Fluorescent Molecular Logic Gates and Pourbaix Sensors in Polyacrylamide Hydrogels.

Polyacrylamide hydrogels formed by free radical polymerisation were formed by entrapping anthracene and 4-amino-1,8-naphthalimide fluorescent logic gates based on photoinduced electron transfer (PET) and/or internal charge transfer (ICT). The non-covalent immobilisation of the molecules in the hydrogels resulted in semi-solid YES, NOT, and AND logic gates. Two molecular AND gates, examples of Pourbaix sensors, were tested in acidic aqueous methanol with ammonium persulfate, a strong oxidant, and displayed greater fluorescence quantum yields than previously reported. The logic hydrogels were exposed to aqueous solutions with chemical inputs, and the fluorescence output response was viewed under 365 nm UV light. All of the molecular logic gates diffuse out of the hydrogels to some extent when placed in solution, particularly those with secondary basic amines. The study exemplifies an effort of taking molecular logic gates from homogeneous solutions into the realm of solid-solution environments. We demonstrate the use of Pourbaix sensors as pE-pH indicators for monitoring oxidative and acidic conditions, notably for excess ammonium persulfate, a reagent used in the polymerisation of SDS-polyacrylamide gels.

Enhanced ion binding by the benzocrown receptor and a carbonyl of the aminonaphthalimide fluorophore in water-soluble logic gates.

Two fluorescent logic gates 1 and 2 were designed and synthesised with a 'receptor1-spacer1-fluorophore-spacer2-receptor2' format. The molecules comprise of an aminonaphthalimide fluorophore, methylpiperazine and either benzo-15-crown-5 or benzo-18-crown-6. Model 3, with a weakly binding 3,4-dimethoxyphenyl moiety, was also synthesised. The compounds were studied both in 1 : 1 (v/v) methanol/water and water by UV-visible absorption and steady-state fluorescence spectroscopy. The green fluorescence of 1-3 is modulated by photoinduced electron transfer (PET) and internal charge transfer (ICT) mechanisms, and by solvent polarity. In 1 : 1 (v/v) methanol/water, logic gates 1 and 2 emit with Φf = 0.21 and 0.28, and bind with pßNa+ = 1.6 and pßK+ = 2.6, respectively, and pßH+ = 7.4 ± 0.1. In water, logic gates 1 and 2 emit with Φf = 0.14 and 0.26, and bind with pßNa+ = 0.86 and pßK+ = 1.6, respectively, and pßH+ = 8.1 ± 0.1. The measured pßNa+ are significantly lower than reported for analogous classic anthracene-based Na+, H+-driven AND logic gates indicating a stronger Na+ binding interaction, which is attributed to direct interaction with one carbonyl moiety within the aminonaphthalimide. Supporting evidence is provided by DFT calculations. Furthermore, we illustrate an example of logic function modulation by a change in solvent polarity. In 1 : 1 (v/v) methanol/water, molecules 1 and 2 function as Na+, H+ and K+, H+-driven AND logic gates. In water, the molecules function as single input H+-driven YES logic gates, while consideration as two-input devices, 1 and 2 function as AND-INH-OR logic arrays.

Aminonaphthalimide hybrids of mitoxantrone and amonafide as anticancer and fluorescent cellular imaging agents.

Novel water-soluble 4-aminonaphthalimides were synthesised and their cellular fluorescent imaging, cytotoxicity and ability to induced apoptosis evaluated. The lead compound 1 was designed from the cross-fertilisation of the basic hydrophilic amino pharmacophore of mitoxantrone, and an aminonaphthalimide scaffold of the drug candidate, amonafide. The compounds are also fluorescent pH probes based on photoinduced electron transfer (PET) and internal charge transfer (ICT). The compounds are sensitive to solvent polarity with large Stoke shifts (>90 nm) and provide emissive-coloured solutions (blue to yellow). Excited state pKas of 9.0-9.3 and fluorescence quantum yields of 0.47-0.58 were determined in water. The cytotoxicity and cellular fluorescent imaging properties of the compounds were tested on human cancer cell lines K562 and MCF-7 by the MTT assay, phase contrast and fluorescence microscopy. Compounds 1 and 3 with flexible aminoalkyl chains exhibited GI50 comparable to amonafide, while 2 and 4 with a rigid piperazine moiety and butyl chain are less cytotoxic. Fluorescence microscopy with 1 allowed for the visualization of the intracellular microenvironment exemplifying the potential utility of such hybrid molecules as anticancer and fluorescent cellular imaging agents.

Molecular engineering of logic gate types by module rearrangement in 'Pourbaix Sensors': the effect of excited-state electric fields.

