Effect of the regulation of quinine in Cinchona Base derived primary amine on the addition reaction of nitrostyrene with 2-methylpropionaldehyde

Effect of the regulation of quinine in Cinchona Base derived primary amine on the addition reaction of nitrostyrene with 2-methylpropionaldehyde | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of the regulation of quinine in Cinchona Base derived primary amine on the addition reaction of nitrostyrene with 2-methylpropionaldehyde Jiang Haiyang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4414411/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The Michael addition of nitrostyrene and 2-methylpropionaldehyde catalyzed via cinchona alkaloid-based primary amines (9-epi-QDA-R'') with the aid of benzoic acid have been carried out at the PCM(toluene)/B3LYP/6-311 + + G(2df,2p)//B3LYP/6-31G(d) level. The calculations showed that the whole reaction consisted of four consecutive steps: ⑴ the production of an imine ion intermediate, ⑵ an addition reaction between the imine ion and nitrostyrene, ⑶ the second proton transfer stage, and ⑷ hydrolysis and regeneration stage of the catalyst. The rate-determining step of the whole reaction is the addition process between the imine ion and nitrostyrene. The correlation calculations determined that 9-epi-QDA-R'' containing -NH electron-absorbing group in the quinine ring exhibit stronger activation than that containing -CH 2 electron-donating group, while 9-epi-QDA-R'' with -NCONHPh electron-absorbing group in the quinine ring exhibit weaker activation than that containing -CH 2 electron-donating group. Natural Bond Orbital analysis of atomic charges of the tertiary amine nitrogen in the quinine ring determined that the electron-absorbing group slightly reduce the negative charges on the nitrogen atom of the tertiary amine, which is favorable for the addition reaction of the imine ion to nitrostyrene. However, the negative charge on tertiary amine nitrogen is much reduced by the electron-absorbing substituents, which is not conducive to the addition reaction of nitrostyrene with the imine ion. Accordingly, the calculations exhibit that the charge distribution of the nitrogen atom of the tertiary amine influences the catalytic efficiency of the whole system. Michael addition Cinchona alkaloid-based primary amines Natural Bond Orbital Catalytic efficiency Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Michael addition is known to be an efficient method for generating carbon-carbon bonds in organic synthesis [ 1 ], and relevant studies are important for the development of precious organic compounds. Organocatalytic Michael addition of carbon-centered nucleophiles with nitroalkenes is one of the most attractive methods for obtaining versatile products, due to the high-reactivity of nitroolefins and the multifunctionality of the nitro [ 2 – 4 ]. Nucleophilic reagents such as malonates [ 5 – 11 ], diketones [ 12 – 18 ], ketoesters [ 19 – 22 ], nitroalkanes [ 23 – 29 ], and enolizable carbonyl compounds [ 30 – 32 ] have been widely used to generate useful chiral adducts. Among the different nucleophilic reagents, 2-methylpropionaldehyde is a typical enolized carbonyl compounds. In this paper, we mainly studied the Michael addition of 2-methylpropionaldehyde and nitroalkene. In recent years, asymmetric organocatalysis as a powerful tool has been developed broadly in organic synthesis [ 33 – 36 ]. The application and design of novel organocatalysts with high catalytic activity have greatly promoted the development of organic synthesis. We were fascinated in the asymmetric catalytic reaction of cinchona alkaloid derivatives, such as primary amine, secondary amine, and tertiary amine catalysts. Since 2001, the first paper about the amine has catalyzed unsymmetric addition reaction of nitroalkenes with ketones [ 37 ], significant progress has been made on the both stereoselectivity and substrate range using secondary amine [ 38 – 40 ] and primary [ 41 – 46 ] amine chiral catalysts. This type of catalysts activated the substrates through the generation of the imine ions and reduced the LUMO Energy of the imine ions. Then primary amines have shown to be effective catalysts for activating carbonyl compounds. At present, as a typical primary amine catalyst, 9-epi-amino cinchona alkaloid derivatives have been used efficaciously in Michael addition reactions to obtain precious chiral adducts [ 47 – 50 ]. More recently, cinchona alkaloid-derived primary amine catalysts for the enamine-catalyzed addition reaction of aldehydes or ketones to nitroolefins was introduced by McCooey et al [ 51 ], they have proven experimentally that 9-epi-DHQDA is a highly efficient catalyst for the Michael addition of 2-methylpropionaldehyde to nitrostyrene, and the reaction required benzoic acid as co-catalyst, which obtained the adducts in 93% yield and 88% enantiomeric excess (ee). On the basis of experiment, a similar catalyst 9-amino-9-deoxyepiquinine (9-epi-QDA) was selected to catalyze the Michael addition of 2-methylpropionaldehyde with nitrostyrene, 9-epi-QDA is more attractive due to its ease of extraction from quinidine (Scheme 1 ) [ 52 ]. Importantly, 9-epi-QDA, which contains C-9 amino and a quinuclidine, is an organic catalyst that has two functions, activating both the nucleophile and electrophile. Moreover, the yield of products and the rate of reaction could be affected by even slight modification of the organocatalysts in the experimental protocols. It inspired us to create novel and effective catalysts based on 9-epi-QDA’s structure in the title reaction. In order to understand how the charge distribution of the tertiary amine affects the system's catalytic efficiency, a thorough analysis of quinuclidine's structure is necessary. In 1963, synthesizing 1,2-diazabicyclo [2.2.2] octanes and their substituted derivatives was undertaken (Scheme 2 ). Carabateas [ 53 ] reported that Z = CH 2 is the most stable molecular structure. Using the structure as a basis, we investigated a new category of catalysts, 9-epi-QDA-R'', by altering R groups of 9-epi-QDA (Scheme 4). We chose NH, CH 2 , and NCONHC 6 H 5 groups as substitutes for representative R'' to make comparison easier. We made an effort to create a highly efficient chiral bifunctional catalyst called 9-epi-QDA-R'', which can be made up of primary amides that originate from cinchona alkaloid. In addition, we examined how the tertiary amine influences reactivity. (Scheme 3 ). Computational details In this system, density functional theory (DFT) is used to optimize all catalysts, reactants, transition states, intermediates, and products at B3LYP/6-31G(d,p) level. The structures are shown in Figs. 1 – 5 and S1–S10. The nature of stationary points was characterized through frequency calculations at B3LYP/6-31G (d,p) level (minimum energy or first-order saddle points are available), which provided thermodynamic quantities such as zero-point energy (ZPE) correction. To verify the energy profiles, the intrinsic reaction coordinate (IRC) [ 54 , 55 ] path was also traced to connect each transition state to correct associated local minimum. Meanwhile, bonding characters and the electronic properties of the system was shown at the same level through NBO [ 56 , 57 ] analysis. The solvent effects have been taken into account when considering all relevant stationary points on the potential energy surfaces (PES). Toluene solvent’s polarizable continuum model (PCM) [ 58 , 59 ] was used to calculate the solvent effects. Optimized structures for B3LYP /6-31G(d) were used to conduct single point calculations at the PCM (toluene) /B3LYP/6-311 + + G (2df,2p) level for accurate energy calculations. The Gaussian 09 software package [ 60 ] was used to compute the DFT (B3LYP). Energy comparison data for each energy level are listed in the Tab. S1-S3 and Fig. S1 –S10 in the Electronic Supplementary Material. Results and discussion The findings demonstrate that the charge distribution of the tertiary amines is directly affects the charge distribution of the R'' substituents (R''=CH 2 , NH, and NCONHPh) of the catalysts. NBO charge analysis is utilized to study the charge distribution of these catalysts, 9-epi-QDA-R''. In order to determine the atomic charges, B3LYP/6-31G(d,p) level is used. The tertiary amine N of quinuclidine is a significant active site, according to the NBO charge analysis for N 2 atom. These catalysts are referred to as 9-epi-QDA-CH 2 , 9-epi-QDA-NH, and 9-epi-QDA-Ns, in that order for convenience. Michael addition reaction A comprehensive investigation of the reaction between 2-methylpropionaldehyde (R1) and nitrostyrene (R2) is carried out in order to determine the mechanism of the catalyzed Michael addition. The computer results indicate that there's four primary steps that make up the entire process. Figures 1 to 5 show the optimal geometries and potential response mechanisms with the geometric characteristics of the respective stationary points produced for each transformation process. In Figs. 1 , S1, and S6, the potential energy profile of the generation of imine ion intermediate has a single point energy of complex COMs set at 0.00 kcal mol − 1 as a reference. In the potential energy profiles of the addition phase, the energy of intermediate 1-IM5s (2-IM5s) is set at 0.00 kcal mol − 1 in Figs. 2 , S2, S7 (Figs. 3 , S3, S8). For the hydrolysis phase, the energy of compound 1-IM9s (2-IM9s) is set at 0.00 kcal mol − 1 in Figs. 4 , S4, S9 (Figs. 5 , S5, S10). The following is an illustration of the computed findings in detail. (a) the production of an imine ion intermediate Relying on the calculations, it can be inferred that the acidic supplement benzoic acid activates the tertiary N atom of 9-epi-QDA-CH 2 (9-epi-QDA-NH, 