Archive for the 'Diels-Alder' Category

An ambiphilic diene for bioorthogonal labeling

I recently posted on a paper proposing 1,2-benzoquinone and related compounds as the diene component for bioorthogonal labeling. Levandowski, Gamache, Murphy, and Houk report on tetrachlorocyclopentadiene ketal 1 as an active ambiphilic diene component.1

1 is sterically congested to diminish self-dimerization and will react with both electron-rich and electron-poor dienes. To test it as an active diene in bioorthogonal labeling applications, they optimized the structures of the transition states at CPCM(water)/M06-2X/6-311+G(d,p)//CPCM(water)/M06-2X/6-31G(d) for the Diels-Alder reaction of 1 with a variety of dienophiles including trans-cyclooctene 2 and endo-bicyclononyne 3. These transition states are shown in Figure 1. The activation free energy is quite low for each: 18.1 kcal mol-1 with 2 and 18.9 kcal mol-1 with 3.



Figure 1. CPCM(water)/M06-2X/6-31G(d) optimized geometries for the TSs of the reaction of 1 with 2 and 3.

Experiments were successfully run using 1 as a label on a neuropeptide.


1) Levandowski, B. J.; Gamache, R. F.; Murphy, J. M.; Houk, K. N., "Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling." J. Am. Chem. Soc. 2018, 140, 6426-6431, DOI: 10.1021/jacs.8b02978.



Diels-Alder &Houk Steven Bachrach 06 Aug 2018 No Comments

MD studies of simple pericyclic reactions

At the recent ACS meeting in New Orleans, Ken Houk spoke at the Dreyfus award session in honor of Michele Parrinello. Ken’s talk included discussion of some recent molecular dynamics studies of pericyclic reactions. Because of their similarities in approaches and observations, I will discuss three recent papers from his group (which Ken discussed in New Orleans) in this post.

The Cope rearrangement, a fundamental organic reaction, has been studied extensively by computational means (see Chapter 4.2 of my book). Mackey, Yang, and Houk examine the degenerate Cope rearrangement of 1,5-hexadiene with molecular dynamics at the (U)B3LYP/6-31G(d) level.1 They examined 230 trajectories, and find that of the 95% of them that are reactive, 94% are trajectories that directly cross through the transition zone. By this, Houk means that the time gap between the breaking and forming C-C bonds is less than 60 fs, the time for one C-C bond vibration. The average time in the transition zone is 35 fs. This can be thought of as “dynamically concerted”. For the other few trajectories, a transient diradical with lifetime of about 100 fs is found.

The dimerization of cyclopentadiene finds the two [4+2] pathways merging into a single bispericylic transition state. 2 Only a small minority (13%) of the trajectories sample the region about the Cope rearrangement that interconverts the two mirror image dimers. These trajectories average about 60 fs in this space, which comes from the time separation between the formation of the two new C-C bonds. The majority of the trajectories quickly pass through the dimerization transition zone in about 18 fs, and avoid the Cope TS region entirely. These paths can be thought of as “dynamically concerted”, while the other set of trajectories are “dynamically stepwise”. It should be noted however that the value of S2 in the Cope transition zone are zero and so no radicals are being formed.

Finally, Yang, Dong, Yu, Yu, Li, Jamieson, and Houk examined 15 different reactions that involve ambimodal (i.e. bispericyclic) transition states.3 They find a strong correlation between the differences in the bond lengths of the two possible new bond vs. their product distribution. So for example, in the reaction shown in Scheme 1, bond a is the one farthest along to forming. Bond b is slightly shorter than bond c. Which of these two is formed next is dependent on the dynamics, and it turns out the Pab is formed from 73% of the trajectories while Pac is formed only 23% of the time. This trend is seen across the 15 reaction, namely the shorter of bond b or c in the transition state leads to the larger product formation. When competing reactions involve bonds with differing elements, then a correlation can be found with bond order instead of with bond length.

Scheme 1


1) Mackey, J. L.; Yang, Z.; Houk, K. N., "Dynamically concerted and stepwise trajectories of the Cope rearrangement of 1,5-hexadiene." Chem. Phys. Lett. 2017, 683, 253-257, DOI: 10.1016/j.cplett.2017.03.011.

