FIELD OF INVENTION:
The present invention relates to a process for the preparation of 2-chloro-4-fluorotoluene.
More particularly, the present invention relates to a process for the preparation of 2-chloro-4-
fluorotoluene in presence of a diazotizing agent and a fluorinating agent.
BACKGROUND OF INVENTION:
In recent years, with the rapid development of pesticides, pharmaceuticals and other chemical
industries, there is a growing demand of aromatic fluoro intermediates e.g. chemicals
containing a fluorophenyl group. Brominated or chlorinated aromatic compounds are easily
obtained by electrophilic halogenation with molecular bromine or chlorine but fluoroaromatic
compounds are rarely synthesized by fluorination with fluorine as this reaction is difficult to
control. Further, traditional and cost-effective fluorinating reagents such as fluorine gas,
hydrogen fluoride and tetrafluoroboric acid are corrosive, toxic and therefore, require special
handling and equipment. In addition, they cannot be used with intermediates containing other
sensitive functional groups. Thus, the synthesis of aromatic fluoro-compounds is not trivial at
industrial scale as it requires special equipment, materials of construction, reaction conditions
and controls to tackle the difficulty in safely handling and disposing of fluorinating reagents.
2-Chloro-4-fluorotoluenes which are useful as pesticide intermediates can be synthesized
through various chemical transformations. The commonly known method for the
regiospecific introduction of a fluorine atom to arenes is the Balz-Schiemann reaction, a
classical method for replacing the diazonium group of aryldiazonium salts with
tetrafluoroboric acid (HBF4).
Fluoroaromatic compounds are generally prepared by diazotizing an aromatic amine, such as
aniline, in anhydrous HF, usually at 0 °C, followed by thermal decomposition of the
aryldiazonium fluoride. When the diazotization is carried out in aqueous medium with
hydrochloric acid and sodium nitrite, chlorinated impurities may be formed during the fluorodediazotization
reaction.
Organic Letters, 2017, 19(12), pp 3075-3078 discloses the synthesis of aryldiazonium salt
using tetrafluoroboric acid (HBF4).
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Chem. Abstr., 1941, pp 7965 and Zhurnal Obshchei Khimii, 1941, 11, p. 243-246 disclose the
synthesis of aryldiazonium salt using tetrafluoroboric acid (HBF4) followed by synthesis of 2-
chloro-4-fluorotoluene.
US4912268 discloses a process for preparing fluoroaromatic compounds in the presence of
HF.
CN108569948 describes the synthesis of 2-chloro-4-fluorotoluene which involves reacting
aniline with anhydrous hydrogen fluoride (HF) to obtain a hydrofluoride salt of an aniline
derivative, which was treated with sodium nitrite to form a diazonium fluoride salt. The
obtained diazonium fluoride salt was decomposed by pyrolysis to obtain the desired product.
Chemical Science Transactions, 2015, 4(4), pp 1149-1155 discloses the synthesis of
fluorinated compounds in the presence of ionic liquids. However, the use of an ionic liquid in
a commercial production of 2-chloro-4-fluorotoluene is not economical.
The prior art documents disclose several methods for the synthesis of fluoroaromatics from
aniline derivatives using hydrogen fluoride (HF) or tetrafluoroboric acid (HBF4) which are
extremely hazardous to handle as these reagents are highly corrosive to skin, eyes, on contact
and inhalation.
Therefore, there is a need to overcome or alleviate deficiencies of the processes as disclosed
in the prior art and to provide a useful alternative process for the preparation of 2-chloro-4-
fluorotoluene which does not require the use of highly corrosive and hazardous reagents such
as hydrogen fluoride or tetrafluoroboric acid. Accordingly, the present invention provides a
simple, environment-friendly and cost-effective process for the preparation of 2-chloro-4-
fluorotoluene.
OBJECTIVE OF INVENTION:
The main objective of the present invention is to provide a simple, environment-friendly, and
cost-effective process for the preparation of 2-chloro-4-fluorotoluene.
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SUMMARY OF INVENTION:
Accordingly, the present invention provides a process for the preparation of 2-chloro-4-
flurotoluene comprising reacting 2-chloro-4-aminotoluene with a diazotizing reagent and a
fluorinating reagent followed by thermal decomposition.
