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Article

A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity

by
Guangli Zhou
1,
Shuangxin Zhai
1,
Xia Leng
1,
Yunzhi Li
1,
Qiying Xia
1,* and
Yi Luo
2,3,*
1
School of Chemistry and Chemical Engineering, Linyi University, Linyi 276000, China
2
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
3
PetroChina Petrochemical Research Institute, Beijing 102206, China
*
Authors to whom correspondence should be addressed.
Inorganics 2026, 14(1), 28; https://doi.org/10.3390/inorganics14010028
Submission received: 26 November 2025 / Revised: 27 December 2025 / Accepted: 14 January 2026 / Published: 16 January 2026
(This article belongs to the Section Coordination Chemistry)
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Abstract

Density functional theory (DFT) calculations elucidate the mechanism of diastereoselective cyclization of 2-picoline with 1,5-hexadiene catalyzed by a cationic half-sandwich scandium complex. The catalytic cycle proceeds through four key stages: formation of active species, initial alkene insertion, cis-selective cyclization, and protonation. Central to the mechanism is the dual role of 2-picoline, which initially coordinates as a supporting ligand to facilitate C–H activation and regioselective 1,2-insertion but must dissociate to enable stereocontrol. The mono(2-picoline)-coordinated complex C3 is identified as the thermodynamically favored active species. C–H activation reactivity follows the trend: ortho-C(sp2)–H (2-picoline-free) > ortho-C(sp2)–H (2-picoline-coordinated) > benzylic C(sp3)–H (2-picoline-free) > benzylic C(sp3)–H (2-picoline-coordinated), a preference governed by a wider Cα–Sc–Cα′ angle and shorter Sc···X (X = Cα, Cα′, H) distances that enhance scandium–substrate interaction. Subsequent 1,5-hexadiene insertion proceeds with high 1,2-regioselectivity through a picoline-assisted pathway. The stereoselectivity-determining step reveals a mechanistic dichotomy: while picoline coordination is essential for initial activation, its dissociation is required for intramolecular cyclization. This ligand displacement avoids prohibitive steric repulsion in the transition state, directing the reaction exclusively toward the cis-cyclized product. The cycle concludes with a sterically accessible mono-coordinated protonation. This work establishes a “ligand-enabled then ligand-displaced” mechanism, highlighting dynamic substrate coordination as a critical design principle for achieving high selectivity in rare-earth-catalyzed C–H functionalization.

