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. 2024 Jul 29;4(10):3777–3787. doi: 10.1021/jacsau.4c00347

Strain-Releasing Ring-Opening Diphosphinations for the Synthesis of Diphosphine Ligands with Cyclic Backbones

Chandu G Krishnan †,‡, Hideaki Takano †,‡, Hitomi Katsuyama †,‡, Wataru Kanna §, Hiroki Hayashi †,‡, Tsuyoshi Mita †,‡,*
PMCID: PMC11522911  PMID: 39483215

Abstract

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Diphosphine ligands based on cyclobutane, bicyclo[3.1.1]heptane, and bicyclo[4.1.1]octane were synthesized from the corresponding highly strained, small, cyclic organic molecules, i.e., bicyclo[1.1.0]butane, [3.1.1]propellane, and [4.1.1]propellane, employing a ring-opening diphosphination. Under photocatalytic conditions, the three-component reaction of a diarylphosphine oxide, one of the aforementioned strained molecules, and a diarylchlorophosphine results in the smooth formation of the corresponding diphosphines in high yield. The obtained diphosphines can be expected to find applications in functional molecules due to their unique structural characteristics, which likely impart specific properties on their associated metal complexes and coordination polymers (e.g., a zigzag-type structure). The feasibility of the initial radical addition can be estimated using density-functional-theory calculations using the artificial force induced reaction (AFIR) method. This study focuses on the importance of integrating experimental and computational methods for the design and synthesis of new diphosphination reactions that involve strained, small, cyclic organic molecules.

Keywords: radical, diphosphine ligands, blue LED, strained molecules, propellane

Introduction

Significant advancements in the development of novel functionalized materials, such as phosphine ligands, have recently been reported.1,2 At present, one fascinating avenue of exploration in this area is the synthesis of diphosphine ligands that coordinate to metal centers in either a bidentate or monodentate fashion. Diphosphine ligands with a bidentate coordination mode allow the formation of metallacycles, which are stabilized by chelation effects,3,4 while those with a monodentate mode serve as molecular linkers, resulting in the formation of supramolecular assemblies.5−12 The reactivity of diphosphine ligands is primarily contingent upon two crucial parameters: the cone angle13−15 and the bite angle.3,4 These angles can be precisely tailored by leveraging the steric effects stemming from the substituents on the phosphorus atoms and the backbone linkers that connect the two phosphorus atoms (Scheme 1a). In the case of the substituents on the phosphorus atoms, electronic effects are also pivotal in orchestrating the reactivity of the metal complex. Unsymmetric diphosphine ligands that carry different substituents on each phosphorus atom, may have, through a judicious selection of substituents, potentially exceptional reactivity profiles. Consider, for instance, a diphosphine ligand where one phosphorus atom bears electron-donating groups, while its counterpart bears electron-withdrawing moieties.

Scheme 1. Importance of Bidentate Phosphine Ligands.

Scheme 1

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This configuration can be expected to endow the ligand with distinctive reactivity and properties compared to its symmetric counterparts. Such modified reactivity and properties arise from the push–pull effect, which contributes to the precise modulation of electron density on the central metal atom. Indeed, unsymmetric diphosphine ligands have, on occasion, demonstrated an enhanced capacity to augment the reactivity, regioselectivity, and enantioselectivity of transition-metal-catalyzed reactions when compared to their symmetrical counterparts.16−21 Consequently, both the architecture of the backbone linkers and the nature of the substituents attached to the phosphorus atoms wield substantial influence over the reactivity of diphosphine metal complexes. This underscores the pressing need for facile and universally applicable methods for the synthesis of both symmetric and unsymmetric diphosphine ligands with a diverse array of carbon frameworks.

