synthetic chemistry

Just a Suggestion

Picture this: you are expected to do a cross-metathesis, Mitsunobu, hydrolize the ensuing ester and cross-couple with (s)-proline.  Not necessarily a difficult order to an experienced organic chemist.  The challenge is finding a procedure/reference that will work on your substrate.  You crawl through several Google searches (because you’re too lazy to get to walk across campus to the library and use SciFinder) and come up with ballpark, unreasonable hits.  Are you seriously going to do a cross-metathesis in cresol just because the paper says there was a “noted rate enhancement”?  How many total syntheses will you crawl through to find the right tosylation procedure?  I encounter this frustrating problem on a weekly basis.  Isn’t there a middle of the road procedure or set of procedures someone can consult?

Look no further than Li, Limberakis and Pflum’s relatively recent book entitled Modern Organic Synthesis in the Laboratory (ISBN-13: 978-0195187991).  Truthfully, I’m not one for plugging media (movies, music, books, etc.), but this text rocks!  It’s on par with Li’s Named Reactions (ISBN-13: 978-3540300304) book, which got me through cumes a few years back. 

Those who know me well also know that I’m obsessed with Leonard, Lygo and Proctor’s Advanced Practical Organic Chemistry (ISBN-13: 978-0748740710)—a splendid reference covering the ins and outs of any organic laboratory.  It’s full of useful information ranging from how to set up a laboratory notebook to Grignard preparation to anoxic techniques.  I’m living proof that any idiot can consult APOC and have a vague idea of how to correctly conduct a majority of laboratory techniques.  

Similarly, Li’s MOS puts a modern twist on most of what APOC covers then throws in generic procedures for running a cross-metathesis or doing a EDCI-mediated peptide coupling, for example.  There’s even a section on lab coats!  (SPOILER ALERT: baggy is not the way to go).  My only criticism is that I wish there were even more information.  Though, both references are conveniently concise (~200 pages) and cut through the BS that most technique books love to cover.

My boss received a desk copy of MOS a few months back, and I think it’s spent more time on my desk than his; I just added the book to my Amazon wishlist.  I encourage you to do the same (even all you nuclear chemists…you never know).

By June 20, 2008 4 comments synthetic chemistry

Danishefsky + Rebek = ?

I recently wrote about the reaction of isonitriles with carboxylic acids under microwave irradiation, as reported by Danishefsky. Rebek’s group took up this idea and tried the reaction inside capsules formed by two cavitands (DOI:10.1021/ja802288k).

In the presence of the capsule, acid 1 and isonitrile 2 react at room temperature to give the intermediate 3. However, the n-butyl intermediate 3a is not detected and immediately rearranges to the product 4a, still trapped inside the capsule. Release of the intermediate and reaction with 1 in the bulk solution gives a small amount of 5a (this side product gets trapped in a capsule again).

In the case of isopropyl substitution, intermediate 3b is actually seen by NMR. It cannot rearrange to product 4b, but is released from the capsule instead and reacts with 1 to give formamide 5b. The authors explain this with the steric bulk of the isopropyl group that prevents the rearrangement inside the capsule.

Reaction of carboxylic acids with isonitriles inside capsules

As far as I know, this is the first experimental evidence for intermediates of the type of 3, which take part in the reaction mechanism suggested by Danishefsky. In addition, it also shows that the carboxylic acid – isonitrile reaction can be “catalyzed” by cavitands without the need for microwave irradiation.

By June 18, 2008 82 comments synthetic chemistry

Better Living through K-Carb – My Salting out Saga

RBFI have run this reaction nearly 20 times; it’s a known procedure that takes ~5-7 days to run, and I do it once every 2-3 months to bring up starting material. Though the reaction offers mediocre yields (~70%), it’s a cheap and effective way of making a synthon I need for research. In one of my previous projects, I realized that adding a fresh portion of reagent to a drawn out reaction could sometimes be the difference between 60% and 85% yields. With that in mind, I added a second, freshly distilled portion of my reagent and let the reaction go another 24 h. Like a charm, the remaining starting material vanished from my TLC plate, and I was left exclusively with the desired product!

