Posts Tagged ‘Dipole’

A record polarity for a neutral compound?

Friday, April 13th, 2018

In several posts a year or so ago I considered various suggestions for the most polar neutral molecules, as measured by the dipole moment. A record had been claimed[1] for a synthesized molecule of ~14.1±0.7D. I pushed this to a calculated 21.7D for an admittedly hypothetical and unsynthesized molecule. Here I propose a new family of compounds which have the potential to extend the dipole moment for a formally neutral molecule up still further.

These molecules derive from a well-known class of molecule known as ortho-quinomethides. If the methide part is substituted with an electron donating substituent such as an amino group in 3, a push-pull opportunity now arises, which is strongly driven by aromatisation of the quinomethide ring. This allows one to design “neutral” molecules such as 1 and 2, which now contain respectively two and three rings that will be aromatised by the process. The aromatisation stabilization energy is balanced of course by an opposing increase in energy resulting from charge separation. You can observe that partially aromatising three independent rings as in 2 can drive a great deal of charge separation. One may indeed wonder how much charge separation can be sustained before a triplet instability occurs, driving the molecule back to being neutral. In the case of 2, the wavefunction is in fact stable to such an open shell state, but higher homologues may not be. An aspect worth investing!

1 2
DM 12.3 DM 31.5
DOI: 10.14469/hpc/4004 DOI: 10.14469/hpc/4059

Molecule 1 does have some precedent in 3[2] but this system exists as a phenol, having abstracted a proton from an acid and leaving behind the acid anion, as per below for 1. Any attempts to deprotonate this phenol with a superstrong base were unreported.

Unsurprisingly therefore, molecules such as 1 and 2 could be regarded as even more highly potent bases than 3, driven again by further aromatisation. The properties of such a potential superbase will be investigated in the next post.

References

  1. J. Wudarczyk, G. Papamokos, V. Margaritis, D. Schollmeyer, F. Hinkel, M. Baumgarten, G. Floudas, and K. Müllen, "Hexasubstituted Benzenes with Ultrastrong Dipole Moments", Angewandte Chemie International Edition, vol. 55, pp. 3220-3223, 2016. https://doi.org/10.1002/anie.201508249
  2. N.R. Candeias, L.F. Veiros, C.A.M. Afonso, and P.M.P. Gois, "Water: A Suitable Medium for the Petasis Borono‐Mannich Reaction", European Journal of Organic Chemistry, vol. 2009, pp. 1859-1863, 2009. https://doi.org/10.1002/ejoc.200900056

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The dipole moments of highly polar molecules: glycine zwitterion.

Saturday, December 24th, 2016

The previous posts produced discussion about the dipole moments of highly polar molecules. Here to produce some reference points for further discussion I look at the dipole moment of glycine, the classic zwitterion (an internal ion-pair).

Dielectric relaxation studies of glycine–water mixtures yield values that range from 15.7D[1] to 11.9D[2] although these have to be derived using various approximations and assumptions for up to 4 independent Debye processes. Before proceeding to calculations, I looked at the properties of ionized amino acids in the solid state, using the following search query for the Cambridge structure database (CSD). 

The distance measures hydrogen bonds to the carboxylate oxygens and the torsion their orientation. The O…H hydrogen bond distances vary between 1.7-1.85Å, which are short. The orientation of the hydrogen bond can be to the in-plane oxygen “σ-lone pair” (torsion 0 or 180°) and also an out-of-plane ~π form (torsion ~60-90°).

In aqueous solution, it is normally assumed that glycine sustains five such strong H-bonds (three to the H3N+ group and two[3] to the carboxylate anion), forming a polarised “salt bridge” across the ion-pair. Two model types were subjected to calculation using ωB97XD/Def2-TZVPP/SCRF=water. Aqueous glycine without any added explicit water molecules yields a dipole moment of 12.9D (DOI: 10.14469/hpc/2000), which is within the range noted above.‡

The solvated form is shown below, in one specific conformation of the three studied (ωB97XD/Def2-TZVPP/SCRF=water). The calculated O…H hydrogen bond lengths fall into the range revealed from crystal structures. The calculated dipole moments range from 12.6 (DOI: 10.14469/hpc/2007), 15.3 (DOI: 10.14469/hpc/2006) and 14.9D (DOI: 10.14469/hpc/2005), which is a modest increase over the model with no explicit water molecules. The actual dipole is of course a Boltzmann average over these and other as yet unexplored conformations, as well as other values for the number of water molecules.

