Selectivity for Exhaustive Cross-Coupling of Dihaloarenes Is Affected by the Interplay between the Halide Byproduct, Solvent, and Ligand
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Selectivity for Exhaustive Cross-Coupling of Dihaloarenes Is Affected by the Interplay between the Halide Byproduct, Solvent, and Ligand
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Organometallics

Cite this: Organometallics 2026, 45, 6, 651–659
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https://doi.org/10.1021/acs.organomet.5c00423
Published February 20, 2026

Copyright © 2026 The Authors. Published by American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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In dihaloarene cross-couplings, the step(s) that take place after reductive elimination and before the start of the next cycle influence selectivity for monofunctionalization versus difunctionalization. When palladium is supported by a bulky ligand “L”, a competition exists between a second oxidative addition (leading to difunctionalization) and bimolecular displacement of Pd0 from the monofunctionalized product by a second smaller ligand. Because the oxidative addition of Ar–Br is faster than that of Ar–Cl, more difunctionalization might be expected with dibromoarenes compared to dichloroarenes. However, the opposite has been reported for some Suzuki–Miyaura cross-couplings. Here, we report that the selectivity outcome is closely tied to solvents: dibromoarenes tend to give less diarylation than dichloroarenes in oxygen-containing solvents of at least moderate polarity (e.g., THF), whereas a high selectivity for diarylation can be achieved in most aromatic and chlorinated solvents. The results suggest that, in polar oxygen-containing solvents, the bromide anion byproduct displaces LPd0 from the monocross-coupled product. The rate of this process is competitive with the rate of intramolecular oxidative addition en route to the diarylated product. In contrast, the analogous displacement of Pd0 by chloride (the byproduct when using dichloroarenes) appears to be a much slower process if it occurs at all.

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Introduction

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Cross-coupling reactions of multihalogenated aromatic substrates are often used in the preparation of biologically relevant small molecules or in the synthesis of highly conjugated organic materials. For the former purpose, it is usually desirable to achieve just a single cross-coupling, leaving behind one or more halides that might be used in a different step or that might be required in the final synthetic target. (1) On the other hand, preparation of highly conjugated organic materials often requires double, triple, or otherwise exhaustive cross-coupling of a di-, tri-, or polyhalogenated (hetero)arene. (2) Thus, for either synthetic purpose, it is important to be able to control the extent of cross-coupling. A better understanding of the mechanistic underpinnings may facilitate the fine-tuning of methods to achieve either selectivity outcome.
During Pd-catalyzed Suzuki–Miyaura cross-couplings of dihalogenated arenes, bulky monodentate ligands─which enable catalysis at 12e– PdL (3)─tend to promote difunctionalization, even with a deficit of the nucleophilic coupling partner. (4) In a recent study, we investigated the rationale for this ligand effect using dichloroarenes as the electrophilic coupling partner in combination with N-heterocyclic carbene (NHC) ligands. (5a) Selectivity for di- versus monoarylation was found to arise from the competition between two possible fates of the π-complex formed upon reductive elimination in the first catalytic cycle (Scheme 1). Pd0L apparently does not spontaneously dissociate from this π-complex, at least not under the room-temperature conditions we examined (likely due to the instability of low-coordinate palladium), but instead it can either ring-walk to the remaining halide and participate in a second intramolecular oxidative addition (leading to the diarylated product) or it can be displaced from the monocross-coupled product by a second incoming ligand L′ via a bimolecular transition state. The relative rates of oxidative addition and associative displacement, and thus the product ratios, depend on several factors, including solvent, additives, and sterics of both dichloroarene and the ancillary ligand L. With dichloroarenes, we found that acetonitrile and aromatic solvents can serve as L′ to break apart the π-complex, resulting in a higher proportion of monoarylated products in such solvents. Similarly, coordinating additives like pyridine and DMSO also promote more monoarylation. However, the energy of the crowded bimolecular transition state is raised by the steric bulk on either the substrate or the ancillary ligand. As such, increased sterics allow oxidative addition to outcompete disruption of the π-complex, resulting in more diarylated products.

Scheme 1

Scheme 1. Prior Work: (A) Competing Pathways Leading to Di- versus Monoarylation in Suzuki–Miyaura Coupling of Dichloroarenes; (B,C) Dibromoarenes Unexpectedly Give Less Diarylation than Dichloroarenes
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Based on this mechanistic picture, replacing dichloroarenes with dibromoarenes was expected to result in more diarylation, because oxidative addition of aryl bromides is generally faster than that of aryl chlorides. (6) This was indeed found to be true when the solvent is benzene. (5) Surprisingly, however, the expected trend was not observed in preliminary trials using THF, a typical solvent for Suzuki couplings (Scheme 1B). Whereas Pd supported by IPr (a bulky NHC ligand) favors diarylation of dichloroarene 1-Cl in a 1:4 ratio, the corresponding dibromoarene 1-Br is actually slightly less selective for diarylation (mono/di = 1:3). The reason for this counterintuitive selectivity was unexplained, but it has also been observed in other contexts. For example, the unexpected result that dichlorinated substrates can lead to better selectivity for “double Suzuki” couplings than dibrominated analogues has been noted for the reaction of dihalofluorenes in a mixture of 1,4-dioxane/water catalyzed by a Pd/IPr complex (Scheme 1C). (7)
The work herein seeks to reconcile the apparently contradictory observations that (a) oxidative addition is faster at aryl bromides than at aryl chlorides, but (b) dibromoarenes sometimes are less likely to undergo a second oxidative addition (to result in double cross-coupling) compared to dichloroarenes. Here, we report that the discrepancy between the expected selectivity (high diarylation) and the observed selectivity (low diarylation) in Suzuki–Miyaura couplings with dibromoarenes primarily appears in oxygen-containing solvents of at least moderate polarity, like THF. Our results suggest that, in such solvents, the bromide anion (a byproduct of oxidative addition) displaces Pd0(NHC) from the monocross-coupled product as anionic [BrPd0(NHC)]−. Based on product distributions, the rate of this process is competitive with the rate of intramolecular oxidative addition en route to the diarylated product. In contrast, the analogous displacement of Pd0 by chloride (the byproduct when using dichloroarenes) appears to be a much slower process, if it occurs at all.

