Oxidation in Flow Using an Ionic Immobilized TEMPO Catalyst on an Ion Exchange Resin

Abstract

An ionic heterogenized catalyst system for Anelli oxidation has been developed using potassium 4-sulfonato-oxy-2,2,6,6-tetramethylpiperidine-1-yloxyl (TEMPO-4-sulfate) and anion exchange beads as support material. The catalytic oxidation of benzyl alcohol by bis(acetoxy)iodobenzene (BAIB) in acetonitrile with the modified beads gives a 94% yield of benzaldehyde within 60 min (batch operation). The beads give about the same conversion of benzyl alcohol in six consecutive cycles when reused after simple washing, albeit with a somewhat longer half-life time. The TEMPO entity could be removed from the beads using a sodium chloride/sodium hydroxy mixture. Reloading the beads with TEMPO-4-sulfate restored about 80% of their initial catalytic action. This exemplifies that the catalytic activity in a fixed bed can be regained without the need for cleaning and repacking the reactor. Preliminary experiments in a fixed bed show that a constant benzyl alcohol conversion of 84% over 10 residence times (as plug flow) can be achieved by the in-flow execution of the oxidation reaction.

1. Introduction

The selective oxidation of alcohols to aldehydes continues to be a key process in the production and synthesis of a wide range of chemicals and intermediates. Conventional oxidation reactions pose a multitude of inherent challenges. Quite reactive oxidizing agents and catalysts such as manganese oxides(IV) [1], pyridinium chlorochromate [2], pyridinium dichromate, and chromium(VI) or ruthenium salts [3] are routinely applied in an industrial setting, and oxidations occur partially under conditions requiring robust equipment. Metal-free, more environmentally friendly oxidation catalysts have had considerable interest as more benign alternatives [4,5,6,7]. Nitroxyl radicals, such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), act as mild oxidants that fulfill the criteria of a non-toxic, recyclable, and efficient oxidation catalyst, but with the disadvantage of being a homogeneous catalyst [8,9,10,11,12,13]. Less than 20% of industrial catalytic processes employ homogeneous catalysts, as they require more effort for product isolation (purification) and are less stable (chemically and/or thermally) [14,15]. The recycling and reuse of catalysts are increasingly significant for efficiency and, consequently, for cost-effectiveness [16]. Heterogeneous or heterogenized catalysts in alcohol oxidation processes continue to be more attractive in everyday operation [17].

The immobilization of TEMPO on support materials followed the general methodology for the preparation of heterogenized homogeneous catalysts, a strategy with a number of elegant successes that were also compiled over the years in a number of reviews [18,19,20,21,22,23,24,25,26]. TEMPO was thus mainly covalently bonded to a support material, either through a direct connection at the surface (e.g., by ether bridges) or via linker moieties [27,28]. The diverse supports include polymers [29,30,31], silicates [32,33,34], and (magnetic) ceramics [30,35,36,37], and, also, ionic liquids may be an option for the “compartmentation” of the TEMPO catalyst [38,39]. The heterogenization also offers the opportunity to co-immobilize “auxiliaries” in the close vicinity of the TEMPO entity, reagents that are useful in promoting its reoxidation, like bromide ions, metal complexes, or electrochemically active ceramics or metals [12,36,39,40,41,42,43,44]. Disadvantageously, heterogenized TEMPO entities that become deactivated may generally not be reactivated easily in such a situation and, e.g., in case of a fixed bed reactor process, a column with a new catalyst will have to be packed after the activity falls below a certain level. The covalent bonds between TEMPO and its support material are generally not designed to be cleaved, nor is a replacement of the catalytic entity foreseen.

Here, a viable approach is presented to improve the efficiency of processes using heterogenized TEMPO catalysts for aldehyde formation from alcohols, i.e., by the reversible fixation of TEMPO entities on the basis of cation–anion interactions. A commercially available strong anion exchange resin type I (ROTI^®Change 20–50 mesh) is used as a support material to bind TEMPO-4-sulfate (Figure 1). The ionic nature of the interactions would involve a higher mobility of the catalytic entity (over the situation of covalent fixation) while the high surface charge of the beads will confine the TEMPO-4-sulfate to its volume. Similar is expected for the reduced form, the ⁻O₃SOC₉H₁₇N⁺O zwitterion. The use of spherical and macroporous particles would have the advantage of reducing pressure loss over a column and avoiding clogging [45].

