A mechanistic approach to the reaction of 2,6-di-tert-butylphenol with an iodinating agent in methanol: Electrophilically assisted solvolysis of intermediary 4-iodocyclohexa-2,5-dienones

Article abstract of DOI:10.1021/jo951455n

Reactions of the title phenol (1) and of 4-iodophenol 2 with an iodinating agent, I₂ and H₂O₂, are conducted in MeOH for varying times with varying amounts of I₂, and the results are compared. The reaction of 1 gives 2, 4,4′-biphenol 3, 4,4′- diphenoquinone 4, 4-methoxyphenol 5, and p-benzoquinone 6, exclusively. The yields of the phenolic products (2, 3, and 5) vary with reaction time, but they disappear or almost disappear eventually, to make 4 and 6 the almost exclusive products. The reaction of 2 always gives 4 and 6 alone. In both of the reactions of 1 and of 2, employment of a higher initial I₂ concentration not only completes the formation of 4 and 6 faster but also makes the final proportion of 6 higher. However, the ultimate yield of 6 from the reaction of 1 is significantly higher than that from the reaction of 2, irrespective of the initial I₂ concentration. These results are interpreted as follows. 4-Iodocyclohexa-2,5-dienone 12, the primary product of electrophilic iodination of 1, undergoes solvolysis (methanolysis), which is electrophilically assisted by I₂. The solvolysis of 12 can be so fast as to overwhelm its prototropic rearrangement to give 2. 4-Methoxycyclohexa-2,5-dienone 13, which is the primary product of the methanolysis of 12 and is suggested to be detectable by ¹H NMR spectroscopy, is converted into 6 via 5. Benzoquinone 6 can also arise from 4,4-diiodocyclohexa-2,5-dienone 7, the product of iodination of 2, by an analogous mechanism. The selectivity of the formation of 6 from 7 is low because the competing reaction, homolytic scission of the C-I bond in 7, predominates. The mechanism of the formation of 3 and 4 is also discussed.

Full text of DOI:10.1021/jo951455n

2006
J . Org. Chem. 1996, 61, 2006-2012
A Mech a n istic Ap p r oa ch to th e Rea ction of 2,6-Di-ter t-bu tylp h en ol
w ith a n Iod in a tin g Agen t in Meth a n ol: Electr op h ilica lly Assisted
Solvolysis of In ter m ed ia r y 4-Iod ocycloh exa -2,5-d ien on es
Kanji Omura
College of Nutrition, Koshien University, Momijigaoka, Takarazuka, Hyogo 665, J apan
Received August 7, 1995X
Reactions of the title phenol (1) and of 4-iodophenol 2 with an iodinating agent, I2 and H2O2, are
conducted in MeOH for varying times with varying amounts of I2, and the results are compared.
The reaction of 1 gives 2, 4,4′-biphenol 3, 4,4′-diphenoquinone 4, 4-methoxyphenol 5, and
p-benzoquinone 6, exclusively. The yields of the phenolic products (2, 3, and 5) vary with reaction
time, but they disappear or almost disappear eventually, to make 4 and 6 the almost exclusive
products. The reaction of 2 always gives 4 and 6 alone. In both of the reactions of 1 and of 2,
employment of a higher initial I2 concentration not only completes the formation of 4 and 6 faster
but also makes the final proportion of 6 higher. However, the ultimate yield of 6 from the reaction
of 1 is significantly higher than that from the reaction of 2, irrespective of the initial I2 concentration.
These results are interpreted as follows. 4-Iodocyclohexa-2,5-dienone 12, the primary product of
electrophilic iodination of 1, undergoes solvolysis (methanolysis), which is electrophilically assisted
by I2. The solvolysis of 12 can be so fast as to overwhelm its prototropic rearrangement to give 2.
4-Methoxycyclohexa-2,5-dienone 13, which is the primary product of the methanolysis of 12 and is
suggested to be detectable by 1H NMR spectroscopy, is converted into 6 via 5. Benzoquinone 6 can
also arise from 4,4-diiodocyclohexa-2,5-dienone 7, the product of iodination of 2, by an analogous
mechanism. The selectivity of the formation of 6 from 7 is low because the competing reaction,
homolytic scission of the C-I bond in 7, predominates. The mechanism of the formation of 3 and
4 is also discussed.
Molecular halogen (or hydrogen halide) and H2O2 in
studying the reaction of 2,6-di-tert-butylphenol (1) with
this mildly iodinating agent under mild conditions. The
reaction proved to be complex in spite of the limited
number of the ultimate products. However, close study
led to the finding of a new mechanism for the benzo-
quinone formation. The mechanism involves I2-assisted
solvolysis of intermediary 4-iodocyclohexa-2,5-dienones.
This paper deals with the details of such a study.
