musings on music and life

September 7, 2017

Should chemists learn to code?

Filed under: Chemistry, Chemistry Jobs, Coding, education — sankirnam @ 9:25 am

I recently posted this comment on a post in Chemjobber earlier this week, so here it is. This is in response to the question in the title.

My two cents:

It’s not just that “chemistry majors should learn to code”; I feel that all college graduates today should learn to code. Programming is becoming a fundamental type of literacy these days. Just like how all college graduates should be fully literate in English and have some exposure to mathematics (e.g. calculus), all graduates should also have some experience with coding or programming.

As to how to incorporate programming into a typical undergraduate chemistry curriculum – I’m not entirely sure. Like a lot of people here, I took a required course as an undergrad on Matlab programming, after which I promptly forgot everything, since we never used it again. My PhD work in synthetic organic chemistry also involved zero programming, and other organic chemists here will probably also have similar experiences. In organic chemistry, programming is one of those things that is nice to know, but not at all necessary for success, and may even be viewed as somewhat of a distraction – is knowing how to program in Java going to get you better separations in your columns? Not really.

Everything I know about programming came AFTER I finished my PhD – I self-taught programming with online courses, starting with Codecademy, and after I felt I had reached a decent level of competency, I enrolled in a “Data Science” bootcamp last year. Everything I learned was completely orthogonal to chemistry; there’s little overlap between training and running a machine learning model using Python/scikit-learn and being able to do asymmetric oxidations at -78 C. 

If you’re doing computational chemistry, then sure, knowing fundamental programming and CS is incredibly important. In experimental synthetic chemistry…I’m not so sure. My academic experiences have proved that programming has limited utility in chemistry. I think it’s time for this part of chemistry to catch up to the modern age as well. Like Anon 3:15 PM says, if you can type print(‘Hello World!’) into a Python interpreter, then congratulations – you know more programming than 99% of organic chemists. But you also know less programming than 100% of professional developers.


August 13, 2017

Still alive

Filed under: Life — sankirnam @ 7:42 pm

Don’t worry – I’m still alive, but I’ve been busy (in a good way) with work commitments, which is why communication has been very sparse here. A lot has happened recently, which I do need to get to, but those will be topics for future posts.

In the meantime, I should share some exciting (or not) news – I crossed 1 million views on Quora, a popular social media-type Q&A site. I’m not a huge fan of social media sites, especially since there are studies that have linked heavy Facebook usage to depression. However, having an online or digital presence is increasingly important, as the products of the tech industry begin to encroach more and more into our lives. I wrote about this before, around this time last year, and my efforts seem to slowly be paying off. It remains to be seen whether this strategy will work for my industry of choice (organic chemistry research) – jobs in that field are obtained through word-of-mouth, hidden handshakes, and backroom deals with influential people. I’m still working on finding out who these influential people are in the companies that have labs around here (Allergan, Pfizer, J&J, Teva, and others).


May 31, 2017

#Chemjobs and H-1 visas

Filed under: Chemistry Jobs — sankirnam @ 10:02 am

The interplay of the chemistry job market and the issuance of H-1 visas is a topic of close interest, as it personally affects me – I was unemployed for 2 years in a futile job search for employment in the chemicals sector, and I strongly believe that one of the main causes for this protracted period of unemployment is the abuse of H-1 visas and shady hiring practices by a lot of companies in the U.S. today.

C&EN paid some lip service to this issue a couple of weeks ago in a brief snippet:


It’s things like these that make me livid. Firstly, there’s no dearth of domestic talent in chemistry – as a U.S. citizen who applied to several of these companies and institutions and was repeatedly turned down, this makes no sense. Why do these companies have to hire foreigners to fill these positions? A potential explanation could be the paltry salaries they’re offering – domestic graduates are smart, and will likely have much better offers.

