Investigation of Pyrazole Compounds. II. The Synthesis of 1-Phenyl-3-hydroxy-5-pyrazolone Imide

52 WEISSBERGERN D H. D. 4 [COMMUNICATION NO.887 FROM THE PORTER Vol. 65 KODAK RESEARCH LABORATORIES] Xnvestigation of Pyrazole Compounds. 1. 1' The Synthesis of hydroxy-5-pyrazolone Imide l-Phenyl-3- BY A. WEISSBERGER H. D. PORTER AND I n the first paper of this series i t was shown that samples, and the color test with p-aminodimethylthe compound synthesized by Conrad and Zart? aniline, confirmed their identity. I1 differs from I by its higher solubility in all and called 1-phenyl-3-hydroxy-5-pyrazolone imide is in fact the isomeric l-phenyl-3-amino-5-pyrazo-solvents. While I is almost insoluble in water, lone I. The real l-phenyl-3-hydroxy-5-pyrazolone I1 can be recrystallized from i t t o give two polyimide I1 has now been prepared. Phenylhydra- morphic forms. The crystals which separate zine was condensed with cyanoacetyl chloride to rapidly from a concentrated (7 ml./g.) solution give 0-cyanoacetylphenylhydrazine 111. In- melt a t 14Z0, and those which separate slowly from stead of the acid chloride, cyanoacetazide3 can be a more dilute (20 ml./g.) solution a t 160'. The used, giving a somewhat higher yield. I11 is a melt of either form on cooling t o room temperacolorless well-crystallizing substance. It is sol- ture yields the lower-melting polymorphic variety. uble in aqueous sodium carbonate, slightly sol- However, if the melt is kept a t a temperature uble in cold water, and the addition of mineral only a few degrees below the lower melting point, acid does not increase its solubility in the latter. the high-melting form is obtained. With acetic anhydride or benzoyl chloride, even H~N-C-CHZ HOC-CHI II I /I I when used in excess, 111 forms a monoacyl deN C=NH N CO rivative only. Both acyl derivatives are soluble *\N/ \N/ in 3% sodium carbonate and stable in cold caustic I I , CEH~ CaHs alkali. They are most likely a-acetyl-@-cyanoI I1 acetylphenylhydrazine and a-benzoyl-b-cyanoHOC-CHL OC-CH2 acetylphenylhydrazine, respectively. II I I I Under the influence of sodium ethylate, 111 HN CN N CO yields an isomer, which is very soluble, not only \NH \N/ I I in bases but also in mineral acids. In sodium carCC" C6Ha bonate solution containing p-aminodimethylaniI11 IV line i t forms a magenta dye on addition of an oxiFor the microanalyses we wish to thank Dr. dizing agent (potassium persulfate). This color L. T. Hallett and his associates. is characteristic for pyrazolone and for many of Experimental its derivatives, e. g., the 1-phenyl-3-amino-5-pyrazolone I,4 while 111, in the same test, gives an Cyanoacetyl Chloride.-Two hundred and fifty grams orange-yellow dye. The new compound therefore of cyauoacetic acid (90%) was extracted with 1 liter of appears to be 11, formed from 1 1by ring closure. ether in three portions, the solution dried with magnesium 1 sulfate, and the solvent removed in vacuo, leaving 200 g. This assignment is confirmed by the acid hydroly- of the acid. Fifty-seven and five-tenths grams of the sis which yields l-phenyl-3-hydroxy-5-pyrazolonelatter was treated with phosphorus trichloride and chloIV, and ammonia. I V was identified by compari- rine according to the 1iterature.O However, instead of son with samples prepared according to the litera- weighing the reaction mixture, it was found convenient to t ~ r e . ~ The interrelation of I and I1 is demon- measure the liquid chlorine, obtained from an inverted J cylinder, into a flask fitted with a tube leading to the reacstrated by the acid hydrolysis of I which likewise tion vessel. The product distilled a t 56-58" (0.5 mm.); gives IV. The yield in this latter reaction, 717; yield 38 g. (54%). I t is advisable to use the chloride the of the theoretical, is good enough t o make it same day, because even in a refrigerator it does not keep practical for the preparation of IV. A peculiar longer than two to three days without considerable decomresolidification above the melting point of all four position. (1) Investigation o Pyrazole Compounds. I , THIS O U R N A L . f J 64, 2133 (1942). (2) Conrad a n d Z a r t , Bcr., 39, 2283 (1906). (3) Caution is necessary i n working with this explosive compound. $1 British P a t e n t 478,990. 