University of Groningen
Autonomy and Chirality in Molecular Motors
Kistemaker, Jozef Cornelis Maria
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Publication date: 2017
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Kistemaker, J. C. M. (2017). Autonomy and Chirality in Molecular Motors. Rijksuniversiteit Groningen.
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143 This chapter has been published as:
J. C. M. Kistemaker, P. Štacko, J. Visser, B. L. Feringa, Nat. Chem. 2015, 7, 890–896, doi:10.1038/nchem.2362.
Chapter 6: Third Generation Molecular Motors
Herein is reported: The development of an achiral molecular motor in which the presence of a pseudo-asymmetric carbon atom proved to be sufficient for exclusive autonomous disrotary motion of two appended rotor moieties. Isomerization around the two double bonds enables both rotors to move in the same direction with respect to their surroundings—like wheels on an axle—demonstrating that autonomous unidirectional rotary motion can be achieved in the third generation of molecular motors.
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Introduction
Taking inspiration from nature’s fascinating motor proteins[1], one of chemistry’s
main challenges is exploiting molecular motion[2–4]. Artificial molecular motors
enable movement at the nanoscale[5–12] and allow molecular systems to operate far
from equilibrium[13,14] and to achieve, among other features, dynamic control of
mechanical, electronic and transport properties[15–20]. Molecular devices and
autonomously operating motors that mimic the dynamic and mechanical functions of complex biological motor systems, yet are simpler in design, robust and tolerant of a broader range of operating conditions, are highly desirable and will form the core of future nanomachines. Important applications of nanomachines began to emerge recently, and include molecular electronics[21,22], molecular logic
devices[23,24], artificial muscles[25,26], delivery systems[27–30], responsive
surfaces[28,31] and adaptive catalysts[32–34]. Key to performing mechanical tasks is
control over the directionality of rotary motion, as is seen with ATPase-mediated transport[35], flagella-based bacterial swimming[36] and the rotation of microscopic
objects at the liquid crystal–air interface by directional rotation of a chiral nematic phase[37].
Leigh and co-workers noted that having chirality embedded in a molecule is not a prerequisite for directionality in a motor system when a specific sequence of chemical steps can be used to induce the rotary motion, as shown for a mechanically interlocked motor[38,39]. In a surface-mounted motor by Vives et al., despite the use
of an achiral molecule, the entire system is non-symmetric, which thus governs directionality[40]. To enable autonomous directional movement and avoid an equal
probability of clockwise and anticlockwise rotation around a single rotary axle connecting rotor and stator, our synthetic rotary motors[41–43] rely on the chirality
of the system. In biological motors[1,44] point chirality is transferred to helical
chirality and chiral macromolecular assemblies determine the rotational direction, and in the overcrowded alkene-based rotary motors the direction of rotation is controlled by point chirality, as it determines the thermodynamically favoured helical chirality. In our first and second generation light-driven molecular motors[41–43], the presence of stereocentres is an essential feature responsible for
unidirectional movement, being one of the basic requirements of a rotary motor besides energy consumption, rotary motion and a repetitive process. However, we address the question of whether chirality is a requirement for autonomous directional rotary motion in these light-driven motors, or can rotary function be achieved with an achiral molecule?
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Symmetry considerations of rotary motion dictate that, from the submolecular level (for example, disrotary motions in electrocyclic reactions) to macroscopic length scales (for example, the rotation of two (car) wheels on an axle), for an observer at the symmetry plane the directionalities of rotary motion are opposite each other (Figure 6.1a). Despite the entire system being symmetric (Cs plane of symmetry),
the rotary motion of two wheels on an axle with respect to their surroundings is identical (for example, both with forward rotation from the perspective of an external observer[38]), allowing concerted rotary motion to induce directional
translational motion. Translating these symmetry considerations to a stereochemical design featuring two integrated rotor moieties in a meso compound, we demonstrate here that a symmetric (achiral) light-driven molecular motor is feasible (Figure 6.1b).
Figure 6.1. Directional rotary motion in symmetric systems. a) Left to right: photochemical disrotary
ring opening; disrotary movement of rotor units in a symmetric molecular motor; disrotary movement of wheels on an axle (Cs = symmetry plane). b) Schematic design of achiral motors:
merging of two enantiomers of motor 1 (opposite helicities (P,M) and central chirality (R,S) indicated) gives rise to symmetric double overcrowded alkene 2 (the pseudo-asymmetric carbon atom is indicated with its stereo descriptor (s)), and substitution of hydrogen at C2 for R1 gives
meso-3, meso-(r)-4 and four E/Z stereoisomers of 5.
Design
The design of the achiral molecular motor system (Figure 6.1b) is based on second generation rotary motors[42,43] featuring a helical structure (P or M helicity) and a
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is governed by the central chirality (R or S) of the molecular motor, and the enantiomer with P helicity induces anticlockwise rotation as a result of repetitive photochemical and thermal isomerization steps, while clockwise rotary motion is observed for the M-helical structure. We envisioned that, upon merging two enantiomers of such a motor 1 (Figure 6.1b), the resulting molecule would lose its chirality (symmetric meso structure 2) but would maintain a pseudo-asymmetric carbon[45–47] at C2 with the potential to control the directionality of rotation. This
pseudo-asymmetric centre allows each rotor part to retain its helicity and undergo unidirectional rotation, provided it is still able to undergo a photochemical E–Z isomerization (PEZ) followed by a subsequent thermal helix inversion (THI). If, alternatively, the PEZ isomerization were to be followed by a thermal E–Z isomerization, no net rotation would be achieved and it would function as a switch. It should be emphasized that symmetric meso structure 2 accommodates two helical moieties with distinct P and M configurations. Although molecular chirality is not a prerequisite to achieve unidirectional rotary motion (vide infra) — that is, permanent point chirality is not required — there is still a need for some chiral information in the form of pseudo-asymmetry.