More evidence, if it were needed, that science hiring is broken…

May 22, 2017

#chemjobs realtalk

Filed under: Chemistry, Chemistry Jobs, Uncomfortable truths — sankirnam @ 10:48 am

Courtesy of u/OldLabRat on Reddit:

“[…] suppose you take your fresh PhD in chemistry/bio/whatever to Cambridge or the Research Triangle or some other center of industry and start knocking on doors. “Do you need any chemistry done?” you may ask “maybe somebody’s out sick? I’ll totally help out cheap, just throw me some lunch money.” They might be tempted, until they ask your qualifications. “We don’t have any PhD level openings”, they will sneer. And I think every Chemistry department has the legend of the guy who left his PhD off his resume, got a bottle-washing job at Big Industry Company, and then was a preferred internal candidate for their next PhD opening so he got it – the corollary of that legend is that the position really had been wired for someone else, and Big Industry Company made a new rule that anyone who was found to have a concealed PhD would be fired. So that sort of pavement-pounding approach won’t work, they’ve seen it already and enacted countermeasures – such is the meaning of this popular tale. Chemistry is a field which has deliberately put up barriers, has institutionalized methods to avoid hiring qualified applicants who really want the job and would do it very well, in favor of seeking members of an elite ‘network’ who possess that elusive quality of ‘fit’.

It’s often posted here that the key to chemistry employment is networking – which seems to mean being popular and charismatic. This really is a sign that becoming a chemist is more like becoming a fine artist, or a philosopher of postmodernism, or a rock star, than it is like becoming a schoolteacher or a car mechanic or a pastry chef. You do not simply offer enthusiasm and hard work, let alone skill, it’s about projecting an image of your awesomeness.

If people really need work done and want to hire somebody to do it, they don’t mess around in quite the same way. I don’t know of any schoolteachers who got their job by following the ‘networking’ methodology. Nobody runs up their credit cards attending teacher networking meetings and conference, where they listen eagerly to presentations from already-employed teachers before politely introducing themselves and passing out their aspiring-teacher business cards, afterwards going to the bar and buying drinks for successful already-employed teachers while asking them to share their wisdom and experiences and oh by the way here’s my card. Teachers don’t have time to sit at a bar and have drinks bought for them by aspiring applicants. They’ve got assessments to grade, activities to develop, chemicals to buy, lesson plans to write, professional development to attend to: work, in other words!

So I’d say chemistry is a ‘luxury’ profession right now, or at least society is treating it like one. Becoming a chemist is less like becoming a master electrician and more like becoming an opera singer.

Of course we’re more dependent upon the products of the chemical industry than ever. But honestly it doesn’t take a chemist to follow a procedure. It takes a chemist to write one, but after that it doesn’t. And even if you did want a chemist, there are plenty in China and India who will work for a slightly lower salary and are able to just dump their waste jugs down the sewer drain, which is ever so much more efficient and globally competitive!”

This. This is what I faced for two years while desperately trying to get a job in chemical research – it’s not enough to be competent, knowledgeable about the field and have domain expertise, but you also have to possess that elusive quality of “fit”, which could be anything, depending on the hiring manager’s mood that day. The “elite network” mentioned above is very real – it used to be solely an academic thing (i.e. 99% of new professors at most universities these days are from Harvard/Stanford/MIT/Caltech/Berkeley), but now, thanks the insane saturation in the chemistry job market at the PhD level, it has percolated into industry. The two biggest questions I would get while trying to convince people to at least give me some kind of opportunity at their companies would be:

  1. “If you’re as competent as you claim, why hasn’t someone hired you yet?”
  2. “If you’re as good as you claim to be, why isn’t your degree from Harvard/Stanford/MIT/Caltech/Berkeley?”

The tech industry, in contrast, is refreshingly egalitarian. It doesn’t have the saturation and craziness present in science hiring, and hiring decisions are not really swayed by academic pedigree or awesome networks but rather by a track record of tangible projects and results that you have brought to the table.

As I have said before, the first thing that needs to be done to fix this situation is to stop oversaturating the market with scientistsUniversities need to stop recruiting graduate students by the droves and invest more into ensuring the career success of existing students and postdocs. Of course, most professors will balk at this since their supply of dirt-cheap labor will be threatened – the incentive to change can only come from the top, from funding agencies such as the NSF and NIH.

May 7, 2017

Course Updates

Filed under: Coding, Data Science — sankirnam @ 2:22 pm

As they say, the path to self-improvement never ends…

I just finished the final exam for the course MITx: 6.00.2x Introduction to Computational Thinking and Data Science on EdX, and this motivated another summary post, similar to what I wrote last year on its prequel course, MITx : 6.00.1x. These two courses make up an introductory sequence to computer science, primarily geared at non-majors; there is a similar corresponding course taught on the MIT campus. While 6.00.1x is focused on getting students up to speed with Python and using it to write simple programs, 6.00.2x then looks at more fundamental CS concepts (e.g. greedy algorithms, search trees, etc.).

