Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING 4-AMINODIPHENYLAMINES
BACKGROUND OF THE INVENTION
1. Field ofi the Invention
The present invention relates to a process for preparing 4-aminodiphenyl-
amines intermediates.
2. Related Art
4-Aminodiphenylamines are widely used as intermediates in the
manufacture of alkylated derivatives having utility as antiozonants and
antioxidants, as stabilizers for monomers and polymers, and in various
specialty
applications. For example, reductive alkylation of 4-aminodiphenylamine (4-
ADPA) with methylisobutyl ketone provides N-(1,3-dimethylbutyl)-N'-phenyl-p-
phenylene-diamine, which is a useful antiozonant for the protection of various
rubber products.
4-Aminodiphenylamine derivatives can be prepared in various ways. An
attractive synthesis is the reaction of an optionally substituted aniline with
an
optionally substituted nitrobenzene in the presence of a base, as disclosed,
for
example, in U.S. 5,608,111 (to Stern et al.) and U.S. 5,739,403 (to Reinartz
et
al.).
U.S. 5,608,111 describes a process for the preparation of an optionally
substituted 4-ADPA wherein in a first step optionally substituted aniline and
optionally substituted nitrobenzene are reacted (coupled) in the presence of a
base. In working examples, aniline and nitrobenzene are. reacted in the
presence of tetramethylammonium hydroxide as the base, and water and aniline
are azeotropically removed during the coupling reaction.
International publication WO 00/35853 discloses a method of preparation
of intermediates of 4-aminodiphenylamine by the reaction of aniline with
nitrobenzene in a liquid medium where the reaction system consists of a
solution
of salts of true zwitterions with hydroxides. A combination of potassium
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hydroxide and betaine hydrate is exemplified. The reaction may take place in
the presence of free oxygen.
EP publication 566 783 describes a method of manufacture of 4-
nitrodiphenylamine by the reaction of nitrobenzene with aniline in the medium
of
a polar aprotic solvent in a strongly alkaline reaction system. A phase
transfer
catalyst such as tetrabutylammonium hydrogen sulfate is employed. This
reference requires that the reaction be carried out in an oxygen-free
atmosphere
in order to prevent undesirable side reactions caused by oxidation.
US Patent No. 5,117,063 and International publication WO 01/14312
disclose processes for preparing 4-nitrodiphenylamine and 4-
nitrosodiphenhlamine, using an inorganic base with crown ether, a phase
transfer
catalyst.
US Patent No. 5,453,541 teaches that an external desiccant, such as
anhydrous sodium sulfate, may be used to absorb excess water in an anaerobic
or aerobic process for producing one or more 4-ADPA intermediates in which
substituted aniline derivatives and nitrobenzene are brought into reactive
contact.
The objective of the present invention is to provide a superior method for
producing one or more 4-ADPA intermediates by reacting aniline and
nitrobenzene in the presence of a strong base and a phase transfer catalyst,
or
in the presence of an organic base and an inorganic salt or a metal organic
salt.
SUMMARY OF THE INVENTION
In brief summary, in one embodiment, the present invention is for a
method of producing 4-aminodiphenylamine or substituted derivatives thereof
comprising the steps of:
(a) bringing an aniline or aniline derivative and nitrobenzene or nitrobenzene
derivative into reactive contact;
(b) obtaining a 4-aminodiphenylamine intermediate product by reacting the
aniline or aniline derivative and nitrobenzene or nitrobenzene derivative in a
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confined zone at a suitable time, pressure and temperature, in the presence
of a mixture comprising a strong base, an oxidant and a phase transfer
catalyst selected from the group of compounds defined by:
UR4)e-Y-(R~ R2RsN+)lcX ab
(Z)~
where R~, R2, R3 are the same or different and selected from any straight
chain or branched alkyl group containing from C~ to C2o, (R4)e is hydrogen for
a = 0, R4 is R~R2R3N~ for a = 1 or 2, Y is alkyl, aryl , alkyl aryl or benzyl
and
substituted derivatives thereof, Z is a substituent selected from the group
consisting of hydroxyl, halo, and other hetero atoms, X is an anionic moiety
of
the form fluoride, chloride, hydroxide, sulfate, hydrogensulfate, acetate,
formate; nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate,
oxalate, carbonate, borate, tartrate, citrate, malonate and mixtures of said
compounds, where a = the valence of the anionic moiety (1, 2 or 3), b and c
are whole number integers of value 1, 2 or 3 and d is a whole number integer
of value 0 to 4; and
(c) reducing the 4-aminodiphenylamine intermediate product of step (b) to
produce 4-aminodiphenylamine or substituted derivatives thereof.
In a second embodiment, the present invention is a method of producing
4-aminodiphenylamine or substituted derivatives thereof comprising the steps
of:
(a) bringing an aniline or aniline derivative and nitrobenzene or nitrobenzene
derivative into reactive contact;
(b) obtaining a 4-aminodiphenylamine intermediate product by reacting the
aniline or aniline derivative and nitrobenzene or nitrobenzene derivative in a
confined zorie at a suitable time, pressure and temperature in the presence of
a mixture comprising an oxidant and a strong base that also functions as a
phase transfer catalyst selected from the group of compounds defined by:
I(R4)e-~'-(R~R2Rsn1+)~c(OI-I)b II
(
(Z)a
.5
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where R~, R2, R3 are the same or different and selected from any straight
chain or branched alkyl group containing from C~ to C2o, (R4)e is hydrogen for
a = 0, R~ is R~R~R3N+ for a = 1 or 2, Y is alkyl, aryl , alkyl aryl or benzyl
and
substituted derivatives thereof, Z is a substituent selected from the group
consisting of hydroxyl, halo, and other hetero atoms, b and c are whole
number integers of value 1, 2 or 3 and d is a whole number integer of value 0
to 4; and
(c) reducing the 4-aminodiphenylamine intermediate product of step (b) to
produce 4-aminodiphenylamine or substituted derivatives thereof.
In a third embodiment, the present invention is a method of producing 4-
aminodiphenylamine or substituted derivatives thereof comprising the steps of:
(a) bringing an aniline or aniline derivative and nitrobenzene or nitrobenzene
derivative into reactive contact; and
(b) obtaining a 4-aminodiphenylamine intermediate product by reacting the
aniline or aniline derivative and nitrobenzene or nitrobenzene derivative in a
confined zone at a suitable time, pressure and temperature, in the presence
of a mixture comprising an inorganic salt or metal organic salt, or mixtures
thereof, having a cation that would be a suitable cation of a strong inorganic
base, an oxidant and one or more of an organic base selected from the group
of compounds defined by:
UR4)e-~'-(R~ R2RsN+)1cX ab I I I
(Z)d
where R~, R2, R3 are the same or different and selected from any straight
chain or branched alkyl group containing from 1 to about 20 carbon atoms, a
is a whole number integer of value 0, 1, 2 or 3, (R4)e is hydrogen for a = 0,
R4
is R~R2R3N~ for a = 1, 2, or 3, X is an anion capable of abstracting a proton
from the nitrogen of an aniline or aniline derivative, Y is alkyl, aryl ,
alkyl aryl
or benzyl and substituted derivatives thereof, Z is a substituent selected
from
the group consisting of hydroxyl, halo, and other hetero atoms, where a = the
valence of the anionic moiety and is a whole number integer of 1, 2, 3 or 4, b
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and care whole number integers of value 1, 2, 3 or 4 and d is a whole number
integer of value 0, 1, 2, 3 or 4, said mixture not including a reaction
product of
betaine and a strong inorganic base; and
(c) reducing the A.-aminodiphenylamine intermediate product of step (b) to
5 produce 4-aminodiphenylamine or substituted derivatives thereof.
Other embodiments of the present invention encompass details about
reaction mixtures and ratios of ingredients, particular phase transfer
catalysts
and particular strong bases, all of which are hereinafter disclosed in the
following
discussion of each of the facets of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method, as described above, for
making intermediates of 4-ADPA that has superior yield and selectivity for
those
intermediates. Such intermediates comprise 4-nitroso- andlor 4-
nitrodiphenylamines (p-NDPA and 4-NDPA, respectively) and salts thereof. The
intermediates may then be hydrogenated to produce 4-aminodiphenylamine.
An example of a substituted and multifunctional phase transfer catalyst
that is consistent with the above formula 1 is (2S, 3S)-bis(trimethylammonio)-
1,4-
butanediol dichloride. Other effective phase transfer catalysts fitting
formula I, in
addition to those shown in the following examples, can be derived from
examples
in the literature, such as C. M. Starks and C. Liotta, Phase Transfer
Catalysis,
Principles and Techniques, Academic Press, 1978 and W. E. Kelley, Fluka-
Compendium, Vol. 1,2,3, Georg Thieme Verlag, New York, 1986, 1987, 1992.
