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Abstract Benzylic and allylic electrophiles are well known to react faster in SN2 reactions than aliphatic electrophiles, but the origins of this enhanced reactivity are still being debated. Galabov, Wu, and Allen recently proposed that electrostatic interactions in the transition state between the nucleophile (Nu) and the sp2carbon (C2) adjacent to the electrophilic carbon (C1) play a key role. To test this secondary electrostatic hypothesis, molecular rotors were designed that form similar through‐space electrostatic interactions with C2 in their bond rotation transition states without forming bonds to C1. This largely eliminates the alternative explanation of stabilizing conjugation effects between C1 and C2 in the transition state. The rotor barriers were strongly correlated with the experimentally measured SN2 free energy. Notably, rotors where C2 was sp2or sp‐hybridized had barriers that were consistently 0.5–2.0 kcal mol−1lower than those for rotors where C2 was sp3‐hybridized. Computational studies of atomic charges were consistent with the formation of stabilizing secondary electrostatic interactions. Further confirmation came from observing the benzylic effect in rotors where the first atom was varied, including oxygen, sulfur, nitrogen, and sp2‐carbon. In summary, these studies provided strong experimental support for the role of secondary electrostatic interactions in the SN2 reaction.
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Molecular Rotors as Reactivity Probes: Predicting Electrophilicity from the Speed of Rotation
Abstract A new empirical electrophilicity reactivity parameter,ERB, was developed based on the rotational barriers of a series ofN‐phenylimide molecular rotors containing various electrophilic groups. In the bond rotation transition state, these electrophilic groups form close contact with an electronegative C═O oxygen. Thus, strong electrophilic groups significantly lowered the rotational barrier. As a result, the rotational barriers were inversely correlated with the strengths of the electrophiles. The rotational barriers were measured by dynamic NMR (EXSY), enabling the quantification across a wide range of types of electrophiles. Computational analysis confirmed that the observed variations arose from intramolecular interactions in the transition state, where the C═O oxygen served as a probe of both the electrophilic group's electrostatic potential and steric accessibility. By simultaneously capturing attractive and repulsive transition state interactions,ERBprovides an effective means of predicting electrophilicity and reactivity trends across a broad range of electrophiles and reaction types. The utility ofERBwas initially validated using a series of rotors containing Michael addition electrophiles, followed by broader application to a diverse array of reactions involvingsp3andsp2electrophiles, including SN2, SNAr, Pd‐oxidative addition, and Sonogashira reactions.
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- Award ID(s):
- 2304777
- PAR ID:
- 10634419
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 64
- Issue:
- 36
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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