Email: laoniulyb@shsmu.edu.cn; chunsen.li@fjirsm.ac.cn; fengcg@shutcm.edu.cn
Keywords: aggregated state, ionic insertion, solvent-free and catalyst-free, atom-and step-economy
Abstract: Molecular aggregation affects the electronic interactions between molecules and has emerged as a powerful tool in material science. Molecular aggregation finds wide applications in the research of new physical effects; however, its value for chemical reaction development has been far less explored. Herein, we report the development of aggregation-enabled alkene insertion into carbon–halogen bonds. The spontaneous cleavage of C–X (X = Cl, Br, or I) bonds generates an intimate ion pair, which can be quickly captured by alkenes in the aggregated state. Additional catalysts or promoters are not necessary under such circumstances, and solvent quenching experiments indicate that the aggregated state is critical for initiating such sequences. The ionic insertion mode and the intimate ion pair mechanism are supported by mechanistic studies, density functional theory calculations, and symmetry-adapted perturbation theory analysis. Results show that the non-aggregated state may quench the transition state and terminate the insertion process.
Introduction
Since Tang and co-worker’s seminal work in 2001,1aggregate science has emerged as a productive area of molecular science.2-4 Unlike previous studies that focused on the properties of isolated molecules, the new perspective brings us the novel characteristics enabled by molecular aggregates. Interactions between molecules in aggregates induce unique physical changes, such as aggregation-induced emission5 and self-assembly-induced crystallization,6 in the system, finding wide applications in biology and material sciences. Therefore, it is an obvious logical extension that the increased interactions between molecules in aggregates may induce chemical reactions between corresponding molecules. While studying the dissociation of HCl(H2O)4 at ultracold temperatures, Birer and co-workers7,8 proposed a mechanism of aggregation-induced dissociation. Although this physical chemistry study is instructive, it falls short of developing synthetically useful chemical processes.
In solvent-free reactions, reactants are in close contact with each other, and such an aggregated state may benefit the reaction. However, while considerable attention has been paid to the green and sustainable features of this type of system,9-10 its potential to promote reactions has been neglected. Therefore, we recently initiated a project to discover novel synthetic methods guided by the aggregated state concept (Figure 1A).
Owing to the diverse and rich reaction chemistry associated with carbon–halogen (C–X) bonds, organohalides are crucial in synthetic chemistry.11-15 Moreover, they are prevalent structural subunits in numerous important natural products and pharmaceuticals.16-19 Although halides can be obtained by numerous methods, efficient, practical, and green methods are currently being developed.20-24 Carbohalogenative 1,2-difunctionalization of double bonds with organohalides has emerged as an appealing method with excellent atom economy, step economy, and versatility.25-28 Insertion of double bonds into C–X bonds is among the most direct and efficient methods for generating C–C and C–X bonds simultaneously.
Figure 1. Insertion of alkene into carbon–halogen bonds.
To initiate the insertion process, a suitable catalyst or promoter for disconnecting C–X bonds has become an essential tool and rendered three viable pathways (Figure 1B). For C(sp2)–X bonds, a palladium-29-36 and nickel-37-41catalyzed oxidative addition/migratory insertion/reductive elimination sequence is a successful route (Figure 1B-i). However, extending this method to the insertion of C(sp3)–X bonds would be problematic owing to the competition of β -H elimination. A complementary strategy for C(sp3)–X insertion is atom transfer radical addition (ATRA) reaction (Figure 1B-ii).42-45 When initially proposed by Kharasch46 in the 1940s, this type of reaction was limited to stoichiometric quantities of harmful oxidants, organotin reagents, and organoboron reagents as radical initiators.47-48 Subsequently, a series of metal-catalyzed49-50 or photocatalytic51-55 ATRA reactions employing haloalkanes were reported. Despite considerable advancements, some major limitations and challenges remain in the methods based on the above mechanism; for example, the need for expensive transition catalysts, the strict requirements of the experimental operations, insufficient accommodation of some reactive functional groups, and difficulty associated with the use of alkyl chloride substrates.
Third is insertion via the heterolytic cleavage of C–X bonds (Figure 1B-iii). However, although such ionic reactions have a long history, only alkyl C–Cl bond insertion with limited substrate scope has been presented and literature reports in this regard are sparse.56-59 Lack of interest might be ascribed to the challenge in controlling carbocation-involved E1 elimination and cationic polymerization.60-62 Furthermore, insertion into more reactive C–Br and C–I via this approach remains elusive. Therefore, developing creative strategies that can address the limitations to provide new opportunities to this research area is highly desirable.
We envisioned that an aggregated state could enable spontaneous cleavage of alkyl C–X bonds to initiate ionic insertion reactions.63 If the reaction is performed under an aggregated state, it is possible to capture a transient ion pair through the contact touch with alkenes.64 Furthermore, the cleavage of the C–X bond may be facilitated by alkenes through the formation of a π complex65 or the stabilization of the generated cations to onium ions, which is not stable under dilute solution state (Figure 1C-i).66 This promotes the insertion of the desired alkene without transition metal catalysts. Compared with ionic insertion through Lewis-acid catalysis, the contact nature under an aggregated state may facilitate a fast cascade process, which avoids competitive E1 elimination reactions and cationic polymerization.67-68
Herein, we report the development of aggregation-enabled alkene insertion into carbon–halogen bonds (Figure 1C-ii). The insertion into C–Cl, C–Br, and C–I bonds can be realized with the completed atom economy and high step economy under catalyst-free conditions. Specifically, the excellent compatibility of functional groups indicates that this methodology has potential applications in the field of organic synthesis.
Results
Reaction Development. After extensive optimization, the reaction of alkene 1a and benzyl chloride 2a afforded the highest yield of 93% at 100°C for 5 h in an aggregated state (Table 1, entry 1). Decreasing the reaction temperature considerably reduced the conversion of 1a and 2a , yielding only 7% of3aa . The yield did not improve by increasing the temperature (entries 7 and 9) or by adjusting the ratio of 1a and2a (entries 10 and 11). Further, the solvent effect of this process was tested. Thus, no product formation was observed in either polar or nonpolar solvents. We believe that nonpolar solvents such as toluene and n -hexane (entries 1 and 2, respectively) increase the free energies of the carbocation transition state, raising the activation energies.64 Conversely, in polar solvents (entries 3–6), the positive charge of the carbocations would be dispersed by coordination with the solvent, reducing the electrophilicity of benzyl cations68. The cage effect of the solvent can also block the reaction by reducing the collision probability of alkenes and benzyl cations.71 A high yield was maintained during the reaction that proceeded in the dark, indicating a nonphotocatalytic process (entry 13).
Table 1. Effect of reaction parameters on the insertion of alkenes into C–Cl bonds.