Results and Discussion

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Solvent Effects on Selectivity with Pd/IPent

We began by interrogating more closely the effect of solvent on selectivity using catalytic (η3-1-tBu-indenyl)Pd(IPent)(Cl) in combination with dichlorobenzene 2-Cl or dibromobenzene 2-Br. IPent is even bulkier than IPr, and we had previously found that it promotes higher selectivity for diarylation of a dichloroarene in THF. (5a) With 2-Cl, diarylation dominates when the reaction is performed in ethers, alcohols, and acetone (Figure 1A). However, the proportion of monoarylation is higher in aromatic solvents, chlorinated solvents, MeCN, and DMSO (although the yield is very poor in DMSO). There is no clear correlation between selectivity and solvent polarity as measured by the dielectric constant. Instead, the solvent trends in Figure 1A may correlate with the solvents’ ability to coordinate to (NHC)Pd0 and displace it from the monocross-coupled product, where more diarylation is seen with less competent coordinators (such as alcohols and ethers).

Figure 1

Figure 1. Solvents exert different effects on the selectivity for monoarylation of (A) a dichloroarene versus (B) a dibromoarene. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). Average of ≥ 2 trials. The area of the bubbles correlates with the combined % yields of mono- and diarylated products with GC % yields calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3 is exclusively formed.

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The relative coordinating abilities of different solvents to Pd(0) are not well established, although some prior anecdotal evidence aligns with the suggestion in Figure 1A that ethers, alcohols, and acetone are worse coordinators for Pd(0) than are MeCN, DMSO, aromatic, and chlorinated solvents. In particular, catalytic and stoichiometric selectivity data indicate that MeCN and DMSO (but not THF) may coordinate to LPd(0) during oxidative addition when L = PtBu3. (8) In support of the coordinating ability of aromatic solvents, rare (NHC)Pd0(solv) complexes have been observed for which solv = benzene, whereas an analogous complex with solv = THF was speculated to be too unstable to detect. (9) Our previously reported studies with dichloroarenes (including concentration and order studies) also suggested that aromatic solvents and substrates can displace (NHC)Pd0 from a monocross-coupled product. (5a) Finally, coordinatively unsaturated dinuclear Pd(0) complexes have been reported to react rapidly with dichloromethane, (10) supporting the ability of such chlorinated solvents to bind to coordinatively unsaturated Pd(0). (11)
Interestingly, the solvent trends are largely inverted with dibromoarene 2-Br (Figure 1B). The use of aromatic and chlorinated solvents results in exclusive or near-exclusive diarylation. In these solvents, the dibromide substrate behaves as originally expected: much more diarylation is seen when compared to the dichloride, which is consistent with fast oxidative addition outcompeting displacement of (IPent)Pd0 from 3-Br by a solvent or by another molecule of 2-Br. However, THF, alcohols, and acetone (bolded labels) promote an increase in monoarylation, affording selectivity ratios closer to 50:50 that reflect more monoarylation than is seen with 2-Cl in the same solvents.
On first consideration, the faster oxidative addition of aryl bromides relative to chlorides seems inconsistent with the larger proportion of monoarylation observed in THF, alcohols, and acetone with 2-Br. However, we noted that these solvents all contain an oxygen atom and have moderate to high dielectric constants. (12) Although these solvents seem unlikely to serve as the incoming ligand that disrupts the intermediate π-complex (soft Pd0 is not oxophilic), oxygen is a good coordinator for harder cations such as K+. Thus, the high proportion of monoarylation in the polar oxygen-containing solvents could suggest that stabilization of ions is relevant to the selectivity with dibromoarenes. In particular, these data are consistent with the involvement of Br– (formally dissolved KBr, a byproduct of cross-coupling) in the selectivity-determining step in the reaction of 2-Br.

Relevance of the Bromide Anion to Selectivity

We conducted a series of experiments to evaluate the relevance of [Br–] to the selectivity. In the first experiment, the Pd/IPent-catalyzed cross-coupling reaction of 2-Br was monitored over time in three different solvents (Figure 2). In THF and acetone, the selectivity changes over the first several time points, with a lower proportion of monoarylation observed at the beginning. In both solvents, the product ratios largely level out after reaching about a 5–10% combined yield of products. At these conversions, the solutions are approximately saturated in KBr (see Supporting Information). In contrast, the reaction in the nonpolar solvent benzene gives exclusive diarylation at all time points (the reaction in benzene is also much faster and reaches higher conversion; see Supporting Information for details). Because the bromide anion is not present until after at least one catalytic turnover, the changing selectivity in THF and acetone is consistent with bromide promoting monoarylation in these solvents.

Figure 2

Figure 2. In acetone and THF, the cross-coupling of 2-Br becomes more monoselective after the first few catalytic turnovers, while the reaction in benzene gives exclusively diarylation throughout the course of the reaction. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). Results based on GC yields calibrated against undecane as an internal standard.