9-epi-QDA-Ns) and generates the protonated catalyst Cat (Cat-nh, Cat-Ns). This pathway starts with the production of the complex COM (COM-nh, COM-Ns), in which R1 interacts with the protonated catalyst through a weakened NH … O hydrogen bond of 0.191 (0.217, 0.227) nm, located 6.2 (7.1, 2.4) kcal mol − 1 lesser in energy than the reactants Cat + R1 (Cat-nh + R1, Cat-Ns + R1). The protonated catalyst is created when the tertiary N atom of the catalyst is activated by the acidic additive benzoic acid. This is seen in Fig. 1 (Fig. S1 , Fig. S6). Next, the intermediate IM1 (IM1-nh, IM1-Ns) is produced concurrently with the formation of the C 1 –N 1 bond and the hydrogen transfer from N 2 to O 1 atom via transition state TS (TS-nh, TS-Ns). It was estimated that the energy barrier would be 15.8 (14.0, 11.1) kcal mol − 1 . The C 1 –N 1 distance for IM1 (IM1-nh, IM1-Ns) is 0.152 (0.152, 0.158) nm, and the matching Wiberg bond index is 0.73 (0.73, 0.70), suggesting the formation of a C 1 –N 1 bond. Next, an extremely low energy barrier of 4.8 (5.9, 8.4) kcal mol-1 causes hydrogen to move from N 1 to N 2 atoms, giving rise to IM2 (IM2-nh, IM2-Ns) via transition state TS1 (TS1-nh, TS1-Ns). A potential energy curve was generated by scanning the distance of the H 2 –N 2 bond in IM1 (IM1-nh, IM1-Ns) in order to identify the transition state TS1 (TS1-nh, TS1-Ns). After that, the potential surface's highest point's structure was optimized, allowing for the generation of the transition state TS1 (TS1-nh, TS1-Ns) at only one imaginary frequency (1041, 1094, and 1110i cm − 1 ). The transition state TS1 (TS1-nh, TS1-Ns), according to IRC calculations as continuations, corresponds to the typical assault mode of H 2 to N 2 . Then, by simultaneously breaking the N 2 –H 2 and C 1 –O 1 bonds via transition state TS2 (TS2-nh, TS2-Ns), one water molecule is released to generate the imine ion intermediate IM3 (IM3-nh, IM3-Ns); the imaginary frequency is 249 (267, 179)i cm − 1 . The energy barrier for this process is 9.5 (8.4, 8.0) kcal mol − 1 . In order to generate the imine ion intermediate IM4 (IM4-nh, IM4-Ns), the water molecule must lastly be extracted from the imine ion intermediate IM3 (IM3-nh, IM3-Ns). The procedure showed that the production of the first imine ion intermediate is significantly influenced by the acidic component. (b) an addition reaction between the imine ion and nitrostyrene The C-C addition process, which begins with the intermediates IM4 (IM4-nh, IM4-Ns), includes two steps: the formation of a carbon-carbon bond and a proton move from the tertiary carbon of IM4s to the tertiary amine N atom of the catalyst. Scheme 4 shows how the intermediate IM5 (IM5-nh, IM5-Ns) forms when the tertiary amine N atom of the imine ion intermediate IM4 (IM4-nh, IM4-Ns) abstracts the hydrogen atom from the tertiary carbon atom C 3 . This gives C 3 a stronger nucleophilic ability than that of IM4 (IM4-nh, IM4-Ns), which encourages C–C bond coupling. The outcome of calculations indicate that the transition state TS3 (TS3-nh, TS3-Ns), with an energy barrier of 15.7 (15.6, 19.2) kcal mol − 1 , is the mechanism by which IM4 (IM4-nh, IM4-Ns) transforms into IM5 (IM5, IM5-Ns). IM5 (IM5-nh, IM5-Ns) and R2 then interact by an NH…O hydrogen bond. While R2 and IM5 (IM5-nh, IM5-Ns) interact to generate the additive products, there are two different paths, designated as pathways 1, 2, which differ in how the reactants approach each other (see 1-IM5, 1-IM5-nh, 1-IM5-Ns in Figs. 2 , S 2 , S7 and 2 -IM5, 2-IM5-nh, 2-IM5-Ns in Figs. 3 , S3, S8). The β-hydrogen atom of R2 in 1-IM5 (1-IM5-nh, 1-IM5-Ns) points in the direction of the chiral scaffold (C 1 atom for chiral center), but in 2-IM5 (2-IM5-nh, 2-IM5-Ns), the β-hydrogen atom of R2 points in the opposite direction. While the protonated amine attacks the O 2 of R2 in 1-IM5 (1-IM5-nh, 1-IM5-Ns), it attacks the O 3 of R2 in 2-IM5. The configurations of the intermediates and transition states (TSs) involved in both of these pathways have been identified, and Figs. 2 – 3 (Figs. S2-S3, Figs. S7-S8) provide the predicted energy profiles for the two paths. Through a weak NH…O hydrogen bond of 0.201 (0.195, 0.255) nm, R2 reacts with the imine ion intermediate IM5 (IM5-nh, IM5-Ns) in path 1 to generate the molecular complex 1-IM5 (1-IM5-nh, 1-IM5-Ns). It is calculated that the energy of the resulting intermediate 1-IM5 (1-IM5-nh, 1-IM5-Ns) is 15.6 (16.5, 9.5) kcal mol − 1 less than those of the reactants IM5 (IM5-nh + R2, IM5-Ns + R2). After the formation of the resulting intermediate 1-IM5 (1-IM5-nh, 1-IM5-Ns), R2 and the imine ion intermediate are added nucleophilically to generate an intermediate 1-IM6 (1-IM6-nh, 1-IM6-Ns). This step is carried out through the transition state of 1-TS3 (1-TS3-nh, 1-TS3-Ns), with a barrier of 24.3 (21.1, 26.1) kcal mol − 1 . One-TS3's distinct imaginary frequency (1-TS3-nh, 1-TS3-Ns) matches the typical way that C 4 attacks C 3 . In 1-TS3 (1-TS3-nh, 1-TS3-Ns), the distance between C 3 and C 4 is 0.206 (0.208, 0.207) nm, and the Wiberg bond index is 0.37 (0.36, 0.37), indicating the formation of C 4 –C 3 bond. In 1-IM6 (1-IM6-nh, 1-IM6-Ns), the bond distance of the C 4 –C 3 is 0.159 (0.159, 0.159) nm, and the Wiberg bond index is 0.93 (0.93, 0.93), showing the formation of the C 4 –C 3 bond. Considering that the reaction lacks any significant steric interactions, the processes of pathways 1 and 2 is similar. Additionally, On pathway 1, the C–C bond-formation phase yields a common intermediate known as 1-IM6 (1-IM6-nh, 1-IM6-Ns), whereas on pathway 2, the C–C bond-formation process yields a common intermediate known as 2-IM6 (2-IM6-nh, 2-IM6-Ns). When looking at transition states from an energy perspective, the energies of 2-TS3 (2-TS3-nh, 2-TS3-Ns) are greater than those of 1-TS3 (1-TS3-nh, 1-TS3-Ns). As a result, pathway 1 is more advantageous than pathway 2. The transition state of this step with the lowest energy, which was predicted to be 1-TS3 by comparing the potential energy surfaces of pathways 1 and 2, and the stability of 1-TS3 is 2.8 (4.8, 0.5) kcal mol − 1 higher than that of the competing transition state 2-TS3 (2-TS3-nh, 2-TS3-Ns). (c) the second proton transfer stage Pathway 1 is further examined for the second proton transfer from 1-IM6 (1-IM6-nh, 1-IM6-Ns). The transition state 1-TS4 (1-TS4-nh, 1-TS4-Ns) is necessary for producing 1-IM7 (1-IM7-nh, 1-IM7-Ns) by transferring proton from the tertiary amine N 1 to nitrogen carbon C 2 . This process requires overcoming the energy barrier of 18.9 (15.3, 16.0) kcal mol − 1 . In 1-TS4 (1-TS4-nh, 1-TS4-Ns), the distances between H 4 and N 1 , and H 4 and C 2 are 0.121 (0.122, 0.121) and 0.151 (0.147, 0.148) nm, in turn, corresponding wiberg bond index is 0.38 (0.39, 0.39) and 0.47 (0.48, 0.48). From 1-TS4 (1-TS4-nh, 1-TS4-Ns) to 1-IM7 (1-IM7-nh, 1-IM7-Ns), C2's NBO charge went up from − 0.33e (-0.33e, -0.34e) to -0.29e (-0.29e, -0.30), while N1's went down from − 0.50e (-0.50e, -0.51e) to -0.53e (-0.53e, -0.52e). The normal mode of transferring H 4 from N 1 to C 2 is indicated by the negative charge on C 2 transfers to N1. Then, the intermediate 1-IM8 (1-IM8-nh, 1-IM8-Ns) is formed after proton transfer from N2 to N1 via 1-TS5 (1-TS5-nh, 1-IM5-Ns) at an energy barrier of 11.2 (9.9, 8.2) kcal mol − 1 . Pathway 2 takes into account the second proton transfer from 2-IM6 (2-IM6-nh, 2-IM6-Ns). Pathway 2 is similar to pathway 1 in that it follows a two-step proton migration process. By passing through 2-TS4 (2-TS4-nh, 2-TS4-Ns), 2-IM6 (2-IM6-nh, 2-IM6-Ns) can be transformed into 2-IM7 (2-IM7-nh, 2-IM7-Ns). This process requires overcoming the high barrier of 19.6 (17.7, 20.7) kcal mol − 1 . Afterwards, the intermediate 2-IM8 (2-IM8-nh, 2-IM8-Ns) is formed by protons being transferred from N 2 to N 1 through 2-TS5 (2-TS5-nh, 2-TS5-Ns) with an energy barrier of 8.5 (9.2, 6.6) kcal mol − 1 . (d) hydrolysis and regeneration stage of the catalyst Hydrogen transfer and C = O bond formation involves one water molecule during the hydrolysis process, just like in the process of forming imine ion intermediates. Figures 4 , 5 , S4, S5, S9, S10 display two possible pathways, marked as pathways 1 and 2. The interaction between the complex 1-IM8 (1-IM8-nh, 1-IM8-Ns) and a water molecule takes place along pathway 1, through weak hydrogen bonds of 0.180 (0.179, 0.196) nm, creating intermediate 1-IM9 (1-IM9-nh, 1-IM9-Ns) during the pathway 1. Compared with the reactant H 2 O + 1-IM8 (H 2 O + 1-IM8-nh, H 2 O + 1-IM8-Ns), so this process is exothermic. Transition state 1-TS6 (TS6-nh, 1-TS6-Ns) results in formation of intermediate 1-IM10 (1-IM10-nh, 1-IM10-Ns), and the transfer of hydrogen from the O 4 atom to the N 2 atom takes place during this transition state. The calculated results indicate that the bond lengths of N 2 –H 5 demonstrate the formation of a bond between N 2 and H 5 . The energy barrier of 8.4 (9.9, 16.1) kcal mol − 1 have been overcome during this process. In 1-IM10 (1-IM10-nh, 1-IM10-Ns), the C 1 –O 4 distance is 0.148 (0.148, 0.148) nm, indicating the formation of a C–O bond. The next step is to consider proton migration. The proton can be transported from N 2 to N 1 through transition state 1-TS7 (1-TS7-nh, 1-TS7-Ns) to generate intermediate 1-IM11 (1-IM11-nh, 1-IM11-Ns). This process require overcoming the energy barrier of 10.2 (9.5, 9.5) kcal mol − 1 . Next, the product is formed by breaking the C-N bond through transition state 1-TS8 (1-TS8-nh, 1-TS8-Ns), which results in the single bond cleavage of H 6 -O 4 and the formation of C = O double bonds, and leads to the creation of products and reduction of catalysts. The energy barrier of 2.5 (4.0, 6.6) kcal mol − 1 have been overcome in the process. It is evident that the hydrolysis