the presence or absence of an acid catalyst is one of the
halogenating agents for phenols.1,2 It also serves as a
reagent for preparation from phenols of benzoquinones
or halogenated benzoquinones such as chloranil or
bromanil.3-5 These benzoquinones have been shown to
be formed by way of halogenated phenols. The active
halogenating or oxidating species is molecular halogen,
and H2O2 serves to generate or regenerate molecular
halogen rapidly from hydrogen halide:
Resu lts a n d Discu ssion
The reaction of 1 was conducted for varying times with
varying amounts of I2 (0.5-2 molar equiv) in MeOH
2HX + H2O2 f X2 + 2H2O (X ) Cl, Br, I)
6
containing 36% H2O2 (excess; 18 molar equiv) (hence-
2,6-Disubstituted benzoquinones can thus be prepared
by exposing 2,6-disubstituted phenols to Br2 (or HBr) and
H2O2 in refluxing MeOH containing an acid catalyst.5 The
quinones have been suggested to arise via 4,4-dibromo-
cyclohexa-2,5-dienones, the products of perbromination
of the phenols:
forth I2/H2O2/MeOH) at 35 °C in the absence of an added
acid catalyst. The product mixture obtained after the
reaction was interrupted by quenching of the residual I2
and H2O2 with aqueous NaHSO3 was subjected to column
chromatography for analysis. The product consisted
exclusively of five compounds. They were 4-iodo-2,6-di-
tert-butylphenol (2), 3,5,3′,5′-tetra-tert-butyl-4,4′-dihy-
droxybiphenyl (3), 3,5,3′,5′-tetra-tert-butyl-4,4′-dipheno-
quinone (4), 4-methoxy-2,6-di-tert-butylphenol (5), and
2,6-di-tert-butyl-p-benzoquinone (6), and their yields are
summarized in Table 1 (runs 1-13). The product com-
position varied with varying reaction time and with
varying the initial concentration of I2. Quinoid products
4 and 6 increased with time until they were the almost
exclusive products. In contrast, phenolic products 2, 3,
and 5 disappeared or almost disappeared eventually. The
higher initial concentration of I2 not only completed the
formation of 4 and 6 faster but also made the final
proportion of 6 higher. The ultimate yield of 6 varied
The reaction of 2,6-disubstituted phenols with I2 and
H2O2 in MeOH may proceed similarly. The method
employing I2 and H2O2 did not seem attractive for
synthesizing the quinones since the selectivity is quite
poor. In an attempt to improve the method, we began
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) Marsh, J . E. J . Chem. Soc. 1927, 3164.
(2) J urd, L. J . Am. Chem. Soc. 1955, 77, 5747.
(3) Cressman, H. W. J .; Thirtle, J . R. J . Org. Chem. 1966, 31, 1279.
(4) Lu¨bbecke, H.; Boldt, P. Tetrahedron 1978, 34, 1557.
(5) Minisci, F.; Citterio, A.; Vismara, E.; Fontana, F.; De Bernar-
dinis, S. J . Org. Chem. 1989, 54, 728.
(6) The concentration of H2O2 in a commercially available 30% H2O2
(from Wako Chemicals) was determined by iodometric titration to be
in fact 36%.
0022-3263/96/1961-2006$12.00/0 © 1996 American Chemical Society

Solvolysis of Intermediary 4-Iodocyclohexa-2,5-dienones
J . Org. Chem., Vol. 61, No. 6, 1996 2007
Ta ble 1. Rea ction of P h en ol 1 w ith I2 a n d H2O2 in
MeOHa
Ta ble 2. Rea ction of P h en ol 2 or 10 w ith I2 a n d H2O2 in
MeOHa
product (%)
product (%)
I2
time recovery
(5 +
6)/2
I2
time recovery of
run (equiv) (min) of 1 (%)
2
3
4
5
6
run phenol (equiv) (min) 2 or 10 (%)
4
6
11a
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
15b
16c
17c
18c
19d
20d
21d
0.5
0.5
0.5
0.5
0.5
1
1
1
1
2
2
2
2
2
2
2
2
2
15
50
120
240
540
6
15
50
150
2
76
43
12
0
6.6 2.4
2.9 5.7 3.6 1.4
1
2
3
4
5
6
7
8
2
2
2
2
2
2
10
10
0.5
0.5
1
1
2
2
2
2
50
240
50
150
15
50
15
50
68
0
36
0
48
2
51
9
30
90
57
87
42
79
trace
trace
1.6
9.0
6.4
12
10
19
20
2.4
3.4
1.5
1.0
11
20
39
60
5.2 16
2.3 30
1.1
1.0
31
22
0
0
0
35
37
0
73
53
5
5.3 1.7
9.0 1.5
2.9 9.1 5.7 2.8
8.1 8.1 18
20 2.0 49
42 54
7.0 6.7
2.9
3.6
8.0
42
80
20
1.0
1.0
0
2.6
0
0
a
The reactions were conducted with 2 (2 mmol) or 10 (2 mmol)
69
50
10
0
66
47
41
5
3.3 1.5
5.1 1.7
9.8 0.5
2.5 15
6.0 13
and 36% H2O2 (3 mL) in MeOH (30 mL) at 35 °C.
5
20
6.5
6.4
15
50
7
15
5
15
50
30
90
360
15
7.4 55
71
4.7 8.9 9.3 2.6
Sch em e 1
0
trace 27
0
6.9 2.0
11
5.9 1.5
10
2.7
9.6 6.1 21
4.2 12 32
9.8 4.4 71
1.0 trace 14 83
7.8 7.2
2.5
7.5
7.5
0.4
0
0
2
2
2
72
49
0
2.9 1.5
4.8 1.2
0.9 13
6.1 10
8.1 1.8 76
25
7.3
7.1
11
0.2
a
Unless stated otherwise, the reactions were conducted using
1 (2 mmol) and 36% H2O2 (3 mL; 36 mmol) in MeOH (30 mL) at
b
35 °C. Conducted in a solvent mixture of MeOH (60 mL) and
H2O (3 mL). c Conducted in the presence of H2SO4 (ca. 1.8 mmol).
d
Conducted at 0 °C.
