Detection of intermediates and isolation of hydroquinone monoacetate in the Dakin

oxidation of p-hydroxyacetophenone
MARTINB. HOCKING,' A. SMYTH
MINGKO, A N D TREVOR
Utli\jersit?,r<f'Vicroriu, Victoria, B. C., Crinuila V8 W 2 Y2
Drpurrmenr c?f'Cl~e~nist~y,
Received April 18, 1978
Downloaded from www.nrcresearchpress.com by 114.125.201.55 on 07/31/17. For personal use only.

MARTLN B. HOCKING, MIYGKO, and TREVOR A. SMYTH. Can. J . Chem. 56.2646 (1978).
Oxidation of o-, m-, and p-hydroxyacetophenone with peracetic acid or terr-butyl hydro-
peroxide, oxidants relatively readily monitored by nmr, failed to generate isolable intermediates
though an intermediate was detected for the p-ketone. Attempted oxidation of a number of
related ketones under Dakin conditions failed either to react, or to generate a detectable inter-
mediate. However, with delicate adjustment of pH and careful timing of the isolation procedure,
hydroquinone monoacetate has for the first time been successfully isolated from an alkaline
aqueous hydrogen peroxide oxidation (Dakin oxidation) of p-hydroxyacetophenone.

M A R T ~£3.V HOCKING, MI~G KO et TREVOR A. SMYTH. Can. J. Chem. 56,2646 (1978)

L'oxydation des o-, nl- et p-hydroxyacetophCnones par l'acide peracetique ou I'hydro-
peroxyde de [err-butyle, des oxydants qui peuvent Ctre facilement detectes par rmn, n'ont pas
conduit a la formation d'intermediaires pouvant Ctre isoles, mCme si on a pu detecter un
intermediaire dans le cas de la cetonepara. Lors d'essais d'oxydation d'un certain nombre de
Can. J. Chem. 1978.56:2646-2649.

cetones apparentees, dans les conditions de Dakin, nous n'avons observe aucune reaction et
nous n'avons pu generer d'intermediaires pouvant Ctre detectes. Toutefois en ajustant d'une
f a ~ o ndelicate le pH et en minutant correctenlent le procede d'isolation, on a pu isoler pour la
premiere fois le monoacetate d'hydroquinone d'une oxydation par le peroxyde d'hydrogine en
milieu aqueux alcalin (oxydation de Dakin) d'une p-hydroxyacetophCnone.
[Traduit par le journal]

Introduction
Oxidation of hydroxyacyl aromatics with aqueous
alkaline hydrogen peroxide to yield dihydroxy
aromatics has received significant attention for its
synthetic utility (1, 2) and its scope was reviewed
some time ago (3). However, the mechanistic path-
way followed by this process has received little atten-
tion, apart from relatively recent proposals that it
proceeds via a n ester intermediate (4), frequently by
analogy to the better understood though only super-
ficially related Baeyer-Villiger oxidation of bisaro-
inatic ketones.
A series of competitive oxidation hydrolysis experi-
ments with initial simultaneous presence of p-
hydroxyacetophenone and hydroquinone monoace-
tate (HMA) substrates showed that loss of ketone
was more rapid than of ester, which suggested that
ester could iiot be an intermediate in this process (5).
However, ester which may have subsequently formed
from ketone made this a potentially ambiguous result
though there was no evidence of ester during a reac-
tion in the absence of initial ester (Scheme I). Kinetic
experiments have established a first-order rate
dependence on ketone concentration for both ortho-
and para-hydroxyacetophenone but at the same time
unexpectedly demonstrated a 1.4 order of dependence
in hydrogen peroxide ( 6 ) , again a n inconclusive
'Visiting Professor, 1978-1979. Department of Chemistry,
McGill University. Montreal. P.Q. H3A 2'47.
-
result. Fortunatelv. however, during a few of the
preliminary runs for the kinetlc experiments at lower
pH which were monitored by ' H nmr, a n occasional
fleeting additional proton resonance at about the
same shift as would be expected for the acetate
methyl of HMA was observed. Here are reported the
results of the exoeriments directed towards es-
tablishing collditions which prolotiged the lifetime of
this and related intermediates to enable inore exten-
sive observation of their formation to be made, and
eveiituallv to enable urocedures to be develoued to
isolate a key intermediate in this process and prove its
identity.
