Dispelling those undergraduate myths…

Mark Mascal, Nema Hafezi, and Michael D. Toney 1,4,7-Trimethyloxatriquinane: SN2 Reaction at Tertiary Carbon J. Am. Chem. Soc. 2010 132 10662-10664

So every once in a while an article comes along that really is an example of my kind of chemistry: pure, unapplied, organic chemistry. In the golden days of organic chemistry, the majority of publications contained chemistry that really did not have tangible application but were just synthetically sweet. For example, look at the numerous syntheses of highly strained molecules or highly symmetrical molecules. Basically, I love the days when physical organic was much more valued than it is today. So when I found this article a while ago, I was thrilled. No applications at all – just pure chemistry ownage in one of the leading journals, JACS. I was very impressed. I must warn you though, this article by Mark Mascal’s group over at UC Davis isn’t what I would call a methodology (or at least not in the traditional sense, I would call it a hybrid between a total synthesis and a methodology.) But nonetheless, this article is awesome and just by chance, I ran into it again recently. I believe it more than deserves a highlight on New Reactions.

So as budding organic chemists, we all learn that it’s impossible to do the reaction I’ve depicted in equation 1 above. Tertiary centers are simply too inaccessible to nucleophiles to get that good old backside attack to occur. However, we know these sorts of substrates are great for SN1 reactions, e.g. equation 2. Later, if we aren’t completely traumatized by organic chemistry and actually enjoy it enough to pursue a career in it, we enter grad school and, to paraphrase Yoda, ‘we must unlearn what we have learned’. We find out that it’s really the steric interactions in the pentavalent-transition state that make tertiary substrates mostly incompatible with the SN2 model. The activation energy is phenomenally high so the reaction just doesn’t go. Now you could argue that all you would have to do is heat it but the energy you would have to put in to get it to go would most likely yield products from less energetically demanding reaction paths. In short, you’d kill the starting material either through decomposition or lose it to a competitive reaction path. Notice how I said mostly and most likely. There have been isolated examples in the literature of SN2 reactions occurring under reasonable conditions at tertiary centers. Some have been explained as addition-elimination reactions, but others truly give evidence for SN2 reactions occurring on tertiary centers. However, they have never been as clear-cut as the work done by Mascal’s group.

Mascal’s group has a relatively broad range of interest, ranging from biofuels to total syntheses. However, his most well-known contributions are in the syntheses of two unusual classes of molecules: triquinanes (1) and triquinacenes(2). Lately he has been interested in the oxonium bad boys you see above (3,4,5). Now I want to draw your attention to the fact that these compounds are stable salts. 3 is highly stable (I don’t mean like glovebox stable, I mean like the AK-47: this compound can be subjected to the harshest conditions and survive). Mascal’s group was able to reflux 3 in water for 72 hours and even column chromatograph it on silica gel without adverse effects. That’s unprecedented for an oxonium ion. While 4 wasn’t as rugged, it still was isolatable and stable in acetonitrile (which you would think would be N-alkylated). Not surprisingly, both compounds reacted well toward harder nucleophiles (N3-, CN-, OH-) but 1 did not react towards weaker (softer) nucleophiles such as amines, iodide, or alkyl thiols/alcohols.

Now all that work was done in 2008. Fast-forward to 2010. In this recent article they disclose not only the synthesis of 5 but its very unique reactivity. I’ve shown the path they took to synthesize 5. Overall, not bad if we put this on a total synthesis scale (1.34% over 18 steps). Reactions up until intermediate 13 (in red) were performed in their 2008 work, so they didn’t actually show that compound. Kind of deceptive because that took 7 steps to make. But regardless, the point of this particular article wasn’t just a total synthesis; it was to construct a highly stable tertiary oxonium ion.

