Halonitroanilides and Their Bacteriostatic Activity Experimental Section
The antibacterial activity oi a variety of halo- and Iiitrosalicylanilides is well docunientecl. *\Iariy of thew compounds possess good bacterioLt:itic*activity and also are substantive to skin arid cloth. IT(>wish to report the preparation arid bacterioqtatic artivity of additional anilides in which the o-hydroxyphenyl nioiety ha5 been (+hangedto alkyl, haloalkyl, allrenyl, cyclonlkyl. benzyl phenet hyl, phenoxy methyl, :ind 1Ihenyl groul)i. Th c S-aryl portions of the conil)ound\ po and halo substituents. The methods of preparation depended upon tlw anilide or starting materials arid were gerierally modifirations of known procedures. For the acid anhydride reactions a trace of sulfuric acid wa< added t o catalyze the condensations with tlie :miline. When an acid chloride was employed, it was allowed t o react in :i solvent with the aniline eithw with or without triethylamine as t h e hydrogeii chloride acceptor. It w a i necessary t o reflux the reaction mixture several hours to remove the HC1 when 110 acceptor wa5 used. The n'-methylanilide (15) \\ab prepared by the action of dimethyl sulfate on the sodium salt of 14. (1) H. Litmaire, C. H Schrrtmm. and (1961), a n d references cited therein
\
C'ollrl
.I
Pli,rirn
hii
50, X i 1
Chemical Procedures.---lIost ~ i the ' &(:id :iiiIiydricl~~,:wit1 chlorides, aiid substituted anilines were obtaiiied conimerc*i:illy. 3-Chloro-~-nitroanili1~e~~ :I-bromo-4-nitro:miline,6 R-c*hloro-.i-iiia-hromonotiai tronniline,? ~,5-d~ch~o~i~-.l-iiitroitnil~iie,~ ritle.9 2,4-di~tilorcil.'hPiii)sy~~et?-l chloride, IO and 2,4,5 I)heiicisyacet >,l chloricle t o were prep:treti. in R nianner rhow reported iii the liternture. a-Chlorononanoyl chloride x i s prepared froin llir c i ~ r re~poiidingacid" anct SOC12 by :I proredure eniployed for t hc, preparation of similar acid c-hlorides:12lip 91-95' 13 mni), ?-iel(l 64c;. This i r i l ~rmrdi:iic~ was vliaracterized 1))- convriuiori t o 23. Anilides. Method 1.---A ~riistureof 0.10 niole of rccluircbtl aniline, IL5-lS nil of the acid anhydride, :ind a drop of ( ~ o i i w t i trated H 2 W , TW. he:ited at reflus for I
~
__ .
ne or :i mixture o f ttie*cL 1 HC1 evoluiioii cra,.ect. . . ~~.
J os I,~"i i ( 2 , I,, ,J, i3ellauiy, "'l'lw Infrared dpri'tra of C o m ~ l r sl l o l e i ~ i ~ l ~, ~ \\ iley a n d Sons, Ini., S e w I;ork, N. Y., 1958. p p 203-223. ( 3 ) 11. J . Heaver, I). 1'. Roman, a n d 1'. .J. Stoffel, J . J l e d . C h e m . . 6 , :Ill ( l Y 6 3 ) ; .I. O r y . C h r m . , 2 4 , 18i6 (1959): .I. A m . Che?n. Soc., 79, 123(i ( 1 9 S i i . ( 4 ) 1%.E . Stensetli, .J. 17.. I3aker, and 11. P. Roman , l963).
