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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 . . .

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24. Nick on August 5, 2010 6:48 PM writes...

They did a coupling experiment in the presence of radical scavengers (TEMPO). Doesn't TEMPO react with KOBu??

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25. kitzbuhel74 on August 6, 2010 2:28 AM writes...

I would suggest that a screen of all reagents used by Inductively Coupled Plasma (ICP)would be sufficinet to reveal ppm levels of any Transition metals.

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26. kitzbuhel74 on August 6, 2010 2:51 AM writes...

I suspect that metal scavenging ability of DMEDA is responsible. Storage at some point in a metal containing vessel allowing leaching of trace amounts of metals into the reagent. Conditions used are then presumably enough to break down the diamine-transition metal complex freeing up the required metal to take part in the metal free coupling.

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27. Jose on August 6, 2010 5:10 AM writes...

Agree with #25. A few ppm of metallic impurities that could could co-sublime. Ferrocene sublimes pretty damn well...

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28. GladToMoveToProcess on August 6, 2010 5:57 AM writes...

Agreed that ICP or the like should be done on all reagents to rule out trace amounts of metals. As to subliming KOtBu, the authors sublimed commercial material, and note "ALMOST the same results were obtained..." (my emphasis). In my grad research, I made KOtBu and sublimed it; in the vacuum sublimation, the residual tBuOH in the solid led to some material being blown from the "pot" onto the condenser. This was much less of a problem in a second sublimation. So, some contaminants could have been carried along by entrainment. Just a thought.

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29. dt on August 6, 2010 12:36 PM writes...

why is this a big concern that there might be some ppm metals present if the main idea is to reduce cost? Are a few ppm palladium affordable? I apologize as I'm not a chemist and I must be missing something.

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30. Hap on August 6, 2010 3:43 PM writes...

1) The key point of the paper is that the cited reaction runs without metals, so if that's not true, it's kind of important. In addition, the problem of metal contamination driving catalysis has occurred often enough that it should be something to be checked for - I haven't looked at the SI, but the only part that they talk about having checked (and not even checked but purified by sublimation) is the base, and there are likely lots of other places for trace metal to pop up. The presence of metal contaminants would be the major item to check if the instrumentation (ICP?) is available, and it would be sloppy of people to have not checked if it were possible.

2) If the reaction is being driven by trace metals, they could come from lots of places - from dust in the lab, from glassware, from base, starting materials, catalyst, or solvent. Not knowing where they come from (if they're driving the reaction) or even what they are means a lot of work to make the reaction useful and reproducible.

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31. Industry Guy on August 6, 2010 6:01 PM writes...

This paper is amazing. The text is exceptionally poorly writting. They see a deuterium isotope effect and then say that it means "proton abstraction is not important" - that alone seems wrong.

The entire article is very suspicious. I agree with above idea's: one should carry out the reaction and then IPC-MS for trace metals. The raical mechanism is strange - why would DMEDA promote radical formation?

I am very suprised that JACS published this in its current form, just based on the data presentation and text alone. My gut feeling is that this is another retraction in the waiting - I guess we will see.

If it is, coupled with the NaH oxidation issue, it would suggest that JACS needs to review their reviewing process.

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32. student on August 9, 2010 8:42 AM writes...

"The text is exceptionally poorly writting."
Hypocritical much?

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33. Nobody on August 9, 2010 9:12 AM writes...

I am wondering if there will be so many negetive words if this paper published from a USA lab. Even after "4. TIG" repeated the reaction and had 97% converseion.....

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34. kitzbuhel74 on August 9, 2010 9:30 AM writes...

In response to No. 33.; I am sure the same level of debate would be held regardless of the papers' origin. The fact that No. 4 has been able to repeat an experiment does not in itself prove theory and reasoning behind the proposed metal-free reactions.

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35. Hap on August 9, 2010 12:10 PM writes...

I think it's mostly the "extraordinary claims/extraordinary evidence" thing rather than the point of origin of the authors. Also that, while metal-free coupling isn't the "perpetual motion machine" of organic chemistry, there have been enough metal contamination issues in coupling reactions to make sure I have an awful lot of evidence before I say my coupling reaction is not metal-mediated.

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36. TsOH on August 9, 2010 8:44 PM writes...

cis and trans-cyclohexanediol give vastly different yields when used as additives. that fact alone merits a serious discussion, if not further study.

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37. IamSPHOS on August 9, 2010 9:03 PM writes...

C&EN will soon be doing an interview with one of the correspondence authors. Also, trace metal analysis was performed on the glassware, chemicals, stirrers, spatulas, etc. I find it interesting that many comments here are so negative and are from individuals that haven't even read the paper. How can you make such a comment? Anyhow, keep in mind the reaction is done at a mild temperature compared to a lot of cross coupling (i.e. 80 degrees instead of 150 degrees) Even in the presence of trace metals one might hypothesize that the activation energy is not met for the trace metal to trigger a radical reaction under these conditions. Many times the supercritical reaction temperatures are needed to make these type of reactions work at all.

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38. student on August 9, 2010 10:57 PM writes...

"Even in the presence of trace metals one might hypothesize that the activation energy is not met for the trace metal to trigger a radical reaction under these conditions. Many times the supercritical reaction temperatures are needed to make these type of reactions work at all."

Ummm, are you saying that with catalysts you need a really high temperature to get it to work, therefore the reaction is probably not catalyzed?

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39. kitzbuhel74 on August 10, 2010 2:11 AM writes...

