Difluorobenzocyclooctyne: Synthesis, reactivity, and stabilization by β-cyclodextrin

Ellen M. Sletten, Hitomi Nakamura, John C Jewett, Carolyn R. Bertozzi

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Highly reactive cyclooctynes have been sought as substrates for Cu-free cycloaddition reactions with azides in biological systems. To elevate the reactivities of cyclooctynes, two strategies, LUMO lowering through propargylic fluorination and strain enhancement through fused aryl rings, have been explored. Here we report the facile synthesis of a difluorobenzocyclooctyne (DIFBO) that combines these modifications. DIFBO was so reactive that it spontaneously trimerized to form two asymmetric products that we characterized by X-ray crystallography. However, we were able to trap DIFBO by forming a stable inclusion complex with β-cyclodextrin in aqueous media. This complex could be stored as a lyophilized powder and then dissociated in organic solvents to produce free DIFBO for in situ kinetic and spectroscopic analysis. Using this procedure, we found that the rate constant for the cycloaddition reaction of DIFBO with an azide exceeds those for difluorinated cyclooctyne (DIFO) and dibenzocyclooctyne (DIBO). Cyclodextrin complexation is therefore a promising approach for stabilizing compounds that possess the high intrinsic reactivities desired for Cu-free click chemistry.

Original languageEnglish (US)
Pages (from-to)11799-11805
Number of pages7
JournalJournal of the American Chemical Society
Volume132
Issue number33
DOIs
StatePublished - Aug 25 2010
Externally publishedYes

Fingerprint

Azides
Cycloaddition
Cyclodextrins
Cycloaddition Reaction
Stabilization
Click Chemistry
Fluorination
Spectroscopic analysis
Halogenation
X ray crystallography
X Ray Crystallography
Biological systems
Complexation
Powders
Organic solvents
Rate constants
Kinetics
Substrates

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Difluorobenzocyclooctyne : Synthesis, reactivity, and stabilization by β-cyclodextrin. / Sletten, Ellen M.; Nakamura, Hitomi; Jewett, John C; Bertozzi, Carolyn R.

In: Journal of the American Chemical Society, Vol. 132, No. 33, 25.08.2010, p. 11799-11805.

Research output: Contribution to journalArticle

Sletten, Ellen M. ; Nakamura, Hitomi ; Jewett, John C ; Bertozzi, Carolyn R. / Difluorobenzocyclooctyne : Synthesis, reactivity, and stabilization by β-cyclodextrin. In: Journal of the American Chemical Society. 2010 ; Vol. 132, No. 33. pp. 11799-11805.
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