musings on music and life

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.

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My copy of Superacid Chemistry…

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…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.

October 13, 2016

NMR data in papers

Filed under: Chemistry — sankirnam @ 1:42 pm

As someone who has written several papers in organic chemistry, and is currently in the process of writing another one, I just had this thought:

Why can’t journals require authors to include the .fid files of NMR spectra in the supplemental information, as opposed to spectral data lists or printouts of the spectra?

Including printouts is a holdover from a bygone era; thanks to the internet, everything is now digital, and storage space is no longer an issue for most people (or companies). Journals should make authors include the .fid files of any NMR spectra required to accompany a publication! At best, they get up to 50-70 MB (for 2-D NMR spectra), which in this day and age is not that big.

Making authors include .fid files has several benefits:

  1. Writing papers becomes a lot less tedious. Yea, its not fun to sit at your computer and adjust the magnification, aesthetics, and other aspects of a spectrum when all you’re really interested in is the data. Yes, I know you want to make it look like a piece of art, but really, if you have pride in your skills as a scientist, and if you have any ethical integrity at all, you should be willing to stand behind the raw .fid files of any NMR spectra of your compounds.
  2. It’s actually easier for other people. Let’s face it – a lot of the times, the integral values and peak numbers are not very visible on a printout. Also, if you have a very complex spectrum (such as from a natural product), then including multiple zoomed-in regions or going into detail on every single multiplet is a hassle. Also, if someone is trying to reproduce your procedure, doing a .fid-to-.fid comparison is a lot easier than looking at printouts.
  3. It reduces the risk for fraud. The Bengü Sezen case could have been partly avoided if she had been forced to submit .fid files for the NMR data of her products, as opposed to doctored NMR spectra. It’s much, much harder to manipulate a raw .fid file than photoshop an NMR printout.

If only journals accepted .fid files – I could just put them all in a folder, upload it, and be on my way! But unfortunately, most journals do not. JOC (Journal of Organic Chemistry) still requires a list of spectral data for synthesized compounds in the experimental section of the manuscript as well as printouts of the spectra in the Supplemental Information. I guess manually entered spectral data is still required because NMR processing software is still not very good at identifying multiplets and picking peaks (it’s especially bad when they overlap). A trained eye will know what to look for, but a computer will not.

These are some of the challenges that lie in bringing organic chemistry to the 21st century!

September 8, 2016

Latest publication

Filed under: Chemistry — Tags: — sankirnam @ 11:06 am

I just saw yesterday that another paper has been published based on work I did in my PhD. I was aware of this because the student wrapping this project up was in touch with me, writing up the paper from one of my thesis chapters and requesting copies of the characterization data (NMR, GC-MS, and HRMS) for all the compounds I had synthesized. This paper is the continuation of the Organic Letters paper that was published several months ago, and I’m relieved that I finally have a first-author paper, even if it is only in Journal of Fluorine Chemistry (which has an impact factor of 2.2), and coming a bit too late (over a year and a half after getting my PhD!) to be useful. But hey – it’s another line under the “publications” section in my CV, and at this point, anything helps.

May 11, 2016

Review of DavidsonX D001x

Filed under: Chemistry, education — sankirnam @ 11:49 am

I recently completed the above course on EdX; the full title is:

DavidsonX: D001x Medicinal Chemistry: The Molecular Basis of Drug Discovery

I have taken biochemistry and medicinal chemistry/drug discovery courses several times in the past during my undergrad and graduate studies, but the quality and coverage of the topics in this course was far, far better than anything I had taken to date. Major kudos to Prof. Erland Stevens (the instructor) for doing a fantastic job. I highly recommend this course to anyone with an interest in medicinal chemistry or drug discovery (even if you’re not interested in doing it for a career).

The course starts from the basics and assumes a basic knowledge of organic chemistry and algebra/arithmetic. The organic background is required just so you know the basic rules of structural organic chemistry; there are no complex synthetic schemes or mechanisms in this course. As far as reactions are concerned, the only reactions really touched upon were those involved in oxidations by the liver.

