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Palladium monophosphine Pd(PPh3): is it really accessible in solution?† Pietro Vidossich,* Gregori Ujaque* and Agustı´ Lledo ´ s*

Received 27th September 2013, Accepted 6th November 2013 DOI: 10.1039/c3cc47404f www.rsc.org/chemcomm

Catalyst speciation is a ubiquitous theme in homogeneous catalysis. Employing realistic models based on an explicit solvent representation and ab initio molecular dynamics simulations we addressed the issue of solvent coordination in the Pd–PPh3 system. We show the accessibility of species such as (Sol)Pd(PPh3), (Sol)Pd(PPh3)2, (Sol)2Pd(PPh3) (where Sol is a solvent molecule). Importantly, we demonstrate that the bare monophosphine Pd(PPh3) species, often depicted in catalytic cycles, is actually not accessible in solution.

The identification of the catalytically competent form of a catalyst is a key step towards understanding its activity. A prerequisite is certainly to know which species are present in solution. When spectroscopic techniques cannot resolve the mixture, molecular modelling may contribute significantly. However, we noticed that molecular modelling is seldom used towards this scope, especially when speciation involves solvent-coordinated species. In this communication we report on the results from an appropriate computational setup to investigate such problems. We focussed on the Pd–phosphine system which plays a central role in today’s organic synthesis, as recognized by the 2010 Nobel Prize for Chemistry.1 In a Pd-catalyzed process (see e.g. Scheme S1, ESI†)2,3 a zerovalent Pd complex is generated in the reaction vessel where it transforms into an active catalyst (precatalyst activation) by ligand loss or ligand exchange, with the incoming ligand being any of the species present in solution capable of coordinating to Pd, including solvent molecules. Pd complexes of bulky and electron-rich phosphine ligands (denoted P hereafter)4 have been widely investigated.5 The preparation of the catalyst6 and the nature of the P ligands have been reported to have an important impact on the reactivity of the system. It was shown that the coordinatively unsaturated bis-phosphine complexes Pd(P)2 were the most reactive7–9 and these complexes could actually be isolated.10,11 Preparation procedures have now been optimized for Departament de Quı´mica, Universitat Auto`noma de Barcelona, 08193 Cerdanyola del Valle´s, Spain. E-mail: [email protected], [email protected], [email protected]; Fax: +34-935811927; Tel: +34-935811716 † Electronic supplementary information (ESI) available: Schemes S1 and S2; computational details; MM potential for toluene; Fig. S1–S7; and binding energies. See DOI: 10.1039/c3cc47404f

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the synthesis of Pd(P)2.6 However, on the basis of reactivity studies of the oxidative addition step, some authors put forward that the catalytically competent species is actually the monophosphine species.12 Although this species could not be detected, the isolation of Pd(P)(R)X13–15 and Pd(P)(diene)16 complexes further supported this hypothesis. The Pd–PPh3 system has been the subject of considerable studies to assess [Pd] speciation.17–19 Computational studies have addressed the relationship between speciation and reactivity.20–30 To the best of our knowledge, equilibria involving solvent coordination (Scheme 1) have not been addressed, likely because of the difficulties encountered in modelling ligand exchange reactions due to the large uncertainty associated with the entropic contribution from small cluster calculations.31,32 In this respect, the dissociation of phosphine ligands has been reported to be particularly problematic by several authors.33–35 Recently, the energetic cost to generate the highly unsaturated 12-electron Pd(PPh3) species (Pd(P)2 - Pd(P) + P) has been reported.35 Formation of such highly unsaturated species has been criticized in the past.36 Here, focusing on the widely used triphenylphosphine PPh3 ligand, we report on an ab initio molecular dynamics (AIMD) simulations study of the ligand exchange processes at Pd0 in a periodically repeating box containing nearly 1000 toluene molecules. A total cumulative simulation time of >500 ps based on hybrid quantum mechanical/molecular mechanical (QM(DFT)/MM, using the PBE37 exchange–correlation functional supplemented by the dispersion correction by Grimme et al.38) interaction potentials was used to determine the accessibility of the species Pd(P), (Sol)Pd(P), (Sol)Pd(P)2 and Pd(P)2. Toluene is a general solvent for cross-coupling reactions. Furthermore, toluene has weak coordinative properties, indicating that for stronger coordinating solvents the occurrence of solvent coordinated species will be even more likely.