They did that and more. Like their previous article, they subjected 5 to a variety of harsh conditions. One would expect that, just as with any other tertiary oxonium ion(usually formed in situ ), solvolysis would proceed rapidly with 5. However, this was not the case whatsoever. That in and of itself is extremely anomalous if we considered what we learned about SN1 reactions in Organic I. Normal unreactivity to an organic chemist is a bad thing but in this case it drove the Mascal group to dig further. They attempted to react 5 under SN2 reactions with the hard nucleophiles mentioned earlier. As one would expect, the majority of these nucleophiles (CN-, OH-) acted as bases yielding E2-like elimination. However, reaction with N3- gave solely the azide product (above). While one could invoke ion-pair arguments, the next two pieces of data seemed to easily dismiss that possibility: The reaction was slowed both by polar protic solvents and by the addition of a non-nucleophilic salt, LiBF4. Now for the nail in the coffin. They performed what may seem like an undergraduate exercise: Determining the rate of reaction and rate constant by NMR and graphing it. And here’s why I said this is a clear-cut example of a tertiary SN2 reaction. The rate constant was determined to be 0.0235 M-1 S-1 . And computational data results suggest that no such equilibrium between a carbocationic form and the oxonium form exists (see below).
So I must say, while this article isn’t as impactful as the discovery of the Dess-Martin reagent or the Prakash procedure for trifluoromethylation, it is very cool to me. And the results don’t lie. If there were any SN1 or ion-pair character to the mechanism, the addition of the salt or running the reaction in a polar protic solvent should have increased the rate of the reaction. The kinetic results clearly show a 2nd order rate dependency and the computational results support that a carbocationic form is not a viable intermediate. Congrats to the Mascal group for an excellent and thorough job and proving that tertiary substrates can be used in SN2 land(and for keeping pure chemistry alive today!) .

This guy needs A LOT more funding, this could revolutionize the food industry…




Your PI

Principle Investigator. Its science’s fancy name for the guy who funds you to do lab work for him.  Basically it translates to “your boss”. Now I mention in an earlier post that one of the perks of being a grad student is you get to choose your boss. And to use another fancy sciencey term, this choice is unprecedented as compared to most other fields. In most corporate structures, you are assigned a supervisor. Whether you like him or not isn’t something that the company considers. And he essentially controls your livelihood and, in part, your life. My dad works for AT&T (via several buy-outs of other companies). But I can tell you, he’s gone through several bosses. You can really tell when he has a shitty one and a good one. Like right now he has one that is really considerate and not overly demanding. Compared to his last one, that’s a god-send. So that choice that us grad students get is quite unique and extremely important. I was very lucky as an undergrad. I got paired up with a man who I can truly call one of my best friends, Dr. Leon Tilley. He introduced me to chemistry at the college level and to research. He is still the person I call when I have a question I just can’t answer or a suggestion for an idea. But I didn’t really chose him as my PI, it just sort of worked out that way. Now when I came to UConn, I needed to make a choice as to who to work for. It was one of the most difficult choices I’ve had to make. Now you may be like im being overly dramatic, but I’d come up with not only a list why this choice is critical but also some qualities to look for in a good PI. Bear in mind that neither of my PIs have all of these qualities, but so long as the ones important to you are met, that person is probably a safe bet:
Why is this choice so important:
• You will be working for this person for the next 4-6 years of your life. You will undoubtedly be spending an ample amount of time with him or her. Do you really want to have to meet with someone you are uncomfortable with for more than half a decade?
• The research that you do as an graduate student is dictated by your PI. This means (most of the time) you become his disciple. The work you will do upon graduation will most likely have something to do (if not be identical) to the work you were doing as a graduate student. So essentially even after you leave you Ph.D. lab, your PI will still be haunting you 😛
• Jobs. The work you do and the reputation of your PI will ultimately determine you likelihood at getting that dream job, be it in pharma or in academia.
• Publications and Timeliness. Your PI also determines how long your indentured servitude lasts and how well known you are in your field based on how often he publishes.

