Phenol Oxidation Reactions

BY PROF. DR. H.MUSS0

CHEMISCHES INSTITUT DER UNI\TRSITAT MARBURG (GERMANY)

Dedicated to Professor Dr. Hans Brockmann on the occasion of his 60th birthday

The use of well-known phenol oxidation reactionsfor the preparation of compounds arising
from C-C and C-0 coupling has recently received increased attention. A selection from
the large number of products obtainable by oxidation of mono- and polyhydric phenols
and a discussion of the reaction mechanisms indicate the scope of this method. The formation
of hydroxyphenylquinones and orceine dyes from resorcinol derivatives is explained. The
synthesis of natural products by way of phenol oxidations is briejiy discussed.

Introduction ketone (3) [4-81. The formation of (3) is explained on

the basis of primary o,p‘-coupling, followed by 1,2-
addition of the a‘-hydroxyl group onto the resulting
Oxidation of phenols often produces a number of cyclohexadienone 171.
products that are sometimes polymeric and quinonoid
in nature. Nevertheless, this reaction can be used to
synthetize complicated compounds because, first of all,
mixtures consisting of a number of similar components
can now be separated nearly quantitatively by chromato-
6 OH
K,Fe(CN),,

011 OH
+ $+$
OH 011 011
graphy ; furthermore several research groups have,
for biogenetic reasons [1,2], renewed their efforts to syn-
thetize natural products by oxidation of phenolic pre-
cursors and have developed procedures which some-
times afford the desired products in good yields. In
the following, the principles and scope of oxidation of
phenols, naphthols, and derivatives of hydroquinone, (3)
pyrocatechol, and resorcinol are discussed.
The same products are formed on oxidation of p-cresol with
ferric chloride 191, Fenton’s reagent (FeS04 + H202) [lo], or
peroxidase plus H202 at pH 6.5 [ I I]; fsendomonas enzymes
preferably attack t h e methyl group instead 1121.
I. Oxidation of Monohydric Phenols and
Naphthols a-Naphthol reacts with ferric chloride to produce all
three possible ortho- and para-C-C-bonded products
( 4 ) , (5), and (6) [13]. In acidic or neutral solution, p-
The variety of the oxidation products obtainable is naphthol affords I,l‘-binaphthol (7) in good yield;
clearly indicated by examples from the classical work after oxidation with potassium ferricyanide in alkaline
of H . Dianin, of R. Pummerrr, and of H. Erdtman, and solution, on the other hand, only a small amount of the
by more recent work [3]. Generally, oxidation involves
[4] R . Pummerer, H . Puttfarcken, dnd P. Sthopflucher, Ber.
the removal of one hydrogen atom from each phenol dtsch. chem. Ges. 58, 1808 (1925).
molecule and leads exclusively to ( I - and p-linked dimeric [ 5 ] C. G.Havnes, A . H . Turner, and W . A . Wtrters, J . chern. SOC.
and polymeric products, predominantly containing C-C, (London) 1956,2823.
and more rarely, C 0 linkaees. [6] W.W. Kaeding, J. org. Chem~stry28, 1063 (1963).
[7] D . H . R. Barton, A . M . Deflorin, and 0 . E. Edwurds, J . thern.
111 aqueous alkalins solution, p-crcsol reacts with potas- SOC.(London) 1956,530.
sium ferricyanide to prodilcc, polymeric products plus [8] V . Arkley, F. M . Dean, A . Rohrrtson, and P. Sidisunthorrl,
t h e o-dimer ( l ) , the o,o’-trimer (2), and Pummerer’s J . chem. SOC. (London) 1956,2322.
[9] K. Bowden and C. H . Reece, J . chem. SOC.(London) IY50,
2249.
[ I ] D . H . R . Barton and T . Cohcn in: Festschrift fur Arthur Stoll.
Birkhauser, Basel 1957, p. 117. [lo] S. L. Cosgrove and W. A . Wtrters, J . chem. SOC.(London)
1951, 1726.
[2] H . Erdtman and C. A . Wachtmeister in: Festschrift fur Arthur
Stoll. Birkhauser, Basel 1957, p. 144.
[l I] W. W. Wc.iterfie/dandCh. LOIIW, J. biol. Chemistry 145, 463
(1942).
[3] The literature u p to 1957 has been reviewed in [ I ] and [2] and
by B. S . Thyagnrnjnn, Chem. Reviews 58, 439 (1958). See also [I21 S. Dagley and M . D. Patel, Blochem. J . 6 6 , 227 (1957).
W . A. Waters, Progr. org. Chem. 5,35 (1961); J . D. Loudon, ibid. [I31 J . D . Edwards and J . L. Cuslrctw, J . Amer. chem. SOC. 76,
5 , 46 (1961). 6141 (1954).

Angcw. Chern. intc>vntrt. Edit. 1 Vol. 2 (1963) 1 No. 12

723
hydroxynaphthyl naphthyl ether (12) could be isolated sodium hydroxide and air at 70 "C affords 20 % of (7) and
[14,15]. The dimer (7) can be oxidized further with 20 % of (Id), in addition to (15) and other products [211,
which, as in the oxidation of p-naphthol with permanganate
[22], indicate incipient degradation.
0

(4)
+

If two of the three 0- and p-positions are occupied by

silver oxide 1161 or potassium ferricyanide [17] to substituents, o,o'- and p,p'-bonded dimers of type (16)
produce (9) and (11). The formation of the purple are produced in high yields. If the oxidizing agent has a
radicals (8) and (10) that were postulated as early as sufficiently high oxidation potential, p,p'-bonding leads
19I4has recently been verified by electron-spinresonance to the corresponding diphenoquinones (17). Numerous
ineasurements [18]. examples of this reaction are known [3]. It is of interest,
for the understanding of the biogenesis of diphenyl

moH derivatives, that the common mushroom Polyporus ver-

sicolor contains an enzyme that catalyses this reaction
P31.
R R

i
FeCI,

" O W

Oxidation of 2-methoxyphenol (guaiacol) or 2,6-di-

methylphenol with silver oxide in benzene affords
dimers of types (16), (17), and (18) but also gives
polymeric phenyl ethers (19) with molecular weights of
up to 1900 1241in yields as high as 40%. If the oxidation
is effected with air and cuprous chloride in nitrobenzene1
pyridine, these yields decrease to zero, in favor of di-
phenoquinone formation, with increasing bulk of
Treatment with hydrogen peroxide and ammonium molyb- R [--CH3, -CH(CH3)2, -C(CH3)31 [25].
date gives a hydroxynaphthyl-o-naphthoquinone(13), un-
doubtedly arising from oxidation of the @-naphtholto the
o-quinone and subsequent addition of a second molecule of
naphthol onto this quinone [19,20]. Treatment with solid

[14] R. Pummerer, Ber. dtsch. chern. Ges. 52,1403 (1919).

