Practical process for the air oxidation of cresols: Part A. Mechanistic investigations

Article abstract of DOI:10.1021/op049845b

The catalytic air oxidation of p-cresol and 2,6-di-tert-butyl-4- methylphenol to the corresponding benzaldehydes was investigated to determine the mechanism at work in these oxidation reactions. A number of intermediates and byproducts, mainly in the form of dimers, were observed during the course of the reactions, and their structures were elucidated by spectroscopic and chromatographic methods. The existence of these compounds in the reaction mixtures, and their proposed methods of formation, provided further insight into the mechanism involved in these oxidations.

Full text of DOI:10.1021/op049845b

Organic Process Research & Development 2005, 9, 62−69
Practical Process for the Air Oxidation of Cresols: Part A. Mechanistic
Investigations
Benita Barton,* Catherine G. Logie, Barbara M. Schoonees, and Bernard Zeelie
Catalysis Research Unit, Faculty of Applied Science, Port Elizabeth Technikon, PriVate Bag X6011,
Port Elizabeth, South Africa, 6000
Abstract:
Studies on the partial air oxidation of substituted methyl
phenols to phenolic aldehydes have been reported in con-
The catalytic air oxidation of p-cresol and 2,6-di-tert-butyl-4-
methylphenol to the corresponding benzaldehydes was inves-
tigated to determine the mechanism at work in these oxidation
reactions. A number of intermediates and byproducts, mainly
in the form of dimers, were observed during the course of the
reactions, and their structures were elucidated by spectroscopic
and chromatographic methods. The existence of these com-
pounds in the reaction mixtures, and their proposed methods
of formation, provided further insight into the mechanism
involved in these oxidations.
9
,10
siderable detail in the literature. To avoid the formation
of polymers and tars, the phenolic group is conventionally
protected as either the acetate (in an acetic anhydride and
1
1
acetic acid medium ) or phenolate (in an alcohol-based
1
2
medium ).
Recently, it was shown that certain supported platinum
group metal (PGM) catalysts could be used to afford ben-
zylic oxidation of a cresol without protection of the phe-
13
nolic group with reasonable success. These procedures
are supposed to be flexible enough, particularly with hin-
dered cresols, to allow for the selective preparation of
various oxidation products, including nucleophilic addi-
tion products and a range of coupled compounds.14 How-
ever, most of these reactions are characterized by low
yields to the desired aldehyde and the formation of further
oxidized and/or oligomerization products. Deactivation of
the very expensive PMG catalysts is partially relieved
by the use of transition metal promoters. Regeneration of
such catalysts is, however, problematic and, therefore,
Introduction
Hydroxy-substituted benzaldehydes are important inter-
mediates for a large variety of chemical products used in
consumables such as soaps, fragrances, pharmaceuticals,
preservatives, plant protection chemicals, etc.
substituted benzaldehydes can be produced either from
phenols1,6 (e.g., by Reimer-Tiemann, Vilsmeier, and Sali-
1
-5
Hydroxy-
genin reactions and by means of glyoxilic acid condensation
with phenol) or from cresols1
,6-8
(e.g., by side-chain halo-
1
3,14
expensive.
genation/hydrolysis or catalytic and electrochemical oxida-
tions). Despite the disadvantage of the higher cost of cresol
feed as opposed to phenol feed, there has been considerable
interest in the use of oxidative technologies for the production
of hydroxybenzaldehydes in view of the potential advantages
in respect of selectivity and decreased effluent problems.
Current oxidation routes include an electrochemical p-cresol
oxidation process and a phenol/glyoxilic acid condensation,
followed by oxidation of the resultant p-hydroxymandelic
acid.
In view of the availability of a wide variety of phenolic
compounds from the Fischer-Tropsch process operated by
Sasol in South Africa, there has been a considerable interest
in the beneficiation of these compounds. The catalytic air
oxidation of p-cresol to 4-hydroxybenzaldehyde/4-hydroxy-
benzoic acid is but one example of such interest in
downstream processing. In this series of two papers, we wish
to report the results of our own efforts to develop a safe,
technically feasible process for the oxidation of p-cresol and
other hydroxy-substituted alkylaromatics. These results are
presented in two parts: Part A deals with aspects of the
mechanisms at work during catalytic air oxidations, and Part
B deals with the evaluation of an approach to effect such
oxidations, postulated on the hand of the proposals described
in Part A.
