Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes

Dommerholt, Jan; Rooijen, Olivia van; Borrmann, Annika; Guerra, Célia Fonseca; Bickelhaupt, F. Matthias; Delft, Floris L. van

doi:10.1038/ncomms6378

Cited by 159 publications

(163 citation statements)

References 44 publications

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“…Even more markedly, picryl azide was found to react with norbornene almost 1000 times faster than phenyl azide [2]. Based on these observations, we recently concluded that the apparent slower reaction of electron-poor azides in SPAAC only holds for benzoannulated cyclooctynes (with low-lying LUMO), while in combination with more electronrich cyclooctynes (like BCN), azides can react by a second, inverse electrondemand mechanism (i.e., SPAAC) as well [20]. As a result, it was first found that strain-promoted cycloaddition of aromatic azides with BCN is nearly eight times faster than with DIBAC, which is the opposite trend for reaction with benzyl azide.…”

Section: Influence Of Azide Structure On Reaction Ratementioning

confidence: 98%

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

Dommerholt

Rutjes

Delft

2016

Cycloadditions in Bioorthogonal Chemistry

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A nearly forgotten reaction discovered more than 60 years ago-the cycloaddition of a cyclic alkyne and an organic azide, leading to an aromatic triazole-enjoys a remarkable popularity. Originally discovered out of pure chemical curiosity, and dusted off early this century as an efficient and clean bioconjugation tool, the usefulness of cyclooctyne-azide cycloaddition is now adopted in a wide range of fields of chemical science and beyond. Its ease of operation, broad solvent compatibility, 100 % atom efficiency, and the high stability of the resulting triazole product, just to name a few aspects, have catapulted this so-called strain-promoted azide-alkyne cycloaddition (SPAAC) right into the top-shelf of the toolbox of chemical biologists, material scientists, biotechnologists, medicinal chemists, and more. In this chapter, a brief historic overview of cycloalkynes is provided first, along with the main synthetic strategies to prepare cycloalkynes and their chemical reactivities. Core aspects of the strain-promoted reaction of cycloalkynes with azides are covered, as well as tools to achieve further reaction acceleration by means of modulation of cycloalkyne structure, nature of azide, and choice of solvent.

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Section: Influence Of Azide Structure On Reaction Ratementioning

confidence: 98%

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

Dommerholt

Rutjes

Delft

2016

Cycloadditions in Bioorthogonal Chemistry

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“…In a combined experimental and theoretical investigation with the van Delft group, we showed that the rate of fast SPAAC reactions between electron‐poor azides (Ar‐N 3 ) and bicyclononyne (BCN) is dictated by an inverse electron demand (IED) FMO interaction (see Scheme 1). 33 …”

Section: Applications In Chemistrymentioning

confidence: 99%

Analyzing Reaction Rates with the Distortion/Interaction‐Activation Strain Model

2017

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The activation strain or distortion/interaction model is a tool to analyze activation barriers that determine reaction rates. For bimolecular reactions, the activation energies are the sum of the energies to distort the reactants into geometries they have in transition states plus the interaction energies between the two distorted molecules. The energy required to distort the molecules is called the activation strain or distortion energy. This energy is the principal contributor to the activation barrier. The transition state occurs when this activation strain is overcome by the stabilizing interaction energy. Following the changes in these energies along the reaction coordinate gives insights into the factors controlling reactivity. This model has been applied to reactions of all types in both organic and inorganic chemistry, including substitutions and eliminations, cycloadditions, and several types of organometallic reactions.

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“…10 Although we were able to achieve diazo group-specific conjugation in the absence of a catalyst (Scheme 1), the reaction rates were low—comparable to those obtained with early SPAAC reagents and exceeded by new SPAAC reagents. 8c,11 Hence, we sought a faster cycloaddition.…”

Section: Introductionmentioning

confidence: 99%

Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Aronoff

Gold

Raines

2016

Tetrahedron Letters

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The cycloaddition of a diazoacetamide with ethyl 4,4,4-trifluorocrotonate proceeds with k = 0.1 M−1s−1. This second-order rate constant rivals those of optimized strain-promoted azide– alkyne cycloadditions, even though the reaction does not release strain. The regioselectivity and a computational distortion/interaction analysis of the reaction energetics are consistent with the formation of an N–H…F–C hydrogen bond in the transition state and the electronic character of the trifluorocrotonate. Analogous reactions with an azidoacetamide dipole or with an acrylate or crotonate dipolarophile were much slower. These findings suggest a new strategy for the design of diazo-selective reagents for chemical biology.

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Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes

Cited by 159 publications

References 44 publications

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

Analyzing Reaction Rates with the Distortion/Interaction‐Activation Strain Model

Rapid cycloaddition of a diazo group with an unstrained dipolarophile

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