An example of a substituted and multifunctional organic base that is
consistent with the above formulas II and III is (2S, 3S)-
bis(trimethylammonio)-
1,4-butanediol dihydroxide. Other effective organic bases fitting formulas 1l
and
III, in addition to those shown in the following examples, can be derived from
the
above phase transfer catalysts, wherein the anion is replaced by hydroxide or
other suitable anion form.
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Phase transfer catalysts known or believed to be particularly effective in
the method of the invention include tetramethylammonium chloride,
tetramethylammonium fluoride, tetramethylammonium hydroxide, bis-
tetramethylammonium carbonate, tetramethylammonium formate and
tetramethylammonium acetate; tetrabutylammonium hydrogensulfate and
tetrabutylammonium sulfate; methyltributylammonium chloride; and
benzyltrimethylammonium hydroxide (Triton B), tricaprylmethylammonium
chloride (Aliquat 336), tetrabutylammonium chloride, tetramethylammonium
nitrate, cetyltrimethylammonium chloride and choline hydroxide .
Phase transfer catalysts of the present invention have several advantages
over crown ethers, such as 18-crown-6, which were described as effective with
alkali metal hydroxides in references such as US Patent No. 5,117,063 and
International publication WO 01/14312 discussed above. The most obvious
disadvantages of crown ethers are very high initial cost and high toxicity. In
addition, most crown ethers have poor solubility in water, so they cannot be
recovered for recycle with an aqueous base stream. Furthermore, the boiling
points of crown ethers are high enough that they cannot be recovered by
distillation without an extra distillation step. Even for the class of crown
ethers
that have good solubility in water, solubility in organics is also good, so
that there
will be a high loss to the organic product stream. Finally, crown ethers are
known
chelating agents, so that there is a high probability of unacceptable loss of
expensive hydrogenation catalyst metal, due to complexation with the crown
ether.
In the method of the invention, the molar ratio of phase transfer catalyst to
nitrobenzene reactant is preferably from about 0.05:1 to about 1.2:1.
The method of the present invention may also start with an organic base
and an inorganic salt or a metal organic salt as in the above third
embodiment.
The organic base is defined by formula Ilf in that embodiment.
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Organic bases known or believed to be particularly effective for the second
and third embodiments include quaternary ammonium hydroxides selected from
the group consisting of, but not limited to, tetramethylammonium hydroxide,
tetrabutylammonium hydroxide, methyltributylammonium hydroxide,
benzyltrimethylammonium hydroxide (Triton B), tricaprylmethylammonium
hydroxide, cetyltrimethylammonium hydroxide and choline hydroxide, and
equivalent quaternary ammonium alkoxides, acetates, carbonates, bicarbonates,
cyanides, phenolics, phosphates, hydrogen phosphates, hypochlorites, borates,
hydrogen borates, dihydrogen borates, sulfides, silicates, hydrogen silicates,
dihydrogen silicates and trihydrogen silicates.
The term '"strong inorganic base" as used with respect to the meaning of a
cation of an inorganic salt or metal organic salt is intended to mean a base
that is
capable of abstracting a proton from the nitrogen of an aniline or aniline
derivative, and may include any base having a pKb less that about 9.4, which
is
the pKb of aniline. Various aniline derivatives may have different pKb values,
but
a pKb of about 9.4 is employed as a general guide. The base will preferably
have
a pKb less than about 7.4.
The term "capable of abstracting a proton from the nitrogen of an aniline
or aniline derivative" as applied to anion "X" of formula III, is intended to
mean
an anion also having a pKb value as discussed above with respect to the strong
inorganic base.
Possible anions for "X" in formula III, in addition to hydroxide, include:
alkoxide (pKb < 1), acetate (pKb = 9.25), carbonate (pKb = 3.75), bicarbonate
(pK~ = 7.6), cyanide (pKb = 4.7), phenolic (pKb = 4.1 ), phosphate (pKb =
1.3),
hydrogen phosphate (pKb = 6.8), hypochlorite (pKb =6.5), borate (pKb < 1 ),
hydrogen borate (pKb < 1), dihydrogen borate (pKb = 4.7), sulfide (pKb = 1.1),
silicate (pKb = 2), hydrogen silicate (pKa = 2), dihydrogen silicate (pKb =
2.2)
and trihydrogen silicate (pKb = 4.1).
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While aniline most effectively couples with nitrobenzene, certain aniline
derivatives comprising amides such as formanilide, phenylurea and carbanilide
as well as the thiocarbanilide can be substituted to produce 4-ADPA
intermediates.
Although the reactants of the method of the invention are referred to as
"aniline" and "nitrobenzene", and when it is 4-ADPA that is being manufactured
the reactants are in fact aniline and nitrobenzene, it is understood that the
reactants may also comprise substituted aniline and substituted nitrobenzene.
Typical examples of substituted anilines that may be used in accordance with
the
process of the present invention include but are not limited to 2-
methoxyaniline,
4-methoxyaniline, 4-chloroaniline, p-toluidine, 4-nitroaniline, 3-
bromoaniline, 3-
bromo-4-aminotoluene, p-aminobenzoic acid, 2,4-diaminotoluene, 2,5-
dichloroaniline, 1,4-phenylene diamine, 4,4'-methylene dianiline, 1,3,5-
triaminobenzene, and mixtures thereof. Typical examples of substituted
nitrobenzenes that may be used in accordance with the process of the present
invention include but are not limited to o- and m-methylnitrobenzene, o- and m-
ethylnitrobenzene, o- and m-methoxynitrobenzene, and mixtures thereof.
The method of the invention includes the step wherein the 4-ADPA
intermediates or substituted derivatives thereof from step (b) are subjected
to a
hydrogenation reaction involving the use of a hydrogenation catalyst. Details
concerning choice of catalyst and other aspects of the hydrogenation reaction
may be found in U.S. Patent No. 6,140,538, incorporated by reference herein.
Other means of reduction, that do not involve the direct use of hydrogen
and are known to one skilled in the art, can also be used to reduce the 4-ADPA
intermediates or substituted derivatives thereof to 4-ADPA or substituted
derivatives thereof.
The present invention further relates to a process for preparing alkylated
derivatives of 4-aminodiphenylamines, in particular for preparing alkyl
derivatives
of 4-ADPA itself, which are useful for the protection of rubber products, in
which
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process an optionally substituted aniline and an optionally substituted
nitrobenzene are coupled and subsequently reduced according to the invention
process, after which the 4-aminodiphenylamine so obtained is reductively
alkylated to an alkylated derivative of the 4-aminodiphenylamine according to
methods known to the person skilled in this technical field. Typically, the 4-
ADPA
and a suitable ketone, or aldehyde, are reacted in the presence of hydrogen
and
platinum-on-carbon as catalyst. Suitable ketones include methylisobutyl
ketone,
acetone, methylisoamyl ketone, and 2-octanone. See for example U.S.
4,463,191, and Banerjee et al, J. Chem. Soc. Chem. Comm. 18, 1275-1276
(1988). Suitable catalysts can be the same as, but not limited to, those
described above for obtaining the 4-ADPA.
In a preferred embodiment of the invention, the reduction is conducted in
the presence of water, e.g. water is added to the reaction mixture. The use of
water is particularly advantageous when the suitable base, used during the
reaction of the aniline or substituted aniline derivative and the nitrobenzene
or
substituted nitrobenzene derivative, is water-soluble. When the base is water-
soluble, the amount of water added is preferably at least the amount needed to
extract the base from the organic phase. Similarly, the addition of water is
also
preferred for reductive alkylation, if it is carried out in the presence of
the suitable
base, which is water-soluble.
The molar ratio of aniline to nitrobenzene in the process according to the
present invention is not particularly important, as the process will be
effective with
an excess of either.
Strong bases particularly effective in the first embodiment of the process
of the present invention include potassium hydroxide, sodium hydroxide, cesium
hydroxide, rubidium hydroxide and potassium-t-butoxide. It is preferred that
mole
ratio of strong base to nitrobenzene is greater than about 1:1. A particularly
preferred mole ratio of strong base to nitrobenzene is about 2:1 to about 6:1.
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Inorganic salts and metal organic salts that may be used in conjunction
with the organic base in the third embodiment of the process of the invention
have a cation that would be a suitable cation of a strong inorganic base.
These
inorganic salts and metal organic salts are selected from the group consisting
of,
5 but not limited to, the fluoride, chloride, bromide, sulfate, hydrogen
sulfate,
nitrate, phosphate, dihydrogen phosphate, formate, acetate, oxalate, malonate,
citrate, tartrate, maleate, chlorate, perchlorate, chromate, rhenate and
carbonate
salts of cesium, rubidium, potassium and sodium. In the method of the
invention,
the inorganic salt or metal organic salt may be used in molar ratio to
10 nitrobenzene from about 0.05:1 to about 6.5:1.
