Dr Jonathan De Tovar
email: jonathan.detovarvillanueva@cea.fr

Dr Franck Rataboul

Dr Laurent Djakovitch
email: laurent.djakovitch@ircelyon.univ-lyon1.fr

Heterogenization of Pd(II) Complexes as Catalysts for the Suzuki-Miyaura Reaction

Keywords: Suzuki-Miyaura, N-heterocyclic carbene, Phosphines, Palladium complexes, Palladium nanoparticles, Heterogeneous homogeneous catalysis, Metal Oxides

This review highlights the potential application and understanding of Pd(II) complexes anchoring onto different supports as catalytic systems for the Suzuki-Miyaura reaction. The combination of the high reactivity of Pd complexes with their facile separation, purification and recyclability makes these systems promising catalysts for the industrial synthesis of fine chemicals. This review focuses on the general developments in this research area in the last three decades comprising the most recent achievements and understanding of these heterogenized systems.

Due to the recent progress on designing and synthesizing supported Pd catalysts, 1-3 these systems are now highly interesting for catalyzing the crosscoupling reactions involved in Suzuki-Miyaura reaction. Generally, soluble Pd complexes are used that usually makes their separation from the reaction mixture highly problematic increasing the risk of contamination of the products by Pd. Furthermore, the reuse of Pd complexes usually fails due to the formation of inactive Pd black. Additionally, given the scarcity of Pd, these limitations appear extremely penalizing for large-scale applications in the industry. The heterogenization of soluble complexes onto a support keeping the advantages of the homogeneous Pd catalysts like high activity and selectivity, associated to easy recovery and reuse, appeared rapidly as a potential solution. 4 However, supporting highly active homogeneous Pd complexes while keeping their properties is not always trivial and advances are still to be performed to transform this potential into a viable solution. Hence, the development of efficient and cost-effective heterogeneous Pd-based catalysts is of paramount importance for transferring their use in the industry. Therefore, studies aiming at supporting Pd-based complexes have attracted enormous interest focusing on combining properties of those homogeneous systems to the advantages of heterogeneous ones like tunable Pd content and stereoelectronic features, and recyclability. 5,6 Concerning the applications, focus is principally on low-cost heterogeneous alternatives capable of catalyzing the Suzuki-Miyaura reaction. Heterogeneous systems often evolve to less active Pd NPs. [7][8][9][10][11] Nevertheless, tuning the nature of the support and that of the supported complex, modifying the grafting procedure or using additive moieties in catalyst formulation, can help to solve such problems. Additionally, additive and supports also typically play a secondary role as stabilizers and help to expand the relatively narrow range of usable aqueous solvents, relative to organic solvents, where these catalysts can exhibit high performances. Supported Pd-complexes have been studied since the 90s, when resin Deloxan®supporting a thiourea-based Pd complex was found to catalyze the reaction in different solvents including water, the catalyst being recycled up to 2-3 cycles with a low Pd leaching in the crude products. 12 Hence, Pd-supported species as catalyst for the Suzuki-Miyaura reaction have attracted particular attention in recent years since their robustness, composition, activity and stability can be controlled through the Pd-coordinating ligand. Anchoring ligands to a scaffold allowing their recovery and reuse would have also the advantage of minimizing the presence of Pd in the reaction products. Additionally, given the importance of working with aryl chlorides less reactive but more affordable than aryl bromides and iodides, the use of supporting robust and high-temperature stable Pd-catalysts has become a necessity. From here, the nature of the Pd-supported complexes as catalysts for the Suzuki-Miyaura reaction has been mainly focused on imines, phosphines and Nheterocyclic carbenes Pd-complexes. However, although molecularly well-defined Pd complexes have been tested in this reaction, 13 a controversy concerning the exact nature of the true catalytic system exists when nanoparticles formation or Pd leaching occurs under turnover conditions. [14][15][16] For instance, very active catalytic species released from pre-catalysts are quite often postulated but their exact nature is elusive. 17,18 Thus, several studies have dealt with the elucidation of the real nature of the catalytically active species since very frequently, the Pd-complex is a precursor of NPs that evolve during the course of the reaction. Then, although the reaction is initiated by a catalyst corresponding to an identified Pd-complex, Pd lability makes that the active species (for most of the activity observed) are really Pd NPs generated in the first turnovers of the cycle as a consequence of slow reoxidation from Pd(0) to Pd(II). In the literature there are several reviews covering the use of Pd NPs suspended in various media as recyclable catalysts for the Suzuki-Miyaura C-C coupling reaction. 14 The aim of this review is to present the approach dealing with the anchoring of Pdcomplexes onto supports. It will be illustrated by the methodologies induced by the different types of supports, highlighting the tunability of the nature of Pd and support entities towards a better reusability of the Pd catalyst.

Oxide supports

SiO2

Among various inorganic supports such as clays, 19,20 zirconium carboxyphosphonate, 21 rare earth oxides 22,23 and magnesium hydroxide/cerium carbonate hydroxide 24 for immobilizing Pd catalysts, mesoporous SiO2 is very promising due to its high surface area, good thermal stability, ready availability and economic viability. Additionally, it is relatively easy to proceed to covalent modifications with organic and organometallic moieties. 25,26 Thus, SiO2 has been used as support for NHC-based, [27][28][29][30][31][32] imine-based, [33][34][35][36][37][38][39][40][41] and phosphine-based [42][43][44] Pd(II) complexes showing in general high reusability. In general, higher performances are observed for catalyst-immobilized in porous supports, compared to those achieved with grafted catalysts on the superficial sites of the inorganic material, since they prevent catalyst depletion. For instance, Ma and co. immobilized an imine-based Pd(II) complex onto the inner surface of the SBA-16 material (Scheme 1). 36 The good reusability of the system is attributed to the isolated nanocages of SBA-16, which could efficiently prevent the aggregation of Pd particles formed during the catalytic reaction. Fig. 1. Synthesis of grafted core-shell γ-Fe2O3/silica MNP-2 and MNP-4. Compared to conventional trialkoxy-type linkers, tripodal linkers are more advantageous and attractive since they prevent degrafting of organic groups from silica support during functional group transformations. These groups allow a reduced extent of metal leaching while improving the catalyst recyclability. For instance, Yasuda and co. prepared a series of silica-immobilized amino-Pd complex containing a tripodal linker (Fig. 2, links). 47 The authors confirmed that these systems showed less metal leaching than conventional trialkoxy-type linkers (Fig. 2, right) resulting thus, in a longer catalyst recyclability. Fig. 2. Organic-functionalized silica materials reported in reference 47. Thiel and co. prepared a mesoporous organosilica-supporting Pd N-heterocyclic carbene complex synthesized by applying an electrostatic grafting method (Scheme 2). 32 The authors examined the heterogeneity of the system by a leaching test and TEM experiences showing neither leaching nor catalyst decomposition, which confirms the high stability of the Pd complex and its strong binding to the surface. Scheme 2. Synthesis of [Pd-NH3 + )( -SO3-PhPMO)] in reference 32.

Additionally, the easy grafting of imine-precursors at the surface of SiO2 heads to unravel additional parameters affecting the catalyst performance. Thus, the lower the binding energy of Pd in the catalysts, the greater their activity in the Suzuki-Miyaura reaction. Paul and Clark prepared a series of imine-based Pd(II) complexes immobilized on silica (Fig. 3) and demonstrated a structure-activity relationship for supported Pdcatalysts based on Pd binding energies and initial reaction rates. 35 As measured by XPS, a more electron rich environment around Pd leads to lower binding energy values. Thus, the lower the binding energy for Pd, the easier the insertion of Pd in the R-X bond and the faster the reaction (Table 1). Fig. 3. Catalytic systems reported in reference 35. Although it is true that the size, shape and composition of the support are parameters of paramount importance to control the activity and the stability of the supported Pd complexes, the crystallinity also plays a key role in these systems. Hence, Sajiki and co. prepared TiO2-supported catalysts on supports possessing different crystalline structures and evaluated the influence on aryl chlorides reactivity. 48 The authors demonstrated that anatase-type TiO2-supported palladium(II) acetate exhibited a superior catalytic activity and the performances were in the order anatase > rutile > brookite. The enhanced activity for the anatase-type structure is attributed to the extensively distributed small Pd NPs formation and the appropriate interaction between the Pd species and the anatase-type TiO2 based on the reduction of the Pd(II) to Pd(0) species. Salimi and co. studied the photocatalytically-triggering effect of TiO2 on grafted Pd catalyst. 49 Thanks to the high content of N-donor moieties, they coordinated the amine-terminated poly(triazine-triamine) dendritic scaffold grafted on TiO2 to palladium(II) acetate giving rise to the consequent band gap modification of the support (Fig. 4). Fig. 4. [Pd(II)PTATA-G2-NH2]@TiO2. Adapted from reference 49. This modification induced an outstanding photocatalytic activity in the Suzuki-Miyaura reaction, under visible light at room temperature, which is attributed to an efficient separation and photogeneration electron-hole pairs and photoredox capability of the nanodendritic architecture. The authors proposed a mechanism where, under visible light irradiation, the nanodendritic catalyst can produce photogenerated electrons and holes able to activate the electron-deficient and electron-rich intermediates to facilitate the C-C coupling. The holes can assist in cleaving the C-B bond to produce biaryl-Pd complex. They confirmed the determining role of TiO2 by adding a hole scavenger such as ammonium oxalate and then a radical scavenger such as TEMPO and observed mainly no product formation. These studies propose that the photogenerated hole and electron pair is crucial for carrying out the coupling reaction. Thus, the authors studied the contribution of light at different wavelengths observing a greater contribution of irradiation for room light lamps, sun light and LED (Fig. 5).

