It’s a TPAP!



Schmidt, A.-K. C.; Stark, C. B. TPAP-Catalyzed Direct Oxidation of Primary Alcohols to Carboxylic Acids through Stabilized Aldehyde Hydrates Org. Lett. ASAP July 27th, 2011.


What stops chemistry dead in its tracks? Waiting for chemicals and supplies. While we had another relatively productive week in the Leadbeater lab, our progress has been slowed (on basically all fronts) by either chemicals or equipment not coming arriving on time. In fact, one of our chemicals has been delayed for over a week now. Despite these setbacks, my lab-mates and I have found plenty to do. Friday, I had the “exciting” opportunity to work with t-Butyl Lithium again. For those unfamiliar with this compound, it’s somewhat pyrophoric, and by that I mean it makes a beautiful purple flame as soon as it hits air. While I’ve worked with it before several times, it’s always a little bit of a rush each time. After titrating it (WHICH IS A MUST!!!! Cannot stress that enough, our bottle said it was 1.7 M but after performing the titration procedure outlined by House we found it to be 2.4M!), I performed a Lithium-Halogen Exchange (LHE), which is one of the coolest reactions I know of. And it worked perfectly and was over in all of 10 minutes even at -78 oC! It’s amazing how fast those reactions are.
Our undergrads are finishing up this week and will be presenting their work shortly. My lab-mates and I are working closely with them to make sure both their presentations and posters come out well. Some of them that go to UConn will be staying on with us and I’m excited to have them in the lab. So unfortunately that’s about it for my week, nothing terribly exciting to report. However, I did find a very well-written article outlining a pretty cool oxidation in the lit this week so let’s get to it!
So if you know anything oxidation chemistry, you know that there are a vast number of reagents out there. You have the traditional Jones oxidation, TEMPO or Oxoammonium Salt based Oxidations, Pinnick Oxidations, MnO2-based Oxidations, Hypervalent Iodine (e.g. Dess-Martin Periodinate), and DMSO-Based (e.g. Swern or Moffat. A great (general) summary of these and some other oxidations can be found here and here. One of, in my opinion, the lesser known oxidations is the Ley Oxidation (using the Ley-Griffith Reagent, TPAP). Typically, the reaction is run anhydrous to give aldehydes from primary alcohols (and considering RuO4 is a tad bit expensive, the reaction is usually catalytic in RuO4 with a bit of NMO tossed in to regenerate it). However, in the absence of a drying agent or with the addition of water, carboxylic acids can be obtained instead. It works something like this (or at least how I understand it anyway…):



However, Ley oxidations in which carboxylic acids are the major product are lesser known in the literature. In fact, until this paper there had never really been an optimization for the acid. The majority of focus had been on stopping at the aldehyde stage. Just adding water to the reaction doesn’t always do the trick because some aldehydes form hydrates at very low levels (i.e. 0.001%). While eventually the reaction would proceed, it is far from effective in a normal time frame. However, this article isn’t primarily an oxidation paper. Its somewhat of a molecular interactions paper. The main focus is in fact using N-methylmorpholine N-Oxide to stabilize hydrates of aldehydes. Initially, the authors took a somewhat electron-deficient aldehyde (which hydrate better than electron-rich ones) and compared the ratios of the hydrate to the aldehyde via H-NMR. They found that by dumping in 10 equivalents of NMO in wet MeCN or DMF, they could alter the ratio from 99:1 aldehyde/hydrate to 67:33. Both observations make sense. Hydrate formations is entropically unfavorable and, according to the article, enthalpically as well. However, by placing NMO into the mix, the hydrate can be stabilized by a hydrogen bonding model:



With this valuable information in hand, they applied it to the Ley oxidation. They still had a bit of work to do here though. First, they needed to establish the optimal water to NMO ratio. Too much water and the catalytic cycle could be destroyed. They found the best ratio to be 10 equivalents of a 1:1 mixture of NMO:H2O. Solvents such as acetone, DMF, DCM, and MeCN were screen and so long as the NMO and TPAP were soluble, the reaction proceeded well (with MeCN proving to be the best). Once these variables were examined, they jumped straight into substrate screening. They looked at everything from branched alcohols to benzyl alcohols to those with halide or epoxide functionalities. In the case of the aryls, a strong dependency on the electronics of the aromatic ring was noted. More electron-rich arenes seemed to fair far worse than their electron-deficient counterparts (likely ability of the intermediate aldehydes to hydrate readily). They seemed to have a pretty good mix of alcohols and yields were relatively good on most substrates.
Overall, while not a groundbreaking article, I really enjoyed this one. I felt it was well-written and shows how intermolecular forces can be exploited. Hats off to the Stark group for a job well-done. That’s all for now, Ckellz…Signing off…

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It’s Just Another Mannich Monday…



Belanger, G.; O’Brien, G.; Larouche-Gauthier, R. Rapid Assembly of Quinolizidines via Consecutive Nucleophilic Cyclizations onto Activated Amides Org. Lett. ASAP July 14th, 2011


