METHOD OF MAKING BENZOTRIFLUORIDE COMPOUND

METHODE DE PREPARATION DE COMPOSE BENZENIQUE TRIFLUORE

English Abstract

METHOD OF MAKING A BENZOTRIFLUORIDE COMPOUND
ABSTRACT OF THE DISCLOSURE
Discloses a method of making a benzotrifluoride compound
by reacting a para-halobenzotrifluoride compound having the
general formula
<IMG>
with a hydrogen transfer agent selected from the group
consisting of alkali metal formates, ammonium formate, and
mixtures thereof, in the presence or at least about 0.05% by
weight of a Group VIII metal hydrogenation catalyst, where X in
the formula is chlorine or bromine and each R is independently
selected from hydrogen, nitro, or amino.

Claims

The embodiments of the invention in which an exclusive pro-
perty or privilege is claimed are defined as follows:
1. A method of making a benzotrifluoride compound comprising
reacting a para-halobenzotrifluoride compound having the
general formula
<IMG>
with a hydrogen transfer agent selected from the group
consisting of alkali metal formates, ammonium formate, and
mixtures thereof, in the absence of a phase transfer
catalyst and in the presence of at least about 0.05 % by
weight, based on the weight of said
para-halobenzotrifluoride compound, of a Group VIII metal
hydrogenation catalyst, where X is chlorine or bromine,
and each R is independently selected from hydrogen, nitro,
and amino.
2. A method according to Claim 1 wherein X is chlorine.
3. A method according to Claim 1 wherein one R is hydrogen
and the other R is nitro.
4. A method according to Claim 3 wherein water or an alkanol
to C3 is present during said reaction.
5. A method according to Claim 1 wherein both R's are
hydrogen.
6. A method according to Claim 5 wherein diethylene qlycol or
n-octanol is present during said reaction.
7. A method according to Claim 1 wherein both R's are amino.
- 13 -

8. A method according to Claim 7 wherein water or an alkanol
to C3 is present during said reaction.
9. A method according to Claim 1 wherein a polar solvent is
present during said reaction.
10. A method according to Claim 9 wherein the weight ratio of
said para-halobenzotrifluoride compound to said solvent is
about 1 to about 5 to 20.
11. A method according to Claim 1 wherein said Group VIII
metal hydrogenation catalyst is a precious metal catalyst.
12. A method according to Claim 11 wherein said precious metal
catalyst is palladium on carbon.
13. A method according to Claim 11 wherein the amount of said
catalyst is about 0.05 to about 1 wt.%, based on the
weight of said para-halobenzotrifluoride compound.
14. A method according to Claim 1 wherein said reaction is
conducted at a temperature of about 60 to about 90°C.
15. A method according to Claim 1 wherein said hydrogen
transfer agent is sodium formate.
16. A method of making benzotrifluoride in the absence of a
phase transfer catalyst comprising
(A) forming a composition which comprises
(1) para-chlorobenzotrifluoride;
(2) at least about a stoichiometric amount of alkali
metal formate;
(3) about 0.05 to about 1 wt.%, based on the weight
of said para-chlorobenzotrifluoride, of a Group
VIII metal catalyst; and
- 14 -

(4) a polar solvent in a weight ratio to said
para-chlorobenzotrifluoride of about 5 to about
20; and
(B) heating said composition at a temperature between
room temperature and the boiling point of said
solvent.
17. A method according to Claim 16 wherein said Group VIII
metal catalyst is palladium on carbon.
18. A method of making meta-aminobenzotrifluoride in the
absence of a phase transfer catalyst comprising
(A) forming a composition which comprises
(1) 3-nitro-4-chlorobenzotrifluoride;
(2) at least a stoichiometric amount of alkali metal
formate:
(3) about 0.05 to about 1 wt.%, based on the weight
of said 3-nitro-4-chlorobenzotrifluoride, of a
Group VIII metal catalyst; and
(4) a polar solvent in a weight ratio to said
3-nitro-4-chlorobenzotrifluoride of about 5 to
about 20; and
(B) heating said composition at a temperature between
room temperature and the boiling point of said
solvent.
19. A method according to Claim 18 wherein said Group VIII
metal catalyst is palladium on carbon.
- 15 -

