V O L U M E 27, NO. 1, J A N U A R Y 1 9 5 5 involved in the development of these methods. Grateful acknowledgment is made for valuable discussions with many colleagues in Shell Development Co., especially Paul E. Porter, Herbert Siegel, Walter R. Haefele, and Daniel B. Luten. LITERATURE CITED
-41x1.SOC. Testing Materials, Philadelphia, “ASTXI Standards on Petroleum Products and Lubricants,” D 664, p. 253, Philadelphia, 1951. Audrieth, L. F., and Kleinberg, Jacob, “Xonaqueous Solvents,” S e w York, John Wiley &: Sons, 1953. Britton, H. T. S.,“Conductometric Analysis,” Xew York, D. Van Nostrand Co., 1934. Rromley, W. H., Jr., and Ludar, W.F., J . A m . Chem. Soc., 66, 107 (1944). Carbide & Carbon Chemicals Corp.. S e w York, “Organic Nitrogen Compounds,” July 31, 1946. Conant, J. B.,and Hall, N. F., J . Am. Chem. Soc., 49, 3047 (1027).
Creamer, R. M., and Chambers, D. H., J.Electrochem. Soc., 101, 162 (1954). Elofson, R. &I., and LIecherly, P. A , , ANAL.CHEM., 21, 565 (1949). Folin, Otto, and Flanders, F. F.,J . Am. Chem. SOC.,34, 774 (1912). Fritz, ,J, S.,and Keen, It. T., ASAL. CHEW,25, 179 (1953). Fritz, J. S.,and Lisicki, S . 31.,Ibid., 23, 589 (1951). Gran, Gunnar, and Althin, Bengt, Acta Chem. Scand., 4, 967 (1950). Grasselli Chemicals Dept., E. I. du Pont de Kemours 8. Co., Inc., Wilmington, Del., “Dimethyl Formamide Product Information.” Hammett, L. P., “Physical Organic Chemistry,” p. 261, New York. McGraw-Hill Book Co., 1940. Hantzsch, A,, and Voigt, W., Ber., 62B, 975 (1929).
55 Higuchi, Takeru, Concha, Jesusa. and Kuramoto. Roy, ANAL. CHEJI.,24,685 (1952). Iliguchi, Takeru, and Zuck, D. A , , J . Am. Chem. Soc., 73, 2676 (1951). Izmailov, N. A., Zhur. A n a l . Khinr., 4 , 267, 275 (1949). Kata, Max, and Glenn, R. A.,ANAL.CHEM.,24, 1157 (1952). Kirrmann, Albert, and Daune-Dubois, Nelly, Compt. rend., 236, 1361 (1953). Lavine, T . F., and Toennies, G . , B m . J . Med. Sci., 185, 302 (1933). Lykken, L. L., Porter, P. E., Ruliffson, H. D., and Tuemmler, F. D., IND. ESG. CHEM.,ANIL. ED., 16, 219 (1944). l l a r o n , S. H., Ulevitch, I. N.. and Elder, h l . E., ANAL.CHEM., 21, 691 (1949). hlasui, SIasaichiro. and Kainura, Yuichi, .J. Pharm. Soc. J a p a n , 71, 1194 (1951). 11osa. XI. I.., Elliott, J. H.. and Hall, R. T., ANAL.CHEM.,20, 784 (1948). Palit. S.R., ISD. ESG. CHEXI., &~N.LL ED., . 18,246 (1946). Pifer, C. W., Wollish, E. G., and Schmall, Morton, ANAL.CEIXM., 25, 310 (1953). Putnam, G. L., and Kobe, K. A.. T r a n s . EEectrochent. Soc., 74, 609 (1938). Ruehle, A. E., IND.ENG.CHEM., TAL. ED.. 10,130 (1938). Ruhoff, J. R., and Reid, E. E., J . Am. Chem. Soc., 59, 401 (1937). - , \ -
Seltz, Harry, and Silverman. Louis, IND.ESG. CHEX, .%SAL. ED., 2, 1 (1930). Sprengling, G. R., J . Am. Chew. Soc., 76, 1190 (19.54). Swick, R. W.,Buchanan, D. L.. and Nakao, Akira, ANAL. CHEM.,24, 2000 (1952). Tomicek, O., and Dolezal. J., Chem. Listy, 43, 193 (1949). Vespe, Vincent, and Fritz, J. S...J. .4?n. Pharm. Assoc., Sei. Ed., 41, 197 (1952). Wolff, J. P., rlnal. Chim.A c t a , 1, 90 (1947). RECEIVED for review July 23, 1954. Accepted October 11, 1954
Determination of Active Hydrogen Atoms IRENE MARY McALPlNE and PATRICK AUGUSTINE ONGLEY‘ University o f Glasgow, Glasgow, Scotland
This work was done in an endeavor to obtain satisfactory analytical data on certain alkaloids. In Zerewitinoff determinations it was found that the influence of temperature is probably often restricted to promoting solution and liberating occluded gases, that the influence of solvent is relatively unimportant, and that the activity of the hydrogen atoms of active methylene groups varies considerably with environment. The role of heat and of solvent in the estimation and the activity of active hydrogen atoms were determined.