[I51 R . Pummerer and E . Cherhuliez, Ber. dtsch. chem. Ges. 52,
1414 (1919).
[I61 R . Pummerer and F. Frankfurter, Ber. dtsch. chem. Ges. 47,
1472 (1914). 1211 G . Brunnstrom, J. Amer. chcm. SOC.77, 2463 (1955).
[I71 R . Pummerer and A . Rieche, Ber. dtsch. chern. Ges. 59,2161 [22] 0. Dischendorfer and W . Danziger, Mh. Chem. 48, 315
(1926). (1927).
[ 181 A . Rieche, B. Elschner, and M . Landheck, Angew. Chem. 72, [23] S. M . Bocks, B. R . Brown. ;md A . H . Todd, Proc. chem. SOC.
385 (1960). (London) 1962, 117.
[I91 I. D . Raarke-Fek, C. H. Wang, R . K . Robins, and B. E. [24] B. 0. Lindgren, Acta chem. scdnd. 14, 1203,2089 (1960).
Christensen, J . org. Chemistry 15, 627 (1950). [25] A . S. Hay, H . S . Blanilrcirtl,G.F. Endres, and J . W . Eustante,
[20] A . Bader, J. Amer. chern. SOC.73,3731 (1951). J. Amer. chem. SOC.81,6335 (1959).

724 Angew. Chem. i n t o i u i t . Edil. 1 Vol. 2 (1963) / Nu. 12

It is noteworthy that, in this case, partial exchange of the Treatment with atmospheric oxygen in alkaline solution
rncta-hydrogen takes place despite the fact that coupling affords the aldehyde (26) besides (24) and (25) [33]. More
occurs only in the para-position 1261 and, moreover, that vigorous conditions lead to degradation of the aldehyde by a
oxidation with oxygen and laccase or peroxidase leads only mechanism which has not yet been explained but which
to C-C coupling, with no formation of ethers [24]. Oxi- probably proceeds via a carboxylic acid intermediate and
dation of p-halogenophenols with potassium ferrycianide yields (27) [34].
or lead dioxide proceeds by way of a radical chain reaction If the methylene groups are protected by substituents such as
and also affords polymeric phenyl ethers (molecular weight = methyl or phenyl residues, the quinone methides (23) can
2000-10000) p71. sometimes be isolated [32,35].
The formation of quinol ethers is preferentially intra-
molecular when the phenol residues to be coupled are
already linked by a C-C bridge, e.g. (20) [28];cf. also 11. Stable Phenoxy Radicals
[29,30].Intermolecular ether formation is favored only
when C-C coupling is sterically hindered [143].
The presence of large substituents, e.g. t-butyl groups
or phenyl residues, at all the o- and p-positions stabilizes
the primary oxidation products, i.e. free phenoxy
radicals. Some of these free radicals form dark-
colored crystals, e.g. (28) [36] and (28a) [38]; cf.
(20) [35-401;others undergo association in the crystals to
form colorless dimeric quinol ethers, which in solution
Linking through methyl groups is particularly noticeable dissociate to varying degrees into radicals, e.g. (29)
in the oxidation of 2,6-di-t-butyl-4-methylphenol (21). [46,47];cf. [41-451.
Oxidation with lead dioxide and silver oxide or potas-
sium ferricyanide leads by way of the radical (22) to the
very unstable quinone methide (23)which then dimerizes
to give (24) and (25) [31,32].

U
solution: deep blue solution: red
crystal: deep blue crystal: colorless, dimer
t (28~)
solution: ,A,, = 423 nili
crystal: deep blue

[331 G. R . Yohe, J. E. Dunhar, R. L . Pedrotti, F. M . Scheidt, F. G .

H. Lee, and E. C. Smith, J. org. Chcmistry21, 1289 (1956).
[34] G. R . Yohe, J. E. Dunbar, M. W.Lansford, R. L. Pedrotti, F.
M . Scheidt, F. G . Lee, and E. C . Smith, J. org. Chemistry24,1251
(1959); see also J. K . Becconsall, S. Clough, and F. Scott, Trans.
k HQ Faraday SOC.56,459 (1960).
[351C. D.CookandN.D.Gilmour,J.org.Chemistry25,1429(1960).
[361 E. Miiller and K . Ley, Chem. Ber. 87,922(1954);C. D . Cook
and R . C. Woodworth, J. Amer. chem. SOC.75, 6242 (1953);C .
D. Cook, J. org. Chemistry 18,261 (1953).
1371E.Miiller, R. Mayer,and K. Ley, Angew. Chem. 70,73(1958).
1261 W. A. Butte and C. C. Price, J. Amer. chem. SOC.84, 3567 [38]G. M . Coppinger, J. Amer. chcm. SOC.79,501 (1957);P . D .
(1962). Bartlett and T. Funahashi, ibid. 84,2596 (1962); M . S. Kharasch
[27]G. D . Staf$n and C. C. Price, J. Amer. chem. SOC.82, 3633 and B. S. Yoshi, J. org. Chemistry 22, 1435 (1957).
(1960);J. Bourdon and M . Calvin, J. org. Chemistry 22, 101 [39]K. Ley, E. Miiller, and K . Scheffler, Angew. Chem. 70, 74
(1957);M. Hedayatullah and U.L. Denivelle, C . R. hebd. SCances (1 958).
Acad. Sci. 254,2369(1962);E. Miiller, A . Rieker, and W.Beckert, 1401 E. Miiller, A. Schick, and K. Scheffler, Chem. Ber. 92,474
2. Naturforsch. 176, 567 (1962). (1959); W . R. Hatchard, R . D . Lipscomb, and F. W . Stacey, J.
[28]E. Miiller, R. Mayer, B. Narr, A. Rieker, and K . Schefller, Amer. chem. SOC.80,3636(1958).
Liebigs Ann. Chern. 645,25(1961). 1411 E. Miiller and K. Ley, Chem. Ber. 88,601 (1955).
[29]R. Pummerer and E. Cherbuliez, Ber. dtsch. chem. Ges. 47, [42]K . Ley, K. Scheffler, A . Rieker, and E. Muller, 2. Natur-
2957 (1914);J . N . Chatterjea, 5. Indian chem. SOC.35,37(1958); forsch. 136,460 (1956); E. Miiller, A. Rieker, K . Ley, R . Mayer,
Ref. C 1960,1499. and K. Scheffler, Chern. Ber. 92,2278(1959).
[30] D . R . Nelan and C. D. Robeson, J. Amer. chem. SOC.84, 1431 K. Ley, E. Miiller, and G. Schlechte, Chem. Ber. 90, 1530
2963 (1962); P . Schudel, H . Mayer, J . Metzger. R. Riiegg, and (1957).
0.Isler, Helv. chim. Acta 46,636(1963); D. McHall and I. Green,
Chern. and 1n.d 1963,982. [44]E. Miiller, K . Ley, and W .Schmidhuber, Chem. Ber. 89,1738
(1956);C. D. Cook, P . A . Kuhn, and P. Fianu, J. Amer. chem. SOC.
[31]S. L. Cosgrove and W . A. Waters, J. chem. SOC.(London) 78,2002 11956).
1951,388;G. R. Yohe, D . R. Hill, J. E. Dunbar, and F. M . Scheidt,
J. Amer. chem. SOC.75,2688(1953);C. D . Cook, N . G . Nahs and,
I451 E. Muller, A. Schick, R . M a y w . lind K . Scheffler, Chem. Ber.
93,2649 (1960).
H . R . Flunagan, ibid. 77,1783(1955); 75,6242(1953).
1461 K . Dimroth, F. Kalk, and G. Nwbauer, Chem. Ber. 90,2058
[32]C . D. Cook and B. Norcross, J. Amer. chern. SOC.78,3797 (1957); K. Dimroth, F. Kalk, R. Seli, and K. Schlomer, Liebigs
(1956);L. J . Filar and S. Winstein, Tetrahedron Letters 1960,25 Ann. Chem. 624, 51 (1959);K. Drmroth, Angew. Chem. 72, 714
9; A. Hubele, H . Suhr, and (I.Heilmann, Chem. Ber. 95, 639
(1960).
(1962);R . H.Bauer and G . M . Coppinger, Tetrahedron 19, 1201
(1963). [47]E. Miiller, K.Ley,and G . Schle~hte,Chern. Ber. 90,2660(1957).

