Nitration reactions with acid anhydride promoters

An improved nitric acid only nitration process wherein the improvement comprises adding an effective amount of a nitration promoting acid anhydride to the reaction mixture to enhance the rate of nitration.

The present invention relates to an improved process for the nitration of 
aromatic compounds. Specifically, in a nitric acid only nitration process, 
the rate of nitration of aromatic compounds may be greatly enhanced by the 
addition of one or more acid anhydrides to the reaction mixture. 
BACKGROUND 
It is known to nitrate various aromatic compounds including, for example, 
phthalimides, phthalic acids, and phthalic anhydrides by treatment with a 
mixture of concentrated sulfuric acid and nitric acid. Specific teachings 
of these nitration reactions may be found in Takekoshi, U.S. Pat. No. 
3,868,389; Bacha et al, U.S. Pat. No. 4,137,419; and Cook et al, U.S. Pat. 
Nos. 3,933,852, 3,981,933 and 3,887,588. 
Recently, it was discovered that aromatic compounds could be nitrated in a 
nitration reaction which employed only nitric acid. Specifically, 
copending patent application Ser. No. 917,926 filed Oct. 10, 1986 and 
having an effective filing date of Dec. 8, 1983, assigned to the same 
assignee as the present invention, discloses the nitration of 
alkylphthalimides in at least 95% concentrated nitric acid. Related 
copending patent application Ser. No. 559,575 filed Dec. 8, 1983, now 
abandoned, also assigned to the same assignee as the present invention 
discloses the nitration of phthalic acids, phthalic anhydrides and 
derivatives thereof in a nitration process using only nitric acid. Both of 
these copending patent application teach the use of high temperatures in 
order to achieve the best rate of nitration, thus short nitration times. 
However, even at such high temperatures, for example above 50.degree. C., 
the time for completion of the nitration, or substantially so, may be 
three hours or more. 
It is an object of the present invention to substantially enhance the rate 
of nitration in the nitric acid only nitration process without elevating 
the temperature of the nitration reaction. 
It is also an object of the present invention to provide a nitric acid only 
nitration process that may be used at lower temperatures without 
detrimentally affecting the rate of nitration. 
SUMMARY 
It has now been discovered that the rate of nitration of aromatic compounds 
in the all nitric acid only nitration process (i.e., one not employing 
sulfuric acid in addition to nitric acid) may be greatly enhanced by the 
addition of acid anhydrides to the reaction mixture. This method gives 
very fast rates of nitration compared to reactions without the addition of 
acid anhydrides, thus greatly shortening the batch time for the production 
of, for example, nitrophthalimides, nitrophthalic acids, or any other 
nitrated aromatic substrate in the nitric acid only nitration process. It 
also makes more viable a continuous system for the all nitric acid 
nitration process. 
Specifically, the improved nitric acid only nitration process of the 
present invention comprises (1) forming a solution of the aromatic 
substrate in a solvent of nitric acid of at least about 95% by weight 
concentration, preferably at least about 97.5% by weight concentration, 
(2) reacting the mixture within a temperature range of from about 
-20.degree. C. to the boiling point of nitric acid, (3) allowing the 
reaction to run to produce the nitrated derivatives of the reactant 
substrate and (4) thereafter recovering the nitrated products by methods 
known in the art, wherein the improvement consists essentially of adding 
one or more acid anhydrides to the aforementioned solvent or solution to 
enhance the rate of nitration. The method of the present invention may 
also comprise the additional step of elevating the temperature of the 
reaction mix during or following nitration to reduce or destroy 
by-products, particularly di-nitro by products, formed during nitration. 
The present invention is most particularly applicable to the nitration of 
such aromatic compounds as phthalimides. Preferred acid anhydrides for use 
as catalysts in the method of the present invention are the inorganic and 
organic acid anhydrides, most preferably phosphoric anhydride, nitric 
anhydride, sulfur trioxide, acetic anhydride and trifluoroacetic 
anhydride, among others. 
DETAILED DESCRIPTION 
The process of the present invention provides for the nitration of aromatic 
substrates at a greatly enhanced rate in the nitric acid only nitration 
process. Specifically, the use of rate enhancing nitration promoters in 
the nitric acid only nitration process provides for greatly enhanced rates 
of nitration even at lower temperatures, with lower weight ratios of 
nitric acid to aromatic substrate, and with lower concentration nitric 
acids. As disclosed in the above-identified copending patent applications, 
the nitric acid only nitration process is one which does not require nor 
employ sulfuric acid in addition to nitric acid in order to conduct the 
nitration. 
