FIELD OF THE INVENTION
The present invention relates to a one step process for the preparation of aromatic ketones. Particularly, the present invention relates to a one step process for the synthesis of aromatic ketones in particular 4-hydroxyacetophenone from aromatic compounds using P2O5.
BACKGROUND AND PRIOR ART OF THE INVENTION
Aromatic hydroxyketones are valuable intermediates in the synthesis of pharmaceuticals, perfumery, acetophenone resins, in particular 4-hydroxyacetophenone is a valuable intermediate for a variety of organic compounds like N-acetyl-Para aminophenolan analgesic, 4-acetoxyacetanilide which can be used for the preparation of poly(ester-amide)s. Aromatic ketones, such as 4-hydroxyacetophenone and 4-methoxyacetophenone are valuable fine chemicals for the synthesis of variety of pharmaceutical substances. 4-hydroxy acetophenone derivative shows trypanocidal and antifungal property. 4-Hydroxyacetophenone (4-HAP) is a possible intermediate for a variety of products having a multiplicity of end uses. 4-HAP may be used to make N-acetyl-para-aminophenol (APAP) better known as acetaminophen, which has wide use as an analgesic, or to make 4-acetoxyacetanilide (4-AAA), which can be used for the preparation of poly(ester-amide)s capable of forming an anisotropic melt phase and suitable for being formed into shaped articles such as moldings, fibers and films. In addition, 4-AAA may also be hydrolyzed to form APAPand 4-methoxyacetopheone (acetanisole) is an aromatic chemical compound with an aroma described as sweet, fruity, nutty, and similar to vanilla. It is used as a cigarette additive, a fragrance, and a flavoring in food. It is used in tear gas (especially as the form of chloroacetophenone) and warfare. It is used as a solvent for plastics, resins, cellulose ethers, and esters. Acetophenone and its derivatives, having additionally substituted saturated alkyls, oxygenated alkyl groups, thio groups, additional aromatic groups, unsaturated aliphatic side chains, and other functional groups, are used as ingredients of flavor & fragrance for in soaps, detergents, cosmetics, and as well as in foods, beverages, and tobacco. 4'-Methoxyacetophenone is used as a component of perfumes and as chemical intermediate in the manufacture of pharmaceuticals, resins, and flavouring agents.
3
The classic synthesis of 4- hydroxy acetophenone commonly involves two steps, esterification of phenols and fries rearrangement which is an intermolecular Friedel-Crafts acylation of phenolic ester. The disadvantages associated with classic procedures include the use of toxic acid chlorides or acid anhydrates as acylating agents and aluminum trichloride as Lewis acids and an excess amount of reagents for separation of phenolic ester, which entains environment pollution and tedious workup. The zeolite H-beta and montmorillonite clay are reported to be used as catalysts for synthesis of aromatic hydroxyketones, but these catalysts both need special treatment before use such as calcination at a high temperature.In the Conventional synthesis of 4-methoxy acetophenoneincludedFriedel−Crafts reactions, with acid chlorides or anhydrides, often require excess quantities of Lewis acid (i.e., AlCl3), and they can produce significant amounts of corrosive vapor and aqueous aluminum waste.
Friedel craft acylation and Fries rearrangement are the most important reactions for the preparation of hydroxy ketone, mainly ortho and para derivative which are very valuable precursors in the pharmaceutical industry to obtain, e.g. p-hydroxyacetanilide, which is used as a pain killer, also known as paracetamol. In recent years many acylated reactions have been reported. In particular, acylation of phenol using different acylating agents were tried. However these reactions face one problem i.e. lack of selectivity and costly reagents.
Article titled, “One-pot synthesis of aromatic hydroxyketones under microwave irradiation and solvent-free conditions” by Y Cao et al. published in International Journal of Chemistry; Feb 2011, 3 (1), pp 123 reports an efficient one-pot synthesis of aromatic hydroxyketones with carboxylic acids as acylating agents without solvent under microwave irradiation was reported. The reaction comprises irradiating the mixture of phenols, carboxylic acids, phosphoric acid and phosphorus pentoxide (85% H3PO4/P2O5) in a microwave oven and the target products were obtained by one-pot.
4
US2587488 discloses the production of aromatic ketones by a novel method in the presence of phosphorous pentoxide and also discloses method to obtain diacetyl derivatives of aryl compounds in presence of phosphorous pentoxide.