Angew. Chem. internat. Edit. Vol. 2 (1963) No. 12

725
The compound known as Goldschmidt’s oxygen radical These radicals were detected by their magnetic susceptibility
[48] also exists in the crystal in the form of the dimeric and electron-spin rcsonance. They all are characteristically
colored and show an absorption band in the infrared near
colorless quinol ether (30) and was shown by electron 1560 cm-1; they differ rnarkcdly from the colorless, dimeric
spin resonance measurements to dissociate on dissolu- quinol ethers which have a doublet at 1660 and 1640 cm-1
tion into the yellow-green radical (31) only to the extent in the infrared spectrum 145,471. Because of resonance
of 0.1 % [49]. stabilization, unsubstituted phenoxyl radicals (38) have a
longer lifetime than alkyl o r aryl radicals and d o not tend
to attack the solvent or to initiate olefin polymerization as
readily.
Analysis of the hyperfine splitting of the ESR spectra shows
that the probability for the occurrence of the free electron
at the para-carbon atom is greater than that at the ortho-
position and, surprisingly, that it is lower at the meta-position,
but not zero; furthermore, [he analysis shows that the free
electron can also distributc itself over alkyl groups and
hetero-atoms in the orthu- and purr-positions 154-571. With
The reactivity of these radicals towards oxygen decreases a phenyl residue in the /)-position, the radical electron is
with increasing phenyl substitution. The 2,4,6-triphenyl- distributed more readily than when this residue is in the o-
phenoxy radical (29) is surprisingly stable towards position where the oxygen forces it out of the molecuIar
plane to a greater extent t40.451.
oxygen [45-471.
Whether and to what extent I hc density of the radical electron
Diradicals such as (32) [50]and (33) 1511 and nitrogen- on the oxygen is reduced or increased by substituents capable
ous radicals such as (34) [52]and (35) [53] - which are of resonance is not yet known. It is to be expected that the
very stable to oxygen -. can be prepared. The existence, hyperfine structure of ESR Spectra of 13C-kabeIled phenoxyl
radicals will provide a n answer to this interesting question
in solution, of the unstable, red radicals containing
t581.
sulfur and phosphorus (36) [54] and (37) [55] has been
demonstrated.
III. Oxidizing Agents and Coupling Mechanisms

In all the cases cited, silver oxide, lead dioxide, and

manganese dioxide in slightly polar solvents, electro-
chemical oxidation [59], or potassium ferricyanide in
alkaline solution afford phenoxyl radicals (38) in the
t first reaction step, which usually undergo further
132) reactions very rapidly.

s
I
11
(36) 137)
O GP- (41)

1481 St. Guldschmidt, Ber. dtsch. chem. Ges. 55, 3194 (1922); St.
Goldschmidt and W. Schmidt, Ber.dtsch. chem. Ges. 55,3 197 (1922).
[49] E. Miiller, K. Schurr, and K. Scheffler, Liebigs Ann. Chem.
627, 132 (1959).
1501 N. C. Yang and A. J . Custro, J. Amer. chem. SOC.82, 6208 [56] E. Miiller, K. Ley, K. Sdrc$ler, and I?. Mrzyer, Chem. Ber.
(1960). 91, 2682 (1958); E. Miil/er, K. Mriyer, H.-D. Spanagel, and K.
[511 E. Miiller, R. Muyar, and K. Scheff[er, 2. Naturforsch. l 3 b , Schefler, Liebigs Ann. Chem. 645, 53 (1961); E. Miiller, R.
825 (1958). Mayer, U. Heilmann, and K. Schefler, ibid. 645, 66 (1961); E.
1521 G. M. Coppinger, Tetrahedron 18, 61 (1962). Miiller, A. Rieker, and K. Sclrtlfl’ler, ibid. 645, 92 (1961).
1531 0.Neunhoeferand P. Heitmann, Chem. Ber. 96,1027 (1963). 1571 K. Schufer, 2. Elektrochrm., Rer. Bunsenges. physik. Chem.
1541 E. Miiller, H. B. Stegmann, and K. Schejjler, Liebigs Ann. 65,439 (1961).
Chem. 645, 79 (1961). [58] Investigations of this k i n d arc in progress: E. Miiller, per-
[55] E. Miiller, H. Eggensparger, and K. Scheffler, Liebigs Ann. sonal communication.
Chem. 658, 103 (1962). [59] F. Fichterand F. Ackertmrm, Helv. chim. Acta 2,583 (1919).

726 Angew. Chem. intarnut. Edit. 1 Vol. 2 (1963) No. 12

Generally, C-C or C-0 coupling can occur in one of two Labile o-quinones [64] and hydroxyquinones r65.661 can
ways. Two radicals can dimerize (A) to give the cyclohexa- be prepared in this manner i n good to very good yields,
dienone (39) which, in the case of the 2,6-t-butyl compound,
can be isolated and which rearranges in methanol, to the provided that the redox potential of the quinone to be
dimeric phenol (40) 1601. Alternatively, when the oxidation is formed is not too high.
slow, dimerization is not likely to occur because of the
low radical concentration. Under these conditions, in
particular, it is possible that the phenoxide ions or phenol
molecules, which are present in high concentrations, undergo
electrophilic substitution by the radical (B), the radical (41)
being dehydrogenated further to give the dienone or di- v
phenol. Support for the latter alternative has not yet been
obtained. It should be noted in this connection that
oxidation of a mixture of 2,6-dimethylphenol and 2,6-di-
methoxyphenol with potassium ferricyanide gives only OH OH
symmetric and no asymmetric diphenoquinones [5].
Oxidizing agents which readily liberate oxygen, e.g.
hydrogen peroxide or OH radicals (Fenton’s reagent),
organic peroxides, periodic acid, persulfate, lead tetra-
16%
acetate, or potassium nitrosodisulfonate (42) [Fremy’s
9H
salt], often produce monomeric p- and o-quinones and
their reaction products or quinol derivatives in
addition to polymers. The preparative synthesis of
quinones is readily accomplished by the Elbs persulfate
oxidation [61] and, in particular, by oxidation with
(471, 90%
Fremy’s salt according to Teuber [62]. In the latter
case, two moles of Fremy’s salt are consumed and pro- Oxidation with hydroxyl radicals affords dimeric or
duce one mole each of imidodisulfonic acid and hy- hydroxylated products [10,67]. Thus, 2,6-di-t-butyl-4-
droxylamine-N,N-disulfonicacid. The first mole of (42) methylphenol reacts with t-butyl hydroperoxide to give
produces the free phenoxyl radical which then reacts the t-butylperoxo-p-quinol [68]. Benzoyl peroxide yields
with the second mole to give the quinol (43). The 6-benzoyloxypyrocatechol(45), diphenoquinones (46),
formation of such quinols can be demonstrated in the or the 0-benzoyl derivatives of p-quinols (47) [69].
case of certain naphthol derivatives, e.g. (44); they
decompose into the quinone and imidodisulfonic acid
[63]. This process yields preferentiallyp-quinones. If the
para-position is occupied by alkyl groups, o-quinones
can be isolated.