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In a second experiment, a Ag(I) salt was used to remove bromide from the solution in the reaction of 2-Br conducted in both acetone and THF (Table 1). Without silver, the reaction in both solvents goes to completion [∼100% conversion of PhB(OH)2], and monoarylation represents a substantial minority of the products (mono/di = 1: <2, entries 1 and 3). With two equiv of Ag2O, the reaction still goes to completion, but diarylated 4 is the only product detected (entries 2 and 4). This result implicates the bromide anion as a promoter of monoarylation in these oxygen-containing solvents. In contrast, Ag2O has no effect on selectivity in the reaction of 2-Cl in THF (entries 5 and 6), suggesting that the minor monoarylated product 3-Cl does not require chloride for its formation.
Table 1. Ag Inhibits Formation of the Monoarylated Product during Cross-Coupling of a Dibromoarene but Has No Effect on Selectivity of Cross-Coupling of a Dichloroarenea
entry2solventAg2O (equiv)343:4
12-Bracetone023341:1.5
22-Br 2n.d521: >99
32-BrTHF022381:1.7
42-Br 2n.d561: >99
52-ClTHF09501:5.4
62-Cl 29491:5.6
a

GC % yields calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials except entry 6 (1 trial). Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3 is exclusively formed. Mass balances slightly over the theoretical maximum are presumed due to boroxine impurity in the PhB(OH)2 reagent. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). “n.d” = not detected.

Finally, a Suzuki coupling was conducted with m-bromochlorobenzene 2-BrCl in either THF or benzene. We expected that, in THF, more monoarylation would be seen with 2-BrCl than with 2-Cl, since bromide would be a byproduct of cross-coupling at the more reactive C–Br position of 2-BrCl, and thus, bromide could displace Pd(0) from the monocross-coupled product. Indeed, consistent with the hypothesis that Br– can intercept Pd0 before a second oxidative addition takes place, the Pd/IPent-catalyzed Suzuki coupling of 2-BrCl in THF favors monoarylated product 3-Cl (Table 2, entry 2), whereas the analogous reaction of dichlorobenzene 2-Cl favors diarylated product 4 (entry 1). In fact, 2-BrCl reacts to give even more monoarylation than 2-Br (compare entry 2 to entry 3). This result is consistent with a slower rate of oxidative addition of the remaining Ar–Cl bond of 3-Cl relative to the Ar–Br bond of 3-Br. Thus, disruption of the π-complex between Pd0 and 3-Cl can more easily outcompete the oxidative addition that would lead to 4. (13)
Table 2. Bromochlorobenzene Gives More Monoarylation Than either Dichloro- or Dibromobenzenea
entrysolvent23-Cl (%)3-Br (%)4 (%)3:4
1THF2-Cl9--501:5.4
2 2-BrCl46n.d291.6:1
3 2-Br--22381:1.7
4benzene2-Cl52--291.8:1
5 2-BrCl64n.d242.6:1
6 2-Brn.d--531: >99
a

GC % yields calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3 is exclusively formed. Mass balances slightly over the theoretical maximum are presumed due to boroxine impurity in the PhB(OH)2 reagent. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). “n.d” = not detected; “--” = not applicable.

In benzene, 2-BrCl gives only slightly more monoarylation than 2-Cl (Table 2, entries 4 and 5). Compared to the dramatic change seen in THF, this result is consistent with worse stability of an ionic transition state (involving displacement of Pd0 by bromide) in benzene. However, the subtle change in selectivity may indicate that─even in benzene─the bromide anion can promote monoarylation to a small degree if oxidative addition is sufficiently slow.

An Updated Description of the Competing Pathways Available after Reductive Elimination

Taken together, these experiments suggest that the observed selectivity differences between dibromo- and dichloroarenes, including their differing responses to solvents, may be explained by the mechanistic scenario shown in Figure 3. The figure depicts possible paths that can be taken from the intermediate π-complex involving Pd0IPent that results from reductive elimination at the end of the first catalytic cycle for a given molecule of substrate. Palladium may ring-walk and oxidatively add into the remaining C–X bond to eventually give 4 (path (i)). Alternatively, Pd may be intercepted by one of several possible coordinating ligands to release 3 (paths ii–iv). (14) These ligands could include another molecule of the dihaloarene substrate (path (ii)), a molecule of solvent (path (iii)), or the halide byproduct of the first cross-coupling event (path (iv)). Selectivity for diarylation vs monoarylation (4 vs 3) depends on the relative rates of path i versus any of paths ii–iv. The differences in solvent effects seen with dibromo- vs dichloroarenes arise from the specifics of which of paths ii–iv (if any) are energetically competitive with path i for a given dihaloarene.

Figure 3

Figure 3. π-Complex between (IPent)Pd0 and the monocross-coupled product (shaded box) can proceed through divergent paths, leading to diarylation (path (i)) or to release of the monoarylated product (paths ii–iv). Selectivity depends on the relative rate of oxidative addition (path (i)) versus displacement of Pd by the substrate (path ii, relevant when X = Cl), by the solvent (path iii, relevant when X = Cl), or by the halide (path iv, relevant when X = Br).

