Mechanistic Origin of Favorable Substituent Effects in Excellent Cu Cyclam Based HNO Sensors

Abstract

HNO has broad chemical and biomedical properties. Metal complexes and derivatives are widely used to make excellent HNO sensors. However, their favorable mechanistic origins are largely unknown. Cu cyclam is a useful platform to make excellent HNO sensors including imaging agents. A quantum chemical study of Cu cyclams with various substitutions was performed, which reproduced diverse experimental reactivities. Structural, electronic, and energetic profiles along reaction pathways show the importance of HNO binding and a proton‐coupled electron transfer mechanism for HNO reaction. Results reveal that steric effect is primary and electronic factor is secondary (if the redox potential is sufficient), but their interwoven effects can lead to unexpected reactivity, which looks mysterious experimentally but can be explained computationally. This work suggests rational substituent design ideas and recommends a theoretical study of a new design to save time and cost due to its subtle effect.

Reusable HNO Sensors Derived from Cu Cyclam: A DFT Study on the Mechanistic Origin of High Reactivity and Favorable Conformation Changes and Potential Improvements

“…As shown in Scheme A, the basic pathway is like those with other Cu complexes and metalloproteins: − , it starts with the HNO-bound intermediate I-1-S (its formation is experimentally facilitated by large excess of the HNO donor), which undergoes a PCET transition state ( TS-S ) to generate another intermediate I-2-S , where a proton transfers from HNO to one coordinated nitrogen and an electron from HNO transmits to Cu. It can be seen by the spin density data of the NO fragment (ρ NO αβ ) for the 14-N 2 S 2 systems increasing from ∼0 e in I-1-S to 0.122 e in TS-S and then to ∼1.0 e in I-2-S and accordingly Cu (ρ Cu αβ ) decreasing from 0.395 e in I-1-S to 0.381 e in TS-S and then to ∼0 e in I-2-S for the electron transfer part.…”

“…Due to the importance of conformation changes here, we first studied the conformation effects of experimental Cu II /Cu I complexes. The used computational method enabled accurate descriptions of HNO reactivities in various metalloproteins and model systems [59][60][61]69,73,78 and accurate structural predictions of related Cu cyclams. 59 The optimized gas phase structures of [Cu II (14-N 2 S 2 )] 2+ and [Cu I (14-N 2 S 2 )] + showed excellent agreement with the crystal structures, with an average mean absolute deviation (MAD) of 0.045 Å for all coordination bond lengths and mean percentage deviation (MPD) of only 2.1% (Table S1).…”

“…It can be seen that the Cu cyclam derivative systems with coordination S/Se atoms studied in this work have a relatively lower reaction barrier range (17−21 kcal/mol) and lower reaction energy range of −19 to −26 kcal/mol than Cu cyclams (19−27 kcal/mol and ∼0 to −17 kcal/mol, respectively) reported recently. 59 These data clearly show that the mixed S/ Se−N coordination systems have better HNO reactivities, which were found to originate from at least three favorable factors described in detail in the HNO Reactivity Section under Results and Discussion Section: (1) less steric hindrance due to the enlarged coordinated sphere facilitates HNO binding; (2) the enlarged coordination sphere weakens the Cu−N 3 bond for lower cleavage cost; and (3) the less electronegative S/Se vs N renders a significantly less positively charged Cu to reduce its attraction with the negatively charged N 3 to decrease the bond cleavage cost. However, the CuZnSOD (SOD, superoxide dismutase) protein has the lowest barrier and reaction energy among all Cu systems (see Table 2), which was found to be a result of a more flexible nonplanar coordination environment in the protein to lower the Cu−N bond-breaking cost and a stronger proton acceptor due to a negatively charged coordination histidine ligand.…”

“…Since a recent computational work revealed beneficial effects of either EDG or EWG substituents on the aza-only 14-N 4 ligand in experimental Cu cyclams, , we examined such effects on the mixed thia/aza ligand, i.e., 14-N 2 S 2 -Ts and 14-N 2 S 2 -Bn (Scheme ). Bn/Ts atoms were installed on similar Cu cyclams and thus are feasible for future experimental synthesis. , The reason to have only one substituent is to minimize the steric hindrance, the primary effect on HNO reactivity found recently …”

“…However, the mechanistic origins of its greater HNO reactivity and favorable conformation changes to retain Cu are unknown. So, we report a density functional theory (DFT) study of these missing mechanistic details, which were based on the previously found proton-coupled electron transfer (PCET) mechanism and some favorable substituent effects in other metal complexes and metalloproteins. − …”