In organic synthesis, batch-type reactors—represented by the familiar glass flask—have been used for over a century. In batch reactors, not only must we consider the microscopic transformations of molecules, but we also need to control the macroscopic aspects of the entire reaction system. This macroscopic control is often complex and challenging. While an enormous number of chemical reactions have been developed over the past 100 years, the reactors used to perform them have remained largely unchanged. As a result, the full potential of many chemical reactions may not be realized within these traditional systems. Therefore, alongside the development of new reactions, research into new types of reaction environments is becoming increasingly necessary.

We focus on flow microreactors as an alternative to conventional batch-type reactors and develop novel molecular transformation methods using this technology. A flow microreactor is a flow-type reaction device containing micro-scale channels, through which reagent solutions are continuously pumped to induce reactions. This system offers three major advantages:

1. Ultrafast Mixing

The time required for molecular diffusion is proportional to the square of the diffusion distance. While the stirring radius of a magnetic stirrer in a flask is typically on the order of centimeters, the channel diameter in a microreactor is in the micrometer range. This dramatically reduces the diffusion distance and thus enables mixing at much faster rates.

2. Precise Reaction Time Control

In flow synthesis, the residence time—the duration a reagent remains in the reaction channel—can be precisely controlled by adjusting the flow rate and the volume of the channel. Microreactors, with their extremely small internal volumes, allow experiments to be conducted on the millisecond timescale—something unachievable with manual operations in batch systems.

3. Precise Temperature Control

Volume increases with the cube of the characteristic length, while surface area increases with the square. As a result, microreactors exhibit much higher surface-to-volume ratios compared to conventional reactors. Since heat transfer in chemical reactions occurs through the reactor’s surface, this large surface-area-to-volume ratio enables highly precise temperature control, including rapid heating and cooling.

By leveraging these unique features of flow microreactors, we aim to develop new molecular transformation methodologies that fully harness the intrinsic power of chemical reactions, and to apply these methods to the creation of novel functional materials.

By leveraging the ultrafast mixing capabilities of flow microreactors, we are conducting research on highly selective reactions that are difficult or even impossible to achieve using conventional flask-based (batch) chemistry when dealing with fast, competitive, and sequential processes. In typical batch reactors, fast reactions often suffer from incomplete mixing, leading to a phenomenon known as disguised chemical selectivity, where kinetic selectivity cannot manifest as intended. Our work has demonstrated that ultrafast mixing in flow systems can overcome this limitation, enabling reactions to proceed under true kinetic control—even for extremely rapid processes—thereby achieving high selectivity useful in synthetic organic chemistry.

Recent Highlights

Selective Reaction of Acid Chlorides with Organometallic Reagents
In reactions between acid chlorides and organometallic reagents, conventional batch reactors tend to yield mixtures of ketones (mono-addition products) and alcohols (di-addition products). However, employing ultrafast mixing in a flow microreactor allows for highly selective formation of ketones (Chem. Eur. J. 2019, 25, 4946). This transformation enables direct access to ketones from acid chlorides without converting them into Weinreb amides, offering an efficient strategy from the viewpoint of step economy and atom economy.

Precision Control of Anionic and Cationic Polymerizations
Ultrafast mixing between initiators and monomers enables kinetically controlled initiation of ionic polymerizations, including both cationic and anionic types. We were the first in the world to achieve living polymerization under such rapid conditions without using capping agents. This allows for the synthesis of polymers with narrow molecular weight distributions, precise terminal functionality, block copolymers, and telechelic polymers—achievements that are extremely difficult to realize via conventional batch processes (Chem. Eur. J. 2019, 25, 13719).

Control of Fast Chemoselective Reactions
Expanding the application to fast intramolecular and intermolecular competitive reactions, ultrafast micro-mixing proves effective in achieving selective transformation of a single functional group among multiple similar groups within a molecule. For instance, when reacting terephthalaldehyde (bearing two aldehyde moieties) with phenyllithium in a batch reactor, a 1:1 molar ratio leads to approximately equal amounts of mono- and di-addition products. In contrast, using a flow microreactor results in highly selective formation of the mono-addition product (Chem. Lett. 2018, 47, 71).

Highly reactive species enable ultrafast reactions due to their strong reactivity, but their inherent instability often limits their practical use. In conventional batch chemistry, the short lifetime of such intermediates means they often decompose before participating in the desired reaction, presenting a major obstacle to the development of new molecular transformations.

Our group addresses this challenge through a unique methodology we call “spatial control of time in synthetic chemistry.” This concept utilizes flow microreactors to generate unstable intermediates quickly and transport them to a different spatial zone for immediate reaction with subsequent reagents—before they have a chance to decompose.

