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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: derekb.lowe@gmail.com Twitter: Dereklowe

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February 19, 2013

More From Blog Syn

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Posted by Derek

I wanted to mention that there are two more entries up on Blog Syn: one of them covering this paper on alkenylation of pyridines. (It's sort of like a Heck reaction, only you don't have to have an iodo or triflate on the pyridine; it just goes right into the CH bond). The short answer: the reaction works, but there are variables that seem crucial for its success that were under-reported in the original paper (and have been supplied, in part, by responses from the original author to the Blog Syn post). Anyone thinking about running this reaction definitely needs to be aware of this information.

The latest is a re-evaluation of a older paper on the use of IBX to (among many other things) oxidize arylmethane centers. It's notable for a couple of reasons: it's been claimed that this particular reaction completely fails across multiple substrates, and the reaction itself is from the Nicolau lab (with Phil Baran as a co-author). Here's the current literature situation:

A day in the library can save you a week in the lab, so let’s examine this paper’s impact using SciFinder: it's been cited 179 times from 2002-2013. Using the “Get Reactions" tool, coupled with SciFinder’s convenient new “Group by Transformation” feature, we identified 54 reactions from the citing articles that can be classified as “Oxidations of Arylmethanes to Aldehydes/Ketones" (the original reaction's designation). Of these 54 reactions, only four (4) use the conditions reported in this paper, and all four of those come from one article: Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151–2153, which describes IBX as “an excellent reagent for the selective oxidation to generate synthetically useful 5-formylpyrroles.” Kirsch's yields range from 53-79% for relatively complex substrates, not too shabby.

I'll send you over to Blog Syn for the further details, but let's just say that not many NMR peaks are being observed around 10 ppm. Phil Baran himself makes an appearance with more details about his recollection of the work (to his credit). Several issues remain, well, unresolved. (If any readers here have ever tried the reaction, or have experience with IBX in general, I'm sure comments would be very welcome over there as well).

Comments (73) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. eugene on February 19, 2013 3:02 PM writes...

I like the theory of unnoticed metal traces. Someone must have sneezed and 5% of Pd nanoparticle landed in some common reagent that was used in the original paper.

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2. eugene on February 19, 2013 3:11 PM writes...

I actually like the previous Blog Syn entry more. The one about the 3 pyridine position catalytic alkylation from the Yu lab. A lot of these recent Pd catalyses have looked underwhelming to me, especially when you only get 4-13 turnovers. Now, I know that the reasoning is that they make hard to get otherwise substrates that you might want to make as a medicinal chemist no matter what the price, but a lot of this stuff, especially from some Chinese groups, seems like a black box where they don't know what's going on and they throw in 10 or 20% Pd and 2 equivalents of silver, and then get maybe 4 turnovers and it gets published in JACS.

Yu is not the head of one of those Chinese groups (he's based in the US), and this reaction deserved to be published in a good journal regardless even if it's 40% yield because it's novel in doing something that is considered very strange (being selective for the meta position via CH activation of pyridine). It is a first report and as such it's a JACS even if it's 2 turnovers. But for much of this chemistry, I just don't believe in the yields when the difference between good yields and meh (80 versus 40 percent), is the difference between 4 or 8 turnovers of Pd.

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3. Observer on February 19, 2013 6:56 PM writes...

Well I've used IBX for making an enone and it saved the day. I've seen Evans, Jacobsen, Corey, and dozens of other groups use it in total synthesis.

Given that there is a report of someone using this to do benzylic oxidation it seems like an issue of IBX quality.

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4. milkshake on February 19, 2013 8:30 PM writes...

@3 Observer: My bet would be on bromide/bromate impurities from the old IBX prep using KBrO3 as oxidant. Br radical is a perfectly able agent for this transformation. (Heating aryl bromides in DMSO produces aldehydes.)

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5. milkshake on February 19, 2013 8:33 PM writes...

I mean heating benzyl bromides in DMSO - sorry for the typo, its late and I am tired

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6. Bender on February 19, 2013 10:07 PM writes...

In contrast to Observer, I was not able to synthesize the enone I wanted. I didn't synthesize fresh IBX and I certainly didn't do a rigorous examination of potential problem areas. I ended up working around it a different way. I guess I can be lumped in the camp of people who figured they'd try this as one of many possible routes to a substrate and quickly stopped when it turned out to need more optimization.

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7. Observer on February 20, 2013 1:59 AM writes...

Wow this much scrutiny over reactions that have been documented to work by multiple groups...

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8. Model on February 20, 2013 2:12 AM writes...

observer- can you provide some citations?

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9. Anonymous on February 20, 2013 3:20 AM writes...

Observer: that's precisely the point. They have been multiply documented and yet some, and possibly many chemists, find their own results at odds with the literature.

