Posts Tagged ‘ATM’

Natural abundance kinetic isotope effects: mechanism of the Baeyer-Villiger reaction.

Wednesday, June 10th, 2015

I have blogged before about the mechanism of this classical oxidation reaction. Here I further explore computed models, and whether they match the observed kinetic isotope effects (KIE) obtained using the natural-abundance method described in the previous post.

BV

There is much previous study of this rearrangement, and the issue can be reduced to deciding whether TS1 or TS2 is rate-limiting. The conventional text-book wisdom is that the carbon migration step TS2 is the “rds” and it was therefore quite a surprise when Singleton and Szymanski[1] obtained KIE which seemed to clearly point instead to TS1 as being rate limiting, inferred from a large 13C effect (~1.05) at the carbonyl carbon (blue star) and none at the α-carbon (red star). This result (for this specific reaction and conditions, which is dichloromethane as solvent) is now routinely quoted[2] when the mechanism is discussed. This latter article reports[2] calculated energetics for TS1 and TS2 (see Table 1 in this article) and after exploring various models, the conclusion is that TS1 and TS2 are essentially isoenergic. However, no isotope effects are computed for their models, and so we do not know if TS1 or TS2 agrees better with the reported values.[2] Since I had managed to get pretty good agreement with experimental KIEs using the ωB97XD/Def2-TZVPP/SCRF=xylenes model for the Diels-Alder reaction, I thought I would try the same method to see how it performs for the Baeyer-Villiger.

It is in fact non-trivial to set up a consistent model. Using arrow pushing, one can on paper draw three variations for TS1, the formation of the peroxyhemiacetal tetrahedral intermediate (TI) and also often called the Criegee intermediate.

BV2

  1. TS1a is the “text-book” variation, involving the production of a zwitterionic intermediate which immediately undergoes a proton transfer (PT). The arrows tend not to be used for this last step, since the direct transfer would involve a 4-membered ring and a highly non-linear geometry at the transferring proton which is understood to be “unfavourable”. Such zwitterions involve a large degree of charge separation and hence a large dipole moment. In a non-protic solvent such as dichloromethane, one is very loath to use such species in a mechanism, and it’s not modelled here either.
  2. Using just cyclohexanone and peracid, it is in fact difficult to avoid ionic species. TS1b is an attempt which shows the proton transfer is done first on the peracid to create a so-called carbonyl ylid, and this then reacts with the ketone
  3. If however a proton transfer agent is introduced as TS1c, one can use this species (shown in red above) to transfer the proton as part of a concerted mechanism; this was in fact the expedient used in the earlier theoretical study[2] and this route tends to avoid much if not all of the charge separation. The acid comes from the product of the reaction, and hence the kinetics may in fact have an induction period when this acid builds up. The initial proton transfer reagent may also be traces of water present in reagents or solvent. Singleton and Szymanski in fact include no supporting information in their article and so we do not know what the concentrations used were (assumed for the present discussion as 1M) whether everything was rigorously dried, or indeed what the kinetic order in [peracid] turned out to be.

The same problem is faced with TS2; how to transfer a proton? Because we want to compare the relative energies of TS1 and TS2, we also have to atom-balance the mechanism, and so the additional acid component introduced into TS1c is also retained in two alternative mechanisms for TS2 (and for TS1b).

BV3

  1. TS2a uses just the components of the tetrahedral intermediate (TI), but again in a fashion that requires no charge separation during the reaction. The additional acid component (red) plays a passive role, hydrogen bonding to the TI.
  2. TS2b now incorporates the additional acid by expanding the ring (green) in an active role.