Experimental
Comnlercial p-hydroxyacetophenone was purified by
crystallization from water and dried (8OZC/24h) before use.
Hydroquinone monoacetate was obtained in poor yield as
previously described (6j, rnle 152. Peracetic acid was freshly
prepared on a n approximately 2 g scale for each experiment
from glacial acetic acid (2.5 g), 90% hydrogen peroxide (1.5 g,
F M C ; normal precautions (7)), and concentrated sulphuric
acid (50 nig) by the method of Greenspan (8). Concentrations
of 50-52% were obtained by titrimetric determination (9, 10)
and were confirmed by 'H nmr measurements (11). The re-
ported mole ratios of hydrogen peroxide are based on deter-
minations of the nominal 30% material immediately before
use (12).
Proton nmr monitoring was carried out and spectra were
obtained at 37'C o n Perkin-Elmer R-12 or R-32 spectrometers,
using 6% TMS in CC1, sealed in a n axially-positioned thin-
wall capillary as external reference for the reported shifts of
aqueous solutions. Mass spectra were obtained on Hitachi
Perkin-Elmer RMU-6E double focussing and Finnigan
 HOCKING ET AL
Downloaded from www.nrcresearchpress.com by 114.125.201.55 on 07/31/17. For personal use only.
S C H E M E1. Competitive oxidation hydrolyses o f p-hydroxy-
acetophenone and hydroquinone monoacetate.
Can. J. Chem. 1978.56:2646-2649.
quadrupole spectrometers. Analytical and preparative gas-
liquid chromatographic (glc) results were obtained on Varian
Aerograph Model 920 instruments fitted with flame ionization
and thermistor thermal detectors, respectively.
Hpdroqltinolle Morloacetate Hydrolysis Rate Experitnents
Hydroquinone monoacetate relative hydrolysis rates were
surveyed by small scale experiments using 'H nmr monitoring
o f the ester and acetate ion resonances at 6 2.72 and 2.35 ppm,
re~pectively.~ One example where the generation o f inter-
mediate peracetic acid was observed is described below.
Hydrogen peroxide (60 rng, 30%) was added to a solution o f
H M A ( 5 mg) in 0.5 ml o f water thermostatted at 37-C. After
75 min a singlet resonance at 2.53 ppm indicated that about
20% o f the residual ester was present, and acetic acid was
absent. After 1 5 h the breakdown o f the reaction progress by
' H nmr was approximately: ester, 50%; peracetic acid 2, 207,;
and acetic acid, 30%. By 66 h the ester had hydrolyzed
completely.
Lxtmction Experirizerzts during Hpriroqrlirzone ~Monorrcetute
Hydrolysrs
Hydroquinone monoacetate (44 mg) was dissolved in 0.5 1111
o f 0.1 M sodium hydroxide containing 120 mg o f 3 0 z hydro-
gen peroxide and 2 min later the resulting solution was ex-
tracted with 3 ml followed by I ml o f deuteriomethylene
chloride. Examination o f the dried extracts by 'H nmr demon-
strated the presence o f four times as lnuch H M A , at 6 2.20, as
intermediate 2, 6 2.10 ppm, in the first extract, and an H M A
concentration o f about 0.8 that o f the intermediate 2, in the
second; ms (room temperature 70 eV) n ~ $ e167,: 152 ( H M A ) ;
I3Cmr (CD2Cl2): two benzene derivatives. The resonance
ascribed to the methyl o f H M A was confirmed by seeding
with genuine material (6). Loss o f the ' H nrnr resonance at
2.10 ppm occurred on careful evaporation and resolution, or
from washing a portion o f the extract with 6 drops o f water.
The original aqueous raffinatecontained H M A , intermediate 2
(predominating), and acetate ion, 6 z 2.20, 2.10, and 2.00
ppm, respcctivcly.
' A copy o f Tables 1 and 2 summarizing the results from 14
experiments in this series is available, at a nominal charge,
from the Depository o f Unpublished Data, CISTI, National
Research Council o f Canada, Ottawa, Ont., Canada K I A OS2.
Seeding experiments with freshly prepared peracetic acid (8)
on a new experiment gave peaks which coincided with the
singlet for intermediate 2 for both a deuteriochloroforn~
extract and the aqueous raffinate.
Stable Iwtermediate Experii?wnts
p-Hydroxj~acetophenonewith Peracetic Acid
A solution o f p-hydroxyacetophenone (97 mg) in 0.46 ml o f
1 M sodiu~ncarbonate at 37'C was rapidly oxidized but failed
to show directly any detectable intermediate with peracetic
acid (260 nig o f 51.5%).
This experiment was repeated and 1 min after mixing was
chilled; saturated with sodium chloride, and then extracted
with 1 ml deuteriochloroforn~.The dried extract contained
H M A , peracetic and acetic acids, by 'H nmr and ir; nis (room
temperature, 70 eV) in,'e: 152, 11I , 109. About 1 5 mg o f impure
hydroquinone uas isolated from the acidified aqueous reaction
solution.
Other experiments conducted are mentioned in the dis-
cussion.
Snzall-scale ' H Nuclear Magnetic Resonal~ceSurc.ej>Oxidntions
of m - and p-Hydroxyacetoplzenone
The hydroxyketone, in varying mole ratios, was dissolved in
aqueous solutions o f 0.10-0.74 M sodium hydroxide or sodium
carbonate and the solutions placed in a thermostat bath at
37'C for several minutes. Via a calibrated dropper the desired
quantity o f stock hydrogen peroxide, also at 37'C, was added
to the solution o f the ketone and the solution vigorously mixed,
and then an aliquot withdrawn and placed in an nmr tube. The
region I to 4 ppm for protons was then repeatedly scanned for
a period o f an hour or so, or until there appeared to be n o
further change, t o observe the loss o f the ketone methyl singlet
and development o f an acetate ion singlet plus the appearance
olany additional resonances o f interest. From a matrix o f some
30 experiments o f this kind the set o f conditions outlined in the
procedure below was devised for the p - k e t ~ n e . ~
Hydroquinone Monoacetate Isolation fi.onr a Dakirz Oxidation
of p-Hydroxyacetophenone
T o a stirred solution o f p-hydroxyacetophenone (20.0 g) in
240 ml o f 0.4 M aqueous sodium carbonate at 37°C was added
20 ml o f 36.8 wt.% hydrogen peroxide. Once the solution
became homogeneous (about 2 min), the reaction was quenched
 2648 C 4 N . J . CHEM. VOL. 56. 1978
by sharp chilling in a salted ice bath and by the addition of
1.0 M sulfuric acid to pH i3 while simultaneo~~sly bubbling
excess sulfur dioxide through the solution. The chilled solution
was then extracted with 4 x 100 ml and 1 x 100 ml of ether
and the two series of extracts dried (Na2S0,) and solvent
removed to yield 21.92 and 0.84 g of pale brown solid. Gas-
liquid chromatography of this material on a 1.3 m x 3 mm,
3% SE30 o n 80,'100 mesh Chrom P packed column at 164'C,
15 mljmin He carrier, gave retention times for benzoquinone,
Downloaded from www.nrcresearchpress.com by 114.125.201.55 on 07/31/17. For personal use only.
1.1 min; hydroquinone, 4.2 min; HMA, 7.0 min; p-hydroxy-
acetophenone, 10.4 min and established that the composition
of the larger sample was approximately 16 and 75% of the
former two, and 3-4% of each of the latter two compounds.
