Posts Tagged ‘simulation’

Computationally directed synthesis: 2,3-dimethyl-2-butene + NO(+).

Saturday, September 6th, 2014

In the previous posts, I explored reactions which can be flipped between two potential (stereochemical) outcomes. This triggered a memory from Alex, who pointed out this article from 1999[1] in which the nitrosonium cation as an electrophile can have two outcomes A or B when interacting with the electron-rich 2,3-dimethyl-2-butene. NO NMR evidence clearly pointed to the π-complex A as being formed, and not the cyclic nitrosonium species B (X=Al4-). If you are wondering where you have seen an analogy for the latter, it would be the species formed when bromine reacts with an alkene (≡ Br+, X=Br- or Br3-). The two structures are shown below[1] tetramethyletylene-NO+ Since the topic that sparked this concerned pericyclic reactions, it seemed possible that if it had been formed, species B would immediately undergo a pericyclic electrocyclic reaction to form the rather odd-looking cation C, which might then be trapped by eg X(-) to form the nitrone D. So this post is an exploration of what happens when X-NO (X= CF3COO, trifluoracetate) interacts with 2,3-dimethyl-2-butene, as an illustration of what can be achieved nowadays from about 2 days worth of dry-lab computation as a prelude to e.g. an experiment in the wet-lab (it would take a little more than two days to achieve the latter I suspect). Hence computationally directed synthesis. The model is set up as ωB97XD/6-311G(d,p)/SCRF=chloroform. A transition state is located[2] and the resulting IRC (below) [3] does not quite have the outcome the above scheme would suggest. NOa NOe NOg Neither A nor B is formed; instead it is the tetrahedral species E, which is ~15 kcal/mol endothermic. NOaa I should immediately point out that this is not inconsistent with the formation of A as previously characterised[1]. That is because this experiment was conducted with a non-nucleophilic counter-anion (X=Al4-), whereas in the computational simulation above, we have a nucleophilic anion (X= CF3CO2-). What a difference the inclusion of a counter-ion in the calculation can have! The barrier however (~35 kcal/mol) is a little too high for a facile thermal reaction. In the second of this two-stage reaction, E now ring-opens to form the anticipated D[4] with quite a small barrier of ~6 kcal/mol, but a highly exothermic outcome. I ask this question about it; can this still be described as a pericyclic process? (there is some analogy to the electrocyclic ring opening of a cyclopropyl tosylate). NObNObe So what are the conclusions? Well, because of the rather high initial barrier, the alkene will need activation (by electron donating substituents, perhaps OMe) for the reaction to become more viable. But if it works, it could be an interesting synthesis of nitrones (I have not yet searched to find out if the reaction is actually known).

References

  1. G.I. Borodkin, I.R. Elanov, A.M. Genaev, M.M. Shakirov, and V.G. Shubin, "Interaction in olefin–NO+ complexes: structure and dynamics of the NO+–2,3-dimethyl-2-butene complex", Mendeleev Communications, vol. 9, pp. 83-84, 1999. http://dx.doi.org/10.1070/MC1999v009n02ABEH000995
  2. Henry S Rzepa., "C8H12F3NO3", 2014. http://dx.doi.org/10.14469/ch/24979
  3. Henry S. Rzepa., "Gaussian Job Archive for C8H12F3NO3", 2014. http://dx.doi.org/10.6084/m9.figshare.1162797
  4. Henry S. Rzepa., "Gaussian Job Archive for C8H12F3NO3", 2014. http://dx.doi.org/10.6084/m9.figshare.1162676

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

Secrets revealed for conjugate addition to cyclohexenone using a Cu-alkyl reagent.

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

Thursday, July 19th, 2012

In the preceding post, I described a fascinating experiment and calculation by Bogle and Singleton, in which the trajectory distribution of molecules emerging from a single transition state was used to rationalise the formation of two isomeric products 2 and 3.  In the present post, I explore possible consequences of including a sodium cation (X=Na+ below) in the computational model.

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Computers 1967-2011: a personal perspective. Part 4. Moore’s Law and Molecules.

Friday, October 28th, 2011

Moore’s law describes a long-term trend in the evolution of computing hardware, and it is often interpreted in terms of processing speed. Here I chart this rise in terms of the size of computable molecules. By computable I mean specifically how long it takes to predict the geometry of a given molecule using a quantum mechanical procedure.

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