2) Yang, Z.; Zou, L.; Yu, Y.; Liu, F.; Dong, X.; Houk, K. N., "Molecular dynamics of the two-stage mechanism of cyclopentadiene dimerization: concerted or stepwise?" Chem. Phys. 2018, in press, DOI: 10.1016/j.chemphys.2018.02.020.

3) Yang, Z.; Dong, X.; Yu, Y.; Yu, P.; Li, Y.; Jamieson, C.; Houk, K. N., "Relationships between Product Ratios in Ambimodal Pericyclic Reactions and Bond Lengths in Transition Structures." J. Am. Chem. Soc. 2018, 140, 3061-3067, DOI: 10.1021/jacs.7b13562.

Cope Rearrangement &Diels-Alder &Dynamics &Houk Steven Bachrach 07 May 2018 No Comments

Strain-promoted cycloaddition to cyclooctyne

Click chemistry has been used in a broad range of applications. The use of metal catalysts has limited its application to biological system, but the development of strain-promoted cycloaddition to cyclooctyne has opened up click chemistry to bioorthogonal labeling.

An interesting variation on this is the use of 1,2-benzoquinone 1 and substituted analogues as the Diels-Alder diene component. Escorihuela and co-workers have reported on the use of this diene with a number of cyclooctyne derivatives, measuring kinetics and also using computations to assess the mechanism.1

Their computations focused on two reactions using cyclooctyne 2 and the cyclopropane-fused analogue 3:

Reaction 1

Reaction 2

They examined these reactions with a variety of density functionals along with some post-HF methods. The transition states of the two reactions are shown in Figure 1. A variety of different density functionals and MP2 are consistent in finding synchronous or nearly synchronous transition states.



Figure 1. B97D/6-311+G(d,p) transition states for Reactions 1 and 2.

In terms of activation energies, all of the DFT methods consistently overestimate the barrier by about 5-10 kcal mol-1, with B97D-D3 doing the best. MP2 drastically underestimates the barriers, though the SOS-MP2 or SCS-MP2 improve the estimate. Both CCSD(T) and MR-AQCC provide estimates of about 8.5 kcal mol-1, still 3-4 kcal mol-1 too high. The agreement between CCSD(T), a single reference method, and MR-AQCC, a multireference method, indicate that the transition states have little multireference character. Given the reasonable estimate of the barrier afforded by B97D-D3, and its tremendous performance advantage over SCS-MP2, CCSD(T) and MR-AQCC, this is the preferred method (at least with current technology) for examining Diels-Alder reactions like these, especially with larger molecules.


1) Escorihuela, J.; Das, A.; Looijen, W. J. E.; van Delft, F. L.; Aquino, A. J. A.; Lischka, H.; Zuilhof, H., "Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies." J. Org. Chem. 2018, 83, 244-252, DOI: 10.1021/acs.joc.7b02614.


1: InChI=1S/C6H4O2/c7-5-3-1-2-4-6(5)8/h1-4H

2: InChI=1S/C8H12/c1-2-4-6-8-7-5-3-1/h1-6H2

3: InChI=1S/C9H12/c1-2-4-6-9-7-8(9)5-3-1/h8-9H,3-7H2

4: InChI=1S/C14H16O2/c15-13-11-7-8-12(14(13)16)10-6-4-2-1-3-5-9(10)11/h7-8,11-12H,1-6H2

5: InChI=1S/C15H16O2/c16-14-12-5-6-13(15(14)17)11-4-2-9-7-8(9)1-3-10(11)12/h5-6,8-9,12-13H,1-4,7H2/t8-,9+,12?,13?

cycloadditions &DFT &Diels-Alder Steven Bachrach 19 Feb 2018 1 Comment

Dynamics in a reaction where a [6+4] and [4+2] cycloadditons compete

Enzyme SpnF is implicated in catalyzing the putative [4+2] cycloaddition taking 1 into 3. Houk, Singleton and co-workers have now examined the mechanism of this transformation in aqueous solution but without the enzyme.1 As might be expected, this mechanism is not straightforward.

