Tuning the Reactivity of TEMPO during Electrocatalytic Alcohol Oxidations in Room-temperature Ionic Liquids

2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) is a promising, sustainable, metal-free mediator for oxidation of alcohols. In this contribution, we describe how the selectivity of TEMPO for electrocatalytic alcohol oxidations in room-temperature ionic liquids (RTILs) can be changed by design of the solvent medium. Cyclic voltammetry of TEMPO in a series of ammonium-, phosphonium-, and imidazolium-based RTILs reveals that the potential at which TEMPO is oxidized increases from 677 mV ( vs. the potential of the decamethylferrocene/ decamethylferrocinium, dmFc/dmFc + , redox couple) to 788 mV as the H-bond basicity of the RTIL anions decreases. The increase in potential is accompanied by an increase in the rate constant for oxidation of benzyl alcohol from about 0.1 dm 3 mol −1 s −1 to about 0.7 dm 3 mol −1 s −1 , demonstrating the ability to manipulate the reactivity of TEMPO by judicious choice of the RTIL anions. The rate of alcohol oxidation in a series of RTILs increases in the order 2-butanol < 1-phenylethanol < octanol < benzyl alcohol, and the RTIL 1-octyl-3-methylmidazolium bis(trifluoromethanesulfonyl)imide ([NTf 2 ] – ) shows clear selectivity towards the oxidation of primary alcohols. In addition, the reaction kinetics and selectivity are better in [NTf 2 ] – -based RTILs than in acetonitrile, often the solvent-of-choice in indirect alcohol electrooxidations. Finally, we demonstrate that electrolytic TEMPO-mediated alcohol oxidations can be performed using RTILs in a flow-electrolysis system, with excellent yields and reaction selectivity, demonstrating the opportunities offered by such systems.


