Anslyn pp. 877 – 934 (Pericyclic reactions)

Everything is crystal clear, and not much to comment about.  

p. 900 — Interesting to see the semi-empirical and ab initio approaches disagreeing on the pericyclic transition states and the explanation for the difference.  This sort of stuff always bothers me about ‘black box’ approaches.  It’s clear that next year. I’m going to make a big effort to really understand computational organic chemistry and molecular dynamics simulations, particularly the latter, since all sorts of conclusions are reached using them in protein folding, drug protein interactions, ion channel and enzyme mechanisms, etc. etc. For a current example see  [ Neuron vol. 72 pp. 713 – 720 ’11 (December) ] where simulations are used to figure out how an ion channel in the membrane of all our neurons looks in the resting state.  Venoms and other poisons target these channels showing how crucial they are for life itself.  For how ion channels are related to a disease I battled:  epilepsy see

        How many grains of salt should I take reading these papers?  The many posts by Curious Wavefunction about computational chemistry are well worth reading (particularly his caveats), but all this takes me back to the days in neurology when we had precious little data, but would quote what various eminent authorities had to say about a given clinical issue.  It was like quoting scripture, hardly scientific, but it provided a certain comfort.  I’m presently in the same boat with the various computational approaches.  A&D are very good about their limitations, and what they sweep under the rug, but I’m going to try to go under the hood with Cramer’s book — “Essentials of Computational Chemistry”.  New Year’s resolution #1.   The part I dipped into concerning secular equations was quite clear. 

p. 907 — The power of theory !  The relative stability of Dewar benzene — trapped in a kinetic prison whose origin is orbital symmetry — it’s this sort of thing that makes the practical man (who has seen many theories come and go) sit up and take notice.  Dewar benzene was made in ’63 probably before the theories in this chapter were extant — was the relative stability a surprise?

The synthesis of Dewar benzene is given on p. 970 — giving a great proof of what photochemistry allows you to accomplish.

p. 910 — Nice to see the mechanism of action of the enediyne antibiotics. However, it isn’t clear (in this text) how they cleave DNA, although the diradical should be reactive as hell.  One mechanism I’ve read about is that they may remove hydrogen atoms from deoxy ribose in the DNA backbone (probably after intercalating with DNA).   More likely (to me) the diradical intercalates with the aromatic nitrogen bases of the DNA and raise hell with them. 

p. 924 — Nice to see a mechanism by which hydroperoxides form with a double bond present.  Quite important in biology.  All sorts of fatty acids in cellular membranes have cis double bonds (so they don’t pack well, which has the effect of liquifying the membrane).  The mechanism explains why these double bonds cause trouble.  The biophysics explains why they have to be where they are. 

End of Chapter — Despite all the cleverness expended on molecular orbitals where carbon is involved, there was nothing in this chapter concerning organometallics, which appear to have revolutionized synthetic organic chemistry in the past 50 years.   Look at Fig 12.17 p. 744 — allylic alkylation appears to involve a pericyclic reaction as do others. 
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  • Curious Wavefunction  On December 20, 2011 at 12:37 pm

    The Messiah is soaring but the Hallelujah chorus is in a class of its own. To understand how far we still have to go, take a look at the April 2011 special issue of the Journal of Computer-Aided Molecular Design which focuses on a contest involving the calculation of two supposedly very simple properties – solvation energies (more precisely vacuum-water transfer energies) and tautomer ratios in water. The fact that even the most sophisticated methods have great difficulty predicting these simple and essential properties tells you how much you should or should not trust simulations of proteins.

  • luysii  On December 20, 2011 at 11:14 pm

    Hopefully things have improved in the 10 years since this was written.

    [ Proc. Natl. Acad. Sci. vol. 98 pp. 10533 – 10540 ’01 ] “Despite the construction of hundreds of model force fields for use in simulations, the great advances in computational technology, and the development of powerful ab initio molecular dynamics methods we remain unable to accurately calculate the properties of liquid water (e.g. heat capacity, density, dielectric constant, compressibility) over wide ranges in conditions. We do not yet have a satisfactory molecular description of how a proton moves in the liquid. We do not fully understand the molecular nature of the surfaces of either ice or liquid water. Although it is clear that the hydrogen bond network and its fluctuations and rearrangement dynamics determine the properties of the liquid, no experimental studies are available showing detalied information about this process (without considerable interpretation).”

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