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Article

Insights into the Mechanism, Regio-/Diastereoselectivities and Ligand Role of Nickel-Initiated [3+2] Cycloadditions between Vinylcyclopropane and N-Tosylbenzaldimine

by
Weihua Mu
*,
Lin Zhu
,
Shuya Xia
,
Xue Tan
,
Liangfei Duan
,
Guanghao Meng
and
Guo Liu
*
Faculty of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650092, China
*
Authors to whom correspondence should be addressed.
Catalysts 2024, 14(1), 82; https://doi.org/10.3390/catal14010082
Submission received: 31 December 2023 / Revised: 14 January 2024 / Accepted: 16 January 2024 / Published: 18 January 2024
(This article belongs to the Special Issue Organometallic Homogeneous Catalysis)
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Abstract

:
Density functional theory (DFT) was employed to explore the reaction mechanism, regio- and diastereoselectivities of nickel-initiated [3+2] cycloaddition between vinylcyclopropane (VCP) and N-tosylbenzaldimine assisted by phosphine ligands. Four different binding modes of the nickel center to VCP substrate were explored during the ring-opening of VCP, among which the C,C_anti and C,C_syn modes were verified to be the most accessible ones. Further explorations about four different phosphine ligand-assisted reactions based on the two most probable binding modes show that the difference in binding mode of bi- and monodentate phosphine ligands can vary the optimal reaction pathway, especially in the [3+2] cycloaddition process between the ring-opened intermediate and N-tosylbenzaldimine. The formation of C–C and C–N bonds between N-tosylbenzaldimine and the ring-opened intermediate through [3+2] cycloaddition is found to be stepwise, with the former acting as the rate-determining step (RDS) in most cases. Computed free energy barriers of RDS transition states on the optimal path I or II not only give out good predictions for reaction rates and half-lives, but also provide reasonable explanations for the major generation of cis-pyrrolidine. Noncovalent interaction analyses of key stationary points suggest the rate is influenced by both electronic effects and steric hindrance, while the diastereoselectivity is mainly controlled by electronic effects.

1. Introduction

Heterocycles such as pyrrolidines are important backbones in organic chemistry and widely distributed in bioactive molecules and natural products [1,2,3,4]. For decades, significant efforts have been made to its stereoselective synthesis, among which transition metal-catalyzed cycloaddition has been established as a powerful tool for its atomic economy and facilities in multi-bond formation in a single step [5,6,7,8,9,10,11,12]. Benefitting from nickel’s wide distribution and availability, as well as the excellent performance of phosphine ligands in controlling selectivities [13,14,15,16,17], nickel-mediated multi-component cycloadditions assisted by phosphine ligands have emerged as a facile strategy for constructing pyrrolidine derivatives for years [18,19].
In 2015, Matsubara and co-workers developed a nickel-catalyzed intermolecular [3+2] cycloaddition of vinylcyclopropanes (R1) to N-tosylbenzaldimine (R2), and obtained substituted pyrrolidines in high yields with good regio- and diastereoselectivities (Scheme 1) [20]. This reaction can proceed under mild conditions, has good tolerance for a variety of imines and led to overwhelming formation of cis-pyrrolidines (P1_cis). Moreover, when the bidentate dmpe ligand was replaced by monodentated PMe2Ph, both the yield and diastereoselectivity ratio (dr, P1_cis:P1_trans) dropped dramatically. This indicates the phosphine ligands should have played an important role in controlling the rate and selectivity of this reaction. To the best of our knowledge, few studies have made explanations for the strong effect of phosphine ligands on the rates and selectivities in this or other similar Ni-catalyzed multi-component cycloadditions involving vinylcyclopropanes and imines, albeit a number of works have demonstrated the importance of ligand effects on other types of reactions theoretically [21,22,23,24,25].
Based on the literature report about the Pd(0)-catalyzed ring-opening of vinylcyclopropanes with aldehydes [26], Matsubara proposed a heteronickelacycle intermediate M1 (in which Ni atom coordinates in C,C,O_syn mode, Scheme 1) would be formed before the pyrrolidines were finally produced through a nucleophilic attack of vinylcyclopropanes on N-tosylbenzaldimine. Interestingly, some lewis acid (LA)-catalyzed ring-openings of vinylcyclopropanes or epoxyethane show an alternative binding mode of LA onto the two oxygen atoms in –CO2Me groups of vinylcyclopropane substrates (M2, O,O binding mode) both experimentally and computationally [27,28,29,30,31,32]. Still, a few other transition metal-catalyzed reactions show a coordination model similar to M3 (C,C_anti mode) in Scheme 1 [33,34]. Considering the differences of coordinates in bidentate and monodentate phosphine ligands such as dmpe and PMe2Ph, the C,C_syn mode (M4) is also possible. Moreover, a C,O mode (M5) would emerge when the nickel center coordinates with the C=O double bond in one of the –CO2Me groups of R1. However, due to the lack of comprehensive explorations at a molecular level, the following issues, such as (1) which mode is the most accessible one, (2) whether the heteronickelacycle intermediate M1 locates on the optimal reaction pathway, and (3) what is the role of phosphine ligand in this reaction, still remain unclear.
To explore the reaction mechanism, the origin of regio- and diastereoselectivities, as well as the role of phosphine ligands in controlling rates and diastereoselectivities, we have conducted comprehensive computational studies on the nickel-initiated [3+2] cycloaddition between vinylcyclopropane and N-tosylbenzaldimine. Detailed microscopic mechanisms leading to the formation of cis-pyrrolidines (P1_cis) are characterized, with the C,C_anti (M3) and C,C_syn (M4) modes being confirmed as the most accessible ones when bi- and monodentate phosphine ligands are employed, respectively (Scheme 1). In addition, the regioselectivities and four different phosphine ligand-assisted diastereoselectivities are also computed and discussed in depth.

