Multiscale Modeling Approach for the Aldol Addition Reaction in Multicompartment Micelle-Based Nanoreactor

Water has emerged as a versatile solvent for organic chemistry in recent years due to its abundance, low cost, and environmental friendliness. However, one of the most important reactions, the aldol reaction, in the presence of excess water exhibits low yields and poor enantioselectivities. In this regard, we have employed a multiscale modeling approach to investigate the aldol addition reaction catalyzed by l-proline in the hydrophobic compartment of multicompartment micelle (MCM) nanoreactor consisting of amphiphilic bottlebrush copolymer, which minimizes the water content at the reactive site. Through performing dissipative particle dynamics (DPD) simulation, it is found that the “clover-like” morphology of the MCM is formed from multiblock copolymer with a sequence of ethylene oxide-based hydrophilic blocks, styrene lipophilic blocks, l-proline catalyst blocks, and a pentafluorostyrene fluorophilic block in aqueous media. We find that the vicinity of the catalyst in the clover-like MCM has a low dielectric environment, which could facilitate the aldol addition reaction. Our DFT calculations demonstrate that the asymmetric aldol addition of l-proline-catalyzed acetone and 4-nitrobenzaldehyde is energetically more favorable under the low dielectric environment in MCM compared with other commonly used solvents such as DMSO, water, and vacuum condition.


INTRODUCTION
The aldol addition reaction, discovered originally by Kane in 1838, stands as one of the fundamental reactions in organic synthesis, wherein the formation of a carbon−carbon (C−C) bond occurs as a result of the reaction. 1,2Despite the discovery of this asymmetric reaction more than a century ago, it continues to present challenges, particularly in achieving high yields and selectivity when conducted in water as a reaction medium. 3,4Water can frequently inhibit the activity of the catalyst or alter the enantioselectivity due to its interference with critical ionic interactions and hydrogen bonds that stabilize the transition states of the reactions. 5,6Consequently, catalytic asymmetric reactions that can be performed with water are of current interest as water is a desirable solvent regarding environmental concerns, safety, and cost. 7,8Hence, special design considerations are necessary for conducting asymmetric reactions in the water phase.
−15 In particular, the presence of a segregated hydrophobic core can establish a favorable microenvironment for encapsulating the guest molecules and facilitating the selective release of incompatible hydrophobic contents. 16,17erefore, utilizing multicompartment micelles (MCMs) as a support system for catalysis seems to be an excellent promise in achieving the site isolation of catalytic moieties. 18,19ovalently attaching the catalyst to the hydrophobic blocks of the copolymer enables multicompartment micelles (MCMs) to establish a hydrophobic microenvironment, making them suitable for the desired reactions within an aqueous medium.This approach allows the effective confinement and protection of catalytic species within the MCMs, leading to enhanced catalytic performance and selectivity. 20−24 Notably, when present in minimal water quantities, L-proline (Proline) exhibits remarkable catalytic activity in promoting aldol addition reactions between ketones and aldehydes, leading to high yields and enantiomeric excesses at room temperature. 25n contrast, at high water concentrations or in the presence of water alone, an adverse effect is observed in the reactions, leading to low yields and a reduction in enantioselectivity. 11,25dditionally, water is often considered an unsuitable solvent for hydrophobic organic compounds. 26,27Therefore, conducting catalytic reactions in water requires the creation of a hydrophobic environment within an overall aqueous medium.
Recently, we established the self-assembled MCM nanoreactor consisting of poly(norbornene)-based amphiphilic bottlebrush copolymers with Proline catalyst covalently attached adjacent to lipophilic (L) styrene or fluorophilic (F) pentafluorostryene blocks in water. 20In this Prolinecatalyzed aldol addition study, surfactants and block copolymers created a hydrophobic core that guards the catalyst from an aqueous environment.This arrangement facilitates the reactivity of organic substrates within the aqueous system.−32 Among various types of micelles, we reported that "clover-like" H-L-Proline-F sequenced bottlebrush copolymers, illustrated in Figure 1a, exhibited the highest yield and selectivity due to the Proline catalyst adjacent to the L domain within the micelle.However, it should be noted that the underlying mechanism for such enhancement remains unclear as cryogenic transmission electron microscopy (cryo-TEM) images cannot provide detailed information about the local microstructures surrounding the catalyst.Compared with experimental endeavors, theoretical calculations and simulations have emerged as essential tools for unraveling the microscopic characteristics of micelles and providing detailed insights into their molecularlevel structures.
In this study, we employed a multiscale modeling approach to thoroughly understand the reaction mechanisms in the selfassembled MCM, mainly focusing on the kinetics and transition-state structures.We first performed dissipative particle dynamics (DPD) simulations to investigate the morphology of MCM and the dielectric environment around the Proline catalysts within the MCM.Then, we performed density functional theory (DFT) calculations with an implicit solvation model to calculate the transition states for the aldol addition reaction of acetone (AT) and 4-nitrobenzaldehyde (NBA).Previously, Yang et al. 16 have reported a direct aldol reaction via an enamine-mediated mechanism in dimethyl sulfoxide (DMSO), and Tafida et al. 33 have reported an asymmetric aldol reaction in acetone medium.Both studies emphasize that the aldol reaction was assisted by solvents with a reduction of energy barriers.In this study, we aim to elucidate the reaction mechanism of the aldol addition reaction of acetone (AT) and 4-nitrobenzaldehyde (NBA) in a unique environment within the self-assembled MCM, which can provide direct information about the rate-determining step for reaction kinetics.We believe this study can shed light on the design guide of MCM to advance the kinetics of the aldol addition reaction in the water phase.

