Archive for the 'Reactions' Category

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

Fused aromatic ring effect on electrocyclization reactions

Aromaticity and orbital symmetry rules, though seemingly of ancient origin, remain areas of active interest. This paper by Fukazawa, et al combine both issues.1 The multiple-step electrocyclization of 1 gives 2 in a reaction that takes 9 days at 80 °C. What would be the effect of diminishing the aromatic character of the fused rings of 1? Would the reaction be faster or slower?

Before discussing the experimental results, let’s examine the B3LYP/6-31G(d) results for the reaction of 1’, 3 and 5. (Note that a slightly smaller pendant substituent is used in the computations than in the experiment.) The optimized geometries of the critical points along the reaction pathway for the cyclization of 3 are shown in Figure 1.

3
(0.0)

3-TS1
(17.9)

3-INT
(10.4)

3-TS2
(13.3)

4
(-60.7)

Figure 1. B3LYP/6-31G(d) optimized geometries and relative energies (kcal mol-1) for the critical points along the reaction 34.
Remember that all structures on my blog can be viewed interactively by clicking on the image of the molecule.

For 1’, the first barrier (for the 8π cyclization) has a barrier of about 23 kcal mol-1, but the second step (the 4π cyclization) has an even larger barrier of 28 kcal mol-1. However, reducing the aromaticity of one of the fused rings (compound 3) leads to lower barriers of 18 and 13 kcal mol-1. For the cyclization of 5, only a single transition state was found – no intermediate and no second TS – with a barrier of 12 kcal mol-1. Thus, removing these external aromatic rings reduces the barrier of the reaction, and that is exactly what is found experimentally!

References

(1) Fukazawa, A.; Oshima, H.; Shimizu, S.; Kobayashi, N.; Yamaguchi, S. "Dearomatization-Induced Transannular Cyclization: Synthesis of Electron-Accepting Thiophene-S,S-Dioxide-Fused Biphenylene," J. Am. Chem. Soc. 2014, 136, 8738-8745, DOI: 10.1021/ja503499n.

InChIs:

1: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)37-25-29-30-26-38(50(15,16)42(4,5)6)46-34(30)23-24-36-32(28-40(48-36)52(19,20)44(10,11)12)31-27-39(51(17,18)43(7,8)9)47-35(31)22-21-33(29)45-37/h25-28H,1-20H3/b30-29-,32-31-
InChIKey=OCNQBMWQONUVNH-IOYDOZLVSA-N

1’:InChI=1S/C32H40S4Si4/c1-37(2,3)29-17-21-22-18-30(38(4,5)6)34-26(22)15-16-28-24(20-32(36-28)40(10,11)12)23-19-31(39(7,8)9)35-27(23)14-13-25(21)33-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=GTFPBRMBCLREPG-ICHHBZPXSA-N

2: InChI=1S/C44H64S4Si4/c1-41(2,3)49(13,14)29-21-25-26-22-30(50(15,16)42(4,5)6)46-38(26)34-33(37(25)45-29)35-36(34)40-28(24-32(48-40)52(19,20)44(10,11)12)27-23-31(47-39(27)35)51(17,18)43(7,8)9/h21-24H,1-20H3
InChIKey=OTDXAOVIIQYYNV-UHFFFAOYSA-N

2’: InChI=1S/C32H40S4Si4/c1-37(2,3)21-13-17-18-14-22(38(4,5)6)34-30(18)26-25(29(17)33-21)27-28(26)32-20(16-24(36-32)40(10,11)12)19-15-23(35-31(19)27)39(7,8)9/h13-16H,1-12H3
InChIKey=IYZNCPPDTHWWCO-UHFFFAOYSA-N

3: InChI=1S/C32H40O2S4Si4/c1-39(2,3)29-17-21-22-18-30(40(4,5)6)37-27(22)15-16-28-24(20-32(38(28,33)34)42(10,11)12)23-19-31(41(7,8)9)36-26(23)14-13-25(21)35-29/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=ZJBDGDJVLGNVOD-ICHHBZPXSA-N