2. Results and Discussion

2.1. Mechanism

To explore the possible binding modes of phosphine ligand to the nickel center in the nickel-initiated [3+2] cycloaddition between vinylcyclopropanes (VCP, R1) and N-tosylbenzaldimine (R2), we have conducted calculations at the IDSCRF(ACN)- B3LYP/DGDZVP level in acetonitrile (ACN) solvent firstly, to see if the active Ni(COD)L species can be generated in situ from the precatalyst Ni(COD)2 and phosphine ligands (L1–L4). As shown in Figure 1, the formation of Ni(COD)L is exothermic and releases about 6.9–16.2 kcal·mol−1 of free energy, indicating a facile formation of Ni(COD)L species under the corresponding experimental temperature (303 K). Thus, Ni(COD)L is taken as the initial catalyst throughout the work and all potential free energy surfaces (PESs) are adjusted to the starting points of Ni(COD)L+R1 accordingly.

2.1.1. The Ring-Opening of VCP

Upon the formation of Ni(COD)L species, three possible reaction channels (paths I–III correspond to C,C_anti, C,C_syn and O,O binding modes, respectively) for C(1)–C(3) bond cleavage in R1 were located (Figure 2). On C,C_anti path I, the Ni-dmpe (L1) center interacts with the vinyl group from the anti side of the two –CO2Me groups so as to avoid possible steric hindrance arising between them, bearing only a 1.0 kcal·mol−1 activation free energy barrier when the ring-opened intermediate INT1_I is formed. Due to possible steric hindrance arising between one of the two –CO2Me groups in R1 and the –Me group in the dmpe fragment, C,C_syn path II bears an activation barrier of 7.0 kcal·mol−1, about 6.0 kcal·mol−1 higher than that of TS1_I on path I. Although TS1_II can also be overcome at a temperature of 303 K, an activation barrier as high as seven times that corresponding to TS1_I would shrink path II’s contribution to some degree. Similar to Tomilov’s speculation in the LA-catalyzed ring-opening of VCP [27], an O,O binding path III in which the Ni-dmpe center coordinates with the two carbonyl oxygen atoms in the –CO2Me groups of R1 can also be located. However, corresponding stationary points (COM1_III, TS1_III and INT1_III) are extraordinarily more unstable than their alternatives on paths I and II, suggesting little possibility for R1 to break the C(1)–C(3) bond through path III, as shown in Figure 2 and Figure S1.
Inspired by Zhang’s report about epoxyethane derivative’s ring-opening through O2–C3 bond cleavage [29] and Wang’s work about VCP’s ring-opening through C(2)–C(3) bond cleavage [35], we continued to explore the possible regioselective ring-opening of R1 through C(1)–C(2) (path IV) and C(2)–C(3) (path V) bonds cleavage. Given Ni-dmpe coordinated with one of the C=O double bonds in the –CO2Me groups, a complex COM1_IV based on the C,O coordination mode could be located, being endothermic of 11.3 kcal·mol−1 of free energies. As shown in Figure 2, the activation free energy barrier of TS1_IV corresponding to C(1)–C(2)’s cleavage is so high, 22.8 kcal·mol−1, that path IV has little competitiveness when compared with paths I and II. Similarly, the extremely high activation barrier of TS1_V (27.6 kcal·mol−1) should block off the possibility of C(2)–C(3)’s cleavage through path V (derived from C,C_anti mode) totally. The extraordinary higher activation barriers of TS1_IV and TS1_V (corresponding to C(1)–C(2) and C(2)–C(3)’s cleavage, respectively) provide good explanations for the disappearance of any regioisomer in experiments [20].
Endeavors had also been made to locate a C,C,O_syn binding complex COM1_V (similar to M1 in Scheme 1), which was speculated based on experiments, but all location failed (Figure S2). It seems a four-coordinated nickel center is saturated already and has no extra coordinate for the oxygen atom in the –CO2Me group. Namely, path I, featuring a C,C_anti binding mode, presents the most accessible pathway of VCP’s ring-opening, while path II, corresponding to the C,C_syn binding mode, is also surmountable. The formation of intermediate INT1_I only needs to overcome a free energy barrier of 1.0 kcal·mol−1 and is exothermic by a free energy of 14.9 kcal·mol−1, and thus very facile under the experimental temperature (303 K). The formation of INT1_II is a little more difficult but also exothermic and practicable.
Optimized structures of stationary points located on paths I–V, accompanied by key geometrical parameters and necessary Wiberg bond indices (WBI) derived from natural bond orbital (NBO) analysis [36,37,38], are presented in Figure 3 and Figure S3, respectively. It is interesting that most stationary points featuring η4-coordinate and planar configuration of the nickel center are stable, while others which feature η5- or η6-coordinated (TS1_IV and TS1_V) and non-planar η4-coordinated nickel centers (TS1_III and COM1_III) are relatively unstable. This fascinating dependence of relative energies on coordinate and coordination mode, similar to Scott’s finding in the Cr(II) Phillips ethylene polymerization catalyst [39], urged us to conduct further QTAIM [40,41] topological analyses about selected stationary points, with corresponding results presented in Figure S4.
The η4-, η5- or η6-coordinates of the nickel center in all stationary points on paths I–V were confirmed by four, five or six bond critical points (BCPs) around the nickel center, respectively, with BCPs electron densities of Ni–X (X=C,O,P) bonds being 0.0471–0.1198 ē·bohr−3 (Figure S4). According to the QTAIM analysis results, the relative instability of non-planar η4-coordinated TS1_III and COM1_III, as well as η5- or η6-coordinated TS1_IV (or TS1_V), is probably caused by a distortion of their geometries from the stable square planar η4-coordinated conformation. The unexpected higher free energies of planar η4-coordinated INT1_III could be attributed to a deviation of several bond angles in it from that in reactant R1 (−7.1–+4.6°, Figure S5), for the distortion effect has already been identified to be essential in elevating the structure’s instabilities [42,43,44,45]. The relative higher free energies and activation barrier of TS1_II over TS1_I should arise from steric hindrance between –Me and –CO2Me groups in the former, as identified by shorter C–H…O distances (3.435–3.711 Å) and four extra BCPs between them (with electron densities at −0.0049–0.0093 ē·bohr−3, Figure S4). Weaker complexation between Ni, P and O atoms in COM1_III than that between Ni, P and vinyl–C atoms in COM1_I also contributes to the former’s instability, as verified by the smaller electron densities of these four BCPs in COM1_III than in COM1_I.
Natural population analysis (NPA) results for key stationary points on paths I–V also support the regioselective ring-opening of R1 well. For example, the WBIs for C(1)–C(3), C(1)–C(2) and C(2)–C(3) in COM1_I are 0.797, 0.917 and 1.027, respectively (Figure 3), indicating the weakest bondage between C(1) and C(3) atoms and the easiest cleavage of it, in good agreement with previous energetic results. In addition, the difference of WBI values corresponding to the breaking C(1)–C(3) bond in COM1_I and TS1_I is −0.258, smaller than all counterparts on paths II–V (C(1)–C(3) on paths II–III, C(1)–C(2) on path IV and C(2)–C(3) on path V, respectively), which evidences the easiest cleavage of the C(1)–C(3) bond in R1 (through C,C_anti path I) well and rationalizes the smooth formation of intermediate INT1_I.

