musings on music and life

November 17, 2016

Classics in Organic Chemistry, Part VIII

Filed under: Classics in Organic Chemistry — sankirnam @ 3:46 pm

This paper was further down on my list, but I’ve decided to bump it up and cover it today.

Modern practitioners of organic synthesis or medicinal chemistry will no doubt be aware of how hot fluorine chemistry is now; every issue of JACS, JOC, Organic Letters, Angewandte Chemie, or Chemical Science has at least one paper on the development of new fluorination methodologies. But this was not always the case. Fluorine chemistry used to be considered very esoteric, primarily because of the reagents required (F2, HF, SF4, among others), which also necessitated special reaction conditions and apparatus. This limited the accessibility of fluorinated compounds, and research in this area was primarily done by groups in academia (such as Olah, Seppelt, Christe, Bartlett, Rozen, Haszeldine, Barton) or industry (DuPont, 3M) that had the infrastructure in place to carry out this chemistry.

One of the long-standing challenges in organofluorine chemistry was the development of a mild, effective method to introduce the trifluoromethyl (-CF3) group into organic molecules. I had briefly discussed the challenges in isolating the trifluoromethide anion earlier; this is why the development of nucleophilic trifluoromethylation methods only came about recently. It is necessary to use reagents that act as “pseudo-anions”, and can do a transfer of the -CF3 group under certain conditions.

Prakash and Olah were motivated by their desire to study carbocations that had an electron-withdrawing group α to the cation, such as the ones below:coc_8_1

The synthesis of the precursors for these cations is rather interesting – each involves a different type of chemistry. The α-nitro cation above is prepared by ionizing the gem-dinitro compound (which was synthesized from benzophenone oxime and N2O4), while the α-fluoro cation is prepared from gem-difluorodiphenylmethane, which can be prepared from benzophenone and SF4. The α-cyano cation is prepared by ionizing benzophenone cyanohydrin, which can be easily prepared using a procedure developed by Prof. Paul Gassman with TMSCN and ZnI2.

The α-CF3 cation can be prepared from 2,2,2-triphenylacetophenone and phenylmagnesium bromide, but substituted derivatives are more challenging to prepare; you’ll need substituted derivates of 2,2,2,-triphenylacetophenone which are either challenging to synthesize, of limited commercial availability, or expensive. The easier route would be to start from benzophenone and add a -CF3 to the carbonyl. This was elegantly solved by Prakash, Olah, and Krishnamurti in 1989. They demonstrated that the compound TMSCF3 could undergo nucleophilic trifluoromethyl transfer to carbonyls very readily, under fluoride-ion catalysis. TMSCF3 had first been prepared by Prof. Ingo Ruppert (Germany) a few years earlier, but he had not demonstrated any potential reactions with it.


This is the proposed mechanism; interestingly, fluoride is not necessarily the only catalyst that can initiate this reaction – Dr. Prakash later showed that carbonates and amine-N-oxides can also act as catalysts. I’m not sure if DMF/imidazole can also initiate this reaction (as they do Corey’s TBS protection), but I’m sure that should also work. One big challenge that still has not been solved is to do this transfer asymmetrically; in other words, a facially-selective trifluoromethyl transfer to carbonyls is still lacking.

This has led to a whole slew of developments which are simply too numerous to list here, leading to TMSCF3 being called the “Ruppert-Prakash reagent”, after the chemists who first synthesized it (Ruppert) and demonstrated its synthetic utility (Prakash). The commercial availability of TMSCF3 also opened up trifluoromethylation to all organic chemists (the original synthesis (adapted from Ruppert’s work) uses CF3Br, which is now banned under the Montreal Protocol). Recently, a postdoc in Prakash’s group (who used to work next to me) came up with an improved synthesis of TMSCF3 from CF3H, which is a byproduct of Teflon manufacturing, and therefore much cheaper and more readily available than CF3Br.

