Flow Synthesis of Gigantic Porphyrinic Cages: Facile Synthesis of P12 L24 and Discovery of Kinetic Product P9 L18.

A continuous flow methodology for the facile and high-yielding synthesis of the porphyrin-based self-assembled organic cage, P12 L24 is reported, along with the serendipitous discovery of a kinetic product, P9 L18 cage, which has been characterized by MALDI-TOF MS, NMR, and AFM analysis. A theoretical study suggests a tricapped trigonal prismatic geometry for P9 L18 . Unlike P12 L24 , P9 L18 is unstable and readily decomposes into monomers and small oligomers. While the batch synthesis produces only the thermodynamic product P12 L24 , the continuous flow process generates not only the thermodynamic product but also kinetic products, such as P9 L18 , illustrating the advantages of the continuous flow process for the synthesis of self-assembled cages and the exploration of new non-equilibrium assemblies.

Synthetic Monosaccharide Channels: Size-Selective Transmembrane Transport of Glucose and Fructose Mediated by Porphyrin Boxes.

Here we report synthetic monosaccharide channels built with shape-persistent organic cages, porphyrin boxes (PBs), that allow facile transmembrane transport of glucose and fructose through their windows. PBs show a much higher transport rate for glucose and fructose over disaccharides such as sucrose, as evidenced by intravesicular enzyme assays and molecular dynamics simulations. The transport rate can be modulated by changing the length of the alkyl chains decorating the cage windows. Insertion of a linear pillar ligand into the cavity of PBs blocks the monosaccharide transport. In vitro cell experiment shows that PBs transport glucose across the living-cell membrane and enhance cell viability when the natural glucose transporter GLUT1 is blocked. Time-dependent live-cell imaging and MTT assays confirm the cyto-compatibility of PBs. The monosaccharide-selective transport ability of PBs is reminiscent of natural glucose transporters (GLUTs), which are crucial for numerous biological functions.

Dramatically Enhanced Reactivity of Fullerenes and Tetrazine towards the Inverse-Electron-Demand Diels-Alder Reaction inside a Porous Porphyrinic Cage.

Inverse-electron-demand Diels-Alder reaction (IEDDA) between fullerenes and 1,2,4,5-tetrazine generally requires harsh conditions and long reaction times due to their strong electron-accepting nature. Herein, we report a dramatic enhancement in the reactivity of the fullerenes (C60 /C70 )-tetrazine reaction inside a porous Zn-porphyrinic cage (Zn-PB) under sustainable conditions by installing a tetrazine-based axle (LA) via metal-ligand coordination bond, which modulates the cavity size to facilitate the encapsulation of fullerenes. Upon encapsulation, the close proximity of fullerenes and the tetrazine group of LA dramatically increase their reactivity towards the IEDDA reaction to form fullerene-tetrazine adducts. Furthermore, the C60 -tetrazine adduct is rearranged upon hydration to a bent-shaped C60 -pyrazoline adduct that can be released from the Zn-PB cavity in the presence of excess LA, thus catalyzing the formation of C60 -pyrazoline adduct inside Zn-PB without product inhibition.

NADH-Activated Dual-Channel Fluorescent Probes for Multicolor Labeling of Live Cells and Tumor Mimic Spheroids.

The 1,4-dihydronicotinamide adenine dinucleotide (NADH) is one of the key coenzymes that participates in various metabolic processes including maintaining the redox balance. Early information on the imbalance of NADH is crucial in the context of diagnosing the pathogenic conditions. Thus, a dual-channel fluorescent probe (MQN) is developed for tracking of NADH/NAD(P)H in live cells. In the presence of NADH, only it showed emission signals at 460 and 550 nm upon excitation at 390 and 450 nm, respectively. The probe could provide accurate information on NADH levels in cancer cells (HeLa) and normal cells (WI-38). We observed that the NADH level in cancer cells (HeLa) is relatively higher than that in normal WI-38 cells. We received similar information on NADH upon calibrating with a commercial NADH kit. Moreover, we evaluated substrate-specific NADH expression in the glycolysis pathway and oxidative phosphorylation process. Also, the dual-channel probe MQN has visualized NADH manipulation in the course of depletion of GSH to maintain cellular redox balance. This dual-channel molecular probe MQN comes out as a new detection tool for NADH levels in live cells and tumor mimic spheroids.

Molecule to Supramolecule: Chirality Induction, Inversion, and Amplification in a Mg(II)porphyrin Dimer Templated by Chiral Diols.

A clear and unambiguous rationalization of chirality induction, amplification, and subsequent inversion processes has been demonstrated using an achiral Mg(II)porphyrin dimer (host) and a series of chiral diols (guests) upon stepwise formation of a 1:1 host-guest polymer and 1:2 host-guest monomer via intermolecular assembling and disassembling processes. Crystallographic characterizations are reported here for both the polymer and the monomeric complexes, which enable us to completely scrutinize the structural and geometrical changes systematically in rationalizing their optical properties. The sign of the CD couplets for both the polymer and monomer are just opposite between R and S guests, which suggests that the chirality is dictated solely by the stereogenic projection of the chiral centers. Stronger intra- and intermolecular coupling in the polymeric complexes is responsible for the highly enhanced CD couplets as compared to the monomer and have only intramolecular coupling as also observed in their X-ray structures. DFT studies clearly support the experimental observations.

Superacid-Mediated Functionalization of Hydroxylated Cucurbit[n]urils.

Herein we report a facile transformation of hydroxylated cucurbit[n]uril (CB[n], n = 6 and 7) to other functionality-conjugated CB[n]s by nucleophilic substitution of the hydroxyl group with a wide range of nitriles and alcohols. The reaction proceeds efficiently via generation of a superelectrophilic carbocation on the CB framework from hydroxylated CB[n]s under superacidic conditions. One of the resulting CB[n] derivatives with reactive functionality, monocarboxylated CB[7], is efficiently conjugated to an enzyme (horseradish peroxidase, HRP) by amide coupling. This provides a CB[7]-conjugated functional biomaterial (CB[7]-HRP) that selectively detects proteins labeled with a guest, adamantylammonium (AdA), based on bioorthogonal high-affinity host-guest interactions between CB[7] and AdA. We demonstrated the potential of overcoming the limitations in preparing reactive functional CB[n] derivatives, enabling the exploration of novel bioapplications of CB[n]-based host-guest chemistry with new CB[n]-conjugated functional materials.

Complexation of Chiral Zinc(II) Porphyrin Tweezer with Achiral Aliphatic Diamines Revisited: Molecular Dynamics, Electronic CD, and 1H NMR Analysis.

We have reported here the complexation and chiroptical behavior of the host-guest complexes using a new chiral Zn(II) bisporphyrin tweezer host and a series of achiral aliphatic diamine guests varying the chain length. (1R,2R)-Cyclohexanediamine covalently links two Zn(II) porphyrin moieties, which thereby produces a strong chiral field around the bisporphyrin tweezer framework. The chiral tweezer upon complexation with achiral guest exhibited large changes in the UV-vis spectra and CD exciton couplets due to a sudden change in the porphyrin disposition, which is controlled by the host-guest stoichiometry as well as the chain lengths of the diamine guest. Addition of smaller diamines (n: 2-5) to the host resulted in the formation of 1:1 sandwich and 1:2 open complexes, respectively, at the low and high guest concentration, which eventually display two-step inversions of the CD couplet. With longer diamines (n: 6-8), however, only 1:1 sandwich complexes are formed with retention of the CD sign. Similar observations were also reported by us recently using another chiral bisporphyrin tweezer having (1R,2R)-diphenylethylenediamine as the spacer. In an effort to obtain deeper insights into the sudden changes of interporphyrin disposition just by changing the length of the achiral diamines, we have extended a series of computational studies and correlated closely with the results obtained from the experiment. While the previously published study has relied on commonly applied Monte Carlo (MC) sampling of the potential energy surface in addition to being guided by porphyrin effective transition moment approximation, the present study uses a considerably more robust molecular modeling protocol, namely Molecular Dynamics (MD) simulations followed by full ab initio geometry optimization and TD-DFT CD prediction. The experimental data corroborate with the results obtained from the theoretical conformational analysis. The latter are also supported by experimental 1H NMR data empowered by the porphyrin ring-current effect. The NMR spectral patterns of pyrrolic protons of the free host and the 1:1 sandwich complexes appear very diagnostic and reflect the changes in the mutual porphyrin disposition on moving from the free host to the complexed ones with short and long diamines. Overall, the experimental NMR data underscore the sensitivity of pyrrolic protons chemical shifts to subtle alterations of the geometrical features, and as such, they come in agreement with the theoretically derived models.

Metal-Center-Driven Supramolecular Chirogenesis in Tweezer Amino Alcohol Complexes: Structural, Spectroscopic, and Theoretical Investigations.

An apparently rigid dibenzothiophene-bridged zinc(II)/magnesium(II) bisporphyrin host (1M) has been explored for an accurate determination of the absolute configuration of a large series of amino alcohols. At lower substrate concentration, a 1:1 sandwich complex is formed which, upon addition of excess of substrate, converts to the 1:2 host-guest complex with complete inversion of the CD exciton couplet. The intensities of the couplet vary widely just by changing the metal ion (Zn vs Mg) and also vary between 1:1 and 1:2 host-guest complexes. Crystallographic characterizations are reported here for both 1:1 sandwich and 1:2 host-guest complexes using the same pair of host and guest, for the first time, which enable us to scrutinize the structural and geometrical changes systematically in rationalizing their optical properties. The intensity of the CD couplet is largely dependent on how strongly the substrate binds with the host and also their mode of binding. No CD couplet is observed in the spectral region of porphyrin absorption when substrate binds in either exo-endo or exo-exo fashion in the 1:2 host-guest complex. However, intermolecular H bonding between two encapsulated substrates in the 1:2 host-guest complex stabilizes the endo-endo conformer in which two porphyrin macrocycles are forced to be oriented in a clockwise/anticlockwise direction to produce an intense CD couplet. Such an endo-endo binding of (S)-2-aminobutan-1-ol (S-AB) has resulted in a highly intense CD couplet with 1Mg, while no chiroptic response was observed upon changing the metal to zinc, since S-AB would then bind in an exo-endo form. With an increase in the bulk of the substrate, the endo-endo form first transforms into an exo-endo form which, upon further increase in the bulk of the substrate, converts into an exo-exo complex.

A Nonempirical Approach for Direct Determination of the Absolute Configuration of 1,2-Diols and Amino Alcohols Using Mg(II)bisporphyrin.

We report here a simple, facile, and direct nonempirical protocol for determining the absolute stereochemistry of a variety of chiral 1,2-diols and amino alcohols at room temperature with no chemical derivatization using Mg(II)bisporphyrin as a host. Addition of excess substrates resulted in the formation of a 1:2 host-guest complex in which two substrates bind in an unusual endo-endo fashion because of interligand H-bonding within the bisporphyrin cavity leading to the formation of a unidirectional screw in the bisporphyrin moiety that allowed us an accurate absolute stereochemical determination of the chiral substrate via exciton-coupled circular dichroism (ECCD). The sign of the CD couplet has also been found to be inverted when the stereogenic center is moved by one C atom simply from the bound to an unbound functionality and thus able to discriminate between them successfully. Strong complexation of the alcoholic oxygen with Mg(II)bisporphyrin rigidifies the host-guest complex, which eventually enhances its ability to stereochemically differentiate the asymmetric center. The ECCD sign of a large number of substrates has followed consistent and predictable trends; thus, the system is widely applicable. Moreover, computational calculations clearly support the experimental observations along with the absolute stereochemistry of the chiral substrate.

Induction and Rationalization of Supramolecular Chirality in the Tweezer-Diamine Complexes: Insights from Experimental and DFT Studies.

A series of supramolecular chiral 1:1 sandwich complexes (1M·L and 2M·L) consisting of diphenylether/ethane bridged metallobisporphyrin host (1M and 2M; M: Zn/Mg) and chiral diamine guest (L) have been presented. The host-guest complexes are compared just upon changing the metal ion (Mg vs Zn) or the bridge (highly flexible ethane vs rigid diphenylether) keeping other factors similar. The factors that would influence the chirality induction process along with their contributions toward the sign and intensity of the CD couplet of the overall complex have been analyzed. Larger CD amplitude was observed in the host-guest complex with the more flexible ethane bridge as compared to the rigid diphenylether bridged one, irrespective of the metal ion used. Also, Zn complexes have displayed larger CD amplitude because of their stronger binding with the chiral diamines. A fairly linear dependence between the binding constant (K) and CD amplitude has been observed. Moreover, the amplitude of the CD couplet has been correlated with the relative steric bulk of the substituent at the stereogenic center: with increasing the bulk, CD intensity gradually increases. However, large increase of steric hindrance, after a threshold value, has diminished the intensity. The observation of a weak positive CD couplet between (1R,2R)-DPEA guest and Zn-bisporphyrin hosts indicates that the clockwise-twisted (steric-controlled) conformer is more populated as compared to the anticlockwise (chirality-controlled) one. In contrast, amplitude of the positive CD couplets is larger with Mg-bisporphyrin hosts, suggesting almost exclusive contribution of the clockwise-twisted conformer guided solely by sterics. DFT calculations support the experimental observations and have displayed the possible interconversion between clockwise and anticlockwise twisted conformers just upon changing the bulk of the substituent irrespective of the nature of chirality at the stereogenic center.

Highly enhanced bisignate circular dichroism of ferrocene-bridged Zn(II) bisporphyrin tweezer with extended chiral substrates due to well-matched host-guest system.

Four new chiral tweezer-diamine complexes, consisting of an achiral ferrocene-bridged Zn(II)bisporhyrin host (1) and two small diamines (1R,2R)-1,2-diphenylethylene diamine {(1R,2R)-DPEA} and (1S,2S)-1,2-cyclohexane diamine {(1S,2S)-CHDA} and two extended diamines (1R,2R)-N,N'-bis-(isonicotinoyl)-1,2-diphenylethylene diamine {(1R,2R)-DPEApy} and (1S,2S)-N,N'-bis-(isonicotinoyl)-1,2-cyclohexane diamine {(1S,2S)-CHDApy} chiral guests, are reported. Additions of (1R,2R)-DPEA and (1S,2S)-CHDA separately to 1 in dichloromethane result in the formation of 1:1 sandwich complexes 1·DPEA(R,R) and 1·CHDA(S,S), respectively, at low guest concentration and 1:2 anti complexes 1·(DPEA(R,R))2 and 1·(CHDA(S,S))2, respectively, at higher guest concentration. In contrast, separate additions of (1R,2R)-DPEApy and (1S,2S)-CHDApy to 1 produce only 1:1 sandwich complexes of 1·DPEApy(R,R) and 1·CHDApy(S,S), respectively. The binding constants at 295 K between 1 and (1R,2R)-DPEA are observed to be (4.7 ± 0.2) × 10(4) M(-1) and (4.3 ± 0.3) × 10(3) M(-1) for 1:1 sandwich and 1:2 anti form, respectively, while the respective values with (1S,2S)-CHDA are (1.5 ± 0.2) × 10(5) M(-1) and (5.9 ± 0.3) × 10(3) M(-1). However, much larger values of (2.5 ± 0.3) × 10(5) M(-1) and (1.3 ± 0.3) × 10(6) M(-1) have been observed with DPEApy(R,R) and CHDApy(S,S), respectively, to produce the corresponding 1:1 sandwich complexes. 1·DPEApy(R,R) (Acal, -1759 cm(-1) M(-1)) (Acal = Δε1 - Δε2, representing the total amplitude of the calculated circular dichroism (CD) couplets) shows ∼10-fold increase in CD amplitude compared to the values observed for 1·DPEA(R,R) (Acal, +187 cm(-1) M(-1)), while 1·CHDApy(S,S) (Acal, +1886 cm(-1) M(-1)) shows nearly 3-fold increase of the CD amplitude compared to the value observed for 1·CHDA(S,S) (Acal, -785 cm(-1) M(-1)) at 295 K. The Acal values of -1759 cm(-1) M(-1) and +1886 cm(-1) M(-1) observed for the 1·DPEApy(R,R) and 1·CHDApy(S,S), respectively, are extremely high. To the best of our knowledge, these are some of the largest values reported for a chirality induction process involving bisporphyrin tweezer receptors. The large enhancement in the CD signal intensity is due to the well complementarity size between Zn(II)bisporphyrin host and the extended chiral diamines guest, which results large unidirectional twisting of two porphyrin units to accommodate the guests having preorganized binding sites with minimum host-guest steric interactions. It is interesting to note that 1·DPEA(R,R) and 1·DPEApy(R,R) show CD signal opposite in sign to each other, which happens to be the case between 1·CHDA(S,S) and 1·CHDApy(S,S) also.

Modulation of supramolecular chirality by stepwise axial coordination in a nano-size trizinc(ii)porphyrin trimer.

Herein, we report a chiral guest's triggered spring-like contraction and extension motions coupled with unidirectional twisting in a novel flexible and 'nano-size' achiral trizinc(ii)porphyrin trimer host upon step-wise formation of 1 : 1, 1 : 2, and 1 : 4 host-guest supramolecular complexes based on the stoichiometry of the diamine guests for the first time. During these processes, porphyrin CD responses have been induced, inverted, and amplified, and reduced, respectively, in a single molecular framework due to the change in the interporphyrin interactions and helicity. Also, the sign of the CD couplets is just the opposite between R and S substrates which suggests that the chirality is dictated solely by the stereographic projection of the chiral center. Interestingly, the long-range electronic communications between the three porphyrin rings generate trisignate CD signals that provide further information about molecular structures.