20. A method of making 3,5-diaminobenzotrifluoride in the
absence of a phase transfer catalyst comprising
(A) forming a composition which comprises
(1) 4-chloro-3,5-diaminobenzotrifluoride;
(2) at least a stoichiometric amount of alkali metal
formate;
(3) about 0.05 to about 1 wt.%, based on the weight
of said 4-chloro-3,5-diaminobenzotrifluoride, of
a Group VIII metal catalyst; and
(4) a polar solvent in a weight ratio to said
4-chloro-3,5-diaminobenzotrifluoride of about 5
to about 20; and
(B) heating said composition at a temperature between
room temperature and the boiling point of said
solvent.
21. A method according to Claim 20 wherein said Group VIII
metal catalyst is palladium on carbon.
- 16 -

Description

2~7~17
Case 6146~59/60
RDF/kmf
METHOD OF MAXING BENzorRIFLuoRID~ CONPOUND
Background of the_Invention
This invention relates to a method of making a
benzotrifluoride compound by reacting a
para-halobenzotrifluoride compound with a hydrogen transfer
agent in the presence of a metal hydrogenation catalyst.
Until now, benzotrifluoride could be made only by
complicated processes that involved the use of materials that
are difficult to handle. In one process, benzoic acid was
reacted with sulfur tetrafluoride, and, in another process,
benzotrichloride was reacted with hydrofluoric acid. A less
complicated route that uses safer reactants would reduce the
cost of producing benzotrifluoride and related compounds.
In U.S. Patent 4,022,795, Example 2, it is suggested that
2-aminobenzotrifluoride can be prepared from 5-chloro-2-
aminobenzotrifluoride. The reaction occurs in water using
sodium hydroxide, a surface active agent such as a phase
transfer catalyst (benzyl triethylammoniu~ chloride in Example
2), and palladium on charcoal. While the reaction conditions
remove halogen ~rom a benzene ring, and will also reduce nitro
; ; groups to amino groups, a competing reaction also occurs in
which two or more aromatic or heteroaro~atic nuclei are joined
together at the positions formerly occupied by nuclear chlorine
or bromine atoms. In the Examples, these dimers can constitute
over 60% of the product. The presence of these unde~irable
~ 022690
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2~37~17
by-products reduces the yield of the benzotrifluoride compound,
adds to the expense of producing the desired product, and ;
complicates purification of the product.
Summary of the Invention
We have discovered that benzotrifluoride compounds can be ~, -
made by reacting a para-halobenzotrifluoride compound with a
hydrogen transfer agent in the presence of a metal
hydrogenation catalyst. Unlike some prior methods of making
benzotrifluoride compounds, the method of this invention does
not involve complicated procedures or the use of dangerous
starting materials.
While U. S. Patent 4,022,795 suggests that the use of a
phase transfer catalyst is necessary to reduce the formation of
dimers (see Examples 1 and 2), we have found that with our
para-halobenzotrifluoride compounds, the presence of a phase
transfer catalyst is not required to reduce the formation of
dimers. By using at least 0.05 wt% of a metal hydrogenation
cotalyst we are able to greatly reduce the production of
undesiroble dimer by-products of the type that were formed in
the reactions in U.S. Patent 4,022,795. Surprisingly, even
though in our reaction the solid catalyst must catalyze a
r-action thot can be betwe-n two immiscible liquids, we have
ound~that the reaction proceeds to completion, even in the
abs-nce of a surface active agent.

- 2~37~:~7
escription of the T~v8a~a
The para-halobenzotrifluoride compounds used in the
process of this invention have the general formula
R~R ~ ~
where X is chlorine or bromine and each R is independently
selected from hydrogen, nitro, and amino. In the formula, X is
preferably chlorine as those compounds are less expensive.
Also in the formula, both R groups are preferably either
hydrogen, as that produces benzotrifluoride (BTF), a valuable
product, or one R group is hydrogen and the other R group is
nitro as that produces m-aminobenzotrifluoride (MABTF), which
is also a valuable product. M ditionally, both R groups are
preferably amino groups, as that produces
3,5-diaminobenzotrifluoride (DABTF), which is al80 a valuable
product. Most of the starting materials included w$thin the
scope in the general formula are commercially available. For
example, 4-chloro-3,5-dinitrobenzotrifluoride (CDNBTF) and
4-chlor3benzotrifluorSde~(PCBTF) are commercially available in
bulk,~3-nltro-4-chlorobenzotrifluoride can be made by nitrating
4-oh~lorob-nzotrifluoride, and 4-chloro-3,5,-diamSnobenzo-
trifluoride (CDA~TF) is readily available via r~duction of
~ ~ -
CDNBTF.
The~para-halobenzotrifluoride compound is reacted with a
hydrogen~transfer agent, which can be an alkali metal formate,
_ 3 _

