Spicing things up with Cyanogen Bromide…

Li, Zhou; Gevorgyan, Vladimir Double Duty for Cyanogen Bromide in a Cascade Synthesis of Cyanoepoxides Angew. Chem. Int. Edn. Early View Feb 21 2011

So I’m back (again). Sorry this one took me a while (way to long in my opinion). With all the excitement I’ve been having over the past couple of weeks, I barely even have time to sleep, let alone review. My paper to Organic Letters should be out by early next week in the ASAPs. We had a bit of an issue with the proofing but other than that things went swimmingly. My project with Dr. Leadbeater has already been submitted to Catalyst Communications so I’ll keep you updated on the progress of that. Our OPRD has made it past the attrition stage and is currently being reviewed. I really hope that works out too so that by the end of the month I will have gone from 1 to 4 publications :D. I have already started the collaborative project with Professor Tilley and Dr. Leadbeater in addition to picking up two more project Dr. Leadbeater is interested in. However, we’ve been having some…technical difficulties with our machines lately which has really slowed down the chemistry and forcing us to play mechanic. In the meantime, I have been keeping up with the lit and this one really caught my eye mostly cause its, as usual, very weird, slightly deadly, involves a strained moiety and just plain cool!
So the article starts out with a review of cyanogen bromide (BrCN) and its use in as a synthetic tool. Surprisingly, it hasn’t been used all that much. That may be due, in part, to the fact that it’s a somewhat dangerous reagent to use. Its moisture sensitive, highly volatile and can be absorbed cutaneously or via inhalation. Worse, it is an acute toxin that can lead to death even at an exposure of 25 mg per kg of body weight. But wait, there’s more! Trying to dispose of the stuff requires NaOH and forms cyanide in the process. Moreover, it has a tendency to explode when being disposed of as the reaction is exothermic. So, if I found one major problem with this article is its impracticality. That being said the chemistry is very well done…so let’s get on to it!

Gevorgyan’s group was doing some amazing work in 2008 regarding a somewhat similar reaction to this work. He took haloalkynes and reacted them with enolates. What he got out was quite surprising. He obtained not the expected a-bromoketone, but instead an alkynyl epoxide. What he deemed a dual cascade reaction is simple a one-pot synthesis going through the mechanism seen below

Using this work as a springboard, they believed that cyanogen bromide should do essentially the same thing. They used isobutyrophenone as a screening reagent and NaHMDS as a base to get the whole thing started. They found that they got pretty much what they expected the first run through. Not surprising considering their results from the alkyne project. It was quite fast as the whole reaction was over in only 20 minutes (as compared to the 1 hour for the alkyne reaction)! They really didn’t do much in the way of optimizing other than playing with the solvent and the base. They found the optimal solvent to be DMF and LiHMDS to be a slightly more ideal base (TEA and Cs2CO3 gave no reaction). They quickly switched over to substrate testing and they certainly did a thorough job there. They seemed to have a general trend, they needed to be disubstituted (at the alpha position) aryl ketones.

I think that’s more for simplicity sake than anything (only one acidic proton and no chance for some sort of isomerization). They tried all sorts of aryl moieties (including pyridine and various substituents on benzene). And here is the kicker. That’s it. No application, no nothing. Just pure chemistry. And it was well written and straight to the point! Well, I hope you enjoyed this one as much as I did. I plan on getting another review up soon, since things (hopefully) should get less crazy in the coming days. Ckellz…Signing off…

New UConn Publication

Congratulation to the Fenteany group! They recently published in Synlett regarding a methodology for the preparation of oxazolidinone and tosyl amines using simple tertiary amines to catalyze the reaction! Check it out:


