Download Lesson 3 Mechanisms of Organic Reactions

Lesson 3
Mechanisms of Organic Reactions
This lesson is concerned with fundamental types of organic reactions, classification of reactants,
and general description of the reactions.
1. TYPES OF ORGANIC REACTIONS
While studying organic chemical reactions two aspects should be taken into account: what types
of reactions exist and how a reaction proceeds. First it is more reasonable to look at the types of
reactions.
Organic reactions can be grouped into several types according to the overall result. They are:
• addition reactions (A);
• substitution reactions (S);
• elimination reactions (E);
• isomerization reactions (or rearrangements);
• oxidation and reduction reactions;
• acid-base interactions.
1.1. Addition reactions (A) are those in which two substances react to form a single compound.
In this case no atom is removed from both reactants. It can be generalized as follows:
An example of this reaction is the addition of a halogen to an alkene:
1.2. Substitution reactions (S) occur when a group of atoms of one reactant replaces a group of
atoms of another reactant. In other words, two reactants exchange their parts to give two new
products:
These reactions are among the most common and most useful ones in organic chemistry. An
example of such a reaction is demonstrated by the action of an aqueous alkali on a haloalkane to
give an alcohol:
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1.3. Elimination reactions are the reverse of addition reactions. The parts of a molecule are
removed from adjacent atoms of the reactant to give two products:
One product is an unsaturated compound and the other is usually a small inorganic molecule
such as hydrogen, water, ammonia, and so on. The reaction is exemplified in dehydration
(elimination of a water molecule) from an alcohol under appropriate conditions:
1.4. Isomerization reactions (or rearrangements) consist in reorganization of chemical bonds
and atoms in a reacting molecule on retention of the molecular formula, i. e. in formation of an
isomeric product.
This process often accompanies reactions of other types, but rearrangements in «pure form» are
known as well, for example, on heating of aromatic allyl ethers:
1.5. Oxidation and reduction reactions are defined in organic chemistry in a different manner
as compared with definitions in inorganic chemistry.
Oxidation of an organic molecule usually corresponds to increasing its oxygen content or
decreasing its hydrogen content.
Reduction of the organic molecule is classified as decreasing the oxygen content of the molecule
or increasing its hydrogen content. The symbols [O] and [H] are often used to indicate oxidation
and reduction processes, respectively.
Oxidation-reduction reactions can be represented as follows:
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2. REACTION MECHANISMS
A reaction mechanism is a step-by-step description of all changes in reacting compounds that
occur at the molecular level, as the reactants become products.
The mechanism describes which bonds are broken and which bonds are formed and in what
order. It takes into account energy changes on the pathway from the reactants to the products
including relative stability of intermediates formed in the reaction. The complete mechanism
must also account for the relative rates of the steps and stereochemical result of the reaction.
2.1. Radical and Polar Processes
All reactions of organic compounds involve the breaking and making of covalent bonds.
Generally speaking, there are two ways in which a covalent bond can break in a hypothetical
molecule A:B. In the first one, the bond breaks in an electronically symmetrical way so that one
electron is retained with each fragment:
Such bond splitting leads to the neutral species A• and B• that have an unpaired electron in one of
its orbitals and are called free radicals, or often simply radicals.
This type of bond breaking is known as homolysis (from the Greek homo - the same, and lysis cleavage), or homolytic process.
Another type of bond breaking called heterolysis or heterolytic process results in formation of
charged fragments or ions (for example, a cation A+ and an anion B-) as it is shown below. This
is a consequence of electronically unsymmetrical splitting in which both bonding electrons
remain with one fragment, leaving the other fragment with an empty orbital:
Similarly, there are two ways in which a covalent bond can form: a homogenic way when each
reactant donates only one electron to the new bond, or a heterogenic way when both bonding
electrons are donated to the new bond by one reactant.
With the foregoing considerations, the overwhelming majority of organic chemical
transformations may be classified as radical reactions and polar reactions.
Radical reactions. A free radical X• can take away a part from a molecule A-B, for example, a
species A• yielding a product A-X and leaving behind a new radical B•. The net result of the
reaction is radical substitution (SR):
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These reactions are typical for nonpolar organic compounds, e. g. alkanes, subjected to reagents
that bear free radicals under appropriate conditions. Chlorination of methane demonstrates this:
Polar reactions. These reactions occur as a result of attractive forces between positive and
negative charges (full or partial) on both reactants. Despite the fact that most organic substrates
are electrically neutral, certain bonds within a molecule are polar. It will be recalled that bond
polarity is a consequence of the difference in atom's electronegativity.
The term substrate originates from biochemical terminology and means a compound that is
exposed to a reagent (the latter is an enzyme in biochemical reactions).
