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 (3ac–3ae ). For example, the reaction with substrates bearing –OCF3 and –SCF3 substitutions, often embedded in pharmaceutical and agrochemical products, afforded the corresponding products in excellent yields (3af and3ag ). 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 atmeta or ortho positions of the phenyl ring were acceptable (3ar–3av ) and showed a similar electronic preference compared with the para substitutions.
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 and3be , we found that the electron-donating substituents at thepara 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 atom, such as –F, –Cl, –Br, and –I, at the phenyl ring (3ba–3bd ), reacted with styrene to afford products in good yields.
Further, 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. Theortho -methyl-substituted substrate provided the product in 92% yield (3bg ). In addition, long alkyl chains provided products (3bi and 3bj ) in moderate yields.
Figure 2. Insertion of alkenes into C–Cl bonds.aReaction conditions: 1 (0.6 mmol) and2 (1.8 mmol) at 80 °C–120 °C for 1–5 h under air. R1 = 1-phenylethyl, R2 = benzhydryl, Ar1 = Ph, Ar2 = 4-CF3-Ph, and Ar3 = 4-MeO-Ph. SI provides the detailed conditions for each substrate.bA gram scale reaction was performed under air using1 (10.0 mmol).
Diphenylmethane has highly important applications in the synthesis of bioactive compounds;72 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.
Figure 3. Insertion into C–Br and C–I bonds.aAr2 = 4-CF3-Ph. SI provides the detailed conditions for each substrate.
We extended the reaction scope of benzyl bromides and iodides (Figure 3). The insertion reaction was explored using styrene as the nucleophile. Alkyl bromide 5aa was successfully obtained with a satisfactory yield under standard reaction conditions. Introduction of an electron-withdrawing 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 but with a slight reduction in yield. When bromodiphenylmethane was used as the electrophile, the yield (5ad ) was improved because C–Br bonds are easier to cleave owing to the conjugation effect. Halogens on the alkyl chains were well tolerated (5ae and 5af ), and their insertion into unactivated carbon–halogen bonds was not observed. Further, benzyl iodides were suitable substrates in the insertion reaction (5ag ), for which the insertion process was difficult.73
One-pot Reaction. To demonstrate the practical application 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.
Figure 4. Carbohalogenative 1,2-difunctionalization of double bonds.
Mechanistic Investigations. To shed light on the reaction mechanism, some control experiments were conducted. The reactions of1b and 2k were performed in the presence of a radical inhibitor, 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT). The insertion product was obtained in 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 alkene by BHT. Subsequently, a cation-exchange experiment was designed (Figure 5B), where benzhydrol was introduced as a cation donor. As expected, the normal insertion product 3ab was obtained in 21% yield, and3bk that 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.74 In addition, the intermolecular competition between styrene 1b and its dideuterated analogd8-1b showed a kinetic isotope effect kH/kD = 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.75 In addition, solvent quenching experiments were designed to elaborate 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, RIC). Next, induction and coordination effects will reduce the transient effective charge produced by the system, which is not conducive to the reaction (charge dispersion, CD). Finally, the solvent effect may quench the intermediates or transition states produced by the reaction, inhibiting the reaction (intermediate quenching or transition state quenching, IQ or TSQ). To confirm the above speculation, density functional theory (DFT) calculations and symmetry-adapted perturbation theory (SAPT) analysis were conducted.
Figure 5. Preliminary mechanistic experiments.
DFT calculations provide mechanistic insights into the abovementioned insertion reactions of alkenes to C–X bonds. For C–Cl bond insertion (Figure 6A), 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 SN1-like 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 2kseemed unfavorable as it required higher energy (by >20 kcal/mol) than that in the heterolysis of the C–Cl bond (Figure S4). Moreover, the SN2 mechanism in which a styrene directly attacks the C(sp3) 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 SN1-like mechanism.
Figure 6. DFT calculations and SAPT analysis.
SAPT analysis evaluates the intermolecular interaction energy between the fragments of the obtained TS in the C–Cl bond insertion reaction (Figure 6B). The results from this energy decomposition calculation clearly show a strong electrostatic stabilization interaction of ~77.2 kcal/mol between the chloride anion and its bounded benzylic counterpart. Interestingly, almost half of the electrostatic stabilization (i.e., ~35.6 kcal/mol) was found between styrene and the remaining fragments in the TS. Furthermore, second-order perturbation analysis based on natural bond orbital calculations showed that a strong orbital interaction existed between the pz orbital of the carbocation and p bonding orbital of the olefin fragment of styrene. The calculated second-order perturbation energy was 108.2 kcal/mol. Therefore, the temporary anchorage of the chloride anion provided a channel for the nucleophilic attack of an olefin and facilitated its subsequent combination with a newly generated carbocation, providing an almost synergetic reaction mode while suppressing the possible side reactions associated with the carbocation. Therefore, the insertion reaction of alkenes into C–X bonds was controlled by intrinsic factors such as strong orbital interactions and electrostatic stabilizations between the fragments involved in the reactions. However, if the reaction is performed under a non-aggregated state, the abovementioned TSs or intermediates would be excluded owing to their inevitable and much stronger interactions with solvent.
Discussion
In summary, a new strategy relying on aggregated state has enabled the catalyst-free insertion of alkenes into C–X bonds. The difunctionalization of 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, CO2H, Me2SiH, alkynes, and CO2Me, which are often incompatible in transition-metal catalyzed or Lewis-acid catalyzed reactions. This work is the first 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
General procedure for probing the scope of insertion of alkenes into carbon-halogen bonds. To an oven-dried, 10 mL Teflon-lined screw-capped Pyrex test tube was added aryl ethylenes (0.6 mmol) and benzyl halides (1.8 mmol) without argon protection. A magnetic stir bar were added to the tube carefully and the mixture was stirred slowly for 5 min at room temperature. Then increase the temperature to 100 °C and continue to stir for extra 5 h. After being cooled down to room temperature, it was purified by flash chromatography on silica gel to afford pure product. DFT calculations were performed using the ORCA program and SAPT analysis was performed using the PSI4 code at the SAPT2+/aug-cc-pVDZ level.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (91940305, 21933009, 81874181, 22271195, 21871284), Natural Science Foundation of Fujian Province (2021J01525), Major Scientific and Technological Special Project for ”Significant New Drugs Creation” (2019ZX09301158), 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.
Conflict of Interests
The authors declare no conflict of interests.
Supporting Information
Supporting Information is available from the Wiley Online Library or from the author.
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Molecular aggregation affects the electronic interactions between molecules and has emerged as a powerful tool in material science. In this study, aggregation strategy was applied to synthetic chemistry, ionic insertion of alkene into carbon–halogen bond can occur smoothly in aggregated state without any catalysts. Results show that the non-aggregated state may quench the transition state and terminate the insertion process.
Keywords aggregation enabled alkene insertion, solvent-free and catalyst-free, atom-and step-economy
Meng-Yao Li,1,2,4 Xiao-Mei Nong,1Han Xiao,3 Ao Gu,1 Shuyang Zhai,1 Jiatong Li,1 Ge Zhang,4 Ze-Jian Xue,4 Yingbin Liu,1* Chunsen Li,3* Guo-Qiang Lin,2,4 Chen-Guo Feng2,4*
Title Aggregation-enabled Alkene Insertion into Carbon–Halogen Bonds
ToC figure