Inorganic salts and metal organic salts known or believed to be particularly
effective in the third embodiment method of the present invention are those
that
afford acceptable solubility for the inorganic salt or metal organic salt -
organic
base combination in the reaction medium, including the fluoride, chloride,
bromide, sulfate, hydrogen sulfate, nitrate, phosphate, formate, acetate and
carbonate salts of cesium, rubidium, potassium and sodium and mixtures
thereof. It is preferred that mole ratio of organic base used with an
inorganic salt
or metal organic salt to nitrobenzene is greater than or equal to about 1:1.
It is
also preferred that mole ratio of inorganic salt or metal organic salt to
organic
y base is greater than or equal to about 1:1. A particularly preferred mole
ratio of
organic base to nitrobenzene is about 1.1:1 to about 6:1.
It may be desirable to use a combination of an inorganic salt with a metal
organic salt, two or more inorganic salts and/or two or more metal organic
salts in
case one of the salts that is otherwise effective for use in the process of
the
invention has a corrosive effect on the equipment used with the process. The
combination might also provide better results than could be obtained with one
salt.
The use of inorganic salts and metal organic salts with the organic base is
also believed to reduce undesirable base decomposition.
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In the process according to the third embodiment of the invention, it
should be noted that an organic base with an inorganic salt or a metal organic
salt will give some in situ formation of the equivalent inorganic base and a
phase
transfer catalyst, wherein the anion in formula I for the so formed phase
transfer
catalyst is the anion from the salt. For example, tetramethylammonium
hydroxide plus potassium bromide will give some KOH plus
tetramethylammonium bromide. So the invention would include the direct use of
an inorganic base with any phase transfer catalyst that can be formed in situ,
such as tetramethylammonium bromide, in lieu of tetramethylammonium
hydroxide and a bromide salt as separate ingredients.
A particularly preferred combination of strong base and phase transfer
catalyst is potassium hydroxide and tetraalkylammonium halide. A
preferred halide is chloride. A particularly preferred combination of
organic base and inorganic salt is tetraalkylammonium hydroxide and a salt
in which the anion is a halide, such as potassium halide. A preferred halide
anion is chloride. The above reactions would be carried out in aqueous
solution
with a continuous distillation of aniline-water azeotrope.
The reactive contact of the process of the first embodiment of the
invention is carried out in the presence of an oxidant. The oxidant may be
free
oxygen, or comprise an oxidizing agent such as a peroxide, particularly
hydrogen
peroxide. Nitrobenzene may also function as an oxidizing agent.
In the process of the invention, the oxidant may advantageously need to
be present only for part of the time during which the aniline and nitrobenzene
react. Such partial oxidative conditions are particularly effective for
improving
selectivity. One of these instances is when an inorganic salt with a fluoride
anion
is employed in the reaction mixture of the third embodiment under partial
oxidative conditions. It is believed that better results, conversion and
selectivity,
would also be obtained under partial oxidative conditions when the salt anion
is
sulfate, carbonate, or nitrate and other anions that give relatively low
selectivity.
Another instance is when TMAH is used as a strong base that can also function
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as a phase transfer catalyst for the second embodiment. Moreover, although it
has not been demonstrated for the first embodiment of the process of the
invention, it is believed that partial oxidative conditions would also be
effective for
combinations of inorganic base and phase transfer catalyst that give low
selectivity.
The oxidant used in the second and third embodiments of the invention
may be the same as in the first embodiment.
The reactive contact may be carried out at a temperature of from about
20°C to about 150°C. Other conditions for the reactive contact
include pressures
in the range of from about 20 mbar to about 20 barg. Reaction time is
typically
less than about 3.5 hours. It is advantageous to agitate the reaction mixture
during the entire reaction.
The reactions of step (b) of the first, second and third embodiments of the
present method may be carried out in the presence of not greater than about
10:1 moles water to moles nitrobenzene. The amount of water does not include
the water that hydrates with the reactants andlor with compounds formed in the
process. When the mixture comprising a strong base and a phase transfer
catalyst, or an organic base and inorganic salt or metal organic salt, is in
aqueous solution, the reaction may be carried out with a continuous
distillation of
aniline-water azeotrope.
The first embodiment of the invention may be carried out with the phase
transfer catalyst being tetramethylammonium bromide and the strong base
comprising one or more inorganic bases.
The aqueous phase may be reused to form a new reaction mixture. Fresh
base and phase transfer catalyst or organic base and inorganic salt or metal
organic salt are added to replace losses by decomposition, by-product
formation
and solubility in the separated organic phase. Excess Aniline recovered by
distillation from the reaction product mixture may be combined with make-up
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fresh aniline for recycle to form a new reaction mixture. Recovery of excess
nitrobenzene is preferably carried out prior to hydrogenation of the 4-ADPA
intermediate by a separation step and the recovered nitrobenzene may be
combined with make-up fresh nitrobenzene for use in the process, or
hydrogenated to aniline.
The method of the present invention for the preparation of 4
aminodiphenylamines intermediates may be conducted as a batch process or
may be performed continuously using means and equipment well known to the
skilled person.
The reactive contact in step (a) in the first, second and third embodiments
of the method of the invention may occur in a suitable solvent system. A
suitable
solvent system comprises a polar aprotic solvent. The polar aprotic solvent
may
be selected form the group consisting of, but not limited to, dimethyl
sulfoxide,
benzyl ether, 1-Methyl-2-pyrrolidinone and N,N-dimethylformamide.
The invention, in its second embodiment, is a method where the strong
base also functions as a phase transfer catalyst and the reaction may be in
the absence of an alkali metal hydroxide. In that case the strong base/phase
transfer catalyst is defined by formula II above.
The invention is illustrated by the following examples.
Experimental conditions are detailed within individual examples. In
examples 1-10 the charging of reactors was performed in open air resulting in
some free oxygen being present during the reactions, even when the reactor was
stoppered, except for experiments, where indicated, run for comparative
purposes. No attempt was made to remove water from the reaction mixtures in
examples 1- 10.
In examples 11-16 a flow of air was supplied to the reactor headspace
during all or part of charging reactants, heat-up to reaction temperature,
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nitrobenzene feed and hold, resulting in free oxygen being present during the
reaction, except where indicated. Water was removed from the reaction mixture
by azeotropic distillation with aniline. However, the reaction can also be
effective
without the azeotropic removal of water with aniline.
ANALYTICAL
Yields of individual components were determined by external standard
HPLC. Approximately 0.6 grams of material to be analyzed is accurately
weighed into a 50-mL volumetric flask and diluted with a buffer solution
containing 39% v/v water, 36% v/v acetonitrile, 24% vlv methanol and 1 % vlv
pH
7 buffer. The solution is injected through a 10 pL loop onto a reversed phase
Zorbax ODS HPLC column (250 x 4.6 mm) using a binary gradient pumping
system and the following elution gradient at a constant flow rate of 1.5
mL/minute:
Time, minutes %A %13
0 100 0
25 75
0 100
37.5 0 100
38 100 0
100 0
Eluent A is 75°l° vlv water, 15% v/v acetonitrife and 10%
v/v methanol.
20 Eluent B is 60% v/v acetonitrile and 40% v/v methanol. Detection is UV at
254
nm.
Conversion for examples 1-10 is calculated by sum addition of known
components plus any unknown peaks {assigned an arbitrary mole weight value of
25 216, aniline + nitrobenzene) as analyzed. In some instances, sum conversion
is
greater than 100% due to the formation of derivatives from aniline only.
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Conversion for examples 11-16 is calculated based on the amount of,
unreacted nitrobenzene remaining in the final coupling reaction mass.
Conversion is assumed to be 100% if no nitrobenzene is detected.
5
Selectivity is defined by the formula: (p-NDPA Yield + 4-NDPA
Yield)/(total yield). 4-NDPA is 4-nitrodiphenylamine and p-NDPA is 4-
nitrosodiphenylamine. Total yield is the sum of the yield of all known and
unknown peaks (assigned an arbitrary mole weight value of 216, aniline +
10 nitrobenzene).
In the tables: "An Recr" refers to compounds from which aniline may be
easily recovered and is a sum total of traps-azobenzene and azoxybenzene;
"Others" are aniline and nitrobenzene coupling by-products e.g. phenazine, N-
15 oxy-phenazine, 2-NDPA, 4-phenazo-diphenylamine and any unknowns.
EXPERIMENTAL
Experimental conditions are detailed within individual examples.
EXAMPLE 1
Example 1 illustrates that 4-ADPA intermediates may be formed from
aniline and nitrobenzene in the presence of an inorganic base (potassium
hydroxide) and phase transfer catalyst (tetramethylammonium chloride, TMACI)
in a solvent-free system under relatively mild conditions. Yield of desired
products is dependent on the amount of phase transfer catalyst added.
Aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99%, 4.97 grams,
40 mrfioles), potassium hydroxide (86% ground powder, 7.83 grams, 120
mmoles) and tetramethylammonium chloride were charged to a 50-mL round
bottom flask equipped with magnetic stirrer in the amount indicated in Table 1
below. The reaction was allowed to proceed for 1 hour at 60°C in a
stoppered
flask. Contents were then sampled and analyzed by HPLC.
i
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Table 1
Yield,
Conversionp-NDPA4-NDPA Other
An
Recr
No TMACI added, KOH Only 26.3% 0.8 4.8 5,5 15.2
1.81 grams TMACI, 16 mmoles 59.2% 10.9 26.9 18.4 3.0
(0.4 vs NB)
3.62 grams TMACI, 32 mmoles 90.1 22.4 36.1 28.6 3.0
(0.8 vs NB) %
5.42 grams TMACI, 48 mmoles 98.2% 27.0 37.8 3.0
(1.2 vs NB)
30.3
7.23 grams TMACI, 64 mmoles g4,4% 26.5 36.2 28.9 2.9
(1.6 vs NB)
9.04 grams TMACI, 80 mmoles 98.9% 26.2 36.7 31.8 4.2
(2.0 vs NB)
Similar results were obtained when running the reaction under slightly
varying conditions (equimolar An/NB, higher reaction temperature, longer cycle
time, water addition, etc.) as given below in Table 2.
Aniline (99%, 2.33 grams, 24.8 mmoles), nitrobenzene (99%, 3.08 grams,
24.8 mmoles), potassium hydroxide (86% ground powder, 9.77 grams, 150
mmoles), tetramethylammonium chloride (97%, see Table 2) and water (Table 2)
were charged to a 50-mL round bottom flask equipped with magnetic stirrer. The
water amount was 20% by weight of total reactor charge assuming 14% w/w H20
from KOH. The reaction was allowed to proceed for 2 hours at 80°C in an
open
flask. Contents were then sampled and analyzed by HPLC.
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Table 2
Yield,
Conversion p-NDPA 4-NDPA An Recr Other
No TMACI, KOH Only & 2.15 g H20 2.3% 0.0 0.4 0.4 1.5
0.17 g TMACI, 1.5 mmoles (.06 vs NB) & 2.19 g H20 8.1 % 0.3 5.9 0.7 1.2
0.34 g TMACI, 3.0 mmoles (.12 vs NB) 14.7% 0.7 12.7 ' 0.3 1.0
& 2.23 g H20
0.69 g TMACI, 6.1 mmoles (.25 vs NB) 34.4% 1.7 27.7 2.9 2.1
& 2.32 g H20
1.03_g TMACI, 9.1 mmoles (.37 vs NB) 47.5% 1.6 39.5 4.2 2.2
& 2.41 g H20
1.37 g TMACI, 12.1 mmoles (.49 vs 57.8% 2.6 46.7 5.2 3.3
NB) & 2.49 g HBO
2.06 g TMACI, 18.2 mmoles (.74 vs 89.6% 7.6 61.3 17.7 3.0
NB) & 2.67 g H20
2.74 g TMACI, 24.3 mmoles (.98 vs 92.2% 11.9 64.9 13.4 2.0
NB) & 2.84 g H20
The yield of 4-ADPA intermediates was increased from < 1 % when no
tetramethylammonium chloride was used to almost 77% when a near equimolar
amount of phase transfer catalyst vs. nitrobenzene was added.
In both instances, more p-NDPA relative to 4-NDPA was produced as the
tetramethylammonium chloride charge was increased. Also, more p-NDPA was
formed in the presence of excess aniline (see Example 7).
EXAMPLE 2
Example 2 demonstrates that any of several phase transfer catalysts may
be used with KOH to produce p-NDPA and 4-NDPA from aniline and
nitrobenzene. Results are arranged in order of descending yield.
Charge to 50-mL round bottom flask equipped with magnetic stirrer:
aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99°I°,
4.97 grams, 40
mmoles), potassium hydroxide (86% ground powder, 7.83 grams, 120 mmoles)
and the indicated phase transfer catalyst given in Table 3 below where the
amount of phase transfer catalyst is equal to the limiting reagent charge.
(NOTE:
Some experiments run on 20 or 30 mmole scale as denoted.) Reaction was
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allowed to proceed for 1 hour at 60°C in a stoppered flask. Contents
were then
sampled and analyzed by HPLC.
Results in Table 3 above illustrate that the addition of a phase transfer
catalyst improves the yield of desired products in all cases.
Tetramethylammonium chloride, fluoride, hydroxide, carbonate, formate and
acetate; tetrabutyiammonium hydrogensuffate and sulfate;
methyltributylammonium chloride; and benzyltrimethylammonium hydroxide
(Triton B) are most effective as phase transfer catalysts in combination with
an
inorganic base. Others such as tricaprylmethylammonium chloride (Aliquat 336),
tetrabutylammonium chloride, tetramethylammonium nitrate, and choline
hydroxide are moderately efficient. Bromide and iodide salts and the
zwitterion
betaine are not as suitable. Periodic trends are observed for the
tetramethylammonium salts as yield, conversion and selectivity are all
decreased
when going down in the series from fluoride to iodide.
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Table 3
Yield,
Conversion p-NDPA Other
4-NDPA
An
Recr
Tetrabutylammonium sulfate, 75% 99.2% 56.1 21.2 20.1 1.8
aq., 15.49 gms~
Tetrabutylammonium hydrogensulfate,96.6% 47.9 25.0 21.2 2.4
97%,
10.50 gms*
Tetramethylammonium carbonate, 97.6% 46.6 24.6 23.7 2.8
60% aq.,
6.94 gms~
Tetramethylammonium fluoride 103.6% 42.4 27.2 27.4 6.6
~ 4 H20, 98%, 6.74 gms
Tetramethylammonium acetate, 104.3% 25.9 43.1 35.0 0.4
95t, 5.61 gms
Tetramethylammonium hydroxide 105.0% 38.4 29.6 30.4 6.5
~ 5 HzO, 97%,
7.47 gms
Tetramethylammonium chloride, 98.8% 24.3 37.1 30.8 6.6
97%, 4.52 gms
Methyltributylammonium chloride,81.7% 23.5 30.6 22.2 5.4
75% aq., 12.58 gms
Tetramethylammonium formate, 74.9% 29.0 23.8 21.0 1.1
50% aq., 9.53 gms
Benzyltrimethylammonium hydroxide,52.5% 39.6 6.2 5.5 1.2
40% aq.,
16.73 gms
Tricaprylmethylammonium chloride,67.0% 19.1 21,3 19.6 7.0
99+%,
16.17 gms
Tetramethylammonium nitrate, 61.3% 12.0 27.4 19.6 2.4
96%, 5,67 gms
Choline hydroxide, 50% aq., 9.6959.0% 26.2 6.7 19.6 6.6
gms
Tetrabutylammonium chloride ~ 42.6!0 8.2 23.8 9.3 1.2
H20, 98%, 8.51 gms*
Betaine, 98%, 4.78 gms 55,0% 13.0 17.2 19.6 5.2
Cetyltrimethylammonium bromide, 36.2% 7.0 19.3 8.7 1.1
95%, 11.51 gms*
Tetramethylammonium bromide, 36.5l0 11.3 12.2 6.7 6.3
98%, 6.29 gms
Tetrabutylammonium bromide, 99%,34.1 8.3 14.2 5.8 5.7
13.03 gms %
Polyethylene glycol (MW = 200), 33.4% 11.9 0.6 17.2 3.7
8.00 gms
Tetramethylammonium iodide, 99%,27.8% 2.4 8.0 5.8 11.6
8.12 gms
Tetrabutylphosphonium bromide, 25.6% 1.6 5.1 9.4 10.0
98!0, 13.58 gms
KOH Only, No phase transfer catalyst19.6% 1.2 4.0 3.3 11.0
added
*30 mmofe scale (16.93 gms aniline, listed)
3.73 gms nitrobenzene, 5.87
gms KOH & PTC as
~20 mmoles (TMA)zC03 & (TBA)ZS04same
(0.5 to 1 vs NB, no.
of
equivalents)
EXAMPLE 3
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Example 3 shows that nitrobenzene may be coupled with a variety of
aniline derivatives to produce 4-ADPA intermediates.
A stoichiometric amount of substrate as listed in Table 4 below;
5 nitrobenzene (99%, 3.08 grams, 24.8 mmoles), potassium hydroxide (86%
ground powder, 9.77 grams, 150 mmofes), tetramethylammonium chloride
(97°!°,
2.74 grams, 24.3 mmoles), and water (2.84 grams) were charged to a 50-mL
round bottom flask equipped with a magnetic stirrer. The reaction was allowed
to
proceed for 2 hours at 80°C in an open flask. Contents were then
sampled and
10 analyzed by HPLC.