H2O2/MeOH provided bis(chlorocyclohexadienone) 11a in
high yield along with a small amount of 6 (Table 2, run
8). It is reasonable that 4 and 6 were found among the
products from the reaction of 1, since 2 was also among
them (Scheme 1). However, it is evident that the path
involving 2 and 7 as the intermediates does not suffice
to account for the formation of all of 6 from the reaction
of 1, since, as described above, the ultimate yield of 6
from this reaction always surpassed that from the
reaction of 2.
within a range of 37-71% while that of 4 ranged from
60% to 27%. Phenol 2 was similarly allowed to react with
I2/H2O2/MeOH (Table 2, runs 1-6). Regardless of the
extent to which the reaction of 2 progressed, 4 and 6 were
the sole products. The ultimate yield of 6 from the
reaction of 2 also increased with an increase in the initial
concentration of I2, although it was always lower than
that from the reaction of 1 and varied within a relatively
narrow range (9-19%). In the absence of H2O2, the
reaction of 1 or 2 with I2 in MeOH containing H2O7
(henceforth I2/H2O/MeOH) also provided the same five
or two products, respectively. The consumption of 1 or
2, however, was reasonably fast only at the early stage
and became significantly slow thereafter.
The obtention of 5 from the earlier stages of the
reaction of 1 provided a clue to finding an additional path
for 6. The lack of 5 in the products from the latter stages
appeared to indicate that 5 was oxidized to 6 under the
reaction conditions. Quantitative oxidation of 5 into 6
with I2/H2O2/MeOH was verified experimentally. Phenol
5 may be formed by solvolysis (methanolysis) of 4-iodocy-
clohexa-2,5-dienone 12, the precursor of 2, and subse-
The formation of 4 and 6 from the reaction of 2 may
be accounted for by paths involving 4,4-diiodocyclohexa-
2,5-dienone 7 as a common intermediate: homolytic
scission of the C-I bond in 7 may lead to the formation
of 4 via radical 8 and bis(iodocyclohexadienone) 9.8 The
reaction of 4-chloro-2,6-di-tert-butylphenol (10) with I2/
(7) The mixture was employed to simulate the solvent system in
the reactions with I2/H2O2/MeOH. The reaction of 1 or 2 with I2 in
MeOH not containing added H2O proceeded similarly, but it was slower
than that in H2O/MeOH.
(8) Ley, K.; Mu¨ller, E.; Mayer, R.; Scheffler, K. Chem. Ber. 1958,
91, 2670.

2008 J . Org. Chem., Vol. 61, No. 6, 1996
Omura
Sch em e 2
of 1 with I2/H2O2/MeOH, described above. They also
disappeared from the spectrum upon addition of pyridine-
d5. The conversion of 7 into 6 may similarly involve a
solvolytic process.
Of particular interest to us was the dependence of the
yield of 6 from the exhaustive reaction of 1 or 2 with I2/
H2O2/MeOH, on the initial concentration of I2. This
seemed to be best accounted for by assuming involvement
of I2 in the solvolytic process of iodocyclohexadienones
12 or 7 and assuming competition between the solvolysis
and the prototropic rearrangement of 12 (to give 2) or
the homolytic scission of the C-I bond in 7 (to give 4
eventually) (cf. Scheme 1 and Scheme 2). To test the
hypothesis, the reactions of the bromoanalogs of 12 and
7 with I2/H2O/MeOH were investigated. They were 14
and 4,4-dibromo-2,6-di-tert-butylcyclohexa-2,5-dienone (15),
which can be prepared by brominating 113,14 or 4-bromo-
2,6-di-tert-butylphenol (16)15 with Br2. Dienone 14 has
quent prototropic rearrangement (Scheme 2).9 Indication
of the formation of intermediary 4-methoxycyclohexa-2,5-
dienone 13, the primary product of methanolysis of 12,
1
was obtained from a H NMR study. Thus, the spectrum
(in CDCl3) of the crude product obtained from the reaction
of 1 with I2/H2O2/MeOH, conducted at 0 °C and inter-
rupted at the relatively early stage, included new, distinct
signals. They appeared as a singlet at δ 3.40 and a triplet
(J ) 3.1 Hz) at δ 4.42 with relative intensities of ca. 3:1.
Upon addition of pyridine-d5, these signals disappeared
from the spectrum, and a singlet at δ 3.76 attributable
to the methoxy group in 5 was remarkably intensified.
Column chromatography of the crude product on SiO2
gave only the five products described above, and their
yields suggested that most of the products were ac-
counted for: no new substance was obtained (Table 1,
run 19). It has been known that 4-hydro-4-substituted-
cyclohexa-2,5-dienones, which are rarely isolable, are
readily and irreversibly rearranged prototropically to give
4-substituted-phenols by catalysis with base or acid
including SiO2.10,11 It is, therefore, reasonable to presume
that the crude product contained 13; the signals at δ 3.40
and 4.42 are attributable to the methoxy group and the
hydrogen, bound to C-4, respectively. The crude product
was estimated from the spectrum to contain 5 and 13 in
approximate yields of 3% and 11% (or 35% based on
reacted 1), respectively. No indication was obtained from
the spectrum of the crude product that it contained
dienone 12. Labile new dienone 13 was found to be
producible in much higher yield from the Ag ion assisted
displacement reaction of 4-bromo-2,6-di-tert-butylcyclo-
been shown to be easily isomerized to 16 in polar solvents
such as EtOH16 and a mixture of AcOH and H2O13b as
well as by catalysis with acid or base.11,16 The dienone-
phenol isomerization of 14 in MeOH containing H2O
(henceforth H2O/MeOH) at 35 °C also was found to be
remarkably rapid; it was complete within 5 min. Expos-
ing 14 to I2 (2 molar equiv) /H2O/MeOH for 5 min at 35
°C provided 5 (6%) and 6 (18%) together with 16 (62%).
Compound 5 was convertible into 6 with I2/H2O/MeOH.