The presentation of the course is excellent – all the movies are in HD, and the text is clearly visible on the screen. Code snippets presented in the video lectures can also be downloaded later so that you can play with them. While Prof. Guttag’s lecturing style may not be quite as engaging as Prof. Malan’s (Harvard CS50), the MIT rigor is definitely there in every slide.

When it comes to the material and choice of topics in the course, the instructors decided to go for breadth rather than depth, and this led to a very rushed coverage of a lot of topics. At the same time, in an introductory course like this, you will have a lot of non-majors taking the course, and you want to give them a flavor of everything the subject has to offer. I have the same issues with the standard introductory general chemistry curriculum that is used today at most universities – in those, the topic coverage doesn’t necessarily translate to knowledge that may be very relevant even for future chemistry courses. In any case, after taking this course, I have the confidence to take future courses in computer science/programming, and am especially interested in trying out some basic algorithms courses. While I may not have the chops yet to crack open Knuth and study that on my own, I think a guided approach in another class would be valuable.

The problem sets, as always, were appropriately challenging. I made it through to the end of the course, which means that I probably fared better than other students who may have dropped out, but among those who stuck till the end, I think I am one of the weaker students. The course has a corresponding Slack channel, and most of the students who took the final said on the Slack channel that they were able to finish the final far faster than I did (of course, this may also be subject to reporting bias). The course lays an emphasis on OOP (Object-Oriented Programming), and so this teaches you how classes, objects, and their instances are implemented in Python.

I did try taking 6.00.2x last year immediately after completing 6.00.1x, but I got hopelessly stuck on the first problem set involving implementing a greedy algorithm. This time around, I powered through it, and was also able to finish the rest of the course. I’ve becoming pretty good at debugging my code using print() statements, and from what I hear, this is an extremely important skill.

I also took the course HarvardX: PH526x Using Python for Research (Edx) last year, and I figured that I would put my thoughts on that course in this post as well. This is a basic-to-intermediate level course that introduces the various Python libraries that are useful in scientific computing. Some of the elements of the Numpy stack are included (Numpy, pandas, matplotlib), as well as some other packages (Bokeh, cartopy, and others). As with any course, there is no way you can cover everything there is in any one of these packages, and so there is always a tradeoff for breadth vs. depth. 

All the coding assignments and homework problems for this course were done through DataCamp, which has its own quirks. I remember having issues getting a question involving PCA correct due to rounding errors (caused by implementing pca.fit_transform() vs. a sequential followed by a pca.transform()) which were not being accounted for by the grader.

PH526x also covers some vanilla python topics, including an introduction to list comprehensions, which is one of my favorite aspects of Python; once you understand the simple concept (e.g. initialize an empty list, iterate through something, and append to the list), you’ll begin to want to use it everywhere, and there’s nothing quite as satisfying as being able to write list comprehensions that compress several lines of code into one line. Prof. Onnela (the instructor) also covers the itertools module briefly, which is handy for generating things like “power sets”, which are used for coming up with brute-force algorithmic solutions.

In retrospect, I wish I had taken both of these courses before the “Data Science” bootcamp last year, but what’s done is done – actually, I wouldn’t have been able to, since PH526x was only released for the first time last November.

Another thing I’m curious about is the attrition rate for these courses; how many people actually finish? Knowing this might help to give me a better idea about whether I actually accomplished something significant or not.

As always, for those who are curious, I’m uploading everything to my github.

May 1, 2017

Mark your calendars!

Filed under: Carnatic Music — sankirnam @ 2:13 pm


I’m super excited for this program – it’s been my dream to play for Smt. Sowmya, especially since I’ve been listening to her concerts regularly since the 90’s. I have heard her concerts with my guru while sitting stage-side at the Madras Music Academy, no less.

Smt. Sowmya is one of my favorite artists; she presents a rare intellectual approach to music that is also purely classical. This is something that is sorely lacking in a lot of concerts by other artists nowadays, which are very flashy with a lot of “gimmicks” and little real substance.

April 24, 2017

Professional Courtesy

Filed under: Carnatic Music, Uncomfortable truths — sankirnam @ 3:05 pm


This situation has happened to me way too many times now, and I need to vent here. It’s just a matter of having basic professional courtesy as a musician. If you don’t have the instrument, or are unwilling to pay for transportation costs, then don’t accept the engagement. It’s that simple.

