Stepwise Operation of a Molecular Rotary Motor Driven by an Appel Reaction

To date, only a small number of chemistries and chemical fueling strategies have been successfully used to operate artificial molecular motors. Here, we report the 360° directionally biased rotation of phenyl groups about a C–C bond, driven by a stepwise Appel reaction sequence. The motor molecule consists of a biaryl-embedded phosphine oxide and phenol, in which full rotation around the biaryl bond is blocked by the P–O oxygen atom on the rotor being too bulky to pass the oxygen atom on the stator. Treatment with SOCl2 forms a cyclic oxyphosphonium salt (removing the oxygen atom of the phosphine oxide), temporarily linking the rotor with the stator. Conformational exchange via ring flipping then allows the rotor and stator to twist back and forth past the previous limit of rotation. Subsequently, the ring opening of the tethered intermediate with a chiral alcohol occurs preferentially through a nucleophilic attack on one face. Thus, the original phosphine oxide is reformed with net directional rotation about the biaryl bond over the course of the two-step reaction sequence. Each repetition of SOCl2–chiral alcohol additions generates another directionally biased rotation. Using the same reaction sequence on a derivative of the motor molecule that forms atropisomers rather than fully rotating 360° results in enantioenrichment, suggesting that, on average, the motor molecule rotates in the “wrong” direction once every three fueling cycles. The interconversion of phosphine oxides and cyclic oxyphosphonium groups to form temporary tethers that enable a rotational barrier to be overcome directionally adds to the strategies available for generating chemically fueled kinetic asymmetry in molecular systems.


S1. General methods and abbreviations
Unless stated otherwise, reagents were obtained from commercial sources and used without purification.All chemicals, reagents, were purchased from Sigma Aldrich, UK (Merck KgaA) or Fluorochem UK.Deionized water was obtained by a milli-Q water purifier (Millipore).Anhydrous solvents were obtained by passing the solvent through an activated alumina column on a Phoenix SDS (solvent drying system; JC Meyer Solvent Systems, CA, USA). 1 H and 13 C{ 1 H}} NMR spectra were recorded on a Bruker Avance III instrument with an Oxford AS600 magnet equipped with a cryoprobe [5 mm CPDCH 13 C-1 H/D] (600 MHz) and 31 P{ 1 H} NMR spectra were recorded on a Bruker Avance III instrument with an B400 magnet (400 MHz) at a constant temperature of 20 °C. 1 H, 13 C, and 31 P chemical shifts are reported in parts per million (ppm) from low to high field and referenced to the literature values for chemical shifts of residual non-deuterated solvent, with respect to tetramethylsilane (0.00 ppm) as an external standard, for 1 H and 13 C NMRs.Standard abbreviations indicating multiplicity are used as follows: s (singlet), bs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets), ddd (doublet of doublets of doublets), ddt (doublet of doublets of triplets), m (multiplet), J (coupling constant -quoted in Hz).All spectra were analyzed using MestReNova (Version 14.1.2).Fully characterized compounds were chromatographically homogeneous.Flash column chromatography was carried out using Silica 60 Å (particle size 40-63 µm, Sigma Aldrich, UK) as the stationary phase.TLC was performed on precoated silica gel plates (0.25 mm thick, 60 F254, Merck, Germany) and visualized using both short and long wave ultraviolet light in combination with standard laboratory stains (basic potassium permanganate, acidic ammonium molybdate and ninhydrin).Low resolution ESI mass spectrometry was performed with a Thermo Scientific LCQ Fleet Ion Trap Mass Spectrometer or an Agilent Technologies 1200 LC system with an Advion Expression LCMS single quadrupole MS detector.High-resolution mass spectrometry (HRMS) was carried out at the Mass Spectrometry Service, Department of Chemistry, University of Manchester.Matrixassisted laser-desorption ionization (MALDI) mass spectrometry was performed with a Brucker rapiflex using dithernol as a matrix.Chiral high performance liquid chromatography (HPLC) was performed on an Agilent 1260 Infinity system.Column and conditions are specified below.HPLC data were analysed in Open Labs CDS software, and traces were exported as .csvdata files for further plotting in OriginPro 2021b.

S2.2 Synthesis and characterization of 1a
Compound 1a was synthesized according to previously reported procedures.S1

S3. Chiral HPLC analysis of 1a and 1b
Chiral stationary phase high-performance liquid chromatography (chiral HPLC) analysis was performed to analyse 1a and 1b (see Figure S1) on a diacel ChiralPak IF column (4.6 mm × 25 mm, 5 µm particle size).A mixture of i-PrOH:n-hexane (15:85 v/v) was used as an eluent at 25 °C with a flowrate of 2 mL min −1 .Traces based on the absorbance at 240 nm are reported.HPLC data was analysed in Open Labs CDS software, and traces were exported as .csvdata files for further plotting in OriginPro 2021b.

S4.4 Directional opening of 1ʹb.
To a stock solution of 1b in CDCl3 [1] = 5.0 mM was added SOCl2, so that [SOCl2] = 50 mM, at room temperature.After completion of the transformation to 1ʹb, the enantioselective Appel reaction (as shown in Figure S8C) was initially screened by the addition of different commercially available chiral alcohols, so that [alcohol] = 50 mM] under different conditions, as given in Table 1 With the optimized procedure in hands, a 5 mM solution of 1b (76.9 µg, 0.200 µmol, 1.0 eq.) in CDCl3 (0.4 mL) was treated with SOCl2 (0.145 µL, 2.00 µmol, 10 eq.).After 5 min at room temperature, the reaction was cooled to 4 °C and either (R)-or (S)-1-phenyl ethan-1-ol (244 µg, 2.00 µmol, 10 eq.) was added.After completion of the reaction (as indicated by 1 H NMR spectroscopy, typically 16 h, see Figure S5) at 4 °C, the samples were allowed to warm up to rt and analyzed, without any further

S5. Molecular modelling of 1ʹa and 1ʹb
The energy minimized molecular structures of 1ʹa and 1ʹb were calculated using the Merck Molecular Force Field (MMFF) method and are displayed below (Figure S8).

S6. Crystallographic data
X-ray diffraction data for compound 1a and 1b were collected using a dual wavelength Rigaku FR-X rotating anode diffractometer using CuKα (λ = 1.54146Å) radiation, equipped with an AFC-11 4-circle kappa goniometer, VariMAX TM microfocus optics, a Hypix-6000HE detector and an Oxford Cryosystems 800 plus nitrogen flow gas system, at temperatures of 100K and 200K, respectively.
Data were collected and reduced using CrysAlisPro v42.S2 Absorption correction was performed using empirical methods (SCALE3 ABSPACK) based upon symmetry-equivalent reflections combined with measurements at different azimuthal angles.The crystal structure was solved and refined against all F2 values using the SHELX and Olex2 suite of programs.S3 All atoms were refined anisotropically.Hydrogen atoms were placed in calculated positions and refined using idealized geometries and assigned fixed isotropic displacement parameters.

Figure S2 :
Figure S2: Chemical transformation of 1b upon treatment with SOCl2 followed by H2O in CDCl3 at room temperature showing the formation and hydrolysis of the oxyphosphonium salt 1ʹb.A Reaction scheme for the chemical transitions.B Partial 1 H NMR (600 MHz, CDCl3, 293 K) spectra of 1b (top), 1 hour following the addition of SOCl2 to form 1ʹb (middle), and 5 minutes following the subsequent addition of H2O to reform 1b (bottom).Changes in the chemical shifts of protons A, B, C and D are indicated by dashed lines.Insert shows MALDI-ToF MS spectrum of 1'b.C Partial 31 P{ 1 H} NMR (126 MHz, CDCl3, 293 K) spectra of 1b (top), 1 hour following the addition of SOCl2 to form 1ʹb (middle), and 5 minutes following the subsequent addition of H2O to reform 1b (bottom).

Figure S8 :
Figure S8: Chemical transitions and proposed mechanisms shown on the example of 1a.A Closing of the intramolecular tether of 1a by treatment with SOCl2.B Opening of tether of 1ʹa by hydrolysis upon treatment with H2O, reforming 1a.C Opening of the tether of 1ʹa by attack of the chiral alcohol, followed by substitution of the hydroxyl group by chloride (Appel reaction) reforming 1a.

Figure S9 :
Figure S9: Ball-and-stick representation of MMFF energy minimized structures of 1ʹa and 1ʹb.