Many, many other types of trifluoromethyl transfer reagents have been developed, and almost all of these use TMSCF3 in their synthesis. The electrophilic trifluoromethylating reagent developed by Togni is illustrative of this. Melanie Sanford has also conducted very nice work in organometallic chemistry studying the reductive elimination of -CF3 from Pd(IV); I particularly remember a very interesting set of papers she had published that showed that “F+” reagents were the only compounds capable of oxidizing the Pd(II) to Pd(IV) and selectively inducing the reductive elimination of the -CF3, because the energy of reductive elimination of -F was greater than that of -CF3. It’s not much though; I think it was 5 kcal or less! Of course, all of these trifluoromethylated metal complexes were synthesized with TMSCF3 as the -CF3 source.

Stephen Buchwald (MIT) also published a couple of papers using TMSCF3 and Pd/Cu complexes for doing -CF3 transfer to a variety of systems.

CuCF3 and AgCF3 are also receiving increased interest now; I talked about CuCF3 earlier. Both of these complexes can be generated in situ from TMSCF3 and appropriate metal salts, and can be used for a variety of transformations, including Sandmeyer-type reactions. I remember that I and my labmates had tried to implement this reaction without much success, and when we saw Goossen’s paper, it seems that the copper counterion is very significant; the reaction only works with CuSCN, which we did not have on hand.

As mentioned earlier, the challenge with developing organometallic reagents for nucleophilic -CF3 transfer (such as LiCF3 or CF3MgBr) is that the CF3 anion is kinetically unstable and tends to undergo fast α-defluorination to yield difluorocarbene. This can be a nuisance, but depending on your needs, can also be synthetically useful. Difluorocarbene can also undergo the usual carbene reactions, such as 2+1 additions to olefins to give gem-difluorocyclopropa(e)nes, as well as insertions into weak bonds, such as S-H or Sn-H. Some friends of mine in Prakash’s group were able to use this to develop useful chemistry – one nice example is the insertion of CF2 carbene so generated into the Sn-H bond of Bu3SnH to make Bu3SnCF2H, which proved to be a useful reagent for -CF2H transfer.


There was a paper published a couple of years ago by a group in Russia describing the synthesis of TMSCF2H from TMSCF3 by a simple reduction using sodium borohydride. This allows improved access to TMSCF2H (which was otherwise difficult to prepare) and related analogues (such as TMSCF2D, TMSCF2Cl, and others). The challenge with TMSCF2H is that it is more difficult to activate compared to TMSCF3 (it is speculated that the reactive species that does the actual -CF3 transfer is a pentavalent siliconate), accounting for the limited substrate scope (with ketones) in this paper by Jinbo Hu.

Anyway, this is a brief overview of trifluoromethylation chemistry, and I hope the huge impact that Dr. Prakash’s initial paper had is evident – TMSCF3 is now the major source of -CF3 in organic chemistry; most research chemists will not think about how it is produced! This is by no means exhaustive, and numerous reviews (such as this one) are being published about this area of chemistry all the time; check those out if you want more details.

October 31, 2016

Review of MITx 6.00.1x

Filed under: Coding, education — sankirnam @ 12:53 pm

just finished the above course – I just completed the last problem on the final exam and completed the exit survey a few minutes ago, so I figured I would write my thoughts on the course while they’re still fresh.

My impressions of the course are unanimously positive. I just finished the current iteration of the course (Aug – Nov 2016), and I found it to be excellent. I just finished writing an email to Prof. Grimson (the professor conducting the course), thanking him for all his efforts in preparing such high-quality materials!

Keep in mind that the title of the course is “Introduction to Computer Science and Programming using Python”, and so it is aimed to be an intro CS course of sorts. Nonetheless, it does serve as a very good introduction to the Python language, and covers fundamental CS concepts while teaching the Python language, including the various data structures (lists, tuples, and dictionaries), functions, and classes. The course isn’t intended to teach Python specifically, and so doesn’t cover a lot of the things unique to Python (such as lambda functions, list comprehensions, and other topics).

In retrospect, I wish I had taken this course before taking the “Data Science” bootcamp this summer – I would have been better prepared and would have had at least a rudimentary understanding of the CS fundamentals. Anyway, what’s done is done, and I’m glad that I was able to take this course.