Table I. Solvent for Reagent Butyl ether None Ethyl ether Amyl ether Pyridine
K THE Zerewitinoff determination of active hydrogen atoms in various Mitragyna alkaloids, i t was found t h a t the values increased considerably with increase in temperature. Little attempt has hitherto been made to investigate t h e influence of either temperature or solvent on t h e results of Zerewitinoff determinations. T h e main work is t h a t of Lieff, Wright, and Hibhert ( 9 ) ) who examined 23 substances in amyl ether, dioxane, a n d pyridine. Little attempt has been made to discuss t h e reasons for anomalous results. Fuchs, Ishler, and Sandhoff (2) attribute t h e low values for certain acids t o insolubility, and 1,ehman a n d Basch (8) suggest t h a t a further contributory factor may be t h a t t h e reaction takes place only at t h e surface. Kohler, Stone, a n d Fuson (6) mention three possible difficultiesrelative insolubility of t h e substance, insolubility of intermediate products, and occurrence of successive reactions. Except for these comments such contradictory results as those for resorcinol (see Table I) seem t o have passed unchallenged 1
Present address, Birkenhoad Technical College, Birkenhead, England.
Solvent for Resorcinol Isoamyl ether Pyridine None Amyl ether Amyl ether
Temp.,
’ C.
90
90 0 140 Room
No. of Active H Atoms 1 1 1.5 2 2
Ref.
8 (7) (8)
(11)
EXPERIMENTAL
Solvents.
I
Literature Values for Resorcinol
T h e pyridine was stored over solid potassium hydroxide a n d distilled before use. The ethyl ether was dried overnight over sodium wire and then distilled. T h e other solvents were first refluxed for 5 hours with sodium wire and stored over t h e wire overnight. Yext they were distilled, first from sodium and then from phosphorus pentoxide Since the butyl ether gave a peroxide test with vanadic acid, the peroxide was destroyed b y treatment with alkaline silver nitrate. Analytical Specimens. 3-Nitrosalicylic acid, 2-nitroresorcinol, purpurogallin, 3-nitro-o-cresol, I-phenyl-3-methyl-5-pyrazolone, and t h e various fluorene derivatives and dibasic esters used mere synthesized b y standard methods. The other substances were obtained from reputable sources All were carefully purified before use. Analytical Procedure. T h e Grignard reagent was prepared in the usual way. To prevent excess methyl iodide producing methane at higher temperatures (see Table I1j, an excess of magnesium was always used. With every batch of solvent and reagent used, control experiments were done a t both room temperature and at 170” C. T h e standard procedures for t h e actual determinations were all found satisfactory (1, 4,10, 11). I n this investigation the substance was dissolved in 2.0 ml. of solvent and about 2 ml. of reagent were added. I n cases of low sol7ibility, 4.0 ml. of solvent were used. At room temperature t h e
ANALYTICAL CHEMISTRY
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ANALYTICAL CHEMISTRY
58 niist,ure was let stand until no more methane wa8 evolved-Le., uiitil there was no difference in two readings of the buret h k e n 10 nlinutes apart. At higher temperatures t h e time allowed w a ~ 5 minutes. If t h e substance and reagent solutions, before mixing, were allowed t o stand in the apparatus until oxygen uptake was complete, it was found uniiecesaary to work in an inert’ atmosp here. RESULTS OBTAINED
Data are tabulated in Tables 11, 111, and IV. For convenience in comparing related compounds some substances are mentioned t w i c e - c g . , salicylic acid is listed as both a n acid and a phenol. I)IscusSrON