Table 4
Yield,
Conversion-NDPA 4-NDPA Other
p An
Recr
Aniline, 99%, 2.33 grams, 95.4% 6.0 68.3 19.9 1.2
24.8 mmoles
Formanilide, 99%, 3.03 grams,84.5% 19.3 47.3 16.3 1.5
24.8 mmoles
Phenylurea, 97%, 3.40 grams, 96.2I 19.2 38.8 13.5 24.8
24.2 mmoles
Carbanilide, 98%, 2.65 grams,48.1 1.3 37.1 9.3 0,4
12.2 mmoles %
Thiocarbanilide, 98%, 2.85 58.6% 5.4 31.6 18.6 3.0
grams,
12.2 mmoles
Acetanilide, 97%, 3.38 grams,8.5l 0.3 2.7 3.6 1.9
24.3 mmoles
Benzamide, 99%, 3.03 grams, 49.4% 0.0 1.0 15.1 33.3
24.8 mmoles
N-Methyl-Benzamide, 99+1, 8.2% 0.0 0.0 0.0 8.2
3.38 grams,
25.0 mmoles
Benzanilide, 98%, 2.47 grams,0.1% 0.0 0.1 0.0 0.0
12.3 mmoles
While aniline most effectively couples with nitrobenzene in a KOH-TMACI
system, amides such as formanilide, phenylurea and carbanilide as well as the
thiocarbanilide can be substituted to produce 4-ADPA intermediates.
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EXAMPLE 4
Example 4 illustrates the reaction of aniline and nitrobenzene using
various bases in combination with tetramethylammonium chloride to produce 4-
ADPA intermediates.
Aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99%, 4.97 grams,
40 mmoles), an appropriate amount of base as given in Table 5 below and
tetramethylammonium chloride (97°l0, 4.52 grams, 40 mmoles) was charged
to a
50-mL round bottom flask equipped with a magnetic stirrer. The reaction was
allowed to proceed for 1 hour at 60°G in a stoppered flask. Contents
were then
sampled and analyzed by HPLG.
Table 5
Yield,
Conversion p-NDPA4-NDPA An Other
Recr
97.1
KOH, 86l0, 7.83 grams, 25.2 35.5 30.6 5.8
120 mmoles (3:1 vs NB)
100.5%
KOH, 86l0, 13.05 grams, 21.5 36.0 32.0 11.0
200 mmoles (5:1 vs NB)
21.3%
NaOH, 98l0, 4.90 grams, 4.7 12.6 3.4 0.6
,
120 mmoles (3:1 vs NB)
50.4%
NaOH, 98l0, 8.16 grams, 11.5 24.5 14.2 0.2
200 mmoles (5:1 vs NB)
98.8%
CsOH~H~O, 95l0, 15.91 grams,20.5 43.2 34.5 0.6
90 mmoles (3:1 vs NB)*
107.1
t BuOK, 95%, 11.84 grams, 15.2 33.4 25.0 33.5
100 mmofes (2'/2:1 vs NB)
51.5%
TMAH~5H20, 22.42 grams, 38.2 7.0 5.9 0.4
120 mmoles (3:1 vs NB)~
*30 mmole scale (16.93 gms 3.73 gms nitrobenzene,
aniline, 3.39 gms TMACI
& base
as
indicated)
~ Tetramethylammonium hydroxide
only. No TMACI added.
Both lithium and calcium
hydroxide were screened
with no reaction
2p observed for either of
these two bases.
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Potassium hydroxide is the preferred base but sodium hydroxide, cesium
hydroxide, potassium t-butoxide and tetramethylammonium hydroxide are also
suitable bases any of which may used in combination with tetramethylammonium
chloride to obtain acceptable rates of conversion.
EXAMPLE 5
Example 5 demonstrates the effect ofi increasing potassium hydroxide
charge on aniline-nitrobenzene coupling products under otherwise constant
reaction conditions with tetramethylammonium chloride as a phase transfer
catalyst.
Aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99%, 4.97 grams,
40 mmoles), potassium hydroxide in the amount given in Table 6 below and
tetramethylammonium chloride (97%, 4.52 grams, 40 mmoles) was charged to a
50-mL round bottom flask equipped with magnetic stirrer. The reaction was
allowed to proceed for 1 hour at 60°C in a stoppered flask. Contents
were then
sampled and analyzed by HPLC.
Table 6
Yield,
Conversion p-NDPA 4-NDPA An Recr Other
No KOH, TMACI Only 0.0% 0.0 0.0 0.0 0.0
1.30 grams KOH, 20 mmoles (0.5;1 54,g% 18.8 19.6 15.7 0.7
vs NB)
2.61 grams KOH, 40 mmoles (1:1 69.2% 21,3 26.8 20.8 0.3
vs NB)
5.22 grams KOH, 80 mmoles (2:1 91.8% 26.0 33.5 29.1 3.2
vs NB)
7.83 grams KOH, 120 mmoles (3:1 97.1 25.2 35.5 30.6 5.8
vs NB) %
10.44 grams KOH, 160 mmoles (4:1 99.1 23.6 36.0 32.0 7.5
vs NB) %
13.05 grams KOH, 200 mmoles (5:1 100.5! 21.5 36.0 32.0 11.1
vs NB)
15.66 grams KOH, 240 mmoles (6:1 101.7% 18.4 33.6 32.7 17.0
vs NB)
Higher excesses of base result ctivity
in poorer reaction sele and
more
by-
product formation. The same trend
is observed when running the
reaction under
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comparatively milder reaction conditions as described in Table 7 below.
Similarly, conversion is a function of the amount of base used.
Aniline (99%, 32.60 grams, 346.5 mmoles), nitrobenzene (99%, 6.16
grams, 49.5 mmoles), potassium hydroxide in the amount given in Table 7 below
(86% ground powder, 16,31 grams, 250 mmoles) and tetramethylammonium
chloride (97%, 5.48 grams, 48.5 mmoles) were charge to a 100-mL round bottom
flask equipped with a Teflon paddle stirrer. The reaction was allowed to
proceed
for 1 hour with no application of external heat (some exotherm generated by
dissolution of KOH in reaction water) in a stoppered flask. Contents were then
sampled and analyzed by HPLC.
Table 7
Yield,
Conversion p-NDPA 4-NDPA An Recr Other
9.77 grams 10.5% 1.3 8.6 0.0 0.6
KOH, 150
mmoles (3:1
vs NB)
13.05 grams 200 mmoles (4:1 64.6% 14.9 26.2 15.4 8.1
KOH, vs NB)
16.31 grams 250 mmoles (5:1 92.2! 21.8 33.0 27.0 10.4
KOH, vs NB)
19.57 grams 300 mmoles (6:1 100.5% 21.7 33.6 31.8 13.5
KOH, vs NB)
22.84 rams 350 mmoles (7:1 104.4% 21.3 33.6 33.5 16.0
KOH, vs NB
EXAMPLE 6
Example 6 indicates the effect that the introduction of an oxidant has on
the conversion of aniline and nitrobenzene to p-NDPA, 4-NDPA and by-products
when utilizing a potassium hydroxide ! tetramethylammonium chloride base-PTC
system.
Aniline (99%, 2.33 grams, 24.8 mmoles), nitrobenzene (99%, 3.08 grams,
24.8 mmoles), potassium hydroxide (86% ground powder, 9.77 grams, 150
mmoles), tetramethylammonium chloride (97%, 0.69 grams, 6.1 mmoles) and
water (2.32 grams) were charged to a 50-mL round bottom flask equipped with a
magnetic stirrer. The reaction was allowed to proceed for 2 hours at
80°C under
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atmospheric conditions described below. Contents were then sampled and
analyzed by HPLC.
The definition of a closed system is a stoppered flask. An open system is
left unstoppered and open to the atmosphere. For gas sweep experiments, a
three-necked flask is substituted for a single-necked fiask, the system
equipped
with both a gas inlet and outlet line, and the appropriate gas swept across
the
reaction mass at a low flow rate.
Table 8
Yield,
Conversion Selectivity p- 4- An Recr Other
NDPA NDPA
Closed System 45.1 % 61.3% 1.4 26.3 15.9 1.5
Open System 34.4% 85.6% 1.7 27.7 2.9 2.1
Gas Sweep, Nitrogen94.8% 58.2% 2.4 52.8 38.3 1.3
Gas Sweep, Air 60.6% 86.8% 2.8 49.8 3.3 4.7
In cases where the reaction is left open to excess air, selectivity is
markedly improved, as opposed to experiments where the amount of oxidant is
limited. Formation of azobenzene is greatly increased in the latter instance.
Improvement in reaction selectivity is reinforced by experiments in Table
9, which demonstrate the effect of hydrogen peroxide addition in the reaction
mixture.
Aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99%, 4.97 grams,
40 mmoles), hydrogen peroxide (50% aqueous, amount indicated in Table 9
below), water (sum total from additional water and peroxide kept constant at
2.16
grams), potassium hydroxide (86% ground powder, 7.83 grams, 120 mmoles)
and tetramethylammonium chloride (97%, 4.52 grams, 40 mmoles) was charged
to a 50-mL round bottom flask equipped with a magnetic stirrer. Peroxide was
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charged to the reaction mixture before adding KOH & TMACI with the flask
quickly stoppered and then the reaction was allowed to proceed for 1 hour at
60°C. Contents were then sampled and analyzed by HPLC.