Compounds 5 and 6 from the reaction of 14 were not
formed via phenol 16, because a similar treatment of 16
with I2/H2O/MeOH provided no 5 and a trace of 6; a large
part (76%) of 16 was recovered unchanged, the major
products being 4 (16%) and bis(bromocyclohexadienone)
11b (8%). Therefore, 14 can undergo displacement with
MeOH when assisted by I2, and the displacement can
compete with its prototropic rearrangement. Dienone 15
was poorly soluble in H2O/MeOH. Treatment of 15 with
H2O/MeOH at 35 °C for 10 min and subsequent filtration
recovered most of 15. The filtrate contained only 1% of
6 as well as an additional amount of 15 (91% recovery in
total). In the presence of I2 (2 molar equiv), in contrast,
15 completely dissolved in H2O/MeOH within 10 min.
After workup, 6 was obtained in 49% yield while no 15
was recovered. The second major product was 16 (25%).
The reaction of 15 with Br2 (in place of I2) /H2O/MeOH
also provided 6 (66%) although some of 15 (23%) was
recovered intact. Therefore, 15 is assumed to be solvo-
lyzed similarly by the assistance of I2 or Br2. Spontane-
ous solvolysis of 15 has been proposed, since refluxing a
solution of 15 in MeOH containing H2O and H2SO4 (in
the absence of added I2 or Br2) provides a significant
1
hexa-2,5-dienone (14) with MeOH. The H NMR spec-
trum of 13 obtained from the reaction of 14 exhibited, in
addition to the signals shown above, a doublet (J ) 3.1
Hz) at δ 6.69 (vinylic hydrogens) and a singlet at δ 1.24
(tert-butyl groups).12 These signals were also observable
in the spectrum of the crude product from the reaction
(9) The substitution reaction of 12 with the other, minor nucleo-
philes, H2O and H2O2, can also be considered (not shown in Scheme
2). 2,6-Di-tert-butylhydroquinone, the product expected from the
hydrolysis of 12, was found in none of the reactions of 1 with I2/H2O2/
MeOH or I2/H2O/MeOH. The hydroquinone is presumed to have been
readily oxidized to 6 under the reaction conditions. The product from
the reaction between 12 and H2O2 is assumed to have also disinte-
grated into 6.
(10) (a) Omura, K. J . Org. Chem. 1991, 56, 921. (b) Omura, K. J .
Org. Chem. 1992, 57, 306.
(11) (a) de la Mare, P. B. D.; Singh, A.; Tillett, J . G.; Zeltner, M. J .
Chem Soc. B 1971, 1122. (b) de la Mare, P. B. D.; Singh, A. J . Chem.
Soc., Perkin Trans. 2 1972, 1801. (c) de la Mare, P. B. D.; Singh, A. J .
Chem. Soc., Perkin Trans. 2 1973, 59. (d) de la Mare, P. B. D. Acc.
Chem. Res. 1974, 7, 361.
(12) Attempted purification of the crude product of 13 obtained from
the reaction of 14 has proved unsuccessful. The crude products of some
other 4-hydro-4-alkoxy-2,6-di-tert-butylcyclohexa-2,5-dienones obtained
by analogous means, however, have been successfully purified, and
their structures have been unambiguously established. The results will
be published elsewhere.
(13) (a) Volod’kin, A. A.; Ershov, V. V. Izv. Akad. Nauk SSSR, Otd.
Khim. Nauk 1962, 2022. (b) Fyfe, C. A.; Van Veen, L., J r. J . Am. Chem.
Soc. 1977, 99, 3366.
(14) Rieker, A.; Rundel, W.; Kessler, H. Z. Naturforsch. 1969, 24b,
547.
(15) Volod’kin, A. A.; Ershov, V. V. Izv. Akad. Nauk SSSR, Otd.
Khim. Nauk 1963, 152.
(16) Ershov, V. V.; Volod’kin, A. A. Izv. Akad. Nauk SSSR, Otd.
Khim. Nauk 1962, 730.

Solvolysis of Intermediary 4-Iodocyclohexa-2,5-dienones
J . Org. Chem., Vol. 61, No. 6, 1996 2009
quantity of 6.5,17 It is, however, unlikely that all of 6 is
produced through the unassisted solvolysis, because Br2
is expected to be generated during the course of the
reaction, from the reaction of 15 with HBr (see below),
which should be generated when 15 is solvolyzed spon-
taneously but slowly.
Sch em e 3
It is proposed that I2 (or Br2) undergoes electrophilic
attack on the halogen atom of 4-halocyclohexa-2,5-
dienones 7, 12, 14, or 15 generating the 4-oxocyclohexa-
2,5-dienyl cations (or the phenoxy cations), which are
readily attacked by MeOH. The reaction is formulated,
for example, as follows.
concluded not only that the decay of 2 or 10 is retarded
by the presence of 1 but also that the decay of 1 is
facilitated by the presence of 2 or 10.
The electrophilic dehalogenation by I2 of the halocy-
clohexadienones contrasts sharply with the nucleophilic
dehalogenation by halide ion of 4-halocyclohexa-2,5-
dienones. This reductive dehalogenation by halide ion
has been established as the reverse of the primary
reaction in the phenol halogenation reaction. Hydrode-
bromination of 14 with HI to give 1 was confirmed to be
remarkably fast. The reaction of 12 or 7 with HI may
be as facile. The reductive deiodination of 12 or 7 with
Table 1 shows that the yield of 2 from the reaction of
1 with I2/H2O2/MeOH increases steadily and begins to
fall only after most or all of 1 is consumed. This perhaps
reflects the suggested “stability” of 2 in the presence of
1. The mechanism of the “stabilization” of 2 by 1 may
be as follows (Scheme 3; cf. also Scheme 1). Phenol 2 is
iodinated by I2/H2O2/MeOH, but the product (7) can
revert to 2 if 1 is coexistent. The reversion is the result
of hydrogen donation by 1 to phenoxy radical 8, which is
generated by the dissociation of 7 and from which 4 can
be derived via 9. The dissociation of 7 may be reversible.