Meso-(s)-2, featuring a methyl group and hydrogen at C2, was inaccessible due to
insurmountable problems in each of the synthetic steps, which is attributed to the acidity of the hydrogen at the pseudo-asymmetric carbon (C2, double allylic position) in 2. Introduction of an additional methyl group at C2, as in meso-3, would afford a quaternary centre and eliminate these problems, but such a molecule would lose its pseudo-asymmetric centre (two methyl substituents at carbon 2) and therefore its potential unidirectionality of rotation. In second generation molecular motors such as 1 (Figure 6.1b) the stereocentre has two substituents, one of which is pseudo-equatorially oriented towards the fluorene moiety, which creates steric hindrance, while the other is in a pseudo-axial orientation away from the fluorene. Being different in size, these substituents allow for the existence of a stable state with the small substituent in the pseudo-equatorial orientation and a metastable state when the larger substituent is oriented pseudo-equatorially[43]. Analogously,
in this symmetric ‘third’ generation of molecular motors (3), the two substituents (methyl and R1) at the pseudo-asymmetric centre C2 in the core part should have a
distinct difference in size to provide a difference in energy between the two possible meso isomers. This energy difference should always thermodynamically drive the two rotor units forward, in the same direction, through sequential photochemical and thermal helix isomerization steps to the global minimum energy configuration, and therefore control the directionality of rotor movement relative to the core part. We anticipated that a quaternary centre at C2 bearing a methyl group and a fluorine
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atom, as present in meso-(r)-4 (Figure 6.1b), would provide a sufficient difference in size. Furthermore, the introduction of R2 at the rotor units induces dissymmetry in the rotors, allowing each individual step in the 360° rotary cycle to be analysed (vide infra).
Theoretical Study
The design of motor 4 was supported by a theoretical investigation of the possible isomerization processes using the Gaussian 09 program[48] for geometry
optimizations and frequency analyses while the Firefly QC package[49], which is
partially based on the GAMESS (US)[50] source code, was used for energy
corrections. First, a potential energy surface (PES) was constructed from two dihedral angles governing the geometry of the aromatic planes of rotor and core units using the semi-empirical PM6 basis set (Figure 6.2).
Figure 6.2. PES of the ground state of 4 (PM6; x axis: 1–2–3–4 dihedral angle (in degrees); y axis:
5–6–7–8 dihedral angle (in degrees)) and corresponding structures of minima, which are interconnected through THI (note that no E–Z isomerizations are depicted and, corresponding to the symmetry plane running diagonally through the minima of meso-(r)-4 and meso-(s)-4 on the PES, TS1’–4’ are the enantiomers of TS1–4 just like (P)-4 is the enantiomer of (M)-4).
The result is a symmetrical surface with a mirror plane through the minima, indicative of the symmetric nature of the molecule. The geometries of the minima and transition states were optimized using density functional theory (DFT; B3LYP, 6-31G(d,p)[51–56], Figure 6.3 Top), and their respective single energies were
calculated (B2GP-PLYP, 6-311G(2d,2p)[57]), revealing two minima possessing C
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symmetry (meso-(r)-4 and meso-(s)-4). In the global minimum meso-(r)-4, the fluorine adopts a pseudo-equatorial orientation and it is significantly lower in energy (ΔG° = 34.4 kJ·mol−1) than its inverted counterpart in which the fluorine is
pseudo-axial (meso-(s)-4). Two metastable local minima possessing C1 symmetry
((P)-4 and (M)-4, ΔG° = 42.7 kJ·mol−1) were found that are enantiomeric helical
configurations and from which multiple pathways for thermal helix inversion are possible (Figure 6.3 Bottom).
Figure 6.3. Top: The geometries of the minima and transition states of 4 were optimized using DFT
B3LYP/6-31G(d,p) and in all cases are shown with the fluorine atom facing the reader and the F– C–CH3 bonds in the y–z plane. Bottom: Intrinsic reaction coordinates were calculated for all THIs (DFT B3LYP/6-31G(d,p); Gibbs free energies are shown in the legend; B3LYP/6-31G(d,p)//B2GP-PLYP/6-311G(2d,2p)).
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These pathways differ in terms of which rotor undergoes the rotation (TS1-4, TS2-4 versus TS3-TS2-4, TSTS2-4-TS2-4; TS, transition state) and whether the helix inversion proceeds with the rotors syn-folded (TS1-4,TS4-4) or anti-folded (TS2-4,TS3-4). These calculations show a low barrier (TS1-4 = Δ‡G° = 73.5 kJ·mol−1) for thermal
helix inversion of metastable (P)-4/(M)-4 to produce meso-(r)-4 and a significantly higher barrier (TS3-4 = Δ‡G° = 98.1 kJ·mol−1) towards meso-(s)-4.
Figure 6.4. Rotational behaviour of 4. A photochemical E–Z isomerization (PEZ) of meso-(r)-4
produces a racemic mixture of (P)-4/(M)-4, and individual rotor units undergo a quarter rotation in a common direction. This photoisomerization is followed by a THI in which the rotating units complete a half-turn rotation continuing in the same direction (note that meso-(r)-4 = meso-(r)-4’). Based on symmetry considerations it is expected that a photochemical E–Z isomerization of the global energy minimum structure meso-(r)-4 will produce a photostationary state (PSS) comprising meso-(r)-4 and racemic (P)-4/(M)-4 (Figure 6.4). This photoisomerization results in a quarter rotation (if a 360° rotation is considered a full rotation) of individual rotors in a common direction. The metastable (P)-4/(M)-4 subsequently undergoes a thermal helix inversion, producing meso-(r)-4’, in which the rotor unit that underwent the rotation during the initial photochemical E–Z isomerization continues rotation with a 24 000:1 preference over the other rotor unit (based on the reaction rate ratio at room temperature; the values of Δ‡G° for the two processes TS1-4 and TS3-4 are 73.5
and 98.1 kJ·mol–1, respectively, equivalent to reaction rates of 0.49 and 2·10−5 s−1).
