Computational techniques are gaining some traction in helping to understand enantioselective organocatalysis. I talk about a few examples in Chapter 6.3 of my book. Lambert and Vetticatt have now used computations to help understand the role of the catalyst 4 in the Michael addition shown in Scheme 1.¹ This reaction proceeds with 99% yield and an ee of 98%.

Scheme 1.

¹³C kinetic isotope effect studies suggest that the rate determining step is the C-C bond formation (the Michael addition step) which follows the deprotonation of the imine 1 by the catalyst 4.

They performed ONIOM computations to search for transition states of this rate limiting step for the reaction in Scheme 1, using the full molecules. From this ONIOM search, the energies for all transition structures with 5 kcal mol^-1 of the lowest energy structure were then obtained at B3LYP/6-31G*. The three lowest energy TS are shown in Figure 1. The two lowest energy structures lead to the major enantiomer, while the third lowest energy structure leads to the minor enantiomer. These energies lead to a prediction of an ee of 92%, in reasonable agreement with the experiment. The computed kinetic isotope effects are in nice agreement with experiment, supporting this step as the overall rate limiting step.

TSs leading to the S isomer
TS1 (0.0)	TS2 (0.9)
TS leading to the R isomer
TS3 (1.7)

Table 1. ONIOM optimized geometries of the three lowest energy TSs. Relative energy (kcal mol^-1) in parenthesis.

Analysis of what factors are important in determining the ee is complicated and ultimately the authors are unable to provide a simple explanation. They properly note that

The observation that the major enantiomer (S) is formed from two very geometrically distinct transition structures … suggests that the prediction of enantioselectivity for other reactions … will require a full consideration of all possible transition state assemblies. (emphasis mine)

I agree with this sentiment, pessimistic as it may be. Answering this type of question is likely to remain very challenging for years to come.

References

1) Bandar, J. S.; Sauer, G. S.; Wulff, W. D.; Lambert, T. H.; Vetticatt, M. J. "Transition State Analysis of Enantioselective Brønsted Base Catalysis Chiral Cyclopropenimines," J. Am. Chem. Soc. 2014, 136, 10700-10707, DOI: 10.1021/ja504532d.

InChIs

1: InChI=1S/C20H23NO/c1-20(2,3)14-18(22)15-21-19(16-10-6-4-7-11-16)17-12-8-5-9-13-17/h4-13H,14-15H2,1-3H3
InChIKey=UZCWUGCTNCNJHI-UHFFFAOYSA-N

2: InChI=1S/C4H6O2/c1-3-4(5)6-2/h3H,1H2,2H3
InChIKey=BAPJBEWLBFYGME-UHFFFAOYSA-N

3: InChI=1S/C24H29NO3/c1-24(2,3)17-21(26)20(15-16-22(27)28-4)25-23(18-11-7-5-8-12-18)19-13-9-6-10-14-19/h5-14,20H,15-17H2,1-4H3/t20-/m0/s1
InChIKey=KTASCPHNNZODSX-FQEVSTJZSA-N

4: InChI=1S/C37H57N3/c1-2-30(28-29-18-8-3-9-19-29)38-35-36(39(31-20-10-4-11-21-31)32-22-12-5-13-23-32)37(35)40(33-24-14-6-15-25-33)34-26-16-7-17-27-34/h3,8-9,18-19,30-34H,2,4-7,10-17,20-28H2,1H3/t30-/m1/s1
InChIKey=GEHSIGXXLTVFFG-SSEXGKCCSA-N

Aromaticity and orbital symmetry rules, though seemingly of ancient origin, remain areas of active interest. This paper by Fukazawa, et al combine both issues.¹ The multiple-step electrocyclization of 1 gives 2 in a reaction that takes 9 days at 80 °C. What would be the effect of diminishing the aromatic character of the fused rings of 1? Would the reaction be faster or slower?

Before discussing the experimental results, let’s examine the B3LYP/6-31G(d) results for the reaction of 1’, 3 and 5. (Note that a slightly smaller pendant substituent is used in the computations than in the experiment.) The optimized geometries of the critical points along the reaction pathway for the cyclization of 3 are shown in Figure 1.

3 (0.0)	3-TS1 (17.9)
3-INT (10.4)	3-TS2 (13.3)
4 (-60.7)

Figure 1. B3LYP/6-31G(d) optimized geometries and relative energies (kcal mol^-1) for the critical points along the reaction 3 → 4.
Remember that all structures on my blog can be viewed interactively by clicking on the image of the molecule.

For 1’, the first barrier (for the 8π cyclization) has a barrier of about 23 kcal mol^-1, but the second step (the 4π cyclization) has an even larger barrier of 28 kcal mol^-1. However, reducing the aromaticity of one of the fused rings (compound 3) leads to lower barriers of 18 and 13 kcal mol^-1. For the cyclization of 5, only a single transition state was found – no intermediate and no second TS – with a barrier of 12 kcal mol^-1. Thus, removing these external aromatic rings reduces the barrier of the reaction, and that is exactly what is found experimentally!

References

(1) Fukazawa, A.; Oshima, H.; Shimizu, S.; Kobayashi, N.; Yamaguchi, S. "Dearomatization-Induced Transannular Cyclization: Synthesis of Electron-Accepting Thiophene-S,S-Dioxide-Fused Biphenylene," J. Am. Chem. Soc. 2014, 136, 8738-8745, DOI: 10.1021/ja503499n.

InChIs:

1: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)37-25-29-30-26-38(50(15,16)42(4,5)6)46-34(30)23-24-36-32(28-40(48-36)52(19,20)44(10,11)12)31-27-39(51(17,18)43(7,8)9)47-35(31)22-21-33(29)45-37/h25-28H,1-20H3/b30-29-,32-31-
InChIKey=OCNQBMWQONUVNH-IOYDOZLVSA-N

1’:InChI=1S/C32H40S4Si4/c1-37(2,3)29-17-21-22-18-30(38(4,5)6)34-26(22)15-16-28-24(20-32(36-28)40(10,11)12)23-19-31(39(7,8)9)35-27(23)14-13-25(21)33-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=GTFPBRMBCLREPG-ICHHBZPXSA-N

2: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)29-21-25-26-22-30(50(15,16)42(4,5)6)46-38(26)34-33(37(25)45-29)35-36(34)40-28(24-32(48-40)52(19,20)44(10,11)12)27-23-31(47-39(27)35)51(17,18)43(7,8)9/h21-24H,1-20H3
InChIKey=OTDXAOVIIQYYNV-UHFFFAOYSA-N

2’: InChI=1S/C32H40S4Si4/c1-37(2,3)21-13-17-18-14-22(38(4,5)6)34-30(18)26-25(29(17)33-21)27-28(26)32-20(16-24(36-32)40(10,11)12)19-15-23(35-31(19)27)39(7,8)9/h13-16H,1-12H3
InChIKey=IYZNCPPDTHWWCO-UHFFFAOYSA-N

3: InChI=1S/C32H40O2S4Si4/c1-39(2,3)29-17-21-22-18-30(40(4,5)6)37-27(22)15-16-28-24(20-32(38(28,33)34)42(10,11)12)23-19-31(41(7,8)9)36-26(23)14-13-25(21)35-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=ZJBDGDJVLGNVOD-ICHHBZPXSA-N

4: InChI=1S/C32H40O2S4Si4/c1-39(2,3)21-13-17-18-14-22(40(4,5)6)36-30(18)26-25(29(17)35-21)27-28(26)32-20(16-24(38(32,33)34)42(10,11)12)19-15-23(37-31(19)27)41(7,8)9/h13-16H,1-12H3
InChIKey=QUSJUOMZBJUGON-UHFFFAOYSA-N

5: InChI=1S/C32H40O8S4Si4/c1-45(2,3)29-17-21-22-18-30(46(4,5)6)42(35,36)26(22)15-16-28-24(20-32(44(28,39)40)48(10,11)12)23-19-31(47(7,8)9)43(37,38)27(23)14-13-25(21)41(29,33)34/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=NNZTUSIYEPMHMP-ICHHBZPXSA-N

6: InChI=1S/C32H40O8S4Si4/c1-45(2,3)21-13-17-18-14-22(46(4,5)6)42(35,36)30(18)26-25(29(17)41(21,33)34)27-28(26)32-20(16-24(44(32,39)40)48(10,11)12)19-15-23(47(7,8)9)43(37,38)31(19)27/h13-16H,1-12H3
InChIKey=JZHQQYXUIQXWLQ-UHFFFAOYSA-N

The click reaction has become a major workhorse of synthetic chemists since its proposal in 2001.¹ Despite its efficiencies, no clear-cut example of its use in nature has been reported until 2012, where Yu and co-workers speculated that it might be utilized in the biosynthesis of lycojaponicumin A and B.² Krenske, Patel, and Houk have examined the possibility of an enzyme activated click process in forming this natural product.³

First they examined the gas-phase intramolecular [3+2] reaction that takes 1 into 2.

They identified (at M06-2X/def2-TZVPP/M06-2X/6-31+G(d,p)) four different low-energy conformations of 1, of which three have the proper orientation for the cyclization to occur. The lowest energy conformer, the TS, and the product 2 are shown in Figure 1. The free energy activation barrier in the gas phase is 19.8 kcal mol^-1. Inclusion of water as an implicit solvent (through a TS starting from a different initial conformation) increases the barrier to 20.0 kcal mol^-1. Inclusion of four explicit water molecules, hydrogen bonded to the nitrone and enone, predicts a barrier of 20.5 kcal mol^-1. These values predict a slow reaction, but not totally impossible. In fact, Tantillo in a closely related work reported a theoretical study of the possibility of a [3+2] cyclization in the natural synthesis of flueggine A and virosaine, and found barriers of comparable size as here. Tantillo concludes that enzymatic activation is not essential.⁴

1

TS12

3

Table 1. M06-2X/6-31+G(d,p) optimized geometries of 1, TS12, and 2.

To model a potential enzyme, the Houk group created a theozyme whereby two water molecules act as hydrogen bond donors to the enone and the use of implicit solvent (diethyl ether) to mimic the interior of an enzyme. This theozyme model predicts a barrier of 15.3 kcal mol^-1, or a 2000 fold acceleration of the click reaction. The search for such an enzyme might prove quite intriguing.

References

(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. "Click Chemistry: Diverse Chemical Function from a Few Good Reactions," Angew. Chem. Int. Ed. 2001, 40, 2004-2021, DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5.

(2) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-g.; Qu, J.; Li, Y. "Lycojaponicumins A–C, Three Alkaloids with an Unprecedented Skeleton from Lycopodium japonicum," Org. Lett. 2012, 14, 2614-2617, DOI: 10.1021/ol3009478.

(3) Krenske, E. H.; Patel, A.; Houk, K. N. "Does Nature Click? Theoretical Prediction of an Enzyme-Catalyzed Transannular 1,3-Dipolar Cycloaddition in the Biosynthesis of Lycojaponicumins A and B," J. Am. Chem. Soc. 2013, 135, 17638-17642, DOI: 10.1021/ja409928z.

(4) Painter, P. P.; Pemberton, R. P.; Wong, B. M.; Ho, K. C.; Tantillo, D. J. "The Viability of Nitrone–Alkene (3 + 2) Cycloadditions in Alkaloid Biosynthesis," J. Org. Chem. 2014, 79, 432–435, DOI: 10.1021/jo402487d.

InChIs

1: InChI=1S/C16H21NO3/c1-11-8-12-10-14(18)13-4-2-6-17(20)7-3-5-16(12,13)15(19)9-11/h4,7,11-12H,2-3,5-6,8-10H2,1H3/b13-4-,17-7+
InChIKey=GVEYMXKHRRHCLV-KYGYAMEJSA-N

2: InChI=1S/C16H21NO3/c1-9-6-10-8-13(19)16-11(17-5-3-14(16)20-17)2-4-15(10,16)12(18)7-9/h9-11,14H,2-8H2,1H3/t9?,10-,11?,14?,15+,16-/m0/s1
InChIKey=QKFAOJHYKPBTKX-SGVNFLFUSA-N

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.

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?

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

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

I think most organic chemists hold dear to their hearts the notion that selectivity is due to crossing over different transition states. Readers of my book and this blog know of the many examples where this notion simply is not true (see here). This post discusses yet another example taking place in a seemingly simple reaction.

Singleton has examined the nucleophilic substitution reaction of 1 with sodium tolylsulfide.¹ The mono substitution gives potentially two different stereoproducts 2 and 3. The experimental ratio of these products 2:3 is 81:19. (Note that things are a bit more complicated because disubstitution can also occur, but this has been factored into the product ratio.)

Based on previous literature, this reaction is likely to proceed in a concerted fashion, and so one might anticipate running computations to locate a transition state leading to 2 and a transition state leading to 3. In fact, Singleton finds six different TSs (the lowest energy TS 4 is shown in Figure 1), all within 2 kcal mol^-1 of each other at PCM(ethanol)/B3LYP/6-31+G**. However, the intrinsic reaction coordinate going forward from each of these six TSs leads solely to 2; no TS could be located that connects to 3! (Computations were also performed at PCM(ethanol)/M06-2x/6-31+G** which give very similar results.) Classical transition state theory would lead
one to conclude that only 2 should be formed, inconsistent with experiment.

4

5

Figure 1. PCM/B3LYP/6-31+G** optimized structures of TSs 4 and 5.

Furthermore, no intermediate could be located. This is consistent with a concerted mechanism. A second transition state was located which interconverts 2 and 3 with the involvement of a chloride – a sort of addition/rotation/elimination process. This TS 5 is also shown in Figure 1.

A direct dynamics study was performed, and 197 trajectories were computed. Of these, 185 trajectories went to product: 156 to 2 and 29 to 3, for a ratio of 84:16 – in amazing agreement with experiment! The product selectivity is due entirely to dynamic effects. In fact, it is one vibrational mode that dictates the product distribution. Essentially, the nature of the rotation about the C=C bond differentiates the eventual route, with a clockwise rotation leading always to 2 and a counterclockwise rotation leading about a third of the time to 3.

References

(1) Bogle, X. S.; Singleton, D. A. "Dynamic Origin of the Stereoselectivity of a Nucleophilic Substitution Reaction," Org. Lett., 2012, 14, 2528-2531, DOI: 10.1021/ol300817a.

InChIs

1: InChI=1S/C4H4Cl2O/c1-3(7)2-4(5)6/h2H,1H3
InChIKey=NXDUHPYJFYSBCT-UHFFFAOYSA-N

2: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7-
InChIKey=NCXXSKTZGJETLW-XFFZJAGNSA-N

3: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7+
InChIKey=NCXXSKTZGJETLW-YRNVUSSQSA-N

Hoffmann¹ reports on a number of new benzene dimer structures, notably 5-8, whose RIJCOSX-MP2/cc-pVTZ² structures are shown in Figure 1. A few of these new dimers are only somewhat higher in energy than the known dimers 1-4. The energies of these dimers, relative to two isolated benzene molecules, are listed in Table 1.

1	2
3	4
5	6
7	8

Figure 1. RIJCOSX-MP2/cc-pVTZ optimized geometries of 1-8.

Table 1. Energy (kcal mol^-1) of the dimers relative to two benzene molecules and activation energy for reversion to two benzene molecules.

The energy for reversion of the isomers 5-8 to two isolated benzene molecules is calculated to be fairly large, and so they should be stable relative to that decomposition mode. They also examined a series of other decomposition modes, including [1,5]-hydrogen migration, all of which had barriers of 21 kcal mol^-1 or greater, retrocyclization ([2+2]), for which they could not locate transition states, electrocyclic ring opening (Cope), with barriers of at least 17 kcal mol^-1 and dimerization – some of which had relatively small enthalpic barriers of 4-5 kcal mol^-1. However, the dimerizations all have very unfavorable entropic activation barriers.

So, the conclusion is that all of the novel dimers (4–8) can be reasonable expected to hang around for some time and therefore are potential synthetic targets.

References

(1) Rogachev, A. Yu.; Wen, X.-D.; Hoffmann, R. "Jailbreaking Benzene Dimers," J.
Am. Chem. Soc., 2012, 134, 8062-8065, DOI:10.1021/ja302597r

(2) Kossmann, S.; Neese, F. "Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method," J. Chem. Theory Comput., 2010, 6, 2325-2338, DOI: 10.1021/ct100199k

InChIs

1: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11-,12+
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYSA-N

2: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11+,12-
InChIKey=WMPWOGVJEXSFLI-IWDIQUIJSA-N

3: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12+
InChIKey=ONVDJSCNMCYFTI-CAODYFQJSA-N

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

5: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11+,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-WYUUTHIRSA-N

6: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12-/m0/s1
InChIKey=ONVDJSCNMCYFTI-QQFIATSDSA-N

7: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-KKOKHZNYSA-N

8: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12-
InChIKey=WMPWOGVJEXSFLI-NQYKUJLISA-N

Here are a couple of articles describing computational approaches to catalytic enantioselective reactions using variations upon the classic proline-catalyzed aldol reaction of List and Barbas¹ that started the whole parade. I have discussed the major computational papers on that system in my book (Chapter 5.3).

Yang and Wong² investigated the proline-catalyzed nitro-Michael reaction, looking at four examples, two with aldehydes and two with ketones (Reactions 1-4).

These four reactions were examined atMP2/311+G**//M06-2x/6-31G**, and PCM was also applied. The key element of this study is that they examined two different types of transition states: (a) based on the Houk-List model involving a hydrogen bond and (b) an electrostatic based model with no hydrogen bond. These are sketched in Scheme 1. For each of the reactions 1-4 there are 8 located transition states differing in the orientation of the attack on to the syn or anti enamine.

Scheme 1. TS models

The two lowest energy TS are shown in Figure 1. TS1-β1-RS is the lowest TS and it leads to the major enantiomer. The second lowest TS, TS1-β3-SR, lies 2.9 kJ mol^-1 above the other TS, and it leads to the minor enantiomer. This lowest TS is of the Houk-List type (Model A) while the other TS is of the Model B type. The enthalpies of activation suggest an ee of 54%, in reasonable
agreement with experiment.

TS1-β1-RS

TS1-β1-RS

Figure 1. M06-2x/6-31G** optimized geometries of TS1-β1-RS and TS1-β1-RS.

The computations of the other three reactions are equally good in terms of agreement with experiment, and importantly the computations indicate the reversal of stereoselection between the aldehydes and the ketones. These computations clearly implicate both the Houk-List and the non-hydrogen bonding TSs in the catalyzed Michael additions.

Houk in collaboration with Scheffler and Mahrwald investigate the use of histidine as a catalyst for the asymmetricaldol reaction.³ Examples of the histidine-catalyzed aldol are shown in Reactions 5-7.

	Reaction 5
	Reaction 6
	Reaction 7

The interesting twist here is whether the imidazole can also be involved in hydrogen bonding to the acceptor carbonyl group, serving the purpose of the carboxylic acid group in the Houk-List TS when proline is the catalyst (Model A). The transition states for these and a few other reactions were computed at M06-2x/6-31+G(d,p) including with the SMD continuum solvent model for water. The two lowest energy TSs for the reaction of isobutyraldehde and formaldehyde are shown in Figure 2; TS1 has the carboxylic acid group as the hydrogen donor while the imidazole is the donor in TS2. Of note is that these two TS are isoenergetic, indicating that both modes of stabilization are at play with histidine as the catalyst.

TS1

TS2

Figure 2. M06-2x/6-31+G(d,p) geometries of the two lowest energy TSs for the reaction of isobutyraldehde and formaldehyde catalyzed by histidine.

The possible TSs for Reactions 5-7 were also located. For example, with Reaction 5, the lowest energy TS involves the imidazole as the hydrogen donor and it leads to the major product. The lowest energy TS that leads to the minor product involves the carboxylic acid as the donor. The computed ee’s for Reactions 5-7 are in very good, if not excellent, agreement with the experimental values. The study should spur further activity in which one might tune the stereoselectivity by using catalysts with multiple binding opportunities.

References

(1) List, B.; Lerner, R. A.; Barbas, C. F., III; "Proline-Catalyzed Direct Asymmetric Aldol Reactions," J. Am. Chem. Soc., 2000, 122, 2395-2396, DOI: 10.1021/ja994280y.