N N H 2 N H 2 N H 2 N NH 2 H 2 N NH 2 NH 2 NH 2 NH 2 NH 2 H 2 N H 2 N NH 2 NH 2 N N N NH 2 H 2 N H 2 N H 2 N H 2 N NH2 H 2 N H 2 N H 2 N H 2 N NH 2 H 2 N H 2 N

Al2O3

Mesoporous materials resulted to be effective catalysts supports because of their unique properties such as large BET surface areas and pore sizes. Additionally, Al2O3 tolerates a straight-forward structure modification allowing doped and mixed materials capable to boost the catalyst activity. [51][52][53][54] In this context, the incorporation of KF in such aluminum oxide increases the basicity character of the support avoiding the use of an external base and solvent. 55,56 Together with the good hydrothermal stability in aqueous media and its commercial availability, Al2O3 has resulted to be a good candidate for the immobilization of easily available palladium complexes. Hence, Feng et al. prepared a mesoporous γ-Al2O3 with the posterior immobilization of Pd(OAc)2 (Fig. 6). 57 The resulting γ-Al2O3-Pd catalyst resulted to be efficient and reusable for the coupling of aryl iodides, bromides and some chlorides in DMF : H2O (3 : 1) under microwave heating even using 0.2 wt% Pd loadings. This has been attributed to both the high dispersion and high affinity of Pd in the mesoporous aluminum oxide structure. Fig. 6. Impregnation of mesoporous γ-Al2O3. Also, Andrzej Gniewek found higher activities and reusabilities for smaller surface areas and pore volumes that after immobilizing PdCl2 on Al2O3-ZrO2 supports with different porosity and pore sizes. 51

Magnetic materials

Several studies have dealt with the use of magnetic supports. 33,46,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] The main advantage of magnetic materials-supporting catalysts is the easy recovery using an external magnetic effect in an effective and economical way. Additionally, the use of magnetic nanoparticles for supporting active species prevents the problems encountered with classical heterogeneous supports, where a high proportion of the catalytic sites are present deep inside the matrix backbones where reactants have limited access. In this context, Gao and co. evaluated a Pd-NHC complex grafted on both maghemite NPs and polystyrene resin (Fig. 7). 60 No significant loss of the catalytic activity for the Fe3O4-immobilized catalyst was observed after 5 cycles. On the other hand, the Fe3O4-Pd catalyst proceeded faster than the solid-phase (polystyrenesupported) catalyst. For instance, the former exhibited 35% conversion after 60 min while the later required at least 180 min to detect the heterocoupled product (Fig. 8). Fig. 7. Structures of maghemite nanoparticle-supported NHC-Pd complexes (Iron Oxide-Pd) and polystyrene (PS) resin-supported NHC-Pd catalyst (Solid Phase-Pd) reported in reference 60. Fig. 8. Suzuki-Miyaura cross-couplings between p-iodoacetophenone and phenylboronic acid catalyzed by Fe3O4-Pd (nanoparticle support) and Solid Phase-Pd (resin support) at 50 °C. Reproduced from reference 60 with permission of RSC publishing (Chem. Commun). Also, Thiel and co. grafted a Pd(II)-phosphine complex (Fig. 9) on three different supports: magnetic NPs ([Pd]@SMP), a commercially available silica gel ([Pd]@SG) and a mesoporous MCM-41 ([Pd]@MCM-41). 61 After recycling these systems, they observed that the activity and stability follows the order [Pd]@SMP>[Pd]@MCM-41>[Pd]@SG (Table 2) due to the fact that the nanoscale particle size and the location of the active sites on the surface prevents limiting effects of the diffusion. Fig. 9. Pd(II)-phosphine complex prepared in reference 61. [Pd]@SMP showed an excellent reusability up to 7 cycles. Analysis showed <0.5% of leached Pd in the reaction filtrate and confirmed the retention of the phosphine ligands on the surface after catalyst recycling. After hot filtration of the catalytic mixture, the catalyst-free portion reacted only to additional 10% after 15 h indicating that the leaching of Pd is not a serious concern.

Recently, De Cattelle et al. have prepared Fe3O4 NPs supporting Pd(OAc)2 and have found that an alternating magnetic field can efficiently enhance the performance of Pd-functionalized magnetic nanoparticles due to magnetic-induced thermal contribution. 64 For instance, as depicted in Fig. 10, increasing the strength and/or the frequency of the magnetic field increased reaction yield. Fig. 10. Influence of the magnetic field strength and frequency on the magnetic Suzuki-Miyaura reaction (black) and the thermal contribution (red). P-Bromophenol (0.18mmol), phenylboronic acid (0.27 mmol), K2CO3 (0.36 mmol), Fe3O4/PEG/Pd (0.1 mg), EtOH/H2O (1:1) (1.0 mL), under air. The reaction was monitored by 1 H NMR. 1 H NMR conversions were determined using 1,3,5-trimethoxybenzene as an internal standard.

Carbonaceous supports

Due to chemical, thermal and physical properties of graphene derivatives 75,76 especially graphene oxide, 77 it is possible to immobilize metal NPs, 78 metal complexes, 79-86 metal oxides, 87 ionic liquids 88 and acidic sites 89,90 on the surface for catalytic applications in organic transformations. Alonso and co. synthesized non-covalent supported oxime palladacycles (Fig. 11) on graphene oxide resulting to efficient catalytic systems for the coupling of aryl bromides and aryl boronic acids in methanol-water mixture (3 : 1) at room temperature. 91 Complex 1 showed the best activity due to low release of the active Pd and agglomeration compared to complexes 2 and 3. The authors demonstrated that graphene oxide can prevent the entirely reduction and further agglomeration to inactive Pd(0) once the complexes are supported. However, the graphene oxidesupporting complex 1 showed to be recovered and reused with loss of catalytic activity up to 2 cycles. After the second cycle, the complexes started to decompose to Pd NPs with further oxidation to PdO, evidencing that Pd is finally easily trapped by the oxygenated sites of graphene oxide. The Pd(II)-TMCPP-GO catalyst could be recovered after 7 runs with low decrease in the catalytic activity in a DMF : water mixture (2 : 1) at 70°C. The amount of Pd in solution (Table 3) indicated no important leaching phenomena. This low release of Pd is attributed to the porphyrin ligand, which delays the agglomeration and deactivation.

In fact, XPS revealed the presence of some Pd NPs aggregates after the 7 th run. This result indicates that the mechanism of deactivation is likely to involve the formation of Pd black. Thus, the authors proposed an operando mechanism (Scheme 5) where free Pd(0) is produced to undergo the reaction and harvested finally by the porphyrin once the reaction was complete, as previously proposed for Köhler and co. for similar homogeneous complexes. 93,94 Scheme 5. The proposed pathway for Suzuki-Miyaura reaction in the presence of Pd(II)-TMCPP-GO. Adapted from reference 92. On the other hand, graphitic materials provide a remarkable advantage for noncovalent grafting via π-stacking interactions with molecules having polyaromatic parts, especially pyrene moieties. Karami and co. demonstrated the recyclability up to 6 cycles of an immobilized palladacycle on rGO surface through non-covalent interactions while the non-immobilized complex revealed only 50% yield in the first run. 82 Among the carbonaceous materials which have attracted the attention of researchers such as fullerene, 95 g-C3N4 is emerging as a promising support. 96 Recently, Wang et al. reported the use of g-C3N4 as support for Pd species to photocatalyze the Suzuki-Miyaura reaction of different aryl iodides and bromides. 96 The catalytic efficiency under visible light irradiation is higher than that of the commercial Pd(PPh3)4 or Pd nanocubes reaching a TOF of 47.3 h -1 , which is almost twice of that of Pd(PPh3)4 under usual heating.