When life is good…

So those who must not be named are actually cooperating for once. Professor Tilley and I just sent the revisions to our manuscript back to Organic Letters and they were immediately accepted. As for the timetable for publication, next week we will get the proofs back for our manuscript and I will have to literally go word by word and make sure the publishers formatted the document correctly. I can’t believe it’s finally done! I’m very excited to see my name up in the ASAPs and I’ll be sure to post all the information here in the pubs section. I’m also working on some other things with Professor Tilley and a possible collaboration with Professor Leadbeater so stay tuned on new from that lead. So even more good news: my second article, the one that got rejected from Organic and Bimolecular Chemistry has been resubmitted to another journal, Organic Process Research and Development. Hopefully, I will know by the end of the month on the result of that. I’d be pretty happy with two ACS publications in less than a month :P. Now for the kicker. I just finished a project!!! It took roughly about a month of hard work but we will be submitting it to Catalyst Communications either tomorrow or Monday. Again, I’ll be sure to keep you updated on that as well. So now comes the hard part: new projects. I think that’s probably the hardest aspect of any graduate student’s career mostly because of my discussion in an earlier post. Plus you feel a sense of complacence because you are kind of owning science (or at least you think so because you defeated the “evil” reviewers and editors of the journal you have submitted to). But the issue is, you need to be a factory of novel and interesting ideas. Not only that, but you have to step outside your comfort zone and trying experiments whose results are unknown (and most likely filled with failure). But, since you know that the only way to escape the clutches of grad school in a reasonable amount of time is to publish publish publish, you need to constantly be motivated. So, that’s the point I’m at right now. I’m excited to go ahead and pick up a few projects, especially with all the new toys in the lab :P.
However, now that I finally have some (and by that I mean the two to three hours at night before I pass out) time, I’d like to reserve just a little commentary on a discussion I was having with a fellow graduate student tonight. This particular student is a 5th year and, since money is tight with his PI, he is TAing for two organic labs, one of which I am also TAing for. Now I’m not going to rant about my students (I’m sure it’s a pastime ubiquitous throughout the graduate student community.) In fact, so far all the classes I’ve taught ( a grand total of three at uconn and one a semester each year at Stonehill from sophomore year on) are generally really sweet and hard workers. However, they are the exception to the rule in my opinion. The majority of today’s students don’t have a good work ethic….or more accurately, they lack one at all. Maybe it is that I am very much invested in chemistry and science itself, but it seems to me with each passing year students get worse and worse while rules at the high school and even college level get more and more lax to accommodate them. And this grad student and I aren’t the only ones that think so. A story was recently released regarding a teacher, who ironically has a blog, posted about the poor quality of her students. It confirmed many of my observations and I can conclude this is a larger phenomenon than I thought. So I think American students really need to step up their game when it comes to academics. I know our culture today no longer stresses academics and that makes me sad. I feel that, if we are to continue on this path, we will be buried by the advancement of other nations. We need to be the leaders of technology and science and the only way to do that is to have a well-educated, interested student base! Well, that’s enough ranting for one night. I promise the next post will be a review. I’ve seen a couple of articles that really impressed me!…Ckellz…Signing Off…

Benzyne Makes Life More Fun!

Łączkowski, K.; Penã, D.; Escudero, S.; Pérez, D.; Guitián, E.; García, D.; Agustín Cobas Highly Selective Insertion of Arynes into a C(sp)-O(sp3) σ Bond Org. Lett. ASAP February 3, 2011

So I’m back. Sorry I’ve hadn’t posted in over a week. Shame on me. But if you want you can blame the chemistry gods for smiling on me. My reactions are [finally] working and I should have my current project completed by the end of next week. Moreover, the paper regarding my undergraduate research got accepted…TO ORGANIC LETTERS! Needless to say, I am pleased. I’m currently working on the revisions for that as well as a few other projects. Not to mention, our group just got the Vapourtec R2+, an amazing new toy! Check out the announcement here. This device is possibly the most badass lab apparatus I have or will ever used. It is like our old Uniqsis Flowsyn on a triple overdose of anabolic steroids. You can pretty much program in reactions and it does the rest (and even sorts them via an automated collection device). It…OWNS. Anyway…on to the chemistry…
I can’t think of one molecule I love more than benzyne. I’ve already given a talk and written a paper on it but I still find myself in awe that it actually exists. I mean think about it, you are adding a triple bond in a very stable aromatic system. I know the p-orbitals end up resting perpendicular to the aromatic pi system and it has significant diradical character but still. It just looks unhappy and the fact that it’s so easy to form is remarkable. Moreover, its reactions are somewhat irregular. So if you put it all together (odd reactions, weird probably strained molecule, and a more physical organic chemistry feel to the research), you’ve basically put all my favorite aspects of organic chemistry . Not to mention the most common way to make benzyne (the Kobayashi protocol) involves a trimethylsilyl (TMS) group and uses fluoride-induced silyl elimination…This has Ckellz written all over it. So anytime I see the words aryne or benzyne in the title of an article, I immediately give it a once over. I was especially interested in this one because it was written by one of the most renowned benzyne groups aside from the Larock group.
The Penã/Guitián/Pérez has had a long standing interest in aryne chemistry. For a while, it seemed like it was a back and forth battle between their group and the Larock group. Fortunately for Penã and coworkers, Larock will be retiring soon so they will have the battlefield to themselves. Before I get started on the review, I just wanted to show you the typical (and cool!) way that benzyne is made from the commercially available o-trimethylsilylphenyl triflate.

It’s a pretty nifty reaction whose driving force relies on the fact that Si-F bonds are quite strong, OTf is a excellent leaving group, and the product of fluoride-induced silyl elimination, trimethylsilylfluoride, is a gas at room temperature. That particular reaction was discovered by the Kobayashi group in the late 1980s but really did not receive a lot of attention at the time. It wasn’t until the past decade or so did it become truly popular. Now it has become the springboard of aryne chemistry because it can reliably generate the aryne under relatively mild conditions.
Much has been going on with benzyne in terms of new reactions. The general theme is ability to use non-conventional reagents (as opposed to the normal dipolar molecules or to Diels Alder candidates) such as C-N or CO-Cl bonds to obtain disubstituted phenyl rings with the substituents in an ortho relationship. The utility of this sort of reaction is clear even to an undergrad straight out of Organic II: you can defy the normal directing effects of various substituents, simultaneously put two groups on a phenyl ring (reducing the number of steps in your synthesis), and finally you avoid the use of expensive metal catalysts. I’d say that sort of method is pretty impactful, wouldn’t you?
Following an observation by Stiles in 1962, Penã and coworkers investigated the possibility of using alkynyl ethers as a new non-conventional reagent to react with benzyne. Surprisingly, there are only a few of benzyne (or any aryne) inserting into a C-O bond. Therefore the authors set out to see if it was possible in other systems besides those reported. They chose the alkynyl ether system for two reasons. First, it would incorporate a, what I would call, protected phenol into the aromatic system. Second it would introduce an alkyne as a substituent on the ring. Currently, the only real viable way of doing the latter is performing a Sonogashira using expensive catalysts and fancy ligands.


