Quantitative Reactivity Scales for Dynamic Covalent and Systems Chemistry

Abstract

Dynamic covalent chemistry (DCC) has become a powerful tool for the creation of molecular assemblies and complex systems in chemistry and materials science. Herein we developed for the first time quantitative reactivity scales capable of correlation and prediction of the equilibrium of dynamic covalent reactions (DCRs). The reference reactions are based upon universal DCRs between imines, one of the most utilized structural motifs in DCC, and a series of O-, N-, and S- mononucleophiles. Aromatic imines derived from pyridine-2-carboxyaldehyde exhibit capability for controlling the equilibrium through distinct substituent effects. Electron-donating groups (EDGs) stabilize the imine through quinoidal resonance, while electron-withdrawing groups (EWGs) stabilize the adduct by enhancing intramolecular hydrogen bonding, resulting in curvature in Hammett analysis. Notably, unique nonlinearity induced by both EDGs and EWGs emerged in Hammett plot when cyclic secondary amines were used. This is the first time such a behavior is observed in a thermodynamically controlled system, to the best of our knowledge. Unified quantitative reactivity scales were proposed for DCC and defined by the correlation log K = S(N) (R(N) + R(E)). Nucleophilicity parameters (R(N) and S(N)) and electrophilicity parameters (R(E)) were then developed from DCRs discovered. Furthermore, the predictive power of those parameters was verified by successful correlation of other DCRs, validating our reactivity scales as a general and useful tool for the evaluation and modeling of DCRs. The reactivity parameters proposed here should be complementary to well-established kinetics based parameters and find applications in many aspects, such as DCR discovery, bioconjugation, and catalysis.

Kinetic Selectivity and Thermodynamic Features of Competitive Imine Formation in Dynamic Covalent Chemistry

“…[1][2][3][4][5] The formationo fr eversible C=Nc onnections from reactiono fp rimary amines, hydrazide, hydrazinea nd hydroxylamined erivatives with carbonyl compounds [6][7][8][9][10] has been actively investigated to developt he core of DCC in view of their dynamicf eaturesa sw ell as for their use for generating conjugates in chemistry and biology.N ucleophiles such as hydrazine and hydroxylamine where the amino group has an a-substituent bearing al one pair have long been known to act as stronger nucleophiles than normal primary amines [11] and their low basicity allowst he formation of more stable imine products. However,t he kinetics of the condensation reactions are also of basic interesta nd have received increasing attention, [25][26][27][28][29][30][31] as they mayb ee xpected to affectt he compositiono fadynamic C=Nl ibrary as af unction of time in the course of its generation from carbonyl and aminoc omponents. [24] Attention has been mainly paidt ot he thermodynamic features of the constituents of DCLsb ased on the formation of C=Nc onnections.…”

Extending substrate sensing capabilities of zinc tris(2‐pyridylmethyl)amine‐based stereodynamic probe

“…In the presence of suitable chromophores, this phenomenon gives rise to an intense chiroptical absorption [38][39][40] which can be monitored by electronic circular dichroism (CD). [48][49][50][51] In the recent years, we have reported several examples on the catalytic and recognition capabilities of tripodal ligands, especially focusing on the TPMA molecular sensing toward α-amino acids ( Figure 1). Imines are usually synthetized in mild reaction conditions, and they show a good stability both in neutral and basic environment.…”

Hampered Subcomponent Self‐Assembly Leads to an Aminal Ligand: Reactivity with Silver(I) and Copper(II)

“…Similarly, two recent dynamic covalent reaction (DCR) studies on imine species derived from 2‐pyA and aromatic amines pointed out the possibility to control the equilibrium mixture through substituent effects. [6a], For instance, electron‐withdrawing groups such as CN and NO 2 facilitate the formation of aminal species over imine products. [6a] Again, it was reported that only trace amounts of products (aminal 4 %, hemiaminal ether 2 %, and imine 9 %) were observed in the reaction of 2‐pyA, 4‐nitroaniline, and ethanol .…”

“…[6a], For instance, electron‐withdrawing groups such as CN and NO 2 facilitate the formation of aminal species over imine products. [6a] Again, it was reported that only trace amounts of products (aminal 4 %, hemiaminal ether 2 %, and imine 9 %) were observed in the reaction of 2‐pyA, 4‐nitroaniline, and ethanol . On the other hand, the reaction between 2‐pyA and aniline or aromatic amines with electron‐donating and weak electron‐withdrawing para substituents led to the formation of imine species as major products.…”

“…On the other hand, the reaction between 2‐pyA and aniline or aromatic amines with electron‐donating and weak electron‐withdrawing para substituents led to the formation of imine species as major products. [6a], , The pyridine group has withdrawing character comparable to that of the nitro group. We postulate that the subcomponent self‐assembly route in the case of 4‐apy is hampered by the electron‐withdrawing effect of pyridine.…”