Orthogonal Fragment Research Articles

9-Borafluoren-9-yl and diphenylboron tetracoordinate complexes of 8-quinolinolato ligands with heavy-atoms substituents: Synthesis, fluorescence and application in OLED devices

This work describes the synthesis and characterisation of new tetrahedral boron complexes, incorporating bromine- or iodine-substituted 8-quinolinolato chelate chromophores connected to 9-borafluoren-9-yl or diphenylboron orthogonal fragments. The molecular features and photophysical properties of these complexes are analysed in both solution and solid state. Steady-state photophysical studies reveal photoluminescence quantum yields (Φf) ranging from 0.02 to 0.15 and prompt fluorescence (PF) lifetimes (τf) between 2 and 16 ns. Time-resolved photophysical experiments show the presence of delayed fluorescence (DF) and phosphorescence at both 77 K and room temperature. The DF intensity increases with a rise in temperature. This variation is ascribed to an enhancement in the intersystem crossing (ISC) process promoted by the bromine or iodine heavy-atom effect. Investigations into the dependence of DF intensity relative to the excitation dose indicate emissions stemming either from Triplet-Triplet Annihilation (TTA), Thermally Activated Delayed Fluorescence (TADF), or a combination of these competing mechanisms. The effect is related to the size and number of heavy-atom substituents in each boron complex. A study of the DF emission intensity as a function of the excitation dose reveals that diiodo-substituted 8-quinolinolato boron complexes, whether rigid or flexible, display TADF emission. Rigid 5,7-dibromo- and 5-chloro-7-iodo-substituted 8-quinolinolato complexes exhibit a combined TADF-TTA mechanism, whereas the other complexes predominantly demonstrate pure TTA emission. DFT and TDDFT calculations showed that the ground state structures reproduced the experimental geometries and only small increases in bond lengths were observed in the excited state geometries. The low energy absorption bands displayed mainly intra-ligand π→π* (8-quinolinato) character. The fluorescence emission energies were well reproduced, while the singlet-triplet energy gaps were relatively high and spin-orbit coupling was relevant for complexes with heavy-atoms. Ultimately, organic light-emitting diodes (OLEDs) are fabricated using the most luminescent boron complexes. The best OLED is obtained when using complex 3a, which displays green electroluminescence (EL) (λEL = 502 nm) with maximum external quantum efficiency (EQEmax) of 2.5% and maximum luminance (Lmax) of 2200 cd m−2.

Identification of a New Zinc Binding Chemotype by Fragment Screening.

The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzenesulfonamides, the classical zinc binding group found in most CA II inhibitors. Protein X-ray crystallography established that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction of the acidic ring nitrogen with the CA II active site zinc, as well as two hydrogen bonds between the oxazolidinedione ring oxygen and the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones appear to be a viable starting point for the development of an alternative class of CA inhibitor, wherein the medicinal chemistry pedigree of primary sulfonamides has dominated for several decades.

Fragment Binding to β-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches.

An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (two-dimensional 15N heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space.

OVB analysis of symmetry allowed and symmetry forbidden chemical reactions

When orthogonal orbitals are used to construct configuration state functions (CSF) the latter are orthogonal to each other. Such CSFs are either neutral or ionic, they never change their character along a reaction path. This is in contrast to conventional Valence Bond CSFs based on non-orthogonal orbitals. When orthogonal, delocalized molecular orbitals from CASSCF (complete active space SCF) calculations are localized to defined fragments using orthogonal transformations, the localized fragment orbitals retain their orthogonality, and the CASSCF configuration state functions constructed are of Valence Bond type describing the same state but in terms of orthogonal fragment orbitals. This analysis of the CASSCF state function reveals local properties and processes that are hidden by the use of delocalized orbitals but that are responsible for symmetry forbiddenness or symmetry allowedness of chemical reactions.

Polarization contributions to intermolecular interactions revisited with fragment electric-field response functions.

The polarization energy in intermolecular interactions treated by self-consistent field electronic structure theory is often evaluated using a constraint that the atomic orbital (AO) to molecular orbital transformation is blocked by fragments. This approach is tied to AO basis sets, overestimates polarization energies in the overlapping regime, particularly in large AO basis sets, and lacks a useful complete basis set limit. These problems are addressed by the construction of polarization subspaces based on the responses of isolated fragments to weak electric fields. These subspaces are spanned by fragment electric-field response functions, which can capture effects up to the dipole (D), or quadrupole (DQ) level, or beyond. Schemes are presented for the creation of both non-orthogonal and orthogonal fragment subspaces, and the basis set convergence of the polarization energies computed using these spaces is assessed. Numerical calculations for the water dimer, water-Na(+), water-Mg(2+), water-F(-), and water-Cl(-) show that the non-orthogonal DQ model is very satisfactory, with small differences relative to the orthogonalized model. Additionally, we prove a fundamental difference between the polarization degrees of freedom in the fragment-blocked approaches and in constrained density schemes. Only the former are capable of properly prohibiting charge delocalization during polarization.

Application of orthogonal L-shaped PLS to chemogenomic data and its chemical interpretation from predictive and orthogonal latent variables

We carried out a validation study of the orthogonal L-shaped PLS (OLPLS) method using chemogenomic data based on adenosine receptor inhibitor activity measurements. Using OLPLS, the ligand and protein descriptors could be connected to eight adenosine receptor inhibitor activities. The fingerprints representing specific chemical substructures on the ligands were used as the ligand descriptors, while z-scales were used as the protein descriptors. Three clusters were observed in the chemical and protein spaces from the predictive scores and loadings. From these, the predictive and orthogonal ligand structure fragments towards three adenosine receptors could be successfully elucidated. The predictive fragment for the human adenosine 2A receptor was confirmed by comparison to the X-ray crystal structure. As expected, the orthogonal fragments contained no physicochemical features required for specific interaction with the adenosine receptors.

Crossover from bosonic to fermionic features in composite boson systems

We study the quantum dynamics of conversion of composite bosons into fermionic fragment species with increasing densities of bound fermion pairs using the open quantum system approach. The Hilbert space of N-state-functions is decomposed into a composite boson subspace and an orthogonal fragment subspace of quasi-free fermions that enlarges as the composite boson constituents deviate from ideal boson commutation relations. The tunneling dynamics of coupled composite bosons states in confined systems is examined, and the appearance of exceptional points under experimentally testable conditions (densities, lattice temperatures) is highlighted. The theory is extended to examine the energy transfer between macroscopically coherent systems such as multichromophoric macromolecules in photosynthetic light harvesting complexes.

Impurity hamiltonian for transition metal complexes based on the exact exchange for correlated electrons hybrid functional

We present a theoretical method that combines density functional theory (DFT) and full configuration interaction (CI). Such a combination is based on the impurity model to (i) incorporate the advantages of DFT in description of the dynamic correlation and (ii) reduce the number of the two-electron integrals. The impurity model has been introduced with the help of a special type of the hybrid functional, namely, the exact exchange for correlated electrons (EECE), and the orthogonal fragment orbitals formalism. The EECE functional, originally based on the formulation of the local density approximation + U (LDA + U) method without the empirical parameter U, has been rewritten in this work in a form that incorporates the projected electron–electron repulsion energy operator. This representation has been compared with other types of nonglobal hybrids: position dependent and range separated hybrids. Further, the obtained Hamiltonian of the generalized Anderson model has been transformed to the form that affords the implementation of the linear scaling density-matrix renormalization group algorithm. © 2011 Wiley Periodicals, Inc.

Sample-based surface coloring.

In this paper, we present a sample-based approach for surface coloring, which is independent of the original surface resolution and representation. To achieve this, we introduce the Orthogonal Fragment Buffer (OFB)-an extension of the Layered Depth Cube-as a high-resolution view-independent surface representation. The OFB is a data structure that stores surface samples at a nearly uniform distribution over the surface, and it is specifically designed to support efficient random read/write access to these samples. The data access operations have a complexity that is logarithmic in the depth complexity of the surface. Thus, compared to data access operations in tree data structures like octrees, data-dependent memory access patterns are greatly reduced. Due to the particular sampling strategy that is employed to generate an OFB, it also maintains sample coherence, and thus, exhibits very good spatial access locality. Therefore, OFB-based surface coloring performs significantly faster than sample-based approaches using tree structures. In addition, since in an OFB, the surface samples are internally stored in uniform 2D grids, OFB-based surface coloring can efficiently be realized on the GPU to enable interactive coloring of high-resolution surfaces. On the OFB, we introduce novel algorithms for color painting using volumetric and surface-aligned brushes, and we present new approaches for particle-based color advection along surfaces in real time. Due to the intermediate surface representation we choose, our method can be used to color polygonal surfaces as well as any other type of surface that can be sampled.

Experimental and Theoretical Study of Excited-State Structure and Relaxation Processes of Betaine-30 and of Pyridinium Model Compounds

The long-wavelength absorption band of 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (betaine-30, B30) in ethanol and 1-chlorobutane shifts to the blue by cooling in the temperature range of 294-128 K. In addition, B30 shows fluorescence in both solvents at 77 K, which is absent at room temperature. The study of the ground and excited state of B30 and its model compound 4-(pyridinium-1-yl)-phenolate PyPo by DFT/TDDFT calculations indicates that for the perpendicular conformation, the ground state possesses a charge-separated closed-shell hole pair (hp) electronic configuration, and the S(1) state corresponds to a biradicaloid electronic structure (dd) with a small dipole moment caused by an unpaired electron on each of the orthogonal fragments. Following the absorption process, there is a driving force for geometrical relaxation within the S(1) state toward an orthogonal arrangement of the phenolate and the pyridinium ring. In this final S(1) equilibrium geometry, the energy gap between the excited and the ground state is strongly reduced and causes very efficient radiationless deactivation of the S(1) state at room temperature. At 77 K, the viscous barrier hindering large-amplitude motion enables the appearance of the fluorescence from the partially or nonrelaxed excited Franck-Condon structure. By variation of the donor and acceptor strength of the two moieties, the energy gap for perpendicular systems can be tuned, allowing, in principle, the switching between the two cases hp < dd and hp > dd. This enables a new access to the efficient construction of mnemonic systems and NLO dyes.

Liquid-phase synthesis of a cyclic hexameric peptide nucleic acid

A cyclic fully N-protected hexameric (aminoethylglycinamide) can be readily obtained by using a divergent approach in liquid phase and consists of coupling orthogonal fragments of suitable oligomers. This cyclic N-protected backbone is then converted into a peptide nucleic acid by a series of selective deprotection–coupling steps affording the desired structure in good overall yields. Such a procedure could provide a general approach for targeting any short cyclic peptide nucleic acids (containing every kind of nucleobase).