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4 position of 2,5-dimethoxy phenethylamines

Anon0631

Bluelighter
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Apr 22, 2012
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London, UK
I hope this isn't considered as synthesis discussion. My aim is to understand more about the molecule rather than to make drugs in my kitchen.

Why is it that when bromine (for instance) is stirred into a solution of 2c-h, it attaches itself to the 4 position and not the 3 or 6 position which are also free of substitutions?
 
Basic organic chemistry teaches that both methoxy and alkyl substitutents are ortho-para directing. Thus, 3-position is least favorable because it is meta to both one methoxy and the alkyl side chain. The 4 and 6-position are electronically almost equal, but the 6-position is sterically more hindered (2 ortho subsitutents) than the 4-position (1 ortho substituent).
 
That's probably a little technical. On a benzene ring with a single substituent, we call the position with the substitution the 1-position. So, we then have the two positions next to the 1-position, 2- and 6-, these are the ortho positions. The next two positions around, 3- and 5- are the meta positions, and the position directly opposite the 1-position is the para, or 4- position (so you can now make sense of names like paramethoxyamphetamine and metachlorophenylpiperazine). Different substituents direct further substitutions to different positions- some groups, for instance alkyl or alkoxyl, tend to direct further substituents to either an ortho or a para position. Now, the 1-,2-,and 5-positions are already occupied by the ethylamino and two methoxy groups, respectively. As cortex says, this means the 3-position is unfavourable. We're now left with the 4- and 6- positions, and it could go either way, except that at the 6- there is steric hindrance (or, in layman's terms, too much shit in the way already). So, para it is. This is probably more suited to the B&D Not-Quite-Advanced questions thread, and if you are hoping to learn a little more drug chemistry, reading through, and posting in, that thread is a really good way to go about it. If you already understood o/m/p notation, then excuse the condescension.
 
I already understood what ortho/meta/para referred to but everything else was pretty enlightening. Thank you.
 
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