Mechanisms of Kobayashi eliminations for the generation of highly strained arynes, cyclic cumulenes, and anti-Bredt olefins

Abstract

First disclosed in 1983, the Kobayashi method for generating transient strained intermediates from 1,2-silyltriflate precursors has become an indispensable tool in organic synthesis. More than 1300 Kobayashi precursors to strained intermediates have been reported to date, leading to the use of these precursors in more than 17 000 strained intermediate trapping reactions. Surprisingly, the mechanism of the Kobayashi elimination to form strained intermediates has been studied only for the formation of benzyne. We report computational studies that determine the timing of Si–C and C–O cleavage, as well as the thermodynamics of strained intermediate formation. The calculated pathway for generating anti-Bredt olefins from Kobayashi precursors differs compared to the mechanism for strained intermediate generation of other species, with a particular dependence on the Si–C–C–O dihedral angle. These studies establish the mechanisms of Kobayashi eliminations and enable the rational design of new strained intermediate precursors for future use in synthesis.

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Introduction

Arynes and related strained intermediates have become common building blocks in organic synthesis.^1–4 Despite being historically avoided and having short lifetimes, such transient species have shown value in many areas, such as natural product synthesis,^5,6 heterocycle synthesis,^7,8 medicinal chemistry,⁹ ligand synthesis,¹⁰ organometallic and materials chemistry,^11,12 agrochemistry,¹³ DNA-encoded library synthesis,¹⁴ and more.¹⁵ Thousands of studies of such intermediates have been reported, with the field continuing to inspire new developments in synthesis.

A key technological advance that has fueled the widespread use of arynes and related strained intermediates in modern synthesis is the discovery of 1,2-silyltriflate precursors to strained intermediates.¹⁶ This strategy was first reported by Kobayashi and coworkers in 1983 and is highlighted in Fig. 1A.¹⁶ Reaction of silyltriflate 1 with furan (2) in the presence of tetramethylammonium fluoride (Me₄NF) delivers cycloadduct 4, presumably through the intermediacy of benzyne (3).

Fig. 1 (A) Seminal report by Kobayashi (1983).¹⁶ (B) Representative strained intermediates and Kobayashi-type precursors. (C) Overview of current study of the mechanism of Kobayashi eliminations.

This methodology was first applied to the preparation of benzyne, but it has been extended to the preparation of many other strained intermediates, such as other arynes,^17–19 non-aromatic cyclic alkynes,^20–22 cumulated alkenes (such as cyclic allenes and cyclic 1,2,3-trienes),^23–29 and anti-Bredt olefins³⁰ (see 5–12, Fig. 1B). More than 1300 distinct Kobayashi precursors to alkenes and alkynes are known,³¹ including heterocyclic Kobayashi precursors (e.g., 13–16),^32–35 which have collectively been deployed in more than 17 000 reactions reported in the literature.³¹ Factors that have rendered the Kobayashi methodology so practical include: (a) mild conditions for strained intermediate generation; (b) functional group compatibility; (c) safe use;³⁶ (d) enablement of different modes of reactivity (including pericyclic reactions, nucleophilic additions, annulations, cascade and tandem reactions, multi-component reactions, metal-catalysed reactions,^37,38 and σ-bond insertions³⁹); and (e) the aforementioned versatility in accessing distinct strained intermediate classes. Of note, transformations of strained intermediates generated from Kobayashi precursors commonly form two bonds, and are increasingly used to access structurally- and stereochemically-complex products.^2,4

What are the mechanisms of Kobayashi eliminations for formation of strained arynes, cycloalkynes, cumulenes and alkenes? Many theoretical studies of arynes and related intermediates exist, but these largely focus on structure and reactivity of the strained intermediates. For example, studies of ground state geometries,^40–42 strain,^43–46 energy of dehydrogenation,⁴⁷ reaction kinetics,^30,39,48,49 regioselective trappings,^{25,28,34,35,50,51} and further computational studies of trapping reactions are known.^52–54 In contrast, studies on how and why the Kobayashi elimination takes place has been reported in just two prior computational studies related to benzyne.^55,56 The aforementioned Yu et al. study was performed at the B3LYP/6-31G(d) level of theory and Biju et al. with M06-2X-D3/6-31G(d,p); both predict fluoride attack to give a pentavalent silicate anion as the rate determining step, with subsequent Si–C cleavage having a small barrier and C–O cleavage negligible, leaving considerable uncertainty about the E2 or E1cB mechanism of the elimination. Furthermore, the mechanisms by which other classes of strained intermediates, such as cyclic alkyne 5, cyclic allene 7, cyclic 1,2,3-triene 9 and anti-Bredt olefin 11 are formed from Kobayashi precursors have not been studied computationally.

We report computational studies of the mechanisms of Kobayashi eliminations to form strained intermediates (17a or 17b → 18a or 18b using fluoride (19), Fig. 1C). Density functional theory (DFT) calculations of the thermodynamics of formation of several distinct classes of strained intermediates are reported, along with mechanisms of generation of 3, 5, 9, and 11.⁵⁷ Although the fluoride-promoted elimination of the 1,2-silyltriflate motif ensures favourable thermodynamics in all cases, different elimination mechanisms are operative depending on the substrate. These studies not only serve to determine reaction mechanisms for Kobayashi eliminations, but provide guidance for the rational design of new strained intermediate precursors for use in synthesis.

Results and discussion

Thermodynamics of Kobayashi eliminations to form strained intermediates

The transient intermediates depicted in Fig. 1A and B, each validated many decades ago,^24,58–60 are well known to possess significant strain energies, ranging from ∼30 to >50 kcal mol⁻¹.^30,43,45,46 Nonetheless, Kobayashi eliminations can be used to access these high-energy species at ambient temperatures. We have computed the thermodynamics of formation of these strained intermediates via Kobayashi's fluoride-promoted elimination from different precursors.

As shown in Fig. 2, we examined reactions where a Kobayashi precursor, generally shown as 17a or 17b,⁶¹ is reacted with fluoride (19) to form alkynes 18a or alkenes 18b, respectively. The process is accompanied by the loss of Me₃SiF (20) and the triflate anion (21). This process was studied using DFT calculations, at the ωB97X-D/def2-QZVPP//ωB97X-D/6-31+G(d,p) level of theory, using SMD models of solvents used in experiments. This high level of theory was recently used to study aryne generation, albeit via a different base-mediated elimination mechanism.^62,63 We are only aware of computations of the thermodynamics for the generation of benzyne from a Kobayashi precursor,^55,56 whereas the corresponding computations for the generation of other strained cyclic intermediates (e.g., nonaromatic alkynes, cumulated alkenes, and anti-Bredt olefins) have not been reported.

Fig. 2 ΔG values for the fluoride-mediated generation of strained intermediates from their trimethylsilyltriflate precursors. All energies are reported in kcal mol⁻¹. Calculations were performed at the ωB97X-D/def2-QZVPP/SMD(solvent)//ωB97X-D/6-31+G(d,p)/SMD(solvent) level. Solvent = MeCN for entries 1–3, DMSO for entry 4, and toluene for entry 5 to mimic experimental conditions.

Results from the computational evaluation of thermodynamic favourability are summarized in Fig. 2. Beginning with the Kobayashi elimination of 1 to give benzyne (3), the reaction is calculated to be exergonic by 8.8 kcal mol⁻¹ (entry 1).⁶⁴ The generation of cyclohexyne (5) from 6 is even more thermodynamically favourable, (ΔG = −22.6 kcal mol⁻¹, entry 2) which is reasonable given the reduced strain present in 5 relative to 3.^22,46 The generation of 1,2-cyclohexadiene (7) from precursor 8 is also computed to be energetically favourable (entry 3).⁵⁷ The more negative ΔG of −31.7 kcal mol⁻¹ again is in line with reduced strain of 7, relative to 3 or 5.⁴⁵ We also considered the generation of 1,2,3-cyclohexatriene (9) and anti-Bredt olefin 11 (entries 4 and 5, respectively). Whereas the thermodynamics for the generation of 9 are akin to that of benzyne (3) (ΔG = −3.3 kcal mol⁻¹, entry 4), the formation of anti-Bredt olefin 11 from silyltriflate 22 is energetically downhill by 21.2 kcal mol⁻¹ (entry 5).

Several lessons are as follows: (a) computations on the thermodynamics for Kobayashi generation of various strained intermediates generally correlate with experimental findings; (b) for similar types of strained intermediates, the relative ΔG values are generally consistent with relative strain energies; (c) the formation of Me₃SiF (20) and the loss of a suitable leaving group (i.e., triflate anion 21; pK_a TfOH ca. −15) are essential for the success of these reactions; and (d) although different leaving groups can be used in Kobayashi eliminations,² the use of a silicon species and fluoride to trigger strained intermediate formation is essential, presumably due to the pronounced strength of the forming Si–F bond (bond dissociation energy (BDE) ≅ 135 kcal mol⁻¹).⁶⁵ Lastly, for practitioners designing new Kobayashi precursors to strained intermediates, the straightforward computations of the type shown in Fig. 2 are an excellent method to assess thermodynamic feasibility, prior to embarking on experiments.

Kobayashi elimination to form benzyne (3)

As noted earlier, computational studies of aryne trapping processes are well-known; however, studies pertaining to how arynes (and other strained intermediates) are actually generated from Kobayashi precursors are sparse, with seminal contributions by Li & Yan in 2017 ⁵⁵ and by Jindal & Biju in 2021.⁵⁶ Thus, we first computed the energy profile for the reaction of silyltriflate 1 with fluoride (19) to generate benzyne (3) (Fig. 3). Although this has been computed previously using B3LYP/6-31G(d),⁵⁵ we sought to examine the transformation using a higher level of theory (ωB97X-D/def2-QZVPP/SMD(MeCN)//ωB97X-D/6-31+G(d,p)/SMD(MeCN)), consistent with the computational methods used earlier in the present study.⁶² Indeed, the more advanced functional used here predicts an overall free energy change of −9 kcal mol⁻¹ versus the earlier value of −31 kcal mol⁻¹ obtained using B3LYP.⁵⁵

Fig. 3 Calculated energy profile for the fluoride-mediated elimination of silyltriflate 1 to generate benzyne (3) (ωB97X-D/def2-QZVPP/SMD(MeCN)//ωB97X-D/6-31+G(d,p)/SMD(MeCN)). All energies are reported in kcal mol⁻¹.

As shown in Fig. 3, addition of fluoride (19) to silyltriflate 1, gives pre-complex 23. From 23, formation of silicate 24 proceeds via TS-1 (ΔG^‡ = 9.4 kcal mol⁻¹). Silicate 24 then undergoes dissociation via TS-2 (ΔG^‡ = 7.5 kcal mol⁻¹) to furnish anion 25. The loss of Me₃SiF⁶⁶ (20) provides a driving force for the reaction (10.4 kcal mol⁻¹ downhill), given the notable strength of the Si–F bond⁶⁵ as discussed earlier. Benzyne (3) is then formed via elimination of triflate anion 21 from 25 via TS-3, with a barrier (ΔG^‡) of 5.7 kcal mol⁻¹. The overall reaction of silyltriflate 1 and fluoride anion (19) to give benzyne (3), Me₃SiF (20), and triflate anion 21 is thermodynamically favourable by 8.8 kcal mol⁻¹ as previously discussed.

We also considered an alternative pathway from 25 that has occasionally been observed experimentally for silyltriflates in specialized cases, which is the thia-Fries rearrangement to give phenoxide 26 (Fig. 3).^67–70 The mechanism of the thia-Fries rearrangement was expected to also proceed via aryl anion 25, lending some support for the intermediacy of 25 since it is common to both pathways (i.e., aryne formation and thia-Fries rearrangement).⁷¹ We examined this rearrangement mechanism and identified TS-4 as a plausible transition state. However, the barrier (ΔG^‡) for this process is 15.2 kcal mol⁻¹ and formation of benzyne (3) is favoured by 9.5 kcal mol⁻¹ (ΔΔG^‡). This explains why thia-Fries rearrangement is typically not observed in reactions of silyltriflate 1 under standard Kobayashi elimination conditions, but may be observed in other systems.⁷²

Several additional considerations should be noted. First, a concerted, E2-like transition state that would allow for the direct conversion of silicate 24 to benzyne (3), via postulated TS-5, was not found (Fig. 3). In addition, the elimination of 25 to form 3 has a barrier of only 5 kcal mol⁻¹. As proposed in Kobayashi's seminal report,¹⁶ the barrier to elimination is likely less than the barrier for the bimolecular reaction that would be required for protonation of 25, especially given the aprotic reaction conditions typically used in experiments. With the hope of finding experimental support for the intermediacy of 25, we have performed aryne generation experiments in the presence of excess t-BuOH and indeed observe the formation of some aryltriflate.⁷³ Overall, we conclude that the Kobayashi elimination to form benzyne (3) involves aryl anion 25 as a key intermediate and proceeds via an E1cB-type mechanism, whereas the direct elimination from silicate 24 to give benzyne (3) is disfavoured.

Mechanisms of Kobayashi eliminations to form cyclohexyne (5) and 1,2,3-cyclohexatriene (9)

Despite possessing differing functional groups (i.e., alkyne vs. cumulene), cyclohexyne (5) and 1,2,3-cyclohexatriene (9) are conceptually similar to benzyne (1), in that each possesses: (a) a functional group that ordinarily prefers a linear geometry, but is bent due to ring constraints; and (b) a highly reactive π bond that is essentially orthogonal to the other alkene or alkenes present in the strained intermediate. Kobayashi precursors to these intermediates and their derivatives have been reported, along with their use in many cycloaddition reactions.^20,22,24,25

As the mechanisms for the Kobayashi eliminations to give 5 or 9 from 6 ²⁰ or 10,²⁴ respectively, have not been reported previously, we studied both computationally (Fig. 4). The energy profiles were determined to be very similar to what we calculated for benzyne (3; see Fig. 3) and the full reaction coordinate diagrams are available in the SI (sections F and G, respectively). Most notably, for both pathways, computations support a mechanism involving silicate formation (not shown), generation of a discrete carbanion (27 or 28) with formation of Me₃SiF (20), followed by loss of the triflate anion (21) to give the strained intermediate (via transition state TS-6 or TS-7).⁷⁴ We note the following findings: (a) the formation of 20 and 21 are important driving forces for these processes, leading to the overall reactions being downhill by 22.6 and 3.3 kcal mol⁻¹ respectively, as noted earlier (see Fig. 2); (b) in the case of cyclohexyne (5), elimination of vinyl anion intermediate 27 is a barrierless pathway, whereas the corresponding elimination of vinyl anion intermediate 28 proceeds with an activation barrier (ΔG^‡) of 6.9 kcal mol⁻¹; (c) this difference is rationalized by comparing the relative strain energies of the two intermediates (∼40 kcal mol⁻¹ vs. ∼50 kcal mol⁻¹ for 5 vs. 3, respectively), and is consistent with the relative exothermicities (ΔG) of the eliminations; and (d) finally, we calculated similar reaction energy profiles and mechanisms for the Kobayashi eliminations to give two other 1,2,3 cyclic trienes, including an azacyclic 1,2,3-triene³⁵ (see the SI, Section I).

Fig. 4 (A) Abbreviated energy profile for the generation of cyclohexyne (5) (ωB97X-D/def2-QZVPP/SMD(MeCN)//(ωB97X-D/6-31+G(d,p)/SMD(MeCN)). All energies are reported in kcal mol⁻¹. (B) Abbreviated energy profile for the generation of 1,2,3-cyclohexatriene (9) (ωB97X-D/def2-QZVPP/SMD(MeCN)//(ωB97X-D/6-31+G(d,p)/SMD(MeCN)). All energies are reported in kcal mol⁻¹.

Kobayashi eliminations to form anti-Bredt olefins

Another intriguing class of Kobayashi precursors are those that allow for the generation of anti-Bredt olefins. The Kobayashi approach to anti-Bredt olefins was only recently disclosed²⁹ as a general method to overcome Bredt's rule and access alkenes that possess severe geometric distortion. A unique aspect of Kobayashi precursors to anti-Bredt olefins is that the substrates typically bear both the silicon and leaving group substituents on saturated carbons. This leads to variations in the relationship of the Si–C and C–O bonds, as well as lower stability of the presumed carbanion that would be generated if Si–C bond cleavage occurred, prior to alkene formation, as seen in the aforementioned cases. We have examined the Kobayashi elimination to generate anti-Bredt olefin 11, including stereochemical ramifications, computationally.

Fig. 5 shows the calculated free energy profile and mechanism for the reaction of silyltriflate 22 to give [2.2.1] anti-Bredt olefin 11. The feasibility of this overall conversion is supported by experiments.²⁹ Beginning with 22, the Si–C–C–O dihedral angle is 33°. Addition of fluoride anion (19), via precomplex 29, leads to transition state TS-8, with a very small overall barrier of 4.9 kcal mol⁻¹. Formation of silicate 30 is exergonic by 2.7 kcal mol⁻¹.

Fig. 5 Mechanism and energy profile for the fluoride-mediated generation of anti-Bredt olefin 11 from silyltriflate 22 (ωB97X-D/def2-QZVPP/SMD(toluene)//ωB97X-D/6-31+G(d,p)/SMD(toluene)). All energies are reported in kcal mol⁻¹.

From 30, we examined two pathways for generating anti-Bredt olefin 11. One pathway, the E1cB mechanism, involves formation of carbanion 31, which would be akin to the pathways found for the other strained intermediates discussed earlier (see benzyne (3), cyclohexyne (5), 1,2,3-cyclohexatriene (9); Fig. 3 and 4). However, a transition state to arrive at carbanion 31 from 30 could not be located, which is reasonable considering that carbanion 31 would be unstabilized and highly disfavourable.^75,76 Regarding the alternative pathway, silicate 30 is calculated to undergo facile E2-type elimination through TS-9, with an activation barrier (ΔG^‡) of 8.9 kcal mol⁻¹, to give anti-Bredt olefin 11. Of note, as the reaction proceeds, there is a progressive contraction of the Si–C–C–O dihedral angle (θ), beginning at 33° in 22, decreasing to 27° in silicate 30, and finally adopting an angle of 20° in TS-9. This suggests a strong stereoelectronic requirement for Kobayashi elimination on strictly aliphatic systems. As noted earlier, the overall process is 21.2 kcal mol⁻¹ downhill, driven by the energetically favourable release of Me₃SiF (20) and the triflate anion (21).

We also performed computations of the epimeric Kobayashi precursor, epi-22, with select results shown in Fig. 6. In this unreactive substrate, the Si–C–C–O dihedral angle is 72°. Silicate epi-30 can be generated analogously to 30 (see SI, Section K for further details); however, this was found to be an unproductive intermediate. More specifically, transition states leading to concerted 1,2-elimination or formation of a discrete carbanion could not be located. Direct elimination of the silicate, which is predicted to occur for epimer 30 (see Fig. 5), is presumably not feasible for epi-30 due to poor orbital overlap between the σ orbital of the breaking C–Si bond and the σ* orbital of the breaking C–O bond, as the Si–C–C–O dihedral angle in silicate epi-30 is 70°. Overall, these calculations are consistent with epi-22 not undergoing fluoride-mediated Kobayashi elimination experimentally²⁹ and further underscore the importance of the Si–C–C–O dihedral angle in allowing for generation of the strained intermediate.

Fig. 6 Study of unreactive substrate (epi-22) under fluoride-mediated conditions ((U)ωB97X-D/def2-QZVPP/SMD(toluene)//(U)ωB97X-D/6-31+G(d,p)/SMD(toluene)).

Study of impact of dihedral angle on Kobayashi eliminations of aliphatic systems

In order to further understand the importance of the Si–C–C–O dihedral angle for successful Kobayashi elimination to generate strained cyclic alkenes, such as anti-Bredt olefins, we performed computations involving the simplest silyltriflate, 32, as a model (Fig. 7A).⁷⁷ Kobayashi elimination of this model system would give ethylene (34). By systematically constraining the Si–C–C–O dihedral angles (θ) from 180° (anti-periplanar) to 0° (syn-periplanar), we could determine the impact of dihedral angle on the transition state barrier for elimination. Thus, optimized structures of silyltriflates 32 and their corresponding silicate anions 33 were calculated for structures with θ constrained to 180°, 0°, and angles at 15° intervals within those boundaries.⁷⁸ Additionally, concerted elimination transition states TS-10 were located for each constrained silicate 33 to give ethylene (34).

Fig. 7 (A) Computational study of fluoride-mediated generation of ethylene (34) from silyltriflate 32 with varying Si–C–C–O dihedral angles θ (ωB97X-D/def2-QZVPP/SMD(MeCN)//ωB97X-D/6-31+G(d,p)/SMD(MeCN)). (B) Key transition states TS-10a–c and geometric parameters. All energies are reported in kcal mol⁻¹.

Fig. 7A shows a plot of the ΔG of the transition state for elimination across the dihedral angles examined. Barriers are lowest for anti- or syn-eliminations, where θ is constrained to roughly 180° (TS-10a, ΔG ≅ 11 kcal mol⁻¹) or 0° (TS-10c, ΔG ≅ 13 kcal mol⁻¹), as these orientations lead to optimal overlap between the C–Si σ orbital and the C–O σ* orbital. Anti-elimination pathways (i.e., TS-10a) are most favourable, as is generally known for E2 eliminations.⁷⁹ The activation barrier for Kobayashi elimination increases dramatically as θ approaches 90° (TS-10b, ΔG ≅ 22 kcal mol⁻¹), reflective of poor orbital overlap in the transition state for elimination and the high strain of the eventual product with p orbitals oriented in an approximately perpendicular fashion.

TS-10a, TS-10b, and TS-10c are shown in Fig. 7B. The transition state geometries show very similar bond lengths in the favourable transition states TS-10a (θ = 180°) and TS-10c (θ = 0°). The breaking C–Si bond is 2.11 Å in both cases, whereas the breaking C–O bond is 1.69 Å or 1.74 Å, respectively. In contrast, the C–Si and C–O bonds in the disfavoured transition state TS-10b are elongated to 2.16 Å and 1.93 Å, respectively, indicative of a later transition state.

Finally, computations on plausible Kobayashi precursors of constrained aliphatic substrates are a valuable predecessor to substrate synthesis, since they can reveal difficulties that might arise in achieving the elimination.⁸⁰ The geometries seen in such Kobayashi precursors tend to be similar to that seen in the intermediate silicates formed after fluoride addition and, therefore, reasonably approximate the expected Si–C–C–O dihedral. Dihedral angles between 180–120° and 35–0° are appropriate for successful Kobayashi eliminations.

Conclusions

Kobayashi precursors to strained intermediates have become valuable building blocks in organic synthesis, resulting in >17 000 chemical reactions, with applications across numerous fields. Kobayashi precursors to arynes, cyclic alkynes, cyclic 1,2,3-trienes, cyclic allenes, and strained alkenes, such as anti-Bredt olefins, have been developed. Although the formation of benzyne had been studied previously, we investigated the mechanism in detail, as well as mechanisms for other classes of strained intermediates: strained alkenes, alkynes, and 1,2,3-trienes.

We find that: (a) Kobayashi eliminations, despite leading to highly strained intermediates, are thermodynamically favourable as a result of formation of the strong Si–F bond, as well as the loss of the excellent triflate leaving group; (b) all mechanisms proceed via initial formation of a silicate anion; and (c) the mechanism of elimination varies, either proceeding through desilylative carbanion formation, followed by elimination (for arynes, cyclic alkynes, and cyclic 1,2,3-trienes), or direct elimination of the silicate anion (for anti-Bredt olefins) in cases where the intermediate carbanion is highly unstable, so that triflate anion loss occurs with breaking of the Si–C bond. In the latter case, stereoelectronic requirements dictate the barrier of elimination.

