Author Archive
Saturday, November 10th, 2012
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[1], 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[1]), and employing a dispersion-corrected DFT method rather than B3LYP. 
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References
- C. Tian, P. Xiu, Y. Meng, W. Zhao, Z. Wang, and R. Zhou, "Enantiomerization Mechanism of Thalidomide and the Role of Water and Hydroxide Ions", Chemistry – A European Journal, vol. 18, pp. 14305-14313, 2012. https://doi.org/10.1002/chem.201202651
Tags:298 4.7, aqueous media, ATM, energy barrier, energy barriers, free energy, Historical, Reaction Mechanism, simulation, zero-point-energy
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Sunday, November 4th, 2012
The text books say that cyclohexenone A will react with a Grignard reagent by delivery of an alkyl (anion) to the carbon of the carbonyl (1,2-addition) but if dimethyl lithium cuprate is used, a conjugate 1,4-addition proceeds, to give the product B shown below. The standard explanation is that the alkyl copper is a “soft” nucleophile attacking the soft conjugate carbon, whereas the alkyl magnesium is a “hard” nucleophile attacking the hard carbonyl carbon. Is this the best explanation?
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Tags:metal, Reaction Mechanism, simulation, Tutorial material
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Sunday, November 4th, 2012
When 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[1] 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“.
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References
- F. Calderazzo, and F.A. Cotton, "Carbon Monoxide Insertion Reactions. I. The Carbonylation of Methyl Manganese Pentacarbonyl and Decarbonylation of Acetyl Manganese Pentacarbonyl", Inorganic Chemistry, vol. 1, pp. 30-36, 1962. https://doi.org/10.1021/ic50001a008
Tags:agostic interaction, pi complex, Reaction Mechanism
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Sunday, October 28th, 2012
The 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[1]. 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?
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References
- T.C. Clarke, and R.G. Bergman, "Olefinic cyclization at a vinyl cation center. Inversion preference for intramolecular nucleophilic substitution by a double bond", Journal of the American Chemical Society, vol. 94, pp. 3627-3629, 1972. https://doi.org/10.1021/ja00765a062
Tags:immediate product, inversion, Reaction Mechanism, triflate leaving, Tutorial material, vinyl carbocation
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Saturday, October 27th, 2012
The 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[1]. 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.
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References
- T.C. Clarke, and R.G. Bergman, "Olefinic cyclization at a vinyl cation center. Inversion preference for intramolecular nucleophilic substitution by a double bond", Journal of the American Chemical Society, vol. 94, pp. 3627-3629, 1972. https://doi.org/10.1021/ja00765a062
Tags:chemical knowledge, Reaction Mechanism, researcher, Tutorial material
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Wednesday, October 17th, 2012
Every once in a while, one encounters a molecule which instantly makes an interesting point. Thus Ruthenium is ten electrons short of completing an 18-electron shell, and it can form a complex with benzene on one face and a ligand known as trimethylenemethane on the other[1].
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References
- G.E. Herberich, and T.P. Spaniol, "Trimethylenemethane complexes of ruthenium via the trimethylenemethane dianion", Journal of the Chemical Society, Chemical Communications, pp. 1457, 1991. https://doi.org/10.1039/c39910001457
Tags:Iron complex, metal, Postscript
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