4: InChI=1S/C32H40O2S4Si4/c1-39(2,3)21-13-17-18-14-22(40(4,5)6)36-30(18)26-25(29(17)35-21)27-28(26)32-20(16-24(38(32,33)34)42(10,11)12)19-15-23(37-31(19)27)41(7,8)9/h13-16H,1-12H3
InChIKey=QUSJUOMZBJUGON-UHFFFAOYSA-N

5: InChI=1S/C32H40O8S4Si4/c1-45(2,3)29-17-21-22-18-30(46(4,5)6)42(35,36)26(22)15-16-28-24(20-32(44(28,39)40)48(10,11)12)23-19-31(47(7,8)9)43(37,38)27(23)14-13-25(21)41(29,33)34/h17-20H,1-12H3/b22-21-,24-23-
InChIKey=NNZTUSIYEPMHMP-ICHHBZPXSA-N

6: InChI=1S/C32H40O8S4Si4/c1-45(2,3)21-13-17-18-14-22(46(4,5)6)42(35,36)30(18)26-25(29(17)41(21,33)34)27-28(26)32-20(16-24(44(32,39)40)48(10,11)12)19-15-23(47(7,8)9)43(37,38)31(19)27/h13-16H,1-12H3
InChIKey=JZHQQYXUIQXWLQ-UHFFFAOYSA-N

Aromaticity &electrocyclization Steven Bachrach 22 Jul 2014 1 Comment

The Click Reaction in Nature?

The click reaction has become a major workhorse of synthetic chemists since its proposal in 2001.1 Despite its efficiencies, no clear-cut example of its use in nature has been reported until 2012, where Yu and co-workers speculated that it might be utilized in the biosynthesis of lycojaponicumin A and B.2 Krenske, Patel, and Houk have examined the possibility of an enzyme activated click process in forming this natural product.3

First they examined the gas-phase intramolecular [3+2] reaction that takes 1 into 2.

They identified (at M06-2X/def2-TZVPP/M06-2X/6-31+G(d,p)) four different low-energy conformations of 1, of which three have the proper orientation for the cyclization to occur. The lowest energy conformer, the TS, and the product 2 are shown in Figure 1. The free energy activation barrier in the gas phase is 19.8 kcal mol-1. Inclusion of water as an implicit solvent (through a TS starting from a different initial conformation) increases the barrier to 20.0 kcal mol-1. Inclusion of four explicit water molecules, hydrogen bonded to the nitrone and enone, predicts a barrier of 20.5 kcal mol-1. These values predict a slow reaction, but not totally impossible. In fact, Tantillo in a closely related work reported a theoretical study of the possibility of a [3+2] cyclization in the natural synthesis of flueggine A and virosaine, and found barriers of comparable size as here. Tantillo concludes that enzymatic activation is not essential.4

1

TS12

3

Table 1. M06-2X/6-31+G(d,p) optimized geometries of 1, TS12, and 2.

To model a potential enzyme, the Houk group created a theozyme whereby two water molecules act as hydrogen bond donors to the enone and the use of implicit solvent (diethyl ether) to mimic the interior of an enzyme. This theozyme model predicts a barrier of 15.3 kcal mol-1, or a 2000 fold acceleration of the click reaction. The search for such an enzyme might prove quite intriguing.

References

(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. "Click Chemistry: Diverse Chemical Function from a Few Good Reactions," Angew. Chem. Int. Ed. 2001, 40, 2004-2021, DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5.

(2) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-g.; Qu, J.; Li, Y. "Lycojaponicumins A–C, Three Alkaloids with an Unprecedented Skeleton from Lycopodium japonicum," Org. Lett. 2012, 14, 2614-2617, DOI: 10.1021/ol3009478.

(3) Krenske, E. H.; Patel, A.; Houk, K. N. "Does Nature Click? Theoretical Prediction of an Enzyme-Catalyzed Transannular 1,3-Dipolar Cycloaddition in the Biosynthesis of Lycojaponicumins A and B," J. Am. Chem. Soc. 2013, 135, 17638-17642, DOI: 10.1021/ja409928z.

