660
COMMUNICATIONS TO THE
EDITOR
VOl. 66
become necessary to prepare additional compounds of the same class. These were prepared and purified and the nitrogen determinations made in the same way as for the others.
cooied. Thesolid wascolIected and dried; it weighed 1.14 g. (70%), m. p. 261-263'. The Ni-acetyl-N4-benzoylsulfanilamide was rectystatlized from ethanol; it formed needles melting at 262-263 Anal Calcd. for ClsH1404NnS: N, 8.80, neut. equiv., 318. Found: N, 9.01; M. p . z 'C. Nitrogen, % Name Formula (cor.) Calcd. Found neut. equiv., 317. Benzoylation of NtAcetyl-sulfanilamide.-To a solution N Ethylpiperon)-!of 0.21 g. of N~acetyl-sulfanilamides(m. p. 181-182') in CipHiiNOi 8 i -X8 7.25 i ? q amide 2 ml. of pyridine, five drops of benzoyl chloride was added, N-Propylpiperon ylThe solution was refluxed in a boiling water-bath for one amide CirH:rN@i 86 7 676 G,-,7 hour. It was then diluted with water and acidified, U-Amylpineronylwhereupon 0.29 g. of Ni-acetyl-N4-benzoyl-sulfanilamide, amide CirHilNOr 104-2 ,;%-I, 5 8 4 m. p. 255-257', precipitated. After crystallization from N-(m-Chlorophenyl)ethanol, it melted at 261-282' alone or when mixed with CI+HaClNOa I f 0 5-112 5 ;. 0 8 4 94 piperonylamide the product obtained by the first method N-(o-Bromophenyl)The N1,N4-dibenzoyl-sulfanilamidehas also been prepiperonylamide C M H M B ~ N O109,5-110 I 4 37 4 35 pared by refluxing either sulfanilamide or N'-benzoyl-sulfN- (m-Bromophenyl)anilamide with e x c m of benzoyl cbloride in the presence of ClrHiaBrNOa 116-117 &37 4 30 piperonylamide pyridine for one hour. The mixture was then diluted with S-(P-Bromophenyl)about ten times its volume of ethanol and allowed to stand ClrHioBrNOa 229-222 5 4.37 .1 .34 piperonylamide in the icebox. The solid was recrystallized from ethanol BUREAUOF ENTOMOLOGY AND PLANT QUARANTINE iii which it is only slightly soluble. The m. p. of the pure AGRICULTURALRESEARCH ADMINISTRATION product was found to be 260" (with decomposition) 3 U.S. DEPT. OF AGRICULTURE S. I. GER~LER Yields in both cases were 70%. Anal. Calcd. for WASHINGTON, D. C. W. F. BARTHECLCmHla04N1S: N,7.37. Found: N, 7.57. RECEIVED.JANUARY 19, 1944 Thanks are due to Dr. T. S. Ma, University of Chicago, for the micro-analyses. NATIONALRESEARCH INSTITUTE OF CHEMISTRY N1-Acetyl-N4-benzoyl-sulfanilamide ACADEMIASINICA, KUNMING, CRINA CHIEN-PEN Lo4 NL-Acetyl-N4-benzoyl-sulfanilaniide, the simplest N1LUCY JU-UUWC CHU acyl-N4-aracylsulfanilamide, has been prepared both by RECEIVED JANUARY 11, 1944 acetylation of N4-benzoyl-sulfanilamide and by benzoyla(2) Crossley. Northey and Hultquist, ibid., 61, 2591 (1939), tion of N1-acetyl-sulfanilamide. Acetylation of N4-Benzoyl-sulfanilamide.-A solution of Huang, Lo and Chu, J Chinese Chem. SOC.,9, 63 (1942). (3) The m. p of N~,N~-dibenzoyl-sulfaniladde has been reported N4-benzoyl-sulfanilamide (m. p. 285-286") (1.4 9.) in acetic anhydride (11 ml.) and anhydrous pyridine (6 ml.) BS 288-270' by Dewing, Gray, Platt and Stephenson, J . Chcm. S o c was refluxed in a boiling water-bath for one hour. and then 239 (1942), and as 252' (dec) by Siebenmann and Schnitzer. THIS 66, 2126 (1043,. (4) Present addreas: Schoot of Chemistry, University of Minncsota. Minneapolis, Minnesota.
JOURNAL,
COhlMUNICA'TIONS T O T H E EDITOR STRUCTURE AND ACTIVITY OF SULFANILAMIDES
state of the molecule to an ionic excited state.'