3 ) Alichaeli.; a n d Schenk, Her 40, 33!jR l1!407! B-Cyanoacetylphenylhydrazine, 111.-1. To a solution of 47 g. of phenylhydrazine in 250 ml. of dry ether, which was stirred and cooled in an ice-bath, was added, during fifteen minutes, 24 g. of cyanoacetyl chloride in 80 ml. of I!;) Schroeter and 'Link. ibid , 71, 675 (1938) Jan., 1943 THESYNTHESIS OF l-PHENYL-3-HYDROXY-5-PYRAZOLONE IMIDE dry ether. Stirring and cooling was continued for one hour, the granular crystalline mass collected at the pump, rinsed with ether, and slurried and filtered twice with 400 ml. of water. The solid was extracted with 150 ml. of boiling 60% ethanol, leaving 7 g. of high melting insoluble residue. The solution on cooling gave 15.5 g. of creamcolored needles, m. p. 98-101', and recrystallized (Norite) twice from 50% ethanol, 10 g. (33%) of fine white needles; m. p. 105-106'. Anal. Calcd. for CQHQN~O: 61.7; H, 5.14; N, C, 24.0. Found: C, 61.59; H, 4.88; N, 24.00. 2. A suspension of 84 g. of cyanoacethydrazide7 in 300 ml. of water and 300 ml. of ethyl ether was cooled to 5' and 71 ml. of concd. hydrochloric acid was added with stirring. After cooling to O', 58 g. of sodium nitrite in 150 ml. of water was added within ten to fifteen minutes, while stirring vigorously, a t a reaction temperature maintained below 10" by the addition of dry-ice. After stirring and cooling for another fifteen minutes, 90 g. of phenylhydrazine was added dropwise during fifteen minutes at 5-10'. After another hour, the mixture was filtered. The residue was slurried with 300 ml. of ether, filtered, rinsed with ether, then washed with 150 ml. of water, and recrystallized from 350 ml. of 35% ethanol, 75 g (52%) of fine white needles; m. p. 105-106'. The isolation of the cyanoacetazide,T after the fmt step in the above reaction, is dangerous. This isolation was done with several samples until a small batch, after one day's standing, detonated with extreme violence when the ethereal solution was concentrated. Moreover, it was found that a better over-all yield was obtained with the procedure given above than when the azide was isolated. If, in the preparation of the azide, the nitrite solution is added more slowly, a solid (up to 16%) separates from the reaction mixture. The compound crystallized from water in thick needles, m. p. 194-196', and is presumably a,@-di(cyanoacetyl)-hydrazine. Anal. Calcd. for CsHsNdOz: C, 43.4; H. 3.61; N, 33.7. Found: C, 43.69; H, 3.89; N, 33.56. Coupling Test with p-Aminodimethylanie.-A small amount (about 0.01 g.) of 8-cyanoacetylphenylhydrazine was dissolved in 5 ml. of 3% aqueous sodium carbonate containing about 0.01 g. of p-aminodimethylanie, and to the solution was added about 2 ml. of 2% potassium persulfate solution. Immediately, a bright yellow-orange color appeared which faded on addition of mineral acid. a-Acetyl-P-cyanoacetylphenylhydrazine.-One gram of b-cyanoacetylphenylhydrazine 5 ml. of acetic anhydride in was heated on the steam-bath for one hour. The solution was vacuum-concentrated, and the residue taken up in 5 ml. of hot benzene from which crystals separated. These were recrystallized twice from methanol, yielding fine white needles; m. p. 149-150'. Anal. Calcd for CIIHIIN~OZ: 19.35. Found: N, N, 19 27. a-Benzoyl-8-cyanoacetylphenylhydrazine.