Excited-State Dynamics in Borylated Arylisoquinoline Complexes in Solution and in cellulo.

Two four-coordinate organoboron N,C-chelate complexes with different functional terminals on the PEG chains are studied with respect to their photophysical properties within human MCF-7 cells. Their excited-state properties are characterized by time-resolved pump-probe spectroscopy and fluorescence lifetime microscopy. The excited-state relaxation dynamics of the two complexes are similar when studied in DMSO. Aggregation of the complexes with the carboxylate terminal group is observed in water. When studying the light-driven excited-state dynamics of both complexes in cellulo, i. e., after being taken up into human MCF-7 cells, both complexes show different features depending on the nature of the anchoring PEG chains. The lifetime of a characteristic intramolecular charge-transfer state is significantly shorter when studied in cellulo (360±170 ps) as compared to in DMSO (∼960 ps) at 600 nm for the complexes with an amino group. However, the kinetics of the complexes with the carboxylate group are in line with those recorded in DMSO. On the other hand, the lifetimes of the fluorescent state are almost identical for both complexes in cellulo. These findings underline the importance to evaluate the excited-state properties of fluorophores in a complex biological environment in order to fully account for intra- and intermolecular effects governing the light-induced processes in functional dyes.

Ir-Catalyzed Atroposelective Desymmetrization of Heterobiaryls: Hydroarylation of Vinyl Ethers and Bicycloalkenes.

A highly regio-, diastereo-, and enantioselective, scalable Ir-catalyzed hydroarylation of electron-rich acyclic and tensioned cyclic olefins with heterobiaryls is described. The reaction of acyclic vinyl ethers, dihydrofuran, and norbornenes with a variety of aryl isoquinoline, quinazoline, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching complete branched/linear or exo/endo ratios and excellent diastereo- and enantiomeric excesses when in situ formed [IrI/Tol-SDP] or [IrI/Tol-BINAP] complexes are used as the catalysts. Deuterium labeling experiments and a comprehensive computational study suggest that, despite fast double bond migratory insertion into Ir-H, the reaction proceeds through a modified Chalk-Harrod mechanism, starting with selectivity-determining insertion into Ir-CAryl. The regioselectivity is controlled by the electron-donating alkoxy group, whereas diastereo- and enantioselectivity have a complex origin, which depend on the relative orientation of the alkoxy group and the establishment of adequate π-π interactions between the biaryl and the phosphine.

π-Extended Four-Coordinate Organoboron N,C-Chelates as Two-Photon Absorbing Chromophores.

Four-coordinate N,C-chelate organoboron dyes with alkynyl spacers were synthesized by Heck alkynylation. These dyes are π-extended analogues of the recently reported class of four-coordinate borylated arylisoquinolines (BAI). Depending on the electron-donor substitution, they feature an intramolecular charge-transfer (ICT) character in the excited state. This translates into pronounced apparent Stokes shifts (up to 8500 cm-1) and a solvatofluorochromic behavior. In general, the observed emission quantum yields are high in nonpolar media (ΦF ca. 0.5-0.6). For the dye with the most pronounced ICT rather high emission quantum yields (ΦF ca. 0.4) are observed for emissions with maxima longer than 600 nm in solvents of moderate polarity. The π-extended dyes show interesting two-photon absorption (TPA) properties, maintaining high cross sections (up to 60 GM) in the near-infrared wavelength window (>900 nm). One of the dyes was designed as dimeric chromophore, integrating the acceptor-π-acceptor (A-π-A) format. This alternative design showed no ICT behavior but led to the observation of high two-photon-absorption (TPA) cross sections (ca. 220 GM at 700 nm). All investigated dyes show pronounced photostability, providing added value to this structural and photofunctional extension of the BAI dye platform.

Arylisoquinoline-derived organoboron dyes with a triaryl skeleton show dual fluorescence.

