Conspectus
Organic
azides are involved in a variety of useful transformations,
including nitrene chemistry, reactions with nucleophiles and electrophiles,
and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute
a major class of highly reliable and versatile reactions, as shown
by the development and rapid adoption of click chemistry and bioorthogonal
chemistry. Metal-catalyzed azide–alkyne cycloaddition (Cu/RuAAC),
the prototypical click reaction, has found wide utility in pharmaceutical,
biomedical, and materials sciences. The strain-promoted, or distortion-accelerated,
azide–alkyne cycloaddition eliminates the need for a metal
catalyst.
In the azide-mediated 1,3-dipolar cycloaddition reactions,
azides
are ambiphilic, i.e., HOMO–LUMO-controlled dipoles where both
the HOMO and LUMO interact strongly with the dipolarophile. Azide–alkyne
cycloaddition proceeds primarily through the HOMOazide–LUMOdipolarophile interaction, and electron-deficient dipolarophiles
react more readily. The inverse-electron-demand reaction, involving
the LUMOazide–HOMOdipolarophile interaction,
is less common because of the low stability of electron-deficient
azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless,
there have been reports since the 1960s showing enhanced reaction
kinetics between electron-poor azides and electron-rich dipolarophiles.
Our laboratory has developed the use of perfluoroaryl azides (PFAAs),
a class of stable electron-deficient azides, as nitrene precursors
and for reactions with nucleophiles and electron-rich dipolarophiles.
Perfluorination on the aryl ring also facilitates the synthesis of
PFAAs and quantitative analysis of the products by 19F
NMR spectroscopy.
In this Account, we summarize key reactions
involving electrophilic
azides and applications of these reactions in materials synthesis
and chemical biology. These electron-deficient azides exhibit unique
reactivity toward nucleophiles and electron-rich or strained dipolarophiles,
in some cases leading to new transformations that do not require any
catalysts or products that are impossible to obtain from the nonelectrophilic
azides. We highlight work from our laboratories on reactions of PFAAs
with enamines, enolates, thioacids, and phosphines. In the reactions
of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition
products undergo further rearrangement to give amidines or amides
as the final products at rates of up to 105 times faster
than their non-fluorinated anlogues. Computational investigations
by the distortion/interaction activation strain model reveal that
perfluorination lowers the LUMO of the aryl azide as well as the overall
activation energy of the reaction by decreasing the distortion energies
of the reactants to reach the transition states. The PFAA–enamine
reaction can be carried out in a one-pot fashion using readily available
starting materials of aldehyde and amine, making the reaction especially
attractive, for example, in the functionalization of nanomaterials
and derivatization of anti...