Polymers as scaffolds of catalysts

As mentioned before, since there is a large interest in developing the Suzuki-Miyaura C-C coupling reaction in green industrial processes, catalysts operating under air atmosphere and stable in aqueous solvents have become necessary. In fact, the main problem here is the low solubility of most of organic reagents. In this context, the use of water-soluble polyethylenglycols (PEGs) or ionic liquids (ILs) would render possible the reaction.

In this well-developed approach, one important issue is to control the formation of Pd NPs of defined sizes and shapes from parent Pd-complexes upon their decomposition. Thus, the presence of scaffolds controlling Pd NPs growth while keeping the recycling capacity has attracted the research community. One of the simplest strategies is the use of bulky environments like polymers and, specially, hyperbranched polymers. Also, the necessity of working in aqueous solutions has prompt the use of polymers with high swelling capacities in polar media.

Modified polymers having NHC as ligands

Some polymer-containing NHC moieties have been reported in the literature, which are able to operate under aqueous environments. 97,98,99,100 From here, the swelling capacity of the polymer scaffold has resulted to be pivotal for the catalyst performance in polar media. Lee and co. prepared two amphiphilic polymer-supported Nheterocyclic carbene-based PdPd(II) complexes (PS-PEG-NHC-Pd with different PEG lengths (PEG-200 and PEG-600, Scheme 6)). 101 Both the PS-PEG 200-NHC-Pd and PS-PEG 600-NHC-Pd catalysts were investigated for Suzuki-Miyaura reaction in water at 50°C in order to confirm the effects of PEG length. The results indicated a longer lifetime for the PS-PEG 600-NHC-Pd catalyst because of its higher swelling capacity in polar media allowing recyclability up to 7 times without loss of activity. Scheme 6. Immobilization of Pd on PS-PEG-NHC precursor resins. The study of polymers containing N-heterocyclic-based 54,102,103, and imine-based [104][105][106][107][108][109][110] complexes have been largely studied for both organic 102,103 and aqueous solvents. 62,104,105,110-112, The Pd content in the systems has become an important parameter to optimize since dramatically affecting the activity, and lifetime of the catalyst. Thus, decreasing the Pd loading or increasing the presence of unsaturated ligand leads to superior activities and recyclabilities. For instance, Kirschning and co. grafted an oxime-based palladacycle to a polyvinylpyridine resin (Fig. 12) with different Pd loadings demonstrating that a higher Pd loading (0.79 mmol.g -1 ) yields to a faster loss of activity than at a lowest Pd doping (0.25 mmol.g -1 ). 106 This observation is ascribed to the formation of larger Pd particles on the polymeric matrix under thermal stress conditions, finally leading to inactive Pd black. De Vries and co. also noted that Pd(0) at low concentrations in solution will aggregate and deactivate much more slowly than for high concentrations for the Mizoroki-Heck reaction. 113 Indeed, Kirschning and co. proposed that both the remarkably low degree of leaching observed and the delayed formation and growth of colloids could be ascribed to the efficient scavenging of the catalytically active species by the large excess of uncoordinated pyridyl sites. This prompt to consider that the polymeric matrix system may act as a reservoir for catalytically active ill-defined Pd(0)-species active in solution (Scheme 7). Scheme 7. Putative mechanistic model proposed in reference 106. On the other hand, the easy terminal functionalization of polymer branches allows evaluating the electronic environment of the Pd core. For instance, Lee and co. prepared a scope of polystyrene-supporting Pd oxime complexes with different electron-richness increasing in the order of 4d<4a<4b<4c (Fig. 13). 104 Interestingly, the catalytic activity in the Suzuki-Miyaura coupling reaction increased in the same order as the electron-richness of the palladated oxime resins indicating that the electronrichness of the ligand promoted the ability of Pd to perform the oxidative-addition. However, the electron density contributed not only to the catalytic activity but also to the recyclability that evolved in the same order when decreasing. Fig. 13. Catalyst prepared in reference 104. More to this point, the imposed structure by the polymer has an influence on the catalytic activity. Ebitani and co. grafted ionic Pd species on an amino-functionalized organozinc coordination polymer (Pd/AZC, Fig. 14). 114 The catalyst was active for coupling aryl iodides, bromides and chlorides to phenylboronic acid with moderate to high yields in EtOH at 80°C. It could be recycled up to 7 times without any significant decomposition and loss of activity. This catalytic performance was attributed to Pd(II) physical environment imposed by the organizing polymer, which facilitates the oxidative-addition step as well as preventing the loss of Pd atoms (Fig. 14c). On the other hand, imidazole and triazole containing scaffolds allow to operate under environmentally-friendly conditions and have shown to boost the coupling of nonactivated aryl chlorides substrates since these moieties allow the stabilization of Pd species under turnover conditions. [115][116][117][118] In this context, Uozomi and co-workers immobilized (NH4)PdCl4 on a poly(imidazole-acrylamide) support (Scheme 9), which resulted to be active for the coupling of aryl chlorides in water with TONs up to 3570000. 116 Scheme 9. Preparation of MEPI-Pd. Also, Trzeciak and co-workers immobilized Pd(OAc)2 on different substituted triazolylfunctionalized polysiloxane supports (Fig. 15). 118 The ability to bind Pd depends on the functional substituents of triazolyl rings since the compact butyl-containing Pd/B catalyst stabilizes Pd species evolved under turnover conditions rather than linear phenyl-containing Pd/A catalyst. However, not only the stabilization of palladium is one of the parameters to control for a long time reusability of the catalyst but also the accessibility to these active sites (higher swelling capacity) is necessary, especially for bulky substrates. In this context, Pd/A is capable of being reused up to 3 runs with high to moderate yields whereas Pd/B depletes after 1 st run using both the same amount Pd and polymer.

Modified polymers having N-donor as ligands

Modified polymers having P-donor as ligands

The use of phosphine-containing polymers has attracted the attention of the research community since they perform the coupling of not only aryl bromides [119][120][121][122][123] but also of several aryl chlorides with arylboronic acids. [124][125][126][127][128][129][130] In 2000, Inada and Miyaura reported the coupling of electron-deficient aryl chlorides or chloropyridines with 4-methylphenylboronic acid in the presence of relatively high amounts of (diphenylphosphino)polystyrene-supported Pd (3 mol%). 127 Later, Parrish and Buchwald have described a five-step preparation of polymersupported dialkylphosphinobiphenyls as Pd ligands for coupling of aryl bromides or chlorides under anhydrous conditions in high yields despite the fact that aryl chlorides required a large excess of arylboronic acids (3 equiv) and up to 1 mol % of Pd. 128 In 2005, Scordia and co. reported polystyrene-supported palladacycles for the coupling of aryl chlorides, but these systems could not be reused although they were easily separated and showed low levels of Pd leaching. 129 Finally, Sinou and co. have developed a polymer-supported (dicyclohexylphosphino)biphenyl ligand for the Pd-catalyzed coupling of electrondeficient aryl chlorides and phenylboronic or 4-methylphenylboronic acid. A single example of coupling of a deactivated aryl chloride was described, affording a very low yield. 130 This low efficiency is strongly influenced by the nature of the solvent due to the swelling capacity of the polymeric matrix (vide supra). As already mentioned for silica and alumina-supporting palladium complexes (vide supra), higher performances are observed for porous supports since they preserve Pd aggregation. For instance, Li and co. prepared two different knitting aryl network polymers immobilizing PdCl2 inside the pores or on the outer shell of the structure (Fig. 16,(a) and (c)). 126 The former (Fig. 16a, Pd inside the pores) exhibited an excellent catalytic performance attributed to disperse Pd complexes in the micropore backbone. On the other hand, for the latter (Fig. 16c, Pd attached to phosphine outside the pores), the Pd bonded on the grafted PPh3 located in superficial section was not tightly locked inside materials, hence, the Pd loss being unavoidable Pd black emerged after the first run.

Hyperbranched polymers

Also, an homogeneous dispersion of Pd(II) complexes in the support has resulted to have an impact on the catalytic activity. A microporous structure ensures a high dispersion of Pd active sites while a macroporous structure improves the diffusion of organic reactants. Li and co. also compared these two different knitting aryl network polymers immobilizing PdCl2 in their micropores and macropores (Fig. 16,(a) and (b), respectively). 126 The former exhibited an excellent catalytic performance attributed to its special highly dispersed Pd complexes in the micropore backbone while the latter was incapable to prevent Pd aggregation and deactivation. Hyperbranched polymers are well-defined polymers which represent an attractive alternative to classic dendrimers due to their higher flexibility than dendritic structures, low cost, simple and versatile synthetic approach, presence of large surface areas and pores and superior chemical and thermal stabilities. In this context, Flaga and co. reported a recyclable system for the coupling of aryl bromides. 131 They prepared a poly(amidoamine) PAMAM type hyperbranched system immobilized on an epoxy functionalized polymer based on glycidyl methacrylate (the GMA resin) incorporating Pd(OAc)2. The catalyst retained its activity up to 10 reuses in an isopropanol-water mixture (1 : 1 v/v) in batch conditions. The SEM images combined with EDS analyses proved the presence of homogeneously distributed Pd NPs on the surface of the recovered dendrimer beads with no important Pd leaching. Also, Anajli and Sreekumar prepared a polymer-supported hyperbranched polyglycidol decorated with NHC-Pd complex at the periphery. 132 The polyglycidol shell grafted on polystyrene contributed to dendritic structure and properties and also to water compatibility. The catalysts exhibited excellent thermal and chemical stability as well as recyclability without metal leaching in a DMF-water mixture (1 : 1). Chen et al. fabricated a conjugated phenanthroline-based porous polymer (CPP) coordinating Pd active sites revealing an excellent performance and recyclability for the coupling of aryl bromides in ethanol-water medium. This performance is attributed to the strong coordinating ability of the CPP support toward metal ions and the rich porosity towards NPs stabilization. 133 Dong and Ye prepared heterogeneous Pd catalysts with the use of a hyperbranched poly(phenylacetylene) (HBPPA) containing pendant alkyne groups as the cross-linkable polymer substrate. 134 In the synthesis, a homogeneous Pd(II) complex catalyzes the cross-linking of the hyperbranched polymer and simultaneously encapsulates itself into the cross-linked matrix, rendering the heterogeneous catalyst at high yield and high percentage of Pd encapsulation (Fig. 17). The authors assessed three homogeneous catalysts having different ligands (triphenylphosphine, a diphenylphosphine and a diamine) for the cross-linking encapsulation and the catalytic performance. The triphenylphosphine-ligated catalyst, HBPPA-Pd-2 appeared to be the best. It showed a high activity catalyzing the Suzuki-Miyaura reaction, under air and water with a Pd loading at as low as ppb levels relative to the reactants. Meanwhile, it facilitated the challenging Suzuki-Miyaura reactions of less reactive aryl chlorides and heteroaryl bromides. In addition, it behaved truly as a heterogeneous catalyst with acceptable reusability (6 cycles) and low leaching. Recently, Liu et al. supported Pd(II) chloride on triazolyl-functionalizated hypercrosslinked polymers, giving a highly active catalyst for biaryl formation with TON values reaching 1.66 x 10 4 . 135 Fig. 17. Synthesis of heterogeneous Pd catalysts (HBPPA-Pd) containing different Pd complexes by Pd-catalyzed cross-linking of HBPPA.

Biopolymers

Very interestingly, the use of natural polymers as supports greatly enhances the catalytic performance of grafted Pd(II) complexes in aqueous media due to their high swelling capacities. 62,110 For instance, Nasrollahzadeh et al. reported the benefits of using calcium lignosulfonate natural polymer as support for Pd(II) tetraazole-based complexes allowing the reaction in pure water. 62 More to this point, the use of biopolymers as supports not only yields eco-friendly and low cost materials but also confers high thermal and chemical stabilities resulting in outstanding performances and high recyclabilities for a wide variety of substrates under mild conditions at short reaction times (4-8 minutes) allowing to work even under solvent-free conditions. Within this context, Menteş and co-workers have been studied the effect of different biopolymers such as chitosan, 136-142 sporopollenin, 74,143 starch, 144 agar 145 and pectin. 146 For instance, the functionalization of sporopollenin with 3-aminopropyltriethoxysilane and further condensation with glyoxal gave Schiff base-contained scaffolds allowing the heterogeneization of Pd(II) (Scheme 10). 143 tolerates a broad range of functional groups. However, bulky substrates did not participate to the catalytic reaction due to the limited diffusion through the pores or to the steric hindrance after coordination to the Pd-center (Fig. 18). 158 Fig. 18. Shape selectivity using bromobenzene and 9-bromoanthracene. Additionally, the presence of uncoordinated sites in the MOF structure is of paramount importance to immobilize a Pd complex in the framework. However, the accessibility to these moieties is building-depending, and thus a pivotal factor for the catalytic activity. For instance, Wu and co. prepared Cu-based MOFs containing a double azolium derivative by following two different procedures. 159 Two differentiated structures [Cu2(L)2(MeOH)2](NO3)4(H2O) (1) and [Cu(L)Cl2](H2O) (2) were obtained (Fig. 19). Then, both structures 1 and 2 were treated with Pd(OAc)2 to form Pd(II) complexes in the bisazolium moieties. The resulting MOF-Pd catalysts were tested for the coupling of aryl iodides and bromides with arylboronic acids resulting in outstanding performances for 1 due to the accessibility of the Pd-azolium species compare to 2 where the corresponding moieties are situated in constrained environment. Thus, even if 2 possesses the carbene precursor of imidazolium moieties like in 1, the relatively low catalytic activity of 2 may be a consequence of the imidazolium groups being held very close to the {CuO2Cl2} units linked by strong hydrogen bonds (Fig. 20c).

Au

An alternative to covalent bonding is physisorption. Within this context, Au is one of the most interesting candidates for molecule adsorption especially for alkyl sulfides and other sulfur-containing molecules. 161 Arisawa and co. immobilized a Pd(II) complex on Piranha-treated Au(111)/mica SAPd (Fig. 21a), which exhibited a high recyclability (up to 10 cycles) with a low Pd-releasing level (72-73 ppb) for the quantitative coupling of aryl iodides and bromides in ethanol after 12 h. 162 The high reusability was attributed to the binding energy of the S 1s peak for the Piranha-treated Au(111)/mica, which is close to that of Na2SO3. Later, the authors demonstrated that catalytic system acts, in fact, as a Pd reservoir and releases catalytically active Pd species in the reaction media (Fig. 21b). 163 Fig. 21. Synthesis of SAPd (a) and its proposed mechanism (b).

The use of supported Pd complexes in microreactors

Among new strategies, micro-chip based microreactor technology has received a great attention in recent years, due to its unique advantages. [164][165][166][167][168][169] Their small sizes prevent hot spots typically generated in closed reactors, 170 offering better selectivities and yields for many organic reactions. High surface-area-to-volume ratios allow reactions that cannot be easily realized in traditional reactors, [171][172][173] providing opportunities to run reactions efficiently with minimal waste. More importantly, microfluidic systems present other advantages such as high integration and easy combination with other techniques making possible useful tools in screening both catalysts and reaction conditions. [174][175][176][177][178] In general, the heterogeneous catalysts with large surface-area-to-volume ratios were often adopted to improve the catalytic performance in the conventional synthesis due to a better molecular diffusion and heat transport. Similar strategies have also been used in microfluidic devices as reported by Tolhurst et al. 166 Also, traditional supports for immobilizing Pd(II) catalysts are porous materials, but more and more studies indicated that mesoporous materials with uniform pore structure might provide better catalytic efficiency. Microfluidic channels, which are small in size and highly uniform in shape, may be used as both the reaction containers and catalyst supports. With this type of flow system, the collection and isolation of products can also be greatly simplified. Here, the larger channel lengths, the smaller axial distances and the laminar flow pattern facilitate the substance exchange (reactant reaching and product leaving the active sites) and thus, consequently, the overall yield of the reaction. Then, some attempts to perform Suzuki-Miyaura reaction in microfluidic format have been reported. For example, Fletcher and co. 179 have developed microwave-assisted reactions in glass microreactors using a syringe pump-driven flow and Pd/Al2O3 catalyst. Guijt and co. 180 have successfully introduced organic monolith supports into narrow bore fused silica capillary microreactors for the formation of carbon-carbon bonds. Additionally, Styrung and co. demonstrated the increased kinetic reaction constant in flow conditions (Kobs,flow = 3.6 h -1 ) relative to a batch reactor (Kobs,batch = 0.18 h -1 ) because of a more efficient contacting of the reactants with the catalysts surface. 112 Although the solution could easily flow through an open channel in a typical laminar flow pattern 166 and it facilitates reactants reaching and products leaving from the active sites of catalysts which are immobilized on the channel surface, Suzuki-Miyaura cross-coupling reaction within open channels of microchips had not been reported since Pu and co. with a cyclic olefin copolymer-based open channel chip. 181 The authors immobilized a Pd complex on a photochemically grafted layer of polymerized N-[3-(dimethylamino)propyl]methacrylamide (Fig. 22) and observed that since the channel size is in micrometer range, diffusion of the molecules between the main stream and the channel surface takes only few seconds or less.

