Importance of Molecular Meshing for the Stabilization of Solvophobic

Subscriber access provided by UNIV OF DURHAM

Importance of Molecular Meshing for the Stabilization of Solvophobic Assemblies Yi-Yang Zhan, Naru Tanaka, Yuka Ozawa, Tatsuo Kojima, Takako Mashiko, Umpei Nagashima, Masanori Tachikawa, and Shuichi Hiraoka J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00495 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Importance of Molecular Meshing for the Stabilization of Solvophobic Assemblies Yi-Yang Zhan,1 Naru Tanaka,1 Yuka Ozawa,1 Tatsuo Kojima,1 Takako Mashiko,2 Umpei Nagashima,3 Masanori Tachikawa,2 and Shuichi Hiraoka1,*

1

Department of Basic Science, Graduate School of Arts and Sciences, The University of Tokyo,

3-8-1 Komaba, Meguro-ku, Tokyo, 153-8902, Japan 2

Quantum Chemistry Division, Graduate School of Science, Yokohama City University, 22-2

Seto, Kanazawa-ku, Yokohama-city, Kanagawa 236-0027, Japan 3

Foundation for Computational Science (FOCUS), 7-1-28, Minatojimaminamimachi, Chuo-ku,

Kobe, 650-0047, Japan

E-mail: [email protected]

ABSTRACT: The effect of the methyl groups in neutral gear-shaped amphiphiles (GSAs) on the stability of nanocubes was investigated using a novel C2v-symmetric GSA, which was synthesized using selective alternate trilithiation of a pentabrominated hexaphenylbenzene derivative. The lack of only one methyl group in the GSA decreased the association constant for the assembly of the nanocube by three orders of magnitude. A surface analysis recently developed

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

by the authors (SAVPR: surface analysis with varying probe radii) was carried out for characteristic isomers of the nanocube consisting of C2v-symmetric GSAs. It was found that the methyl groups near the equator of the nanocube play a significant role in the stabilization of the nanocubes.

Introduction van der Waals (vdW) forces1 are ubiquitous interaction that only occur between molecules in close vicinity. Though vdW forces are considered to be the weakest molecular interaction, their importance is recognized as the major component of the adhesive force formed between a gecko's foot and a surface.2 Recently, we have reported that thermally very stable cube-shaped assemblies, nanocubes, are self-assembled from six gear-shaped amphiphiles (GSAs) in water3 and that the contribution of vdW interactions to the extremely high thermal stability of the nanocubes is non-negligible. This was clearly demonstrated by our recent semi-quantitative analysis of molecular meshing (SAVPR: surface analysis with varying probe radii).4 Previously, we reported that six molecules of neutral GSA, 1, assemble into nanocube, 16, in CH3OH and H2O (3:1, v/v) by the solvophobic effect (Figure 1a).5 The crystal structure of 16 indicated that six GSAs of 1 tightly mesh with each other and that three 3-pyridyl groups from different GSAs stack with each other. On the other hand, when the three methyl groups in 1 are replaced with hydrogen atoms, the resulting GSA, 3, (Figure 1b) did not show any aggregation. This result indicates the importance of the vdW interactions around the methyl groups of 1 for the stability of the nanocube, which was supported by our theoretical calculations.6


Page 2 of 19

Page 3 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. (a) The formation of nanocube 16 from gear-shaped amphiphile 1. (b) Chemical structures of GSAs, 2 and 3. (c) Schematic description of a nanocube structure compared with the Earth. Red circle indicates methyl group. Cyan circle indicates 3-pyridyl ring. Purple circle and C indicate the 3-pyridyl ring placed in the middle of a triple-π stack. 1 and 2 indicate the methyl groups near the equator, which is indicated by a green broken line. 3 indicates the methyl group around the north or south poles.

Although the nanocube is a cube-shaped structure, the symmetry of the nanocube is far from that of a cube. As the nanocube has only an S6-axis and an inversion center, it belongs to S6 point group. The structure of the nanocubes can be described by analogy to the hemispheres of the Earth spinning about an axis. Along the S6-axis (axis of the Earth), the three GSAs around the



north pole (the northern hemisphere in Figure 1c) and the other three GSAs around the south pole (the southern hemisphere) have an enantiomeric relationship. Although the six GSAs in the nanocube are chemically equivalent, each 1 molecule in the nanocube is desymmetrized to be C1-symmetry (Figure 1c), which is the reason why the 1H NMR spectrum of the nanocube, 16, is much more complicated than that of monomer 1 measured in CD3OD.5 The upfield shifts of three chemically inequivalent methyl signals are indicative of the formation of the nanocube. Two of the three methyl groups in 1 (red 1 and 2 indicated in Figure 1c) are near the equator of the nanocube, while the other methyl group (red 3) is around the north or south poles (Figure 1c). Thus, it is expected that the three chemically inequivalent methyl groups contribute differently to the stability of the nanocube. A recent molecular dynamics simulation of 16 suggested that the methyl groups 1 and 2 are highly important for the stability of the nanocube and form a chain of CH-π contacts along the equator.7 In order to confirm the contribution of the methyl groups by experiment, we have designed a novel GSA, 2, that contains two methyl groups (Figure 1b). Because of the low symmetry of 2, there are 138 possible isomers (see below) for the nanocube 26. If the positioning of methyl groups around the equator of the nanocube is highly stabilizing, then this isomer would be obtained in preference to the isomers in which the methyl groups are positioned over the north or south poles. Here we report the synthesis of a novel GSA 2, the stability of the nanocube 26 determined by 1H NMR and isothermal titration calorimetry (ITC) measurements, and the effect of the number of the methyl groups on the thermodynamic parameters of the nanocubes. In addition, SAVPR was performed for several isomers of 26 to examine the role of the positions of methyl groups to the stabilization of the nanocube by molecular meshing.

Results and Discussion Structural isomers of 26 When six molecules of GSA 2 are assembled into a nanocube, a total of 138 structural isomers arising from the arrangement of 2 on the six faces of a cube should be considered. The 11


Page 4 of 19

Page 5 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


possible arrangements of three GSAs 2 on the three faces of a hemisphere (A–K) are shown in Figure 2. The isomers of the nanocube 26 are constructed from the combination of the eleven isomers of the hemisphere. The isomers of 26 can thus be classified using two alphabetic characters (Table 1). Among the isomers of the hemisphere (A–K), the ones with a C3-axis, A, D, and G, simply provide a single isomer of the nanocube by the combination with another hemisphere (A–K), while three isomers are generated for each nanocube consisting of the combination of the other eight hemispheres (B, C, E, F, H, I, J, and K) (for example, BB has three isomers). None of the methyl groups are located around the equators of isomers AA and DD, while GG lacks all the methyl groups around the north and south poles. We will later discuss characteristic isomers in terms of the molecular meshing.

Figure 2. Possible isomers of the hemisphere composed of three GSAs 2. The (a, b, c) indicates the positions of the hydrogen atoms in GSAI, GSAII, and GSAIII, respectively. The positions refer to Figure 1c.



Table 1. Possible isomers# of nanocube, 26 AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK BB*, BC*, BD, BE*, BF*, BG, BH*, BI*, BJ*, BK* CC*, CD, CE*, CF*, CG, CH*, CI*, CJ*, CK* DD, DE, DF, DG, DH, DI, DJ, DK EE*, EF*, EG, EH*, EI*, EJ*, EK* FF*, FG, FH*, FI*, FJ*, FK* GG, GH, GI, GJ, GK HH*, HI*, HJ*, HK* II*, IJ*, IK* JJ*, JK* KK* * indicates the existence of three isomers. # The number of all the possible isomers is calculated by the following equation, 30 + 36 × 3 = 138.

Synthesis of GSA 2 GSA 2 was synthesized according to Scheme 1. A C2v-symmetric hexaphenylbenzene derivative, 4, was synthesized by the selective alternate trilithiation of pentabrominated hexaphenylbenzene.8 Methoxymethyl groups were introduced by the dilithiation of 4 followed by the reaction with methoxymethyl chloride to afford 5 in 48%. The direct methylation after the lithiation of 4 with methyl iodide suffered from a contamination of a trace amount of protonated byproduct with different number of methyl groups, which prevented the purification of 6 due to their low polarity and very similar structures. Methoxymethyl groups were thus introduced as a polar equivalent of methyl groups to facilitate a chromatographic separation and to avoid the ambiguity of the number of the methyl groups in the GSA. The reductive conversion of methoxymethyl groups9 of 5 to methyl groups with lithium naphthalenide gave compound 6 in 86%. The transformation of the three TMS groups into iodide substituents by ICl and the following Suzuki-Miyaura coupling reaction with 3-pyridylboronic acid led to 2.


Page 6 of 19

Page 7 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 1. Synthetic route to GSA 2.

Figure 3. Partial 1H NMR spectra (500 MHz, aliphatic region, CD3OD and D2O (4:1, v/v)) of (a) 16 and (b) 26. Red and blue solid circles indicate the methyl signals for the monomer and the nanocube, respectively. The full 1H NMR spectra are shown in Figures S4 and S5.

Self-assembly of nanocube 26



The formation of the nanocube 26 from 2 was examined in an aqueous methanol. Upon the addition of D2O into a solution of 2 in CD3OD, a new broad signal for the methyl groups appeared in the up-field region, indicating the formation of the nanocube. The characteristic methyl signals are shown in Figure 3b (Full scale 1H NMR spectra are shown in Figures S1 and S5). Upon decreasing the temperature to 258 K, the methyl signal derived from monomer 2 disappeared and the signal at 1.1 ppm became larger, suggesting almost all the monomers were converted to the nanocube at low temperature. The formation of the nanocube was demonstrated by 1H DOSY spectroscopy (Figure S2). Compared with the diffusion coefficient of the signals for monomer 3’ (3’ indicates 3 whose three hydrogen atoms are replaced with deuterium atoms) under the same conditions (Figure S3), the signals for the nanocube (D = 1.33 × 10–10 m2 s–1) and the monomer (D = 2.05 × 10–10 m2 s–1) were assigned. The decomposition temperatures (T1/2), at which half of the nanocubes are disassembled into the monomer, were determined by the integrations of the methyl signals assigned to the nanocube and the monomer for 16 and 26 (Figures 3, S4, and S5).10 T1/2 for 26 was 15 °C, which is 20 °C lower than that of 16, indicating that the lack of six methyl groups greatly destabilized the nanocube. As discussed above, 26 has structural isomers. However, because of the very broad 1H NMR spectrum of 26, the isomers could not be distinguished. Thus, the contribution of the chemically inequivalent methyl groups on the stability of the nanocube, 26, will be discussed by SAVPR for characteristic isomers of 26 in the later section.

Thermodynamic parameters of the nanocubes The thermodynamic parameters for the self-assembly of the nanocube, 16, were previously determined by dilution ITC measurement.11 The large negative enthalpy and entropy changes (∆H293 = –213.6 kJ mol–1 and ∆S293 = –355.7 J mol–1 K–1) for the self-assembly of 16 (Table 2) indicates that the formation of 16 is mainly driven by the intermolecular interactions between the neighboring GSAs, which is consistent with the extremely stable water-soluble nanocube assembled from the structurally similar cationic GSA.3 The thermodynamic parameters for the


Page 8 of 19

Page 9 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


self-assembly of 26 in CH3OH:H2O (3:1, v/v) at 293 K were determined by dilution ITC measurements in the same way (Figure S6). The association constant of 26 is about three orders of magnitude lower than that of 16, so the replacement of one of the methyl groups of 1 significantly destabilized the resulting nanocube of 26, which indicates that the methyl groups of 16 greatly contribute to the stability of the nanocube. The energetic distributions in the enthalpy and entropy changes for 26 are much different from that for 16. The formation enthalpy of 26 (∆H = –43.6 kJ mol–1) is about one-fifth of the value of 16 (Table 1), which suggests the significant decrease in the attractive interaction (mainly vdW interactions) between the GSAs in 26 arising from the lack of the methyl groups. On the other hand, the positive entropy change associated with the assembly of 26 is consistent with a solvophobically driven process in which there is only a small entropy penalty arising from the loss of translational and rotational freedom upon the assembly of 26. Considering that the desolvation surface areas (∆SASs) for 16 and 26 are very similar (Table 2) (the ∆SASs for 16 and several isomers of 26 will be discussed later), the large difference in the entropy change between 16 and 26 must be derived from the difference in the molecular meshing. The lack of one methyl group in 2 decreased the molecular meshing in the nanocube, leading to the small enthalpy change, while the loose molecular meshing in 26 decreased the entropic penalty. This is well known as enthalpy-entropy compensation, but the difference in the stability between 16 and 26 indicates that as far as molecular meshing is concerned, the energy gain from tight molecular meshing is higher than the entropic penalty.



