Seifallah Abid

Ben Sarra

Zhipeng Hassine

Nicolas Sun

Franck Richy

Bassem Camerel

Mireille Jamoussi

Olivier Blanchard-Desce

Frédéric Mongin

Christine O Paul
email: christine.paul@univ-rennes1.fr

Paul-Roth

Hassine

Zhipeng Sun

Nicolas Richy

Franck Camerel

Bassem Jamoussi

Mireille Blanchard-Desce

Olivier Mongin

Frédéric Paul

Christine O Paul- Roth

Olivier Blanchard- Desce

Near-Ir Paul-Roth

Two-Photon Absorption

Impact of Changing the Core in Tetrapyrrolic Dendrimers Designed for Oxygen Sensitization: New Fluorescent Phthalocyanine-Based Dendrimers with High Two-Photon Absorption Cross-sections

Keywords:

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

■ INTRODUCTION

In the molecular world, following the seminal works of Vogtle, [1] Tomalia, [2] Newkome [3] and others, [4] dendrimers form nowadays a wonderful class of molecules presenting peripheral branches with a tree-like structure (dendrons) assembled around a central core. [5] Such structures are usually obtained via the repetition of a similar sequence of reactions to increase the number of molecular units present within each dendron and therefore allowing to control several key properties of the dendrimer such as its size, its shape and the relative positions of various functional groups located at its periphery. [5] In this respect, it was shown that dendrons can work as efficient "light-harvesting antenna" in selected porphyrin-based dendrimers presenting molecular architectures recalling those collecting natural light in various photosystems. [6] After photoexcitation, the dendrons at the periphery of these systems were demonstrated to quantitatively transfer their energy to the central porphyrin core. [7a, 7b , 7c-e] Their chemical structure proves therefore determining for this remarkable process to occur. For instance, with dendrons made of benzyl polyether chains, Fréchet demonstrated that the "antenna effect" was more efficient in branched architectures than in star-shaped architectures. [7b] Later on, fluorenyl units were identified as efficient aromatic chromophores in such systems, allowing to perform directly two-photon excitation of the peripheral dendrons [START_REF]FT-IR (cm -1 ): ῡ = 3305[END_REF] or promoting 2PA via the first 2PA-allowed excited states. [9] With closely related dendrimers, we have previously shown than when progressing from the derivatives 1a-c [9b, 10a-c, 10d ] to their more rigid carbon-rich analogues 2a-c [11] (Scheme 1), the figures of merit for two-photon excited fluorescence and oxygen photosensitization were significantly improved. [11b] Thus, for nearly similar emission and oxygen photosensitization quantum yields, the two-photon absorption (2PA) cross-sections (σ2) of 2b-c dramatically increased compared to those of 1b-c. [9b, 11b] Then, we could recently show that after proper functionalization, 2a-b give rise to fluorescent photosensitizers adapted to one-photon photodynamic therapy (PDT), [12] but also to more advanced developments, such as two-photon PDT (2P-PDT) [13] or even theranostic [14] uses. [15] More generally, this result suggested that replacing the polyether backbone of dendrimers such as 1a-c by a polyarylalkynyl backbone constitutes a way to significantly boost their biphotonic photosensitizing and emissive performances. If correct, this hypothesis provides a simple design criterium for improving the performances of related dendritic systems, especially when these are intended to be used as luminescent photosensitizers. Motivated by further enhancing the efficiency of such systems and inspired by the phthalocyanine-cored dendrimers reported by Kimura [16] and others, [17] we recently wondered ACCEPTED MANUSCRIPT about the impact of replacing the central free-base meso-tetraphenylporphyrin (H2TPP) by zinc(II) phthalocyanine (ZnPc). Thus, we synthesized then compounds 3-5 and probed their photonic properties (Scheme 2). [18] The idea behind this structural variation was to enhance the emission of these photosensitizers by using a more luminescent tetrapyrrolic central unit than H2TPP, but also able to activate oxygen with similar efficiency. This goal was perfectly reached with phthalocyanines 3-5 since all these compounds proved more fluorescent than porphyrins 1a-c (with luminescence quantum yields around 29-37%) and even presented an improved twophoton photosensitizing ability for oxygen in THF. For these phthalocyanines, the comparison with the naked ZnPc complex also demonstrated the critical role of the peripheral fluorenylcontaining antenna on the relevant biphotonic properties. [18] Scheme 2. Reference compound (ZnPc) and substituted phthalocyanines with non-conjugated alkoxy and phenoxy ether-based arms (3-5).

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Thus, these phthalocyanine-cored assemblies 3-5 exhibited larger intrinsic 2PA cross-sections which somewhat increased with the size of the -manifold appended to the peripheral () positions. Quite remarkably, the cross-section found for 5 featuring extended phenylalkynyl spacers was significantly above these of the larger porphyrin-based dendrimers such as 1b-c or 2b-c, resulting in better figures of merit for two-photon imaging or two-photon sensitization of oxygen in THF. Based on the previous observations made for porphyrin-based dendrimers (see above), it appeared likely to us that the photonic properties of these phthalocyanine-based systems might be further improved by moving to more conjugated carbon-rich backbones and also to dendrimers of higher generations.

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Accordingly, we have now decided to investigate the photonic properties of the set of new dendrimers 6a-c and 7 (Scheme 3), featuring polyarylethynyl dendrons similar to these present in previous porphyrins 2a-c (Scheme 1). We will therefore describe hereafter the isolation and characterization of these new dendrimers using an efficient and convergent synthetic approach.

Subsequently, we will describe their linear and nonlinear optical (NLO) properties, as well as their oxygen photosensitizing capabilities, before briefly discussing their electronic structure and spatial organization with the help of DFT calculations. Notably, while several classes of phthalocyanines have already been used for imaging or PDT, [19] to the best of our knowledge, such "carbon-rich" phthalocyanine-cored dendrimers have never been envisioned for such applications and their biphotonic properties are still unknown.

■ RESULTS AND DISCUSSION

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We synthesized these new dendrimers 6a-c and phthalocyanine 7 (the extended analogue of 6a), by using a strategy similar to that previously used in our group to synthesize consecutive generations of tetrathienylporphyrin-cored dendrimers. [20] It basically involves three steps; (i) synthesis of dendritic alkyne precursor, (ii) formation of the tetra-iodo macrocycle core and (iii) coupling of four alkyne-terminated dendrons (8a-c and 9) to the central core. Such a convergent synthetic approach was preferred over alternative ones because the targeted dendrimers proved sufficiently soluble to be easily purified by chromatography. The zinc(II) complex of tetraiodophthalocyanine (ZnI4Pc in Scheme 4), our starting platform described in 1998 by T.

Torres [21] was used as a common intermediate to access the four targeted molecules 6a-c and 7, featuring up to sixteen fluorenyl groups. To do so, a fourfold Sonogashira coupling was carried out at ambient temperature in tetrahydrofuran-triethylamine mixtures. Whereas the alkynes 8ab and 9 were known compounds, [22] 8c was obtained in two steps by a Corey-Fuchs reaction from the known aldehyde precursor 10 [11b] with a total yield of 71% (Scheme 5). Compared to the more classical method consisting in cyclization of pre-functionalized phthalonitriles (the yield of which does generally not exceed 40%), this convergent approach gave remarkably good yields (higher than 70% for each compound). For instance, when the synthesis of 6a was attempted by cyclizing 4-((9,9-dibutyl-9H-fluoren-2yl)ethynyl)phthalonitrile (12) in presence of zinc(II) acetate, the phthalocyanine 6a was only isolated with a total yield of 23% (Scheme 6).

ACCEPTED MANUSCRIPT Scheme 6. Alternative synthesis of zinc complex 6a.

Characterization of the Dendrimers. After chromatographic purification and recrystallization, all dendrimeric (6a-c) and star-shaped (7) compounds were characterized by usual techniques, including elemental analysis. Thanks to the n-butyl chains on the peripheral fluorene groups, they all exhibited sufficient solubilities in THF for NMR characterization, in which solvent they appeared to be essentially non-aggregated, at least below concentrations of 10 mM (Figure 1a). 1[23] This is remarkable, since the low solubility of phthalocyanines, which usually results from their tendency to aggregate in solution, [22,24] is often an obstacle to their NMR characterization and practical use. Moreover, based on the previous investigation with phthalocyanines 3a-b (Scheme 2), [18] the introduction of the various n-butyl chains should have almost no effect on their electronic structure nor on their optical properties, apart perhaps slightly decreasing their fluorescence quantum yields.

As expected, 1 H NMR confirms that 6a-c and 7 are isolated as mixtures of positional regioisomers (Figure 1b), the phthalocyanine protons being observed as large multiplets in line with the presence of overlapping sets of closely lying signals belonging to the various regioisomers. Thus, their 1 H NMR spectra present diagnostic signals in three distinct spectral ranges (Figure 1a); (i) between 8.1 and 9.6 ppm for the twelve phthalocyanine protons; (ii) between 7.2 and 8 ppm for the aromatic protons of the fluorenyl and phenyl groups and (iii) between 0.5 and 2.4 ppm for the aliphatic protons of the n-butyl chains. In line with the increasing number of peripheral fluorenyl, the intensity of the two latter sets of signals increases 1 Notably, all these compounds were amenable to partial 13 C NMR characterization in THF-d [START_REF]FT-IR (cm -1 ): ῡ = 3305[END_REF] .

relative to that of the low field phthalocyanine signals (i) along the series 6a-c.

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A slight downfield shift of the signals corresponding to the twelve protons of the central phthalocyanine core can also be noticed when progressing from 6a to 6c (Figure 1b). By comparison, an upfield shift of these protons is stated when proceeding from 6a to 7. These shifts, which are not observed for the other aromatic protons, likely reflect a change in the magnetic shielding of the central tetrapyrrolic unit. The latter could result from ring current effects originating from the specific conformations adopted in solution by the peripheral dendrons in the higher generations dendrimers (see DFT section).

One-and two-photon absorption (1PA and 2PA) and emission properties, as well as oxygen photosensitization properties were next determined for 6a-c and 7 in THF solution (Table 1), using the zinc phthalocyanine ZnPc as a reference. The UV/Vis absorption spectra of all these new phthalocyanines and of the starting zinc complex ZnI4Pc were recorded between 250 and 800 nm (Figure 2). Without surprise, the spectrum of the latter compound is almost similar to that of the reference compound ZnPc. The new compounds 6a-b and 7 also feature the characteristic absorption bands of phthalocyanines already seen on the spectra of ZnPc and ZnI4Pc, [25] which are: (i) the Q-band, corresponding to the main absorption band, detected in the visible range between 650 and 750 nm, and resulting from π-π* transitions from the HOMO to the LUMO and LUMO+1 with a vibronic sub-band around 630 nm; 2[17g, 22, 26] (ii) the B-(or Soret) band, corresponding to a wide band between 300 and 500 nm and resulting from π-π* transitions from deeper lying MOs to the LUMO and LUMO+1, and, finally, (iii) the N band, a less intense and narrower band centered around 280-300 nm. The latter still corresponds to a set of more energetic π-π* transitions within the phthalocyanine core. These last two absorptions are not plainly detected for 6a-b and 7 because they are overlapped by another intense absorption band, absent in ZnPc and ZnI4Pc, which grows in intensity and shifts toward the blue when progressing from 7 to 6a and then to 6b-c (Figure 2) i.e. roughly with the increasing size of the conjugated π-manifold within the arms. This broad band, which becomes more intense than the Q-band for the two largest dendrimers (6b-c), can be confidently attributed to dendron-centered π-π* transitions. When this absorption is compared to these previously observed around 300 nm with phthalocyanines presenting non-conjugated dendrons, such as 3b-5 (Scheme 2), [18] a red shift is stated for it in 6a-c and 7. This shift reflects at least in part the better π-conjugation existing between the peripheral arms and core in these compounds. In a similar way, a bathochromic shift is experienced by the main Q-band following roughly the same order. Thus, this maximum shifts towards the red, from 674 to 697 nm, along the order: ZnPc < ZnI4Pc < 6b ≈ 6c < 6a ≈ 7. The Q-band of 6a-c and 7 grows in intensity following roughly the same order, the star-shaped phthalocyanine 6a presenting the most shifted and strongest Q-band. Again, this shift reflects the importance of the -manifold present on the peripheral dendrons, conjugating with the central core, in line with the existence of an effective mesomeric interaction between these parts in 6a-c and 7. Figure 3 shows the emission spectra of dendrimers 6a-c and 7 in THF, as well as that for their synthetic precursor (ZnI4Pc) and also that of ZnPc used as reference. After excitation at 606 nm i.e. in the Q vibronic sub-band, a strong red emission between 650 and 800 nm, characteristic of the phthalocyanine core, is observed. As for one-photon absorption, these dendrimers present a red-shifted emission relative to that of ZnI4Pc and ZnPc. Without surprise, the wavelength ordering between the new compounds follows that previously observed in absorption for the Q-band (ZnPc < ZnI4Pc < 6b ≈ 6c < 7 ≈ 6a).

Increase in size/generation ACCEPTED MANUSCRIPT As previously done with phthalocyanines 3-5, [18] the fluorescence quantum yields (ФF) were determined by comparison with ZnPc in a toluene/pyridine mixture (99:1). Compared to this standard ZnPc (ФF = 26%), all quantum yields found for the new compounds are higher than this value, excepted for ZnI4Pc (ФF = 11%). Actually, among the dendrimer series 6a-c, there is a regular increase in their fluorescence quantum yield with increasing generations (29% < 32% < 36%), suggesting that the increase of the -manifold on the peripheral dendrons favors the non-radiative deactivation of the phthalocyanine core. When 6a and 7 are compared, a marginally better quantum yield (30%) is found for 7, possibly in line with the previous observation. When compared to the fluorescence quantum yield of zinc complexes 3-5

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previously investigated (29-37%), [18] these quantum yields span a nearly similar range of values, but only the yield found for largest compound 6c compares to that previously obtained for 5, which was the most luminescent compound among 3-5 series.

Then, to probe the efficiency of the energy transfer process (EnT) between the peripheral dendrons as energy donors and the central phthalocyanine as energy acceptor, we have excited the dendrimers in their specific π-π* band, at about 300 nm (Figure 3b). By doing so, we observed no residual emission of the dendrons in the 350-450 nm range, [10b, 11b, 27] but only the characteristic emission band from the phthalocyanine core (between 650 and 800 nm), with similar fluorescence quantum yields than when the compounds are excited in their Q-band.

This reveals that for all these derivatives, the energy absorbed by the dendrons is almost quantitatively transferred to the central macrocycle, pointing to an optimal process (ФEnT ~ 100%), regardless of the generation considered.

For one-photon (1PA) fluorescence imaging purposes, one-photon brightness (ex.ФF) must be considered. [28] This figure of merit depends on the fluorescence quantum yield and on the absorption coefficient at the excitation wavelength (ex). Thus, when excitation is performed at the maximum of the Q-band, comparable or better one-photon brightnesses are obtained for 6a-c than for 5. As a result, all these compounds will perform better than the phthalocyanines 3b-5 previously studied. Notably, thanks to the efficient energy transfer previously discussed, significantly improved 1PA brightnesses (around 153 000 and 336 000 M -1 cm -1 , respectively) can be obtained for 6b and 6c if the excitation is performed at the wavelength corresponding to the dendron-specific π-π* absorption band (around 320 nm). Therefore, imaging might be more efficiently performed by exploiting the light harvesting capability of these dendrimers, by using a more energetic (blue shifted) excitation light beam, although the gain will be achieved at the expense of the penetration depth of the exciting light beam and might induce potentially larger background fluorescence due to intrinsic fluorophores.

Table 1. Photophysical properties of the zinc phthalocyanine complexes and of the reference ZnPc in THF at 293 K. Related data are also given for selected phthalocyanines in THF.

Cpnd 111.9 --a Fluorescence quantum yield determined relative to (Py)ZnPc in a toluene/pyridine (99:1) mixture after excitation at 606 nm. [29] b One-photon brightness. [28] c Singlet oxygen formation in a toluene/pyridine (99:1) mixture relative to ZnPc ( = 0.61) in the same mixture. [30] d Figure of merit for  equivalent to one-photon brightness. e Lit. ФF = 0.23 (± 0.03) determined in THF by the comparative method using chlorophyll in diethylether as a standard. [26] f Overlapped by the dendron absorption.

abs Dend abs B abs Q max Den  max Q em ФF a max Den ФF b max Q ФF b   c max Den Ф b max Q Ф d   (nm)  (10 3 M -1 .cm -1 ) (nm) (10 3 M -1 .cm -1 )  (10 3 M -1 .cm -1 ) ZnPc - 343
To evaluate the oxygen photosensitizing properties of 6a-c, the singlet oxygen formation yields were determined by measuring the luminescence of the singlet oxygen photogenerated in a toluene/pyridine (99:1) mixture. The values obtained for these compounds show a first decrease upon progressing from generation G0 to G1 (60% for 6a vs. 51% for 6b) and then a slight increase from generation G1 to G2 (51% for 6b vs. 53% for 6c). These values are similar or slightly lower than that of the ZnPc reference compound (61%). [30] This can be explained considering that the increase in the fluorescence quantum yields stated for these dendrimers is obtained at the expense of the singlet oxygen production, as already stated for 3-5. [18] Actually, the yield presently determined for 6c is nearly similar to that previously found for 5. Thus, when compared to phthalocyanines 3b-5, these results, along with the larger ex Q .ФF products for 6a-c, make them comparably better one-photon photosensitizers for singlet oxygen generation than 5 when excitation is performed at the wavelength of the Q-bands (i.e. at 690-700 nm for 6a-c). Likewise, to what was previously stated for fluorescence imaging, using the light-harvesting capability of the peripheral dendrons, the performance of the higher generation dendrimers 6b and 6c for oxygen sensitization might be further improved by selecting an excitation corresponding to the dendrimer absorption band (320-350 nm). Again, the increase in photosensitizing efficiency will be achieved at the expense of some tissular penetration depth of the exciting light beam.

The two-photon absorption (2PA) cross-sections of 6a-c dendrimers were next determined by two-photon excitation fluorescence (TPEF) and compared to that of ZnPc also used here as a reference compound (Table 2). A totally quadratic dependence of the fluorescence intensity as a function of the laser excitation power was observed for each compound at all the wavelengths (Figures S15 andS16; ESI), indicating that the cross-sections (σ2) so determined are solely due to two-photon absorption. However, past a limit (typically below 840 nm), which certainly corresponds to the upsurge of residual one-photon absorption, [31] the quadratic dependence of emission intensity on the laser power is lost. Thus, below this wavelength no intrinsic 2PA cross-sections can be determined anymore (Figure 4).

In such a case, one of the very specific advantages of 2PA for bio-oriented applications is lost; namely ultra-dense focalization of the excitation volume. [32] As found previously for the phthalocyanines 3-5, [18] the cross-sections of all these compounds increase when the wavelength of the incoming laser beam decreases (i.e. when the incoming light becomes more energetic). The best σ2 values are therefore obtained at the above-mentioned limit (840 nm) for ZnI4Pc and 6a-c and 7 (σ2 lim ; Table 2). Among the new derivatives, significantly larger σ2 values are found at this wavelength for the higher generation dendrimers 6b (G1) and 6c (G2).

At this limit, 6a (G0) absorbs significantly better than ZnPc, while ZnI4Pc is the least 2PAactive compound of this series. Thus, both 6b and 6c have σ2 maxima of 1640 and 1880 GM, respectively, against 1010 GM for 6a and 90 GM for ZnI4Pc (Figure 4). At higher wavelengths, a maximum can then be detected as a peak or as a shoulder (around 900 nm) on the 2PA plots recorded for 6a-c and 7 (σ2 max ). While the intensities of these 2PA maxima appear slightly less sensitive to the dendrimer size than σ2 lim values, they present a similar size-dependence. In addition, a second 2PA maximum, around 960 nm (130 GM), can also be detected for small 6a.

As previously discussed, [18] these different 2PA maxima can be attributed to population of various one-photon forbidden g-g excited states located at energies between these of the B-band and the Q-band, the nature of which being impossible to infer from the 1PA spectra (Figures S17 andS18; ESI). [33] While, the exact nature of these states (to which the various dendrons might contribute) is certainly determining for establishing the 2PA cross-sections, the bathochromic shift experienced by the first Q-state in 6a-c and 7 possibly contributes to promote 2PA via a resonance enhancement mechanism, [33a] especially when its energy comes closer to that of the exciting beam, as was previously demonstrated for phthalocyanines functionalized by conjugated carbon-rich substituents at one of their -positions. 3[32] [8, 34] 3 Contrary to was done with related compounds for which the absorption of the peripheral substituents was used to boost the 2PA cross-section of the central tetrapyrrolic unit via a biphotonic light-harvesting process, [13,14,16] the dendron-based state detected in the range 320-360 nm on 1PA spectra of 6a-c and 7 cannot be used for performing two-photon excitation of these nonlinear chromophores, since the required wavelengths (640-720 nm) would be below the limit (840 nm) where processes other than pure 2PA come in play. a Maxima of the intrinsic 2PA cross-sections measured in THF solutions by TPEF in the femtosecond regime; a fully quadratic dependence of the fluorescence intensity on the excitation power is observed. b Two-photon brightness (or 2P action cross-section) at the 2PA maximum. [35] c Two-photon brightness corrected for the molecular weight (M). d Enhancement factor for 2PA imaging relative to ZnPc at the limiting 2PA wavelength; EF1 = σ2 lim .ФF/52. [11b] e Two-photon efficiency for PDT. f Two-photon efficiency for PDT corrected for the molecular weight. g Enhancement factor for 2P-PDT relative to ZnPc at the limiting 2PA wavelength; EF2 = σ2 lim .Ф/122. [11b] ACCEPTED MANUSCRIPT

Regardless the exact origin of 2PA, the cross-sections of all these maxima appear to strongly depend on the chemical composition of the peripheral dendrons. As expected, according to Figure 4, the existence of an extended π-system on the dendrons seems to induce larger σ2 values among 6a-c and 7. In this respect, a great improvement is presently observed for all these compounds when the σ2 lim or σ2 max values are compared to those previously found for phthalocyanines 3-5. The largest of them was obtained for 5 (510/240 GM) and remains two to three times lower than those of 6a-c or 7 (Table 2). Then, an even larger improvement in σ2

values is obtained relative to the porphyrin-based dendrimers 2a-c. Furthermore, compared to these molecules, the 2PA maxima are significantly shifted to the red for the phthalocyanine derivatives 6a-c, which is also beneficial for most bio-oriented applications. [36] Given that S1). They should permit a better comparison between them regardless of their different -manifolds. [37]4 According to these figures, the lower generation dendrimer 6a presents the optimal 2PA response among the new dendrimers, with a ranking in the order: 6a > 6b > 6c ≈ 7. In other words, the increase in 2 when progressing from 6a to 6c in not proportional to the number of the most NLO-active electrons in these compounds. Furthermore, all the new compounds presently isolated appear to perform better, per active electron, then 2a-c and 3b-5, pointing to a better structural design for the new dendrimers 6a-c.

