CA1260500A - Process for producing 4-hydroxyacetophenone - Google Patents

Abstract

Abstract A process of acetylating phenol to 4-hydroxyacetophenone by contacting phenol with about 0.9 to 2.0 moles per mole of phenol of acetic anhydride as acetylating agent in the presence of about 8 to 60 moles per mole of phenol of hydrogen. fluoride as catalyst at a temperature of reaction of about 30 to 95°C for a reaction period of at least about 10 minutes, said temperature of reaction being at least about 45°C when said number of moles of hydrogen fluoride per mole of phenol is no greater than about 12. The process generally results in phenol conversions of at least about 90% and reaction selectivities to 4-hydroxyacetophenone of at least about 70%.

Description

o~

This inven-tion relates to a process for producing 4-hydroxyacetophenone.
BACKGROUND OE' THE I~VENTION
4-Hydroxyacetophenone (4-HAP) is a possible inter-mediate for a variety of products having a multiplicity of end uses. Thus, pending Canadian application Serial No. 479,446, discloses a process for using 4-HAP to make N~acetyl-para-aminophenol (APAP), bet-ter known as acetaminophen, which has wide use as an analgesic. Pending Canadian application Serial No. 479,446, also discloses the use of 4-HAP as an intermediate for the production of 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 APAP. Pending Canadian application Serial No. 486,113, discloses a process wherein 4-HAP is used to produce 4-acetoxybenzoic acid (4-ABA) which are also capable of being used directly to make polymers which can be formed into an anisotropic melt suitable for the formation of shaped articles. Moreover, 4-ABA can be hydro-lyzed to 4-hydroxybenzoic acid (4-HBA) which can be used as an ~.

~26~S~Q

intermediate for the production of preservatives, dyes, and fungicides. Pending Canadian applications Serial No. 491,528, and Serial No. 498,418 disclose processes wherein 4-HAP is used as an intermediate for the production of hydroquinone (HQ) which has utility as a photographic developer, polymerization inhibitor, dye intermedia-te, and anti-oxidant.
Dann and Mylius in a dissertation included as part of a series of Reports from the Institute Eor Applied Chemistry of the University of Erlangen, received for publication on January 7, 1954 and published in Annalen der Chemie 587 Band, pages 1 to 15, disclose the reaction of phenol and glacial acetic acid in the presence of hydrogen ~luoride to produce 4-hydroxyacetophenone (4-HAP) in a yield of 61.6~. This reaction may be conventionally characterized as a Friedel-Crafts acetylation of phenol with acetic acid as the acetylating agen-t.
Simons et al, Journal of the American Chemical Society, 61, 1795 and 1796 (1939) teach the acylation of aromatic compounds using hydrogen fluoride as a condensing agent and in Table 1 on page 1796 show the acetylation of phenol with acetic acid to produce p-hydroxyacetophenone (4-HAP) in 4U% yieldO
European Patent Publication No. 69,597, published January 12, 1983, discloses the preparation of p-phenoxybenzoyl compounds by reacting diphenyl ether and an appropriate acyl compound such as acetic anhydride in the presence of hydrogen fluoride.
Meussdoerffer et al, German Offenlegungsschrift 26 16 986, published October 27, 1977 and assigned to Bayer AG, , ?~ -2-. . i, iO500 di lose the hy;rogen fluor1de-catalyzed -ylation of phenolic compounds such as phenol itse1f with an acyl halide such as acety1 chloride to fonm hydroxy aromatic ketones.
S~MMARY OF T~E IMVENTION
___ I~ accoxdance with thi.s in~ention, 4-hydroxyacetophenone ~4-EAP) i; produced by the Friede1-Craft~ acetylation of phenol wi~h acetic anhydride using hydrogen ~luoride as cata1yst, under certain specified reaction conditions so as to obtain unexpected1y high conversions o~ phe~o1 and high selectivity to 4-~AP, concurren~1y.
The preparation of 4~AP by the acety1ation of phenol with acetic anhydride using hydrogen f1uoride as catalyst proceeds in ac~ordance with the fo11Owing a~uation:
, . ' O