DPD Simulation of Multicompartment Micelle.
To characterize the internal morphology of the MCM, we performed DPD simulations.For DPD simulation, we calculated the Flory−Huggins χ AB -parameter for molecular A−B pairs such as polymer−water, water−water, and polymer−polymer pairs, from the mixing energy ΔE AB mix by eq 1 The Journal of Physical Chemistry B In the previous study, 29,34 we developed a computational method to estimate the χ-parameter consistently and accurately using the improved mixing energy as defined by eq 2 where Z ij , V ij , n, V ref , and E ij refer to the coordination number of the molecule j around the molecule i, the volume enclosed by the Connolly surface over the combined pair of molecules i and j, the number of monomeric units, reference volume, and interaction energy between molecules i and j, respectively.Since the ΔE ij mix in eq 2 utilizes more molecular information compared with the original form of mixing energy, = * * + * , the χ-parameter values were in good agreement with the experimental values. 34o calculate molecular information for eq 2, we prepared molecular models using DFT calculation with B3LYP functional and 6-31G(d,p) basis set in Jaguar. 35The Connolly volume, interaction energy, and the coordination numbers of polymer−water, water−water, and polymer−polymer pairs were obtained using the modeling software Materials Studio 36 to calculate the mixing energy ΔE AB mix .For DPD simulation, the bead−spring model was employed, and the motions of beads are described by integrating Newton's equations of motion as follows 3737 where r⃗ i , v⃗ i , and m i denote the position, velocity, and mass of the ith particle, respectively, and f ⃗ i denotes the force acting on the ith particle.The force acting on a bead contains three parts where and F ⃗ ij R denote conservative repulsive, dissipative, and random force depending on the position and velocity of the ith particle, respectively.−30,32,34,44−46 In our DPD simulations, the simulated systems were set to have 5% polymer (H 60 -L 15 -Proline 36 -F 15 in Figure 1b) and 95% water.Although this polymer concentration is higher than that used in experiments, a high concentration is employed in our simulations to ensure more intensive polymer−polymer interactions and thereby to better accomplish the self-assembly process during DPD simulation. 12,20,28,30The cubic simulation box size was set as 30 × 30 × 30 reduced DPD length units (r c 3 ) with a grid spacing of 1.0 and a bead density of 3.0 (r c 3 / V m ) to use the linear relationship between the repulsion parameter a ij and the corresponding Flory−Huggins χ ij parameter, as derived by Groot and Warren. 41.2.DFT Modeling for Proline-Catalyzed Aldol Addition Reaction.To investigate the Proline-catalyzed aldol condensation of acetone (AT) and 4-nitrobenzaldehyde (NBA) in MCM (Figure 1c), we implemented DFT calculation through Jaguar package 35 using B3LYP functional 47 and 6-31G(d,p) basis set with Poisson−Boltzmann implicit solvation model 48−50 to consider local molecular environment in the vicinity of reaction site within the multicompartment micelle.For the Poisson−Boltzmann implicit solvation model, we employed the dielectric constant (ε) of 80.37 and 47.24 for water and DMSO with probe radius values of 1.40 and 2.41 Å, respectively.Transition states were obtained from the quadratic synchronous transit (QST) search method, 51 and the analytical frequency calculations were performed to ensure the transition states have exactly one imaginary frequency.Additionally, intramolecular reaction coordinate (IRC) analysis was performed to indicate that the resulting transition state can serve as a pathway leading from the reactants to the products.