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In cross-couplings of dichloroarenes, there is evidence that substrate-mediated path ii accounts for the minor amount of monocross-coupled product in THF. In particular, we had previously shown that, in THF, the proportion of monoarylated product increases with the starting concentration of dichloroarene, an effect that could not be explained by an intermolecular competition between 2-Cl and 3-Cl. (5a), (15) Similarly, solvent-mediated path iii is also possible with some solvents. Specifically, more monoarylation is detected in aromatic solvents (e.g., Table 2, entry 4), chlorinated solvents, and acetonitrile (Figure 1A), suggesting that these solvents are sufficiently coordinating to facilitate release of 3-Cl via path iii. Thus, both paths ii and iii may compete with path i in the reaction of dichloroarenes. In contrast, there is no evidence that chloride-mediated path iv contributes meaningfully to the selectivity with 2-Cl; for example, the addition of Ag2O as a chloride scavenger has no effect on the selectivity in THF (Table 1).
Conversely, substrate- and solvent-mediated paths ii and iii are typically too slow to outcompete fast C–Br oxidative addition (path (i)) in the cross-coupling of dibromoarenes catalyzed by Pd/IPent. In aromatic and halogenated solvents, exclusive or near-exclusive selectivity for diarylation is seen (e.g., Table 2, entry 6, and Figure 1B). However, bromide-mediated path iv becomes available for the reaction of 2-Br in oxygen-containing solvents of even moderate polarity, like THF, and significant quantities of monoarylation are seen in these solvents (e.g., Table 2, entry 3, and Figure 1B). The much higher proportion of monoarylation seen with dibromoarenes compared to dichloroarenes in THF─despite having a faster path (i)─indicates that bromide is much more capable of effecting path iv than chloride. KBr is modestly more soluble in organic solvents than KCl, but solubility differences between these salts do not appear to be sufficient to explain the different selectivities (see Supporting Information). Instead, the increased ability of bromide to effect path iv may relate to the nucleophilicity of bromide and/or an increased ability of solvents to stabilize the charged transition state for path iv when X = Br.
We also considered an alternative hypothesis to explain the differences between dibromoarenes and dichloroarenes, wherein bromide could promote a change in catalyst speciation. For example, bromide might promote the formation of Pd clusters/nanoparticles that result in “NHC-disconnected” catalysis. (16,17) We have not found evidence to support this alternative hypothesis (see Supporting Information), although it cannot be completely ruled out.

Selectivity with Other Bulky Ligands

Finally, we were interested in comparing the selectivity trends using IPent to those obtained with other bulky ligands. The Suzuki–Miyaura coupling of 2-Br was evaluated in benzene, THF, and acetone with the somewhat smaller NHC ligands IPr and IMes, as well as a series of bulky monophosphine ligands (Figure 4). The phosphines were chosen from a set of ligands whose size is believed to be large enough to promote oxidative addition at 12 e– Pd(PR3) rather than at Pd(PR3)2. (3,18)

Figure 4

Figure 4. Solvent has a different effect on selectivity for NHC ligands compared to phosphine ligands. GC % yields were calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3-Br is exclusively formed. Mass balances slightly over the theoretical maximum are presumed due to boroxine impurity in the PhB(OH)2 reagent.

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For the phosphine ligands, the selectivity for mono- vs diarylation showed poor correlation with ligand size (quantified by minimum percent buried volumes; see Supporting Information). (19) Instead, selectivity correlates somewhat with ligand electronics based on the parameter Vmin, (19) as shown in Figure 4 (the phosphine ligands are ordered from left to right by increasing Vmin values). Overall, the phosphine ligands are less selective for diarylation in benzene compared to THF and acetone, whereas the reverse is true for the NHC ligands (i.e., the NHCs are more selective for diarylation in benzene). Cross-coupling in benzene (column on the left of each triad in Figure 4) results in exclusive diarylation (blue)) with IPent and near-exclusive diarylation with IPr. With the other ligands, the amount of monoarylation (pink) in benzene ranges from 3% with SPhos to 57% yield with P(o-tol)3. These results may suggest that displacement of LPd0 by benzene via path iii (Figure 3) is at least slightly competitive with oxidative addition (path (i)) for all of the ligands except IPent and, to a first approximation, IPr.
In THF and acetone (middle and right columns of each triad), the monoarylated product represents at least one-third of the total products for the NHC ligands, but most of the phosphines afford relatively little monoarylation in these solvents. The exceptions are the two most electron-deficient phosphines [CyJohnPhos and P(o-tol)3], for which nearly half of the product yield is 3-Br. We initially interpreted these data as suggesting that, like the NHC ligands, CyJohnPhos and P(o-tol)3 facilitate bromide-mediated path iv at a rate that is similar to that of C–Br oxidative addition. The increased π-accepting ability of CyJohnPhos, and especially of P(o-tol)3, could be consistent with increased stability of the anionic transition state for path iv.
However, experiments with a halide scavenger suggest that the monoarylation observed in THF and acetone with electron-deficient phosphine ligands has a different mechanistic origin than the monoarylation with NHC ligands. With IPent, a silver(I) salt completely inhibits the formation of a monoarylated product, supporting the idea that Br– is responsible for the monoarylated product with this ligand (Table 1 and Figure 5). Ag(I) was found to have essentially the same effect on the selectivity with IPr and IMes in THF (Figure 5). In stark contrast, Ag(I) has a negligible effect on selectivity with nearly all of the phosphine ligands. The exception is PtBu3, for which monoarylation actually increases in the presence of Ag2CO3; however, unlike all of the others, this reaction mixture immediately turns black, suggesting that silver reacts with PtBu3. (20) The relatively high proportion of monoarylation seen with the more electron-deficient phosphine ligands, even in the presence of a halide scavenger, suggests that Br– is not necessary for promoting the release of the monoarylated product with these ligands. The mechanism by which 3-Br is released with bulky electron-deficient phosphines is a topic for future study, but possibilities include the following: (1) more electron-deficient phosphines like these may enable direct dissociation of 12e– PdL; (2) displacement of PdL by a different anion (such as hydroxide) or by an oxygen-containing solvent may become relevant with these phosphines; (3) displacement of PdL by another molecule of the substrate may better outcompete oxidative addition for these phosphines; and/or (4) some proportion of phosphine might be oxidized in the course of catalysis, and the phosphine oxide could serve as a ligand that displaces PdL from the monoarylated product.

Figure 5

Figure 5. Ag(I) suppresses monoarylation in THF for NHC ligands but not for phosphine ligands. GC % yields were calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3-Br is exclusively formed. Mass balances slightly over the theoretical maximum are presumed to be due to boroxine impurity in the PhB(OH)2 reagent.

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Taken together, the results in Figures 4 and 5 suggest that (1) in the right solvent, IPent may promote higher selectivity for diarylation than any phosphine ligand; (2) in oxygen-containing solvents, Br– binds more readily to Pd0 when it is supported by NHC ligands than by trialkyl phosphines; and (3) although Br– appears to be responsible for monoarylation in reactions involving NHC ligands, the mechanistic origin of monoarylation in noncoordinating solvents is different with phosphine ligands.

Methods

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Representative Procedure

(η (3)-1-tBu-indenyl)Pd(IPent)(Cl) (2.0 mg, 0.0024 mmol, 3 mol %), phenylboronic acid (9.8 mg, 0.08 mmol, 1 equiv), K2CO3 (27.6 mg, 0.2 mmol, 2.5 equiv), and a magnetic stir bar were combined in a 1-dram vial. Liquid reagents were premeasured by a syringe and added in quick succession: the N2-sparged solvent (0.32 mL) was added via a 1 mL syringe; N2-sparged deionized water (14.4 μL, 0.8 mmol, 10 equiv) was added via a 50 μL syringe; and 2-Br (9.7 μL, 0.08 mmol, 1 equiv) was added via a 25 μL syringe. The vial was immediately fitted with a PTFE-lined silicone septum cap equipped with a N2-ingas needle and an outgassing needle. The reaction mixture was sparged with N2 for 30–45 s. Then, with continuous flushing of the headspace, the septum cap was unscrewed and immediately replaced with a PTFE-lined solid cap. The reaction mixture was allowed to stir vigorously at room temperature (∼23 °C) for 18 h. Reactions were quenched by dilution with ethyl acetate (∼3 mL), and undecane was added as an internal standard for GC-FID analysis.

Conclusions

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For synthetic chemists whose desired outcome is exhaustive cross-coupling, the practical interpretation of this work is that dibromoarenes (and presumably other polybromoarenes) provide better potential for exhaustive cross-coupling than the corresponding chloroarenes, but only if an appropriate solvent is used. If oxygen-containing solvents (e.g., THF) are necessary, then better success may be achieved with bulky electron-rich phosphine ligands than with NHCs. For example, we tested such conditions on the reaction of 2,7-dibromofluorene, which had previously been found to afford poor selectivity for diarylation under other Suzuki–Miyaura conditions even with an excess of arylboronic acid (Figure 1C). (7) Using a bulky monophosphine in THF, we obtained exclusive selectivity for the diarylated product despite a deficiency of arylboronic acid (Figure 6A, entry 1). On the other hand, if oxygen-containing solvents can be avoided (e.g., benzene), bulky NHC ligands may offer a slight advantage over bulky phosphine ligands─an advantage that could become more significant in the context of chain-growth polymerization. With 2,7-dibromofluorene, we also obtained exclusive diarylation using IPent in benzene (entry 2). These conditions are also effective for diarylation of ortho- and para-dibromobenzene (Figure 6B). Silver salts can be added to scavenge bromide and thereby improve the selectivity for exhaustive cross-coupling if using NHC ligands, although the use of such stoichiometric additives may have limited practical utility.

Figure 6

Figure 6. Evaluating the conditions from this work that provided the highest selectivity in either direction using (A) dihalofluorene (NMR yields) and (B) ortho- and para-dibromobenzene (calibrated GC yields assume that the products have a response factor similar to 3-Br and 4).

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For synthetic chemists whose desired outcome is a single cross-coupling of a dihalogenated substrate, there are also a few practical takeaways from this work. First, it might be better to avoid bulky monodentate ligands in the first place, as smaller monodentate or bidentate ligands provide a low-energy path for palladium to be released as a 14e– PdL2 after a single cross-coupling. (5a) However, bulky ligands may be unavoidable as they often promote better reactivity than smaller or bidentate ligands. (3,21,22) If bulky ligands must be used, this work suggests that even before manipulating stoichiometry, the highest selectivity and yields for monoarylation might be achieved with dichloroarenes in aromatic solvents or with dibromoarenes in polar oxygen-containing solvents. For the Suzuki couplings, we investigated using one of the bulkiest possible NHC ligands (IPent); the highest yield of monoarylation was seen for the reaction of dichloroarene 2-Cl in nitrobenzene (Figure 1A, 88% yield of 3-Cl vs 12% yield of 4). We tested these conditions for the cross-coupling of 2,7-dichlorofluorene, which had previously been found to afford very high selectivity for diarylation under different conditions (Figure 1C). In contrast, using IPent in nitrobenzene (Figure 6A, entry 3), the major product is indeed monoarylation (albeit with relatively poor yield).
The results also reveal differences between NHC ligands and phosphines. NHC ligands are considered to be strongly σ-donating, like trialkyl phosphines. (23) However, in oxygen-containing solvents, the high proportion of monoarylation in the cross-coupling of 2-Br using the bulky NHC ligands IPr and IPent more closely resembles the outcome with electron-deficient bulky phosphines. The difference in selectivity between NHC ligands and trialkylphosphines is consistent with the better π-accepting ability of NHCs. (24) Furthermore, silver addition studies suggest that bromide plays a role in selectivity with NHC ligands but not with phosphine ligands.
From a mechanistic perspective, these studies illuminate details about what is likely to happen during the turnover between consecutive catalytic cycles. Multiple pathways are possible (Figure 3), and the competition between these pathways and therefore between products depends on multiple factors, including the identity of the halide leaving group, the solvent, and the ligand.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.organomet.5c00423.