Conclusions and outlook

One of the focus concerns actually the reuse of Pd-catalysts for improving the Pd-turnover for producing compounds via the Suzuki-Miyaura reaction enhancing thus the economical balance. Furthermore, the easiness for separating and recovering the Pd-catalysts from the reaction mixture, lowering contamination of added valuable products, and improving the Pd-reuse, has attracted the research community in the last decades. In this regard, the immobilization of Pd complexes, which have become widespread along the years, have shown the comparable or even superior performances to those for their homogeneous counterparts. At the same time, the comparison of catalyst grafting through different strategies and to different supports also have allowed to identify both the main advantages and drawbacks of these systems. More to this last point, high leaching due to decoordination or degrafting phenomena, ill swelling capacity, low porosity, large pore size lead to the formation of Pd black and further catalyst depletion. A quick glance at the primary figures of merit for the most representative immobilized catalysts highlights the main factors affecting the catalytic performance for such a C-C coupling reaction. Together with the general effect of the nature of the ligand coordinating the Pd, the architecture of the support (well-isolated heterogenization sites, moderate porosity and small pore diameter), and compact rather to linear scaffolds, hinder the diffusion of Pd atoms and can prevent their aggregation under turnover conditions improving the catalyst durability. In this context, pores diameters have proven to be a key parameter of these systems since larger sizes, higher diffusion of bulky substrates to the active sites but worst towards preventing Pd NPs formation. Thus, the establishment of structure-activity/stability relationships remains as the main challenge in the Suzuki-Miyaura reaction. All in all, the development of simple, scalable and cost-effective Pd-supported catalysts as well as their reuse are the two main challenges the field will face in the upcoming years. From here, a very encouraging field has been emerged with continuous flow operating reactors because of the feasible implementation of the heterogenized Pd complexes into a practical industrial device, the new separation procedures they exhibit as well as their innovative technologies for an accelerated industrial development. Within this context, the physical architecture of flow channels results to serve as both reaction container and catalyst-support ensuring a high substrate-catalyst contact and yielding high conversions at low catalyst loadings.

  Fig. 5. Dependence of the catalytic activity of [Pd(II)PTATA-G2-NH2]@TiO2 for Suzuki-Miyaura cross-coupling on the irradiation wavelength. Reaction conditions: iodobenzene (0.125 mmol), phenylboronic acid (0.126 mmol), [Pd(II)PTATA-G2-NH2]@TiO2 (1.46 %) in H2O-EtOH (0.5 mL) at room temperature after 30 min. Recently, De Tovar et al. reported the immobilization of Pd(II) complexes bearing bis(NHC) ligands onto TiO2 nanoparticles.50 The authors founded that under turnover conditions, the Pd complexes evolved to Pd NPs at the surface of the support generating Mott-Schottky heterojunctions. In accordance with the work of Salimi and co-workers, 49 the catalytic performance was boosted upon light irradiation. The photogenerated holes activate the phenylboronic acid shifting its equilibrium under basic medium towards its conjugated base whereas the photogenerated electrons assist the activation of aryl bromide substrates (Scheme 3). Interestingly, this work unraveled that the Pd NPs acted as reservoirs of active Pd species through leaching/redeposition sequences.

Fig. 11 .

 11 Fig. 11. Oxime palladacycles employed in the study of reference 91.An alternative to protect the active metal from oxygenated sites is an appropriate steric hindrance. For instance, Sun and Li prepared an isopropyl-diamine-Pd complex supported on graphene oxide. The system could be recycled 4 times with high yields due to low Pd leaching (<1ppm).81 Recently, Liang and co. have demonstrated the crucial role of bulky α-diimine Pd complexes covalently bounded to graphene oxide, which prevent the loss of Pd and agglomeration to Pd NPs.86 Interestingly, since Pd porphyrins complexes are thermal and chemical stable, complete coordinative saturation of the central atom and preference for the Pd(II) oxidation state, it is thought that the release of Pd under coupling reaction conditions would be controllable. Bagheri and co. introduced an efficient Pd porphyrin macrocyclic complex covalently grafted on the surface of graphene oxide (Pd(II)-TMCPP-GO, Scheme 4).92

  ), 70°C, 60 min. b Isolated yield. c Determined by ICP.

Fig. 12 .

 12 Fig. 12. Oxime-based palladacycle grafted to a PVP resin prepared as described in reference 106.

Fig. 14 .

 14 Fig. 14. Proposed structure of AZC on the basis of spectroscopic characterization. Ball and stick model structure of (a) Pd/AZC; (b) local structure around Pd and zinc in Pd/AZC; (c) (i) side view of the local structure of Pd in Pd/AZC. (d)-(f) Simplified structure of (a)-(c). Carbon (gray), oxygen (red), nitrogen (light purple), Pd (green), and zinc (dark purple). The hydrogen atoms are not shown for simplicity. Adapted from reference 114. Thus, a general reaction mechanism was proposed (Scheme 8) where an oxidativeaddition of aryl bromide on the exposed Pd(II) center of Pd(O)2(NH2)2 followed by ligand exchange with the base and arylboronic acid are considered as sequential steps.

Fig. 15 .

 15 Fig. 15. Proposed structures for Pd/A and Pd/B. 4.3 Modified polymers having P-donor as ligands

Fig. 16 .

 16 Fig. 16. Synthetic route of: a) KAPs(Ph-PPh3)-Pd, b) PS-PPh2-Pd and, c) KAPs(Ph)-PPh3-Pd. Big balls represent PPh3 or PPh2 functional groups. Small balls represent PdCl2. Solid line represents boundary of material particles. Dashed lines represent inner network of material particles. Adapted from reference 126. 4.4 Hyperbranched polymers

Fig. 19 .

 19 Fig. 19. Ligand (L) and MOFs (1 and 2) prepared in reference 159.

Fig. 22 .

 22 Fig. 22. Schematic illustration of COC-based microfluidic reactor and its surface modification processes. Adapted from reference 181.

3

  Carbonaceous supports…………………………………………………………………………………………..15 4 Polymers as scaffolds of catalysts...............................................................................

		5.2
	Au………………………………………………………………………………………………..…………...30
	6	The	use	of	supported	Pd	complexes	in
	microreactors……………………………………………...31
	7 Conclusions and Outlook…………………………………………………………………………………………32
		Acknowledgements………………………………………………………………………………………..33
		References………………………………………………………………………………………………..……33
	1 Introduction and Scope
								.19
		4.1	Modified	polymers	having	NHC	as
	ligands………………………………………………...19
		4.2	Modified	polymers	having	N-donor	as
	ligands……………………………………….....20
		4.3	Modified	polymers	having	P-donor	as
	ligands…………………………………………….24
		4.4 Hyperbranched polymers……………………………………………………………….………...25
		4.5
	Biopolymers……………………………………………………………………………………………...27
								2

Table 1 . Binding energies (eV) of Pd in catalysts and Pd(OAc)2 and rate constants in the Suzuki-Miyaura reaction between bromobenzene and phenylboronic acid using K2CO3 as base and o-xylene as solvent. Reference 35. Catalyst Binding energy (eV) Rate constant Pd(OAc)2 336.25 - Cat 1 333.45 36.4 • 10 -3 Cat 2 335.95 1.98 • 10 -3 Cat 3 334.95 6.01 • 10 -3 Cat 4 335.15 6.01 • 10 -3 Cat 5 334.05 7.55 • 10 -3 Cat 6 334.05 9.43 • 10 -3 Cat 7 334.35 14.03 • 10 -3 Cat 8 336.35 1.67 • 10 -3 2.2 TiO2 TiO2

 1 -supported Pd catalysts have been applied to the Suzuki-Miyaura reaction.

Table 2 . Suzuki-Miyaura coupling a of bromobenzene and phenylboronic acid using the different materials presented in reference 61.

