fastandbulbous said:
The activity about the substituent on the 3 position is all about the orientation of lone pairs for their interaction with DAT & SERT. A methylenedioxy ring is just the closest to ideal Not sure how much it would suffer by having the two lone pairs if an oxygen replaced by a single lone pair from a nitrogen (I suppose someone could make it and see! ), but replacing the oxygen with a CH2 just leaves it with mostly SERT activity (as with IAP), which isn't enough on it's own
Both the imidazole and oxazole would, obviously, be planar moieties as well. With the quadrapole of electronegativity/carbon/electronegativity sandwich presenting itself very similarly to the dioxole.
Now I'm having a brain fart, but in an oxygen aromatic heterocycle, one lone pair is participating in the aromaticity. what is the other pair doing? sticking straight out with the plane of the molecule ala the trigonal planar conformation adopted by a nitrogen in the same predicament (sp2)? It just seems really strained on what would normally want to be a tetrahedral atom.-a 4th year pHD student seems to agree with me on this one...
looking it up in my organic book does indeed show the lone pair sticking out with the plane of the aromaticity.
anyway
If this is true, than I can't see the difference between having an aromatic nitrogen there and an oxygen. The lone pair on the oxazole is not participating in the aromaticity and the oxygen is behaving as would be expected. IMHO, the oxazole would be almost undistinguishable.
Looking at it again, the imidazole would certainly be more tricky as only one lone pair is not participating in the aromaticity at any given time although this changes with resonance so it would seem that it would be almost a wild card where you would get both the IAP-like effects and binding to either the 3 or 4 position electron pair seekers (at different times) with the same molecule.
I'm sure this is most confusing, I'll try to chem draw up some pictures later in the week.