NOTITS
TABLE I
1-02
SITRATIOX OF SUBSTITUTED MALONIC ESTERS,R-C( ~
R
a
Yield
Isopropyl Isobutyl n-Butyl Cyclohexyl n-Decyl -411alysisby the
BO
cc.
83-84 88-88 93---94 110-120
Pressure
0 . 3 mm. 0 . 5 mm. iJ.,?mm,
n25n
1.4337 1.4351 1.4340 1.4597
c
FI
COpC2Hj)y ..
-r
Reaction of Tyrosine with Formaldehyde in Acid Solution BY HAROLD S. OLCOTT RECEIVED M A Y31, 1955
In a study of protein reactions,‘ we wished to have available, as one type of model, a non-dialyzable substance containing a number of free amino groups. I t occurred to us that tyrosine should react with formaldehyde in acid solution? to form such a polymer. The authors of the only previous studies on this ~ y s t e r nbelieved ~.~ that they had obtained isoquinoline derivatives. We have prepared products by the methods they described and also under other reaction conditions and find that they are not isoquinoline derivatives but that instead they display the properties to be expected of acidcatalyzed tyrosine-formaldehyde polymers. The preparations were soluble in dilute acid and alkali but insoluble in the neutral range. Depending upon the conditions used in the polymerization, 40-7070 was retained in dialyzing bags (Visking tubing) after extensive dialysis. Free amino nitrogen (by Van Slyke) was equivalent to 75-93% of the total nitrogen. These observations, together with the known reactions of other substituted phenols with f ~ r m a l d e h y d eindicate ,~ that the polymer is composed for the most part of units with the structure OH
The low total nitrogen and amino nitrogen analyses in all likelihood reflect the presence of additional methylol groups and methylene cross-links involving amino nitrogen in parts of the polymer. (1) A. Mohammad, H. Fraenkel-Conrat a n d H. S . Olcott, Arch. Biochem., 24, 157 (1949). ( 2 ) T h e polymer formed from tyrosine a n d formaldehyde in alkaline solution has been described b y A. E. Brown, THISJOURNAL, 68, 1011 (1946). It contains no free amino nitrogen. (3) A . Pictet and T. Spengler, Ber., 44, 2030 (1911). (4) J. Wellisch, Biochem. Z., 49, 173 (1913). f.5) Reviewed in J. F. Walker, “Formaldehyde,” 2nd Ed., Reinhold Publ. Corp., New York, N. Y.,19.53.
.48.B 50.6
6.89
~~. .
alyqe. N
5.67 7.29 5.37 I i) 50.6 7.29 ,?.87 15 ,5p 54,4 7.31 4.88 8Th l4p 1.4450 30.2 905 4.06 120-130 Elek Microanalytical Laboratories, Los Angeles, Calif. Yield based on
i8
hour a t 60” then cooled and poured onto 200 g. nf chipped ice. After the ice had melted the oily layer was extracted with ether, and washed with 5% sodium bicarbonate solution until neutral, then with water. After drying, the ether was removed by distillation and the remaining liquid distilled through a small Vigreuu column. The diethyl alkylnitromalonates were obtained as colorless oil>- liquids. AEROJET-GENERAL CORPORATIOX AZUSA,CALIFORSIA
/
__
_..-- ~. -. ...Calcd.
R.p.
I‘oiind-- H
~
s 5. 3 ) ,
U 3
.-b
c
i
I
41;
zcE
d
3436
NOTES
aminopyridine with acrylonitrile, a non-cyclic analog of 2-vinylpyridineI also have failed.* I t should be noted that while cyclohexylamine was pyridylethylated in 60y0 yield under acidic conditions, the same reaction failed when it was attempted earlier5 under non-catalytic conditions. The mechanism for the acid-catalyzed pyridylethylation of primary amines is probably the same as that suggested earlier4 for the analogous reactions with secondary amines.