 2

	Entry	Sample	Yield (%)
			1 st	4 th
	1	[Pd]@SMP	>99	94
	2	[Pd]@MCM-41 88	78
	3	[Pd]@SG	85	73

a Reaction conditions: PhBr (1 mmol), PhB(OH)2 (1.5 mmol), Cs2CO3 (1.2 mmol), Pd (1 mol%), solvent (5 mL), 80°C; 15 h.

Table 3 . Reusability of the Pd(II)-TMCPP-GO catalyst in the Suzuki-Miyaura Reaction a prepared in reference 92.

 3

	Entry	Yield b (%)	Pd-leached c (%)
	1	92	0.65
	2	92	0.60
	3	91	-
	4	90	-
	5	87	-
	6	86	-
	7	85	1.12

Acknowledgements

Financial support from ANR research program is gratefully acknowledged (HYPERCAT, contract N° ANR-18-CE07-0021-03).

Scheme 10. Design of sporopollenin microcapsules supporting Pd(II). The synthesized catalyst allowed the conversion of aryl iodides, bromides and some chlorides with high TONs and TOFs (up to 40000 and 400000) in 6 minutes at 50°C under microwave irradiation.

Other supports

MOFs

Porous coordination metal-organic frameworks (MOFs) present interesting perspectives for applications in catalysis as they exhibit chemical and physical properties differing from the usual metal oxides supports, such as high surface area and porosity. [147][148][149][150][151][152][153][154][155] MOFs with open metal sites are promising candidates to be modified for a further metal-grafting leading possibilities in designing and functionalizing these novel crystalline hybrid materials. Thus, some studies have dealt with the effect of the MOF structure as a support for Pd(II) complexes, focusing on recovery. [156][157][158][159][160] The pore diameter of MOFs-supporting Pd(II) complexes appears as a pivotal parameter for substrate tolerance. For instance, Koner and co. anchored a Pd(II) Schiff base moiety into microporous IRMOF-3 and observed that the catalytic system

Conflicts of interest

The authors declare that there are no conflicts to declare.


Brochard

Dr Aurélien Venara
email: auvenara@chu-angers.fr

Management of obstetrical injuries to the anal sphincter: A survey of French current practice and perceptions according to the specialties

Keywords: Obstetric anal sphincter injury, Anal incontinence, Management, Caesarean section

Introduction

Grades III and !V obstetrical perineal tears are defined as obstetrical anal sphincter injuries (OASI); they occur in around 0.8% of deliveries in France [1], or 6000 women per year. These obstetrical lesions correspond respectively to a tear of the external sphincter, either isolated or associated with a rupture of the internal sphincter and the mucosa of the anal canal [START_REF]Obstetrical Perineal Injury and Anal Incontinence -Abdul H. Sultan[END_REF]. Early management of these lesions is critical since failure to repair a sphincteric lesion is correlated with an increased long-term risk of anal incontinence (AI) [3]. Thus, at 15-25 years after OASI, 61% of women present with AI versus only 22% of women without OASI [START_REF] Mous | Long-term effects of anal sphincter rupture during vaginal delivery: faecal incontinence and sexual complaints[END_REF].

The initial management of OASI is well codified and the National College of French Gynecologists and Obstetricians (CNGOF) has issued recommendations, particularly recommending layer-by-layer suture repair of the perineum [START_REF] Ducarme | Perineal prevention and protection in obstetrics: CNGOF clinical practice guidelines[END_REF]. The performance of sphincter repair can be delayed 8 to 12 hours, allowing time for an experienced operator to intervene, without affecting the functional prognosis at one year [6]. There is much less consensus regarding the medium-term management of symptomatic or non-symptomatic OASI even though this may affect the long-term functional prognosis [7]. This lack of consensus is most likely due to the fact that the different specialists who manage OASI often intervene at different times in this clinical setting.

The objective of this study was to conduct a survey of management practices for OASI and to compare the short, medium and long-term approaches, according to whether the care provider was a specialist in ano-rectal surgery or OB-GYN.

Material and methods

A questionnaire was sent to obstetrician-gynecologists via the French National College of Obstetrician Gynecologists (CNGOF), to colo-proctologists and colorectal surgeons via the French National Society of Colo-Proctology (SNFCP) and the Proctology Research Group (GREP), to gastro-intestinal and general surgeons via the French Association of Surgery (AFC) and to midwives via the Collège National des Sages-Femmes de France (CNSF) between January 15 and April 1, 2020. This letter provided a link to a Google Form® survey. Several reminders were sent over the period (1 to 3 reminders depending on the learned society). Only practitioners who managed OASI in the short, medium or long term were asked to respond to the questionnaire.

The questionnaire consisted of 50 questions, five of which specified the specialty, age, sex, mode and region of the practitioner's activity. The questionnaire (Annex 1) was broken down into three parts depending on when care took place (short term, medium term, long term). Practitioners were asked to respond only if they took charge of OASI within a given time. Responses to the questionnaire were anonymous.

Short-term management of OASI was defined by repair within 21 days of childbirth, long-term management was defined by management occurring after six months post-partum and medium-term management was defined as occurring during the interim (21 days to 6 months).

The third portion of the questionnaire (long-term) asked practitioners about their management of OASI discovered in the long term; most of the questions were left Open-ended.

The objective of the statistical analysis was to compare the practices and opinions of practitioners according to their specialization in the obstetrical sector (gynecologists-obstetricians, gynecological surgeons, midwives) and in the digestive sector (proctologists, gastroenterologists, digestive surgeons, colorectal surgeons, general surgeons). Results were expressed as median (interquartile interval range (IQI)) or percentage and were compared using nonparametric tests (Fischer test and U Mann Whitney test).

Results

General results

One hundred and thirty-five specialists from the relevant learned societies responded to the survey, 57 were specialists in ano-rectal surgery (42.2%) and 78 were specialists in childbirth (57.8%). Out of approximately 5,300 obstetrician gynecologists, 7,000 midwives, 1,130 visceral surgeons and 3,595 hepatogastroenterologists listed in France, only those practitioners who managed OASI were asked to respond to the questionnaire. The characteristics of the responders are reported in Table 1. Forty-three were anal incontinence specialists (33.1%) while 87 were not (66.9%).

Depending on the practice setting, cases of Grade III OASI was treated by an obstetrician-gynecologist in 101 cases (74.8%), a digestive surgeon in 12 cases (24.5%) or a proctologist in 1 case (0.7 %). Only one patient was transferred to a referral center (0.7%). Cases of Grade IV OASI were treated by an OB-GYN in 77 cases (57%), a digestive surgeon in 31 cases (23%) and a proctologist in six cases (4.4%), and one patient was transferred to a referral center (0.7%).

Early management

During the acute period, 16.7% of OB-GYN specialists did not manage OASI at all, while half of the ano-rectal specialists did not manage OASI acutely (50.9%) (Table 2).

There was no real difference in short-term management between specialists apart from a longer duration of antibiotic coverage by the OB-GYN specialists (15 days; IQI: 10-37.5) than by digestive specialists (7 days; IQI: 5-10) (p <0.0001).

In addition, digestive surgeons cautioned against anal sex for a median of 60 days (IIQ: 30-90) versus 42 days for OB-GYN specialists (IQI: 30-60) (p = 0.03).

In addition, female practitioners recommended avoiding anal sex for 40 days (IQI: 30-60) while male practitioners recommended 60 days (IQI: 30-67.5). The median recommended abstinence from vaginal intercourse for OB-GYN practitioners (42 days (IIQ: 30-60)) and for digestive practitioners (60 days (IQI: 30-90)) was not statistically significant nor was there a statistically significant difference between female practitioners (30 days (IQI: 22, 75-42)) and male practitioners (30 days (IQI: 30-36)).

Patients were seen in post-operative consultation after a median of 30 days in both specialties.

In addition, only 17.7% of OB-GYN specialists recommended systematic consultation with an ano-rectal specialist, while 52.9% of digestive surgeons recommended consultation with a specialist in the management of AI (p <0.001).

Medium-term care

Conversely, there were statistically significant differences in medium-term treatment between the two specialties (Table 3). The majority of ano-rectal specialists treated at least five AI patients/year (36.9%) while OB-GYN specialists managed fewer than five patients/year (73.1%) (p = 0.06).

In addition, ano-rectal specialists informed their patients of the risks of long-term anal incontinence more often than OB-GYN specialists (p = 0.005). Likewise, ano-rectal specialists were more interested in the need to strain to (p = 0.006).