Polar reagents of different types can react with organic substrates. Examples of substitution
reactions are represented below where both substrates A-B and polar reagents XY differ from
each other in reactions (1) and (2):
Polar reactions are of very common occurrence in organic chemistry.
2.2. Types of Reagents
We saw in the preceding section that two types of reagents take part in a polar reaction, namely
the electron-poor reagent X+ in reaction (1) or the electron-rich reagent Y- in reaction (2).
The former has an electron-poor site and seeks electrons in the substrate. The latter has an
electron-rich site and can form a bond by donating a pair of electrons to an electron-poor site in
the substrate.
Polar reagents are classified on this basis as either electrophiles or nucleophiles (literally,
electron-loving or nucleus-loving, respectively).
An electrophile is an electron-poor reagent; a nucleophile, by contrast, is an electron-rich
reagent.
These two types of reagents are illustrated in the addition reaction of ethylene and in the
substitution reaction of ethyl bromide (detailed mechanisms of these reactions will be considered
in further chapters).
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Electrophiles are often positively charged. Typical electrophiles are a proton, halonium ions (Cl+
and Br+), carbocations, or neutral molecules such as sulfur trioxide, SO3, or compounds of the
general formula R-X, where X is an electron-withdrawing group.
Nucleophiles are often, though not always, negatively charged. The most widely known
nucleophiles are a hydroxide ion, alkoxide ions (RO-), thiolate ions (RS-), halide ions, a hydride
ion (H-), carbanions (particles with negatively charged carbon), and many neutral compounds
such as water, alcohols, thiols, ammonia, and amines.
Free radicals. These neutral species contain an atom with an unpaired electron in its outer shell;
they are usually highly reactive for this reason. Halogen radicals such as Cl• and Br• are of great
importance in organic chemistry, particularly in some industrial processes. They can be produced
from halogens on heating or by ultra-violet radiation. The process represents homolytic cleavage
of relatively weak bond in halogen molecules:
A compound that possesses unpaired electrons in an outer shell is ordinary molecular oxygen.
The O2 molecule can be described as a biradical
in a ground state. As it is well known,
oxygen is responsible for many oxidation reactions both in vitro, including industrial processes,
and in living systems.
Thus, taking into consideration a type of reaction and the nature of reagents we can classify
addition reactions as electrophilic AE, nucleophilic AN, and radical AR ones.
Substitution reactions can be classified in a similar way as electrophilic SE, nucleophilic SN,
and radical SR ones.
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Problem 1. Classify the following reactions according to the types:
Problem 2. Classify the following reactions according to the types:
Problem 3. Which of the following species would you expect to belong to electrophiles and
which to nucleophiles, if any:
(a) methane; (b) carbon dioxide; (c) water; (d) a phenoxide ion, C6H5O-; (e) a hydronium ion,
H3O+?
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ACIDITY AND BASICITY OF ORGANIC COMPOUNDS
Acidity and basicity are the main notions determining many fundamental physico-chemical and
biochemical properties of organic compounds. First of all, acid and basic catalyses are the most
widespread enzymic reactions. Besides, the acid-base behaviour of organic compounds helps
explain much of their chemistry.
1. GENERAL CONCEPTS OF ACIDS AND BASES
At present, there are two main concepts of acids and bases in organic chemistry. In the first one,
independently proposed by the Danish physico-chemist J.N. Branstedt and the English chemist
T.M. Lowry (in the 1920's), it is stated that:
An acid is a neutral molecule or an ion that can donate a proton, and a base is a neutral
molecule or an ion that can accept a proton.
For example, when gaseous hydrogen chloride dissolves in water, the latter accepts a proton
from hydrogen chloride:
Here hydrogen chloride acts as a proton donor (an acid), and water acts as a proton acceptor (a
base). The products of this reaction are the hydronium ion, H3O+ (the conjugate acid of water),
and the chloride ion, Cl- (the conjugate base of hydrogen chloride). Note that the term conjugate
is used in another sense different from that in Chapter 3.
In a general sense, acid-base reaction can be expressed in the following way:
Other examples of acid-base interaction are presented below:
In the above examples water acts either as an acid or as a base, as well as it represents either a
conjugate acid or conjugate base.
Another definition of acids and bases was proposed by G.N. Lewis (1926).
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A Lewis acid is any substance that can accept an electron pair, and a Lewis base is any
substance that can donate an electron pair in forming a covalent bond.
According to this definition, a Lewis acid must have a vacant orbital for bonding. The simplest
Lewis acid is a proton because it can accept an electron pair from a Lewis base to fill its 1 s
shell, for example:
Not only proton donors belong to Lewis acids but also many other species with an atom whose
valence shell is unfilled, such as various metal cations or compounds of Group 3A elements
(BF3, AlCl3). Thus, boron trifluoride (a gaseous Lewis acid) reacts with diethyl ether (a liquid
Lewis base, boiling point 36 °C) to form a stable addition product:
The Lewis definition of acids is much broader than the Bronstedt definition, whereas bases are
defined very similar in both theories. The Lewis conception finds a use for a big variety of
organic reactions. The only, but substantial, disadvantage of the Lewis theory consists in the
absence of quantitative acidity and basicity scales. The Bronstedt concept is therefore more
widely used in organic chemistry.
