Tommaso
Fantoni‡
a,
Chiara
Palladino‡
a,
Riccardo
Grigolato
a,
Beatrice
Muzzi
b,
Lucia
Ferrazzano
a,
Alessandra
Tolomelli
a and
Walter
Cabri
*a
aTolomelli-Cabri Lab, Center for Chemical Catalysis, Department of Chemistry “Giacomo Ciamician”, University of Bologna, via Gobetti, 85-40129 Bologna, Italy. E-mail: walter.cabri@unibo.it
bICCOM-CNR, Sesto Fiorentino FI, I-50019, Italy
First published on 22nd January 2025
Palladium-catalyzed cross-coupling reactions are among the most used methods for carbon–carbon bond formation in the agrochemical and pharmaceutical segments. The key step common to all methodologies based on Pd(0) catalysis is the in situ generation of the active catalyst. This paper describes how to control pre-catalyst reduction in order to generate the target complex species while avoiding phosphine oxidation or, as in the case of the Heck–Cassar–Sonogashira and the Suzuki–Miyaura reactions, reactant consumption via dimerization. For PPh3, DPPF, DPPP, Xantphos, SPhos, RuPhos, XPhos and sSPhos, we identified protocols that are able to maximize reduction via alcohols while preserving ligands and reagents. The correct combination of counterion, ligand, and base allowed the perfect control of the Pd(II) reduction to Pd(0) in the presence of primary alcohols.
Simple Pd(II) complexes are available, stable at room temperature, and cost-effective compared to preformed pre-catalysts or the direct use of Pd(0) complexes, making them a practical choice for both academic and industrial applications. However, a complete guide to perform efficiently in situ pre-catalyst reduction to generate the active Pd(0) is not available. To address this, several strategies have emerged.8 The use of Pd2(dba)3 allows the generation of the Pd(0)phosphine complex by a simple ligand exchange. Unfortunately, the palladium manipulation increases the costs and the presence of nanoparticles in the Pd2(dba)3 complex is a serious issue.9 On the other hand, well-defined Pd(II) pre-catalysts have been designed to undergo rapid reductive elimination,10 facilitating the formation of the target Pd(0) complex. Although these approaches minimize side reactions and ensure a smoother transition into the catalytic cycle, they have drawbacks limiting their industrial application. In fact, Pd(II) catalysts may have intellectual property protection11 and/or synthesis requires further manipulation of the ligand and the expensive metal, thus decreasing the overall efficiency and increasing costs.
The simple mixing of Pd(II) salts, ligands, auxiliaries, and substrates under standard reaction conditions does not guarantee the efficient formation of the active Pd(0)Ln species necessary to initiate and sustain catalytic cycles in cross-coupling reactions. Fig. 1 describes the first step of the Pd(II) reduction process where different reducing agents enter the palladium coordination sphere.
Phosphine ligands, which play a key role in many reactions, are sometimes expensive, and not recyclable.
Efficient in situ reduction of Pd(II) to Pd(0) is essential for optimizing reaction performance, reducing palladium usage, decreasing the costs and enhancing sustainability. This is not applicable to very basic phosphines, such as tri-tert-butylphosphine (tBu3P) and tricyclohexylphosphine (Cy3P),12 which are rapidly oxidized. Inefficient reduction can lower catalytic activity, requiring higher palladium loadings to achieve the desired results. The Pd(II)/Pd(0) conversion process has been extensively studied by various scientists, with significant contributions from Amatore/Jutand.13 In these studies, the palladium source was Pd(OAc)2, which is a trimer in the solid state.14 However, for clarity, in the present study, we will describe palladium acetate in its monomeric form since in solution we have never detected the trimeric one.15 Typically, the reduction of the metal occurs at the expense of the phosphine ligand or some reagents. While Amatore/Jutand and many other scientists have studied metal reduction at the expense of phosphine ligands, it has not been clearly described how to avoid scenarios where the phosphine ligand undergoes oxidation to form phosphine oxide altering the ligand-to-metal ratio. Indeed, this oxidative pathway can impact the structure and stability of the desired catalysts. For example, when BINAP or any chiral bidentate phosphine is used as a ligand, the transfer of chiral information is ensured only if the ligand remains unoxidized.16 In addition, the primary risk is the formation of mixed catalysts or nanoparticles,17 which exhibit significantly different reactivity compared to the intended catalysts. Employing a large excess of ligand can overcome the oxidation issue, but this approach can influence the reaction outcome. It can stabilize unreactive complexes or inhibit specific steps of the catalytic cycle that require ligand dissociation.18 Therefore, careful consideration and balance are necessary to optimize the ligand usage without compromising the desired catalytic activity.
