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Reactivity of 7‐Azanorbornenes in Bioorthogonal Inverse Electron‐Demand Diels–Alder Reactions
Author(s) -
Karaki Fumika,
Ohgane Kenji,
Imai Hirotaka,
Itoh Kennosuke,
Fujii Hideaki
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201700411
Subject(s) - bioorthogonal chemistry , tetrazine , chemistry , reactivity (psychology) , conformational isomerism , diels–alder reaction , alkyl , substituent , derivative (finance) , photochemistry , click chemistry , molecule , stereochemistry , combinatorial chemistry , organic chemistry , medicine , alternative medicine , financial economics , economics , catalysis , pathology
In the preparation of multicomponent compounds, the accumulation of components through sequential click reactions is an attractive strategy. In this work we examined the reactivity of various N ‐substituted 7‐azanorbornenes in inverse electron‐demand Diels–Alder (iEDDA) reactions with tetrazines to explore the potential of 7‐azanorbornenes as clickable hub molecules. The iEDDA reaction of 7‐azanorbornene is expected to proceed faster when the nitrogen atom at the 7‐position is substituted with an electron‐donating substituent. Contrary to this expectation, the electron‐donating alkyl‐bearing derivative reacted much more slowly than those bearing electron‐withdrawing acyl groups. The results of DFT calculations indicate that the reaction rates correlate well with an increase in sp 2 character of the 7‐nitrogen atoms: The ease of conversion of the more stable exo conformer into the more reactive endo conformer may lower the activation energy of the first rate‐determining hetero‐Diels–Alder step. Indeed, the reaction rates of N ‐acylated 7‐azanorbornenes, which have a more planar nitrogen atom, were found superior to those of other derivatives and comparable to those of norbornenes. Finally, we successfully labeled a tetrazine on a protein surface by fluorophore‐conjugated 7‐azanorbornene in the presence of other proteins.