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Formation of Reactant Complex Structure for Initiation Reaction of Lactone Ring-Opening Polymerization by Cooperation of Multiple Cyclodextrin Masayoshi Takayanagi, Shoko Ito, Kentaro Matsumoto, and Masataka Nagaoka J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b04372 • Publication Date (Web): 04 Jul 2016 Downloaded from http://pubs.acs.org on July 6, 2016

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The Journal of Physical Chemistry

Formation of Reactant Complex Structure for Initiation Reaction of Lactone Ring-Opening Polymerization by Cooperation of Multiple Cyclodextrin

Masayoshi Takayanagi,†,‡ Shoko Ito,† Kentaro Matsumoto,† Masataka Nagaoka*,†,‡,§

†

Graduate School of Information Science, Nagoya University, Furo-cho, Chikusa-ku,

Nagoya 464-8601, Japan ‡

Core Research for Evolutional Science and Technology, Japan Science and

Technology Agency, Honmachi, Kawaguchi 332-0012, Japan §

ESICB, Kyoto University, Kyodai Katsura, Nishikyo-ku, Kyoto 615-8520, Japan

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Abstract Ring-opening polymerization of lactones initiated by cyclodextrins have been reported as a promising polymer synthetic method. To investigate the unknown molecular level mechanism of the initiation reaction, we executed molecular dynamics simulations of model systems composed of single or multiple β-cyclodextrin (β-CD) molecules in δ-valerolactone (VL) solvent and explored the reactant complex structures satisfying three conditions (VL inclusion in the β-CD cavity, hydrogen bonding, and nucleophilic attack) at the same time. As a result, we confirmed the formation of the reactant complex structure. Comparison between the single and multiple β-CD models revealed that the formation is more frequent and the distance for the nucleophilic attack is shorter in the multiple model. Therefore, we anticipate that the reaction proceeds more efficiently by the cooperation of multiple β-CDs. This finding will contribute to understanding the reaction mechanism from the atomistic point of view.

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Introduction Cyclodextrin (CD) is a type of cyclic oligosaccharide composed of glucose (GL) units1 and has attracted many researchers since its discovery in the late 19th century.2 CDs consist of 6, 7 and 8 GL units are named α-, β- and γ-CD, respectively, and each GL unit has three OH groups at the C2, C3, and C6 positions. The inside and outside of the CD cavity are hydrophobic and hydrophilic, respectively. By the hydrophobic character of the cavity, CDs form inclusion complexes as host molecules by including various guest molecules, especially hydrophobic molecules. The amphiphilic nature of CDs are utilized as solubilizing agents for water insoluble hydrophobic molecules. Simple CDs and their derivatives, whose OH groups of the GL units were substituted to introduce desired functions, are widely used by utilizing their encapsulation capabilities in various fields of applications. As a prominent application, CDs are used as reactant or catalyst, often referred to as biomimetic catalyst. Early works revealed that several reactions such as hydrolysis proceed at the OH groups of CD utilizing their inclusion capabilities.3 As a catalyst, a first report was for the acceleration of phenyl ester cleavage.4 Many researches followed these early works and a variety of reactions have been reported.5,6 In some interesting cases, the formation of a 1:2 substrate:CD complex was shown to be important for

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enhancing reactions.7,8 Harada et al. reported ring-opening polymerization of lactones initiated by CDs. In their procedure, lactone monomer liquid was added onto the CD powder without solvent and heated at 373 K to evoke the ring-opening polymerization of lactones.9–11 It should be noted that CD is insoluble in lactones.11 The polymerization proceeds at a mild condition 373 K and does not require extreme conditions of very high temperature and pressure.9 The method shows the possibility of the ideal polymerization method without metal catalysts and organic solvent, which are often expensive in cost and hazardous. If the method is realized on an industrial scale, it will contribute to promoting green chemistry. According to experimental observations by Harada et al., it was elucidated that the CDs function not only as a initiator but also as a “clamp” by threading the elongating polymer to prevent the CD cavity from being plugged by the random-coiled elongating polymer.11 This elucidation was confirmed to improve the efficiency of the lactone polymerizations by using the CD dimers, which compose two CD molecules connected by appropriate length of linkers for the catalyst and clamp functions.12 In this way, understanding the atomistic level of behavior can help to develop more efficient polymerization method.