Article titled, “Friedel–Crafts acylation of aromatic compounds with carboxylic acids in the presence of P2O5/SiO2 under heterogeneous conditions” by A Zarei et al. published in Tetrahedron Letters, Volume 49, Issue 47, 17 November 2008, Pages 6715–6719 reports a convenient and efficient procedure for the Friedel–crafts acylation of aromatic compounds with carboxylic acids in the presence of P2O5/SiO2. Both aromatic and aliphatic carboxylic acids reacted easily to afford the corresponding aromatic ketones. The use of non-toxic and inexpensive materials, simple and clean work-up, short reaction times and good yields of the products are the advantages of this method.
Article titled,“Improvement of selectivity in the Fries rearrangement and direct acylation reactions by means of P2O5/SiO2 under microwave irradiation in solvent-free media” by Eshghi, Hosseinet al. inJournal of Chemical Research (Miniprint), Volume 2003, Number 12, 1 December 2003, pp. 763-764(2) reports P2O5 / SiO2 to be an efficient new reagent in the Fries rearrangement of acyloxy benzene or naphthalene derivatives and the direct acylation reactions of phenol and naphthol derivatives with carboxylic acids under microwave irradiation in solvent-free media.
Article titled,“Tf2O-Mediated Direct and Regiospecific para-Acylation of Phenols with Carboxylic Acids” in M. M. Khodaei and E. Nazari reports a simple, mild, and convenient method for the preparation of para-hydroxyaryl ketones from the direct acylation of phenols with carboxylic acids activated with Tf2O.
5
EP0167286A1 relates to a process of acetylating phenol to 4-hydroxyacetophenone by contacting phenol with acetic acid or acetic anhydride.
CA1298316C relates to a process of acetylating phenol to 4-hydroxyacetophenone by contacting phenol with about 0.9 to 1.4 moles of acetic acid per mole of phenol as acetylating agent in the presence of about 20 to 50 moles of hydrogen fluoride per mole of phenol as catalyst at a temperature of reaction of about 40 to 90°C for a reaction period of about 10 to 120 minutes.
US4868256A relates to a process for the production of 3-mono or 3,5-disubstituted-4-acetoxystyrene wherein the 3- or 3,5-substitution is independently C1 to C10 alkyl, chlorine, bromine, iodine, --NO2, --NH2, or --SO3H, a process for its polymerization, hydrolysis, and use in a variety of compositions.
Article titled, “Trypanocidal and antifungal activities of p-hydroxyacetophenone derivatives from Caleauniflora (Heliantheae, Asteraceae).” ByNascimento AMet al. in Journal of Pharmacy and Pharmacology, 2004;56(5); 663-669 reports the dichloromethane extract of underground parts of Caleauniflora (Heliantheae, Asteraceae) exhibited trypanocidal and antifungal activities. Four p-hydroxyacetophenone derivatives were isolated as the main compounds: 2-senecioyl-4-(hydroxyethyl)-phenol (1), 2-senecioyl-4-(angeloyloxy-ethyl)-phenol (2), and two new derivatives, 2-senecioyl-4-(methoxyethyl)-phenol (3) and 2-senecioyl-4-(pentadecanoyloxyethyl)-phenol (4). 1 and 4 were active towards Trypanosoma cruzitrypomastigotes, reducing their number by 70 and 71% at 500 microg x mL-1, whereas 2 and 3 were inactive. All the compounds tested showed antifungal activity with minimal inhibitory concentration values between 500 and 1000 microg x mL-1 against pathogenic Candida spp. and dermatophytes.
Article titled, “Continuous acylation of anisole by acetic anhydride in mesoporous solid acid catalysts: Reaction media effects on catalyst deactivation” by VidyaSagar R. et al.; in Journal of Catalysis; 245; 184–190; 2007 reports the acylation of anisole with acetic
6
anhydride was carried out in a continuous slurry reactor over mesoporous supported Nafion® (SAC-13) and heteropolyacid (HPA) catalysts.
Article titled“Friedel–Crafts Acylation of Anisole Catalysed by H–Zeolite Beta of Crystalline Rice Husk Ash” by Zainab Ramliet al. in Journal Teknologi; 36(C); 41–54; 2002 reports the reactivity of H-Beta zeolite, synthesized directly from crystalline rice husk ash in various SiO2/Al2O3 gel ratios, was studied in the Friedel-Crafts acylation of anisole with propionic anhydride.
Article titled, “Solid Acid Catalysts for Acylation of Aromatics” by Rakesh V.Jasra in Bulletin of the catalysis Society of India; 2; 157183; 2003 reports the acylation of anisole and veratrole with rare earth exchanged zeolites and clays without using any solvent.