The problem sets were very well crafted. They were appropriately challenging, and I probably did spend around the recommended 15 hours/week or so on them, and they weren’t too difficult where I would have ended up throwing my computer out the window and quitting in frustration. The bonus is that I ended up also learning how to use my computer better – since this course uses Python 3, I ended up using Anaconda to install that (so that I could manage that alongside my existing Python 2 install). I also ended up using Spyder as my IDE of choice for the course, and I’ve come to like that a lot.

As always, if you want to take a look at the problem sets, exercises, and my solutions, I’m posting everything to my github.

Proof of completion (I blacked out my username and email to dodge spambots):mitx6001x

Anyway, onwards to the sequel course, 6.00.2x! I started this course and it’s proving to be MUCH tougher, since the barrier is no longer the Python language, but abstractly developing algorithms before implementing them in Python.

October 18, 2016

Still on the job search

Filed under: Chemistry Jobs — sankirnam @ 4:09 pm

It has been about 20 months since I got my PhD in chemistry, and I’m still on the search applying for my first job. It’s been a really emotionally draining, tough ride. Before I graduated, I had heard horror stories from others about the chemistry job market and how brutal it is…but there’s nothing like experiencing it firsthand yourself. There are several major hurdles, which I’ll try and document here.

  • Applying online. The major portal for job applications is now online. This is convenient for both job seekers and employers; job seekers can electronically send applications for positions (which normally include a cover letter, resume and/or supplemental information such as a research summary) from the comfort of their home or office. With the internet, employers and recruiters also have a larger talent pool. The process is still time-consuming, however; I would estimate that it takes me on average about 45 minutes to fill out an online application; this includes filling out the information in the online forms (I always end up having to manually do this since the resume parsing never works), making edits to my resume to tailor it for the position, and writing a cover letter. I put in all this work, only to be greeted with:
  • The cone of silence. This is the most frustrating aspect of the job search. You’ll submit your application online, and usually within 1 minute receive an e-mail saying “Thank you for your application, it has been successfully received, and will be reviewed by our team”. This will be followed by….. silence. You won’t hear anything for weeks, or even months on end. I have a list of all the jobs I have applied to, and at least 85% of them have a note saying “Status: No reply”. I would follow up… if I knew who to follow up with! The internet is only so helpful in this regard, and its not always possible to find out who the particular recruiter or hiring manager is for a particular position.
    Case in point: I recently applied to 3 positions in Allergan in August, and still have not heard anything back. The recruiter for the position (as listed on LinkedIn) was unresponsive to my e-mails, and it was only by following up with a friend of a friend in the company that I was informed that yes, they had my application and that it was still under consideration. The funny thing is, these positions are still being listed on job boards and are still accepting applications!
  • The insane saturation of this particular job market. Don’t listen to the politicians – we don’t have a shortage of scientists in this country. We have a massive, massive, glut, and anyone who does any kind of scientific hiring will be able to corroborate this. It’s especially bad at the PhD level – back to my example at Allergan, I was discreetly informed not to get my hopes up since they received 500+ applications for 1 opening in medicinal chemistry. Plus, I did happen to have some nice chats with senior executives at [unnamed pharma companies], and they (somewhat condescendingly) told me to stop wasting my time, because pharma hiring is focused on pedigree; if you don’t have a degree from Harvard/Stanford/MIT/Caltech, etc. your application will be immediately discarded. The irony is that these executives did not have degrees from those schools.

That being said, it seems to me that there’s really only one surefire way to get a job out of school, and that is through campus recruiting. Unfortunately no companies in my area of study (chemistry) came to hire at my university, so that ruled out that approach. The other way is to join a position through a friend’s referral, which works for smaller companies and startups. Applying to big companies is seemingly slower, since the application has to go through several stages – a recruiter (who may or may not know the subject and understand your resume), followed by an interview with the hiring manager (who will be knowledgeable in the domain), and further interviews. I have been told that ‘80% of jobs never get advertised’ and other statistics like that, but those are only relevant for experienced job seekers looking to move laterally; it’s not relevant for fresh graduates looking for their first job. For your first job, you need to play by the company’s rules for applications. Once you get experience and make contacts, then you can get your friends to backdoor you into positions at other companies.

