Posts Tagged ‘CF 3 CO’

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. https://doi.org/10.1070/mc1999v009n02abeh000995
  2. H.S. Rzepa, "C8H12F3NO3", 2014. https://doi.org/10.14469/ch/24979
  3. H.S. Rzepa, "Gaussian Job Archive for C8H12F3NO3", 2014. https://doi.org/10.6084/m9.figshare.1162797
  4. H.S. Rzepa, "Gaussian Job Archive for C8H12F3NO3", 2014. https://doi.org/10.6084/m9.figshare.1162676

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Posted in pericyclic, reaction mechanism | 2 Comments »

Mechanism of the Boekelheide rearrangement

Wednesday, June 26th, 2013

A reader asked me about the mechanism of the reaction of 2-picoline N-oxide with acetic anhydride to give 2-acetoxymethylpyridine (the Boekelheide Rearrangement[1]). He wrote ” I don’t understand why the system should prefer to go via fragmentation-recombination (… the evidence being that oxygen labelling shows scrambling) when there is an easy concerted pathway available (… a [3,3]sigmatropic shift). Furthermore, is it possible for two pathways to co-exist?” Here is how computation might enlighten us.

boeckelheide

The first model I built discards the apparently extraneous product in the first reaction, ethanoic acid. A transition state is located (ωB97XD/6-311G(d,p)/SCRF=dichloromethane) and its intrinsic reaction coordinate is shown below.[2]

Boek1

Boek1 Boek1G
  1. One first notes that the reaction is concerted, with no intermediates along the route.
  2. The reaction barrier (~21 kcal/mol) is quite reasonable for a [3,3] sigmatropic reaction.
  3. There is an almost undiscernible blip (inflexion) in the gradient norm at about +1 and a more obvious one at IRC +8. The latter is a hidden intermediate corresponding to a conformational rotation about the newly formed C-O bond. The former is more significant, since it is providing the faintest of hints that a hidden intermediate[3] corresponding to an ion-pair (in red in the scheme above) might be attempting to form. But it is only a hint, no more.

So an easy concerted pathway is indeed available. But the solvent model (dichloromethane) is not really very polar. How about water, which should better stabilise any ion-pair intermediate? That tiny blip in the gradient norm of the IRC (@~1) becomes a bit more prominent, but the reaction is computed as resolutely concerted.

Boek2G

So to explain why oxygen label scrambling is possible, we have to adopt a better model. That ethanoic acid discarded from our first attempt is re-instated. It serves the purpose of potentially stabilising any ion-pair which might form via explicit hydrogen bonds.[4]

Click for 3D.

Click for 3D.

The IRC[5] for this variation does indeed show a change; at IRC +3, there is now a very prominent hidden intermediate feature, showing that the additional molecule of ethanoic acid formed in the first step is stabilizing the ion-pair. It also serves to reduce the barrier to the reaction (by ~4 kcal/mol).‡

Boek4
Boek4  Boek4G

Although the Boekelheide rearrangement sounds like a rather obscure reaction that few have heard of, discussing it actually introduces an important concept common to many reactions. That is that they can proceed via either relatively neutral or highly ionic pathways, and that the balance between these two may be both subtle and influenced by external factors. In this case, the formation of a hydrogen bond stabilising the transition state for the reaction. This of course is also how many an enzyme achieves its action! For the Boekelheide rearrangement, a single hydrogen bonded ethanoic acid promotes, but does not fully establish the ion-pair mechanism over the neutral [3,3] pericyclic rearrangement. However, one might imagine that adding perhaps a second explicit stabilising H-bond might swing the balance over from merely a hidden intermediate to a real (ion-pair) intermediate. It is also possible that changing the acidity of this component (by replacing e.g. CH3CO2H by e.g. CF3CO2H) might achieve the same result.

As to whether “it is possible for two pathways to co-exist”, a nice example of this in my experience comes from the enantiomerisation of isobornyl chloride in cresol,[6] which has been shown by extensive isotope labelling to proceed by two concurrent but very different pathways. It is probably more common than we realise.

‡ It is worth noting that the [3,3] sigmatropic reaction is unimolecular, whereas the ethanoic-assisted variation is bimolecular. Apart from taking into account the entropic requirements of the latter, it is also necessary to redefine the standard state for the free energy from 1 atm to a more reasonable 1M, which reduces the free energy barrier by about 1.9 kcal/mol, and a correction which reduces the free energy of a bimolecular reaction a further 2.6 kcal/mol can be applied as a solvent correction.[7]. These two corrections mean that bimolecular solution reactions are often not so unfavourable compared to unimolecular equivalents as is often made out.

