4 Hydroxy Acetophenone

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SYNTHETIC ROUTE

For

p-HYDROXY ACETOPHENONE U s e o f t h i s r e p o r t o t h e r t h a n b y t h e s a i d c o m p a n y a m o u n t s t o a l e g a l o f f e n c e .

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T a b l e o f C o n t e n t s 1 . 1 L i t e r a t u r e S u r v e y f o r

1 . 1 1 B a s i c i n f o r m a t i o n & M S D S

1 . 2 S y n t h e s i s R o u t e f o r p - H y d r o x y a c e t o p h e n o n e

1 . 2 1 R o u t e 1

1 . 2 2 E x p l a n a t i o n

1 . 2 3 R e c o m m e n d a t i o n

1 . 2 4 R e f e r e n c e

1 . 2 5 R o u t e 2 ( a )

1 . 2 6 E x p l a n a t i o n


1 . 2 8 R o u t e 2 ( b )

1 . 2 9 E x p l a n a t i o n


1 . 3 1 R e f e r e n c e

1 . 3 2 R o u t e 3

1 . 3 3 E x p l a n a t i o n

1 . 3 4 P u r i f i c a t i o n

1 . 3 5 R e f e r e n c e �

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T a b l e o f C o n t e n t s 1 . 4 A n n e x u r e s

1 . 4 1 A n n e x u r e 1

1 . 4 2 A n n e x u r e 2

1 . 4 3 A n n e x u r e 3

1 . 4 4 A n n e x u r e 4

1 . 4 5 A n n e x u r e 5

1 . 4 6 A n n e x u r e 6

1 . 4 7 A n n e x u r e 7

1 . 4 8 A n n e x u r e 8

1 . 4 9 A n n e x u r e 9

1 . 5 A n n e x u r e s

1 . 5 1 A n n e x u r e 1 0

1 . 5 2 A n n e x u r e 1 1

1 . 5 3 A n n e x u r e 1 2

1 . 5 4 A n n e x u r e 1 3

1 . 5 5 A n n e x u r e 1 4

1 . 5 6 A n n e x u r e 1 5

1 . 5 7 A n n e x u r e 1 6

1 . 5 8 A n n e x u r e 1 7

1 . 5 9 A n n e x u r e 1 8 �



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T a b l e o f C o n t e n t s

1 . 6 A n n e x u r e s

1 . 6 1 A n n e x u r e 1 9

1 . 6 2 A n n e x u r e 2 0

1 . 6 3 A n n e x u r e 2 1

1 . 6 4 A n n e x u r e 2 2

1 . 6 5 A n n e x u r e 2 3

1 . 6 6 A n n e x u r e 2 4

1 . 6 7 A n n e x u r e 2 5

1 . 6 8 A n n e x u r e 2 6

1 . 6 9 A n n e x u r e 2 7

1 . 7 A n n e x u r e s

1 . 7 1 A n n e x u r e 2 8

1 . 7 2 A n n e x u r e 2 9

1 . 7 3 A n n e x u r e 3 0

1 . 7 4 A n n e x u r e 3 1

1 . 7 5 A n n e x u r e 3 2

1 . 7 6 A n n e x u r e 3 3

1 . 7 7 A n n e x u r e 3 4

1 . 7 8 A n n e x u r e 3 5

1 . 7 9 A n n e x u r e 3 6

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T a b l e o f C o n t e n t s

1 . 8 0 A n n e x u r e s

1 . 8 1 A n n e x u r e 3 7

1 . 8 2 A n n e x u r e 3 8

1 . 8 3 A n n e x u r e 3 9

1 . 8 4 A n n e x u r e 4 0

1 . 8 5 A n n e x u r e 4 1

1 . 8 6 A n n e x u r e 4 2



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[1.1]

LITERATURE SURVEY

for

p-HYDROXY ACETOPHENONE



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[1.11]

p-Hydroxy acetophenone

O

OH

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Chemical Name p-Hydroxy acetophenone Synonym �� Formula C8H8O2�

CAS No. 99-93-4�

Molecular weight ��



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MSDS for 4'-Hydroxyacetophenone

SOURCE: WWW.chemexper.com

**** SECTION 1 - CHEMICAL PRODUCT **** MSDS Name: 4'-Hydroxyacetophenone, 98% Synonyms: 4-Acetylphenol **** SECTION 2 - COMPOSITION, INFORMATION ON INGREDIENTS **** +----------------+--------------------------------------+----------+-----------+ | CAS# | Chemical Name | % | EINECS# | |----------------|--------------------------------------|----------|-----------| | 99-93-4 |4'-Hydroxyacetophenone | 98% | 202-802-8 || +----------------+--------------------------------------+----------+-----------+ Hazard Symbols: XI Risk Phrases: 38 **** SECTION 3 - HAZARDS IDENTIFICATION **** EMERGENCY OVERVIEW Irritating to skin. Potential Health Effects The toxicological properties of this material have not been investigated. Use appropriate procedures to prevent opportunities for direct contact with the skin or eyes and to prevent inhalation. **** SECTION 4 - FIRST AID MEASURES **** Eyes: Immediately flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower lids. Skin: Flush skin with plenty of soap and water for at least 15 minutes while removing contaminated clothing and shoes. Ingestion: Do NOT induce vomiting. Allow the victim to rinse his mouth and then to drink 2-4 cupfuls of water, and seek medical advice. Inhalation: Remove from exposure to fresh air immediately. Notes to Physician: Treat symptomatically and supportively. **** SECTION 5 - FIRE FIGHTING MEASURES **** General Information: As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full

