A Proton-Coupled Electron Transfer Strategy to the Redox-Neutral Photocatalytic CO2 Fixation

Herein, we report our study on the design and development of a novel photocarboxylation method. We have used an organic photoredox catalyst (PC, 4CzIPN) and differently substituted dihydropyridines (DHPs) in combination with an organic base (1,5,7-triazabicyclodec-5-ene, TBD) to access a proton-coupled electron transfer (PCET) based manifold. In depth mechanistic investigations merging experimental analysis (NMR, IR, cyclic voltammetry) and density-functional theory (DFT) calculations reveal the key activity of a H-bonding complex between the DHP and the base. The thermodynamic and kinetic benefits of the PCET mechanism allowed the implementation of a redox-neutral fixation process leading to synthetically relevant carboxylic acids (18 examples with isolated yields up to 75%) under very mild reaction conditions. Finally, diverse product manipulations were performed to demonstrate the synthetic versatility of the obtained products.

Chromatographic purification of products was accomplished using flash chromatography on silica gel (SiO2, 0.04-0.063 mm) purchased from Machery-Nagel, with the indicated solvent system according to the standard techniques. Thin-layer chromatography (TLC) analysis was performed on pre-coated Merck TLC plates (silica gel 60 GF254, 0.25 mm). Visualization of the developed chromatography was performed by checking UV absorbance (254 nm and 365 nm) as well as with phosphomolybdic acid and potassium permanganate solutions. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator.
NMR spectra were recorded on a Bruker Avance 300 spectrometer equipped with a BBO-z grad probehead, a Bruker 400 AVANCE III HD equipped with a BBI-z grad probehead, and a Bruker AVANCE Neo 600 equipped with a TCI Prodigy cryoprobe. The chemical shifts (δ) for 1 H and 13 C are given in ppm relative to residual signals of the solvents (CHCl3 @ 7.26 ppm 1 H NMR, 77.2 ppm 13 C NMR; acetone @ 2.05 ppm 1 H NMR, 29.84 ppm 13 C NMR). Coupling constants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, broad signal; qd, quartet of doublets; brs, broad singlet; brd, broad doublet; brt, broad triplet. NMR yields were calculated by using dibromomethane (4.95 ppm, s, 2H) as internal standard.
High-Resolution Mass Spectra (HRMS) were obtained using Waters GCT gas chromatograph coupled with a time-of-flight mass spectrometer (GC/MS-TOF) with electron ionization (EI).
Steady-state absorption spectroscopy studies have been performed at room temperature on a Varian Cary 50 UV-Vis double beam spectrophotometer; 10 mm path length Hellma Analytics 100 QS quartz cuvettes have been used.
IR measurements were carried out at room temperature on a JASCO FT/IR-4100 spectrophotometer; 1 mm path length Hellma Analytics 100 QX quartz cuvettes have been used.
The electrochemical characterizations were carried out at room temperature, on a BASi EC Epsilon potentiostat-galvanostat. A typical three-electrode cell was employed, which was composed of glassy carbon (GC) working electrode (3 mm diameter), a platinum wire as counter electrode and a silver/silver chloride electrode (Ag/AgCl (NaCl 3 M)) as reference electrode. The reference electrode is a silver wire that is coated with a thin layer of silver chloride; the electrode body contains sodium chloride (NaCl 3 M). The GC electrode was polished before any measurement with diamond paste and ultrasonically rinsed with deionized water for 15 minutes.

A.2. PHOTOREACTOR SETUP
The experiments have been carried out in 4 mL vials equipped with PTFE/silicone septum caps, both purchased from Sigma Aldrich, or in a 50 mL Schlenk tube. Whether three vials, or the Shlenk tube are wrapped together using LED strip covered with a rubber waterproof case, as illustrated in Figure S4, and immersed in a thermostat water-bath to maintain a stable reaction temperature (20±2°C) as depicted in Figure S5. For safety and contamination reason, during the experiments, the photoreactor was enveloped with Aluminum sheets. The reactions were stirred vigorously using a stirring plate.

B.9. UNREACTIVE SUBSTRATES
The following list of substrates gave no product at all or gave poor reactivity. Figure S6. List of unreacted substrates tested in this work.

