[CONTRIBUTIONFROM THE SCHOOL OF CHEMISTRY OF THE UNIVERSITY OF MINNESOTA]
T H E CHEMISTRY OF VITAMIN E. VII. PREPARATION OF QUINONES FROM METHYLPHENOLS LEE IRVIN SMITH, J. W. OPIE, STANLEY WAWZONEK, W. W. PRICHARD
AND
Received March Sf, 1989
In connection with the synthesis of tocopherols and the many simpler compounds related to them, large amounts of methylated quinones were required. The preparation of a kilogram of trimethylquinone by the method used in previous work2 would represent a truly formidable task, even if the necessary starting material, pseudocumidine-5, were available in quantity. Consequently, before undertaking to prepare large amounts of the quinone by this method, we sought to find other, less laborious methods of preparation, and especially those which did not require the expensive and rare amine. I n pseudocumene, however, the first point of attack by a reagent is usually at the 5-position, therefore, in any synthesis of trimethylquinone from pseudocumene, the molecule must first be modified in some way which avoids attack at this point. Pseudocumene is converted by direct bromination into a mixture of the 5- and 3-bromo derivatives, the former predominating. But Smith and Moyle3 have shown that 5-bromopseudocumene undergoes the Jacobsen reaction giving the 3-bromo compound in good yield, and that the mixture of bromo compounds obtained from pseudocumene can in this way serve as a good source for the pure 3-bromo isomer. Previous experiments upon the conversion of bromopolymethylbensenes to polymethylphenol~~ had shown that good results could be obtained by heating the bromo compounds with alkali and copper in a bomb at 250-300'. Applied to 3bromopseudocumene, this method gave pseudocumenol-3 (I) in fair overall yield from pseudocumene, and most important, the method appeared to be feasible on a large scale-4 or 5 moles. Since preliminary experiments had shown that duroquinone could be prepared from durenol in about 50 per cent. yields by direct oxidation with dichromate, this method was applied to pseudocumenol-3, and Paper VI: J. ORG. CHEM.,4, 311 (1939). SMITH,J . Am. Chem. SOC.,66,472 (1934). SMITH AND MOYLE, ibid., 68, 1 (1936). 4 A. C. KEYL, Unpublished work, this laboratory. 318 1
2
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CHEMISTRY OF VITAMIN E
.with about the same results, for trimethylquinone was produced in about 50 per cent. yields on small-scale runs. OH
OH
OH
I
I1
I11
Our work was at this point when Dr. E. C. Williams of the Shell Development Company informed us that he had available pilot-plant quantities of pseudocumenol-6 (11) and durenol, and he very kindly sent us a most generous supply of each of these phenols.* To our astonishment, however, we were unable to obtain more than traces of trimethylquinone by direct oxidation of the phenol 11. Under all of the conditions tried by us, the product was either unchanged phenol, or a dark oily material from which no pure products could be obtained, and which gave no quinone when it was steam-dis tilled. We then decided to try converting the phenol to the quinone by coupling it with a diazonium compound as the first step. Although the phenol is open to attack a t two points, ortho and para, respectively, to the hydroxyl group, it was thought that conditions might be found under which the coupling would occur largely or entirely in the para position. Using the method described by Fieser5 diazotized sulfanilic acid was coupled with the phenol in strongly alkaline solution. There was produced an excellent yield of the para hydroxyazo compound, which was readily cleaved by stannous chloride and hydrochloric acid to give the p-aminophenol (111). The aminophenol was converted to the quinone without isolation. After the reduction, excess ferric chloride was added, the mixture was at once steam-distilled, and the quinone was isolated from the distillate. The overall yields of quinone, based upon the phenol I1 were always 90 per cent. and often were over 95 per cent. At least a kilogram of the quinone has been prepared in this way, and the conspicuous success of this method led us to apply it to other phenols, several of which are now available commercially ina very pure state. By this procedure 3 ,5-dimethylphenol was converted *We wish a t this point to thank Dr. Williams and the Shell Development Company for thiis magnificent gift. It is not exaggerating to say that this gift made i t possible for us 1;o do many times as much experimentation in the time at our disposal as would have been the case otherwise, and that the successful outcome of our researches so far hac, in no small measure been due t o this aid. ~ F I E S EOrganic R, Syntheses 17, 9. John Wiley & Sons, Inc., New York, 1937.