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10. Anonymous on February 20, 2013 4:30 AM writes...

Have added my experience with IBX, which is very recent, over on the blog syn website. We aimed for benzylic oxidation, but landed up with a double bond at the benzylic position. More details about what I did can be found on the Blog Syn website in the comments.

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11. Observer on February 20, 2013 10:55 AM writes...

Well for benzylic oxidation there is the Org. Lett. paper that is referenced above (2006, 2151) with some pretty impressive examples of Nicolaou's reaction. There is also a catalytic version here: https://www.thieme-connect.de/ejournals/pdf/10.1055/s-0028-1087384.pdf

For enone preparation from ketones it has been used at least 50 times in synthesis. The most recent use is from Dave Evans (JACS 2012).

I think the problem is that the blog syn people are doing these reactions on toluene and bromotoluene and the aldehydes may be difficult to isolate from DMSO. All the literature examples from other groups use IBX on high molecular weight compounds that are easier to isolate.

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12. Anonymous on February 20, 2013 11:38 AM writes...

@10 Observer: In the original IBX paper, table 5, entry 1 is toluene, entry 6 is bromotoluene, and they report 85% and 73% yields, respectively.

I'm sure IBX works great for enone preps, but that's not what they're examining at blogsyn.

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13. Anonymous on February 20, 2013 11:38 AM writes...

@11 Observer: In the original IBX paper, table 5, entry 1 is toluene, entry 6 is bromotoluene, and they report 85% and 73% yields, respectively.

I'm sure IBX works great for enone preps, but that's not what they're examining at blogsyn.

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14. See Arr Oh on February 20, 2013 12:08 PM writes...

@Observer - Hi there, I'm See Arr Oh, one of the experimenters on Blog Syn #003. Let's see:

1. I, too, have used IBX to make enones. If you look at my entry on Blog Syn, you'll note that the same batch I used for this chemistry had been applied to several batches of enone (50 g scale). I think we're all in agreement that enone formation works just fine as described.

2. As you, Milkshake, and others on Blog Syn have noted, there exists a different impurity profile between bromate-prepared and Oxone-prepared IBX batches. Since it is not fully documented in the 2002 JACS SI, I cannot tell you which method the original authors used, but I assume (see original paper) that they prepare the reagent from Oxone. My batch, prepared from Oxone following JOC 1999, 4537, was soluble in DMSO at 50 and matched lit NMR.

3. Purification of Lab Chemicals (6th Ed, Armarego, Chai) indicates that 2-naphthaldehyde (my substrate) boils at 260 / 19 mm. I performed the same workup as the authors, and concentrated my organic extract (after H2O wash) on a 40 degree rotovap bath / 10 torr.

If they didn't "lose" the compound, how could I?

4. Bonus - I only see faint traces of aldehyde by TLC.

Please, Observer, what am I missing? If you have previous experience running the reaction, or can point me to a well-written protocol to follow, I'm all ears.

(Well, I'm always all ears, since I'm a blogging, talking dog. Woof!)

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15. D-Not on February 20, 2013 12:29 PM writes...

@See Arrrr Oh. do you have a day job ? I wonder what your employer thinks of this over scrutinizing a single reaction. for any transformation there are plenty of alternatives. as a good chemist why dont you try one of the alternatives and move on.

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16. See Arr Oh on February 20, 2013 12:41 PM writes...

@D-Not: Sure do! My employer is supportive. I don't really care about the alternatives, as I don't usually get calls to make aryl aldehydes. If it were me, I'd buy the alcohol and MnO2 that puppy straightaway.

But we're off-topic. And I'm about done with lunch.

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17. Observer on February 20, 2013 1:24 PM writes...

I guess the onus is on YOU to explain how you can't reproduce a reaction that others already have. Perhaps you should write to the german group in the Org. Lett. and ask them too how they were able to reproduce Nicolaou's reaction.

Perhaps it is an impurity in the IBX that is doing it? The procedure that uses catalytic IBX to do benzylic oxidation uses Oxone as the stoichiometric oxidant so why don't you try adding a little Oxone to your reaction. Maybe you'll actually solve a problem and add something useful to the literature with your little anonymous blog instead of casting doubt with a weekend of work on reactions that are already working in other people's hands.

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18. D-Not on February 20, 2013 1:44 PM writes...

@ 16. CRO. your real objective seems to be a witch hunt of sorts. I agree with Observer that - you should put your mind into this and "figure it out" and then enlighten the community - not just merely numbly re-produce. Looking at the TLC picture you posted, I would not take your reactions very seriously. My sympathies to your employer.

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19. Incha on February 20, 2013 1:50 PM writes...