7
8
*
To whom correspondence should be addressed. E-mail: barton@yebo.co.za
or benita@botsnet.bw.
(1) Clonts, K. E.; McKetta, R. A. Cresols and Cresylic Acids. Kirk-Othmer,
Encyclopedia of Chemical Technology, 3rd ed.; InterScience: New York,
1
978; Vol. 3, pp 212-227.
(2) Common Types of Food Adulteration, http://www.eurofins.com/authenticity/
common_food_adulteration.asp.
(
3) TGSC Perfumery Raw Materials, 3-ethoxy-4-hydroxybenzaldehyde and
3
-methoxy-4-hydroxybenzaldehyde, http://www.execpc.com/∼goofscnt/data/
rw1002653.html.
(9) Yoshikuni, T. J. Mol. Catal. 1992, 72, 29.
(
4) Burdock, G. A. Encyclopedia of Food and Color AdditiVes; CRC Press:
New York, 1997; Vol. 3, pp 371-376, 2485-2486, 2891-2904.
5) Sittig, M. Chemical Technology ReView No. 124: Pharmaceutical Manu-
facturing Encyclopedia; Noyes Data Corporation: New Yersey, 1997; p
(10) Peeters, M. P. J.; Busio, M.; Leijten, P. Appl. Catal., A 1994, 118, 51.
Vidyasagar, A.; Nalawala, K. J.; Varshney, A. K.; Murthy, C. S.; Metha,
M. H. Indian J. Chem. Technol. 1996, 3 (5), 295.
(11) Constantini, M.; Laucher, D.; Fache, E. U.S. Patent 5,354,919c, 1994.
(12) Sharma, S. N.; Chandalia, S. B. J. Chem. Technol. Biotechnol. 1990, 49,
141.
(13) Fache, E.; Laucher, D.; Constantini, M.; Beclere, M.; Perrin-Janet, F.
The Roots of Organic Development. In Industrial Chemistry Library;
Desmurs, J., Ratton, S., Eds.; Elsevier: Amsterdam, 1996; Vol. 8, pp 380-
390.
(
6
26.
(
(
(
6) Fiege, H. Cresols and Xylenols. Kirk-Othmer, Encyclopedia of Chemical
Technology; VCH Verlagsgesellschaft: 1991; Vol. A8, pp 25-59.
7) Barl, M.; Degner, D.; Siegel, H.; Hoffmann, W. German Patent 2,935,398
A1, 1979.
8) Kalikar, R. G.; Deshpande, R. S.; Chandalia, S. B. J. Chem. Technol.
Biotechnol. 1986, 36, 38.
(14) Diephouse, T. R.; Strom, R. M. U.S. Patent 4,915,875, 1990.
6
2
•
Vol. 9, No. 1, 2005 / Organic Process Research & Development
10.1021/op049845b CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/06/2005

Scheme 1. Sheldon and de Heij17 mechanism for cresol
oxidation in alkaline medium
Scheme 2. Fache et al.13 reaction pathway for cresol
oxidation in acetic acid medium
to the corresponding aldehyde 5, with concomitant release
of a hydroxy-cobalt(III) complex. This Co(III) complex may
then participate, as shown in the scheme, in the initiation
step.
According to this scheme, neither the benzylic alcohol 6
nor the benzyl methyl ether 7 is considered to be major
intermediates in the formation of the aldehyde. Conversion
of the benzylic radical 3 to the carbocation 8 (a resonance
form of quinomethide 9), followed by subsequent reaction
with ROH to afford 6 or 7, is merely perceived as being
parallel side reactions only.
Other authors have carried out similar oxidations and
proposed mechanisms that do not involve their corresponding
benzyl alkyl ethers as significant intermediates in the
formation of the aldehyde. The schematic reaction path-
ways for their proposals are omitted here for the sake of
brevity.
Results and Discussion
There have been a number of studies reported in the open
1
4-21
literature
that explored the nature of the mechanism of
alkylphenol autoxidation, both in alkaline alcoholic media
and in carboxylic acid media. These reports formed the basis
of our investigations, as our primary interest was to determine
the feasibility of manipulating aspects of the mechanism to
improve the said oxidations in respect of safety, yields and
selectivity, and decreased environmental impact. We there-
fore need to give a very brief summary of those aspects of
mechanisms that have been reported in the literature that are
of direct interest to this investigation.
