Aggregation‐enabled alkene insertion into carbon–halogen bonds

Molecular aggregation affects the electronic interactions between molecules and has emerged as a powerful tool in material science. Aggregate effect finds wide applications in the research of new physical phenomena; 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 an aggregated state. Additional catalysts or promoters are not necessary under such circumstances, and solvent quenching experiments indicate that the aggregated state is critical for achieving such sequences. The ionic insertion mode is supported by mechanistic studies, density functional theory calculations, and symmetry‐adapted perturbation theory analysis. Results also show that the non‐aggregated state may quench the transition state and terminate the insertion process.

[12] However, recent studies have suggested that the restriction of access to the dark state is also an important factor in explaining the AIE mechanism. [13]n addition, the aggregate effect on intermolecular packing style and electronic interaction has also become the focus of aggregated state chemistry. [14]Therefore, it is logical to say that the increased interactions between molecules in aggregates may induce chemical reactions between corresponding molecules.While studying the dissociation of HCl(H 2 O) 4 at ultracold temperatures, Birer and co-workers [15,16] 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 such a system, [17,18] 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).
[35][36] Alkenes insertion into C-X bonds is among the most direct and efficient methods for generating C-C and C-X bonds simultaneously.
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(sp 2 )-X bonds, a palladium [37][38][39][40][41][42][43] and nickel [44][45][46][47][48] catalyzed oxidative addition/migratory insertion/reductive elimination sequence is a successful route (Figure 1B-i).However, extending this method to the insertion of C(sp 3 )-X bonds would be problematic owing to the competition of β-H elimination.[51][52] When initially proposed by Kharasch [53] in the 1940s, this type of reaction was limited to stoichiometric quantities of harmful oxidants, organotin reagents, and organoboron reagents as radical initiators. [54,55]Subsequently, a series of metalcatalyzed [56,57] or photocatalytic [58][59][60][61][62] 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).69] Furthermore, insertion into more reactive C-Br and C-I via this approach remains elusive.Therefore, developing creative strategies that can address these limitations to provide new opportunities in this research area is highly desirable.
We envisioned that the aggregate effect could enable spontaneous cleavage of alkyl C-X bonds to initiate ionic insertion reactions. [70]If the reaction is performed in an aggregated state, it is possible to capture a transient ion pair through the contact touch with alkenes. [71]Furthermore, the cleavage of the C-X bond may be facilitated by alkenes through the formation of a π complex [72] or the stabilization of the generated cations to onium ions, which is not stable in dilute solution (Figure 1C-i). [73]This promotes the insertion of the desired alkene without transition metal catalysts.Compared with ionic insertion through Lewis-acid catalysis, the contact nature in an aggregated state may facilitate a fast cascade process, which avoids competitive E1 elimination reactions and cationic polymerization. [74,75]erein, 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 [76,77] conditions.Specifically, the excellent compatibility of functional groups indicates that this methodology has potential applications in the field of organic synthesis.

Reaction development
After extensive optimization, the reaction of alkene 1a and benzyl chloride 2a afforded the highest yield of 3aa (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% of 3aa (entry 2).The yield did not improve by increasing the temperature (entry 3) or by adjusting the ratio of 1a and 2a (entries 4 and 5).Further, the solvent effect of this process was tested.Thus, no product formation was observed in either polar or nonpolar solvents.We speculate that nonpolar solvents such as toluene and n-hexane (entries 6 and 7, respectively) increase the free energies of the carbocation transition state, raising the activation energies. [71]Conversely, in polar solvents (entries 8-11), the positive charge of the carbocations would be dispersed by coordination with the solvent, reducing the electrophilicity of benzyl cations. [75]The cage effect of the solvent can also block the reaction by reducing the collision probability of alkenes and benzyl cations. [78]A high yield was maintained during the reaction that proceeded in the dark, indicating a non-photocatalytic process (entry 13).