Recent Highlights

Generation and Utilization of o-Bromophenyllithium
o-Bromophenyllithium is an extremely reactive species that typically requires ultralow temperatures (−110 °C) to be handled safely in batch reactors. Using our approach based on spatial control of time, we demonstrated that this intermediate can be generated within a flow microreactor and made to react with a second reagent just one second later. As a result, even at −70 °C, the species can be successfully utilized before it decomposes (J. Am. Chem. Soc. 2007, 129, 3046; Angew. Chem. Int. Ed. 2010, 49, 7543).

In addition to this, we have developed methods for:

• Utilizing chemically unstable intermediates in downstream reactions (Angew. Chem. Int. Ed. 2020, 59, 10924),
• Switching between competing reaction pathways (Chem. Eur. J. 2021, 27, 16107),
• Controlling stereochemically labile intermediates in isomerization reactions (J. Am. Chem. Soc. 2011, 133, 3744; J. Am. Chem. Soc. 2009, 131, 1654).

These studies showcase our new methodology for controlling highly reactive and unstable intermediates that are difficult or impossible to handle in conventional flask-based chemistry, opening up new avenues for the development of ultrafast and highly selective reactions.

The use of heterogeneous catalysis in flow chemistry has gained significant attention due to its potential for enhanced process efficiency, particularly through catalyst reusability and simplified product separation. However, when conventional heterogeneous catalysts are simply packed into flow reactors, considerable pressure drop often occurs, necessitating operation under low flow rates. Moreover, in reactions requiring extended residence times, the method of catalyst immobilization can significantly affect catalytic activity, often resulting in longer reaction durations.

To address these challenges, we have focused our research on the question of how catalysts should be immobilized and on what kind of support, aiming to optimize both catalytic efficiency and flow performance.

Recent Highlights

Monolith-Supported Catalytic Reactors
We have utilized porous monolithic materials with interconnected micron-scale skeleton structures as catalyst supports. These monoliths, characterized by their high void fraction and large specific surface area, allow for significantly reduced pressure drop and support high flow rates in catalytic flow reactions (Catal. Today 2022, 388–389, 231).

Supercritical CO₂-Assisted Catalyst Immobilization
In another approach, we employed supercritical carbon dioxide as a deposition solvent to immobilize catalysts onto monolithic supports. This method enabled the formation of highly active catalytic environments with minimal pressure loss. Using these reactors, we successfully achieved a range of coupling reactions and hydrogenation reactions under continuous-flow conditions (Catal. Sci. Technol. 2020, 10, 6359; Green Process. Synth. 2021, 10, 722).

In recent years, electron-transfer reactions such as electrolysis have garnered increasing attention in the context of global environmental concerns. By replacing traditional chemical reagents—which often generate hazardous waste—with electricity, electrochemical methods offer a powerful strategy for significantly reducing environmental impact. Furthermore, in the field of reactive intermediate chemistry, electrochemical techniques enable the irreversible and high-concentration generation of highly reactive species, which is particularly advantageous.

However, organic electrochemical reactions typically proceed at the surface of electrodes and are inherently heterogeneous. In conventional batch-type electrolysis setups, the size of the electrode is limited relative to the reactor volume, often requiring reaction times of several hours. This poses a significant challenge for the utilization of unstable reactive intermediates, which may decompose during the electrolysis process.

To address this issue, we have developed a novel flow electrolysis device that enables rapid and controlled generation of reactive intermediates.

Recent Highlights

Development of a Flow Electrolysis Reactor for Sub-Second Electrochemical Reactions
Through precise engineering of the internal structure of the flow electrolysis cell, we have developed a device capable of completing electrochemical reactions within seconds. Using this system, electrolysis can be completed in as little as 4 seconds. The unstable intermediates generated are immediately transferred to a subsequent reaction zone before decomposition occurs, enabling high-speed follow-up transformations that were previously unattainable using conventional batch setups. This strategy allows for the effective utilization of unstable carbocation intermediates in organic synthesis. Using our rapid-flow electrolysis platform, we have successfully demonstrated the 20-second synthesis of a key intermediate for an ADHD treatment drug (Angew. Chem. Int. Ed. 2022, 61, e202116177).

When synthesizing complex organic molecules such as pharmaceuticals, multiple functional groups often coexist within a single molecule. Selectively reacting only one functional group among several is generally challenging. As a result, traditional organic synthesis has relied heavily on protecting groups—functional groups that are temporarily added to mask certain reactive sites. Typically, a protecting group is introduced, followed by the desired transformation, and finally removed through a deprotection step. Although this strategy has enabled the synthesis of many complex compounds, it increases the number of reaction steps, reduces overall efficiency, and generates additional waste.

To address these challenges, we are pursuing a new approach to streamline synthetic routes by utilizing our concept of “syntheses that control time through space.” This methodology employs flow microreactors to precisely manage the residence time of reactive intermediates, enabling protecting-group-free synthesis and reducing the total number of steps in synthetic sequences.