A rotor unit on meso-(r)-4’ will have completed a half-turn rotation in the same direction (as initiated by the photochemical process) going through either of the metastable states. Because the formation of meso-(s)-4 from (P)-4/(M)-4 is not likely due to the much higher TS3-4 with respect to TS1-4 (Figure 6.3), there is no pathway available that results in a zero net rotation.
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Experimental Study of Third Generation Motor 4
Overcrowded bis-alkenes 4 and 5 were prepared in a manner analogous to the second generation molecular motors[43] by Peter Stacko.[58,59] The photochemical
and thermal isomerization processes for 4 were followed by UV–vis spectroscopy (Figure 6.5). Irradiation of meso-(r)-4 with ultraviolet light (365 nm in CH2Cl2,
Figure 6.5) at −80 °C was accompanied by a bathochromic shift in the UV–vis absorption spectrum, in accordance with the response of second generation motors[43] and indicative of an increase in alkene strain as expected for
(P)-4/(M)-4. After reaching the PSS, the sample was allowed to warm to room temperature, and full reversal to the original UV–vis spectrum was observed, in accordance with the anticipated helix inversion to meso-(r)-4’ (Figure 6.4). No sign of decomposition was observed over two photochemical–thermal isomerization cycles. During both the thermal and photochemical processes an isosbestic point was observed at the same wavelength (412 nm), establishing the absence of formation of meso-(s)-4 (Figure 6.2) during the photochemical or thermal isomerizations. The calculated barrier for thermal interconversion of meso-(s)-4 to
meso-(r)-4 is Δ‡G° = 106 kJ·mol−1 and for (P)-4/(M)-4 to meso-(r)-4 is Δ‡G° =
73.5 kJ·mol−1 (vide supra). This means that, at room temperature, (P)-4/(M)-4 will
quickly isomerize (t½ at room temperature of one second), while meso-(s)-4 would
be slow to isomerise (t½ at room temperature of four days), therefore resulting in a
lasting change in the absorption spectra of 4.
Figure 6.5. UV–vis absorption spectrum of 4 in CH2Cl2 at room temperature, irradiation (365 nm)
to PSS at −80 °C and warming to room temperature. Inset: isosbestic point at 412 nm with absorptions during both processes.
Independent NMR spectroscopy experiments confirmed that the starting isomer is the expected meso-(r)-4 with a Cs symmetrical configuration (Figure 6.6, 1H NMR
spectrum i) with the fluorine in a pseudo-equatorial configuration indicated by the strong through-space coupling of the fluorine and the proximal aromatic protons (Figure 6.7). The 19F NMR spectrum of meso-(r)-4 shows an A
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and the quadruple triplet has coupling constants of 17.2 and 5.6 Hz (Figure 6.7 Right, see Figure 6.6 for assignments of 4). 3J
AM(H9,F) = 17.2 Hz is clearly
observed in the 1H NMR spectrum of 4 in which the absorption of the hydrogens
at the methyl on the pseudo-asymmetric carbon is split to form a doublet with a coupling constant of exactly 17.2 Hz (Figure 6.6, 1H NMR spectrum i). The
coupling of 6J
MX(F,H1) = 5.6 Hz is not as clearly observed in the 1H NMR
spectrum, this is due to the complex spin system of H1 (AA’BH1M), which makes
the absorption appear as a broad multiplet at 8.10 ppm. The broadening of this signal compared to that of H4 (ABCH4 coupling system) which appears as a
broadened doublet at 7.43 ppm is evident of an additional spin-spin coupling (the broadening is also partially due to the isochronosity of H5 and H5’).
Figure 6.6. Left: (i) 1H-NMR spectrum of meso-(r)-4, with proton assignments depicted on top
(CD2Cl2, 500 MHz, rt); (ii) after transfer to a Shigemi tube and irradiation in the NMR probe to PSS
(meso-(r)-4:(P)-4/(M)-4), 7.5:92.5) (CD2Cl2, 600MHz, −56 °C, 365 nm); (iii) increasing the
temperature to −38 °C for 30 min in the NMR probe without illumination allowed for a thermal isomerization to take place (CD2Cl2, 600MHz, −38 °C); (iv) after 12 h in the dark at −38 °C, no
further isomerization was observed (CD2Cl2, 600MHz, −38 °C). Right: meso-(r)-4 with numbered
labels for proton assignment of NMR absorptions (for a complete assignment of 1H and 13C
absorptions of meso-(r)-4 see ref. [58]).
The F-H1 distances for meso-(r)-4 and meso-(s)-4 are calculated to be 2.2 and 2.3 Å, respectively. F-H coupling constants increase with decreasing distance and are dependent on C-F-H-C dihedral angle.[60,61] If meso-(s)-4 would have been
obtained synthetically, it could have been differentiated from meso-(r)-4 by NMR and, based on calculations, would have turned into meso-(r)-4 through two THI’s over time (vide supra).
