Showing posts with label synthetic methodology. Show all posts
Showing posts with label synthetic methodology. Show all posts

Thursday, January 17, 2013

Blog Syn: B.S. to cut through the B.S.

Something I find very exciting happened today: the inaugural post of online synthetic peer-review community Blog Syn. Head over and check it out; remember also to subscribe to it (you'll note no exorbitant subscription fees).

The website is a rapid, international, and open source of peer-review of the synthetic literature focused especially on reproducibility. Essentially, it's a curated set of data: chemists point out interesting or provocative procedures, other chemists try the procedures and document the process and results, and then the efforts are cataloged and published for broader review and comment by the chemically-inclined portion of the internet.

The amount of "junk" in the literature is a well-established problem (if every procedure you've ever tried has worked as advertised, congrats, though). Sometimes you can get difficult literature procedures to work if you discover a variable that wasn't included in the original source (e.g. source of the material, trace impurities, level of rigor in keeping things dry, heating method, etc.) -- but then, since you're merely reproducing a literature procedure, this detail often doesn't make it into your subsequent paper ("Material X was prepared according as described by Author Z."). Moreover, since the publication timescale is slow and synthetic corrections/retractions are rare, lots of money might be wasted on trying to repeat useless procedures (counterpoint: some procedures work really well, and it's in everyone's best interest to hear of those, too!). 

Blog Syn is a really exciting idea, and I think it fills a niche neglected by the current traditional literature. I'll elaborate.

Blog Syn's closest analog is Org Syn, of course (hence the quasi-tongue-in-cheek name). Org Syn is a great journal if you ignore the clunky online interface. It's based on reproducibility. Proposals that are accepted are checked at least twice in a reviewer's lab using meticulous detail supplied by the authors about reagent quality, purification method, etc. The procedure must be reproducible to within 5% yield as written. A tall order--how many chemical steps in the literature would survive those strict guidelines? Accordingly, Org Syn has a good reputation: if you can't reproduce a procedure, it's likely an issue on your end, not on the literature side.

However, Org Syn isn't a panacea for problematic protocols. Procedures are submitted intentionally by authors; Org Syn doesn't review existing publications. Hence, there's self-selection. Authors choose to send things they know will (likely) work. Sketchy stuff is submitted elsewhere.

That's where Blog Syn has an advantage. It's democratic--any interested chemist with the time and materials can potentially contribute. It's an actual dialogue--those without access to the means to carry out experiments can still suggest techniques and comment on the data. And it's rapid. It's very rapid. Take the first post for example, which was compiled less than a month after the article was made available as an ASAP (many of the experiments were done before the article was even assigned a page number). Hence, before the broader chemical community became aware of the article, it had been vetted, including a discussion with the authors.

That's cool. 

There's been a lot of support from bloggers, including inaugural contributors B.R.S.M., Organometallica, and  Matt Katcher, project starter See Arr Oh, and chemblogging king Derek Lowe. There's been some doubt in the comments of the blogs, as well: chiefly about who verifies that the checking was done correctly, and how the whole thing will operate organizationally. I think these concerns are fairly minor hurdles; with sufficient checkers, the number of trials is way over the standard n = 1 for publication. The idea, as I understand it, is for a small group of volunteers to check a reaction that has sufficient interest and feasibility.

I think it would be helpful and important to get some PIs on board. There's two reasons: (1) a PI might become irate if they discover their student burning time and reagents behind their back (after all, reagents and NMR time cost grant money); however, a PI who gives their blessing to a student to conduct trials can contribute resources; and (2) there's a lot of chemists who still doubt that non-traditional publication venues (read: the Internet) offer anything of value; while I think Blog Syn will prove itself, having some PIs contribute might be quite transformative in shaping the face of peer review--a combination of open access and acknowledgement of social media. Attaching "established" names could mollify the perceived connotation of anonymity/sketchiness that lies with blogging in the eyes of many academics.

Anyhow, it'll be quite fascinating to see how it shapes up. Maybe it won't go much further. Or maybe it'll force authors to be more accountable for the science they preach.

Saturday, December 1, 2012

Conjugate addition, aqueous edition

Organocopper chemistry is one of those fields that doesn't get the attention it deserves in advanced undergraduate and many graduate synthesis courses. Usually, we settle for writing "R2CuLi" and being done with it, but cuprates do some pretty neat things that plain old Grignards and organolithiums just aren't as good at. Just like pretty much any organometallic species, though, their reactivity is dependent on additives, solvent, aggregation state, etc., which all ties in to the method of generation as well. (For a good review, if you get Organic Reactions, see Lipshutz).


There's a bunch of flavors (Gilman homocuprates, mixed Gilman cuprates, controversial "higher-order" cuprates, cyano-Gilman cuprates, etc.) that people have argued over (especially the alleged higher-order variety). Organocuprate reactions are, of course, moisture-sensitive, which means fun with cannula transfer and good Schlenk technique when you need to use them (this is annoying, by the way, when adding one needs to add solids at various points of the reaction). Additionally, additives can make a big difference:


Thus, this JACS article came as a surprise: "C–C Bond Formation via Copper-Catalyzed Conjugate Addition Reactions to Enones in Water at Room Temperature." (Lipshutz, B. et al. JACS 2012, DOI: 10.1021/ja309409e). Note that it's from Bruce Lipshutz, who has been fairly influential in the cuprate field.

From the abstract (with Fig. 1 from the paper): (note typo from the abstract, red emphasis mine)
"Conjugate addition reactions to enones can now be done in water at room temperature with in situ generated organocopper reagents. Mixing an enone, zinc powder, TMEDA, and an alkyl halide in a micellar environemnt containing catalytic amounts of Cu(I), Ag(I), and Au(III) leads to 1,4-adducts in good isolated yields: no organometallic precursor need be formed."

Sounds pretty good, doesn't it? The development of aqueous conditions for organic reactions is challenging, of course, due to the sensitivity of many reagents to water as well as the utterly poor aqueous solubility of many (most?) substrates. Nevertheless, Lipshutz points out examples, including an aqueous conjugate addition by Luche that beat this paper by 26 years, and a more recent aqueous Negishi reaction by his own group.

The reaction:
Both the Negishi reaction and this new work are powered by "nanomicelles", tiny nonpolar environments formed by a catalytic amount of an expensive-looking detergent added to the reaction medium. The amphiphile is a vitamin E derivative (polyoxyethanyl-α-tocopheryl succinate; aka. TPGS-750-M), interestingly enough (other compounds were screened and didn't work). The authors include the structure in their paper (I've included the image from their manuscript rather than drawing it myself in order to point out a curiosity: is it weird to use "Me" and "CH3" in the same structure?)


Of course, you can read for yourself the details. A variety of conditions/additives were screened, and the reaction was found to be generalizable to primary/secondary alkyl iodides/bromides. The best loadings and rates were found for what was described as the "coinage metal triad" (copper acetate, AgBF4, and AuCl3) along with zinc metal.

It's probably worth noting that all the enones presented were relatively uncrowded; this isn't exactly surprising, since usually TMSCl, borane, or some other additive is needed in the normal, water-sensitive route in order to effect conjugate addition to highly substituted enones. It's a bit trickier to find additives like that here.

Still, this seems, at first read, to be pretty interesting. It's aqueous, it's catalytic, you can recycle the catalyst/medium, and you can buy all the reagents. Yields seem to be good (but that doesn't always mean anything). Most importantly, the reaction looks to be facile. Facile is nice. Though I would have called the nanomicelles "transient nanoroundbottoms".