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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-
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- cycle 4a (path a),' o r the renloval of the methyl
lization must have resulted in decomposition of group of the original phenol t o give a para-
the initial adduct. Accordingly, conditions were quinonemethide, 6a (path c) (see Scheme 3).
sought where the initial yellow adduct could be T h e above evidence is insufficient to allow a
purified without decomposition. This was simply decision between these possibilities. Accordingly,
achieved by using non-hydroxylic solvents in the t o find mhich of the two C-methyl groups was
recrystallization step. A bright yellow solid was involved in the above rearrangements, the reac-
obtained, whose spectrum displayed the tion was carried out with p-ethylphenol under
three methyl singlets required for 3a. conditions where the rearranged product would
The p.m.r. spectra of the two compounds differ be expected. In this case, it should be simple to
notably in the removal of a C-Me singlet at distinguish the formation of 46 o r 56 from that
6 1.52 originally present in 3a, and its replace- of the p-quinoneniethide 66.
nient by a two proton singlet at 6 5.00 in the In fact, the p.m.r. spectrum of the reaction
rearranged product. The position of the latter product clearly reveals that path c cannot be the
signal is suggestive of the formation from a operative reaction, since the retention of the
methyl group of either an exocyclic methylene ethyl group, a n d also the formation of the
group o r the allylic protons of an ally1 ether. In methylene group as a two proton singlet at an
the i.r. spectrum of the rearranged product, identical position t o that of the rearrangement
bands at 2.95 and 3.05 p, absent in starting 3a, product from p-cresol can be seen. On the basis
indicate the formation of an -OH o r -NH of the spectroscopic evidence alone, it is difficult
group. Further evidence for this is seen in the t o distinguish between the formation of the
p.m.r. spectruni of the rearranged compound by phenols 5a and b o r their ring closed counter-
the presence of a broad, one proton singlet at parts, the substituted dihydro-oxazepines 4a a n d
6 6.12, which is removed on deuteration. From 6. The observation that the methylene protons
these observations, two different reactions appear appear as a singlet might seem t o favor 4a and 6 ,
possible, either the loss of the antipyryl C-methyl
group to form a phenol 5a (path 6 ) o r the hetero- '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 cyclization
[1,71 sigmatropic
Me rearrangement

whose allylic protons are equivalent, whereas the was recovered in good yield from the thermolysis
methylene protons of 5a and b should be non- mixture.
equivalent. However, it is frequently found that The thermal reaction may proceed through an
non-equivalent exocyclic methylene protons do intramolecular cyclization mechanism, possibly
not show geininal coupling (4a), therefore the with an initial [1,7] sigmatropic rearrangement
phenol structures cannot be ruled out on this to the isojneric phenol 5a, which then undergoes
basis. They may be rejected on chemical evi- cyclization (see Scheme 4). This would pre-
dence, however, since thep-cresol rearrangement suppose that the o-quinoneimide must be in a
product is completely insoluble in 5% aqueous suitable configuration for interaction, namely
sodium hydroxide and gives no color with ferric with the antipyryl ring syri to the carbonyl group.
chloride, both reactions which are used to The unusually high field position of the antipyryl
characterize phenols (5). C-methyl signal of 3a at 6 1.52 p.p.m., being
Unusual behavior on melting of the o- shielded by approximately 1 p.p.m. compared
quinoneimide adduct 3a suggested that the above with the corresponding group in paru-quinonei-
rearrangement might also occur thermally. The mides, where the signal appears in the range
yellow compound melted at 148-1 50". With 6 2.49-2.60 p.p.m. (I), would indicate that 3a
increase in temperature, the melt decolorized and does exist in the ground state configuration
partially crystallized. Final remelting occurred shown. Shielding of a proton located above the
at 210-220°, suspiciously similar to the m.p. of plane of the carbonyl group is well documented
rearranged 4a. The thermolysis could be con- (4b).
veniently followed by p.m.r. spectroscopy in The proposed initial [1,7] sigmatropic shift is
bronlobenzene solvent, in which 3a showed allowed thermally as an antarafacial process by
methyl singlets at 6 1.00, 1.90, and 2.21 p.p.m. the Woodward-Hoffmann rules (6).
