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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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January 16, 2013

Blog Syn: An Idea Whose Time Has Come?

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Posted by Derek

Here's something I've been following for the last couple of weeks in the chemical blogging world, and now it's up on its own site: "Blog Syn", an initiative of the well-known chemblogger See Arr Oh. The idea here is to take interesting new reactions that appear in the literature, and. . .well, see if they actually work. (A radical concept, I know, but stick with me here).

The first example is this recent paper in JACS, which shows an unusual iron-sulfur reaction that ends up generating a benz-azole directly from an active methyl group in one pot. There are now three repeats of the reaction, and the verdict (so far) is that it works, but not quite as well as hoped for. You probably have to be careful to exclude oxygen (the paper itself just says "under argon"), and the yield of the test reaction is not has high as reported. As you'll see, there are spectral data, sources of reagents, photos of experimental setups - everything you'd need to see how this reaction is actually being (re)run.

I like this idea very much, and I look forward to seeing it applied to new reactions as they appear (and I hope to contribute the occasional run myself, when possible). They're accepting nominations for the next reaction to test, so if you have something you've seen that you're wondering about, put it into the hopper.

Comments (19) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. See Arr Oh on January 16, 2013 1:58 PM writes...

Thanks for the mention, Derek! But I wouldn't be able to start up without the contributions of BRSM, Matt, and Organometallica. They're the "good eggs" on this one.

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2. student on January 16, 2013 2:02 PM writes...

Great idea. EJ Corey is shaking in his boots.

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3. Anonymous on January 16, 2013 2:17 PM writes...

Great idea, although I'm a little curious about the vision for it: Are people running reactions they would not otherwise have run specifically to test the literature procedures? Or is the idea that whenever someone happens to be reproducing a literature procedure, that they should send a note to the blog about how well it worked?

In the former case, I feel like it will be hard to keep this going beyond the initial publicity and novelty since most of us don't have enough time in the day for all of our own work, and there is no real incentive to participate in this.

In the latter case, there is a much lower bar since people have already done the work and it's just a matter of submitting it. But I feel like things could get really messy and disorganized, with procedures linked to all sorts of journals and time periods, and unless it somehow gets integrated into the primary literature searching tools or otherwise works its way into people's daily workflow, nobody will see these results and the value will be lost. People will just run the literature reactions without seeking out this information.

Sounds like a good idea, but I'm just trying to see how it can actually take off.

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4. Lyle Langley on January 16, 2013 2:25 PM writes...

Who will check the checkers? I can easily foresee a scenario where someone will post - intentionally - disparaging data to refute someone else's data. If someone is publishing data in a journal and their methods aren't as robust as published, why would someone posting on a site be any different?

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5. imatter on January 16, 2013 2:52 PM writes...

I'd compare this to online cooking recipe websites. Someone would try a recipe and see if works as advertised and comment on what worked for them and what they did differently. For the most part, it has worked for those sites. Pretty cool--I just hope that it's done with good intentions and positive and civil discussions.

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6. BRSM on January 16, 2013 5:25 PM writes...

Lyle:
Well, yes, that could certainly happen. I suppose the fact that people can do so anonymously won't help. But I still think that the net outcome of this will be good. People can of course say what they like in the comments, as they can on any blog, but if there's conflict ("oh notice doesn't" "oh yes it does"...) then I imagine a few more people will just run the thing and see. If we post our own findings on a reaction the original authors will always be notified to give their response. I speak for all of the 'editors' when I say that we will be very careful about what goes into each post. I think that a single person out to make another group look unfairly bad won't have much impact.

I'm not sure how active this thing will be when the initial hype dies down, but I think there are lots of reasons that people will contribute. Myself, I am a very curious person and I love to try new chemistry. I hate the publication of substandard, exaggerated or irreproducible work that will just waste people's time. Look at all the time that's sunk into chemistry blogs already, by busy people at good institutions...

I do worry about how the data will be organised if it does grow to a decent size, but we'll cross that bridge when we come to it?

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7. Stephen on January 16, 2013 6:09 PM writes...

This is a good idea but this should be integrated into every synthetic (and other) paper. There should be a comments section after every paper on the online journal site where people can (nonanomalously) post comments such as tried it didn't work, or works better at this temperature or with this catalyst. Might help cut down the yield inflation endemic.

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8. souls_at_zero on January 16, 2013 7:11 PM writes...

I support the idea, although I can make no predictions as to how it will progress in the long term.

The immediate attraction for me is to get into the lab with the experimenter, see how they do things and see the crude results. You can always learn from observing other peoples style.

Also, that stirrer plate looks so clean - did someone take the plastic cover off to look cool, or are they so meticulous that they never had a protective cover in the first place?

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9. Anonymous on January 17, 2013 9:09 AM writes...