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protective gear. During a fire, irritating and highly toxic gases may be generated by thermal decomposition or combustion. Extinguishing Media: In case of fire, use water, dry chemical, chemical foam, or alcohol-resistant foam. Autoignition Temperature: Not available. Flash Point: 166 deg C ( 330.80 deg F) NFPA Rating: Not published. Explosion Limits, Lower: Not available. Upper: Not available. **** SECTION 6 - ACCIDENTAL RELEASE MEASURES **** General Information: Use proper personal protective equipment as indicated in Section 8. Spills/Leaks: Clean up spills immediately, observing precautions in the Protective Equipment section. Sweep up, then place into a suitable container for disposal. **** SECTION 7 - HANDLING and STORAGE **** Handling: Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Avoid contact with eyes, skin, and clothing. Avoid ingestion and inhalation. Storage: Store in a cool, dry place. Keep container closed when not in use. **** SECTION 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION **** Engineering Controls: Use adequate general or local exhaust ventilation to keep airborne concentrations below the permissible exposure limits. Use process enclosure, local exhaust ventilation, or other engineering controls to control airborne levels. Personal Protective Equipment Eyes: Wear safety glasses and chemical goggles if splashing is possible. Skin: Wear appropriate protective gloves and clothing to prevent skin exposure. Clothing: Wear appropriate protective clothing to minimize contact with skin. Respirators: Wear a NIOSH/MSHA or European Standard EN 149 approved full-facepiece airline respirator in the positive pressure mode with emergency escape provisions.

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**** SECTION 9 - PHYSICAL AND CHEMICAL PROPERTIES **** Physical State: Solid Appearance: Very slightly beige crystalline powder Odor: Not available. pH: Not available. Vapor Pressure: Not available. Viscosity: Not available. Boiling Point: 147 - 148 deg C @ 3.00mm Hg Freezing/Melting Point: 106 - 108 deg C Decomposition Temperature: Not available. Solubility: 10 g/l (22 c) Specific Gravity/Density: 1.1090g/cm3 Molecular Formula: HOC6H4COCH3 Molecular Weight: 136.15 **** SECTION 10 - STABILITY AND REACTIVITY **** Chemical Stability: Stable under normal temperatures and pressures. Conditions to Avoid: Incompatible materials. Incompatibilities with Other Materials: Oxidizing agents, bases, acid chlorides, acid anhydrides. Hazardous Decomposition Products: Carbon monoxide, irritating and toxic fumes and gases, carbon dioxide. Hazardous Polymerization: Has not been reported. **** SECTION 11 - TOXICOLOGICAL INFORMATION **** RTECS#: CAS# 99-93-4: AM8750000 LD50/LC50: CAS# 99-93-4: Oral, mouse: LD50 = 1500 mg/kg. Carcinogenicity: 4'-Hydroxyacetophenone - Not listed by ACGIH, IARC, NIOSH, NTP, or OSHA. See actual entry in RTECS for complete information. **** SECTION 12 - ECOLOGICAL INFORMATION **** For further information, contact Acros Organics. **** SECTION 13 - DISPOSAL CONSIDERATIONS **** Dispose of in a manner consistent with federal, state, and local regulations. **** SECTION 14 - TRANSPORT INFORMATION **** US DOT No information available IMO Not regulated as a hazardous material. IATA

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Not regulated as a hazardous material. RID/ADR Not regulated as a hazardous material. Canadian TDG No information available. **** SECTION 15 - REGULATORY INFORMATION **** European/International Regulations European Labeling in Accordance with EC Directives Hazard Symbols: XI Risk Phrases: R 38 Irritating to skin. Safety Phrases: S 37 Wear suitable gloves. WGK (Water Danger/Protection) CAS# 99-93-4: 2 Canada CAS# 99-93-4 is listed on Canada's DSL/NDSL List. CAS# 99-93-4 is not listed on Canada's Ingredient Disclosure List. Exposure Limits US FEDERAL TSCA CAS# 99-93-4 is listed on the TSCA inventory. **** SECTION 16 - ADDITIONAL INFORMATION **** MSDS Creation Date: 7/16/1996 Revision #0 Date: Original. The information above is believed to be accurate and represents the best information currently available to us. However, we make no warranty of merchantability or any other warranty, express or implied, with respect to such information, and we assume no liability resulting from its use. Users should make their own investigations to determine the suitability of the information for their particular purposes. In no way shall the company be liable for any claims, losses, or damages of any third party or for lost profits or any special, indirect, incidental, consequential or exemplary damages, howsoever arising, even if the company has been advised of the possibility of such damages

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[1.21] ROUTE 1

p-HYDROXY ACETOPHENONE�

Synthetic route # 1 FRIES MIGRATION

SOURCE : Chemical Abstract�

OH O OH

O

OH O

O

Phenol Phenyl acetate

+

o-hydroxy acetophenone

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��EXPLANATION �

This method involves the conversion of phenyl acetate to ortho& para- hydroxy acetophenone. The reaction is carried out using various modes: a) Vapour phase b) Liquid phase c) Photo fries d) Microwave assisted Fries migration Various catalysts used in the reaction are namely zeolites dopped with heteropoly acids, aluminum chloride, beta cyclodextrin, para toluene sulfonic acid etc.



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[1.23] RECOMMENDATION

FRIES MIGRATION Synthetic route # 1 SOURCE : Chemical Abstract

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T h e p ro c es s i s ca r r i e d ou t a t h i gh t emp e r a t u r es . D u e t o t he h i gh t em p er a tu r e s e l e c t i v i t y t o d es i r e d p - h yd r o x y a c e t op h en on e i s r e l a t i v e l y p o o r . D e a c t iv a t i o n o f c a t a l ys t c an m an y a t im e s c au s e po o r s e l e c t i v i t y t o d e s i r ed p a r a i s om e r .

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1.24 REFERENCES

REACTION

CA CHEMISTRY

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[1.25] ROUTE 2(a)


Synthetic route # 2(a) FRIEDEL CRAFTS REACTION

Source : Chemical Abstract��

OH O OH

O

OH

Phenol

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[1.26] EXPLANATION �

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FRIEDEL CRAFT ACYLATION Synthetic route # 2(a) Source : Chemical Abstract �

1) Acylation is carried out at lower temperature hence selectivity towards p-hydroxy acetophenone is observed over o-hydroxy acetophenone

2) Usage of hydrofluoric acid as a medium cum reagent in the reaction results in high para:ortho

ratio of the hydroxy acetophenones.

