446 C. Hansch and R. M. Muir 



Suppose we introduce a second chlorine atom at one of the ortho 

 positions. It will intensify this charge, and so we get one of our most 

 active auxins. However, if chlorine is present at both ortho positions, 

 we have 2,4,6-trichlorophenoxyacetic acid in which the positive site 

 is occupied and the compound is, as might be predicted, inactive. 



Recently we have conducted a study of the phenylacetic acids, 

 which we obtained through the courtesy of Drs. Steward and Schantz 

 at Cornell, who got them in turn from Dr. Brian of Imperial Chem- 

 ical Industries in England. I will not discuss them in detail, because 

 Dr. Wain has already mentioned something of their activity, but 

 will make one point, namely that in phenylacetic acid, the side chain 

 is shortened by 1 atom, so that in order to get the most favorable 

 distance to the positive charge, we want it at the meta (instead of the 

 ortho) position. It is interesting that in the phenylacetic acid series, 

 the activities of differently substituted compounds do not vary as 

 widely as they do in the benzoic acid series or in the phenoxyacetic 

 acid series, but the activities are more nearly constant, which suggests 

 that while the meta is the most favored position, still the compound, 

 through its free rotation, is able to react at the ortho or the para posi- 

 tion. Tests with the tri-substituted phenylacetic acids show this very 

 nicely. Substitution in the 2,4,5 positions should force the compound 

 to react at the 3 position, and this tmns out to be the most active. 

 Substitution at 3,4,5 forces reaction at the 2 or 6 positions, and this 

 compound is less active. The same is true when the compound is 

 forced to react at the para position. 



The effect of methyl substituents was mentioned by Dr. Miur. 

 Methyl substituents do enhance activity. Every English farmer who 

 uses methoxone to kill his weeds knows very well that this is the case; 

 2-methyl-4-chlorophenoxyacetic acid is an extremely active substance. 

 Now since methyl activates the ring, while chlorine deactivates it, one 

 wonders how two oppositely effective groups can have essentially the 

 same effect. The concept of the spatial distribution of charges ex- 

 plains that perfectly because both are ortho-para directive. That 

 means that, although they do it to different degrees, they essentially 

 act in the same general direction. In a series of substituted phenyl- 

 glycines, which were reported by Takeda a few years ago, it was very 

 characteristic that only the chloro and the methyl derivatives were 

 appreciably active. 



There are two or three outstanding special compounds; one is 

 2,6-dichlorobenzoic acid. This compound is blocked in the ortho 

 position; therefore according to Muir and Hansch it should not be 

 active, but of course in benzoic acids the side chain is shortened, and 

 as Dr. Leopold and I pointed out in 1955 (The Hormones, Vol. Ill, 



