Drug Delivery by Controlling a Supramolecular Host–Guest Assembly with a Reversible Photoswitch

The reversibly switchable trans‐chalcone/flavylium photochromic system was successfully coupled to the complexation equilibrium of a drug‐cucurbit[7]uril host–guest assembly. Hence, the phototriggered release of memantine under illumination at 366 nm was observed. The process can be partially reverted through a thermally activated back reaction.     

Flavylium Network of Chemical Reactions in Confined Media: Modulation of 3′,4′,7‐Trihydroxyflavilium Reactions by Host–Guest Interactions with Cucurbit[7]uril

In moderately acidic aqueous solutions, flavylium compounds undergo a pH‐, and in some cases, light‐dependent array of reversible chemical reactions. This network can be described as a single acid–base reaction involving a flavylium cation (acidic form) and a mixture of basic forms (quinoidal base, hemiketal and cis and trans chalcones). The apparent pK′_a of the system and the relative mole fractions of the basic forms can be modulated by the interaction with cucurbit[7]uril. The system is studied by using ¹H NMR spectroscopy, UV/Vis spectroscopy, flash photolysis, and steady‐state irradiation. Of all the network species, the flavylium cation possesses the highest affinity for cucurbit[7]uril. The rate of interconversion between flavylium cation and the basic species (where trans‐chalcone is dominant) is approximately nine times lower inside the cucurbit[7]uril.     

Anthocyanidins and related compounds—XVII : Reactions of flavylium salts and 2-hydroxychalcones with hydroxylamine and hydrazine

Flavylium salts and 2-hydroxychalcones (1-phenyl-3-(2-hydroxyphenyl)-2-propen-1-ones) react with hydroxylamine in pyridine to form 2,5-dihydroisoxazoles. These undergo thermal and acid-catalyzed rearrangements to isomeric 4,5-dihydroisoxazoles and chalcone oximes, respectively. With hydrazine, flavylium salts yield phenolic 4,5-dihydro-3,5-diphenyl-1H-pyrazoles. Since these readily condense with acetone to form cyclic acetonides, the hydrazination reaction involves initial nucleophilic attack at position 2 of the flavylium nucleus.     

Multistate/multifunctional systems. A thermodynamic,kinetic, and photochemical investigation of the 4'-dimethylaminoflavylium compound

The 4'-dimethylaminoflavylium ion in aqueous solution undergoes an intricate network of chemical reactions controlled by pH and light excitation. It is shown that nine different forms are involved, including two species that are not present in previously investigated compounds of the flavylium family. The thermodynamic and kinetic constants of the equilibria and interconversion processes have been obtained by pH jump (included stopped-flow) experiments. The photochromic properties exhibited by the trans/cis chalcone forms have been investigated. The peculiar aspect of 4'-dimethylaminoflavylium, as compared to previously investigated compounds of the same family, is a close to planarity structure, as demonstrated by the X-ray analysis on the parent 4'-aminoflavylium compound (2.3 degrees torsion angle between the benzopyrylium and benzene ring). The results obtained show that the flavylium cation is strongly stabilized by the electron-donor character of the dimethylamino substituent on the benzene ring. The donor-acceptor interaction makes both the protonation of the amino group and the hydration of the flavylium cation difficult, with consequences on the tautomerization and cis/trans isomerization reactions. The multistate/multifunctional properties of 4'-dimethylaminoflavylium have been discussed in the frame of write-lock-read-unlock-erase cycles.     

Light- and pH-regulated Water-soluble Pseudorotaxanes Comprising a Cucurbit[7]uril and a Flavylium-based Axle

A linear double pyridinium-terminated thread comprising a central chalcone moiety is shown to provide two independent binding sites with similar affinity for cucurbit[7]uril (CB7) macrocycles in water as judged from NMR, UV-Visible and fluorescence spectroscopies. Association results in [2] and [3]pseudorotaxanes, which are both pH and photosensitive. Switching from the neutral chalcone to the cationic flavylium form upon irradiation at 365 nm under acidic conditions provided an enhanced CB7 association (K_1:1 increases from 1.2×10⁵ M⁻¹ to 1.5×10⁸ M⁻¹), limiting spontaneous on-thread cucurbituril shuttling. This co-conformational change in the [2]pseudorotaxane is reversible in the dark with k_obs=4.1×10⁻⁴ s⁻¹. Threading the flavylium moiety into CB7 leads to a dramatic increase in the fluorescence quantum yield, from 0.29 in the free axle to 0.97 in the [2]pseudorotaxane and 1.0 in the [3]pseudorotaxane.     