Small cyclic hydrocarbons can exhibit substantial ring strain, that primarily stems from the unconventional bond angles adopted by the sp3-hybridized carbon atoms.22−24 In recent years, considerable research attention has been devoted to polycyclic hydrocarbons, bicyclo[1.1.0]butane,25−32 and propellanes.33−49 These intriguing compounds are characterized by two or three interconnected rings, each sharing a common C–C bond. [1.1.1]Propellane32−44 has garnered significant interest due to its high reactivity with cations, anions, and radicals. This heightened reactivity can be attributed to the exceptionally strained C–C bonds between the bridgehead carbons (charge-shift bonds). The reaction of [1.1.1]propellane with an anion or a radical leads to a bicyclo[1.1.1]pentane (BCP) skeleton, which represents a biological isostere of benzene rings, alkynes, or tert-butyl groups (Scheme 1b).50−54 Notably, our research group has previously reported a three-component reaction (3CR) for the synthesis of symmetric/unsymmetric diphosphine ligands,55,56 and one of these ligands is a straight-shaped diphosphine derived from [1.1.1]propellane (Scheme 1c).56 The key to this significant synthetic advancement lies in the 3CR strategy, where a diarylphosphine oxide, a highly strained hydrocarbon scaffold, and a diarylchlorophosphine can be assembled under photocatalytic conditions.

Taking into consideration the reactivity of highly strained small-ring compounds and the utility of the three-dimensional hydrocarbon structures generated from their reactions, the development of a 3CR involving small-ring compounds would facilitate the creation of novel functional diphosphine ligands. In the present study, we have determined the activation barriers for the addition of electron-withdrawing phosphoryl radicals (Ph2P(=O)·) to seven strained hydrocarbon molecules based on cyclopropane, bicyclo[1.1.0]butane, [n.1.1]propellane, and [n.n.n]propellane scaffolds (Scheme 2). Based on these calculated results, we successfully synthesized several diphosphine ligands via a 3CR using the strained hydrocarbons bicyclo[1.1.0]butane,25−32 [3.1.1]propellane,43,45,46 and [4.1.1]propellane.47−49

Scheme 2. 3CR for the Synthesis of Diphosphine Ligands.

Scheme 2

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Results and Discussion

Prior to conducting experimental trials of the diphosphination procedures, our investigation commenced with density-functional-theory (DFT) calculations using the artificial force induced reaction (AFIR) method57−60 at the UωB97X-D/Def2-SVP level in dichloromethane (SMD model). Subsequently, we directed our attention to simulating the addition of the phosphoryl radical (Ph2P(=O)·, 1′) to different highly strained molecules (Table 1). We calculated the energies of the two species independently, assuming that the phosphoryl radical and the substrate are infinitely far apart. We then combined these energies, which serves as the reference for drawing an energy diagram. The phosphoryl radical exhibits greater reactivity toward hydrocarbons than the phosphinyl radical (Ph2P·) because the electron-withdrawing radical prefers to react with electron-rich hydrocarbon substrates (for details, see the Supporting Information (S37)). The phosphoryl radical can be readily generated via photoirradiation from the in situ-formed diphosphine oxide (Ph2P(=O)–PPh2) derived from the phosphine oxide (Ph2P(=O)H) and the chlorophosphine (Ph2PCl).55,56

Table 1. DFT-Calculated Activation Barriers for the Addition of a Phosphoryl Radical to Strained Molecules.

