When I first heard about the four quadrants of science, I was instantly captivated by the clarity with which three distinct philosophies can be compared and contrasted. There are indeed three different ways of doing relevant science (1, 2, 3 below): the Bohr quadrant (1) amounts to pure science without contemplation of downstream utility, the Edison quadrant (3) pursues empirical science and does not aim to understand the underlying causes, whereas the Pasteur quadrant (2) involves fundamental research with consideration of use. While I have no comment on the remaining quadrant (I am not even going to mark it because no one wants to be associated with this sort of activity), I would argue that almost all of us want to belong to the Pasteur quadrant. Indeed, it appears to be the most meaningful segment that balances utility with fundamental significance. Having said that, time and again important discoveries are made by those researchers who are perfectly happy to have their work associated with either quadrant (1) or (3). Thus, it is somewhat short-sighted to say that we must strive to be in the Pasteur quadrant at all costs and that not being there is a failure…
Monthly Archives: September 2014
The wonders of alkyl chains
Earlier today, my friend and colleague, Professor Dwight Seferos (http://www.chem.utoronto.ca/wp/seferos/), gave the 2014 John Polanyi lecture. The talk showcased the Seferos lab’s command over conjugated materials based on heterocyclic frameworks (mainly seleno- and tellurophenes). One particular structural piece that seems to be central to this kind of research is the alkyl chain-containing repeating unit shown below.
As you might imagine, all of the electronic properties of such polymers are ascribed to the aromatic nucleus, whereas the aliphatic side chain is there to ensure packing, ultimately controlling the interchain interactions and material morphology. I just wanted to comment on this “alkyl chain business” as I think some folks might have a tendency to trivialize the unique structural aspects of straight alkyl chains. Indeed, many practitioners of synthesis view them as fairly boring bystanders that, while central to function, are really not that exciting. All they do is pack parallel to each other, so what’s the big deal, you might say? Well, not so fast… While I was listening to Dwight’s expertly delivered presentation, I remembered one of my favourite old papers by the one and only – K. Barry Sharpless (my mentor). This manuscript hails from 1975 and describes a property that makes you realize that there is nothing remotely boring when it comes to straight alkyl chains. In the graphic below you can see the craziest separation ever performed (in my humble opinion). The two long chain alcohols differ by just two methylene units, yet are separable upon shaking the mixture over calcium chloride. These are the real wonders of chemistry, ladies and gentlemen. I am curious if subtle effects such as this can exert an influence on properties other than alcohol separation.
Surprises in the Midwest
This past Monday night I flew into Indianapolis, where Prof. Mark Lipton met me at the airport and took me to West Lafayette, home of Purdue University. Mark organized this trip for me, and I am truly grateful for it because I got to see people whose work I have known and admired for a long time. I also got to meet new faculty members, whose science I discovered only recently. I previously blogged about some nice chemistry coming out of Prof. Mingjie Dai’s lab. This time around I also met Chris Uyeda, another Assistant Professor at the Chemistry Department, whose cool catalysis will undoubtedly grace the pages of a top-level chemistry journal some time soon (he has a great story to tell, and it is too bad that I cannot mention any details as this is still unpublished…).
There were some really interesting science vignettes I was exposed to and there was a theme to my visit: I kept getting pleasantly surprised while learning about methods I had known very little about. Take, for instance, a very nice paper by Prof. Alex Wei. In it, an attempt is made to rationalize the remarkably high level of relative stereochemistry observed in the following epoxidation:
This system was subjected to a thorough DFT analysis, but neither of the two diastereomeric transition states revealed specific enthalpic interactions that could account for the observed differentiation. Upon further analysis, the authors came to the conclusion that the early transition state and low activation energy might allow for an intrinsic polarization in pi-orbital reactivity. They employed PPFMO (Polarized-pi Frontier Molecular Orbitals) approach, which is a perturbation method that desymmetrizes 2p orbitals by introducing s-functions near each lobe… This method provides an important clue that suggests that facial selectivity is predetermined by the polarized-pi model. Very interesting stuff, in my view.
There is another notable rarity I got exposed to. If you are aware of the USA map, you would know that West Lafayette, Indiana, is not exactly the place where one would expect to find good sushi. However, I was amazed by the quality of food at the Heisei restaurant, Professor Negishi’s favorite place. Mark took me there last night, along with Mingjie and Chris. Apparently, there is a good explanation for the outstanding quality of fish: there is a Subaru plant nearby. Their management wanted to make sure that Subaru employees had access to top of the line sushi. Apparently, Prof. Negishi ordered a take-out from that place on the day he received his Nobel Prize in 2010…
P. S. There was another surprise today: one of my readers alerted me that there are some weird ads that appear next to my posts from time to time. Upon further digging, I realized that I have to pay extra so that my readers do not see this stuff (by the way, as the writer of this blog, I never see any ads). This was a rather unpleasant surprise, the one I just fixed by paying a significantly higher annual fee. Let me know if you still see those stupid things. I will kick someone’s teeth in at WordPress if I hear about these ads again. The gospel of science must be spread without commercial interruptions.
