Archive for June, 2015

Dyotropic rearrangement

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.






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(krel). 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.


(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.


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

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

Houk Steven Bachrach 29 Jun 2015 1 Comment

Structure of 2-oxazoline

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.


Planar TS

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


(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.


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

MP &vibrational frequencies Steven Bachrach 15 Jun 2015 1 Comment

Making superacidic phenols

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 pKa 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.


Conjugate base of 2


Conjugate base of 3

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


(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.


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


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

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

Acidity &Kass Steven Bachrach 02 Jun 2015 No Comments