It is shown that effective Anelli oxidation can be carried out on the column and that leakage of the TEMPO entities is at a low level [46]. In addition, TEMPO-4-sulfate can intentionally be removed from the solid phase and substituted for a fresh catalyst batch without much effort. At the same time, bromide anions can be kept in the close vicinity of the TEMPO entities on the support. A few other studies describe the use of ionic nitroxides as catalysts for Anelli oxidation [47,48,49,50], for example, in form of an intercalate in a saponite clay [51,52]. The heterogenized TEMPO was active during several cycles; however, the turnover frequency was low, leading to reaction times of 3–5 h. Analogous continuous flow experiments would be hampered by large (re)cycle volumes when using reasonable residence times (i.e., flow rates and/or reactor volume). This study also aims to demonstrate the potential of the system by transferring batch oxidations to a continuous flow execution, using the oxidation of benzyl alcohol to benzyl aldehyde with the co-catalyst bis(acetoxy) iodobenzene (BAIB) as the model reaction. The effectivity of the catalyst system was mapped for various alcohols.

2. Results and Discussion

2.1. Preparation and Characterization of the Catalyst

A strong basic type 1 anion exchanger with particle sizes distributed between 300–840 µm was loaded to the total exchange capacity (TEC of 2.1 µmol·g⁻¹) of the ion exchanger, using an excess of 250 mol% of TEMPO-4 sulfate in water (at a concentration of 12 mmol∙L⁻¹). The substitution of chloride ions by TEMPO-4 sulfate results in the swelling of the beads and increases the volume of the ion exchange resins by roughly 20% (Scheme 1; Figure 2). The color transition from the clear, transparent ion exchange beads into the orange color typical of TEMPO derivatives indicates the effective absorption of TEMPO-4-sulfate. The catalyst loading of TEMPO-4 sulfate after 3 h in the batch was 1.34 mmol∙g⁻¹ (determined using the characteristic UV broad absorption band of TEMPO compounds in the range of λ_max = 430–470 nm [53,54,55,56]). This corresponds to a catalyst loading of 65% of the chloride ions found in the maiden state of the beads (and to 125% of the guaranteed minimum of chloride anions of 1.2 eq L⁻¹; Figure 3, black line). The loading appears to be limited by the establishment of an equilibrium between the anions for binding to the column. A higher absorption of TEMPO-4 sulfate of 1.94 mmol∙g⁻¹ was achieved by a loading of the beads (vide infra) with a solution of TEMPO-4-sulfate (350 mL, 120 mmol∙L⁻¹) in a column. This corresponds to a loading of 95%, an increase of 29% with respect to the batch-loading procedure (Figure 3). Sodium or potassium salts are basically absent on the beads after loading or regeneration. Atomic absorption spectroscopy (AAS) on the ion exchange resins showed an Na content of 0.02 mol% and a K content of <0.004 mol%. Larger residues of sodium hydroxide/chloride (from regeneration) or potassium 4-sulfonato-oxy-2,2,6,6-tetramethyl piperidine-1-yloxyl in the ion exchange resins can, therefore, be ruled out.

