Synthesis and Reactivity of Poly(propyleneimine) Dendrimers Functionalized with Cyclopentadienone N -Heterocyclic-Carbene Ruthenium(0) Complexes

: Ligand design in metal chemistry is a fundamental step when pursuing compounds with speciﬁc reactivity. In this paper, the functionalization of the OH group in the lateral chain of the N -heterocyclic-carbene (NHC) ligand bound to a bis -carbonyl cyclopentadienone NHC ruthenium(0) complex allowed the decoration of ﬁve generations of poly(propyleneimine) (PPIs) dendrimers with up to 64 organometallic moieties. The coupling was achieved by employing carbonyldiimidazole and the formation of carbamate linkages between dendritic peripheral NH 2 and lateral OH groups on ruthenium complexes. The synthetic procedure, chemical puriﬁcation, and spectroscopic characterization of the ﬁve generations of dendrimers ( 3g1 – 5 ) are here described. The ruthenium-modiﬁed dendrimers were activated as catalysts in the transfer hydrogenation of the model compound 4-ﬂuoroacetophenone in the presence of cerium ammonium nitrate as their mononuclear congeners. The catalytic activity, being similar for the ﬁve generations, shows a decrease if compared to mononuclear complexes. This detrimental e ﬀ ect might be ascribed to the –CH 2 NH– functionalization, largely present in dendrimer skeleton and that can compete with the hydrogen transfer mechanism, but also partially to a dendritic e ﬀ ect caused by steric encumbrance.


Introduction
Dendritic catalysts are functional macromolecules with precise and unambiguous structures, which, thanks to their monodisperse nature, maintain the advantages of homogeneous catalysts showing fast kinetic responses and easy tunability [1][2][3][4][5][6][7][8][9][10][11][12]. Furthermore, they can be removed from the reaction mixture by membrane or nanofiltration techniques and precipitation, exploiting their bigger sizes compared to products, and this confers the advantages of heterogeneous catalysts [13]. Catalytic sites grafted on the periphery of dendrimers can give rise to active, multivalent species that might result in high reaction rates. Several reviews report on the use of dendrimers in catalysis [1][2][3][4][5][6][7][8][9][10][11], but few of them are specifically dedicated to the dendrimer effect [14][15][16]. The consequences of dendritic effects are known to be like substrate activation and influence the reaction rate and selectivity. On one hand, a dendrimer brings together a large number of catalytically active species in a nanoobject, while, on the selectivity. On one hand, a dendrimer brings together a large number of catalytically active species in a nanoobject, while, on the other hand, limitation to the access of substrate molecules can lead to a negative effect, i.e., lowering of reaction rates caused by bulk hindrance.
The majority of the reported dendritic catalysts for hydrogenation contain phosphines since they have proved to be optimal ligands for grafting metal complexes, thanks to their ability to firmly coordinate metal ions and lead to high catalytic performances [17][18][19][20][21][22][23]. Both negative [24] and positive [25][26][27] dendritic effects have been observed when hydrogenation is carried out with increasing sizes of dendrimers. On the contrary, less examples regarding transfer hydrogenation are reported [13,28,29]. Worthy of note is the tetrabranched phosphoranyl-terminated carbosilane ruthenium(II) derivative able to catalyze the transfer hydrogenation of cyclohexanone, where cyclohexadiene or formic acid acts as stoichiometric hydrogen donor species. This first-generation dendrimer, which contains the lowest number of peripheral ruthenium functionalities, namely four, was found to be less active than the mononuclear complex [28]. There are also examples in which the dendritic system is given by the surrounding part of the catalytic center [30,31], as in the case of the "green" application of the fluorinated dendritic chiral mono-N-tosylated-1,2-diphenylethylenediamine (FTsDPEN), which was employed in the asymmetric transfer hydrogenation of prochiral ketones in aqueous media catalyzed by ruthenium(II) centers [32].