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SMITH, OPIE, WAWZONEK, AND PRICHARD
into m-xyloquinone in 74 per cent. yield; 2,5-dimethyIphenol was converted into p-xyloquinone in 55 per cent. yield, and durenol into duroquinone in in 60 per cent. yield. Only traces of toluoquinone could be obtained by this method, starting with either 0- or m-cresol. We believe that the method represents the most rapid and efficient procedure known at present for preparation of the polymethylquinones in quantity. While other diazonium salts may be used, that derived from sulfanilic acid has given the best results in our hands. Diazotized aniline couples well with the phenols, but reduction of the azo compounds so obtained either produces aniline which may later react with the quinones, or else reduction of the azo compounds in the strongly acid solution causes a rearrangement of the semidine type. In any event, when aniline is used, the yields of quinones are a t best only about half as much as when sulfanilic acid is used. When sodium hydrosulfite instead of stannous chloride was used for reduction of the azo compounds derived from aniline, no quinone was obtained. Catalytic reduction of the azo compounds followed by the usual oxidation, gave as a maximum a 43 per cent. yield of trimethylquinone. In this connection, the azo compopnds derived from sulfanilic acid cannot be reduced catalytically because of the sulfonic acid group6 although those derived from aniline are easily attacked, even a t moderate temperatures, provided high pressure of hydrogen is used, an much ammonia usually results. EXPERIMENTAL
Pseudocumenol-3 (Z).-3-Bromopseudocumene (50 g.), cuprous oxide (7.5 g.), and copper powder (2.5 g.) were placed in a bomb, and aqueous sodium hydroxide solution (50 g. in 500 cc.) was added. The bomb was closed and heated a t 275" for 3 hours. After cooling, the mixture was filtered and the filtrate was acidified with sulfuric acid (30%) and steam distilled. The phenol (28 g., 82%) which crystallized from the cooled distillate melted a t 55-56'. 0ddations.-The phenol I (5 9.) was dissolved in a mixture of concentrated sulfuric acid (75 9.) and water (7.5 g,). The hot solution was allowed to stand for a few minutes and was then cooled to 5". Sodium dichromate (12.5 g.) in water (50 cc.) was added a t such a rate that the temperature was maintained between 10-20'. After the addition was complete, the mixture was heated to 40" for 15 minutes, then cooled and extracted with ether. Removal of the ether left trimethylquinone as a liquid; yield, 50%. A similar oxidation of durenol (5 g.) produced duroquinone, m.p., 110-111", in 50% yield. Pseudocumenol-6 (11),when similarly oxidized, gave no quinone. A part of the phenol was recovered, and the rest was converted into a dark tar. Addition of solid sodium dichromate to a solution of the phenol in concentrated sulfuric acid a t 5", or a t -5", produced no better result. Chromic oxide in acetic acid, ferric chloride, ~
6
Private communication from Dr. R. T. Major, Rahway, New Jersey.
321
CHEMISTRY OF VITAMIN E
potassiium ferricyanide, and mercuric oxide were all tried as oxidizing agents, but no quinone could be obtained by the use of any of them. Trimethylquinone from the azo compound.-Sulfanilic acid (105 g.) was dissolved in water (500 cc.) containing sodium carbonate (26.5 g.) by warming. The solution was cooled to 15' and a solution of sodium nitrite (37 g.) in water (100 cc.) was added and the mixture was immediately poured into ice (600 g.) and hydrochloric acid (106 cc.), and allowed to stand for 20-30 minutes. The diazonium solution was poured slowly into a well-stirred solution of pseudocumenol-6 (63 g.) in water (300 cc.) containing sodium hydroxide (75 g.) An excess of alkali at this point is very important. The mixture was allowed to stand for a t least 2 hours-best over night-allowing the ice to melt and the temperature to rise to that of the room. The solution was made strongly acid with hydrochloric acid (200-250 cc.). Without removal of the red azo compound, stannous chloride (164 9.) in hydrochloric acid (2CO cc.) was added, and solution was heated almost to boiling until the solution cleared and the color became orange-brown. The mixture was transferred to a steam-distillation flask, excess ferric chloride (about 800 9.) mas added, and the mixture mas az once steam-distilled. In the case of trimethylquinone i t is particularly important that the steam distillaTABLE
PREPARATION OF QUINONES PHENOL
3,ELDimethyl2,ti-DimethylTr:imethylTetramethyl-
(G.)
(27) (27) (63) (10)
I
QUINONE
('3.)
