Mechanistic Insights into Rapid Generation of Nitroxyl from a Photocaged N-Hydroxysulfonamide Incorporating the (6-Hydroxynaphthalen-2-yl)methyl Chromophore

Abstract

HNO is a highly reactive molecule that shows promise in treating heart failure. Molecules that rapidly release HNO with precise spatial and temporal control are needed to investigate the biology of this signaling molecule. (Hydroxynaphthalen-2-yl)methylphotocaged N-hydroxysulfonamides are a new class of photoactive HNO generators. Recently, it was shown that a (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM)-photocaged derivative of N-hydroxysulfonamide incorporating the trifluoromethanesulfonamidoxy group (1) quantitatively generates HNO. Mechanistic studies have now been carried out on this system and reveal that the ground state protonation state plays a key role in whether concerted heterolytic C−O/N−S bond cleavage to release HNO occurs versus undesired O−N bond cleavage. N-Deprotonation of 1 can be achieved by adding an aqueous buffer or a carboxylate salt to an aprotic solvent. Evidence is presented for C−O/N−S bond heterolysis occurring directly from the singlet excited state of the N-deprotonated parent molecule on the picosecond time scale, using femtosecond time-resolved transient absorption spectroscopy, to give a carbocation and 1 NO − . This is consistent with the observation of significant fluorescence quenching when HNO is generated. The carbocation intermediate reacts rapidly with nucleophiles including water, MeOH, or even (H)NO in the absence of a molecule that reacts rapidly with (H)NO to give an oxime.

Exploring the Potential of 2-(2-Nitrophenyl)ethyl-Caged N-Hydroxysulfonamides for the Photoactivated Release of Nitroxyl (HNO)

“…The ground state p K a for each 2-NPE-caged compound was determined, prior to investigating the effect of the pH of the aqueous component of a solvent mixture on the observed photoproducts. The p K a value for the N­(H) of the structurally similar (6-hydroxy-2-naphthalenyl)­methyl-photocaged N -hydroxysulfonamide [6,2-HNM-ON­( H )­SO 2 CF 3 ] is 4.4 ± 0.1 . Deprotonation of the N­(H) of 7a–c would also be expected to occur in an aqueous solution (eq ).…”

“…According to literature precedent, 2-NPE-caged compounds generally undergo C–O bond cleavage to release the leaving group and the byproduct 2-nitrostyrene ( 2 ). , However, photo-uncaging of the newly developed 2-NPE derivatives 7a–c occurred via three competing pathways (see Scheme ) that were dependent on the nature of the RSO 2 moiety. In related N -hydroxysulfonamide systems caged with o -nitrobenzyl ( o- NB), (3-hydroxy-2-naphthalenyl)­methyl (3,2-HNM), and (6-hydroxy-2-naphthalenyl)­methyl (6,2-HNM) chromophores, three photodecomposition pathways were also observed. − …”

“…The pK a value for the N(H) of the structurally similar (6-hydroxy-2naphthalenyl)methyl-photocaged N-hydroxysulfonamide [6,2-HNM-ON(H)SO 2 CF 3 ] is 4.4 ± 0.1. 34 Deprotonation of the N(H) of 7a−c would also be expected to occur in an aqueous solution (eq 1). 19 F NMR spectra for 7a were recorded in D 2 O with the pD of the aqueous component of the D 2 O/CH 3 CN solvent mixture varying from pD 1.9 to 10.2, to obtain an estimate for the pK a value.…”

“…To date, we have reported the synthesis and photochemistry of caged N -hydroxysulfonamide derivatives using O -(3-hydroxy-2-naphthalenyl)­methyl (3,2-HNM), , O -(6-hydroxy-2-naphthalenyl)­methyl (6,2-HNM), , and O - o -nitrobenzyl ( o -NB) phototriggers. Depending on the leaving group, ≤70% release of HNO from 3,2-HNM-caged derivatives under neutral-pH conditions was observed, while the best analogous 6,2-HNM-caged substrates rapidly and selectively (98%) released HNO under the same conditions.…”