References

  1. A. Massaro, A. Mordini, A. Mingardi, J. Klein, and D. Andreotti, "A New Sequential Intramolecular Cyclization Based on the Boekelheide Rearrangement", European Journal of Organic Chemistry, vol. 2011, pp. 271-279, 2010. https://doi.org/10.1002/ejoc.201000936
  2. H.S. Rzepa, "Gaussian Job Archive for C8H9NO2", 2013. https://doi.org/10.6084/m9.figshare.730627
  3. E. Kraka, and D. Cremer, "Computational Analysis of the Mechanism of Chemical Reactions in Terms of Reaction Phases: Hidden Intermediates and Hidden Transition States", Accounts of Chemical Research, vol. 43, pp. 591-601, 2010. https://doi.org/10.1021/ar900013p
  4. H.S. Rzepa, "Gaussian Job Archive for C10H13NO4", 2013. https://doi.org/10.6084/m9.figshare.730621
  5. H.S. Rzepa, "Gaussian Job Archive for C10H13NO4", 2013. https://doi.org/10.6084/m9.figshare.731688
  6. J. Kong, P.V.R. Schleyer, and H.S. Rzepa, "Successful Computational Modeling of Isobornyl Chloride Ion-Pair Mechanisms", The Journal of Organic Chemistry, vol. 75, pp. 5164-5169, 2010. https://doi.org/10.1021/jo100920e
  7. J.R. Alvarez-Idaboy, L. Reyes, and J. Cruz, "A New Specific Mechanism for the Acid Catalysis of the Addition Step in the Baeyer−Villiger Rearrangement", Organic Letters, vol. 8, pp. 1763-1765, 2006. https://doi.org/10.1021/ol060261z

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Posted in Interesting chemistry, pericyclic, reaction mechanism | 3 Comments »

Hidden intermediates in the (acid catalysed) ring opening of propene epoxide.

Monday, May 6th, 2013

In a previous post on the topic, I remarked how the regiospecific ethanolysis of propene epoxide[1] could be quickly and simply rationalised by inspecting the localized NBO orbital calculated for either the neutral or the protonated epoxide. This is an application of Hammond’s postulate[[2] in extrapolating the properties of a reactant to its reaction transition state. This approach implies that for acid-catalysed hydrolysis, the fully protonated epoxide is a good model for the subsequent transition state. But is this true? Can this postulate be tested? Here goes.

pe_cf3Here, I show eight transition state models. As the acid I use CF3CO2H, with methanol as the nucleophile attacking propene epoxide, and I have initially included one additional methanol helping facilitate the proton transfers. Isomeric transition states differ in where the methyl substituent is located (1/2 and 3/4) and in the relative position of the acid and the additional methanol (1/3 and 2/4). In 1/2, the acid is directly protonating the oxygen of the epoxide. In 3/4, it is instead inducing methanol to act as its proxy. Two further transition states 5 and 6 directly replace the CF3CO2H with one (much less acidic) methanol, to test the effect the presence of the acid has on the reaction barriers. Finally,  7 and 8 remove from these models the non-nucleophilic proxy methanol from the ring to test the effect of reducing ring size from 10 to 8.

With no catalyst present, we know that the rate of hydrolysis is very slow[1], and that the major product (55%) is the 1-alkoxy-2-propanol, with the 2-alkoxy-1-propanol being the minor component (16%). As acid concentration increases, the amount of the latter eventually exceeds the former. The computed barriers (ωB97XD/6-311G(d,p)SCRF=methanol) for this mode (transition states 5 and 6) are ~29 kcal/mol, which pretty much matches the experimental observation (for ethanol). What does not match is the preference for nucleophilic attack at the least substituted carbon resulting in 1-alkoxy-2-propanol; instead the  2-alkoxy-1-propanol is predicted to have the lower free energy barrier of activation by 1.7 kcal/mol. This will need further investigation in a future post.

Property 5, 2-alkoxy-1-propanol 6, 1-alkoxy-2-propanol.
ΔΔG‡, kcal/mol 0.0 +1.7
IRC animation pe-meOH pe-meOH-iso
IRC Energy pe-meOH pe-meOH-iso
IRC Gradients pe-meOHG pe-meOH-isoG
IRC [3] [4]

What of the IRCs? Both isomers show an interesting dip in the gradient norms (at~-1.5 for 5 and +1.5 for 6), typical of a “hidden intermediate“. The geometry at this point (below) shows that the erstwhile epoxide bonds are largely formed/cleaved, and this has resulted in a zwitterionic intermediate attempting to form (the nucleophilic oxonium being +ve and the cleaved oxyanion -ve). Such species have no permanence however (not for even one molecular vibration), and are immediately destroyed by three more or less synchronous proton transfers (IRC -2.5 or +3.0). I would add that in many a text-book illustration of this process, this “hidden intermediate” would in fact be exposed as an explicit actual intermediate.

Click for 3D.

Click for 3D.

What happens when we replace one methanol in the above model with one molecule of trifluoracetic acid, resulting in transition states 1–4 (below). 

