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Derek Lowe The 2002 Model

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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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August 5, 2010

Metal-Free Coupling Reactions: Now Wait A Minute. . .

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Posted by Derek

I've written several times about how important metal-catalyzed coupling reactions are to organic synthesis - they're the single biggest change since my grad school days in the 1980s, when they were considered sort of squirrely and exotic. Now they're everywhere, and the literature on them is almost beyond counting.

A lot of work gets done trying to extend these reactions to starting materials that are more easily available but don't tend to work as well, to make the catalysts cheaper and more robust, and to find replacements for the palladium that's so often at the center of things. But people have been scorched in the attempt - several "palladium-free" couplings using other metals have turned out to be actually catalyzed by ridiculous trace amounts of palladium contamination instead.

Now there's a paper in JACS that's getting a lot of attention, and a lot of raised eyebrows. The authors claim that they can couple aryl iodides with plain unfunctionalized aromatic compounds with either amines or alcohol as catalysts - and no transition metals at all - just potassium t-butoxide as base. Organic chemists will recognize that this is a very unusual reaction indeed, since carbon-carbon bonds between aryl groups are not supposed to be so easy to form. This reaction, in fact, would suggest that a lot of the palladium-catalyzed work is some sort of odd detour to get to a process that happens fairly easily anyway.

But that doesn't seem right, somehow. The mechanism for the metal-catalyzed reactions is pretty well worked out (in its broad strokes, anyway), and the metal really is crucial. How can these things be going? The authors suggest that since they're using iodides that a free radical mechanism is operating. Addition of radical scavengers, they say, shuts the reaction down. And while it's true that iodides are great radical precursors, these couplings seem too clean for that mechanism - unless you take care to give them limited opportunities, free radicals tend to react with most everything in sight. (The fact that they don't tend to get regioisomers rules out another possible mechanism through benzyne intermediates).

The other problem I have with that is that potassium t-butoxide is not the sort of thing one generally needs in a radical reaction, although they are proposing a radical anion. Lithium and sodium t-butoxide don't work, interestingly, and I'm not sure what to make of that, either - these sorts of counterion effects can certainly be real (I've seen some myself), but they do call for an explanation.

And what's more, just this morning I've heard from a reader, an experienced chemist in a good lab, who's tried to reproduce this work and (so far) failed. I'd be very interested in hearing from others who've taken a crack at it, too. Real or not? Let's find out.

Comments (64) + TrackBacks (0) | Category: Chemical News


1. Iridium on August 5, 2010 11:11 AM writes...

Sadly, I do not have access to JACS at the moment, so I cannot investigate some of the details of the paper myself.

The first things that springs to mind for me is that some potential metals from previous chemistry reactions might be contaminating the schlenk tubes/flask used for these investigations. Given the cost of schlenk tubes/flasks, it wouldn't be too surprising if all of the reported work was performed in a series of five or less vessels, which may very well have been used for metal-catalyzed coupling reactions in prior lab work.

I would hope that the authors would be good enough scientists to run the control experiment where they used a fresh flask from a supplier, washed with nitric acid or some equivalent there of, for some of their reactions. If the reactions worked, let head scratching commence. If not, shame on the reviewers for not demanding this be done as it is quite possible this paper may turn out to be another 'sodium hydride oxidation' fiasco.

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2. Nick K on August 5, 2010 11:16 AM writes...

My bet is that this will turn out like the oxidations with sodium hydride.

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3. nitrosonium on August 5, 2010 11:34 AM writes...

planning on trying to reproduce one of these today. i'll let you know what happens.

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4. TIg on August 5, 2010 11:42 AM writes...

I'm involved in a very similar area to this, and the first thing to note is that the same authors published a paper in Angewandte earlier this year (ACIE 2010, 49, 2004-2008) on an iron-catalysed reaction carried out under very very similar conditions. In the Angewandte paper the authors carry out several control experiments in the absence of iron, but not *quite* under identical conditions to those published in the JACS paper. I've tried the JACS reaction, and was somewhat surprised that I could reproduce the results in the paper, getting around 97% conversion. I'm doing my reactions in new vials, so no contamination issues there (hopefully!), and I believe I may have used a brand new stirrer bar (although not entirely sure, will have to repeat to check). I'm baffled...

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5. Greg Hlatky on August 5, 2010 11:42 AM writes...

Looks like we need a laboratory version of Kashrut for conducting these experiments.

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6. alig on August 5, 2010 11:53 AM writes...

Well it's not going to have a broad reaction scope. They run the reaction in benzene to get benzene to couple and they say toluene doesn't couple.

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7. Wavefunction on August 5, 2010 11:54 AM writes...

Isn't there some Pd indicator that turns bright and colorful in the presence of trace quantities of Pd? Maybe they could drop some of it in the flask and look at the color of the solution.

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8. milkshake on August 5, 2010 12:15 PM writes...

They should spike the reaction with a little TMS-CN, just to see if they still get a "metal-free" coupling. The quality of solid tBuOK tends to be pretty atrocious, I would not be that surprised if it turned out to be their metal source. Vacuum-sublimated butoxide would be the way to go.

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9. Iridium on August 5, 2010 12:27 PM writes...

Quoted from Milkshake

"They should spike the reaction with a little TMS-CN, just to see if they still get a "metal-free" coupling. The quality of solid tBuOK tends to be pretty atrocious, I would not be that surprised if it turned out to be their metal source. Vacuum-sublimated butoxide would be the way to go."

This would have been my next idea, but I figured it would be pretty difficult to screw up making tBuOK of decent purity. Granted, I have know idea how it is manufactured on large scale (treatment of tBuOH with K metal, KOH, or KH, followed by drying?), but this would imply the potassium source used has a reasonable amount of transition metal contaminant. That would be unfortunate. Milkshake's suggestion is spot on.