9
,18
Oxidations of cresols through acetoxylation of the cresolic
methyl group using acetic acid media in the presence of
palladium catalysts have also been investigated exten-
17
Sheldon and de Heij proposed the reaction pathway that
is illustrated in Scheme 1 to explain the observed formation
of oxidation products during the cobalt-based catalytic air
oxidation of cresols and substituted cresols in alkaline
methanolic solutions. They suggested that the phenolate anion
1
3,14
sively.
Fache et al. have proposed the following reac-
tion pathway to explain their observations under these
1
3
reaction conditions (Scheme 2): According to their pro-
posal, p-cresol 10 is oxidized primarily to 4-hydroxybenzyl
acetate 11 when the solvent is glacial acetic acid. This acetate
is then only slowly oxidized to the aldehyde 13. However,
in the additional presence of water, an equilibrium is
established between 11 and 4-hydroxybenzyl alcohol 12, the
latter being readily oxidized to 13. The main disadvantage
of their system is the requirement that low substrate loadings
1, present in this form due to the basic nature of the reaction
medium, is oxidized to the phenoxyl radical 2 by means of
reaction with the Co(III) species present in the medium.
Radical 2 then undergoes further reaction to form the
benzylic radical 3, followed by its conversion to the
peroxycobalt(III) complex 4, and subsequent decomposition
(2-5 mass%) be used, since dimers and oligomers result at
higher loadings.
(
15) Borgaonkar, H. V.; Chandalia, S. B. J. Chem. Technol. Biotechnol. 1984,
3
4A, 107.
In our investigations, observations have been made that
have led us to propose a more detailed and, compared to
some authors, different mechanism at work in these reactions.
The results of oxidation reactions carried out in both aqueous
acetic acid and alkaline methanol media using either p-cresol
or a substituted analogue are now reported.
(
(
16) Bushweller, C. H. Tetrahedron Lett. 1968, 58, 6123.
17) Sheldon, R. A.; de Heij, N. Aromatic Aldehydes via Catalytic Oxidation.
In Role of Oxygen in Chemistry and Biochemistry; Ando, W., Moro-Oka,
Y., Eds.; Elsevier: Amsterdam, 1988; pp 243-256.
(
18) Shimizu, M.; Watanabe, Y.; Orita, H.; Hayakawa, T.; Takehira, K. Bull.
Chem. Soc. Jpn. 1993, 66, 251.
19) Yoshikuni, T. J. Mol. Catal. 1992, 72, 29.
20) Omura, K. J. Org. Chem. 1984, 49, 3046.
21) Metro, S. J. J. Am. Chem. Soc. 1955, 77, 2901. Hewitt, D. G. J. Chem. Soc.
C 1971, 2967. Filar, L. J.; Winstein, S. Tetrahedron Lett. 1960, 25, 9.
(
(
(
p-Cresol Oxidation in Aqueous Acetic Acid Medium.
p-Cresol 10 (20 mmol) was oxidized in aqueous acetic acid
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63

2,6-Di-tert-butyl-4-methylphenol Oxidation in Aqueous
Acetic Acid Medium. The oxidation, in aqueous acetic acid,
of the 2,6-disubstituted cresol 17 was studied as an example
of a hindered cresolic substrate. The substrate was not very
soluble in this medium, and so the substrate loading was
kept low. Oxidations were initially performed in glacial acetic
acid, and 10% water was added only after the elapse of 20
min. The main product in this 10% water/acetic acid mixture
was 3,5-di-tert-butyl-4-hydroxybenzyl acetate 18, with trace
amounts of the alcohol 19, aldehyde 20, and acid 21 being
detected. One prominent secondary product identified was
the diphenoquinone 22 (Scheme 3).
Once again, supplementary experiments were carried out
using the hindered cresol, the corresponding benzyl alcohol,
and mixtures of the two, in 10% aqueous acetic acid at 100
°
C. Both the catalyst and oxygen were omitted in these
Figure 1. Product distribution diagram for the oxidation of
p-cresol in aqueous acetic acid medium. [4-HB alcohol ) 12,
reactions. Below is a summary of the experiments together
with the results thus obtained.
4
-HBOAc ) 11, 4-HBA ) 13, and 4-HB acid ) 14; Total )
(1) The hindered cresol 17 was heated in aqueous acetic
the sum of amounts of compounds 10-14.]
acid; no reaction occurred under these conditions.
(2) A high concentration (20% m/m) of alcohol 19 was
heated in 10% aqueous acetic acid; the benzyl acetate 18
and quinomethane 23 were formed as the main products.