The workup, however, was disastrous. Instead of a typical bilayer upon quench, I had this cloudy, colorless solution—much more worse than any emulsion I have ever encountered. Instincively, I figured that I could use NaCl to salt the hell out of the reaction and separate the two layers. Two problems: (1) in retrospect I realize that this technique really only works on non-polar solvents (like hexane) and water; I had methylene chloride and water. (2) My aqueous layer was already saturated to begin with. Dilution with additional DI water did nothing productive.

Then it hit me. We encountered a similar problem this past semester while we were trying to hydroborate octene in the undergraduate organic labs (see: J. Chem. Ed. 1990, 67, 975-976). Kabalka’s solution to the mono-phasic cloudiness? Saturate the reaction mixture with K2CO3. I thought it was one of the coolest tricks I’ve ever seen in an organic lab (and I’ve seen Grignards go in wet ether). Sure enough, the technique worked well in my case. The cloudy, colorless solution transformed into a clear, bilayer with a tinted-yellow aqueous layer and a clear, colorless organic layer.

A word of caution! Be careful using this technique with base-sensitive reactions! Remember that while pKa of carbonic acid is ~6.5, H2CO3 dissociates to CO2 and H2O, and the pKa of water is 15.6.

By May 30, 2008 6 comments synthetic chemistry

A Proverbial Fork in the Road

 

I hate knocking on my boss’s door. I hate it even more when I have to beg for money so I can buy a reagent/reactant. Fortunately for him, I’ve been good though in my years as a graduate student (relative to other colleagues). Why buy the acid chloride when we have 3 L of SOCl2 and a kilo of the carboxylic acid? Similarly, why pay $200/night for a hotel room on the Strip in Vegas when we can pay $75.95 on a side street? I call my actions “pennywise”; my wife calls them “cheap.”

 

The reality of research, especially for a fledgling group, is the almighty dollar. All of the countless columns, long hours and the associated b.s. yields more breakthroughs and, with them, more papers. With more papers comes more exposure; with more exposure comes more money (i.e. for the University, unless you know a damn good IP attorney…à la Robert Holton). So, we work long ours, run numerous columns, attempt to cure cancer, etc., and at the end of the road, what’s left? Typically, a meeting with your boss where he says the following gem: “The American Cancer Society ranked our proposal 6th out of 47. So, I’m glad about that. But they’re only funding the top 5 projects.”

As chemists, we perpetually attempt to improve our standing by spending more hours in the lab, running more columns, washing more disposable test tubes, using other groups NMR time, etc. I’ll drag myself back to point by reiterating the old cliché, “Necessity is the mother of invention.” With respect to our research group, as the money tree becomes less fruitful, I’ve been forced to think outside the box and rely on other methods besides picking up a Sigma-Aldrich catalog. “I’m a synthetic chemist,” I tell myself, “I can make crystal meth in my bathtub if I feel so inclined.” The overall message is pretty clear: why buy it if you can make it?

Most synthesis geeks, are probably familiar with Rochester’s Not Voodoo website—a resource promising to demystify the magic that is organic synthesis. Out of all of the pages, I’m a huge fan of, “Buy it or Make it Yourself.” On this page, scientists are encouraged to vote over whether you’d make LDA or buy it, for example. While most of these reagents are no-brainers to a synthetic chemist with a few years under his or her belt, what about the borderline reagents? Sure, you can buy 9-BBN, or you can make it from borane and 1,5-cyclooctadiene (if your technique is good enough). Are you confident enough to handle as expensive as a task of making Wilkinson’s catalyst, or is it more advantageous to buy it? Would you really derivatize Hoveyda/Grubbs-II or contract Strem to make the water-soluble version?

Though chemists can argue over whether you should buy or make a reagent, I’m surprised at how many of my colleagues favor the catalog to the benchtop. It’s refreshing to open up a brand new bottle of 6-methoxytetralone. But, at what point do you suck it up, make the damn synthon, and save your group $200? My philosophy is simple. While I’m in grad school, learning new techniques anyhow, why not make a reactant if I can?

 

P.S. My previous readers love to play the game “which one doesn’t belong.” Good luck with this one:

Yamaguchi, Lester, Corey, Keck, Nicolaou, Buchholz

 

P.P.S. There’s actually 2 that don’t belong.

By May 20, 2008 5 comments synthetic chemistry