2.1.2. The [3+2] Cycloaddition of INT1 with N-Tosylbenzaldimine

After confirmation of C,C_anti path I as the dominant pathway in generating intermediate INT1_I through C(1)–C(3) cleavage of R1 (Figure 2), we continued to explore if the C,C_anti path is still dominant in the subsequent [3+2] cycloaddition process of intermediate INT1 with N-tosylbenzaldimine. Since paths IV and V, which correspond to C(1)–C(2) and C(2)–C(3) bonds cleavage of R1, are precluded by extremely high activation barriers of TS1_IV and TS1_V (Figure 2 and Figure S1), only the C,C_anti, C,C_syn and O,O binding modes (paths I–III) were explored in Section 2.1.2, with the most probable paths Ia_cis and IIa_cis presented in Figure 4 and Figure 5, respectively.
On C,C_anti path I, the C(5) atom in N-tosylbenzaldimine (R2) attacks the C(1) atom in INT1_I firstly, overcomes an activation barrier of 25.1 kcal·mol−1 (TS2_Ia_cis) and leads to the formation of intermediate INT2_Ia_cis (Figure 4). Then the N(4) atom in INT2_Ia_cis bonds with the C(3) atom through TS3_Ia_cis, overcoming an activation barrier of 8.1 kcal·mol−1 and transforming itself into the cis-pyrrolidine product (P1_cis) smoothly. As the activation barrier of TS3_Ia_cis (8.1 kcal·mol−1) is much lower than that of TS2_Ia_cis (25.1 kcal·mol−1), and TS3_Ia_cis is apparently more stable than TS2_Ia_cis, the bonding between C(1) and C(5) atoms (through TS2_Ia_cis) acts as the rate-determining step (RDS) of the whole reaction. Finally, the re-involving of the COD ligand helps to recycle Ni(COD)L1 species accompanying P1_cis’s production.
The formation of INT1_II through C,C_syn path II has also been verified to be practicable during the VCP’s ring-opening process (Figure 2), so massive efforts were made to see if its subsequent process is still accessible. The stepwise mechanism and RDS characteristic on C,C_syn path II are similar to the C,C_anti path I. However, the whole PESs of the C,C_syn path II are above that of C,C_anti path I, and the RDS step’s activation barrier on path II is as high as 34.7 kcal·mol−1 (TS2_IIa_cis, Figure 5), about 9.6 kcal·mol−1 higher than that of TS2_Ia_cis. Moreover, the activation barrier of TS3_IIa_cis is elevated to be 18.2 kcal·mol−1, more than twice that of TS3_Ia_cis (8.1 kcal·mol−1). These energetic results illustrate C,C_anti path I has absolute priority in directing the formation of P1_cis when the bidentate phosphine ligand dmpe (L1) is employed.
Further explorations about O,O binding path III locate even higher potential energy surfaces than C,C_syn path II (Figure S6), and the whole PESs lay much higher above the starting materials (R1+Ni(COD)L1, Figure 2). Although the computed PESs for O,O binding path III are comparable with previously reported Sn(OTf)2-catalyzed C–O cleavage of epoxyethane [29], the difficulty in generating INT1_III plus the extraordinarily higher-located PESs of O,O binding path III leave no possibility for this reaction to proceed along it according to the lowest-energy principle framed in transition state theory [46]. Other mechanistic possibilities such as C(3)–N(4)’s bonding prior to C(1)–C(5) on C,C_anti path I (path Ib_cis) and C,C_syn path II (path IIb_cis), as well as C(1)–C(5)’s bonding prior to C(3)–N(4) on O,O binding path III (path IIIa_cis) were also checked, with corresponding results summarized in Figure S7. The activation barriers corresponding to TS2_Ib_cis and TS2_IIb_cis are predicted to be 51.5 and 51.8 kcal·mol−1, respectively, both too high to be overcome under the given experimental temperature (303 K). Similarly, reaction along O,O binding path IIIa_cis, in which the C(1)–C(5) bonding occurs, is blocked off totally by the higher activation barrier of TS2_IIIa_cis than TS2_Ia_cis (29.0 versus 25.1 kcal·mol−1), as well as by the extraordinarily higher relative energies of TS2_IIIa_cis than TS2_Ia_cis (58.5 versus 10.2 kcal·mol−1).
As shown in Figure 6, a smaller cavity volume and surface of TS2_IIa_cis (1042.5 Å3 and 709.5 Å2, respectively) than that of TS2_Ia_cis (1056.3 Å3 and 746.9 Å2, respectively) indicates the more compacted geometry of the former. Thereby, the relative instability of TS2_IIa_cis to TS2_Ia_cis is attributed to the greater spatial hinderance arising in it between the nickel center and the carbon chain in the ring-opened INT1_I fragment. Noncovalent interaction (NCI) [47] analysis about TS2_Ia_cis and TS2_IIa_cis shows more serious spatial repulsion (in red) and weaker noncovalent interaction (in green) in TS2_IIa_cis than in TS2_Ia_cis, and thus rationalizes the former’s relative instability and higher activation barrier.

