Title of Invention

IMPROVED PROCESS FOR NITRATION OF PHENOLS USING DILUTE NITRIC ACID ALONE AS THE NITRATING AGENT USING ULTRASOUND

Abstract The present invention relates to an improved process in which phenols are slectively nitrated dilute nitric acid (6-40 wt%) alone as the nitrating agent using ultrasound. The para isomer is selectively obtained in high yield under sonication. The nitration of phenols takes at ambient conditions under sonication with a significant enhancement in the reaction rate.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 OF 1970) &
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
(Section 10 and rule 13 )
1. "IMPROVED PROCESS FOR NITRATION OF PHENOLS USING DILUTE NITRIC ACID
ALONE AS THE NITRATING AGENT USING ULTRASOUND."
2. (a) Bhanage Bhalchandra Mahadeo
(b) Department of Chemistry, Institute of Chemical Technology, University of Mumbai, Nathalal Parekh Marg., Matunga. Mumbai 400019, Maharashtra, India.
(c) INDIAN.
The following specification particularly describes the invention and the manner in which it is to be performed.

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IMPROVED PROCESS FOR NITRATION OF PHENOLS USING DILUTE NITRIC ACID ALONE AS THE NITRATING AGENT USING ULTRASOUND.
Abstract:
The present invention relates to an improved process in which phenols are selectively nitrated using dilute nitric acid (6-40 wt%) alone as the nitrating agent using ultrasound. The para isomer is selectively obtained in high yield under sonication. The nitration of phenols takes place at ambient conditions under sonication with a significant enhancement in the reaction rate.

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FIELD OF THE INVENTION:
The present invention relates to an improved process for the selective nitration of phenols under sonication. Specifically the invention relates to a process for the
nitration of phenols using dilute nitric acid (6-40 wt%) alone as the nitrating agent under sonication. The process is applicable for nitration of wide range of phenols consisting of one or more functional groups of the type hydroxy, chloro, nitro, methoxy, methyl etc. The improved process results in significant enhancement in the reaction rate with high para selectivity under sonication.
The reaction system comprises of two phases viz- the Organic phase and the Aqueous phase. The organic phase consists of a substrate and the aqueous phase consists of reactant such as nitric acid. The cavitation effect, which is predominant in aqueous solution (aq nitric acid in the present case) plays an important role of solublization of reactants in such a biphasic system maximizing mass transfer effects, which is difficult to achieve without ultrasound.
BACKGROUND OF THE INVENTION:
The nitrated products have wide range of industrial applications in fine chemicals, dyes and pharmaceuticals. This invention relates to a significant improvement in the biphasic nitration of phenols with high para selectivity under sonication. This is illustrated by a variety of substrates with different functional groups.
Nitration of the aromatic compounds is one of the most widely studied reaction and finds extensive applications in the synthesis of variety of fine chemicals and pharmaceuticals "Nitration Methods and Mechanisms" by G. A. Olah (1989) published by VCH publications. Conventional method for nitration of phenol utilizes the mixture of nitric acid and sulfuric acid. This process has limitation such as the use of nitrating mixture, which in turns generate large quantity of acid waste posing its neutralization and disposal problems. Overnitration, oxidation and poor selectivity are also the associated problems. Further, it is noteworthy that the typical yield of direct nitration never exceed 60% " A Textbook of Practical Organic Chemistry" 4* ed. A.
Vogel (1978) published by Longman, London.