Dimer 24 was found to be a major secondary product, with
small amounts of the other dimeric compounds 25, 26, and
27 also being detected.
using oxygen in the presence of KOAc and palladium
supported on activated carbon. The reaction was carried out
at 100 °C and was continued for 8 h. Initially, the substrate
loading was kept below 5% (m/m). The main reaction
products detected by chromatographic techniques were ace-
tate 11, alcohol 12, and aldehyde 13. Increasing the substrate
loading above 5% (m/m) resulted in the formation of
4-hydroxybenzyl 4-methylphenyl ether 15 and trace amounts
of bis(4-hydroxyphenyl)methane 16. Figure 1 illustrates a
typical product distribution diagram for the oxidation of
p-cresol in aqueous acetic acid solutions.
It is important to note that, under these oxidative condi-
tions, m-cresol did not oxidize at all, whilst o-cresol did, in
fact, oxidize, but to a lesser extent as compared with p-cresol.
To obtain further information related to the mechanism
at work in this reaction, a few supplementary experiments
were conducted in the absence of catalyst and oxygen feed,
but otherwise under the same reaction conditions. These
experiments and the results thereof are listed below:
(1) p-Cresol 10 was heated in aqueous acetic acid;
irrespective of the loading, no reaction occurred under these
conditions.
(2) p-Hydroxybenzyl alcohol 12 was heated in aqueous
acetic acid; this substrate reacted rapidly with the acetic acid
to afford p-hydroxybenzyl acetate 11. The amounts of 11
and 12 in the final reaction mixture were approximately
equivalent; small amounts of the methane 16 were also
present.
(3) A 1:1 mixture of a high (20% m/m) concentration of
17 and 19 was heated in the aqueous solvent; this afforded
the same compounds as was observed with alcohol 19 alone
(see above), but obviously with some of the cresol 17 also
being detected, as expected.
(
3) A mixture of alcohol 12 and cresol 10, at high cresol
p-Cresol Oxidation in Alkaline Methanolic Medium.
p-Cresol 10 (200 mmol) was oxidized in an alkaline (NaOH)
loadings, was heated in aqueous acetic acid; the diaryl
compounds 15 and 16 were observed in the reaction mixture,
indicating that these do not require catalysis to form.
2 2
methanolic medium in the presence of a CoCl ‚6H O catalyst.
The reaction was carried out at 60 °C and was continued
64
•
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Scheme 3. Compounds formed in the oxidation of a hindered cresol in acetic acid medium
for 8 h. A typical product distribution diagram for this system
is illustrated in Figure 2. (Note that samples were worked
up prior to analysis to hydrolyze the sodium phenolates back
to the neutral phenolic compounds.)
the relative amounts of the alcohol 12 and ether 28 during
this process, it may be suggested that the ether is the major
oxidation intermediate leading from the cresol to the ben-
zaldehyde. These observations are in contrast to those re-
1
7
ported by other authors. Sheldon, for example, reported
that the amount of alcohol dominated over that of the ether
and that neither of these compounds underwent further
oxidation to the aldehyde.
In two additional experiments, benzyl alcohols 12 and
19 were separately stirred with heating in methanol contain-
ing solid sodium hydroxide for 4 h without the addition of
a catalyst or oxygen. After the workup, a significant amount
of 10 had been converted to ether 28, whilst most of 17 had
also reacted to form ether 29.
Figure 2. Product distribution diagram for the oxidation of
p-cresol in alkaline methanolic medium. [4-HB alcohol ) 12,
4
-HB methyl ether ) 28, and 4-HBA ) 13; Total ) the sum of
amounts of compounds 10, 12, 13, and 17.]
Proposed Mechanism. The progress of the oxidation of
p-cresol in our investigations was found to be remarkably
similar in both aqueous acetic acid and alkaline alcoholic
solutions despite the use of different catalysts and differ-
ences in reaction conditions. The primary products of the
oxidation of p-cresol 10 are the acetate 11 (in 50% aque-
ous acetic acid media) or the benzyl methyl ether 28 (in
alkaline alcoholic solutions), with the alcohol 12 also being
formed in both solvent media. These are then converted to
either the benzaldehyde 13, or dimeric byproducts (for
example 15 and 16, when the reaction is carried out in acidic
medium). As discussed earlier, these dimers do not neces-
sarily require oxidative conditions or catalysis for their for-
mation. Interestingly, their formation is suppressed in alkal-
ine methanolic solutions, and possible reasons for this are
discussed later.