3) Recovery, recyclability & reusability of hydrofluoric acid makes this process technocommercially feasible.

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[1.28] ROUTE 2(b)


Synthetic route # 2(b)

FRIEDEL CRAFT REACTION

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O O

O

OH

OAnisole

4-methoxy acetophenonep-hydroxy actophenone



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[1.29] EXPLANATION �

Friedel Craft reaction of anisole with acetyl chloride to 4-methoxy acetophenone followed by demethylation to give p-hydroxyacetophenone.

Various Demethylating reagents reported in literature are

1) Aluminum trichloride

2) Iodotrimethyl silane

3) Pyridine hydrochloride

4) Mixture of sodium cyanide-dimethyl sulfoxide



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Friedel Craft acylation of anisole results into major p-substituted product which on de-etherification gives desired p-hydroxy acetophenone. Protection & deprotection makes this process less attractive commercially.

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[1.31] REFERENCES

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REACTION CA CHEMISTRY

Friedel Craft acylation

2a) Using Phenol �� . ��)�� . ��-�� . �/,�� . �/�� . �//�� . �/�� . �/��

2b) Using Anisole �� . �/�� . �/�� . �/(�� . �/)�� . �/-�� . ��,�� . �� . ��/�� . �� . �� . �� . �� . ��(�� . ��)

133: 237638s 131: 352791g 130: 124891p 129: 150325f 128:321426f 128: 218583a 127: 278063v

124: 59785s

122: 313942b 122: 242725v 121: 258445u 120: 273489j 115: 231796y 112: 231793j 109: 54423c 107: 96437z 107: 9346c

104: 148513f 104: 109223s 97: 215756q

O O O

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O

OH

OAnisole

4-methoxy acetophenonep-hydroxy actophenone

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[1.32] ROUTE 3


Synthetic route # 3 OXIDATION

SOURCE : Chemical Abstract

OH OH

O

4-Ethyl-phenol p-hydroxy acetophenone �

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[1.33] EXPLANATION

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Oxidation of 4-hydroxy ethyl benzene using oxygen in the presence of an oxidation catalyst .

Ruthenium tetraoxide (RuO4) is also used as an oxidising agent. However commercial non-availability

of 4-hydroxy ethyl benzene does not make this process practically feasible. The oxidizing agent

ruthenium tetraoxide employed in the reaction is expensive.

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[1.34] PURIFICATION

p-HYDROXY ACETOPHENONE

SOURCE : Chemical Abstract

Various methodologies reported in literature to carry out various purification are :

I) Separation of ortho/para hydroxy acetophenones by selective solubilisation & sorption

onWeak Base Ion Exchange Resins.

II) Mixtures of 4-hydroxy acetophenone & hydrofluoric acid in Friedel Crafts acylation are

separated & purified by distillation.

III) For the preparation of p-hydroxy acetophenone of a high purity methods like zone melting

& zone sublimation. are utilized.



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[1.35] REFERENCES �

REACTION

3) Oxidation Annexure 39 4) Purification Annexure 40 Annexure 41 Annexure 42

CA

134:162822g 136: 281120c 136: 150997w 107: 39402k

CHEMISTRY

OH OH

O

4-Ethyl-phenol p-hydroxy acetophenone



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CAS reference: 134: 328189h

Catalysis by heteropoly acids : hydroxyacetophenones via phenyl acetate by vapour phase acetylation of phenol.

Indian J. Chem. Technol. 2000, 7(6), 273-275-(Eng)

National Institute of Science Communication, CSIR.

A continuous catalytic process for the acetylation of phenol to Ph acetate followed by simultaneous Fries rearrangement to provide o- and p-hydroxyacetophenones has been described. A silica supported heteropolyacid has been used as the catalyst for the condensation and rearrangement. The expt. has been carried out in the vapour phase and a complete conversion of phenol to Ph acetate has been achieved at 140 deg C. Upon increasing the temp to 200 deg C, the Ph acetate formed isomerised into hydroxyacetophenones with 10% yield and 90% selectivity to the para isomer.

O O O

O

O O

O


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CAS reference: 130: 296477z

Fries rearrangement at atmospheric pressure using microwave irradiation.

Synth. Commun. 1999. 29 (7) 1195-1200 (Eng.) Marcel Dekker, Inc.

A very safe fast and practical Fries rearrangement with conventional AlCl3 catalyst, carried out in a modified domestic microwave oven at atm. pressure is reported.

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Highly selective Fries rearrangement over zeolites and Na ion in silica composite catalysts : a comparison.

J. Catal. 1998. 176 (1), 260-263 (Eng.). Academic Press.

Heterogeneous catalysts for the Fries rearrangement of phenyl acetate were compared, including zeolites, Na ion acidic resin, and a Na ion silica composite catalyst; all provided o- and p-hydroxyacetophenones in low conversions and low to moderate selectivites. The Na ion silica composite catalyst was more selective than most of the zeolites at 150 deg, with a selectivity of 4.3:1 for the p-hydroxyacetophenone over the ortho isomer, while the most selective zeolite, H-BEA, gave a 4.7:1 mixture of the p-hydroxyacetophenone and o-hydroxyacetophenone. The Na ion silica composite catalysts were more selective in the Fries rearrangement than the pure Na ion resin, although the conversion decreased as the concentration of the Na ion resin in the composite decreased. Changing the solvent resin for the heterogeneous Fries rearrangement of phenyl acetate from cumene to phenol increased the conversion significantly.

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CAS reference: 128: 217159e �

Selective Fries rearrangement of phenyl acetate into hydroxyacetophenones catalyzed by high-silica zeolite NCL-1.

Stud. Surf. Sci. Catal 1997, 105B (Progress in Zeolite and Micro porous Materials, Pt. B.), 1197-1202 (Eng.)., Elsevier Science. B.V.