The combined evaporated crude extracts were triturated
with cold benzene (4 x 50 ml) and the combined solutions
dried and chilled to OcC, which brought down 1.58 g of pale
y e l l o ~crystals, mp 82-105"C, of impure p-hydroxyaceto-
phenone (nmr). After drying, the benzene was removed from
the filtrate leaving 4.3 g of pale orange crystals in oil. The oil
(1.68 g) was filtered off and was then extracted with 3 x 3 ml of
benzene. The first extract (0.85 g) contained 38 m o l x H M A
(plus 58%~-hydroxyacetophenone),4% acetic acid, by ' H nmr,
and the second and third extracts contained negligible further
H M A . It was not possible to crystallize this extract from a
Can. J. Chem. 1978.56:2646-2649.
variety of solvents either directly or from colllbined appro-
priate fractions, obtained after solvent chromatographing on
activated alumina columns twice. However, after successful
preliminary separate sublimation tests with authentic H M A
and p-hydroxyacetophenone, about 130 mg of 86% (('H nmr)
HMA was sublimed (90-llO"Cj15 l'orr) from the first extract.
Recrystallization from hexane twice, with charcoal, gave a few
milligrams of colourless plates (needles occasionally obtained
if crystallization was rapid) of HMA, mp 60-63°C; ms,
methane chemical ionization, 152, 153 ( M + I), 181 ( M + 291,
and 193 (M + 41), were obtained both for this material and for
authentic hydroquinone monoacetate (6); ir (Nujol) v,,,: 3440
(s, OH), 1745 and 1726 (s, C=O); electron impact ms (room
temperature, 70 eV) t ? ~ / (relative
e intensity > 10%): 152(13),
llO(lOO), 109(11), 82(12), 81(19), 55(12), 54(14), 53(18), 43(51),
39113).
- \ ,
From extracts of later oxidations ofp-hydroxyacetophenone,
HMA was separated with difficulty by preparative glc using
100 p1 injections of a 10% ethereal solution onto a 1 m x 6 m ~ n
column of 1.5% OV 701 o n Chronl G H I P lOOjl2O at 19OCC,
70 ml/min He carrier. Retention times observed were hydro-
quinone diacetate 1.8 min; HMA, 3.1 niin; andp-hydroxyace-
tophenone, 6 min. One recrystallization of the H M A fraction
from hexane gave colourless square plates identical to the
above, mp 63-64°C (lit. (13) mp 65-66'C).
Results and Discussion
Preliminary nmr tube scale experiments established
that H M A alone in water at 37°C remained virtually
unchanged even after 17 h although addition of a
small amount of sodium hvdroxide t o the solution
brought about hydrolysis in less than 2 min, ex-
tremely rapid compared to control experiments with
phenyl acetate. Aqueous hydrogen peroxide alone
also caused rapid disappearance of the HMA inter-
estingly enough generating peracetic acid, 2, and
possibly a per ortho ester (see Scheme 2) giving a 'H
nmr resonance a t 6 2.14, which then quite slowly
faded to the methyl shift for aqueous acetic acid, plus
hydroquinone (not specifically monitored). Eventu-
unstable intermediates
CHI
I
HOO-C-OH
+ H,O,IH,O -+ + CH,CO,H, and
ally conditions were devised prolongil-ig the lifetime
of these intermediates to more than an hour. Extrac-
tion experiments were successful in obtaining stable
methylene chloride solutions of the intermediates in
which the presence of peracetic acid was confirmed by
seeding experiments. But apart from obtaining mass
spectrometric confirmation of the per ortho ester by
an m,'e of 167 it was not possible to further charac-
terize this material.
The results obtained from the monoester experi-
ments above initially discouraged direct pursuit of
the intermediate from alkaline hydrogen peroxide
oxidation of p-hydroxyacetophenone. It had also
been noted that solvent changes, for instance to
acetone or pyridine, completely alter the course of
the reaction (14). Therefore: consideration was then
given to oxidant variants or more stable aryl ketone
substrates in a n attempt to obtain a somewhat
longer-lived and less sensitive intermediate to facili-
tate isolation.
Peracetic acid oxidation of acetophenone at low
p H has been reported to give phenyl acetate, phenol,
and benzoic acid (15). Accordingly, peracetic acid
oxidations of p-l~ydroxyacetophei~onein aqueous
sodium carbonate were conducted. Deuteriochloro-
form extracts gave a 'H nmr singlet resonance
coinciding nith added HMA, and the correct nqe 152,
but the solution concentration was low and the
experimental procedure was difficult to scale up to
permit confir~nationof this result by isolation.
terf-Butyl hydroperoxy radical has been used to
oxidize aromatic substrates (16) and the hydro-
peroxide to oxidize aliphatic aldehydes (17, 18).