IRCs using the 6-311G(d,p) basis) for TS1[3] and TS2[4] are interesting in revealing relative synchronicity of the proton transfers for TS1 but asynchronicity for TS2 involving a hidden intermediate.
BV1a

BV2a

The energy, energy gradient and dipole moment magnitudes for this second step are particularly fascinating. The dipole moment starts off quite small (3.1D) at the TI, and is still so at the TS, but almost immediately afterwards, it shoots up to ~12D as the hidden intermediate develops (IRC ~4) Two successive proton transfers (IRC ~6, 7) then reduce the value down again.
BV2E
BV2G
BV2D

A table of results can now be constructed for these various models, evaluating two different basis sets for the calculation.

system ΔΔG298 (1M)
ωB97XD/6-311G(d,p)/SCRF=DCM, kcal/mol		 Dipolemoment,D ΔG298 (1M)
ωB97XD/Def2-TZVPP/SCRF=DCM
Reactants +1.4a – -3.3a[5],[6],[7]
Complexed state 0.0[8] 5.0 0.0[9]
TS1a n/a n/a n/a
TS1b 32.9[10] 8.6 32.2[11]
TS1c 14.9[12] 3.0 16.1[13]
TI -1.7[14] 3.1 -0.3[15]
TS2a 22.2[16] 9.3 25.0[17]
TS2b 20.2[12] 5.4 22.7[18]
Product -69.8[19] 5.3 [20]

aThis value is corrected to a standard state of 1M for a termolecular reaction by 3.78 kcal/mol from the computed free energies at 1 atm as described previously.[21]

  1. Firstly, one must note that the resting state for the reactants depends on the concentration. At 1M at the higher basis set, its the separated reactants, but at the lower it is the hydrogen bonded complex between them. Increasing the concentration would favour the latter.
  2. TS1c is significantly lower in free energy than TS2b, a result somewhat at variance with the earlier report.[2] The functional used in the present calculation, the basis set, the dispersion model and the solvation model are all improvements on the original work.
  3. Likewise, the energy of TI, the Criegee intermediate emerges as similar to the reactants. Coupled with the magnitude of the barrier for TS1c this does tend to point to a relatively rapid pre-equilibrium and that TS2b determines the rate of reaction.

Kinetic isotope effects for our models

Having constructed models, we can now subject them to testing against the measured kinetic isotope effects.[1]

bv4

  1. The measured values are shown above. The first set (a) are what are described as intermolecular isotope effects and result from measuring changes in the isotopic abundance obtained by recovering unreacted starting material after a large proportion of the reaction has gone to completion. This was interpreted as indicating TS1 was rate limiting. Using instead the uncomplexed cyclohexanone has only a small effect (C1: 1.023 complexed, 1.021 uncomplexed).
  2. The values in parentheses were obtained using the TS1c model above and are relative to the complexed reactant involving hydrogen bonds between the cyclohexanone, the peracid and the acid catalyst. The agreement can only be described as partial.
    •  The predicted 13C isotope effect at C1 is about half of the measured value. The previous calibration of the method being used had resulted in agreement within experimental error for the Diels Alder reaction, and so this large disagreement is unexpected.
    • The 2H KIE at C2 is within experimental error.
    • The  2H KIE at C3 is badly out. Here, it is the experimental result that seems wrong, since there is no reason to expect any KIE at this position especially since the 13C at the same position is 1.00 for both measured and calculated values.
  3. So we might infer an inconclusive result. I can only speculate on the computed model here, and invoke in effect the variation principle. If the model is wrong, we would expect a more correct model to have a lower rather than higher energy relative to reactants. The free energy of activation however is already low, corresponding to a very fast room temperature reaction; too fast indeed to easily recover any unreacted starting material if that were to be rate limiting!
  4. Set (b) corresponds to what is described as an intramolecular KIE as defined by TS2, since it is measured from isotopic ratio changes in the product rather than reactant as the reaction progresses.
    • The value in (…) is relative to the complexed reactants and the value in […] is relative to TI.
    • The predicted 13C isotope effect at C2m (the migrating carbon) agrees within experimental error with the measured value if the TI is used as the reference. This nicely shows how isotope effects for what may not be a rate limiting step can be measured by this technique.
    • The predicted 13C isotope effect at C1 (which is not reported in the original article) relative to TI is significant, and it would be nice to confirm the computed model by a measurement at this position.
    • The other KIE also agree reasonably with experiment when TI is specified as the reactant for this step.

