Rearrangement and nucleophilic trapping of bicyclo[4.1.0]hept-2-yl derived nonclassical bicyclobutenium ions

Saunders, James; Adamson, Christopher; Ganga-Sah, Yumeela; Lewis, Andrew R.; Bennet, Andrew J.

doi:10.1139/cjc-2017-0569

Cited by 3 publications

(2 citation statements)

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“…The base cyclopropylcarbinyl/bicyclobutonium cation (C 4 H 7 + ) system has been heavily studied since Roberts’ 1951 report that cyclobutyl and cyclopropylcarbinyl electrophiles solvolyze readily to form the same mixture of cyclobutyl, cyclopropylcarbinyl, and homoallyl products, hinting at a common intermediate . CPC/BCB cations have since been proposed as intermediates in a variety of organic reactions/rearrangements − and terpene biosynthetic pathways. − An array of spectroscopic, NMR, and computational techniques have been used to probe the C 4 H 7 + system, − which is now understood as an equilibrating mixture of triply degenerate σπ-bisected cyclopropylcarbinyl I and non-classical bicyclobutonium II cations (Figure B). These are similar in energy and interconvert stereospecifically through low-energy transition structures (TSs) on a flat potential energy surface (PES).…”

Section: Introductionmentioning

confidence: 99%

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

Larmore

Champagne

2023

J. Org. Chem.

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The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek (J. Am. Chem. Soc. 2020, 142, 5543−5548), is one of the few reported examples of stereospecific nucleophilic substitution involving chiral bridged carbocations. However, for the phenylsubstituted substrates, poor specificity is observed and mixtures of diastereomers are obtained. To understand the nature of the intermediates involved and explain the loss of specificity for certain substrates, we have performed a computational investigation of the reaction mechanism using ωB97X-D optimizations and DLPNO-CCSD(T) energy refinements. Our results indicate that cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures that are not involved. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations were located, including ring openings to homoallylic cations. The activation barriers required to reach such structures are correlated to the nature of the substituents; while direct nucleophilic attack on the chiral cyclopropylcarbinyl cations is kinetically favored for most systems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of specificity through rearranged carbocation intermediates. As such, stereospecific reactions of chiral cyclopropylcarbinyl cations depend on the energies required to access their corresponding homoallylic structures, from which selectivity is not guaranteed.

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Section: Introductionmentioning

confidence: 99%

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

Larmore

Champagne

2023

J. Org. Chem.

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“…7 The CC-BB system has found applications in glycosidase inhibition by aiding the generation of an aspartate trapping agent through neighbouring group participation. [8][9][10] CC-BB has also been proposed as an intermediate in fatty acid, steroid, and terpene biosynthesis (Fig. 1b).…”

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confidence: 99%

Taming non-classical carbocations to control small ring reactivity

McNamee

Frank

Christensen

et al. 2023

Preprint

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The positional selectivity of ring opening of small, strained organic rings is often considered to be governed by the maximal release of ring strain. However, reactions under cationic conditions can lead to multiple products due to the intermediacy of non-classical carbocations (carbonium ions cations featuring a formally pentavalent carbon atom). A famous example is the solvolysis of cyclobutyl or cyclopropylmethyl derivatives, which proceed via two equilibrating non-classical carbocations the cyclopropylcarbinyl ion (CC), and the bicyclobutonium ion (BB) generating up to three products on nucleophilic capture. The utility of such reactions is therefore often limited, despite the value of the small ring products. Using bicyclo[1.1.0]butanes (BCBs) as a template, we show that the regiochemical outcome of small ring opening can be controlled by subtle changes to the structure of non-classical carbocation intermediates, in turn enabling the rational prediction of regioselectivity. We find that the regio- and stereochemistry of ring opening depends not only on the degree of substitution, but also the nature of the substituents, of the BCB ring system and its resulting cationic intermediate. We show that these outcomes can be rationalised by computational models, where bond lengths in the non-classical carbocation inform on the site of reaction. As BCBs are finding increasing use as tools in chemical synthesis and bioconjugation, understanding the factors that control their ring opening offers new opportunities for applications of these molecules. These findings also have consequences for the design of other chemical transformations that proceed through such non-classical intermediates.

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Carbocations

Moreira

2021

Organic Reaction Mechanisms Series

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Rearrangement and nucleophilic trapping of bicyclo[4.1.0]hept-2-yl derived nonclassical bicyclobutenium ions

Cited by 3 publications

References 18 publications

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

Cyclopropylcarbinyl-to-Homoallyl Carbocation Equilibria Influence the Stereospecificity in the Nucleophilic Substitution of Cyclopropylcarbinols

Taming non-classical carbocations to control small ring reactivity

Carbocations

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