Pre-catalyst reduction can also be performed at the expense of reagents with the concomitant formation of impurities. At the industrial level, especially in the pharmaceutical and agrochemical segments, this can be an issue in terms of efficiency because most of the time expensive fragments are consumed. In addition, for example, using a 0.1–1 mol% catalyst loading to produce 1000 tons of the product, as in the case of the fungicide Boscalid,19 generates 1–10 tons of waste in the boronate palladium reduction step as side products.
The combination of the factors discussed above based on a uncontrolled balance between palladium and the ligand can lead to a complete misinterpretation of the reaction data that are not based on the formation of the targeted Pd(0) catalyst. Typical examples are ligand screenings that are generally performed under standard reaction conditions.20 The pre-catalyst reduction efficiency is determined by several components: ligand, base, temperature, and solvent. Moreover, the sequence of addition of pre-catalysts, ligands and auxiliaries affects the efficiency of catalyst formation.
Our previous research on the HCS reaction using triphenylphosphine (PPh3) allowed carrying out straightforward mechanistic studies through DFT calculations, kinetic studies, NMR experiments, and the isolation of Pd(II) complexes.21 However, transitioning to bidentate phosphines or Buchwald's first-generation ligands introduces significant complexity as proved by the inconclusive 31P NMR spectra, due to the poor control over the formation of the Pd(0) catalyst which leads to unexpected Pd(0) complexes. The variations in ligand properties, such as steric and electronic effects, further complicate the formation and stability of the active Pd(0) species, affecting the catalytic cycle and reaction efficiency. To address these challenges, systematic studies and a combination of experimental and computational evaluations have been performed to understand and control the behavior of these ligands in the catalytic system.
This paper aims to shed light on the Pd(II) reduction process by studying the effects of ligands, salts, bases, and reagents in order to perfectly control the process, maximizing the rapid formation of the active Pd(0) catalyst, avoiding substrate consumption and preventing the formation of nanoparticles by maintaining the correct metal/ligand ratio. In particular, we have focused the study on the HCS, SM, MH and Stille reactions.
Entry | Reactant | T (°C) | Reaction | Pd(0)/Pd(II)b |
---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of DMF for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the reactant. | ||||
1 | — | 25 | — | 0/100 |
2 | Styrene | 25 | MH | 0/100 |
3 | Styrene | 60 | MH | 0/100 |
4 | PhSnBu3 | 25 | Stille | 0/100 |
5 | PhSnBu3 | 60 | Stille | 0/100 |
6 | PhB(OH)2 | 25 | SM | 0/100 |
7 | PhB(OH)2 | 60 | SM | 100/0 |
8 | PhC![]() |
25 | HCS | 0/100 |
9 | PhC![]() |
60 | HCS | 100/0 |
The appropriate PPh3/Pd(II) ratio was established to be 3/1, to avoid the formation of palladium nanoparticles and also to compensate for the reduced amount of available phosphine due to oxidation. The PdCl2(PPh3)2 precomplex was stable in DMF (Table 2, entry 1) and it was reduced to Pd(0) only after the addition of TMG with the concomitant formation of OPPh3 (entry 2). TMG and secondary amines can coordinate with palladium, displacing 1 equiv. of PPh3. This mechanism facilitates the oxidation of PPh3 (Fig. 4, mechanism D). In contrast, no reaction occurred in the presence of TEA even at 80 °C (entry 3). With inorganic bases, the pre-catalyst reduction was slower than the one promoted by TMG. Partial conversion was observed in 20 minutes only at 60 °C (entries 4–6), following mechanism E (Fig. 4). By adding HEP in a 1/2 ratio with DMF, the supplementary reduction pathway via mechanism A allowed for complete pre-catalyst reduction at 25 °C with TMG and Cs2CO3 (entries 7 and 8).