Article titled, “Friedel–Crafts acylation of anisole and toluene with acetic anhydride over nano-sized Beta zeolites” by Xiangfei Jiet al.in Catalysis Letters; 117; 3–4; 2007 reports the nano-sized HBeta zeolites exhibit much higher activity and stability in the Friedel–Crafts acylation of anisole and toluene with acetic anhydride than the conventional zeolites of large particle size. The small crystal size of nano-sized zeolites may bring on more accessible active sites and then enhance the catalytic activity.
Article titled, “Regioselective Acylation of Anisole with Carboxylic Acids over HZSM-5 Catalyst” by Q. L. Wang, et al. in Journal of Chemical Society Chemical Communication2307-08; 1995 reports acylation of Anisole with Carboxylic Acids over HZSM-5 Catalyst gives only two products 4-acyl anisole and the phenyl carboxylic ester.
Article titled, “Kinetic measurements of the acetylation of anisole by acetic acid in the presence of boron trifluoride” by V. Gold and T.Reily in Journal of Chemical Society; 1676-78; 1961reports the aralkylation of anisole catalyzed by sulphuric acid, zinc chloride: or boron trifluoride in acetic acid solution can be conveniently observed without interference by disturbing side-reactions. During kinetic studies of these reactions it was
7
found that, in the absence of an aralkylating agent, the interaction of acetic acid and anisole is slow and comparatively unimportant at catalyst concentrations in the range used in the aralkylation experiments.
The methods which are available in the literature for the synthesis of aromatic ketones from aromatic compound employs either hazardous starting materials, drastic reactions conditions, longer reaction sequences, often resulting in poor product (ortho, meta and para) selectivity and yields. Therefore, there is need in the art to develop a process which gives improved selectivity and yields. Accordingly, the invention provides the acylation reaction to produce selectively aromatic ketones with high yields and purity in a single step.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a one step process for the synthesis of aromatic ketones with better selectivity from aromatic compound and carboxylic acid compound in presence of suitable dehydrating agent.
Another objective of the present invention is to provide a one step, eco-friendly process for the synthesis of 4-hydroxyacetophenone from phenol and 4-methoxyacetophenone (4-MAP) from anisole using acetic acid in the presence of solvent or without solvent and P2O5 as dehydrating agent.
SUMMARY OF THE INVENTION
Accordingly, present invention provides a one step process for the preparation of p-substituted aromatic ketones of formula 3
wherein
R1 and R2 are independently selected from O-alkyl, O-aryl, H or NHAc;
R3 and R4 are independently selected from O-alkyl, O-aryl, H, NHAc, alky, aryl, OH; and
8
R5 is selected from hydrogen, alkyl, alkene, aryl;
R6=alkyl, alkene or aryl;
and the said process comprising the step of:
a. dissolving aromatic compound of formula 1 in a solvent followed by mixing with carboxylic acid compound of formula 2 and dehydrating agent;
R6COOH
1 2
wherein, R1, R2, R3, R4, R5 and R6 are as described above;
b. stirring the reaction mixture for the period ranging from 3 to 18 h at temperature ranging from 40 to 180°C to obtain p-substituted aromatic ketones of formula 3.
In an embodiment of the present invention, said aromatic compound is selected from the group consisting of phenol, 3,5 dimethoxy phenol, m-cresol, o-cresol, resorcinol, acetanilide, anisole and guiacol.
In another embodiment of the present invention, said carboxylic acid is selected from the group consisting of acetic acid, propanoicacid, hexanoic acid, decanoic acid, crotonic acid, benzoic acid and malonic acid.
In yet another embodiment of the present invention, said dehydrating agent is selected from the group consisting of aluminium phosphate (AlPO4), calcium oxide (CaO), cyanuric chloride [(NCCl)3], Ferric chloride (FeCl3), orthoformic acid [HC(OH)3], phosphoryl chloride (POCl3), Sulphuric acid (H2SO4) and Phosphorous pentaoxide (P2O5).
In yet another embodiment of the present invention, said solvent used for dissolving the aromatic alcohol is selected from the group consisting of acetic acid, toluene, dichloromethane, ethyl acetate and ethylene dichloride.
In yet another embodiment of the present invention, the yield of p-substituted aromatic ketones of formula 3 is ranging from 10 to 80%.