Graphical Abstract

1. Introduction

Cationic rare-earth metal complexes demonstrate high activity and stereoselectivity in the functionalization [1,2,3,4,5,6,7] of olefins with a variety of heteroatom-containing substrates (e.g., pyridines [8,9,10,11,12,13,14,15,16,17,18,19], anilines [20,21,22,23,24,25,26,27], amines [28,29,30] aldimines [31,32,33,34,35,36,37,38,39], quinolines [40,41,42,43], imidazoles [44,45], sulfides [46,47,48], anisoles [49,50,51,52]) due to their distinctive chemical properties (Scheme 1). Among these substrates, pyridine has been the most extensively investigated due to its prevalence in functional molecules. The development of efficient synthetic pathways for pyridine-containing compounds is of considerable importance, as the pyridine motif is a key heterocyclic unit present in numerous natural products, pharmaceuticals, bioactive molecules, functional materials, and organic ligands. In this regard, direct catalytic C–H alkylation of pyridines with olefins represents a particularly attractive, 100% atom-economical route to valuable alkylated derivatives. While significant progress has been made in reactions with monoolefins like ethylene and styrene, the engagement of more complex substrates, such as non-conjugated dienes, remains less explored mechanistically [53,54].
Catalytic cyclizations of dienes offer efficient pathways for constructing cyclic frameworks, yet controlling stereochemistry, particularly toward the kinetically disfavored cis isomers from 1,5-dienes remains a significant synthetic challenge, as conventional post-transition-metal catalysts predominantly deliver the more thermodynamically stable trans-configured products [55,56,57,58,59,60,61,62,63,64,65,66]. In contrast to this context, rare-earth catalysts have emerged as versatile platforms capable of overriding inherent stereochemical preferences. For instance, Hou and co-workers have systematically demonstrated the stereochemical versatility of half-sandwich rare-earth complexes, employing scandium catalysts to achieve trans-selective [3+2] annulations via β′-allylic C–H activation, and utilizing cerium or yttrium catalysts to deliver cis-selective [4+2] annulations via γ-allylic or benzylic C–H activation [36,67]. The same group reported the first remarkable scandium-catalyzed diastereoselective cyclization of 1,5-hexadiene with 2-picoline that defies conventional selectivity patterns (Scheme 2) [68]. While their novel mono(phosphinoamido) (NP) ligand system achieved an excellent 99% yield with high cis selectivity (cis/trans > 98:2), the more conventional half-sandwich scandium alkyl catalyst (Cp*) also successfully delivered the C–H addition/cyclization product in 70% yield while maintaining comparably high cis selectivity (cis/trans > 98:2). For our detailed computational mechanistic investigation, we strategically elected to employ the Cp-ligated system as our model. This decision is primarily motivated by the need to circumvent the significant conformational complexity introduced by the flexible, non-symmetric NP ligand. The high symmetry and rigid coordination sphere of the Cp* (C5Me5) scaffold present a well-defined catalytic center, drastically reducing the number of low-energy conformers and enabling a more tractable and focused analysis of the core reaction pathway.
However, several fundamental questions about this transformation remain unanswered by experiment alone. What is the true catalytically active species? How does the number of coordinated 2-picoline molecules influence the reaction trajectory? Why does the reaction favor diastereoselective cyclization over simple mono-alkylation, and what is the electronic and steric origin of the overwhelming preference for the cis product? In particular, the role of the 2-picoline substrate itself, whether it acts merely as a reactant or also as a critical coordinating ligand that modulates the catalyst’s behavior, is a key open question.
Herein, we report a comprehensive DFT study to address these questions. Our investigation goes beyond mapping the energy profile. It aims to decipher the nuanced factors that control this unique selectivity. We identify a “ligand-enabled then ligand-displaced” mechanism, wherein 2-picoline coordination is essential to initiate the reaction, but its subsequent dissociation is imperative to achieve the high diastereoselectivity. This work not only refines the mechanistic picture of rare earth-catalyzed C–H functionalization with dienes, but also highlights the dynamic role of substrate coordination as a versatile design principle for selective catalysis.