Recent Highlights

Protecting-Group-Free Synthesis of Ketones
Ketone carbonyl groups, which are common in organic compounds, readily react with many nucleophiles such as organometallic reagents. Therefore, in conventional flask-based chemistry, ketones are often protected as acetals prior to subsequent reactions. In contrast, we have successfully developed a protecting-group-free synthesis method by exploiting spatial control in microreactors. By setting the residence time in a flow system to as short as 3 milliseconds, highly reactive organolithium intermediates bearing ketone moieties can be generated and reacted with electrophiles before decomposition occurs. This innovative methodology has been applied in the total synthesis of complex natural polyphenols such as Macbecin I and Pauciflorol F, demonstrating its utility in the rapid synthesis of complex molecules (Nat. Commun., 2011, 2, 264).

Generation and Reactions of Organolithium Intermediates Bearing Internal Functional Groups
Using the concept of “spatial control of reaction time,” we have achieved the generation and subsequent reactions of organolithium species bearing electrophilic functional groups. By finely tuning the residence time to as short as 10 milliseconds, we have enabled the rapid generation of organolithium intermediates containing alkoxycarbonyl, cyano, and nitro groups, and allowed their immediate reactions with electrophiles before decomposition (Angew. Chem., Int. Ed., 2008, 47, 7833; Angew. Chem., Int. Ed., 2009, 48, 8063; Org. Biomol. Chem., 2010, 8, 1212). Furthermore, we have reported the successful generation and reactions of highly unstable intermediates—such as benzyllithium species with formyl groups and alkyllithium species with epoxide, cyano, or alkoxycarbonyl groups—using flow residence times as short as 1 millisecond (Angew. Chem., Int. Ed. 2019, 58, 4027; Org. Biomol. Chem. 2015, 13, 7140).

Domino and one-pot reactions—where multiple reactions are carried out either concertedly or sequentially within a single flask—have long been studied as efficient synthetic strategies. However, most such strategies are centered around transformations involving stable “substances.” In contrast, we have proposed a novel concept of spatial reaction integration that leverages highly reactive intermediates rather than stable substances. By combining multiple rapid reactions in a spatially and temporally controlled manner using flow microreactors, complex synthetic sequences can be executed within an exceptionally short time.

Furthermore, we classify this integration into two distinct modes: linear integration, in which a single starting material is transformed through sequential steps to the desired product, and convergent integration, in which multiple key intermediates are generated independently and then merged at a defined stage to furnish the final compound. These strategies enable streamlined syntheses that are difficult or impossible to achieve using traditional batch chemistry.

Recent Highlights

Linear Integration for the Synthesis of Retinoids
By linearly connecting multiple microreactors, we have established a seamless process involving the consecutive generation and reaction of three different organolithium intermediates, achieving the single-step synthesis of the novel retinoid TAC-101. Owing to the high reactivity of the intermediates, six reaction steps can be completed in just 13 seconds (RSC Adv. 2011, 1, 758).

Direct Integration for the Synthesis of Bimetallic Arenes
Through sequential halogen-lithium exchange reactions of polybromoarenes, we have developed a strategy for synthesizing bimetallic arene compounds—structures bearing two different metal substituents—which were previously inaccessible by conventional methods. The entire process, completed within 30 seconds, paves the way for new types of metal-selective cross-coupling reactions (J. Am. Chem. Soc. 2020, 142, 17039).

Convergent Integration of Benzyne and Organolithium Coupling
Our flow-based strategy enables the simultaneous generation of multiple short-lived reactive intermediates in separate zones under different thermal and temporal conditions. For instance, by generating 2-bromophenyllithium and another aryllithium species independently, and combining them in a convergent fashion, we achieved the carbolithiation of benzyne with aryllithium to form biphenyl-type lithium intermediates. The subsequent in-flow reaction with an electrophile yielded the precursor to the agrochemical boscalid in just 3.8 seconds. This transition-metal-free three-component coupling process exemplifies how convergent spatial integration in flow systems can unlock new synthetic pathways beyond the scope of conventional batch chemistry (J. Am. Chem. Soc. 2014, 136, 12245).

In the field of synthetic chemistry, experimental conditions are often determined based on the intuition and experience of the chemist. To address this empirical approach, we are developing strategies that employ machine learning to accelerate the exploration and optimization of reaction conditions.

Recent Highlights

Rapid Optimization of Flow Electrochemical Reactions
In a hydrogenation reaction using a PEM (Proton-Exchange Membrane) flow electrochemical reactor, it is necessary to optimize multiple parameters, such as reaction temperature, residence time, and substrate concentration. By applying Bayesian optimization to this system, we successfully identified the optimal conditions by conducting only four reaction experiments—dramatically reducing the number of trials required (Front. Chem. Eng. 2022, 3, 819752).