Archive for the 'Diels-Alder' Category

A stepwise Diels-Alder

Halskov, et al.1 reported the interesting Diels-Alder selectivity shown in Scheme 1. The linear trienamine 1 did not undergo the Diels-Alder addition, while the less stable cross-conjugated diene 2 does react with 3 with high diastereo- and enantioselectivity. Their MPW1K/6-31+G(d,p) computations on a model system, carried out for a gas-phase environment, indicated a concerted mechanism, with thermodynamic control. However, the barrier for the reverse reaction for the kinetic product was computed to be greater than 30 kcal mol-1, casting doubt on the possibility of thermodynamic control.

Scheme 1.

Houk and co-workers2 have re-examined this reaction with the critical addition of performing the computation including the solvent effects. Since the stepwise alternatives involve the formation of zwitterions, solvent can be critical in stabilizing these charge-separated species, intermediates that might be unstable in the gas phase. Henry Rzepa has pointed out in his blog and on many comments in this blog about the need to include solvent, and this case is a prime example of the problems inherent in neglecting solvation.

Using models of the above reaction Houk located two zwitterionic intermediates of the Michael addition for both the reactions of 4 with 6 and of 5 with 6. The second step then involves the closure of the ring to give what would be Diels-Alder products. This is shown in Scheme 2. They were unable to locate transition states for any concerted pathways. The computations were done at M06-2x/def2-TZVPP/IEFPCM//B97D/6-31+G(d,p)/IEFPCM, modeling trichloromethane as the solvent.

Scheme 2. Numbers in italics are energies relative to 4 + 6.

The activation barrier for the second step in each reaction is very small, typically less than 5 kcal mol-1, so the first step is rate determining. The lowest barrier is for the reaction of 5 leading to 9, analogous to the observed product. Furthermore, 9 is also the thermodynamic product. Thus, the regioselectivity is both kinetically and thermodynamically controlled through a stepwise reaction. This conclusion is only possible by including solvent in order to stabilize the zwitterionic intermediates, and should be a word of caution for everyone doing computations: be sure to include solvent for any reactions that involved charged or charge-separated species at any point along the reaction pathway!

References

(1) Halskov, K. S.; Johansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. "Cross-trienamines in Asymmetric Organocatalysis," J. Am. Chem. Soc. 2012, 134, 12943-12946,
DOI: 10.1021/ja3068269.

(2) Dieckmann, A.; Breugst, M.; Houk, K. N. "Zwitterions and Unobserved Intermediates in Organocatalytic Diels–Alder Reactions of Linear and Cross-Conjugated Trienamines," J. Am. Chem. Soc. 2013, 135, 3237-3242, DOI: 10.1021/ja312043g.

Diels-Alder &Houk Steven Bachrach 02 Apr 2013 4 Comments

Proximity-induced Diels-Alder Reaction

The intramolecular Diels-Alder reaction of 1 occurs slowly, but quantitatively, at room temperature.1 This 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 2 and 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. 2008, 47, 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. 1997, 119, 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. 2012, 14, 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

Diels-Alder &Houk Steven Bachrach 08 Oct 2012 2 Comments

Reaction dynamics in the Diels-Alder reaction

Has there been an organic reaction more examined by computational methods than the Diels-Alder reaction? You’d think we would have covered all aspects of this reaction by now, but no, it appears that this reaction remains fertile hunting grounds.

Doubleday and Houk have examined the Diels-Alder reaction with an eye towards its synchronicity,1 an area that Houk has delved into throughout his career. While most experiments show significant stereoselectivity, a few examples display a small amount of stereo loss. Computed transition states tend to have forming C-C bond distances that are similar, though with proper asymmetric substitution, the asymmetry of the TS can be substantial. In this paper,1 they utilize reaction dynamics specifically to assess the time differential between the formation of the two new C-C single bonds. They examined the eight reactions shown below. The first six (R1-R6) have symmetric transition states, though with the random sampling about the TS for the initial condition of the trajectories, a majority of asymmetric starting conditions are used. The last two (R7 and R8) reactions have asymmetric TSs and the random sampling amplifies this asymmetry.

Nonetheless, the results of the dynamics are striking. The time gap, the average time between the formations of the first and second new C-C bond, for R1-R6 is less than 5 fs, much shorter than a C-C vibration. These reactions must be considered as concerted and synchronous. Even the last two reactions (R7 and R8), which are inherently more asymmetric, still have very short time gaps of 15 and 56 fs, respectively. One might therefore reasonably conclude that they too are concerted and synchronous.

