Letter Cite This: ACS Macro Lett. 2017, 6, 1251-1256
pubs.acs.org/macroletters
Impact of Precatalyst Activation on Suzuki-Miyaura Catalyst-Transfer Polymerizations: New Mechanistic Scenarios for Pre-transmetalation Events Roberto Grisorio* and Gian Paolo Suranna DICATECh − Dipartimento di Ingegneria Civile, Ambientale, del Territorio, Edile e di Chimica, Politecnico di Bari, via Orabona, 4, I-70125 Bari, Italy CNR-NANOTEC − Istituto di Nanotecnologia, Polo di Nanotecnologia c/o Campus Ecotekne, via Monteroni, 73100 Lecce, Italy S Supporting Information *
ABSTRACT: The relevance of LnPdX2 precatalyst activation on the Suzuki-Miyaura reaction course was investigated in the case of catalyst-transfer polymerizations. A catalytic study, backed up by theoretical calculations, allowed to ascertain the coexistence of a neutral and an anionic mechanistic pathways in the precatalyst activation, in which the bulky tBu3P external ligand plays a crucial role. The fine-tuning of the catalytic conditions can steer the activation step toward the anionic pathway, leading to the full control over the polymerization course. While providing insights and perspectives into the catalyst-transfer polymerizations, these results uncover unexplored scenarios for the pre-transmetalation events of SuzukiMiyaura reactions contributing to its full understanding.
T
he wide versatility of Suzuki-Miyaura cross-coupling1,2 to forge carbon−carbon bonds in modern synthetic chemistry has fostered scientific efforts toward deeply understanding the mechanistic pathway of the individual steps, that is, oxidative addition,3−5 transmetalation,6−9 and reductive elimination,10−12 involved in the catalytic cycle. At the same time, although directly impacting on the overall catalyst performance, the role of the precatalyst, on which the concentration of the catalytically active species strictly depends after the activation step, remains poorly investigated.13−15 A paradigmatic example of palladium-catalyzed reactions crucially subordinated to the precatalyst activation is the catalyst-transfer polymerization,16−19 during which the monomer scaffold and the catalytically active species sinergically cooperate for the concerted one-by-one addition of the monomeric units to the growing chain. By controlling the initiation stage of the polymerization, the precatalyst activation strongly influences the chain length distribution of the incipient polymer chain. To this purpose, a consolidated protocol contemplates the use of (tBu3P)ArPdX precatalysts (Ar: aryl group, X: Br or I) being suitably designed to readily generate the catalytically active species after transmetalation with the monomer and subsequent reductive elimination20−22 (Scheme 1 and Scheme S1). In principle, soluble and readily available LnPdX2 precatalysts (where L is an ancillary ligand and X is a leaving group) can efficiently promote the monomer homocoupling and πassociation of the catalytically active species to the incipient growing chain, thus initiating the polymerization through a catalyst-transfer mechanism23−25 (Scheme S2). In this case, however, the precatalyst activation pathway requires an © XXXX American Chemical Society
Scheme 1. (Top) Traditional Suzuki-Miyaura Chain-Growth Approach Using “Pre-Formed” LnArPdX External Initiators; (Bottom) Polymerization Reaction of a Fluorene-Based Monomer Employing Prototypical LnPdX2 Complexes as the Palladium Source (L = PhCN, CH3CN or Cl−) in the Presence of tBu3P as the External Ligand
additional step to release the catalytically active species, which could have a marked influence on the initiation stage (and, hence, on the polymerization course) being structurally different with respect to the individual propagation steps due to the absence of aryl groups on the palladium center.26 To shed light on these aspects, we carried out preliminary Pd/tBu3P polymerization tests (Table 1, entries 1−3) employReceived: September 14, 2017 Accepted: October 11, 2017
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DOI: 10.1021/acsmacrolett.7b00696 ACS Macro Lett. 2017, 6, 1251−1256
Letter
ACS Macro Letters Table 1. Pd/tBu3P-Catalyzed Suzuki Cross-Coupling Polymerizations Using LnPdX2 Precatalystsa entry 1 2 3 4 5 6 7 8 9 10 10 11 12 13
precatalyst PdCl2(PhCN)2 PdCl2(CH3CN)2 Na2PdCl4 Na2PdCl4 Na2PdCl4 Na2PdCl4 Na2PdCl4 Pd-PEPPSI-IPr Pd-PEPPSI-IPr Pd-PEPPSI-IPr Na2PdCl4 Na2PdCl4 Na2PdCl4 Na2PdCl4
ligand t
Bu3P Bu3P t Bu3P t Bu3P t Bu3P t
t
Bu3P Bu3P t Bu3P t Bu3P t
additiveb
base K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 Et4NOHg Na2CO3 K2CO3 Cs2CO3
n
Bu4NCl LiCl n Bu4NCl LiCl n
Bu4NCl LiCl
yieldc (%)
Mnd (Da)
PDIe
81 83 84 79 82 41 40 41 39 40 79 79 80 82
26900 26700 26600 24500 24700 5000 7400 13600 14500 13500 27800 28500 27700 30300
1.83 1.79 1.51 1.71 1.27 1.76f 1.32f 1.87 1.88 1.85 1.65 1.52 1.50 1.24
a
Polymerization conditions: monomer (1.0 equiv), precatalyst (5% mol/mol), ligand (10% mol/mol), base (2 M aqueous solution, 0.5 mL), THF (5.0 mL), rt, 30 min. b0.5 equiv. cIsolated yields. dNumber-average molecular weights as determined by GPC (PS standards, THF, rt). e Polydispersities index = Mw/Mn. fIncomplete monomer conversion. g0.1 M.
