Well, here’s my vote for paper of the year (at least so far!). It is work from Barry Carpenter’s lab¹ and pertains to many topics discussed in my book, including pericyclic and psuedopericylic reactions, non-statistical dynamics, and the use of high-level computations to help understand confusing experimental results. The paper is in an interesting read – and not just for the great science. It is told as a story, recounting the experiments and interpretation as they took place in chronological order with a surprising and critical contribution made from a referee!

The story begins with Carpenter’s continuing interest in unusual dynamic effects and the supposition that non-statistical dynamics might be observed in the rearrangements of carbenes. So, they took on the Wolff rearrangement, specifically the rearrangement of 3 into 4. Using labeled starting material 1, one should observe equal amounts of 4a and 4b if normal statistical dynamics is occurring (Scheme 1).

Scheme 1.

In fact, the ratio of products is not unity, but rather 4a:4b = 1:4.5. But the excess of 4b could be the result of another parallel rearrangement, 2 to 5 to 4b (Scheme 2).

Scheme 2.

To try to distinguish whether 5 is intervening, they carried out the photolysis of a different labeled version of 1 (namely 1’). The product distribution of the products is shown in Sheme 3. It appears that the reaction through 5 dominates, but the ratio of products that come from 3 still shows non-statistical behavior.

Scheme 3.

CCSD(T) computation suggested that 5 is higher in energy than 3, and this does not help understand the experiments. At this point, Carpenter decided to write up the work as a communication, with the main point that non-statistical dynamics were occurring.

Now here an unusual event took place that offers up hope that the peer-review system still works! A referee, later identified as Dan Singleton, offered an alternative mechanism for the production of 5. Shown in Scheme 4 is the novel pseudopericylic reaction that leads from 1 directly to 5. In fact, the transition state for this pseudopericyclic reaction is 19.0 kcal mol^-1 lower in energy than the transition state for the retro-Diels-Alder reaction of Scheme 1 (computed at MPWB1K/ 6-31+G(d,p), and this pseudopericyclic TS is shown in Figure 1).

Scheme 4.

Figure 1. MPWB1K/6-31+G(d,p) optimized geometry of the transition state for the pseudopericyclic reaction shown in Scheme 4.¹

The revised mechanism was then modified to include the additional complication of the formation of 6, and is shown in Scheme 5, along with their relative CCSD(T) energies. The CCSD(T)/cc-pVTZ//CCSD/cc-pVTZ optimized geometries of the critical points of Scheme 5 are drawn in Figure 2.

Scheme 5.

5
TS 5 → 3	3
TS 5 → 6	6
TS 5 → 4	4

Figure 2. CCSD/cc-pVTZ optimized geometries.¹

Any non-statistical effect would occur in the transition from 5 to 3. A direct dynamics trajectory analysis was performed starting in the neighborhood of this TS using three different functionals to generate the potential energy surface. Though only 100 trajectories were computed, the results with all three functionals are similar. About 2/3rds of these trajectories led to 3 followed by the shift of the C₅ methyl group. Another 15% led to 3 and then the C₁ methyl shifted. This MD simulation supports the non-statistical Wolff rearrangement, with a clear preference for the C₅ shift, consistent with experiment. A larger MD study is underway and will hopefully shed additional insight onto this fascinating reaction.

References

(1) Litovitz, A. E.; Keresztes, I.; Carpenter, B. K., "Evidence for Nonstatistical Dynamics in the Wolff Rearrangement of a Carbene," J. Am. Chem. Soc., 2008, 130, 12085-12094, DOI: 10.1021/ja803230a.

