Diels-Alder reactions of some arenes

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

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.

References

(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.

Interesting chemistry of biphenalenylidene

Uncategorized Steven Bachrach 19 Apr 2016 No Comments

Uchida and co-workers reported on the preparation of biphenalenylidene 1 and its interesting electrocyclization to dihydroperopyrene 2.1 The experimental barrier they find by experiment for the conversion of 1-Z to 1-E is only 4.3 kcal mol-1. Secondly, the photochemical electrocyclization of 2-anti to 1-Z proceeds rapidly, through an (expected) allowed conrotatory pathway. However, the reverse reaction did not occur photochemically, but rather did occur thermally, even though this is formally forbidden by the Woodward-Hoffman rules.

To address these issues, they performed a number of computations, with geometries optimized at UB3LYP(BS)/6-31G**. First, CASSCF computations indicated considerable singlet diradical character for 1-Z. Both 1-Z and 1-E show significant twisting about the central double bond, consistent with the singlet diradical character. 1-Z is 1.8 kcal mol-1 lower in energy than 1-E, and the barrier for rotation interconverting these isomers is computed to be 7.0 kcal mol-1, in reasonable agreement with the experiment. These geometries are shown in Figure 1.

1-Z

1-E

TS (Z→E)

Figure 1. UB3LYP(BS)/6-31G** optimized geometries of 1-Z and 1- and the transition state to interconvert these two isomers.

The conrotatory electrocyclization that takes 1-Z into 2-anti has a barrier of 26.0 kcal mol-1 and is exothermic by 3.4 kcal mol-1. The disrotatory process has a higher barrier (34.2 kcal mol-1) and is endothermic by 8.4 kcal mol-1. These transition states and products are shown in Figure 2. So, despite being orbital symmetry forbidden, the conrotatory path is preferred, and this agrees with their experiments.

TS (con)

TS (dis)

2-anti

2-syn

Figure 2. UB3LYP(BS)/6-31G** optimized geometries of 2-anti and 2-syn and the transition states leading to them.

The authors argue that the large diradical character of 1 leads to both its low Z→E rotational barrier, and the low barrer for electrocyclization. The Woodward-Hoffmann allowed disrotatory barrier is inhibited by its highly strained geometry, making the conrotatory path the favored route.

References

(1) Uchida, K.; Ito, S.; Nakano, M.; Abe, M.; Kubo, T. "Biphenalenylidene: Isolation and Characterization of the Reactive Intermediate on the Decomposition Pathway of Phenalenyl Radical," J. Am. Chem. Soc. 2016, 138, 2399-2410, DOI: 10.1021/jacs.5b13033.

InChIs

1-E: InChI=1S/C26H16/c1-5-17-9-3-11-23-21(15-13-19(7-1)25(17)23)22-16-14-20-8-2-6-18-10-4-12-24(22)26(18)20/h1-16H/b22-21+
InChIKey=LOZZANITCNALJB-QURGRASLSA-N

1-Z: InChI=1S/C26H16/c1-5-17-9-3-11-23-21(15-13-19(7-1)25(17)23)22-16-14-20-8-2-6-18-10-4-12-24(22)26(18)20/h1-16H/b22-21-
InChIKey=LOZZANITCNALJB-DQRAZIAOSA-N

2-anti: InChI=1S/C26H18/c1-3-15-7-11-19-21-13-9-17-5-2-6-18-10-14-22(26(21)24(17)18)20-12-8-16(4-1)23(15)25(19)20/h1-14,19,21,25-26H/t19-,21-,25?,26?/m0/s1
InChIKey=BZIOOLOJBUBMSS-ATJINXRDSA-N

2-syn: InChI=1S/C26H18/c1-3-15-7-11-19-21-13-9-17-5-2-6-18-10-14-22(26(21)24(17)18)20-12-8-16(4-1)23(15)25(19)20/h1-14,19,21,25-26H/t19-,21+,25?,26?
InChIKey=BZIOOLOJBUBMSS-YXGNQKCYSA-N

Cyclization reaction of 1,2-cyclohexadiene

cycloadditions &Houk Steven Bachrach 11 Apr 2016 No Comments

1,2-Cyclohexadiene 1 is a very strained and highly reactive species. Houk, Garg and co-workers report on its use as the ene component in a cyclization with a 1,3-dipole, namely nitrones.1 For example, 1 reacts with nitrone 2 to give the cycloadducts 3a and 3b in a ratio of 8.9:1.