Ortho effect in the fragmentation of 2-acetoxychalcones under electron impact

2-Acetoxychalcones decompose under electron impact conditions by loss of an acetoxy fragment to form flavylium ions. The effect is restricted to the ortho position and is reduced after hydrogenation of the chalcone double bond. The intense flavylium ion originates—as shown by specific labelling with ¹⁸O—from two different fragmentation lines: (a) direct loss of an acetoxy radical by cleavage of the phenolic Ar? O bond and (b) sequential elimination of ketene and a hydroxy radical.     

Hydroxypyridinechromene and Pyridinechalcone: Two Coupled Photochromic Systems

Substitution of the phenyl group in 2‐hydroxychalcones by a 4‐pyridine unit dramatically changes the network of chemical reactions of this compound: trans‐chalcone‐type ( Ct ), cis‐chalcone‐type ( Cc ), and a hemiketal (hydroxy‐4‐pyridinechromene) ( B ) and their protonated forms are formed, but the presence of a flavylium‐type cation could not be detected even at very acidic pH values. Moreover, whereas in 2‐phenyl‐2‐benzopyrylium compounds B and Cc are generally elusive species whose kinetic processes in aqueous solutions occur on the sub‐second timescale, in the present compound these species equilibrate on a timescale four orders of magnitude lower. Complete characterization of the equilibrium and kinetics of the reaction network could thus be achieved by ¹H NMR spectroscopy and UV/Vis spectrophotometry. The network of chemical reactions exhibits cis–trans photoisomerization, as well as photochromism between the hemiketal and the chalcone‐type species. The irradiation of Ct in MeOH/H₂O (1:1) at 365 nm produces B almost quantitatively through two consecutive photochemical reactions: Ct → Cc photoisomerization followed by Cc → B photo ring closure with a global quantum yield of 0.02. On the other hand, irradiation of B at 254 nm leads to a photostationary state composed by 80 % Ct and 20 % B , with a quantum yield of 0.21.     

Über die Wirkung von Auxochromen in Flavyliumsalzen,II. 5,6-Benzo-flavyliumsalze

Analogously to the 7-hydroxyflavyliumion the 5,6-benzoflavyliumion affects auxochromes in 4′-position not as strongly as the flavylium ion. In the flavylium series the dimethyl-amino group e.g. causes a bathochromic effect of 137 nm; in the 5,6-benzoflavylium series however the bathochromic effect is only 109 nm. The absorption maxima of both series converge; in the case of the dimethylamino group the convergence amounts to 28 nm.     

Phase-dependent photochromism of a lactone-stabilized chromene from a flavylium reaction network

New trans‐2‐hydroxychalcones bearing a carboxylate group at position 2′ ( Ct ^?) were synthesized (compounds 2 and 3 ). These compounds lead to a network of chemical reactions depending on pH value, light, and solvent. In water, when the pH value is lowered, the ionized trans‐chalcone is protonated and the flavylium cation A H⁺ is formed at very acidic pH values through hemiketal B and cis‐chalcone Cc , with global acidity constants of pK′_a ≤?1 and ≈0.1, respectively, for 2 and 3 . The electron‐acceptor character of the carboxylic substituent not only increases the observed acidity of the flavylium cation, but also decreases the rate of the ring‐opening/‐closing from a subsecond timescale to hours relative to model compound 1 (without carboxylate). The photochemistry of the network was studied in detail by means of continuous irradiation, monitored by UV/Vis absorption and ¹H and ¹³C NMR spectroscopic analysis. Although compound 3 is only slightly photoactive, compound 2 ( Ct^? ) reacts in aqueous solutions (λ_irr=313 nm) to form B^? and Cc^? , with a global quantum yield of 0.15, and fully reverts back to Ct^? with a rate constant of k=6.7×10^?5 s^?1. The flavylium cation is no longer formed in methanol, and irradiation of Ct^? leads to the formation of B ^? and the new lactone‐trapped chromene species La . The formation of La takes place through a sequence of three photochemical steps: photoisomerization of Ct ^?, photo‐ring‐closing reaction of Cc ^?, and photolactonization of B ^?. Only the cis/trans isomerization and ring‐closing reactions are thermally reversible on a timescale of seconds and hours, respectively. A photochromic system was achieved in rigid matrices of methanol (at 77 K) and 1‐dodecanol (5 °C) by irradiating lactone La to give a red ortho‐quinone allide through a photo‐ring‐opening reaction; the color disappears with a rate constant of k=1.25×10^?2 s^?1 in 1‐dodecanol at 5 °C.     

Über die Wirkung von Auxochromen in Flavyliumsalzen,III. 7-Dimethylamino-flavyliumsalze

The absorption maximum at longest wave lengths of the 7-dimethylaminoflavylium perchlorate being shifted by 121 nm to longer wave lengths than the maximum of the flavylium perchlorate and yet the auxochromes in 4′-position having a less strong effect in the 7-dimethylamino-flavylium salts than in the flavylium salts, the absorption maxima of both series converge strongly. In the case of the 4′-dimethylamino derivatives the convergence reaches the high value of 61 nm.     