At least, that’s my observation. I don’t know what other avenues there are for gaining employment (I should specify that I mean relevant employment that would utilize my education and background; I could always go and be a cashier at a grocery store, but that would be a massive waste of my education and also the taxpayer money that went into funding that education). If anyone has any ideas, let me know!

The other question that comes up is “so, what about Data Science?”. Yes, that is still on the table; I’m still working with recruiters from Harnham, but nothing has panned out yet. To be honest, I’m not totally thrilled. After doing some soul-searching, I have realized that I don’t necessarily have the mentality to go into “Data Science” or software development. It’s one of those things that I am simultaneously overqualified (I have a PhD, after all) and underqualified (PhD in a irrelevant subject) for. I don’t have years of software development experience or deep knowledge of a lower-level language (e.g. Java, C, C++), or a degree in math, statistics, computer science, or physics (which are considered sexy in this field). I have actually been advised that maybe I should hide my PhD in organic chemistry since it is irrelevant to Data Science. At the same time, I’m glad I took that bootcamp – I can now study the material at my own pace, and the knowledge of programming and computational thinking is becoming increasingly critical today, what with the amount of time we spend interfacing with digital devices in the form of laptops, cellphones, tablets, and other computers.

So….I’m still looking for my first job in chemistry! If anyone has any leads, please do let me know.

I forgot to include this gem as an example to illustrate my point:
I applied to this position at BBraun in Irvine in March – on paper, it is a typical Analytical chemist position, and one that I am reasonably well-suited for. The only weird thing is that they explicitly want “Pharmaceutical industry or a relevant post-doc experience of 3-6 years for PhD”, which doesn’t make much sense (but can be chalked up to “credential inflation” in this over-saturated job market). In any case, I was swiftly rejected by the company, but to my surprise, the position is still up, over 6-7 months later! Stuff like this just really infuriates me. Companies like these waste so much time searching for the perfect “purple unicorn” candidate, and then raise a hue and cry about a “STEM shortage” when they’ve rejected everyone for the most random reasons.jackie-chan-wtf

I know people are curious, so here are the stats:

Jobs applied to: 1465
Interviews: 9

EDIT (10/26/2016): This morning, I was greeted with this e-mail from Merck: “Thank you for your interest in Merck.  We appreciate you taking the time to pursue career opportunities with us.  We have chosen at this time to suspend the search for this position and may reopen the search at a later date”. I applied to this position 2 months ago (August 25, 2016, to be exact), never heard anything back, and then received this notification. Seriously, something is screwy in hiring – has this happened to other people, or is it just me? Also, I honestly think there should be less of a stigma against unemployment – just look at how much time elapses in the job search! The companies are the ones that are slow in getting back to job seekers; in other words, the rate-determining step in the job search is waiting to hear back from companies, which means that individuals should not be held completely responsible for long periods of unemployment if they are applying aggressively.

2ND EDIT (11/16/2016): Yesterday, I got this email from Eli Lilly: “Thank you for your recent inquiry for the Research Scientist-Small Molecule Design and Development-Developability position, requisition #28370BR.

The position in which you originally expressed interest has unfortunately been cancelled and was not filled. Please feel free to review current openings and submit your interest accordingly”. At least this position didn’t leave me hanging for that long – I applied to it on 10/13/2016. I’m just completely nonplussed here…

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!

October 12, 2016

Classics in Organic Chemistry, Part VII

Filed under: Classics in Organic Chemistry — sankirnam @ 6:04 pm

Ok, let’s keep the train rolling here…

This next topic is related to an ill-defined project I worked on early in my PhD, where I was investigating synthetic reactions related to isocyanide synthesis using TMSCN. One of the first places my advisor told me to look was at an intriguing 1982 JACS communication by Prof. Paul Gassman. To preface, it is well-established that the cyanide ion is ambident and can react from either the or the C position; the conditions employed can influence whether a nitrile or isonitrile will be obtained as the product. Gassman’s paper revisited this topic using epoxides as the electrophile, and he demonstrated that by intelligently choosing the right Lewis Acid (ZnI2 in this case), one can obtain β-isocyano alcohols as the product upon ring-opening with TMSCN (followed by desilylation with KF).cyanide1

Now that I reflect about the background for this paper, it is actually not as serendipitous as I had used to think as a first/second year grad student. Gassman had previously published a few papers, including an Organic Syntheses procedure, for converting ketones to cyanohydrins; the conditions employed in the above reaction are pretty much identical, save for switching out the ketone for an epoxide.