(4) Painter, P. P.; Pemberton, R. P.; Wong, B. M.; Ho, K. C.; Tantillo, D. J. "The Viability of Nitrone–Alkene (3 + 2) Cycloadditions in Alkaloid Biosynthesis," J. Org. Chem. 2014, 79, 432–435, DOI: 10.1021/jo402487d.

InChIs

1: InChI=1S/C16H21NO3/c1-11-8-12-10-14(18)13-4-2-6-17(20)7-3-5-16(12,13)15(19)9-11/h4,7,11-12H,2-3,5-6,8-10H2,1H3/b13-4-,17-7+
InChIKey=GVEYMXKHRRHCLV-KYGYAMEJSA-N

2: InChI=1S/C16H21NO3/c1-9-6-10-8-13(19)16-11(17-5-3-14(16)20-17)2-4-15(10,16)12(18)7-9/h9-11,14H,2-8H2,1H3/t9?,10-,11?,14?,15+,16-/m0/s1
InChIKey=QKFAOJHYKPBTKX-SGVNFLFUSA-N

cycloadditions &Houk Steven Bachrach 04 Feb 2014 No Comments

A stepwise Diels-Alder

Halskov, et al.1 reported the interesting Diels-Alder selectivity shown in Scheme 1. The linear trienamine 1 did not undergo the Diels-Alder addition, while the less stable cross-conjugated diene 2 does react with 3 with high diastereo- and enantioselectivity. Their MPW1K/6-31+G(d,p) computations on a model system, carried out for a gas-phase environment, indicated a concerted mechanism, with thermodynamic control. However, the barrier for the reverse reaction for the kinetic product was computed to be greater than 30 kcal mol-1, casting doubt on the possibility of thermodynamic control.

Scheme 1.

Houk and co-workers2 have re-examined this reaction with the critical addition of performing the computation including the solvent effects. Since the stepwise alternatives involve the formation of zwitterions, solvent can be critical in stabilizing these charge-separated species, intermediates that might be unstable in the gas phase. Henry Rzepa has pointed out in his blog and on many comments in this blog about the need to include solvent, and this case is a prime example of the problems inherent in neglecting solvation.

Using models of the above reaction Houk located two zwitterionic intermediates of the Michael addition for both the reactions of 4 with 6 and of 5 with 6. The second step then involves the closure of the ring to give what would be Diels-Alder products. This is shown in Scheme 2. They were unable to locate transition states for any concerted pathways. The computations were done at M06-2x/def2-TZVPP/IEFPCM//B97D/6-31+G(d,p)/IEFPCM, modeling trichloromethane as the solvent.

Scheme 2. Numbers in italics are energies relative to 4 + 6.

The activation barrier for the second step in each reaction is very small, typically less than 5 kcal mol-1, so the first step is rate determining. The lowest barrier is for the reaction of 5 leading to 9, analogous to the observed product. Furthermore, 9 is also the thermodynamic product. Thus, the regioselectivity is both kinetically and thermodynamically controlled through a stepwise reaction. This conclusion is only possible by including solvent in order to stabilize the zwitterionic intermediates, and should be a word of caution for everyone doing computations: be sure to include solvent for any reactions that involved charged or charge-separated species at any point along the reaction pathway!

References

(1) Halskov, K. S.; Johansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. "Cross-trienamines in Asymmetric Organocatalysis," J. Am. Chem. Soc. 2012, 134, 12943-12946,
DOI: 10.1021/ja3068269.

(2) Dieckmann, A.; Breugst, M.; Houk, K. N. "Zwitterions and Unobserved Intermediates in Organocatalytic Diels–Alder Reactions of Linear and Cross-Conjugated Trienamines," J. Am. Chem. Soc. 2013, 135, 3237-3242, DOI: 10.1021/ja312043g.