Irradiation of meso-(r)-4 at subzero temperatures produces a metastable state in which the isochronosity of the absorptions of the two rotors is lost in 1H NMR,
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spectrum ii), and a single additional absorption in the 19F NMR spectrum is
observed which is assigned to racemic (P)-4/(M)-4 (Figure 6.7, 19F NMR spectrum
ii). Prolonged irradiation of the sample at −56 °C provided a photostationary state of 7.5:92.5 (meso-(r)-4: (P)-4/(M)-4) (Figure 6.6, 1H NMR spectrum ii). No trace
of meso-(s)-4 was observed during irradiation, nor when the sample was allowed to warm, as indicated by the emergence and disappearance of only one additional
19F absorption (Figure 6.7, 19F NMR spectrum ii and iii). In theory, it is possible
that meso-(s)-4 could be formed by two E–Z photoisomerizations at both carbon– carbon double bonds, in which the first forms metastable (P)-4/(M)-4 and the second forms meso-(s)-4 which is expected to be stable at these temperatures (t½calc.
at rt = 4 d, vide supra). Photo-excitation of meso-(r)-4 or (P)-4/(M)-4 has never been observed to lead to the formation of meso-(s)-4. This might be explained by an asymmetric excited-state surface of (P)-4/(M)-4, which is to be expected of molecules with C1 symmetry; such an asymmetry could lead to the exclusive E–Z
photoisomerization of the carbon–carbon double bond that forms meso-(r)-4.
Figure 6.7. 19F NMR spectra of 4. Left: (i) 19F NMR spectrum of meso-(r)-4 (CD
2Cl2, 564 MHz, rt);
(ii) 19F NMR spectrum of sample irradiated to PSS in NMR (CD
2Cl2, 564 MHz, −20 °C); (iii) 19F NMR
spectrum at t = 30 min (CD2Cl2, 564 MHz, −20 °C). Right: 19F NMR spectrum blowup of meso-(r)-4
(CD2Cl2, 470 MHz, rt).
The 1H NMR spectrum of meso-(r)-4’ was obtained after 12 h by increasing the
temperature to −38 °C, (Figure 6.6, 1H NMR spectrum iv, which is identical to the 1H NMR spectrum i of meso-(r)-4 due to the symmetry of the rotors). This sequence
is in accordance with a photoequilibrium between meso-(r)-4 and metastable states (P)-4/(M)-4, followed by a thermal isomerization of (P)-4/(M)-4 to afford meso-(r)-4’. Following this thermal process over time using NMR (Figure 6.8), the energies of activation were derived (Δ‡H° = 78.3±1.6 kJ·mol−1, Δ‡S° =
10.0±6.5 J·K−1·mol−1, Δ‡G° = 75.3±0.3 kJ·mol−1, t
½=1 h at T = −31.8±0.1 °C), in
good agreement with the calculated barrier (vide supra, Δ‡G°
calc = 73.5 kJ·mol−1).
No sign of fatigue was observed over seven photochemical–thermal isomerization cycles.
i
ii
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Figure 6.8. Thermal behaviour of 4. Left: Normalized integral of the ratio of the NMR absorptions
of H1meso-(r)-4 over H1(P)-4/(M)-4 over time. Right: Eyring plot of thermal decay of (P)-4/(M)-4, standard
errors displayed as 3 to avoid the symbols obscuring the error bars.
Proving Unidirectionality in Desymmetrized Motor 5
The observed behaviour of this third generation molecular motor is anticipated to be unidirectional for both rotors. If observed from the exterior of the molecule, the rotations of both fluorene rotors in any of the steps are in the same forward direction (Figure 6.1a and Figure 6.4), but when observed from the mirror plane, one unit rotates clockwise and the other anticlockwise. To prove unequivocally the unidirectionality in the rotor motion, asymmetric substitution of the rotors is required in order to identify a single PEZ–THI sequence for each of the isomers involved in the rotary cycle. To this end, a methoxy substituent was introduced into each of the rotor units, providing compounds 5 (Figure 6.9 Right). The four isomers of 5 were separated using preparative supercritical fluid chromatography (SFC) on a chiral stationary phase (Figure 6.9 Left).
6 6 16 17 15 2 11 3 4 8 10 5 12 9 1 8 7 3 F 6 6 16 15 17 1 8 7 3 4 12 9 4 8 10 5 2 11 3 F 6 6 16 15 15 1 8 7 3 4 12 9 4 12 9 1 8 7 3 F 6 6 16 17 17 2 11 3 4 8 10 5 4 8 10 5 2 11 3 F 3:(r,E,E)-5 2:(S,(Z,P),(E,M))-5 1:(R,(Z,M),(E,P))-5 4:(r,Z,Z)-5 O O 13 14 O 14 O 13 O O 14 14 O 13 O 13
Figure 6.9. Isolation of isomers of 5. Left: SFC Chromatogram of 5, identical conditions were used
for the separation of the four stereoisomers of 5 (Chiralpak IA, 32% 2-propanol in CO2, 340 nm,
3.5 mL·min−1, T = 40 °C, 180 bar). Right: Four isomers of 5 shown in their stable configurations
with fluorine in a pseudo-equatorial orientation; 1: (R,(Z,M),(E,P))-5; 2: (S,(Z,P),(E,M))-5; 3: (r,E,E)-5; 4: (r,Z,Z)-5, numbered for 1H NMR assignment (vide infra).
To assign the absolute stereochemistry to each isolated isomers of 5 the circular dichroism (CD) spectrum of (S,(Z,P),(E,M))-5 was calculated in order to differentiate between the two expected enantiomers (isomers ‘1’ and ‘2’ in Figure 6.9). The optimized geometry of meso-(r)-4 was substituted with methoxy groups
0 1000 2000 3000 4000 5000 6000 7000 8000 0.0 0.2 0.4 0.6 0.8 1.0 In tegral Time (s) T (°C) 236.0 239.0 241.9 244.9 247.8 250.8 253.7 236 238 240 242 244 246 248 250 252 254 0.0 2.0x10-4 4.0x10-4 6.0x10-4 8.0x10-4 1.0x10-3 1.2x10-3 1.4x10-3 k (s -1) T (K)
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to give 5. There are four possible conformations of (S,(Z,P),(E,M))-5 in which the methoxy substituents are in the plane of the rotor and pointing towards or away from the core (denoted as a,b,c and d, Table 6.1). The geometries of these four conformers of (S,(Z,P),(E,M))-5 were optimized using the same method as for 4 (DFT B3LYP/6-31G(d,p)) followed by a time-dependent DFT (TD-DFT) calculation (B3LYP/6-311++G(2d,2p)).[62,63] The obtained energies
allowed for an estimation of the expected Boltzmann-weighted population of the different conformations at rt (Table 6.1).
Table 6.1. Calculated geometries and expected populations of (S,(Z,P),(E,M))a-d-5.
(S,(Z,P),(E,M))x-5 a b c d
B3LYP/6-311++G(2d,2p) SCF
Energy (hartree) −1793.708811 −1793.708681 −1793.708793 −1793.708862 B3LYP/6-31G(d,p) Gibbs free
energy correction (hartree) 0.531327 0.531706 0.531694 0.531831
ΔG° (kJ·mol−1) 0 1.34 1.01 1.19
Population° as fractions 0.351 0.203 0.231 0.215
Figure 6.10. CD spectra (CH2Cl2, rt) of (R,(Z,M),(E,P))-5 and (S,(Z,P),(E,M))-5 with opposite Cotton
effects indicative of their enantiomeric relationship and the calculated CD-spectra of the conformers of (S,(Z,P),(E,M))x-5 and their normalized corrected spectrum used for the assignment of the
absolute stereochemistry (TD-DFT B3LYP/6-311++G(2d,2p)).
The CD-spectra obtained from the TD-DFT calculation are shown in Figure 6.10 and marked differences are found, most notably between the calculated CD-spectra of (S,(Z,P),(E,M))a-5 and (S,(Z,P),(E,M))b-5, signifying the influence of a
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fractions from Table 6.1 were used as corrections for the expected populations at rt, affording a corrected spectrum of (S,(Z,P),(E,M))-5.
Figure 6.11. 1H NMR spectra of 5 (CD
2Cl2, 500 MHz, rt) where the labels on the y-axis correspond
to the numbered isomers in Figure 6.9 with proton assignments under the peaks corresponding to the implicit hydrogens on the numbered carbons shown for each isomer in Figure 6.9 (the NMR absorptions and their peak assignment of 1 is identical to that of 2 because of their enantiomeric relationship).
The first two isomers (indicated by ‘1’ and ‘2’) were identified by NMR as the enantiomeric pair (Z,E)-5 by their identical 1H NMR spectra (Figure 6.11).
Comparing their experimental CD spectra to the corrected calculated CD spectrum of (S,(Z,P),(E,M))-5 (Figure 6.10) identified isomer ‘1’ (tR = 6.3 min) as
(R,(Z,M),(E,P))-5 and isomer 2 (tR = 7.0 min) as (S,(Z,P),(E,M))-5. The
experimental CD spectrum of isomer ‘2’, identified as (S,(Z,P),(E,M))-5, overlapped significantly better with the conformer-population corrected calculated CD spectrum than with any of the calculated CD spectra of the individual conformers by themselves, highlighting the importance of the conformer correction. Isomers 3 and 4 did not show Cotton effects, and their NMR absorptions were characteristic for the expected Cs symmetry of meso-(r)-5. From the 1H,
COSY and H-HOMO2DJ-Resolved NMR a full assignment of the 1H NMR
absorptions of isomers ‘3’ and ‘4’ of 5 was accomplished (Figure 6.11) making use of the proton–fluorine coupling behaviour exemplified below (Figure 6.12), which identified isomer ‘3’ (tR = 9.2 min) as (r,E,E)-5 and isomer ‘4’ (tR = 11.3min) as
(r,Z,Z)-5.
The spin system for fluorine in (r,Z,Z)-5 is the same (A3MX2, 3JAM(H16,F) =
17.1 Hz, 6J
MX(F,H2) = 5.1 Hz) as that of meso-(r)-4 (all isomers of 5 possess this
spin system), and the coupling of 3J
AM(H16,F) = 17.1 Hz is still visible in the 1H NMR spectrum of (r,Z,Z)-5 as a doublet at 2.20 ppm (Figure 6.11). However,
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the H2 hydrogen responsible for the 6J
MX(F,H2) = 5.1 Hz is much better resolved
in the 1H NMR spectrum as a double doublet at 7.66 ppm (Figure 6.12 Left). This
is due to the absence of a hydrogen in the ortho-position with respect to H2 in (r,Z,Z)-5 compared to H1 in meso-(r)-4 and H1 in (r,E,E)-5. H-HOMO2DJ-Resolved NMR (Figure 6.12 Right) identifies the spin system of H2 in (r,Z,Z)-5 as ABCH2M with the H-H couplings resolved on the y-axis (5JAC(H3,H2) = 0.8 Hz, 4J
BC(H11,H2) = 2.3 Hz) but the H-F coupling unresolved on the x-axis (6JCM(H2,F)
= 5.3 Hz) (the red box in Figure 6.12 Right). This coupling behaviour is less complicated in (r,Z,Z)-5 with respect to (r,E,E)-5 due to the methoxy group preventing additional H-H coupling, and the two isomers are easily distinguished by the upfield shift of H2 in (r,Z,Z)-5 with respect to H1 in (r,E,E)-5.
Figure 6.12. NMR spectra of isomer ‘4’ of 5, identified as (r,Z,Z)-5. Left: aromatic region of 1H-NMR
spectrum of (r,Z,Z)-5 (CD2Cl2, 600 MHz, rt), for assignment see Figure 6.9 and Figure 6.11. Right:
HOMO2DJ-NMR spectrum of (r,Z,Z)-5 (CD2Cl2, 600 MHz, rt).