Scheme 1

Catalyst speciation involving solvent (S) coordination.

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Pd(PPh3) in toluene solution. Hybrid DFT/MM molecular dynamics simulation of the Pd monophosphine complex was started from the last snapshot of a classical MD simulation in which the Pd complex was maintained at the gas-phase optimized structure. Four toluene molecules close to the Pd atom were treated at the DFT level. After about 100 fs simulation, a toluene molecule (Tol, hereafter) was observed to approach the Pd atom and form a p complex (Fig. 1). Further simulation for 20 ps reveals that the (Tol)Pd(PPh3) complex is a stable species. Actually, at about 11 ps simulation, a second toluene molecule was observed to coordinate to the Pd forming a (Tol)2Pd(PPh3) species which survives for few ps (Fig. 1a). PPh3 remains bound to the Pd throughout the simulation (Fig. S1, see ESI†). Toluene molecules coordinate to Pd showing Z2 conformations (Fig. 1b), with the carbon atoms of the aromatic ring interchanging on the ps time scale (Fig. S2, ESI†). In order to ascertain that the observed solvent coordination was not an artefact of the initial conditions, control calculations were performed as described in the ESI† (Fig. S3). From these simulations we conclude that the bare monophosphine species has a lifetime too short to be accessible in toluene solution, as at least one solvent molecule coordinates to the Pd. The species with one toluene coordinated appears to be the most favourable, but a second molecule may interact with the metal, at least transitorily. The equilibrium (Tol)Pd(PPh3) + Tol 2 (Tol)2Pd(PPh3), which may lead to Tol exchange, appears to take place on the ps time scale. Pd(PPh3)2 in toluene solution. The observed formation of a tricoordinated (Tol)2Pd(PPh3) suggests that the tri-coordinated (Tol)Pd(PPh3)2 may also be formed. Simulation starting from

Fig. 1 AIMD simulation of Pd(PPh3). The toluene molecules closest to the Pd were described at the DFT level. (a) Number of toluene molecules (NTol) coordinated to Pd. (b) The bis-coordinated (Tol)Pd(PPh3) complex surrounded by the toluene solvent taken from a snapshot during the simulation. An isosurface of the electron density is superimposed onto the complex to appreciate the overlap of the p cloud of one toluene and the Pd atom. The shortest Pd–C distances in the snapshot shown are 2.18 and 2.28 Å.

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Fig. 2 AIMD simulation of Pd(PPh3)2. The simulation features one toluene molecule described at the DFT level and was started from a tri-coordinated (Tol)Pd(PPh3)2 configuration. (a) Toluene moves on and off the Pd within the time span of few ps. (b) The tri-coordinated (Tol)Pd(PPh3)2 complex surrounded by the toluene solvent taken from a snapshot during the simulation. An isosurface of the electron density is superimposed onto the complex to appreciate the overlap of the toluene p cloud and the Pd atom. The shortest Pd–C distances in the snapshot shown are 2.30 and 2.47 Å.

the latter state showed the toluene to move on and off the Pd twice during the 20 ps of investigation (Fig. 2), until it moves further away from the Pd (in our setup, only this one toluene molecule was described at the QM level, and thus the only one which could coordinate to the Pd center). An umbrella sampling simulation was set up to reconstruct the potential of mean force (pmf) for toluene coordination to the bisphosphine complex (see Fig. 3a). In line with what was observed in the free MD simulation, toluene coordination to Pd requires overcoming a small free energy barrier (2.4  0.5 kcal mol 1). The tri-coordinated species lies 1.8  0.6 kcal mol 1 higher in energy than the biscoordinated complex. Thus, a toluene molecule may easily coordinate to the bis-phosphine complex.

Fig. 3 Potential of mean force (F) of (a) toluene coordination to Pd(Ph3)2 and (b) PPh3 dissociation from (Tol)Pd(Ph3)2. Note the change of the free energy scale between graphs a and b.