Reactant 1, transition states, and products 2 and 3 were optimized at SMD(H2O)/M06-2X/def2-TZVPP//B3LYP-D3(BJ)//6-31+G(d,p). Geometries and relative energies are shown in Figure 1. The reaction 12 is a formal [6+4] cycloaddition, and the reaction 13 is a formal [4+2] cycloaddition. Interestingly, only a single transition state could be located TS1. It is a bispericyclic TS (see Chapter 4 of my book), where these two pericyclic reaction sort of merge together. After TS1 is traversed the potential energy surface bifurcates, leading to 2 or 3. This is yet again an example of a single TS leading to two different products. (See the many posts I have written on this topic.) The barrier height is 27.6 kcal mol-1, with 2 lying 13.1 kcal mol-1 above 3. However, the steepest descent pathway from TS1 leads to 2. There is a second transition state TScope that describes a Cope rearrangement between 2 and 3. Using the more traditional TS theory description, 1 undergoes a [6+4] cycloaddition to form 2 which then crosses a lower barrier (TScope) to form the thermodynamically favored 3, which is the product observed in the enzymatically catalyzed reaction.

1 (0.0)

TS1 (27.6)

2 (4.0)

3 (-9.1)


Figure 1. B3LYP-D3(BJ)//6-31+G(d,p) optimized geometries and relative energies in kcal mol-1.

Molecular dynamics computations were performed on this system by tracking trajectories starting in the neighborhood of TS1 on a B3LYP-D2/6-31G(d) PES. The results are that 63% of the trajectories end at 2, 25% end at 3, and 12% recross back to reactant 1, suggesting an initial formation ratio for 2:3 of 2.5:1. The reactions are very slow to cross through the “transition zone”, typically 2-3 times longer than for a usual Diels-Alder reaction (see this post).

Once again, we see an example of dynamic effects dictating a reaction mechanism. The authors pose a tantalizing question: Can an enzyme control the outcome of an ambimodal reaction by altering the energy surface such that the steepest downhill path from the transition state leads to the “desired” product(s)? The answer to this question awaits further study.


(1) Patel, A; Chen, Z. Yang, Z; Gutierrez, O.; Liu, H.-W.; Houk, K. N.; Singleton, D. A. “Dynamically
Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A,” J. Amer. Chem. Soc. 2016, 138, 3631-3634, DOI: 10.1021/jacs.6b00017.


1: InChI=1S/C24H34O5/c1-3-21-15-12-17-23(27)19(2)22(26)16-10-7-9-14-20(25)13-8-5-4-6-11-18-24(28)29-21/h4-11,16,18-21,23,25,27H,3,12-15,17H2,1-2H3/b6-4+,8-5+,9-7+,16-10+,18-11+/t19-,20+,21-,23-/m0/s1

2: InChI=1S/C24H34O5/c1-3-19-8-6-10-22(26)15(2)23(27)20-12-11-17-14-18(25)13-16(17)7-4-5-9-21(20)24(28)29-19/h4-5,7,9,11-12,15-22,25-26H,3,6,8,10,13-14H2,1-2H3/b7-4-,9-5+,12-11+/t15-,16-,17-,18-,19+,20+,21-,22+/m1/s1

3: InChI=1S/C24H34O5/c1-3-19-5-4-6-22(26)15(2)23(27)11-10-20-16(9-12-24(28)29-19)7-8-17-13-18(25)14-21(17)20/h7-12,15-22,25-26H,3-6,13-14H2,1-2H3/b11-10+,12-9+/t15-,16+,17-,18-,19+,20-,21-,22+/m1/s1

cycloadditions &Diels-Alder &Dynamics &Houk &Singleton Steven Bachrach 30 Aug 2016 1 Comment

Reaction selectivity in the synthesis of paeoveitol

Xu, Liu, Xu, Gao, and Zhao report a very efficient synthesis of paeoveitol 1 by the [4+2]-cycloaddition of paeveitol D 2 with the o-quinone methide 3.1 What is interesting here is the selectivity of this reaction. In principle the cyloadditon can give four products (2 different regioisomeric additions along with endo/exo selectivity) and it could also proceed via a Michael addition.

