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. 2025 Dec 30;11(1):980–994. doi: 10.1021/acsomega.5c08037

Base-Regulated Spiroannulation: Insights into the Palladium-Catalyzed [2 + 2 + 1] Annulation of 1,2-Dihaloarenes, Alkynes, and 2‑Naphthol

Jin-Feng Zhong †, Jie-Yang Li †, Yu-Bing Shi †, Xi-Yun Feng †, Guo Liu ‡,*, Liang-Fei Duan †, Zi-Tong Hu †, Wei-Hua Mu †,*
PMCID: PMC12809289  PMID: 41552458

Abstract

Density functional theory (DFT) was employed to systematically elucidate the mechanism of the palladium-catalyzed [2 + 2 + 1] spiroannulation between 1,2-dihaloarenes, alkynes, and 2-naphthol. It is found the reaction undergoes a series of key steps, including C–I oxidative addition, alkyne insertion, C­(sp2)–H activation, C–C coupling, C–Br oxidative addition, O–H activation, and reductive elimination, ultimately culminating in the formation of the spirocyclic product P (Pa/Pb1/Pb2). The final reductive elimination and spiroannulation process is confirmed to be the rate-determining step (RDS) under default conditions (K3PO4 as the base additive and dppp as the ligand), with a free energy barrier of 33.1 kcal·mol–1 at 130 °C. Predicted kinetics such as the half-life of reaction (20 h) are in good agreement with experimental observation of achieving 90% of spiroindanone product Pa after reacting 16 h at 130 °C. Theoretical predictions regarding the base additive effects (K3PO4 and Na3PO4 vs Cs2CO3) and ligand effects (dppp vs PPh3), as well as regioselectivity (Pb1 vs Pb2), all correspond well with experimental trends, which indicate the choice of base additive can notably influence the reaction pathway and thereby modulate the reaction efficiency and yields. These findings provide valuable insights for the optimization of reaction conditions and novel design of such transition metal-catalyzed transformations.

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1. Introduction

Spirocyclic architectures containing all-carbon quaternary stereocenters constitute the core skeletons of numerous functional molecules such as Spirobrasinin, Satavaptan, and Coixspirolactom, which exhibit significant biological activity or photophysical properties. The literature synthesis of spirocyclic architectures is predominantly achieved through intramolecular reactions, with their efficiency being largely determined by the structural complexity of substrates. To avoid this, transition metal-catalyzed transformations, such as [3 + 2], [4 + 1], and [2 + 2 + 1] cycloadditions have emerged as important strategies for synthesizing spirocyclic compounds, among which the palladium-catalyzed transformations have attracted particular attention due to the high activity and ability of palladium to readily initiate oxidative/reductive reactions.

Compared to intramolecular spiroannulations and two-component spiroannulations, three-component spiroannulations often exhibit higher complexity in the following aspects: (1) the presence of multiple reactive sites in three-component reactions often leads to challenges in site-specific reaction control, resulting in the generation of multiple isomers; (2) the inherent reactivity differences among components usually cause deviations from predicted reaction sequences and pathways; (3) substrate compatibility variation with specific reaction conditions in three-component reactions can notably influence product diversities. All of these poses substantial challenges in achieving selectivity control over three-component spiroannulations. Besides, three-component spiroannulations typically involve multiple elementary steps with numerous intermediates, where the stability and reactivity of these intermediates play crucial roles in determining the overall outcome. Consequently, the development of efficient methodologies for constructing spirocyclic architectures through three-component reactions by using simple and readily available starting materials remains a significant focus in organic synthesis, whereas a comprehensive understanding of these three-component spiroannulations at the atomic and molecular level serves as a fundamental driving force for advancing more precise control over reaction products and selectivities.

In 2021, Wu’s group reported a [2 + 2 + 1] spiroannulation of 1-bromo-2-iodobenzene (R1), 1,2-diphenylethyne (R2a), and 2-naphthol (R3) by taking Pd­(OAc)2 as the catalyst and dppp as the ligand (Scheme ). The reaction generated spiroindanone product Pa in excellent yield after reacting for 16 h at 130 °C in the 1,4-dioxane solvent. It is worth noting that the reaction exhibited remarkable regioselectivity (Pb1/Pb2 > 19:1) when an unsymmetrical alkyne (R2b) was employed, and both the phosphine ligands and base additives can notably influence the outcome. Specifically, replacing K3PO4 with Na3PO4 additive resulted in a sharp decline in the yield of product Pa (from 90 to 0%); the use of Cs2CO3, which has demonstrated excellent performance in many palladium-catalyzed annulations, yielded no product either. A simple reaction mechanism, as shown in Scheme , was proposed. However, it provides no explanations regarding the aforementioned ligand effects, the regioselectivity origin, and the impact of base additives.