2~37~ 7
ammonium formate, or a mixture thereof. The alkali metal
formate or ammonium formate can be added as such, or can be
formed in situ by reacting formic acid with a base. Alkali
metal formates are preferred because they work well, they are ;
inexpensive, and the by-products formed in the reaction are
easier to handle; sodium formate is especially preferred
because it is inexpensive. A stoichiometric amount of the
hydrogen transfer agent can be present to remove the chlorine
and to reduce any nitro groups that are present to amino
groups, but it is preferable to use up to 10 mole% excess of
the hydrogen transfer agent in order to insure completion of
the reaction.
The reaction is catalyzed by a metal hydrogenation -
catalyst, which is a Group VIII metal; examples of such
catalysts include activated nickel and precious metals such as,
for example, palladium, platinum, rhodium, and ruthenium. The
preferred catalyst is palladium on a carbon substrate (Pd/C) as
lt has been found to work very well. In order to avoid the
production of large amounts of dimer by-product, it is
necessary to use at least about 0.05% by weight catalyst, based
on the weight of the halobenzotrifluoride. While more catalyst
than about 1% by weight can be used, the small additlonal
beneflt 1- usually not worth the additional expense.
It~1- poss1ble to conduct the reaction by melting the
reactants, but it is preferable to conduct the reaction in a
solv-nt.~ Since some of the starting materials are relatively
iD~soluble in~most solvents, they may be present as solids until
the~dissolved starting~material reacts and additional solid
4 -
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: :.......... : . : :: . : ~ : . . .

2~37~ 7
starting material dissolves. A polar solvent, either protic or
aprotic, can be used. Examples of suitable polar aprotic
solvents include dimethylformamide, dimethylsulfoxide, and
n-methylpyrrolidinone. Examples of suitable polar protic
solvents include water and alcohols such as methanol,
n-octanol, and diethylene glycol. Preferably, the solvent
should differ sufficiently in boiling point from the
benzotrifluoride compound product so as to permit one to easily
boil off either the solvent or the benzotrifluoride compound.
If the starting material is a nitro-halobenzotrifluoride, the
solvent is preferably water or an alkanol up to C3, as the
aminobenzotrifluoride product will have a higher boiling point
than the solvent and the solvent can be easily separated by
distillation. If the starting materiaI is PCBTF, the solvent
is preferably diethylene glycol or n-octanol as the
benzotrifluoride product can then be distilled off a~d,
thereby, separated from the solvent. Any amount of solvent can
be used but it is preferable to use a ratio of about S to about
20 parts by weight solvent to 1 part by weight
halobenzotrifluoride compound.
The reaction proceeds by heating the reactants to a
temperature between about room temperature and about the
bolllng;point of the solvent, ir a solvent is present.
Preferably, the~reactants are heated to about 60 to about 90oC.
While the pH of the reaction mixture is not critical, it is
usually basic. Mhen a palladium on carbon catalyst is used, it
is~preferable to cover~the reaction mixture with an inert
atmospheré such as nitrogen to prevent the ignition of the
.

2~37~7 :
~
palladium in air. The reaction can be monitoxed by gas
chromatography to determine when it is complete.
The benzotrifluoride products can be used for making a
variety of products. For example, the diaminobenzotrifluorides
can be used to make specialty polymers, meta-aminobenzotri-
fluoride and ~enzotrifluoride can be used in making pesticides
and herbicides, and benzotrifluoride can be used to make
p~armaceuticals.
The following examples further illustrate this invention.
EXAMPLE 1
Preparation o BTF by the Hydrodechlorination of PCBTF
using Sodium Formate in Methanol
A 20 mL round-bottom flask was charged with 1.01 g PCBTF,
0.56 g sodium formate, and lO mL methanol. After purging the
flask with a nitrogen atmosphere, 0.10 g of 10% Pd/C was added
and the reaction mixture was heated, with stirring, in an oil
bath (45 to 95C, 1.5 h). After diluting the reaction mixture
with methanol and filtering, gas chromatographic (GC) analysis
indicated a 98.3% yield of BTF.
EXAMPLE 2 ~ -
Prepa~ 5lon of BTF by the Hydrodechlorination of PCBTF
using Ammonium Formate in Methanol
Th~ above experiment was run using ammonium formate (0.50
g) in place of sodium formate; a 99.5% yield was determined
after 1.1 h at 67 to 71C (bath temperature).
6 - -
~ .
.: ~ .; : , . . . . ..

