Bond length, 3033, 55, 64
Anomer carbon atom, 149 Boyle, R., 71
Anomers, (-anomer, -anomer), 149 Bridgehead carbon atom, 16
Anthracene, 53, 55 Bromonium complex, 120
Antibonding orbital, 2628, 44, 45 1-Bromopropane, 48, 65, 68
Antiparallel structure of polypeptides, 141 Brnsted acids and bases, 74
Arabinose, 145 Brnsted, J., 74
Arginine, Arg, 133, 135 Brutto formula, 4
Arndt, F., 22 Butane
Aromatic compounds, 1, 18, 53, 54, 56, i-butane, 3
119, 121 n-butane, 3
Aromatic effect, 55, 56 Butane amine, 81
Arrhenius, S., 67, 73 Butanol, 66, 113
Asparagine, Asp, 134 But-2-ene, 41, 107
Aspartic acid, Asp, 133, 134 Butlerov, A., xii, 53
Aspirin, 165 Butyl chloride, 66
Asymmetric carbon atom, 9, 107 Butylpropylamine, 81
Atomic orbitals, 2527, 55, vii Butyl radical, 60
ATP. See Adenozine triphosphate (ATP) Butyne, 40
Axial (hydrogen atom), 1, 1315, 25, 35, 37,
61, 68, 81, 109, 120, 149, 156, 168
Azeotrope, 71, 72 C
Azo compounds, 19 CahnIngoldPrelog (CUP) system, 42
Azomethane, 19 Cahn, R.S., 42, 108
Camphor, 88, 164
Carbaldehyde, 87
B Carbocation, 4951, 68, 69, 77, 78, 120, 124,
Base, 7477, 82, 83, 100, 114, 117, 119, 133, 125, 162, 167
154, 160, 166, vii Carbohydrates, 72, 131, 136, 143153
Bayer strain, 15 Carbon acids, 92
Benzaldehyde, 88, 91, 96 Carbonyl group, 85101, 117, 136, 137, 139,
Benzanal, 94, 96 149, 150
Benzene, 18, 5356, 75, 117, 119124, 126 Carboxylate anion, 98, 100
Benzoic acid, 96, 114, 115 Carboxyl group, 95, 97, 99, 111113, 132,
Benzoyl-, 115 133, 136, 138
Benzoyl chlorsulfonate, 115 Carboxylic acids, 18, 95101, 111118, 158,
Benzyl group, 53, 54 163, 167
Benzylidene, group, 94 Catalyst, 46, 52, 53, 166168
Benzyl radical, 60 Catalytic hydrogenation, 46, 48, 51, 53
Benzyltrimethylammonium iodide, 81 Cationic micelles, 101
Bergman, T., xi Cellulose, 143, 153
Berzelius, J.J., xi, 2 Cembrane A pheromone, 57
Bicyclo-, 16 Cetyltrimethylammonium bromide
Bicyclo[2.2.1]heptane, 16 (CTAB), 101
Bicyclo[2.2.2]octane, 16 Chain reaction, 61, 62
Bicyclo[4.3.2]undecane, 16 Chair conformer, 13
Bimolecular reactions, 6668, 77 Chemical reaction, 1, 3, 15, 17, 23, 28, 29, 33,
Bioorganic chemistry, 131 39, 42, 48, 49, 59, 60, 63, 6567, 71,
Biosynthesis, 73, 97, 136, 137, 146, 163, 75, 85, 89, 107, 124
166168 Chemical shift, 36
Biot, J.B., 104 Chemistry of natural compounds, vii, 131, 163
Bolzmann constant, 67 Chemotaxy, 56
Bond energy, 3033, 60, 62 Chiral center, 108, 109
Index 173
Chirality, 104, 105, 107109, 136, 144146, D