In an embodiment, the present invention provides a simple, environment-friendly and costeffective
process for the preparation of 2-chloro-4-fluorotoluene comprising reacting 2-
chloro-4-aminotoluene with diazotizing reagents and fluorinating reagents to afford
diazonium fluorophosphate or fluoroborate salt, followed by thermal decomposition of the
diazonium fluorophosphate or fluoroborate salt to afford 2-chloro-4-fluorotoluene.
In another embodiment, the present invention provides a compound of formula A,
N+
Cl
N
PF6
Formula A .
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated.
In view of the above, the present invention relates to a simple, environment-friendly and costeffective
process for the preparation of 2-chloro-4-fluorotoluene.
In an embodiment, the present invention provides a process for the preparation of 2-chloro-4-
flurotoluene comprising reacting 2-chloro-4-aminotoluene with a diazotizing reagent and a
fluorinating reagent followed by thermal decomposition.
In preferred embodiment, the present invention provides a process for the preparation of 2-
chloro-4-fluorotoluene comprising reacting 2-chloro-4-aminotoluene with a diazotizing
reagent and a fluorinating reagent to afford a diazonium fluorophosphate or fluoroborate salt
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followed by thermal decomposition of the said diazonium fluorophosphate or fluoroborate
salt to afford 2-chloro-4-fluorotoluene.
In a preferred embodiment, the diazotizing reagent is selected from metal nitrite such as
sodium nitrite (NaNO2), tert-Butyl nitrite or Isoamyl nitrite.
In a preferred embodiment, the fluorinating reagent is selected from metal salts of
fluorophosphates or fluoroborates. In a more preferred embodiment, the fluorinating reagent
is selected from sodium tetrafluoroborate (NaBF4), potassium hexafluorophosphate (KPF6).
In one embodiment of the present invention, the process for the preparation of 2-chloro-4-
fluorotoluene is carried out under acidic conditions.
In another embodiment of the present invention, the process for the preparation of 2-chloro-4-
fluorotoluene is carried out under neutral conditions.
The thermal decomposition is carried out by heating the diazonium fluorophosphate or
fluoroborate salt at a temperature in the range of 70 to 150 oC. Preferably, thermal
decomposition is carried out by heating the diazonium fluorophosphate or fluoroborate salt at
a temperature in the range of 100 to 120 oC.
In one embodiment of the present invention, the thermal decomposition of the diazonium
fluorophosphate or fluoroborate salt is carried out in presence of a solvent.
In one embodiment of the present invention, the thermal decomposition of the diazonium
fluorophosphate or fluoroborate salt is carried out in absence of a solvent.
In preferred embodiment, the solvent is selected from toluene, xylene, halobenzene e.g.
chorobenzene, dihalobenzene e.g. dichlorobenzene, halotoluene e.g. chlorotoluene,
fluorotoluene, dihalotolune e.g. dichlorotolune, chloroflurotoluene, sulfolane, N,Ndimethylformamide,
N-Methyl-2-pyrrolidone, mixture thereof and the like.
The by-product generated BF3 gas is recycled and further used in the synthesis of BF3
etherate /sodium fluoroborate.
The process for the preparation of 2-chloro-4-fluorotoluene is as depicted in scheme 1 below:
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Scheme: 1
NH2
Cl
N+
Cl
N
PF6/BF4 F
Cl
The present invention discloses the process for the preparation of 2-chloro-4-fluorotoluene,
wherein the process is carried out by reacting of 2-chloro-4-aminotoluene with sodium
tetrafluoroborate or potassium hexafluorophosphate under diazotization reaction conditions to
afford the diazonium hexafluorophosphate or tetrafluoroborate salt which is then subjected to
thermal decomposition at temperature in the range of 100 to 120 oC.
In another embodiment, the present invention provides a compound of formula A,
N+
Cl
N
PF6
Formula A
Following examples are given by way of illustration and therefore should not be construed to
limit the scope of the invention.
Example 1: Preparation of 2-Chloro-4-fluorotoluene using sodium tetrafluoroborate:
2-Chloro-4-aminotoluene (150 g) was added to an aq. hydrochloric acid (386.65 g) solution.