Entry | X | Sol. | Base | T (°C) | Mech. | Pd(0)/Pd(II)b | P/OHc |
---|---|---|---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the base. c P/OH is the ratio between the reduction via phosphine (P) and alcohol (OH) and “n.d.” means not determined. d DMF/HEP were used in a 2/1 ratio. | |||||||
1 | Cl | DMF | — | 60 | — | 0/100 | — |
2 | Cl | DMF | TMG | 25 | D | 100/0 | 100/0 |
3 | Cl | DMF | TEA | 80 | — | 0/100 | — |
4 | Cl | DMF | Cs2CO3 | 25 | — | 0/100 | — |
5 | Cl | DMF | Cs2CO3 | 60 | E | 34/66 | 100/0 |
6 | Cl | DMF | K2CO3 | 60 | E | 12/88 | 100/0 |
7 | Cl | DMF/HEPd | TMG | 25 | A/D | 100/0 | n.d. |
8 | Cl | DMF/HEPd | Cs2CO3 | 25 | A | 100/0 | 0/100 |
9 | Cl | DMF/HEPd | K2CO3 | 25 | A | 28/72 | 0/100 |
10 | Cl | DMF/HEPd | K2CO3 | 60 | A/D | 100/0 | n.d. |
11 | AcO | DMF | — | 25 | E | 42/58 | 100/0 |
12 | AcO | DMF | — | 60 | E | 100/0 | 100/0 |
13 | AcO | DMF | TMG | 25 | D/E | 100/0 | 100/0 |
14 | AcO | DMF | Cs2CO3 | 25 | D | 43/57 | 100/0 |
15 | AcO | DMF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | n.d. |
16 | AcO | DMF/HEPd | K2CO3 | 25 | A/E | 100/0 | n.d. |
Complete reduction was observed with K2CO3 only when the temperature was increased to 60 °C (entries 9 and 10).
As expected, the reduction of Pd(OAc)2 was much faster than the one of PdCl2. In DMF, indeed, even in the absence of a base, Pd(0) was partially formed at 25 °C and it was then completely obtained at 60 °C (entries 11 and 12). With TMG, the reduction was completed at 25 °C (entry 13). These data indicate that the base is playing a key role in accelerating the reduction process with Pd(OAc)2.
With the inorganic bases and Pd(OAc)2, 100% reduction was achieved at 25 °C only in the presence of HEP (entries 14–16). While for the above-described experiments, the preferred pathways could be envisaged, in a few cases (entries 7, 10, 15, and 16), it was not possible to determine the predominant reduction mechanism clearly. In general, the acetate can easily dissociate from the metal generating a cationic palladium species that is stabilized by excess inorganic salts, following mechanism E. These results suggested that with PPh3 it is difficult to avoid phosphine oxidation, and the only exceptions were the reaction with chloride as the counterion and Cs2CO3 or K2CO3 as the base at 25 °C (entries 8 and 9).
![]() | ||
Fig. 5 Complexes 1, 2, and 3 are potential Pd(0) species, generated during pre-catalyst reduction in the presence of DPPF or DPPP. |
Using 31P NMR with Pd(DPPF)X2 it was possible to discriminate between reduction mechanisms A and D/E, comparing Pd0(DPPF) 1a that is in equilibrium with Pd0(DPPF)24a,31 Pd0(DPPF)DPPF(O) 2a, DPPF and DPPF(0) (for details, see Fig. S73–S96†). Pd(DPPF)Cl2 is stable in DMF at 60 °C (Table 3, entry 1) and can be efficiently and rapidly reduced in the presence of a base (entries 2–4) such as TMG via mechanism D or the inorganic ones via mechanism E. The presence of HEP favors reduction (entries 5–8). However, only with K2CO3 at 25 °C was the reduction selectively achieved via mechanism A (entry 7). With Pd(OAc)2 the pre-catalyst reduction was efficient even in the absence of a base (entries 9 and 10) while in the presence of any base, the reduction was completed at 25 °C within 20 minutes (entries 11–13). Summing up, independent of the Pd(II) source in the presence of HEP, K2CO3 at 25 °C was able to selectively generate Pd0(DPPF) (entries 7 and 12).