Given the difficulties in interpreting the dipole moment of a complex Debye system such as hydrated glycine, the agreement between the limited range of solvated models and the measured values seems reasonable, and provides at least some measure of “calibration” for the polar molecules commented on previously.

‡Optimized with the solvent field on. If a vacuum model is used, the proton transfers from the N to the O.

References

  1. M.W. Aaron, and E.H. Grant, "Dielectric relaxation of glycine in water", Transactions of the Faraday Society, vol. 59, pp. 85, 1963. https://doi.org/10.1039/tf9635900085
  2. T. Sato, R. Buchner, . Fernandez, A. Chiba, and W. Kunz, "Dielectric relaxation spectroscopy of aqueous amino acid solutions: dynamics and interactions in aqueous glycine", Journal of Molecular Liquids, vol. 117, pp. 93-98, 2005. https://doi.org/10.1016/j.molliq.2004.08.001
  3. T. Shikata, "Dielectric Relaxation Behavior of Glycine Betaine in Aqueous Solution", The Journal of Physical Chemistry A, vol. 106, pp. 7664-7670, 2002. https://doi.org/10.1021/jp020957j

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Forking “The most polar neutral compound synthesized” into m-benzyne.

Wednesday, December 21st, 2016

A project fork is defined (in computing) as creating a distinct and separate strand from an existing (coding) project. Here I apply the principle to the polar azulene 4 explored in an earlier post, taking m-benzyne as a lower homologue of azulene as my starting point.

m-Benzyne is a less stable 1,3 isomer of o-benzyne (1,2-dehydrobenzene), and is often represented as a 1,3-biradical of 1,3-dehydrobenzene. But, could it be stabilized with cyano and amino groups as shown in 5 above? Here the idea is that charge transfer from the 3-ring to the 5-ring will create a lower homologue of azulene (a well known molecule), with the 3-ring a 4n+2 π-electron aromatic (n=0) and the five ring similarly so (n=1).

I start with the computed (wB97XD/Def2-TZVPP/SCRF=thf) structure of m-benzyne itself, as a closed shell molecule (DOI: 10.14469/hpc/1995). The C-C bond connecting the two rings is long (with a biradical tendency) and hence the conjugation is restricted to the outer periphery. The dipole moment is 0.51D (the dipole vector as shown in blue has the expected direction of polarity).

Now compare this to the substituted version 5; the bond lengths are all more characteristic of aromatic values and most significantly the central bond is as well (DOI: 10.14469/hpc/1996). The dipole moment is augmented thirty fold to 14.6D, which would rank alongside that reported for the most polar neutral molecule.

So I suggest this is substituted “m-benzyne” well worth trying to make and one very much unlikely to have any dispute about the nature of its wavefunction, i.e. biradical or closed shell.

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Forking "The most polar neutral compound synthesized" into m-benzyne.

Wednesday, December 21st, 2016

A project fork is defined (in computing) as creating a distinct and separate strand from an existing (coding) project. Here I apply the principle to the polar azulene 4 explored in an earlier post, taking m-benzyne as a lower homologue of azulene as my starting point.

m-Benzyne is a less stable 1,3 isomer of o-benzyne (1,2-dehydrobenzene), and is often represented as a 1,3-biradical of 1,3-dehydrobenzene. But, could it be stabilized with cyano and amino groups as shown in 5 above? Here the idea is that charge transfer from the 3-ring to the 5-ring will create a lower homologue of azulene (a well known molecule), with the 3-ring a 4n+2 π-electron aromatic (n=0) and the five ring similarly so (n=1).

I start with the computed (wB97XD/Def2-TZVPP/SCRF=thf) structure of m-benzyne itself, as a closed shell molecule (DOI: 10.14469/hpc/1995). The C-C bond connecting the two rings is long (with a biradical tendency) and hence the conjugation is restricted to the outer periphery. The dipole moment is 0.51D (the dipole vector as shown in blue has the expected direction of polarity).

Now compare this to the substituted version 5; the bond lengths are all more characteristic of aromatic values and most significantly the central bond is as well (DOI: 10.14469/hpc/1996). The dipole moment is augmented thirty fold to 14.6D, which would rank alongside that reported for the most polar neutral molecule.

So I suggest this is substituted “m-benzyne” well worth trying to make and one very much unlikely to have any dispute about the nature of its wavefunction, i.e. biradical or closed shell.

1
Henry Rzepa, 2016. [Source]
2
Henry Rzepa, 2016. [Source]

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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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