149, 151 Dalton, J., 2
Chiral molecules, 103110, 136 D-arabinose, 145
Chloral hydrate, 89 D-configuration, 136, 145, 148
Chloroform, 61 DDT. See Dichlorodiphenyltrichloroethane
Chloromethane, 20 (DDT)
Chloronium complexes, 120 Debye, 64
Cholesterol, 73, 163, 164 Debye, P., 64
Cholic acid, 96, 97, 163 Decaline, 15, 16
Choline, 160, 161 Decane, 3, 6
18-Chown-6, 79 Delocalization, 23, 75, 82, 98
cis, 42, 45 Delocalization of charge, 99, 100
cis-decaline, 15, 16 Delocalized electrons, 23, 54, 55, 75, 82, 83,
cis-trans isomery, 42, 44, 165 92, 99, 100, 117, 119, 125
Citric acid, 96 Deoxyribofuranose, 155
Citronellol, 73 Deoxyribonucleic acid (DNA), 155157
Codeine, 166 Deoxyribose, 156, 157
Coenzyme A, leaving group, 167 Deprotonation, 77
Complementarity, 156, 157 D-erithrose, 147, 148
Composition, 116, 71, 144 Detergents, 101
Concerted reactions, 68, 77 -D-fructofuranose, 149, 151
Condensation, 9294, 112 -D-fructofuranose, 149, 151152
Condensed rings, 15, 53 D-fructose, 145, 149
Configuration, xiii, 116, 22, 42, 43, 45, 51, -D-glucopyranose, 149, 151152
108, 109, 136, 144146, 149 -D-glucopyranose, 149, 152, 153
Configuration of alkenes, 4043 D-glucose, 144, 149
Conformation, 1014, 17, 45, 162 D-glyceraldehyde, 148
Conformation analysis, 12 Diamond, xii, 7, 16
Conformer, 1114 Diastereomers, 107, 146, 148
Conjugated acid, 75, 82, 92, 98, 100 Diazo compounds, 19
Conjugated alkenes, 40, 45, 55 Diazomethane, 19
Conjugated base, 74, 75, 91, 92, 98, 100 Dichlorodiphenyltrichloroethane (DDT), 63
Consecutive reactions, 69 Dichlorodiphenyltrichloroethane deactivation
Constitution, 116, 22, 3940, 53, 78, 87, 107 (DDT) (of benzene ring), 63
Couper, A., xii, 53 DielsAlder addition, 129
Covalent bond, 10, 2123, 46, 51, 63, 117 Diels, O., 129
Crafts, J.M., 120 Diethyl-ether, 77, 78, 93, 114
Crown ethers, 79, 80 Digyre, 106107
CTAB, surfactant, 101 Dimethyl sulfide, 20
C-terminus, 139, 141143 Dimethyl sulfone, 20
Cumulated bonds, 40 Dimethyl sulfoxide, 20
Cumulene, 40, 41 Diols, 71, 88, 89
Curl, R., xiii Dioxane, 78, 79
Cyanohydrin, 91 Dipeptide, 138, 139
Cycloadditions, 129130 Dipolar ion, Zwitterion, 132, 133
Cycloalkanes, 1215 Dipole momentum, 6364, 85
Cyclobutane, 15 Disaccharides, 151153
Cyclohexane, 1215, 53, 149 Dissociation energy, 3233
Cyclooctane, 12 Disulfide bond, 139, 143
Cyclopentane, 12, 14, 15, 51 Diterpenes, 162, 165
Cyclopentylcarbaldehide, 87 D-mannose, 145
Cyclopropane, 12, 15 DNA. See Deoxyribonucleic acid (DNA)
Cysteine, Cys, 134, 138, 143 -D-ribofuranose, 149
Cytosine, 154157 -D-ribofuranose, 149
174 Index
D-ribose, 145, 149, 154 Fats, 72, 96, 97, 100, 101, 113,
D-series (monosaccharides), 148 158161
D-threose, 147, 148 Fatty acids, 96, 97, 100,
Dynamite, 72 158, 159
-3 Fatty acids, 159
Fischer formulas, 136, 145, 150, 151
E Fischer, H.E., 146
Eclipsed conformation, 1012 Flavine adenine dinucleotide (FAD),
Ectocarpene pheromone, 57 168, 169
E isomer, 43, 44, 108 Formaldehyde, 8789, 106, 107
Electron density, distribution, 29, 41 Formamide, 116, 117
Electrophile, 48, 49, 51, 59, 119121, 123125 Formic acid, acidum formicum,
Electrophile substitution, 56, 119127 96, 100
Element of symmetry, 105106 Formol, 89
Elimination (of hydrogen halides), 77 Formyl-, 115
Elimination reaction, 7577 Freon 11, 62
E1 mechanism, elimination, 77, 78 Freon 12, 62
E2 mechanism, elimination, 77 Freon 123, 62
Enantiomers, 107, 108, 136, 137 Freons, 6163
Enzymes, 72, 137, 138, 155, 161, 162, 166168 Friedel, C., 120
Epoxide resins, 79 FriedelCrafts acylation, 120
Epoxides, 78, 162 FriedelCraftsovo alkylation, 120
Equatorial (hydrogen atom), 13, 15 Frontier orbitals, 28
Erithrose, 147, 148 Fructofuranose, 151
Essential amino acids, 135 Fructose, 149
Esterification, 112, 158 Fullerene, xiii
Esters, 18, 111114, 155, 158, 167 Fuller, R.B., xiii
Estradiol, 164 Functional groups, 1, 5, 1720, 3031, 35, 39,
Ethanal, 18, 87, 89 42, 43, 65, 87, 92, 120, 122, 132, 133,
Ethanamide, 19 144, 168
Ethan-1,2-diol, ethyleneglycol, 72 Furane, 78, 149
Ethane, 1, 3, 10, 11, 29 Furanose, 149, 150
Ethanethiol, 80
Ethanoic acid, 18, 96, 98, 100, 113
Ethanol, 18, 33, 36, 37, 70, 72, 114 G
Ethene, 1, 29, 39, 52 Geminal diols, 88
Ethers, 18, 7681, 114, 116, 149 Geminal position, 88
Ethyl acetate, 113, 116 Gerhardt, C.-F., 2
Ethyl alcohol, 72 Global energy minimum, 12
Ethyl amine, 19, 82 Glucopyranose, 153
Ethylammonium ion, 82 Glucose, 72, 144145, 152
Ethylene, 39 Glutamic acid (Glu),
Ethylene glycol, 71, 72, 134, 137, 138
113, 114 Glutamine (Gln), 134
Ethylene oxide, 78 Glyceraldehyde, 146
Ethyl ethanoate, 113, 116 Glycerol, 7173, 158160
Ethyl group, 120121 Glycine (Gly), 135, 136
Excited state, 45 Glycoside, 154157
Eyring, H., 67 Glycoside bond, 152, 156157
Graphite, xii, 4041
Grignard reagents, 93, 94
F Grignard, V., 93
FAD. See Flavine adenine dinucleotide (FAD) Ground state, 28
Faraday, M., 53 Guanine, 154157
Index 175
H Isoprene, 161, 162, 164, 165