Entry | X | Sol. | Base | T (°C) | Mech. | Pd(0)/Pd(II)b | P/OHc |
---|---|---|---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the base. c P/OH is the ratio between the reduction via phosphine (P) and alcohol (OH). d DMF/HEP were used in a 2/1 ratio. | |||||||
1 | Cl | DMF | — | 60 | — | 0/100 | — |
2 | Cl | DMF | TMG | 25 | D | 100/0 | 100/0 |
3 | Cl | DMF | Cs2CO3 | 60 | E | 100/0 | 100/0 |
4 | Cl | DMF | K2CO3 | 60 | E | 100/0 | 100/0 |
5 | Cl | DMF/HEPd | TMG | 25 | A/D | 100/0 | 91/9 |
6 | Cl | DMF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | 30/70 |
7 | Cl | DMF/HEPd | K2CO3 | 25 | A | 100/0 | 0/100 |
8 | Cl | DMF/HEPd | K2CO3 | 60 | A/E | 100/0 | 78/22 |
9 | AcO | DMF | — | 25 | E | 20/80 | 100/0 |
10 | AcO | DMF | — | 60 | E | 100/0 | 100/0 |
11 | AcO | DMF | TMG | 25 | D | 100/0 | 100/0 |
12 | AcO | DMF/HEPd | K2CO3 | 25 | A | 100/0 | 0/100 |
13 | AcO | DMF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | 45/55 |
The DPPP pre-catalyst generated with PdCl2(ACN)2 was perfectly stable at 60 °C in DMF (Table 4, entry 1). Interestingly, the addition of TMG did not promote metal reduction (entry 2). While TMG is able to compete with DPPF in coordinating PdCl2, promoting mechanism D (Table 3, entry 2), in the case of the more basic DPPP, TMG was not able to compete with the phosphine in coordinating Pd(II) and mechanism D was completely inhibited even at 60 °C (Table 4, entry 2). Only by moving to inorganic bases like Cs2CO3 and K2CO3 at 60 °C was the reduction completed via mechanism E (entries 3 and 4). The addition of HEP allowed switching to alcohol-based mechanism A at 25 °C (Fig. 2), generating selectively 2b (entries 5 and 6). On moving to acetate as the counterion, the trend was identical to that of DPPF, with the reduction taking place even in the absence of a base via mechanism E (entries 7 and 8), and it was accelerated at 25 °C by the addition of inorganic bases and HEP as a cosolvent (entries 9 and 10). Only by using PdCl2 in the presence of HEP and inorganic bases (K2CO3 or Cs2CO3) at 25 °C could ligand oxidation be avoided (entries 5 and 6).
Entry | X | Sol. | Base | T (°C) | Mech.b | Pd(0)/Pd(II)b | P/OHc |
---|---|---|---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the base. c P/OH is the ratio between the reduction via phosphine (P) and alcohol (OH) and “n.d.” means not determined. d DMF/HEP were used in a 2/1 ratio. | |||||||
1 | Cl | DMF | — | 60 | — | 0/100 | — |
2 | Cl | DMF | TMG | 60 | — | 0/100 | — |
3 | Cl | DMF | Cs2CO3 | 60 | E | 100/0 | 100/0 |
4 | Cl | DMF | K2CO3 | 60 | E | 100/0 | 100/0 |
5 | Cl | DMF/HEPd | Cs2CO3 | 25 | A | 100/0 | 0/100 |
6 | Cl | DMF/HEPd | K2CO3 | 25 | A | 55/45 | 0/100 |
7 | AcO | DMF | — | 25 | E | 11/89 | 100/0 |
8 | AcO | DMF | — | 60 | E | 100/0 | 100/0 |
9 | AcO | DMF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | n.d. |
10 | AcO | DMF/HEPd | K2CO3 | 25 | A/E | 100/0 | n.d. |
In Table 5 the experiments with Xantphos are reported. The pre-catalyst with chloride as the counterion was stable even in the presence of bases (entries 1–4). Upon addition of NaOAc, a rapid exchange with chloride promoted palladium reduction via mechanism E (see entries 5 and 9). Eastgate and Blackmond, in an interesting paper resulting from the collaboration between academia and industry, pointed out the role of Xantphos monophosphine oxide in a CH activation reaction as an “hemilabile” efficient ligand 3c.29
Entry | X | Sol. | Base | T (°C) | Mech.b | Pd(0)/Pd(II)b | P/OHc |