Using unsubstituted benzyne and a model substrate, namely ethoxyacetylene (side note: this must be a pain to work with, since it boils so low and probably polymerizes if it is not in a solvent), they screened reactivity. It doesn’t seem like they did much in the way of optimization most likely due to the fact that their test reactions worked on the first try in 51% yield. That’s not terrible but also not amazing considering how that the benzyne precursor is somewhat expensive. The conditions, though, were extremely mild: Just dump the stuff together, let it sit for twelve hours and you have your product. Typical of benzyne papers, the author tested substituent effects on the aryne. The tested only a few substituents on the aryne such as -OMe, CH3, and polyaromatic or polycyclic systems (most likely because the benzyne precursors are somewhat difficult to prepare). Yields were reasonable but regioselectivity was substrate specific. The methoxy derivative gave only one regioisomers while the tolyl gave a one to one mixture of regioisomers. Interestingly they did not alter the ether what so ever. To me, that means it may only work with that particular ether but it is nonetheless interesting because you can do reactions with either the alkyne or the ethearl moiety to customize your system. The comparison study that they did next is what really sold me on this article. It (see below) wasn’t intended to do that but rather it was to prove the identity of one of the compounds they had prepared.

As you can see from the synthesis of this ortho-methoxy derivative, the authors can do what should take four steps in one. And in substantially better yield (54% using benzyne chemistry vs. 37% by employing a Sonogashira). Now here is where the paper really began to shine. The sought out to develop a mechanistic rationale for the reactivity that they were observing. I won’t bore you with the calculation details (which actually showed me the power of transition state modeling and the meticulous nature of the authors) but I will present to you what they believe is the likely mechanism. To me it’s a little odd but it does make sense with considering their observations :

Overall, a pretty good paper by Penã and coworkers. I truly look forward to more benzyne in the near future!

My First Publication on ChemSpider Synthetic Pages!

Check it out, a way to make tropylium tetrafluoroborate!

ChemSpider-Synthetic Pages and Links

So you may have noticed I’ve been adding quite a few links to the site. I can’t believe how many good chemistry site their are out there. And I don’t just mean blogs (but there are quite a few of those that I’ve been reading). I mean actual useful tools for an organic chemist. For example, I’m a huge fan of the synthetic pages of ChemSpider. If you don’t know what ChemSpider is, it is a free database of chemistry sponsored by the RCS. The orginal project was simply a strucuture database which would allow users to dump their data regardig a particular molecule they synthesized. They have acquired quite the collection and have a excellent method for retrieiving desired structures (similar to Scifinder or Reaxys, a structure search or a text search). And it is all 100% completely free to the user. I don’t mean like your “university pays a subscription” free. I mean I can go on any computer anyway with internet capabilities (so basically not Egypt who has the power to turn the internet off and on at will) and search. No strings attached. The only limits to the database is its based on user submissions. So only compounds that people submit will appear and if no one likes it, the database is gone be quite limited. This frankly was not the case as ChemSpider is extremely popular and has sumbission numbers in the millions. Recently, the RCS has started another similar project: the Synthetic Pages. Instead of indexing just compounds, the synthetic pages (which are still only in the beta stages) index reactions with the ultimate goal or finding procedures that work. As you can imagine, not every piece of literature is…lets say reliable. Some articles (and I have and will be reviewing some) are just crap and their procedures are either incomplete or inaccurate to the true yield/purity. CSSP hopes to assist in that problem by only publishing highly detailed, highly reproducable procedures. Think of it as a more modern Organic Syntheses. Users submit procedures that they have done (either ones that they have developed or those existing in the literature) that are accurate and reliable. The submission goes through a screening process much like a peer-review. Once that’s done, the article will then be uploaded to the database and indexed. The nice part is its very in tune with today’s generation. You can leave comments regarding uploaded procedures so as to confirm the procedure works, add an addition modification, or even refute an authors claim. And it’s not just limited to organic reactions. Inorganic and organometallic procedures can be submitted as well! Moreover, pages can be filled with multimedia, from spectral files to videos. You can even cite CSSP procedures in journals or publish them as a supplement to your supporting information (maybe in more detail). I found it quite useful and have even published one article already. So go visit CSSP! The other link I want to quickly highlight that is SO cool is Chem Reference Resolver (thanks to the Stoltz Group for finding this one and letting me know about it). I’ve called it chemistry reference finder in the links. Its basically a DOI search engine. You can put in a reference (even if you only have the journal, the year and the page) in any ACS or other chemical journal format and it will find it for you. Not only that it will take you direct to the site hosting the article! Try it out for yourself! Ckellz…Off to UConn…