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Energetics of PPh3 dissociation. The facile coordination of toluene to Pd(PPh3)2 indicates that the phosphine/solvent exchange to generate the (Tol)Pd(PPh3) species will proceed through the (Tol)Pd(PPh3)2 associative intermediate (see also Fig. S4, ESI†). We set up an umbrella sampling simulation to investigate the energetics of the process using the Pd–P coordination number as the control parameter (see ESI†). The pmf (Fig. 3b) features a deep minimum corresponding to the coordinated phosphine (actually, the tricoordinated (Tol)Pd(PPh3)2). Dissociation of a phosphine from this complex has a free energy cost of 17.3  0.6 kcal mol 1 monotonically increasing along the Pd–P coordinate. The results clearly indicate that the 12-electron Pd(PPh3) fragment is not accessible in toluene solution because it forms a p complex with (at least) one solvent molecule. This species resembles Pd complexes with alkenes and arenes as reported in the literature. Although the possibility of solvent coordination to Pd(PPh3) has been put forward by other authors in their discussion on [Pd] speciation in solution, no clear answer is given in the literature. Moreover, as far as computational work is concerned, this situation has been scarcely considered.20,24,39 Results have been obtained for toluene (a solvent generally considered as non-coordinating) but we believe that it is a general result. The (Tol)Pd(PPh3) species lies B20 kcal mol 1 higher in energy than Pd(PPh3)2, with no barrier separating the two species, in line with the outcome of NMR studies which could not detect the monophosphine species,6,18,19,40 not even at low temperatures. The coordinating properties of the solvent are expected to impact the equilibrium, with stronger coordination favouring the formation of (Sol)Pd(PPh3). The mechanism by which (Tol)Pd(PPh3) forms goes via an associative (Tol)Pd(PPh3)2 intermediate; nevertheless, this mechanism may not be operative for more hindered phosphine ligands (like e.g. PtBu3). When additives are used in the catalyst preparation (e.g. bases and halides) further species may be formed.39,41 In the context of cross-coupling reactions, the present results clearly indicate that for the modelling of the reactivity of the Pd–PPh3 system the bare Pd(PPh3) species should not be considered (pathway A in Scheme S2, ESI†).20,23 (Tol)Pd(PPh3) should stand for Pd(PPh3) in all catalytic cycles where the latter appears (such as in pathway B). The occurrence of monophosphine species has been discussed in regard to the oxidative addition of aryl halide (PhX) substrates (Scheme S1, ESI†). Previous work has shown that (PhX)Pd(PPh3) is more reactive than (PhX)Pd(PPh3)2 towards the breakage of the Ph–X bond.20,23,25 The present calculations, showing the high energy of the (Tol)Pd(PPh3) species, suggest that the main pathway leading to formation of (PhX)Pd(PPh3) will proceed via the substitution of a PPh3 ligand of Pd(PPh3)2 by the incoming PhX substrate (pathway C in Scheme S2, ESI†). In summary, we investigated Pd–PPh3 speciation in toluene solution by means of explicit solvent simulations, providing computational evidence for the formation of [Pd] solvent adducts, including (Tol)Pd(PPh3)2, (Tol)Pd(PPh3) and (Tol)2Pd(PPh3). Importantly, the bare Pd(PPh3) shows a limited lifetime as it promptly coordinates to a toluene molecule. This conclusion has been commented in the literature but is demonstrated here for the first time. On the basis of these findings, we argued that studies aimed at elucidating the reactivity of the Pd–PR3 system should take solvent coordination into account.

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We acknowledge the Spanish Ministerio de Economı´a y Competitividad (DGICYT, CTQ2011-23336 and ORFEO Consolider-Ingenio 2010 CSD2007-00006) for financial support and the RES for ˜o providing computing resources. We thank Manuel A. Ortun for useful discussions and Giovanna Procopio for help in the preparation of the TOC graphics.

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Chem. Commun., 2014, 50, 661--663 | 663

Palladium monophosphine Pd(PPh3): is it really accessible in solution?

Catalyst speciation is a ubiquitous theme in homogeneous catalysis. Employing realistic models based on an explicit solvent representation and ab init...
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