-To a solution of 1.75 g. of 6-cyanoacetylphenylhydrazine and 1.6 g. of pyridine in 3.5 ml. of dioxane, was added 2.8 g. of benzoyl chloride. After heating on the steam-bath for half an hour, excess benzoyl chloride was decomposed by adding (7) Darapsky and Hillers J p r a k f Chem , Sa, 297 (1915) 53 5 m . of methanol, and the mixture poured into water. l The precipitated o l was washed with water and crystali lized from benzene, yielding 1.2 g. (43%) of white needles; m. p. 153-155'; recrystallization from methanol raised the m. p. to 155-156'. Anal. Calcd. for CIBHIIIN~OZ: 15.05. Found: N, N, 15.12. Both acyl derivatives were recovered unchanged on acidification after standing for one hour in 2% sodium hydroxide solution. l-Phenyl-3-hydroxy-5-pyrazolone Imide, 11.-A solution of 80 g. of p-cyanoacetylphenylhydrazine in sodium methylate (21 g. of sodium in 320 ml. of methanol) was refluxed for one hour. It was then concentrated in uucuo to dryness and the residue dissolved in 400 ml. of water. On acidifying with 60 ml. of glacial acetic acid, heating, Noriting, cooling, and filtering, 70.5 g. of crude product was obtained which half melted at about 140', and totally a t 158'. Recrystallized from 500 ml. of water, it formed fine white needles, m. p. 142-143'; yield, including 7.5 g. from the filtrate, 59.5 g. (74%). A polymorphous form of m. p. 160.5-161.5' was obtained as described on page 52. Anal. Calcd. for CeHsNaO: C. 61.7; H, 5.14; N, 24.0. Found: (142') C, 61.81; H, 4.96; N, 24.01. Found: (160') C, 61.55; H, 5.36; N, 23.8. l-Phenyl-3-hydroxy-5-pyrazolone imide was also formed when a solution of 6-cyanoacetylphenylhydrazine in 2% sodium hydroxide stood at room temperature for one hour. However, under these conditions, the solution darkened considerably and the yield was not as good as in the above procedure. In the coupling test (carried out by the method described above), I1 formed a magenta dye which faded on addition of mineral acid or of caustic alkali. l-Phenyl-3-hydroxyy-5-pyrazolone, IV.-1. A suspension of 150 g. of l-phenyl-3-amino-5-pyrazolone~a mixin ture of 3 liters of water, 450 ml. of 95% ethanol, and 110 ml. of concd. hydrochloric acid was stirred on the steambath. As soon as solution was complete (fifteen minutes), it was Norited and filtered, heating the filtrate for fortyfive minutes longer. After cooling, the crystals were collected a t the pump and washed with water to give 107.5 g. (710/o) of cream-colored plates; m. p. on rapid heating (5' per min.) 193-195' dec. The melt reset to a semi-solid a t 205'. 2. A solution of 0.25 g. of l-phenyl-3-hydroxy-5pyrazolone imide in 5 ml. of water and 0.25 ml. of concd. hydrochloric acid was heated on the steam-bath for one hour. On cooling, 0.05 g. of white needles crystallized out. The yield was not increased by extending the time of heating to three hours, probably because IV itself is destroyed by hydrolysis. The product was recrystallized from water t o give fine white plates; m. p. on rapid heating 193-195' dec. The melt reset to a semi-solid a t 205'. Mixed melting points of both preparatioq with each other and with samples of l-phenyl-3-hydroxy-5-pyrazolone, prepared according to the literature,*Vsshowed no depression. I and I1 were recovered unchanged on acidification, after heating their solutions in 2% sodium hydroxide for one hour on the steam-bath. HERBERT s. HARNED AND CLAIR M. BIRDSALL 54 Vol. 65 summary razolone imide and l-phenyl-3-arnino-5-pyrazolone is shown by acid hydrolysis of both com1. 