1. Palladium-Catalyzed [2 + 2 + 1] Spiroannulation of 1-Bromo-2-iodobenzene (R1), Alkynes (R2a/R2b), and 2-Naphthol (R3).

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We have previously investigated the microscopic mechanism of a Pd-catalyzed two-component spiroannulation by means of density functional theory (DFT) and clarified the impacts of carbonate additives (Cs2CO3/K2CO3) on the reaction. However, owing to the heightened mechanistic complexity inherent in three-component spiroannulations and the appreciable differences between phosphate (K3PO4/Na3PO4) and carbonate additives (Cs2CO3/K2CO3), the detailed molecular mechanism underlying the phosphate-assisted Pd-catalyzed [2 + 2 + 1] three-component spiroannulations remains elusive. For this, we conducted comprehensive computations on this palladium-catalyzed [2 + 2 + 1] spiroannulation involving 1,2-dihaloarenes, alkynes, and 2-naphthol by employing the DFT method. Based on elucidation of the detailed reaction mechanism, a theoretical framework was established to rationalize several experimental observations, including ligand effects, regioselectivity, and base additive effects. Notably, it reveals that the Cs2CO3 additive modulates the reaction pathway fundamentally, thereby decreasing the reaction feasibility compared to K3PO4 or Na3PO4. These insights not only offer valuable insights for screening experimental conditions but also provide significant guidance for the design of novel palladium-catalyzed transformations.

2. Results and Discussion

Based on previous experiments and mechanistic studies on other palladium-catalyzed reactions, we hypothesized and validated the most likely reaction pathway for this transformation, as depicted in Scheme . Initially, the precatalyst Pd­(OAc)2 interacts with dppp ligand to form the active species CAT1 (see Figure S1 and corresponding discussion in the Supporting Information for the precatalysis details). , CAT1 then undergoes C–I oxidative addition with substrate R1, generating intermediate INT1a_I. Afterward, 1,2-diphenylethyne (R2a) inserts into the Pd–C bond of INT1a_I, forming intermediate INT2a_I via an alkyne insertion process. INT2a_I then complexes with substrate R3, and the C­(sp2)–H bond is activated with the assistance of the base additive K3PO4 to form intermediate INT5a_I. Subsequently, INT5a_I experiences C–C coupling, releasing one molecule of K2HPO4 and converting to complex COM5a_I. COM5a_I undergoes C–Br oxidative addition to form intermediate INT6a_I. Subsequently, the released K2HPO4 reparticipates in the reaction, assisting in O–H activation and forming intermediate INT7a_I after removing the KH2PO4·KBr cluster. Finally, INT7a_I undergoes reductive elimination and spiroannulation to generate spiroindanone product Pa, while simultaneously regenerating active species CAT1. The detailed reaction mechanism and corresponding potential free energy surfaces (PESs) are presented in Figures –, respectively.

2. Probable Mechanism of Palladium-Catalyzed [2 + 2 + 1] Spiroannulation between 1-Bromo-2-iodobenzene (R1), 1,2-Diphenylethyne (R2a), and 2-Naphthol (R3).

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Calculated solution-phase potential free energy profiles for C–I oxidative addition and alkyne insertion processes of the palladium-catalyzed [2 + 2 + 1] spiroannulation between R1, R2a, and R3, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level, with key bond lengths (Å) and Wiberg bond indexes (WBIs) depicted at the bottom. The basis sets are defined as follows: BS1 and BS2 denote employing the 6-31G­(d) and 6-311++G­(d,p) basis sets, respectively, for the C, H, O, K, P, Si, and Na atoms, while both make use of the LANL2DZ basis set for Pd, Br, I, and Cs atoms. These conventions are used hereinafter.

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Calculated solution-phase potential free energy profiles for the O–H activation and reductive elimination processes of the palladium-catalyzed [2 + 2 + 1] spiroannulation between R1, R2a, and R3, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level, with key bond lengths (Å) and Wiberg bond indexes (WBIs) depicted at the bottom.

2.1. Mechanism

2.1.1. C–I Oxidative Addition and Alkyne Insertion Processes

As illustrated in Figure , the catalytic cycle initiates with the formation of complex COM1a_I through the interaction between the active species CAT1 and substrate R1, releasing 11.1 kcal·mol–1 of free energy. Subsequently, COM1a_I undergoes C–I oxidative addition via transition state TS1a_I, yielding the Pd­(II) intermediate INT1a_I. This transformation exhibits an exceptionally low activation barrier of 1.5 kcal·mol–1, suggesting a highly favorable and rapid process under the corresponding reaction conditions. The catalytic cycle then proceeds with the coordination of 1,2-diphenylethyne (R2a) to INT1a_I, forming complex COM2a_I. The subsequent alkyne insertion step, mediated by transition state TS2a_I, converts COM2a_I to intermediate INT2a_I with an activation barrier of 21.1 kcal·mol–1. The transferred reaction half-life is approximately 0.02 s, indicating facile occurrence at an experimental temperature of 130 °C.

The computed 3D structures and Wiberg bond indexes (WBIs) for COM2a_I, TS2a_I, and INT2a_I (Figure ) provide insights into the bonding interactions within these species. In COM2a_I, the Pd1–C3 and Pd1–C4 distances are 2.55 and 2.52 Å, respectively, with corresponding WBI values being 0.238 and 0.248, respectively. The C3–C4 bond length is 1.22 Å, characteristic of a typical carbon–carbon triple bond. In contrast, the C2–C3 distance is 3.20 Å, with a WBI value of only 0.040, indicating very weak interaction. All of these suggest that the alkynyl group exhibits only very weak coordination with the Pd atom in COM2a_I. In the transition state TS2a_I, significant changes in bonding are observed. The C2–C3 distance is shortened to 2.04 Å, with a WBI value of 0.417, indicating a clear trend toward bonding between C2 and C3 atoms. Concurrently, the C3–C4 bond length increases to 1.27 Å, while the Pd1–C3 and Pd1–C4 distances reduce to 2.37 Å and 2.11 Å, respectively. The WBI value for Pd1–C4 increases to 0.659, a substantial rise compared to 0.248 in COM2a_I, signifying a marked enhancement in coordination. In intermediate INT2a_I, the C2–C3 bond is further shortened to 1.50 Å, characteristic of a typical C–C single bond, while the C3–C4 bond lengthens to 1.35 Å, transferring from a carbon–carbon triple bond to a double bond. The WBI values for Pd1–C4 and C2–C3 bonds increase to 1.000 and 0.819, respectively. These findings indicate that alkyne R2a has inserted fully into the Pd1–C2 bond during this process.

2.1.2. C­(sp2)–H Activation Process

As depicted in Figure , the Pd­(II) intermediate INT2a_I, generated from the alkyne insertion process, undergoes K2PO4 –-assisted metalation-deprotonation through interaction with K3PO4 and substrate R3, converting into intermediate INT3a_I by removing one KI molecule. This transformation occurs through transition state TS3a_I with an activation barrier of 11.4 kcal·mol–1. Subsequently, INT3a_I undergoes sequential C­(sp2)–H activation and hydrogen migration processes via transition states TS4a_I and TS5a_I, facilitated by K2HPO4, ultimately yielding intermediate INT5a_I. The activation barriers for this two-step transformation are 16.3 and 5.9 kcal·mol–1, respectively, which are readily accessible at the experimental temperature of 130 °C, ensuring efficient progression of the catalytic cycle. Readers are referred to Figures S2 and S3 as well as the corresponding discussion in the Supporting Information for further mechanistic details on alternative C­(sp2)–H activation (Path a_II and Path a_III) and H migration (Path a_IV) processes.

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Calculated solution-phase potential free energy profiles for the metalation-deprotonation, C­(sp2)–H activation, and H migration processes of the palladium-catalyzed [2 + 2 + 1] spiroannulation between R1, R2a, and R3, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level, with key bond lengths (Å) and Wiberg bond indexes (WBIs) depicted at the bottom.

The optimized 3D structures and Wiberg bond indexes (WBIs) for intermediates INT3a_I and INT4a_I, and transition state TS4a_I (Figure ) provide valuable insights into the evolution of the Pd1–C5 bond during the C­(sp2)–H activation process. As the Pd1–C5 distance contracts from 2.34 Å in INT3a_I to 2.14 Å in TS4a_I, and further to 2.04 Å in INT4a_I, with corresponding WBI values increasing progressively from 0.383 to 0.615 and then to 0.765. This trend clearly illustrates the gradual strengthening of the Pd1–C5 bond, ultimately leading to typical coordination. Following this, the relatively unstable intermediate INT4a_I undergoes hydrogen migration to transform into the more stable INT5a_I, providing the necessary configuration for the subsequent C–C coupling.

2.1.3. C–C Coupling and C–Br Oxidative Addition Processes

Following the aforementioned C­(sp2)–H activation and hydrogen migration processes, intermediate INT5a_I undergoes C–C coupling via a three-centered transition state TS6a_I, accompanied by the elimination of one K2HPO4 molecule and forming complex COM5a_I (Path a_I, Figure ). This transformation only requires getting across an activation barrier of 16.3 kcal·mol–1, suggesting a very feasible transformation at the experimental temperature of 130 °C. However, the C–C coupling process via transition state TS6a_IV on Path a_IV (in which the K2HPO4 moiety coordinates to the Pd center), requires a higher overall activation barrier of 30.5 kcal·mol–1 (INT3a_I → TS6a_IV → COM5a_I, Figure S3). This indicates that the C–C coupling preferentially occurs along Path a_I through the dppp-bidentate-coordinated TS6a_I. Afterward, complex COM5a_I undergoes C–Br bond oxidative addition through transition state TS7a_I, forming the Pd­(II) intermediate INT6a_I. This step exhibits a remarkably low activation barrier of 7.9 kcal·mol–1 and proceeds as an exothermic process, indicating a high thermodynamic favorability.

