Shared posts

28 Mar 15:28

Depression and Anxiety in Graduate School

by Derek Lowe
Blake Baker

Interesting read, comforting to see that stress is found in lots of graduate students

According to this new survey, depression and anxiety are far more common among graduate students than in the general population. This should surprise no one at all, but it’s good to have some quantitative data on the problem. There are limitations to the study – for one thing, it’s quite possible that (self-selected) respondents were among those more likely to have experienced these problems. The survey was done across 26 different countries (over 2200 respondents), 70% female/28% male/2% transgender, and the fields of study involved were 56% humanities and 38% physical sciences – no breakdown of the numbers by these categories is available.

Even with these reservations, I have no trouble believing the overall conclusions – based on my own experience and my observations since, I think that anxiety and depression are very close to inevitable in graduate study, and that students should be aware of what they’re getting into. What’s happening, in any field, is the rubber finally meeting the road: you’re not just sitting in classrooms; you’re doing what practitioners of your chosen line of work actually do, and you’re finding out what that’s really like and whether or not you’re any good at it. If that doesn’t bring on the occasional bout of anxiety and self-doubt, then something is off.

Moving from that to depression is not such a huge jump, either. All of us who have been through grad school have seen people who sort of freeze up at some point in their progress. Sometimes it happens near the beginning, such as when chemistry graduate students move out of classes and into the labs – some of them just can’t seem to get anything going. I remember people who were always just about to start something, just about to figure out what went wrong with the last thing (which was spread out into a bunch of inconclusive samples around their hoods), just about to really start making some progress. But they never did. Later in the process, another familiar figure is the person who’s been hanging around for years in the lab, running ever more experiments to avoid writing up, as is their near-relative, the person who’s actually out of the lab, writing up that dissertation/thesis, expected to set a defense date pretty soon. . .and who in the end, is never heard from again after a while, finding themselves unable to get the thing done. After a while, the official notices from the department come back stamped “Addressee unknown”.

Depression might well be a good description of what’s going on in many of these situations. Someone finds themselves in an untenable situation and sinks into a state that makes it more untenable every day. David Foster Wallace defined a harmful addiction as something that offered itself as the remedy for the problems that it itself was causing (as with alcohol), and the downward-spiral mode of life has some similarities, as a big factor in what put you into this spot makes you ever less likely to do anything about it. The canonical view of major depression from the inside is William Styron’s Darkness Visible, but you don’t have to be as far along as Styron was to be in real trouble.

I don’t think I got quite as far as depression myself, but there’s no doubt that I was under significant stress. Even the stock of stories that I have from grad school illustrates that. So many of them feature me losing my temper about something, and honestly, I rarely do that out here in the real world. I well recall unnerving bouts of fear and uncertainty, wondering if I was doing the right thing with my life, wondering if it was too late to do much about that even if I were, wondering if my research was any good or if I was any good at doing it, and what I was going to do about it if the answer to either or both of those were actually “No”. And so on. By the end of it, I was thoroughly sick of my project, wildly ready to get out the door and see what the post-doc life was going to be like (and very much wondering if it would turn out to be more of the same, in a different location).

I saw some outright breakdowns while I was in grad school – there’s no other way to describe them. In some cases a person’s hours and behavior would become erratic, their actions hard to understand or predict. Sometimes in these the ship would apparently right itself and sometimes it wouldn’t. I saw examples of just those situations mentioned above, with people unable to make a real start in research or unable to write up at the end of it. And there was one flat-out suicide attempt, very nearly successful and permanently damaging to the person involved.

At my own worst moments, I would be standing there in the lab feeling like a pitcher out on the mound who had just shaken off every pitch he knew how to throw. I was hauling material up the mountainside of a long linear synthesis, and I was frustrated to a degree beyond anything I’d ever experienced. I didn’t feel like working up the reactions in front of me, and I didn’t feel like setting up others. Waiting for me was my reward at the end of twenty-odd linear steps, the chance to risk all my hard work by trying (finally) some new chemistry that would probably not work and might well destroy my starting material in the process. Oh joy.

