This is the accepted version of the journal article: Faggi, Enrico; Aguilera-Sigalat, Jordi (CUANTUM Medical Cosmetics S.L.); Sáez, Rubén (CUANTUM Medical Cosmetics S.L.); [et al.]. «Wavelength- Tunable Light-Induced Polymerization of Cyanoacrylates Using Photogenerated Amines». Macromolecules, Vol. 52, Issue 6 (March 2019), p. 2329-2339. DOI 10.1021/acs.macromol.8b02318 This version is available at https://ddd.uab.cat/record/266068 under the terms of the license Wavelength-Tunable Light-Induced Polymerization of Cyanoacrylates Using Photogenerated Amines Enrico Faggi,a Jordi Aguilera,b Rubén Sáez,b Ferran Pujol,b Jordi Marquet,a Jordi Hernando,a,* and Rosa María Sebastiána,* a Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain b CUANTUM Medical Cosmetics S.L., 08193 Cerdanyola del Vallès, Spain KEYWORDS: cyanoacrylates, photopolymerization, photocleavable amine protection group ABSTRACT Cyanoacrylate photopolymerization has already been described, but it generally requires the use of organometallic photoinitiators and highly reactive monomers, which often leads to photoinitiator-monomer mixtures with limited stability. In this work we report a method to tackle these limitations, which relies on the use of amines bearing photoremovable protecting groups as light-responsive nucleophilic cyanoacrylate initiators. By exploiting the versatility of amine 1 photorelease strategies, we have developed a series of all-organic initiators that: (a) enable fast, on demand photocuring of commercial formulations of various cyanoacrylates, including less reactive, biologically-relevant long alkyl chain monomers; (b) show wavelength-tunability along the UV-visible spectrum and good thermal stability in the dark; (c) lead to polymeric materials with excellent adhesive behavior. Because of this combination of properties, photogenerated amines appear as ideal candidates to bring cyanoacrylate photopolymerization into real application, especially in the biomedical field. INTRODUCTION Cyanoacrylates (CAs) are low-viscosity, fast-acting liquid adhesives with high bonding strength to diverse materials upon polymerization (e.g. glass, paper, wood, plastic, textile).1,2 As such, they have been widely applied as general adhesives for industrial and consumer markets since first CA- based "super glues" were commercially introduced in the 1950s. Nowadays, their use has spread to the medical, veterinary and cosmetic fields, where CAs are employed as bio-compatible adhesives or sealants for replacing sutures and staples,3 in dentistry,4,5 and for gluing fake nails or eyelashes extension.6 In addition, CAs are currently finding application in other emerging areas, such as in drug-delivery systems,7,8 3D printing processes,9,10 high-resolution lithography,11 and forensic sciences.12,13 Although free radical initiation has also been described,14 CA polymerization is normally triggered by anionic or neutral nucleophiles.1-2 Industrially, these nucleophiles can be sprayed on the surfaces to be glued before cyanoacrylate is applied, thus greatly enhancing the curing rate.1-2 However, this is not possible in many other cases (e.g. wound closure), where the polymerization 2 rate is ultimately limited by the concentration of naturally occurring activating nucleophiles. An alternative approach to minimize the adhesive setting time of CAs would be light-induced polymerization, especially for long alkyl chain monomers (e.g. octyl 2-cyanoacrylate), which are less reactive but possess superior properties for many applications (i.e. lower toxicity, and higher stability, viscosity and flexibility).1-2 More importantly, photopolymerization would enable spatial and temporal control of CA adhesives using light as an external stimulus, which should not only ameliorate their performance in current applications but also open new avenues for the use of cyanoacrylates. Unfortunately, while this is a very popular strategy extensively applied to radical and cationic polymerization reactions, much less progress has so far been achieved in the field of light-induced anionic polymerization, mainly due to the need for further development of anionic (or nucleophilic) photoinitiators.15-18 Actually, only a very limited number of photoinitators have been described to promote CA light-induced polymerization, which essentially function for very reactive, short alkyl chain cyanoacrylates (i.e. methyl 2-cyanoacrylate and ethyl 2-cyanoacrylate). Most of these photoinitiators consist of organometallic compounds such as chromium,19,20 platinum21 and tungsten20 complexes as well as metallocenes,22-25 which generate anionic or neutral nucleophiles via ligand substitution reactions upon irradiation. Reports of all-organic photoinitiators for CA polymerization are even more scarce (pyridinium26 and phosphonium27 salts, and crystal violet leuconitrile and malachite green leucohydroxide28), and none of them were tested in neat cyanoacrylate, since dilution in inert solvents was needed. In view of these precedents, the preparation of metal-free photoinitiators that could be directly used in commercial formulations of more biologically-relevant, long alkyl chain cyanoacrylates is required, especially aiming to bring CA photopolymerization into real application in the biomedical field. In addition, wavelength 3 tunability of the latent photoinitiators would be highly desired, thus allowing the most appropriate excitation wavelength to be selected in every case. To address all these challenges at once, in this work we propose the use of photogenerated amines for CA polymerization (Scheme 1). Our strategy relies on two core principles. First, the well-known activity of free amines as nucleophilic activators of cyanoacrylate polymerization.1- 2,29 Second, the development of a plethora of photoremovable protecting groups (PG) during the last years that enable the light-induced release of amines with a wide range of irradiation wavelengths, expanding from the UV to the visible and even near-infrared regions.30 Scheme 1. Strategy proposed in this work for the light-induced polymerization of cyanoacrylates based on photoreleasable amines. 4 RESULTS AND DISCUSSION Design and synthesis of photoinitiators. Photoreleasable amines have already been used in light- induced polymerization processes,31 either as nucleophiles that directly trigger polymer curing26,32,33 or as bases for activating the actual initiator of the reaction.34-37 However, owing to the high reactivity of CAs, care has to be taken in this case when selecting the photoremovable group for amine protection, since it should not contain nucleophilic centers capable to initiate cyanoacrylate polymerization in the dark prior to light irradiation. According to this design concept and aiming to develop an extended palette of photoinitiators for CA polymerization, we explored herein three different, well-established PGs for primary and secondary amines based on a carbamate linker: (a) the UV-responding nitrophenylpropyloxycarbonyl group (NPPOC), initially introduced for nucleotide and nucleoside chemistry38 and already exploited for the preparation of photocatalysts for thiol-Michael addition reactions with acrylates;39 (b) the violet light-absorbing benzothiophene imino-phenylacetonitrile (BTIPA) group, which was developed for peptide synthesis;40 (c) a green light-absorbing, diiodated boron-dipyrromethene (BODIPY) derivative, which was recently derived to enable efficient photorelease of a variety of functional groups,41 including amines.42 Based on these light-responsive groups, we designed carbamates NPPOC- DEA, BTIPA-DEA, and BODIPY-DEA (Scheme 2), which should release a secondary amine (diethylamine, DEA) upon irradiation with distinct illumination sources. DEA was chosen because it is a powerful initiator of CA polymerization that has been described to activate cyanoacrylate formulations for biomedical applications.43 Indeed, when a droplet of DEA was added to any of the liquid CA monomers investigated in this work, very fast, local polymerization was observed. 5 Scheme 2. Synthesis of photoinitiators NPPOC-DEA, BTIPA-DEA, and BODIPY-DEA. Scheme 2 summarizes the synthetic procedures applied to prepare the three photoinitiators used. NPPOC-DEA (as a racemic mixture) was synthesized in only one step and in high yield (90%) by simple reaction between 2-(2-nitrophenyl)propyl chloroformate (1) and free DEA in the presence of DIPEA, as already described.39 BTIPA-DEA was prepared in 4 steps and 9% yield starting from commercially available 3-bromothianaphthalene (2). First, key intermediate 3 was obtained following a previously reported procedure,40 and by reaction with diethylcarbamoyl chloride, the target photoinitiator was afforded. BODIPY-DEA was synthesized through a 5-steps procedure from 2,4-dimethyl-1H-pyrrole (4), which was converted into BODIPY derivative 5 as already described.42 From this compound, carbamate 6 was prepared by reaction with DEA in the presence of pyridine and, upon posterior electrophilic iodination with ICl and ZnO, BODIPY- 6 DEA was finally obtained. The overall yield for the preparation of this compound was rather low (5%) due to both the cumbersome purification of the low-solubility BODIPY derivatives obtained along the synthesis and the limited efficiency of the first step in our hands. HPLC analysis of the photoinitiators prepared demonstrated that all of them were obtained with high purity (ca. 99% or higher). Photochemical characterization of NPPOC-DEA, BTIPA-DEA and BODIPY-DEA. Figure 1a depicts the absorption spectra of the three photoinitiators prepared in acetonitrile. Clearly, they absorb in different spectral regions (abs,max = 254, 415 and 550 nm, Table 1), which should allow DEA photorelease using distinct irradiation wavelengths: UV (NPPOC-DEA), violet (BTIPA- DEA) and green (BODIPY-DEA) light. In the case of UV excitation, it cannot be overlooked that CAs present non negligible absorption at ca.  < 350 (Figure S1). For this reason and the broad absorption tail shown by NPPOC-DEA, this compound was not irradiated at its absorption maximum but at significantly lower energies (exc = 355 nm). On the contrary, illumination of visible-light absorbing photoinitiators BTIPA-DEA and BODIPY-DEA could be conducted at wavelengths closer to their spectral maxima (exc = 405 and 532 nm, respectively). 7 Figure 1. (a) Absorption spectra of NPPOC-DEA (c = 1.60·10-4 M), BTIPA-DEA (c = 4.76·10- 5 M), and BODIPY-DEA (c = 1.68·10-5 M) in acetonitrile. (b) Variation of the absorption spectra of BTIPA-DEA (c = 4.76·10-5 M) in acetonitrile upon continuous irradiation at exc = 405 nm (power = 2.8 mW). Spectra recorded every 60 s for a total irradiation (tirr) of 600 s. The arrows show the spectral changes in time. 8 Table 1. Photochemical properties of NPPOC-DEA, BTIPA-DEA and BODIPY-DEAa λmax λexc Compound abs,max (nm) ɛλabs max (M-1 cm-1) ph b,c ph ɛabs (M-1 cm-1) ph ɛabs (M-1 cm-1)c NPPOC-DEA 254 4990 0.10 499 47 BTIPA-DEA 415 3845 0.081 311 303 BODIPY-DEA 550 65180 5.9 10-4 38 22 a In acetonitrile at room temperature. b Photoreaction quantum yield. c exc = 355, 405 and 532 nm for NPPOC-DEA, BTIPA-DEA and BODIPY-DEA, respectively. To investigate their light-induced response, we first irradiated diluted solutions of the three photoinitiators in acetonitrile and monitored the changes observed by UV-vis absorption spectroscopy (Figures 1b and S2). For all the compounds, dramatic spectral variations were registered, which according to previous data39,40,42 could be ascribed to the photolysis of the carbamate groups and release of the corresponding DEA molecules. To corroborate these results, additional photoexcitation experiments were performed in concentrated CD3CN solutions of NPPOC-DEA, BTIPA-DEA and BODIPY-DEA that were analyzed by 1H NMR (Figures 2 and S3-S4). In all the cases, gradual disappearance of the 1H NMR signals of the initial compounds was observed upon continuous irradiation, which largely faded after sufficiently long irradiation times. Moreover, new sets of resonances corresponding to the photoinduced products concomitantly appeared. In particular, the two multiplets arising from free DEA at  = 2.63 and 1.07 ppm were clearly identified for NPPOC-DEA and BTIPA-DEA, while the other 1H NMR signals formed could be tentatively assigned to the o-nitro--methyl-styrene (7)39 and benzo[4,5]thieno[2,3-b]quinolone-11-carbonitrile (8)40 main by-products described in previous works (Scheme 3). It must be noted that compound 8 bears a nucleophilic pyridine group and, 9 therefore, it could participate in the initiation of CA polymerization together with free DEA. In the case of BODIPY-DEA, signals of free DEA were not observed, while two new multiplets at  = 3.01 and 1.26 ppm arose during irradiation, the chemical shift and multiplicity of which were in accordance with an amine of general formula NEt2R. Formation of amine 9 was therefore proposed, and subsequently confirmed by HPLC-MS analysis (Figure S5). Although different signals were observed in the chromatogram, the most intense peak could be unambiguously assigned to the protonated form of 9. We speculate that, upon irradiation, BODIPY-DEA releases CO2, DEA and a benzylic BODIPY cation, which cannot form the expected alcohol42 in anhydrous media and, instead, readily reacts with DEA to afford amine 9. Actually, the affinity of free amines for this very electrophilic carbocation was already observed,42 and it is the reason why the iodination step is performed at the end of the synthetic pathway during the preparation of BODIPY-DEA. It must be noted that 9 is a tertiary amine that can also activate CA polymerization.29 Therefore, upon irradiation of BODIPY-DEA in cyanoacrylate solution, we expect polymerization to be initiated either directly by the photoreleased DEA molecules or by amine 9. 10 Figure 2. 