Bicyclobutane FTW!

So if you’ve been following me for a while you know that I recently published an article in organic letters regarding the synthesis of a trifluoromethyl derivative of bicyclobutane. Apparently the ACS liked it enough to feature it on its “Noteworthy Chemistry” :

“Noteworthy Chemistry is a weekly feature produced by the American Chemical Society that collects and summarizes innovative ideas from the larger body of chemical literature. Originally designed as the “Heart Cut” department in the ACS publication CHEMTECH, “Noteworthy Chemistry” has become a valuable stand-alone resource for today’s informed chemistry professional.”

So go check it out! Heres the link!

Won’t you be my neighbor?


Sakthivel, K.; Srinivasan, K. Eur. J. Org. Chem. Early View Apr. 11th 2011


I’m back again, after yet another week of chemistry ownage. Our collaborative projects are fairing well; I can’t wait to tell you more about the details of those projects (all in due course :P). But me and those who must not be named (knock on wood) have been getting along lately. My own research has hit some stumbling blocks, but nothing that can’t be overcome in time. Plus I already have three articles to my name so I’m not that worried. I have to rehash an old issue namely old procedures versus new ones. So I attempted a Tsuji-Trost reaction to access some interesting structures based on an Organic Letters article from 2007. Being the naive chemist that I am, I put my trust in the article completely and attempted to follow their procedure to the letter (which was hard because it was somewhat scarce in detail). Needless to say I was most displeased with the result. Not only did I waste a good amount of time, but I later realized they clearly did not know what they were talking about. Whatever they did, they definitely did not use PdCl2 as their palladium source. I honestly don’t know what they did (or if they did it at all) but I couldn’t replicate their results. But I’m not all that surprised at all. On the flip side, I’ve been doing old procedure that just plain work. No tricks, just followed it (and the thing I liked about this procedure is they even told you what color the solution would turn etc.). There is just something that has been lost in the current literature, probably because chemistry has become too business-like and competitive. But let’s get on with the, at least interesting, chemistry for this week!

Until somewhat recently, I really had not been a fan of EJOC. Most of the stuff coming out really didn’t interest me and none of the names of the authors were all too familar. However, the journal has really grown on me in the past year or so. I don’t know why, but I keep finding interesting articles (like this one) in it on a regular basis. Maybe it is getting a better name for itself or maybe my tastes in reactions have changed, I don’t really know. But regardless, this article really caught my eye. I like simplicity in chemistry. The more complicated it is, the more impractical it becomes. Hence why, while I respect it, I’m not a big fan of most total syntheses. They are great achievements in chemistry, don’t get me wrong, but the majority are of little importance to the greater chemical community. This article, however, is quite practical in its approach.



The article starts out by detailing how important neighboring group participation (NGP), a topic I am quite familiar with :P, is a well-documented phenomenon in organic chemistry. However, it’s less commonly employed as a tool for oxidation. Specifically, oxidation of alkynes using NGP has been quite popular lately. Riding on this trend, Srinivasan’s group has been focusing on the use of the formyl group as a tool for NGP-mediated oxidation. The target was the synthesis of 1,2 diketones, which normal are quite difficult to synthesize and usually require the use of a transition metal. However, this article results more from an accident than from a desire to “go green”. Apparently Srinivasan’s group was trying to replicate some work done by R. C. Larock (see above), but used a “wet” solvent instead of an alcohol as a nucleophile. Their results were in stark contrast to Larock’s as they obtained the tricarbonyl compound instead of the predicted (and probably desired) isochromenol. Fortunately, following their nose ultimately lead them to a new reaction! Not only that but a reaction that is far superior to any other iodine-mediated alkyne oxidation (I know, somewhat specific but still cool!).



Interestingly, their simple reaction conditions did not need to be optimized; they simply just went on to test substrates. And the scope was relatively wide; all sorts of activated and deactivated arenes could be used and even alkyl groups proved amendable to their reaction.They even did a dialkynyl system and formed a hexacarbonyl compound. Moreover, they suggested a pretty legitimate mechanism (which was developed based on deuterium-monitoring studies and investigations with ester and ketone substrates).



They found that an ester was unamendable to formation of the tricarbonyl compounds (they actually formed the isochromenes instead) whereas a ketone also formed tricarbonyl compounds in a similar manner as with the aldehyde substrates. This makes sense since the ester can kick off an alkoxide as a leaving group instead proceeding with the desired mechanism.



