Origin of regioselectivity in α-humulene functionalization

Area of Science:

• Biochemistry
• Computational Chemistry
• Organic Chemistry

Background:

• Humulene is a sesquiterpene with a significant biochemical structure.
• It possesses an 11-membered ring with three nonconjugated C═C double bonds.
• A notable observation is the differential reactivity of its two triply substituted C═C double bonds.

Purpose of the Study:

• To computationally investigate the conformational space of humulene.
• To rationalize the observed regioselectivity in humulene's reactions.
• To understand the influence of conformation on reactivity.

Main Methods:

• Density Functional Theory (DFT) functionals were employed.
• Exploration of the conformational landscape and potential energy surfaces.
• Intrinsic Reaction Coordinate (IRC) analyses for interconversion pathways.
• Microcanonical partition function evaluation for entropy contributions.
• Nuclear Magnetic Resonance (NMR) spectroscopy at variable temperatures.

Main Results:

• Four distinct chiral conformations of humulene were identified, totaling eight conformers.
• The potential energy surface and interconversion pathways were characterized.
• Entropy contributions and temperature-dependent equilibrium compositions were calculated.
• A strong, hyper-conjugative orbital overlap (σ(Cα-Cβ)-π(C═C)) was identified as the cause of regioselectivity.
• Calculated activation energies for conformer interconversions align with NMR data.

Conclusions:

• The peculiar regioselectivity of humulene is attributed to specific orbital interactions in its predominant conformations.
• Computational modeling provides a robust explanation for experimental observations.
• Conformational analysis is crucial for understanding the reactivity of sesquiterpenes like humulene.