E~O~)+ (C~33CO)20 ~0~-C~3 ~ C}13COO~

In carrying out the reaction so as to obtain particu1ar1y high yields of 4-HAP within this inven~ion, phenol is reacted with about 0.9 to 2.0 moles, preferably about 1O0 to 1.1 molés of acetic anhydride per mole of phenol at a temperature of reaction of about 30 to 95C, preferably about 40 to 80~C in the presence of hydrogen fluoride catalyst in an amount of about 8 to 60 moles, preferab1y about 15 to 40 moles per mole of phenol for a reaction period of at least .
about 1~ preferably about 10 to 300 minutes, and most preferab1y about 30 to 180 minutes, said temperature of ~- ~
reaction being at least about 45C when said number of moles of hydro~en fluoride per mole of phenol is no greater than about 12.
Using a corrosion-resistant reactor, the reaction is initlated by either: 1) charging hydrogen fluoride to a mixture o phenol and acetic anhydride at a temperature less than th~ specified reaction temperaturef 2) charging ace~ic anhydride to a solution of phenol and hydrogen fluoride at reaction temperature, or 3) charging acetic anhydride and phenol simul~aneously ~o hydrogen fluoride at reaction temperature. Regardless of the method of initially mixing ~he acetic a~hydride, phenol, and hydrogen fluoride, the reaction is then adju~ted to the specified reaction temperature for the specified reaction period. The hydrogen fluoride may ~e charged as a liquid or a.gas usiny technologies of handling well known t~ those skilled in the art. In carrying out the reaction, an in rt gas such as nitrogen may be used to keep the reaction space under th~ desired pressure, about 2.5 to about 500 psig., thereby keeping su~ficient HF in contact with the reacting liquid.
In yeneral, the p~ocess of this invention results in a conversion of phenol of at least about 90%,preferably at least about 95% with a selectivity to 4-hydxoxyacetophenone (4-HAP) of at least a~out 70~, preferably at least about 9~%.
lOY or _ C FIC EMBo~IM~NTS
~e~l' These examples illustrate the process o~ this .
invention. The term "molar equivalent~ as used in these examples denotes moles of the specified reactant per mole of phenol. .

I ExamP ~ ~

A 300 cc Hastelloy C*au~ocla~e was charged With 27.6 g (0.~ mol) of phenol, cooled to -30C using a carbon dioxide/isopropanol bath~ and then evacuated to ca. 175 Torr.
To the auto~lave was added 60 g (3.0 mol) of anhydrous hydrogen fluoride during which time an exotherm was noted.
The contents of the autoclave were again allowed to cool to -30C whereupon3~J6 g (0.3 mol) of acetic anhydride was added over a.3 minute period during which time another exoth0rm was observea. The mixture was warmed to 60C and maintained at that temperature ~or 180 minutes with stirring. The hydrogen fluoride was then vented through a caustic scrubber while simultaneously using a nitrogen puxge. The contents of the autoclave were then poured onto ice and the p~ of the .
resulting aqueous phase was adjusted to 6.0 using a solution of 45% potassium hydroxideu The aqueous phase was extracted with 75 mL of ethyl acetate (3x~. The organic extracts were combined, dried over anhydrous maynesium sulfate, and the .
sol~ent was removed on a rotary e~aporator to yield a crystalline product. The reaction proceeded with 97.6%
conversion of phenol and with the indicated selectivities to phenyl acetate (0.6%), 4-hydroxyacetophenone (79.6~),

2-hydroxyacetophenone (6.2~), and 4-acetoxyacetophenone~
(1.3%).
Exam~le 2 The procedure of Example 1 was repeated, but employing a reaction time of 270 minutes. The reaction proceeded with 99.0~ conversion of phenol and with the indicated selectivities to phenyl acetate (0.2%), . 4 hydroxyacetophenone (89.2~), 2-hydroxyacetophenone (4.8%), *Trade ~ark 5 O~

and 4-aceto~yacetophenone (O.7%).
~ le 3 The procadure of Ex~m~le 1 was repeated, but employing 40 molar equivalents o~ anhy~rous hydrogen fluoride, a reaction temperature of 75C and a reaction time of 60 minutes. The reaction proGeeded with 99.6~ conversion of phenol and with the indicated selec~ivities to phenyl acetate ( n . 1~ ), 4-hydroxyacetophenone (84.1%), 2-hydroxyacetophenone (4.7~), and 4-acetoxyacetophenone (0.4%).