Enough of the blog-syn bashing. See Arr Oh, I think this is a fantastic website and you and your colleagues are doing an excellent service to the synthetic community by not only scutinizing these reactions, but also in teaching students how to conduct research (and how reactions are really run - no I am not going to freshly prepare/purify my IBX(or insert any other finicky reagent) for every reaction. If that is the only way to get your procedure to work then its not really that useful.
Can't wait for the next post!!

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20. Derek Lowe on February 20, 2013 2:18 PM writes...

Incha, I agree. There are a lot of important details that don't make it into the experimental sections, and I think that this is a good way to work these things out. D-Not and Observer puzzle me, in a "Methinks he doth protest too much" way.

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21. a. nonymaus on February 20, 2013 2:18 PM writes...

Kirsch et al. are working with a methylpyrrole, which should be more reactive via single electron transfer. What seems to be the problem is that these reactions are irreproducible as originally published. Observer, have you run an IBX benzylic oxidation? Can you offer definitive commentary on what both BRSM and CRO should be doing that you have had work? Perhaps, have you published more IBX benzylic oxidations than you have had work?

As for witch-hunts, the community is well-served by having irreproducible protocols called out. I welcome public testing of potentially useful methods like this. Then again, I publish reactions that work and include detailed enough SI that others can use the techniques.

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22. D-Not on February 20, 2013 2:35 PM writes...

@20. I agree that public testing and blog discussions are useful tools. How LEGIT are these forums. Derek - a NOT SO LEGIT forum will do more harm in the long run. People work very hard to build a reputation and should not be undone by a handful of observers on forums like yours. On the other hand - why stop at one reaction. why not look at the workability of EVERY IMPORTANT REACTION. Where were you when Dali reported "those useful C-H functionalizations" reactions ?

BTW - working Chemists in my lab (my lab is not in california and I dont have students) learn to do TLCs properly as well as proper mechanistic understanding of the reactions they perform. I have serious reservations taking CRO at face value after the TLC he/she has posted. I would ask readers not to take CRO too seriously.

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23. D-Not on February 20, 2013 2:42 PM writes...

On the topic of public verification of important reactions, Can CRO also look into reproducing the "LAST STEP" of every complex total synthesis. take Taxol or Vancomycin or Halichondrin etc.. I am sure folks out there could use assurancs that these syntheses were actually carried out !!

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24. eugene on February 20, 2013 3:18 PM writes...

"People work very hard to build a reputation and should not be undone by a handful of observers on forums like yours."

Yes, Baran and Nicolaou are delicate flowers who are going to have their reputations ruined by this. You lay off them damn vigilante chemists! And they would have gotten away with their IBX reaction too if it wasn't for those damn meddling kids!

Geez, CRO even tries to accommodate you by saying the reaction 'requires mojo' and not outright 'doesn't work' like it should probably say.

I was pretty sure that high-profile groups publish questionable things (whether through hubris or design) once in a while even before reading all these 'public blogs'.

"On the topic of public verification of important reactions, Can CRO also look into reproducing the "LAST STEP" of every complex total synthesis. take Taxol or Vancomycin or Halichondrin etc."

Nice try, but not close. Nobody needs to make Taxol, but people need to do benzylic oxidations on a regular basis. When you publish, you should know the stakes. Publishing a full synthesis is playing it safe, but a regular catalytic method with lots of promise, and you better be telling the whole story. It was people in industry checking the reactions who were keeping Sames honest. You could use your time to contribute a fourth entry to this reaction on CROs blog if you feel that strongly about this issue, along with your NMRs and TLCs. And we did you the favor of checking J.J. LaClair's total synthesis of hexacyclanol by the way. Including the last two steps. Now say 'thank you'.

Your welcome.

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25. Derek Lowe on February 20, 2013 3:24 PM writes...

D-Not, this is 2013. Could you define "LEGIT", as you put it, and provide the criteria for determining what forums are and aren't?

I don't think that the Blog Syn repeats are being done with any malicious intent at all. They're being done, as far as I can see, in the way that the patent lawyers put it, as someone "skilled in the art" would do them. Follow the experimental protocol as given, and see what you get. If someone's reputation is damaged by that process, their reputation was too fragile to begin with. I hope to join in on some future Blog Syn effort myself; I hope that my TLC technique passes muster.

As for the last steps of the big total syntheses. . well, I don't think, in many cases, that those are very important reactions. Take that as you will.

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26. M.C. Hammer on February 20, 2013 3:42 PM writes...

Please allow me to supply a definition:

"You don't want none i hustle for my muscle and you look / Weak son (real weak) yea!... i'm goin for all that i can get / Kickin at the top cause i'm too legit to quit!"

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27. See Arr Oh on February 20, 2013 3:50 PM writes...

@Bender, @Eugene, @Derek, @Incha - Thanks, everyone.

@Observer, @D-Not: Please feel free to contact me if you'd like to submit an entry to Blog Syn.