  • Experimental details and NMR spectra (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Nathaniel G. Larson - Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States;  Orcidhttps://orcid.org/0000-0002-7631-3332
    • Matthew P. Sandin - Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by the National Institute of General Medical Sciences (NIGMS) of the NIH under Award Number R35GM137971. Support for MSU’s NMR Center was provided by the NSF (Grant Nos. NSF-MRI:CHE-2018388 and NSF-MRI:DBI-1532078), MSU, and the Murdock Charitable Trust Foundation (2015066:MNL). We are grateful to Umicore for gifts of (η3-1-tBu-indenyl)2(μ-Cl)2Pd2, (η3-1-tBu-indenyl)Pd(IPr)(Cl), and (η3-1-tBu-indenyl)Pd(IPent)(Cl). We also thank Colin McLeod, who was supported by an NSF REU (CHE-2349748), for assistance with solubility studies.

References

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  • Abstract

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    Scheme 1

    Scheme 1. Prior Work: (A) Competing Pathways Leading to Di- versus Monoarylation in Suzuki–Miyaura Coupling of Dichloroarenes; (B,C) Dibromoarenes Unexpectedly Give Less Diarylation than Dichloroarenes
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    Figure 1

    Figure 1. Solvents exert different effects on the selectivity for monoarylation of (A) a dichloroarene versus (B) a dibromoarene. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). Average of ≥ 2 trials. The area of the bubbles correlates with the combined % yields of mono- and diarylated products with GC % yields calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3 is exclusively formed.

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    Figure 2

    Figure 2. In acetone and THF, the cross-coupling of 2-Br becomes more monoselective after the first few catalytic turnovers, while the reaction in benzene gives exclusively diarylation throughout the course of the reaction. “Pd/IPent” = (η3-1-tBu-indenyl)Pd(IPent)(Cl). Results based on GC yields calibrated against undecane as an internal standard.

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    Figure 3

    Figure 3. π-Complex between (IPent)Pd0 and the monocross-coupled product (shaded box) can proceed through divergent paths, leading to diarylation (path (i)) or to release of the monoarylated product (paths ii–iv). Selectivity depends on the relative rate of oxidative addition (path (i)) versus displacement of Pd by the substrate (path ii, relevant when X = Cl), by the solvent (path iii, relevant when X = Cl), or by the halide (path iv, relevant when X = Br).

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    Figure 4

    Figure 4. Solvent has a different effect on selectivity for NHC ligands compared to phosphine ligands. GC % yields were calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3-Br is exclusively formed. Mass balances slightly over the theoretical maximum are presumed due to boroxine impurity in the PhB(OH)2 reagent.

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    Figure 5

    Figure 5. Ag(I) suppresses monoarylation in THF for NHC ligands but not for phosphine ligands. GC % yields were calibrated against undecane as the internal standard and calculated based on 2 as the limiting reagent. Average of ≥2 trials. Due to the stoichiometry of the coupling partner, the maximum possible % yield is only ∼50% if 4 is exclusively formed and ∼100% if 3-Br is exclusively formed. Mass balances slightly over the theoretical maximum are presumed to be due to boroxine impurity in the PhB(OH)2 reagent.

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    Figure 6

    Figure 6. Evaluating the conditions from this work that provided the highest selectivity in either direction using (A) dihalofluorene (NMR yields) and (B) ortho- and para-dibromobenzene (calibrated GC yields assume that the products have a response factor similar to 3-Br and 4).