The procedure of Example 1 was repeated except ~hat the autoclave was initially charged with 13.8 g (0.2 mol) of phenol a~d 20.4 g (0.2 mol) o~ acetic anhydride, cooled to 30C, and eva~uated ~o ca. 175 Torr, 80 g (4.0 mol) of anhydrous hydrogen fluoride was added t and the mixture was warmed to 75C and maintained at that temp~rature for 60 mlnutes without cooling i~ a second time to -30~C as described in Example 1. The hydrogen fluoride was then vented and the remaining procedure of Example 1 followed to recover the product~ The reaction proceeded with a 99.7~ conversion of phenol and w~th the indicated selectivities to phenyl acetate (0.1%), 4-hydroxyacetophenone ~92.3%), 2-hydroxyacetophenone (5.5%~, and 4-acetoxyacetophenone (0.6%).
. ~ .
A 300 cc ~astelloy C autoclave was charged with 27.6 . .g ~0.3 mol) of phenol, cooled to -30C using a carbon dioxide/isopropanol bath, and then e~acuated to ca. 175 Torr.
To the autoclave was added 120 g (6.0 mol) of anhydrous hydrogen fluoride during which time an exotherm was noted.
The contents of the autoclave were heated to 50C whereupon . ~2~ Q

30. g (0.3 mol) of acet~c anhydride wa~ added over 1 3 minute period. An exotherm resulted; the internal temperature of the autoclave was lowexed ~o 50C and was maintained at that temperature for 120 minutes with stirring. The hydrogen fluoride was then vented through a caustic scrubber while simultaneously using ~ nitrogen purge. The contents of the autocla~e were then poured ~ver ice and the p~ o~ the resulting a~u~ous phase was adjusted to 6.0 using a s~lution of 45~ potas~ium hydroxide. The a$ueous phas~ was extracted with 75 ml. of etAyl acetate (3x). The organic ex~racts were combined, dried over anhydrous magnesium sulfate, and th~
solvent was removed on a rotary evaporator to yield a crystalline product. The reaction proceeded with 99.6%
. conversion of phenol and with the indicated selectivities to phenyl acetate (0,0%), 4 hydroxyacetophenone (77.5%), 2-hydroxyacetophenone (7.2%), and 4-acetoxyacetophenone (Oo396) .
Example 6 The procedure o~ Example 5 was repeated, but employing 1. 5 molar equivalents of acetic anhydride . The reaction proceeded with 99.9~ conversion and with the indicated electivitie~ to phenyl acetate ~0.1%~, 4-hydroxyacetophenone (84.8%), 2-hydroxyacetophenone (7-.2~), and 4-acetoxyacetophenone (1.9%).

ExamPle ?
' The procedure of Example 5 was repeated, but employing 1. 5 molar equivalents of acetic anhydride and a reaction temperature of 75C, The reaction proceeded with 99.4% conversion and with the indicated selectivities to phenyl acetate (0.1~), 4-hydroxyacetophenorle (79.3%),-:
lZ60S0~) 2-hydroxyacetophenone (8.8%~, and 4-acetoxyacetophenone (2.1%).
~ e 8 The procedure of ExamE~le 5 was repeated, but employing 2.0 molar equivalents of a~etic anhydride and a reaction ~emperature of 75C. The reaction proceeded with 99.8% conversion and with the indica~ed selectivitie~ to ph~nyl aceta~e ~0.3%), 4-hydroxyacetophenone,.~(71.4%), 2-hydroxyacetophenone (8.2~, and 4-ac~toxyacetophenone (3.2%).
Exam~e 9 The procedure of Example S was repeated, but employing 30 molar e~uivalents of anhydrous hydrogen fluoride and 1.5 molar equivale~s of acetic anhydride. The reaction proceeded with 99.9% conversion and with ~he indicated selectivities to phenyl acetate (0.0%), 4-hydrox~acetophenone (86.6%), 2-hydroxyacetophenone (6~3%), and 4-ace~oxyacetophenone (1.6~3.
. ~'` .
The procedure of Example 5 was repeated, ~ut emp}oying 30 molar equivalents of anhydrous hydrogen fluoride, 1.5 molar equivalents of acetic anhydride, and a reaction temperature of 75C. The reaction proceeded wi~h 99.9~
conv~rsion and with the indicated selectivities to phenyl .acetate (0.1~), 4-hydroxyacetophenone (84.~%), 2-hydroxyacetophenone ~8.3~), and 4 aceto~yacetophenone (1.3%). ~
. ~
A 300 cc Hastzlloy C autoclave was cooled to -30C
. using a carbon dioxide/isopropanol bath, and then evacuated to ca 175 Torr. Tc ~he autoclave was added 120 g ~6.0 mol) of anhydrous hydroqen fluoride. The contents o the autoclave were heated to 7SC whereupon ~7.6 g (0.3 mol) of phenol and 30.6 g (0.3 mol) of a~etic anhydride were simultaneously added over a 3 minute period. An exotherm resulted; the internal temperatur~ of the autoclave wa'~ lowered t~ 75C and was maintained a~ that ~emperature :Eor 100 minutes with stirring.
The hydrogen fluoride wa~ then ven~ed through a ca~stic scrubber while simultaneously using a nitrogen purge. The contents of the autoclave were then poured onto ice and the pH
of the resulting aqueous pha~e was adjusted to 6.0 using a solution o~ 45% potassium hydroxide. The aqueous phase was .
extracted with 75 mL of ethyl acetate ( 3x) . The organic extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed on a rotary evaporator to yield a crystallinè product. The reaction proceeded with 99.6% conversion of phenoL and with the indicated selectivities to phenyl acetate ~0.0%), 4-hydroxyacetophenone (90.5~), 2-hydroxyacetophenone (7.8~), and 4 acetoxyacetophenone (1.1%).
Exam~le 12 The procedure of Example 11 was repeated, but employing 30 molar equivalents of anhydrous hydrogen fluoride, a reaction t~mperature of 50C, and .reaction time of 60 minutes. The reaction proceeded with 99.6% conversion of phenol and with the indicated selectivities to phenyl acetate (0.1~), 4-hydroxyacetophenone (91.3~), 2-hydroxyacetophenone (5.2%), and 4-acetoxyacetophenone (1.3~).

