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Nuances in Fundamental Suzuki–Miyaura Cross-Couplings Employing [Pd(PPh3)4]: Poor Reactivity of Aryl Iodides at Lower Temperatures
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Organometallics

Cite this: Organometallics 2018, 37, 11, 1745–1750
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https://doi.org/10.1021/acs.organomet.8b00189
Published May 23, 2018

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Abstract

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We have explored fundamental Pd-catalyzed Csp2–Csp2 Suzuki–Miyaura cross-couplings of aryl iodides (Ar–I) employing “classical” Pd/PPh3 catalyst systems. Surprisingly, we observed particularly inefficient couplings of these ostensibly reactive electrophiles in a range of conventional solvent mixtures at lower temperatures (∼50 °C), which was in stark contrast to analogous reactions featuring the equivalent aryl bromides. This feature of well-established Pd/PPh3-mediated Suzuki–Miyaura reactions has received scant attention in the literature. Most significantly, our studies suggest that the inefficient coupling of aryl iodides at lower temperatures derives from the unexpectedly poor turnover of the key on-cycle intermediate trans-[Pd(PPh3)2(Ar)(I)] (or related PdII–I species) in the presence of PPh3.

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Introduction

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The Suzuki–Miyaura reaction is arguably one of the most important transition-metal-catalyzed C–C coupling processes in organic synthesis. (1,2) Underscoring this, the 2010 Nobel Prize was awarded to Heck, Negishi, and Suzuki “for palladium-catalyzed cross-couplings in organic synthesis”. (3) The identification and development of various alkylphosphine ligands have contributed to enhancing the scope, efficiency, and utility of a range of Pd-catalyzed Csp2–Csp2 couplings, including the Suzuki–Miyaura reaction. (4) Nevertheless, more traditional catalyst systems featuring arylphosphine ligands, including the venerable precatalyst [Pd(PPh3)4], still feature heavily in these pivotal transformations. (1b) The oxidative addition of aryl halides to phosphine-ligated Pd(0) complexes has been studied extensively, (5) and it is generally accepted that the relative rates for the oxidative addition of aryl halides (Ar–X) to these Pd(0) species typically follow the trend Ar–I > Ar–Br > Ar–Cl. (5b,6)
While we were in the process of developing a new undergraduate laboratory experiment focused on exploring key features of the Suzuki–Miyaura reactions utilizing a Pd/PPh3 catalyst system, (7) we were intrigued by results that counterintuitively suggested the very poor reactivity of aryl iodides at ∼50 °C. This was in stark contrast to efficient couplings of the equivalent aryl bromides at the same temperatures. After searching the literature, we could only identify one published report of similar behavior in Suzuki–Miyaura reactions, which was disclosed by Novak and Wallow over 20 years ago (Scheme 1). (8,9) These two data points, which were not directly discussed in their work, also tentatively suggested the inefficient coupling of 1-iodo-4-nitrobenzene under these conditions. To our knowledge, the specific reasons for this surprising behavior has not been investigated further: hence, the study reported herein.

Scheme 1

Scheme 1. Results of Pd-Catalyzed Suzuki–Miyaura Couplings Reported by Novak and Wallow in 1994 (8)
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Results and Discussion

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In order to explore these observations in more detail, we employed standard Suzuki–Miyaura reaction conditions that would allow us to conduct experiments across a broad temperature range. (10) Thus, reactions of phenylboronic acid with p-iodo- and p-bromotoluene, respectively, in the presence of [Pd(PPh3)4] at 100 and 80 °C, provided efficient couplings (Table 1, entries 1 and 2). When the analogous Suzuki–Miyaura couplings were conducted at 70 and 60 °C, the efficiency of reactions featuring p-iodotoluene (1) decreased significantly; especially in comparison to equivalent reactions using bromide 2 (entries 3 and 4). Most notably, in reactions with iodide 1 at 50 °C, limited cross-coupling occurred and the results clearly suggested that reaction with bromide 2 was much more efficient in comparison (Table 1, entry 5, and Figure 1). (11,12) Analogous results were observed in THF/H2O or acetone/H2O solvent mixtures, while employing DMF/H2O provided a notable difference in the relative efficiencies of electrophiles 1 and 2 (entries 6–8). The substitution of Na2CO3 for either K2CO3 or NaOH did not provide significant differences (entries 9 and 10). (13) In general, the substitution of 1% [Pd(PPh3)4] for 1% Pd(OAc)2/PPh3 (2 or 4%) provided similar results (entries 11–16). (14−16) Notably, employing either 1% Pd(OAc)2/1% PPh3 or “ligandless” conditions (no PPh3) provided efficient iodide couplings at 50 °C (entries 17 and 18). This demonstrates the adverse effect that the presence of PPh3 has on the efficiency of the coupling of aryl iodides relative to bromides at ∼50 °C, which is consistent with Novak and Wallow’s observations (Scheme 1) and other pioneering studies highlighting the acceleration of Suzuki–Miyaura couplings under “ligandless” conditions. (8,17)
Table 1. Respective Suzuki–Miyaura Couplings of Iodide 1 and Bromide 2 with PhB(OH)2: Influence of Reaction Parameters
a

Determined via gas chromatography (GC) with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

b

THF used instead of n-PrOH.

c

Acetone used instead of n-PrOH.

d

DMF used instead of n-PrOH.

e

K2CO3 used instead of Na2CO3.

f

NaOH used instead of Na2CO3.

Figure 1

Figure 1. Formation of biaryl 3 in respective Suzuki–Miyaura couplings employing iodide 1 (red) and bromide 2 (blue) at 50 °C (conditions: Table 1, entry 5). Each data point represents the average of two experiments with yields determined via GC with the aid of a calibrated internal standard.

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Next, we investigated the role of electronic and steric effects on reactions using various pairs of electrophiles and nucleophiles. In this way, we demonstrated more generally that iodides were less efficient coupling partners relative to the equivalent bromides, and this uniform trend was observed across a range of sterically and electronically varied aryl halides and boronic acids (Table 2). In reactions at 50 °C, featuring sodium phenyltrihydroxyborate as the nucleophile, couplings were also more efficient employing bromide 2 in comparison to iodide 1 (Table 3, entry 1). We then explored whether substituting phenylboronic acid with either phenylboronic acid pinacol ester or potassium phenyltrifluoroborate would also provide similar results. In general, analogous trends were observed using phenylboronic acid pinacol ester (Table 3, entries 2–4). Less discernible trends were evident in coupling reactions using potassium phenyltrifluoroborate (Table 3, entries 5–7). (18,19)
Table 2. Investigating Electronic and Steric Effects in Suzuki–Miyaura Couplings
   yield (%)a
entryAr′Ar″using Ar–Iusing Ar–Br
1o-tolPh8 (6)59 (40)
2m-tolPh5 (3)52 (35)
3p-OMeC6H4Ph10 (8)55 (38)
4p-NO2C6H4Ph17 (11)74 (53)
5Php-tol12 (10)59 (49)
6Php-OMeC6H415 (14)52 (41)
7bPhp-NO2C6H416 (13)50 (39)
a

Determined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

b

Reaction performed at 70 °C.

Table 3. Respective Suzuki–Miyaura Couplings of Iodide 1 and Bromide 2: Influence of Nucleophiles
   yield (%)a
entrynucleophiletemp (°C)using 1using 2
1bPh-B(OH)3Na5015 (13)57 (57)
2Ph-Bpin10089 (89)95 (81)
3Ph-Bpin8087 (62)85 (79)
4Ph–Bpin507 (7)61 (43)
5Ph-BF3K10077 (72)67 (43)
6Ph-BF3K8047 (34)50 (25)
7Ph-BF3K50<2 (<2)12 (2)
a

Determined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are provided in parentheses.

b

Na2CO3 not added.

We then investigated the effects of other ligands in Pd-catalyzed Suzuki–Miyaura couplings. Employing monodentate ligands that are bulkier than PPh3 provided both efficient (P(o-tol)3) and inefficient (TTMPP) couplings of iodides (Table 4, entries 1–3). Ligands with cone angles similar to that of PPh3 (AsPh3 and P(p-tol)3) facilitated cross-couplings of iodides effectively (entries 4 and 5). The presence of monodentate ligands that are electronically similar to PPh3 (AsPh3, P(o-tol)3, P(p-tol)3, and PBn3) and more electron deficient (P(2-furyl)3, P(OPh)3) all led to efficient couplings (entries 1, 2, and 4–8). Thus, no clear correlations between the steric or electronic properties of monodentate ligands and reaction efficiency could be identified on the basis of these results. However, in general, these data are consistent with relevant observations reported by Farina and Krishnan in Pd-catalyzed Stille couplings. (9) We also performed reactions with bidentate phosphine ligands dppf and dppe, which provided differing results (entries 9–12).
Table 4. Respective Suzuki–Miyaura Couplings of Iodide 1 and Bromide 2: Influence of Ligands
    yield (%)a
entryligandeθ (deg)bν (cm–1)cusing 1using 2
1PPh31452068.911 (9)68 (57)
2P(o-tol)31942066.666 (50)61 (56)
3TTMPP184 6 (5)47 (27)
4AsPh31422067.957 (50)22 (18)
5P(p-tol)31452066.743 (35)51 (39)
6P(2-furyl)31332078.451 (44)9 (9)
7P(OPh)31302075.966 (53)54 (49)
8PBn3139.52066.139 (26)42 (34)
9dppf  42 (20)28 (9)
10ddppf  47 (31)25 (9)
11dppe  3 (3)<2 (<2)
12ddppe  <2 (<2)<2 (<2)
a

Determined via gas chromatography (GC) with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

b

Tolman cone angle. (9,20)

c

Tolman electronic parameter (IR frequency of Ni(CO)3L). (9,20a,21)

d

1% ligand used.

e

Abbreviations: TTMPP, tris(2,4,6-trimethoxyphenyl)phosphine; dppf, 1,1′-ferrocenediylbis(diphenylphosphine); dppe, bis(diphenylphosphino)ethane.

In competition experiments between p-iodo- and p-bromotoluene employing [Pd(PPh3)4], the catalyst differentiated effectively between these electrophiles at both 50 and 80 °C (eq 1). These data are consistent with oxidative addition not being the turnover-limiting step of the catalytic cycle in the case of iodide 1 at these temperatures. (22)31P NMR spectroscopy indicates that the predominant resting states of the Pd catalyst are trans-[Pd(PPh3)2(p-tol)(I)] and trans-[Pd(PPh3)2I2] during the early stages of the reaction (eq 2). (23−25) When taken together, these results suggest that transmetalation may be the turnover-limiting step in the process featuring iodide 1 at 50 °C.
Indeed, in Pd-catalyzed Csp2–Csp2 Suzuki–Miyaura transformations employing aryl iodides, it is often proposed that the turnover-limiting step involves transmetalation. (22,26) Two fundamental pretransmetalation pathways are postulated to operate. (27,28) Specifically, pretransmetalation intermediate C (28a,b) may be generated either by the reaction of oxidative addition adduct A with a boronate (path A, Figure 2) or via the reaction of hydroxo-Pd species B with a boronic acid (path B). It is acknowledged that this transmetalation process is particularly complicated, nuanced, and subtly influenced by a range of factors. (22,26−28) A number of research groups have investigated the kinetics of transmetalation experimentally, and in these particular cases their results indicated that path B was more kinetically favorable than path A (Figure 2). (22,26,28e,f) Specifically, the results of studies exploring the transmetalation of trans-[Pd(PPh3)2(Ar)(X)] (X = Br, I) under both stoichiometric and catalytic conditions demonstrate that the respective rates of the Suzuki–Miyaura reactions are consistent with transmetalation likely occurring via the reaction of hydroxo-Pd species with arylboronic acids (Path B). (22,26,28a,b) This process is orders of magnitude faster than the reaction of trans-[Pd(PPh3)2(Ar)(X)] with an aryltrihydroxyborate (path A). (22,26,29)

Figure 2

Figure 2. Two fundamental pathways leading to pretransmetalation intermediate C in Suzuki–Miyaura couplings.

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With the aforementioned issues in mind, we focused on investigating the chemical competence of trans-[Pd(PPh3)2(p-tol)(I)] in both n-PrOH/H2O and DMF/H2O. We chose to also perform experiments in the latter solvent, as we had previously demonstrated that, in this particular mixture, the relatively efficient coupling of p-iodotoluene conspicuously contrasted with results obtained in n-PrOH and other organic cosolvents (Table 1, entries 5–8). Reactions in both solvent mixtures clearly demonstrated that trans-[Pd(PPh3)2(p-tol)(I)] is a chemically competent species at 50 °C (Table 5, entry 1). Interestingly, when the equivalent reactions were performed in the presence of 2% PPh3, very low yields of product 3 were obtained in n-PrOH/H2O while cross-coupling still occurred in DMF/H2O (Table 5, entry 2). These data indicated that the poor turnover of key on-cycle intermediate trans-[Pd(PPh3)2(p-tol)(I)], in the presence of PPh3, may be responsible for inefficient Suzuki–Miyaura couplings of aryl iodides in n-PrOH cosolvent mixtures at lower temperatures.
Table 5. Exploring the Chemical Competence of Various Pd(II) Species in Suzuki–Miyaura Couplings
a

Determined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

b

0.5% [Pd] employed.

In related experiments, we illustrated the chemical competence of trans-[Pd(PPh3)2I2], [Pd(PPh3)(p-tol)(μ-I)]2, and [Pd(PPh3)(p-tol)(μ-OH)]2 (Table 5, entries 3–5). The results of equivalent experiments performed in the presence of 2% PPh3 led to less efficient Suzuki–Miyaura couplings (entries 6–8). It is possible that the inability of these PdII–I intermediates to efficiently re-enter the catalytic cycle, in the presence of PPh3, may also contribute to the inefficient couplings of iodides. Notably, we determined that trans-[Pd(PPh3)2(p-tol)(Br)] is a chemically competent species in reactions employing p-bromotoluene in the presence of 2% PPh3 (Scheme 2).

Scheme 2

Scheme 2. Investigating the Chemical Competence of trans-[Pd(PPh3)2(p-tol)(Br)] in Suzuki–Miyaura Couplings
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aDetermined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

Next, we investigated transmetalation in Suzuki–Miyaura couplings employing trans-[Pd(PPh3)2(p-tol)(I)] (4a, red), trans-[Pd(PPh3)2(p-tol)(Br)] (4b, blue), and [Pd(PPh3)(p-tol)(μ-OH)]2 (5, black), respectively (Figure 3). (30) When these experiments were performed in the presence of PPh3, the rate of product formation significantly decreased for complexes 4a (dashed red) and 4b (dashed blue), respectively. These observations are consistent with recent studies by Denmark and co-workers which illustrated that added phosphine reduces the rate of transmetalation in Suzuki–Miyaura couplings. (28a,b,31) Interestingly, the presence of PPh3 did not significantly affect the rate of product formation from Pd–OH complex 5 (dashed black). Our experiments illustrate that, in the presence of PPh3, productive cross-coupling from trans-[Pd(PPh3)2(p-tol)(I)] is particularly inefficient. (32) It is possible that the poor reactivity of aryl iodides observed in couplings performed in the presence of PPh3 may relate to the inefficient formation of key PdII–OH intermediate B (Figure 2) under the reaction conditions.

Figure 3

Figure 3. Formation of biaryl 3 in reactions employing trans-[Pd(PPh3)2(p-tol)(I)] (4a) (solid red line), [Pd–I] 4a + 6 equiv of PPh3 (dashed red line), trans-[Pd(PPh3)2(p-tol)(Br)] (4b) (solid blue line), [Pd–Br] 4b + 6 equiv PPh3 (dashed blue line), [Pd–OH] 5 (solid black line), and [Pd–OH] 5 + 6 equiv PPh3 (dashed black line). A 0.5 equiv amount of [Pd(PPh3)(p-tol)(μ-OH)]2 was used in these experiments (and no Na2CO3 was used in these reactions). Yields were determined via GC with the aid of a calibrated internal standard (average of two experiments).

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When we monitored Pd-catalyzed Suzuki–Miyaura couplings employing either 6% PPh3 (Figure 4, red) or 6% P(2-furyl)3 (blue), we observed results consistent with our aforementioned data (Tables 1 and 4). In an experiment featuring both PPh3 and P(2-furyl)3 (Figure 4, black), (33) it appeared that the former phosphine had a greater influence on the progress of the reaction than the latter. Farina and Krishnan noted similar effects in Pd-catalyzed Stille couplings employing this mixed ligand system. (9) Their subsequent NMR experiments demonstrated the “stronger thermodynamic affinity” of PPh3 for Pd(II) relative to P(2-furyl)3 (eq 3). (9,34) We explored the effects of either PPh3 or P(2-furyl)3 on Suzuki–Miyaura reactions employing trans-[Pd{P(2-furyl)3}2(p-tol)(I)] (Scheme 3). These results reinforce the poor reactivity observed in couplings performed in the presence of PPh3.

Figure 4

Figure 4. Formation of biaryl 3 in reactions employing: 6% PPh3 (red), 6% P(2-furyl)3 (blue), and 3% PPh3 and 3% P(2-furyl)3 (black). Yields were determined via GC with the aid of a calibrated internal standard (average of two experiments).

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Scheme 3

Scheme 3. Investigating the Chemical Competence of trans-[Pd{P(2-furyl)3}2(p-tol)(I)] in Suzuki–Miyaura Couplings
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aDetermined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

When the aforementioned results described in this study are taken together, we suggest that the poor turnover of trans-[Pd(PPh3)2(p-tol)(I)] (or related PdII–I species) in the presence of PPh3 may be responsible for inefficient Suzuki–Miyaura couplings of aryl iodides employing [Pd(PPh3)4] at lower temperatures. Throughout, where we have suggested potential reasons for the poor reactivity of aryl iodides in Suzuki–Miyaura cross-couplings at lower temperatures, we have refrained from making direct comparisons to analogous reactions featuring bromide electrophiles as part of this discussion. We have also avoided speculating on the reasons for the differing efficiency of couplings of aryl iodides performed in n-PrOH/H2O in comparison to DMF/H2O solvent mixtures. In these cases, the differing biphasic natures of these reaction conditions and related issues, such as the common ion effect and boron speciation, complicate these matters and limit our capacity to make such comparisons. Lloyd-Jones and Lennox have provided an erudite overview considering these issues within the context of Suzuki–Miyaura coupling chemistry. (27)

Conclusions

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Although an array of phosphine-ligated Pd catalyst systems are employed in Suzuki–Miyaura couplings, the use of [Pd(PPh3)4] (or related PPh3-based systems) is still prevalent, particularly in more applied settings. This study, which notably had its origins in the undergraduate laboratory, has revealed the profound (and somewhat surprising) effects that subtle changes in reaction conditions can have on the efficiency of fundamental Csp2–Csp2 Suzuki–Miyaura couplings of aryl iodides employing “classical” Pd/PPh3 catalyst systems. Our data indicate that, in the presence of PPh3, the poor turnover of trans-[Pd(PPh3)2(p-tol)(I)] (or related PdII–I species) may be responsible for the inefficient coupling of aryl iodides in various conventional solvent mixtures at lower temperatures. These findings are worth considering, particularly when Csp2–Csp2 cross-couplings of aryl iodides are performed at lower temperatures, and can inform the development of optimized reaction conditions in this manifold. We anticipate that our work will contribute to providing a more nuanced understanding of “textbook” Pd-catalyzed Suzuki–Miyaura couplings of fundamental electrophile classes employing the prototypical phosphine ligand PPh3.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00189.

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Author Information

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  • Corresponding Author
  • Authors
    • Curtis C. Ho - School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
    • Angus Olding - School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
    • Jason A. Smith - School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia;  Orcidhttp://orcid.org/0000-0001-6313-3298
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors acknowledge the University of Tasmania School of Natural Sciences − Chemistry for financial support, the University of Tasmania Central Science Laboratory for access to NMR spectroscopy services, Mr. Brendon Schollum for assistance with gas chromatography, and Prof. Allan Canty and Prof. Justin Mohr for helpful discussions. A.O. thanks the University of Tasmania for a Dean’s Summer Research Scholarship.

References

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    Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize
    Johansson Seechurn, Carin C. C.; Kitching, Matthew O.; Colacot, Thomas J.; Snieckus, Victor
    Angewandte Chemie, International Edition (2012), 51 (21), 5062-5085CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel Laureate chemists for their roles in discovering and developing highly practical methodologies for C-C bond construction. From their original contributions in the early 1970s the landscape of the strategies and methods of org. synthesis irreversibly changed for the modern chemist, both in academia and in industry. In this review, we attempt to trace the historical origin of these powerful reactions, and outline the developments from the seminal discoveries leading to their eminent position as appreciated and applied today.
  4. 4

    For selected reviews on the applications of alkylphosphane ligands in Pd-catalyzed C–C cross-coupling reactions, see:

    (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.; Marianetti, G.; Perego, L. A. Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products. Curr. Org. Chem. 2015, 19, 1302– 1409,  DOI: 10.2174/1385272819666150506230050
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    4a
    Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products
    Rossi, Renzo; Bellina, Fabio; Lessi, Marco; Manzini, Chiara; Marianetti, Giulia; Perego, Luca A.
    Current Organic Chemistry (2015), 19 (14), 1302-1409CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
    A review with refs. on This review with 800 refs. illustrates applications of Suzuki-Miyaura (S.-M.) reactions in the total syntheses of 147 natural products that were made in the period 2010-2013. The review has been organized on the basis of the seven classes of phosphane-based Pd catalysts that have been used in the reported total syntheses. Emphasis has been given to describe and discuss the exptl. conditions of the Pd-catalyzed (S.-M.) cross-coupling reactions also outlining the methods used to prep. the reactants. A focus has also been set on the biol. and pharmacol. properties of the reported natural products as well as on the most significant steps of the reported total syntheses.
    (b) Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2, 1147– 1164,  DOI: 10.1021/cs300082f
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    4b
    Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize
    Li, Hongbo; Johansson Seechurn, Carin C. C.; Colacot, Thomas J.
    ACS Catalysis (2012), 2 (6), 1147-1164CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A review. Strategies for the development of Pd catalysts based on utilization of L2Pd and LPd (L = ligand) species, beyond the contributions of the 2010 Nobel Laureates Richard Heck, Ei-ichi Negishi, and Akira Suzuki, along with their contemporaries, are reviewed. These well-defined, preformed Pd catalysts improve the selectivity and activity of selected cross-coupling reactions by reducing the metal loading and the ligand-to-metal ratios. This review describes predominantly the development of Pd precatalysts over the last 10 years and highlights the benefits often obsd. when using well-defined preformed catalysts relative to those generated in situ.
    (c) Fu, G. C. The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands. Acc. Chem. Res. 2008, 41, 1555– 1564,  DOI: 10.1021/ar800148f
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    4c
    The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands
    Fu, Gregory C.
    Accounts of Chemical Research (2008), 41 (11), 1555-1564CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Metal-catalyzed coupling reactions of aryl electrophiles with organometallics and with olefins serve as unusually effective tools for forming new carbon-carbon bonds. By 1998, researchers had developed catalysts that achieved reactions of aryl iodides, bromides, and triflates. Nevertheless, many noteworthy challenges remained; among them were couplings of aryl iodides, bromides, and triflates under mild conditions (at room temp., for example), couplings of hindered reaction partners, and couplings of inexpensive aryl chlorides. This Account highlights some of the progress that has been made in our lab. over the past decade, largely through the appropriate choice of ligand, in achieving these synthetic objectives. In particular, we have established that palladium in combination with a bulky trialkylphosphine accomplishes a broad spectrum of coupling processes, including Suzuki, Stille, Negishi, and Heck reactions. These methods have been applied in a wide array of settings, such as natural-product synthesis, materials science, and bioorg. chem.
  5. 5

    For selected studies on oxidative addition to Pd(0) complexes featuring phosphine ligands, see:

    (a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Mechanistic Pathways for Oxidative Addition of Aryl Halides to Palladium(0) Complexes:  A DFT Study. Organometallics 2005, 24, 2398– 2410,  DOI: 10.1021/om0500220
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    (b) Senn, H. M.; Ziegler, T. Oxidative Addition of Aryl Halides to Palladium(0) Complexes:  A Density-Functional Study Including Solvation. Organometallics 2004, 23, 2980– 2988,  DOI: 10.1021/om049963n
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    (c) Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions. Acc. Chem. Res. 2000, 33, 314– 321,  DOI: 10.1021/ar980063a
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    5c
    Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions
    Amatore, Christian; Jutand, Anny
    Accounts of Chemical Research (2000), 33 (5), 314-321CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review with 17 refs. The anions of PdCl2L2 and Pd(OAc)2, precursors of palladium(0) used in cross-coupling and Heck reactions, play a crucial role in these reactions. Tricoordinated anionic complexes Pd0L2Cl- and Pd0L2(OAc)- are the effective catalysts instead of the usually postulated Pd0L2 complex. The anion ligated to the palladium(0) affects the kinetics of the oxidative addn. to ArI as well as the structure and reactivity of the arylpalladium(II) complexes produced in this reaction. Thus, pentacoordinated anionic complexes are formed, ArPdI(Cl)L2- or ArPdI(OAc)L2-, the precursor of neutral trans-ArPd(OAc)L2, instead of the usually postulated trans-ArPdIL2 complex (L = PPh3).
    (d) Casado, A. L.; Espinet, P. On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide). Organometallics 1998, 17, 954– 959,  DOI: 10.1021/om9709502
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    5d
    On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide)
    Casado, Arturo L.; Espinet, Pablo
    Organometallics (1998), 17 (5), 954-959CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    The oxidative addn. of RI to Pd(0) and further cis-to-trans isomerization, which are involved in the Stille reaction and other Pd-catalyzed syntheses, have been studied. C6Cl2F3I (C6Cl2F3 = 3,5-dichlorotrifluorophenyl) adds to Pd(PPh3)4 in THF at room temp. giving cis-[Pd(C6Cl2F3)I(PPh3)2] (2), which could be isolated before isomerization to the more stable trans-[Pd(C6Cl2F3)I(PPh3)2] (3). A 19F NMR kinetic study of the isomerization of 2 in THF at 322.6 K reveals a first-order law riso = kiso[2], with kiso = f + g[2]0 + (h + i[2]0)/([PPh3] + j) (f = (1.66 ± 0.03) × 10-4 s-1, g = (2.5 ± 0.2) × 10-3 mol-1 L s-1, h = (1.3 ± 0.7) × 10-8 mol L-1 s-1, i = (4 ± 2) × 10-4 s-1, and j = (1.4 ± 0.7) × 10-5 mol L-1). A four-pathway mechanism accounts for these results: two are assigned to the associative replacements of PPh3 coordinated to 2 by an iodide ligand of I-[Pd] (I-[Pd] = 2 or 3), both THF-assisted (coeff. h) or direct (coeff. i), leading to a monoiodide-bridged intermediate cis-{Pd(C6Cl2F3)I(PPh3)(μ-I)-[Pd]}. The later rearranges via terminal-for-bridging iodide exchange to trans-{Pd(C6Cl2F3)I(PPh3)(μ-I)-[Pd]}, which is finally cleaved by PPh3 yielding complex 3. The other two concurrent pathways are assigned to the isomerization via two consecutive Berry pseudorotations in the pentacoordinated species derived from 2 by coordination of THF (coeff. f) or I-[Pd] (coeff. g). The apparent activation entropy assocd. with kiso is neg. (ΔS⧧ = -21 ± 3 J K-1 mol-1), in agreement with the proposed bimol. mechanisms.
    (e) Hartwig, J. F.; Paul, F. Oxidative Addition of Aryl Bromide after Dissociation of Phosphine from a Two-Coordinate Palladium(0) Complex, Bis(tri-o-tolylphosphine)Palladium(0). J. Am. Chem. Soc. 1995, 117, 5373– 5374,  DOI: 10.1021/ja00124a026
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    5e
    Oxidative Addition of Aryl Bromide after Dissociation of Phosphine from a Two-Coordinate Palladium(0) Complex, Bis(tri-o-tolylphosphine)Palladium(0)
    Hartwig, John F.; Paul, Frederic
    Journal of the American Chemical Society (1995), 117 (19), 5373-4CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The 14-electron Pd(0) complex [(o-tol)3P]2Pd (1) undergoes oxidative addn. reactions with aryl bromides that occur by a dissociative mechanism. The products of aryl bromide addn. are dimeric with only one phosphine bound to each palladium. In contrast to typical oxidative addns. to Pt(0), Pd(0), and Ni(0) phosphine compds. that occur to intermediates with two or three phosphine ligands, the addn. to 1 occurs after phosphine dissocn. and generation of a monophosphine intermediate. Clean first order kinetics were obsd. when monitoring the disappearance of 1. Inverse first order rate behavior in phosphine demonstrated that the reaction is dissociative. Reaction rates in benzene, toluene, and xylene were essentially identical, suggesting that solvent coordination does not stabilize the unsatd. intermediate. Rather, displacement of a phosphine by coordinated aryl bromide before irreversible oxidative addn., or coordination of a ligand C-H bond appears to stabilize the monophosphine complex. This mechanism is unusual, but falls in accord with those for the opposite reaction, reductive elimination from Pd(II). Many of these elimination reactions occur after phosphine dissocn. and, therefore, lead to initial products that contain only one phosphine ligand. This initial product from reductive elimination is analogous to the intermediate generated from 1 that undergoes oxidative addn.
    (f) Paul, F.; Patt, J.; Hartwig, J. F. Structural Characterization and Simple Synthesis of {Pd[P(o-Tol)3]2}. Spectroscopic Study and Structural Characterization of the Dimeric Palladium(II) Complexes Obtained by Oxidative Addition of Aryl Bromides and Their Reactivity with Amines. Organometallics 1995, 14, 3030– 3039,  DOI: 10.1021/om00006a053
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    5f
    Structural Characterization and Simple Synthesis of {Pd[P(o-Tol)3]2}. Spectroscopic Study and Structural Characterization of the Dimeric Palladium(II) Complexes Obtained by Oxidative Addition of Aryl Bromides and Their Reactivity with Amines
    Paul, Frederic; Patt, Joe; Hartwig, John F.
    Organometallics (1995), 14 (6), 3030-9CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    The Pd(0) complex {Pd[P(o-Tol)3]2} was prepd. by addn. of P(o-Tol)3 to crude [Pd(DBA)2], which is an approx. equimolar mixt. of Pd2(DBA)3 and Pd(DBA)3, followed by crystn. from the reaction medium by addn. of ether. The formation of {Pd[P(o-Tol)3]2} appeared to be driven by its insoly. in the benzene/ether solvent mixt. Benzene solns. of [Pd(DBA)2] and P(o-Tol)3 did not contain amts. of the L2Pd compd. that could be detected by 31P NMR spectroscopy. {Pd[P(o-Tol)3]2} was characterized crystallog. and showed an exactly linear geometry. Similar Pd(0) compds. {Pd[P(2,4-dimethylphenyl)3]2}, {Pd[P(2-methyl-4-fluorophenyl)3]2}, and the low-coordinate trialkylphosphine complex {Pd[P(t-Bu)3]2} were also prepd. by this method, but [Pd(PCy3)2(DBA)] was produced from reactions involving PCy3 and [Pd(DBA)2], and [Pd(TMPP)(DBA)2] was isolated after addn. of tris(1,3,5-trimethoxyphenyl)phosphine (TMPP) to [Pd(DBA)2]. The oxidative addn. of aryl halides to {Pd[P(o-Tol)3]2} at room temp. led to dimeric {Pd[P(o-Tol)3](Ar)(Br)}2. An example of these compds. was characterized crystallog. as well as by soln. mol. wt. anal. This aryl halide complex is dimeric in the solid state as well as in soln. The NMR spectra of the large triarylphosphine complexes showed temp. dependent behavior, presumably due to isomerizations and ligand rotations that occurred on the NMR time scale. The aryl halide compds. did not form four-coordinate monometallic species in the presence of excess P(o-Tol)3, but they did undergo cleavage to four-coordinate monometallic complexes upon addn. of primary and secondary amines.
    (g) Amatore, C.; Jutand, A.; Suarez, A. Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions. J. Am. Chem. Soc. 1993, 115, 9531– 9541,  DOI: 10.1021/ja00074a018
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    5g
    Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions
    Amatore, Christian; Jutand, Anny; Suarez, Alejandra
    Journal of the American Chemical Society (1993), 115 (21), 9531-41CODEN: JACSAT; ISSN:0002-7863.
    The mechanism of oxidative addn. of aryl halides to low-ligated zerovalent palladium species obtained by redn. of their divalent precursor complexes, PdIICl2(PR3)2, was investigated on the basis of 31P NMR and electrochem. In strong contrast to usual expectations, the reaction proceeds via a complex sequence of steps: (i) fast addn. of the aryl halide to a halide ligated zerovalent palladium center, so as to afford a pentacoordinated anionic arylpalladium(II) center; (ii) a fast but reversible uphill elimination from the pentacoordinated anionic arylpalladium(II) center of a halide ion ligand, possibly through its substitution by a solvent ligand; (iii) rearrangement of this second short-lived intermediate into the thermodynamically stable trans-arylpalladium(II) product of the reaction. On the basis of this detailed mechanism, a new mechanism is proposed for the catalysis of nucleophilic substitutions by palladium complexes. In contrast to the catalytic cycles that are usually considered, this new catalytic cycle accounts for the well-used effects of halide ions as well as that of small metal cations and rationalizes their role in the overall efficiency of palladium-catalyzed nucleophilic substitutions.
    (h) Amatore, C.; Pflüger, F. Mechanism of oxidative addition of palladium(0) with aromatic iodides in toluene, monitored at ultramicroelectrodes. Organometallics 1990, 9, 2276– 2282,  DOI: 10.1021/om00158a026
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    5h
    Mechanism of oxidative addition of palladium(0) with aromatic iodides in toluene, monitored at ultramicroelectrodes
    Amatore, Christian; Pfluger, Fernando
    Organometallics (1990), 9 (8), 2276-82CODEN: ORGND7; ISSN:0276-7333.
    The mechanism and rates of oxidative addn. of substituted iodobenzenes to tetrakis(triphenylphosphine)palladium(0) is investigated in toluene by means of electrochem. at ultramicroelectrodes. The mechanism is identical with that previously reported in THF (F. F. Fauvarque et al., 1981) and to correspond to a similar slope for Hammett's correlation (ρ = +2 in THF vs +2.3 ± 0.2 in toluene). Moreover, the important change in polarity (εs ≈ 7.58 in THF and 2.38 in toluene) does not affect the enthalpy of activation and leads to similar activation entropies in both solvents. This suggests that the transition state of addn. of aryl halides to the coordinately unsatd. zerovalent palladium complex Pd0(PPh3)2 has no significant ionic character.
    (i) Fauvarque, J.-F.; Pflüger, F. Kinetics of oxidative addition of zerovalent palladium to aromatic iodides. J. Organomet. Chem. 1981, 208, 419– 427,  DOI: 10.1016/S0022-328X(00)86726-1
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    5i
    Kinetics of oxidative addition of zerovalent palladium to aromatic iodides
    Fauvarque, Jean Francois; Pfluger, Fernando; Troupel, Michel
    Journal of Organometallic Chemistry (1981), 208 (3), 419-27CODEN: JORCAI; ISSN:0022-328X.
    The kinetics of oxidative addn. of Pd(0) to arom. iodides in THF contg. the ligand Ph3P were studied by amperometry on the Pd oxidn. wave. The reaction is 1st order each in arom. iodide and Pd(0), and the rate const. is inversely proportional to the free-ligand concn. The reactive Pd(0) intermediate is Pd(PPh3)2. With substituted arom. iodides, the rate consts. give a linear Hammett relationship with ρ = +2. The mechanism is related to an arom. nucleophilic substitution with some assistance from halogen-Pd interaction.
    (j) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434,  DOI: 10.1021/ar50120a002
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    (k) Fitton, P.; Rick, E. A. The addition of aryl halides to tetrakis(triphenylphosphine)palladium(0). J. Organomet. Chem. 1971, 28, 287– 291,  DOI: 10.1016/S0022-328X(00)84578-7
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    5k
    Addition of aryl halides to tetrakis(triphenylphosphine)palladium(0)
    Fitton, P.; Rick, Edward A.
    Journal of Organometallic Chemistry (1971), 28 (2), 287-91CODEN: JORCAI; ISSN:0022-328X.
    The order of reactivity of halobenzenes towards oxidative addn. to Pd(PPh3)4 was PhI > PhBr > PhCl. Iodobenzene will react with Pd(PPh3)4 in benzene at room temp., and bromobenzene will react at 80°. Chlorobenzene, however, is unreactive even at 135°. Aryl chlorides substituted with electron-donating groups similarly are unreactive, but aryl chlorides substituted with electron-withdrawing groups are reactive. This increased reactivity, and order of reactivity 4-O2NC6H4Cl > 4-CNC6H4Cl > 4-PhCOC6H4Cl > PhCl suggests that the mechanism of the oxidative addn. is similar to that of a bimol. nucleophilic aromatic displacement reaction in which breaking of the bond to the leaving group is involved in the rate detg. step.
  6. 6
    Organotransition Metal Chemistry From Bonding to Catalysis; Hartwig, J. F., Ed.; University Science Books: Sausalito, CA, 2010; Chapter 19.
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  7. 7
    Pullen, R.; Olding, A.; Smith, J. A.; Bissember, A. C. Manuscript in preparation.
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  8. 8
    Wallow, T. I.; Novak, B. M. Highly Efficient and Accelerated Suzuki Aryl Couplings Mediated by Phosphine-Free Palladium Sources. J. Org. Chem. 1994, 59, 5034– 5037,  DOI: 10.1021/jo00096a056
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    Highly efficient and accelerated Suzuki aryl couplings mediated by phosphine-free palladium sources
    Wallow, Thomas I.; Novak, Bruce M.
    Journal of Organic Chemistry (1994), 59 (17), 5034-7CODEN: JOCEAH; ISSN:0022-3263.
    Suzuki aryl cross-couplings employing aryl bromides and aryl iodides proceed under mild conditions (65°) with high efficiency (substrate-to-catalyst ratios >500) in the presence of phosphine-free Pd catalysts derived from Pd acetate, Pd2(dba)3·C6H6 (dba = dibenzylideneacetone), and [(η3-C3H5)PdCl]2. Phosphine inhibition is shown to play a key role in limiting catalytic efficiency; qual. comparison studies show that the phosphine-free systems are 1-2 orders of magnitude more active than phosphine-supported catalytic systems. Pd[P(Ph)3]4 proved to be the least active of the catalytic species screened. The phosphine-free methodol. appears to be generally applicable; cross-couplings of aryl iodides yielding biaryls p-MeOC6H4C6H4CF3-p 6 and p-MeOC6H4C6H4Me-o 7 proceed without noticeable steric or electronic effects. Cross-couplings employing aryl bromides are insensitive to electronic effects in the synthesis of 6 but are slowed by steric hindrance in the synthesis of 7. Acceleration of cross-coupling is obsd. in the presence of polar cosolvents and at high pH.
  9. 9

    The poor reactivity of aryl iodides with vinyltributyltin in Stille couplings employing Pd/PPh3 at ∼50 °C has been reported; see:

    Farina, V.; Krishnan, B. Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications. J. Am. Chem. Soc. 1991, 113, 9585– 9595,  DOI: 10.1021/ja00025a025
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    Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications
    Farina, Vittorio; Krishnan, Bala
    Journal of the American Chemical Society (1991), 113 (25), 9585-95CODEN: JACSAT; ISSN:0002-7863.
    The effect of changing the palladium ligands on the rates of typical Stille cross-coupling reactions was studied. Large rate enhancements (typically 102-103 over triphenylphosphine-based catalyst) were obsd. with tri-2-furylphosphine and triphenylarsine, which are recommended as the new ligands of choice in the palladium-catalyzed coupling between olefinic stannanes and electrophiles. On the basis of the evidence presented, the transmetalation, which is the rate-detg. step in the catalytic cycle, is postulated to involve a π-complex between the metal and the stannane double bond. In general, ligands that readily dissoc. from Pd(II) and allow ready formation of this π-complex are the ones that produce the fastest coupling rates. The utility of the new ligands is demonstrated with several synthetic examples.
  10. 10
    Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Synthesis of unsymmetrical biaryls using a modified Suzuki cross-coupling: 4-biphenylcarboxaldehyde. Org. Synth. 1998, 75, 53,  DOI: 10.1002/0471264180.os075.07
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  11. 11

    In general, iodide consumption was comparable to product yield.

    There is no corresponding record for this reference.
  12. 12

    Analogous results were obtained in experiments employing higher [Pd(PPh3)4] loadings (2.5% and 5%) (see the Supporting Information).

    There is no corresponding record for this reference.
  13. 13

    We also investigated the effect of incrementally varying the Na2CO3 loading on the outcome of the reaction at 70 °C. Our results suggest that the Na2CO3 loading (1–5 equiv) has little effect on the efficiency of reactions employing p-iodotoluene (see the Supporting Information). Substituting either Cs2CO3 or NMe4OH for Na2CO3 also provided inefficient couplings of p-iodotoluene (see the Supporting Information).

    There is no corresponding record for this reference.
  14. 14

    We also performed experiments employing higher PPh3 loadings (see the Supporting Information).

    There is no corresponding record for this reference.
  15. 15

    It has been established that PPh3 can effect the reduction of Pd(OAc)2 to generate catalytically active Pd(0) species. See, for example: ref (5c).