I think I’ve told this next story before, but can’t track down the post where I did. At any rate, a pivotal moment was when I was bashing along with the largest load of starting material I’d ever made. Up at around step 9 (I was still in liter-sized flask territory) I was ready to work up the whole batch after a late-night reaction. I added some ammonium chloride and extracted the black mixture. That didn’t worry me; it was always black. I evaporated it down to a bunch of black oil and loaded it on a big gravity column of coarse silica gel – from prior runs, I knew that would hold the black crud at the top and allow a big yellow band of product to elute. Except this time the whole column turned black. Must have overloaded the column with this big pile of material, I thought. I collected a bunch of black fractions and rota-vapped them down, only to find what I sort of thought was a lot less oil than I’d been expecting. Reserving worry, I set up another column on that stuff, and this time the whole column turned black again, and nothing at all came out the other end but slightly discolored solvent. I had, in fact, destroyed my entire huge batch, because at 2 AM I was too groggy to remember that I was supposed to work it up with saturated bicarb, not ammonium chloride. All gone.

I stood there, alone, in the middle of the night, looking at all the mess I’d created. Ruined, all that batch of material that was going to finally get my synthesis finished and get me out of this place. I shook my head, cursed loudly, and went home, and to my surprise I fell asleep fairly quickly. What else was there to do? I woke up the next morning and went through that terrible disorienting feeling when after a few seconds you suddenly remember that something bad happened the night before. And then I got up and went to the lab, and set up an even larger batch back at the beginning of the synthesis, step one. Looking back, that night and that morning were a key episode in my graduate career and my life in general, because that batch I started that next day really did get me out in the end. I had bent and come very close to breaking at times, but it turned out that the worst had happened and I was still in one piece.

Things definitely could have gone in other ways, though, and if they had there’s no telling where I would be now or what I would be doing. If that incident had happened to me a year before, I don’t know how I would have taken it. By the time I speak of, I had my eyes on the door and a PhD defense, having decided that the shortest way out of this awful situation was in that direction. I was devoting all my efforts to it, in an “OK, did today get me closer to defending, or not?” sort of way. Earlier, though, I was too far from the beginning and too far from the end to have that mindset, and a whopping failure would not have gone down well.

I think it’s important for graduate students to realize that everyone has these doubts and bad stretches. Everyone has these moments when they wonder what they’ve done to their lives, but having these thoughts is not a sign that the exact failure you’re fearing has arrived. That doesn’t mean that thinking about your purpose in grad school is a bad thing, but it probably is a bad thing to try to do it at periods of peak emotional stress. If you feel that it really is getting too much, definitely talk to someone. Universities have people around for just that purpose – more so than in my day, fortunately – and if you find yourself wondering if you should reach out like that, then odds are that you should. Do it. I wish some of the people I worked with had, or had been able to.

Any meaningful graduate degree is going to be a test of your abilities and your resilience. Recognize this, and avoid the two extremes. On one end are the macho types whose response is “Eat stress for breakfast! That’s what I did in my day! If you don’t have the fire in your belly you don’t belong here!”. And on the other end are the voices, some perhaps external and some internal, telling you that you’re a failure already, an imposter, and that you’re never going to measure up anyway. These are two different sets of lies, and everyone has to steer their course between them.

07 Mar 09:03

Retrosynthesis: Here It Comes

by Derek Lowe
Blake Baker

Interesting computational application of retrosynthesis to improve medicinal chemistry routes

Behold the rise of the machines. It’s been going on for a while, but there are landmarks along the way, and we may have just passed another one with the publication of this paper. It’s open-access,  from an interestingly mixed team: the Polish Academy of Science, Northwestern University, the University of Warsaw, the Ulsan Institute in South Korea, and. . .MilliporeSigma. Those who are into scientific computing may have already guessed that the Polish connection is to the Chematica retrosynthesis software. It’s the MilliporeSigma one that makes things of particular interest here (a company that to certain generations of chemists will always be Aldrich or Sigma-Aldrich in their hearts).