In general the improved nitric acid only nitration process of the present 
invention comprises (1) forming a solution of the aromatic substrate in a 
solvent of nitric acid and an effective amount of a rate enhancing acid 
anhydride nitration promoter, (2) reacting the mixture within a 
temperature range of from about -20.degree. C. to the boiling point of 
nitric acid, (3) allowing the nitration to run to produce the nitrated 
derivatives of the aromatic substrate and (4) thereafter recovering the 
nitrated products. 
The nitric acids useful for the nitric acid only nitration process should 
have a concentration of at least about 95% by weight and is preferably 
within the range of from about 97.5 to about 100% concentration. Nitric 
acids of lower concentration may be used, however, their use results in 
processes which are too slow to be cost effective. Nitric acids of such 
concentration are available commercially or may be prepared by known 
concentrating methods from more widely available commercial nitric acid of 
60 to 67% concentration. 
The amount of concentrated nitric acid used should be at least of about the 
stoichiometric amount necessary to attach one nitro(NO.sub.2) group on the 
aromatic nucleus of the aromatic substrate. Generally, the mole ratio of 
nitric acid to the aromatic substrate should be from about 1 to about 20, 
preferably from about 1 to about 12, most preferably from about 1 to about 
6. Obviously, lower or higher amounts of nitric acid may be used in the 
all nitric acid nitration process, however, lower amounts of nitric acid 
result in poor yields and too slow a reaction rate to be cost effective, 
whereas higher amounts of nitric acid may result in unnecessary spoiling 
of concentrated nitric acid and increased costs for such acid and its 
recycling. 
The temperature at which the reaction should run should generally fall 
within the range of from about -20.degree. C. to the boiling point of 
nitric acid, preferably from about 10.degree. C. to about 70.degree. C., 
most preferably from about 20.degree. C. to about 60.degree. C. More 
specifically the actual temperature to be employed is dependent upon the 
desired rate of reaction and, in part, the aromatic substrate and the 
desired nitration products. In general, the lower the temperature the 
slower the reaction and the greater the ratio of the 4-isomer to 3-isomer 
formed in the nitrated aromatic products. Conversely, with higher 
temperatures, the reaction rate is increased and the ratio of the 4-isomer 
to 3-isomer is smaller. Further, as disclosed by the aforementioned 
copending patent applications, aromatic substrates having a high 
propensity to nitrate, such as N-methyl phthalimide, do not require as 
high a reaction temperature as substrates having less propensity to 
nitrate, for example phthalic acid, in order to obtain a good rate of 
nitration. 
For the purpose of this specification and the appended claims, the "boiling 
point of nitric acid" is defined as the temperature at which the specific 
nitric acid used, under the pressure employed, boils. This definition is 
necessitated by the fact that nitric acids of less than 100% concentration 
have a higher boiling point than 100% concentrated nitric acid and that 
the boiling point of nitric acid may be elevated by raising the pressure 
under which the reaction takes place above atmospheric. Such instances are 
clearly intended to be within full scope of the present invention as set 
forth in this specification and claimed by the appended claims. 
It should also be noted that temperatures outside the range of temperatures 
disclosed above may be employed with the present process. However, lower 
temperatures result in a reaction rate which is too slow to be cost 
effective, whereas higher temperatures require operation at above 
atmospheric pressure to prevent boiling and subsequent loss of nitric 
acid. 
Briefly, the pressure range under which this process operates may vary from 
vacuum to above atmospheric pressure. Depending on the type of reactor or 
reactors employed, they may preferentially operate under slight vacuum for 
process and safety reasons. Otherwise, the process is generally run at 
about atmospheric pressure. 
The nitric acid only nitration process is generally applicable to the 
nitration of aromatic compounds, particularly the phthalimides, phthalic 
acids, phthalic anhydrides and derivatives thereof. Most preferably, the 
present invention relates to the improved nitric acid only nitration of 
N-substituted phthalimides, especially the N-alkyl phthalimides and their 
derivatives. Suitable N-alkyl phthalimides may be represented by the 
formula: 
##STR1## 
wherein R is a C.sub.1 to C.sub.10, preferably a C.sub.1 to C.sub.4, 
hydrocarbon. These may be prepared by effecting reaction between an 
alkylamine and phthalic anhydride, as taught by Markezich in U.S. Pat. No. 
4,020,089, incorporated herein by reference. The N-alkyl phthalimide may 
be added to the reactor or solvent in any suitable form, e.g. powder, 
flake, etc. This process is particularly suitable for the nitration of 
N-alkyl phthalimide wherein the alkyl group is methyl, ethyl, n-propyl, 
i-propyl or n-butyl. 