The utility of this reaction lies in the fact that isocyanides are extremely valuable synthons – there are a family of extremely useful multicomponent reactions based on isocyanides, including the Ugi Reaction and the Passerini Reaction. These reactions succeed because the isocyanide is a rare example of a (1,1)-amphoteric molecule; the same atom (the R-carbon) establishes a connection with both the nucleophile (carboxylic acid) and electrophile (aldehyde or imine). The Ugi reaction was developed by Prof. Ivar Ugi (no surprise), and I discovered a cool fact about him when I happened to check out his book Isonitrile Chemistry from the library, and I saw that it said “Prof. Ivar Ugi, University of Southern California”. Apparently he was a faculty member at USC for a short time (around a year or two) in the early 70’s, before Prof. Olah came to USC.

In any case, the next question is, how does this isocyanation work? In my mind, the mechanism is pretty straightforward; it’s simply a variant of the Ritter reaction with TMSCN, avoiding the use of aqueous acids to prevent hydration of the intermediate nitrilium ion or isocyanide to an amide. This reaction has seen a slow stream of contributions – you can see the references for a list of papers that describe the conversion of various types of compounds to isocyanides or amides. Recently, Ryan Shenvi (Scripps) revisited this chemistry and somehow got a paper in Nature; I don’t understand why this was selected for publication, because as you can see here, there’s nothing truly original about it, and the conditions are not really practical:

A solution of trifluoroacetate 13 (32.0mg, 0.1 mmol) in TMSCN(0.1ml) was cooled to 0 ℃ and treated with a solution of anhydrous Sc(OTf)3 (1.5 mg, 0.003 mmol) in TMSCN (0.1 ml). […]”

The reaction is carried out neatusing TMSCN as the solvent! Not really scalable, and only for the truly desperate.

If you ask me, the cyanation reactions are more intriguing, because the mechanism is more unclear. Prof. Weber (who used to be at USC) demonstrated a complementary reaction to Gassman’s reaction above; when Et2AlCl is used as the Lewis acid instead of ZnI2nitriles are obtained instead. The mechanism invoked by Prof. Weber involves a little more hand-waving, however:


The first step involves the interconversion of TMSCN with its isocyano isomer. It’s not far-fetched on paper, and you can certainly defend this using the Curtin-Hammett principle. However, the literature support for this is rather weak; detailed spectroscopic studies of triorganosilyl cyanides gave no evidence for the presence of the isocyano form. However, another Japanese group studied this set of reactions with more Lewis Acids, and what seems apparent to me is that soft Lewis acids seem to promote formation of the isocyanide, whereas hard Lewis acids promote formation of the cyanide. Thus, two different mechanisms are at play depending on the Lewis acid involved. With reactions involving cyanide, the nitrogen preferentially attacks hard electrophiles (i.e. carbocations, giving the Ritter reactions, as well as other electron-deficient species). My proposal is that the first step would be a nitrilium ion formed from TMSCN attacking the aluminum atom; this species would be the active cyanating agent. If anyone is up for it, it may be possible to characterize this species; Melanie Sanford recently wrote about rapid-injection (RI)-NMR being used to characterize transient Cu(III) intermediates, and the same technique could possibly be used here. In contrast, other Lewis acids (ZnI2, Pd salts, etc.) activate the epoxide for nucleophilic ring-opening by attack of the nitrogen in TMSCN, which is drawn to the nascent carbocation by Coulombic forces.

do have some ideas for new synthetic reactions based on this chemistry, but that will have to be explored once I can get back in a lab.