INTRODUCTION
The oxidation of alcohols is one of the most widely used industrial transformations.
However, traditional methods for oxidizing alcohols are often energetically demanding, suffer from poor atom efficiencies, require harsh reaction conditions, and generate significant amounts of potentially hazardous wastes. [1][2][3] Consequently, the development of clean and sustainable methods for oxidizing alcohols is of increasing importance to the chemical-using industries. 4,5 2,2,6,6,-tetramethylpiperidine-1-oxyl (TEMPO) is a metal-free, sustainable alternative to traditional reagents for the oxidation of primary and secondary alcohols to carbonyl compounds, and which attracted increasing interest in this context in recent years. [6][7][8] As well as growing interest in the development of sustainable processes for the chemicalusing industry, there is increasing interest in the development of sustainable electrosynthetic methods, which offer the prospects of high atom economy and cleanliness. The renaissance in the use of electrosynthetic methods is also being driven by increasing availability and accessibility of electrochemical equipment. [9][10][11] Electrochemical methods have been used in TEMPO-mediated oxidations as the catalytically-active oxoammonium species (TEMPO + ) can be formed electrochemically using simple carbon electrodes held at positive potentials. This approach eliminates the requirement for dedicated molecular oxidants such as hypervalent iodine 3 and bleach 12 , and increases the sustainability of the process. 13 Despite these advantages, unfamiliarity with electrosynthetic methods, as well as the use of volatile organic solvents and expensive supporting electrolytes may be contributing the slow uptake of electrosynthesis for industrial-scale processes. 11 Room temperature ionic liquids (RTILs) are salts that are liquid below 100 °C, inherently conductive, non-volatile, and generally more electrochemically stable than conventional solvents such as acetonitrile. The unique properties of RTILs offer clear advantages during the development of electrosynthetic processes, due to their stability and the fact that they can be used as both the solvent and electrolyte. 14,15 RTILs can also be used as dissolved electrolytes, which in some cases has improved the efficiency of electrochemical reactions. For example, addition of the 1-ethyl-3methylimidazolium methanesulfonate to alkaline water improved water electrolysis significantly. 16 A particularly attractive feature of RTILs is the ability to tune their physicochemical and electrochemical properties by judicious choice of the cations and anions (leading to their labelling as "designer" solvents). 17 For example, the rates of mass transfer of redox species to electrodes in RTILs can be changed significantly by altering the ionic composition of RTILs; significant differences in the rates of mass transfer of a single redox couple in different oxidation states in an RTIL have even been observed. 18 The redox reactivity of solutes can also be changed by varying the composition of RTILs; for example, the redox potentials of 2,2-diphenyl-1-picylhydrazyl (DPPH) 19 and 1,2-diferrocenylethylene 20 in RTILs have been tuned by varying the RTIL anions. In this context, the possibility of tuning the reactivity and selectivity of TEMPO by using RTIL electrolytes is attractive, as it can potentially provide a means to boosting the performance of TEMPO-mediated alcohol oxidations.
A handful of studies on the electrochemical behavior of TEMPO in RTILs have been conducted, and demonstrate that the behavior of TEMPO in RTILs is similar to that in acetonitrile and water. Doherty and coworkers observed that the global rate constant of TEMPO-mediated alcohol oxidation was a factor of six larger in N-butyl-N-methyl pyrrolidinium than in acetonitrile, despite the fact that mass transfer was slower in the RTIL. 21,22 These experiments show that, not only is the use of RTILs advantageous in terms of eliminating the need for volatile molecular solvents and extraneous electrolytes, but also for the efficiency of the alcohol oxidations.
In this contribution, we describe tuning the reactivity and selectivity of RTILs for TEMPOmediated electrooxidations, by changing RTIL parameters such as the length of alkyl chains, the presence of aromatic rings, and the H-bond basicity of the anions. We first describe changes in the redox properties of TEMPO in a series of imidazolium-, pyrrolidinium-, phosphonium-and ammonium-based RTILs (Table 1). Voltammetric analysis shows that the TEMPO/TEMPO + redox potential depends on the choice of RTIL anion, due to differing degrees of stabilization of the TEMPO + cation within the RTILs. This tuning of the redox properties of TEMPO in turn affects the rates of alcohol oxidation in the RTILs. We then demonstrate that the use of RTILs allows the introduction of kinetic selectivity into the oxidation of primary and secondary alcohols.
To allow comparison with conventional systems, we also describe the effects of using RTILs as dissolved electrolytes in acetonitrile during alcohol oxidations. Our studies show that stabilization of TEMPO + by the RTIL anions is also observed when the RTILs are dissolved. Moreover, the identity and concentration of the dissolved RTIL clearly affect the rates of alcohol oxidations, demonstrating that tuning the electrolyte is also important when using conventional solvents. mA cm -2 , 1.5 mA cm -2 or 2 mA cm -2 ). Products were collected from the cell outlet and were extracted into 5 cm -3 of toluene for analysis by gas chromatography using a flame ionization detector.

RESULTS AND DISCUSSION
Electrochemical Behavior of TEMPO in RTILs. Figure 1 shows a cyclic voltammogram . Anodic and cathodic peaks due to oxidation of TEMPO and reduction of TEMPO + are labeled a and c, respectively. Anodic and cathodic peaks due to oxidation of dmFc to dmFc + , and reduction of dmFc + , are also visible. 25 The CV is representative of those of TEMPO dissolved in each RTIL (Figures S2-S13 in the supporting information). In all cases, the ratio of the anodic to cathodic peak current, ip,a/ip,c, for TEMPO/TEMPO + oxidation/reduction is close to unity, and ip,a and ip,c are proportional to the square root of the voltammetric scan rate, ν 1/2 , as expected for freely-diffusing, electrochemically-reversible, redox couples. Such electrochemical reversibility has also been observed previously during voltammetry of TEMPO in organic 21,22,26 , aqueous 27,28 , and RTIL electrolytes. 21,22 The separation between the anodic and cathodic peak potentials, ∆Ep, for TEMPO oxidation/reduction in each RTIL is 60-70 mV, which is slightly higher than expected for an electrochemically-reversible system involving the transfer of a single electron (59 mV). Given that ohmic-drop compensation was performed using positive-feedback correction during all voltammetric measurements, the high ∆Ep is attributed to sluggish electron-transfer kinetics across the electrode/RTIL interface, as observed previously when performing cyclic voltammetry using RTIL electrolytes. 29 The most notable observation from the cyclic voltammetry of TEMPO is that the potential of the TEMPO/TEMPO + redox couple varies as the composition of the RTIL changes. The TEMPO/TEMPO + mid-point potential varies from 677 mV to 788 mV vs. dmFc/dmFc + as the 9 composition of the RTIL changes ( Figure 2). This shift can be explained by considering the   Figure 3 shows

