Improving the Selectivity of the C–C Coupled Product Electrosynthesis by Using Molecularly Imprinted Polymer—An Enhanced Route from Phenol to Biphenol

We developed a procedure for selective 2,4-dimethylphenol, DMPh, direct electro-oxidation to 3,3′,5,5′-tetramethyl-2,2′-biphenol, TMBh, a C–C coupled product. For that, we used an electrode coated with a product-selective molecularly imprinted polymer (MIP). The procedure is reasonably selective toward TMBh without requiring harmful additives or elevated temperatures. The TMBh product itself was used as a template for imprinting. We followed the template interaction with various functional monomers (FMs) using density functional theory (DFT) simulations to select optimal FM. On this basis, we used a prepolymerization complex of TMBh with carboxyl-containing FM at a 1:2 TMBh-to-FM molar ratio for MIP fabrication. The template–FM interaction was also followed by using different spectroscopic techniques. Then, we prepared the MIP on the electrode surface in the form of a thin film by the potentiodynamic electropolymerization of the chosen complex and extracted the template. Afterward, we characterized the fabricated films by using electrochemistry, FTIR spectroscopy, and AFM, elucidating their composition and morphology. Ultimately, the DMPh electro-oxidation was performed on the MIP film-coated electrode to obtain the desired TMBh product. The electrosynthesis selectivity was much higher at the electrode coated with MIP film in comparison with the reference nonimprinted polymer (NIP) film-coated or bare electrodes, reaching 39% under optimized conditions. MIP film thickness and electrosynthesis parameters significantly affected the electrosynthesis yield and selectivity. At thicker films, the yield was higher at the expense of selectivity, while the electrosynthesis potential increase enhanced the TMBh product yield. Computer simulations of the imprinted cavity interaction with the substrate molecule demonstrated that the MIP cavity promoted direct coupling of the substrate to form the desired TMBh product.


Table of content
Table S1.

Section S2
Detailed description of the used instruments S7 Scheme S2.The cross-sectional view of the three-electrode V-shaped electrochemical glass minicell S11 Table S2.
Standard Gibbs free energy gain (∆G 0 bind ) accompanying formation of prepolymerization complexes S12 Table S3.AFM analysis of morphological and nanomechanical parameters of MIP and NIP films before and after TMBh extraction S20

Section S2 Detailed description of the used instruments
An expanded and more detailed instrumentation description is given here.A Bio-Logic SAS SP-300 potentiostat/galvanostat electrochemistry system controlled by EC-Lab v.10.37 software of the same manufacturer was used for the potentiodynamic electropolymerization, differential pulse voltammetry (DPV) measurements, polymer conditioning, and potentiostatic electrosynthesis.MIP films and electrosynthesis were preliminarily characterized and optimized using soft-glass shrouded Pt disk working electrodes with a 0.44 mm 2 area.The electrosynthesis was upscaled using Pt plate working electrodes with a 2.74 cm 2 area.The active surface area in electrosynthesis was 1.90 cm 2 .A silver wire was used as the quasi-reference electrode, with its potential calibrated using a ferrocene (C 10 H 10 Fe) internal redox probe.A 4-mm diameter 45-mm long graphite rod was used as the counter electrode.The Shimadzu UV-2501 spectrophotometer was used to record UV-vis spectra of the pre-polymerization complex solution and the solution components with 0.1-nm resolution.All spectra have been recorded using an acetonitrile (ACN) : dichloromethane (DCM) (9 : 1, v/v) solution.For comparison, spectra of 1 : 1 and 2 : 1 BTMA : TMBh mixture were calculated from spectra of pure BTMA and TMBh using Lambert-Beer law and compared to experimental spectra recorded for those mixtures in solution.This procedure allowed finding regions where experimental and calculated spectra changes occurred.The transmission FTIR spectroscopy measurements were performed using a Bruker Vertex 80v spectrophotometer equipped with a DTGS detector to understand the binding within the pre-polymerization complex.The spectra were recorded on ZnSe windows coated with drop-cast samples.The pre-polymerization complex solution and solutions of individual components of MIP were prepared using the acetonitrile (ACN) : dichloromethane (DCM) (9 : 1, v/v) solution.The FTIR spectra of the MIP and NIP films before and after exposure to (acetic acid) : methanol extraction solution were recorded with a

