Photoswitchable Diazocine-Based Estrogen Receptor Agonists: Stabilization of the Active Form inside the Receptor.

Photopharmacology is an emerging approach in drug design and pharmacological therapy. Light is used to switch a pharmacophore between a biologically inactive and an active isomer with high spatiotemporal resolution at the site of illness, thus potentially avoiding side effects in neighboring healthy tissue. The most frequently used strategy to design a photoswitchable drug is to replace a suitable functional group in a known bioactive molecule with azobenzene. Our strategy is different in that the photoswitch moiety is closer to the drug's scaffold. Docking studies reveal a very high structural similarity of natural 17ß-estradiol and the E isomers of dihydroxy diazocines, but not their Z isomers, respectively. Seven dihydroxy diazocines were synthesized and subjected to a biological estrogen reporter gene assay. Four derivatives exhibit distinct estrogenic activity after irradiation with violet light, which can be shut off with green light. Most remarkably, the photogenerated, active E form of one of the active compounds isomerizes back to the inactive Z form with a half-life of merely several milliseconds in water, but nevertheless is active for more than 3 h in the presence of the estrogen receptor. The results suggest a significant local impact of the ligand-receptor complex toward back-isomerization. Thus, drugs that are active when bound but lose their activity immediately after leaving the receptor could be of great pharmacological value because they strongly increase target specificity. Moreover, the drugs are released into the environment in their inactive form. The latter argument is particularly important for drugs that act as endocrine disruptors.

Calculations on the Ruthenium-Catalyzed Diene and Dienyne Ring-Closing Metathesis Reactions in the Synthesis of Taxol Derivatives.

Density-functional and semiempirical calculations (M06, M06L, and PM6) on intermediates in the ring-closing metathesis (RCM) reactions in the synthesis of Taxol derivatives give results in excellent agreement with the results of previous experimental work. The results suggest that the degree of steric overloading plays a decisive role in determining the outcome (ene-ene or ene-yne-ene metathesis). Due to the rigidity of the Taxol skeleton being formed in the ene-yne-ene cascade reaction, the transition states in its final ene-ene metathesis reaction stage are particularly sensitive to steric effects. Thus, the reaction is predicted to be preferred for one diastereomer of the precursor in which the diol functionality is protected with a compact cyclic carbonate moiety, whereas the use of a bulkier benzoate-protecting group results in activation barriers for Taxol formation that are prohibitive. The reason why one diastereomer of the carbonate-protected precursor undergoes formation of a tricycle via an ene-yne-ene RCM cascade, whereas the other diastereomer undergoes cyclooctene formation via an ene-ene RCM, likely lies in the orientation of the pseudoaxial methyl group on the cyclohexene ring, which in the latter case would unfavorably point toward the reactive center of the Ru-complex, leading to Taxol formation.

Attempted characterisation of phenanthrene-4,5-quinone and electrochemical synthesis of violanthrone-16,17-quinone. How does the stability of bay quinones correlate with structural and electronic parameters?

In bay quinones, two carbonyl moieties are forced into close proximity by their spatial arrangement, resulting in an interesting axially chiral and nonplanar structure. Two representatives of this little-explored class of compounds were investigated experimentally in this work. Electrochemical oxidation of 4,5-dihydroxyphenanthrene failed to provide evidence for the reversible formation of phenanthrene-4,5-quinone. Even at temperatures as low as T = 229 K, cyclic voltammograms did not show any evidence for reversibility, indicating that phenanthrene-4,5-quinone likely is a reactive intermediate even at low temperatures. Electrochemical oxidation of the larger homologue 16,17-dihydroxyviolanthrone, on the other hand, was reversible, and the quinone could be characterised by spectroelectrochemical means. The results of quantum chemical calculations confirm the experimental findings and indicate that a bay dicarbonyl moiety, also found in a number of angucycline antibiotics, does not necessarily have to confer extreme reactivity. However, in a series of phenanthrene quinones with an equal number (zero) of Clar sextets and a varying number of bay carbonyl groups (zero to two), there was a clear correlation between the triplet energy, taken as a measure of biradical character, and the number of bay carbonyl moieties, with the lowest triplet energy predicted for phenanthrene-4,5-quinone (two bay carbonyl moieties).

Correlating ionic liquid solvent effects with solvent parameters for a reaction that proceeds through a xanthylium intermediate.

A unimolecular nucleophilic substitution reaction that proceeds through a xanthylium carbocation was studied in seven ionic liquid solvents. It was found that the general trend in the rate constant with changing proportion of ionic liquid in the reaction mixture was different to that seen for other unimolecular processes, with the rate constant increasing as more ionic liquid was added to the reaction mixture. A significant correlation was found between the natural logarithm of the rate constant and a combination of the Kamlet-Taft solvent parameters. This relationship indicated that the principal interaction involved hydrogen bonding between the ionic liquid and some species along the reaction coordinate. Further, this correlation enables prediction of the effects that other ionic liquids will have on this, and other, reactions that proceed through a similar intermediate.