---|---|---|---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with internal standard 20 minutes after the addition of the base. c P/OH is the ratio between the reduction via phosphine (P) and alcohol (OH). d DMF/HEP were used in a 2/1 ratio. | |||||||
1 | Cl | DMF | — | 60 | — | 0/100 | — |
2 | Cl | DMF | TMG | 60 | — | 0/100 | — |
3 | Cl | DMF | Cs2CO3 | 60 | — | 0/100 | — |
4 | Cl | DMF | K2CO3 | 60 | — | 0/100 | — |
5 | Cl | DMF | NaOAc | 60 | E | 100/0 | 100/0 |
6 | Cl | DMF/HEPd | Cs2CO3 | 60 | A | 100/0 | 0/100 |
7 | Cl | DMF/HEPd | K2CO3 | 60 | A | 100/0 | 0/100 |
8 | AcO | THF | — | 25 | — | 0/100 | — |
9 | AcO | THF | — | 60 | E | 100/0 | 100/0 |
10 | AcO | THF | TMG | 25 | — | 0/100 | — |
11 | AcO | THF | K2CO3 | 25 | — | 0/100 | — |
12 | AcO | THF | Cs2CO3 | 25 | E | 40/60 | 100/0 |
13 | AcO | THF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | 47/53 |
14 | AcO | THF/HEPd | K2CO3 | 25 | A | 100/0 | 0/100 |
The catalyst (4 mol%) was generated using dimethyl acetamide and the conditions very similar to entry 5 in Table 5. The role of the acetate was not only critical for the cross-coupling step but also for palladium reduction via mechanism E and the selective formation of the monophosphine oxide. In the presence of HEP, the inorganic salts allowed the achievement of the reduction of the pre-catalyst via mechanism A (entries 6 and 7). Since the combination Pd(OAc)2/Xantphos is not soluble in DMF, THF was used. Under these conditions, complete catalyst reduction occurred at 60 °C (Table 5, entries 8 and 9), and the process was accelerated in the presence of Cs2CO3 (entry 12) at 25 °C but not with TMG and K2CO3 (entries 10 and 11). Again, the addition of HEP was able to favor Pd(II) reduction via mechanism A at 25 °C (entries 13 and 14). Interestingly, when the Xantphos ligand was combined with K2CO3 as a base, with both PdCl2 and Pd(OAc)2, it was possible to reduce the metal without phosphine oxidation at 60 °C and 25 °C, respectively, in the presence of HEP (entries 6 and 13). With Cs2CO3, only with chloride as the counterion was it possible to achieve complete reduction via mechanism A at 60 °C (entry 6).
The reduction via phosphorus oxidation using PdCl2 did not take place even in the presence of bases (Table 6, entries 1–4). However, adding HEP enabled reduction via primary alcohol oxidation of the pre-catalyst in the presence of bases, with inorganic ones proving to be more efficient (entries 5–8). Also with Pd(OAc)2, the reduction took place in DMF with or without the bases (entries 9–12). In the presence of HEP, Pd(0) was selectively generated via mechanism A with only K2CO3 at 25 °C (entry 14).
Entry | X | Sol. | Base | T (°C) | Mech.b | Pd(0)/Pd(II)b | P/OHc |
---|---|---|---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the base. c P/OH is the ratio between the reduction via phosphine (P) and alcohol (OH) and “n.d.” means not determined. d DMF/HEP were used in a 2/1 ratio. | |||||||
1 | Cl | DMF | — | — | — | 0/100 | — |
2 | Cl | DMF | TMG | 60 | — | 0/100 | — |
3 | Cl | DMF | Cs2CO3 | 60 | — | 0/100 | — |
4 | Cl | DMF | K2CO3 | 60 | — | 0/100 | — |
5 | Cl | DMF/HEPd | Cs2CO3 | 25 | A | 56/44 | 0/100 |
6 | Cl | DMF/HEPd | Cs2CO3 | 60 | A | 100/0 | 0/100 |
7 | Cl | DMF/HEPd | K2CO3 | 60 | A | 100/0 | 0/100 |
8 | Cl | DMF/HEPd | TMG | 60 | A | 15/85 | 0/100 |
9 | AcO | DMF | — | 60 | E | 29/71 | 100/0 |
10 | AcO | DMF | TMG | 60 | E | 15/85 | 100/0 |
11 | AcO | DMF | Cs2CO3 | 25 | E | 71/29 | 100/0 |
12 | AcO | DMF | K2CO3 | 25 | E | 54/46 | 100/0 |
13 | AcO | DMF/HEPd | Cs2CO3 | 25 | A/E | 100/0 | 42/58 |
14 | AcO | DMF/HEPd | K2CO3 | 25 | A | 100/0 | 0/100 |
