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Electron Density Studies on Quinoline Analogs of N,N'-Dimcthy\-P- Phenylazoaniline

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Electron Density Studies on Quinoline Analogs of N,N'-Dimcthy\-P- Phenylazoaniline [CANCER RESEARCH 30, 2089-2090, August 1970] Electron Density Studies on Quinoline Analogs of N,N'-Dimcthy\-p- phenylazoaniline Ellis V. Brown and William H. Kipp Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506 SUMMARY azobenzenes. The K for the addition of 1 proton to the quinolinium salt would be determined (designated pKfl). The This paper continues the study of the relationship between amino nitrogen of the quinolinium salt would be quater- electron density and carcinogenic activity for compounds nized, and then the K for the addition of a proton to the azo related to p-dimethylaminoazobenzene (Cancer Res., 29: nitrogen in the presence of 2 positive charges would be 1341-1344, 1969) and reports on the seven p-dimethyl- determined. It would then be possible to determine KT, aminophenylazoquinolines. A relationship was found pKam, and pKaz in the manner described in the previous between carcinogenic activity and the pKfl of the amino paper (Chart 1). nitrogen in these compounds, and in this new series a H relationship also was found for carcinogenic activity and the *;]-«•I pKa of the azo nitrogen. INTRODUCTION CH, C-H N -N=NC,H.N(CH,), ^=îiC_H,N - N' - "UC,H,N (CH, ) We have previously reported (2) on the resolution of KT y o o 4 J ¿ y o o 4 J ¿ into pKam and pKaz for a series of alkyl derivatives of AVV-dimethyl-p-phenylazoaniline. KT is the tautomerie a2 equilibrium between the aniline nitrogen and the azo nitro gens in 20% ethanol-sulfuric acid solution described by Isak's and Jaffe (5). pKam and pKaz are the pKfl of the amino and azo nitrogen, respectively. The quinoline analogs of AVV-dimethyl-p-phenylazoaniline are a series of compounds with a wide range of hepatocar- cinogenic activity (3). There are 3 basic sites in the molecule, the nitrogen of the quinoline ring, the azo linkage, CH, and the amino nitrogen. Klotz et al. (6) proved that in the - If pyridine analogs of p-dimethylaminoazobenzene the most basic site was the pyridine nitrogen. Pyridine and quinoline have approximately the same pKa (1), pyridine 5.25 and quinoline 4.94. It therefore seemed obvious that the quinoline nitrogen would be the most basic site in the Chart 1. Scheme for the determination of KT of p-dimethylamino- p-dimethylaminophenylazoquinoline molecule. This as phenylazoquinolines. sumption was confirmed by H. H. Jaffe (personal communi cation). The electron density of the p-dimethylaminophenylazoquin- MATERIALS AND METHODS olines can then be determined in the following manner. In The 3-, 5-, 6-, and 7-isomers of the p-dimethylaminophenyl- acid solution, the first proton would go to the quinoline nitrogen. The pKfl (designated pKj) of the quinoline nitro azoquinolines, available in the laboratory, were recrystallized gen could be determined with a pH meter and a spectro- from ethanol to a constant melting point. photometer. The quinoline nitrogen could then be quater- 4-Aminoquinoline was prepared by the low-pressure re duction of 4-nitroquinoline 1-oxide, which was prepared nized. The resulting problem is then exactly the same as for determining the pKa for the basic sites in p-dimethylamino- from quinoline by the method of Ochiai (7). 8-Nitroquinoline (Aldrich Chemical Co., Inc., Milwaukee, Wis.), 12.5 g, was subjected to low-pressure reduction to give 9.5 g of 8-aminoquinoline. 