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In this work, as a first step toward understanding the polymerization process of polyester initiated by CDs, we investigated the initiation reaction mechanism of δ-valerolactone (VL) ring-opening polymerization by β-CD with molecular simulation technique. The molecular simulation technique is widely used to understand how chemical reactions proceed at the atomistic level. This technique have been also used to investigate behaviors of CDs focusing on the host-guest interactions. For example, Ruiz-López et al. reported a atomistic mechanism of how CDs can distinguish chiral molecules by quantum mechanical/molecular mechanical (QM/MM) simulations.13,14 Lawtrakul et al. investigated the behavior of included solvent molecules and host CDs by molecular dynamics (MD) simulations.15 The transition state recognition mechanism of ester hydrolysis reaction in a β-CD was also investigated by quantum mechanical (QM) and MD calculations.16 Here we chose the polymerization process of VL initiated by β-CD because this combination exhibited an efficient polymerization result and was most thoroughly investigated by the experiments.9,10 Based on the experimental findings, we assumed that the reactant VL have to satisfy the following three conditions for the initiation reaction. First, the reactant VL must be included in the β-CD cavity. This condition comes from the experimental observation that when adamantane was added, they form

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adamantane/β-CD

inclusion

complex with

high

affinity and interfered the

polymerization reactions.10 Second, the oxygen atom of the OH group at the C2 position nucleophilically attacks the carbonyl carbon of the included VL. From the results of NMR experiments, it was confirmed that the product polyester grows on a OH group at the C2 position, indicating the nucleophilic attack on the C2 position.9 Third, the included VL forms a hydrogen bond with the OH group of the β-CD to activate the VL. The existence of the hydrogen bonds between the host β-CD and guest VL were suggested by the IR experiments of VL/β-CD inclusion complex, which showed a red shift of the C=O stretching mode of the included VL by the formation of the inclusion complex.10 In summary, in order to initiate the ring-opening reaction, we assume that the VL have to be included by the β-CD, accepts a hydrogen bond, and nucleophilically attacked by the OH groups of β-CD. We mainly use MD simulation technique as a method to clarify the initiation reaction mechanism. In MD simulation trajectories, we can observe structural dynamics and diffusion behavior under the same thermodynamic conditions of the experiments. Although MD simulations by classical force fields cannot treat chemical reactions, the process of reactant structure formation before the reaction can be analyzed. Thus we searched the reactant complex structures of the initiation reaction from MD trajectories.

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Based on the reported reaction mechanisms of the lactone ring-opening reactions, we assumed two reaction mechanisms in which the orientations of the OH group for the nucleophilic attack were different, and confirmed their validity by QM calculations using a small model system composed of a VL and two ethanol molecules. Considering these mechanisms, we performed MD calculations with two model systems composed of a single β-CD or multiple β-CDs in the VL liquid and searched the reactant complex structures to understand the reaction mechanism.

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Computational Methods Procedure of MD Simulations of β -CDs in Liquid VL All the MD simulations were executed by AMBER 1217 sander module under periodic boundary conditions in the NPT ensemble (constant pressure and temperature). Temperature and pressure were controlled by the Berendsen thermostat18 at 373 K and 1 atm according to the experimental conditions. The SHAKE method was used to constrain the hydrogen-heavy atom bond distances, and the integration time step was 1 fs. We saved snapshots every 0.5 ps. We employed GLYCAM 06h force field19 for β-CD and General AMBER Force Field (GAFF) version 1.420 for VL. We obtained the atomic charges of VL by the Merz-Singh-Kollman scheme at the B3LYP/6-31G level of DFT calculation at the optimized structure in vacuum by Gaussian 09 software21. All the images of molecular structures were drawn with VMD1.9.122 We prepared two MD simulation models: single β-CD model (model 1) and multiple β-CDs model (model 2). The computational procedure of model 1 is as follows. We allocated 164 VL and a β-CD molecules in a periodic boundary box (Figure 1a), assuming the β-CD dissolved in VL solvent. The average size of the box at equilibrium 373 K and 1 atm condition was about 30.23 Å3. First, we executed a 10 ns equilibration

