Sciencemadness Discussion Board

Chlorination of an aromatic ring

mycotheologist - 3-4-2012 at 13:51

What would be some viable methods of chlorinating this compound:

at the para position on the benzene ring? I assume the amino group will form an intermediate with the Cl atom and consequently, the compound would get chlorinated at the ortho position. I suppose that could be prevented by protecting the amine with a bulky protecting group. Any other problems one might encounter in their attempt to chlorinate only at the para position? Maybe if bulky protecting groups are attached to the amine and the acid group then these protecting groups would sterically block the ortho and meta positions, leaving only the para position open.

[Edited on 3-4-2012 by mycotheologist]

bfesser - 3-4-2012 at 14:03

So you're trying to prepare a substituted β-(p-chlorophenyl)ethylamine? What purpose do you have for the target compound?

mycotheologist - 4-4-2012 at 01:15

I'm learning about EAS reactions and decided to pick that GABA analogue as a precursor for a thought experiment. The fact it has an amino group as well as a carboxyl group poses a challenge.

[Edited on 4-4-2012 by mycotheologist]

Nicodem - 4-4-2012 at 08:43

Quote: Originally posted by mycotheologist  
I assume the amino group will form an intermediate with the Cl atom and consequently, the compound would get chlorinated at the ortho position. I suppose that could be prevented by protecting the amine with a bulky protecting group.

The chaperon effect in chlorination is only observed in nonpolar solvents and freebase amines. Neither of this conditions is possible due to the nature of your substrate and its solubility issues.
Quote:
Any other problems one might encounter in their attempt to chlorinate only at the para position? Maybe if bulky protecting groups are attached to the amine and the acid group then these protecting groups would sterically block the ortho and meta positions, leaving only the para position open.

A bulky group on the amine is already too distant to have a worthy enough steric influence on the ortho/para selectivity. Your substrate already has a relatively bulky aromatic substituent so there is not much else to do here. It is however poorly activated for an electrophilic aromatic substitution and chlorinations are poorly ortho/para selective. The chlorination of the related cumene commonly gives a 1 : 1 ratio of the ortho vs. para chlorinated product, so I would expect a small excess of the para isomer in your case. Chlorination in water might give a better para selectivity due to the charge and consequent strong solvation around the substituent, but this is just guesswork.

In regard to any need for the protecting groups, the carboxy group is not really a problem and the amino group can be protected by protonation. In principle, you might get a good monochlorination selectivity by chlorination in aqueous sulfuric acid. You could try with either chlorine or trichloroisocyanuric acid (TCCA) as the electrophilic chlorinating reagents (chlorine, being a gas, is not as easy to quantify, though). I would try with 20-60% H2SO4(aq) as a solvent and TCCA in about 20% excess.
There is no easy way to monitor such a reaction, except if you have an HPLC method suitable for such amino acids. There would be precipitation of cyanuric acid if you use TCCA in dilute H2SO4, but this does not necessarily correlate with the desired reaction pathway. There are some types of TLC plates that could work, but the more common silica plates are not suitable as far as I know. The isolation would be difficult as you would have to catch the isoelectric point. The separation of the desired para-chloro product would also be difficult if the reaction would not have enough para selectivity to allow a separation via recrystallization (in any case the yield would suffer from the isolation losses).

PS: Please open referenceless threads only in the Beginnings section. Once you equip the thread with a minimum of references (if you UTFSE you can use plenty already on this forum) I might get interested enough to complement with further literature data.