On heating the sample at 139", these signals The ease of rearrangement of the o-quinonei-
diminished in intensity, and the build-up of new mides in hydroxylic solvent at or below room
signals at 6 1.75, 2.1 1, and 4.44 p.p.m. was seen. temperature suggests the operation of an alter-
After 20 min the starting signals had been com- native mechanism, possibly involving a base-
pletely removed, and the new signals, in the ratio catalyzed reaction with an external nucleophile,
3:3:2, were the only ones present. They were presumably ethoxide ion (Scheme 5). Some evi-
found to be identical to those of an authentic dence to support a base-catalyzed rearrangement
sample of 4a in bromobenzene. Rearranged 4a has been obtained. Thus 3a appeared to be stable
3736 CAN. J. CHEM. VOL. 51, 1973

in deuterochloroform solvent, only 8% rearrange- 7.70-6.85 (m, 6H, aromatic + vinyl), 2.74 (s, 3H, NMe),
ment being observed after 3 days at room 2.37 (s, 3H, CMe), 1.52 (s, 3H, antipyryl CMe); i.r.
(CHCI,) 5.89, 6.06 p (C=O).
temperature. However, addition of pyridine to Anal. Calcd. for C I s H , 7 N 3 0 , : C, 70.34; H, 5.58; N,
the reaction mixture accelerated the rearrange- 13.67. Found: C, 70.40; H, 5.67; N, 13.70.
nient since 78% isomerization occurred after a
Reactiot~o ~ ~ - A I I I ~ I I o cwith~ ~p-Etl~ylphet~ol
further 3 days. After rearrangement was seen to T o a stirred mixture of 0.35 g (0.0029 mol) of p-ethyl-
be complete, 4a was isolated in 56% yield. 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-
Experimental tate immediately formed. The reaction mixture was
4-Aminoantipyrine (Aldrich) and the starting phenols filtered after 30 min and the yellow solid obtained was
were purchased from commercial suppliers and were used dissolved in 95% ethanol. The solution on cooling
without further purification. Buffer solution of p H 10.4 deposited 0.24 g of 46, m.p. 199-201". Addition of water
was prepared by dissolving dry buffer salt (Fisher) in to the filtrate gave, on standing, further solid, m.p. 198-
distilled water. 200". The total yield of 4b was 0.39 g (42%). Further
Melting points were taken on a hot stage apparatus recrystallization from ethanol gave the analytical sample,
and are uncorrected. Microanalyses were performed by m.p. 199-201". P.m.r. 6 7.7-6.6 (m, 8 H , aromatic), 6.35
Galbraith Laboratories Inc., Knoxville: Tennessee. P.m.r. (broads, IH, NH), 5.00 (s, 2H, CHI), 2.81 (s, 3H, NMe),
spectra were recorded on a Varian A-60 spectrometer in 2.53 (q, J = 8 Hz, 2H, CH2CH3), 1.16 (t, J = 8 Hz, 3H,
deuterochloroform solvent and with tetramethylsilane as C H 2 C H 3 ) ; i.r. (CHCI,), 2.95, 3.05 ( N H ) , 6.02 11(C=O).
an internal standard. 1.r. spectra were obtained on a Anal. Calcd. for C1,H,,N30,: C, 71.01; H, 5.96; N,
Beckman IR 8 instrument with polystyrene calibration. 13.08. Found: C, 71.27; H, 6.10; N, 13.08.
Reaction of ~ - A ~ ~ I ~ ~ I o ~~'itlr
~ ~ p-CI
I ~ ~c~.\o/
~ J ~ I ' ~ I I c Ther-tila1Rearrntrgeti~et~tof 3a
((I) T o a stirred mixture of 0.35 g (0.0032 mol) of p- A 60 mg (0.0002 mol) sample of 3n was dissolved in
cresol and 1.1 g (0.0054 rnol) of 4-aniinoantipyrine in approximately 0.5 ml of bromobenzene. A p.m.r. spectrum
250 ml of buffer solution was added, in one portion. 21 g of the solution showed three singlets a t 6 1.00, I .90, and
(0.064 n ~ o l )of potassi~ln~
ferricyanide. A yellow precipi- 2.21 p.p.m. (external TMS). The n.m.r. sample tube was
tate immediately formed. The reaction mixture was stirred placed in a preheated oil bath at 139". The sample was
for 30 min and the solid was filtered off, washed with withdrawn after 10 niin and the p.1n.r. spectrum was
water, and was allowed to dry in air in the dark. The examined. It showed a diminution of the intensities of the
crude yellow product, 1.16 g, n1.p. 29-12O0, was re- above three singlets and the formation of new singlets at
crystallized from 95% ethanol to give 0.25 g of 4a as 6 1.75, 2.1 1, and 4.45 p.p.m. These new signals were in
gleaming cream flakes, n1.p. 218-222". Addition of water the ratio 3 :3 :2 and subsequent examination of an authen-
to the filtrate gave, on standing, further solid. m.p. tic sample of 4a in bromobenzene revealed peaks at
210-220". Both crops had identical spectra and the total identical positions. T h e ratio of 3a:4a was 24:76, as
yield of 411 was 0.38 g (38%). Further recrystallization estimated from peak heights. After a further 10 min at
from ethanol gave the analytical sample, n1.p. 224-227". 13g0, the signals of starting 3a were completely removed
P.m.r. 6 7.7-6.7 (ni, 8H, aromatic), 6.12 (broad s, I H , and 40 appeared to be the sole product. Addition of
removed on addition of D,O, N H ) , 5.00 (s, 2H, CH,), petroleum ether (b.p. 100-115") to the sample precipi-
2.81 (s, 3H, NMe), 2.25 (s, 3H, CMe); i.r. (CHCI,) 2.95, tated 48 mg (80%) of crude 40, m.p. 200-214". A solution
3.05 (NH), 6.02 (C=O). of this product in deuterochloroform showed a p.m.r.
Anal. Calcd. for C l s H 1 7 N 3 0 2 :C, 70.34; H, 5.58; N, spectrum identical t o that of authentic 4a. Further
13.67. Found: C, 70.44; H, 5.61 ; N, 13.62. purification by recrystallization from 95% ethanol gave
The product was completely insoluble in 5% aqueous 25 m g (42%) of pure 4a, m.p. 217-221".
sodium hydroxide, even on heating, and an ethanolic
solution showed no noticeable color change on addition Base-catalyzed Rearrat~gett~e/ltof 3a
of ferric chloride solution. A 50 mg (0.00016 mol) sample of 3 a was dissolved in
(b) The dried yellow precipitate, prepared as above approximately 0.5 ml of deuterochloroform. The solution
from 0.31 g (0.0029 rnol) of p-cresol, 1.1 g (0.0054 rnol) was stored in the dark a t room temperature. After 3 days,
of 4-aminoantipyrine, and 20 g (0.061 mol) of potassium the p.m.r. spectrum showed 8% rearrangement to 4a.
ferricyanide in 250 ml of buffer solution. was dissolved in Pyridine, approximately 0.26 g (0.0032 rnol), was added
methylene chloride. Addition of petroleum ether (b.p. by dropper to the solution. The mixture was stored in the
100-115") precipitated 0.17 g of amorphous solid, m.p. dark and its p.m.r. spectrum was examined at intervals.
115-140". whose p.m.r. spectruni was similar to that of T h e observed extent of rearrangement t o 4a was 14 (3h),
unidentified impurities obtained during the preparation 36 (24 h), 60 (44 h), and 78% (70 h). Examination after
of some p-quinoneimides (I). The clear yellow filtrate 6 days showed complete rearrangement t o 4a. Addition of
was evaporated and the resulting solid was recrystallized petroleum ether (b.p. 100-1 15") precipitated 28 mg (56%)
from pentane to give 0.39 g (44%) of yellow 3a, m.p. of 4a, m.p. 215-222".
145-155". The p.m.r. spectrum indicated the product was
an 87:13 mixture of 3a and 40. Several recrystallizations Grateful acknowledgement is made to the National
from pentane gave pure 3a, m.p. 148-150" (resolidifies Research Council of Canada for its generous support of
and remelts 210-220"). P.m.r. 6 8.22-8.00 (m, 2H, vinyl), this work.
1. PETER F. JONES and K. E. JOHNSON.Can. J. 5. A. I. VOGEL.Elementary practical organic an-
Chem. In press. alysis. Part 2. 2nd Ed. Longman, London. 1971.
2. E. EMERSON. J. Org. Chem. 8, 417 (1943). p. 202.
3. D. SVOBODOVA and J. GASPARIC.Coll. Czech. 6. R. B. WOODWARD and R. HOFFMANN. The con-
Chem. Commun. 35, 1567 (1970). servation of orbital symmetry. Verlag Chernie,
4. R. K. NORRISand S. STERNHELL.Applications Weinheim. 1971. Chapt. 7.
of nuclear magnetic resonance spectroscopy in
organic chemistry. 2nd Ed. Pergamon Press, Lon-
don. 1969. ( a ) p. 278; ( b ) p. 91.