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We first performed calculations for the addition of a phosphoryl radical to the simple ring-strained molecule cyclopropane, which was found to have an extremely high activation barrier (ΔG‡ = 30.3 kcal/mol; entry 1). In contrast, bicyclo[1.1.0]butane25−32 has a much lower activation barrier (ΔG‡ = 14.0 kcal/mol; entry 2). As calculated in our previous study, [1.1.1]propellane33−44 has a reasonably low activation barrier (ΔG‡ = 8.5 kcal/mol; entry 3). The calculations performed for the reaction with [2.1.1]propellane61 revealed the lowest activation barrier (ΔG‡ = 5.7 kcal/mol) of the compounds shown in Table 1 (entry 4). Unsymmetric propellanes, such as [3.1.1]propellane43,45,46 and [4.1.1]propellane,47−49 have two geometries that the phosphoryl radical can access, with a large difference in activation barriers between the two paths. One geometry has a low barrier while the other has a high barrier (entries 5–8). The geometries where the bulky cyclopentane or cyclohexane faces the same direction as the oxygen atom of the phosphoryl radical have higher activation barriers (ΔG‡ = 13.4 and 12.0 kcal/mol; entries 5 and 7). Conversely, when the cyclic hydrocarbon is orientated in the opposite direction to the oxygen atom of the phosphoryl radical, a much lower activation barrier is observed (ΔG‡ = 8.1 and 9.2 kcal/mol; entries 6 and 8). We also performed calculations for the reactions of [2.2.2]propellane62,63 and [3.3.3]propellane,64,65 which revealed that the former exhibits a reasonable activation barrier (ΔG‡ = 12.2 kcal/mol), while the latter has a very high activation barrier (ΔG‡ = 54.9 kcal/mol) with an endergonic reaction profile (entries 9 and 10). Based on these calculations, all listed strained compounds, except cyclopropane and [3.3.3]propellane, exhibit reasonable activation barriers. However, [2.1.1]propellane61 and [2.2.2]propellane62,63 have been reported to be insufficiently stable toward isolation (vide infra), and the diphosphination of [1.1.1]propellane has been already reported by our research group.56 Therefore, we focused on experimentally verifying the diphosphination of bicyclo[1.1.0]butane,25−32 [3.1.1]propellane,43,45,46 and [4.1.1]propellane,47−49 in addition to the confirmation of the nonreactivity of cyclopropane.

Cyclopropane

As expected, given the formidable activation barrier (ΔG‡ = 30.3 kcal/mol) estimated by DFT calculations (vide supra), several attempts at the 3CR involving the opening of cyclopropane (10% in N2 gas under 10 atm pressure) using phosphine oxide 1 and chlorophosphine 2 were unsuccessful (Figure 1). Instead of the targeted 1,2-bis(diarylphosphino)propane derivatives, unsymmetric and symmetric diphosphines 3aa and 3bb were obtained in a ca. 20% yield.

Figure 1.

Figure 1

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3CR of cyclopropane with 1 and 2.

Bicyclo[1.1.0]butane

Next, we examined the 3CR involving bicyclo[1.1.0]butane because its calculated activation barrier is reasonably low (ΔG‡ = 14.0 kcal/mol). Bicyclo[1.1.0]butane was prepared as a Et2O solution according to a slightly modified literature procedure28 (for details, see the Supporting Information (S3)). Unfortunately, when using (p-NMe2-C6H4)2P(=O)H (1a) and (p-CF3–C6H4)2PCl (2a) as substrates for the 3CR with bicyclo[1.1.0]butane, several unidentified compounds were formed, while the formation of the targeted unsymmetric 4aa was not observed. Instead of the generation of 4aa, diphosphine 3aa was obtained in 37% yield (Figure 2). However, when Ph2P(=O)H (1b) and Ph2PCl (2b) were used as substrates, symmetric derivative 4bb was obtained in 12% yield with a trans/cis ratio of 3.8/1 together with diphosphine 3bb in 41% yield. The structure of the minor 4bb-cis isomer was determined by an nOe experiment with an 8% correlation (for details, see the Supporting Information (S17)).

Figure 2.

Figure 2

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3CR of bicyclo[1.1.0]butane.

Despite obtaining a small amount of 4bb, a substantial quantity of unidentified byproducts were formed, probably due to the generation of rather reactive secondary radicals after the addition of the phosphoryl radical. Moreover, as bicyclo[1.1.0]butane is a gaseous substance that could potentially evaporate during light irradiation (the reported bp is 8 °C27), it was decided to use a solid bicyclobutane, which does not evaporate and is easier to handle. Benzensulfonyl-substituted bicyclo[1.1.0]butane (5), which is readily prepared from inexpensive benzenesulfinic acid sodium salt and 4-bromobut-1-ene,34 was subsequently employed for the 3CR. The sulfonyl group can be readily removed under reductive conditions. The activation barrier of the addition of phosphoryl radical 1′ to 5 (ΔG‡ = 15.2 kcal/mol) is sufficient to allow experiments to be conducted. As a result, the product yields increased compared to when bicyclo[1.1.0]butane was used, and unsymmetric 6aa was obtained in 23% yield (cis/trans = 1.6/1) and symmetric derivative 6bb in 53% yield (cis/trans = 4/1) (Figure 3). A 0.7 mmol-scale reaction also worked well, resulting in the formation of 6bb in 57% yield with a cis/trans ratio of 3.4/1. The major diastereomer of 6bb was unambiguously determined to have a cis configuration via X-ray diffraction (XRD) analysis of a suitable single crystal.66

Figure 3.

Figure 3

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3CR of sulfonylated bicyclo[1.1.0]butane. a0.7 mmol-scale synthesis.

The sulfonylated compound 6bb (cis/trans mixture) was smoothly desulfonylated using Mg powder in the presence of NiBr2 (20 mol %) to afford the target molecule 4bb in good yield (Figure 4). In this process, the stereochemistry of 6bb was not maintained, affording 4bb with a trans/cis ratio that was different to the original ratio of 6bb. As the desired Mg-mediated process involves a radical process, the resulting secondary radial formed after the desulfonylation undergoes epimerization to give 4bb in an almost 1:1 trans/cis ratio. In the case of unsymmetric 6aa, a significantly simultaneous defluorination of the CF3 group occurred during the desulfonylation, and the reductive desulfonylation with Mg was therefore deemed to be unsuitable for CF3-containing compounds.

Figure 4.

Figure 4

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Removal of the sulfonyl group under Mg-mediated conditions.

We then investigated the use of 4bb-cis in the synthesis of a cis-coordinate bidentate ligand (Figure 5). After oxidative exchange of the S atom on the phosphine sulfide moiety of 4bb-cis with an O atom via treatment with mCPBA, the corresponding dioxide 7bb-cis was obtained in 70% yield. 7bb-cis was readily reduced using air-stable 1,3-diphenyl-disiloxane (PhH2Si–O–SiH2Ph; DPDS)67,68 in toluene under reflux conditions without the need for a glovebox to afford 8bb-cis in 36% yield. The obtained 8bb-cis reacts with NiCl2(dme) to form a red powder of NiCl2(8bb-cis). Recrystallization from CH2Cl2/hexane yielded red/orange single crystals that contain one molecule of CH2Cl2 per unit cell. A single-crystal X-ray diffraction analysis revealed a bidentate chelating coordination of the diphosphine to Ni with a cyclobutane backbone.66 It should be noted here that the cyclobutane ring is slightly distorted, most likely as a result of the propensity of the ligand to form a chelate. This type of chelating diphosphine-metal complex has not been reported so far; interestingly, while the number of bridging carbon atoms is the same as in dppp (three carbons), the bite angle is larger. Specifically, the X-ray structure reveals that its bite angle is 94.95 °, thus exceeding the reported value for dppp in NiCl2(dppp) (91.77 °).69 This difference should most likely be attributed to the reduced flexibility of the carbon chain caused by the constrained cyclobutane ring, suggesting potential for future applications in catalysis.1−4

Figure 5.

Figure 5

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Conversion of 4bb-cis to cis-coordinate Ni-complex NiCl2(8bb-cis). Bottom right: crystal structure of NiCl2(8bb-cis) with thermal ellipsoids at 50% probability; all hydrogen atoms as well as one molecule of CH2Cl2 have been omitted for clarity.

Subsequently, we conducted a theoretical examination of the mechanism of the light-promoted radical reaction in order to investigate the trans-selectivity. For that purpose, we carried out DFT calculations using Ph2P(=O)–PPh2 (3bb′), which should be initially generated from 1b and 2b in the presence of a base (Figure 6). When using 3bb′ for the reaction with 5, 6bb was obtained in similar yield (48% yield), which indicates 3bb′ is an intermediate of this radical reaction. The calculations were again conducted using the AFIR method57−60 at the UωB97X-D/Def2-SVP level in dichloromethane (SMD model) (for details, see the Supporting Information (S36)). Under blue LED irradiation, [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 absorbs light at 440 nm and is excited to its triplet state (ΔET = 61.8 kcal/mol),70 which then transfers energy to 3bb′, which in turn is excited to the triplet state (ΔG = 44.7 kcal/mol).56 Simultaneous dissociation of the P(=O)–P single bond occurs from the triplet state of 3bb′, and the resulting phosphoryl radical (Ph2P(=O)·) reacts with bicyclo[1.1.0]butane to generate a secondary-alkyl radical (ΔG‡ = 14.0 kcal/mol). When radical addition occurs with the phosphinyl radical (Ph2P·) instead of with the phosphoryl radical, the resulting activation barrier is higher (ΔG‡ = 19.2 kcal/mol vs 14.0 kcal/mol). The thus obtained secondary-alkyl radical may react associatively with the remaining phosphinyl radical (radical–radical coupling) to afford the target molecule 4bb′.

Figure 6.

Figure 6

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Plausible reaction mechanism based on DFT calculations for the 3CR with bicyclo[1.1.0]butane. The reaction diagrams were calculated at the UωB97X-D/Def2-SVP/SMD(DCM) level.

However, both the secondary-alkyl radical and the phosphinyl radical exhibit transient character,71 and they seem to be present at low concentrations. Therefore, we calculated another possibility involving a radical-chain mechanism, which revealed an activation barrier of 6.4 kcal/mol for the radical addition of the secondary-alkyl radical to another molecule of diphosphine 3bb′ in a trans-selective fashion through I-trans. However, the cis-selective phosphination via I-cis proceeds with a bit higher activation energy (8.6 kcal/mol). Accordingly, both paths could give the products with an exergonic energy profile. Based on the activation barrier for the radical-chain addition, which can be reasonably overcome at room temperature, we currently consider that the radical-chain process may be operative, even though the termination process with radical–radical coupling can also be expected to be operative in the system, similar to the case of [1.1.1]propellane.56 We also conducted calculations for the reaction of the secondary-alkyl radical with another molecule of bicyclo[1.1.0]butane. Our calculations indicate that the activation barriers for the radical dimerization of bicyclo[1.1.0]butane via II-trans and II-cis are higher than that of the anticipated radical-chain pathway (ΔG‡ = 19.2/19.5 kcal/mol (trans/cis for dimerization) vs 6.4/8.6 kcal/mol (trans/cis for product formation)), effectively ruling out the possibility of product polymerization.

[1.1.1]Propellane and [2.1.1]Propellane

Our research group has previously reported the diphosphination of [1.1.1]propellane.56 In contrast, [2.1.1]propellane, distinguished by a central carbon atom bonded to one cyclobutane ring and two cyclopropane rings, is known to be unstable and difficult to isolate, rendering its synthesis exceedingly difficult.48,61

[3.1.1]Propellane

Subsequently, our investigation shifted toward [3.1.1]propellane as a substrate for the 3CR given its suitably low activation barrier (ΔG‡ = 8.1 kcal/mol). We investigated the reaction of 1 with [3.1.1]propellane and 2 and were able to successfully synthesize several diphosphines (Figure 7). This synthetic process yielded both unsymmetric and symmetric diphosphine derivatives 9 in yields of up to 74%. A variety of electron-donating phosphine oxides and electron-withdrawing chlorophosphines can be used in this 3CR. We first examined the electron-donating phosphine oxide (p-NMe2-C6H4)2P(=O)H (1a) and electron-deficient chlorophosphine (p-CF3–C6H4)2PCl (2a) under photochemical reaction conditions. Under photocatalytic conditions using blue LED irradiation, the unsymmetric diphosphine derivative 9aa was obtained in 74% yield. The 3CR also proceeded without the need for a photocatalyst under white LED irradiation for 24 h, which is similar to reaction conditions that we have developed previously.55,56 Without protection using S8, 9aa′ was obtained in a similar yield (69%). Symmetric derivative 9bb was prepared from 1b and 2b in 60% yield. Without sulfur protection, 9bb′ was obtained in 64% yield. We then continued to extend the substrate scope. For that purpose, we screened various electron-donating phosphine oxides in the reaction with the electron-withdrawing chlorophosphine 2a. The 3CR between electron-donating (p-OMe-C6H4)2P(=O)H (1c) and 2a proceeded well under otherwise identical conditions. Furthermore, the 3CR with electron-withdrawing (p–Cl-C6H4)2P(=O)H (1d) and bulky (1-naphthyl)2P(=O)H (1e) proceeded smoothly. Next, electron-donating 1a was used as the phosphine oxide and several chlorophosphines were screened. Electron-withdrawing (p–Cl-C6H4)2PCl (2c) afforded the desired product 9ac in moderate yield. Furthermore, the use of electron-donating (p-OMe-C6H4)2PCl (2d) provided 9ad, albeit that the yield was somewhat low (25%).

