A Convenient Synthesis of High-Purity 1-Chloro-2,6-difluorobenzene

Article abstract of DOI:10.1021/op0340816

A convenient preparation of high-purity 1-chloro-2,6-difluorobenzene has been developed. The key to the isolation of the desired isomer, without contamination of the difficult-to-separate isomer 1-chloro-2,3-difluorobenzene, is the use of sulfonyl chloride to direct fluorine substitution to the ortho and para positions of the aryl ring. Although activation with sulfonyl chloride requires additional reaction steps, the process results in good overall yield and requires only low-cost commodity chemicals. The high-purity 1-chloro-2,6-difluorobenzene is useful as an intermediate for active ingredients in agricultural and pharmaceutical applications.

Full text of DOI:10.1021/op0340816

Organic Process Research & Development 2003, 7, 921−924
A Convenient Synthesis of High-Purity 1-Chloro-2,6-difluorobenzene
Robert M. Moore, Jr.*,1
Strategic DeVelopment, Albemarle Corporation, Gulf States Road, Baton Rouge, Louisiana 70805, U.S.A.
Abstract:
if excess CsF is used as the fluorinating agent. Yields with
KF are considerably lower, even when an excess of KF is
used. The fluorination requires very high temperatures (>250
°C) and exotic-metal pressure equipment. The reduction also
requires a pressure reactor, a hydrogen-transfer agent, and
an acid scavenger. However, since the process requires only
two reaction steps to the product, 1, it has been the most
convenient process to date.
We have now developed a new, high-purity synthesis of
1-chloro-2,6-difluorobenzene. Although the process requires
five reaction steps, it does offer some advantages. It uses
cheap raw materials, such as chlorosulfonic acid, potassium
fluoride, and trichlorobenzene. It requires no exotic pressure
equipment, although the use of chlorosulfonic acid requires
some caution. Less fluoride salt is wasted due to less excess
needed for the reaction and smaller losses to undesirable side
products. Isolation of intermediates is simple and requires
no chromatography. Best of all, the desired product can be
produced in greater than 99.5% purity since no hard-to-
separate 1-chloro-2,3-difluorobenzene is produced. With
proper control of reaction variables, less than 10% total of
trifluorobenzene and monofluorodichlorobenzene results. The
process is also convenient to carry out on a small scale using
simple, available laboratory equipment.
A convenient preparation of high-purity 1-chloro-2,6-difluo-
robenzene has been developed. The key to the isolation of the
desired isomer, without contamination of the difficult-to-
separate isomer 1-chloro-2,3-difluorobenzene, is the use of
sulfonyl chloride to direct fluorine substitution to the ortho and
para positions of the aryl ring. Although activation with sulfonyl
chloride requires additional reaction steps, the process results
in good overall yield and requires only low-cost commodity
chemicals. The high-purity 1-chloro-2,6-difluorobenzene is use-
ful as an intermediate for active ingredients in agricultural and
pharmaceutical applications.
Difluorobenzene compounds such as 1-chloro-2,4-difluo-
robenzene or 2,6-difluorobenzonitrile are used as intermedi-
ates for active ingredients in agricultural and pharmaceutical
applications.2 Syntheses of these compounds are relatively
straightforward. However, there are few, direct regiospecific
methods for preparing 1-chloro-2,6-difluorobenzene (1).
We required a synthesis of 1 that used economic raw
materials and could be easily scaled up into a commercial
reactor. Preparations from the economic starting material
1,2,3-trichlorobenzene are known but suffer from a number
of significant drawbacks. In 1972, Shiley3 attempted the KF
exchange of 1,2,3-trichlorobenzene. A number of isomers
were produced, with no single isomer present in greater than
30% yield. A patent by Soula4 describes the chlorination of
1,3-difluorobenzene as a successful route to the desired
compound, but even though 1 is the major product, a
substantial amount (10%) of the difficult-to-separate 1-chloro-
2,4-difluorobenzene and 1-chloro-3,5-difluorobenzene are
present as well. A patent by Dow Elanco5 describes a
preparation for 1 relatively free of contamination from other
isomers. 1,2,3-Trichlorobenzene is partially fluorinated to
produce a mixture of components, with the monofluoro-
dichlorobenzene and the chlorodifluorobenzene isomers
comprising up to 20 and 60 mol %, respectively, of the final
reaction mixture. The chlorodifluorobenzenes are separated
from the other components of the mixture by distillation.