The rate of oxidation of p-cresol is fast initially but tails
off rapidly as the concentration of substrate decreases. Apart
from 4-hydroxybenzaldehyde 13, other detected compounds
were 4-hydroxybenzyl alcohol 12 and 4-hydroxybenzyl
methyl ether 28.
It is of interest to note that the sum of the substrate 10,
alcohol 12, ether 28, and aldehyde 13 remains virtually
constant throughout the reaction, suggesting the absence of
other intermediates/products in significant amounts. Dimers
The Pd-catalyzed benzylic acetoxylation of alkyl aromat-
ics such as toluene in acetic acid solutions is well-
1
6,22-24
known.
These reactions are normally carried out in
15 and 16 were not detected in this oxidation. By considering
the presence of potassium acetate using a cocatalyst (nor-
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65

mally Sn(OAc)
2
) and are optionally carried out in the
Experiments suggested too that the benzyl alcohol may,
however, also be formed as a result of an equilibrium reaction
between the acetate and alcohol. In all cases, the driving
force for the rapid formation of the benzylic-substituted
products is the rearomatization of the quinomethide. In the
case of the hindered quinomethide 23, the large, bulky
tertiary-butyl groups are responsible for reducing the rate
of rearomatization significantly enough so that it may be
detected in solution, as was the case in this investigation;
this increased stability of the hindered quinomethide relative
to the unhindered methide is due to the stabilizing effect of
the positive inductive bulky alkyl groups on the electron poor
ring. Experiments further suggested that an equilibrium
existed between the hindered alcohol 19 and quinomethide
presence of a carrier material such as activated charcoal. In
earlier studies, it was suggested that Pd(II) catalyzed the
nucleophilic substitution of the substrate while dioxygen
reoxidized Pd(0) to Pd(II). In later studies, a free radical
process was proposed which generates a tolyl radical cation
2
which reacts with Pd(OAc) to give Pd(I)OAc and the
benzylic acetate. Still later studies showed that the existence
of a free radical mechanism is unlikely, since it was shown
that these reactions are catalyzed by heterogeneous pal-
ladium-tin species and that the addition of radical scavengers
to such reactions has no influence on the reaction progress.
Thus, in the case of the oxidation of toluene catalyzed by
palladium-tin in acetic acid and in the presence of KOAc,
the mechanism appears to be a nonradical nucleophilic attack
of an acetate ion on an initially formed palladium-toluene
intermediate to give benzyl acetate and palladium(I) hydride,
the latter being oxidized by molecular oxygen.
In the case of the oxidation of hydroxy-substituted
toluenes, as in our investigations, two important observations
indicate that the mechanism differs significantly from that
observed for toluenes not containing a hydroxy-substituent:
first, m-cresol is not oxidized under the present reaction
conditions, but both p-cresol and, to a lesser extent, o-cresol
are smoothly oxidized; and, second, the detection of signifi-
cant quantities of the coupled dimer 22 suggests that the
reaction proceeds initially through the formation of a
phenoxyl radical, since 22 is most likely the result of the
para-para (C-C) coupling of two such phenoxyl radicals.
We therefore propose that the oxidation of hydroxy-
substituted toluenes, in both aqueous acetic acid and alkaline
methanolic media, rather proceeds through the initial forma-
tion of a phenoxyl radical followed by the subsequent
formation of the corresponding quinomethide (9 and 23), and
it is this quinomethide that serves as the main intermediate
to all the products that were observed in these reactions,
including many of the dimeric species (Scheme 4). This
would serve to explain why m-cresol does not oxidize under
these conditions: it is not possible to construct m-quinonoid
2
3.
Whilst, in acidic media, the benzylic alcohols are readily
oxidized to the corresponding benzaldehydes, the corre-
sponding acetates are oxidized only very slowly, and the
quinomethides, hindered or not, are not oxidized at all. Since
the alcohol and acetate appear to be in equilibrium, oxidation
of the acetate to the aldehyde will always be slow, and this
provides an explanation for the observation that the major
products from the oxidation of 10 and 17 in acidic medium
are the acetates 11 and 18.