Overall, a good read and well presented article by the Srinivasan group. I look forward to seeing more by them and more excellent articles in EJOC. Until next time…Ckellz…Signing off…

A Friedel-Crafts Goes Awry…


Dolbier, W.R. Jr.; Cornett, E.; Martinez, H.; Xu, W. Friedel-Crafts Reactions of 2,2-Difluorocyclopropanecarbonyl Chloride: Unexpected Ring-Opening Chemistry J. Org. Chem. ASAP April 1st, 2011


Another long week in the lab. Research continues (knock on wood) to go quite well. Me and my lab-mates certainly have enough chemistry to get done to keep us busy. The odd thing to me about grad school is the lack of “school”. I really don’t feel the same sort of pressure to perform at 110% in class. I mean don’t get me wrong I sure as hell still try and still do the assignments early, but its different (and clearly hard to explain). I treat grad school more like I would a transitional job (where I’m there pretty much to pump out good research) rather than an extension of my undergraduate career. Hence why I work 12+ hour days because its my job to make chemistry (and make a lot of it ) happen. Because I’m always there late, I’ve made a friend in one of the other groups (a 5th year doing some pretty cool organic synthesis). We hope to do a collaboratory project (adding to my ever-long list of things to do) at some point on a project he has been developing. In other news Dr. Ronald Breslow paid UConn a visit as part of our R.T. Major symposium. I had met Breslow before when I was down at Columbia so I had an idea of what he did and the kind of guy he is. Nonetheless, I was very impressed with his talks, in particular, one regarding the origins of why natural amino acids are (L) and natural sugars are (D). I also read up on it following the talk in a recent article published by his group. While one can never really “prove” with absolute certainty that the process proposed by Breslow is truly what lead to all amino acids (natural) being (L) it does at least give us a theory to possibly explaining it. But enough about all that, you’re here for the chemistry aren’t ya? So let’s talk chemistry!

So, this article also has a bit of irony to it (though not the element). My wonderful girlfriend recently got me a book I’ve been dying to have: A Guide to Fluorine NMR for Organic Chemists. It is by far one of the best organic chemistry books I’ve gotten besides the holy bible of named reactions, Strategic Applications of the Named Reactions in Organic Synthesis. The book only has one author and he has somewhat of an unusual last name. So, unknowingly, when I was scrolling through the ASAPs, I stumbled onto this gem of an article in JOC. Low and behold, it was written by the same chemist that wrote my F-NMR book (therefore I have to review it right?)!



The article starts out by outlining how the synthesis of 2,2, difluorocyclopropyl ketones has been realized by the discovery of a difluorocarbene source, trimethylsilyl fluorosulfonyldifluoroacetate (TFDA). The Dolbier group pretty much has been pioneering this reagent and exploring its applications/reactivity. I wouldn’t say it’s terribly well-known simply because there often isn’t a call for geminal difluorocyclopropanes. However, Dolbier (who is the editor of J. Fluorine Chem. which I found pretty awesome) has been exploring the reactions of 2,2, difluorocyclopropyl ketones and found some interesting reactions.

One of the main drawbacks to his sort of carbene chemistry is that aryl alpha, beta unsaturated ketones make poor coupling partners because of competitive polymerization. Hence, they wanted to see if you could reach these aryl substrates via standard sort of Friedel -Crafts chemistry. Based on the fact that dichlorocycloproylcarbonyl chlorides had been utilized to this effect with no adverse effect to the cyclopropyl moiety, it stood to reason that the fluorine analog should react the same (if not better due to the inert nature of organofluoro compounds). But, as usual, fluorine doesn’t play by the rules…

Instead of giving the normal, unrearranged acylation product, it gave the straight chain compound via a ring-opening reaction. Not only that, it gave a mixed halogen ketone which is until this paper would be near impossible to synthesize. Since these are new compounds, their synthetic potential has yet to be explored so the authors really couldn’t give too much in the way of an application. But they certainly did decide to determine the scope of the reaction. The reaction seemed to work best with alkyl benzene derivatives (toluene, ethylbenzene, p-xylene). Moreover they were sensitive to sterics: the higher the substitution on the benzene ring the slower the reaction (discovered via a competition reaction between toluene and p-xylene).



