Archive for the 'Reactions' Category

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.

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.

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

Cyclization reaction of 1,2-cyclohexadiene

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

cycloadditions &Houk Steven Bachrach 11 Apr 2016 No Comments

Mechanism of organocatalysis by Cinchona alkaloids

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

Houk &Michael addition &stereoinduction Steven Bachrach 03 Mar 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.

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.

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

[5]Radialene

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).

1

TS

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.

References

(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.

InChIs

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

Diels-Alder Steven Bachrach 07 Dec 2015 No Comments

Dynamics in the reaction of tetrazine with cyclopropene

Houk and Doubleday report yet another example of dynamic effects in reactions that appear to be simple, ordinary organic reactions.1 Here they look at the Diels-Alder reaction of tetrazine 1 with cyclopropene 2. The reaction proceeds by first crossing the Diels-Alder transition state 3 to form the intermediate 4. This intermediate can then lose the anti or syn N2, through 5a or 5s, to form the product 6. The structures and relative energies, computed at M06-2X/6-31G(d), of these species are shown in Figure 1.

3
17.4

4
-33.2

5a
-28.9

5s
-20.0

6
-86.2

Figure 1. M06-2X/6-31G(d) optimized geometries and energies (relative to 1 + 2) of the critical points along the reaction of tetrazine with cyclopropene.

The large difference in the activation barriers between crossing 5a and 5s (nearly 9 kcal mol-1) suggests, by transition state theory, a preference of more than a million for loss of the anti N2 over the syn N2. However, quasiclassical trajectory studies, using B3LYP/6-31G(d), finds a different situation. The anti pathway is preferred, but only by a 4:1 ratio! This dynamic effect arises from a coupling of the v3 mode which involves a rocking of the cyclopropane ring that brings a proton near the syn N2 functionality, promoting its ejection. In addition, the trajectory studies find short residence times within the intermediate neighborhood for the trajectories that lead to the anti product and longer residence times for the trajectories that lead to the syn product. All together, a very nice example of dynamic effects playing a significant role in a seemingly straightforward organic reaction.

References

(1) Törk, L.; Jiménez-Osés, G.; Doubleday, C.; Liu, F.; Houk, K. N. "Molecular Dynamics of the Diels–Alder Reactions of Tetrazines with Alkenes and N2 Extrusions from Adducts," J. Am. Chem. Soc. 2015, 137, 4749-4758, DOI: 10.1021/jacs.5b00014.

InChIs

1: InChI=1S/C2H2N4/c1-3-5-2-6-4-1/h1-2H
InChIKey=HTJMXYRLEDBSLT-UHFFFAOYSA-N

2: InChI=1S/C3H4/c1-2-3-1/h1-2H,3H2
InChIKey=OOXWYYGXTJLWHA-UHFFFAOYSA-N

4: InChI=1S/C5H6N4/c1-2-3(1)5-8-6-4(2)7-9-5/h2-5H,1H2
InChIKey=JGSMBFYJCNPYDM-UHFFFAOYSA-N

6: InChI=1S/C5H6N2/c1-4-2-6-7-3-5(1)4/h2-5H,1H2
InChIKey=RYJFHKGQZKUXEH-UHFFFAOYSA-N

Diels-Alder &Dynamics &Houk Steven Bachrach 09 Nov 2015 No Comments

Diels-Alder of yne-diyne species

Cramer, Hoye, Kuwata and coworkers have examined the intramolecular cyclization of an alkyne with a diyne.1 Their model system is 1, which can cyclize through a concerted transition state TSC togive the benzyne product 2, or it can proceed through a stepwise pathway, first going through TS1 to form the intermediate INT¸ before traversing through a second transition state TS2 and on to product 2. Using both computations and experiments, they examined a series of compounds with
differing substituents at the ends of the two yne moieties.

