Conversion of amino-terephthalonitriles to multi-substituted single benzene fluorophores with utility in bioimaging.

Substitution of two fluorine atoms of the tetrafluoroterephthalonitrile (TFTN) ring (ortho to each other) by amine nucleophiles through SNAr chemistry is achievable. However, tri- and tetra-substitution towards multi-substituted single benzene fluorophores (SBFs) is harder due to increased electron richness of the TFTN moiety. Tertiary amine donors promote the molecule towards such multi-substitution guided by the steric obstruction to intramolecular charge transfer to the TFTN ring. Contrarily, secondary amine substituents with better lone pair donation to the TFTN ring cannot induce the SNAr pathway and instead promote hydrolysis of the nitrile groups of the TFTN moiety. Theoretical investigations have helped unearth the reasons for this observed difference in chemical reactivities and also explain the differences in the emission spectra. Finally, the success of the synthetic method towards multi-substitution is showcased through creation of a highly lipophilic SBF bearing an octyl unit and demonstrating its utility in in vitro cellular imaging.

The photochemical trans → cis and thermal cis → trans isomerization pathways of azobenzo-13-crown ether: A computational study on a strained cyclic azobenzene system.

The isomerization of azobenzo-13-crown ether can be expected to be hindered due to the polyoxyethylene linkage connecting the 2,2'-positions of azobenzene. The mixed reference spin-flip time-dependent density functional theory results reveal that the planar and rotational minima of the first photo-excited singlet state (S1) of the trans-isomer pass through a barrier (2.5-5.0 kcal/mol) as it goes toward the torsional conical intersection (S0/S1) geometry (

Diamino-Terephthalonitrile-based Single Benzene Fluorophores Featuring Strong Solution State Fluorescence and Large Stokes Shifts.

1°- and 2°-amines react with tetrafluoroterephthalonitrile through SNAr chemistry, creating the strongly emissive para-diamino-terephthalonitrile type single benzene fluorophores. The regioselectivity of reaction is dictated by the sterics of the initial secondary amine adduct. The molecules exhibit strong green-yellow emission and large (nearly 150 nm) Stokes shifts. Excited state analysis reveals a cooperative effect between the para-positioned amino groups through the electron-poor terephthalonitrile unit resulting in the fluorescence amplification.

Unexplored Isomerization Pathways of Azobis(benzo-15-crown-5): Computational Studies on a Butterfly Crown Ether.

Computational studies on trans → cis and cis → trans isomerizations of photoresponsive azobis(benzo-15-crown-5) have been reported in this work. The photoexcited ππ* state (S2) of the trans isomer relaxes through the planar S2 minimum and the planar S2/S1 conical intersection (both situated around 9 kcal/mol below the vertically excited S2 state) arising along the N═N stretching coordinate. The nπ* state (S1) of this isomer has both planar and rotated (clockwise and anticlockwise) minima, which may lead to a torsional conical intersection (S0/S1) geometry having a

Investigation on the Unexplored Photochemistry of 5,5-Dimethyl-1-pyrroline 1-Oxide (DMPO).

A comparative study of 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) and its 2-methyl-substituted analogue (2-Me-DMPO) has revealed their contrasting reaction pathways of oxaziridine and lactam (pyrrolidone) formation. The initial photoexcitation populates the second excited singlet states (S2) in both the systems with S0-S2 transition moment value of 3 D (oscillator strength 0.4); this subsequently undergoes (S0/S1) conical intersection through a structure having a CNO-kink and situated around 35-40 kcal/mol below the vertically excited geometry of the first excited singlet state (S1). This conical intersection is found to be responsible for the formation of the oxaziridine photoproduct in these systems. In DMPO, this oxaziridine eventually forms the corresponding lactam compound through a [1,2]-H shift after overcoming a barrier of 35 kcal/mol and following the imaginary frequency of 1517 i cm-1. The reverse thermal process of parent nitrone formation proceeds through a transition state situated at 60 kcal/mol above the oxaziridine geometry, and the corresponding imaginary frequency is 1514 i cm-1. On the other hand, in 2-Me-DMPO, the oxaziridine formed is more stable, and lactam formation does not happen from it in a similar manner.

Synthesis and electronic properties of ester substituted 1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line.

1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta-ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4-dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3-dicyano variants). A number of derivatives showed anti-tumor activity in µM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway.

Computational Investigation of the Photochemical Reaction Path of Some Synthesized and Experimentally Analyzed Small-Chain Conjugated Nitrones.

This combined theoretical and experimental study has revealed the photochemistry of two small open-chain conjugated N-methylnitrone systems with phenyl substitutions at the C-terminal positions. The UV spectra of these synthesized nitrones have shown intense peaks around 330 nm while the new bands formed near 260 nm after their photoirradiation are predicted to be arising from the photoproduct oxaziridine. Photoexcitation of α-styryl N-methylnitrone populates the first excited singlet state which relaxes by 8 kcal/mol from the vertically excited state and subsequently goes toward the lowest-energy conical intersection (CI) geometry (situated 27-30 kcal/mol below) with a terminal CNO-kink. Following the gradient difference vectors of this CI, we have located the oxaziridine structure with its characteristic geometry at roughly 14 kcal/mol above the ground state. This whole process is triggered by a transfer of electronic cloud from oxygen to the conjugated chain side. On the other hand, the photoexcitation of the nonplanar 3,3-diphenylethylene N-methylnitrone has two strong singlet-singlet absorptions with almost 5 D transition moment values. Here the initial S2-S1 relaxation is followed by oxaziridine formation through the terminally twisted CI. However, the initially photoexcited S1 state in this nitrone is found to head toward some other direction with transfer of huge amount of nonbonding electron cloud of oxygen to the π* orbital, creating a stable excited state geometry with an elongated N-O bond which gets involved in a sloped CI with the ground state.

Synthesis and photophysical characterization of quasi push-pull dicyanodibenzodioxins and their anti-tumor activity against glioma cell line C6.

Dibenzodioxins bearing multiple electron withdrawing groups were synthesized using a simple one-step methodology including examples of molecules possessing electron acceptor groups in both ends. As a consequence internal charge delocalization occurs and the optical spectra are found to be bathochromically shifted compared to similar examples known thus far. A theoretical analysis of the molecular orbitals reveals the origin of the peaks in the dibenzodioxin optical spectra. Select examples exhibit in vitro neuro-cytotoxicity against glioma cell line C6, a finding which enhances existing knowledge about the pharmacologically relevant structural motifs in dibenzodioxins.

Amino-Terephthalonitrile-Based Single Benzene Fluorophores with Large Stokes Shifts and Solvatochromic Behavior.

We have synthesized a small library of blue-to-green emissive single benzene-based fluorophores (SBFs) in a short synthetic sequence. The molecules exhibit good Stokes shift in the range of 60-110 nm and select examples also possess very high fluorescence quantum yields of up to 87%. Theoretical investigations into the ground state and excited state geometries of many of these compounds reveal that good degree of planarization between the electron donor secondary amines and electron accepting benzodinitrile units can be achieved under certain solvatochromic conditions, giving rise to the strongly fluorescent behavior. On the other hand, the excited state geometry which lacks co-planarity of the donor amine and the single benzene moiety can open up a non-fluorescent channel. Additionally, in molecules with a dinitrobenzene acceptor, the perpendicular nitro moieties render the molecules completely non-emissive.

To Quench or Not: Extending a ß-Carboline Fluorophore for TNT Detection in Aqueous Media via Simultaneous ESPT Destabilization and AIE.

Molecules relying on the excited-state intramolecular proton transfer/excited-state proton transfer (ESIPT/ESPT) mechanism are widely used in material science. In the current work, a known ß-carboline-based probe TrySy was used to selectively detect explosive trinitrotoluene (TNT) in water. Compared to conventional TNT sensing, which relies mainly on the quenching of the fluorescence signal, TrySy could perform nanomolar detection of TNT via ESPT destabilization and AIE, with a significant fluorescence output. The mechanism followed was validated by computational and experimental results.

A combination of a graphene quantum dots-cationic red dye donor-acceptor pair and cucurbit[7]uril as a supramolecular sensor for ultrasensitive detection of cancer biomarkers spermine and spermidine.

In a unique approach, the combination of a donor-acceptor pair of hydroxy graphene quantum dots (GQDs-OH) and a red-emissive donor-two-acceptor (D-2-A) type dye with pyridinium units (BPBP) and the well-known host cucurbit[7]uril (CB[7]) has been exploited as a supramolecular sensing assembly for the detection of cancer biomarkers spermine and spermidine in aqueous media at the sub-ppb level based on the affinity-driven exchange of guests from the CB[7] portal. In the binary conjugate, green fluorescent GQDs-OH transfers energy to trigger the emission of the dye BPBP and itself remains in the turn-off state. CB[7] withdraws the dye from the surface of GQDs-OH by strong host-guest interactions with its portal, making GQDs-OH fluoresce again to produce a ratiometric response. In the presence of spermine (SP) or spermidine (SPD), their strong affinity with CB[7] forces the ejection of the fluorophore to settle on the GQDs-OH surface, and the strong green emission of GQDs-OH turns off to device a supramolecular sensor for the detection of SP/SPD. The DFT studies revealed interesting excited-state charge-transfer conjugate formation between BPBP and GQDs leading to turn-on emission of the dye, and further supported the stronger binding modes of BPBP-CB[7], indicating the retrieval of the emission of GQDs. The assembly-disassembly based sensing mechanism was also established by Job's plot analysis, particle size analysis, zeta potential, time-resolved spectroscopy, ITC studies, microscopic studies, etc. The supramolecular sensing assembly is highly selective to SP and SPD, and showed nominal interference from other biogenic amines, amino acids, various metal ions, and anions. The limits of detection (LODs) were 0.1 ppb and 0.9 ppb for spermine and spermidine, respectively. The potential for the real-world application of this sensing assembly was demonstrated by spiking SP and SPD in human urine and blood serum with a high %recovery.

Design, synthesis, physicochemical studies, solvation, and DNA damage of quinoline-appended chalcone derivative: comprehensive spectroscopic approach toward drug discovery.

The present study epitomizes the design, synthesis, photophysics, solvation, and interaction with calf-thymus DNA of a potential antitumor, anticancer quinoline-appended chalcone derivative, (E)-3-(anthracen-10-yl)-1-(6,8-dibromo-2-methylquinolin-3-yl)prop-2-en-1-one (ADMQ) using steady state absorption and fluorescence spectroscopy, molecular modeling, molecular docking, Fourier-transform infrared spectroscopy (FTIR), molecular dynamics (MD) simulation, and gel electrophoresis studies. ADMQ shows an unusual photophysical behavior in a variety of solvents of different polarity. The dual emission has been observed along with the formation of twisted intramolecular charge transfer (TICT) excited state. The radiationless deactivation of the TICT state is found to be promoted strongly by hydrogen bonding. Quantum mechanical (DFT, TDDFT, and ZINDO-CI) calculations show that the ADMQ is sort of molecular rotor which undergoes intramolecular twist followed by a complete charge transfer in the optimized excited state. FTIR studies reveals that ADMQ undergoes important structural change from its native structure to a ß-hydroxy keto form in water at physiological pH. The concentration-dependent DNA cleavage has been identified in agarose gel DNA electrophoresis experiment and has been further supported by MD simulation. ADMQ forms hydrogen bond with the deoxyribose sugar attached with the nucleobase adenine DA-17 (chain A) and result in significant structural changes which potentially cleave DNA double helix. The compound does not exhibit any deleterious effect or toxicity to the E. coli strain in cytotoxicity studies. The consolidated spectroscopic research described herein can provide enormous information to open up new avenues for designing and synthesizing chalcone derivatives with low systematic toxicity for medicinal chemistry research.