Speeding Up Sigmatropic Shifts—To Halve or to Hold

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Speeding Up Sigmatropic ShiftsTo Halve or to Hold Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Dean J. Tantillo* University of CaliforniaDavis, Davis, California 95616, United States CONSPECTUS: Catalysis is common. Rational catalyst design, however, is at the frontier of chemical science. Although the histories of physical organic and synthetic organic chemistry boast key chapters involving [3s,3s] sigmatropic shifts, catalysis of these reactions is much less common than catalysis of ostensibly more complex processes. The comparative dearth of catalysts for sigmatropic shifts is perhaps a result of the perception that transition state structures for these reactions, like their reactants, are nonpolar and therefore not amenable to selective stabilization and its associated barrier lowering. However, as demonstrated in this Account, transition state structures for [3s,3s] sigmatropic shifts can in fact have charge distributions that differ significantly from those of reactants, even for hydrocarbon substrates, allowing for barriers to be decreased and rates increased. In some cases, differences in charge distribution result from the inclusion of heteroatoms at specific positions in reactants, but in other cases differences are actually induced by catalysts. Perhaps surprisingly, strategies for complexation of transition state structures that remain nonpolar are also possible. In general, the strategies for catalysis employed can be characterized as involving either mechanistic intervention, where a catalyst induces a change from the concerted mechanism expected for a [3s,3s] sigmatropic shift to a multistep process (cutting the transformation into halves or smaller pieces) whose overall barrier is decreased relative to the concerted process, or transition state complexation, where a catalyst simply binds (holds) more tightly to the transition state structure for a [3s,3s] sigmatropic shift than to the reactant, leading to a lower barrier in the presence of the catalyst. Both of these strategies can be considered to be biomimetic in that enzymes frequently induce multistep processes and utilize selective transition state stabilization for the steps involved. In addition, transition state complexation was the principle around which catalytic antibodies were originally designed. The field of catalysis of sigmatropic shifts is now ready for rational design. The studies described here all provide evidence for the origins of rate acceleration, derived in large part from the results of quantum chemical calculations, that can now be applied to the design of new catalysts for [3s,3s] and other sigmatropic shifts.

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INTRODUCTION Studies of [3,3] sigmatropic shifts (Scheme 1), Cope reactions when X, Y, and Z in Scheme 1 are all carbon based,1 have

the catalyst actually changes the mechanism of the sigmatropic shift from a single-step (i.e., concerted) process to a multistep process with an overall lower barrier. In TS complexation-based strategies, the catalyst does not alter the mechanism, but binds more tightly to the transition state structure for rearrangement than to the reactant, thereby lowering the activation barrier and inducing rate acceleration. The intervention approach is encountered frequently in the realms of enzyme catalysis and organometallic chemistry, for example. The concept of accelerating a single-step reaction by binding to its transition state structure more tightly than to the reactant(s) also has a long history. Perhaps the best-known formulations of this principle are Pauling’s model for enzyme catalysis (“I think that enzymes are molecules that are complementary in structure to the activated complexes of the reactions that they catalyze”)4 and Jencks’ extension of this principle to a model for antibody catalysis (“If complementarity between the active site and the transition state contributes significantly to enzymatic catalysis,

Scheme 1. Sigmatropic Shifts Discussed

played key roles in both the development of the field of physical/mechanistic organic chemistry2 and in the success of many syntheses of complex natural products.3 Nonetheless, catalysis of such reactions is an underdeveloped area. This Account will highlight studies that demonstrate a variety of strategies for accelerating the rates of [3,3], and potentially other, sigmatropic shifts. These strategies can be classified as involving either “intervention” or “transition state (TS) complexation” (Figure 1). In intervention-based strategies, © XXXX American Chemical Society

Received: January 18, 2016

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Figure 1. General reaction coordinate diagrams for an uncatalyzed concerted rearrangement (black), a reaction that has been transformed from a concerted to a multistep process by “intervention” of a catalyst (blue), and a reaction that has been accelerated by selective complexation of its transition state structure (“Transition State Complexation”; red).