9
In yet another embodiment of the present invention, said process is for the synthesis of 4-hydroxyacetophenone comprising stirring the reaction mixture of phenol, acetic acid and P2O5 for the period ranging from 18 to 20 hrs at temperature ranging from 40 °C to 120°C to obtain 4-hydroxyacetophenone.
In yet another embodiment of the present invention, the conversion is greater than 85% and p-selectivity of more than 70%.
In yet another embodiment of the present invention, the said process is for the synthesis of 4-methoxyacetophenone comprising stirring the reaction mixture of anisole, acetic acid, solvent and P2O5 for the period ranging from3 to 8 hrs at temperature ranging from 60 to 120°C to obtain 4-methoxyacetophenone.
In yet another embodiment of the present invention, the conversion is range of 12 to 87% and p-selectivity in the range of 75 to 96%.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 represents experimental setup for acylation of anisole using acetic acid and P2O5as dehydrating agent.
Scheme 1 represents process steps for the preparation of p-substituted aromatic ketones of formula 3.
Scheme 2 represents process for acylation of phenol gave 4-hydroxyacetophenone.
DETAILED DESCRIPTION OF THE INVENTION
Present invention provides a one step process for the preparation of p-substituted aromatic ketones with better selectivity comprising the step of:
a) mixing aromatic compound with carboxylic acid and dehydrating agent;
b) stirring the reaction mixture for the period ranging from 3 to 18 hrs at temperature ranging from 40 to 180°C to obtain desired aromatic ketones.
Aromatic compound is dissolved before addition of carboxylic acid in a solvent selected from the group consisting of acetic acid, dichloromethane, ethyl acetate, toluene and ethylene dichloride.
10
The aromatic compound is selected from the group consisting of phenol, 3,5 dimethoxy phenol, m-cresol, o-cresol, resorcinol, acetanilide, anisole and guiacol.
The carboxylic acid is selected from the group consisting of acetic acid,propanoicacid, hexanoic acid, decanoic acid, crotonic acid, benzoic acid and malonic acid.
The dehydrating agent is selected from the group consisting of aluminium phosphate (AlPO4), calcium oxide (CaO), cyanuric chloride [(NCCl)3], Ferric chloride (FeCl3), orthoformic acid [HC(OH)3], phosphoryl chloride (POCl3), Sulphuric acid (H2SO4)and Phosphorous pentaoxide (P2O5).
The process for acylation of aromatic compounds with carboxylic acids in the presence of P2O5 is shown in scheme 1.
The present invention provides a process for the synthesis of 4-hydroxyacetophenone comprising stirring the reaction mixture of phenol, acetic acid using solvent like dichloromethane, ethyl acetate, toluene and ethylene dichloride or without solvent in presence of P2O5 as dehydrating agent for the period of 12 to 18 hrs at temperature ranging from 40 °C to 120°C to obtain 4-hydroxyacetophenone.
The process for acylation of phenol gave 4-hydroxyacetophenone with conversion of 90% and p-selectivity of more than 70% is shown in scheme 2.
The present invention provide a one step process for the synthesis of 4-methoxyacetophenone (4-MAP) comprising stirring the reaction mixture of anisole, acetic acid, solvent like dichloromethane, ethyl acetate, toluene and ethylene dichloride or without solvent and P2O5 for the period ranging from 3 to 8 hrs at temperature ranging from 60 to 120°C to obtain 4-MAP.
The process for acylation of anisole gave 4-methoxyacetophenone with conversion of 12-87% and p-selectivity in the range of 75-96%.
The present invention provides a one step process for the synthesis of aromatic ketones of formula 3,
11
wherein,
R1 and R2 are independently selected from the group consisting of O-alkyl, O-aryl, H or NHAc;
R3 and R4 are independently selected from the group consisting of O-alkyl, O-aryl, H, NHAc, alky, aryl, OH;
R5 is selected from the group consisting of hydrogen, alkyl, alkene or aryl;
R6=alkyl, alkene or aryl
with more than 70 % selectivity from aromatic compound of formula 1,
1
wherein R1, R2, R3, R4 and R5 are as described above;
and carboxylic acid compound of formula 2,
R6COOH
2
wherein R6 is as described above;
in presence of suitable dehydrating agent.