The hydrogenation of 8 with 1 will help displace the
equiliblium between 7 and the dissociation products (8
and atomic iodine) in favor of the products and will thus
make the selectivity of the formation of 6 from 7 even
poorer. In the presence of a sufficient quantity of 1,
therefore, 7 mostly reverts to 2 via 8 whereas the
formation of 4 (via 9) and 6 from 7 is negligible. Phenoxy
radical 17 generated from 1 after the dehydrogenation
by 8 dimerizes affording bis(cyclohexadienone) 18.18 This
rationalizes the obtention of 3, the product of prototropic
rearrangement of 18, albeit in generally low yield from
the reaction of 1 with I2/H2O2/MeOH. The low yield may
be inevitable since 3 is expected to be subjected to
oxidation under the reaction conditions, and this is
another path for the formation of 4. The path accounts
for the steady and significant increase in the yield of 4
even at the early stage of the reaction of 1 with I2/H2O2/
MeOH (see Table 1) where product 2 is “stable” and the
formation of 4 by the dimerization of 8 is negiligible.
Quinones 4 and 6 can be concluded to be formed from
the reaction of 1 mainly by the paths shown in Scheme
3 and Scheme 2, respectively, at the earlier stage where
1 amply resides and principally by the paths shown in
Scheme 1 at the latter stage where 1 barely resides.
HI rationalizes the aforementioned slowdown with time
of the reaction of 1 or 2 with I2/H2O/MeOH, respectively.
As shown in Table 2, the decay of 2 or 10 proceeds
reasonably fast after treatment with I2/H2O2/MeOH. As
illustrated below, the decay of 2 or 10 was found to be
markedly retarded if 1 is coexistent in an appropriate
quantity. This fact proved to be related to the mecha-
nism of the formation of 4,4′-biphenol 3, from which 4 is
also assumed to be derived, as the minor product from
the reaction of 1 with I2/H2O2/MeOH. An equimolar
mixture of 1 and 2 was exposed to I2 (2 equiv per equiv
of 1 or 2)/H2O2/MeOH, and the consumptions of 1 and 2
were compared. The exposure for 15 min at 35 °C
consumed most of 1 (95%) but recovered most of 2 (98%),
although a small amount of 2 produced from the reaction
of 1 must have been included in the total recovery of 2.
If 1 was omitted in this experiment, only 48% of 2 was
found to be recovered (Table 2, run 5). If 2 was omitted,
on the other hand, 90% of 1 was found to be consumed
(Table 1, run 12). The exposure for 30 min of the 1:1
mixture of 1 and 2 made the cosumption of 1 complete
and that of 2 significant (37% consumption). When an
equimolar mixture of 1 and 10 was treated similarly with
I2/H2O2/MeOH for 15 min, most of 1 (97%) was consumed
while most of 10 (94%) remained intact. If 1 was omitted,
49% of 10 was found to be consumed (Table 2, run 7).
The treatment for 30 min of the 1:1 mixture of 1 and 10
made the cosumption of 1 complete and that of 10
significant (32% consumption). It can, therefore, be
The mechanism suggested above for the solvolysis of
12 proposes that the reaction between 12 and I2 (the rate-
determining step in the solvolysis) is second order overall,
first order in 12 and in I2, whereas the competing
prototropic rearrangement of 12 in the present system
may be assumed to be first order or pseudo first order.
Thus, the rate of the solvolysis of 12 relative to that of
its prototropic rearrangement (S/R ratio) is expected to
(18) Other reactions of 17 may be couplings with 8 and with atomic
iodine (to give 12) (not shown in Scheme 3).
(17) See also: Karhu, M. J . Chem. Soc., Perkin Trans. 1 1980, 1595.

2010 J . Org. Chem., Vol. 61, No. 6, 1996
Omura
be proportional to the I2 concentration. It was desirable
to prove this experimentally. This was originally thought
to be a difficult task owing to the complexity of the overall
reaction of 1 with I2/H2O2/MeOH. After finding the
“stabilization” of 2 by 1, however, the task now seemed
possible, to some extent. At the early stage of the
reaction of 1, the yield of 2 can represent the rate of the
prototropic rearrangement of 12 because product 2 is
“stable”, while the total yield of 5 and 6 can represent
the rate of the solvolysis of 12 because the formation of
6 by the other path is negligible. Then the (5 + 6)(yield)/
2(yield) ratio should represent the S/R ratio. Table 1 also
lists the calculated (5 + 6)/2 ratios (runs 1-3, 6-8, and
10-12). At each initial I2 concentration, the (5 + 6)/2
ratio varies with reaction time but only within a rela-
tively narrow range. The (5 + 6)/2 ratio is expected to
be kept constant provided that the I2 concentration is
maintained constant throughout the early stage of the
reaction. The observed lack of strict constancy of the (5
+ 6)/2 ratio may be ascribable not only to experimental
error but also to the lack of strict constancy of the I2
concentration during the reaction: the I2 concentration
in the reacting mixture may be decreased, though not
substantially, as the reaction progresses, that is, as the
formation of 2 progresses.19 Indeed, the (5 + 6)/2 ratio
appears to tend to decline accordingly within that narrow
range, as the reaction progresses. It is noteworthy that
the approximate constancy of the (5 + 6)/2 ratio is
maintained until the concentration of 1 in the reacting
mixture becomes quite low, probably indicating that the
retardation of the decay of 2 was brought about even by
a small amount of 1. As anticipated, the (5 + 6)/2 ratios
are higher when the initial I2 concentration is higher.
As anticipated, employment of a larger quantity of
solvent resulted in the smaller (5 + 6)/2 ratios (Table 1,
runs 14 and 15; compare with runs 10-12 in the table).