Figure 7.

Figure 7

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3CR of [3.1.1]propellane. aWhite LED irradiation for 24 h without a photocatalyst.

Next, we embarked on an in-depth exploration of the transformation of both 9aa and 9bb into their corresponding diphosphine dioxide derivatives, i.e., 10aa and 10bb. We also examined the subsequent production of diphosphine ligands 11aa and 11bb from 10aa and 10bb (Figure 8). The reaction process began with the oxidative substitution of the sulfur atoms on the phosphine sulfide moiety with oxygen atoms, achieved via treatment with mCPBA, which led to the synthesis of the targeted diphosphine dioxide compounds 10 in reasonable yield. Subsequently, the thus obtained diphosphine dioxides 10 underwent reduction by air-stable DPDS67,68 in toluene under reflux conditions. This reduction proved efficient, yielding unsymmetric and symmetric diphosphine ligands 11 in good yield, thus underscoring the robustness and versatility of the synthetic methodology employed.

Figure 8.

Figure 8

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Synthesis of diphosphine ligands and metal complexes. Bottom right: crystal structures of 12 and 12′ with thermal ellipsoids at 30% probability; fluorine atoms on the hfa ligands and all hydrogen atoms are omitted for clarity.

Another notable result is the possibility to subsequently using the unsymmetric dioxide 10aa in the synthesis of a novel Eu-based coordination polymer 12 via the reaction with Eu(hfa)3(H2O)2 (hfa = hexafluoroacetylacetonate). The resulting coordination polymer 12 was obtained in 39% yield after crystallization. A detailed single-crystal X-ray diffraction (XRD) analysis unambiguously confirmed the coordination mode of the europium ions within polymer 12.66 In 12, each europium ion is intricately coordinated by three hfa ligands and two phosphine-oxide ligands. Notably, each phosphine-oxide moiety in the ligand exhibits different electronic characteristics, i.e., one is electron-donating and the other electron-withdrawing. An octacoordinated metal center, which is similar to the coordination polymer 12′ derived from [1.1.1]propellane,56 is formed. However, the packing structure of polymer 12 differs significantly from that of the polymer 12′. While 12′ forms an approximately straight-shaped wire, 12 exhibits a wire-shaped structure with zigzag bends on the same plane (Figure 8), wherein the bends to ∼98° occur every three Eu centers.

This structural difference arises from variances in the linker structures. Two C–P bonds are positioned in nearly the same straight line (174°) due to the linkage of the BCP skeleton. Conversely, the [3.1.1]bicycloheptane skeleton introduces two C–P bonds at a specific angle (117°), which most likely influences the zigzag structure in the crystal packing. However, the intrinsic origin of the bent structure for every three Eu units remains unexplained at present. The resulting polymeric architecture, dictated by this unique coordination pattern and the packing structure, showcases exceptional alignment, thereby establishing a promising framework with potential applications in the realm of luminescent photonic materials. Our ongoing research in this area is focused on exploring the optical properties of this intriguing polymeric complex.