The experiments show almost the exact same rate of reaction regardless of the terminal substituents. This includes the parent case where the terminal substituents are hydrogens and also the case where the terminal substituents (which end up on adjacent centers on the benzyne ring) are bulky TMS groups. And though there is no real rate effect due to changes in solvent or the presence of light or triplet oxygen, which suggest a concerted reaction, these substituent effects argue for a step wise reaction.

SMD(o-dichlorobenzene)/B3LYP-D3BJ/6-311+G-(d,p)//M06-2X/6-311+G(d,p)
computations help explain these observations. Shown in Figure 1 are the optimized geometries and relative energies of the critical points on the reaction surface for the conversion of 1 into 2, and these results are similar with the other substituents as well.

1
(0.0)

2
(-56.9)

TSC
(31.5)

 

TS1
(25.5)

INT
(18.8)

TS2
(18.1)

 

Figure 1. SMD(o-dichlorobenzene)/B3LYP-D3BJ/6-311+G-(d,p)//M06-2X/6-311+G(d,p) optimized geometries and relative energies (kcal mol-1).

The first thing to note is that the concerted TSC is higher in energy than the stepwise TS1. The wavefunction for TSC unstable towards moving from a restricted to unrestricted formalism. Reoptimization of some of these concerted TSs actually led to the stepwise TS.

The next item of note is that TS2 for this case is actually lower in energy than the intermediate (this is a true TS on the energy surface, but when zero-point energy and other thermal corrections are included, it becomes lower in energy than INT). For some of the cases the second TS lies above the intermediate, but typically by a small amount.

Therefore, the mechanism of this reaction is stepwise, but the second step might have such a small barrier (or even no barrier) that one might consider this to be concerted, though highly asymmetric and really bearing little resemblance to more traditional concerted pericyclic reactions.

The authors obliquely hinted at some potential interesting dynamics. I suspect that molecular dynamics calculations will show no effect of that second TS, and one might observe some interesting dynamics, which could be seen in kinetic isotope experiments.

References

(1)  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 ASAP, DOI: 10.1021/acs.joc.5b01356.

InChIs

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

2: InChI=1S/C8H4O2/c9-8-7-4-2-1-3-6(7)5-10-8/h2,4H,5H2
InChIKey=MYFORDRJCVOBTH-UHFFFAOYSA-N

Cramer &Diels-Alder &diradicals Steven Bachrach 05 Oct 2015 2 Comments

Dynamics in the Wittig reaction

If you hadn’t noticed, I am a big fan of the work that Dan Singleton is doing concerning the role of dynamics in discerning reaction mechanisms. Dan’s group has reported another outstanding study combining experiments, traditional QM computations, and molecular dynamics – this time on the Wittig reaction.1

The key question concerning the mechanism is whether a betaine intermediate is accessed along the reaction (path A) or whether the reaction proceeds in a concerted manner (path B). Earlier computations had supported the concerted pathway (B).

Experimental determination of the heavy atom kinetic isotope effect was made for Reaction 1.

Reaction 1

Using the 6-31+G(2df,p) basis set, three different density functionals predict three different potential energy surfaces. With M06-2x, the surface indicates path A (stepwise), with the first step rate-limiting. B3P86 also predicts the stepwise reaction, but the second step is rate-limiting. The Lc-wPBE functional predicts a concerted reaction. Using these surfaces, they predicted the carbon isotope effect and compared it to the experimental values. The best agreement is with the M06-2x surface with a weighting of the vibrational energies of the two different TSs. The optimized structures of the two transition states, the betaine intermediate, and the product are shown in Figure 1.

TS1

Betaine

TS2

Product

Figure 1. M06-2x/6-31+G(2df,p) optimized geometry of the critical points of Reaction 1.

The agreement of the predicted and experimental KIE is not ideal. So, they performed molecular dynamics computations with the ONIOM approach using M06-2x/6-31G* for Reaction 1 and 53 THF molecules treated at PM3. 360 trajectories were begun in the region of the first transition state (TS1), and they can be organized into 4 groups. The first group (128 trajectories) are reactions that produce product. The second group (76 cases) form the C-C bond but then it ruptures and returns to reactant. The third group (82 cases) have an immediate recrossing back to reactant, and the last group (16 cases) takes product back to the first TS and then returns to product. The predicted KIE using this weighted MD results gives values in outstanding agreement with the experiments.