step is characterized by the most significant barrier 1-TS6 (1-TS6-nh, 1-TS6-Ns) throughout the entire hydrolysis process, and it is the energy bottleneck during the hydrolysis stage. Pathway 2 and pathway 1 share some similarities during the hydrolysis process. Figures 4 , 5 , S4, S5, S9, and S10 demonstrate that pathway 2 has higher relative energies than pathway 1. In the hydrolysis step of pathway 2, however, the most difficult barrier (2-TS6, 2-TS6-nh, 2-TS6-Ns) is required, with a higher barrier value of only 5.0 (2.4, 8.2) kcal mol − 1 than that of 1-TS6 (1-TS6-nh, 1-TS6-Ns). Furthermore, the energy profiles of the hydrolysis steps exhibit exothermic processes, whereas the reaction's addition steps exhibit endothermic processes. These can be considered fast processes compared with the first two stages of the overall Michael reaction. When compared to the first two steps of the whole Michael addition reaction, these processes can be described as speedy. Comparison of the catalytic activity of three catalysts in toluene solvent The pathway begins with the generation of the composite COMs (COM, COM-nh, COM-Ns), in which R1 interacts with the protonated catalysts. By calculating that this process is exothermic compared to the energy of (R1 + Cat, R1 + Cat-nh, R1 + Cat-Ns), it can be inferred that the generation process of composite COMs is energetically advantageous. For the molecular complexes COMs, the distances between O 1 and H 1 are 0.191, 0.217, and 0.227 nm (Figs. 1 , S1, S6), lying 6.2, 7.1, and 2.4 kcal mol − 1 lower energy than reactants (Cats + R1), respectively. That is to say, the stability of these COMs complexes follows the order of COM-Ns < COM < COM-nh, which is caused by the gradually enhancement of the hydrogen bond interaction between R1 and the protonated catalysts. The formation of the C 1 -N 1 bond happens at the same time as the transfer of hydrogen from N 2 to O 1 atom through transition states TSs (TS, TS-nh, and TS-Ns), and this stage is the rate-limiting step in the forming process of an imine ion intermediate. The energy barriers were predicted to be 15.8, 14.0, 11.1 kcal mol − 1 , indicating that the order of catalysts 9-epi-QDA-R'' involved in the formation of C 1 –N 1 bond is 9-epi-QDA-Ns > 9-epi-QDA-nh > 9-epi-QDA. Despite this, this is not the stage that determines the rate for the entire reaction. In order to test whether the catalysts 9-epi-QDA-R'' shows high reactivity in all the process of the headline reaction, the reactants R1, R2, and imine ion intermediate IM4s (IM4, IM4-nh, IM4-Ns) were analyzed using frontier molecular orbital (FMO) methods [ 61 , 62 ]. The C 2 and C 4 atoms tend to have the highest occupied molecular orbital (HOMO) of R2, and the major C 3 atom has the lowest unoccupied molecular orbital (LUMO) in IM4s (Fig. 6 ). The inductive effect leads to C 4 having a higher electrophilic ability than C 2 and favoring attacking C 3 , because the C 2 atom is connected to the electron-withdrawing nitrogen group. Figure 7 shows the LUMO and HOMO energy levels R1, R2 and imine ion intermediate IM4s. The HOMO of R1 has a difference of 4.25 eV in energy. With the generation of imine ion intermediate IM4s (IM4, IM4-nh, IM4-Ns), The energy difference between R2's HOMO and IM4s' LUMO has been lowered to 1.76, 1.57, and 1.89 eV, respectively. In other words, 9-epi-QDA-R'' significantly reduces HOMO-LUMO energy difference remarkably, indicating that catalytic ability of catalysts 9-epi-QDA-R'' in the addition between R2 and the imine ion step follows the order of 9-epi-QDA-NH > 9-epi-QDA-CH 2 > 9-epi-QDA-Ns. In the subsequent step, the imine ion is nucleophilically added to R2 to form intermediates 1-IM6 and 2-IM6 (1-IM6-nh, 2-IM6-nh, 1-IM6-Ns, 2-IM6-Ns). The lengths (N 1 -C 1 ) between catalyst and R1 in 1-IM5, 2-IM5 (1-IM5-nh, 2-IM5-nh, 1-IM5-Ns, 2-IM5-Ns) are stretched from 0.142 to 0.144 nm 0.139 to 0.142 nm and 0.139 to 0.142 nm, 0.141 to 0.143 nm, respectively, as illustrated in Figs. 2 , 3 , S2, S3, S7, and S8. The distances that exist (H 3 -O 2 /O 3 ) between catalysts and R2 in 1-IM5, 2-IM5 (1-IM5-nh, 2-IM5-nh, 1-IM5-Ns, 2-IM5-Ns) are reduced from 0.201 to 0.172 nm, 0.199 to 0.172 nm (0.195 to 0.177 nm, 0.197 to 0.170 nm, and 0.255 to 0.187 nm, 0.202 to 0.194 nm), respectively, because of the transfer of charge from R1 to R2 and charge decentralization on the C-C bond. The hydrogen-bonding connection between catalyst and R1 decreases, whereas the connection between catalyst and R2 increases.The wavelengths (C 3 -C 4 ) between R1 and R2 in 1-IM6, 2-IM6 (1-IM6-nh, 2-IM6-nh, 1-IM6-Ns, 2-IM6-Ns) are 0.159 nm and 0.161 nm (0.159 nm, 0.160 nm, 0.159 nm, and 0.160 nm), respectively. Studies show that this phase is expected to be the rate-determining step of the overall reaction, and the barrier to energy for C-C bond formation lowers in the following order: R''= NCONHPh > CH 2 > NH. Furthermore, the computed HOMO-LUMO gaps between IM4, 1-IM4-nh, IM4-Ns and R2 are 1.66, 1.57 and 1.89 eV, respectively (Fig. 7 ). All of the aforementioned show that the catalytic capacity of catalysts 9-epi-QDA-R'' engaged in the C-C bond-making phase follows the order 9-epi-QDA-NH > 9-epi-QDA-CH2 > 9-epi-QDA-Ns. The second proton transfer is taken into account after the C-C bond generation. The second proton migration from the nucleophile (N 1 ) of catalysts to the carbon (C 2 ) of the reactant is via the transition states 1-TS4, 2-TS4, (1-TS4-nh, 2-TS4-nh, 1-TS4-Ns, and 2-TS4-Ns), respectively. This step’s energy barrier is not the rate-determining phase in the whole reaction because it has a slightly lower energy barrier than the C-C bond formation. According to the NBO charge distributions, the atomic charge of tertiary amine N in 9-epi-QDA-R'' was − 0.358e, -0.373e, and − 0.451e, if R'' was displaced by -NH, -NH, and -CH 2 , respectively. That is to say, the electron-withdrawing ability of these substituents follows the order of -NCONHPh>-NH>-CH 2 . R''= -NH > NCONHPh > -CH 2 is the order of decreasing the energy barrier for the proton transfer step (the energy difference between 1-IM6s and 1-TS4s, 2-IM6s and 2-TS4s) according to calculations. The reason for this is the fact that the substituents -NCONHPh and -NH of the quinuclidine enhance the acidity of the N-H in the protonated amine, which promotes the transfer of H 4 into C 2 of adduct, whereas the acidity of the protonated amine is significantly decreased by the -CH 2 electron-donating group. From the information above, it can be inferred that the catalytic efficiency of the system is influenced by the charge distribution of tertiary amine nitrogen, and the catalytic activity of 9-epi-QDA-NH is better than that of 9-epi-QDA-NCONHPh/QD-CH 2 in toluene solvent. Finally, the formation of an imine ion intermediate is similar to the hydrolysis process in that one water molecule is involved in both hydrogen transfer and bond formation. The hydrolysis steps have exothermic energy profiles, unlike the reaction's addition steps.The first two stages of the Michael reaction are slower than these processes, which can be considered fast processes. Conclusion The novel organic catalysts are generated from cinchona alkaloid-based primary amines (9-epi-QDA) by altering the substituent R'' (R''=CH 2 , NH, and NCONHPh), showed high catalytic activity when nitrostyrene was added to 2-methylpropionaldehyde in toluene solvent. Our study is motivated by the desire to enhance the catalytic efficiency of primary amines based on cinchona alkaloids and gives a theoretical framework for analyzing their catalytic activity. The DFT calculations investigated the mechanism of adding nitrostyrene to 2-methylpropionaldehyde by catalyzing the new catalysts 9-epi-QDA-R, which involved the addition of nitrostyrene to 2-methylpropionaldehyde. According to calculations, four intermediate processes are involved in the overall reaction:(1) the first phase is the generation of an imine ion intermediate, and the generation of the imine ion intermediate is influenced by the proton from acidic additives, as we have learned. (2) In the second stage, the imine ion and nitrostyrene are added together to form an addition reaction, and it was found that the rate-determining step. (3) The third stage consists of the second transfer of protons from the amine group to the β-carbon of nitrostyrene and the third transfer of protons between two N atoms. (4) The catalyst is finally hydrolyzed and regenerated in the final step. It has come to our attention that the catalyst efficiency can be further enhanced by substituents on quinuclidine, because they have a significant effect on the charge division of the tertiary amine N atom. Taking into account the energy profile of the Michael addition that is catalyzed by 9-epi-QDA-CH 2 , 9-epi-QDA-NH, and 9-epi-QDA-NCONHPh, our conclusion is that the electronic nature of substituent groups R'' on the quinuclidine has a slight impact on the tertiary amine N atom, resulting in a marked impact on the reaction's reactivity. The relevant calculations also found that 9-epi-QDA-R'' with -NH electron-withdrawing substituent was more active than the -CH 2 electron-donating substituent, while the system is more sensitive to the 9-epi-QDA-R'' with an electron-withdrawing -NCONHPh substituent than the one with an electron-donating -CH 2 substituent. In additions, we can infer from the NBO charge analysis of the tertiary amine nitrogen, it can be inferred that the negative charge on tertiary amine nitrogen atoms is slightly reduced by electron-withdrawing substituents, thus the addition reaction between the imine ion and nitrostyrene can be facilitated by this property. However, the negative charge on tertiary amine nitrogen is much reduced by the electron-absorbing substituents, which is not conducive to the addition of the imine ion with nitrostyrene. As a result, the calculation indicates that the catalytic efficiency of the system is influenced by the charge distribution of tertiary amine nitrogen, and the 9-epi-QDA-NH is the most effective catalyst among the three studied ones. In conclusion, the reactions listed above were carried out by the novel 9-epi-QDA- R'' catalysts, which clearly showed the impressive potential of primary amine organic catalysts based on cinchona alkaloid. Synthesizing and utilizing these catalysts are expected. Declarations Conflict of interest the authors declare no competing interests. Funding This work is supported by the foundation of Liaoning Education Department (Grants No. LJ2019JL027). Acknowledgments The authors thank the Shanxi Institute of Technology for its supports. Data availability This article and its supplementary information files include all data generated or analyzed during this study. Author Contribution Haiyang Jiang wrote the manuscript text and prepared all of the figures. References J. Liu, K. Engholm-Keller, M. M. Poojary, M. Bevilacqua, M. L. Andersen, and M. N. Lund, Food chemistry. 