They performed PCM(CH2Cl2)/M06-2x/6-311+G(d,p) computations on the reaction of 2 with 3 and located two different transition states for the Michael addition and the four cycloaddition transition states. The lowest energy Michael and cycloaddition transition states are shown in Figure 1. The barrier for the cycloaddition is 17.6 kcal mol-1, 2.5 kcal mol-1 below that of the Michael addition. The barriers for the other cycloaddition paths are at more than 10 kcal mol-1 above the one shown. This cycloaddition TS is favored by a strong intermolecular hydrogen bond and by π-π-stacking. In agreement with experiment, it is the transition state that leads to the observed product.

Michael TS

[4+2] TS

Figure 1. Optimized geometries of the lowest energy TSs for the Michael and [4+2]cycloaddtion routes. Barrier heights (kcal mol-1) are listed in parenthesis.


(1) Xu, L.; Liu, F.; Xu, L.-W.; Gao, Z.; Zhao, Y.-M. "A Total Synthesis of Paeoveitol," Org. Lett. 2016, ASAP, DOI: 10.1021/acs.orglett.6b01736.

paeoveitol 1: InChI=1S/C21H24O3/c1-5-21-10-14-6-11(2)17(22)8-15(14)13(4)20(21)24-19-7-12(3)18(23)9-16(19)21/h6-9,13,20,22-23H,5,10H2,1-4H3/t13-,20-,21-/m1/s1

paeveitol D 2: InChI=1S/C9H10O2/c1-3-7-5-8(10)6(2)4-9(7)11/h3-5,10H,1-2H3/b7-3+

3: InChI=1S/C9H10O2/c1-3-7-5-8(10)6(2)4-9(7)11/h3-5,10H,1-2H3/b7-3+

Diels-Alder Steven Bachrach 02 Aug 2016 No Comments

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

Diels-Alder reaction of buckybowls

Fullerenes can undergo the Diels-Alder reaction with some specificity: the diene preferentially adds across the bond shared by two fused 6-member rings over the bond shared by the fused 6- and 5-member rings. Garcia-Rodeja and colleagues have examined the analogous Diels-Alder reaction of cyclopentadiene with five curved aromatic compounds, 1-5.1

The computations were performed at BP86-D3/def2-TZVPP//RI-BP86-D3/def2-SVP. Representative transition states for the addition of cyclopentadiene with 3 over the 6,6-bond and 5,6-bond are shown in Figure 1.



Figure 1. RI-BP86-D3/def2-SVP optimized transition states for the reaction of cyclopentadiene with 3.

For the reactions of cyclopentadiene with 2-5 the reactions with the 6,6-bond is both kinetically and thermodynamically favored, while with 1 the 6,6-bond is kinetically preffered and the 5,6-adduct is the thermodynamic product. As the molecules increase in size (from 1 to 5), the activation barrier decreases, and the barrier for the reaction with 5 is only 1.4 kcal mol-1larger than the barrier with C60. The reaction energy also becomes more exothermic with increasing size. There is a very good linear relationship between activation barrier and reaction energy.

Use of the distortion/interaction model indicates that the preference for the 6,6-regioselectivity come from better interaction energy than for the 5,6-reaction, and this seems to come about by better orbital overlap between the cyclopentadiene HOMO and the 6,6-LUMO of the buckybowl.


(1) García-Rodeja, Y.; Solà, M.; Bickelhaupt , F. M.; Fernández, I. "Reactivity and Selectivity of Bowl-Shaped Polycyclic Aromatic Hydrocarbons: Relationship to C60," Chem. Eur. J. 2016, 22, 1368-1378, DOI: <10.1002/chem.201502248.