As a professional, I do this myself – before accepting a concert engagement, I always inquire for the sruthi (pitch) of the main artist and make sure I have access to the correct instrument. It’s amazing to me how so many others don’t do this, and instead hope that someone else will lend their instrument for their use. I have actually had some of my mrudangams come back basically destroyed after loaning them out for concerts.

I do not go to all the trouble of maintaining my instruments just so that others can use them in concerts. This would not be such a big deal if I were living in India (or Chennai specifically), where access to mrudangam artisans and repairers is easy. The mrudangam is an incredibly finicky, high-maintenance instrument, and I don’t put a lot of my own time, effort, and money into maintaining my instruments just so that other people can use them.

The same thing can hold for concert organizers, if they read this: don’t expect one musician to give his/her instrument (especially a high-maintenance instrument like the mrudangam in the US) to another musician.

</end rant>

April 9, 2017

Classics in Organic Chemistry, Part X

Filed under: Classics in Organic Chemistry — sankirnam @ 8:14 pm

It’s been over a month since Prof. Olah passed away, and I haven’t made a post here since then, so this one can also be dedicated to some of the work that he did.

Prof. Olah may have been best known for carbocation and superacid chemistry, but his research covered a very broad swath of organic chemistry, including novel synthetic methods, nitration, Friedel-Crafts chemistry, onium ion chemistry, fluorine chemistry, polymer chemistry (carbocationic polymerization), and physical organic chemistry. This post will be about work that I did during my PhD (2008-2014), and was in full force during the time Prof. Olah received the Nobel Prize (1994).

This topic is called superelectrophilic activation and can be thought of as a way to rationally design new electrophiles for Friedel-Crafts chemistry, as well as develop new types of Friedel-Crafts reactions. But first, some background is required.

In the 1970’s, Prof. Olah’s group (then at Case Western Reserve University, Cleveland), as well as Brouwer and Kiffen at Shell Amsterdam, had noted that acetylium salts could carry out hydride abstraction from tertiary alkanes. Prof. Olah noted the solvent dependence of this reaction – it took place in superacid media (e.g. HF-BF3 or FSO3H), but not in aprotic solvents. A similar phenomenon was observed with the nitronium ion (NO2+ salts); in superacid solution, the nitronium ion was capable of reacting with methane, forming nitromethane (although the yields are low and this is not preparatively useful, it is in stark contrast to the usual scenario of no reaction).


Slides are from my PhD Defense, University of Southern California, 2014.

Around the same time, Prof. Koichi Shudo (University of Tokyo), was doing independent but related research in a similar area. Prof. Shudo had just come back to Japan after doing a postdoc with Prof. Paul G. Gassman (University of Minnesota). Gassman’s influence is evident in Prof. Shudo’s research in Physical Organic Chemistry, as he was doing research at the time on nitrenium ion chemistry. Prof. Shudo was a brilliant chemist and bought a lot of rigor to his investigations on superelectrophiles. I never met him, but I did meet his junior colleague, Prof. Tomohiko Ohwada, at Prof. Olah’s 85th birthday at USC a few years ago.

In any case, Prof. Shudo and his colleagues observed that when N-phenylhydroxylamine or nitrosobenzene was mixed with benzene and TFA (trifluoroacetic acid), N-arylation was observed, yielding diphenylamines. On the other hand, when TFSA (triflic or trifluoromethanesulfonic acid) was substituted for the acid, completely different products were obtained – the reaction yields aminobiphenyls, indicating attack on carbon rather than nitrogen. One thing to keep in mind is that triflic acid has a Hammett acidity of -14.1, while TFA’s is -2.7; triflic acid is therefore about 1012 times more acidic than TFA! In addition, most people would expect that simply increasing the acidity would just affect the reaction kinetics, and that this would be subject to general acid catalysis. However, since the products and product distribution is completely different, a different reaction or mechanism is now involved.


Prof. Olah’s insight was to propose that in a superacidic medium, positively charged cations (or “onium” ions) could undergo further interaction with the solvent to yield even more electron-deficient species. The nature of this interaction can vary anywhere from a hydrogen-bonding interaction to a complete protonation yielding dications or dicationic species in the limiting case. This is still an area of research, and it is quite possible that the observed effects could also be due to dielectric or field effects alone, with no contribution from protonation (since superacids are a high-dielectric medium). Prof. Olah dubbed this interaction of the superacid medium with onium ions protosolvation, and this general concept came to be called superelectrophilic activation.

superelectrophile_slide_3There are a couple of things to keep in mind here. The resulting species are known as superelectrophiles and are transient, short-lived, high-energy intermediates. Prof. Olah and his coworkers put a lot of effort into trying to characterize the protonitronium dication (HNO22+) by NMR and other methods, but these were largely unsuccessful. But just because an intermediate cannot be characterized, it doesn’t mean that it doesn’t exist at all; we now know that stability and reactivity are opposing properties, and that just because a particular species is amenable to isolation and characterization, it may not be the true reactive intermediate in the reaction coordinate.

