Archive for the ‘crystal_structure_mining’ Category

Geometries of proton transfers: modelled using total energy or free energy?

Monday, April 18th, 2022

Proton transfers are amongst the most common of all chemical reactions. They are often thought of as “trivial” and even may not feature in many mechanistic schemes, other than perhaps the notation “PT”. The types with the lowest energy barriers for transfer often involve heteroatoms such as N and O, and the conventional transition state might be supposed to be when the proton is located at about the half way distance between the two heteroatoms. This should be the energy high point between the two positions for the proton. But what if a crystal structure is determined with the proton in exactly this position? Well, the first hypothesis is that using X-rays as the diffracting radiation is unreliable, because protons scatter x-rays very poorly. Then a more arduous neutron diffraction study is sometimes undertaken, which is generally assumed to be more reliable in determining the position of the proton. Just such a study was undertaken for the structure shown below (RAKQOJ)[1], dataDOI: 10.5517/cc57db3 for the 80K determination. The substituents had been selected to try to maximise the symmetry of the O…H…N motif via pKa tuning (for another tuning attempt, see this blog). The more general landscape this molecule fits into[2] is shown below:



  1. T. Steiner, I. Majerz, and C.C. Wilson, "First O−H−N Hydrogen Bond with a Centered Proton Obtained by Thermally Induced Proton Migration", Angewandte Chemie International Edition, vol. 40, pp. 2651-2654, 2001.<2651::AID-ANIE2651>3.0.CO;2-2
  2. I. Majerz, and M.J. Gutmann, "Mechanism of proton transfer in the strong OHN intermolecular hydrogen bond", RSC Advances, vol. 1, pp. 219, 2011.

Protein-Biotin complexes. Crystal structure mining.

Sunday, December 12th, 2021

In the previous post, I showed some of the diverse “non-classical”interactions between Biotin and a protein where it binds very strongly. Here I take a look at two of these interactions to discover how common they are in small molecule structures.


First came Molnupiravir – now there is Paxlovid as a SARS-CoV-2 protease inhibitor. An NCI analysis of the ligand.

Saturday, November 13th, 2021

Earlier this year, Molnupiravir hit the headlines as a promising antiviral drug. This is now followed by Paxlovid, which is the first small molecule to be aimed by design at the SAR-CoV-2 protein and which is reported as reducing greatly the risk of hospitalization or death when given within three days of symptoms appearing in high risk patients.


More examples of crystal structures containing embedded linear chains of iodines.

Sunday, October 17th, 2021

The previous post described the fascinating 170-year history of a crystalline compound known as Herapathite and its connection to the mechanism of the Finkelstein reaction via the complex of Na+I2 (or Na22+I42-). Both compounds exhibit (approximately) linear chains of iodine atoms in their crystal structures, a connection which was discovered serendipitously. Here I pursue a rather more systematic way of tracking down similar compounds.


Herapathite: an example of (double?) serendipity.

Thursday, October 14th, 2021

On October 13, 2021, the historical group of the Royal Society of Chemistry organised a symposium celebrating ~150 years of the history of (molecular) chirality. We met for the first time in person for more than 18 months and were treated to a splendid and diverse program about the subject. The first speaker was Professor John Steeds from Bristol, talking about the early history of light and the discovery of its polarisation. When a slide was shown about herapathite[1] my “antennae” started vibrating. This is a crystalline substance made by combining elemental iodine with quinine in acidic conditions and was first discovered by William Herapath as long ago as 1852[2] in unusual circumstances. Now to the serendipity!



  1. B. Kahr, J. Freudenthal, S. Phillips, and W. Kaminsky, "Herapathite", Science, vol. 324, pp. 1407-1407, 2009.
  2. W.B. Herapath, "XXVI. On the optical properties of a newly-discovered salt of quinine, which crystalline substance possesses the power of polarizing a ray of light, like tourmaline, and at certain angles of rotation of depolarizing it, like selenite", The London, Edinburgh, and Dublin Philosophical Magazine and Journal of Science, vol. 3, pp. 161-173, 1852.

More record breakers for the anomeric effect involving C-N bonds.

Saturday, September 4th, 2021

An earlier post investigated large anomeric effects involving two oxygen atoms attached to a common carbon atom.


Sterically stabilized cyclopropenylidenes. An example of Octopus publishing?

Sunday, August 15th, 2021

Whilst I was discussing the future of scientific publication in the last post, a debate was happening behind the scenes regarding the small molecule cyclopropenylidene. This is the smallest known molecule displaying π-aromaticity, but its high reactivity means that it is unlikely to be isolated in the condensed phase. A question in the discussion asked if substituting it with a large sterically hindering group such as R=Et3C might help prevent its dimerisation and hence allow for isolation of the monomer so that its properties can be studied.


Another very large anomeric effect – with a twist.

Thursday, July 22nd, 2021

In the earlier post on the topic of anomeric effects, I identified a number of outliers associated with large differences in the lengths of two carbon-oxygen bonds sharing a common carbon atom.


Two record breakers for the anomeric effect; one real, the other not.

Thursday, July 1st, 2021

The classic anomeric effect operates across a carbon atom attached to oxygens. One (of the two) lone pairs on the oxygen can donate into the σ* orbital of the C-O of the other oxygen (e.g. the red arrows) tending to weaken that bond whilst strengthening the donor oxygen C-O bond. Vice versa means e.g. the blue arrows weakening the other C-O bond. This effect tends to increase charge separation and the question then arises: how large can this effect get? To try to find out, we are going to do some crystal structure mining in this post!


A reality-based suggestion for a molecule with a metal M⩸N quadruple bond.

Thursday, May 13th, 2021

I noted in an earlier post the hypothesized example of (CO)3Fe⩸C[1] as exhibiting a carbon to iron quadruple bond and which might have precedent in known five-coordinate metal complexes where one of the ligands is a “carbide” or C ligand. I had previously mooted that the Fe⩸C combination might be replaceable by an isoelectronic Mn⩸N pair which could contain a quadruple bond to the nitrogen. An isoelectronic alternative to FeC could also be FeN+. Here I explore the possibility of realistic candidates for such bonded nitrogen.



  1. A.J. Kalita, S.S. Rohman, C. Kashyap, S.S. Ullah, and A.K. Guha, "Transition metal carbon quadruple bond: viability through single electron transmutation", Physical Chemistry Chemical Physics, vol. 22, pp. 24178-24180, 2020.