Halides, 20, 4751, 6063, 65, 76, 77, 80, Isopropanol, 72, 95
90, 93, 94, 96, 111, 115116,
120, 167
Halohydrins, 90, 91 K
Haworth formulas, 150, 151 Ka, acidity constant, 74, 75, 98
Haworth, Sir Norman, 150 Kauffman, S., xi
HCH. See Hexachlorocyclohexane (HCH) Kb, basicity constant, 82
Heissenberg, W., 24 Kekul, A., xii, 53, 54
Helix, 140 Ketals, 90
-Helix, 140, 156 -Ketoacid, 137
Heme, 169, 170 Keto-enol tautomery, 86
Hemiacetals, 90, 150 Ketohexose, 145
Hemiketals, 90 Ketones, 18, 51, 52, 8695, 112, 114, 144,
Hemoglobin, 169 145, 163, 168
Heptane, 3, 6, 16 Ketopentose, 144
Heroin, 165 Ketose, 144
Heteroatom, 17, 22, 23, 30, 85, 117, 122, KilianiFischer synthesis, 148
168, 169 Kiliani, H., 146
Hexachlorocyclohexane (HCH), 56 Kroto, H., xiii
Hexane, 3, 4, 6
Histidine (His), 133, 135, 170
1
Hnmr spectroscopy, 35 L
Hoffmann, R., 130 Lactose, 152
Hofmann, Alexander von, 81 Lanosterol, 162, 163
Hofmann, August von, 2 Lauric acid, 158
Homologous series, 3 Lavoisier, A., 73
HOMO orbitals, 28, 65 L configuration, 136, 137, 145, 146, 148
Hughes, E.D., 67 Leaving group, 59, 60, 65, 66, 68, 77, 80, 167
Hydrogenation, 46, 48, 51, 53, 159 LeBel, C., 7
Hydrogen bond, 71, 78, 97, 98, 140, Lecithin, 161
141, 156 Leucine (Leu), 135
Hydrolyse, 90, 91, 95, 114, 118, 132, 143, Lewis definition of acids and bases, 82, 119
150, 155, 158, 161 Lewis, G.N., 21
Hydrophilicity, 100, 101, 161, 167 Lewis structure, 21
Hydrophobicity, 100, 101, 161, 167 L-glyceraldehyde, 148
Liebig, Justus von, 95
Linear polarization, 104
I Linolenic acid, 158
Imines, 94 Lipids, 113, 131, 158165
Incoming group, 59, 68 Lithium aluminium hydride, 94
Inductive effect, 99, 100, 126 Local energy minimum, 12
Infrared (IR), 31, 34 Localized electrons, 82, 83, 92
Infrared spectroscopy, 31, 34 Lone electron pair, 22, 23, 28, 48, 65, 74, 79,
Ingold, Sir Christopher, 42, 48, 67 80, 82, 112, 117, 122, 124
Initiation, 6062 Lowry, T.M., 74
Isoamyl acetate, 113 L-series (of monosaccharides), 148
Isoamyl alcohol, 113 LUMO orbitals, 28
Isobutane, 3 Lysine (Lys), 133, 135
Isoelectric point, 133
Isoelectric point (pI), 133
Isoleucine (Ile), 135 M
Isomers, 25, 7, 15, 42, 43, 54, 56, 72, 86, 91, Maleic acid, 112
107, 144 Maleic anhydride, 112
176 Index
Mannose, 145 Nitroso compounds, 19