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28. darwinsdog on February 20, 2013 4:50 PM writes...

I'm not taking a side (i.e. your not a good chemist...no your not a good chemist) but interested to see how this develops. I have never tried this reagent but when something doesn't work I start with analytical on the reagent(s). I expect an excellent clarification from Baran's lab will come in time, it is due.

On the reputations issue - Org Syn, Fieser and Fiesier, Beilstein - we have a long treasured history of verifying reactions, methods, materials, that is fundamental to us as chemists. The internet is opening this up, maybe too much when I am looking at strangers crude NMRs and TLCs (T.M.I.), but that isn't going to go away and if these blog sites result in better procedures getting published then everyone benefits.

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29. D-Not on February 20, 2013 5:03 PM writes...

Derek - this is 2013 !! which is why the merits of a synthetic methodology can be argued in the back waters and not through a publication. Legit - my friend is what gets published in premier publications - through peer review.

Out of three Blog-syn "repeats" two of them are from methods coming out of Scripps. do I sense a *** ??

Do all the methodologies work as stated in literature procedures ? have we even repeated a small fraction of the important ones ?

And derek you could not resist taking a shot at total synthesis. was that malicious maybe not !!

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30. See Arr Oh on February 20, 2013 5:16 PM writes...

Blog Syn #004 covers chemistry coming out of Michigan. And #005 (which isn't fully planned-out yet) will likely be from outside the US.

As @Darwinsdog alluded to, we're picking interesting and useful chemistry to test. The selection of a Blog Syn paper should be viewed in a positive light - it means we really want to use your method!

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31. Anonymous on February 20, 2013 5:24 PM writes...

I think the implications of this work could be far reaching. I'm absolutely serious.
I sense some squirming amongst the higher echelons of our science. The convenient assumption that what is being published is cast iron fact, both from the point of view of the PI and the student, could come under scrutiny as never before.

It's beautiful.

(I'm a Brit who spent 14 months trying to replicate a JACS communication from within our own group)

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32. Anon on February 20, 2013 5:27 PM writes...

@#28 this is not Baran lab's publication it's Nicolaou's. and he is not the only author.although, Knowing Phil I expect responses from him and other authors to be forthcoming.

You should all download that full paper and look at it. It's really well done and I hope they get to the bottom of what CRO and friends may or may not be doing correctly cause its clear to me (and the German group that used the chemistry successfully) that they weren't making things up.

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33. cpc on February 20, 2013 5:46 PM writes...

I'm with the Blog Syn guys on this one. If your intention is to produce a synthetic protocol which is to be widely used in the community, surely it's best for everyone to go for full disclosure. Even if you don't list every last detail in the body of the paper, there's plenty of space in the SI. If you've developed a reaction, then the chances are that you know, more or less, what the tolerances are. We should not be disheartened or disappointed to read things like
"the reagent purchased from Acros gave yields as below, while that from Sigma gave no reaction"
"material prepared by method X and method Y differed substantially in their reactivity (see below), despite identical 1H NMR spectra"
"freshly degassed ether is recommended for this reaction - yields are ca. 15% lower if the solvent is not degassed".

This is all useful data. Knowing how tolerant a reaction is towards x, y and z *even if you don't know why* is going to help you plan your work. I've done reactions in the past which have performed better under air than under an inert atmosphere, despite the experimental stating "all reactions were performed using standard schlenk technique under an atmosphere of Ar". I've done reactions with only the slightest regard to anhydrous technique which authors insist can only be achieved in a glovebox - they didn't work as well, but they still worked. I'm not necessarily insisting that everyone developing methodology should test their reactions to breaking point (although it would be nice!), but at the least actually disclosing what you have found out along the way is the decent and honest thing to do.

Derek once joked about "Goodwin’s Book of Tolerances" - to quote:

"I think he envisioned this as a thick volume like one of those old unabridged dictionaries, something that would live on its own special stand down the hall. “That way,” he told me, “when some student comes up and says ‘Dr. Goodwin, I added cheese dip instead of HCl – will that make a difference?’, I can walk over, flip to page thousand-and-whatever, and say ‘No. Cheese dip is fine.’”"

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34. Incha on February 20, 2013 6:10 PM writes...

@33 CPC makes some excellent points. Frank, open and informed discussion about the reproducibility of a reaction is informative to the community and a huge nod to the authors about the importance of their work. It can also highlight issues with commercial reagents or key information that may have been accidentally omitted from an experimental. I don't think there is any kind of bad feelings towards the authors of any publication they have selected - they have so far been extremely interesting reactions.
I can think of two great examples that Blogsyn may have picked up on, had it existed - copper in the iron (Bolm group) for example and a personal experience I had with a trace contaminant in ligand from a certain supplier, where the reactions would go from almost full conversion to no reaction at all.