Substrate scope
The scope of the reaction under optimized conditions was investigated.Various aryl ethylenes were tested as nucleophiles, and the corresponding ionic insertion products delivered moderate to excellent reaction yields (Figure 2A).
For substrates with substitutions on the para position, electron-deficient substrates usually gave higher reaction yields, which were primarily ascribed to their relatively low reactivity toward the newly generated benzyl chloride.Further, excellent functional-group tolerance was observed.For example, the reaction with substrates bearing -OCF 3 and -SCF 3 substitutions, often embedded in pharmaceutical and agrochemical products, afforded the corresponding products in excellent yields (3af and 3ag).The -Br (3ae), -I (3ap), alkyne (3aj), and boronate (3an and 3ao) substitutions, which may have been incompatible in previous transition-metal catalyzed processes, were all well tolerated, thereby providing handles for further derivation.Some reactive functional groups in conventional synthetic methods, including aryl esters, aldehydes, carboxyl, and benzyl chloride groups, were well accommodated (3ak-3am and 3aq).Furthermore, functional groups at meta or ortho positions of the phenyl ring were acceptable (3ar-3av) and showed a similar electronic preference compared with the para substitutions.It was with pleasure to note that the internal alkene was also a viable substrate (3aw).Subsequently, the feasibilities of benzyl chlorides 2 were explored, beginning with the examination of the electronic effects of the substituents (Figure 2B).After comparing 3ba and 3be, we found that the electron-donating substituents at the para position increased the reaction yield.The electron-donating conjugation effect on the aromatic ring decreased the activation energy of the heterolytic cleavage of the C-Cl bond.The substrates featuring halogen atoms, such as -F, -Cl, -Br, and -I, at the phenyl ring (3ba-3bd), reacted with styrene to afford products in good yields.
Further, the steric effect was analyzed by changing the position of the methyl group.This showed that the steric effect of an aryl ring has a slight influence on the proposed reaction.The ortho-methyl-substituted substrate provided the product with a 92% yield (3bg).In addition, long alkyl chains provided products (3bi and 3bj) in moderate yields.
Diphenylmethane has highly important applications in the synthesis of bioactive compounds; [79] thus, a series of diarylmethyl chlorides as substrates were investigated.Owing to the stability of a carbocation, excellent compatibility of these substrates was observed for the proposed reaction.Both electron-withdrawing (3bl) and electron-donating (3br) substituents underwent insertion reactions with good yields.A heteroaromatic thienyl group (3bq) was also well tolerated in the reaction.In addition to benzyl chlorides, primary and secondary allyl chlorides were verified as suitable coupling partners (3bs and 3bt).Furthermore, the scalability of the proposed reaction was evaluated by performing a reaction with 10.0 mmol of 1b.An improved yield of 95% was obtained compared with small-scale trials.
We extended the reaction scope of benzyl bromides and iodides (Figure 3).The insertion reaction was explored using styrene derivative as the nucleophile.Alkyl bromide 5aa was successfully obtained with a satisfactory yield under standard reaction conditions.The introduction of an electronwithdrawing substituent decreased the reaction yield (5ab), which can be attributed to an increased difficulty for the heterolytic cleavage of the C-Br bond.The replacement of methyl with ethyl provided 5ac with a slight reduction in yield.When bromodiphenylmethane was used as the electrophile, the yield (5ad) was improved because C-Br bonds were easier to cleave owing to the conjugation effect.Halogens on the alkyl chains were well tolerated (5ae and 5af), and insertion into inert carbon-halogen bonds was not observed.Further, benzyl iodides were suitable substrates in the insertion reaction (5ag), which was unfeasible in the previous work. [80]

One-pot reaction
To demonstrate the practical applications of the proposed reaction, a series of one-pot transformation sequences was investigated (Figure 4).The C-C, C-O, C-S, C-N, and C-B difunctionalizations of alkenes were realized through this reaction (6aa-6af).Reductive coupling (6ag) and deprotonation (6ah) products were obtained after treating 3bk with a reductant and base, respectively.