I just came back from Moscow, carrying with me some fond memories of the MCMC-2014 conference. There is one particular presentation I would like to comment on. Last Thursday, I heard a very interesting talk by Professor Terent’ev of the Zelinsky Institute for Organic Chemistry, who showed some mind-numbing examples of organic peroxides that are stable despite what their oxygen-rich frameworks might signal. Below is one of the molecules that possesses an impressively high melting point.
While it is possible to speculate on the origins of this unusual stability, I think a fundamentally important caveat needs to be clarified. This point goes back to my PhD years with Prakash and Olah. If you recall, one of the central discoveries of Olah’s career were the so-called stable ion conditions, which enabled isolation and characterization of carbocations in solution for the first time.
In contrast to their carbon congeners, the corresponding trivalent silicon species (above) have eluded characterization for a very long time, which might seem counter-intuitive given the fact that silicenium ions are considerably more stable thermodynamically. But this is precisely what I wanted to mention: the silicon species is more stable thermodynamically, not kinetically. In terms of kinetics, trivalent silicon is so electrophilic that the barrier to covalent bond formation with some of the weakest nucleophiles is exceedingly small. Coming back to peroxides, there are probably a number of causes (metal impurities?) that might trigger violent decomposition, despite the apparent kinetic stability of some notable cases. I do encourage you to look at the papers by Terent’ev as there are some real gems there.
Yesterday I heard an interesting talk by Professor Rick Danheiser of MIT. Here is a bit of trivia that puts Rick’s contributions to science into perspective: he developed his first named reaction when he was still an undergraduate student. This took place when he was studying chemistry under the direction of Professor Gilbert Stork of Columbia University. The reaction I refer to is now known as the Stork-Danheiser alkylation of the kinetic enolates of beta-alkoxy enones, which should serve as an inspiration to undergraduate students who are interested in organic chemistry: you have a chance to make important contributions at any age.
Over the years, Rick has made many distinguished contributions to the field of organic chemistry. Many of the recent examples were on display in his talk, which I enjoyed a lot. I am just going to mention one case that stems from his 2010 JACS report. The reaction shown below should be a great question on any cumulative examination. You see a fairly rich, “triple bond-endowed” molecule that undergoes cyclization leading to the formation of a tricyclic pyridine-containing system. A curious thing is that one would probably expect some metal to orchestrate ring-forming events of this kind, yet there are no metals in this purely thermal process. As you might suspect, there is an important role attributed to one of the hydrogens in this molecule. Overall, the process amounts to an ene reaction followed by a Diels-Alder process. Or is it the other way around? Take a look as both pathways are conceivable.
Some notes from Moscow
I am writing this blog post from Moscow, Russia, where I currently am. Some time ago, Professor Valentin Ananikov of the Zelinsky Institute of Organic Chemistry sent me a kind invitation to speak at the MCMC-2014 meeting, which I immediately accepted. MCMC stands for “Molecular Complexity in Modern Chemistry”:
Particularly meaningful for me is the location of the venue, which is literally 5 minutes away from the high school I attended. On its walls, the Zelinksy Institute has a number of imposing pictures of luminaries who worked here in the years past, including Favorsky, Nazarov, Kishner (of the Wolff-Kishner reduction), Chichibabin, and many others. The program has been spectacular thus far and I really enjoyed all of the talks. The topics have ranged from organo- and photocatalysis (Dave MacMillan of Princeton) to gold chemistry (Steve Hashmi of the University of Heidelberg) to click chemistry (Valery Fokin of Scripps) to homogeneous catalysis (Carsten Bolm of the University of Aachen) to clusters in catalysis (Valentin Ananikov of the Zelinsky Institute of the Russian Academy of Sciences) to metathesis catalyst design (Deryn Fogg of the University of Ottawa), among others. There are many more talks to come and a lot more vodka to drink. I plan to mention some highlights later this week. Thus far everything has been spectacular and our hosts were able to show their warm hospitality to all of the participants. I just want to say something that will represent the sentiment shared by absolutely everyone at this conference: these are not the simplest of times in these parts of the world and we need to keep in mind that science should serve its uniting role and be immune to politics of any kind. I was impressed by the fact that all of the foreign invitees were able to join the conference. From what I heard and felt during the first two days of the conference, we are off to an awesome start.
Peptides in Florida next June
Here is an update for the 2015 American Peptide Society Meeting in Florida. My co-host Ved Srivastava and I expect some 1000+ attendees. The fund-raising is coming along nicely and we have secured some really impressive contributions (I really have to tip my hat off to Ved as he is a real pro in fund-raising). Importantly, an awesome scientific program awaits you in Florida (and I do hope that many of my blog readers will be there). The program will be very diverse and the topics will range from purely fundamental peptide science to the latest trends in drug approval from the FDA. In time, we will post the complete list of speakers on our website, but for now I just want to announce our “anchors”, so to say: Professor Richard Lerner will kick off the meeting and Professor Bob Grubbs will be our closer. I am truly grateful to them and to the rest of our outstanding speakers for accepting our invitation. Here are some preliminary details:
As long as I can remember, I have always had a problem with the concept of isolated yield. I mentioned this in the past, and I will say it again: this fuzzy metric is driving me insane. Isolated? By whom? By a first year undergraduate student or by a postdoc? We work at educational institutions and there is a lot to be said about how students grow in confidence and experience. This always has a direct effect on their technique.
