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Reason for the chlorine in ketamine

Smyth

Smyth

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Nov 10, 2004
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I have a theory (unproven) that the chlorine is put there to try hinder intermolecular imine formation.

What are peoples thoughts on this logic?
180px-Ketamine.png
 
How are you proposing it does that? Steric effects? Electronic effects?
 
At the time of making the post, steric reasons.

It is not unreasonable to make the suggestion that it could also render the methylamino less nucleophilic.

Infact that actually reminds me of a subject called "Consonance and dissonance" in one of my ochem books.

Oxford University Press: Organic Synthesis: Christine L. Willis

Here it is online although it is not on wikipedia.
 
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Firstly, it is a secondary amine adjacent to a quarternary center so IMMINIUM ION/ENAMINE formation is very unlikely (Mucho heat and removal of water would be required and even then it would be unlikely). Secondly, ketamine is generally seen as the hydrochloride salt. The chlorine is likely for receptor affinity.

EDIT: Also, for your own interest, the molecule is chiral and you should build a 3-D model to see just how little hindrance chlorine atom provides relative to the other nearby atoms including hydrogens
 
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Quanta said:
Firstly, it is a secondary amine adjacent to a quarternary center so IMMINIUM ION/ENAMINE formation is very unlikely (Mucho heat and removal of water would be required and even then it would be unlikely). Secondly, ketamine is generally seen as the hydrochloride salt. The chlorine is likely for receptor affinity.

EDIT: Also, for your own interest, the molecule is chiral and you should build a 3-D model to see just how little hindrance chlorine atom provides relative to the other nearby atoms including hydrogens
Click to expand...

smyth is suggesting itERmolecular not intRAmolecular imine formation.

I think the reason for the chlorine is it has a shorter duration than the unchlorinated compound (called MCPH I think), the ortho substitutent also appears to effect the level of dopinergic activity with less dopaminergic activity being desirable as it reduces the level of agitation and so called 'emergence phenomena'
for certain the unsubstituted compound is long lasting 6-12hrs and not very pleasant.
 
Switching the methylamine to ethylamine would also increase potency about 2-fold. Removing the ketone would increase it too, but if you remove the chlorine and the ketone, and change the amine substitution you'll end up with PCE...
 
I was reffering to intermolecular formation as stated in the question. You cannot form an imine with a secondary amine, it would form an iminium ion which often tautamerize with enamines. The chemistry aside, if this reaction did occur on any reasonable timescale, ketamine would not be stable enough to be a drug.

As far as the pharmacology of the chlorine, I cannot comment.
 
I don't think there's any specific reason.

It results in higher MOR affinity
Shorter duration
Compound was better tolerated

That's it.
 
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