Interacting Practices: Quantum Chemistry and Organic Synthesis

If the core of chemistry is making molecules, then the construction of those found in nature—natural products—has long been regarded as one of the highest forms of the art in synthesis. These molecules, produced by living organisms for a variety of purposes, are a key source of pharmaceuticals such as antibiotics and anticancer agents. The medicinal value of natural products has been known for centuries via herbal treatments, and such compounds are still collected, refined and screened for potential drugs today, sometimes being identified from local ‘folk medicine’ practices. By identifying the active ingredients of natural extracts used in traditional medicine, chemists can then synthesize modified forms that may be even more active: this was how the analgesic aspirin was first identified as a derivative of the plant hormone salicylic acid from willow bark. As well as offering such derivatives, natural-product synthesis in organic chemistry can potentially provide a more plentiful alternative source of natural products that are available in only tiny amounts from their natural sources. Efforts to devise cheap and efficient synthetic strategies for molecules such as paclitaxel (Taxol, an anticancer agent present in the Pacific yew) and artemisinin (an anti-malarial extracted from the herb sweet wormwood, qinghao (青蒿), and recognized by the 2015 Nobel Prize for Medicine) are still on-going to satisfy global demand. Organic synthesis is about much more than making natural products: it contributes, for example, to catalysis, polymer chemistry, food science and the development of wholly synthetic drugs. Yet efforts to make complex natural products may supply a motivational testing ground for developing new synthetic techniques with broader applications. Indeed, many chemists prize the discovery of a new synthetic method above the recreation of some complex natural molecule: it is the means, not the end, that matters. The field of organic and natural-product synthesis has a strong history in China, where there is a long tradition of herbal medicine. The use of the qinghao extract for treating malaria is first recorded in AD 340, in a manual that the 2015 Nobel laureate Tu Youyou says she consulted for clues about isolating the compound in the beginning of 1970s. Some say that, in the past decade, Chinese natural-product chemistry has entered a ‘golden era’ (Zheng Q-Y and Li A. Sci China Chem 2016;59: 1059–60). Qi-Lin Zhou of Nankai University and Xiaoming Feng of Sichuan University have been at the forefront of this upsurge. Both of them have developed methods for making so-called chiral molecules: arrangements of atoms that have a handedness, so that they can exist in two mirror-image versions. Natural products typically are chiral molecules, and their biological activity may depend on having the correct handedness. The selective synthesis of chiral molecules (asymmetric synthesis) is therefore vital to natural-product chemistry, and typically involves the use of catalysts that are chiral themselves. National Science Review spoke to Zhou and Feng about their work and their perspectives on organic synthesis in China. Qi-Lin Zhou of College of Chemistry at Nankai University, China. (Courtesy of Q Zhou)