There are some exceptions – a few trajectories in the last two reactions involve a long-lived (~1000 fs) diradical intermediate. At very high temperature, about 2% of the trajectories invoke a diradical intermediate. But the overall message is clear: the Diels-Alder reaction is inherently concerted and synchronous.

References

(1) Black, K.; Liu, P.; Xu, L.; Doubleday, C.; Houk, K. N. "Dynamics, transition states, and timing of bond formation in Diels–Alder reactions," Proc. Nat. Acad. Sci. USA, 2012, 109, 12860-12865, DOI: 10.1073/pnas.1209316109

Diels-Alder &Houk Steven Bachrach 18 Sep 2012 2 Comments

Distortion energy and the Diels-alder reaction

In a follow-up to their experimental study that found that cyclobutenone is an excellent dienophile (and which I blogged about here), Danishefsky teams up with Houk and provides an insight into the reactivity.1 In the Diels-Alder reaction of cyclopentadiene with 2-cyclohexenone, 2-cyclopentenone and cyclobutenone, the product yield increases in the order 36%, 50% and 77%. M06-2x activation enthalpies decrease in this series 15.0, 13.3 and 10.5 kcal mol-1.

While these activation energies do not correlate with reaction energies, the activation energies do correlate nicely with the distortion energy. (Distortion energy is the energy required to distort reactants to their geometries in the transition state, but without their interaction.) Houk and Danishefsky argue that it is much easier to distort cyclobutenone to its geometry in the TS (and this distortion is primarily moving the alkenyl hydrogens out of plane, away from the incoming diene) than for the larger rings. This is due to (a) the larger s-character of the C-H bond in the smaller ring and (b) the C-C-C angle in the smaller ring is closer to the angle in the pyramidalized TS structure.

References

(1) Paton, R. S.; Kim, S.; Ross, A. G.; Danishefsky, S. J.; Houk, K. N., "Experimental Diels–Alder Reactivities of Cycloalkenones and Cyclic Dienes Explained through Transition-State Distortion Energies," Angew. Chem. Int. Ed., 2011, 44, 10366–10368, DOI: 10.1002/anie.201103998

Diels-Alder &Houk Steven Bachrach 08 Nov 2011 2 Comments

Acene Dimerization

Bendikov and co-workers have examined the dimerization of linear acenes at M06-2x/6-31G(d).1 They have looked at the formal forbidden [4+4] reaction that takes, for example, 2 molecules of benzene into three possible dimer products 1Panti1-2, 1Psyn1-2, and 1Psyn1-4. The relative energies of these products increases in that order, and all three are much higher in energy than reactants; the lowest energy dimer is 1Panti1-2, lying 47.4 kcal mol-1 above two benzene molecules. Similarly, the dimerization of naphthalene is also endothermic, but the formation of the symmetric dimer of anthracene 3P-2,2’ is exothermic by 5.4 kcal mol-1. This gibes nicely with the best estimate of -9 ± 3 kcal mol-1.2 Dimerization of the higher acenes are increasingly exothermic.

The transition state for the dimerization of benzene is concerted, though very asymmetric, as seen in Figure 1. Its energy is quite high (77.79 kcal mol-1) and so this reaction can be completely discounted. The TS for the dimerization of naphthalene is also concerted and asymmetric, but the reaction pathway for the dimerization is stepwise, with a diradical intermediate. Furthermore, the highest barrier for this stepwise reaction is 33.3 kcal mol-1. The activation energy of the back reaction (anthracene dimer to two anthrecene molecules) was measured 36.3 kcal mol-1,3 and the computed barrier of 38.7 kcal mol-1 is in nice agreement. The computed barriers for the dimerization of the higher acenes are predicted to be even lower than that of anthracene, consistent with the observation of dimers of these molecules.

1Panti1-2

1TSanti1-2

1P-42

1TS-42

Figure 1. M06-2x /6-31G(d) optimized structures.

I was curious that the authors did not consider the formally allowed [4+2] dimerization, leading for example to 1P-42. So, I optimized this product and the concerted transition state leading to it. These are shown in Figure 1. The barrier through this transition state is still very large (54.1 kcal mol-1) but it is 23 kcal mol-1 lower in energy than the barrier of the [4+4] reaction! The Product of the [4+2] is also lower in energy (by 9 kcal mol-1) than 1Panti1-2. It seems to me that this type of dimerization is worth examining too – though I must say I have not as yet looked to see if anyone has explored this already.