EXAMPLES
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1: Experimental Procedure for the preparation of 4-hydroxyacetophenones
12
A round bottomed flask was charged with Phenol (500 mg, 5.319 mmol), Phenol was dissolved by using EDC or AcOH as solvent (10 mL) into this reaction mixture aliphatic, aromatic, saturated and unsaturated acid (5 equiv.), P2O5 (744.66 mg, 5.319 mmol) was added and the mixture stirred for 12 h at 120oC. The reaction was then monitored by TLC and after the completion of reaction it was quenched with sodium bicarbonate solution. The workup of reaction mixture was done with DCM (50 ml) and water (15 ml) to remove traces phosphoric acid. Organic layer was dried on sodium sulphate, Solvent was removed in vacuum distillation to furnish of 4-Hydroxy ketone.
Yield of 4-hydroxyacetophenone: 80 %; mp: 109˚C; GC purity: 99%.
P2O5 in 50 mol % gave the desire product in 80% yield with a greater than 70% p-selectivity. However, under this condition, 50g of phenol has been converted into corresponding p-hydroxyacetophenone in 80% yield as shown in Table 1. Also Table 2 shows P2O5 mediated p-acylation of different aromatic compounds.
Table-1: P2O5-mediated acylation of phenol: optimization study
Sr.no
P2O5
(mol %)
solvent
Temp (ºC)
Time (h)
Product Yields (%)
3aa
4aa
5aa
1
100
CH2Cl2
40
12
-
20
30
2
100
EDC
80
18
70
20
5
3
100
toluene
120
18
30
10
-
4
100
THF
80
18
-
-
-
5
100
CH3CN
120
18
-
-
-
6
100
DMF
120
18
-
-
-
7
100
AcOH
120
18
20
65
5
8
50
AcOH
120
18
80
10
5
A process of acetylating electron rich aromatic systems to corresponding acetophenones by reacting aromatic compounds such as phenol with acetic acid. When acetic acid is the acetylating agent, per mole (1 equivalent) of aromatic systems like phenol, about 3 to 5 moles (3 to 5 equivalent) of acetic acid is used in the presence of about 50 moles% of phosphorous pentoxide (P2O5) as dehydrating agent, at a temperature of reaction of about 40 to 120°C, for a reaction period of about 12-18 hours. In all instances, the invention
13
results in aromatic compound conversions of at least about 80% and p-selectivity to more than 70%.
Table 2: P2O5 mediated p-acylation of different aromatic compounds:
Example 2: Synthesis of 4 - hydroxy acetophenone:
Yield: 80%, colorless solid, Mp: 106-107°C;1H NMR (200 MHz, CDCl3) δ 1.84 (br. s., 1 H) 2.58 (s, 3 H) 6.92 (d, J =8.84 Hz, 2 H) 7.92 (d, J=8.72 Hz, 2 H): 13C NMR (50 MHz CDCl3) δ 25.6, 29.0, 114.8, 128.8, 130.5, 160.7, 197.9.
Example 3: Synthesis of 4 - acetyl phenyl acetate:
Yield: 10 %, colorless liquid; 1H NMR (200 MHz, CDCl3) δ 1.57 (s, 1 H) 2.34 (s, 3 H) 2.61 (s, 3 H) 7.19 (d, J=8.84 Hz, 2 H) 8.00 (d, J= 8.84 Hz, 2 H).
Example 4: Synthesis of 4- hydroxy phenyl hexanone:
Yield: 80 %, colorless solid, Mp: 91-92 °C; 1H NMR(200 MHz CDCl3),) δ 0.86 - 0.96 (m, 3 H) 1.34 - 1.39 (m, 3 H) 1.64 - 1.79 (m, 2 H) 2.80 - 3.00 (m, 2 H) 6.89 (d, J=8.84 Hz, 2 H) 7.91 (d, J=8.84 Hz, 2 H); 13C NMR (200 MHz, CDCl3) δ 14.0, 22.56, 24.5, 31.6, 38.3, 115.4, 130.8, 200.1.
Example 5: Synthesis of 3,5 dimethoxy 1-hydroxy acetophenone:
Yield: 60 %, yellow solid, Mp: 124-126 °C;1H NMR (200 MHz, CDCl3) δ 2.60 (s, 3 H) 3.84 (d, J=7.71 Hz, 3 H) 5.89 (d, J=2.27 Hz, 1 H) 6.04 (d, J=2.27 Hz, 1 H) 13.99 (s, 7 H)
Sr.No.
