Stereodifferentiating drug-biomolecule interactions in the triplet excited state: studies on supramolecular carprofen/protein systems and on carprofen-tryptophan model dyads

Stereoselective interaction between a chiral nonsteroidal antiinflammatory drug, namely carprofen (CP), and human serum albumin (HSA) was studied, and the results were compared with those obtained with model dyads. In the presence of albumin the same triplet-triplet transition was detected for both CP stereoisomers; however, time-resolved measurements revealed a remarkable stereodifferentiation in the CP/HSA interaction. For each stereoisomer, the decay dynamics evidenced the presence of two components with different lifetimes that can be correlated with complexation of CP to the two possible albumin binding sites (site I and site II). This assignment was confirmed by using ibuprofen, a site II displacer. Thus, the shorter lived components, for which stereodifferentiation was more important (tauR/tauS ca. 4), were ascribed to the CP triplet state in site I; the lifetime shortening can be attributed to electron-transfer quenching by the only tryptophan (Trp) of the protein. Laser flash photolysis of model dyads containing covalently linked CP and Trp revealed formation of the expected Trp radical cation, providing support for such a mechanism. Moreover, significant stereodifferentiation was observed between the (R)- and (S)-CP-Trp dyads. In the case of CP/HSA complexes, as well as in the model compounds, the stereodifferentiation detected in the decays is in good agreement with that observed in the formation of the only CP photoproduct, resulting from a photodehalogenation process. Moreover, stereodifferentiation was also found to occur for the photobinding of CP to the protein.     

2-Aminopurine excited state electronic structure measured by stark spectroscopy

2-Aminopurine (2AP) is an adenine analogue that has a high fluorescence quantum yield. Its fluorescence yield decreases significantly when the base is incorporated into DNA, making it a very useful real-time probe of DNA structure. However, the basic mechanism underlying 2AP fluorescence quenching by base stacking is not well understood. A critical element in approaching this problem is obtaining an understanding of the electronic structure of the excited state. We have explored the excited state properties of 2AP and 2-amino,9-methylpurine (2A9MP) in frozen solutions using Stark spectroscopy. The experimental data were correlated with high level ab initio (MRCI) calculations of the dipole moments, mu0 and mu1, of the ground and excited states. The magnitude and direction of the dipole moment change, Deltamu01 = mu1 - mu0, of the lowest energy optically allowed transition was determined. While other studies have reported on the magnitude of the dipole moment change, we believe that this is the first report of the direction of Deltamu, a quantity that will be of great value in interpreting absorption spectral changes of the 2AP chromophore. Polarizability changes due to the transition were also obtained.     

Intramolecular excited state interactions in amino-esters

N,N-Dimethylaminoalkyl and N-methyl-N-phenylaminoalkyl esters of 1- and 2-naphthoic acid, 9-anthroic acid and 3-pyrenoic acid exhibit excited intramolecular charge transfer interactions which lead to quenching of the fluorescence of the ester. In these bichromophoric systems excitation of either the aromatic amine or the hydrocarbon group leads to fluorescent exciplex formation, the ratio of exciplex-to-monomer intensities being greater when the amine is excited.The exciplex emission was also detected at 77 K, both in polar and non-polar solvents, suggesting that the interaction in these systems is of a dynamic type but also has a static contribution.In these systems transfer of amine excitation to the ester competes with direct exciplex formation from the aromatic amine.     

On the excited electronic state dissociation of nitramine energetic materials and model systems

