Halogenation

Learning objectives
After completion of this section, you will be able to:
 Understand the application and importance of halogenation

 Describe what is florination and applications

 Discuss various types of florination

 Describe what is chlorination and its applications

 Understand the thermodynamics of halogenation

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Introduction
 A Halogenation reaction occurs when one or more fluorine,
chlorine, bromine or iodine atoms replace hydrogen atoms in
organic compound.
 The order of reactivity is fluorine > chlorine > bromine > iodine.
 Fluorine is especially aggressive and can react violently with
organic materials.
 It also tends to make the most stable of the organo-halogens and it
is difficult to remove a fluorine atom once added.
 Conversely, iodine is more difficult to add to an organic molecule
but once an iodo-organic forms, the iodine atom is easily removed.
 Thus the electronegativity of the halogen atom is a driving force
for halogenation reactions.

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Introduction
 The reactions also depend on the nature of the substrate molecule
that is being halogenated.
 Halogenations occur by several different processes depending on
the substrate:
◦ saturated hydrocarbons halogenate via a free radical process;
◦ unsaturated organics halogenate via an addition reaction;
◦ aromatics halogenate via electrophilic substitution.

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Why are Halogenation Reactions Important?
 Halogenation reactions are important in both bulk and fine
chemical synthesis and the products and intermediates generated
via halogenation are well represented in pharmaceuticals,
polymers and plastics, refrigerants, fuel additives, fire retardants,
agro-products, etc.
 Halogenated compounds constitute ca. 20% of the repertory of
active pharmaceutical ingredients (APIs), and 30% of current
agrochemicals.
 Halogenated compounds also find applications as dyes, flame
retardants, imaging agents in medical diagnosis, and in materials
science.
 The significance of halogenated compounds is increasing rapidly.
Thus, ca. 80% of newly developed agrochemicals during the first
decade of the 21st century contained one or more halogen atoms.
Halogenation of organic compounds using continuous flow and microreactor technology 5
Why are Halogenation Reactions Important?
 Notably, 7 out of the top-10 best-selling drugs in the US in 2014
were halogenated compound
 Almost 5000 naturally occurring organic halogenated compounds
have been identified so far.
 The beneficial effects of a carbon–halogen bonds within the
structure of organic compounds, such as increased durability,
stability towards biodegradation and oxidation, and higher
biological activity and membrane permeability, are shared by
synthetic APIs and natural compound.

Halogenation of organic compounds using continuous flow and microreactor technology 6

 A notable difference is the relative distribution of the halogen
elements among synthetic and naturally occurring organic
compounds (Fig. 1).

Fig. 1 Distribution of halogens within the structure of naturally occurring

compounds (a) and synthetic APIs and agrochemicals (b).

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  While chlorinated and brominated derivatives predominate in
natural metabolites, with a relatively small number of compounds
containing fluorine and iodine, synthetic APIs and agro-chemicals
with fluorine and chlorine are more abundant.
 Despite the high incidence of chlorine and fluorine atoms in the
final structure of APIs, brominations and iodinations are very often
carried out for the generation of synthetic intermediates.
 Halogenated building blocks have seen increased relevance owing
to the development of cross-coupling chemistry* over the past four
decades
 *A cross-coupling reaction in organic synthesis occurs when two fragments are
joined together with the aid of a metal catalyst. Cross-coupling has been an
essential reaction in catalytic chemistry for the past 30 years starting with the
pioneering work by Heck, Negishi, and Suzuki, who were awarded the Nobel
Prize in Chemistry in 2010 for palladium-catalyzed cross-coupling.
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methods/cross-coupling
 Bioavailability: When a medicine is given orally, only part of the
administered dose appears in the plasma. (Example: if 100 mg of a
medicine are administered orally and 70 mg of this medicine are
absorbed unchanged, the bioavailability is 0.7 or seventy percent).*
 Bioavailability**
 Medicines contain an active substance, also referred to as Active
Pharmaceutical Ingredient (API) and they are used in order to cure,
treat or prevent illness in human beings or in animals. But they can
also be used for other purposes, such as diagnosis of certain
diseases. In all these use cases, the API must be able to enter the
body. But in order to have a therapeutic effect, the API is also
needed in the correct dose at the specific site in the body where it
has to work. This specific site is referred to as the target site. In
addition, the API needs to reach the target within a certain time
and to stay there for a defined period.
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 Bioavailability
 The rate and degree to which the API is available at the target site
is known as bioavailability. This comes closest to defining a “true”
or “ideal” bioavailability for a medicine. It is mirrored in the
definition by a regulatory authority, the United States FDA. They
define bioavailability as "the rate and extent to which the active
drug ingredient or therapeutic moiety is absorbed from a drug
product and becomes available at the site of drug action", whereas
the European EMA simply defines it as “The extent to which an
active ingredient is absorbed from a medicine and becomes
available in the body”. The latter, while less precise, is however
closer to what is measured in reality.
 Lipophilicity refers to the ability of a chemical compound to
dissolve in fats, oils, lipids, and non-polar solvents such as hexane
or toluene.
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Fluorination
 Organo-fluorine compounds have become one of the most
important and common class of substances among
pharmaceuticals and agrochemicals
 Decoration of an organic compound with fluorine atoms typically
results in a significant enhancement of its biological properties.
 Increased bioavailability, lipophilicity, and metabolic stability
otherwise difficult to obtain are typically acquired by the
compounds after the introduction of one or more fluorine groups.
 The growing interest in this area has motivated intense research
efforts for the development of novel catalytic methods and greener
and more selective fluorinating agents.
 Elemental fluorine (F2) and hydrogen fluoride HF are among the
most difficult to handle reagents in organic synthesis.