When switching to what I would call more activated aromatic systems (anisole, thiophene) the preferred product ended up being the “normal” Friedel-Crafts product. Even more unusual was that if 5 equivalents of the starting arene were used, a reversal in the product was seen (favoring the cyclopropyl-containing product). No obvious explanation could be give as to why the difluorocyclopropyl system behaved so much differently than the dichlorocycloproyl system nor could they explain the trends seen in their substrates. Hence the authors turned to computation. The results were astounding. First, they noted that alpha-fluorine substituents are known to stabilize carbocations substantially as compared to chlorines. I found that quite surprising due to the fact that fluorine is such a strongly destabilizing substituent in all other cases. My guess is that, since it is in the same row as carbon, that it possesses the proper orbital overlap to participate in stabilization as compared to the orbital mismatch seen with chlorine. The authors also note that geminal difluorocycloprpanes are under a substantial degree of strain as compared to their fluorine analogs (which I assume relates to inductive and hybridization effects). Therefore they proposed the following reaction intermediate:



They argue that this intermediate explains the reactivity they were observing in that the chloride anion competes with acylation of the arene. Since the more activated arenes react faster, it’s no surprise that these give more of the non-ring-opened product as they can actually compete with the chloride ion. Likewise, having additional amounts of the arene (5 equiv) leads to out competition of the chloride ion from a statistical standpoint (and why it never fully gives 100 percent of the unrearragned product).



What I really loved about this article is the thoroughness. Not only did they back up their hypotheses computationally, they were sure to do several control study to ensure that their proposed mechanism wasn’t an artifact of decomposition of the unrearranged product. First, they extended the reaction times and noted no increase in the quantity of rearranged product. Also they took the unrearranged product and treated it with AlCl3 under the normal reaction conditions and noted no reactions. To further verify their findings, they then compared the Friedel-Crafts reaction to other reactions done by the group.



One such reaction, the solvolysis of 2,2-difluorocyclopropyl-methyl tosylate (the nostalgia to my undergrad work is ever present :P) leads to the ring opening reaction to produce O-alkylation by the solvent or by the tosyl anion. However, this also proceeds through the stabilized difluorocarbocation. Moreover, a drastic difference in reactivity is observed when the mechanism becomes more SN2 like. Dolbier’s group treated these same sorts of difluorocyclopropyl ketones with HBR and observed the following:



The nucleophile actually ends up substituting the “less” hindered and more reactive CH2 group over the CF2 group. Therefore, if the reaction is truly more SN2 like (which its not) we would expect to see more substitution at the CH2 group. Since we see a more analogous reactivity to the solvolysis studies, one must conclude that the difluorocarbocation is the reaction intermediate!

Overall, this is one of the best papers I’ve read in some time and look forward to hearing more about the crazy fluorine chemistry done by Dolbier’s group. Congrats!!! Ckellz…Signing off…

Third Publication!

So its FINALLY official. I got my third publication today, and its up on the ASAPs for Organic Process Research and Development, an ACS journal (my favorite kind, followed closely by Wiley). Check it out here. Basically what me and my labmates did in this article is we modified our Uniqsis Flowsyn flow reactor so that we could introduce gas into the reactor coil. We initially tested it with just plain old air, but then we tried to come up with an application. Since hydrogenations had been done (and there are commercial, specialized reactor for them) we checked to see if anyone had done a straight out carbonylation in flow. While carbonylations yielding amides had been done, no carbonylation to form esters had yet been done. Therefore we used this to determine the feasibility of doing carbonylations this way in flow. Turns out it works really well with little problems in the area of clogging. So, while it may not be earth-shattering chemistry, it does allow for a quick (10-20 minutes) way to convert aryl iodides into esters!

Fun with Fluorinated Furans!



Li, Y.; Wheeler, K.A.; Dembinski, R. Electrophilic Cyclizations of 2-Fluoroalk-3-yn-1-ones: Room-Temperature Synthesis of Diversely 2,5-Disubstituted 3,4-Fluorohalofurans Euro. J. Org. Chem. Early View Apr. 8th 2011