Mechanistic investigations
To shed light on the reaction mechanism, some control experiments were conducted.The reactions of 1b and 2k were performed in the presence of a radical inhibitor, 2,6-bis(1,1dimethylethyl)-4-methylphenol (BHT).The insertion product obtained an 86% yield, indicating that the proposed reaction is unlikely to proceed via a radical pathway (Figure 5A).The increased yield (compared with Figure 2B) may be explained by the inhibition of the radical polymerization of an alkene by BHT.Subsequently, a cation-exchange experiment was designed (Figure 5B), where benzhydrol 7 was introduced as a cation donor.As expected, the normal insertion product 3ab was obtained in 21% yield and 3bk which was generated using benzhydrol as the benzhydryl cation donor was obtained in 55% yield.The formation of these products implied that the proposed reaction proceeded through an ionic mode. [81]In addition, the intermolecular competition between styrene 1b and its deuterated analog d 8 -1b showed a kinetic isotope effect k H /k D = 1.00 (Figure 5C); however, a secondary isotope effect was not observed, suggesting that C-C and C-Cl bond formations were not involved in the rate-determining step. [82]Moreover, solvent quenching experiments were designed to elaborate on the influence of the aggregated states on such ionic insertion processes.As shown in Figure 5D, while a trace amount (three equivalents) of commonly used solvent was introduced into the reaction system, the desired transformation could be interrupted, which may be ascribed to the disconnection of the aggregated state of reactants by the solvent molecules.Notably, even nonpolar, weak coordinating solvents such as mesitylene were competent blockers.Possibly, there are three reasons why the solvent prevents the above reaction.First, the cage effect of the solvent can reduce effective collision between substrates and increase the activation energy of the insertion process (restricted intermolecular collision).Next, induction and coordination effects will reduce the transient effective charge produced by the system, which is not conducive to the reaction (effective charge dispersion).Finally, the solvent effect may quench the stable intermediates or transition states produced by the reaction, inhibiting the reaction (stable intermediate quenching or transition state quenching).To confirm the above speculation, density functional theory (DFT) calculations, and symmetry-adapted perturbation theory (SAPT) analysis were conducted.DFT calculations performed with ORCA modeling package [83,84] provide mechanistic insights into the above-mentioned insertion reactions of alkenes to C-X bonds.For C-Cl bond insertion (Figure 6), the benzyl chloride substrate 2k heterolytically dissociated to carbocation and chloride anion before styrene attacked the so-generated carbocation via a chloride anion-bound transition state (TS).Such an S N 1like reaction pathway was exergonic (3.5 kcal/mol) with an overall free-energy barrier of 26.2 kcal/mol.Consistent with the mechanistic studies, the radical mechanism was ruled out because the homolysis of the C-Cl bond in 2k seemed unfavorable as it required higher energy (by >20 kcal/mol) than that in the heterolysis of the C-Cl bond (Figure S3).Moreover, the S N 2 mechanism in which styrene directly attacks the C(sp 3 ) atom of 2k to release a chloride anion was ruled out because it encounters a 5 kcal/mol higher energy barrier than that in the S N 1-like mechanism.More exhaustive information about DFT calculations, SAPT analysis, and interaction region indicator (IRI) calculations are discussed in the Supporting Information.

DISCUSSION
In summary, a new strategy relying on the aggregated state has enabled the catalyst-free insertion of alkenes into C-X bonds.The difunctionalization of an alkene can be realized without using any transition metal catalysts in the aggregated state.Practically, alkenes were inserted into C-X (X = Cl, Br, and I) bonds via ionic mode.The method exhibits excellent atom and step economy and environmental sustainability.Moreover, its practicality is highlighted by a broad substrate scope, excellent functional-group tolerance, and extremely simple operation.The method tolerates active functional groups such as CHO, B(OH) 2 , CO 2 H, Me 2 SiH, alkynes, and CO 2 Me, which are often incompatible in transition-metal catalyzed or Lewis-acid catalyzed reactions.We tentatively explained the reason for aggregated state facilitating such a reaction from the perspective of the reaction collision theory, electrostatic interaction, and transition state quenching according to the exhaustive mechanism experiments, DFT calculations, SATP analysis, and IRI diagrams.This work is an attempt to apply aggregate science to the field of synthetic chemistry, which further expands the application reaction of aggregation strategy as well as provides a new idea for designing new reactions in organic chemistry.

MATERIALS AND METHODS
The general procedure for probing the scope of insertion of alkenes into carbon-halogen bonds is described here.To an oven-dried, 10 mL Teflon-lined screw-capped Pyrex test tube, aryl ethylenes (0.6 mmol), and benzyl halides (1.8 mmol) were added without argon protection.A magnetic stir bar was added to the tube carefully and the mixture was stirred slowly for 5 min at room temperature.Then the temperature was increased to 100 • C and the stir was continued for 5 h.After it cooled down to room temperature, it was purified by flash chromatography on silica gel to afford the pure product.Geometry optimizations and vibrational frequency calculations were performed with the B3LYP [85][86][87] functional with a dispersion term D3BJ [88,89] in conjunction with the def2-SVP [90,91] basis set (ma-def2-SVP [90,91] basis set for chlorine atom).Single-point energy calculations were done with def2-TZVPP [90,91] basis set to obtain more accurate values of energy.The solvent effects have been included in all calculations by using the solvent model based on density (SMD) [92] implementation in the Orca package.The a-chlorobenzene in the Orca SMD library, which has a similar dielectric constant as benzyl chlorides, was taken as a solvent during the calculations.
SAPT is a useful method to investigate intermolecular interactions.SAPT was first introduced by Eisenschitz and London [93] in the 1930s.It divided the aim system into isolated monomers and treat the interactions as small perturbations of this system.In the study, SAPT analysis was carried out by Psi4 software [94] on the level of sapt2+, and the aug-cc-pVDZ basic set was used in SAPT calculation.In SAPT analysis, the intermolecular interactions were divided into electrostatic, exchange, induction, and dispersion interaction.
IRI (Interaction Region Indicator) is a real space function introduced by Lu and Chen. [95]This real space function is aimed to reveal intermolecular interactions in terms of graphical.The function IRI is simply defined as follows: Where ρ(r) is electron density and ∇ρ(r) is the gradient of electron density.Factor a is an adjustable parameter, it was chosen to be 1.1 in this paper.In this paper, the IRI was calculated and drawn by Multiwfn software. [96]Figure 7 shows the standard color illustration on isosurfaces.For example, blue isosurfaces mean that there is strong bonding interaction in the blue region.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interest.

D ATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E T H I C S S TAT E M E N T
There are no ethical issues in this work.

F I G U R E 1
Alkenes insertion into carbon-halogen bonds.

F I G U R E 2 F I G U R E 3
Insertion of alkenes into C-Cl bonds.a Reaction conditions: 1 (0.6 mmol) and 2 (1.8 mmol) at 80-120 • C for 1-5 h under air.R 1 = 1phenylethyl, R 2 = benzhydryl, Ar 1 = Ph, Ar 2 = 4-CF 3 -Ph, and Ar 3 = 4-MeO-Ph.SI provides detailed conditions for each substrate.The ratio of diastereomers is calculated by 1 H NMR analysis (major/minor).b A gram scale reaction was performed under air using 1 (10.0 mmol).Insertion into C-Br and C-I bonds.a Ar 2 = 4-CF 3 -Ph.SI provides detailed conditions for each substrate.The ratio of diastereomers is calculated by 1 H NMR analysis (major/minor).

F I G U R E 4
One-pot transformation sequences.F I G U R E 5 Preliminary mechanistic experiments.

F I G U R E 6
Density functional theory (DFT) calculations and proposed mechanism.

F I G U R E 7
r)] a Standard color illustration on interaction region indicator (IRI) isosurfaces.
This work was supported by the National Natural Science Foundation of China (91940305, 21933009, 81874181, 22271195, and 21871284), Natural Science Foundation of Fujian Province (2021J01525), Major Scientific and Technological Special Project for "Significant New Drugs Creation" (2019ZX09301158), The Emerging Frontier Program of Hospital Development Centre (SHDC12018107), Shanghai Science and Technology Development Fund from Central Leading Local Government (YDZX20223100001004), and Shanghai Municipal Health Commission/Shanghai Municipal Administration of Traditional Chinese Medicine (ZY(2021-2023)−0501).The authors would like to thank Shiyanjia Lab (www.shiyanjia.com) for the language editing service.