2.2. Selectivities

2.2.1. Regioselectivities

Explorations about the alternative P2_cis regioisomer’s formation through C(1)–N(4) bonding explains well its nondetectability by an activation barrier of TS2_Ic_cis being as high as 56.0 kcal·mol−1 (Figure 7), in good accordance with both Matsubara’s [20] and Dieskau’s [48] experimental results. Further NPA charge population results show there are −0.372, −0.225, −0.735 and +0.185 charges distributed on C(1), C(3), N(4) and C(5) atoms in INT1_I and R2, respectively (Table 1). That is, when the intermediate INT1_I reacts with substrate R2, the more negative C(1) atom in INT1_I prefers to attack the more positive C(5) atom in R2, which supports well the prior bonding of C(1)–C(5) to C(3)–N(4). NCI analysis about TS2_Ic_cis shows obvious steric repulsion around the nickel center in it, and weaker noncovalent interactions than that displayed in TS2_Ia_cis. Thus, TS2_Ic_cis is much less stable than TS2_Ia_cis, and no P2_cis regioisomer could be detected in experiments.

2.2.2. Diastereoselectivities

Based on the aforementioned investigations on the reaction mechanism and regioselectivities, path Ia_cis has been confirmed as the optimal reaction pathway leading to the formation of product P1_cis in the bidentate dmpe ligand-assisted case, with the C(1)–C(5) bonding process (through TS2_Ia_cis) acting as the RDS of the whole reaction. To investigate why the diastereoisomer P1_trans could not be detected in experiment (Scheme 1), we have located all possible stationary points on path Ia_trans, as shown in Figure 8. The mechanism of path Ia_trans is similar to path Ia_cis; however, the whole PESs of path Ia_trans are generally located above path Ia_cis. Namely, all stationary points located on path Ia_trans are less stable than those located on path Ia_cis. The free energy barrier corresponding to the RDS transition state on path Ia_trans (TS2_Ia_trans) is predicted to be 26.9 kcal·mol−1, about 1.8 kcal·mol−1 higher than its cis counterpart (TS2_Ia_cis). A difference of 1.8 kcal·mol−1 in the activation energy barrier between TS2_Ia_cis and TS2_Ia_trans transfers to a deviation in the reaction rate of 19.9 times (P1_cis:P1_trans = 19.9:1, Table S1), in good accordance with the corresponding experimental dr ratio of P1_cis:P1_trans > 99:1. In addition, the free energy barrier of TS3_Ia_trans is predicted to be 10.9 kcal·mol−1, about 2.8 kcal·mol−1 higher than that of TS3_Ia_cis. This would accelerate the formation of product P1_cis further and make P1_trans undetectable. Computations about path IIa also show the higher activation barrier of TS3_IIa_trans than TS2_IIa_cis (36.1 versus 34.7 kcal·mol−1, Figure S8) and confirm P1_cis’s dominance well.
Optimized structures accompanied by key geometrical parameters for TS2 and TS3 on path I are presented in Figure 9. The forming C(1)–C(5) bond in TS2_Ia_cis is 2.20 Å, being 0.01 Å longer than its counterpart in TS2_Ia_trans. The longer-forming C1–C5 bond in TS2_Ia_cis demonstrates it is earlier than TS2_Ia_trans and thus possesses a lower activation barrier (25.1 versus 26.9 kcal·mol−1). Additionally, the –Ts group in TS2_Ia_cis directs away from the C(1)–C(2)–C(3) fragment but overlaps on it in TS2_Ia_trans. The overlapping of the –Ts group on the C(1)–C(2)–C(3) fragment in TS2_Ia_trans causes bigger steric hindrance, as reflected by NCI analysis results (Figure S9). Similarly, the –Ts group overlaps again and even more on the C(1)–C(2)–C(3) fragment in TS3_Ia_trans than in TS3_Ia_cis, thus the energy gap between TS3_Ia_trans and TS3_Ia_cis is enlarged to 5.0 kcal·mol−1. NCI analysis results also show more pronounced noncovalent interactions between the INT1_I and dmpe ligand fragments in the cis ones (TS2_Ia_cis and TS3_Ia_cis) than in the trans ones (TS2_Ia_trans and TS3_Ia_trans). Clearly, both the steric hindrance and noncovalent interactions play vital roles in guaranteeing the dominant formation of cis-pyrrolidine (P1_cis). Theoretical predictions for diastereoselectivities are in good accordance with experimental observations (Scheme 1).