    (a) Carole, W. A.; Colacot, T. J. Understanding Palladium Acetate from a User Perspective. Chem. - Eur. J. 2016, 22, 7686– 7695,  DOI: 10.1002/chem.201601450
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    15a
    Understanding Palladium Acetate from a User Perspective
    Carole, William A.; Colacot, Thomas J.
    Chemistry - A European Journal (2016), 22 (23), 7686-7695CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The behavior of palladium acetate is reviewed with respect to its synthesis, characterization, structure (in both soln. and solid state), and activation pathways. In addn., comparisons of catalytic activities between pure palladium acetate and two common byproducts, Pd3(OAc)5(NO2) and polymeric [Pd(OAc)2]n, typically present in com. available material are reviewed. Hence, this minireview serves as a concise guide for the users of palladium acetate from both academia and industry.
    (b) Amatore, C.; Carré, E.; Jutand, A.; M’Barki, M. Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions. Organometallics 1995, 14, 1818– 1826,  DOI: 10.1021/om00004a039
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    15b
    Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions
    Amatore, Christian; Carre, Emmanuelle; Jutand, Anny; M'Barki, Mohamed Amine
    Organometallics (1995), 14 (4), 1818-26CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    Mixts. of Pd(OAc)2 and tertiary phosphines spontaneously afford Pd(0) complexes. Kinetic studies demonstrate that this reaction proceeds from the complex Pd(OAc)2(PR3)2 via an inner-sphere redn. which is the rate-detg. step of the overall reaction. The phosphine is thus oxidized to the corresponding phosphine oxide. The formation of the Pd(0) complex is sensitive to electronic and steric factors. The more the triarylphosphine is substituted by electron-withdrawing groups, the faster the reaction. The Pd(0) complex thus formed reacts with Ph iodide via an oxidn. addn., and this reaction is faster when the phosphine is more electron-rich.
    (c) Amatore, C.; Jutand, A.; M’Barki, M. Evidence of the formation of zerovalent palladium from Pd(OAc)2 and triphenylphosphine. Organometallics 1992, 11, 3009– 3013,  DOI: 10.1021/om00045a012
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    15c
    Evidence of the formation of zerovalent palladium from Pd(OAc)2 and triphenylphosphine
    Amatore, Christian; Jutand, Anny; M'Barki, Mohamed Amine
    Organometallics (1992), 11 (9), 3009-13CODEN: ORGND7; ISSN:0276-7333.
    The mixt. Pd(OAc)2 + nPPh3 (n ≥2) and Pd(OAc)2(PPh3)2, commonly used as catalysts in reactions involving aryl and vinyl halides, aryl triflates or allylic acetates, spontaneously generate a zerovalent Pd complex that reacts with PhI. PPh3 reduces the PdII from Pd(OAc)2(PPh3)2 by an intramol. reaction and is oxidized to OPPh3. In the presence of an excess of PPh3, the zerovalent Pd complex generated in situ has the same 31P NMR and cyclic voltammetry properties as those of Pd0(PPh3)4.
  16. 16

    Pd(OAc)2 was used in preference to Pdx(dba)y, as challenges in establishing the exact speciation and purity of the latter have been identified. See, for example:

    (a) Amatore, C.; Jutand, A. Role of dba in the reactivity of palladium(0) complexes generated in situ from mixtures of Pd(dba)2 and phosphines. Coord. Chem. Rev. 1998, 178–180, 511– 528,  DOI: 10.1016/S0010-8545(98)00073-3
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    16a
    Role of dba in the reactivity of palladium(0) complexes generated in situ from mixtures of Pd(dba)2 and phosphines
    Amatore, Christian; Jutand, Anny
    Coordination Chemistry Reviews (1998), 178-180 (Pt. 1), 511-528CODEN: CCHRAM; ISSN:0010-8545. (Elsevier Science S.A.)
    A review with 98 refs. The ligand dba plays a crucial role both on the structure and on the reactivity of Pd(0) complexes generated in situ in mixts. of Pd(dba)2 and phosphine ligands. Whatever the ligand, the major complex is always Pd(dba)L2 where L is a monodentate phosphine ligand or Pd(dba)(L-L) where L-L is a bidentate phosphine ligand. In all cases, the most reactive species in the oxidative addn. with Ph iodide is the lowest ligated complex PdL2 or Pd(L-L) in equil. with the major complex and dba. However, Pd(dba)(L-L) also reacts with Ph iodide. The presence of the major complexes ligated by dba diminishes the concn. of the more reactive species PdL2 or Pd(L-L) and consequently controls the rate of the overall reaction. The overall reactivity is governed both by the intrinsic reactivity of the reactive species and its concn., two factors which can be antagonistic and a nonlinear Hammett correlation of the oxidative addn. with the basicity of the phosphine is obsd. for monodentate ligands.
    (b) Zalesskiy, S. S.; Ananikov, V. P. Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis. Organometallics 2012, 31, 2302– 2309,  DOI: 10.1021/om201217r
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    16b
    Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis
    Zalesskiy, Sergey S.; Ananikov, Valentine P.
    Organometallics (2012), 31 (6), 2302-2309CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) is ubiquitously used as a source of sol. Pd species for catalysis and as a precursor in the synthesis of more complex Pd structures. In spite of the massive usage of this convenient Pd complex, its nature in soln. was not revealed in detail and the applications rely on the assumed state and purity of the compd. A convenient NMR procedure is developed to reveal the nature of Pd2(dba)3 and to det. the purity of the complex. Surprisingly, com. available samples of Pd2(dba)3 may readily contain up to 40% of Pd nanoparticles in a wide range of sizes (10-200 nm). The routinely accepted practice of use of Pd2(dba)3 without anal. of the purity (both com. available and prepd. by common procedures) can introduce significant errors in the estn. of catalyst efficiency and lead to incorrect values of TON, TOF, and reported mol % values in the catalytic procedures. The presence of Pd nanoparticles in the catalyst precursor provides an opportunity for heterogeneous catalytic systems of different nature to be directly accessible from Pd2(dba)3. A modified procedure for the synthesis of Pd2(dba)3·CHCl3 with 99% purity is reported.
  17. 17

    See, for example:

    Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Synthesis of diaryls from phenylboric acid and aryl iodides in an aqueous medium. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1989, 38, 2206,  DOI: 10.1007/BF00962156
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    Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1989, 38, 2206,  DOI: 10.1007/BF00962156
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    There is no corresponding record for this reference.
  18. 18

    We also performed experiments investigating the effect of halide additives (20% NH4I, NH4Br, NH4F, NMe4I, NMe4Br, NMe4Cl, LiBr, LiCl, KBr, KCl, CsBr, or CsCl) on Suzuki–Miyaura couplings (see the Supporting Information).

    There is no corresponding record for this reference.
  19. 19

    It is generally acknowledged that defining key transmetalation intermediates is even more complicated with aryltrifluoroborate nucleophiles. See, for example:

    Lennox, A. J. J.; Lloyd-Jones, G. C. The Slow-Release Strategy in Suzuki–Miyaura Coupling. Isr. J. Chem. 2010, 50, 664– 674, and references cited therein  DOI: 10.1002/ijch.201000074
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    19
    The slow-release strategy in Suzuki-Miyaura coupling
    Lennox, Alastair J. J.; Lloyd-Jones, Guy C.
    Israel Journal of Chemistry (2010), 50 (5-6), 664-674CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Despite great advances in metal-catalyzed cross-coupling reactions, their efficacy is often compromised by side reactions, reducing the yield, or requiring a large excess of one component. Suzuki-Miyaura cross-coupling is no exception, as the boronic acid functionality can be susceptible to a range of undesired processes. A no. of methods were developed to mitigate these side reactions, and herein we focus on the slow-release strategy. These conditions involve deployment of a masking reagent that protects the vulnerable boronic acid functionality from degrdn., particularly protodeboronation, while simultaneously facilitating controlled liberation of the active reagent into the catalytic milieu. Under suitably tailored conditions, this dual-action approach ensures that the concn. of the free boronic acid is minimized, thus attenuating its degrdn. but still facilitating transmetallation of the organoboron species with the key organopalladium intermediate.
  20. 20
    (a) Andersen, N. G.; Keay, B. A. 2-Furyl Phosphines as Ligands for Transition-Metal-Mediated Organic Synthesis. Chem. Rev. 2001, 101, 997– 1030,  DOI: 10.1021/cr000024o
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    20a
    2-Furyl Phosphines as Ligands for Transition-Metal-Mediated Organic Synthesis
    Andersen, Neil G.; Keay, Brian A.
    Chemical Reviews (Washington, D. C.) (2001), 101 (4), 997-1030CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review with 177 refs.
    (b) Niemeyer, Z. L.; Milo, A.; Hickey, D. P.; Sigman, M. S. Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes. Nat. Chem. 2016, 8, 610– 617,  DOI: 10.1038/nchem.2501
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    20b
    Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes
    Niemeyer, Zachary L.; Milo, Anat; Hickey, David P.; Sigman, Matthew S.
    Nature Chemistry (2016), 8 (6), 610-617CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The mechanistic foundation behind the identity of a phosphine ligand that best promotes a desired reaction outcome is often nonintuitive, and thus was addressed in numerous exptl. and theor. studies. Multivariate correlations of reaction outcomes using 38 different phosphine ligands were combined with classic potentiometric analyses to study a Suzuki reaction, for which the site selectivity of oxidative addn. is highly dependent on the nature of the phosphine. These studies shed light on the generality of hypotheses regarding the structural influence of different classes of phosphine ligands on the reaction mechanism(s), and deliver a methodol. that should prove useful in future studies of phosphine ligands.
  21. 21
    (a) Tolman, C. A. Electron donor-acceptor properties of phosphorus ligands. Substituent additivity. J. Am. Chem. Soc. 1970, 92, 2953– 2956,  DOI: 10.1021/ja00713a006
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    21a
    Electron donor-acceptor properties of phosphorus ligands. Substituent additivity
    Tolman, Chadwick A.
    Journal of the American Chemical Society (1970), 92 (10), 2953-6CODEN: JACSAT; ISSN:0002-7863.
    A rapid method is described for detg. electron donor-acceptor properties of triply connected P ligands based on the A1 carbonyl stretching frequency of Ni(CO)3L in CH2Cl2. Data are given for 70 ligands and a substituent additivity rule is proposed. Forty-seven substituent parameters χi are derived and found to correlate well with Kabachnik's σ parameters, based on ionization consts. of P acids.
    (b) Otto, S.; Roodt, A. Quantifying the electronic cis effect of phosphine, arsine and stibine ligands by use of rhodium(I) Vaska-type complexes. Inorg. Chim. Acta 2004, 357, 1– 10,  DOI: 10.1016/S0020-1693(03)00436-5
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    21b
    Quantifying the electronic cis effect of phosphine, arsine and stibine ligands by use of rhodium(I) Vaska-type complexes
    Otto, Stefanus; Roodt, Andreas
    Inorganica Chimica Acta (2004), 357 (1), 1-10CODEN: ICHAA3; ISSN:0020-1693. (Elsevier Science B.V.)
    The cis effects of phosphine, arsine and stibine ligands were evaluated by measuring the IR stretching frequency in dichloromethane of the carbonyl ligand in Rh(I) Vaska-type complexes, trans-[RhCl(CO)(L)2]. These data were correlated with those obtained by Tolman for the electronic trans influences in [Ni(L)(CO)3]. The electronic contribution, χFc, of ferrocenyl was detd. as 0.8 from these plots by evaluating PPh2Fc as ligand. To accommodate arsine and stibine ligands an addnl. correction term, to compensate for differences in the donor atom, was added to Tolman's equation for calcn. of the Tolman electronic parameter of phosphine ligands. In the resulting equation: v(CONi) = 2056.1 + Σ3i=1 χi + CL values for CL of CP = 0, CAs = -1.5 and CSb = -3.1 are suggested for phosphine, arsine and stibine ligands, resp. The crystal and mol. structures of trans-[RhCl(CO)(PPh2Fc)2]·2C6H6, trans-[RhCl(CO){P(NMe2)3}2] and trans-[RhCl(CO)(AsPh3)2] are reported. The Tolman cone angles for PPh2Fc and P(NMe2)3 were detd. as 169° and 166°, while the effective cone angles for PPh2Fc, P(NMe2)3 and AsPh3 were detd. as 171°, 168° and 147°, resp.
    (c) Ackermann, M.; Pascariu, A.; Höcher, T.; Siehl, H.-U.; Berge, S. Electronic Properties of Furyl Substituents at Phosphorus and Their Influence on 31P NMR Chemical Shifts. J. Am. Chem. Soc. 2006, 128, 8434– 8440,  DOI: 10.1021/ja057085u
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    21c
    Electronic Properties of Furyl Substituents at Phosphorus and Their Influence on 31P NMR Chemical Shifts
    Ackermann, Marco; Pascariu, Aurelia; Hoecher, Thomas; Siehl, Hans-Ullrich; Berger, Stefan
    Journal of the American Chemical Society (2006), 128 (26), 8434-8440CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The electronic properties of 2-furyl and 3-furyl substituents attached to phosphines and phosphonium salts were studied by IR spectroscopy and exptl. and computational 31P NMR spectroscopy. The heteroarom. systems proved to be electron withdrawing with respect to Ph substituents. However, phosphorus atoms with attached furyl substituents are strongly shielded in NMR. The reason for this phenomenon was studied by solid state 31P MAS NMR expts. The chem. shift tensor was extd., and the orientation within the mols. was detd. The tensor component σ33, which is effected the most by furyl systems, is oriented perpendicular to the P-C bonds of the substituents. P-furyl bonds are shorter than P-Ph bonds. We assume therefore a lower ground-state energy of the mols., because of the electron withdrawing properties of the 2-furyl systems. The σpara component of the 31P NMR magnetic shielding is therefore smaller, which results in an overall increase of the magnetic shielding.
  22. 22

    The observation that oxidative addition is not the turnover-limiting step in this reaction is consistent with previous studies. See, for example:

    Amatore, C.; Jutand, A.; Le Duc, G. Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki–Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base. Chem. - Eur. J. 2011, 17, 2492– 2503, and references cited therein  DOI: 10.1002/chem.201001911
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    22
    Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base
    Amatore, Christian; Jutand, Anny; Le Duc, Gaetan
    Chemistry - A European Journal (2011), 17 (8), 2492-2503CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The mechanism of the reaction of trans-[ArPdX(PPh3)2] (Ar = p-Z-C6H4; Z = CN, F, H; X = I, Br, Cl) with Ar'B(OH)2 (Ar' = p-Z'-C6H4; Z' = CN, H, OMe) has been established in DMF in the presence of the base OH- in the context of real palladium-catalyzed Suzuki-Miyaura reactions. The formation of the cross-coupling product ArAr' and [Pd0(PPh3)3] has been followed through the application of electrochem. techniques. Kinetic data have been obtained for the first time, with detn. of the obsd. rate const., kobs, of the overall reaction. trans-[ArPdX(PPh3)2] is not reactive in the absence of the base. The base OH- plays three roles. It favors the reaction: (1) by formation of trans-[ArPd(OH)(PPh3)2], a key complex which, in contrast to trans-[ArPdX(PPh3)2], reacts with Ar'B(OH)2 (rate-detg. transmetalation), and (2) by unexpected promotion of the reductive elimination from the intermediate trans-[ArPdAr'(PPh3)2], which generates ArAr' and a Pd0 species. Conversely, the base OH- disfavors the reaction by formation of the unreactive anionic Ar'B(OH)3-. As a consequence of these antagonistic effects of OH-, the overall reactivity is controlled by the concn. of OH- and passes through a max. as the concn. of OH- is increased. Therefore, the base favors the rate-detg. transmetalation and unexpectedly also the reductive elimination.
  23. 23

    It was reported that trans-[Pd(PPh3)2I2] was formed in reactions with [Pd(PPh3)4] and (iodoethynyl)benzene (in addition to the expected oxidative addition product). See:

    (a) Weigelt, M.; Becher, D.; Poetsch, E.; Bruhn, C.; Steinborn, D. Zur oxidativen Addition von 1-Halogenalk-1-inen – Synthese und Struktur von Phenylalkinylpalladium-Komplexen. Z. Anorg. Allg. Chem. 1999, 625, 1542– 1547,  DOI: 10.1002/(SICI)1521-3749(199909)625:9<1542::AID-ZAAC1542>3.0.CO;2-9
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    There is no corresponding record for this reference.

    The formation of trans-[Pd(PPh3)2I2] from trans-[Pd(PPh3)2(R)(I)] has also been reported:

    (b) Gulia, N.; Pigulski, B.; Szafert, S. Palladium End-Capped Polyynes via Oxidative Addition of 1-Haloalkynes to Pd(PPh3)4. Organometallics 2015, 34, 673– 682,  DOI: 10.1021/om501105w
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    23b
    Palladium End-Capped Polyynes via Oxidative Addition of 1-Haloalkynes to Pd(PPh3)4
    Gulia, Nurbey; Pigulski, Bartlomiej; Szafert, Slawomir
    Organometallics (2015), 34 (4), 673-682CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    Reported here is the use of 1-haloacetylenes and 1-halopolyynes as synthons for the prepn. of new palladium(II) end-capped polyynes. The 1-haloalkynes were obtained in a series of transformations from para-substituted bromoarenes that included Sonogashira coupling followed by halogenation and chain elongation via Cadiot-Chodkiewicz protocol. The key step for the synthesis of metal complexes was oxidative addn. of 1-haloalkynes to Pd(PPh3)4, which allowed obtaining a series of metal compds. 1-5-CnX with carbon chains up to hexatriyne in 75-100% yield. All the compds. were characterized by NMR and HRMS or elemental anal. The 13C spectra of the 1-haloalkynes showed interesting, although expected, shifts of the carbon chain atoms close to the halogen termini. X-ray crystal structures were obtained for three polyynes-two butadiynes (2-C4[Pd]Br and 3-C4[Pd]Br) and one hexatriyne (1-C6[Pd]Br)-and the latter is the first reported X-ray crystal structure of palladium end-capped hexatriyne.

    trans-[Pd(PPh3)2I2] was also formed in reactions with [Pd(PPh3)4] and 9-iodo-m-carborane. See:

    (c) Marshall, W. J.; Young, R. J., Jr.; Grushin, V. V. Mechanistic Features of Boron–Iodine Bond Activation of B–Iodocarboranes. Organometallics 2001, 20, 523– 533,  DOI: 10.1021/om0008575
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  24. 24

    We were also able to isolate and characterize trans-[Pd(PPh3)2I2]. The spectroscopic data obtained on this compound were consistent both with equivalent data reported in the literature and also with an authentic sample of trans-[Pd(PPh3)2I2] that we prepared via a literature procedure:

    Hahn, F. E.; Lugger, T.; Beinhoff, M. Palladium(II) Complexes with Benzoxazol-2-ylidene Ligands: Crystal Structures of trans-Chloro(benzoxazol-2-ylidene)bis(triphenylphosphine)palladium(II) Chloride and cis-Diiodo(benzoxazol-2-ylidene)(triphenylphosphine)palladium(II). Z. Naturforsch. B Chem. Sci. 2004, 59, 196– 201
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    24
    Palladium(II) complexes with benzoxazol-2-ylidene ligands: crystal structures of trans-chloro(benzoxazol-2-ylidene)bis(triphenylphosphine)palladium(II) chloride and cis-diiodo(benzoxazol-2-ylidene)(triphenylphosphine)palladium(II)
    Hahn, F. Ekkehardt; Luegger, Thomas; Beinhoff, Matthias
    Zeitschrift fuer Naturforschung, B: Chemical Sciences (2004), 59 (2), 196-201CODEN: ZNBSEN; ISSN:0932-0776. (Verlag der Zeitschrift fuer Naturforschung)
    The Pd(II) complexes trans-[PdCl(L)(PPh3)2]Cl, 5, and cis-[PdI2(L)PPh3], 7, (L = benzoxazol-2-ylidene) were synthesized by treatment of trans-[PdX2(PPh3)2] (4: X = Cl, 6: X = iodo) with 2-(trimethylsiloxy)phenyl isocyanide 1, and subsequent hydrolysis of the Si-O bond. The crystal structures of 5 and 7·CH2Cl2 were established by x-ray diffraction. NMR and IR studies indicate that the unexpected cis-configuration of 7 obtained from trans-[PdI2(PPh3)2] is not the result of a soln. equil. between the cis and the trans isomers.
  25. 25

    When the study shown in eq 2 was performed in DMF/H2O instead of n-PrOH/H2O, similar results were obtained. When the experiment shown in eq 2 was performed using p-bromotoluene instead of p-iodotoluene, 31P NMR spectroscopy indicated that trans-[Pd(PPh3)2Br2] was not present in the reaction mixture. trans-[Pd(PPh3)2Br2] was also not observed in equivalent experiments performed in DMF/H2O.

    There is no corresponding record for this reference.
  26. 26
    Carrow, B. P.; Hartwig, J. F. Distinguishing Between Pathways for Transmetalation in Suzuki–Miyaura Reactions. J. Am. Chem. Soc. 2011, 133, 2116– 2119,  DOI: 10.1021/ja1108326
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    26
    Distinguishing between pathways for transmetalation in Suzuki-Miyaura reactions
    Carrow, Brad P.; Hartwig, John F.
    Journal of the American Chemical Society (2011), 133 (7), 2116-2119CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Transmetalation of arylpalladium complexes proceeds rather via palladium hydroxo complex and arylboronic acid pathway, than via arylpalladium halide and aryl(trihydroxo)borate. A systematic study of the stoichiometric reactions of isolated arylpalladium hydroxo and halide complexes with arylboronic acids and aryltrihydroxyborates is performed to evaluate the relative rates of the two reaction pathways commonly proposed to account for transmetalation in the Suzuki-Miyaura reaction. On the basis of the relative populations of the palladium and organoboron species generated under conditions common for the catalytic process and the obsd. rate consts. for the stoichiometric reactions between the two classes of reaction components, we conclude that the reaction of a palladium hydroxo complex with boronic acid, not the reaction of a palladium halide complex with trihydroxyborate, accounts for transmetalation in catalytic Suzuki-Miyaura reactions conducted with weak base and aq. solvent mixts.
  27. 27

    For a recent review on transmetalation in the Suzuki–Miyaura cross-coupling, see:

    Lennox, A. J. J.; Lloyd-Jones, G. C. Transmetalation in the Suzuki-Miyaura coupling: the fork in the trail. Angew. Chem., Int. Ed. 2013, 52, 7362– 7370,  DOI: 10.1002/anie.201301737
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    27
    Transmetalation in the Suzuki-Miyaura Coupling: The Fork in the Trail
    Lennox, Alastair J. J.; Lloyd-Jones, Guy C.
    Angewandte Chemie, International Edition (2013), 52 (29), 7362-7370CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The Suzuki-Miyaura coupling is one of the few transition-metal-catalyzed C-C bond-forming reactions that were used in applications ranging from discovery chem. to manufg. processes. Although coupling proceeds through the generic three-stage oxidative addn., transmetalation, reductive elimination' sequence, there are a no. of features that differentiate the Suzuki-Miyaura process from other transition-metal-catalyzed cross-couplings. Most of these features are centered around, or are a consequence of, activation of the boron reagent for transmetalation through one or both of two distinct pathways. This review focuses on the evidence that was presented for this fork in the trail, and the potential to apply such mechanistic insight to the design of reaction conditions.
  28. 28

    For selected studies on transmetalation in the Suzuki–Miyaura cross-coupling, see: refs (22and26).

    (a) Thomas, A. A.; Wang, H.; Zahrt, A. F.; Denmark, S. E. Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki–Miyaura Reaction. J. Am. Chem. Soc. 2017, 139, 3805– 3821,  DOI: 10.1021/jacs.6b13384
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    28a
    Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki-Miyaura Reaction
    Thomas, Andy A.; Wang, Hao; Zahrt, Andrew F.; Denmark, Scott E.
    Journal of the American Chemical Society (2017), 139 (10), 3805-3821CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The existence of the oft-invoked intermediates contg. the crucial Pd-O-B subunit, the "missing link", has been established in the Suzuki-Miyaura cross-coupling reaction. The use of low-temp., rapid injection NMR spectroscopy (RI-NMR), kinetic studies, and computational anal. has enabled the generation, observation, and characterization of these highly elusive species. The ability to confirm the intermediacy of Pd-O-B-contg. species provided the opportunity to clarify mechanistic aspects of the transfer of the org. moiety from boron to palladium in the key transmetalation step. Specifically, these studies establish the identity of two different intermediates contg. Pd-O-B linkages, a tri-coordinate (6-B-3) boronic acid complex and a tetra-coordinate (8-B-4) boronate complex, both of which undergo transmetalation leading to the cross-coupling product. Two distinct mechanistic pathways have been elucidated for stoichiometric reactions of these complexes: (1) transmetalation via an unactivated 6-B-3 intermediate that dominates in the presence of an excess of ligand, and (2) transmetalation via an activated 8-B-4 intermediate that takes place with a deficiency of ligand.
    (b) Thomas, A. A.; Denmark, S. E. Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link. Science 2016, 352, 329– 332,  DOI: 10.1126/science.aad6981
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    28b
    Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link
    Thomas, Andy A.; Denmark, Scott E.
    Science (Washington, DC, United States) (2016), 352 (6283), 329-332CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Despite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temp. rapid injection NMR spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species contg. palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsatd. palladium center in the crit. transmetalation event.
    (c) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque, G. The Transmetalation Process in Suzuki–Miyaura Reactions: Calculations Indicate Lower Barrier via Boronate Intermediate. ChemCatChem 2014, 6, 3132– 3138,  DOI: 10.1002/cctc.201402326
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    28c
    The transmetalation process in Suzuki-Miyaura reactions: Calculations indicate lower barrier via boronate Intermediate
    Ortuno, Manuel A.; Lledos, Agusti; Maseras, Feliu; Ujaque, Gregori
    ChemCatChem (2014), 6 (11), 3132-3138CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Recent exptl. reports have called into question the validity of the boronate mechanism (through a R-B(OH)3- intermediate) for the transmetalation step in the Suzuki-Miyaura cross-coupling, favoring instead the palladium hydroxo pathway (through an [LnPd(R')(OH)] intermediate). Herein we report DFT calcns. with the M06 functional performed on realistic model systems, including a combination of explicit solvent mols. along with a continuum method. These computational results support the boronate mechanism. The mechanistic proposal is shown to be compatible with the available exptl. evidence.
    (d) Lima, C. F. R. A. C.; Rodrigues, A. S. M. C.; Silva, V. L. M.; Silva, A. M. S.; Santos, L. M. N. B. F. Role of the Base and Control of Selectivity in the Suzuki–Miyaura Cross-Coupling Reaction. ChemCatChem 2014, 6, 1291– 1302,  DOI: 10.1002/cctc.201301080
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    28d
    Role of the Base and Control of Selectivity in the Suzuki-Miyaura Cross-Coupling Reaction
    Lima, Carlos F. R. A. C.; Rodrigues, Ana S. M. C.; Silva, Vera L. M.; Silva, Artur M. S.; Santos, Luis M. N. B. F.
    ChemCatChem (2014), 6 (5), 1291-1302CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The outcome of the Suzuki-Miyaura cross-coupling for the direct competition reaction between two boronic acids was evaluated under routine synthesis conditions. The reaction selectivity depends on the amt. of the base used, with fewer bases favoring the reactivity of the boronic acid with lower pKa (stronger acid). The dependence of the reaction selectivity on base stoichiometry increases with the increase in the difference in the pKa values of the competing boronic acids. These results confirm a relation between acid-base chem. and the Suzuki-Miyaura reaction catalytic cycle. Also, under these specific conditions, the most reactive organoboron species toward transmetalation is the borate anion R-B(OH)3- instead of the neutral boronic acid R-B(OH)2. Hence, the main role of the base in the reaction mechanism is to increase the reactivity of the boronic acid toward the Pd-halide complex by converting it into the resp. organoborate. Boric acid, an important reaction byproduct, affects the selectivity in the Suzuki reaction because its gradual formation in the reaction medium disturbs the acid-base equil.
    (e) Amatore, C.; Jutand, A.; Le Duc, G. Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH–, CO32–) as Modulated by their Countercations (Na+, Cs+, K+) in Palladium-Catalyzed Suzuki–Miyaura Reactions. Chem. - Eur. J. 2012, 18, 6616– 6625,  DOI: 10.1002/chem.201200516
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    28e
    Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH-, CO32-) as Modulated by their Countercations (Na+, Cs+, K+) in Palladium-Catalyzed Suzuki-Miyaura Reactions
    Amatore, Christian; Jutand, Anny; Le Duc, Gaetan
    Chemistry - A European Journal (2012), 18 (21), 6616-6625, S6616/1-S6616/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The mechanism of the reaction of trans-ArPdBrL2 (Ar = p-Z-C6H4, Z = CN, H; L = PPh3) with Ar'B(OH)2 (Ar' = p-Z'-C6H4, Z' = H, CN, MeO), which is a key step in the Suzuki-Miyaura process, was established in DMF with two bases, acetate (Bu4NOAc) or carbonate (Cs2CO3) and compared with that of hydroxide (Bu4NOH). As anionic bases are inevitably introduced with a countercation M+ (e.g., M+OH-), the role of cations in the transmetalation/reductive elimination was 1st studied. Cations M+ (Na+, Cs+, K+) are not innocent since they induce an unexpected decelerating effect in the transmetalation via their complexation to the OH ligand in the reactive ArPd(OH)L2, partly inhibiting its transmetalation with Ar'B(OH)2. A decreasing reactivity order is obsd. when M+ is assocd. with OH-: Bu4N+> K+> Cs+> Na+. Acetates give trans-ArPd(OAc)L2, which does not undergo transmetalation with Ar'B(OH)2. This explains why acetates are not used as bases in Suzuki-Miyaura reactions that involve Ar'B(OH)2. Carbonates (Cs2CO3) give rise to slower reactions than those performed from Bu4NOH at the same concn., even if the reactions are accelerated in the presence of H2O due to the generation of OH-. The mechanism of the reaction with carbonates is then similar to that established for Bu4NOH, involving ArPd(OH)L2 in the transmetalation with Ar'B(OH)2. Due to the low concn. of OH- generated from CO32- in H2O, both transmetalation and reductive elimination result slower than those performed from Bu4NOH at equal concns. as Cs2CO3. Therefore, the overall reactivity is finely tuned by the concn. of the common base OH- and the ratio [OH-]/[Ar'B(OH)2]. Hence, the anionic base (pure OH- or OH- generated from CO32-) assocd. with its countercation (Na+, Cs+, K+) plays four antagonist kinetic roles: acceleration of the transmetalation by formation of the reactive ArPd(OH)L2, acceleration of the reductive elimination, deceleration of the transmetalation by formation of unreactive Ar'B(OH)3- and by complexation of ArPd(OH)L2 by M+.
    (f) Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Role of a base in Suzuki-Miyaura reaction. Russ. J. Gen. Chem. 2011, 81, 1573– 1574,  DOI: 10.1134/S1070363211070334
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    28f
    Role of a base in Suzuki-Miyaura reaction
    Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V.
    Russian Journal of General Chemistry (2011), 81 (7), 1573-1574CODEN: RJGCEK; ISSN:1070-3632. (MAIK Nauka/Interperiodica)
    There is no expanded citation for this reference.
    (g) Butters, M.; Harvey, J.; Jover, J.; Lennox, A.; Lloyd-Jones, G.; Murray, P. Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride. Angew. Chem., Int. Ed. 2010, 49, 5156– 5160,  DOI: 10.1002/anie.201001522
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    28g
    Aryl Trifluoroborates in Suzuki-Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride
    Butters, Mike; Harvey, Jeremy N.; Jover, Jesus; Lennox, Alastair J. J.; Lloyd-Jones, Guy C.; Murray, Paul M.
    Angewandte Chemie, International Edition (2010), 49 (30), 5156-5160, S5156/1-S5156/68CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The Suzuki-Miyaura coupling (SM) of 4-FC6H4BF3- K+ (I) with 3,5-(CF3)2C6H3Br was studied in a toluene/ water biphasic soln., and in a THF/ water soln.; both systems are commonly employed for the SM of trifluoroborates. The reactions in toluene/water, failed to go to completion: turnover ceased after 6 h, affording 55% of the base-catalyzed protodeboronation product PhF and ≤ 32% of coupling product 4-[3,5-(CF3)2C6H3]C6H4F (II). In aq. THF the reaction proceeded much more efficiently (5.5 h; > 95% yield of II), with few side products (< 0.1-2% ), even when the reaction was performed in air. But reaction of 4-C6H4B(OH)2 under identical conditions, gave II in variable yield, and afforded substantially more of side products 4-(4-FC6H4)C6H44-F and 4-FC6H4OH (2-40% ), compared to trifluoroborate substrate I. The reaction intermediates were established and a mechanism, supported by B3LYP calcns. was proposed for the SM.
    (h) Huang, Y.-L.; Weng, C.-M.; Hong, F.-E. Density Functional Studies on Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions Assisted by N- or P-Chelating Ligands. Chem. - Eur. J. 2008, 14, 4426– 4434,  DOI: 10.1002/chem.200800011
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    28h
    Density functional studies on palladium-catalyzed Suzuki-Miyaura cross-coupling reactions assisted by N- or P-chelating ligands
    Huang, Yi-Luen; Weng, Chia-Ming; Hong, Fung-E.
    Chemistry - A European Journal (2008), 14 (14), 4426-4434CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    DFT studies with the B3LYP functional have been carried out on the Suzuki-Miyaura cross-coupling reactions of Ph chloride and phenylboronic acid catalyzed by palladium complexes with N- or P-chelating ligands. The full catalytic cycle, from the addn. of reactants to the catalyst to the release of the cross-coupled product from the complexed intermediate, has been examd. The stages within the cycle, such as oxidative addn., transmetalation, and reductive elimination, were validated by linking the mechanistically relevant intermediates and transition states. Various derivs. of diimine, diphosphine, and diamine were considered as potential model ligands. The catalytic reaction employing diimine as the chelating ligand has been verified as the one with the most energetically feasible route.
    (i) Braga, A. A. C.; Ujaque, G.; Maseras, F. A DFT Study of the Full Catalytic Cycle of the Suzuki–Miyaura Cross-Coupling on a Model System. Organometallics 2006, 25, 3647– 3658,  DOI: 10.1021/om060380i
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    28i
    A DFT Study of the Full Catalytic Cycle of the Suzuki-Miyaura Cross-Coupling on a Model System
    Braga, Ataualpa A. C.; Ujaque, Gregori; Maseras, Feliu
    Organometallics (2006), 25 (15), 3647-3658CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    A computational study with the Becke3LYP DFT functional is carried out on the cross-coupling reaction of vinyl bromide, H2C:CHBr and vinylboronic acid, H2C:CHB(OH)2 catalyzed by Pd diphosphine [Pd(PH3)2] in the presence of an excess of OH- base. The full catalytic cycle is computed, starting from the sepd. reactants and the catalyst and finishing with the cross-coupled product and the regeneration of the catalyst. The different stages in the cycle (oxidative addn., isomerization, transmetalation, reductive elimination) were characterized through calcn. of the corresponding intermediates and transition states. Different alternative mechanisms are considered, depending on the no. of phosphine ligands at Pd, and on the cis or trans isomery around the metal center. The results indicate the existence of a no. of competitive pathways of reasonably low energy.
    (j) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledós, A.; Maseras, F. Computational study of the transmetalation process in the Suzuki–Miyaura cross-coupling of aryls. J. Organomet. Chem. 2006, 691, 4459– 4466,  DOI: 10.1016/j.jorganchem.2006.02.015
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    28j
    Computational study of the transmetalation process in the Suzuki-Miyaura cross-coupling of aryls
    Braga, Ataualpa A. C.; Morgon, Nelson H.; Ujaque, Gregori; Lledos, Agusti; Maseras, Feliu
    Journal of Organometallic Chemistry (2006), 691 (21), 4459-4466CODEN: JORCAI; ISSN:0022-328X. (Elsevier Ltd.)
    The transmetalation step of the Suzuki-Miyaura cross-coupling between aryl groups is analyzed by DFT calcns. with the Becke3LYP functional. The halide considered is PhBr, and the organoboronic acid is PhB(OH)2. The model catalyst is Pd(PH3)2, and the base, OH-. The transmetalation is considered to start from the Pd(Ph)(PH3)2Br complex, the product of the oxidative addn. The results are compared with those of a previous study on the analogous reaction with vinyl groups, and it is shown that the reaction mechanism is very similar.
    (k) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. Computational Characterization of the Role of the Base in the Suzuki–Miyaura Cross-Coupling Reaction. J. Am. Chem. Soc. 2005, 127, 9298– 9307,  DOI: 10.1021/ja050583i
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    Computational characterization of the role of the base in the Suzuki-Miyaura cross-coupling reaction
    Braga, Ataualpa A. C.; Morgon, Nelson H.; Ujaque, Gregori; Maseras, Feliu
    Journal of the American Chemical Society (2005), 127 (25), 9298-9307CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The role of the base in the transmetalation step of the Suzuki-Miyaura cross-coupling reaction is analyzed computationally by means of DFT calcns. with the Becke3LYP functional. The model system studied consists of Pd(CH:CH2)(PH3)2Br as the starting catalyst complex, CH2:CHB(OH)2 as the organoboronic acid, and OH- as the base. The two main mechanistic proposals, consisting of the base attacking first either the palladium complex or the organoboronic acid, are evaluated through geometry optimization of the corresponding intermediates and transition states. Supplementary calcns. are carried out on the uncatalyzed reaction and on a process where the starting complex is Pd(CH:CH2)(PH3)2(OH). These calcns., considered together with available exptl. data, strongly suggest that the main mechanism of transmetalation in the catalytic cycle starts with the reaction of the base and the organoboronic acid.
    (l) Miyaura, N. Cross-coupling reaction of organoboron compounds via base-assisted transmetalation to palladium(II) complexes. J. Organomet. Chem. 2002, 653, 54– 57,  DOI: 10.1016/S0022-328X(02)01264-0
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    28l
    Cross-coupling reaction of organoboron compounds via base-assisted transmetalation to palladium(II) complexes
    Miyaura, Norio
    Journal of Organometallic Chemistry (2002), 653 (1-2), 54-57CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science B.V.)
    A review. Until recently, organoboronic acids have been of limited use in org. synthesis due to their low reactivity for ionic reactions. During the past two decades, however, it has become increasingly clear that they are valuable reagents capable of undergoing many carbon-carbon bond formations in org. syntheses. In 1979, catalytic carbon-carbon bond formation via transmetalation between organoboron compds. and palladium(II) halides was found to proceed in the presence of a base.
    (m) Matos, K.; Soderquist, J. A. Alkylboranes in the Suzuki–Miyaura Coupling:  Stereochemical and Mechanistic Studies. J. Org. Chem. 1998, 63, 461– 470,  DOI: 10.1021/jo971681s
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    (n) Aliprantis, A. O.; Canary, J. W. Observation of Catalytic Intermediates in the Suzuki Reaction by Electrospray Mass Spectrometry. J. Am. Chem. Soc. 1994, 116, 6985– 6986,  DOI: 10.1021/ja00094a083
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    Observation of Catalytic Intermediates in the Suzuki Reaction by Electrospray Mass Spectrometry
    Aliprantis, Antonios O.; Canary, James W.
    Journal of the American Chemical Society (1994), 116 (15), 6985-6CODEN: JACSAT; ISSN:0002-7863.
    Pyridyl bromides, e.g., I (R = H, CHO, X = 2, 3-Br), couple with phenylboronic acids II (R1 = H, Me, R2 = H, Me) in the presence of Pd[PPh3]4 catalyst to give (2- and 3-aryl-substituted)pyridines III. Intermdiate formation of palladium complexes for this coupling reaction, e.g., [(pyrH)(R1R2C6H3)Pd(PPh3)2]+, are obsd. by electrospray Mass Spectrometry.
    (o) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. Mechanistic Studies of the Suzuki Cross-Coupling Reaction. J. Org. Chem. 1994, 59, 8151– 8156,  DOI: 10.1021/jo00105a036
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    Mechanistic Studies of the Suzuki Cross-Coupling Reaction
    Smith, George B.; Dezeny, George C.; Hughes, David L.; King, Anthony O.; Verhoeven, Thomas R.
    Journal of Organic Chemistry (1994), 59 (26), 8151-6CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The key step in the synthesis of the drug losartan is a palladium-catalyzed cross-coupling reaction of an aryl bromide and a boronic acid. The reaction scheme was defined in kinetic studies using HPLC, and computer simulation served to depict the time dependence of the concns. of palladium species, which were not obsd. exptl. Two catalyst poisons were identified and characterized. One was an isomeric impurity of the aryl bromide; the other was formed in the reaction mixt. upon hydrolysis of the boronic acid and two of its impurities.
    (p) Thomas, A. A.; Zahrt, A. F.; Delaney, C. P.; Denmark, S. E. Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations. J. Am. Chem. Soc. 2018, 140, 4401– 4416,  DOI: 10.1021/jacs.8b00400
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    28p
    Elucidating the Role of the Boronic Esters in the Suzuki-Miyaura Reaction: Structural, Kinetic, and Computational Investigations
    Thomas, Andy A.; Zahrt, Andrew F.; Delaney, Connor P.; Denmark, Scott E.
    Journal of the American Chemical Society (2018), 140 (12), 4401-4416CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The Suzuki-Miyaura reaction is the most practiced palladium-catalyzed, cross-coupling reaction because of its broad applicability, low toxicity of the metal (B), and the wide variety of com. available boron substrates. A wide variety of boronic acids and esters, each with different properties, have been developed for this process. Despite the popularity of the Suzuki-Miyaura reaction, the precise manner in which the org. fragment is transferred from boron to palladium has remained elusive for these reagents. Herein, we report the observation and characterization of pretransmetalation intermediates generated from a variety of commonly employed boronic esters. The ability to confirm the intermediacy of pretransmetalation intermediates provided the opportunity to clarify mechanistic aspects of the transfer of the org. moiety from boron to palladium in the key transmetalation step. A series of structural, kinetic, and computational investigations revealed that boronic esters can transmetalate directly without prior hydrolysis. Furthermore, depending on the boronic ester employed, significant rate enhancements for the transfer of the B-aryl groups were obsd. Overall, two crit. features were identified that enable the transfer of the org. fragment from boron to palladium: (1) the ability to create an empty coordination site on the palladium atom and (2) the nucleophilic character of the ipso carbon bound to boron. Both of these features ultimately relate to the electron d. of the oxygen atoms in the boronic ester.
  29. 29

    Lloyd-Jones and Lennox note that “Elucidation of the dominant pathway to transmetalation is not at all straightforward: one must establish the kinetically active boron and palladium intermediates, and they may not necessarily be the most abundant species present in the medium.”. (27)

    There is no corresponding record for this reference.
  30. 30

    Detailed studies exploring the transmetalation of trans-[Pd(PPh3)2(Ph)(I)] with p-tol-B(OH)3K (and 18-crown-6) and Pd(PPh3)(Ph)(μ-OH)]2 with p-tol-B(OH)2 under stoichiometric conditions were performed in THF/H2O solvent mixtures. (26) Extensive studies employing electrochemical methods to investigate the transmetalation of trans-[Pd(PPh3)2(Ar)(X)] with Ar-B(OH)2 (n-Bu4NOH as the base) under catalytic conditions were performed in a DMF/MeOH solvent mixture. (22)

    There is no corresponding record for this reference.
  31. 31

    Germane observations regarding the adverse effect of PPh3 have also been reported in Pd-catalyzed Stille cross-couplings; see ref (9).