+ (421

OCH,

depending on the substituents. Oxidation with lead

tetraacetate leads to 2,2-diacetoxycyclohexadienones
(“quinone diacetates”) (48) and (49), 0-acetylquinols
(44)
[64] H . J. Teuber and G. Stuiger, Chem. Ber. 88,802 (1955).
[65] H. Musso, Chem. Ber. 91, 349 (1958).
[60] M . S. Kharasch and B. S . Yoshi, J. org. Chemistry 22, 1439 [66] H. Muss0 and H . Beecken, Cliem. Ber. 92, 1416 (1959); H.
(1957); K . Ley, E. Miller, R . Mayer, and K . Scheffler, Chem. Ber. Musso and H.-G. Matthies, ibld. 94. 356 (1961).
91, 2670 (1958). [67] D. G. H . Daniels and B . C. Saunders, J. chern. SOC.(London)
[61] W . Baker and N . C. Brown, .I.chem. SOC. (London) ZY48, 1951,2112, 3433.
2303; Review: J. D.Loudon, Progr. org. Chem. 5,56 (1961). [68] T . W . Campbell and G. M . Coppinger, J. Amor. chem. SOC.
[62] H . J . Teuber and W. Rau, Chem. Ber. 86, 1036 (1953); H . J . 74, 1469 (1952).
Teuber and N . Gotz, ibid. 87, 1236 (1954). [69] C. Walling and R . B. Hodgduri, J . Amer. chem. SOC. 80, 228
[63] H. J . Teuber and N . Gbtz, Chem. Ber. 89,2654 (1956); H. J. (1958); S. L. Cosgrove and W . A. Wuiers, J. chem. SOC. (London)
Teuber and G . Thaler, ibid. 92,667 (1959). 1949,3189; 1951,388.

Angew. Chem. internat. Edit. 1 Vol. 2 (1963) No. I2 727

(“quinol acetates”), (50) and (51) [67], and quinones (56) and (57)) which in alkaline solution undergo de-
[70-721. composition to quinols (58). ‘If the p-position is free,
The reaction mechanism has not been definitely elucidated, no oxygen is absorbed; instead, diphenoquinone (59) is
because the solution gives an ESR signal only after the quinol
formation is complete [72]. Periodic acid affords oxidation
products that are similar t o those obtained with lead tetra-
acetate; the free quinols dimerize readily, e . g . to (52);
hydroquinone monoethers are readily cleaved [73].

produced. This shows that a sterically unhindered

phenoxyl radical reacts faster with itself than with
oxygen [60,79, SO].
Oxidations with persulfate and silver ions [74], perchloryl
Each of the pure hydroperoxycyclohexadienones (56)
fluoride [75], or trifluoroperoxyacetic acid [76] offer n o
preparative advantages. and (57) undergoes isomerization in the presence of
alkali and oxygen to the equilibrium mixture of (56) and
Hydroxylation of phenols in the o-position can be
(57). If nitrogen is bubbled through the solution the
accomplished with oxygen and copper(I1) ions, in the
oxygen is removed and 70 ‘x of the originalphenol can be
presence of a secondary amine such as morpholine [77].
recovered. The reaction is of the first order with respect
However, the resulting pyrocatechols are oxidized fur-
to phenol and oxygen and is catalysed by both 2,6-di-t-
ther to o-quinones which rapidly add onto the base. The
butylbenzoquinone and m-dinitrobenzene [81]. Its rever-
exclusive attack at the ortho-position can be explained
sibility can be explained by the greater resonance
by assuming the formation of a copper complex (53).
stabilization of the phenoxide ion compared to the
Analogous products are obtained enzymatically using
cyclohexadienonyl hydroperoxide anion; it is represen-
tyrosinase [78]; the formation of a complex with copper
ted by the following equilibria [Sl] (C = catalyst):
can be considered as a model for the mode of activity
of the latter.
C - t R” I 0 2 L.5 Cf+Re+Ot + C?
-t R - 0 - 0. ’-,C + R-0-08

IV. Redox Potential and Rate of Oxidation

(5.7)
The potential of reversible redox systems can be readily
determined by a redox titration. This is not possible for
Sterically hindered free phenoxyl radicals, e.g. the irreversible oxidations. With the exception of the stable
dark-blue tri-t-butylphenoxyl radical (54), react ra- phenoxyls, most of the radicals cited herein react fur-
pidly with oxygen to produce quinol peroxides, e.g. ther at a rate which is too fast for determining their
(55) [36]. Direct oxidation of phenoxide ions with potential by titration of the phenol with the oxidizing
oxygen affords 2- and 4-hydroperoxycyclohexadienones agent. The semi-quantitative method of Fieser [82] is
[70] W. Metlesics, E. Schinzel, H . ViIesek, and F. Wessely, Mh.
useful in this respect. It consists of testing the phenol
Chem. 88, 1069 (1957); G. Billek, J. Swoboda, and F. Wessely, with different oxidizing agents of known redox poten-
Tetrahedron 18, 909 (1962) and previous publications. tial to determine which one is just insufficient to oxizide
[71] E. Hecker, Chem. Ber. 92, 1386,3198 (1959). the phenol under standard conditions. These “critical
[72] E. Hecker and R . Lattrell, Liebigs Ann. Chem. 662,48 (1963). potentials” are not accurate; however, they do provide
[73] E. Adler, J. DahlPn, and G . Westin, Acta chem. scand. 14,
1580 (1960); E. Adler, 1. Faikehag, and B. Smith, ibid. 16, 529 useful orientation in the “electrochemical series” of
(1962) and previous publications. phenols [5,83]. Since a linear relationship exists between
[741 R. G. R. Bacon and D. J. Munro, J. chem. SOC.(London) the empirically determined critical potentials and the
1960, 1339. theoretical energy values for the highest occupied phenol
[751 A . S. Kende and P. McGregor, J. Amer. chem. SOC.83,4197
(1961). orbitals as calculated by Ihe LCAO-MO method, it can
[76] J . D . McClure, J . org. Chemistry 28, 69 (1963).
[79] K.Ley, Angew. Chem. 71). 74 (1958).
[77] W. Brackman and E‘. Havinga, Recueil Trav. chim. Pays-Bas [80] H. S . Blanchurd, J. org. Chemistry 25, 264 (1960).
74,937, 1021, 1070, 1100, I107 (1955); E. Talman, Ph. D. Thesis,
Universitat Leiden (Holland) 1961. [81] H . R . Gersmunw and A . 1;. Sickel, J. chem. SOC. (London)
1959,271 1 ; 1962,2356.
1781 C. E. M . Pugh and H. S . Raper, Biochem. J . 21,1370(1927);
J. Neumann, G. Legmnd, G. Lehongre, and J . Lavollay, C. R. [82] L. F. Fiesev, J . Amer. chom. SOC.52, 4915, 5204 (IY30).
hebd. Seances Acad. Sci. 252,309 (1963). [83] N . S. Hush, J. chem. SOL. (London) 1953,2375.