The data obtained here are not sufficient to prove
rigorously the proportionality of the S/R ratio to the I2
concentration, but they may suffice to show at least that
the ratio does increase with an increase in the I2
concentration and that the solvolysis of 12 in the presence
of enough I2 overwhelms its prototropic rearrangement.
The reaction in the presence of a small amount of H2SO4
was found to increase the (5 + 6)/2 ratio and thus to
improve the ultimate yield of 6 up to over 80% (Table 1,
runs 16-18). Lowering the reaction temperature also
served to increase the ratio, although the reaction was
slowed down (Table 1, runs 19-21). The acid and
temperature effects were not investigated further.
The reaction of phenol 1 with I2 and H2O2 in MeOH
proves complex, although the ultimate products are
quinoid products 4 and 6 alone. Through the detailed
analyses of the products from the reaction conducted
under various conditions, the paths leading to 4 and 6
are elucidated. Molecular iodine cannot electrophilically
iodinate phenols 1 and 2 only but also electrophilically
deiodinates the products, 4-iodocyclohexa-2,5-dienones 12
and 7. The electrophilic deiodination by I2 of the iodo-
cyclohexadienones contrasts with the nucleophilic deha-
logenation by halide ion of 4-halocyclohexa-2,5-dienones.
The attack by I2 on the iodocyclohexadienones results in
their solvolysis (methanolysis), and the solvolysis prod-
ucts are converted into 6 eventually. Labile 4-methoxy-
cyclohexa-2,5-dienone 13, the primary product of the
1
methanolysis of 12, is suggested to be detectable by H
NMR spectroscopy. The I2-induced solvolysis of 12 can
be so fast as to compete well with or overwhelm its rapid
prototropic rearrangement to give 2. The present study
may provide a new aspect to the chemistry of the phenol
halogenation reaction. The generality of electrophilic
dehalogenation of halocyclohexadienones by positive
halogen reagents is being investigated. The results of
preliminary experiments include that the reaction of
4-bromo-2,4,6-tri-tert-butylcyclohexa-2,5-dienone with
MeOH at 0 °C in the presence of N-iodosuccinimide
provides 4-methoxy-2,4,6-tri-tert-butylcyclohexa-2,5-di-
enone rapidly and quantitatively.
Exp er im en ta l Section
1H NMR (60 or 90 MHz) and IR spectra were taken in CDCl3
and in CHCl3, respectively. GC analyses were performed at
150 °C on a column packed with Silicone OV-17 on Chromosorb
W. Column chromatography was conducted with Merck SiO2
60 (25 g) by using gradient elution (100% petroleum ether to
50%/50% petroleum ether/benzene). TLC was run on SiO2.
P r ep a r a tion of 4-Iod op h en ol 2. To a stirred solution of
phenol 1 (41.2 g, 0.2 mol) in a mixture of MeOH (400 mL) and
ethylenediamine (75 mL) was added dropwise a solution of I2
(41.0 g, 0.16 mol) and KI (62 g, 0.37 mol) in water (40 mL)
over a 20-min period. The mixture was stirred for 20 min and
filtered. The filtrate was poured into water and extracted with
petroleum ether. The extract was washed with water, dried
over anhydrous Na2SO4, and evaporated to dryness. The
residue was passed through a column packed with SiO2 (120
g) with petroleum ether. The first fraction provided a nearly
colorless crystalline mixture, which was recrystallized from
hexane yielding 2 (33.3 g, 50%) as colorless crystals, mp 88-
90 °C (lit.20 mp 88-90 °C). The 2 was free from 1 as suggested
by GC.
P r ep a r a tion of 4,4-Dibr om ocycloh exa -2,5-d ien on e 15.
To a stirred solution of 1 (20.6 g, 0.1 mol) in MeOH (300 mL)
was added a solution of Br2 (32.0 g, 0.2 mol) in MeOH (50 mL)
over a 10-min period. The mixture was stirred for 50 min at
room temperature (ca. 20 °C). Water (50 mL) was added
slowly to the mixture, and the resulting mixture was cooled
with ice. Filtration provided a light brown crystalline mixture,
which was recrystallized from petroleum ether yielding 15
(16.1 g, 44%) as light yellow crystals, mp 127.5-129.5 °C (lit.14
mp 129-131 °C).
Rea ction of P h en ol 1 w ith I2 a n d H2O2 in MeOH (Ta ble
1). Gen er a l P r oced u r e (Ru n s 1-13). To a magenetically
6
stirred solution of 1 (412 mg, 2 mmol) and 36% H2O2 (3 mL,
1.24 g, 36 mmol) in MeOH (20 mL) was added at 35 °C a
solution of I2 [254 mg (1 mmol), 508 mg (2 mmol), or 1.016 g
(4 mmol)] in MeOH (10 mL) in ca. 30 s. The mixture in a
stoppered bottle was stirred at 35 °C for the time indicated in
the table. The mixture was filtered into a flask containing a
stirred, cold solution of NaHSO3 (4.5 g) in water (200 mL).
The filtration afforded 4,4′-diphenoquinone 4: reddish brown
crystals from benzene, identical with an authentic sample20
(1H NMR and TLC); mp 240-242 °C (lit.20 mp 240-241 °C).
The contents of the flask were extracted with petroleum ether
(200 mL × 2). The extract was washed with water, dried over
anhydrous Na2SO4, and evaporated under reduced pressure.