Of the first group, about 50% pass from TS1 to TS2 in less than 150 fs, or in other words look like a concerted path. But a good number of trajectories reside in the betaine region for 1-2 ps.

In contrast, trajectories initiated from the betaine with equilibrated THF molecules indicate a median of 600 ps to travel from TS1 to TS2 and do not resemble a concerted path.

They argue that this bimodal distribution is in part associated with a solvent effect. When the first TS is crossed the solvent molecules are not equilibrated about the solute, and 10-20% of the trajectories immediately pass through the betaine region due to “dynamic matching” where the entering motion matches with exiting over the second transition state. The longer trajectories result from improper dynamic matching, but faster motion in the solute than motion amongst the solvent needed to stabilize the betaine. So, not only do we need to be concerned about dynamic effects involving the reactants, we need to be concerned about dynamics associated with the solvent too!

References

(1) Chen, Z.; Nieves-Quinones, Y.; Waas, J. R.; Singleton, D. A. "Isotope Effects, Dynamic Matching, and Solvent Dynamics in a Wittig Reaction. Betaines as Bypassed Intermediates," J. Am. Chem. Soc. 2014, 136, 13122-13125, DOI: 10.1021/ja506497b.

Singleton &Wittig Steven Bachrach 18 Nov 2014 No Comments

Diels-Alder reactions of Fullerene

Diels-Alder reaction involving fullerenes have been known for some time. They occur across the [6,6] double bond of C60, the one between two fused 6-member rings. Houk and Briseno report on the Diels-Alder reaction of C60 with pentacene 1 and bistetracene 2 and compare their computations with experiments.1


Pentacene and bistetracene ring numbering convention

Computations were performed for the reaction of 1 and 2 with C60 at M06-2x/6-31G(d)//M062x-3-21G*. The reaction can occur with the dienophile being either ring 1, 2, or 3 of pentacene and ring 1, 2, 3, or 4 of bistetracene. They located TSs and products for all of these possibilities. Select TSs and products are shown in Figure 1.

For the reaction of 1a, the lowest energy TS is for the reaction at the central ring (ring 3), and the resulting product is the lowest energy product. The transition state (PT_TS3) is shown in Figure 1. This TS has the least distortion energy of the three possibilities, because reacting at this central ring destroys the least amount of aromaticity of pentacene. For the reaction of 1b, the lowest barrier is again for reaction of ring 3 (through TMSPT_TS3). However, the product from the reaction with ring 2 (TMSPT_P2) is lower in free energy than TMSPT­_P3, likely caused by steric interactions with the silyl substituents. This actually matches up with experiments which indicate that an analogue of TMSPT_P2 is the kinetic product but TMSPT_P3 is the thermodynamic product.

PT_TS3

TMSPT_­TS3

TMSPT_P2

TMSPT_P3

BT_TS2

BT_P2

Figure 1. M06-2x/3-21G* optimized geometries.
(Once again a reminder that clicking on any of these structures will launch JMol and you’ll be able to visualize and manipulate this structure in 3-D.)

The computations involving the Diels-Alder reaction of C60 with either 2a or 2b come to the same conclusion. In both cases, the lowest barrier is for the reaction at ring 2, and the product of the reaction at this same ring is the only one that is endoergonic. The geometries of BT_TS2 and BT_P2 are shown in Figure 1. More importantly, the barrier for the Diels-Alder reaction involving 2a and 2b are at least 6 kcal mol-1 higher than the barriers for the reaction of 1a and 1b, in complete agreement with experiments that show little reaction involving analogues of 2b with C60, while analogues of 1b are reasonably rapid.

