7-(ALKYL- AND ARALKYLAMINOALKYLAMINO)-BENZ [CIACRIDINES
Jan. 5 , 1958
Ether, Dioxane, Methanol and Acetic Acid.-When s o h tions of I in the preceding solvents were refluxed for 3 hours and the solvents evaporated, there remained orange-colored
323
oils from which only P C P was isolated; P C P was obtained in yields of 57,64 and 68% respectively. CHINALAKE,CALIF.
[CONTRIBUTION FROM THE RESEARCH LABORATORIES, PARKE,DAVISAND Co.]
Synthetic Amebicides. 111. 7- (3-0 ctylaminopropylamino)-benz [c ]acridine (PAA-2056) and Related 7-(Alkyl- and Aralkylaminoalky1amino)-benz[c]acridines'v2
w.
BY FRANKLIN SHORT, EDWARD F. ELSLAGER, ALEXANDER M. R ~ O O R E MARIE , J O SULLIVAN FRANK H. TENDICK
AND
RECEIVED JULY 26, 1957
A series of new 7-(alkyl- and aralky1aminoalkylamino)-benz[clacridines have been prepared by the condensation of a 7-chlorobenz [clacridine with the appropriate N-(alkyl or aralkyl)-diaminoalkane, by the action of an alkylamine on a 7haloalkylaminobenz IC] acridine, or by ring-closure of an N-(alkylaminoalky1)Q-( 1-naphthy1amino)-benzamide with phosphorus oxychloride. Acylation of 7-(3-hexyl- and heptylaminopropy1amino)-benz[c] acridines with acetic anhydride gave the corresponding N- [3-(benz[c]acridin-7-ylamino)-propyl] -N-hexyl- and heptylacetamides. The 7-(alkyl and aralkylaminoalky1amino)-benz[ clacridines were highly active when tested against Endamoeba histolytica in vitro, acute intestinal amebiasis in rats, amebic colitis in dogs and amebic hepatitis in hamsters.
In a previous communication, we reported the preparation of a number of 7-dialkylaminoalkylaminobenz [clacridines which possessed good antiamebic activity against Endamoeba histolytica in vitro, against intestinal amebiasis in rats and against amebic hepatitis in hamsters. During the course of continuing efforts in these laboratories to develop new antiamebic drugs, we have synthesized a group of 7-(alkyl and aralkylaminoalky1amino)-benz [clacridines (V). I n structure V, X represents hydrogen or chlorine, Y a divalent alkyl group and R an alkyl or aralkyl radical.
aralkyl)-diaminoalkane in phenol. The 7-chlorobenz [clacridines were prepared by ring-closure of an N-1-naphthylanthranilic acid (I) with phosphorus oxychloride as described previously.* Alternatively, the N-l -naphthylanthranilic acid was converted to the N-1-naphthanthraniloyl chloride by the action of phosphorus pentachloride in boiling benzene. Treatment of an N-alkyldiaminoalkane with the acid chloride yielded the corresponding amide IV which was not isolated but was ringclosed in situ with phosphorus oxychloride to the desired aminobenz [clacridine. A third route in-
TABLE I N-(ALKYL-AND ARALKYL)-1,3-DIAMINOPROPANES,HzK( CHz)sNHR R
OC.
110-120 -(CHz)&& 64-68 -CHCzHr( CHz)aCHt 110-115 -(CHz)zCe" - C H [ ( C H Z ) ~ C H ~ ] ( C H ~ ) ~ C H72-77 ~ 75-80 -CHzCHCnHb( CH2)aCHs 90-95 -CHCHs( CH2)sCHj 120-126 -(CHz)aC&
B.P.,
Mm.
7.5-8.0 0.9 1.5
0.7 0.6 2.0 1.5
nZ1D
Bases" 1.4512 1.4487 1.5268 1.4488 1.4518 1.4506 1.5213
Yield,
Yo
Procedure
45 54 34 22 73 51 57
I I1 I11 111 I11 11 I11
h-itrogeu, % Calcd. Found
Formula
CioHziNz CioHzdh7z CiiHi.&z CiiHzeN2 CiiH26Nz CiiHz6xz
CizNzoNzd
16.26 16.26 15.73 15.04 15.04 15.04 14.57
16.38 16.47 15.87 15.01 15.19 15.51' 13.96
Dihydrochloridesb R
M.P., OC.