Zeolite NCL-1 catalyzes Fries rearrangement of phenyl acetate into o-and p-hydroxyacetophenone with good (65-80%) selectivity under vapor phase conditions. The p/o ratio ranged between 0.5 and 0.6. Phenol was major byproduct (15-25%) along with some unidentified higher boiling compounds. By increasing the Si/Al ratio of the catalyst, the conversion decreased and selectivity for hydroxyacetophenone increased. The effect of reaction temp., feed rate, and time on stream on activity and selectivity was studied. However, under liquid phase reaction conditions the conversion was less with higher o-/p-hydroxyacetophenone ratio.

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CAS reference: 125: 167453m �

Microwave assisted Fries rearrangement on K 10 montmorillonite.

Indian J. Chem. Sect. B: Org. Chem. Incl. Med. Chem. 1996, 35B (7), 734-736 (Eng.).

An expeditious solvent free Fries rearrangement is described which occurs under mild condition on K 10 montmorillonite using microwave radiations. Thus RC6H4OAc gave 90-7%I and II (R=H, O-, P-NO2, m-,p-Me).

OH

Ac

OH

Ac

R R

I II

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CAS reference: 124: 29346g

Solid-state Fries rearrangement of phenyl acetates in beta- cyclodextrin.

Fudan Xue bao, Ziran Kexueban 1995, 34 (3) 355-8 (Ch.).

The Fries rearrangement of phenyl acetates complexed in beta-cyclodextrin in solid state was reported. Eg. reaction of beta-cyclodextrin phenyl acetate inclusion compound with AlCl3 in the presence of small amount of PhNO2 at room temp for 3 hour gave only ortho-product 2-HOC6H4COMe.

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CAS reference: 122: 190959c

Fries rearrangement over zeolite catalysts.

Appl. Catal., A. 1995. 123 (1), 37-49 (Eng.).

The Fries rearrangement of phenyl acetate, p-tolyl acetate, and phenyl benzoate to the corresponding

aromatic ketones was studied using zeolite-H forms as catalysts. The zeolites use include: beta USY,

Mordenite: ZSM-12; ZSM-5, and Nu-10. Experiments were carried out in batch rectors at 453 k and

for phenyl acetate at several temps.both in liquid phase and in gas phase in a continuous reactor.

Product distribution and catalyst deactivation were strongly dependent on zeolite structure.

Deactivation of external acidic sites enhanced the yield of para products and improved the selectivity of

catalysts based on ZSM-5 and ZSM-12

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CAS reference: 121: 35018f

Preparation of 4-hydroxyacetophenone from phenol.

Indian IN, (27 Sept. 1991, 10 pp) 171, 970 (C1,CO7C49/76), 20 Feb 1993, Appl. 91/MA735, 27 Sept. 1991, 10 pp.

4-hydroxyacetophenone, a pharmaceutical intermediate is prepared by reacting phenol with acetic anhydride in the presence of 10% NaOH soln. to give phenyl acetate and sodium acetate and the phenyl acetate is subjected to a para-selective Fries rearrangement with AlCl3 under anhyd. conditions at 60-100deg.

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CAS reference: 120: 244250u �

Microwave-induced rate enhancement of Fries rearrangement.

Indian J. Chem. Sect. B. 1994, 33B (2), 184-5 (Eng. ).

Rate enhancement in several Fries rearrangements has been observed under microwave irradiation. Thus 2-naphthyl acetate provided exclusively 1-acetyl-2-naphthol in 70% yield within 2 minutes.

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CAS REFERENCE: 120: 133957K

Synthesis of ortho-hydroxyacetophenone and para-hydroxyacetophenone.

Huaxue Shiji 1993, 15 (4), 254 (Ch.).

Treating phenyl acetate with AlCl3 in phenyl chloride at 60-65 deg for 2 hours gave 69% para-hydroxyacetophenone and 23% ortho-hydroxyacetophenone

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CAS reference: 112: 54641j �

Para-selective Fries rearrangement of phenyl acetate in the presence of zeolite molecular sieves..

Tetrahedron Lett. 1989. 30 (17) 2281-4.

The Fries rearrangement of phenoxy acetate is catalysed by acidic zeolites, such as H-Nu-2 and H-ZSM-5 with selectivites of 2-6:1 in favor of para-substituted products.

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Synthesis of p-hydroxyacetophenone.

Huaxue Shiji 1988, 10 (6), 359-60 (Ch.).

Refluxing phenol with acetic anhydride for 6 hours gave 90% MeCO2Ph, which was treated with AlCl3 in PhNO2 to give 32% the title compound (I).

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CAS reference: 111: 153309t �

The Fries rearrangement of phenyl esters in nitromethane.

Chem. Express 1969, 4 (1) 37-40.

Fries rearrangement of phenyl acetate, phenyl phenyl acetate, o-tolyl phenyl acetate and phenyl diphenyl acetate in nitroethane gave the corresponding p-hydroxy ketones in good yields. Thus MeCO2Ph was treated with AlCl3 in EtNO2 at room temp. to give up to 70.3% 4-HOC6H4COMe.

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CAS reference: 108: 37337 �

Zeolite-catalyzed rearrangement of phenyl acetate.

T. Mol. Catal 1987 40 (2) 231-3.

The Fries rearrangement of PhOAc over fluorided Al2O3 and HY and HZSM-5 catalysts was studied. With HZSM-5 the p-/o- HOC6H4COMe molar ratio was 10 times higher than that with other catalysts.

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CAS reference: 105: 152640h �

The Fries rearrangement of phenyl phenylacetate.

Nippon Kagaku Kaishi 1985 (11) 2107-10.

The AlCl3-catalyzed Fries rearrangement of PhCH2CO2Ph (I) to HOC6H4COCH2Ph in PhCl

proceeded more rapidly with a higher ortho-para ratio than the TiCl4-catalyzed reaction. In the Fries

rearrangement of I in PhCl, MePh and PhNO2 the highest yield was in PhNO2, but the order of ortho-

para ratio was PhCl>PhMe>PhNO2. 2-and 4-MeC6H4COCH2Ph were formed in the AlCl3-catalyzed

Fries rearrangement of I in PhMe. The ortho-para ratio in the Fries rearrangement of I without solvent

increased rapidly at 50 deg C compared to that at 40 deg. In the Fries rearrangement of I, BzOPh and

AcOPh without solvent, the highest yield and ortho-para were observed for I.