calculations and found that a multistep mechanism is likely for the radical cation rearrangement.11 In this mechanism (Figure 2, bottom), C−C bond formation first occurs leading to a cyclic

it should be possible to synthesize an enzyme by constructing such an active site”).5 Despite these notable applications, simple TS complexation remains an underexploited method for catalyst design, especially in nonbiological settings. Some words on what this Account is and what it is not. The focus will be on reactions that have been subjected to analysis using quantum chemical computations. While 1,5-dienes and heterosubstituted analogs will be discussed, systems containing allenes or alkynes will not be discussed and the extensive literature on substrate substitutent effects will be given short shrift. Only systems fitting the depiction in Scheme 1 (X, Z = CR2, NR, O; Y = CR, N) will be discussed; while other substitution patterns are certainly possible, studies on the catalysis of such systems do not appear to have received significant attention. The following conventions will be used throughout this Account: (a) Concerted mechanisms will be highlighted in red, stepwise mechanisms in blue. (b) The simple term “[3,3] shift” will be used to indicate “[3s,3s] sigmatropic shift,” whether the mechanism is concerted or stepwise; systems with antarafacial geometries (forbidden or allowed by orbital symmetry) are not discussed, nor are pseudopericyclic reactions.6

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Figure 2. Predicted energetics (B3LYP/6-31+G(d,p), kcal/mol) for stepwise [3,3] shift of N-allylhydrazone promoted by electron abstraction.11 Only one resonance structure of each radical cation is shown.

ELECTRON TRANSFER Perhaps the simplest means of promoting a reaction is via the addition or removal of a single electron.7 While this means of rate acceleration is not catalysis of the sort described above (i.e., a catalyst does not simply bind to or bond to a substrate), this approach has been applied to accelerate [3,3] shifts. For example, Wenthold and co-workers showed that addition of a single electron to 2,5-dicyano-1,5-hexadiene in the gas phase leads to cyclization to form a species resembling what one would expect to be a transition structure for a [3,3] shift, consistent with their computational predictions (B3LYP/631+G*).8 This result is consistent with complete removal of the barrier for [3,3] shift upon the addition of an electron, that is, the difference in electron affinity between the reactant and transition structure is greater than the barrier for neutral Cope rearrangement. A similar scenario was observed for radical cations of 1,5-hexadienes, again consistent with preliminary predictions (based on semiempirical calculations).9 In 2008, Thomson and co-workers described a [3,3] shift of N-allylhydrazones promoted by electron removal.10 We examined this process using density functional theory (DFT)

intermediate, as expected based on the results just described for the hydrocarbon rearrangement. This intermediate does not, however, simply undergo C−N bond cleavage to form the product of a [3,3] shift; instead, a 1,2-shift first produces another cyclic intermediate, which then opens to product. This multistep pathway is predicted to have an overall free energy barrier of 11 kcal/mol from the reactant (Figure 2, bottom), much lower than the barrier predicted for the neutral Nallylhydrazone rearrangement (34 kcal/mol; Figure 2, top). Here, not only does electron removal promote the rearrangement, but internal intervention leads to an unexpected “extra” intermediate.

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ANOTHER CASE OF INTERVENTION FROM THE INSIDE In collaboration with the Thomson group, we further examined [3,3] shifts of N-allylhydrazonesin this case, acid, rather than B

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Accounts of Chemical Research hole, catalyzed rearrangements with both N−H and N−Boc groups.12 Results for the simplest system examined are shown in Figure 3. Barriers for [3,3] shift with the N-allylhydrazone

Scheme 2. Proposed Mechanism for Palladium-Promoted [3,3] Shift

pathways (depending, in the uncatalyzed case, on the nature and position of appended substituents).15 For example, quantum chemical calculations (qualitatively similar results were obtained at many levels of theory), using PdCl2(MeCN) bound to 2-phenyl-1,5-hexadiene revealed that although a cyclohexyl cation-like species can indeed exist as a minimum, this minimum is extremely shallow, only ∼1 kcal/ mol deep.16 The fact that this minimum is so shallow caused us to wonder whether the presence of the phenyl substituent was inducing a stepwise pathway. For all aryl-substituted systems explored (Scheme 2, R = C6H4X), the stepwise mechanism persisted, but electron-withdrawing groups generally reduced the depth of the well in which the intermediate resides and increased the barrier for its formation. This trend is expected for the mechanism shown in Scheme 2,14 in which conversion of the palladium complexed reactant to the C−C bond-forming transition state structure to the intermediate involves progressive removal of electron density from the benzylic carbon. Several nonaryl substituents (R) were also examined. When the aryl group was replaced with a hydrogen (Scheme 2, R = H), the rearrangement (for the “parent” system) was found to be concerted (see Figure 4a for the geometry of the transition state structure) and the barrier for this rearrangement was predicted to be higher than those for all of the aryl-substituted systems. This observation is still consistent with a cyclohexyl cation-like structure occurring along the reaction coordinate, but in this case it is a transition state structure rather than a minimum. On the basis of the results of calculations with other R groups,16,17 the generalization that 1,5-hexadienes with cation-stabilizing groups at the 2-position follow stepwise pathways, with shallow intermediates, and those without such groups follow concerted pathways, appears valid. Note that the geometries of the intermediates, when present (e.g., Figure 4b), and the geometries of transition state structures for concerted processes (e.g., Figure 4a) are extraordinarily similar, i.e., the geometric changes along the reaction coordinates in both cases are essentially the same, but these reaction coordinates differ in their curvature. Very few other examples of straightforward TS complexation by transition metal catalysts have been described.18 What is the origin of rate-accleration for concerted [3,3] shifts promoted by Pd(II)? A simple orbital argument provides an answer to this question. The relevant molecular orbital of the complexed transition state structure, shown in Figure 4e for the R = H case, is comprised primarily of the HOMO of the uncomplexed transition structure (Figure 4d) interacting in a

Figure 3. Predicted (B3LYP/6-31G(d,p)) relative energies (kcal/mol) of stationary points involved in [3,3] shifts of protonated Nallylhydrazone and selected transition state structure and intermediate geometries (distances in Å).12

protonated at the imine or amine nitrogen are predcited to be 19 and 23 kcal/mol, respectvely (Figure 3, center and right). Both of these are considerably lower than the predicted barrier for [3,3] shift of the nonprotonated N-allylhydrazone (33 kcal/ mol at the level of theory used here), consistent with expectations for [3,3] shifts of cationic species (a result, at least in part, of increasing the electrophilicity of the imine).2,13 A stepwise pathway with an overall barrier of only 14 kcal/mol was also found, however (Figure 3, left). In this pathway, C−C bond formation occurs first, but this event is decoupled from C−N bond breaking and instead coupled to attack of the amine nitrogen onto an incipient carbocation center. In this case, intervention again occurs from within the molecule during rearrangement. In addition, computations were used to make predictions about alterations to N-allylhydrazone substrates that would facilitate reaction (e.g., the use of hydrazones derived from glyoxylates) and some of these predictions were validated experimentally by the Thomson group.12

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THE BORDERLINE BETWEEN EXTERNAL INTERVENTION AND TRANSITION STATE COMPLEXATION: TRANSITION METAL PROMOTED [3,3] SHIFTS Palladium-promoted Cope rearrangements have been utilized to advantage by synthetic chemists,14 and, in particular, substantial attention has been given to the Pd(II)-promoted Cope reaction.14 This process has been characterized as proceeding through the stepwise mechanism shown in Scheme 2.14 Our calculations indicate, however, that the mechanistic picture in Scheme 2 is not necessarily applicable to all Pd(II)promoted Cope rearrangements. Rather, the potential energy surfaces for such reactions show some of the same peculiarities as those of their metal-free cousins,2 including “chameleonic” behavior, that is, variation between concerted and stepwise C

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Figure 4. Selected structures (B3LYP/LANL2DZ distances in Å) involved in complexed and uncomplexed Cope rearrangements (a−c). PdCl2(MeCN) was used in these calculations. (d) Kohn−Sham HOMO for the transition state structure shown in (c). (e) Kohn−Sham HOMO-4 for the transition state structure shown in (a). Reproduced with permission from ref 16. Copyright 2007 American Chemical Society.

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bonding, stabilizing, manner with a dz2 orbital of the Pdan interaction that is stronger for the transition state structure than for the reactant. Simple matching of orbitals for transition state structures and MLn fragments is largely unexplored as a catalyst design strategy.18 We also examined a Cope rearrangement promoted by gold, which was developed by the Gagné group.19 In this case, a stepwise mechanism (intervention) was predicted to predominate (Figure 5), but the cationic substructures in the species

TS COMPLEXATION VIA CONVENTIONAL HYDROGEN BONDING In principle, [3,3] shifts of heteroatom-containing 1,5hexadienes can be promoted by hydrogen bonding, if said hydrogen bonding is stronger for the transition state structure than for the reactant. For example, both the Strassner and Jacobsen groups examined this possibility for Claisen rearrangements in the presence of urea-derived catalysts (Figure 6).21 In

Figure 5. Predicted (CPCM(1,2-dichloroethane)-M06 with 6-31G(d) for P, C, and H, and LANL2DZ for Au) stationary points involved in a Cope reaction rendered multistep by gold complexation.19 Relative energies shown in kcal/mol and distances shown in Å.

Figure 6. Claisen rearrangements promoted by thiourea and guanidinium ion catalysts examined computationally by the Strassner (top; B3LYP/6-311++G**) and Jacobsen (bottom; B3LYP/631G(d)) groups.21

examined were tertiary or next to a cyclopropane. Stepwise [3,3] shifts of appropriately alkyl-substituted systems promoted by [Pt(PR3)3]2+ and heteroatom-containing systems (Scheme 2, X = NR, Y = C(CCl3), Z = O) promoted by PdCl2(NCR) have also been characterized theoretically,18,20 the latter of which involve attack by a nitrogen lone pair rather than a CN π-bond.6

line with a model proposed earlier by Jorgensen (who examined water molecules as model catalysts for Claisen rearrangements),22 hydrogen bonding between the catalyst and both the ether and ester oxygens of the substrate were proposed to polarize the transition state structure, lead to selective TS complexation and thereby lower the barrier of the [3,3] shift (with the effect apparently being larger for the cationic catalyst). Reduction of the overall barrier for reaction, however, is complicated by issues with substrate conformational D

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Accounts of Chemical Research preferences.21a,23 Computations on the chorismate-to-prephenate Claisen rearrangements catalyzed by chorismate mutase and catalytic antibodies show similar effects.24 In addition, the Jacobsen group used a chiral nonracemic guanidinium ion to induce enantioselectivity.21b

the indole N−H greatly reduces activity and selectivity) and is now being applied to the design of new catalysts that work at lower temperatures and accept new substrates.

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TRANSITION STATE COMPLEXATION VIA SELECTIVE ELECTROSTATIC INTERACTIONS Schleyer and Jiao were pioneers in the field of TS complexation for pericyclic reactions. They applied this concept (but did not at the time name it) to acceleration of Cope reactions (and other pericyclic reactions) in the early 1990s.27 Their demonstration that complexation of the C2v form of semibullvalene, usually the transition state structure for a degenerate Cope rearrangement, by Li+ (Figure 8) is stronger than

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TRANSITION STATE COMPLEXATION VIA C−H···O INTERACTIONS In collaboration with the Tambar group, we examined the [3,3] shift shown in Scheme 3.25 In this reaction, the chiral Scheme 3. Phosphoric Acid Promoted [3,3] Shift Examined by Tambar and Co-Workers

Figure 8. Predicted PES minimum for Li+ complexed semibullvalene.27a

complexation of the localized 1,5-hexadiene form stands as a landmark in this field.27a They predicted that not only does such selective complexation lower the barrier for rearrangement (which was low to begin with), it removes it entirely, an effect arising from enhanced electrostatic interactions with the delocalized C2v form, that is, a concerted reaction is selectively stabilized to the point that there is no longer a reaction. This case appears to be the first for which rate acceleration of a pericyclic reaction was shown to arise from direct interaction with rearranging electrons.

phosphoric acid presumably protonates the N-allylindole reactant at the allylic nitrogen and engages in an ammonium ion/phosphate ion complex. [3,3] Shift then ensues, followed by deprotonation/tautomerization. The results of our DFT calculations on the rearrangement process indicate that the ion pair is bound not only by an N−H···O hydrogen bond, but also by C−H···O and C−H···π interactions (Figure 7).26 One of these interactions involves a C−H group of the indole whose carbon supports rearranging electrons. The predicted binding mode allowed us to rationalize the stereoselectivity of this reaction, was consistent with available experimental data (e.g., substitution of the indole C−H is not tolerated, substitution of

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TRANSITION STATE COMPLEXATION VIA HALOGEN BONDING INVOLVING PARTIAL C−C BONDS While examining the mechanism of semibullvalene bromination,28 we located a potential energy surface (PES) minimum resembling a complex of Br2 with the transition state structure for the [3,3] shift in semibullvalene (Figure 9).28,29 This case of

Figure 9. Predicted complex between Br2 and the transition state structure for [3,3] shift of semibullvalene, which, as a complex, is a PES minimum. Reproduced with permission from ref 29. Copyright 2007 American Chemical Society.

Figure 7. Predicted (B3LYP/6-31G(d)) complex of chiral phosphate and protonated aza-Claisen transition state structure. Reproduced with permission from ref 25a. Copyright 2013 American Chemical Society. E

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Accounts of Chemical Research TS complexation is noteworthy for several reasons. First, like complexation by Li+ cations described above, this complexation entirely removes the small barrier for [3,3] shift. However, complexation involves a species that is neutral and interacts directly with only one of the partial C−C bonds. The favorable and selective transition state binding likely arises in part from the orbital interactions shown in Figure 10one in which a Br2

Figure 11. Computed transition state structure for ammonium ion promoted Cope reaction of a trimethyl-1,5-hexadiene.33

conjugation. This scenario represents a particularly unusual mode of transition state complexation, which involves an N− H···C hydrogen bond, the carbon of which supports rearranging electrons (this effect was described as “partial protonation”). Also of interest is the observation that the presence of the ammonium ion appears to induce a large dipole in the otherwise nonpolar transition state structure. This effect is not unlike that described above for palladium-promoted Cope reactions, with the Lewis acidic palladium replaced by the Brønsted acidic ammonium ion. In fact, we initially expected the ammonium ion to act as a true Brønsted acid, protonating one of the CC π-bonds of the reactant and opening up a stepwise pathway for net [3,3] shift. This type of intervention is indeed observed for systems with different numbers of alkyl groups on the 1,5-hexadiene and/or ammonium ion (Figure 12), again highlighting the shades of gray that obscure the distinction between stepwise reactions and concerted reactions with asynchronous events.34 The possibility of ammonium ionpromoted [3,3] sigmatropic shifts of hydrocarbons has not yet,

Figure 10. Favorable donor−acceptor orbital interactions between a halogen and C2v-symmetric semibullvalene.

orbital acts as an electron donor and the other in which it acts as an acceptor (like back-bonding for transition metals). In the latter of these, the interaction involves a delocalized semibullvalene orbital with a node that encourages interaction with only one partial C−C bond. While electrostatic interactions also were computed to contribute to binding, these were predicted to be lesser in magnitude, in sum, than orbital interactions. Complexation by various different halogens X2, X−Y (X, Y = F, Cl, Br) were examined, as were trimolecular complexes with two halogen molecules and complexes with barbaralane; in all cases similar effects were observed. In pursuit of more experimentally relevant systems, complexes of partial C−C bonds with common Lewis acids (e.g., AlCl3, BF3; through their formally empty p-orbitals or halogen−group 13 element bonds) were examined. These led to barrier lowering, but not complete barrier removal. Complexes with alkyl halides (free or tethered to semibullvalene) were also examined, but these did not show appreciable effects.30 Although the systems described in this section may appear to be of little more than theoretical interest, they do demonstrate the possibility that halogen bonding, which has only recently come to the fore as an intermolecular interaction useful for design,31 can involve partical σ-bonds, an observation that could no doubt be exploited by a clever chemist.

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TRANSITION STATE COMPLEXATION VIA PARTIAL PROTONATION While examining a terpene-forming carbocation rearrangement,32 we happened upon the transition state structure shown in Figure 11, a transition state structure for concerted Cope rearrangement in the presence of the trimethylammonium cation.33 In this transition state structure there appears to be a hydrogen bond between the ammonium N−H group and one carbon that supports the rearranging electrons. This structure is perhaps best viewed as a complex with a dipolar transition state structure with its anionic side near to the ammoimum cation and its positive side internally stabilized through hyper-

Figure 12. Effects of ammonium ion complexation on selected Cope reactions:33 cases benefiting from intervention to induce a stepwise pathway highlighted in blue; those benefiting from selective TS complexation highlighted in red. F

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Figure 13. Summary of approaches to rate acceleration described herein. These range from mechanistic intervention (converting a concerted process to a stepwise one; blue) to selective TS complexation (red), from internal to external TS stabilization and from engagement of the core of rearranging electrons to groups on the periphery.

to our knowledge, been put to the test in the wet lab (whether this is due to the relatively short time since publication, to complications associated with the likelhood that phase transfer conditions may be necessary, or to simple lack of interest is not yet clear), but such a process may well have synthetic utility and/or biological relevance.

Professor of Chemistry. Dean loves to stew on the origins of unexpected structures and mechanisms in the areas of catalysis, biosynthesis, reactive intermediate chemistry, stereoselectivity, and weak noncovalent interactions.

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ACKNOWLEDGMENTS The research from the Tantillo group described in this Account was supported in part by UC Davis and grants from the National Science Foundation (including its XSEDE program and predecessors) and the American Chemical Society Petroleum Research Fund. The concept for this Account germinated at the 2014 “Accelerating Reaction Discovery” Telluride Science Research Center meeting.

SUMMARY AND OUTLOOK The catalyst-promoted [3,3] shifts described in this Account are summarized in Figure 13. Note that catalysts can lower the barriers for concerted reactions (red) or convert them to stepwise processes (blue). For some cases, e.g., palladiumpromoted and ammonium ion-promoted Cope reactions, both types of reaction are possible (purple). Note also that selective transition state stabilization can occur from outside the substratefrom the catalystor from within the substrate promoted by the catalyst, and stabilizing interactions can involve the rearranging electrons directly or can involve atoms attached to those that support the rearranging electrons. Although the examples discussed in this Account are not all of obvious synthetic relevance, they highlight a wide range of approaches for modulating the rates of [3,3] shifts that could, and hopefully will, be applied to the development of new synthetically useful sigmatropic rearrangements.35

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REFERENCES

(1) Cope, A. C.; Hardy, E. M. The Introduction of Substituted Vinyl GroupsA Rearrangement Involving the Migration of an Allyl Group in a Three-Carbon System. J. Am. Chem. Soc. 1940, 62, 441−444. (2) Leading references: (a) Graulich, N. The Cope Rearrangement− The First Born of a Great Family. Comput. Mol. Sci. 2011, 1, 172−190. (b) Houk, K. N.; Gonzalez, J.; Li, Y. Pericyclic Reaction TransitionStatesPassions and Punctillios, 1935−1995. Acc. Chem. Res. 1995, 28, 81−90. (c) Dewar, M. J. S.; Jie, C. Mechanisms of Pericyclic Reactions: The Role of Quantitative Theory in the Study of Reaction Mechanisms. Acc. Chem. Res. 1992, 25, 537−543. (d) Wiest, O.; Montiel, D. C.; Houk, K. N. Quantum Mechanical Methods and the Interpretation and Prediction of Pericyclic Reaction Mechanisms. J. Phys. Chem. A 1997, 101, 8378−8388. (3) Leading references: (a) Nubbemeyer, U. Recent Advances in Asymmetric [3,3]-Sigmatropic Rearrangements. Synthesis 2003, 2003, 961−1008. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Cascade Reactions in Total Synthesis. Angew. Chem., Int. Ed. 2006, 45, 7134− 7186. (c) Davies, H. M. L.; Lian, Y. The Combined C−H Functionalization/Cope Rearrangement: Discovery and Applications in Organic Synthesis. Acc. Chem. Res. 2012, 45, 923−935. (4) Pauling, L. Nature of Forces between Large Molecules of Biological Interest. Nature 1948, 161, 707−709. (5) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGrawHill: New York, 1969.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biography Dean J. Tantillo was born and raised in Quincy, Massachusetts. After earning an A.B. degree in Chemistry in 1995 from Harvard and a Ph.D. in 2000 from UCLA (working with Ken Houk), he carried out postdoctoral research with Roald Hoffmann at Cornell. He joined the Department of Chemistry at UC Davis in 2003, where he is currently a G

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Accounts of Chemical Research Hilvert, D.; Krengel, U. Electrostatic Transition State Stabilization Rather than Reactant Destabilization Provides the Chemical Basis for Efficient Chorismate Mutase Catalysis. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 17516−17521. (25) (a) Maity, P.; Pemberton, R. P.; Tantillo, D. J.; Tambar, U. K. Bronsted Acid Catalyzed Enantioselective Indole Aza-Claisen Rearrangement Mediated by an Arene CH-O Interaction. J. Am. Chem. Soc. 2013, 135, 16380−16383. (b) A related study: Beare, K. D.; McErlean, C. S. P. Revitalizing the Aromatic aza-Claisen Rearrangement: Implications for the Mechanism of ‘On-Water’ Catalysis. Org. Biomol. Chem. 2013, 11, 2452−2459. (26) (a) Johnston, R. C.; Cheong, P. H.-Y. C-H—O Non-classical Hydrogen Bonding in the Stereomechanics of Organic Transformations: Theory and Recognition. Org. Biomol. Chem. 2013, 11, 5057−5064. (b) Nishio, M. The CH/π Hydrogen Bond in Chemistry. Conformation, Supramolecules, Optical Resolution and Interactions Involving Carbohydrates. Phys. Chem. Chem. Phys. 2011, 13, 13873− 13900. (27) (a) Jiao, J.; von Rague Schleyer, P. Elimination of the Barrier to Cope Rearrangement in Semibullvalene by Li+ Complexation. Angew. Chem., Int. Ed. Engl. 1993, 32, 1760−1763. (b) Jiao, H.; Schleyer, P. v. R. Electrostatic Acceleration of Electrocyclic Reactions by Metal Cation Complexation: The Cyclization of 1,3-cis-5-Hexatriene into 1,3-Cyclohexadiene and the 1,5-Hydrogen Shift in Cyclopentadiene. The Aromaticity of the Transition Structures. J. Am. Chem. Soc. 1995, 117, 11529−11535. (c) Related studies on solvent effects: Seefelder, M.; Heubes, M.; Quast, H.; Edwards, W. D.; Armantrout, J. R.; Williams, R. V.; Cramer, C. J.; Goren, A. C.; Hrovat, D. A.; Borden, W. T. Experimental and Theoretical Study of Stabilization of Delocalized Forms of Semibullvalenes and Barbaralanes by Dipolar and Polarizable Solvents. Observation of a Delocalized Structure that is Lower in Free Energy than the Localized Form. J. Org. Chem. 2005, 70, 3437−3449. (28) Wang, S. C.; Tantillo, D. J. The Mechanism of Semibullvalene Bromination. Eur. J. Org. Chem. 2006, 2006, 738−745. (29) Wang, S. C.; Tantillo, D. J. Selective Stabilization of Transition State Structures for Cope Rearrangements of Semibullvalene and Barbaralane through Interactions with Halogens. J. Phys. Chem. A 2007, 111, 7149−7153. (30) Wang, S. C.; Tantillo, D. J. University of CaliforniaDavis, Davis, CA. Unpublished results, 2006. (31) Leading references: (a) Riley, K. E.; Hobza, P. The Relative Roles of Electrostatics and Dispersion in the Stabilization of Halogen Bonds. Phys. Chem. Chem. Phys. 2013, 15, 17742−17751. (b) Ford, M. C.; Ho, P. S. Computational Tools to Model Halogen Bonds in Medicinal Chemistry. J. Med. Chem. 2016, 59, 1655−1670. (32) Tantillo, D. J. Biosynthesis via Carbocations: Theoretical Studies on Terpene Formation. Nat. Prod. Rep. 2011, 28, 1035−1053. (33) Painter, P. P.; Wong, B. M.; Tantillo, D. J. Facilitating the Cope Rearrangement by Partial ProtonationImplications for Synthesis and Biosynthesis. Org. Lett. 2014, 16, 4818−4821. (34) Tantillo, D. J. Recent Excursions to the Borderlands between the Realms of Concerted and Stepwise: Carbocation Cascades in Natural Products Biosynthesis. J. Phys. Org. Chem. 2008, 21, 561−570. (35) An older but thorough review, with a different perspective on the catalysis of [3,3] shifts: Lutz, R. P. Catalysis of the Cope and Claisen Rearrangements. Chem. Rev. 1984, 84, 205−247.

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DOI: 10.1021/acs.accounts.6b00029 Acc. Chem. Res. XXXX, XXX, XXX−XXX