Recent Advances in Visible Light Photoinitiating Systems Based on Flavonoids

Abstract

The design of biosourced and/or bioinspired photoinitiators is an active research field as it offers a unique opportunity to develop photoinitiating systems exhibiting better biocompatibility as well as reduced toxicity. In this field, flavonoids can be found in numerous fruits and vegetables so these structures can be of interest for developing, in the future, polymerization processes, offering a reduced environmental impact but also better biocompatibility of the polymers. In this review, the different flavonoids reported to date as photoinitiators of polymerization are presented. Over the years, different modifications of the flavonoid scaffold have been examined including the grafting of well-known chromophores, the preparation of Type II photoinitiators or the introduction of photocleavable groups enabling the generation of Type I photoinitiators. Different families of flavonoids have also been investigated, enabling to design of high-performance photoinitiating systems.

1. Introduction

Photopolymerization is an active research field. Nowadays, tremendous efforts are devoted to developing highly efficient photoinitiating systems activable under visible light. Indeed, photopolymerization is used in a wide range of applications of photopolymerization from coatings and varnishes, adhesives, solvent-free paints and dental restoration materials to 3D/4D printing and microelectronics [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. If the reactivity of photoinitiators remains the main parameter governing the design of new structures, their toxicities and biocompatibilities are more and more regarded [16,17,18,19]. Indeed, for applications such as food packaging and different bioapplications, the toxicity of the final polymers and more generally the final composites (obtained by the introduction of fillers in polymers) is of crucial importance. Therefore, a good balance between toxicity and reactivity has to be found [16,20,21,22,23,24,25,26]. For decades, a great deal of effort has been devoted to developing greener photopolymerization processes, consisting in the use of biosourced photoinitiators and/or biosourced monomers [27,28,29], the use of sunlight instead of artificial light to initiate the polymerization [30,31,32,33,34,35] or the development of water-soluble photoinitiating systems enabling to avoid the use of organic solvents [36,37,38,39]. In order to identify the appropriate scaffold for designing high-performance visible light photoinitiators, a wide range of structures have been screened over the years, as exemplified with diketopyrrolopyrroles [40], bodipy [41,42,43,44,45,46], perylenes [47], dithienophosphole derivatives [48], thiophenes [49], cyclohexanones [50,51,52], quinoxalines [53,54,55,56,57,58,59,60,61,62,63,64,65,66], glyoxylates [67], cyanines [68], benzylidene ketones [69,70,71,72,73], phenothiazines [74], iodonium salts [75,76,77,78,79,80,81], naphthalimides [82,83,84,85], triphenylamines [86,87,88], photochroms [89], pyridinium salts [90], helicenes [91], silane, germane and stannane [92,93], push–pull dyes [32,33,94,95], acridine-1,8-diones [96], zinc complexes [97], biosourced photoinitiators [98], copper complexes [99,100,101,102,103], iron complexes [104,105], thioxanthones [37,41,106,107,108,109,110,111,112,113,114,115,116,117,118], furan derivatives [119], camphorquinone [120,121], anthracenes [122], benzophenones [123,124], chalcones [125,126,127,128,129,130,131], terphenyls [132], phenacyl bromide [133], NIR dyes [134], pyrenes [135,136,137], carbazoles [138,139,140,141,142], coumarins [143,144,145,146], gold complexes [147] and iridium complexes [148]. Natural compounds were also examined as photoinitiators of polymerization such as curcumin [149,150,151,152], different anthraquinones [153,154,155] or naphthoquinones [156]. Flavonoids that can be found in numerous fruits and vegetables [157,158,159,160,161,162,163,164,165], but also in plant products such as chocolate, tea and wine, were identified as promising candidates for the design of visible light photoinitiators. Flavonoids are a family of compounds including more than six thousand low-molecular-weight phenolic compounds derived from flavan [166].

Flavonoids are composed of nine main subgroups including flavones, flavonols, flavanols, flavononols, flavonones, isoflavones, anthocyanines, neoflavonoids and chalcones (see Figure 1). Plants clearly constitute an inexhaustible source of flavonoids on earth.

Flavonoids are extensively used in the biomedical field, due to their anti-oxidative, anti-inflammatory, anti-mutagenic, anti-carcinogenic and anti-diabetic properties [167,168,169]. Flavonoids are important therapeutic agents used in a variety of heath disorders including hypoglycemia, cancer, chronic inflammation or cardiovascular complications [170,171]. These natural dyes are also used in food and cosmetic industries since these structures can be used as pigments and biopreservatives [172]. Among flavonoids, chalcones have been extensively studied as visible light photoinitiators of polymerization due to their easiness of synthesis, low cost and chemical stability [173,174]. The other subgroups of flavonoids have been less studied, attributable to more difficult synthetic routes and the low availability of these structures in nature, inducing high costs for the commercially available flavonoids and thus drastically limiting their potential use as photoinitiators for the industrial production of polymers. In addition, numerous structures have been identified as interesting scaffolds for the design of Type I and Type II photoinitiators. Indeed, photoinitiators can be divided into two main groups, namely Type I photoinitiators, which are monocomponent systems and can generate radicals by homolytic cleavage of a specific bond [175,176,177], and parallel to this, Type II photoinitiators, which can only generate initiating species by means of a multi-step reaction mechanism when combined to a hydrogen donor or an electron acceptor/donor. The first flavonoids to be studied as visible light photoinitiators were flavonols which could efficiently promote the cationic polymerization (CP) of epoxides upon irradiation with a laser diode emitting at 457 nm but also in soft irradiation conditions with an LED emitting at 462 nm [178]. Following this work, various flavonoids were studied, paving the way toward biosourced or bioinspired photoinitiators. In this review, an overview of the different flavonoids examined as visible light photoinitiators of polymerization is given.

2. Flavonoids as Visible Light Photoinitiators

2.1. Flavonols

Flavonols have been extensively studied in health sciences, due to their low toxicities but also due to their antioxidant and anticancer activities [179,180,181,182,183,184,185,186,187]. Flavonols also possess excellent optical properties [188,189,190,191,192]. Due to the presence of the hydroxy group close to the ketone group, these dyes also exhibit excited state intramolecular proton transfer (ESIPT) properties, enabling these dyes to have large Stokes shifts and a dual emission associated with the formation of two excited states, the first one corresponding to the Franck–Condon excited state and the second one attributed to the tautomeric form issued from ESIPT [193,194,195,196,197,198,199,200,201,202,203,204,205]. Despite these appealing features, several drawbacks can be cited, especially regarding the stability of flavonols under light irradiation. In addition to the aforementioned intramolecular proton transfer [193,194,195,196,206,207,208,209,210,211], photooxidation [212,213,214], reverse proton transfer [215] or photorearrangement reaction [216,217] can be cited as the main photoinduced chemical reactions. Despite this attested instability under irradiation, flavonols were used in photopolymerization. Notably, the remarkable fluorescence of a flavonol derivative was used for the real-time monitoring of the FRP of an acrylate-based E-Shell 300 biocompatible polymer by using the flavanol derivative as a fluorescent probe. However, this flavonol derivative was not used as a photoinitiator/photosensitizer but only as a probe [205].

The first report mentioning the use of flavonoids as photoinitiators of polymerization was reported in 2013 by Lalevée and coworkers [178]. In order to provide sufficient absorption in the visible range, different chromophores were connected to the flavonol scaffold, namely pyrene, anthracene or a para-dimethylaminophenyl group (see Figure 2).

From the absorption viewpoint, modification of the side groups strongly impacted the absorption properties of the dyes. All dyes exhibited an absorption maximum located in the near-UV-visible range, except for CH_4 for which an absorption maximum located at 431 nm was determined in acetone. In the case of CH_1-CH_3 and CH_5, maxima located at 394, 377, 325 and 385 nm were respectively measured in acetonitrile. Noticeably, alkylation of the phenolic group in CH_1 blueshifted the absorption of CH_2 by ca. 17 nm, from 394 nm for CH_1 up to 377 nm for CH_2. Improvement in the electron-donating ability of the side group contributed to the redshift of the absorption, as exemplified with CH_2 exhibiting an absorption redshifted by ca. 50 nm compared to CH_3 bearing a weak electron donor (See Figure 3). Considering that the absorption of all dyes extends until the visible range, these dyes were thus appropriate candidates for polymerization experiments performed at 457 nm with a laser diode (I = 100 mW/cm²), at 462 nm with an LED (I = 15 mW/cm²) and upon irradiation with a halogen lamp (370–800 nm range, I = 12 mW/cm²). Two different mechanisms were investigated, an oxidative and a reductive pathway. Among the two possible mechanisms, the oxidative pathway proved to be the most reactive one. By using the three-component dye/Iod/NVK systems (where Iod and NVK respectively stand for [methyl-4-phenyl-(methyl-1-ethyl)-4-phenyl]iodonium tetrakis(pentafluorophenyl)borate and N-vinylcarbazole), the phenyl radicals formed by photoinduced electron transfer from the excited dye toward the electron-deficient iodonium salt can further react with NVK, producing Ph-NVK^●. These radicals can also react with Iod, generating Ph-NVK⁺ [97,218,219]. Therefore, this mechanism can contribute to promoting both the free radical polymerization (FRP) of acrylates and the free-radical-promoted cationic polymerization (FRPCP) of epoxides (see Equations (r1)–(r3)). By UV-visible absorption spectroscopy, the formation of CH_1^●+ could be detected at ca. 500 nm, supporting the oxidation step. The formation of CH_1^●+ and Ph^● was also evidenced by electron spin resonance (ESR).

CH → ¹CH (hν)

¹CH + Ph₂I⁺ → CH ^●+ + Ph₂I^● and Ph₂I^● → Ph^● + Ph-I

(r1)

Ph^● + NVK → Ph-NVK^●

(r2)

Ph-NVK^● + Ph₂I⁺ → Ph-NVK⁺ + Ph-I + Ph^●

(r3)

In the case of the three-component dye/MDEA/R-Br system (where MDEA and R-Br stand for N-methyldiethanolamine and phenacyl bromide), the formation of phenacyl radicals could be identified as the unique radicals formed with this three-component system during the ESR experiments (see Equations (r4) and (r5)).

¹CH + MDEA → CH ^●− + MDEA^●+

(r4)

CH^●− + R-Br → CH + R^● + Br⁻

(r5)

Examination of the photoinitiating abilities of CH_1–CH_5 during the CP of (3,4-epoxycyclohexane)methyl 3,4-epoxycyclohexylcarboxylate (EPOX) upon irradiation with a halogen lamp revealed CH_1 to outperform the other dyes. Thus, a conversion of 60% after 800 s of irradiation was determined, contrarily to 30–40% for CH_2-CH_5 in the same conditions (see Figure 4). Using CH_1 as the chromophore, a slightly higher EPOX conversion was determined at 457 nm (65% conversion vs. 60% with the halogen lamp).

Comparison with the reference three-component phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO)/Iod/NVK system revealed CH_1 to furnish similar monomer conversions to BAPO in three-component systems. While examining the FRP of trimethylolpropane triacrylate (TMPTA) using the reductive pathway, only CH_1 and CH_2 could furnish acceptable monomer conversions (see Figure 5). If no monomer conversion could be detected with the two-component CH_1 or CH_2/MDEA systems, a conversion of ca. 40 and 35% could be obtained after 300 s of irradiation with a halogen lamp using the three-component CH_1/MDEA/R-Br (0.5%/4%/3% w/w) and CH_2/MDEA/R-Br (0.5%/4%/3% w/w) systems. This conversion could be significantly increased by using a laser diode emitting at 457 nm. In these conditions, a conversion of 60% could be determined using the three-component CH_1/MDEA/R-Br (0.5%/4%/3% w/w) system. Comparison with the reference two-component Eosin-Y/MDEA (0.1%/3% w/w) system (30% conversion after 300 s) revealed the two three-component systems based on CH_1 and CH_2 to outperform the reference system. Considering that cations and radicals are both formed with the three-component CH_1/Iod/NVK system, the elaboration of interpenetrated polymer networks by the concomitant polymerization of TMPTA and EPOX was examined under air. After 1000 s of irradiation at 457 nm with a laser diode, photopolymerization of a TMPTA/EPOX blend (50%/50%) under air furnished tack-free polymers. Using low light intensities (LED@462 nm and a halogen lamp), 30 min. was required to get tack-free coatings.

In 2016, the first natural flavonoid dye, namely quercetin (3,5,7,3′,4′-pentahydroxyflavone), was examined by Versace and coworkers both as a photosensitizer and an antibacterial agent for the design of antibacterial coatings (see Figure 6) [220]. Indeed, an efficient strategy to cause the apoptosis of bacteria consists in producing reactive oxygen species (ROS) that will be capable of degrading cells [221,222,223,224]. Among ROS, singlet oxygen constitutes the best approach to prevent microorganism adhesion and proliferation on any surface. Prior to this work, several photoinitiators of polymerization have been identified as providing antimicrobial properties to coatings such as hydroxyethyl Michler’s ketone [225], rose Bengal [226,227], porphyrins and phthalocyanines [228,229], eosin Y [226,230], toluidine blue [231] or methylene blue [231,232,233]. If these synthetic dyes showed interesting properties, a step further consists in using natural dyes to act as antibacterial agents, which constitutes a major environmental challenge. Quercetin was selected as the dye in this study as this flavonoid is among the most abundant ones in nature [234,235,236,237,238,239]. It can notably be found in numerous fruits and vegetables (onion, lemon, apple, grape, tomato, etc.), different beverages such as tea and red wine and even olive oil [240,241,242].

Quercetin also exhibits antiviral, anti-inflammatory, anti-allergic and antioxidant activities, and this natural compound is also beneficial to limit cancer risks and cardiovascular problems [243,244,245]. Considering that quercetin is responsible for the green color of oak leaves, an absorption extending up to 430 nm was determined in acetonitrile, with an absorption maximum at 370 nm (ε = 19,000 M⁻¹·cm⁻¹). An emission peak was also determined at 535 nm so that a Stokes shift of 8350 cm⁻¹ could be calculated (see Figure 7). This large Stoke shift is indicative of a significant electronic change between the ground state and the excited state. Photolysis experiments performed with the two-component quercetin/Iod1 system revealed the photogeneration of Bronsted acid (H⁺) using rhodamine B as an acid indicator. Quercetin was thus identified as a promising candidate for CP.

Using glycerol triglycidyl ether (GTE) as the monomer and upon irradiation with a Xe lamp (I = 70 mW/cm²), a GTE conversion of 75% could be determined after 1200 s of irradiation using the two-component quercetin/Iod1 (2.5%/4% w/w) system (where Iod1 stands for 4-(2-methylpropyl)phenyl iodonium hexafluorophosphate). Interestingly, the quercetin-based coatings exhibited remarkable thermal stability since a decomposition temperature higher than 375 °C could be determined by thermogravimetric analysis (TGA). Examination of the fluorescence of the polymer films revealed the presence of remaining quercetin that could be advantageously used to generate reactive oxygen species upon light activation. Antibacterial properties were examined with Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus). Noticeably, quercetin-based coatings only exhibited antiproliferation properties for Gram-positive bacteria. In the case of E. coli, the development of bacteria was neither inhibited by light nor affected by the presence of quercetin within the polymer film. On the contrary, a total death of Gram-positive bacteria (S. aureus) was determined after 2 h of irradiation. The insensitivity of Gram-negative bacteria to singlet oxygen was assigned to the presence of lipopolysaccharides in the cell wall offering some protection against exogenous agents.

More recently, quercitin and morin, which are two isomers of position, were compared for their photoinitiating abilities during the FRP of a BisGMA/TEGDMA (1/1) blend (where BisGMA and TEGDMA stand for bisphenol A-glycidyl methacrylate and triethylene glycol dimethacrylate, respectively) or TMPTA, the cationic polymerization of tri(ethylene glycol) divinyl ether (DVE-3), and the polymerization thiol-ene of a DVE-3/trimethylolpropane tris(3-mercaptopropionate) (Trithiol) (1/1) blend or a 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (Trione)/Trithiol (1/1) blend (see Figure 8) [246]. Morin is a natural compound that can be extracted from Osage orange and is well known to exert antioxidant, anti-inflammatory and anti-carcinogenic effects [247,248,249,250].

From the absorption viewpoint and despite the similarity of structures between quercetin and morin, totally different absorption spectra were determined in ethanol. If no absorption peaks could be detected for morin, an absorption peak could be clearly detected for quercetin (λ_max = 372 nm, ε = 23,300 M⁻¹·cm⁻¹) (see Figure 9). In addition, the absorption spectrum of morin extends up to 575 nm so that polymerization experiments could be carried out at 374, 394, 410 and 445 nm (see

Table 1. Absorption properties of morin and quercetin in ethanol at different wavelengths.