  1. The barrier drops dramatically, from ~29 kcal/mol to ~13 kcal/mol. This changes the reaction from a very slow one at room temperatures to a very fast one at room temperatures.
  2. The IRC now shows an extra “hidden intermediate” before the transition state, as well as one after. The synchronicity of the proton transfers is broken, and now they occur in two distinct stages, one before and one after the transition state. The one before corresponds to protonation of the epoxide oxygen by the trifluoracetic acid, which occurs before the C-O bond is formed/cleaved at the transition state itself. The second hidden intermediate corresponds to the zwitterion arising from the  trifluoracetic anion and the oxonium cation located at the original attacking methanol. This is then subjected to proton transfer (IRC ~ -2.5 in both cases) to transfer the proton onto the auxiliary methanol to form what appears to be the final ring-opened neutral product in the presence of methyl oxonium trifluoroacetate.
  3. So adding a species which can form a stable anion (in other words a strong acid) de-synchronises the reaction. However, all the intermediates are still hidden, and the process is still concerted!
  4. But, oddly, the predicted preference for 1 is if anything slightly decreased compared to the use of methanol only in the model (i.e. 5/6). This does not seem to correspond to the increased prevalence of 1 in the presence of acid as observed in the experiments.
Property 1,2-alkoxy-1-propanol 2, 1-alkoxy-2-propanol.
ΔΔG‡ 0.0  +1.4 
IRC animation pe-MeOH-CF3CO2Ha pe-MeOH-CF3CO2H-isoa
IRC Energy pe-MeOH-CF3CO2Ha pe-MeOH-CF3CO2H-isoa
IRC Gradients pe-MeOH-CF3CO2HG pe-MeOH-CF3CO2H-isoG
IRC [5] [6]

Before moving on to the last models 7/8, I must mention the aspect of where the strong acid is located in the model. If it is located away from the epoxide oxygen, the IRC changes again, now revealing three hidden intermediates.

  1. The first corresponds to the acid transferring a proton to the non-nucleophilic methanol to form incipient methyl oxonium trifluoracetate
  2. The second has the methyl oxonium as an acid transferring its proton to the epoxide oxygen.
  3. Then comes the transition state when the O-C bonds are formed/broken.
  4. The last hidden intermediate is the oxonium trifluoracetate zwitterion resulting from ring opening, prior to a final proton transfer to reform trifluoroacetic acid.
  5. This pathway overall in free energy, is about 2.0 kcal/mol higher than the previous one involving direct proton transfer from the acid itself.
Property 3, 2-alkoxy-1-propanol 4, 1-alkoxy-2-propanol.
ΔΔG‡ 1.8 +3.5 
IRC animation pe-MeOH-CF3CO2H-other  pe-cf3-other
IRC Energy pe-MeOH-CF3CO2H-other  pe-cf3-other
IRC Gradients pe-MeOH-CF3CO2H-otherG  pe-cf3-otherG
IRC [7] [8]

The final model 7/8 tests what happens when that additional methanol is removed from the proton transfer sequence in 1-4. The smaller ring for the transition state induces an increase in the barrier from ~13 to ~20 kcal/mol; this model also naturally “absorbs” an addition methanol to decrease the free energy and mutate into 1-4. The preference for 7 over 8 is increased compared to the other models. The presence of two hidden intermediates in this model is particularly noticeable.

Property 7, 2-alkoxy-1-propanol 8, 1-alkoxy-2-propanol
ΔΔG‡ 0.0 +3.5 
IRC animation  pe-cf3+meoha pe-cf3-nome-othera 
IRC Energy  pe-cf3+meoh  pe-cf3-nome-other
IRC Gradients  pe-cf3+meohG  pe-cf3-nome-otherG

To answer the question posed at the start of this post, in the IRC explorations above we see that in the presence of trifluoroacetic acid, the transition state is indeed preceded by a proton transfer. This reassures that Hammond’s principle can indeed be applied. The (relative) free energies of the acid catalysed transition state models used here all correctly predict the observed regiochemistry, but we still have to explore the base catalysed route. Watch this space.

References

  1. H.C. Chitwood, and B.T. Freure, "The Reaction of Propylene Oxide with Alcohols", Journal of the American Chemical Society, vol. 68, pp. 680-683, 1946. https://doi.org/10.1021/ja01208a047
  2. G.S. Hammond, "A Correlation of Reaction Rates", Journal of the American Chemical Society, vol. 77, pp. 334-338, 1955. https://doi.org/10.1021/ja01607a027
  3. H.S. Rzepa, "Gaussian Job Archive for C6H18O4", 2013. https://doi.org/10.6084/m9.figshare.694931
  4. H.S. Rzepa, "Gaussian Job Archive for C6H18O4", 2013. https://doi.org/10.6084/m9.figshare.694918
  5. H.S. Rzepa, "Gaussian Job Archive for C7H15F3O5", 2013. https://doi.org/10.6084/m9.figshare.694894
  6. H.S. Rzepa, "Gaussian Job Archive for C7H15F3O5", 2013. https://doi.org/10.6084/m9.figshare.694907
  7. H.S. Rzepa, "Gaussian Job Archive for C7H15F3O5", 2013. https://doi.org/10.6084/m9.figshare.697508
  8. https://doi.org/

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Posted in Interesting chemistry | 1 Comment »