As mentioned previously, some dimers (15 and 16) are
formed in aqueous acidic media in the absence of catalyst
and oxygen feed, from the benzyl alcohol or cresol/benzyl
alcohol mixtures. Since experiments suggest that the alcohol
is in equilibrium with the quinomethide (since it too was
detected in the absence of oxygen and catalyst), it is very
N
likely that these dimers are formed either by S reactions
involving these substrates or by means of substrate or
intermediate acetate/alcohol addition to the reactive qui-
nomethides, with rearomatization once again being a driving
force. This explains why the selectivity to dimer 15 increases
so significantly in the presence of higher p-cresol 10
concentrations.
During the oxidation of the hindered cresol 17, the steric
bulk around the hydroxyl moiety ensures a decrease in the
rate of formation of the initial phenoxyl radical but, once
formed, results in a radical that is reasonably stable (due to
the steric bulk of the tertiary-butyl groups and also to their
electron-donating inductive ability and thus stabilization of
the radical). This results in a low instantaneous concentration
of the benzyl acetate 18 and alcohol 19, and so the only
dimer detected during the oxidation reaction is 22 (formed
by para-para coupling of two phenoxyl radicals). The
formation of dimers 24 to 27 requires a high concentration
of either the benzyl acetate or alcohol, as confirmed by the
supplementary experiments discussed previously. Further-
more, due to steric hindrance and, therefore, unlike the
unhindered species, the presence of additional cresolic
substrate does not influence the formation of the last-
mentioned dimers.
2
5
systems using the normal requirements for bonding.
Furthermore, o-cresol does not behave as efficiently as does
p-cresol due to the fact that the o-quinomethide is much less
stable (and is thus higher in energy) than its para analogue.
This difference in stability is known for the quinones in
2
6
general.
For unsubstituted quinomethides (such as 9), rapid nu-
cleophilic addition by acetic acid leads to the formation of
the benzylic acetate 11; if the nucleophile is water, the benzyl
alcohol 12 is formed, or if the nucleophile is methanol, the
benzyl methyl ether 28. Due to the rate of these conversions,
the unhindered quinomethide 9 could not be detected.
(
22) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981.
(
23) March, J. AdVanced Organic Chemistry. Reactions, Mechanisms and
Structure, 4th ed.; John Wiley & Sons: New York, 1992; pp 108-111.
Sheldon, R. A.; Kochi, J. K. AdV. Catal. 1976, 25, 274.
24) Bryant, D.; McKeon, J.; Ream, B. Tetrahedron Lett. 1968, 30, 3371.
25) Beyer, H.; Walter, W. Handbook of Organic Chemistry; Prentice Hall
Europe, United Kingdom, 1996; p 515.
The observation that, in alkaline methanolic medium
without the addition of a catalyst or oxygen, benzyl alcohols
(
(
12 and 19 are readily converted to their corresponding methyl
(26) Wade, L. G. Organic Chemistry, 3rd ed.; Prentice-Hall: New Jersey, 1995;
p 802.
ethers strongly suggests that this conversion occurs Via the
66
•
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Scheme 4. Proposed mechanism for the oxidation of p-cresolsa
a
Note that, for the sake of brevity and where relevant, compounds present in basic methanolic media are shown as neutral phenolics rather than the sodium
phenolates.
quinomethide (see Scheme 4): in general, alcohols are
usually converted to ethers by specific methods such as,
amongst others, the Williamson synthesis in which an
intermediate species (the result of which would have led
to dimer formation). Furthermore, it is envisaged that the
formation of the benzyl methyl ether from the quino-
methide, in this basic methanolic medium, is a rapid reaction,
and so side reactions involving the quinomethide and other
substrate/intermediate species to form dimers are also sup-
pressed.
N
alkoxide anion is reacted with an alkyl halide in an S 1
27
reaction. However, it is obvious that when the alcohols are
substrates such as 12 and 19, the reactive quinomethide
intermediate facilitates their conversion without, for example,
the Williamson requirements.
The suppression of dimer formation in basic medium is
Conclusion
-
probably a result of the nature of the leaving group (CH
3
O )
The results described above for the oxidation of p-cresol
in alkaline methanolic and aqueous acetic acid solutions
strongly suggest that the reaction pathways are similar despite
the differences in catalyst and reaction medium (Scheme 4).
The mechanism proposed envisages the formation of qui-
nomethide as the primary oxidation intermediate, via the
phenoxyl radical. The manner in which this intermediate is
stabilized determines the efficiency of the oxidation process
present in the benzyl methyl ether, which is not as stable as,
for example, the AcO leaving group in acidic medium. (It
is common knowledge that alkoxy groups are not good
leaving groups.) The methyl ethers are therefore less in-
-
clined to undergo S
N
reactions with other substrate/
(
27) March, J. AdVanced Organic Chemistry. Reactions, Mechanisms and
Structure, 4th ed.; John Wiley & Sons: New York, 1992; pp 386-387.
