Estimation of Phenols by the 4-Aminoantipyrine Method. II. Products from para-substituted Alkylphenols

Transcription

1 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 0A2 Received May 17, Aminoantipyrine reacts with p-alkylphenols on oxidation with potassium ferricyanide to give yellow ortl~o-quinoneimides. These undergo a thermal and base-cataiyzed rearrangement to benzodihydrooxazepines. 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 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 reported that when the Emerson reaction is carried out with p-alkylphenols using higher concentrations of reagents, a turbidity is produced. The precipitate was isolated from p-cresol. Although initially yellow, on purification it gave a white, photochromic solid, m.p ". On the sole basis of a molecular formula, itself incorrectly computed from elemental analyses, it was concluded that the latter compound arose from ortho coupling. The lack of conclusive evidence for this, the first reported example of oxidative ortho coupling in this system, has led us to 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). Recrystallization from ethanol gave a cream solid, m.p. 22&227", which appears to be the same product as that previously reported. However, the p.m.r. (X = H, CI, C02H, OMe) h e h~~ spectrum of this compound revealed that it could not be the o-quinoneimide adduct 3a, since it displayed only two methyl singlets, whereas 3a should have three such signals. Comparison of the p.m.r. spectrum of the crude original product with that of the purified sample showed that the latter was not present to

2 CAN. J. CHEM. VOL. 51, 1973 any extent initially. This suggests that recrystallization 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 originally present in 3a, and its replacenient by a two proton singlet at 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 or 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 or -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 , 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) or the hetero- cycle 4a (path a),' or the renloval of the methyl group of the original phenol to give a paraquinonemethide, 6a (path c) (see Scheme 3). The above evidence is insufficient to allow a decision between these possibilities. Accordingly, to find mhich of the two C-methyl groups was involved in the above rearrangements, the reaction 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 or 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, and also the formation of the methylene group as a two proton singlet at an identical position to that of the rearrangement product from p-cresol can be seen. On the basis of the spectroscopic evidence alone, it is difficult to distinguish between the formation of the phenols 5a and b or their ring closed counterparts, the substituted dihydro-oxazepines 4a and 6. The observation that the methylene protons appear as a singlet might seem to favor 4a and 6, 'We thank a referee for pointing out this possibility.

3 JONES AND JOHNSON: ESTIMATION OF PHENOLS. 11 I Me 0 A [1,71 sigmatropic rearrangement t cyclization whose allylic protons are equivalent, whereas the methylene protons of 5a and b should be nonequivalent. 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 evidence, 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 ". With increase in temperature, the melt decolorized and partially crystallized. Final remelting occurred at , suspiciously similar to the m.p. of rearranged 4a. The thermolysis could be conveniently followed by p.m.r. spectroscopy in bronlobenzene solvent, in which 3a showed methyl singlets at , 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 , 2.1 1, and 4.44 p.p.m. was seen. After 20 min the starting signals had been completely 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 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 presuppose 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 p.p.m., being shielded by approximately 1 p.p.m. compared with the corresponding group in paru-quinoneimides, where the signal appears in the range 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-quinoneimides in hydroxylic solvent at or below room temperature suggests the operation of an alternative mechanism, possibly involving a basecatalyzed reaction with an external nucleophile, presumably ethoxide ion (Scheme 5). Some evidence to support a base-catalyzed rearrangement has been obtained. Thus 3a appeared to be stable

4 3736 CAN. J. CHEM. VOL. 51, 1973 in deuterochloroform solvent, only 8% rearrangement being observed after 3 days at room temperature. However, addition of pyridine to the reaction mixture accelerated the rearrangenient 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 ph 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) To a stirred mixture of 0.35 g ( mol) of p- cresol and 1.1 g ( rnol) of 4-aniinoantipyrine in 250 ml of buffer solution was added, in one portion. 21 g (0.064 n~ol) of potassi~ln~ ferricyanide. A yellow precipitate 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 O0, was recrystallized from 95% ethanol to give 0.25 g of 4a as gleaming cream flakes, n1.p ". Addition of water to the filtrate gave, on standing, further solid. m.p ". 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 ". P.m.r (ni, 8H, aromatic), 6.12 (broad s, IH, removed on addition of D,O, NH), 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 ClsH17N302: C, 70.34; H, 5.58; N, Found: C, 70.44; H, 5.61 ; N, 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 ( rnol) of p-cresol, 1.1 g ( 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 ") precipitated 0.17 g of amorphous solid, m.p ". 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 ". 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 " (resolidifies and remelts "). P.m.r (m, 2H, vinyl), (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 CIsH,7N30,: C, 70.34; H, 5.58; N, Found: C, 70.40; H, 5.67; N, Reactiot~ o~~-aiii~iioc~~~~@~i'~ii~ with p-etl~ylphet~ol To a stirred mixture of 0.35 g ( mol) of p-ethylphenol and 1.2 g ( mol) of 4-aminoantipyrine in 250 n~l of buffer solution was added, in one portion, 20 g (0.061 mol) of potassium ferricyanide. A yellow precipitate 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 ". Addition of water to the filtrate gave, on standing, further solid, m.p ". The total yield of 4b was 0.39 g (42%). Further recrystallization from ethanol gave the analytical sample, m.p ". P.m.r (m, 8H, 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, CH2CH3); i.r. (CHCI,), 2.95, 3.05 (NH), (C=O). Anal. Calcd. for C1,H,,N30,: C, 71.01; H, 5.96; N, Found: C, 71.27; H, 6.10; N, Ther-tila1 Rearrntrgeti~et~t of 3a A 60 mg ( mol) sample of 3n was dissolved in approximately 0.5 ml of bromobenzene. A p.m.r. spectrum of the solution showed three singlets at , 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 , 2.1 1, and 4.45 p.p.m. These new signals were in the ratio 3 :3 :2 and subsequent examination of an authentic sample of 4a in bromobenzene revealed peaks at identical positions. The 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 ") to the sample precipitated 48 mg (80%) of crude 40, m.p ". A solution of this product in deuterochloroform showed a p.m.r. spectrum identical to that of authentic 4a. Further purification by recrystallization from 95% ethanol gave 25 mg (42%) of pure 4a, m.p ". Base-catalyzed Rearrat~gett~e/lt of 3a A 50 mg ( mol) sample of 3a was dissolved in approximately 0.5 ml of deuterochloroform. The solution was stored in the dark at room temperature. After 3 days, the p.m.r. spectrum showed 8% rearrangement to 4a. Pyridine, approximately 0.26 g ( 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. The observed extent of rearrangement to 4a was 14 (3h), 36 (24 h), 60 (44 h), and 78% (70 h). Examination after 6 days showed complete rearrangement to 4a. Addition of petroleum ether (b.p ") precipitated 28 mg (56%) of 4a, m.p ". Grateful acknowledgement is made to the National Research Council of Canada for its generous support of this work.

5 JONES AND JOHNSON: ESTIMATION OF PHENOLS. I 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 E. EMERSON. J. Org. Chem. 8, 417 (1943). p 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. NORRIS and S. STERNHELL. Applications Weinheim Chapt. 7. of nuclear magnetic resonance spectroscopy in organic chemistry. 2nd Ed. Pergamon Press, London (a) p. 278; (b) p. 91.