We subsequently conducted a theoretical examination of the mechanism of the light-promoted radical reaction of [3.1.1]propellane, supported by DFT calculations (Figure 9). In this substrate, not only blue LED light but also white LED light without any photocatalyst proves suitable for promoting the reaction (cf. 9aa in Figure 7).55,56 Under white LED irradiation, 3bb′ directly absorbs light to facilitate its radical-dissociation reaction. After the homolytic cleavage of the P(=O)–P single bond, phosphoryl radical (Ph2P(=O)·) reacts with [3.1.1]propellane to generate a tertiary-alkyl radical (ΔG‡ = 8.1 kcal/mol). When radical addition occurs with the phosphinyl radical (Ph2P·) instead of the phosphoryl radical, the resulting activation barrier is higher (ΔG‡ = 13.8 kcal/mol vs 8.1 kcal/mol). The tertiary-alkyl radical thus obtained may undergo an associative reaction with the remaining phosphinyl radical (radical–radical coupling) to yield the target molecule 9bb′. We also explored another possibility involving a radical-chain mechanism, which revealed an activation barrier of 5.9 kcal/mol for the radical addition of the tertiary-alkyl radical to another molecule of diphosphine 3bb′. Considering the low likelihood of an encounter between the two radical species discussed above, in this case we also believe that the radical-chain process may be operative together with radical–radical coupling during the termination process.56 We also conducted calculations for the reaction of the tertiary-alkyl radical with another molecule of [3.1.1]propellane, indicating that the activation barrier for the radical dimerization of [3.1.1]propellane is higher than that of the anticipated radical-chain pathway (ΔG‡ = 13.0 kcal/mol vs 5.9 kcal/mol), which prevents the dimerization with another [3.1.1]propellane.

Figure 9.

Figure 9

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Plausible reaction mechanism based on DFT calculations for the 3CR with [3.1.1]propellane. The reaction diagrams were calculated at the UωB97X-D/Def2-SVP/SMD(DCM) level.

[4.1.1]Propellane

[4.1.1]Propellane is a fused compound that has already been synthesized.47−49 However, our slightly modified method using PhLi-mediated cyclization leads to a robust and reproducible synthetic procedure for the synthesis of [4.1.1]propellane (for details, see the Supporting Information (S10)). Due to the reasonably favorable activation barrier for the process (ΔG‡ = 9.2 kcal/mol), we mixed phosphine oxide 1 with [4.1.1]propellane and chlorophosphine 2, which resulted in the formation of diphosphines 13aa and 13bb in good yield (Figure 10). Furthermore, similar to the [3.1.1]propellane synthesis, S to O exchange by mCPBA followed by reduction using air-stable DPDS67,68 afforded unsymmetric and symmetric free diphosphine ligands 15aa and 15bb in good yields (Figure 11).

Figure 10.

Figure 10

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3CR of [4.1.1]propellane.

Figure 11.

Figure 11

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Conversion to free diphosphine ligands.

We further calculated the pathway of the reaction of 3bb′ with [4.1.1]propellane (Figure 12). The generated phosphoryl radical (Ph2P(=O)·) reacts with [4.1.1]propellane to generate the tertiary-alkyl radical (ΔG‡ = 9.2 kcal/mol). The activation energy for the reaction with the phosphinyl radical (Ph2P·) is higher than that for the reaction with the phosphoryl radical (ΔG‡ = 17.2 kcal/mol). Compared to the radical addition to [3.1.1]propellane, the activation barriers for the reaction with [4.1.1]propellane are slightly higher. The radical-chain mechanism, whereby an additional molecule of 3bb′ reacts with the tertiary-alkyl radical, which leads to the formation of 13bb′, has a reasonable activation barrier of 8.4 kcal/mol. However, the activation barrier for the pathway where the tertiary-alkyl radical reacts with another molecule of [4.1.1]propellane is higher than that for the generation of 13bb′ (ΔG‡ = 16.8 kcal/mol vs 8.4 kcal/mol), which is similar to the case of [3.1.1]propellane. This result indicates that selective product formation occurs along the possible reaction pathways examined here.

Figure 12.

Figure 12

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Plausible reaction mechanism based on DFT calculations for the 3CR with [4.1.1]propellane. The reaction diagrams were calculated at the UωB97X-D/Def2-SVP/SMD(DCM) level.