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CAS reference: 104: 186149z �

N-acyl acyloxy- and hydroxyaromatic amines.

Eur. Pat. Appl. EP 168, 908 (CI CO7C103/38) 22 Jan 1986, US Appl. 616, 989, 4 Jun 1984; 24pp.

Hydroxyaromatic ketones react with a NH2OH salt and a base to give the ketoxime, which is contacted with a Beckmann rearrangement catalyst to give an N-acylhydroxyacroamtic amine or with said catalyst and a carboxylic acid anhydride to give an N-acylacyloxyaromatic amine. Thus 4-HOC6H4Ac (prepared from PhOAc by Fries rearrangement or from PhOH by Freidel-Crafts acetylation) was treated with NH2OH.HCl to give 99% 4-HOC6H4 CMe :NOH. Beckmann rearrangement of the oxime using MeSO3H in HOAc-Ac2O gave 4-AcOC6H4NHAc (52.4%) constn. Yield 32.0% in liquors.) Rearrangement of the oxime by SOCl2 in SO2 gave 88.7% 4-HOC6H4NHAc (APAP) 2,4-Me (OH) C6H3CMe: NOH and 2-HOC6H4CMe : NOH were similarly rearranged to the corresponding hydroxyacetanilides.

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N –Acyl hydroxy aromatic amines.

U.S. US 452, 217 CI.564-223, (O7C103/12) 18 Jun 1985. Appl. 618, 659, 8 Jun 1984, 5 pp.

N-Acyl(hydroxy) anilines were prepared by reaction of ketoximes with Beckmann rearrangement

catalysts. The ketoximes were prepared by reaction of hydroxyaryl ketones with salts of NH2OH and a

base. Thus Fries rearrangement of PhOAc in HF-Ac2O gave 4-HOC6H4Ac, which reacted with

NH2OH.HCl in aq. EtOH-NH3 to give 4-HOC6H4CMe:NOH (I). Beckmann rearrangement of I in

SOCl2-SO2 gave 89% 4-HOC6H4NHAc

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CAS reference: 133: 237638s �

Acylation of activated aromatics without added acid catalyst.

Chem. Commun. (Cambridge) 2000. (14) (Eng.). (1295-1296)

Phenol and the resorcinol can be acetylated to the corresponding esters and ketones in aq. acetic acid at high temp (250-300 deg C) to substantial equil. conversion without any added acid catalyst. Kinetics of the reaction are reported.

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CAS reference: 131:352791g �

Acylation of phenol with acetic acid over beta zeolite.

Proc. Int. Zeolite Conf, 12th 1998(Pub 1999) 2, 1463-1470 (Eng.).

Beta zeolites having various Si/Al ratios were used as catalysts for gas phase phenol acylation. Rapid PhOAc formation is followed by slow o-hydroxyacetophenone production. Also, p-hydroxyacetophenone is formed as a typical secondary product. A high o-/p- ratio was obsd .even at low conversions. Moreover, the lower the Si/Al ratio, the higher is the rate of hydroxyacetophenone formation, suggesting that this reaction requires more than one site on the catalyst



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CAS reference: 130: 124891p �

Preparation of o-hydroxyacetophenone.

Appl. 94, 111, 457, 27 Sept 1994. [ Faming Zuanli Shening Gongkai Shuomingshu CN 1,119, 639 (CI. CO7C49178) 3 Apr. 1996.] 4 pp.

The title compound is prepared by reaction of phenol with acetic anhydride at 60-90 deg in

chlorobenzene with AlCl3 as catalyst. Thus reaction of 37.6 g phenol with 50 ml acetic anhydride in

chlorobenzene in the presence of 170g AlCl3 at 60-70 deg for 2 hours gave 39.5 g o-

hydroxyacetophenone and 9.57g p-hydroxyacetophenone



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CAS reference: 129: 150325f �

Acylation of aromatics over a HBEA zeolite effect of solvent and of acylation agent.

Stud. Surf. Sci. Catal 1997 (108) (Heterogeneous catalysis and Fine chemicals IV) 91-98 (Eng.).

A kinetic study of the acylation of phenol with phenyl acetate was carried out in liquid phase at 160 deg over HBEA zeolite samples, sulfolane or dodecane being used as solvents. The initial rates of hydroxyacetophenone (HAP) production were similar in both solvents. However, the catalyst deactivation was faster in dodecane, most likely because of the faster formation of heavy reaction products such as bisphenol A derivatives. Moreover, sulfolane had a very positive effect on p-HAP formation and a negative effect on o-HAP formation. To explain these observations as well as the influence of phenol and phenyl acetate concentrations on the rates of o- and p-HAP formation it is proposed that sulfolane plays two independent roles in phenol acylation solvation of acylium ions intermediates and competition with phenyl acetate and phenol for adsorption on the acid sites. Donor substituents of phenyl acetate have a positive effect on the rate of anisole acylation, provided, however, there are no diffusion limitations in the zeolite pores.

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CAS reference: 128: 321426a �

Origin of the deactivation of HBEA zeolites during the acylation of phenol with phenyl acetate.

J. Mol. Catal. A: Chem. 1998; 129 (1), 69-78 (Eng.) Elsevier Science. B.V.

During the transformation of a phenol-phenyl acetate mixture over a HBEA zeolite (Si/Al=10) carried out in a batch reactor at 160 deg C in sulfolane or in dodecane solvents, a rapid initial decrease in the formation of hydroxyacetophenones is observed. The compounds of the reaction mixture of the organic material recovered in methylene chloride by a direct soxhlet treatment and of the compounds retained in the zeolite pores (‘coke’) were compared after 2 hour and 24 hour reaction. ‘Coke’ is mainly constituted of phenol and hydroxyacetophenones and of a small amount of heavy secondary reaction products bisphenol A and acetylated derivatives, hydroxy or acetoxy phenyl benzoate, hydroxy or acetoxydypnone, 4-methylcoumarin and 2-methylchromone and of sulfolane but not of dodecane. Only a very small quantity of phenyl acetate is found. The rate of hydroxyacetophenone formation depends on the order of introduction of the reactants. It is shown that the rapid initial deactivation is not due to the heavy reaction products but to the limitations by phenols (reactants and products) of the access of phenyl acetate to the inner acid sites.

