Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

Starting from substituted alkynones, α-pyrones and/or 1H-pyridines were generated in a Michael addition–cyclocondensation with ethyl cyanoacetate. The peculiar product formation depends on the reaction conditions as well as on the electronic substitution pattern of the alkynone. While electron-donating groups furnish α-pyrones as main products, electron-withdrawing groups predominantly give the corresponding 1H-pyridines. Both heterocycle classes fluoresce in solution and in the solid state. In particular, dimethylamino-substituted α-pyrones, as donor–acceptor systems, display remarkable photophysical properties, such as strongly red-shifted absorption and emission maxima with daylight fluorescence and fluorescence quantum yields up to 99% in solution and around 11% in the solid state, as well as pronounced emission solvatochromism. Also a donor-substituted α-pyrone shows pronounced aggregation-induced emission enhancement.


Introduction
A high sensitivity and precise tuneability of fluorescence colors are prerequisites for the application of fluorescent substances in chemistry, medicine and materials science [1]. With this respect emissive small molecules [2], fluorescent proteins [3], and quantum dots have received considerable attention and remarkable progress in their synthesis and photophysics has been achieved [4]. Small molecule organic fluorophores are particularly advantageous due to the potential of a tailored fine-tuning of their photophysical properties through synthetic modifications [5]. Based on their structural features, functionalized organic chromophores, containing N-, O-or S-atoms, are increasingly used in OLEDs [6][7][8][9][10] and LCDs [11][12][13] of mobile phones [14]. Fluorescent compounds often intensively emit in solution but only weakly or not in the solid state [15]. Dyes which fluoresce both in the solid state and in solution are still relatively rare, due to the fact that often molecular aggregation in the solid state causes fluorescence quenching [16].
While most α-pyrones neither fluoresce in solution nor in the solid state specific substitution patterns have been identified for fluorophore design for this heterocyclic family. Tominaga and co-workers synthesized a series of α-pyrone derivatives with emission maxima between 400 and 675 nm in the solid state and between 486 and 542 nm in chloroform [16,[24][25][26], including fluorescence quantum yields as high as 95% in solution and 58% in the solid state [16,24]. While these fluorophores were synthesized by cyclocondensation with ketene dithioacetals and substituted acetophenones other cyano-containing derivatives became accessible by desymmetrizing cyclocondensation of 1,2-diaroylacetylenes with ethyl cyanoacetate [27], similar to related studies with dialkyl malonates [28]. Here, we report on effects of base and temperature on Michael addition-cyclocondensation sequences in the formation of α-pyrones and/or 1H-pyridines starting from diversely substituted alkynones and cyanoethylacetate. This bifurcating domino process furnishes small chromophore libraries which were characterized by photophysical studies (absorption and emission spectroscopy) and the studies on the electronic structure were accompanied by TD-DFT calculations for assigning the dominant longest-wavelength absorption bands.

Synthesis and tentative mechanism
Recently, we reported a straightforward access to α-pyrones through a consecutive alkynylation-Michael addition-cyclocondensation (AMAC) multicomponent synthesis [23]. The reaction can be rationalized by a Sonogashira coupling between an acid chloride and a terminal alkyne furnishing an alkynone, which is transformed without isolation by addition of dialkyl malonates in a Michael addition-cyclocondensation to form α-pyrones (Scheme 1).

Scheme 4:
Model system for the optimization of the Michael addition-cyclocondensation reaction step to 1H-pyridine 5a or/and α-pyrone 6a.
were detected. On the one hand a 1H-pyridine derivative 5a (2% yield) and on the other hand an aniline derivative with two ester groups (4% yield). Both compounds indicate that two molecules of ethyl cyanoacetate (4) were incorporated in the final structure.
With an increased amount of ethyl cyanoacetate the yield of both products could be increased. By the addition of ethanol as a cosolvent in the second step of the sequence, 1H-pyridine 5a could be isolated in 30% yield, while the aniline derivative was not formed (Scheme 3).
There are only a few known methods for the synthesis of this kind of 1H-pyridines. In a cyclocondensation, starting from 1,3dicarbonyl compounds, Elnagdi and co-workers synthesized 1H-pyridines with an additional cyano substituent in the 3-position [29]. Most syntheses generating 1H-pyridines make use of ethyl cyanoactate as a starting material. It can react with itself and forms a dimer by selfcondensation, catalyzed by transition metals [30,31].
Intrigued by the unusual pseudo-four-component AMAC synthesis we investigated the reaction conditions of the terminal Michael addition-cyclocondensation step starting from alkynone 3a. By varying the amount of the base we could observe the formation of 1H-pyridine 5a, but also of α-pyrone 6a (Scheme 4, Table 1), similarly to the reaction of compound 4 with 1,2-diaroylacetylenes [28]. a All reactions were carried out on a 0.500 mmol scale (c 0 (3a) = 0.50 M, c 0 (4) = 2.0 M; b all yields refer to isolated and purified products; c additional water (5.6 equiv).
With either 0.8 or 1.0 equiv of Na 2 CO 3 ·10H 2 O α-pyrone 6a is formed as the main product (50-64%), while 1H-pyridine 5a can also be isolated in around 15% yield ( Table 1, entries 1 and 2). By increasing the amount of Na 2 CO 3 ·10H 2 O, exclusively 1H-pyridine 5a can be isolated in low yield (Table 1, entries 3 and 4). Using anhydrous sodium carbonate α-pyrone 6a is again formed as the main product in 41% yield, but the yield of 1H-pyridine 5a drops to 3% (Table 1, entry 5). By the addition of water, the yield of 6a could be increased (Table 1, entries 6 and 7).
Next we evaluated the use of a mixture of two bases, sodium carbonate and sodium acetate, and water ( Table 2). With Scheme 5: Formation of α-pyrone 6a and 1H-pyridine 5a at 20 °C.

Scheme 6:
Formation of α-pyrone 6a starting from alkynone 3b having an electron-donating substituent.  0.80 equiv of sodium carbonate, 0.60 equiv of sodium acetate and 5.6 equiv of water 1H-pyridine 5a could be isolated in 56% yield. Decreasing the amount of ethyl cyanoacetate (4) the yields drops ( Only lowering the reaction temperature to 20 °C α-pyrone 6a was isolated as the main product in 78% yield and 1H-pyridine 5a was obtained in only 7% yield (Scheme 5).
Since base(s) and reaction temperature exert a significant impact on which heterocyclic compound is formed, we also tried to change the electronic nature of the starting material. Therefore, an electron-donating substituent was introduced in the alkynone 3b and the reaction was performed at 75 °C. To our surprise, we only could isolate α-pyrone 6b (Scheme 6).
However, when we introduced an electron-withdrawing group 1H-pyridine 5b was the only product (Scheme 7).
For elucidating whether 1H-pyridine 5a is formed from α-pyrone 6a and ethyl cyanoacetate (4) a reaction between α-pyrone 6a and ethyl cyanoacetate (4) under the same reaction conditions as for the 1H-pyridine from alkynone 3a was conducted, but only starting material could be isolated. Another option for the formation of the 1H-pyridine 5a was envisioned by an in situ generation of a dimer of ethyl cyanoacetate (4). The dimer 7 can be synthesized by iridium catalysis [30]. With Scheme 7: Formation of 1H-pyridine 5b starting from alkynone 3d having an electron-withdrawing substituent.

Scheme 8:
Formation of 1H-pyridine 8a by Michael addition-cyclocondensation reaction. a All reactions were carried out on a 0.500 mmol scale (c 0 (3a) = 0.50 M, c 0 (4) = 2.0 M; b all yields refer to isolated and purified products.
dimer 7 in hand, we performed the reaction at 75 °C for 16 h, but we only could isolate 1H-pyridine 8a, which still contains an ester group (Scheme 8). Therefore, the in situ formation of the dimer starting from the alkynone 3a and ethyl cyanoacetate (4) was excluded for the formation of the 1H-pyridine 5a.
While the in situ generation of dimer 7 does not happen during the formation of 1H-pyridine 5a, we examined the reaction between ethyl cyanoacetate (4) and the optimized base system by adding alkynone 3a to the reaction after different times (Table 3).
In the first attempt, alkynone 3a was added after 2 h. 1H-Pyridine 5a was isolated in 53% yield ( Table 3, entry 1), indicating that the time of addition of the alkynone is not relevant within the first two hours of the reaction. However, if alkynone 3a was added after 6 h α-pyrone 6a was the main product and 1H-pyridine 5a could only be isolated in 5% yield (Table 3, entry 2). Upon the addition of alkynone 3a after 24 h, both 1H-pyridine 5a and α-pyrone 6a were isolated in only around 3% yield. This finding supports that within the first two hours ethyl cyanoacetate (4) is consumed and thereafter the ethyl cyanoacetate concentration is just too low for the formation of 1H-pyridine Scheme 9: Mechanistic rationale for the formation of the 1H-pyridine 5a.
5a, therefore α-pyrone 6a is formed. At longer initial reaction times (6 and 24 h) there is no ethyl cyanoacetate (4) left for the formation of any product. Also, ethyl cyanoacetate (4) probably does not form dimer 7 because in that case under these conditions 1H-pyridine 8a would have been detected.
Therefore, the tentative mechanistic rationale takes into account that the formation of 1H-pyridine 5a rather proceeds via stepwise condensation of alkynone 3 with two equivalents of ethyl cyanoacetate (4) than by reaction with dimer 7 (Scheme 9).
First, a molecule of ethyl cyanoacetate (4) attacks the alkynone 3a in a Michael addition. A second molecule 4 then attacks the cyano substituent and an imine is formed. The ester substituent of the initially reacted more electrophilic ethyl cyanoacetate (4) is presumably cleaved by a base-mediated acyl cleavage furnishing directly 1H-pyridine 5a after protonation.
For examining the influence of the electronic nature of the alkynone 3 on the product formation, a range of differently substituted alkynones 3 (for experimental details on their preparation, see chapters 2.1 and 2.2 in Supporting Information File 1) bearing electron-donating and/or electron-withdrawing substituents were synthesized and employed in the cyclocondensation step under the optimized reaction conditions [32][33][34].
Alkynones 3b-e with only one electron-donating substituent furnish the corresponding α-pyrones 6b-e, while the alkynone with a single electron-withdrawing substituent furnishes 1H-pyridines 5b-e. Interestingly, the position of substitution on the alkynone does not affect the outcome (Table 4, entries 2 and 6). Also, for alkynone 3j bearing an electron-donating substituent on either aryl ring, α-pyrone 6f is formed likewise ( Table 4, entry 10). For electronically unsymmetrically substituted alkynones 3 the product formation depends rather on the strength of the employed electron-donating group. Whereas the p-anisyl substituent leads to the formation of 1H-pyridine (Table 4, entries 11 and 12), the N,N-dimethylaminophenyl substituent furnishes α-pyrone 6g (Table 4, entry 13).
For synthesizing 1H-pyridine derivatives 8 with an electron-donating group we employed the isolated dimer 7 and were able to isolate 1H-pyridines 8 in 52 and 34% yield (Scheme 10).
All compounds show three absorption maxima at around 275, 320 and 430 nm, where the longest wavelength absorption maxima exhibit extinction coefficients of around 9500 L·mol −1 ·cm −1 (Table 5). Upon introducing electron-withdrawing substituents on the aryl rings the longest wavelength maxima shift bathochromically ( Upon excitation at the longest wavelength absorption band dichloromethane solutions of all compounds 5 fluoresce with emission maxima at around 565 nm (Table 5, entries 2-5).
Upon the introduction of electron-withdrawing substituents the maxima are shifted bathochromically, similarly as the absorp-  tion maxima, and the shift is qualitatively correlated with the acceptor strength. In comparison, the introduction of another electron-donating substituent does not significantly change the luminescence characteristics (Table 5, entries 2, 4, 6 and 7). The Stokes shifts fall in a range between 5000 and 6100 cm −1 and the fluorescence quantum yields of the 1H-pyridines 5 account between 1 and 3%.
Besides solution fluorescence all 1H-pyridines 5 also luminesce in the solid state (Figure 3, bottom). The emission maxima of two selected 1H-pyridines 5 were determined ( Figure 5, Table 6), showing a similar behavior in the solid state as in solution. The emission maximum of the unsubstituted 1H-pyridine 5a appears at 540 nm, while the CF 3 -substituted 1H-pyridine 5b emits bathochromically shifted at 604 nm.
In addition, both ester-substituted 1H-pyridines 8a and 8b also possess interesting photophysical properties ( Figure 6, Table 7). Under daylight they are yellow and they fluoresce in solution and in the solid state. The three absorption maxima are found at around 270, 315 and 415 nm. The methoxy group in the spectrum of compound 8b only has a minor influence on the absorption maximum, however, slightly more on the emission maximum. The fluorescence quantum yields Φ f of both compounds are lower than 1%.
With the addition of the second ester group in the 3-position to 1H-pyridine 8a the fluorescence in the solid state appears to shift to blue. If the phenyl substituent in the 4-position bears an additional methoxy substituent the fluorescence of the 1H-pyridine 8b appears yellow again (Figure 7).

Photophysical properties of α-pyrones 6
All α-pyrone derivatives 6 are yellow or red under daylight (Figure 8, top) and some of them fluoresce in solution (Figure 8, center) and in the solid state (Figure 8, bottom). Therefore, the photophysical properties were studied by absorption and emission spectroscopy ( Figure 9, Table 8).
All compounds show 2-4 absorption maxima and the shortest wavelength maxima appear at around 255 nm. The unsubsti-   tuted α-pyrone 6a exhibits its longest wavelength maximum at 381 nm (Table 8, entry 1). A p-methoxyphenyl substituent in the 6-position causes a bathochromic shift (Table 8, entry 2), whereas the same substituent in 4-position leads to a hypsochromic shift (Table 8, entry 4). Interestingly, p-methoxyphenyl substituents at positions 4 and 6 split the longest absorption band into two maxima at 358 nm (arising from the p-methoxyphenyl substituent in the 4-position and at 400 nm arising from the p-methoxyphenyl substituent in the 6-position) ( In solution only N,N-dimethylaminophenyl-substituted derivatives fluoresce (Figure 10). While the 6-substituted α-pyrone 6c has a fluorescence maximum at 567 nm, the one for the regioisomer 6e is shifted bathochromically to 634 nm (Table 8, entries 3 and 5). Donor-acceptor substitution in positions 4 and 6 causes a further bathochromic shift to 673 nm (Table 8, entry  7). Most remarkably, the regioisomers 6c and 6e differ quite significantly with respect to their fluorescence quantum yields Φ f . While chromophore 6e only emits with an efficiency of 1%, the regioisomer 6c accounts for an extraordinarily high relative quantum yield of 99%.
Furthermore, the N,N-dimethylaminophenyl-derivative 6c shows a pronounced emission solvatochromism (Figure 11,    Table 9). While the polarity effect on the absorption maximum is only minor within a range of the longest wavelength maximum between 469 and 490 nm, the emission maximum is shifted bathochromically with increasing solvent polarity in a range from green fluorescence (529 nm) in toluene to red fluorescence in DMSO (638 nm) ( Figure 12). The observed positive emission solvatochromism is a consequence of a significant change in the dipole moment from the electronic ground to    the vibrationally relaxed excited state [59]. Plotting Stokes shifts Δν̃ against the orientation polarizabilities Δƒ of the respective solvents (Lippert plot) [60] gives a reasonable linear correlation with a moderate fit of r 2 = 0.970 ( Figure 13). The orientation polarizabilities Δƒ were calculated according to Equation 1 where ε r is the relative permittivity and n the optical refractive index of the respective solvent.
The change in dipole from the ground to the excited state can be calculated according to the Lippert-Mataga equation where νã bs represents the absorption and νẽ m the emission maxima (in m −1 ), µ E and µ G are the dipole moments in the   All α-pyrones 6 fluoresce in the solid state (Figure 8, bottom) and for five selected α-pyrones 6 the emission maxima were determined ( Figure 14, Table 9). The fluorescence maximum of unsubstituted α-pyrone 6a lies at 499 nm and the maxima of the monomethoxy-substituted regioisomers 6b (540 nm) and 6d (489 nm) appear at quite different energies, similar to their corresponding absorption maxima in solution. In comparison to α-pyrone 6a the introduction of two methoxy substituents in derivative 6f results in a bathochromic shift to 526 nm. The solidstate emission of N,N-dimethylaminophenyl derivative 6c  shows an enormous redshift to 694 nm. The solid-state fluorescence quantum yield Φ f of compound 6c was determined to 11%.
Interestingly, the α-pyrone 6e with the N,N-dimethylaminophenyl substituent in 4-position only fluoresces weakly in solution but shows a strong fluorescence in the solid state. This finding suggests that by restricting intramolecular motion and vibration, which enables radiation-less deactivation of the excited state [61], an AIE (aggregation-induced emission) or AIEE (aggregation-induced enhanced emission), might become operative [62][63][64].
The AIE or AIEE effect was assessed by measuring the emission spectra of α-pyrone 6e in THF/water at variable ratios ( Figure 15). In pure THF α-pyrone 6e displays an emission maximum at 644 nm with a relative intensity of 54. The addition of water first quenches the fluorescence and at a water/THF ratio of 80% aggregates are formed and the emission maximum is shifted to 632 nm. The maximal relative intensity of 130 is reached for a ratio of 85%, which is more intense than in pure THF, therefore, an AIEE effect occurs. Further increasing the water content slightly quenches the emission.

Computational studies
Computational studies on 1H-pyridines 5 and 8 For a further elucidation of the electronic structure the geometries of the electronical ground-state structures of the 1H-pyridines 5 and 8 were optimized using Gaussian 09 with the B3LYP functional [65][66][67][68] and the Pople 6-311G** basis set [69], applying vacuum calculations as well as the polarizable continuum model (PCM) with dichloromethane as a solvent [70]  The computed Kohn-Sham frontier molecular orbitals show that the coefficient density of the HOMO of the 1H-pyridines 5f and 5g with an electron-withdrawing and an electron-donating  substituent is located on the 1H-pyridine core, the ester and cyano substituents and also on the electron-rich aryl substituent. For the LUMO, the coefficient density is spread over the whole scaffold ( Figure 16).

Computational studies on α-pyrones 6
For further elucidation of the electronic structure the geometries of the electronical ground-state structures of the α-pyrones 6 were optimized using Gaussian 09 with the B3LYP functional [65][66][67][68] and the Pople 6-311G** basis set [69], applying vacuum calculations as well as the polarizable continuum model (PCM) with dichloromethane as a solvent [70] (for details on the DFT calculations, see Supporting Information File 1). The optimized geometries were verified by frequency analyses of the local minima. The electronic absorptions of the α-pyrones 6 were calculated on the level of TDDFT theory em- ploying the B3LYP functional and the Pople 6-311G** basis set. The calculated absorption maxima are in accordance with the experimentally determined maxima (for details, see Table S10 in Supporting Information File 1). For all α-pyrones 6 the longest wavelength maxima are characterized by Franck-Condon S 1 states representing HOMO-LUMO transitions ( Figure 17).
The computed Kohn-Sham frontier molecular orbitals show that the coefficient density of the HOMO in the parent α-pyrone 6a is localized on the α-pyrone core and on the phenyl substituent in the 6-position. For an N,N-dimethylaminophenyl substituent, there is no difference, but for an N,N-dimethylaminophenyl substituent in the 4-position the coefficient density is shifted towards this substituent. With electron-donating substituents in the 4-and 6-position, the coefficient density is again located on the core and the phenyl substituent in 6-position. Donor substituents in 4-position and acceptor substituents in 6-position cause a coefficient density shift towards the 4-substituent. The coefficient density in the LUMO in all compounds is spread over the whole scaffold.

Conclusion
The cyclocondensation of alkynones and ethyl cyanoacetate, depending on the reaction conditions, the type of base, and the reaction temperature, as well as the electronic nature of the alkynone 3 furnishes either 1H-pyridines or α-pyrones. Optimized reaction conditions finally give rise to 8 examples of 1H-pyridines and 6 examples of α-pyrones. While the presence of electron-withdrawing substituents mainly furnish 1H-pyridines and electron-donating groups lead to the forma-tion of α-pyrones. The strongly electron-donating p-N,Ndimethylaminophenyl group furnishes α-pyrones.
1H-Pyridines absorb and emit intensively in solution and in the solid state. While the absorption behavior is not affected by the substitution pattern the emission maxima are shifted bathochromically with increasing acceptor strength. The same trend manifests for the solid-state emission.
For α-pyrones the photophysical properties are considerably depending on the substituent pattern. The absorption and emission maxima are shifted bathochromically with increasing donor strength. α-Pyrones are only weakly fluorescent in solution. However, with distinct p-N,N-dimethylaminophenyl substitution in 6-position, an extraordinarily high fluorescence quantum yield of 99% in solution and 11% in the solid state was achieved. Interestingly, the isomeric p-N,N-dimethylaminophenyl substitution in 6-position represents a system with aggregation-induced emission enhancement. These design principles of luminescent 1H-pyridines and α-pyrones as polarity sensitive tunable luminophores and the observed aggregationinduced emission enhancement are currently under further investigation.