To separate 1 from 1-chloro-2,3-difluorobenzene (1b),
compound 1b is selectively reduced with hydrogen and
palladium on carbon. The resulting 1,2-difluorobenzene is
easily separated from 1 by distillation. However, the Dow
Elanco process for 1 still has a number of drawbacks. On
the basis of information from the patent, the best yield of 1,
after reduction of the other isomers, is 44%, and that is only
Results and Discussion
Kageyama et al., reported on an efficient preparation of
2,6-difluorotoluene via chlorosulfonation of dichlorotoluene,
followed by KF exchange, and desulfonation.6,7 We specu-
lated that, like other electron-withdrawing groups, the
sulfonyl chloride was activating the ortho- and para-
substituted chlorines to KF exchange. Thus, it might be
possible to selectively fluorinate only two of the chlorines
in 1,2,3-trichlorobenzene (1,2,3-TCB) and prepare the desired
compound 1.
The potential commercial process is shown in Figure 1.
A good yield of 2,3,4-trichlorobenzenesulfonyl chloride (2)
resulted when melted 1,2,3-TCB (mp ) 55 °C) was added
to an excess of chlorosulfonic acid. Heating to about 75-
85 °C was required to complete the reaction. When the
mixture was heated to 50 °C for 1 h after the addition of
1,2,3-TCB, the conversion was only 60%. The major isomer
produced was 2, although significant amounts of the 3,4,5-
trichlorobenzenesulfonyl chloride (7) were also produced
(Figure 2). The ratio of the two isomers varied from about
12:1 to 8:1, although the factors which influenced this ratio
have not been determined. The minor isomer should be
minimized since fluorination of this compound, followed by
desulfonation, will result in 1,3-dichloro-2-fluorobenzene (9).
(1) Mailing address: Albemarle Corporation P.O. Box 341, Baton Rouge, LA
70821. E-mail: Bob_M_Moore@albemarle.com
(2) Finger, G. C.; Oesterling, R. E. J. Am. Chem. Soc. 1956, 78, 2593.
(3) Shiley, R. H.; Dickerson, D. R.; Finger, G. C. J. Fluorine Chem. 1972, 2
(1), 19.
(6) Kageyama, H.; Suzuki, H.; Kimura, Y. J.Fluorine Chem. 2000, 101, 85.
(7) Suzuki, H.; Kageyama, H.; Yoshida, Y.; Kimura, Y. J. Fluorine Chem.
1991, 55, 335.
(4) Soula, G. U.S. Patent 4,417,081, 1983.
(5) Pews, R. G.; Gall, J. A. U.S. Patent 5,091,580, 1992.
10.1021/op0340816 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
Vol. 7, No. 6, 2003 / Organic Process Research & Development
•
921

Figure 1. Commercial preparation of 1-chloro-2,6-difluorobenzene.
in a polar aprotic solvent at 150-200 °C. Replacement of
chlorine with fluorine at the position meta to the sulfonyl
chloride is not observed until the other chlorines have first
been exchanged. Thus, 2,3,4-trifluorobenzenesulfonyl fluo-
ride (10) will form, but 2-chloro-3,4-difluorobenzenesulfonyl
fluoride (11) will not form. The amount of potassium fluoride
added should be optimized to minimize the formation of 10.
A small excess of potassium fluoride (3.2 equiv) is all that
is needed to obtain complete conversion of the starting
material. One of the three fluorides is lost during hydrolysis
of the sulfonyl fluoride, 3. Sulfolane is an excellent solvent
for the reaction. Other solvents, such as nitrobenzene,
DMSO, or benzonitrile, resulted in lower product yields than
sulfolane. Kageyama6,7 has recommended the use of a
catalyst such as tetraphenylphosphonium bromide for the
fluorination of chlorinated toluenes, but we find that no
catalyst is required for the chlorinated benzenes if sulfolane
is used as the solvent (nitrobenzene requires a phosphorus-
based catalyst). Distilling out added toluene with any water
present in the reactor was sufficient to dry the reagents for
the fluorination step. For a noncatalytic, KF exchange, the
process is rapid. Conversion of the starting material is
complete in less than 2 h at 195 °C.