So is there support from the calculations for the formation of the semi-peroxyacetal being rate limiting, as claimed by Singleton and Szymanski[1]? There is no doubt that the KIE obtained from measuring the product is different from measuring the reactant, but the lack of agreement for two of the measured values for TS1 is a concern. Perhaps one might conclude that this is an experiment well worth repeating. Of the two computed models, TS1 and TS2, the variation principle would again lead us to suspecting that the one with higher energy can only be decreased by improvement, whereas improvement of the one with the lower energy cannot also increase its relative energy. So if a new model for the carbon migration step can be found, its activation free energy must be lower than that already identified. But the excellent agreement between TS2b shown in (b) suggests that this model is already pretty good! Lowering its energy by >7kcal/mol to make TS1 rate limiting would probably require quite a different model.

What I think is more certain is the value of subjecting the measured KIE to computed models, in the knowledge that if the model is indeed realistic a good agreement should be expected. And it is a shame that the natural abundance KIE method cannot be applied to oxygen isotope effects, which would surely settle the issue.‡ And I should end by reminding that there is evidence that the mechanism may be quite sensitive to variation of solvent, ketone, peracid, pH, etc, and so these conclusions only apply to this specific reaction in  dichloromethane.

‡ For TI > TS2, the 18O KIE is predicted as 1.048 (peroxy oxygen) and 1.032 (acyl oxygen). For Reactant > TS1, the values are respectively 0.998 and 1.003.

References

  1. D.A. Singleton, and M.J. Szymanski, "Simultaneous Determination of Intermolecular and Intramolecular <sup>13</sup>C and <sup>2</sup>H Kinetic Isotope Effects at Natural Abundance", Journal of the American Chemical Society, vol. 121, pp. 9455-9456, 1999. https://doi.org/10.1021/ja992016z
  2. J.R. Alvarez-Idaboy, and L. Reyes, "Reinvestigating the Role of Multiple Hydrogen Transfers in Baeyer−Villiger Reactions", The Journal of Organic Chemistry, vol. 72, pp. 6580-6583, 2007. https://doi.org/10.1021/jo070956t
  3. H.S. Rzepa, "C20H20Cl2O6", 2015. https://doi.org/10.14469/ch/191318
  4. H.S. Rzepa, "C20H20Cl2O6", 2015. https://doi.org/10.14469/ch/191317
  5. H.S. Rzepa, "C 7 H 5 Cl 1 O 2", 2015. https://doi.org/10.14469/ch/191322
  6. H.S. Rzepa, "C 7 H 5 Cl 1 O 3", 2015. https://doi.org/10.14469/ch/191323
  7. H.S. Rzepa, "C 6 H 10 O 1", 2015. https://doi.org/10.14469/ch/191324
  8. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191307
  9. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191315
  10. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191313
  11. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191325
  12. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191306
  13. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191312
  14. H.S. Rzepa, "C20H20Cl2O6", 2015. https://doi.org/10.14469/ch/191311
  15. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191319
  16. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191314
  17. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191321
  18. H.S. Rzepa, and H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191320
  19. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191310
  20. H.S. Rzepa, "C 20 H 20 Cl 2 O 6", 2015. https://doi.org/10.14469/ch/191327
  21. 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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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 »

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.

Keto-enol tautomerisation occupies a unique position in the history of mechanistic chemistry[2]. In 1889, Beckmann got the whole field rolling by proposing an inferred enol intermediate (which he did not observe) to explain the isomerism of menthone to iso-menthone in conc. sulfuric acid. In modelling the enolisation of thalidomide, I have used both implicit and explicit solvents acting in a self-consistent manner. This approach is not yet much adopted in the wider literature[3]. I have deployed it extensively in this blog as an encouragement to others (selected examples are listed at the bottom of this post). It is worth noting at the outset that the transition state reported previously[1] has a computed dipole moment of ~10D. My experience[3] suggests that any geometry with a dipole moment of this magnitude (or greater) is likely to relax when placed into a continuum field, and this relaxation becomes an important perturbation of both the computed geometry of the transition state and the intrinsic reaction coordinate profile computed from that starting point.