Monitoring glutathione dynamics in DNA replication (S-phase) using a two-photon reversible ratiometric fluorescent probe.

The redox regulator glutathione (GSH) migrates to the nucleus to give a safeguard to DNA replication in the S-phase. The fluctuation of GSH dynamics in the cell cycle process may help to understand cancerogenesis or other abnormalities in DNA replication. For the first time, we attempted to track the time-dependent S-phase change using the newly developed ratiometric fluorescent probe Nu-GSH. This probe is highly chemoselective towards glutathione and shows an emission intensity shift from 515 nm to 455 nm. It has shown fluorescence reversibility from blue to green channels while scavenging reactive oxygen species H2O2. Both ratiometric fluorescence images and FACS analysis have provided quantitative information on the GSH levels in the nucleoli during DNA replication in the S-phase. Furthermore, GSH fluctuation reciprocated the decay of the S-phase on a time scale. Additionally, its two-photon ability guaranteed its capability to study GSH dynamics in live cells/tissues noninvasively. We envision that the probe Nu-GSH can be used to get high-throughput quantitative information on glutathione dynamics and give an opportunity to monitor its perturbation during the course of cell division.

One-pot Synthesis of a Truncated Cone-shaped Porphyrin Macrocycle and Its Self-assembly into Permanent Porous Material.

Here, we report the synthesis of a truncated cone-shaped triangular porphyrinic macrocycle, P3 L3 , via a single step imine condensation of a cis-diaminophenylporphyrin and a bent dialdehyde-based linker as building units. X-ray diffraction analysis reveals that the truncated cone-shaped P3 L3 molecules are stacked on top of each other by π⋯π and CH⋯π interactions, to form 1.7 nm wide hollow columns in the solid state. The formation of the triangular macrocycle is corroborated by quantum chemical calculations. The permanent porosity of the P3 L3 crystals is demonstrated by several gas sorption experiments and powder X-ray diffraction analysis.

Induction, control, and rationalization of supramolecular chirogenesis using metalloporphyrin tweezers: a structure-function correlation.

Supramolecular chirogenesis is one of the most rudimentary topics in the interdisciplinary sciences and essentially deals with various natural processes and innovative modern technologies. A comprehensive and rigorous understanding of such phenomenon is necessary to have a clear insight into the fundamental mechanisms and the various controlling factors, which would eventually lead to a range of practical applications of chiral supramolecular science. Metalloporphyrin tweezers have been extensively employed for such chirogenic processes due to their exciting physicochemical and tunable spectral properties, large stabilities, easily available synthetic protocols, and excellent abilities to form molecular assemblies. During the last few decades, various metalloporphyrin tweezers have been developed and considerably utilized by several research groups for assigning the absolute configuration to a variety of chiral diamines, conjugates of primary and secondary amines, amino alcohols, secondary alcohols, α-chiral carboxylic acids, etc. Our group has been at the forefront in trying to establish the structure-property correlation in this important area of interdisciplinary research. A brief account of our systematic investigation for understanding the underpinning mechanism of chirality induction and control at the molecular level over the last few years is presented in this Perspective article. The comprehensive understanding of such mechanistic details will be helpful in understanding various natural processes and designing modern technologies for various chirogenic functions in the fields of molecular sensors, nanotechnology, and supramolecular chemistry.

Metal-coordination-driven mixed ligand binding in supramolecular bisporphyrin tweezers.

Mg(II)bisporphyrin has been used as an efficient host for the selective binding of guest ligands. In the presence of heterogeneous guest pairs, 2-aminopyrimidine/pyrazine and 2-aminopyrimidine/1,4-dioxane, 2-aminopyrimidine is bound selectively inside the bisporphyrin cavity whereas pyrazine/1,4-dioxane is bound outside to produce 1D mixed ligand polymers. UV-vis, (1)H NMR spectra and X-ray structure confirm such a selective and orthogonal binding of the guest ligands. The mixed ligand polymer has been synthesized just by mixing the host and guests in one pot and easily isolated as a solid in nearly quantitative yield due to its high stability.