Posts Tagged ‘chemical synthesis’

Feist’s acid. Stereochemistry galore.

Thursday, April 4th, 2013

Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (1, with Me replaced by CO2H). Compound 1 itself nowadays is used to calibrate chiroptical calculations[1], which is what brought it to my attention. But about four decades ago, and now largely forgotten, both 1 and the dicarboxylic acid were famous for the following rearrangement that gives a mixture of 2 and 3[2]. I thought I might here unpick some of the wonderfully subtle stereochemical analysis that this little molecule became subjected to.
methylene-cyclopropane

Feist’s acid and its derivatives have attracted constant attention a long while. The rearrangement shown above was identified in 1932, and by 1960 it was shown that 1 as a pure enantiomer gave products 2 and 3 that retained optical activity (read about all of this here[3]). By 1970 attention had shifted to the absolute configurations of the molecules involved and the mechanism of the reaction. Why? Woodward and Hoffmann had just put pericyclic reactions on the map[4], and one of the examples they cited was this one. They identified the reaction as a [1,3]sigmatropic rearrangement (the red bond breaks and the blue bond forms) and their new theory required the configuration at carbon 1 to be inverted by the reaction, from (R) to (S) as shown above. In order to verify this, von Doering (who had been a student of Woodward’s) subjected Feist’s ester and its rearrangement products to a series of chemical transformations[4] in order to relate its absolute stereochemistry to that of known compounds. Gajewski[5] took over and with four further chemical transformations, was able to assert that the (S,S)-dimethyl enantiomer of 1 has an optical rotation of -59.4°.‡ The molecules 2 and 3 were subjected to a similar stereochemical analysis, which finally revealed them to have (S) configuration at the carbon labelled 1, thus confirming the inversion of configuration so confidently predicted by Woodward and Hoffmann. I imagine Feist never imagined the molecule which came to bear his name would be used as a confirmation of one of the pivotal 20th century stereochemical theories of organic chemistry.

So what of the mechanism for this rearrangement? Well, a ωB97XD/6-311G(d,p) calculation reveals the transition state as shown below. The two dashed lines represent the red and blue bonds shown schematically above, and these bond either break or form to the same face of the three-carbon allyl fragment (suprafacially), but that carbon 1 (pointed to by the blue arrow below) suffers an Sn2-like inversion of configuration (= antarafacial) as proven by all that hard chemical synthesis noted above. methylene-cyclopropane

The reaction is concerted, with a predicted barrier of around 50 kcal/mol. This is a little higher than the measured value of ~41 kcal/mol[6]. This is taken to indicate that the wavefunction has a contribution from an open-shell biradical configuration (indeed it is unstable at the transition state, having a lower energy triplet state) which would lower the barrier by 10-15 kcal/mol. The observation that the product has NOT lost optical activity suggests that the mechanism cannot simply be that of an achiral biradical, and that a “memory” of the starting stereochemical configuration must be retained throughout the dynamic reaction trajectory. Modelling such a process requires more sophisticated (multi-configuration) techniques than the one I have illustrated here, and quite probably a smattering of reaction dynamics thrown in. It goes to show that quite innocent looking molecules can be devils to model (both for their reaction dynamics and their optical activity!). 

methylenecyclopropane–[7] methylenecyclopropane

Feist’s acid itself reveals a profile for the computed rearrangement IRC (ωB97XD/6-311G(d,p)/SCRF=water) that I have never seen as prominently before, a veritable table top of a mountain! This feature (and its reflection in the gradient norm) is a nice example of a “hidden intermediate”. In this case, it is a species which may be either biradical or zwitterionic, and which sits atop the mountain plateau. It can drop (bifurcate) off the mountain to form either compound 2 or 3, a process which must likely be best studied by dynamics rather than purely as an intrinsic reaction coordinates.

feist1

Click for 3D



[8]		 feiste
 feistg

 

‡See comment here.

References

  1. E.D. Hedegård, F. Jensen, and J. Kongsted, "Basis Set Recommendations for DFT Calculations of Gas-Phase Optical Rotation at Different Wavelengths", Journal of Chemical Theory and Computation, vol. 8, pp. 4425-4433, 2012. https://doi.org/10.1021/ct300359s
  2. J.J. Gajewski, "Hydrocarbon thermal degenerate rearrangements. IV. Stereochemistry of the methylenecyclopropane self-interconversion. Chiral and achiral intermediates", Journal of the American Chemical Society, vol. 93, pp. 4450-4458, 1971. https://doi.org/10.1021/ja00747a019
  3. W. von E. Doering, and H. Roth, "Stereochemistry of the methylenecyclopropane rearrangement", Tetrahedron, vol. 26, pp. 2825-2835, 1970. https://doi.org/10.1016/s0040-4020(01)92859-5
  4. R.B. Woodward, and R. Hoffmann, "The Conservation of Orbital Symmetry", Angewandte Chemie International Edition in English, vol. 8, pp. 781-853, 1969. https://doi.org/10.1002/anie.196907811
  5. J.P. Chesick, "<b>Kinetics of the Thermal Interconversion of 2-Methylmethylenecyclopropane and Ethylidenecyclopropane</b>", Journal of the American Chemical Society, vol. 85, pp. 2720-2723, 1963. https://doi.org/10.1021/ja00901a009
  6. H.S. Rzepa, "Gaussian Job Archive for C6H10", 2013. https://doi.org/10.6084/m9.figshare.670632
  7. H.S. Rzepa, "Gaussian Job Archive for C6H6O4", 2013. https://doi.org/10.6084/m9.figshare.674600

