Ylidenenorbornadiene Carboxylates: Experimental Kinetic Analysis of a Nucleophile-Induced Fragmentation Reaction

Abstract

Ylidenenorbornadienes (YNDs), prepared by [4 + 2] cycloadditions between fulvenes and acetylene carboxylates, react with betamercaptoethanol to yield a mixture of four diastereomers. These four diastereomers fragment via a retro-[4 + 2] cycloaddition at differing rates. A simulated kinetics approach extrapolated the rate constants of the diastereomers from the observed rate data. YNDs display wide variability in rate of fragmentation, dependent on the stereoelectronics of the ylidene substituents. A substrate containing one carboxylic ester proved exceptionally stable to fragmentation.

Experimental and Theoretical Exploration of the Kinetics and Thermodynamics of the Nucleophile-Induced Fragmentation of Ylidenenorbornadiene Carboxylates

“… a Our previous report provided k obs values from linear fits of the curved integrated rate data for the fragmentation of the mixture of diastereomers taken to 90% completion. Herein, we report more representative k obs values obtained from the reaction taken to 50% completion. b Diastereomer ratios were determined from 1 H NMR resonances of alkene protons. c 1 H NMR resonances for the signals corresponding to d1 and d2 were slightly overlapping. …”

“…Full experimental details, including synthetic and kinetic procedures and characterization details (PDF) Full computational methods, energies, and Cartesian coordinates for all optimized structures and transition state structures and 1 H and 13 C NMR spectra for new compounds (PDF) The temperature was increased to 90 °C for the Hammett study substrates such that the study of slower-to-fragment substrates could be completed in overnight NMR experiments. b Our previous report 23 provided k obs values from linear fits of the curved integrated rate data for the fragmentation of the mixture of diastereomers taken to 90% completion. Herein, we report more representative k obs values obtained from the reaction taken to 50% completion.…”

“…We previously utilized these reactions as dynamic covalent linkages to understand and manipulate polymer topology and solubility. − Seminal work by the Finn group has shown that furans can react via [4 + 2] cycloadditions with alkyl acetylenedicarbonyls to yield oxanorbornadienes (ONDs), which can be fragmented via a retro-[4 + 2] cycloaddition after conjugate addition of an appropriate nucleophile. − The furan component is thus “clicked” on to an alkyl acetylenedicarboxylate and subsequently “clipped” off again after reaction with the nucleophile, as depicted in Scheme . These OND “click-and-clip” systems have already shown utility as fluorogenic probes, , pharmaceutical delivery systems, ,− linkages in degradable hydrogels, , and scaffolds toward the synthesis of difficult-to-prepare substituted heterocycles. , We have further built on this “click-and-clip” strategy by reacting fulvene substrates in the place of furans with alkyl acetylenedicarboxylates to yield ylidenenorbornadienes (YNDs) …”

“…However, the DFT functional M06-2X identified 6a:d1 and 6a:d2 as faster to fragment than the other two diastereomers (6a:d3 and 6a:d4) but calculated Table 4. Effect of Ester Substitution on Fragmentation Kinetics of YND−BMEs a Our previous report 23 provided k obs values from linear fits of the curved integrated rate data for the fragmentation of the mixture of diastereomers taken to 90% completion. Herein, we report more representative k obs values obtained from the reaction taken to 50% completion.…”

“…Energies in kcal/mol. Energies were calculated at 25 °C and 1 atm with DMSO implicit solvent, and the experimental energies were calculated at 25 °C using the parameters from Arrhenius plot 23. a experimental free energy of activation for 6a:d4 was not measured because this diastereomer was rerecovered as only 4% of the total diastereomeric mixture, and it fragmented much slower relative to the other three diastereomers.…”