444 C. Hansch and R. M. Muir 



a protein. The 2-point contact theory does not explain the speci- 

 ficity of stereoisomers. We have shown that for activity, the molecule 

 should, in general, have at least one hydrogen attached to the carbon 

 adjacent to the carboxyl group. This hydrogen may well be involved 

 in the growth reaction. If you accept this point, then you are able 

 not only to explain the specificity of stereoisomers but, as Dr. Wight- 

 man has shown, you can put competitive antagonism on a logical 

 basis. 



Dr. Hansch: I feel perfectly easy with respect to the 2-point at- 

 tachment theory and stereoisomerism in the side chain. There are a 

 lot of things that bother me much more than that. There are so 

 many cases in organic and biochemistry where two asymmetric cen- 

 ters react. You can get an enormous difference in reactivity between 

 D and L forms. This difference that you mentioned is very important. 

 It is one of the things that reinforces our ideas about the fact that 

 the carboxyl group does react to form an amide, covalent bond. If 

 it were only an ionic bond, then both stereoisomers could react at the 

 same point with little interference. When there are two optically-ac- 

 tive centers forming a chemical bond, you get into such differences 

 of activity with stereoisomers. 



Dr. Thimann: With a colleague and student, Mr. W'illiam Porter, 

 we have spent a great deal of time in reviewing the whole problem 

 of structure and activity again, and I woidd like to make a new sug- 

 gestion. It could not be dignified by the name of a fully developed 

 theory yet. First let me say this owes a great deal to various earlier 

 theories; I need not remind you that in the last 20 years a large num- 

 ber of ideas have been proposed, such as that the side chain is at an 

 angle to the ring, that a free hydrogen is needed in the side chain, 

 the concept of an essential distance between the carboxyl and the 

 ring, the concept of lipophilia, and the more recent argument about 

 reactivity at the ortho position. Of course, the idea of studying struc- 

 ture and activity is to get some clue as to what the receptor is like, 

 and I will say nothing about the receptor except to remind you of 

 the suggestion 1 made some time ago (Amer. Naturalist 90: 145. 1956), 

 that the receptor may be a family of closely related bodies; even 

 within one plant there would be a group of slightly different recep- 

 tors—an idea which makes it easily possible to cx])lain some of the 

 phenomena of synergism. 



Now, if we simply review the accumulated data, what can we de- 

 duce? Let me start with indoleacetic acid and its family of similar 

 isosteric substances, in which instead of nitrogen there occur methy- 

 lene, oxygen, or sulfin- in the same position. It is appropriate to start 

 with these because the compound with a carbon atom in place of ni- 