The math required is tedious but not terribly overcomplicated; the majority of the questions involved calculations with Michaelis-Menten and Lineweaver-Burke plots, or using IC50 values and the Cheng-Prusoff equation. These can all be done with Excel or Google spreadsheets, and Prof. Stevens demonstrates clearly how to do it, but that still doesn’t reduce the tedium of going through the calculations. The main thing to watch out for when doing calculations is that the EdX system only gives you 1 or 2 opportunities to input the answer before closing it off, so you have to make doubly sure to check your math and make sure the answer is correct!

This was my first proper exposure to the concepts of ADME (Absorption, Distribution, Metabolism, Excretion), which is central to pharmaceutical science. Each of these concepts was covered in detail; for absorption, the main methods of delivery that were covered were the IV bolus and oral ingestion, although one should keep in mind that these are only 2 out of the many ways of getting a compound into the body (others include suppositories, inhalation, transdermal diffusion, etc.). Distribution covered the basic “one-compartment” and “two-compartment” models, different ways of thinking about how a compound gets around the body. In this case, the bloodstream can be thought of as a “compartment”, and the fatty tissues as another compartment, both with different volumes, and so the concentration of the compound in each will be different. The blood-brain barrier was not touched upon in this course; this is a topic of personal interest to me, and it can be thought of as a barrier that divides one of the compartments.

In the context of drug discovery, Prof. Stevens gave an overview of the major approaches used in the industry today, such as combinatorial chemistry, HTS, peptidomimetics, fragment-based and phenotype-based screening, and natural products. Functional group replacements and isosteres were also discussed, common ones being replacement of a -CH3 group by a -Cl and tetrazole for a carboxylic acid. As an organofluorine chemist, I know that it is common to use -F substitution in this regard, but this was not really touched upon. The lecture on SOSA (Selective Optimization of Side Activities) was a little confusing; Prof. Stevens used the classic example of the discovery of Viagra’s ability to treat erectile dysfunction to illustrate this, but I remember being misled by the associated questions. This could be improved in future iterations of the course.

The cool thing about the course was the Virtual Lab component, and this really brings to life the concepts taught in the course, allowing the students to see the challenges that medicinal chemists face. Using the “bioactivity predictor” feature of Molinspiration, one can input the structures of small organic compounds and conduct a rudimentary screen against some receptors, and further details can be interrogated with the admetSAR website. The challenge in these labs was to design molecules with an affinity for a certain receptor (as predicted by Molinspiration), but still having good ADME properties. This is really fun to play with, as it gives a sense to the interplay between organic structure and function (which is what structure-activity relationships (SARs) are all about).

This course is a great introduction to medicinal chemistry, and I highly recommend taking it in the future, if it is offered again. After this, one can dive into the medicinal chemistry literature (e.g. Journal of Medicinal Chemistry or BMCL) and gain a deeper understanding of the topics covered in the course and how they are actually being used right now.

March 31, 2016

PhD in chemistry = ?

Filed under: Chemistry, Chemistry Jobs — sankirnam @ 11:29 pm

Derek Lowe had an interesting post earlier about outsourcing and the effect that free trade agreements have had on chemical employment in the US.

This raised a question in my mind: what does a PhD in chemistry enable you to do? If you get a degree in organic chemistry, that usually implies you have some kind of expertise in organic synthesis, but as we’re seeing lately, more and more synthesis is being farmed out to CROs internationally. These CROs may have PhDs in their labs carrying out the synthesis for their clients, but that’s besides the issue; I am concerned with holders of PhDs in chemistry in the US. Generally speaking, fresh PhD graduates will usually enter industry positions working on early-stage projects, if they are doing synthesis. If the early-stage synthesis is being shipped out to other countries, then how can fresh graduates get their foot in the door? Derek Lowe states that companies are generally wary about outsourcing late-stage API synthesis to other countries due to IP security issues, but “for early-stage material, it generally works pretty well.”

Now here’s the kicker: Derek Lowe concludes by saying, “there probably be shouldn’t be that many basic-level organic chemistry services in the US. There are times when it makes sense, and the further up the value chain the more sense it makes, but “grunt work”, however you define it, is (other things being equal) going to migrate to lower-wage situations”. If fresh PhDs are generally expected to work on basic synthesis when they are first hired by industry, does that mean that a PhD simply certifies you to do “grunt work”? And does that mean there is no longer a market for fresh PhD’s in the US to do synthetic work? This would go a long way to explaining why postdoctoral experience has become a requirement for industry positions in chemistry, to ensure that fresh entrants are more experienced and can begin at a more advanced stage.