Two types of fluorescent logic gates are accessed from two different arrangements of the same modular components, one as an AND logic gate (1) and the other as a PASS 0 logic gate (2). The logic gates were designed with an 'electron-donor-spacer1-fluorophore-spacer2-receptor' format and demonstrated in 1 : 1 (v/v) methanol/water. The molecules consist of ferrocene as the electron donor, 4-aminonaphthalimide as the fluorophore and a tertiary alkylamine as the receptor. In the presence of high H+ and Fe3+ levels, regioisomers 1a and 1b switch 'on' as AND logic gates with fluorescence enhancement ratios of 16-fold and 10-fold, respectively, while regioisomers 2a and 2b are functionally dormant, exhibiting no fluorescence switching. The PASS 0 logic of 2a and 2b results from the transfer of an electron from the excited state fluorophore to the ferrocenium unit under oxidising conditions as predicted by DFT calculations. Time-resolved fluorescence spectroscopy provided lifetimes of 8.3 ns and 8.1 ns for 1a and 1b, respectively. The transient signal recovery rate of 1b is ∼10 ps while that of 2b is considerably longer on the nanosecond timescale. The divergent logic attributes of 1 and 2 highlight the importance of field effects and opens up a new approach for regulating logic-based molecules.

Redox-Enabled, pH-Disabled Pyrazoline-Ferrocene INHIBIT Logic Gates.

Pyrazoline-ferrocene conjugates with an "electron-donor-spacer-fluorophore-receptor" format are demonstrated as redox-fluorescent two-input INHIBIT logic gates.

Correction: Photoinduced electron transfer as a design concept for luminescent redox indicators.

Correction for 'Photoinduced electron transfer as a design concept for luminescent redox indicators' by David C. Magri, Analyst, 2015, 140, 7487-7495.

Proof of principle of a three-input AND-INHIBIT-OR combinatorial logic gate array.

A designed molecule fluoresces according to a combinatorial logic circuit equivalent to wiring together three-input AND, three-input INHIBIT and two-input OR logic gates.

A fluorescent combinatorial logic gate with Na+, H+-enabled OR and H+-driven low-medium-high ternary logic functions.

A novel fluorescent molecular logic gate with a 'fluorophore-spacer1-receptor1-spacer2-receptor2' format is demonstrated in 1 : 1 (v/v) methanol/water. The molecule consists of an anthracene fluorophore, and tertiary alkyl amine and N-(2-methoxyphenyl)aza-15-crown-5 ether receptors. In the presence of threshold concentrations of H+ and Na+, the molecule switches 'on' as an AND logic gate with a fluorescence quantum yield of 0.21 with proton and sodium binding constants of log ßH+ = 9.0 and log ßNa+ = 3.2, respectively. At higher proton levels, protonation also occurs at the anilinic nitrogen atom ether with a log ßH+ = 4.2, which allows for Na+, H+-enabled OR (OR + AND circuit) and H+-driven ternary logic functions. The reported molecule is compared and contrasted to classic anthracene-based Na+ and H+ logic gates. We propose that such logic-based molecules could be useful tools for probing the vicinity of Na+, H+ antiporters in biological systems.

Fluorescent Photoinduced Electron Transfer (PET) Logic Gates for Acidity (pH) and Redox Potential (pE).

This mini-review highlights the photophysical properties of fluorescent molecular logic gates responsive to acids and oxidants, particularly those developed in our laboratory the past few years. The review pays tribute to earlier developments that lay the foundation for this emerging class of molecules. The logic gates incorporate design concepts based on photoinduced electron transfer from the cross-fertilization of the fluorophore-spacer-receptor and fluorophore-spacer-electron-donor formats. The molecular logic gates explored in detail consist of anthracene and/or naphthalimide fluorophores, while the receptor and electron-donor are typically alkyl amines and ferrocene, respectively. This emerging class of molecule has numerous probable uses, most notably, in corrosion science, geochemistry, molecular cell biology and biomedical diagnostics.

Photoinduced electron transfer as a design concept for luminescent redox indicators.

The general design principle for developing luminescent redox indicators based on photoinduced electron transfer is described. The first part of the review introduces colorimetric and fluorimetric redox indicators. The second part of the review highlights recent developments regarding molecular luminescent redox switches and logic gates. Potential future applications in biology, environmental analysis, biomedical diagnostics, corrosion science and materials science are mentioned.

UV-visible and (1)H-(15)N NMR spectroscopic studies of colorimetric thiosemicarbazide anion sensors.