References

(1) Zade, S. S.; Zamoshchik, N.; Reddy, A. R.; Fridman-Marueli, G.; Sheberla, D.; Bendikov,
M., "Products and Mechanism of Acene Dimerization. A Computational Study," J. Am. Chem. Soc., 2011, 133, 10803-10816, DOI: 10.1021/ja106594v

(2) Grimme, S.; Diedrich, C.; Korth, M., "The Importance of Inter- and Intramolecular van der Waals Interactions in Organic Reactions: the Dimerization of Anthracene Revisited," Angew. Chem. Int. Ed., 2006, 45, 625-629, DOI: 10.1002/anie.200502440

(3) Greene, F. D., "Problems of stereochemistry in photochemical reactions in the anthracene area," Bull. Soc. Chim. Fr., 1960, 1356-1360

InChIs

Benzene: InChI=1/C6H6/c1-2-4-6-5-3-1/h1-6H
InChIKey=UHOVQNZJYSORNB-UHFFFAOYAH

1Panti1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYAP

1Psyn1-2: InChI=1/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYAP

1Psyn1-4: InChI=1/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H
InChIKey=BCBHEUOKKNYIAT-UHFFFAOYAI

1P-42: InChI=1/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H
InChIKey=ONVDJSCNMCYFTI-UHFFFAOYAY

Anthracene: InChI=1/C14H10/c1-2-6-12-10-14-8-4-3-7-13(14)9-11(12)5-1/h1-10H
InChIKey=MWPLVEDNUUSJAV-UHFFFAOYAK

3P-2,2’: InChI=1/C28H20/c1-2-10-18-17(9-1)25-19-11-3-4-12-20(19)26(18)28-23-15-7-5-13-21(23)27(25)22-14-6-8-16-24(22)28/h1-16,25-28H
InChIKey=JUTIJVADGQDBGY-UHFFFAOYAY

Aromaticity &Diels-Alder &electrocyclization Steven Bachrach 11 Oct 2011 1 Comment

de Novo Enzyme Design

The de novo design of catalysts for specific purposes remains an inspired goal for chemists and biochemists. Ken Houk and David Baker have been pursuing this goal, and their recent paper on the design of a catalyst for the bimolecular Diels-Alder1 is a real significant step forward.

Their model enzyme is one that will provide a hydrogen bond acceptor to the carbamate proton of 1 and a proton donor to the carbonyl oxygen of the amide 2. This model is sketched in Figure 1. Glutamine or asparagines will serve as the acceptor and serine, threonine, or tyrosine will serve as the proton donor. The catalytic site is then modeled, and then this active site is fit within 207 protein scaffolds. About 1019 active site configurations are reduced to about 106 possible protein scaffolds. Optimization of these led to 84 protein designs.

Figure 1. Enzyme model

These 84 possible proteins were then synthesized within E. coli and then tested for catalytic behavior
in the Diels-Alder reaction of 1 + 2. Only 2 enzymes have activity, and with some protein modifications, quite reasonable enzyme activity is found. These enzymes show strong selectivity for the substrates – addition of a methyl group significantly diminishes catalytic activity. Perhaps most important is that of the 8 possible isomers that can be formed (4 isomers are produced in the uncatalyzed reaction) only 1 is produced here, the 3R,4S isomer 3.

All-in-all, a quite remarkable accomplishment!

References

(1) Siegel, J. B.; Zanghellini, A.; Lovick, H. M.; Kiss, G.; Lambert, A. R.; St.Clair, J. L.; Gallaher, J. L.; Hilvert, D.; Gelb, M. H.; Stoddard, B. L.; Houk, K. N.; Michael, F. E.; Baker, D.,
"Computational Design of an Enzyme Catalyst for a Stereoselective Bimolecular Diels-Alder Reaction," Science, 2010, 329, 309-313, DOI: 10.1126/science.1190239.

