Mechanistic Studies on the Photodecomposition of Caged N-hydroxysulfonamides Incorporating the 2-Nitrobenzyl, (2-Nitrophenyl)ethyl and (6-Bromo-7-Hydroxycoumarin-4-Yl)methyl Chromophores

Bangalore Shashidhar, Vinay Bharadwaj
Brasch, Nicola
Simpson, Cather
Blackman, Allan
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Doctor of Philosophy
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Auckland University of Technology

There is accumulating evidence that the redox cousin of nitric oxide (NO), nitroxyl (HNO), is a biologically important signaling molecule. HNO reacts rapidly with thiols and metal centres of metalloproteins. HNO prodrugs also show promise in treating congestive heart failure. Since HNO is highly unstable, several classes of molecules that decompose to release HNO, HNO donors, have been developed. The vast majority of these HNO donors release HNO slowly (minutes to hours).

Extremely reactive biological molecules such as HNO can be made inactive by binding a photoprotecting group (PPG) to the molecule of interest. Upon irradiation by light, the biological molecule (BM) will be rapidly released from the PPG-BM complex at the desired location in a highly controlled manner (Figure 1). This strategy has been utilized to generate various BM such as neurotransmitters, proteins, and nucleic acids, upon demand.

Our research team recently developed the first N-hydroxysulfonamides caged with the 3-hydroxynaphthalen-2-yl and 6-hydroxynaphthalen-2-yl chromophores, as potential photoactive HNO donors. The selectivity of the desired HNO generation pathway versus competing pathways involving C-O or O-N bond cleavage was found to be dependent on the N-hydroxysulfonamide, the chromophore and the solvent conditions.

In this thesis the mechanisms of photodecomposition of three new classes of photocaged N-hydroxysulfonamides have been investigated. In Chapter 2 the photodecomposition of N-hydroxysulfonamides caged with the well-established 2-nitrobenzyl moiety is presented. O-N bond cleavage to give the corresponding sulfonamide rather than the desired concerted C-O/N-S bond cleavage was the primary decomposition pathway. The results support a Norrish type II mechanism, with the 1,5 hydrogen atom abstraction occurring in the excited state to give a (Z)-acinitro intermediate. The (Z)-aci-nitro intermediate either undergoes O-N bond cleavage to generate the sulfonamide and 2-nitrobenzaldehyde or instead isomerizes to the (E) isomer, ultimately undergoing C-O/N-S bond cleavage to release HNO and CF3SO2-. The aci-nitro intermediate was detected by laser flash photolysis and decomposes on the microsecond timescale. For the related 2-NO2Bn-OC(O)-ON(H)-SO2CH3 analogue, photodecomposition primarily occurred via C-O bond cleavage.

In Chapter 3 the photodecomposition of 2-(2-nitrophenyl)ethyl (2-NPE) photocaged Nhydroxysulfonamides is presented. The proposed mechanism of photodecomposition was also via a Norrish type II reaction. However in this case the (Z)-aci-nitro intermediate either undergoes C-O bond cleavage to release the parent sulfohydroxamic acid, concerted C-O/N S bond cleavage to generate a sulfinate and HNO, or isomerises to the (E) isomer and undergoes O-N bond cleavage. The pKa of the N(H) of the N-hydroxysulfonamide plays a key role in determining whether C-O or concerted C-O/N-S bond cleavage occurs.

Finally, in Chapter 4 the mechanisms of photodecomposition were investigated for two (6-bromo-7-hydroxycoumarin-4-yl)methyl – caged N-hydroxysulfonamides. Heterolytic O-N, C-O and/or C-O/N-S bond cleavage are extremely rapid for these systems, occurring in the singlet excited state. Once again the pKa of N(H) plays a key role in determining the mechanism of photodecomposition. Upon concerted heterolytic C-O/N-S bond cleavage a solvent-caged carbocation and 1NO- are released. The carbocation reacts rapidly with solvent, or with (H)NO to generate an oxime.

HNO donor , (6-bromo-7-hydroxycoumarin-4-yl)methyl chromophore , 2-nitrobenzyl chromophore , (2-nitrophenyl)ethyl chromophore , Photoproduct quantum yield , Laser flash photolysis , HNO trapping
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