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In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. Th

• twomoretime 7y ago
  Your anecdote seems to confirm a number of problems which are ravaging academia at large. Having gone through a master's myself, I think when we pushed two generations of children into college, we generally lowered the bar - across the board, effectively. And that's related to what's happening in the US today.
• wesleywt 7y ago
  You are describing my life. Except I am in biotechnology.
• djaque 7y ago
  That's kind of my experience with research, but in physics. Already have three projects under my belt w/ no publishable results. All of them involved much more work than the other grad. students in my lab including building like three different instruments from scratch, but the other students have published. Their projects were much more "safe" than mine and their papers are pretty small, but at least they have papers.
  • dguest 7y ago
    What branch of physics? There are hundreds of published null results looking for dark matter or Supersymmetry, for example. Instead of documenting a failed search, the papers focus on what versions of the theories the experiment excludes to 95% confidence.
    • djaque 7y ago
      I'm in acceleraror physics and study photocathodes. Unfortunately the state of those projects is that we thought a material should have great photoemission properties under some very specific circumstances. When we measured it, the material was actually terrible and we don't understand why it's that way outside of some speculation. Unfortunately it also feels like our lab doesn't have the type of expertise to explain why it's so bad either at least not without years of learning. My advisor's explanation on publishing was that if we had great results that followed our initial theory of what's going on then we could write a paper and nobody would question it. But, now that we contradict theory the threshold of evidence is much higher and he doesn't want to go ahead with it. We trust our data, but he's concerned about getting it through peer review. For what it's worth we did publish it in a conference proceeding, but it doesn't have the same weight as a journal article.
      • darawk 7y ago
        > My advisor's explanation on publishing was that if we had great results that followed our initial theory of what's going on then we could write a paper and nobody would question it. But, now that we contradict theory the threshold of evidence is much higher and he doesn't want to go ahead with it. Isn't that sort of the most important thing to publish? Something that contradicts theory means something new. Seems like all the more reason to pursue it, no?
• girvo 7y ago
  > So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions In a different but related world, clandestine chemists share failures more often than they do their successes, at least in the communities I was a part of a very long time ago. I'd wager this is because our substrates, reagents and solvents are such a pain in the arse to get compared to an actual lab, that wasting any of them is a no-go if it can be avoided. Related to that, but we reused solvents and recycled material a lot more than I did doing my B.Sci in Chemistry, for the same reasons!
  • disillusioned 7y ago
    Do they then go on to be script consultants for Breaking Bad?
  • orbifold 7y ago
    I actually think it is the same in chemistry, knowledge of which approaches don't work are a competitive advantage that is passed around under the hand. I've definitely observed this is in theoretical physics and pure mathematics, it is often much more important to know about things that have never been published then it is to read close to incomprehensible publications. So for example it is much more valuable to have attended the right seminars and have private copies of lecture notes, because by the time something is published it probably is out of date 1-3 years.
• eru 7y ago
  Thanks for the insights! Sounds very much like the replication crisis in the social sciences. I got similar stories about how to (not..) grow mammalian cells in vats.
• fouc 7y ago
  Sharing failures seems like the best way to make progress. I mean we're talking about SCIENCE here. If we don't have a comprehensive list of what does not work, that's just going to make progress so much slower.
  • spockz 7y ago
    I also wonder how many breakthroughs we would not have because of somebody saying that something didn’t work.
    • fouc 7y ago
      That's true. Failures need to be reproduced too.
• avian 7y ago
  As someone who spent 4 years working on a PhD (wireless/RF technology) and then quit, your points 2 and 3 ring a lot of bells. I think "journal of failed experiments" is a wonderful idea.
  • jcelerier 7y ago
    already has existed for some time : https://blogs.plos.org/collections/positively-negative-new-plos-one-collection-focusing-negative-null-inconclusive-results-everyone/ https://blogs.plos.org/collections/positively-negative-new-p...
  • dguest 7y ago
    Anyone can put a paper on arXiv. The bigger problem is that most journal editors will be skeptical of citing arXiv. If you're collaborating with more traditional academics it can be a challenge to even submit a paper with such citations. I've had to push my colleagues to cite a number of non-traditional sources: arXiv, github, and zenodo for example. Fortunately most of them agree that citations are cheap and that giving more people credit is generally a good thing. One thing that helps is publicly stating how you want your research cited. If you don't have a peer reviewed publication in the pipeline, tell people how to cite your work on a blog or your github page or somewhere. Most people default to peer-reviewed journals for citations and get confused when one doesn't exist, so an explicit statement really helps.