1H NMR spectra (360 MHz, CD3CN) of: (a) BTIPA-DEA; (b-d) BTIPA-DEA after (b) 20 min, (c) 40 min, and (d) 60 min irradiation at 405 nm (power = 280 mW); (e) free DEA. The arrows show the signals due to free DEA. 11 Scheme 3. Photolysis reactions established for NPPOC-DEA, BTIPA-DEA and BODIPY-DEA in acetonitrile. To assess the efficiency of amine photorelease from NPPOC-DEA, BTIPA-DEA and BODIPY-DEA, their photoreaction quantum yields (ph) were determined in acetonitrile by means of UV-vis absorption measurements (Table 1). For NPPOC-DEA and BTIPA-DEA, rather large ph values were measured (ph  0.1), which indicate that they undergo very effective light- induced deprotection. On the other hand, a very low photolysis quantum yield was registered for BODIPY-DEA (ph = 5.9 10-4), in agreement to the results reported for similar products.42 However, it must be taken into account that the efficacy of photoreactions does not only depend 12 on the quantum yield of the process, but also on the absorptivity of the irradiated compound at the excitation wavelength (i.e. on the ph ɛabs factor, Table 1). As a consequence, the much larger molar extinction coefficient of BODIPY-DEA compared to NPPOC-DEA and BTIPA-DEA largely counterbalances for the difference in ph values. Actually, if all the compounds were illuminated with the same photon flux at their absorption maxima, amine photorelease from BODIPY-DEA would only take place with about 10-fold less efficiency according to our data. This, together with its red-shifted absorption with respect to NPPOC-DEA and BTIPA-DEA, makes it a very appealing photoinitiator for CA polymerization. Photopolymerization of cyanoacrylates. To evaluate the scope of the photoinitiators developed in this work to promote light-induced CA polymerization, a wide range of cyanoacrylate monomers were considered: highly reactive ethyl 2-cyanoacrylate (ECA) and methoxyethyl 2- cyanoacrylate (BMCA), as well as long alkyl chain, less reactive butyl 2-cyanoacrylate (BCA), hexyl 2-cyanoacrylate (HCA) and 2-octyl 2-cyanoacrylate (OCA). For each of these monomers, two different batches were subjected to photopolymerization experiments. On one hand, we directly tested the commercial CA samples received (ECA0, BMCA0, BCA0, HCA0, OCA0), which contain radical scavengers (e.g. butylated hydroxytoluene) and acids (e.g. boron trifluoride, sulfur dioxide) to prevent premature, undesired radical and anionic polymerization, respectively. Since the nature and concentration of acid stabilizers vary for each cyanoacrylate monomer, they could differently interact with the amine molecules released during light-induced polymerization and, as such, hamper the comparison of the results obtained for distinct CAs. In fact, when determining the acid content on these samples by viscosity acid value determination (AVD) measurements upon free amine addition,44 strikingly distinct results were encountered for the CA monomers under investigation (Table S1), which however may also be affected by their different 13 reactivity. For this reason, a second batch of CA samples was prepared, where an acid stabilizer (methanesulfonic acid, MSA) was added to each of the commercial formulations of cyanoacrylate monomers until they presented the same AVD value (ECAst, BMCAst, BCAst, HCAst, OCAst, Table S1). Therefore, we expect the photopolymerization results obtained for these additional samples to directly report on the intrinsic response of each of the CA monomers considered to the light-induced activation process triggered by the three photoinitiators prepared. Different methods are described in the literature to assess the efficacy of the (photo)activation of cyanoacrylate polymerization, including IR absorption spectroscopy, gravimetric experiments, calorimetric measurements or even visual determination of the viscosity increase by analyzing the rotation of magnetic stirring bars.19-29 In this work we primarily performed calorimetric experiments in order to allow simple, fast and repetitive in situ analysis of photopolymerization for the large number of conditions scanned (i.e. 3 photoinitiators and 5 CA monomers), while preventing possible artifacts arising in visual viscosity measurements due to the different mechanical properties of the cyanoacrylates tested. In our calorimetric experiments, very small volumes of liquid CA samples (75 µL) were used to minimize heat diffusion effects on their thermal behavior, to which rather low photoinitiator concentrations were added (15 mM), in agreement to previous works on cyanoacrylate photopolymerization.19-24 Because of the exothermic character of CA polymerization, temperature increments (typically, ΔT = 7-16 ºC) were registered upon continuous illumination for all the monomer-photoinitiator pairs investigated (Figures 3a and S6), and a solid, tack-free polymeric material was finally obtained in all the cases (Figure 3b). Since no polymerization was observed in control experiments performed in the absence of photoinitiator or light irradiation, this clearly demonstrates the capacity of NPPOC-DEA, BTIPA-DEA and BODIPY-DEA to light-induce the curing of all 14 types of cyanoacrylates. Noticeably, colored polymers were formed for all the photoactivators assayed (pale yellow for NPPOC-DEA, bright yellow for BTIPA-DEA, and intensely pink for BODIPY-DEA), which result from the visible-light absorbing properties of the unreacted fraction of these compounds and of the by-products formed. To quantify the efficiency of CA photopolymerization, we took as a reference the time at which each sample reached half of the overall thermal increase associated with polymer curing (tphoto). By conducting additional experiments by IR spectroscopy and visual inspection of the rotation of a magnetic stirring bar, we demonstrated that: (a) about 90% of the CA monomers had reacted by tphoto according to the decrement in the =C-H stretching band at 3127 cm-1 (Figure S7); (b) rotation of the stirring bar ceased slightly before tphoto (~ 4-10 seconds, as found for ECA0+BTIPA-DEA and OCA0+BTIPA-DEA mixtures), as a relatively small increase in viscosity is enough to prevent it.45 15 Figure 3. (a) Photopolymerization exotherms of the mixtures containing BTIPA-DEA and commercial CA monomers (exc = 405 nm, power = 280 mW). (b) Polymers obtained upon illumination of ECA0-photoinitiator mixtures (left: NPPOC-DEA; center: BTIPA-DEA; right: BODIPY-DEA). Table 2 shows the tphoto values measured for all the samples investigated. Different conclusions can be derived from this data. First, the presence of additional acid stabilizer in ECAst, BMCAst, BCAst, HCAst and OCAst monomers resulted in longer photoinitiation times, which confirms that polymerization takes place via nucleophilic activation upon amine photorelease. To further corroborate this result, a systematic analysis of tphoto variation with the concentration of acid stabilizer was performed for BTIPA-DEA upon addition of increasing amounts of methanesulfonic acid to ECA0. As expected, this led to a continuous enlargement of the photopolymerization time (Figure S8). Table 2. Photopolymerization times (tphoto) for different CA monomer-photoinitiator pairsa,b Monomer NPPOC-DEAc,f BTIPA-DEAd,f BODIPY-DEAe,f ECA0 28 s 18 s 108 s ECAst 75 s 34 s 143 s BMECA0 13 s 15 s 100 s BMECAst 49 s 38 s 126 s BCA0 84 s 37 s 126 s 16 BCAst 91 s 51 s 169 s HCA0 88 s 42 s 138 s HCAst 99 s 64 s 177 s OCA0 94 s 76 s 168 s OCAst 110 s 91 s 185 s a Determined as the time at which half of the overall thermal increase is reached for the exotherms registered for each sample at room temperature; average of 3 independent measurements. b cphotoinitiator = 15 mM. c exc = 355 nm, photon flux = 8.9 10-7 Einstein s-1, light intensity: 465 mW cm-2. d exc = 405 nm, photon flux = 9.5 10-7 Einstein s-1, light intensity: 1120 mW cm-2. e exc = 532 nm, photon flux = 1.1 10-6 Einstein s-1, light intensity: 390 mW cm-2. f In the absence of irradiation, polymerization of the monomer-photoinitiator mixtures was observed at a much longer time scale both in air (> 30 min) and when stored in closed, opaque polypropylene bottles: NPPOC-DEA (from 4 months in ECA to more than 6 months in OCA) BTIPA-DEA (from 40 min in ECA to 2 h in OCA), and BODIPY-DEA (from 2 days in ECA to 6 days in OCA). Based on tphoto evaluation, we also ascertained differences in the efficacies of the three photoinitiators assayed at rather similar photon fluxes (~ 1 10-6 Einstein s-1), which were consistent λ for each of the CA monomers tested and generally followed the trend of their ph ɛabs exc values in acetonitrile. BTIPA-DEA and, in a lesser extent, NPPOC-DEA led to the shortest photopolymerization times, whereas 2- to 8-fold larger tphoto values were determined for BODIPY- DEA as a result of its lower photoreaction quantum yield. In the latter case, the slower curing time may also be ascribed to the generation of tertiary amine 9, which is sterically hindered and probably less prone to initiate CA polymerization. Notably, the photoinitiator-dependent variation in tphoto was found to decrease for the less active cyanoacrylates (i.e. BCA, HCA and, especially, OCA), which we attribute to the different contributions of amine photodeprotection and intrinsic monomer reactivity to the overall rate of the photopolymerization process in each case. This can 17 be clearly inferred from the analysis of tphoto for the more photoactive initiators BTIPA-DEA and NPPOC-DEA. For those compounds, much shorter photopolymerization times were measured for ECA and BMECA than for the other monomers, as expected owing to their higher reactivity.1-2 Therefore, one can assume that the very low tphoto values encountered in this case (e.g. tphoto = 13 or 15 s for BMECA0 and NPPOC-DEA or BTIPA-DEA, respectively, Table 2) essentially report on the fast rate of amine photodeprotection accomplished for those two photoinitiators. As a consequence, the fact that larger photocuring times were registered for long alkyl chain CAs with NPPOC-DEA and BTIPA-DEA under the same irradiation conditions (e.g. tphoto = 94 and 76 s for OCA0, respectively) indicates that the photopolymerization rate of these monomers is limited by their low reactivity in this case (i.e. slow nucleophile activation and/or propagation steps). As for BODIPY-DEA, amine light-induced deprotection takes place in a longer time scale and, consequently, ultimately determines photopolymerization kinetics even for the less reactive monomers. Hence, this explains the rather similar tphoto values measured for all the cyanoacrylates under study. In spite of this, relatively fast photopolymerization times (< 190 s) were determined in all the cases, even for the less active monomer-photoinitiator pairs considered (i.e. OCAst and BODIPY- DEA). This is unambiguously demonstrated by comparing the light-induced results with the kinetics of thermal polymerization for the same cyanoacrylates. On one hand, the monomer- photoinitiator mixtures subjected to photopolymerization experiments were found to remain in the low viscosity, liquid state for at least 30 minutes in the dark and under ambient conditions. Actually, when stored in closed, opaque polypropylene bottles, those mixtures were stable for hours (from 40 min in ECA to 2 h in OCA for BTIPA-DEA), days (from 2 days in ECA to 6 days in OCA for BODIPY-DEA) or even months (from 4 months in ECA to more than 6 months in 18 OCA for NPPOC-DEA). On the other hand, to thermally polymerize small volumes (~ 1 mL) of the cyanoacrylates under study inside non-treated glass vials, they had to be exposed to ambient conditions for several hours (ECA and BMECA) or days (BCA, HCA and OCA). Therefore, light- induced polymerization of these monomers with any of the photoinitiators developed in this work dramatically enhances their curing time, a required feature for many applications, especially for the less reactive, but more biologically relevant, long alkyl chain cyanoacrylates. To illustrate this result, we carried out adhesion tests on polycarbonate (Makrolon® mono clear 099 FR; PC) and poly(methyl methacrylate) (PMMA) substrates. In particular, we compared the maximum tensile strength (σmax) needed to detach two strips of these materials previously glued either (a) thermally with fast-curing monomer ECA0, or (b) photochemically with a mixture of BTIPA-DEA and ECA0. As clearly shown in Table 3, photoinduced adhesion efficiently took place after just 2 min irradiation for both PC and PMMA and, actually, σmax values measured in this case corresponded to substrate failure instead of adhesive debonding. By contrast, only partial thermal curing was observed after 30 min with ECA0, which allowed PC and PMMA sticks to be detached by applying low to modest tensile strengths. Actually, efficient thermal adhesion required a much longer period (24 h), only after which mechanical substrate failure was registered in our experiments. Therefore, this demonstrates the capacity of light-induced polymerization using photoreleasable amines to dramatically accelerate the adhesion process of cyanoacrylates, even in the case of high-reactivity monomers such as ECA. Table 3. Mechanical performance of thermally- and photochemically-cured ECA adhesives. Substrate Adhesive σmax at 30 min (MPa) a σmax at 24 h (MPa) a PC ECA0 5.50 ± 1.07 16.52 ± 1.93 c 19 ECA0+BTIPA-DEAb 10.89 ± 0.42 c 11.76 ± 3.11 c PMMA ECA0 1.50 ± 0.38 8.40 ± 1.35 c ECA0+BTIPA-DEAb 7.28 ± 1.28 c 8.98 ± 2.68 c a Maximum tensile strength registered 30 min and 24 h after gluing two plastic sticks; average of three replicates. b cBTIPA-DEA = 15 mM; irradiation conditions: 405 nm, 280 mW, 2 min. c σmax corresponding to substrate failure instead of detachment. Characterization of photogenerated CA polymers. To assess the efficiency of photopolymerization, we analyzed the polymers obtained by means of 1H NMR. In all the cases, 1 H NMR spectra of photopolymerized materials showed no residual olefinic signals (Figure S9), thus demonstrating that CA monomers had reacted quantitatively under our experimental conditions. To evaluate the effect of photopolymerization on the properties of the cyanoacrylate polymers generated, we determined their molecular weight distribution by gel permeation chromatography (GPC). In particular, we focused on the commercially received formulations of three of the CA monomers investigated in this work: ECA0, BCA0 and OCA0, which are excellent models of high-, intermediate- and low-reactivity cyanoacrylates. For these monomers, molecular weights distributions were measured both upon photopolymerization with NPPOC-DEA, BTIPA- DEA and BODIPY-DEA as well as after slow, glass-initiated thermal polymerization at ambient conditions. Because of the well-known instability of polycyanoacrylates, which can undergo depolymerization and subsequent repolymerization to afford low molecular weight "daughter" polymer chains even in the solid state,46 GPC experiments were performed right after polymer formation and a slight amount of MSA was added to slow down degradation upon dissolution (as demonstrated in Figure S10 for thermally cured polymers). The number average molecular weight (Mn) values obtained in this way are shown in Table 4 (see Figure S11 for molecular weight distributions). As evidenced by dispersity values, broad distributions with low molecular weight 20 tails were obtained in most cases, to which inevitable CA depolymerization after polymer dissolution may contribute. Table 4. Number average molecular weight (Mn, g mol-1) and dispersity (Ð) of photogenerated cyanoacrylate polymersa Monomer NPPOC-DEA BTIPA-DEA BODIPY-DEA Thermal b ECA0 5.59·104 (1.83) 4.98·104 (1.85) 7.24·104 (1.69) 5.92·104 (2.34) c BCA0 8.57·104 (3.23) d 5.08·104 (3.22) e 4.19·104 (2.18) 1.56·105 (3.25) f OCA0 2.04·105 (2.73) 2.25·105 (3.21) 2.49·105 (1.80) 2.74·105 (2.80) a As determined by GPC for freshly prepared polymers, which were photogenerated as described in Table 2; calibration made by using PMMA standards. Ð values shown in parentheses. b Slow, glass-initiated thermal polymerization under ambient conditions (16 hours). c Bimodal distribution with Mn = 6.17 104 and 2.28 105 g mol-1. d Bimodal distribution with Mn = 4.53 104 and 3.53 105 g mol-1. e Bimodal distribution with Mn = 1.34 105 and 1.06 106 g mol-1. f Bimodal distribution with Mn = 1.91 105 and 9.32 105 g mol-1. For ECA0 and OCA0 similar molecular weight distributions and Mn values were measured for thermally- and photochemically-cured samples. Therefore, this demonstrates that no detrimental effects in polymer chain length, structure and dispersity arise from the much faster polymerization times achieved upon irradiation of photoactivable amines. Actually, this is in agreement with the high adhesion forces described above for photocured samples of ECA0+BTIPA-DEA even at very short times. In the case of BCA0, more diverse results were obtained for the different polymerization conditions assayed. Thus, very broad, nearly bimodal molecular weight distributions were measured after thermal curing and photopolymerization with NPPOC-DEA and BTIPA-DEA, the highest Mn values being obtained thermally and for NPPOC-DEA. In spite of 21 this, large polymer chain lengths were observed in all the cases that resemble those registered for ECA0. Consequently, excellent adhesive properties must also expected for light-sensitive BCA0 formulations prepared from the color-tunable photoactivable amines developed in this work. CONCLUSIONS In this work we described a new strategy to accomplish cyanoacrylate photopolymerization based on the use of photogenerated amines. Aiming to develop an extended palette of photoinitiators allowing excitation along the UV-visible spectrum, we prepared three different light-responsive carbamate derivatives of diethylamine, a well-known cyanoacrylate curing agent. Upon irradiation of these compounds, amine photorelease was induced, which we exploited to initiate cyanoacrylate polymerization. In this way, very fast, on demand polymer curing was achieved even for poorly reactive, biologically-relevant long alkyl chain cyanoacrylates, while no polymerization was observed in the dark. Noticeably, when applied to light-controlled material bonding, photogenerated amines led to a dramatic reduction of setting times, without detrimentally affecting neither the final adhesion strength nor the molecular weight of the final polymers obtained. This, in combination with the organic, metal-free nature of the initiators, their wavelength-tunability and their capacity to activate multiple cyanoacrylate commercial formulations, makes the photopolymerization strategy developed in this work very promising. Of especial relevance would be its use in the biomedical field, where high performance applications could be targeted that might outweigh the cost of photoinitiator synthesis. EXPERIMENTAL SECTION 22 Materials and general methods. Reagents and solvents for the synthesis of NPPOC-DEA, BTIPA-DEA, and BODIPY-DEA were purchased and used without further purification. When required, solvents were dried using standard procedures. Reactions requiring an inert atmosphere were conducted under nitrogen or argon using standard Schlenk techniques. CA monomers ECA, BMCA, BCA, HCA and OCA were provided by Cuantum Medical Cosmetics S.L. and used as received. Methanesulfonic acid was further added to these CA monomers to increase their stability against nucleophiles. Thin-layer chromatography (TLC) was performed using Merck aluminum backed plates of TLC silica gel 60 F254, and flash column chromatography was carried out using silica gel (60 Å pore size, 230−400 μm mesh size). NMR spectra were recorded using Bruker spectrometers DPX-250, DXP360, and AVANCE-III 400 (250 MHz (1H); 62.5 MHz (13C), 360 MHz (1H); 90 MHz (13C) and 400 MHz (1H); 100 MHz (13C), respectively). 1H and 13C chemical shifts are reported in ppm relative to tetramethylsilane, using residual proton and 13C resonances from solvent as internal standards. Infrared spectra were recorded using a Bruker Tensor 27 instrument equipped with an ATR Golden Gate cell and a diamond window. High resolution ESI mass spectra were registered in a Bruker MicroTOF-Q spectrometer using a direct inlet system. HPLC analyses were carried out on a Waters 2690 separations module equipped with a Waters 996 photodiode array detector and a chiral Daicel OD column (0.46 cm x 25 cm). Isocratic elution was performed with 90% hexane and 10% 2-propanol. To irradiate the photoinitiators and induce CA photopolymerization, the following illumination sources were used: the second (λexc = 532 nm) and third harmonic (λexc = 355 nm) of a ns-pulsed Nd:YAG laser (Brilliant, Quantel); a cw diode laser (λexc = 405 nm, SciTec). Synthesis of NPPOC-DEA. This compound was prepared from commercially available products DEA and 2-(2-nitrophenyl)propyl chloroformate (1) in the presence of DIPEA according to a 23 reported procedure (90% yield).39 1H NMR (250 MHz, CDCl3): δ 7.72 (dd, J = 8.2, 1.5 Hz, 1H), 7.61 – 7.43 (m, 2H), 7.34 (ddd, J = 8.2, 7.1, 1.5 Hz, 1H), 4.28 – 4.15 (m, 2H), 3.68 (h, J = 7.0 Hz, 1H), 3.21 (bs, 2H), 3.08 (bs, 2H), 1.35 (d, J = 7.0 Hz, 3H), 1.05 (bs, 3H), 0.90 (bs, 3H). 13C NMR (75 MHz, CDCl3): δ 155.5, 150.5, 137.8, 132.5, 128.2, 127.2, 123.9, 69.0, 41.8, 41.2, 33.4, 18.0, 13.8, 13.4. Synthesis of BTIPA-DEA. Synthesis of (Z)-2-((Z)-2-(hydroxyimino)benzo[b]thiophen-3(2H)- ylidene)-2-phenylacetonitrile (3). Intermediate 3 was prepared from 3-bromothianaphthalene (2) according to a 3-step reported procedure (15% yield overall).40 1H NMR (250 MHz, DMSO-d6): δ 13.18 (bs, 1H), 7.72−7.49 (m, 6H), 7.40−7.28 (m, 1H), 6.90 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H). Synthesis of BTIPA-DEA. This photoinitiator was prepared adapting a procedure described for a similar compound.47 Diethylcarbamoyl chloride (103 µL, 0.81 mmol) was dissolved in anhydrous DCM (5 mL) and added dropwise to a stirred solution of 3 (150 mg, 0.54 mmol) and triethylamine (228 µL, 1.62 mmol) in anhydrous DCM (5 mL). The solution was heated at reflux for 4 hours. After this time, the solution was cooled, diluted with DCM (30 mL) and washed with water (3 x 20 mL) and brine (3 x 20 mL). The organic phase was then dried over anhydrous Na2SO4 and the solvent evaporated in vacuo. The product was purified by flash column chromatography over silica gel (hexane:AcOEt 9:1 to 2:1) to afford the pure product as a yellow powder (122 mg, 0.32 mmol, 60% yield). Melting point: 164-166 °C. 1H NMR (400 MHz, CDCl3): δ 7.52-7.45 (m, 5H), 7.29- 7.27 (m, 2H), 6.86-6.82 (m, 1H), 6.60 (d, J = 8.2 Hz, 1H), 3.42 (bs, 4H), 1.29-1.23 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 157.9 (Cq), 152.2 (Cq), 141.7 (Cq), 138.5 (Cq), 134.2 (Cq), 132.1 (CH), 131.9 (Cq), 130.3 (CH), 129.9 (2 x CH), 128.7 (2 x CH), 127.3 (CH), 125.7 (CH), 123.1 (CH), 118.4 (Cq), 111.8 (Cq), 43.1 (CH2), 42.1 (CH2), 14.2 (CH3), 13.4 (CH3). ATR-IR: υmax (cm- 24 1 ) 2924, 2194, 1738, 1412, 1259. HRMS (ESI) (m/z) calculated for C21H19N3NaO2S ([M + Na]+): 400.1090; experimental: 400.1102. Synthesis of BODIPY-DEA. Synthesis of (5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ4,5λ4- dipyrrolo[1,2-c:2’,1’-f][1,2,3]diazaborinin-10-yl)methyl (4-nitrophenyl)carbonate (5). Compound 5 was prepared from 2,4-dimethyl-1H-pyrrole (4) according to a 3-step reported procedure.42 1H NMR (360 MHz, DMSO-d6): δ 8.34 (d, J = 9.2 Hz, 2H), 7.50 (d, J = 9.2 Hz, 2H), 5.56 (s, 2H), 2.54 (s, 6H), 2.46 (s, 6H). Synthesis of (5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ4,5λ4-dipyrrolo[1,2-c:2’,1’- f][1,2,3]diazaborinin-10-yl)methyl N-N’-diethylcarbamate (6). To a solution of 5 (1.20 g, 2.71 mmol) in dry THF (60 mL), pyridine was added (196 μL, 2.44 mmol, 0.9 eqs.) under a nitrogen atmosphere. After the mixture was stirred for 15 min at room temperature, DEA (420 μL, 4.06 mmol, 1.5 eqs.) was added. The reaction was then stirred in the dark during 16 h. After that time, solvents were evaporated, and the crude residue was dissolved in DCM (80 mL). The organic layer was washed with 1 M HCl (2 × 50 mL), 0.1 M NaOH (2 × 50 mL) and brine (2 × 50 mL), then dried with MgSO4 and, finally, the solvent was evaporated in vacuo. The crude mixture was then purified by flash chromatography on silica gel using DCM as the eluent. Compound 6 was obtained as an orange-pink powder (562 mg, 1.49 mmol, 55% yield). Melting point: 164-167 °C. 1H NMR (360 MHz, CDCl3): δ 6.07 (s, 2H), 5.27 (s, 2H), 3.32 (q, J = 7.1 Hz, 2H), 3.21 (q, J = 7.1 Hz, 2H), 2.53 (s, 6H), 2.38 (s, 6H), 1.14 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 156.4 (Cq), 155.3 (Cq), 141.8 (Cq), 134.5 (Cq), 132.9 (Cq), 122.2 (CH), 58.3 (CH2), 42.2 (CH2), 41.4 (CH2), 15.6 (CH3), 14.8 (CH3), 14.3 (CH3), 13.5 (CH3). ATR-IR: υmax (cm-1) 2963, 1699, 1555, 1427, 1158. HRMS (ESI) (m/z) calculated for C19H26BF2N3NaO2 ([M + Na]+): 400.1982; experimental: 400.1987. 25 Synthesis of BODIPY-DEA. To a suspension of 6 (360 mg, 0.95 mmol) and ZnO (280 mg, 3.42 mmol) in dry THF (25 mL), a solution of ICl (465 mg, 2.86 mmol, 3 equiv) in dry THF (5 mL) was added at 0 °C and under nitrogen atmosphere. The ice bath was removed and the reaction mixture was stirred for 30 minutes, after which the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (hexane:DCM 1:1 to DCM only). BODIPY-DEA was obtained as a dark purple powder (430 mg, 0.68 mmol, 72% yield). Melting point: 178-180 °C. 1H NMR (360 MHz, CDCl3): δ 5.29 (s, 2H), 3.34 (q, J = 7.2 Hz, 2H), 3.21 (q, J = 7.2 Hz, 2H), 2.63 (s, 6H), 2.43 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.8 (Cq), 154.9 (Cq), 143.8 (Cq), 133.9 (Cq), 132.8 (Cq), 87.1 (Cq), 58.7 (CH2), 42.3 (CH2), 41.5 (CH2), 18.1 (CH3), 16.4 (CH3), 14.3 (CH3), 13.5 (CH3). ATR-IR: υmax (cm-1) 2978, 1699, 1538, 1162, 985. HRMS (ESI) (m/z) calculated for C19H24BF2I2N3NaO2 ([M + Na]+): 651.9915; experimental: 651.9913. Photochemical characterization. Steady-state UV-vis absorption measurements were recorded on a HP 8453 spectrophotometer using 1 cm-thick quartz cuvettes in acetonitrile (HPLC quality). DEA photorelease from NPPOC-DEA (λ = 355 nm), BTIPA-DEA (λ = 405 nm) and BODIPY- DEA (λ = 532 nm) was monitored by: (a) registering UV-vis absorption spectra under continuous irradiation of diluted acetonitrile solutions (c ~ 1.68·10-5 M – 1.60·10-4 M); (b) measuring 1H NMR spectra upon continuous illumination of concentrated CD3CN solutions (c ~ 10 mg mL-1). Photorelease quantum yields (ph) in acetonitrile solution were determined from the UV-vis absorption measurements using the methodology reported in ref. 48 and the following reference data: (a) NPPOC-DEA: the photorelease quantum yield reported for this compound in methanol (ph = 0.20 39); (b) BTIPA-DEA and BODIPY-DEA: the photoisomerization quantum yield 26 reported for the closed isomer of 1,2-bis(5-chloro-2-methyl-3-thienyl)perfluorocyclopentene in hexane (ph = 0.13 49). Stabilization of CA monomers. The batches of CA monomers commercially acquired were already loaded with certain amounts of acid (typically, SO2) and radical (typically, butylated hydroxytoluene (BHT)) stabilizers. To estimate the quantity of acid stabilizers in these samples that could interfere with the amine nucleophiles released during the photopolymerization experiments, a viscosity acid value determination technique previously described was employed.44 In this technique, an organic solution of a tertiary amine is mixed quickly with 0.5 mL of a chosen CA monomer. The resulting mixture is manually stirred with a wooden stick until it cannot be separated from the mixture anymore, as it gets stuck in it. The time elapsed between the mixing and the sticking is defined as tAVD. tAVD is used to quantify the amount of acid stabilizers, which were found to be different for each type of CA monomer (Table S1). For this reason, a new batch of cyanoacrylate monomers was prepared, in which increasing quantities of an acid stabilizer (methanesulfonic acid) were added to each sample until all of them presented the same tAVD (tAVD ~ 210 s). Photopolymerization experiments. To characterize the light-induced polymerization of CAs, calorimetric experiments were performed. In each of these experiments, a closed polypropylene well (diameter: 8 mm) was filled with 75 µL of a liquid CA monomer where the photoinitiator of choice had been previously dissolved (15 mM). Full dissolution was achieved in all cases after shaking the preparation during 10 minutes. The absence of undissolved photoinitiator was visually checked every time. The sample was then irradiated with a selected laser beam (spot size ~ 0.5 cm2) at room temperature (NPPOC-DEA: λ = 355 nm, power = 300 mW, photon flux = 8.9 10-7 Einstein s-1; BTIPA-DEA: λ = 405 nm, power = 280 mW, photon flux = 9.5 10-7 Einstein s-1; 27 BODIPY-DEA: λ = 532 nm, power = 250 mW, photon flux = 1.1 10-6 Einstein s-1) and its temperature was monitored with an infrared probe and recorded every second until minimal thermal changes were observed. In all the cases, an increase of temperature (typically, ΔT = 7-16 ºC) was observed as a consequence of CA polymerization, which is a strongly exothermic process. To estimate the time period needed for photopolymerization to occur, we determined the time at which the sample temperature rise was half of the overall increase observed during the calorimetric experiment (i.e. when T = T0 + 0.5 ΔT). Because of the sigmoidal shape of temperature variation for most cases, this means that tphoto corresponds to the time at which the temperature variation is higher and, assuming fast heat diffusion for the small sample volume, at which polymerization reaction rate reaches its maximum. Several replicates (n = 3) were conducted for each CA monomer-photoinitiator pair and reproducible tphoto values were retrieved. Additional calorimetric experiments were undertaken where a small Teflon stirring bar was added to the polypropylene well (~ 50 rpm), which was found to stop spinning when the sample became viscous enough as a result of photopolymerization. In all the cases, this phenomenon was observed to occur slightly before tphoto. Finally, we also monitored the photopolymerization of BCA0 with BTIPA-DEA by means of IR spectroscopy. To this end, the ATR-IR spectra of BCA0 monomer, a fully cured BCA0+BTIPA-DEA mixture and a BCA0+BTIPA-DEA mixture at tphoto = 37 s were acquired in the same conditions. The integrals (I) of the peaks at 3150 cm-1 (=C-H stretching band) and 2900 cm-1 (-C-H stretching band) were compared. For BCA0, I3150/I2900 = 0.0506; for the fully cured BCA0+BTIPA-DEA mixture, I3150/I2900 = 0 as the peak at 3150 cm-1 is not present; for a BCA0+BTIPA-DEA mixture at tphoto= 37 s, I3150/I2900 = 0.0055. From this data we estimated that in the latter case the mixture is composed by 89% polymer and 11% monomer. 28 Thermal polymerization experiments. For sake of comparison with the results of the photopolymerization experiments, thermal polymerization of CAs was also conducted by simply adding 0.5 mL of each monomer in a non-passivated glass vial and storing the sample at room temperature and in the dark for the appropriate time (typically, overnight). Characterization of CA polymers. The molecular weight distribution of thermally- and light- cured CA polymers was determined by gel permeation chromatography using an Agilent Technologies 1260 Infinity chromatograph and THF as solvent. The instrument is equipped with three gel columns: PLgel 5μm Guard/50×7.5 mm, PLgel 5μm 10000 Å MW 4K−400K, and PL Mixed gel C 5μm MW 200−3M. Calibration was made by using PMMA standards. In each experiment, the freshly-prepared polymer sample of interest was dissolved (5 mg/mL) in THF containing 0.05% MSA and immediately analyzed by GPC (1 mL/min flow; 40 °C column temperature). Adhesion test. The adhesion test was carried out following the specifications of the “ISO 4587 Adhesives Tensile Lap Shear Strength Rigid to Rigid” standard method, using an Instron 3366 instrument. The test has been performed on PC (Makrolon® mono clear 099 FR) and PMMA rectangular cuboid (100 x 20 x 2 mm) specimens bound with 25 µL of two different adhesives: ECA0 alone and a 15 mM solution of BTIPA-DEA in ECA0. The lap joint area was approximately 100 mm2. In the case of the ECA0+BTIPA-DEA mixture, the specimens were clamped together and the lap joint area was irradiated at 405 nm (power = 280 mW) during 2 minutes, and then they were left standing during 30 min or 24 h. In the case of ECA0 alone, the specimens were clamped together after the application of the adhesive, and left standing during 30 min or 24 h. 29 ASSOCIATED CONTENT Supporting Information. Additional data on the synthesis of the photoinitiators (NMR, IR and HRMS spectra, HPLC chromatograms), and on the polymerization and characterization of cyanoacrylates. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * (J.H.) E-mail: jordi.hernando@uab.cat * (R.M.S.) E-mail: rosamaria.sebastian@uab.cat Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGEMENTS Financial support by MINECO/FEDER (RTC-2016-5683-1 project within "Retos Colaboración" program and CTQ2015-65439-R project) and by Generalitat de Catalunya (2017 SGR00465 project) is gratefully acknowledged. We also thank Sara Ortego and Feliu Pizà for their help. ABBREVIATIONS CA, cyanoacrylate; NPPOC, nitrophenylpropyloxycarbonyl group; BTIPA, benzothiophene imino-phenylacetonitrile group; BODIPY, boron-dipyrromethene dye; DEA, diethylamine; DIPEA, N,N-diisopropylethylamine; ECA, ethyl 2-cyanoacrylate; BMCA, methoxyethyl 2- cyanoacrylate; BCA, butyl 2-cyanoacrylate; HCA, hexyl 2-cyanoacrylate; OCA, 2-octyl 2- 30 cyanoacrylate; TAD, total acid determination; tphoto, photopolymerization time; GPC, gel permeation chromatography; Mn, number average molecular weight; TLC, thin-layer chromatography; DCM, dichloromethane; THF, tetrahydrofuran; MSA, methanesulfonic acid; PC, polycarbonate (Makrolon® mono clear 099 FR) ; PMMA, poly(methyl methacrylate). REFERENCES (1) Fink, J. K. In Reactive Polymers Fundamentals and Applications, 2nd ed.; William Andrew Publishing: Norwich, 2013; pp. 317-330. (2) Burns, B. Polycyanoacrylates. In Encyclopedia of Polymer Science and Technology, 4th ed.; JohnWiley & Sons: Hoboken, 2016; Volume 4, pp. 1–27. 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Chem. 2005, 91-97. 36 Table of contents graphic 37 Supporting Information for: Wavelength-Tunable Light-Induced Polymerization of Cyanoacrylates Using Photogenerated Amines Enrico Faggi,a Jordi Aguilera,b Rubén Sáez,b Ferran Pujol,b Jordi Marquet,a Jordi Hernando,a,* and Rosa María Sebastiána,* a Departament de Química, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain b CUANTUM Medical Cosmetics S.L., 08193 Cerdanyola del Vallès, Spain S1 TABLE OF CONTENTS: 1. 1H NMR, 13 C NMR, IR, HRMS SPECTRA AND HPLC CHROMATOGRAMS OF PHOTOINITIATORS AND INTERMEDIATES………………...........................................S3 2. ABSORPTION SPECTRA OF CA MONOMERS………………………………………S17 3. AMINE PHOTORELEASE FROM NPPOC-DEA AND BODIPY-DEA…………...….S18 4. TOTAL ACID DETERMINATION OF CYANOACRYLATE MONOMERS………..S22 5. PHOTOPOLYMERIZATION OF CYANOACRYLATE MONOMERS……………...S23 6. CHARACTERIZATION OF POLYCYANOACRYLATES……………………………S26 7. REFERENCES………………………….………………………………………………….S29 S2 1. 1H NMR, 13 C NMR, IR AND HR-MS SPECTRA OF PHOTOINITIATORS AND INTERMEDIATES NPPOC-DEA. 1H NMR and 13 C NMR spectra are shown for NPPOC-DEA, which perfectly agree with previously reported data.1 Chiral HPLC chromatogram is also shown for this compound. 1 H NMR (250 MHz, CDCl3) S3 13 C NMR (90 MHz, CDCl3) S4 Chiral HPLC S5 BTIPA-DEA. Spectral data and HPLC chromatogram are given for the target photoinitiator. 1 H NMR (360 MHz, CDCl3) S6 13 C NMR (90 MHz, CDCl3) DEPT 135 (90 MHz, CDCl3) S7 ATR-IR 1.0 0.9 0.8 0.7 0.6 0.5 0.4 2923.87 2194.43 1737.83 1583.35 1470.90 1441.74 1412.84 1309.17 1259.74 1138.27 1029.37 967.47 770.43 748.39 731.00 703.19 3500 3000 2500 2000 1500 1000 Wavenumber cm-1 HR-MS (ESI+) Intens. 2. +MS, 1.3-1.7min #(75-104), -Peak Bkgrnd x105 400.1102 4 3 2 401.1102 1 402.1065 0 x105 2. C 21 H 19 N 3 Na O 2 S ,400.11 400.1090 4 3 2 401.1123 1 402.1051 0 399.0 399.5 400.0 400.5 401.0 401.5 402.0 402.5 403.0 m/z Meas. m/z Formula m/z err [mDa] err [ppm] mSigma 400.1102 C21H19N3NaO2S 400.1090 ‐1.2 ‐2.9 10.0 S8 HPLC S9 BODIPY-DEA. Spectral data are given for both intermediate 6 and the target photoinitiator. HPLC chromatogram of the photoinitiator is also shown. 1 H NMR (360 MHz, CDCl3) S10 13 C NMR (90 MHz, CDCl3) DEPT 135 (90 MHz, CDCl3) S11 ATR-IR 1.0 0.9 0.8 0.7 0.6 0.5 0.4 2963.40 2927.69 1698.63 1555.03 1508.16 1427.00 1372.05 1308.42 1267.01 1222.65 1194.32 1156.88 1057.80 972.01 798.51 717.17 3500 3000 2500 2000 1500 1000 Wavenumber cm-1 HR-MS (ESI+) Intens. +MS, 1.6-1.6min #(96-97) x104 400.1987 3 2 1 399.2007 401.2006 0 x104 C 19 H 26 B F 2 N 3 Na O 2 ,400.20 4 400.1982 3 2 1 399.2015 401.2012 402.2045 0 398 399 400 401 402 m/z Meas. m/z Formula m/z err [mDa] err [ppm] mSigma 400.1987 C19H26BF2N3NaO2 400.1982 ‐0.5 ‐1.2 44.7 S12 1 H NMR (360 MHz, CDCl3) S13 13 C NMR (90 MHz, CDCl3) DEPT 135 (90 MHz, CDCl3) S14 ATR-IR 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 2978.13 2934.08 2363.13 1698.64 1538.92 1475.78 1453.52 1427.24 1379.16 1340.88 1315.22 1267.69 1219.03 1162.69 1127.78 1084.91 1060.58 985.33 861.30 812.14 783.04 764.28 717.28 670.02 3500 3000 2500 2000 1500 1000 Wavenumber cm-1 HR-MS (ESI+) Intens. 2. +MS, 1.2-1.7min #(72-104), -Peak Bkgrnd x104 651.9913 2.0 1.5 1.0 0.5 650.9990 652.9971 0.0 x104 2. C 19 H 24 B F 2 I 2 N 3 Na O 2 ,651.99 2.5 651.9915 2.0 1.5 1.0 0.5 650.9948 652.9945 0.0 648 649 650 651 652 653 654 655 m/z Meas. m/z Formula Calc.m/z err [mDa] err [ppm] mSigma 651.9913 C19H24BF2I2N3NaO2 651.9915 0.1 0.2 113.9 S15 HPLC S16 2. ABSORPTION SPECTRA OF CA MONOMERS Figure S1. Absorption spectra of neat ECA0, BMCA0, BCA0, HCA0 and OCA0. S17 3. AMINE PHOTORELEASE FROM NPPOC-DEA AND BODIPY-DEA Figure S2. (a) Variation of the absorption spectra of NPPOC-DEA (c = 3.17ꞏ10-4 M) in acetonitrile upon continuous irradiation at exc = 355 nm (power = 3.5 mW). Spectra recorded at different times (0-600 seconds). The arrow shows the spectral change in time. (b) Variation of the absorption spectra of BODIPY-DEA (c = 1.48ꞏ10-5 M) in acetonitrile upon continuous irradiation at exc = 532 nm (power = 28.2 mW). Spectra recorded at different times (0-1800 seconds). The arrow shows the spectral change in time. S18 Figure S3. Variation of the 1H NMR spectrum (360 MHz, CD3CN) of NPPOC-DEA (c = 35 mM) upon continuous irradiation at exc = 355 nm (power = 300 mW). Spectra recorded at different times (0, 25, 60 and 130 minutes; spectra (a)-(d)). For sake of comparison, the 1H NMR spectrum (360 MHz, CD3CN) of DEA is also shown (spectrum (e)). S19 Figure S4. Variation of the 1H NMR spectrum (360 MHz, CD3CN) of BODIPY-DEA (c = 17 mM) upon continuous irradiation at exc = 532 nm (power = 250 mW). Spectra recorded at different times (0, 25, 90, 180 and 300 minutes; spectra (a)-(e)). For sake of comparison, the 1H NMR spectrum (360 MHz, CD3CN) of DEA is also shown (spectrum (f)). S20 Figure S5. (a) HPLC-MS chromatogram of BODIPY-DEA in acetonitrile after irradiation (exc = 532 nm; power = 250 mW; 300 minutes). (b) HRMS spectrum of the most intense peak of the chromatogram, eluted at 11.7 minutes. Inset: detail of the experimental (above) and calculated (below) HRMS spectrum of [9ꞏH]+ ion. In addition, the peak eluted at 15.8 minutes is attributed to the [BODIPY-DEAꞏNa]+ ion (experimental m/z = 651.9894; calculated m/z = 651.9917). S21 4. ACID VALUE DETERMINATION OF CYANOACRYLATE MONOMERS Table S1. Viscosity acid value determination of CA monomers Monomer tAVD (s) ECA0 40 ECAst 210 BMCA0 22 BMCAst 210 BCA0 65 BCAst 210 HCA0 120 HCAst 210 OCA0 140 OCAst 210 S22 5. PHOTOPOLYMERIZATION OF CYANOACRYLATE MONOMERS Figure S6. Photopolymerization exotherms measured for: (a) NPPOC-DEA and commercial monomers; (b) NPPOC-DEA and stabilized monomers ([NPPOC-DEA] = 15 mM; exc = 355 nm; power = 300 mW); (c) BTIPA-DEA and commercial monomers; (d) BTIPA-DEA and S23 stabilized monomers ([BTIPA-DEA] = 15 mM; exc = 405 nm; power = 280 mW); (e) BODIPY-DEA and commercial monomers; (f) BODIPY-DEA and stabilized monomers ([BODIPY-DEA] = 15 mM; exc = 532 nm; power = 250 mW). Figure S7. IR spectra of BCA0 monomer, a fully cured BCA0+BTIPA-DEA mixture and a BCA0+BTIPA-DEA mixture at tphoto= 37 s. The arrow shows the peak at 3127 cm-1, which decreases as polymerization takes place. S24 Figure S8. (a) Photopolymerization exotherms measured for mixtures of BCA0 and BTIPA- DEA (15 mM) upon increasing addition of methanesulfonic acid. (b) Variation of the polymerization time (tphoto) with the added quantity of methanesulfonic acid. S25 6. CHARACTERIZATION OF POLYCYANOACRYLATES Figure S9. 1H-NMR spectra (360 MHz, acetone-d6) of BCA0 in its monomeric form and after photopolymerization with BODIPY-DEA, BTIPA-DEA and NPPOC-DEA. S26 Figure S10. GPC traces for polycyanoacrylates obtained upon either thermal polymerization. Red lines: polymers dissolved in THF; black lines: polymers dissolved in THF containing 0.05% of MSA (methanesulfonic acid). S27 Figure S11. GPC traces for polycyanoacrylates obtained upon either photopolymerization or thermal polymerization of (a) ECA0, (b) BCA0 and (c) OCA0. S28 7. REFERENCE (1) Xi, W.; Peng, H.; Aguirre-Soto, A.; Kloxin, C. J.; Stansbury, J. W.; Bowman, C. N. Spatial and Temporal Control of Thiol-Michael Addition via Photocaged Superbase in Photopatterning and Two-Stage Polymer Networks Formation. Macromolecules 2014, 47, 6159-6165. S29 S30