However, even u p to five times excess of this oxidant
failed to give any detectable (1 1) oxidation or inter-
mediate formation with p-hydroxyacetophenone in
aqueous sodium hydroxide, or with the mono- or
diacetates of hydroquinone in carbon tetrachloride,
either cold or hot. A slow oxidation occurred with
tert-butyl hydroperoxide and o-hydroxyacetophe~lone
at 85°C although it was not possible to detect any
intermediate. Possibly the reported inhibiting effect
of phenols generally on the decomposition of tert-
butyl hydroperoxide (19) may be the explanation for
this uniformly observed sluggish reactivity.
 HOCKING ET A L . 2649

Acyl aromatics such as 172-hydloxyacetophenone panied by a t least one othei- pathway for the progres-
and p-n~troacetophenonehave been reported to be sion of Dakin oxidation. Evidently further experi-
stable to D a k ~ no x ~ d a t ~ ocond~tlons
n (1). If the ~ n e n t a results
l are necessary before the details of this
1eact:on pioceeds via the pathway outllned e a l l ~ e (4),
r process can be established with any greater certainty.
~t was l~kelythat t h ~ slack of reactlvlty was the con-
sequence of the low migratory a p t ~ t u d eof the phenyl Acknowledgements
group rdther than from the reduced nucleophil~cityof The authors thank the National Research Councll
the carbonyl carbon towards hydroperoxide anion. of Canada and the University of Victoria for
Downloaded from www.nrcresearchpress.com by 114.125.201.55 on 07/31/17. For personal use only.

With this in mind, m-hydroxyacetophenone was financial support and D. L. McGillivray for mass
exposed to Dakin conditions while monitoring by ' H spectra.
nlnr. Small arnounts of acetate ion were generated - H . D. D A K I N4. m . Chem. J . XLII. 477(1909).
but at no time was there a detectable amount of 2.1. W. BAKER.H . F. BONDY.J . G L V B , and D. M I L E S 3. .
intermediate. It had been determined that if resorcinol Chem. Soc. 1615(1953): W. B A K ~ F R.,J . W . M C O M I Eand
.
had formed, it would not have been more than slightly T . L . V. ULBRICHT. J . Chem. Soc. 1825 (1952): G . B A R G ~ R .
affected under the experimental conditions used. J . Chem. Soc. 113, 219 (1918): cf. W. W. WESIERFELD. J.
Separate parallel experiments were conducted with Biol. Chem. 143, 177 (1942).
3. M. H U D L I C K YChem.
. Listy. 46. 567 (1952); J . P L I M L .
p-methoxyacetophenone, 5-nitrosalicylaldel~yde,and Chemie (Prague). 10, 647 (1958).
3-nitro-4-hydroxyacetophenone 1 ~ 1 t silnilar
h negative 3. A. G . DAVIES.Organic peroxide5. B ~ ~ t t e r w o r t hLondon.s,
results. 1961. p . 155; .I.B. LEE and B. C . UFF. Q. Rev. Chern. Soc.
Accordingly. a number of small-scale Dakin oxida- 21.429 (1967): W. A. WATERS.,Mechanisms ofoxidation of
Can. J. Chem. 1978.56:2646-2649.

organic conlpounds. Methuen and Co. Ltd.. London. 1964.

tions ofp-hydroxyacetophenone were carried out and pp. 47 and 4 8 ; L. J . C H I N N .Selection of oxidants in sqnthe-
monitored by 'El nmr to determine whether condi- sis. Marcel Dekkel-. Inc., New York, NY. 1971. p. 112.
tions could be suitably adjusted, not only to generate 5. M. B. HOCKING. Can. J. Chem. 51,2384(1973).
the same nmr resonance coincident in shift to that of 6. M. B. H O C K I N Gand J . H. O r c . Can. J . Chem. 55. 102
the methyl of H M A fleetingly observed previously, (1977).