2.3. Ligand Role

Matsubara and co-workers found the yield of P1_cis varied a lot when different phosphine ligands were employed in their experiments (Scheme 1). For example, when the bidentate ligand L1 (dmpe) was replaced by the monodentate ligand L2 (PMe2Ph), the reaction yield decreased from >99% to 47%; when the bidentate ligand L3 (dppe) was employed, the yield rose to 73%; the reaction yield reduced to 62% while replacing L3 with the monodentate ligand L4 (PMe3). Moreover, the ratio of P1_cis:P1_trans changed significantly, ranging from >99:1 to 3.3:1 when different phosphine ligands were used. These fantastic results motivated us to conduct calculations on ligand L2, L3 and L4-assisted reactions further at the same computational level, to explore the nature and influence of phosphine ligands on the yields and selectivities of the reaction.
Computed mechanism and energy results for the aforementioned paths Ia_cis and Ia_trans assisted by monodentate L2 (denoted Ia_cis_L2 and Ia_trans_L2, respectively) are shown in Scheme 2 and Figure S10, respectively. The monodentate L2-assisted reaction also needs to go through the ring-opening of VCP and subsequent stepwise [3+2] cycloaddition sequentially, similar to the bidentate L1-assisted one. However, the RDS step on paths Ia_cis_L2 and Ia_trans_L2 corresponds no longer to the C(1)–C(5) bonding (TS2_Ia_cis/trans_L2); instead, it corresponds to their subsequent C(3)–N(4) bonding process (TS3_Ia_cis/trans_L2). Furthermore, the total free energy barriers of TS3_Ia_cis_L2 and TS3_Ia_trans_L2 are 40.8 and 41.9 kcal·mol−1, respectively (Figure S10). Such high activation barriers are too difficult to be overcome at an experimental temperature of 303 K, and are inconsistent with a 47% yield of P1 in experiments (Scheme 1).
The above contradiction made us speculate if the monodentate ligand L2-assisted paths Ia_cis_L2 and Ia_trans_L2 are still the optimal pathways. Thereby, calculations were conducted further on L2-assisted path II, which is also practicable in the VCP’s ring-opening process (Figure 2), with results shown in Figure 10. The RDS step on path IIa_cis_L2 is similar to path Ia_cis_L2, but the free energy barrier of TS3_IIa_cis_L2 is only 30.4 kcal·mol−1, about 10.4 kcal·mol−1 lower than that of TS3_Ia_cis_L2 (40.8 kcal·mol−1, Figure S10). Meanwhile, the free energy barrier of the RDS transition state on path IIa_trans_L2 (TS2_IIa_trans_L2) is only 31.2 kcal·mol−1, also lower than that of TS3_Ia_trans_L2 (41.9 kcal·mol−1, Figure S10). Clearly, when the monodentate phosphine ligand L2 is employed, the optimal pathway is path II rather than path I.
To confirm this inference, we continued to compute paths I and II assisted by the bidentate ligand L3 and monodentate ligand L4 (denoted paths Ia_cis_L3, Ia_trans_L3, IIa_cis_L3, IIa_trans_L3, Ia_cis_L4, Ia_trans_L4, IIa_cis_L4 and IIa_trans_L4, respectively), with their potential free energy profiles presented in Figures S11 and S12. Indeed, the dominant pathway for the bidentate ligand L3-assisted one is path I (Figure S11), while the optimal pathway for the monodentate ligand L4-assisted reaction corresponds to path II (Figure S12). The L3-assisted RDS free energy barriers on path I (TS2_Ia_cis_L3 and TS2_Ia_trans_L3) are 26.7 and 28.3 kcal·mol−1, respectively, in good accordance with the major formation of P1_cis in experiment (Scheme 1). The L4-assisted free energy barriers of RDS transition states on path II (TS3_IIa_cis_L4 and TS2_IIa_trans_L4) are 30.2 and 31.8 kcal·mol−1, respectively, also being consistent with the advantageous generation of P1_cis over P1_trans. Thus, it is believed the different coordination modes of monodentate and bidentate phosphine ligands can lead to alteration of the dominant pathway here.
This can also be well seen from the optimized geometries of some key transition states (Figure 11). For the bidentate ligand L1- and L3-assisted transition states, the nickel center coordinates with two P and two C atoms in them, so there are no more coordinate for surrounding hetero-atoms such as O or N atoms. Thus, the smaller steric hindrance between the phosphine ligand L1/L3 and the rest of the molecule in the RDS transition states (TS2_Ia_cis_L1/L3 and TS2_Ia_trans_L1/L3) on path I make it more feasible than path II. Nevertheless, in the monodentate ligand L2- and L4-assisted transition states, the nickel center coordinates with only one P and two C atoms, so it will coordinate extra with the O atom in the –Ts group or with the N atom in the N-tosylbenzaldimine fragment, resulting in more stable RDS transition states (TS3_IIa_cis_L2/L4 and TS2_IIa_trans_L2/L4) on path II and making path II more preferred than path I in energy. Due to a significant reduction in relative energies caused by strong Ni–N or Ni–O coordination in TS2_IIa_cis_L2/L4 (Figure 11a), TS3_IIa_cis_L2/L4 becomes higher and the C(3)–N(4) bonding process acts as the RDS step on path IIa, as shown in Figure 10 and Figure S12b. NCI analysis results show more pronounced noncovalent interactions in TS2_IIa_cis_L2/L4 than in TS3_IIa_cis_L2/L4 accordingly, reflects well the different coordination modes of monodentate ligand L2/L4 from bidentate ligand L1/L3 to the nickel center result in different stabilities (Figure 11b). It also demonstrates that the electronic effects play a dominant role in controlling the rates and selectivities of the reaction.
As summarized in Table 2, the activation free energy barriers of L1–L4-assisted RDS transition states on their optimal pathway are completely consistent with the corresponding experimental trend in yield, and there is a good negative correlation between the RDS free energy barriers and the yields (Figure 12). Namely, the higher the RDS free energy barrier, the lower the yield of P1. What is more, the computationally predicted diastereoselectivity ratios (drcalc.) for P1_cis:P1_trans are in good agreement with experimentally detected dr values (drExpt.), no matter the bidentate ligand L1/L3 or the monodentate ligand L2/L4 used. For example, the L2-assisted generation rate of P1_cis, which transferred from the free energy barriers of the corresponding RDS transition state, is 3.8 times faster than that of P1_trans, in perfect agreement with an experimental ratio of P1_cis:P1_trans = 3.3:1. To sum up, only product P1_cis can be observed experimentally, no matter whether a bidentate phosphine ligand or a monodentate one is employed. The yields and selectivities predicted by theory have reproduced corresponding experimental results well, and showed the reliability of the computational predictions presented in this work.