Markovnikov rule, 48, 50 Nitrosomethane, 19
Markovnikov, Vladimir Vasiljevic, 48 N,N-dimethylformamide, DMF, 117
Menthol, 73, 165 Nobel, A., 72, 161
Mercaptanes, 80 Nomenclature, 56, 12, 16, 17, 3940, 42, 53,
meta-dimethylbenzene, 54 61, 67, 80, 87, 96, 97, 100, 108, 113,
meta position, 122, 123, 125 115, 117, 132, 136, 144
Methanal, 87 Nonane, 3, 6
Methanamide, 117 Nonbonded electron pair, 22, 28, 48, 65, 82
Methanoic acid, 96, 100 Nonbonding orbitals, 28, 65
Methanol, 7173, 113, 114 Nonpolar solvents, 64, 68, 131, 158
Methionine, Met, 135 n-orbitals, 28, 85
Methyl alcohol, 71 Norbornane, 16, 129
Methylamine, 81 N-terminus, 139, 141, 143
Methyl chloride, 20, 61, 106, 107 Nuclear magnetic resonance (nmr), 3437
Methylene (group), 3 Nuclear magnetic resonance spectroscopy,
Methyl ethanoate, 18, 113 3437
Methyl group, 3, 6, 10, 12, 14, 31, 93, 107, Nucleic acids, 154156
124, 127 Nucleophile, 48, 49, 51, 59, 65, 68, 70, 76, 80,
Methyl radical, 60, 61 85, 88, 9095, 112, 115, 116, 146, 167
Micelles, 100101, 159, 160 Nucleophilic additions, 85101, 112, 137, 146
Molecular dynamics, 1012, 17 Nucleophilicity, 65
Molecular mechanics, 12 Nucleophilic order, 65
Molecular orbitals, vii, 2429, 41, 55, 65, Nucleophilic substitutions, 6583, 96,
106, 130 112116, 167
Molecular vibrations, Nucleosides, 154, 155
3033, 67 Nucleotides, 131, 154157
Monomer, 52, 162 Nylon, 117
Monosaccharides, (D-series, L-series),
143152, 154, 155
Monoterpene, 162 O
Morphine, 166 Octane, 3, 6
Morse curve, 32 Oleic acid, 97, 158
Multifidene pheromon, 57 Oligosaccharides, 144
Multiplet, 37 Opium, 165
Myristic acid, 158 Optical activity, 105
Orbitals, 2528, 45, 83
Organic bases, 82
N Orientation (of substituents), 109, 124
NADP+, 168 ortho-dimethylbenzene, 54
NADPH, 168 ortho position, 124
Nanotechnology, xiii Overlapping of orbitals, 2728
Naphthalene, 53, 55 Oxalic acid, 96
Newman formulas, 10, 13, 14 Oxetane, 78, 79
Nicotinamide adenine dinucleotide Oxidation, 47, 5152, 86, 94, 95, 146, 168
(NAD+), 168 Oxidative agens, 95
Nicotine, 165 Oxirane, 78
Nitriles, 19, 90, 96 Oxo-, 87
Nitrobenzene, 121123 Oxonium ion, 7375, 124, 125
Nitro compounds, 19, 165
Nitroglycerin, 72
Nitro group, 19, 127 P
Nitromethane, 19 Palmitic acid, 158
Nitronium ion, 121 para-dimethylbenzene, 54
Index 177
Paraformaldehyde, 89 Porphyrin, 169, 170

