Prof. George Whitesides on the future of the field

Let me preface with this: before this week, I’d not had the pleasure of hearing a talk by Professor Whitesides.

Recently, Whitesides wrote an essay in ACIE in which he discussed the past, present, and future of the field of chemistry.  Chemistry, he argued is a field in flux.  Many fundamental problems have been worked out pretty well by now.  If you can draw a molecule on a piece of paper, someone, somewhere can figure out how to make it*.  Total synthesis for the sake of total synthesis is no more.

The real challenge in modern chemistry is figuring out what molecules are worth making.  Or even discovering new uses for ones we’ve already made.  That can range from drug candidates to polymers, organic conductors to explosives.

To this end, Professor Whitesides posed a hypothetical question:

Suppose you are given unlimited resources.  All the funding, personnel, and equipment you need.  And further suppose your research project achieves all of its goals and is completely successful.  Who cares?

It’s always useful to keep the big picture in mind.  What will your research contribute to society?  And sometimes, it’s perfectly OK if the answer to that question is a slightly ambiguous “Well, we’ll know a bit more about how subject x works.”  But, Whitesides argued, going forward that won’t be OK any more.  After all, we as researchers are using taxpayer money to do our work (in many cases).  Even corporate interests receive government funds through the NIH, NSF, DOE, other TLA.  And philosophically, we have both a moral and utilitarian duty to provide a return on the investment that the taxpayer has made in us.

This leads us to something of a conflict between scientists and the public.  Scientists want to work on cool science.  It’s what we do.  We want to look at tough problems (whether they exist or not is the subject of a different discussion) and find solutions to them.

Generally, the public couldn’t care less about solutions to arcane scientific problems.  They want solutions to everyday problems.  Not ones that are invented ex post facto to justify the expense of a program.

So, how do scientists and the public rectify this situation?  About halfway through his talk, Prof. Whitesides put up a slide with a simple, four quadrant chart.  Along the Y-axis was increasing scientific interest.  Along the X-axis was increasing contribution to society at large.  The bottom-left quadrant represented research no one, not even scientists care about: topics with little scientific merit and no potential for societal improvement.  Top-left represented interesting research areas which lack obvious applications.  Bottom-right would be areas which provide high return on the public’s investment, but which are not particularly interesting to scientists.

But it’s the top-right quadrant that’s the sweet spot.  How do we find areas of research which are scientifically interesting and provide a significant benefit to society?

The answer is simple: we invent new fields of science.

Louis Pasteur is the archetypal scientist in this regard.  Immunology did not exist before he invented it.  Vaccines did not exist before he postulated that they’d work.  His research literally created an entirely new field of science.  And moreover, it has probably had the greatest net-positive impact on society of any discovery scientists have ever made.  Louis Pasteur was a real top-right kind of scientist.

And that’s what, if nothing else, we should take away from Whitesides’ talk: try to be a top-right scientist.

______________________________________

* Given sufficient time and money.

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Awesome experimental shout-out

Every so often you come across a paper with chemistry so awesome you get pulled in like a good novel. But even rarer still are the papers with incredibly complete “experimental” sections. I’m talking complete NMR data on every compound.  Melting points. Conditions for HPLC, like retention times, injection volumes, exact column specifications, and even flow rates. But this paper in OPRD by Lipton et al may take the cake for best experimental I’ve ever seen.

Now admittedly, I don’t often read any of the process development journals.  Maybe this level of attention to detail is commonplace in process development research; I can say it’s generally not in more traditional synthesis journals.  In this case, the authors not only described in complete detail each and every synthesis, but they even saw it fit to include, well, a table like this for each compound:

TLC eluent information, method of visualization, and Rf values?!

TLC eluent information, method of visualization, and Rf values?!

This kinda work really warms the cockles of my heart.  Because this is generally stuff you’d do anyway in the course of synthesis research, the authors just wrote it all down.

On making pretty structures

I had an exchange with @fluorogrol today talking about poorly thought out chemical structures.  It began when the pseudonymous blogger tweeted out the (less than optimal) structure of this alkaloid:

Wrong, indeed. Representing complex stereochemistry can be quite tricky.  But bonds extending halfway across the molecule is generally not the way to go.  Chemical structures must satisfy two requirements: 1) they must be unambiguous, and 2) they must accurately represent the 3-dimensional shape of the the actual molecule.  I responded with my take:

…which was straightened out and rotated a bit, giving us this final, unambiguous structure:

No exaggerated bonds, no stereocenters consisting of a cluster of wedges.  Plus, now you can quickly get an idea for the actual shape of the molecule.  Now, admittedly, I have no idea where the original structure appeared, but I’m going to assume it’s from a publication.  Which means a group of scientists, and presumably at least one organic chemist, collectively decided that structure was the best way to represent akuammine (the wikipedia page structure is equally bad).

And to think, this tragedy could have been easily avoided.  Here’s a quick checklist on how to draw an accurate, sexy structure of your molecule.

1) Does the molecule have any cyclic or bicyclic motifs common in organic chemistry?

To list a few...

…to list a few

If yes, start there.  These structures are so ubiquitous in organic chemistry that they give readers a quick and easy 3-D reference point.  Not sure if there’s one of these in your molecule? Proceed to step 2.

2) Load you molecule up in the three-dimensional molecule viewer of your choice.  The professional edition of ChemDraw comes with Chem3D, which will do the trick.  As will whatever you may use for energy calculations.  Don’t have access to any 3D chemistry software?  MolView has you covered with its in-browser tool, which can even perform simple energy minimization calculations.

Rotate the structure around a bit.  Look for any of the aforementioned motifs.

Picture1

Still can’t find one?  Then…

3) Find and angle from which all atoms are more or less visible.  Of course, your ChemDraw structure doesn’t need to perfectly match all bond angles and distances, but try to replicate them as faithfully as possible.  A good angle is one from which stereochemistry is unambiguous and doesn’t require dashes and wedges everywhere to makes sense of the structure.  Also, don’t forget the ever underutilized “structure perspective” tool in ChemDraw; make judicious use of it.

Maybe I’ll start featuring a “bad structure of the week” here.

Strain energy for days: an in silico study of xinghaiamine A

SeeArrOh (via Twitter) reminded me of something I’ve been wanting to check out since this paper surfaced.

The paper in question features a supposed natural product, named “xinghaiamine A,” with some pretty wonky bonding.  Readers at Just Like Cooking and In the Pipeline brought up some issues regarding the evidence for this compound’s existence.  And rightly so; there appears to be something off about the supplemental data¹.  But, ignoring the (very real) issues readers have brought up with the supporting info for this paper, just look at this structure:

Oh dear

One half of the proposed compound.

At first glance, there’s some serious strain going on in there.  I figured I’d take a look at what xinghaiamine A looks like in 3D-space.  Getting it to behave in Spartan was a challenge on its own.  Chiefly, that bicyclo[2.2.0]hexane system was quite problematic.  Initial geometry optimizations at the semi-empirical level of theory produced some odd results.  I ended up settling on MMFF geometry optimization, which gave me the reasonably acceptable structure shown below²:

MMFF geometry optimization

MMFF geometry optimization of the xinghaiamine A “monomer”

Check out that bowl-shaped aromatic system.  That thing is supposed to be planar.

Check out that torsion angle: 40 degrees!

A torsion angle of 40 degrees.  And how!

The next logical step is to figure out exactly how much strain energy is in this thing.  This was done by taking the MMFF optimized geometry of xinghaiamine A and using it as a starting point for Spartan’s “T1 thermochemical recipe.”³  The T1 recipe is a post-Hartree-Fock method which consists of:

  • A quick and dirty HF/6-31G* geometry optimization
  • MP2 single point energy calculation with expanded basis set

This set of calculations yielded a heat of formation for xinghaiamine A of 1098.65 kJ/mol

Now, if we break that C-C bond joining the acenaphthalene and the bicyclo[2.2.0]hexane systems, repeat the calculations, and compare the results we can get a pretty decent idea of how much strain energy this proposed structure contains:

That planar acenaphthalene system looks so much happpier

That planar acenaphthalene system looks so much happpier

The answer is: a lot.