Vol. 77
pared from the material made by the pyridylethylation of N-methylaniline. CONTRIBUTION S o . 951 DEPARTMENT OF CHEMISTRY UNIVERSITY OF PITTSBURGH PITTSBURGH 13, PEXNSVLVANIA
The Structure of Tribromophenol Bromide BY J O H N A. PRICE RECEIVED MAY28, 1955
Experimental I t has not been possible to choose with confidence Reaction of Equivalents of Aniline, 2-VinylpyridineQ and Acetic Acid in Methanol Solution.-A solution of aniline between the structures I' and 112for the product ob(85.0 g., 0.914 mole), 2-vinylpyridine (96.0 g., 0.914 mole), tained from the further bromination of 2,4,6-tribroglacial acetic acid (54.8 g., 0.914 mole) and 250 ml. of abmophenol. However, I1 appears to be favored by solute methanol was refluxed for eight hours, allowed to the most recent physical evidence2cand the results cool to room temperature and then allowed to stand a t room temperature for nine hours. The methanol was removed a t of Forman and Sears on the halogenation of :3atmospheric pressure and the reaction mixture was then methyl-4,B-di-t-butylphenol" and of Coppinger and poured onto ice and made strongly basic m-ith 10% sodium Campbell on the bromination of 2,(i-di-t-butyl-4hydroxide solution. The basic solution was extracted with ether, the extracts dried over anhydrous sodium sulfate, the methylphenol. solvent removed a t atmospheric pressure and the residue OBr 0 0 distilled in vacuum to give 142 g . (78%) of 2-(2-anilinoethyl)pyridine, b.p. 167-168" a t 2.5 mm., m.p. 40.6-41.5' (from 60-70" petroleum ether). Anal. Calcd. for ClsHtaS2: C, 78.79; H, 7.07; N, 14.14. Found: C, 78.62; H , 6.78; N, 13.88. The amine gave a monopicrate, m.p. 169.5170.5' (from ethanol). Anal. Calcd. for CIQHI,A O7Nj: N, 16.39. Found: N, 16.45. From this reaction Br Br Br Br there were also obtained 11.0 g. of 2-vinylpyridine, b.p. 111 I I1 80-82" a t 50 mm., 14.7 g. of aniline, b.p. 74-80' a t 23 mm., and 12.0 g. of a non-distillable tarry nitrogenous residue. A clear choice in favor of I1 can be made on the The procedure described above was used in all the pyridylbasis of its infrared spectrum, which shows a charethylations. Reaction of Aniline with 2-Vinylpyridine Using Clifford's acteristic strong maximum a t 5.99 k, clearly indicProcedure.-A mixture of aniline (93.0 g., 1.0 mole), 2ative of a conjugated carbonyl. Infrared absorpvinylpyridine (105 g., 1.0 mole), glacial acetic acid (4.5 g., 0.075 mole) and copper(I1) acetate (0.7 g., 0.04 mole) was tion a t closely similar wave lengths wasobserved with refluxed for ten hours and then distilled directly to give the related cyclohexadienones studied by Forman 126.0 g. (64%) of 2-(2-anilinoethyl)-pyridine,b.p. 166and Sears3 and by Coppinger and Campbell.* Fur168" a t 2.5 mm., m.p. 40.5-41.4O (from 60-70" petroleum thermore, its ultraviolet spectrum which shows a ether); 38.7 g. of aniline. b.p. 58' a t 2 mm.; 1.0 g. of 2 vinylpyridine, b.p. 65-70" a t 32 mm., and 31.0 g. of a non- maximum a t 280 mM, E 9270,5 allows a choice between the cross-conjugated p-quinonoid structure I1 distillable tarry nitrogenous residue. Mixed melting points between the pyridylethylated aniline obtained in this and the o-quinonoid form I11 in favor of the former. experiment with the material of the same melting point ob- The values show excellent correspondence with tained in the preceding experiment as well a s mixed melting points of their respective monopicrates showed no depression. those of IV, Am, 274 mp, E 10,600, and may be conPreparation of 2-Pyridylacetanilide.