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10. Metalate on August 5, 2010 12:51 PM writes...

The SI claims they use sublimed KOtBu, though I think that's the grade they purchase, not that they sublimed it themselves.

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11. Martyn on August 5, 2010 1:00 PM writes...

Quote from the paper:

In order to eliminate the possibility of the presence of trace transition metal elements in the commercially available potassium tert-butoxide that would potentially affect our investigation, we indeed purified the KOBut by sublimation prior to our examination.

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12. Old_School on August 5, 2010 1:07 PM writes...

Back in the day, I did a lot of Schlosser's anion chemistry (KOtBu + nBuLi) to make Roush crotylboration reagents, and I found that freshly prepared KOtBu was the only way to go (I made a stock solution using distilled tBuOH + K metal in THF). Solid KOtBu was crap, and subliming it was a royal PITA. With that in mind, I'm more than a bit curious about the KOtBu these guys are would be easy enough to generate fresh material as described above and simply pump off the THF. One would hope that K metal is pure...

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13. cubsguy on August 5, 2010 1:52 PM writes...

If benzene and naphthalene work and toluene doesn't... wouldn't that imply that the substrate is their metal source? I know nothing about how benzene and napthalene are made - anyone with more insight care to comment?

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14. barry on August 5, 2010 2:09 PM writes...

re: #13

The failure of toluene may just be that the benzylic C-H bond is too labile, either to radical abstraction or to deprotonation. Without access to the full text I can't tell if there is regiochemical slop in the products consistent with a benzyne or "cine" mechanism

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15. CMCguy on August 5, 2010 2:28 PM writes...

#13 I assume benzene and napthalene as well as toluene are isolated products from petroleum refining. There is probably much contact with metal sources from distillation towers, tanks, drums and canisters along the way prior to any glass bottles typically seen in lab.

Although "free radical" reactions have a deserved reputation from promiscuity there is many "controlled radical" transformations known so may not be as far fetched (however I think most of the controlled radicals do involve metals complexes so back to similar questions). If a radical mechanism is invoked then a couple things come to mind: I vaguely recall tBuO- do form peroxides on standing (although freshly sublimed unlikely?) so maybe K adduct has greater propensity that others for that. Toluene may not work well as radical acceptor simply because quench by abstraction of a Me hydrogen alternate pathway competes more favorably.

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16. andrewD on August 5, 2010 2:46 PM writes...

If you are worried about the quality of the benzene us AR or the US equivelent as this has a tight spec. Alternativly Benzene can be made by the dry distallation of sodium benzoate and calcium hydroxide-the benzoate could be recrystallised several times to remove matals(but I would expect metals to stay in the calcium hydroxide), We used the latter process to make high purity benzene for use as an analytical standard, we had a BTX plant and needed a standard for product analysis

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17. gtg8r on August 5, 2010 3:07 PM writes...

No longer on a university campus, but someone ought to look into t-butoxide radical initiators for radical polymerizations.

From memory, an old but pretty standard recipe.

And I know I've used TMEDA as an aqueous initiating system here in the horrible biology world I work in.

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18. anonymoose on August 5, 2010 3:20 PM writes...

What about adding a radical scavenger to show the reaction doesn't work in its presence? Or follow the reaction by ESR? Should be able to do it in a sealed tube.

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19. CRH on August 5, 2010 3:44 PM writes...

They used TEMPO (20 mol% and 100 mol%) as well as diyldibenzene (100 mol%) as radical scavengers and there was no reaction.

As noted previously, the same group reported Fe catalysis and I wonder if the same glassware was used?

Or, depending where they are in China, could be enough heavy metals floating around in the air to catalyze the reaction.

More suspicious than the KOtBu is the fact that they did not purify the DMEDA. I would suspect there is some copper coordinated and that is the metal culprit.

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20. InfMP on August 5, 2010 3:58 PM writes...

see paper titled "Potassium t-Butoxide Alone Can Promote the Biaryl Coupling of Electron-Deficient Nitrogen Heterocycles and Haloarenes"
Proven to be radical

Org. Lett. 10.1021/ol8019764

On the first attempt at submitting their Iron-cat. arylation to Angew, the charette group was directed to the Org. Lett. and then they scavenged to find it is indeed radical. Re-submitted to JACS - it was accepted.

J. Am. Chem. Soc. 10.1021/ja910687u

So basically these guys just took out the iron and now we are back to Itami's Org. Lett.

I'm pretty insulted by these papers. None of the compounds are useful at all.

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21. Anonymous on August 5, 2010 4:24 PM writes...

If you think you are making such huge advances then they should be sent to journals that repeat procedures before publishing so we don't waste time on the 'what if'. I wouldn't have the balls to make such bold statements without being absolutely sure.

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22. Phil on August 5, 2010 4:54 PM writes...


It's not the same as Itami's paper because Itami's substrates are all nitrogen heterocycles. These guys report regular old aryl rings participating, a very different class of substrates in C-H activation. That said, I'm pretty skeptical of the results as well.

Regarding the usefulness of the compounds, I would state that you're pretty hard pressed to find useful examples in JACS papers. When the research is still in its infancy, it's hard to figure out how to get interesting substrates to work. It's great when they do, but it's also not common. Academics working on methodology generally leave it up to the people who want to use their method to work out the specifics for their particular substrate, and I can't say I fault them for it.

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23. weirdo on August 5, 2010 5:10 PM writes...

#21 Anon:

"journals that repeat procedures before publishing"

Perhaps you would be so kind as to point out exactly which journal(s) this is (are)?

Also, why do you think these authors aren't already "absolutely sure"? Seems like they have performed the usual control reactions to me. Maybe they haven't done all the elemental metal trace analysis others have pointed out, but still . . .