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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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June 12, 2013

Product Inhibition, Or Grinding To A Halt

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Posted by Derek

Here's a neat bit of reaction optimization from the Aubé lab at Kansas. Update: left the link out before - sorry!) They're trying to make one of their workhorse reactions, the intramolecular Schmidt, a bit less nasty by cutting down on the amount of acid catalyst. The problem with that is product inhibition: the amide that's formed in the reaction tends to vacuum up any Lewis acid around, so you've typically had to use that reagent in excess, which is not a lot of fun on scale.

By varying a number of conditions, they've found a new catalyst/solvent system that's quite a bit friendlier. I keep meaning to try some of these reactions out (they make some interesting molecular frameworks), and maybe this is my entry into them. But the general problem here is one that every working organic chemist has faced: reactions that, for whatever reason, stop partway through. In this situation, there's at least a reasonably hypothesis why things grind out, and there's always been a less-than-elegant way around it (dump in more Lewis acid).

I'm sure, though, that everyone out there at the bench has had reactions that just. . .stop, for reasons unknown, and can't be pushed forward by addition of more anything. I've always wondered what's going on in those situations (probably a lot of things, from case to case), and they're always a reminder of just how little we sometimes really understand about what's going on inside our reaction flasks. Aggregates or other supramolecular complexes? Solubility problems? Adsorption onto heterogeneous reactants? Getting a handle on these things isn't easy, and most people don't bother doing it, unless they're full-out process chemists in industry.

Comments (12) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


1. Novice on June 12, 2013 8:15 AM writes...


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2. Old Timer on June 12, 2013 9:24 AM writes...

I heard Dave Collum respond to a question about a stalled LDA reaction that wouldn't respond to the addition of more LDA by saying "That's like saying you have a problem with kids pooping in the pool, and to solve it, you try adding more kids!" I'm not sure if it's completely accurate analogy, but I still like the quote.

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3. Anonymous on June 12, 2013 9:48 AM writes...

Dithionite reductions of nitro groups anyone?

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4. jabali on June 12, 2013 11:52 AM writes...

#3: You are right about the dithionite reductions: They either go to completion very quickly or will stall for no apparent reason. But when they work they are great.

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5. BG on June 12, 2013 12:12 PM writes...

I've seen reactions just give up too- I hate it.
I had thought that maybe it was a concentration dependence issue. As the reaction progresses, the concentration of the reagents drops as they are converted to product and, if the reaction rate is extremely sensitive to concentration, the rate will slow down. At the end of the reaction, when there is very little reagent around, the rate has slowed down to the point that the reaction has basically stalled out. At this point, if adding more reagent doesn't help, I would guess that the added reagent doesn't factor into the rate determining step.

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6. anon on June 12, 2013 12:46 PM writes...

I've found that as synthetic chemists a lot of the time we tend to ignore the effects of changing reaction pH. Many pharma-type reactions involve the formation or consumption of amines, and the resulting pH changes that occur during a reaction can have interesting effects upon both reaction rate and selectivity.

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7. anon on June 12, 2013 1:48 PM writes...

Methinks Scott Denmark would eat this paper alive.

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8. Pieter on June 12, 2013 4:45 PM writes...

That's why there are process chemists that solve these problems.

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9. Nick K on June 12, 2013 7:37 PM writes...

I've had a number of cycloadditions which would stop at 30-40% conversion, for no reason I could understand. It wasn't a question of equilibrium as the isolated products did not revert under the reaction conditions. Inexplicable.

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10. newnickname on June 13, 2013 3:30 PM writes...

Free radical reactions can terminate or get poisoned. I've had NBS reactions kind of conk out, even with excess NBS; add more, re-initiate, repeat til done.

I've had tin hydride reductions conk out that I would have to titrate to completion by adding more R3SnH and more initiator. One of them needed to be freeze-thaw degassed before each new addition so maybe there was something volatile getting in (O2) or being co-generated (??) in the system.

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11. Dave Collum on June 13, 2013 7:11 PM writes...

I, BTW, did say that almost verbatim and did note that the analogy was slightly lacking in content. I get asked this a lot and haven't a clue why some reactions stall. Inhibition by all sorts of occlusion mechanisms is the most obvious, but more reagent should help. You could have something there in trace quantities that plays a role (like copper in your iron catalyst) that gets poisoned. Equilibria are overlooked a lot. I've sensed that physical properties of solutions may play a role. Since we watch reactions pretty carefully, when one stalls we can document that it didn't run out of the obvious reagents...but it still stalls occasionally. Mystery of science (like the yellow in your oils and fur between the layers.)

Former postdoc alerted me to this post. Hi folks.

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12. Secondaire on June 15, 2013 10:09 AM writes...

#10 - Free-radical brominations/halogenations are the worst, esp. with AIBN. I actually think some of them may be super-sensitive to water, because I generally see a lower rate of conking out under super-anhydrous conditions than I do when I'm not as rigorous about keeping the water out.

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