Structural Analysis of MCM for Dielectric
Environment around Catalyst.First, we prepared the MCM-based nanoreactor consisting of H 60 -L 15 -Proline 36 -F 15 using DPD simulation.For this, we calculated Flory−Huggins χ-parameters using eqs 1 and 2. 29,34 As summarized in Table 1, we found that, among the amphiphilic blocks, pentafluorostyrene−water (F−W) pair exhibits the highest χ-parameter value (χ F−W = 0.963), followed by styrene−water (L−W) pair (χ L−W = 0.756), L-proline−water (Proline−W) pair (χ P−W = 0.459), and ethylene oxide−water (H−W) pair (χ H−W = 0.197), implying that blocks F and H are expected to be the most hydrophobic and hydrophilic, respectively.Please note that, in our coarse-grained modeling approach, we have scaled down the polymer chain H 60 -L 15 -Proline 36 -F 15 to H 12 -L 3 -Proline 7 -F 3 to improve the efficiency of DPD simulations.Additionally, we have further scaled down the number of units in each side chain by considering the reference molecular volume of the L- proline catalyst.This scaling approach allows us to achieve computational efficiency while preserving essential characteristics of the system.
The amphiphilic bottlebrush block copolymers (H 12 -L 3 -Proline 7 -F 3 ) self-assemble in water to form a multicompartment micelle with hydrophilic blocks (H) forming the outermost shell directly in contact with water molecules and hydrophobic blocks (L and F) forming the inner structures, such as the core of the micelle.Regarding molecular interactions, distinct phase separation of block H from block L in the micelle is expected since the highest χ-parameter Proline may be sandwiched between the core (L and F) and shell (H) within the micelle.We conducted DPD simulations to predict the morphologies of MCM using the χ-parameters in Table 1.We observe a distinct phase separation in the core region between blocks L and F, which is consistent with the immiscibility of blocks L and F as confirmed by the large χ L−F value (0.945).MCM yields core−shell morphology as the block L domain covers block F domains.To further quantitatively characterize the structure of MCM, we implemented the pair correlation function (ρ i g(r)) for the pairs between Proline and other blocks using the following equation g r n r r ( ) where ρ i denotes the number density of block i such as blocks H, L, and F, and r and Δr denote the distance between Proline and block i and the shell thickness, respectively.
From Figure 1d, we found that ρ L g Proline-L (r) with red color and ρ F g Proline-F (r) with green color exhibit stronger intensities than other pair correlations such as ρ W g Proline-W (r) with black color and ρ H g Proline-H (r) with blue color up to r = ∼5.5, indicating that block Proline is located in the vicinity of blocks L and F. Particularly, ρ L g Proline-L (r) exhibits slightly stronger intensity than ρ F g Proline-F (r) up to r = ∼ 4.5, which is consistent with the χ-parameters in Table 1.Please note that the ρ i g(r) information is useful to estimate the local environment around the block Proline within MCM.
Since the aldol reaction takes place at block Proline, the local environment of Proline will affect the reaction as a dielectric environment.To perform DFT calculations investigating homogeneous catalytic process, we estimated the dielectric constant of this local environment of Proline by summing up the contribution of each block linearly using eq 6 where Z Proline-i and ε i denote the coordination number and dielectric constant for block i such as L, F, H, and W, respectively.Z Proline-i is calculated by integrating the ρ i g(r) in eq 5 up to r = 3.45, where the position of the first peak in the Proline-L pair is identified as the highest among all Proline-i pairs and is then used to determine the number of beads in the first coordination sphere.Consequently, the dielectric constant (ε) estimated by eq 6 is 20.38, which is used to calculate the reaction energies and barriers in homogeneous catalysis through DFT calculation (Table 2).