728 A n g t w . Clwm. inlsrntrt. Edit. Vol. 2 (1963) 1 No. 12

be assumed that the rate-determining step, in all cases,
involves removal of one electron from the highest
I / -
occupied orbital [84]. The higher the redox potential
of the oxidizing agent [96] compared to that of the
phenol, the faster the oxidation should be (cf. [84a]).
On the other hand, polarographic analysis of many
irreversibly oxidizable phenols shows waves [85,86]
which correspond to “relative oxidation potentials”.
Since the half-wave potential obtained for reversible
systems, e.g. quinones/hydroquinones, are comparable,
at least in their sequence, with the actual redox poten-
111331.21 1000 2000 3000 4000 5000
tials [87], it should also be possible to use the relative
oxidation potentials of irreversible phenol oxidations as Fig. 2. Rate of autoxidation of phenols in methanollwater ( I :1) at
pH 13.
a measure of phenol oxidizability (Fig. 1).
Curve I : Hydroquinone and pyrocateclrol
Curve 2: Resorcinol
Curve 3: 2,3,S-TrimethylphenoI
The curve for hydroxyhydroquinone coincides with the ordinate.
The curve for phenol coincides with the abscissa.
Ordinate: Oxygen absorbed [moles of 0 2 1
Abscissa: Time [min]

obtained between the redox potentials and the loga-

rithms of the time for absorption of one half of the
oxygen [91] (Fig. 3).
T h e redox potential a n d stability of a phenoxyl radical
determine its effectiveness as an autoxidation inhibitor
[85,86,92]. 2,6-Di-t-butyl-Cmethylphenol is particularly
well suited for this purpose [93].
-0.5 0 +0.5 +1.0
5.0 -
Fig. 1. Dependence on pH of the relative oxidation potentials of
some phenols [85,86].
1. Hydroquinone 4. Phoroglucinol 4.0 -
2. Resorcinol 5. Pyrocatechol
3. PyrogaIlol 6. Phenol 3.0 -
Ordinate: pH
Abscissa: Relative oxidation potential [v]
2.0 -

Qualitative and quantitative data for the rate of oxida- 1.0 -.

tion of several phenols with the diphenylpicrylhydrazyl
radical [97] and periodic acid [88] show that monohydric
phenols and resorcinol react much slower than hydro- 2.3.5.6 -CH,
quinone and pyrocatechol I891 and that the reaction rate
@$jJ 500 600 700
of phenol increases with increasing alkyl substitution
1901.The same is true for the oxidation with atmospheric Fig. 3. Dependence of tho half-life period for the autoxidation of
alkyt-substituted hydroquinones on the redox potential at pH =
oxygen in aqueous alcoholic alkali hydroxide (Fig. 2) (pKz--3.8).
[9 I]. On autoxidation of alkyl-substituted hydroquino- Ordinate: log tl/z [ t l l z in minl
nes in aqueous alcoholic buffer solutions with equal Abscissa: Redox potential EI,[mvl
phenoxide concentrations, a linear relationship is
As indicated by Figure 1, the oxidation of, for example,
[84] T. Fueno, T. Lee, and H . E y i n g , J. physik. Chem. 63, 1940 pyrocatechol with potassium ferricyanide in alkaline
(1 959).
solution is definiteIy possible. Oxidation occurs even if
[84a] 0.Dimroth, Angew. Chem. 46, 571 (1933).
the potential of the oxidizing agent is 0.1 volt lower than
1851 G . E. Penketh. J . appl. Chem. 7, 512 (1957).
1861 We thank Dr. H . Berg, Jena, for polarographic determina-
that of the phenol, provided that the resulting phenoxyl
lions of further compounds. For the polarography of stable i s rapidly removed from the equilibrium (e.g. by di-
phenoxy radicals see F. W . Sfeuher, Ph. D. Thesis, Universitgt merization).
Marburg, 1963.
It should be mentioned that attempts have been m a d e [941
1871 H . Musso, K . Figge, and D . Becker, Chem. Ber. 94, 1107
(1961).
to determine t h e position of t h e etl~iilibriumbetween vdrious
[88] J . P . Feiser, M . A . Smith. and B. R . Willeford,J. org. Chem- [92] J . L. Bolland and P . ten Have, Discuss. Fardday SOC. 2, 252
istry 24, 9 0 (1959). (1947); vgl. auch K. U.Ingoldand J . A . Howard, Nature(London)
[89] P . Venkrr and H . Hevztrzunn, Naturwissenschaften 47, 133 195, 280 (1962).
( I 960). 1931 W . A . Waters, Progr. org. Chcm. 5,21 (1‘961).
1901 J . C . MrGowan and 7’.Pou~cll,J. chern. SOC.(London) 1961, 1941 C. D . Cook, C. B. Depatie, and E. S. English, J. org.
2160. Chemistry 24, 1356 (1959); see also [XS] and K. I . K r a f f , Ph. D.
[91] H . Musso and H . Frank?, unpublished results. Thesis, Universitiit Marburg, 1963.

Angew. Chem. internot. Edit. 1 Vul. 2 (1963) Nu. 12 729

stable phenoxyl radicals, e.g. (60~)and (60b), and hence hydroxyhydroquinone is substantially slower, with k = 2.3
to evaluate their redox potentials, and that the rate constant [991. In the case of 2,4-di-t-butylpyrocatechol,the Li, Na,
for hydrogen transfer for R = R' = t-butyl has been deter- and K salts of the semiquinone radical anion have been
mined by measurement of the broadening of NMR signals isolated in the form of their crystalline etherates [102].
in carbon tetrachloride and found to be k = 300 mole-lx A method that is very suitable for the preparative synthesis of
sec-1. The temperature-dependence of this constant indicated labile o-quinones from pyrocatechol, in addition to Will-
an activation energy of only 1 kcal/mole [95]. statter'a silver oxide method and the Teuber oxidation, is the
oxidation with tetrachloro-o-quinone (o-chloranil) [I031 be-
cause, in this case, no water is formed.

