Estimation of Phenols by the 4-Aminoantipyrine Method. II.

Products from para-Substituted Alkylphenols

Reginn Water Researclt Itwtitute, Utiiuersit)~of Snskatche,vatt, Regina, Saskatclte~~~ml

S4S 0 A 2
Received May 17, 1973

4-Aminoantipyrine reacts with p-alkylphenols on oxidation with potassium ferricyanide t o give yellow
ortl~o-quinoneimides.These undergo a thermal and base-cataiyzed rearrangement t o benzodihydro-
oxazepines.
L'amino-4 antipyrine reagit avec les p-alkylphenols oxydes par le ferricyanure de potassium pour
donner des ortlro-quinonimides jaunes. Ces derniires se transforment sous I'influence de la chaleur ou
des bases pour fournir des benzodihydrooxazepines. [Traduit par le journal]
Can. J. Chem. 51, 3733 (1973)

We have recently confirmed (1) that the

colorimetric estimation, using 4-aminoantipyrine
(I), of phenols which are either unsubstituted, or
have a readily eliminated substituent at the para
position, involves oxidative para coupling to (X = H , CI, C02H, OMe) h e h~~
form red p-quinoneimide dyes 2 (see Scheme 1).
We now report the results of a study where the
para position of the phenol is blocked by an alkyl
group. Emerson (2) found that phenols having an
alkyl, aryl, nitro, nitroso, benzoyl, ester, or
aldehyde group in the para position did not show
a color response to the 4-aminoantipyrine test.
From this he correctly concluded that a positive
color reaction involved oxidative para coupling.
However, Czech workers (3) have recently re-
ported that when the Emerson reaction is carried
out with p-alkylphenols using higher concentra- spectrum of this compound revealed that it could
tions of reagents, a turbidity is produced. The not be the o-quinoneimide adduct 3 a , since it
precipitate was isolated from p-cresol. Although displayed only two methyl singlets, whereas 3a
initially yellow, on purification it gave a white, should have three such signals.
photochromic solid, m.p. 225-227". On the sole Comparison of the p.m.r. spectrum of the
basis of a molecular formula, itself incorrectly crude original product with that of t h e purified
computed from elemental analyses, it was con- sample showed that the latter was not present to
cluded that the latter compound arose from
ortho coupling.
The lack of conclusive evidence for this, the
first reported example of oxidative ortho cou-
pling in this system, has led us t o reinvestigate
the reaction. The oxidation of a mixture of p-
cresol and 4-aminoantipyrine by potassium
ferricyanide did indeed result in the formation
of a yellow precipitate (Scheme 2). Recrystal-
lization from ethanol gave a cream solid, m.p.
22&227", which appears t o be the same product
as that previously reported. However, the p.m.r.
 CAN. J . CHEM. VOL. 51, 1973
any extent initially. This suggests that recrystal-
lization must have resulted in decomposition of
the initial adduct. Accordingly, conditions were
sought where the initial yellow adduct could be
purified without decomposition. This was simply
achieved by using non-hydroxylic solvents in the
recrystallization step. A bright yellow solid was
obtained, whose p.ni.r. spectrum displayed the
three methyl singlets required for 3a.
The p.m.r. spectra of the two compounds differ
notably in the removal of a C-Me singlet at
6 1.52 originally present in 3a, and its replace-
nient by a two proton singlet at 6 5.00 in the
rearranged product. The position of the latter
signal is suggestive of the formation from a
methyl group of either an exocyclic methylene
group o r the allylic protons of an ally1 ether. In
the i.r. spectrum of the rearranged product,
bands at 2.95 and 3.05 p, absent in starting 3a,
indicate the formation of an -OH o r -NH
group. Further evidence for this is seen in the
p.m.r. spectruni of the rearranged compound by
the presence of a broad, one proton singlet at
6 6.12, which is removed on deuteration. From
these observations, two different reactions appear
possible, either the loss of the antipyryl C-methyl
group to form a phenol 5a (path 6 ) o r the hetero-
cycle 4a (path a),' o r the renloval of the methyl
group of the original phenol t o give a para-
quinonemethide, 6a (path c) (see Scheme 3).