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35. Post-Newtonian on February 20, 2013 6:21 PM writes...

The Observer is part of the Experiment...

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36. another process chemist on February 20, 2013 7:10 PM writes...

As a process chemist, I'm amazed that this is controversial in the slightest. Our deliverable is the knowledge used to execute the chemistry, which could then be carried out by an operator anywhere in the world. If we can't define our methodology clearly enough for somebody without a chemistry degree to execute successfully, we have failed.

I would think anyone looking to build a reputation through discovering new methodology would love to have BlogSyn around. You get your new work tested (and validated) for free - we have to keep management around to test that our processes can be done by somebody who is less than skilled in the art.

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37. Derek Lowe on February 20, 2013 7:50 PM writes...

#36 above is absolutely right. And we may be seeing a big of an academic/industrial divide here. I'm quoting the patent examiner's manual, and "Another process chemist" above is talking about how a good procedure is supposed to be bulletproof (because it's going to be run by workers in some plant somewhere who've never seen you).

On the other hand, there are the comments here that seem to suggest that the whole thing is an impertinent exercise at best, and character assassination at worst. The suggestion that Blog Syn take on the last steps of total synthesis papers was, I'm sure, meant to be snarky. But I meant what I said in #25. I really do think that a reaction that might be used by labs all over the world, and is put to all kinds of possible uses, is more important than one step of a long bespoke synthesis which will never be run again.

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38. Sue Denim on February 20, 2013 10:56 PM writes...

Honestly, I think the Blog Syn idea is a great one, and I wish it had been around when I was a graduate student. The first few times I tried to do an Evans aldol reaction were pretty awful. It wasn't until I spoke with somebody else who had done the reaction that I was told that you "had to" make your dibutylboron triflate immediately before doing the reaction, and that "everybody knew" the Aldrich Bu2BOTf was crap. Well I didn't know it!

It seems to me that there is plenty to learn when certain reactions are capricious. A great example was the finicky nature of the Nozaki chromium coupling that resulted in the discovery of the importance of nickel in the reaction. I don't think anybody was dismissing the Kishi group based on the quality of their TLC plates.

Which reminds me. I still run TLC's, but many of my younger colleagues look at me like I'm a dinosaur as they walk past me to monitor their reactions via LC/MS. Evaluating a chemist based on how much you like the look of their TLC plates is a bit like evaluating an author based on their handwriting.

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39. D-Not on February 21, 2013 2:46 AM writes...

1. forums like this are great for water cooler talk; one can discuss the latest round of pfizer firings or merck's phase-III failures.

2. Like Sue Denim mentioned above, its also a great platform for passing on "secrets" to getting delicate reactions done. we all know plenty of reactions require that "MOJO".

3. Blog Syn should continue to look at workability of reactions - but should drop labeling reactions as "not reproducible or moderately reproducible or requires MOJO"; Such characterizations MAR the service rendered by Blog Syn (cf point 2 above and @38).

4. Perhaps Blog Syn should consider overcoming the peer-review process and put into actual publication their findings OR engage the concerned lab for clarifications (as done in the case of syn# 2 and 3).

5. I wish Blog Syn was around when Dali published sensational "important" trnsformations !!

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40. Anonymous on February 21, 2013 9:31 AM writes...

@37 - Derek, just wanted to throw in my two cents as an academic, which is that this blog (and the associated desire to explore/demystify/robustify [that should be a word] reactions) is super awesome.

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41. anonymous on February 21, 2013 9:32 AM writes...

@37 - Derek, just wanted to throw in my two cents as an academic, which is that this blog (and the associated desire to explore/demystify/robustify [that should be a word] reactions) is super awesome.

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42. biochembelle on February 21, 2013 9:40 AM writes...

Perhaps Blog Syn should consider overcoming the peer-review process and put into actual publication their findings...

I'm curious, D-Not, where you would suggest BlogSyn submit their findings. Most journals will not publish replicate studies, regardless of the results. Occasionally one might be able to find a journal that will accept contradictory results. Even if contradictory results are reported, peer-reviewed publications likely would not reflect the true frequency of success or failure.

But suppose we do find a journal willing to publish replicate studies, regardless of their outcomes. Consider the amount of time it takes to move a paper through the review process. It could easily take months, even a year or more.

Digital media is an integral part of modern communication. More people can weigh in on a topic more rapidly. We should be thinking about we can use technology to accelerate the advancement and dissemination of research, instead of glaring suspiciously.

Let's not forget that, before journals, research findings were communicated via (non-peer-reviewed) letters and public readings among colleagues and rivals. It worked out pretty well for Newton and Darwin. I think peer-review has an important place in disseminating scientific results, but I also think that open, post-publication review and replication has immense potential to push research forward.

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43. Analytical Chemist on February 21, 2013 9:44 AM writes...