The (re)computed geometry of the aqueous transition state for enolisation of thalidomide is shown below, and for which the entropy-corrected ΔG†298 is 31.0 kcal/mol (the barrier for the prototypical enolisation of propanone is computed as 34.4 kcal/mol). The value in the literature[1] is given as 27.7 kcal/mol for the zero-point-energy corrected total energy barrier, but this value notably does NOT include any entropic corrections. The measured literature value for ΔG†298 is reported as 24.3 kcal/mol at pH 8, a value which probably also includes contributions from both the pure water catalysed route and those from hydroxide anion catalysis (see below). At this point, I should remind that the free energy of activation for a bi- or termolecular reaction in solution must be obtained by correcting the value obtained for a standard state of 1 atmosphere (the state used for the value quoted above). According to Alvarez-Idaboy and co-workers[4], this amounts to a total correction of -4.5 kcal/mol for a bimolecular reaction, and -8.73 kcal/mol for a termolecular reaction. Where one of the components of a termolecular reaction is also the solvent, these corrections probably need to be themselves reduced. But this does achieve a reduction in the computed value of 31.0 kcal/mol to something quite close to the experimental value! 

Aqueous transition state for enolisation of thalidomide. Click for 3D.

Next, I want to consider the base-catalysed enolisation pathway. As with the reaction of dichlorobuteneone with tolyl-thiolate about which I wrote in another post, the authors of the thalidomide study[1] modelled this route by introducing a solvated hydroxide anion, “OH–·H2O” into the structure without any accompanying counter-ion. In other words, their total system has an overall negative charge. I argued before, and I argue again here, that there is no real need to have to do this. Why not for example introduce NaOH•H2O instead? One might argue that the cationic counter-ion so introduced cannot be properly modelled, but the combination of explicit first-sphere water molecules coupled with a continuum model actually handles these counter-ions reasonably well. So may I introduce you to my version of the base-catalysed reaction, involving a contact-ion-pair:

Base-catalysed (NaOH) enolisation of thalidomide. Click for 3D.

This has ΔG†298 4.7 kcal/mol, much lower than the neutral water catalysed reaction. This value is of course for a standard state for [Na+OH–] (1 atm). At pH 8, [OH–] is at least six orders of magnitude less, which may rationalise why the experimental rate is so much slower than this barrier might imply. The IRC corresponds to proton transfer.

I would like to end by noting that many mechanisms which would otherwise involve the development of charge-separation may well borrow a protic solvent molecule in the manner shown here to reduce the degree of charge-separation needed.  Further examples of this are listed below.

  1. Oxime formation from hydroxylamine and ketone. Part 2: Elimination.
  2. Oxime formation from hydroxylamine and ketone: a (computational) reality check on stage one of the mechanism.
  3. Transition state models for Baldwin dig(onal) ring closures.
  4. Transition state models for Baldwin’s rules of ring closure.
  5. The mechanism (in 4D) of the reaction between thionyl chloride and a carboxylic acid.
  6. Mechanism of the diazomethane alkylation of a carboxylic acid.
  7. The mechanism of the Baeyer-Villiger rearrangement.
  8. Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions.
  9. Secrets of a university tutor: tetrahedral intermediates.

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. https://doi.org/10.1002/chem.201202651
  2. E. Beckmann, "Untersuchungen in der Campherreihe", Justus Liebigs Annalen der Chemie, vol. 250, pp. 322-375, 1889. https://doi.org/10.1002/jlac.18892500306
  3. 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
  4. 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 | 1 Comment »