15 | AcO | DMF/HEPd | TMG | 60 | A/E | 31/69 | n.d. |
![]() | ||
Fig. 6 Heck–Cassar–Sonogashira and Suzuki–Miyaura cross-coupling effects of the presence of the reactants in HEP. |
The PdCl2(ACN)2/ligand/alcohol/base protocol worked perfectly in several green solvent combinations33 with SPhos via mechanism A (Table 7, entries 1–5). The protocol was successfully applied to 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (RuPhos)34 and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos). With XPhos it was necessary to use toluene as a cosolvent because of the solubility of the ligand. As expected, the complex reduction was less efficient with organic bases like TMG and PYR. The presence of these bases that enter the coordination sphere of Pd(II) destabilized Pd(SPhos)2Cl2 and the formation of Pd(0)SPhos was less efficient (entries 8 and 9). The amount of Pd(0)SPhos did not increase over time and macroscopically, we observed the formation of palladium black after 1 h. The formation of palladium black suggests the rapid formation of soluble nanoparticles likely due to ligand loss. This negative outcome was observed with a conservative base excess at only 5 equivalents, whereas a typical reaction features a base/ligand ratio greater than 100.
Entrya | Ligand | Base | Solvent | Pd(0)/Pd(II)b |
---|---|---|---|---|
a Reactions were carried out with 0.013 mmol in 600 μL of solvent for 20 minutes. b Conversion of Pd(II) into Pd(0) was calculated by 31P NMR with an internal standard 20 minutes after the addition of the base. | ||||
1 | SPhos | K2CO3 | Anisole/EtOH 2/1 | 100/0 |
2 | SPhos | K2CO3 | CPME/EtOH 2/1 | 100/0 |
3 | SPhos | K2CO3 | MeTHF/EtOH 2/1 | 100/0 |
4 | SPhos | K2CO3 | Anisole/MeOH 2/1 | 100/0 |
5 | SPhos | K2CO3 | Anisole/HEP 2/1 | 100/0 |
6 | RuPhos | K2CO3 | Anisole/EtOH 2/1 | 100/0 |
7 | XPhos | K2CO3 | Toluene/EtOH 2/1 | 100/0 |
8 | SPhos | PYR | Anisole/EtOH 2/1 | 25/0 |
9 | SPhos | TMG | Anisole/EtOH 2/1 | 28/0 |
10 | sSPhos | K2CO3 | HEP/H2O 4/1 | 100/0 |
11 | sSPhos | K2CO3 | EtOH/H2O 4/1 | 100/0 |
12 | sSPhos | PYR | EtOH/H2O 4/1 | 52/0 |
13 | sSPhos | K2CO3 | IPA/H2O 4/1 | 0/100 |
The use of sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonatehydrate (sSPhos) allowed the introduction of water as a cosolvent in the green protocol (see entries 10 and 11).26b,35,36 Also in this case the use of PYR generated only 52% of the expected Pd(0)sSPhos complex within 20 min (entry 12). Secondary alcohols like isopropanol (IPA), used to replace HEP or EtOH, were not able to reduce the pre-catalyst (entry 13). The solvent mixtures described in Table 6 were not optimized but simply demonstrated the general applicability of using alcohols for Pd(II) pre-catalyst reduction, provided the pre-catalyst was soluble at those concentrations and inorganic bases were preferred.
![]() | ||
Fig. 7 DFT-calculated reaction profile and solution-state Gibbs free energies (ΔGDMF, kcal mol−1) at the B3LYP/DEF2-TZVP level of theory at 298 K for stationary points of mechanism A. |
DFT studies identified the deprotonation process as the rate-determining step of mechanism A. This observation was confirmed by a kinetic isotope effect (KIE) study using 31P NMR (Fig. 8). In fact, the reaction with CH3OH was consistently faster than the one in CD3OD, with a KIE of 1.6.
Footnotes |
† Electronic supplementary information (ESI) available: 31P NMR experiments, table with complete data and DFT calculations. See DOI: https://doi.org/10.1039/d4qo02335h |
‡ These authors contributed equally to this work. |
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