If Blog Syn had been around during my undergrad days, I may not have gone into inorganic chemistry with such ease.

What is so wrong with having chemical methodology verified at no cost by chemists who are happy to discuss their results openly? Do people so dead against this have any idea how much it costs?

@D-not This is BEYOND water cooler talk. This is the stuff that saves precious time and money wasted working out what the original chemists did when your replication of their work fails. Have lost weeks working out the "mojo" nonsense. It's no wonder I view any new "LEGIT" article with cynicism.

Full disclosure (sort of): Have worked in academia and industry

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44. Am I Lloyd on February 21, 2013 9:47 AM writes...

D-not and others: Lighten up and give credit where credit is due. We do what we can. It's ridiculous to accuse SeeArrOh of "witch hunts" when he is doing what almost none of us do, which is being vigilant and skeptical about the literature. It's also ridiculous to sarcastically ask SeeArrOh to reproduce the last steps of every total syntheses. Perhaps your comments would serve the community better if they stuck to the technical details and did not stray off into personal insinuations.

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45. nikodem tomczak on February 21, 2013 10:02 AM writes...

What you guys are doing is exactly what is missing in the scientific community - a solid post-publication peer review. What bothers me the most is that the scientific record is not being corrected even after the authors admit that their experimental section is not up to standards.

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46. Hap on February 21, 2013 10:11 AM writes...

1) When you publish something, other people are supposed to be able to reproduce it. When multiple people can't, it's possible that they're all incompetent, but it's more likely that something hasn't been made explicit (or known) that should be. Knowing those factors more clearly delineates what people can use the reaction for and what they can't - it might also make it more general, which would seem to be a good thing.

2) This wouldn't be a "witch hunt" if the reaction worked as advertised. Not liking results doesn't make them untrue, or the intent from which they were obtained bad.

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47. See Arr Oh on February 21, 2013 10:15 AM writes...

@Analytical, @Biochembelle, @Sue, @Hap, @Nikodem, @AmILloyd - Thank you for your kind support. Please reach out to me if you'd like to participate in a future Blog Syn.

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48. Anonymous on February 21, 2013 11:45 AM writes...

This dustup proves why academics shouldn't give career advice to undergrads or grad students. They don't know how the outside world works. Pretty pathetic that one of the fundamental tenets of chemistry (following a procedure) has been compared to a witch hunt.

I'll also note that the whole "This should only be addressed in peer reviewed format, bloggers don't know science" argument was used most recently by Felisa Wolfe-Simon. Rosie Redfield (a blogger) put her experiments (which were posted on her blog) into a publication and disproved Wolfe-Simon's work. The legitimacy of her findings had nothing to do with where they were disseminated, it only served to meet the author's challenge. Wolfe-Simon is still wrong and continues to deny it, despite Redfield's publication. And of course, there's the NaH oxidation paper that was published in JACS and disproven by the blogging community, which forced a retraction. This is the last desperate argument of scientists who are afraid of their work being put under the microscope of reviewers who aren't part of their good ole boys network.

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49. Simon Higgins on February 21, 2013 12:17 PM writes...

As someone who doesn't do much 'discovery' organic chemistry, but who needs to do synthesis as a means to an end, I think the Blog Syn idea is a good one, and deserves support. Some of the negative comments in this thread (anonymous, I note) are just silly. Perhaps if blogging about unsatisfactory experiences with synthetic procedures became more common, it might encourage more attention to detail in the SI of synthesis papers. Of course, doing so opens you to the charge that you're just being incompetent, so it requires a certain amount of courage.

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50. cenbons on February 21, 2013 12:23 PM writes...

I've really enjoyed watching BlogSyn get off the ground, and only hope that it leads to more accurate reporting of SI. It's incredibly annoying relying on something that someone else has published and it not working out.

Case in point, the synthesis of a reagent I needed (fairly late) in my total synthesis had been published and reaxys claimed 100% yield (granted the paper didn't) but we got no product at all. We went back to the authors and it turned out that they had only got an 8% yield!

As a side note, I've run TLC's that look much worse than SRO's. It's hardly a beauty competition, and certainly doesn't devalue the result.

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51. z on February 21, 2013 12:37 PM writes...

How can people say this is a witch hunt? The blog is looking at a potentially very useful reaction that some people have had trouble reproducing. Nobody is accusing any of the original authors of any wrongdoing. Most people who are skilled in the art understand that, when dealing with a new reaction, there may be variables that are more important than originally thought. These variables were not discussed in the original report because the reaction worked just fine the way they ran it, so nobody knew these variables were important, so they didn't examine them. By reporting on these attempts in an open and transparent way, the bloggers can draw upon the collective wisdom of the community to try to figure out what went wrong so they can fix the problem and make the reaction more reproducible This will help the reputation of the original authors! It means the people who otherwise would have tried the reaction once then given up can now do it successfully. That makes the method better and increases its impact.