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Posted in Interesting chemistry | 2 Comments »

Feist's acid. Stereochemistry galore.

Thursday, April 4th, 2013

Back in the days (1893) when few compounds were known, new ones could end up being named after the discoverer. Thus Feist is known for the compound bearing his name; the 2,3 carboxylic acid of methylenecyclopropane (1, with Me replaced by CO2H). Compound 1 itself nowadays is used to calibrate chiroptical calculations[1], which is what brought it to my attention. But about four decades ago, and now largely forgotten, both 1 and the dicarboxylic acid were famous for the following rearrangement that gives a mixture of 2 and 3[2]. I thought I might here unpick some of the wonderfully subtle stereochemical analysis that this little molecule became subjected to.
methylene-cyclopropane

Feist’s acid and its derivatives have attracted constant attention a long while. The rearrangement shown above was identified in 1932, and by 1960 it was shown that 1 as a pure enantiomer gave products 2 and 3 that retained optical activity (read about all of this here[3]). By 1970 attention had shifted to the absolute configurations of the molecules involved and the mechanism of the reaction. Why? Woodward and Hoffmann had just put pericyclic reactions on the map[4], and one of the examples they cited was this one. They identified the reaction as a [1,3]sigmatropic rearrangement (the red bond breaks and the blue bond forms) and their new theory required the configuration at carbon 1 to be inverted by the reaction, from (R) to (S) as shown above. In order to verify this, von Doering (who had been a student of Woodward’s) subjected Feist’s ester and its rearrangement products to a series of chemical transformations[4] in order to relate its absolute stereochemistry to that of known compounds. Gajewski[5] took over and with four further chemical transformations, was able to assert that the (S,S)-dimethyl enantiomer of 1 has an optical rotation of -59.4°.‡ The molecules 2 and 3 were subjected to a similar stereochemical analysis, which finally revealed them to have (S) configuration at the carbon labelled 1, thus confirming the inversion of configuration so confidently predicted by Woodward and Hoffmann. I imagine Feist never imagined the molecule which came to bear his name would be used as a confirmation of one of the pivotal 20th century stereochemical theories of organic chemistry.

So what of the mechanism for this rearrangement? Well, a ωB97XD/6-311G(d,p) calculation reveals the transition state as shown below. The two dashed lines represent the red and blue bonds shown schematically above, and these bond either break or form to the same face of the three-carbon allyl fragment (suprafacially), but that carbon 1 (pointed to by the blue arrow below) suffers an Sn2-like inversion of configuration (= antarafacial) as proven by all that hard chemical synthesis noted above. methylene-cyclopropane

The reaction is concerted, with a predicted barrier of around 50 kcal/mol. This is a little higher than the measured value of ~41 kcal/mol[6]. This is taken to indicate that the wavefunction has a contribution from an open-shell biradical configuration (indeed it is unstable at the transition state, having a lower energy triplet state) which would lower the barrier by 10-15 kcal/mol. The observation that the product has NOT lost optical activity suggests that the mechanism cannot simply be that of an achiral biradical, and that a “memory” of the starting stereochemical configuration must be retained throughout the dynamic reaction trajectory. Modelling such a process requires more sophisticated (multi-configuration) techniques than the one I have illustrated here, and quite probably a smattering of reaction dynamics thrown in. It goes to show that quite innocent looking molecules can be devils to model (both for their reaction dynamics and their optical activity!). 

methylenecyclopropane–[7] methylenecyclopropane

Feist’s acid itself reveals a profile for the computed rearrangement IRC (ωB97XD/6-311G(d,p)/SCRF=water) that I have never seen as prominently before, a veritable table top of a mountain! This feature (and its reflection in the gradient norm) is a nice example of a “hidden intermediate”. In this case, it is a species which may be either biradical or zwitterionic, and which sits atop the mountain plateau. It can drop (bifurcate) off the mountain to form either compound 2 or 3, a process which must likely be best studied by dynamics rather than purely as an intrinsic reaction coordinates.

feist1

Click for 3D



[8]		 feiste
 feistg

 

‡See comment here.