., ' Il' ,_ ~60~r)~

The procedure of Example 11 was repeated, but employing 30 molar e~uivalents of anhydrous hydrogen fluoride, a reaction temperature ~f 50 C, and reaction time of 110 minutes. The reaction proceedecl with 99.9~ conversion o phenol and with the ind~cated se!lecti~ities to phenyl acetate (O.O%), 4-hydroxyacetophenone (89.7%), 2-hydroxyacetophenone (4.9~), and 4-acetoxyacetophenone ~0.0~).
Example 14 The procedure o Example ll was repea~ed, but employing 30 molar equivalen~s of anhydrous hydrogen fluoride.
The reaction proceeded with 99.7% conversion of phenol and with the indicated selectivities to phenyl acetate (0.0%), 4-hydroxyacetophenone (91.4%), 2-hydraxyacetophenone (7.2~), an~ 4-acetoxyacetophenon~ (1.1%).

The procedure of Example 11 was repeated, but employing 30 molar equivalents of anhydrous hydro~en fluoride, a reaction temperature of 100C, and reaction time of 10 minutes. The reaction proceeded with 93.4~ conversion of phenol and with the indicated selectiv-ties to phenyl acetate ( 2 ~ 5 ~ ) r 4-hydroxyacetophenone ~74.6%), 2-hydxoxyacetophenone (13.5%), and 4-acetoxyacetophenone (0.0%).
S~
" Thes~ examples utilize at least one process variable outside the scope of this invention. The results obtained in terms of the s~lectivity of the reaction for 4-HAP and in most cases phenol conversion, illustrate the significance of carrying out the process using conditions within the ranges defined by the invention~

n ..

Comparative ~xample ~
The procedure of Example 1 was repeated, but employing S molar equivalents of anhydrous hydrogen fluoride and a reaction temperature of 25C. The reaction proceede~
with 83.5% conversion o~ phenol and with ~he indicated sel~ctivities to phenyl acetate (76.0%~, 4-hydroxyacetophenone (6.1%), 2-hydroxyace~ophenone (0.4~), and .
4-acetoxyacetophenone (1.9~).
9~5~
q'h~ procedure of Example 1 was repe ted, bu~
employing 5 molar equivalents of anhydrous hydrogen fluoride and a reaction ~mperature of 75C. The reaction proceeded with 87.0~ conversion of phenol and with ~he indica~ed selec~i~ities to phenyl acetat~ (10.3%), 4-hydroxyacetophenone t64.5~), 2-hydroxyacetophenone (10.4%)~ and 4-acetoxyacetophenone ~1.8%), Co~arative Exam~le C
The procedure of Example 11 was repea~ed, bu~
emplGying 5 molar equivalents o~ anhydrous hydrogen fluoride and reaction time of 30 minutes. The r2action proceeded with 93..3% c~nversion o phenol and ~ith ~h~ indicated s~lectivities to phenyl acetate (96.2%) a~d 4-hydroxyacetophenone (0.3%), 2-hydroxyacetophenone (0.0%), and 4 acetoxy~cetophenone (0.0%~. .
. . 5~5~
Th~ procedure of Example 11 was repeated, but employing 30 molar equivalents of anhydrous hydrogen fluoride, a reaction te:mperature of 20 C, and reaction time of 110 minutes. The reaction proceeded with 82.0% con~ersion of phenol and with t~e indicated selectivities to phenyl acetate ~ l -~ ~z~o~:~

