Electronic Effect of Sitbstittieuts on Phenoxyacetic Acids 439 



tion gives the biologically quite active tetrachlorophenoxyacetic acid. 

 Fawcett et al. (7) have also shown that 2,3,5-trimethylphenoxyacetic 

 acid has very slight activity. Here again, 2-substitution would inhibit 

 the -f-M effect of the oxygen and enhance its — I effect on the ortho 

 position. We have found that 3,5-dimethylphenylacetic acid, al- 

 though less active than phenylacetic acid, is still very definitely active. 

 Although the methyl groups would affect the ortho positions by hy- 

 perconjugation, the -\-M. effect of the methylene group would be 

 very weak compared to the oxygen atom of the phenoxyacetic acid 

 series. A check on the above hypothesis can be made by testing the 

 activity of phenoxyacetic acid substituted in both meta positions with 

 trifluoromethyl groups. On the basis of information now available 

 such a molecule would be expected to be highly active. 



If a reaction does indeed occur at an ortho position or under spe- 

 cial conditions at another ring position, one would expect that sta- 

 bilization of the charged intermediates, such as IV shown on page 434, 

 would be very important in determining the relative activities of 

 closely related compounds. Differences in the activities of closely 

 related compounds can, in certain instances, be explained in terms 

 of one molecule forming an intermediate more ably than a closely 

 related isomer to delocalize an electron pair. It has long been 

 known that for chemical attack, the a position on naphthalene is 

 much more reactive than the (3 position (16), be the attack by an 

 electron-rich or electrophilic reagent (40). The well-known fact that 

 2-naphthoxyacetic acid is much more reactive than 1-naphthoxyacetic 

 acid can be explained by assuming better resonance stabilization of 

 the intermediate with the former than with the latter. With 2-naph- 

 thoxyacetic acid, reaction could occur at the 1 position to give an in- 

 termediate stabilized by seven relatively stable resonance structures, 

 four of which would not disturb the benzenoid resonance of the 

 nonreacting ring. In 1-naphthoxyacetic acid, reaction would occur 

 at the 2 position, the intermediate of which would be stabilized by 

 only six relatively stable structures, in only two of which woiild the 

 benzenoid resonance in the nonreacting ring be preserved. The fact 

 that reaction might occur at an a position by reaction at the 8 position 

 in the case of 1-naphthoxyacetic acid must be considered, however. 

 That the 8 position is much less favorably situated for reaction with 

 an -OCHoCOOH side chain is evident from the work of Toothill et 

 al. (35). These workers have amply demonstrated that the introduc- 

 tion of another atom in the oxyacetic acid side chain destroys activity. 

 Such would be the situation if two-point reaction in 1-naphthoxy- 

 acetic acid were required to occur by means of an 8 position. The 

 unsuitability of the 8 position sterically is nicely illustrated by the 

 inactivity of 2,4-dichloro-l-naphthoxyacetic acid (35, 36). An even 