	λmax (nm)	εmax (M−1·cm−1)	ε374nm (M−1·cm−1)	ε394nm (M−1·cm−1)	ε410nm (M−1·cm−1)	ε445nm (M−1·cm−1)
morin	-	-	5700	4300	3360	1560
quercetin	372	23,300	23,200	13,960	3260	360

).

FRP experiments performed with morin and quercetin revealed the two-component morin/Iod2 system to be unable to initiate the FRP of the BisGMA/TEGDMA (70/30 w/w) blend upon irradiation at 410 and 445 nm. Conversely, a conversion of 26% was obtained with the quercetin/Iod2 system upon excitation at 410 nm (I = 110 mW/cm²) for 300 s. No polymerization was detected at 445 nm with quercetin due to the lack of absorption. A significant improvement in the monomer conversion was obtained by using the three-component quercetin/Iod2/N-phenylglycine (NPG) (0.5%/2%/2% w/w/w) system. A conversion of 60% at 410 nm and 57% at 445 nm. These values are higher than those obtained with the reference NPG/Iod2 system (26% at 410 nm, 47% at 445 nm). While examining the cationic polymerization (CP) of DVE-3, the best monomer conversion was obtained at 410 nm with the two-component quercetin/Iod2 (0.5%/2% w/w) system (89% after 300 s of irradiation) vs. 78% with the morin/Iod2 system. Parallel to this, an induction time of 25 s was determined with the quercetin-based system contrarily to 110 s with morin. Finally, the two-component quercetin/Iod2 (0.5%/2%, w/w) system was examined for the thiol-ene polymerization of the DVE-3/Trithiol (1/1) and Trione/Trithiol (1/1) blends (see Figure 10).

Interestingly, DVE-3 was entirely polymerized in the presence of Trithiol for which a trithiol conversion of only 51% was detected. A shorter induction time was determined for DVE-3, reduced to only 8 s contrarily to 25 s for the homopolymerization of DVE-3. By replacing DVE-3 with Trione, a similar conversion was obtained for Trione and Trithiol, around 80% for the two monomers (see Figure 10b). To support the unequal monomer conversion determined during the thiol-ene polymerization of a DVE-3/Trithiol blend, the occurrence of a homopolymerization of DVE-3 concomitant to the thiol-ene polymerization was suggested. Conversely, homopolymerization of Trione is difficult, avoiding this undesired reaction [251,252,253].

In 2018, another flavonol, i.e., 3-hydroxyflavone (3HF) was used in combination with an amino acid, namely N-phenylglycine (NPG), to produce free radicals upon irradiation at 385, 405 and 477 nm (see Figure 11) [254].

From the absorption viewpoint, the absorption maximum of 3HF was blue-shifted by ca. 20 nm compared to quercetin (350 nm vs. 370 nm for 3HF). Only low molar extinction coefficients could be determined in the visible range, ranging between ε ~ 250 M⁻¹·cm⁻¹ at 405 nm and ε ~ 40 M⁻¹·cm⁻¹ at 470 nm. Conversely, at 350 nm, a molar extinction coefficient of ε~14,000 M⁻¹·cm⁻¹ could be calculated. The high reactivity of 3HF was evidenced when combined with NPG. Thus, using the 3HF/NPG (0.5%/1% w/w) couple, a conversion as high as 71% could be determined during the FRP of a BisGMA/TEGDMA (1/1) blend (where BisGMA and TEGDMA stand for bisphenol A-glycidyl methacrylate and triethylene glycol dimethacrylate, respectively) (see

Table 2. Monomer conversions obtained during the FRP and CP experiments using different photoinitiating systems.

Resin/PIS	Conditions	Conversion (%) at 100 s	Light Source
BisGMA/TEGDMA	3HF/Iod3 (0.5%/1% w/w) 3HF/NPG (0.5%/1% w/w) 3HF/NPG (0.5%/1% w/w) 3HF/Iod3/NPG (0.5%/1%/1% w/w/w) 3HF/Iod3/NPG (0.5%/1%/1% w/w/w) 3HF/Iod3/EDB (0.5%/1%/1% w/w/w)	19 71 48 79 65 17	LED@405 nm LED@405 nm LED@477 nm LED@405 nm LED@477 nm LED@385 nm
EPOX	3HF/Iod3/EDB (0.5%/1%/1% w/w/w)	55	LED@385 nm

) upon irradiation at 405 nm with an LED (I = 110 mW/cm²).

This value is higher than that obtained with the reference Iod3/EDB (1%/1% w/w) system (68% after 100 s of irradiation at 405 nm) [255]. If an excellent monomer conversion could be obtained with the reductive pathway, a different situation was found using the oxidative one. Thus, only a low monomer conversion of 19% was obtained with the two-component 3HF/Iod3 (0.5%/1% w/w) system upon irradiation at 405 nm. By using the three-component 3HF/Iod3/NPG (0.5%/1%/1% w/w/w) system, high monomer conversions could be determined at 405 and 477 nm (79 and 65%, respectively). In particular, the monomer conversion of 65% obtained at 477 nm is remarkable, considering the weak molar extinction coefficient of 3HF at 477 nm. The crucial role of the amine in the monomer conversion was evidenced by replacing NPG with ethyl 4-(dimethylamino)benzoate (EDB). In this case, the conversion was reduced to only 17%. The difference in reactivity for the three-component system based on EDB and NPG can be ascribed to the decarboxylation reaction occurring with NPG, avoiding back electron transfer [256,257]. Upon irradiation at 385 nm, the CP of EPOX furnished the high conversion of 55% after 100 s of irradiation with the three-component 3HF/Iod3/EDB (0.5%/1%/1% w/w/w) system. For comparison, only an EPOX conversion of 15% was obtained with the reference BAPO/Iod3 (0.5%/1% w/w) system in the same conditions. Considering the high performance of the different photoinitiating systems designed with 3HF as a photosensitizer, interest in these photoinitiating systems was demonstrated during direct laser writing experiments (see Figure 12) and during the design of composites (see Figure 13). In the case of the direct laser writing experiments, 3D patterns exhibiting an excellent spatial resolution could be evidenced.

