A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogenated Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd Nanoparticles-the Case for Exploiting Pd Catalyst Speciation.

Site-selective dihalogenated heteroarene cross-coupling with organometallic reagents usually occurs at the halogen proximal to the heteroatom, enabled by intrinsic relative electrophilicity, particularly in strongly polarized systems. An archetypical example is the Suzuki-Miyaura cross-coupling (SMCC) of 2,4-dibromopyridine with organoboron species, which typically exhibit C2-arylation site-selectivity using mononuclear Pd (pre)catalysts. Given that Pd speciation, particularly aggregation, is known to lead to the formation of catalytically competent multinuclear Pdn species, the influence of these species on cross-coupling site-selectivity remains largely unknown. Herein, we disclose that multinuclear Pd species, in the form of Pd3-type clusters and nanoparticles, switch arylation site-selectivity from C2 to C4, in 2,4-dibromopyridine cross-couplings with both organoboronic acids (SMCC reactions) and Grignard reagents (Kumada-type reactions). The Pd/ligand ratio and the presence of suitable stabilizing salts were found to be critically important in switching the site-selectivity. More generally, this study provides experimental evidence that aggregated Pd catalyst species not only are catalytically competent but also alter reaction outcomes through changes in product selectivity.

Introduction

Dihalogentated organic compounds, particularly heteroarenes, serve as synthetically useful structural templates for increasing molecular complexity. They enable multiple modes of connectivity, providing access to a vast array of compounds with interesting properties, from agrochemicals and pharmaceuticals to advanced materials.[1,2] Classical cross-coupling reaction methodologies are powerful tools for enabling site-selective processes to be realized, as outlined in two critical reviews by Fairlamb in 2007[3] and Spivey et al. in 2017.[4] Leading examples are given in Scheme , showing the preferred cross-coupling site for a series of dihalogenated heteroarenes. Normally, site-selectivity is seen at halogens activated by the ring heteroatom, either through proximity or favorable bond polarization in the extended π-ring system. Houk et al. explained the origin of normal site-selectivity in the context of the distortion of the C–X bond from a given substrate and interaction energies on approach to the active Pd0L catalyst.[5] Consideration can further be made for the bond dissociation energies (BDE) at different C–X bonds. Handy et al. demonstrated that cross-coupling site-selectivity could be predicted, with caveats, by comparing the 1H NMR chemical shifts of the parent heteroarene—the most deshielded proton being the typical site for coupling in the corresponding C–X derivative.[6] Switching site-selectivity in the cross-coupling reactions of dihalogenated heteroarenes, which effectively possess biased intrinsic reactivity (through relative electrophilicity), is a difficult task. For 2,4-dibromopyridine 1, it is very challenging, as C2 site-selectivity dominates as described in the extensive screening work carried out by Cid[7] and Zhou et al.[8,9] There are only a few examples where atypical C4 site-selectivity in cross-coupling is known.[10] A C4 site-selective Suzuki–Miyaura cross-coupling example on 1 was reported by Hardie and Willans et al.,[11] which employs Pd-NHC precatalysts, possessing distinctive ligand architectures. For the best precatalyst, C4:C2 site-selectivity was ∼10:1. However, as is common to an eclectic array of dihalogenated heteroarene substrates, diarylation was found to be a competing process and overall product yields were moderate as a consequence (∼35% for monoarylation product). Dai et al. switched the site-selectivity in Suzuki–Miyaura cross-coupling reactions (SMCCs) involving 2,4-dichloropyridine using a Q-Phos/Pd(OAc)2 precatalyst system, resulting in a marginal bias toward the atypical C4-arylated product, but accompanied by low yields.[12] Higher C4-selectivities at 2,4-dichloropyridine were obtained by changes to exogenous ligands at Pd, as reported in 2020 by Yang et al.[13]

Scheme 1

Site-Selectivity in Suzuki–Miyaura Cross-Couplings of Heteroarenes, Exemplified by Dihalogenated Pyridines and Related Derivatives

A guiding example, for which many catalyst systems/reaction conditions have been investigated, is given, showing high C2 site-selectivity.

The background literature therefore highlights that switches from typical to atypical site-selectivity are feasible, but that fundamental reasoning is frustratingly lacking—the focus has often been placed on ligand changes, assuming a mononuclear Pd catalyst.[14−17] While logical, in our opinion Pd catalyst speciation is a bigger issue, where changes in mechanism might better account for typical to atypical site-selectivity changes.