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In recent years the use of ultrasound in organic transformations is well known as it can enhance the rates, yield and selectivity of the reactions "Synthetic Organic Sonochemistry" by J. L. Luche in 1998 published by plenum press, New York. This
can also facilitate reactions at ambient conditions which otherwise requires drastic
conditions such as temperature, pressure or concentrations. The ultrasound promoted nitration of phenol in expensive media such as ionic liquid has been reported R. Rajgopalan in Ultrasonic Sonochemistry 2003, 10, 41. The process is feasible only with the activated phenol and are not applicable to deactivated phenols. Also nitration of phenol using ZnCb, which involves the use of concentrated HNO3 under sonication has been reported by Ahmed Kamal in Ultrasonic Sonochemistry 2004, 11, 455. There are few other patents witnessed in the art for nitration of phenols without ultrasound such as US Patent No PL367032 which involves the use of isopropyl nitrate, PTC and sulphuric acid; JP Patent No 5032589 which involves nitration 2,6 dichloro phenol using 10-70 % nitric acid; US Patent No 3694513 relates to a method for nitrating alkyi phenols with nitric acid in presence of tertiary alcohol, a secondary alkyi nitrate, an aldehyde or a ketone. However, all the above process mainly focuses on the preparation of different catalyst to increase the rate and selectivity of nitration reaction. Also apart from nitric acid, there is an essential requirement for use of a co-catalyst to drive the reaction. The regioselective nitration of phenol using dilute nitric acid alone as a nitrating agent has been seldomly studied.
It is an object of the invention to provide a useful, high yielding and generally applicable process for the regioselective nitration of phenols using nitric acid alone as the nitrating agent under sonication. A further object of the invention is to provide a process, which avoids the disadvantage of the prior art.
SUMMARY OF THE INVENTION:
The main objective of the present invention is to provide a process for regioselective nitration of phenol using nitric acid alone as a nitrating agent under sonication. Another objective of the present invention is to provide a process for nitration of phenols giving significant rate enhancement under sonication. Yet another objective of the present invention is to provide process for nitration of phenols in a Diphasic media containing functional groups like hydroxy, chloro, methoxy, methyl etc.

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Still another objective of the present invention is to provide a process for the nitration of phenols and substituted phenols with high para selectivity under sonication.
The improved process in the present invention has the following advantages over the processes described in the prior art:
Nitration of phenols using dilute nitric acid (9 wt%) alone as a nitrating agent under sonication.
This invention shows a significant enhancement in the reaction rate under sonication. Whereas the same reaction at room temperature requires longer time.
The process is general in nature and is compatible with many pedant electron donating and withdrawing substituents on phenol.
High selectivity towards para position in case of substituted as well as unsubstituted phenol under sonication.
Typical nitration procedure is not ecofriendly, as it requires use of mixed acids such as concentrated nitric acid and sulfuric acid. This leads to generate excessive acid waste. The improved process involves the use of dilute nitric acid as the nitrating agent thus minimizing the handling and disposal problems.
This process can also be applied to deactivated substrates under milder conditions.
According to present invention, it becomes possible to carry out regioselective nitration of phenol at a low cost without necessity to invest a large sum of money in plant and equipment.
Reaction occurs at ambient temperatures.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is concerned with the modification of the conventional nitration reactions.
The reaction system comprises of two phases viz- the Organic phase and the Aqueous phase. The organic phases consist of a substrate and the aqueous phases consist of reactant such as nitric acid. The cavitation generated due to ultrasound plays an important role of solublization of reactant in such a biphasic reactive system maximizing the mass transfer effect.

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The phenols useful in the practice of this invention are those having the . formula R1, R2, R3—Ar-OH, wherein Ar is a substituted/unsubstituted aromatic compound and Ri, R2, R3 are each individually monovalent substituents, which may be same or different. Typical of such radicals are alky groups, such as methyl, ethyl, propyl and the like; alkoxy groups, such as methoxy, ethoxy, and the like; halo groups, such as fluoro chloro, bromo and the like; hydroxyl and nitro groups. Most preferably Ri, R2 and R3 is hydrogen, methyl, chloro and nitro group. Illustrative examples of said phenols are phenol, o-cresol, m-cresol, p-cresol, o-chloro phenol, m-chloro phenol, p-chloro phenol, o-hydroxy phenol, m-hydroxy phenol p-hydroxy, o-methoxy phenol, m-methoxy phenol p-methoxy phenol, o-nitro phenol, m-nitro phenol, p-nitro phenol etc.
As the solvent for the nitration of phenol with nitric acid, an organic solvent can be used without any restriction. The solvent preferable is a solvent immiscible in water and has a good cavitational effect. Therefore, preferable solvent is a chlorinated solvent having 1 to 3 carbon atoms. Illustrative examples of such solvents include ethylene dichloride, methylene dichloride, chloroform, carbon tetrachloride etc. Water may be used but it is generally not desired, since reaction rates are much slower than those conducted in chlorinated solvents and the quality of the product is diminished.
The quantity ratio between the phenol and the nitric acid varies depending upon the
type of the substituents. Obviously the amount of nitric acid employed need only be sufficient to produce the amount of nitrated phenol desired.
The reaction can be conducted over a wide range of temperatures and pressure. For convenience the reaction is conducted at atmospheric pressure. The reaction temperature is not lower than the melting point of the solvent and not higher than the boiling point thereof. Since the reaction is exothermic and also the cavitation of ultrasound is effected at higher temperatures. It is desirable not to allow the reaction medium to reach a temperature, which would cause excessive loss of reactants by evaporation or effect the cavitation created by ultrasound. When the reaction is carried out at a temperature in the vicinity of room temperature any trouble is not brought about. Accordingly the reaction is preferable in the range of 10 to 40 °C, more particularly 28 to 30 °C.