Within the field of transfer hydrogenation, our group has recently developed novel ruthenium compounds for bifunctional catalysis [33,34] by combining cyclopentadienones, which cooperate with the metal centers in catalytic redox reactions [35][36][37][38], and N-heterocyclic carbenes (NHCs) [39,40], largely used and very versatile ligands due to their easy preparation and the tunability of their steric and electronic properties [41][42][43][44]. In particular, the reduction of the model compound 4fluoroacetophenone catalyzed by complexes 1a-c ( Figure 1) can be activated by addition of cerium ammonium nitrate (CAN), which favors the release of CO [34]. NHCs are effective tools for the rational design of transition metal catalysts [45][46][47][48][49][50][51][52] in that their skeleton can be provided with suitable substituents for heterogenization (e.g., -OH in 1c, Figure 1). Despite the fact that NHCs can be considered ancillary ligands as outstanding as phosphines, examples of NHC-decorated dendrimers reported in the literature are still contained [53][54][55][56]. These include the NHC-rhodium dendrimer showing a positive dendrimer effect in hydrosilylation of ketones [54], and an NHC-ruthenium derivative employed in olefin metathesis, in which the catalytic center is bonded to the dendrimer through a Ru=C double bond involving the aromatic moiety without exploiting the ancillary NHC ligand [53]. In order to evaluate a possible dendrimer effect and inspired by previous works on dendritic systems [57], we report here on the development of an efficient method for the straightforward synthesis, chemical purification, and spectroscopic characterization of five generations of poly(propyleneimine) (PPIs) NHC-ruthenium(0) functionalized dendrimers with up to 64 organometallic moieties. Their catalytic activity in transfer hydrogenation has been tested for the reduction of 4-fluoroacetophenone in iPrOH, and the results obtained will be compared with the ones previously obtained for the mononuclear ruthenium complexes (Table 1) [34]. NHCs are effective tools for the rational design of transition metal catalysts [45][46][47][48][49][50][51][52] in that their skeleton can be provided with suitable substituents for heterogenization (e.g., -OH in 1c, Figure 1). Despite the fact that NHCs can be considered ancillary ligands as outstanding as phosphines, examples of NHC-decorated dendrimers reported in the literature are still contained [53][54][55][56]. These include the NHC-rhodium dendrimer showing a positive dendrimer effect in hydrosilylation of ketones [54], and an NHC-ruthenium derivative employed in olefin metathesis, in which the catalytic center is bonded to the dendrimer through a Ru=C double bond involving the aromatic moiety without exploiting the ancillary NHC ligand [53]. In order to evaluate a possible dendrimer effect and inspired by previous works on dendritic systems [57], we report here on the development of an efficient method for the straightforward synthesis, chemical purification, and spectroscopic characterization of five generations of poly(propyleneimine) (PPIs) NHC-ruthenium(0) functionalized dendrimers with up to 64 organometallic moieties. Their catalytic activity in transfer hydrogenation has been tested for the reduction of 4-fluoroacetophenone in iPrOH, and the results obtained will be compared with the ones previously obtained for the mononuclear ruthenium complexes (Table 1) [34].

Synthesis and Characterization of the Ruthenium-Decorated Dendrimers
The new ruthenium(0) complex 2 with CO2-imidazole (CO2Im) functionalized NHC ligand was prepared in 84% yield by reacting 1c with a slight excess of carbonyldiimidazole (CDI:1c = 1.1:1) in CH2Cl2 at room temperature for 2 h, as shown in Scheme 1. The compound 2 was then easily purified by washing the imidazolium co-product with water. The off-white solid 2 is air stable and was characterized by analytical measurements (Figures S1-S4 in the Supplementary Materials, SM). The 1 H and 13 C NMR spectra were registered in CDCl3 and they are comparable to the ones of the initial complex 1c for the unaltered structural parts [34]. In particular, the downfield-shifted resonance of the coordinated carbon atom of the carbene (δ = 174.80 ppm) appeared in the 13 C NMR spectrum. In addition, the imidazole moiety displays signals at chemical shifts ( 1 H NMR: δ = 8.03, 7.33, 7.08 ppm; 13 C NMR: δ = 136.95, 130.88, 116.97 ppm) close to those of the starting material CDI, while the C=O group resonates at 147.89 ppm, typical for a carbamate moiety (-OC(O)N-). In the infrared spectrum in CH2Cl2, CO stretching bands (νCO = 2007 and 1948 cm -1 ) are consistent with those of 1c, and the stretching at 1768 cm -1 is ascribable to the carbamate group formed during the reaction. Further evidences of the occurred functionalization reaction were given by Electron-Spray Ionization mass spectrometry (MS-ESI) measurements, where the protonated molecular ion [M + H] + at m/z 823 could be detected.
The reaction in CH2Cl2 at room temperature for 2 h of a 4.8 fold excess of 2 with the dendrimer DAB-dendr-(NH2)4 (g1) led to the formation of the dendrimer 3g1 decorated with four ruthenium(0) moieties (Scheme 2). The CO2Im group of 2 easily reacted with DAB-dendr-(NH2)n (n = 8, 16, 32, 64, gn, see Scheme S1 in the SM), up to the fifth generation, under the same experimental conditions yielding the fully functionalized new dendritic organometallic dendrimers 3gn ( Figure 2) in acceptable yields. The excess of 2 and the side products could be easily removed from the crude product by extraction with water and washing with Et2O. All five generation macromolecules 3gn were isolated as light brown solids and were revealed to be stable to air and moisture.

Synthesis and Characterization of the Ruthenium-Decorated Dendrimers
The new ruthenium(0) complex 2 with CO 2 -imidazole (CO 2 Im) functionalized NHC ligand was prepared in 84% yield by reacting 1c with a slight excess of carbonyldiimidazole (CDI:1c = 1.1:1) in CH 2 Cl 2 at room temperature for 2 h, as shown in Scheme 1. The compound 2 was then easily purified by washing the imidazolium co-product with water.

Synthesis and Characterization of the Ruthenium-Decorated Dendrimers
The new ruthenium(0) complex 2 with CO2-imidazole (CO2Im) functionalized NHC ligand was prepared in 84% yield by reacting 1c with a slight excess of carbonyldiimidazole (CDI:1c = 1.1:1) in CH2Cl2 at room temperature for 2 h, as shown in Scheme 1. The compound 2 was then easily purified by washing the imidazolium co-product with water. The off-white solid 2 is air stable and was characterized by analytical measurements (Figures S1-S4 in the Supplementary Materials, SM). The 1 H and 13 C NMR spectra were registered in CDCl3 and they are comparable to the ones of the initial complex 1c for the unaltered structural parts [34]. In particular, the downfield-shifted resonance of the coordinated carbon atom of the carbene (δ = 174.80 ppm) appeared in the 13 C NMR spectrum. In addition, the imidazole moiety displays signals at chemical shifts ( 1 H NMR: δ = 8.03, 7.33, 7.08 ppm; 13 C NMR: δ = 136.95, 130.88, 116.97 ppm) close to those of the starting material CDI, while the C=O group resonates at 147.89 ppm, typical for a carbamate moiety (-OC(O)N-). In the infrared spectrum in CH2Cl2, CO stretching bands (νCO = 2007 and 1948 cm -1 ) are consistent with those of 1c, and the stretching at 1768 cm -1 is ascribable to the carbamate group formed during the reaction. Further evidences of the occurred functionalization reaction were given by Electron-Spray Ionization mass spectrometry (MS-ESI) measurements, where the protonated molecular ion [M + H] + at m/z 823 could be detected.
The reaction in CH2Cl2 at room temperature for 2 h of a 4.8 fold excess of 2 with the dendrimer DAB-dendr-(NH2)4 (g1) led to the formation of the dendrimer 3g1 decorated with four ruthenium(0) moieties (Scheme 2). The CO2Im group of 2 easily reacted with DAB-dendr-(NH2)n (n = 8, 16, 32, 64, gn, see Scheme S1 in the SM), up to the fifth generation, under the same experimental conditions yielding the fully functionalized new dendritic organometallic dendrimers 3gn ( Figure 2) in acceptable yields. The excess of 2 and the side products could be easily removed from the crude product by extraction with water and washing with Et2O. All five generation macromolecules 3gn were isolated as light brown solids and were revealed to be stable to air and moisture. The off-white solid 2 is air stable and was characterized by analytical measurements (Figures S1-S4 in the Supplementary Materials, SM). The 1 H and 13 C NMR spectra were registered in CDCl 3 and they are comparable to the ones of the initial complex 1c for the unaltered structural parts [34]. In particular, the downfield-shifted resonance of the coordinated carbon atom of the carbene (δ = 174.80 ppm) appeared in the 13 C NMR spectrum. In addition, the imidazole moiety displays signals at chemical shifts ( 1 H NMR: δ = 8.03, 7.33, 7.08 ppm; 13 C NMR: δ = 136.95, 130.88, 116.97 ppm) close to those of the starting material CDI, while the C=O group resonates at 147.89 ppm, typical for a carbamate moiety (-OC(O)N-). In the infrared spectrum in CH 2 Cl 2 , CO stretching bands (νCO = 2007 and 1948 cm -1 ) are consistent with those of 1c, and the stretching at 1768 cm -1 is ascribable to the carbamate group formed during the reaction. Further evidences of the occurred functionalization reaction were given by Electron-Spray Ionization mass spectrometry (MS-ESI) measurements, where the protonated molecular ion [M + H] + at m/z 823 could be detected.
The reaction in CH 2 Cl 2 at room temperature for 2 h of a 4.8 fold excess of 2 with the dendrimer DAB-dendr-(NH 2 ) 4 (g1) led to the formation of the dendrimer 3g1 decorated with four ruthenium(0) moieties (Scheme 2). The CO 2 Im group of 2 easily reacted with DAB-dendr-(NH 2 ) n (n = 8, 16, 32, 64, gn, see Scheme S1 in the SM), up to the fifth generation, under the same experimental conditions yielding the fully functionalized new dendritic organometallic dendrimers 3gn (Figure 2) in acceptable yields. The excess of 2 and the side products could be easily removed from the crude product by extraction with water and washing with Et 2 O. All five generation macromolecules 3gn were isolated as light brown solids and were revealed to be stable to air and moisture.  The dendritic compounds are soluble in THF and CH2Cl2, sparingly soluble in Et2O, and totally insoluble in hexane, toluene as well as aqueous solvents. They were characterized by 1 H and 13 C NMR, IR spectroscopy and mass spectrometry, when feasible ( Figure S5-S21 in the SM). Considering the NMR spectra registered in CDCl3, they show the signals due to the diaminobutane-based PPIs skeleton ( 1 H: four broad multiplets in the range 3.8-1.3 ppm; 13 C: four resonances in the range 63-25 ppm) and those given by the anchored peripheral NHC ruthenium moieties (see Materials and Methods section). Even if all the proton signals appear as broad peaks typical of a polymer-like structure, it is clearly detectable that the resonances of the two methylene groups belonging to the -NHCCH2CH2OC(O)NH-unit of the organometallic moieties are at 3.77 and 3.59 ppm, which are more shielded than those of 2 (4.05 and 3.99 ppm in -NHCCH2CH2OC(O)Im). The signal of the NH proton of the carbamate linkers close to the surface of the PPIs dendrimer moves along the whole spectrum and it is often not clearly detected due to either that it can resonate in the same region of  The dendritic compounds are soluble in THF and CH2Cl2, sparingly soluble in Et2O, and totally insoluble in hexane, toluene as well as aqueous solvents. They were characterized by 1 H and 13 C NMR, IR spectroscopy and mass spectrometry, when feasible ( Figure S5-S21 in the SM). Considering the NMR spectra registered in CDCl3, they show the signals due to the diaminobutane-based PPIs skeleton ( 1 H: four broad multiplets in the range 3.8-1.3 ppm; 13 C: four resonances in the range 63-25 ppm) and those given by the anchored peripheral NHC ruthenium moieties (see Materials and Methods section). Even if all the proton signals appear as broad peaks typical of a polymer-like structure, it is clearly detectable that the resonances of the two methylene groups belonging to the -NHCCH2CH2OC(O)NH-unit of the organometallic moieties are at 3.77 and 3.59 ppm, which are more shielded than those of 2 (4.05 and 3.99 ppm in -NHCCH2CH2OC(O)Im). The signal of the NH proton of the carbamate linkers close to the surface of the PPIs dendrimer moves along the whole spectrum and it is often not clearly detected due to either that it can resonate in the same region of The dendritic compounds are soluble in THF and CH 2 Cl 2 , sparingly soluble in Et 2 O, and totally insoluble in hexane, toluene as well as aqueous solvents. They were characterized by 1 H and 13 C NMR, IR spectroscopy and mass spectrometry, when feasible ( Figures S5-S21 in the SM). Considering the NMR spectra registered in CDCl 3 , they show the signals due to the diaminobutane-based PPIs skeleton ( 1 H: four broad multiplets in the range 3.8-1.3 ppm; 13 C: four resonances in the range 63-25 ppm) and those given by the anchored peripheral NHC ruthenium moieties (see Materials and Methods section). Even if all the proton signals appear as broad peaks typical of a polymer-like structure, it is clearly detectable that the resonances of the two methylene groups belonging to the -NHCCH 2 CH 2 OC(O)NHunit of the organometallic moieties are at 3.77 and 3.59 ppm, which are more shielded than those of 2 (4.05 and 3.99 ppm in -NHCCH 2 CH 2 OC(O)Im). The signal of the NH proton of the carbamate linkers close to the surface of the PPIs dendrimer moves along the whole spectrum and it is often not clearly detected due to either that it can resonate in the same region of aromatic signals or that it could be engaged in hydrogen bonds like -NH· · · (O)CO-or -NH· · · cyclopentadienone, fact that becomes more relevant upon increasing the dendritic generation where the interacting groups get in closer contact. The IR spectra of all five dendritic species in CH 2 Cl 2 solution show a strong absorption at 1718 cm −1 attributable to both C=O and -O 2 CNH-stretching bands. The structure of the first generation dendrimer 3g1 (Scheme 2) could be also confirmed by MS-ESI, which shows the molecular ion with sodium [M + Na] + at m/z 3355. The high molecular weights of the upper generations 3g2-5 prevented the use of MS-ESI technique for mass detection.

Catalytic Transfer Hydrogenation
The five generations of functionalized dendrimers 3g1-5 were tested as precursors under catalytic transfer hydrogenation conditions employing 4-fluoroacetophenone as model substrate in refluxing iPrOH (hydrogen source). Catalytic runs were performed in order to investigate the stability of the peripheral organometallic moieties on the PPIs dendrimers and to detect any possible dendritic effect. Results obtained are reported in Table 2, and in all cases, selectivity is complete and conversion corresponds to yield. aromatic signals or that it could be engaged in hydrogen bonds like -NH ⋯ (O)CO-or -NH ⋯ cyclopentadienone, fact that becomes more relevant upon increasing the dendritic generation where the interacting groups get in closer contact. The IR spectra of all five dendritic species in CH2Cl2 solution show a strong absorption at 1718 cm −1 attributable to both C=O and -O2CNH-stretching bands. The structure of the first generation dendrimer 3g1 (Scheme 2) could be also confirmed by MS-ESI, which shows the molecular ion with sodium [M + Na] + at m/z 3355. The high molecular weights of the upper generations 3g2-5 prevented the use of MS-ESI technique for mass detection.

Catalytic Transfer Hydrogenation
The five generations of functionalized dendrimers 3g1-5 were tested as precursors under catalytic transfer hydrogenation conditions employing 4-fluoroacetophenone as model substrate in refluxing iPrOH (hydrogen source). Catalytic runs were performed in order to investigate the stability of the peripheral organometallic moieties on the PPIs dendrimers and to detect any possible dendritic effect. Results obtained are reported in Table 2, and in all cases, selectivity is complete and conversion corresponds to yield.  3g1 pyridine 3 0 20 3g1-5 did not show any catalytic activity in the absence of additives, as already observed in the case of the mononuclear congeners [34]. Addition of 1 equivalent of CAN, with respect to Ru loading, promotes CO release [34,35] and leads to the pre-catalyst activation [58] resulting in some catalytic activity. Nevertheless, only 15-17% conversion could be reached after 24 h for all the five generations, which allow us to discard any positive dendritic effect. These conversions are lower than those obtained with the mononuclear alkyl-substituted NHC complexes 1a and 1b but similar to 1c (see Table 1). This peculiar behavior could be then ascribed to -CH2NH-dendrimer functionalization, which might compete with the hydrogen transfer mechanism as indeed depicted previously for the -CH2OH group in 1c [34].

Entry [Ru] Additive Conversion (%) 8 h Conversion (%)
A similar outcome was found by adding 10 eq. of pyridine for each ruthenium(0) center to 3g1 (entry 6 of Table 2), confirming the activation effect of the latter additive stated for pyridyl functionalized NHC ligands [58]. Although the pre-catalyst activation could be achieved also by pyridine, this was not used to test the following generations of dendrimer due to the high amount of additive required compared to CAN and the limited enhancement in the conversion (20% vs 17%).  19 F NMR spectroscopy; 2 1 mol eq. of CAN per ruthenium center; 3 10 mol eq. of pyridine per ruthenium center. 3g1-5 did not show any catalytic activity in the absence of additives, as already observed in the case of the mononuclear congeners [34]. Addition of 1 equivalent of CAN, with respect to Ru loading, promotes CO release [34,35] and leads to the pre-catalyst activation [58] resulting in some catalytic activity. Nevertheless, only 15-17% conversion could be reached after 24 h for all the five generations, which allow us to discard any positive dendritic effect. These conversions are lower than those obtained with the mononuclear alkyl-substituted NHC complexes 1a and 1b but similar to 1c (see Table 1). This peculiar behavior could be then ascribed to -CH 2 NH-dendrimer functionalization, which might compete with the hydrogen transfer mechanism as indeed depicted previously for the -CH 2 OH group in 1c [34].
A similar outcome was found by adding 10 eq. of pyridine for each ruthenium(0) center to 3g1 (entry 6 of Table 2), confirming the activation effect of the latter additive stated for pyridyl functionalized NHC ligands [58]. Although the pre-catalyst activation could be achieved also by pyridine, this was not used to test the following generations of dendrimer due to the high amount of additive required compared to CAN and the limited enhancement in the conversion (20% vs 17%).

Conclusions
Five generations of novel cyclopentadienone-NHC-ruthenium(0)-functionalized PPIs dendrimers 3g1-5 with up to 64 organometallic peripheral moieties have been here successfully prepared and provide a precious route for the immobilization of hydroxy-functionalized NHC complexes onto organic and inorganic amino-decorated supports. The dendrimers 3g1-5 also represent one of the few examples in which NHC ligands are exploited as ancillary ligands for the functionalization of high-generation dendrimers. The stability shown by these dendrimers highlights a significant opportunity to obtain nanosized multinuclear systems, which have the potential to work in between homogeneous and heterogeneous catalytic regimes.
Dendrimers 3g1-5, thanks to the ruthenium(0) centers present at the periphery, are active in the transfer hydrogenation of 4-fluoroacetophenone in the presence of additives like CAN or pyridine.
In line with what previously observed for the corresponding mononuclear species 1c, the limited catalytic activity is more likely due to dendrimer -CH 2 NH-functionalization rather than ascribable to a sterically induced detrimental dendrimer effect. Nevertheless, taking advantage of the synthetic strategy here described, further studies will be devoted in the future to improve the catalytic activity, for example by modifying the dendritic linker.