The questionnaire also queried the practitioners about their recommendations for rehabilitation. This topic was not consensual and there was a statistically significant difference in recommendations between the two groups. The anorectal specialists recommended ano-rectal rehabilitation more often (93.5% vs. 87.8%), while they were less likely to recommend perineal muscle rehabilitation exercises (69.1% vs. 97.8%) (Table 3).

Ano-rectal specialists were more likely to recommend testing by anorectal manometry or a transanal ultrasound.

Likewise, the treatment of the various sphincter lesions diagnosed during workup of AI diagnosed in the medium term were different for the two specialties. Thus, in the case of isolated internal sphincter lesions without symptoms, 61.4% of digestive specialists did not propose specific management, while the OB-GYN specialists proposed rehabilitation strategies (23.1%) or a consultation with an ano-rectal specialist (21.8%) (p = 0.005). On the other hand, when the lesion involved the external sphincter alone or in combination with internal sphincter injury, digestive specialists were more likely to recommend rehabilitation (49.1%) while OB-GYN specialists recommended either rehabilitation (26.9%), abstention from treatment (32.1%) or consultation with an ano-rectal specialist (21.8%) (p = 0.01).

If OASI was symptomatic, digestive specialists essentially offered rehabilitation for isolated internal sphincter injury or sphincterorraphy for external or combined sphincter injury while OB-GYN specialists were more likely to refer the patient to a specialist in anal incontinence (p <0.001).

Delivery by cesarean section for future pregnancies in OASI patients was equally but infrequently recommended by the two specialties. However, about a quarter of practitioners consistently recommended it.

Long-term management

Finally, management of OASIs in the long term (> 12 months) was significantly different not only between the two specialties but also within the same specialty (data not shown). Almost all specialists had varying recommendations for diagnostic studies, as well as different recommendations for sphincter repair (thickness of the defect, width, angle of the defect, time from OASI).

Discussion

This survey of current practices and opinions received responses from 135 specialists (57.8% OB-GYN specialists and 42.2% digestive or ano-rectal specialists) from the members of the various learned societies contacted. The management of short-term OASI was mainly provided by OB-GYN specialists, while medium-and long-term management was mainly provided by ano-rectal specialists. There was fairly good consensus regarding short-term management.

There was considerable variation in the management strategies for medium-and long-term OASI patients between the two spheres or even within the same sphere.

First, the number of responses may, at first glance, appear very small when compared to the number of members of the different learned societies. However, it is important to note that only practitioners who actually cared for patients with Grades 3 and 4 OASI were asked to complete the questionnaire. It is more likely then that the response rate is correct but that few practitioners are "ultraspecialized" in the management of these patients who represent only 0.8% of deliveries in France [1], or 6000 cases per year.

With regard to short-term management, it is interesting to note that early management was mainly performed by OB-GYN specialists and followed the recommendations of learned societies. This is because OASI is usually diagnosed in the delivery room and it is only natural for obstetricians to deal with this sort of birth trauma. Moreover, this explains why most of the recommendations for acute management come from obstetrical and gynecological societies [START_REF] Ducarme | Perineal prevention and protection in obstetrics: CNGOF clinical practice guidelines[END_REF][8][START_REF]Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 198: Prevention and Management of Obstetric Lacerations at Vaginal Delivery[END_REF][10]. It is interesting, however, that ano-rectal specialists were more often involved in the acute management of Grade IV OASI.

This may be due to the fact that the long-term prognosis is worse, with a reported AI rate of 30-60% between six weeks and six months after repair [START_REF] Fenner | Fecal and urinary incontinence after vaginal delivery with anal sphincter disruption in an obstetrics unit in the United States[END_REF]12].

However, in our survey, there was no difference according to specialty in the rate of internal sphincter (IS) repair and only half of the practitioners performed an individual IS suture repair, even though the IS plays an essential role in passive continence and several studies suggest that it also plays a role in long-term anal incontinence [START_REF] Fornell | Obstetric anal sphincter injury ten years after: subjective and objective long term effects[END_REF][START_REF] Norderval | Anal incontinence after obstetric sphincter tears: outcome of anatomic primary repairs[END_REF]. Learned societies also recommend specific repair of the injured IS [START_REF] Ducarme | Perineal prevention and protection in obstetrics: CNGOF clinical practice guidelines[END_REF][8][START_REF]Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 198: Prevention and Management of Obstetric Lacerations at Vaginal Delivery[END_REF][10]. However, it may be difficult to individualize this layer, especially in the case of an early tear, which probably explains why only half of the practitioners systematically do so. This raises questions about current practices and should possibly lead to a discussion of specialization for practitioners who perform acute perineal repair.

In the medium term, ano-rectal surgeons were more likely to inform patients of the long-term risk of anal incontinence (95%) than OB-GYN specialists (75%). This is probably explained by the fact that the management of anal incontinence in France is provided by ano-rectal specialists and that AI often does not develop until several years after childbirth, and therefore, at a distance from OB-GYN monitoring. However, in view of the estimated 40-60% risk of AI and the 14.6-30.6% risk of fecal incontinence [START_REF] Jangö | Long-term anal incontinence after obstetric anal sphincter injury-does grade of tear matter?[END_REF] at 11.6 years after Grade III or IV OASI, it seems necessary to mention the possibility of this complication.

It is also probably for the same reasons that ano-rectal specialists requested more additional diagnostic studies than OB-GYN specialists.

The management of sphincter lesions also varied according to specialties and within specialties. This is due to the lack of consensus on early sphincter repair after OASI. Indeed, early systematic sphincter repair after OASI, even when asymptomatic, can be performed up to 21 days after childbirth, providing results similar to late repair [START_REF] Faltin | Diagnosis of anal sphincter tears to prevent fecal incontinence: a randomized controlled trial[END_REF][START_REF] Barbosa | Early secondary repair of obstetric anal sphincter injury: postoperative complications, long-term functional outcomes, and impact on quality of life[END_REF] although results often deteriorate during follow-up [START_REF] Johnson | Short-and long-term results of secondary anterior sphincteroplasty in 33 patients with obstetric injury[END_REF]. In various series of sphincterorraphy performed at a distance from the acute episode, the long-term results are also mixed with approximately 50% of patients eventually becoming incontinent again [START_REF] Mevik | Long-term results after anterior sphincteroplasty for anal incontinence[END_REF][START_REF] Lamblin | Long-term outcome after overlapping anterior anal sphincter repair for fecal incontinence[END_REF]. However, it has been shown that young patients benefit the most from surgery [START_REF] Lehto | Seven-year follow-up after anterior sphincter reconstruction for faecal incontinence[END_REF], arguing for early suture repair as an essential part of incontinence management/prevention. Conversely, suturing of isolated IS injury is not recommended [START_REF] Deen | Randomized trial of internal anal sphincter plication with pelvic floor repair for neuropathic fecal incontinence[END_REF].

In addition, it was observed that ano-rectal specialists were more likely to recommend ano-rectal rehabilitation while OB-GYN specialists were more likely to recommend perineal muscle rehabilitation, even though the CNGOF recommends this only in the event of persistent post-partum urinary or anal incontinence [START_REF] Deffieux | Postpartum pelvic floor muscle training and abdominal rehabilitation: Guidelines[END_REF]. Moreover, a randomized controlled study has shown that anoperineal rehabilitation improves symptoms of anal incontinence [START_REF] Johannessen | Do pelvic floor muscle exercises reduce postpartum anal incontinence? A randomised controlled trial[END_REF]. Both types of rehabilitation are compatible and can be complementary. Ano-perineal rehabilitation targets defecation mechanisms, synchronization between the sphincters and abdominal muscles, as well as ano-rectal coordination (measured with an intra-anal probe). Perineal rehabilitation is essentially based on strengthening and coordination of the perineal muscles (possibly assessed with an intravaginal probe).

Regarding the advisability of cesarean section, all practitioners agree that it should be offered on a case-by-case basis. Indeed, the literature is quite supportive of a case-by-case discussion. A recent study proposed that cesarean section be performed for all parturients who had suffered Grade 4 OASI because of an increased risk of AI [START_REF] Taithongchai | Management of subsequent pregnancies following fourth-degree obstetric anal sphincter injuries (OASIS)[END_REF], however other authors did not find a cesarean section advantageous in this context [START_REF] Jangö | Long-term anal incontinence after obstetric anal sphincter injury-does grade of tear matter?[END_REF][START_REF] Fitzpatrick | Does anal sphincter injury preclude subsequent vaginal delivery?[END_REF]. Vaginal birth is reported to be feasible for post-OASI patients without symptomatic AI or who have normal sphincters on ultrasound examination, but a caesarean section should be offered for all others [START_REF] Webb | The impact of mode of subsequent birth after obstetric anal sphincter injury on bowel function and related quality of life: a cohort study[END_REF]. Furthermore, recurrent birth trauma with OASI appears to be associated with an increased long-term risk of AI [START_REF] Jangö | Recurrent obstetric anal sphincter injury and the risk of long-term anal incontinence[END_REF].

