Electronic Effect of Siibstitueuts on Plienoxyacetic Acids 437 



acetic acids is the jDieferred point for 2-point reaction, a study of 

 the substituents in the 3 and 4 positions should throw some light on 

 the nature of this reaction. Substitution in the 2 position will be 

 more difficult to evaluate because of steric interaction with the side 

 chain. As mentioned earlier, there are three important variables con- 

 nected with each substituent: steric, electronic, and H/L factor. The 

 latter factor has two components which one must consider. The rel- 

 ative hydrophilic-lipophilic character of the molecule must be such 

 that rapid penetration to the reaction site is possible. A second point 

 which may or may not be of importance is the possibility that reac- 

 tion may take place on a solid surface and adsorption might be gov- 

 erned by small H/L differences. To try to hold other variables con- 

 stant so that the electronic factor could be evaluated, we chose to 

 look at substitution in the 3 and 4 positions, and to consider groups 

 relatively inert chemically which would have closely related H/L fac- 

 tors. In addition to the above points it must be borne in mind that if 

 a substitution reaction occurred, it could be promoted by enzymatic 

 stretching of a carbon-hydrogen bond. 



A consideration of the data in Table 1 indicates that in general 

 those groups which are placed so that their electronic effect is to re- 

 duce the electron density at the ortho positions, give an increase in 

 activity over the unsubstituted plienoxyacetic acid. It is interesting 

 to note that the activity of the 4-substituted acids falls off as the — I 

 effect of the substituent on the ortho position decreases. The activity 

 we have found for the 4-halo and 4-methylphenoxyacetic acids is essen- 

 tially that reported by Aberg (1) except that he finds the 4-methyl sub- 

 stituent to be deactivating. Comparison of the 4-chloro and 4-methyl 

 groups is particularly instructive since both groups have about the 

 same size and effect on the H/L factor. The chlorine derivative is 

 about 100 times more active. The fact that iodine in the 4 position 

 gives an inactive molecule is significant and would lend support to 

 Aberg's observation that the size of the group in the 4 position is 

 particularly important. We have noted that 4-iodophenylacetic acid is 

 inactive, and Kato has observed (17) that an iodine in the 4 position 

 of phenylthioglycolic acid essentially destroys the activity of this mole- 

 cule. Aberg has also pointed out that large alkyl groups in the 4 posi- 

 tion also destroy activity. That 4-methoxy substitution gives an active 

 molecule, although it is a bulky group, is probably due to the non- 

 linear carbon-oxygen-carbon bonding which permits the methyl group 

 to assume a skewed position somewhat above the plane of the ring. 



From Table 1 it is evident that 2 substitution has little effect. 

 The introduction of halogen or methyl groups results in a slight in- 

 crease in activity. No obvious correlation between activity and the 

 three factors — electronic, steric, or H/L — appears. One might ex- 