References

(1) Cao, Y.; Liang, Y.; Zhang, L.; Osuna, S.; Hoyt, A.-L. M.; Briseno, A. L.; Houk, K. N. "Why Bistetracenes Are Much Less Reactive Than Pentacenes in Diels–Alder Reactions with Fullerenes," J. Am. Chem. Soc. 2014, 136, 10743-10751, DOI: 10.1021/ja505240e.

Diels-Alder &fullerene &Houk Steven Bachrach 29 Sep 2014 No Comments

Organocatalytic Enantioselective Michael Addition

Computational techniques are gaining some traction in helping to understand enantioselective organocatalysis. I talk about a few examples in Chapter 6.3 of my book. Lambert and Vetticatt have now used computations to help understand the role of the catalyst 4 in the Michael addition shown in Scheme 1.1 This reaction proceeds with 99% yield and an ee of 98%.

Scheme 1.

13C kinetic isotope effect studies suggest that the rate determining step is the C-C bond formation (the Michael addition step) which follows the deprotonation of the imine 1 by the catalyst 4.

They performed ONIOM computations to search for transition states of this rate limiting step for the reaction in Scheme 1, using the full molecules. From this ONIOM search, the energies for all transition structures with 5 kcal mol-1 of the lowest energy structure were then obtained at B3LYP/6-31G*. The three lowest energy TS are shown in Figure 1. The two lowest energy structures lead to the major enantiomer, while the third lowest energy structure leads to the minor enantiomer. These energies lead to a prediction of an ee of 92%, in reasonable agreement with the experiment. The computed kinetic isotope effects are in nice agreement with experiment, supporting this step as the overall rate limiting step.

TSs leading to the S isomer

TS1
(0.0)

TS2
(0.9)

TS leading to the R isomer

TS3
(1.7)

Table 1. ONIOM optimized geometries of the three lowest energy TSs. Relative energy (kcal mol-1) in parenthesis.

Analysis of what factors are important in determining the ee is complicated and ultimately the authors are unable to provide a simple explanation. They properly note that

The observation that the major enantiomer (S) is formed from two very geometrically distinct transition structures … suggests that the prediction of enantioselectivity for other reactions … will require a full consideration of all possible transition state assemblies. (emphasis mine)

I agree with this sentiment, pessimistic as it may be. Answering this type of question is likely to remain very challenging for years to come.

References

1) Bandar, J. S.; Sauer, G. S.; Wulff, W. D.; Lambert, T. H.; Vetticatt, M. J. "Transition State Analysis of Enantioselective Brønsted Base Catalysis Chiral Cyclopropenimines," J. Am. Chem. Soc. 2014, 136, 10700-10707, DOI: 10.1021/ja504532d.

InChIs

1: InChI=1S/C20H23NO/c1-20(2,3)14-18(22)15-21-19(16-10-6-4-7-11-16)17-12-8-5-9-13-17/h4-13H,14-15H2,1-3H3
InChIKey=UZCWUGCTNCNJHI-UHFFFAOYSA-N

2: InChI=1S/C4H6O2/c1-3-4(5)6-2/h3H,1H2,2H3
InChIKey=BAPJBEWLBFYGME-UHFFFAOYSA-N

3: InChI=1S/C24H29NO3/c1-24(2,3)17-21(26)20(15-16-22(27)28-4)25-23(18-11-7-5-8-12-18)19-13-9-6-10-14-19/h5-14,20H,15-17H2,1-4H3/t20-/m0/s1
InChIKey=KTASCPHNNZODSX-FQEVSTJZSA-N

4: InChI=1S/C37H57N3/c1-2-30(28-29-18-8-3-9-19-29)38-35-36(39(31-20-10-4-11-21-31)32-22-12-5-13-23-32)37(35)40(33-24-14-6-15-25-33)34-26-16-7-17-27-34/h3,8-9,18-19,30-34H,2,4-7,10-17,20-28H2,1H3/t30-/m1/s1
InChIKey=GEHSIGXXLTVFFG-SSEXGKCCSA-N

Michael addition Steven Bachrach 08 Sep 2014 No Comments

Next Page »