Paraldehyde, 89 Prelog, V., 16, 42, 108
Parallel structure of polypeptides, 142 Primary alcohol, 71, 86, 94
para position, 122, 123, 125, 127 Primary amide, 116, 117
Partial charge, 51, 63, 65, 68, 85, Primary amine, 81, 94, 116
93, 99 Primary carbocation, 50, 68
Pasteur, L., 7, 103, 104 Primary carbon atom, 5, 66
Pauling, L., 63 Primary metabolites, 131, 143, 146, 154, 158,
PCB. See Polychlorinated 162164
biphenyls (PCB) Priority (configuration), 43, 109
Penicillin G, 118 Product of reaction, vii, 43, 44, 48, 60, 61, 65,
Pentanal, 88, 91, 93, 95 71, 89
Pentane, 35 Progesterone, 88, 163, 164
Pentanoic acid, 95 Proline, Pro, 135
Pent-2-ene, 40 Propagation, 61, 62, 104
Peptide bond, 138, 139 Propane, 3, 5
Peptides, 132143 Propane-1,2,3-triol, glycerol, 72
Phenanthrene, 53 Propanol, 72, 76, 86, 95, 114
Phenol, 75, 100 Propanone, 18
Phenolate anion, 75 Propan-2-one, 87
Phenylalanine, Phe, 135 Propene, 18, 47, 76
Phenyl group, 53 Propyne, 18
Phenyl radical, 53, 60 Protonation, 49, 50, 74, 75, 82, 83, 88, 90,
Pheromones, 56, 113 113, 119, 120, 132, 162
Phosphatidic acid, 160 Proton donors, 74, 91, 98
Phospholipids, 158, 160161 Purine, 154
Phthalic acid, 112 Purine bases, 154
Phthalic anhydride, 112 PVC. See Polyvinyl chloride (PVC)
Pi, -orbitals, 27, 28, 41, 44, 45 Pyran, 78, 149
Pi, -symmetry, 27 Pyranose, 149, 150
pKa, 74, 75, 98100 Pyridine, 82, 83, 116, 117
pKb, 82 Pyrimidine, 154
Planck constant, 32 Pyrimidine base, 154
Planck, Max, 32 Pyrophosphate leaving group, 167
Plane of symmetry, 106, 107
Polarization (of bond), 51, 65
Polarized light, 104, 105, 108 Q
Polarizer, 104, 105 Quantum mechanics, 7, 8, 24, 29, 65,
Polar molecules, 64, 78 98, 130
Polar solvents, 64, 68, 70, 131, 158 Quantum of light, 28, 60
Polyamide, 117 Quaternary ammonium salt, 81, 101
Polychlorinated biphenyls (PCB), 63 Quaternary carbon atom, 4, 5
Polycyclic hydrocarbons, 1516 Quinine, 165
Polyethylene, 52
Polyethylene glycol terephthalate (PET),
113, 114 R
Polyfunctional compounds, 96 Racemate, 108, 137
Polymerization of alkenes, 5152 Radical, 5962
Polymers, 52, 79, 89, 104, 113, 138, 143, Radical substitutions, 6064
152, 155 Rate determining step, 69
Polypeptides, 117, 138140, 143, 170 Rate of the reaction, 69
Polypropylene, 52 Reactant, 43, 48, 60, 6567, 69, 74, 88, 120,
Polysaccharides, 144, 151153 123, 129, 130
Polyvinyl chloride (PVC), 52 Reaction center, 59, 68
178 Index
Reaction mechanism, 23, 4649, 51, 59, Sodium ethanoate, 100