Conclusion

The acute management of OASI differs little between specialties, but published recommendations are not fully followed. On the other hand, the management of OASI in the medium-term varies considerably due to a lack of consensus on which specialty should manage these patients and the lack of available recommendations. For patients presenting with post-OASI incontinence in the long term, care is generally provided by ano-rectal specialists but there is no consensus on the specific details of management. Building a consensus among the practitioners who provide such management, especially in the medium-and long-term, could help improve long-term continence outcomes. An inter-specialty discussion is therefore necessary.

Tables:

Table 1: Characteristics of responders

Table 2 :

 2 Short-term management of OASI according to specialty (digestive or ano-rectal surgeons and obstetrical/gynecological surgeons)

Table 3 :

 3 Mid-term management of OASI by either digestive/ano-rectal surgeons or obstetrical/gynecological surgeons .

Annex 1 Questionnaire on management of Grade III-IV Obstetrical Anal Sphincter Injury (OASI)

		Number, (%)
	Sex
	Male	64 (47.4%)
	Female	71 (52.6%)
	Age
	20-35 yrs	25 (18.5%)
	35-45 yrs	50 (37%)
	45-50 yrs	12 (8.9%)
	50-60yrs	29 (21.5%)
	> 60 yrs	19 (14.1%)
	Specialty
	Proctologist	18 (13.3%)
	Gastro-enterologist	2 (1.5%)
	General surgeon	17 (12.6%)
	Colo-rectal surgeon	20 (14.8%)
	Total of digestive specialists	57 (42.2%)
	Gynecologic surgeon	4 (3%)
	Obstetrician-gynecologist	55 (40.7%)
	Midwife	19 (14.1%)
	Total of obstetrical/gynecological
	specialties	78 (57.8%)
	Specialist in anal incontinence
	Yes	43 (33.1%)
	No	87 (66.9%)
	Work setting
	Public hospital	79 (58.5%)
	Private practice	37 (27.4%)
	Mixed activity	18 (13.3%)
	Region of France
	Center	7 (5.2%)
	East	20 (14.8%)
	North	10 (7.4%)
	Northeast	1 (0.7%)
	West	42 (31.1%)
	Paris	31 (23%)
	South	17 (12.6%)
	Southeast	1 (0.7%)
	Southwest	1 (0.7%)
	Unknown	5 (3.7%)

Table 1 :

 1 Characteristics of responding practitioners

	Gynecologic	Digestive	p
	sphere (n=78)	sphere
		(n=57)

Do you recommend the use of post-operative laxatives? Yes (%)

	52 (80%)	31 (93.9%) 0.07

Do you recommend consultation with an ano-rectal specialist? Yes (%)

	11 (17.7%)	18 (52.9%) <0.001

Table 2 :

 2 Management of obstetrical anal sphincter injuries (OASI) according to the practitioner's specialty.

	Gynecology	Digestive
	sphere (n=78)	sphere (n=57)

p Do you manage grade III-IV OASI in the medium-term (< 6 months post-injury)?

				0.06
	never	12 (15.6%)	13 (24.1%)
	occasionally (<5/ yr)	45 (58.4%)	20 (37%)
	often (5-20/yr)	18 (23.4%)	16 (29.6%)
	very often (>20/yr)	2 (2.6%)	5 (9.3%)
	Do you ask whether the patient has anal	69 (92%)	42 (95.5%)	0.71
	incontinence? Yes (%)
	Do you inform the patient of the risks of	54 (75%)	41 (95.3%)	0.005
	long-term incontinence? Yes (%)
	Do you ask whether the patient needs to	23 (39%)	30 (68.2%)	0.003
	strain to empty their bowels? Yes (%)
	Do you recommend ano-rectal			0.006
	rehabilitation?
	no (%)	21 (30.9%)	3 (6.5%)
	occasionally (%)	31 (45.6%)	25 (54.3%)
	always (%)	16 (23.5%)	18 (39.1%)
	Do you recommend perineal muscle			0.01
	rehabilitation?
	no (%)	2 (2.7%)	5 (12.2%)
	occasionally (%)	14 (18.9%)	14 (34.1%)
	always (%)	58 (74.4%)	22 (53.7%)
	Do you recommend performance of anal			<0.001
	manometry?
	no (%)	31 (44.9%)	6 (13.3%)
	occasionally (%)	34 (49.3%)	28 (62.2%)
	always (%)	4 (5.8%)	11 (24.4%)

Do you recommend performance of endo-anal ultrasound? 0.004

	no (%)	23 (33.8%)	4 (8.9%)
	occasionally (%)	34 (50%)	26 (57.8%)
	always (%)	11 (16.2%)	15 (33.3%)
	Do you recommend caesarean delivery		0.66
	for future pregnancies?
	never (%)	0	1 (1.8%)
	case-by-case (%)	47 (60.3%)	33 (57.9%)
	always (%)	18 (23.1%)	12 (21.1%)
	no response (%)	13 (16.7%)	11 (19.3%)
	If

there is asymptomatic injury of the internal sphincter, do you propose? 0.002

	rehabilitation	18 (27.3%)	13 (26.5%)
	consultation with an ano-rectal specialist	17 (25.8%)	1 (2%)
	consultation with a gynecologist	2 (3%)	0
	suture repair	1 (1.5%)	0
	follow-up exam at one year	0	0
	For a combined injury of the internal		0.007
	and external sphincters, do you
	propose?
	nothing	25 (37.9%)	28 (56%)
	rehabilitation	21 (31.8%)	16 (32%)
	consultation with an ano-rectal specialist	17 (25.8%)	1 (2%)
	consultation with a gynecologist	1 (1.5%)	0
	suture repair	2 (3%)	4 (8%)
	follow-up exam at one year	0	1 (2%)
	For a symptomatic injury of the internal		<0,001
	sphincter, do you propose?
	nothing	2 (3,1%)	5 (10%)
	rehabilitation	26 (40%)	38 (76%)
	consultation with an ano-rectal specialist	33 (50.8%)	4 (8%)
	consultation with a gynecologist	1 (1.3%)	0
	suture repair	4 (4.6%)	3 (6%)
	follow-up exam at one year	0	0
	For an external or combined		<0.001
	internal/external sphincter injury, do
	you propose?
	nothing	2 (3.1%)	0
	rehabilitation	19 (29.2%)	19 (38%)
	consultation with an ano-rectal specialist	0	0
	consultation with a gynecologist	28 (43.1%)	2 (4%)
	suture repair	16 (24.6%)	29 (58%)
	follow-up exam at one year	0	0
	nothing	28 (42.4%)	35 (71.4%)

Table 3 :

 3 Medium-term management of obstetrical anal sphincter injuries (OASI), according to specialty of the practitioner. Statistically significant results are in bold face.

Acknowledgments:

The authors would like to thank all the members of the Association Française de Chirurgie (AFC), the National College of French Gynecologists and Obstetricians (CNGOF), the National College of Midwives (CNSF), the Research Group In Proctology (GREP) and the French National Society of ColoProctology (SNFCP) who participated in this study.

Summary

Aim of the study: To conduct a survey of current practice in the management of obstetrical anal sphincter injuries (OASI) and to compare short, medium and long-term practices according to the specialty of the surgeon.

Patients and methods: A 50-item questionnaire was addressed by mail to various specialists via the national learned societies. The questionnaire was addressed only to practitioners who currently managed OASI in their practice.

Results: Of the 135 healthcare professionals who responded, 57 were subspecialists in ano-rectal surgery (42.2%) and 78 were obstetrical or gynecological specialists (OB-GYN) (57.8%). Management in the acute period after OASI was similar among the specialties and 50% of the practitioners did not perform suture repair of the internal sphincter. Furthermore, few gynecological specialists recommended systematic consultation with an ano-rectal specialist during acute management.

In the medium term, ano-rectal specialists were more likely to explore gastrointestinal symptoms, either clinically or through para-clinical studies. However, these studies did not systematically lead to interventional management in the absence of consensus, particularly for medium-term sphincter repair. In addition, 25% of practitioners recommended that patients undergo systematic delivery by caesarean section for further pregnancies after OASI.

Conflicts of interest:

The authors report no conflicts of interest with regard to this study.

Funding: none