Figure 2. Production of 1,3-dichloro-2-fluorobenzene from
2,3,4-trichloro-1-benzenesulfonyl chloride.
Although this compound can be separated from the desired
product, it has a negative impact on yield. Once the excess
chlorosulfonic acid was quenched in chilled water,8 a white
precipitate formed, which could be isolated and washed on
a filter. The wet cake may or may not need drying, depending
on how water is removed from the reactor in preparation
for KF exchange. For most laboratory preparations, air-dried
sulfonyl chloride 2 should be sufficiently dry for the
fluorination procedure. Reuse of the diluted sulfuric acid
filtrate from this first step for the final desulfonation step
can reduce the number of waste streams that would require
treatment or disposal.
The yield for the chlorosulfonation step can be dramati-
cally improved from the typical 80-85% to over 98% by
adding thionyl chloride to the reaction after the addition of
trichlorobenzene. Thionyl chloride reacts with the water of
reaction, which prevents hydrolysis of the sulfonyl chloride,
2, and formation of 2,3,4-trichlorobenzenesulfonic acid.
During a mass balance experiment, it was determined that
much of the yield loss was due to the formation of the
arylsulfonic acid. Excess chlorosulfonic acid can be distilled
and recovered for recycle.
To minimize the number of operations, it does not seem
necessary to distill the high-boiling sulfonyl fluoride products
from the solvent. After filtration to remove potassium
chloride, the sulfonyl fluoride 3, in sulfolane solution, can
be hydrolyzed without further purification.
The removal of the sulfonyl fluoride group proved to be
one of the more challenging aspects of this project. Sulfonyl
fluorides are essentially inert to acidic hydrolysis. Sodium
hydroxide hydrolysis occurred rapidly; however, hydroxide
also attacked the chlorine of the aryl ring. Instead of detecting
4, we observed the formation of fluorinated-diaryl ethers.
An inexpensive, non-nucleophilic base, sodium acetate, was
chosen. Addition of acetic acid reduced the amount of diaryl
ether byproduct formation even further. With sulfolane as
the solvent, a homogeneous solution of 3, in water, sodium
acetate, acetic acid, and sulfolane resulted at the reaction
temperature. The success of the hydrolysis reaction can be
attributed to this homogeneous condition. Nitrobenzene
formed a two-phase system with aqueous sodium acetate.
As a result, slow conversion of the sulfonyl fluoride, 3, to
the desired sodium salt, 4, was observed with nitrobenzene.
To remove excess sodium acetate and acetic acid from
the reaction mixture, concentrated hydrochloric acid was
added to the solution containing the sodium salt, 4. Water,
acetic acid, and excess HCl were distilled from the pot.
Heating the remaining solution under vacuum to remove
sulfolane resulted in the recovery of a solid that consisted
Activation by sulfonyl chloride permits fluorination of 2
with potassium fluoride to form 3 in the absence of catalyst
(8) Safety tip: The typical laboratory procedure instructs that the contents of
a chlorosulfonation reaction be quenched by pouring onto crushed ice. The
much safer procedure of transferring the reaction contents to an addition
funnel and slowly adding the solution to chilled ice water in a large flask
is recommended.
922
•
Vol. 7, No. 6, 2003 / Organic Process Research & Development

Conclusions
We have successfully prepared high-purity, 1-chloro-2,6-
difluorobenzene. The compound can be prepared easily in
either routine, laboratory glassware or in large-scale equip-
ment since difficult separations are avoided and operations
are kept simple. Purity of greater than 99% is achievable
with multistage distillation equipment. Although our attempts
to extend this chemistry to tetrachlorinated benzenes were
not successful, this chemistry was not extensively explored
nor optimized.