As taught by the aforementioned copending patent applications, the rate of 
reaction may be varied based on the weight ratio of reactants, the 
specific reactants and nitric acid used, and, most importantly, the 
temperature at which the nitration reaction is conducted. It has now been 
found that the rate of nitration may be greatly enhanced by adding to the 
reaction mix a nitration promoter. Preferred nitration promoters are 
organic and inorganic acid anhydrides. These are generally known compounds 
and available commercially. 
Suitable organic acid anhydrides will generally be of the formula: 
##STR2## 
wherein each G is independently a substituted or non-substituted C.sub.1 
to C.sub.6, preferably C.sub.1 to C.sub.4, alkyl group, or a substituted 
or non-substituted phenyl group. Substituted organic acid anhydrides are 
preferably substituted with halogens, especially fluorine. Especially 
preferred organic acid anhydrides are, for example, acetic anhydride and 
trifluoroacetic anhydride. 
Likewise, most inorganic acid anhydrides will be suitable for use in the 
practice of the present invention. Exemplary of suitable inorganic acid 
anhydrides include for example boric anhydrides, phosphoric anhydride, 
chromic anhydride, nitric anhydride, sulfur trioxide and the like. 
Especially preferred are phosphoric anhydride, nitric anhydride and sulfur 
trioxide. 
Generally, the acid anhydride, whether it be organic or inorganic, should 
be added to the reaction mixture in an effective amount sufficient to 
enhance the rate of nitration. While it is expected that smaller amounts 
will enhance the rate of nitration, it is preferred that the amount of 
acid anhydride promoters be from about 0.5 times to about 5 times the 
stoichiometric amount, preferably from about 0.8 to about 2 times the 
stoichiometric amount, based on the substrate to be nitrated. Most 
preferably, the amount of acid anhydride used should be of about the 
stoichiometric amount. 
Of course it is to be understood that the effectiveness of certain acid 
anhydrides will vary depending upon the particular substrate to be 
nitrated and in certain limited instances are inoperable. (See e.g. 
copending U.S. patent application Ser. No. 170,708 filed Mar. 14, 1988, 
having an effective filing date of Jan. 3, 1984, now abandoned). However, 
it may be possible to predict the effectiveness of certain acid anhydrides 
by assessing their effectiveness with a particular substrate and then 
comparing that substrate's propensity to nitrate with the subsequent 
substrate to be nitrated. For example, it would be expected that all acid 
anhydrides that show rate enhancement for e.g. N-methylphthalimide would 
greatly enhance nitrations of other substrates whose propensity to 
nitration was equal to or greater than that of N-methylphthalimide. 
The mode of mixing and the sequence of addition of reactants is not 
critical to the operability of the process of the present invention. For 
example, the acid anhydride promoter may be added to the nitric acid prior 
to, simultaneous with or following addition of the substrate to be 
nitrated. Additionally, any or all of the reactants may be premixed and 
then added to the reactor vessel. Again, whether the premix of any two 
reactants preceeds the addition of the third reactant is not important. It 
is also possible that any or all reactants or premixes be maintained at 
the desired reaction temperature, or any other temperature, prior to 
mixing or entering the reactor. 
It is preferred, however, that the nitric acid or nitric acid substrate 
premix be cooled, preferably to about 0.degree. C. prior to the addition 
of the nitration promoter and that such mixing takes place in the reactor 
vessel due to the high reactivity and, more importantly, to the extremely 
exothermic nature of such mixing. For example, addition of the promoter to 
nitric acid at room temperature causes immediate and excessive boiling of 
the nitric acid and may, especially at higher temperatures, result in an 
explosion. 
Generally, the process of the present invention comprises mixing the 
aromatic substrate to be nitrated and the acid anhydride together with the 
concentrated nitric acid in a reactor or reactors preferably equipped with 
a stirrer or agitating means and means for heating and cooling the 
reactor. The reactor(s) may be such as to allow for either batch or 
continuous processing. 
Specific variations in the design of the process systems employable to 
practice the present invention are known to those skilled in the art. For 
example, it is possible to use one or more reactors in series or in 
parallel which operate in the plug flow mode with or without radial mixing 
and with or without heating or cooling. Alternatively, it is possible to 
use one or more reactors in series or in parallel which operate in the 
back mixing mode, again with or without heating or cooling and operating 
in a batch or continuous mode. Finally, it is also possible to use a 
combination of reactors with features of both foregoing. 