The residue was chromatographed. The first fraction gave a
mixture of 1 and 2 (1H NMR and GC), and their contents were
determined by GC. The second fraction provided a mixture
of 4,4′-biphenol 3, a small amount of an additional crop of 4,
and 4-methoxyphenol 5 (1H NMR and TLC), and the contents
of the mixture was determined by 1H NMR spectroscopy. The
third fraction afforded p-benzoquinone 6: orange crystals from
(19) The formation of the other iodine-containing products (7, 9, 12,
HI, etc.) may also contribute to the decrease in the I2 concentration,
but they are assumed to be only of transient existence and their
concentrations in the reacting mixture are assumed to be extremely
low. The content of I2 (in mol) in the reacting mixture, therefore, is
tentatively assumed to be the difference between the initial content
of I2 (in mol) and half the content of product 2 (in mol) in that mixture.
(20) Omura, K. J . Org. Chem. 1984, 49, 3046.

Solvolysis of Intermediary 4-Iodocyclohexa-2,5-dienones
J . Org. Chem., Vol. 61, No. 6, 1996 2011
petroleum ether, identical with an authentic sample21 (1H
NMR and TLC); mp 67-69 °C (lit.21 mp 65-68 °C). For
isolation and further identification of 3 and 5, the mixture
obtained from the second fraction was chromatographed on
SiO2 (15 g) with petroleum ether/benzene (10:1). The first
fraction gave 3: light yellow crystals from petroleum ether,
identical with an authentic sample10a (1H NMR and TLC); mp
186-187 °C (lit.10a mp 184.5-185.5 °C). The second fraction
gave 4. The third fraction yielded 5: colorless crystals from
MeOH, identical with a commercially available sample of 5
(1H NMR, IR, and TLC); mp 105-107 °C (lit.22 mp 106-107
°C).
In runs 14 and 15, the reaction was initiated by addition of
a solution of I2 (4 mmol) in MeOH (10 mL) to a solution of 1 (2
mmol) and 36% H2O2 (3 mL) in a mixture of MeOH (50 mL)
and H2O (3 mL).
In runs 16-18, the reaction was initiated by addition of a
solution of I2 (4 mmol) in MeOH (10 mL) to a solution of 1 (2
mmol), 36% H2O2 (3 mL), and concd H2SO4 (5 drops, ca. 1.8
mmol) in MeOH (20 mL).
In runs 19-21, the reaction was conducted at 0 °C.
Rea ction of P h en ol 2 w ith I2 a n d H2O2 in MeOH (Ta ble
2, r u n s 1-6). These reactions were conducted and worked
up according to the general procedure described for the
reaction of 1 with I2 and H2O2 in MeOH (runs 1-13) except
that 2 (664 mg, 2 mmol) replaced 1.
Rea ction of P h en ols 1 or 2 w ith I2 in H2O/MeOH. The
reaction of 1 was conducted by using I2 (4 mmol), and the
reaction mixture was worked up, according to the general
procedure described for the reaction of 1 with I2 and H2O2 in
MeOH (runs 1-13) except that H2O (3 mL) replaced 36%
H2O2.23 The reaction conducted for 5 min gave 1 (306 mg, 74%
recovery), 2 (20 mg, 3%), 3 (6 mg, 1%), 4 (24 mg, 6%), 5 (23
mg, 5%), and 6 (40 mg, 9%). The reaction for 50 min gave 1
(68% recovery), 2 (5%), 3 (1%), 4 (10%), 5 (trace), and 6 (15%).
The reaction carried out similarly for 5 min by using 2 (2
mmol) in place of 1 gave 2 (505 mg, 76% recovery), 4 (92 mg,
23%), and 6 (7 mg, 2%). The reacion for 50 min gave 2 (50%
recovery), 4 (48%), and 6 (3%).
Rea ction of P h en ol 10 w ith I2 a n d H2O2 in MeOH
(Ta ble 2, r u n s 7 a n d 8). The reaction was undertaken and
the reaction mixture was worked up, according to the general
procedure described for the reaction of 1 with I2 and H2O2 in
MeOH (runs 1-13) except that 1024 (481 mg, 2 mmol) replaced
1. Filtration of the reaction mixture afforded bis(chlorocyclo-
hexadienone) 11a as yellow crystals, identical with an au-
thentic sample8 (1H NMR, IR, and TLC); mp 155-157 °C (lit.8
mp 150-151 °C). The product mixture recovered from the
filtrate was chromatographed. The first fraction provided 10.
The second fraction gave a mixture of 4 (trace) and a small
amount of an additional crop of 11. The third fraction gave
6.
Rea ction of a n Equ im ola r Mixtu r e of P h en ol 1 a n d
P h en ols 2 or 10 w ith I2 a n d H2O2 in MeOH. The reaction
was conducted by using I2 (4 mmol), and the reaction mixture
was worked up, according to the general procedure described
for the reaction of 1 with I2 and H2O2 in MeOH (runs 1-13)
except that a mixture of 1 (2 mmol) and 2 (2 mmol) or 10 (2
mmol) replaced 1 alone.
and 6. Compond 11a was not obtained. Reaction for 30 min
gave 10 (68% recovery) while 1 was not recovered. The
products were 2 (1%), 4, 5, 6, and 11a .
Rea ction of P h en ol 5 w ith I2 a n d H2O2 in MeOH. The
reaction was conducted for 50 min by using I2 (4 mmol),
according to the general procedure described for the reaction
of 1 with I2 and H2O2 in MeOH (runs 1-13) except that 5 (472
mg, 2 mmol) replaced 1. The reaction mixture was poured
into a stirred, cold solution of NaHSO3 (4.5 g) in water (200
mL). Extractive workup of the resulting mixture with petro-
leum ether yielded 6 (439 mg, quantitative).
The reaction carried out similarly by using H2O (3 mL) in
place of 36% H2O2 gave a mixture of 5 (26% recovery) and 6
(74%).23
Rea ction of Dien on e 14 w ith I2 or HI in H2O/MeOH.