InChIs

1: InChI=1/C13H13NO4/c1-2-3-8-14-13(17)18-9-10-4-6-11(7-5-10)12(15)16/h2-8H,1,9H2,(H,14,17)(H,15,16)/p-1/b8-3+/fC13H12NO4/h14H/q-1
InChIKey=HGMJQUSLRHRARW-OSXKDGDFDJ

2: InChI=1/C5H9NO/c1-4-5(7)6(2)3/h4H,1H2,2-3H3
InChIKey=YLGYACDQVQQZSW-UHFFFAOYAD

3: InChI=1/C18H22N2O5/c1-20(2)16(21)14-5-3-4-6-15(14)19-18(24)25-11-12-7-9-13(10-8-12)17(22)23/h4,6-10,14-15H,3,5,11H2,1-2H3,(H,19,24)(H,22,23)/p-1/t14-,15+/m0/s1/fC18H21N2O5/h19H/q-1
InChIKey=WWWDBAXWGWLFSD-AFFTYDCXDH

Diels-Alder &Houk Steven Bachrach 08 Sep 2010 No Comments

Cyclobutenone as a dienophile

Li and Danishefsky report a study of the Diels-Alder reaction involving cyclobutenone 1 as the dienophile.1 They claim that “perhaps the ring strain of 1 might well serve to enhance its dienophilicity relative to corresponding cyclopentenones or cyclohexenones.” In fact, 1 is an excellent dienophile, with reactions at or below 0° being accomplished in less than half a day with yields upwards of 90%. The reaction goes with endo selectivity.

What is surprising to me is the statement in the article:

While the magnitude of the effect could not have been predicted in advance, the rate enhancement with 1 must reflect the favorable effects of rehybridization of two particularly strained sp2 carbons in the cycloaddition transition state.

Now, Danishefsky alludes to upcoming computations results in a future paper, but I don’t see why the rate enhancement could not have been “predicted in advance”. So, I have optimized the structures of reactants, endo and exo transition states, and products of the reaction of 1,3-butadiene with 1, cyclopentenone 2 and cyclohexenone 3 at B3LYP/6-311G(d) – Reactions 1-3.

The endo TS is preferred for the reaction of 1 and 2, while the endo and exo TSs for 3 are essentially isoenergetic. The optimized geometries are shown in Figure 1.

1TSendo

2TSendo

3TSendo

Figure 1. B3LYP/6-311G(d) optimized geometries of the endo TSs of Reactions 1-3.

The computed activation barriers and overall reaction energies are listed in Table 1. Clearly, the cycloaddition of 1 is favored both in terms of kinetics (having the lowest barrier) and thermodynamically (having the most exothermic reaction energy). In fact, the reaction barriers increases in going from 1 to 2 to 3 and the exothermicity decreases in that same order. This nicely dovetails with the strain energies of the dienophiles and the fact that cyclopententones and cyclohexenones are generally poor dienophiles. Thus, one clearly could have predicted these results in advance!

Table 1. Activation and Reaction Energy (kcal mol-1) for Reactions 1-3.

Reaction

Ea

ΔE

1

18.8

-35.2

2

24.1

-27.1

3

25.7

-27.1

Nonetheless, the experimental work is extremely nice and this work offers a new avenue into some interesting bicyclic structures.

Note: This post has been modified to correct the errors in the product structures and their associated InChIs and InChIKeys.

References

(1) Li, X.; Danishefsky, S. J., "Cyclobutenone as a Highly Reactive Dienophile: Expanding Upon Diels-Alder Paradigms," J. Am. Chem. Soc., 2010, 132, 11004-11005, DOI: 10.1021/ja1056888

InChIs

1: InChI=1/C4H4O/c5-4-2-1-3-4/h1-2H,3H2
InChIKey=DFLRGCFWSRELEL-UHFFFAOYAP

1prod: InChI=1/C8H10O/c9-8-5-6-3-1-2-4-7(6)8/h1-2,6-7H,3-5H2/t6-,7-/m0/s1
InChIKey=AYXQRXAAJYZWJJ-BQBZGAKWBC

2: InChI=1/C5H6O/c6-5-3-1-2-4-5/h1,3H,2,4H2
InChIKey=BZKFMUIJRXWWQK-UHFFFAOYAH

2prod: InChI=1/C9H12O/c10-9-6-5-7-3-1-2-4-8(7)9/h1-2,7-8H,3-6H2/t7-,8-/m0/s1
InChIKey=LOJATDUUSCWAOA-YUMQZZPRBU

3: InChI=1/C6H8O/c7-6-4-2-1-3-5-6/h2,4H,1,3,5H2
InChIKey=FWFSEYBSWVRWGL-UHFFFAOYAT

3prod: InChI=1/C10H14O/c11-10-7-3-5-8-4-1-2-6-9(8)10/h1-2,8-9H,3-7H2/t8-,9-/m0/s1
InChIKey=LFDGSLNQYSSFGI-IUCAKERBBQ

Diels-Alder Steven Bachrach 24 Aug 2010 4 Comments

More dynamic effects in Diels-Alder reactions

Dynamic effects rear up yet again in a seemingly simple reaction. Singleton has examined the Diels-Alder cycloaddition of acrolein with methyl vinyl ketone to give two cross products 1 and 2.1 Upon heating the product mixture, 1 is essentially the only observed species. The retro-Diels-Alder is much slower than the conversion of 2 into 1. Using a variety of rate data, the best estimate for the relative formation of 1:2 is 2.5.