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CAS reference: 128: 218583a �

Acylation of phenol with acetic acid. Effect of density and strength of acid sites on the properties of MFI metallosilicates.

Stud. Surf. Sci. Catal. 1997, 105B (Progress in Zeolite and Micro porous Materials. Pt. B.) 1149-1156(Eng.). Elsevier Science. B.V.

The C-acylation of phenol with acetic acid was carried out over [Al]-and [Ga]-MFI-type zeolites with different Si/Al or Si/Ga ratios. The greater strength of the acid sites of aluminosilicates is confirmed with NH3 TPD and with m-xylene isomerasation. Whatever the sample phenol undergoes two main reactions. O-acylation into phenyl acetate and C-acylation selectively into ortho-hydroxyacetophenone. While the rate of m-xylene isomerisation depends only on the acidity of the MFI samples (density and strength of the acid sites). The rate of o-hydroxyacetophenone production is also determined by the diffusion path (characterized by the para/ortho xylene ratio). This effect of the diffusion path can be related to the strong adsorption of reactants and products on the acid sites of the zeolite pores. A slow deactivation is observed which can be attributed to the trapping in the zeolite pores of relatively simple secondary reaction products.

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CAS reference: 127: 278063v �

Hafnium triflate as acylation catalysts and preparation of acylphenols or acyl naphthols using the catalysts.

Jpn. Kokai Tokkyo Koho JP, 09,227,442[97,227,442] (CI. CO7C49/825), 2 Sept 1997, Appl. 96/61, 782, 23 Feb. 1996, 8 pp. (Japan).

Fries rearrangement catalysts for acyloxy benzenes or acyloxy naphthalenes and direct acylation catalysts for phenols or naphthols with acyl halides or carboxylic acids involve Hf (OSO2CF3)4 (I). Acylphenols or acylnaphthols are prepared by Fries rearrangement of acyloxyphenols or acyloxynaphthols or direct acylation of phenols or naphthols with acyl halides, carboxylic acids, or their anhydrides in the presence of I. The reaction may be performed in the presence of LiClO4. A mixture of I (preprn given) LiClO4, toluene ,MeNo2, and phenyl acetate was stirred at 50 deg for 6 hours to give 52% 4-HOC6H4-COMe and 5% 2-HOC6H4COMe.

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An improved acylation of phenol over modified ZSM-5 catalysts.

Appl. Catal, A 1995, 133(1), L1-L6 (Eng.).

The acylation of phenol with acetic anhydride was carried out over different metal-modified ZSM 5 catalysts. Co, Cu, and Ce showed a promoting effect. The best temp. and weight hourly space velocity for this reaction were 250 deg and 0.5 h-1, respective ZSM-5(30) was a better catalyst than ZSM-5(150) and ZSM-5(250) in the acylation of phenol. A plausible reaction mechanism is also discussed.

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CAS reference: 122: 313942b �

Kinetic study of the acylation of phenol with acetic acid over a HZSM5 zeolite.

515-19 (Eng.). Chem. Ind. 1995 (Dekker), 62 (Catalysis of organic reactions.)

A kinetic study of hydroxyacetophenones formation from acylation of phenol with acetic acid was carried out on a HZSM5 zeolite (Si/Al=42). Only ortho-and para- isomers are formed. The reaction orders with respect to phenol was close to zero and was negative with respect to acetic acid. Curiously, the rate of formation of ortho-isomer passes through a max. at about 550 k that of the para-isomer increases with the reaction temp. The optimal conditions for a selective production of ortho-hydroxyacetophenone are specified.

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CAS reference: 122: 242725v �

Kinetic modeling of phenol. Acylation with acetic acid on HZSM5.

(Guisnet, Michel, Lokyanov) Ind. Eng. Chem. Res. 1995- 34(5), 1624-9 (Eng.).

We have developed a kinetic model that quantitatively describes the formation of the main products of phenol acetylation with acetic acid on HZSM5 at 280 deg namely, phenyl acetate, o-and p-hydroxyacetophenones (o-HAP and p-HAP resp.), p-acetoxyacetophenone (p-AXAP), and water. Analyses of experimental data and kinetics modeling results lead to the following conclusions. Formation of PA occurs rapidly via o-acetylation of phenol. O-AAP is produced via C-acetylation of phenol with acetic acid and phenyl acetate. The latter reaction is responsible for the formation of 90% of o-HAP. A part of p-HAP is produced via acetylation of phenol with phenyl acetate, the other one through hydrolysis of p-AXAP resulting from the autoacetylation of phenoxy acetate. Kinetic modeling of the acetylation shows that the max. possible selectivity and yield of the desires product (o-HAP) can be obtained with reactant mixtures with a low phenol/acetic acid ratio.

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Acylation of phenol with acetic acid over a HZSM5 zeolite reaction scheme.

J. Mol. Catal. 1994, 93 (2), 169-79 (Eng.).

A scheme of gas-phase phenol acetylation with acetic acid on HZSM5 zeolite is established from the effect of contact time (hence of conversion) on the product distribution. Phenyl acetate and o-hydroxyacetophenone (I) are primary products. O-acylation being much faster than C-acylation. At high conversion, part of the o-hydroxyacetophenone results from the acetylation of phenol with phenyl acetate. The formation of (I) which does not occur through phenol acetylation involves the hydrolysis of p-hydroxyaetophenone selectivity formed through the autoacetylation of phenoxy acetate. The ortho-selectivity of phenol acetylation can be related to a pronounced stabilization of the transition state while the para-selectivity of phenyl acetate autoacetylation may be due to a steric hindrance to the approach of the acetyl group in the ortho-position of phenyl acetate.

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Phenol acylation: unexpected improvement to the selectivity to o-hydroxyacetophenone by passivation of the external sites of HZSM5.

J. Chem. Soc, Chem. Commun. 1994 (6), 717-18 (Eng.).

The acylation of phenol by acetic acid on zeolite HZSM5 is unexpectedly oriented towards o-hydroxyacetophenone by dealumination of the outer surface of the crystallites, which can be ascribed to the existence of two different pathways for the formation of o-and p-hydroxyacetophenones.

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CAS reference: 115: 231796y �

Friedel-Crafts acylation of phenol catalysed by boron trifluride.

Huaxue Shiji 1991 13 (3) 191,152 (Ch.).

Treatment of phenol with CnH2n+1COOH (n=1,3,5,7,9,10,11) and BF3 gave 53.3-72.9% CnH2n+1COC6H4OH-4.

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Water removal in recycle of HF and carboxylic acids in Fridel-Crafts acylation.

U.S. US 4894482 CI. 568-319, CO9 (45/46) 16 Jan 1990, Appl. 281, 302, 06 Dec 1988, 9pp.

Water is removed from the title mixture by extractive distn. in the presence of Lewis base solvents which do not form azeotropes with water, do form thermally labile bonds with HF and carboxylic acids and boil � 20 deg higher than the carboxylic acid. Extractive distn of a mixture of HF 25, H2O 41, AcOH 75 and N-methylpyrrolidone (I) 347g at 144 deg/215 mm gave an overhead contg. H2O 81.5, HF 0.06, AcOH 13.0 and I 5.4%.

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CAS reference: 109: 54423c

Reaction of acetic anhydride/zinc chloride reagent with phenols: improved yields of hydroxyacetophenones.

Indian J. Chem., Sect. B. 1987 26B (9) 823-6.

Acetic anhydride /zinc chloride is a better acylating system for phenol and polyphenols resulting in improved yields of the resp. hydroxyacetophenones. The phenols used are phenol, resorcinol, hydroquinone, catechol, phoroglucinol and pyrogallol. With resorcinol, the isomeric diacetyl derivatives are formed in excellent yields in a single step, while catechol and hydroquinone give only mono acetyl derivatives like phenol. Pyrogallol gives a monoacetyl derivative while phoroglucinol gives both mono and diacetyl derivatives, but not triacetyl derivatives.

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CAS reference: 107: 96437z �

A process for the preparation of p-hydroxyacetophenone as a material for pharmaceuticals.

Jpn. Kokai Tokkyo Koho JP. 62, 53, 938 [87,53, 938] (CI. CO7C49/84) 9 Mar 1987. Appl 85/193, 571, 02 Sept. 1985, 3pp.

The title compound (I) useful as a material for pharmaceuticals (no data) is prepared. To a mixture of 280g AlCl3 and 172g AcCl in 2000 ml Cl(CH2)2Cl was added dropwise 216 g PhOMe at 0-2 deg for 2 hours and the resulting mixture was stirred at 0-2 deg for an additional 1 hour and 267g AlCl3 was added. The mixture was stirred at 35-40 deg for 8 hours to give 86.1% I and 0.87% of the ortho isomer.

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CAS reference: 107: 9346c �

Process for producing acetyl-substituted aromatic compounds.

Eur. Pat. Appl. EP. 215, 351 (CI. CO7C45/46) 25 Mar. 1987, JP Appl. 85/191, 521, 31 Aug. 1985, 9pp.

Title compounds are prepared by reacting aromatic hydrocarbons with AcF in the presence of anhydride HF at 0-70 deg/�2 kg/cm2-guage. A stainless steel packed column containing top reflux app. And bottom rebolier was fed 22 mol/h AcO and 21.0 mol/h HF. The reactor was operated at < 1.0 kg/cm2-gage and heated such that the head temp. was 35 deg and AcF was distilled out of the head at 21 mol/h and a liquid mixture comprising 21 mol AcOH and 1 mol AC2O was withdrawn every hour from the bottom. Another reactor was charged with PhOMe, AcF and HF so that the AcF/PhOMe molar ratio was 0.95 and the HF/AcF molar ratio was 20 and the temp. was maintained at 25 deg for 2 hours producing an acetylation yield (relative to PhOMe) of 89% consisting of 97% 4-MeOC6H4Ac.

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CAS reference: 104: 148513f �

4-hydroxyacetophenone.

Eur.Pat.Appl. EP 167, 286 (CI CO7C49/825) 8 Jan 1986, US.Appl. 616, 989, 4 Jun 1984; 20pp.

4-HOC6H4Ac (I) was prepared by acetylation of phenol with either: (1) 0.9-2.0 molar equiv. Ac2O in the presence of 8-60 equiv. HF at 30-95 deg for � 10 min. and at � 45 deg when � 12 equiv. HF are used or (2) 0.9-1.4 equiv. HOAc in the presence of 20-50 equiv. HF at 40-90 deg for 10-120 min, or (3) 0.4-0.8 equiv. Ac2O in the presence of HF. Thus an autoclave was charged with 0.2 mol each of phenol and Ac2O cooled to -30 deg evacuated to 175-Torr, charged with 4.0 mol anhyd. HF and the mixture warmed to 75 deg and held at that temp. for 60 min. HF was vented and the reaction mixture extd. To give PhOAc 0.1 I 92.3, 2-HOC6H4Ac 5.5, and 4-AcOC6H4Ac 0.6% selectivity with 99.7% conversion of phenol.

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Aromatic ketones.

Jpn. Kokai Tokkyo Koho JP. 60, 188, 343 [85,188, 343] (CI.CO7C49/76) 25 Sept. 1985 Appl 84143091 7 Mar. 1984, 6pp.

Aromatic ketones were prepared by acylation of aromatic compounds with acyl fluorides, which were obtained by treating acid anhydrides with HF in the presence of HF and optional BF3. Thus autoclaving 14 mol. Ac2O and 13.4 mol HF gave 13.4 mol AcF which (0.85 mol) was treated with 1 mol beta-methylnaphthalene in the presence of HF and BF3 to give acylation product containing 84.7% alpha-acetyl-6-methylnaphthalene.