Yield, % '
Procedure
Formula
Nitrogen, % Calcd. Found
290-292 dec." -(CHz)eCH3 79' I1 CtzHzsN2.2HCI 10.25 9.5P -(CHz)gCHs 293-295 dec." 86/ I1 CiaH30Nz.2HCl 9.75 9 . 3Sh 70f I1 -(CHz)i6CHa 275-278" CioH&"*2HCl 7.54 7.35 a The bases were obtained as colorless liquids. Ir The dihydrochlorides were isolated as colorless solids. Anal. Calcd;: C, 70.90; H, 14.07. Found: C, 70.86; H, 14.13. Dihydrochloride crystallized from aqueous 2-propanol, m.p. 272-273 . Anal. Calcd.: N, 10.56. Found: N, 10.80. e Crystallized from ethanol. Crude. Anal. Calcd.: C, 52.73; H, 11.07. Found: C, 53.01; H, 10.81. Anal. Calcd.: C, 54.34; H, 11.23. Found: C, 54.40; H, 11.29.
The synthesis of the 7-(alkyl- and aralkylaminoalky1amino)-benz [clacridines (Table 11) was achieved by three routes as illustrated by formulas I through VI. The method most extensively employed was the condensation of a 7-chlorobenz[clacridine (11) with the appropriate N-(alkyl or (1) Presented before the Division of Medicinal Chemistry at the 131st National A. C.S. Meeting, April, 1957, in Miami, Fla. (2) For previous paper in this series see E . F Elslager, A. hT. hloore, F. W. Short, M. J. Sullivan and F. H. Tendick, THISJOURNAL, 79, 4699 (1957).
volved the condensation of a 7-chlorobenz [c]acridine with an aminoalkanol to give a benz [c]acridin-7-ylaminoalkanol (111) , 2 which upon treatment with thionyl chloride or a constant boiling hydrobromic acid-sulfuric acid mixture yielded the 7-haloalkylaminobenz [clacridine (VI, where Hal represents c1 O r Br). The condensation of a 7haloalkylaminobenz [clacridine with an alkyl amine in '-pentan'' at ' O o 0 gave the desired 7-a1ky1aminoalkylaminobenz [clacridine (V). However, in one
F. ITr. SHORT, E. F. ELSLAGER, -4.hi.
224
W
~~OORE h!f. ,
J. SULLIVAN AND F. H. 'TENDICK
ITd. 80
Jan. 5 , 1958
7- (ALKYL-
c1
COOH
r
CONH-Y-SHK
AND ARALKYLAMINOALKYLAMINO) -BENZ [CIACRIDINES
1
NH-Y-OH
225 NH-Y-Hal
n"-Y-KHR
4-benzylaininoquinolines increased with elevation of reaction temperatures. .Absorption in the ultraviolet and low wave length visible range was advantageously employed in the characterization of many of the :-aminobenz [clacridines reported herein. =Ibsorption curves for representative 7-aminobenz [clacridines have been described previously.2 Iv v A number of the intermediate N-(alkyl and case in which a large excess of the boiling amine aralkyl)-diaminoalkanes (Table I) which were was employed as solvent, a side reaction involving prepared have not been reported previously. X displacement of the 7-haloalkylamino group oc- majority of these new diamines were synthesized by curred with the formation of the 7-alkylamino- alkylation of a diaminoalkane with an alkyl brobenz[c]acridine. Thus, when IO-chloro-i-(2-chlo- mide or chloride. IVhere this reaction yielded a roethylamino)-benz [clacridine hydrochloride (VII) solid crude product, it was expedient to convert the was boiled under reflux for four hours with a large crude material to the dihydrochloride for purificaexcess of hexylamine, 10-chloro-7-hexylaminobenz- tion and characterization. N-Heptyl-l,3-diamino[clacridine (VIII) was isolated in i7yo yield. propane was obtained by cyanoethylation of Under similar conditions, VI11 was obtained in heptylaniine followed by catalytic hydrogenation Sayo yield from 10-chloro-7-[j-(1-piperidiny1)-pen- of the intermediate 3-heptylaminopropionitrile tylamino]-benz [clacridine dihydrochloride (IX) according to standard procedures.4 and hexylamine; the melting point of a mixture of Two N-acetyl derivatives in the 7-alkylaminoeither sample with an authentic sample of VI11 alkylaminobenz [clacridine series were prepared in older to study the influence of acetylation on S H (CH2)2C1 antiamebic activity. Acylation of 7-(3-hexyl and heptylaminopropy1amino)-benz[clacridines with acetic anhydride gave the corresponding S-[3(benz[c]acridin - T - ylamino) - propyl] - S - hexyland heptylacetamides (Xa and b). /