Vol. 9, No. 1, 2005 / Organic Process Research & Development
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67

in terms of selectivity to the corresponding aldehyde.
Stabilization of the quinomethide as the methyl ether, as in
alkaline methanolic solutions, prevents the formation of
dimeric byproducts in view of the poor leaving-group
properties of alkoxy anions. The ether is, however, smoothly
oxidized further to the desired aldehyde which is thus
obtained in reasonable yields. Stabilizing the quinomethane
as the acetate, as in aqueous acetic acid solutions, however,
presents two major problems. First, the acetate, since it is
only slowly oxidized to the aldehyde, needs first to be
hydrolyzed to the corresponding alcohol before further
oxidation can occur to a significant extent. Since the acetate
and the alcohol are always in equilibrium, the rate of
oxidation (of the alcohol) will always be slow. Second, the
acetate anion is a good leaving group, and so undesired
dimeric products are able to form readily.
In Part B, following this paper, and using the knowledge
gained from the work the results of which have been
discussed here, we present a novel practical method for
carrying out the oxidation of p-cresol and other hydroxy-
substituted alkylbenzenes under either alkaline or acidic
conditions. It will be shown that these oxidations may be
carried out safely and efficiently, without the formation of
dimers, in either medium, thus adding credence to proposals
made in this current paper.
reaction. The reaction was continued for 8 h, and aliquots
(1.00 g) were withdrawn every hour and analyzed (HPLC,
as for the reaction in acidic medium).
Stability of Substrates and Intermediates in Aqueous
Acetic Acid Media. The stabilities of 10 or 17 (20 mmol)
and/or 12 or 19 (20 mmol), in the absence of catalyst and
oxygen feed, were determined by stirring these substrates,
and mixtures thereof, in separate aqueous acetic acid media
3
(H
2
O/AcOH ) 1:1, 100 cm ) containing KOAc (1.96 g; 20
mmol), for 30 min at 100 °C, followed by sampling and
analyses (HPLC). Intermediates, products, and byproducts
were identified by means of GC/MS (performed on a
Hewlett-Packard 5890 Series II Plus Gas Chromatograph
coupled to a 5972 Series Mass Selective Detector; data were
manipulated by means of the HP ChemStation software
version B.02.05). In addition, dimer 22 was isolated and
1
13
characterized by means of H NMR, C NMR, and
DEPT-135 techniques.
A. 4-Hydroxybenzyl 4-Methylphenyl Ether (15): m/z
+
+
+
+
2
1
1
14 (M ), 199 (M - 15), 181 (M - 33), 165 (M - 49),
+
+
+
52 (M - 62), 141 (M - 73), 121 (100%, M - 93),
+
07 (M - 107), 94, and 77.
+
B. Bis(4-hydroxyphenyl)methane (16): m/z 200 (M ),
+
+
+
+
1
83 (M - 17), 165 (M - 35), 152 (M - 48), 128 (M
+
Experimental Section
- 72), 107 (100%, M - 93), 94, 77, and 51. This was
confirmed by comparison with an authentic sample (Aldrich
chemical).
General. All standards, reagents, authentic samples, and
solvents were obtained from local suppliers and used without
further purification.
General Oxidation Setup and Procedure. A 250 cm3
jacketed glass reactor, fully baffled, mechanically agitated,
and equipped with a water-cooled condenser, was used for
oxidation reactions. A 4.50 cm diameter, four-bladed stain-
less steel impeller was used for agitation at approximately
C. 3,3′,5,5′-Tetra-tert-butyldipheno-4,4′-quinone (22):
δ
δ
H
(CDCl
(CDCl
3
)/ppm 1.35 (36H, s, CH
3 3
)/ppm 29.57 (CH ), 36.01 (C(CH )
3
) and 7.70 (4H, s, Ar);
C
3
3
), 126.00
(
Ar), 136.12 (Ar), 150.42 (Ar), and 186.46 (CdO);
DEPT-135 indicated the total absence of CH
2
carbons; m/z
+
+
+
+
4
3
08 (M ), 393 (M - 15), 368 (M - 40), 351 (M - 57),
800 rpm. The reaction temperature was kept constant ((0.50
+
+
+
38 (M - 70), 323 (M - 85), 309 (M - 99), 296
°
C) by circulating glycerine through the external heating/
+
+
+
+
(M - 112), 281 (M - 127), 239 (M - 169), 225 (M
cooling jacket of the reactor. Oxygen was supplied to the
reactor from the top using a single glass tube inlet. The end
of the tube was positioned about 1 cm above the impeller
blades.