So the semester is finally winding down, and I’ve had a bit more time (like a few hours per week :P) to do some research. Things are still progressing well in our lab. In fact, just this week I put the finishing touches of the group’s new website. Check it out! Took me a while to learn all the proper coding but I’d say it came out fairly well. In other news I did not, unfortunately, get the NSF fellowship grant. It basically was the same story as last year. I got one really bad review (which it didn’t even seem like the reviewer even read my application) and it prevented me from getting it. You can tell there is a serious bias in that competition (if you look there are pages upon pages from places like Harvard, MIT, CIT etc. but little to none from other institutions). And I’m not saying people from those schools have bad ideas at all. I’m sure their applications are quite strong. What I believe occurs is that the name of their institution gives them an unfair advantage as the reviewer will give them more leeway/more of a in-depth review, then someone from a non-ivy institution. But, unfortunately, that is how the world works. Regardless, I plan on applying for future scholarships and fellowships such as the ACS Divisional Fellowship in due course. In terms of my own research, it goes well! I’m still at the making substrates stage in my multiple projects. But that just means I get to do more and more reactions! Also this week, I got to view the OPRD proofs, which look quite amazing! I’ll be sure to link you to the article as soon as it’s on the ASAPs for OPRD. And now, on with teh chemistry!
So I found this one early yesterday morning, after some of the Wiley journals came back online. I guess they were down for maintenance yesterday, but this article was well worth the wait. So as I mentioned earlier, I love the use of the trifluoromethyl group in organic synthesis mostly cause of its unique properties and medicinal applications. But as a whole, I find organofluorine chemistry fascinating, because it defies most of the normal rules of organic chemistry. Moreover, I love cascade reactions as it’s like the two for one deal of organic chemistry. So it’s no surprise this article attracted my attention.
So the article begins by outlining how furans are common moieties in drugs and natural products as well as in polymer science. However, preparing multi-substituted furans can be a pain. While they do your standard EAS sort of chemistry, adding substituents at the 3/4 (or beta) position in the ring can be difficult. Moreover, it’s hard to substitute all four carbons with unique substituents in good yield. These furans can be especially useful if they bare a halogen (as they can be stitched on to larger systems via organometallic chemistry i.e. via Suzuki coupling etc.). But what if you could not only prepare highly substituted, halogenated furans but also fluorinate them as well? Not only would you have a component of, let’s say, a natural product but you would also be able to prepare a more lipophilic and chemically resistant molecule as well! So that was the goal of this paper.



In a previous report, the Dembinski group has already developed a method for the preparation of tri-substituted furans. Seen above, they would take alkynyl silyl-enol ethers and transform them, via Selectfluor , into alpha fluoro-alkynyl-ketones. Treatment of these systems with a gold (I) catalyst and a silver co-catalyst facilitated cyclization to the tri-substituted furan. In fact, since such ketones are unstable species, they made this furan procedure a one-pot method. While neither this paper nor their previous publication gave a mechanism for this transformation, I’ve come up with my own (which may or may not be correct):



Now for this paper, they wanted to retain the ability to put a fourth substituent on furan. What better way then to put what is essentially a placeholder at that fourth position? But what place holder would be best? Well, as I mentioned early, Suzuki coupling reactions are excellent for stitching two molecules together and the best sort of halide for oxidative addition in this type of reaction is iodide.



Unfortunately incorporation of iodine wasn’t simple. They first tried to use a “more green” metal-free method to induce cyclization by just using NIS or N-iodosuccinimide a I+ source. attempting iodocyclization (which has been pretty popular lately and I even reviewed an article a while back). While the desired reaction did occur, yields were unacceptably low even after extended reaction times. The authors rationalized that the fluorine substituent was simply decreasing the nucleophilicity of the oxygen of the carbonyl, preventing cyclization in addition to decreasing the reactivity of the alkyne to electrophiles. Therefore they went back to the drawing board. If we consider the mechanism that I believe is in operation, the final step involve quenching the Au-C bond by protonlysis. However, if one intercepted that species with electrophilic iodine or I+, a C-I bond could be formed. Based on their previous work, they were essentially at the stage where all they had to do was combine their previous system with NIS to get their desired iodofluorofuran!
To further enhance their methodology, and improve yields, they tossed in a Lewis acid catalyst to magnify the electrophilicity of the iodide. Essentially, the Lewis acid (in their case Zn2+ from ZnBr2) would interact with the oxygen’s of the NIS causing further induction electron density from the iodine. Using this concept, they optimized their conditions and explored the scope which was reasonably wide. But they didn’t limit themselves to iodine. They also utilized NBS, or N-bromosuccinimide, to incorporate bromine at this position. What I think would have been really interesting (but outside the scope of this paper) would have been to use Selectfluor again, to get difluoro-substituted furans! Anyway, they ultimately showed the importance of their method by performing a Suzuki coupling to give the desired tetra-substituted furan



I must say I am really impressed in the level of depth of this article. It is one of the more thorough I’ve reviewed, and while it may not be as “impactful”, they really presented their story well, covering all bases. They even got a crystal structure to prove that they were indeed making their iodofluorofurans. Excellent work Dembinski and coworkers!!!

