Posts Tagged ‘free energy’

Kinetic vs Thermodynamic control. Subversive thoughts for electrophilic substitution of Indole.

Sunday, March 10th, 2013

I mentioned in the last post that one can try to predict the outcome of electrophilic aromatic substitution by approximating the properties of the transition state from those of either the reactant or the (presumed Wheland) intermediate by invoking Hammond’s postulate[1]. A third option is readily available nowadays; calculate the transition state directly. Here are the results of exploring this third variation.



  1. G.S. Hammond, "A Correlation of Reaction Rates", J. Am. Chem. Soc., vol. 77, pp. 334-338, 1955.

The conformation of acetaldehyde: a simple molecule, a complex explanation?

Friday, February 8th, 2013

Consider acetaldehyde (ethanal for progressive nomenclaturists). What conformation does it adopt, and why? This question was posed of me by a student at the end of a recent lecture of mine. Surely, an easy answer to give? Read on …


Sharpless epoxidation, enantioselectivity and conformational analysis.

Thursday, January 3rd, 2013

I return to this reaction one more time. Trying to explain why it is enantioselective for the epoxide product poses peculiar difficulties. Most of the substituents can adopt one of several conformations, and some exploration of this conformational space is needed.


How to tame an oxidant: the mysteries of “tpap” (tetra-n-propylammonium perruthenate).

Monday, December 24th, 2012

tpap[1], as it is affectionately known, is a ruthenium-based oxidant of primary alcohols to aldehydes discovered by Griffith and Ley. Whereas ruthenium tetroxide (RuO4) is a voracious oxidant[2], its radical anion countered by a tetra-propylammonium cation is considered a more moderate animal[3]. In this post, I want to try to use quantum mechanically derived energies as a pathfinder for exploring what might be going on (or a reality-check if you like). 



  1. S.V. Ley, J. Norman, W.P. Griffith, and S.P. Marsden, " Tetrapropylammonium Perruthenate, Pr 4 N + RuO 4 - , TPAP: A Catalytic Oxidant for Organic Synthesis ", Synthesis, vol. 1994, pp. 639-666, 1994.
  2. D.G. Lee, U.A. Spitzer, J. Cleland, and M.E. Olson, "The oxidation of cyclobutanol by ruthenium tetroxide and sodium ruthenate", Canadian Journal of Chemistry, vol. 54, pp. 2124-2126, 1976.
  3. D.G. Lee, Z. Wang, and W.D. Chandler, "Autocatalysis during the reduction of tetra-n-propylammonium perruthenate by 2-propanol", J. Org. Chem., vol. 57, pp. 3276-3277, 1992.

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.



  1. E.J. Corey, and A.G. Hortmann, "The Total Synthesis of Dihydrocostunolide", J. Am. Chem. Soc., vol. 87, pp. 5736-5742, 1965.

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.



  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.
  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.

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.


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.


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!


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]



  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.