TEMPO-mediated Alcohol Oxidation in RTILs.
The relationship between icat and CA was then explored and Figure 5 shows     The increase in rates of mass transfer is evident by comparing the Fc/Fc + waves in the voltammograms. The relative increase in icat as the concentration of 2,6-lutidine increases is drastically higher than that of the Fc/Fc + peaks, demonstrating that the increase in the catalytic rate is due to a combination of the increased mass transfer in the solution and a higher k. We also performed our voltammetric analysis in reaction mixtures containing 2,4,6-collidine (pKaH = 7.43) and pyridine (pKaH =5.25), instead of 2,6-lutidine (pKaH = 6.75) as the base, and Figure 7B shows that icat increases as the pKaH of the base increases. These effects have been observed previously when using organic 21,22 aqueous 28 and RTIL media. 21,34 The increase in icat with increasing concentration and increasing pKaH of the base is because both the alcohol and hydroxylammonium species are deprotonated more rapidly, giving the reactive alcoholate anion, which is oxidized by TEMPO + . 21 The selectivity of the process was determined by performing TEMPO-mediated  green triangles, and red diamonds, respectively). k is generally lower than in neat RTILs when the concentration is >0.05 mol dm -3 and, interestingly, is similar to that in neat RTILs when the concentration is 0.05 mol dm -3 , potentially suggesting that the environments within the dilute electrolyte and neat RTILs are similar. A lot of recent work has addressed the nature of the ionic environment within RTILs. For example, recent surface-force measurements have indicated that RTILs behave as dilute electrolytes, 35 containing long-lived ion pairs and relatively low numbers of free ions. However, there is some disagreement on the true "ionicity" of RTILs, [36][37][38][39][40] and recent computational modelling led to the conclusion that RTILs behave not as dilute electrolytes, but as concentrated electrolytes. 41 While a lot more work on this topic is needed, the data described 20 here suggest that electrochemical analyses such as that described here could potentially provide some new insights into the nature of RTILs.

Flow Electrolysis. Preparative-scale, constant-current electrolysis was conducted in order
to determine the efficiency and selectivity of the catalytic TEMPO-mediated alcohol oxidations in RTILs. Products emanating from the flow cell were recovered from the RTIL medium by extraction into toluene and were analyzed using GC analysis.   44 if any imidazole radical is formed it will react with TEMPO, which can explain the loss of TEMPO.
However, at lower current densities and higher flow rates, the solution did not change color and better faradaic selectivities were obtained.
To investigate how the efficiency of the TEMPO-mediated alcohol oxidations in RTILs compares to alcohol oxidations in acetonitrile, flow electrolysis of benzyl alcohol oxidation was conducted in acetonitrile containing 1 mol dm -3 [C8C1Im][NTf2] (see Table 3)  To investigate the reaction selectivities in RTILs, electrolysis of a mixture of a primary alcohol and a secondary alcohol was conducted. Table 4 shows flow electrolysis data for the oxidation of a mixture of benzyl alcohol (primary) and 1-phenylethanol (secondary) in   secondary alcohols are oxidized efficiently with excellent yields using the same conditions as for oxidation of the primary alcohol analogue. For example, the electrolysis of primary alcohol 4methoxybenzyl alcohol yielded 4-methoxybenzaldehyde at 88% yield and electrolysis of the secondary alcohol 1-(4-methoxyphenyl)ethanol yielded 92% of 1-(4-methoxyphenyl)ethanone, under the same conditions. 28 Stahl and coworkers showed that the TEMPO modified 4-acetamido-TEMPO, electrooxidation of benzyl alcohol and 1-phenylethanol yielded 88% of benzaldehyde and 88% acetophenone respectively (in two separate experiments) using identical conditions and 25 electrolysis time. 27 These results demonstrate good reaction efficiency of oxidation secondary alcohols, however it also demonstrates poor alcohol selectivity of TEMPO.

Conclusion
The salts. It is also significant that the global rate constant for the oxidation rate constant for the oxidation reaction is larger in RTILs with low H-bond basicity anions than that observed in acetonitrile.