3. Computational Methods

All stationary points along the mechanistic profiles were initially optimized, with their identities verified and relative free energies determined employing the B3LYP density functional method [49,50] and the DGDZVP basis set [51,52] as implemented in the Gaussian 09 Program [53]. All models involved the full-sized systems for accurate representation of the real chemical transformations under investigation. Solvent effects were taken into account by optimizing all stationary points in acetonitrile (ACN, ԑ = 37.5) solvent, using the IDSCRF atomic radii [54] as implemented in the default self-consistent reaction field (SCRF) polarisable continuum model (PCM) [55], denoted IDSCRF(ACN)–B3LYP. All minima and transition states (TSs) are confirmed by frequency analysis. Intrinsic reaction coordinate (IRC) [56,57,58] calculations were carried out on selected transition states to confirm their correct connection to the two adjacent minima. All free energies reported throughout this work have been corrected to include translational entropy contributions in the condensed phase (Strans(l)) using the THERMO program [59], towards avoiding the pitfalls associated with default gas-phase determinations of Strans originating from Strans(g). Natural bond orbital (NBO) analyses [36,37,38], as implemented in G09, were also performed on selected stationary points at the same level as geometry optimization, to investigate their electronic properties and bonding characteristics. NCI analyses [47] were carried out using Multiwfn [60], with the NCI isosurfaces (blue, interaction; green, weak interaction; brown, repulsion; red, strong repulsion) shown by employing Visual Molecular Dynamics (VMD) [61]. All 3D structures were drawn with CYLview [62].
To confirm the reliability of the methods used and discussed in the text, the dispersion-corrected DFT–D method [63,64] (denoted B3LYP–D3) and the most popular M06–2X functional [65] were chosen to optimize all stationary points involved on the dmpe (L1)-assisted paths Ia_cis and Ia_trans, with corresponding PESs shown in Figure S13 and the RDS transition state barriers summarized in Table S2 (the B3LYP results are also listed for the convenience of comparison). The RDS barriers on path Ia_cis obtained by employing B3LYP, B3LYP–D3 and M06–2X functionals are predicted as 25.1, 8.7 and 14.3 kcal·mol−1, respectively, while their counterparts on path Ia_trans are predicted as 26.9, 9.1 and 17.4 kcal·mol−1, respectively. Regardless of whether dispersion correction is included or not, all three functionals can predict the distereoselectivities correctly. However, the half-lives predicted by B3LYP–D3 and M06–2X methods deviate 7–11 orders of magnitude from corresponding reaction time, while the reaction half-lives predicted by the B3LYP method deviate only one order of magnitude. Namely, both B3LYP–D3 and M06–2X methods underestimated the RDS step’s activation barriers, as people have found out in their work [66,67,68,69]. This underestimation is probably caused by overestimation of weak interactions [68,70] between INT1_I and R2 fragments. Thus, all free energies reported throughout this work are based on IDSCRF(ACN)–B3LYP/DGDZVP level’s computations and have been corrected to the experimental temperature of 303 K by using the THERMO program, unless noted elsewhere.

4. Conclusions

Based on comprehensive density functional theory (DFT) studies on both bidentate (L1/L3)- and monodentate phosphine ligands (L2/L4)-assisted nickel-initiated [3+2] cycloaddition between vinylcyclopropanes (VCP) and N-tosylbenzaldimine, the following conclusions can be drawn: (1) The VCP substrate (R1) prefers to open its three-numbered ring through C(1)–C(3) bond cleavage along path I or II and converts to intermediate INT1_I/INT1_II smoothly. In the bidentate (L1, L3)-assisted cases, C,C_anti path I is verified to be the most accessible one in generating the [3+2] cycloaddition products from the ring-opened intermediate INT1_I, for it is more advantageous in avoiding possible spatial hindrance. C,C_syn path II become more feasible in generating the [3+2] cycloaddition products from the ring-opened intermediate INT1_II in the monodentate (L2, L4)-assisted cases, because extra Ni–O or Ni–N coordination can effectively reduce the activation barriers of corresponding RDS transition states. (2) The formation of C–C and C–N bonds between N-tosylbenzaldimine and the ring-opened intermediate (INT1_I or INT1_II) through [3+2] cycloaddition is found to be stepwise, with the former acting as the rate-determining step (RDS) in most cases (except for paths IIa_cis_L2 and IIa_cis_L4, in which the C–N bonding process acts as the RDS step due to strong Ni–N and Ni–O coordination in corresponding C–C bonding transition states). Computed free energy barriers of RDS transition states on L1–L4-assisted optimal path I or II transfer to good predictions for reaction half-lives and rate contents, and provide reasonable explanations for the diastereoselectivities detected in experiments. (3) Noncovalent interaction (NCI) analyses of key stationary points suggest the rate of this reaction is influenced by both electronic effects and steric hindrance, with the diastereoselectivity being mainly controlled by electronic effects. These results not only shed light on the mechanism of the nickel-initiated [3+2] cycloaddition between VCP and imines, but also provide new insights into the ligand role and selectivity-controlling mode of similar transition metal-catalyzed cycloadditions assisted by phosphine ligands.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal14010082/s1, Figure S1: PESs for paths I–V, Figure S2: The expected structure of complex COM1_V, Figure S3: Optimized geometries of some stationary points located on paths I–V, Figure S4: QTAIM analysis results for some stationary points located on paths I–V, Figure S5: Key geometrical parameters in R1 and INT1_III, Figures S6–S8: PESs for paths IIIb_cis, Ib_cis, IIb_cis, IIIa_cis, IIa_cis and IIa_trans, Figure S9: NCI analysis results for TS2_Ia_cis, TS2_Ia_trans, TS3_Ia_cis and TS3_Ia_trans, Figures S10–S12: PESs for paths Ia_cis_L2, Ia_trans_L2, Ia_cis_L3, Ia_trans_L3, IIa_cis_L3, IIa_trans_L3, Ia_cis_L4, Ia_trans_L4, IIa_cis_L4 and IIa_trans_L4, Figure S13: PESs for paths Ia_cis and Ia_trans obtained by employing B3LYP, B3LYP–D3 and M06–2X methods, Tables S1 and S2: Free energy barriers and corresponding kinetic data for RDS transition states, Tables S3–S8: Optimized Cartesian coordinates for stationary points, Tables S9–S14: The first three vibrational frequencies for stationary points, Tables S15–S20: Energetic results for stationary points obtained at different computational levels.