Four model thiosemicarbazide anion chemosensors containing three N-H bonds, substituted with phenyl and/or 4-nitrophenyl units, were synthesised and studied for their anion binding abilities with hydroxide, fluoride, acetate, dihydrogen phosphate and chloride. The anion binding properties were studied in DMSO and 9 : 1 DMSO-H2O by UV-visible absorption and (1)H/(13)C/(15)N NMR spectroscopic techniques and corroborated with DFT studies. Significant changes were observed in the UV-visible absorption spectra with all anions, except for chloride, accompanied by dramatic colour changes visible to the naked eye. These changes were determined to be due to the deprotonation of the central N-H proton and not due to hydrogen bonding based on (1)H/(15)N NMR titration studies with acetate in DMSO-d6-0.5% water. Direct evidence for deprotonation was confirmed by the disappearance of the central thiourea proton and the formation of acetic acid. DFT and charge distribution calculations suggest that for all four compounds the central N-H proton is the most acidic. Hence, the anion chemosensors operate by a deprotonation mechanism of the central N-H proton rather than by hydrogen bonding as is often reported.

Dissociative electron transfer to diphenyl-substituted bicyclic endoperoxides: the effect of molecular structure on the reactivity of distonic radical anions and determination of thermochemical parameters.

The heterogeneous electron transfer reduction of the bicyclic endoperoxide 1,4-diphenyl-2,3-dioxabicyclo[2.2.1]hept-5-ene (4) was investigated in N,N-dimethylformamide at a glassy carbon electrode. The endoperoxide reacts by a concerted dissociative ET mechanism resulting in reduction of the O-O bond with an observed peak potential of -1.4 V at 0.2 V s-1. The major product (90% yield) resulting from the heterogeneous bulk electrolysis of 4 at -1.4 V with a rotating disk glassy carbon electrode is 1,4-diphenyl-cyclopent-2-ene-cis-1,3-diol with a consumption of 1.73 electrons per mole. In contrast, 1,4-diphenyl-2,3-dioxabicyclo[2.2.2]oct-5-ene (1), undergoes a two-electron reduction mechanism in quantitative yield. This difference in product yield between 1 and 4 is suggestive of a radical-anion mechanism, as observed with 1,4-diphenyl-2,3-dioxabicyclo-[2.2.2] octane (2) and 1,4-diphenyl-2,3-dioxabicyclo[2.2.1]heptane (3). Convolution potential sweep voltammetry is used to determine unknown thermochemical parameters of 4, including the O-O bond dissociation energy and the standard reduction potential and a comparison is made to the previously studied bicyclic endoperoxides 1-3 with respect to the effect of molecular structure on the reactivity of distonic radical anions.

Lab-on-a-molecule and multi-analyte sensing.

The concept of a lab-on-a-molecule, which was proposed just short of two decades ago, has captured the imagination of scientists. From originally being proposed as an AND logic gate driven by three chemical inputs as a direct way of detecting congregations of chemical species, the definition of what constitutes a lab-on-a-molecule has broadened over the years. In this review, molecules that can detect multiple analytes by fluorescence, among other techniques, are reviewed and discussed, in the context of molecular logic and multi-analyte sensing. The review highlights challenges and suggestions for moving the frontiers of research in this field to the next dimension.

Luminescent 'On-Off' CdSe/ZnS quantum dot chemodosimeter for hydroxide based on photoinduced electron transfer from a carboxylate moiety.

A CdSe-ZnS quantum dot (QD) has been surface functionalised by a place exchange reaction with p-mercaptomethyl benzoate synthesized by a three-step procedure. The resulting lumophore-spacer-receptor QD-conjugate was characterized by IR, UV-visible and fluorescence spectroscopy. The emission profile of the QD reveals a narrow emission peak centred at 542 nm. Addition of hydroxide to the solution containing the QD-conjugate results in quenching of the original fluorescence, which is attributed to a photoinduced electron transfer reaction from the electron-rich benzoate moiety to the QD valence band. This is the first reported example of fluorescent quenching of a CdSe-ZnS QD luminescence by an aryl carboxylate moiety.

Cinchona alkaloids - acid, anion-driven fluorescent INHIBIT logic gates with a receptor1-fluorophore-spacer-receptor2 format and PET and ICT mechanisms.

The fluorescent natural products, quinine, quinidine, cinchonine and cinchonidine are demonstrated as H+-enabled, halide-disabled (Cl-, Br- or I-) INHIBIT and INHIBIT-OR combinatorial logic gates in water. More fluorescent natural products with intrinsic logic properties await to be discovered.

A white light emitting reconfigurable pyrazoline-naphthalimide logic gate with magnesium, sodium and proton inputs.

A 3-pyrazolinyl-naphthalimide with a benzo-15-crown-5 receptor operates as a wavelength-reconfigurable dual-output logic gate. Excited with 365 nm light, Na+ and Mg2+ are detected by orange and white light emission, respectively.

Solvent-polarity reconfigurable fluorescent 4-piperazino-N-aryl-1,8-naphthalimide crown ether logic gates.

Four compounds 1-4 were designed and synthesised, comprising a 4-amino-N-aryl-1,8-naphthalimide fluorophore, a piperazine receptor, and an aryl group, as fluorescent logic gates. At the imide position, the substituent is phenyl (1), 1,2-dimethoxyphenyl (2), benzo-15-crown-5 (3), or benzo-18-crown-6 (4). Molecules 1 and 2 are constructed according to a fluorophore-spacer-receptor format, while 3 and 4 are engineered according to a receptor1-spacer1-fluorophore-spacer2-receptor2 format based on photoinduced electron transfer and internal charge transfer mechanisms. The compounds were studied in water, water/methanol mixtures of different ratios, and methanol by UV-visible absorption and steady-state fluorescence spectroscopy, as a function of pH, metal ions and solvent polarity. The excited state of 1-4 is 8.4 ± 0.2 in water, 7.6 ± 0.1 in 1 : 1 (v/v) water/methanol, and 7.1 ± 0.3 in methanol. The of 3 in water is 0.92 and the and of 4 in water are 2.3 and 2.9. 1H NMR data in D2O and CD3OD confirm H+ interaction at the piperazine moiety, and Na+ and Ba2+ binding at the benzo-15-crown-5 and benzo-18-crown-6 moieties of 3 and 4. By altering the solvent polarity, the fluorescent logic gates can be reconfigured between TRANSFER logic and AND logic. Molecules with polarity reconfigurable logic could be useful tools for probing the microenvironment of cellular membranes and protein interfaces.

4-Amino-1,8-naphthalimide-ferrocene conjugates as potential multi-targeted anticancer and fluorescent cellular imaging agents.

Herein we present eight ferrocenyl 4-amino-1,8-naphthalimides. Designed as fluorescent logic gates for acidity and oxidisability, the molecules have been repurposed as anti-proliferation and cellular imaging agents. The compounds were studied in vitro against MCF-7 and K562 cancer cell lines by the MTT method. Compounds with protonable secondary amines tended to exhibit greater cytotoxicity than those with tertiary amines. Compounds with no measurable GI50 values within a 24 hour time window, as well as at shorter exposure times, may be suitable as fluorescent cellular imaging probes.

Efficient homogeneous radical-anion chain reactions initiated by dissociative electron transfer to 3,3,6,6-tetraaryl-1,2-dioxanes.

A series of 3,3,6,6-tetraaryl-1,2-dioxanes (TADs) have been investigated at an inert electrode by using cyclic voltammetry, constant potential electrolysis and digital simulations. The series consists of the phenyl-substituted TAD (1 a), p-methoxy-aryl TADs (1 b, 1 c) and the p-methoxy/nitro-bearing TAD (1 d). The heterogeneous electron-transfer (ET) reduction is dissociative, causing rupture of the oxygen-oxygen bond, which generates a distonic radical-anion that reacts competitively either by beta-scission fragmentation or ET. Fragmentation of the distonic radical anion yields an alkene, a substituted benzophenone, and a benzophenone radical anion. The benzophenone radical-anion propagates an efficient homogeneous ET-fragmentation chain reaction that accounts for the potential dependence of the product ratios and the low charge consumption observed in the controlled potential electrolysis experiments. Digital simulation of the experimental cyclic voltammograms allowed for estimates of the rate constants of the heterogeneous ET to the O--O bond, and for the rate constants for the beta-scission fragmentation of the distonic radical-anions. Density functional theory calculations corroborate the differences in the heterogeneous kinetics of the initial dissociative ET. The endoperoxides 1 a-1 c react predominantly by a concerted dissociative ET mechanism, although the data suggests a stepwise dissociative pathway is also competitive. Bearing a nitro-aryl substituent, 1 d provides a rare example of an endoperoxide that proceeds by a stepwise dissociative ET mechanism. Irrespective of the initial mechanistic details, we find a propagating radical-anion cycle is a general mechanistic feature.

A lab-on-a-molecule with an enhanced fluorescent readout on detection of three chemical species.

A molecular three-input AND logic gate with a naphthalimide fluorophore communicates the presence of a congregation of three biologically relevant cations in aqueous methanol with a 25-fold fluorescence enhancement and ΦFmax of 0.203.