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CAS reference: 97: 215756q �

o- and p-Acylphenols.

Ger. Offen. DE. 3,108, 076, (CI CO7C49/825), 16 Sept 1982, Appl. 4 Mar. 1981, 9 pp.

I (RCO is o-or p- to the OH group; R= alkyl, cycloalkyl, aralkyl ) were prepared by acylation of phenol with ROCl-AlCl3 in a benzene, first at 15-35 deg, then at 755-200 deg. Thus 350 parts AlCl3 were added to 940 parts phenol in 500 parts PhCl at < 40 deg, 1017 parts EtCOCl added over 60 min. at < 50 deg and the mixture was stirred 2 hours at 105 deg to give 1083 parts (68%) o-and 330 parts p-HOC6H4-COEt.

OH

RCO

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CAS reference: 134: 162822g �

Preparation of hydroxy-substituted aromatic aldehydes and ketones by catalytic oxidation of alkyl phenols using oxygen.

PCT Int. Appl. WO 01, 09, 072, 30 Jul. 1999. 27 pp.(Eng.)

Alkyl phenols [I, II ; X= Me, Et R1-R4= H, Cl, Br, alkyl, alkoxy; R1R2, R2R3, R3R4=(CH2)n n=3-6; only 1 of R1R2, R2R3, R3R4=(CH2)n ] were oxidized to the corresponding hydroxybenzaldehydes or hydroxyacetophenones by creating a reaction medium containing. the alkyl phenol in a dihydric alc. solvent which is acidic or basic and treatment with oxygen in the presence of an oxidation catalyst. Thus a mixture of p-cresol, NaOH and MeOH was stirred 8 hours at 60 deg C with addition of oxygen to give 79% p-hydroxybenzaldehyde.

X

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R2

R1 R3

R4

X

R2

R1

R4

OH

R3

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CAS reference: 136: 281120c �

Separation of o-/p-Hydroxyacetophenones by selective solubilization and sorption on Weak Base Ion Exchange Resins.

Industrial and Engineering Chemistry Research 2002. 41 (5). 1335-1343.

A two-stage process has been developed for the separation of o-/p- hydroxyacetophenones (o-/p-HAP), both of which are intermediated for the pharmaceutical industry. The first step is the selective solubilization in a hydrocarbon solvent; o-HAP dissolves well in heptane and toluene but p-HAP does not. The intermolecular hydrogen bonding among p-HAP mols. makes it almost insoluble in heptane and has solubility in toluene as low as 0.03 mol/kg solvent. The first step gives a hydrocarbon solution of o-HAP with a very small amount of dissolved p-HAP, while pure p-HAP ppts. as a solid in high yield (90%). The traces of p-HAP from the org. solution can be removed in the second step using its selective sorption in weakly basic resins, giving a solution with o-HAP. The sorption of p-HAP on the resins by acid-base interactions between the resin’s amino group and p-HAP’s acidic hydroxy group is aided by the unfavorable solvation of p-HAP in the org. phase.

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CAS reference: 136: 150997w �

A process for separating o-and p-substituted benzene compounds by preferential solubilization and/or resin adsorption of one isomer.

Pct. Int. Appl.WO, 02, 10,097 (CI CO7B63/00) 7 Feb 2002 Appl 2000/IN72, 27 Jul. 2000.

A process for producing o-and p-substituted benzene compounds by separation from a binary mixture in any proportions of said compounds is described. The said o-and p-substituted benzene compounds comprise isomeric 1,2-substituted benzene compounds of formula (I) and 1,4-substituted benzene compounds of formula (II) resp.

R1

R2R1

R2

I II (wherein R1 is selected from the group of OH, CO2H, NH2, NR3R4[where R3 and R4 are selected

from the group H, (CH2)n Me (n=0, 0-4) and R2 is selected from the group consisting of COMe, NH2, OH, NO2, X, OMe, CO2H, CHO, OEt(wherein X is halogen selected from F, Cl, Br, and iodol)].

This process basically involves (i) treating the said binary mixture first with an org. solvent to phase separation by preferential solubilization. One of the said two compounds (ii) contacting the solution phase with an ion exchange resin for preferentially adsorbing and recovering further any of said undissolved compound present to thereby further phase separation from the said compound is said solution phase the other compound as substantially pure undissolved compound and (iii) recovering from the said solution phase of step (ii) above the said solution compound in substantially pure from by solvent removal from the solution phase in conventional manner The process provides a simple and cost effective method of producing pure compounds of formula I and II in high yield. Thus a reaction vessel (200 ml) equipped with a stirrer was charged with a mixture containing 2.68g of o-hydroxyacetophenone (o-HAP) and 0.22g of p-hydroxyacetophenone (p-HAP). To this mixture 50 ml of n-heptane was added and stirred for a period of 30 min at room temp. at 303deg k. The mixture was filtered to separate the precipitated p-HAP from the org. phase and then washed with pure heptane to give 0.176g p-HAP (80% recovery) in pure form (100% purity). The ext. solution phase containing 0.044g of p-HAP and 2.6g of o-HAP as determined by HPLC was taken and 5 g of macroporous weakly basic ion exchange resin, Indian 850 was added to this solution and kept for shaking for a period of 8 hours. The solution was separated from the resin by decantation to give the solution containing 2.55 g by weight of o-HAP (95.15% recovery), which was recovered by solvent removal with a purity of 100%. The resin was then washed with methanol to regenerate the resin for reuse.

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CAS reference: 107: 39402k �

Process for purifying 4-hydroxyacetophenone.

U.S., US 4, 663, 485 (CI-568-319 CO7C45/58), 5 May 1987, Appl. 888, 197, 22 Jul 1986.

Mixtures containing the title compound (I) and HF are separated by distillation in the presence of C4-16 alkane solvents such that the overhead vapors contain mainly HF and alkane and the residue contains alkane and I. The overhead vapor is then condensed forming two immiscible phases and the alkane is returned to the system. The liquid residue is also separated into two layers, one contain alkane and the other contain I. Variations in the process conditions and their results are given.

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4 Hydroxy Acetophenone