The real proof of the existence of superelectrophiles comes from kinetic studies done with varying acidities. The rationale behind these studies is as follows: if the monoprotonated species is the key intermediate in the rate-determining step of the reaction, then the rate should level off once the acidity required for complete monoprotonation of the substrate has been achieved. If on the other hand, the reaction rate continues to increase with increasing acidity, then it is not the monoprotonated species that is involved in the reaction, but a diprotonated (or protosolvated) species.

The slide above shows some examples of this; the Friedel-Crafts hydroxyalkylation of benzaldehyde with benzene is particularly illustrative. The rate of the reaction increases dramatically with increasing acidity! Although the superelectrophile has not been characterized, one can use this kinetic data as support for its intermediacy. The nature of the superelectrophile is also up for debate; experimental data suggests that the O,O-diprotonated species is involved, while theoretical data suggests an O,C-diprotonated species.

This concept can therefore be used for the design of new electrophiles in Friedel-Crafts chemistry. Protonated moieties, substituents than can become positively charged (by protonation or ionization), or other highly electron-withdrawing groups can be used to activate carbenium ions nearby in the substrate towards reaction. N-halosuccinimides can be activated in superacid media and do halogen (“X+“) transfer to arenes; this reaction was investigated by Prof. Olah and can be carried out in BF3-H2O. BF3-H2O is a particularly interesting superacid; it was first discovered by Hans Meerwein and is probably the cheapest superacid available today (apart from anhydrous HF). It can be prepared by bubbling one equivalent of BF3 into ice-cooled water, and can be stored as a frozen solid and thawed when needed. In related chemistry, the nitronium ion can be activated in superacid in order to carry out nitrations of challenging substrates, such as nitrobenzene other nitrated aromatics (which are used in explosives and synthetic musks). Benzoyl esters can also be activated in superacid, giving protoacyl dications or diprotonated esters which can undergo condensation with arenes to conveniently yield benzophenones.


Currently, Prof. Douglas Klumpp (Northern Illinois University) is doing research in this area; he started as a postdoctoral fellow with Prof. Olah at the time he received the Nobel Prize. Prof. Klumpp has extended Prof. Olah’s concept to design new types of electrophiles and superelectrophiles, including novel condensations and domino reactions.


R. R. Naredla, C. Zheng, S. O. N. Lill, D. A. Klumpp, J. Am. Chem. Soc., 2011

Once these multiply-charged species are generated, new types of reactions can be designed based on charge-charge repulsion; this enables regioselectivity at a different position, such as an aryl carbon, similar to what Shudo did earlier with N-phenylhydroxylamine in TFSA.

This should serve as a brief introduction to this fascinating topic, and if you’re interested in reading further, there are several excellent manuscripts and reviews available, including a book Superelectrophiles and their Chemistry*.

*I’m not condoning the use of illegitimate PDFs – this was the first hit when I searched for “Superelectrophiles and their Chemistry”, so its not like nobody else would have found it anyway.

March 8, 2017

Rest in Peace, Prof. Olah

Filed under: Chemistry — sankirnam @ 11:54 pm

I just heard the news today that Prof. George A. Olah had passed away.

This affects me personally, as I did my PhD in his laboratories, and was the last student to actually do research in superacid chemistry and carbocations, which is what Prof. Olah received the Nobel Prize for.

Prof. Olah was truly a giant not just in Physical Organic Chemistry, or Organic Chemistry, but Chemistry in general. I don’t need to rehash what has already been inscribed in the annals of scientific history – Prof. Olah has written several autobiographical accounts of his life and his research career, and these do a much better job at explaining things than I ever could.