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The process of the instant invention is unique, since in the absence of ultrasound the extent of interaction between the phenol/substituted phenol and nitric acid may be so slight that no physical evidence of reaction is apparent within the expected time. While in the presence of ultrasound the nitration of phenol/substituted phenol is generally completed within a matter of few hour. The probable reason may be that the well known cavitational effect generated due to ultrasound playing an important role of enhancing the interaction between the phenol/substituted phenol and nitric acid thereby forming the corresponding nitrated compounds at a faster rate than those observed without ultrasound
No process in hitherto known for the nitration of phenol using dilute nitric acid alone as the nitrating agent under sonication in which there is a dramatic increase in the rate of a biphasic reaction system. The process of the invention is described in detail in the examples given below that are presented by the way of illustration only and should not be confined to limit the scope of the invention.
Example 1
In a typical reaction phenol (5 mmol), nitric acid (70 wt %, 10 mmol) water to makeup nitric acid concentration to 9 wt% and ethylene dichloride 10 mi was sonicated at room temperature (28-30 °C) in an ultrasonic cleaning bath. The ultrasonic bath used for reactions had a frequency of 33 kHz and electric power rating of 100 W. The reaction was carried out in a round bottom flask of 50 ml capacity equipped with a mechanical agitator and the flask was suspended at the center of the ultrasonic bath. After the completion of the reaction monitored by gas chromatographic analysis, the organic layer was separated and subsequent evaporation of 1,2-dichloroethane in vaccuo afforded the crude product. Which was purified using column chromatography (silica gel, 60-120 mesh) with EtOAc-Petroleum ether (1:9) as an eluent. The reaction showed 94% conversion and 70% selectivity towards para nitro phenol in 2 h under sonication. The concentration time profile of the reaction was also monitored and showed good agreement between phenol consumed and total products formed. Thus eliminating possibility of any undesired side reaction / product formation (Figure 1). In comparison the reaction

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carried out under silent conditions (oilier charge is same as above) took 48 h for 30 % conversion and 49 % selectivity towards pom nitro phenol.
Example 2
The charge similar to that given in example 1 was taken except that ortho cresol was used instead of phenol. The reaction was completed in 2 h. Conversion of this reaction was 90% and selectivity towards para position was 67% under
sonication. In comparison the reaction carried out under silent conditions (other charge is same as above) took 48 h for 29% conversion and selectivity of 50% towards pttra position.
Example 3
The charge similar to that given in example 1 was taken except that meta crcsol was used instead of phenol. The reaction was completed in 2 h. Conversion of mis reaction was 85% and selectivity towards para position was 63% under sonication. In comparison the reaction carried out under silent conditions (other charge is same as above) took 48 h for 25% conversion and selectivity of 50% towards pom position.
Example 4
The charge similar to that given in example 1 was taken except that para cresol was used instead of phenol. The reaction was completed in 2 h. Conversion of mis reaction was 90% and selectivity towards ortho position was 96% under sonication. In comparison the reaction carried out under silent conditions (other charge is same as above) took 48 h for 27 conversion and selectivity of 85 % towards ortho postion.
Example 5
The charge similar to that given in example 1 was taken except that o-chloro phenol was used instead of phenol. The reaction was completed in 2 h. Conversion of mis reaction to 83% and selectivity towards para position was 60% under sonication. In comparison the reaction carried out under silent conditions (other charge is same as above) took 48 h for 22% conversion and 49% selectivity towards pom position.