I had the opportunity to have an in-depth chat with the current ACS president Donna Nelson and the ACS president-elect Peter Dorhout at the ACS convention in San Diego earlier this month about the issue of underemployment and unemployment of chemists today. Interestingly enough, they pointed out that there has been a 100% increase in the number of BA/BS degrees awarded in chemistry over the last 15 years, but the unemployment gap has also grown to about 14% today (the link is from 2013, but that is the latest figure I could find). Another thing to keep in mind is that students can dodge unemployment/underemployment by going back to school for another degree, so this statistic can be difficult to measure. This is key at both the BS and the PhD levels, and PhD’s have the additional option of doing a postdoc, which is becoming increasingly common – and as Chemjobber says, “postdoctoral positions are quite often the scientific equivalent of an inferior good, that is a position that one would not take, if one had a better option”. There is also not enough effort being done by universities to track the career paths of their graduates; at the bachelor’s level, that may be prohibitive due to the volume of data (but of course, that should not be an issue for a “data scientist” skilled with “big data”), but at the PhD level, it is more feasible, and should be done. There should be a database where students and postdocs should be able to look up PI’s and track the careers of their graduates; a PI who has too many students going to get additional degrees after their PhD would raise a red flag. There should also be some way to tie federal grant funding for PIs with student career success – but the issue there is what metric would you use? My idea is to track the number of students gainfully employed in their field of training and with a salary of at least $100,000 within 3 years of graduation (I think that’s reasonable, but feel free to tell me I’m crazy). The exception would be those on the academic track, either as an assistant professor or a postdoc.

The other thing that crossed my mind is that the ACS should put out an advisory to all students interested in chemistry about the poor job market, similar to what was done by Texas A&M University for its incoming Petroleum Engineering students in 2013! If the ACS were to really be looking out for its members, it should do what the AMA does, and start restricting the supply of chemistry graduates. In any case, it is amusing (and heartening) now to see the word percolating out. If the Chemistry subreddit is any indication, the level of realtalk nowadays is increasing, which is a good sign.

The modern scientific-academic complex as it exists today in the US is the legacy of Vannevar Bush. In a document called Science, the Endless Frontier, he advised the president at the time (Truman) to continue funding fundamental science in a big way, setting up the huge expansion of the university system in the US, and the eventual founding of the NSF in order to publicly fund science. This rapid expansion of the US university system in the latter half of the 20th century made it relatively easy for PhDs and postdocs at the time to find academic positions. Unfortunately, the market has long since saturated, resulting in the situation below, summarized by Jorge Cham in a tongue-in-cheek manner:phd030909s

I know people are tired of reading this over and over again, but I wanted to get these thoughts down, as they’ve been in my mind for a while. I’ll do my best to refrain from this topic in the near future, since people have told me that they do find this depressing.

January 28, 2016

Kudos for methanol!

Filed under: Chemistry — Tags: , , — sankirnam @ 8:53 am

I was rather pleased to see that my PhD advisor’s work had made the front page of Reddit this morning. Reddit is one of the most viewed sites on the internet, and the presence (or absence) of topics on this website serves as a heuristic for what is in the mind of the public. The quality of the discussion in the Reddit thread is also very good; it was heartening to see that everyone (at least, nerds with internet access) has their facts correct.

I have talked in some depth about the Methanol Economy before; I strongly believe that this will be a viable energy solution for the future. Of course, this isn’t the only solution, as it has to be used in tandem with a mix of energy sources, including solar, wind, hydroelectric, and nuclear, depending on location. Methanol serves as a very convenient energy carrier and energy storage medium due to it’s convenient physical and chemical properties.