The eight possible transition states for this reaction were computed with a variety of methodologies, all providing very similar results. The lowest energy TS is TS3. A TS of type TS4 could not be found; all attempts to optimize it collapsed to TS3.

IRC computations indicate the TS3 leads to 1. The lowest energy TS that leads to 2 is TS6, but a second TS (TS5) lower in energy than TS6 also leads to 1. The other TS are still higher in energy. A Cope-type TS that interconverts 1 and 2 (TS7) was also located. The geometries of these TSs are shown in Figure 1.

TS3
(0.0)

TS5
(4.2)

TS6
(5.2)

TS7
(-0.4)

Figure 1. MP2/6-311+G** optimized geometries and relative energies (kcal mol-1) of TS3-TS7.1

Ordinary transition state theory cannot explain the experimental results – the energy difference between the lowest barrier to 1 (TS3) and to 2 (TS6) suggests a rate preference of over 700:1 for 1:2. But the shape of the potential energy surface is reminiscent of others that have been discussed in both my book (Chapter 7) and this blog (see my posts on dynamics) – a surface where trajectories cross a single TS but then bifurcate into two product wells.

To address the chemical selectivity on a surface like this, one must resort to molecular dynamics and examine trajectories. In their MD study of the 296 trajectories that begin at TS3 with motion towards product, 89 end at 1 and 33 end at 2, an amazingly good reproduction of experimental results! Interestingly, 174 trajectories recross the transition state and head back towards reactants. These recrossing trajectories result from “bouncing off” the potential energy wall of the forming C4-C5 bond.

In previous work, selectivity in on these types of surfaces was argued in terms of which well the TS was closer to. But analysis of the trajectories in this case revealed that a strong correlation exists between the initial direction and velocity in the 98 cm-1 vibration – the vibration that corresponds to the closing of the second σ bond, the one between C6-O1 (forming 1), in the negative direction, and closing the C­3-O8 bond (forming 2) in the positive direction. Singleton argues that this is a type of dynamic matching, and it might be more prevalent that previously recognized.

References

(1) Wang, Z.; Hirschi, J. S.; Singleton, D. A., "Recrossing and Dynamic Matching Effects on Selectivity in a Diels-Alder Reaction," Angew. Chem. Int. Ed., 2009, 48, 9156-9159, DOI: 10.1002/anie.200903293

InChIs

1: InChI=1/C7H10O2/c1-6(8)7-4-2-3-5-9-7/h3,5,7H,2,4H2,1H3
InChIKey=AOFHZPHBPUYLAG-UHFFFAOYAJ

2: InChI=1/C7H10O2/c1-6-3-2-4-7(5-8)9-6/h3,5,7H,2,4H2,1H3
InChIKey=PLZQHPPETMMEED-UHFFFAOYAD

Diels-Alder &Dynamics &Singleton Steven Bachrach 27 Apr 2010 No Comments

MacMillan’s imidazolidinone: origins of stereoselection

Organic catalysis is a major topic of Chapter 5 of my book. The use of iminium ions as a catalyst and to provide stereoselection, pioneered by MacMillan,1 was not discussed in the book.

Macmillan had proposed that the iminium 2 formed of imidazolinone 1 and (E)-3-phenylprop-2-enal has conformation A. This conformation blocks access to one face of the alkene and directs, for example, dienophiles to the opposite face. Houk found that conformer B is lower in energy at B3LYP/6-31G(d).2


1


2

Now Tomkinson3 has produced a study that convincingly shows that 2 exists as conformer B. An x-ray structure shows this conformation in the solid state. Proton NMR shows that the methyl group signals are interpretable only as coming from B. Finally, SCS-MP2/aug-cc-pVTZ//BHandH/6-31+G(d,p) (see Figure 1) computations show that B is 1.2 kcal mol-1 more stable than A in the gas phase, and PCM computations indicate that this gap is reduced by less then 0.5 kcal mol-1 in methanol or acetonitrile.