The rotational behaviour of isomer ‘1’, (R,(Z,M),(E,P))-5, was studied (Figure 6.13a) in CD2Cl2 by irradiation using 365 nm light at −100 °C (for no more than
3 h to prevent any thermal isomerization), with subsequent warming to room temperature in the dark to allow thermal isomerization to take place. The products were identified by SFC and 1H NMR as the expected (r,E,E)-5 and (r,Z,Z)-5
isomers (Figure 6.13b). These data provide unequivocal evidence for a sequence of two steps: a single photochemical E–Z isomerization of either rotor (step 1), yielding a mixture of the starting material and two helical metastable isomers ((M,Z,Z)-5 and (P,E,E)-5)), followed by a thermal helix inversion of the rotating unit to (r,Z,Z)-5 and (r,E,E)-5 (step 2), completing a half-turn rotation of either rotor unit. These experiments were repeated for each of the individual isomers ‘2’, ‘3’ and ‘4’ ((S,(Z,P),(E,M))-5, (r,E,E)-5 and (r,Z,Z)-5) and they show identical behaviour (Figure 6.14). 1.00 1.00 0.97 0.93 0.99 0.94 0.97 0.93 6.91 6.92 6.93 6.93 7.04 7.05 7.06 7.25 7.26 7.27 7.30 7.44 7.45 7.59 7.60 7.61 7.62 7.66 7.66 7.66 7.67
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THIRD GENERATION MOLECULAR MOTORS
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a F (R,(Z,M),(E,P))-5 F O F O F F (r,E,E)-5 (r,Z,Z)-5 O O h + + 65% 1.00 : 1.16 O O O O O O (M,Z,Z)-5 (P,E,E)-5 b
Figure 6.13. Unidirectional rotation of (R,(Z,M),(E,P))-5 followed by SFC and 1H NMR. a)
Photochemical E–Z isomerization of (R,(Z,M),(E,P))-5 yields metastable helical intermediates that undergo thermal helix inversions to produce a mixture of (r,Z,Z)-5 and (r,E,E)-5. b) Left: SFC chromatograms (Chiralpak IA, 32% 2-propanol in CO2, 340 nm, 3.5 ml·min−1, T=40 °C, 180 bar).
Right: 1H NMR spectra (CD
2Cl2, 500 MHz, rt) of the methoxy absorptions. Top: isolated isomer ‘1’,
(R,(Z,M),(E,P))-5, in red. Middle: mixture after irradiation of R,(Z,M),(E,P))-5 with 365 nm light for 3 h at −100 °C in CD2Cl2, directly followed by thermal isomerization in the dark for 1 h at room
temperature. Bottom: SFC chromatograms and 1H NMR spectra of all isolated isomers of 5
superimposed for reference with individual colour-coded isomers: isomer ‘1’, red,
(R,(Z,M),(E,P))-5; isomer ‘2’, green, (S,(Z,P),(E,M))-(R,(Z,M),(E,P))-5; isomer ‘3’, blue, (r,E,E)-(R,(Z,M),(E,P))-5; isomer ‘4’, purple, (r,Z,Z)-5 (note
that the 1H NMR spectra of isomers ‘1’ and ‘2’ overlap because of their enantiomeric relationship).
As for 4, no isomers of 5 other than those indicated are observed, as supported by chiral SFC, NMR and CD analysis. Each of the four isomers produces the anticipated products of a PEZ–THI sequence with a single rotor unit undergoing a 180° rotation, providing evidence for unidirectionality of rotary motion in these double overcrowded alkenes. In all cases, the rotor unit that undergoes the initial photochemical isomerization continues rotary motion in the same forward direction through a subsequent thermal helix inversion in accordance with the process shown in Figure 6.4. The products of each two-step rotational sequence will keep rotating unidirectionally following the absorption of another photon, so this achiral molecular motor undergoes sequential rotation of its rotor units upon irradiation with ultraviolet light at room temperature, with each rotation proceeding in the same forward direction. Use the bottom corner of this thesis as a flipbook to see an animation of the rotary process.
158
6
a b
Figure 6.14. Overview for photo/thermal behaviour of all isomers of 5. a) Top to bottom, SFC
chromatogram (Chiralpak IA, 32% IPA, 340 nm, 3.5 mL·min−1, T = 40 °C, 180 bar) of: isomer ‘1’,
R,(Z,M),(E,P))-5 after a PEZ–THI sequence (in CD2Cl2,−100 °C, 3 h, 365 nm; dark, rt, 1 h), isomer
‘2’ (S,(Z,P),(E,M))-5 after a PEZ–THI sequence, isomer ‘3’ (r,E,E)-5 after a PEZ–THI sequence, isomer ‘4’ (r,Z,Z)-5 after a PEZ–THI sequence and 5, SFC chromatograms of isolated isomers of 5 superimposed for reference (all colour coded to each individual isomer). b) As in a, top to bottom,
1H NMR spectra (CD
2Cl2, 500 MHz, rt) of the methoxy absorptions of: isomer ‘1’, R,(Z,M),(E,P))-5
after a PEZ–THI sequence (in CD2Cl2, −100 °C, 3 h, 365 nm; dark, rt, 1 h), isomer ‘2’
(S,(Z,P),(E,M))-5 after a PEZ–THI sequence, isomer ‘3’ (r,E,E)-5 after a PEZ–THI sequence, isomer ‘4’ (r,Z,Z)-5 after a PEZ–THI sequence and 5, 1H NMR spectra (CD
2Cl2, 500 MHz, rt) of the
methoxy absorptions of the isolated isomers of 5 superimposed for reference (all colour coded to each individual isomer).
Conclusion
In conclusion, while the first and second generation molecular motors feature stereogenic centres, we have demonstrated that in the third generation molecular motors presented here, the presence of a pseudo-asymmetric centre is sufficient to induce unidirectional rotary motion. Although the molecule is achiral and possesses a plane of symmetry, the pseudo-asymmetric carbon atom with two substituents of distinct size imposes the necessary bias to result in unidirectional rotation of the two rotor moieties powered by light. Despite its symmetric nature, there is still a need for some form of chiral information, that is, pseudo-asymmetry facilitating the presence of both P and M helices, brought about by restricted configurational freedom. Photochemical E–Z isomerization, followed by thermal helix inversion around two double bonds, allows both rotors to move in the same direction with respect to their surroundings, like wheels on an axle. This study proves that intrinsic directionality in autonomous rotary motion at the molecular level can be obtained in a genuine achiral molecular motor, and provides important insight into controlling nanoscale movement in order to meet the challenge of designing future molecular machines. 0 1 2 3 4 5 0 4 8 12 16
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Acknowledgements
The concept of third generation molecular motors was conceived by Johan Visser.[64] Peter Štacko performed the synthesis of motors 4 and 5.[59]
Experimental Section
General remarksReagents were purchased from Aldrich, Merck or Fluka and were used as provided unless otherwise stated. The solvents were distilled and dried, if necessary, by standard methods. Column chromatography was performed on silica gel (Grace Reveleris or Merck type 9385 230–400 mesh) using positive pressure, TLC: silica gel 60, Merck, 0.25 mm. High Resolution Mass spectra (HRMS) were recorded on an LTQ Orbitrap XL. NMR spectra were obtained using a Varian Gemini-200 (1H: 200 MHz, 13C: 50 MHz), a Varian Mercury Plus (1H: 400 MHz, 19F: 376 MHz, 13C: 100 MHz), a Varian Unity Plus (1H: 500 MHz, 19F: 470 MHz, 13C: 125 MHz) or a Varian Innova (1H: 600 MHz, 19F: 564 MHz) in CDCl
3 or CD2Cl2. Chemical shifts are reported in δ units (ppm) relative to the residual deuterated solvent signal of CDCl3 (1H NMR, δ 7.26 ppm; 13C NMR, δ 77.0 ppm) or CD2Cl2 (1H NMR, δ 5.32 ppm; 13C NMR, δ 54.0 ppm). The splitting patterns are designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), td (triplet of doublets), qt (quartet of triplets), m (multiplet) and br (broad). SFC was performed on a Thar SFC system consisting of a fluid delivery module (FDM10-1), an autosampler (a modified Alias 840), a semi-prep column oven, PDA detector, a back pressure regulator (ABPR20), heat-exchanger, and a fraction collector (modified Thar SFC-FC). UV-vis absorption spectra were measured on a Jasco V-630 or a Hewlett-Packard 8453 spectrometer. CD spectra were measured on a Jasco J-815 CD spectrometer. Dichloromethane used for spectroscopic studies was of spectroscopic grade (UVASOL Merck). Irradiations were performed using a spectroline ENB-280C/FE lamp (λmax = 365 nm), a Lot-Oriel 75 W ozone free Xenon lamp coupled to a Zolix 150 monochromator with slit widths set to 20 microns (monochromated light was focused on the sample using a 5 cm diameter lens (F 15 mm, Thorlabs)), or an LED (5 W, 365 nm, 10 nm width at half-height), mounted in a modified Nalorac Z-Spec probe in the Varian Innova-600 NMR.
Characterization of 4.
9,9'-(2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(9H-fluorene) meso-(r)-4 is a bright yellow solid. M.p. 240.9–241.2 °C (deg.); 1H NMR (500 MHz, CD 2Cl2): δ (ppm) 8.10 (m, 2H), 7.697.73 (m, 4H), 7.43 (d, J = 7.9 Hz, 2H), 7.287.35 (m, 4H), 7.267.29 (m, 4H), 7.12 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 2H), 2.19 (d, J = 17.2 Hz, 3H), 2.14 (s, 6H); 13C NMR (126 MHz, CD 2Cl2): δ (ppm) 145.7 (d, J = 19.4 Hz), 141.1 (d, J = 5.0 Hz), 139.8, 139.4, 138.2, 136.8, 134.5, 132.6, 131.0, 127.8, 127.4, 127.1 (d, J = 14.1 Hz), 126.6, 126.4, 123.4, 119.2, 119.0, 109.4 (d, J = 206.2 Hz), 21.9 (d, J = 24.2 Hz), 21.2; 19F NMR (376 MHz, CDCl3): δ (ppm) −133.2 (qt, J1 = 16.7 Hz, J2 =
160
6
Isolation and characterization of isomers of 5
9,9'-(2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(2-methoxy-9H-fluorene) 5 as a mixture of isomers (1:1:2 by NMR) inseparable by column chromatography is a bright yellow solid. M.p. 240.5–241.4 °C (deg.); 1H NMR (400 MHz, CDCl 3): δ (ppm) 8.06 (dd, J1 = 6.5 Hz, J2 = 6.5 Hz, 2H), 7.66 (m, 2H), 7.60 (dd, J1 = 8.6 Hz, J2 = 8.6 Hz, 8H), 7.44 (d, J = 7.9 Hz, 2H), 7.247.32 (m, 10H), 7.03–7.08 (m, 4H), 6.92 (dd, J1 = 8.4 Hz, J2 = 1.1 Hz, 2H), 6.87 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 2H), 3.93 (s, 6H), 3.69 (s, 3H), 3.67 (s, 3H), 2.172.25 (m, 18H); 13C NMR (100 MHz, CDCl 3): δ (ppm) 159.99, 159.60, 159.58, 146.39, 146.37, 146.3, 146.19, 146.18, 146.1, 142.3, 142.21, 142.19, 142.15, 142.13, 142.07, 141.14, 141.12, 141.00, 140.95, 140.67, 140.64, 139.42, 139.36, 139.33, 139.30, 137.74, 135.52, 135.50, 135.43, 135.41, 135.34, 135.32, 135.22, 135.20, 134.32, 134.30, 133.95, 133.54, 133.40, 133.26, 132.35, 132.32, 132.30, 132.27, 128.75, 128.31, 127.85, 127.81, 127.71, 127.67, 126.34, 126.29, 126.20, 126.18, 126.13, 126.11, 124.09, 124.06, 120.39, 120.36, 119.13, 119.01, 114.49, 114.35, 114.07, 114.00, 113.92, 113.86, 113.43, 111.07, 111.00, 110.24, 109.88, 109.01, 108.94, 56.14, 56.01, 55.90, 55.79, 22.58, 22.34, 21.65, 21.62; 19F NMR (376 MHz, CDCl3): δ (ppm) −132.7 (qt, J1 = 16.9 Hz, J2 = 4.8 Hz), −133.1 (qt, J1 = 16.9 Hz, J2 =
5.2 Hz), −133.3 (qt, J1 = 16.8 Hz, J2 = 5.4 Hz); HRMS (APCI-Ion trap): calcd for
C40H32FO2+ [M + H]+ 563.2381 found 563.2364.
9,9'-((R,1-(Z,M),3-(E,P))-2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(2-methoxy-9H-fluorene) ((R,(Z,M),(E,P))-5). A solution of 5 was subjected to SFC
(Chiralpak®IA, 32% IPA, 340 nm, 3.5 mL·min−1, T = 40 °C, 180 bar) tR = 6.3 min. The collected solution was concentrated
in vacuo and the residue was subjected to column chromatography on silica gel (pentane : CH2Cl2 – 5 : 1) affording (R,(Z,M),(E,P))-5. 1H NMR (599 MHz, CD 2Cl2) δ = 8.04 (t, J = 6.5 Hz, 1H), 7.64 (dd, J1 = 4.9 Hz, J2 = 2.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.33 – 7.22 (m, 5H), 7.05 – 7.03 (m, 2H), 6.91 (dd, J1 = 8.3 Hz, J2 = 2.1 Hz, 1H), 6.85 (dd, J1 = 8.2 Hz, J2 = 2.3 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 2.23 (s, 3H), 2.18 (d, J =17.1 Hz, 3H), 2.18 (s, 3H). 9,9'-((S,1-(Z,P),3-(E,M))-2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(2-methoxy-9H-fluorene) ((S,(Z,P),(E,M))-5). A solution of 5 was subjected to SFC
(Chiralpak®IA, 32% IPA, 340 nm, 3.5 mL·min−1, T = 40 °C, 180 bar) tR = 7.0 min. The collected solution was concentrated
in vacuo and the residue was subjected to column chromatography on silica gel (pentane : CH2Cl2 – 5 : 1) affording (S,(Z,P),(E,M))-5. 1H NMR (599 MHz, CD
2Cl2) δ = 8.05 (t, J = 6.5 Hz, 1H), 7.66 (dd, J1 = 4.9 Hz, J2 = 2.2 Hz, 1H),
7.62 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.44 (d, J =
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THIRD GENERATION MOLECULAR MOTORS
6
1H), 6.87 (dd, J1 = 8.3 Hz, J2 = 2.3 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.24 (s, 3H), 2.19 (d,
J =17.2 Hz, 3H), 2.19 (s, 3H).
9,9'-((r,1-(E,P),3-(E,M))-2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(2-methoxy-9H-fluorene) ((r,E,E)-5). A
solution of 5 was subjected to SFC (Chiralpak®IA, 32% IPA, 340 nm, 3.5 mL·min−1, T = 40 °C, 180 bar) t
R = 9.2 min. The collected solution was concentrated in vacuo and the residue was subjected to column chromatography on silica gel (pentane : CH2Cl2 – 5 : 1) affording (r,E,E)-5. 1H NMR (599 MHz, CD2Cl2) δ = 8.06 (t, J = 6.7 Hz, 2H), 7.61 (d, J = 7.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.32 (s, 2H), 7.30 (t, J = 7.1 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.06 (d, J = 2.3 Hz, 2H), 6.87 (dd, J1 = 8.3 Hz, J2 = 2.3 Hz, 2H), 3.67 (s, 6H), 2.25 (s, 6H), 2.19 (d, J =17.1 Hz, 3H). 9,9'-((r,1-(Z,P),3-(Z,M))-2-fluoro-2,4,7-trimethyl-1H-indene-1,3(2H)-diylidene)bis(2-methoxy-9H-fluorene) ((r,Z,Z)-5). A
solution of 5 was subjected to SFC (Chiralpak®IA, 32% IPA, 340 nm, 3.5 mL·min−1, T = 40 °C, 180 bar) t
R = 11.3 min. The collected solution was concentrated in vacuo and the residue was subjected to column chromatography on silica gel (pentane : CH2Cl2 – 5 : 1) affording (r,Z,Z)-5. 1H NMR (599 MHz, CD2Cl2) δ = 7.66 (dd, J1 = 4.9 Hz, J2 = 2.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.30 (s, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.05 (t, J = 7.5 Hz, 2H), 6.92 (dd, J1 = 8.3 Hz, J2 = 2.1 Hz, 2H), 3.92 (s, 6H), 2.20 (d, J =17.1 Hz, 3H), 2.19 (s, 6H).
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