The nitration products prepared by the process of the present invention may 
be recovered from the reaction mix by any of the known methods for 
recovery of nitrated products. Exemplary of the methods available include: 
extraction; spray drying; precipitation and drying and the like. Recovered 
unreacted substrate may be reused and the spoiled or used nitric acid may 
be recycled by known methods for reuse. 
The process of the present invention may be modified by the additional step 
of elevating the temperature of the reactor during or following nitration 
for a sufficient period of time to reduce or eliminate by-products, 
particularly dinitro by-products, formed during the nitration process. 
While essentially any increase in temperature will increase the 
destruction of such undesirable by-products, it is preferred that the 
temperature of the reactor be elevated to at least about 40.degree. C., 
preferably from about 50.degree. C. to about 60.degree. C. Obviously, 
nitration reactions run at 50.degree. C. or higher will inherently destroy 
some of the undesirable by-products, however, increasing the temperature 
even higher will enhance the destruction of said by-products and result in 
the production of essentially pure nitrated products. 
In order that those skilled in the art may better understand how the 
present invention may be practiced, the following examples are given by 
way of illustration and not by way of limitation. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Generally, all reaction products were analyzed by High Pressure Liquid 
Chromotography (HPLC) wherein 50 .mu.l aliquots of the reaction mix were 
quenched in 3.8 mls. of 0.96M sodium acetate and 0.05M tetraethylammonium 
bromide for the phthalic acid and phthalic anhydride reactions and 3.8 mls 
of a 1:1 mixture of an aqueous phase consisting of 0.005M 
tetraethylammonium bromide, 0.035M acetic acid, and 0.07M sodium acetate 
and acetonitrile. 
The samples were analyzed on a Waters .mu. Bondpak/C.sub.18 column, using a 
flow rate of 1.5 ml/min and a 280 nm detector. The mobile phase for the 
phthalic acid/anhydride determinations consisted of a solution of 0.005M 
tetraethyl-ammonium bromide, 0.035M acetic acid and 0.07M sodium acetate. 
The mobile phase for the alkylphthalimide determinations consisted of 70% 
of the above mobile phase and 30% of a 90:10 acetonitrile:methanol 
solution. 
TABLE I 
__________________________________________________________________________ 
Enhanced Nitration of N-methyl Phthalimide 
% N-Methyl Phthalimide Remaining 
After Time 
Nitration Promoter 
Amount 
2 min. 10 min. 4-NPI/3-NPI 
__________________________________________________________________________ 
Phosphoric Anhydride 
1.25 88.5 28.1 19.6 
(P.sub.2 O.sub.5) 
Sulfur Trioxide 
2.07 5.45 .29 20.2 
(SO.sub.3) 
Nitric Anhydride 
3.03 30.1 0 21.3 
(N.sub.2 O.sub.5) 
Acetic Anhydride 
2.69 55.2 .79 20.5 
(CH.sub.3 CO).sub.2 O 
Trifluoro Acetic Anhydride 
5.56 64.4 .38 20.9 
(CF.sub.3 CO).sub.2 O 
Control -- 97.4 87.3 21.1 
__________________________________________________________________________

EXPERIMENTAL 1 
A series of nitric acid only nitration reactions were run demonstrating the 
effectiveness of various inorganic and organic acid anhydrides as 
nitration promoters. These examples and the specific nitration promoters 
were as shown in Table 1. Specifically, 15 parts by weight of 99% 
concentrated nitric acid was added to a reaction vessel along with a 
stirring means and cooled until the nitric acid began to freeze. The 
appropriate amount of acid anhydride, as shown in Table 1 was slowly added 
to the cooled nitric acid and the mixture was then allowed to come to the 
desired reaction temperature. To this stirred solution, 1.5 parts by 
weight of N-methyl phthalimide was added and the nitration reaction 
allowed to run at 25.degree.-30.degree. C. The result of these nitration 
reaction and the ratio of 4- to 3-nitro-N-alkylphthalimide formed are 
shown in Table 1. 
As is clearly shown in Table 1, each of the acid anhydrides tested resulted 
in exceptional enhancement of the rate of nitration. Essentially, all of 
the N-methyl phthalimide was completely reacted within ten minutes at 
25.degree.-30.degree. C., as opposed to only 13.6% in the control sample 
were no nitration promoter was used. 
