Thalidomide is a chiral molecule, which was sold in the 1960s as a sedative in its (S,R)-racemic form. The tragedy was that the (S)-isomer was tetragenic, and only the (R) enantiomer acts as a sedative. What was not appreciated at the time is that interconversion of the (S)- and (R) forms takes place quite quickly in aqueous media. Nowadays, quantum modelling can provide good in-silico estimates of the (free) energy barriers for such processes, which in this case is a simple keto-enol tautomerism. In a recently published article[cite]10.1002/chem.201202651[/cite], just such a simulation is reported. By involving two explicit water molecules in the transition state, an (~enthalpic) barrier of 27.7 kcal/mol was obtained. The simulation was conducted just with two water molecules acting as solvent, and without any additional continuum solvation applied. So I thought I would re-evaluate this result by computing it at the ωB97XD/6-311G(d,p)/SCRF=water level (a triple-ζ basis set rather than the double-ζ used before[cite]10.1002/chem.201202651[/cite]), and employing a dispersion-corrected DFT method rather than B3LYP. 
Mechanisms of carbon monoxide insertion reactions: A reality check on carbonylation of methyl manganese pentacarbonyl
November 4th, 2012When methyl manganese pentacarbonyl is treated with carbon monoxide in e.g. di-n-butyl ether, acetyl manganese pentacarbonyl is formed. This classic experiment conducted by Cotton (of quadruple bond fame) and Calderazzo in 1962[cite]10.1021/ic50001a008[/cite] dates from an era when chemists conducted extensive kinetic analyses to back up any mechanistic speculations. Their suggested transition state is outlined below. Here I subject their speculations to a quantum mechanical “reality check“.
Secrets of a university tutor. An exercise in mechanistic logic: second dénouement.
October 29th, 2012Following on from our first mechanistic reality check, we now need to verify how product A might arise in the mechanism shown below, starting from B.
Secrets of a university tutor. An exercise in mechanistic logic: first dénouement.
October 28th, 2012The reaction described in the previous post (below) is an unusual example of nucleophilic attack at an sp2-carbon centre, reportedly resulting in inversion of configuration[cite]10.1021/ja00765a062[/cite]. One can break it down to a sequence of up to eight individual steps, which makes teaching it far easier. But how real is that sequence?
Secrets of a university tutor. An exercise in mechanistic logic, prequel.
October 27th, 2012The reaction below plays a special role in my career. As a newly appointed researcher (way back now), I was asked to take tutorial groups for organic chemistry as part of my duties. I sat down to devise a suitable challenge for the group, and came upon the following reaction[cite]10.1021/ja00765a062[/cite]. I wrote it down on page 2 of my tutorial book, which I still have. I continue to use this example in tutorials to this day, some 35 years later.
How is the bromination of alkenes best represented?
October 14th, 2012I occasionally delve into the past I try to understand how we got to our present understanding of chemistry. Thus curly arrow mechanistic notation can be traced back to around 1924, with style that bifurcated into two common types used nowadays (on which I have commented and about which further historical light at the end of this post). Here I try to combine these themes with some analysis of wavefunctions for a particularly troublesome reaction to represent, the dibromination of an alkene, which I represented in the previous post as shown below.
Text-books and the bromination of ethene.
October 14th, 2012There is often a disconnect between how a text-book (schematically) represents a reaction and a more quantitive “reality” revealed by quantum mechanics. Is the bromination of ethene to give 1,2-dibromoethane one such example?
Ring-flipping in cyclohexane in a different light
October 12th, 2012The conformational analysis of cyclohexane is a mainstay of organic chemistry. Is there anything new that can be said about it? Let us start with the diagram below: