Rapid Sequentially Palladium Catalyzed Four-Component Synthesis of Novel Fluorescent Biaryl-Substituted Isoxazoles

: A series of novel 3-and 5-biaryl-substituted isoxazoles was prepared by a rapid microwave-assisted four-component three-step synthesis: concatenating Sonogashira coupling, cyclocondensation

Isoxazole syntheses have been known for a long time, and various approaches to the formation of the isoxazole core can be found in the literature [13,14].In the past decade alone, multicomponent reactions (MCR) of isoxazoles as one-pot accesses were reported for 3,5-disubstituted isoxazoles [15][16][17][18], 4-acyl-3,5-disubstituted isoxazoles [19], and 3,4,5-trisubstituted isoxazoles [20,21].Surprisingly, isoxazoles with biphenyl substituents are scarcely found.Because of the biphenyl twist in the electronic ground state S 0 (θ~34 • ), which transforms into coplanarity after photonic excitation and vibrational relaxation to S 1 , a favorable property of fluorescent chemosensors with large Stokes shifts can be derived [22][23][24].Therefore, we envisioned an MCR approach to biaryl-substituted isoxazoles, enabling the design of functional π-systems based on diversity-oriented synthesis [25][26][27].Inspired by our four-component synthesis of biaryl-substituted pyrazoles [28], we assumed that a sequentially Pd-catalyzed process can be transposed to the MCR formation of biarylated isoxazoles.Sequential catalysis is a particularly attractive concept, featuring multiple uses of an initially employed catalyst for a subsequent reaction step [29][30][31].In line with the advantages of MCR, the catalyst is also Here, we report a novel sequentially Pd-catalyzed one-pot synthesis of biaryl-substituted isoxazoles in a consecutive four-component fashion.Furthermore, by a suitable donor-acceptor substitution enhancing the emission characteristics, the photonic properties are investigated by UV/vis and fluorescence spectroscopy, as well as by DFT (density functional theory) and TDDFT (time-dependent density functional theory) studies to rationalize the electronic structure.

Synthesis and Structure
Biaryl-substituted isoxazoles, as their pyrazole congeners [28], might be best accessible by catalytic ynone formation [32], with bromine containing aroyl chlorides or alkynes, setting two points of diversity in this type of level-two functionalization.The isoxazole core itself forms by regioselective Michael addition-cyclocondensation [18].For the one-pot synthesis of 3-biaryl-substituted isoxazoles, we set out with a Pd-catalyzed Sonogashira coupling of an aroyl chloride 1 with p-bromophenyl acetylene (2a).After formation of the corresponding alkynone (monitored by TLC), the subsequent cyclocondensation with hydroxylamine was rapidly performed in the microwave reactor followed by Suzuki coupling of various boronic acids 3, without further addition of Pd catalysts to the reaction mixture (Scheme 2).The desired 3-biaryl-substituted isoxazoles 4 were isolated in moderate to very good yields for the overall reaction sequence of this four-component synthesis in less than 2 h (Table 1).
The structures of compounds 4 were unambiguously assigned by 1 H and 13 C NMR spectroscopy and mass spectrometry.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 15 less than 2 h (Table 1).The structures of compounds 4 were unambiguously assigned by 1 H and 13 C NMR spectroscopy and mass spectrometry.
Entry Acid Chloride 1 Boronic Acid 3 3-Biaryl-substituted Isoxazoles 4 Assuming that four new bonds are being formed in the sequence, the average yield per bond-forming step accounts for 65-95%.Aroyl chlorides with halogen substituents (Table 1, entries 3-5) or strongly electron donating and withdrawing boronic acids, such as 3d and 3f (Table 1, entries 8 and 10), give considerably lower yields after isolation by chromatography.However, in principle, both electron-rich (Table 1, entries 2, 6, 8) and electron-poor substituents (Table 1, entries 3-5, 7, 9) can be present on both aryl rings of the isoxazole.The introduction of an aldehyde functionality (Table 1, entry 9) opens up possibilities for further functionalization.A donor-acceptor conjugate with a methoxy and a nitrile substituent can be readily established (

Entry
Acid Chloride 1 Boronic Acid 3 3-Biaryl-substituted Isoxazoles 4 Assuming that four new bonds are being formed in the sequence, the average yield per bondforming step accounts for 65-95%.Aroyl chlorides with halogen substituents (Table 1, entries 3-5) or strongly electron donating and withdrawing boronic acids, such as 3d and 3f (Table 1, entries 8 and 10), give considerably lower yields after isolation by chromatography.However, in principle, both electron-rich (Table 1, entries 2, 6, 8) and electron-poor substituents (Table 1, entries 3-5, 7, 9) can be present on both aryl rings of the isoxazole.The introduction of an aldehyde functionality (Table 1, entry 9) opens up possibilities for further functionalization.A donor-acceptor conjugate with a methoxy and a nitrile substituent can be readily established (Table 1, entry 11).
For compound 4k, the molecular structure was additionally corroborated by single crystal structure analysis (Figure 1) [33] Assuming that four new bonds are being formed in the sequence, the average yield per bondforming step accounts for 65-95%.Aroyl chlorides with halogen substituents (Table 1, entries 3-5) or strongly electron donating and withdrawing boronic acids, such as 3d and 3f (Table 1, entries 8 and 10), give considerably lower yields after isolation by chromatography.However, in principle, both electron-rich (Table 1, entries 2, 6, 8) and electron-poor substituents (Table 1, entries 3-5, 7, 9) can be present on both aryl rings of the isoxazole.The introduction of an aldehyde functionality (Table 1, entry 9) opens up possibilities for further functionalization.A donor-acceptor conjugate with a methoxy and a nitrile substituent can be readily established (Table 1, entry 11).
For compound 4k, the molecular structure was additionally corroborated by single crystal structure analysis (Figure 1) [33]  For compound 4k, the molecular structure was additionally corroborated by single crystal structure analysis (Figure 1) [33].The torsion angles θ of the four ring planes account for 13.The packing of isoxazole 4k was analyzed by a quantitative analysis of intermolecular interactions with Hirshfeld surfaces using the program CrystalExplorer [34] following a specific methodology [35][36][37].The Hirshfeld surface (dnorm, Figure 2) displays close intermolecular contacts (red circles on the dnorm surface) from the nitrile nitrogen atom N2 to the hydrogen atom of C2 and the hydrogen atom of C18, as well as between the methoxy oxygen atom O2 and the methyl hydrogen atoms of C23.The majority of the surface is white or blue, representing the sum or longer than vander-Waals contact distances, especially between molecules that are stacked side by side (Figure 2).The packing of isoxazole 4k was analyzed by a quantitative analysis of intermolecular interactions with Hirshfeld surfaces using the program CrystalExplorer [34] following a specific methodology [35][36][37].The Hirshfeld surface (d norm , Figure 2) displays close intermolecular contacts (red circles on the d norm surface) from the nitrile nitrogen atom N2 to the hydrogen atom of C2 and the hydrogen atom of C18, as well as between the methoxy oxygen atom O2 and the methyl hydrogen atoms of C23.The majority of the surface is white or blue, representing the sum or longer than van-der-Waals contact distances, especially between molecules that are stacked side by side (Figure 2).

Entry Alkyne 2
Boronic Acid 3 5-Biaryl-substituted Isoxazoles 5 Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.Entry Alkyne 2 Boronic Acid 3 5-Biaryl-substituted Isoxazoles 5 Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.

Entry Alkyne 2
Boronic Acid 3 5-Biaryl-substituted Isoxazoles 5 Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.
Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.
Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.

5e (34%)
bromobenzoyl chloride (1f) as a substrate (Scheme 3, Table 2).For this series, the yields after chromatography are considerably lower, and the targeted 5-biaryl-substituted isoxazoles 5 are obtained in 6-49% yield.However, three particularly photophysically interesting donor-acceptor decorated 5-biaryl-substituted isoxazoles were prepared (Table 2, entries 3-5).The structures of compounds 5 were unambiguously assigned by 1 H and 13 C NMR spectroscopy and mass spectrometry.Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.
Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3).Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum.In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.

Photophysical Properties
Compounds 4k, 5c, 5d, and 5e are distinctive push-pull systems and fluoresce strongly in solution already visible to the unaided eye.Therefore, the photophysical properties were thoroughly investigated by UV/vis and static fluorescence spectroscopy in solution (Figure 4, Table 3).Compound 4k is the only representative in this series bearing a biaryl substituent in 3-position and shows the most hypsochromically shifted absorption maximum at 294 nm with the highest molecular absorption coefficient ε (66,000 m −1 cm −1 ).The emission maximum of 4k appears at 423 nm, giving the largest Stokes shift in this series (10,400 cm −1 ).On the other hand, the fluorescence quantum yield Φ F = 0.17 is rather low.While the absorption maxima of compounds 5c and 5d are identical and appear at 311 nm (ε = 40,000 and 45,100 m −1 cm −1 , resp.), compound 5e shows a large bathochromic shift to 356 nm (ε = 34,100 m −1 cm −1 ).The emission maximum of derivative 5d (411 nm) is bathochromically shifted in comparison to isoxazole 5c (376 nm), which implies the electronic influence of the stronger electron-withdrawing cyano substituent in comparison to the trifluoromethyl substituent.Beyond this, the introduction of the strong dimethylamino donor in compound 5e leads to a large bathochromic shift of the emission maximum to 554 nm.The resulting Stokes shifts for the consanguineous series of compounds 5c, 5d, and 5e are 5600, 7800 and 10,000 cm −1 and the fluorescence quantum yields are considerably high at Φ F = 0.86 (5c), Φ F = 0.62 (5d) and Φ F = 0.69 (5e).
Compound 4k also shows fluorescence in a solid state that is visible to the unaided eye.Therefore, isoxazoles 4k, 5c, 5d and 5e were additionally investigated by solid-state fluorescence spectroscopy (Figure 5, Table 4).All compounds show measurable fluorescence, although the fluorescence quantum yields of 5c,d are only minor.The emission maxima follow the same trend as in solution with 5c showing the most blue-shifted emission at 391 nm, followed by 5d (405 nm), 4k (448 nm), and 5d with the most redshifted emission maximum at 508 nm.
emission spectra of 5c in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs)) and S2 (Normalized emission spectra of 5d in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs))).Since specific interactions such as hydrogen bonding are absent, this steady diminution of fluorescence intensity with increasing redshift of the emission band is in full agreement with the energy gap law [40].
Compound 4k also shows fluorescence in a solid state that is visible to the unaided eye.Therefore, isoxazoles 4k, 5c, 5d and 5e were additionally investigated by solid-state fluorescence spectroscopy (Figure 5, Table 4).All compounds show measurable fluorescence, although the fluorescence quantum yields of 5c,d are only minor.The emission maxima follow the same trend as in solution with 5c showing the most blue-shifted emission at 391 nm, followed by 5d (405 nm), 4k (448 nm), and 5d with the most redshifted emission maximum at 508 nm.Within the consanguineous series of isoxazoles 5c, 5d, and 5e, the photophysical properties generally follow the expected trend in accordance with the electronic nature of their substituents.However, the properties of isoxazole 4k clearly stand out.Compared to isomer 5d, changing the biphenyl positioning from the 5-position to the 3-position causes a hypsochromic shift of the absorption band, and a bathochromic shift of the emission band of compound 4k.Simultaneously, the fluorescence quantum yield drops from 0.62 (5d) to 0.17 (4k).Although different solvents were employed for determining the fluorescence quantum yield, further experiments clearly showed that the polarity of the solvent is not solely responsible for the differences in the quantum yields.

Computational Studies and Electronic Structure
A deeper understanding of the electronic structure of compounds 4k, 5c, 5d, and 5e was sought by DFT calculations using Gaussian09 [41].The ground state geometries were optimized using the B3LYP functional [42][43][44][45][46] with the Pople 6-311G(d,p) basis set [47] applying the polarizable continuum model (PCM) [48] with dichloromethane as a solvent.The DFT optimized structures were confirmed as local minima by frequency analyses.
Based upon the crystal structure of compound 4k (vide supra), a closer look was taken at the conjugation of the π-electron system, comparing the computed torsion angles of isomers 4k and 5d in solution and of 4k in the solid state (Table 5).Expectedly, in solution angle γ of the biphenyl torsion of ~35 • becomes apparent [49].In the crystal structure of compound 4k, this torsional angle only amounts to 4.8 • .The other torsional angles (around the isoxazole core) fall cum grano salis in the same margin.With regard to the crystal structure, it can be stated that the remarkably low biphenyl torsion angle in the crystal is probably a consequence of the observed packing effects.

Computational Studies and Electronic Structure
A deeper understanding of the electronic structure of compounds 4k, 5c, 5d, and 5e was sought by DFT calculations using Gaussian09 [41].The ground state geometries were optimized using the B3LYP functional [42][43][44][45][46] with the Pople 6-311G(d,p) basis set [47] applying the polarizable continuum model (PCM) [48] with dichloromethane as a solvent.The DFT optimized structures were confirmed as local minima by frequency analyses.
Based upon the crystal structure of compound 4k (vide supra), a closer look was taken at the conjugation of the π-electron system, comparing the computed torsion angles of isomers 4k and 5d in solution and of 4k in the solid state (Table 5).Expectedly, in solution angle γ of the biphenyl torsion of ~35° becomes apparent [49].In the crystal structure of compound 4k, this torsional angle only amounts to 4.8°.The other torsional angles (around the isoxazole core) fall cum grano salis in the same margin.With regard to the crystal structure, it can be stated that the remarkably low biphenyl torsion angle in the crystal is probably a consequence of the observed packing effects.Additionally, TD-DFT [50][51][52] calculations were employed to compute the absorption maxima for these compounds (CAM-B3LYP functional [53]; 6-311++G(d,p) basis set; PCM: dichloromethane).In general, the computed values for the absorption maxima are in good agreement with the experiment (Table 6).Only derivative 5e shows an even stronger bathochromic shift in the absorption maximum (356 nm) than predicted by the calculation (333 nm).

Computational Studies and Electronic Structure
A deeper understanding of the electronic structure of compounds 4k, 5c, 5d, and 5e was sought by DFT calculations using Gaussian09 [41].The ground state geometries were optimized using the B3LYP functional [42][43][44][45][46] with the Pople 6-311G(d,p) basis set [47] applying the polarizable continuum model (PCM) [48] with dichloromethane as a solvent.The DFT optimized structures were confirmed as local minima by frequency analyses.
Based upon the crystal structure of compound 4k (vide supra), a closer look was taken at the conjugation of the π-electron system, comparing the computed torsion angles of isomers 4k and 5d in solution and of 4k in the solid state (Table 5).Expectedly, in solution angle γ of the biphenyl torsion of ~35° becomes apparent [49].In the crystal structure of compound 4k, this torsional angle only amounts to 4.8°.The other torsional angles (around the isoxazole core) fall cum grano salis in the same margin.With regard to the crystal structure, it can be stated that the remarkably low biphenyl torsion angle in the crystal is probably a consequence of the observed packing effects.Additionally, TD-DFT [50][51][52] calculations were employed to compute the absorption maxima for these compounds (CAM-B3LYP functional [53]; 6-311++G(d,p) basis set; PCM: dichloromethane).In general, the computed values for the absorption maxima are in good agreement with the experiment (Table 6).Only derivative 5e shows an even stronger bathochromic shift in the absorption maximum (356 nm) than predicted by the calculation (333 nm).Additionally, TD-DFT [50][51][52] calculations were employed to compute the absorption maxima for these compounds (CAM-B3LYP functional [53]; 6-311++G(d,p) basis set; PCM: dichloromethane).In general, the computed values for the absorption maxima are in good agreement with the experiment (Table 6).Only derivative 5e shows an even stronger bathochromic shift in the absorption maximum (356 nm) than predicted by the calculation (333 nm).According to TD-DFT calculations, the longest wavelength absorption bands of compounds 5c, 5d, and 5e, possess dominant contributions of HOMO→LUMO and HOMO→LUMO+1 transitions.It is noteworthy that compound 4k does not involve the HOMO→LUMO transition as a constituent of the longest wavelength absorption band.The calculated electronic structure reveals that the longest wavelength absorption band consists of dominant contributions of HOMO-1→LUMO and HOMO→LUMO+1 transitions, which both reveal local excitation character at higher energies in the p-cyano biphenyl oxazole part (HOMO-1→LUMO) and in the p-anisyl isoxazole moiety (HOMO→LUMO+1) (Figure 6, left).The relative contribution of the HOMO→LUMO transition decreases gradually from 5c to 5e, possibly caused by diminished orbital overlap due to increasing charge-transfer character.With increasing acceptor strength, the amount of the HOMO→LUMO+1, representing charge transfer transition over the complete molecule, steadily increases.The HOMO→ LUMO, also charge transfer in its nature, only possesses a moderate overlap in the central isoxazole.Expectedly, stronger acceptor substituents attenuate the central overlap on the isoxazole, and, consequently, the HOMO→LUMO+1 transition prevails (Figure 6, right).
According to TD-DFT calculations, the longest wavelength absorption bands of compounds 5c, 5d, and 5e, possess dominant contributions of HOMO→LUMO and HOMO→LUMO+1 transitions.It is noteworthy that compound 4k does not involve the HOMO→LUMO transition as a constituent of the longest wavelength absorption band.The calculated electronic structure reveals that the longest wavelength absorption band consists of dominant contributions of HOMO-1→LUMO and HOMO→LUMO+1 transitions, which both reveal local excitation character at higher energies in the p-cyano biphenyl oxazole part (HOMO-1→LUMO) and in the p-anisyl isoxazole moiety (HOMO→LUMO+1) (Figure 6, left).The relative contribution of the HOMO→LUMO transition decreases gradually from 5c to 5e, possibly caused by diminished orbital overlap due to increasing charge-transfer character.With increasing acceptor strength, the amount of the HOMO→LUMO+1, representing charge transfer transition over the complete molecule, steadily increases.The HOMO→LUMO, also charge transfer in its nature, only possesses a moderate overlap in the central isoxazole.Expectedly, stronger acceptor substituents attenuate the central overlap on the isoxazole, and, consequently, the HOMO→LUMO+1 transition prevails (Figure 6, right).This behavior can be additionally quantified by coefficient density analysis of the corresponding DFT data for ground state optimization using Multiwfn (Table 7) [54].The distance between coefficient density focal points of HOMO and LUMO, d FMO , increases from structure 5c to 5d, while the overlap integral of HOMO and LUMO, <HOMO|LUMO>, gradually decreases.The distinct charge transfer character of 5e in comparison to 5c can be illustrated by HOMO-LUMO difference plots (Figure 7).This behavior can be additionally quantified by coefficient density analysis of the corresponding DFT data for ground state optimization using Multiwfn (Table 7) [54].The distance between coefficient density focal points of HOMO and LUMO, dFMO, increases from structure 5c to 5d, while the overlap integral of HOMO and LUMO, <HOMO|LUMO>, gradually decreases.The distinct charge transfer character of 5e in comparison to 5c can be illustrated by HOMO-LUMO difference plots (Figure 7).A conclusion from the study of the electronic structures is that the 5-biaryl-substituted isoxazoles 5 are better suited for fine-tuning of the absorption and emission properties over a broad part of the spectrum.With the highly emissive compound 5c as a model system, the optimized geometry of the vibrationally relaxed excited state (S1) was calculated with Gaussian09, employing the same A conclusion from the study of the electronic structures is that the 5-biaryl-substituted isoxazoles 5 are better suited for fine-tuning of the absorption and emission properties over a broad part of the spectrum.With the highly emissive compound 5c as a model system, the optimized geometry of the vibrationally relaxed excited state (S 1 ) was calculated with Gaussian09, employing the same functional and basis set as for ground state optimization in dichloromethane.Via TD-DFT, the emission from S 1 to the Franck-Condon state S 0 FC2 was calculated.In addition to the optimization of S 0 and excitation to S 1 FC1 , the whole excitation-emission cycle of 5c could be computationally simulated (Figure 8).
The computed emission maximum λ max,em,DFT = 361 nm is in good agreement with the experiment (λ max,em,exp = 376 nm).It is noticeable that the geometry of the S 1 is essentially planarized compared to the equilibrium geometry of S 0. A conclusion from the study of the electronic structures is that the 5-biaryl-substituted isoxazoles 5 are better suited for fine-tuning of the absorption and emission properties over a broad part of the spectrum.With the highly emissive compound 5c as a model system, the optimized geometry of the vibrationally relaxed excited state (S1) was calculated with Gaussian09, employing the same functional and basis set as for ground state optimization in dichloromethane.Via TD-DFT, the emission from S1 to the Franck-Condon state S0 FC2 was calculated.In addition to the optimization of S0 and excitation to S1 FC1 , the whole excitation-emission cycle of 5c could be computationally simulated (Figure 8).The computed emission maximum λmax,em,DFT = 361 nm is in good agreement with the experiment (λmax,em,exp = 376 nm).It is noticeable that the geometry of the S1 is essentially planarized compared to the equilibrium geometry of S0.

Conclusions
A concise consecutive four-component synthesis of novel biaryl-substituted isoxazoles was successfully established.Interestingly, the palladium catalyst can be employed sequentially for both Sonogashira coupling and Suzuki coupling without addition of further catalyst.The one-pot process is intercepted by a regioselective cyclocondensation of the initially formed alkynone with hydroxyl amine.Selected derivatives with a donor-acceptor substitution pattern display pronounced fluorescence in solution and remarkably high relative fluorescence quantum yields in most cases, a property which has been scarcely described for isoxazoles.In a consanguineous series of 5-biaryl-substituted isoxazoles with increasing donor and acceptor strengths, the tunability of Stokes shift between 5600 to 10,000 cm −1 (sic!) can be impressively shown.The same compounds are also emissive in the solid state, though with rather low fluorescence quantum yields.Quantum chemical calculations plausibly rationalize the electronic properties in good agreement with the experimental results.These novel biaryl-substituted isoxazoles are intensively emissive in nonpolar environments and are therefore perfectly suited for developing lipophilic luminophores for biophysical application.Studies to incorporate biaryl oxazole luminophores into polystyrene particles and ligating them to biologically interesting lipophilic targets, such as bilayer membranes, are currently underway.

Author Contributions:
The work is part of the Ph.D. thesis of T.D., which was supervised by T.J.J.M.The conceptualization was outlined and accompanied by T.J.J.M. Synthetic studies, analytical assignments, and photophysical investigations were performed by T.D., who compiled and interpreted the obtained data.Quantum chemical calculations were performed by L.M. and T.D., and the crystal structure analysis was carried out and interpreted by G.J.R. Writing of the original draft was done by T.D., and review and editing by T.J.J.M. Project administration and funding acquisition was conducted by T.J.J.M.All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by Jürgen-Manchot-Stiftung Düsseldorf (scholarship for T.D.), and by Fonds der Chemischen Industrie (scholarship for L.M. and ad personam support for T.J.J.M.).

Figure 2 .
Figure 2. Hirshfeld surface of isoxazole 4k in the crystal lattice mapped with the d norm property [37].Red represents the closest, blue the most distant contacts.

Figure 8 .
Figure 8. Computed results for excitation to the Franck-Condon state S1 FC1 , vibrational relaxation to S1, emission to Franck-Condon state S0 FC2 and relaxation to S0 of compound 5c.Geometry optimization of

Table 6 .
Experimental (recorded in CH 2 Cl 2 at 293 K) and TDDFT (time-dependent density functional theory) calculated of the absorption maxima of isoxazoles