Houk and Vanderwal have examined the dyotropic rearrangement of an interesting class of polycyclic compounds using experimental and computational techniques.¹ The parent reaction takes the bicyclo[2.2.2]octadiene 1 into the bicyclo[3.2.1]octadiene 3. The M06-2X/6-311+G(d,p)/B3LYP/6-31G(d) (with CPCM simulating xylene) geometries and relative energies are shown in Figure 1. The calculations indicate a stepwise mechanism, with an intervening zwitterion intermediate. The second step is rate determining.

1 (0.0)	TS1 (35.6)
2 (21.9)	TS2 (40.1)
3 (-4.2)

Figure 1. B3LYP/6-31G(d) and relative energies (kcal mol^-1) at M06-2X/6-311+G(d,p).

Next they computed the activation barrier for the second TS for a series of substituted analogs of 1, with various electron withdrawing group as R₁ and electron donating groups as R₂, and compared them with the experimental rates.

Further analysis was done by relating the charge distribution in these TSs with the relative rates, and they find a nice linear relationship between the charge and ln(k_rel). This led to the prediction that a cyano substituent would significantly activate the reaction, which was then confirmed by experiment. Another prediction of a rate enhancement with Lewis acids was also confirmed by experiment.

A last set of computations addressed the question of whether a ketone or lactone would also undergo this dyotropic rearrangement. The lactam turns out to have the lowest activation barrier by far.

References

(1) Pham, H. V.; Karns, A. S.; Vanderwal, C. D.; Houk, K. N. "Computational and Experimental Investigations of the Formal Dyotropic Rearrangements of Himbert Arene/Allene Cycloadducts," J. Am. Chem. Soc. 2015, 137, 6956-6964, DOI: 10.1021/jacs.5b03718.

InChIs

1: InChI=1S/C11H11NO/c1-12-10(13)7-9-6-8-2-4-11(9,12)5-3-8/h2-5,7-8H,6H2,1H3
InChIKey=MNYYUIQDOAXLTK-UHFFFAOYSA-N

3: InChI=1S/C11H11NO/c1-12-10(13)6-9-3-2-8-4-5-11(9,12)7-8/h2-6,8H,7H2,1H3
InChIKey=OHEBSZKLNGLATD-UHFFFAOYSA-N

A recent reinvestigation of the structure of 2-oxazoline demonstrates the difficulties that many computational methods can still have in predicting structure.

Samdal, et al. report the careful examination of the microwave spectrum of 2-oxzoline and find that the molecule is puckered in the ground state.¹ It’s not puckered by much, and the barrier for inversion of the pucker, through a planar transition state is only 49 ± 8 J mol^-1. The lowest vibrational frequency in the non-planar ground state, which corresponds to the puckering vibration, has a frequency of 92 ± 15 cm^-1. This low barrier is a great test case for quantum mechanical methodologies.

And the outcome here is not particularly good. HF/cc-pVQZ, M06-2X/cc-pVQZ, and B3LYP/cc-pVQZ all predict that 2-oxazoline is planar. More concerning is that CCSD and CCSD(T) with either the cc-pVTZ or cc-pVQZ basis sets also predict a planar structure. CCSD(T)-F12 with the cc-pVDZ predicts a non-planar ground state with a barrier of only 8.5 J mol^-1, but this barrier shrinks to 5.5 J mol^-1 with the larger cc-pVTZ basis set.

The only method that has good agreement with experiment is MP2. This method predicts a non-planar ground state with a pucker barrier of 11 J mol^-1 with cc-pVTZ, 39.6 J mol^-1 with cc-pVQZ, and 61 J mol^-1 with the cc-pV5Z basis set. The non-planar ground state and the planar transition state of 2-oxazoline are shown in Figure 1. The computed puckering vibrational frequency does not reproduce the experiment as well; at MP2/cc-pV5Z the predicted frequency is 61 cm^-1 which lies outside of the error range of the experimental value.

Non-planar

Planar TS

Figure 1. MP2/cc-pV5Z optimized geometry of the non-planar ground state and the planar transition
state of 2-oxazoline.

References

(1) Samdal, S.; Møllendal, H.; Reine, S.; Guillemin, J.-C. "Ring Planarity Problem of 2-Oxazoline Revisited Using Microwave Spectroscopy and Quantum Chemical Calculations," J. Phys. Chem. A 2015, 119, 4875–4884, DOI: 10.1021/acs.jpca.5b02528.

InChIs

2-oxazoline: InChI=1S/C3H5NO/c1-2-5-3-4-1/h3H,1-2H2
InChIKey=IMSODMZESSGVBE-UHFFFAOYSA-N

Kass and coworkers looked at a series of substituted phenols to tease out ways to produce stronger acids in non-polar media.¹ First they established a linear relationship between the vibrational frequency shifts of the hydroxyl group in going from CCl₄ as solvent to CCl₄ doped with 1% acetonitrile with the experimental pK_a in DMSO. They also showed a strong relationship between this vibrational frequency shift and gas phase acidity (both experimental and computed deprotonation energies).

A key recognition was that a charged substituent (like say ammonium) has a much larger effect on the gas-phase (and non-polar solvent) acidity than on the acidity in a polar solvent, like DMSO. This can be attributed to the lack of a medium able to stable charge build-up in non-polar solvent or in the gas phase. This led them to 1, for which B3LYP/6-31+G(d,p) computations of the analogous dipentyl derivative 2 (see Figure 1) indicated a deprotonation free energy of 261.4 kcal mol^-1, nearly 60 kcal mol^-1 smaller than any other substituted phenol they previously examined. Subsequent measurement of the OH vibrational frequency shift showed the largest shift, indicating that 1 is extremely acidic in non-polar solvent.

Further computational exploration led to 3 (see Figure 1), for which computations predicted an even smaller deprotonation energy of 231.1 kcal mol^-1. Preparation of 4 and experimental observation of its vibrational frequency shift revealed an even larger shift than for 1, making 4 extraordinarily acidic.

2	Conjugate base of 2
3	Conjugate base of 3

Figure 1. B3LYP/6-31+G(d,p) optimized geometries of 2 and 3 and their conjugate bases.

Reference

(1) Samet, M.; Buhle, J.; Zhou, Y.; Kass, S. R. "Charge-Enhanced Acidity and Catalyst Activation," J. Am. Chem. Soc. 2015, 137, 4678-4680, DOI: 10.1021/jacs.5b01805.

InChI

1 (cation only): InChI=1S/C23H41NO/c1-4-6-8-10-12-14-20-24(3,21-15-13-11-9-7-5-2)22-16-18-23(25)19-17-22/h16-19H,4-15,20-21H2,1-3H3/p+1
InChIKey=HIQMXPFMEWRQQG-UHFFFAOYSA-O

2: InChIKey=WMOPRSHYZNVZKF-UHFFFAOYSA-O

3: InChI=1S/C6H7NO/c1-7-4-2-3-6(8)5-7/h2-5H,1H3/p+1
InChIKey=FZVAZYLFYPULKX-UHFFFAOYSA-O

4 (cation only): InChI=1S/C13H21NO/c1-2-3-4-5-6-7-10-14-11-8-9-13(15)12-14/h8-9,11-12H,2-7,10H2,1H3/p+1
InChIKey=HSFRKOBOATYXAH-UHFFFAOYSA-O