The removal of the TEMPO entities from the ion exchange resin in a column after several oxidation experiments is effective using a basic brine solution (10 mol% NaCl/1 mol% NaOH) [57]. Although not understood, the presence of some base seems to enhance the removal of TEMPO from the beads as the color of the beads weakens faster when using a neutral brine. The concentration of TEMPO entities was continuously reduced through elution (three times the bed volume of 250 mL was finally used in the current protocol). The infrared spectra of single beads show the decline of TEMPO-specific bands, indicative of the exchange of TEMPO-4 sulfate for chloride ions (Figure 4a). The characteristic aryl sulfate group at 1208 cm⁻¹, the C-N stretching vibration at 1241 cm⁻¹, and a C-H band at 2981 cm⁻¹ are good spectroscopic probes [58]. The measurement of the basic brine solution by UV–Vis spectroscopy towards the end of the regeneration still shows some signature of TEMPO-4-sulfate at λ_abs = 460 nm (after 120 min of regeneration; Figure S2). This can be related to the presence of residual TEMPO-4 sulfate or derivatives (decomposition products) on the ion exchanger, which is in accordance to the slightly orange color of the beads (the latter could also result from the oxidation of the reduced TEMPO sulfate zwitterion ⁻O₃SOC₉H₁₇N⁺O by oxygen during regeneration). EDX analyses indicate that about 80% ± 6% of the original chloride content could be restored after the treatment of the ion exchange resin with the basic NaCl solution (Figure 4b; Table S1; 20% of the initial chloride content of the ion exchangers could not be restored by the chosen regeneration process). This was taken as sufficient in this orientating study, and most certainly can be optimized.

2.2. Batch Oxidation Reactions with Batch-Immobilized TEMPO-4 Sulfate

Initially, benzyl alcohol oxidations involving ionically immobilized TEMPO-4-sulfate as the catalyst were performed using [bis(acetoxy)iodo] benzene (BAIB) as the co-catalyst in batch reactions in acetonitrile (MeCN) as the medium (i.e., using the beads in a flask with all the reagents present in solution). These experiments were performed at 35 °C and had a duration of 60 min. TEMPO-mediated oxidation can result in the over-oxidation of the alcohol in the presence of water, which was to be prevented. The TEMPO-loaded ion exchange resins were, therefore, dried for 24 h under a dynamic vacuum to remove residual moisture [59]. A variety of oxidizing reagents are known to induce the Anelli oxidation for preparing aldehydes. These comprise NaOCl [60], trichloro isocyanuric acid [61], and BAIB [62]. The effectiveness of combining BAIB with bromide ions was demonstrated before and was used in this work (s. Scheme S1 for the mechanism) [63]. The reactions of benzyl alcohol with catalytic amounts of TEMPO-4-sulfate but without BAIB as an oxidant or bromide ions showed no conversion under the standard reaction conditions (Figure S3).

MeCN was found to have the best combination of solubility of the components and a moderate macroscopic swelling of the ion exchange resin (Figure 5). High conversions of up to 99% of benzyl alcohol were also achieved in DMSO and dichloromethane solutions (and in neat benzyl alcohol). The oxidation of benzyl alcohol by the immobilized catalyst beads with BAIB also takes place in water; however, conversions were low in the 60 min of observation. The limited conversion in water most likely results from the poor solubility of BAIB in combination with the low miscibility of benzyl alcohol and water. Overoxidation was not observed at the low conversion.

The heterogenized TEMPO-4 sulfate also catalyzes the oxidation of further primary alcohols with BAIB in MeCN (

Table 1. Primary alcohols oxidized by BAIB in MeCN, catalyzed by heterogenized TEMPO-4 sulfate.

Entry	Alcohol	Conv./%	t/min	Products	Selectivity %
1	butane-1-ol	95	30	butanal	~100
2	benzyl alcohol	99	20	benzaldehyde	~100
3	1,4-benzene dimethanol	100	20	1,4-benzene dialdehyde 4-(hydroxymethyl) benzaldehyde	99 1
4	1,4-butanediol	75	90	γ-butyrolactone	~100

¹H NMR spectra of the product mixtures in Figures S3–S6, resp.; selectivity related to oxidation product.

). It is demonstrated that both aromatic and aliphatic mono- and diols are oxidized, both with known trends [64,65]. 1,4-Benzene dimethanol is transformed at a high rate to terephthalic dialdehyde, albeit with the formation of small amounts of benzaldehyde. 1-Butanol is transformed into butanal at a somewhat lower rate, but again with a high conversion. The oxidation of 1,4-butanediol results in the formation of γ-butyrolactone, contrary to expectations. This can be explained by the known tautomerization of 4-hydroxy butanal to tetrahydrofuran-2-ol, which is oxidized in a second step (Scheme S2) [66]. The conversion of 1,4-butanediol reaches 75% after 90 min. The selectivity of the system, thus, overall is quite high; the ¹H NMR spectra of the reaction mixtures do not show any substantial intensity of further signals next to educts and products.

2.3. Catalyst Robustness in Batch Oxidations with Batch-Loaded Catalysts

The catalyst beads only slowly lose their activity with benzyl alcohol as the substrate, leading to a yield of 94% after the sixth cycle of 60 min (Figure 6). The TEMPO-4-sulfate-loaded beads were isolated after each cycle by filtration and washed with acetonitrile before starting a new round of the 1 h batch experiments. The half-life of the benzyl alcohol ${\tau }_{ox}(=\ln \left(2\right)/k)$ increased in the sequence of six cycles from 10 to 65 min (of an exponential growth: $d\left[benzaldehyde\right]/dt=-k[benzyl alcohol]$). The decrease in activity can be related to a loss of the TEMPO-4 sulfate entities on the beads. ICP-AES analysis of the solution revealed a sulfur concentration of (only) 120.4 mg∙L⁻¹ after the first oxidation cycle. It is expected that the presence of bromide (from the phase-transfer catalyst tetrabutyl ammonium bromide TBAB) in the reaction solution results in ion exchange in favor of the bromide ions, causing a 7% loss of TEMPO-4 sulfate on the beads. The decline in reactivity ceased after the fourth cycle and remained constant, which can be explained by the equilibration of the absorbed anions on the beads: the co-absorption of bromide and TEMPO-4-sulfate will lead to some loss of the anionic TEMPO derivative in the first cycles. The bromide content of the beads increases with the number of cycles and changes become small. The initial reactivity could be re-established through a sequence of unloading, using a basic brine solution, andreloading with TEMPO-4 sulfate (Figure 6).

No morphological or major structural changes on the surface of the beads can be detected after six cycles of oxidation catalysis (Figure 7). The mechanical stress from swelling, stirring, washing, and drying, however, does give cracks in the surface of some beads (not shown in the image).

2.4. Oxidation Catalysis in a Flow Reactor with Flow-Loaded Catalyst

The beads loaded with TEMPO-4 sulfate are also useful catalysts for the continuous oxidation of benzyl alcohol in a fixed bed reactor. Therefore, a 10 cm SEC column (V = 5 cm³) was prepared with untreated ROTI^®Change ion exchange resin (9.6 g). This was reached by transferring a slurry of the beads in water on to the column. The water was drained, and the beads were, again, dried at room temperature under a dynamic vacuum. The column was subsequently conditioned with dry MeCN solvent and the beads were loaded with the TEMPO-4 sulfate. Loading in flow for a duration of 3 h led to the TEMPO-4-sulfate absorption of 1.94 mmol∙g⁻¹ and a total quantity of 18.6 mmol (350 mL, c = 120 mmol∙L⁻¹ of TEMPO-4-sulfate; Scheme 2). The swelling of the resin beads (~25%) leads to a compression within the column, leading to a pressure drop over the column of a maximum of 5 bar during the entire loading period. The subsequent washing of the TEMPO-loaded ion exchange resin with MeCN relieved some of the swelling of the beads, reducing the pressure drop in a range between 1 and 2 bar.

The oxidation of benzyl alcohol over the column with BAIB was performed under the same reaction conditions (concentration and temperature) as the batch experiments; i.e., the concentration was 0.24 mol∙L⁻¹ of BAIB and 0.22 mol∙L⁻¹ of BzOH at 35 °C. The reagents were combined in a T-mixer shortly before the column in order to minimize a non-catalytic oxidation (Scheme 2). Two syringe pumps were used with an initial combined flow rate of 635 µL min⁻¹, resulting in a residence time of the solution in the reactor ${\tau }_R$ of 6 min. This was calculated assuming an ideal plug flow in a reactor with a free volume of 3.8 mL (next to the beads). A very stable conversion of 39% on average could be found under these conditions for more than 10 ${\tau }_R$ (Figure 8). Doubling the residence time to 12 min by reducing the flow rate to 317.5 µL∙min⁻¹ resulted in an average benzaldehyde conversion of 84%, again with a very constant profile over 10 ${\tau }_R$. A decrease in a sulfur concentration from 4.4% to 4.1% was observed of the ion exchange resins before and after 10 ${\tau }_R$ (by ICP-AES analysis). This did not lead to fluctuations in the yield of benzaldehyde. These preliminary results demonstrate the ability of the batch oxidation experiments to be transferred to flow systems and indicates the robustness of the system. These results are taken as a first step towards a system with oxygen as the oxidizer in a TEMPO-mediated Anelli oxidation, e.g., analogous to the successful three-phase fixed bed approach with a TEMPO covalently anchored to silica and to be extended with the co-catalysis by Cu(II) complexes for the reduction in oxygen [41,42,67].