Unfortunately, I do not have journal access right now, so I cannot comment on the article. I do remember that this project has been going on for a long time; it was started back when I was still there, around 2014 or so. This seems to be a continuation of work done earlier, in which it was observed that polyamines (specifically ethyleneimine) adsorbed on silica could reversibly adsorb CO2. This CO2 adsorption process was then combined with CO2 to methanol reduction in the same flask. Since I don’t have journal access right now, I don’t know how good the yield, selectivity, or catalyst TON (Turn Over Number) is. These numbers are critical to evaluating if this process is really a big breakthrough or just another incremental improvement.

January 1, 2016

Latest paper

Filed under: Chemistry — Tags: — sankirnam @ 7:31 pm

So this actually came out over a month ago, but I couldn’t get around to posting about it until now. Link for those interested. The sad part is that I currently cannot access this, even though it is my own work!

The research in this paper was developed as part of my thesis work on superelectrophilic activation, in order to develop new electrophiles for Friedel-Crafts reactions.

This is the only place where I can mention the contributions of an undergraduate student who worked with me on this project – Mr. Billy Stevens. I don’t know why his name was omitted from the list of authors on this paper, even though I had reminded my advisor to include his name multiple times.

This paper originated from work we had previously carried out on the superelectrophilic activation of acrylic acids; we found that they could undergo one-pot alkylation and cyclic acylation with arenes. Thus, we extended this work to include thiophenols, as sulfur can serve as an interesting nucleophile under these conditions. I optimized the conditions and prepared a variety of thiochroman-4-ones using crotonic acid; I was also able to extend this to the use of 4,4,4,-trifluorocrotonic acid for the synthesis of trifluoromethylated thiochroman-4-ones, which unfortunately is not included in the Org. Lett. paper.

I’m rather pleased to have a publication in Organic Letters. This is one of the premier journals in the field of organic chemistry, specializing in short communication-style reports, rather than full-length articles or reviews. Even though the journal started very recently (1999), it is very successful, has a high impact factor, and routinely publishes very interesting, highly-cited papers. At the NOS last year, I got a free Organic Letters shirt, among other things. I suppose wearing this shirt has probably resulted in me getting a paper in this journal, in some karmic fashion.

November 23, 2015

My thesis, for those interested

Filed under: Chemistry — Tags: , — sankirnam @ 10:57 pm

I was bored and during the course of my browsing, found the link for my thesis on the USC Digital Libraries.

It is interesting that USC changed the procedure for thesis submission; graduates no longer have to submit their dissertations to UMI Proquest, and in the process of making the whole process digital, it is no longer possible to order hard copies of the thesis (at least to my knowledge). Not that I wanted a physical reminder of the wasted years of my life…

November 2, 2015

My thoughts on the broad state of chemistry (2015 edition)

Filed under: Chemistry — Tags: , — sankirnam @ 12:34 am

I had to fill out a questionnaire regarding my thoughts on the broad state of chemistry as part of the 2nd round of a job application; I feel like some of what I’ve written is worth sharing. Of course, I’ve omitted anything that explicitly references the position.

2) Please identify three chemistry papers that have been published in other journals within the last year (excluding Nature and Science) that, in your view, would have been of the standard required for consideration in a chemistry journal being launched by [journal company]? Why have you selected these papers and who would you recommend as potential reviewers for each?

I think it is also worthwhile to demonstrate what would not be worth publishing, so I will include one example of an inferior quality manuscript here, as well as 2 examples of good papers.