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      (j) Yang, M.; Chen, J.; He, C.; Hu, X.; Ding, Y.; Kuang, Y.; Liu, J.; Huang, Q. Palladium-Catalyzed C-4 Selective Coupling of 2,4-Dichloropyridines and Synthesis of Pyridine-Based Dyes for Live-Cell Imaging. J. Org. Chem. 2020, 85, 6498– 6508,  DOI: 10.1021/acs.joc.0c00449
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      (l) Groombridge, B. J.; Goldup, S. M.; Larrosa, I. Selective and general exhaustive cross-coupling of dichloroarenes with a deficit of nucleophiles mediated by a Pd–NHC complex. Chem. Commun. 2015, 51, 3832– 3834,  DOI: 10.1039/C4CC08920K
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      (m) Kosaka, K.; Uchida, T.; Mikami, K.; Ohta, Y.; Yokozawa, T. AmPhos Pd-Catalyzed Suzuki–Miyaura Catalyst-Transfer Condensation Polymerization: Narrower Dispersity by Mixing the Catalyst and Base Prior to Polymerization. Macromolecules 2018, 51, 364– 369,  DOI: 10.1021/acs.macromol.7b01990
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      (n) Bryan, Z. J.; Smith, M. L.; McNeil, A. J. Chain-Growth Polymerization of Aryl Grignards Initiated by A Stabilized NHC-Pd Precatalyst. Macromol. Rapid Commun. 2012, 33, 842– 847,  DOI: 10.1002/marc.201200096
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      (o) Leone, A. K.; Mueller, E. A.; McNeil, A. J. The History of Palladium-Catalyzed Cross-Coupling Schould Inspire the Future of Catalyst-Transfer Polymerization. J. Am. Chem. Soc. 2018, 140, 15126– 15139,  DOI: 10.1021/jacs.8b09103
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      (a) Larson, N. G.; Norman, J. P.; Neufeldt, S. R. Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes. ACS Catal. 2024, 14, 7127– 7135,  DOI: 10.1021/acscatal.4c00646
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      (b) Larson, N.; Sandin, M.; Neufeldt, S. Selectivity for Exhaustive Cross-Coupling of Dihaloarenes is Affected by the Interplay Between Halide Byproduct, Solvent, and Ligand. ChemRxiv 2025, chemrxiv-2025-kzb89,  DOI: 10.26434/chemrxiv-2025-kzb89
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      Review:Reeves, E. K.; Entz, E. D.; Neufeldt, S. R. Chemodivergence between Electrophiles in Cross-Coupling Reactions. Chem.─Eur. J. 2021, 27, 6161– 6177,  DOI: 10.1002/chem.202004437
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    7. 7
      Peng, Y.-Q.; Li, Y.-Q.; Liu, M.-M.; Ni, C.; Cao, Y.-C. Unexpectedly superior efficiency of chloride-directed double Suzuki–Miyaura cross-coupling reactions to bromide-directed reactions for the synthesis of sterically hindered 2,7-diaryl fluorenes. New J. Chem. 2024, 48, 12130– 12137,  DOI: 10.1039/D4NJ00718B
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    8. 8
      (a) Reeves, E. K.; Bauman, O. R.; Mitchem, G. B.; Neufeldt, S. R. Solvent Effects on the Selectivity of Palladium-Catalyzed Suzuki-Miyaura Couplings. Isr. J. Chem. 2020, 60, 406– 409,  DOI: 10.1002/ijch.201900082
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      (b) Elias, E. K.; Rehbein, S. M.; Neufeldt, S. R. Solvent coordination to palladium can invert the selectivity of oxidative addition. Chem. Sci. 2022, 13, 1618– 1628,  DOI: 10.1039/D1SC05862B
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      Semeniuchenko, V.; Sharif, S.; Rana, N.; Chandrasoma, N.; Braje, W. M.; Baker, R. T.; Manthorpe, J. M.; Pietro, W. J.; Organ, M. G. Experimental Evidence for Zerovalent Pd(NHC) as a Competent Catalyst in C–N Cross-Coupling (NHC = DiMeIHeptCl). J. Am. Chem. Soc. 2024, 146, 29224– 29236,  DOI: 10.1021/jacs.4c12203
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      (a) Young, S. J.; Kellenberger, B.; Reibenspies, J. H.; Himmel, S. E.; Manning, M.; Anderson, O. P.; Stille, J. K. Synthesis and Reactions of Dinuclear Palladium Complexes Containing Methyls and Hydride on Adjacent Palladium Centers: Reductive Elimination and Carbonylation Reactions. J. Am. Chem. Soc. 1988, 110, 5744– 5753,  DOI: 10.1021/ja00225a026
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      (b) Lumbreras, E., Jr.; Sisler, E. M.; Shelby, Q. D. Synthesis, X-ray Crystal Structure, and Reactivity of Pd2(μ-dotpm)2 (dotpm = bis(di-ortho-tolylphosphino)methane). J. Organomet. Chem. 2010, 695, 201– 205,  DOI: 10.1016/j.jorganchem.2009.10.010
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    11. 11

      Dichloromethane has been observed as a ligand for Ag(I), which is isoelectronic with Pd(0); see

      (a) Newbound, T. D.; Colsman, M. R.; Miller, M. M.; Wulfsberg, G. P.; Anderson, O. P.; Strauss, S. H. Dichloromethane is a Coordinating Solvent. J. Am. Chem. Soc. 1989, 111, 3762– 3764,  DOI: 10.1021/ja00192a052
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      (b) Colsman, M. R.; Newbound, T. D.; Marshall, L. J.; Noirot, M. D.; Miller, M. M.; Wulfsberg, G. P.; Frye, J. S.; Anderson, O. P.; Strauss, S. H. Silver(I) Complexes of Dichloromethane and 1,2-Dichloroethane. J. Am. Chem. Soc. 1990, 112, 2349– 2362,  DOI: 10.1021/ja00162a040
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    12. 12

      It is not clear how MeCN and DMF fit into the trends with 2-Br, as the yields were low in these solvents (19% and 8%, respectively), suggesting that coordination of solvent to Pd inhibits catalysis. DMSO and nitromethane were also tested with 2-Br, but 0% yield was obtained in both cases (see Supporting Information).

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

      In further experiments, the effect of adding substoichiometric quantities of bromide salts (NBu4Br or KBr) to the cross-coupling of 2-Cl was examined. As expected, both additives increase the proportion of monoarylation in THF and acetone, but the results are complicated by low yields, reflecting an inhibitory effect of these additives on catalysis (see Supporting Information).

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

      Our prior work with dichloroarenes (ref (5)) suggests that coordinating additives like pyridine can also break up the π-complex. Since these are not typical components of the reaction mixture, they are not included in Figure 3 for simplicity.

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

      For example, in the reaction of 1-Cl, the ratio of mono:di increased from about 1:4 to about 1:2 when the starting concentration of substration was doubled, and this effect remains even when the data are normalized to account for the competition between dichloroarene and monocross-coupled product as substrates for Pd. See ref (5)a for details.