Detection and Identification of Reaction Intermediates in the Photorearrangement of Pyridazine N-Oxide: Discrepancies between Experiment and Theory.

Photolysis of pyridazine N-oxide (PNO) results in the detection of a complex series of transient phenomena. On the ultrafast (fs) timescale, we could detect the decay of the first singlet excited state of PNO and the formation of a short-lived transient species, which, based on its time-resolved resonance Raman (TR3) spectrum, we assign to oxaziridine 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene. On a longer (hundreds of ns) timescale, this species rearranges to a ring-opened diazo compound, which we have also detected by time-resolved infrared and TR3 spectroscopy. In addition, we identify 1-oxa-3,4-diazepine as a long-lived species formed in the photochemistry of PNO. This species is formed via its oxirane isomer, which in turn is likely formed directly from the S1 state of PNO via a conical intersection. The barrier determined experimentally for the decay of 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene (Ea = (7.1 ± 0.5) kcal mol-1) is far larger than any barrier calculated by any method that includes dynamic electron correlation but very close to the barriers calculated at the RHF or CASSCF levels of theory. Many methods (B3LYP, MP2, and MP4) fail to give a minimum structure for 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene, while M06, M06-2X, MP3, CCSD, or CCSD(T) yield activation energies for its electrocyclic ring opening that are far too small. In addition, we note that several important geometric parameters, both of 1,2-diaza-7-oxa-bicyclo[4.1.0]hepta-2,4-diene and of the transition state of its ring opening reaction, clearly have reached no convergence, even at the fully optimized CCSD(T)/cc-pVTZ level of theory. We therefore suggest that the transient species described in this contribution might be excellent test molecules for further development of highly correlated and density functional theory methods.

Fragmentation of a dioxolanyl radical via nonstatistical reaction dynamics: characterization of the vinyloxy radical by ns time-resolved laser flash photolysis.

The photochemistry of two Barton esters, one derived from a dioxolane carboxylic acid and the other from pivalic acid, was investigated by product analysis and nanosecond laser flash photolysis (LFP). As expected, photolysis of the pivalate ester resulted in formation of the pyridine-2-thiyl and the t-butyl radical. Photolysis of the Barton ester of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid, on the other hand, revealed a complex multi-step fragmentation. In addition to the pyridine-2-thiyl and dioxolanyl radical, we gained evidence for the formation of the vinyloxy radical, CH2[double bond, length as m-dash]CHO˙. The latter was identified in the LFP by its π-complexes with benzene and diphenylether, its rapid quenching by electron-rich arenes and tri-n-butyl tin hydride, and its oxidative power in presence of trifluoroacetic acid as demonstrated by the oxidation of ferrocene to ferrocenium. Formation of CH2[double bond, length as m-dash]CHO˙ can be rationalized via fragmentation of the dioxolanyl radical. As the calculated barriers are too high for the reaction sequence to occur on the LFP time scale, we investigated the fragmentation of the photoexcited Barton ester via Born-Oppenheimer molecular dynamics simulations. In one trajectory, we could observe all reaction steps including ring opening of the dioxolanyl radical, suggesting that the excess energy gained in the ester cleavage and decarboxylation may lead to fragmentation of the hot dioxolanyl radical.

Electronically Stabilized Nonplanar Phenalenyl Radical and Its Planar Isomer.

Stable phenalenyl radicals have great potential as the basis for new materials for applications in the field of molecular electronics. In particular, electronically stabilized phenalenyl species that do not require steric shielding are molecules of fundamental interest, but are notoriously difficult to synthesize. Herein, the synthesis and characterization of two phenalenyl-type cations is reported: planar benzo[i]naphtho[2,1,8-mna]xanthenium (8(+)) and helical benzo[a]naphtho[8,1,2-jkl]xanthenium (9(+)), which can be reduced to the corresponding radicals. Radical 9 represents the first stable, helical phenalenyl radical which does not rely on bulky substituents to ensure its stability. Both cations are water-soluble, and the radicals are stable for weeks at room temperature under air. These compounds were characterized crystallographically, and also by NMR, EPR, electrochemistry, and electronic spectra. The synthesis of the previously reported compound benzo[5,6]naphthaceno[1,12,11,10-jklmna]xanthylium (5(+)), the largest oxygen-containing polycyclic hydrocarbon, was undertaken for comparison with 8(+) and 9(+), allowing us to report its crystal structure here for the first time. The different properties of these compounds and their radicals are explained by considering their differing aromaticities using in-depth computational methods.