2~7~17
EXAMPLE 3
~ xample 1 was repeated using different solvents and
reactions conditions: the results are summarized in the
following table.
Pd/C Catalvst GC ANALYSIS
Solvent _~ Wt% hours BTF PCBTF Dimer
methanol 1 10 1 85.8 0 14~2
methanol 5 lo 3 93.2 o 6.8
methanol 10 10 3 97.7 0 1.8
methanol 10 1 5 81.0 0 16.0
methanol 10 5 3 97.6 o 2.4
methanol l 1 18 54.1 13 32.4
n-octanol 10 11.6 3.2 78.2 o.s 14.0
diethylene 10 12.1 1 87.4 0 11.7
glycol
EXAMPLE 4
Preparation of BTF by the Hydrodechlorination of PCBTF -
usin~ Sodium Formate in Diethylene Glycol
A 500 mL round-bottom flask equipped with a magnetic
stirrer and a condenser was charged with 20.07 g PCBTF, 32.16 g
sodium formate, and 200 mL diethylene glycol, and was purged
with nitrogen. To this was then added 1.0111 g 10% Pd/C and
the flask was immersed in a preheated oil bath and stirred at
60 to 66~C for lO h. After allowing to cool to room
temperature, the flask was adapted for distillation and 11.05 g ~!-
BTF ~68.1% yield, 96.0% purity by GC) was collected by
distillation at water aspirator pressure (15 to 25 mm Hg, 60 to
65C).
The reaction mixture was then reused by adding fresh PCBTF
(20.6 g) and fresh sodium formate (30.4 g). After heating for
,
18.5 h (60 to 90~C), 11.02 g of BTF (66.1% yîeld, 91.1% purity
by GC) were collected by distillation in a æimilar fashion.
:; ' ' -
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'' ' : :. ~: , ' " ' . . - ':

20~7~ 7
The catalyst from the reaction mixture was then reused a
third time by first filtering and washing it with methanol (4 X
loo mL), then water (4 X 100 mL), followed by methanol (4 X 100
mL), then drying under full vacuum ( about 0.5 mm Hg, 7h., 0.97
g recovered). This was then charged in a 250 mL flask with
PCBTF (10.05 g), sodium formate (16.22 g), and diethylene
glycol (100 mL), and heated at 80 to 84OC for 7.4 h. In a
similar fashion to above, 5.94 g of BTF (73.1% yield, 96.5
purity by GC) was collected by distillation.
EXAMPLE 5
Preparation of MABTF
Example 1 was repeated using
m-nitro-p-chlorobenzotrifluoride (MNPCBTF). The following
table gives the conditions and the results.
Sodium
NNPCBTF Formate Methanol Temp. h GC Area %
grams equiv. mL MABTFMNBTF
1 1.9 10 69-88C 215.2%79 9%
1 4.0 10 66-77C 986.7%11 0%
+1.9 69--80C 2 94-0% 0,0%
1006.4 1000 56-68C 2100.0%0.0%
1 6.4 5 69-70C 1 60.7S MNBTF gc istd2
(78.6% conversion)
1 6.4 5 85-98C 4.4 13.3% 78.4%
~3.2 10 57.5~ ~ABTF gc istd
6.6 100 78-79C 2.3 87.8% MAB~F gc istd
96.0% i801. (97.5% pure)
Catalyst Recycle:
25 6.6 100 80-84C 4.5 72.1% MABTF gc istd
65.5% isolated
Water + 4.4 wt~ ~Aliquat-336~ -no solvent:
6.6 10 mL H20 81-82C 2.5 16.9 39.6%
~5~ mL H20 75-82C 6.6 78.4% ~ABTF gc istd
77.1% isolated
' ~
~ ~ :
~ .
- 8 -
'! ' . .