In order to elucidate the difference between nitramine energetic materials, such as RDX (1,3,5-trinitro-1,3,5-triazacyclohexane), HMX (1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane), and CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane), and their nonenergetic model systems, including 1,4-dinitropiperazine, nitropiperidine, nitropyrrolidine, and dimethylnitramine, both nanosecond mass resolved excitation spectroscopy and femtosecond pump-probe spectroscopy in the UV spectral region have been employed to investigate the mechanisms and dynamics of the excited electronic state photodissociation of these materials. The NO molecule is an initial decomposition product of all systems. The NO molecule from the decomposition of energetic materials displays cold rotational and hot vibrational spectral structures. Conversely, the NO molecule from the decomposition of model systems shows relatively hot rotational and cold vibrational spectra. In addition, the intensity of the NO ion signal from energetic materials is proportional to the number of nitramine functional groups in the molecule. Based upon experimental observations and theoretical calculations of the potential energy surface for these systems, we suggest that energetic materials dissociate from ground electronic states after internal conversion from their first excited states, and model systems dissociate from their first excited states. In both cases a nitro-nitrite isomerization is suggested to be part of the decomposition mechanism. Parent ions of dimethylnitramine and nitropyrrolidine are observed in femtosecond experiments. All the other molecules generate NO as a decomposition product even in the femtosecond time regime. The dynamics of the formation of the NO product is faster than 180 fs, which is equivalent to the time duration of our laser pulse.     

Testing electronic structure methods for describing intermolecular H...H interactions in supramolecular chemistry

In this article a wide variety of computational approaches (molecular mechanics force fields, semiempirical formalisms, and hybrid methods, namely ONIOM calculations) have been used to calculate the energy and geometry of the supramolecular system 2-(2'-hydroxyphenyl)-4-methyloxazole (HPMO) encapsulated in beta-cyclodextrin (beta-CD). The main objective of the present study has been to examine the performance of these computational methods when describing the short range H. H intermolecular interactions between guest (HPMO) and host (beta-CD) molecules. The analyzed molecular mechanics methods do not provide unphysical short H...H contacts, but it is obvious that their applicability to the study of supramolecular systems is rather limited. For the semiempirical methods, MNDO is found to generate more reliable geometries than AM1, PM3 and the two recently developed schemes PDDG/MNDO and PDDG/PM3. MNDO results only give one slightly short H...H distance, whereas the NDDO formalisms with modifications of the Core Repulsion Function (CRF) via Gaussians exhibit a large number of short to very short and unphysical H...H intermolecular distances. In contrast, the PM5 method, which is the successor to PM3, gives very promising results. Our ONIOM calculations indicate that the unphysical optimized geometries from PM3 are retained when this semiempirical method is used as the low level layer in a QM:QM formulation. On the other hand, ab initio methods involving good enough basis sets, at least for the high level layer in a hybrid ONIOM calculation, behave well, but they may be too expensive in practice for most supramolecular chemistry applications. Finally, the performance of the evaluated computational methods has also been tested by evaluating the energetic difference between the two most stable conformations of the host(beta-CD)-guest(HPMO) system.     

Glycine in an electronically excited state: ab initio electronic structure and dynamical calculations

The goal of this study is to explore the photochemical processes following optical excitation of the glycine molecule into its two low-lying excited states. We employed electronic structure methods at various levels to map the PES of the ground state and the two low-lying excited states of glycine. It follows from our calculations that the photochemistry of glycine can be regarded as a combination of photochemical behavior of amines and carboxylic acid. The first channel (connected to the presence of amino group) results in ultrafast decay, while the channels characteristic for the carboxylic group occur on a longer time scale. Dynamical calculations provided the branching ratio for these channels. We also addressed the question whether conformationally dependent photochemistry can be observed for glycine. While electronic structure calculations favor this possibility, the ab initio multiple spawning (AIMS) calculations showed only minor relevance of the reaction path resulting in conformationally dependent dynamics.     

Ab initio electronic structure theory as an aid to understanding excited state hydrogen transfer in moderate to large systems

Hypocrellin and hypericin are naturally occurring polycyclic perylene quinones, and they have both been found to exhibit photoactivated antiviral and anticancer activity. One mode of action proposed involves excited-state hydrogen transfer. Consequently these compounds have been widely studied using spectroscopic methods, and are found to both absorb and emit in the visible region. Recently an analog dihydroxy perylene quinone was synthesized in order to examine its antiviral activity in relation to the naturally occurring compounds. Its UV-visible absorption and emission spectra are quite different to those of hypocrellin and hypericin, with very weak absorption and no visibility of emission at all. The ab inito excited-state methods, configuration interaction singles (CIS), state-averaged complete active space self-consistent field (SA–CASSCF), and SA-multireference perturbation theory (SA–MRMP2) are used to examine the origin of this different absorption and emission behavior. Owing to the size of these systems (between 24 and 40 heavy atoms) extensive use of parallel processor algorithms was made, especially a parallel atomic orbital-based CIS energy and gradient code developed at the ABCC. The performance of these methods, and possible ,as well as future directions and prospects are discussed.     