Two Colour Photoflow Chemistry for Macromolecular Design

We report a photochemical flow setup that exploits λ‐orthogonal reactions using two different colours of light (λ₁=350 nm and λ₂=410 nm) in sequential on‐line irradiation steps. Critically, both photochemically reactive units (a visible‐light reactive chalcone and a UV‐activated photo‐caged diene) are present in the reaction mixture. We demonstrate the power of two colour photoflow by the wavelength‐selective end group modification of photo‐caged polymer end groups and the subsequent polymer ring closure driven by a [2+2] cycloaddition. Importantly, we evidence that the high energy gate does not induce the visible light reaction of the chalcone, which attests the true λ‐orthogonal nature of the flow reaction system. For the first time, this study opens the realm of photoflow reactions to λ‐orthogonal photochemistry.     

Modulation of color changing paths for flavylium salts by solvent and concentration

The modulations of the color changing paths for flavylium salt (2-phenylbenzopyrilium, abbreviated as FV) by solvent and their concentrations have been studied by observing changes in the UV-Vis absorption spectra. The feature of the spectral changes varies with the solvent and solution FV concentration. The color of the solutions in ethanol at high concentration changed from yellow to red via green. It has been proposed that the yellow, green, and red species of FV are a monomer, a monomer with charge-transfer character, and a dimer and/or aggregate of FV, respectively. The spectral changes showed different behaviors in different solvents. In ethanol solution with a low concentration, a chalcone was generated by nucleophilic addition. The PM3 calculation revealed a new reaction path where the green FV is converted to a chalcone in propylene glycol. The color changing paths for FVs were able to be modulated in different solvents and by their concentration change. The previous proposed scheme well explained the experimental results in various solvents.     

Über die Wirkung von Auxochromen in Flavyliumsalzen,I. 7-Hydroxy-flavyliumsalze

7-Hydroxy-flavylium salts absorb at longer wave lengths than the corresponding flavylium salts, yet auxochromes in 4′-position have a less bathochromic effect in the 7-hydroxy-flavylium series than in the flavylium series. As a result the absorption maxima converge. 4′-Dimethylamino derivatives show a convergence of 22 nm.     

Formation of a leuco Spirolactone from 4‐(2‐Carboxyphenyl)‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium: Design of a Phase‐Change Thermochromic System Based on a Flavylium Dye

A phase‐change thermochromic system was designed through the reversible transformation of the 4‐substituted flavylium dye 4‐(2‐carboxyphenyl)‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium into its leuco form, in the presence of a developer (ethyldiisopropylamine) and a suitable solvent (e.g., acetonitrile, n‐pentadecanonitrile). The leuco form of the flavylium‐based dye is a spirolactone species whose ring opens at low temperature (below the solvent melting point) to form the blue flavylium cation. Decarboxylation of the lactone to give 4‐phenyl‐7‐diethylamino‐4′‐dimethylamino‐1‐benzopyrylium was observed upon irradiation of the system with UV light, erasing the thermochromic effect.     

Synthesis of novel chalcone derivatives and their stabilization effect of spiropyran in PMMA films

Three novel bis-chalcone derivatives with different alkyldioxy spacers were synthesized and dispersed into polymethyl methacrylate(PMMA) chloroform solution with 6-nitro-1’-ethyl-3’,3’-dimethylspiro-2H-1-benzopyran-2,2’-indoline(ESP) to prepare photochromic PMMA films in a facile way.After irradiation with 365 nm UV light,the photocrosslinking reaction between chalcone units was proved to retard the dccolorization of merocyanine form of the photochromic spiropyran effectively,as results of the steric hindrance produced by photocycloaddition of chalcone groups.It has been found that the bis-chalcone molecule with the shortest spacer has the most effective stabilizing effect on retardation of decoloration of spiropyran.     

Q-mode curve resolution of UV-vis spectra for structural transformation studies of anthocyanins in acidic solutions

Chemometric analysis of ultraviolet-visible (UV-vis) spectra for pH values 1.0, 3.3, 5.3, and 6.9 was used to investigate the kinetics and the structural transformations of anthocyanins in extracts of calyces of hibiscus flowers of the Hibiscus acetosella Welw. ex Finicius for the first time. Six different species were detected: the quinoidal base (A), the flavylium cation (AH⁺), the pseudobase or carbinol pseudobase (B), cis-chalcone (C_C), trans-chalcone (C_t), and ionized cis-chalcone (⁻CC). Four equilibrium constant values were calculated using relative concentrations, hydration, pK_h = 2.60 ± 0.01, tautomeric, K_T = 0.14 ± 0.01, acid-base, pK_a = 4.24 ± 0.04, and ionization of the cis-chalcone, pKCC=8.74±1.5×1⁰−2. The calculated protonation rate of the tautomers is KH+=0.08±7.6×10⁻³. These constants are in excellent agreement with those measured previously in salt form. From a kinetic viewpoint, the situation encountered is interesting since the reported investigation is limited to visible light absorption in acid medium. These models have not been reported in the literature.     