2. Results and Discussion

Generation of Active Catalytic Species. The cationic scandium monoalkyl species 1 is generated via cationization of the rare-earth dialkyl precursor (C5Me5)Sc(CH2C6H4NMe2-o)2 with one equivalent of [Ph3C][B(C6F5)4]. As depicted in Figure 1, two potential C–H bonds in 2-picoline (a) can be activated under the influence of the directing group, viz. ortho-C(sp2)–H and benzylic C(sp3)–H. The reaction initiates with coordination of 2-picoline to the Sc center in 1, forming the more stable π-complex A1, which lies 12.3 kcal/mol (‡ = transition state) lower in energy. Subsequently, the π-complex A1 then undergoes σ-bond metathesis (σ-BM) via transition state TS1a (path a), with a barrier of 23.7 kcal/mol, leading to the Sc-η2-picolyl species B1 accompanied by a coordinated o-Me2NC6H4Me (b). Dissociation of b from B1 yields the proposed naked cationic scandium species C1, featuring a three-membered metallacycle. This step is endergonic by 6.2 kcal/mol. Alternatively, coordination of 2-picoline to species 1 can also form the thermodynamically stable adduct A2 (ΔG = −13.9 kcal/mol). From A2, benzylic C(sp3)–H activation proceeds via transition state TS1b (path b), affording Sc-η2-picolyl species B2. Subsequent release of b gives the cationic four-membered scandium species C2. The computed free energy barriers reveal a definitive kinetic preference for ortho-C(sp2)–H activation. The barrier for this process in the absence of an additional picoline ligand (TS1a) is 23.7 kcal/mol, which is 2.5 kcal/mol lower than the barrier for the corresponding benzylic C(sp3)–H activation via TS1b (26.2 kcal/mol).
Given the heteroatom affinity of the rare-earth metal center, we further examined ortho-C(sp2)–H and benzylic C(sp3)–H activation in the presence of an additional coordinating 2-picoline ligand. Upon coordination of a second 2-picoline molecule, C(sp2)–H activation proceeds along A3 → TS1c → B3 (path c), whereas the benzylic C(sp3)–H activation follows A4 → TS1d → B4 (path d). This preference is maintained upon coordination of a second 2-picoline molecule, with the ortho-C(sp2)–H activation barrier via TS1c (24.7 kcal/mol) being 4.7 kcal/mol lower than the benzylic activation via TS1d (29.4 kcal/mol). While the barrier for the naked cation pathway (TS1a) is marginally the lowest, the resultant species C1 is thermodynamically unstable (ΔG = +6.2 kcal/mol). In contrast, dissociation of the amine byproduct from B3 yields the mono(2-picoline)-coordinated complex C3, which is both kinetically accessible and the thermodynamic minimum of the system (ΔG = −11.7 kcal/mol). Since C3 can also be generated by coordination of 2-picoline to C1, consequently, C3 is identified as the catalytically competent active species. Such a favorable activation manner has also been reported in previous theoretical study on cationic systems [2e, 9d].
Figure 2 provides a geometric and electronic rationale for the observed reactivity trends in C–H activation. The computed energy barriers for TS1a–d are markedly different, with values of 23.7, 26.2, 24.7, and 29.2 kcal/mol, respectively. All transition states confirm a concerted σ-bond metathesis mechanism [69,70], characterized by their four-membered Sc–Cα–H–Cα′ ring geometries, as supported by key interatomic distances: Sc–Cα (2.39~2.45 Å), Sc–Cα′ (2.26~2.47 Å), Cα–H (1.40~1.46 Å), Cα′–H (1.43~1.46 Å), and Sc–H (1.86~1.92 Å). These parameters are consistent with geometries reported for scandium-alkyl-catalyzed reactions of 2-ethylpyridine or amines with olefins [71]. Further analysis revealed a strong negative correlation between the Cα–Sc−Cα′ angle and the activation barrier: TS1a (76.1°, 23.7 kcal/mol) > TS1c (75.8°, 24.7 kcal/mol) > TS1b (72.1°, 26.2 kcal/mol) > TS1d (70.5°, 29.2 kcal/mol). The activation barrier decreases with an increasing Cα–Sc–Cα′ angle. This angle was widest in the most favorable TS1a (76.1°) and most acute in the least favorable TS1d (70.5°). A wider angle facilitates shorter Sc···C/H distances, thereby enhancing the interaction between the metal center and the substrate. This geometric analysis was corroborated by Natural Bond Orbital (NBO) charge analysis. The natural population analysis (NPA) on the Sc center increases as follows: 1.20 (TS1a) < 1.29 (TS1c) < 1.32 (TS1b) < 1.43 (TS1d). This trend suggests that a reduced Lewis acidity at the metal center, likely due to enhanced charge transfer from the substrate and/or ligands, contributes to transition state stabilization. The increasing NBO charge on Sc from TS1a to TS1d reflects a greater degree of electron transfer from the substrate to the metal center during the C–H cleavage event. This enhanced charge transfer stabilizes the transition state, and the extent of this stabilization correlates with the lower barriers.
Regioselectivity and the Facilitating Role of 2-Picoline in Alkene Insertion. Having established C3 as the active species, DFT investigations were conducted to elucidate the origin of regioselectivity in the insertion of 1,5-hexadiene (c). As illustrated in Figure 3, coordination of c to C3 forms the π-complex D1. Subsequent 1,2-insertion of 1,5-hexadiene into the Sc–C bond proceeds via a conventional four-center transition state [72,73,74,75,76], TS2a, yielding the more stable ring-expanded five-membered metallocycle intermediate E1. This step exhibits a free energy barrier of 17.9 kcal/mol. In contrast, the alternative 2,1-insertion pathway forms intermediate E2. Obviously, the 2,1-insertion transition state TS2b presents a barrier of 19.5 kcal/mol, which is 1.6 kcal/mol higher than that for the 2,1-insertion via TS2a (17.9 kcal/mol). Furthermore, the precursor coordination complex D2 is less stable than D1 by 1.6 kcal/mol. The computational results demonstrate that 1,2-insertion is both kinetically and thermodynamically favored over 2,1-insertion. Given that coordination of the C=C double bond in 1,5-hexadiene might induce dissociation of 2-picoline from C3, pathways involving the picoline-dissociated scandium center were also examined for comparison. The results revealed that the initial C=C bond insertion via 1,2-insertion on the ligand-free pathway (TS2c) had a free energy barrier of 29.3 kcal/mol, while the corresponding 2,1-insertion via TS2d exhibited a prohibitively high barrier of 31.0 kcal/mol. Notably, the energy barriers for insertion were significantly lower via the 2-picoline-coordinated transition states TS2a or TS2b compared to their picoline-dissociated counterparts TS2c or TS2d. Consequently, terminal C=C bond 1,2-insertion through the 2-picoline-coordinated mechanism (via TS2a) represents the most favorable pathway among the four options, producing the thermodynamically stable exothermic insertion intermediate E1 (ΔG = −21.9 kcal/mol). The geometric structures and NBO analyses of the four key transition states (TS2a, TS2b, TS2c, and TS2d) were examined. Their free energy barriers were 17.9, 19.5, 29.3, and 31.0 kcal/mol, respectively. The NPA charges on Sc (QSc) were 1.32, 1.34, 1.59, and 1.64, respectively. This underscores the indispensable role of 2-picoline coordination in stabilizing the Lewis acidic metal center and enabling the alkene insertion step.
To elucidate the physical origin of the 1,2-regioselectivity, a distortion/interaction analysis (EDA) [77,78] was performed on the most favorable transition states TS2a and TS2b (Figure 4). Each transition state was divided into two fragments: the 1,5-hexadiene moiety (F2) and the remaining metal complex (F1). The total energy of the transition state (ΔEtotal) relative to the separated fragments was decomposed into deformation and interaction components using single-point energy calculations. The deformation energy for each fragment (ΔEdef) was defined as the energy difference between its geometry within the transition state and its fully optimized structure. The interaction energy (ΔEint) was then evaluated as the difference between the single-point energy of the full transition state and the sum of the single-point energies of the individual fragments, each held in their transition-state geometries. This approach leads to the fundamental relationship: ΔEtotal = ΔEdef(F1) + ΔEdef(F2) + ΔEint, thereby quantitatively separating the intrinsic strain within the fragments from the energy associated with their interaction in the transition state. The results indicate that the total deformation energy required to achieve the 1,2-insertion geometry (TS2a) is 5.0 kcal/mol higher than for the 2,1-insertion (TS2b) (27.6 vs. 22.6 kcal/mol). However, this greater distortion is overcompensated by a significantly more favorable interaction energy in TS2a (−30.9 vs. −23.5 kcal/mol). The total electronic energy of TS2a (−3.3 kcal/mol) is thus lower than that of TS2b (−0.9 kcal/mol). This establishes that the regioselectivity is governed by superior stabilizing interactions in the 1,2-insertion transition state, rather than the strain required to form it.
In addition, the 1,2-insertion of 1,5-hexadiene into the Sc–alkyl bond in complex D3 assisted by an additional coordinated molecule was also considered. This process requires overcoming an energy barrier of 30.1 kcal/mol through transition state TS2e (Figure S1), which is significantly higher than that of the 2-picoline-coordinated pathway. Therefore, this process can be excluded due to its unfavorable relative energy.
Generation of Monoalkylation Product. Following the formation of the alkyl insertion intermediate E1, the reaction pathway diverges towards either monoalkylation or cyclization. It is worth noting that direct protonation of the Sc–alkyl bond in E1 via hydrogen abstraction by coordinated specie a through transition state TS3a requires overcoming an energy barrier of 22.2 kcal·mol−1 (Figure 5, left). Subsequent coordination of an additional 2-picoline leads to the formation of complex F2 at a higher energy level due to steric effects. From F2, the reaction proceeds via a σ-bond metathesis transition state (TS3b) to afford the monoalkylation product G2 with two 2-picoline ligands. This pathway exhibits a higher energy barrier of 29.5 kcal·mol−1.
Comparison of the two C–H activation transition states revealed that TS3a has a significantly lower energy barrier than TS3b (22.2 vs. 29.5 kcal·mol−1). Therefore, if a reductive elimination process were to take place, it would be more likely to proceed via the species with one coordinated ligand (1a) rather than the one with two ligands (2a).
Consistent with the trend observed for TS1i, both the Lewis acidity and the geometry of the metal center correlated well with the energy barriers. Specifically, the lower-barrier TS3a exhibited a lower NPA charge on Sc (1.18) compared to TS3b (1.23), and a wider Cα−Sc−Cα’ angle (77.4° in TS3a vs. 72.7° in TS3b). These structural and electronic features aligned with the relative activation energies of 22.2 and 29.5 kcal·mol−1 for TS3a and TS3b, respectively.
Ligand Dissociation and the Origin of Diastereoselectivity. As illustrated in Figure 6, following the coordination–insertion pathway, the subsequent intramolecular C=C insertion into the Sc–C bond of intermediate E1, assisted by one molecule of 2-picoline, affords the corresponding cyclization intermediate. The cis-cyclization proceeds via H1 → TS4a → J1 (Path a), whereas trans-cyclization follows H2 → TS4b → J2 (Path b). The cis-pathway exhibits a lower energy barrier (16.0 vs. 23.0 kcal·mol−1), indicating that cis-cyclization is more favorable. For comparison, the decoordination of 2-picoline from E1 was also examined. Upon ligand dissociation, the system rises in energy to form the less stable alkyl insertion intermediate E3. This is followed by energy stabilization through intramolecular C=C coordination of the 1,5-hexadien, yielding coordination complexes H3 or H4. From H3, the reaction proceeds via transition state TS4c to form the thermodynamically more stable cis-cyclization product J3. Alternatively, H4 undergoes trans-cyclization via TS4d to give J4 in the absence of 2-picoline. To our surprise, in contrast to the initial insertion, the cis-cyclization pathway through the picoline-free transition state TS4c exhibits a barrier of only 12.0 kcal/mol. This is 4.0 kcal/mol lower than the cis-pathway with coordinated picoline (TS4a) and a substantial 14.8 kcal/mol lower than the picoline-free trans-cyclization via TS4d (26.8 kcal/mol). This identifies a “ligand-dissociation” mechanism for cyclization.
