One Of These Halogens (Is Not Like The Other)

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John, J. P.; Colby, D. A. J. Org. Chem. ASAP October 13, 2011

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What’s one way to relax after a somewhat stressful week in lab? Some good ol’ fashion blogging! That and a bit of sleep, food, range time (Yes, I am in fact an avid shooter), and pumpkin picking. As promised, I plan on delivering more updates. So let’s start with lab. While this week was somewhat overwhelming for me, all in all, the deity of organic chemistry must have been smiling on me. We have once again resumed out collaboration with Dr. Tilley, and things are going exceeding well. We were finally able to isolate a few key compounds, which were necessary to continue the project. Isolating these compounds (sorry I can’t be more descriptive) is unbelievable difficult, but we were able to obtain about 4.5 grams of them each! We owe this to a little luck and using very pure reagents. We found out really quickly early on that the reaction is very sensitive to impurities. Hence, me and Mike spent a good deal of time purifying our starting materials as well as the reagents going into the mix.
Our other projects are also coming to fruition. Barring any unforeseen problems, our next paper should be submitted shortly (we are just tying up a few loose ends). We’ve had some mixed results with a continuous flow project we’ve been working on (a project that seems to have many highs and lows unfortunately). I’ve also begun thinking a bit about the future and I have a few projects in mind, one of which may be more synthetically driven (and by that I mean I would like to attempt small molecule synthesis, possibly using methods developed by our lab). I think Mike is also is looking into doing the same (though with a different target molecule in mind).
I really have gained some valuable skills in the past few months: becoming pro at columns, developing much more concise and elaborate synthetic skills, and enhancing my skills as a scientific writer. While grad school isn’t the most exciting job (and yes I do say it’s a job) on the planet, it sure as hell is fun, challenging, and at the end of the day, I really couldn’t envision myself doing anything else right now. As for non-research related events, I successfully presented a few syntheses of the Welwitindolinones alkaloids to my synthesis class (the Wood, Baran, and Garg syntheses). I seriously love presenting. It’s a rush of adrenaline right before I start, but once I get into it, I’m very relaxed (and almost on autopilot). Plus, it time to talk about one of my favorite items to discuss: organic chemistry. Speaking of which, let’s get on with the organic!
So this week’s article comes from JOC and its more organofluorine chemistry (Sorry, I promise next time I’ll pick a fluorine-free article but this one was too good to pass up). So if you have been following me for a while, you clearly know why organofluorine chemistry is so popular right now: new ways of getting fluorine into synthetic targets is very appealing to Med Chem. And if you read my last post, you know that the introduction of the CF2 group is currently very difficult to do. The Colby group has recently become interested in tackling this problem. Not long ago they introduced an extraordinary strategy for the rapid formation of alpha, alpha difluoroenolates:

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It appears as if Colby stumbled upon some findings by Ogden in the 1960s regarding the decomposition of hexafluoroacetone. Ogden found that, in the presence of metal hydroxides, hexafluoroacetone underwent a fragmentation to yield trifluormethylacetate and CF3-. Colby reasoned that a similar fragmentation could be achieved in 1,1,1-trifluoro-2,4-dione systems to yield trifluormethylacetate as well as the corresponding difluoroenolate. Colby and his group therefore set out to first prepared some 1,1,1-trifluoro-2,4-diones via trifluoroacetylation of various methyl ketones followed by alpha difluorination with Selectfluor. They then used conditions that can best describe as (very roughly) Krapcho-like (lithium salt to induce fragmentation). With conditions to facilitate trifluoroacetate-release in hand, he was successfully able to induce an Aldol between the other fragment, the difluoroenolate, and an aldehyde additive. Unfortunately, they really didn’t give a mechanistic rationale for why it worked, but it worked well (great yields, reactions completing in 3 minutes at room temp).

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With that impressive work behind them, Colby and his group set out exploit their newly developed trifluoroacetate-release strategy by synthesizing alpha-halo difluoromethyl ketones (which aren’t at all easy to make). All Colby really needed to do was find the appropriate electrophilic source of each halogen and couple it with his lithium-salt induced trifluoroacetate-release strategy. While that may seem trivial, it wasn’t as easy as one may think. First they attempted bromination using Br2. While this simple approach worked, excess base was required (which they attributed to acidic impurities in the Br2). They then opted for NBS, a logical Br+ source. However this failed to react whatsoever. Finally, they switched back to utilizing Selectfluor to generate electrophilic bromine from LiBr (a modification pioneered by Shreeve . This proved provide a reliable source of electrophilic bromine without requiring excess base.