Author Contributions

Data curation, W.M., S.X. and X.T.; Funding acquisition, W.M. and G.M.; Conceptualization and supervision, W.M.; Project administration, W.M. and G.L.; Visualization, W.M., L.Z. and X.T.; Writing—original draft, W.M. and S.X.; Writing—review and editing, W.M., L.Z., L.D., G.M. and G.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (grant number 22363012, 21763033), Top Young Talents of Yunnan Ten Thousand People Plan, Yunnan Fundamental Research Projects (grant number 202301AT070081) and the PhD Scientific Research Start–up Projects of Yunnan Normal University.

Data Availability Statement

The original data are included in the article and Supplementary Materials. Further inquiries can be directly addressed to the corresponding author.

Acknowledgments

The authors acknowledge Jingxuan Zhang and Tao Yu (in Faculty of Chemistry and Chemical Engineering, Yunnan Normal University) for helpful discussion during the organization, writing and revision of this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 14 00082 sch001
Scheme 1. Nickel-mediated intermolecular [3+2] cycloaddition of vinylcyclopropanes (VCP) to imines assisted by phosphine ligands [20], with literature-speculated intermediates (M1–M5) depicted as well.
Scheme 1. Nickel-mediated intermolecular [3+2] cycloaddition of vinylcyclopropanes (VCP) to imines assisted by phosphine ligands [20], with literature-speculated intermediates (M1–M5) depicted as well.
Catalysts 14 00082 sch001
Catalysts 14 00082 g001
Figure 1. Energetics (ΔG, in kcal·mol−1) during the in situ generation of Ni(COD)L species from Ni(COD)2 and different phosphine ligands (L1–L4).
Figure 1. Energetics (ΔG, in kcal·mol−1) during the in situ generation of Ni(COD)L species from Ni(COD)2 and different phosphine ligands (L1–L4).
Catalysts 14 00082 g001
Catalysts 14 00082 g002
Figure 2. Possible reaction mechanism and energetics (ΔG, in kcal·mol−1) for the ring-opening of vinylcyclopropane (VCP).
Figure 2. Possible reaction mechanism and energetics (ΔG, in kcal·mol−1) for the ring-opening of vinylcyclopropane (VCP).
Catalysts 14 00082 g002
Catalysts 14 00082 g003
Figure 3. Optimized geometries (with bond length in Å and angle in °) of key stationary points located on paths I–V, accompanied by necessary Wiberg bond indices (WBI).
Figure 3. Optimized geometries (with bond length in Å and angle in °) of key stationary points located on paths I–V, accompanied by necessary Wiberg bond indices (WBI).
Catalysts 14 00082 g003
Catalysts 14 00082 g004
Figure 4. Potential free energy surfaces (PESs) for path Ia_cis.
Figure 4. Potential free energy surfaces (PESs) for path Ia_cis.
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Catalysts 14 00082 g005
Figure 5. Potential free energy surfaces (PESs) for path IIa_cis (black), with that for path Ia_cis (blue) plotted for the convenience of comparison.
Figure 5. Potential free energy surfaces (PESs) for path IIa_cis (black), with that for path Ia_cis (blue) plotted for the convenience of comparison.
Catalysts 14 00082 g005
Catalysts 14 00082 g006
Figure 6. NCI analysis results for transition states TS2_Ia_cis and TS2_IIa_cis, with their cavity volumes (in Å3) and surfaces (in Å2) depicted.
Figure 6. NCI analysis results for transition states TS2_Ia_cis and TS2_IIa_cis, with their cavity volumes (in Å3) and surfaces (in Å2) depicted.
Catalysts 14 00082 g006
Catalysts 14 00082 g007
Figure 7. Potential free energy surfaces (PESs, ΔG in kcal·mol−1) for path Ic_cis (black), with the NCI analysis results of transition states TS2_Ia_cis and TS2_Ic_cis depicted.
Figure 7. Potential free energy surfaces (PESs, ΔG in kcal·mol−1) for path Ic_cis (black), with the NCI analysis results of transition states TS2_Ia_cis and TS2_Ic_cis depicted.
Catalysts 14 00082 g007
Catalysts 14 00082 g008
Figure 8. Potential free energy surfaces (PESs) for path Ia_trans (black dotted), with that for path Ia_cis (blue) plotted for the convenience of comparison.
Figure 8. Potential free energy surfaces (PESs) for path Ia_trans (black dotted), with that for path Ia_cis (blue) plotted for the convenience of comparison.