DFT Modeling of Aldol Addition of Acetone and 4-Nitrobenzaldehyde in MCM.
We investigated the asymmetric aldol addition between AT and NBA using the DFT method within the MCM obtained from DPD simulation.In the previous studies, 16,33 the L-proline-catalyzed aldol reaction mechanisms have been reported to have two stages: first, L-proline catalysts react with acetone to enamine as depicted in Scheme 1; subsequently, C−C bond connection is formed upon the addition of NBA as depicted in Scheme 2.
Figure 2a−d presents the free energy profiles of the aldol reaction as a function of reaction coordinate, which displays the energy barriers of all of the elementary reaction steps under the different solvent environments, including water, DMSO, vacuum, and MCM.The energy change of the overall reaction (ΔE net_solvent ) required to convert reactants I 1 (AT and NBA) into I 9 is found to be smallest when using water as the solvent (ΔE net_water = 12.6 kcal/mol).This is followed by MCM (ΔE net_MCM = 13.4 kcal/mol) and then DMSO (ΔE net_DMSO = 13.6 kcal/mol).Although the variation in the net reaction energy across different solvent environments is not substantial, the rate of the chemical reaction is predominantly determined by the activation energies of individual elementary steps.This relationship is elucidated by the Arrhenius equation.Hence, accurately predicting the reaction rate necessitates a thorough consideration of the activation energies associated with each elementary step.
Scheme 1-TS12.The first reaction, often known as the ratedetermining step in the aldol addition reaction between AT and NBA, where acetone reacts with the L-proline catalyst, denoted as I 1 at 0.0 kcal/mol, becomes hemiaminal intermediate I 2 in Scheme 1.The asymmetric aldol reaction starts with the nucleophilic attack of the N atom in the Lproline catalyst to the C atom of the carbonyl group in AT as LUMO and HOMO are reported to be localized on the C atom of carbonyl in AT and the N atom of L-proline catalyst, respectively, and thus forming a C−N bond. 33At the same time, there is proton transfer occurring from AT to L-proline.
Herein, we consider the two proton transfer mechanisms.One, a proton is transferred between the carbonyl oxygen of acetone and the amine group of L-proline via the strained fourmembered cyclic transition state TS12 in one step as proposed by Boyd et al. 52 On the other hand, the oxygen atom of the ketone group in AT attacks the hydrogen atom of the hydroxyl group in L-proline (denoted as TS1a), resulting in the formation of a zwitterionic intermediate state I a .
The next step involves an additional intramolecular proton transfer from N + to O − (TSa2).Regardless of solvent environments, our calculation results indicate that the twostep proton transfer mechanism is energetically much more favorable for the formation of hemiaminal intermediate I 2 than the one-step proton mechanism.Under DMSO, the activation energy (E a ) of TS1a is 21.7 kcal/mol, whereas TS12 requires 54.9 kcal/mol to proceed further.This aligns with a previous report showing a lower energy barrier for TS1a (E a = 95 kJ/ mol, equivalent to 22.7 kcal/mol) compared with TS12 (E a = 179 kJ/mol, equivalent to 42.8 kcal/mol). 16Likewise, Under the MCM environment, TS12 exhibits the lowest E a among different solvent environments with E a = 54.0 kcal/mol, and TS1a has a lower E a than TS12 with 20.4 kcal/mol.The same trend is observed under the water solvent.−56 Therefore, it is essential to explicitly consider water molecules to properly address the hindrance of water in the aldol addition reaction.The presence of water molecules surrounding the AT and L-proline catalysts can significantly alter the reaction mechanism.−60 To evaluate the dual behaviors of water, we calculated the reaction kinetics in the presence of a single water molecule, as depicted in Figure 3. Unlike TS12 and TS1a, water in TS1a+H 2 O allows for proton transfer to the carbonyl oxygen of acetone, which requires E a = 41.2 kcal/mol for the reaction to proceed.Although E a for TS1a+H 2 O is higher than TS1a under the implicit water solvent, considering that the aldol addition is the least energetically favorable in the water solvent experimentally, I 2 formation via TS1a+H 2 O may be more reasonable.
Scheme 1-TS23, T34, T45, and T35.As hemiaminal intermediate completely forms in I 2 , the O−H bond of Lproline breaks to remove a water molecule to form a zwitterionic iminium ion I 3 , which is an exothermic reaction regardless of solvents, and our calculation predicts the substantially higher exothermicity in DMSO medium with ΔE 23_DMSO = −9.6 kcal/mol, followed by MCM with ΔE 23_MCM = −8.4kcal/mol, water with ΔE 23_water = −4.4kcal/mol, and vacuum with ΔE 23_vacuum = −3.9kcal/mol.Although the reaction energy ΔE 23 is the most exothermic in DMSO, its E a for TS23 is 19.4 kcal/mol, which is twice larger than E a of water (8.8 kcal/mol).This result indicates that removing water is most feasible in a water solvent.
There are two possible reaction pathways for the iminiumto-enamine transformation (reactions from I 3 to I 5 via I 4 ).One possible reaction path is the two-step mechanism in which the reaction is initiated with the attack of the O − atom to the C atom from the C−O bond to form I 4 via TS34, followed by the dissociation of the C−O bond (TS45) to form enamine I 5 .According to the free energy diagram, the transition state of the endothermic reaction I 4 to I 5 , denoted as TS45, generally exhibits higher activation barriers than TS34, indicating the C−O bond activation requires higher energy than the attack of O − to carbon in the imine group.For example, TS34 is the lowest under the MCM environment with E a = 3.0 kcal/mol, and TS45 is significantly higher with E a = 15.5 kcal/mol.
A similar trend is observed in other dielectric environments.Alternatively, as illustrated in Figure 4, the O − atom can  The Journal of Physical Chemistry B directly attack the hydrogen in the methyl group to form I 5 in a single step via TS35 as initially suggested by List and coworkers. 22We compared the energy barriers of a single-step transition state TS35 with TS45, which is the rate-determining step of the two-step iminium-to-enamine transformation.Even though the positions of TS35 and TS45 in the free energy profiles may seem similar for DMSO and MCM, the E a of TS35 is slightly smaller than the E a of TS45.For example, the E a of TS45 under the MCM environment is 15.5 kcal/mol, whereas the E a value of TS35 is 14.6 kcal/mol.
While the E a difference may appear marginal at room temperature, the single-step transformation becomes more energetically favorable, resulting in a faster reaction rate as the temperature increases, irrespective of the solvent environment.In water, however, the two-step mechanism is preferred over the single-step mechanism due to the highly exothermic nature of I 4 formation from I 3 , leading to TS45 lying lower than TS35 in the free energy diagram.To sum up, Proline-catalyzed asymmetric aldol addition of acetone to enamine is the fastest under the MCM environment as the highest activation barrier TS23 among the reaction pathways from I 1 to I 5 is the lowest compared with DMSO, water, and vacuum conditions.Scheme 2-T567, TS78, and TS89.As proposed in Scheme 2, once the enamine is formed, the C = C double bond of enamine reacts with the C atom of carbonyl in NBA to form a C−C bond, and the proton transfer from the oxygen of the aldehyde group to the oxygen of carboxylic acid as seen in the intermediate I 7 .To proceed with this reaction, the energy barrier required to overcome TS567 is the lowest under water with 19.9 kcal/mol, followed by MCM with 21.3 kcal/mol, vacuum with 27.9 kcal/mol, and DMSO with 37.4 kcal/mol.While the ΔE 567 remains exothermic under water and vacuum, it is endothermic for MCM and DMSO with ΔE 567_MCM = 2.9 kcal/mol and ΔE 567_DMSO = 0.9 kcal/mol, respectively.It is noted that the E a for TS567 under the MCM environment (E a = 21.3 kcal/mol) is marginally higher than that for TS1a (E a = 20.5 kcal/mol), indicating that TS567 is potentially the ratedetermining step.Likewise, E a for TS567 under the DMSO solvent is higher than TS1a.It can also be inferred that the reactions involving the nucleophilic attack at the carbonyl carbon group, such as TS12 and TS567, typically require a lot of energy to overcome the barrier compared with reactions involving proton transfers.
Next, reactions from intermediate state I 7 to final product I 9 include the cleavage of the C−N + bond by adding a water molecule for the hydrolysis.As depicted in TS78, the oxygen of water attacks the carbon atom of the imine complex, and at the same time, the O−H bond of water breaks apart to form the zwitterionic intermediate state I 8 .This water-assisted reaction energy, ΔE 78 , one of the most endothermic reactions, is the most sluggish in the water medium as E a for TS78 is the highest with E a = 19.2kcal/mol in the water, followed by DMSO (E a = 13.1 kcal/mol) and MCM (E a = 9.4 kcal/mol).Finally, the zwitterionic intermediate state I 8 is split into Lproline and the aldol product, I 9 , through the scission of the C−N + bond and the formation of a C�O double bond via a proton transfer from the O − atom.This exothermic reaction needs relatively small energy barriers (as small as 3.4 kcal/mol under DMSO) compared with the previous transition states.
Overall, the reaction energy for L-proline-catalyzed aldol addition of AT and NBA is calculated to be similar for water, DMSO, and MCM.However, the kinetic energy exhibits a The Journal of Physical Chemistry B significant difference based on the solvent environment, which impacts the reaction rate.Our calculation indicates that the rate-determining step in the MCM has the lowest energy barrier (21.3 kcal/mol), followed by those of DMSO (37.4 kcal/mol) and water (41.2 kcal/mol).These results suggest that the MCM nanoreactor facilitates the aldol addition reaction by providing a local hydrophobic environment that reduces the water concentration around the reactant species and catalyst, enhancing enantioselectivity.

CONCLUSIONS
The aldol addition reaction, an essential reaction in organic chemistry, has often been reported to exhibit poor yields and low enantioselectivities when excessive water is present.However, we can utilize multicompartment micelle as a nanoreactor to facilitate the aldol reaction by providing a proper local hydrophobic environment around L-proline.In this study, we investigated probable mechanisms of the aldol reaction catalyzed by L-proline of block proline within the hydrophobic core of MCM using multiscale modeling.
Amphiphilic bottlebrush copolymers were self-assembled to form an MCM with a "clover-like" morphology.The amphiphilic bottlebrush copolymer comprises an ethylene glycol-based hydrophilic block, a styrene-based lipophilic block, an L-proline-attached block, and a pentafluorostyrenebased fluorophilic block in a sequence along the chain copolymer.From the internal structure of the MCM, the effective dielectric constant was estimated by summing the dielectric constant of each component linearly, which was considered for the implicit solvent media in our DFT calculations.
Through this study, we demonstrated that the L-proline- catalyzed asymmetric aldol addition reaction of acetone and 4nitrobenzaldehyde is energetically more favorable in the micelle with the lowest energy barrier (21.3 kcal/mol) for the rate-determining step in comparison to other environments such as DMSO (37.4 kcal/mol) and vacuum (32.7 kcal/mol).In the case of the reaction in the water solvent, it is crucial to consider an explicit water molecule around acetone and the L- proline catalyst, as the reaction from I 1 to I 2 via TS1a+H 2 O becomes the rate-limiting step, with a corresponding energy barrier of 41.2 kcal/mol, the highest among other solvents.
Our finding indicates that the MCM nanoreactor facilitates the aldol addition reaction by creating a local hydrophobic environment that reduces the water concentration around the reactant species and catalyst, thus enhancing enantioselectivity.

Figure 1 .
Figure 1.(a) Colored beads used as a visual representation of chemical structures (H, L, F blocks and Proline catalyst are represented by blue, red, green, and purple colors, respectively); (b) coarse-grained model of bottlebrush copolymer; (c) DPD simulation results for MCM; (d) pair correlation function analysis for the pairs of block Proline with blocks H, L, F, and water represented by blue, red, green, and gray lines, respectively.

Scheme 1 .Figure 2 .
Scheme 1. Proposed Mechanism of the Proline-Catalyzed Asymmetric Aldol Reaction of Acetone via One-Step (Blue Box) and Two-Step (Red Box) Protonation Mechanisms

Figure 3 .
Figure 3. Reaction pathway of hemiaminal intermediate I 2 formation from I 1 under the presence of a water molecule and the corresponding reaction and kinetic energies are shown in the red bar.The blue and black bars represent one-step and two-step mechanisms, respectively.

Figure 4 .
Figure 4. Schematic illustration of a single-step transformation mechanism from iminium to enamine, I 3 to I 5 via TS35, and the free energy diagram of a single-step (yellow square) and a two-step mechanism via TS34, I 4 , and TS45 (blue bar) under DMSO, water, and MCM environments.

Table 1 .
Calculated Flory−Huggins χ-Parameters for Molecular Pairs (χ H−L = 1.462) in Table1indicates that blocks H and L are immiscible.Likewise, blocks L and F are highly prone to phase separation within the core of the micelle due to their relatively high χ L−F value of 0.945.Block Proline is less hydrophilic than block H (χ P−W > χ H−W ).At the same time, block Proline is not readily miscible with blocks L and F, indicating that block

Table 2 .
Summary of Dielectric Constant (ε) of Each Molecule (i) and the Coordination Number (Z proline−i) of Proline and i