1: InChI=1S/C20H10/c1-2-12-5-6-14-9-10-15-8-7-13-4-3-11(1)16-17(12)19(14)20(15)18(13)16/h1-10H


3: InChI=1S/C26H12/c1-5-13-14-6-2-11-19-20-12-4-8-16-15-7-3-10-18-17(9-1)21(13)25(22(14)19)26(23(15)18)24(16)20/h1-12H

4: InChI=1S/C30H12/c1-2-14-6-10-18-20-12-8-16-4-3-15-7-11-19-17-9-5-13(1)21-22(14)26(18)29(25(17)21)30-27(19)23(15)24(16)28(20)30/h1-12H

5: InChI=1S/C36H12/c1-7-16-17-9-3-14-5-11-20-21-12-6-15-4-10-19-18-8-2-13(1)22-25(16)31-32(26(18)22)34-28(19)24(15)30(21)36(34)35-29(20)23(14)27(17)33(31)35/h1-12H

Diels-Alder &fullerene Steven Bachrach 23 May 2016 No Comments

Diels-Alder reactions of some arenes

Houk has examined the Diels-Alder reaction involving ethene with benzene 1 and all of its aza-substituted isomers having four or fewer nitrogen atoms 2-11.1 The reactions were computed at M06-2X/6-311+G(d,p).

All of the possible Diels-Alder reactions were examined, and they can be classified in terms of whether two new C-C bonds are formed, one new C-C and one new C-N bond are formed, or two new C-N bonds are formed. Representative transition states of these three reaction types are shown in Figure 1, using the reaction of 7 with ethene.

Figure 1. M06-2X/6-311+G(d,p) optimized transition states for the Diels-Alders reactions of 7 with ethene.

A number of interesting trends are revealed. For a given type of reaction (as defined above), as more nitrogens are introduced into the ring, the activation energy decreases. Forming two C-C bonds has a lower barrier than forming a C-C and a C-N, which has a lower barrier than forming two C-N bonds. The activation barriers are linearly related to the aromaticity of the ring defined by either NICS(0) or aromatic stabilization energy, with the barrier decreasing with decreasing aromaticity. The barrier is also linearly related to the exothermicity of the reaction.

The activation barrier is also linearly related to the distortion energy. With increasing nitrogen substitution, the ring becomes less aromatic, and therefore more readily distorted from planarity to adopt the transition state structure.


(1) Yang, Y.-F.; Liang, Y.; Liu, F.; Houk, K. N. "Diels–Alder Reactivities of Benzene, Pyridine, and Di-, Tri-, and Tetrazines: The Roles of Geometrical Distortions and Orbital Interactions," J. Am. Chem. Soc. 2016, 138, 1660-1667, DOI: 10.1021/jacs.5b12054.

Aromaticity &Diels-Alder &Houk Steven Bachrach 26 Apr 2016 No Comments

QM/MM trajectory of an aqueous Diels-Alder reaction

I discuss the aqueous Diels-Alder reaction in Chapter 7.1 of my book. A key case is the reaction of methyl vinyl ketone with cyclopentadiene, Reaction 1. The reaction is accelerated by a factor of 740 in water over the rate in isooctane.1 Jorgensen argues that this acceleration is due to stronger hydrogen bonding to the ketone than in the transition state than in the reactants.2-4

Rxn 1

Doubleday and Houk5 report a procedure for calculating trajectories including explicit water as the solvent and apply it to Reaction 1. Their process is as follows:

  1. Compute the endo TS at M06-2X/6-31G(d) with a continuum solvent.
  2. Equilibrate water for 200ps, defined by the TIP3P model, in a periodic box, with the transition state frozen.
  3. Continue the equilibration as in Step 2, and save the coordinates of the water molecules after every addition 5 ps, for a total of typically 25 steps.
  4. For each of these solvent configurations, perform an ONIOM computation, keeping the waters fixed and finding a new optimum TS. Call these solvent-perturbed transition states (SPTS).
  5. Generate about 10 initial conditions using quasiclassical TS mode sampling for each SPTS.
  6. Now for each the initial conditions for each of these SPTSs, run the trajectories in the forward and backward directions, typically about 10 of them, using ONIOM to compute energies and gradients.
  7. A few SPTS are also selected and water molecules that are either directly hydrogen bonded to the ketone, or one neighbor away are also included in the QM portion of the ONIOM, and trajectories computed for these select sets.

The trajectory computations confirm the role of hydrogen bonding in stabilizing the TS preferentially over the reactants. Additionally, the trajectories show an increasing asynchronous reactions as the number of explicit water molecules are included in the QM part of the calculation. Despite an increasing time gap between the formation of the first and second C-C bonds, the overwhelming majority of the trajectories indicate a concerted reaction.


