Dynamically Complex [6+4] and [4+2] Cycloadditions in the Biosynthesis of Spinosyn A

Patel, A; Chen, Z. Yang, Z; Gutierrez, O.; Liu, H.-W.; Houk, K. N.; Singleton, D. A.  J. Amer. Chem. Soc. 2016,138, 3631-3634
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

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 reaction1 → 2 is a formal [6+4] cycloaddition, and the reaction 1 → 3 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)
(24.7)

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.

References

(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.

InChIs

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
InChIKey=JEKALMRMHDPSQK-ZTRRSECRSA-N

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
InChIKey=AVLPWIGYFVTVTB-PTACFXJJSA-N

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
InChIKey=BINMOURRBYQUKD-MBPIVLONSA-N

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Ab Initio Calculation of Rate Constants for Molecule–Surface Reactions with Chemical Accuracy

GiovanniMaria Piccini, Maristella Alessio, and Joachim Sauer (2016)

Contributed by Jan Jensen

Piccini et al. reproduce experimental rate constants for the reactions of methanol with ethene, propene, and trans-2-butene catalyzed by an acidic zeolite (H-MFI), to within one order of magnitude. Key to this is the inclusion of anharmonic effects using the method I highlighted earlier, but it should be noted that the reaction is biomolecular so entropy effects may be larger than for unimolecular reactions such as most enzyme catalysed reactions. However, anharmonic effects also changed the activation enthalpy by as much as 8 kJ/mol.

The PBE/plane wave electronic energy is corrected using MP2/CBS computed for a smaller systems plus a CCSD(T)/TZVP correction computed on an even smaller system.  Such corrections are becoming increasingly feasible for many problems and this study shows that the usual harmonic treatment of the vibrational free energy may become the limiting factor in terms of accuracy. However, anharmonic methods such as the one used here must be implemented, in a black box-fashion, in at least one of the major quantum chemistry packages before we'll see them widely applied.

See also this highlight of the article



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Effect of Complex-Valued Optimal Orbitals on Atomization Energies with the Perdew–Zunger Self-Interaction Correction to Density Functional Theory

Susi Lehtola, Elvar Ö. Jónsson, and Hannes Jónsson J. Chem. Theory Comput. in press (2016)

Contributed by David Bowler
Reposted from Atomistic Computer Simulations with permission

One of the biggest problems facing DFT is that of self-interaction: each electron effectively interacts with itself, because the potential derives from the total charge density of the system. This is not an issue for the exact (unknown) density functional, or for Hartree-Fock, but is the cause of significant error in many DFT functionals. Approaches such as DFT+U[1],[2],[3] and hybrid functionals (far too many to reference !) are aimed in part at fixing this problem.

Probably the earliest attempt to remove this error is the self-interaction correction of Perdew and Zunger[4] which corrects the potential for each Kohn-Sham orbital, complicating the calculation considerably over a standard DFT calculation. (Ironically, this paper, which has over 11,000 citations, is best known for its appendix C, where a parameterisation of the LDA XC energy is given.) However, this process is notoriously slow to converge and is not widely used.

A recent paper[5] showed that, even for isolated molecules, complex orbitals were required to achieve convergence, and this approach has now been tested for atomisation energies of a standard set of 140 molecules[6]. The tests compare the new complex SIC implementation against the standard, real implementation, as well as various GGAs, hybrid functionals and meta-GGAs. The complex SIC, when coupled with the PBEsol functional[7], gives good results (though ironically the PBEsol functional was developed to improve PBE for solids). Not surprisingly, the best results are from hybrids, but meta-GGA improves the energies almost as well.

This study highlights the problem with DFT at the moment: there are many different approaches, which often work well for specific problems. SIC is cheaper than hybrid calculations, and can be important for charge transfer problems (and Rydberg states). The results for convergence and complex orbitals are interesting, but based on these results, I would use meta-GGA for atomisation energies, as a good compromise between accuracy and cost (almost the same as GGA).