Table
9
Yield,
An
Conversion p-NDPA 4-NDPARecrOther
Selectivit
No H~Oz & 2.16 g water 96.6% 67.9% 27.9 37.7 30.60.5
0.27 g HzOZ, 4 mmol, (0.1 90.3% 73.8% 27.3 39.4 23.00.7
vs NB)
& 2.02 g water
0.54 g Hz02, 8 mmol, (0.2 86.6% 77.7% 27.3 40.0 18.31.0
vs NB)
& 1.89 g water
1.09 g H202, 16 mmol, (0.486.4% 77.3% 25.5 41.3 18.31.3
vs NB)
& 1.62 g water
1.63 g H202, 24 mmol, (0.686.4% 78.4% 26.9 40.9 17.61.1
vs NB)
& 1.34 g water
2.18 g H202, 32 mmol, (0.879.8% 80.3% 25.6 38.4 14.31.4
vs NB) ~
& 1.07 g water
2.72 g H~O2, 40 mmol, (1.080.8% 82.0% 25.9 40.4 13.01.6
vs NB)
& 0.80 water
The same trend noted for opening the reaction contents to air is also seen
10 for peroxide, namely exposure to an oxidant improves selectivity. This
observation is reinforced by experimental trials where excess nitrobenzene is
used to act as an oxidant. (see Example 7).
EXAMPLE 7
15 Example 7 shows how the ratio of 4-ADPA intermediates can be
controlled by adjusting the amount of aniline charged into the reaction.
Aniline (99%, amount given in Table 10), nitrobenzene (99%, 4.97 grams,
40 mmoles), potassium hydroxide (86% ground powder, 7.83 grams, 120
20 mmoles) and tetramethylammonium chloride (97%, 4.52 grams, 40 mmoles) was
charged to 50-mL round bottom flask equipped with magnetic stirrer. The
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reaction was allowed to proceed for 1 hour at 60°C in a stoppered
flask.
Contents were then sampled and analyzed by HPLC.
Table 10
Yield,
Conv Ratio p-NDPA 4-NDPA An Recr Other
35.28 grams Aniline, 375 mmoles, 87.20 1.34 36.7 27.3 22.2 1.1
15:1 vs NB*
36.69 grams Aniline, 390 mmoles, 93.2% 1.31 37.1 28.4 26.3 1.4
13:1 vs NB~
36.22 grams Aniline, 385 mmoles, 94.7% 1.14 35.2 30.9 26.5 2.2
11:1 vs NB#
33.87 grams Aniline, 360 mmoles, 95.4% 0.96 32.0 33.2 27.5 2.6
9:1 vs NB
26.34 grams Aniline, 280 mmoles, 96.8% 0.75 27.1 36.0 30.3 3.5
7:1 vs NB
18.81 grams Aniline, 200 mmofes, 95.9% 0.60 23.1 38.8 31.1 2.8'
5:1 vs NB
11.29 grams Aniline, 120 mmoles, ~ 92.3% 0.37 15.7. 42.4 30.9 3.4
3:1 vs NB
3.76 rams Aniline, 40 mmoles, 1:1 vs NB 80.1% 0.14 6.1 43.8 24.7 5.5
*25 mmole scale (35.28 gms aniline, 3.11 gms nitrobenzene, 4.89 gms KOH & 2.82
gms TMACI)
~30 mmole scale (36.69 gms aniline, 3.73 gms nitrobenzene, 5.87 gms KOH & 3.39
gms TMACI)
#35 mmole scale (36.22 gms aniline, 4.35 gms nitrobenzene, 6.85 gms KOH & 3.95
gms TMACI)
As more aniline is charged to the reaction, more p-NDPA is formed
relative to 4-NDPA. The same trend is noted under differing reaction
conditions
as outlined in Table 11 below.
Aniline (99%, amount given in Table 11), nitrobenzene (99%, 3.08 grams,
24.8 mmoles), potassium hydroxide (86% ground powder, 9.77 grams, 150
mmoles), tetramethylammonium chloride (97%, 0.69 grams, 6.1 mmoles) and
water (Table 11, 20% wlw) were charged to a 50-mL round bottom flask
equipped with a magnetic stirrer. The reaction was allowed to proceed for 2
hours at 80°C in an open flask. Contents were then sampled and analyzed
by
MPLC.
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Table 11
Yield,
Conv Ratio ,o-NDPA 4-NDPA An Recr Other
12.48 g An, 133 mmol, (5.4 vs NB) & 18.6% 0.52 5.6 10.9 1.0 1.1
4.89 g HBO
8.57 g An, 91.1 mmol, (3.7 vs NB) & 26.5% 0.37 6.5 17.7 1.4 0.8
3.90 g H20
4.66 g An, 49.6 mmol, (2 vs NB) & 28.9% 0.12 2.6 20.9 3.2 2.1
2.91 g HZO
2.33 g An, 24.8 mmol, (1 vs NB) & 34.4% 0.06 1.7 27.7 2.9 2.1
2.32 g H20
1.75 g An, 18.6 mmol, (.75 vs NB) & 42.6% 0.05 1.8 34.6 4.2 2.1
2.17 g H20
1.16 g An, 12.3 mmol, (.50 vs NB) & 56.1 % 0.02 0.8 51.7 1.1 2.5
2.02 g H20
0.58 g An, 6.2 mmol, (.25 vs NB) & 76.7% 0.01 0.9 72.9 1.1 1.8
1.88 g HZO
Yields of 4-ADPA intermediates (p-NDPA + 4-NDPA) remain relatively flat
when aniline is used in excess (approx. 20°I°) but improve
significantly (73.8% at
0.25 to 1 AnINB) when aniline becomes the limiting reagent as noted in Table
11.
Also, selectivity is improved (96.1% at 0.25 to 1 An/NB) when nitrobenzene is
used in excess despite less overall water. As shown in Example 9, less water
typically decreases selectivity in an inorganic base system. Excess
nitrobenzene
here acts as an oxidant, improving selectivity as shown in Example 6 with air
and
peroxide.
EXAMPLE 8
Example 8 illustrates that the reaction between aniline and nitrobenzene
using potassium hydroxide as a base in conjunction with tetramethyiammonium
chloride can be conducted over a wide range of temperatures.
Aniline (99%, 2.33 grams, 24.8 mmoles), nitrobenzene (99%, 3.08 grams,
24.8 mmoles), potassium hydroxide (86% ground powder, 9.77 grams, 150
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mmoles), tetramethylammonium chloride (97%, 0.69 grams, 6,1 mmoles) and
water (2.32 grams, 20°lo wlw) were charged to a 50-mL round bottom
flask
equipped with magnetic stirrer. The reaction was allowed to proceed for 2
hours
at the given temperature in an open flask. Contents were then sampled and
analyzed by HPLG.
Table 12
Yield,
Conversion -NDPA 4-NDPA An RecrOther
Reaction Temperature, g,3% 0.1 8.3 0.0 1.0
20C
Reaction Temperature, 21.6% 0,5 19.5 0.2 1.4
35C
Reaction Temperature, 25.2% 0,8 22.3 0.1 1.9
50C
Reaction Temperature, 26.0% 0,6 22.8 0.4 2.2
65C
Reaction Temperature, 34.4% 1.7 27.7 2.9 2.1
80C
Reaction Temperature, 39,3% 2.3 27.8 7.5 1.7
95C
Reaction Temperature, 53.8% 3.5 33.4 12.8 4.0
110C
Reaction Temperature, 72.7% 9.1 34.0 17.3 12.4
125C
Increasing reaction temperature results~in improved yields and conversion
but reaction selectivity is lost. The amount of p-NDPA, relative to 4-NDPA,
increases With inct~easing temperature.
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Table 13
Yield, Selectivit -NDPA I 4-NDPA
% , l
Reaction Temperature, g,3 89.0 0.01
20C
Reaction Temperature, 20.0 92.3 0.03
35C
Reaction Temperature, 23.1 91.8 0.04
50C
Reaction Temperature, 23.4 90.0 0.03
65C
Reaction Temperature, 29.4 85.6 0.06
80C
Reaction Temperature, 30.1 78.7 0.08
95C
Reaction Temperature, 37.0 68.7 0.11
110C
Reaction Temperature, 43.1 59.2 0.27
125C
10
EXAMPLE 9
Example 9 emphasizes the effect of water in the reaction of aniline and
nitrobenzene with a KOH-TMACI base/phase transfer system to form 4-ADPA
intermediates.
Aniline (99%, 22.58 grams, 240 mmoles), nitrobenzene (99%, 4.97 grams,
40 mmoles), potassium hydroxide (86% ground powder, 7.83 grams, 120
mmoles), tetramethylammonium chloride (97%, 4.52 grams, 40 mmoles), and
water as listed in Tables 14 and 15 was charged to a 50-mL round bottom flask
equipped with a magnetic stirrer. The reaction was aNowed to proceed for 1
hour
at 60°C in a stoppered flask. Contents were then sampled and analyzed
by
HPLC.
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Table 14
Yield,
Conversion p-NDPA 4-NDPA An Recr Other
No Water added 98.6°l0 26.4 38.5 30.4 3.3
2.16 grams H20, 120 mmoles 94.7% 28.5 37.3 28.6 0.4
(3:1 vs NB)
4.32 grams H20, 240 mmoles 67.0% 27.2 21.1 18.4 0.3
(6:1 vs NB)
6.48 grams H20, 320 mmoles 28.3!0 16.3 6.7 5.1 0.2
(9:1 vs NB)
8.64 grams H20, 480 mmoles 5.5% 4.1 1.3 0.0 0.0
(12:1 vs NB)
5 Table 15
Selectivit , % -NDPA / 4-NDPA
No Water added 65.8 0.69
3:1 H~O/NB (1 mole Water vs. KOH) 69.4 0.77
6:1 H20lNB (2 moles Water vs. KOH) 72.1 1.28
9:1 H20/NB (3 moles Water vs. KOH) 81.3 2.44
12:1 HZO/NB (4 moles Water vs. KOH) 100.0 3.08
A general improvement in selectivity and higher levels of p-NDPA relative
to 4-NDPA becomes evident as the amount of water is increased.
The effect of too much water may also be noted from Example 2 and
Table 3 where the effectiveness of a 60% aqueous solution of
tetramethylammonium carbonate as a phase transfer catalyst is shown.
Previous unreported data obtained from a dilute 25% solution indicated
practically no conversion.
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EXAMPLE 10
Example 10 shows that the reaction may be carried out in any of several
solvents.
Aniline (99%, 11.29 grams, 120 mmoles), nitrobenzene (99%, 2.49 grams,
20 mmoles), potassium hydroxide (86% ground powder, 3.91 grams, 60
mmoles), tetramethylammonium chloride (97%, 2.26 grams, 20 mmoles) and 20-
mL of the appropriate solvent as represented in Table 16 was charged to a 50-
mL round bottom flask equipped with a magnetic stirrer. The reaction was
allowed to proceed for 1 hour at 60°C in a stoppered flask. Contents
were then
sampled and analyzed by HPLC.
Table 16
Yield, t
Conversionp-NDPA4-NDPA An Other
Recr
No solvent added 97.1 % 25.2 35.5 30.6 5.8
Dimethyl sulfoxide 99.5% 34.2 37.6 26.1 1.6
Dimethyl sulfoxide, No 36.5% 10.9 15.8 6.4 3.4
phase transfer
catalyst added
Benzyl ether 93.7% 30.6 32.1 28.1 3.0
1-Methyl-2-pyrrolidinone 80.1% 29.3 27.3 17.9 5.6
N,N-Dimethylformamide 74.0% 27.2 27.2 19.1 0.6
p-Xylene 65.9% 8.8 10.1 44.6 2.4
Toluene 63.3% 3.0 3.7 51.1 5.5
Notable is a roughly two-thirds reduction in yield when the phase transfer
catalyst is omitted (26.7% in DMSO without TMACI increasing to 71.8% with
TMACI).
2p Selectivity remains relatively unchanged in polar solvents (~ 70%) but
plunges significantly when non-polar hydrocarbons such as p-xylene or toluene
are selected as azobenzene yields in each of these two solvents exceed 40%.
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EXAMPLE 11
Example 11 demonstrates the reaction of aniline and nitrobenzene in
combination with an aqueous solution of potassium hydroxide and
tetramethyalammonium chloride by continuous distillation of the aniline-water
azeotrope.
111.8 grams aniline (99°l°, 1.19 moles), 31.2 grams aqueous
potassium
hydroxide solution (45%, 0.250 moles) and 50.0 grams aqueous
tetramethylammonium chloride solution (55%, 0.25 moles) were charged to a
500-mL flask equipped with a Teflon paddle stirrer, thermocouple, nitrobenzene
feed tube and needle valve. A vacuum was pulled on the mixture to 120 mm Hg,
regulating pressure by bleeding air across the reactor. Heating was begun and
nitrobenzene flow was started (24.6 grams, 99%, 0.20 moles) when the desired
reaction temperature of 80°C was reached. The temperature was
controlled by
increasing the vacuum so as to complete the NB feed in approximately one hour
at a final pressure of 60 mm Hg. The pressure was held for 45 minutes at 60
mm Hg to insure completeness of reaction. The mixture was quenched with 40
mL of water. HPLC analysis: 32.1% aniline, 0% NB, 20.3% p-NDPA, 7.6% 4-
NDPA, 0.50% t-azobenzene and 0.05% pheanzine. Yields based on 100%
conversion of NB: 72.6% p-NDPA, 25.3%, 4-NDPA, 1.9% t azobenzene, 0.2%,
phenazine.
As shown in Table 17 below, running the identical reaction in the absence
of air resulted in a 12% lower yield (97.9% vs. 85.5%) and a seven fold
increase
in the azobenzene level. A summary of other reactions in this series is also
given
in Table 17 below:
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Table
17
Yield,
ConversionSelectivit-NDPA 4-NDPA
t-Azo
Phenazine
BASELINE:
See conditions below*100.0% 97.9% 72.6 25.3 1.9 0.2
ATMOSPHERE:
Baseline conditions 100.0% 85.5% 66.5 19.0 14.2 0.3
(Vacuum,
No Air)
ANILINE CHARGE:
74.5 gms Aniline, 99.5% 96.2% 56.4 39.8 2.7 0.5
0.79 moles,
4:1 vs NB
149.0 gms Aniline, 100.0% 97.9% 73.8 24.1 1.8 0.3
1.58 moles,
8:1 vs NB
TEMPERATURE
70C 100.0% 98.1 65.1 33.0 1.4 0.5
%
~90C 100.0% 97.1 71.9 25.1 2.7 0.2
%
NITROBENZENE FEED
RATE:
29 minutes 1 D0.0% 85.2% 62.7 22.5 14.4 0.4
86 minutes 99.9% 96.1 76.8 19.2 3.5 0.4
%
BASE CHARGE:
18.7 g 45% KOH, 0.1583.0l0 97.6% 63.1 17.9 1.8 0.2
mol,
0.75;1 vs NB
37.4 g 45% KOH, 0.30100.0% 96.9% 72.7 24.2 2.7 0.4
mol,
1.5:1 vs NB
ATMOSPHERE:
Vacuum, No Air 100.0% 85.5% 66.5 19.0 14.2 0.3
*6:1 Aniline/NB, NB feed NB,
80C, 49 min. time, air
1.25 atmosphere
moles
KOH
vs
EXAMPLE 12
This example demonstrates the reaction of aniline and nitrobenzene in the
presence of an oxidant in combination with an aqueous solution of
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tetramethylammonium hydroxide and various inorganic salts by continuous
distillation of the aniline-water azeotrope. The TMAHlsalt combination
represents an ionic mixture of a potential base recycle stream from a process
comprising an inorganic base and phase transfer catalyst after reduction of
the
coupling reaction mass to 4-ADPA.
Charged to a 500-mL round bottom flask equipped with a Teflon paddle
stirrer, thermocouple, nitrobenzene feed tube and air bleed valve were: 139.7
grams aniline (99%, 1.49 moles), 73.9 grams aqueous tetramethylammonium
hydroxide solution (35.5%, 0.29 moles) and an equivalent amount of salt (vs.
base, in 15% molar excess over nitrobenzene) as listed in Table 18 below. The
mixture was heated for 30 minutes at 120 mm Hg and then nitrobenzene feed
(30.8 grams, 99%, 0.25 moles) was started. The system pressure was regulated
by adjusting the air bleed valve throughout the duration of the reaction cycle
to
maintain the desired temperature of 80°C and to complete the NB charge
in
approximately 75 minutes at a final pressure of 72 mm Hg. The mixture was held
for 30 minutes at 70 mm Hg to insure completeness of reaction and then
quenched with 25 mL water. Air was bled into the reactor headspace during the
entire cycle of charging reactants, heating to reaction temperature, feeding
nitrobenzene and holding for reaction completion. The salts are charged in
molar
equivalence to nitrobenzene at Salt/NB = 1.15. For example, potassium
carbonate and sodium sulfate have two equivalents of inorganic cation, so that
the molar ratio is 0.575.
The results with KCI at a slightly lower mole ratio to nitrobenzene agree
welt with results obtained from the use of strong base and phase transfer
catalyst
(KOH and TMACI), with continuous distillation of the aniline-water azeotrope.