Sir:
h increase in the number or contribution of ionic
In a recent paper, Kumler and Daniels' have suggested that the activity of sulfonamides may be correlated with the contribution of the resoO H f (1) to the strucname form, H1N=
a-kk. -0
ture of the molecule. To account for the fact that the sulfonamide ahion seems to be the active form of the drug, they have postulated that the coritributiori of the resonance structure with the separation of charge is greater in the anion than in the undissociated molecule. A priori, one would be inclined to the contrary conclusion, and we believe the spectral evidence2 confirms this interpretation. High intensity ultraviolet absorption spectra are due to transitions from the neutral ground (1) Kumler aad Danrels, THISJOURNAL, 66, 2190 (1943)
(2) Kumler and Strait, rbid , 66, 2349 (1943)
resonance stmctures stabilizes the excited state,
i. e., decreases its energy relative to that of the ground state, and hence shifts the maximum of the absorption toward larger wave lengths. Consequently, the fact that the maximum absorption of sulfanilamide in neutral solution is a t 2600 k.,whereas that in basic solution is a t 2509 A., indicates that ionic resonance forms contribute less to the anion than they do to the undissociated molecule. The Kumler and Daniels theory also does not explain the low activity of sulfanilylurea and 3-sulfanilamido-l,2,4-triazole.Resonance structures similar to those written for these molecules could be written for N1-acetylsulfanilamide, p-NHnCaH~SOIN=C -CHs , for sulfadiazine,
(
' 1
0-
( 3 , Mulliken J Chcm Phrs , 7, 20 (1939), 7, 121 (1939); 7 , 339 (1939), O'bbauyhnessy and Rodebush, Ters J O U R N A L , 62, 290B I'WI~
COMMUNICATIONS TO THE EDITOR
April, 1944
66 1
isobutene, b. p. -6.6'; butene-1, b. p. -6.1') and methylamine (b. p. -6.5"), although the former are very unlikely because they all are polyother active sulfanilamides: It should be observed that Bell and Roblin' originally suggested merized by and form stable complexes with alumithat the indiefiduel unions in more acidic sulfanil- num bromide, and the latter could come only from amides such as sulfadiazine, sulfunilylureu, and decomposition of the ethanolamine, which is RX3-sdfunilamido-l,2,4-triazole are less active than tremely improbable. The distillate was shaken with 96% sulfuric sulfanilamide anions because of the decrease in acid a t room temperature for two days and renegative character of the 4 0 2 group, but that fractionated. I t showed the same distillation this effect is counteracted by a greater number as before, with the exception of a characteristics of anions.b slight diminution of the methyl bromide fraction, Simple vinylogs of sulfanilamide such as which was to be expected. ~ - N H z C ~ H I C H = C H - S O Z N Hhave R occupied Sulfuric acid will absorb unsaturates and amines the attention of one of us for some time. These readily, and these possibilities are therefore elimicompounds are now of especial interest since the nated. The only hypothesis that will fit the contribution of resonance structures with a coplanar amino group should be appreciable due to facts is that n-butane and methyl bromide form a the possibility of a contribution from structures of minimum boiling mixture. Indeed, when the product reacted with excess fresh ethanolamine + ~ H - C H - S O ~ N H Rin,addi- and was refractionated, the flat a t -5' disapthe type H:N= tion to those attributed 6 sulfanilamides by peared and the expected n-butane fraction apKumler and Daniels. If, as Kumler and Daniels peared, in accord with the hypothesis. To determine the properties of the azeotrope, a suggest, the sulfonamide group is significant for activity only insofar as i t affects the amino group, synthetic mixture of 49.1 mole % of n-butane and these vinylogs should be active. Up to now only 50.9 mole % of methyl bromide,was prepared and one compound of this type has been tested. fractionated in a Podbielniak micro-precision 2-fi-Aminophenylethene-1-sulfonamide(R = H) type R column3 with 3.0 mm. unpackec' inner bore, manually operated. the pressure being appears to be practically inactive in vitro. regulated a t 760 mm. (cor.). The distillation (4) Bell and Roblin, Tms JOURNAL, 64, 2905 (1942). curve is shown below. Each mm. of distillate (5) Kumler and Daniels attribute tae low activity of very acidic sulranilarnides to the impenetrability of the cell wall toward anions. mole a t 2 6 O , the temcorresponds to 1.85 X as originally Suggested by Cowles, Yale J . B i d . Med., 14, 599 (1942), perature of the vapor receiving bulb in this case, rather than to the concentration effects postulated by Bell and and the thermocouple-galvanometer system gives Roblin. a deflection of almost exactly 2 per deg. (R, t < 0' ; DEPARTMENT OF CHEMISTRY NORTHWESTERN UNIVERSITY FREDERICK G . BORDWELLL,t > 0') in the range - 15 to 15'. EVANSTON, ILLINOIS IRVINGM . &on RECEIVED JANUARY 3, 1944 AN AZEOTROPE IN THE SYSTEM n-BUTANE-METHYL BROMIDE
Sir : In analyzing the products of reactions of mixtures containing butanes, methyl bromide, and aluminum bromide, a successful procedure has been to remove excess methyl bromide from the volatile fraction by reaction with ethanolamine and to determine the paraffin hydrocarbons remaining by low temperature micro-fractionation. In one such experiment, where there was poor contact between the halide and amine, the distillation showed no n-butane (b. p. -O.S'), but did give a methyl bromide flat (b. p. 3.502), and in addition a puzzling fraction boiling a t approximately -5' (atm. pressure). The only possibilities for this -5' fraction would be unsaturates (butadiene, b. p. -4.8'; (1) These experiments are to be presented shortly for publication THISJOURNAL. in (2) The value 4.6' in the "Handbook of Chemistry and Physics," 25th Edition, Chemical Rubber Publishing Co., Cleveland, Ohio, I). 880. is in error. See Egan and Kemp, THISJOURNAL, 80, 2097 (1938).
50
loo 150 Distillate, mm. Fig. 1.
200
250
From the distillation plot, it is apparent that the A material balance azeotrope boils a t -4.4'. suffices to fix its composition a t 58.1 * 0.5 mole yo n-butane. A detailed study of the vapor-liquid equilibrium in the above system is now in progress. CHEMICAL. LABORATORY UNIVERSITY OF CALIFORNIA BERKELEY, CALIFORNIA JULIUS D. HELDMAN RECEIVED MARCH6, 1944 (3) Podbielniak, Ind. Enp. Chem., Anal. E d . , S, 177 (1931); 6, iig (ma).