Conformation B provides little steric hindrance at the β-carbon of the iminium ion, explaining its poor stereoselectivity in conjugate additions.

A

B

Figure 1. BHandH/6-31+G(d,p) optimized structures of conformers A and B of 2.

References

(1) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C., "New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction," J. Am. Chem. Soc., 2000, 122, 4243-4244, DOI: 10.1021/ja000092s.

(2) Gordillo, R.; Houk, K. N., "Origins of Stereoselectivity in Diels-Alder Cycloadditions Catalyzed by Chiral Imidazolidinones," J. Am. Chem. Soc., 2006, 128, 3543-3553, DOI: 10.1021/ja0525859.

(3) Brazier, J. B.; Evans, G.; Gibbs, T. J. K.; Coles, S. J.; Hursthouse, M. B.; Platts,
J. A.; Tomkinson, N. C. O., "Solution Phase, Solid State, and Theoretical Investigations on the MacMillan Imidazolidinone," Org. Lett., 2009, 11, 133-136, DOI: 10.1021/ol802512y.

InChIs

1: InChI=1/C13H18N2O/c1-13(2)14-11(12(16)15(13)3)9-10-7-5-4-6-8-10/h4-8,11,14H,9H2,1-3H3/t11-/m0/s1
InChIKey=UACYWOJLWBDSHG-NSHDSACABQ

2: InChI=1/C22H25N2O/c1-22(2)23(3)21(25)20(17-19-13-8-5-9-14-19)24(22)16-10-15-18-11-6-4-7-12-18/h4-16,20H,17H2,1-3H3/q+1/b15-10+,24-16+/t20-/m0/s1
InChIKey=ZPEHVNACGWTABV-BYFMJTDEBT

Diels-Alder Steven Bachrach 23 Feb 2009 1 Comment

Errors in DFT: computation of the Diels-Alder reaction

Concern about the use of DFT for general use in organic chemistry remains high; see my previous posts (1, 2, 3). Houk has now examined the reaction enthalpies of ten simple Diels-Alder reactions using a variety of functionals in the search for the root cause of the problem(s).1

The ten reactions are listed in Scheme 1, and involve cyclic and acyclic dienes and either ethylene or acetylene as the dienophile. Table 1 lists the minimum and maximum deviation of the DFT enthalpies relative to the CBS-QB3 enthalpies (which are in excellent accord with experiment). Clearly, all of the DFT methods perform poorly, with significant errors in these simple reaction energies. The exception is the MO6-2X functional, whose errors are only slightly larger than that found with the SCS-MP2 method. Use of a larger basis set (6-311+G(2df,2p)) reduced errors only a small amount.

Scheme 1

Table 1. Maximum, minimum and mean deviation of reaction enthalpies (kcal mol-1) for the reactions in Scheme 1 using the 6-31+G(d,p) basis set.1

Method

Maximum Deviation

Minimum Deviation

Mean Deviation


B3LYP

11.4

2.4

7.9

mPW1PW91

-8.7

-0.2

-3.6

MPWB1K

-9.8

-3.6

-6.2

M05-2X//B3LYP

-6.4

-1.6

-4.1

M06-2X//B3LYP

-4.4

-0.4

-2.5

SCS-MP2//B3LYP

-3.2

-0.5

-1.9


In order to discern where the problem originates, they next explore the changes that occur in the Diels-Alder reaction: two π bonds are transformed into one σ and one π bond and the conjugation of the diene is lost, leading to (proto)branching in the product. Reactions 1-3 are used to assess the energy consequence of converting a π bond into a σ bond, creating a protobranch, and the loss of conjugation, respectively.

The energies of these reactions were then evaluated with the various functionals. It is only with the conversion of the π bond into a σ bond that they find a significant discrepancy between the DFT estimates and the CBS-QB3 estimate. DFT methods overestimate the energy for the π → σ exchange, by typically around 5 kcal mol-1, but it can be much worse. Relying on cancellation of errors to save the day for DFT will not work when these types of bond changes are involved. Once again, the user of DFT is severely cautioned!

References

(1) Pieniazek, S. N.; Clemente, F. R.; Houk, K. N., "Sources of Error in DFT Computations of C-C Bond Formation Thermochemistries: π → σ Transformations and Error Cancellation by DFT Methods," Angew. Chem. Int. Ed. 2008, 47, 7746-7749, DOI: 10.1002/anie.200801843

DFT &Diels-Alder &Houk Steven Bachrach 01 Dec 2008 3 Comments

Next Page »