Archive for July, 2016

Dehydro-Diels-Alder Reactions

I have been delinquent in writing about the dehydro-Diels-Alder reactions, but really can’t put it off any further. These sets of reactions really deserve a fuller analysis than I am going to summarize here, but this post will provide a good jumping off point for anyone interested in further investigation.

So the Diels-Alder reaction is among the most famous and most important reactions in organic chemistry. The reaction creates a 6-member ring and sets up to four stereocenters. In the past couple of years many chemists have expressed interest in the variant where the four-carbon component is more highly unsaturated, i.e. enyne or diyne. I will summarize the results of three recent computational papers dealing with the reaction of a diyne with an yne.

The first paper is by Skraba-Joiner, Johnson, and Agarwal.1 They discuss, among a number of interesting pericyclic reactions, the intramolecular Diels-Alder reaction of triyne 1 to give 2. They examined a concerted and stepwise pathway at (U)M05-2X/6-311+G(d,p) and find the concerted to be favored by 6.0 kcal mol-1. CCSD(T) using these geometries increases the difference to 8.2 kcal mol-1. The T1 diagnostic is fairly large for both the concerted and stepwise transition states, so they also performed CCSD(T)/CBS computations, which had much lower T1 values. The concerted TS remained favorable, but by only 2.7 kcal mol-1.

In the same special issue of the Journal of Organic Chemistry, Cramer, Hoye, and Kuwata examined a reaction closely related to what Johnson examined above.2 They looked at the reaction taking 3 into 4 via both experiments and computations. The M06-2x/6-311+G(d,p) geometries for the concerted and first TS along the stepwise path (with R1=R2=H) are shown in Figure 1. Evaluating the energies at SMD(o-dichlorobenzene)/B3LYP-D3BJ/6-311+G-(d,p)//M06-2X/6-311+G(d,p) find in this case (along with all of the other R1/R2 variants they examined) that the stepwise path has a lower barrier than the concerted path. In the case where R1=R2=H, the stepwise path is favored by 6.0 kcal mol-1. Additionally, these stepwise barriers are in reasonable agreement with the experimentally-derived barriers.

Concerted TS

Stepwise TS

Figure 1. M06-2x/6-311+G(d,p) optimized geometries of the concerted and stepwise TSs for the reaction of 3H going to 4H.

It should be pointed out that the wavefunctions for the concerted TSs were all found to be unstable with regard to a restricted to unrestricted relaxation. Given this problem, they also performed a CASPT2 energy evaluation of the concerted and stepwise transition states for the case R1=R2=H. CASPT2 finds the stepwise barrier to be 3.7 kcal mol-1 lower than the concerted barrier.

The last paper comes from the Houk lab, and examines the simplest set of intermolecular dehdro-Diels-Alder reactions.3 I will focus here on the most unsaturated analogue, the reaction of 1,3-butadiyne 5 with ethyne to give benzyne 6.

The concreted and stepwise transition states for this reaction (at (U)M06-2X/6-311+G(d,p)) are shown in Figure 2. The concerted barrier is 36.0 kcal moml-1 while the stepwise barrier is slightly lower: 35.2 kcal mol-1. The distortion energy for the concerted reaction is large (43.2 kcal mol-1) due mostly to angle changes in the diyne. Its interaction energy is -7.2 kcal mol-1, similar to the interaction energy in other similar Diels-Alder reactions. In contrast, the distortion energy for the stepwise pathway is 27.5 kcal mol-1, but the interaction energy is +7.7 kcal mol-1. These values are very similar to the distortion and interaction energy of the related (but less saturated DA reactions).

Concerted TS

Stepwise TS

Figure 2. (U)M06-2X/6-311+G(d,p) optimized concerted and stepwise TS for the reaction of 1,3-diyne with ethyne.

Molecular dynamics trajectories for both the concerted and stepwise paths reveal interesting differences. The concerted trajectories show an oscillatory behaviour of bending the angles at the C2 and C3 carbons prior to the TS, and then near synchronous formation of the new C-C bonds. The trajectories initiated at the stepwise TS show no systematic motion. Once the bond is formed, the biradical exhibits a long lifetime, on the order of picoseconds, much longer than the trajectory runs.

These three studies indicate the nature of the dehydro Diels-Alder reaction is very sensitive to reaction conditions, substituents, solvation, and all other manner of effects and will likely prove an area of interest for some time. It should keep a number of computational chemists busy for some time!


(1) Skraba-Joiner, S. L.; Johnson, R. P.; Agarwal, J. "Dehydropericyclic Reactions: Symmetry-Controlled Routes to Strained Reactive Intermediates," J. Org. Chem. 2015, 80, 11779-11787, DOI: 10.1021/acs.joc.5b01488.

(2) Marell, D. J.; Furan, L. R.; Woods, B. P.; Lei, X.; Bendelsmith, A. J.; Cramer, C. J.; Hoye, T. R.; Kuwata, K. T. "Mechanism of the Intramolecular Hexadehydro-Diels–Alder Reaction," J. Org. Chem. 2015, 80, 11744-11754, DOI: 10.1021/acs.joc.5b01356.

(3) Yu, P.; Yang, Z.; Liang, Y.; Hong, X.; Li, Y.; Houk, K. N. "Distortion-Controlled Reactivity and Molecular Dynamics of Dehydro-Diels–Alder Reactions," J. Am. Chem. Soc. 2016, 138, 8247-8252, DOI: 10.1021/jacs.6b04113.


1: InChI=1S/C9H8/c1-3-5-7-9-8-6-4-2/h1-2H,5,7,9H2

2: InChI=1S/C9H8/c1-2-5-9-7-3-6-8(9)4-1/h1,4H,3,6-7H2

3H: InChI=1S/C8H4O2/c1-3-5-6-7-10-8(9)4-2/h1-2H,7H2

4H: InChI=1S/C10H8O4/c1-6(11)14-8-2-3-9-7(4-8)5-13-10(9)12/h2-4H,5H2,1H3

5: InChI=1S/C4H2/c1-3-4-2/h1-2H

6: InChI=1S/C6H4/c1-2-4-6-5-3-1/h1-4H

benzynes &Cramer &Diels-Alder &Houk Steven Bachrach 25 Jul 2016 No Comments

Identifying the n→π* interaction

The weak n→π* interaction has been proposed to explain some conformational structure. Singh, Mishra, Sharma, and Das have now provided the first spectroscopic evidence of this interactions.1 They examined the structure of phenylformate 1. This compound can exist as two conformational isomers, having the carbonyl oxygen pointing towards (cis) or away (trans) from the phenyl ring. They optimized the structures of these two conformers at M05-2X/aug-cc-pVDZ and find that the cis isomer is lower in energy by 1.32 kcal mol-1. Unfortunately, the authors do not provide the structures of these isomers, but since they are so small, I reoptimized them at ωB97XD/6-311g(d) and they are displayed in Figure 1. At this computational level, the cis isomer is lower in enthalpy than the trans isomer by 1.35 kcal mol-1.



Figure 1. ωB97XD/6-311g(d) optimized structures of the cis and trans conformations of 1.

One-color resonant 2-photon ionization (1C-R2PI) spectroscopy followed by UV-VIS hole burning spectroscopy identified two isomers of 1, one present in greater amount that the other. The IR spectra of the dominant isomer showed a carbonyl stretch at 1766 cm-1, in nice agreement with the predicted frequency of 1cis (1770 cm-1). The carbonyl stretch for the minor isomer is at 1797 cm-1, again in nice agreement with the computed frequency for 1trans (1800 cm-1). The cis isomer has the lower carbonyl frequency due to partial donation of the carbonyl oxygen electrons to the π* orbital of the phenyl ring.


(1) Singh, S. K.; Mishra, K. K.; Sharma, N.; Das, A. "Direct Spectroscopic Evidence for an n→π* Interaction," Angew. Chem. Int. Ed. 2016, 55, 7801-7805, DOI: 10.1002/anie.201511925.


1: InChI=1S/C7H6O2/c8-6-9-7-4-2-1-3-5-7/h1-6H

Uncategorized Steven Bachrach 18 Jul 2016 1 Comment

Changes to the blog

I have been posting regularly on this blog for over nine years, beginning in July 2007. I have used this blog as a way to keep my book Computational Organic Chemistry current for its readers. I have also used it as a way for me to keep current with the literature.

It has been a terrific adventure for me, but an important change will be taking place in my life that will have an impact on the blog. Starting on August 1, 2016 I will become the Dean of the School of Science at Monmouth University in West Long Branch, NJ. (See the announcement.) I am extraordinarily excited to take on the challenges of leading the School. I suspect that my duties as Dean will keep me from finding the time to post as often as I have been for this past years. I will try to occasionally write a post as I intend to keep connected to the computational chemistry community. I have a few posts backlogged but expect a more infrequent posting schedule come August.

I fully intend to maintain the blog so that past posts remain accessible.

I want to thank all of the readers of this blog, those who read me through the Computational Chemistry Highlights blog, and especially those of you who have posted comments.

Uncategorized Steven Bachrach 11 Jul 2016 5 Comments

Redox switching

In searching for a redox switch, Matsuda, Ishikawa and co-workers1 landed on 13,14-picenedione 1, which could, at least in principle, be reduced by reacting with H2 to form the diol 2. The back reaction could then occur via the reaction with oxygen gas.

They first optimized the geometries of both compounds at B3PW91/6-311+G(2d), and these geometries are shown in Figure 1. TD-DFT computations then predicted that 1 would be yellow (maximum absorption at 412nm) and 2 would be colorless (maximum absorption at 378nm). Furthermore, 1 should have no fluorescence while 2 should fluoresce at 464nm and be blue.



Figure 1. B3PW91/6-311+G(2d) optimized geometries of 1 and 2.

Of particular note is that the geometry of 1 is twisted, with the O-C-C-O dihedral angle being 34.9°, while there is essentially no such twisting in 2 (its O-C-C-O dihedral angle is 0.7°). The twisting in 1 manifests in antiaromatic character of the central ring, with NICS(0)=+13.2ppm, while the central ring of 2 is aromatic, with NICS(0)=-10.0. The redox properties therefore reflect the change in the aromatic character.

They next synthesized 2 and reduced it with hydrogen gas to 1. The x-ray crystal structure of 1 shows a twisted structure (O-C-C-O dihedral of 28.87°). As predicted, 1 is yellow and 2 is colorless, and 1 has no fluorescence while 2 fluoresces blue.


(1) Urakawa, K.; Sumimoto, M.; Arisawa, M.; Matsuda, M.; Ishikawa, H. "Redox Switching of Orthoquinone-Containing Aromatic Compounds with Hydrogen and Oxygen Gas," Angew. Chem. Int. Ed. 2016, 55, 7432-7436, DOI: 10.1002/anie.201601906.


1: InChI=1S/C22H12O2/c23-21-19-15-7-3-1-5-13(15)9-11-17(19)18-12-10-14-6-2-4-8-16(14)20(18)22(21)24/h1-12H

2: InChI=InChI=1S/C22H14O2/c23-21-19-15-7-3-1-5-13(15)9-11-17(19)18-12-10-14-6-2-4-8-16(14)20(18)22(21)24/h1-12,23-24H

Aromaticity Steven Bachrach 06 Jul 2016 No Comments