    (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C., Jr Palladium catalysis in cephalosporin chemistry: general methodology for the synthesis of cephem side chains. J. Org. Chem. 1990, 55, 5833– 5847,  DOI: 10.1021/jo00310a014
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    Farina, Vittorio; Baker, Stephen R.; Benigni, Daniel A.; Hauck, Sheila I.; Sapino, Chester, Jr.
    Journal of Organic Chemistry (1990), 55 (23), 5833-47CODEN: JOCEAH; ISSN:0022-3263.
    The Pd-catalyzed coupling of 3-(triflyloxy)cephems with organotin compds.leads to 3-alkenyl-, 3-alkynyl-, and 3-arylcephems under exceptionally mild conditions. While this approach was not satisfactory for 3-allylcephems, the related coupling of easily available 3-(chloromethyl)cephems with stannanes provided a high-yielding route to such 3-allylcephems and also to 3-benzyl- and 3-homoallylcephems. The choice of the catalyst was crucial in both cases. PPh3-based catalysts were quite unsatisfactory. A much better ligand in this respect was tri(2-furyl)phosphine, which is introduced as a useful new ligand in organopalladium chem. The effect of this ligand on coupling rates is discussed. It is suggested that reduced electron d. at Pd enhances the rate of the transmetalation, considered to be the rate-detg. step in these coupling reactions. Cases of unexpected transfer order among unsym. substituted stannanes were obsd., as well as a complex coupling reaction between (chloromethyl)cephems and alkynylstannanes. These new facets of the Stille coupling, as well as the potential of this chem. for the development of new cephalosporin antibiotics, are discussed.
    (b) Scott, W. J.; Stille, J. K. Palladium-catalyzed coupling of vinyl triflates with organostannanes. Synthetic and mechanistic studies. J. Am. Chem. Soc. 1986, 108, 3033– 3040,  DOI: 10.1021/ja00271a037
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    The palladium-catalyzed coupling reaction of vinyl triflates, e.g., (I), with acetylenic, vinyl, allyl, and alkyl tin reagents in the presence of LiCl or another suitable salt takes place in high yields under mild reaction conditions; however, benzyl and Ph tin reagents give poor yield of coupled product. The utilization of a tin or silicon hydride reagent in place of the organotin partner yields the alkene by reductive cleavage of the triflate group. The palladium-catalyzed reaction of vinyl triflates with Me3SnSnMe3 gives vinyl stannanes in high yields. Regioselectively formed vinyl triflates can be used to produce 1,3-dienes as the regioisomeric coupled products.
  32. 32

    The reaction of trans-[(Pd(PPh3)2(p-NCC6H4)(X)] (X = Cl, Br, I) with PhB(OH)2 was studied as a function of initial hydroxide concentration in DMF. In this way, the following reactivity order was determined: [Pd–I] > [Pd–Br] > [Pd–Cl]. (22)

    There is no corresponding record for this reference.
  33. 33

    For a study focused on the reactivity of Pd(0) complexes derived from mixtures of Pd(dba)2 and PPh3 and P(2-furyl)3 ligands, see for example:

    Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.; Khalil, F.; Chahdi, F. O. Comparative Reactivity of Palladium(0) Complexes Generated in Situ in Mixtures of Triphenylphosphine or Tri-2-furylphosphine and Pd(dba)2. Organometallics 1998, 17, 2958– 2964,  DOI: 10.1021/om971064u
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    Comparative Reactivity of Palladium(0) Complexes Generated in Situ in Mixtures of Triphenylphosphine or Tri-2-furylphosphine and Pd(dba)2
    Amatore, Christian; Jutand, Anny; Meyer, Gilbert; Atmani, Hamid; Khalil, Fouad; Chahdi, Fouad Ouazzani
    Organometallics (1998), 17 (14), 2958-2964CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
    For PPh3, mixts. of Pd(dba)2 and nTFP (TFP = tri-2-furylphosphine, n ≥ 2) in DMF and THF (S) lead to the formation of Pd(dba)(TFP)2, SPd(TFP)3 in equil. with SPd(TFP)2. The substitution of dba by the phosphine in Pd(dba)L2 to form SPdL3 is easier for L = TPF than for L = PPh3. The less ligated complex SPd(TFP)2 is the reactive species in the oxidative addn. with Ph iodide. In THF, {Pd(dba)2 + nTFP}, a mixt. often used as a catalyst promoter in several synthetic org. reactions, is found to be less reactive than {Pd(dba)2 + nPPh3} for small values of n (n = 2 or 4) whereas it is more reactive for higher values of n (n > 6). Conversely, in DMF, {Pd(dba)2 + nTFP} is always found to be more reactive than {Pd(dba)2 + nPPh3} whatever n (n ≥ 2).
  34. 34

    Farina and Krishnan also state “When a large excess of P(2-furyl)3 was added to a solution of trans-[Pd(PPh3)2(Ph)(I)] and PPh3, no trace of trans-[Pd{P(2-furyl)3}2(Ph)(I)] was observed, the corresponding signal for P(2-furyl)3 being the only new peak in the spectrum.”. (9)

    There is no corresponding record for this reference.

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  16. Gyandshwar Kumar Rao, Anirban Dutta, Nisha Yadav, Preeti Oswal, Arun Kumar, Ajai K. Singh. Palladium( ii )-complexes of bi- and tri-dentate phosphine ligands: precursor for palladium–phosphorous nanoparticles and activity towards Suzuki–Miyaura coupling. New Journal of Chemistry 2023, 47 (9) , 4218-4227. https://doi.org/10.1039/D2NJ05357H
  17. Sheng-Bo Hong, Lan-Chang Liang. Aqueous Suzuki couplings mediated by a hydrophobic catalyst. RSC Advances 2022, 12 (44) , 28862-28866. https://doi.org/10.1039/D2RA05230J
  18. Sepideh Samiee, Ahmadreza Shiralinia, Elham Hoveizi, Robert W. Gable. A new Pd(II) complex containing acetophenone oxime and 1,3-Bis(diphenylphosphino)propane ligands; crystal structure, catalytic activity, molecular docking and in vitro cytotoxic evaluation. Inorganica Chimica Acta 2022, 538 , 120964. https://doi.org/10.1016/j.ica.2022.120964
  19. Suvam Bhattacharjee, Sudip Laru, Alakananda Hajra. Remote difunctionalization of 2 H -indazoles using Koser's reagents. Chemical Communications 2022, 58 (7) , 981-984. https://doi.org/10.1039/D1CC06129A
  20. Kohtaro Osakada, Yasushi Nishihara. Transmetalation of boronic acids and their derivatives: mechanistic elucidation and relevance to catalysis. Dalton Transactions 2022, 51 (3) , 777-796. https://doi.org/10.1039/D1DT02986J
  21. M. R. Crampton. Nucleophilic Aromatic Substitution. 2021, 167-189. https://doi.org/10.1002/9781119531975.ch5a
  22. Angus Olding, Curtis C. Ho, Allan J. Canty, Nigel T. Lucas, James Horne, Alex C. Bissember. Synthesis of Arylpalladium(II) Boronates: Confirming the Structure and Chemical Competence of Pre‐transmetalation Intermediates in the Suzuki–Miyaura Reaction. Angewandte Chemie 2021, 133 (27) , 15023-15027. https://doi.org/10.1002/ange.202104802
  23. Angus Olding, Curtis C. Ho, Allan J. Canty, Nigel T. Lucas, James Horne, Alex C. Bissember. Synthesis of Arylpalladium(II) Boronates: Confirming the Structure and Chemical Competence of Pre‐transmetalation Intermediates in the Suzuki–Miyaura Reaction. Angewandte Chemie International Edition 2021, 60 (27) , 14897-14901. https://doi.org/10.1002/anie.202104802
  24. Amine Bourouina, Valérie Meille, Claude de Bellefon. About Solid Phase vs. Liquid Phase in Suzuki-Miyaura Reaction. Catalysts 2019, 9 (1) , 60. https://doi.org/10.3390/catal9010060
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  • Abstract

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    Scheme 1

    Scheme 1. Results of Pd-Catalyzed Suzuki–Miyaura Couplings Reported by Novak and Wallow in 1994 (8)
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    Figure 1

    Figure 1. Formation of biaryl 3 in respective Suzuki–Miyaura couplings employing iodide 1 (red) and bromide 2 (blue) at 50 °C (conditions: Table 1, entry 5). Each data point represents the average of two experiments with yields determined via GC with the aid of a calibrated internal standard.

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    Figure 2

    Figure 2. Two fundamental pathways leading to pretransmetalation intermediate C in Suzuki–Miyaura couplings.

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    Scheme 2

    Scheme 2. Investigating the Chemical Competence of trans-[Pd(PPh3)2(p-tol)(Br)] in Suzuki–Miyaura Couplings
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    aDetermined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

    Figure 3

    Figure 3. Formation of biaryl 3 in reactions employing trans-[Pd(PPh3)2(p-tol)(I)] (4a) (solid red line), [Pd–I] 4a + 6 equiv of PPh3 (dashed red line), trans-[Pd(PPh3)2(p-tol)(Br)] (4b) (solid blue line), [Pd–Br] 4b + 6 equiv PPh3 (dashed blue line), [Pd–OH] 5 (solid black line), and [Pd–OH] 5 + 6 equiv PPh3 (dashed black line). A 0.5 equiv amount of [Pd(PPh3)(p-tol)(μ-OH)]2 was used in these experiments (and no Na2CO3 was used in these reactions). Yields were determined via GC with the aid of a calibrated internal standard (average of two experiments).

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    Figure 4

    Figure 4. Formation of biaryl 3 in reactions employing: 6% PPh3 (red), 6% P(2-furyl)3 (blue), and 3% PPh3 and 3% P(2-furyl)3 (black). Yields were determined via GC with the aid of a calibrated internal standard (average of two experiments).

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    Scheme 3

    Scheme 3. Investigating the Chemical Competence of trans-[Pd{P(2-furyl)3}2(p-tol)(I)] in Suzuki–Miyaura Couplings
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    aDetermined via GC with the aid of a calibrated internal standard (average of two experiments). Yields after 0.25 h are given in parentheses.

  • References

    This article references 34 other publications.

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      A review was given summarizing large-scale applications of transition metal-catalyzed coupling reactions for the manuf. of drug components in pharmaceutical industry. In addn. to showcasing bond-forming chemistries, focus was given on reaction work-ups and purifications that purge metal catalysts to provide material of sufficient purity. Most of the examples presented originated on process chem. groups in pharmaceutical companies and were selected based on 2 criteria: (a) the transformation was realized on a large scale (at least 100 mmol); (b) the article contains a detailed exptl. procedure. A list of publications reporting coupling reactions for the large-scale synthesis of pharmaceuticals, but do not provide exptl. procedures was also included.
      (d) Torborg, C.; Beller, M. Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries. Adv. Synth. Catal. 2009, 351, 3027– 3043,  DOI: 10.1002/adsc.200900587
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      Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries
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      Advanced Synthesis & Catalysis (2009), 351 (18), 3027-3043CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Palladium-catalyzed coupling reactions have become a central tool for the synthesis of biol. active compds. both in academia and industry. Most of these transformations make use of easily available substrates and allow for a shorter and more selective prepn. of substituted arenes and heteroarenes compared to non-catalytic pathways. Notably, mol.-defined palladium catalysts offer high chemoselectivity and broad functional group tolerance. Considering these advantages, it is not surprising that several palladium-catalyzed coupling reactions have been implemented in the last decade into the industrial manuf. of pharmaceuticals and fine chems. In this review different examples from 2001-2008 are highlighted, which have been performed at least on a kilogram scale in the chem. and pharmaceutical industries.
      (e) Corbet, J.-P.; Mignani, G. Selected Patented Cross-Coupling Reaction Technologies. Chem. Rev. 2006, 106, 2651– 2710,  DOI: 10.1021/cr0505268
      1e
      Selected patented cross-coupling reaction technologies
      Corbet, Jean-Pierre; Mignani, Gerard
      Chemical Reviews (Washington, DC, United States) (2006), 106 (7), 2651-2710CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review dealing with cross-coupling reactions : carbon-carbon coupling reactions (Miyaura-Suzuki reaction, Corriu-Kumada-Tamao reaction, Negishi reaction, etc.) and carbon-nitrogen coupling reactions.
    2. 2

      For selected reviews on the Suzuki–Miyaura cross-coupling reactions, see:

      (a) Hussain, I.; Capricho, J.; Yawer, M. A. Synthesis of Biaryls via Ligand-Free Suzuki–Miyaura Cross-Coupling Reactions: A Review of Homogeneous and Heterogeneous Catalytic Developments. Adv. Synth. Catal. 2016, 358, 3320– 3349,  DOI: 10.1002/adsc.201600354
      2a
      Synthesis of Biaryls via Ligand-Free Suzuki-Miyaura Cross-Coupling Reactions: A Review of Homogeneous and Heterogeneous Catalytic Developments
      Hussain, Ibrar; Capricho, Jaworski; Yawer, Mirza A.
      Advanced Synthesis & Catalysis (2016), 358 (21), 3320-3349CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The recent developments in the field of Suzuki-Miyaura cross-coupling reaction, in particular with regard to ligand-free catalysis were described. The catalysts outlined here allowed convenient and green synthetic pathways specifically for the construction of C-C bonds. They enabled the synthesis of biaryls by the coupling arylboronic acids with aryl halides. The literature reporting ligand-free synthesis of biaryls from 2010 to May 2015 was reviewed.
      (b) Lennox, A. J. J.; Lloyd-Jones, G. C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc. Rev. 2014, 43, 412– 443,  DOI: 10.1039/C3CS60197H
      2b
      Selection of boron reagents for Suzuki-Miyaura coupling
      Lennox, Alastair J. J.; Lloyd-Jones, Guy C.
      Chemical Society Reviews (2014), 43 (1), 412-443CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Suzuki-Miyaura (SM) cross-coupling is arguably the most widely-applied transition metal catalyzed carbon-carbon bond forming reaction to date. Its success originates from a combination of exceptionally mild and functional group tolerant reaction conditions, with a relatively stable, readily prepd. and generally environmentally benign organoboron reagent. A variety of such reagents were developed for the process, with properties that were tailored for application under specific SM coupling conditions. This review analyses the seven main classes of boron reagent that were developed. The general phys. and chem. properties of each class of reagent are evaluated with special emphasis on the currently understood mechanisms of transmetalation. The methods to prep. each reagent are outlined, followed by example applications in SM coupling.
      (c) Suzuki, A. Carbon–carbon bonding made easy. Chem. Commun. 2005, 4759– 4763,  DOI: 10.1039/b507375h
      2c
      Carbon-carbon bonding made easy
      Suzuki, Akira
      Chemical Communications (Cambridge, United Kingdom) (2005), (38), 4759-4763CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A review. The palladium-catalyzed cross-coupling reaction between organoboranes and org. electrophiles in the presence of base was first developed 30 years ago. It offers a powerful and general methodol. for forming carbon-carbon bonds. The scope of the reaction has continued to evolve and broaden to meet modern synthetic requirements. The role of base additives and the reaction mechanism were discussed. Coupling reactions of arom. halides with boranes were mentioned. Problems involving sterically hindered substrates were addressed. Coupling reactions of alkyl compds. and alkynyl borane derivs. were also discussed. The applicability of Suzuki coupling reactions toward environmentally friendly processes was also pointed out.
    3. 3
      Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize. Angew. Chem., Int. Ed. 2012, 51, 5062– 5085,  DOI: 10.1002/anie.201107017
      3
      Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize
      Johansson Seechurn, Carin C. C.; Kitching, Matthew O.; Colacot, Thomas J.; Snieckus, Victor
      Angewandte Chemie, International Edition (2012), 51 (21), 5062-5085CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel Laureate chemists for their roles in discovering and developing highly practical methodologies for C-C bond construction. From their original contributions in the early 1970s the landscape of the strategies and methods of org. synthesis irreversibly changed for the modern chemist, both in academia and in industry. In this review, we attempt to trace the historical origin of these powerful reactions, and outline the developments from the seminal discoveries leading to their eminent position as appreciated and applied today.
    4. 4

      For selected reviews on the applications of alkylphosphane ligands in Pd-catalyzed C–C cross-coupling reactions, see:

      (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.; Marianetti, G.; Perego, L. A. Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products. Curr. Org. Chem. 2015, 19, 1302– 1409,  DOI: 10.2174/1385272819666150506230050
      4a
      Recent Applications of Phosphane-based Palladium Catalysts in Suzuki-Miyaura Reactions Involved in Total Syntheses of Natural Products
      Rossi, Renzo; Bellina, Fabio; Lessi, Marco; Manzini, Chiara; Marianetti, Giulia; Perego, Luca A.
      Current Organic Chemistry (2015), 19 (14), 1302-1409CODEN: CORCFE; ISSN:1385-2728. (Bentham Science Publishers Ltd.)
      A review with refs. on This review with 800 refs. illustrates applications of Suzuki-Miyaura (S.-M.) reactions in the total syntheses of 147 natural products that were made in the period 2010-2013. The review has been organized on the basis of the seven classes of phosphane-based Pd catalysts that have been used in the reported total syntheses. Emphasis has been given to describe and discuss the exptl. conditions of the Pd-catalyzed (S.-M.) cross-coupling reactions also outlining the methods used to prep. the reactants. A focus has also been set on the biol. and pharmacol. properties of the reported natural products as well as on the most significant steps of the reported total syntheses.
      (b) Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2, 1147– 1164,  DOI: 10.1021/cs300082f
      4b
      Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize
      Li, Hongbo; Johansson Seechurn, Carin C. C.; Colacot, Thomas J.
      ACS Catalysis (2012), 2 (6), 1147-1164CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A review. Strategies for the development of Pd catalysts based on utilization of L2Pd and LPd (L = ligand) species, beyond the contributions of the 2010 Nobel Laureates Richard Heck, Ei-ichi Negishi, and Akira Suzuki, along with their contemporaries, are reviewed. These well-defined, preformed Pd catalysts improve the selectivity and activity of selected cross-coupling reactions by reducing the metal loading and the ligand-to-metal ratios. This review describes predominantly the development of Pd precatalysts over the last 10 years and highlights the benefits often obsd. when using well-defined preformed catalysts relative to those generated in situ.
      (c) Fu, G. C. The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands. Acc. Chem. Res. 2008, 41, 1555– 1564,  DOI: 10.1021/ar800148f
      4c
      The Development of Versatile Methods for Palladium-Catalyzed Coupling Reactions of Aryl Electrophiles through the Use of P(t-Bu)3 and PCy3 as Ligands
      Fu, Gregory C.
      Accounts of Chemical Research (2008), 41 (11), 1555-1564CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Metal-catalyzed coupling reactions of aryl electrophiles with organometallics and with olefins serve as unusually effective tools for forming new carbon-carbon bonds. By 1998, researchers had developed catalysts that achieved reactions of aryl iodides, bromides, and triflates. Nevertheless, many noteworthy challenges remained; among them were couplings of aryl iodides, bromides, and triflates under mild conditions (at room temp., for example), couplings of hindered reaction partners, and couplings of inexpensive aryl chlorides. This Account highlights some of the progress that has been made in our lab. over the past decade, largely through the appropriate choice of ligand, in achieving these synthetic objectives. In particular, we have established that palladium in combination with a bulky trialkylphosphine accomplishes a broad spectrum of coupling processes, including Suzuki, Stille, Negishi, and Heck reactions. These methods have been applied in a wide array of settings, such as natural-product synthesis, materials science, and bioorg. chem.
    5. 5

      For selected studies on oxidative addition to Pd(0) complexes featuring phosphine ligands, see:

      (a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Mechanistic Pathways for Oxidative Addition of Aryl Halides to Palladium(0) Complexes:  A DFT Study. Organometallics 2005, 24, 2398– 2410,  DOI: 10.1021/om0500220
      There is no corresponding record for this reference.
      (b) Senn, H. M.; Ziegler, T. Oxidative Addition of Aryl Halides to Palladium(0) Complexes:  A Density-Functional Study Including Solvation. Organometallics 2004, 23, 2980– 2988,  DOI: 10.1021/om049963n
      There is no corresponding record for this reference.
      (c) Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions. Acc. Chem. Res. 2000, 33, 314– 321,  DOI: 10.1021/ar980063a
      5c
      Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions
      Amatore, Christian; Jutand, Anny
      Accounts of Chemical Research (2000), 33 (5), 314-321CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review with 17 refs. The anions of PdCl2L2 and Pd(OAc)2, precursors of palladium(0) used in cross-coupling and Heck reactions, play a crucial role in these reactions. Tricoordinated anionic complexes Pd0L2Cl- and Pd0L2(OAc)- are the effective catalysts instead of the usually postulated Pd0L2 complex. The anion ligated to the palladium(0) affects the kinetics of the oxidative addn. to ArI as well as the structure and reactivity of the arylpalladium(II) complexes produced in this reaction. Thus, pentacoordinated anionic complexes are formed, ArPdI(Cl)L2- or ArPdI(OAc)L2-, the precursor of neutral trans-ArPd(OAc)L2, instead of the usually postulated trans-ArPdIL2 complex (L = PPh3).
      (d) Casado, A. L.; Espinet, P. On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide). Organometallics 1998, 17, 954– 959,  DOI: 10.1021/om9709502
      5d
      On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4 and the Mechanism of the cis-to-trans Isomerization of [PdRX(PPh3)2] Complexes (R = Aryl, X = Halide)
      Casado, Arturo L.; Espinet, Pablo
      Organometallics (1998), 17 (5), 954-959CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      The oxidative addn. of RI to Pd(0) and further cis-to-trans isomerization, which are involved in the Stille reaction and other Pd-catalyzed syntheses, have been studied. C6Cl2F3I (C6Cl2F3 = 3,5-dichlorotrifluorophenyl) adds to Pd(PPh3)4 in THF at room temp. giving cis-[Pd(C6Cl2F3)I(PPh3)2] (2), which could be isolated before isomerization to the more stable trans-[Pd(C6Cl2F3)I(PPh3)2] (3). A 19F NMR kinetic study of the isomerization of 2 in THF at 322.6 K reveals a first-order law riso = kiso[2], with kiso = f + g[2]0 + (h + i[2]0)/([PPh3] + j) (f = (1.66 ± 0.03) × 10-4 s-1, g = (2.5 ± 0.2) × 10-3 mol-1 L s-1, h = (1.3 ± 0.7) × 10-8 mol L-1 s-1, i = (4 ± 2) × 10-4 s-1, and j = (1.4 ± 0.7) × 10-5 mol L-1). A four-pathway mechanism accounts for these results: two are assigned to the associative replacements of PPh3 coordinated to 2 by an iodide ligand of I-[Pd] (I-[Pd] = 2 or 3), both THF-assisted (coeff. h) or direct (coeff. i), leading to a monoiodide-bridged intermediate cis-{Pd(C6Cl2F3)I(PPh3)(μ-I)-[Pd]}. The later rearranges via terminal-for-bridging iodide exchange to trans-{Pd(C6Cl2F3)I(PPh3)(μ-I)-[Pd]}, which is finally cleaved by PPh3 yielding complex 3. The other two concurrent pathways are assigned to the isomerization via two consecutive Berry pseudorotations in the pentacoordinated species derived from 2 by coordination of THF (coeff. f) or I-[Pd] (coeff. g). The apparent activation entropy assocd. with kiso is neg. (ΔS⧧ = -21 ± 3 J K-1 mol-1), in agreement with the proposed bimol. mechanisms.
      (e) Hartwig, J. F.; Paul, F. Oxidative Addition of Aryl Bromide after Dissociation of Phosphine from a Two-Coordinate Palladium(0) Complex, Bis(tri-o-tolylphosphine)Palladium(0). J. Am. Chem. Soc. 1995, 117, 5373– 5374,  DOI: 10.1021/ja00124a026
      5e
      Oxidative Addition of Aryl Bromide after Dissociation of Phosphine from a Two-Coordinate Palladium(0) Complex, Bis(tri-o-tolylphosphine)Palladium(0)
      Hartwig, John F.; Paul, Frederic
      Journal of the American Chemical Society (1995), 117 (19), 5373-4CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The 14-electron Pd(0) complex [(o-tol)3P]2Pd (1) undergoes oxidative addn. reactions with aryl bromides that occur by a dissociative mechanism. The products of aryl bromide addn. are dimeric with only one phosphine bound to each palladium. In contrast to typical oxidative addns. to Pt(0), Pd(0), and Ni(0) phosphine compds. that occur to intermediates with two or three phosphine ligands, the addn. to 1 occurs after phosphine dissocn. and generation of a monophosphine intermediate. Clean first order kinetics were obsd. when monitoring the disappearance of 1. Inverse first order rate behavior in phosphine demonstrated that the reaction is dissociative. Reaction rates in benzene, toluene, and xylene were essentially identical, suggesting that solvent coordination does not stabilize the unsatd. intermediate. Rather, displacement of a phosphine by coordinated aryl bromide before irreversible oxidative addn., or coordination of a ligand C-H bond appears to stabilize the monophosphine complex. This mechanism is unusual, but falls in accord with those for the opposite reaction, reductive elimination from Pd(II). Many of these elimination reactions occur after phosphine dissocn. and, therefore, lead to initial products that contain only one phosphine ligand. This initial product from reductive elimination is analogous to the intermediate generated from 1 that undergoes oxidative addn.
      (f) Paul, F.; Patt, J.; Hartwig, J. F. Structural Characterization and Simple Synthesis of {Pd[P(o-Tol)3]2}. Spectroscopic Study and Structural Characterization of the Dimeric Palladium(II) Complexes Obtained by Oxidative Addition of Aryl Bromides and Their Reactivity with Amines. Organometallics 1995, 14, 3030– 3039,  DOI: 10.1021/om00006a053
      5f
      Structural Characterization and Simple Synthesis of {Pd[P(o-Tol)3]2}. Spectroscopic Study and Structural Characterization of the Dimeric Palladium(II) Complexes Obtained by Oxidative Addition of Aryl Bromides and Their Reactivity with Amines
      Paul, Frederic; Patt, Joe; Hartwig, John F.
      Organometallics (1995), 14 (6), 3030-9CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      The Pd(0) complex {Pd[P(o-Tol)3]2} was prepd. by addn. of P(o-Tol)3 to crude [Pd(DBA)2], which is an approx. equimolar mixt. of Pd2(DBA)3 and Pd(DBA)3, followed by crystn. from the reaction medium by addn. of ether. The formation of {Pd[P(o-Tol)3]2} appeared to be driven by its insoly. in the benzene/ether solvent mixt. Benzene solns. of [Pd(DBA)2] and P(o-Tol)3 did not contain amts. of the L2Pd compd. that could be detected by 31P NMR spectroscopy. {Pd[P(o-Tol)3]2} was characterized crystallog. and showed an exactly linear geometry. Similar Pd(0) compds. {Pd[P(2,4-dimethylphenyl)3]2}, {Pd[P(2-methyl-4-fluorophenyl)3]2}, and the low-coordinate trialkylphosphine complex {Pd[P(t-Bu)3]2} were also prepd. by this method, but [Pd(PCy3)2(DBA)] was produced from reactions involving PCy3 and [Pd(DBA)2], and [Pd(TMPP)(DBA)2] was isolated after addn. of tris(1,3,5-trimethoxyphenyl)phosphine (TMPP) to [Pd(DBA)2]. The oxidative addn. of aryl halides to {Pd[P(o-Tol)3]2} at room temp. led to dimeric {Pd[P(o-Tol)3](Ar)(Br)}2. An example of these compds. was characterized crystallog. as well as by soln. mol. wt. anal. This aryl halide complex is dimeric in the solid state as well as in soln. The NMR spectra of the large triarylphosphine complexes showed temp. dependent behavior, presumably due to isomerizations and ligand rotations that occurred on the NMR time scale. The aryl halide compds. did not form four-coordinate monometallic species in the presence of excess P(o-Tol)3, but they did undergo cleavage to four-coordinate monometallic complexes upon addn. of primary and secondary amines.
      (g) Amatore, C.; Jutand, A.; Suarez, A. Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions. J. Am. Chem. Soc. 1993, 115, 9531– 9541,  DOI: 10.1021/ja00074a018
      5g
      Intimate mechanism of oxidative addition to zerovalent palladium complexes in the presence of halide ions and its relevance to the mechanism of palladium-catalyzed nucleophilic substitutions
      Amatore, Christian; Jutand, Anny; Suarez, Alejandra
      Journal of the American Chemical Society (1993), 115 (21), 9531-41CODEN: JACSAT; ISSN:0002-7863.
      The mechanism of oxidative addn. of aryl halides to low-ligated zerovalent palladium species obtained by redn. of their divalent precursor complexes, PdIICl2(PR3)2, was investigated on the basis of 31P NMR and electrochem. In strong contrast to usual expectations, the reaction proceeds via a complex sequence of steps: (i) fast addn. of the aryl halide to a halide ligated zerovalent palladium center, so as to afford a pentacoordinated anionic arylpalladium(II) center; (ii) a fast but reversible uphill elimination from the pentacoordinated anionic arylpalladium(II) center of a halide ion ligand, possibly through its substitution by a solvent ligand; (iii) rearrangement of this second short-lived intermediate into the thermodynamically stable trans-arylpalladium(II) product of the reaction. On the basis of this detailed mechanism, a new mechanism is proposed for the catalysis of nucleophilic substitutions by palladium complexes. In contrast to the catalytic cycles that are usually considered, this new catalytic cycle accounts for the well-used effects of halide ions as well as that of small metal cations and rationalizes their role in the overall efficiency of palladium-catalyzed nucleophilic substitutions.
      (h) Amatore, C.; Pflüger, F. Mechanism of oxidative addition of palladium(0) with aromatic iodides in toluene, monitored at ultramicroelectrodes. Organometallics 1990, 9, 2276– 2282,  DOI: 10.1021/om00158a026
      5h
      Mechanism of oxidative addition of palladium(0) with aromatic iodides in toluene, monitored at ultramicroelectrodes
      Amatore, Christian; Pfluger, Fernando
      Organometallics (1990), 9 (8), 2276-82CODEN: ORGND7; ISSN:0276-7333.
      The mechanism and rates of oxidative addn. of substituted iodobenzenes to tetrakis(triphenylphosphine)palladium(0) is investigated in toluene by means of electrochem. at ultramicroelectrodes. The mechanism is identical with that previously reported in THF (F. F. Fauvarque et al., 1981) and to correspond to a similar slope for Hammett's correlation (ρ = +2 in THF vs +2.3 ± 0.2 in toluene). Moreover, the important change in polarity (εs ≈ 7.58 in THF and 2.38 in toluene) does not affect the enthalpy of activation and leads to similar activation entropies in both solvents. This suggests that the transition state of addn. of aryl halides to the coordinately unsatd. zerovalent palladium complex Pd0(PPh3)2 has no significant ionic character.
      (i) Fauvarque, J.-F.; Pflüger, F. Kinetics of oxidative addition of zerovalent palladium to aromatic iodides. J. Organomet. Chem. 1981, 208, 419– 427,  DOI: 10.1016/S0022-328X(00)86726-1
      5i
      Kinetics of oxidative addition of zerovalent palladium to aromatic iodides
      Fauvarque, Jean Francois; Pfluger, Fernando; Troupel, Michel
      Journal of Organometallic Chemistry (1981), 208 (3), 419-27CODEN: JORCAI; ISSN:0022-328X.
      The kinetics of oxidative addn. of Pd(0) to arom. iodides in THF contg. the ligand Ph3P were studied by amperometry on the Pd oxidn. wave. The reaction is 1st order each in arom. iodide and Pd(0), and the rate const. is inversely proportional to the free-ligand concn. The reactive Pd(0) intermediate is Pd(PPh3)2. With substituted arom. iodides, the rate consts. give a linear Hammett relationship with ρ = +2. The mechanism is related to an arom. nucleophilic substitution with some assistance from halogen-Pd interaction.
      (j) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434,  DOI: 10.1021/ar50120a002
      There is no corresponding record for this reference.
      (k) Fitton, P.; Rick, E. A. The addition of aryl halides to tetrakis(triphenylphosphine)palladium(0). J. Organomet. Chem. 1971, 28, 287– 291,  DOI: 10.1016/S0022-328X(00)84578-7
      5k
      Addition of aryl halides to tetrakis(triphenylphosphine)palladium(0)
      Fitton, P.; Rick, Edward A.
      Journal of Organometallic Chemistry (1971), 28 (2), 287-91CODEN: JORCAI; ISSN:0022-328X.
      The order of reactivity of halobenzenes towards oxidative addn. to Pd(PPh3)4 was PhI > PhBr > PhCl. Iodobenzene will react with Pd(PPh3)4 in benzene at room temp., and bromobenzene will react at 80°. Chlorobenzene, however, is unreactive even at 135°. Aryl chlorides substituted with electron-donating groups similarly are unreactive, but aryl chlorides substituted with electron-withdrawing groups are reactive. This increased reactivity, and order of reactivity 4-O2NC6H4Cl > 4-CNC6H4Cl > 4-PhCOC6H4Cl > PhCl suggests that the mechanism of the oxidative addn. is similar to that of a bimol. nucleophilic aromatic displacement reaction in which breaking of the bond to the leaving group is involved in the rate detg. step.
    6. 6
      Organotransition Metal Chemistry From Bonding to Catalysis; Hartwig, J. F., Ed.; University Science Books: Sausalito, CA, 2010; Chapter 19.
      There is no corresponding record for this reference.
    7. 7
      Pullen, R.; Olding, A.; Smith, J. A.; Bissember, A. C. Manuscript in preparation.
      There is no corresponding record for this reference.
    8. 8
      Wallow, T. I.; Novak, B. M. Highly Efficient and Accelerated Suzuki Aryl Couplings Mediated by Phosphine-Free Palladium Sources. J. Org. Chem. 1994, 59, 5034– 5037,  DOI: 10.1021/jo00096a056
      8
      Highly efficient and accelerated Suzuki aryl couplings mediated by phosphine-free palladium sources
      Wallow, Thomas I.; Novak, Bruce M.
      Journal of Organic Chemistry (1994), 59 (17), 5034-7CODEN: JOCEAH; ISSN:0022-3263.
      Suzuki aryl cross-couplings employing aryl bromides and aryl iodides proceed under mild conditions (65°) with high efficiency (substrate-to-catalyst ratios >500) in the presence of phosphine-free Pd catalysts derived from Pd acetate, Pd2(dba)3·C6H6 (dba = dibenzylideneacetone), and [(η3-C3H5)PdCl]2. Phosphine inhibition is shown to play a key role in limiting catalytic efficiency; qual. comparison studies show that the phosphine-free systems are 1-2 orders of magnitude more active than phosphine-supported catalytic systems. Pd[P(Ph)3]4 proved to be the least active of the catalytic species screened. The phosphine-free methodol. appears to be generally applicable; cross-couplings of aryl iodides yielding biaryls p-MeOC6H4C6H4CF3-p 6 and p-MeOC6H4C6H4Me-o 7 proceed without noticeable steric or electronic effects. Cross-couplings employing aryl bromides are insensitive to electronic effects in the synthesis of 6 but are slowed by steric hindrance in the synthesis of 7. Acceleration of cross-coupling is obsd. in the presence of polar cosolvents and at high pH.
    9. 9

      The poor reactivity of aryl iodides with vinyltributyltin in Stille couplings employing Pd/PPh3 at ∼50 °C has been reported; see:

      Farina, V.; Krishnan, B. Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications. J. Am. Chem. Soc. 1991, 113, 9585– 9595,  DOI: 10.1021/ja00025a025
      9
      Large rate accelerations in the stille reaction with tri-2-furylphosphine and triphenylarsine as palladium ligands: mechanistic and synthetic implications
      Farina, Vittorio; Krishnan, Bala
      Journal of the American Chemical Society (1991), 113 (25), 9585-95CODEN: JACSAT; ISSN:0002-7863.
      The effect of changing the palladium ligands on the rates of typical Stille cross-coupling reactions was studied. Large rate enhancements (typically 102-103 over triphenylphosphine-based catalyst) were obsd. with tri-2-furylphosphine and triphenylarsine, which are recommended as the new ligands of choice in the palladium-catalyzed coupling between olefinic stannanes and electrophiles. On the basis of the evidence presented, the transmetalation, which is the rate-detg. step in the catalytic cycle, is postulated to involve a π-complex between the metal and the stannane double bond. In general, ligands that readily dissoc. from Pd(II) and allow ready formation of this π-complex are the ones that produce the fastest coupling rates. The utility of the new ligands is demonstrated with several synthetic examples.
    10. 10
      Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Synthesis of unsymmetrical biaryls using a modified Suzuki cross-coupling: 4-biphenylcarboxaldehyde. Org. Synth. 1998, 75, 53,  DOI: 10.1002/0471264180.os075.07
      There is no corresponding record for this reference.
    11. 11

      In general, iodide consumption was comparable to product yield.

      There is no corresponding record for this reference.
    12. 12

      Analogous results were obtained in experiments employing higher [Pd(PPh3)4] loadings (2.5% and 5%) (see the Supporting Information).

      There is no corresponding record for this reference.
    13. 13

      We also investigated the effect of incrementally varying the Na2CO3 loading on the outcome of the reaction at 70 °C. Our results suggest that the Na2CO3 loading (1–5 equiv) has little effect on the efficiency of reactions employing p-iodotoluene (see the Supporting Information). Substituting either Cs2CO3 or NMe4OH for Na2CO3 also provided inefficient couplings of p-iodotoluene (see the Supporting Information).

      There is no corresponding record for this reference.
    14. 14

      We also performed experiments employing higher PPh3 loadings (see the Supporting Information).

      There is no corresponding record for this reference.
    15. 15

      It has been established that PPh3 can effect the reduction of Pd(OAc)2 to generate catalytically active Pd(0) species. See, for example: ref (5c).

      (a) Carole, W. A.; Colacot, T. J. Understanding Palladium Acetate from a User Perspective. Chem. - Eur. J. 2016, 22, 7686– 7695,  DOI: 10.1002/chem.201601450
      15a
      Understanding Palladium Acetate from a User Perspective
      Carole, William A.; Colacot, Thomas J.
      Chemistry - A European Journal (2016), 22 (23), 7686-7695CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The behavior of palladium acetate is reviewed with respect to its synthesis, characterization, structure (in both soln. and solid state), and activation pathways. In addn., comparisons of catalytic activities between pure palladium acetate and two common byproducts, Pd3(OAc)5(NO2) and polymeric [Pd(OAc)2]n, typically present in com. available material are reviewed. Hence, this minireview serves as a concise guide for the users of palladium acetate from both academia and industry.
      (b) Amatore, C.; Carré, E.; Jutand, A.; M’Barki, M. Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions. Organometallics 1995, 14, 1818– 1826,  DOI: 10.1021/om00004a039
      15b
      Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions
      Amatore, Christian; Carre, Emmanuelle; Jutand, Anny; M'Barki, Mohamed Amine
      Organometallics (1995), 14 (4), 1818-26CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      Mixts. of Pd(OAc)2 and tertiary phosphines spontaneously afford Pd(0) complexes. Kinetic studies demonstrate that this reaction proceeds from the complex Pd(OAc)2(PR3)2 via an inner-sphere redn. which is the rate-detg. step of the overall reaction. The phosphine is thus oxidized to the corresponding phosphine oxide. The formation of the Pd(0) complex is sensitive to electronic and steric factors. The more the triarylphosphine is substituted by electron-withdrawing groups, the faster the reaction. The Pd(0) complex thus formed reacts with Ph iodide via an oxidn. addn., and this reaction is faster when the phosphine is more electron-rich.
      (c) Amatore, C.; Jutand, A.; M’Barki, M. Evidence of the formation of zerovalent palladium from Pd(OAc)2 and triphenylphosphine. Organometallics 1992, 11, 3009– 3013,  DOI: 10.1021/om00045a012
      15c
      Evidence of the formation of zerovalent palladium from Pd(OAc)2 and triphenylphosphine
      Amatore, Christian; Jutand, Anny; M'Barki, Mohamed Amine
      Organometallics (1992), 11 (9), 3009-13CODEN: ORGND7; ISSN:0276-7333.
      The mixt. Pd(OAc)2 + nPPh3 (n ≥2) and Pd(OAc)2(PPh3)2, commonly used as catalysts in reactions involving aryl and vinyl halides, aryl triflates or allylic acetates, spontaneously generate a zerovalent Pd complex that reacts with PhI. PPh3 reduces the PdII from Pd(OAc)2(PPh3)2 by an intramol. reaction and is oxidized to OPPh3. In the presence of an excess of PPh3, the zerovalent Pd complex generated in situ has the same 31P NMR and cyclic voltammetry properties as those of Pd0(PPh3)4.
    16. 16

      Pd(OAc)2 was used in preference to Pdx(dba)y, as challenges in establishing the exact speciation and purity of the latter have been identified. See, for example:

      (a) Amatore, C.; Jutand, A. Role of dba in the reactivity of palladium(0) complexes generated in situ from mixtures of Pd(dba)2 and phosphines. Coord. Chem. Rev. 1998, 178–180, 511– 528,  DOI: 10.1016/S0010-8545(98)00073-3
      16a
      Role of dba in the reactivity of palladium(0) complexes generated in situ from mixtures of Pd(dba)2 and phosphines
      Amatore, Christian; Jutand, Anny
      Coordination Chemistry Reviews (1998), 178-180 (Pt. 1), 511-528CODEN: CCHRAM; ISSN:0010-8545. (Elsevier Science S.A.)
      A review with 98 refs. The ligand dba plays a crucial role both on the structure and on the reactivity of Pd(0) complexes generated in situ in mixts. of Pd(dba)2 and phosphine ligands. Whatever the ligand, the major complex is always Pd(dba)L2 where L is a monodentate phosphine ligand or Pd(dba)(L-L) where L-L is a bidentate phosphine ligand. In all cases, the most reactive species in the oxidative addn. with Ph iodide is the lowest ligated complex PdL2 or Pd(L-L) in equil. with the major complex and dba. However, Pd(dba)(L-L) also reacts with Ph iodide. The presence of the major complexes ligated by dba diminishes the concn. of the more reactive species PdL2 or Pd(L-L) and consequently controls the rate of the overall reaction. The overall reactivity is governed both by the intrinsic reactivity of the reactive species and its concn., two factors which can be antagonistic and a nonlinear Hammett correlation of the oxidative addn. with the basicity of the phosphine is obsd. for monodentate ligands.
      (b) Zalesskiy, S. S.; Ananikov, V. P. Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis. Organometallics 2012, 31, 2302– 2309,  DOI: 10.1021/om201217r
      16b
      Pd2(dba)3 as a Precursor of Soluble Metal Complexes and Nanoparticles: Determination of Palladium Active Species for Catalysis and Synthesis
      Zalesskiy, Sergey S.; Ananikov, Valentine P.
      Organometallics (2012), 31 (6), 2302-2309CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) is ubiquitously used as a source of sol. Pd species for catalysis and as a precursor in the synthesis of more complex Pd structures. In spite of the massive usage of this convenient Pd complex, its nature in soln. was not revealed in detail and the applications rely on the assumed state and purity of the compd. A convenient NMR procedure is developed to reveal the nature of Pd2(dba)3 and to det. the purity of the complex. Surprisingly, com. available samples of Pd2(dba)3 may readily contain up to 40% of Pd nanoparticles in a wide range of sizes (10-200 nm). The routinely accepted practice of use of Pd2(dba)3 without anal. of the purity (both com. available and prepd. by common procedures) can introduce significant errors in the estn. of catalyst efficiency and lead to incorrect values of TON, TOF, and reported mol % values in the catalytic procedures. The presence of Pd nanoparticles in the catalyst precursor provides an opportunity for heterogeneous catalytic systems of different nature to be directly accessible from Pd2(dba)3. A modified procedure for the synthesis of Pd2(dba)3·CHCl3 with 99% purity is reported.
    17. 17

      See, for example:

      Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Synthesis of diaryls from phenylboric acid and aryl iodides in an aqueous medium. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1989, 38, 2206,  DOI: 10.1007/BF00962156
      There is no corresponding record for this reference.
      Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1989, 38, 2206,  DOI: 10.1007/BF00962156
      There is no corresponding record for this reference.
    18. 18

      We also performed experiments investigating the effect of halide additives (20% NH4I, NH4Br, NH4F, NMe4I, NMe4Br, NMe4Cl, LiBr, LiCl, KBr, KCl, CsBr, or CsCl) on Suzuki–Miyaura couplings (see the Supporting Information).