ß-Phenyl quenching of 9-phenylphenalenones: a novel photocyclisation reaction with biological implications.

The singlet and triplet excited states of 9-phenylphenalenones undergo ß-phenyl quenching (BPQ) via addition of the carbonyl oxygen to the ortho position of the phenyl substituent. This reaction leads to the formation of naphthoxanthenes , which, in the absence of quenchers, undergo a very rapid electrocyclic ring opening reaction reverting to within a few microseconds. Naphthoxanthene contains a remarkably weak C-H bond, which enables efficient hydrogen transfer reactions to suitable acceptors, giving rise to the production of the naphthoxanthenyl radical or the naphthoxanthenium cation, depending on the solvent polarity. The study uncovers a number of new aspects of BPQ and suggests an excited state-mediated metabolic pathway in the biosynthesis of plant fluorones.

(π*,σ*), (σ*,π*) and Rydberg triplet excited states of hydrogen peroxide and other molecules bearing two adjacent heteroatoms.

The properties of the lowest triplet excited states of a series of small molecules containing two or more adjacent heteroatoms have been investigated. High-level coupled cluster and MRCI+Q calculations were employed to probe the properties of the triplet excited states of hydrogen peroxide, hydrazine, hydroxylamine, fluoroamines, oxygen difluoride, hypofluorous acid, chlorine, fluorine, and disulfane. All of the molecules investigated except hydroxylamine are predicted to have bound lowest triplet excited states that are either (π*,σ*) or (σ*,π*) as in H2O2, HOF, OF2, H2S2, Cl2, NH2F, NHF2, or NF3, or are Rydberg states (hydrazine, also H2O2 and H2S2). The heteroatom-heteroatom bond dissociation enthalpies of the triplet states range from very small values as predicted for hydrogen peroxide or fluorine, to BDEs around 8-9 kcal mol(-1) that should allow for an experimental observation of the triplet state, such as in disulfane or monofluoroamine. For all triplet minima investigated except NF3 and F2, CCSD(T) gave results in agreement with the multireference method MRCI+Q, and in excellent agreement with available experimental data (BDEs, ground-state geometries). Due to multireference problems, CCSD(T) does not provide a good description for longer heteroatom-heteroatom distances, and in some cases (e.g., Cl2) it wrongly predicts the presence of a transition state for bond formation on the triplet spin manifold, where the reaction is known experimentally and, as predicted by MRCI+Q, is known to be barrierless. Finally, the (3)Π(u) state of F2 is poorly described by CCSD(T) theory, the equilibrium bond distance is significantly underestimated relative to MRCI+Q, and CCSD(T) places the triplet state above the energy of two fluorine atoms. The T1 diagnostic, frequently used to assess the quality of CCSD(T) calculations, does not appear to provide a valid criterion for the systems studied. The formation of H2O2 on the triplet potential energy hypersurface might possibly open up an additional channel for formation of hydrogen peroxide from two hydroxyl radicals. Due to a low density of states in triplet H2O2, and due to competing formation of water + O((3)P) from a hydrogen-bridged HO···HO triplet radical pair, such a reaction channel probably only can play a role at low temperatures.

A novel neutral organic electron donor with record half-wave potential.

Tricyclic donor 26 has been prepared and is the most reducing neutral ground-state organic molecule known, with an oxidation potential 260 mV more negative than the previous record. Cyclic voltammetry shows that a 2-electron reversible redox process occurs in DMF as solvent at -1.46 V vs. Ag/AgCl.

Thermochemistry and photochemistry of spiroketals derived from indan-2-one: Stepwise processes versus coarctate fragmentations.

Coarctate reactions are defined as reactions that include atoms at which two bonds are made and two bonds are broken simultaneously. In the pursuit of the discovery of new coarctate reactions we investigate the fragmentation reactions of cyclic ketals. Three ketals with different ring sizes derived from indan-2-one were decomposed by photolysis and pyrolysis. Particularly clean is the photolysis of the indan-2-one ketal 1, which gives o-quinodimethane, carbon dioxide and ethylene. The mechanism formally corresponds to a photochemically allowed coarctate fragmentation. Pyrolysis of the five-ring ketal yields a number of products. This is in agreement with the fact that coarctate fragmentation observed upon irradiation would be thermochemically forbidden, although this exclusion principle does not hold for chelotropic reactions. In contrast, fragmentation of the seven-ring ketal 3 is thermochemically allowed and photochemically forbidden. Upon pyrolysis of 3 several products were isolated that could be explained by a coarctate fragmentation. However, the reaction is less clean and stepwise mechanisms may compete.

Naphthoxanthenyl, a new stable phenalenyl type radical stabilized by electronic effects.