S8
Bruker Vertex 80v FTIR spectrophotometer using polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS).The spectrophotometer was equipped with a PMA50 module for those experiments.A (liquid nitrogen)-cooled MCT (Hg-Cd-Te) detector was used to reach a reasonably high signal-to-noise ratio.Grazing angle FTIR (GA-FTIR) spectroscopy was used to characterize the MIP-a films deposited on Au-layered glass slides under potentiodynamic conditions.The measurements were performed using the same Bruker Vertex 80v spectrophotometer with GS19650 grazing-angle accessory of SPECAC at the 70° incident angle with pressure decreased to 6 hPa in the sample compartment.FTIR spectra of the synthesized functional monomer were recorded using a single reflection attenuated total reflection (ATR) Platinum accessory of Bruker mounted in the same FTIR spectrophotometer.OPUS 7 software of Bruker was used to analyze all IR spectra.
Nuclear magnetic resonance (NMR) 13 C and 1 H spectra of functional monomers were recorded using an Agilent DD2 400 MH spectrometer.Methanol with a 100 µL/min flow rate was used as the mobile phase.The measurement was performed in the negative ion mode with the resolving power of the qTOF analyzer at 20,000 full widths at half maximum.The lock-spray source generated the lock-spray spectrum of S10 Leucine-enkephalin, and the recorded spectra in the range of m/z = 50 -1200 were corrected.
The desolvation and cone gas used was nitrogen, and their flow rates were set to 600 and 100 L/h, respectively.The ion source and probe temperatures were 120 and 550 °C, respectively.The nebulizer gas pressure was 5.0 bar.The corona current was 12.0 µA, and the sampling cone voltage and source offset were 30 V. The instrument was controlled, and the data were processed using the MassLynx V4.1 software package (Waters).Exemplary HPLC chromatograms at 280 nm for fractions collected after 14-h electrosynthesis at the bare, as well as the MIP-a and NIP-a film-coated electrodes.The compounds were analyzed using a Luna 5μm C18(2) 100 Å reversed-phase liquid chromatography column.A mobile phase composed of ultrapure water (Solvent A) and ACN (Solvent B) was used for gradient elution.A linear gradient was used from a 50 : 50 ratio (Solvent A : Solvent B, v/v) at 0 time to a 5 : 95 ratio at 20 minutes.

Figure S1 .
Figure S1.Current-potential curves for the potentiodynamic electropolymerization of diphenylamine-2-carboxylic acid, DACA S14 Figure S2.Experimental and simulated UV-vis spectra for TMBh complexation with FM at the TMBh S14 Figure S3.FTIR spectroscopic analysis of TMBh complexation with FM S15 Figure S4.FTIR spectral region of interest for TMBh complexation with FM S16 Figure S5.PM-IRRAS and GA-FTIR spectra for MIP-b and NIP-b film-coated Au electrodes before and after extraction S17 Figure S6.Atomic force microscopy images of the thick MIP-a films S18 Figure S7.Atomic force microscopy images of the thin MIP-b films S19

Figure S10 .Figure S11 .Figure S12 .Figure S13 .Figure S14 .S3Figure S15 .Figure S17 .
Figure S8.Young modulus maps of MIP and NIP films S21 Figure S9.The cyclic voltammogram of 2,4-dimethylphenol S22 Figure S10.CV curves recorded during pre-treatment of the MIP-a film-coated Pt electrode S23 Figure S11.The charge passed as a function of electrosynthesis time during electrooxidation of DMPh S23 Figure S12.HPLC chromatograms for the DMPh substrate and the desired TMBh product.S24 Figure S13.Exemplary HPLC chromatograms for fractions collected after 14-h electrosynthesis S25 Figure S14.Mass spectra of fractions of the reaction mixture and DMPh and TMBh S26 Before and after exposure to extraction solution, the MIP and NIP films were also imaged by atomic force microscope (AFM) in the Tapping™ or PFQNM mode with a MultiMode 8 AFM of Bruker controlled by a Nanoscope V controller.A p-doped Si cantilever and tip (RTESP) with a spring force constant of 58.3 N/m were used for measurements.Simultaneously, film topography and nanomechanical properties were measured.Further, the AFM analysis, which included the determination of film roughness, thickness, and phase changes within the film, was performed using NanoScope Analysis v.1.2software of Bruker.The Derjaguin-Muller-Toporov model was used to calculate the Young modulus and unravel the nanomechanical properties.The electrosynthesis products were analyzed using an analytical high-performance liquid chromatograph (HPLC) system from Shimadzu Corp. (Kyoto, Japan) with a gradient chromatography set consisting of a DGU-20A degassing unit, LC-20AT liquid S9 chromatograph to control the gradient mobile-phase solutions and an SPD-M20A UV-vis diode array detector.This system also contained the SIL-20A autosampler of the same manufacturer.The compounds' mixtures were separated using a Luna® 5μm C18(2) 100 Å reversed-phase liquid chromatography column (250 × 4.6 mm i.d., Torrance CA, USA).A mobile phase composed of ultrapure water of 18.2 MΩ cm resistivity at 25 °C and a total organic carbon (TOC) value below 5 ppb (Solvent A) and ACN (Solvent B) was used for gradient elution.A linear gradient was used from a 50 : 50 ratio (Solvent A : Solvent B, v/v) to a 5 : 95 ratio at 20 min.Reference compounds of the DMPh substrate and the desired TMBh product were used for identifying compounds and calibrating chromatograms.An FRC-10A fraction collector from Shimadzu attached to the HPLC system was used to collect different fractions of the reaction mixture at retention times of6.7,11.0, 14.1, 14.9, and 19.7    min.These fractions were then passed through a silica gel 60 (0.040 -0.063 mm, mesh 230 -400, Merck KGaA) LC 50-mm long homemade column with a 10 mm diameter using DCM as the mobile phase to remove the supporting electrolyte from the solution.Afterward, the DCM was evaporated from the eluate, and the solid left was resuspended in 1 mL of an ACN : DCM (9 : 1, v/v) solution.The reference DMPh compound was used directly after diluting with the ACN : DCM (9 : 1, v/v) solution for the mass spectrometry (MS) analysis.MS analyses were performed using a Synapt G2-S mass spectrometer (Waters, Milford, MS, USA) equipped with an atmospheric pressure chemical ionization (APCI) system and a quadrupole-time-of-flight (qTOF) mass analyzer.Samples were dissolved in methanol (Honeywell, LC-MS Chromasolv™, purity ≥ 99.9%) and then injected into the APCI ion source.The injection volume was 1 to 8 µL, depending on the concentration of the samples.

Figure S11 .Figure S12 .
Figure S11.The charge passed as a function of electrosynthesis time during electrooxidation of 20 mM DMPh at the bare, as well as MIP-a, MIP-b, as well as NIP-a and NIPb film-coated 1.90-cm 2 active area Pt plate electrode at 1.20 V vs. Ag quasi-reference electrode in the acetonitrile : dichloromethane (9 : 1, v/v) solution of 100 mM (TBA)ClO 4 .

Figure S14 .
Figure S14.Mass spectra of reference compounds of (a) DMPh and (b) TMBh, as well as HPLC fractions of the reaction mixture collected at the retention time of (c) 6.7,(d) 11.0, (e) 14.9, and (f) 19.7 min.All spectra were acquired using the negative ion mode and the atmospheric pressure chemical ionization (APCI).

Figure S15 .
Figure S15.UV-vis spectra for (a) the DMPh substrate and (b) the desired TMBh product, as well as for HPLC fractions of the reaction mixture collected at the retention time of (c) 6.7,(d) 11.0, (e) 14.9, and (f) 19.6 min.All spectra were acquired using a diode-array UV-vis detector.

Figure S17 .
Figure S17.The computationally simulated interactions of two DMPh •+ substrate radical cations, indicated with dash segments, in the skeleton model of the MIP cavity.

Table S3 .
AFM analysis of morphological and nanomechanical parameters of MIP and NIP films before and after TMBh extraction/incubation for 180 min.in the (acetic acid) : methanol (1 : 1, v/v) solution.