6470, 123, 124, 137, vii Sodium ethanolate, 77
Reactive intermediate, 49, 50, 68, 78, 86, 113, Sodium ethoxide, 77
120, 124, 167 Sodium hydride, 94
Rearrangements, 48, 86, 115, 129, Sodium methanolate, 71, 72
137, 163 Sodium methoxide, 71
Reduction, 15, 47, 9495, 168 Spin, 34, 35
Relative configuration, 136, 145, 146 Squalene, 162, 163
Replication, 157 Squalene oxide, 162
Resonance effect, 100 Staggered conformation, 10, 11, 13
Resonance hybrid, 22 Starch, 143, 152
Resonance structure, 22, 23, 55, 75, 82, Stearic acid, 97, 158
83, 85, 92, 98, 99, 117, 119, 124, Stereochemical reactions, 51, 146
125, 139 Stereochemistry, 44, 51, 103110, 117,
Retinal, 44, 45, 165 136, 146
Ribofuranose, 154, 155 Stereoisomers, 15, 42, 107, 144, 149
Ribonucleinc acid (RNA), 155, 156 Steric hindrance, 10, 1214
Ribose, 149, 154156 Steroids, 161165
RNA. See Ribonucleinc acid (RNA) STM. See Scanning tunneling
Robinson arrows, 23 microscopy (STM)
Robinson circle, 55 STM microscopy, 8
Robinson, R., 48 Strain energy, 15
Ruika, L., 161 Strecker, A., 136
Strecker synthesis, 136, 166
Structure, vii, xixiii, 15, 79, 12, 1517,
S 2137, 4045, 48, 51, 5356, 6567,
Saccharose, 152 73, 78, 79, 81, 85, 87, 93, 98, 100, 101,
Saponification, 114, 158160 105, 108, 112, 113, 116, 120, 123, 132,
Saturated hydrocarbons, 35, 12, 46 139, 140, 143, 144, 146, 148152, 156,
Scanning tunneling microscopy (STM), 8 158, 160163, 165, 167170
Schiff bases, 94 Structure formula, 2, 3, 5, 8, 17, 22, 63
Schrdinger, E., 24 Substituent, 5, 6, 14, 17, 50, 53, 68, 81, 87, 89,
SDS. See Sodium dodecyl sulfate (SDS) 97, 105, 107, 109111, 117, 121127,
Secondary alcohol, 86, 94 132, 136, 137, 144146, 149, 151, 154,
Secondary amide, 116, 117 155, 160
Secondary amine, 81, 116 Substitution, 5983, 122
Secondary carbocation, 50 Sulfides, 20, 80
Secondary carbon atom, 4, 5, 70 Sulfones, 20
Secondary metabolites, 131, 164165 Sulfoxides, 20
Self-organization of molecules, 100 Supramolecular chemistry, 80
-Selinene, 165 Supramolecular structure, 156
Serine, Ser, 134, 138, 160 Surfactants, 101
Sesquiterpenes, 162, 165 Surfactant, SDS, 101
Shape of molecules, 710, 29 Symmetry axis, 106, 107
-Sheet, 140, 141, 143 Symmetry center, 106, 107
Sigma, -orbitals, 27, 28, 45 Symmetry plane, 106, 107
Sigma, -symmetry, 27
Smalley, R., xiii
SN1 mechanism, 6770, 167 T
SN2 mechanism, 6770, 76, 167 Tautomery, 86
Soaps, 100, 101, 159, 160 Teflon, 52
Sodium acetate, 100 Terminal amino acids, 139
Sodium borohydride, 94 Termination, 61
Sodium dodecyl sulfate (SDS), 101 Terpenes, 131, 161165
Index 179
tert-butanol, 68, 69 U
tert-butyl cation, 68, 69 Unimolecular reactions, 66, 67, 69, 77
tert-butyl chloride, 68 Uracil, 154, 155
Tertiary alcohol, 76 Urea, xi, 2
Tertiary amide, 116, 117
Tertiary amine, 81
Tertiary carbocation, 50, 68, 77, V
124, 125 Valence shell electron pair repulsion (VSEPR),
Tertiary carbon atom, 5, 66, 69, 77 7, 40
Testosterone, 88, 163, 164 Valine, Val, 135
Tetrahydrofuran, 78 vant Hoff, J., 7, 67, 105, 108
Tetrahydropyran, 78 Vibration (angle deformation), 24, 3032,
Theory of symmetry, 105 68, 104
Thiols, 20, 80 Vibration (stretching), 3032
Thionyl chloride, SOCl2, 115, 116 Vitamin A, 165
Thomson, J.J., 21 Vitamin D3, 163, 164
Threonine, Thr, 134, 135 VSEPR. See Valence shell electron pair
Threose, 147, 148 repulsion (VSEPR)
Timin, 155, 156
TNT. See Trinitrotoluene (TNT)
Tollens, B., 95 W
Tollens test, 96 Wallach, O., 161
trans, 42 Waxes, 113, 158
trans-decaline, 15, 16 Werner, A., 7
Transition state, 67, 68, 77 Williamson, A.W., 76, 78
Transition state theory, 67, 69 Whler, F., 2, xi
Transition structure, 67 WoodwardHoffmann pravila, 130
Triethylamine, 82 Woodward, R.B., 130
Trigyre, 107
Trinitrotoluene (TNT), 127
Triols, 71, 72 Z
Triphenylmethane, 54 Zajtsev, A., 76
Tristearin, 159 Zajtsev rule, 76
Triterpenes, 163 Zero point energy, 32, 33
Tryptophan, Trp, 135 Z-isomer, 43, 44, 108
Tyrozine, Tyr, 134 Zwitterion, dipolar ion, 132