I’ll let the summary to the paper lay out the case:

Here, we describe an experiment where the software program Chematica designed syntheses leading to eight commercially valuable and/or medicinally relevant targets; in each case tested, Chematica significantly improved on previous approaches or identified efficient routes to targets for which previous synthetic attempts had failed. These results indicate that now and in the future, chemists can finally benefit from having an “in silico colleague” that constantly learns, never forgets, and will never retire.

All right, then. As advertised, what this paper has done is to pick out six molecules of interest to the MilliporeSigma folks, all chosen because they are of strong commercial interest but had troublesome syntheses (low or inconsistent yields, or failed routes altogether). In addition, the cardiovascular drug dronedarone is on the list because there are numerous process patents detailing routes to its preparation, making this a good reality check for the software, and there is also a natural product (engelheptanoxide C) that has been recently described in the literature but not yet synthesized. The structures of these are shown at right, and the chemists in the crowd will not that this is a perfectly reasonable test: these are real compounds, all the way. Medicinal chemists will note that several of these are hydroxylated metabolites of known drugs, which are valuable reference compounds from a commercial standpoint.

The software was turned loose on all these structures to come up with what it regarded as plausible retrosyntheses, with the starting materials defined as things easily available in the Sigma-Aldrich catalog (naturally). And these routes were put to an interesting real-world test (as suggested by the DARPA funding that went into the project): the routes were put into practice in the lab in the four cases by chemists at MilliporeSigma (an experienced bunch), and in the bottom four cases by students with little or no practice in multistep organic synthesis, just to see if the routes were practicable by less-experienced hands.

The software generated routes in about 20 minutes for each of these. If the top-rated route was sufficiently different from what had been tried before, and if the starting materials were readily available, it was chosen as is. Otherwise, the second-ranked route was used (this happened in three cases). The reactions had to be taken as given, in their general form, although modifying conditions (temperature, solvent, etc.) was permitted. The MilliporeSigma targets were to deliver at least several hundred milligrams within 8 weeks, at 98% purity, while the student syntheses were more like three months but with similar purity.

I won’t go into all the details of the syntheses, since the paper is open-access and you can read them there. But when I will say is that for the four MilliporeSigma targets, the existing routes were substantially improved in all cases. The improvements were of several kinds (shorter routes, fewer chromatography steps, higher yields, more reproducible) and came from several directions (completely different synthetic approaches, different starting materials, etc.) The improvements in the latter four compounds were similar, and in the case of the third one down on the right (a metabolite of lurasidone) the software not only improved the synthesis, but in doing so broke the patented route to the compound. One interesting feature that shows up several times is that the software predicted (based on its knowledge of the literature) some “don’t bother protecting that OH” reactions that some chemists might have worried about trying, but which can be gotten away with.

This is very impressive work. Even discounting for having to do more work on the suggested reactions, which I’m sure was the case, it’s still impressive. One thing to note is that the software may (in those three cases mentioned above) have suggested routes that were very close to the existing (problematic) ones, which highlights the well-known fact that what looks good on the board doesn’t always go so well in the fume hood. This isn’t explicitly addressed in the paper. But overall, this paper is a pretty strong argument for the whole approach.

And from a theoretical standpoint, it seems clear that this is how things are going to go. I recently read Gary Kasparov’s Deep Thinking, about his experience with IBM and its Deep Blue program, and one of the points he makes is that even when he beat an earlier version of the program, he knew that it was going to surpass human chess play. That’s because it was constantly improving, faster than humans do (or can). And working out a retrosynthesis, versus playing chess, is similar enough that the same considerations apply. Chematica (and its competition in the software field) is getting better all the time. More reactions are entered, existing ones are extended and curated more precisely, adjustments are made to the algorithms, the hardware gets more capable.

So the fact that the program – or any such program – does as well as it does here means, folks, that the handwriting is on the wall. Not this afternoon, and not next week, but in the easily foreseeable future retrosynthesis and synthetic organic chemistry planning are going to be taken out of the hands of chemists. At least, that’s how it’s going to seem to us, the chemists of the present. But to future chemists, the ones who will enter the science once this transformation is complete, it won’t seem like that at all. To them, synthesis planning will always have been something that you have machine help with – why would you do it any other way? Who can carry a zillion reaction examples around in their head?

Kasparov mentions the idea of “centaur” chess players, humans aided by software in their analysis of games and positions. We organic chemists have been centaurs for a long time now, considering how much help we get from our machines and instruments, and this is going to be another example. It is certainly different in degree, and may well feel a bit different in kind, but it’s coming no matter what we feel about it. Prepare yourselves.

22 Jan 16:39

Oxidative [small beta]-C-H sulfonylation of cyclic amines

Chem. Sci., 2018, 9,2295-2300
DOI: 10.1039/C7SC04900E, Edge Article
Open Access Open Access
R. J. Griffiths, W. C. Kong, S. A. Richards, G. A. Burley, M. C. Willis, E. P. A. Talbot
A new and efficient process to access [small beta]-functionalisation of cyclic amines via a mild oxidative [small beta]-sulfonylation.
The content of this RSS Feed (c) The Royal Society of Chemistry
31 Jan 17:25

Lewis Acid-Mediated [3+3] Annulation for the Construction of Substituted Pyrimidine and Pyridine Derivatives

by Yao Zhou, Zhonghe Tang, Qiuling Song


A direct and single-step procedure towards substituted pyrimidine and pyridine derivatives via Lewis acid-promoted [3+3] annulation between 3-ethoxycyclobutanones and enamines or amidines is presented. Diverse substituted pyrimidine and pyridine derivatives were obtained in good to high yields with a wide substrate scope.

Thumbnail image of graphical abstract
18 Jan 09:35

Four-Component Reaction between Secondary Phosphines, Primary Amines, Aldehydes, and Chalcogens: A Facile Access to Functionalized α-Aminophosphine Chalcogenides

by Artem’ev, Alexander V.

DOI: 10.1055/s-0036-1588127

The original four-component reaction between secondary phosphines, primary amines, aldehydes, and elemental sulfur or selenium occurs chemoselectively under mild conditions (60 °C, benzene, 3–9 h) to afford the hitherto unknown functionalized α-aminophosphine sulfides and selenides in good to excellent yields.

© Georg Thieme Verlag Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

17 Jan 09:43

Organocatalytic activation of isocyanides: N-heterocyclic carbene-catalyzed enaminone synthesis from ketones

Chem. Sci., 2017, 8,2401-2406
DOI: 10.1039/C6SC05266E, Edge Article
Open Access Open Access
Jungwon Kim, Soon Hyeok Hong
The first NHC-catalyzed C-C bond formation reaction between ketones and isocyanides was achieved via activation of the isocyanide into an imidoyl intermediate.
The content of this RSS Feed (c) The Royal Society of Chemistry
09 Dec 16:13

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

by Nicholas D. Measom, Kenneth D. Down, David J. Hirst, Craig Jamieson, Eric S. Manas, Vipulkumar K. Patel and Don O. Somers

TOC Graphic

ACS Medicinal Chemistry Letters
DOI: 10.1021/acsmedchemlett.6b00281
10 May 14:56

Silicone Brushes: Omniphobic Surfaces with Low Sliding Angles

Silicone Brushes: Omniphobic Surfaces with Low Sliding Angles

Losing contact: Omniphobic surfaces can be readily produced by acid-catalyzed graft polycondensation of dimethyldimethoxysilane (PDMS). Droplets show a very small contact angle hysteresis as well as a low sliding angle of only a few degrees. The nm-thick PDMS layer is neither easily washed away nor depleted. This method offers a novel approach towards the preparation of super-liquid-repelling surfaces.

Sanghyuk Wooh, Doris Vollmer
Angew. Chem. Int. Ed., May 09, 2016, DOI: 10.1002/anie.201511895. Read article