Influence of Temperature. Teniperature plays a dual role. I n certain cases, particularly with miino, amido, and avtive methylene groups, activity increases with increase in temperature, I n the other cases, as long as the substance and the reaction product are in solution, the expected values are obtained a t room temperature. In cases of insolubility the effect of heating niay be threefold-substances insoluble in the cold nxiy dissolve in t h e hot solvent; agitation, especially i i i a reflusing mixture, niay help t o bring t h e substance into closer contact Pvith the rt.agent; and gases occluded iii a gelatinous reaction product niay be expelled. With the exception of 2-nitroaniline, none of the 78 compounds r ~ a r n i n e da t 170” C. showed aiiy abnormally high value. On t h e other hand, although 100” C. is often regarded as the upper temperature limit in Zereivit inoR determinations, many substances f i l e d t o show the full amount of active hydrogen until refluxed. Examples are phthalic arid 4-hydroxylieneoic acids, purpurogallin, aniline, arid cyclohexylamine. Since chelated acids are inore readily decarboxylated, the high value (3.66) for 2,B-dihqdros?-l)enxoic acid a t 170” C. is due t o tlie partial decari)o~qlationat higher temperatures of this highly chelat,ed acid. Yitiiilar high values would also I)e expected of 2.6-diamino- and 2,-L,G-trihydrosyl~erizoicwids. This docarbosy1:ttion effect is not, I i o ~ e v e r ,shobvn by the inonochelated acids-e.g., 2-:imino- and -hydroxy-, and 2,.4- and 2 , j - d i h y d r o u ~ e n z o i c:ici(ls-nor by the a-hydro. and mandelic acidc. Influence of Solvents. JVith the mixed solvent of n-butyl and isoamyl ether, Fuclis, Isliler, and Saitdhoff ( 2 ) obtained low values for the various phthalic acids aiid diliytlroxylucinol and diethyl malonate. Since ctory results itt phenetole, a series of is \ Y ~ Rclonc with the reagent, in either phenetole or dibutyl other arid thrs sul)stance in one of :L vuriety of solvents. .4s is s1ion.ii b y tlie data in T a l ~ l rIV, as long as the substance is so1ut)le tlie inflric:ice of solvent is negligil~le. Influence of Groupings and Structural Considerations. TNDOLTC C o ~ ~ o r r s n s Th:Lt. . the extra active hydrogen atom shown by indole at higlwr teniper:ttures occurs i n neither skittole (d-methylindole) nor c:irbszole suggests Pome activation of the betn position in the pyrrole nucleus by the aioniatic nucleus on the one side and the double bond of the heterocylic ring on the other. This is paralleled of course by the viell-kiioa-11P:LSP of suhstitution of indole in the heta position. Jurecek (,5) awerl? that nitro NITROC o ~ r ~ o v s u s.ilthough . compounds shorn ahnormal results, an eraniitmtiorr of Table I1 shows t h a t 2-nitroaniline is tlie only nit,ro conipourid t o ~ 1 1 0 1 a, n~ y abnormality. h r I s E s A N D .\mi)I~:s. The reault,s in Tai)le 11 nupport the contention in t h e literature that in the amino group the second hydrogen is active only a t high temper:itures. It is interesting t h a t N-methglnniline i3 fully active a t room temperature. HALOGEN COMPOUNDS. From the results availal~lcit seems as if t h e clilorine at,oni h:~s no activating influence. O n the other hand, comparison of the values for aniline arid 2,4,6tribromoaniline aiid for fluorene and 2,‘i-di1)roniofluorene suggests t h a t the brominc atoni does :ictiv:ttr.
