“ AMITY INSTITUTE OF PHARMACY, AMITY
UNIVERSITY, NOIDA “
UTTAR PRADESH
ROLE OF HALOGENATION ON COMMERCIAL SCALE IN
PROCESS CHEMISTRY
In partial fulfillment of the requirement for the degree of
M.PARM (PHARMACEUTICAL CHEMISTRY)
Submitted to Submitted by
DR. RAMANPREET WALIA Harshit rathi
Faculty Guide A10655019007
(2019-2021)
ABSTRACT
“halogenation is the reaction of a halogen with an alkane in which the introduction of halogen
atoms occurs into the organic molecule by an addition reaction or by a substitution reaction. In
organic synthesis this may involve the addition of molecular halogens: chlorine, bromine, iodine,
or fluorine (Cl2, Br2, I2, or F2) or hydrohalogenation using: hydrogen chloride, hydrogen bromide,
hydrogen iodide, or hydrogen fluoride (HCl, HBr, HI, or HF) to carbon-carbon double bonds.
The halogenation reactions of organic substrates requires of halogens like chlorine, bromine, or
iodine. transportation and storage of fluorine, chlorine, bromine, and iodine4. Halogenation
reactions can be divided according to the type of halogen: fluorination, chlorination,
bromination, and iodination. Halogens can be very important for active agents as vital parts of
their binding mode,on the one hand, but are on the other hand instrumental in the synthesis of
most active agent”
Introduction
“Halogenation is a chemical reaction in which a compound usually react with a halogen or
chemical reaction where a halogen atom combined with the organic molecule. More specifically
it is defined as chlorination, bromination, iodination and fluorination. It is an organic reaction
investigated and discussed thoroughly in a wealth of halogenation chemical literature1. The
product formed during halogenation process are employed in various ways, such as polymer
intermediates, refrigerants, insecticides, fumigants, sterilants, additives for gasoline, and
materials used in fire extinguishers.”
In “chemical defense role various halogenated compounds plays a very important role to keep
predators away from a particular organism. Other areas of application of halogenated compound
is in pharmacological interest due to their wide range biological activities, these include
antifungal, antibacterial, antineoplastic, antiviral, anti-inflammatory, and additional biological
activities also. The structural features and types of functional grouppresent in an organic
substrate as well as the typeof halogen used, all these determine the pathway and stoichiometry
of halogenation reactions for example Alkenes readily react with halogens if reaction carried out
under standard laboratory condition “.
Example chlorination of methane
Mechanism of action
Alkanes “(the most basic of all organic compounds) undergo very few reactions. One of these
reactions is halogenation, or the substitution of a single hydrogen on the alkane for a single
halogen to form a haloalkane. This reaction is very important in organic chemistry because it
opens a gateway to further chemical reactions.”
Introduction
While there are few feasible reactions with alkanes, there are several reactions including
haloalkanes. To further explain the system (a thorough look at the step-by-step phase by which a
reaction occurs), we would be looking closely at methane chlorination. If methane (CH4) and
chlorine (Cl2) combine together at room temperature in the absence of light little occurs. If the
circumstances change, therefore, such that either the reaction takes place at high temperatures
(referred to as somewhere) or ultra-violet irradiation happens, a compound is produced,
chloromethane (CH3Cl).
Energetics
“Why does this reaction occur? Is the reaction favorable? A way to answer these questions is to
look at the change in enthalpy me(ΔHΔH) that occurs when the reaction takes place.”
ΔH = “(Energy put into reaction) – (Energy given off from reactionIf more energy is put into a
reaction than is given off, the ΔH is positive, the reaction is endothermic and not” energetically
“favorable. If more energy is given off in the reaction than was put in, the ΔH is negative, the
reaction is said to be exothermic and is considered favorable. The figure below illustrates the
difference between endothermic and exothermic reactions.”
ΔH can also be calculated using bond dissociation energies (ΔH°):
ΔH=∑ΔH∘ of bonds broken−∑ΔH∘ of bonds formed(15.4.1)
(15.4.1)ΔH=∑ΔH° of bonds broken−∑ΔH° of bonds formed
“Let’s look at our specific example of the chlorination of methane to determine if it is
endothermic or exothermic:”
Since, “the ΔH for the chlorination of methane is negative, the reaction is exothermic.
