Electronic Effect of Substituents on Phenoxyacetic Acids 447 



ed. G. Pincus and K. V. Thimann. Academic Press, New York. p. 13. 

 1955) one would not expect the approach to take place in the ortho 

 position, but further down the molecule, so if a chlorine is present at 

 the 2 position, positivity accumulates at the 4, and if a second one 

 is present at the 6 position, the effect is reinforced. So 2,6-dichloro- 

 benzoic acid would be expected to be very markedly active; 2,3,6- is 

 also active and, as was pointed out a little earlier, 2,5- is active. 2,6- 

 Dichlorophenoxyacetic acid is, of course, the comparable opposite 

 case, for the positive charge is at the 4 position, which is rather far 

 for the group to operate, and correspondingly it is only very weakly 

 active (though it has real activity). Another rather striking fact, 

 brought out by the French biochemist Julia, is that when there are 

 two carboxyl groups in the molecule, activity disappears. Thus, 4- 

 chloro-2-carboxymethylphenoxyacetic acid is like methoxone, 2- 

 methyl-4-chlorophenoxyacetic acid, except that it has a second car- 

 boxyl. One might expect it to partake to some extent of the activity 

 of its parent compound, but it does not at all; its activity is reported 

 to be zero. Presumably an additional negative charge at the wrong 

 point would prevent activity. 



And lastly, the vexing question of the 3,5-disubstituted compounds. 

 You remember that in the phenoxyacetic acids the optimum site for 

 the positive charge at 5i/4 angstrom units from the negative is close 

 to position 6. A chlorine atom in the 3 or 5 position has the opposite 

 effect, conferring positivity only on the 1 position where it is impos- 

 sible for it to react. So one could deduce that 3,5-dichlorination is 

 doing nothing to increase the reactivity of the molecule. Correspond- 

 ingly we find that it is totally inactive, like the parent compound. 

 This is also true in the case of benzoic acid where again the 3,5-di- 

 substituted molecule is just as inactive as is the parent benzoic acid. 

 In the case of phenylacetic acid, however, the 3,5-disubstituted de- 

 rivative has some activity, and again it is about the activity of the 

 parent molecule, which in the case of phenylacetic acid is quite ap- 

 preciable. Thus a number of the observed phenomena can be ex- 

 plained. Now if this view is correct, the impression it gives us of the 

 site of reactivity of auxin is something like that outlined by Dr. 

 Freed, that the auxin approaches a surface in which charges are 

 placed in characteristic positions and the relatively flat benzene ring 

 is borne down with van der Waals forces to rest upon the surface. 

 There is a similarity here to the discussions about the mode of action 

 of chymotrypsin. 



Dr. Crosby: For some time, we've been arguing with Prof. Hansch 

 and others about the importance of the ortJio position in simple 

 cases, such as p-chlorophenoxyacetic acid. We decided that perhaps 