After another long week and a half in the lab, its nice to return to blogging! The Leadbeater lab has been incredibly busy these past couple of days. On Monday we received a planned visit from Dr. Tilley and his students to discuss the progress of our work in a joint group meeting. It proved quite productive and has possibly lead to new avenues for us to explore down the line (and have further collaborations). Meanwhile back at the lab, we have made much progress not only in terms of our collaboration but in terms of renovating our lab. We recently acquired (thanks to myself and Mike Mercadante, my lab-mate and close friend) a new vacuum pump. Not only is it in good condition (it is slightly used), it pulls an excellent vacuum (0.05 mmHg!). There is nothing like a good pump to make your life easier (especially when stripping off those pesky high boiling solvents like DMF or performing vacuum distillations on particularly heavy substrates). Our work with Dr. Fenteany, which feels like a long time ago now, should be submitted soon (very excited!). Also, the link to my new article is up. It was a relatively quick project but showed how microwaves can significantly shorten reaction times (in this case for disulfide formation)by allowing one to reach extreme high temperatures. In other news, our undergrads are really doing quite well. One of them just completed a short synthesis of a substrate for a project that we are currently working on (and in good yield!) while the other has solved the problems we have been having with another project Mike and I developed. The latter is well on her way to completing the project by the end of the summer (or at least getting close to it) while the other (a UConn student) will be staying on into next semester! So in terms of chemistry, I really have nothing to complain about besides the norm (reaction not working or having a difficult purification). So without further adieu, on with the review!
So this week’s article comes from, surprise surprise, Organic Letters, a journal consistently gives me good articles not only to review but just to read for pleasure. What really grabbed me about this article is the complexity of the structures being created. Not only is it a relatively simple reaction to do (or so it appears) but it yields a quad center and a tertiary nitrogen-fused bicycle (known as a quinolizidine).
These sorts of structures are often nestled into the larger framework of various alkaloid.



According to the article, there are a relatively limited number of ways to make these sorts of compounds and most are somewhat entailed or lengthy. Even few examples exist of performing a dual cyclization to form both rings in one shot. Most methods make one ring with some sort of functionality in it to allow for a second ring closure later. Existing dual or “one-pot” preparations include RCMs, Michael additions, Pictet-Spengler like condensations, cycloadditions or reductive amininations. Seeking to expand the tool box, Belanger and co-workers sought to apply their existing monocyclization parameters (for the formation of nitrogen-containing bicycles) to performing a dual cyclization (starting from acyclic materials). They believed that they could first induce a Vilsmeier-Haack-like reaction to give monocyclization and follow it up with a intramolecular manic…I mean Mannich :P. In my opinion, it’s not a true Mannich per say. I would argue it’s more analogous to the Pictet-Spengler reaction (a modified Mannich).



Initially the authors were worried that such a cyclization would be difficult and possibly disfavored. They assumed monocyclization would be facile. However, this would remove the more reactive internal nucleophile (olefin) with the more active electrophile (iminium ion). The second iminium ion could easily tautomerized to an enamine (and is already less electrophilic and the first imine) and the remaining nucleophile (the other olefin) is likely to be the less reactive of the two. Both these factors could have destroyed their chance at a second cyclization. But, thankfully, their fears were abated when they observed dual cyclization on their symmetrical test substrate. They did not however that two isomeric products were obtained but the ratio could be tweaked by altering the sterics of the system (i.e. making it a acetamide etc.).



Not all of their substrates behaved as planned. One of the biggest issues they ran into is competitive aromatization (at elevated temperatures) to a pyridinium ion. The authors attribute this to steric hindrance in some of their substrates with significantly slows the second cyclization. As a way to overcome this limitation and to gain better control over the reaction, they decided to attempt to utilize a “latent” nucleophile for the second cyclization. They hypothesized that the second cyclization could be promoted by the “unmasking” of this latent nucleophile (aka enhancing its reactivity to improve the chance of the second “Mannich-like” step).



To test this, the authors relied on some old chemistry developed by the Overman group. In their case the “masked” nucleophile would be an alkyne, a normally unreactive substrate to cyclizations of this type. Moreover, instead of using a allylsilyl “nucleophile” they used the substantially more reactive silylenol ether. However, this was very strategic. While the enol ether is more reactive to monocyclization, it inhibits a second cyclization by iminium deactivation via “electrodonation”. The second cyclization could be promoted by the addition of a bromide salt in acetonitrile while spontaneously converting the enol ether to its corresponding ketone. Not only does this provide enhance control, by leads to a halide containing product which could be further functionalized.

Overall, I would say this is one of the more impressive (and detailed) articles that I’ve seen. While nitrogen chemistry isn’t my normal cup of tea, I really enjoyed reading this article so go check it out! Congratulations to Belanger and co-workers on a job well done! Ckellz…Signing off…

Look Ma’, No Leaving Group!