Alkynes of Irony…


Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. Iron-Catalyzed Synthesis of Functionalized 2H-Chromenes via Intramolecular Alkyne -Carbonyl Metathesis J. Org. Chem. ASAP March 18, 2011


So another week in the lab and things just keep getting better. My methodology is actually coming along quite nicely and I’ve been doing a few new reactions (my first Diels-Alder!) to begin preparing my substrate scope. My boss thinks it’s good enough for Angewandte Chemie so that kind of made my week. Also, I picked up a copy of the manual for our auto-column. I’m really not big on columns, I am more of a recrystallization and vacuum distillation sort of guy. But if I can get this thing up and running again, I’d be more than happy to start doing some more columns. I mean, don’t get me wrong, I do columns somewhat regularly, but if I can avoid them by another means, I will certainly go for that. As for the progress with my collaboration with Professor Tilley, that’s also going pretty well. Lastly, keep a look out in Org. Proc. Res. Dev. Our article has been accepted and should be published soon regarding some work I did last semester. And I should be hearing about that NSF anytime now…not that I’m worrying about it or anything :P…but let’s hit the lit!



So this article really grabbed my attention because of its stark similarity to some of the research I encountered when I was at Columbia. Prior to going down to NYC, I was given a good deal of literature that Dr. Dailbor Sames had published. One of the articles, detailing the research of one of the group’s best organic chemist Stefan Pastine, involved the formation of enantiopure chromenes using platinum-mediated C-H bond activation. The general idea was that the platinum (in their case, PtCl4) would coordinate to the alkyne making it electron-deficient (see below). It is electrophilic enough that EAS occurs to giving cyclization. After restoring the aromaticity and protonolysis of the platinum, the more favorable 6-endo product is formed. So when I saw this new method for forming chromenes using a much easier to work with and substantially less expensive catalyst (FeCl3) I had to take a peek.



So the article starts out by detailing how 2H-chromenes are important from both a biological standpoint and from an industrial perspective. They then discuss how these structures are currently constructed and they even refer to Pastine paper when mentioning Pt catalysis as a viable method. They point out, much the way I did, that using Pt or Au catalysts, while useful, is impractical due to their expensive and moisture-sensitive nature. So, as an alternative, they suggest alkyne-carbonyl metathesis would be of use in constructing these molecules. I had never really heard that term before but apparently it involves a 2+2 cycloaddition between the alkyne and the carbonyl group followed by a 2+2 cycloreversion to give a alpha, beta unsaturated carbonyl species (see below).



The authors then go into their desire to get this carbonyl-metathesis to occur under “environmentally-friendly” conditions and, since iron has been all the craze lately, they suggest that Lewis acidic iron complexes could be used for this purpose. Iron has the added bonus of being readily available and cheap. So to test their hypothesis, they decided to construct some propargylic ethers based on a salicylaldehyde core. They were pretty practical about it. They simply took salicylaldehyde, which is extremely cheap, and alkylated with propargyl bromide. They then took that compound and did a Sonogashira with an aryl halide to access a variety of substrates. If that didn’t work, they simply took the corresponding propargyl alcohol, treated it with PBr3 and then did a subsequent alkylation of salicylaldehyde. Using a phenyl substituted alkyne as their screening substrate, they ultimately found that FeCl3 was their optimal catalyst for this reaction and that the best solvent was in fact acetonitrile. Other solvents (which I would considered “non-coordinating”) such as DCE or toluene failed to give acceptable yields.



The authors really did do a good job of optimizing their reaction. Interestingly the iron (III) chloride had to be anhydrous or yields were diminished. Other Lewis acids, such as indium (III) chloride and aluminum (III) chloride either gave no product or very low yield. The only problem I had with their optimization was the fact that they didn’t really screen temperature (Okay okay, they did one room temperature run…but not in their optimized solvent!). They just assumed reflux was necessary. But I guess that’s just me being picky :P. Anyway, they went on to show that both the substituent off the alkyne and the substitution pattern of the salicylaldehyde moiety could be varied with little effect on the yield. The exception to that statement was when they attempted to but alkyl groups off the alkyne or leave it simply unsubstituted. While the alkyl compound did give acceptable yields, reaction times were a lot longer (3 times as long!). Moreover, the unsubstituted derivative failed to react completely! However, if you consider the mechanism, these results make sense:



The authors proposed that the iron is acting simply as a Lewis acid and coordinating to the oxygen. The alkyne then attacks to give a vinyl cation. That explains why the alkyl groups gave the authors such difficult while phenylated alkynes went without issue. That cation is then attacked by the carbonyl giving that oxetene-containing intermediate. The oxetene moiety then undergoes their desired cycloreversion to give the chromene. Congratulations to the Jana group for an excellent article and a job well done! That’s enough chemistry for tonight. I’ll be sure to update again soon! Ckellz…Signing off…

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