A. Oxidations in Aqueous Acetic Acid Media: The
reactor setup described above was allowed to equilibrate at
+
-
183), 203 (M - 205), 165, 146, 128, 91, 57 (100%),
and 41.
+
D. 3,5-Di-tert-butyl-4-quinomethide (23): m/z 218 (M ),
+
+
+
203 (M - 15), 189 (M - 29), 175 (M - 43), 161 (100%,
+
+
+
+
M - 57), 147 (M - 71), 128 (M - 90), 115 (M -
103), 105, 91, 77, 57, and 41.
1
00 °C for 1 h, after which the substrate (20 mmol), KOAc
3
(1.97 g; 20 mmol), AcOH/H
2
O (1:1, 100 cm ), and 5% Pd/C
E. 1,2-Di(3′,5′-di-tert-butyl-4′-hydroxyphenyl)ethane
(0.53 g) were introduced. The mixture was allowed to stand
+
+
+
+
(
-
-
24): 438 (M ), 423 (M - 15), 355 (M - 83), 341 (M
at 100 °C for 20 min after which the reaction was initiated
+
+
+
97), 281 (M - 157), 267 (M - 171), 219 (100%, M
219), 204, 189, 178, 161, 145, 133, 119, 105, 91, 79, and
3
-1
by means of the introduction of oxygen (40 cm min ). The
reaction was monitored at intervals of 2 h, for a total reaction
5
7.
3
time of 8 h, by analyzing aliquots (1.00 cm ) of the reaction
F. Bis(3,5-di-tert-butyl-4-hydroxyphenyl)methane (25):
mixture by HPLC (using a C18 column and CH
3 2
CN/H O at
+
+
+
m/z 424 (M ), 409 (100%, M - 15), 393 (M - 31), 381
pH 3 (H PO ) as mobile phase).
3
4
+
+
+
+
(
8
2
M - 43), 367 (M - 57), 351 (M - 73), 337 (M -
B. Oxidations in Alkaline Methanolic Media: The same
reactor setup described above was allowed to equilibrate at
+
+
+
7), 281 (M - 143), 267 (M - 157), 251 (M - 173),
+
+
33 (M - 191), 219 (M - 205), 207, 197, 183, 169, 147,
6
0 °C for 1 h after which p-cresol (21.6 g; 200 mmol), solid
3
129, 115, 103, 91, 77, and 57.
NaOH (24.0 g; 600 mmol), CH
O (0.42 g) were introduced. The mixture was left to
stabilize at this temperature for a further 20 min, and then
3 2
OH (100 cm ), and CoCl ‚
G. 1,2-Di(3′,5′-di-tert-butyl-4′-hydroxyphenyl)ethene
6H
2
+
+
+
(26): m/z 436 (100%, M ), 421 (M - 15), 281 (M - 155),
3
-1
+
+
+
the oxygen was introduced (40 cm min ) to initiate the
267 (M - 169), 253 (M - 183), 231 (M - 205), 219
68
•
Vol. 9, No. 1, 2005 / Organic Process Research & Development

(
M+ - 217), 207, 191, 175, 159, 147, 133, 115, 96, 73,
and 57.
H. 2,2′,6,6′-Di-tert-butylstilbenequinone (27): m/z 434
Acknowledgment
We thank the National Research Foundation, the Port
Elizabeth Technikon, and Dow AgroSciences for their
continued support, financial and otherwise.
+
+
+
+
(
5
100%, M ), 419 (M - 15), 404 (M - 30), 378 (M -
+
+
+
6), 364 (M - 70), 349 (M - 85), 333 (M - 101), 321
+
+
+
+
(M - 113), 307 (M - 127), 293 (M - 141), 281 (M
+
+
+
-
2
1
153), 267 (M - 167), 247 (M - 187), 231 (M -
Received for review August 12, 2004.
OP049845B
+
03), 219 (M - 215), 207, 191, 173, 159, 145, 133, 115,
03, 91, 77, and 57.
Vol. 9, No. 1, 2005 / Organic Process Research & Development
•
69