T h e above evidence is insufficient to allow a
decision between these possibilities. Accordingly,
t o find mhich of the two C-methyl groups was
involved in the above rearrangements, the reac-
tion was carried out with p-ethylphenol under
conditions where the rearranged product would
be expected. In this case, it should be simple to
distinguish the formation of 46 o r 56 from that
of the p-quinoneniethide 66.
In fact, the p.m.r. spectrum of the reaction
product clearly reveals that path c cannot be the
operative reaction, since the retention of the
ethyl group, a n d also the formation of the
methylene group as a two proton singlet at an
identical position t o that of the rearrangement
product from p-cresol can be seen. On the basis
of the spectroscopic evidence alone, it is difficult
t o distinguish between the formation of the
phenols 5a and b o r their ring closed counter-
parts, the substituted dihydro-oxazepines 4a a n d
6. The observation that the methylene protons
appear as a singlet might seem t o favor 4a and 6 ,
'We thank a referee for pointing out this possibility.
 J O N E S A N D J O H N S O N : E S T I M A T I O N O F P H E N O L S . 11
0 A
t
[1,71 sigmatropic
I
Me rearrangement
whose allylic protons are equivalent, whereas the
methylene protons of 5a and b should be non-
equivalent. However, it is frequently found that
non-equivalent exocyclic methylene protons do
not show geininal coupling (4a), therefore the
phenol structures cannot be ruled out on this
basis. They may be rejected on chemical evi-
dence, however, since thep-cresol rearrangement
product is completely insoluble in 5% aqueous
sodium hydroxide and gives no color with ferric
chloride, both reactions which are used to
characterize phenols (5).
Unusual behavior on melting of the o-
quinoneimide adduct 3a suggested that the above
rearrangement might also occur thermally. The
yellow compound melted at 148-1 50". With
increase in temperature, the melt decolorized and
partially crystallized. Final remelting occurred
at 210-220°, suspiciously similar to the m.p. of
rearranged 4a. The thermolysis could be con-
veniently followed by p.m.r. spectroscopy in
bronlobenzene solvent, in which 3a showed
methyl singlets at 6 1.00, 1.90, and 2.21 p.p.m.
On heating the sample at 139", these signals
diminished in intensity, and the build-up of new
signals at 6 1.75, 2.1 1, and 4.44 p.p.m. was seen.
After 20 min the starting signals had been com-
pletely removed, and the new signals, in the ratio
3:3:2, were the only ones present. They were
found to be identical to those of an authentic
sample of 4a in bromobenzene. Rearranged 4a
cyclization
was recovered in good yield from the thermolysis
mixture.
The thermal reaction may proceed through an
intramolecular cyclization mechanism, possibly
with an initial [1,7] sigmatropic rearrangement
to the isojneric phenol 5a, which then undergoes
cyclization (see Scheme 4). This would pre-
suppose that the o-quinoneimide must be in a
suitable configuration for interaction, namely
with the antipyryl ring syri to the carbonyl group.
The unusually high field position of the antipyryl
C-methyl signal of 3a at 6 1.52 p.p.m., being
shielded by approximately 1 p.p.m. compared
with the corresponding group in paru-quinonei-
mides, where the signal appears in the range
6 2.49-2.60 p.p.m. (I), would indicate that 3a
does exist in the ground state configuration
shown. Shielding of a proton located above the
plane of the carbonyl group is well documented
(4b).
The proposed initial [1,7] sigmatropic shift is
allowed thermally as an antarafacial process by
the Woodward-Hoffmann rules (6).