Naphthoxanthenyl 1 is a new stable phenalenyl-type radical. Electrochemical studies indicate that 1 has two reversible redox processes that occur on comparatively short time scales. Crystals containing 1 can be grown by electrocrystallization, suggesting that they are conductive.

Mechanisms of the thermal decay of chlorpropham.

DFT calculations were performed on the thermal reactions of chlorpropham 1, a carbamate pesticide and plant growth regulator frequently used in the storage of potatoes. At the conditions normally used in applying 1 (injection of a methanolic solution of 1 into a hot air stream, T ≈ 500°C), both ester pyrolysis of 1 and a methanol-or water-catalysed isocyanate cleavage are expected to proceed rapidly (lifetime of 1 less than a second). In both reactions, the final reaction product will be toxic and carcinogenic m-chloroaniline 2. Matrix-isolation experiments indicate that 1 undergoes thermal decay at temperatures as low as 250°C. Up to temperatures of ca. 500°C, formation of m-chlorophenylisocyanate 4 and isopropanol was the predominant reaction observed, while formation of propene, CO(2), and m-chloroaniline 2 was the most important reaction channel at higher pyrolysis temperatures. m-Chlorophenyl carbamic acid 3 could not be observed. The results indicate that at lower temperatures, 1 decays exclusively via isocyanate cleavage of 1, provided that traces of catalytic water or other protic compounds are present. At higher temperatures, ester cleavage of 1 becomes competitive and outweighs the isocyanate cleavage by a factor of ca. 10:1.

Tools to study the degradation and loss of the N-phenyl carbamate chlorpropham--a comprehensive review.

Chlorpropham (CIPC) was introduced in 1951 and is a primary N-phenyl carbamate belonging to a group of pesticides known as carbamates which are estimated to account for 11% of the total insecticide sales worldwide. They were considered less toxic than organochlorines due to their easier breakdown but, subsequent concerns regarding the environmental impact and their breakdown products have shown them to be environmental toxins and toxic and/or carcinogenic for humans. CIPC is used in growing crops to control weeds and also as a sprout suppressant on crops during long-term storage and while its degradation has been studied and rates quoted these vary greatly. Here published rates of degradation by hydrolysis, biolysis, photolysis and thermal processes are reviewed as well as data on partitioning in air, water and soil. In addition the details of the experimental procedures are reviewed and compared showing how the half-lives and partitioning coefficients have been calculated leading to an understanding of how such vastly different values are achieved. The legislation regarding the use of CIPC and its maximum residue level is also discussed particularly in reference to recent European Commission (EC) legislation. In view of the fact that analytical data on the breakdown of CIPC play an important role in decision-making by regulatory agencies, the authors feel that it is time for an up-to-date review of the data available, including very recent developments in methodology.

Triplet excited states of cyclic disulfides and related compounds: electronic structures, geometries, energies, and decay.

We have performed a computational study on the properties of a series of heterocycles bearing two adjacent heteroatoms, focusing on the structures and electronic properties of their first excited triplet states. If the heteroatoms are both heavy chalcogens (S, Se, or Te) or isoelectronic species, then the lowest excited triplet state usually has (π*, σ*) character. The triplet energies are fairly low (30-50 kcal mol(-1)). The (π*, σ*) triplet states are characterized by a significantly lengthened bond between the two heteroatoms. Thus, in 1,2-dithiolane (1b), the S-S bond length is calculated to be 2.088 Å in the singlet ground state and 2.568 Å in the first triplet excited state. The spin density is predicted to be localized almost exclusively on the sulfur atoms. Replacing one heavy chalcogen atom by an oxygen atom or an NR group results in a significant destabilization of the (π*, σ*) triplet excited state, which then no longer is lower in energy than an open-chain biradical. The size of the heterocyclic ring also contributes to the stability of the (π*, σ*) triplet state, with five-membered rings being more favorable than six-membered rings. Benzoannulation, finally, usually lowers the energy of the (π*, σ*) triplet excited states. If one of the heteroatoms is an oxygen or nitrogen atom, however, the corresponding lowest triplet states are better described as σ,π-biradicals.

Quenching of triplet benzophenone by benzene and diphenyl ether: a DFT study.

The reaction of triplet benzophenone with benzene and diphenyl ether has been studied by density functional theory. Quenching of the triplet ketone is predicted to occur by addition of the carbonyl oxygen to the arene chromophores. The reaction is accompanied by a significant degree of charge transfer. In case of the reaction of triplet benzophenone with diphenyl ether (DPE), addition is predicted to occur preferentially at the ortho position of the DPE molecule. Addition to the ipso-position of DPE, which provides a pathway for formation of the phenoxy radical, is predicted to occur as a minor reaction pathway.