Mechanism of action of base-catalyzed oxygenation of phenol derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.09.029

Cyclopropyl derivative of 2,6-di-tert-butylphenol is synthesized as a probe to investigate the mechanism of base-catalyzed autooxidation of phenol derivatives. Our study indicates that one electron reduction of molecular oxygen from phenolate gives phenoxyl radical 3, a key intermediate of autooxidation. The coupling of phenoxyl radical and superoxide radical gives peroxylate anion 4 and produces the final epoxy alcohol adduct 6.

Full text of DOI:10.1016/j.tetlet.2005.09.029

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7721–7723
Mechanism of action of base-catalyzed oxygenation
of phenol derivatives
Duck-Hyung Lee,a Jung Beom Son,a Seokwon Jung,b Jihey Songb and
Seung Wook Hamb,*
aChemistry Department, Sogang University, Seoul 121-742, Republic of Korea
bDepartment of Chemistry, Chung-Ang University, Seoul 156-756, Republic of Korea
Received 8 August 2005; revised 5 September 2005; accepted 7 September 2005
Available online 21 September 2005
Abstract—Cyclopropyl derivative of 2,6-di-tert-butylphenol is synthesized as a probe to investigate the mechanism of base-catalyzed
autooxidation of phenol derivatives. Our study indicates that one electron reduction of molecular oxygen from phenolate gives phen-
oxyl radical 3, a key intermediate of autooxidation. The coupling of phenoxyl radical and superoxide radical gives peroxylate anion
4 and produces the final epoxy alcohol adduct 6.
Ó 2005 Published by Elsevier Ltd.
The base-catalyzed oxygenation of phenol or naphthol
derivatives has been of interest in both biological and
synthetic system.1–8 In general, when phenoxide or naph-
thoxide anions are exposed to molecular oxygen, the
corresponding epoxy alcohols are formed in nearly quan-
titative yield. Possible reaction pathway for the oxidation
process is proposed as shown in path 1 (Scheme 1).7,8
Molecular oxygen directly reacts with phenoxide anion
1. The resulting peroxide 4 then undergoes intra-
molecular conjugate addition to form the dioxetane
enolate anion 5. Finally, dioxetane ring opening by
nucleophilic displacement yields the epoxy-p-quinol 6.
From the mechanism proposed in path 1 (Scheme 1), the
reaction of molecular oxygen and phenolate anion 2 to
form peroxide 4 has been considered as a key step.
-
O
O
O
O
O
t-Bu
t-Bu t-Bu
t-Bu
t-Bu
Path 1
t-Bu
-
-
t-Bu
t-Bu t-Bu
t-Bu
O2
O
O
-
R
R
OH
R
O O
O
R
R
1
2
4
5
6
Path 2
O
O2
rebound
t-Bu
t-Bu
-
.
+
O2
.
R
3
Scheme 1.
Keywords: Autooxidation; Phenolate; Mechanism; Radical.
*
Corresponding author. Tel.: +82 2 820 5203; fax: +82 2 825 4736; e-mail: swham@cau.ac.kr
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.09.029

7722
D.-H. Lee et al. / Tetrahedron Letters 46 (2005) 7721–7723
However, this reaction might be unfavorable because
the spin-forbidden rule states that the singlet phenolate
anion 2 will not react in a single step with triplet molec-
ular oxygen to yield the singlet product 4.9 To address
this mechanistic issue, we propose here an alternative
pathway (Scheme 1, path 2). We suggest that the pheno-
late anion 2 reacts with molecular oxygen to give the
phenoxy radical 3 and superoxide by electron transfer.
The phenoxyl radical 3 then traps superoxide to yield
the peroxylate anion 4, which is converted to the epoxy
alcohol adduct 6.
lated intermediates were characterized by 1H NMR
analysis.
With a probe molecule 9 in hands, we next conducted
the mechanistic study of the oxygenation of phenol
derivative (Scheme 3). A THF solution of potassium
phenoxide 10 generated from the reaction of potassium
hydride and cyclopropanyl phenol 9, was slowly treated
with 2 equiv of molecular oxygen by a gas tight-syringe
and the reaction mixture was stirred at room tempera-
ture for 30 min. After protonation with saturated
ammonium chloride solution, the corresponding ring-
opening product 13 was obtained as the only product.
To prove our hypothesis, we have synthesized cyclopro-
pyl derivative 9 of 2,6-di-tert-butylphenol as a probe.
This molecule can be used to distinguish the phenolate
anion 2 from the phenoxyl radical 3 because the ring-
opening reaction of cyclopropylcarbinyl radical has
a rate constant of ꢀ1011 sÀ1, which has been shown
to be an effective trap for short-lived radicals.10,11 As
shown in Scheme 2, chalcone derivative obtained from
aldol condensation of 3,5-di-tert-butyl-4-hydroxyaceto-
phenone and benzaldehyde in the presence of H2SO4
was refluxed with hydrazine in ethanol to yield pyrazo-
line derivative 8.12 This compound was then reacted
with sodium hydroxide without solvent and the mixture
was heated at 180 °C for 30 min under a nitrogen atmo-
sphere. The crude product was purified by column chro-
matography to give cyclopropane derivative 9. We
found compound 9 underwent slow oxygenation at
room temperature, even in the solid state. All of the iso-
1
This was easily identified by H NMR spectrum from
the crude product and no other product was observed
1
by a 500 MHz H NMR analysis. Purification by the
crude product by flash chromatography afforded the
stable hydroperoxide 13 in 89% yield. Although authen-
tic sample of 13 was not able to be prepared for identi-
fication, all spectral data of 13 are in good agreement
with the expected product.13 Moreover, reduction of
the hydroperoxide 13 with sodium thiosulfate provided
the hydroxyl compound 14, which showed clearly the
different spectral characteristics.
Throughout the mechanism study, we believe that elec-
tron transfer in the first step (Scheme 1, path 2) is reason-
able because there is a reported example that reduction
of molecular oxygen by the phenolate anion of a vitamin
E model produced superoxide anion which has been
OH
OH
OH
t-Bu
t-Bu
i) Benzaldehyde, H+
t-Bu
t-Bu
NaOH, 180oC
t-Bu
t-Bu
ii) Hydrazine
O
N
Ph
HN
Ph
7
8
9
Scheme 2.
-
O
O
O
t-Bu
t-Bu
O2
t-Bu
t-Bu
OH
t-Bu
t-Bu
Na2S2O3
THF
OOH
Ph
Ph
14
10
13
Ph
O
O
t-Bu
t-Bu
t-Bu
t-Bu
.
.
Ph
Ph
11
12
Scheme 3.

