Aiichiro Nagaki

Modern Strategies in Electroorganic Synthesis

4.2. Solid-Supported Electrolytes 2280 4.3. Solid-Supported Mediators 2282 4.4. Supported Substrate-Product Capture 2283 4.5. A Unique Electrolyte/Solvent System 2285 5. Reaction Conditions 2285 5.1. Supercritical Fluids 2285 5.1.1. Electrochemical Properties of scCO2 2285 5.1.2. Electroreductive Carboxylation in scCO2 2286 5.1.3. Electrochemical Polymerization in scCO2 2286 5.2. The Cation-Pool Method 2286 5.2.1. Generation of N-Acyliminium Ion Pools 2286 5.2.2. Generation of Alkoxycarbenium Ion Pools 2287 5.2.3. Generation of Diarylcarbenium Ion Pools 2288 5.2.4. Generation of Other Cation Pools 2289 6. Electrochemical Devices 2289 6.1. Electrode Materials 2289 6.2. Ultrasound and Centrifugal Fields 2290 6.3. Electrochemical Microflow Systems 2290 7. Combinatorial Electrochemical Synthesis 2292 7.1. Parallel Electrolysis Using a Macrosystem 2292 7.2. Parallel Electrolysis Using a Microsystem 2293 7.3. Serial Electrolysis Using a Microsystem 2294 8. Conclusions 2294 9. Acknowledgments 2294 10. References 2294

Flash Chemistry: Fast Chemical Synthesis by Using Microreactors

This concept article provides a brief outline of the concept of flash chemistry for carrying out extremely fast reactions in organic synthesis by using microreactors. Generation of highly reactive species is one of the key elements of flash chemistry. Another important element of flash chemistry is the control of extremely fast reactions to obtain the desired products selectively. Fast reactions are usually highly exothermic, and heat removal is an important factor in controlling such reactions. Heat transfer occurs very rapidly in microreactors by virtue of a large surface area per unit volume, making precise temperature control possible. Fast reactions often involve highly unstable intermediates, which decompose very quickly, making reaction control difficult. The residence time can be greatly reduced in microreactors, and this feature is quite effective in controlling such reactions. For extremely fast reactions, kinetics often cannot be used because of the lack of homogeneity of the reaction environment when they are conducted in conventional reactors such as flasks. Fast mixing using micromixers solves such problems. The concept of flash chemistry has been successfully applied to various organic reactions including a) highly exothermic reactions that are difficult to control in conventional reactors, b) reactions in which a reactive intermediate easily decomposes in conventional reactors, c) reactions in which undesired byproducts are produced in the subsequent reactions in conventional reactors, and d) reactions whose products easily decompose in conventional reactors. The concept of flash chemistry can be also applied to polymer synthesis. Cationic polymerization can be conducted with an excellent level of molecular-weight control and molecular-weight distribution control.

Green and sustainable chemical synthesis using flow microreactors.

Several features that allow flow microreactors contribute to green and sustainable chemical synthesis are presented: (1) For extremely fast reactions, kinetics often cannot be used because of the lack of homogeneity of the reaction environment when they are conducted in batch macroreactors. Better controllability, by virtue of fast mixing based on short diffusion paths in microreactors, however, leads to a higher selectivity of the products, based on kinetics considerations. Therefore, less waste is produced. (2) Reactions involving highly unstable intermediates usually require very low temperatures when they are conducted in macrobatch reactors. By virtue of short residence times, flow microreactors enable performing such reactions at ambient temperatures, avoiding cryogenic conditions and minimizing the energy required for cooling. (3) By virtue of the precise residence time control, flow microreactors allow to avoid the use of auxiliary substances such as protecting groups, enabling highly atom- and step-economical straightforward syntheses. The development of several test plants based on microreaction technology has proved that flow microreactor synthesis can be applied to the green and sustainable production of chemical substances on industrial scales. (4) Microreactor technology enables on-demand and on-site synthesis, which leads to less energy for transportation and easy recycling of substances.

A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds

Protecting-group-free synthesis has received significant recent research interest in the context of ideal synthesis and green sustainable chemistry. In general, organolithium species react with ketones very rapidly, and therefore ketone carbonyl groups should be protected before an organolithium reaction, if they are not involved in the desired transformation. If organolithium chemistry could be free from such a limitation, its power would be greatly enhanced. Here we show that a flow microreactor enables such protecting-group-free organolithium reactions by greatly reducing the residence time (0.003 s or less). Aryllithium species bearing ketone carbonyl groups are generated by iodine-lithium exchange reactions of the corresponding aryl iodides with mesityllithium and are reacted with various electrophiles using a flow-microreactor system. The present method has been successfully applied to the formal synthesis of Pauciflorol F.