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52. z on February 21, 2013 12:40 PM writes...

And who cares what anybody's TLCs look like! As long as you can get the information you need from them, that's all that matters. I can't understand why anyone would waste their time over something so trivial.

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53. Andrew on February 21, 2013 12:45 PM writes...

@Anon #48: Thanks for bringing up the arsenic life controversy. This (and others like it) demonstrate the gaping holes in peer review. I'm skeptical that the reviewers of the IBX paper actually ran (or rather, had their graduate students) run the reactions in lab to verify their reproducibility. Why? Because these things take time and resources. If an author has a detailed procedure, with requisite spectra, then why should the reviewer doubt it? This is exactly why Blog Syn is useful! And it also demonstrates what's great about the internet.

@ D-Not: You've mentioned the Sames retractions a few times, saying that you wish Blog Syn was around to disprove that. Exactly right! It was only because of several groups' failures (as well as Sames' own grad students') that the papers got pulled. If this service helps prevent more nonsense like that, the community is much better off.

@ See Arr Oh: Keep up the good work.

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54. lost academic on February 21, 2013 12:46 PM writes...

As an instrument developer in a more specific chemistry area, I am deeply frustrated with publications asserting that certain methods produce results that our lab cannot - in my most recent experience, I got lucky and an author on the paper in question confided to me that the results published were not reproducible and he was just glad to be past that particular endeavor. That paper will surely never be retracted, and I am forced to publish a veiled denial of their results.... but people will still cite their results. I'm glad to see things like Blog Syn. It's too easy to just assume you're doing it wrong and if you just keep at it, it'll all work out the way someone else said it should....

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55. Sue Denim on February 21, 2013 2:19 PM writes...

@48: "This dustup proves why academics shouldn't give career advice to undergrads or grad students. They don't know how the outside world works."

Let's be careful about making sweeping generalizations. Off the top of my head, I'd say that Paul Reider, Amir Hoveyda and Arun Ghosh are examples of academics who have a pretty good idea how the outside world works.

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56. Freda on February 21, 2013 2:35 PM writes...

As a PhD student I am really glad that BlogSyn took off and I am learning a lot of chemistry from it. When results aren't reproducible it makes me reflect on the chemistry more and I don't immediately start questioning the integrity of the researchers that published the paper (at least not immediately, can't jump to conclusions here). My respect for the professors of the papers being looked at on BlogSyn has not changed, and credit must go to those that really took the effort to reply and address the variable results.

I agree with another process chemist, z and Andrew. I really can't see how this blog could be interpreted as a witch hunt, if anything this is really helping science and ensuring that the methodology is 'bullet-proof' and can be used everywhere in world. When we can pick out the important variables surely that's a good thing for future optimisation?!

@See Arr Oh: keep up the good work. I love good science and I love a good methodology discussion.

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57. Anonymous on February 21, 2013 7:03 PM writes...

Shots fired! i'm only halfway through these comments and i'm breaking out the popcorn

hope blog syn is here to stay

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58. A Canadian on February 21, 2013 11:01 PM writes...

Hudlicky would be proud! I wholeheartedly support blog syn.

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59. Jose on February 22, 2013 2:11 AM writes...

I am surprised at the witch hunt accusations. My original comment was motivated by the fact that co-workers and I wasted FAR too much time trying to get a seemingly trivial reaction to go. I am confident that it worked well in La Jolla in 2000/2001, but the fact that we totally failed, and there have been essentially no subsequent publications suggests there is something very crucial missing somewhere....

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60. D-Not on February 22, 2013 4:04 AM writes...

If CRO can selflessly devote time for the betterment of the chemistry community, Perhaps, I can too find the time to contribute RESPONSIBLY (without malice) to the Syn Blog effort in some small measure.

I am a MS synthetic organic chemistry graduate from an average school, could not muster enough chops to get a PhD, but I am a "closet academic". At 49, I am still feverishly carrying out synthetic lab work at a small biotech, even managing to guide a small group of chemists in drug discovery. If there is any way we can help (while I still have a job that is !!) please let us know the modus operandi.

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61. Observer on February 22, 2013 9:20 AM writes...

Hi Jose - perhaps you didn't see prof Kirsch paper that uses ibx to oxidize 4 extremely complex substrates and also their glowing praise of that reaction? Org lett 2006 referenced above. I suspect he is not cursing Nicolaou.

I think you should all give it a few days for the original authors to respond before jumping to the conclusion that the reaction is not reproducible....

By the way there's a really good review on reactions that you can't possibly fuck up written by Barry Sharpless - it's called click chemistry. Maybe you should run some of those reactions Jose.

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62. See Arr Oh on February 22, 2013 9:57 AM writes...

