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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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May 19, 2010

Pyridines and Dichloromethane

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Posted by Derek

Here's a quick warning for the bench chemists in the crowd: look out if you're making pyridines and using dichloromethane as solvent. This paper reports that the two can react, forming bis-pyridinium compounds - which isn't too surprising, in theory. What's alarming is that this happens at an appreciable rate at room temperature, which is something that I don't think a lot of people knew. I didn't.

As you'd imagine, electron-rich pyridines are the worst offenders. So keep an eye on these guys. . .

Comments (11) + TrackBacks (0) | Category: Chemical News


1. RandChemist on May 19, 2010 12:00 PM writes...


Thanks for the tip.


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2. Tim McDaniel on May 19, 2010 12:14 PM writes...

Um, for those of us who aren't bench chemists, would anyone like to briefly explain the significance? Are bis-pyridinium compounds Parts Like To Flee At High Speed compounds, or There's No Warning Smell Because It Kills You Too Fast, or what?

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3. Hap on May 19, 2010 12:20 PM writes...

I don't know - you shouldn't isolate the wrong compound, but you might, if you didn't know better. The byproducts might hydrolyze to formaldehyde on workup, which wouldn't be good (and might lead to further side products). You might have problems with long-term storage of substituted pyridines in chlorinated solvents, though I didn't think that people did that much, anyway. The authors mostly worry about byproduct formation in reactions using pyridine in DCM.

It's probably filed under "Oops, I didn't think that would happen.", but when it happens it probably won't blow you up or kill you.

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4. SK on May 19, 2010 12:21 PM writes...

I can't say I'm surprised. In process work we always tried to avoid any subjection of basic amines with methylene chloride over extended periods of time (though this was more common with 3ยบ amines) because of the formation of the chloromethyl ammonium salt as a hard-to-remove impurity.

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5. anchor on May 19, 2010 1:31 PM writes...

As an experimental chemist, I am not going to react the Pyridine derivatives with DCM for days, as the paper claims. Even with e-donating substituent it takes days. My point is it is OK and no sweat!

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6. tedthechemist on May 19, 2010 1:41 PM writes...

Most amines will react with dichloromethane - in my 30 years in process chemistry, I have seen many instances where this has caught folk with their pants down- especially when scaling-up with increasing contact times etc. I recall ordering 300 Kg of a substituted piperidine and telling the supplier not to use DCM/aqueous base in the isolation. What we got was 300Kg of the resulting aminal.Of course, on analysis via reverse phase HPLC, this rapidly broke down to what is was meant to be, the amine! When it was twigged what we had, the supplier was challenged - yes, they used DCM/NaOH/water in the isolation !

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7. exAZ on May 19, 2010 1:47 PM writes...

The wheel keeps getting reinvented.

Check out this reference: Mills, J. E.; Maryanoff, C. A.; Cosgrove, R. M.; Scott, L.; McComsey, D. F., The Reaction of Amines with Methylene Chloride. A Brief Review. Org. Prep. Proc. Int. 1984, 16, 97-114.

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8. Tim McDaniel on May 19, 2010 2:20 PM writes...

I should have written "For those of us who aren't chemists at all".

Aw, shucks. Sand Won't Save You This Time compounds were impossible, but it's not even Smells Like A Burning Skunk? Drat.

(N.B. can affect your writing style. See their subpage TVTropesWillRuinYourLife.)

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9. Arjun on May 19, 2010 2:45 PM writes...

Wow, would not have thought of this one.

Reminds me of the time when I was making aminoferrocene. There was a pesky trace impurity that we couldn't get rid of, even after two columns. We were taking the NMR in d6-acetone, and eventually we found out that we were making a bit of the imine in the NMR tube!

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10. Tony on May 20, 2010 4:12 AM writes...

I don't think this should worry many people - the second order rate constants are very low. As tedthechemist points out, increased contact times are the thing to watch.

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11. sepisp on May 20, 2010 9:08 AM writes...

Not very surprising in the context that similar compounds can be prepared quantitatively by just heating an alkyl halide and an amide.

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