-A solution of ethyl trasted with those of V, Amax 296, e 19,400.6 2-pyridylacetate' (10.0 g., 0.06 mole) and aniline (7.5 g., 0.08 mole) was heated a t 170' for three hours and then allowed to cool t o room temperature. T h e solid which precipitated was filtered and recrystallized from benzene to give 8.2 g. (6570) of 2-pyridylacetanilide, 1n.p. 134-135°."J Alkylation of 2-(2-Anilinoethyl)-pyridine with Methyl Iodide.-To an ether solution of phenyllithium, prepared Rr Rr from 5.6 g. (0.8 mole) of lithium ribbon, 62.8 g. (0.4 mole) \' of bromobenzene and 400 ml. of anhydrous ether, was added 79.2 g. (0.4 mole) of 2-(2-anilinoethyl)-pyridine,dissolved 111 would be expected to absorb a t even longer in 100 ml. of anhydrous ether followed by 56.8 g. (0.4 mole) wave lengths than V.? of methyl iodide, dissolved in 100 ml. of anhydrous ether and added a t such B rate that the ether refluxed gently. Experimental After the addition of the methyl iodide was completed, the Tribromophenol bromide was prepared according to reaction mixture was refluxed for one hour, poured onto ice Henedikt'n and recrystallized from chloroform, rn .p. 124" and made strongly basic by 10% sodium hydroxide solution. -. --The inixture w a s extracted wit11 several portions of ether, ( I ) i a ) R . Renedikt. A n n . , 199, 127 (18711); ( b j W. M 1,auer' the combined extracts \\-ere dried over sodium sulfate and THIS J O U R N A L , 48, 442 (1926); ( c ) I . Ssuknewitsch and S . Budnitzkii, the solvent was removed a t atmospheric pressure. T h e residue ivas distilled ill vacuum t o give 57.7 g. (6~5'%)of 2- .I. f i v n k l . C h o n . . 138,22 (1933). 12) ( a ) J . Thtele and H. Eichaede, Be?., 33, 673 (1900); ( b ) J. H (2-N-methy-lanilinoethyl)-pyridine, h.p. 118-151O at 3 . 3 Kastle and R . Speyer, THISJ O U R N A L , 27, 40 (1902); (c) C. H. K mm., and 19.4 g. of a non-distillable tarry residue. Thc Elston, A . T . Peters and P.M. Rowe, .I. Chem S O L .367 , (1948). 2-(2-I\'-methylanilinoethyl)-pyridine formed a monopicrate, ( 3 ) L. E. Forman and W. C. Sears, Tars JOURNAL, 76, 4977 (1954) m.p. 167-167.7' alone and when mixed with a sample pre~~
18) F. C . Whitmore, H. S . Alosher, K . R. Adams, R. B. Taylor, E C. Chapin, C. Weisel a n d W. Yanko, THISJ O V R N A L , 6 6 , 725 (1944). ( 9 ) T h e 2-vinylpyridine was supplied t h r o i i x h the m,iirtesy o f Dr 1;. 1%: C'i\lak, Reilly T a r a n d Chemical Corlr , I l l ) li (:dliuc*v,k> duel (.> K a i i z . \ f k ~ ~ i , , l \ l77, ~ 137 ( i Y 4 7 )
(4) G. If.Coppinger a n d T . U'. Campbell, i b i d . , 76, 735 (19531 ( 3 ) Compare t h e spectrum of t h e related tribromophenol chloride examined b y Elston. Peters and Rowe. ref. 2 c , which has hmar 275-280,
10,000 i o ) I. r h d u i a , (-/iriii, R W L , 63, 47 i1!1:d1 )1:
K B. \ ~ ' w x ~ w a r '1'Hra ~l,
JIIVKNAI ,
6 4 , 7:' l 1 ! # < ? 1