P\"(CHz)&( CHt),CHz I
1-11 XH(CH2)bCHa I
I
NH( CH2)5-N I
b,x=6
When an aqueous solution of two molar equivalents of potassium penicillin G was added in one portion to a methanol solution of 7- (3-octylaminoprepared from 7,lO-dichlorobenz [c]acridine2 and propylamino) -benz [clacridine dihydrochloride, a hexylamine was not depressed. An analogous dis- monopenicillin salt was obtained. However, when placement reaction involving the quinoline nucleus more dilute solutions were used and the benzacrihas been reported by Fultori and co-workers3; dine solution was added dropwise to the penicilli11 -I-methylaniiiioquinaldiiie and ~~-(3,-inethylaiiiirit~solution, a dipenicillin salt separated. Identifiethy1arnino)-quinaldine were isolated from thc cation of the salts was based upon elementary interaction of methylamine and 4-(2-chloroethyl- analysis. amino)-quinaldine, while 2-anilino-4-benzylaminoThe 7-(alkyl- and aralkylaminoalkylamino) quinoline together with 2-anilino-4-(2-benzylam- benz [clacridines and N- [a-(benz[c]acridin-7-yla inoethy1amino)-quinoline were obtained from ben- mino)-propyl]-N-hexyl and heptylacetamides dczylamine and 2-anilino-4-(2-chloroethylatnirio)-scribed in the present communication were tested quinoline. The proportion of the 4-methyl- and by Thompson and co-workers of these laboratories VI11
IX
(3) J. D Fulton, L. P. Joyner, H Kmg, J. M. Osbond a n d J. Wright, Proc Roy. Soc., Ser B , 13'7, 339 (1950).
(4) D S. Tarbell, X. Shakespeare, C J. Claus a n d J F Bunnett, THISJOURNAL, 68, 1218 (1946).
226
F. W. SHORT,E.
€7.
ELSLAGER, A. AI. MOORE, AI. J. SULLIVAN AND P.H. ' I ' E ~ I C E ; Y d . SO
against Endamoeba Iaistolytica in vitro,6 and when Subsequently, a solution of 73 g. (0.445 mole') of 3-hcptylindicated, against acute intestinal amebiasis in aminopropionitrile in 200 ml. of ethanol saturated vvitli \vas hydrogenated over Raiiej- nickel (lV-41 .it rats,6 amebic colitis in dogs7 and amebic hepatitis ammonia 1300 p.s.i.g. and 1.17' initial pressure :rnd temperature. in illthough details of these test results The mixture was filtered, the volatile materials were rcwill be published in a separate comm~nication,~iiiovcd and the residue distilled in ' L ' U C ~ L Otlirougii a six-incli it might be mentioned here that 7-(3-octylamino- l'igreux column, Method 11.-The following procedure illustrates tlie g a l propy1amino)-benz [clacridine, dihpdrochloride (XI) era1 method emplo>-cdfor t h e alkylation of l,~~-diaminolir(i(PAA-2056) was one of the most promising coin- pane with an alk!-l broiiiide: pounds tested. This compound was active against 1,.';-:)iaininopropane (100 iiil., 1.20 moles) w;is stirrcti
heiltetl to 100'. :LUroInoheptane (53.3 g., 0.30 mole t h e n :iddetl dropwise over a period of 30 minutes, tlic e \vas boiled gently under reflux for 3 hr. aild stirred X solution of 15 g. (0.3h I? tenijierature f i r 18 l:r. molei of sodium hydroxide in 23 nil. of water was added, tile mixture \vas extracted with several portions of etlicr ,iiitl the combined ether extracts were dried over anhydrous potassium carbonate. The ether \vas removed, and the residue distilled iiz ^I'QCUIJ tliruugh a Vigreus column. Method 111.