The reaction mixture was cooled and an aq. solution of sodium nitrite (201 g) and aq. solution
of sodium tetrafluoroborate (NaBF4) (290.7 g) were added slowly at -5 to 0 °C. The reaction
mixture was stirred till completion. After completion of the reaction, the precipitated solid
was filtered and washed with water, followed by methanol and dried under vacuum. The
dried solid was heated slowly at 110 °C to obtain 2-Chloro-4-fluorotoluene in 87% yield with
a purity of 96.3% which can be further purified by distillation to get 99.6% pure material.
1H NMR (400 MHz, Chloroform-d3): 7.17 (m, 1H), 7.10 (m, 1H), 6.88 (m, 1H), 2.33 (s, 3H).
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Example 2: Preparation of 2-Chloro-4-fluorotoluene using Potassium
hexafluorophosphate:
2-Chloro-4-aminotoluene (50 g) was added to an aq. hydrochloric acid (HCl) (128.8 g)
solution. The reaction mixture was cooled and a 40% aq. solution of sodium nitrite (68.3 g)
and aq. solution of potassium hexafluorophosphate (KPF6) (12% solution, 566.5 g) were
added slowly at -5 to 0 °C. The reaction mixture was stirred till completion. After completion
of the reaction, the precipitated solid was filtered and washed with water, followed by
methanol and dried under vacuum to obtain 102.4 g solid with purity 99.6%. 5.0 g of the
dried solid was mixed with paraffin oil (25 g) and heated slowly at 120 °C to obtain 2-
Chloro-4-fluorotoluene with a purity of 94.7%.
Comparative example 1: Preparation of 2-Chloro-4-fluorotoluene using fluoroboric
acid:
2-Chloro-4-aminotoluene (100 g) was added to an aq. hydrochloric acid (234 g HCl) solution.
The reaction mixture was cooled and an aq. solution of sodium nitrite (118 g) and freshly
prepared aq. solution of fluoroboric acid (HBF4) [48 g boric acid in 120 g aq. hydrofluoric
acid (HF) (50%)] were added slowly at -5 to 0°C. The reaction mixture was stirred till
completion. After completion of the reaction, the precipitated solid was filtered and washed
with 2% aq. solution of sodium tetrafluoroborate (50 g) followed by ethanol (50 g) and dried
under vacuum to obtain 210 g of solid. 50 g of the above solid was heated slowly at 105-115
°C to obtain 2-Chloro-4-fluorotoluene with 64.8% purity. Yield=16%.
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WE CLAIM:
1. A process for the preparation of 2-chloro-4-flurotoluene comprising reacting 2-
chloro-4-aminotoluene with a diazotizing reagent and a fluorinating reagent followed
by thermal decomposition according to reaction scheme as depicted below;
NH2
Cl
F
Cl
.
2. The process as claimed in claim 1, wherein said process comprising reacting 2-chloro-
4-aminotoluene with a diazotizing reagent and a fluorinating reagent to afford
diazonium fluorophosphate or fluoroborate salt followed by thermal decomposition of
said diazonium fluorophosphate or fluoroborate salt to afford 2-chloro-4-flurotoluene
wherein the fluorophosphate or fluoroborate salt may optionally be isolated,
according to reaction scheme as depicted below:
NH2
Cl
N+
Cl
N
PF6/BF4 F
Cl
.
3. The process as claimed in claim 1, wherein said diazotizing reagent is selected from
sodium nitrite (NaNO2), tert-butyl nitrite or isoamyl nitrite.
4. The process as claimed in claim 1, wherein said fluorinating reagent is selected from
metal salt of fluorophosphate or fluoroborate.
5. The process as claimed in claim 4, wherein said metal salt of fluorophosphate or
fluoroborate is selected from sodium tetrafluoroborate (NaBF4) or potassium
hexafluorophosphate (KPF6).
6. The process as claimed in claim 1, wherein said fluorinating reagent is sodium
tetrafluoroborate (NaBF4).
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7. The process as claimed in claim 1, wherein said thermal decomposition is carried out
at temperature in the range of 70 to 150 oC.
8. The process as claimed in claim 1, wherein said thermal decomposition is carried out
at temperature in the range of 105 to 120 oC.
9. The process as claimed in claim 1, wherein said thermal decomposition is carried out
in presence or absence of a solvent.
10. A compound of formula A,
N+
Cl
N
PF6
Formula A