Archive for the ‘reaction mechanism’ 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.

Dimerisation of cyclopropenylidene: what are the correct “curly arrows” for this process?

Wednesday, July 21st, 2021

In another post, a discussion arose about whether it might be possible to trap cyclopropenylidene to form a small molecule with a large dipole moment. Doing so assumes that cyclopropenylidene has a sufficiently long lifetime to so react, before it does so with itself to e.g. dimerise. That dimerisation has an energy profile shown below, with a free energy of activation of 14.4 kcal/mol, so a facile reaction that will indeed compete with reaction with Ph-I+-CC.


Dimethyl ketal hydrolysis catalysed by hydroxide and hydronium ions

Wednesday, April 7th, 2021

In the preceding post, I looked at a computed mechanism for the hydrolysis of a ketal by water. Of course, pure water consists of three potential catalysts, water itself or [H2O], and the products of autoionisation, [OH] and [H3O+]. The latter are in much smaller concentration, equivalent to a penalty of ~11.9 kcal/mol on any free energy barrier. Here I take a look at these ion-catalysed routes to see if that penalty can be overcome.


A computational mechanism for the aqueous hydrolysis of a ketal to a ketone and alcohol.

Thursday, April 1st, 2021

The previous post was about an insecticide and made a point that the persistence of both insecticides and herbicides is an important aspect of their environmental properties. Water hydrolysis will degrade them, a typical residency time being in the order of a few days. I noted in passing a dioxepin-based herbicide[1] which contains a ketal motif and which in water can hydrolise to a ketone and alcohol. The reverse (acid catalysed) formation of a ketal is a staple of the taught organic chemistry curriculum. Here as a prelude to looking at the hydrolysis of that dioxepin, I take a look at a possible computational mechanism for the hydrolysis of 2,2-dimethoxypropane using pure water, without the help of acid or base.



  1. P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1265-1269, 1989.

The Stevens rearrangement: how history gives us new insights.

Friday, January 29th, 2021

In a recent post, I told the story of how in the early 1960s, Robert Woodward had encountered an unexpected stereochemical outcome to the reaction of a hexatriene, part of his grand synthesis of vitamin B12. He had constructed a model of the reaction he wanted to undertake, perhaps with the help of a physical model, concluding that the most favourable of the two he had built was not matched by the actual outcome of the reaction. He was thus driven to systematise such (Pericyclic) reactions by developing rules for them with Roald Hoffmann. This involved a classification scheme of “allowed” and “forbidden” pericyclic reactions and his original favoured model in fact corresponded to the latter type. When physical model building in the 1960s was gradually replaced by models based on quantum mechanical calculations from the 1970s onwards, the term “allowed” morphed into “a relatively low energy transition state for the reaction can be located” and very often “no transition state exists for a forbidden reaction”. The famous quote “there are no exceptions” (to this rule) was often interpreted that if a “forbidden reaction” did apparently proceed, its mechanism was NOT that of a pericyclic reaction. Inspired by all of this, I recollected a famous “exception” to the rules which is often explained by such non-pericyclic character, the Stevens rearrangement[1],[2],[3] by a 1,2-shift.



  1. T.S. Stevens, E.M. Creighton, A.B. Gordon, and M. MacNicol, "CCCCXXIII.—Degradation of quaternary ammonium salts. Part I", J. Chem. Soc., vol. 0, pp. 3193-3197, 1928.
  2. T.S. Stevens, "CCLXX.—Degradation of quaternary ammonium salts. Part II", J. Chem. Soc., vol. 0, pp. 2107-2119, 1930.
  3. T.S. Stevens, W.W. Snedden, E.T. Stiller, and T. Thomson, "CCLXXI.—Degradation of quaternary ammonium salts. Part III", J. Chem. Soc., vol. 0, pp. 2119-2125, 1930.

Is cyanogen chloride (fluoride) a source of C⩸N(+)? More mechanistic insights.

Friday, December 4th, 2020

I asked the question in my previous post. A computational mechanism revealed that AlCl3 or its dimer Al2Cl6 could catalyse a concerted 1,1-substitution reaction at the carbon of Cl-C≡N, with benzene displacing chloride which is in turn captured by the Al. Unfortunately the calculated barrier for this simple process was too high for a reaction apparently occuring at ~room temperatures. Comments on the post suggested using either a second AlCl3 or a proton to activate the carbon of the C≡N group by coordination on to nitrogen. A second suggestion was to involve di-cationic electrophiles. Here I report the result of implementing the N-coordinated model below.


Is cyanogen chloride (fluoride) a source of C⩸N(+)?

Saturday, November 28th, 2020

In 2010 I recounted the story of an organic chemistry tutorial, in which I asked the students the question “how would you synthesize 3-nitrobenzonitrile“.


The Willgerodt-Kindler reaction. Completing the Box set.

Monday, September 7th, 2020

These four posts (the box set) set out to try to define the energetics for a reasonable reaction path for the Willgerodt-Kindler reaction. The rate of this reaction corresponds approximately to a free energy barrier of ~30 kcal/mol. Any pathway found to be >10 kcal/mol at its highest point above this barrier was deemed less probable. The first three efforts at defining such pathways all gave such a result. Here I try a fourth pathway in search of the hitherto elusive appropriately low energy barrier.


The Willgerodt-Kindler Reaction: mechanistic reality check 3. A peek under the hood for transition state location.

Thursday, August 27th, 2020

The two previous surveys of the potential energy surface for this, it has to be said, rather obscure reaction led to energy barriers that were rather to high to be entirely convincing. So here is a third possibility.


The Willgerodt-Kindler Reaction: mechanistic reality check 2.

Friday, August 14th, 2020

Continuing an exploration of the mechanism of this reaction, an alternative new mechanism was suggested in 1989 (having been first submitted to the journal ten years earlier!).[1] Here the key intermediate proposed is a thiirenium cation (labelled 8 in the article) and labelled Int3 below.



  1. M. Carmack, "The willgerodt-kindler reactions. 7. The mechanisms", Journal of Heterocyclic Chemistry, vol. 26, pp. 1319-1323, 1989.