Cyclopropylcarbinyl-to-homoallyl carbocation equilibria influence the stereospecificity in the nucleophilic substitution of cyclopropylcarbinols

Abstract

The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek in 2020 (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 phenyl-substituted substrates the stereoselectivity of the reaction is poor and a mixture of diastereomers is obtained. In order to understand the nature of the intermediates involved in this transformation and explain the loss of selectivity for certain substrates, we have performed a Density Functional Theory investigation of the reaction mechanism at the DLPNO-CCSD(T)/Def2TZVPP level of theory. Our results indicate that cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures and as such are not involved, regardless of the substitution pattern on the substrate. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations have been located, including rotations around their π-bonds and ring openings to homoallylic cations. Importantly, the relative energies of these homoallylic cations and of the activation barriers to reach them are correlated to the nature of the substituents. While direct nucleophilic attack on the chiral cyclopropylcarbinyl cation is kinetically favored for most systems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of selectivity through a mixture of rearranged carbocation intermediates. As such, it appears that stereospecific reactions of chiral cyclopropylcarbinyl cations depend on the ability of these cations to access homoallylic structures, from which selectivity is not guaranteed.

Taming nonclassical carbocations to control small ring reactivity

“…2B and section S11). The influence of a noncoordinating tetrafluoroborate counterion on the structure of CC and BB cations has been calculated by Larmore and Champagne (22); their findings highlight the possibility that different counterions could also have an impact on the stereoselectivity of nucleophilic additions, which may explain the consistent stereoselectivity observed in the individual and competition experiments using acetate and chloride nucleophiles (see Figs. 2 and 3A).…”

“…Elegant examples of specific outcomes from systems predisposed to form one product have been described (Fig. 1C) (15)(16)(17)(18)(19)(20)(21), as well as computational explorations (22)(23)(24), but a general predictive model is yet to emerge.…”

Highly Diastereoselective Preparation of Tertiary Alkyl Thiocyanates en Route to Thiols by Stereoinvertive Nucleophilic Substitution at Nonclassical Carbocations

“…Remarkably, these strategies result in a complete inversion of configuration, further enhancing our understanding and control of stereochemical outcomes in these reactions. Recent computational studies validate the existence of a stable nonclassical cyclopropylcarbinyl cation intermediate B, which undergoes the nucleophilic substitution at the most substituted quaternary carbon center in a stereoinvertive manner, 35 providing a new approach for achieving challenging adjacent tertiary and quaternary carbon stereocenters that are otherwise difficult to access. Taking inspiration from these findings, we hypothesized that an efficient method for the preparation of acyclic tertiary alkyl thiocyanates with complete diastereocontrol could originate from an appropriate combination of a thiocyanate precursor with a Lewis acid (Scheme 1c).…”

“…The highest density of positive charge is located at the quaternary carbon stereocenter that reacts with the nucleophile (TMSNCS) to furnish thiocyanate 2a with a complete inversion of configuration. 35 In a noteworthy transformation, thiocyanate 2p easily produced tertiary thiol 3 when exposed to lithium aluminum hydride (LAH) in THF as a solvent at room temperature. 37 This reaction offers a practical route for obtaining tertiary thiols with excellent yields and diastereomeric ratios (Scheme 4).…”

Stereoselective Nucleophilic Halogenation at CF3-Substituted Nonclassical Carbocation

“…Indeed, we have recently reported that cyclopropyl carbinol derivatives 1 5a featuring a quaternary carbon stereocenter at C 4 undergo a smooth Lewis acidcatalyzed ring opening, resulting in the formation of the nonclassical cyclopropylcarbinyl carbocation intermediate CPC. 6 Given the asymmetrical substitution pattern at C 3 and C 4 of CPC, the C 2 −C 4 bond exhibits a slightly longer bond length, compared to the C 2 −C 3 bond. 5e Consequently, the nucleophile is expected to preferentially react at C 4 , resulting in the stereospecific formation of 2 with a complete inversion of configuration with a very high diastereoselectivity as a single Eisomer (Scheme 1b).…”