Energetically this reaction is favorable. In order to better understand this reaction we need to
look at the mechanism ( a detailed step by step look at the reaction showing how it occurs) by
which the reaction occurs.”
Radical Chain Mechanism
The “reaction proceeds through the radical chain mechanism. The radical chain mechanism is
characterized by three steps: initiation, propagation and termination. Initiation requires an
input of energy but after that the reaction is self-sustaining. The first propagation step uses up
one of the products from initiation, and the second propagation step makes another one, thus the
cycle can continue until indefinitely.”
Step 1: Initiation
Initiation breaks “the bond between the chlorine molecule (Cl2). For this step to occur energy
must be put in, this step is not energetically favorable. After this step, the reaction can occur
continuously (as long as reactants provide) without input of more energy. It is important to note
that this part of the mechanism cannot occur without some external energy” input, “through light
or heat.”
Step 2: Propagation
The "next two steps are considered propagation stages in the process. During the first step of
propagation a radical chlorine interacts on the methane with a hydrogen. This gives both
hydrochloric acid (HCl, the reaction's inorganic product) and methyl radical. During the second
propagation stage further use is made of the chlorine starting content (Cl2), Some of the chlorine
atoms is radical while the other interacts with the methyl radical ”
The “first phase of propagation is endothermal, meaning it takes in heat (requires 2 kcal / mol)
and is not energy-friendly. The second propagation stage at con11qtrast is exothermic, releasing
27 kcal / mol. Since the second propagation stage is so exothermic it happens really quickly.
The second stage of propagation requires a product from the first stage of propagation (the
methyl radical) and according to the theory of Le Chatelier, as the product of the first step is
eliminated, the balance is changed against the goods. This theory is what regulates the incidence
of the unfavorable first propagation phase”
Step 3: Termination
“In the termination steps, all the remaining radicals combine (in all possible manners) to form
more product (CH3Cl), more reactant (Cl2) and even combinations of the two methyl radicals to
form a side product of ethane (CH3CH3).”
Problems with the Chlorination of Methane
The “chlorination of methane does not necessarily stop after one chlorination. It may actually be
very hard to get a monosubstituted chloromethane. Instead di-, tri- and even tetra-
chloromethanes are formed. One way to avoid this problem is to use a much higher concentration
of methane in comparison to chloride. This reduces the chance of a chlorine radical running into
a chloromethane and starting the mechanism over again to form a dichloromethane. Through this
method of controlling product ratios one is able to have a relative amount of control over the
product”
Halogenation reactions
Chlorination
Chlorination “of arenes is a prominent organic reaction with wide laboratory use and industrial
applications. The introduction of chlorine onto aromatic ring is an important synthetic
transformation because chlorinated compounds are recognized as versatile starting materials and
additives in the production of high quality insecticides, fungicides, herbicides, dyes,
pharmaceutical etc. therefore, there are several known methods available in the literature that
have been developed for the chlorination of aromatic compound”
Example
Chlorination “is an important reaction of organic chemistry because of wide variety of uses of
chloro-substituted organic compounds in fine chemicals and pharmaceutical intermediates.
Therefore, large number of methods are available in the prior art for chlorination of organic
compounds”
Bromination
Bromination of "organic compound" is one of the most common industrial processes due to
numerous uses such as: water purification, "farming," healthcare, photography etc. Organic
materials are either brominated by incorporation or by substitution reactions. Bromine is applied
to unsaturated hydrocarbons (alkenes and alkynes) through the intermediate cyclic bromonium
This provides di-bromo compounds in non-aqueous solvents, such as carbon disulfide. Ex-
bromination process.
Iodination:
Few "typical procedures like bromobenzene are identified. Usage of the catalyst tends to increase
the halogens' electrophilic behavior. Through utilizing the oxidizing agent, the iodination may be
carried out since iodine is less reactive of all halogens. The nature of the electrophile that acts as
I+ when using nitric acid fuming as a catalyst, I+ figured it was [O = N(I) OH]+. In the presence
of aluminum chloride, CuCl2 is recently reported as a type of oxidant. iodobenzene was obtained
in reasonable yield in both methods but the latter approach is more suited for alkylbenzene
iodination. Easily condensed aromatic hydrocarbons "react with electrophilic reagents. For
Naphthalene in carbon tetrachloride solution is readily brominated without the usage of any
catalyst
.Fluorination
Organic compounds, both saturated and unsaturated, react with fluorine readily, typically explosively.