No. 37; Full details of the elemental analyses performed are required, namely what metals they looked for and what the limits of detection were for the instrument used. I would hope that we don't have a case of "I didn't look for it, so it's not there" Also, is it really such a surprise that synthetic chemists are sceptical about the metal free claims made in this paper? We are not doubting that the transformations have occurred (evidence provided by No. 4 would appear to indicate that the reactions are reproducible), merely that the proposed metal free and radical aspects of the proposed reaction mechanism seem a bit odd and require further probing. I am also amazed that you can tell who has or hasn't read the paper from blog postings;)

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40. tony on August 10, 2010 6:39 AM writes...

J. Org. Chem. 1961, 30, 2493
Angew. Chem. Int. Ed. 1968, 7, 36

It seems Iodobenzene is quite easy to form a radial, just need photons and oxygen. It is quite likely in this jacs paper, a radical is generated from the idobenzene. But the generality of the so called organocatalytic CH actiation is quite unlikely to be good. Maybe it just work for this case.

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41. IamSPHOS on August 10, 2010 7:42 AM writes...

#39. I am telling you, the trace metal analysis was performed. I am telling you this as privilege information because the authors did take the necessary steps to ensure that their work was suitable for publication. The paper was submitted in April and published months later. This should suggest to many that the referees had a back and forth with the authors, whether it be for additional experiments or information.

I am not psychic; many posters at the beginning said they did not read the paper.

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42. peter on August 10, 2010 7:43 AM writes...

Given the alarmingly high number of irreproducible papers published by Asian authors, all work from this part of the world should be subjected to a particularly strict review process.

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43. Derek Lowe on August 10, 2010 8:21 AM writes...

Peter, I'm going to assume that you're trolling and trying to stir things up. I'd rather you not do that in the comments here, to be honest.

If your suggestion is meant to be taken seriously, then you're going to end up defining where Asia begins and ends, apologizing to highly reputable groups and institutions you've lumped in with everyone else, and explaining how you'd deal with the significant cohort of non-reproducible non-Asian papers. Good luck. I'm staying out.

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44. sepisp on August 10, 2010 8:38 AM writes...

Any simple radical trap reagents? It'd be interesting to put just the iodoarene and iron with that and see if we get an aryl radical. I wouldn't be surprised for a second if iodine, iron or combination thereof did some radical shuffling.

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45. Hap on August 10, 2010 9:22 AM writes...

Then why wasn't the ICP analysis published in the SI? It's not like the authors couldn't have put it in there (if the reviewers had asked for it), and particularly since the work is in a lab that's been doing lots of metal-mediated couplings, that would have to be on the short list of things that reviewers and readers are going to ask. Heck, there isn't much of anything in the SI that wasn't in the comm other than the full data on the products, which doesn't tell anyone anything about the mechanism. Also, other than purification of the base (which, admittedly, was the source of problems for Leadbeater), there isn't any mention of how other potential sources of contamination were dealt with. If the referees were worried about this, then why wouldn't one have have assumed that readers might, as well?

As above, the appropriate aphorism would be "Extraordinary claims require extraordinary evidence." (or, at least, "Claims require evidence proportionate to their scope and import.") If the authors had the evidence, publishing it would have been the thing to do, for themselves and everyone else. If JACS had the evidence it would have been to their benefit to publish it early rather than wait for people to complain.

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46. anon on August 10, 2010 9:24 AM writes...

in the words of Regan- Trust but Verify

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47. student on August 10, 2010 10:22 AM writes...

"#39. I am telling you, the trace metal analysis was performed. I am telling you this as privilege information because the authors did take the necessary steps to ensure "

There should never be "privileged information" in published work. It should all be in the paper or the supp info. Should we just assume that the authors did work not reported in the paper?

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48. Anonymous on August 10, 2010 10:37 AM writes...

This really is an amazingly poorly written manuscript. I can only imagine the reviewers' frustration when trying to review this manuscript. I have had several of these cross my desk and I usually just send it back until the grammar can be corrected - independent of content.

However, getting to the content...there are so many issues with this that it's hard to believe that it actually went through the review process. From the abstract - "The arylation of unactivated benzene with aryl iodides, or aryl bromides and even chlorides under the assistance of an iodo-group..." Where is there evidence that the iodo group assists the Br or Cl reaction? Table 3? Which group reacts first? The iodine? If that is the case, then one should give the example example 10, Table 1 with PhC6H5Br. The only reported Br was entry 12, Table 1 which employed 4-CNC6H5Br. The authors note that in the diiodo reaction they see 74% bis-arylated and 8% monoarylated - however, they cite the monoarylated as 3j which is the monoarylated de-iodo compound with no mention that it dehalogenated. A true monoarylated compound would be the product with the iodo intact. They then mention that the I,Br and I,Cl compounds react to give the bis-arylated compounds in 71% and 68% with no mention of mono-arylated compounds? What happened? They only mention this in the ortho compounds.

Even though it appears there is an author commenting on this board "IamSPHOS" it is still hard to believe that rigorous metal analysis was performed (sorry, hard to believe "privileged information". The only mention was the sublimation of KOtBu - which gave similar results; however, there could have been contamination in any of the glassware that was used before and after sublimation. With all of the "metal-free" reactions that have been reported/debunked it should only be reported after rigorous determination of metal analysis. If this has been done it should have been required by the reviewers - if it was and not reported - shame on the reviewers/authors...if it wasn't done/not required - shame on both.

I agree with #46, "Trust but Verify".

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49. ScrippsFlorida on August 10, 2010 5:40 PM writes...

Hello, all:

I have recently reproduced the reaction, since I read through all the comments and found only 4. TIg to have actually DONE the reaction in question.

All reagents were newly ordered from Aldrich, benzene distilled from Na / benzophenone, glassware washed with aqua regia overnight and then flame dried (to reduce metal contamination) commercial KOTBu, new stirbar, carried out under +P of Ar gas.

I tried Entry 3, Tab