CHEL.ATIOS.T h a t intermolecular hydrogen bonding has rto deactivating influence on active hydrogen atoms is obvious froin t h e readiness with which so many acids, alcohols, and phenols show their activit,y. T h a t the intramolecular bond may have ;L deactivating influence is suggested by the low values for tlie 2,z-dihydroxybenzoic acids. This suggestion is cont,radictetl, however, by the results with salicylic acid, ethyl salicylato, salicylaldehyde, 2-hydrosyacetophe1ione, 2-nitrophenol, and the very strongly chelated 2-ititrore~orcinol. T h e absence of an?activating influerice is shown by the nornml behavior of the 2amino- compounds. As already mentioned, the facility wit11 which tjhehydrogen atoms of the weakly chelated 2,4,G-trihromoaniline react is probably due t o halogen activation. One chelation efl’ert does exist. I n t h a t intramolecularly bonded phenols arid acids are more soluble than their isomers in orgmic solvents, chelatioil may be said to decrease inactivity because of insolubility. STERICHISI)RANCE.T h e al~sciiceof steric hindrance is shown b y the complete activity of sucli compounds m 2-nitroresorcinol, 2,6-diinethosybenzoic acid, and 2,4,6-trinitroresorciriol. ACTIVE R~ETHYLENE GROUPS. One dctivating Groicp. .\Ithough the y-hydrogen atom in esters, nitro compounds, etc., enters into a variety of reactions-e.g., the Claisen and Ilieckmann condensations of esters and the reaction of primary and secondary nitro compounds arid of methyl ethyl ketone wit11 nitrous acid-one activating group is insufficient to cause tliv production of methane. Tzu0 Activuting Groups. With a methylene group betwcen t v o activating groups bot,h hydrogen atoms may be active-e.g,. in diethyl malonate. Often ho\vever, as i n acetylacetone, aritl in cyan- and acetoacetstes! even a t higher temperatuws only one atom is active. Thus the -(;OLTe group is less of an activator than is the --COOEt group. T h a t the p h ~ n y lgroup is even Feaker is show1 l)y the iiegligihle activity of tli- a n d even t r iph en ylnieth ane. The result with malonnmitl~is frankly puzzling. far as the fluorenes are conwrrlcd t,hree facts are significant: I n fluorene itself, although there is riot complete activity, nevertheless it is greater than that of di- or PVHII triphenylniethane. Ortho bridging between the two ‘phenyl groups hm grmtly increased the activity. Introduction of a 9-carbosy or -carboniethouy group great1)- increases the activity. Although 2,;dichloro- compounds usually show less activity, the iiitroductioii of tIvo liromine atoms in these positions increxses activity. ACKNOWLEDGRZENT
This a o r k was donc while P. -4.Ongley held first a Coats Fellowship and then a grant from the British Medical Research Counril. Thanks are due to IT.B. Thoi,rlley and S. H. l’ucsker for the gift of compounds a n d to Rachel Courley for permission t o quote analytical data. The authors w e especially indebted t o J. \I7.Cook. F. R. S., 2nd t o S. €1. Tuckrsr for their helpful advice. L1TERATI:RE CITED
Braude, E. A , , and Stern, E. S.,6.Chenz. SOC..1946, 401. Fuchs, W., Iiihler, X’. H., and Sandhoff. d.G., IND.EXG.CHEM., . h . A L . E D . . 12, 507 (1910). Hibbert, €I. I € . , and Sudboroiigh, J. J., J . Clrem. SOC.,1904, 933. Houben-Weil, “.\lethoden der organischen Chemie.” p. 317. “Anal. JIethoden,” Phrenie, Stuttgart, 1952. Jurecek, 11.. Chrwz. Listy, 40, 2:?9 (1946): Brit. Ahfit,.. -411. 913 (1950). ICohler, E. P.. Stone. ,J, I‘’,, ntid 17i~son,R. C.. .J. A m . Chcm. S o c . . 49. 3181 (1927). Kmitsky. J. A . , .Johnson, ,J. L., and Carhart, H. W., Ibid.. 70, 486 (1918). Lehman, R . d.,and Rasch, TI.. h i ) . ESG.CHEM.,~ \ N A I . .ED.,17, 428 (1945). Lieff, RI.. K r i g h t , G . F., and Hihhert. H., J . S n i . Chem. SOC.,61, 865 (1939). Wild, F., “Estimation of Organic Compounds,” p. 55, Carnhridge University Press, Cambridge. E m . , 1953. Zeren-itinoff, T., Bel.., 40, 20% (1907) RECEITED for review April 12. 1934.
Accepted October 2 , 1954.
