Alkyne and Reversible Nitrile Activation: <i>N</i>,<i>N</i>′-Diamidocarbene-Facilitated Synthesis of Cyclopropenes, Cyclopropenones, and Azirines

Moerdyk, Jonathan P.; Bielawski, Christopher W.

doi:10.1021/ja3014105

Cited by 68 publications

(43 citation statements)

References 66 publications

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“…[19] Additionally, the appended tag should be of low molecular weight to minimize steric perturbation. In his previous studies, Sauer demonstrated that cyclopropene and 3-methylcyclopropene were both highly reactive with 1,2,4,5-tetrazine, but the 3,3-dimethylcyclopropene lowered the rate of reaction by more than three orders of magnitude.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Yang

Liang

Šečkutė

et al. 2014

Chemistry A European J

117

115

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Substituted cyclopropenes have recently attracted attention as stable “mini-tags” that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1-methyl-3-substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels–Alder cycloadditions with 1,2,4,5-tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3-amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1-methyl-3-substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3-amidomethyl substituted methylcyclopropene reacts faster than trans-cyclooctenol with a sterically hindered and extremely stable tert-butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Yang

Liang

Šečkutė

et al. 2014

Chemistry A European J

117

115

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“…p-Accepting classes of NHCs such as CAACs (7) and the carbonyl-containing DACs (9) are particularly well suited to these processes. As revealed in a series of reports by Bielawski and co-workers, these latter NHCs are capable of activating small molecules such as NH 3 , while [2 1 1] cycloaddition reactivity analogous to that of classical transient carbenes has been observed with electron-neutral alkenes and alkynes 82,83 .…”

Section: Review Researchmentioning

confidence: 99%

An overview of N-heterocyclic carbenes

Hopkinson

Richter

Schedler

et al. 2014

Nature

3,688

1,907

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The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

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“…(4) The ability of the hydrogen adduct 4H to store hydrogen is also enhanced with the substitution of electrondonating groups on N 2 and N 5 . [36][37][38][39]. For example, Lee et al [36] discovered that N,N′-diamidocarbenes are ambiphilic and can behave as electrophiles and nucleophiles.…”

Section: Discussionmentioning

confidence: 99%

A theoretical study on the hydrogen adducts of diamidocarbenes and diaminocarbenes

Lai¹

2013

J Mol Model

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The hybrid-meta GGA DFT functional M06-2X was used to examine the potential of N,N'-diamidocarbenes for use as hydrogen storage materials. We previously discovered that borylene, which is isoelectronic with an Arduengo-type carbene, was a suitable candidate for a hydrogen storage material. We compared the capabilities of N,N'-diamidocarbenes and N-heterocyclic carbenes as hydrogen storage materials. The results indicate that diamidocarbenes are not suitable hydrogen storage materials because the removal of H₂ is more endothermic for diamidocarbenes than for diaminocarbenes.

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Alkyne and Reversible Nitrile Activation: N,N′-Diamidocarbene-Facilitated Synthesis of Cyclopropenes, Cyclopropenones, and Azirines

Cited by 68 publications

References 66 publications

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

An overview of N-heterocyclic carbenes

A theoretical study on the hydrogen adducts of diamidocarbenes and diaminocarbenes

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