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Calculated solution-phase potential free energy profiles for the C–C coupling and C–Br oxidative addition processes of the palladium-catalyzed [2 + 2 + 1] spiroannulation between R1, R2a, and R3, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level.

2.1.4. O–H Activation and Reductive Elimination Processes

As depicted in Figure , the complex formed between intermediate INT6a_I and K2HPO4 during the previous C–C coupling is converted into a more stable complex, COM6a_I. COM6a_I subsequently undergoes O–H activation with the assistance of K2HPO4, leading to the formation of complex COM7a_I. Upon removal of the KH2PO4·KBr cluster, COM7a_I transforms into intermediate INT7a_I. The entire process requires overcoming only a free energy barrier of 3.6 kcal·mol–1 (TS8a_I) and releasing 19.6 kcal·mol–1 of free energy, indicating highly favorable thermodynamic and kinetic profiles. Then, the eight-membered-ring intermediate INT7a_I is converted into INT8a_I, wherein pronounced steric hindrance between the Pd atom and the C5 atom of the naphthol fragment is observed. This interaction is corroborated by noncovalent interaction (NCI) plus independent gradient model (IGM) analyses (Figure S4), which accounts for the significant free energy increase of 19.9 kcal·mol–1 associated with this transformation. Afterward, INT8a_I undergoes reductive elimination and spiroannulation via transition state TS9a_I to yield the final product Pa. This step also achieves the regeneration of the active species CAT1, with a total free energy barrier of 33.1 kcal·mol–1 and represents the rate-determining step (RDS) of the entire reaction. The corresponding reaction rate constant and half-life are 3.4 × 10–2 h–1 and 20 h, respectively, aligning well with the experimental observation of yielding 90% of Pa after 16 h at 130 °C. The C5–C6 distance in INT7a_I is 3.40 Å (Figure ), which is notably shortened to 2.03 Å (with a WBI value of 0.436) in TS9a_I and further reduced to 1.53 Å (with a WBI value of 0.919) in the final product Pa. These changes confirm that the C–C coupling and spiroannulation process have been effectively achieved.

Comprehensive analysis of the entire reaction profile (Figures –) reveals that the overall transformation from reactants (R1 + R2a + R3) to the product (Pa) is highly exothermic, releasing a total 122.0 kcal·mol–1 of free energy and indicating significant thermodynamic feasibility. The final reductive elimination and spiroannulation sequence (INT7a_I → INT8a_I → TS9a_I → Pa) constitutes the rate-determining step of the catalytic cycle, requiring an overall free energy barrier of 33.1 kcal·mol–1. Kinetic data of this step (with the rate constant being 3.4 × 10–2 h–1 and corresponding half-life being 20 h) are in excellent agreement with experiments, in which 90% of product Pa was achieved after 16 h of reaction at 130 °C. This excellent agreement between computational predictions and experiments not only validates the computational methodology employed but also confirms the reliability of the results obtained here.

2.2. Base Effects

Previous experiments revealed that base additives exert significant influence on the reaction yields (Scheme ). For instance, the use of K3PO4 resulted in a product yield of Pa up to 90%, while replacing K3PO4 with Na3PO4 failed to produce the desired product. Notably, Cs2CO3, which has demonstrated exceptional performance in many other palladium-catalyzed transformations, also failed to yield Pa. These observations hint that different types of base additives may alter the reaction mechanism, thereby affecting the feasibility of the reaction. To test this, we investigated the rate-determining step (RDS) assisted by Na3PO4 (Path a_Na in Figure ) at the same computational level and found that the Na3PO4-assisted RDS step’s potential free energy surfaces (PESs) were generally similar to those assisted by K3PO4. However, due to the poorer stability of most stationary points on Path a_Na compared to Path a_I (Figures S5 and S6) and the fact that COM7a_Na is more stable than COM7a_I (Figure ), the free energy barrier for the Na3PO4-assisted RDS step was as high as 38.8 kcal·mol–1. The transferred reaction half-life was as long as 2.5 × 104 h (approximately 1042 days), rationalizing the experimental observation that no product could be obtained in the Na3PO4-assisted case.

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Calculated solution-phase potential free energy profiles for the rate-determining step (RDS) of Path a_Na, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level. The K3PO4-assisted Path a_I is replotted in gray for comparison.

