FerriCast: A Macrocyclic Photocage for Fe³⁺

Abstract

The non-siderophoric Fe(3+) photocage FerriCast (4,5-dimethoxy-2-nitrophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl] methanol (2) has been prepared in high yield using an optimized two-step reaction sequence that utilizes a trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted electrophilic aromatic substitution as the key synthetic step. Spectrophotometric assessment of Fe(3+) binding to FerriCast revealed a binding stoichiometry and metal ion affinity dependent on the nature of the counterion. Exposure of FerriCast to 350 nm light initiates a photoreaction that converts FerriCast into FerriUnc (4,5-dimethoxy-2-nitrosophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl]-methanone), which binds Fe(3+) less strongly owing to resonance delocalization of the anilino lone pair into the benzophenone pi-system. The release of Fe(3+) upon photolysis of FerriCast also was evaluated using a previously reported turn-on fluorescent sensor that utilizes the same macrocyclic ligand (4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl, AT(2)12C4). In contrast to the original reports on AT(2)12C4-based Fe(3+) sensors, FerriCast does not interact with ferric iron in aqueous solution. Introduction of oxygen containing solvents (MeOH, H(2)O, DMSO, MES, and phosphate buffers) to CH(3)CN solutions of metalated FerriCast lead to rapid decomplexation as measured by UV-visible spectroscopy. Further investigations contradicted the published conclusions on the aqueous coordination chemistry of AT(2)12C4, but also confirmed the unique and unexpected selectivity of the macrocycle for Fe(3+) in nonaqueous solvents. The crystallographic analysis of [Cu(AT(2)12C4)Cl](+) provides a rare example of a bifurcated hydrogen bond, and evidence for redox chemistry with the ligand. Spectrophotometric analysis of the model ligand with redox active metal ions provide evidence for AT(2)12C4(*+), a quasi-stable species the presence of which suggests caution should be taken when evaluating the interaction of aniline-containing systems with redox active metal ions.

Probing oxidative stress: Small molecule fluorescent sensors of metal ions, reactive oxygen species, and thiols

“…The second design consists of a mixed-donor (N,S,O) macrocycle and was originally reported to have selective affinity for Fe 3+ in aqueous solutions (pH of 5) [141]. More recently, the same macrocycle was incorporated into a UV-light activated Fe 3+ photocage and was shown to have no affinity for Fe 3+ in aqueous solvents [142]. Although formation of the iron complex was confirmed in 100% CH 3 CN, the macrocycle’s binding affinity is compromised in oxygen-donating solvents such as MeOH causing iron to be released.…”

“…Although formation of the iron complex was confirmed in 100% CH 3 CN, the macrocycle’s binding affinity is compromised in oxygen-donating solvents such as MeOH causing iron to be released. The authors further described that the originally reported iron-dependent fluorescence increase was an off-target response to protonation of the ligand’s aniline nitrogen in slightly acidic solutions [142]. …”

Buffering Heavy Metal Ions with Photoactive CrownCast Cages

“…The selectivity derives primarily from favorable sulfur–mercury interactions. In a manner analogous to our design rational of FerriCast for Fe 3+ ,16 we reasoned that the established selectivity of the AT 2 15C5 receptor in sensors would translate into a caged complex for Hg 2+ . In addition to heteroatom substitution, expansion of the A15C5 ring by one ethylene glycol unit provides the corresponding 16‐phenyl‐1,4,7,10,13‐pentaoxa‐16‐azacyclooctadecane (A18C6, 6 ) ligand.…”

“…By decreasing the bonding interaction, the binding affinity of the uncaged chelator is reduced. This strategy was initially developed by Tsien and co‐workers to investigate Ca 2+ signaling,13 and recently expanded to cage Zn 2+ and other metal ions 14–16. All the caged complexes utilizing the attenuation of aniline ligand interactions consist of the receptor incorporated into a nitrobenzhydrol caging scaffold.…”

A reversible rhodamine 6G-based fluorescence turn-on probe for Fe3+ in water and its application in living cell imaging

“…A number of fluorescent probes for the selective detection of Fe 3+ ion have been exploited [17][18][19][20][21][22][23][24][25] . Most early probes showed a fluorescence quenching (turn-off) response due to paramagnetic of the Fe 3+ ion, which limits their application in biological systems 26,27 .…”