2-Chloroquinoline (Aldrich), 50 g, was dissolved in phenol Received December 15, 1969; accepted April 8, 1970. and acetamide, and the reaction mixture was heated to 140°. AUGUST 1970 2089 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1970 American Association for Cancer Research. Ellis V. Brown and William H. Kipp Ammonia was bubbled through the hot solution for 2 hr. (2), there is a relationship between carcinogenic activity and The amine hydrochloride was collected by filtration and the electron density at the amino nitrogen (see Table 1). In neutralized with 10% sodium hydroxide. The amine was contrast to the alkyl derivatives, the quinoline analogs also taken up in ether and dried over magnesium sulfate; then the show a narrow range of pKaz associated with carcinogenic ether was removed. Thirty-eight g of crude amine were activity. obtained. The corresponding p-dimethylaminophenylazoquinolines ACKNOWLEDGMENTS were made by coupling the diazonium salts with NJV- dimethylaniline in the manner described by Brown et al. (4). We extend our thanks to Dr. Hans Jaffe of the University of For proof that the first proton went on the ring nitrogen, Cincinnati for the many fruitful discussions during the course of this the 5-, 6-, and 7-aminoquinoline-l-methyl chlorides were study. prepared by methylating the corresponding nitroquinoline with methyl iodide and reducing to the amine. The resulting REFERENCES salt was purified and passed through a Dowex 2-X8 ion- 1. Albert, A., Goldacre, R., and Phillips, J. The Strength of exchange resin. The resulting products were the same as Heterocyclic Bases. J. Chem. Soc., 2240-2249, 1948. those obtained by reacting the azo dyes with methyl iodide 2. Brown, E. V., and Kipp, W. H. A Comparison of Electron at room temperature in the presence of a layer of water to Density and Hepatocarcinogenic Activity for Various Derivatives dissolve the salt as it was formed. The salt was purified as of 4-Dimethylaminoazobenzene. Cancer Res., 29: 1341-1344, described in our previous paper (2) and passed through the 1969. Dowex 2-X8 ion-exchange resin. Carbon, hydrogen, and 3. Brown, E. V., Novak, R. M., and Hamdan, A. A. Carcinogenic nitrogen analyses were within 1% of the calculated values. Activity of Analogues of p-Dimethylaminoazobenzenes. IV. The trimethylamminophenylazoquinoline-1 -methyl dichlo- Activity of the Quinoline Analogues. J. Nati. Cancer Inst., 26: rides were prepared by refluxing the azo dye for 2 1461-1464, 1961. 4. Brown, E. V., Novak, R. M., and Hamdan, A. A. Carcinogenic days with methyl iodide and purifying in the same way as Activity of Analogues of p-Dimethylaminoazobenzene. III. The above. Carbon, hydrogen, and nitrogen analyses for these Quinoline Series. J. Org. Chem., 26. 2831-2833, 1961. salts were within 1% of the calculated values. All pKfl's were determined in the same manner as pre 5. Isaks, M., and Jaffe, H. H. Tautomerie Equilibrium. VII. Substit uent Effects in Dimethylaminoazobenzenes. J. Am. Chem. Soc., viously reported (2). 86: 2209-2213, 1964. 6. Klotz, I. M., Fiess, H. A., Chen Ho, J. Y., and Mellody, M. The Position of the Proton in Substituted Azobenzene Molecules. J. RESULTS AND DISCUSSION Am. Chem. Soc., 76: 5136-5140, 1954. 7. Ochiai, E. Recent Japanese Work on the Chemistry of Pyridine The results indicate that, for the quinoline analogs of 1-Oxide and Relation Compounds. J. Org. Chem., 18: 534-551, p-dimethylaminoazobenzene as well as its alkyl derivatives 1953. Table 1 Basicity values of the p-dimethylaminophenylazoquinolines Positionofattachmentto quinoline2345678pKi4.674.495.855.395.395.525.00PKa2.313.013.513.563.573.123.01PK„2-7.52-50.1-5.42-4.22-4.35-4.99-7.27PK4-6.19-4.08-4.31-3.54-3.59-4.12-6.00KT19.97.529.033.794.766.4217.2PKam0.381.962.392.782.692.161.64PKaz2.182.843.453.363.372.762.81Carcinogenicactivity0"72°15°150200+0a0a ^Reference 3, compared to p-dimethylaminoazobenzene at 6. 2090 CANCER RESEARCH VOL. 30 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1970 American Association for Cancer Research. Electron Density Studies on Quinoline Analogs of N,N′ -Dimethyl-p-phenylazoaniline Ellis V. Brown and William H. Kipp Cancer Res 1970;30:2089-2090. Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/30/8/2089 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected]. Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/30/8/2089. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1970 American Association for Cancer Research. .
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