Preface. Personal Foreword. 1. Introduction: Microwave Synthesis in Perspective. 1.1 Microwave Synthesis and Medicinal Chemistry. 1.2 Microwave: Assisted Organic Synthesis (MAOS) - A Brief History. 1.3 Scope and Organization of the Book. 2. Microwave Theory. 2.1 Microwave Radiation. 2.2 Microwave Dielectric Heating. 2.3 Dielectric Properties. 2.4 Microwave Versus Conventional Thermal Heating. 2.5 Microwave Effects. 2.5.1 Thermal Effects (Kinetics). 2.5.2 Specific Microwave Effects. 2.5.3 Non-Thermal (Athermal) Microwave Effects. 3. Equipment Review. 3.1 Introduction. 3.2 Domestic Microwave Ovens. 3.3 Dedicated Microwave Reactors for Organic Synthesis. 3.4 Multimode Instruments. 3.4.1 Milestone s.r.1. 3.4.2 CEM Corporation. 3.4.3 Biotage AB. 3.4.4 Anton Paar GmbH. 3.5 Single-Model Instruments. 3.5.1 Biotage AB. 3.5.2 CEM Corporation. 3.6 Discussion. 4. Microwave Processing Techniques. 4.1 Solvent-Free Reactions. 4.2 Phase-Transfer Catalysis. 4.3 Reactions Using Solvents. 4.3.1 Open-versus Closed-Vessel Conditions. 4.3.2 Pre-Pressurized Reaction Vessels. 4.3.3 Non-Classical Solvents. 4.4 Parallel Processing. 4.5 Scale-Up in Batch and Continuous-Flow. 5. Starting with Microwave Chemistry. 5.1 Why Use Microwave Reactors? 5.2 Translating Conventionally Heated Methods. 5.2.1 Open and Closed Vessels? 5.2.2 Choice of Solvent. 5.2.3 Temperature and Time. 5.2.4 Microwave Instrument Software. 5.3 Reaction Optimization and Library Generation - A Case Study. 5.3.1 Choice of Solvent. 5.3.2 Catalyst Selection. 5.3.3 Time and Temperature. 5.3.4 Reinvestigation by a Design of Experiments Approach. 5.3.5 Optimization for Troublesome Building Block Combinations. 5.3.6 Automated Sequential Library Production. 5.4 Limitations and Safety Aspects. 6. Literature Survey Part A: General Organic Synthesis. 6.1 Transition Metal-Catalyzed Carbon-Carbon Bond Formations. 6.1.1 Heck Reactions. 6.1.2 Suzuki Reactions. 6.1.3 Sonogashira Reactions. 6.1.4 Stille Reactions. 6.1.5 Negishi, Kumada, and Related Reactions. 6.1.6 Carbonylation Reactions. 6.1.7 Asymmetric Allylic Alkyations. 6.1.8 Miscellaneous Carbon-Carbon Bond-Forming Reactions. 6.2 Transition Metal-Catalyzed Carbon-Heteroatom Bond Formations. 6.2.1 Buchwald-Hartwig Reactions. 6.2.2 Ullmann Condensation Reactions. 6.2.3 Miscellaneous Carbon-Heteroatom Bond-Forming Reactions. 6.3 Other Transition Metal-Mediated Processes. 6.3.1 Ring Closing Metathesis. 6.3.2 Pauson-Khand Reactions. 6.3.3 Carbon-Hydrogen Bond Activation. 6.3.4 Miscellaneous Reactions. 6.4 Rearrangement Reactions. 6.4.1 Claisen Rearrangements. 6.4.2 Domino/Tandem Claisen Rearrangements. 6.4.3 Squaric Acid-Vinylketene Rearrangements. 6.4.4 Vinylcyclobutane-Cyclohexene Rearrangements. 6.4.5 Miscellaneous Rearrangements. 6.5 Diels-Alder Cycloaddition Reactions. 6.6 Oxidations. 6.7 Catalytic Transfer Hydrogenations. 6.8 Mitsunobu Reactions. 6.9 Glycosylation Reactions and Related Carbohydrate-Based Transformations. 6.10 Multicomponent Reactions. 6.11 Alkylation Reactions. 6.12 Nucleophilic Aromatic Substitutions. 6.13 Ring-Opening Reactions. 6.13.1 Cyclopropane Ring-Opening. 6.13.2 Aziridine Ring-Openings. 6.13.3 Epoxide Ring-Opening. 6.14 Addition and Elimination Reactions. 6.14.1 Michael Additions. 6.14.2 Addition to Alkenes. 6.14.3 Addition to Alkenes. 6.14.4 Addition to Nitriles. 6.15 Substitution Reactions. 6.16 Enamine and Imine Formations. 6.17 Reductive Aminations. 6.18 Ester and Amide Formation. 6.19 Decarboxylation Reactions. 6.20 Free Radical Reactions. 6.21 Protection/Deprotection Chemistry. 6.22 Preparation of Isotopically Labeled Compounds. 6.23 Miscellaneous Transformations. 6.24 Heterocycle Synthesis. 6.24.1 Three-Membered Heterocycles with One Heteroaton. 6.24.2 Four-Membered Heterocycles with One Heteroatom. 6.24.3 Five-Membered Heterocycles with One Heteroatom. 6.24.4 Five-Membered Heterocycles with Two Heteroatom. 6.24.5 Five-Membered Heterocycles with Three Heteroatom. 6.24.6 Five-Membered Heterocycles with Four Heteroatom. 6.24.7 Six-Membered Heterocycles with One Heteroatom. 6.24.8 Six-Membered Heterocycles with Two Heteroatom. 6.24.9 Six-Membered Heterocycles with Three Heteroatom. 6.24.10 Larger Heterocyclic and Polycyclic Ring Systems. 7. Literature Survey Part B: Combinatorial Chemistry and High-Throughput Organic Synthesis. 7.1 Solid-Phase Organic Synthesis. 7.1.1 Combinatorial Chemistry and Solid-Phase Organic Synthesis. 7.1.2 Microwave Chemistry and Solid-Phase Organic Synthesis. 7.1.3 Peptide Synthesis and Related Examples. 7.1.4 Resin Functionalization. 7.1.5 Transition Metal Catalysis. 7.1.6 Substitution Reactions. 7.1.7 Multicomponent Chemistry. 7.1.8 Microwave-Assisted Condensation Reactions. 7.1.9 Rearrangements. 7.1.10 Cleavage Reactions. 7.1.11 Miscellaneous. 7.2 Soluble Polymer-Supported Synthesis. 7.3 Fluorous Phase Organic Synthesis. 7.4 Grafted Ionic Liquid-Phase-Supported Synthesis. 7.5 Polymer-Supported Reagents. 7.6 Polymer-Supported Catalysts. 7.6.1 Catalysts on Polymeric Supports. 7.6.2 Silica-Grafted Catalysts. 7.6.3 Catalysts Immobilized on Glass. 7.6.4 Catalysts Immobilized on Carbon. 7.6.5 Miscellaneous. 7.7 Polymer-Supported Scavengers. 8. Outlook and Conclusions. Index.

This review deals with typical reactions of vinyl acetals (or 1-alkenyl acetals) with a vinyl ether subunit as part of an acetal moiety, involving carboxonium ions and enol ethers as intermediates. Related N- and S- containing compounds are also considered. Rearrangements, fragmentations, addition reactions and cycloadditions are most common among these compounds. The vinyl acetal structure may be incorporated in a ring system or may be part of an acyclic chain. Common reactions as well as differences in reactivity are discussed, emphasizing the application of vinyl acetals in synthetic organic chemistry and natural product synthesis. 1. Introduction 2. Cyclic Vinyl Acetals and Related Compounds 2.1. Reactions of 1,3-Dioxoles, 4-Methylene-1,3-dioxolanes and Analogues 2.1.1. Rearrangements and Fragmentations 2.1.2. Isomerizations, Cycloadditions and Addition Reactions 2.1.3. Miscellaneous 2.2. Reactions of 4H-1,3-Dioxins and 4-Methylene-1,3-dioxanes 2.2.1. Isomerizations and Fragmentations 2.2.2. Addition Reactions 2.2.3. Miscellaneous 2.3. Reactions of 4,5-Dihydro-1,3-dioxepins 2.3.1. Rearrangements 2.3.2. Addition Reactions, Cycloadditions and Substitutions 2.3.3. Miscellaneous 3. Acyclic Vinyl Acetals 3.1. Rearrangements 3.2. Miscellaneous 4. Concluding Remarks

Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R1R2N-O•. The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R1 and R2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R1R2N═O+) or reduced to anions (R1R2N-O-), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C-O bonds, allowing for the thermal generation of C radicals through reversible C-O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.

Chapter 5 - Isocoumarins in Medicinal Chemistry and Organic Synthesis

Decarboxylative sulfinylation is reported by Oleg V. Larionov and co-workers in their Research Article (e202210525), as illustrated in the cover picture. The reaction is enabled by radicalophilic reactivity of the sulfinyl sulfones shown in the top left that is distinct from the known dissociation and nucleophilic substitution pathways. Given the importance of carboxylic acids and sulfoxides for medicinal chemistry, agroscience, and organic synthesis, decarboxylative sulfination addresses the unmet need for a direct interconversion between the two functional groups and provides access to new sulfoxide chemical space. Decarboxylative sulfinylation is reported by Oleg V. Larionov and co-workers in their Research Article (e202210525), as illustrated in the cover picture. The reaction is enabled by radicalophilic reactivity of the sulfinyl sulfones shown in the top left that is distinct from the known dissociation and nucleophilic substitution pathways. Given the importance of carboxylic acids and sulfoxides for medicinal chemistry, agroscience, and organic synthesis, decarboxylative sulfination addresses the unmet need for a direct interconversion between the two functional groups and provides access to new sulfoxide chemical space. Coordination Chemistry Bioanalytics Microporous Materials

Chloramine-T (CAT), the sodium salt of N-chloro-p-toluenesulfonamide, is a low-cost mild oxidizing agent with a wide range of uses. Most importantly, it can be used in acidic, neutral, and basic conditions. As a result, it’s been widely used in chemistry, particularly in organic synthesis and analytical chemistry. Chloramine-T acts as a source of halonium cation and nitrogen anion and thus acts as base and nucleophile. It reacts with a wide range of functional groups and carries different molecular transformations. This paper thoroughly summarises and highlights the synthetic and analytical effectiveness of CAT. This study focuses on current developments as well as some older techniques in which CAT has been employed as an oxidizing agent. This review article stretches a comprehensive profile of the CAT reagent in organic synthesis and analytical chemistry, which will be very useful for further research exploration in this field.