Computed dual descriptor potential (DDP) for complexes COM7a_I and COM7a_Na based on Hirshfeld charges (Table ) reveals significant insights into the electronic properties of them. The dual descriptors (Δf) for C6 sites in both complexes are positive, with a slight difference of 0.00064 bohr·e–3, suggesting a comparable electrophilic character at this position. In contrast, the C5 sites in both complexes exhibit negative Δf values, with that in COM7a_I being 0.01102 bohr·e–3 lower than that in COM7a_Na, indicating stronger nucleophilicity at this site in the former. This observation is further supported by the contour maps of DDP, which reveal a more pronounced Fukui potential (represented by the cyan isosurface) at the C5 site in K3PO4-assisted COM7a_I compared to Na3PO4-assisted COM7a_Na. The more negative DDP on the C5 site in COM7a_I suggests superior activation of the C5 site in it. Further examination of the optimized geometrical parameters reveals that the Na–O bonds in complex COM7a_Na are shorter than the corresponding K–O bonds in COM7a_I (Figure S7). This suggests a stronger electrostatic interaction between Na+ and PO4 3– in COM7a_Na compared to that between K+ and PO4 3– in COM7a_I, which also accounts for the enhanced stability of COM7a_Na relative to that of COM7a_I.

1. Hirshfeld Charges (au) and Dual Descriptor (Δf, bohr·e–3, Based on Hirshfeld Charges) of Key Atoms in COM7a_I and COM7a_Na, with Their Contour Maps of the Dual Descriptor Potential (DDP) Depicted (the Isosurface Value is Set to 0.005 au, Green for the Positive Phase and Cyan for the Negative Phase).

2.2.

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Consequently, COM7a_I exhibits greater reactivity than COM7a_Na during the subsequent reductive elimination involving C5–C6 coupling, resulting in a lower activation barrier for the K3PO4-assisted case compared to the Na3PO4-assisted one.

To further elucidate why Cs2CO3, a base additive that has demonstrated excellent performance in many palladium-catalyzed spiroannulations, , failed to produce any product here (Scheme ), we conducted computational studies on the Cs2CO3-assisted reaction (Path a_Cs in Figure ) at the same level. It is revealed that the Cs2CO3-assisted reaction mechanism undergoes significant changes compared to the K3PO4-assisted one. Initially, intermediate INT2a_I undergoes ligand exchange with Cs2CO3 to form complex COM3a_Cs, which subsequently complexes with substrate R3 to form COM4a_Cs. Both of these are barrier-free and spontaneous, releasing 19.7 kcal·mol–1 of free energy. Subsequently, COM4a_Cs undergoes C­(sp2)–H activation via the transition state TS3a_Cs to form complex COM5a_Cs. This step requires overcoming a free energy barrier of 32.9 kcal·mol–1, corresponding to a reaction half-life of 16 h, which is feasible at 130 °C. However, COM5a_Cs is not stable enough and will further undergo C–C coupling via transition state TS4a_Cs, transforming into a more stable complex COM5a_I while releasing one molecule of CsHCO3. The overall free energy barrier for the conversion of COM4a_Cs to COM5a_I via transition state TS4a_Cs is 30.3 kcal·mol–1, about 2.6 and 18.1 kcal·mol–1 lower than that of TS3a_Cs and the TS6a_IV-alike transition state TS4a_Cs′, respectively (see Figure S3 for TS6a_IV and Figure S8 for TS4a_Cs′). As illustrated in Figure , the transformation from COM5a_I to product Pa involves three transition states (TS7a_I, TS5a_Cs, and TS9a_I) and is accompanied by a free energy release of 55.7 kcal·mol–1. The free energy barriers for TS7a_I, TS5a_Cs, and TS9a_I are 7.9, 1.4, and 38.5 kcal·mol–1, respectively, among which the highest one (TS9a_I, 38.5 kcal·mol–1) plays an RDS step role in the whole reaction. The transferred reaction half-life is so long, 1.7 × 104 h (approximately 708 days, Table ), that this conversion should be very difficult at the experimental temperature of 130 °C. Therefore, when Cs2CO3 is employed as the base additive, no product Pa could be obtained. The computed free energy barriers and kinetic data accurately predicted the infeasibility of the Cs2CO3-assisted reaction and are in complete agreement with the experimental observations. In a word, the mechanistic altering induced by the replacement of K3PO4 with Cs2CO3 is primarily manifested in the following two aspects: (1) variation of the reaction mechanism and (2) substantial increase of the RDS step’s free energy barrier. These changes collectively explain the disappearance of product Pa in experiments in the Cs2CO3-assisted case and provide atomic/molecular-level insights into the yield variations observed when employing different base additives.

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Calculated solution-phase potential free energy profiles for the ligand exchange, C­(sp2)–H activation, and C–C coupling processes of Path a_Cs, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level.

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Calculated solution-phase potential free energy profiles for the C–Br oxidative addition, O–H activation, and reductive elimination processes of Path a_Cs, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level. The K3PO4-assisted Path a_I is replotted in gray for comparison.