  1. Synthesis and Characterization of 1,2,3,4,5-Pentafluoroferrocene – Karlheinz Sünkel, Stefan Weigand, Alexander Hoffmann, Sebastian Blomeyer, Christian G. Reuter, Yury V. Vishnevskiy, and Norbert W. Mitzel, Journal of the American Chemical Society, 2015, 137, 126. This paper describes the first successful preparation of pentafluoroferrocene, and while this may not have immediate practical applications, this is still worth publishing, especially since it represented a synthetic challenge, which is why it was not synthesized until now. Potential reviewers for this include Heinrich Lang, Ian Manners, and Janusz Zakrzewski.
  2. Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry – Paul M. Osterberg, Jeffry K. Niemeier, Christopher J. Welch, Joel M. Hawkins, Joseph R. Martinelli, Thomas E. Johnson, Thatcher W. Root, and Shannon S. Stahl, Organic Process Research and Development, article ASAP. Work in process chemistry is also very important, but since this mainly happens in industry, a lot of work in this area goes unpublished. Publications like these should be published not only because they afford outsiders a look at industry processes, but also because it is important to promote safety and good practices, which is what this article is about. This features general, non-protected work that is relevant to all who do (or are considering doing) aerobic oxidation chemistry. Reviewers include Chris Senanyake (Boehringer Ingelheim), and anyone else working on process chemistry in industry.
  3. Simple Amine-Directed Meta-Selective C−H Arylation via Pd/Norbornene Catalysis – Zhe Dong, Jianchun Wang, and Guangbin Dong, Journal of the American Chemical Society, 2015, 137, 5887. This manuscript is an example of what should not be published. The experimental work is rather sloppy; when optimizing the reaction conditions, the authors do not state how they first came up with the “acetate cocktail” in the first place. That issue aside, this reaction is also highly impractical; nobody will use it not only because it involves an unusual ligand (AsPh3) as opposed to the more common phosphine or NHC ligands, but also because it requires super-stoichiometric amounts of other metal reagents (e.g. 4.5 equiv. AgOAc and 3.0 equiv. CsOAc). The consequence is that this reaction will never be scaled up. This reaction is not that original either, as Gaunt was the first to publish on directed meta-arylation back in 2009.

3) Can you list three research areas that are generating a lot of interest in chemistry at present? Which investigators are actively involved in pursuing these areas? (Ideally, one suggestion should come from your own area of expertise and the others from different aspects of chemistry.

  1. Organofluorine chemistry is generating immense interest in the chemistry community at present, so much so that practitioners talk of a “bubble”. Research that is not very novel or incremental at best is published in very high impact factor journals simply due to the involvement of fluorine. On the other hand, these statements should not imply that the field is not important; it is, which is why it is receiving so much attention lately. Several people are publishing in this area, including my Ph.D. advisor, Prof. G. K. Surya Prakash. Others include Veronique Gouverneur (Oxford), Tobias Ritter (Harvard), John Welch (SUNY-Albany), Jinbo Hu (SIOC), and Stephen DiMagno (UN-Lincoln).
  2. Organocatalysis is also a very active area of research in modern organic chemistry, and has really only developed over the last 15 years, even though the seeds can be found in publications from the 90’s, 80’s and 70’s. It continues to receive attention from the organic chemistry community and was prominently featured in the National Organic Symposium this year. Key investigators in this area include D. W. C. MacMillan (Princeton), Benjamin List (Max Planck Institute), Karl Anker Jørgensen (Aarhus), and Yujiro Hayashi (Science University of Tokyo).
  3. Cliché as it may seem, palladium catalysis is still a topic of current interest in chemistry. While reactions such as the Heck, Suzuki, and Negishi reactions are now well established in the chemists’ toolkit now (as exemplified by the Nobel Prize in Chemistry in 2010), there are still many orthogonal modes of reactivity that are being uncovered in this area. Melanie Sanford bought to attention the scope of oxidative Pd catalysis and the potential of Pd(II)-Pd(IV) catalytic cycles for organic and organometallic chemistry. Similarly, Jin-Quan Yu and Matthew Gaunt are also continuing to demonstrate new applications of Pd catalysis to solving problems in organic synthesis based on new ligand motifs and catalytic cycles.

4) Can you look through a recent copy of a top tier general chemistry journal and identify research topics that are currently not well represented. Please explain your thoughts on the importance of these fields (if any). How would you go about avoiding similar omissions in [chemistry journal]? Do you think that such omissions are important?

One example of a topic that is not well represented today is origin-of-life chemistry. The origin of life on this planet is a puzzle that is purely chemical in nature, and so chemists are uniquely poised to solve it. One way to remedy this is to seek out chemists doing research in this area and invite them to publish in this journal. However, the number of potential topics in chemistry in practically infinite, and so this is not really a long-term solution. On the other hand, this is what is beautiful about chemistry. A journal will therefore always have topics that are omitted or poorly covered if its issues are to be considered truly representative of research in the field.

