Search Results for "bispericyclic"

Bispericyclic reaction involving two [6+4] cycloadditions

Bispericyclic transition states arise when two pericyclic reactions merge to a common transition state. This leads to a potential energy surface with a bifurcation such that reactions that traverse this type of transition state will head towards two different products. The classic example is the dimerization of cyclopentadiene, involving two [4+2] Diels-Alder reactions. Unusual PESs are discussed in my book and in past blog posts.

Houk and coworkers have now identified a bispericyclic transition state involving two [6+4] cycloadditions.1 Reaching back to work Houk pursued as a graduate student with Woodward for inspiration, these authors examined the reaction of tropone 1 with dimethylfulvene 2. Each moiety can act as the diene or triene component of a [6+4] allowed cycloaddition:

The product with fulvene 2 as the 6 π-e component and tropone as the 4 π-e component [6F+4T] is 3, while reversing their participation in the [6T+4F] cycloaddition leads to 4. A variety of [4+2] reactions are also possible. All of these reactions were investigated at PCM/M06-2X/6-311+G(d,p)//B3LYP-D3/6-31G(d). The reaction leading to 3 is exothermic by 3.0 kcal mol-1, while the reaction to 4 endothermic by 1.3 kcal mol-1.

Interestingly, there is only one transition state that leads to both 3 and 4, the first known bispericyclic transition state for two conjoined [6+4] cycloadditions. The barrier is 27.9 kcal mol-1. The structures of the two products and the transition state leading to them are shown in Figure 1. 3 and 4 can interconvert through a Cope transition state, also shown in Figure 1, with a barrier of 26.3 kcal mol-1 (for 43).



TS [6+4]

TS Cope

Figure 1. B3LYP-D3/6-31G(d) optimized geometries.

Given that a single transition leads to two products, the product distribution is dependent on the molecular dynamics. A molecular dynamics simulation at B3LYP-D3/6-31G(d) with 117 trajectories indicates that 4 is formed 91% while 3 is formed only 9%. Once again, we are faced with the reality of much more complex reaction mechanisms/processes than simple models would suggest.


1) Yu, P.; Chen, T. Q.; Yang, Z.; He, C. Q.; Patel, A.; Lam, Y.-h.; Liu, C.-Y.; Houk, K. N., "Mechanisms and Origins of Periselectivity of the Ambimodal [6 + 4] Cycloadditions of Tropone to Dimethylfulvene." J. Am. Chem. Soc. 2017, 139 (24), 8251-8258, DOI: 10.1021/jacs.7b02966.


1: InChI=1S/C7H6O/c8-7-5-3-1-2-4-6-7/h1-6H

2: InChI=1S/C8H10/c1-7(2)8-5-3-4-6-8/h3-6H,1-2H3


4: InChI=1S/C15H16O/c1-9(2)14-10-7-8-11(14)13-6-4-3-5-12(10)15(13)16/h3-8,10-13H,1-2H3

cycloadditions &Dynamics &Houk Steven Bachrach 07 Aug 2017 No Comments

Dynamics in a [3,3]-rearrangement

Bispericyclic reactions occur when two different pericyclic reactions merge to have a single transition state. An example of this is the joining of two [3,3]-sigmatopic rearrangements of 1 that merge to have a single transition state. Lopez, Faza, and Lopez have examined the dynamics of this reaction.1

Because of the symmetry of the species along this reaction pathway, the products of the two different rearrangements are identical, and will be formed in equal amounts, though they are produced from a single transition state with the reaction pathway bifurcating due to a valley-ridge inflection post TS.

The interesting twist that is explored here is when 1 is substituted in order to break the symmetry. The authors have examined 3x with either fluorine, chlorine, or bromine. The critical points on the reactions surface were optimized at M06-2X/Def2TZVPP. In all three cases a single bispericyclic transition state 3TS1x is found, which leads to products 4a and 4b. A second transition state 4TSx corresponds to the [3,3]-rearrangement that interconverts the two products. The structures of 1TS, 3TS1F, and 3TS1Cl are shown in Figure 1.




Figure 1. M06-2X/Def2TZVPP optimized geometries of 1TS, 3TS1F, and 3TS1Cl.

The halogen substitution breaks the symmetry of the reaction path. This leads to a number of important changes. First, the C4-C5 and C7-C8 distances, which are identical in 1TS, are different in the halogen cases. Interestingly, the distortions are dependent on the halogen: in 3TS1F C4-C5 is 0.2 Å longer than C7-C8, but in 3TS1Cl C7-C8 is much longer (by 0.65 Å) than C4-C5. Second, the products are no longer equivalent with the halogen substitution. Again, this is halogen dependent: 4bF is 4.0 kcal mol-1 lower in energy than 4aF, while 4aCl is 8.2 kcal mol-1 lower than 4bCl.