Composites were obtained by impregnating a BisGMA/TEGDMA (70%/30%) resin with glass fibers (50% glass fiber/50% resin). Using the 3HF/NPG combination, composites could be fully cured in only one pass (2 m/min belt speed) upon irradiation with an LED emitting at 395 nm.

To support the high efficiency of the 3HF/NPG and 3HF/Iod3 systems, the following mechanisms could be determined by combining steady-state photolysis and fluorescence quenching experiments, ESR and electrochemistry (see Equations (r6)–(r12)).

3HF → ^1,33HF (hν)

(r6)

^1,33HF+ NPG → (3HF-H)^● + NPG_(-H)^●

(r7)

NPG_(-H)^● → NPG_(-H;-CO2)^●

(r8)

^1,33HF + Iod → 3HF^●+ + Ar₂I^● → Ar^●

(r9)

NPG + Iod ↔ [NPG- Iod]_CTC

(r10)

[NPG- Iod]_CTC →→→ Ar^● (hν)

(r11)

NPG_(-H;-CO2)^● + Ar₂I⁺ → NPG_(-H;-CO2)⁺ + Ar^● + ArI

(r12)

In 2020, 3HF was revisited by Wang and coworkers in a series of seven flavonols differing in the substitution pattern (see Figure 14) [258]. The influence of halogens on the photoinitiating ability of flavonols could be examined, these groups being introduced at different positions on the flavonol core.

Noticeably, the absorption of the different dyes was not significantly affected by the halogen substitution, and absorption in the 280–450 nm range could be determined for all dyes. Thus, absorption maxima between 342 nm for 3HF and 3HF-B-F and 349 nm for 3HF-A-F were determined in methanol (see Figure 15 and

Table 3. Optical characteristics of different 3HF derivatives in methanol.

3HF	λmax (nm)	εmax (M−1·cm−1)	ε385 nm (M−1·cm−1)
3HF-H	342	17,800	1900
3HF-B-CH3	347	14,700	2600
3HF-B-F	342	16,200	1850
3HF-B-Cl	345	19,900	2100
3HF-B-Br	346	20,500	2250
3HF-A-F	347	16,900	2400
3HF-A-Br	349	13,800	3200

). Examination of the fluorescence properties of the different 3HF revealed the presence of two emission peaks, the first one at ca. 450 nm, corresponding to the Franck–Condon excited state, and the second one at 550 nm, corresponding to the emission of the tautomer formed by ESIPT. In the case of 3HF-A-F and 3HF-A-Br, emission peaks at 450 nm could not be detected for these tow dyes, attributable to a fast ESIPT process.

Based on their absorption spectra, photopolymerization experiments were carried out at 385 nm. Photolysis experiments performed at 385 nm for the two-component dye/triethanolamine (TEOA) and dye/Iod4 systems revealed the photolysis rate to be higher for the two-component dye/Iod4 systems. The different dyes are thus easier to oxidize than to reduce. Fluorescence quenching experiments performed in methanol revealed the fluorescence of the ESIPT tautomer to be drastically reduced by increasing the concentration of Iod4 and TEOA, evidencing the reaction with the additives to be faster than the ESIPT process. In the case of the two-component dye/Iod4 systems, the formation of three different 3HF-based toluene adducts resulting from the addition of the toluene radical (formed by photoinduced electron transfer between the excited dye and the iodonium salt) to the 3HF dyes was detected by mass spectrometry.

Photopolymerization experiments were carried out on a difunctional monomer, namely tripropylene glycol diacrylate (TPGDA). Among the four amines tested for the two-component dye/amine systems (TEOA, morpholine (MP), triethylamine (TEA) and NPG) and irrespective of the 3HF derivatives examined, the highest monomer conversions were obtained with TEOA, whereas the lowest conversions were determined with NPG. Using TEOA as the amine, the influence of the substitution pattern on the photoinitiating ability could be examined. Thus, it was found that the introduction of halogens on the pendant phenyl ring was favorable for monomer conversions compared to the flavonol core. As shown in Figure 16b, higher monomer conversions were obtained with 3HF-B-F and 3HF-B-Br compared to their 3HF-A-F and 3HF-A-Br analogs. Except for 3HF-B-CH₃ and 3HF-A-Br, which furnished monomer conversions around 70% after 180 s of irradiation, all the other dyes furnished similar monomer conversions, peaking at 80%. While examining the series of flavonols substituted with different groups on the pendant phenyl ring, the introduction of electron-donating groups (such as 3HF-B-CH₃) reduced the monomer conversion and the polymerization rate, whereas the introduction of electron-withdrawing groups improved both the conversion and the polymerization rates. A different trend was found for the dye/Iod3 system. Using the dye/Iod4 (0.2%/1% w/w) system, the highest polymerization rate was obtained with 3HF-B-CH₃, followed by 3HF-B-Cl, 3HF-B-Br, 3HF-B-F and 3HF. If different polymerization rates were determined using Iod4 as the co-initiator, similar conversions were obtained after 120 s of irradiation at 385 nm. A comparison with identical halogen atoms revealed the brominated derivatives to be more reactive than the fluorinated ones, and this trend of reactivity is comparable to that determined with the two-component dye/TEOA systems.

In 2021, the same group developed an innovative strategy for the design of photoinitiating systems based on flavonols. Considering that the presence of the OH group is responsible for the ESIPT process which is a competitive process to photoinitiation, this intramolecular proton transfer could be efficiently avoided by etherifying or esterifying the OH group with benzoyl or benzenesulfonyl groups [259]. Using this strategy, the ESIPT process could be suppressed, and the design of highly efficient Type I photoinitiators became possible (see Figure 17). In particular, the triplet lifetime could be increased, and a reduction in the fluorescence intensity was jointly observed, resulting in an improvement in the photopolymerization efficiency.

Noticeably, 3HF-S and 3HF-C could act as efficient monocomponent systems during the FRP of TPGDA but also in combination with TEOA or Iod4 upon irradiation at 405 and at 460 nm with LEDs. Photopolymerization results also revealed the polymerization efficiency of 3HF-S to be higher than that of 3HF-C and 3HF-OH. In particular, the polymerization efficiency of 3HF-S could be greatly improved by decreasing the photoinitiator content, 3HF-S exhibiting aggregation-induced emission (AIE) properties adversely affecting its polymerization efficiency. From the absorption viewpoint, the presence of the triphenylamine moiety was the key element to redshift the absorption of 3HF-C, 3HF-S and 3HF-OH compared to those previously reported by Lalevée and coworkers [178]. Thus, absorption maxima located at 384, 386 and 396 nm were determined for 3HF-C, 3HF-S and 3HF-OH (see Figure 18). Interestingly, the broad absorption band extending up to 480 nm enabled the polymerization tests to be carried out at 405 nm but also at a longer wavelength, namely 460 nm. The solubility of photoinitiators is an important parameter governing the reactivity. Indeed, a low solubility in monomers will adversely affect the polymerization efficiency. As shown in

Table 4. Solubility of different flavonols in various solvents at room temperature (g/100 mL).

	Toluene	Ethyl Acetate	THF	CH3OH	CH3CN	DMSO	CH3OH:H2O (1:1)	CH3CN:H2O (1:1)	DMSO:H2O (1:1)
3HF-OH	0.9	2.0	2.0	1.4	0.8	3.5	0.5	0.7	0.7
3HF-S	8.0	5.0	>10	1.7	1.8	>10	0.8	1.0.	2.0
3HF-C	6.4	3.9	8.2	1.5	1.3	>10	0.6	0.8	1.6

, 3HF-S exhibited the highest solubility of the three dyes. In particular, compared to 3HF-OH, an improvement in the solubility was determined for the OH-substituted dyes, namely 3HF-C and 3HF-S. Among these dyes, 3HF-S showed the best solubility in aqueous solutions, favorable to polymerization processes used in green conditions. The photoacid generation abilities of 3HF–S and 3HF–C were also examined in acetonitrile using Rhodamine B as an acid indicator upon irradiation with an LED at 405 nm. Interestingly, 3HF-S exhibited the best photoacid generation ability (ϕ_H+ = 0.2), significantly higher than that of 3HF-C for which a value of only 0.002 was determined. This is directly related to the fact that benzenesulfonic acid is generated with 3HF-S after photocleavage, contrary to benzoic acid in the case of 3HF-C.

FRP experiments of TPGDA performed at 405 and 460 nm revealed the photoinitiating ability of 3HF-C and 3HF-S to outperform that of the reference 3HF-OH. Using 3HF-S as a monocomponent system at 405 nm, a photoinitiator concentration as low as 0.125 wt% could be used while maintaining a high monomer conversion. Eighty-percent conversions could thus be obtained after 180 s of irradiation at 405 nm using 3HF-S. Conversely, no monomer conversion could be detected with 3HF-OH when used as a monocomponent system. The use of 3HF-S in a two-component system enabled drastic shortening of the reaction time using additives such as triethanolamine (TEOA) or triethylamine (TEA) as the amines. By using TEA and TOEA, 80% conversions could be obtained within 20 s. A threefold elongation of the reaction time was determined by using MP and EDB as the amines. Finally, by using NPG as the additive for 3HF-S, 180 s were required to get 80% TPGDA conversion (see Figure 19). Comparisons of the TPGDA conversions obtained with camphorquinone (CQ) in one- and two-component systems revealed the 3HF-S-based systems to outperform those prepared with camphorquinone, irrespective of the irradiation wavelength (405 nm or 460 nm). 3HFs were also used for the sensitization of Iod4 (see Figure 20). In this case, short reaction times (i.e., 20 s) were determined with all systems, evidencing that 3HFs were easier to oxidize than to reduce. Conversions ranging between 85 and 90% could be obtained within 30 s.

Considering the good solubility of 3HF-S in water, the polymerization of hydrogels could be performed at 405 nm. Using PEGDA (70% in water), an excellent monomer conversion could be determined by using a photoinitiator content as low as 0.042 wt%. After 60 s of irradiation at 405 nm, final conversions of 33, 75 and 85% were determined by using 3HF–S (0.042 wt%), 3HF-S/TEOA (0.042%/3% w/w) and 3HF-S/Iod4 (0.042%/3% w/w), respectively (see Figure 21).

By ESR spin-trapping experiments, the photochemical mechanism involved with the one- and two-component systems could be determined, and the results are summarized in Scheme 1.

Examination of the cytotoxicity of the polymer films prepared with CQ, 3HF-S and 3HF-C revealed the cell viability of HeLa cells to be higher than 80%, whereas cell viability lower than 80% was determined for polymers prepared with 3HF-OH. Considering that sulfonate derivatives can outperform all other derivatives, another sulfonate derivative, i.e., 3HF-F, was examined, bearing a pendant carbazoyl group (see Figure 22) [260]. Using this high-performance photoinitiator in three-component 3HF-F/Iod4/TEOA (0.5%/2%/1% w/w/w) systems, 4D-printed objects could be designed and synthesized. As shown in Figure 23, the presence of the carbazoyl moiety was crucial in order to get a significant absorption in the visible range. Indeed, the reference compound, namely 3HF-A, bearing a tolyl group, only exhibited UV-centered absorption, evidencing the role of the carbazole moiety in the absorption properties. In particular, 4D-printed objects could be prepared using a hydrophilic monomer, namely PEGDA, enabling the use of a sequence of hydration/dehydration for designing shape memory objects (snowflake and airplane) (see Figure 24).

It has to be noticed that this strategy (hydration/dehydration) has been extensively used by Lalevée and coworkers for designing 4D-printed objects by using chalcones as the chromophores [9,127,261,262].

In 2023, an interesting strategy was developed for the design of Type I photoinitiators, consisting in introducing a camphorquinone derivative on the photocleavable side [263]. Five derivatives were investigated, differing by the substitution of the flavonol core (see Figure 25).

The choice of camphorsulfonic acid as the additional chromophore was motivated by the different advantages this photoinitiator exhibits such as low sensitivity to oxygen, good water solubility and low toxicity [264,265]. From the absorption viewpoint, almost similar absorption maxima were determined for the different dyes, except for MeO-HF-Cas bearing an electron donating group and for which a redshifted absorption was determined. Thus, absorption maxima located at 294, 295, 296, 300 and 313 nm were respectively determined for H-HF-Cas, F-HF-Cas, Br-HF-Cas, Me-HF-Cas and MeO-HF-Cas (see Figure 26 and

Table 5. Optical characteristics of different flavonol camphorsulfonates and quantum yield of photoacid generation in acetonitrile.

Compounds	λmax (nm)	εmax (M−1·cm−1)	ε365 nm (M−1·cm−1)	λem1 (nm)	λem1 (nm)	Stokes Shift (cm−1)	ϕ(H+) a
H-HF-Cas	294	13,150	106	378	531	5235	0.06
Me-HF-Cas	300	16,000	34	381	530	5347	0.31
F-HF-Cas	295	12,100	285	377	528	5319	0.22
Br-HF-Cas	296	14,850	189	382	535	5154	0.39
MeO-HF-Cas	313	18,200	395	396	532	5494	0.29

^a quantum efficiency of photoacid generation.

).

Examination of their fluorescence properties also revealed that the different dyes exhibit a dual emission, with an emission in the UV range and a second one in the visible range. Even if the ESIPT effect is hindered by the substitution of the OH group at the C₃-position, the intramolecular charge transfer still exists, with the presence of tautomers in the excited state, as shown in Scheme 2. Considering the similarity of emission around 530 nm, the low contribution of the aromatic ring on the fluorescence de-excitation process was determined.

Photolysis experiments performed in acetonitrile confirmed the Type I behavior of the different flavonol camphorsulfonates. Upon irradiation at 365 nm, photocleavage of flavonols can clearly be evidenced by NMR. Investigation of the photolysis products by mass spectrometry enabled us to confirm the formation of camphorsulfonic acid and the corresponding flavonol due to water traces in acetonitrile (see Scheme 3). Flavonol camphorsulfonates can thus behave as photoacid generators [266].

The highest photoacid generation quantum yield was determined for Br-HF-Cas bearing a halogen atom upon excitation at 365 nm (see Table 5). In this context, the cationic polymerization of DVE-3 was examined with the different photoinitiators. Upon excitation at 365 nm, only low monomer conversions were obtained using a 1 wt% photoinitiator, consistent with the low photoacid generation ability of camphorsulfonic acid and the inability of the flavonol moiety to initiate a cationic polymerization process. By using flavonol camphorsulfonates as monocomponent systems (1 wt%), the free radical polymerization of PEGDA could be efficiently initiated, and conversions of 80, 96, 91, 88 and 67% were respectively obtained with Me-HF-Cas, F-HF-Cas, Br-HF-Cas, MeO-HF-Cas and H-HF-Cas. By using the different flavonol camphorsulfonates as photosensitizers for Iod4, a slight improvement in the PEGDA conversion could be detected with the two-component dye/Iod4 (0.1%/0.1% w/w) systems. Thus, PEGDA conversions of 90, 84, 86 and 85% could be obtained after 120 s of irradiation at 365 nm using MeO-HF-Cas, Me-HF-Cas, Br-HF-Cas, F-HF-Cas and Me-HF-Cas.

2.2. Flavones

Flavonoids are composed of a large group of polyphenolic dyes, and flavone is one of them. Flavone was used as early as 2016 for the photoinduced controlled/“living” polymerization of MMA [267]. Using an LED emitting in the 350–440 nm range, linear PMMA polymers with a polydispersity index (PDI) ranging between 1.34 and 1.42 could be prepared by photopolymerization. Even if the approach is promising, the control of the polymerization process is still lower than what can be currently obtained by thermal polymerization. Photopolymerization is more classically used for the polymerization of multifunctional monomers, and this point was only recently examined by Lalevée and coworkers for the FRP of a dental resin, i.e., a BisGMA/TEGDMA 70/30 blend (see Figure 27) [268]. Different flavones were investigated in this work, all these derivatives being natural products. Notably, chrysin can be found in the flowers of blue passionflower (Passiflora caerulea) and myricetin in various edible plants such as onion leaves, Semambu leaves, bird chili, black tea, papaya shoots and guava [269,270,271,272,273,274,275,276]. As specificities, these dyes are also (poly)phenolic dyes, and phenols are extensively used as stabilizers for monomers [277,278]. In addition, efficient polymerization processes could be performed with these structures.

As shown in Figure 28, all dyes exhibit UV-centered absorption, except for myricetin for which a redshift of the absorption was detected for this dye. It can be assigned to the presence of the numerous OH groups acting as electron-withdrawing groups, improving the electronic delocalization existing in this structure. An absorption extending up to 450 nm could be determined for Myricetin, whereas almost no absorption could be detected anymore for the other dyes. The efficiency of the polymerization process is also strongly related to the solubility of the photosensitizers in resins. This point was notably examined in TMPTA and BisGMA/TEGDMA. Noticeably, the increase in the OH groups per dye adversely affected the solubility of dyes. Thus, the worse solubilities were determined for Chrysin and Myricetin (see

Table 6. Absorption properties of dyes at 405 nm in methanol and monomers.

	F	6HF	7HF	Chrysin	Myricetin
Absorption properties at 405 nm (M−1·cm−1) in methanol	~70	~70	~427	~336	4800
Solubility in BisGMA/TEGDMA	+	+	+	-	-
Solubility in TMPTA	+	+	+	-	-

).

Examination of their photoinitiating abilities during the FRP of TMPTA in thin films revealed the two-component dye/Iod3 system to be inefficient for promoting any polymerization. Conversely, by using the two-component dye/NPG system and the three-component dye/Iod3/NPG system, a monomer conversion could be detected with the different dyes. Among them, 6HF furnished good monomer conversions both at 385 and 405 nm, as shown in Figure 29. The highest monomer conversion was obtained at 385 nm, using the three-component 6HF/Iod3/NPG (0.5%/1%/1% w/w/w) system, resulting from the perfect adequation between the emission of the LED and the absorption of the chromophore. At 405 nm, a reduction in the monomer conversion by ca. 10% could be determined, consistent with a decrease in the molar extinction coefficient. Noticeably, an important effect of the additives could be evidenced. Thus, by using EDB as the amine in three-component systems, a severe reduction in the monomer conversion could be determined, compared to that obtained with NPG. This was assigned to the strong oxygen inhibition competing with initiation [26,228,279,280,281,282,283]. This point was evidenced by using 4-dppba as the additive. Indeed, phosphines are well known to convert the unreactive peroxyl radicals as initiating alkoxyl radicals [279,284,285]. Using the three-component 6HF/Iod3/4-dppba (0.5%/1%/1% w/w/w) system at 385 nm, a conversion comparable to that obtained with the three-component 6HF/Iod3/NPG (0.5%/1%/1% w/w/w) system could be obtained.

The high reactivity of the three-component 6HF/Iod3/NPG (0.5%/1%/1% w/w/w) system was confirmed during the FRP experiments performed on another resin, i.e., a BisGMA/TEGDMA blend. Surprisingly, if 3-hydroxyflavone 3HF previously studied proved to be an efficient photoinitiator for promoting the CP of EPOX at 385 nm, only a low monomer conversion could be obtained with the two-component 6-hydroxyflavone/Iod3 (0.5%/1% w/w) (40% conversion after 800 s of irradiation at 385 nm vs. 55% for the three-component 3HF/Iod3/EDB (0.5%/1%/1% w/w/w)) system, evidencing the strong influence of the substitution pattern on the overall reactivity of the photoinitiating system. In addition, the high monomer conversion obtained during the FRP of BisGMA/TEGDMA paves the way for dental applications of flavones [286].

2.3. Proanthocyanidins

Proanthocyanidins are flavonoids that can be found in black, red and purple rice, in other strongly colored fruits and vegetables and also in cereals such as blueberries, grapes, red cabbages and purple sweet potatoes [287,288,289,290,291,292,293]. Due to their high molar extinction coefficients, proanthocyanidins were thus ideal candidates for photopolymerization performed under visible light. In 2021, Wang and coworkers examined a series of proanthocyanidins substituted with methacrylate groups (see Figure 30) [294,295].

By the presence of methacrylate groups, polymerizable crosslinkers could be obtained, and the resulting polymers could be advantageously used for collagen stabilization in 2-hydroxyethylmethacrylate (HEMA)-based dental adhesive systems. In particular, an improvement in the longevity of the dental restoration could be evidenced by using these modified proanthocyanins.

3. Conclusions

Flavonoids are composed of numerous families of dyes, and only a few of them have been examined to date in photopolymerization. Even if more than 6000 flavonoids have been identified in nature, the scarcity of these structures renders their uses as photoinitiators of polymerization relatively improbable. In addition, for the most abundant ones, polymerization results obtained with these structures are remarkable, including excellent biocompatibility, the possibility to perform polymerization experiments at low photoinitiator content and the design of antibacterial coatings. At present, flavonoids could efficiently promote the FRP of acrylates or the CP of epoxides by the use of two- and three-component systems. To expend the scope of applications of flavonoids to photopolymerization, several points can be examined:

• At present, no monocomponent systems have been developed. In addition, by chemical modification, the covalent linkage of hydrogen donors or iodonium salts could contribute to simplifying the composition of the photocurable resins.
• Polymerization in water has only been scarcely examined.
• The design of Type I photoinitiators with the development of structures such as two oxime esters or glyoxylates should be explored.

Future works will consist of developing and exemplifying these different research topics.