Role of conformation and electronic structure in the chemistry of ground and excited state o-pyrazolylphenylnitrenes

The chemistry of 2-(1-pyrazolyl)- (2a) and 2-[1-(3,5-dimethylpyrazolyl]phenylnitrene (2b) has been studied in EtOH solution at room temperature, in EtOH glasses at 90 K, and in Ar matrices at 12 K. These nitrenes were chosen as suitable models for clarifying the mechanism of intramolecular reactions because attack at the pyrazole ring can occur according to different modes and the asymmetry of the substituent gives rise to different conformations. Detailed DFT and CASSCF/CASPT2 studies on the conformation and decay paths of both spin states of the nitrenes have been carried out. Ring expansion to dehydroazepines (via benzoazirines) is calculated to be competitive in both nitrenes, but in the dimethyl derivative, 2b, attack onto the N lone pair (which is made more nucleophilic by the methyl groups) is favored. The higher barriers (by 4-8 kcal/mol) in singlet 2a cause 60-70% of this nitrene to decay by intersystem crossing to the triplet. Thus, the seemingly straightforward formation of benzo-fused heterocycles through intramolecular attack of the pyrazoline N lone pair by the singlet phenylnitrene can only overcome ring expansion and intermolecular reactions under favorable circumstances. The comparatively persistent triplet nitrenes are characterized in matrices, and the yields of photocyclization products (mainly pyrazolo[1,5-a]benzimidazole (7) from 2a and 5,6-dihydropyrazolo[1,5-a]quinoxaline (8) from 2b) are shown to depend on the preferred conformation of the starting azide and nitrene.     

Resonance Raman spectra of β-carotene and its molecular structure in the excited electronic state

The resonance Raman spectra of β-carotene have been obtained at low temperature. The excitation profiles of ν₁ (1525 cm^?1) and 2ν₁ (3043 cm^?1) are analysed in terms of the Albrecht theory. The overlap integrals between the vibrational wavefunctions of the ground and the first excited electronic states are shown to be the most important factor in determining the resonance Raman intensities of this molecule. Information on the structure of the electronically excited state has been obtained.     

Electron-phonon interactions in photoinduced excited electronic states in fluoroacenes

The electron-phonon coupling constants [l(B1u(HOMO-->LUMO))] in the photoinduced excited electronic states in fluoroacenes are estimated and compared with those in the monoanions (l(LUMO)) and cations (l(HOMO)). The l(B1u(HOMO-->LUMO)) values are much larger than the l(LUMO) and l(HOMO) values in fluoroacenes. Furthermore, the Coulomb pseudopotential mu* values for the excited electronic states are estimated to be smaller than those for the monoanions and cations. The complete phase patterns difference between the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) is the main reason why the electron-phonon coupling constants and the mu* values are larger and smaller, respectively, in the photoinduced excited electronic states than in the monoanions and cations. The possible electron pairing and Bose-Einstein condensation in the excited electronic states of fluoroacenes are discussed. Because of larger electron-phonon coupling constants and smaller mu* values in the excited electronic states than in the charged states, the conditions under which the electron-electron interactions become attractive can be more easily realized, in principle, in the excited electronic states than in the charged states in fluoroacenes. The l(B1u(HOMO-->LUMO)) values hardly change by H-F substitution, even though the l(LUMO) and l(HOMO) values significantly increase by H-F substitution in acenes. Antibonding interactions between carbon and fluorine atoms in the HOMO and LUMO are the main reason why the l(B1u(HOMO-->LUMO)) values hardly change by H-F substitution in acenes.     

Quantum chemical study of the electronic structure of NiCH2 + in its ground state and low-lying electronic excited states

The electronic structure of NiCH(2) (+), representative of transition metal carbene ions, is investigated by means of several methods of quantum chemistry. The relative stabilities of the four low-lying doublet electronic states ((2)A(1), (2)A(2), (2)B(1), and (2)B(2)) are determined at the coupled cluster singles and doubles level (CCSD) and triples level [CCSD(T) and CCSDT-3] with both a Hartree-Fock and density functional theory (Kohn-Sham) reference. The equation-of-motion coupled cluster for treatment of excited states in singles and doubles approximation (EOM-CCSD) is used to characterize the transition energies from the (2)A(1) electronic ground state to the low-lying doublet excited states. The (2)A(2) and (2)B(1) states are nearly degenerate, found to be separated by 940 cm(-1) at the EOM-CCSD level, in agreement with the CASSCF energy ordering. The (2)B(2) state is calculated to be higher in energy by more than 1.0 eV. The spin purity of the low-lying doublet and quadruplet states described by CCSD calculations based on the unrestricted open-shell Hartree-Fock reference is discussed.     

The electronic structure of low-lying excited states of two model systems of retinal

2,4-pentadienal and 2,4,6,8-nonatetraenal were studied as simple model systems of retinal. Four kinds of CI were performed on low-lying excited states of 2,4-pentadienal by using a split valence basis set. The results show that MR SD π CI is not adequate for the π–π* state and the single excitation σπ CI is a good compromise between cost and effectiveness as far as singly excited states are concerned. This CI was applied to the bigger model system. All-trans and 11-cis forms of aldehyde, Schiff base, and protonated Schiff base of the model system were studied. A fairly large energy lowering of about 1 eV of the first allowed excited state (π → π*) occurs when the Schiff base is protonated for both all-trans and 11-cis forms.     

Charge transfer and intraligand excited state interactions in platinum-sensitized dithienylethenes

The photophysical behavior for two photochromic Pt-terpyridine acetylide complexes containing pendant dithienylethenes (DTEs) bound to the metal through the alkynyl linkage is presented. Selective excitation of the Pt complex with visible light resulted in the metal-sensitized ring closing of the DTE unit. The central purpose of this study was to understand how excited state interactions govern the photophysics by correlating differences in the linkage of the two components with differences in the intramolecular energy transfer processes that occur between the Pt complex and the DTE. A series of model complexes without photochromic ligands were prepared and studied to elucidate the contributions of the triplet metal-to-ligand charge transfer and triplet intraligand states. It is demonstrated that reducing the orbital overlap of the metal-based and intraligand states by lengthening the linkage and eliminating a conjugated pathway is effective at dramatically decreasing the efficiency of intramolecular energy transfer. This is evidenced by the appearance of Pt-terpyridine based phosphorescence and a significant decrease in the observed rate of metal-sensitized ring closing of the DTE.     

Hydrophobic ligand-ligand interactions in multicomponent systems and their analytical significance

Summary The presence of hydrophobic ligand-ligand interaction between chromophoric complexing ligands of the triphenylmethane series and cationic surface active agents (c-SAS) in M-R-c-SAS systems has been established. Hydrophobic interaction has been found to be the underlying principle of the formation of stable ionic associates R(c-SAS)_n in aqueous solutions. Peculiarities of ion metal complexation in the systems and their importance for analysis have been revealed.

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Hydrophobe Ligand-Ligand-wechselwirkungen in Vielkompontensystemen und ihre analytische Bedeutung

     

Consequences of strong coupling between solvation and electronic structure in the excited state of a betaine dye

The electronic ground and excited-state structures of the betaine dye molecule pyridinium- N-phenoxide [4-(1-pyridinio)phenolate] are investigated both in the gas phase and in aqueous solution, using the reference interaction site model self-consistent-field (RISM-SCF) procedure within a CASSCF framework. We obtain the total free energy profiles in both the ground and excited states with respect to variation in the torsion angle between the phenoxide and pyridinium rings. We analyze the effect of solvent on the variation of the solute dipole moment and on the charge transfer character in the excited state. In the gas phase, it is shown that the potential energy profile in the excited-state decreases monotonically toward a perpendicular ring orientation and the dipole moment decreases along with decreasing charge localization. In water, the free energy surface for twisting is better characterized as nearly flat along the same coordinate for sterically accessible angles. These results are analyzed in terms of contributions of the solvation free energy, the solute electronic energy, and their coupling. Correspondingly, the dependence of the charge transfer character on solute geometry and solvation are analyzed, and the important roles in the excitation and subsequent relaxation processes for the betaine dye are discussed. It is found that there is considerable solute electronic reorganization associated with the evolution of solvation in the excited state, and it is suggested that this reorganization may contribute significantly to the early time evolution of transient spectra following photoexcitation.     

Solid-state NMR studies of weak interactions in supramolecular systems

The field of application of solid-state NMR to the study of supramolecular systems is growing rapidly, with many research groups involved in the development of techniques for the study of crystalline and amorphous phases. This Feature Article aims to provide an overview of the recent contributions of our research group to this field, paying particular attention to the study of the weak interactions such as hydrogen bonds in supramolecular systems through solid-state NMR investigations. The structure and dynamic behaviour of selected host-guest systems will be also discussed.     

Evidence for excited electronic state interference in resonance raman scattering

The complex resonance Raman spectra of molecular bromine have been analyzed quantitatively and a clear demonstration of interference in the Raman intensity from the B(³11₀⁺_u) and ¹17_1u excited states has been found.     

Decomposition of excited electronic state s-tetrazine and its energetic derivatives

Decomposition of excited electronic state s-tetrazine and its energetic derivatives, such as 3-amino-6-chloro-1,2,4,5-tetrazine-2,4-dioxide (ACTO), and 3,3(')-azobis (6-amino-1,2,4,5-tetrazine)-mixed N-oxides (DAATO(3.5)), is investigated through laser excitation and resonance enhanced multi photon ionization techniques. The N(2) molecule is detected as an initial product of the s-tetrazine decomposition reaction, through its two photon, resonance absorption transitions [a(") (1)Σ(g)(+) (v(') = 0) ← X (1)Σ(g)(+) (v(") = 0)]. The suggested mechanism for this reaction is a concerted triple dissociation yielding rotationally cold (～20 K) ground electronic state N(2) and 2 HCN molecules. The comparable decomposition of excited electronic state ACTO and DAATO(3.5) yields an NO product with a cold rotational (～20 K) but a hot vibrational (～1200 K) distribution. Thus, tetrazine and its substituted energetic materials ACTO and DAATO(3.5) evidence different decomposition mechanisms upon electronic excitation. N(2)O is excluded as a potential intermediate precursor of the NO product observed from these two s-tetrazine derivatives through direct determination of its decomposition behavior. Calculations at the CASMP2∕CASSCF level of theory predict a concerted triple dissociation mechanism for generation of the N(2) product from s-tetrazine, and a ring contraction mechanism for the generation of the NO product from the energetic s-tetrazine derivatives. Relaxation from S(n) evolves through a series of conical intersections to S(0), upon which surface the dissociation occurs in both mechanisms. This work demonstrates that the substituents on the tetrazine ring change the characteristics of the potential energy surfaces of the derivatives, and lead to a completely different decomposition pathway from s-tetrazine itself. Moreover, the N(2) molecule can be excluded as an initial product from decomposition of these excited electronic state energetic materials.     

Vibrational structure of the electronic transition to the third excited singlet state of pyridine N-oxide

The electronic absorption spectrum of pyridine N-oxide vapor in the region of the third electronic transition (43,000-46,000 cm_-1) was recorded. The frequencies and intensities of vibronic bands, including the 0–0 band at 43,896 cm_-1, were measured An assignment of the frequencies of fundamental vibrations in the third electronically excited state is suggested The matrices of rotation and shift of normal coordinates due to electronic excitation are calculated, and the vibronic spectrum of pyridine N-oxide is interpreted on the basis of these matrices. Translated fromZhurnal Struktumoi Khimii, Vol. 38, No. 2, pp. 357–362, March–April, 1997.