Lanthanide and actinide chemistry is also poorly represented at the moment. Some of the lanthanides have found use in organic synthesis (such as cerium (CeCl3) and samarium (SmI2)) as reagents or Lewis Acids. Their organometallic chemistry remains relatively unexplored, with only a handful of people doing research in this area, such as William Evans (UC Irvine).

5) Please identify three areas or topics appropriate for a minireview or review in [chemistry journal] and make suggestions for potential authors. On what basis did you choose the three topics?

  1. CO2 capture technologies and alternative energy derived from recycling CO2. This is an incredibly important topic, as it relates to global warming, which affects everyone on this planet. Potential authors include Prof. George A. Olah (USC), Robert Zubrin, Anne Korin, and R. James Woolsey, Jr.
  2. “Asymmetric olefin difunctionalization reactions”. These reactions are epitomized by the 3 Sharpless reactions, AA (Asymmetric Aminohydroxylation), AD (Asymmetric Dihydroxylation), and AE (Asymmetric Epoxidation). However, since then, there has been very little work done on developing other types of reactions in this class. Potential authors for a minireview on this topic include K. C. Nicolaou (Rice University), Scott Denmark (UIUC), and Noah Z. Burns (Stanford).
  3. “Hypervalent Bromine chemistry”. The chemistry of bromine in higher oxidation states (such as +3 or +5) or with multiple ligands has not been explored in depth. This area was pioneered by the late Prof. J. C. Martin (UIUC), and is now continued by Prof. Masahito Ochiai (University of Tokushima). Although the practical uses of this chemistry may be limited due to the necessity of using aggressive oxidizing agents (such as BrF3), it is nonetheless a fascinating academic topic.

5) In your opinion do you feel that chemistry is well represented in leading journals such as Nature or Science? Please give some explanation about how and why you came to this conclusion?

In general, whenever I look through an issue of Nature or Science, I am usually disappointed that there are usually 0-1 chemistry articles present. This is partly due to the interdisciplinary nature of the journals; pure chemistry articles are not perceived as “sexy” when compared to other, more applied fields. But there is also a self-selection bias present. Most of the chemists I know generally have an idea of the kind of work they would like to submit to Nature and Science, and so do not frequently submit manuscripts to these journals.

6) A key feature of [chemistry journal] will be the publication of unique discussion-type formats. An example would be differing perspectives written by experts, with the opportunity for online commenting by the community. Can you provide three potential topics/questions that would be of interest to chemistry academics and also non-chemistry experts such as economists, philosophers, government, funders etc? In each case, potential author candidates should be provided.

  1. “The current state of Organic Synthesis”. Many people have written on this topic over the decades, but this is something needs to be continually addressed by the organic chemistry community at large. What is the motivation for academic research in organic chemistry? What are the challenges that lie in this field? Potential author candidates include: Prof. Dieter Seebach (ETH), Prof. George Whitesides (Harvard), Prof. D. W. C. MacMillan (Princeton), and Prof. L. E. Overman (UC Irvine).
  2. “The current state of chemical education”. This is an important topic as it affects every student graduating with a degree in chemistry. In various courses, it will be worthwhile to examine what is relevant in school curricula and what has become outmoded. For example, in most general chemistry courses, why is the syllabus structured the way it is, with an overemphasis on analytical chemistry, and a lack of emphasis on qualitative methods? Also, one can discuss the mismatch between the academic production of chemistry graduates and the number of positions available in industry and academia; this is most clearly evident when looking at the employment statistics of PhD graduates. The contributing authors can literally be anyone who works in education (or academia) or has gone through it (which is basically anyone with a degree).
  3. “The current model of chemical research”. There are a lot of people who believe that advances in chemistry (or research in general) are made in small, incremental steps, and that is one of the justifications for having such a large research industry in the United States (consisting of thousands of undergraduates, graduate students, postdoctoral scholars, and university faculty in hundreds of universities and institutes). However, in my opinion, most major advances in science are quantum leaps, discoveries that significantly advance their field and cannot be predicted beforehand. These breakthroughs are usually not the result of incremental research. Examples are: Kary Mullis’ discovery of PCR, the “scotch tape” synthesis of graphene, and F. Sherwood Rowland’s observation of the ozone-depleting effects of CFCs. In this light, chemistry research would be observed to be hugely inefficient, and is it worth justifying on such a large scale? Potential author candidates could include: Nassim Taleb (author of The Black Swan), ACS (American Chemical Society) executives, as well as economists working in the US government.