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Example 6
The charge similar to that given in example 1 was taken except that p-chloro phenol was used instead of phenol. The reaction was completed in 2 h. Conversion of this reaction to 80% and selectivity towards ortho position was 94% under sonication. In comparison the reaction carried out under silent conditions (other charge is same as above) took 48 h for 20% conversion and selectivity of 87% towards ortho position.
Example 7
The charge similar to that given in example 1 was taken except that 12 wt% of nitric acid with respect to substrate was taken instead of 9 wt%. The reaction was completed in 1.5 h. Conversion of this reaction was 80% and selectivity towards para position was 69% under sonication.
Example 8
The charge similar to that given in example 1 was taken except that 15 wt% of nitric acid with respect to substrate was taken instead of 9 wt%. The reaction was completed in 45 min. Conversion of this reaction was 100% and selectivity towards para position was 72% under sonication.

As exemplified in the text (Example 1) b Based on gas chromatographic analysis.

Table 1.
Comparison of nitration of phenols using dilute nitric acid with and without
ultrasound.

Example" Substrate Condition Time (h) Conversion (%) Selectivity/o)
Para ortho others
L Phenol Silent 48 30 49 48 2
1 Phenol (((( 2 94 70 27 2
2 o-cresol Silent 48 29 50 48 1
2 o-cresol (((( 2 90 67 29 3
3 m-cresol Silent 48 25 50 47 2
3 m-cresol (((( 2 85 63 34 3
4 p-cresol Silent 48 27 - 85 -
4 p-cresol (((( 2 90 - 96 -
5 o-chlorophenol Silent 48 22 49 48 2
5 o-chlorophenol (((( 2 83 60 36 4
6 p-chlorophenol Silent 48 20 - 87 -
6 p-chlorophenol (((( 2 80 - 94 -
a As exemplified in the text
b Isolated Yields
It is evident from these examples that ultrasound promotes a regioselective nitration of phenol using dilute nitric acid alone as the nitrating with a significant enhancement in the rate of the reaction.

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I claim:
1. An improved process for selective nitration of phenol and substituted
phenol using nitric acid alone as the nitrating agent without any additive
utilizing ultrasound, comprising of two phases viz- the Organic phase and
the Aqueous phase.
a) The organic phase consist of phenol/substituted phenol in a solvent being immiscible in water and the amount of solvent is in the range of 0.2 to 50 times by mol based on phenol, particularly 1 to 20 times by mol.
b) The aqueous phase consist of reactant such as nitric acid (9-40 wt %) more particularly 9-18 wt% and the amount of nitric acid is in the range of 1 to 10 times by mol based on phenol, particularly 1 to 4 times by mol.

2. A process as claimed in claim 1, wherein nitration of phenols is been conducted using 9 wt% nitric acid without any additive with ultrasound as the promoter.
3. A process as claimed in claim 1, wherein the starting material comprises of phenol and substituted phenols such as o-cresol, m-cresol, p-cresol, o-chloro phenol, m-chloro phenol, p-chloro phenol, o-nitro phenol, p-nitro phenol etc.
4. A process as claimed in claim 1, wherein the solvent immiscible in water selected is ethylene dichloride, chloroform, carbon tetrachloride, methylene dichloride etc.
5. A process as claimed in claim 3, wherein the solvent immiscible in water is ethylene dichloride.
6. A process as claimed in claim 1, wherein the reaction is conducted in the temperature range of 20-80 °C under atmospheric pressure.
7. A process as claimed in claim 5, wherein the reaction temperature is in the range of 28-30 °C under atmospheric pressure.
8. A process as claimed in claim 1, wherein the ultrasound bath utilized for the process has a frequency of 20-100 kHz and electric power of 50-200 W.
9. A process as claimed in claim 6, wherein the ultrasound bath utilized has a frequency 33 kHz and electric power of 100 W.