      There is no corresponding record for this reference.
    19. 19

      It is generally acknowledged that defining key transmetalation intermediates is even more complicated with aryltrifluoroborate nucleophiles. See, for example:

      Lennox, A. J. J.; Lloyd-Jones, G. C. The Slow-Release Strategy in Suzuki–Miyaura Coupling. Isr. J. Chem. 2010, 50, 664– 674, and references cited therein  DOI: 10.1002/ijch.201000074
      19
      The slow-release strategy in Suzuki-Miyaura coupling
      Lennox, Alastair J. J.; Lloyd-Jones, Guy C.
      Israel Journal of Chemistry (2010), 50 (5-6), 664-674CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Despite great advances in metal-catalyzed cross-coupling reactions, their efficacy is often compromised by side reactions, reducing the yield, or requiring a large excess of one component. Suzuki-Miyaura cross-coupling is no exception, as the boronic acid functionality can be susceptible to a range of undesired processes. A no. of methods were developed to mitigate these side reactions, and herein we focus on the slow-release strategy. These conditions involve deployment of a masking reagent that protects the vulnerable boronic acid functionality from degrdn., particularly protodeboronation, while simultaneously facilitating controlled liberation of the active reagent into the catalytic milieu. Under suitably tailored conditions, this dual-action approach ensures that the concn. of the free boronic acid is minimized, thus attenuating its degrdn. but still facilitating transmetallation of the organoboron species with the key organopalladium intermediate.
    20. 20
      (a) Andersen, N. G.; Keay, B. A. 2-Furyl Phosphines as Ligands for Transition-Metal-Mediated Organic Synthesis. Chem. Rev. 2001, 101, 997– 1030,  DOI: 10.1021/cr000024o
      20a
      2-Furyl Phosphines as Ligands for Transition-Metal-Mediated Organic Synthesis
      Andersen, Neil G.; Keay, Brian A.
      Chemical Reviews (Washington, D. C.) (2001), 101 (4), 997-1030CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review with 177 refs.
      (b) Niemeyer, Z. L.; Milo, A.; Hickey, D. P.; Sigman, M. S. Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes. Nat. Chem. 2016, 8, 610– 617,  DOI: 10.1038/nchem.2501
      20b
      Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes
      Niemeyer, Zachary L.; Milo, Anat; Hickey, David P.; Sigman, Matthew S.
      Nature Chemistry (2016), 8 (6), 610-617CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The mechanistic foundation behind the identity of a phosphine ligand that best promotes a desired reaction outcome is often nonintuitive, and thus was addressed in numerous exptl. and theor. studies. Multivariate correlations of reaction outcomes using 38 different phosphine ligands were combined with classic potentiometric analyses to study a Suzuki reaction, for which the site selectivity of oxidative addn. is highly dependent on the nature of the phosphine. These studies shed light on the generality of hypotheses regarding the structural influence of different classes of phosphine ligands on the reaction mechanism(s), and deliver a methodol. that should prove useful in future studies of phosphine ligands.
    21. 21
      (a) Tolman, C. A. Electron donor-acceptor properties of phosphorus ligands. Substituent additivity. J. Am. Chem. Soc. 1970, 92, 2953– 2956,  DOI: 10.1021/ja00713a006
      21a
      Electron donor-acceptor properties of phosphorus ligands. Substituent additivity
      Tolman, Chadwick A.
      Journal of the American Chemical Society (1970), 92 (10), 2953-6CODEN: JACSAT; ISSN:0002-7863.
      A rapid method is described for detg. electron donor-acceptor properties of triply connected P ligands based on the A1 carbonyl stretching frequency of Ni(CO)3L in CH2Cl2. Data are given for 70 ligands and a substituent additivity rule is proposed. Forty-seven substituent parameters χi are derived and found to correlate well with Kabachnik's σ parameters, based on ionization consts. of P acids.
      (b) Otto, S.; Roodt, A. Quantifying the electronic cis effect of phosphine, arsine and stibine ligands by use of rhodium(I) Vaska-type complexes. Inorg. Chim. Acta 2004, 357, 1– 10,  DOI: 10.1016/S0020-1693(03)00436-5
      21b
      Quantifying the electronic cis effect of phosphine, arsine and stibine ligands by use of rhodium(I) Vaska-type complexes
      Otto, Stefanus; Roodt, Andreas
      Inorganica Chimica Acta (2004), 357 (1), 1-10CODEN: ICHAA3; ISSN:0020-1693. (Elsevier Science B.V.)
      The cis effects of phosphine, arsine and stibine ligands were evaluated by measuring the IR stretching frequency in dichloromethane of the carbonyl ligand in Rh(I) Vaska-type complexes, trans-[RhCl(CO)(L)2]. These data were correlated with those obtained by Tolman for the electronic trans influences in [Ni(L)(CO)3]. The electronic contribution, χFc, of ferrocenyl was detd. as 0.8 from these plots by evaluating PPh2Fc as ligand. To accommodate arsine and stibine ligands an addnl. correction term, to compensate for differences in the donor atom, was added to Tolman's equation for calcn. of the Tolman electronic parameter of phosphine ligands. In the resulting equation: v(CONi) = 2056.1 + Σ3i=1 χi + CL values for CL of CP = 0, CAs = -1.5 and CSb = -3.1 are suggested for phosphine, arsine and stibine ligands, resp. The crystal and mol. structures of trans-[RhCl(CO)(PPh2Fc)2]·2C6H6, trans-[RhCl(CO){P(NMe2)3}2] and trans-[RhCl(CO)(AsPh3)2] are reported. The Tolman cone angles for PPh2Fc and P(NMe2)3 were detd. as 169° and 166°, while the effective cone angles for PPh2Fc, P(NMe2)3 and AsPh3 were detd. as 171°, 168° and 147°, resp.
      (c) Ackermann, M.; Pascariu, A.; Höcher, T.; Siehl, H.-U.; Berge, S. Electronic Properties of Furyl Substituents at Phosphorus and Their Influence on 31P NMR Chemical Shifts. J. Am. Chem. Soc. 2006, 128, 8434– 8440,  DOI: 10.1021/ja057085u
      21c
      Electronic Properties of Furyl Substituents at Phosphorus and Their Influence on 31P NMR Chemical Shifts
      Ackermann, Marco; Pascariu, Aurelia; Hoecher, Thomas; Siehl, Hans-Ullrich; Berger, Stefan
      Journal of the American Chemical Society (2006), 128 (26), 8434-8440CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The electronic properties of 2-furyl and 3-furyl substituents attached to phosphines and phosphonium salts were studied by IR spectroscopy and exptl. and computational 31P NMR spectroscopy. The heteroarom. systems proved to be electron withdrawing with respect to Ph substituents. However, phosphorus atoms with attached furyl substituents are strongly shielded in NMR. The reason for this phenomenon was studied by solid state 31P MAS NMR expts. The chem. shift tensor was extd., and the orientation within the mols. was detd. The tensor component σ33, which is effected the most by furyl systems, is oriented perpendicular to the P-C bonds of the substituents. P-furyl bonds are shorter than P-Ph bonds. We assume therefore a lower ground-state energy of the mols., because of the electron withdrawing properties of the 2-furyl systems. The σpara component of the 31P NMR magnetic shielding is therefore smaller, which results in an overall increase of the magnetic shielding.
    22. 22

      The observation that oxidative addition is not the turnover-limiting step in this reaction is consistent with previous studies. See, for example:

      Amatore, C.; Jutand, A.; Le Duc, G. Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki–Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base. Chem. - Eur. J. 2011, 17, 2492– 2503, and references cited therein  DOI: 10.1002/chem.201001911
      22
      Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base
      Amatore, Christian; Jutand, Anny; Le Duc, Gaetan
      Chemistry - A European Journal (2011), 17 (8), 2492-2503CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The mechanism of the reaction of trans-[ArPdX(PPh3)2] (Ar = p-Z-C6H4; Z = CN, F, H; X = I, Br, Cl) with Ar'B(OH)2 (Ar' = p-Z'-C6H4; Z' = CN, H, OMe) has been established in DMF in the presence of the base OH- in the context of real palladium-catalyzed Suzuki-Miyaura reactions. The formation of the cross-coupling product ArAr' and [Pd0(PPh3)3] has been followed through the application of electrochem. techniques. Kinetic data have been obtained for the first time, with detn. of the obsd. rate const., kobs, of the overall reaction. trans-[ArPdX(PPh3)2] is not reactive in the absence of the base. The base OH- plays three roles. It favors the reaction: (1) by formation of trans-[ArPd(OH)(PPh3)2], a key complex which, in contrast to trans-[ArPdX(PPh3)2], reacts with Ar'B(OH)2 (rate-detg. transmetalation), and (2) by unexpected promotion of the reductive elimination from the intermediate trans-[ArPdAr'(PPh3)2], which generates ArAr' and a Pd0 species. Conversely, the base OH- disfavors the reaction by formation of the unreactive anionic Ar'B(OH)3-. As a consequence of these antagonistic effects of OH-, the overall reactivity is controlled by the concn. of OH- and passes through a max. as the concn. of OH- is increased. Therefore, the base favors the rate-detg. transmetalation and unexpectedly also the reductive elimination.
    23. 23

      It was reported that trans-[Pd(PPh3)2I2] was formed in reactions with [Pd(PPh3)4] and (iodoethynyl)benzene (in addition to the expected oxidative addition product). See:

      (a) Weigelt, M.; Becher, D.; Poetsch, E.; Bruhn, C.; Steinborn, D. Zur oxidativen Addition von 1-Halogenalk-1-inen – Synthese und Struktur von Phenylalkinylpalladium-Komplexen. Z. Anorg. Allg. Chem. 1999, 625, 1542– 1547,  DOI: 10.1002/(SICI)1521-3749(199909)625:9<1542::AID-ZAAC1542>3.0.CO;2-9
      There is no corresponding record for this reference.

      The formation of trans-[Pd(PPh3)2I2] from trans-[Pd(PPh3)2(R)(I)] has also been reported:

      (b) Gulia, N.; Pigulski, B.; Szafert, S. Palladium End-Capped Polyynes via Oxidative Addition of 1-Haloalkynes to Pd(PPh3)4. Organometallics 2015, 34, 673– 682,  DOI: 10.1021/om501105w
      23b
      Palladium End-Capped Polyynes via Oxidative Addition of 1-Haloalkynes to Pd(PPh3)4
      Gulia, Nurbey; Pigulski, Bartlomiej; Szafert, Slawomir
      Organometallics (2015), 34 (4), 673-682CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      Reported here is the use of 1-haloacetylenes and 1-halopolyynes as synthons for the prepn. of new palladium(II) end-capped polyynes. The 1-haloalkynes were obtained in a series of transformations from para-substituted bromoarenes that included Sonogashira coupling followed by halogenation and chain elongation via Cadiot-Chodkiewicz protocol. The key step for the synthesis of metal complexes was oxidative addn. of 1-haloalkynes to Pd(PPh3)4, which allowed obtaining a series of metal compds. 1-5-CnX with carbon chains up to hexatriyne in 75-100% yield. All the compds. were characterized by NMR and HRMS or elemental anal. The 13C spectra of the 1-haloalkynes showed interesting, although expected, shifts of the carbon chain atoms close to the halogen termini. X-ray crystal structures were obtained for three polyynes-two butadiynes (2-C4[Pd]Br and 3-C4[Pd]Br) and one hexatriyne (1-C6[Pd]Br)-and the latter is the first reported X-ray crystal structure of palladium end-capped hexatriyne.

      trans-[Pd(PPh3)2I2] was also formed in reactions with [Pd(PPh3)4] and 9-iodo-m-carborane. See:

      (c) Marshall, W. J.; Young, R. J., Jr.; Grushin, V. V. Mechanistic Features of Boron–Iodine Bond Activation of B–Iodocarboranes. Organometallics 2001, 20, 523– 533,  DOI: 10.1021/om0008575
      There is no corresponding record for this reference.
    24. 24

      We were also able to isolate and characterize trans-[Pd(PPh3)2I2]. The spectroscopic data obtained on this compound were consistent both with equivalent data reported in the literature and also with an authentic sample of trans-[Pd(PPh3)2I2] that we prepared via a literature procedure:

      Hahn, F. E.; Lugger, T.; Beinhoff, M. Palladium(II) Complexes with Benzoxazol-2-ylidene Ligands: Crystal Structures of trans-Chloro(benzoxazol-2-ylidene)bis(triphenylphosphine)palladium(II) Chloride and cis-Diiodo(benzoxazol-2-ylidene)(triphenylphosphine)palladium(II). Z. Naturforsch. B Chem. Sci. 2004, 59, 196– 201
      24
      Palladium(II) complexes with benzoxazol-2-ylidene ligands: crystal structures of trans-chloro(benzoxazol-2-ylidene)bis(triphenylphosphine)palladium(II) chloride and cis-diiodo(benzoxazol-2-ylidene)(triphenylphosphine)palladium(II)
      Hahn, F. Ekkehardt; Luegger, Thomas; Beinhoff, Matthias
      Zeitschrift fuer Naturforschung, B: Chemical Sciences (2004), 59 (2), 196-201CODEN: ZNBSEN; ISSN:0932-0776. (Verlag der Zeitschrift fuer Naturforschung)
      The Pd(II) complexes trans-[PdCl(L)(PPh3)2]Cl, 5, and cis-[PdI2(L)PPh3], 7, (L = benzoxazol-2-ylidene) were synthesized by treatment of trans-[PdX2(PPh3)2] (4: X = Cl, 6: X = iodo) with 2-(trimethylsiloxy)phenyl isocyanide 1, and subsequent hydrolysis of the Si-O bond. The crystal structures of 5 and 7·CH2Cl2 were established by x-ray diffraction. NMR and IR studies indicate that the unexpected cis-configuration of 7 obtained from trans-[PdI2(PPh3)2] is not the result of a soln. equil. between the cis and the trans isomers.
    25. 25

      When the study shown in eq 2 was performed in DMF/H2O instead of n-PrOH/H2O, similar results were obtained. When the experiment shown in eq 2 was performed using p-bromotoluene instead of p-iodotoluene, 31P NMR spectroscopy indicated that trans-[Pd(PPh3)2Br2] was not present in the reaction mixture. trans-[Pd(PPh3)2Br2] was also not observed in equivalent experiments performed in DMF/H2O.

      There is no corresponding record for this reference.
    26. 26
      Carrow, B. P.; Hartwig, J. F. Distinguishing Between Pathways for Transmetalation in Suzuki–Miyaura Reactions. J. Am. Chem. Soc. 2011, 133, 2116– 2119,  DOI: 10.1021/ja1108326
      26
      Distinguishing between pathways for transmetalation in Suzuki-Miyaura reactions
      Carrow, Brad P.; Hartwig, John F.
      Journal of the American Chemical Society (2011), 133 (7), 2116-2119CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Transmetalation of arylpalladium complexes proceeds rather via palladium hydroxo complex and arylboronic acid pathway, than via arylpalladium halide and aryl(trihydroxo)borate. A systematic study of the stoichiometric reactions of isolated arylpalladium hydroxo and halide complexes with arylboronic acids and aryltrihydroxyborates is performed to evaluate the relative rates of the two reaction pathways commonly proposed to account for transmetalation in the Suzuki-Miyaura reaction. On the basis of the relative populations of the palladium and organoboron species generated under conditions common for the catalytic process and the obsd. rate consts. for the stoichiometric reactions between the two classes of reaction components, we conclude that the reaction of a palladium hydroxo complex with boronic acid, not the reaction of a palladium halide complex with trihydroxyborate, accounts for transmetalation in catalytic Suzuki-Miyaura reactions conducted with weak base and aq. solvent mixts.
    27. 27

      For a recent review on transmetalation in the Suzuki–Miyaura cross-coupling, see:

      Lennox, A. J. J.; Lloyd-Jones, G. C. Transmetalation in the Suzuki-Miyaura coupling: the fork in the trail. Angew. Chem., Int. Ed. 2013, 52, 7362– 7370,  DOI: 10.1002/anie.201301737
      27
      Transmetalation in the Suzuki-Miyaura Coupling: The Fork in the Trail
      Lennox, Alastair J. J.; Lloyd-Jones, Guy C.
      Angewandte Chemie, International Edition (2013), 52 (29), 7362-7370CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The Suzuki-Miyaura coupling is one of the few transition-metal-catalyzed C-C bond-forming reactions that were used in applications ranging from discovery chem. to manufg. processes. Although coupling proceeds through the generic three-stage oxidative addn., transmetalation, reductive elimination' sequence, there are a no. of features that differentiate the Suzuki-Miyaura process from other transition-metal-catalyzed cross-couplings. Most of these features are centered around, or are a consequence of, activation of the boron reagent for transmetalation through one or both of two distinct pathways. This review focuses on the evidence that was presented for this fork in the trail, and the potential to apply such mechanistic insight to the design of reaction conditions.
    28. 28

      For selected studies on transmetalation in the Suzuki–Miyaura cross-coupling, see: refs (22and26).