-The following procedure is tl-pica1 liir tlic with an a l k ~ -chloride: l intestinal amebiasis in rats and dogs arid against ure, 50 g . i0.49 r n o k ( i f I,,;amebic hepatitis in hamsters.I0 The salts of 7(0.12 mole! of octyl chliiritie (;j-octylaminopropylamino)-benz [clacridine with gave 19 g. (74741 of crude serni-solid product. -1 solution of this crude dianiiiie in &propanol wits treated witli a 2-prO8-hydroxy-7-iodod-quinolinesulfonic acid and ben- panol-hydrogen chloride solution to give the crude S-oct! Izyl penicillin were likewise observed to have par- 1,5-dianiiriopentane tlili~-droc'iiloride. Cr:-stalliz:itiiin from ticularly interesting antiamebic properties. N- [3- 2-propanol gave the pure salt 4s colorless cryst:ils, 1n.p. (Benz [c]acridin-7-ylarnino)-propyl]-N-hexyl and 295" dec. heptylacetarnide possessed only slight antiamebic .l?zal. Calcd. for C13H30S2.2HCl: S , 9.75. Found: 9.61. activity in vitro and in rats. Methods for Preparing 7-(Alkyl- and AralkylaminoalkylAcknowledgment.-We thank Dr. Loren 11. amino)-benz[c]acridines (Table 11). Method I.-A mixturc Long and Dr. George Rieveschl, Jr., for encourage- of 0.042 to 0.200 mole of the appropriate amine, 40 to 70 g. ment in this investigation, Dr. Paul E. Thompson, of phenol and 0.035 to 0.120 mole of the 7-chlorobenz[clacriw v : ~stirred and heated a t 100-140" for 2 h r . , coole(l Miss Anita Bayles, Mr. D. A. LlcCarthy and Mr. dine2 and poured with stirring into a mixture of 125 to 500 1111. ( i f J. W. Reinertson for the biological testing, and acetone and 5 t o 25 ml. of concentrated hydrochloric :vi;!. Miss Gladys 2 . LIanougian and Mrs. Doris R. Upon standing for 20 to 18 hr., a yellow precipitate forine(1, Tlioiiias for synthesizing several of the compounds which was collected by filtration, waslied with acetone n1l(l ion (decoloriziug charcoal 1 frcm t lic described herein. The authors also are indebted to elrled the desired amiue hydroehloritli~. 1 I r . Charles E. Childs and associates for the inicro.ture o f 0.07I) t o 0 . analyses, and to Dr. J. 31. Irandenbelt and associ- clilorobenz [c]acritlirie, 0.075 to O.:;OO mole (of the aiii)rwriatcs for determination aiid interpretation of the ate amine and 60 to l(j0 g. of plicnol wis stirred m r l hc:ltc(i on the steam-bath for 3 to 4 hr. The reactiori \vas protectcl] infrared and ultraviolet absorption spectra. from moisture by- ii calcium chloride tubc. T h e rc:icti~)l1 mixture was cooled, :ind poured slowly with stirrit~ginto 2 Experimental to 4 I . of acetone containing a n excess of etlianolic l i y c f r ~ w : ~ cliloride. The cruclc Iirotluct w:is ccillcctcd by i i l t r a t ~ ~ ~ ~ ~ l Methods for Preparing N-(Alkyl- and Aralkyl!-1,3-diwashed with acetone and di-icd iiz 18ncuo at fino for 18 111.. aiiiinopropanes (Table I). Method I.--The following procedure is illustrative of the tiiethoc! involving cyanoetliyla- Tlie hytlrocliloritle \\':is dissol\-erl it1 water xntl t ! i c J K I ~ C ' ~ solution extracted tliorouglily with cliloroli Irm. The C O I I I tion of an alkl-laxnine followed bl- catalytic hydrogenation bined chloroforin extracts were washed twice witli tlilu! c of the intermediate alkylaniinol,ropionitrile: .I procedure analogous to that employed by Tarbell, cl h~-drocliloricacid :in11tlic :icid extr:tcts combirletl wit11 t original acid 1,iyer. The chloroform solutirin W I S (lis~ t l . for , ~ tlie preparation of the butyl homolog was used; 32.9 I d . (0.50 molei of acrylonitrile was added dropwise carded. Tlic acitl solution wcis filtered and macle strorlgl!. with stirring over a period of 80 minutes to 111 nil. (0.75 alkaline with concentr cl :itnirioniurn hyrlroxitle. Frll(: extracted with sever:il pc~rtiCIiI5 mole) of heptylatnine, maiiitaining the temperature below base which sep:ir300°. fonic Acid.