2~37~1.7
Other catalyst loadinas:
10 wt% Pd-C: MABTF MNBTF
25 4.0 100 73-86C 22 o 57.3%
(69% conversion)
+4.0 75-81C 22.8 84.6% 0
5 wt% 10% Pd-C: 54.1% MABTF gc istd
4.0 100 73-83C 22 44.4~ 46.1%
+4.0 81-85C 22.8 90.0% 0
78.1% MABTF qc istd
1 m-nitro benzotrifluoride intermediate
2 GC, internal standard
3 reused catalyst from previous experiment
4 tricaprylmethylammonium chloride sold by Aldrich Chemical
Co. This is a phase transfer catalyst and this experiment
is, therefore, outside the scope of this invention.
EXAMPLE 6
Preparation o~_~ABTF using ~queous sodium ~ormate
Example 1 was repeated using 6.6 equivalents of sodium .
formate
CF3 CF3
105-110C ~ `
Y~N2H2O/HCO2Na NH2 '~
MNPCBTFFd/C - MA8TF
., .
Com~ents EL 10% Pd-C h YI~L~
- Water GC IS~ Iso~a~ç~
"standard" 100 10 wt% 4.6 86.3
+4.4 wt% 1100 10 wt% 23.3 5%
"Aliquat 336"
les~ water 35 10 wt% 1.~ 82.1% 91.3%
recycle cat.35 reuse 1.1 99.6% 92.0%
recycIe again35 reuse 13.4 60.5%
less catalyst35 2 wt% 8.3 84.4% 89.9%
les~ cat~lyst35 3 wt% 2.1 85.5% 93.6%
rèpéat 3S~e~ t.35 3 wt% 2.7 90.0% 92 9%
le6s~ HCOONa35 3 wt~ 8.6 73%
50 g scale 175 3 w~% 1.4 94.8% 88.3%
rècycle c~t.175~ reuse 20.5 9g.2% 100%
outsid- the scope of thi~ invention
2 ~ 5.6~equiv. of HCOONa were used in this experiment

2~7 ~ 7 ~
B~ ~e~ction Balance
Two reactions are taking place hydrogenolysis of an aryl
chlorine and reduction of a nitro-group to an amine The
separate equations are
ArCl + NaOOCH -----> ArH + NaCl + C02
ArN02 + 3 NaOOCH -----> ArNH2 + Co2 ~ Na2C03 + Na~CO
also 2NaHCo3 <======> Na2C03 + H20 + Co2
Thus, the overall eguation is:
CF3 CF3
~ + 4NaOOCH ~ ~
NO2 NH2
+ NaCl - . -
+ 2.5 CO2
+ 1.5 Na2CO3
* 0 5 H20
EXAMPLE ~
Pre~aration of MABTF by the Reduction/Hydrodechlorination
of MN~C~TF
A~250 mL ~ingle-neck flask equipped with a condenser was
:
charged with~25 09 g ~NPC8TF (Marshallton, 111 2~mmol), 50 24 g
sodium~formate (738 7 l,~ 6 6~ 1e -quiv ), and lOO mL
methanol; This w~ th-n purged with nitrogen, 2 57 g (10 2
wt~) o~10%~Pd~on C~(Aldrich~ was~added,~and the reaction flask
was~im~me~rsed~in;a~pr-h~ated oil bath~;at 79 C Aft-r stirring -;
2 3~h under r flux~the~r action mixture wa cooled to room - -
er~tyr-~and~l50~mL~eaoh-of~wat-r and methylen chloride
w~ro~dded~with ~tirring ~ The~r~action mixture was filtered to

~37~:~ 7
recover the catalyst, and this was washed with 3 X 100 mL of
methylene chloride, the washings being added to the filtrate.
The layers were separated and the aqueous layer was extracted
with a further 100 mL or methylene chloride. Analysis of the
extracts by gc using n-hexadecane as internal standard
indicated the presence of MABTF amounting to an 87.8% yield.
The extracts were dried over anhydrous ssdium sulfate,
filtered, and stripped on a rotary evaporator to yield 17.21 g
of MABTF (96.0% yield, 97.5% purity by gc istd).
EXAMPLE 8
Preparation of DABTF by Hydrodechlorination
of CDABTF in Water
To 10 m~ of water was added 1.0 g (4.76 mmol) of CDABTF.
Solid sodium formate was added (0.39 g, 5.73 mmol), along with
0.1 g of 10% palladium on activated carbon. The mixture was
heated at 90DC until complete. The catalyst was filtered cff
and washed with ethyl acetate. The aqueous layer was extracted
twice with ethyl acetate and dried over magnesium sulfate.
After removal of the solvent, 0.76 g (91.5%) of crude DABTF was
isolated, mp 89 to 90C.
--
- 11 - ".. -
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.: . , . , : , . : . . .

2~7~ 7
EXAMPLE g
Preparation of DABTF by HYdrodechlorination of CDABTF in
Methanol
To 100 mL of methanol was added 10.0 g (0.0476 mol) of
CDABTF. Solid sodium formate was added (8.1 g, o.l19 mmol),
along with l.0 g of 10% palladium on activated carbon. The
mixture was heated at 70C until complete and 200 mL of water
was added to dissolve the salts. The catalyst was filtered off
and washed with toluene. The aqueous layer was extracted with
toluene and the combined extracts were dried over magnesium
sulfate. After removal of the solvent, 6.75 g (80.5%) of crude
DABTF was isolated.
.: ~ :
: