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Mar 22, 2018 - Determination of a thermal E/Z isomerization barrier of first generation molecular motors is reported. Stable (E)-1a directly converts ...
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Cite This: J. Org. Chem. 2018, 83, 4800−4804

Thermal E/Z Isomerization in First Generation Molecular Motors Shunsuke Kuwahara,*,†,‡ Yuri Suzuki,† Naoya Sugita,† Mari Ikeda,§ Fumi Nagatsugi,∥ Nobuyuki Harada,∥ and Yoichi Habata†,‡ †

Department of Chemistry, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan Research Center for Materials with Integrated Properties, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan § Education Center, Faculty of Engineering, Chiba Institute of Technology, 2-1-1 Shibazono, Narashino, Chiba 275-0023, Japan ∥ Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba, Sendai, Miyagi 980-8577, Japan ‡

S Supporting Information *

ABSTRACT: Determination of a thermal E/Z isomerization barrier of first generation molecular motors is reported. Stable (E)-1a directly converts to stable (Z)-1c without photochemical E/Z isomerization. The activation Gibbs energy of the isomerization was determined to be 123 kJ mol−1 by circular dichroism spectral changes. Density functional theory calculations show that (Z)-1c is ∼11.4 kJ mol−1 more stable than (E)-1a.

M

Scheme 1. Rotary Cycle of Molecular Motor 1

olecular machines are a single molecule or a molecular system capable of converting external energy into mechanical motion.1−4 The molecular motors in molecular machines have recently attracted much attention. The motors have the potential to control complex machine-like functions. Since the first light-driven molecular motor based on an overcrowded alkene was reported in 1999,5 various symmetrical (first generation)6−13 and unsymmetrical (second generation)14−32 motors have been developed. The motors operate by a one-directional rotation around the central double bond in a four-step rotation mechanism involving two photochemical E/Z isomerizations and two thermal helix inversions (Scheme 1).7,9 Upon irradiation by UV light, stable (S,S)-(M,M)-(E)-1a is converted to metastable (S,S)-(P,P)-(Z)-1b, which relaxes to stable (S,S)-(M,M)-(Z)-1c via thermal helix inversion (THI). Another photochemical E/Z isomerization followed by THI completes the one-directional 360° rotation. The rotation has a variety of applications, including DNA-binders,11 asymmetric catalysts,33 molecular stirrers,34 nanocars,35−38 and functional materials.39−43 Symmetrical motors have been synthesized from the corresponding ketones by McMurry coupling (Table 1). Recently, we prepared the molecular motor (E)-6a, which is an intermediate used in preparation of DNA-binding motors,11 by McMurry coupling using TiCl4 and Zn in 26% yield (Table 1, entry 6). Sterically hindered (Z)-6c was obtained in 33% yield when TiCl3 and LiAlH4 were used (Table 1, entry 7). Similar reported reactions also show inconsistencies in the E/Z © 2018 American Chemical Society

ratio,7,8,11,34 which does not depend on the reaction conditions (Table 1, entries 1−5). Because the reactions were performed in the absence of light (Table 1, entries 2, 3, and 5−7), photochemical E/Z isomerization might not occur. We expect that thermal E/Z isomerization (TEZI) occurs during McMurry coupling. Some Received: December 25, 2017 Published: March 22, 2018 4800

DOI: 10.1021/acs.joc.7b03264 J. Org. Chem. 2018, 83, 4800−4804

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The Journal of Organic Chemistry Table 1. McMurry Coupling of Cyclic Ketones 2−4

entry g

1 2h 3h 4i 5j 6 7

ketones (±)-2 (±)-2 (S)-(+)-2 (±)-3 (±)-4 (±)-4 (R)-(−)-4

conditiona A B B A A A B

time (h) 2 96 4 2 2 3 48

yield (%) (E)-1a (E)-1a (E)-1a (E)-5a (E)-6a (E)-6a trace

yield (%) b

(22) (14) (21)d (23)c (14) (26)

(Z)-1c (Z)-1c (Z)-1c (Z)-5c (Z)-6c trace (Z)-6c

(54)b (6) (5)e (23)c (7)

Figure 1. 1H NMR spectral change of (S*,S*)-(M*,M*)-(±)-(E)-6a (1.5 × 10−3 M, DMSO-d6, 23 °C) before (a) and after heating at 150.0 °C for 10 min (b), 20 min (c), and 40 min (d).

TEZI of (S*,S*)-(M*,M*)-(±)-(E)-6a to (S*,S*)-(M*,M*)(±)-(Z)-6c at several temperatures was monitored by UV spectroscopy. A solution of (S*,S*)-(M*,M*)-(±)-(E)-6a in nonane was heated at 147.2 °C for 0−80 min (Figure 2). With

(33)f

a

Method A: TiCl4, Zn/THF, reflux. Method B: TiCl3, LiAlH4/THF, reflux. bObtained as a mixture of E and Z isomers (ratio 2:5) in a combined yield of 76%. cObtained as a mixture of E and Z isomers (ratio 1:1) in a combined yield of 45%. dAbsolute configuration: (S,S)(M,M)-(−)-(E)-1a. eAbsolute configuration: (S,S)-(M,M)-(−)-(Z)-1c. f Absolute configuration: (R,R)-(P,P)-(+)-(Z)-6c. gReference 7. h Reference 8. iReference 34. jReference 11.

overcrowded alkenes undergo TEZI from the Z-form to the Eform with activation Gibbs energies of 61−105 kJmol−1.44 Chiroptical molecular switches27 and fluorine-substituted motors32 undergo TEZI from the photochemically generated metastable E-form to the stable Z-form. tert-Butyl-substituted molecular motors, which rotate in a different mechanism for previously examined motors, undergo TEZI from stable E-form to the stable Z-form. However, the dynamics of TEZI have not been elucidated.10 To clarify TEZI in this case, stable (S*,S*)-(M*,M*)(±)-(E)-6a and (S,S)-(M,M)-(−)-(E)-1a were heated in solution in the absence of light (Scheme 2). A solution of

Figure 2. UV spectral change owing to TEZI of (S*,S*)-(M*,M*)(±)-(E)-6a to (S*,S*)-(M*,M*)-(±)-(Z)-6c at 147.2 °C (1.85 × 10−4 M, nonane, 23 °C).

Scheme 2. TEZI of (E)-1a and (E)-6a in the Absence of Light

an increasing reaction time, the absorption bands at 374.6 and 358.0 nm decrease and a new band appears at 400.0 nm and increases with several clear isosbestic points, indicating that (S*,S*)-(M*,M*)-(±)-(E)-6a thermally isomerizes to (S*,S*)(M*,M*)-(±)-(Z)-6c. The ratio of (S*,S*)-(M*,M*)-(±)-(E)6a to (S*,S*)-(M*,M*)-(±)-(Z)-6c was determined from the absorbance at 374.6 nm. The rate constants at 136.1, 140.9, 144.4, and 147.2 °C were obtained from first-order reaction kinetics equations (Table S1, Supporting Information). The activation energy Ea = 119 kJmol−1 was obtained from the Arrhenius plot, while the activation enthalpy ΔH‡ = 116 kJmol−1 and activation entropy ΔS‡ = −31.3 JK−1 mol−1 were obtained from the Eyring plot (Figures S7 and S8). The activation Gibbs energy was determined to be ΔG‡293 = 126 kJmol−1. TEZI of the chiral motor (S,S)-(M,M)-(−)-(E)-1a was also observed. The 1H NMR spectra show that the signals of (S,S)(M,M)-(−)-(E)-1a decrease to the noise level and signals of (S,S)-(M,M)-(−)-(Z)-1c appear after heating at 150.0 °C for 40 min (Figure S9). TEZI of (S,S)-(M,M)-(−)-(E)-1a was

(S*,S*)-(M*,M*)-(±)-(E)-6a in DMSO-d6 was heated at 150.0 °C for 40 min. Figure 1 shows the 1H NMR spectra of (S*,S*)(M*,M*)-(±)-(E)-6a before and after heating. The proton signals of (S*,S*)-(M*,M*)-(±)-(E)-6a decrease, and new signals corresponding to (S*,S*)-(M*,M*)-(±)-(Z)-6c appear (Figure 1). 4801

DOI: 10.1021/acs.joc.7b03264 J. Org. Chem. 2018, 83, 4800−4804

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The Journal of Organic Chemistry

Photochemical E/Z isomerization of (S,S)-(M,M)-(−)-(Z)1c and subsequent THI of (S,S)-(P,P)-[CD(+)269]-(E)-1d has previously been reported.7,9 Therefore, the motors rotate around the central double bond in a three-step sequence involving TEZI, photochemical E/Z isomerization, and THI. We have proposed a new TEZI pathway where stable (S,S)(M,M)-(−)-(E)-1a directly converts to stable (S,S)-(M,M)(−)-(Z)-1c without photochemical E/Z isomerization. The activation Gibbs energy of TEZI was determined to be ΔG‡293 = 123 kJmol−1 by CD spectral changes. DFT calculations show that (S,S)-(M,M)-(Z)-1c is 11.4 kJmol−1 more stable than (S,S)-(M,M)-(E)-1a. Detailed rotation mechanisms of the TEZI and photochemical E/Z isomerization have not been clarified. However, subsequent THI from metastable (S,S)(P,P)-[CD(+)269]-(E)-1d to stable (S,S)-(M,M)-(−)-(E)-1a proceed in one direction.7,9 Therefore, the motors totally undergo one-directional rotation in a three-step sequence involving two thermal isomerizations and one photochemical E/Z isomerization. The three-step sequence has the advantage that rotation can be controlled by UV light irradiation with a single fixed wavelength. The present findings offer important guidelines for the design of new molecular motors and development of more advanced rotating systems. Theoretical investigation of the detailed TEZI mechanism is in progress.

monitored by circular dichroism (CD) and UV spectroscopy. A solution of (S,S)-(M,M)-(−)-(E)-1a in nonane was heated at 146.8 °C for 0−60 min. With an increasing reaction time, the intensity of the CD Cotton effect at 258.8 nm decreases and the intensity at 270.2 nm increases with an isosbestic point at 262.6 nm (Figure 3). The ratio of (S,S)-(M,M)-(−)-(E)-1a to

Figure 3. CD spectral change owing to TEZI of (S,S)-(M,M)-(−)-(E)1a to (S,S)-(M,M)-(−)-(Z)-1c at 146.8 °C (2.66 × 10−4 M, nonane, 23 °C).

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(S,S)-(M,M)-(−)-(Z)-1c was determined from the intensity at 270.2 nm. From the first-order reaction kinetics equations, the rate constants are 132.2, 136.7, 141.1, and 146.8 °C. From the rate constants, the kinetic parameters are Ea = 113 kJmol−1, ΔH‡ = 110 kJmol−1, ΔS‡ = −42.3 JK−1 mol−1, and ΔG‡293 = 123 kJmol−1 (Table S2, Figures S20 and S21). The kinetic parameters are similar to those of (S*,S*)-(M*,M*)-(±)-(E)6a. To clarify the mechanism of TEZI, the density functional theory (DFT) calculations of (S,S)-(M,M)-(E)-1a and (S,S)(M,M)-(Z)-1c were performed at the B3LYP/6-31G* level of theory (Figure 4).45 The dihedral angles (C2−C1−C1′−C2′

EXPERIMENTAL SECTION

General Methods. All reagents and solvents were commercially available and used without further purification. IR spectra were obtained as KBr disks or film on KBr on a JASCO FT/IR-410 spectrophotometer. 1H NMR spectra were recorded on JEOL JNMLA400 and ECP400 (400 MHz) spectrometers. 13C NMR spectra were obtained on JEOL JNM-LA400 and ECP400 (100 MHz) spectrometers. All NMR spectroscopic data of CDCl3, CD2Cl2, and DMSO-d6 solutions are reported in ppm (δ) downfield from TMS. CD spectra were recorded on JASCO J-720WI and J-820 spectrometers. CD spectra were recorded with the following measurement parameters: scan speed, 20 nm/min; resolution, 0.2 nm; bandwidth, 1.0 nm; response, 4.0 s; 4−10 accumulations. UV spectra were recorded on JASCO V-410 and V-650. Silica gel 60 F254 precoated plates on glass from Merck Ltd. were used for thin layer chromatography (TLC). (R)-(−)-7-Bromo-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one (4). A mixture of (1S,2R)-(+)-7-bromo-2-methyl2,3-dihydro-1H-cyclopenta[a]naphthalen-1-ol46 (0.13 g, 0.48 mmol), PCC (0.21 g, 0.96 mmol), molecular sieves 3 Å (0.33 g) in CH2Cl2 (6 mL) was stirred at room temperature for 1 h. The reaction mixture was filtrated with Celite, and the organic layer was evaporated to dryness. The crude product was purified by a column chromatography on silica gel (hexane/CHCl3, v/v 1:1) to yield (R)-(−)-4 (0.31 g, 96%) as a white solid: mp 65−66 °C; 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.72 (dd, J1 = 8.9 Hz, J2 = 2.0, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.46 (dd, J1 = 18.3 Hz, J2 = 8.1, 1H), 2.78−2.86 (m, 2H), 1.87 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.7, 156.7, 134.5, 133.9, 132.0, 130.3, 130.1, 127.9, 125.7, 125.2, 120.6, 42.4, 35.3, 16.5; IR (KBr) 3062, 2957, 2926, 2868, 1695, 1582, 1505, 1195, 1167, 1065, 886, 802 cm−1; FAB-MS (matrix DTT/TG = 1:1) m/z 274 ([M(79Br)]+, 100%), 276 ([M(81Br)]+, 100%); [α]25 D −69.2 (c 1.00, CHCl3). Anal. Calcd for C14H11BrO: C, 61.11; H, 4.03. Found: C, 61.29; H, 4.14. (S*,S*)-(M*,M*)-(±)-(E)-7,7′-Dibromo-2,2′-dimethyl-2,2′,3,3′-tetrahydro-1,1′-bi[1H-cyclopenta[a]naphthylidene] (6a).11 To a stirred suspension of zinc powder (197.3 mg, 3.02 mmol) in dry THF (2 mL) was added slowly TiCl4 (0.17 mL, 1.51 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then refluxed for 1.5 h. After a solution of methyl ketone (±)-4 (200.0 mg, 0.75 mmol) in dry THF (2 mL) was added, the reaction mixture was refluxed for 3 h. The

Figure 4. Optimized structures of (S,S)-(M,M)-(E)-1a and (S,S)(M,M)-(Z)-1c at the B3LYP/6-31G* level.

and C9b−C1−C1′−C9b′) and distances (C1−C1′) of the optimized structures of (S,S)-(M,M)-(E)-1a and (S,S)-(M,M)(Z)-1c are similar to those of the reported X-ray structures (Table S3). The twist of the central double bond of (S,S)(M,M)-(E)-1a is larger than that of (S,S)-(M,M)-(Z)-1c. Relaxation of the twist leads to TEZI from (S,S)-(M,M)-(E)1a to (S,S)-(M,M)-(Z)-1c. The calculations show that (S,S)(M,M)-(Z)-1c is 11.4 kJmol−1 more stable than (S,S)-(M,M)(E)-1a. Similar results were obtained for (S,S)-(M,M)-(E)-6a and (S,S)-(M,M)-(Z)-6c (Table S3). 4802

DOI: 10.1021/acs.joc.7b03264 J. Org. Chem. 2018, 83, 4800−4804

Note

The Journal of Organic Chemistry reaction mixture was filtrated with Celite, treated with a saturated aqueous solution of NH4Cl (10 mL), and extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with brine, dried with anhydrous MgSO4, and evaporated to dryness. The crude product was purified by a short column chromatography on silica gel (hexane/ AcOEt, v/v 20:1) and was further purified by HPLC (ODS, MeOH). From the less polar fraction, trans-dimethyl olefine (S*,S*)-(M*,M*)(E)-(±)-6a was obtained as a colorless solid (13.2 mg, 26%): mp 198−200 °C; 1H NMR (400 MHz, CD2Cl2) δ 8.11 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 2.0 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.61 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 3.02−2.90 (m, 4H), 2.36 (d, J = 14.6 Hz, 2H), 1.26 (d, J = 6.3 Hz, 6H); IR (KBr) νmax 3049, 2958, 2926, 2852, 1571, 1499, 1450, 1341, 1064, 877, 798 cm−1; FAB-MS (matrix DTT/TG = 1:1) m/z 516 ([M(79Br, 79Br)]+, 50%), 518 ([M(79Br, 81Br)]+, 95%), 520 ([M(81Br, 81Br)]+, 50%). The MS, 1 H NMR, and IR data were consistent with those reported.11 (R,R)-(P,P)-(+)-(Z)-7,7′-Dibromo-2,2′-dimethyl-2,2′,3,3′-tetrahydro-1,1′-bi[1H-cyclopenta[a]naphthylidene] (6c). To a stirred suspension of TiCl3 (0.177 mg, 1.15 mmol) in dry THF (2 mL) was added slowly LiAlH4 (33.1 mg, 3.02 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then refluxed for 2 h. After a solution of methyl ketone (R)-(−)-4 (100.5 mg, 0.365 mmol) in dry THF (2 mL) was added, the reaction mixture was refluxed for 2 d. The reaction mixture was filtrated with Celite, treated with a saturated aqueous solution of NH4Cl (10 mL), and extracted with CHCl3 (3 × 10 mL). The combined organic layers were washed with brine, dried with anhydrous MgSO4, and evaporated to dryness. The crude product was purified by a short column chromatography on silica gel (hexane/ AcOEt, v/v 20:1) and was further purified by HPLC (silica gel, hexane/AcOEt, v/v 60:1) to yield (R,R)-(P,P)-(+)-(Z)-6c (31.7 mg, 33%) as a yellow solid: mp 203−204 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.46 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 2H), 6.32 (d, J = 9.0 Hz, 2H), 3.61−3.51 (m, 4H), 2.67 (d, J = 15.2 Hz, 2H), 1.15 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ 145.5, 140.1, 136.4, 133.7, 130.4, 128.5, 128.0, 127.9, 127.3, 125.6, 117.7, 42.1, 40.6, 21.0; IR (KBr) νmax 3048, 2963, 2852, 1577, 1503, 1455, 1352, 1070, 883, 800 cm−1. CD (MeOH/10% dioxane): λext = 397.0 nm (Δε = +6.4), 303.0 (+11.9), 278.2 (+119.9), 241.8 (−116.8), 228.8 (+101.1), 217.8 (+2.8), 200.8 (−76.5). UV (MeOH/10% dioxane): λmax = 378.8 nm (ε = 7900), 254.8 (22800), 227.8 (52800), 201.8 (38800). FAB-MS (matrix DTT/TG = 1:1): m/z 516 ([M(79Br, 79Br)]+, 35%), 518 ([M(79Br, 81Br)]+, 70%), 520 ([M(81Br, 81Br)]+, 35%). [α]25 D +148 (c 0.16, CHCl3). Anal. Calcd for C28H22Br2: C, 64.89; H, 4.28. Found: C, 64.55; H, 4.44. Check of the Enantiopurity of (R,R)-(P,P)-(+)-(Z)-6c by HPLC. The racemic motor (±)-(Z)-6c was separated by HPLC on a column of Chiralcel OD-H (0.46 mm × 250 mm), MeOH as an eluent, and a UV detector. The compound eluted first was assigned from the CD spectra as (R,R)-(P,P)-(+)-(Z)-6c and the second one as (S,S)-(M,M)(−)-(Z)-6c. The chiral motor (R,R)-(P,P)-(+)-(Z)-6c synthesized above was subjected to the same HPLC treatment, and the other enantiomer (S,S)-(M,M)-(−)-(Z)-6c was not detected. Therefore, it was concluded that the motor synthesized above was enantiopure. Determination of Kinetic Parameters of (S*,S*)-(M*,M*)-(±)-(E)6a. A motor (S*,S*)-(M*,M*)-(±)-(E)-6a in nonane (1.85 × 10−4 M) was placed in glass ampules. The ampules were closed and heated at 136.1, 140.9, 144.4, and 147.2 °C in the absence of light. After a certain period of time, the ampules were cooled to room temperature. The progress of the reaction was followed by UV spectra at 23 °C. The ratio of (S*,S*)-(M*,M*)-(±)-(E)-6a to (S*,S*)-(M*,M*)-(±)-(Z)6c was determined from the absorbance at 374.6 nm. The rate constants were obtained from first-order reaction kinetic equations at 136.1, 140.9, 144.4, and 147.2 °C. Determination of Kinetic Parameters of (S,S)-(M,M)-(−)-(E)-1a. A motor (S,S)-(M,M)-(−)-(E)-1a in nonane (2.66 × 10−4 M) was placed in glass ampules. The ampules were closed and heated at 132.2, 136.7, 141.1, and 146.8 °C in the absence of light. After a certain period of time, the ampules were cooled to room temperature. The progress of reaction was followed by CD spectra at 23 °C. The ratio of

(S,S)-(M,M)-(−)-(E)-1a to (S,S)-(M,M)-(−)-(Z)-1c was determined from the CD intensity at 270.2 nm. The rate constants were obtained from first-order reaction kinetic equations at 132.2, 136.7, 141.1, and 146.8 °C.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications Web site. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03264. 1 H and 13C NMR spectra of all new compounds, UV and CD spectra of compounds, kinetic data of isomerization, and energies of compounds and their Cartesian coordinates (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone/Fax: +81-47472-4304. ORCID

Shunsuke Kuwahara: 0000-0002-9673-4580 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI (Grant nos. JP22750159 and JP17K05845) and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2012−2016) for S.K.

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DOI: 10.1021/acs.joc.7b03264 J. Org. Chem. 2018, 83, 4800−4804

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DOI: 10.1021/acs.joc.7b03264 J. Org. Chem. 2018, 83, 4800−4804