The ease of rearrangement of the o-quinonei-
mides in hydroxylic solvent at or below room
temperature suggests the operation of an alter-
native mechanism, possibly involving a base-
catalyzed reaction with an external nucleophile,
presumably ethoxide ion (Scheme 5). Some evi-
dence to support a base-catalyzed rearrangement
has been obtained. Thus 3a appeared to be stable
3736 CAN. J. CHEM. VOL. 51, 1973
in deuterochloroform solvent, only 8% rearrange-
ment being observed after 3 days at room
temperature. However, addition of pyridine to
the reaction mixture accelerated the rearrange-
nient since 78% isomerization occurred after a
further 3 days. After rearrangement was seen to
be complete, 4a was isolated in 56% yield.
Experimental
4-Aminoantipyrine (Aldrich) and the starting phenols
were purchased from commercial suppliers and were used
without further purification. Buffer solution of p H 10.4
was prepared by dissolving dry buffer salt (Fisher) in
distilled water.
Melting points were taken on a hot stage apparatus
and are uncorrected. Microanalyses were performed by
Galbraith Laboratories Inc., Knoxville: Tennessee. P.m.r.
spectra were recorded on a Varian A-60 spectrometer in
deuterochloroform solvent and with tetramethylsilane as
an internal standard. 1.r. spectra were obtained on a
Beckman IR 8 instrument with polystyrene calibration.
Reaction of ~ - A ~ ~ I ~ ~ I o ~~'itlr
~ ~ p-CI
I ~ ~c~.\o/
~ J ~ I ' ~ I I c
((I) T o a stirred mixture of 0.35 g (0.0032 mol) of p-
cresol and 1.1 g (0.0054 rnol) of 4-aniinoantipyrine in
250 ml of buffer solution was added, in one portion. 21 g
(0.064 n ~ o l )of potassi~ln~
ferricyanide. A yellow precipi-
tate immediately formed. The reaction mixture was stirred
for 30 min and the solid was filtered off, washed with
water, and was allowed to dry in air in the dark. The
crude yellow product, 1.16 g, n1.p. 29-12O0, was re-
crystallized from 95% ethanol to give 0.25 g of 4a as
gleaming cream flakes, n1.p. 218-222". Addition of water
to the filtrate gave, on standing, further solid. m.p.
210-220". Both crops had identical spectra and the total
yield of 411 was 0.38 g (38%). Further recrystallization
from ethanol gave the analytical sample, n1.p. 224-227".
P.m.r. 6 7.7-6.7 (ni, 8H, aromatic), 6.12 (broad s, I H ,
removed on addition of D,O, N H ) , 5.00 (s, 2H, CH,),
2.81 (s, 3H, NMe), 2.25 (s, 3H, CMe); i.r. (CHCI,) 2.95,
3.05 (NH), 6.02 (C=O).
Anal. Calcd. for C l s H 1 7 N 3 0 2 :C, 70.34; H, 5.58; N,
13.67. Found: C, 70.44; H, 5.61 ; N, 13.62.
The product was completely insoluble in 5% aqueous
sodium hydroxide, even on heating, and an ethanolic
solution showed no noticeable color change on addition
of ferric chloride solution.
(b) The dried yellow precipitate, prepared as above
from 0.31 g (0.0029 rnol) of p-cresol, 1.1 g (0.0054 rnol)
of 4-aminoantipyrine, and 20 g (0.061 mol) of potassium
ferricyanide in 250 ml of buffer solution. was dissolved in
methylene chloride. Addition of petroleum ether (b.p.
100-115") precipitated 0.17 g of amorphous solid, m.p.
115-140". whose p.m.r. spectruni was similar to that of
unidentified impurities obtained during the preparation
of some p-quinoneimides (I). The clear yellow filtrate
was evaporated and the resulting solid was recrystallized
from pentane to give 0.39 g (44%) of yellow 3a, m.p.
145-155". The p.m.r. spectrum indicated the product was
an 87:13 mixture of 3a and 40. Several recrystallizations
from pentane gave pure 3a, m.p. 148-150" (resolidifies
and remelts 210-220"). P.m.r. 6 8.22-8.00 (m, 2H, vinyl),
7.70-6.85 (m, 6H, aromatic + vinyl), 2.74 (s, 3H, NMe),
2.37 (s, 3H, CMe), 1.52 (s, 3H, antipyryl CMe); i.r.