Four new dyes that derive from borylated arylisoquinolines were prepared, containing a third aryl residue (naphthyl, 4-methoxynaphthyl, pyrenyl or anthryl) that is linked via an additional stereogenic axis. The triaryl cores were synthesized by Suzuki couplings and then transformed into boronic acid esters by employing an Ir(I)-catalyzed reaction. The chromophores show dual emission behavior, where the long-wavelength emission band can reach maxima close to 600 nm in polar solvents. The fluorescence quantum yields of the dyes are generally in the range of 0.2-0.4, reaching in some cases values as high as 0.5-0.6. Laser-flash photolysis provided evidence for the existence of excited triplet states. The dyes form fluoroboronate complexes with fluoride anions, leading to the observation of the quenching of the long-wavelength emission band and ratiometric response by the build-up of a hypsochromically shifted emission signal.

Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality.

A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sulfonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol % in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially chiral heterobiaryl α-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily transformed into N, N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a ß-hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction.

Azabora[5]helicene Charge-Transfer Dyes Show Efficient and Spectrally Variable Circularly Polarized Luminescence.

Three helicenes based on a borylated arylisoquinoline skeleton have been prepared in their enantiopure forms and characterized with respect to their photophysical properties, including the use of chiroptical spectroscopies. The dyes show varying charge-transfer characteristics and efficient emission (quantum yields between 0.13 and 0.30, in toluene), which is governed by the electron-donor substitution (p-MeO-phenyl, p-Me2 N-phenyl) at the helicene. Marked differences in the emission wavelength and Stokes shift are observed, with the dimethylamino-substituted derivative emitting most red-shifted (maximum at ca. 590 nm) and displaying the highest Stokes shift (ca. 6000 cm-1 ) in toluene. The helicenes show electronic circular dichroism (ECD) and significant circularly polarized luminescence (CPL) with dissymmetry factors of up to 3.5×10-3 . The sign of the ECD band corresponding to the first transition and of the CPL spectrum depend sensibly on the electron-donor substitution.

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation.

A diastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald-Hartwig Amination.

The Pd(0)-catalyzed coupling of racemic heterobiaryl bromides, triflates, or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter and suggest that coordination of the amine to the Pd center is the stereodetermining step.

Red-Emitting Tetracoordinate Organoboron Chelates: Synthesis, Photophysical Properties, and Fluorescence Microscopy.

Seven tetracoordinate organoboron fluorophores with heterobiaryl N,O- or N,N-chelate ligands were prepared and photophysically characterized (in toluene). The electronic variation of the heteroaromatic moiety provided a means for the fine-tuning of the UV/vis absorption and emission spectra. In the most interesting cases, the spectra were red-shifted to maximum absorbance at wavelengths longer than 500 nm and emission maxima between 620 and 660 nm. The pronounced intramolecular charge-transfer character of the dyes yielded large Stokes shifts (3500-5100 cm-1), while maintaining appreciable fluorescence quantum yields of up to 0.2 for emission maxima longer than 600 nm. The lipophilic character of the dyes enabled their application as stains of vesicle substructures in confocal fluorescence microscopy imaging.

Strongly Emissive and Photostable Four-Coordinate Organoboron N,C Chelates and Their Use in Fluorescence Microscopy.

Six strongly fluorescent four-coordinate organoboron N,C chelates containing an aryl isoquinoline skeleton were prepared. Remarkably, the fluorescence quantum yields reach values of up to 0.74 in oxygen-free toluene. The strong B-N interaction was corroborated by the single-crystal X-ray analysis of two dyes. The intramolecular charge-transfer character of the fluorophores was evidenced by solvatochromism studies and time-dependent DFT calculations at the PCM(toluene)/CAM-B3LYP/6-311++G(2d,p)//PCM(toluene)/B3LYP/6-311G(2d,p) level of theory. The compounds combine high chemical stability with high photostability, especially when equipped with electron-donating substituents. The strong fluorescence and the large Stokes shifts predestine these compounds for use in confocal fluorescence microscopy. This was demonstrated for the imaging of the N13 mouse microglial cell line. Moreover, significant two-photon absorption cross sections (up to 61 GM) allow the use of excitation wavelengths in the near-infrared region (>800 nm).

Organic fluorescent thermometers based on borylated arylisoquinoline dyes.

Borylated arylisoquinolines with redshifted internal charge-transfer (ICT) emission were prepared and characterized. Upon heating, significant fluorescence quenching was observed, which forms the basis for a molecular thermometer. In the investigated temperature range (283-323 K) an average sensitivity of -1.2 to -1.8% K(-1) was found for the variations in fluorescence quantum yield and lifetime. In the physiological temperature window (298-318 K) the average sensitivity even reaches values of up to -2.4% K(-1). The thermometer function is interpreted as the interplay between excited ICT states of different geometry. In addition, the formation of an intramolecular Lewis pair can be followed by (11)B NMR spectroscopy. This provides a handle to monitor temperature-dependent ground-state geometry changes of the dyes. The role of steric hindrance is addressed by the inclusion of a derivative that lacks the Lewis pair formation.

Azaborahelicene fluorophores derived from four-coordinate N,C-boron chelates: synthesis, photophysical and chiroptical properties.

A series of six azaborahelicenes with varying electron-donor substitution at the 4-position of the aryl residue (i.e., naphthyl) or with variable π-extension of the aryl residue (thianthrenyl, anthryl, pyrenyl) was prepared with an efficient and flexible synthetic protocol. These different types of functionalization afforded notably pronounced intramolecular charge-transfer (ICT) character for the dyes with the strongest electron donor substitution (NMe2) or easiest to oxidize aryl residues, as evidenced by photophysical investigations. These effects also impact the corresponding chiroptical properties of the separated M- and P-enantiomers, which notably display circularly polarized luminescence (CPL) with dissymmetry factors in the order of magnitude of 10-4 to 10-3. Theoretical calculations confirm the optical spectroscopy data and are in agreement with the proposed involvement of ICT processes.

Dual luminescence and infrared circularly polarized luminescence up to 900 nm with platinum complexes bearing a helical donor-acceptor ligand.

Chiral molecular materials able to emit circularly polarized luminescence (CPL) have attracted considerable interest in the last few decades, due to the potential of CP-light in a wide range of applications. While CP luminescent molecules with blue, green, and yellow emissions are now well-reported, NIR CPL from organic and organometallic compounds lags behind due to the dual challenge of promoting radiative deexcitation of the excited state in this low energy region while assuring a significant magnetic dipole transition moment, a prerequisite for generating CPL. Based on a versatile axially chiral arylisoquinoline ligand, we report the synthesis and chiroptical properties of chiral donor-acceptor platinum(ii) complexes displaying CPL that extends up to almost 900 nm. Interestingly, these emitters show both fluorescence and phosphorescence emissions in solution, with intensities depending on the charge-transfer character of the organic ligand. Experimental and theoretical investigations show that this feature strongly impacts the intersystem crossing event between the singlet and triplet excited states of these complexes and the related phosphorescence lifetime. The effect is less important regarding the CPL, and most complexes show luminescence dissymmetry factors with values up to ca. 2 × 10-3 around 800 nm.

Dynamic kinetic cross-coupling strategy for the asymmetric synthesis of axially chiral heterobiaryls.

A dynamic kinetic asymmetric transformation (DYKAT) technique has been designed for the synthesis of 2'-substituted 2-aryl pyridines/isoquinolines and related heterobiaryls. In this way, the Pd(0)-catalyzed coupling of racemic 2-triflates with aryl boroxines using a TADDOL-derived phosphoramidite as the ligand provides the corresponding coupling products with good to excellent enantioselectivities. Structural studies support that the formation of configurationally labile oxidative addition palladacycles is the key for the success of the methodology.

Borylated arylisoquinolines: photophysical properties and switching behavior of promising tunable fluorophores.

A series of nine borylated arylisoquinolines has been prepared with systematic variation in their electronic properties and their photophysical properties were investigated. The color of their fluorescence can be finely tuned by changing the properties of the aryl moiety, which is involved in internal-charge-transfer processes. For example, methoxy-substituted compound 5 showed an intense green emission, whereas dimethylamino-substituted compound 6 showed an orange-red emission. These new fluorophores were tested for their potential as molecular switches with external ionic stimuli, such as protons and fluoride ions. On the one hand, protonation of the isoquinoline moiety led to fluorescence enhancement for compounds that showed weak charge transfer and fluorescence quenching for compounds that showed strong charge transfer. On the other hand, the formation of ate complexes with fluoride led to strong fluorescence quenching in all of the investigated cases.

Preparation and pH-switching of fluorescent borylated arylisoquinolines for multilevel molecular logic.

The preparation of pH-switchable fluorescent borylated arylisoquinoline dyes via a flexible iridium-catalyzed route is reported. The obtained dyes feature aromatic amino substitution and lateral aliphatic amino groups as electron donors. The photophysical properties of the internal charge transfer dyes were studied, which was complemented by density functional theory calculations. Appreciable fluorescence quantum yields (Φf up to ca. 0.4) and characteristic spectral fingerprints in the green to red emission range were observed. The fluorescence modulation upon multiple and orthogonal protonation with triflic acid was studied and led to the interpretation of multilevel switching including off-on-off, ternary, and quaternary responses.

Dynamic Kinetic Resolution of Indole-Based Sulfenylated Heterobiaryls by Rhodium-Catalyzed Atroposelective Reductive Aldol Reaction.

A highly enantio- and diastereoselective dynamic kinetic resolution (DKR) of configurationally labile 3-aryl indole-2-carbaldehydes is described. The DKR proceeds via a Rh-catalyzed intermolecular asymmetric reductive aldol reaction with acrylate esters, with simultaneous generation of three stereogenic elements. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a transient Lewis acid-base interaction (LABI) between the formyl group and a thioether moiety strategically located at the ortho' position. The atropisomeric indole products present a high degree of functionalization and can be further converted to a series of axially chiral derivatives, thereby expanding their potential application in drug discovery and asymmetric catalysis.

Hydrazone as the directing group for Ir-catalyzed arene diborylations and sequential functionalizations.

The use of hemilabile pyridine-hydrazone N,N-ligands allows the highly selective Ir-catalyzed ortho,ortho'-directed diborylation of aromatic N,N-dimethylhydrazones in near-quantitative yields. One-pot sequential Suzuki-Miyaura cross-coupling with different aryl bromides provides a short entry to unsymmetrically substituted 2,6-diarylbenzaldehyde derivatives.

Pinacolborane as the boron source in nitrogen-directed borylations of aromatic N,N-dimethylhydrazones.

A mild procedure for the Ir(III)-catalyzed nitrogen-directed ortho borylation of aromatic N,N-dialkylhydrazones using pinacolborane as the boron source has been developed. The methodology relies on a modified, hemilabile N,N ligand built on a 4-N,N-dimethylaminopyridine unit that provides high reactivity while maintaining exclusive ortho-selectivity. This procedure can be combined with Suzuki-Miyaura cross-couplings in a 'one-pot' fashion to afford functionalized biaryl derivatives that, upon subsequent 'one-pot', high yielding transformations, provide a convenient entry for the preparation of advanced benzonitrile intermediates for the synthesis of Sartan-type drugs.

Phosphino hydrazones as suitable ligands in the asymmetric Suzuki-Miyaura cross-coupling.

Phosphino hydrazones derived from C(2)-symmetric hydrazines exhibit excellent catalytic activity and provide good enantioselectivities in the asymmetric Suzuki-Miyaura cross-coupling to axially chiral biaryls, in particular for the most challenging reactions of monocyclic, functionalized aryl bromides and triflates. X-ray analysis of preformed [Pd(P/N)Cl(2)] precatalysts [(P/N) = phosphino hydrazone] revealed a strong n-π conjugation in the hydrazone moiety, identified by a high planarity degree at the pyrrolidine N(sp(3)) atom, that makes rotations around N-N bonds inconsequential. The complexes are also characterized by an envelope-like conformation with the Pd atom placed at the opposite side to the 2-phenyl group on the nearest stereogenic center of the pyrrolidine group. The isolation and structural analysis of oxidative addition intermediates indicate that the configurational stability of Pd-C(Ar) bonds is dependent on the substitution pattern in the aryl bromide.