Elemental fluorine fluorination (F2) requires extremely specific environments and apparatuses. Most of
the economically important organic compounds are electrochemically fluorinated using hydrogen
fluoride as the fluorine supply. The process is called electrochemical flourination
Chloride and iodine can be introduce into aromatic ring by electrophilic subsititution
Toulene o-fluorotoulene p-
fluorotoulene
75%. 25%
But flourine Is too reactive and only poor monoflourinated products are obtianed
Type of Halogenation:
“There are two types of reactions which are possible with these halogenating elements. These
include substitution halogenation and addition halogenation.”
Substitution Halogenation:
Substitution” halogenation is the reaction in which an atom, often a hydrogen atom or group of
atoms which are usually functional groups, are substituted by the halogen atom i.e; achlorination
reaction of great importance involves the substitution of a hydrogen atom from the methane by
chlorine atom. “
Aromatic Substitution:
An example of aromatic substitution is the "reaction between aromatic compounds such as
benzene and bromine in the presence of aluminum chloride resulting in the formation of
bromobenzene. The mechanism formally consists of a two-stage process: (1) Lewis-base-Lewis
acid reaction between benzene and Br+ followed by (2) an E1 reaction resulting in loss of proton
to regenerate the aromatic benzene ring.”
Addition Halogenation:
This “reaction generally takes place with unsaturated hydrocarbons. In this the halogenating
elements are attached with the hydrocarbons. Chlorine, bromine, and iodine readily react with
most olefins. The reaction between ethylene and Chlorine that form 1, 2-dichloroethane is of
great commercial importance as the formed compound is used for the manufacturing of vinyl
chloride. To measure quantitatively the numbers of CH (or ethylenic-type) and bond in organic
compounds, these addition reactions with bromine or iodine are frequently used. Numbers of
bromine or values of iodine are the important measures of the degree of unsaturation of the
hydrocarbons. Substitution halogenations for aromatic” compounds are made “through ionic
reactions, while the chlorination reactions using elemental chlorine is similar to the reaction used
for addition chlorination of olefins. “
Halogenation on commercial scale
Bromination as commercial process
Bromination “of aromatic compounds specially of aromatics has catched a considerable amount
of attention during recent years because of its significant commercial importance as compound
produced through it acts as potent antitumor, antibacterial, “antifungal antineoplastic, antiviral
and antioxidizing agents and and also” act as industrial intermediates for the manufacturing of of
pure chemicals, pharmaceuticals, and agrochemicals.”
Industrial-Importance of Some Brominated Compounds
The “aromatic bromine compounds find industrial applications in many ways: “
• “P-Bromoaniline is used in the preparation of azo dyes.”
•” P- Bromophenol is used as disinfectant. “
• “2, 4, 6- Tribromophenol used as an intermediate for the formation of flameretardants, in
manufacture of selective fungicide, germicide, and fire extinguishing fluids. “
• “P- Bromoacetanilide is used as analgesic, antipyretic.
• 2-Bromo-4-nitroacetanilide is used as drug intermediate, in preparation of Nimenslide.
• 3-Bromo-4-fluoronitrobenzene is a potential intermediate for ciprofloxacin and other antibiotic
drugs. “
• 2, 4, 6-Tribromo-3-nitroaniline is a precursor for the nthesis of substituted thiazoles which are
used as fungicides.”
• Bromobenzene is used as a motor oil additive and bromonaphthalene is used in spectroscopy
andrefractomee”
. “4, 4-isopropylidine- bis-(2, 6-dibromophenol) commonly known as Tetrabromobisphenol -A
(TBBPA) is a specialty chemical which has a wide range of industries applications. It's used in
epoxy, vinyl esters, polystyrene, phenolic resins, and polycarbonate resins as a reactive flame
retardant. TBBPA can be used as the parent compound for other flame” retardant development.