434, 137473 (2024). V. Cascales, H. Carneros, A. Castro-Alvarez, A. M. Costa, and J. Vilarrasa, Organic letters. 23, 651 (2021). P. Čmelová, D. Vargová, and R. Šebesta, The Journal of organic chemistry. 86, 581 (2021). M. Yoshida, Chemical record. 23 , e202200276 (2023). M. Yamamoto, S. Hayashi, K. Isa, and M. 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Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Jr Montgomery, T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 09 , revision A.1 , Gaussian Inc, Wallingford (2009). R. C. Allen, Journal of Modern Physics. 12 , 1162 (2021). R. Hoffmann, Reviews of Modern Physics. 60 , 601 (1988). Schemes Schemes 1 and 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files supportinginformation.doc scheme1.tif Scheme 1 The reaction of nitrostyrene with 2-methylpropionaldehyde catalyzed by 9-epi-QDA as organic catalyst and benzoic acid as co-catalyst scheme2.tif Scheme 2 Modes of 1,2-diazabicyclo [2.2.2] octanes, as well as some substituted derivatives scheme3.tif Scheme 3 Modes of catalysts 9-epi-QDA-R'' based on cinchona alkaloid-based primary amines Scheme4.tif Scheme 4 Mechanism for a proton transfer from the tertiary carbon of IM4s to the tertiary amine N atom of the catalyst. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4414411","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304603763,"identity":"cdfcd444-01a2-4ccb-891f-d1232cc35990","order_by":0,"name":"Jiang Haiyang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYBACxmYQ0cDAA+Z9qLCRY2NvP0C8FsYZZ9KM+XjOJBBhVQOEZuZtO5w4T8LBAK9q5nbmZw+/7rCTMTh+9vBroJb0NgmGBIYfFdvwOIzN3Fj2TDKPwZm8NMs559Jz26QbDzD2nLmNzy9m0pJtzDwGB3LMDN6UWee2yRxIYGZsw6eF/RtQSz2Pwfk3ZgY8bMzpbBIJBgS08JhJfmw7zGNwI8f4IU+bcwIxWsqkGduO80jeeGMGCmTDNmAgH8TnF8P+49skf7ZV2/OdzzH+AIxKefn29oMPflTg0dIADGhQPCocYGCTgIkewKkeCORBjvsBYjQwMH/Ap3IUjIJRMApGLgAA8rRagSFIQncAAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Haiyang","suffix":""}],"badges":[],"createdAt":"2024-05-13 16:10:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4414411/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4414411/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57008415,"identity":"03e9c979-99cc-48de-b11c-054d6c1bafc2","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":205234,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy profile for the formation of imine ion intermediate (IM4). Some hydrogen atoms not involved in reaction sites are omitted. Distances are in Å. Values of △G are given in parentheses.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/29489fa65fac2389b1317e7b.png"},{"id":57008885,"identity":"3216a5c3-eee4-40d1-b0a8-791f460f4504","added_by":"auto","created_at":"2024-05-23 10:45:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":158425,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy profile for the addition process along path 1 between imine ion intermediate (IM4) and nitrostyrene and the proton migration step along pathway 1. Some hydrogen atoms not involved in reaction sites are omitted. Distances are in Å. Values of △G are given in parentheses.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/89398578641571f8592d0edb.png"},{"id":57008422,"identity":"a3a69eaf-606f-4a50-99f2-0445904144a5","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160554,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy profile for the addition process along path 2 between imine ionintermediate (IM4) and nitrostyrene and the proton migration step along pathway 2. Some hydrogen atoms not involved in reaction sites are omitted. Distances are in Å. Values of △G are given in parentheses.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/400d4cef32b406db1d1a3957.png"},{"id":57008419,"identity":"99b5a838-2141-4d44-941c-9e39b337c533","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":233920,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy profile for the product is generated along the hydrolysis step along Path 1. Some hydrogen atoms not involved in reaction sites are omitted. Distances are in Å. Values of △G are given in parentheses.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/d101d76106a0dfa9add62a8e.png"},{"id":57008421,"identity":"7001cc5d-0265-4786-a94e-da6bde962b82","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":223125,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy profile for the product is generated along the hydrolysis step along Path 2. Some hydrogen atoms not involved in reaction sites are omitted. Distances are in Å. Values of △G are given in parentheses.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/9605d88234d28d85fd85f24d.png"},{"id":57008423,"identity":"7426b6be-36ec-4854-bb02-b156cc95796a","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":79432,"visible":true,"origin":"","legend":"\u003cp\u003eThe HOMO of R2 and the LUMO of imine ion intermediate.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/4620b35d98c8e513a7319d2c.png"},{"id":57008424,"identity":"05b31b3d-737c-4c57-85d4-0d0fa60a35d1","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":42204,"visible":true,"origin":"","legend":"\u003cp\u003eEnergy levels of the HOMOs and LUMOs for 2-methylpropionaldehyde (R1), nitrostyrene (R2), and imine ion intermediate (IM4s). Energy levels are in eV.\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/13731625a2baa1b093cf984d.png"},{"id":57582788,"identity":"50d5c91d-6799-47be-af3f-f2097c4e7398","added_by":"auto","created_at":"2024-06-03 02:01:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1252895,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/a323a6e0-1384-4c96-9949-35c287095782.pdf"},{"id":57008417,"identity":"50929887-bb5d-4de9-950b-066930144006","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2245120,"visible":true,"origin":"","legend":"","description":"","filename":"supportinginformation.doc","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/fc44c602965ffc88d81c42fe.doc"},{"id":57008886,"identity":"a355e06f-c255-4ad4-b6bd-a6e7ea989782","added_by":"auto","created_at":"2024-05-23 10:45:43","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":45956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003e The reaction of nitrostyrene with 2-methylpropionaldehyde catalyzed by 9-epi-QDA as organic catalyst and benzoic acid as co-catalyst\u003c/p\u003e","description":"","filename":"scheme1.tif","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/40b777acf00dc48882f51245.tif"},{"id":57008420,"identity":"420c550a-add7-4363-9aea-76cb6e13fa16","added_by":"auto","created_at":"2024-05-23 10:37:43","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":68242,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2 \u003c/strong\u003eModes of 1,2-diazabicyclo [2.2.2] octanes, as well as some substituted derivatives\u003c/p\u003e","description":"","filename":"scheme2.tif","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/a53c7068258f87202bcb5afe.tif"},{"id":57008425,"identity":"4ed91264-fd5a-4591-9922-6a09ef879c68","added_by":"auto","created_at":"2024-05-23 10:37:44","extension":"tif","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":73478,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3 \u003c/strong\u003eModes of catalysts 9-epi-QDA-R'' based on cinchona alkaloid-based primary amines\u003c/p\u003e","description":"","filename":"scheme3.tif","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/10781e7f4a27dd83b7e1e287.tif"},{"id":57008426,"identity":"ff3a981f-8994-4034-9de8-991821c795d0","added_by":"auto","created_at":"2024-05-23 10:37:44","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":82108,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 4\u003c/strong\u003e Mechanism for a proton transfer from the tertiary carbon of IM4s to the tertiary amine N atom of the catalyst.\u003c/p\u003e","description":"","filename":"Scheme4.tif","url":"https://assets-eu.researchsquare.com/files/rs-4414411/v1/527e59491f29aea621285149.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of the regulation of quinine in Cinchona Base derived primary amine on the addition reaction of nitrostyrene with 2-methylpropionaldehyde","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMichael addition is known to be an efficient method for generating carbon-carbon bonds in organic synthesis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], and relevant studies are important for the development of precious organic compounds. Organocatalytic Michael addition of carbon-centered nucleophiles with nitroalkenes is one of the most attractive methods for obtaining versatile products, due to the high-reactivity of nitroolefins and the multifunctionality of the nitro [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Nucleophilic reagents such as malonates [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], diketones [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], ketoesters [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], nitroalkanes [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and enolizable carbonyl compounds [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] have been widely used to generate useful chiral adducts. Among the different nucleophilic reagents, 2-methylpropionaldehyde is a typical enolized carbonyl compounds. In this paper, we mainly studied the Michael addition of 2-methylpropionaldehyde and nitroalkene.\u003c/p\u003e \u003cp\u003eIn recent years, asymmetric organocatalysis as a powerful tool has been developed broadly in organic synthesis [\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The application and design of novel organocatalysts with high catalytic activity have greatly promoted the development of organic synthesis. We were fascinated in the asymmetric catalytic reaction of cinchona alkaloid derivatives, such as primary amine, secondary amine, and tertiary amine catalysts. Since 2001, the first paper about the amine has catalyzed unsymmetric addition reaction of nitroalkenes with ketones [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], significant progress has been made on the both stereoselectivity and substrate range using secondary amine [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and primary [\u003cspan additionalcitationids=\"CR42 CR43 CR44 CR45\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] amine chiral catalysts. This type of catalysts activated the substrates through the generation of the imine ions and reduced the LUMO Energy of the imine ions. Then primary amines have shown to be effective catalysts for activating carbonyl compounds. At present, as a typical primary amine catalyst, 9-epi-amino cinchona alkaloid derivatives have been used efficaciously in Michael addition reactions to obtain precious chiral adducts [\u003cspan additionalcitationids=\"CR48 CR49\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. More recently, cinchona alkaloid-derived primary amine catalysts for the enamine-catalyzed addition reaction of aldehydes or ketones to nitroolefins was introduced by McCooey et al [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e], they have proven experimentally that 9-epi-DHQDA is a highly efficient catalyst for the Michael addition of 2-methylpropionaldehyde to nitrostyrene, and the reaction required benzoic acid as co-catalyst, which obtained the adducts in 93% yield and 88% enantiomeric excess (ee). On the basis of experiment, a similar catalyst 9-amino-9-deoxyepiquinine (9-epi-QDA) was selected to catalyze the Michael addition of 2-methylpropionaldehyde with nitrostyrene, 9-epi-QDA is more attractive due to its ease of extraction from quinidine (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImportantly, 9-epi-QDA, which contains C-9 amino and a quinuclidine, is an organic catalyst that has two functions, activating both the nucleophile and electrophile. Moreover, the yield of products and the rate of reaction could be affected by even slight modification of the organocatalysts in the experimental protocols. It inspired us to create novel and effective catalysts based on 9-epi-QDA\u0026rsquo;s structure in the title reaction. In order to understand how the charge distribution of the tertiary amine affects the system's catalytic efficiency, a thorough analysis of quinuclidine's structure is necessary. In 1963, synthesizing 1,2-diazabicyclo [2.2.2] octanes and their substituted derivatives was undertaken (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Carabateas [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e] reported that Z\u0026thinsp;=\u0026thinsp;CH\u003csub\u003e2\u003c/sub\u003e is the most stable molecular structure. Using the structure as a basis, we investigated a new category of catalysts, 9-epi-QDA-R'', by altering R groups of 9-epi-QDA (Scheme 4). We chose NH, CH\u003csub\u003e2\u003c/sub\u003e, and NCONHC\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e5\u003c/sub\u003e groups as substitutes for representative R'' to make comparison easier. We made an effort to create a highly efficient chiral bifunctional catalyst called 9-epi-QDA-R'', which can be made up of primary amides that originate from cinchona alkaloid. In addition, we examined how the tertiary amine influences reactivity. (Scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e "},{"header":"Computational details","content":"\u003cp\u003eIn this system, density functional theory (DFT) is used to optimize all catalysts, reactants, transition states, intermediates, and products at B3LYP/6-31G(d,p) level. The structures are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and S1\u0026ndash;S10. The nature of stationary points was characterized through frequency calculations at B3LYP/6-31G (d,p) level (minimum energy or first-order saddle points are available), which provided thermodynamic quantities such as zero-point energy (ZPE) correction. To verify the energy profiles, the intrinsic reaction coordinate (IRC) [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] path was also traced to connect each transition state to correct associated local minimum. Meanwhile, bonding characters and the electronic properties of the system was shown at the same level through NBO [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] analysis.\u003c/p\u003e \u003cp\u003eThe solvent effects have been taken into account when considering all relevant stationary points on the potential energy surfaces (PES). Toluene solvent\u0026rsquo;s polarizable continuum model (PCM) [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] was used to calculate the solvent effects. Optimized structures for B3LYP /6-31G(d) were used to conduct single point calculations at the PCM (toluene) /B3LYP/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G (2df,2p) level for accurate energy calculations. The Gaussian 09 software package [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] was used to compute the DFT (B3LYP). Energy comparison data for each energy level are listed in the Tab. S1-S3 and Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u0026ndash;S10 in the Electronic Supplementary Material.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eThe findings demonstrate that the charge distribution of the tertiary amines is directly affects the charge distribution of the R'' substituents (R''=CH\u003csub\u003e2\u003c/sub\u003e, NH, and NCONHPh) of the catalysts. NBO charge analysis is utilized to study the charge distribution of these catalysts, 9-epi-QDA-R''. In order to determine the atomic charges, B3LYP/6-31G(d,p) level is used. The tertiary amine N of quinuclidine is a significant active site, according to the NBO charge analysis for N\u003csub\u003e2\u003c/sub\u003e atom. These catalysts are referred to as 9-epi-QDA-CH\u003csub\u003e2\u003c/sub\u003e, 9-epi-QDA-NH, and 9-epi-QDA-Ns, in that order for convenience.\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eMichael addition reaction\u003c/h2\u003e\n\u003cp\u003eA comprehensive investigation of the reaction between 2-methylpropionaldehyde (R1) and nitrostyrene (R2) is carried out in order to determine the mechanism of the catalyzed Michael addition. The computer results indicate that there's four primary steps that make up the entire process. Figures\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e to \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e show the optimal geometries and potential response mechanisms with the geometric characteristics of the respective stationary points produced for each transformation process. In Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, S1, and S6, the potential energy profile of the generation of imine ion intermediate has a single point energy of complex COMs set at 0.00 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e as a reference. In the potential energy profiles of the addition phase, the energy of intermediate 1-IM5s (2-IM5s) is set at 0.00 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, S2, S7 (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, S3, S8). For the hydrolysis phase, the energy of compound 1-IM9s (2-IM9s) is set at 0.00 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, S4, S9 (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, S5, S10). The following is an illustration of the computed findings in detail.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e(a) the production of an imine ion intermediate\u003c/h2\u003e\n\u003cp\u003eRelying on the calculations, it can be inferred that the acidic supplement benzoic acid activates the tertiary N atom of 9-epi-QDA-CH\u003csub\u003e2\u003c/sub\u003e (9-epi-QDA-NH, 9-epi-QDA-Ns) and generates the protonated catalyst Cat (Cat-nh, Cat-Ns). This pathway starts with the production of the complex COM (COM-nh, COM-Ns), in which R1 interacts with the protonated catalyst through a weakened NH\u003csup\u003e\u0026hellip;\u003c/sup\u003eO hydrogen bond of 0.191 (0.217, 0.227) nm, located 6.2 (7.1, 2.4) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e lesser in energy than the reactants Cat\u0026thinsp;+\u0026thinsp;R1 (Cat-nh\u0026thinsp;+\u0026thinsp;R1, Cat-Ns\u0026thinsp;+\u0026thinsp;R1). The protonated catalyst is created when the tertiary N atom of the catalyst is activated by the acidic additive benzoic acid. This is seen in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e (Fig. \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e, Fig. S6). Next, the intermediate IM1 (IM1-nh, IM1-Ns) is produced concurrently with the formation of the C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;N\u003csub\u003e1\u003c/sub\u003e bond and the hydrogen transfer from N\u003csub\u003e2\u003c/sub\u003e to O\u003csub\u003e1\u003c/sub\u003e atom via transition state TS (TS-nh, TS-Ns). It was estimated that the energy barrier would be 15.8 (14.0, 11.1) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;N\u003csub\u003e1\u003c/sub\u003e distance for IM1 (IM1-nh, IM1-Ns) is 0.152 (0.152, 0.158) nm, and the matching Wiberg bond index is 0.73 (0.73, 0.70), suggesting the formation of a C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;N\u003csub\u003e1\u003c/sub\u003e bond. Next, an extremely low energy barrier of 4.8 (5.9, 8.4) kcal mol-1 causes hydrogen to move from N\u003csub\u003e1\u003c/sub\u003e to N\u003csub\u003e2\u003c/sub\u003e atoms, giving rise to IM2 (IM2-nh, IM2-Ns) via transition state TS1 (TS1-nh, TS1-Ns). A potential energy curve was generated by scanning the distance of the H\u003csub\u003e2\u003c/sub\u003e\u0026ndash;N\u003csub\u003e2\u003c/sub\u003e bond in IM1 (IM1-nh, IM1-Ns) in order to identify the transition state TS1 (TS1-nh, TS1-Ns). After that, the potential surface's highest point's structure was optimized, allowing for the generation of the transition state TS1 (TS1-nh, TS1-Ns) at only one imaginary frequency (1041, 1094, and 1110i cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e). The transition state TS1 (TS1-nh, TS1-Ns), according to IRC calculations as continuations, corresponds to the typical assault mode of H\u003csub\u003e2\u003c/sub\u003e to N\u003csub\u003e2\u003c/sub\u003e. Then, by simultaneously breaking the N\u003csub\u003e2\u003c/sub\u003e\u0026ndash;H\u003csub\u003e2\u003c/sub\u003e and C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;O\u003csub\u003e1\u003c/sub\u003e bonds via transition state TS2 (TS2-nh, TS2-Ns), one water molecule is released to generate the imine ion intermediate IM3 (IM3-nh, IM3-Ns); the imaginary frequency is 249 (267, 179)i cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. The energy barrier for this process is 9.5 (8.4, 8.0) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. In order to generate the imine ion intermediate IM4 (IM4-nh, IM4-Ns), the water molecule must lastly be extracted from the imine ion intermediate IM3 (IM3-nh, IM3-Ns). The procedure showed that the production of the first imine ion intermediate is significantly influenced by the acidic component.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003e(b) an addition reaction between the imine ion and nitrostyrene\u003c/h2\u003e\n\u003cp\u003eThe C-C addition process, which begins with the intermediates IM4 (IM4-nh, IM4-Ns), includes two steps: the formation of a carbon-carbon bond and a proton move from the tertiary carbon of IM4s to the tertiary amine N atom of the catalyst.\u003c/p\u003e\n\u003cp\u003eScheme 4 shows how the intermediate IM5 (IM5-nh, IM5-Ns) forms when the tertiary amine N atom of the imine ion intermediate IM4 (IM4-nh, IM4-Ns) abstracts the hydrogen atom from the tertiary carbon atom C\u003csub\u003e3\u003c/sub\u003e. This gives C\u003csub\u003e3\u003c/sub\u003e a stronger nucleophilic ability than that of IM4 (IM4-nh, IM4-Ns), which encourages C\u0026ndash;C bond coupling. The outcome of calculations indicate that the transition state TS3 (TS3-nh, TS3-Ns), with an energy barrier of 15.7 (15.6, 19.2) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, is the mechanism by which IM4 (IM4-nh, IM4-Ns) transforms into IM5 (IM5, IM5-Ns).\u003c/p\u003e\n\u003cp\u003eIM5 (IM5-nh, IM5-Ns) and R2 then interact by an NH\u0026hellip;O hydrogen bond. While R2 and IM5 (IM5-nh, IM5-Ns) interact to generate the additive products, there are two different paths, designated as pathways 1, 2, which differ in how the reactants approach each other (see 1-IM5, 1-IM5-nh, 1-IM5-Ns in Figs.\u0026nbsp;\u0026lt;link rid=\"fig2\"\u0026gt;\u003cspan class=\"InternalRef\"\u003e2\u0026lt;/link\u0026gt;\u003c/span\u003e, S\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, S7 and \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e-IM5, 2-IM5-nh, 2-IM5-Ns in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, S3, S8). The \u0026beta;-hydrogen atom of R2 in 1-IM5 (1-IM5-nh, 1-IM5-Ns) points in the direction of the chiral scaffold (C\u003csub\u003e1\u003c/sub\u003e atom for chiral center), but in 2-IM5 (2-IM5-nh, 2-IM5-Ns), the \u0026beta;-hydrogen atom of R2 points in the opposite direction. While the protonated amine attacks the O\u003csub\u003e2\u003c/sub\u003e of R2 in 1-IM5 (1-IM5-nh, 1-IM5-Ns), it attacks the O\u003csub\u003e3\u003c/sub\u003e of R2 in 2-IM5. The configurations of the intermediates and transition states (TSs) involved in both of these pathways have been identified, and Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e (Figs. S2-S3, Figs. S7-S8) provide the predicted energy profiles for the two paths.\u003c/p\u003e\n\u003cp\u003eThrough a weak NH\u0026hellip;O hydrogen bond of 0.201 (0.195, 0.255) nm, R2 reacts with the imine ion intermediate IM5 (IM5-nh, IM5-Ns) in path 1 to generate the molecular complex 1-IM5 (1-IM5-nh, 1-IM5-Ns). It is calculated that the energy of the resulting intermediate 1-IM5 (1-IM5-nh, 1-IM5-Ns) is 15.6 (16.5, 9.5) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e less than those of the reactants IM5 (IM5-nh\u0026thinsp;+\u0026thinsp;R2, IM5-Ns\u0026thinsp;+\u0026thinsp;R2). After the formation of the resulting intermediate 1-IM5 (1-IM5-nh, 1-IM5-Ns), R2 and the imine ion intermediate are added nucleophilically to generate an intermediate 1-IM6 (1-IM6-nh, 1-IM6-Ns). This step is carried out through the transition state of 1-TS3 (1-TS3-nh, 1-TS3-Ns), with a barrier of 24.3 (21.1, 26.1) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. One-TS3's distinct imaginary frequency (1-TS3-nh, 1-TS3-Ns) matches the typical way that C\u003csub\u003e4\u003c/sub\u003e attacks C\u003csub\u003e3\u003c/sub\u003e. In 1-TS3 (1-TS3-nh, 1-TS3-Ns), the distance between C\u003csub\u003e3\u003c/sub\u003e and C\u003csub\u003e4\u003c/sub\u003e is 0.206 (0.208, 0.207) nm, and the Wiberg bond index is 0.37 (0.36, 0.37), indicating the formation of C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;C\u003csub\u003e3\u003c/sub\u003e bond. In 1-IM6 (1-IM6-nh, 1-IM6-Ns), the bond distance of the C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;C\u003csub\u003e3\u003c/sub\u003e is 0.159 (0.159, 0.159) nm, and the Wiberg bond index is 0.93 (0.93, 0.93), showing the formation of the C\u003csub\u003e4\u003c/sub\u003e\u0026ndash;C\u003csub\u003e3\u003c/sub\u003e bond.\u003c/p\u003e\n\u003cp\u003eConsidering that the reaction lacks any significant steric interactions, the processes of pathways 1 and 2 is similar. Additionally, On pathway 1, the C\u0026ndash;C bond-formation phase yields a common intermediate known as 1-IM6 (1-IM6-nh, 1-IM6-Ns), whereas on pathway 2, the C\u0026ndash;C bond-formation process yields a common intermediate known as 2-IM6 (2-IM6-nh, 2-IM6-Ns). When looking at transition states from an energy perspective, the energies of 2-TS3 (2-TS3-nh, 2-TS3-Ns) are greater than those of 1-TS3 (1-TS3-nh, 1-TS3-Ns). As a result, pathway 1 is more advantageous than pathway 2. The transition state of this step with the lowest energy, which was predicted to be 1-TS3 by comparing the potential energy surfaces of pathways 1 and 2, and the stability of 1-TS3 is 2.8 (4.8, 0.5) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e higher than that of the competing transition state 2-TS3 (2-TS3-nh, 2-TS3-Ns).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e(c) the second proton transfer stage\u003c/h2\u003e\n\u003cp\u003ePathway 1 is further examined for the second proton transfer from 1-IM6 (1-IM6-nh, 1-IM6-Ns). The transition state 1-TS4 (1-TS4-nh, 1-TS4-Ns) is necessary for producing 1-IM7 (1-IM7-nh, 1-IM7-Ns) by transferring proton from the tertiary amine N\u003csub\u003e1\u003c/sub\u003e to nitrogen carbon C\u003csub\u003e2\u003c/sub\u003e. This process requires overcoming the energy barrier of 18.9 (15.3, 16.0) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. In 1-TS4 (1-TS4-nh, 1-TS4-Ns), the distances between H\u003csub\u003e4\u003c/sub\u003e and N\u003csub\u003e1\u003c/sub\u003e, and H\u003csub\u003e4\u003c/sub\u003e and C\u003csub\u003e2\u003c/sub\u003e are 0.121 (0.122, 0.121) and 0.151 (0.147, 0.148) nm, in turn, corresponding wiberg bond index is 0.38 (0.39, 0.39) and 0.47 (0.48, 0.48). From 1-TS4 (1-TS4-nh, 1-TS4-Ns) to 1-IM7 (1-IM7-nh, 1-IM7-Ns), C2's NBO charge went up from \u0026minus;\u0026thinsp;0.33e (-0.33e, -0.34e) to -0.29e (-0.29e, -0.30), while N1's went down from \u0026minus;\u0026thinsp;0.50e (-0.50e, -0.51e) to -0.53e (-0.53e, -0.52e). The normal mode of transferring H\u003csub\u003e4\u003c/sub\u003e from N\u003csub\u003e1\u003c/sub\u003e to C\u003csub\u003e2\u003c/sub\u003e is indicated by the negative charge on C\u003csub\u003e2\u003c/sub\u003e transfers to N1. Then, the intermediate 1-IM8 (1-IM8-nh, 1-IM8-Ns) is formed after proton transfer from N2 to N1 via 1-TS5 (1-TS5-nh, 1-IM5-Ns) at an energy barrier of 11.2 (9.9, 8.2) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePathway 2 takes into account the second proton transfer from 2-IM6 (2-IM6-nh, 2-IM6-Ns). Pathway 2 is similar to pathway 1 in that it follows a two-step proton migration process. By passing through 2-TS4 (2-TS4-nh, 2-TS4-Ns), 2-IM6 (2-IM6-nh, 2-IM6-Ns) can be transformed into 2-IM7 (2-IM7-nh, 2-IM7-Ns). This process requires overcoming the high barrier of 19.6 (17.7, 20.7) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Afterwards, the intermediate 2-IM8 (2-IM8-nh, 2-IM8-Ns) is formed by protons being transferred from N\u003csub\u003e2\u003c/sub\u003e to N\u003csub\u003e1\u003c/sub\u003e through 2-TS5 (2-TS5-nh, 2-TS5-Ns) with an energy barrier of 8.5 (9.2, 6.6) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e(d) hydrolysis and regeneration stage of the catalyst\u003c/h2\u003e\n\u003cp\u003eHydrogen transfer and C\u0026thinsp;=\u0026thinsp;O bond formation involves one water molecule during the hydrolysis process, just like in the process of forming imine ion intermediates. Figures\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, S4, S5, S9, S10 display two possible pathways, marked as pathways 1 and 2.\u003c/p\u003e\n\u003cp\u003eThe interaction between the complex 1-IM8 (1-IM8-nh, 1-IM8-Ns) and a water molecule takes place along pathway 1, through weak hydrogen bonds of 0.180 (0.179, 0.196) nm, creating intermediate 1-IM9 (1-IM9-nh, 1-IM9-Ns) during the pathway 1. Compared with the reactant H\u003csub\u003e2\u003c/sub\u003eO\u0026thinsp;+\u0026thinsp;1-IM8 (H\u003csub\u003e2\u003c/sub\u003eO\u0026thinsp;+\u0026thinsp;1-IM8-nh, H\u003csub\u003e2\u003c/sub\u003eO\u0026thinsp;+\u0026thinsp;1-IM8-Ns), so this process is exothermic. Transition state 1-TS6 (TS6-nh, 1-TS6-Ns) results in formation of intermediate 1-IM10 (1-IM10-nh, 1-IM10-Ns), and the transfer of hydrogen from the O\u003csub\u003e4\u003c/sub\u003e atom to the N\u003csub\u003e2\u003c/sub\u003e atom takes place during this transition state. The calculated results indicate that the bond lengths of N\u003csub\u003e2\u003c/sub\u003e\u0026ndash;H\u003csub\u003e5\u003c/sub\u003e demonstrate the formation of a bond between N\u003csub\u003e2\u003c/sub\u003e and H\u003csub\u003e5\u003c/sub\u003e. The energy barrier of 8.4 (9.9, 16.1) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e have been overcome during this process. In 1-IM10 (1-IM10-nh, 1-IM10-Ns), the C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;O\u003csub\u003e4\u003c/sub\u003e distance is 0.148 (0.148, 0.148) nm, indicating the formation of a C\u0026ndash;O bond. The next step is to consider proton migration. The proton can be transported from N\u003csub\u003e2\u003c/sub\u003e to N\u003csub\u003e1\u003c/sub\u003e through transition state 1-TS7 (1-TS7-nh, 1-TS7-Ns) to generate intermediate 1-IM11 (1-IM11-nh, 1-IM11-Ns). This process require overcoming the energy barrier of 10.2 (9.5, 9.5) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Next, the product is formed by breaking the C-N bond through transition state 1-TS8 (1-TS8-nh, 1-TS8-Ns), which results in the single bond cleavage of H\u003csub\u003e6\u003c/sub\u003e-O\u003csub\u003e4\u003c/sub\u003e and the formation of C\u0026thinsp;=\u0026thinsp;O double bonds, and leads to the creation of products and reduction of catalysts. The energy barrier of 2.5 (4.0, 6.6) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e have been overcome in the process. It is evident that the hydrolysis step is characterized by the most significant barrier 1-TS6 (1-TS6-nh, 1-TS6-Ns) throughout the entire hydrolysis process, and it is the energy bottleneck during the hydrolysis stage.\u003c/p\u003e\n\u003cp\u003ePathway 2 and pathway 1 share some similarities during the hydrolysis process. Figures\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, S4, S5, S9, and S10 demonstrate that pathway 2 has higher relative energies than pathway 1. In the hydrolysis step of pathway 2, however, the most difficult barrier (2-TS6, 2-TS6-nh, 2-TS6-Ns) is required, with a higher barrier value of only 5.0 (2.4, 8.2) kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e than that of 1-TS6 (1-TS6-nh, 1-TS6-Ns). Furthermore, the energy profiles of the hydrolysis steps exhibit exothermic processes, whereas the reaction's addition steps exhibit endothermic processes. These can be considered fast processes compared with the first two stages of the overall Michael reaction. When compared to the first two steps of the whole Michael addition reaction, these processes can be described as speedy.\u003c/p\u003e\n\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n\u003ch2\u003eComparison of the catalytic activity of three catalysts in toluene solvent\u003c/h2\u003e\n\u003cp\u003eThe pathway begins with the generation of the composite COMs (COM, COM-nh, COM-Ns), in which R1 interacts with the protonated catalysts. By calculating that this process is exothermic compared to the energy of (R1\u0026thinsp;+\u0026thinsp;Cat, R1\u0026thinsp;+\u0026thinsp;Cat-nh, R1\u0026thinsp;+\u0026thinsp;Cat-Ns), it can be inferred that the generation process of composite COMs is energetically advantageous. For the molecular complexes COMs, the distances between O\u003csub\u003e1\u003c/sub\u003e and H\u003csub\u003e1\u003c/sub\u003e are 0.191, 0.217, and 0.227 nm (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, S1, S6), lying 6.2, 7.1, and 2.4 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e lower energy than reactants (Cats\u0026thinsp;+\u0026thinsp;R1), respectively. That is to say, the stability of these COMs complexes follows the order of COM-Ns\u0026thinsp;\u0026lt;\u0026thinsp;COM\u0026thinsp;\u0026lt;\u0026thinsp;COM-nh, which is caused by the gradually enhancement of the hydrogen bond interaction between R1 and the protonated catalysts. The formation of the C\u003csub\u003e1\u003c/sub\u003e-N\u003csub\u003e1\u003c/sub\u003e bond happens at the same time as the transfer of hydrogen from N\u003csub\u003e2\u003c/sub\u003e to O\u003csub\u003e1\u003c/sub\u003e atom through transition states TSs (TS, TS-nh, and TS-Ns), and this stage is the rate-limiting step in the forming process of an imine ion intermediate. The energy barriers were predicted to be 15.8, 14.0, 11.1 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, indicating that the order of catalysts 9-epi-QDA-R'' involved in the formation of C\u003csub\u003e1\u003c/sub\u003e\u0026ndash;N\u003csub\u003e1\u003c/sub\u003e bond is 9-epi-QDA-Ns\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA-nh\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA. Despite this, this is not the stage that determines the rate for the entire reaction.\u003c/p\u003e\n\u003cp\u003eIn order to test whether the catalysts 9-epi-QDA-R'' shows high reactivity in all the process of the headline reaction, the reactants R1, R2, and imine ion intermediate IM4s (IM4, IM4-nh, IM4-Ns) were analyzed using frontier molecular orbital (FMO) methods [\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e]. The C\u003csub\u003e2\u003c/sub\u003e and C\u003csub\u003e4\u003c/sub\u003e atoms tend to have the highest occupied molecular orbital (HOMO) of R2, and the major C\u003csub\u003e3\u003c/sub\u003e atom has the lowest unoccupied molecular orbital (LUMO) in IM4s (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). The inductive effect leads to C\u003csub\u003e4\u003c/sub\u003e having a higher electrophilic ability than C\u003csub\u003e2\u003c/sub\u003e and favoring attacking C\u003csub\u003e3\u003c/sub\u003e, because the C\u003csub\u003e2\u003c/sub\u003e atom is connected to the electron-withdrawing nitrogen group. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e shows the LUMO and HOMO energy levels R1, R2 and imine ion intermediate IM4s. The HOMO of R1 has a difference of 4.25 eV in energy. With the generation of imine ion intermediate IM4s (IM4, IM4-nh, IM4-Ns), The energy difference between R2's HOMO and IM4s' LUMO has been lowered to 1.76, 1.57, and 1.89 eV, respectively. In other words, 9-epi-QDA-R'' significantly reduces HOMO-LUMO energy difference remarkably, indicating that catalytic ability of catalysts 9-epi-QDA-R'' in the addition between R2 and the imine ion step follows the order of 9-epi-QDA-NH\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA-CH\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA-Ns.\u003c/p\u003e\n\u003cp\u003eIn the subsequent step, the imine ion is nucleophilically added to R2 to form intermediates 1-IM6 and 2-IM6 (1-IM6-nh, 2-IM6-nh, 1-IM6-Ns, 2-IM6-Ns). The lengths (N\u003csub\u003e1\u003c/sub\u003e-C\u003csub\u003e1\u003c/sub\u003e) between catalyst and R1 in 1-IM5, 2-IM5 (1-IM5-nh, 2-IM5-nh, 1-IM5-Ns, 2-IM5-Ns) are stretched from 0.142 to 0.144 nm 0.139 to 0.142 nm and 0.139 to 0.142 nm, 0.141 to 0.143 nm, respectively, as illustrated in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, S2, S3, S7, and S8. The distances that exist (H\u003csub\u003e3\u003c/sub\u003e-O\u003csub\u003e2\u003c/sub\u003e/O\u003csub\u003e3\u003c/sub\u003e) between catalysts and R2 in 1-IM5, 2-IM5 (1-IM5-nh, 2-IM5-nh, 1-IM5-Ns, 2-IM5-Ns) are reduced from 0.201 to 0.172 nm, 0.199 to 0.172 nm (0.195 to 0.177 nm, 0.197 to 0.170 nm, and 0.255 to 0.187 nm, 0.202 to 0.194 nm), respectively, because of the transfer of charge from R1 to R2 and charge decentralization on the C-C bond. The hydrogen-bonding connection between catalyst and R1 decreases, whereas the connection between catalyst and R2 increases.The wavelengths (C\u003csub\u003e3\u003c/sub\u003e-C\u003csub\u003e4\u003c/sub\u003e) between R1 and R2 in 1-IM6, 2-IM6 (1-IM6-nh, 2-IM6-nh, 1-IM6-Ns, 2-IM6-Ns) are 0.159 nm and 0.161 nm (0.159 nm, 0.160 nm, 0.159 nm, and 0.160 nm), respectively. Studies show that this phase is expected to be the rate-determining step of the overall reaction, and the barrier to energy for C-C bond formation lowers in the following order: R''= NCONHPh\u0026thinsp;\u0026gt;\u0026thinsp;CH\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;NH. Furthermore, the computed HOMO-LUMO gaps between IM4, 1-IM4-nh, IM4-Ns and R2 are 1.66, 1.57 and 1.89 eV, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e). All of the aforementioned show that the catalytic capacity of catalysts 9-epi-QDA-R'' engaged in the C-C bond-making phase follows the order 9-epi-QDA-NH\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA-CH2\u0026thinsp;\u0026gt;\u0026thinsp;9-epi-QDA-Ns.\u003c/p\u003e\n\u003cp\u003eThe second proton transfer is taken into account after the C-C bond generation. The second proton migration from the nucleophile (N\u003csub\u003e1\u003c/sub\u003e) of catalysts to the carbon (C\u003csub\u003e2\u003c/sub\u003e) of the reactant is via the transition states 1-TS4, 2-TS4, (1-TS4-nh, 2-TS4-nh, 1-TS4-Ns, and 2-TS4-Ns), respectively. This step\u0026rsquo;s energy barrier is not the rate-determining phase in the whole reaction because it has a slightly lower energy barrier than the C-C bond formation. According to the NBO charge distributions, the atomic charge of tertiary amine N in 9-epi-QDA-R'' was \u0026minus;\u0026thinsp;0.358e, -0.373e, and \u0026minus;\u0026thinsp;0.451e, if R'' was displaced by -NH, -NH, and -CH\u003csub\u003e2\u003c/sub\u003e, respectively. That is to say, the electron-withdrawing ability of these substituents follows the order of -NCONHPh\u0026gt;-NH\u0026gt;-CH\u003csub\u003e2\u003c/sub\u003e. R''= -NH\u0026thinsp;\u0026gt;\u0026thinsp;NCONHPh \u0026gt; -CH\u003csub\u003e2\u003c/sub\u003e is the order of decreasing the energy barrier for the proton transfer step (the energy difference between 1-IM6s and 1-TS4s, 2-IM6s and 2-TS4s) according to calculations.\u003c/p\u003e\n\u003cp\u003eThe reason for this is the fact that the substituents -NCONHPh and -NH of the quinuclidine enhance the acidity of the N-H in the protonated amine, which promotes the transfer of H\u003csub\u003e4\u003c/sub\u003e into C\u003csub\u003e2\u003c/sub\u003e of adduct, whereas the acidity of the protonated amine is significantly decreased by the -CH\u003csub\u003e2\u003c/sub\u003e electron-donating group. From the information above, it can be inferred that the catalytic efficiency of the system is influenced by the charge distribution of tertiary amine nitrogen, and the catalytic activity of 9-epi-QDA-NH is better than that of 9-epi-QDA-NCONHPh/QD-CH\u003csub\u003e2\u003c/sub\u003e in toluene solvent.\u003c/p\u003e\n\u003cp\u003eFinally, the formation of an imine ion intermediate is similar to the hydrolysis process in that one water molecule is involved in both hydrogen transfer and bond formation. The hydrolysis steps have exothermic energy profiles, unlike the reaction's addition steps.The first two stages of the Michael reaction are slower than these processes, which can be considered fast processes.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe novel organic catalysts are generated from cinchona alkaloid-based primary amines (9-epi-QDA) by altering the substituent R'' (R''=CH\u003csub\u003e2\u003c/sub\u003e, NH, and NCONHPh), showed high catalytic activity when nitrostyrene was added to 2-methylpropionaldehyde in toluene solvent. Our study is motivated by the desire to enhance the catalytic efficiency of primary amines based on cinchona alkaloids and gives a theoretical framework for analyzing their catalytic activity. The DFT calculations investigated the mechanism of adding nitrostyrene to 2-methylpropionaldehyde by catalyzing the new catalysts 9-epi-QDA-R, which involved the addition of nitrostyrene to 2-methylpropionaldehyde.\u003c/p\u003e \u003cp\u003eAccording to calculations, four intermediate processes are involved in the overall reaction:(1) the first phase is the generation of an imine ion intermediate, and the generation of the imine ion intermediate is influenced by the proton from acidic additives, as we have learned. (2) In the second stage, the imine ion and nitrostyrene are added together to form an addition reaction, and it was found that the rate-determining step. (3) The third stage consists of the second transfer of protons from the amine group to the β-carbon of nitrostyrene and the third transfer of protons between two N atoms. (4) The catalyst is finally hydrolyzed and regenerated in the final step.\u003c/p\u003e \u003cp\u003eIt has come to our attention that the catalyst efficiency can be further enhanced by substituents on quinuclidine, because they have a significant effect on the charge division of the tertiary amine N atom. Taking into account the energy profile of the Michael addition that is catalyzed by 9-epi-QDA-CH\u003csub\u003e2\u003c/sub\u003e, 9-epi-QDA-NH, and 9-epi-QDA-NCONHPh, our conclusion is that the electronic nature of substituent groups R'' on the quinuclidine has a slight impact on the tertiary amine N atom, resulting in a marked impact on the reaction's reactivity. The relevant calculations also found that 9-epi-QDA-R'' with -NH electron-withdrawing substituent was more active than the -CH\u003csub\u003e2\u003c/sub\u003e electron-donating substituent, while the system is more sensitive to the 9-epi-QDA-R'' with an electron-withdrawing -NCONHPh substituent than the one with an electron-donating -CH\u003csub\u003e2\u003c/sub\u003e substituent. In additions, we can infer from the NBO charge analysis of the tertiary amine nitrogen, it can be inferred that the negative charge on tertiary amine nitrogen atoms is slightly reduced by electron-withdrawing substituents, thus the addition reaction between the imine ion and nitrostyrene can be facilitated by this property. However, the negative charge on tertiary amine nitrogen is much reduced by the electron-absorbing substituents, which is not conducive to the addition of the imine ion with nitrostyrene. As a result, the calculation indicates that the catalytic efficiency of the system is influenced by the charge distribution of tertiary amine nitrogen, and the 9-epi-QDA-NH is the most effective catalyst among the three studied ones.\u003c/p\u003e \u003cp\u003eIn conclusion, the reactions listed above were carried out by the novel 9-epi-QDA- R'' catalysts, which clearly showed the impressive potential of primary amine organic catalysts based on cinchona alkaloid. Synthesizing and utilizing these catalysts are expected.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003ethe authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work is supported by the foundation of Liaoning Education Department (Grants No. LJ2019JL027).\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors thank the Shanxi Institute of Technology for its supports.\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eThis article and its supplementary information files include all data generated or analyzed during this study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eHaiyang Jiang wrote the manuscript text and prepared all of the figures.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJ. Liu, K. Engholm-Keller, M. M. Poojary, M. 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Hoffmann, Reviews of Modern Physics. \u003cstrong\u003e60\u003c/strong\u003e, 601 (1988).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Schemes ","content":"\u003cp\u003eSchemes 1 and 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Michael addition, Cinchona alkaloid-based primary amines, Natural Bond Orbital, Catalytic efficiency","lastPublishedDoi":"10.21203/rs.3.rs-4414411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4414411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Michael addition of nitrostyrene and 2-methylpropionaldehyde catalyzed via cinchona alkaloid-based primary amines (9-epi-QDA-R'') with the aid of benzoic acid have been carried out at the PCM(toluene)/B3LYP/6-311\u0026thinsp;+\u0026thinsp;+\u0026thinsp;G(2df,2p)//B3LYP/6-31G(d) level. The calculations showed that the whole reaction consisted of four consecutive steps: ⑴ the production of an imine ion intermediate, ⑵ an addition reaction between the imine ion and nitrostyrene, ⑶ the second proton transfer stage, and ⑷ hydrolysis and regeneration stage of the catalyst. The rate-determining step of the whole reaction is the addition process between the imine ion and nitrostyrene. The correlation calculations determined that 9-epi-QDA-R'' containing -NH electron-absorbing group in the quinine ring exhibit stronger activation than that containing -CH\u003csub\u003e2\u003c/sub\u003e electron-donating group, while 9-epi-QDA-R'' with -NCONHPh electron-absorbing group in the quinine ring exhibit weaker activation than that containing -CH\u003csub\u003e2\u003c/sub\u003e electron-donating group. Natural Bond Orbital analysis of atomic charges of the tertiary amine nitrogen in the quinine ring determined that the electron-absorbing group slightly reduce the negative charges on the nitrogen atom of the tertiary amine, which is favorable for the addition reaction of the imine ion to nitrostyrene. However, the negative charge on tertiary amine nitrogen is much reduced by the electron-absorbing substituents, which is not conducive to the addition reaction of nitrostyrene with the imine ion. Accordingly, the calculations exhibit that the charge distribution of the nitrogen atom of the tertiary amine influences the catalytic efficiency of the whole system.\u003c/p\u003e","manuscriptTitle":"Effect of the regulation of quinine in Cinchona Base derived primary amine on the addition reaction of nitrostyrene with 2-methylpropionaldehyde","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-23 10:37:38","doi":"10.21203/rs.3.rs-4414411/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0157a1fc-eb70-4f27-bcfd-6b5518ad57aa","owner":[],"postedDate":"May 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-03T01:53:23+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-23 10:37:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4414411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4414411","identity":"rs-4414411","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}