ing 7-bromo-9,9-di-n-octylfluoren-2-yl boronic acid pinacol ester as the monomer27 and LnPdX2 precatalysts, which led to broad dispersities (1.51−1.83), notwithstanding all prerequisites for warranting the chain-growth behavior had been fulfilled (Scheme S3, Figures S1 and S2).28−30 Artfully, the catalytically active species in Suzuki-Miyaura chain-growth polymerizations is invariably constituted by a (tBu3P)Pd0 complex π-associated with the growing polymer chain and the proposed polymerizations constitute the most suitable case to investigate the precatalyst activation process, taking the polydispersity index of the obtained polymers as an indicator of the precatalyst activation rate. Searching for a theoretical background to direct our investigations, we first gained insights into the precatalyst activation step by density-functional theory (DFT) investigations, prior to speculate on the plausible reasons for the polymerization behavior promoted by LnPdX2 palladium sources (Figure 1). Concerning the generation of the catalyst precursor, DFT calculations suggests that the tBu3P coordination to PdCl2 affords the coordinatively unsaturated species 1, while the ancillary chloride removal from the anionic complex 2 (resulting from the tBu3P coordination to PdCl42−) is thermodynamically unfavored (3.6 kcal/mol). At this stage, notwithstanding the boronate pathway has been evaluated as operative in the course of the Suzuki-Miyaura crosscoupling,31,32 the formation of the palladium hydroxo complexes anticipating the transmetalation step was modeled aiming at investigating the reaction pathway leading to the catalyst precursor activation.33 Due to the peculiar features of the sterically hindered tBu3P to confer an empty site to the corresponding complexes,34 the formation of the hydroxo complexes 3 (neutral) and 4 (anionic) was evaluated, revealing that the formal addition of the hydroxy group to the complex 1 is thermodynamically more favored (−69.4 kcal/mol) than the formal chloride substitution leading to the neutral complex 3 (−64.0 kcal/mol). Subsequently, taking into account that the reactivity of boronic esters and the relevant boronic acids is the same,35 the adduct formation with the monomer (exemplified by the phenyl boronic acid in DFT calculations) forming complexes 5 or 6 from the corresponding hydroxo complexes was found to be exergonic (4.4 kcal/mol) and endergonic (5.6
Figure 1. DFT energy profile (kcal/mol) for the steps anticipating the first transmetalation formally employing PdCl2 or PdCl42−in the presence of tBu3P as the external ligand and phenyl boronic acid (no cation). Free energies (kcal/mol) are calculated using PBE0/ LANL2DZ-6-311G+(d,p) with CPCM solvation modeling (THF). Insets: geometrically optimized structures for the monomer adducts 5 and 7 in the case of the neutral (black trace) and anionic (red trace) pathway, respectively. For clarity, the energy levels are not exactly scaled.