(CHCI,) 5.89, 6.06 p (C=O).
Anal. Calcd. for C I s H , 7 N 3 0 , : C, 70.34; H, 5.58; N,
13.67. Found: C, 70.40; H, 5.67; N, 13.70.
Reactiot~o ~ ~ - A I I I ~ I I o cwith~ ~p-Etl~ylphet~ol
~~@~I'~II~
T o a stirred mixture of 0.35 g (0.0029 mol) of p-ethyl-
phenol and 1.2 g (0.0059 mol) of 4-aminoantipyrine in
250 n ~ of
l buffer solution was added, in one portion, 20 g
(0.061 mol) of potassium ferricyanide. A yellow precipi-
tate immediately formed. The reaction mixture was
filtered after 30 min and the yellow solid obtained was
dissolved in 95% ethanol. The solution on cooling
deposited 0.24 g of 46, m.p. 199-201". Addition of water
to the filtrate gave, on standing, further solid, m.p. 198-
200". The total yield of 4b was 0.39 g (42%). Further
recrystallization from ethanol gave the analytical sample,
m.p. 199-201". P.m.r. 6 7.7-6.6 (m, 8 H , aromatic), 6.35
(broads, IH, NH), 5.00 (s, 2H, CHI), 2.81 (s, 3H, NMe),
2.53 (q, J = 8 Hz, 2H, CH2CH3), 1.16 (t, J = 8 Hz, 3H,
C H 2 C H 3 ) ; i.r. (CHCI,), 2.95, 3.05 ( N H ) , 6.02 11(C=O).
Anal. Calcd. for C1,H,,N30,: C, 71.01; H, 5.96; N,
13.08. Found: C, 71.27; H, 6.10; N, 13.08.
Ther-tila1Rearrntrgeti~et~tof 3a
A 60 mg (0.0002 mol) sample of 3n was dissolved in
approximately 0.5 ml of bromobenzene. A p.m.r. spectrum
of the solution showed three singlets a t 6 1.00, I .90, and
2.21 p.p.m. (external TMS). The n.m.r. sample tube was
placed in a preheated oil bath at 139". The sample was
withdrawn after 10 niin and the p.1n.r. spectrum was
examined. It showed a diminution of the intensities of the
above three singlets and the formation of new singlets at
6 1.75, 2.1 1, and 4.45 p.p.m. These new signals were in
the ratio 3 :3 :2 and subsequent examination of an authen-
tic sample of 4a in bromobenzene revealed peaks at
identical positions. T h e ratio of 3a:4a was 24:76, as
estimated from peak heights. After a further 10 min at
13g0, the signals of starting 3a were completely removed
and 40 appeared to be the sole product. Addition of
petroleum ether (b.p. 100-115") to the sample precipi-
tated 48 mg (80%) of crude 40, m.p. 200-214". A solution
of this product in deuterochloroform showed a p.m.r.
spectrum identical t o that of authentic 4a. Further
purification by recrystallization from 95% ethanol gave
25 m g (42%) of pure 4a, m.p. 217-221".
Base-catalyzed Rearrat~gett~e/ltof 3a
A 50 mg (0.00016 mol) sample of 3 a was dissolved in
approximately 0.5 ml of deuterochloroform. The solution
was stored in the dark a t room temperature. After 3 days,
the p.m.r. spectrum showed 8% rearrangement to 4a.
Pyridine, approximately 0.26 g (0.0032 rnol), was added
by dropper to the solution. The mixture was stored in the
dark and its p.m.r. spectrum was examined at intervals.
T h e observed extent of rearrangement t o 4a was 14 (3h),
36 (24 h), 60 (44 h), and 78% (70 h). Examination after
6 days showed complete rearrangement t o 4a. Addition of
petroleum ether (b.p. 100-1 15") precipitated 28 mg (56%)
of 4a, m.p. 215-222".
Grateful acknowledgement is made to the National
Research Council of Canada for its generous support of
this work.
 JONES AND JOHNSON: ESTIMATION O F PHENOLS. I1
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3737
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