Electrochemical oxo-functionalisation of cyclic alkanes and alkenes using nitrate and oxygen

doi:10.21203/rs.3.rs-2494674/v1

Download PDF

Article

Electrochemical oxo-functionalisation of cyclic alkanes and alkenes using nitrate and oxygen

https://doi.org/10.21203/rs.3.rs-2494674/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 28 Jul, 2023

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Direct functionalization of C(sp³)–H bonds allows a fast, synthetic access to valuable products, starting from simple petrochemicals. Chemical transformation of inactivated methylene groups, however, remains challenging for organic synthesis. Here, we present a general electrochemical method for the oxidation of C(sp³)–H and C(sp²)–H bonds, in which cyclic alkanes and (cyclic) olefins are converted into cycloaliphatic ketones as well as aliphatic (di)carboxylic acids. This resource-friendly method is based on nitrate salts in a dual role as anodic mediator and supporting electrolyte, which can be fully recovered and recycled. Reduction of molecular oxygen as cathodic counter reaction leads to an efficient convergent use of both electrode reactions. By avoiding the use of transition metals and chemical oxidisers, this protocol represents a sustainable oxo-functionalization method, leading to a valuable contribution for the sustainable conversion of petrochemical feedstocks into synthetically usable fine chemicals and commodities.

Physical sciences/Chemistry/Electrochemistry/Electrocatalysis

Physical sciences/Chemistry/Green chemistry/Renewable energy

Transforming a chemically inert C(sp³)–H bond into a functional group is described as a vibrant topic, great challenge and even as “Holy Grail” for synthetic organic chemistry^1,2,3. Indeed, functionalization and modelling of molecular structures starting from hydrocarbons requires the breakage of carbon-hydrogen or carbon-carbon bonds. Due to the limited preparative application fields these compounds are commonly used as fuels⁴ and organic solvents⁵. Furthermore, the missing functionalities and lipophilic nature of alkanes lead to ecological issues, since their bioavailability for microorganisms is poor⁶. Naturally occurring monocyclic alkanes were discovered in the 1890’s by Markovnikov in caucasian crude oil, called naphtha^7,8. Cyclohexane, as the most prominent example and ubiquitous structural motif in natural and synthetic compounds, is industrially produced via hydrogenation of benzene⁹. Monocyclic aliphatics with larger ring sizes, especially eight and twelve membered rings, are formed through cyclooligomerisation of butadiene and subsequent hydrogenation¹⁰. While the fully saturated cyclododecane serves as an important intermediate for the production of laurolactame via a Bashkirov oxidation to primarily cyclododecanol¹¹, other saturated cyclic hydrocarbons emerge as by-products and are usually incinerated or discarded. The aforementioned Bashkirov oxidation produces additional reagent waste due to the use of boric acid, which is toxic to reproduction and fertility¹², making it therefore necessary to improve this process towards greater sustainability. Apart from that example, usually the unsaturated representatives of the same ring size, are of huge commercial interest. Cyclohexene, cyclooctene and cyclododecene serve as important starting materials for the synsthesis of distinct polymer precursors like dicarboxylic acids, which are annually produced in several ten thousends of tons with strongly increasing demand^13,14. The incorporation of saturated hydrocarbons back into the value chain, provides both economic and also environmental advantages. Therefore, a valorisation by installation of an oxygen containing group like a carbonyl function leads to synthetic versatility¹⁵.

Over the past decades, different methodes were developed to realise these oxo-functionalisation reactions. Conventional methods for the oxidation of cycloalkanes are predominantly based on transition metal catalysed reactions in combination with chemical oxidisers, mainly peroxides. Frequently, the use of hydrogen peroxide in combination with a variety of catalytically active transition metals such as iron¹⁶, manganese¹⁷, copper, nickel, and vanadium¹⁸ is reported. Ruthenium often serves as a transition metal catalyst in combination with peracids¹⁹ or tert-butyl hydroperoxide²⁰. Popular ligand systems are based on porphyrins including manganese or iron centers, with peroxide species²¹ and oxygen²² serving as oxidisers. Examples using an iridium catalyst with sodium periodate²³ and an iron(III) nitrate/N-hydroxyphthalimide/oxygen system²⁴ have been also reported.

With regards to C = C double bond cleavage, a large number of conventional methods are already known which lead to the formation of dicarboxylic acids. Comparable to the before mentioned ones, these usually take place in a transition metal-catalysed manner. Osmium^25,26, ruthenium^27,28 and tungsten^29,30 catalysts are the most frequently described ones. Older protocols refer to the use of potassium permanganate³¹. In contrast to these, metal-free processes are also known. For example, via hypervalent iodine species in combination with peracids or oxone^32,33, or classically, via the ozonolysis reaction³⁴.

Electrochemical protocols for the oxidation of C(sp³)−H bonds to ketones are barely described. The Gif-Orsay system, developed in the 1980s, serves as an example^35,36. Also the use of an electrocatalytic MnO_x layer on a Titanium anode with the use of oxygen³⁷, or the oxidation of cyclohexane with water on an iridium-supported carbon anode³⁸ were reported. The group of Baran published in 2017 an electrochemical protocol for C(sp³)−H oxidation via quinuclidine as a mediator in the presence of oxygen³⁹. Adversely, the method is barely suitable for large technical applications as 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) is used as solvent, which global warming potential (GWP₁₀₀) is approximately 200 times higher then carbon dioxide⁴⁰. Similarly to the alkane oxidation, a few electrochemical methods for the double bond cleavage to dicarboxylic acids are known, as shown by Schäfer and Bäumer via ruthenium catalysis with electrochemically regenerated periodate⁴¹. The same authors also described an electrochemical ozonolysis from water using a lead dioxide anode⁴². Older electrochemical methods use methanol as an oxygen source at constant potential in a divided cell⁴³. The disadvantages of the aforementioned methods relate to the use of toxic or, due to their mining, socially and environmentally problematic transition metals⁴⁴. Furthermore, the use of ligands and additional, over-stoichiometric amounts of oxidisers leads to reagent waste. The known electrochemical processes, often use expensive or toxic electrode materials or require a high material input due to the separate roles of electrochemical mediator and supporting electrolyte, devaluing the economic efficiency of these protocols.

With the method presented here, both a direct oxo-functionalisation of chemically stabile C(sp³)−H bonds and a cleavage of C = C double bonds to carbonyl and carboxyl compounds can be implemented by using electric current as a clean and safe reagent⁴⁵. In terms of sustainability and resource preservation, the use of transition metals and additional oxidising agents is avoided^46,47. Furthermore, the method is characterised by an effective use of materials through the dual use of the supporting electrolyte as an electrochemical mediator⁴⁸. Here, the initial anodic oxidation of nitrate anions serves as radical source, which was inspired by literature reports^49,50,51. Commonly described oxygen reduction to superoxide radicals were found to be the cathodic counter reaction^52,53, completing the electric cycle in a convergent electrolysis type⁵⁴. Advantageously, the supporting electrolyte can be extractively recovered after electrolysis, which further supports the sustainability of this electrochemical procedure (see Supplementary Results 2.7). The products are important substrates for organic synthesis and monomer building blocks for polymers, and therefore highly relevant for industrial applications.

Reaction development

Electrochemical oxidation of saturated hydrocarbons is a very challenging task for several reasons. Direct oxidation of these chemically inert species on the electrode surface is difficult due to their high oxidation potentials³⁹. Usually, the electrolyte, consisting of the solvent and the supporting electrolyte salt, is getting oxidised prior to these substrates. Furthermore, to avoid high electrical resistance within the electrochemical cell polar solvents with high permittivity are required. Very lipophilic substrates like saturated hydrocarbons showing often solubility issues in these solvents. Therefore, a mediated electrochemical system in which the mediator is transformed into a highly reactive species, that allows the target reaction to occur, is a suitable strategy.

As set-up, a commercially available electrochemical screening system from IKA was used which was co-developed⁵⁵ (see Supplementary Fig. 1). Inspired by literature, the focus was set to nitrate salts as supporting electrolyte and electrochemical mediator in a dual role, since upon oxidation the highly reactive nitrate radicals are able to split C(sp³)−H bonds. In initial reactions of converting cyclooctane (1c) as model substrate to cyclooctanone (2c) tetra-butylammonium (TBA) nitrate proved itself suitable. Commercially available acetonitrile, as a standard solvent in electro-organic applications, was used without further purification. As electrodes glassy carbon was used as a robust, long-term durable material with great electric conductivity properties.

First experiments were conducted under ambient conditions with air above the reaction solution. Electrolysis was carried out with 4 F regarding 1c and 10 mA/cm² leading to a yield of 23% of 2c (Fig. 2, entry 2). The reaction proved itself to be outstandingly selective, as only cyclooctanol (3c) and cyclooctane-1,4-dione (4c) were obtained as significant by-products with yields of 2% and 3%. If the reaction was carried out at 100 vol.% of N₂, no reaction to oxidised species occurred (Fig. 2, entry 3), which underlines the necessity of O₂ in the reaction medium. Remarkably, increasing the O₂ content in the atmosphere to 100 vol.% lead to only 16% of 2c (Fig. 2, entry 1). This decrease in yield is assumed to be caused by mutual influences of the atmospheric O₂ amount and the applied current density. However, a maximum yield of 31% was obtained for 2c under 20 vol.% O₂ and 10 mA/cm² (Fig. 2, entry 4).

The necessity of nitrate as anion is demonstrated by comparison with other TBA salts. Tetrafluoroborate (BF₄⁻), hexafluorophosphate (PF₆⁻) and perchlorate (ClO₄⁻) anions only lead to a formation of 2c in yields of 3%, 3% and 4%. Apart from TBA as cation, also longer chained tetra-alkylammonium nitrate salts provided product formation in comparable yields of 17−28% (see Supplementary Table 1) and also tetra-butylphosphonium nitrate was suitable with 20% (Fig. 2, entry 7). Furthermore, the reaction takes place in different solvents like isobutyronitrile (i-PrCN) (24%), acetone (29%) and nitropropane (17%) (see Supplementary Table 1). The agitation speed of the stirrer within the cell, has a significant influence on the reaction as a yield drop appears at higher and lower stirring rates then 350 rpm (see Supplementary Table 1). This circumstance is addressed to a disturbed O₂ adsorption on the electrode at higher speed and the reduced reaction partner contact due to reduced convection at lower speed. The reaction also takes place with lower yields at different carbon-based electrodes like boron-doped diamond (BDD) and graphite (see Supplementary Table 1).

The C = C double bond splitting of cyclic alkenes 5 (Fig. 3) has been discovered by applying the same methodology. Following the observation via HPLC-MS of a dicarboxylic acid 6 formation, the reaction conditions were varied using cyclooctene (5b) as model substrate. Application of the same standard conditions as for the cyclooctane oxidation, led to 33% yield of suberic acid (6b), while lowering the temperature to 5°C led to 47% (Fig. 2, entry 1,8). Increasing the charge to 8 F, caused a yield drop to 28% (Fig. 2, entry 9). The exclusion of O₂ showed no reaction to the dicarboxylic acid, indicating here as well the necessity for atmospheric oxygen (Fig. 2, entry 3). Decreasing the substrate concentration and the current density to 0.05 mol/L and 5 mA/cm² by varying the applied charge from 4 F to 6 F and 8 F led to similar yields of 39−44% (Fig. 2, entry 10,11,12). Using isobutyronitrile as solvent did not influence the yield (Fig. 2, entry 13).

Besides the reaction development trials on 5b a further intensified optimisation has been carried out with cyclododecene (5c), since it results in the highly industry-relevant dodecanedioic acid (6c) (see Supplementary Table 2). Due to the poor solubility of 5c in acetonitrile, the reactions were conducted in isobutyronitrile. Here, a decrease of the substrate concentration and the current density to 0.05 mol/L and 5 mA/cm² from the standard conditions, lead to a yield of 78% of 6c, as best conditions. As molecular oxygen can act as an oxidising agent itself it is noteworthy that the reaction does not take place if no electricity is applied to the reaction mixture (see Supplementary Table 2).

Scope, batch-type and flow electrolysis

After varying several reaction parameters with the model substrates for both reaction types, scale-up reactions as well as different substrates were tested to investigate the method’s applicability. A scale-up experiment regarding the cyclooctane oxidation in a three necked 100 mL round-bottom flask (see Supplementary Fig. 2), pure oxygen atmosphere, provided the ketone 2c in a yield of 42%. The increased yield can be explained by the different cell set-up that allows a larger contact area between the oxygen containing atmosphere and the reaction solution. Following this result, other different membered rings from six to twelve methylene groups were tested in this set-up (Fig. 3a). In comparison, the yield of cyclooctanone stayed the highest. Smaller and larger ring sizes seem to be more difficult to convert as mostly starting material remained after electrolysis. Remarkably, the general trend regarding the ketone yields, compared to the increasing ring sizes, is approximately following the transannular Prelog strain⁵⁶, as cyclohexanone (2a, 6% yield) and cyclododecanone (2e, 4% yield) gave the lowest yields, compared to cyclooctanone (2c, 42% yield). Because of the poor solubility of cyclododecane (1e) in acetonitrile, the solvent was replaced by isobutyronitrile, leading to a yield of 21% of cyclododecanone (2e).

The reactions for the substrate variation of the cycloalkenes were carried out in 5 mL PTFE cells under 100 vol.% oxygen atmosphere, since here the best result for cyclododecene (5c) oxidation was observed (Fig. 3b). Besides of suberic acid (6b, 46% yield) and dodecanedioic acid (6c, 78% yield) also adipic acid (6a) could be synthesised with 19%. As an example of a bicyclic substrate, norbornene lead to the formation of 1,3-cyclopentane diacid (6d) with 45% yield. Besides the synthesis of diacids from disubstituted double bonds, trisubstituted ones lead to formation of α,ω-ketocarboxylic acids, as shown on the example 6e. With the presented method, not only cyclic alkenes 5, but also linear alkenes, here fatty acids 7, can be converted to their corresponding acids (Fig. 3e). The reaction was performed with elaidic acid and oleic acid, as prominent examples for fatty acids, which only differ from their E-Z isomerism. Furthermore, the corresponding methyl oleate, which is a component of biodiesel, was used to investigate stability of ester groups under the applied conditions. In all cases the double bond splitting successfully led to pelargonic acid (8), azelaic acid (9b), and mono-methyl azelate (9a) respectively, with yields between 33−46%.

For the purpose of an industrial application, conversion of impure starting materials is beneficial, if the impurities do not interfere with the target reaction. Cycloalkenes of technical grade contain their fully saturated analogues as impurities from industrial synthesis steps, to certain percentages. To test the applicability of this protocol, a co-electrolysis of 1e and 5c has been successfully performed, whereby the yields of ketone 2e and dicarboxylic acid 6c depend on the composition of the starting materials (Fig. 3c). For example, the yield of cyclododecanone (2e) increases with lower molar amounts of cyclododecane (1e) within the substrate composition, and vice versa. The same observation has been made for the unsaturated ring 5c and the diacid 6c. Despite of that, both substrates can be converted by their own target reactions parallel to each other. A further co-electrolysis example for cyclooctane (1c) and cyclooctene (5b) is given in the Supplementary Table 3. Here the received products show generally lower yields with 2−4% of cyclooctanone (2c) and 40−45% of suberic acid (6b).

Besides batch-type electrolysis, the application of flow electrolysis methods is becoming increasingly popular due to the inherent advantages of continuous process control^57,58. Adaptability of the presented method towards different cell and process designs is presented by conducting the dicarboxylic acid synthesis also in an electrochemical flow set-up (Fig. 3d). The experiment has been carried out in a cycling mode⁵⁹, pumping the electrolyte multiple times through the cell into a reservoir, until the applied charge amount passed through. A small-scale trial with cyclododecene (5c) in a concentration of 0.05 mol/L in isobutyronitrile lead to a dodecanedioic acid (6c) formation of 76%. For larger technical application, the solvent was exchanged as well as a scale-up was pursued. After a few variation trials within the same set-up (see Supplementary Table 4), the reaction could be optimised with a non-toxic dimethyl carbonate/isopropanol (DMC/i-PrOH) mixture and a substrate concentration of (0.5 mol/L) to yield 6c in 52%.

Mechanistic studies

To investigate mechanistical correlations of the cycloalkane (Fig. 4f) and alkene (Fig. 4h and 4i) oxidation reactions, several experiments have been conducted. The initial electrochemical oxidation step originates from the nitrate supporting electrolyte, as shown via cyclic voltammetry experiments (Fig. 4e and 4j). The resulting nitrate radicals could be indirectly observed due to a control experiment, conducted on cyclooctene (5b) under argon atmosphere, whereby among others the nitrated intermediates (10b) and (11b) were detected via GC-MS and illustrated by a mechanistic proposal (Fig. 4k). Further GC-MS analysis results are given in Supplementary Fig. 13. In case of the cycloalkanes, the nitrate radicals serve as mediator, as the anion is reformed. This observation was supported by anion chromatography, as solely nitrate remains in the aqueous layer subsequently to an extractive work up after the electrolysis (Fig. 4a). Furthermore, nitrate is not getting electrochemically reduced to nitrite as shown by an anion chromatography measurement (see Supplementary Fig. 11) and a negative Griess test (Fig. 4g). Instead, the cathodic counter reaction is provided by reduction of dissolved oxygen, that originates from the atmosphere above the reaction solution (Fig. 4b). The hereby formed superoxide radicals, that are presumably stabilised by lipophilic organic cations like TBA⁶⁰, are assumed to react with the hydrocarbon radicals to peroxide intermediates. A peroxide specific detection test using titanyl sulfate^61,62 showed a positive result for these species directly after electrolysis (Fig. 4c). The dissolved oxygen concentration at a partial pressure of 1 atm. has been determined by cyclic voltammetry studies and applying the Randles-Ševčík equation (see Supplementary Note 3.1). At 100 vol.% of O₂ in the reaction atmosphere a concentration of 9.5 ± 0.4 mmol/L was observed, which is comparable to literature values⁶³. Furthermore, a steady pH value before and after the reaction of 5−6 was observed with standard pH indicator paper, implying no drift into acidic or alkaline environment (see Supplementary Fig. 12). A Karl Fischer titration to investigate the water content after electrolysis with and without substrate revealed an increased water content, if the sample contained the hydrocarbon substrate (Fig. 4d). For the C = C double bond cleavage, an addition of the nitrate radical onto the double bond is proposed, according to the findings of the control experiment (Fig. 4k) as well as to literature discriptions⁶⁴. Further reaction with a superoxide radical lead via an unknown pathway to the formation of aldehydes, that are obtained as by-products (Fig. 4h). Afterwards, a literature described autooxidation like mechanism from aldehydes to carboxylic acids is assumed to happen⁶⁵ (Fig. 4i).

Further method application

For the presented method, a further application field has been demonstrated by applying the reaction conditions to toluene substrates 12. Benzylic oxidation to either the benzaldehydes 13’, including subsequent derivatisation with semicarbazide hydrochloride 15 to the corresponding semicarbazones 13, or the benzoic acids 14 could be promoted selectively via tuning the reaction conditions (Fig. 5a). Reaction monitoring via ¹H NMR spectra recording shows the aldehyde as intermediate, that is further converted to the corresponding carboxylic acid, when the toluene substrate is almost fully converted (Fig. 5b). No alcohol containing intermediates were observed. Optimisation reactions were carried out in undivided 5 mL PTFE cells (see Supplementary Table 5), while for the scale-up reactions a 25 mL beaker-type glass cell was used. Suitable conditions for the aldehyde formation differ from the ones for the acid formation significantly by changing the current density, the charge quantity and the substrate concentration. With lower conditions around 10 mA/cm², 5 F, and 0.02 moL/L of 12 the reaction can be stopped after selective formation of the aldehyde 13’, while increasing these conditions to 30 mA/cm², 7−12 F and 0.1 moL/L of 12, the acid formation 14 can be promoted. As substrates mainly methylated toluenes (xyloles) were chosen, to investigate over-oxidation reactions at the remaining benzylic positions. Selectively, only one methyl group is oxidised to the aldehyde and then further into the carboxylic acid. As by-products of the benzoic acid synthesis, N-acetylbenzamides 14’ were obtained in a range of 3−4% yield. A plausible explanation leads via the formation of acyl radicals (as postulated in Fig. 4), which react with acetonitrile as a radical scavenger and are subsequently further oxidised (see Supplementary Fig. 14). Derivatisation of the aldehydes to semicarbazones 13 were carried out on one hand to prevent further autooxidation of the aldehyde and therefore falsification of the yield determination, and on the other hand to provide a simple protocol for semicarbazone 13 synthesis. Semicarbazones show pharmacological versatility and are known for their anticonvulsant^66,67 as well as potential anticancer⁶⁸ properties.

In summary, two challenging electrochemical oxidation reactions were facilitated in one simple sustainable approach. With the presented method, cyclic alkanes and (cyclic) alkenes can be oxidised into ketones and (di)carboxylic acids respectively. The overall moderate yields, are balanced out by the resource and material saving advantages that are provided, like the dual role usage of supporting electrolyte and electrochemical mediator. Atmospheric oxygen is crucial for the reaction’s success, making additional oxidising agents redundant. No transition metal use is needed for the procedure, as even the electrode material is based on simple glassy carbon. Furthermore, the method shows widely applicable oxo-functionalisation properties, as an application for a benzylic oxidation successfully led to aldehydes and benzoic acids. This work provides a valuable contribution to sustainable, preparative chemical processes, and allows the production of industrial relevant chemicals for large-scale technical plastics production.

Electrolysis of hydrocarbons in 5 mL PTFE cells (GP 1)

The electrolysis set-up is commercially available as IKA Screening System from IKA-Werke GmbH & Co. KG, Staufen, Germany. Gas distributor and associated caps can be purchased separately from IKA. In a 5 mL undivided PFTE cell with magnetic stirrer, the substrate (0.25−1 mmol) and the supporting electrolyte (NBu₄NO₃, 0.5 eq.) are dissolved in acetonitrile or isobutyronitrile (5 mL). The cell is equipped with a cap, including a gas adapter, where two glassy carbon electrodes (7 cm x 1 cm x 0.3 cm) are fixed in a distance of 0.5 cm to each other. The immersed electrode surface is 1.8 cm². The cell is fixed in a stainless-steel set-up and, while stirring, the atmosphere within the cell is filled with oxygen gas (2.5 technical grade, purity ≥ 99.5%). A constant current electrolysis with a current density of 10 mA/cm² with an applied charge of 4−8 F is performed. During electrolysis, a constant flow of oxygen of 20 mL/min into the cell is ensured. For set-up information see Supplementary Fig. 1.

Electrolysis of hydrocarbons in a 100 mL round-bottom flask (GP 2)

In a 100 mL three necked round-bottom flask with a NS29 teflon plug incl. electrode holders, magnetic stirrer and bubble counter, the substrate (5 mmol) and supporting electrolyte (NBu₄NO₃, 0.5 eq.) are dissolved in acetonitrile or isobutyronitrile (25 mL). The cell is equipped with two glassy carbon electrodes (3 cm x 1 cm x 0.3 cm), which are fixed in a distance of 0.5 cm to each other. The immersed electrode surface is 1.3 cm². While stirring, the atmosphere within the cell is filled with oxygen gas (2.5 technical grade, purity ≥ 99.5%). A constant current electrolysis with a current density of 10 mA/cm² with an applied charge of 4−8 F is performed at 20−30 °C. During electrolysis, a constant flow of oxygen of 20 mL/min into the cell is ensured. For set-up information see Supplementary Fig. 2.

Electrolysis of hydrocarbons in 25 mL beaker-type glass cells (GP 3)

The cells are commercially available as SynLectro™ Electrolysis Platform from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). In a 25 mL beaker-type glass cell with gas inlet attachment, a NS45/40 teflon plug incl. electrode holders and magnetic stirrer, the substrate (0.55 mmol) and supporting electrolyte (NBu₄NO₃, 0.51 eq.) are dissolved in acetonitrile (25 mL). The cell is equipped with two glassy carbon electrodes (7 cm x 1 cm x 0.3 cm), which are fixed in a distance of 0.5 cm to each other. The immersed electrode surface is 4.5 cm². While stirring, the atmosphere within the cell is filled with oxygen gas (2.5 technical grade, purity ≥ 99.5%). A constant current electrolysis with a current density of 10−30 mA/cm² with an applied charge of 5−13 F is performed at 27−33 °C. During electrolysis, a constant flow of oxygen of 20 mL/min into the cell is ensured. For set-up information see Supplementary Fig. 3.

Electrolysis of hydrocarbons in a flow cell (GP 4)

The electrolysis set-up is made in the university’s machine shop^69,70 and is commercially available as IKA ElectraSyn flow. As pumping system a peristaltic Ismatec Reglo ICC with a TYGON 2765 − 175 (ID 2.06 mm) hose was used. The undivided flow cell was equipped with glassy carbon electrodes (2 x 6 cm²). In a 20 mL snap cap vial, the substrate (0.55 mmol) and supporting electrolyte (NBu₄NO₃, 0.51 eq.) are dissolved in isobutyronitrile or a dimethyl carbonate/isopropanol mixture (10 mL). The reaction solution is pumped with 1018 mL/min through a t-piece, where oxygen gas is passed through with 1020 mL/min. The combined, segmented flow is pumped through the flow cell (electrode gap: 0.05 cm) back into the snap cap vial in a cycling operation mode. A constant current electrolysis with a current density of 5−20 mA/cm² with an applied charge of 2−4 F is performed at 20−50 °C, whereby the reservoir is exposed to the heating. During electrolysis, a constant flow of oxygen into the t-piece is ensured. For set-up information see Supplementary Fig. 4.

Work-up protocol for (di)carboxylic acid and benzoic acid synthesis

After electrolysis, the solvent is recovered by distillation under reduced pressure. Leftover of low boiling starting material can be recovered by extraction with n-pentane out of the nitrile distillate and monitored via thin-layer chromatography (TLC). The distillation residue, is extracted with HCl aq. (0.1 mol/L, 10 mL) and ethyl acetate (10 mL), whereby the supporting electrolyte remains in the aqueous layer and can be recovered quantitatively. The organic fraction is reduced in vacuo to yield the crude product. For purification, the residue is washed with NaOH aq. (1 mol/L, 10 mL) and extracted with diethyl ether or n-pentane (10 mL), monitored via TLC. After dropwise acidification of the aqueous layer with conc. HCl aq. to pH 1 and extraction with ethyl acetate (2x10 mL), the combined organic layers are dried over MgSO₄ and reduced in vacuo to yield the desired product.

Work-up protocol for the cyclic ketones and benzaldehyde synthesis

After electrolysis, the solvent is recovered by distillation under reduced pressure. Leftover of low boiling starting material can be recovered by extraction with n-pentane out of the nitrile distillate. The distillation residue, is extracted with water (20 mL) and cyclohexane (20 mL) or diethyl ether (20 mL), whereby the supporting electrolyte remains in the aqueous layer and can be recovered quantitatively. The organic layer is dried over MgSO₄ and reduced in vacuo to yield the desired product. Special attention has to be paid to the distillations, since short chained cyclic ketones are volatile. Solvent evaporation was carried out to a maximum of, 250 mbar at 50°C for cyclohexane or 970 mbar at 40°C for diethyl ether respectively.

For derivatisation of the benzaldehydes to the semicarbazones: After extraction and evaporation of the solvent from the dried organic layer, the residue is immediately dissolved in 3 mL abs. ethanol and is added dropwise to a 90°C preheated solution of semicarbazide hydrochloride (2 eq.) and sodium acetate trihydrate (2.4 eq.) in 10 mL water. Heating and stirring is continued for 15 min. Afterwards the solvents are evaporated and the precipitating semicarbazone is suspended in cold, deionised water, filtrated, washed with cold water and dried in vacuo.

Work-up protocol for the co-electrolysis

After electrolysis, 10 mg of 1,3,5-trimethoxybenze as internal standard were added to the reaction solution. Three drops were eluted with ethyl acetate through approx. 330 mg silica 60M and filled into a vial for quantitative GC-FID analysis. Prior to the analysis, an external calibration of the ketone has been performed (see Supplementary Fig. 6). The dicarboxylic acid has been isolated regarding the work-up procedure described above.

Work-up procedure for the carboxylic acid synthesis from the fatty acid cleavage

After electrolysis, 50.5 µL propionic acid as internal standard were added to the reaction solution. Three drops were eluted with ethyl acetate through approx. 330 mg silica 60M and filled into a vial for quantitative GC-FID analysis. Prior to the analysis, an external calibration of the mono-carboxylic acid has been performed (see Supplementary Fig. 7). The dicarboxylic acid has been isolated via column chromatography (cyclohexane/ethyl acetate = 1:1 with 1 vol.% glacial acetic acid).

Data Availability

Further study details about general analytical methods, mechanistical experiments, reaction development and compound characterisation are available in the Supplementary information.

Acknowledgements

The authors gratefully acknowledge the financial support by Forschungsinitiative Rheinland-Pfalz in the frame of SusInnoScience. J.N. thanks J. L. Schröder for preparative support, A. L. Rauen for initial guidance in the subject area and helpful discussions, S. Hofmann for helpful discussions and invention disclosure support, S. Arndt for the introduction in ion chromatography measurements and J. Herszman for introduction into the coulometric titration apparatus.

Ethics declarations

Competing interests

The authors declare no competing interests.

Contributions

J.N., F.W., F.-E.B. and S.R.W. conceived this work and designed the experiments. J.N., K.H., S.M., I.C.M. and D.M.M. conducted the experiments and analysed the data. J.N. and S.R.W wrote the manuscript and Supplementary information. F.W. and F.-E.B. discussed the results and commented on the manuscript.

Parasram, M. & Gevorgyan, V. Silicon-tethered strategies for C–H functionalization reactions. Acc. Chem. Res. 50, 2038–2053 (2017).
Zhao, J. & Han, J. Metal-free functionalization of alkanes. In Alkane Functionalization 1st edn (eds Pombeiro, A. J. L. & Guedes da Silva, M. F. C.) (John Wiley & Sons Ltd., 2019).
Govaerts, S., Nyuchev, A. & Noël, T. Pushing the boundaries of C–H bond functionalization chemistry using flow technology. J. Flow Chem. 10, 13–71 (2020).
Simmie, J. M. Detailed chemical kinetic models for the combustion of hydrocarbon fuels. Prog. Energ. Combust. 29, 599–634 (2003).
Sogorb M. Á., Mangas, I., & Vilanova, E. Petroleum distillates. In Encyclopedia of Toxicology 3rd edn (Elsevier Inc., 2014).
Singh, S. N., Kumari, B. & Mishra, S. Microbial degradation of alkanes. In Microbial Degradation of Xenobiotics. Environmental Science and Engineering (ed Singh, S. N.) (Springer, 2012).
Markovnikov, V. V. Occurrence of hexanaphthene in caucasian naphtha. Ber. Dtsch. Chem. Ges. 28, 577-578 (1895).
Markovnikov, V. V. Some new constituents of caucasian naphtha. Ber. Dtsch. Chem. Ges. 30, 974-977 (1897).
Campbell, M. L. Cyclohexane. In Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, 2000).
Schiffer, T. & Oenbrink, G. Cyclododecatriene, Cyclooctadiene, and 4-vinylcyclohexene. In Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, 2000).
Bashkirov, A. N. et al. The production of cyclododecanol by the liquid-phase oxidation of cyclododecane. Neftekhimiya 1, 527–534 (1961).
ECHA. CLH report for boric acid and borates. https://echa.europa.eu/documents/10162/2842450/clh_rep_boric+acid+and+borates_10344_en.pdf/74c34c0b-2129-abf5-a0f4-2c5b21d7d926 (2018).
Lisicki, D. & Orlińska, B. Oxidation of cyclic ketones to dicarboxylic acids. Pol. J. Chem. Tech. 20, 102-107 (2018).
Mills, B. M., Talati, M. M. & Winter, G. A. Bio-dodecanedioic acid (DDDA) production. https://repository.upenn.edu/cbe_sdr/100/?utm_source=repository.upenn.edu%2Fcbe_sdr%2F100&utm_medium=PDF&utm_campaign=PDFCoverPages (2018).
Smith, M. B. & March, J. Marchs´s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 5th edn, 1172–1298 (John Wiley & Sons, Inc., 2001).
Yu, H. et al. Iron-catalyzed oxidative functionalization of C(sp3)–H bonds under bromide synergized mild conditions. Chem. Commun. 55, 7840–7843 (2019).
Wang, W., Xu, D., Sun, Q. & Sun, W. Efficient aliphatic C–H bond oxidation catalyzed by manganese complexes with hydrogen peroxide. Chem. Asian J. 13, 2458–2464 (2018).
Silva, T. F. S. et al. V(IV), Fe(II), Ni(II) and Cu(II) complexes bearing 2,2,2-tris(pyrazol-1-yl)ethyl methanesulfonate: application as catalysts for the cyclooctane oxidation. New J. Chem. 40, 528–537 (2016).
Murahashi, S.-I., Oda, Y., Komiya, N. & Naota, T. Ruthenium-catalyzed oxidation of alkanes with peracids. Tetrahedron Lett. 35, 7953–7956 (1994).
Denicourt-Nowicki, A., Lebedeva, A., Bellini, C. & Roucoux, A. Highly selective cycloalkane oxidation in water with ruthenium nanoparticles. ChemCatChem 8, 357–362 (2016).
Jiang, J., Luo, R., Zhou, X., Wang, F. & Ji, H. Metalloporphyrin-mediated aerobic oxidation of hydrocarbons in cumene: co-substrate specificity and mechanistic consideration. Molecular Catalysis 440, 36–42 (2017).
Tabor, E., Połtowicz, J., Pamin, K., Basąg, S. & Kubiak, W. Influence of substituents in meso-aryl groups of iron l-oxo porphyrins on their catalytic activity in the oxidation of cycloalkanes. Polyhedron 119, 342–349 (2016).
Gupta, S. K. & Choudhury, J. Templating an N-heterocyclic carbene (NHC)-cyclometalated Cp*IrIII-based oxidation precatalyst on a pendant coordination platform: assessment of the oxidative behavior via electrochemical, spectroscopic and catalytic probes. Dalton Trans. 44, 1233–1239 (2015).
Miao, C., Zhao, H., Zhao, Q., Xia, C. & Sun, W. NHPI and ferric nitrate: a mild and selective system for aerobic oxidation of benzylic methylenes. Catal. Sci. Technol. 6, 1378–1383 (2016).
Travis, B. R., Narayan, R. S. & Borhan, B. Osmium tetroxide-promoted catalytic oxidative cleavage of olefins: an organometallic ozonolysis. J. Am. Chem. Soc. 124, 3824–3825 (2002).
Henry, J. R. & Weinreb, S. M. A convenient, mild method for oxidative cleavage of alkenes with Jones reagent/osmium tetraoxide. J. Org. Chem. 58, 4745–4745 (1993).
Zimmermann, F., Meux, E., Mieloszynski, J.-L., Lecuire, J.-M. & Oget, N. Ruthenium catalysed oxidation without CCl₄ of oleic acid, other monoenic fatty acids and alkenes. Tetrahedron Lett. 46, 3201–3203 (2005).
Che, C.-M., Yip, W.-P. & Yu, W.-Y. Ruthenium-catalyzed oxidation of alkenes, alkynes, and alcohols to organic acids with aqueous hydrogen peroxide. Chem. Asian J. 1, 453–458 (2006).
Kadyrov, R. & Hackenberger, D. Oxidative cleavage of long chain olefins to carboxylic acids with hydrogen peroxide. Top. Catal. 57, 1366–1371 (2014).
Bhuyan, B., Paul, B., Vadivel, S. & Dhar, S. S. Preparation and characterization of WO₃ bonded imidazolium sulfonic acid chloride as a novel and green ionic liquid catalyst for the synthesis of adipic acid. RSC Adv. 6, 99044–99052 (2016).
Choudary, B. M., Valli, V. L. K. & Prasad, A. D. A novel montmorillonite - KMnO₄ system for the oxidation of alkenes under triphase conditions. Synth. Commun. 21, 2007–2013 (1991).
Miyamoto, K., Sei, Y., Yamaguchi, K. & Ochiai, M. Iodomesitylene-catalyzed oxidative cleavage of carbon−carbon double and triple bonds using m-chloroperbenzoic acid as a terminal oxidant. J. Am. Chem. Soc. 131, 1382–1383 (2009).
Thottumkara, P. P. & Vinod, T. K. Oxidative cleavage of alkenes using an in situ generated iodonium ion with oxone as a terminal oxidant. Org. Lett. 12, 5640–5643 (2010).
Habib, R. M., Chiang, C. Y. & Bailey, P. S. Dicarboxylic acids from ozonolysis of cycloalkenes. J. Org. Chem. 49, 2780–2784 (1984).
Balavoine, G. et al. An efficient electrochemical process for the oxidation of saturated hydrocarbons: the Gif-Orsay system. J. Chem. Soc., Chem. Commun. 1727–1729 (1986).
Balavoine, G. et al. Selective oxidation of saturated hydrocarbons using an electrochemical modification of the Gif system. Tetrahedron Lett. 27, 2849–2852 (1986).
Fang, X. et al. Controllable oxidation of cyclohexane to cyclohexanol and cyclohexanone by a nano-MnO_x/Ti electrocatalytic membrane reactor. J. Catal. 329, 187–194 (2015).
Yamanaka, I., Furukawa, T. & Otsuka, K. Oxidation of alkanes with H₂O on Ir(acac)₃ supported on a carbon fiber-anode. Chem. Commun. 2209–2210 (2000).
Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).
Godin, P. J., Le Bris, K. & Strong, K. Conformational analysis and global warming potentials of 1,1,1,3,3,3-hexafluoro-2-propanol from absorption spectroscopy. J. Quant. Spectrosc. Ra. 203, 522–529 (2017).
Bäumer, U.-St. & Schäfer, H. J. Cleavage of olefinic double bonds by mediated anodic oxidation. Electrochim. Acta 48, 489−495 (2003).
Bäumer, U.-St. & Schäfer, H. J. Cleavage of alkenes by anodic oxidation. J. Appl. Electrochem. 35, 1283–1292 (2005).
Torii, S., Inokuchi, T. & Oi, R. Electrooxidative cleavage of carbon-carbon linkages. 1. Preparation of acyclic oxoalkanoates from 2-hydroxy- and 2-acetoxy-l-cycloalkanones and cycloalkanone enol acetates. J. Org. Chem. 47, 47–52 (1982).
Lèbre, É. et al. The social and environmental complexities of extracting energy transition metals. Nat. Commun. 11, 4823 (2020).
Pollok, D. & Waldvogel, S. R. Electro-organic synthesis – a 21st century technique. Chem. Sci. 11, 12386–12400 (2020).
Wiebe, A. et al. Electrifying organic synthesis. Angew. Chem. Int. Ed. 57, 5594–5619 (2018).
Möhle S. et al. Modern electrochemical aspects for the synthesis of value-added organic products. Angew. Chem. Int. Ed. 57, 6018–6041(2018).
Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 43, 2492–2521 (2014).
Schmidt, H. & Stange, H. Electrolyses of nitrates in acetonitrile. Z. Anorg. Allgem. Chem. 293, 274–285 (1957).
Rao, R. R., Milliken, S. B., Robinson, S. L. & Mann, C. K. Anodic oxidation of lithium, cadmium, silver, and tetra-n-butylammonium nitrates. Anal. Chem. 42, 1076–1080 (1970).
Takahira, Y. et al. Electrochemical C(sp³)–H fluorination. Synlett 30, 1178–1182 (2019).
Li, D., Ma, T.-K., Scott, R. J. & Wilden, J. D. Electrochemical radical reactions of alkyl iodides: a highly efficient, clean, green alternative to tin reagents. Chem. Sci. 11, 5333–5338 (2020).
Imada, Y., Okada, Y., Noguchi, K. & Chiba, K. Selective functionalization of styrenes with oxygen using different electrode materials: olefin cleavage and synthesis of tetrahydrofuran derivatives. Angew. Chem. Int. Ed. 58, 125−129 (2019).
Klein, M. & Waldvogel, S. R. Counter electrode reactions – important stumbling blocks on the way to a working electro-organic synthesis. Angew. Chem. Int. Ed. (2022), accepted. https://doi.org/10.1002/anie.202204140.
Gütz, C., Klöckner, B. & Waldvogel, S. R. Electrochemical screening for electroorganic synthesis Org. Process Res. Dev. 20, 26–32 (2016).
Dunitz, J. D. & Prelog, V. Röntgenographisch bestimmte Konformationen und Reaktivität mittlerer Ringe. Angew. Chem. 72, 896−902 (1960).
Atobe, M., Tateno, H. & Matsumura, Y. Applications of flow microreactors in electrosynthetic processes. Chem. Rev. 118, 4541–4572 (2018).
Noël, T., Cao, Y. & Laudadio, G. The fundamentals behind the use of flow reactors in electrochemistry. Acc. Chem. Res. 52, 2858–2869 (2019).
Gleede, B., Selt, M., Franke, R. & Waldvogel, S. R. Developments in the dehydrogenative electrochemical synthesis of 3,3′,5,5′‐tetramethyl‐2,2′‐biphenol. Chem. Eur. J. 27, 8252–8263 (2021).
Zimmermann, M. Oxygen reduction reaction mechanism on glassy carbon in aprotic organic solvents. (Université Grenoble Alpes, Grenoble, 2015).
Jander, G. & Blasius, E. Lehrbuch der analytischen und präparativen anorganischen Chemie 16th edn, 290−291 (Hirzel, 2006).
Blaschette, A., Büchel, K.-H., Dahlmann, J., de Meijere, A. & Dankowski, M. Organic Peroxo Compounds. In Houben-Weyl: Methods of Organic Chemistry 4th edn, vol. E 13, 1387 (Thieme, 1989).
Achord, J. M. & Hussey, C. L. Determination of dissolved oxygen in nonaqueous electrochemical solvents. Anal. Chem. 52, 601−602 (1980).
Berndt, T. & Böge, O. Products and mechanism of the reaction of NO₃ with selected acyclic monoalkenes. J. Atmos. Chem. 21, 275–291 (1995).
Sankar, M. et al. The benzaldehyde oxidation paradox explained by the interception of peroxy radical by benzyl alcohol. Nat. Commun. 5, 3332 (2014).
Beraldo, H. & Gambino, D. The wide pharmacological versatility of semicarbazones, thiosemicarbazones and their metal complexes. Mini-Rev. Med. Chem. 4, 31–39 (2004).
Ahsan, M. J. Semicarbazone analogs as anticonvulsant agents: a review. Cent. Nerv. Syst. Agents Med. Chem. 13, 148–158 (2013).
Nascimento da Cruz, A. C. et al. Biological evaluation of arylsemicarbazone derivatives as potential anticancer agents. Pharmaceuticals 12, 169 (2019).
Gütz, C., Stenglein, A. & Waldvogel, S. R. Highly modular flow cell for electroorganic synthesis. Org. Process Res. Dev. 21, 771–778 (2017).
Gleede, B., Selt, M., Gütz, C., Stenglein, A. & Waldvogel, S. R. Large highly modular narrow gap electrolytic flow cell and application in dehydrogenative cross-coupling of phenols. Org. Process Res. Dev. 24, 1916–1926 (2020).

There is NO Competing Interest.

Download PDF

Journal Publication

published 28 Jul, 2023

Read the published version in Nature Communications →

Version 1

posted

You are reading this latest preprint version

Electrochemical oxo-functionalisation of cyclic alkanes and alkenes using nitrate and oxygen

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Discussion

Methods

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1