kcal/mol) in the case of the neutral and anionic pathway, respectively. The conversion of the anionic into the neutral pathway (4 → 3 or 6 → 5) by means of the chloride loss, even if energetically unfavorable (5.4 kcal/mol), is nonetheless possible and generates a free coordination site required for the transmetalation step.33 At the same time, the theoretical predictions suggest that, in the case of the anionic pathway, the decoordination of the bulky tBu3P ligand from complex 6 affording the coordinatively unsaturated anionic complex 7 is an energetically favored process (1.7 kcal/mol). We also explored the possibility to generate the dianionic complex 8 from complex 7 in the presence of chloride anions, which was found to be remarkably endergonic (9.4 kcal/mol). On these bases, the role of precatalyst ancillary ligands (PhCN, CH3CN or Cl−) on the 1252
DOI: 10.1021/acsmacrolett.7b00696 ACS Macro Lett. 2017, 6, 1251−1256
Letter
ACS Macro Letters polymerization behavior concerns with the population distribution of the hydroxo complexes and monomer adducts, that, in the case of polymerizations promoted by Na2PdCl4 (entry 3), is reasonably in favor of the anionic complexes 4 and 6 for the presence of chloride anions deriving from the precatalyst. Therefore, the anionic pathway should lead to a more favorable situation in the course of the first transmetalation step, determining the lower dispersities observed in the case of entry 3, but the coexistence of two activation pathways for LnPdX2 precatalysts, if characterized by different rates, is arguably responsible for the observed broad dispersities.36,37,38 Although with minor discrepancies in comparison with PBE0 calculations, the coexistence of an anionic pathway was substantially confirmed by applying the M06 functional characterized by a different dispersion approach (Figure S3). To experimentally substantiate the coexistence of an anionic pathway in the course of the pre- and transmetalation events, the formation of both the catalyst precursors and the hydroxo palladium complexes was investigated by 31P-NMR analyses (Figure S4). The addition of tBu3P (1.0 equiv with respect to the Pd source) to a solution of (PhCN)2PdCl2 or Na2PdCl4 led to the quantitative formation of tBu3PPdCl2 (δ = 85.4 ppm) and [tBu3PPdCl(μ-Cl)]2 (two isomers: δ = 83.4 and 83.3 ppm). The monomeric and dimeric species are reasonably in equilibrium, but the dynamic of this equilibrium is relatively slow compared to the time-scale of the NMR experiment. The addition of LiCl (10.0 equiv. with respect to the Pd source) generated a new signal (δ = 66.4 ppm), that can be ascribed to the anionic tBu3PPdCl3− complex and the simultaneous disappearance of the monomeric species. When a 2 M K3PO4 aqueous solution was added to the catalyst precursor solution produced by tBu3P and Na2PdCl4, new species formed that can be tentatively associated with tBu3PPdClOH (δ = 86.2 ppm) and tBu3PPdCl2OH− (δ = 66.9 ppm) hydroxo complexes (Figure S4e). When the same experiment was carried out in the presence of excess LiCl (Figure S4f), the free tBu3P signal also appeared, confirming the theoretical prediction regarding the generation of anionic complexes deprived of the tBu3P ligand (as 9 in Figure 1). To scrutinize the origin of the plausible different rate (concerning the precatalyst activation process) between the neutral and anionic pathway, we noted that the theoretical calculations indicated that, in the case of the neutral pathway, the geometrical constrains of complex 5 hamper the aryl transfer for the transmetalation event, which indeed requires an empty site on the palladium center. The two bridging hydroxyl groups are nonequivalent and their cleavage leads to the corresponding coordinatively unsaturated complexes, as described in Scheme 2. The subsequent rotation of the aryl group toward the empty coordination site on the palladium atom (required for the transmetalation event) exclusively leads to species 10, which is remarkably less stable (+6.3 kcal/mol) than 5. The steric congestion around the palladium center dictated by the bulky tBu3P ligand exerts a crucial role over the aryl approach in the presence of a free coordination site adjacent to the ligand. This implies that approximately half of the palladium centers prone to the transmetalation event are statistically inactive, directly impacting on the overall precatalyst activation rate. The removal of the tBu3P ligand before the transmetalation step symmetrizes the adduct intermediate 7 accelerating the pre-transmetalation events (complex 11, Scheme 2) and paving the way toward the full
Scheme 2. Modeled Reaction Steps (DFT) Anticipating the First Transmetalation in the Case of the Neutral (Top) and Anionic Pathway (Bottom)a
a
Geometrically optimized structures for the monomer adducts 10 and 11 using PBE0/LANL2DZ-6-311+G(d,p) with CPCM solvation modeling (THF). The approach of the aryl group to the free palladium site adjacent to the phosphine is hampered by steric hindrance in the course of neutral pathway.