2. Calculated Free Energy Barriers (ΔΔG, kcal·mol–1), Rate Constants (h–1), and Reaction Half-Lives (h) Corresponding to the K3PO4-, Na3PO4- and Cs2CO3-Assisted Rate-Determining Transition State (TSRDS).

Bases additives TSRDS ΔΔG RDS (kcal·mol–1) k (h–1) t 1/2 (h)
K3PO4 TS9a_I 33.1 3.4 × 10–2 20
Na3PO4 38.8 2.8 × 10–5 2.5 × 104
Cs2CO3 38.5 4.1 × 10–5 1.7 × 104
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The computed dual descriptor potential (DDP) based on Hirshfeld charges (Table ) for complex COM7a_Cs provides further insight into its electronic properties. The dual descriptor (Δf) at the C6 site in COM7a_Cs is positive, with a value of 0.01142 bohr·e–3, and is 0.01928 bohr·e–3 smaller than that in COM7a_I, indicating weaker electrophilicity at this site in COM7a_Cs compared to that in COM7a_I. Conversely, the C5 site exhibits a negative Δf value (−0.04807 bohr·e–3), similar to that in COM7a_I but 0.04354 bohr·e–3 higher, suggesting reduced nucleophilicity at this site in COM7a_Cs relative to that in COM7a_I. These observations are corroborated by the DDP contour maps (Table ), which show more pronounced Fukui potentials at the C5 and C6 sites (represented by cyan and green isosurfaces, respectively) in the K3PO4-assisted COM7a_I compared to the Cs2CO3-assisted COM7a_Cs. This implies that COM7a_I possesses superior reactivity over COM7a_Cs during the subsequent reductive elimination step involving the C5–C6 bond formation. Consequently, the K3PO4-assisted reaction can proceed with a lower activation barrier than the Cs2CO3-assisted analogue.

2.3. Ligand Effects

PPh3 ligand has been shown to notably enhance the reaction smoothness of many palladium-catalyzed spiroannulations. However, replacing the bidentate dppp ligand with the monodentate PPh3 ligand in the reaction resulted in a notable decrease in the yield of product Pa (from 90 to 62%, Scheme ). To elucidate the ligand effect, we investigated the rate-determining step of the PPh3-assisted reaction computationally (Figure ). Generally, the reaction mechanism of the PPh3-assisted rate-determining step is similar to the dppp-assisted one (Path a_I), while two possible pathways were identified: Path a_PPh3 and Path a_2PPh3. The overall free energy barriers for the rate-determining transition states on Path a_PPh3 and Path a_2PPh3 (TS9a_PPh3 and TS9a_2PPh3 ) were calculated to be 34.4 and 35.6 kcal·mol–1, respectively, which are 1.3 and 2.5 kcal·mol–1 higher than that of the dppp-assisted pathway (TS9a_I). This suggests that the monodentate PPh3-assisted reaction is indeed more challenging than the bidentate dppp-assisted one. Moreover, the reaction is more likely to proceed along the pathway assisted by a single PPh3 ligand (Path a_PPh3). As shown in Table S1, the PPh3-assisted reaction rate transferred from the corresponding free energy barrier (TS9a_PPh3 , 34.4 kcal·mol–1) is approximately five times slower than that of the dppp-assisted one. These computational predictions align acceptably with the experimental observation that the reaction yield decreases from 90 to 62% when using PPh3 to replace the dppp ligand. Readers who are interested in the entire potential free energy profiles of Path a_PPh3 can refer to Figures S9–S11 in the Supporting Information.

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Calculated solution-phase potential free energy profiles for the O–H activation and reductive elimination processes of Path a_PPh3 and Path a_2PPh3, obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level. The dppp-assisted Path a_I is replotted in gray for comparison.

NCI and IGM analyses of transition states TS9a_I, TS9a_PPh3 , and TS9a_2PPh3 (Figures and S12) reveal evident but barely distinguishable steric repulsion between the C5 and C6 atoms (highlighted by black circles) in them, as well as distinct π­(Ar)···π­(Ar) weak interactions between phenyl groups in all three structures (highlighted by purple circles). Complementary atoms-in-molecules (AIM) analysis shows that the electron density at the bond critical point (ρ­(BCP)) for this π­(Ar)···π­(Ar) interaction is 0.0058 au in TS9a_I and 0.0039 au in TS9a_2PPh3 , respectively, both notably bigger than that in TS9a_PPh3 (ρ­(BCP) = 0.0030 au). This indicates stronger stabilizing interactions in TS9a_I and TS9a_2PPh3 compared to TS9a_PPh3 , consistent with their lower relative free energy. Meanwhile, the electron density between C5 and C6 atoms in TS9a_I (0.0845 au) is bigger than that in TS9a_2PPh3 (0.0732 au), suggesting a relatively more stable geometry of the former than the latter and thus greater ease of the C–C bond formation through TS9a_I. Collectively, the NCI and AIM results provide a coherent rationale for the observed gradual deterioration of stability and corresponding increase of free energy barriers from TS9a_I to TS9a_2PPh3 and then to TS9a_PPh3 , and they also underscore the critical role of both electronic effects and steric hindrance in modulating the reaction yields.