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MD simulation with positional restraints on all the β-CD atoms to equilibrate the solvent VL. Second, from the final structure of the equilibration MD with different initial atomic velocities, we executed three independent production MD simulations for 100 ns without any restrains. By saving snapshots every 0.5 ps, we obtained 600,000 snapshots from the three equilibrium MD trajectories in total 300 ns.

Figure 1. MD simulation models of (a) model 1 (a single β-CD model) and (b) model 2 (multiple β-CDs model). Atoms of the β-CD and VL are drawn by spheres and lines, respectively.

Next, we explain the computational procedure of the multiple β-CDs model, model 2. We allocated 180 VL and 12 β-CD molecules in the periodic boundary box (Figure 1b), assuming the interface between solid β-CD and liquid VL. Since there is no experimental information of the alignment of β-CDs at the interface, we prepared four different initial alignment of β-CDs (Figure S1). The average size of the periodic

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boundary box at equilibrium 373 K and 1 atm condition was about 34.63 Å3. From each initial alignment, we executed MD simulations as follows. First, we executed a 2 ns equilibration MD simulation with positional restraints on the β-CD atoms to equilibrate the solvent VL. Second, we executed a production MD simulation for 50 ns without any restrains. By saving snapshots every 0.5 ps, we obtained 400,000 snapshots from the four production MD trajectories in total 200 ns.

Conditions for Reactant Complex Structure Following definitions were used for analyzing MD trajectories. Several non-hydrogen atoms of VL and GL units of β-CD were named as shown in Figure 2. For each VL, we calculated a distance from the center of mass (COM) of β-CD as the shortest distance between the COM and each VL atom. Then, we defined the included VL as that with the shortest distance from the COM of β-CD. We also defined a reactant complex structure of the initiation reaction as the VL/β-CD inclusion complex that the OC atom of the included VL is hydrogen-bonded by an OH group of the β-CD and, at the same time, the CC atom is subjected to nucleophilic attack by a different OH group at the C2 position of the β-CD. Here, we defined a hydrogen bond when an OH group and the OC atom satisfy both two conditions, the distance between the OC atom and

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hydrogen atom of OH group is shorter than 3.0 Å and the O-H･･･OC angle is wider than 150°.

Figure 2. Atom names of (a) VL and (b) β-CD GL units.

We assumed two nucleophilic attack mechanisms, nucleophilic attack 1 and 2 (hereafter denoted as Nu attack 1 and 2) (Figure 3), by the OH group of β-CD at the C2 position (O2 and H2) since our density functional theory (DFT) calculations of a model system predicted similar reaction barriers for both the mechanisms (see details in Supporting Information). For both Nu attack 1 and 2, we assumed three conditions and two of them were common. First, the O2-CC distance is shorter than 3.2 Å as the most essential condition. Second, the O2-CC-CR-OC dihedral angle Ψ (Figure S2a) (we calculate dihedral angle between -180° and 180°) is Ψ < -150° or -30° < Ψ < 30° or

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150° < Ψ to consider the overlap between π orbital of the CC atom and unshared electron pair of the O2 atom. Third, we assumed a different condition for Nu attack 1 and 2 to consider the direction of the H2 atom of the OH group relative to the OC or OE atom. In Nu attack 1, the H2-O2-CC-OE dihedral angle φ1 (Figure S2b) is between -30° and 30° to consider the attack of OE to H2. In Nu attack 2, the H2-O2-CC-OC dihedral angle φ2 (Figure S2c) is between -30° and 30° to form the hemiacetal intermediate. We arbitrarily assumed all of these structural criteria.

