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

The role of dispersion in understanding organic chemistry, both structure and reactivity, is truly coming into prominence (see for example this blog post for a compound whose stability is the result of dispersion). This has been driven in part by new computational techniques to properly account for dispersion. An interesting recent example is the structure of long chain alkanes, with a question posed and answered by Mata and Suhm:¹ What is the largest alkane whose most stable conformation is the extended chain?

The question is attacked by computation and experiment. The computational methodology involves corrections to the local MP2-F12 energy involving the separation of orbital pairs that are treated with a coupled clusters method. The straight chain (having only anti arrangements about the C-C bonds) and the hairpin conformer (having three gauche arrangements) were completely optimized. The C₁₇H₃₆ hairpin isomer is shown in Figure 1. For chains with 16 or fewer carbons, the all-anti straight chain is lower in energy, but for chains with 17 or more carbon atoms, the hairpin is lower in energy. Gas-phase low temperature IR and Raman spectra suggest that dominance of the hairpin occurs when the chain has 18 carbons, though careful analysis suggests that this is likely an upper bound. At least tentatively the answer to the question is that heptadecane is likely the longest alkane with a straight chain, but further lower temperature experiments are needed to see if the C16 chain might fold as well.

Figure 1. Optimized geometry of the hairpin conformation of heptadecane.

(I thank Dr. Peter Schreiner for bringing this paper to my attention.)

References

(1) Lüttschwager, N. O. B.; Wassermann, T. N.; Mata, R. A.; Suhm, M. A. "The Last Globally Stable Extended Alkane," Angew. Chem. Int. Ed. 2012, ASAP, DOI: 10.1002/anie.201202894.

InChIs

Heptadecane: InChI=1S/C17H36/c1-3-5-7-9-11-13-15-17-16-14-12-10-8-6-4-2/h3-17H2,1-2H3
InChIKey=NDJKXXJCMXVBJW-UHFFFAOYSA-N

Can a hydrogen bonding network affect acidity? Kass has examined the polyol 1 whose conjugate base 1cb can potentially be stabilized by a large hydrogen bonding network.¹ Kass had previously found a significant acidy enhancement in comparing t-butanol (ΔG(deprotonation) = 369.2 kcal mol^-1) with that of 2 (ΔG(deprotonation) = 334.4 kcal mol^-1).²

Table 1 lists the computed and experimental free energies of deprotonation of 1. The experimental values are computed at M06-2x/maug-cc-pVT(+d)Z. The structure of 1cb is drawn in Figure 1.

Table 1. Computed and experimental free energies (kcal mol^-1 of deprotonation of some alcohols.

The difference in the acidity of t-butanol and 2, some 30 kcal mol^-1, reflects the stability afforded by three intramolecular hydrogen bonds to the oxyanion. In going from 2cb to 1cb, each of the hydroxyl groups that donate to the oxyanion act as the acceptor of a hydrogen bond from the more removed hydroxyl groups. There is in effect a first and second layer of hydrogen bond network in 1cb. These secondary hydrogen bonds lead to further stabilization of the anion, as reflected in the diminished DPE of 1 over 2: 320.2 vs. 335.0 kcal mol^-1. Note that this secondary layer does not stabilize the anion to the same degree as the primary layer, but nonetheless its effect is large and quite striking.

1cb

Figure 1. M06-2x/maug-cc-pVT(+d)Z optimized structure of 1cb.

Even in solution these more remote hydrogen bonds can stabilize the anion. So, using the CPCM approach and modeling DMSO, 2 is predicted have a pK_a that is 15 units below that of t-butanol, and 1 is predicted to be 3 pK_a units more acidic than 2. Experiments verify this prediction with the pK_as of 16.1 for 2 and 11.4 for 1.

References

(1) Shokri, A.; Abedin, A.; Fattahi, A.; Kass, S. R. "Effect of Hydrogen Bonds on pKa Values: Importance of Networking," J. Am. Chem. Soc. 2012, 134, 10646-10650, DOI: 10.1021/ja3037349

(2) Tian, Z.; Fattahi, A.; Lis, L.; Kass, S. R. "Single-Centered Hydrogen-Bonded Enhanced Acidity (SHEA) Acids: A New Class of Brønsted Acids," J. Am. Chem. Soc. 2009, 131, 16984-16988, DOI: 10.1021/ja9075106

InChIs

1: InChI=1S/C13H28O7/c14-4-1-10(17)7-13(20,8-11(18)2-5-15)9-12(19)3-6-16/h10-12,14-20H,1-9H2
InChIKey=HGTVPOTWAYDRSM-UHFFFAOYSA-N

1cb: InChI=1S/C13H27O7/c14-4-1-10(17)7-13(20,8-11(18)2-5-15)9-12(19)3-6-16/h10-12,14-19H,1-9H2/q-1
InChIKey=UQPPTNIHRICITD-UHFFFAOYSA-N

2: InChI=1S/C7H16O4/c8-4-1-7(11,2-5-9)3-6-10/h8-11H,1-6H2
InChIKey=FAQWYKIIWYVDPQ-UHFFFAOYSA-N

2cb: InChI=1S/C7H15O4/c8-4-1-7(11,2-5-9)3-6-10/h8-10H,1-6H2/q-1
InChIKey=WSCPTRIAWKZJFZ-UHFFFAOYSA-N

Henry Rzepa and Peter Murray-Rust were awarded the Henry Skolnik Award from the Division of Chemical Information of the American Chemical Society at the 2012 fall national ACS meeting in Philadelphia. Henry and Peter have been the pioneers in creating a chemicaly-aware semantically-rich web presence and have been leaders in pushing for open data and open source. Both of them have been quite influential on my own ideas and projects, and I have worked with them both on a number of projects. I was honored to participate in the symposium surrounding this award.

My talk was on blogging and chemical communication, and you can download my PowerPoint presentation.

The activation energy for the 5-endo-dig reaction of the anion 1 is anomalously low compared to its 4-endo-dig and 6-endo-dig analogues. Furthermore, the TS is quite early, earlier than might be expected based on the Hammond Postulate. Alabugin and Schleyer have examined this reaction and found some interesting results.¹

First, NICS(0) values for a series of related intermolecular anionic attack at alkynes show some interesting trends (Table 1). Two of the transition states look like they might be aromatic: the TSs for the 3-exo-dig and the 5-endo-dig reaction have NICS(0) values that are quite negative. However, given the geometry of these TSs, particularly the close proximity of the σ bonds to the ring center, one might be concerned about contamination of these orbitals. So, NICS(0)_MOzz computations, which look at the tensor component perpendicular to the ring using just the π-MOs, shows that the 3-exo-dig is likely non-aromatic (NICS(0)_MOzz is near zero), the TS for the 4-endo-dig reaction is antiaromatic (NICS(0)_MOzz very positive) and the TS for the 5-endo-dig reaction is aromatic (NICS(0)_MOzz is very negative. So this last reaction is the first example of an aromatic transition that is not for a pericyclic reaction!

Table 1. NICS(0) and NICS(0)_MOzz for the TS of some anionic alkyne cyclizations.

These authors argue that the reaction of 1 is an “aborted” sigmatropic shift. A normal pericyclic reaction is a single step with a single (concerted) transition state. An interrupted sigmatropic shift has an intermediate that lies higher in energy than the reactants, such as in the Bergman cyclization of an enediyne. The aborted sigmatropic shift has an intermediate that lies lower in energy than the reactants, such as in the cyclization of 1.

References

(1) Gilmore, K.; Manoharan, M.; Wu, J. I. C.; Schleyer, P. v. R.; Alabugin, I. V. "Aromatic Transition States in Nonpericyclic Reactions: Anionic 5-Endo Cyclizations Are Aborted Sigmatropic Shifts," J. Am. Chem. Soc. 2012, 134, 10584–10594, DOI: 10.1021/ja303341b

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

Schreiner has written a very nice review of the role of tunneling in organic chemistry.¹ This includes tunneling in the conformations of carboxylic acids and in hydrogen abstractions. But the major emphasis is on his own group’s contributions regarding tunneling on a variety of hydroxycarbenes (see these posts: cyclopropylhydroxycarbene, methylhydroxycarbene, phenylhydroxycarbene, dihydroxycarbene, and hydroxymethylene). This led to the development of a third means for controlling reactions: not just kinetic and thermodynamic control, but tunneling control as well.

Recommended reading for anyone interested in learning how quantum mechanical tunneling can have very real-world chemical consequences.

References

(1) Ley, D.; Gerbig, D.; Schreiner, P. R. "Tunnelling control of chemical reactions – the organic chemist’s perspective," Org. Biomol. Chem., 2012, 10, 3781-3790, DOI: 10.1039/C2OB07170C.

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

How should one assess the aromatic stabilization energy of non-planar compounds like corannulene 1? The standard approach might be to employ the homodesmotic reaction, like Reaction 1. The energy of this reaction is however quite different whether one chooses s-cis or s-trans butadiene: 67.5 kcal mol^-1 with the former and 14.8 kcal mol^-1 with the latter. Exactly how one balances the total number of cis/trans relationships is problematic, but worse still is that Reaction 1 does not remove the effect of strain and non-planarity of 1.

Reaction 1
15 H₂C=CH-CH=CH₂ + 20 H₂C=C(CH₃)₂ → 1 + 10 H₂C=CH₂ + 20 H₂C=CH-CH₃

Dobrowolski, Ciesielski and Cyranski¹ propose a series of reactions that extend the isomerization stabilization energy concept of Schleyer. References are chosen that involve fixed alternate polyenes by appending methylene groups, creating radialene-like compounds. Reaction 2 and 3 are two such reactions that attempt to remove strain and non-planarity effects along with balancing the cis/trans relationships and potential H-H clashes between the pendant methylene groups. They report an additional 18 variations, because there is no unique method for portioning these effects.

Reaction 2

Reaction 3

Using B3LYP/6-311G** energies with zero-point vibrational energy, the reaction energies are 46.7 and 46.3 kcal mol^-1 for Reactions 2 and 3, respectively. Using all of the variations, the mean value is 44.7 kcal mol^-1 with a standard deviation of only 1.2 kcal mol^-1. It is clear that corranulene has a rather substantial artomatic stabilization energy, reflecting its decided aromatic character.

In a similar vein, they have also estimated the aromatic stabilization energy of coronene 2 as 58.4 kcal mol^-1, which, while clearly demonstrating the 2 is aromatic, it does not express any “superaromaticity”.

References

(1) Dobrowolski, M. A.; Ciesielski, A.; Cyranski, M. K. "On the aromatic stabilization of corannulene and coronene," Phys. Chem. Chem. Phys., 2011, 13, 20557-20563, DOI: 10.1039/C1CP21994D

InChIs

1: InChI=1S/C21H14/c1-3-13-6-7-15-10-11-16-9-8-14-5-4-12(2)17-18(13)20(15)21(16)19(14)17/h3-11H,1H2,2H3
InChIKey=ZJQHTVPYWDRMLD-UHFFFAOYSA-N

2: InChI=1S/C24H12/c1-2-14-5-6-16-9-11-18-12-10-17-8-7-15-4-3-13(1)19-20(14)22(16)24(18)23(17)21(15)19/h1-12H
InChIKey=VPUGDVKSAQVFFS-UHFFFAOYSA-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