Our studies help to inform the future design of Kobayashi precursors. We recommend that, prior to experiment, one calculate the thermodynamic feasibility of the conversion of the proposed Kobayashi precursor to the corresponding strained intermediate. Such calculations are relatively straightforward, not requiring transition state analysis, but provide important insight that can be used to encourage or discourage specific experiments. This process may be particularly useful in considering substituted versions of the strained intermediates we study here, as well as new strained intermediates that have not yet been generated using the Kobayashi approach. With regard to specific mechanisms, aryne, cyclic alkyne, and cyclic 1,2,3-triene generation pathways are thought to proceed via intermediate aryl or vinyl anions that eliminate a synperiplanar leaving group. Thus, in designing substrates, one can choose where to position the silicon and the leaving group, as well as the specific silicon and leaving group substituents. Generally speaking, one need not worry extensively about other stereoelectronic effects in these aryl or alkenyl systems (i.e., compared to stereoelectronic effects in anti-Bredt olefins), although the presence of adjacent substituents could plausibly impact the stability of the intermediate aryl or vinyl anion, leading to changes in mechanism or the rate of leaving group ejection. Lastly, in the case of aliphatic Kobayashi precursors to strained alkenes, such as anti-Bredt olefins, stereoelectronic considerations become important, as such reactions are thought to not proceed via an intermediate carbanion.⁸¹ It is advised to target Si–C–C–leaving group dihedral angles between 180–120° (for trans elimination) and 35–0° (for cis elimination) in the substrate to optimize chances of successful Kobayashi elimination.

Our studies provide fundamental insight regarding the thermodynamics and mechanisms of Kobayashi eliminations, which enable the rational design of new strained intermediate precursors for future uses in synthesis.

Author contributions

Z. G. W. and D. C. W. designed, performed, and analysed computational studies. K. N. H. advised on computational findings. N. K. G. directed the computational investigation and prepared the manuscript with contributions from all authors; all authors contributed to discussions.

Conflicts of interest

There are no conflicts to declare.

Data availability

Full details on the computational methods used, supplementary computations, and experimental protocolsare accessible in the SI. See DOI: https://doi.org/10.1039/d5sc03943f.

Acknowledgements

The authors are grateful to the NIH-NIGMS (R35 GM139593 for N. K. G.), the Trueblood Family (for N. K. G.), the Foote Family (for Z. G. W.), the UCLA Graduate Division Dissertation Year Fellowship (for D. C. W.), the Stone Family (for D. C. W.), and the National Science Foundation (CHE-2153972 to K. N. H.). Calculations were performed on the Hoffman2 cluster and the UCLA Institute of Digital Research and Education (IDRE) at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575). These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631)

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74. We also considered direct E2-like elimination of the silicate intermediate in both cases but were unable to locate transition states for those possible pathways. However, in our computational studies of a substituted cyclic 1,2,3-triene and its Kobayashi precursor (see SI, Section H for details), the barrier for this type of direct elimination was located. The barrier for the silicate intermediate undergoing direct elimination was found to be higher than the barrier for vinyl anion formation, supporting the notion that vinyl anion formation is the preferred pathway.
75. Prior studies have shown this carbanion is not a stationary point on the potential energy surface and undergoes spontaneous elimination upon attempted geometry optimization; see: G. W. Breton and J. V. Ridlehoover, Spontaneous formation of strained anti-Bredt bridgehead alkenes upon computational geometry optimization of bicyclic β-halo carbanions, Organics, 2024, 5, 205–218.
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77. Calculations were performed in MeCN as this is a common solvent for strained intermediate generation.
78. Optimization of the starting silyltriflate 32 and silicate 33 were performed using dihedral constraints on the Si–C–C–O bond set to the given angle. See SI, Section L for further details.
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80. In unconstrained aliphatic systems, free rotation or conformational changes may be readily achieved, which may render such calculations unnecessary. Thus, what we propose is likely most valuable on rigid or otherwise constrained systems, such as anti-Bredt olefins.
81. This present study is limited to the aliphatic systems shown that do not possess adjacent substituents that could plausibly stabilize an intermediate alkyl anion, such as ketones, olefins, or aromatic rings. In such cases, the mechanisms may vary depending on the exact substrate.

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Footnote

† These authors contributed equally to this work.

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