Overall, the results summarized in Figure 6 indicate that among the four possible insertion pathways (Paths a–d), the cis-cyclization mechanism without 2-picoline coordination proceeding through TS4c is the most favorable both kinetically and thermodynamically. This contrasts with the earlier first C=C insertion results (Figure 3), where the 2-picoline-coordinated mechanism was more advantageous. The origin of the high cis-diastereoselectivity is unambiguously steric. The dissociation of 2-picoline creates a sterically open coordination sphere, permitting the diene chain to cyclize via the least hindered cis trajectory. The persistence of the picoline ligand in other pathways exacerbates this steric congestion, rendering them non-competitive. This presents a mechanistic dichotomy, the very 2-picoline coordination that is indispensable for the first insertion becomes detrimental in the cyclization step. This necessitates a ligand displacement event to unlock the observed high diastereoselectivity.
A comparison between the cis-cyclization pathway (Figure 6) and the reductive elimination pathway (Figure 5) reveals that the energy barrier for monoalkylated reductive elimination is significantly higher than that for the corresponding cyclization process (22.3 vs. 12.0 kcal·mol−1). This indicates that after the first C=C bond of 1,5-hexadiene inserts into the Sc–C bond, intramolecular cis-cyclization is strongly favored over alkyl elimination. These computational results are in excellent agreement with experimental observations, in which the cis-cyclization product was detected rather than a simple alkylated species.
Cycle Completion and Overall Mechanism. The catalytic cycle is concluded through protonolysis of the Sc–C bond in the cyclized intermediates. As shown in Figure 7, starting from the cis-cyclization intermediate J3 and trans-cyclization intermediate J4, protonation of the Sc–C bond via C–H bond activation of coordinated 2-picoline yields the corresponding cis-cyclization product Pcis or trans-cyclization product Ptrans, regenerating the active species C3 to complete the catalytic cycle. Similar to TS1, the protonation transition states TS5i (i = a, b, c, d) represent typical σ-bond metathesis processes. The cis-cyclic pathway proceeds via K1cis→ TS5acis→ L1cis, while the trans-cyclic pathway follows K2trans→ TS5btrans→ L2trans. Although the activation barriers for these two pathways are similar (20.3 kcal·mol−1 for cis-pathway and 20.2 kcal·mol−1 for trans-pathway), the cis-cyclization complex K1cis is energetically more stable than K2trans by 6.1 kcal·mol−1 (−24.5 vs. −18.4 kcal·mol−1). A similar energy difference was observed between the transition states TS5acis and TS5btrans (−4.3 vs. +1.8 kcal·mol−1), indicating that the formation of the cis-cyclization product Pcis is strongly favored. Consistent with the preceding steps, pathways involving a dicoordinated scandium center via TS5ccis or TS5dtrans are disfavored due to their high energy barriers (29.3 and 24.5 kcal·mol−1, respectively). This can be attributed to increased steric hindrance in TS5ccis or TS5dtrans relative to TS5acis and TS5btrans.
Notably, the energy barrier for the C–H activation step was significantly higher than that for the olefin insertion process. The overall energy profile confirms that the initial C–H activation is the rate-determining step, which is consistent with reported experimental kinetic isotope effects. Besides, in view of the gas phase statistical mechanic calculations of entropy are in error for solution state reactions, the entropies have also been further corrected [79,80,81,82]. A free energy of solvation calculated was added to the thermodynamic corrections for Gibbs free energy and 1.9 kcal/mol (accounting for the standard state change from 1 atm (gas) to 1 mol/L (solution) at 298.15 K to obtain the final solution-phase Gibbs free energies for all species. The final solution-phase Gibbs free energies, incorporating this correction and the solvation free energy, are summarized in Table S1. These corrected values confirm that all mechanistic conclusions, including the identity of the active species, the regioselectivity of insertion, and the stereoselectivity of cyclization, remain fully consistent with those derived from the uncorrected energies. The fully elucidated catalytic cycle, integrating all elementary steps, is depicted in Figure 8.
The mechanistic insights presented in this work establish a new paradigm for rare-earth catalysis based on hemilabile substrate coordination, wherein a substrate dynamically coordinates to and dissociates from the metal center. This dual role enables sequential functions, promoting challenging bond activations initially and then vacating the coordination sphere to achieve high stereoselectivity. Characterized by an initial heteroatom-assisted activation step followed by sterically driven ligand dissociation, this mechanistic model is anticipated to exhibit broad applicability in alkylation reactions involving diverse functional substrates (e.g., pyridines, anilines, amines, aldimines, quinolines, imidazoles, sulfides, anisoles) with alkenes. The governing principles of regioselectivity and steric modulation are further extendable to a range of alkene and diene coupling partners. While energetic landscapes remain substrate-dependent, the deliberate utilization of dynamic substrate coordination as a stereocontrol strategy establishes a rational and generalizable framework for advancing rare-earth-catalyzed C–H functionalization. Moreover, this perspective offers valuable guidance for the design of coordination-auxiliary pendant ligands and for the controlled polymerization of polar monomers, thereby bridging molecular C–H activation with precision macromolecular synthesis.

