Microwave Irradiation in Micro‐ Meso‐Fluidic Systems; Hybrid Technology has Issued the Challenge

A combination of microwave irradiation and flow chemistry has been described as a promising smart and hyphenated technology that can fuse and synergize the benefits of the techniques. The cells and tissues of all living organisms promote a huge number of bioorganic reactions that occur as flow systems and not the batch‐type conditions typically used by chemists and biotechnologists. Microwave‐assisted chemical conversion carried out in continuous flow mode with micro‐ or meso‐channel reactors can offer significant processing advantages, including improved thermal exchange, energy efficiency, safety, mixing control, a wider range of reaction conditions, repeatability and scalability as well as dramatic reductions in side‐reactions and degradations. This review will discuss relevant examples of organic synthesis and nanoparticles production performed in continuous flow mode with integrated microwave irradiation in micro‐ or mesofluidic systems.     

Calcium Carbide: A Unique Reagent for Organic Synthesis and Nanotechnology

Acetylene, HC≡CH, is one of the primary building blocks in synthetic organic and industrial chemistry. Several highly valuable processes have been developed based on this simplest alkyne and the development of acetylene chemistry has had a paramount impact on chemical science over the last few decades. However, in spite of numerous useful possible reactions, the application of gaseous acetylene in everyday research practice is rather limited. Moreover, the practical implementation of high‐pressure acetylene chemistry can be very challenging, owing to the risk of explosion and the requirement for complex equipment; special safety precautions need to be taken to store and handle acetylene under high pressure, which limit its routine use in a standard laboratory setup. Amazingly, recent studies have revealed that calcium carbide, CaC₂, can be used as an easy‐to‐handle and efficient source of acetylene for in situ chemical transformations. Thus, calcium carbide is a stable and inexpensive acetylene precursor that is available on the ton scale and it can be handled with standard laboratory equipment. The application of calcium carbide in organic synthesis will bring a new dimension to the powerful acetylene chemistry.     

Reactions of Difunctional Electrophiles with Functionalized Aryllithium Compounds: Remarkable Chemoselectivity by Flash Chemistry

Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting‐group‐free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules.     

Flow Technology for the Genesis and Use of (Highly) Reactive Organometallic Reagents

In the field of organic synthesis, the advent of flow chemistry and flow microreactor technology represented a tremendous novelty in the way of thinking and performing chemical reactions, opening the doors to poorly explored or even impossible transformations using batch methods. In this Concept article, we would like to highlight the impact of flow chemistry for exploiting highly reactive organometallic reagents, and how, alongside the well-known advantages concerning safety, scalability, and productivity, flow chemistry makes possible processes that are impossible to control by using the traditional batch approach.     

Alkyne–Azide Cycloadditions with Copper Powder in a High‐Pressure Continuous‐Flow Reactor: High‐Temperature Conditions versus the Role of Additives

A safe and efficient flow‐chemistry‐based procedure is presented for 1,3‐dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder as a plausible Cu^I source. To maximize the reaction rates, high‐pressure/high‐temperature conditions are utilized; alternatively, the harsh reaction conditions can be moderated at room temperature by the joint application of basic and acidic additives. A comparison of the performance of these two approaches in a series of model reactions has resulted in the formation of useful 1,4‐disubstituted 1,2,3‐triazoles in excellent yields. The risks that are associated with the handling of azides are lowered, thanks to the benefits of flow processing, and gram‐scale production has been safely implemented. The synthetic capability of this continuous‐flow technique is demonstrated by the efficient syntheses of some highly functionalized derivatives of the antifungal cispentacin.     

High‐Throughput Synthetic Chemistry Enabled by Organic Solvent Disintegrating Tablet

Synthetic chemistry remains a time‐ and labor‐intensive process of inherent hazardous nature. Our organic solvent disintegrating tablet (O‐Tab) technology has shown potential to make industrial/synthetic chemistry more efficient. As is the case with pharmaceutical tablets, our reagent‐containing O‐Tabs are mechanically strong, but disintegrate rapidly when in contact with reaction media (organic solvents). For O‐Tabs containing sensitive chemicals, they can be further coated to insulate them from air and moisture.     

Computational Chemistry to the Rescue: Modern Toolboxes for the Assignment of Complex Molecules by GIAO NMR Calculations

The calculations of NMR properties of molecules using quantum chemical methods have deeply impacted several branches of organic chemistry. They are particularly important in structural or stereochemical assignments of organic compounds, with implications in total synthesis, stereoselective reactions, and natural products chemistry. In studying the evolution of the strategies developed to support (or reject) a structural proposal, it becomes clear that the most effective and accurate ones involve sophisticated procedures to correlate experimental and computational data. Owing to their relatively high mathematical complexity, such calculations (CP3, DP4, ANN‐PRA) are often carried out using additional computational resources provided by the authors (such as applets or Excel files). This Minireview will cover the state‐of‐the‐art of these toolboxes in the assignment of organic molecules, including mathematical definitions, updates, and discussion of relevant examples.     

