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Bergmann, Jochanan Blum, Sarah Butanaro and Adam Heller Department of Organic Chemistry,Hebrew University,Jerusalem (Received10 February 1959)

FROM the etrongly ortho-B-directing

nature of fluorine atome in

electrophilicreactions of aromatic compounds,and the unusually large one must conclude that the electroreactivity of the ortho-positions, philic electron looalisationenergies decreaee strongly in the immediate neighbourhoodof the fluorine-substituted carbon atom. Therefore,if one assumes 1,2 that the determiningstep in the carcinogenicprocess in an aromatic hydrocarbonis an electrophilic reaction of the "K" region, and if one compares the electrophilicelectron localisationenergies of the compounds (a) with an unsubstituted"K" region and (b) with fluorine in the "K" region, one arrives at the following predictions: First possibility:if the electrophilicsubstitutiontakes place only at the fluorinatedcarbon atom, the carcinogenicactivity will

' C.A. Coulaon, Advances in Cancer Research,Vol.1, p. 2, New

York (1953).
2 A. Pullman and B. Pullman, Advances in Cancer Research,Vol. 3 P. 117,New York (1955).


p. einoe this carbon atom will be ecreened by the fluorine. 174'1 picrate.a number of fluoro-derivatives of carcinogenic polycyclicshas been eyntheeieed. 187-189' (2 mm).and @olylderivatives 80 obtained (I.p.The methoda of synthesisare briefly reported here. 53' b. 5.p. (1) 4-Fluoro-l-naphthylamine wae condensed in the presence of a trace of iodine with E.p. I?. (Anal.&rate. 74-75'. m. Aa It seemed interestingto compare these theoreticalresults with the experiment. Found: (III) C. 173-175'. m.5.0. 5.16 Polycycllc carcinogeniccompounds deareaee. m.6. 7.p.9. 218-220' (deo.9. 5.11 IJ. b.2 C19E14FN requires C. 4.6.))and 3-fluoro-5r8-dimethyl-l:2-benz~Orldine (Iv.)). 83.reepectively. N. Second possibility:if the substitutiontakes place only at the non-fluorinated atom or eimultaneouely on both oarbon atome.9. m. 210-213' (deo. m.0. 208' (10 mm)) were cyclised with zinc ohlorlde and acetic anbydride to 3-fluoro-5:7dimethyl-ltP-bensaoridine (III.p. I.6.2.The I-p. H. m. H. the carcinogenioactivity will increase. 82. F.p.P.1.. 82. F. 5. H.9$) . II.and g-toluidine.8 (IV) C.

and fluoro-eubetltuted lr2-benzanthraoenee started from z-(4-fluoro-l-naphthoyl)benzolo acid (V. 3-fluoro-q-methyl-1-1*2-benaanthrabene (IX. (2) The synthesis of suitably methyl. from nitromethane. Y Yu Reaction of V with methylmagneelum bromide gave the lactane VI (from ethanol. . 170.p.p. m. from ethanol m. Cyclieationwith sulphuricacid gave in 8% yield J-fluoroq-methyl-lr2-bensanthr-lo-one (VIII. from toluene. 130') and reduction with zinc dust and sodium hydroxide and subsequentdehydrationwith alcoholichydrochloricacid.8 mm) and melted at 36’). which oould be 17 prepared in 53%~ yield from phthalio anhydride and 4-fluoro1-naphthylmagnesium bromide (4-fluoro-1-bromonaphthalene boiled at 108' (0. 140') which wae reduced by zinc and hydroohloricacid in 4pk and by phosphorusand hydriodic acid in lOO$ yield to 4-fluoro-l-a(g-oarboxy-phenyl -ethyl) naphthalene (VII. m. 161’).p. m.171').5 .p.Polyoycllo carcinogeniccompounde .

342 + (4. 336 w (3.2. 300 w A more detailed descriptionof these and related experimentsas well as the results of the biological testing of the compoundsIII. 5. Reaction of VIII with methylmagnesium iodide gave IX (Rl-R2-CH3)(from oyclohexane.04).65).83).78).65). 294 w (4. 285 w (3.4. F.58). 369 nc1 (3. 87.52).7.88).70).5. 295 JW (4. U.76).p. (3.b 5. 390 w (4.83).): 289 w (4. 322 IIIP (3.18 Polycyclic carcinogeniccompounds R1=CH3.75).V.W. 5.41 F.71).H. (4. (&g.R2 = Crr.90). 54'. .5.35).CH3.64). 366 w (3. 87. from ethanol. 8%).72). yield. 7. 284 w (4. 283 IQI(4.9~R.9. R2-H) will be reported elsewhere.68).95). R2-R) hp. 272 w (4. IV and IX (R~=R~=cHJand Rl-cH3. 374 w (3.92). 87. Found:C. C20H15F requirea C. (3. 7. (3. 87.m.5. spectra(in CRC13)III: 274 w (4. ClVH13F rewires C.HI 5. 348 mc~ (3. 2% w I'JI 264 w (4. &al. 395 w (4.90). 94'. 7. Found: C.79)5 396 w IX: (RI . 6. F.89)~ 355 w IX: (Rl . F.yield.38).0. R2 = H): 285 w (3.78).