3. Computational Details

All density functional theory (DFT) calculations were performed using the Gaussian 09 software package [83]. Geometry optimizations of all reactants, intermediates, transition states, and products were carried out in the gas phase using the B3PW91 hybrid functional [83,84,85,86,87]. The 6-31G(d) basis set was used for C, H, and N atoms, while the scandium atom was treated with the Stuttgart/Dresden effective core potential (ECP) and its associated basis set (SDD) [88]. No symmetry constraints were applied during the optimization process. Vibrational frequency calculations were performed at the same level of theory to confirm the nature of each stationary point: minima (zero imaginary frequencies) and transition states (one imaginary frequency). The obtained frequencies, unscaled, were also used to compute the thermodynamic corrections (enthalpy and Gibbs free energy) at 298.15 K and 1.0 atm. To achieve higher accuracy in the energetics, single-point energy calculations were conducted on the optimized geometries using the M06 meta-hybrid functional [89,90], which has been shown to perform well for organometallic thermochemistry and non-covalent interactions. For these calculations, a larger basis set, 6-311+G(d,p), was employed for C, H, and N atoms, while the SDD ECP and basis set were retained for Sc. To model the solvation effects of the experimental solvent, chlorobenzene (ε = 5.6968), the conductor-like polarizable continuum model (CPCM), was employed during the single-point calculations [91,92,93]. The final reported solution-phase Gibbs free energies (Gsol) were calculated by combining the M06/6-311+G(d,p)/SDD/CPCM(chlorobenzene) single-point electronic energies with the thermal and entropic corrections obtained at the B3PW91/6-31G(d)/SDD level of theory: Gsol = E_SP(M06/CPCM) + Gcorr(B3PW91). Intrinsic reaction coordinate (IRC) calculations were performed for all transition states to verify that they correctly connect the intended reactants and products. All molecular structures depicted in this work were rendered using CYLview [94].