Diels-Alder &Houk Steven Bachrach 02 Apr 2013 4 Comments

Proximity-induced Diels-Alder Reaction

The intramolecular Diels-Alder reaction of 1 occurs slowly, but quantitatively, at room temperature.1 This is unusual as most Diels-Alder cyclizations require heating to typically 200 °C. For example, the related cyclization of 2 requires heating to 170 °C.2 What is the cause for this proximity-induced reaction?

Reaction 1

Reaction 2

Reaction 3

Houk and Baran address this question using a computational approach.3 The Diels-Alder reaction of 2 and a simplified analogue of 1, namely 3, were computed at CPCM/M06-2x/6-311+G(d,p)//B3LYP/6-31G(d). The optimized transition states for the reaction of 2 and 3 are shown in Figure 1. The free energy of activation of 3 is 5.4 kcal mol-1 lower in energy than the free energy of activation of 2. This is consistent with the much faster reaction of 1 than 2 observed in the experiment.

TS2

TS3

Figure 1. B3LYP/6-31G(d) for the transition states of Reactions 2 and 3.

Partitioning 3 into fragments allows Houk and Baran to apply the distortion model. They find that the rigid diene in 3 (and thereby 1) accelerates the reaction relative to the more flexible diene of 2. Further, strain relief in going from 3 (and thereby 1) to TS3 (and thereby to TS of reaction 1) and the formation of an intramolecular hydrogen bond leads to the lower activation energy of 3, and therefore of 1.

References

(1) Maimone, T. J.; Voica, A.-F.; Baran, P. S. "A Concise Approach to Vinigrol," Angew. Chem. Int. Ed. 2008, 47, 3054-3056, DOI: 10.1002/anie.200800167.

(2) Diedrich, M. K.; Klärner, F.-G.; Beno, B. R.; Houk, K. N.; Senderowitz, H.; Still, W. C. "Experimental Determination of the Activation Parameters and Stereoselectivities of the Intramolecular Diels−Alder Reactions of 1,3,8-Nonatriene, 1,3,9-Decatriene, and 1,3,10-Undecatriene and Transition State Modeling with the Monte Carlo-Jumping Between Wells/Molecular Dynamics Method," J. Am. Chem. Soc. 1997, 119, 10255-10259, DOI: 10.1021/ja9643331.

(3) Krenske, E. H.; Perry, E. W.; Jerome, S. V.; Maimone, T. J.; Baran, P. S.; Houk, K. N. "Why a Proximity-Induced Diels–Alder Reaction Is So Fast," Org. Lett. 2012, 14, 3016-3019, DOI: 10.1021/ol301083q.

InChIs

1: InChI=1S/C23H40O2Si/c1-10-12-19(24)21-20(16(3)4)18-13-14-23(21,15-17(18)11-2)25-26(8,9)22(5,6)7/h10-11,15-16,18-21,24H,1-2,12-14H2,3-9H3/t18?,19-,20?,21?,23+/m0/s1
InChIKey=NGVNTJGCNDZDEY-RHDCMTSYSA-N

2: InChI=1S/C10H16/c1-3-5-7-9-10-8-6-4-2/h3-5,7H,1-2,6,8-10H2/b7-5+
InChIKey=HXZJJSYHNPCGKW-FNORWQNLSA-N

3: InChI=1S/C20H34O2Si/c1-8-10-18(21)20(15(3)4)14-17-11-12-19(20,13-16(17)9-2)22-23(5,6)7/h8-9,13,15,17-18,21H,1-2,10-12,14H2,3-7H3/t17?,18-,19+,20?/m0/s1
InChIKey=GDQHAOHEZAJKPI-FUFFSDJGSA-N

Diels-Alder &Houk Steven Bachrach 08 Oct 2012 2 Comments

Reaction dynamics in the Diels-Alder reaction

Has there been an organic reaction more examined by computational methods than the Diels-Alder reaction? You’d think we would have covered all aspects of this reaction by now, but no, it appears that this reaction remains fertile hunting grounds.