Figure 3. Reaction scheme for the VL ring-opening reaction initiated by CD. 12


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Results & Discussions Two Possible Reaction Pathways for VL Ring-Opening Reaction To elucidate the reaction mechanism of the VL ring-opening reaction by β-CD, we assumed two reaction pathways of Nu attack 1 and 2 (Figure 3). Nu attack 1 is based on the mechanism described by Harada et al10. In this pathway, a hydrogen atom of OH group at the C2 position of β-CD approaches to the ester OE of the VL directly. Nu attack 2 proceeds via a hemiacetal intermediate. The hemiacetal is formed by moving the proton of OH group to the OC atom of the VL. This mechanism has been shown by QM calculations of a ε-caprolactone ring-opening reaction catalyzed by sulfonic acids.23 Using a model system composed of a VL and two ethanol molecules, we calculated the reaction barriers for Nu attack 1 and 2 at M06-2X/6-31G(d,p) level of DFT calculations (see details in Supporting Information). The M06-2X functional was shown to be suitable for analyzing intermolecular interaction energies.24–26 The obtained barriers were similar (41.4 and 37.7 kcal/mol for Nu attack 1 and 2, respectively) and thus we assumed both the mechanisms for the ring-opening reaction.

Formation of VL/β β -CD Inclusion Complex We first investigated the behavior of the β-CD and VL in the MD simulations of model 1 at 373 K. Focusing on the structure of the β-CD, we found that the average

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structure of the β-CD did not change drastically from the initial structure in spite of the temperature as high as 373 K. In the initial structure, β-CDs form intramolecular hydrogen bonds between OH groups at the C2 and C3 positions of adjacent GL units. The β-CD partially formed these hydrogen bonds during the MD simulations. These hydrogen bonds should contribute to the structural stability of the β-CD in the current MD simulations. It should be noted that, focusing on the dynamics of the individual GL units, they occasionally inclined to a large extent from the initial structure. Next, we focused on the behavior of the VL/β-CD inclusion complex. The empty β-CD in the VL liquid formed the inclusion complex within a few picoseconds of the equilibration MD trajectory. During the MD calculations, there was always a VL molecule in the β-CD cavity. The residence time of the VL in the cavity is about 1 ns and the included VL exchanges with another VL from solvent. We show a typical solvation structure of a VL/β-CD inclusion complex in the VL liquid in Figure 4. In addition to the included VL, two VL molecules stay near the narrow and wide opening sides of the β-CD, respectively, and have tendency to form hydrogen bonds with OH groups at the C2, C3, and C6 positions of GL units.

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Figure 4. Typical snapshot of VL/β-CD inclusion complex. The β-CD and VLs are drawn as transparent thin lines and thick lines, respectively.

During the MD trajectories, we confirmed that the β-CD keeps the space of the cavity and the VL/β-CD inclusion complex was easily formed. It is expected that the energy barrier to form the inclusion complex is very low because the β-CD can include the VL quickly, and the included VL can exchange frequently in a few nanoseconds time scale.

Formation of Reactant Complex Structure by Isolated β -CD Now we explore the reactant complex structure. This is the main purpose of our current study. First, we analyze model 1. This model assumes the condition that a single β-CD is dissolved and isolated in the VL liquid. From the three independent 100 ns MD

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trajectories, we explored the reactant complex structure satisfying the three conditions (VL inclusion in the β-CD cavity, hydrogen bonding, and nucleophilic attack) at the same time. With regard to the nucleophilic attack, we assumed two pathways, Nu attack 1 and 2. We investigated the 600,000 snapshots saved every 0.5 picosecond during the three independent 100 ns MD simulation to find out the reactant complex structure. First, the reactant complex structures were explored by the condition of Nu attack 1. Only 7 out of the 600,000 snapshots satisfied the three conditions. This frequency indicates how often the reactant complex structure is formed and will be compared with those by different conditions later. The seven structures were classified into three depending on the location of the OH group (C2, C3, and C6 location) of β-CD which forms the hydrogen bond with the included VL. Each typical structure with which OH group of the VL forms hydrogen bond is drawn in Figure 5.