To investigate the mechanism of this reaction, they optimized the structures of all compounds at CPCM(acetonitrile)B3LYP/6-31G(d) and single-point energies were obtained using the B3LYP-D3 functional. The structures of some pertinent critical points are shown in Figure 1. They did locate a concerted transition state (TS1) leading to 3a, with a barrier of 14.5 kcal mol-1, but could not find a concerted TS leading to 3b. (Also, the barriers leading to the other regioisomer are much higher than the ones leading to the observed products.) Rather, they identified a stepwise transition state (TS2) with a barrier of nearly the same energy (14.4 kcal mol-1) that leads to the intermediate (INT), which lies 16.5 kcal mol-1 below reactants. They located two transition states from his intermediate, TS3a and TS3b, leading to the two different products. The barrier to 3a is 1.2 kcal mol-1 lower than the barrier leading to 3b, and this corresponds nicely with the observed diastereoselectivity.

1
(0.0)

TS1
(14.5)

TS2
(14.4)

 

INT
(-16.5)

 

TS3a
(-7.4)

TS3b
(-6.2)

Figure 1. CPCM(acetonitrile)B3LYP/6-31G(d) optimized geometries and CPCM(acetonitrile)B3LYP-D3/6-31G(d) free energies.

References

(1) Barber, J. S.; Styduhar, E. D.; Pham, H. V.; McMahon, T. C.; Houk, K. N.; Garg, N. K.
"Nitrone Cycloadditions of 1,2-Cyclohexadiene," J. Am. Chem. Soc. 2016, 138, 2512-2515, DOI: 10.1021/jacs.5b13304.

InChIs

1: InChI=1S/C6H8/c1-2-4-6-5-3-1/h1,5H,2,4,6H2
InChIKey=NMGSDTSOSIPXTN-UHFFFAOYSA-N

2: InChI=1S/C11H15NO/c1-11(2,3)12(13)9-10-7-5-4-6-8-10/h4-9H,1-3H3/b12-9-
InChIKey=IYSYLWYGCWTJSG-XFXZXTDPSA-N

3a: InChI=1S/C17H23NO/c1-17(2,3)18-16(13-9-5-4-6-10-13)14-11-7-8-12-15(14)19-18/h4-6,9-11,15-16H,7-8,12H2,1-3H3/t15-,16-/m0/s1
InChIKey=HQIBSHJEOJPFTI-HOTGVXAUSA-N

3b: InChI=1S/C17H23NO/c1-17(2,3)18-16(13-9-5-4-6-10-13)14-11-7-8-12-15(14)19-18/h4-6,9-11,15-16H,7-8,12H2,1-3H3/t15-,16+/m1/s1
InChIkey=HQIBSHJEOJPFTI-CVEARBPZSA-N

A linear acene with 13 rings

Aromaticity Steven Bachrach 04 Apr 2016 No Comments

Bunz and co-workers have synthesized the novel aromatic compound 1 that contains 13 acenes in a row.1

They optimized the geometry of 1 at B3LYP/6-311G*, and its geometry is shown in Figure 1. Even though this compound has quite an extensive π-system, an unrestricted computations collapses to the closed-shell wavefunction.

1

Figure 1. B3LYP/6-311G* optimized geometry of 1. (As always, don’t forget to click on this image to launch JMol and visualize the molecule in 3-D.)

NICS(1)πzz values for the rings are given in Table 1. Interestingly, the aromaticity of the coronene moiety is reduced; in fact the central ring (ring A, with rings labeled sequentially working towards either end from the center) has a very small NICS value of only -3.77.

Table 1. NICS(1)πzz values for the rings of 1.

Ring

NICS(1)πzz

A
B
C
D
E
F
G
H

-3.7
-12.2
-27.7
-28.7
-35.8
-36.1
-40.5
-29.8

References

(1) Endres, A. H.; Schaffroth, M.; Paulus, F.; Reiss, H.; Wadepohl, H.; Rominger, F.; Krämer, R.; Bunz, U. H. F. "Coronene-Containing N-Heteroarenes: 13 Rings in a Row," J. Am. Chem. Soc. 2016, 138, 1792-1795, DOI: 10.1021/jacs.5b12642.