Our research group has been engaged in understanding the role played by catalytically competent aggregated Pd clusters and nanoparticles in SMCCs, and related cross-couplings, for many years.[18−23] We presented the first compelling experimental evidence implicating heterogeneous surface catalysts in SMCCs,[24,25] which is supported by recent evidence using time-resolved fluorescence studies[26] and surface-enhanced Raman spectroscopic techniques.[27]

The knowledge outlined above is important in the context of understanding that mononuclear Pd species, generally thought to be the dominant catalytically active species in SMCCs, can aggregate to form higher order Pd nanoparticles that are capable of mediating further substrate turnover. A serious question facing the field of cross-coupling catalysis is the involvement of small Pd clusters (n < 13), as such species provide a potential bridge from mononuclear Pd1 species to Pd nanoparticles (PdNPs).[28] Indeed, in a recent study Li et al.[29] presented some evidence that [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]+[30,31] not only was an active Pd catalyst for SMCCs but also appears to invert the order of the oxidative addition and transmetalation steps within the catalytic cycle, proposing the activation of the aryl halide as being less like oxidative addition and more like σ-bond metathesis. Our recent findings showed that similar [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]X cluster species derive from a Pd3(OAc)6/6PPh3 precatalyst, by reaction of an organohalide (R–X, including 2-bromopyridine) with the intermediate formed PdI dinuclear species.[32] The outcome sparked our interest in understanding how higher order Pd species might affect site-selectivity in cross-coupling reactions of 2,4-dibromopyridine 1 with organoboronic acids 2, as well as other nucleophiles, such as Grignard reagents. We were encouraged as [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]X species were found to be more active in the reported SMCC reactions than Pd0(PPh3)3 (in terms of substrate turnover frequency). [Pd3(μ-X)(μ-PR2)2(PR3)3]X species have been invoked as catalytically relevant species under a range of conditions.[29,33,34]

Schoenebeck et al. have investigated the use of multinuclear catalysts for chemoselective cross-coupling reactions at substrates containing two or more different (pseudo)halide identities. For example, the reactivity of [Pd(μ-I)(Pt-Bu3)]2 enabled successive selective couplings at Br then OTf then Cl sites on aromatic substrates.[35,36] A Pd3 cluster catalyst, derived from highly active [Pd(μ-Br)(Pt-Bu3)]2,[37] facilitated selective cross-couplings at aryl iodide over the less activated aryl bromide sites.[34] Additionally, a nanoparticulate active catalyst, derived in situ from Pd2(dba)3, was found to enable chemoselective cross-couplings between aryl iodides and arylgermanes.[38] Despite the clear synthetic utility of chemoselective reactions at multiply halogenated compounds for rapid molecular diversification, the preferential site of cross-coupling is generally quite clear-cut, defined by the BDE of the C–X bond (e.g., for halides (X), I < Br < Cl ≪ F).[3,4] We note that regioselective control of cross-coupling at substrates featuring multiple halogens of the same type (i.e., with similar BDEs) constitutes a greater challenge than a chemoselective approach involving different halogens.

In this paper we examine the behavior of Pd3-type cluster and Pd nanoparticle catalysts that derive from Pd(OAc)2/nPPh3 precatalyst systems under working reaction conditions. Varying the number of PPh3 ligands (relative to Pd) enables us to switch between higher order Pd catalysis and mononuclear Pd1 catalysis. This has an impact on switching regioselectivity—the reaction outcome—from typical C2 to atypical C4, in 2,4-dibromopyridine 1 cross-couplings with either organoboronic acids 2 (SMCC reactions) or Grignard reagents 5 (Kumada–Corriu type reactions). The activity of PdNPs is modulated by additive stabilizing salts, which proved to be critical in switching catalyst site-selectivity. While PdNPs are established cross-coupling catalysts, this is the first time that site-selectivity in a dihalogenated heteroarene has been reversed through exploitation of conditions that facilitate the in operando (under working reaction conditions) generation of Pd nanoparticles.

Results and Discussion

A benchmark SMCC test reaction [1] is shown in Scheme , involving 2,4-dibromopyridine 1 and p-fluorophenyl boronic acid 2a to give three products: 3a, 3a, and 3a. The calculated bond dissociation energies for the C2–Br and C4–Br bonds in 1 were calculated to be 63.3 and 66.9 kcal mol–1 respectively (determined by Density Functional Theory calculations using the B3LYP/DGTZVP level of theory), which indicate that the C2–Br bond is weaker that the C4–Br bond, mirroring the expected typical site for functionalization.

Scheme 2

Benchmark SMCC of 1 with p-Fluoro-phenylboronic Acid 2a To Give Typical Product 3a, Atypical Product 3a, and Diarylated Product 3a [1]; the Proposed Equilibrium for 2a and n-Bu4NOH, Which Is Expected to Lie to the Right-Hand Side Is Shown in [2]

The reaction conditions described in Scheme [1] are drawn from our earlier studies,[32] informed by the work of Jutand et al.[39] The reaction conditions benefit from being homogeneous (THF/H2O/[n-Bu4N]OH base at 40 °C, with a ratio of THF:H2O of 1:1). The high basicity ensures that the dominant boron species present in solution is the aryl boronate species 2a′, stabilized by an nBu4N+ cation [2].[40a,40b] We anticipated the importance of this in terms of exploiting site-selectivity changes brought about by Pd catalyst speciation, under varying Pd/ligand ratios. Consistent with the findings reported by Cid,[7] our reaction conditions employing Pd(PPh3)4 as the catalyst, gave rise to typical C2 site-selectivity at 1 although conversion was low at 40 °C. The latter finding parallels the low reactivity of 2-bromopyridine under identical conditions (i.e., the presence of higher PPh3 equivalents results in lower catalyst efficacy).[32]

C2-selectivity was also observed when employing Pd2(dba)3·CHCl3 (ca. 93% purity)[41] with 2 or 4 equiv of PPh3 under the identical conditions {forming Pd0(dba)3–/(PPh3) where n = 1 or 2}. Significant differences in catalyst efficacy were revealed using Pd3(OAc)6/PPh3 precatalyst ratios, hereafter referred to as Pd(OAc)2/nPPh3 (where n = 0.5 to 4) under conditions as summarized in Scheme . For each catalytic regime, the conversion of 1 to products 3a, 3a, and 3a is given in Figure (note that competing homocoupling reactions/protodebromination or protodeborylation were not observable).

Figure 1

Summarizing Pd catalyst efficacy under different precatalytic Pd:PPh3 regimes, showing reaction conversions of which product selectivities for the SMCC (Scheme ) of 1 with p-fluoro-phenylboronic acid 2a to give typical product 3a and atypical product 3a and bis-arylated product 3a.

For the Pd(OAc)2/nPPh3 ratios of 1:3 or 1:4, C2-site selectivity was observed, giving 3a as the major product, an outcome consistent with that observed, including lower product conversions, for the ubiquitous Pd0(PPh3)4 catalyst system. It is well established that Pd0(PPh3) species (where n = 2 or 3), and/or anionic derivatives, are formed from the Pd(OAc)2/nPPh3 ratios of 1:3 or 1:4, respectively.[32,42−45]

Altering the Pd(OAc)2/nPPh3 ratio to n = 2.5 results in a switch in site-selectivity to the atypical 3a product. Concomitant with this switch in site-selectivity is an increase in substrate 1 conversion, an outcome particularly evident on lowering nPPh3 in the system to n < 2. The highest catalyst efficacy and C4-site selectivity are seen for Pd(OAc)2/nPPh3, in a 1:1 or 1:1.5 ratio. Of particular note is the activity observed for the [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3]Cl cluster precatalyst (referred to as ‘PdCl’ in Figure ). This latter finding correlates with the Pd/P ratio in the PdCl cluster which contains three donating PPh3 ligands (1 PPh3 per Pd) and two pseudohalogen-like anionic PPh2 ligands (the average oxidation state per Pd being 4/3). Where n = 0, thus under an exogenous phosphine ligand-free regime, the reactivity drops off significantly, although overall 3a product selectivity is maintained. Hence, under our SMCC conditions, merely changing the Pd(OAc)2/nPPh3 ratio results in a switch in site-selectivity and catalyst efficacy, with markedly increased reaction conversions and higher selectivity for the atypical 3a product.

With the knowledge that Pd(OAc)2 and 1 equiv of PPh3 provided increased C4-site selectivity in SMCC reactions of 1, we investigated whether other aspects of the conditions contributed to the atypical site-selectivities (Scheme ) of 1 with p-anisylboronic acid (2b), which gave overall 3b selectivity under “benchmark” conditions (entry 1, Table ).

Scheme 3

Testing Additive and Base Effects for the SMCC between 1 and 2b

Table 1

Modifying the Base and Additives in the SMCC Reaction between 1 and 2b (Scheme )

Precatalyst	Entry	Base	Additive	Conv (%)a	3bC2–Ar:3bC4–Ar:3bdiaryla
Pd(OAc)2/1PPh3	1	n-Bu4NOH	none	100	10:70:20
	2	KOH	none	89	26:46:28
	3	KOH	n-Bu4NBr	88	3:70:26
Pd(OAc)2/2PPh3	4	n-Bu4NOH	none	100	18:58:24
	5	KOH	n-Bu4NBr	100	8:79:6
Pd3Cl2	6	n-Bu4NOH	none	100	15:69:16
	7	KOH	none	92	38:38:24
	8	KOH	n-Bu4NBr	94	9:82:10
	9	KOH	n-Oct4NBr	100	7:90:3

Determined by 1H NMR analysis of the crude reaction mixture, after 1 h.

Using KOH (aq.) as the base in place of n-Bu4NOH (aq.) (entry 2, Table ) resulted in a marginal reduction in conversion but, more strikingly, a marked reduction in site-selectivity, as exemplified by the reduced 3b:3b ratio when using a Pd(OAc)2/1PPh3 catalytic system. This observation indicated the cation of the base, n-Bu4NOH(aq.), as a critical factor in the higher site-selectivities observed. Indeed, employing KOH (aq.) base alongside an n-Bu4NBr additive increased the 3b:3b site-selectivity at the expense of relatively higher amounts of 3b (entry 3, Table ). Cations have been shown to be able to influence SMCC reaction rates, principally the transmetalation step,[39,46−48] but to our knowledge this is the first example of such a cation affecting the site-selectivity outcome of a cross-coupling reaction involving a dihalogenated heteroarene. Using a Pd(OAc)2/2PPh3 catalytic system alongside a KOH (aq.)/n-Bu4NBr base system similarly boosted C4 selectivity (entries 4 and 5, Table ). Analogous observations were made employing catalytic PdCl (entries 6–9, Table ). Arguably the best outcome in terms of global 3b product selectivity was obtained using Pd(OAc)2/2PPh3 or PdCl along with KOH/n-Bu4NBr (entries 3 and 5 respectively). Switching to the longer-chain quaternary ammonium salt n-octylammonium bromide (n-Oct4NBr) in place of n-Bu4NBr gave the highest product selectivity for 3b (entry 9, Table ).

An assay was designed to track the product evolution of 3b, 3b, and 3b products over time in the SMCC reaction between 1 and p-anisylboronic acid 2b, enabled by the Pd(OAc)2/2PPh3 and PdCl catalyst systems and an n-Bu4NOH(aq.) base (Scheme , Graphs A and B Figure ) .

Scheme 4

Conditions, Reagents, and Catalysts Used for Kinetic Product Distribution Analysis in SMCC Reactions of 1

Figure 2

Product distribution of 3b, 3b, and 3b as functions of time in the SMCC reaction between 1 and 2b. Using (A) Pd3Cl2 and (B) Pd(OAc)2/2PPh3 as the precatalyst.

Graphs A and B (Figure ) show that employing PdCl or Pd(OAc)2/2PPh3 as a precatalytic system resulted in broadly comparable overall reactivities with time. In both cases 3b was the predominant product, the quantity of which reached a maximum conversion at approximately 35 and 25 min for PdCl and Pd(OAc)2/2PPh3, respectively. After this time, 3b was slowly converted into 3b while the amount of 3c remained approximately constant. This study indicated that, with the Pd loading fixed at 3 mol %, the Pd(OAc)2/2PPh3 catalyst is marginally more efficacious than PdCl, accounting for the increased 3b conversion observed with Pd(OAc)2/2PPh3, compared with PdCl in Table .

Given our observations on the importance of the Pd/PPh3 ratio and aliphatic cation n-Bu4N+ as necessary requirements for atypical 3b site-selectivity in SMCCs, it was decided to assess whether such effects emerge in the Kumada cross-coupling of 1 with phenylmagnesium bromide (5) forming 3c, 3c, and 3c (Scheme ).

Scheme 5

Conditions for the Kumada Cross-Coupling of 1 with Phenylmagnesium Bromide 5

Variables changed are highlighted in bold.

The Pd(OAc)2/nPPh3 ratio and catalyst prestir time (in THF) were altered, with reactions being run in the presence and absence of n-Oct4NBr, enabling conversions of 1 and selectivity changes to monoarylated products: 3c and 3c to be fully assessed (Table ).

Table 2

Changes in Conversion of 1 and Product Site-Selectivity Outcomes, upon Changing Reaction Variables in Kumada Cross-Couplings (Scheme )

Entry	Pd(OAc)2:nPPh3	Catalyst prestir time (h)	n-Oct4NBr	Conv (%)a	3cC2Ar:3cC4Ar:3cdiaryla
1	No cat.	0.5	–	0	N/A
2	1:4	0.5	–	100	83:0:17
3	1:2	0.5	–	100	91:3:6
4	1:1	0.5	–	99	84:6:9
5	1:1	24	–	85	80:11:8
6	1:1	0.5	+	83	21:68:12
7	1:1	24	+	96	15:77:8
8	1:4	0.5	+	96	67:26:7

Determined by 1H NMR of the crude reaction mixture after 1 h.

In the absence of n-Oct4NBr, high selectivity for the 3c product was observed (entries 2–4,Table ). Selectivity for 3c remained, albeit diminishing, when the catalyst prestir time was extended to 24 h (entry 5, Table ). Employing n-Oct4NBr instigated a switch in site-selectivity favoring 3c as the major product, thus mirroring the requirement for a quaternary ammonium salt observed for C4-site-selectivity in the SMCC regime vide supra.