Concentrated hydrogen peroxide. Technical Data Bulletin
but to extend the lifetime of H M A sufficiently to No. 46. FMC Col-p., New York. NY. 1975; E. S . SHAYLEY
enable isolation of the material. With two of these, and J . R. P E K R I U Jet . PI-opul. 28, 382 (1968): W . C .
namely these havingp-hydroxyacetophenone, sodium S c ~ u n r s .C. N . SATTERFIELD. and R. L. WEK-IWORTH.
carbonate. and hydrogen peroxide in the amounts Hydrogen peroxide. Reinhold Publishing Corp., Kew
0.74, 0.12, 0.66 and 1.48, 0.12, 1.41 mmol, respec- York. NY. 1955. pp. 152-188.
F. P. GREENSPAN. J. Am. Chem. Soc. 68.907 (1946).
tively, in 1.2 n ~ of
l water, an nrnr singlet a t the desired 3: D'AYSand W. F R E Y Ber. . 45. 1845 (1912): J . D'ANs (sic)
shift was observed and, for the latter experiment at and W. FREY.Z. Anorg. Chem. 84, 145 (1913).
least, a confirmed lifetime for the desired intermediate M. W. C . SMII. Recl. Trav. Chim. Pays-Bas,49.675 (1930):
of more than an hour was obtained. B. D. SULLYand P. L. WILLIAMS. Analyst (London), 87.
653 (1962).
From a scaled-up Dakin oxidation of p-hydroxy- '4. I. VOGEL.4 textbook of quantitative inorganic a n a l p i s .
acetophenone, using the conditions established by including elementary instrumental analysis. 3rd ed. Wiley.
these small-scale experiments, pure H M A was Ncw York. NY. 1961. pp. 348,349, and 363.
eventually obtained. Initial difficulties with relatively C. A. BUNTONand J. HELLYER.J . Am. Chem. Soc. 89,
large quantities of co-produced and easily sublimed 6252 (1967).
A. VOY WACEKand H. 0. EPPINGER. Chem. Ber. 73. 644
benzoquinone were largely avoided by the applica- (1940); A. VON WACEKand A. v o s BEZARD.Chem. Ber.
tion of gaseous sulfur dioxide to the quenched reac- 74,845 (1941).
tion solutions early in the work-up. Benzene tritura- A. BALLIOand L . ALMIRANTE. 4 n n . Chim. (Rome), 41,421
tion followed by evaporation served to recover the (1951): Chem. Abstr-. 46, 2518(1952); W. E. V O N D O ~ R I X G
and L. SPEERS.J . Am. Chem. Soc. 72. 5515 (1950); S . L.
monoester still associated with ketone but virtuallv FRIESS.J. Am. Chem. Soc. 71, 14(1949).
free of associated, less soluble hydroquinone. Either J . A. HOWARDand J . H. B. C H ~ N I E JR. .Am. Chem. Soc.
careful sublimation o r preparative glc followed by 95.3054 (1973).
crystallizatioll then gave pure HMA. I. SCHLOSS~IAN (to Halcon International Inc.). Fr. Patent
No. 1,395.951 (April 16, 1965); Chem. Abstr. 63, 98178
Although- this first isolation of H M A from a Dakin
(1965).
oxidation of p-hydroxyacetophenone certainly impli- M . C . V. SAUERand J . 0.EDWARDS.J . Phys. Chem. 75,
cates the ester as a n intermediate in this process, the 3377 (1971).
evidence obtained here is insufficient to establish this G . A. WARDand R. D. MAIR.Anal. Chem. 41, 538 (1969);
as the sole intermediate. Consideration of the kinetic D. S. SWERN.A. H . CLEMENTS, and T. M . JUONG.Anal.
Chem. 41.412 (1969).
results obtained earlier (6), which were inconsistent E. G. GINTSBERG,V. V. GUR'YASOVA.and B. M .
with a pathway only involving ester, strengthens this KOVARSKAYA. Zh. Obshch. Khim. 40. 2319 (1970); Chem.
proposal that ester formation is probably accom- Abstr. 74,75841 m (1971).