Posts Tagged ‘free energy’

Vitamin B12 and the genesis of a new theory of chemistry.

Thursday, December 20th, 2012

I have written earlier about dihydrocostunolide, and how in 1963 Corey missed spotting the electronic origins of a key step in its synthesis.[1]. A nice juxtaposition to this failed opportunity relates to Woodward’s project at around the same time to synthesize vitamin B12. The step in the synthesis that caused him to ponder is shown below.

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References

  1. E.J. Corey, and A.G. Hortmann, "", J. Am. Chem. Soc., vol. 87, pp. 5736-5742, 1965. http://dx.doi.org/10.1021/ja00952a037

Why is the Sharpless epoxidation enantioselective? Part 1: a simple model.

Sunday, December 9th, 2012

Sharpless epoxidation converts a prochiral allylic alcohol into the corresponding chiral epoxide with > 90% enantiomeric excess[1],[2]. Here is the first step in trying to explain how this magic is achieved.

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References

  1. J.M. Klunder, S.Y. Ko, and K.B. Sharpless, "Asymmetric epoxidation of allyl alcohol: efficient routes to homochiral .beta.-adrenergic blocking agents", J. Org. Chem., vol. 51, pp. 3710-3712, 1986. http://dx.doi.org/10.1021/jo00369a032
  2. R.M. Hanson, and K.B. Sharpless, "Procedure for the catalytic asymmetric epoxidation of allylic alcohols in the presence of molecular sieves", J. Org. Chem., vol. 51, pp. 1922-1925, 1986. http://dx.doi.org/10.1021/jo00360a058

The mechanism of the Birch reduction. Part 2: a transition state model.

Monday, December 3rd, 2012

I promised that the follow-up to on the topic of Birch reduction would focus on the proton transfer reaction between the radical anion of anisole and a proton source, as part of analysing whether the mechanistic pathway proceeds O or M.

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The mechanism of the Birch reduction. Part 1: reduction of anisole.

Saturday, December 1st, 2012

The Birch reduction is a classic method for partially reducing e.g. aryl ethers using electrons (from sodium dissolved in ammonia) as the reductant rather than e.g. dihydrogen. As happens occasionally in chemistry, a long debate broke out over the two alternative mechanisms labelled O (for ortho protonation of the initial radical anion intermediate) or M (for meta protonation). Text books seem to have settled down of late in favour of O. Here I take a look at the issue myself.

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Di-imide reduction with a twist: A Möbius version.

Monday, November 26th, 2012

I was intrigued by one aspect of the calculated transition state for di-imide reduction of an alkene; the calculated NMR shieldings indicated an diatropic ring current at the centre of the ring, but very deshielded shifts for the hydrogen atoms being transferred. This indicated, like most thermal pericyclic reactions, an aromatic transition state. Well, one game one can play with this sort of reaction is to add a double bond. This adds quite a twist to this classical reaction!

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The “unexpected” mechanism of peroxide decomposition.

Sunday, November 18th, 2012

A game chemists often play is to guess the mechanism for any given reaction. I thought I would give it a go for the decomposition of the tris-peroxide shown below. This reaction is known to (rapidly, very rapidly) result in the production of three molecules of propanone, one of ozone and a lot of entropy (but not heat).[1]

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References

  1. F. Dubnikova, R. Kosloff, J. Almog, Y. Zeiri, R. Boese, H. Itzhaky, A. Alt, and E. Keinan, "Decomposition of Triacetone Triperoxide Is an Entropic Explosion", J. Am. Chem. Soc., vol. 127, pp. 1146-1159, 2005. http://dx.doi.org/10.1021/ja0464903

Thalidomide. The role of water in the mechanism of its aqueous racemisation.

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

  1. 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. http://dx.doi.org/10.1002/chem.201202651

Dynamic effects in nucleophilic substitution at trigonal carbon (with Na+) revisited.

Monday, August 13th, 2012

This reaction looks simple but is deceptively complex. To recapitulate: tolyl thiolate (X=Na) reacts with the dichlorobutenone to give two substitution products in a 81:19 ratio, a result that Singleton and Bogle argue arises from a statistical distribution of dynamic trajectories bifurcating out of a single transition state favouring 2 over 3. On the grounds (presumably) that the presence of both the cation X (=Na+) and H-bonded solvent (ethanol) are uninfluential, neither species was explicitly included in the transition state model used to derive the dynamics. I speculated whether in fact the spatial distribution of counterions and solvent (set up by explicit hydrogen bonds and O…Na+ interactions) might in fact be perturbed from un-influential randomness by co-ordination to the carbonyl group present in the system. I also raised the issue of what the origin of the electronic effects leading to the major product might be. 

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Transition state models for Baldwin dig(onal) ring closures.

Sunday, June 10th, 2012

This is a continuation of the previous post exploring the transition state geometries of various types of ring closure as predicted by  Baldwin’s rules. I had dealt with bond formation to a trigonal (sp2) carbon; now I add a digonal (sp) example (see an interesting literature variation). 

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The mechanism of the Baeyer-Villiger rearrangement.

Monday, May 7th, 2012

The Baeyer-Villiger rearrangement was named after its discoverers, who in 1899 described the transformation of menthone into the corresponding lactone using Caro’s acid (peroxysulfuric acid). The mechanism is described in all text books of organic chemistry as involving an alkyl migration. Here I take a look at the scheme described by Alvarez-Idaboy, Reyes and Mora-Diez[1], and which may well not yet have made it to all the text books!

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References

  1. J.R. Alvarez-Idaboy, L. Reyes, and N. Mora-Diez, "The mechanism of the Baeyer–Villiger rearrangement: quantum chemistry and TST study supported by experimental kinetic data", Org. Biomol. Chem., vol. 5, pp. 3682, 2007. http://dx.doi.org/10.1039/b712608e