There was, however, some, although slight, variation in the effectiveness 
of the nitration promoters. For example, in the phosphoric anhydride 
promoted reaction, 28.1 mole percent of the N-methylphthalimide remained 
unreacted after ten minutes, however, this still represented about a six 
fold increase over the control. Also, as is evident, certain nitration 
promoters are shown to start faster than others, yet the same end result 
of overall rate enhancement is achieved. Finally, it is to be noted that 
the use of any one acid anhydride nitration promoter had very little 
impact on the ratio of 4-nitro-N-methyl phthalimide to 3-nitro-N-alkyl 
phthalimide formed. 
From these results it is expected that all of the acid anhydrides that show 
rate enhancement for N-methyl phthalimide would greatly enhance nitrations 
of other substrates whose propensity to nitration is equal to or greater 
than that of the phthalimide. 
EXPERIMENTAL II 
A series of all nitric acid nitration reactions were prepared as in 
Experimental 1, except that 1.5 parts of phthalic acid or phthalic 
anhydride, as set forth in Table 2, was substituted for 
N-methylphthalimide. 
The results shown in Table II once again demonstrate the great enhancement 
in the rate of nitration achieved by the use of various acid anhydrides as 
nitration of aromatic compounds. However, these results also demonstrate 
selectivity of certain nitration promoters for certain substrates. 
Specifically, these examples demonstrate the efficiency of the inorganic 
acid anhydrides, especially phosphoric anhydride and sulfur trioxide, as 
opposed to the apparent inoperability of the organic acid anhydride 
promoters in the enhancement of nitration of phthalic anhydride and 
phthalic acid. Further, it is evident that certain operable acid 
anhydrides have a greater effect than others upon a particular substrate. 
In particular, it is clear that sulfur trioxide is especially effective 
for the nitration of phthalic acid and phthalic anhydride and as such 
would likely promote the nitration of substrates even less active than 
phthalic anhydrides. 
Table II also demonstrates the effectiveness of elevating the temperature 
of nitration on the rate. Comparison of the examples in which phthalic 
anhydride is nitrated at 40.degree. C. and 70.degree. C. with sulfur 
trioxide demonstrates the dramatic improvement in rate achieved by the use 
of both promoter and higher temperature. On the other hand, comparison of 
those examples wherein phosphoric anhydride is used demonstrates the 
ability to get great rate enhancement with lower amounts of nitration 
promoter at higher temperatures. 
TABLE II 
__________________________________________________________________________ 
Temperature 
Acid-Anhydrides 
Amount 
% Substrate Remaining After Time 
Run 
Substrate .degree.C. 
Promoter (pts.) 
(M.D.) % Substrate (Min.) 
__________________________________________________________________________ 
1 Phthalic Anhydride 
30-45 Control -- 98.3(10) 71.6(120) 
2 Phthalic Anhydride 
30-45 Nitric Anhydride 
1.6 98.6(10) 81.1(120) 
(N.sub.2 O.sub.5) 
3 Phthalic Anhydride 
40 Control -- 97.3(10) 
83.2(60) 
62.4(156) 
4 Phthalic Anhydride 
40 Phosphoric Anhydride 
1.25 88.7(10) 
61.9(60) 
38.8(156) 
P.sub.2 O.sub.5 
5 Phthalic Anhydride 
40 Sulfur Trioxide 
2.07 67.4(10) 
3.96(60) 
0.49(156) 
SO.sub.3 
6 Phthalic Anhydride 
40 Acetic Anhydride 
2.69 99.2(10) 
97.7(60) 
96.2(156) 
(CH.sub.3 CO).sub.2 O 
7 Phthalic Anhydride 
40 Trifluoroacetic 
5.56 99.3(10) 
-- 93.4(156) 
Anhydride 
(CF.sub.3 CO).sub.2 O 
8 Phthalic Anhydride 
70 Control -- 92.7(10) 
64.4(10) 
14.1(120) 
9 Phthalic Anhydride 
70 Phosphoric Anhydride 
0.87 82.0(5) 
46.5(30) 
7.70(120) 
10 Phthalic Anhydride 
70 Sulfur Trioxide 
2.07 7.98(5) 
1.96(15) 
-- 
11 Phthalic Acid 
40 Control -- 92.7(10) 
81.2(60) 
63.8(156) 
12 Phthalic Acid 
40 Sulfur Trioxide 
2.07 39.0(10 
1.14(60) 
-0(156) 
13 Phthalic Acid 
40 Trifluoroacetic 
5.56 98.5(10 
96.2(60) 
92.2(156) 
Anhydride 
__________________________________________________________________________ 
Obviously, other modifications and variations of the present invention are 
possible in light of the above teachings. It is, therefore, to be 
understood that changes may be made in the particular embodiments of the 
invention described which are within the full intended scope of the 
invention as defined by the appended claims.