Questions to ask:
• Funding: What are your sources? Are they relible and renewable? How much? How often does this potential PI apply for grants? (If your PI is writing grants too often, you will never see him. However if not often enough, you will be underfunded. I am not of the school of thought that believes you PI’s only job is to get your group money; there needs to be time to talk to your PI. You generally want NIH or NSF funding because its that’s not easy to get, meaning that PI is doing impactful work. and it can be renewed. And as will most things in life, the more money the better.)
• Publications: How often does he published? Is it at least more than once a year? How often has he published in the past three years? How many students have several publications? Where does he publish? Is this the kind of journal you want to be publishing in? (Depending on the types of journals and the number of students a PI has working for him, how often he published is relative. However if you look at the first three questions, you can get a general prediction on how many pubs you can expect to see working in his lab. I would say don’t restrict yourself to a PI that only publishes to ACS journals. They are hard to get into and you may only walk away with one publication. I know the old saying is quality over quantity but I’d take a few OBC papers* over a single JOC paper during my career as a graduate student. Its important to get as many publications as possible so look for repeat names on their papers!)
• Website, Technology and Age: Does the group have a website? Is it well maintained and up-to-date? Does the PI have a grasp on the current tools available to chemists? Is he willing to purchase new tools? How old is the PI and when did that PI get Tenure? (Unlike previous generations, our generation grew up with the internet. So we have a tendency to want to see things as up-to-date as possible. And moreover its not hard to maintain a webpage with all the tools available today like Dreamweaver or its open-source alternative nVu. So look for a well maintained page, it means the PI is up on the times. Technology is also key in the lab. My group is well-known for microwave chemistry and we are slowly acquiring flow reactors to get into that as well. Not only does this give you experience but it would likely lead to publications just simply by using a new instrument. Now for the weird question age and tenure. It’s important to chose a PI who is tenured. I wouldn’t risk your research on the chance that your PI could lose his position at your institution. That being said, I would recommend that you look for someone that just recently has acquired tenure. They are likely to be highly active in their field because they still have the pre-tenure publish-as-much-as-possible mentality. However, they may be not as…harsh…as they were pre-tenure. I also tend too look for younger PIs just because you are more likely to relate to them/they are more likely to be up on the times. That is not a rule but a trend I’ve seen.)
• Communication and Personality: Does he seem like a reliable nice guy? Is he “driven” or demanding? Is he prompt at replying to e-mails? Does he use text messaging? Does he care about his students (I think these are sort of obvious questions except for the text messaging one. I really love the fact that my PI and former PI use text messaging. Its very convenient when you are in a situation where e-mail is just too slow.)
So that’s all I got for today. Just my thoughts on PIs and what you should look for. By no means are these all the criteria you should look for. And these are only my opinions, what you look for will vary from what I do. However, I hope these thoughts give you some guidance if you are reading and you are a pre-grad student or if you are currently looking for a PI! Ckellz…Signing off….
*As a side note,  we unfortunately got rejected from Organic and Biomolecular Chemistry because we got one bad reviewer. We are either going to appeal or resubmit elsewhere. It was a disappointment but not the first time I’ve had an article rejected. So just keep your fingers crossed for me and I will update you on the status of that article.

Keep your fingers crossed…

Please keep your fingers crossed for me…I recently (in conjunction with Dr. Leon Tilley as well as one with Dr. Leadbeater) two articles! Hopefully the Tilley one goes through to Organic Letters and the Leadbeater one to Organic and Biomolecular Chemistry!

Cyclopropanes FTW!

Benot de Carn-Carnavalet, Alexis Archambeau, Christophe Meyer, Janine Cossy, Benot Follas, Jean-Louis Brayer, and Jean-Pierre Demoute Copper-Free Sonogashira Coupling of Cyclopropyl Iodides with Terminal Alkynes Organic Letters ASAP January 26, 2011

So I have a confession. I’m not only a sucker for fluorinated molecules, I absolutely love strained hydrocarbons. They are just freaking cool. Like cubane. I mean how can you not like them? They are potent explosives, they have unusual properties that defy conventional reactivity, and they are a challenge for an organic chemistry to make. In short they have limited application but they are equivalent to getting all the golden skulltulas in Zelda: Orcarina of Tme (aka ownage). And certainly, the most strained cyclic system I can think off has to have a cyclopropane in it. That’s really the most distorted you can get as far as organic chemistry goes. In part because of my undergrad research, I have a fond place in my heart for the cyclopropane motif. So its no surprise this article, which enables cyclopropanes to be substituted with ease, caught my attention. Plus it invovles palladium catalysis! One of my more recent specialties!