InChIs

3: InChI=1/C5H6O2/c1-4(6)3-5(2)7/h1-2H3
InChIKey = IGYQBMPIQGLNRU-UHFFFAOYAO

4: InChI=1/C5H6O2/c1-4(3-6)5(2)7/h1-2H3
InChIKey = ABVJXABNYINQLN-UHFFFAOYAA

5: InChI=1/C5H6O2/c1-3-5(7)4(2)6/h1-2H3
InChIKey = FJJXVDYICOYKRN-UHFFFAOYAD

6: InChI=1/C5H6O2/c1-4-3(6)5(4,2)7-4/h1-2H3
InChIKey = CAMBQRQJZBTNNS-UHFFFAOYAB

Ken Houk has produced a very nice minireview on bifurcations in organic reactions.¹ This article is a great introduction to a topic that has broad implication for mechanistic concepts. Bifurcations result when a valley-ridge inflection point occurs on or near the intrinsic reaction coordinate. This inflection point allows trajectories to split into neighboring basins (to proceed to different products) without crossing a second transition state. In the examples discussed, the reactant crosses a single transition state and then leads to two different products. This is the so-called “two-step no intermediate” process.

I discuss the implications of these kinds of potential energy surfaces, and other ones of a pathological nature, in the last chapter of my book. Very interesting reaction dynamics often are the result, leading to a mechanistic understanding far from the ordinary!

References

(1) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; Çelebi-Ölçüm, N.; Houk, K. N., "Bifurcations on Potential Energy Surfaces of Organic Reactions," Angew. Chem. Int. Ed. 2008, DOI: 10.1002/anie.200800918

I guess one can never know enough about the S_N2 reaction! Wester and co-workers have performed careful crossed molecular beam imagining on the reaction Cl^– + CH₃I.¹ In collaboration with Hase, they have employed MP2/ECP/aug-cc-pVDZ computations to get the potential energy surface for the reaction and direct molecular dynamics. The PES is exactly as one would expect for a gas phase ion-molecule reaction: the transition state has backside attack of the nucleophile and it connects to two ion-dipole complexes (see Chapter 5.1.1).

The experiments are interpreted with the help of the MD computations. At low energy one sees formation of the complex. At higher energies, the direct backside attack reaction occurs. And at higher energies a new reaction path emerges, as sketched out in Figure 1. As the nucleophile (chloride) approaches methyl iodide, the methyl group rotates towards the nucleophile. The methyl group then collides with the nucleophile, which sends the methyl group spinning about the iodine atom in the opposite direction. The methyl group rotates all the way around the iodine atom and when it approaches the chloride a second time, the displacement reaction occurs and product is formed. They term this process a “roundabout mechanism”, and they have some experimental evidence for the occurrence of the double roundabout (two rotations of the methyl group about the iodine)! I think we should anticipate seeing more and more interesting reaction pathways as experimental and theoretical techniques continue to allow us a more detailed and precise view of motion of individual molecules across barriers.

Figure 1. Schematic of the trajectory illustrating the roundabout mechanism.
Chlorine is yellow, iodine is pink and carbon is black.

References

(1) Mikosch, J.; Trippel, S.; Eichhorn, C.; Otto, R.; Lourderaj, U.; Zhang, J. X.; Hase, W. L.; Weidemüller, M.; Wester, R., "Imaging Nucleophilic Substitution Dynamics," Science 2008, 319, 183-186, DOI: 10.1126/science.1150238.

In Chapter 7.3.5.1 I discuss the computational and experimental results of Singleton¹ regarding C₂-C₆ enyne allene cyclization. The reaction is shown below, and though Singleton could locate no transition state that connects the reactant to the diradical, molecular dynamics trajectory calculations show that the diradical is sampled, though the dominant pathway is the concerted route.

Schmittel has expanded on this work by determining the kinetic isotope effects for four more analogues.2 The results are summarized in Table 1. Depending on the substituent, the predominant pathway can be concerted or stepwise or even a mixture of these two (termed “boundary”). Schmittel argues that the region about the single transition state, the one that directly connect reactant to product through a concerted path, is actually quite flat. This is a “broad transition state zone”. Trajectories can traverse through various regions of the zone, some that go on to diradical, some that go on to product. Substituents can alter the shape of the TS zone and thereby shift the set of trajectories in one direction or the other. The upshot is further support for the importance on non-statistical dynamics in dictating the course of reactions.

Table 1. Kinetic isotope effects for C₂-C₆ enyne allene cyclizations

References

(1) Bekele, T.; Christian, C. F.; Lipton, M. A.; Singleton, D. A., ""Concerted" Transition State, Stepwise Mechanism. Dynamics Effects in C²-C⁶ Enyne Allene Cyclizations," J. Am. Chem. Soc. 2005, 127, 9216-9223, DOI: 10.1021/ja0508673.

(2) Schmittel, M.; Vavilala, C.; Jaquet, R., "Elucidation of Nonstatistical Dynamic Effects
in the Cyclization of Enyne Allenes by Means of Kinetic Isotope Effects," Angew. Chem. Int. Ed. 2007, 46, 6911-6914, DOI: 10.1002/anie.200700709

Dynamic and non-statistical behavior is the subject of Chapter 7 in my book. Hase and co-workers have uncovered another interesting case of dynamic behavior.¹ The reaction of interest here is F^– + CH₃OOH. A number of different critical points and reactions exist on this surface. The complex CH₃OOH^…F^– (1) lies 36.5 kcal mol^-1 below separated reactants. 1 can rearrange through TS1 (with a barrier of 24.1 kcal mol^-1) to give F^–…CH₃OOH (2). 2 can then cross a second transition state (TS2) with a barrier of 4.7 kcal mol^-1) to give CH₂(OH)₂^…F^– (3), which lies in a very deep well. The B3LYP/6-311+G(d,p) geometries of these critical points are shown in Figure 1.

1 -36.5	TS1 -12.4	2 -16.2
TS2 -11.5	3 -104.8

Figure 1. B3LYP/6-311+G(d,p) optimized geometries of the critical points on the PES for the reaction of F^– with CH₃OOH.¹ Energies in kcal mol^-1 relative to separated reactants

What drew Hase to this problem were the interesting experimental results of Blanksby, Ellison, Bierbaum and Kato.² The gas phase reaction produced HF + CH₂O + OH^–, not 3 or HF + CH₂(OH)O^–. Hase and coworkers ran a number of trajectories simulating reaction at 300 K, the experimental condition. Reactions were started at three points: (1) F^– separated by 15 Å from CH₃OOH, (2) at TS2 or (3) at a point along the intrinsic reaction coordinate (IRC) of the form HOCH₂O^–…HF.

76 of the 80 trajectories that start from TS2 result in the formation of HF + CH₂O + OH^–. The majority of the trajectories that start with separated reactants produce the complex 1 (97 out of 200), reflecting its low energy and high exit barriers. 55 of these200 trajectories remain as isolated reactants. However, 45 trajectories give HF + CH₂O + OH^–, as do all 5 trajectories that start with HOCH₂O^–…HF. No trajectories give 3, the product expected from following the IRC. The computations are in complete agreement with the experimental results; the unusual decomposition products result from following a non-IRC pathway!

Since motion along the imaginary frequency of TS2 initially is to cleave the O-O bond and the C-H bond, momentum in that direction carries the reaction over to the decomposition product rather than making a tight turn on the PES necessary to make 3. These computations show once again that reactions can follow pathways that lie far from steepest descent or IRC pathways.

References

(1) Lopez, J. G.; Vayner, G.; Lourderaj, U.; Addepalli, S. V.; Kato, S.; deJong, W. A.; Windus, T. L.; Hase, W. L., "A Direct Dynamics Trajectory Study of F^– + CH3OOH Reactive Collisions Reveals a Major Non-IRC Reaction Path," J. Am. Chem. Soc. 2007, 129, 9976-9985, DOI: 10.1021/ja0717360.

(2) Blanksby, S. J.; Ellison, G. B.; Bierbaum, V. M.; Kato, S., "Direct Evidence for Base-Mediated Decomposition of Alkyl Hydroperoxides (ROOH) in the Gas Phase," J. Am. Chem. Soc. 2002, 124, 3196-3197, DOI: 10.1021/ja017658c.