Breaking that one bond liberates quite a bit of energy.  But that’s not what makes this structure so implausible.  No, as others have pointed out, some of the motifs in this molecule have never been seen in a natural product.  And if you’re going to propose something never-before-seen, you best have the evidence to back it up.

Which raises the question: did the authors think the chemistry community would look at that structure and collectively go “yup, looks good to me, moving on then”?


  1. Something that rhymes with “fata dabrication”
  2. Note: the published structure is a dimer.  I’ve modeled it as a monomer, with a methyl R-group for computational simplicity
  3. Not a shill for Spartan, I promise

DOI’s for Blog Posts?

I received an interesting email over the weekend from the founder of “a DIY scholarly publishing platform” (full text below).

Some of what the folks at The Winnower are proposing sounds familiar: there are inherent problems with the current model of scientific publishing.  What stuck out a bit to me is the idea of assigning DOI’s to blog posts.  While I don’t see posting original research to blogs happening any time soon, perhaps the post-peer-review format of blogging could benefit from some more structure.

I’ve reproduced the email below if you care to read.  Thoughts?

Dear Mitchell,

My name is Josh Nicholson and I am the founder of The Winnower (thewinnower.com), a DIY scholarly publishing platform launched in the middle of last year.   We have just launched the first service to assign DOIs to blog posts (https://wordpress.org/plugins/the-winnower-publisher/) in an effort to empower scholarly blogging (https://thewinnower.com/papers/science-the-pursuit-of-the-truth-complicated-by-the-pursuit-of-mortgages).  I wonder if you would be interested in this service.  In short, we hope to archive and aggregate scholarly blogs from across the internet and preserve them FOREVER using CLOCKSS, much like traditional scholarly articles.
We think our service will be beneficial to bloggers/institutions as it should increase readership, and make blogs “count” more in scholarly discussions.  You can read our official announcement here: https://thewinnower.com/posts/archiving-and-aggregating-alternative-scholarly-content-dois-for-blogs
The workflow would be quite similar to what you do now, except you would cross post to The Winnower and assign a DOI to your blogposts at your discretion via the plugin.
Let me know your thoughts and I would be happy to answer any questions or discuss more.
Best,
Josh Nicholson

My Nature Chemistry Blogroll Column: The bad and the ugly

As some of my readers know, a few months ago I was asked to pen the Blogroll column for the February publication of Nature Chemistry.  The column was published at the end of January both in print and online.  Stuart Cantrill, Nature Chemistry’s chief editor, posted the column to the Nature Chemistry Blog The Sceptical Chymist where you can read it for free.  If you like fancy-looking PDFs as much as I do, and have institutional access, you can download the article ($) here.

In my column, titled “The bad and the ugly,” I write about misinformation in science, be it in popular culture, advertising, or the press.  It’s short, and, in my opinion, worth a read.

-Mitch

Reporting Adverse Results in Publications

Here’s a question: to what extent should authors describe the limitations of their results in publications?

I’m not talking about failed experiments and negative results or null-hypotheses.

For example, say a compound is synthesized, but is highly unstable in air, causing it to decompose rapidly.  Should that be noted?  Or maybe someone makes a new polymer that undergoes depolymerization after a couple days on the bench.  Should the researchers describe that in their publication?

Of course, it’s contextual.  Does the negative observation directly impact potential applications of the material?  If yes, then one would think it imperative accurately describe the limitations of research, especially if they are known at the time of publication.  It seems irresponsible to intentionally leave out these details.  And it is exceedingly frustrating as a scientist to discover these sort of details independently, when replicating others’ results.

Obviously, it hurts your chances of getting into a high impact journal if your results are muddled by adverse circumstances at the back-end.  And not every single negative result is noteworthy.  Library synthesis papers don’t describe every single failed substrate, but they often note something along the lines of “[class of compound] did not react to produce the desired product.”

I don’t have a perfect answer to this question.  Thoughts are welcome by comment or email.