Cross-coupling in a flow microreactor: space integration of lithiation and Murahashi coupling.

Cross-coupling reactions of aryl metals with organic halides serve as a powerful method for carbon–carbon bond formation in the synthesis of a variety of functional materials and biologically active compounds. Aryl–boron, aryl–silane, aryl–tin, aryl–zinc, and aryl–magnesium compounds are often used for these cross-coupling reactions because these organometallic compounds are relatively stable. In contrast, the use of less stable but more reactive aryllithium compounds in cross-coupling has been rather limited, 3] although many aryl metals including arylboron compounds are often prepared from aryllithium compounds. In 1979 Murahashi et al. reported pioneering work on the palladium-catalyzed cross-coupling of organolithium compounds with organic halides. Since then, to the best of our knowledge, additional studies have not been reported, one of the major reasons being that X–Li exchange of ArX with BuLi, which is one of the most powerful methods for generating ArLi, leads to the formation of BuX. However, ArLi reacts with BuX if the subsequent coupling is slow. This is indeed the case. Usually, cross-coupling reactions take hours to reach completion at room temperature or higher temperatures, whereas reactions of ArLi with alkyl halides such as BuX are complete within minutes at 0 8C. If this problem is solved, the combination of X–Li exchange and Murahashi coupling will then enable the cross-coupling of two aryl halides, hence providing a powerful method in organic synthesis [Eq. (1)]. 6] Though tBuLi does not suffer from this problem, the use of two equivalents of highly reactive tBuLi is not suitable for large-scale laboratory synthesis and industrial production.

Asymmetric Carbolithiation of Conjugated Enynes: A Flow Microreactor Enables the Use of Configurationally Unstable Intermediates before They Epimerize

We found that a flow microreactor system enables the generation of a configurationally unstable chiral organolithium intermediate and allows for its use in a reaction with an electrophile before it epimerizes. Based on this method, the enantioselective carbolithiation of conjugated enynes followed by the reaction with electrophiles was accomplished to obtain enantioenriched chiral allenes.

Oxiranyl Anion Methodology Using Microflow Systems

Deprotonation of epoxides followed by trapping with electrophiles was carried out using microflow systems with varying temperature and residence time. Time-dependence of the yields of products provides a deeper insight into chemical and configurational stabilities of oxiranyllithiums. With the thus-obtained information, reactions of oxiranyllithiums with various electrophiles were successfully carried out without decomposition and isomerization.

Three-Component Coupling Based on Flash Chemistry. Carbolithiation of Benzyne with Functionalized Aryllithiums Followed by Reactions with Electrophiles

A flow microreactor method for three-component coupling of benzyne was developed based on flash chemistry. o-Bromophenyllithium generated from 1-bromo-2-iodobenzene and a functionalized aryllithium generated from the corresponding aryl halide were mixed at -70 °C. In the subsequent reactor o-bromophenyllithium is decomposed to generate benzyne without affecting the functionalized aryllithium at -30 °C, and carbolithiation of benzyne with the aryllithium took place spontaneously. The resulting functionalized biaryllithium was reacted with an electrophile in the subsequent reactor to give the corresponding three-component coupling product. The precise optimization of reaction conditions using the temperature-residence time mapping is responsible for the success of the present transformation. The present method has been successfully applied to the synthesis of boscalid.

A Flow Microreactor System Enables Organolithium Reactions without Protecting Alkoxycarbonyl Groups

A flow microreactor system consisting of micromixers and microtube reactors provides an effective tool for the generation and reactions of aryllithiums bearing an alkoxycarbonyl group at para-, meta-, and ortho-positions. Alkyl p- and m-lithiobenzoates were generated by the I/Li exchange reaction with PhLi. The Br/Li exchange reactions with sBuLi were unsuccessful. Subsequent reactions of the resulting aryllithiums with electrophiles gave the desired products in good yields. On the other hand, alkyl o-lithiobenzoates were successfully generated by the Br/Li exchange reaction with sBuLi. Subsequent reactions with electrophiles gave the desired products in good yields.

Extremely fast gas/liquid reactions in flow microreactors: carboxylation of short-lived organolithiums.

Carboxylation of short-lived organolithiums bearing electrophilic functional groups such as nitro, cyano, and alkoxycarbonyl groups with CO2 to give carboxylic acids and active esters was accomplished in a flow microreactor system. The successful reactions indicate that gas/liquid mass transfer and the subsequent chemical reaction with CO2 are extremely fast.