9.

9

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Independent gradient model (IGM) analyses and key electron densities (au) at the bond critical point (ρ­(BCP)) for transition states TS9a_I, TS9a_PPh3 , and TS9a_2PPh3 (the isosurface value is set to 0.003 au).

2.4. Regioselectivities

Experimental results indicate that when an unsymmetrical alkyne, such as R2b, is employed as a substrate, the resulting spirocyclic product Pb exhibits good regioselectivity (Pb1/Pb2 > 19:1), with the major product corresponding to the 3,4-insertion of alkyne R2b (Scheme ). To elucidate the origin of this regioselectivity, we performed computations on reaction b at the same computational level, with the results presented in Figures , S13, and S14 accordingly. The reaction mechanism of reaction b is analogous to that of reaction a, with its rate-determining step (RDS) corresponding to the final reductive elimination and spiroannulation process. However, due to different orientations of alkyne insertion, reaction b can proceed via two possible pathways: Path b_I (3,4-insertion) and Path b′_I (4,3-insertion). For Path b, the overall free energy barrier of TSRDS (TS9b_I) is 29.8 kcal·mol–1 (Figure ). In contrast, the corresponding free energy barrier of TSRDS on Path b′_I (TS9b′_I) is 33.3 kcal·mol–1, which is 3.5 kcal·mol–1 higher than that of Path b_I. This difference indicates that the alkyne R2b in reaction b preferentially undergoes 3,4-insertion, facilitating the reaction to proceed along Path b_I and ultimately yielding the major product Pb1. Based on the free energy barriers of TSRDS on both Path b_I and Path b′_I, the predicted generation rate of Pb1 to Pb2 is approximately 79:1 (Table ). This prediction agrees well with experimentally observed regioselectivity (Pb1/Pb2 > 19:1), thereby corroborating the computational predictions as reliable representatives for the experimental findings.

10.

10

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Calculated solution-phase potential free energy profiles for the O–H activation and reductive elimination processes of the palladium-catalyzed [2 + 2 + 1] spiroannulation between 1-bromo-2-iodobenzene (R1), 1-phenyl-2-(trimethylsilyl)­acetylene (R2b), and 2-naphthol (R3), obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level.

3. Calculated Free Energy Barriers (ΔΔG, kcal·mol–1) for the Rate-Determining Transition States (TSRDS) on Path b_I and Path b′_I, with the Calculated and Experimental Yields Depicted for Comparison.

path TSRDS ΔΔG RDS (kcal·mol–1) Yield (%)Calc Pb1/Pb2 Yield (%)Expt Pb1/Pb2
Path b_I TS9b_I 29.8 79:1 >19:1
Path b′_I TS9b′_I 33.3
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Comprehensive NCI, IGM, and AIM analyses for transition states TS9b_I and TS9b′_I reveal significant differences in noncovalent interactions that govern the regioselectivity. As shown in Figures and S15, NCI and IGM analyses reveal obvious but indistinguishable steric repulsion between the C5 and C6 atoms (highlighted by black circles); meanwhile, there are distinct π­(Ar)···π­(Ar) weak interactions (highlighted by purple circles) in both TS9b_I and TS9b′_I. Further AIM analysis shows that the electron density at the bond critical point (ρ­(BCP)) for the phenyl–phenyl π­(Ar)···π­(Ar) interaction in TS9b_I (0.0053 au) is notably bigger than its counterpart in TS9b′_I (ρ­(BCP) = 0.0034 au). Meanwhile, the electron density between C5 and C6 atoms in TS9b_I (0.0839 au) is also bigger than that in TS9b′_I (0.0801 au). Consequently, TS9b_I exhibits superior stability compared to TS9b′_I, explaining the preferential formation of spirocyclic product Pb1 (through Path b_I) over Pb2 (through Path b′_I). To summarize, the observed regioselectivity is mainly governed by the electronic stabilization effects, while steric hindrance also contributes some.

11.

11

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Independent gradient model (IGM) analyses and key electron densities (au) at the bond critical point (ρ­(BCP)) for transition states TS9b_I and TS9b′_I (the isosurface value is set to 0.003 au).