[1] Phys. Rev. B 52, R5467 (1995) DOI:10.1103/PhysRevB.52.R5467

[2] Phys. Rev. B 57, 1505 (1998) DOI:10.1103/PhysRevB.57.1505

[3] Int. J. Quantum Chemistry 114, 14 (2014) DOI:10.1002/qua.24521

[4] Phys. Rev. B. 23, 5048 (1981) DOI:10.1103/PhysRevB.23.5048

[5] J. Chem. Theory Comput. 12, 3195 (2016) DOI:10.1021/acs.jctc.6b00347

[6] J. Chem. Theory Comput. in press (2016) DOI:10.1021/acs.jctc.6b00622

[7] Phys. Rev. Lett. 100, 136406 (2008) DOI:10.1103/PhysRevLett.100.136406

A Total Synthesis of Paeoveitol

Xu, L.; Liu, F.; Xu, L.-W.; Gao, Z.; Zhao, Y.-M. Org. Lett. 2016, ASAP
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

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 (20.1)

[4+2] TS (17.6)

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.

References

(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
InChIKey=LCLFTLPUJXVULB-OBVPDXSSSA-N

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+
InChIKey=KWDDAFOCZGDLEG-XVNBXDOJSA-N

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

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Diverse Optimal Molecular Libraries for Organic Light-Emitting Diodes

Chetan Rupakheti, Rachael Al-Saadon, Yuqi Zhang, Aaron M. Virshup, Peng Zhang, Weitao Yang, and David N. Beratan (2016)
Contributed by Jan Jensen

This paper uses the property-optimizing ACSESS (PO-ACSESS) method to create a set of diverse set of candidates for organic light-emitting diodes (OLEDs) with efficient blue emissions.  There are over 10$^{60}$ synthetically feasible, low molecular eight organic molecules so it is impossible to do an exhaustive search of this so-called small molecule universe looking for better blue OLEDs. Yang and Beratan have therefore developed PO-ACSESS, a stochastic genetic algorithm to extract a set of diverse molecules with a given set of properties.

PO-ACSESS starts with a set of seed molecules (in this case organic molecules that are known blue emitters) that are then randomly mutated and mated. A mutation may be any of a set of elementary steps such a change in bond order, ring formation, atom addition/deletion, etc. and mating is done by randomly fragmenting the molecules at a rotateable bond followed by re-combination of fragments from different parents. The new molecules that do not meet the desired stability, synthetic-feasibility, and electronic criteria are removed. To enforce diversity, molecules that are too close in chemical space are also removed and the entire process is repeated starting with these molecules. The chemical space distance between two compounds is defined as the distance between compounds based on their descriptors, such as atomic number, Gasteiger−Marsili partial charge, atomic polarizability, and topological steric index.

In the case of blue OLEDs the electronic criteria are a vertical singlet excitation energy in the 2.4−4.1 eV range (blue region), an oscillator strength of ≥0.4, and a singlet-triplet gap ≤ 0.3 eV. “Initially, the threshold is set to a less stringent value … to ensure that the population does not collapse to zero, because of the fitness constraint.” The electronic properties were calculated using semiempirical methods such as AM1, ZINDO/S, and DFTB.

The design process was done in two stages: First PO-ACSESS was used to identify 195 molecules with the desired vertical singlet excitation energies and oscillator strengths.  I could not find any details on what seed molecules were used nor the number of iterations. These 195 molecules where then used as seeds for further optimization of the singlet-triplet gap. This PO-ACSESS search was run for 50 iterations where ∼90 molecules were generated per iteration that satisfied the required singlet-triplet gap constraint, which was completed in 7 days on a 16-core CPU. I’d be very curious to know how many molecule were actually screened as part of the process. Anyway, ∼60 structures with a computed singlet-triplet gap-value of ∼0.3 eV that are predicted to emit in the blue region and to have reasonably high oscillator strengths. 

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Dehydro-Diels-Alder Reactions

Contributed by Steven Bacharach

Reposted from Computational Organic Chemistry with permission

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!

References

(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.

InChIs

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

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

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

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

5: InChI=1S/C4H2/c1-3-4-2/h1-2H
InChIKey=LLCSWKVOHICRDD-UHFFFAOYSA-N

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

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Direct Spectroscopic Evidence for an n→π* Interaction

Singh, S. K.; Mishra, K. K.; Sharma, N.; Das, A. Angew. Chem. Int. Ed. 2016, 55, 7801-7805
Contributed by Steven Bacharach
Reposted from Computational Organic Chemistry with permission

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 methylformate 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.

1cis

1trans

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.

References

(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.

InChIs

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

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