  1. Gassman, P. G.; Guggenheim, T. L. J. Am. Chem. Soc. 1982104, 5849 
  2. Spessard, G. O.; Ritter, A. R.; Johnson, D. M.; Montgomery, A. M. Tetrahedron Lett. 198324, 655 (This paper was published independently and at the same time as Gassman’s paper above, and describes the same results)
  3. Gassman, P. G.; Talley, J. J. Org. Synth. 198160, 14  (Gassman’s 1981 prep for converting aldehydes/ketones to cyanohydrins with TMSCN)
  4. Okada, I.; Kitano, Y. Synthesis 201124, 3997 (Refs. 3-9 cover converting various functional groups to isocyanides)
  5. Kitano, Y; Chiba, K.; Tada, M. Tetrahedron Lett. 199839, 1911
  6. Kitano, Y.; Chiba, K. Tada, M. Synthesis20013, 437
  7. Kitano, Y.; Chiba, K. Tada, M. Synlett19993, 288
  8. Kitano, Y.; Manoda, T.; Miura, T.; Chiba, K.; Tada, M. Synthesis 20063, 405
  9. Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013501, 195
  10. Mullis, J. C.; Weber, W. P. J. Org. Chem. 1982 47, 2873 (Weber’s conditions for the ring-opening of epoxides and oxetanes with TMSCN + Et2AlCl)
  11. Seckar, J. A.; Thayer, J. S. Inorg. Chem. 1976 15, 501 (Detailed spectroscopic study on the interconversion of the iso- and normal forms of triorganosilyl cyanides)
  12. Hickman, A. J.; Sanford, M. S. Nature2012484, 177 (Review in which various methods for characterizing transient high-valent metal intermediates are discussed, including RI-NMR)

This is by no means an exhaustive list; I have many more papers with me on this topic. If you want them, let me know.

Finally, I have to include this link to Prof. Andrei Yudin’s blog, which got this whole discussion started in my mind.

September 28, 2016

Another clip!

Filed under: Carnatic Music — sankirnam @ 10:29 pm

Just found this clip on Youtube of a small performance I did in Irvine last year:

September 14, 2016

Portal 1 Screenshots

Filed under: Video Gaming — sankirnam @ 2:52 pm

I recently played through Valve’s Portal. Even though the game is approximately 10 years old, the graphics still hold up rather well. The biggest thing that surprised me is how far integrated graphics chips have come in the last decade; I remember when I was first played this game, it required a very good graphics card for its time. Now my laptop can run it rather smoothly!



the cake is a lie?



getting the portal device!


final boss


the mystery thickens


oh hello there

September 11, 2016

Classics in Organic Chemistry, Part VI

Filed under: Classics in Organic Chemistry — sankirnam @ 8:31 pm

Sorry for the hiatus – back to our regularly scheduled programming!

In this post, we transition from the “classical” methods of organic chemistry, and move to modern material. The “classical” reactions are those generally taught in undergraduate organic chemistry, and while reactions such as oxymercuration, alkynylation with acetylide anions, and PCC oxidation are no doubt useful, they are not used that much anymore. Reactions dealing with mercury and superstoichiometric amounts of chromium are no longer palatable in today’s environmentally conscious era.

One of the holdovers from classical organic chemistry is the necessity of conducting reactions with as little water as possible. Water is generally thought of as a “bad” solvent, one that will rapidly quench any reactive species present and bring everything to a grinding halt. This thought process is not unfounded; after all, when working in the lab, frequently you will quench a reaction with water before working it up in order to extract any products formed. However, given the recent interest in Green chemistry from the chemical research and manufacturing sector, there is now a lot of interest in developing water-tolerant reactions. These reactions also have the added benefit of being milder, but the caveat is that one has to put more thought into extracting and purifying the organic material afterwards.

The papers covered in today’s post are on Shu Kobayashi’s work on water-tolerant Lewis Acids and their application in organic synthesis. This paper really marks a distinct gap between “classical” and modern organic chemistry, because when most people think of Lewis Acids, they will think of Friedel-Crafts promoters such as AlCl3, FeCl3, Al2Br6, BrF3, and others. These are very strong Lewis Acids and are also notoriously water-sensitive; they all react with water or undergo hydrolysis. One of Kobayashi’s early papers from 1998 demonstrated the possibility of doing a Lewis Acid-catalyzed Mukaiyama aldol reaction with water-tolerant Lewis acids – this is a big step from the previous versions of the Mukaiyama aldol reaction, which commonly used TiCl4 as the Lewis acid. Even this Evans’ asymmetric aldol reaction makes use of some very water sensitive reagents – namely, n-butyllithium and dibutylboron triflate.