(1) Breslow, R.; Guo, T. "Diels-Alder reactions in nonaqueous polar solvents. Kinetic
effects of chaotropic and antichaotropic agents and of β-cyclodextrin," J. Am. Chem. Soc. 1988, 110, 5613-5617, DOI: 10.1021/ja00225a003.

(2) Blake, J. F.; Lim, D.; Jorgensen, W. L. "Enhanced Hydrogen Bonding of Water to Diels-Alder Transition States. Ab Initio Evidence," J. Org. Chem. 1994, 59, 803-805, DOI: 10.1021/jo00083a021.

(3) Chandrasekhar, J.; Shariffskul, S.; Jorgensen, W. L. "QM/MM Simulations for Diels-Alder
Reactions in Water: Contribution of Enhanced Hydrogen Bonding at the Transition State to the Solvent Effect," J. Phys. Chem. B 2002, 106, 8078-8085, DOI: 10.1021/jp020326p.

(4) Acevedo, O.; Jorgensen, W. L. "Understanding Rate Accelerations for Diels−Alder Reactions in Solution Using Enhanced QM/MM Methodology," J. Chem. Theor. Comput. 2007, 3, 1412-1419, DOI: 10.1021/ct700078b.

(5) Yang, Z.; Doubleday, C.; Houk, K. N. "QM/MM Protocol for Direct Molecular Dynamics of Chemical Reactions in Solution: The Water-Accelerated Diels–Alder Reaction," J. Chem. Theor. Comput. 2015, , 5606-5612, DOI: 10.1021/acs.jctc.5b01029.

Diels-Alder &Houk &Solvation Steven Bachrach 02 Feb 2016 1 Comment


What may be something of a surprise, [5]radialene 1 has only just now been synthesized.1 What makes this especially intriguing is that [3]radialene 2, [4]radialene 3 and [6]radialene 4 have been known for years.

Paddon-Row, Sherburn, and coworkers speculated that [5]radialene must undergo polymerization much more rapidly than the other radialenes. They computed the activation barrier for the Diels-Alder dimerization of the radialenes at G4(MP2). (The optimized structure of 1 and the transition state for the dimerization of 1 are shown in Figure 1.) The activation barrier for the dimerization of 1 is computed to be only 14.3 kJ mol-1, much lower than for the dimerization of 3 (59.2 kJ mol-1) or 4 (31.5 kJ mol-1).



Figure 1. G4(MP2) optimized geometries of 1 and the TS for the dimerization of 1.

Application of the distortion/interaction energy model helps to understand why 1 is the outlier among the radialenes. The distortion energy to bring two molecules of 1 to the transition state geometry is about 63 kJ mol-1, and this is much less than for [4]radialene (102 kJ mol-1) or [6]radialene (96 kJ mol-1). The reason lies in that [5]radialene is close to planarity and so only the pyramidalization at one carbon is necessary to reach the TS geometry. For 4, which is in a chair geometry, significant distortion is needed to bring the double bonds into conjugation. For 3, the high distortion energy is due to the significant pyramidalization energy needed.

Another interesting note is that the TSs for the Diels-Alder reactions of the radialenes is bis-pericyclic. The authors point out that dynamic effects may be important – though they did not perform any MD studies.

These computations drove the synthesis of 1 by coordinating it to two equivalents of Fe(CO)3 and then driving off the metals with cerium ammonium nitrate in acetone at -78 °C. The free [5]radialene was then detected by NMR, and it decomposes with a half-life of about 16 min at -20 °C.


(1) Mackay, E. G.; Newton, C. G.; Toombs-Ruane, H.; Lindeboom, E. J.; Fallon, T.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. "[5]Radialene," J. Am. Chem. Soc. 2015, 137, 14653–14659, DOI: 10.1021/jacs.5b07445.


1: InChI=1S/C10H10/c1-6-7(2)9(4)10(5)8(6)3/h1-5H2

Diels-Alder Steven Bachrach 07 Dec 2015 No Comments

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