Henry Rzepa's Blog Chemistry with a twist

May 29, 2011

The inner secrets of an ion-pair: Isobornyl chloride rearrangements.

Observation of the slow racemization of isobornyl chloride in a polar solvent in 1923-24 by Meerwein led to the recognition that mechanistic interpretation is the key to understanding chemical reactivity. The hypothesis of ion pairs in which a chloride anion is partnered by a carbocation long ago entered the standard textbooks (see DOI 10.1021/ed800058c and 10.1021/jo100920e for background reading). But the intimate secrets of such ion-pairs are still perhaps not fully recognised. Here, to tease some of them them out, I use the NCI method, which has been the subject of several recent posts.


May 18, 2011

The inner secrets of the DNA structure.

In earlier posts, I alluded to what might make DNA wind into a left or a right-handed helix. Here I switch the magnification of our structural microscope up a notch to take a look at some more inner secrets.


April 9, 2011

Why are α-helices in proteins mostly right handed?

Understanding why and how proteins fold continues to be a grand challenge in science. I have described how Wrinch in 1936 made a bold proposal for the mechanism, which however flew in the face of much of then known chemistry. Linus Pauling took most of the credit (and a Nobel prize) when in a famous paper[1] in 1951 he suggested a mechanism that involved (inter alia) the formation of what he termed α-helices. Jack Dunitz in 2001[2] wrote a must-read article[3] on the topic of “Pauling’s Left-handed α-helix” (it is now known to be right handed). I thought I would revisit this famous example with a calculation of my own and here I have used the ωB97XD/6-311G(d,p) DFT procedure[4] to calculate some of the energy components of a small helix comprising (ala)6 in both left and right handed form.



  1. L. Pauling, R.B. Corey, and H.R. Branson, "The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain", Proceedings of the National Academy of Sciences, vol. 37, pp. 205-211, 1951. http://dx.doi.org/10.1073/pnas.37.4.205
  2. J.D. Dunitz, "Pauling's Left-Handed α-Helix", Angewandte Chemie International Edition, vol. 40, pp. 4167-4173, 2001. http://dx.doi.org/10.1002/1521-3773(20011119)40:22<4167::AID-ANIE4167>3.0.CO;2-Q
  3. K.S. Thanthiriwatte, E.G. Hohenstein, L.A. Burns, and C.D. Sherrill, "Assessment of the Performance of DFT and DFT-D Methods for Describing Distance Dependence of Hydrogen-Bonded Interactions", Journal of Chemical Theory and Computation, vol. 7, pp. 88-96, 2010. http://dx.doi.org/10.1021/ct100469b

March 5, 2011

The thermodynamic energies of left and right handed DNA.

In this earlier post, I noted some aspects of the calculated structures of both Z- and B-DNA duplexes. These calculations involved optimising the positions of around 250-254 atoms, for d(CGCG)2 and d(ATAT)2, an undertaking which has taken about two months of computer time! The geometries are finally optimised to the point where 2nd derivatives can be calculated, and which reveal up to 756 all-positive force constants and 6 translations and rotations which are close to zero! This now lets one compute the thermodynamic relative energies using ωB97XD/6-31G(d) (for 2nd derivatives) and 6-31G(d,p) (for dispersion terms). All geometries are optimized using a continuum solvent field (water), and are calculated, without a counterion, as hexa-anions. (more…)

January 7, 2011

Do electrons prefer to move in packs of 4, 6 or 8 during proton exchange in a calixarene?

This story starts with a calixarene, a molecule (suitably adorned with substituents) frequently used as a host to entrap a guest and perchance make the guest do something interesting. Such a calixarene was at the heart of a recent story where an attempt was made to induce it to capture cyclobutadiene in its cavity.


December 29, 2010

The handedness of DNA: an unheralded connection.

Science is about making connections. Plenty are on show in Watson and Crick’s famous 1953 article on the structure of DNA[1] but often with the tersest of explanations. Take for example their statement “Both chains follow right-handed helices“. Where did that come from? This post will explore the subtle implications of that remark (and how in one aspect they did not quite get it right!).



  1. J.D. WATSON, and F.H.C. CRICK, "Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid", Nature, vol. 171, pp. 737-738, 1953. http://dx.doi.org/10.1038/171737a0

November 19, 2010

Can a cyclobutadiene and carbon dioxide co-exist in a calixarene cavity?