-A filtered solution of 15.1 g. (0.030 mole) of 7Anal. Calcd. for C,8H15ClN2.HC1.0.5H20: C, 64.78; (3-octylaminopropylamino)-benz [c]acridine dihydrochloride H,4.87; N, 7.95. Found: C,64.89; H,4.71; N,8.10. monohydrate in 1 1. of hot water was added with stirring 1O-Chloro-7-(2-chloroethylamino)-benz [c]acridine, Hyto a filtered solution of 2.4 g. (0.060 mole) of sodium hydroxdrochloride.-A mixture of 26 g. (0.081 mole) of 2-(10ide and 22.1 g. (0.063 mole) of 8-hydroxy-7-iodo-5-quinochlorobenz [clacridin-7-y1amino)-ethanol2and 100 ml. of linesulfonic acid in 1 1. of hot water. The red oil which de- thionyl chloride was stirred and heated under reflux for 1 hr . posited solidified on cooling, was ground up with water, col- The mixture was cooled, and the product collected by filtralected by filtration, washed with water and dried a t room tion and vashed with water. Crystallization from ethanol temperature in vacuo giving 30.0 g. (goyG) of the salt as a yielded 20 g. (66%) of yellow crystals, m.p. 260-262'. red solid of indefinite melting point. Anal. Calcd. for C19H14Cl~h'2.HCl:N, 7.42. Found: Anal. Calcd. for C Z ~ H ~ ~ N ~ . ~ G H BC, I N49.51; O ~ S : H , N, 7.28. 4.24; N,6.28. Found: C,49.14; H,4.17; N,6.19. 7-(3-Chloropropylamino)-benz [c]acridine, Hydrochloride. 7-~3-Octvlaminopropylamino~-benz [c]acridine, Salt with -A mixture of 60.5 g. (0.2 mole) of 3-(benz[c]acridin-7One Formula Weight of Penicillin G.-A solution of 14.5 g. ylamino)-propanol2 and 300 ml. of thionyl chloride was (0.0390 mole) of potassium penicillin G in 100 ml. of water stirred and heated on the steam-bath for 1 hr. The excess was added in one portion to a solution of 10.0 g. (0.0195 thionyl chloride was removed in vacuo, the residue was mole) of 7-(3-octylarninopropylarnino)-benz[c]acridine di- triturated with ether, and the product crystallized from hydrochloride sesquihydrate in 40 ml. of methanol. A gold- absolute etha2ol; yield 63.5 g. (87%) of yellow crystals, colored gum deposited. The mixture was chilled, the super- m.D. 228-230 natant liquid decanted and the gum washed with water by Calcd. for CzoH1,ClN2~HC1~O.5H~O: C, 65.58; decantation and triturated with ether. The yellow solid H ,Anal. 5.23: N, 7.65; C1, 19.36. Found: C, 65.44; H, 5.31; obtained was collected rapidly by filtration, washed with N,7.70: C1, 19.39. ether and petroleum ether (b.p. 30-60') and dried a t room 7-(3-Bromopropylamino)-benzIC] acridine.-A mixture of temperature in vacuo, giving 13.5 g. (57%) of a hydrated 82 g. (0.28 mole) of 3-(benz [c]a~ridin-7-ylamino)-propanol,~ salt with indefinite melting point. 90 ml. of redistilled colorless constant boiling hydrobromic Anal. Calcd. for C28H35N3G H ~ ~ N Z O.5H20 ~ S :. ~ C, acid (sp. gr. 1.48) and 30 ml. of sulfuric acid (sp. gr. 1.84) 66.64; H , 7.37; N, 8.83; S,4.04. Found: C, 66.81, 66.93; was boiled under gentle reflux for 1.5 hr. The mixture was H, 7.61, 7.54; K, 8.85; S,4.18,4.29. quenched in ice-water and made basic with ammonium hy7-(3-Octylaminopropylamino~-benz [c]acridine, Salt with droxide. The resulting insoluble mass was induced to crysTwo Formula Weights of Penicillin G.-A chilled, filtered tallize by scratching and the yellow crystalline product was solution of 50.5 g. (0.10 mole) of 7-(3-octylaminopropyIcollected b z filtration, washed with water and dried in amino)-benz [clacridine dihydrochloride monohydrate in vacuo a t 45 . Crystallization from methanol (decolorizing 750 ml. of methanol was added dropwise to a chilled, filtered charcoal) gave yellow crystals, m.p. 200-202". Anal. Calcd. for C2oH1?BrN2.0.5H20: C, 64.17; H, (12) We are indebted to Dr. C. F. H. Allen of the Eastman Kodak 4.85; N, 7.49; Br, 21.35. Found: C, 63.81, 63.84; H , Cu. for making this diamine available to US. 4.90, 4.89; N, 7.24; Br, 21.80,21.71.
