Organic chemistry research comprises three fundamental elements, including synthesis, separation, and analysis. The long and untiring efforts of synthetic chemists have established countless useful reactions to enable the preparation of nearly anything. Beneficial and complex structures can be elaborated from abundant and simple starting materials. For example, several elegant synthetic strategies for Oseltamivir (commonly known as “Tamiflu“), an effective antiviral drug for the flu virus, have been proposed (Fig. 1) [1-6]. With concerns about the environmental aspects of these syntheses, various green processes, e.g., transition-metal-free transformations or the use of water as a reaction solvent, have been studied intensively. In addition, outstanding technological advances have been achieved in the field of analysis, realizing numerous powerful methods. Spectroscopy in particular can yield much information about the structure of both naturally-occurring and artificial compounds.
In these contexts, separation has assumed a key role in organic chemistry. It is generally meaningless if the desired compound cannot be isolated from the reaction mixture even though it was prepared and characterized in a precise manner. Typically, recrystallization and silica gel column chromatography are employed as isolation methodologies in industrial and academic fields. While these separation techniques offer high-performance compound isolation, time-consuming preliminary experiments and the use of large amounts of silica gel are required. Solid-phase techniques are one solution to provide great advantages with respect to compound separation and have also proven to be effective for automated synthesis and combinatorial chemistry. Reaction substrates are generally bound to a solid-phase, enabling their separation from the reaction mixture merely through filtration and washing with solvents. Based on this strategy, efficient multistep chemical transformations, especially for peptide synthesis, can be accomplished. Additionally, the immobilization of reaction catalysts on a solid-phase is efficient for their consecutive recycling, and can also serve as a promising application in combination with a flow strategy.
In addition to the solid-phase technique, the liquid-biphasic technique can also provide a facile separation of compounds by simple liquid-liquid extraction. A representative liquid-biphasic technique is based on the insolubility of perfluorinated hydrocarbons with both polar and less-polar organic solvents, known as fluorous systems [7-11]. In these systems, fluorous compounds, including substrates, products, and catalysts, or designed fluorous platforms, are preferentially dissolved into the fluorous phase to enable their rapid separation. Moreover, “thermomorphic” systems have been developed to offer unique liquid-biphasic separation techniques that change thermally from biphasic conditions to monophasic conditions [12-19].
In organic electrochemistry, electrodes have been utilized as solid-phase redox reagents to trigger either one- or two-electron transfers that afford various functional group transformations and a wide variety of carbon-carbon bond formations in a controlled manner [20-25]. In particular, there is good chemistry between electrochemical approaches and cyclic compounds to produce complex ring systems in one step. For example, five-, six-, and seven-membered rings can be constructed through ring rearrangement or intramolecular cycloaddition (Fig. 2) [26-28]. We have also been developing a series of electrochemical intermolecular cycloadditions initiated by anodic oxidation to give four-, five, and six-membered rings (Fig. 3) [29-31].
Although electrodes can be rapidly removed from the reaction mixtures after the completion of electrochemical transformations, the separation of products from supporting electrolytes that are necessary for imparting electrical conductivity to polar organic solvents is still required. In order to address this problem, various ingeniously designed electrochemical reaction systems have been developed [32-36]. In this chapter, we describe cyclohexane-based liquid-biphasic systems as unique separation techniques that are well-combined with organic electrochemistry. The combination of electrodes as solid-phase redox reagents and cyclohexane-based liquid-biphasic systems has paved the way for organic electrochemistry.
2. Cyclohexane-based liquid-biphasic systems
Cyclohexane-based liquid-biphasic systems have their roots in the initial discovery that cyclohexane has unique thermomorphic properties . Numerous investigations aimed at constructing new liquid-biphasic systems have led to the finding that cyclohexane can be used to successfully form thermomorphic biphasic solutions with typical polar organic solvents and that the regulation of their separation and mixing can be achieved by moderate control in a practical temperature range. A 1:4 (v/v) mixture of cyclohexane and nitromethane, for example, exhibits biphasic conditions at 25 °C, then forms a monophasic condition at
Moreover, several other polar organic solvents can be introduced into the cyclohexane-based liquid-biphasic system and their phase switching temperatures are tunable based on the choice of polar organic solvents and their ratio to cyclohexane. For instance, a 1:3 (v/v) mixture of cyclohexane and acetonitrile is heated to form a monophasic condition at
3. Kolbe-coupling assisted by cyclohexane-based liquid-biphasic systems
In order to apply cyclohexane-based liquid-biphasic techniques to organic electrochemistry, we initially investigated a wide variety of compositions of electrolyte solutions composed of polar organic solvents and supporting electrolytes that showed practical thermomorphic properties in combination with cyclohexane. Through numerous trials, we found that a 1:1:2:4 (v/v/v/v) mixture of pyridine, methanol, acetonitrile, and cyclohexane could be thermally mixed to form a monophasic condition even in the presence of saturated potassium hydroxide as a supporting electrolyte. Heating to
With these results in hand, Kolbe-coupling, known as a representative electrochemical reaction in organic chemistry, was then carried out in the cyclohexane-based liquid-biphasic system (Fig. 6). Essentially, electrochemical approaches have the requirement that both substrates and products should be soluble in polar electrolyte solutions. This is due to the following reasons. First, electron transfer events take place only at the surface of the electrodes such that insoluble compounds are unable to access their neighborhood, which means that the use of hydrophobic compounds is generally restricted. Second, the formation of insoluble hydrophobic products during the electrochemical transformations might result in electrode passivation in which the surface of the electrodes is covered with polymeric films that severely suppress electric current. In this regard, the thermally-mixed monophasic conditions in the cyclohexane-based liquid-biphasic system can be deemed as a “less-polar” electrolyte solution because it contains an equal volume of less-polar cyclohexane as the polar electrolyte solution.
To test this idea, octanoic acid (
Several carboxylic acids (
4. Five-membered ring formation assisted by cyclohexane-based liquid-biphasic systems
Undesired overoxidation also becomes problematic in organic electrochemistry. While this is not a concern for the Kolbe-coupling because the oxidation potential of the product is generally lower than that of the substrate, it might severely decrease the reaction yield in some instances. For example, a creative solution to the electrochemical five-membered ring formation between 4-methoxyphenol (
On the basis of this concept, the electrochemical five-membered ring formation between 4-methoxyphenol (
5. Four-membered ring formation assisted by cyclohexane-based liquid-biphasic systems
From the environmental viewpoint, the separation process of products and supporting electrolytes is not the only problem in organic electrochemistry. The use of a large amount of supporting electrolytes, which are essential to impart electrical conductivity to polar organic solvents, also causes disposal issues. As described above, although various ingeniously designed electrochemical reaction systems have been reported so far that avoid the use of supporting electrolytes, there are also many electrochemical reactions that are dependent on the presence of a high concentration of supporting electrolytes. We have been developing several electrochemical four-membered ring formations between enol ethers and olefins in nitromethane using high concentrations of lithium perchlorate [45-51]. Because a high concentration of lithium perchlorate in nitromethane can effectively stabilize carbocations and enhance nucleophilicity of olefins, these reactions only take place under such conditions. Therefore, not only organic electrochemistry without supporting electrolytes but also the possibility of their reuse should be considered. For this purpose, cyclohexane-based liquid-biphasic systems are powerful. The less-polar cyclohexane phase does not have dissolving power for supporting electrolytes, thus, they can be confined in the polar electrolyte solution phase, which can be reused for the next reaction (Fig. 13).
Based on this concept, the electrochemical four-membered ring formation between 1-(prop-1-en-1-yloxy)-4-propylbenzene (
6. Continuous flow electrochemical synthesis assisted by cyclohexane-based liquid-biphasic systems
Cyclohexane-based liquid biphasic systems have been well combined with three types of organic electrochemistry, including Kolbe-couplings, five-, and four-membered ring formations, to realize rapid separation of the resulting products. In all cases, the products were selectively dissolved in the cyclohexane phase and could be isolated by simple liquid-liquid extraction to give the desired compounds in almost pure fashion without additional separation steps. Moreover, cyclohexane-based liquid-biphasic systems also offer many valuable functions as follows. In Kolbe-couplings, the biphasic condition was thermally mixed to a monophasic condition to form a less-polar electrolyte solution, which avoided electrode passivation effectively to improve the reaction efficiency. In electrochemical five-membered ring formations, the cyclohexane phase selectively dissolved the products to protect them from undesired overoxidation. High reusability of the supporting electrolyte was also demonstrated and improvement of productivity was achieved in electrochemical four-membered ring formations. Here we have set an ultimate aim to accomplish flow electrochemical synthesis assisted by cyclohexane-based liquid-biphasic systems.
For the construction of a flow electrochemical synthetic device, the composition of several cyclohexane-based liquid-biphasic systems was studied in detail (Fig. 16). Three electrolyte solutions were prepared using 1.0 M lithium perchlorate as a supporting electrolyte in methanol, acetonitrile, or nitromethane. The same volume of cyclohexane was then added to investigate the compositions of both upper and lower phases.
Remarkably, although cyclohexane and these polar solvents were partially miscible even at ambient temperature, only a trace amount of lithium perchlorate was recovered from the cyclohexane phase. This meant that the supporting electrolyte could be confined in polar solvents. As described, electrodes function as solid-phase redox reagents; therefore, they should be well combined with a flow strategy (Fig. 17) . Substrates in cyclohexane are injected into an electrochemical reactor, which is equipped with electrodes and a filter that is selectively permeable to cyclohexane. In this system, the outlet ejected from the reactor might be almost pure product in cyclohexane.
Based on these preliminary experiments, we designed and prepared a new flow electrochemical synthetic device (Fig. 18). The device was built with three compartments, which are mainly made of polytetrafluoroethylene, and could contain 5.0 mL of electrolyte solution. The third compartment was filled with polytetrafluoroethylene fiber that is known to be permeable for less-polar cyclohexane rather than polar electrolyte solutions. Substrates could be pumped into the reactor as a cyclohexane solution from the inlet, which would then emerge from the outlet after the electrochemical reaction.
With this device in hand, initially, electrochemical methoxylation, another representative electrochemical reaction in organic chemistry, was attempted (Fig. 19). The methoxylation of hydrophobic furan (
Finally, electrochemical four-, five-, and six-membered ring formations were carried out in this flow system (Fig. 21). All reactions took place selectively in the reactor and it should be noted that only vacuum concentration of the outlet cyclohexane solution was required. The corresponding ring products could be obtained in almost pure fashion without any additional separation processes. It is perhaps fair to say that the desired products emerge automatically from the flow electrochemical synthetic device assisted by the cyclohexane-based liquid-biphasic system.
As described in this chapter, the discovery that cyclohexane had a unique thermomorphic nature has led to the development of cyclohexane-based liquid-biphasic systems, which can be well-combined with organic electrochemistry. Rapid and high-performance separations, which have been assuming a larger role in modern organic chemistry, were accomplished by this system. Cyclohexane-based liquid-biphasic systems offer not only effective separation but also several additional functions of value, including suppressing electrode passivation, protecting products from overoxidation, and enabling reuse of supporting electrolytes.
Desired compounds can be synthesized precisely, and then characterized carefully. Organic chemists have made significant advances in these techniques to realize the preparation of almost anything with detailed structural information. In this context, the development of effective separation methodologies should maximize their vitality. For this purpose, the cyclohexane-based biphasic-system is one of the most promising techniques, especially in organic electrochemistry.
This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology.
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