On 8th August this year, I posted on a fascinating article that had just appeared in Science[1] in which the crystal structure was reported of two small molecules, 1,3-dimethyl cyclobutadiene and carbon dioxide, entrapped together inside a calixarene cavity. Other journals (e.g. Nature Chemistry[2] ran the article as a research highlight (where the purpose is not a critical analysis but more of an alerting service). A colleague, David Scheschkewitz, pointed me to the article. We both independently analyzed different aspects, and first David, and then I then submitted separate articles for publication describing what we had found. Science today published both David’s thoughts[3] and also those of another independent group, Igor Alabugin and colleagues[4]. The original authors have in turn responded [5]. My own article on the topic will appear very shortly[6]. You can see quite a hornet’s nest has been stirred up!



  1. Y. Legrand, A. van der Lee, and M. Barboiu, "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix", Science, vol. 329, pp. 299-302, 2010. http://dx.doi.org/10.1126/science.1188002
  2. A. Pichon, "Structure of a strained ring", Nature Chemistry, 2010. http://dx.doi.org/10.1038/nchem.823
  3. D. Scheschkewitz, "Comment on "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix"", Science, vol. 330, pp. 1047-1047, 2010. http://dx.doi.org/10.1126/science.1195752
  4. I.V. Alabugin, B. Gold, M. Shatruk, and K. Kovnir, "Comment on "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix"", Science, vol. 330, pp. 1047-1047, 2010. http://dx.doi.org/10.1126/science.1196188
  5. Y. Legrand, A. van der Lee, and M. Barboiu, "Response to Comments on "Single-Crystal X-ray Structure of 1,3-Dimethylcyclobutadiene by Confinement in a Crystalline Matrix"", Science, vol. 330, pp. 1047-1047, 2010. http://dx.doi.org/10.1126/science.1195846
  6. H.S. Rzepa, "Can 1,3-dimethylcyclobutadiene and carbon dioxide co-exist inside a supramolecular cavity?", Chem. Commun., vol. 47, pp. 1851-1853, 2011. http://dx.doi.org/10.1039/C0CC04023A

August 8, 2010

Reactions in supramolecular cavities – trapping a cyclobutadiene: ! or ?

Cavities promote reactions, and they can also trap the products of reactions. Such (supramolecular) chemistry is used to provide models for how enzymes work, but it also allows un-natural reactions to be undertaken. A famous example is the preparation of P4 (see blog post here), an otherwise highly reactive species which, when trapped in the cavity is now sufficiently protected from the ravages of oxygen for its X-ray structure to be determined. A colleague recently alerted me to a just-published article by Legrand, van der Lee and Barboiu (DOI: 10.1126/science.1188002) who report the use of cavities to trap and stabilize the notoriously (self)reactive 1,3-dimethylcyclobutadiene (3/4 in the scheme below). Again sequestration by the host allowed an x-ray determination of  the captured species!


July 15, 2010

Non-covalent interactions (NCI): revisiting Pirkle

Filed under: Interesting chemistry — Tags: , , — Henry Rzepa @ 8:50 am

NCI (non-covalent interactions) is the name of a fascinating new technique for identifying exactly these. Published recently by Johnson, Keinan, Mori-Snchez, Contreras-Garca, Cohen and Yang, it came to my attention at a conference to celebrate the 20th birthday of ELF when Julia Contreras-Garcia talked about the procedure. It is one of those methods which may seem as if it merely teases out the obvious about a molecule, but it is surprising how difficult seeing the obvious can be sometimes. I have blogged about this previously, in discussing the so-called Pirkle reagent. On that occasion, I used the QTAIM technique to identify so-called critical points in the electron density. NCI goes one stage further in identifying surfaces of interaction rather than just single points, the idea being that this focuses attention on regions in molecules which are primarily responsible for binding, stereoselection and other aspects of molecular selectivity.


January 11, 2010

Chemical intimacy: Ion pairs in carbocations

The scheme below illustrates one of the iconic reactions in organic chemistry. It is a modern representation of Meerwein’s famous experiment from which he inferred a carbocation intermediate, deduced from studying the rate of enantiomerization of isobornyl chloride when treated with the Lewis acid SnCl4.


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