Tuesday, October 9, 2012

Why a Proximity-Induced Diels–Alder Reaction Is So Fast

Krenske, E. H.; Perry, E. W.; Jerome, S. V.; Maimone, T. J.; Baran, P. S.; Houk, K. N. Org. Lett. 2012, 14, 3016-3019 (Paywall)
Contributed by Steven Bachrach.
Reposted from Computational Organic Chemistry with permission

The intramolecular Diels-Alder reaction of 1 occurs slowly, but quantitatively, at room temperature.1This is unusual as most Diels-Alder cyclizations require heating to typically 200 °C. For example, the related cyclization of 2 requires heating to 170 °C.2 What is the cause for this proximity-induced reaction?
Reaction 1
Reaction 2
Reaction 3
Houk and Baran address this question using a computational approach.3 The Diels-Alder reaction of 2and a simplified analogue of 1, namely 3, were computed at CPCM/M06-2x/6-311+G(d,p)//B3LYP/6-31G(d). The optimized transition states for the reaction of 2 and 3 are shown in Figure 1. The free energy of activation of 3 is 5.4 kcal mol-1 lower in energy than the free energy of activation of 2. This is consistent with the much faster reaction of 1 than 2 observed in the experiment.

TS2

TS3
Figure 1. B3LYP/6-31G(d) for the transition states of Reactions 2 and 3.
Partitioning 3 into fragments allows Houk and Baran to apply the distortion model. They find that the rigid diene in 3 (and thereby 1) accelerates the reaction relative to the more flexible diene of 2. Further, strain relief in going from 3 (and thereby 1) to TS3 (and thereby to TS of reaction 1) and the formation of an intramolecular hydrogen bond leads to the lower activation energy of 3, and therefore of 1.

References
(1) Maimone, T. J.; Voica, A.-F.; Baran, P. S. "A Concise Approach to Vinigrol," Angew. Chem. Int. Ed.200847, 3054-3056, DOI: 10.1002/anie.200800167.
(2) Diedrich, M. K.; Klärner, F.-G.; Beno, B. R.; Houk, K. N.; Senderowitz, H.; Still, W. C. "Experimental Determination of the Activation Parameters and Stereoselectivities of the Intramolecular Diels−Alder Reactions of 1,3,8-Nonatriene, 1,3,9-Decatriene, and 1,3,10-Undecatriene and Transition State Modeling with the Monte Carlo-Jumping Between Wells/Molecular Dynamics Method," J. Am. Chem. Soc.1997119, 10255-10259, DOI: 10.1021/ja9643331.
(3) Krenske, E. H.; Perry, E. W.; Jerome, S. V.; Maimone, T. J.; Baran, P. S.; Houk, K. N. "Why a Proximity-Induced Diels–Alder Reaction Is So Fast," Org. Lett. 201214, 3016-3019, DOI: 10.1021/ol301083q.

InChIs
1: InChI=1S/C23H40O2Si/c1-10-12-19(24)21-20(16(3)4)18-13-14-23(21,15-17(18)11-2)25-26(8,9)22(5,6)7/h10-11,15-16,18-21,24H,1-2,12-14H2,3-9H3/t18?,19-,20?,21?,23+/m0/s1
InChIKey=NGVNTJGCNDZDEY-RHDCMTSYSA-N
2: InChI=1S/C10H16/c1-3-5-7-9-10-8-6-4-2/h3-5,7H,1-2,6,8-10H2/b7-5+
InChIKey=HXZJJSYHNPCGKW-FNORWQNLSA-N
3: InChI=1S/C20H34O2Si/c1-8-10-18(21)20(15(3)4)14-17-11-12-19(20,13-16(17)9-2)22-23(5,6)7/h8-9,13,15,17-18,21H,1-2,10-12,14H2,3-7H3/t17?,18-,19+,20?/m0/s1
InChIKey=GDQHAOHEZAJKPI-FUFFSDJGSA-N

Creative Commons License
This work is licensed under a Creative Commons Attribution-NoDerivs 3.0 Unported License.