3. Materials and Methods

3.1. Materials

The materials are as follows: 1,4-benzene dimethanol ≥ 99.0% (TCI Chemicals, 65760 Eschborn, Germany), 1,4-butanediol (Sigma Aldrich, 82024 Taufkirchen, Germany), 1-butanol (B&J Brand, Morrisville, PA, USA), 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL, Evonik Industries, 45128 Essen, Germany), acetone (Walter CMP, 24116 Kiel, Germany), acetonitrile anhydrous ≥ 99.95% (VWR Chemicals, 64295 Darmstadt, Germany), benzyl alcohol ≥ 98% for synthesis (Carl Roth, 76185 Karlsruhe, Germany), (diacetoxyiodo) benzene ≥ 97.0% (DAIB, TCI Chemicals, 65760 Eschborn, Germany), dimethyl sulfoxid-d₆ (Deutero GmbH, 56288 Kastellaun, Germany), ion exchange resin ROTI^®Change 1 × 8 (Carl Roth, 76185 Karlsruhe, Germany), potassium hydrogen carbonate ≥ 99% (BLD pharm, 21465 Reinbek, Germany), dipotassium chromate ≥ 99.0% (Merck, 64293 Darmstadt, Germany), potassium hydrogen carbonate ≥ 99% (BLD pharm, 21465 Reinbek, Germany), potassium nitrate (Merck, 64293 Darmstadt, Germany), silver nitrate solution Titripur^® 0.1 N (Merck, 64293 Darmstadt, Germany), sodium chloride (VWR Chemicals, 64295 Darmstadt, Germany), sodium hydroxide Supelco^® (Merck, 64293 Darmstadt, Germany), sulfuric acid ROTIPURAN^® ≥ 96% (Carl Roth, 76185 Karlsruhe, Germany), and tetrabutyl ammonium bromide ≥ 98.0% (TBAB, TCI Chemicals, 65760 Eschborn, Germany).

3.2. Characterization

¹H nuclear magnetic resonance (NMR) spectra were obtained in DMSO-d₆ using a Bruker (Billerica, MA, USA) Avance I-III 400 MHz and a Bruker Avance I 500 MHz, both at a temperature of 298 K. The chemical shift (δ) was expressed in parts per million (ppm) relative to the internal standard, Tetramethylsilane (TMS, δ = 0.00 ppm). The results were reported as chemical shift (multiplicity, coupling constant in Hz, integral). For infrared spectroscopic (IR) analysis, the ion exchange resins were dried overnight in a vacuum oven at 40 °C to remove residual moisture, and then processed into powder. Attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectra were measured on a Bruker Vertex 70 at a range of 4000–400 cm⁻¹ at a resolution of 2 cm⁻¹ and a scan rate of 32 scans. Offline UV–Vis spectroscopic measurements were performed on an Agilent (Santa Clara, CA, USA) Cary 60 with a xenon flash lamp (80 Hz) as light source. The measurements were performed at a wavelength range of 300–600 nm with a scanning rate of 600 nm min⁻¹. Continuous flow experiments were performed using a Syrris Asia syringe pump (Royston, Hertfordshire, UK) with two independent flow channels with integrated pressure sensors and Syrris Asia Blue syringes (500 µL/1 mL) with a flow rate of 10 µL up to 2.5 mL min⁻¹. An HPLC column oven from Schambeck SFD (Bad Honnef, Germany) was used for maintaining the temperature of the packed column. A Leica DMi8 A (Leica, Bad Honnef, Germany) inverted light microscope was used to observe the ion exchange resin beads before and after loading. Images were evaluated using the ImageJ 1.54g image processing software for circular objects. The beads are presumed to be spherical.

