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 (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.

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, 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 c).…”

“…Hence, the reaction produces cyclopropyl cation A that is transformed into cyclopropylcarbinyl cation (CPC) B . 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 …”

“…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).…”

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations

“…For instance, Feringa, Houk and Fujita reported in 2018 that cycloheptenyl bromide III undergoes an enantiospecific rearrangement to its cyclohexenyl derivative IV under Lewis acid catalysis, a process that involves CPC cation V . Similarly, Marek has published a series of reports starting in 2020, discussing how cyclopropylcarbinols VI form homoallylic products VII with high diastereoselectivity, as long as no aromatic substituent is located at the R 3 or R 4 positions. − Our group studied this system computationally and showed that CPC intermediate VIII is responsible for the observed selectivity . This cation only rearranges faster than nucleophilic trapping when R 3 is an aryl substituent, which enables a classical homoallylic cation to intervene, leading to reduced specificity.…”

Stereoselective Nucleophilic Halogenation at CF3-Substituted Nonclassical Carbocation

“…Inspired by previous results from our group in controlling the stereochemistry of S N 1 reactions involving nonclassical carbocations (Scheme b), we wondered whether we could employ a similar strategy to prepare acyclic molecular backbones containing the CF 3 groups with adjacent stereocenters, alongside additional halogens, including fluorine (Scheme c). Indeed, we have recently reported that cyclopropyl carbinol derivatives 1 featuring a quaternary carbon stereocenter at C 4 undergo a smooth Lewis acid-catalyzed ring opening, resulting in the formation of the nonclassical cyclopropylcarbinyl carbocation intermediate CPC . 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 .…”