This demonstrates that use of an inorganic salt and organic base is equivalent
to
use of a strong base and phase transfer catalyst. It may be noted that sodium
is
not as effective as potassium for completing the reaction. Nitrate and bromide
are also less effective anions for reaction completion at the conditions of
this
example. However, it should be possible to increase conversion for these salts
by modifying reaction conditions, such as increasing reaction temperature.
Most
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significant is the positive effect of salt addition on reaction selectivity.
Comparison of the second and third experiments in Table 18 above shows that
with the addition of KCI only, azobenzene was reduced by nearly two-thirds and
relatively small amounts of "Other" compounds such as 4-Phenazo-
5 diphenylamine were formed. The "TMAH Only" run was also characterized by
high levels of compounds such as N-methylaniline and a stench of
trimethylamine, both of which are indicative of base degradation.
Table 18
Conversion Selectivity Yield,
p- 4- An Other
NDPA NDPA Recr
Comparison: KOH + TMACI,100.0 97.9 72.6 25.3 1.9 o.z
*
TMAH Only, No Salt 100.0 83.8 62.4 21.4 4.4 11.8
Added
21.44 g Potassium Chloride100.0 97.2 72.3 24.8 1.5 1.4
16.82 g Sodium Chloride62.7 97.2 15.6 45.3 0.6 1.1
19.87 g Potassium Carbonate100.0 89.1 72.8 16.3 3.8 7.1
20.42 g Sodium Sulfate100.0 85.0 63.8 21.2 4.5 10.5
24.44 g Sodium Nitrate27.8 94.3 8.3 17.9 0.9 0.6
34.22 g Potassium Bromide27.0 98.4 15.6 11.0 0.3 0.2
23.58 g Sodium Acetate80.5 96.9 56.6 21.4 1.5 1.0
19.55 g Sodium Formate71.8 97.3 46.2 23.6 1.0 1.0
24.18 g Potassium Formate89.5 96.4 64.2 22.1 2.4 0.8
39.13 g KH2P04 39.3 97.4 10.0 28.3 0.8 0.2
* Mole ratios are slightly
higher: KOH/NB and
TMACI/NB = 1.25
EXAMPLE 13
This example demonstrates the effect of the mole ratio of inorganic salt to
nitrobenzene. Reaction conditions were comparable to those for Example 12,
except that the mole ratio of KCI to nitrobenzene was varied. The results in
Tabie 19 indicate the addition of only a small amount of inorganic salt will
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increase selectivity. Therefore, in situations where corrosion due to high
salt
level is a concern, at least a modest selectivity improvement can be obtained.
Table
19
Mole ConversionSelectivity Yield,
Ratio
SaItINB % % p-NDPA 4-NDPA An RecrOther
TMAH Only, 0 100.0 83.8 62.4 21.4 4.4 11.8
No Salt
Added
4.66 g KCI 0.25 100.0 87.1 63.4 23.7 7.8 5.1
13.05 g 0.70 100.0 93.8 72.3 21.5 5.0 1.2
KCI
21.44 g 1.15 100.0 97.2 72.3 24.8 1.5 1.4
KCi
EXAMPLE 14
This example demonstrates the effect of adding a non-salt compound on
selectivity and conversion of nitrobenzene. Reaction conditions were
comparable to those for Example 12. Betaine, i.e. (acetyl)trimethylammomnium
hydroxide inner salt, is a salt formed by the acetate group with the
positively
charged tetraalkylammonium group. So despite the name, the compound does
not actually have hydroxide associated with the tetraalkylammonium group.
However, when a strong base is added, betaine is converted to a compound that
contains both an acetate salt group and a tetraalkylammonium hydroxide group.
So with TMAH, betaine is converted to a compound with a
tetramethylammonium-acetate group and an (acetyl)trimethylammomnium
hydroxide group. With KOH, the compound has a potassium -acetate group with
the (acetyl)trimethyfammomnium hydroxide group. In the KOH case, the
compound represents a metal organic salt and a organic base in one molecule.
Betaine is known in the literature to be a phase transfer compound or PTC
(Starks and Liotta, ibid), as it carries the inorganic or organic base into
the
organic phase.
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The results in Table 20 show that betaine has only a modest effect on
selectivity or conversion with TMAH. The results with betainelNB =1.15 are
only
equivalent to KCI/NB = 0.25. Furthermore, addition of an anion without an
inorganic cation (am,monium acetate) is essentially ineffective. Therefore,
the
use of an inorganic salt or metal organic salt is the key to best results.
Table
20
ConversionSelectivity Yieid,
Mole Ratio% I p- 4- An Other
to NB NDPA NDPA Recr
TMAH Only, No 0 100.0 83.8 62.4 21.4 4.4 11.8
Salt
or PTC Added
4.66 g KCI 0.25 100.0 87.1 63.4 23.7 7.8 5.1
21.44 g KCI 1.15 100.0 97.2 72.3 24.8 1.5 1.4
22.16 g Ammonium1.15 0.5 100.0 0.3 0.2 0.0 0.0
Acetate
33.68 g Betaine1.15 100.0 87.6 70.7 16.9 4.8 7.6
EXAMPLE 15
This example illustrates that use of partial oxidative conditions can give a
significant increase of selectivity. Reaction conditions were comparable to
those
for Example 12, except as indicated. The results are shown in Table 21.
Reaction 1 had comparable conditions to those for Example 12 throughout. For
Reaction 2, the air bleed was used only during nitrobenzene feed and was
stopped when 75% of the feed was completed. For Reaction 3, the nitrobenzene
feed time was shortened to 45 minutes and the hold time was increased to 60
minutes, while the air bleed was used only during the nitrobenzene feed time.
It
is expected that higher selectivity will also be attained for sulfate,
carbonate and
nitrate by use of partial oxidative conditions.
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Table 21
ConversionSelectivity Yield,
p-NDPA 4-NDPA An Recr Other
16.70 g KF-199.9 84.8 67.3 17.4 4.2 11.0
16.70 g KF-2100.0 91.1 80.1 11.0 6.3 2.6
16.70 g KF-3100.0 93.8 83.2 10.6 4.3 1.9
EXAMPLE 16
This example shows that use of an oxidant with a strong base, which also
functions as a phase transfer catalyst, can increase selectivity. The
reactions
were done with azeotropic removal of water and aniline.
Charged to a 500-mL round bottom flask equipped with a Teflon paddle
stirrer, thermocouple, nitrobenzene feed tube and air bleed valve were: 145.28
grams aniline (1.56 moles) and 87.36 grams aqueous tetramethylammonium
hydroxide solution (36.0%, 0.345 moles) for Runs 1 - 3. The mixture was heated
for 30 minutes at 120 mm Hg and then nitrobenzene feed (36.93 grams, 0.30
moles) was started. The system pressure was held constant at 70 mm Hg
throughout the reaction period. Temperature rose from about 66°C to
about
80°C during the reaction period. Nitrobenzene was charged over about 80
minutes, after which the batch was held for 40 minutes at 70 mm Hg to insure
completeness of reaction and then quenched with 25 mL water. Hydrogen
peroxide was charged as 20.40 grams (0.03 moles) of a 5 wt.% aqueous solution
concurrently with nitrobenzene. Since water can also affect selectivity, by
protecting TMAH from degradation and shifting reaction equilibria, a control
was
run with 20.40 grams of water that was also fed concurrently with
nitrobenzene.
Runs 4 - 7 had slightly different conditions. The main difference was starting
with 25 wt.% TMAH with removal of water and some aniline in the reactor prior
to
the nitrobenzene feed. Air was added either during the entire nitrobenzene
feed
or for half of the feed time.
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The results in Table 22 show that hydrogen peroxide gives a larger
selectivity improvement than water alone, showing that use
of an oxidant can be
beneficial. The results also show that addition of air as
oxidant over the entire
reactor cycle has a deleterious effect on selectivity. However,
a selectivity
improvement is obtained when the air addition is limited
to part of the reaction
cycle, showing that partial oxidative conditions can be
beneficial. These
reactions were run somewhat wetter than the case for 100%
air in Table 18,
which explains the lower selectivity in Table 18. Runs 4
and 5 show the excellent
repeatability of the reactions, so that selectivity increases
of 1 - 2% are
significant.
Table 22
Conversion Selectivity Yield,
TMAH as base/PTC % % p-NDPA 4-NDPA An Recr Other
1. No oxidant 100.0 93.3 86.3 7.0 4.6 2.1
2. Water only 100.0 94.9 89.3 5.5 3.4 1,8
3. Hydrogen Peroxide 100.0 96.1 89.7 6.4 1.9 2.0
4. No oxidant 100.0 92.3 86.5 5.8 5.9 1.8
5. No oxidant 100.0 92.2 86.2 6.0 6.1 1.7
6. Air, 100% NB Feed 99.7 89.4 79.0 10.1 7.4 3.2
7. Air, 50% NB Feed 100.0 94.5 88.4 6.2 4.2 1.3