4. Conclusions

In conclusion, our DFT study unveils a sophisticated “ligand-enabled, then ligand-displaced” mechanism for the Sc-catalyzed diastereoselective cyclization of 2-picoline with 1,5-hexadiene. This mechanism resolves the apparent paradox of how 2-picoline acts as both a substrate and essential ligand, yet its dissociation is key to selectivity.
The catalytic cycle is initiated by the ligand-enabled phase. Here, the 2-picoline substrate coordinates to the metal center to form the active species C3, which is crucial for facilitating both the C–H activation and the regioselective 1,2-insertion of 1,5-hexadiene. During this phase, the ligand stabilizes the Lewis-acidic Sc center and enables superior orbital overlap that dictates regiochemistry.
The cycle then undergoes a decisive switch to the ligand-displaced phase for the critical diastereoselective controlling step. The dissociation of 2-picoline is mandatory to relieve steric congestion around the metal center, opening a low-energy pathway for cis-cyclization. This creates a powerful steric gating effect, where the bulky Cp* ligand selectively destabilizes the trans-cyclization transition state, thereby enforcing the high observed diastereoselectivity.
This refined mechanistic understanding, which highlights the dynamic and context-dependent role of substrate coordination, provides a new design principle for rare-earth catalysis. It demonstrates that strategic ligand association and dissociation can be harnessed to sequentially control reactivity and selectivity, offering a versatile blueprint for developing next-generation catalysts for C–H functionalization and challenging diastereoselective transformations.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics14010028/s1, Figure S1: The computed energy profiles for 1,5-hexadiene insertion based on species D1 with a coordinated 1,5-hexadiene; Figure S2: The computed energy profiles for cis-cyclization and trans-cyclization processes based on 1,5-hexadiene insertion intermediate; Table S1: Computed free energy ΔG (kcal/mol) for all the species including solution-phase single point energies, the gas phase zero-point correction, thermal correction to enthalpy, thermal correction to Gibbs free energy.