1- Phenyl - 3 - hydroxy - 5 - pyrazolone imide was prepared by ring closure of @-cyano- pounds to l-PhenYl-3-hYdroxY-5-PYraZOlOne. acetylphenylhydrazine obtained from phenyl3. Color reactions of p-cYanoacetYlPhenYlhYhydrazine and cyanoacetyl chloride or cyano- drazine and of the pyrazolone derivatives are deacetazide. scribed. 2. The relation of 1-phenyl-3-hydr0xy-j-p~ROCHESTER, YORK RECEIVED NEW OCTOBER 14,1942 [CONTRIBUTION FROM THE DEPARTMENT CHEMISTRY YALEUNIVERSITY] OF OF The Acidic Ionization Constant of Glycine in Dioxane-Water Solutions BY HERBERT S. HARNED CLAIRM. BIRDSALL' AND The ionization constants of acetic, formic, propionic acids and water2 have been determined from 0 to 50' in water and in dioxane-water solutions from cells without liquid junction. In order t o extend these results to include an ionization of another type of weak electrolyte, cells of the type H&* ( m A , HZCl ( m d , X%D, Y%H20IAgCl-Ag have been employed to evaluate the acidic ionization constant of glycine as a function of the composition of a medium of varying dielectric constant and of the temperature. In this cell, 2" represents the amphion, +NHaCHsCOO-, HZCl, glycine hydrochloride and X the percentage by weight of dioxane in the solvent. From these ionization data, the entropy, heat content and heat capacity of the ionization reaction may be evaluated with a fair degree of accuracy. Cells of this type have been employed frequently3 in recent years to determine the acidic ionization constant of amino acids in water, and without modification may be adapted to the investigation of ionization equilibrium in waterorganic solvent mixtures. The ionization under consideration is given by the expression "HZ Z* + Hi' and the corresponding equation for the thermodynamic ionization constant is (1) This contribution contains material from a dissertation presented by Clair M. Birdsall t o the Graduate School of Yale University in partial fulfillment of the requirements for the degree of Doctor of Philosophy, June, 1942. (2) Harned and Kazanjian, THIS JOURNAL, 68, 1912 (1936); Hnrned and Fallon, ibid., 61,2374 (1939); Harned and Done,ibid., 63,2579 (1941); Harnedand Dedell, i b i d . , 63,3308 (1941). (3) Harned and Owen, ibid., 62, 5091 (1930); Harned and Owen, JOURNAL, 66,24(1934); Nims Chem. Rev., fl, 31 (1939); Owen, THIS 101,401 (1933); P. K. Smith, A . C.Taylor and Smith, J. Biol. Chen.. and E . R . R S m i t h , ibid., 12.2, 109 (1937). where m represents molality, y activity coefficient and the ionic species are designated by the subscripts, 2, ZH and H. The thermodynamic equation for the cell is E = Eo* - R T / N F In Y H Y c ~mHmCl (2) where Eo* is the standard potential in a given solvent. Since YHYCl in a solution containing glycine is not exactly known but can only be approximated by employing values for hydrochloric acid a t the appropriate ionic strength in a solvent which does not contain glycine, i t is necessary to define the quantities M H ' and KA' by the equations (4) since mCl = m = mHZ. As the ionic strength 2 decreases, the apparent hydrogen ion concentration m H ' approaches the actual hydrogen ion concentration mH so that at infinite dilution KA' equals KA. Eo* and YHCl have been deter2 mined by Harned and Morrison,4 m is known, so that measurement of E yields all the data necessary for the computation of m H ' . From these values of mH' determined a t a number of suitable concentrations, KA' is determined by equation (3) and extrapolated to zero ionic strength where it equals the thermodynamic ionization constant KA * Experimental Procedure and Observed Electromotive Forces.-The experimental technique described in detail by Harned and Morrison5 (4) Harned and M o m s o n , THISJOURNAL, 1908 (1936). 68, (5) Harned and M o m s o n , A m . J . Sci., 33,161 (1937)