control over the polymerization initiation and eventually on the polymer dispersity. On these bases, the reaction of entry 3 was repeated in the presence of suitable additives (nBu4NCl or LiCl). These experiments were conceived on the bases of the theoretical calculations to force the precatalyst activation toward the anionic pathway with the intentional addition of chloride ions, thus conferring a crucial role to the counterion of the alleged anionic palladium hydroxo complexes on the adduct formation with the monomer (Scheme 3). To rationalize the selective effect of additives on the initial stage of the reaction, i.e. in the precatalyst activation step, it should be kept in mind that the synthetic protocol contemplated the addition of the external ligand (tBu3P) to the THF solution containing the monomer, the precatalyst and the eventual additive (promoting the formation of the phosphine-based complex) while the base is deliberately introduced after 5 min to trigger the polymerization. Subsequently, the aqueous phase serves not only as a reservoir for the base, but also for the additives, forming halide and boron salts, depleting the amount of these species from the bulk reaction medium in the course of reaction. In these conditions, the countercation of the anionic hydroxo complexes exerted a dramatic effect on the resulting polymer dispersities, since the sterical burden associated with the bulky countercation (nBu4N+) for the anionic pathway hampers the uptake of the organo-boron compound for the subsequent transmetalation. This situation leads to an increase of the polymer dispersity (1.71, entry 4) reducing the weight of the anionic pathway on the precatalyst activation. Conversely, a remarkable improvement in terms of polymer dispersity (1.27, entry 5) was observed using LiCl as the chloride source, since the small Li+ ion has an irrelevant influence in terms of steric hindrance, not hampering the formation of the adduct with the monomer. The anionic pathway for the precatalyst activation confers a marginal role to tBu3P ligand as far as the transmetalation event is concerned. To prove this scenario, we carried out the reaction of entries 4 and 5 in the absence of tBu3P as the external ligand (entries 6 and 7). While the resulting polymer dispersities are in line with those of entries 4 and 5, their 1253
DOI: 10.1021/acsmacrolett.7b00696 ACS Macro Lett. 2017, 6, 1251−1256
Letter
ACS Macro Letters Scheme 3. (Top) Reaction Steps for the Precatalyst Activation Required to Generate the Catalytically Active Species in the Case of the Neutral and Anionic Pathway with the Bu4N+ Countercation; (Bottom) Reaction Steps for the Second Transmetalation of the Precatalyst Activation Required to Generate the Catalytically Active Species in the Case of the Neutral and Anionic Pathwaya
Figure 2. DFT energy profile (referred to that of Figure 1) for the first transmetalation event in the case of the neutral (black line) and anionic (red line) pathways using PBE0/LANL2DZ-6-311+G(d,p) with CPCM solvation modeling (THF).
a
is quantitative and considerably faster in the case of Na2PdCl4, i.e. the reaction not employing the bulky ligand.41 Moreover, even if not contributing to the precatalyst activation process in the course of the anionic pathway, the subsequent coordination of tBu3P to the formed zerovalent palladium center promotes the fast oxidative addition of the transition metal to one of the bromine atoms of the bifluorene scaffold, preventing the dissociation of the catalyst from the incipient polymer chain during the propagation stage (Scheme 3). The two pathways lead to the same catalytically active species because the “hard” chloride ligands are not suitable for the stabilization of the “soft” Pd0 species and readily dissolve in the aqueous phase.38 The rate of the precatalyst activation also depends on several other processes, which are not directly imputable to the catalyst. Actually, the hydroxide ions are scarcely soluble in the organic solvent, conferring an important role to the respective countercation for increasing the concentration of base in the organic solvent. The effect of the base countercation was scrutinized by repeating the reaction of entry 3 using Et4NOH, Na2CO3, K2CO3 and Cs2CO3 (entries 10−13). Since the macroscopic properties of the employed bases (such as their solubility, intrinsic basicity or countercation coordination ability) influenced both the initiation and the propagation step in the same manner, the observed differences in polymer dispersities (1.24−1.65) has to be ascribed to the precatalyst activation pathway. Differently from organic cation (Et4N+), inorganic cations show affinity with oxygen and chlorine atoms.42 After the hydroxide attack to the complex 1, the fate of the formed anionic hydroxo complexes is strongly related to the interactions of the countercation with the chloride ligands of the complex. As previously discussed, the steric hindrance of the ammonium countercation lowers the rate of the adduct formation in the case of the anionic pathway. No improvements in terms of MWs and PDIs of the resulting polymers were observed using the use of alkali metal cations (entries 11 and 12), while an impressive outcome was obtained using Cs2CO3 as the base (entry 13). The rationale behind these results is that soft Cs+ ions show a lower affinity toward Cl− ions favoring the formal addition of the hydroxy groups (reacting as CsOH) on the neutral catalyst precursor 1 (Scheme 4) and, as a
The aryl fragment represents the fluorene unit.
polymerization courses are severely compromised by the reduced catalyst activity. These results strongly corroborate the assumption that the adduct formation between the palladium hydroxo complexes and the monomer strongly influences the rate of the anionic pathway in the course of the initiation stage, which, in turn, also proceeded smoothly in the absence of the tBu3P ligand. In fact, the transmetalation activation energy both in the neutral and the anionic pathway is low (