Experimental Section
General. All reagents were obtained commercially and
used as purchased. The potassium fluoride purchased was
spray-dried quality. 1H NMR spectra were determined on a
400 MHz spectrometer.
Figure 3. Attempts to extend the methodology to tetrachlo-
robenzenes.
of aryl sulfonic acids, such as 5, and NaCl. The recovered
sulfolane was suitable for recycle. Sulfolane is difficult to
isolate after the addition of sulfuric acid. Removing the
sulfolane before desulfonation permitted reuse of this
expensive solvent. One negative aspect of this procedure was
the addition of a solid isolation step.
Preparation of 2,3,4-Trichlorobenzenesulfonyl Chlo-
ride (2) with Addition to Chilled Water. A three-neck, 500-
mL round-bottom flask was charged with 189.8 g (1.63 mol)
of chlorosulfonic acid. 1,2,3-TCB9 (80.5 g, 0.444 mol) was
charged to a jacketed addition funnel, attached to the flask
and heated to 80 °C. The melted 1,2,3-TCB was added to
the chlorosulfonic acid at 70° for 30 min. The temperature
was then raised to 85 °C for 3 h. The reaction mixture was
transferred to another addition funnel and added to a three-
neck, 1-L flask containing 300 g of water at 2 °C.8 The
resulting precipitate was isolated by filtration, air-dried, and
The isolated solid was charged to a reactor with 66%
sulfuric acid. After heating to 205 °C for 2 h, water was
added dropwise to the pot. The water distilled out as an
azeotrope with an organic material. The two phases were
recovered in a receiving flask and separated by a simple
phase cut. The volatile organic product distilled out of the
pot was 95% pure 1. The major impurities at about 2% each
were 1,2,3-trifluorobenzene and 1,3-dichloro-2-fluorobenzene
(9). An additional 1% of the mixture consisted of heavier
boiling components such as 1,2,3-TCB with trace amounts
of sulfolane and diaryl ethers. To obtain higher-purity
material (99%+), fractional distillation of the recovered
product was necessary. Distillation with a small-scale Vi-
greux-indented glass column (4-5 plates) resulted in the
isolation of 99.2% pure 1. The above impurities have at least
a 30 °C boiling-point difference from that of 1 so that it
should be feasible to obtain a purity of 99.8%+ with the
use of a larger, multistage, distillation column. Spectral data
from fluorine NMR, proton NMR, and carbon NMR were
consistent with the desired product and compared to analo-
gous compounds on file. Because of the presence of solvent,
only GC and fluorine NMR were routinely used to monitor
the intermediates in the process. The overall isolated yield
of 99.2% pure 1 from 1,2,3-TCB was 33%.
Attempts to extend this reaction to the tetrachlorobenzenes
were not successful in obtaining high-yield, high-purity
products. Chlorosulfonation of 1,2,4,5-tetrachlorobenzene
failed at temperatures below 150 °C. When the reaction was
carried out at higher temperatures, only decomposition
products were observed. Although we did obtain good yields
of 2,3,4,5-tetrachlorobenzenesulfonyl chloride (6) from
1,2,3,4-tetrachlorobenzene (based on GC area %) with
moderate conditions, we did not observe the desired selectiv-
ity during the fluorination reaction. Over a range of potassium
fluoride to arylsulfonyl chloride ratios, a distribution of
mono-, di-, and trifluorobenzenesulfonyl fluorides was
isolated (Figure 3). No single compound was detected in
greater than 50% yield.
1
analyzed by H NMR spectroscopy. The conversion was
99%+, and the yield of 2 was 81%. The ratio of 2 to 7 was
10 to 1.1H NMR (Major isomer, 2: doublet, δ 7.55, 1H;
doublet, δ 7.95, 1H. Minor isomer, 7: doublet, δ 7.25, 1H;
doublet, δ 7.85, 1H.)
Attempted Preparation of 2,3,4-Trichlorobenzene-
sulfonyl Chloride (2) at 50 °C. A three-neck, 500-mL
round-bottom flask was charged with 157.4 g (1.35 mol) of
chlorosulfonic acid. 1,2,3- Trichlorobenzene (71.4 g, 0.394
mol) was charged to a jacketed addition funnel attached to
the flask and heated to 80 °C. The melted 1,2,3-TCB was
added to the chlorosulfonic acid at room temperature for 30
min. A solid formed, and the reaction was heated to 50 °C
for 1 h. Eventually, the solid dissolved, and the solution
turned blue. The reaction contents were added to water at
15 °C. The precipitate was filtered and analyzed by 1H NMR
spectroscopy. Yield of 2 was 60%.