To pulverized crystals of 1413b (570 mg, 2 mmol) was added at
35 °C a solution of I2 (4 mmol) in a mixture of MeOH (30 mL)
and H2O (3 mL) in one portion. The mixture in a stoppered
bottle was stirred magnetically for 5 min at 35 °C, poured into
a stirred, cold solution of NaHSO3 (0.55 g) in water (200 mL),
and extracted with petroleum ether (200 mL × 2). The extract
was washed with water, dried and evaporated to dryness under
reduced pressure. The residual product mixture, which was
suggested by 1H NMR spectroscopy not to contain 14, was
chromatographed. The first fraction provided a mixture of 1
(21 mg, 5%), 4-bromophenol 16 (354 mg, 62%), and 2 (8 mg,
1%), as suggested by GC. The second fraction gave a mixture
of 3 (3 mg, 1%), 4 (27 mg, 7%), and 5 (29 mg, 6%), as analyzed
by 1H NMR spectroscopy. The third fraction yielded 6 (77 mg,
18%). Reaction for 60 min gave 1 (2%), 2 (2%), 3 (trace), 4
(13%), 6 (24%), and 16 (59%).
The reaction of 14 was carried out similarly for 5 min in
the absence of added I2. The 1H NMR spectrum of the residual
product (565 mg) obtained after a similar workup of the
reaction mixture suggested that it consisted exclusively of 16.
The reaction of 14 was carried out similarly for 5 min by
using 57% HI (0.90 g, 4 mmol) and H2O (2 mL) in place of I2
and H2O (3 mL), respectively. Column chromatography of the
residual product mixture obtained after a similar workup of
the reaction mixture gave a mixture of 1 (82%) and 16 (14%).
Other products were 3 (0.5%), 4 (0.2%), and 5 (0.2%).
Rea ction of P h en ol 16 w ith I2 in H2O/MeOH. The
reaction was conducted for 5 min by using I2 (4 mmol) in the
manner described for the reaction of 1 or 2 with I2 in H2O/
MeOH except that 168 (570 mg, 2 mmol) replaced 1 or 2. The
reaction mixture was worked up in the manner described for
the reaction of 14 with I2 in H2O/MeOH. The residual product
mixture was chromatographed. The first fraction gave 16 (436
mg, 76% recovery). The second fraction provided a mixture
of 4 (67 mg, 16%) and bis(bromocyclohexadienone) 11b (43 mg,
8%) as suggested by 1H NMR spectroscopy. Comparison with
an authentic sample of 11b25 by TLC also suggested that the
mixture contained 11b. The third fraction yielded a trace
amount of 6.
Rea ction of Dien on e 15 w ith I2 or Br 2 in H2O/MeOH.
The reaction with I2 was conducted for 10 min in the manner
described for the reaction of 14 with I2 in H2O/MeOH except
that 15 (728 mg, 2 mmol) replaced 14. The reaction mixture
was filtered into a flask containing a stirred, cold solution of
NaHSO3 (0.55 g) in water (200 mL). The filtration provided a
crystalline mixture of 4 (32 mg) and 11b (15 mg, 3%).
Extractive workup of the contents of the flask with petroleum
ether afforded a residual product mixture, which was sug-
gested by 1H NMR spectroscopy not to contain 15. The residue
was chromatographed to provide successively 16 (144 mg,
25%), 4 (5 mg, 9% in total), and 6 (216 mg, 49%).
Reaction of the mixture of 1 and 2 conducted for 15 min
provided 1 (21 mg, 5% recovery) and 2 [649 mg, 98% recovery
(see the text)]. The reaction for 30 min provided 2 (63%
recovery): phenol 1 was not recovered.
The product obtained from the reaction of the mixture of 1
and 10 was filtered into aqueous NaHSO3. The product
mixture recovered from the filtrate was chromatographed. The
first fraction provided a mixture of 1, 2, and 10. The contents
of the mixture was determined by GC. Thus, the reaction
conducted for 15 min gave 1 (14 mg, 3% recovery) and 10 (454
mg, 94% recovery). The products were 2 (51 mg, 8%), 3, 4, 5,
The reaction of 15 was carried out similarly by using Br2
(640 mg, 4 mmol) in place of I2, and the reaction mixture was
worked up analogously. Filtration provided 15 (81 mg) (1H
NMR). The crystalline residue (450 mg) recovered from the
1
filtrate was estimated by H NMR spectroscopy to contain 15
(21) Omura, K. J . Org. Chem. 1989, 54, 1987.
(22) Mu¨ller, E.; Ley, K. Chem. Ber. 1955, 88, 601.
(23) In the workup of the reaction mixture, NaHSO3 (0.55 g) was
employed.
(84 mg, 23% recovery in total), 6 (0.29 g, 66%), and 16 (14 mg,
(24) Starnes, W. H., J r. J . Org. Chem. 1966, 31, 3164.
(25) Becker, H.-D. J . Org. Chem. 1965, 30, 982.

2012 J . Org. Chem., Vol. 61, No. 6, 1996
Omura
2%). Dienone 15 suffered decomposition when chromato-
graphed on SiO2.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
the crude products containing compound 13, obtained from run
19, Table 1, and from the Ag ion induced reaction, as well as
the spectrum of compound 5 for comparison (6 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
The reaction of 15 was carried out similarly in the absence
of added I2 or Br2, and the reaction mixture was worked up
analogously. Filtration provided 15 (549 mg). The crystalline
mixture (170 mg) recovered from the filtrate was estimated
1
by H NMR spectroscopy to contain 15 (0.11 g, 91% recovery
in total), 6 (5 mg, 1%), and 16 (9 mg, 2%).
Ackn owledgm en t. The author is thankful to Hideyu-
ki Matsubara and Sayoko Kamatani (students) for
experimental contributions.
J O951455N