.
~
l0-Chloro-7-hexylaminobenz[c]acridine. A . From 10Chloro-7-(2-chloroethylamino)-benz[c]acridine, Hydro-
aqueous mixture was acidified with lU(1; liydrocliloric acid, and the waxy precipitate which separated wx collected b>chloride.-A mixture of 6.0 g. (0.016 mole) of lO-chloro-7filtration, washed with water and air-dried. The crutic (2-chloroethylamino)-benz [c]acridine hydrochloride and 100 product was dissolved in 9555 ethanol, inade alkulinc with 1111. of hexylamine was boiled under reflux for 4 hr. Upon ammonium hydroxide and the base collectetl b>- filtration, cooling, the reaction mixture was poured into a large volume dried and crystallized from ethanol. Tlic Ixisc ivcighetl of ice-watcr and the precipitate collected by filtration and I .1 g. (82i;b),ni.11. 90-92"; the melting point o f :L rnistui-c water. Cr)atallization from ethanoI yielded with the product from -1.above showed nu depression. of yellow crystals. For analysis, a sample 4-Chloro-N-1-naphthylanthraniloyl Chloride.--Ph)sed from isopropyl alcohol, rn.p. 90-.92". phorus pentachloride ((30.8g., 0.148 mulei i m s atltletl partionwise to a suspension of 40 g. (0.135 mcllei uf 4-chloro-Sctl. for C&?sC1N2: C, 76.12; 11, 6.39; ?;, 7.72; CI, 9.77. Found: C , X . 9 4 ; 11, 6.98;X, 7.90; CI, (1-nalJhthj-1I-anthranilic acid in 350 iIt1. i ~ fdi-3. ~ ~ c t r o ~ e u r l i ether (b.p. 80-1 IO"). As each portioii \ v a \ atltle(i, the m i x 9.91. B . From 7,10-Dichlorobenz [c]acridine.--A mixture of 0.5 ture wvas warmed gently until the reactioii subsided. Tlic g. (0.0017 mole) of 7,10-dichlorobenz [c]acridine* and 100 mixture was boiled under reflux for 40 minutes atid the I I C troleum ether soIution decanted from the heavy sediiiierir nil. of hexylamine was boiled under reflux for 4 hr. The eswhich separated. The residue was boiled with petroleurii cess hexylamine was removed in m c z ~ o ,the residue was ether (b.p. S0-llO";i and the petroleum ether solutiuns were treated with 10yo hydrochloric acid, the aqueous solution was decanted and the residue dissolved in absolute ethanol. discarded. The residue was dissolved in boiling beiizeiic was made alkaline with ammonium hy- and diluted with petroleum ether [b.p. 80-110° I , whercupi~ii ecipitated base was collected by filtra- a flocculent purple solid separated. This iinpurit>-W;LS colstaliized from ethanol; yield 0.4 g. lected by filtration and discarded. The filtrate was cliilletl the melting point of a mixture with the and the crude acid chloride collected by fi1tr;itioii. .I second crop was obtained by concentratiun o f t h e filtrate; product from A above showed no depression. C. From lo-Chloro-7- [5-(l-piperidinyl)-pentylamino] - crude yield 36 g. (84Yo). Crysta1liz:ition frurri :L beiizeni,-benzIcJacridine, Dihydroch1oride.-A mixture of 2.0 g. petroleum ether (b.1). 80-1 10") mixture (decolorizing c1i:ir10.037 mole) of 10-chloro-7- [5-(l-piperidinyl)-pc1ltyla1nino]- c o d ) gave 3 3 g. (8253'1o f !-elIow needles, m . p . 143" tlcc. benz [clacridine dihydrochloride dihydrate2 and 100 ml. of .4~zul. Calcd. for CI:II,,CISNO: C, 64.37: 11, :l.-?l; S , hexylamine was boiled under reflux for 16 hr., cooled, and 4.43. Found: C. 65.00: H . .'3.75; S . 4.77. 73 ml. of hexylamine was removed in ~ ' U C Z L O . The residue W:LS pocired with vigorous stirring into ;io0 ml. of water, the DETROIT,MICTIIGAN
[CONTRIBUTIONFROM
THE
CIIEMISTRY DEPARTMESTO F
COLUMBIA
UNIVERSITY1
The Reaction of Acyl Peroxides with Phenols1 BY
CHEPES JvALLIiiG .4ND
RUSSELLR.HODGDON, JR.2
RECEIVED J U L Y 19, 19.57 The reaction betiwen benzoyl (and similar) peroxides and phenols follows second-order kinetics, first order in peroxide and in phenol. The reaction is accelerated by electron-supplying groups on the phenol and retarded by bulky ortho-substituents. Measurements with 0-deuterated phenols give k E / k n = 1.32 i 0.03 in several systems. The reactioii shows iicither acid nor base catalysis, but the rate varies significantly with solvent, being slow in strongly hydrogen bonding media Radical traps, polymerizable monomers and iodine, have no effect on reaction rate. I t is concluded that the reaction is not a radical chain process, b u t probably involves a simple bimolecular "four-center" process without radical Formation, and :I possible reaction path is proposed,
In 1944 it was reported3 that, while styrene undergoes an only slightly retarded thermal polymerization in phenolic solvents, the benzoyl peroxide initiated polymerization was essentially inhibited. At the same time, it was noted that benzoyl peroxide decomposed very rapidly in mcresol solution, and both results were suggested as arising from either a fast non-radical reaction between peroxide and phenol, or a radical-forming process yielding radicals which were too rapidly consumed by reaction with each other or the phenol to initiate polymerization. In 1947, as part of their now-classic investigation of the induced decomposition of benzoyl peroxide, Bartlett and Nozaki4 obtained more quantitative data on the decomposition rate in various phenols, noted that the reaction rate was first order in peroxide, anti interpreted their results as the consequence of (1) Taken from t h e dissertation of Russell B. Hodgdon, Jr., submitted in partial fulfillment of t h e requirements of the Ph.D. degree, 10.57. Support of this work b y a research contract with t h e Office of Ordnance Research, U. S. Army, is gratefully acknowledged. (2) Texas Co. Fellow, 1955-1956. (3) C. Walling, THISJOURNAL, 6 6 , 1602 (1944). ( 4 ) P. n. B a r t l e t t and K. Nozaki, ibis',, 69, 2299 (1947).
an induced radical chain process. Subsequently, the nature of the products formed on refluxing equimolecular quantities of phenols and benzoyl peroxide in chloroform solution have been studied by Cosgrove and Waters5 who found that phenols with free o-positions give chiefly catechol nionobenzoates (I), 2,6-dimethylphenol is converted to 3,3,3'3'-tetramethyldiphenoquinone(II) in high yield and 2,4,6-trimethylphenol gives chiefly 2,4,G-triniethyl--l.-benzoyloxycyclohexa-2,~~ -dienone (111). I n every case most of the benzoyl perouitlcb residues not attached to aromatic nuclei are recovered as benzoic acid. In their discussion, Cosgrove and Waters have interpreted their products as the results of radical coupling and disproportionation, without considering the possible consequences of induced decomposition. Subsequently Wesseley and Schinze16 have investigated the decomposition of acetyl peroxide in acetic acid in the presence of each of the three isomeric cresols, obtaining catechol monoacetates (together with latc( 5 ) S L. Cosgroie and \\. A Waters, J Chem. S o c , ,318CJ ( 1 ' ) 4 ~ I l , zbzd ,'388 (1951). (6) F. Wesseley a n d If.Schmzel, Monutsh., 8 4 , 909 (195'3)
