Halogen bonding and the curious case of the poisoned dogs

In this blog post, written specially for #RealTimeChem week on an #OldTimeChem theme, I'm going to start in the current century and work back to just a couple of years after the Kaiser's grandmother became Queen of the United Kingdom of Great Britain and Ireland. Readers might want to consider how history might have turned out differently had her eldest child succeeded her to the throne.

One can be forgiven for thinking that halogen bonding is a new phenomenon.  The term halogen bonding refers to attractive interactions between halogens and hydrogen bond acceptors which should be repulsive because hydrogen bond acceptors and halogens are electronegative and would therefore be expected to carry negative partial charges. Nevertheless halogens (other than fluorine) do seem to rather enjoy the company of hydrogen bond acceptors and molecular interaction 'catalogs' such as A Medicinal Chemist's Guide to Molecular Interactions and Molecular Recognition in Chemical and Biological Systems ensure that the medicinal chemist of 2015 is made aware of the importance of halogen bonding and of potential opportunities for exploiting them.

I was first made aware of halogen bonding in the mid 1990s through interactions with Zeneca colleagues at Jealotts Hill and, some time after that, The Nature and Geometry of Intermolecular Interactions between Halogens and Oxygen or Nitrogen was published with one of those colleagues (who had by then moved to CCDC) as a co-author.  A few years ago, I reproduced some of the analysis from that paper for a talk and here is one of the slides which shows how the closest contacts between the carbonyl oxygen and halogen are observed when the two atoms approach along along the axis defined by the halogen and the carbon atom to which it is bound.

If the halogen is bound to something that is sufficiently electron-withdrawing, the molecular electrostatic potential (MEP) on a circular patch on the van der Waals surface of the halogen becomes positive and sometimes this is described as a s-hole.  This article shows that of the s-hole is most pronounced for iodine and non-existent for fluorine, which is consistent with what X-ray crystal structures tell us about halogen bonding. I created a slightly different picture of the s-hole for my talk which shows MEP as a function of distance along two orthogonal directions of approach to the chlorine.  The significance of the  s-hole is that you doesn't actually have to invoke polarization to 'explain' halogen bonding even though it will always happen when atoms get up close and personal. 

When I first encountered halogen bonding, I remembered learning about the reaction of iodine with iodide anion as a schoolboy in Port-of-Spain in the 1970s. Iodine is not particularly water-soluble and this is a way to coax it into solution. That iodine forms complexes with Lewis bases has been known for many years and the Nantes group, better known for their extensive studies of hydrogen bond basicity, have used this to develop a halogen bond basicity scale based on this chemistry.

So in the spring of 2008 I found myself charged with doing a talk on halogens at EuroCUP (OpenEye European user group meeting) and halogen bonding was clearly going to be an important topic. To understand why I was doing this, we need to go back to the 2007 Computer-Aided Drug Design Gordon Conference and specifically the election of the vice chair for the 2009 conference. My good friend Anthony Nicholls was one of the nominees and in his candidacy speech said that he was going to have a session on halogens.  Although Ant didn't win that election, this is by far the most lucid and sensible suggestion that I've heard in a GRC candidacy speech. Needless to say the session on halogens happened in Strasbourg at EuroCUP (the morning after the conference dinner in a winery) and it was on the bus ride to that dinner that I had this conversation with my favorite Austro-Hungarian:

 "Onkel Hugo, where are you from in Germany?   
I am from AUSTRIA!   
Is that in Bavaria?"

While preparing the harangue, I decided to follow the iodine/iodide trail to see how far back it led and I was thrilled to encounter The Periodides by Albert B Prescott, writing in 1895, in which it was noted that, 

"In I839 Bouchardat, a medical writer in Paris, recounts that, when dogs were being surreptitiously poisoned with strychnine in Paris, and an antidote was asked for, first Guibourt recommended powdered galls, and then Donne advised iodine tincture, whereupon Bouchardat himself, approving the use of iodine, said they should use it in potassium iodide solution."

Thirty one years after the nefarious activities of the notorious Parisian dog poisoners  a sudden influx of Prussian visitors demonstrated the inadequacy of Strasbourg's supply of sunbeds and and I probably should now let you take a look at that infamous EuroCUP2008 harangue.