,
m-Xylo p-Xylo Trimethyl Duro-
(32.2) (15) (72) (6.5)
1
Y.P.,
'c.
73-75' 123.&1258 262 111-1129
1
YIELD,
% '
74.5 50
95
sot
NOELTING AND BAUMANN, Ber., 18, 1151 (1885), give the m.p. as 72-73'. NIETZKI, Ann., 216,168 (1882), gives the m.p. as 125". 9 SMITHAND DOBROVOLNY, J . Am. Chem. S,c., 48, 1422 (1926); m.p. 111". t Tlhis quinone was not steam-distilled [but was merely filtered from the cold reaction mixture. 7
8
tion be performed a t once to avoid formation of trimethylchloroquinone. The quinone was removed from the distillate by ether extraction which must be continued until the aqueous layer is colorless as this quinone is fairly soluble in the large volume of water. The combined ether solutions were dried over sodium sulfate, and the solvent was removed by distilling it through a short packed column. The residue which weighed 72 g. (95%) solidified in an ice bath and then melted a t 26". Although this melting point is a few degrees low (Smith2, m.p. 29-30) the quinone does not need t o be purified further for most purposes. For purification i t is best distilled: b.p., 9,3"under 10 mm., 108" under 18 mm. The other quinones were prepared by the same method, using 0.2 molar quantities of materials. The results are given in the accompanying table. It must be emphasized again that the coupling reaction must be allowed plenty of time for completion. Thus in one run in which durenol (69.6 9.) was used, and in which coupling was allowed to proceed for only an hour and a half, there resulted 25.4 g. of a product which melted a t 91.5-108", and which was a mixture of the quinone and unchanged phenol. A Rimilar run, in which 3,5-dimethylphenol was used, and in which only an hour and a half was allowed for the coupling, gave only a red oil as the product.
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SMITH, OPIE, WAWZONEK, AND PRICHARD
If any unchanged phenols are present when the quinones are produced, red phenoquinones are apparently formed. These substances are extremely difficult to separate from the quinones, either by crystallization or by distillation. About the only feasible separation is to dissolve the mixture in petroleum ether and remove the phenol by extraction with Claisen's alkali, and since some of the quinones, especially trimethylquinone, are extremely sensitive t o alkali, this method often involves great losses. Coupling with aniline.-Aniline (112 g.) was diazotized in the usual manner in sulfuric acid solution; volume of the solution 2400 cc. The diazonium compound was coupled with trimethylphenol (126 g.) as described above. After acidification, the red azo compound was collected by filtration and dried. It weighed 218 g. (98%). Reduction of the azo compound (20 9.) by stannous chloride (50 g.), and subsequent oxidation as outlined above, produced 2.5 g. of trimethylquinone (20.8%). Reduction of the azo compound (10 9.) by boiling in sodium hydroxide (15 g.) and water (100 cc.) with sodium hydrosulfite (18 g.) in water (100 cc.) for 2 hours a t loo', followed by acidification and subsequent oxidation as before produced no quinone. Catalytic reduction.-The azo compound (49 8.) was suspended in alcohol (100 cc.), and about 0.2 g. of Raney nickel catalyst was added. The mixture was reduced in a bomb a t 120" for 2 hours with hydrogen under 20001bs. initial pressure. The mixture which smelled strongly of ammonia, was acidified, excess ferric chloride was added, and the quinone was removed by steam distillation; yield 13 g. (43%); b.p., 98-103' under 11 mm. In a similar experiment, cl'ith water (150 cc.) substituted for the alcohol, 20 g. of the azo compound gave 5 g. (41%) of quinone which boiled at 99-101" under 12 mm. Although these reductions were carried out at 120", the reaction started even a t room temperature under the high pressure of hydrogen; in a low pressure apparatus (40 lbs.), however, no reduction occurred in 15 hours. SUMMARY
1. This paper contains the description of a convenient and rapid method for preparing polymethylquinones in quantity starting with polymethylphenols. 2. The method comprises coupling the phenol with diazotized sulfanilic acid, reductive cleavage of the azo compound, and oxidation of the aminophenol, followed by removal of the quinone by steam-distillation or filtration. The quinones are obtained quite pure if certain precautions are taken during the preparation. 3. Duroquinone, pseudocumoquinone, o- and p-xyloquinones have been prepared in overall yields of from 50 to over 90 per cent. by the method, which fails, however, when applied to the preparation of toluoquinone.