@D-Not: Please email me at seearroh_AT_gmail if you'd like to have a go. We appreciate any and all help.

@Jose: (You, too, if you're so inclined!)

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63. Stiv on February 22, 2013 10:08 AM writes...

Hi Observer-

Perhaps you didn't notice that the Kirsch paper gave ZERO experimental details in the SI section of their paper with regard to their claim that they oxidized methylpyrroles to formylpyrroles with IBX.

Perhaps you didn't notice that the title of Blog Syns latest entry is "Benzylic Oxidation of Arylmethanes by IBX", _methane_ being the key word.

Perhaps you didn't notice that what is being questioned is the original paper's claim that IBX can oxidize aryl methyl groups to aryl aldehydes.

Parhaps you didn't notice that there are ZERO reported reactions in SciFinder which corroborate Nicolau et al's claim of oxidation of aryl methyl groups by IBX AND report experimental details.

Perhaps you didn't notice that there have numerous reports of (skilled in the art) chemists who cannot reproduce the original paper's claim.

Perhaps you should wonder why that is, rather than be a wise-guy and criticize See Arr Oh for his work at using the scientific method (http://en.wikipedia.org/wiki/Scientific_method)

Stiv

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64. Nick on February 22, 2013 10:44 AM writes...

Here's an interesting list of "erratic" chemistry:

http://chem.chem.rochester.edu/nvdcgi/mojo.cgi

Oh look, the Nicolaou IBX procedure is listed...must be another witch-hunt.

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65. See Arr Oh on February 22, 2013 12:05 PM writes...

@Nick - Actually, Prof. Frontier's "Not Voodoo" site has a wealth of information for the practicing chemist. Part of Blog Syn's inspiration springs from the site you've just shared.

Also of note: a young Prof. Baran was an original contributor to Prof. Frontier's "Day in the Life" section:
http://chem.chem.rochester.edu/nvdcgi/contrib.cgi

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66. Jose on February 22, 2013 6:19 PM writes...

Observer- pipe down, there youngster....

I fail to see how bromotoluene + IBX + heat requires anything approaching a good set of hands, let alone "skill in the art." If the yield had been even 30% I would have written it off as bad IBX and moved on. But when we re-ran the reaction with multiple chemists and a range of IBX, all with the same results, well... I went to SciFinder and found essentially nothing.

OK, no more feeding the trolls for me.

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67. Nature on February 23, 2013 5:44 AM writes...

@66-Jose, Obsrver has a point. In order to establish baseline (controls) it would be beneficial to give the Click chemistry a try. also please post a picture of your TLCs !! good luck.

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68. Jose on February 23, 2013 6:36 AM writes...

@67, Riiiiiight. I am quite confident about our reactions, See Arr Oo's reactions, and the TLC skills of mt three cowrokers, however in pharma we don't waste so much time on TLCs... :)

Please, good sir, point to a single SciFinder reference using this method on a *benzylic* substrate... or maybe you can show the way by posting your glorious shining yield with photos to Blog Syn?

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69. Groggy on February 23, 2013 10:21 AM writes...

Maybe I'm missing something Jose but that org lett referenced above oxidizes benzylic methyl (aryl methane) not once but 4 times? And in the paper they wax poetic about how great the reaction is? Is your scifinder broken?

You couldn't oxidize toluene? Was there no benzaldehyde available you actually needed 4 equivalent ibx to make benzaldehyde? The sm and product are volatile under the conditions maybe that's why you didn't see it?

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70. Nick on February 23, 2013 11:31 AM writes...

@65 CRO - I agree, its a great site. Thanks for your efforts with blogsyn, don't let haters get you down!

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71. Jose on February 23, 2013 8:09 PM writes...

Perhaps I was unclear- the single report in the literature is with pyrroles, which are not strictly benzylic.

Groggy, we used bromotulene as a test case for exactly the reason you cite (and it is in the original paper). Again, please show us the way with your laboratory brilliance and share the results at BlogSyn...

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72. Stiv on February 23, 2013 9:51 PM writes...

Jose

Give it up ... Observer aka Groggy is the same disgruntled troll.... Just don't respond

Stiv

Ps - SEE ARR OH - Great Blog, but you are clearly ruffling someone's feathers

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73. Not-Stiv on February 24, 2013 11:58 AM writes...

why are these discussions deviating from merit to personal attacks !! Talk of troll etc.. is not dignified. Can Derek put a stop to folks like Stiv that use degenerate language. if a reaction could not be done -- its one thing to discuss TLCs and expwerimental conditions -- but it is totally out of bounds to start name calling and patronising S-A-O etc.. Eminent capable scientists such as yourselves that have PhDs from premier groups should not indulge in this fashion. if you dont have a PhD and are slogging away in the lab - one can understand !!

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