Author Contributions

Conceptualization, G.Z., S.Z., X.L. and Y.L. (Yunzhi Li) Methodology, G.Z., X.L., Y.L. (Yunzhi Li) and Y.L. (Yi Luo); Software, G.Z., S.Z., X.L. and Y.L. (Yunzhi Li); Formal analysis, G.Z. and Y.L. (Yi Luo); Investigation, G.Z., S.Z., X.L. and Y.L. (Yunzhi Li); Data curation, G.Z., Q.X. and Y.L. (Yi Luo); Writing—original draft, G.Z.; Writing—review & editing, G.Z., Q.X. and Y.L. (Yi Luo); Supervision, G.Z., Q.X. and Y.L. (Yi Luo). All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 22003021), the Natural Science Foundation of Shandong Province (Nos. ZR2021QB153 and ZR2022QB043), the Key Research and Development Program of Shandong Province (No. 2025TSGCCZZB0827), and the Open Funding Project of Key Laboratory of Functional Polymer Materials, Ministry of Education, Nankai University (KLFPM202301).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Free energy profile (kcal/mol) for the formation of potential active species Ci (i = 1, 2, 3, 4) via C–H activation of 2-picoline by cationic complex 1.
Figure 1. Free energy profile (kcal/mol) for the formation of potential active species Ci (i = 1, 2, 3, 4) via C–H activation of 2-picoline by cationic complex 1.
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Figure 2. Optimized geometries of the key C–H activation transition states TS1i (i = a, b, c, d). Selected distances are shown in Ångströms (Å) and angles in degrees (°). The natural bond orbital (NBO) charge on the Sc center is given in parentheses, with the corresponding free energy barrier (ΔG‡, kcal/mol) listed below each structure. Hydrogen atoms, except for the transferring hydrogen, are omitted for clarity.
Figure 2. Optimized geometries of the key C–H activation transition states TS1i (i = a, b, c, d). Selected distances are shown in Ångströms (Å) and angles in degrees (°). The natural bond orbital (NBO) charge on the Sc center is given in parentheses, with the corresponding free energy barrier (ΔG‡, kcal/mol) listed below each structure. Hydrogen atoms, except for the transferring hydrogen, are omitted for clarity.
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Figure 3. Computed free energy profile (kcal/mol) for the Sc-catalyzed 1,5-hexadiene insertion into the active species C3 via 1,2- or 2,1-insertion manners along with 2-picoline-free or 2-picoline-coordinated fashion.
Figure 3. Computed free energy profile (kcal/mol) for the Sc-catalyzed 1,5-hexadiene insertion into the active species C3 via 1,2- or 2,1-insertion manners along with 2-picoline-free or 2-picoline-coordinated fashion.
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Figure 4. Optimized geometries of the 1,5-hexadiene insertion transition states TS2i (i = a, b, c, d) with key distances (Å) and angles (°). NBO charges are shown in parentheses and corresponding energy barriers (ΔG‡) are shown below the structures. Energy decomposition analysis (EDA) for the competing 1,2- and 2,1-insertion transition states.
Figure 4. Optimized geometries of the 1,5-hexadiene insertion transition states TS2i (i = a, b, c, d) with key distances (Å) and angles (°). NBO charges are shown in parentheses and corresponding energy barriers (ΔG‡) are shown below the structures. Energy decomposition analysis (EDA) for the competing 1,2- and 2,1-insertion transition states.
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Figure 5. Free energy profile (kcal/mol) for the formation of the monoalkylated product Pmono via a protonation/reductive elimination pathway.
Figure 5. Free energy profile (kcal/mol) for the formation of the monoalkylated product Pmono via a protonation/reductive elimination pathway.
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Figure 6. Computed energy profiles for the diastereoselective cyclization from intermediate E1. Pathways on cis-cyclization or trans-cyclization process with (TS4a, TS4b) and without (TS4c, TS4d) a coordinated 2-picoline molecule are compared.
Figure 6. Computed energy profiles for the diastereoselective cyclization from intermediate E1. Pathways on cis-cyclization or trans-cyclization process with (TS4a, TS4b) and without (TS4c, TS4d) a coordinated 2-picoline molecule are compared.
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Figure 7. Free energy profile (kcal/mol) for the protonolysis step that concludes the catalytic cycle, regenerating the active species C3 and releasing the final cis- or trans-cyclized product (Pcis or Ptrans) via mono-coordinated pathways (i,ii) or dicoordinated pathways (iii,iv).
Figure 7. Free energy profile (kcal/mol) for the protonolysis step that concludes the catalytic cycle, regenerating the active species C3 and releasing the final cis- or trans-cyclized product (Pcis or Ptrans) via mono-coordinated pathways (i,ii) or dicoordinated pathways (iii,iv).
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Figure 8. The complete catalytic cycle for the Sc-catalyzed diastereoselective cyclization of 2-picoline with 1,5-hexadiene.
Figure 8. The complete catalytic cycle for the Sc-catalyzed diastereoselective cyclization of 2-picoline with 1,5-hexadiene.
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Scheme 1. Representative examples of rare-earth-catalyzed C–H functionalization of heteroatom-containing substrates with olefins by cationic half-sandwich rare-earth alkyl complexes.
Scheme 1. Representative examples of rare-earth-catalyzed C–H functionalization of heteroatom-containing substrates with olefins by cationic half-sandwich rare-earth alkyl complexes.
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Scheme 2. The cis-selective cyclization of 1,5-hexadiene with the ortho-C(sp2)-H bond of 2-picoline catalyzed by the [Sc]/B(C6F5)3 combination.
Scheme 2. The cis-selective cyclization of 1,5-hexadiene with the ortho-C(sp2)-H bond of 2-picoline catalyzed by the [Sc]/B(C6F5)3 combination.
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MDPI and ACS Style

Zhou, G.; Zhai, S.; Leng, X.; Li, Y.; Xia, Q.; Luo, Y. A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity. Inorganics 2026, 14, 28. https://doi.org/10.3390/inorganics14010028

AMA Style

Zhou G, Zhai S, Leng X, Li Y, Xia Q, Luo Y. A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity. Inorganics. 2026; 14(1):28. https://doi.org/10.3390/inorganics14010028

Chicago/Turabian Style

Zhou, Guangli, Shuangxin Zhai, Xia Leng, Yunzhi Li, Qiying Xia, and Yi Luo. 2026. "A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity" Inorganics 14, no. 1: 28. https://doi.org/10.3390/inorganics14010028

APA Style

Zhou, G., Zhai, S., Leng, X., Li, Y., Xia, Q., & Luo, Y. (2026). A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity. Inorganics, 14(1), 28. https://doi.org/10.3390/inorganics14010028

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