      (a) Thomas, A. A.; Wang, H.; Zahrt, A. F.; Denmark, S. E. Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki–Miyaura Reaction. J. Am. Chem. Soc. 2017, 139, 3805– 3821,  DOI: 10.1021/jacs.6b13384
      28a
      Structural, Kinetic, and Computational Characterization of the Elusive Arylpalladium(II)boronate Complexes in the Suzuki-Miyaura Reaction
      Thomas, Andy A.; Wang, Hao; Zahrt, Andrew F.; Denmark, Scott E.
      Journal of the American Chemical Society (2017), 139 (10), 3805-3821CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The existence of the oft-invoked intermediates contg. the crucial Pd-O-B subunit, the "missing link", has been established in the Suzuki-Miyaura cross-coupling reaction. The use of low-temp., rapid injection NMR spectroscopy (RI-NMR), kinetic studies, and computational anal. has enabled the generation, observation, and characterization of these highly elusive species. The ability to confirm the intermediacy of Pd-O-B-contg. species provided the opportunity to clarify mechanistic aspects of the transfer of the org. moiety from boron to palladium in the key transmetalation step. Specifically, these studies establish the identity of two different intermediates contg. Pd-O-B linkages, a tri-coordinate (6-B-3) boronic acid complex and a tetra-coordinate (8-B-4) boronate complex, both of which undergo transmetalation leading to the cross-coupling product. Two distinct mechanistic pathways have been elucidated for stoichiometric reactions of these complexes: (1) transmetalation via an unactivated 6-B-3 intermediate that dominates in the presence of an excess of ligand, and (2) transmetalation via an activated 8-B-4 intermediate that takes place with a deficiency of ligand.
      (b) Thomas, A. A.; Denmark, S. E. Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link. Science 2016, 352, 329– 332,  DOI: 10.1126/science.aad6981
      28b
      Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link
      Thomas, Andy A.; Denmark, Scott E.
      Science (Washington, DC, United States) (2016), 352 (6283), 329-332CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Despite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temp. rapid injection NMR spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species contg. palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsatd. palladium center in the crit. transmetalation event.
      (c) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque, G. The Transmetalation Process in Suzuki–Miyaura Reactions: Calculations Indicate Lower Barrier via Boronate Intermediate. ChemCatChem 2014, 6, 3132– 3138,  DOI: 10.1002/cctc.201402326
      28c
      The transmetalation process in Suzuki-Miyaura reactions: Calculations indicate lower barrier via boronate Intermediate
      Ortuno, Manuel A.; Lledos, Agusti; Maseras, Feliu; Ujaque, Gregori
      ChemCatChem (2014), 6 (11), 3132-3138CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Recent exptl. reports have called into question the validity of the boronate mechanism (through a R-B(OH)3- intermediate) for the transmetalation step in the Suzuki-Miyaura cross-coupling, favoring instead the palladium hydroxo pathway (through an [LnPd(R')(OH)] intermediate). Herein we report DFT calcns. with the M06 functional performed on realistic model systems, including a combination of explicit solvent mols. along with a continuum method. These computational results support the boronate mechanism. The mechanistic proposal is shown to be compatible with the available exptl. evidence.
      (d) Lima, C. F. R. A. C.; Rodrigues, A. S. M. C.; Silva, V. L. M.; Silva, A. M. S.; Santos, L. M. N. B. F. Role of the Base and Control of Selectivity in the Suzuki–Miyaura Cross-Coupling Reaction. ChemCatChem 2014, 6, 1291– 1302,  DOI: 10.1002/cctc.201301080
      28d
      Role of the Base and Control of Selectivity in the Suzuki-Miyaura Cross-Coupling Reaction
      Lima, Carlos F. R. A. C.; Rodrigues, Ana S. M. C.; Silva, Vera L. M.; Silva, Artur M. S.; Santos, Luis M. N. B. F.
      ChemCatChem (2014), 6 (5), 1291-1302CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The outcome of the Suzuki-Miyaura cross-coupling for the direct competition reaction between two boronic acids was evaluated under routine synthesis conditions. The reaction selectivity depends on the amt. of the base used, with fewer bases favoring the reactivity of the boronic acid with lower pKa (stronger acid). The dependence of the reaction selectivity on base stoichiometry increases with the increase in the difference in the pKa values of the competing boronic acids. These results confirm a relation between acid-base chem. and the Suzuki-Miyaura reaction catalytic cycle. Also, under these specific conditions, the most reactive organoboron species toward transmetalation is the borate anion R-B(OH)3- instead of the neutral boronic acid R-B(OH)2. Hence, the main role of the base in the reaction mechanism is to increase the reactivity of the boronic acid toward the Pd-halide complex by converting it into the resp. organoborate. Boric acid, an important reaction byproduct, affects the selectivity in the Suzuki reaction because its gradual formation in the reaction medium disturbs the acid-base equil.
      (e) Amatore, C.; Jutand, A.; Le Duc, G. Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH–, CO32–) as Modulated by their Countercations (Na+, Cs+, K+) in Palladium-Catalyzed Suzuki–Miyaura Reactions. Chem. - Eur. J. 2012, 18, 6616– 6625,  DOI: 10.1002/chem.201200516
      28e
      Mechanistic Origin of Antagonist Effects of Usual Anionic Bases (OH-, CO32-) as Modulated by their Countercations (Na+, Cs+, K+) in Palladium-Catalyzed Suzuki-Miyaura Reactions
      Amatore, Christian; Jutand, Anny; Le Duc, Gaetan
      Chemistry - A European Journal (2012), 18 (21), 6616-6625, S6616/1-S6616/8CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The mechanism of the reaction of trans-ArPdBrL2 (Ar = p-Z-C6H4, Z = CN, H; L = PPh3) with Ar'B(OH)2 (Ar' = p-Z'-C6H4, Z' = H, CN, MeO), which is a key step in the Suzuki-Miyaura process, was established in DMF with two bases, acetate (Bu4NOAc) or carbonate (Cs2CO3) and compared with that of hydroxide (Bu4NOH). As anionic bases are inevitably introduced with a countercation M+ (e.g., M+OH-), the role of cations in the transmetalation/reductive elimination was 1st studied. Cations M+ (Na+, Cs+, K+) are not innocent since they induce an unexpected decelerating effect in the transmetalation via their complexation to the OH ligand in the reactive ArPd(OH)L2, partly inhibiting its transmetalation with Ar'B(OH)2. A decreasing reactivity order is obsd. when M+ is assocd. with OH-: Bu4N+> K+> Cs+> Na+. Acetates give trans-ArPd(OAc)L2, which does not undergo transmetalation with Ar'B(OH)2. This explains why acetates are not used as bases in Suzuki-Miyaura reactions that involve Ar'B(OH)2. Carbonates (Cs2CO3) give rise to slower reactions than those performed from Bu4NOH at the same concn., even if the reactions are accelerated in the presence of H2O due to the generation of OH-. The mechanism of the reaction with carbonates is then similar to that established for Bu4NOH, involving ArPd(OH)L2 in the transmetalation with Ar'B(OH)2. Due to the low concn. of OH- generated from CO32- in H2O, both transmetalation and reductive elimination result slower than those performed from Bu4NOH at equal concns. as Cs2CO3. Therefore, the overall reactivity is finely tuned by the concn. of the common base OH- and the ratio [OH-]/[Ar'B(OH)2]. Hence, the anionic base (pure OH- or OH- generated from CO32-) assocd. with its countercation (Na+, Cs+, K+) plays four antagonist kinetic roles: acceleration of the transmetalation by formation of the reactive ArPd(OH)L2, acceleration of the reductive elimination, deceleration of the transmetalation by formation of unreactive Ar'B(OH)3- and by complexation of ArPd(OH)L2 by M+.
      (f) Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V. Role of a base in Suzuki-Miyaura reaction. Russ. J. Gen. Chem. 2011, 81, 1573– 1574,  DOI: 10.1134/S1070363211070334
      28f
      Role of a base in Suzuki-Miyaura reaction
      Schmidt, A. F.; Kurokhtina, A. A.; Larina, E. V.
      Russian Journal of General Chemistry (2011), 81 (7), 1573-1574CODEN: RJGCEK; ISSN:1070-3632. (MAIK Nauka/Interperiodica)
      There is no expanded citation for this reference.
      (g) Butters, M.; Harvey, J.; Jover, J.; Lennox, A.; Lloyd-Jones, G.; Murray, P. Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride. Angew. Chem., Int. Ed. 2010, 49, 5156– 5160,  DOI: 10.1002/anie.201001522
      28g
      Aryl Trifluoroborates in Suzuki-Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride
      Butters, Mike; Harvey, Jeremy N.; Jover, Jesus; Lennox, Alastair J. J.; Lloyd-Jones, Guy C.; Murray, Paul M.
      Angewandte Chemie, International Edition (2010), 49 (30), 5156-5160, S5156/1-S5156/68CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The Suzuki-Miyaura coupling (SM) of 4-FC6H4BF3- K+ (I) with 3,5-(CF3)2C6H3Br was studied in a toluene/ water biphasic soln., and in a THF/ water soln.; both systems are commonly employed for the SM of trifluoroborates. The reactions in toluene/water, failed to go to completion: turnover ceased after 6 h, affording 55% of the base-catalyzed protodeboronation product PhF and ≤ 32% of coupling product 4-[3,5-(CF3)2C6H3]C6H4F (II). In aq. THF the reaction proceeded much more efficiently (5.5 h; > 95% yield of II), with few side products (< 0.1-2% ), even when the reaction was performed in air. But reaction of 4-C6H4B(OH)2 under identical conditions, gave II in variable yield, and afforded substantially more of side products 4-(4-FC6H4)C6H44-F and 4-FC6H4OH (2-40% ), compared to trifluoroborate substrate I. The reaction intermediates were established and a mechanism, supported by B3LYP calcns. was proposed for the SM.
      (h) Huang, Y.-L.; Weng, C.-M.; Hong, F.-E. Density Functional Studies on Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions Assisted by N- or P-Chelating Ligands. Chem. - Eur. J. 2008, 14, 4426– 4434,  DOI: 10.1002/chem.200800011
      28h
      Density functional studies on palladium-catalyzed Suzuki-Miyaura cross-coupling reactions assisted by N- or P-chelating ligands
      Huang, Yi-Luen; Weng, Chia-Ming; Hong, Fung-E.
      Chemistry - A European Journal (2008), 14 (14), 4426-4434CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      DFT studies with the B3LYP functional have been carried out on the Suzuki-Miyaura cross-coupling reactions of Ph chloride and phenylboronic acid catalyzed by palladium complexes with N- or P-chelating ligands. The full catalytic cycle, from the addn. of reactants to the catalyst to the release of the cross-coupled product from the complexed intermediate, has been examd. The stages within the cycle, such as oxidative addn., transmetalation, and reductive elimination, were validated by linking the mechanistically relevant intermediates and transition states. Various derivs. of diimine, diphosphine, and diamine were considered as potential model ligands. The catalytic reaction employing diimine as the chelating ligand has been verified as the one with the most energetically feasible route.
      (i) Braga, A. A. C.; Ujaque, G.; Maseras, F. A DFT Study of the Full Catalytic Cycle of the Suzuki–Miyaura Cross-Coupling on a Model System. Organometallics 2006, 25, 3647– 3658,  DOI: 10.1021/om060380i
      28i
      A DFT Study of the Full Catalytic Cycle of the Suzuki-Miyaura Cross-Coupling on a Model System
      Braga, Ataualpa A. C.; Ujaque, Gregori; Maseras, Feliu
      Organometallics (2006), 25 (15), 3647-3658CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      A computational study with the Becke3LYP DFT functional is carried out on the cross-coupling reaction of vinyl bromide, H2C:CHBr and vinylboronic acid, H2C:CHB(OH)2 catalyzed by Pd diphosphine [Pd(PH3)2] in the presence of an excess of OH- base. The full catalytic cycle is computed, starting from the sepd. reactants and the catalyst and finishing with the cross-coupled product and the regeneration of the catalyst. The different stages in the cycle (oxidative addn., isomerization, transmetalation, reductive elimination) were characterized through calcn. of the corresponding intermediates and transition states. Different alternative mechanisms are considered, depending on the no. of phosphine ligands at Pd, and on the cis or trans isomery around the metal center. The results indicate the existence of a no. of competitive pathways of reasonably low energy.
      (j) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledós, A.; Maseras, F. Computational study of the transmetalation process in the Suzuki–Miyaura cross-coupling of aryls. J. Organomet. Chem. 2006, 691, 4459– 4466,  DOI: 10.1016/j.jorganchem.2006.02.015
      28j
      Computational study of the transmetalation process in the Suzuki-Miyaura cross-coupling of aryls
      Braga, Ataualpa A. C.; Morgon, Nelson H.; Ujaque, Gregori; Lledos, Agusti; Maseras, Feliu
      Journal of Organometallic Chemistry (2006), 691 (21), 4459-4466CODEN: JORCAI; ISSN:0022-328X. (Elsevier Ltd.)
      The transmetalation step of the Suzuki-Miyaura cross-coupling between aryl groups is analyzed by DFT calcns. with the Becke3LYP functional. The halide considered is PhBr, and the organoboronic acid is PhB(OH)2. The model catalyst is Pd(PH3)2, and the base, OH-. The transmetalation is considered to start from the Pd(Ph)(PH3)2Br complex, the product of the oxidative addn. The results are compared with those of a previous study on the analogous reaction with vinyl groups, and it is shown that the reaction mechanism is very similar.
      (k) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. Computational Characterization of the Role of the Base in the Suzuki–Miyaura Cross-Coupling Reaction. J. Am. Chem. Soc. 2005, 127, 9298– 9307,  DOI: 10.1021/ja050583i
      28k
      Computational characterization of the role of the base in the Suzuki-Miyaura cross-coupling reaction
      Braga, Ataualpa A. C.; Morgon, Nelson H.; Ujaque, Gregori; Maseras, Feliu
      Journal of the American Chemical Society (2005), 127 (25), 9298-9307CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The role of the base in the transmetalation step of the Suzuki-Miyaura cross-coupling reaction is analyzed computationally by means of DFT calcns. with the Becke3LYP functional. The model system studied consists of Pd(CH:CH2)(PH3)2Br as the starting catalyst complex, CH2:CHB(OH)2 as the organoboronic acid, and OH- as the base. The two main mechanistic proposals, consisting of the base attacking first either the palladium complex or the organoboronic acid, are evaluated through geometry optimization of the corresponding intermediates and transition states. Supplementary calcns. are carried out on the uncatalyzed reaction and on a process where the starting complex is Pd(CH:CH2)(PH3)2(OH). These calcns., considered together with available exptl. data, strongly suggest that the main mechanism of transmetalation in the catalytic cycle starts with the reaction of the base and the organoboronic acid.
      (l) Miyaura, N. Cross-coupling reaction of organoboron compounds via base-assisted transmetalation to palladium(II) complexes. J. Organomet. Chem. 2002, 653, 54– 57,  DOI: 10.1016/S0022-328X(02)01264-0
      28l
      Cross-coupling reaction of organoboron compounds via base-assisted transmetalation to palladium(II) complexes
      Miyaura, Norio
      Journal of Organometallic Chemistry (2002), 653 (1-2), 54-57CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science B.V.)
      A review. Until recently, organoboronic acids have been of limited use in org. synthesis due to their low reactivity for ionic reactions. During the past two decades, however, it has become increasingly clear that they are valuable reagents capable of undergoing many carbon-carbon bond formations in org. syntheses. In 1979, catalytic carbon-carbon bond formation via transmetalation between organoboron compds. and palladium(II) halides was found to proceed in the presence of a base.
      (m) Matos, K.; Soderquist, J. A. Alkylboranes in the Suzuki–Miyaura Coupling:  Stereochemical and Mechanistic Studies. J. Org. Chem. 1998, 63, 461– 470,  DOI: 10.1021/jo971681s
      There is no corresponding record for this reference.
      (n) Aliprantis, A. O.; Canary, J. W. Observation of Catalytic Intermediates in the Suzuki Reaction by Electrospray Mass Spectrometry. J. Am. Chem. Soc. 1994, 116, 6985– 6986,  DOI: 10.1021/ja00094a083
      28n
      Observation of Catalytic Intermediates in the Suzuki Reaction by Electrospray Mass Spectrometry
      Aliprantis, Antonios O.; Canary, James W.
      Journal of the American Chemical Society (1994), 116 (15), 6985-6CODEN: JACSAT; ISSN:0002-7863.
      Pyridyl bromides, e.g., I (R = H, CHO, X = 2, 3-Br), couple with phenylboronic acids II (R1 = H, Me, R2 = H, Me) in the presence of Pd[PPh3]4 catalyst to give (2- and 3-aryl-substituted)pyridines III. Intermdiate formation of palladium complexes for this coupling reaction, e.g., [(pyrH)(R1R2C6H3)Pd(PPh3)2]+, are obsd. by electrospray Mass Spectrometry.
      (o) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.; Verhoeven, T. Mechanistic Studies of the Suzuki Cross-Coupling Reaction. J. Org. Chem. 1994, 59, 8151– 8156,  DOI: 10.1021/jo00105a036
      28o
      Mechanistic Studies of the Suzuki Cross-Coupling Reaction
      Smith, George B.; Dezeny, George C.; Hughes, David L.; King, Anthony O.; Verhoeven, Thomas R.
      Journal of Organic Chemistry (1994), 59 (26), 8151-6CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
      The key step in the synthesis of the drug losartan is a palladium-catalyzed cross-coupling reaction of an aryl bromide and a boronic acid. The reaction scheme was defined in kinetic studies using HPLC, and computer simulation served to depict the time dependence of the concns. of palladium species, which were not obsd. exptl. Two catalyst poisons were identified and characterized. One was an isomeric impurity of the aryl bromide; the other was formed in the reaction mixt. upon hydrolysis of the boronic acid and two of its impurities.
      (p) Thomas, A. A.; Zahrt, A. F.; Delaney, C. P.; Denmark, S. E. Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations. J. Am. Chem. Soc. 2018, 140, 4401– 4416,  DOI: 10.1021/jacs.8b00400
      28p
      Elucidating the Role of the Boronic Esters in the Suzuki-Miyaura Reaction: Structural, Kinetic, and Computational Investigations
      Thomas, Andy A.; Zahrt, Andrew F.; Delaney, Connor P.; Denmark, Scott E.
      Journal of the American Chemical Society (2018), 140 (12), 4401-4416CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The Suzuki-Miyaura reaction is the most practiced palladium-catalyzed, cross-coupling reaction because of its broad applicability, low toxicity of the metal (B), and the wide variety of com. available boron substrates. A wide variety of boronic acids and esters, each with different properties, have been developed for this process. Despite the popularity of the Suzuki-Miyaura reaction, the precise manner in which the org. fragment is transferred from boron to palladium has remained elusive for these reagents. Herein, we report the observation and characterization of pretransmetalation intermediates generated from a variety of commonly employed boronic esters. The ability to confirm the intermediacy of pretransmetalation intermediates provided the opportunity to clarify mechanistic aspects of the transfer of the org. moiety from boron to palladium in the key transmetalation step. A series of structural, kinetic, and computational investigations revealed that boronic esters can transmetalate directly without prior hydrolysis. Furthermore, depending on the boronic ester employed, significant rate enhancements for the transfer of the B-aryl groups were obsd. Overall, two crit. features were identified that enable the transfer of the org. fragment from boron to palladium: (1) the ability to create an empty coordination site on the palladium atom and (2) the nucleophilic character of the ipso carbon bound to boron. Both of these features ultimately relate to the electron d. of the oxygen atoms in the boronic ester.
    29. 29

      Lloyd-Jones and Lennox note that “Elucidation of the dominant pathway to transmetalation is not at all straightforward: one must establish the kinetically active boron and palladium intermediates, and they may not necessarily be the most abundant species present in the medium.”. (27)

      There is no corresponding record for this reference.
    30. 30

      Detailed studies exploring the transmetalation of trans-[Pd(PPh3)2(Ph)(I)] with p-tol-B(OH)3K (and 18-crown-6) and Pd(PPh3)(Ph)(μ-OH)]2 with p-tol-B(OH)2 under stoichiometric conditions were performed in THF/H2O solvent mixtures. (26) Extensive studies employing electrochemical methods to investigate the transmetalation of trans-[Pd(PPh3)2(Ar)(X)] with Ar-B(OH)2 (n-Bu4NOH as the base) under catalytic conditions were performed in a DMF/MeOH solvent mixture. (22)

      There is no corresponding record for this reference.
    31. 31

      Germane observations regarding the adverse effect of PPh3 have also been reported in Pd-catalyzed Stille cross-couplings; see ref (9).

      (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C., Jr Palladium catalysis in cephalosporin chemistry: general methodology for the synthesis of cephem side chains. J. Org. Chem. 1990, 55, 5833– 5847,  DOI: 10.1021/jo00310a014
      31a
      Palladium catalysis in cephalosporin chemistry: general methodology for the synthesis of cephem side chains
      Farina, Vittorio; Baker, Stephen R.; Benigni, Daniel A.; Hauck, Sheila I.; Sapino, Chester, Jr.
      Journal of Organic Chemistry (1990), 55 (23), 5833-47CODEN: JOCEAH; ISSN:0022-3263.
      The Pd-catalyzed coupling of 3-(triflyloxy)cephems with organotin compds.leads to 3-alkenyl-, 3-alkynyl-, and 3-arylcephems under exceptionally mild conditions. While this approach was not satisfactory for 3-allylcephems, the related coupling of easily available 3-(chloromethyl)cephems with stannanes provided a high-yielding route to such 3-allylcephems and also to 3-benzyl- and 3-homoallylcephems. The choice of the catalyst was crucial in both cases. PPh3-based catalysts were quite unsatisfactory. A much better ligand in this respect was tri(2-furyl)phosphine, which is introduced as a useful new ligand in organopalladium chem. The effect of this ligand on coupling rates is discussed. It is suggested that reduced electron d. at Pd enhances the rate of the transmetalation, considered to be the rate-detg. step in these coupling reactions. Cases of unexpected transfer order among unsym. substituted stannanes were obsd., as well as a complex coupling reaction between (chloromethyl)cephems and alkynylstannanes. These new facets of the Stille coupling, as well as the potential of this chem. for the development of new cephalosporin antibiotics, are discussed.
      (b) Scott, W. J.; Stille, J. K. Palladium-catalyzed coupling of vinyl triflates with organostannanes. Synthetic and mechanistic studies. J. Am. Chem. Soc. 1986, 108, 3033– 3040,  DOI: 10.1021/ja00271a037
      31b
      Palladium-catalyzed coupling of vinyl triflates with organostannanes. Synthetic and mechanistic studies
      Scott, William J.; Stille, J. K.
      Journal of the American Chemical Society (1986), 108 (11), 3033-40CODEN: JACSAT; ISSN:0002-7863.
      The palladium-catalyzed coupling reaction of vinyl triflates, e.g., (I), with acetylenic, vinyl, allyl, and alkyl tin reagents in the presence of LiCl or another suitable salt takes place in high yields under mild reaction conditions; however, benzyl and Ph tin reagents give poor yield of coupled product. The utilization of a tin or silicon hydride reagent in place of the organotin partner yields the alkene by reductive cleavage of the triflate group. The palladium-catalyzed reaction of vinyl triflates with Me3SnSnMe3 gives vinyl stannanes in high yields. Regioselectively formed vinyl triflates can be used to produce 1,3-dienes as the regioisomeric coupled products.
    32. 32

      The reaction of trans-[(Pd(PPh3)2(p-NCC6H4)(X)] (X = Cl, Br, I) with PhB(OH)2 was studied as a function of initial hydroxide concentration in DMF. In this way, the following reactivity order was determined: [Pd–I] > [Pd–Br] > [Pd–Cl]. (22)

      There is no corresponding record for this reference.
    33. 33

      For a study focused on the reactivity of Pd(0) complexes derived from mixtures of Pd(dba)2 and PPh3 and P(2-furyl)3 ligands, see for example:

      Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.; Khalil, F.; Chahdi, F. O. Comparative Reactivity of Palladium(0) Complexes Generated in Situ in Mixtures of Triphenylphosphine or Tri-2-furylphosphine and Pd(dba)2. Organometallics 1998, 17, 2958– 2964,  DOI: 10.1021/om971064u
      33
      Comparative Reactivity of Palladium(0) Complexes Generated in Situ in Mixtures of Triphenylphosphine or Tri-2-furylphosphine and Pd(dba)2
      Amatore, Christian; Jutand, Anny; Meyer, Gilbert; Atmani, Hamid; Khalil, Fouad; Chahdi, Fouad Ouazzani
      Organometallics (1998), 17 (14), 2958-2964CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
      For PPh3, mixts. of Pd(dba)2 and nTFP (TFP = tri-2-furylphosphine, n ≥ 2) in DMF and THF (S) lead to the formation of Pd(dba)(TFP)2, SPd(TFP)3 in equil. with SPd(TFP)2. The substitution of dba by the phosphine in Pd(dba)L2 to form SPdL3 is easier for L = TPF than for L = PPh3. The less ligated complex SPd(TFP)2 is the reactive species in the oxidative addn. with Ph iodide. In THF, {Pd(dba)2 + nTFP}, a mixt. often used as a catalyst promoter in several synthetic org. reactions, is found to be less reactive than {Pd(dba)2 + nPPh3} for small values of n (n = 2 or 4) whereas it is more reactive for higher values of n (n > 6). Conversely, in DMF, {Pd(dba)2 + nTFP} is always found to be more reactive than {Pd(dba)2 + nPPh3} whatever n (n ≥ 2).
    34. 34

      Farina and Krishnan also state “When a large excess of P(2-furyl)3 was added to a solution of trans-[Pd(PPh3)2(Ph)(I)] and PPh3, no trace of trans-[Pd{P(2-furyl)3}2(Ph)(I)] was observed, the corresponding signal for P(2-furyl)3 being the only new peak in the spectrum.”. (9)

      There is no corresponding record for this reference.

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