(2) Yang, H.; Wong, M. W. "(S)-Proline-catalyzed nitro-Michael reactions: towards a better understanding of the catalytic mechanism and enantioselectivity," Org. Biomol. Chem.,
2012, 10, 3229-3235, DOI: 10.1039/C2OB06993H

(3) Lam, Y.-h.; Houk, K. N.; Scheffler, U.; Mahrwald, R. "Stereoselectivities of Histidine-Catalyzed Asymmetric Aldol Additions and Contrasts with Proline Catalysis: A Quantum Mechanical Analysis," J. Am. Chem. Soc. 2012, 134, 6286-6295, DOI: 10.1021/ja2118392

Once again the Singleton group reports experiments and computations that require serious reconsideration of our notions of reaction mechanisms.¹ In this paper they examine the reaction of dichloroketene with labeled cis-2-butene. With ¹³C at the 2 position of 2-butene, two products are observed, 1 and 1’, in a ratio of 1’:1 = 0.993 ± 0.001. This is the opposite what one might have imagined based on the carbonyl carbon acting as an electrophile.

The first interesting item is that B3LYP/6-31+G** fails to predict the proper structure of the transition state. It predicts an asymmetric structure 2, shown in Figure 1, while MPW1k/6-31+G**, M06, and MP2 predict a C_s transition structure 3. The C_s TS is confirmed by a grid search of M06-2x geometries with CCSD(T)/6-311++G88/PCM(CH₂Cl₂) energies.

2

3

Figure 1. Optimized TSs 2 (B3LYP/6-31+G**) and 3 (MPW1K/6-31+G**).

The PES using proper computational methods is bifurcating past TS 3, falling downhill to product 1 or 1’. Lying on the C_s plane is a second transition state that interconverts 1 and 1’. On such a surface, conventional transition state theory would predict equal amounts of 1 and 1’, i.e. no isotope effect! So they must resort to a trajectory study – which would be impossibly long if not for the trick of making the labeled carbon super-heavy – like ²⁸C,⁴⁴C, ⁷⁶C and ¹⁴⁰C and then extrapolating back to just ordinary ¹³C. These trajectories indicate a ratio of 1’:1 of 0.990 in excellent agreement with the experimental value of 0.993.

Interestingly, most trajectories recross the TS, usually by reaching into the region near the second TS. However, the recrossing decreases with increasing isotopic mass, and this leads to the isotope effect. It turns out the vibrational mode 3 breaks the C_s symmetry; movement in one direction along mode 3 has no mass dependence but in the opposite direction, increased mass leads to decreased recrossing – or put in another way, in this direction, increased mass leads more often to product.

But one can understand this reaction from a statistical point of view as well. If one looks at the free energy surface, there is a variational TS near 3, but then there is a second set of variational transition states (one leading to 1 and one to 1’) which are associated with the formation of the second C-C bond. In a sense there is an intermediate past 3 that leads to two entropic barriers, one on a path to 1 and one on the path to 1’. RRKM using this model gives a ratio of 0.992 – again in agreement with experiment! It is as Singleton notes “perplexing”; how do you reconcile the statistical view with the dynamical (trajectory) view? Singleton has no full explanation.

Lastly, they point out that a similar situation occurs in the organocatalyzed Diels-Alder reaction of MacMillan shown below.² (This reaction is also discussed in a previous post.) Now Singleton finds that the “substituent effects, selectivity, solvent effects, isotope effects and activation parameters” are all dictated by a second variational TS far removed from the conventional electronic TS.

References

(1) Gonzalez-James, O. M.; Kwan, E. E.; Singleton, D. A., "Entropic Intermediates and Hidden Rate-Limiting Steps in Seemingly Concerted Cycloadditions. Observation, Prediction, and Origin of an Isotope Effect on Recrossing," J. Am. Chem. Soc. 2012, 134, 1914-1917, DOI: 10.1021/ja208779k

(2) 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.

InChIs

2-butene: InChI=1/C4H8/c1-3-4-2/h3-4H,1-2H3/b4-3-
InChIKey=IAQRGUVFOMOMEM-ARJAWSKDBO

Dichloroketene: InChI=1/C2Cl2O/c3-2(4)1-5
InChIKey=TVWWMKZMZALOFP-UHFFFAOYAY

1 (no isotope): InChI=1/C6H8Cl2O/c1-3-4(2)6(7,8)5(3)9/h3-4H,1-2H3/t3-,4+/m0/s1
InChIKey=BAEYWHUXGUIZSP-IUYQGCFVBH