Preparation of 2,3,4-Trichlorobenzenesulfonyl Chlo-
ride (2) with Addition of Thionyl Chloride To Eliminate
Water of Reaction. A three-neck, 500-mL round-bottom
flask was charged with 72.5 g of 1,2,3-TCB (0.40 mol). After
melting the trichlorobenzene at 70 °C, 140.7 g of chloro-
sulfonic acid (1.21 mol) was added dropwise over 30 min.
An exotherm increased the temperature to 90 °C. After
cooling to 85 °C, 47.6 g of thionyl chloride (0.40 mol) was
added over 2 h to react with water of reaction. The reaction
was heated at 85 °C for an additional 1.5 h. The reaction
mixture was transferred to another addition funnel and added
to a three-neck, 1-L flask containing 300 g of ice and 100 g
of water. Additional ice (approximately 50 g) was added to
keep the temperature below 20 °C.8 The precipitate was
1
isolated by filtration, air-dried, and analyzed by H NMR
(9) In the absence of a jacketed addition funnel, the order of addition can be
reversed with chlorosulfonic acid added to 1,2,3-TCB.
Vol. 7, No. 6, 2003 / Organic Process Research & Development
•
923

spectroscopy. The conversion was 99%+ and the isolated
yield of 2 was 110.4 g or 98%. The ratio of 2 to 7 was 11
to 1. Neutralization of the filtrate resulted in the recovery of
1.2 g or 1% of the aryl sulfonic acid.
and as a result, the extraction was subsequently eliminated.
The aqueous solution containing sulfolane, inorganic salts,
and 4 was then acidified with concentrated HCL (25 mL).
Acetic acid, water, and excess HCL were removed by
distillation. The remaining suspension contained sulfolane
and the aryl sulfonic acid, 5. The sulfolane was distilled at
175 °C (30 Torr). A dark solid consisting of the aryl sulfonic
acid and inorganic solids remained in the pot. 19F NMR of
hydrolysis reaction in DMSO-d6, 4 (δ 110.7, δ 112.1). 19F
NMR of acidification reaction in DMSO-d6, 5 (δ 111.0, δ
111.3).
Preparation of 1-Chloro-2,6-difluorobenzene(1) 8687-
16. To the remaining solid from the above reaction was added
150 mL of 66% H2SO4. The solution was heated for 2 h at
205 °C. Water was added dropwise, which resulted in an
azeotropic distillation of water and volatile organic material.
The two phases were separated, and 5.1 g of 95% pure 1,2,6-
CDFB was recovered (42% yield based on the fraction of
filtrate used from 2). The major impurities were 1,2,3-
trifluorobenzene, 2,6-dichloro-1-fluorobenzene, 1,2,3-TCB,
and a mixture of halogenated diaryl ethers. Distillation with
a one-piece vigeroux column (4-5 plates) resulted in the
isolation of 99.2% pure 1. Overall yield of 1 from 1,2,3-
TCB was 33%. 1H NMR (multiplet, δ 6.9-7.0, 2H;
multiplet, δ 7.1-7.25, 1H). 13C NMR (triplet, δ 110.3, JCCF
) 20.6 Hz; multiplet, δ 112.3, J ) 24.4 Hz for primary
doublet; multiplet, δ 128.0, JCCCF ) 9.16 Hz; doublet of
doublets, δ 158.3, δ 160.8, J ) 251 Hz). 19F NMR (triplet,
δ 113.7).