Lengthening the prestir time to 24 h resulted in a moderate increase in 3c:3c site-selectivity from 3.2:1 to 5.1:1, accompanied by an increase in conversion. The outcome provides an indication that an active and selective Pd catalyst species was generated during this time. The catalyst, generated from Pd(OAc)2 and 4PPh3, prestirred alongside n-Oct4NBr (0.5 h, THF), led to 3c product selectivity, confirming the dual requirement of a high Pd:P ratio as well as an additive salt for overall selectivity under the specified conditions.

To gain insight into the mechanistic dichotomy in site-selectivity seen for 1, the effect of para-aromatic substituents on reaction conversion and site-selectivity was assessed in the SMCC reactions employing appropriate substituted arylboronic acids (Figure and Scheme ).

Figure 3

Effect of product selectivities in SMCC reactions as a function of catalyst system employed and para-substituent on the phenylboronic acid substrate. (A) Using Pd2(dba)3·CHCl3/2PPh3. (B) Pd3Cl2. (C) Pd(OAc)2/1PPh3.

Scheme 6

Conditions, Reagents, and Catalysts Used for para-Substituent Analysis of Site-Selective SMCC Reactions at 1

Determined by 1H NMR analysis of the crude reaction mixture, after 1 h.

The model SMCC reaction was carried out with a series of para Z-substituents to determine whether an electronic contribution influenced the overall site-selectivity, in selecting the C2–Br or C4–Br bonds in 1. Three different precatalytic systems were employed for this part of the study: first, Pd2(dba)3·CHCl3 (∼93% purity) with 2 PPh3, which proved to be an effective 3 site-selective catalyst under the conditions. Second, the 3 site-selective catalyst systems, namely PdCl cluster and Pd(OAc)2/1PPh3, were assessed (Figure ).

An important observation from this series of experiments is that the greater the electron-withdrawing capacity of the Z-substituent, the higher the selectivity for the atypical 3 product. Concomitant with these observations was lower overall product conversions, indicating that the transmetalation step as rate-determining or that, in some form, the Z-substituent influences reaction site-selectivity involving 1. Taking the Pd2(dba)3·CHCl3/2PPh3 catalyst system (Figure A), the most active aryl boronic acid is para-anisylboronic acid 2b, affording high selectivity for 3b, although competing 3b is apparent. Similar behavior was noted for para-methyl phenylboronic acid 2d and phenylboronic acid 2e.

The response of the PdCl cluster catalyst to changes in the para Z-substituents of the phenylboronic acids is predictable, in that high selectivity for the 3 products were recorded (Figure B). A similar but more subtle response is seen for the Pd(OAc)2/1PPh3 catalyst system (Figure C).

A plot of ΔΔG‡ against σP reveals the reaction sensitivity to the phenylboronic acid para-substituent Z (Figure ). One sees that PdCl cluster and Pd(OAc)2/1PPh3 catalyst systems behave quite differently to Pd2(dba)3·CHCl3/2PPh3. The magnitude for the gradient (∼0.24) for the latter catalyst system is in-keeping with the presumption that the aryl boronic acid substituent ought not to affect site-selectivity in 1, as oxidative addition occurs prior to transmetalation for mononuclear Pd catalysts. However, larger gradients are seen for the PdCl cluster (∼0.77) and Pd(OAc)2/1PPh3 (∼0.48), providing evidence that these catalyst systems behave in a similar manner.

Figure 4

Plot of ΔΔG‡ against σP for para-substituent changes in SMCC reactions of 1 with p-Z-C6H4-B(OH)2 (2a–f).

Given the response of the SMCC reactions of 2,4-dibromopyridine 1 toward the ubiquitous ligand PPh3, we decided to screen other widely used phosphorus-containing ligands (Scheme , Figure ). We tested catalyst mixtures with Pd(OAc)2/ligand ratios of 1:2 in the reaction of 1 with phenylboronic acid 2c to give products 3c, 3c, and 3c. Based on consumption of 1 we see low conversions to the monoarylated products, albeit with a bias toward 3c. However, the dominant product is 3c resulting from diarylation.

Scheme 7

Conditions and Reagents Used for Determining the Effects of a Variety of P-Ligands on Site-Selective SMCC Reactions at 1

Figure 5

Performance of phosphorus-containing Pd precatalysts systems in site-selective Suzuki–Miyaura cross-coupling of 1.

Post-rationalization and Further Analysis

The important take-home message from the examples presented thus far is that a switch in site-selectivity for the 3 product in SMCC and Kumada cross-coupling reactions occurs when a quaternary ammonium salt n-R4NX (R = butyl or octyl, X = Br– or HO–) is employed alongside a low catalytic equivalence of nPPh3 per Pd(OAc)2 (where 0.5 < n ≥ 2.5 in the case of the SMCC reaction). The results point to the existence of different mechanisms being available to Pd, as the Pd(OAc)2/nPPh3 ratios are changed; i.e., the Pd catalyst speciation is different, which is in-keeping with our earlier studies.[32] The higher C2 site-selectivity for 3 using higher equivalences of PPh3 relative to Pd mirrors that reported by Cid et al.[7] using a Pd0(PPh3)4 catalyst which is closely related to the [Pd0(PPh3)(OAc)]− active species that arises from Pd(OAc)2/≥3 PPh3.[32,42−45] Indeed, in our study, in line with observations by Cid et al.,[7] we found that the direct reaction of 1 with Pd0(PPh3)4 in toluene at 23 °C (Figure ) gave the C2-oxidative addition product OA as the major regioisomer (OA/OA ≈ 25:1 by 31P NMR spectral analysis of a crude reaction mixture).