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Figure 5. Reactant VL/β-CD inclusion complex structures found by the condition of Nu attack 1 from MD simulations of model 1. The hydrogen bond (H bond) is provided by the OH group at (A) C2, (B) C3, and (C) C6 locations. Left and right figures are a top view and a side view.

Next, the reactant complex structures were explored by the condition of Nu attack 2 from the same 600,000 snapshots. Only 6 snapshots out of 600,000 satisfied the three conditions. In contrast to scheme 1, we found that the included VL forms the hydrogen 18


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bond only with the OH group at the C6 position. One of the reactant complex structures is shown in Figure 6.

Figure 6. Reactant VL/β-CD inclusion complex structure found by the condition of Nu attack 2 from MD simulations of model 1.

Formation of Reactant Complex Structure by Cooperation of Host and Adjacent CDs Next, we explored the reactant complex structures from the four independent 50 ns MD trajectories (in total 400,000 snapshots) of model 2, which contains 12 β-CD molecules in VL solvent. In this model, we investigated the possibility of a contribution not only from the host β-CD but also from other adjacent β-CDs to form the reactant complex structure. First, we explored the reactant complex by the conditions of Nu attack 1. As a result, 700 snapshots out of 400,000 satisfied the three conditions. In most of the selected structures, not only the host β-CD but also the adjacent one provides the hydrogen bond or nucleophilic attack. The reactant complex structures were classified

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into four groups. First, the included VL forms the hydrogen bond with the host β-CD and is nucleophilically attacked by the adjacent β-CD (Figure 7a). Second, in contrast, the included VL forms a hydrogen bond with the adjacent β-CD and is attacked by the host β-CD (Figure 7b). Third, the adjacent β-CD provides both the hydrogen bond and nucleophilic attack (Figure 7c). Fourth, the host β-CD provides both the hydrogen bond and nucleophilic attack (Figure 7d).

Figure 7. Sandwich-like structures of reactant VL/β-CD inclusion complex found by the condition of Nu attack 1 from MD simulations of model 2. (A) Hydrogen bond by the host β -CD and nucleophilic attack by the adjacent β-CD. (B) Hydrogen bond by the adjacent β-CD and nucleophilic 20


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attack by the host β-CD. (C) Hydrogen bond and nucleophilic attack by the adjacent β-CD. (D) Hydrogen bond and nucleophilic attack by the host β-CD.

All the four structures shown in Figure 7 form a sandwich-like structure, in other words, two β-CDs are nearly parallel and contact at the rims. Interestingly, we also found different type of reactant complex structures not forming the sandwich-like structure. We show an example in Figure 8. In this structure, the host β-CD and the adjacent β-CD are not parallel and nearly vertical.

Figure 8. Example of the reactant VL/β-CD inclusion complex not forming the sandwich-like structure.

Next, we explored the reactant complex structure by the condition of Nu attack 2. We obtained 1,118 snapshots out of 400,000. As in the case of Nu attack 1, we can

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classify them into the four groups (Figure 9).

Figure 9. Structures of reactant VL/β-CD inclusion complex found by the condition of Nu attack 2 from MD simulations of model 2. (A) Hydrogen bond by the host β-CD and nucleophilic attack by the adjacent β-CD. (B) Hydrogen bond by the adjacent β-CD and nucleophilic attack by the host β-CD. (C) Hydrogen bond and nucleophilic attack by the adjacent β-CD. (D) Hydrogen bond and nucleophilic attack by the host β -CD.

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Multiple β -CDs Form Reactant Complex Structure More Frequently Than Isolated β-CD In this section, we discuss the advantage of the existence of multiple β-CDs compared to the situation with an isolated β-CD to form the reactant complex structure in the VL solvent by comparing the results of model 1 and 2. First, we focus on the frequency of forming the reactant complex structures. In model 1, 7 and 6 snapshots out of 600,000 were found by the conditions of Nu attack 1 and 2, respectively, and the probabilities are on the order of 0.001%. In contrast, in model 2, 700 and 1,118 snapshots out of 400,000 were found by the conditions of Nu attack 1 and 2, respectively, and the probabilities are on the order of 0.1%. It should be noted that there are 12 β-CDs in model 2 and thus the probability per β-CD is on the order of 0.01% by dividing the probability 0.1% by the number of β-CDs. Therefore, the probability of reactant formation in model 2 is still one order of magnitude larger than that in model 1. The difference of probability suggests that the existence of the adjacent β-CD helps the formation of the hydrogen bond and nucleophilic attack at the same time. Second, we focus on the O2-CC distance for the nucleophilic attack. In model 1, the observed shortest distance of O2-CC was 3.02 Å in Nu attack 1 and 3.08 Å in Nu attack 2 and no structure exhibited the distance shorter than 3.0 Å. In contrast, in model 2, 158 and 208 reactant complex structures exhibited the distance for the nucleophilic attack

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shorter than 3.0 Å by the Nu attack 1 and 2, respectively. The shortest distance was much shorter than 3.0 Å: 2.68 and 2.73 Å by the Nu attack 1 and 2, respectively. From the force field parameters of the Lennard-Jones (LJ) interaction term between the O2 and CC atoms (equilibrium distance 3.629 Å and potential well depth 0.1345 kcal/mol), the distances 3.02 and 2.68 Å show 0.4 and 3.3 kcal/mol repulsive energy, respectively (Figure S5). This means that the shortest distance in model 2 is as short as the minimum distance possible in the MD simulations with the LJ type interatomic interactions. Third, in model 2, the included VL can form two hydrogen bonds at the same time with the OH groups of β-CDs. An example is shown in Figure 10. In this structure, the two hydrogen bonds are formed between the included VL and the OH groups at the C2 and C3 position of the adjacent β-CD. In model 1, no reactant complex structure was obtained with such two hydrogen bonds. Since it is expected that the hydrogen bonds lower the activation barrier by activating the carbonyl group of the VL, the formation of the two hydrogen bonds can further enhance the ring-opening reaction by significantly lowering the activation barrier.

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Figure 10. Structure of a reactant VL/β-CD inclusion complex found by the condition of Nu attack 2 from MD simulations of model 2. The Oc atom of the VL has two hydrogen bonds with the two OH groups at the C2 and C3 positions.

In this section, we have obtained the following three results in model 2: first, the higher frequency of the formation of the reactant complex, second, the shorter distance for the nucleophilic attack, and third, the formation of the double hydrogen bonds between the β-CD and the included VL. These results suggest that the VL ring-opening reaction occurs easier with the cooperation of multiple β-CDs. We anticipate that these three factors should be related to the deformation of the β-CDs to form the hydrogen bonds and nucleophilic attack. In model 1, although it was shown that the VL/β-CD inclusion complex can form the reactant complex structure by satisfying both the conditions of hydrogen bond and nucleophilic attack at the same time, the frequency was very low about 0.001%. We 25



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suppose that the low frequency originates from the necessity of the large deformation of the host β-CD to satisfy the hydrogen bond formation and nucleophilic attack at the same time. For example, in the reactant structure shown in Figure 5a, the shape of the β-CD cavity (Figure 5a left from the top view) deformed from the circular shape into the elliptical one. This deformation was supposed to be necessary because the two OH groups have to approach the included VL to form the hydrogen bond and nucleophilic attack. Moreover, the GL units deform largely to extend their OH group at the C6 position toward the inside of the cavity to form the hydrogen bond with the included VL. The most illuminating example is shown in Figure 5c that the GL unit forming the hydrogen bond is largely inclined to head its OH group at the C6 position toward the included VL. Thus, the isolated β-CD dissolved in the VL liquid needs to deform its GL units to form the reactant complex structure. It is plausible that the low frequency of forming the reactant complex structure comes from the necessity of large deformation of the β-CD, which should coincide with a large deformation energy. On the other hand, when multiple β-CDs participate in the reactant complex formation, such large deformation is not always necessary by cooperating the roles of the hydrogen bond and nucleophilic attack by the host and adjacent β-CDs. However, in some of the complex structures, it is interesting that both conditions for the hydrogen

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bond and nucleophilic attack are satisfied between the included VL and host β-CD (Figure 7d,8,9d) with the distance shorter than 3.0 Å for the nucleophilic attack. This suggests that the existence of the adjacent and surrounding β-CDs induces the conformational change of the host β-CD which is necessary for the hydrogen bond and nucleophilic attack. Generally,

catalytic

reaction

mechanisms

are

considered

in

a

single-catalyst-molecule fashion, as we have analyzed with model 1. This is valid for typical cases with low-concentration catalysts at effectively infinite dilution. However, our current target does not meet this condition because β-CD is insoluble in lactones11 and most of β-CD exist in the solid state during the polymerization process. Therefore, we can assume that the VL ring-opening reaction mainly occurs at the interface between the solid β-CD and liquid VL. This assumption makes the multiple catalyst model plausible and justifies the results with model 2. In summary, current MD simulations revealed that, compared to the isolated β-CD in the VL solvent, the reactant complex structures are formed more frequently when multiple β-CDs exist. This result indicates the cooperative effect of the multiple β-CDs for the VL ring-opening reactions, as revealed for reactions enhanced by 1:2 substrate:CD complex formation.7,8 Reported induction of β-CD self-assembly by the

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existence of guest molecules27,28 should also contribute to the formation of the reactant structure. Conclusion In this work, the molecular mechanism of the VL/β-CD reactant complex formation for the initiation reaction of the VL ring-opening polymerization was analyzed by molecular simulations. From the results of DFT calculation with a simple model system composed of VL and two ethanol molecules, we assumed two reaction pathways for the VL ring-opening reaction. In the MD calculations, the 1:1 VL/β-CD inclusion complex was easily formed. In both model 1 (single β-CD model) and model 2 (multiple β-CDs model), we confirmed that the reactant complex structure was formed by satisfying the three conditions of the VL inclusion, hydrogen bonding, and nucleophilic attack. The frequency of the reactant complex structure formation was more frequent in model 2 than in model 1. In addition, the distance for the nucleophilic attack was shorter and formation of two hydrogen bonds was observed in model 2. Therefore, we anticipate that the reaction proceeds more efficiently by the cooperation of multiple β-CDs. Here we focused only on the reactant complex formation for the initiation reaction of the VL ring-opening polymerization. As a future task, the following elongation reactions should be focused on to understand the comprehensive mechanism of the VL ring-opening polymerization. Moreover, since the model system used in the current QM 28


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calculations is very simple and MD simulation can predict only structures before reactions, we need further QM calculations with a more realistic model considering the effects of the β-CD cavity to investigate the reaction pathways and energies. We expect that the activation energy for the VL ring-opening reaction will be affected by forming the inclusion complex and, in addition, the approach direction of the OH groups to the included VL should be restricted in the inclusion complex. To take such inclusion effect into consideration, we need DFT calculations of the VL/β-CD inclusion complex to obtain the reaction pathways and reaction barriers. By using the reactant complex structures obtained in this work as the initial structure for the DFT calculations, we expect to identify which of the assumed reaction mechanisms, Nu attack 1 or 2, is the real reaction mechanism of the VL ring-opening. This work will contribute to understanding the reaction mechanism from the electronic structure point of view.

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ASSOCIATED CONTENT Supporting Information Full citation for ref 21, DFT calculation procedure and results, initial snapshots of model 2, definitions of dihedral angles Ψ, φ1, and φ2, energy profiles obtained by the DFT calculations, and LJ type interaction curve between O2 and Cc.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Phone: +81-52-789-5623 Notes The authors declare no competing financial interest.

Acknowledgement This work was partially supported by the Core Research for Evolutional Science and Technology (CREST) of the Japan Science Technology Agency (JST); by a Grant-in-Aid for Science Research from the Ministry of Education, Culture, Sport, Science and Technology (MEXT) in Japan; and by the MEXT programs “Elements Strategy Initiative to Form Core Research Center (ESICB)” and the FLAGSHIP2020

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within the priority study5 (Development of new fundamental technologies for high-efficiency energy creation, conversion/storage and use).

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Formation of Reactant Complex Structure for Initiation Reaction of

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