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Catalysts 14 00082 g009
Figure 9. Optimized geometries (with bond length in Å) for transition states TS2_Ia_cis/trans and TS3_Ia_cis/trans.
Figure 9. Optimized geometries (with bond length in Å) for transition states TS2_Ia_cis/trans and TS3_Ia_cis/trans.
Catalysts 14 00082 g009
Catalysts 14 00082 sch002
Scheme 2. Probable reaction mechanism for the mono- and bidentate phosphine ligand-assisted nickel-initiated [3+2] cycloaddition between VCP and N-tosylbenzaldimine.
Scheme 2. Probable reaction mechanism for the mono- and bidentate phosphine ligand-assisted nickel-initiated [3+2] cycloaddition between VCP and N-tosylbenzaldimine.
Catalysts 14 00082 sch002
Catalysts 14 00082 g010
Figure 10. Potential free energy surfaces (PESs) for paths IIa_cis_L2 (blue) and IIa_trans_L2 (black dotted).
Figure 10. Potential free energy surfaces (PESs) for paths IIa_cis_L2 (blue) and IIa_trans_L2 (black dotted).
Catalysts 14 00082 g010
Catalysts 14 00082 g011
Figure 11. (a) Optimized geometries (with bond length in Å) for transition states TS2_Ia_cis_L1/L3 and TS2_IIa_cis_L2/L4, (b) NCI analysis results for transition states TS2_IIa_cis_L2/L4 and TS3_IIa_cis_L2/L4.
Figure 11. (a) Optimized geometries (with bond length in Å) for transition states TS2_Ia_cis_L1/L3 and TS2_IIa_cis_L2/L4, (b) NCI analysis results for transition states TS2_IIa_cis_L2/L4 and TS3_IIa_cis_L2/L4.
Catalysts 14 00082 g011
Catalysts 14 00082 g012
Figure 12. Correlations between RDS transition state barriers (ΔΔG, in kcal·mol−1) and experimentally detected yield (%) of P1_cis.
Figure 12. Correlations between RDS transition state barriers (ΔΔG, in kcal·mol−1) and experimentally detected yield (%) of P1_cis.
Catalysts 14 00082 g012
Table 1. NPA charge population (unit: ē) of key atoms in reactant R2 and intermediate INT1_I.
Table 1. NPA charge population (unit: ē) of key atoms in reactant R2 and intermediate INT1_I.
C(1)C(3)N(4)C(5)
Catalysts 14 00082 i001−0.372−0.225−0.735+0.185Catalysts 14 00082 i002
Table 2. Free energy barriers (ΔΔG, in kcal·mol−1) of RDS transition states (TSRDS) located on paths Ia_cis/trans_L and IIa_cis/trans_L, as well as the rate constants (k, L·mol−1·s−1 or s−1), reaction half-lives (t1/2, h) and corresponding experimental reaction time, yield and dr ratios.
Table 2. Free energy barriers (ΔΔG, in kcal·mol−1) of RDS transition states (TSRDS) located on paths Ia_cis/trans_L and IIa_cis/trans_L, as well as the rate constants (k, L·mol−1·s−1 or s−1), reaction half-lives (t1/2, h) and corresponding experimental reaction time, yield and dr ratios.
LigandTSRDSΔΔGkt1/2 (h)tExpt. (h)Yield (%)drCalc.drExpt.
L1: dmpeTS2_Ia_cis_L125.14.969 × 10−65.590 × 1015 h>9919.9:1>99:1
TS2_Ia_trans_L126.92.500 × 10−71.111 × 103
L2: PMe2PhTS3_IIa_cis_L230.47.474 × 10−102.576 × 105 473.8:13.3:1
TS2_IIa_trans_L231.21.979 × 10−101.403 × 106
L3: dppeTS2_Ia_cis_L326.73.485 × 10−77.970 × 102 7314.3:15.2:1
TS2_Ia_trans_L328.32.445 × 10−81.136 × 104
L4: PMe3TS3_IIa_cis_L430.21.042 × 10−91.848 × 105 6214.3:16.0:1
TS2_IIa_trans_L431.87.307 × 10−113.802 × 106
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MDPI and ACS Style

Mu, W.; Zhu, L.; Xia, S.; Tan, X.; Duan, L.; Meng, G.; Liu, G. Insights into the Mechanism, Regio-/Diastereoselectivities and Ligand Role of Nickel-Initiated [3+2] Cycloadditions between Vinylcyclopropane and N-Tosylbenzaldimine. Catalysts 2024, 14, 82. https://doi.org/10.3390/catal14010082

AMA Style

Mu W, Zhu L, Xia S, Tan X, Duan L, Meng G, Liu G. Insights into the Mechanism, Regio-/Diastereoselectivities and Ligand Role of Nickel-Initiated [3+2] Cycloadditions between Vinylcyclopropane and N-Tosylbenzaldimine. Catalysts. 2024; 14(1):82. https://doi.org/10.3390/catal14010082

Chicago/Turabian Style

Mu, Weihua, Lin Zhu, Shuya Xia, Xue Tan, Liangfei Duan, Guanghao Meng, and Guo Liu. 2024. "Insights into the Mechanism, Regio-/Diastereoselectivities and Ligand Role of Nickel-Initiated [3+2] Cycloadditions between Vinylcyclopropane and N-Tosylbenzaldimine" Catalysts 14, no. 1: 82. https://doi.org/10.3390/catal14010082

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