This is a great idea, kind of in the spirit of JoVE (Journal of Visualized Experiments). They film a procedure from start to finish and publish the short movie and corresponding protocol. A good idea that now seems to be growing. They are adding an chemistry edition this year it looks like. http://www.jove.com

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10. Anonymous on January 17, 2013 9:25 AM writes...

Who has the spare time and unrestricted grants/funds to test these reactions, unless you were happening to need that exact reaction at the time 2 others were trying it out?

I also found it curious that people went to so much effort to take ideal-looking photos of their experimental setup and raw data, but didn't bother to adhere to the protocol specified in the paper (e.g. argon vs. air).

Granted, it is likely a realistic representation of how people would try to reproduce a protocol (i.e. quick, dirty and sloppy), but hardly a way to judge if their method is reproducible.

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11. See Arr Oh on January 17, 2013 10:06 AM writes...

@Anon9:25 -
1. None of us have spare time. We all work day jobs or are in school full-time. But we're all passionate about the result.

2. The photos aren't ideal, but rather accurate. All taken using smartphones at the bench.

3. The first reaction was deliberately set up "med chem style," after a conversation I had with the experimenter. Subsequent reactions were run strictly under Argon. Also, have you looked through the authors' SI? If you can tell me what a "pressure equalization tube" is, you win a prize.

4. The final reaction was run in a glovebox, in a new lab with all new reagents and glassware. If that's not rigorous enough, please suggest another avenue.

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12. Steve Chamberland on January 17, 2013 12:48 PM writes...

I wish to commend the authors of BlogSyn for doing what those in the chemical community should be doing anyway. I agree with other commenters though, that the community should not have to police each other. Who has time for that? Instead, we should police ourselves. PIs are responsible for the research that comes out of their lab just as we are accountable for the safety of our lab members. Honest reporting of experimental results is just good science, good citizenship, and what an ethical person would do. Each procedure reported in a synthetic or methodology paper should be written without the omission of key and useful details. For example, why is it so difficult to report TLC data for pure chemicals? If precise temperature control is required, why is that not always stated? Sometimes, reaction conditions and molar equivalents are not even included. This is simply absurd. A technically trained undergraduate should be able to reproduce any procedure within 10% of the reported yield on the first try.

As a professor who performs synthetic organic chemistry research exclusively with undergraduates, I cannot tell you how many precious hours have been wasted in the lab trying to realize the reported outcome of reactions from the literature. Students get so frustrated when they cannot repeat a reaction that is reported without sufficient details or procedural steps.

Maybe those who take shortcuts and do not report their data honestly want to protect their results from easy reproduction. If that's the case, they should write a patent. Maybe they don't care or are oblivious to the impact of lazy reporting. Either way, they shouldn't be allowed to practice science and be published. Many important reactions were discovered by serendipity, careful observation, and good scientific practice, but there should be no such thing as a magic flask or magic hands. Adroit chemists with good hands, the same equipment, and the same quality of chemicals should be able to report any literature procedure. Why is that not always the case? The last time I repeated a procedure from Organic Synthesis (Murray Goodman's procedure to make N,N'-Di-Boc-N"-triflylguanidine - Org. Syn. Coll. Vol. 10, p. 266, 2004; Vol. 78, p. 91, 2002), I was able to obtain precisely their reported yield on the first attempt. All the data matched. Every necessary detail and condition was reported. Org. Syn. has earned a reputation for repeatability. Maybe not 100%, but it's quite good, the gold standard.

This is not to say that every synthetic procedure reported in the literature needs to be optimized, but at the very least, reproducibility should be paramount. If we are to train the next generation to practice science ethically, honest reporting of research results with full disclosure should be our top priority. I want others to have faith in our work. There are no shortcuts. It is our duty. It has to be done right.

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13. a. nonymaus on January 17, 2013 1:21 PM writes...

Building on some of the above, especially 12, this level of detail and documentation is something that we should consider expecting when reviewing manuscripts describing new syntheses or techniques. If the SI or experimental section is not detailed enough to be reproducible, then send it back. Obviously, the acid test is when someone else needs to do the same procedure, but the initial publication must be good enough to let non-wizards try to reproduce it.

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14. Matthew Katcher on January 17, 2013 1:45 PM writes...

@souls_at_zero - Thanks for the compliment! Took the plastic cover off since it was getting dirty and hard to clean. If only the rest of my hood was that clean...

@Anon9:25 - What See Arr Oh said.

I agree with others that, while BlogSyn or OrgSyn can't check every reaction, procedures in general should be better. Would be especially nice for journals where SI's are often absent and reactions sometimes look too good to be true. Some of those reactions do work, but it would be useful to know ahead of time which ones those are.

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15. z on January 17, 2013 4:19 PM writes...