Page 10 of 19

Table 2. Parameters for the nanocubes

a

nanocube

T1/2 [°C]a

Ka [M–5]b

∆G293 [kJ mol–1] b

∆H293 [kJ mol–1]b

∆S293 [J mol–1 K–1]b

∆SASf [Å2]

16 AA AD DD FG GG GH 36

35

3.2 × 1019 c

–109.4 c

–213.6 c

–355.7 c

4175.80 3982.39 4002.62 4003.99 3998.17 4003.77 4001.20 3632.15

15d

4.0 × 1016 d

–93.1 d

–43.6 d

169.1 d

nde

nde

nde

nde

nde

total energy [kcal mol–1]g 897.95 895.90 896.32 887.11 888.40 888.13

T1/2 was determined in CD3OD and D2O (4:1, v/v) by variable temperature 1H NMR. bDetermined by dilution ITC

measurements in CD3OD and D2O (3:1, v/v). cPreviously reported in Ref. 10. dDetermined for a mixture of the isomers for 26 that may contain other isomers shown in Table 1. eNot determined. fDesolvation surface area (∆SAS) is the difference between the molecular surface of the six monomers and that of the nanocube. gDetermined by MM calculation.

Surface analysis of the nanocubes The molecular meshing between the GSAs in the nanocubes are evaluated by SAVPR, which is a method to visualize the degree of molecular meshing in molecular assemblies and host-guest complexes, recently developed by ourselves.4 SAVPR provides the distributions of contact surface areas with contact distance (Figure 4). A molecular assembly that has a large contact surface with short distances indicates that the components in the assembly tightly mesh with each other. SAVPR was carried out for 16, 36, and six isomers of 26. The geometries of the nanocubes used for SAVPR were energy-minimized using molecular mechanics (MM) calculations (Figure S7). ∆SAS for the nanocubes are listed in Table 2. The ∆SASs for all of the isomers of 26 lie between the corresponding values for 16 and 36, suggesting that the ∆SAS is simply dependent on the number of methyl groups in GSA. If the ∆SASs for the isomers of 26 are compared, no significant difference was found (the differences are within 22 Å2). This indicates that the solvophobic contributions, which are related to the number of solvent molecules released upon


Page 11 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


assembly, are almost the same for each other, while the association enthalpies should be related to the extent of intermolecular molecular meshing. The results of SAVPR for the nanocubes are shown in Figure 4. The SAVPR profile for GG, in which all the six methyl groups around the north and south poles in 16 are replaced with hydrogen atoms, is very similar to that of 16 (Figure 4a), indicating that the contribution of these six methyl groups to the stability of the nanocube is low. On the other hand, the SAVPR profile for AA, in which six of the 12 methyl groups near the equator in 16 are replaced with hydrogen atoms, is much different from that of 16, but is similar to that of 36 (Figure 4b), suggesting that there is less molecular meshing between the GSAs in AA than in GG. Indeed, the stability of the isomers of 26 is closely related to the degree of the molecular meshing (Table 2). Similar SAVPR profiles are obtained for the isomers, GG, FG, and GH (Figure 4c), which suggests that the stabilities of these isomers with slight difference of the position of the GSAs are similar. The same is true for the isomers, AA, AD, and DD (Figure 4d). Therefore, as the arrangement of the 12 methyl groups near the equator are perfectly retained in GG, GG would be the most stable, even though a similarly high extent of molecular meshing is also found in FG and GH (Figure 4c), in which only one methyl group on the equator is replaced with a hydrogen atom. The broad 1

H NMR spectrum of 26 is probably due to a mixture of these isomers in equilibrium.



Figure 4. SAVPR for the nanocubes. D indicates the contact distance (Å) between the surfaces and dA(D) indicates the surface area with contact with a separation of D Å. (a) SAVPR profiles for GG, 16, and 36 are shown in blue, red, and black lines, respectively. (b) SAVPR profiles for GG and AA are shown in blue and red lines, respectively. (c) SAVPR profiles for GG, FG, and GH are shown in blue, red, and black lines, respectively. (d) SAVPR profiles for AA, DD, and AD are shown in blue, red, and black lines, respectively. SAVPR were carried out for the energy-minimized structures by MM calculations.