Anxionnat, B.; Pardo†, D. G.; Ricci, G.; Cossy, J. Monoalkylation of Acetonitrile by Primary Alcohols Catalyzed by Iridium Complexes Org. Lett. ASAP July 6, 2011


So after a long hiatus from blogging, I finally got time to catch up on the lit. Let me tell you, summer is the best time for a (chemistry) graduate student. Not only can you get a lot of work done due to being free from classes and teaching, but you can do all sorts of other fun non-chemistry things like softball. The UConn chemistry department team is really doing well this year and I’m proud to be a part of the team. As far as research goes, we’ve made some really great breakthroughs recently and I have begun preparing the SI (UGH!) and manuscript for our work with Dr. Tilley. I also have an article of my own coming out shortly in Tetrahedron Letters which I’ll be sure to post a link to. I’m also really proud of the undergrads that are working with me. One of them came in with minimal organic training in June and now I can just tell her to run a column and she does so without help. Our other undergrad is tackling an entire methodology project by herself and doing a bang up job of it. So life in lab is pretty good (for now…)

One of most beautiful aspects of organic chemistry (at least to me) is the skill set required to succeed. Not only do you have to be good at your standard laboratory practices (calculations, safety, etc) but you also need to be a master of a plethora of spectroscopic tools. Moreover, you are always learning whether it be new reactions or new lab skills. For example, until this past week, I had never performed a “prep plate” (preparative TLC). I had seen it done both in my time at Columbia and at UConn but I had never had a need to do one before this week. I loved it. It was even easier than a column and just as selective. One of my fifth year friends taught me how to do one and it worked well! So the question for the week is what do you love most about organic chemistry or chemistry in general?
So this week’s article comes from, surprise surprise, Organic Letters. When I spotted this article, I didn’t even scan the author names, I went right to the article. Later I realized that the author was none other than an excellent organic chemist from France, Janine Cossy. This isn’t the first time that a Cossy article is appearing on my blog. She puts out some excellent work and this article is no exception.
The article begins by describing a particular problem with acetonitrile when alkylation is attempted. Namely, acetonitrile always seems to undergo multiple alkylations instead of simple monoalkylation in your standard basic deprotonation and alkyl halide addition. Alternatively, a copper-mediated coupling using cyanomethylcopper (CuMeCN) could achieve monoalkylation of allyl bromide to acetonitrile. But the article points out that all these methods rely on “toxic” alkyl halides (which is a stretch in my opinion, they aren’t that bad if you are careful). Recently alkylation of nitriles(albeit activated ones in which the group coming off nitrile at the alpha position is anion-stabilizing), using alcohols has been accomplished via transition metal catalysis. This is touted as a substantially more environmentally-friendly means of alkylation due to the only by-product being water. Additionally, the starting materials are orders of magnitude less toxic. Seeking to eliminate limitation that only activated nitriles can be used, Cossy and coworkers looked into the possibility of using acetonitrile as a model nonactivated nitrile and alcohol to perform monoalkylation.
Initially they chose a very cheap alcohol, benzyl alcohol, to screen conditions. The iridium catalyst was the first stepping stone, ultimately finding [IrcodCl]2 was the best catalyst for their reaction. However, the reaction was unacceptably slow (roughly 3 days). Hence they sped it up by heating it via microwave irradiation. They found that, if one loading of iridium was used, acceptable conversion could be obtained after nine hours. However, Cossy did something interesting here. Instead of loading all of the iridium, it was loaded in two portion. Not only did this up the conversion, it cut the reaction to 1 hour! This dramatic improvement likely relates to catalyst lifetime in the reaction conditions.



With the conditions for alkylation established, they sought to see how well this reaction performed when other (more complicated) alcohols were used. They didn’t just limit themselves to various benzyl alcohols (i.e. just changing the substitution pattern on the phenyl ring) they looked at various heterocycles and even alkyl alcohols such as heptanol. Interestingly, alkyl alcohols required much longer reaction times (12 hrs) but yield were reasonable. In general yield were good usually in the mid 70 percent range. But wait, there’s more!

Due to the number of groups studying these sorts of reactions, several mechanisms have been tossed around. Cossy decided to modify one of the more popular ones to reflect her reaction:



It’s somewhat complex but nonetheless amazing. First, you have your standard acid-base reaction creating a cesium alkoxide. That alkoxide then coordinates to the iridium and undergoes an oxidation, creating a metal hydride species and an aldehyde. The aldehyde then reacts with the acetonitrile in a condensation reaction to yield a vinyl nitrile. This olefinic species is quickly reduced by the iridium hydride to yield the product and regenerate the catalyst. Overall, this was an excellent piece of work by Cossy and coworkers. I look forward to follow up work on this reaction!

New Chemistry Blog: B.R.S.M.

So while browsing though my Twitter and a few chem blogs, I stumbled onto a new (and awesome) chem blog, B.R.S.M (Based on Recovered Starting Materials). It’s pretty well written and focuses primarily on total synthesis. So go check it out! And be sure to stay tuned here, new post coming soon (I promise!).