Substrates
(1)
Carboxylic acid
R6COOH (2)
Products (%)
3
4
5
1
Phenol (1a)
Acetic acid (2a)
80 (3aa)
10 (4aa)
5 (5aa)
2
Phenol (1a)
Propanoicacid (2b)
70 (3ab)
20 (4ab)
5(4ab)
3
Phenol (1a)
Hexanoicacid (2c)
80 (3ac)
-
-
4
Phenol (1a)
Decanoicacid (2d)
-
-
70 (5ad)
5
Phenol (1a)
Crotonicacid (2f)
-
-
65 (5af)
6
Phenol (1a)
Benzoic acid (2c)
-
-
70(5ac)
7
3,5 dimethoxy phenol(1b)
Acetic acid (2a)
60 (3ba)
20(4ba)
-
8
m-cresol (1c)
Acetic acid (2a)
20 (3ca)
60 (4ca)
10 (5ca)
9
o-cresol (1d)
Acetic acid (2a)
20 (3da)
65 (4da)
-
10 Resorcinol (1e)
Acetic acid (2a)
70 (3ea)
15 (4ea)
-
11
Acetanilide (1f)
Acetic acid (2a)
65 (3fa)
-
-
12
Guiacol(1h)
Acetic acid (2a)
60 (ha)
-
-
14
Example 6: Synthesis of 3,5dihydroxyacetophenone:
Yield: 60 %, white solid; Mp: 143-145 °C; 1H NMR(200 MHz CDCl3) δ 2.39 (s, 3 H) 6.66 - 6.77 (m, 2 H) 7.31 (s, 1H).
Example 7: Synthesis of Phenyl decanoate:
Yield: 70%, colourless liquid;1H NMR (200 MHz, CDCl3) δ0.87 - 0.93 (m, 3 H) 1.28 (br. s, 6 H) 1.66 - 1.84 (m, 2 H) 2.55 (t, J=7.45 Hz, 2 H) 7.08 (d, J=8.59 Hz, 2 H) 7.16 - 7.48 (m, 3 H).
Example 8: Synthesis of Phenyl benzoate:
Yield: 70%, colorless liquid; Mp:65-68o C1H NMR (200 MHz, CDCl3) δ 7.19 - 7.35 (m, 3 H) 7.40 - 7.72 (m, 6 H) 8.24 (d, J=7.96 Hz, 2 H)
Example 9: Synthesis of 4- Methoxy phenyl propanone:
Yield: 60 %, colorless liquid; Mp: 143-145 °C;1H NMR (200 MHz, CDCl3) δ0.88 (t, 3 H) 2.95 (q, J=7.33 Hz, 2 H) 3.87 (s, 3 H) 6.91 (m, J=8.84 Hz, 2 H) 7.94 (m, J=8.97 Hz, 2 H)
Example 10: Experimental procedure for the preparation of 4-MAP
The acylation reaction was performed in stirred tank reactor shown in Fig. 1. It consists of three neck glass reactor, three necks are used for connecting glass condenser, inserting the temperature indicator and deep tube for taking sample with regular interval of time respectively. The experimental set-up for batch mode was designed to see the influence of various operating reaction parameters. A round-bottomed flask was charged with known quantities of anisole, glacial acetic acid. The P2O5 was added at the staring of reaction or in the middle of reaction or during the course of reaction in stepwise manner. The acylation reaction also studied in the presence of solvent such as ethylene dichloride, dichloromethane, ethyl acetate etc.as solvent. The whole reaction mixture continuously stirred at 500 rpm. The reaction mass was heated via oil bath to desired, once the expected reaction temperature is reached then a sample was withdrawn from the reactor as initial reading. The reaction samples were periodically removed from the reactor and analyzed for its content by gas chromatography.
The acylation reaction was performed at different operating conditions such as reaction temperature, reactant molar ratios, catalyst loading, using different solvents. The details of reaction each experiment are summered in the following Tables 3, 4 and 5
15
respectively. The acylation reaction was also scaled up from 3 g/batch to 1000 g per batch.
Table 3: Results of acylation of anisole: solvent effect
Batch
Reaction experimental conditions
Wt (grms)
Eq. mole
% Conversion Anisole
% Formation 2-MAP
% Formation 4-MAP
% selectivity p-MAP
1
Temperature = 85 °C
Anisole
150
1
P2O5
100
0.5
48.6
1.6
43.6
89.71%
Acetic Acid
416
5
EDC
961
7
2
Temperature = 85 °C
Anisole
300
1
P2O5
194.4
0.50
77
1.9
63.8
82.85%
Acetic Acid
834
5
3
Temperature = 85 °C
Anisole
100
1
P2O5
64.4
0.5
50.1
1.6
48.2
96.20%
Acetic Acid
277.5
5
Cyclohexene
544.93
7
4
Temperature = 120°C
Anisole
200
1
P2O5
128
0.50
73
2.2
56.9
77.94%
Acetic Acid
555
5.00
5
Temperature =80°C
Anisole
200
1
P2O5
128
0.5
57
2.5
50
87.71%
Acetic Acid
555.3
5
EDC
1924.16
7
Table 4: Results of acylation of anisole: Catalyst loading effect
Batch
Reaction experimental conditions
Wt (g)
Eq. mole
% Conversion Anisole
% Formation 2-MAP
% Formation 4-MAP
Selectivity for p-MAP
Remark
1
Temperature = 120 °C
P2O5 was added
at 120 °C
16
Anisole
200
1
along with
acetic acid and
anisole.