Figure 6

Confirmation of mechanistic reasoning for C2–Br site-selectivity in the reaction of Pd0(PPh3)4 with 1 at 23 °C.

The major regioisomer OA was characterized by X-ray diffraction analysis (corroborated by NMR spectroscopic analysis of the single crystal analyzed by X-ray diffraction). Cid et al. characterized the dinuclear Pd complex, OA (Figure ), resulting from loss of PPh3 from OA and subsequent dimerization of the putative 14-electron PdII species. These results indicate that oxidative addition of Pd0(PPh3) (n = 2 or 3) is the starting point for the SMCC of 1 when Pd0(PPh3)4 or Pd(OAc)2/≥3PPh3 is used as the precatalyst system, accounting for the overall C2 site-selectivity observed in our study, in addition to the previously reported cross-coupling reactions involving 1.[7,8]

Further experiments however showed that by stirring a solution of Pd(OAc)2 and 1 PPh3 at 0 °C for 5 min, layering of the solution with hexane and subsequent storage at −18 °C led to the growth of reddish-brown crystals. These have been confirmed by single crystal X-ray diffraction analysis to be the dinuclear PdII complex [PdII(μ2-OAc)(κ-OAc)(PPh3)]2 (4), containing bridging and terminal acetate groups, with one terminal PPh3 ligand at each Pd center (Figure A). The structure of 4 was also confirmed by 1H NMR spectroscopic analysis to be the major solution species formed immediately after mixing Pd(OAc)2 and 1 PPh3 (diagnostic peaks for the acetoxy methyl group at δH 1.34 ppm) (Figure B). We did not see any evidence of low-ligated phosphine adducts of Pd3(OAc)6.[49,50] The broadness of the single methyl resonance (for the OAc ligands) suggests that the two acetate environments are in exchange at 25 °C, supported by the proximal relationship as indicated in the solid-state.

Figure 7

Analysis of the THF-d. solution arising from the mixture of Pd(OAc)2/1PPh3. (A) XRD structure of a single crystal of 4 is shown (selected atoms). (B) 1H NMR analysis, confirming solution presence of 4 ca. 10 min after mixing at 25 °C. (C. i. and ii.) 31P NMR spectral data and reaction speciation, showing the decay of 4 and growth of multiple P-containing species over 12 h, 25 °C.

Complex 4 was originally reported by Wilkinson et al., who described it as unstable in the solid-state[51]—we concur with this description but were fortunate in being successful in obtaining a solid-state structure. Interestingly, the reactivity of 4 under (hydrogenative) reducing conditions has been investigated.[52,53]

We further investigated the solution behavior of 4 in dry d8-THF at room temperature by 31P NMR spectroscopic analysis (Figure C). Over time, a darkening of the solution was noted concomitant with the formation of multiple different phosphorus-containing species (Figure C. ii.). While Pd(OAc)2/2 or ≥3PPh3 is known to reduce/activate at the expense of concomitant oxidation of PPh3via. trans-[Pd(OAc)2(PPh3)2], in this case, O=PPh3 was only observed as a minor biproduct of the process. 1H NMR spectroscopic analysis of the post reaction solution indicated that Ac2O formed as a major byproduct, alongside AcOH, in a 1:3 ratio, respectively. This observation points toward 4 facilitating a different mechanism for activation of Pd(OAc)2 in the presence of 1 equiv of PPh3, when compared with trans-[Pd(OAc)2(PPh3)2].[32,42−45] TEM analysis of the decomposed solution of 4 (after overnight reaction at room temperature) demonstrated the presence of large, spherical Pd particles (micron-sized).[32] When Pd(OAc)2 was similarly treated with 2PPh3 at room temperature, a dinuclear PdI species was found to be transiently stable in THF. The observation that optimal catalyst activity and selectivity occur when relatively low precatalytic ratios of PPh3 to Pd(OAc)2 are employed, i.e. enabling formation of aggregated Pd clusters and particles, strongly correlates with the observed reactivity and selectivity involving cross-coupling reactions of 1, in keeping with differences in reactivity seen for the related 2-bromopyridine substrate.[32]Scheme summarizes our overall findings, linking catalyst speciation under differing Pd(OAc)2/nPPh3 regimes.

