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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Alkyne-Localized Strain Engineering toward Next-Generation High-Reactivity Bridged Cyclooctynes
Abdulkader Baroudi1, Hajer Makhseed1, Khaled Jaradat1
1College of Engineering and Technology, American University of the Middle East, Egaila 54200, Kuwait.
The Journal of Organic Chemistry
|June 1, 2026
Summary
Bridge topology in cyclooctynes significantly impacts bioorthogonal chemistry reactivity. Specifically, alkyne-localized distortion, not overall ring strain, dictates reaction speed in Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC).
Area of Science:
- Bioorthogonal Chemistry
- Computational Chemistry
- Organic Chemistry
Background:
- Strain engineering is key for tuning cycloalkyne reactivity in bioorthogonal chemistry.
- The impact of bridge topology on cycloalkyne structure and reactivity is not well understood.
Purpose of the Study:
- To investigate how bridge topology influences alkyne-localized distortion, independent of overall ring strain.
- To identify cyclooctyne architectures with enhanced reactivity for Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC).
Main Methods:
- High-level DLPNO-CCSD(T) calculations were employed.
- A series of bridged cyclooctynes were systematically examined.
- Correlation between alkyne distortion and activation barriers was analyzed.
Main Results:
- Activation barriers in SPAAC correlate with alkyne-localized strain, not total ring strain or reaction thermodynamics.
- Propargylicly bridged cyclooctynes, particularly with larger bridges, show reduced activation barriers.
- Alkyne bond angles serve as a reliable predictor of reactivity (R² = 0.95).
Conclusions:
- Alkyne-localized distortion is the primary determinant of SPAAC reactivity.
- Bridge topology is a critical factor in designing next-generation cyclooctynes.
- Geometric effects of heteroatom substitutions depend on their position within the cyclooctyne scaffold.
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