3.3. Determination of the Actual Total Exchange Capacity of the Ion Exchange Resin by Chloride Ion Measurement Using Mohr’s Titration

An amount of untreated ion exchange resin (2.02 g) was transferred into a 1 N KNO₃ solution (10.1 g, 100 mL) and treated for 12 h at room temperature to inflict the exchange of chloride ions. For chloride determination, 25 mL of the prepared solution was pipetted into an Erlenmeyer flask (100 mL), and potassium chromate (5 mg, 0.03 mmol) was added as an indicator. The solution was titrated with a silver nitrate solution (0.1 N, T = 0.995–1.005) from the burette until a permanent brick-red endpoint was reached. Each titration was performed in triplicate (2.06 mmol Cl⁻ g⁻¹).

$$\mathrm{T}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l} \mathrm{E}\mathrm{x}\mathrm{c}\mathrm{h}\mathrm{a}\mathrm{n}\mathrm{g}\mathrm{e} \mathrm{C}\mathrm{a}\mathrm{p}\mathrm{a}\mathrm{c}\mathrm{i}\mathrm{t}\mathrm{y} (\mathrm{m}\mathrm{m}\mathrm{o}\mathrm{l}·{\mathrm{g}}^{-1})={\displaystyle \frac{{\mathrm{V}}_{{\mathrm{A}\mathrm{g}\mathrm{N}\mathrm{O}}_3}·{\mathrm{c}}_{{\mathrm{A}\mathrm{g}\mathrm{N}\mathrm{O}}_3}·\mathrm{T}·4}{{\mathrm{m}}_{\mathrm{r}\mathrm{e}\mathrm{s}\mathrm{i}\mathrm{n}}}}$$

3.4. Preparation of Potassium 4-Sulfonato-Oxy-2,2,6,6-Tetramethylpiperidine-1-Yloxyl (TEMPO-4-Sulfate)

Potassium 4-sulfonatooxy-2,2,6,6-tetramethylpiperidine-1-oxyl was synthesized based on a previously reported method [68]. First, (4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (10 g, 58 mmol) was added in small amounts to concentrated sulfuric acid (7 mL, 96.4%) and then dissolved for 40 min under vigorous stirring. The solution was transferred to a dropping funnel and added dropwise to a KHCO₃ solution (295 g, 2.2 L) over 4 h for neutralization. The aqueous solution was subsequently extracted with ethyl acetate (3 × 400 mL). The aqueous phase was then evaporated at 60 °C and 1 mbar vacuum using a rotary evaporator. The resulting white–orange solid was treated with acetone (300 mL) and the mixture was stirred for 2 h to yield a solution. The solution was dried over MgSO₄ and filtered, and the filtrate concentrated using a rotary evaporator (40 °C, 300 mbar). This resulted in an orange–red solid (12.97 g, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ 4.29 (tt, J = 11.5, 4.2 Hz, 1H), 1.96–1.89 (m, 2H), 1.30 (d, J = 11.8 Hz, 2H), 1.04 (d, J = 12.4 Hz, 12H). ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 67.89, 58.06, 45.40, 32.64, 20.20. ESI-TOF-MS: C₉H₁₇KNO₅S: m/z = 251.08; found: m/z = 251.079 (Figure S7); Elemental Analysis: calculated: C, 37.22%; H, 5.90%; N, 4.82%; O, 27.55%; S, 11.04%; found: C, 36.95%; H, 6.09%; N, 4.79%; O, 28.72%; S, 10.81%; IR: characteristic vibrations for the R–O–SO₃ group at 1208 cm⁻¹; m.p. 217–221 °C.

3.5. General Procedure for the Immobilization of TEMPO-4-Sulfate Derivatives on the Ion Exchange Resins

The untreated ion exchange resins (1.0 g, 1.07 mmol) were added to an aqueous solution consisting of TEMPO-4-sulfate potassium salt (20 mL, 2.68 mmol) and stirred vigorously for 4 h at room temperature. Thus, 2.68 mmol of the TEMPO compound was provided to the ion exchanger, corresponding to 250% of the (minimum) anion exchange capacity (AEC). The amount of TEMPO-4-sulfate potassium salt absorbed was determined by UV–VIS spectroscopic analysis.

3.6. General Procedure for Regeneration of the Used Catalytic Ion Exchange Resin

For regeneration, the ion exchange resins (160 mg, 0.30 mmol) were packed into a glass column (volume 2 cm³) and washed with sodium hydroxide brine solution (10% NaCl/1% NaOH, volume 200 mL) for 20 min. The ion exchange resins were washed with water (100 mL), dried in a vacuum-drying oven (1 mbar, 40 °C) and used for reloading.

3.7. Catalytic Tests

3.7.1. Heterogeneous Catalysis

The ion exchange resins loaded with TEMPO-4-sulfate (160 mg, 0.30 mmol) were added to 4 mL acetonitrile and allowed to swell for 20 min. Next, benzyl alcohol (1.0 eq, 1 mL, 1 mmol), (diacetoxyiodo) benzene (1.1 eq, 0.354 g, 1.1 mmol), and tetrabutyl ammonium bromide (0.05 eq, 0.161 g, 0.05 mmol) were added and dissolved, and the reaction was stirred for 1 h at 35 °C. After the oxidation reaction, the ion exchange resins were filtered off, washed with acetonitrile (3 × 10 mL), and dried in a vacuum-drying oven (1 mbar, 40 °C).

3.7.2. Immobilization and Heterogeneous Catalysis in Flow

The unloaded ion exchange resin beads (9.6 g) were slurried up in water and charged directly into a stainless-steel column (diameter 0.8 cm, length 30 cm, volume 15.1 cm³ with stainless-steel frits, PEE-Encased Type), and subsequently treated with an aqueous solution of TEMPO-4-sulfate (350 mL, 120 mmol, flow rate 2 mL∙min⁻¹) using an HPLC pump and then washed with water (3 × 100 mL). The loaded column was then heated in a column oven at 35 °C. The reaction mixture was pumped through the column at different flow rates by means of an HPLC pump.

3.7.3. Yield Determination of Aldehydes

The yield was determined by collecting 0.1 mL of the reaction solution at intervals of 10, 20, 30, 45, and 60 min during the oxidation reaction. and diluted with 0.5 mL of dimethyl sulfoxide-d₆. The mixture was analyzed by ¹H NMR spectroscopy. The yield was determined by integrating the aldehyde and alcohol signals ($I_x$) and using the formula $\mathrm{Y}\mathrm{i}\mathrm{e}\mathrm{l}\mathrm{d}\left(\mathrm{\%}\right)={\mathrm{I}}_{\mathrm{a}\mathrm{l}\mathrm{d}\mathrm{e}\mathrm{h}\mathrm{y}\mathrm{d}\mathrm{e}}/\left({\mathrm{I}}_{\mathrm{a}\mathrm{l}\mathrm{d}\mathrm{e}\mathrm{h}\mathrm{y}\mathrm{d}\mathrm{e}}+{\mathrm{I}}_{\mathrm{a}\mathrm{l}\mathrm{c}\mathrm{o}\mathrm{h}\mathrm{o}\mathrm{l}}\right)\times 100\mathrm{\%}$.

4. Conclusions

The preparation and use of TEMPO-4-sulfate-loaded ion exchange resins have revealed promising perspectives for the continuous selective oxidation reactions of alcohols to aldehydes. The loading is determined by the equilibrium between the anions; in the batch case, a TEMPO loading of about 65% was reached, whereas loading on a column by percolating a solution of TEMPO through the beads leads to an almost 100% exchange of the anions. The equilibrium possibly also makes some of the TEMPO entities leave the beads in the presence of bromide anions, which are essential mediators in the reduction in the BAIB. The use of immobilized TEMPO-4-sulfate as a catalyst in the flow experiments indicated that the low loss of TEMPO had no effect on the oxidation reaction for over 2 h at a conversion of 84%. Further flow experiments for optimization will be conducted to determine the impact of the TEMPO loss on the reaction, also with the objective to balance the loading with bromide and anionic TEMPO derivatives, and to enable the oxidation with oxygen.