C.1. PREPARATION OF ALDEHYDES S1-S7 AS SYNTHETIC PRECURSORS
The corresponding alcohol (2.5 mmol, 1.0 equiv.) was added under Argon atmosphere to 20 mL of anhydrous dichloromethane in a flame-dried 100 mL round-bottom flask and left stirring at room temperature. Separately, 1.27 g of Dess-Martin periodinane (3 mmol, 1.2 equiv.) were added to 25 mL of anhydrous dichloromethane under Argon atmosphere in a flame-dried 50 mL round-bottom flask. The resulting mixture was stirred until a homogenous solution has been obtained, then it was added dropwisely to the solution of the alcohol. The final mixture was stirred for 1.5 hours at room temperature; precipitate formation was observed. The reaction was quenched by slow addition of saturated NaHCO3 (aq), then the organic phase was collected and washed with a 6% (m/V) aqueous solution of NaS2O4 (3 x 50 mL). The resulting organic phase, obtained discarding the solid residuals, was dried over MgSO4, filtered and concentrated under reduced pressure.
Crude aldehydes S1-S7 were used in further synthetic steps without further purification.
These data matched with the previously reported in literature. 4
These data matched with the previously reported in literature. 4

C.2. PREPARATION OF ALDEHYDE S8 AS SYNTHETIC PRECURSOR
S8 was synthesized following a procedure reported in literature. 7 1.48 g of trans-anethol (10 mmol, 1 eq.) were dissolved in 60 ml mixture of 1,4-dioxane:water 5:1. 3.60 g of Ag2O (15.5 mmol, 1.55 eq.) was added in one portion. To the vigorously stirred suspension, 3.93 g (15.5 mmol, 1.55 eq.) iodine was added portionwise during 5 min. The first purple and then red-coloured solution was stirred for an hour at room temperature, then it was filtered. The clear red solution was washed with 50 mL of saturated Na2S2O3 (aq), with disappearance of the red colour, then extracted with diethyl ether (3 x 50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure yielding S8 in 87% yield (1.43 g, 8.7 mmol) as a pale-yellow oil. These data matched with the previously reported in literature. 8

C.3. PREPARATION OF ALDEHYDE S9 AS SYNTHETIC PRECURSOR
S9 was prepared following a previously reported procedure. 7 To a suspension of 12.9 g of (methoxymethyl)triphenylphosphonium chloride (37.5 mmol, 1.5 eq.) in 50 ml diethyl ether under inert gas were added dropwise at -78 °C 7.75 ml of a 1.6 M solution of n-BuLi in hexane (9.9 mmol 0-4 equiv.) and then 16.5 ml of a 1.9 M PhLi solution in dibuthyl ether (31.5 mmol 1.25 equiv.). The yellow suspension was then stirred at 0 °C for another hour and became brown. The suspension was again cooled to -78 °C and a solution of 3.65 g of α-tetralone (25 mmol) in 18.75 ml of ether was added to the suspension. The mixture was stirred for 2 hours more at rt and became an orange suspension. The mixture was poured into 50 mL of saturated ice-cold NH4Cl (aq) and extracted with ethyl acetate (3 x 50 mL). The reunited organic phases were washed once with water and once with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was isolated by flash chromatography on silica gel (cyclohexane:ethyl acetate 5:1) in 54% yield (2.35 g, 13.5 mmol). Without further purification, this was dissolved in 15.7 ml of formic acid and stirred at room temperature for 16 hours resulting in a brown solution. Saturated NaHCO3(aq) was added until pH = 8.2 was reached, then the mixture was extracted with ethyl acetate (3 x 50 mL). The collected organic phase was washed once with water and once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Product S9 was isolated by silica gel flash chromatography (cyclohexane:ethyl acetate 50:1) in 29% (625 mg, 3.9 mmol) as a colourless oil. These data matched with the previously reported in literature. 9 S25 C.4. PREPARATION OF ALDEHYDE S10 AS SYNTHETIC PRECURSOR S10 was prepared according to reported literature procedure. 10 4.4 g of NaH 60% dispersion in paraffine oil (110 mmol, 1.1 equiv.) was suspended in 40 mL of anhydrous THF and the solution was cooled to 0°C. A solution of 13.4 mL of 2-phenylpropanal (100 mmol 1.0 equiv.) in 40 mL of THF was added dropwise over an hour and the suspension was stirred a further 30 minutes before 12.5 mL of methyl iodide (200 mmol, 2.0 equiv.) was carefully added dropwise, maintaining the temperature below 15°C. The reaction was stirred a further hour at 15°C before being brought to room temperature. The reaction was quenched by the addition of 200 mL saturated NaHCO3(aq) and extracted with diethyl ether (3 x 50 mL). The organic phases were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by vacuum distillation to give S10 in 48% yield (7.18 g, 48 mmol) as a yellow oil. These data matched with the previously reported in literature. 11 S26 C.5. PREPARATION OF ALDEHYDE S11 AS SYNTHETIC PRECURSOR S11 was obtained following a procedure reported in literature. 7 1.25 g of 1-(naphthalen-2yl)ethanone (7.4 mmol, 1.0 equiv.) was dissolved in 25 ml of toluene under argon atmosphere. 3.80 g of (methoxymethyl)triphenylphosphonium chloride (11.1 mmol, 1.5 equiv.) were added at room temperature, then 1.33 g of t-BuOK (11.8 mmol, 1.6 eq.) were added in four portions every 15 minutes to the suspension. The orange suspension was stirred until the mixture turned deep red and clear, with consumption of starting material, in 3 h. The solution was added dropwise to 100 ml water and stirred for 10 min, then extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. 2-(1-methoxyprop-1-en-2-yl)naphthalene is obtained as a white solid by flash chromatography on silica gel (cyclohexane:ethyl acetate 4:1) in 80 % yield (1.17 g, 5.9 mmol). This was dissolved in 33 ml of THF, and 33 ml of 1M HCl solution were added dropwise in 4 portions every 10 min. Finally, 130 ml of ethanol were added to the solution, which was then heated to 50 °C, using an oil bath, under reflux condenser for 6 hours. After cooling to room temperature, solid NaHCO3 was added to the colourless solution (with CO2 development), until neutral pH value. The aqueous solution was extracted with ethyl acetate (3 x 50 mL) and the collected organic phase was washed once with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Pure S11 was obtained by flash chromatography on silica gel (cyclohexane:ethyl acetate 4:1) in 52% yield (563 mg, 3.1 mmol) as white solid. These data matched with the previously reported in literature. 12 S27

C.6. PREPARATION OF ALDEHYDE S12 AS SYNTHETIC PRECURSOR
Following a reported procedure, 13 to 355 mg of anhydrous CuSO4 (2.2 mmol, 10 mol%) 10 mL of chloroform and 2.5 mL of styrene (21.7 mmol, 1.0 equiv.) were added. Then a solution of 4.6 mL of ethyl diazoacetate (43.4 mmol, 2.0 equiv.) in 20 mL of chloroform was added dropwise over 1.5 h. After stirring for 14 h at 75°C, using an oil bath, the mixture was concentrated in vacuo to a green oil. This was purified by flash chromatography on silica gel using hexane: ethyl acetate 9:1 as eluent giving a mixture of ethyl 2-phenylcyclopropane-1carboxylate isomers as a clear oil in 51% yield (2.11 g, 11.1 mmol) In an oven-dried round-bottom flask 842 mg of LiAlH4 (22.2 mmol, 2.0 equiv.) were dissolved in 25 mL of anhydrous diethyl ether under a nitrogen atmosphere. The reaction mixture was cooled to 0°C and a solution of 2.11 g of the ethyl 2-phenylcyclopropane-1carboxylate (11.1 mmol, 1.0 equiv.) in 25 mL of anhydrous THF was added dropwise. The reaction mixture was stirred for 12h at reflux, using an oil bath, then the slurry was quenched with 1 mL of NaOH (aq) 15 % w/w and 3 mL of water. The ethereal solution was filtered, and the solid residue was triturated with ether. The combined organic solutions were washed with saturated aqueous NaCl solution and dried (MgSO,). The solvent was removed at reduced pressure yielding 92% of the corresponding alcohol (1.51 g, 10.2 mmol) which was used without further treatment. In an oven-dried round-bottom flask 970 µL of oxalylchloride (11.3 mmol, 1.1 equiv.) were dissolved in 30 mL of anhydrous dichloromethane under a nitrogen atmosphere. The reaction mixture was cooled to -78°C, then 1.8 mL of anhydrous DMSO (24.5 mmol, 2.4 equiv.) and a solution of 1.51 g of the previously synthesized (2-phenylcyclopropyl)methanol (10.2 mmol, 1.0 equiv.) in 15 mL of anhydrous dichloromethane was added dropwise. The reaction mixture was stirred for 15 min, then 7.9 mL of anhydrous triethylamine (51 mmol, 5.0 equiv.) were added and the reaction was stirred for an additional 2h at room temperature. After reaction completion monitored by TLC, the slurry was quenched with the addition of 15 mL of water and extracted with diethylether (2 x 20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. 2-phenyl-cyclopropane-1-carbaldehyde was obtained in 82% yield (1.23 g, 8.4 mmol) as pale-yellow oil after column chromatography on silica gel (hexane:ethyl acetate 9:1).
In a 250-mL oven-dried round-bottomed flask 3.26 g of methyltriphenylphosphonium bromide (9.1 mmol, 1.1 equiv.) were suspended in 50 mL of anhydrous THF under a nitrogen atmosphere. The mixture was cooled to 0 °C and 3.7 mL of 2.5 M solution of n-butyllithium in hexanes (9.1 mmol, 1.1 equiv.) was added in a dropwise fashion. The cooling bath was removed, and the mixture was stirred at room temperature for 30 min. Next, a solution of 1.22 g of 2-phenylcyclopropane-1-carbaldehyde (8.3 mmol, 1.0 equiv.) in 15 mL of anhydrous THF was added through the septum at room temperature. The mixture was left stirring at room temperature overnight, then it was quenched adding 30 mL of saturated NH4Cl (aq). The aqueous layer was washed with diethylether (3 x 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure, finally the crude alkene was purified using column chromatography on silica gel (hexane:ethyl acetate 95:5). Pure 2-vinylcyclopropylbenzene was obtained in 64% yield (771 mg, 5.3 mmol) as a pale-yellow oil.
To 765 mg of 2-vinylcyclopropylbenzene (5.3 mmol, 1 equiv.) dissolved in 25 mL of anhydrous THF, a solution of 17 mL of 0.5 M solution of 9-BBN in hexanes (8.5 mmol, 1.6 equiv.) in 48 mL of THF was added dropwise at 0°C. After stirring for 2 h at 0°C and for 1 h at room temperature, excess of the 9-BBN was quenched with 6 mL of ethanol. Then the reaction mixture was oxidized with 4 mL of hydrogen peroxide 30% and 4 mL of a 3 M NaOH (aq) solution stirring the mixture for 1 h at reflux, using an oil bath. After saturating with K2CO3, the organic layer was separated and the aqueous phase was extracted with diethylether (3 x 30 mL). The combined diethyl ether and THF solutions were dried over MgSO4, filtered, and concentrated under reduced pressure, pure 2-(2phenylcyclopropyl)ethan-1-ol was obtained in 58% yield (503 mg, 3.1 mmol) as a colourless oil after column chromatography on silica gel (hexane:ethyl acetate 8:2).
Finally, the alcohol was oxidized to the corresponding aldehyde following the procedure given in chapter C.1 giving S12 in 86% yield (424 mg, 2.6 mmol) as a colourless oil.

C.7. PREPARATION OF 3-AMINOBUT-2-ENENITRILE AS SYNTHETIC PRECURSOR
6.970 g (62 mmol, 1.03 equiv,) of t-BuOK were added in a 500 mL flame-dried round-bottom flask and stirred under Argon atmosphere at room temperature. After 20 minutes, 130 mL of anhydrous toluene and 3.1 mL (60 mmol, 1.0 equiv.) of anhydrous acetonitrile were added subsequently in anhydrous condition. The resulting mixture was stirred for 1.5 hours refluxing at 80°C, using an oil bath. Other 3.13 mL (60 mmol, 1.0 equiv.) of anhydrous acetonitrile were added to the grainy viscous white mixture which started becoming yellow. The suspension was stirred at 80°C for 12 more hours. The mixture was then added to 100 mL of a water-ice mixture and extracted with ethyl acetate (3 x 100 mL). The collected organic phases were washed once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure giving a clean mixture of Z and E products in 54% yield (2.67 g, 33 mmol).   Table S9.

B) A)
pKa calculation of 4a. The pKa value of 4a was estimated from spectroscopic data using the following formulas; in short, the concentration of 4a upon subsequent TBD additions was estimated by the abatement of the absorption at 343 nm (Abs 370 , with Abs0 370 being the initial absorbance); the concentration of the conjugate base 4a(N -) was then calculated from the difference between the initial concentration of 4a and the concentration of 4a after TBD addition. The concentration of TBDH + was assumed equivalent to the concentration of 4a(N -). The pKa(4a) was then estimated 30.5±0.3, from the average of the values reported in table, and with an error bar corresponding to the maximum semidispersion.

F. DFT CALCULATIONS
DFT calculations were performed with Gaussian 16, 19 using the density functional theory (DFT) employing the B3LYP method, a 6-311G basis set and (d, p) polarization functions. The self-consistent reaction field (SCRF) was used with DFT energies, optimizations, and frequency calculations to model systems in acetonitrile solution.