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Fluorination
 F2 is the most powerful oxidant known, and both HF and F2 are
highly corrosive and toxic compounds.
 Even some N-fluoro derivatives that are generally easier to handle
are highly reactive, hazardous compounds.
 Fluorination reactions, especially those using F2 directly as fluorine
source, are very exothermic and difficult to control.
 Lack of reaction selectivity* is a common drawback.
 Not surprisingly, many research groups have studied the
fluorination of organic materials using microreactor technology.

 * The selectivity of a reaction is the ratio of the desired product

formed (in moles) to the undesired product formed (in moles).

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Fluorination
 Direct Fluorination:
 Direct vapor-phase fluorination using elemental fluorine is
accomplished by using large volumes of an inert gaseous fluorine
and hydrocarbon carrier, such as nitrogen, a mixing system that
rapidly and intimately brings the two reactants into contact, and a
reactor design that effectively removes the heat of reaction.
 Under these conditions, hydrocarbons can be fluorinated to their
corresponding fluorides:
 CH4 4F2 CF4 + 4HF

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Fluorination
 Dilute fluorine reacts with metal carbides such as UC2, ThC2, and
CaC2, producing fluorocarbons and metal fluorides.
 All these direct fluorination reactions are accompanied with high-
energy type of condensation reactions where fluorocarbons of
higher carbon chain length are formed.
 HF as a Fluorinating Agent
 Hydrogen fluoride adds in vapor phase by means of catalysts to
acetylene

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Fluorination
 Hydrogen fluoride may also replace chlorine in aliphatic
chlorofluoro-carbons, liberating hydrogen chloride:

 Hydrogen fluoride in a liquid-phase reaction readily replaces

chlorine in many organic compounds:

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Chlorination
 The importance of chlorinated organic compounds in the field of
agrochemicals and pharmaceuticals is comparable to that for
organofluorines regarding improved pharmacological properties.
 In addition, chlorinated compounds are useful building blocks for
the generation of more complex structures, as well as for the
preparation of plastic materials or dyes.
 One of the most widely utilized procedures for the generation of
organochlorines is the transformation of alcohols into the
corresponding chlorides by substitution of the OH group.
 Chlorinating reagents such as SOCl2 or PCl5 are often used for this
reaction.
 The greenest alternative for these chloro-dehydroxylation reactions
is the use of HCl as reagent.

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Chlorination
 Using directly anhydrous HCl gas, the neat alcohols were converted
into the corresponding chlorides at 120 °C and 10 bar pressure
 Special precautions had to be taken to keep the HCl dosing part of
the system anhydrous, as moisture in the HCl produced significant
damage of metal parts such as the mass flow controller.
 Elemental chlorine (Cl2) is a powerful and atom-economic*
chlorinating agent for organic compounds, as well as one of the
cheapest oxidizing agents available.

 *Atom economy is the conversion efficiency of a chemical process in terms of all

atoms involved and the desired products produced. The simplest definition was
introduced by Barry Trost in 1991 and is equal to the ratio between the mass of
desired product to the total mass of products, expressed as a percentage.
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Chlorination
 Despite the importance of Cl2 as an oxidizing and chlorinating
agent in organic synthesis, its extremely high reactivity limits its use
in many instances, as undesired overreactions and exotherms
typically occur.
 The efficient mixing and enhanced mass transfer achieved under
continuous flow conditions minimize these problems.
 Apart from the problems associated with the high reactivity of Cl2
towards organic compounds, handling and storage of Cl2 gas
cylinders in organic synthesis labs and production facilities is an
important safety issue on his own.
 Use, handling, and transportation regulations for this substance are
strictly regulated.

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Chlorination
 Sites where Cl2 gas is used normally need to be isolated, and the
personnel specifically equipped and trained for the handling of
chlorine.

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Thermodynamics of
Halogenation Reactions

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 Many reactions of halogens with organic compounds are recorded
in the literature, and many of them are utilized in commercial
processes.
 In the consideration of both equilibrium and reaction
rates, reference to the "bond energies" of the chemical bonds
involved is
frequently helpful; some pertinent bond energies are given in Table
1

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 The heat of a reaction is given approximately by the sum of the
energies of the bonds formed minus the sum of the energies of the
bonds broken. The ∆H of reaction is the negative of this.
 Thermodynamics of Halogenation Reactions
 Substitution Halogenation
 A survey of the thermodynamics of substitution halogenation
reactions shows that All ∆H (change in heat content) is extremely
exothermic in the case of fluorine, highly exothermic for chlorine,
moderately exothermic for bromine, and endothermic for iodine
and that ∆S is very small in all cases.
 The equilibrium is in favor of the right-hand side of the reaction at
all temperatures for fluorine, chlorine, and bromine but in favor of
the left-hand side at all temperatures for iodine.

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 Thermodynamics of Halogenation Reactions
 Substitution Halogenation
 These deductions are illustrated by data on the following reactions
at 25°C, in which all reactants and products are in the gaseous state
at 1 atm.

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 The ∆H of chlorination of aliphatic compounds tends to increase
,with the chain length and the possibility of substitution in other
than the primary position.
 Addition Halogenation
 A survey of the thermodynamics of the addition of halogens to
double bonds shows that ∆H is highly exothermic for all the
halogens and ∆So is of the order of -20 cal per mole deg, since
there is a change of negative one in the number of molecules. ∆Fo
is therefore negative, and equilibrium is in favor of the right-hand
side of the reaction at all temperatures up to about 1000°C for Cl,
up to about 700°C for Br, and up to about 50°C for I.
 These conclusions are illustrated by the accompanying reactions, in
which the data are for the same conditions as given above.

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