Scheme 8

Dichotomy in Site-Selectivity at 1: Different Pd Species Arising from Different Ratios of Pd(OAc)2/nPPh3 Result in Different Cross-Coupling Selectivities under Cross-Coupling Conditions

In addition to the Pd/P ratio, a key requirement for high 3 selectivity is the presence of a quaternary ammonium salt R4NX (R = n-butyl or n-octyl, X = Br–, OH–). The latter requires further comment and experimental corroboration, as there is a wealth of literature that explores the stabilization of highly active anionic PdNP catalyst species by salts. Dupont et al. reported that catalytic Pd particles, generated by in situ reductive activation of a palladacyclic compound, could be stabilized by imidazolium salts for applications in Heck coupling.[54] The immediate electropositive outer layer of a metal nanoparticle can be stabilized by anions, the sterics and basicity of which influence PdNP stability.[55,56] In a regime analogous to the electrical double layer, the anionic layer can in turn be stabilized by a layer of cations. Astruc et al. explored this electrosteric stabilization in the design of bespoke architectures for the stabilization of PdNPs.[57,58] This valuable prior knowledge underpins our hypothesis that electrosteric stabilization of PdNPs is critical to the site-selectivity switch seen in the cross-coupling reactions of 1. Thus, stabilized PdNPs, formed in situ from either precatalysts Pd(OAc)2 and 1PPh3 or PdCl by additive or in situ generated salts, are the catalyst species responsible for this atypical selectivity and relatively high activity, compared to that of the dominant mononuclear catalytic species generated from Pd(OAc)2 and ≥3PPh3, Pd(PPh3)4, or Pd2(dba)3·CHCl3/2PPh3.

We have tested our hypothesis further and shown that a tris-imidazolium tribromide salt can effectively stabilize PdNPs enabling a marked rise in site-selectivity at 1, exhibiting a 3b:3b ratio of 17.6:1, with a relatively low formation of 3b product (see Supporting Information (SI) for further details).

The notion that changes to Pd catalyst speciation might result in different chemoselectivities has been reported by Schoenebeck et al., elaborating on earlier findings by Fu et al.[14,16,59] They rationalized that cross-coupling selectivities at 4-chlorophenyl triflate occurred at the C–Cl site in reactions catalyzed by [Pd0(L)1] and the C–OTf side in reactions catalyzed by the analogous [Pd0(X)(L)]− complex (where X = an anion present in the system, L = PtBu3). In this case, however, both active catalysts were proposed to be mononuclear Pd0 ligated species (based on experimental and computational evidence). Indeed, subsequent work used 4-chlorophenyl triflate as a probe to differentiate between mechanisms arising from a dinuclear PdI precatalyst.[60]Our work has similarly shown two different mechanisms for the activation of different sites of the dibrominated heterocycle 1. However, in the case of selectivity for the C4 position, under the reaction conditions that we have identified, it is highly unlikely that such mononuclear Pd0 species can be present, an assertion based on what is known about Pd speciation as the Pd(OAc)2/nPPh3 ratio is altered (vide supra).[32]

Finally, the synthetic utility of the Pd3(OAc)6/3PPh3 catalytic system was demonstrated in the synthesis of a novel 2,4-disubstituted pyridine by successive C4-selective arylation by an SMCC reaction at 1, followed by an Ullman etherification[61] at its C2-position (see SI for further details).

Mechanistic Hypotheses

Given that such profound site-selectivity changes are seen for cross-couplings of 2,4-dibromopyridine 1, on changing Pd catalyst speciation in the presence of stabilizing salt additives, a discussion concerning the mechanistic implications is pertinent. If one assumes that only mononuclear Pd species are the relevant catalyst species (dependent on reaction conditions), then selection of the C2–Br over C4–Br bond occurs on activation of 1 by a Pd0(PPh3) complex (where that n is typically ≥2).[7] A neutral pathway is depicted in Scheme A. Here, the relative rates of oxidative addition would explain the typical site-selectivity for C2–Br, presuming this step is irreversible and that the associated higher intrinsic electrophilicity of this bond lowers the barrier to its activation. The case for this catalytic cycle has been made strongly elsewhere;[7] however, oxidative addition must be reversible (in Scheme A) in order to account for our experimental observations. Switching site-selectivity from C2–Br to C4–Br, i.e. 3 over 3, arguably requires a quite different ligand environment,[14,59,60,62] or a complete change in mechanism. We have not shown anionic mononuclear Pd species here, but clearly in the presence of n-R4NBr, such a pathway could be operative, with n-R4N+ acting as the stabilizing cation.[43,45,63]

Scheme 9

Mechanistic Hypotheses: (A) Catalytic Cycle Involving Mononuclear Pd Species, via Classical Pd Intermediates or Alternative Route Involving a SNAr-Type Mechanism; (B) Catalyst Cycle Based on That Evidenced by Li et al.[29] Involving Pd3 Cluster Species; (C) Proposed Involvement of Higher Order Pd Agglomerates (Note: Only Details of Key Steps Are Shown – trans–cis Isomerizations and Ligand Dissociation/Association Are Involved)

Note: (P) = PPh2; P = PPh3; X = anion, e.g. Br or OH.