What I can say is that Prof. Olah’s approach to science was extremely rigorous, thanks to the education he received in Hungary prior to the Communist revolution. This rigor was carried into everything he studied in Organic Chemistry. Prof. Olah was also extremely fearless when it came to exploring new ideas in chemistry, and this quality stuck with him the rest of his life. He started his career off in a makeshift laboratory (which was pieced together in a balcony) in the Technical Institute in Budapest, where, much to the disapproval of his PhD advisor, he did work in fluorine chemistry, Friedel-Crafts chemistry, and superacid chemistry, the subjects that would be a recurring theme in his life.

Lately, there’s been a trend in popular media, whether it’s books, blogs, or news media, to pit foxes and hedgehogs against each other. Foxes are people who have a very shallow understanding of lots of topics, whereas hedgehogs are said to be people who have a deep understanding of one topic. All of these sources tout the superiority of foxes, claiming that they make better predictions due to the fact that they don’t get caught up on one idea. Ever since I first read about this in Nate Silver’s The Signal and the Noise, I was unconvinced, because I knew scientists who worked on one (or a few) big ideas for their entire careers. Prof. Olah was one such individual, and he truly made the case for the superiority of hedgehogs!

Prof. Olah’s modus operandi was to throw all his effort in one area until he was satisfied that he had learned as much as he could there. He would then collect all his manuscripts and write a large review either as an independent review article or as a book, and then move on to the next topic. In this fashion, he covered a large swath of chemistry, from synthetic methodologies, to carbocation chemistry, Friedel-Crafts chemistry, onium ions, nitration, and methanol. If you want to learn more about these topics, I wrote about them briefly here.

Prof. Olah was extremely organized and methodical in his approach to science, and this is revealed in his publications, the majority of which are in various series. He has a series of 300+ papers on “Stable carbocations”, 60+ papers on “Friedel-Crafts chemistry”, 200+ papers on “Synthetic methods and reactions”, and so on. Each of these papers is a gem. Prof. Olah’s command over English is impeccable, and the papers are all carefully written to make the science not just understandable but accessible. Prof. Olah also had the good fortune to get married to a fellow chemist, Judith Olah, and they published several papers in Friedel-Crafts chemistry together.

Prof. Olah was one of the few chemists to get a reagent named after himself – Olah’s reagent is a mixture of HF and pyridine that is much easier to handle than pure HF itself, since it is a liquid at room temperature. Prof. Olah also came up with the use of SO2ClF as a cosolvent for superacids, as well as discovering that the mixture of HSO3F and SbF5 could form an extremely powerful liquid superacid system convenient for studying carbocations. The oft-repeated story of how that mixture came to be called “Magic Acid” is something that doesn’t need to be told again here.

There are a few things that set Prof. Olah apart from other chemists, not just from his generation, but also the current generation. The first is that he was able to do Nobel-Prize winning work while not being at a top university (e.g. Harvard/Stanford/Caltech/MIT/Berkeley etc.)! This was always a matter of pride for him, and really does go to show the quality of his ideas and his thinking. The second was his concern to do research that was truly practical and addressed the problems facing humanity today, such as climate change and energy storage. It was due to this concern that he spent the last 2 decades focused solely on a pet idea – The “Methanol Economy”. He also developed the process of methanol “bi-reforming”, which is based on existing Fischer-Tropsch chemistry, in order to make it practical.

Of course, success always breeds contempt, and unfortunately Prof. Olah did have enemies in his lifetime. Plenty of older chemists will remember the scientific rivalry (bordering on animosity) between Prof. H. C. Brown and Prof. Saul Winstein, and after Prof. Winstein suddenly passed away in 1969, Prof. Olah took his place. Another injustice is that Prof. Olah was never invited to give a lecture at Caltech or Harvard University. This is unconscionable, given his scientific accomplishments in chemistry!

I am proud to belong to the scientific family of Prof. Olah (which extends back to Emil Fischer), and grateful to have had the opportunity to learn and practice organic chemistry in his laboratories at the Loker Hydrocarbon Research Institute, USC.


My copy of Superacid Chemistry…


…signed by all the authors, including Prof. Olah!

EDIT (3/9/2017): USC has issued a press release in memory of Prof. Olah, which is well-written and very detailed.

2nd EDIT (3/14/2017): C&EN has written an article in memory of Prof. Olah, and some of his former students and colleagues have commented online.

February 27, 2017

Classics in Organic Chemistry, Part IX

Filed under: Classics in Organic Chemistry — sankirnam @ 10:05 pm

Apologies for the hiatus, I’ve just been busy with getting settled into the routine of work while also juggling everything else going on in my life.