InChIs

1: InChI=1S/C100H76N8O4Si4/c1-49(2)56-31-24-32-57(50(3)4)75(56)84-95(111)72-47-68-80-78-66(89-91(68)107-99-97(105-89)101-85-58(33-37-113(5,6)7)62-41-52-27-20-22-29-54(52)43-64(62)60(87(85)103-99)35-39-115(11,12)13)45-70-76-71(94(110)74(93(70)109)51-25-18-17-19-26-51)46-67-79(82(76)78)81-69(48-73(96(84)112)77(72)83(80)81)92-90(67)106-98-100(108-92)104-88-61(36-40-116(14,15)16)65-44-55-30-23-21-28-53(55)42-63(65)59(86(88)102-98)34-38-114(8,9)10/h17-32,41-50,74,84H,1-16H3
InChIKey=GNQHLGPUXJMSCH-UHFFFAOYSA-N

1,3,5-Trifluorenylcyclohexane

Uncategorized Steven Bachrach 28 Mar 2016 No Comments

Reid, Rathore and colleagues report on the attempted preparation of the interesting molecule 1,3,5-trifluorenylcyclohexane (TFC) 1.1 They had hoped to prepare it by subjecting the precursor 2 to acid, which might then undergo a Friedel-Crafts reaction to prepare the last fluorenyl group, and subsequent loss of a proton would give 1. Unfortunately, they could not get this step to occur, even at high temperature and for long reaction times. What made it particularly frustrating was that they could get 3 to react under these conditions to give 1,4-difluorenylcyclohexane (14-DFC) 4, and convert 5 into 1,4-difluorenylcyclohexane (13-DFC) 6.

To get at why 1 could not be formed they utilized PCM(CH2Cl2)/M06-2X/6-31G(d) calculations. The lowest energy conformations of 1 and 4 are shown in Figure 1. While 4 is in a chair conformation, 1 is not in a chair conformation since this would bring the three fluorenyl groups into very close contact. Instead, the cyclohexyl ring of 1 adopts a twist-boat conformation, with a much flattened ring. They estimate that 1 is strained by about 17 kcal mol-1, with 10 kcal mol-1 coming from strain in the twist-boat conformation and another 7 kcal mol-1 of strain due to steric crowding of the fluorenyl groups.

They next optimized the structures of the intermediates and transition states on the path taking 2 into 1 and 3 into 4. The transition states of the Friedel-Crafts reaction are the highest points on these paths, and their geometries are shown in Figure 1. The barrier through the TS for the Friedel-Crafts step forming 1 is about 17 kcal mol-1 higher than for the barrier to form 4. This very large increase in activation barrier, due to the strains imposed by that third fluorenyl group, explains the lack of reaction. Furthermore, since the reaction 21 is 2.0 kcal mol-1 endothermic, at high temperature the reaction is likely to be reversible and favors 2.

1

4

TS to 1

TS to 4

Figure 1. PCM(CH2Cl2)/M06-2X/6-31G(d) optimized geometries.

References

(1) Talipov, M. R.; Abdelwahed, S. H.; Thakur, K.; Reid, S. A.; Rathore, R. "From Wires to Cables: Attempted Synthesis of 1,3,5-Trifluorenylcyclohexane as a Platform for Molecular Cables," J. Org. Chem. 2016, DOI: 10.1021/acs.joc.5b02792.