2. ACIDS
Acids differ greatly in their proton-donating properties. Stronger acids, such as sulfuric, nitric,
hydrochloric and similar acids, react almost completely with water, whereas weaker acids, such
as acetic acid (and most of organic acids), react only slightly.
The Bronstedt definition of acidity is extremely useful in organic and bioorganic chemistry
because almost all organic compounds contain hydrogen and are therefore potential acids.
Usually, organic acids are classified into:
• OH acids (carboxylic acids, alcohols, and phenols);
• SH acids (thiols);
• NH acids (amines, amides, some heterocycles, and ammonium salts);
• CH acids (hydrocarbons and their derivatives).
A part of a molecule that involves hydrogen together with an atom attached to it is called an
acidic site.
The difference in acidity of thiols and alcohols is displayed in the reactions with alkali. Thiols do
react to give salts, whereas alcohols practically do not react:
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Alkoxides (alcohol salts) can be obtained only in the reaction of alcohols with active metals or
with extremely strong bases, such as sodium hydride, NaH, or sodium amide, NaNH2. For
example:
Metal salts of alcohols are themselves strong bases used frequently as reagents in organic
chemistry.
As we have seen, there are three types of OH acids, namely carboxylic acids, alcohols, and
phenols. As follows from their general name, carboxylic acids are acidic compounds. They
therefore react with bases such as metal hydroxides to give metal carboxylate salts:
Unlike alcohols, phenols react with alkalis to give water-soluble salts, phenoxides:
The carboxylate ion is also an oxygen anion, but the negative charge is delocalized over both
oxygen atoms through conjugation (Fig. 1, a). This results in stabilization of the anion. In
resonance terms, the carboxylate ion is a stabilized resonance hybrid of two equivalent structures
(Fig. 1, b) neither of which contains a localized charge (Fig. 1, c).
Figure 1. Representation of charge delocalization in the carboxylate ion: ρ,π conjugation (a),
resonance hybrid (b), and equal charges on both oxygens (c).
3. BASES
According to the Bronstedt-Lowry definition given earlier, any anion or neutral compound,
containing a heteroatom with a lone-pair of electrons, can act as a base. This is the main group of
bases called n-bases (having nonshared electrons). They are further classified into the following
types, depending on the nature of heteroatom, which represents the basic sife:
• N-bases (amines and many heterocycles);
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• O-bases (alcohols, phenols, ethers, and compounds with the >C=O group);
• S-bases (thiols and sulfides).
Organic N-bases react with acids to yield stable ammonium salts, which, usually, are soluble in
water. Many drugs are used as salts because of their better solubility.
Bases differ too much in their proton-accepting ability. The strength of bases depends on
electronegativity and polarizability of the atom, which represents the basic site. Within one row
of the Periodic table, an atom with higher electronegativity is less capable of proton acceptance;
therefore amines are more basic than alcohols (just as ammonia is a stronger base than water).
When we compare basicity of alcohols (as O-bases) and thiols (as S-bases), the difference in
polarizability of oxygen and sulfur should be taken into consideration. The size of the sulfur
atom is larger than that of the oxygen atom; therefore electron density is less on sulfur. For this
reason thiols, as well as organic sulfides, are not able to form a strong bond with a proton, i.e.
they are weaker bases than alcohols. Thus we can say, that the strength of bases with the same or
similar R substituents increases in the following way1:
4. ACIDIC AND BASIC SITES IN A MOLECULE
Many organic compounds are amphoteric. That is, they are capable of functioning either as an
acid or as a base, depending on the circumstances.
Typical examples of these compounds are natural (or protein) amino acids. Their structure is
usually written as RCH(NH2)COOH with two independent functional groups. The presence of an
acidic (COOH) and a basic (NH2) sites in the same molecule results in an acid-base interaction to
produce a salt-like compound.
Therefore, the real structure of amino acids in neutral solution and in crystalline state is a dipolar
ion structure, sometimes called zwitterion (from the German Zwitter- hybrid).
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The amino acids can be protonated in acidic solution, thus converting into a cationic
(ammonium) form. In alkaline medium they exist as carboxylate ions with a free amino group:
Molecules containing a weak acidic and weak basic site in their structure can form an
intramolecular or intermolecular hydrogen bond. Water is the simplest and most known
amphoteric compound that forms intermolecular hydrogen bonds (shown usually by a dotted
line).
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