P2O5
40
0.15
27.2
1.4
25.5
=25.5/27.2=93.75%
Acetic Acid
220
5
2
Temperature = 120 °C
Initial 100 g P2O5
was added along
with
acetic acid and
anisole
remaining
20 g added after
5 h of reaction.
Anisole
200
1
P2O5
120
0.5
82.9
2.3
80.02
96%
Acetic Acid
560
5
3
Temperature = 85 °C
Initially 20 g. P2O5
Was added, after
2 h of reaction again
20 g was
added, then 15 g
after 2 h and
then finally 10g
after 1 h into
the reaction mixture
Anisole
200
1
P2O5
100
0.4
70
2.6
64.5
92.14%
Acetic Acid
560
5.0
EDC
920
5.0
4
Temperature = 120 °C
Initially 20 g P2O5
was added after
that addition of 20g
P2O5 and 50 g acetic
acid was done for
every 1 h
Anisole
200
1
P2O5
100
0.4
70
2.1
63.3
90.42%
Acetic Acid
555
5.0
5
Temperature = 120 °C
54 g of P2O5 and 110 g of Acetic Acid was added for every 1 hr
Anisole
500
1
P2O5
324
0.50
65.89
3
59.32
90.02%
Acetic Acid
1388.7
9
6
Temperature = 120°C
54 g of P2O5 and 110 g of Acetic Acid was added for every 45 min
Anisole
500
1
P2O5
324
0.50
51.8
2.9
46.7
90.15%
Acetic Acid
1389
5
7
Temperatur
108 g of P2O5
17
e = 120°C
and 220 g of Acetic Acid was added for every 1 hr
Anisole
1000
1
P2O5
648
0.50
58.96
2.8
52.78
89.51%
Acetic Acid
2777
5
8
Temperature = 120°C
108 g of P2O5 and 220 g of Acetic Acid was added for every 1hr
Anisole
1000
1
P2O5
648
0.50
50.96
2.8
43.5
85.36%
Acetic Acid
2778
5
9
Temperature = 120°C
108 g of P2O5 and 220 g of Acetic Acid was added for every 1 hr
Anisole
1000
1
P2O5
648
0.50
55.2
2.4
44.8
81.16%
Acetic Acid
2778
5
10
Temperature = 80°C
Addition of P2O5was done in two parts
Anisole
100
1
P2O5
64.82
0.5
65
2.3
60.82
93.56%
Acetic Acid
278
5
EDC
641
7
11
Temperature = 80°C
Addition of 0.4 mole equivalent P2O5 in two parts
Anisole
100
1
P2O5
51.8
0.4
66.7
2.1
59.6
89.35%
Acetic Acid
278
5
EDC
641
7
12
Temperature = 120°C
Addition of 0.4 mole equivalent P2O5 in two parts without E.D.C.