[2.2.2]Propellane and [3.3.3]Propellane

[2.2.2]Propellane, characterized by a central carbon atom bonded to three cyclobutane rings, is notoriously unstable, making its synthesis formidably challenging. Numerous attempts to synthesize [2.2.2]propellane have been made to date, but regrettably, all of these endeavors have met with failure due to the thermal instability of [2.2.2]propellane.62,63 On the other hand, the synthesis of [3.3.3]propellane, which features a central carbon atom connected to three cyclopentane rings in a slightly different arrangement, has been shown to be possible,64,65 and the existing literature provides a viable synthetic route to [3.3.3]propellane.64,65 However, the calculated activation barriers shown in Table 1 revealed that achieving diphosphination for this molecule would be highly unlikely due to a high activation barrier and an endergonic reaction pathway. Consequently, we have decided to forego the synthesis of [3.3.3]propellane due to the unfavorable energy profile.

Conclusions

In conclusion, this research represents a remarkable achievement in the synthesis of strained hydrocarbon-based diphosphine ligands, including diphosphinated cyclobutane, bicyclo[3.1.1]heptane, and bicyclo[4.1.1]octane, as evident by our rigorous DFT calculations. Furthermore, the results presented here hold immense promise for various potential applications in functional molecules. For example, a bicyclo[1.1.0]butane-derived cis-coordinated diphosphine was transformed into the corresponding Ni-complex, wherein the bite angle is wider than that in the structurally closely related complex NiCl2(dppp). Moreover, a [3.1.1]propellane-derived diphosphine dioxide was transformed into a unique Eu-based coordination polymer that exhibits a zigzag-type polymeric structure. These results underscore the profound impact of our work within this field of chemistry, reaching far beyond the confines of the laboratory. Furthermore, the synergy between our experimental research and computational calculations is pivotal for the strategic design of radical difunctionalization processes for highly strained molecules. This amalgamation of experimental and theoretical work not only advances our understanding of chemical transformations, but also offers valuable insights into the manipulation of high-energy substrates, paving the way for groundbreaking advancements in the realm of chemical synthesis.

Methods

General Procedure for Diphosphination of Small Ring Molecules.

In an oven-dried round-bottom flask were placed phosphine oxide 1 (0.20 mmol, 1.0 equiv) and [Ir{dF(CF3) ppy}2(dtbbpy)]PF6 (0.4 mg, 0.4 μmol, 0.20 mol %). DCE (1.5 mL), chlorophosphine 2 (0.20 mmol, 1.0 equiv) and Et3N (28 μL, 0.20 mmol, 1.0 equiv) were added under nitrogen. After the resulting mixture was stirred at room temperature for 15 min, then 0 °C for 5 min, a substrate (0.20 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 0 °C for 4 h under the irradiation of blue LED lights (PR160L-440 nm Kessil light ×2). The test tube was positioned between the two lamps, approximately 2 cm away from one of them. Sulfur (7.7 mg, 0.24 mmol, 1.2 equiv of S) was added into the reaction mixture, and the mixture was stirred for 1 h. After the solvent was evaporated to give the crude mixture, the crude product was purified by silica-gel column chromatography to afford the product.

Acknowledgments

Dr. Mingoo Jin and Kosuke Higashida are gratefully acknowledged for performing the X-ray crystallographic analyses. Miyu Harukawa, Makoto Tsurui, and Prof. Yasuchika Hasegawa of the Faculty of Engineering at Hokkaido University are greatly acknowledged for their contributions to preparing the Eu-based coordination polymer and conducting its crystallographic analysis. This work was financially supported by JST-ERATO (JPMJER1903), JSPS-WPI, and Grants-in-Aid for Scientific Research (B) (22H02069), Transformative Research Areas (A) (Digitalization-driven Transformative Organic Synthesis (Digi-TOS)) (22H05330), and Young Scientists (22K14673). T.M. thanks the Naito Foundation for financial support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c00347.

  • Additional experimental details, materials, and methods, including photographs of the experimental setup (PDF)

Author Contributions

The manuscript was written through contributions from all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

au4c00347_si_001.pdf (19.3MB, pdf)

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