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Hrvoj Vanik

Basic Organic Chemistry

ISBN 978-3-319-07604-1 ISBN 978-3-319-07605-8 (eBook)

Library of Congress Control Number: 2014941923

Springer International Publishing Switzerland 2014

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Zagreb, Croatia Hrvoj Vanik

1 Alkanes, Composition, Constitution and Configuration ..................... 1

5 Substitutions on Saturated Carbon Atoms ........................................... 59

In graphite, every carbon is surrounded by three neighboring carbon atoms in

is surrounded by four neighbors, which are configured in tetrahedral geometry.

In principle, the organic molecules may be considered as consisting of a hydrocar-

H. Vanik, Basic Organic Chemistry for the Life Sciences, 1

nineteenth century, Jn Jacob Berzelius calculated formulas for a series of organic

Number of possible constitutional

1.1 On the Nomenclature of Organic Compounds

When discussing chemistry as a discipline we must be aware of three different

1.2 Configurations and Shapes of Molecules

Bearing this shape in mind, it is possible to write the structural formula in an

CH3CH2CH3 CH3CH2CH2CH3 CH3CH2CH2CH2CH3

Although simplified, this geometry model explains molecular shapes satis-

1.3 Molecular Dynamics and Conformations

The consideration of long-chained alkane molecules leads to the question of whether

By investigating the conformations of butane and considering only the rotation

Configuration of cycloalkanes is based on the combinations of tetrahedrons,

In contrast to cyclohexane the cyclopentane molecule is almost planar. While four

1.4.3 Cyclobutane and Cyclopropane

1.5 Polycyclic Hydrocarbons

In chemical nomenclature, the polycyclic hydrocarbons are named regarding the

Let us describe some frequently encountered polycyclic structures. Bicyclo[2.2.1]

H. Vanik, Basic Organic Chemistry for the Life Sciences, 17

3.1 The Covalent Bond

Using this model the methane molecule is represented as:

H. Vanik, Basic Organic Chemistry for the Life Sciences, 21

As shall be demonstrated later in this book, the knowledge of resonance

3.2 Molecular Orbitals

Bonding between carbon atoms could be described analogously, except that

The same reasoning applies to the antibonding combinations. The antibonding

3.3 Distribution of Electron Density,

Description of the electronic structure of molecules by using this molecular orbital

Although a lot of information about molecular properties can be obtained from

3.4 Bond Lengths, Bond Energy, and Molecular Vibrations

Functional group Wave number in cm1 Mode of vibration

Functional group Wave number in cm1 Mode of vibration

In analogy with the energy of electrons, the energy of molecular vibration

Covalent bond Bond length in pm Bond energy in kJ/mol

3.5 Deducing Molecular Structure by Nuclear Magnetic

The frequency or radiation depends on the energy difference between nuclei HA

4.1 Constitution and Nomenclature

H. Vanik, Basic Organic Chemistry for the Life Sciences, 39

4.2 Configuration of Alkenes

Transformation A A* B includes the breaking and re-forming of a chemical

4.3 Electronic Structure and Reactions of Alkenes

The simplest reaction of alkenes, the Z E isomerization, was already mentioned in

However, many cis-trans (Z-E) isomerizations of natural products are known to

Such photoisomerizations are typical of alkenes and can be explained by a shift

A molecule in which electrons, after absorption of a photon, become shifted to

4.4 Addition Reactions of Alkenes, and the Concept

5.1 Radical Substitutions

5.1.1 Alkyl Halides

5.1.2 Bond Polarity andtheDipole Moment

5.2 Reactions ofNucleophilic Substitutions andEliminations

5.2.1 Reaction Mechanisms ofNucleophilic Substitutions

5.2.4 Thiols andSulfides