Kobayashi’s main insight was that both the hydrolysis constant and water exchange rate constant (WERC) were critical features for determining if a metal salt would be a good Lewis acid in aqueous media. Basically, if you can choose a metal cation that has a low enough affinity for water (as determined by the hydrolysis constant), but yet can exchange it’s ligands with water at a fast enough rate, you have a good aqueous Lewis acid. This can be seen from the figure below – all the lanthanide cations are good Lewis acids because they have WERC values and hydrolysis constants right in that sweet spot. It’s like Goldilocks – not too low, not too high.


This simple observation then opens the door to a whole plethora of possibilities. The next question is – are asymmetric reactions possible in aqueous media? The answer is… yes.


The ligand in the figure above is a chiral bis-pyridino-18-crown-6 derivative, but the point is yes, asymmetric reactions are possible in aqueous media! I mean, this should be no surprise – all biochemistry is asymmetric, and it occurs in aqueous media too.

Friedel-Crafts reactions are also possible with these lanthanide triflates in aqueous media, but the issue here is reactivity. A traditional Friedel-Crafts reaction with benzene generates a benzenium ion as the intermediate, which will immediately quench itself with any adventitious water present. Therefore, one can only do aqueous Friedel-Crafts reactions involving less reactive (or more reactive depending on how you look at it) species, such as indoles.


So now you’re familiar with one of the most important advances of modern organic chemistry – water-tolerant Lewis Acids!


  1. Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998120, 8287 (link)
  2. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002102, 2227 (link)
  3. Kobayashi, S.; Manabe, K. Acc. Chem. Res. 200235, 209 (link)

September 9, 2016

The rise and fall of Theranos

Filed under: Philosophy — sankirnam @ 11:30 pm

I’ve been meaning to write something about Theranos for a while, and seeing this rather dramatic article in Vanity Fair yesterday spurred me to action.

Theranos is a Silicon Valley company that was started by Elizabeth Holmes as a 19-year-old undergraduate student at Stanford. I don’t have any personal involvement or interest in the company, but the story of Theranos is reflective of the biotech industry as a whole, and as a rather large company with a multibillion-dollar valuation, all eyes are on it as well as the other large startups. Back in 2014, when it was around the time of my graduation, people were telling me to look up Theranos and apply there since “it was hot” and “Liz Holmes was going to change the world”. In hindsight, I’m extremely glad that I dodged that bullet.

I remember reading this New Yorker article shortly afterwards and feeling a great deal of skepticism. One of the things that tipped me off was this passage:

One day, in her freshman year, Robertson said, she came to his office to ask if she could work in his lab with the Ph.D. students. He hesitated, but she persisted and he gave in.

[…] That summer, at the Genome Institute, Holmes worked on testing for severe acute respiratory syndrome, or SARS, an often fatal virus that had broken out in China. Testing was done in the traditional manner, by collecting blood samples with syringes and mucus with nasal swabs. These methods could detect who was infected, but a separate system was needed to dispense medication, and still another system to monitor results. Holmes questioned the approach. At Stanford, she had been exploring what has become known as lab-on-a-chip technology, which allows multiple measurements to be taken from tiny amounts of liquid on a single microchip.

Over the years, I have worked with many high-school students and undergraduates in research, and I also did “research” myself in an organic synthesis lab while in high school. The one thing in common that all new researchers have is this: they don’t know anything. I’m not saying this to be mean, but to lay the reality – working in a research lab is a vastly different experience from doing coursework. For instance, all undergraduates will study diazotization of anilines  and learn the variety of transformations they can undergo (Sandmeyer and other reactions). But carrying out one of these reactions yourself is vastly different from simply drawing the structures and reaction arrows on paper; you wouldn’t know just how explosive diazonium salts can be unless you have actually worked with them before. One of the key things you learn in research is humility, which is why getting any kind of research degree is often described as an ego-shattering process; 99.99% of the time, when you think of something, chances are, it has been done before.