D.-H. Lee et al. / Tetrahedron Letters 46 (2005) 7721–7723
7723
O
O
t-Bu
t-Bu
t-Bu
t-Bu
-
-
.
O2
.
3
O
R
O O
R
t-Bu
t-Bu
4
O
-
.
O2
O2
R
OH
6
O
O
t-Bu
t-Bu
t-Bu
t-Bu
.
R
O O
R
O OH
15
16
Scheme 4.
directly detected by a low-temperature EPR measure-
ment.14 In the second step (Scheme 1, path 2), the reac-
tion between radical 3 and superoxide is also plausible
since it has been reported that peroxide anion was
obtained from the reaction of thianthrene cation radical
and superoxide ion.15 However, one may also argue
another product, peroxylate radical 15, from the addi-
tion of oxygen to phenoxyl radical 3, forming the corre-
sponding hydroperoxide 16 by abstraction of hydrogen
in an environment (Scheme 4). If the resulting superoxide
anion can serve a base, compound 16 will rearrange to
epoxy alcohol 6. Although the pKa for HO2, conjugate
acid of superoxide, in water is 4.88,16 which implies
that superoxide is a weak base, a number of weakly
acidic organic compounds are deprotonated efficiently
in the presence of superoxide ion.17 However, when reac-
tion of 4-acetyl-2,6-di-tert-butyl-6-hydroperoxy-2,4-
cyclohexadione18 with potassium superoxide was carried
out in THF, no epoxy alcohol was detected and the start-
ing material was recovered. Moreover, the base-cata-
lyzed oxidation of 4-alkyl-2,6-di-tert-butylphenol with
molecular oxygen in protic solvents (methanol, ethanol,
or 2-propanol) gave rise to the para-hydroperoxide 16
in nearly quantitative yield, while oxygenation of pheno-
late in aprotic solvents such as DMF, DMSO, HMPT
containing t-BuOK yielded the corresponding epoxy
hydroxyl adduct 6.18 These results clearly indicated the
presence of peroxide anion intermediate 4.
References and notes
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4.1 Hz), 4.98 (br t, 1H, J = 7 Hz), 6.08 (d, 1H, J = 3 Hz),
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Previously, it has been proposed that superoxide ion
does not couple with 2,6-di-tert-butylphenoxy radicals
but reduces radicals to give the corresponding pheno-
lates, and mechanism involving for the base-catalyzed
oxygenation of 2,6-di-tert-butylphenols is an ionic pro-
cess.19 Another mechanism proposed based on the con-
sideration of spin forbidden rule was that the peroxylate
anion occurred through the direct combination of phe-
nolate and singlet oxygen produced by charge transfer
and intersystem crossing.14 However, our evidence pre-
sented here provides the novel mechanism for base-cat-
alyzed oxygenation of phenol derivatives, involving one
electron reduction of molecular oxygen from phenolate
to give phenoxyl radical. This is the key intermediate
for autooxidation and coupling of phenoxy radical
and superoxide radical anion to give peroxylate anion
and then lead the final epoxy alcohol adduct.
15. Ando, W.; Kabe, Y.; Kobayashi, S.; Takyu, C.; Yamag-
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