These difference manifest in very different reaction dynamics. With trajectories initiated at the first (bispericyclic) transiting state, 89% end at 4bF and 9% end at 4aF, a ratio far from unity that might be expected from both products resulting from passage through the same TS. The situation is even more extreme for the chlorine case, where all 200 trajectories end in 4aCl. This is yet another example of the role that dynamics play in reaction outcomes (see these many previous posts).


1) Villar López, R.; Faza, O. N.; Silva López, C., "Dynamic Effects Responsible for High Selectivity in a [3,3] Sigmatropic Rearrangement Featuring a Bispericyclic Transition State." J. Org. Chem. 2017, 82 (9), 4758-4765, DOI: 10.1021/acs.joc.7b00425.


1: InChI=1S/C9H12/c1-3-9-6-4-8(2)5-7-9/h1-2,4-7H2

2: InChI<=1S/C9H12/c1-7-4-5-8(2)9(3)6-7/h1-6H2

3F: InChI=1S/C9H8F4/c1-3-7-5-4-6(2)8(10,11)9(7,12)13/h1-2,4-5H2

3Cl: InChI=1S/C9H8Cl4/c1-3-7-5-4-6(2)8(10,11)9(7,12)13/h1-2,4-5H2

4aF: InChI=1S/C9H8F4/c1-5-4-6(8(10)11)2-3-7(5)9(12)13/h1-4H2

4aCl: InChI=1S/C9H8Cl4/c1-5-4-6(8(10)11)2-3-7(5)9(12)13/h1-4H2

4bF: InChI=1S/C9H8F4/c1-5-4-6(2)8(10,11)9(12,13)7(5)3/h1-4H2

4bCl: InChI=1S/C9H8Cl4/c1-5-4-6(2)8(10,11)9(12,13)7(5)3/h1-4H2

Cope Rearrangement &Dynamics Steven Bachrach 05 Jun 2017 No Comments

SpnF revisited

Medvedev, et al. have examined the cyclization step in the formation of Spinosyn A, which is catalyzed by the putative Diels-Alderase enzyme SpnF.1 This work follows on the computational study done by Houk, Singleton and co-workers,2 which I have discussed in this post (Dynamics in a reaction where a [6+4] and [4+2] cycloadditons compete). In fact, I recommend that you read the previous post before continuing on with this one. In summary, Houk, et al. found that a single transition state connects reactant 1 to both 2 and 3. The experimental product with the enzyme SpnF is 3. In the absence of enzyme, Houk, et al. suggest that reactions will cross the bispericyclic transition state TS-BPC (TS1 in the previous post) leading primarily to 2, which then undergoes a Cope rearrangement to get to product 3. Some molecules will follow pathways that go directly to 3.

The PCM(water)/M06-2x/6-31+G(d) study by Medvedev, et al. first identifies 560 conformations of 3. Next, they identified 384 TSs lying within 30 kcal mol-1 from the lowest TS. These can be classified as either TS-DA (leading directly to 3) or TS-BPC (which may lead to 2 by steepest descent, but can bifurcate towards 3). They opt to utilize the Atoms-in-Molecules theory to identify bond critical points to categorize these TS, and find that 144 are TS-BPC and 240 are TS-DA. (The transition state found by Houk, et al. is the second lowest energy TS found in this study, 0.29 kcal mol-1 higher in energy that the lowest TS and also of TS-BPC type.)

They also examined two alternative routes. First, they propose a path that first takes 1 to 4 via an alternative Diels-Alder reaction, and a second Cope rearrangement (TS-Cope2) takes this to 2, which can then convert to 3 via TS-Cope1. The other route involves a biradical pathway to either A or B. These alternatives prove to be non-competitive, with transition state energies significantly higher than either TS-DA or TS-BPC.

Returning to the set of TS-DA and TS-BPC transition states, while the former are more numerous, the latter are lower in energy. In summary, this study further complicates the complex situation presented by Houk, et. al. In the absence of catalyst, 1 can undergo either a Diels-Alder reaction to 3, or pass through a bispericyclic transition state that can lead to 3, but principally to 2 and then undergo a Cope rearrangement to get to 3. The question that ends my previous post on this subject — “ just what role does the enzyme SpnF play?” — remains to be answered.