Here’s an interesting story that illustrates my skepticism: There was a high-school student who used to work in my lab when I was doing a PhD. We all knew that this student had no interest in science, beyond getting some “research lab experience” to bolster her CV and improve her chances for admission to an Ivy league university. She would come and “work” for only 2-3 hours once a week every Friday. Anyone who has any kind of experience doing research or any kind of lab work knows that you can’t get anything done on that schedule. This student had never set up a single reaction from start to finish (which involves setting up the reaction, monitoring it, quenching it when complete, working it up, purifying the crude, isolating and weighing the product(s), and finally characterizing the product(s)). And yet somehow she managed to win first place in the state science fair, presenting a chemistry project with practically no self-generated data!

That’s why I’m skeptical about “child prodigies” in science, because it takes a long time to develop the foundational knowledge required to make serious contributions, or even to understand the subject matter properly. I’m highly doubtful that after doing basic “research” for a few months, one would have the necessary domain expertise to be able to start a company. I’ve been studying chemistry for 12 years and I feel like I don’t have the necessary expertise! To put things in perspective, one of the criticisms about Theranos is that “finger-stick blood tests aren’t reliable for clinical diagnostic tests; because the blood isn’t drawn from a vein, the sample can be contaminated by lanced capillaries or damaged tissue“. This is true, and anyone with a proper understanding of high-school biology would be able to tell you that. Another issue is statistical – when your sample sizes are smaller, your error bars are going to be correspondingly larger, and this is an important consideration when you’re trying to do measurements on vanishingly small concentrations of analytes (oftentimes ng/L). I guess this would be an instance of people succumbing to groupthink. I mean, the premise of Theranos is awesome, don’t get me wrong. Miniaturizing diagnostics is a huge challenge, and is on the cutting edge of science, engineering, and medical research. George Whitesides (Harvard) is actively working in this area, as are many others. But is it really possible that a 19-year old could solve a problem that the smartest people in the world are struggling with? Color me skeptical.

I remember I was once watching the lectures from Stanford’s Intro to Chemical Engineering class a few months ago, and I stopped watching in disgust once I realized that the instructor, Channing Robertson, was now on the board of Theranos.

Also, I remember my father asking me multiple times about how Theranos was able to secure so much funding if the scientific foundation was so shaky. This article explained everything:

“[…] none of the big V.C. outlets invested in Theranos. When the company raised an additional $200 million in early 2014—which gave Theranos a $9 billion valuation and made Holmes “the world’s youngest self-made billionaire,” worth about $4.5 billion (on paper, a point that few stories ever noted)—that money largely came from private equity.

You couldn’t find Michael Moritz, John Doerr, or Peter Thiel on the Theranos board. And while Marc Andreessen has repeatedly come to Holmes’s defense—blocking Twitter followers who have questioned her and even implying that she could be the next Steve Jobs—his firm, Andreessen Horowitz, did not invest in Theranos. (And even those V.C.s who did are now trying to distance themselves. Theranos is no longer listed among Draper Fisher Jurvetson’s “featured investments,” even though its logo was there this time last year.) When I’ve asked V.C.s why they didn’t pour millions of dollars into a company that appeared to be changing the world, I was told that it wasn’t for lack of trying on Holmes’s part. She met with most top venture firms. But when the V.C.s asked how the technology worked, I was told, Holmes replied that it was too secret to share, even to investors. When they asked if it had been peer-reviewed, she insisted once again it was too secret to share—even to other scientists.

But that Vanity Fair article was eye-opening. I didn’t know that Theranos’ chief scientist ended up committing suicide due to the pressure and unreasonable expectations put upon him. Yikes. That scenario can be traced back to Holmes’ lack of scientific training; as I mentioned before, a proper experience in scientific research and a proper scientific education will teach you humility, as well as the fact that the laws of nature bend for no one.


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.

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