InChIs

1 (TFC): InChI=1S/C42H30/c1-7-19-34-28(13-1)29-14-2-8-20-35(29)40(34)25-41(36-21-9-3-15-30(36)31-16-4-10-22-37(31)41)27-42(26-40)38-23-11-5-17-32(38)33-18-6-12-24-39(33)42/h1-24H,25-27H2
InChIKey=CXXRVQFQMRJLAI-UHFFFAOYSA-N

4 (14-DFC): InChI=1S/C30H24/c1-5-13-25-21(9-1)22-10-2-6-14-26(22)29(25)17-19-30(20-18-29)27-15-7-3-11-23(27)24-12-4-8-16-28(24)30/h1-16H,17-20H2
InChIkey=ZZTDGVHNROVFMK-UHFFFAOYSA-N

6 (13-DFC):InChI=1S/C30H24/c1-2-11-22(12-3-1)24-14-4-5-15-25(24)23-13-10-20-30(21-23)28-18-8-6-16-26(28)27-17-7-9-19-29(27)30/h1-9,11-19H,10,20-21H2
InChIKey=TTZIUDUAWUTKAI-UHFFFAOYSA-N

FEP study

FEP Steven Bachrach 21 Mar 2016 No Comments

The ACS National Meeting this week in San Diego had computers in chemistry as its theme. A number of sessions featured computer-aided drug design, and the paper that garnered a lot of attention in many of these sessions was one I missed from last year. The work, done by the Schrödinger company, presents the application of some improved techniques for performing free energy perturbation (FEP) computations.1 FEP involves changing a small number of atoms from one type to another and determining the free energy change with this perturbation. Since so much of the system is left unaffected, the idea is that errors in the non-perturbed parts of the system will cancel, allowing for accurate determination of the free energy change due to the perturbation.

This study features a number of new technologies that have enabled much more accurate predictions. First, they have employed a new force field, OPLS2.1, which appears to provide much improved energies. Second, they have improved sampling of configuration space using the Desmond program and replica exchange with solute tempering (REST). Third, these have been implemented on GPUs that results in dramatically improved throughput. And fourth, they developed a workflow to automate the selection of ligands, created by the perturbations with the protein of interest. They examined up to 10 atom perturbations within the initial ligand.

In a validation study of 8 proteins involving 330 ligands, the RMS error in the free energy of binding was about 1 kcal mol-1. Case studies of different types of perturbations leading to gain or loss of hydrophobic or electrostatic interactions, loss of a binding water and exposure to solvent are detailed. Lastly, in a study of two new proteins, they report a high success in predicting both strong binders and weak binders, with very few false positives.

References

(1) Wang, L.; Wu, Y.; Deng, Y.; Kim, B.; Pierce, L.; Krilov, G.; Lupyan, D.; Robinson, S.; Dahlgren, M. K.; Greenwood, J.; Romero, D. L.; Masse, C.; Knight, J. L.; Steinbrecher, T.; Beuming, T.; Damm, W.; Harder, E.; Sherman, W.; Brewer, M.; Wester, R.; Murcko, M.; Frye, L.; Farid, R.; Lin, T.; Mobley, D. L.; Jorgensen, W. L.; Berne, B. J.; Friesner, R. A.; Abel, R. "Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field," J. Am. Chem. Soc. 2015, 137, 2695-2703, DOI: 10.1021/ja512751q.

Mechanism of organocatalysis by Cinchona alkaloids

Houk &Michael addition &stereoinduction Steven Bachrach 03 Mar 2016 No Comments

Cinchona alkaloids cat catalyze reactions, such as shown in Reaction 1. Wynberg1 proposed a model to explain the reaction, shown in Scheme 1, based on NMR. Grayson and Houk have now used DFT computations to show that the mechanism actually reverses the arrangements of the substrates.2

Reaction 1

Scheme 1.


Wynberg Model


Grayson and Houk Model

M06-2X/def2-TZVPP−IEFPCM(benzene)//M06-2X/6-31G(d)−IEFPCM(benzene) computations show that the precomplex of catalyst 3 with nucleophile 1 and Michael acceptor 2 is consistent with Wynberg’s model. The alternate precomplex is 5.6 kcal mol-1 higher in energy. These precomplexes are shown in Figure 1.

Wynberg precomplex

Grayson/Houk precomplex

Figure 1. Precomplexes structures

However, the lowest energy transition state takes the Grayson/Houk pathway and leads to the major isomer observed in the reaction. The Grayson/Houk TS that leads to the minor product has a barrier that is 3 kcal mol-1 higher in energy. The lowest energy TS following the Wynberg path leads to the minor product, and is 2.2 kcal mol-1 higher than the Grayson/Houk path. These transition states are shown in Figure 2. The upshot is that complex formation is not necessarily indicative of the transition state structure.