1) Medvedev, M. G.; Zeifman, A. A.; Novikov, F. N.; Bushmarinov, I. S.; Stroganov, O. V.; Titov, I. Y.; Chilov, G. G.; Svitanko, I. V., "Quantifying Possible Routes for SpnF-Catalyzed Formal Diels–Alder Cycloaddition." J. Am. Chem. Soc. 2017, 139, 3942-3945, DOI: 10.1021/jacs.6b13243.

2) Patel, A.; Chen, Z.; Yang, Z.; Gutiérrez, 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. Am. 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

Uncategorized Steven Bachrach 11 Apr 2017 2 Comments

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

Computational Organic Chemistry, Second Edition – what’s new in Chapters 1-4

In this and the next post I discuss some of the new materials in the Second Edition of my book Computational Organic Chemistry. Every chapter has been updated, meaning that the topics from the First Edition that remain in this Second Edition (and that’s most of them) have been updated with any new relevant work that have appeared since 2007, when the First Edition was published. What I present in this and the next post are those sections or chapters that are entirely new. This post covers chapters 1-4 and the next post covers chapters 5-9.

Chapter 1: Quantum Mechanics for Organic Chemistry

The section on Density Functional Theory has been expanded and updated to include

  • a presentation of Jacob’s ladder, Perdew’s organizational model of the hierarchy of density
  • a discussion of dispersion corrections, principally Grimme’s “-D” and “-D3” corrections
  • a discussion of Grimme’s double hybrid functions and Martin’s DSD-DFT method (dispersion corrected, spin-component scaled double hybrid)
  • and a brief discussion of functional selection

The discussion of basis set superposition error (BSSE) is expanded and includes intramolecular BSSE. A new section has been added to discuss QM/MM methods including ONIOM. The discussion of potential energy surfaces is expanded, including presentation of more complicated surfaces that including valley-ridge inflection (VRI) points. Lastly, the chapter concludes with an interview of Prof. Stefan Grimme.

Chapter 2. Computed Spectral Properties and Structure Identification

This is essentially a brand new chapter dealing with how computed spectral properties have been used in structural identification. The chapter begins with a presentation of computed structural features (bond lengths and angles) and how they compare with experiment. Next, I present some studies of computer IR spectra and their use in structure identification. The bulk of this chapter deals with NMR. I present methods for computing NMR with scaling techniques. The statistical methods of Goodman (CP1 and DP4) are described in the context of discriminating stereoisomers. The section ends with five case studies where computed NMR spectra were used to identify chemical structure. Next, computed optical activity including ORD and ECD and VCD used for structure determination are described through 6 case studies. This chapter ends with an interview of Prof. Jonathan Goodman.

Chapter 3. Fundamentals of Organic Chemistry

The main addition to this chapter is an extensive discussion of alkane isomerism, and the surprising failure of many standard density functionals (including B3LYP) to properly account for isomer energies. The work in this area led to the recognition of the importance of dispersion and medium-range correlation, and the development of new functionals and dispersion corrections. Other new sections include a case study of the acidity of amino acids (especially cysteine and tyrosine where the most acidic proton in the gas phase is not the carboxylic acid proton), and two added studies of aromaticity: (a) the competition between aromaticity and strain and (b) π-π stacking.

Chapter 4. Pericyclic Reactions

The chapter is updated from the first addition with two major additions. First, a section on bispericyclic reactions is added. This type of reaction is important in the context of a number of reactions that display dynamic effects (see Chapter 8). Second, the notion of transition state distortion energy as guiding reaction selectivity is described.

The highlights of the new materials in Chapters 5-9 will appear in the next blog post.

Second Edition Steven Bachrach 15 Apr 2014 No Comments

Insights into dynamic effects

Singleton has taken another foray into the murky arena of “dynamic effects”, this time with the aim of trying to provide some guidance towards making qualitative product predictions.1 He has examined four different Diels-Alder reaction involving two diene species, each of which can act as either the diene or dienophile. I will discuss the results of two of these reactions, namely the reactions of 1 with 2 (Reaction 1) and 1 with 3 (Reaction 2).

Reaction 1

Reaction 2

In the experimental studies, Reaction 1 yields only 4, while reaction 2 yields both products in the ratio 6:7 = 1.6:1. Standard transition state theory would suggest that there are two different transition states for each reaction, one corresponding to the 4+2 reaction where 1 is the dienophile and the other TS has 1 as the dienophile. Then one would argue that in Reaction 1, the TS leading to 4 is much lower in energy than that leading to 5, and for Reaction 2, the TS state leading to 6 lies somewhat lower in energy than that leading to 7.

