I React With a Little Help From My Friends…

Accurso, A. A.; Cho, S.-H.; Amin, A.; Potapov, V. A.; Amosova, S. V.; Finn, M.G. Thia-, Aza-, and Selena[3.3.1]bicyclononane Dichlorides: Rates vs Internal Nucleophile in Anchimeric Assistance J. Org. Chem. ASAP May 5th, 2011

Another week in the lab, another round of owning chemistry. This week was quite good for me. Things with our collaboration with Dr. Fenteany’s lab have taken an unexpected (but very good!!!) turn. I cannot wait to finish that project and get it out there so I can tell/show you what I’m talking about. Not only is it a good conceptual project, but it also has been a learning experience for me and some of my labmates. I’ve had to do substantially more recrystallizations and columns than I have in the whole of my career as an undergrad. Moreover, I’ve gotten to do reactions I had never done before, like a Friedel-Crafts acylation! And in return, Fenteany’s group is way ahead of schedule on this project thanks to our help so it really has been beneficial to both groups. As for our work with Professor Tilley, we have most of the substrates at the final stage (only three more need some work) and then we can start writing up the manuscript! So my goal is to have at least two additional (if not more) Org. Lett. publications by the end of this year. And now that classes are finalllllllllllly done and I no longer have to teach, I will have a lot of time to investigate some of my own ideas as well. So overall, life in the Leadbeater lab is good. And I’m happy to say New Reactions has been getting quite popular. I’ve been averaging 100 hits a day and I am now linked on many other famous chemistry blogs. So thank you very much for visiting and reading!!! And now, its chemistry time!

So as you all probably know, I love carbocations. I just find them fascinating and, thus far in organic chemistry, there are few examples where they can readily be controlled. One of the few times they can be is when you have a local (internal) nucleophile which can participate in anchimeric assistance (another term I am intimately familiar with :P). It’s no surprise then that this article grabbed my attention, despite its lack of methodology nature. It’s pretty basic chemistry, but that’s really the kind I like mostly because that is where the best discoveries occur.

The article starts out by jumping right into the chemistry. It talks about how, back in the late 60s, Corey, Weil, and Lautenschlaeger all investigated the synthesis of 9-thiabicyclo[3.3.1]dichloride by the addition of SCl2 to 1,5 cyclooctadiene (COD). Apparently, it adds just as a traditional electrophile would (think Br2 addition to double bonds) but since there are two olefin moieties, it reacts twice. Interestingly, this reactions fails to work with smaller cyclic dienes (e.g. 1,4 cyclohexadiene) unless performed at very low concentrations (likely due to competing polymerization) but works perfectly with COD. Now here is why the authors were interested in this molecule (which they colloquially dubbed a WCL electrophile): many early workers noted that this halogenated heterocycle could be easily substituted. However, no one followed up on it (i.e. scope, kinetics etc.). It was more of a “hey we can synthesize these!” sort of deal. The goals for the authors were then as follows: First, use it as a substrate to test anchimeric assistance (which should be at its maximum due the proper and restricted conformation of WCL electrophiles; Second, develop this substrate as a “click” substrate where it can be easily added to a larger molecule like that of azides to alkynes; Third, continue their investigation into the reactivity and kinetics of WCL electrophiles.

Not wanting to limit their scope, the authors prepared several derivatives of 9-thiabicyclo[3.3.1]dichloride. They prepared fresh SeX2 by combining Br2 or SO2Cl2 with elemental selenium (aka awesome!) and reacted it with 1,5 COD in a similar manner to the analogous sulfur reaction. To prepare their nitrogen substrates, they chose a slightly more elaborate route. First they epoxidized COD to give the cis-diepoxide via a rhenium catalyst and hydrogen peroxide. They followed it up with a nitrogen-meditated double ring opening reaction to give the diol. The hydroxyl groups were then converted to chlorides either via MsCl and DMAP or thionyl chloride.

The next step was to explore the reactivity of their newly constructed WCL electrophiles. To perform kinetic studies, they used benzyl amine as the incoming nucleophile and observed the conversion by NMR in acetonitrile. Not surprisingly, the order of reactivity turned out to be: Se > N-Alkyl > S > N-Alkynyl > N-Pheny. What I found funny was the results of when they utilized the selenium substrate. Not only did it react so fast it was not observable, but the product could not be isolated as it was unstable. It decomposed readily on silica and on storage at low temperatures! By altering the solvent to THF, they were able to slow down the reactions substantially. This was due to the fact that THF is many times less polar than MeCN. Now there was the first tip off that this reaction’s rate-determining step was first-order (or carbocation-like/SN1-like). If the reaction was SN2 like, we should have seen a slight rate acceleration by switching to a less polar solvent. Since they were able to slow down the rate, they were able to determine the kinetics of the selenium derivative. It turns out that, in THF, the order of the rates is relatively the same (with the exception that N-alkynyl > S).

The authors then checked into the reactivity of these WCL electrophiles. They tested five nucleophiles of various strength with the benzyl amine derivative as the model WCL electrophile (chosen as its easily observed by UV-Vis). While the rates were greatly accelerated due to the aqueous nature required for these reactions, the nature of the nucleophile had little to no effect on the rate of the reaction. Hence the authors concluded that the mechanisms must be proceeding through a carbocationic intermediate. They propose the following as the mechanism:

Therefore the authors were able to show quantitatively, as the first documented case, the relative donating abilities of Se, S, and N in providing anchimeric assistance. I always love these sorts of articles. They are always to the point and very definitive. I mean how can you argue with rate data? Congratulations to Finn and coworkers on an excellent and thorough job!


  1. It is just a bicyclo version of a mustard gas “yperite”. I wonder if anyone has tried to test these dichloro compounds as a anti-cancer agent. Or as a weapon.

  2. I’d be curious as well, I think they would be a pretty decent weapon system though I think unlike mustard gas these wouldn’t fair as well cause I assume they are liquids. As anti-cancer compounds…that’d at least be interesting. Small molecules tend to do unexpected things, I mean look at dichloroacetate…

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