Archive for the ‘reaction mechanism’ Category

The mechanism of Michael 1,4-Nucleophilic addition: a computationally derived reaction pathway.

Wednesday, March 25th, 2020

In 2013, I created an iTunesU library of 115 mechanistic types in organic and organometallic chemistry, illustrated using video animations of the intrinsic reaction coordinate (IRC) computed using a high level quantum mechanical procedure. Many of those examples first derived from posts here. That collection  is still available and is viewable  in the iTunesU app on an iPhone or an iPad. The realisation struck me now that one of the types not described in that library was Michael-type 1,4-nucleophilic addition to an activated alkene, as described at Wikipedia. So here is that addition.


Catalytic Mitsunobu reaction.

Wednesday, October 9th, 2019

If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. Now a catalytic version has been published, [1] along with a proposed mechanism. Here I apply computation as a reality check to see what the energetics of this mechanism might be.



  1. R.H. Beddoe, K.G. Andrews, V. Magné, J.D. Cuthbertson, J. Saska, A.L. Shannon-Little, S.E. Shanahan, H.F. Sneddon, and R.M. Denton, "Redox-neutral organocatalytic Mitsunobu reactions", Science, vol. 365, pp. 910-914, 2019.

An Ambimodal Trispericyclic Transition State: the effect of solvation?

Thursday, May 2nd, 2019

Ken Houk’s group has recently published this study of cycloaddition reactions, using a combination of classical transition state location followed by molecular dynamics trajectory calculations,[1] and to which Steve Bachrach’s blog alerted me. The reaction struck me as being quite polar (with cyano groups) and so I took a look at the article to see what both the original[2] experimental conditions were and how the new simulations compared. The reaction itself is shown below.



  1. X. Xue, C.S. Jamieson, M. Garcia-Borràs, X. Dong, Z. Yang, and K.N. Houk, "Ambimodal Trispericyclic Transition State and Dynamic Control of Periselectivity", Journal of the American Chemical Society, vol. 141, pp. 1217-1221, 2019.
  2. C.Y. Liu, and S.T. Ding, "Cycloadditions of electron-deficient 8,8-disubstituted heptafulvenes to electron-rich 6,6-disubstituted fulvenes", The Journal of Organic Chemistry, vol. 57, pp. 4539-4544, 1992.

Smoke and mirrors. All is not what it seems with this Sn2 reaction!

Thursday, April 4th, 2019

Previously, I explored the Graham reaction to form a diazirine. The second phase of the reaction involved an Sn2′ displacement of N-Cl forming C-Cl. Here I ask how facile the simpler displacement of C-Cl by another chlorine might be and whether the mechanism is Sn2 or the alternative Sn1. The reason for posing this question is that as an Sn1 reaction, simply ionizing off the chlorine to form a diazacyclopropenium cation might be a very easy process. Why? Because the resulting cation is analogous to the cyclopropenium cation, famously proposed by Breslow as the first example of a 4n+2 aromatic ring for which the value of n is zero and not 1 as for benzene.[1] Another example of a famous “Sn1” reaction is the solvolysis of t-butyl chloride to form the very stable tertiary carbocation and chloride anion (except in fact that it is not an Sn1 reaction but an Sn2 one!)



  1. R. Breslow, "SYNTHESIS OF THE s-TRIPHENYLCYCLOPROPENYL CATION", Journal of the American Chemical Society, vol. 79, pp. 5318-5318, 1957.

Free energy relationships and their linearity: a test example.

Sunday, January 13th, 2019

Linear free energy relationships (LFER) are associated with the dawn of physical organic chemistry in the late 1930s and its objectives in understanding chemical reactivity as measured by reaction rates and equilibria.


Dyotropic Ring Expansion: more mechanistic reality checks.

Sunday, October 1st, 2017

I noted in my WATOC conference report a presentation describing the use of calculated reaction barriers (and derived rate constants) as mechanistic reality checks. Computations, it was claimed, have now reached a level of accuracy whereby a barrier calculated as being 6 kcal/mol too high can start ringing mechanistic alarm bells. So when I came across this article[1] in which calculated barriers for a dyotropic ring expansion observed under mild conditions in dichloromethane as solvent were used to make mechanistic inferences, I decided to explore the mechanism a bit further.



  1. H. Santalla, O.N. Faza, G. Gómez, Y. Fall, and C. Silva López, "From Hydrindane to Decalin: A Mild Transformation through a Dyotropic Ring Expansion", Organic Letters, vol. 19, pp. 3648-3651, 2017.

Hydrogen capture by boron: a crazy reaction path!

Thursday, September 21st, 2017

A recent article reports, amongst other topics, a computationally modelled reaction involving the capture of molecular hydrogen using a substituted borane (X=N, Y=C).[1] The mechanism involves an initial equilibrium between React and Int1, followed by capture of the hydrogen by Int1 to form a 5-coordinate borane intermediate (Int2 below, as per Figure 11). This was followed by assistance from a proximate basic nitrogen to complete the hydrogen capture via a TS involving H-H cleavage. The forward free energy barrier to capture was ~11 kcal/mol and ~4 kcal/mol in the reverse direction (relative to the species labelled Int1), both suitably low for reversible hydrogen capture. Here I explore a simple variation to this fascinating reaction.



  1. L. Li, M. Lei, Y. Xie, H.F. Schaefer, B. Chen, and R. Hoffmann, "Stabilizing a different cyclooctatetraene stereoisomer", Proceedings of the National Academy of Sciences, vol. 114, pp. 9803-9808, 2017.

The conformation of enols: revealed and explained.

Thursday, April 6th, 2017

Enols are simple compounds with an OH group as a substituent on a C=C double bond and with a very distinct conformational preference for the OH group. Here I take a look at this preference as revealed by crystal structures, with the theoretical explanation.


What is the (calculated) structure of a norbornyl cation anion-pair in water?

Saturday, April 1st, 2017

In a comment appended to an earlier post, I mused about the magnitude of the force constant relating to the interconversion between a classical and a non-classical structure for the norbornyl cation. Most calculations indicate the force constant for an “isolated” symmetrical cation is +ve, which means it is a true minimum and not a transition state for a [1,2] shift. The latter would have been required if the species equilibrated between two classical carbocations. I then pondered what might happen to both the magnitude and the sign of this force constant if various layers of solvation and eventually a counter-ion were to be applied to the molecule, so that a bridge of sorts between the different states of solid crystals, superacid and aqueous solutions might be built.


Reaction coordinates vs Dynamic trajectories as illustrated by an example reaction mechanism.

Monday, March 20th, 2017

The example a few posts back of how methane might invert its configuration by transposing two hydrogen atoms illustrated the reaction mechanism by locating a transition state and following it down in energy using an intrinsic reaction coordinate (IRC). Here I explore an alternative method based instead on computing a molecular dynamics trajectory (MD).