The structures of the dimeric o-quinones were identified

as the diene adducts (63) [104]. For the mechanism
V. Oxidation of Derivatives of Hydroquinone, of oxidation of pyrocatechol lo cis&-muconic acid, see [105].
Pyrocatechol, and Pyrogallol o-Diphenoquinones can also be prepared [ 1061.
Pyrogallol [lo71 or gallic acid esters [I081 can undergo
biphenyl coupling, for example to produce (64). The
Oxidation of derivatives of hydroquinone and pyro- reaction probably involves the addition of a pyrogallol
catechol with all oxidizing agents first yields p- or o- anion onto a molecule of hydroxy-o-quinone.
quinones. Depending on the reaction conditions, these
can be isolated or they rapidly react further with nucleo-
philic reactants. Humic acid-type polymers are usually
the final products. Here, too, the first step involves a
one-electron transfer with formation of the semiquinone i64)
which has such a long life-time - in strongly alkaline
solution in the form of the symmetric resonance-
The formation of purpurogallin (65) from pyrogallol by
the action of potassium iodate was explained by Scheme
stabilized anion (61) and in strongly acidic solution as
1 [109,110]:
the cation (62) - that it can be identified by titration
[98], spectroscopically [99,100], or by ESR measure-
ments [ l o l l . H y j

HO \

do01I (6.5)

OH Scheme 1. Formation of purpurogallin from pyrogallol.

(62)
[lo21 K . Ley and E. Miiller, Angew. Chem. 70,469 (1958).
The equilibrium quinorie + hydroquinone +
semiquinone [I031 L. Horner and W . Diir/theimer, 2. Naturforsch. 146, 741
radical anion (61) is established very rapidly, with kl = 2 . 6 ~ (1959).
108 mole-.I.sec--l, whereas the subsequent reaction affording [I041 L. Horner and K. Sturm. Liebigs Ann. Chem. 597, 1 (1955);
B. Witkop, J. org. Chemistry 22, 1477 (1957); J. Harley-Mason
1951 R. W. Kreilick and S. 1. Weissmann, J. Amer. chem. SOC.84, and A . H. Laird, J. chem. SOC.(London) 1958, 1718.
306 (1962). [I051 A . A . Patchett and B . Witkop, J. org. Chemistry 22, 1477
[96] Redox potentials or oxidizing agents are reviewed by F. Seel: (1957); 0. Hayaishi, A . A . Palchett, and B. Witkop, Liebigs Ann.
Grundlagen der analytischen Chemie in waRrigen Systemen. Ver- Chem. 608, 158 (1957).
lag Chemie, Weinheim/Bergstr.1955. [I061 D.Schulte-Frohlinde and F. Erhordt, Angew. Chem. 74, 116
[97] According to E. A . Rraude, A . G . Brook, and R . P . Linstead, (1962); Angew. Chem. internat. Edit. I , I12 (1962).
J. chem. SOC.(London) 1954, 3574, the redox potential of di- [I071 C.Hurries, Ber. dtsch. chem. Ges. 35,2954 (1902); H.Erdt-
phenylpikrylhydrazyl is 1.20 v at pH 0. man, Proc. Roy. SOC.(London), Ser. A 143, 196 (1933).
[98] L. Michaelis, M . P. Schuhert, and S . Granick, J. Arner. chern. [I081 J . Herzig, J . Pollak, and M. Y. Bronnek, Mh. Chem. 29,277
SOC.61, 1981 (1939). (1908); H. Erdtmun, Svensk. kem. Tidskr. 47, 230 (1935); G.
[99] H . Diehler, M . Eigerr, and P . Matthies, Z. Elektrochem.,Ber. Pastuska, Naturwissenschaften 48, 457 (1961); 0. Th. Schmidt
Bunsenges. physik. Chem. 6 5 , 634 (1961); M . Eigen and P . Mat- and W . Mayer, Angew. Chem. 6 8 , 103 (1956).
thies, Chem. Ber. 94, 3309 (1960). [lo91 J. C. Salfeld, Angew. Chem. 69, 723 (1957).
[IOO] W. Fluig and J. Ch. Salfeld, Naturwissenschaften 47, 516 [110] L. Horner and W . Diirltheimer, 2. Naturforsch. 146, 744
(1960). (1959); L.Horner, K . H . Weher, and W . Durkheimer, Chem. Ber.
[IOI] Review: A . Carrington, Quart. Rev. 17, 67 (1963). 94, 2881 (1961).

730 Angew. Chem. internut. Edit. Vol. 2 (1963) 1 No. 12

 VI. Oxidation of Remrcinol Derivatiws between the hydroxyl groups could not be detected
[112].

The oxidation of resorcinol derivativeshas been studied Oxidation of orcinol (66) with oxygen affords a mix-
ture of more than 50% of the dimeric monoquinone (76)
for a long time in connection with the formation of
plus the dimeric diquinone (77) [65].
orceine and litmus dyes from orcinol. The structure of
these products and the mechanism of their formation, The reaction course depicted in Scheme 2 is supported by the
however, have only recently been elucidated [lll]. following considerations. The electrophilic attack of oxygen
on the orcinol anion is rate-determining; this is indicated by
Since resorcinol cannot give rise to o- or p-quinonoid the fact that, during autoxidation, only the final products can
products on removal of two electrons, its behavior in the be identified spectroscopically. Whcther a pair of electrons is
transferred to the oxygen in the first step, with formation
first oxidation step is that of a monophenol whose of the hydroperoxide derivative (71). or whether at first only
oxidation potential is lowered by the second hydroxy one electron changes its location, leading to the radical pair
group. (70), has not been resolved [I 131. Free orcinol radicals (62),
are not formed as intermediates, as is indicated by the fact
that the dimer (68) cannot be detected at any time in solu-
c tion. The dimer (68) reacts with oxygen as fast as orcinol
(66) does, and the presence of the latter can be readily
HO
determined chromatographically until the absorption of
HO
oxygen is complete. If potassium ferricyanide is added during
OH the react.ion, (68) can be found in the solution, and the
(69) oxygen absorption does not increase. This indicates that the
orcinol radicals (67) react faster among themselves or with
orcinol(66) to produce dimer (68) than with oxygen.
Since the rate of the autoxidation of orcinol corresponds
approximately to its relative oxiddion potential, it can be
assumed that the rate-determining step is the same for all
phenol oxidations and that here, loo, only one electron is
first transferred to the oxygen [I 141. The transfer of the
second electron in the radical pair (70) must take place
rapidly before radical (67) is liberated and can dimerize to
'*

0 'OH '
0-OH

OH
- (68).
The occurrence of the hydroperoxide intermediate (71) -
although it cannot be demonstrated directly - is made
probable by the formation of the highly stable hydroperoxide
(57) and by the following reactions. Oxidation of 4,6-di-t-
butylresorcinol (78) with air at -20 O C gives good yields of
the hydroperoxide (79), which is analogous to (71) 11151and
OH which undergoes thermal decomposition to 2-t-butyl-S-
HO hydroxybenzoquinone (80), isobutylene, and other products.
Whether the intermediates (72) and (73) are also formed in
the case of orcinol has not been determined.
HO OH
I741 (73)

HO H
( 781

Scheme 2. Products resulting from the oxidation of orcinol (66).