Documents:

247-MUM-2007-ABSTRACT(25-1-2010).pdf

247-MUM-2007-ABSTRACT(9-2-2007).pdf

247-MUM-2007-ABSTRACT(GRANTED)-(6-6-2011).pdf

247-mum-2007-abstract.doc

247-mum-2007-abstract.pdf

247-mum-2007-cancelled pages(25-1-2010).pdf

247-MUM-2007-CANCELLED PAGES(25-4-2011).pdf

247-MUM-2007-CLAIMS(AMENDED)-(25-1-2010).pdf

247-MUM-2007-CLAIMS(AMENDED)-(25-4-2011).pdf

247-MUM-2007-CLAIMS(GRANTED)-(6-6-2011).pdf

247-mum-2007-claims.doc

247-mum-2007-clamis.pdf

247-mum-2007-correspondance-received.pdf

247-MUM-2007-CORRESPONDENCE(25-4-2011).pdf

247-mum-2007-correspondence(ipo)-(1-6-2009).pdf

247-MUM-2007-CORRESPONDENCE(IPO)-(9-6-2011).pdf

247-mum-2007-description (complete).pdf

247-MUM-2007-DESCRIPTION(GRANTED)-(6-6-2011).pdf

247-MUM-2007-DRAWING(25-1-2010).pdf

247-MUM-2007-DRAWING(GRANTED)-(6-6-2011).pdf

247-mum-2007-form 18(17-4-2007).pdf

247-MUM-2007-FORM 2(GRANTED)-(6-6-2011).pdf

247-MUM-2007-FORM 2(TITLE PAGE)-(25-1-2010).pdf

247-mum-2007-form 2(title page)-(complete)-(9-2-2007).pdf

247-MUM-2007-FORM 2(TITLE PAGE)-(GRANTED)-(6-6-2011).pdf

247-MUM-2007-FORM 3(25-1-2010).pdf

247-MUM-2007-FORM 3(9-2-2007).pdf

247-MUM-2007-FORM 5(25-1-2010).pdf

247-MUM-2007-FORM 5(9-2-2007).pdf

247-MUM-2007-FORM 9(25-1-2010).pdf

247-mum-2007-form-1.pdf

247-mum-2007-form-2.pdf

247-mum-2007-form-3.pdf

247-mum-2007-form-5.pdf

247-mum-2007-form-9.pdf

247-MUM-2007-REPLY TO EXAMINATION REPORT(25-1-2010).pdf

247-MUM-2007-SPECIFICATION(AMENDED)-(25-1-2010).pdf


Patent Number 247957
Indian Patent Application Number 247/MUM/2007
PG Journal Number 23/2011
Publication Date 10-Jun-2011
Grant Date 06-Jun-2011
Date of Filing 09-Feb-2007
Name of Patentee BHANAGE BHALCHANDRA MAHADEO
Applicant Address DEPARTMENT OF CHEMISTRY INSTITUTE OF CHEMICAL TECHNOLOGY UNIVERSITY OF MUMBAI NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI.
Inventors:
# Inventor's Name Inventor's Address
1 BHANGAE BHALCHANDRA MAHADEO DEPARTMENT OF CHEMISTRY INSTITUTE OF CHEMICAL TECHNOLOGY UNIVERSITY OF MUMBAI NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI - 400 019.
2 NANDURKAR NITIN SUBHASH DEPARTMENT OF CHEMISTRY INSTITUTE OF CHEMICAL TECHNOLOGY UNIVERSITY OF MUMBAI NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI - 400 019.
3 BHANUSHALI MAYUR JAGDISH DEPARTMENT OF CHEMISTRY INSTITUTE OF CHEMICAL TECHNOLOGY UNIVERSITY OF MUMBAI NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI - 400 019.
4 PANDA ANIL GODAVARI DEPARTMENT OF CHEMISTRY INSTITUTE OF CHEMICAL TECHNOLOGY UNIVERSITY OF MUMBAI NATHALAL PAREKH MARG, MATUNGA (EAST), MUMBAI - 400 019.
PCT International Classification Number C07C201/06, C07C205/14
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA