Diverse Approaches for the Difunctionalization of PPH Dendrimers, Precise Versus Stochastic: How Does this Influence Catalytic Performance?

Random difunctionalization of dendrimer surfaces, frequently employed in biological applications, provides the advantage of dual functional groups through a synthetic pathway that is simpler compared to precise difunctionalization. However, is the random difunctionalization as efficient as the precise difunctionalization on the surface of dendrimers? This question is unanswered to date because most dendrimer families face challenges in achieving precise functionalization. Polyphosphorhydrazone (PPH) dendrimers present a unique opportunity to obtain precise difunctionalization at each terminal branching point. The work concerning catalysis we report with PPH dendrimers, whether precisely or randomly functionalized, addresses this question. Across PPH dendrimers, from generations 1 to 3, precise functionalization consistently outperforms random functionalization in terms of efficiency. This finding introduces a novel concept in dendrimer science, emphasizing the superiority of precise over random functionalization methodologies. Introducing a groundbreaking concept in the field of dendrimers.

D endrimers are macromolecules synthesized step-by-step (generation after generation), to ensure a supposed perfect structure. 1Paradoxically, a random difunctionalization of the surface of dendrimers is frequently applied, thus affording "imperfect" nano-objects from "perfect" ones.The random difunctionalization is generally applied with the aim of affording two different properties to the dendrimers, for instance, one function for increasing the solubility in a given solvent such as water, the second affording the desired properties.The random difunctionalization is in particular used when studying biological properties of dendrimers. 2 However, inconsistencies between batches have been already pointed out, leading to batches with varying biological activities. 3eanwhile, to the best of our knowledge, no study up to now has compared the influence of random versus precise difunctionalization on all of the surfaces of dendrimers on a given property.In fact, such a comparison is not easy to carry out, as the precise difunctionalization of most types of dendrimers is not possible, except when using difunctionalized reagents, such as those based on triazine, 4 or Janus-type dendrimers, 5 or eventually after tedious purification by HPLC of one, two, or three functions on the surface of dendrimers. 6nterestingly, polyphosphorhydrazone (PPH) dendrimers 7 possess the rare property of an easy sequential difunctionalization on one Cl, then on a second Cl, at each P(S)Cl 2 terminal function. 8n this Letter we describe both the precise and random difunctionalization of PPH dendrimers, from generation 1 to generation 3, with a perfluoroalkyl chain and an iminophos-phine, suitable for the complexation of palladium.Both families were then used in catalytic experiments for detecting their different or similar properties.
The PPH dendrimers were synthesized as described previously, 6 to have P(S)Cl 2 terminal functions at each generation, from generation 1 (6 P(S)Cl 2 ) to generation 3 (24 P(S)Cl 2 ).The ligand chosen for the catalytic experiments of type iminophosphine was previously used by us for complexing palladium on a monomer and a first generation dendrimer 9 and was found efficient and usable in several catalytic experiments. 9,10The other function that we chose was a perfluoroalkyl chain, which could potentially modify the solubility of the PPH dendrimers.
The P(S)Cl 2 functions of the PPH dendrimers react easily with phenols and amines.The easy and precise difunctionalization was previously observed essentially with amines. 8It was carried out only one time with two phenol derivatives, 11 affording a difunctional dendrimer with a purity of ca.95%.As in our experience, it is generally easier to functionalize the PPH dendrimers with phenols than with primary amines; we choose to use a phenol for both types of substituents.The perfluoroalkyl derivative 1 (HOAr 1 ) was synthesized by a substitution reaction between 4-mercaptophenol and 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodooctane in the presence of triethylamine in refluxing THF overnight, instead of K 2 CO 3 in refluxing acetone for 1 day. 12The ligand 2 (HOAr 2 ) was synthesized as previously described 9 by a condensation reaction between 2-(diphenylphosphino) benzaldehyde and 4aminophenol.
Having both phenols in hand, the first step was to study their grafting on a model compound (M) bearing a single P(S)Cl 2 function.It was decided to graft first phenol 1, as it is a very stable compound, contrarily to phenol 2, in which the phosphine can be easily oxidized.The monofunctionalized monomer M-mono was isolated and characterized, then phenol 2 bearing a phosphine was reacted to afford the difunctionalized monomer 3prc.Both reactions were carried out under basic conditions, using cesium carbonate, whereas sodium sulfate was used as a drying agent.The monofunctionalization with phenol 1 was then attempted with generations 1 (G1), 2 (G2), and 3 (G3) of the PPH dendrimers in basic conditions.A very small proportion of unreacted P(S)Cl 2 and of doubly reacted P(S)(OAr 1 ) 2 was observed in all cases by 31 P{ 1 H} NMR (less than 5%) (Scheme 1).
The main 31 P{ 1 H} NMR signal corresponding to the monosubstitution is observed at 68 ppm for all generations.The second phenol (2) was then reacted, also in the presence of cesium carbonate and sodium sulfate.After completion of this second reaction, dendrimers 3prc-Gn (n = 1, 2, 3) (Scheme 1) were isolated, having less than 5% of symmetrical P(S)(OAr 1 ) 2 and P(S)(OAr 2 ) 2 terminal functions.
In the next experiment, generations 1, 2, and 3 of the PPH dendrimers were reacted simultaneously with both phenols 1 and 2 under basic conditions.As expected, this reaction provided randomly functionalized dendrimers 3rdm-Gn (n = 1, 2, 3), in which ca. 50% of the terminal functions are of type P(S)(OAr 1 )(OAr 2 ), ca.25% of type P(S)(OAr 1 ) 2 , and ca.25% of type P(S)(OAr 2 ) 2 .Scheme 1 illustrates the reaction for the first generation and the structure of 3rdm-G1.
Figure 1 displays the 31 P{ 1 H} NMR spectra (only the part corresponding to the P�S groups) of both the 3prc-G1 and 3rdm-G1 dendrimers (only one of the numerous possible structures is shown for the latter), pointing to the large difference between both families of dendrimers.It should be emphasized that 31 P NMR is a unique and very precious tool for the accurate characterization of dendrimers, 13 in particular, of highly sophisticated dendritic structures. 14Indeed, neither Scheme 1. Synthesis of the (a) Precisely Difunctionalized Monomer (3prc) (b) of the First-Generation Dendrimer (3prc-G1 Reaction Also Carried out to Synthesize 3prc-G2 and 3prc-G3) (c) and of 3rdm-G1 (Reaction Also Carried out to Synthesize 3rdm-G2 and 3rdm-G3); Structure of 3prc-G2 and 3prc-G3 1 H nor 19 F NMR were found suitable to detect any difference between the families of random (3rdm-Gn) and precise (3prc-Gn) difunctionalization of the dendrimers surface. 13C{ 1 H} NMR displays slight differences on some signals, but not as easily interpretable as 31 P{ 1 H} NMR spectra (see spectra in SI).Mass spectrometry is unusable, as cleavages and rearrangements are always observed with PPH dendrimers in MALDI-Tof experiments. 15he complexation ability of the iminophosphine was checked on the model compound 3prc and then on dendrimers 3prc-Gn and 3rdm-Gn (n = 1−3), respectively, using Pd(1,5-cyclooctadiene)Cl 2 (Scheme 2).The complexation was, in particular, characterized by 31 P{ 1 H} NMR, which displayed the disappearance of the signal corresponding to the free phosphine at ca. δ = −13 ppm, on behalf of the appearance of the signal corresponding to the phosphine complex at ca. δ = 30.8ppm.It can be noted that there is no control of the chirality on the P(S)(OAr 1 )(OAr 2 ) surface groups, and thus, all catalytic tests were carried out with nonchiral ligands, reagents, and reactions.
Having in hand two families of dendrimer complexes, namely, precisely and randomly difunctionalized, from generations 1−3, they were then tested in the Stille coupling 16 of iodobenzene with tributylvinyltin in THF at 50 °C.In order to have an accurate comparison between the different generations, the same quantity of catalytic sites was used in all cases.For instance, the efficiency of 1 equiv of generation 3 having 24 ligands complexing Pd is compared with that of 4 equiv of generation 1 having 6 ligands complexing Pd, and with that of 24 equiv of the monomeric complex.Even if the distance between the catalytic sites and their accessibility changes with the generations, this is the only way to compare the efficiency between generations.Figure 2 displays the results of these catalytic experiments monitored by NMR for 7 h.All experiments were carried out in duplicate, and the uncertainty is given in Figure 2. The precisely functionalized dendrimers display a slightly positive dendritic effect on going from generation 1 to generation 3. 17 An analogous, slightly positive dendritic effect is observed with the randomly functionalized dendrimers.However, it is important to note that in all cases from generation 1 to generation 3 the precisely difunctionalized dendrimers 3prc-Gn-[Pd] are more efficient catalysts than the randomly functionalized dendrimers 3rdm-Gn-[Pd].The difference is most accurate between the first generations 3prc- Reaction was also carried out with the monomer 3prc and dendrimers 3prc-Gn (n = 1, 2) and 3rdm-Gn (n = 1−3).
Part B of Figure 2 displays the results after 7 h, with additional information about the use of PdCl 2 alone and of the monomer.There is a large difference in the efficiency between monomer 3prc-[Pd], which is less efficient than PdCl 2 alone, and the different generations of the dendrimers, illustrating again a dendritic effect.As we had previously demonstrated a different efficiency of the Pd-iminophosphine catalysts, depending on the type of Stille couplings carried out, 9 we decided to test 3prc-G1-[Pd] and 3rdm-G1-[Pd] in another type of Stille couplings.The reagents used in this case were methyl-2-iodobenzoate and 2-(tributylstannyl) thiophene, and the catalysis was carried out for 22 h at 50 °C in THF.As shown in Figure 3, in this case also the precisely difunctionalized dendrimer 3prc-G1-[Pd] was more efficient than the randomly difunctionalized dendrimer 3rdm-G1- [Pd].
In order to confirm more (or not) the large difference in efficiency between random and precisely difunctionalized dendrimers observed in the catalysis of Stille couplings, the model 3prc-[Pd] and the first generations 3prc-G1-[Pd] and 3rdm-G1-[Pd] were tested in another type of cross-coupling reactions, the Heck reaction. 18The reagents used were iodobenzene and methyl acrylate, in the presence of NEt 3 . 18t was shown previously that the presence of triethylamine increases the selectivity of the Heck coupling product. 19In our case, we observed 100% selectivity in the trans product.
As the reaction occurs more slowly than the previous ones, experiments were carried out for a longer time, 30 h.A weak dendritic effect was observed on going from monomer 3prc-[Pd] to 3prc-G1-[Pd].In this case as previously, the precisely difunctionalized dendrimer 3prc-G1-[Pd] was found more efficient than the random difunctionalized dendrimer 3rdm-G1-[Pd], as illustrated in Figure 4.
In this paper, we have demonstrated for the first time that the precise difunctionalization on all of the surface of dendrimers affords different results than their random difunctionalization.We have shown that the precise functionalization of PPH dendrimers is more efficient in two types of cross-coupling catalytic reactions.The difference is clearly visible for all generations, from the first to the third.Thus, besides the problems of reproducibility between batches   previously known, 3 the difference in efficiency between precisely and randomly difunctionalized dendrimers must be taken into account and should be checked in each case.Indeed, examples in which randomly functionalized dendrimers are more efficient than precisely functionalized dendrimers can probably also exist.We believe that this original finding is not limited to catalysis, but can be considered as a global warning when using randomly functionalized dendrimers in any field, such as in biology where it is widely used with only very few questions. 20ASSOCIATED CONTENT

Figure 2 .
Figure 2. Stille cross-coupling catalytic experiments with precisely and randomly difunctionalized dendrimers from generation 1 to generation 3 and monomers: (A) evolution with time; (B) comparison of efficiency after 7 h.