Conclusions In conclusion, the contribution of the methyl groups on the gear-shaped amphiphiles to the stability of the nanocubes was investigated. The association constant of 26 assembled from the C2v-symmetric GSA 2 with two methyl groups on the periphery of a hexaphenylbenzene is about three orders of magnitude lower than that of 16, though the desolvation surface areas (∆SAS) for 16 and 26 are very similar to each other. This result strongly indicates that much higher thermal stability of 16 than that of 26 is due to van der Walls (vdW) interactions around methyl groups of GSAs in the nanocube. Thermodynamic parameters for the formation of the nanocubes, 16 and 26, determined by ITC measurements indicate that while 16 is enthalpically stabilized by the tight molecular meshing between the GSAs in 16, 26 is stabilized by enthalpically (∆H293 = –43.6 kJ mol–1) and entropically (–T∆S293 = –49.5 kJ mol–1). The higher stability of 16 than 26 indicates


Page 12 of 19

Page 13 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


that even though 16 is greatly entropically destabilized, the stabilization due to the molecular meshing overcomes the entropic penalty. SAVPR for the isomers of nanocube 26 indicates that the contribution of the methyl groups near the equator is key of the stability of the nanocubes. These findings suggest that even though vdW interaction is the weakest molecular interactions, complimentary molecular surfaces that tightly mesh each other in solvophobic environment cause a strong associative interaction. This concept, molecular Hozo, would widely be utilized for the formation of discrete assemblies with high thermal stability.

Experimental Section General Experimental Methods. 1H,

13

C, and other 2D NMR spectra were recorded using a

Bruker AV-500 (500 MHz) spectrometer. Chemical data are reported in parts per million (ppm, δ scale) downfield from tetramethylsilane (δ 0.00) and are referenced to proton resonance of a residual peak of NMR solvents. The data are presented as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and/or m = multiplet resonances), coupling constants in Hertz (Hz), and integration. High-resolution mass spectra (HRMS) were obtained using a Waters Xevo G2-S QTOF mass spectrometer. Dilution isothermal titration calorimetry (ITC) experiments were conducted on a Malvern MicroCal iTC200. Column chromatography was carried out with Merck Silica gel 60 (0.063–0.200 mm), unless otherwise noted. Unless otherwise noted, all solvents and reagents were obtained from commercial suppliers (TCI Co., Ltd., WAKO Pure Chemical Industries Ltd., KANTO Chemical Inc., and Sigma-Aldrich Co.) and were used as received. Compounds 1, 3,5 3’,12 and 48 were prepared according to the literature.

(2',4'-bis(4-(methoxymethyl)phenyl)-6'-phenyl-5'-(4-(trimethylsilyl)phenyl)-[1,1':3',1''-terp henyl]-4,4''-diyl)bis(trimethylsilane) (5). A freshly titrated pentane solution of t-BuLi (1.43 M, 1.56 mL, 2.23 mmol) was added to a suspension of compound 4 (0.450 g, 0.495 mmol) in anhydrous THF (9 mL) at –78 °C. The solution was stirred for 15 min at –78 °C, and then



quenched by addition of chloromethyl methyl ether (0.151 mL, 1.98 mmol). After removal of the cooling bath, the mixture was stirred for 1 h. After addition of water and CH2Cl2, the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over anhydrous MgSO4 and filtered. Then the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography (silica gel 60 0.040–0.063 mm, Et2O/AcOEt = 1/30 to 1/15) to obtain 5 (0.198 g, 48%) as a colorless solid. 5: m.p. 200–201 °C; 1H NMR (500 MHz, C6D6, 298 K): δ 7.18–7.14 (m, 8H), 7.12 (d, J = 8.0 Hz, 4H), 7.08 (d, J = 8.0 Hz, 4H), 7.07 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 4H), 6.79 (t, J = 7.5 Hz, 2H), 6.66 (t, J = 7.5 Hz, 1H), 3.91 (s, 4H), 2.93 (s, 6H), 0.02 (s, 18H), 0.01 (s, 9H); 13C NMR (126 MHz, CDCl3, 298 K): δ 141.1, 140.6, 140.5, 140.5, 140.3, 140.2, 136.6, 134.4, 131.6, 130.9, 126.6, 126.5, 125.2, 74.4, 57.0, –1.1; HRMS (ASAP) m/z: [M]+ calcd. for C55H62O2Si3 838.4058, found 838.4058.

(4'-phenyl-2',6'-di-p-tolyl-5'-(4-(trimethylsilyl)phenyl)-[1,1':3',1''-terphenyl]-4,4''-diyl)bis(tr imethylsilane) (6). A mixture of granular lithium (20.6 mg, 2.96 mmol) and naphthalene (0.455 g, 3.55 mmol) in THF (4 mL) was vigorously stirred for 4 h at room temperature to afford the black solution of lithium naphthalenide (LiNaph). The freshly prepared LiNaph solution (2.6 mL; LiNaph 1.9 mmol) was added to the suspension of compound 5 (0.198 g, 0.236 mmol) in THF (2.5 mL) at –43 °C. The solution was stirred for 40 min at –43 °C and then quenched with MeOH (1 mL). After addition of water and CH2Cl2, the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over anhydrous MgSO4 and filtered. Then the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography (AcOEt/Hex = 0:1 to 1:50) to obtain 6 (0.159 g, 86%) as a colourless solid. 6: m.p. >300 ˚C; 1H NMR (500 MHz, CDCl3, 298 K): δ 6.98 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 4H), 6.83–6.74 (m, 11H), 6.64 (d, J = 8.0 Hz, 4H), 6.61 (d, J = 8.0 Hz, 4H), 2.08 (s, 6H), 0.10 (s, 9H), 0.09 (s, 18H);

13

C NMR (126 MHz, CDCl3, 298 K): δ 141.5, 141.4, 140.9, 140.7,


Page 14 of 19

Page 15 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


140.4, 140.4, 140.3, 137.7, 136.4, 136.4, 134.3, 131.6, 131.5, 131.5, 130.9, 127.26, 126.54, 125.01, 21.1, –1.02, –1.03; HRMS (ASAP) m/z: [M]+ calcd. for C53H58Si3 778.3846, found, 778.3846.

4-iodo-3',5'-bis(4-iodophenyl)-4''-methyl-4'-phenyl-6'-(p-tolyl)-1,1':2',1''-terphenyl (7). A solution of ICl in CH2Cl2 (1.0 M, 0.61 mL, 0.61 mmol) was added to a solution of compound 6 (0.145 g, 0.186 mmol) in CH2Cl2 (2 mL) at –78 °C. After removal of the cooling bath, the mixture was stirred for 30 min and then quenched with sat.Na2SO3. After addition of water and CH2Cl2, the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the combined extracts were dried over anhydrous MgSO4 and filtered. Then the solvent was removed in vacuo to obtain 7 (0.164 g, 94%) as a colourless solid. 7: 1H NMR (500 MHz, CDCl3, 298 K) δ 7.18 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 4H), 6.92-6.86 (m, 3H), 6.76-6.71 (m, 2H), 6.70 (d, J = 7.8 Hz, 4H), 6.61 (d, J = 7.8 Hz, 4H), 6.52 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 8.5 Hz, 4H), 2.15 (s, 6H);

13

C NMR (126 MHz, CDCl3, 298 K) δ

140.5, 140.3, 140.2, 140.0, 139.7, 139.4, 136.8, 135.9, 135.3, 133.3, 131.3, 131.1, 127.9, 127.2, 125.8, 91.3, 21.3; HRMS (ASAP) m/z: [M]+ calcd. for C44H31I3 939.9560, found, 939.9561.

3,3'-(4'-phenyl-5'-(4-(pyridin-3-yl)phenyl)-2',6'-di-p-tolyl-[1,1':3',1''-terphenyl]-4,4''-diyl)di pyridine (2). A suspension of 7 (0.164 g, 0.174 mmol), 3-pyridylboronic acid (96.5 mg, 0.785 mmol), Pd2(dba)3 (8.0 mg, 8.7 µmol), PCy3·HBF4 (15.4 mg, 42 µmol), and K2CO3 (0.166 g, 0.783 mmol) in dioxane (2 mL) and water (1 mL) was degassed and heated at 100 °C for 6 h in a sealed tube. After addition of water and CH2Cl2, the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over anhydrous MgSO4 and filtered. Then the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography (Wakogel® 50NH2 AcOEt/Hex = 1/2) and recrystallized from CH3CN to obtain 2 (33 mg, 24%) as a colourless solid.



Page 16 of 19

2: m.p. >300 ˚C; 1H NMR (500 MHz, CDCl3, 298 K) δ 8.71 (dd, J = 2.3, 0.6 Hz, 1H), 8.69 (dd, J = 2.3, 0.6 Hz, 2H), 8.50–8.48 (m, 3H), 7.76–7.71 (m, 3H), 7.28–7.24 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 4H), 6.94 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 4H), 6.90–6.84 (m, 5H), 6.75 (d, J = 8.0 Hz, 4H), 6.68 (d, J = 8.0 Hz, 4H), 2.09 (s, 6H);

13

C NMR (126 MHz,

CDCl3, 298 K) δ 148.2, 148.2, 141.0, 140.9, 140.7, 140.6, 140.2, 140.0, 137.3, 136.4, 136.3, 135.0, 134.3, 134.2, 134.0, 132.3, 131.5, 131.3, 127.8, 127.0, 125.6, 125.3, 123.5, 21.2; HRMS (ASAP) m/z: [M]+ calcd. for C59H43N3 793.3457, found, 793.3459.

Supporting Information The Supporting Information (1H and

13

C NMR spectra of 2, 5, 6, and 7, 1H DOSY and variable

temperature 1H NMR spectra of the nanocube 26, ITC data, and optimized structures of isomers of the nanocube 26) is available free of charge on the ACS Publications website at http:// pubs.acs.org.

Acknowledgements We thank E. Suzuki (Nihon Waters K.K.) for mass spectrometry measurements. This research was supported by JSPS Grants-in-Aid for Scientific Research on Innovative Areas “Dynamical Ordering of Biomolecular Systems for Creation of Integrated Functions” (25102005, 25102001, and 16H00780).

References (1)

(a) Ilczyszyn, M.; Selent, M.; Ilczyszyn, M. M. Participation of Xenon Guest in Hydrogen Bond Network of β-Hydroquinone Crystal. J. Phys. Chem. A 2012, 116, 3206−3214. (b) Schneider, H. J. Binding Mechanisms in Supramolecular Complexes. Angew. Chem. Int. Ed. 2009, 48, 3924–3977. (c) Schreiner, P. R.; Chernish, L. V.; Gunchenko, P. A.; Tikhonchuk, E. Y.; Hausmann, H.; Serafin, M.; Schlecht, S.; Dahl, J. E. P.; Carlson, R. M. K.; Fokin, A. A. Overcoming Lability of Extremely Long Alkane Carbon–Carbon Bonds Through Dispersion Forces. Nature 2011, 477, 308–311. (d) Yang,


Page 17 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


L.; Adam, C.; Nichol, G. S.; Cockroft, S. L. How Much Do van der Waals Dispersion Forces Contribute to Molecular Recognition in Solution? Nat. Chem. 2013, 5, 1006–1010. (e) Hunter, C. A. van der Waals Interactions in Non-polar Liquids. Chem. Sci. 2013, 4, 834–848. (f) Van Craen, D.; Rath, W. H.; Huth, M.; Kemp, L.; Räuber, C.; Wollschläger, J. M.; Schalley, C. A.; Valkonen, A.; Rissanen, K.; Albrecht, M. Chasing Weak Forces: Hierarchically Assembled Helicates as a Probe for the Evaluation of the Energetics of Weak Interactions. J. Am. Chem. Soc. 2017, 139, 16959–16966. (g) Liptrot, D. J.; Power, P. P. London Dispersion Forces in Sterically Crowded Inorganic and Organometallic Molecules. Nat. Rev. Chem. 2017, 1, 0004. (h) Yang, L.; Brazier, J. B.; Hubbard, T. A.; Rogers, D. M.; Cockroft, S. L. Can Dispersion Forces Govern Aromatic Stacking in an Organic Solvent? Angew. Chem. Int. Ed. 2016, 55, 912–916. (i) Hwang, J.; Li, P.; Smith M. D.; Shimizu, K. D. Distance-Dependent Attractive and Repulsive Interactions of Bulky Alkyl Groups. Angew. Chem. Int. Ed. 2016, 55, 8086–8089. and references cited therein. (2) (a) Autumn, K.; Sitti, M.; Liang, Y. A.; Peattie, A. M.; Hansen, W. R.; Sponberg, S.; Kenny, T. W.; Fearing, R.; Israelachvili, J. N.; Full, R. J. Evidence for van der Waals Adhesion in Gecko Setae. Proc. Natl. Acad. Sci. 2002, 99, 12252–12256. (b) Gobbi, M.; Orgiu, E.; Samorì, P. When 2D Materials Meet Molecules: Opportunities and Challenges of Hybrid Organic/Inorganic van der Waals Heterostructures. Adv. Mater. 2018, DOI: 10.1002/adma.201706103. (c) Lalatonne, Y.; Richardi, J.; Pileni, M. P. Van der Waals Versus Dipolar Forces Controlling Mesoscopic Organizations of Magnetic Nanocrystals. Nat. Mater. 2004, 3, 121–125. (d) Fokin, A. A.; Zhuk, T. S.; Blomeyer, S.; Pérez, C.; Chernish, L. V.; Pashenko, A. E.; Antony, J.; Vishnevskiy, Y. V.; Berger, R. J. F.; Grimme, S.; Logemann, C.; Schnell, M.; Mitzel, N. W.; Schreiner, P. R. Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers. J. Am. Chem. Soc. 2017, 139, 16696–16707. (e) Koenig, S. P.; Boddeti, N. G.; Dunn, M. L.; Bunch, J. S. Ultrastrong Adhesion of Graphene Membranes. Nat. Nanotechnol. 2011, 6, 543–546. (f) Atwood, J. L.; Barbour, L. J.; Jerga, A. Storage of Methane and Freon by Interstitial van der Waals Confinement. Science 2002, 296, 2367–2369. (3) (a) Zhan, Y.-Y.; Ogata, K.; Kojima, T.; Koide, T.; Ishii, K.; Mashiko, T.; Tachikawa, M.; Uchiyama, S.;



Page 18 of 19

Hiraoka, S. Hyperthermostable Cube-shaped Assembly in Water. Communications Chemistry 2018, 1, 14. (b) Hiraoka, S.; Nakamura, T.; Shiro, M.; Shionoya, M. In-water Truly Monodisperse Aggregation of Gear-Shaped Amphiphiles Based on Hydrophobic Surface Engineering. J. Am. Chem. Soc. 2010, 132, 13223–13225. (4) Tanaka, N.; Zhan, Y.-Y.; Ozawa, Y.; Kojima, T.; Koide, T.; Mashiko, T.; Nagashima, U.; Tachikawa, M.; Hiraoka, S. Semi-quantitative Evaluation of Molecular Meshing by Surface Analysis with Varying Probe Radii. Chem. Commun. 2018, 54, 3335–3338. . (5) Hiraoka, S.; Harano, K.; Shiro, M.; Shionoya, M. A Self-Assembled Organic Capsule Formed from the Union of Six Hexagram-Shaped Amphiphile Molecules. J. Am. Chem. Soc. 2008, 130, 14368– 14369. (6) Koseki, J.; Kita, Y.; Hiraoka, S.; Nagashima, U.; Tachikawa, M. Role of CH-π Interaction Energy in Self-Assembled Gear-Shaped Amphiphile Molecules:

Correlated

ab

initio Molecular Orbital

and Density Functional Theory Study. Theor. Chem. Acc. 2011, 130, 1055–1059. (7) Mashiko, T.; Hiraoka, S.; Nagashima, U.; Tachikawa, M. Theoretical Study on Substituent and Solvent Effects for Nanocubes Formed with Gear-shaped Amphiphile Molecules. Phys. Chem. Chem. Phys. 2017, 19, 1627–1631. (8) (a) Kojima, T.; Hiraoka, S. Selective Alternate Derivatization of the Hexaphenylbenzene Framework through a Thermodynamically Controlled Halogen Dance. Org. Lett. 2014, 16, 1024–1027. (b) Kojima, T.; Hiraoka, S. Mesityllithium and p-(Dimethylamino)phenyllithium for the Selective Alternate Trilithiation of the Hexaphenylbenzene Framework. Chem. Commun. 2014, 50, 10420– 10423. (9)

Liu, H.-J.; Yip, J.; Shia, K.-S. Reductive Cleavage of Benzyl Ethers with Lithium Naphthalenide. A Convenient Method for Debenzylation. Tetrahedron Lett. 1997, 38, 2253–2256.

(10) T1/2 of 16 and 26 were determined in CD3OD and D2O (4/1, v/v) by variable temperature 1H NMR spectroscopy, because of the low solubility of 26 in CD3OD and D2O (3/1, v/v) at low temperature. (11) Hiraoka, S.; Harano, K.; Nakamura, T.; Shiro, M.; Shionoya, M. Induced-fit Formation of a Tetrameric Organic Capsule consisting of Hexagram-Shaped Amphiphile. Angew. Chem. Int.


Page 19 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ed. 2009, 48, 7006–7009. (12) Tsujimoto, Y.; Kojima, T.; Hiraoka, S. Rate-Determining Step in the Self-Assembly Process of Supramolecular Coordination Capsules. Chem. Sci. 2014, 5, 4167–4172.


Importance of Molecular Meshing for the Stabilization of Solvophobic

Recommend Documents