Now the interesting aspect of the potential energy surfaces for these two reactions is that there are only two transition states. The first corresponds to the Cope rearrangement between the two products (connecting 4 to 5 on the PES of Reaction 1 and 6 to 7 on the PES of Reaction 2). That leaves only one TS connecting reactants to products! These four TSs are displayed in Figure 1.

Reaction 1

Reaction 2

TS 12→45

TS 13→67

Cope TS 4→5

Cope TS 6→7

Figure 1. MPW1K/6-31+G** TSs on the PES of Reactions 1 and 2.1

These transition states are “bispericyclic” (first recognized by Caramella2), having the characteristics of both possible Diels-Alder reactions, i.e. for Reaction 1 these are the [4π1+2π2] and [4π2+2π1]. What this implies is that the reactants come together, cross over a single transition states and then pass over a bifurcating surface where the lowest energy path (the IRC or reaction path) continues on to one product only. The second product, however, can be reached by passing over this same transition state and then following some other non-reaction path. This sort of surface is ripe for experiencing non-statistical behavior, or “dynamic effects”.

Trajectory studies were then performed to explore the product distributions. Starting from TS 12→45, 39 trajectories were followed: 28 ended with 4 and 10 ended with 5 while one trajectory recrossed the transition state. Isomerization of 5 into 4 is possible, and the predicted low barrier for this explains the sole observation of 4. For Reaction 2, of the 33 trajectories that originated at TS 13→67, 12 led to 6 and 19 led to 7. This distribution is consistent with the experimental product distribution of a slight excess of 7 over 6.

Once again we see here a relatively simple reaction whose product distribution is only interpretable using expensive trajectory computations, and the result leave little simplifying concepts to guide us in generalizing to other (related) systems. Singleton does provide two rules-of-thumb that may help prod us towards creating some sort of dynamic model. First, he notes that the geometry of the single transition state that “leads” to the two products can suggest the major product. The TS geometry can be “closer” to one product over the other. For example, in TS 12→45 the two forming C-C bonds that differentiate the two products are 2.95 and 2.99 Å, and the shorter distance corresponds to forming 4. In TS 13→67, the two C-C distances are 2.83 and 3.13 Å, with the shorter distance corresponding to forming 6. The second point has to do with the position of the second TS, the one separating the two products. This TS acts to separate the PES into two basins, one for each product. The farther this TS is from the first TS, the greater the selectivity.

As Singleton notes, neither of these points is particularly surprising in hindsight. Nonetheless, since we have so little guidance in understanding reactions that are under dynamic control, any progress here is important.


(1) Thomas, J. B.; Waas, J. R.; Harmata, M.; Singleton, D. A., "Control Elements in Dynamically Determined Selectivity on a Bifurcating Surface," J. Am. Chem. Soc. 2008, 130, 14544-14555, DOI: 10.1021/ja802577v.

(2) Caramella, P.; Quadrelli, P.; Toma, L., "An Unexpected Bispericyclic Transition Structure Leading to 4+2 and 2+4 Cycloadducts in the Endo Dimerization of Cyclopentadiene," J. Am. Chem. Soc. 2002, 124, 1130-1131, DOI: 10.1021/ja016622h


1: InChI=1/C7H6O3/c1-10-7(9)5-2-3-6(8)4-5/h2-4H,1H3

2: InChI=1/C8H12/c1-2-8-6-4-3-5-7-8/h2,6H,1,3-5,7H2

3: InChI=1/C6H6O/c1-2-6-4-3-5-7-6/h2-5H,1H2

4: InChI=1/C15H18O3/c1-18-14(17)15-9-8-13(16)12(15)7-6-10-4-2-3-5-11(10)15/h6,8-9,11-12H,2-5,7H2,1H3/t1,12-,15+/m1/s1

5: InChI=1/C15H18O3/c1-18-15(17)13-8-11-10(7-12(13)14(11)16)9-5-3-2-4-6-9/h5,8,10-12H,2-4,6-7H2,1H3

6: InChI=1/C13H12O4/c1-16-13(15)10-6-8-7(5-9(10)12(8)14)11-3-2-4-17-11/h2-4,6-9H,5H2,1H3

7: InChI=1/C13H12O4/c1-16-12(15)13-6-4-10(14)8(13)2-3-11-9(13)5-7-17-11/h3-9H,2H2,1H3/t8-,9?,13-/m1/s1

Dynamics &Singleton Steven Bachrach 09 Dec 2008 No Comments