Anisole
100
1
58.8
2.3
44.6
75.85%
P2O5
51.8
0.4
Acetic Acid
278
5
13
Temperature = 80°C
Addition of 0.3 mole equivalent P2O5 in two parts + 5 g P2O5 after 6 h
Anisole
100
1
P2O5
38.3
0.3
57
2
52.6
92.28%
Acetic Acid
278
5
EDC
644
7
14
Temperature = 80°C
Addition of 0.2 mole equivalent P2O5 in two parts
Anisole
100
1
P2O5
25.9
0.2
12.7
0.5
12.1
95.27%
Acetic Acid
278
5
18
EDC
644
7
15
Temperature = 80°C
3 mole equivalent of Acetic Acid with stepwise addition of P2O5
Anisole
100
1
P2O5
38.3
0.3
36.3
1.5
34.3
94.45%
Acetic Acid
167
3
EDC
644
7
16
Temperature = 80°C
4 mole equivalent of Acetic Acid with stepwise addition of P2O5
Anisole
100
1
P2O5
38.3
0.3
39.5
1.4
37.7
95.44%
Acetic Acid
222
4
EDC
641
7
17
Temperature = 80°C
5 mole equivalent of E.D.C. with stepwise addition of P2O5
Anisole
100
1
P2O5
38.3
0.3
51.6
1.9
47.8
92.63%
Acetic Acid
222
4
EDC
641
5
18
Temperature = 80°C
3 mole equivalent of E.D.C. with stepwise addition of P2O5
Anisole
100
1
P2O5
38.3
0.3
47.3
1.8
42.3
89.43%
Acetic Acid
222
4
EDC
275
3
19
Temperature = 80°C
Dropwise addition of Anisole using dip-tube
Anisole
100
1
P2O5
38.3
0.3
26.7
1
25.6
95.88
Acetic Acid
222
4
EDC
458
5
20
Temperature = 80°C
Addition of P2O5 in two parts
Anisole
100
1
P2O5
64
0.5
87.93
2.1
78.41
89.17%
Acetic Acid
222
4
EDC
458
5
21
Temperature = 80°C
Addition ofP2O5 in two parts
Anisole
100
1
P2O5
51.8
0.4
38.8
1.7
35.7
91.49%
19
Acetic Acid
222
4
EDC
428
5
Table 5: Results of acylation of anisole: In autoclave
Batch
Reaction experimental conditions
Wt (grms)
Eq. mole
% Conversion Anisole
% Formation 2-MAP
% Formation 4-MAP
% selectivity p-MAP
3
Temperature = 80°C
Anisole
100
1
P2O5
51.8
0.4
44.5
1.5
34.9
78.42%
Acetic Acid
222
4
EDC
458
5
4
Temperature = 80°C
Anisole
600
1
P2O5
233
0.3
43.7
1.9
42.4
97.02%
Acetic Acid
1332
4
EDC
1647
3
5
Temperature = 80°C
Anisole
500
1
P2O5
260
0.4
51.5
2.2
47.6
92.42%
Acetic Acid
1390
5
EDC
1832
4
6
Temperature = 80°C
Anisole
500
1
P2O5
195
0.3
51.5
2.2
47.6
92.42
Acetic Acid
1390
5
EDC
1375
3
ADVANTAGES OF INVENTION
1. Dehydrating agent used in catalytic amounts.
2. No waste generated and exclusive para substituted products.
3. p- Hydroxyl acetophenone is used as intermediates in industry.
4. p-Methoxy acetophenone is used as a cigarette additive, a fragrance and a flavoring in food.

WE CLAIM
1. A one step process for the preparation of p-substituted aromatic ketones of formula 3
wherein
R1 and R2 are independently selected from O-alkyl, O-aryl, H or NHAc;
R3 and R4 are independently selected from O-alkyl, O-aryl, H, NHAc, alky, aryl, OH; and
R5 is selected from hydrogen, alkyl, alkene, aryl;
R6=alkyl, alkene or aryl;
and the said process comprising the step of:
a. dissolving aromatic compound of formula 1 in a solvent followed by mixing with carboxylic acid compound of formula 2 and dehydrating agent to obtain a mixture;
R6COOH
1 2
wherein, R1, R2, R3, R4, R5 and R6 are as described above;
b. stirring the reaction mixture as obtained in step (a) for the period ranging from 3 to 18 h at temperature ranging from 40 to 180°C to obtain p-substituted aromatic ketones of formula 3.
2. The process as claimed in claim 1, wherein said aromatic compound is selected from the group consisting of phenol, 3,5 dimethoxy phenol, m-cresol, o-cresol, resorcinol, acetanilide, anisole and guiacol.
21
3. The process as claimed in claim 1, wherein said carboxylic acid is selected from the group consisting of acetic acid, propanoic acid, hexanoic acid, decanoic acid, crotonic acid, benzoic acid and malonic acid.
4. The process as claimed in claim 1, wherein said dehydrating agent is selected from the group consisting of aluminium phosphate (AlPO4), calcium oxide (CaO), cyanuric chloride [(NCCl)3], Ferric chloride (FeCl3), orthoformic acid [HC(OH)3], phosphoryl chloride (POCl3), Sulphuric acid (H2SO4) and Phosphorous pentaoxide (P2O5).
5. The process as claimed in claim 1, wherein said solvent used for dissolving the aromatic alcohol is selected from the group consisting of acetic acid, toluene, dichloromethane, ethyl acetate and ethylene dichloride.