References

  1. E.D. Hedegård, F. Jensen, and J. Kongsted, "Basis Set Recommendations for DFT Calculations of Gas-Phase Optical Rotation at Different Wavelengths", Journal of Chemical Theory and Computation, vol. 8, pp. 4425-4433, 2012. https://doi.org/10.1021/ct300359s
  2. J.J. Gajewski, "Hydrocarbon thermal degenerate rearrangements. IV. Stereochemistry of the methylenecyclopropane self-interconversion. Chiral and achiral intermediates", Journal of the American Chemical Society, vol. 93, pp. 4450-4458, 1971. https://doi.org/10.1021/ja00747a019
  3. W. von E. Doering, and H. Roth, "Stereochemistry of the methylenecyclopropane rearrangement", Tetrahedron, vol. 26, pp. 2825-2835, 1970. https://doi.org/10.1016/s0040-4020(01)92859-5
  4. R.B. Woodward, and R. Hoffmann, "The Conservation of Orbital Symmetry", Angewandte Chemie International Edition in English, vol. 8, pp. 781-853, 1969. https://doi.org/10.1002/anie.196907811
  5. J.P. Chesick, "<b>Kinetics of the Thermal Interconversion of 2-Methylmethylenecyclopropane and Ethylidenecyclopropane</b>", Journal of the American Chemical Society, vol. 85, pp. 2720-2723, 1963. https://doi.org/10.1021/ja00901a009
  6. H.S. Rzepa, "Gaussian Job Archive for C6H10", 2013. https://doi.org/10.6084/m9.figshare.670632
  7. H.S. Rzepa, "Gaussian Job Archive for C6H6O4", 2013. https://doi.org/10.6084/m9.figshare.674600

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Posted in Interesting chemistry | 2 Comments »

Perbromate. A riddle, wrapped in a mystery, inside an enigma; but perhaps there is a key.

Friday, April 6th, 2012

Chemists love a mystery as much as anyone. And gaps in patterns can be mysterious. Mendeleev’s period table had famous gaps which led to new discovery. And so from the 1890s onwards, chemists searched for the perbromate anion, BrO4–. It represented a gap between perchlorate and periodate, both of which had long been known. As the failure to turn up perbromate persisted, the riddle deepened. Finally, in 1968, the key was found, but talk about sledgehammer to crack a nut! It was done by alchemical-like radioactive transmutation of selenium into bromine:

Se83O42- → Br83O4– + β–

Once the psychological barrier had been surmounted, a chemical synthesis provided enough perbromic acid to show it was a stable, high boiling liquid. So, the failure to make it was not because it was unstable!

XeF2 + NaBrO3 → NaBrO4

Once quantities were available, the thermodynamic and redox properties could be measured. This did little to solve the riddle. Although it was found to be a better oxidant than periodate, this was not considered enough to explain why it had proved so elusive. The theoreticians got in on the act, but their article too did little to resolve matters; the calculations merely verified the experimental measurements.

To this day, little perbromate has been made, and so much of its chemistry remains a mystery. Only in 2011 has a synthesis appeared which could potentially result in large and hence cheap quantities, by formation through the carefully controlled reaction of hypobromite and bromate ions in an alkaline sodium hypobromite solution.

Periodate has found much utility in organic synthesis as an oxidant, and perchlorate is a very interesting non-coordinating counter ion in metal catalysis. Who knows what use might transpire for perbromate!

So, unlike the gaps in the periodic table, plugging the perbromate gap has not yet resulted in unexpected discoveries. But it is worth speculating why any given compound may be non-existent. It may be thermodynamically unstable, and hence have too short a lifetime to be isolated (not the case for perbromate). Or all of the possible kinetic pathways to its formation may have unfeasibly large barriers. The key here is the word all; if one searches long enough, a route that works will probably be found.

The other side of the coin is novel types of compounds that may well exist, but no-one has anticipated trying to make them precisely because they are so novel. I am thinking here of the wonderfully entitled article “Mindless Chemistry” where systematic exploration of ALL possible minima for a given molecular formula revealed a whole zoo of species which the speculative chemist would never have dreamt of trying to make (in other words, they did not manifest as obvious gaps in the patterns that constitute our present chemical knowledge). I do often think about all of these undiscovered molecules, and if they could indeed be synthesised and their properties studied. One such occurred in silicon chemistry; truly the existence of an isomer of hexasilabenzene was not predicted before it was made, and its properties (aromaticity) did indeed prove fascinating and new.

Too long the focus of synthetic chemistry has been to try to make molecules that nature has already synthesized. Perhaps we should focus as well on molecules that nature has never deigned to make, but which are nevertheless entirely viable (as was the case for perbromate).

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Posted in Interesting chemistry | No Comments »