Click reaction under scrutiny

It is amazing how Huisgen azide-alkyne cycloaddition, once resurrected and reinvented by K. Barry Sharpless, generated so many application papers while we are still digging to understand its copper-catalyzed mechanism.

A recent JACS paper from Don Tilley lab sheds some more light on the catalytic cycle. And it’s not that easy as setting up the reaction itself. Disrupting catalytic cycle in step-by-step fashion is a tricky business but it was beautifully done in this study. First, trapping elusive cycloadduct within dinuclear copper complex:

Then displacing it with a fresh alkyne to get the product and the complex ready for another catalytic cycle:

But then look at the scheme below, which is arguably the least dramatic change one can imaging from a chemical transformation (involving organic compounds).

For those still scratching their head about what did actually happen here, it’s a one-electron oxidation of Cu(I)-Cu(I) dicopper complex into mixed-valence Cu(I)-Cu(II). That slight tilt of the bridging alkyne ligand seems to be the only indicator that reaction indeed took place without much of competing disproportionation or whatever could happen to the complex. Yes, it takes X-ray crystallography to prove that, and I wonder if Micah Ziegler, the first author, a priori knew what to look for to monitor the reaction success. EPR? Cyclic voltammetry? Maybe color change was enough?[1]

Anyway, attempts to get the mixed complex 3 to react with tolylazide didn’t succeed. So authors concluded that CuAAC does not involve mixed-valence dicopper complexes. In addition, they excluded a bunch of alternatively proposed intermediates. This was in fact contradicting with earlier results published by Jin et al of Bertrand lab. The key difference between papers was that in the latest study authors forced two copper atoms to sit close to each other, while Jin et al used mononuclear copper complex to initiate the reaction [2]. This may bring up a discussion of what study is more relevant for ‘real world’ cycloaddition. I wonder more, however, if knowing the exact mechanism will help one to improve the reaction in any way. It already is pretty well-optimized and reliable (to a point).

More generally, it seems like the dissociation of practical application from (strictly unambiguous) theoretical explanation is a genuine feature of science. Take for instance CRISPR-Cas9, which leading experts are still trying to understand how it works in native systems (i.e. bacteria) while other scientists are ready to tweak human embryos with it.

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[1] 19F NMR had enough difference due to different stoichiometry of triflimide anions.

[2] It still might be that both results are ‘right’ and one intermediate can turn into the other.

No fail no gain

While astronomers recently have been celebrating great discoveries (gravitational waves from colliding black holes keep rolling), at the opposite end of matter size ruler things don’t look as brightly. For instance, the search for ‘sterile’ neutrinos didn’t spot anything, despite the IceCube, a massive 2-km long neutrino detector buried in the Antarctic ice.

Extracting ChemDraw schemes as .cdx files from MS Word/Excel/PowerPoint documents

I couldn’t find a free software that would easily do exactly what I want (see the subject). So here’s my ghetto solution, which can be easily automated.

Can blog writing get you a real job?

Regular readers of this blog (all five of you, guys) have probably noticed that nothing appeared here in the past two months. As one could guess from the energy conservation law, my activity was mainly concentrated offline during this time. As a quick summary, I have left academia and landed an industry job as a research chemist in a small biotech company. And, quite surprisingly, this blog played a crucial role in this dramatic transition.

Thesis in LaTeX.

The background.

When I was writing my diploma thesis in 2009, I wanted to do it somewhat ‘special’ and I tried to write it in LaTeX (more precisely in LyX). That time there were so many geeks around Internet that praised LaTeX to be superior to any other typesetting method that I was eventually persuaded to give it a try. That time I failed miserably. Eventually I ended up writing the diploma in OpenOffice (currently LibreOffice).

Four years later I again faced the choice: either to take an easy way and to compile the PhD thesis in MS Word, or to overcome the challenge of steep learning curve of LaTeX.

Compiling structures to pdf-file (linux)

During my job-searching campaign I was once asked to show all the structures that I have synthesized. Drawing 200+ molecules seemed no fun to me. Even opening all .cdx files generated in 3.5 years, to copy-paste in a single one, was too boring. So I’ve used openbabel for this job.

Once I had all the .cdx in one folder I’ve ran

babel *.cdx allStruc.svg -xe -xl -xC
rsvg-convert -f pdf -o allStruc.pdf allStruc.svg

But the output was weird. All the charged molecules were assigned unrealistic charges over +2000, so all my potassium trifluoroborate and ammonium salts were crap.

Then I turned to molconvert tool from Chemaxon, which is free for academic non-commercial use. To convert all .cdx files to correct smiles I used a simple script:

#!/bin/bash
for i in $(ls -1 .|grep .cdx)
do
~/marvin/bin/molconvert smiles $i -o tmp.smi
cat tmp.smi >> smiles.smi
done

Followed by openbabel (I’ve decided to sort the molecules by molecular weight so the complexity will increase more or less steadily down the list):

babel smiles.smi allStruc.svg -xe -xl -xC --sort MW
rsvg-convert -f pdf -o allStruc.pdf allStruc.svg

Still, the conversion wasn’t ideal. Particularly, BF₃¯ groups were represented as BF₂·F¯. Fortunately, simple replacement of SMILES code ‘B(F)F’ to ‘[B-](F)(F)F’ and removal of extra fluoride (‘[F-].’ in SMILES) solved the problem.

So, here we go, the work of 3.5 years as almost square matrix 15×14: