Conformational Characteristics of Feet-to-Feet-Connected Biscavitands

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Conformational Characteristics of Feet-to-Feet-Connected Biscavitands Daisuke Shimoyama, and Takeharu Haino J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01730 • Publication Date (Web): 28 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019

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The Journal of Organic Chemistry

Conformational Characteristics of Feet-to-Feet-Connected Biscavitands Daisuke Shimoyama and Takeharu Haino* Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, 739-8526, Japan. E-mail: [email protected].

KEYWORDS: Resorcinarene • Conformation • Activation parameters

ABSTRACT: X-ray crystallography of an acetoxy-protected bisresorcinarene and biscavitands possessing phosphonate and dialkylsilyl bridges revealed that the bisresorcinarene and the biscavitands adopt helical forms in the solid state. Helical conformations were also found in solution. The helix-helix interconversions of the biscavitands occurred with high activation barriers of more than 50 kJ mol–1. The activation parameters of the helix-helix interconversions were determined using exchange spectroscopy (EXSY). The positive activation enthalpies and the negative activation entropies suggest that the transition states of the helix-helix interconversion process are most likely more strained and symmetric than the ground states. The compensatory enthalpy−entropy correlation is found in the series of activation parameters, giving rise to a compensation temperature of 254 K.

INTRODUCTION Macrocyclic hosts possessing a cyclic framework are endowed with unique structural characteristics and fascinating host–guest properties and represent the main workhorses in the major field of supramolecular chemistry.1-4 Macrocyclic hosts offer promising applications in molecular machines,5-8 molecular catalysis,9-15 and supramolecular polymers.16-20 During the past decade, a large number of macrocyclic hosts, such as calixarenes,21-25 calixpyrroles,2629 pillararenes,30-33 resorcinarenes,34-39 etc.,40-44 have been synthesized as a class of three-dimensional (3D) containers with cavities, leading to a substantial increase in research activity into all aspects of these supramolecular systems. Among these compounds, a resorcinarene is well known as a macrocyclic host that possesses a concave cavity that captures a variety of guests. Introducing interannular bridges onto a resorcinarene produces a cavitand that possesses a rigid and enforced cavity where a sizable guest is encapsulated.37,45-51 An enforced cavity shows a slow guest exchange on the NMR timescale and is responsible for reactive molecule isolation52-54 and facilitating molecular reaction by encapsulation.55-60 During our studies on calixarene chemistry,61-65 we developed bisresorcinarene 1 as a handy scaffold for homoditopic hosts, which is composed of two concave cavities connected in a feet-to-feet fashion (Fig. 1).66,67 The upperrim functionalization of 1 with phosphonate groups produced the octaphosphonate biscavitand 5, which demonstrated cooperative regulation in guest binding.68 In the solid state, the structure of 5 adopts the (P)- and (M)-helical conformations, which rapidly exchange between each other in solution. In this study, we describe the detailed

conformational characteristics of bisresorcinarenes 1 and 2, biscavitands 3–5, and the host-guest complex G12@5. Their helix-helix interconversions are highly influenced by the structures of the interannular bridges. The activation barriers of the helix-helix interconversion were determined with the activation parameters, resulting in a compensatory enthalpy-entropy correlation, whereas 2 deviates from the correlation.

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Figure 1. Schematic representation of helix-helix interconversion and the structure of bisresorcinarenes 1 and 2, biscavitands 3–5, and guest G1.

RESULTS AND DISCUSSIONS Synthesis: The syntheses of protected bisresorcinarene 2 and biscavitands 3 and 4 are outlined in Scheme 1. Acetylation of the sixteen phenolic hydroxyl groups of 1 afforded the protected bisresorcinarene 2 in 88% yield. Dichlorodimethylsilane reacted with the sixteen phenolic hydroxyl groups of 1 to give rise to the silyl-bridged biscavitand 3 in 80% yield. Biscavitand 4 with the dibutylsilyl bridges was prepared in the same manner.

Scheme 1. Synthesis of 2–4. Crystal structures: Single crystals of 2 and 3 were obtained from chloroform solutions of the respective compounds by the slow diffusion of hexane (Fig. 2). A mixture of chloroform and methanol was used to prepare the single crystals of 5 by the slow diffusion of diethyl ether. For the single crystals of 2, 3 and 5, X-ray diffraction analysis was performed at −150 °C.69,70 The single crystal of 2 was in the triclinic crystal system with the space group P–1 (#2). The four molecules of 2 were located in the unit cell. There are two molecules that are crystallographically independent. 3 formed in the monoclinic crystal system with the space group C2/c (#15). The unit cell contained eight molecules of 3. One of the molecules was found to be crystallographically independent.

eighth of 5. The side- and top-view structures of 1, 2, 3 and 5 are shown in Figure 2. The (P)‐ and (M)‐helical conformations were in the unit cells. 1, 2, 3 and 5 adopted helical structures with dihedral angles of 32.0°, 24.6°, 26.7° and 29.0°, respectively. The acetoxy-protected bisresorcinarene 2 adopts a boat conformation where two of the facing aromatic rings at each cavitand are flattened with an interannular angle of 159(3)° and the others are aligned in a parallel fashion with an angle of 100(4)°. In contrast, the interannular linkages of 3 and 5 are responsible for the C4-symmetric cone conformations with average interannular angles of 126(2)° and 122°, respectively. Conformational characteristics: The conformational characteristics of protected bisresorcinarene 2 were studied using variable-temperature 1H and 13C NMR measurements (Fig. 3). The protected form of the resorcinarene moiety can adopt two possible conformations: one is a cone conformation, and the other is a boat conformation (Fig. 4a).71,72 A set of proton and carbon signals for Ha–Hd and C1–C5 is indicative of the D4h-symmetric nature of the conformation at room temperature. Upon cooling the solution of 2, all the proton signals became broadened, and a coalescence temperature of –25 °C was determined for Hb with a free energy barrier of 45.8 kJ mol–1.73 At –80 °C, all the proton and carbon signals became sharpened. The aromatic protons Hd and He split into the four signals Hdv, Hdh, Hev and Heh, suggesting that each resorcinarene moiety adopted the boat conformation. A further symmetry reduction of 2 at low temperature was found. Proton Hc and carbons C1, C2 and C3 appeared as two magnetically nonequivalent signals, and the acetyl proton Hf and the respective carbonyl and methyl carbons C4 and C5 split into four signals. These findings reduce the D4h symmetry to the D2 symmetry, where the two protected resorcinarene moieties adopted the boat conformations in the D2-symmetric helical conformation as described for the crystal structure of 2.

Figure 3. Variable temperature 1H and 13C NMR spectra of 2. Figure 2. Side and top views of X-ray crystal structures of (a) 166,67, (b) 2, (c) 3, and (d) 5; only (M)-conformers are shown. Color scheme: gray (carbon), red (oxygen), blue (silicon), orange (phosphorus). The hydrogen atoms are omitted for clarity except on entrapped solvents.

5 was found in the tetragonal crystal system with the space group P4/nnc (#126). The asymmetric unit contained one-

To reveal the plausible conformational structures in solution, the conformational search of 2 was performed by lowmode search using MacroModel v9.1 with an MMFFs force field.74 The 1000 initial geometries were optimized to give two major conformations without considering rotational isomers about the acetoxy groups (Fig. 4b). The aromatic flattened ring and the opposite aromatic ring located between the two resorcinarenes are both either proximal or


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The Journal of Organic Chemistry distal. The proximal conformation is 33.4 kJ mol–1 more stable than the distal conformation, which is consistent with the conformation discovered in the solid state. Considering the symmetry of the 1H and 13C NMR spectra, it can be concluded that the D2-symmetric proximal conformations are predominantly formed. The helix-helix interconversion of 2 most likely occurs between the proximal form and its enantiomer. a) He Hev Heh Hdh Hd

Cone

Hdv

Boat

b)

Proximal

Distal

The methylene protons Ha and Hb of 3, 4 and 5 appeared to be broad singlets above room temperature, which is indicative of the D4h symmetric conformation (Fig. 5). The methylene protons Ha and Hb split into two signals in an integration ratio of 1:1, and the system reduces to D4 symmetry at –50 °C. These findings suggest that the helix-helix interconversion of the D4 symmetric helical conformations occurred and that the rate of interconversion was slow on the NMR timescale. Coalescence behaviors were observed in the variable-temperature 1H NMR spectra of 3, 4 and 5. The free barriers of the helix-helix interconversions were determined at coalescence temperatures of 25, 30, and 39 °C for 3, 4 and 5, respectively (Table 1). A free energy barrier of 60.0 kJ mol–1 for 5 appears to be slightly larger than that for 1, 2, 3 and 4; therefore, the interannular bridges might influence the free energy barrier of the helix-helix interconversion. To gain detailed energetic insights into the interconversion processes for 2–5, an EXSY technique using NOESY pulse sequences was used to determine the exchange rate constants.48,75-78 The rate constants of the helix-helix interconversions for 2–5 were determined at various temperatures (Table S2). The rate constants and the free energy of activation (ΔG‡) of these interconversions were temperature dependent. Plotting ln(k/T) versus 1/T for 2–5 resulted in straight line correlations in Figure 6, which were analyzed using Eyring equation to yield the enthalpic (ΔH‡) cost and entropic (ΔS‡) cost of the free energy of activation for the helix-helix interconversions. (Fig. 6, Table 1) The activation parameters are described as follows: ΔH⧧ indicates the barrier to the interconversion, being a measure of rigidity, and ΔS⧧ indicates the gain or loss of order proceeding from the ground state to the transition state for the interconversion.

Figure 4. Schematic representation of (a) the cone and boat conformations of the resorcinarene moiety and (b) the calculated structures of the proximal and distal conformations of 2 and their cartoon representations.

Figure 6. Eyring plot of the interconversion. (2: open rhombus, 3: filled square, 4: open square, 5: open circle, G12@5: filled circle).

Figure 5. Variable temperature 1H NMR spectra of 3, 4, and 5 in chloroform-d1.

All the helix-helix interconversions of 1–5 gave rise to positive activation enthalpic contributions and large negative activation entropic costs, with the rationale being that the transition states of the helix-helix interconversions become more distorted and symmetric than their ground states. Biscavitands 3–5 have activation enthalpic costs that are 10 kJ mol–1 higher than that of 1. These results suggest



that the transition state structures of 3–5 are more strained due to the covalent interannular linkages. In the helix-helix interconversion process, biscavitands 3–5 can be considered to have pseudo-D4h symmetry at the transition state; this increased symmetry rationalizes the activation entropic penalties at the transition states. The activation parameters of the protected bisresorcinarene 2 describe the contribution of the interannular linkages in the helix-helix interconversion process. Surprisingly, the activation enthalpic contribution of 2 is twice as large as those of 3–5,

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whereas the entropic penalty is reduced to approximately 80% less than that of 3–5. These results suggest that the lack of an interannular bridge reduces the structural rigidity of 2, which might stabilize the ground state more than the transition state, increasing the activation enthalpy. In addition, the conformational flexibility of 2 at the transition states remains due to the rotational freedom about the rotatable single bonds, which might explain the fairly small activation entropic penalty.

Table 1. Activation parameters for the helix-helix interconversions.

1

Solvent

H‡ (kJ mol–1)

S‡ (J mol–1 K–1)

G‡ (kJ mol–1)b

G‡ (kJ mol–1)c

DMF-d7

10.7 ± 0.3a

-187 ± 1a

54.22 ± 0.02a

53.1a

40.0 ± 0.3

-32 ± 2

46.52 ± 0.02

45.8

19.4 ± 0.5

-151 ± 2

55.47 ± 0.04

55.3

24.2 ± 0.7

-134 ± 3

56.27 ± 0.05

55.7

22.4 ± 0.4

-141 ± 2

55.99 ± 0.08

60.0

2 3 4

Chloroform-d1

5 5

Methanol-d4

N. D.

N. D.

N. D.

60.8

G12@5

Chloroform-d1

24 ± 1

-136 ± 4

57.75 ± 0.06

N. D.

aReported in Ref67. bDetermined at –40, –65, –35, –35, –35 and –35 °C for 1, 2, 3, 4, 5 and G1 @5, respectively. cDetermined at 2 coalescence temperatures.

The guest complexation can influence both the ground state and transition state structures in the helix-helix interconversion process. In the presence of the hexyl ammonium guest G1, the helix-helix interconversion process was studied, while the two binding cavities were estimated to be fully occupied with G1 based on its binding constants to the cavities. The positive enthalpic contribution and the negative entropic cost in activation were found in the helix-helix interconversion process of G12@5, as seen in those of 5. The values of the activation parameters for G12@5 are quite consistent with those in the absence of G1. Although guest binding can introduce a favorable enthalpic contribution and unfavorable entropic cost both to the ground and transition states, a limited influence on the activation enthalpy and entropy suggests that the guest complexation equally participates both in the ground state and the transition state. Enthalpy-Entropy Compensation: A compensatory enthalpy−entropy correlation has been empirically discussed with respect to the thermodynamic and kinetic parameters determined for various reactions and equilibria.79-82 Regarding mechanistic insights into the helix-helix interconversion processes, plots of the activation enthalpies and the activation entropies gave rise to a remarkably linear relationship (R2 = 0.998) (Fig. 7). The graph of enthalpy versus entropy for the interconversion provides a highly linear trend and can be expressed in the following equation:

The slope (β) of the correlation has a compensation temperature of 254 K (approx. –19 °C). At this temperature, any variation in the activation enthalpy in the transition states is balanced by a compensating variation in the activation entropy in the transition states so that the total activation energy (ΔG‡) of the interconversion remains constant at +58.1 kJ mol-1, given as the intercept of the plots. The enthalpic loss arising from the helix-helix interconversion processes is completely canceled out by the entropic gain from the flexibility in the transition states required upon helical conformational change. Therefore, bisresorcinarene 1, biscavitands 3–5 and G12@5 with any combination of ΔH‡ and ΔS‡ values that lie on this slope have the same mechanism for the helix-helix interconversion. In contrast, 2 markedly deviates from the entropy–enthalpy compensation plot. A lack of the interannular bridge allows the resorcinarene moiety to adopt the boat conformation, which might lead to a difference in the transition state for the interconversion.

∆H‡ = β∆S‡ + 58.1 kJ mol–1 (1)


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The Journal of Organic Chemistry a white solid. M.p. >300 °C; 1H NMR (500 MHz, chloroform-d1): δ 7.02 (s, 8H), 6.93 (s, 8H), 4.18 (t, J = 7.3 Hz, 8H), 2.21 (s, 48H), 1.92–1.71 (m, 16H), 1.36–1.20 (m, 16H) ppm; 13C{1H} NMR (75 MHz, chloroform-d ): δ 168.4, 146.5, 132.6, 1 125.1, 116.2, 36.0, 34.7, 26.6, 21.0 ppm; FTIR-ATR (neat): ν 2930, 2861, 1759, 1492, 1368 cm–1; HRMS (ESI-Orbitrap) m/z: [M + 2Na]2+ Calcd for C104H104O32Na2 955.3148; found 955.3137; Anal. Calcd for C104H104O32: C 66.94, H 5.62, found C 66.26, H 5.61.

Figure 7. Enthalpy–entropy compensation plot of interconversion.

CONCLUSIONS In conclusion, we demonstrated that the protected bisresorcinarene and the biscavitands adopt the helical conformation both in solution and in the solid state. The helixhelix interconversions of the biscavitands resulted in high activation barriers of more than 50 kJ mol–1. The positive activation enthalpies and negative activation entropies suggest that the transition states of the helix-helix interconversion process are most likely more strained and symmetric than the ground states. The compensatory enthalpy−entropy collation is found in the series of the activation parameters, giving rise to a compensation temperature of 254 K. Although the enthalpy−entropy compensation study revealed that the activation parameters of the helix-helix interconversions depended on the interannular bridges on the resorcinarene units regardless of the covalent and noncovalent bonds, a lack of the interannular bridge results in a different mechanism for the interconversion. The interannular bridge, regardless of the substituent and host-guest complex, equalizes the interconversion mechanism.

Biscavitand 3. To a solution of bisresorcinarene 1 (150 mg, 0.126 mmol) in dry pyridine (6.3 mL), dimethyldichlorosilane (0.366 mL, 3.03 mmol) was added under an argon atmosphere. After stirring for 5 hr at 80 °C with the use of an oil bath, the reaction mixture was extracted with dichloromethane after the addition of water. The organic layer was concentrated in vacuo. The crude product was purified using silica gel column chromatography (5% ethyl acetate–dichloromethane) to give 3 (166 mg, 80%) as a white solid. M.p. >300 °C; 1H NMR (500 MHz, chloroformd1): δ 7.56 (s, 8H), 6.24 (s, 8H), 4.59 (t, J = 8.1 Hz, 8H), 2.70– 2.18 (m, 16H), 1.55–1.36 (m, 16H), 0.46 (s, 24H), –0.48 (s, 24H) ppm; 13C{1H} NMR (75 MHz, chloroform-d1): δ 149.9, 132.1, 122.1, 113.6, 35.5, 31.8, 27.9, –2.8, –6.1 ppm; FTIR-ATR (neat): ν 2923, 2860, 1487, 1346, 1258, 1028 cm–1; HRMS (ESIOrbitrap) m/z: [M + H]+ Calcd for C88H105O16Si8 1641.5551; found 1641.5518; Anal. Calcd for C88H104O16Si8•H2O: C 63.65, H 6.43, found C 63.71, H 6.38.

General. Commercially available reagents and solvents were used without purification except where noted. Chemical shifts were recorded as parts per million (ppm) relative to chloroform (chloroform-d1,  = 7.26 ppm for 1H and 77.0 ppm for 13C), methanol (methanol-d4  = 3.29 ppm for 1H), dichloromethane (dichloromethane-d2,  = 5.30 ppm for 1H), and tetrachloroethane (tetrachloroethane-d ,  = 5.98 2 ppm for 1H). Chromatographic purification was carried out on silica gel (Silica Gel 60N (spherical, neutral)).

Biscavitand 4. A solution of dibutyldichlorosilane (0.261 mL, 1.21 mmol) in dry THF (20 mL) was added dropwise over 18 hr into a suspension of bisresorcinarene 1 (150 mg, 0.126 mmol) and triethylamine (1.30 mL, 9.33 mmol) in dry THF (60 mL) under an argon atmosphere. After stirring at room temperature for 12 hr, the reaction mixture was extracted with dichloromethane after the addition of water. The organic layer was concentrated in vacuo. The crude product was purified using silica gel column chromatography (20% ethyl acetate–hexane) to give 4 (186 mg, 64%) as a white solid. M.p. >300 °C; 1H NMR (500 MHz, chloroform-d1): δ 7.52 (s, 8H), 6.26 (s, 8H), 4.52 (t, J = 7.7 Hz, 8H), 2.78–2.04 (m, 16H), 1.58 (quint, J = 6.4 Hz, 16H), 1.50–1.31 (m, 32H), 1.14 (quint, J = 6.4 Hz, 16H), 1.00–0.86 (m, 56H), 0.54 (t, J = 7.7 Hz, 24H), 0.29 (t, J = 8.0 Hz, 16H) ppm; 13C{1H} NMR (75 MHz, chloroform-d1): δ 149.8, 131.6, 121.8, 112.7, 35.5, 31.8, 28.0, 26.1, 25.9, 24.7, 24.6 13.8, 13.8, 12.6, 11.4, 1.0 ppm; FTIR-ATR (neat): ν 2955, 2924, 2857, 1488, 1348, 1256, 1026 cm–1; HRMS (ESI-Orbitrap) m/z: [M]+• Calcd for C136H200O16Si8 2313.2942; found 2313.2985; Anal. Calcd for C136H200O16Si8•2H2O: C 69.46, H 8.74, found C 69.50, H 8.88.

Bisresorcinarene 2. Acetic anhydride (0.30 mL, 3.17 mmol) and 4-dimethylaminopyridine (33 mg, 0.27 mmol) were added to a solution of bisresorcinarene 1 (200 mg, 0.172 mmol) in dry pyridine (2.5 mL) under an argon atmosphere. After the mixture was stirred at room temperature for 5 hr, a small portion of water was added, and extraction was performed with dichloromethane. The organic layer was concentrated in vacuo. The chromatographic purification of the crude product was performed on silica gel (5% ethyl acetate–dichloromethane) to give 2 (282 mg, 88%) as

X-ray Crystallography. X-ray crystallographic data were recorded on a Bruker SMART AEPX II ULTRA CCD diffractometer. The crystals were irradiated using Mo-Kα radiation (λ = 0.71073 Å) at 123 K. A direct method using the SHELXS-2013 program was applied to solve the crystal structures that were refined by successive differential Fourier syntheses and full-matrix least-squares procedures using the SHELXL-2013 program. For all atoms except the hydrogen atoms, anisotropic thermal factors were evaluated. The hydrogen atoms were geometrically produced. Diffuse

EXPERIMENTAL



electron densities were removed using the SQUEEZE routine in the PLATON program. Conformational Analysis. The conformations of 2–5 and G12@5 were analyzed using 1H NMR spectroscopy. Deuterated solvents, chloroform-d1, methanol-d4 and dichloromethane-d2 were used for the VT NMR measurements. The temperature range of chloroform-d1 was +50 ~ –50 °C, the range of methanol-d4 was +60 ~ –50 °C, and the range of dichloromethane-d2 was +25 ~ –80 °C. The activation barrier to the helix-helix interconversion (∆G‡) of 2–5 was obtained by the coalescence temperature (Tc), and the chemical shifts (δν) in the frozen structures. ∆G‡ was calculated according to equation (2). ∆G‡ = 8.314Tc[22.96 + ln(Tc/δν)]

(2)

The exchange rate constants (k) between the enantiomeric conformations of 2–5 and G12@5 under the given temperatures were obtained using the EXSYcalc program. The activation parameters were estimated using a weighted leastsquare method by the Origin 7.5 program. Computational Methods. For a broad structural survey of the conformational isomers for 2, a low-mode sampling algorithm was applied using MacroModel V.9.1 with an MMFF94s force field to generate the initial geometries. The PRCG algorithm was applied for the geometry optimization with a convergence threshold of 0.05 kJ mol–1.74 Redundant conformations were eliminated while the maximum distance threshold was set to 1.0 Å. Two unique conformations were obtained within a 50 kJ mol–1 energy window limit.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: @. Detailed information regarding 1H, 13C and 2D NMR spectra, X-ray data, and computational analysis. • X-ray data for compound 2 (CIF) • X-ray data for compound 3 (CIF) • X-ray data for compound 5 (CIF)

AUTHOR INFORMATION Corresponding Author *Email: [email protected]

ORCID Takeharu Haino: 0000-0002-0945-2893

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank the Natural Science Center for Basic Research and Development (N-BARD), Hiroshima University, for the X-ray measurement. This work was supported by the Grants-in-Aid for Scientific Research, the JSPS KAKENHI Grant Numbers JP24350060 and JP15H03817, and by the Grants-in-Aid for Scientific Research on Innovative Areas, JSPS KAKENHI Grant Numbers JP15H00946, JP17H05375 (Coordination Asymmetry), and JP17H05159 (π-figuration). T.H. thanks Takahashi

Industrial and Economic Research Foundation and Iketani Science and Technology Foundation. D.S. thanks the Grantin-Aid for JSPS Fellows, JSPS KAKENHI Grant Number JP18J13703.

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Conformational Characteristics of Feet-to-Feet-Connected Biscavitands

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