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Next they targeted iodination. Attempting to capitalize on Selectfluor-mediated halogenation, they initially tried using lithium iodide (serving both as their lithium salt and as their iodine source) in the presence of Selectfluor. However, due to the fact that no sufficiently electrophilic iodine was present, self-coupling reactions occurred. Colby then made a slight tweet to his conditions: add I2 and exchange LiI with LiBr. That managed to do the trick and they were able to isolate alpha iododifluoroketones in excellent yields (though these species decomposed rapidly over times upon storage). With this in mind, they decided to demonstrate the power of their iodination method by synthesizing one of these ketones in situ followed by an immediate copper coupling to an alkene. Coupling proceed well and had the advantage of not having to isolate the somewhat sensitive iodoketone

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Finally, to wrap things up, chlorination was examined. Unlike iodination and bromination, molecular chlorine was not examined due to its hazardous nature (a good call in my opinion). Instead, Colby opted straight for NCS/LiCl. Lucky this proved perfect for chlorination (though ketones with alpha hydrogen atoms were over chlorinated).
I really enjoyed this article quite a bit. While it may not have been as impact as Colby’s previous work, it certainly was interesting and very well done. I still am really curious on the exact mechanism of the trifluoroacetate-release, because it’s so unusual! Anyway, that’s all for now. 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:

https://www.thieme-connect.com/ejournals/abstract/synlett/doi/10.1055/s-0030-1259561

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…

Food’s Worst Enemy: The Graduate Student

I can’t say I can think of anything more scary for any food service employee than a pack of graduate students. Like hyenas descending on a limping antelope, grad students appear and within mere minutes all that is left is some bone that has been picked clean, some half-eaten pizza crusts and a tray of Brussel sprouts. You would think that these young adults hadn’t eaten a morsel in their lives (but in reality they ate, on average, a mere hour ago…). Now, I am no exception to this rule, as my peers at both Stonehill and UConn know. I can demolish food with the best of them, though my tastes are slightly different from my comrades in chemistry (mountains of fruit fall to my hunger).
Now I am convinced that if you put the term “free food” in the context of any notification, you are sure to have graduate students appear (even if they aren’t explicitly invited). So long as the event does not prohibit graduate student attendance, they will be there (oddly enough they would show up at almost the exact time the food is served). The allure of food is (almost) enough to get most students to attend all of the guest or faculty seminars (though most times they pull a “pearl harbor”: sneak in, take out half a tray of cookies, stuff some in their pockets, and evacuate back to their lab before anyone knows what happened). You would think by now that at the end of every thesis template they would put…”And if you complete this ahead of schedule, you will be treated to the restaurant of your choice on the university’s tab”. How much more of an incentive would a grad student need?
Now being the scientist that I am, I tried to rationalize why this “free food” phenomena occurs. Is it that graduate students have overactive metabolisms? Is it the fact that the majority of us get paid less than minimum wage? Or is it some synergistic effect of free and food that makes the graduate student such a force to be reckoned with at the dinner table? And what of the “pearl harbor” observation?
Since I currently am snowed in, I really don’t have access to the pool of data that I would want. I merely can tell you based on past experiences and my own thoughts on what the ravenous hunger of the grad student stems from. I tend to believe that the food cravings of the grad student more relate to their income than to actual metabolism. I mean we do work 10 to 12+ hours per day on average and we are likely to be somewhat more hungry than the average joe but not to the point of constant hunger. So to offer them something that saves them money and could even makes them more productive by saving them time preparing a meal or cooking one is greatly appealing (I know that last part may be a stretch but I think you get the point). But why do we eat as if we have been stranded on an island for weeks? Well I can liken it to the insanity that occurs in supermarkets before winter storms. People shop not because they think they will be forever snowed in, but because they don’t know when they will have time again to get out and shop due to the disruption of their regular schedule. Grad students consume like they do because they have such busy schedules that they don’t know they will have time again later. But what about “pearl harboring”. I think the same principle applies. Grad students are so focused on their work they it takes a really strong force to pull them away from it. Food is good enough but at the expense of losing time to a seminar they could care less about, they take the less demanding hit-and-run path (like most chemical reactions :P).

So that’s it for today. Hopefully this snow storm doesn’t seal me in my apartment for the rest of the week (although its not looking too promising right now). I have some interesting news coming shortly and a new review on its way so stay tuned! Ckellz…Signing off…