NOTES TABLE
429
1
HAI,O?JITIZO.~NILIDES 0
RCNH
Cornuda R CHI 1 CHaCH2 2 CHa(CHdz 3 (CHdzCH 4 CHa(CH2) a 5 (CHdzCHCHz 6 CHaCHzCH(CH3) 7 (CHa)aC 8 CHa(CH2)a 9 (CHa)*CH(CHdz 10 CHa(CH2)s 11 CHa(CHi)zC(CHd? 12 13 CH3(CHde 14 CHdCHd7 CHI ( C H2)7' 15 CHa(CH2)s 16 CHI(CHdsC(CHI)? 17 CHI(CHd 18 CHI(CHz) io 19 CHa(CH?)ii 20 CHa(CHz)aC(CHa)? 21 CHs(CHdi2 22 CHa(CH2)sCHCl 23 CHa( CH2)eCHBr 24 CH*=CH(CH?) s 25 Cyclobutyl 26 Cyclopentyi 27 Cyclohesyl 28 29 CsHa 3.4-CI?CsHa 30 31 32 33 2,4,5-ClaCeHzOCHz 34 CHa(CHdi 35 CHI 36 CHaCH? 37 CHa(CHd7 38 39 CHs(CHd8 CHa(CHd9 40 CHs(CHd; 41 CHs(CHd7 42 CHa(CHd7 43 CHs(CHd7 44 C H3 (CHd 7 45 CHa(CHd7 46 CHa 47 CHa(CH2)r 48 CHa(CH?)r 49 CHa(CHd7 50 CHa (CH?)7 51 CHs(CHdi 52
X 3-C1-4-N0? Y-CI-4-NO2 Y-Cl-4-iYO2 3-Cl-4-NO2 3-Cl-4-NO2 3-CI-4-NO2 3-Cl-4-NOl 3-Cl-4-NO9 3-CI-4-NOz 3-Cl-4-NOz 3-Cl-4-NOz 3-CI-4-NOs 3-Cl-4-NO1
3-CI-4-NO2 3-CI-4-NOz 3-Cl-4-NOz 3-CI-4-X0? 3-C1-4-N0, 3-CI-4-NOj 3-CI-4-NO? 3-CI-4-NO2 3-Cl-4-NOz 3-Cl-4-SOs 3-Cl-4-NO2 3-CI-4-NO1 3-C1-4-3702 3-CI-4-SOz 3-C1-4-30? 3-Cl-4-NO2 3-CI-4-N0? 3-CI-4-NOs 3-Cl-4-NOz 3-CI-4-NOz 3-CI-4-NO2
3-Br-4-NO2 3-NO2-4-Ci 3-NO2-4-Cl 3-NO2-4-CI 3-NOa-4-CI 3-NOz-4-Ci 3-Cl-5-NO2 3-1-5-NO2 2-Cl-4-1302 2-Br-4-N0? 2-NO2-4-CI 2-Cl-5-NOz 3,5-Clz-4-N02 3,5-C12-4-N0z 2,5-CI?-4-N0z
2,6-C12-4-N0z 2-N02-4,5-C12 2-CHa-4-XOz-5-Cl
RePrepn crystn Yield, method solventa 1 T 98 T 1 88 2 hl-T 53 2 T 75 3 H-T 65 2 T 59 T 2 43 T 2 59 2 37 2 >I-T 62 2 T 49 2 T 64 2 hl-T 21 3 T 92 4 58 2 H-T 86 2 64 2 h1 77 3 H-T 94 2 T 51 3 27 2 M-T 63 2 M 90 2 T 20 2 73 2 T 74 2 M-T 60 2 T 67 T 2 94 2 84 C T 2 62 2 T 53 2 T 92 2 T 20 M-T 2 43 1 T go 1 T 90 3 AM-T 99 2 T 52 2 M 77 2 M-H 33 2 M 90 2 M 30 T 2 59 hl 2 61 hl 2 72 E-W 65 2 HP-T 39 2 59 2 T 46 2 H 88 2 hl 59
W
Rlp, OCb 144-145' 159-160 83-84 145- 147 64-65 116-118 123-125 133-134 40-42 81-83 55-56 109-111 70-71 79-80 1.54361 65-66 1,53021 69-71 70-71 73-75 1.52861 83-84 91-92 139-140 36-38 115-116 135-136 118-119 162-164h 227-228 112-114 111-1 13 223-226 224-226 82-83 155-156' 100-101 39-40 60-61 59-60 70-71 89-90 64-65 58-60 73-74 104-106 226-228l 101-102 74-75 126-127 61-62 111-112
-Halogen, 7%- -Nitroe ;en. %Found Calcd Found Calcd Formula CsHiCINzOs 12.2 15.5 15.5 12.3 CeHeClNrOa 11.4 14.6 14.8 11.5 CisHiiClNiOs 11.6 14.6 14.7 11.5 CioHiiCINzOa 10.9 13.8 14.0 10.9 CiiHnCINzOa 10.5 13.8 14.1 10.9 CiiHnCINzOa 11.2 14.0 10.9 13.8 CiiHisClN~Oa 11.2 13.8 14.0 10.9 CiiHiaClN20a 10.1 13.1 13.2 10.3 CizHiaClN2Os 10.1 13.1 13.0 10.3 CizHiaCIN20s 12.5 12.6 CisHirClNzOa 10.1 12.5 12.7 9.80 CisHnClNzOa 9.21 11.9 12.2 9.38 CiaHieClNzOa 8.79 11.3 11.6 8.96 CiaH2iClNzOa 8.46 10.8 10.4 8.57 CiaHzaClNzOaQ 8.23 10.8 11.2 8.57 CisH2sClNzOa 8.57 8.36 CiaHzaClNaOs 8.40 10.4 10.5 8.22 C11HzsC1N20a 8.03 9.99 10.2 7.89 CisHnCINzOa i.55 9.61 9.70 7.59 C19HzeClN20~ 7.45 9.61 9.92 7.59 CigH2gClN20a 7.42 CzoHnCIN~Oa 9.26 9.40 7.32 8 .13 20.5 20.3 8.08 Ci6HroC12N20a 7.15 7.55 CiaHmBrCINzOa 8.2i 10.5 10.3 7.91 Ci7Hz3ClN20a 14.1 11 0 10.7 13.9 CiiHiiClNzO~ 1 3 . 4 1 0 . 