3. Conclusion

Density functional theory (DFT) was employed to investigate the microscopic mechanism, base effects, ligand effects, and regioselectivity of the palladium-catalyzed [2 + 2 + 1] spiroannulation involving 1-bromo-2-iodobenzene (R1), alkynes (R2a/R2b), and 2-naphthol (R3). Based on the results obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level, the following conclusions can be drawn: (1) the reaction primarily proceeds through C–I oxidative addition, alkyne insertion, C­(sp2)–H activation, C–C coupling, C–Br oxidative addition, O–H activation, and reductive elimination, ultimately yielding the spirocyclic product Pa. The final reductive elimination and spiroannulation process constitutes the rate-determining step (RDS) of the entire reaction, with a free energy barrier of 33.1 kcal·mol–1. The transferred reaction half-life is 20 h, being in good agreement with the experimental observation that 90% of product Pa was obtained after 16 h of reaction at 130 °C; (2) computations for the K3PO4-, Na3PO4-, and Cs2CO3-assisted reactions reveal that similar bases (K3PO4 and Na3PO4) exhibit analogous mechanisms, with their rate-determining steps both corresponding to the final reductive elimination and spiroannulation process. However, different types of bases (Cs2CO3) can alter the reaction mechanism to some extent. The high RDS step’s free energy barriers observed for the Na3PO4- and Cs2CO3-assisted reactions (38.8 and 38.5 kcal·mol–1, respectively) accurately reproduced the experimental findings that no product Pa could be obtained in these two cases; (3) computed results for ligand effects (1PPh3 and 2PPh3 vs dppp) and regioselectivity (Pb1 vs Pb2) consist well with previous experimental observations, and indicate that the feasibility and regioselectivity of this reaction are collectively influenced by both electronic effects and steric hindrance. These mechanistic insights are helpful for an in-depth understanding of the observed reactivity and selectivity trends in such palladium-catalyzed spiroannulation transformations.

4. Computational Methods

Density functional theory (DFT) methods and the Gaussian 09 software package were employed to computationally investigate the palladium-catalyzed [2 + 2 + 1] spiroannulation of 1,2-dihaloarenes, alkynes, and 2-naphthol. The M06-2X functional was initially adopted in geometry optimization and vibrational analyses, followed by single-point corrections performed employing the PBE0 functional and D3­(BJ) dispersion correction, with details about method- and basis set-screening presented in the Supporting Information. All free energy results reported in the main text are Gibbs free energy obtained at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 level of theory and have already been corrected to the experimental temperature of 130 °C by using the THERMO program. Vibrational analyses were performed on all stationary points to confirm that all vibrational frequencies of intermediates (excluding transition states) are positive, while transition states possess only one imaginary frequency. Intrinsic reaction coordinate (IRC) analyses were conducted on key transition states to ensure that they correctly connect the appropriate minima. An “ultrafine” grid is used in all calculations. In addition, Wiberg bond indexes (WBIs) between selected atoms and Hirshfeld charges on them, as well as electron densities at the bond critical points (ρ­(BCP)) between them, were calculated by using the Multiwfn program. Noncovalent interaction (NCI), independent gradient model (IGM), and dual descriptor potential (DDP) analyses (in which the most positive and negative regions designate preferred sites for nucleophilic and electrophilic reactions, respectively) were performed on key stationary points by employing Multiwfn and VMD programs. All the above property analyses were also conducted at the IDSCRF­(1,4-dioxane)-PBE0-D3­(BJ)/BS2//IDSCRF­(1,4-dioxane)-M06-2X/BS1 computational level, with all three-dimensional structures being visualized by using CYLview software.

Supplementary Material

ao5c08037_si_001.pdf (5.8MB, pdf)

Acknowledgments

This work was supported by The National Natural Science Foundation of China (22363012, 21763033), The Yunnan Provincial Graduate Supervisor Team Construction Project (2024), and the Top Young Talents of Yunnan Ten Thousand People Plan.

The data supporting the findings of this study are available within the article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c08037.

  • Potential free energy surfaces, tables containing kinetic data, total electronic and free energy, vibrational frequencies (PDF), and optimized Cartesian coordinates for all stationary points (XYZ) (PDF)

∥.

School of Traditional Dai Medicine, West Yunnan University of Applied Sciences, No. 93, Xuanwei Avenue, Yunjinghong Subdistrict, Jinghong, Yunnan, 666100, China

§.

J.-F.Z. and J.-Y.L. contributed equally to this work. Data curation, J.-F. Zhong, J.-Y. Li, Y.-B. Shi, and Z.-T. Hu; funding acquisition, W.-H. Mu; conceptualization, supervision, and project administration, W.-H. Mu and G. Liu; visualization, J.-F. Zhong and J.-Y. Li; writingoriginal draft, J.-F. Zhong, J.-Y. Li, and W.-H. Mu; writingreview and editing, W.-H. Mu, G. Liu, L.-F. Duan, and X.-Y. Feng.

The authors declare no competing financial interest.

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Data Availability Statement

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