This next paper is one that I feel has not received the attention it deserves – it is incredibly groundbreaking and really should get the author, A. J. Arduengo, a Nobel Prize. Every October, I wait eagerly for the Nobel Committee’s decision in hope that Arduengo’s name comes up, but so far have been disappointed. Oh well… there’s still time for them to redeem themselves.

As students of organic chemistry know, carbon is unique among the elements in terms of the number and variety of stable bonds it can form with itself and other elements. This ability of carbon is central to life and biochemistry; no other element has these properties to the same degree that carbon does. While silicon is also tetravalent like carbon (and has provided inspiration to countless sci-fi writers), it polymerizes through Si-O linkages, forming polysiloxanes. Si forms bonds with itself with great difficulty, in contrast to carbon.

When undergraduate students learn organic chemistry, they are introduced to the concept of “arrow pushing”, which is a formalism that allows one to keep track of electrons – after all, reaction mechanisms are simply the rearrangement of electron pairs (e.g. σ bonds, lone pairs, and π bonds) relative to the nuclei. Most organic mechanisms proceed through carbon intermediates in a variety of oxidation states that students quickly become familiar with. The major ones are carbocations, carbanions, and carbenes.

Prof. G. A. Olah received the Nobel Prize in Chemistry in 1994 for the work he had done studying carbocations over the course of his (now 70-year) career. Prof. Olah’s big breakthrough was the isolation of carbocations – particularly the t-butyl cation, as stable, isolable species that were amenable to spectroscopic characterization (e.g. NMR and IR spectroscopy). This was a big deal at the time of discovery, because prior to that, chemists had proposed the intermediacy of carbocations as intermediates in acid-catalyzed organic reactions and rearrangements, but had not been able to conclusively prove their existence. Regular readers of this blog will know that I had the privilege of working under Prof. Olah and Prof. Surya Prakash, continuing research on new classes of carbocations – but that is not relevant to this discussion.

While carbocations have been isolated, free carbanions still have not been (at least to my knowledge). This also leads into a discussion on solvent effects and solvation. When carbocations are generated in the condensed phase in superacid media, one has to also consider the counterion, which is the conjugate base of the acid (e.g. SbF6). Is the anion also associated with the carbocation, and if so, what is the nature of the ion pair? These questions were studied by Prof. Saul Winstein at UCLA in the early 20th century, and he came up with the concept of the “intimate ion pair” based on solvolytic studies he had carried out in order to probe the the SN1-SN2 continuum.

In organic synthesis, when you want to generate a carbon nucleophile, you don’t actually use a “free” carbanion – instead, you use a pseudo-carbanion, and most common organometallics are exactly that (e.g. Grignard reagents and organolithiums). Grignard reagents and organolithiums are commonly employed as souces of nucleophilic carbon, but the C-Mg or C-Li bond is actually rather covalent. The ionic character increases as you go down the periodic table, and so C-Cs bonds would be expected to be very ionic. I haven’t looked much into organocesium chemistry, but since I have not heard much about it, I can safely assume that it is pretty esoteric – cesium is not the easiest metal to handle, since it ignites spontaneously in air.

Anyway, the main thing is that “free” carbanions have not really been isolated or studied the same way that Prof. Olah was able to study carbocations – perhaps there’s another Nobel Prize up for grabs there?

After carbocations and carbanions, the final carbon intermediate is carbenes. Carbenes are unusual in that they are formally neutral, and have properties of both carbocations and carbanions. They have an empty orbital like a carbocation, and also have a lone pair of electrons. The other complication is that what I just mentioned holds true for one particular spin state of carbenes; the empty orbital allows carbenes to have 2 potential spin states, namely the singlet and triplet states. When the lone electrons are paired, then it is said to be in the singlet state, and when the electrons are unpaired, then it is said to be a triplet species.carbenes

Carbenes are important species because of their utility in a variety of areas – most significantly, the Grubbs 2nd generation catalyst has an NHC (N-heterocyclic carbene) ligand, which confers extra stability compared to phosphines due to its ability to strongly donate electrons as well as engage in π-backbonding.grubbs_catalyst_2nd_generation

With that context, today’s paper is on the isolation of the first stable, crystalline carbene. This was carried out by A. J. Arduengo and coworkers at the DuPont Central Research and Development laboratories in Delaware in 1990. The DuPont laboratories were the place to be in the 20th century for cutting-edge chemistry research – they basically single-handedly revolutionized not just the field of chemistry, but the lives of everyone on the planet. It’s difficult to overstate the impact that DuPont’s research had; here’s a brief list:

  • Wallace Carothers in the 1930’s single-handedly developed the field of polymer chemistry while at DuPont, creating Nylon, Neoprene, and the concept of step-growth polymerization.
  • Roy Plunkett discovered Teflon by accident when he saw that the pressure in a cylinder of tetrafluoroethylene had dropped to zero. Upon sawing the cylinder open, he obtained a white powdery solid that was very chemically inert, had a low surface friction, and had a very high heat resistance. Plunkett became infamous for later developing Freons (fluorochlorocarbons which were extensively used as refrigerants due to their heat capacity, until Prof. Rowland (UCI) discovered that they were responsible for ozone depletion in the upper atmosphere) and tetraethyllead (which was used as an anti-knock additive for gasoline until it was realized how undesirable lead pollution is).
  • Stephanie Kwolek invented Kevlar while at DuPont, and showed that when woven, the strands of aramids were incredibly strong, thus leading to their use in bulletproof vests.
  • Charles J. Pedersen synthesized crown ethers while at DuPont, and showed that 12-C-4 had a high affinity for Li+, 15-C-5 for Na+, and 18-C-6 for K+. Pedersen later received the Nobel Prize in Chemistry for this work, and was one of the few recipients not to have a PhD!
  • Richard Shrock started his research career at DuPont investigating tantalum alkylidenes, which are metallic carbene intermediates in olefin metathesis. Shrock continued these investigations as a professor at MIT, and eventually received the Nobel Prize along with Prof. Robert Grubbs (Caltech) for his work in developing well-defined olefin metathesis catalysts.
  • F. N. Tebbe developed the eponymous Tebbe’s reagent for methylenation of carbonyl compounds. This led to the later development of the Petasis reagent, which I might cover later.
  • Norman Borlaug also worked at DuPont CR&D for 2 years, but did his major Nobel-Prize (and humanitarian) work afterwards. Norman Borlaug’s impact on humanity cannot be overstated; it’s mindboggling to think that just due to three people (himself, Fritz Haber, and Carl Bosch), we have been able to support an estimated extra 3 billion people on the planet!
  • T. V. Rajanbabu (now at OSU) and coworkers did some very elegant work in the 80’s developing a new polymerization method called group-transfer polymerization, and also demonstrated some very nice radical-mediated ring closures using Ti(III) reagents.

Arduengo’s work therefore follows a long line of high-impact research that was conducted by some of the best minds in the world at one of the most productive laboratories in the world! Shrock and Tebbe had done some carbene research at DuPont earlier, so there was a precedent for that. Arduengo generated the first stable persistent carbene by deprotonating the imidazolium species below. arduengo_1Catalytic DMSO is needed, and the actual base is the dimsyl anion, as NaH is basically insoluble in THF. In fact, NaH and THF reminds me of a spectacular gaffe by a research group in China that found its way into JACS in 2009 claiming the discovery of a NaH-mediated oxidation of secondary alcohols to ketones (which turned out to actually be mediated by peroxides in the THF or atmospheric oxygen).

The incredible thing is that the carbene so generated is stable and can be isolated in pure form. It can be recrystallized, and Arduengo was able to get X-ray diffraction data, as well as NMR data. The 13C NMR shows that C2 still has some electrophilic character even though it formally also has a lone pair. Part of the stability enjoyed by the carbene is due to the blocking provided by the very bulky adamantyl groups – in fact, the carbene can be melted and remelted without depression of the melting point!

As Arduengo concludes in the paper:

Carbenes have long been recognized as important reaction intermediates. The aggressive study of carbenes as reactive intermediates has provided much fundamental knowledge for chemical science. Until now there have not been any “bottle-able” carbenes, and we hope that the production of these stable nucleophilic carbenes will allow for convenient study of this class of compounds. We are currently investigating both the electronic structure and chemical reactivity of 1 and related isolable carbenes.

If NHC’s and related compounds are being used as versatile ligands in organometallic chemistry, organic synthesis, and as organocatalysts in their own right, it is all thanks to the seminal work of Prof. A. J. Arduengo. I sincerely hope that one day, he and his work get the recognition that is due.

Addendum: After all this, I hope you will share my disbelief that DuPont gutted the CR&D in 2015-2016.

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