      There is no corresponding record for this reference.
    16. 16
      Review:Chernyshev, V. M.; Denisova, E.; Eremin, D. B.; Ananikov, V. P. The key role of R–NHC coupling (R = C, H, heteroatom) and M–NHC bond cleavage in the evolution of M/NHC complexes and formation of catalytically active species. Chem. Sci. 2020, 11, 6957– 6977,  DOI: 10.1039/D0SC02629H
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    17. 17
      Semeniuchenko, V.; Sharif, S.; Rana, N.; Chandrasoma, N.; Braje, W. M.; Baker, R. T.; Manthorpe, J. M.; Pietro, W. J.; Organ, M. G. Unexpected Deactivation of PdCl(cinnamyl)(NHC Cl) Precatalysts Mediated by Alkylamines. Organometallics 2025, 44, 2654– 2662,  DOI: 10.1021/acs.organomet.5c00318
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    18. 18
      Newman-Stonebraker, S. H.; Smith, S. R.; Borowski, J. E.; Peters, E.; Gensch, T.; Johnson, H. C.; Sigman, M. S.; Doyle, A. G. Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis. Science 2021, 374, 301– 308,  DOI: 10.1126/science.abj4213
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    19. 19
      Gensch, T.; dos Passos Gomes, G.; Friederich, P.; Peters, E.; Gaudin, T.; Pollice, R.; Jorner, K.; Nigam, A.; Lindner-D’Addario, M.; Sigman, M. S.; Aspuru-Guzik, A. A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis. J. Am. Chem. Soc. 2022, 144, 1205– 1217,  DOI: 10.1021/jacs.1c09718
      There is no corresponding record for this reference.
    20. 20

      If silver oxidizes PtBu3, the observed selectivity would no longer reflect the selectivity of Pd(PtBu3) catalyst. Indeed, in the absence of any phosphine (or NHC) ligand at all, the reaction favors monoarylation (see Supporting Information).

      There is no corresponding record for this reference.
    21. 21

      For selected reviews of cross-couplings catalyzed by Pd/NHC complexes, see:

      (a) Marion, N.; Nolan, S. P. Well-Defined N-Heterocyclic Carbenes–Palladium(II) Precatalysts for Cross-Coupling Reactions. Acc. Chem. Res. 2008, 41, 1440– 1449,  DOI: 10.1021/ar800020y
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      (b) Fortman, G. C.; Nolan, S. P. N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union. Chem. Soc. Rev. 2011, 40, 5151– 5169,  DOI: 10.1039/c1cs15088j
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      (c) Valente, C.; Calimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. The Development of Bulky Palladium NHC Complexes for the Most-Challenging Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2012, 51, 3314– 3332,  DOI: 10.1002/anie.201106131
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      (d) Froese, R. D. J.; Lombardi, C.; Pompeo, M.; Rucker, R. P.; Organ, M. G. Designing Pd N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications. Acc. Chem. Res. 2017, 50, 2244– 2253,  DOI: 10.1021/acs.accounts.7b00249
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      (e) Yang, S.; Zhou, T.; Yu, X.; Nolan, S. P.; Szostak, M. [Pd(NHC)(μ-Cl)Cl]2: The Highly Reactive Air- and Moisture-Stable, Well-Defined Pd(II)-N-Heterocyclic Carbene (NHC) Complexes for Cross-Coupling Reactions. Acc. Chem. Res. 2024, 57, 3343– 3355,  DOI: 10.1021/acs.accounts.4c00549
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      (f) Bera, S. S.; Utecht-Jarzynska, G.; Yang, S.; Nolan, S. P.; Szostak, M. Metal–N-Heterocyclic Carbene Complexes in Buchwald–Hartwig Amination Reactions. Chem. Rev. 2025, 125, 5349– 5435,  DOI: 10.1021/acs.chemrev.5c00088
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    22. 22

      For selected reviews of Pd-catalyzed cross-couplings using bulky phosphine ligands, see:

      (a) 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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      (b) Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41, 1461– 1473,  DOI: 10.1021/ar800036s
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      (c) Fleckenstein, C. A.; Plenio, H. Sterically demanding trialkylphosphines for palladium-catalyzed cross coupling reactions─alternatives to PtBu3. Chem. Soc. Rev. 2010, 39, 694– 711,  DOI: 10.1039/B903646F
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      (d) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and preparation of new palladium precatalysts for C–C and C–N cross-coupling reactions. Chem. Sci. 2013, 4, 916– 920,  DOI: 10.1039/C2SC20903A
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      (e) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564– 12649,  DOI: 10.1021/acs.chemrev.6b00512
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    23. 23
      Review:Durand, D. J.; Fey, N. Computational Ligand Descriptors for Catalyst Design. Chem. Rev. 2019, 119, 6561– 6594,  DOI: 10.1021/acs.chemrev.8b00588
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    24. 24
      (a) Antonova, N. S.; Carbó, J. J.; Poblet, J. M. Quantifying the Donor-Acceptor Properties of Phosphine and N-Heterocyclic Carbene Ligands in Grubbs’ Catalysts Using a Modified EDA Procedure Based on Orbital Deletion. Organometallics 2009, 28, 4283– 4287,  DOI: 10.1021/om900180m
      There is no corresponding record for this reference.
      (b) Vummaleti, S. V. C.; Nelson, D. J.; Poater, A.; Gómez-Suárez, A.; Cordes, D. B.; Slawin, A. M. Z.; Nolan, S. P.; Cavallo, L. What can NMR spectroscopy of selenoureas and phosphinidenes teach us about the π-accepting abilities of N-heterocyclic carbenes?. Chem. Sci. 2015, 6, 1895– 1904,  DOI: 10.1039/C4SC03264K
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.organomet.5c00423.

    • Experimental details and NMR spectra (PDF)


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