Fluorination of 2,3,4,5-Tetrachlorobenzenesulfonyl Chlo-
ride. A five-neck, 500-mL round-bottom flask was equipped
with a mechanical stirrer, a nitrogen inlet, a condenser, and
a thermometer. The flask was charged in a nitrogen-flush
box with 22.5 g of KF (0.39 mol), 147.2 g of sulfolane, and
40.9 g of toluene. The flask was then connected to a
mechanical stirrer and trace water distilled out of the flask
with the toluene. The sulfonyl chloride, 6 (31.1 g, 0.099 mol),
was charged to the flask, and the contents were heated to
195 °C for 2 h. After the reaction was complete, the contents
were filtered to remove potassium chloride. Analysis by gas
chromatography indicated that a minimum of six fluorinated
compounds had formed, including di- and trifluoroaryl
species. 19F NMR (major peaks; δ 66.3, δ 65.7, δ 65.2, δ
98, δ 107, δ 108, δ 110, δ 120, δ 130, δ 137, δ 139, δ
152).
Attempted Chlorosulfonation of 1,2,4,5-Tetrachlo-
robenzene. A three-neck, 500-mL round-bottom flask was
charged with 43.3 g (0.20 mol) of 1,2,4,5-tetrachlorobenzene
and 115.1 g (0.988 mol) of chlorosulfonic acid. The contents
were heated to 90 °C for 4 h. The resulting viscous material
was quenched over ice. The recovered solid was identified
as the starting material. The reaction was repeated at 150
°C to melt the starting material, but after heating for 2 h, a
significant amount of solid had formed. The recovered solid
consisted of starting material and large amounts of insoluble
solids.10
Preparation of 2,3,4,5-Tetrachlorobenzenesulfonyl Chlo-
ride (6). A three-neck, 500-mL round-bottom flask was
charged with 53.7 g of 1,2,3,4-tetrachlorobenzene (0.25 mol).
After melting the tetrachlorobenzene at 70 °C, 142.0 g of
chlorosulfonic acid (1.2 mol) was added dropwise over 30
min. The reaction was heated for 4 h at 95 °C and quenched
in ice water. A white solid was isolated by filtration (83%
yield). mp 74-76 °C (lit.10 76 °C). 1H NMR (singlet, δ 7.92).
Preparation of 3-Chloro-2,4-difluorobenzenesulfonyl
Fluoride (3). A five-neck, 500-mL round-bottom flask was
equipped with a mechanical stirrer, a nitrogen inlet, a
condenser, and a thermometer. The flask was charged in a
nitrogen-flush box with 27.5 g of KF (0.473 mol), 165.2 g
of sulfolane, and 47.9 g of toluene. The flask was then
connected to a mechanical stirrer, and trace water distilled
out of the flask with the toluene. 2 (42.6 g, 0.152 mol) was
charged to the flask, and the contents were heated to 195
°C for 3 h. After the reaction was complete, the contents
were filtered to remove potassium chloride. The filtrate was
weighed (156.3 g), analyzed, and used without further
purification in the hydrolysis step. 19F NMR of filtrate in
DMSO-d6 (δ 65.5, δ 98.4, δ 106.7).
Hydrolysis of 3-Chloro-2,4-difluorobenzenesulfonyl
Fluoride (3), Acidification of the Sodium Salt of 3-Chloro-
2,4-difluorobenzenesulfonic Acid (4). A three-neck, 500-
mL round-bottom flask was charged with 84.0 g (82 mmol
of 3, theoretical) of the filtrate from the KF exchange
containing 3 in sulfolane. To this solution was charged 92.7
g of an aqueous 25% sodium acetate solution with ap-
proximately 10 mL of glacial acetic acid added to reduce
the pH to 5.5. The temperature of this mixture was raised to
80 °C, resulting in a single homogeneous layer. After 4 h,
the sulfonyl fluoride was 97% converted (GC area %) to
the sodium salt. At this point, the solution can be extracted
with toluene to remove organic impurities; however, we did
not observe an improvement in the purity of the final product,
Acknowledgment
I thank the many fine colleagues at Albemarle Corporation
who consulted with me on this project.
(10) During the review process, it was discovered that previous authors had
had difficulty with the chlorosulfonation of this isomer. Bernard, I.; Chivers,
G.; Cremlyn, R.; Mootoosamy, K. Aust. J. Chem. 1974, 27, 171.
Received for review June 24, 2003.
OP0340816
924
•
Vol. 7, No. 6, 2003 / Organic Process Research & Development