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Can we get chloroquine from 4-amino-7-chloroquinoline (7-chloroquinolin-4-amine) by adding 4-chloro-N,N-diethylpentan-1-amine $(\ce{CH3CHCl(CH2)3N(Et)2})$ ?

proposed chloroquine synthesis

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    $\begingroup$ Looking at the formulas for your two compounds, it seems like a simple substitution. What are you looking for in particular? $\endgroup$
    – F'x
    Jun 11, 2012 at 22:17
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    $\begingroup$ I've added a drawing of the proposed synthesis with hydrogen chloride as the inferred elimination product. I flipped the pendant alkylamine to save space on the page. ChemFig rocks, btw. $\endgroup$ Jun 12, 2012 at 3:55

3 Answers 3

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My intuition tells me that the nitrogen in the ring is more nucleophilic than the exocyclic amine. A quick-and-dirty electrostatic potential calculation using B88LYP/6-31G(d) on the PM3 geometry shows a large electron density (blue and violet) on the ring nitrogen and lower density (yellow) on the exocyclic amine:

enter image description here

Are there conditions that might work? Yes. Should you try it, if you need that molecule? Yes. Will it be difficult? Yes.

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It's a pretty untypical approach to chloroquine and you didn't tell how you would synthesize 7-chloro-3-aminoquinoline and the secondary chloride.

There is a good chance that the planned reaction will furnish a quarternary ammonium salt as a side product:

formation of a quartenary ammonium salt

The reaction will not necessary stop at this point.

Ia addition, there's a good chance to bis-alkylate the $\ce{-NH2}$ group of the quinoline.

All this is not very promising and any attempt to optimize this reaction is fighting problems you would not have if you had decided for a more reasonable and well-established alternative in the first!

That would be the synthesis of chloroquine from 4,7-dichloroquinoline and 4-diethylamino-1-methylbutylamine, where both starting materials are available through well-known procedures.

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    $\begingroup$ Yeah, and even synthesis of aliphatic amine chloride looks like a real problem $\endgroup$
    – Mithoron
    May 19, 2015 at 21:53
  • $\begingroup$ @Mithoron Yes, 4-diethylamino-1-methylbutylamine is definitely easier to synthesize. $\endgroup$ May 19, 2015 at 21:56
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    $\begingroup$ As an additional note, the aliphatic chloride could also be displaced by nitrogen in an intramolecular cyclisation to give a five-membered ring. Not to forget that multiple alkylations of the desired product would be observed, too. $\endgroup$
    – Jan
    Nov 15, 2016 at 15:10
  • $\begingroup$ @Jan Yes, OP is looking for as much trouble as possible :D $\endgroup$ Nov 15, 2016 at 15:12
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yes, it is quite possible as aromatic anines nitrogen being moore nucleophilic further the secondary chloro reacts easily, the reaction may either be SN1 or SN2. I have done couple of reaction of this type, if you need help feel free to contact me.

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    $\begingroup$ Could you elaborate on how this reaction works, maybe with a breakdown of the mechanism? $\endgroup$ Jan 26, 2013 at 8:44
  • $\begingroup$ I would be skeptical. I would assume multiple alkylations to take place even aside of the problems others pointed out. $\endgroup$
    – Jan
    Nov 15, 2016 at 15:11

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