    • avian 7y ago
      > Anyone can put a paper on arXiv. Unfortunately as an academic it's really hard to justify spending time on writing up a paper that's only going to be published on arXiv. Regardless of citations, it doesn't count towards your publication quotas or PhD requirements.
    • mattkrause 7y ago
      I think that's less true than it used to be: a lot of papers now cite bioarxiv or arxiv preprints. I've never gotten any pushback and most journals explicitly allow it. Science: "We do allow citations to papers posted at arXiv or bioRxiv." https://www.sciencemag.org/authors/instructions-preparing-initial-manuscript https://www.sciencemag.org/authors/instructions-preparing-in... Nature (and other NPG journals): "Preprints may be cited in the reference list of articles under consideration at Nature Research journals...." https://www.nature.com/nature-research/editorial-policies/preprints-and-conference-proceedings https://www.nature.com/nature-research/editorial-policies/pr... Cell (and other Cell Press journals, including Neuron and Current Biology): "Posted preprints may also be included in the References list with appropriate identification information...." https://www.cell.com/cell/authors https://www.cell.com/cell/authors PNAS: "Preprints are cited as follows with a DOI or preprint ID number, and the date of posting...."https://www.cell.com/cell/authors https://www.cell.com/cell/authors
• nython 7y ago
  > There were happy go lucky chemists that fell into projects that were smooth as butter If it makes you feel any better (I 'quit' at the start of my bioinformatics PhD), there's a high chance that their projects went smooth as butter because they were also happy-go-lucky about double-checking their results. See for example that 75% yield paper you mentioned.
• dguest 7y ago
  In point 3: did you try to contact the authors of the paper you were trying to reproduce? I don't know organic chemistry, but in my field the authors are often willing to discuss their results, especially if it might mean more citations for them.
  • tralarpa 7y ago
    May I ask what your field is? Is it CS? I am asking because we computer scientists are sometimes a little bit naive when it comes to research and publications. In other fields, like pharmaceutics, where future patents can be worth hundreds of millions of dollars, authors are very careful what they tell others.
    • dguest 7y ago
      > May I ask what your field is? Collider physics. I'm guessing that a lot of the less applied sciences are the same way: we're looking for fundamental laws so it's more about convincing people that your result is valid than about trying to make money off of some application. It's very hit or miss of course: there are still some groups that act very secretive and some that are more open.
• z3t4 7y ago
  I sometimes bake stuff. But had problems with one particular recipe. When changed the proportions I always failed. Tried it over and over. Only to find out one of the baking measurements that's over 20 years old showed the correct measure at 1dl but incorrect on 2 and 2.5 dl. And the recipe only worked when I used the incorrect measurement.
• rwmj 7y ago
  To what extent can synthesis steps be automated? Do you use a computer to plan how to get to a chemical? Do you use robots to carry out some or all steps?
  • simlan 7y ago
    In a usual lab no automation whatsoever. When something goes commercial there are two routes. One is adapting to bigger batches where you will get some automation (dosing, temperatur controll, mixing). The last step is to have full blown process where you pipe stuf from reaction a to b. However, that last one works best with large scale basic chemicals. Think all kinds of polymer materials. There is a trend to get pharmaceuticals to a stage where flow chemistry can be used (like a small version of the full blown basic chemicals processes). This is however still a research field because a lot of processes don't lend themselves to continue flow. The most automation in chemistry can be found in the analytical side of things. A good example right now are the covid tests that are run on large automated liquid handling systems.
  • CamperBob2 7y ago
    I asked this question once. I couldn't figure out why there's no SPICE for chemistry (SPICE being any of several accurate, refined, and well-understood simulation programs for EE work). You know the whole deal with the three-body problem? How closed-form solutions become intractable in a hurry once you go past two or three mutually-influential orbiting bodies? As it was explained to me, that's why there's no SPICE for chemistry. Modeling exactly what happens when complex orbitals with dozens or hundreds of electrons interact with each other is one of those things we just have no clue how to implement in a practical application.