4 10.2 13.2 CizHiaClN203 12.7 9.98 9.89 12.6 CisHisClNzOa 9.82 13.1 10.1 12.8 CiaHsCINzOs 30.9 8.11 7.99 30.8 CiaH1ClaNz03 12.2 12.4 9.64 9.98 CiiHiiClNzOa 11.6 9.19 8.89 11.6 CiaHiaClNrOa 7.34 28.3 28.2 7.46 Ci4HeClaNzOa 34.2 6.83 34.6 6.53 Ci4H8ClrNz04 22.6 7.84 22.4 7.66 CiaHziBrN20a 44.81' 44.9 3 . ~ 9 3.13 ~ CsHiCiNzOa 12.0 CeHeClNzOa 15.5 15.5 12.3 11.3 11.0 8.96 9.05 CisHziClN20a 10.9 10.9 8.57 8.29 CisHzsClNzOa 8.16 10.4 10.6 8.22 CirHr6ClN20a 11.3 11.7 8.96 8.99 CiaHziC1N?Oa 6.93 6.91 CisHnINzOs 11.3 11.7 8.96 9.12 CiiH2iClNzOa 22.4 22.6 7.84 7.88 ClaHziBrNzOa 8.96 11.3 11.3 9.21 CuHziClNzOs 11.3 11.2 8.96 8.78 CisHriCINzoa CsHeC12NzOa 20.4 20.7 8.07 8.28 CisHzaChN?Oa 20.4 20.7 8.07 8.02 CisHzoChNzOa 20.4 8.07 8.10 C L ~ H Z O C L N Z O ~2 0 . 4 20.4 20.8 8.07 8.21 CisH2aC1zNz0a 11.0 8.57 10.9 8.71 C1eHzaClNzOa
Concn for inhibition of
s
(1
c
+T
10T
+
lOOT 10T 10T
+
JI .\I AI
+
JI AI
+
AI
'r
.\1
AI lOOT 1OOT
+
.\I hI
hl lOOT
lOOT lOOT
+
+ +
+ + + JI T T
Y i ,M
hI hl hI
+
+ + + + hl + + + +
5 T = toluene, 1 1 = methylcyclohexane, H = hexane, C = chlorobenzene, E = ethanol, W = water, HP = heptane. All melting points, taken on a Fisher-Johns melting point apparatus, are corrected. S.a. = Staphylococcus aureus; represents growth a t a concentration of 1 X 103; T, IOT, 100T, and > represent 'I no growth at a concentration of 1 X lo3, 1 x lo4, 1 x 106, and 1 x 106, respectively. d F. Beilstein and A. Kurbatow [Ann., 182,94 (1876)l give mp 141-142'. e Methyl group substituted on N. f Refractive index, nZ5D. g Bnal. Calcd: C, 58.8; H, 7.09. Found: C, 58.6; H, 7.28. * R. Adams and L. 31. Werbel [J.Org. Chem., 22, 1287 (1957)] give mp 163-164". a F. D. Chattaway, K. J. P. Orton, and R. C. T. Evans [Ber., 33, 3057 (1900)] give mp 145'. j C analysis. k H analysis. 1 Lit.8 mp 222'.
+
The product was obtained either by cooling the solution to allow precipitation or by removal of the solvent with a rotary evaporator. The solid products were purified by recrystallization after decolorization with activated carbon. Method 3.-The appropriate acid chloride (0.05 mole) was added dropwise to a stirred solution of the aniline and triethylamine (0.05 mole of each) in 200-300 ml of ethyl ether. The mixture was refluxed for 2-4 hr and cooled, and the insoluble triethylamine hydrochloride was separated by filtration. The solvent was removed with a rotary evaporator and the product was recrystallized, using activated carbon. Method 4.-An equimolar mixture (0.016 g-atom or mole) of sodium and the anilide in 50 ml of toluene was refluxed for 2 hr.
Dimethyl sulfate (0.009 mole) was added and the mixture was refluxed for 2 hr. The mixture was extracted with water, dried, and treated with activated carbon, and the soIvent was evaporated to yield the product. Infrared Spectra.-The infrared spectra of the solid anilides were taken as Nujol mulls using a Beckman IR-5 spectrophotometer. The liquids were examined as thin layers between NaCl plates. Bacteriostatic Test Procedure.-The standard procedure used in screening the compounds against Staphylococcus aureus was as follows. Stock solutions were prepared by dissolving 100 mg of the test compound in 10 ml of acetone, alcohol, or other solvent. The stork solutions were diluted serially by pipetting 2 ml of