The importance of TBBPA can be understood by the fact that it is one of the most widely used
and largest selling brominated flame-retardant globally. It is used broadly to deliver flame
retardancy for styrenic thermoplastics and for some thermoset resins. TBBPA is fully
ecologically sfe and fulfills all legislations for recycling and recovery. “
• “2, 6-Dibromo-4-nitroaniline [Br2C6H2(NO2)NH2] is a potent antifungal and also useful in
the synthesis of diazonium salts t h a t are helping in the production of aligomeric disperse dyes.
• 3, 5-Dibromosalicylaldehyde serves as an inhibitor of stearoyl-CoA desaturase, in
pharmaceutical industry, obesity is being trated by using this specify chemicals”
Industrial-Importance of Some Chlorinated Compounds
The chlorinated organic compounds find industrial applications in many ways:
• “3, 5-Dichloro-4-hydroxybenzonitrile is used as pesticide.
• 2-Chloro-4-methylphenol is a valuable intermediate for the preparation of crop protection
agents and pharmaceuticals.
• The chlorinated benzoates can be used as chemical intermediates to make pharmaceuticals,
agricultural chemicals and other products.
• Chlorobenzenes are useful as starting materials for Medicines and agricultural chemicals. “
• “2-Chlorobenzothiazole can be used as intermediate product for t h e preparation of specific
herbicides.
• The major use of p-chlorotoluene is in the manufacture of pchlorobenzotrifluoride, a key
intermediate in dinitroaniline and diphenyl ether herbicides.
• 4-Bromo-2-chloroacetanilide compound finds application as intermediate in research and
development.
• 2-Bromo-6-chloro-4-nitroaniline is used as a dye and intermediate for dyes.
• 5-Chloroisatin is used as intermediate for pharmaceuticals and agrochemicals.
• 5-Chlorosalicylic acid is used as intermediate of pharmaceutical, agrochemicals and dyes.”
Halogenation of Organic Compounds Using
New Reagent
Firouzabadi et.al. (2009) “Find that the direct bromination and iodination of various
aromatic compounds with NaBr and NaI using oxone (2KHSO5·KHSO4·K2SO4) in water was
successfully achieved with good to excellent yields. The key advantage of this procedure is the
success of the water reactions in the presence of a harmless oxidant without any organic co-
solvents being used. The benefit in procedure is the usage in NaBr and NaI as the secure sources
of halogens. To large-scale projects this approach is simple to implement. We have successfully
implemented this approach for iodocyclizing an unsaturated alcohol and an unsaturated
carboxylic acid”
Firouzabadi et.al. (2009)
reported a “new environmentally friendly catalytic method for the efficient monoiodination and
bromination of arenes and also iodoetherification and iodolactonization of olefins using
hydrogen peroxide as the terminal oxidant. The method is based on using sodium iodide or
sodium bromide, hydrogen peroxide (35%) and cerium(III) chloride as an effective catalyst in
water at room temperature or under reflux conditions. By this protocol, iodination of anilines
proceeded with high regioselectivity at the para position with the formation of small amounts of
the ortho isomers. However, bromination of anilines proceeded with absolute regioselectivity to
give the para isomers as the sole products in high yields.”. “Iodination and bromination of m-
xylene, toluene, chloro- and bromobenzenes have been carried out with outstanding
regioselectivity in order to generate para-isomers as the only ingredients. This catalytic method
also halogenated benzene to give the "monohalogenated benzene in" reasonable yields.
Iodoetherification and iodolactonisation of olefins at room temperature have proceeded quickly
in large yields. however, the bromination of olefins by this protocol failed and the starting
materials were detected intact.” “
Zhdankin (2009)
Opinion that the increasing interest in iodine (III) compounds is mainly due to their very useful
oxidizing abilities, coupled with friendly environmental and commercial availability character.
For some areas of hypervalent iodine chemistry, there has been a major increase in activity. Such
fields include the use of hypervalent iodine reagents in various oxidative transformations. The
production and synthetic usage of hypervalent iodine reagents assisted by polymer and
recyclable and catalytic applications of organoiodine compounds.
Hajipour(2006)
The “brominated phenolic compounds are very important materials from the point of view of
antiseptic hygienic and disinfectant character and they are also useful in industry for
manufacturing biologically active agrochemical, antioxidancy “and flame retardancy. “1-Benzyl
4-aza-1-azoniabicyclo[2.2.2] octane tribromide has been e. The reaction gives brominated
phenols in good to excellent yields. (Hajipour, 2006)”
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