Wynberg TS (major)
Rel ΔG = 5.3

Wynberg TS (minor)
Rel ΔG = 2.2

Grayson/Houk TS (major)
Rel ΔG = 0.0

Grayson/Houk TS (minor)
Rel ΔG = 3.0

Figure 2. TS structures and relative free energies (kcal mol-1).

References

(1) Hiemstra, H.; Wynberg, H. "Addition of aromatic thiols to conjugated cycloalkenones, catalyzed by chiral .beta.-hydroxy amines. A mechanistic study of homogeneous catalytic asymmetric synthesis," J. Am. Chem. Soc. 1981, 103, 417-430, DOI: 10.1021/ja00392a029.

(2) Grayson, M. N.; Houk, K. N. "Cinchona Alkaloid-Catalyzed Asymmetric Conjugate Additions: The Bifunctional Brønsted Acid–Hydrogen Bonding Model," J. Am. Chem. Soc. 2016, 138, 1170-1173, DOI: 10.1021/jacs.5b13275.

InChIs

1: InChI=1S/C10H14S/c1-10(2,3)8-4-6-9(11)7-5-8/h4-7,11H,1-3H3
InChIKey=GNXBFFHXJDZGEK-UHFFFAOYSA-N

2: InChI=1S/C8H12O/c1-8(2)5-3-4-7(9)6-8/h3-4H,5-6H2,1-2H3
InChIKey=CDDGRARTNILYAB-UHFFFAOYSA-N

3: InChI=1S/C18H22N2O/c1-12-11-20-9-7-13(12)10-17(20)18(21)15-6-8-19-16-5-3-2-4-14(15)16/h2-6,8,12-13,17-18,21H,7,9-11H2,1H3/t12?,13?,17?,18-/m1/s1
InChIKey=ZOZLJWFJLBUKKL-NKHWWFDVSA-N

4: InChI=1S/C18H26OS/c1-17(2,3)13-6-8-15(9-7-13)20-16-10-14(19)11-18(4,5)12-16/h6-9,16H,10-12H2,1-5H3/t16-/m0/s1
InChIKey=XUTYYZOSKLYWLW-INIZCTEOSA-N

Calculating large fullerenes

fullerene Steven Bachrach 22 Feb 2016 4 Comments

What is the size of a molecule that will stretch computational resources today? Chan and co-workers have examined some very large fullerenes1 to both answer that question, and also to explore how large a fullerene must be to approach graphene-like properties.

They are interested in predicting the heat of formation of large fullerenes. So, they benchmark the heats of formation of C60 using four different isodesmic reactions (Reaction 1-4), comparing the energies obtained using a variety of different methods and basis sets to those obtained at W1h. The methods include traditional functionals like B3LYP, B3PW91, CAM-B3LYP, PBE1PBE, TPSSh, B98, ωB97X, M06-2X3, and MN12-SX, and supplement them with the D3 dispersion correction. Additionally a number of doubly hybrid methods are tested (again with and without dispersion corrections), such as B2-PLYP, B2GPPLYP, B2K-PLYP, PWP-B95, DSD-PBEPBE, and DSD-B-P86. The cc-pVTZ and cc-pVQZ basis sets were used. Geometries were optimized at B3LYP/6-31G(2df,p).

C60 + 10 benzene → 6 corannulene

Reaction 1

C60 + 10 naphthalene → 8 corannulene

Reaction 2

C60 + 10 phenanthrene → 10 corannulene

Reaction 3

C60 + 10 triphenylene → 12 corannulene

Reaction 4

Excellent results were obtained with DSD-PBEPBE-D3/cc-pVQZ (an error of only 1.8 kJ/mol), though even a method like BMK-D3/cc-pVTZ had an error of only 9.2 kJ/mol. They next set out to examine large fullerenes, including such behemoths as C180, C240, and C320, whose geometries are shown in Figure 1. Heats of formation were obtained using isodesmic reactions that compare back to smaller fullerenes, such as in Reaction 5-8.