    • tikej 7y ago
      (Quantum) Many body problem is indeed at the very heart of chemistry. If it was solved creation of new materials and chemicals would be less of trial and error. In principle it comes down to the fact that problem space explodes tensorially with number of electrons e.g. in principle you need grid size of 3N dimensions per every electron so for helium a^6 where a is number of points in the grid (and you probably need at least thousands of tens of thousands to accurately solve differential equations). This can’t be done in practice so other methods (expansion of problem in basis usually) are used. Unfortunately solving Schrödinger precisely requires incredible amounts of both computing power and theoretical expertise. Qualitative results are up there for most systems thanks to developments in theoretical chemistry but it is still quite manual process that requires expert computational scientist to make sure results are reliable.
• wuschel 7y ago
  Former chemist here. What are you doing in this life? Feel free to contact me - see email in profile.
• godzillabrennus 7y ago
  A great deal of published research is not reproducible regardless of field.
• lazyjones 7y ago
  As an IT guy, I am wondering why this is still a mostly manual and rather dangerous process. Surely programmable machines can be built to process reagents in a safe and flexible way?
  • londons_explore 7y ago
    This is especially true since the number of possible "instructions" is pretty low. Heat it, cool it, mix it, filter it, centrifuge it, compress it, take a sample and put it through a test instrument. Pretty much all chemistry is some sequence of the above.
    • girvo 7y ago
      But your number of inputs is huge, and cleaning steps in between others in a reusable/reconfigurable machine is a difficult challenge to overcome all on its own. It’s not impossible and smart people are working on it, but it is incredibly hard.
  • LeifCarrotson 7y ago
    I'm a controls engineer. We're very good at making machines that will do a single process over and over. It's insanely difficult to do arbitrary processes with one machine.
    • wuschel 7y ago
      Hi, That is a very good question. In my PhD I built, among other things, a very primitive parallel stirring system in order to speed up the synthesis of test batches. Although a very crude device, there was tons of stuff that I needed to optimize. There are many steps in the practical work that is chemical synthesis. It might be removing air, adding reagents in different elemental states, cooling/heating/keeping and certain temperature, observing the reaction, taking aliquots, terminating reaction, and the many steps of purification. I'd argue that while automation is possible to a certain degree (continuous reactor systems are the most the most interesting IMHO), the resulting mashines are always problem (reagent, reaction, etc) specific. And here lies the problem.
• wenc 7y ago
  > They need a journal of failed chemistry because only the working stuff gets published. I think there's theoretical value in this, and many have tried, but the incentives/disincentives for doing so isn't favorable. Here's some reasons why I think it's difficult to motivate people to publish negative results: 1) Negative results, while important in advancing science, don't get you grants. 2) Negative results need to be peer-reviewed -- there are "good" negative results (good protocol, failed result) and "bad" negative results due to bad data collection, wrong conclusions (bad protocol, failed result). 3) Given that it's so much easier to get a negative result than a positive one (as in anything there are only few ways to be right, tons of ways to be wrong), the volume of papers to review is orders of magnitude higher. Reviewers have to really sift to find the needle in the haystack. Between teaching classes, sitting on mindless committees, writing grants, mentoring grad students, etc. academics don't have that kind of time. 4) It would incentivize poor/mediocre labs to publish a lot of negative results to get their pub count up (these are the ones that currently publish unsubstantiated positive results in fly-by-night journals). 5) Bad faith authors may publish fake negative results to throw others off a promising line of inquiry. (Note: some of these disincentives also apply to positive results in journals today) The current method I know for exchanging "good" negative results is word-of-mouth, usually during post-conference drinks at the bar. (works for tech too!) I'm not sure if it's possible to arrange incentives in such a way as to make publishing "good" negative results worthwhile. EDIT: there are exceptions. If the space of solutions is known a priori and bounded (say only n ways to do something), then publishing n results if even all n are failures is worthwhile. This situation doesn't come up all the time (the solution space is often open), but when it does, it's worth publishing all n results.
  • ggcdn 7y ago
    Maybe instead of full-fledged journal model, negative results should be published in a short (few pages) failure report. This addresses at least a few of the points you highlight. Skip all the cruft: here’s what we tried to do, here’s our methodology, and here’s the result. Then these could be classified by methodology/process/chemicals/etc for people to look up before starting their research.
    • 7y ago
• foobarian 7y ago
  Something that is not obvious from article or posts in this thread, but seems to be taken for granted: how exactly do you know how much of some target molecule you created? The article for example mentions 1g of remdesivir, but that seems like a complicated chemical so how do they tell it apart from something very similar but different? Some kind of GCM or electron microscope?
  • Metacelsus 7y ago
    NMR and mass spectrometry are two powerful analytical tools, both of which they used