The point is, there are subjective and objective metrics in science. While isolated yields are clearly subjective in nature (there is a real person behind the number), conversion and selectivity (I primarily refer to chemoselectivity here) are parameters that exist irrespective of our meddling with reactions. Personally, I am in favour of not considering anything subjective when it comes to process control and optimization. This means that our students need to have a good grasp of monitoring reaction selectivity. If you multiply selectivity by conversion, you get assay yield, which is just perfect as it decouples us from our inadequacies and focuses on what’s of interest to anyone who wants to read our papers – I refer to what actually happens in our reactions. There are many analytical tools available to our students and I want to focus on one of them tonight: GC and its use in catalysis. Choosing the right internal standard is the first step: one needs to ensure that the corresponding molecule is not being chewed up while the reaction of interest is taking place. Once you have the right internal standard figured out, there is a tendency to assume that things should be fairly straightforward. Not so fast. Here is a great paper we discussed at our group meeting earlier today. When I visited the UK a number of years ago, I became aware of this short, yet highly educational piece by Professor Fairlamb. The central message is simple: the fact that you have a nice GC vial containing a mini-worked-up aliquot does not mean that the reaction has stopped. This paper emphatically demonstrates that colloidal palladium cannot be seen by a naked eye, and that no matter how clear your vial is, your analysis might be in jeopardy. I love Figure 1: you can clearly see that the Sonogashira reaction still goes on in the GC vial as you wait for your sample to be processed. I wonder how many other reactions display this behavior during analysis…
The mystery of solubility (or lack thereof)
Professor Shawn Collins of the University of Montreal visited us today as the external examiner at Ramsey Beveridge’s PhD defense (Ramsey is one of Rob Batey’s PhD students). The defense went really smoothly and it was great to hear about Ramsey’s accomplishments in the area of total synthesis of macrocyclic natural products. Shawn gave a really nice talk earlier in the day. Some of his lab’s methods tackle the challenge of ring-chain equilibrium in macrocycle synthesis. They bias reactions away from oligomers and polymers without relying on high-dilution. In order to do that, Shawn resorts to biphasic systems that sequester catalysts in a highly polar and/or hydrophilic phase through the use of hydrophilic ligands (http://pubs.acs.org/doi/abs/10.1021/ja208902t). Time and again, it was clear that polyethylene glycol (PEG) has been playing a major role in this research. Shawn’s talk reminded me of a discussion I had with Professor Frey at the University of Mainz last week where we were contemplating some of the mysteries of PEG. Seriously, what is the deal with all these linear PEG-like polyethers? PEG is widely used in areas that range from drug formulation to materials chemistry. The bizarre solvent properties of this and related polether polymers are perhaps best illustrated using a comparison shown below. It is intuitively clear that addition of a methyl group to PEG would increase hydrophobicity, which is the experimentally observed result with PPG (it becomes less water-soluble). However, removal of a methylene group from PEG leads to POM, which is not soluble in water at all (remember those clamps for holding flasks in fume hoods? They are made of POM…). There are models that aim to rationalize this difference in properties and one of them suggests that solvation of water accounts for the observed difference in properties.
Young wine in Mainz and some chemoselectivity lessons
Professor Sigi Waldvogel picked me up from the Frankfurt airport yesterday and we went straight to his lab’s barbeque, which was an awesome way to meet the students and sample some local delicacies, including the delicious federweisser, the likes of which I have never tasted before. This is the so-called “young wine” that can be bought locally and can certainly not be transported very far because it is still brewing. There is no tight cover on the bottle, as you can see – just a bit of foil (otherwise there would be an explosion due to CO2). This stuff, along with beer and sausages, made for a memorable evening.
Earlier today, I had a great time visiting the University of Mainz. I already blogged about one of Sigi’s great Angewandte papers in the past. He continues to trail blaze in the area of electroorganic synthesis and I hope we will find ways to collaborate, particularly given Sigi’s experience with boron-doped diamond as electrode material. I will post something on that in the future.
I also had a pleasure of meeting Professor Till Opatz, who is running a very innovative program in natural products chemistry. Amongst many interesting vignettes he shared with me was a paper that I completely missed several years ago. I am now glad that I have discovered this work as it serves an important lesson in compound characterization. Below is what I am talking about. The nucleophilic attack at the I(+)-activated alkyne was reported some years ago by Larock and colleagues. These authors postulated the regiochemistry shown in the top box. As it turns out, the reaction outcome is different, which was Till’s discovery. I know for sure that there are people in my lab who will be interested in reading this work. The clarification made by Till’s group goes to show that it is prudent to exercise utmost care in structural assignment and to consider all possible outcomes that fit the data. And how many gold-catalyzed reactions might be revisited, ladies and gentlemen? I don’t know. Just saying.