Finally, the two-photon action cross-section (σ2.ΦF), also called two-photon brightness, provides information about the suitability of two-photon absorbers to be used for fluorescence imaging (Table 3). [35] Likewise, the product σ2.Φ informs about their suitability to perform two-photon PDT. In line with the enhancement factors (EF1 and EF2) presently derived (Table 2), the significantly larger values found for 6a-c outline a clear advantage for these dendrimers relative to 3-5 or to the porphyrin-based dendrimers 2a-c for these tasks and highlight the existence of a dendrimeric effect, which makes it possible to boost their performances upon moving to higher generations. Then, considering figures of merit, which correct these values for the molecular weight (or for the volume) of the molecules (Table 2), we see that the advantage in favor of the higher generations is lost. This indicates that the increase in performances does not scale anymore with the increase in their size, in line with the statement made above for effective -electrons. 5 However, while comparison with other phthalocyaninebased photosensitizers is not always easy due to the lack of comparable data in the literature, [19a, 19b, 38] the photonic performances presently determined for 6a-c and 7 are clearly better than those of most of the systems currently in use for cancer treatment or imaging. [19b] DFT calculations and molecular dynamics (MD) simulations were undertaken to gain more insight about the electronic and steric impact of the peripheral dendrons on the properties of the central macrocycle in these new dendrimers. Following geometry optimization in vacuum, the electronic structure of 6a-c and 7 were computed using the model compounds 6a'-c' and 7' in which the n-butyl groups on the 9 position of the 2-fluorenyl groups have been replaced by methyl groups. These molecular models correspond to tetra-substituted -regioisomers symmetrically functionalized in positions 2, 9, 16 and 23. After geometry optimization, the molecules 6a' and 7' (Figures S19 and5) appear completely flat with the fluorene moieties and the phthalocyanine core (and also the phenyl linkers for 7') lying in the same plane. As stated for 7', the various possible orientations of the fluorene fragments in this plane do not appear to affect significantly the energy ordering of the frontier molecular orbitals (FMOs). As shown on Figure 5, the fluorene fragments cannot all remain in the phthalocyanine plane for higher generations due to steric congestion. Thus, for 6b', the arms start twisting out of this plane (9.57°). This effect is much more marked with 6c', for which the molecule adopts a 3D geometry with fluorene fragments distributed all around the phthalocyanine core. From these studies, only 6a'-b' and 7' appear liable to undergo stacking interactions via their phthalocyanine core in solution, although the presence of the various n-butyl chains in the real molecules might interfere, especially in 6a and 7. The HOMOs of 6a' and 7' in these conformers are completely delocalized over the whole molecule (Figure 6), in line with a good electronic conjugation though the parasubstituted phenyl linkers in 7. In contrast, the HOMOs of 6b' and 6c' only extend to the first phenyl ring of the dendrons, indicating that the meta-substitution hinders conjugation, which is possibly also disfavored by the less coplanar conformations adopted by the dendrons in these molecules. Then, for all compounds, the degenerate LUMO and LUMO+1 set is essentially located on the phthalocyanine core. In line with the blue shift experimentally observed for the Q-band between 7, 6a and 6b/6c, the HOMO/LUMO gap increases from 2.00 eV for 7' to 2.03 eV for 6a' to 2.08 eV for 6b' and finally to 2.14 eV for 6c'. However, the increase in gap predicted by the calculations between 6b' and 6c' does not reflect the Q-band energy experimentally found for 6b and 6c. Actually, the gaps predicted for 6b' and 6c' recall values computed for phthalocyanines such as 3b (2.11 eV) or 5 (2.14 eV), presenting four unconjugated arms at their periphery. Thus, the significantly lower gaps calculated for 6a' and 7' likely originate from existence of -conjugation between the peripheral arms and the central phthalocyanine core and from the extended -conjugation within these peripheral arms, at least compared to 6b' and 6c'. Time-dependent density functional theory (TD-DFT) calculations were next undertaken on 6a' and 7' to assess the nature of the main electronic transitions experimentally observed for their real counterparts 6a and 7. 6 In this respect, the simulated spectra (Figure S20, ESI) display a set of nearly degenerate transitions in the 670-680 nm range corresponding to HOMO→LUMO and HOMO→LUMO+1 excitations with high oscillator strengths, formally corresponding to those of the Q-Band. 7[39] Then, another set of allowed →* transitions partly centered on the phthalocyanine core and formally giving rise to the B-band [39] is computed at about 380 nm for 6a' and around 409-433 nm for 7'. Due to the intimate admixture of fluoreneand phthalocyanine-based  and  MOs, all these →* transitions present some chargetransfer (CT) character between the peripheral dendrons and the central core and none of them remains strictly localized on the tetrapyrrolic core. Finally, several moderate-to-intenselyallowed →* transitions, heavily weighted on the peripheral dendrons, are computed between 380 and 359 nm for 6a' and between 409 and 373 nm for 7'. These excitations, which again present various degree of CT character with the central phthalocyanine core, give rise to an 6 Such calculations were found to be too time and resource consuming for the higher generation dendrimers 6b' and 6c'. [START_REF]FT-IR (cm -1 ): ῡ = 3063 (w, Ar-H), 2956-2861[END_REF] Given that the vibronic splitting of that band is not reproduced by TD-DFT calculations, we have only listed the most intense vibronic band in Table 3. Evidently, this will contribute to decrease the match between the experimental and simulated spectra.

intense band located on the high energy side of the B-band, recalling the band which was attributed to arm-centered transitions on the absorption spectra of 6a and 7 (Figure 2).

Interestingly, two moderately allowed excitations are also found at wavelengths between those of the Q-and B-bands, a spectral range in which no transitions were experimentally detected.

These transitions actually correspond to Flu→*Pc CT processes in 6a' and 7'. We believe that these transitions take place at slightly different energies in the real molecules 6a and 7, and might therefore either be hidden beneath the vibronic sub-bands experimentally observed on the high energy-side the Q-band or could correspond to the shoulder observed on the low energy-side of the B-Band. Similar transitions were previously also calculated (and not observed) for the Zn(II) phthalocyanine complex 5. [18] Notably, other excitations of the same kind, but with negligible oscillator strength, are also computed in the same energy range. These might correspond to the forbidden g-g states giving rise to 2PA (see above). Considering that the experimental measurements were obtained with mixtures of stereoisomers and that neither the dielectric constant of the solvent nor the vibronic coupling were taken in consideration during the calculations, the agreement between the simulated and experimental UV-Vis spectra can be considered as correct for the main transitions. Considering the conformational evolution of 6b in solution, a related statement can be made; the central phthalocyanine core also remains almost coplanar during the simulation, while extensive flapping and twisting of the fluorenyl groups within their peripheral arms are observed. This motion is also accompanied by large rotations of each dendron around the triple bond linking its first phenyl group to the central core (Figure 7, SI Video S5). In this compound 6b, the extended arms are well isolated and can freely rotate and no interactions between the

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neighbouring arms through the butyl chains or the fluorene fragments is observed. Also, notably, a conformation with the four peripheral dendrons oriented perpendicular to the phthalocyanine core is never observed among the most stable ones for this molecule. Then, in contrast to 6b, the dendrimer 6c appears much more flexible in solution and strong interactions between the neighbouring arms can be observed. During the simulation the large dendrons rotate and curve to eventually interact in an intramolecular way through -stacking interactions.

This evolution contributes to flattening the molecule from a ball-shaped conformation into transitory a donut-like shaped conformation (Figure 7, bottom, SI Video S6). The bending and the clustering of the fluorene arms is driven here by strong intramolecular - interactions between fluorene fragments but also between fluorene fragments and phenyl rings of neighbouring arms (see white circles, on Figure 7). [START_REF]FT-IR (cm -1 ): ῡ = 3305[END_REF] In spite of this flattening process, the dendron shell remains too bulky to allow any intermolecular - stacking process to occur between phthalocyanine cores (SI Video S7). 9

These results confirm that, at concentration as high as 7.874 10 -3 mol.L -1 , these dendrimers remain well isolated in THF solution. In addition, the Brownian "paddlewheel" motions of the dendrons evidenced by MD certainly contributes to disfavour spontaneous aggregation for the largest dendrimers (6b-c) it may also restrict direct access to the central Zn(II) phthalocyanine unit for molecules localized in equatorial positions. A contrario, the overall disk-shaped or donut-shaped conformation eventually adopted by 6b and 6c, respectively, can restore an easier axial access to this unit, especially for small molecules (such as oxygen). Ultimately, these nearly coplanar conformations adopted in solution, will contribute to optimize the electronic interactions between the peripheral dendrons and the central phthalocyanine core (via -conjugation) and might possibly also reinforce the magnetic deshielding of its protons at the same time. [START_REF]FT-IR (cm -1 ): ῡ = 3305[END_REF] In the absence of solvent, this dendrimer 6c adopts a pocket-like conformation, with the arms all aggregated on one side of the phthalocyanine core, showing the high flexibility of this molecule (Figure S21). 9 Stacking distances of 24.6 ± 3.5 Å are usually observed between phthalocyanine cores in MD simulations with the large dendrimer G3. Note that concentrations used during these simulations (7.874 10 -3 M) are much higher than the experimental ones. * (B-Band) 409 [1.26] 409 [1.35] H→L+4 (82%) H→L+5 (82%)

*Flu Pc

[289]

393 [1.63] 393 [1.78] 373 [1.30] 373 [1.38] H

-2→L+2 (70%) H-3→L+2 (70%) H-2→L+2 (14%), H-2→L+3 (51%) H-3→L+2 (14%), H-3→L+3 (51%)
*Pc Flu a in nm. b Experimental absorption coefficient (in 10 3 M -1 .cm -1 ). c Computed oscillator strength. d Vibronic sibbands (not modelled by computations). e Tentative assignment.

■ CONCLUSIONS

In this work we investigate the impact of changing the core in tetrapyrrolic Dendrimers. So, we have described herein the synthesis and characterization of a series of new dendrimers (6a-c and 7) presenting "carbon-rich" dendrons conjugated with a central Zn(II) phthalocyanine core and having four to sixteen 9,9-dibutyl-2-fluorenyl groups at their periphery. These new dendrimers were actually isolated as mixtures of tetra-substituted -regioisomers. Thanks to the

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presence of numerous n-butyl side-chains, but also thanks to the rigidity of the peripheral dendrons, which contribute (upon randomly rotating) to disfavor stacking in solution for the higher generations below 10 -3 M, a good solubility is observed for all these dendrimers in organic solvents. In terms of linear photophysical properties, these dendrimers exhibit a high luminescence, with quantum yields up to 36%. These yields depend on the dendron structure (e.g. compare 6a and 7) and also, for a given structure, on the generation considered (e.g. compare 6a-c) increasing for higher generations (i.e. from G0 to G2). As previously stated for related porphyrin-and phthalocyanine-based dendrimers, a very energy transfer from the peripheral fluorenyl units toward the central tetrapyrrolic core allows these photochromic systems to efficiently "harvest" energy from UV-visible light and to funnel it toward the central phthalocyanine Zn(II) complex. There, it can be re-emitted or re-used to photosensitize molecular oxygen with good efficiency, making all these new dendrimers appealing photosensitizers. In this respect, MD calculations reveal that a "donut-shaped" structure is adopted in solution for the higher generation members which allows axial access to the central tetrapyrrolic unit to small molecules such as oxygen. Thus, albeit the quantum yields of 6a-c or 7 for singlet oxygen formation are slightly lower (around 51-55%) than that of the zinc(II) phthalocyanine complex (ZnPc) often used as reference, these new photosensitizers retain a sufficient ability to produce cytotoxic oxygen for envisioning applications in PDT, especially if the light-harvesting capabilities of the peripheral dendrons is exploited in the choice of the excitation wavelength. In this respect and considering their relative one-photon brightness, 6ac and 7 appear better suited for performing simultaneously one-photon imaging and PDT than the related systems previously studied, such as phthalocyanine-based dendrimers featuring nonconjugated fluorenyl groups at their periphery (3-5) or series of analogous mesotetraphenylporphyrin-cored dendrimers (2a-c) previously developed. More remarkably and in line with our expectations, 6a-c and 7 function as efficient two-photon absorbers. Thanks to their peripheral dendrons featuring an extended -manifold conjugated to the central tetrapyrrolic core, these nonlinear chromophores, exhibit fairly large intrinsic 2PA crosssections (up to 1 880 GM for 6c), which increase with the size of their peripheral dendrons. The values presently found are significantly larger than those previously determined for 3-5 and for 2a-c. This in turn induces better figures of merit for two-photon imaging and for oxygen sensitization, making these new systems more appealing than the former ones for applications in two-photon bioimaging or PDT. However, when their size or the number of active electrons (Neff) is taken into consideration for evaluating their nonlinear absorption properties, the dendrimers of higher generation appear to be not as efficient as some of the smaller systems,

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leaving some room for further improvement. More generally, based on the available data regarding the relevant photonic performances, these new dendrimers stand the comparison with other phthalocyanine-based systems currently used as one-or two-photon photosensitizers in cancer therapy. [19b] These first results are therefore very encouraging to explore further their applied potential in PDT, theranostic or related medical uses. [19d, 19e, 40] Work along these lines is currently in progress in our group.

■ EXPERIMENTAL SECTION

Supplementary tables and figures are provided in the Supporting Information: Reagents were purchased from commercial suppliers and used as received. The dendron precursors 8a-b [20] and 9 [41] , as well as the benzaldehyde 10 [11b] and tetraiodophthalocyanine complex ZnI4Pc [21] were obtained as previously described in the literature.

Synthesis. General Procedure for 4-((9,9-Dibutyl-9H-fluoren-2-yl)ethynyl) phthalonitrile ( 12): In a Schlenk tube, to a mixture of ethynyfluorenyl 8a (227 mg, 0.75 mmol, 1.5 eq), 4-iodophthalonitrile (127 mg, 0.5 mmol, 1 eq), Pd(PPh3)2Cl2 (3.5 mg, 0.005 mmol, 1% eq) and CuI (0.6 mg, 0.003 mmol, 0.6% eq), were added THF (2 mL) and NEt3 (8 mL) under argon. The mixture was degassed and stirred for 16 h at room temperature. After being evaporated, the residue was filtered and extracted three times with CH2Cl2. The organic layer was dried with MgSO4, filtered and the solvent was evaporated. The crude product was adsorbed onto silica and further purified by chromatography using heptane/CH2Cl2 (3:1) as eluent, leading to 12 as a white powder (167 mg, 78% yield). 7.69 (m, 2H), 7.57 -7.51 (m, 2H), 7.40 -7.33 (m, 3H), 2.06 -1.93 (m, 4H), 1.09 (h, J = 7.4 Hz, 4H), 0.68 (t, J = 7.3 Hz, 6H), 0.64 -0.52 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ = 151. 2, 151.1, 143.1, 139.9, 135.9, 135.4, 133.5, 131.1, 129.7, 128.2, 127.1, 126.3, 123.0, 120.3, 119.9, 116.3, 115.3, 114.8, 114.0, 98.2, 86.0, 55.2, 40.1, 25.9, 23.0, 13.8. FT-IR (cm -1 ): ῡ = 3052 (w, Ar-H), 2958-2854 (s, Aliph. C-H), 2237 (m, C≡N), 2206 (s, C≡C), 1593, 1543, 1494, 1464, 1451, 1419, 1271, 1186, 1086, 940, 894, 842, 780, 741 added into Schlenk and the mixture was kept stirring at low temperature for 2 min. The bath was removed and the solution was stirred overnight at room temperature. At last, the mixture was cooled to 0 o C again and aldehyde 10 (420 mg, 0.27 mmol, 1 eq) in 20 mL of dry CH2Cl2 was added under argon, and then, the solution was stirred at room temperature for 4 h. After the evaporation of volatiles, the residue was adsorbed onto silica and further purified by chromatography using petroleum ether/CH2Cl2 (10:1) as eluent system. Intermediate 11 was obtained as a white powder (400 mg, 89% yield). General Procedure for 2,2',2'',2'''-((((5-Ethynyl-1,3-phenylene)bis(ethyne-2,1diyl))bis(benzene-1,3,5 triyl))tetrakis(ethyne-2,1-diyl))tetrakis(9,9-dibutyl-9H-fluorene) (8c). In a Schlenk tube, n-BuLi (0.22 mL, 0.36 mmol, 3 eq) was added to a cold solution of i Pr2NH (0.05 mL, 0.36 mmol, 3 eq) in dry THF (3 mL) at -78 o C. After warming up to room temperature, the mixture was injected dropwise into the solution of compound 11 (202 mg, 0.12 mmol, 1 eq) in dry THF (7 mL) at -78 o C in liquid nitrogen-acetone bath. The mixture was stirred at low temperature for 1 h, then quenched with saturated NH4Cl (5 mL). The reaction allowed warming to room temperature. After evaporation of volatiles, the residue was adsorbed onto silica and further purified by chromatography using a mixture of heptane/CH2Cl2 (20:1) as eluent, showing 8c as a white powder (146 mg, 81% yield). 1 H NMR (400 MHz, CDCl3): δ

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General Procedure for Phthalocyanine 6a (G0): Phthalocyanine 6b (G1): In a Schlenk tube, to a mixture of tetraiodophthalocyanine (ZnI4Pc) (27 mg, 0.025 mmol, 1 eq), 8b (105 mg, 0.15 mmol, 6 eq), Pd(PPh3)2Cl2 (0.18 mg, 2.5 x 10 -4 mmol, 1% eq) and CuI (0.029 mg, 1.5 x 10 -4 mmol, 0.6% eq) were added THF (5 mL) and NEt3 (5 mL) under argon. Then, the system was degassed by freeze-pump-thaw twice and stirred overnight at room temperature. After being evaporated, the suspension was poured into cold methanol. The blue precipitate was then filtered off and washed with hot methanol. The crude product was purified by column chromatography on silica gel using heptane/THF (2:1) as an eluent system and then recrystallized from MeOH/CH2Cl2. The title compound 6b was obtained as a blue solid (69 mg, 82% yield). 3, 151.1, 142.4, 140.8, 134.2, 131.2, 127.9, 127.2, 126.4, 125.2, 125.1, 123.1, 121.6, 120.4, 120.1, 92.4, 92.3, 88.2, 55.4, 40.5, 26.4, 23.4, 13.6.

FT-IR (cm -1 ): ῡ = 3063 (w, Ar-H), 2955-2859 (s, Aliph. C-H), 2212 (w, C≡C), 1609, 1579, 1489, 1466, 1453, 1379, 1308, 1154, 1137, 1096, 1050, 980, 894, 876, 830, 776, 739 General Procedure for Phthalocyanine 6a (G0): Phthalocyanine 6c (G2): In a Schlenk tube, to a mixture of tetraiodophthalocyanine (ZnI4Pc) (10 mg, 0.009 mmol, 1 eq), 8c (83 mg, 0.055 mmol, 6 eq), Pd(PPh3)2Cl2 (0.06 mg, 9 x 10 -5 mmol, 1% eq) and CuI (0.01 mg, 5.4 x 10 - 5 mmol, 0.6% eq) were added THF (3 mL) and NEt3 (3 mL) under argon. Then, the system was degassed by freeze-pump-thaw twice and stirred overnight at room temperature. After being evaporated, the suspension was poured into cold methanol. The blue precipitate was then filtered off and washed with hot methanol. The crude product was purified by column chromatography on silica gel using heptane/THF (3:1) as an eluent system and then recrystallized from MeOH/CH2Cl2. Complex 6c was obtained as a blue solid (46 mg, 76% yield). 2, 151.1, 142.4, 142.2, 140.8, 134.5, 131.2, 131.1, 127.9, 127.2, 126.3, 125.1, 125.0, 124.5, 124.1, 123.1, 121.5, 121.4, 120.4, 120.0, 92.3, 88.0, 87.9, 55.3, 40.4, 26.3 23.3, 13.6. FT-IR (cm 1584, 1489, 1466, 1453, 1378, 1306, 1156, 1143, 1097, 1051, 893, 877, 830, 776, 739 General Procedure for Phthalocyanine 6a (G0): Phthalocyanine 7: In a Schlenk tube, to a mixture of tetraiodophthalocyanine (ZnI4Pc) (27 mg, 0.025 mmol, 1 eq), 9 (60 mg, 0.15 mmol, 6 eq), Pd(PPh3)2Cl2 (0.18 mg, 2.5 x 10 -4 mmol, 1% eq) and CuI (0.029 mg, 1.5 x 10 -4 mmol, 0.6% eq) were added THF (5 mL) and NEt3 (5 mL) under argon. Then, the system was degassed by freeze-pump-thaw twice and stirred overnight at room temperature. After being evaporated, the suspension was poured into cold methanol. The dark green precipitate was then filtered off and washed with hot methanol. The crude product was purified by column chromatography on silica gel using heptane/THF (2:1) as an eluent system and then recrystallized from MeOH/CH2Cl2. The title compound 7 was obtained as a green solid (48 mg, 88% yield). 1 H NMR (400 MHz, THF-d8): δ = 9. 16 -8.85 (m, 8H), 8.26 -8.12 (m, 4H), 8.02 -7.86 (m, 8H), 7.81 -7.63 (m, 20H), 7.62 -7.57 (m, 4H), 7.46 -7.40 (m, 4H), 7.38 -7.30 (m, 8H), 2.22 -1.99 (m, 16H), 1.21 -1.06 (m, 16H), 0.76 -0.52 (m, 40H). 13 C NMR (101 MHz, THF-d8): δ = 152. 4, 152.2, 151.4, 151.3, 142.4, 141.1, 138.3, 137.6, 132.5, 132.4, 132.2, 131.5, 128.1, 127.4, 126.4, 126.1, 124.3, 124.2, 124.0, 123.3, 122.9, 122.1, 120.6, 120.4, 93.3, 93.2, 91.5, 89.8, 55.6, 40.7, 23.6, 13.8. FT-IR (cm -1 ): ῡ = 3063 (w, Ar-H), 2954-2858 (s, Aliph. C-H), 2206 (w, C≡C), 1609, 1510, 1466, 1451, 1397, 1320, 1298, 1268, 1148, 1091, 1048, 938, 894, 831, 776, 743. HRMS-MALDI (m/z): [M] + (C156H128N8Zn) 2176.855 (calcd: 2176.955).

Anal. Calcd. (%) for C156H128N8Zn: C, 85.94; H, 5.92; N, 5.14. Found: C, 85.19; H, 5.94; N, 5.11.

Spectroscopic Measurements. All photophysical properties have been performed with freshly-prepared air-equilibrated solutions at room temperature (298 K). UV-Vis absorption spectra were recorded on a BIO-TEK instrument UVIKON XL spectrometer or on a Jasco V-570 spectrophotometer in THF (HPLC grade). Steady-state fluorescence measurements were performed on dilute solutions (ca. 10 6 M, optical density < 0.1) contained in standard 1 cm quartz cuvettes using an Edinburgh Instrument (FLS920) spectrometer in photon-counting mode. Fully corrected emission spectra were obtained, for each compound, after excitation at the wavelength of the absorption maximum, with Aex < 0.1 to minimize internal absorption. [42] Measurements of singlet oxygen quantum yields (). Measurements were performed on a Fluorolog-3 (Horiba Jobin Yvon), using a 450W Xenon lamp, with air-equilibrated solutions. The optical density of the reference and the sample solution were set equal to 0.15 at

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the excitation wavelength (maximum of the Soret band). The emission at 1272 nm was detected using a liquid nitrogen-cooled Ge-detector model (EO-817L). The emission spectra were corrected for the wavelength dependence of the lamp intensity and the excitation monochromator efficiency (excitation correction). Singlet oxygen quantum yields ΦΔ were determined in toluene/pyridine (99:1) v/v solutions, using zinc(II) phthalocyanine (ZnPc) in a toluene/pyridine (99:1) mixture as reference solution (ΦΔ[ZnPc] = 0.61) [30] and were estimated from corrected 1 O2 luminescence at 1272 nm. The uncertainty of the values of the singlet oxygen quantum yields determined by this method was estimated to be ±0.05. were measured relative to fluorescein in 0.01 M aqueous NaOH using the well-established method described by Xu and Webb [43] and the appropriate solvent-related refractive index

Two-Photon Absorption

Scheme 1 .

 1 Scheme 1. Molecular structures of increasing generations of TPP-based dendrimers with non-conjugated (1a-c) or conjugated (2a-c) peripheral fluorenyl arms.

Scheme 3 .

 3 Scheme 3. Targeted phthalocyanines dendrimers 6a-c and star shaped 7 (the extended analogue of 6a).

Scheme 4 .

 4 Scheme 4. Synthesis of new conjugated dendrimers 6a-c and Pc 7.

Scheme 5 .

 5 Scheme 5. Synthesis of new dendron precursor 8c.

Figure 1 .

 1 Figure 1. a) Complete 1 H NMR spectra of phthalocyanine 6a in THF-d8 (solvent and water peaks labelled by asterix); b) Low-field section of the 1 H NMR spectra of phthalocyanine derivatives 7 and 6a-c in THF-d8.

Figure 2 .

 2 Figure 2. The UV-visible absorption spectra of the new series 6a-c and 7, the ZnI4Pc precursor and ZnPc used as a reference in THF.

Figure 3 .

 3 Figure 3. a) Normalized emission spectra of dendrimers 6a-c, 7, ZnI4Pc and ZnPc after excitation at 606 nm in THF; b) Normalized emission spectra of 6a-c and 7 under similar conditions after excitation at 300 nm.

Figure 4 .

 4 Figure 4. Two-Photon Absorption Spectra for phthalocyanine-Cored Dendrimers 6a-c, 7, ZnI4Pc and ZnPc.

  similar dendrons are present in 6a-c and 2a-c, part of this enhancement can be attributed to the change in the central tetrapyrrolic unit, while the improvement stated for 6a-c and 7 over 3b-5 can be traced back to the existence of a better conjugation between the peripheral dendrons and the central ring. To understand better the structural dependence of these nonlinear absorptions, we have normalized them by dividing the 2PA cross-sections σ2 by the square of the effective number of -electrons (Neff 2 ). These σ2/Neff 2 values are figures of merit allowing to take into consideration the influence of the different numbers of -electrons present in each compound on σ2 values (See ESI, Table

Figure 5 .

 5 Figure 5. Optimized geometry for 7', 6b' and 6c' dendrimers (view from above and side view).

Figure 6 .

 6 Figure 6. Frontier molecular orbitals (bottom: HOMO, top: LUMO), of dendrimers 6a'-c' and 7' (isocontour value of 0.01 [e bohr -3 ] 1/2 ).

Finally, in order

  to obtain additional insight about possible geometrical issues related to the dendritic structures, the conformations of the real dendrimers 6a-c and 7 (with butyl chains) have been simulated by molecular dynamics (MD) in vacuum and in THF solution. MD simulations run for 6a and 7, with or without THF over 4 ns, reveal that these molecules remain almost flat during all the simulation time, undergoing only flapping or twisting of the peripheral fluorene arms around their initial position (Figure7, SI Video S1 and S2). Now, when such molecules are considered in the same volume, they show some interactions through the extended arms but no tendency to stack (SI Video S3). On contrary, in CH2Cl2 (starting from the same positions), these molecules stack readily and form well-eclipsed dimers with a good overlap of their phthalocyanine cores (SI Video S4), which is in line with their insolubility in dichloromethane.

Figure 7 .

 7 Figure 7. Left: Starting configuration of one molecule of 6a, 7, 6b and 6c. Right: molecular configuration after energy relaxation and 4ns simulation in NVT ensemble (fixed Number of molecules, Volume and Temperature) in a unit cell of a = 75 Å, b = 75 Å, c = 75 Å,= =  = 90° filled with THF molecules (density = 1). For large 6c, the image was caught after 1.7 ns.

1 H

 1 NMR and13 C NMR characterization of all new compounds, selected FMO plots, TD-DFT and MD results, cartesian coordinate of the model compounds, two-photon absorption data for 6a-c and 7. Seven video clips representing selected MD simulations.Materials.Compounds were purified by chromatography on silica gel using different mixtures of eluents as specified. Unless otherwise stated, all solvents used in reactions were distilled using common purification protocols, except DMF and i Pr2NH which were dried on molecular sieves (3 Å).. 1 H and13 C NMR spectra were recorded on Bruker Ascend 400 and 500 at 298 K. The chemical shifts are referenced to internal tetramethylsilane (TMS). Highresolution mass spectra were recorded on different spectrometers: a Bruker MicrOTOF-Q II, a Thermo Fisher Scientific Q-Exactive in ESI positive mode and a Bruker Ultraflex III MALDI Spectrometer at CRMPO (Centre Regional de Mesures Physiques de l'Ouest) in Rennes.

  Experiments. To span the 790-920 nm range, a Nd:YLFpumped Ti:sapphire oscillator (Chameleon Ultra, Coherent) was used generating 140 fs pulses at a 80 MHz rate. The excitation power is controlled using neutral density filters of varying optical density mounted in a computer-controlled filter wheel. After five-fold expansion through two achromatic doublets, the laser beam is focused by a microscope objective (10×, NA 0.25, Olympus, Japan) into a standard 1 cm absorption cuvette containing the sample. The applied average laser power arriving at the sample is typically between 0.5 and 40 mW, leading to a time-averaged light flux in the focal volume on the order of 0.1-10 mW/mm 2 . The fluorescence from the sample is collected in epifluorescence mode, through the microscope objective, and reflected by a dichroic mirror (Chroma Technology Corporation, USA; ''red'' filter set: 780dxcrr). This makes it possible to avoid the inner filter effects related to the high dye concentrations used (10 -4 M) by focusing the laser near the cuvette window. Residual excitation light is removed using a barrier filter (Chroma Technology; ''red'': e750sp-2p). The fluorescence is coupled into a 600 µm multimode fiber by an achromatic doublet. The fiber is connected to a compact CCD-based spectrometer (BTC112-E, B&WTek), which measures the two-photon excited emission spectrum. The emission spectra are corrected for the wavelengthdependence of the detection efficiency using correction factors established through the measurement of reference compounds having known fluorescence emission spectra. Briefly, the set-up allows for the recording of corrected fluorescence emission spectra under multiphoton excitation at variable excitation power and wavelength. 2PA cross sections (σ2) were determined from the two-photon excited fluorescence (TPEF) cross sections (σ2.ΦF) and the fluorescence emission quantum yield (ΦF). TPEF cross sections of 10 -4 M THF solutions

Table 2 .

 2 Two-photon absorption of phthalocyanine Zn(II) complexes and related tetrapyrrolic macrocycles in THF at 20 °C.

	Cpnd	λADP lim	σ2 lim a	λADP max	σ2 max a	σ2 lim .ФF b	σ2 max .ФF b	σ2 lim .ФF/M c	EF1 d	σ2 lim .Ф e	σ2 lim .Ф/M f	EF2 g	Refs
		(nm)	(GM)	(nm)	(GM)	(GM)	(GM)	(GM/g.mol)	(GM)	(GM)	(GM/g.mol)	(GM)
	ZnPc	820	200	880	150 c	52	39	0.090	1.00	122	0.212	1.00	[33a]
	ZnI4Pc	820	90	880	40	10	4	0.009	0.19		-		This work
	2a	790	380	-	-	76	-	0.042	1.46	266	0.147	2.18	[11b]
	2b	790	200	-	-	22	-	0.007	0.69	118	0.039	0.97	[11b]
	2c	790	290	-	-	38	-	0.012	0.73	162	0.052	1.33	[11b]
	3b	830	330	880	160	109	53	0.060	2.10	188	0.104	1.54	[18]
	4	860	160	880	140	37	32	0.020	0.71	96	0.053	0.79	[18]
	5	830	510	880	240	189	89	0.088	3.63	275	0.128	2.26	[18]
	6a	840	1010	880	630	293	189	0.165	5.83	606	0.341	4.97	This work
	6b	840	1640	880 (sh)	670	525	214	0.155	10.10	836	0.248	6.86	This work
	6c	840	1880	880 (sh)	670	677	241	0.103	13.02	996	0.151	8.17	This work
	7	840	900	870 (sh)	420	270	126	0.124	5.19	-	-	-	This work

Table 3 .

 3 Computed (B3LYP /6-31G*/LANL2DZ) values (nm). Energy and composition of the first singlet excited states (wavelength, oscillator strength f, transition percentage).

	Real/Model	Observed Transitions for Real	Calculated Transitions for Model Cpnds
	Cpnds	Cpnds a,b max [max]	Energy a,c max [f]	Composition	Major Assignment
	6a/6a'	697 [398] d	666 [0.96]	H→L (95%)	*(Q-Band)
		628 [69.2] d	667 [0.96]	H→L+1 (95%)
		/	556 [0.30] 556 [0.30]	H-1→L (90%) H-1→L+1(90%)	*Pc Flu
			505 [0.28]	H-4→L (93%)
			505 [0.28]	H-4→L+1 (93%)
		380 (sh) [122]	384 [0.28]	H-5→L (30%),	* (B-Band)
				H-5→L+1 (34%)
			384 [0.29]	H-5→L (33%),
				H-5→L+1 (29%)
			380 [0.74] 380 [0.74]	H→L+4 (56%) H→L+5 (57%)	*Flu Pc
			371 [0.24] 371 [0.25]	H-8→L (67%) H-8→L+1 (67%)	*Pc Flu
		338 [179]	359 [1.21] 359 [1.21]	H-2→L+2 (62%) H-3→L+2 (62%)	*Flu+Pc Flu
			346 [0.22]	H-21→L+1 (55%)	*(N-Band) e
			346 [0.23]	H-21→L (57%)
	7/7'	696 [373] d	681 [1.20]	H→L (91%)	* (Q-Band)
		627 [69.2] d	680 [1.23]	H→L+1 (91%)
		/	596 [0.33] 596 [0.31]	H-1→L (98%) H-1→L+1(98%)	*Pc Flu
			549 [0.23]	H-4→L (94%)
			548 [0.23]	H-4→L+1 (94%)
		388 (sh) [153]	433 [0.54]	H-8→L (87%)
			433 [0.55]	H-8→L+1 (87%)

  1 H NMR (400 MHz CDCl3): δ = ACCEPTED MANUSCRIPT 7.95 (d, J = 1.6 Hz, 1H), 7.85 (dd, J1 = 8.2, J2 = 1.6 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.75 -

  . HRMS-MALDI (m/z): [M+H] + (C496H449N8Zn) 6586.389 (calcd: 6586.482). Anal. Calcd. (%) for C496H448N8Zn: C, 90.45; H, 6.86; N, 1.70. Found: C, 89.88; H, 6.72; N, 1.73.

In line with the 1 H NMR data, the shape of the Q-band (with no shoulder), which remains constant throughout the whole series of new compounds, is suggestive of absence of aggregates in solution, at the concentrations used (10 -4 -10 -7 M).[39,51,56]

The effective numbers of -electrons (Neff values) were derived for each compound considering peripheral dendrons disconnected from the central phthalocyanine core (TableS1, ESI).

The molecular mass and volume of molecules are usually related through the relative constancy of their volumic mass (or density).

■ ACKNOWLEDGEMENTS

The authors acknowledge CNRS for their financial support and "the Ministère de l'Enseignement Supérieur et de la Recherche Scientifique de Tunisie" for PhD funding (SA and SB) as well as China Scholarship Council (CSC) for PhD funding (ZS). This project was supported by the departmental committees CD35 and CD28 of the "Ligue contre le Cancer du Grand-Ouest". We also thank Guillaume Clermont (ISM) for his help in the two-photon and singlet oxygen measurements. This work was granted access to the high-performance computing resources of CINES (Montpellier, France) under allocation 2020-A0080805032 awarded by GENCI.

ACCEPTED MANUSCRIPT

corrections. [44] The quadratic dependence of the fluorescence intensity on the excitation power was checked for each sample and all wavelengths.

DFT Computations and molecular dynamics simulations. Density functional theory [45] calculations were performed with the hybrid Becke-3 parameter exchange functional [46] and the Lee-Yang-Parr nonlocal correlation functional (B3LYP) [47] implemented in the Gaussian 09 (Revision B.01) program suite [START_REF] Frisch | Gaussian[END_REF] using the pseudo-potentials LANL2DZ for zinc and the 6-


Marie Peng

Jinqiang Lin

Wei Lu

Thierry Roisnel

Véronique Guerchais
email: veronique.guerchais@univ-rennes1.fr

Henri Doucet
email: henri.doucet@univ-rennes1.fr

Jean-François Soulé
email: jean-francois.soule@univ-rennes1.fr

Palladium-Catalyzed C-H Bond Arylation of Cyclometalated Difluorinated 2-Arylisoquinolinyl Iridium(III) Complexes

come   L'archive ouverte pluridisciplinaire

access to newly functionalized C^N-ligands, a crucial and determining step in the way to luminescent complexes. A plethora of examples of chemical modifications of 2-phenylpyridine (ppy) core by adding functional groups have been used as a tool to control the luminescence properties. [1,[START_REF] You | [END_REF] Moreover, the introduction of reactive functional groups on the cyclometalated ligands paves the way for bioimaging applications by tuning their photophysical properties and/or hooking up interactions with biological substrates. [START_REF] Zhang | Luminescent and Photoactive Transition Metal Complexes as Biomolecular Probes and Cellular Reagents[END_REF] The most widely used strategy for the preparation of bis-cyclometalated C^Nbased Ir(III) complexes [Ir(C^N)2(L^X)] (L^X is a monoanionic ligand), involves a multi-step synthetic procedure, starting by the synthesis of the organic pro-ligands followed by their complexation using IrCl3.nH2O as precursor (Figure 1, Pathway A). Although this conventional synthetic method provides the expected Ir(III) complexes in satisfactory reaction yields, the complexation steps often require drastic conditions, which are sometimes not compatible with some functionalities borne by the proligands. An alternative approach to functionalize such species is to perform the C-C coupling directly on the complexes, using the so-called "catalysis-on-the-complex" (Figure 1, Pathway B). Besides expending the panel of functional groups that can be incorporated on the C^N-ligands, this postfunctionalization strategy accelerates the synthesis of a library of novel metal complexes: only three manipulations are required to prepare three complexes, where formerly six steps were necessary (Figure 1 pathway A vs B).

Figure 1. Different approches to prepare functionalized Ir(III) complexes

Following the seminal work of Williams on Suzuki cross-coupling reaction of bromo-functionalized (bis-terpyridyl)iridium(III) complexes (Figure 2A), [START_REF] Leslie | [END_REF] post modification Suzuki reactions have become a straightforward approach to tune the photophysical properties of the Ir(III) complexes. [8] A few examples of Suzuki cross-coupling reactions onto the ancillary ligand were also reported. [9] Figure 2. Pd-catalyzed arylation of cyclometalated Ir(III) vomplexes Although Pd-catalyzed C-H bond arylation has emerged as a suitable alternative to Suzuki crosscouplings for the synthesis of poly(hetero)aryls -since no pre-functionalization is required- [10] their applications for catalytic C-H functionalization of cyclometalated ligands, has been barely explored.

So far, only one procedure of "catalysis-on-the-complex" for C-H bond functionalization has been reported by some of us for the direct arylation of thienyl rings of tris-homoleptic fac-Ir(C^N-thpy)3

[thpy = 2,2′-thienylpyridine], and bis-cyclometalated [Ir(C^N-thpy)2(acac)] (acac = acetylacetonate) (Figure 2B). [11] The arylation took place regiospecifically at the C5-H bond position of the metalated thienyl rings inducing as red-shifted of their emission wavelengths. In contrast, C-H bond arylation of metalated C-aryl ring in 2-arylpyridine-based Ir(III) complexes is not reported yet. This is probably due to the lower reactivity of aryl C-H bond compared to heteroaryl C-H bond in Pd catalysis. [12] We have previously succeeded to perform Pd-catalyzed direct arylation of the polyfluorinated aryl unit of 2-(polyfluorophenyl)pyridine derivatives to prepare bis-cyclometalated luminescent Ir(III) complexes. [13] We showed that the incorporation of an aryl group between the two fluorine atom induces the enhancement the luminescence quantum yields of the resulting cationic Ir(III) species to near-unity. However, this synthetic approach required several manipulations to access the targeted Ircomplexes. To speed up their preparation, we decided to assess the reactivity of cyclometalated 2arylpyridine in Pd-catalyzed C-H bond arylations (Figure 2C). Several questions remain pending about this strategy of catalysis-on-the complex: i) is the regioselectivity still driven by the F atoms or C-Ir bond will affect it? ii) will Ir(III) complexes be stable enough under the required catalytic reaction conditions i.e. temperature, presence of Pd catalyst, base, and additives? Catalysis-on-the Complex. We began our study by preparing the Ir(III) complexes 3 and 4 via reported procedures (Scheme 1). [14] Firstly, the pro-ligands 1-(2,4-difluorophenyl)isoquinoline (1) and 1-(3,5difluorophenyl)isoquinoline (2) were obtained in 84% and 50% yields, via Suzuki coupling from the appropriate difluorinated aryl boronic acids and 2-chloroisoquinoline using 2 mol% PdCl(C3H5)(dppb)

[dppb = 1,4-bis(diphenylphosphino)butane)] as catalyst in the presence of K2CO3 as the base in toluene-MeOH-water as a solvent mixture. Secondly, the reaction of 1 and 2 with IrCl3•nH2O afforded the corresponding cyclometalated µ-chloro-bridged dimers, which then reacted with 2,2,6,6tetramethylheptane-3,5-dione in the presence of a base (K2CO3) to produce complexes 3 [14] and 4 in 75% and 40% yield, respectively.

Scheme 1. Preparation of bis[2-(3,5-difluorophenyl)isoquinolinyl)](2,2,6,6-tetramethyl-3,5- heptanedionato)-Ir(III) (3) and bis[2-(4,6-difluorophenyl)isoquinolinyl](2,2,6,6-tetramethyl-3,5- heptanedionato)-Ir(III) (4).
Having the neutral complex 3 in hands, we explored the most suitable conditions for Pd-catalyzed C-H bond arylations of the metalated difluorinated phenyl ring, namely (i) Pd-based precursors (ii) additives (ligands or bases) and (iii) solvents, using 4-bromobenzotrifluoride as the aryl source for this late-stage coupling (Table 1). The optimized conditions, namely, 4 equivalents of 4-bromobenzotrifluoride, 5 mol% PdCl2(CH3CN)2 associated with dppb as phosphine ligand in the presence of 4 equivalents of KOPiv (KOPiv = potassium pivalate) as the base in DMA (DMA = N,N-dimethylacetamide) at 125 ºC for 16 h, afforded the diarylated complex 5a in 89% isolated yield (Table 1, entry 1). Noteworthy, a trace amount of the monoarylated complex 5b was also detected (< 5%) by NMR spectroscopy of the crude mixture. A significant decrease in yield was observed using the stable, well-defined PdCl(C3H5)(dppb) catalyst or replacing PdCl2(CH3CN)2 by Pd(OAc)2 (Table 1, entries 2 and 3). A diphosphine ligand with a smaller bite angles, dppe (dppe = 1,2-bis(diphenylphosphino)ethane), or mono-phosphine P(2-furyl)3, gave lower yields in 5a with the additional presence of the monoarylated complex 5b in 10-15% yield (Table 1, entries 4 and5). When a lower amount of aryl bromide was employed, the yield of 5a dropped without affording 5b in a yield higher than 15% -even using only 1 equivalent of 4-bromobenzotrifluoride, due to the formation of Ullmann-type aryl bromide homocoupling as the main side-product (Table 1, entries 6 and7). [15] Our studies clearly show that KOPiv as base outperformed KOAc (Table 1,entry 8). Reactions carried out in other solvents than DMA such as DMF, NMP (DMF = N,N-dimethylformamide, NMP = N-methylpyrrolidone), or toluene gave significantly lower yields in 5a (Table 1, entry 9-11). We also tried our optimized conditions for the C-H bond arylation of the pro-ligand 1 (Table 1, entries 12 and 13). We observed the same regioselectivity (the arylation took place at the C-H bond flanked by the two fluorine atoms while the ortho-C-H bond to the isoquinoline remains untouched). However, a longer reaction time (72 h) was required to obtain 5c in 66% yield. We also performed a competitive reaction using 1 equivalent of 4bromobenzotrifluoride, 1 equivalent of iridium complex 3 and 2 equivalents of proligand 1 (Table 1, entry 14). Surprisingly, the reaction was not complete and a mixture of the diarylated complex 5a (12%) and the arylated proligand 5c (31%) was obtained. This result suggests that the cyclometalation did not enhance the reactivity of the C-H bond but prevented the coordination of the nitrogen atom of the isoquinoline unit to Pd, which seems to deactivate the catalyst. NMP as solvent 28 [a] 11 xylene as solvent 7 [a] 12 [b] -19 [c] 13 [b] 72 h 66% [c] 14 [d] -12% (31%) [c] [a] 5b was also observed (<10-15% yield). [b] reaction performed with 1 (2 equiv.) instead of 3. [c] yield in 5c. [d] reaction performed with 3 (1 equiv.), 1 (2 equiv.), 4-bromobenzotrifluoride (1 equiv.).

Kinetics studies have been performed on the reaction between complex 3 and 4-bromobenzotrifluoride (4 equivalents) in the presence of 5 mol% PdCl2(CH3CN)2 associated with dppb using 4 equivalents of KOPiv in DMA at 125 ºC (Figure 3). As expected, the reaction starts by the formation of the monoarylated complex 5b, which is then quickly converted into the diarylated complex 5a. The kinetic formation of 5b shows a steady-state profile with a yield not exceeding 28%. This profile suggests that the second arylation proceed faster than the first one which might give a clue on the difficulty to obtain the mono-arylated complex 5b in good yield. Using these optimized reaction conditions, the direct arylation of complex 3 with 4-bromobenzonitrile, 4-bromobenzophenone, and ethyl 4-bromobenzoate was investigated in order to verify the applicability of the above method to the access to systems with sensitive functional groups (Scheme 2). In all cases, the diarylation occurred, affording the bis-arylated iridium complexes 6-8 in 88%, 55%, and 44% yield, respectively.

Scheme 2. Post-functionalization of cyclometalated Ir(III) complex 3 via Pd-catalyzed C-H bond arylation.

X-ray Crystal Structures. Single crystals of complexes 3, 4, 5a, 7, and 8 suitable for X-ray analysis were grown by slow diffusion of n-pentane into a CH2Cl2 solution of the respective complexes. The Xray crystal structures of the neutral complexes 4, 5a, 7, and 8 are depicted in Figure 4. Selected bond distances and bond angles, as well as selected bite angles, are tabulated in Table S1. All neutral complexes exhibited distorted octahedral geometries, with the two C^N ligands adopting a C,C-cis, and N,N-trans configuration similar to that of the archetype complexes. [16] The Ir-C and Ir-N bond distances in all crystal structures are in the same range. The introduced aryl pendant group is not coplanar with the C^N ligand. The torsion angles between the plane of the incorporated aryl group and that of the cyclometalated phenyl ring of the two C^N ligands are 52.10(5) / 43.00( 6), 41.6(11) / 48.1(10), and 43.4(13) / 43.4(13) for 5a, 7 and 8, respectively. Notably, the distance between two iridium centers for adjacent complexes in the crystal packing varies slightly from 9.726 Å to 9.587 Å for the parent complexes 3 and 4. A significant increase of Ir…Ir distance is observed of 10.088, 13.557 and 13.237 Å for the arylated complexes 5a, 7, and 8, respectively. Notably, 7 exhibits the longer intermetallic distance of 13.557 Å showing the dramatic influence of the steric hindrance of the added p-benzophenone substituents. Thermal ellipsoids are at the 50% probability level.

Electrochemical studies. Depicted in Figures S1 are cyclic voltammograms of complexes 3-8

recorded in deoxygenated dichloromethane with 0.1 M nBu4NPF6 as supporting electrolytes and with redox potentials referenced against the ferrocene/ferrocenium (Fc 0/+ ) oxidation couple. Complexes 3, 4, 5a, 6, and 8 show reversible oxidation waves at 0.60, 0.49, 0.63, 0.65, and 0.60 V vs Fc 0/+ , respectively, while complex 7 with a benzoyl group, exhibits a quasi-reversible oxidation wave at 0.61 V vs Fc 0/+ . These oxidation waves are negatively shifted from the Ir(III)/(IV) redox couple that is usually at around 1.0 V vs Fc 0/+ , [13b] and hence could be tentatively assigned to be the oxidation of the difluorinated 2-arylisoquinoline ligand. The oxidation couple of 3 (0.60 V) is positively shifted from that of 4 (0.49 V), which is in line with our previous report on the phenylpyridyl Ir(III) analogues [13b] and signifies the importance of the positions of the fluorine atoms, i.e. their electronic effects, on the cyclometalated ligands for Ir(III) complexes. Evidently, the substituents conferred by the Pd(II)-catalyzed C-H bond arylation of the cyclometalated difluorinated 2-arylisoquinoline ligands only slightly shift the oxidation couples of 5a and 6-8 for 0-0.05 V from the unsubstituted complex 3.

Among the complexes under study, 4 and 7 show identifiable but irreversible reduction wave at around 2.0 V vs Fc 0/+ , and hence the HOMO-LUMO gaps could be estimated to be around 2.6 eV, which is slightly smaller than that (2.7-2.8 eV) for the phenylpyridyl Ir(III) analogues. [13b] Electronic absorption and emission properties. The photophysical parameters of complexes 3-8 are listed in Table 2, and the UV-vis absorption and emission spectra recorded in deoxygenated CH2Cl2 solutions are depicted in Figure 5. The salient features of the electronic absorption spectrum of these complexes are comparable to those recorded for the typical cyclometalated Ir(III) complexes. [1,2] The intense absorption bands in the 230-350 nm range could be attributed to the π-π* intraligand (IL) transitions of the difluorinated 2-arylisoquinoline ligands. The relatively weaker absorption bands in 400-500 nm range tailing beyond 550 nm could be assigned to be metal-to-ligand charge transfer ( 1/3 MLCT) and ligand-to-ligand charge transfer ( 1/3 LLCT) transitions. Notably, the lowest-energy transition of complex 4 at 471 nm is red-shifted from that of complex 3 at 455 nm, which is in line with the electrochemical study mentioned above. Again, introduction of substituents by the Pd(II)-catalyzed C-H bond arylation of the C^N-ligands impart minor effects on the low-energy transitions of the series complexes, except increased molar extinction coefficients in the UV region. The HOMO-LUMO gaps estimated from the electronic absorption spectra are around 2.6 eV (475 nm), which is coincident with the energy gap estimated from the electrochemical measurements.

Table 2. Photophysical data of complexes 3-8.

Complex

Absorption [a] λmax / nm (ε / 10 4 M -1 cm -1 ) Emission Medium T / K λmax / nm τem / µs Φem [d] / % 3 236 (6.06), 287 (3.84), 341 (1.86), 455 (0.66) CH2Cl2 [b] 298 622 2.0 52 MeTHF [c] 77 583, 625 8.4 CH2Cl2 [b] 298 616 5.0 51 MeTHF [c] 77 591, 622 6.0 5a 236 (6.07), 283 (4.48), 387 (sh, 0.83), 456 (0.43)

CH2Cl2 [b] 298 632 1.9 33 MeTHF [c] 77 596, 634 5.6 6 233 (8.29), 287 (5.67), 333 (3.94), 449 (0.59) CH2Cl2 [b] 298 627 2.0 39 MeTHF [c] 77 586, 633 5.5 7 239 (6.37), 281 (5.06), 342 (2.98), 444 (0.45) CH2Cl2 [b] 298 622 1.9 34 MeTHF [c] 77 590, 636 4.4 8 233 (6.61), 287(4.64), 322 (3.31), 453 (0.51) CH2Cl2 [b] 298 627 2.0 41 MeTHF [c] 77 586, 633 6.8 [a] UV-vis spectra were recorded in CH2Cl2 at a concentration of 10 -5 M at 298 K. [b] PL spectra, lifetimes, and quantum yields were recorded in deaerated CH2Cl2 solutions at a concentration of 10 -5 M at 298 K. [c] PL spectra and lifetimes were recorded in 2-methyltetrahydrofuran at a concentration of 10 -5 M at 77 K. [d] Absolute quantum yields measured with an integrating sphere. Complexes 3-8 in deoxygenated CH2Cl2 solutions emit intense orange-yellow light, upon photo-excited at 350 nm. Broad emission spectra (Figure 5b) were recorded for complex 3, 5a, and 6-8 with emission maxima, quantum yields, and lifetimes of 622-627 nm, 33-52%, and 1.9-2.0 μs, respectively, which is slightly red-shifted, but comparable with the parameters recorded with the mono-fluorinated parent complex [IrC^N-pic-F)2(acac)] (emission maximum at 600 nm in CH2Cl2 with quantum yield and lifetime of 33% and 1.2 µs, respectively). [17] As previously reported, the incorporation of aryl groups has no significant impact on the emission wavelength. [13] Complex 4 with F-substituents at 3,5positions shows emission maximum at 616 nm but with a vibronically structured emission profile. The excitation spectrum (Figure S2) monitored at the emission maximum for each of the complexes are identical to their respective absorption spectrum, indicating that the emissions essentially came from the cyclometalated Ir(III) complexes. Interestingly, all these complexes under study show similar structured emission spectra (Figure S3) in the 77 K glassy 2-methyltetrahydrofuran solutions with peak maximum around 590/630 nm and lifetimes in the 4.4-8.4 μs, implying that the emission could be the same parentage most likely due to the difluorinated 2-arylisoquinoline ligands with little contribution from the metal and the aryl-substituents on the difluorinated phenyl-group.

In summary, Pd-catalyzed C-H bond arylation was successfully applied to the cyclometalated 2-(3,5difluorophenyl)isoquinoline of neutral heteroleptic Ir(III) complexes giving rise to aryl-substituted complexes in good to excellent yields. The arylation regioselectively occurred at the C-H bond of the 3,5-difluorophenyl ring flanked by two fluorine atoms with a good functional group tolerance (i.e, trifluoromethyl, cyano, ketone, or ester). The arylation of the cyclometalated ligand seems to proceed faster than on the proligand due to the absence of interactions between the nitrogen atom of the isoquinoline unit and Pd complex. The introduced pendent aryl groups have a negligible impact on the emission properties, all post-functionalized complexes remain good red emitters. In addition, the ACCEPTED MANUSCRIPT 11 incorporation of these aryl unit increases the intermetallic Ir…Ir distance (up to 3.8 Å) between two adjacent complexes in the crystal packing, an important parameter to reduce intermolecular quenching in optoelectronic devices. This catalysis-on-the-complex strategy based on aryl C-H bond arylation simplifies and opens new chemical space to design cyclometalated Ir(III) complexes featuring target functions that are essential for their applications in material science and biology especially for the chemical modulation of biological properties of metal complexes.

Figure 3 .

 3 Figure 3. Kinetic profile of Pd-catalyzed C-H bond arylation of complex (3) with 4bromobenzotrifluoride. 19 F NMR yield using fluorobenzene as internal standard.

Figure 4 .

 4 Figure 4. . Solid-state structures of complexes 3, 4, 5a, 7, and 8. hydrogen atoms are omitted for clarity.

Figure 5 .

 5 Figure 5. (a) Absorption and (b) normalized emission spectra of complexes 3-8 in deoxygenated CH2Cl2 (λex = 365 nm, concentration ~1×10 -5 M) at 298 K.

Table 1 .

 1 Control reactions of optimized conditions

	Entry Deviation from standard conditions	Yield in 5a (%)
	1	-	89
	2	PdCl(C3H5)(dppb) as catalyst	54
	3	Pd(OAc)2/dppb as catalyst	62
	4	dppe as ligand	28 [a]
	5	10 mol% tri(2-furyl)phosphine as ligand	30 [a]
	6	3 equiv. of ArBr	39 [a]
	7	1 equiv. of ArBr	24 [a]
	8	KOAc as base	54 [a]
	9	DMF as solvent	19 [a]
	10

Acknowledgements

We thank the CNRS, University of Rennes 1 and French Scientific Ministry of Higher Education for providing financial support.


est destinée au dépôt

Knowledge representation (KR)

► "How to represent the knowledge efficiently to be able to reason on it?"

Representation Learning (RL)

► "How to efficiently learn representations of the data that make it easier to extract usefull information when building AI models such as classifiers or predictor ?"

Explainable•

  Explainable AI: a narrative review at the crossroad of Knowledge Discovery, Knowledge Representation and Representation Learning Ikram Chraibi Kaadoud, Lina Fahed, Philippe Lenca To cite this version: Ikram Chraibi Kaadoud, Lina Fahed, Philippe Lenca. Explainable AI: a narrative review at the crossroad of Knowledge Discovery, Knowledge Representation and Representation Learning. Twelfth International Workshop Modelling and Reasoning in Context (MRC) @IJCAI 2021, Aug 2021, Montréal, Canada. 2021. hal-03345286 design explainable models and results 2) Make AI models more intelligible and accessible: • For a given question about an AI model inner mecanisms and/or results, provide an explanation to a target audience Information in a semantically complete format, which is self-sufficient and chosen according to the target audience regarding its knowledge, expectations and the context • Interface between AI model-target audience • Contextual by its very nature : specific to a given target audience, and context

  Illustrative and schematic representation of the position of a low level representation and a high level representation in a deep neural network. hx refers to the xth hidden layer in the network. Examples for XAI applications using RL subfeild Two schematic ways for data transformation into knowledge: On the left, within a Knowledge Discovery process, and on the right within a XAI process Knowledge and representation for XAI…questions asked since 1960 XAI should take advantage of recent works in KDP, KR and RL domains, as well as older works Contact: ikram.chraibi-kaadoud@imt-atlantique.fr


► Coefficient of thermal expansion (@RT)

• Cr ~6.5*10 -6 K -1 • Mo ~5.5*10 -6 K -1 ► Thermal conductivity • Cr 94 W.m -1 .K -1 • Mo 139 W.m -1 .K -1
► Neutron cross-section ► Coefficient of thermal expansion (@RT)

• Cr ~6.5*10 -6 K -1 • Mo ~5.5*10 -6 K -1 ► Thermal conductivity • Cr 94 W.m -1 .K -1 • Mo 139 W.m -1 .K -1 ► Neutron cross-section • Cr 3.1 barn • Mo 2.

••✓

  Alexandre MICHAU -CEA -NuMat 2020 Zr-based claddings with a Cr coating ► Substantial improvements compared to uncoated solutions • Corrosion kinetics reduced in primary water chemistry • Oxidation rate decreased in steam during LOCA • … ► Beyond design basis accident • Fast Cr-Zr interdiffusion → metastable Zr x Cr y • Zr x Cr y + β-Zr → liquid eutectic phase • Liquid eutectic consumes all available Cr • Precipitation of β-Zr dendrites, Cr-enriched inter-dendritic areas → Cr-Zr diffusion barrier to mitigate this effect μm thick Cr-coated M5 Framatome cladding sample after 100 s at 1400 °C followed by direct water quenching (one-sided steam oxidation) [J.-C. Brachet et al., Corrosion Science 167 (2020) 108537] Slow the coating consumption by diffusion • Extend the coating available for protection against oxidation • Prevent embrittlement during and after quenching due to the diffusion and the formation of brittle phases ► Improve everything else ! At least do not degrade anything else… Lower interdiffusion coefficients Cr-X and Zr-X with T and/or lower solubility in β-Zr (and reciprocally) • No eutectic reaction or eutectic reaction at higher T ► ATF application • Material resisting to HT, HT oxidation, corrosion, irradiation • Compatible CTE, ductile • Low impact on neutron cross-section, thermal conductivity • Toxicity, costs, criticality • Decommissioning compatible ► Deposition process • Possible to deposit a thin layer • No contamination • No degradation of existing solution Alexandre MICHAU -CEA -NuMat 2020 Technical criteria -diffusion barrier ► Diffusion barrier • Lower interdiffusion coefficients Cr-X and Zr-X with T and/or lower solubility in β-Zr (and reciprocally) • No eutectic reaction or eutectic reaction at higher T ► ATF application • Material resisting to HT, HT oxidation, corrosion, irradiation • Compatible CTE, ductile • Low impact on neutron cross-section, thermal conductivity • Toxicity, costs, criticality • Decommissioning compatible ► Deposition process • Possible to deposit a thin layer • No contamination • No degradation of existing solution → in a first approach Mo fills most of these criteria Mo

•

  Cr 3.1 barn • Mo 2.6 barn Criticality maps for (A) supply risk, (B) environmental implications, and (C) vulnerability to supply restriction. T.E. Graedel et al., PNAS April 7, 2015 112 (14) 4257-4262 More complex data to collect ► Behaviour under and after irradiation ► Compatibility with primary water and steam ► Corrosion rate in concentrated nitric acid ► Coupled effects ► … Alexandre MICHAU -CEA -NuMat 2020 Easy access to numerous tables ► Melting temperature • Cr 1907°C • Mo 2623°C

►•AS•AS•AS►►►•Conclusions►►

  6 barn More complex data to collect ► Behaviour under and after irradiation ► Compatibility with primary water and steam ► Corrosion rate in concentrated nitric acid ► Coupled effects ► … 1340°C 1350°C Isothermal cross-sections of Cr-Mo-Zr ternary diagrams Thermocalc calculations with Zircobase database • 12-15 µm Cr reference coating • 2-5 µm Mo interlayer + 10-12 µm Cr • Flat coupons (1.2 mm thick) • Single face vs 3d 4. Characterization • Crystal structure, XRD • Microstructure and composition, SEM and EPMA • Composition profile, GDOES • …3. Tests• Heat treatment in argon, air and steam• 1100 and 1400°C• 1.2 to 60 minutes2. Characterization• Crystal structure, XRD • Microstructure and composition, SEM and EPMA • Composition profile, GDOES • … Laboratory scale (pre-study) ► Configuration • 2 circular cathodes (12.5 cm), 1 Cr and 1 Mo • Co-planar configuration • Translatable substrate-holder • Fixed source-substrate distance • Single face deposition on flat samples ~ 5 cm ► Processes • Magnetron sputtering, DC, pulsed, HiPIMS Pilot scale ► Configuration • 4 rectangular cathodes (15 x 65 cm), 2 Cr and 2 Mo • Triple rotation substrate-holder • Variable source-substrate distance • Deposition on 3d samples ~ 50 cm ► Processes • Magnetron sputtering, DC, pulsed, HiPIMS • Cathodic arc • In situ etching • Remove surface pollutants • Remove the native oxide layer • HiPIMS mode (Cr and Ar ions) instead of standard diode (Ar) ► Deposition • Pure HiPIMS mode (Cr, Mo and Ar ions) • Low growth rates ~ 0.3 µm.h -1 due to the deposition configuration Dense columnar on cleaved Si and polished Zr alloy • Sharp interfaces ► Crystallinity • Polycrystalline coatings • Single phase cubic centered Cr (2.89 Å), (110) texture • Single phase cubic centered Mo (3.15 Å) ► Composition • Interfaces with GDOES not so sharp compared to EPMA • Cr enrichment at the interface due to implantation during etching Dense columnar on cleaved Si and polished Zr alloy • Sharp interfaces ► Crystallinity • Polycrystalline coatings • Single phase cubic centered Cr (2.89 Å), (110) texture • Single phase cubic centered Mo (3.15 Å) ► Composition • Interfaces with GDOES not so sharp compared to EPMA • Cr enrichment at the interface due to implantation during etching Dense columnar on cleaved Si and polished Zr alloy • Sharp interfaces ► Crystallinity • Polycrystalline coatings • Single phase cubic centered Cr (2.89 Å), (110) texture • Single phase cubic centered Mo (3.15 Å) ► Composition • Interfaces with GDOES not so sharp compared to EPMA • Cr enrichment at the interface due to implantation during etching Shift of the liquid formation for Mo/Cr towards higher temperatures (~40°C) → should be greater in dynamic conditions Similar between Cr and Mo/Cr • Growth of Cr 2 O 3 layer at the same rate • Formation of an interdiffusion layer ► Advantageous for Mo/Cr • Thickness of the Cr layer decreases, slower for Mo/Cr • Formation and growth of porosities, slower for Mo/Cr Alexandre MICHAU -CEA -NuMat 2020 Oxidation in air at 1100°C followed by a water quench ► Similar between Cr and Mo/Cr • Growth of Cr 2 O 3 layer at the same rate • Formation of an interdiffusion layer ► Advantageous for Mo/Cr • Thickness of the Cr layer decreases, slower for Mo/Cr • Formation and growth of porosities, slower ZrO 2 formation • 160 µm for uncoated • 90 µm for Cr-coated • None Mo/Cr-coated ► Cr 2 O 3 formation • Partially consumed the Cr for Cr-coated • Residual Cr and Mo layers on Mo/Cr-coated ► Cr diffusion • Cr-Zr eutectic structure at the specimen surface after quenching • None for Mo/Cr-coated → Better resistance of Mo/Cr at higher temperatures which delays the Cr-Zr eutectic reaction → Decreases the O ingress in β-Zr and may induce a better PQ residual strength,Formation of wrinkles due to the eutectic reaction • Growth of ZrO 2 and formation α-Zr(O) • Only Cr 2 O 3 left, no residual metallic layers ► 600 and 1000 s • Partial loss of integrity • Larger ZrO 2 and α-Zr(O) areas Quench cracking initiated at preexisting stress concentrations 300 s, Mo/Cr-coated Zr1Nb 600 s, Mo/Cr-coated .cm -2 † [O] in β Zr (+potential α Zr (O) incursions) ~ 1.45 wt.wt.% † Alexandre MICHAU -CEA -NuMat 2020 Choosing an interlayer material is a complex compromise • Quick selection based on tables • Longer identification due to complex data and coupled effects • Safety gains to quantify compared to the complexity and cost ► Mo diffusion barrier has a beneficial effect in both slow and dynamic conditions on a Cr-coated Zr alloy • Compatibility in the PVD elaboration process that provides dense microstructures • The eutectic reaction is shifted towards higher temperatures • Metallic Cr is available for longer times → Mo interlayer shows promising results for longer coping times at higher temperatures but further characterization is needed to fully quantify benefits Perspectives Keep characterizing the Mo interlayer for further evaluation ► Extend selection criteria to more complex materials (alloys and multi-elements phases, doping…) Thank you for your attention ! Do you have any questions? Commissariat à l'énergie atomique et aux énergies alternatives -www.cea.fr

Alexandre MICHAU -CEA -NuMat 2020

Acknowledgements : Michel Tabarant for GDOES, Caroline Toffolon-Masclet for thermodynamic calculations

Oxidation in air at 1100°C followed by a water quench ► Similar between Cr and Mo/Cr