I don't expect to always be able to reproduce the yields of reactions I find in the literature. There are a lot of subtle variables that somebody who has months of experience gained while developing this reaction learned to deal with, a lot of times unconsciously and intuitively. If I'm just doing it for the first time, I obviously don't have those kinds of intuitions. I expect the reaction to work, but in my plan I always assume I will get lower yields (I usually aim for twice as much as I think I'll need).

And maybe the problem is that the community isn't spending enough time trying to pin down which of those minor variables is actually important. Speaking for myself, I've done a lot of synthesis and med chem but not much methodology development, and I certainly haven't spent much time worrying about those things--if I can make, great, I make it and move on. But if I were involved in methodology development, I would spend a little extra time trying to determine just how important things really are, like the order of addition, temperature, air sensitivity, time, vigorousness of stirring, etc.

Each of us has a way of doing things that we take for granted but which may be somewhat idiosyncratic. Most of the time it isn't important, so we don't write it down. Every once in a while it is important, but we don't realize it because the reaction works for us, so we don't write it down. And sometimes our lab mate may repeat the reaction, and the whole group shares this idiosyncrasy, so it still works just fine, so we don't write it down. Someone else reads it and does things differently, and it doesn't work. So that's the great value of this sort of endeavor, to help identify the times when those variables are important. Whether there are enough cases where they find useful information to justify the effort remains to be seen, but maybe the visibility will help raise awareness among groups publishing these papers to do a little more experimentation up front and write stronger experimentals.

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16. Chemist of Sorts on January 17, 2013 9:43 PM writes...

Great idea in theory, but completely unworkable in practice (Best of luck anyway!). Org syn takes a lot of time and effort. Yield inflation stinks but should just be accepted- I have much more important things to obcess over. Really, does anyone who is experienced with the literature believe all the yields they read? I look for references from reputable labs and expect to be able to see comparable yields. For me, the key point is does the reaction work in the ball park that is claimed.

I think reproducing lit preps would actually be a good exercise for advanced organic undergraduate lab courses (not the for someones first organic lab). Certainly the chemistry would be more interesting, they could actually make intersting things (graduate labs could put in suggestions/requests), and I gotta think TAing would be a lot more fun when you don't know what should happen. Maybe the shame of having an entire lab class fail to reproduce your result could reinstill some more forthcoming reporting in the literature.

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17. Vinylogous on January 18, 2013 12:06 AM writes...

@ChemistofSorts -- I think you may be rather missing the point. I don't see Blog Syn as an exhaustive crusade to seek out every example of yield inflation in the literature. I don't see it as a punitive audit system designed to embarrass authors. Rather, I see it as a constructive dialogue to accomplish a few tasks: (1) highlight some questionable procedures (and how to improve them); (2) seek to improve the quality of experimental reporting in the literature; (3) showcase GOOD, robust procedures -- surely authors would like the extra publicity, especially since this review system will be much more rapid than a subsequent publication employing the chemistry.

Re: "I look for references from reputable labs and expect to be able to see comparable yields. For me, the key point is does the reaction work in the ball park that is claimed." --- your perspective is probably the one most commonly shared by practicing chemists. But look back to what you said previously: synthesis "takes a lot of time and effort." It does take a lot of both! One of the reasons is figuring out the unwritten magic tricks employed but accidentally omitted (or not noticed!) from the published writeup. Surely a *dialogue* can only serve to make everyone's lives easier - why reinvent the wheel, after all, if you can draw on a broad range of real-time experience? Moreover, you say to look for references from reputable labs: I question the validity here. Labs don't do the work----grad students do. Within a lab at a given time, quality of work and attention to detail can vary substantially between students, and this can vary longitudinally too between years and decades. Plus, I'd be willing to bet that many almost-unknown labs produce results on par with (and often better than) "top" labs in terms of reproducibility and robustness (it would be foolish, after all, to ignore the pressure to generate rapid results in high-profile labs, which can lead to turning a blind eye to reproducibility).

My old advisor was fond of telling us of a procedure he'd been once trying to reproduce from the literature. The procedure called for "anhydrous DMF." Lots of trials gave failure, despite more and more rigorous drying protocols. Turns out he had dried his solvent with greater rigor than the authors had (they had not stated their drying method, and a trace amount of water was indeed integral for the reaction's success).

I also, obviously, disagree that Blog Syn is "completely unworkable in practice." What leads you to that conclusion? Dialogue is what the synthetic community needs--and I think it'll be accepted with enthusiasm!

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18. See Arr Oh on January 18, 2013 1:17 AM writes...

@VA - Well said. Bravo!

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19. nord on January 18, 2013 3:52 PM writes...

pressure equalisation tube is what I would call a bubbler. does that mean anything to you? what do I win?

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