(6,3~, 4-hydroxyacetophenone ~7l.5~), 2-hydroxyacetophenon-(3.0%), and 4-ac~toxyacetopheno~ (1.7%).

The procedure o Example 11 was repeated, but employi~g 30 lar equi~ale~ts of anhydrou~ hyd~ogen fluoride, a reactio~ t~mp~rature of 120C~ and reaction tL~e o~ 2 mlnu~e~. The reactio~ proceeded with 83.2% co~ve~ion of phenol and with tha indicated ~,electi~itie3 to phenyl acetate ~10.9%), 4-hydroxyacetophe~o~e (55.8~), 2-hydroxyacetophenone (12.8%), and 4-acetoxyacetophenone (1.8%).
The ignificance of the mole ratio o~ ~F to phenol in the claimed proce~ illustrated by comparing the results of Example~ 3, 4, 11, and 14 und~r th~ invention wherein phe~ol con~ex~ion~ of ov@r 99% a~d 4-~P selectiv~tie~ of over B4~ to o~er 91% were obtained using ~/ phenol mole ra~ios in the ranqe o~ lO ~o 40~ with ~he re~ult~ of Comparative Example B wher~in a phenol con~r~ion of 87% a~d a 4 ~AP selectivity o~ 64.5~ were obtained using an ~F/phenol mole ra~io of 5, the other ~i~nificant proce~s ~ariables being equal or non~critical.
The signifi.canre ~f the lower lLmit of the reaction temperature rang~ defin~d by the inven~ion i3 illus~rated by co~aring the results o~ Examples 13 and 14 under the .
invention wh~rein phenol con~ersions of over 99~ and 4 ~AP-selec~ivities of 89.7% and gl.4 were ob~ained using reaction te~peratures of 50 a~d 75C, with the results of Comparative Example ~ wherein a phenol con~ersion of 82.0% and a 40~AP
sPlectivity of 71.5% were obtained using a reaction temperature ~ 20~ C~
~ h~ signi~icance of the upper limit of the reaction ~LZ6c~50~3 te~perature range in combination with the lower limit of the range o~ reaction time~ d2~ined by th~ inve~tion is showTl by co~paxing the result~ of Examples 13 and 14 given previously wi~ch ;tkLose oi~ Go~parativ~ Exampl.e E wherein a con~Jer~ion oi~
83 . 2% a~d a 4~AP selectivil:y of 55 . 8% was obtained using a reactio~ tQmperat~r~ o~ 120C and a reaction tim~ of 2 minut~s~

Claims (6)

1. A process comprising acetylating phenol with 0.9 to 2.0 moles per mole of phenol of acetic anhydride as acetylating agent in the presence of about 8 to 60 moles per mole of phenol of hydrogen fluoride as catalyst, at a temperature of reaction of about 30 to 95°C for a reaction period of at least about 10 minutes, to produce 4-hydroxyacetophenone, said temperature of reaction being at least about 45°C when said number of moles of hydrogen fluoride per mole of phenol is no greater than about 12.

2. The process of claim 1 wherein a phenol conversion of at least about 90% and a reaction selectivity to 4-hydroxyacetophenone of at least about 70% are obtained.

3. The process of claim 1 wherein about 1.0 to 1.1 moles of acetic anhydride per mole of phenol are employed.

4. The process of claim 3 wherein about.15 to 40 moles of hydrogen fluoride per mole of phenol are employed.

5. The process of claim 4 wherein said temperature of reaction is about 40 to 80°C and said reaction period is 30 to 300 minutes.

6. The process of claim 5 wherein the phenol conversion is at least about 95% and the selectivity to 4-hydroxyacetophenone is at least about 90%.