Doubleday and Houk have examined the Diels-Alder reaction with an eye towards its synchronicity,1 an area that Houk has delved into throughout his career. While most experiments show significant stereoselectivity, a few examples display a small amount of stereo loss. Computed transition states tend to have forming C-C bond distances that are similar, though with proper asymmetric substitution, the asymmetry of the TS can be substantial. In this paper,1 they utilize reaction dynamics specifically to assess the time differential between the formation of the two new C-C single bonds. They examined the eight reactions shown below. The first six (R1-R6) have symmetric transition states, though with the random sampling about the TS for the initial condition of the trajectories, a majority of asymmetric starting conditions are used. The last two (R7 and R8) reactions have asymmetric TSs and the random sampling amplifies this asymmetry.

Nonetheless, the results of the dynamics are striking. The time gap, the average time between the formations of the first and second new C-C bond, for R1-R6 is less than 5 fs, much shorter than a C-C vibration. These reactions must be considered as concerted and synchronous. Even the last two reactions (R7 and R8), which are inherently more asymmetric, still have very short time gaps of 15 and 56 fs, respectively. One might therefore reasonably conclude that they too are concerted and synchronous.

There are some exceptions – a few trajectories in the last two reactions involve a long-lived (~1000 fs) diradical intermediate. At very high temperature, about 2% of the trajectories invoke a diradical intermediate. But the overall message is clear: the Diels-Alder reaction is inherently concerted and synchronous.

References

(1) Black, K.; Liu, P.; Xu, L.; Doubleday, C.; Houk, K. N. "Dynamics, transition states, and timing of bond formation in Diels–Alder reactions," Proc. Nat. Acad. Sci. USA, 2012, 109, 12860-12865, DOI: 10.1073/pnas.1209316109

Diels-Alder &Houk Steven Bachrach 18 Sep 2012 2 Comments

Dynamic effects in nucleophilic substitution

I think most organic chemists hold dear to their hearts the notion that selectivity is due to crossing over different transition states. Readers of my book and this blog know of the many examples where this notion simply is not true (see here). This post discusses yet another example taking place in a seemingly simple reaction.

Singleton has examined the nucleophilic substitution reaction of 1 with sodium tolylsulfide.1 The mono substitution gives potentially two different stereoproducts 2 and 3. The experimental ratio of these products 2:3 is 81:19. (Note that things are a bit more complicated because disubstitution can also occur, but this has been factored into the product ratio.)

Based on previous literature, this reaction is likely to proceed in a concerted fashion, and so one might anticipate running computations to locate a transition state leading to 2 and a transition state leading to 3. In fact, Singleton finds six different TSs (the lowest energy TS 4 is shown in Figure 1), all within 2 kcal mol-1 of each other at PCM(ethanol)/B3LYP/6-31+G**. However, the intrinsic reaction coordinate going forward from each of these six TSs leads solely to 2; no TS could be located that connects to 3! (Computations were also performed at PCM(ethanol)/M06-2x/6-31+G** which give very similar results.) Classical transition state theory would lead
one to conclude that only 2 should be formed, inconsistent with experiment.

4

5

Figure 1. PCM/B3LYP/6-31+G** optimized structures of TSs 4 and 5.

Furthermore, no intermediate could be located. This is consistent with a concerted mechanism. A second transition state was located which interconverts 2 and 3 with the involvement of a chloride – a sort of addition/rotation/elimination process. This TS 5 is also shown in Figure 1.

A direct dynamics study was performed, and 197 trajectories were computed. Of these, 185 trajectories went to product: 156 to 2 and 29 to 3, for a ratio of 84:16 – in amazing agreement with experiment! The product selectivity is due entirely to dynamic effects. In fact, it is one vibrational mode that dictates the product distribution. Essentially, the nature of the rotation about the C=C bond differentiates the eventual route, with a clockwise rotation leading always to 2 and a counterclockwise rotation leading about a third of the time to 3.

References

(1) Bogle, X. S.; Singleton, D. A. "Dynamic Origin of the Stereoselectivity of a Nucleophilic Substitution Reaction," Org. Lett., 2012, 14, 2528-2531, DOI: 10.1021/ol300817a.

