Intra- versus Intermolecular Carbon-to-Carbon Proton Transfers in the Reactions of Arynes with Nitrogen Nucleophiles: A DFT Study

Abstract

Carbon-to-carbon proton transfer (PT) is an elementary reaction in organic chemistry. Herein we report a systematic DFT study on the carbon-to-carbon proton transfers in the reactions of arynes with nitrogen nucleophiles, including tertiary amines, aziridines, imines, and N-heteroarenes. DFT calculations indicated that the Gibbs energies of activation for the 1,4- and 1,5-proton transfers involved are lower than 20 kcal/mol in most cases. We also found that the Bell-Evans-Polanyi principle applies to the 1,4-proton transfers, indicating that the more exergonic an intramolecular proton transfer is (the more stable a carbanion is generated), the faster it will be. Previous experimental studies have shown that, in the presence of a carbon nucleophile (NuH; e.g., CHCl and MeCN) as the third component (also as the solvent), intermolecular proton abstractions may compete with the intramolecular proton transfers and lead to different products. Our theoretical rationalization of these competitions is that the introduction of an electron-withdrawing group at the acidic site can accelerate the intramolecular proton transfer dramatically (owing to the generation of a more stable carbanion), making it compete with the intermolecular processes. In addition, we have also discussed the competition between intra- and intermolecular proton transfers when NuH is used as the reactant rather than the solvent.

Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow

“…Using the optimized conditions, a collection of substituted arynes and imides was reacted. According to the proposed mechanism, the aryne insertion proceeds via intermediacy of 8 . ,, Greaney et al showed that a major byproduct results from premature protonation of 8 . Remarkably, under flow conditions, even the use of wet acetonitrile did not increase the amount of byproduct, thus rendering the flow process more sustainable.…”

Domino Processes of Arynes Reacting with Three Classes of Nucleophiles for Organic Syntheses

“…The formation of epoxides 9 , 14 , and 16 includes sequential 1,2‐elimination, 1,2‐nucleophilic addition, 1,4‐proton shift, [16] and the Johnson‐Corey‐Chaykovsky [17,18] reaction (i. e., three‐membered ring formation followed by α‐elimination) shown in Scheme 3. Reactions involving arynes as the intermediates are sensitive to the media, such as chloroform and acetonitrile [19] . The protons therein might offer a chance of intermolecular transfer to the betaine intermediates like 11 through the pathway “b”.…”

“…Reactions involving arynes as the intermediates are sensitive to the media, such as chloroform and acetonitrile. [19] The protons therein might offer a chance of intermolecular transfer to the betaine intermediates like 11 through the pathway "b". This possible interference, however, was overwhelmed by the intramolecular 1,4-proton shift pathway "a", which led betaines 11 to sulfonium ylides 12.…”

Formal Insertion of Imines (or Nitrogen Heteroarenes) and Arynes into the C–Cl Bond of Carbon Tetrachloride

“…During our recent exploration of the chemistry of imines activated by arynes, − we unexpectedly found that a three-component mixture of imine 1a , 2-(trimethylsilyl)­phenyl triflate ( 2a ) (as a benzyne precursor), and carbon tetrachloride ( 3a ) in the presence of CsF proceeded in acetonitrile at 65 °C to afford polychlorinated compound 4a in 87% yield (Table , entry 1). This three-component reaction involves an unprecedented formal insertion of an imine and an aryne into the C–Cl bond of carbon tetrachloride.…”

“…In addition to the reaction pathway mentioned above, there are two competing pathways for aryl anion A (Figure b). One is the intramolecular 1,4-proton transfer via transition state TS3 (the Gibbs energy of activation is 20.8 kcal/mol). , The other is the intermolecular proton abstraction from MeCN via transition state TS4 (the Gibbs energy of activation is 13.0 kcal/mol). , In comparison to the chlorine transfer, these two proton transfer processes are both kinetically disfavored . To verify whether the same conclusions hold for nitrogen heteroarenes, we performed additional DFT calculations by using isoquinoline as a representative example of nitrogen heteroarenes (Figure c).…”