Composite Polymer/Oxide Hollow Fiber Contactors: Versatile and Scalable Flow Reactors for Heterogeneous Catalytic Reactions in Organic Synthesis

Flexible composite polymer/oxide hollow fibers are used as flow reactors for heterogeneously catalyzed reactions in organic synthesis. The fiber synthesis allows for a variety of supported catalysts to be embedded in the walls of the fibers, thus leading to a diverse set of reactions that can be catalyzed in flow. Additionally, the fiber synthesis is scalable (e.g. several reactor beds containing many fibers in a module may be used) and thus they could potentially be used for the large‐scale production of organic compounds. Incorporating heterogeneous catalysts in the walls of the fibers presents an alternative to a traditional packed‐bed reactor and avoids large pressure drops, which is a crucial challenge when employing microreactors.     

Flow Photochemistry as a Tool in Organic Synthesis

Photochemical transformations of molecular building blocks have become an important and widely recognized research field in the past decade. Detailed and deep understanding of novel photochemical catalysts and reaction concepts with visible light as the energy source has enabled a broad application portfolio for synthetic organic chemistry. In parallel, continuous-flow chemistry and microreaction technology have become the basis for thinking and doing chemistry in a novel fashion with clear focus on improved process control for higher conversion and selectivity. As can be seen by the large number of scientific publications on flow photochemistry in the recent past, both research topics have found each other as exceptionally well-suited counterparts with high synergy by combining chemistry and technology. This review will give an overview on selected reaction classes, which represent important photochemical transformations in synthetic organic chemistry, and which benefit from mild and defined process conditions by the transfer from batch to continuous-flow mode.     

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

In the past few years, continuous‐flow reactors with channel dimensions in the micro‐ or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous‐flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.     

充满生机和科学机遇的磷化学研究所

简要地综述了第十五届国际磷化学会议的报告内容，介绍了目前磷化学的主要 研究领域，包括不对称合成、配合化学，生物碱化学，药物化学，农业化学等相关 领域的研究动态及新进展。     

Porous Polyelectrolytes: The Interplay of Charge and Pores for New Functionalities

The past decade has witnessed rapid advances in porous polyelectrolytes and there is tremendous interest in their synthesis as well as their applications in environmental, energy, biomedicine, and catalysis technologies. Research on porous polyelectrolytes is motivated by the flexible choice of functional organic groups and processing technologies as well as the synergy of the charge and pores spanning length scales from individual polyelectrolyte backbones to their nano‐/micro‐superstructures. This Review surveys recent progress in porous polyelectrolytes including membranes, particles, scaffolds, and high surface area powders/resins as well as their derivatives. The focus is the interplay between surface chemistry, Columbic interaction, and pore confinement that defines new chemistry and physics in such materials for applications in energy conversion, molecular separation, water purification, sensing/actuation, catalysis, tissue engineering, and nanomedicine.     

Continuous‐Flow Microwave Synthesis of Metal–Organic Frameworks: A Highly Efficient Method for Large‐Scale Production

Metal–organic frameworks are having a tremendous impact on novel strategic applications, with prospective employment in industrially relevant processes. The development of such processes is strictly dependent on the ability to generate materials with high yield efficiency and production rate. We report a versatile and highly efficient method for synthesis of metal–organic frameworks in large quantities using continuous flow processing under microwave irradiation. Benchmark materials such as UiO‐66, MIL‐53(Al), and HKUST‐1 were obtained with remarkable mass, space–time yields, and often using stoichiometric amounts of reactants. In the case of UiO‐66 and MIL‐53(Al), we attained unprecedented space–time yields far greater than those reported previously. All of the syntheses were successfully extended to multi‐gram high quality products in a matter of minutes, proving the effectiveness of continuous flow microwave technology for the large scale production of metal–organic frameworks.     

Practical and Scalable Organic Reactions with Flow Microwave Apparatus

Microwave irradiation has been used for accelerating organic reactions as a heating method and has been proven to be useful in laboratory scale organic synthesis. The major drawback of microwave chemistry is the difficulty in scaling up, mainly because of the low penetration depth of microwaves. The combination of microwave chemistry and flow chemistry is considered to overcome the problem in scaling up of microwave‐assisted organic reactions, and some flow microwave systems have been developed in both academic and industrial communities. In this context, we have demonstrated the scale‐up of fundamental organic reactions using a novel flow microwave system developed by the academic‐industrial alliance between the University of Shizuoka, Advanced Industrial Science and Technology, and SAIDA FDS. In this Personal Account, we summarize the recent progress of our scalable microwave‐assisted continuous synthesis using the SAIDA flow microwave apparatus.     

流动化学在卤化反应中的应用

有机物的卤化反应是有机合成中最重要的转化之一.传统釜式卤化反应存在高放热及选择性差等问题,且卤化试剂一般具有毒性和腐蚀性.流动化学在传质和传热方面具有显著优势,可精确控制反应温度及试剂用量,并且可在线淬灭危险试剂,避免其暴露.按有机化合物卤化反应分类,系统地归纳了流动化学在氟化反应、氯化反应、溴化反应和碘化反应中的应用进展,并展望了其发展趋势.     

Multistep Continuous‐Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands

A three‐step continuous‐flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49–94 %. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure–activity‐relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single‐digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.     

Design of Organic Transformations at Ambient Conditions: Our Sincere Efforts to the Cause of Green Chemistry Practice

This account summarizes our recent efforts in designing a good number of important organic transformations leading to the synthesis of biologically relevant compounds at room temperature and pressure. Currently, the concept of green chemistry is globally acclaimed and has already advanced quite significantly to emerge as a distinct branch of chemical sciences. Among the principles of green chemistry, one principle is dedicated to the “design of energy efficiency” – that is, to develop synthetic strategies that require less or the minimum amount of energy to carry out a specific reaction with optimum productivity – and the most effective way to save energy is to develop strategies/protocols that are capable enough to carry out the transformations at ambient temperature! As part of on‐going developments in green synthetic strategies, the design of reactions under ambient conditions coupled with other green aspects is, thus, an area of current interest. The concept of developing reaction strategies at room temperature and pressure is now an emerging field of research in organic chemistry and is progressing steadily. This account is aimed to offer an overview of our recent research works directly related to this particular field of interest, and highlights the green chemistry practice leading to carbon–carbon and carbon–heteroatom bond‐forming reactions of topical significance. Green synthetic routes to a variety of biologically relevant organic molecules (heterocyclic, heteroaromatic, alicyclic, acyclic, etc.) at room temperature and pressure are discussed.

     

有机化学进展(2011~2012)

本文综述了中国大陆地区有机化学研究人员2011至2012年两年内在合成方法学、有机合成化学、元素有机化学以及天然产物化学等领域获得的重要成果。文章中共引用参考文献355篇,其中110多篇手性金属配合物和有机小分子催化的不对称反应、金属催化的碳氢键活化等合成方法学论文和30余篇氟有机化学论文基本来源于德国《应用化学》(国际版)和《美国化学杂志》。本文汇集了中国有机化学家两年中合成的150多个具有生物活性和化学结构多样性的天然产物,其中不乏具有高度挑战性的复杂天然分子。在近两年中中国有机化学家从陆地和海洋的生物体内发现各种不同类型新天然产物90多个。     

Fast‐Geomimicking using Chemistry in Supercritical Water

Herein we introduce a powerful and fast method to produce nanominerals using a bottom up approach. The supercritical hydrothermal flow synthesis is exploited to produce model nanominerals by mimicking natural environments at high temperatures under pressure. This innovative concept is demonstrated with the talc synthesis; this represents a major technical breakthrough since it allows decreasing the mineral‐synthesis time from tens of hours to tens of seconds. Through this example, we show these nanominerals exhibit new crystal‐chemistry signals and new properties. This approach provides a means to reproduce the early stages of formation of minerals in different natural environments from sedimentary environments (low temperature and pressure) to hydrothermal/metamorphic environments (high temperature and high pressure).     

Automated,Accelerated Nanoscale Synthesis of Iminopyrrolidines

Miniaturization and acceleration of synthetic chemistry is an emerging area in pharmaceutical, agrochemical, and materials research and development. Herein, we describe the synthesis of iminopyrrolidine‐2‐carboxylic acid derivatives using chiral glutamine, oxo components, and isocyanide building blocks in an unprecedented Ugi‐3‐component reaction. We used I‐DOT, a positive‐pressure‐based low‐volume and non‐contact dispensing technology to prepare more than 1000 different derivatives in a fully automated fashion. In general, the reaction is stereoselective, proceeds in good yields, and tolerates a wide variety of functional groups. We exemplify a pipeline of fast and efficient nanomole‐scale scouting to millimole‐scale synthesis for the discovery of a useful novel reaction with great scope.