Effect of Methyl,Hydroxyl, and Chloro Substituents in Position 3 of 3′,4′,7‐Trihydroxyflavylium: Stability,Kinetics, and Thermodynamics

The effect of methyl, hydroxyl, and chloride substituents in position 3 of the 3′,4′,7‐trihydroxyflavylium core structure was studied. The stability, relative energy of each of chemical species (thermodynamics), and their rates of interconversion (kinetics) are very dependent on these substituents. By comparing the mole fraction distribution at equilibrium of the three multistate systems with the parent 3′,4′,7‐trihydroxyflavylium, introduction of a methyl substituent in position 3 increases the mole fraction of hemiketal at the expense of the trans‐chalcone and increases the hydration rate very significantly; a hydroxyl substituent in position 3 gives rise to a degradation process, as observed in anthocyanidins. In the case of 3‐chloro‐3′,4′,7‐trihydroxyflavylium, a dramatic increase of the flavylium cation acidity was observed and a photochromic system can be operated upon irradiation of the respective trans‐chalcone in 1 m HCl. According to the photochromic response of 3,3′,4′,7‐tetrahydroxyflavylium and 3′,4′,7‐trihydroxyflavylium, some requirements for a good photochromic performance are discussed.     

Synthesis and characterization of a symmetric bis(7-hydroxyflavylium) containing a methyl viologen bridge

A symmetric bis(flavylium) constituted by two 7-hydroxyflavylium moieties linked by a methylviologen bridge was synthesized. The thermodynamic and kinetics of the network of chemical reactions involving bis(flavylium) and the model compound 7-hydroxy-4'-methylflavylium was completely characterized by means of direct and reverse pH jumps (stopped flow) and flash photolysis. Both compounds follow the usual pH-dependent network of chemical reactions of flavylium derivatives. The equilibrium species of the model compound are the flavylium cation (acidic species) and the trans-chalcone (basic species) with an apparent pK'(a)=2.85. In the case of the bis(flavylium) it was possible to characterize by (1)H NMR spectroscopy three species with different degrees of isomerization: all flavylium, flavylium-trans-chalcone, and all trans-chalcone. Representation of the time-dependent mole fraction distribution of these three forms after a pH jump from equilibrated solutions of all-flavylium cation (lower pH values) to higher pH values, shows that formation of trans-chalcone is not completely stochastic (two independent isomerizations), the isomerization of one flavylium showing a small influence on the isomerization of the other. The radical of the methyl viologen bridge is formed upon reduction of the bis(trans-chalcone) with dithionite. The system is reversible after addition of an oxidant in spite of the occurrence of some decomposition.     

Visibly observed photocrosslinking reaction in indolyl based pendant liquid crystalline polymers: Synthesis and optical property

Visibly observed photocrosslinkable pendant liquid crystalline polymers containing indolyl based chalcone were synthesized by free‐radical polymerization and characterized spectroscopically. The differential scanning calorimetry and polarized optical microscopy were used to examine liquid crystalline property. The photocrosslinking and luminescence properties were monitored by UV‐Vis spectrophotometer and spectrofluorimeter, respectively. It demonstrates the chalcone unit did not manifest cis ? trans‐isomerization reaction along with 2π+2π photodimerization upon irradiation with UV light like other chalcones hitherto reported. The photocrosslinking was visibly monitored in solution through change of fluorescent color to colorless. The spacer lengths play a key role in the reaction. The fluorescence maximum was blue shifted around 70 nm in chloroform solution upon irradiation with UV light confirms the 2π+2π photodimerization of chalcone unit. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5208–5220, 2009     

Effect of SDS micelles on the reactivity of 4′-methoxyflavylium ion: A stopped-flow and photochemical study

The network of chemical reactions of the compound 4′-methoxyflavylium was studied in the presence of SDS micelles, using stopped-flow, UV–vis absorption and flash photolysis techniques. The results were compared with analogous experiments carried out in water. The large stabilization of the flavylium cation onto the micelles was proven to be due to an increase in the rate of the dehydration reaction, rather than a decrease of the hydration reaction; the cis–trans isomerisation of the chalcone was not affected by the micelles. It is shown that SDS micelles can be considered as an external stimulus capable of changing the system from one state to another.