C70 + 5 styrene → C60 + 5 naphthalene

Reaction 5

C180 → 3 C60

Reaction 6

C320 + 2/3 C60 → 2 C180

Reaction 7

C180

C240

C320

Figure 1. B3LYP/6-31G(2df,p) optimized geometries of C180, C240, and C320. (Don’t forget that clicking on these images will launch Jmol and allow you to manipulate the molecules in real-time.)

Next, taking the heat of formation per C for these fullerenes, using a power law relationship, they were able to extrapolate out the heat of formation per C for truly huge fullerenes, and find the truly massive fullerenes, like C9680, still have heats of formation per carbon 1 kJ/mol greater than for graphene itself.

References

(1) Chan, B.; Kawashima, Y.; Katouda, M.; Nakajima, T.; Hirao, K. "From C60 to Infinity: Large-Scale Quantum Chemistry Calculations of the Heats of Formation of Higher Fullerenes," J. Am. Chem. Soc. 2016, 138, 1420-1429, DOI: 10.1021/jacs.5b12518.

Atropisomerization within a cyclic compound

Stereochemistry Steven Bachrach 10 Feb 2016 1 Comment

Atropisomers are stereoisomer that differ by axial symmetry, such as in substituted biphenyls or allenes. These acyclic systems have received a fair amount of attention, but now Buevich has looked at atropisomerization that occurs in a ring system.1 1 has a biphenyl as part of the eight-member ring, and the biphenyl can exist in either an M or P orientation. Since C3 is chiral (S), the two isomers are (M,S)-1 and (P,S)-1. Variable temperature NMR analysis concludes that (P,S)-1 is 1.19 kcal mol-1 more stable than (M,S)-1, and the barrier for the interchange (P,S)-1 → (M,S)-1 is 26.77 kcal mol-1.

To identify the process for this atropisomerization process, he utilized B3LYP/6-31G(d) computations of the model system 2. A variety of different techniques were used to identify the local energy minimum conformations of both (M,S)-2 and (P,S)-2, and the lowest energy conformers (M1 for (P,S)-2 and M4 for (M,S)-2) are shown in Figure 1. He then produced a series of 2-D potential energy surfaces varying two of the dihedral angles defining the eight-member ring to help identify potential initial geometries for searching for transition states. (As an aside, this procedure ended up identifying a few additional local energy minima not identified in the initial conformational search – and these all have trans amide groups instead of the cis relationship found initially. These trans isomer are considerably higher in energy than the conformers.) With this model and this computational level, (P,S)-2 is 0.76 kcal mol-1 lower in energy than (M,S)-2.

M1
0.0




TS1
3.54




M2
2.21




TS4
25.83




M4
0.76

 

Table 1. B3LYP/6-31G(d) optimized geometries and relative free energies of some critical points along the lowest energy pathway taking (P,S)-2 → (M,S)-2.

A number of transition states were identified, and the lowest energy pathway that takes M1 into M4 first crosses TS1 to make the minimum M2, which than passes a high barrier (25.8 kcal mol-1) to go to M4. This barrier is in reasonable agreement with the experimental barrier for 1. These TSs are also shown in Figure 1.

Buevich analyzes the conformational process by examination of the changes in the ring dihedral angles following this reaction path. As expected, crossing the highest barrier requires a combination of torsional rotations, but essentially one at a time moving clockwise about the ring.

References

(1) Buevich, A. V. "Atropisomerization of 8-Membered Dibenzolactam: Experimental NMR and Theoretical DFT Study," J. Org. Chem. 2016, 81, 485–501 DOI: 10.1021/acs.joc.5b02321.

InChIs

1: InChI=1S/C27H26N2O/c1-3-12-26-27(30)29(20-21-13-6-5-7-14-21)25-18-11-9-16-23(25)22-15-8-10-17-24(22)28(26)19-4-2/h3-11,13-18,26H,1-2,12,19-20H2/t26-/m0/s1
InChIKey=IYYACMIVKDJSJD-SANMLTNESA-N

2: InChI=1S/C17H18N2O/c1-12-17(20)19(3)16-11-7-5-9-14(16)13-8-4-6-10-15(13)18(12)2/h4-12H,1-3H3/t12-/m0/s1
InChIKey=NIBPKKMKNFOPRM-LBPRGKRZSA-N

QM/MM trajectory of an aqueous Diels-Alder reaction

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

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.

References

(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.

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