Maes and Jutand et al.[64] have reported strong evidence for the existence of an SNAr mechanism for the activation of 5-substituted-2-bromo-pyridines, which is therefore shown in A for the C2-arylation pathway, important given the structural similarity to 1.

An alternative mechanism based on the strong experimental support reported by Li et al. “Pd3 cluster” catalysis is shown in Scheme B.[29] In this case the Pd3Cl2 cluster catalyst, via formation of a Pd3-hydroxo species, was proposed to activate the organoboronic acid first, the adduct of which could then activate the aryl halide. Inversion of the oxidative addition/transmetalation steps could explain the higher than expected Z-substituent sensitivity in the site-selective SMCC reaction involving 1, particularly in the region where Pd3 clusters/Pd nanoparticles are catalytically competent (Figure and Figure ).

A third scenario (Scheme C) highlights the potential role of Pd nanoparticles (agglomerates) in the activation of 1, in essence like the mechanism depicted in Scheme B. The Pd nanoparticles are shown ligated by PPh3 and halide ligands, as it is established that such stabilizing surface interactions are important.[65,66] In this case, an aryl boronate complex could be activated by the Pd nanoparticle surface, prior to oxidative addition of the C4–Br bond of 1. The interaction of base and anionic aryl boron species at Pd nanoparticle surfaces has been proposed by El-Sayed et al.[67] Such a situation aligns with the Z-substituent effect (aryl boronic acid) on reaction efficacy and site-selectivity. The scenario also fits with the observed speciation arising from Pd(OAc)2/1PPh3vide supra—the optimized catalyst system. There can be no doubt that the mechanistic complexity presented in Scheme requires significant independent investigation. (We have embarked on computational studies (DFT) to support the mechanistic hypotheses described in Scheme . However, we are yet to obtain reasonable results, as the conformational flexibility in these large Pd3Cl2 cluster species, and related downstream intermediates, is high, leading to local energy minima. We selected to not simplify the Pd3 structural models, as the ligand microenvironment surrounding these is clearly important in stabilization and in controlling how substrates approach the Pd centers and their activation.) We anticipate that specialist experimental methods (real-time fluorescence[26] and X-ray absorption spectroscopy[24,25]) might reveal insight into the underlying catalyst speciation behavior and complexity.

Conclusions

In conclusion, our studies have shown that site-selective cross-couplings of 2,4-dibromopyridine 1 are affected by the type of catalyst system used and catalyst speciation that ultimately results under working reaction conditions. The observations are clear for both SMCC and Kumada cross-coupling reactions. We have confirmed that Pd(OAc)2/≥3PPh3, and related catalyst systems, enable typical C2-selctivity. However, for the Pd(OAc)2/≤2PPh3 catalytic system, atypical C4-selectivity is seen, an outcome that is mirrored using the PdCl cluster catalyst. The addition of a quaternary ammonium salt proved to be a critical additive for atypical C4-selectivity, supporting the hypothesis that high site-selectivity is attributable to PdNPs formed in situ, for which the quaternary ammonium salt plays a stabilizing role. The hypothesis was supported using a bespoke tris-imidazolium tribromide salt, capable of stabilizing Pd nanoparticles.[54,55,57] Addition of such a salt to the SMCC reaction system led to a significant increase in the C4-selectivity. Our findings mark the first examples of site control of a dihalogenated heteroarene, switching between two halogens of the same type, while using the same Pd source [Pd3(OAc)6] and the same ligand type PPh3. It underlines the importance of controlling precise metal–ligand ratios for optimal catalyst performance. Interestingly, in the context of site-selective SMCCs, Spivey et al.[4] stated that “...caution must be applied when trying to rationalise switches in site-selectivities as a function of changes of conditions as the observed products may not arise from the ligated species expected.” We can now confirm that is the case, but that reaction outcomes can be controlled through understanding fundamental changes in Pd catalyst speciation.

More generally our study has demonstrated that the activity of well-established Pd catalyst mixtures can be very easily altered by small changes to the reaction conditions. We can recognize that understanding and controlling catalytic speciation may allow simple Pd catalytic precursors and simple inexpensive ligands (e.g., PPh3) to exhibit unique properties in catalytic cross-coupling chemistries. Such an approach could be potentially exploited to avoid the use of expensive ligand architectures. Furthermore, our approach to understanding the Pd catalyst speciation may serve to complement understanding in other powerful site-selective cross-couplings.[12,13,68−71]