8) What was your opinion on the recent Nobel Prize in Chemistry awarded on the 7th October 2015?

I have mixed feelings. On one hand, the topic that the prize was awarded for is tremendously important; understanding the mechanism of DNA repair allows us to better understand the aging process, as well as the proliferation, growth, and treatment of cancer. On the other hand, this topic is not really “pure” chemistry, and is more of a biology topic. One can say that it is a biochemistry topic, and that it lies in the intersection of the two fields. However, the result is that the contributions of practicing chemists to science and the welfare of humanity is overlooked each time the prize is awarded in this manner; this also affects the public perception of chemistry and chemists, and will result in the public thinking that chemists do not do anything of importance. On the other hand, this is where the future of chemistry is headed. Now that chemistry has matured, the next generation of research will be interdisciplinary.

I’m pleased to share that thanks to these answers, I was selected to the next round of interviews for this position! So hopefully that means I have written something of value of here. Readers, feel free to let me know what you think as well.

August 14, 2015

CBS catalysis…and trifluoromethylation shenanigans

Filed under: Chemistry, Classics in Organic Chemistry — Tags: — sankirnam @ 12:20 pm

In order to wash the previous paper from our minds, it is often good to step back and read some of the really important  manuscripts from decades past. One example is the classic 1987 JACS paper by Corey on the enantioselective reduction of ketones, which after this publication, came to be known as the “CBS” method, after the authors (Corey, Bakshi, Shibata).

In the introduction, Corey, Bakshi, and Shibata state that Itsuno had already discovered that mixtures of borane and chiral vicinal amino alcohols (derived from enantiopure amino acids) were very effective for the stereospecific reduction of ketones. However, Corey states that “reagent structure, scope, and mode of reduction has remained at a primitive level, limiting both application and further development“. Thus, they isolated the complex formed from borane and (R)-1-phenylethanol as well as borane and (S)-diphenylprolinol by vacuum sublimation.

CBS catalyst

The complex derived from prolinol and borane turned out to be extremely active, and Corey reports reductions of around 95% ee with >99% conversion at room temperature! The simplicity and practicality of this paper should be noted; according to Google, it has at least 1,200 citations! The catalyst derived from prolinol soon became commercially available from several vendors, and is now popularly known as the “CBS catalyst”. Interestingly enough, this can also be thought of as one of the early modes of organocatalysis, but the term does not appear even once in this paper. The use of prolinol here laid the foundation for the future development of the Hayashi-Jorgensen catalyst, which is now an exceedingly popular organocatalyst.

Upon typing this, I became reminded of a similar incident that occurred in the fluorine chemistry community while I was doing my PhD. One of the developments in trifluoromethylation chemistry that occurred during that time was the discovery of a copper-catalyzed trifluoromethylation of aryl iodides by Prof. Hideki Amii. The proposed mechanism involved the intermediacy of phenanthroline-ligated copper(I) complex [(phen)CuCF3], but that complex was not characterized or isolated. Prof. John Hartwig (UIUC, now at Cal) soon published a paper where all he did was synthesize the [(phen)CuCF3] complex and use that as a trifluoromethylating agent! In his talks, Hartwig claimed that using the pre-synthesized complex in this manner greatly expanded the substrate scope beyond what Amii reported, although he always skirted around the issue that he had taken a reaction that was previously catalytic in copper and made it stoichiometric in copper! Hartwig soon started a company based on this chemistry, selling the [(phen)CuCF3] complex, which is now known as “Trifluoromethylator“.

But really, is this any different than what E. J. Corey did in 1987 with Itsuno’s chemistry? I’m not trying to justify or defend Hartwig’s research, but there is a precedent for this kind of stuff, from a Nobel Laureate, no less. Having some distance from fluorine chemistry at this point gives me a valuable outsider’s perspective now, without which I would not have come to this realization.

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