So it starts out as most methodology articles do: “Why is the product I’m making so awesome”. I was impressed with this part. Cossy (who I will refer to as the principle author, although the work has two with Christophe Meyer, a member of her lab, being the second) really went all out with info about cyclopropanes. I didn’t realize how common it was to put a cyclopropane in a drug. She cites that they are relatively easy to prepare due to the large number of methodology known to produce them, to which I agree with some reservation. A lot of those methods are very substrate specific or involve highly reactive intermediates which are not compatible with every functional group under the sun (think carbenes). She goes on to say that there have been a variety of methods to substitute these cyclopropanes once they are formed (which rely on the formation of some sort of organometallic cyclopropane or palladium cross coupling reactions). However, Cossy then states that are few electrophilic cyclopropanes being used in these sorts of coupling reactions. Following a report from Charette group in the late 90s, Cossy investigated whether such cyclopropanes could be functionalized using some sort of cross-coupling technique. Cossy picked alkynyl functionalization as their challenge because it looks like alkynylcyclopropanes have some applications from a pharma standpoint and they are somewhat of a pain to synthesize traditionally.

So they selected the model reaction above to test whether they could even get one of the standards of organometallic chemistry the Sonogashira reaction to go. Unfortunately for them, the normal conditions just plain failed hard. I say hard, because their starting material needed to be synthesized (3 steps in fact, I back tracked the lit for that one). So I you invest all that time in synthesizing a compound just to test your reaction and find oh no FAIL! it hurts a looooot more. So kudos to the Cossy group for not giving up right there and pursuing it. Interestingly, Buckwald played a role in their next move. Since he’s been using a lot of X-Phos lately with success with difficult substrates, Cossy’s group tossed that into the mix and that did the trick. They got 100% conversion to the desired product in 93% isolated yield. They screened other ligands too, but none worked as good as trusty X-Phos (I must admit, that’s a kind of badass name as far as ligands go). After screening solvent, temperature, and base they were ready to go (I’ve put the optimized conditions above in the figure). It’s substrate scope time.
The scope was impressive. They had all sorts of acetylene coupling partners. Some exotic ones too like a m-fluorophenylacetylene, a TIPS (Triisopropylsilyl) protected alkyne, 1-pentyne and ethoxy acetal. Quite the range! And the yields were excellent ranging from 81% to 97% with minimal alteration to the optimal conditions (one intially gave low yield 44%). They next altered the cyclopropane coupling partners by altering the stereochemistry as well as the substitution pattern. The majority of reactions went in good to excellent yield (72-97%). Moreover they really did put alot of effort into their reactions. They didn’t just screen one generic acetylene with a test cyclopropane. They would test 2-5 alkynes with each cyclopropane in question. So again, kudos to the Cossy group. However, here’s where I encountered an issue. They relied a lot on using a cyclopropanol, not a simply cyclopropane. So they (and I) wondered if that was playing some role in the mechanism. So they PMB (p-methoxybenzyl) protected it, making the argument that it’s no longer a free hydroxyl. Granted this is true, but if you think about it, the oxygen lone pairs are still untouched; they can still participate in the reaction. Now you could come back to me and make arguments about steric restrictions (which are perfectly legitimate). Still, I would of preferred to see not a protected but a functional group free cyclopropyl iodide as a substrate. Despite that small qualm, the next line makes up for it: The reaction “proceeded stereoselectively and with retention of configuration”. That right there is powerful chemistry: high yields (with a class of substrates that are quite strained) and stereospecificity.

Now they could of just stopped there. But they didn’t, and I think that’s what really set this paper apart from others I was reading. They next investigated derivatives cyclopropyl amides and esters to see if these types of compounds were also compatible their coupling strategy. After a little bit of re-optimization (new conditions are above), they found that yes, indeed it was. Not only that but it was relatively broad and both the alkyne substitution pattern and the substitution on the nitrogen of the amide could be modulated without compromising yield. And esters are esters…so they only did one lol. Interestingly, it was extremely important to add the alkyne slow to the cyclopropane solution. Apparently they observed oligomerization mediated by the amide when added directly so they extended the addition time to 2 hours. Adding over two hours isn’t that bad at all, especially when you have the awesomeness that is an addition funnel or better yet a syringe pump. Overall an excellent job on this work, it’s really well done and thorough. Great article Cossy and co-workers!!!

Congrats Burdette Group

The lab next to mine just got a paper in Organic and Biomolecular Chemistry! Pretty cool stuff check it out:
Iodination of anilines and phenols with 18-crown-6 supported ICl2-