InChIs

1: InChI=1S/C4H4Cl2O/c1-3(7)2-4(5)6/h2H,1H3
InChIKey=NXDUHPYJFYSBCT-UHFFFAOYSA-N

2: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7-
InChIKey=NCXXSKTZGJETLW-XFFZJAGNSA-N

3: InChI=1S/C11H11ClOS/c1-8-3-5-10(6-4-8)14-11(12)7-9(2)13/h3-7H,1-2H3/b11-7+
InChIKey=NCXXSKTZGJETLW-YRNVUSSQSA-N

Dynamics &Singleton &Substitution Steven Bachrach 03 Jul 2012 12 Comments

Benzene Dimers – [2+2] and [4+2]

Hoffmann1 reports on a number of new benzene dimer structures, notably 5-8, whose RIJCOSX-MP2/cc-pVTZ2 structures are shown in Figure 1. A few of these new dimers are only somewhat higher in energy than the known dimers 1-4. The energies of these dimers, relative to two isolated benzene molecules, are listed in Table 1.

1

2

3

4

5

6

7

8

Figure 1. RIJCOSX-MP2/cc-pVTZ optimized geometries of 1-8.

Table 1. Energy (kcal mol-1) of the dimers relative to two benzene molecules and activation energy for reversion to two benzene molecules.


Compound

Erel

Eact

1

50.9

29

2

49.9

 

3

38.2

9

4

58.7

19

5

71.9

30

6

49.9

36

7

60.8

27

8

98.8

28


The energy for reversion of the isomers 5-8 to two isolated benzene molecules is calculated to be fairly large, and so they should be stable relative to that decomposition mode. They also examined a series of other decomposition modes, including [1,5]-hydrogen migration, all of which had barriers of 21 kcal mol-1 or greater, retrocyclization ([2+2]), for which they could not locate transition states, electrocyclic ring opening (Cope), with barriers of at least 17 kcal mol-1 and dimerization – some of which had relatively small enthalpic barriers of 4-5 kcal mol-1. However, the dimerizations all have very unfavorable entropic activation barriers.

So, the conclusion is that all of the novel dimers (4-8) can be reasonable expected to hang around for some time and therefore are potential synthetic targets.

References

(1) Rogachev, A. Yu.; Wen, X.-D.; Hoffmann, R. "Jailbreaking Benzene Dimers," J.
Am. Chem. Soc.
, 2012, 134, 8062-8065, DOI:10.1021/ja302597r

(2) Kossmann, S.; Neese, F. "Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method," J. Chem. Theory Comput., 2010, 6, 2325-2338, DOI: 10.1021/ct100199k

InChIs

1: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11-,12+
InChIKey=WMPWOGVJEXSFLI-UHFFFAOYSA-N

2: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10+,11+,12-
InChIKey=WMPWOGVJEXSFLI-IWDIQUIJSA-N

3: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12+
InChIKey=ONVDJSCNMCYFTI-CAODYFQJSA-N

4: InChI=1S/C12H12/c1-2-10-4-3-9(1)11-5-7-12(10)8-6-11/h1-12H
InChIKey=BCBHEUOKKNYIAT-UHFFFAOYSA-N

5: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11+,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-WYUUTHIRSA-N

6: InChI=1S/C12H12/c1-2-4-12-10-7-5-9(6-8-10)11(12)3-1/h1-12H/t9?,10?,11-,12-/m0/s1
InChIKey=ONVDJSCNMCYFTI-QQFIATSDSA-N

7: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12+/m1/s1
InChIKey=WMPWOGVJEXSFLI-KKOKHZNYSA-N

8: InChI=1S/C12H12/c1-2-6-10-9(5-1)11-7-3-4-8-12(10)11/h1-12H/t9-,10-,11-,12-
InChIKey=WMPWOGVJEXSFLI-NQYKUJLISA-N

Aromaticity &cycloadditions &electrocyclization Steven Bachrach 04 Jun 2012 No Comments

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