Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale.


General Information
Unless otherwise stated, all non-electrochemical reactions were conducted in flame-dried glassware under an atmosphere of dry nitrogen or argon, sealed with septum seals and were stirred with Tefloncoated magnetic stirrer bars. Unless stated otherwise, all electrochemical reactions were performed using oven-dried 10 mL ElectraSyn vials under an atmosphere of dry nitrogen, sealed with an ElectraSyn Teflon cap fitted with a graphite anode and graphite cathode (see Chapter 6 for reaction set-up), and were stirred with Teflon-coated magnetic stirrer bars. Dry tetrahydrofuran (THF), diethyl ether (Et2O) and acetonitrile (MeCN) were obtained after passing these previously degassed solvents through activated alumina columns (Mbraun, SPS-800). Tetra-n-butylammonium hexafluorophosphate (TBAPF6) and tetra-n-butylammonium tetrafluoroborate (TBABF4) were recrystallised from ethanol or water, respectively, and dried in the oven before use. All other solvents and commercial reagents were used as supplied without further purification unless stated otherwise.
All electrochemical reactions were conducted using an ElectraSyn 2.0 apparatus, purchased from IKA.
Graphite, reticulated vitreous carbon (RVC), glassy carbon (GC) and Pt electrodes were purchased from IKA and are of uniform dimensions. Graphite electrodes were used as supplied from IKA or were cut from a sheet of carbon foil (2 mm thickness) purchased from Goodfellow. The electrodes were cut to the dimension of 8 mm × 52 mm using a Dremel 3000 multi-tool fitted with an SC545 EZ SpeedClic Diamond Cutting Wheel (38 mm dia.) attachment. Graphite electrodes could be used several times by renewing the top surface of the graphite. This was achieved by scraping away the top layer with a razor blade, sonicating in MeCN for 5 minutes, followed by oven-drying for 30 mins.
Cyclic voltammetry (CV) experiments were conducted using an Autolab PGSTAT204, controlled using Nova 2.1 software. The working electrode was a GC disc (3 mm dia., BASi part number MF-2012), the counter electrode was a Pt-wire (BASi part number MW-4130) and a Ag/AgCl reference electrode was used (BASi part number -MF-2052).
Room temperature (rt) refers to 20-25 °C. Ice/water and CO2(s)/acetone baths were used to obtain temperatures of 0 °C and -78 °C respectively. All reactions involving heating were conducted using DrySyn blocks and a contact thermometer. In vacuo refers to reduced pressure through the use of a rotary evaporator.
Analytical thin layer chromatography was carried out using aluminium plates coated with silica (Kieselgel 60 F254 silica) and visualisation was achieved using ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO4 solution, or a 10% w/v solution of phosphomolybdic acid in ethanol. Flash column chromatography was performed according to the method of Still [1] using Kieselgel 60 silica in the solvent system stated using head-pressure by means of a compressed air line.
Melting points were recorded on an a Gallenkamp melting point apparatus and are reported corrected by linear calibration to benzophenone (47 -49 °C) and benzoic acid (121 -123 °C).
Infrared spectra were recorded on a Shimadzu IRAffinity-1 Fourier Transform ATR spectrometer as thin films using a Pike MIRacle ATR accessory. The most intense peaks and structurally important peaks are quoted. Absorption maxima (νmax) are recorded in wavenumbers (cm -1 ). 1 H, 13  Multiplicites are reported with the following symbols: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and combinations of these were used to denote higher order multiplicities.
High resolution mass spectrometry (HRMS, m/z) data was acquired at Cardiff University on a Micromass LCT Spectrometer.
"Petrol" refers to the fraction boiling in the range of 40-60 °C unless otherwise stated.
Current density values for the anode, janode, were calculated by dividing the current, i, passed during electrolysis by the exposed active surface area of the electrode. The exposed active surface of the electrode was calculated to be the submerged surface of the electrode that was directly facing the other electrode, since electrons travel through the shortest available circuit (See Figure S1). See relative electrochemical General Procedures for specific current density values.

General Procedure A -Generation and Addition of Grignard Reagents to Cycloalkanones
To a three-necked RBF fitted with a condenser, a glass stopper, and a septum seal was added magnesium turnings (1.65 eq.) and the system was flame-dried under a high vacuum. After cooling under a N2 atmosphere, a crystal of iodine was added followed by THF (1 M with respect to RBr). RBr (1.5 eq.) was added dropwise and the mixture was stirred at rt for 5 min, or until the exotherm had finished. The reaction mixture was then heated at reflux for 1-3 h. Upon cooling to 0 °C, THF was added (0.2 M with respect to cycloalkanone), followed by drop-wise addition of the cycloalkanone (1.0 eq.). The resulting mixture was left to warm to rt and stirred overnight. A saturated solution of NH4Cl (aq.) was added and the mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was further extracted with EtOAc (× 2). The combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant crude material was purified by flash column chromatography to afford the desired compound.

General Procedure B -Addition of Commercially-Available Grignard Reagents to Cycloalkanones
To a flame-dried RBF fitted with a septum seal was added a pre-made Grignard reagent (1.5 eq.) under a N2 atmosphere. After cooling to 0 °C, the cycloalkanone (1.0 eq.) was added dropwise. After complete addition, the resulting mixture was left to warm to rt and stirred overnight. A saturated solution of NH4Cl (aq.) was added, followed by a few drops of 1 M HCl (aq.), and the mixture was diluted with Et2O. The layers were separated, and the aqueous layer was further extracted with Et2O (× 2). The combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant crude material was purified by flash column chromatography to afford the desired compound.

General Procedure C -Generation and Addition of Organolithium Reagents to Cycloalkanones
To a flame-dried RBF fitted with a septum seal was added a solution of alkyl or aryl halide (1.3 eq.) in THF (0.3 M). The mixture was cooled to -78 °C, and a solution of n-butyllithium (solution in hexanes, 1.3 eq.) was added dropwise. The solution was left to stir for 1-3 h before adding a solution of the cycloalkanone (1.0 eq.) in THF (1.0 M) dropwise. The reaction mixture was left to stir for 1-3 h, whilst warming to rt. Water was added dropwise, followed by extraction with EtOAc (× 3). The combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant crude material was purified by flash column chromatography to afford the desired compound.

General Procedure D -Synthesis of Substituted Cyclobutanones
To a flame-dried three-necked RBF fitted with an addition funnel, a reflux condenser and a septum seal was added Zn(Cu) couple [2] (2.5 eq.), alkene (1.0 eq.) and Et2O (0.5 M). The dropping funnel was charged with trichloroacetyl chloride (2.0 eq.), phosphoryl chloride (2.0 eq.) and Et2O (1.0 M). The contents of the dropping funnel were added slowly over ~2 h. The reaction mixture was stirred at 70 °C for 16 h. Upon cooling, the suspension was filtered through a pad of celite, washing with Et2O and the filtrate was concentrated to ~25% of its original volume. To the resultant mixture was cautiously added water and the organic layer was further washed with a saturated solution of NaHCO3 (aq.). The aqueous layer was extracted with Et2O (× 3) and the combined organic layers were dried (MgSO4), filtered and concentrated. The resultant oil was submitted to the next step without further purification.
The crude residue from the previous step was dissolved in AcOH (0.5 M) and Zn dust (4.0 eq.) was added. The reaction mixture was stirred at 70 °C for 2 h. Acetic acid was removed under reduced pressure and the resultant mixture was filtered through a pad of celite, washing with Et2O. The filtrate was concentrated and the crude residue was purified by flash column chromatography to afford the desired compound.

General Procedure E -Synthesis of Cyclopropanols via Kulinkovich Reaction
To a flame-dried RBF fitted with a septum seal was added the ester (1.0 eq.), Ti(O i Pr)4 (1.4 eq.), and THF (0.16 M with respect to the ester). The mixture was cooled to 0 °C and a solution of Grignard reagent (2.8 eq.) was added dropwise. After complete addition, the resulting mixture was left to warm to rt and stirred overnight. After completion water was added and the resulting precipitate was filtered under vacuum through celite and washed with EtOAc. The layers of the filtrate were separated, and the aqueous layer was further extracted with EtOAc (× 2). The combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant crude material was purified by flash column chromatography to afford the desired compound.

4-(1-Hydroxycyclobutyl)benzonitrile (S18)
Preparation of Turbo-Grignard (i-PrMgCl.LiCl): To a flame-dried RBF was added dry LiCl (1.75 g, 38.0 mmol, 1.00 eq.), magnesium turnings (1.20 g, 50.0 mmol, 1.30 eq.) and a crystal of iodine followed by THF (20 mL). The mixture was cooled to 0 ˚C and 2-chloropropane (3.5 mL, 38.0 mmol, 1.00 eq.) was added dropwise maintaining the temperature of the bath at 0˚C. After the addition was complete, the reaction mixture was brought to rt and stirred for 12 h. The resulting black reaction mixture (1.1 M) was kept under nitrogen and used as such in the following reaction.

Bicyclo[5.2.0]nonan-8-one (S33)
Following a literature procedure: [10] To a solution of cycloheptene (2.33 mL, 20.0 mmol) in hexane (60 mL) was added dichloroacetyl chloride (2.89 mL, 30.0 mmol) and the resulting mixture was heated at reflux for 20 minutes, followed by slow addition of a solution of triethylamine (4.21 mL, 30.2 mmol) in hexane (30 mL). The reaction mixture was stirred at reflux overnight. Upon cooling, the formed precipitate was removed by filtration and the resultant filtrate was washed with sat. NaHCO3 (2 × 100 mL). The organic layer was dried (MgSO4), filtered and the hexane was removed under vacuum to give a yellow oil.
The material from the previous step was taken up in MeOH (140 mL) and stirred at 0 °C. Zinc powder (14.4 g, 220 mmol) was added, followed by NH4Cl (7.90 g, 148 mmol) and the reaction mixture was allowed to stir at rt overnight. The unreacted zinc was removed by filtration and the filtrate was concentrated in vacuo. The residue was taken up in Et2O (100 mL) and washed with sat. NaHCO3 (2 × 100 mL). The combined aqueous layers were extracted with Et2O (2 × 100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (2% Et2O/Pentane, silica gel) afforded S33 (1.10 g, 40% over 2 steps) as a yellow oil which was used in the next step without further purification.

Ethyl heptanoate (S46)
To an RBF charged with heptanoic acid (1.42 mL, 10.0 mmol) in EtOH (12.5 mL, 0.8 M) was added conc. H2SO4 (0.54 mL, 10 mmol) dropwise at 0 °C. After complete addition, the reaction mixture was allowed to warm to rt, then heated to reflux overnight. After completion of the reaction, the solution was cooled to rt, and then concentrated under reduced pressure. The resulting residue was then dissolved in CH2Cl2 and washed with 1 M NaOH (3 × 10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated under reduced pressure to give S46 (934 mg, 59%) as a colourless oil that was used without further purification.

1.0]heptan-1-ol (S50)
To a solution of S49 (852 mg, 5 mmol, 1.0 eq.) and diethylzinc (7.8 mL, 7 mmol, 0.9 m in hexane, 1.4 eq.) in Et2O (5 mL) at 0 °C was added a solution of diiodomethane (565 μL, 7 mmol, 1.4 eq.) in Et2O (5 mL) dropwise and the reaction mixture was heated at reflux for 3 h. After cooling, the reaction was quenched by the dropwise addition of pyridine (1.0 mL) and the mixture was filtered through a pad of celite, washing with Et2O. The filtrate was concentrated and the resulting residue was taken up in MeOH (15 mL). K2CO3 (69 mg, 0.5 mmol, 10 mol %) was added and the reaction mixture was left to stir for 30 min at rt. Water (15 mL) and EtOAc (50 mL) were added and the layers separated. The aqueous layer was further extracted with EtOAc (2 × 15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (20% Et2O in petrol, silica gel) to afford S50 (347 mg, 62%) as a colourless oil.

General Procedure G -Standard Procedure
To an oven-dried 10 mL ElectraSyn vial equipped with a magnetic stirrer bar, was added substrate (0.30 mmol), Mn(OTf)2 (11 mg, 0.03 mmol), MgCl2 (143 mg, 1.50 mmol) and LiClO4 (64 mg, 0.60 mmol). The threaded glass was wrapped with PTFE tape and connected to the ElectraSyn cap, which was fitted with a graphite anode and a graphite cathode. The vial was purged with N2 gas via evacuate-refill cycles (× 3). MeCN (5.25 mL) was added, followed by AcOH (0.75 mL) and the mixture was stirred for a minute to ensure solvation of the MgCl2. The mixture was then purged via bubbling with N2 gas for 10 minutes. During this time, the vial was connected to an ElectraSyn GoGo module and submerged in a 25 °C water bath mounted on a magnetic stirrer. Electrolysis at 10 mA was conducted for 3 h under N2 with continuous stirring. After electrolysis was complete, the reaction mixture was left to stir at 25 °C for an additional 30 minutes. The crude reaction mixture was diluted with Et2O (10 mL) and washed with sat. NaHCO3 (2 × 15 mL). The aqueous layer was extracted with Et2O (3 × 10 mL) and the combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford the pure product. N.B.: If the substrate is an oil, it is weighed directly into the ElectraSyn vial before addition of solid reactants.

General Procedure H -Syringe Pump Addition of Substrate
To an oven-dried 10 mL ElectraSyn vial equipped with a magnetic stirrer bar, was added Mn(OTf)2 (11 mg, 0.03 mmol), MgCl2 (143 mg, 1.50 mmol) and TBAOAc (181 mg, 0.60 mmol). The threaded glass was wrapped with PTFE tape and connected to the ElectraSyn cap, which was fitted with a graphite anode and a graphite cathode. The vial was purged with N2 gas via evacuate-refill cycles (× 3). MeCN (3.25 mL) was added, followed by AcOH (0.75 mL) and the mixture was stirred for one minute to ensure solvation of the MgCl2. The mixture was then purged via bubbling with N2 gas for 10 minutes. During this time, the vial was connected to an ElectraSyn GoGo module and submerged in a 25 °C water bath mounted on a magnetic stirrer. In a separate 5 mL vial, substrate (0.30 mmol) and MeCN (2 mL) was added and the mixture was purged via bubbling with N2 gas for 2 minutes before it was transferred into a 3 mL disposable syringe and connected to a syringe pump. Electrolysis at 10 mA was conducted for 3 h under N2 with continuous stirring, while syringe pump addition of the tertiary alcohol solution in MeCN (1 mL/h) was started after 2 minutes of electrolysis. After electrolysis was complete, the reaction mixture was left to stir at 25 °C for an additional 30 minutes. The crude reaction mixture was diluted with Et2O (10 mL) and washed with sat. aq. NaHCO3 (2 × 15 mL). The aqueous layer was further extracted with Et2O (3 × 10 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford the pure product.

Rf
These data are consistent with those previously reported in the literature. [15]
These data are consistent with those previously reported in the literature. [18]
The electrochemical reactor was used in three modes of operation, mode 1 for exploring single pass parameters, mode 2 for recirculating experiments and mode 3 for scale up and continuous extraction.

Preparation of reagent solutions:
Three 25 mL round-bottom flasks were flame dried; one was charged with 1-phenylcyclobutan-1-ol (1) (0.6 mmol, 0.0890 g) and sealed with a Suba-seal and parafilm. The second RBF was charged with MnCl2•4H2O (0.06 mmol, 0.0119 g), MgCl2 (3 mmol, 0.2865 g) and LiClO4 (1.2 mmol, 0.1279 g). Both reagent flasks were evacuated on a Schlenk line and back filled with nitrogen gas for three cycles. The third RBF was charged with dry degassed MeCN (12.25 mL) and glacial acetic acid (1.75 mL). After deoxygenating, (bubbling with nitrogen for 15 min), the solvent mixture (6 mL) was added to each reagent flask under a nitrogen atmosphere and swirled until dissolution occurred.

Flow running order:
The electrochemical flow system was flushed with nitrogen gas for 5 min by connecting the inlet tubing directly to the dry nitrogen line. The reagent solutions were drawn up into 10 mL syringes and promptly connected to the flow system. The syringe pumps were set to 1.125 mL/min, giving a combined total flow rate of 2.5 mL/min at the mixing-tee. Syringe pumping was initiated, and the outlet of the flow system was set to waste for the first 3.46 mL (representing 1 whole flow path volume, inclusive of tubing, connectors and reactor) of reaction mixture to allow the flow system to be filled. After this initial priming, the power supply was switched on and the electrolysis commenced at a constant current with the system outlet still set to waste for a further 2.5 mL (representing a total volume from 'in' to 'out' of the electrochemical reactor; exposed electrochemical path = 1 mL). The outlet stream of the flow system was then collected for 6 mL (representing 0.3 mmol of A processed). Mesitylene (0.1 mmol, 13.9 μL) was added to the product mixture, stirred for 5 min and then the 1 H NMR spectrum was recorded to give a crude reaction yield.

Optimization
Single pass electrochemical flow was explored initially to see whether the reaction would proceed successfully via this mode. The optimisation allowed for physical parameters to be screened using a simple flow system. Initially, mass balance was optimised to give a clean reaction with a high productivity and an efficient mixing regime (k value). These parameters were met, however, when optimising for yield, the reaction required prolonged exposure to the electrochemical system therefore mode 2, recirculation, was explored. Italicised conditions in bold (4.2.2.6, entry 1) were carried forward into mode 2, recirculation.

mmol scale
A 25 mL round-bottom flask and stirrer bar was flame dried and charged with 1-phenylcyclobutan-1-ol (1) (0.6 mmol, 0.0890 g), MnCl2•4H2O (0.06 mmol, 0.0119 g), MgCl2 (3 mmol, 0.2865 g) and sealed with a Suba-seal and parafilm. The reagent flask was evacuated on a Schlenk line and back filled with nitrogen gas for three cycles. Both the inlet and outlet tubing of the electrochemical flow system were pushed through the Suba-seal and the reagents dissolved with dry degassed MeCN (11.5 mL) and glacial acetic acid (1.5 mL). The HPLC pump was primed with the reaction mixture and set to recirculate at 2.5 mL/min while the contents of the flask were degassed by bubbling nitrogen for 15 min. The electrolysis was then commenced and conducted at a constant current of 400 mA, the recirculated reaction was monitored by TLC until completion, which, at this scale required 1 hour.
Upon completion, electrolysis was turned off and the product mixture was transferred to a 100 mL separatory funnel. The flow system was purged and flushed with clean solvent (7:1 MeCN:AcOH; 3 x 20 mL), into the separatory funnel. The crude reaction mixture was washed with a saturated solution of NaHCO3 (25 mL) and Et2O (25 mL). The aqueous layer was extracted with Et2O (3 x 25 mL) and the organic layer dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a gradient of Et2O in hexane (2% to 6%) to afford compound 2 as a colourless oil (0.0920 g, 0.5037 mmol, 84% yield).

Gram scale
A 250 mL round-bottom flask and stirrer bar was flame dried and charged with 1-phenylcyclobutan-1-ol (1) (8.44 mmol, 1.25 g), MnCl2•4H2O (0.844 mmol, 0.1670 g), MgCl2 (42.2 mmol, 4.0179 g) and sealed with a Suba-seal and parafilm. The reagent flask was evacuated on a Schlenk line and back filled with nitrogen gas for three cycles. Both the inlet and outlet tubing of the electrochemical flow system were pushed through the Suba-seal and the reagents dissolved with dry degassed MeCN (147.87 mL) and glacial acetic acid (21.13 mL). The HPLC pump was primed with the reaction mixture and set to recirculate at 2.5 mL/min while the contents of the flask were degassed by bubbling nitrogen for 30 min. The electrolysis was then commenced and conducted at a constant current of 400 mA, the recirculated reaction was monitored by TLC until completion, which, at this scale required 5 hours.
Upon completion, electrolysis was turned off and the product mixture was transferred to a 1 L separatory funnel. The flow system was purged and flushed, with clean solvent (7:1 MeCN:AcOH; 3 x 20 mL), into the separatory funnel. The crude reaction mixture was washed with a saturated solution of NaHCO3 (2 x 100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (3 x 100 mL) and the organic layer dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a gradient of Et2O in hexane (2% to 10%) to afford compound 2 as a colourless oil (1.2 g, 6.57 mmol, 78% yield).

Gram scale
A 250 mL round-bottom flask and stirrer bar was flame dried and charged with 1-phenylcyclobutan-1-ol (1) (8.44 mmol, 1.25 g), MnCl2•4H2O (0.844 mmol, 0.1670 g), MgCl2 (42.2 mmol, 4.0179 g) and sealed with a Suba-seal and parafilm. The reagent flask was evacuated on a Schlenk line and back filled with nitrogen gas for three cycles. Both the inlet and outlet tubing of the electrochemical flow system were pushed through the Suba-seal and the reagents dissolved with dry degassed MeCN (147.87 mL) and glacial acetic acid (21.13 mL). The HPLC pump (①) was primed with the reaction mixture and set to recirculate at 2.5 mL/min while the contents of the flask were degassed by bubbling nitrogen for 30 min. The electrolysis was commenced and conducted at a constant current of 400 mA, the recirculated reaction was monitored by TLC until completion, which, at this scale 1 2 required 5 hours. Once judged as complete, electrolysis was turned off, pump ① was set to 4 mL/min and pumps ⑥ and ⑦ were turned on and set to 4 mL/min, the mixing device (⑧) was switched on and set to mix at 1500 rpm. The 6-port, 2-position valve (④) was switched to the inject position, thus diverting the re-circulating stream into the in-line work up. Upon depletion of the reaction mixture from the flask, the flask was washed and rinsed with clean solvent three times (20 mL 7:1 MeCN:AcOH). The in-line workup took 60 minutes for the entire reaction mixture to be processed, (42 min reaction mixture processing, 10 min rinse of flow system, 8 min solvent flush for work up line cleaning). The separated organic layer (⑪) was dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by column chromatography and eluted with a gradient of Et2O in hexane (2% to 10%) to afford compound 2 as a colourless oil (1.2 g, 6.57 mmol, 78% yield).

Cyclic Voltammetry Studies
General Information: Cyclic Voltammetry (CV) experiments were conducted with in a 10 mL glass vial fitted with a glassy carbon working electrode (3 mm dia., BASi), a Ag/AgCl reference electrode and a platinum wire counter electrode. The solution of interest was purged with N2 for 5 minutes before data collection. After data collection, ferrocene (5 mM) was added and an additional scan was run. The parent data was referenced relative to the Fc +/0 couple that was recorded.

LEFT.
Reagents used in this procedure -substrate is home-made (see 1); Mn(OTf)2 is purchased from Apollo Scientific and used as found (stored under N2); MgCl2 is purchased from Acros Organics and used as found (stored under N2); LiClO4 is purchased from Sigma-Aldrich (now Merck) and is used as found. MIDDLE. All solid reagents are added to the dried ES vial and the cap is screwed tightly in place. Any liquid substrates are weighed directly into the ES vial before addition of the other reagents.
RIGHT. The solid reagents are subjected to three evacuate-refill cycles using an atmosphere of N2.
MeCN and AcOH are added. The MgCl2 is not usually dissolved until addition of the AcOH. However, sometimes, it does not fully dissolve, giving a suspension. In these cases, we proceed as normal and have not noticed any detriment to the reaction.
LEFT. The reaction mixture is purged with N2, ensuring the needle spewing N2 gas is kept at the bottom of the vial. The reaction is vented to the atmosphere during this time with another needle. Take care not to bubble the N2 too vigorously or the solvent can begin to evaporate. The purging takes places for 10 minutes. MIDDLE. During the purge, the ElectraSyn 2.0 is switched on and arranged as pictured using a GOGO module to position the vial in a water bath, set at 25 °C. RIGHT. Once the reaction mixture is purged, it is placed onto the GOGO module and positioned in the water bath, under a N2 atmosphere, either by balloon or connected to a Schlenk line.
LEFT. Input title of experiment. Here we have selected "10mA_3h". MIDDLE. Screen displaying reaction conditions. Select "Start". RIGHT. After a few minutes have passed, the reaction mixture will typically turn green. This is indicative of the formation of Mn(III) catalyst. There are some examples where this green colour is not observed, or does not persist, until towards the end of the experiment, but good yields are still obtained in these instances. This is presumably due to a faster reaction rate resulting in faster consumption of the electrogenerated catalyst.

Graphical Guide for Set-Up of Electrochemical Mn-Catalyzed Deconstructive Chlorination of Cycloalkanols Using Syringe Pump Addition of Substrate
Photos were taken from the deconstructive chlorination reaction of 1-(4-(tert-butyl)phenyl)cyclobutan-1-ol using General Procedure H.
The reaction vial was set-up in the same way as in Graphical Guide 5.1.

LEFT.
Reagents used in this procedure -substrate is home-made (see S1); Mn(OTf)2 is purchased from Apollo Scientific and used as found (stored under N2); MgCl2 is purchased from Acros Organics and used as found (stored under N2); TBAOAc is purchased from Apollo Scientific and is used as found. MIDDLE. The substrate is added to a flame-dried 10 mL RBF and all other reagents are added to the oven-dried ES vial. RIGHT. MeCN (3.25 mL) and AcOH (0.75 mL) are added to the ES vial and MeCN (2 mL) is added to the 10 mL RBF.
LEFT. The reaction mixture is purged with N2, ensuring the needle spewing N2 gas is kept at the bottom of the vial. The reaction mixture is vented to the atmosphere during this time with another needle. Take care not to bubble the N2 too vigorously or the solvent can begin to evaporate. The purging takes places for 10 minutes in the ES vial. For the solution in the RBF, purging is conducted for 2 minutes, after which a slow N2 stream is introduced just above the solvent level to avoid evaporation/concentration of the solution. MIDDLE. During the purge, the ElectraSyn 2.0 is switched on and arranged as pictured using a GOGO module to position the vial in a water bath, set at 25 °C. Next to this arrangement, a syringe pump is placed on a lab jack just above the level of the GOGO adapter. RIGHT. The settings of the syringe pump are set. The internal diameter of the syringe (brand and volume exclusive) is input. The volume is set to 2.5 mL. The flow rate is set to 1 mL/h. The delay is set to 2 minutes. These parameters are not changed on occasions where the substrate solution is greater or less than 2 mL. The ElectraSyn 2.0 is also set up in the same as way as General Guide 5.1. If the experiment has been saved, this can be accessed in the "Experiments" section from the "Main Menu".

LEFT.
Once the reaction mixture is purged, it is placed onto the GOGO module and positioned in the water bath, under a N2 atmosphere, either by balloon or connected to a Schlenk line. The substrate solution is drawn up into a NORM-JECT® 2 mL disposable syringe, fitted with a Sterican® 120 mm, 21gauge needle. The syringe is positioned into the syringe pump with the needle inserted through the septum of the ES cap, ensuring that the end of the needle can be seen through the side of the reaction vial -this ensures efficient addition to the reaction mixture. Balloon omitted for clarity. MIDDLE. Close-up of LEFT image. RIGHT. Full set-up with balloon. The ElectraSyn experiment is started at the same time as the start of the syringe pump program.
LEFT. Reaction mixture after 60 seconds of experiment. Note the needle tip between the electrodes. MIDDLE. Reaction mixture after 5 minutes -substrate addition has begun. Usually, the reaction mixture turns a darker green initially indicating a higher concentration of Mn(III) catalyst. Depending on the substrate, this may disappear or become less persistent. RIGHT. After the syringe pump program has complete, the pump will stall. At this point, the syringe is backfilled with the N2 atmosphere, and re-injected into the reaction mixture to help clear the head space of the syringe/needle and ensure complete addition of substrate.