0&: (82)

The oxidation of orcinol (66) with potassium ferri-

cyanide in alkaline solution or with lead dioxide in
benzene and its photo-dehydrogenation with benzo-
phenone produce a mixture of polymers, e.g. (as),
containing only small percentages of dimer (68). The
formation of (68)can be consideredas proof that radical
(67) is involved in the reaction. Boiling of the polymers [112] H. Kramer, Ph. D. Thesis, Universitat Giittingen, 1960.
with sodium in pyridine causes them to undergo partial [113] U.v. Gizycki, Ph. D. Thesis, Universitiit Marburg. 1963.
[114] See the discussion of the similar mechanism of the autoxi-
cleavage into (66) and (68).This indicates that polymer dation of enolate ions to hydroperoxy ketones: E. J. Bailey, D.
(69) also contains ether linkages. The formation of H . R. Barton, J. Elks. and J. F. Templeton. J. chem. SOC.(London)
products with rings coupled through the positions 1962; 1518; H.R. Gersman, H.J. Nieuwenhuis, and A. F. Bickel,
Proc. chem. SOC.(London) 1962,219; G. A. Russell, E. G. Jamen,
[ill] Review: € . U. v. Gizycki, E. M . Gottschalk, H.
Beecken,
I H. D. Becker, and F. J. Srnentowslti, J. Amer. chem. SOC. 84,
Kramer, D . Maapen, H . 4 . Matthies, H. Musso, C. Rathjen, and 2652 (1962).
U.I. Zbhorszky, Angew. Chem. 73,665 (1961). [115] H.Musso and D. Maajen, unpublished results.

Angew. Chem. internat. Edit. Vol. 2 (1963) No. 12 731

In the autoxidation of 4,5,6-trimethylresorcinol (81), only oxidation of hydroxyhydroquinones to quinones, and slower
the quinol (82) was isolated but in 60 "/, yield [116]. In the than the addition of resorcinol, the introduction of nitrogen,
autoxidation of 5-t-butylresorcinol (83), biphenyl coupling and the ring closure "201 (also cf. Fig. 2). The introduction
to give (84b) is sterically so hindered that it is possible to of the second and third nitrogcn atoms into dyes (886) and
isolate the monomeric quinone ( 8 4 4 [117]. On oxidation (884 also takes place at thc hydroquinone stdge, vir. (75)
o f orcinol, biphenyl coupling takes place by way of addition and (85) [120].
ofthe orcinol anion onto the hydroxyquinone (74) [118]. The The substitution of a hydroxyl group, by an amino group i n
dimeric diquinone (77) is formed both as a result of further the presence of air apparcntly a free-radicdl process -. was
oxidation of the monoquinone (76) and by addition of (73) recently also reported for derivatives of pyrocatechol and
onto (74) [113]. pyrogallol [ 1231.
It should be noted that hydroquinones and pyrocatechok
readily undergo enzymatic oxidation, but that derivatives of
resorcinol and phloroglucinol are not attacked by tyrosinase VII. Addition of Phenols onto Quinones
[78]. Resorcinol and phloroglucinol inhibit the oxidation of
p-cresol with a phenol oxidase from potatoes [I 191.
Autoxidation of resorcinol derivatives in the presence of Addition of a hydroxyquinone (91) to a n alkaline
ammonia affords orceine and litmus dyes. These consist solution of a resorcinol derivative or oxidation of a
of mixtures of 7-hydroxy- and 7-aminophenoxazones hydroxyhydroquinone with oxygen in the presence of
and 7-aminophenoxazimes of type (88) [I 111. Ammonia resorcinol anions affords ( hydroxyary1)hydroxyquinone.s
(92) sometimes in high yields (Table I).

1 1 0% N f l 011 HO

(87)
I10
0 '
0 0
I1 II
' 011
OH
- H 11 (861

participates in the autoxidation of resorcinol derivatives Table 1 . Yields c d (hydroxyaryl)hydroxyquinones (92).

by replacing a hydroxy group of the hydroxyhydro-

quinone intermediate (7.5), thus affording (85) and (86)
[ 1201. After the diphenylamine derivative (86) has been
oxidized to the indophenol (87), ring closure to the
orceine dye (88) can take place.
The autoxidation of resorcinol [121] and 2,5-dimethylresor-
cinol [122] proceeds analogously. On treatment with air,
2,4,5,2',4'-pentahydroxy-6,6-dimethyl biphenyl (75) in aque-
ous ammonia affords a 33 yield of p- and y-hydroxyorceine
( 8 8 ~ )Autoxidation
. of 2-amino-orcinol in the presence of
resorcinol in aqueous sodium bicarbonate solution and
autoxidation of hydroxyhydroquinone in ammoniacal or-
cinol solution afford 19 and 25 "/, yields, respectively, of the
orceines (89) and (YO) which are isomeric with respect to the
methyl group. The syntheses o f (89) and (YO) show that the
formation of the simple orceines by oxidation of resorcinol
or orcinol in the presence of NH3 is much slower than the Hydroxyquinones and liydroxyhydrsquinones produce
hydroxydiquinones (9.3)
[I161 H . Musso, D. M u f f l h , and D. Bormann, Chem. Ber. 95,
2837 (1962).
[ I 171 H. Musso and I). Hormann, unpublished results.
[ t t 8 ] The coupling mechanism discussed in [ t t l ] is no longer
valid, since a repetition or the experiments led to appreciably
higher yields of the dimeric mono- and diquinones.
[I191 G. Schneider and S. Schmidt, Hoppe-Seylers Z. physiol.
Chem. 315, 20 (1959).
[I201 U.I. Zdhorszky, Hi. D. Thesis, Universitat Marburg, 1963.
[I211 H. Musso, L). MtraJen, U . I. Zhhorszky, and I. Seeger,
Chem. Ber. 96, 1579 ( I 963). [I231 K. Ley, Angew. Chuni. 74, 871 (1962); Angew. Chem.
11221 H. MNSSO and C. KathiPn, Chem. Ber. 96,1593 (1963). internal. Edit. I, 591 (1962).

732 Angew. Chvm. inti,^ r i t r t . Edit. I Vol. 2 (1963) 1 No. I?

Treatment of benzoquinone with phenol yields com-
plicated mixtures from which, in additiqn to hydroxy-
quinone and polymers, the dirneric and trimeric
compounds ( 9 4 4 -- (94r) have been isolated by
chromatography and identified by comparison with
authentic samples [ 1 131. The yields are listed in Table 2.
With phenoxide in benzene or dioxan, only polymers
and hydroquinone are formed. Phenoxide in dimethyl-
formamide or dimethyl sulfoxide affords (94e;).

T a b l e 2. Yields obtained from t h e reaction of p-benzoquinone with

phenol under various conditions.

ll
0
iY4a), I t = H, It' 011
/ 9 4 h ) , ] { = O H , lt'=ii

In BF,/ether 1 16 I7 1 1
It is noticeable that phenols in contrast to thiophenol and
aniline - . undergo substitution with quinone, preferably at
the u- o r p-positions. The reaction via the phenoxyl oxygen
becomes appreciable only in neutral solution. These ex- VIII. Syntheses of Natural Products
periments are of interest with regard t o the structure of the
synthetic humic acid that i s obtained by oxidation of hydro-
quinone. They show that ether linkages are also formed in the
As early as 1911, Gadumrr [I281 attempted to explain
reaction of phenols with quinones, particularly in neutral
solution [124]. the biosynthesis of glaucine (102) by assuming that
laudanosoline (101) was dehydrogenated in plant cells.
The addition of a nucleophilic reagent onto a labile
quinone is advantageously carried out by oxidizing the
hydroquinone in the presence of the reagent. This is
exemplified by the syntheses of the binaphthylquinone
(95) [ 1251, brevifolin (98) [126], and wedelolactone
(100) [127] by addition of the anions (97) and (99) onto
the o-quinone derived from methyl gallate (96) and
onto o-benzoquinone, respectively. The o-quinones are
prepared in situ by oxidation with potassium ferri-
cyanide.
This scheme probably explains all, even intramolecular,
Later Robinson [129] and S'chijpf [ I301 applied this
C - - C couplings occurring during the oxidation of
concept in view of the synthesis of morphine. A
phenols whereby one residue has an 0- or p-hydro-
few years ago, Erdtnian and Wuchtmristw [2] and Barton
quinone structure.
and Cohen [ I ] pointed out that the biosynthesis of
[I241 CT. W. EIIer, Ber. dtsch. chern. Gcs. 53, 1473 (1920); H. numerous alkaloids, lichen substances, and metabolites
Erdrnion, 2. I'flanzcnerniihr., Dung., Bodenkunde 69, 38 (1955);
W . Ziechmnnn, Naturwissenschaften 48, 456 (1961). [I281 J. Gndamer, Arch. Pharmaz. Rcr. dtsch. pharmaz. Ges. 24Y,
[ I 251 F. SrrauJ, 0 . Bernoully, and P. Mnutner, Licbigs Ann. 498 (191 I).
Chern. 444, 165 (1925). [I291 R . Robinsonand S. Sugasnwo, I . chern. SOC.(London) 1931,
[126j H . W. Wanzlick, Chern. Ber. Y2, 3006 (1959). 3163; 1936, 1079.
11271 11. W . Wantlick, R . Gritzky, and H . Hcidepriern, Chem. [I301 C. Sch~pf'andK. Tier/;.lder, Liebigs Ann. Chern. 4Y7, 22.
Rer. 96, 305 (1963). 47, 59 (1932).

733
from microorganisms can often be explained by oxida- Model experiments for the biosynthesis of thyroxine
tion of phenols in the cell. Although it is extraordinarily have shown that treatment of dibromotyrosine (110)
difficult to prove that such oxidations really occur in the with the tri-t-butylphenoxy radical leads to the quinol
living cell, it has been possible within recent years to ( l l l ) , which on acid catalysis, undergoes dewmposi-
synthetize many complex natural products or closely tion into the thyroxine analogue (112) and isobutylene
related compounds by oxidation of phenols [131]. As [141].
oxidizing agents, ferric chloride or potassium ferri-
cyanide in water, or manganese dioxide or lead dioxide
in benzene or chloroform were found to be particularly 2 - 0 9 I i O ~ C H 2 - ~ H - C O O+
R
suitable for this purpose. In formulae (103) to (109), NH2
the bonds established by phenol oxidation are crossed
(110)
by dashed lines. Further examples are podototarine
[138],geodine[135], geodoxine [I391and diploicine[140].

&+pO @

OCH,
OC'13 :;::3:; OH

OH
0 NO

0 HO
+
oo

H o ~ o
Br.

~
1/11)

H q
I -cooR
cHrcH
NH2

i ~ - c m R
NHZ
1/03) 11321 (104) 11331
3-Libocedroxy- Hypericin 1112)
- thymoquinone

The numerous oxidation products obtained from coniferyl

y 3
alcohol and their significance f o r t h e elucidation of the
structure a n d mechanism of the formation of lignin will not
be discussed in view of a comprehensive report o n this subject
recently published by Freudenberg 11421. For t h e synthesis of
alkaloids by phenolic oxidation see [143].
A '
Admittedly, oxidation of the postulated precursor occasionally
(105) 11341 1106) 17)
Magnolol Usnic acid does not lead to the natural product. For example, o n

1107) 11351 ll0Hj 11361 1109) 11371

Griseofulvrn I'icrolichenic Asteric acid
acid

[I311 Review: E. E. v. Tamelen, Fortschr. Chem. org. Natur- autoxidation of orcinol in alkaline solution, n o t even a trace
stoffe 19,224 (1961); J. R . Lewis, Chem. and lnd. 1962, 159. of phenicine (113) b u t only the quinones (76) and (77) a r e
[I321 E. Zavarin, J. org. Chemistry 23, 1198 (1958). produced 1651.
[I331 H . Brockmann, Fortschr. Chem. org. Naturstoffe 14, 141
(1957). 0 OH 0
[I341 J . Runeberg, Acta chem. scand. 12, 188 (1958).
[I351 A. I. Scott, Proc. chem. Soc. (London) 1958, 195; A. C. H s c W H3
Day, J. Nabney, and A. I . Scott, J. chem. SOC. (London) 1961,
4061; C . H . Kuo, R . D. Hoffsommer, H . L. S a t e s , D. Taub, and 0 HO 0
N.L. Wendler, Chem. and Ind. 1960, 1627; D. Taub and N. L. (113)
Wendler, Angew. Chem. 74, 586 (1962); Angew. Chem. internat.
Edit. I , 506 (1962).
[I361 T . A . Davidson and A . I . Scott, Proc. chem. SOC. (London) [I411 T. Matsuura and H.J . ('ahnmantz, J. Amer. chem. SOC. 82,
1960, 390. 2050, 2055 (1960); T. Matsuurcr and A . Nishinaga, J. org. Chem-
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134 Angew. Chem. internut. Edit. 1 Vol. 2 (1963) 1 No. 12

 IX. Conclusion cerning the mechanism of this reaction and the electronic
structure of the free phenoxyl radicals are still missing.
Nevertheless, numerous interesting compounds will be
From the Preceding review, it can be Seen that the synthetized by this method in the future as a result of
oxidation of phenols is Of great interest in many areas the continuing discoveries or new natural products
of organic chemistry. The study of stable PhenoxYl which may be envisioned as arising by phenolic oxida-
radicals, in particular, has contributed to an under- tion, e.g, (114)-(124).
standing of this reaction, although many details con-

H3N=c
Ho \ /
/ N=C

OCH,
0 011
(121)
HO
[153]
Actinorhodine
0

(114) (116)
Xanthocillin [ 1441 Otabin and Schizandrin; R = OH [ 1,461
other lignans 11451 Deoxyschizandrin; R = €1 [ I

6H OH
11541
Erpoflavin

(1171 (118)
Elsinochrome A [1481 [Crythroaphin [ 1501
Phycarone 11491
I

1123) 11551

(119)
Xylindein 1151)
H
OCHS

(124) 11561
Thalica rpine

(120) [152]
Received, J u l y 26th, 1963 [A 331/124 IE]
Xanthomegnin German version: Angew. Chem. 75, 965 (1963)

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