Recent advancements in visible-light-induced direct C(3)–H functionalization of quinoxalin-2(1H)-ones

Over the years, ionic liquids have gained significant attention in organic synthesis and other areas of chemistry as environmentally benign solvents. Unlike traditional solvents, ionic liquids offer several advantages such as being nonvolatile, noncorrosive, immiscible in organic solvents, easily stored and handled, producing less hazardous waste, and easily recovered in terms of materials during the reaction work-up. Their role in enhancing reaction rates and selectivity is well documented in the literature. Ionic liquids have proved to be an important alternative over traditional solvents in a variety of synthetic transformations. In this account, we highlight some of the advancements over the last decade in the development of ionic liquids as solvents in organic synthesis.

Allyl-Palladium Complexes in Organic Synthesis

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

Arynes are among the most intensively studied systems in chemistry. However, many aspects of the chemistry of these reactive intermediates are not well understood yet and their use as reagents in synthetic organic chemistry has been somewhat limited, due to the harsh conditions needed to generate arynes and the often uncontrolled reactivity exhibited by these species. Recently, o-silylaryl triflates, which can generate the corresponding arynes under very mild reaction conditions, have been found very useful in organic synthesis. This thesis describes several novel and useful methodologies by employing arynes, which generate from o-silylaryl triflates, in organic synthesis. An efficient, reliable method for the N-arylation of amines, sulfonamides and carbamates, and the O-arylation of phenols and carboxylic acids is described in Chapter 1. Amines, sulfonamides, phenols, and carboxylic acids are good nucleophiles, which can react with arynes generated from a-silylaryl triflates to afford the corresponding N- and O-arylated products in very high yields. The regioselectivity of unsymmetrical arynes has also been studied. A lot of useful, functional groups can tolerate our reaction conditions. Carbazoles and dibenzofurans are important heteroaromatic compounds, which have a variety of biological activities. A variety of substituted carbazoles and dibenzofwans are readily prepared in good to excellent yields starting with the corresponding o-iodoanilines or o-iodophenols and o-silylaryl triflates by a treatment with CsF, followed by a Pd-catalyzed cyclization, which overall provides a one-pot, two-step process. By using this methodology, the carbazole alkaloid mukonine has been concisely synthesized in a very good yield. Insertion of an aryne into a σ-bond between a nucleophile and an electrophile (Nu-E) should potentially be a very beneficial process from the standpoint of organic synthesis. A variety of substituted ketones and sulfoxides have been synthesized in good yields via the intermolecular C-N σ-bond addition of amides and S-N σ-bond addition of sulfinamides to arynes under mild reaction conditions. The indazole moiety is a frequently found subunit in drug substances with important biological activities. Indazole analogues have been readily synthesized under mild reaction conditions by the [3+2] cycloaddition of a variety of diazo compounds with o-silylaryl triflates in the presence of CsF or TBAF. Polycyclic aromatic and heteroaromatic hydrocarbons have been synthesized in high yields by two different processes involving the Pd-catalyzed annulation of arynes. Both processes appear to involve the catalytic, stepwise coupling of two very reactive substrates, an aryne and an organopalladium species, to generate excellent yields of cross-coupled products.

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

Understanding reaction kinetics is fundamental to organic synthesis, yet traditional quantum chemistry-based transition state searches are computationally expensive. Here we present DeePEST-OS, a reactive machine learning potential designed for rapid and accurate transition state optimization and energy barrier prediction spanning ten chemical elements. Trained on approximately 75,000 reactions generated by a low-cost data preparation strategy, this model integrates physical priors from semi-empirical quantum chemistry with equivariant message passing networks to predict potential energy surfaces nearly 10,000 times faster than quantum chemistry methods, while achieving high accuracy for transition state geometry (averaged root mean square deviation of 0.12 Å) and energy barriers (mean absolute error of 0.60 kcal/mol) on unseen reactions. DeePEST-OS enables practical applications including transition state conformer screening, barrier prediction for retrosynthesis of complex pharmaceuticals, and experimentally validated diastereoselectivity prediction in Diels-Alder reactions. Collectively, these results establish DeePEST-OS as a powerful tool for accelerating reaction kinetics studies in multi-element organic synthesis.

In the past four years we have created a set of sophisticated and realistic laboratory simulations for use in freshman- and sophomore-level chemistry classes and laboratories called Virtual ChemLab. We have completed simulations for Inorganic Qualitative Analysis, Organic Synthesis and Organic Qualitative Analysis, Fundamental Experiments in Quantum Chemistry, Gas Properties, Titration Experiments, and Calorimetry. The purpose of our simulations is to reinforce concepts taught in the classroom, provide an environment for creative learning, and emphasize the thinking behind instructional laboratory experiments. We have used the inorganic and organic simulations extensively with thousands of students in our department at Brigham Young University. Some important learnings from our evaluation include: (i) students enjoy using these simulations and find them to be an asset in learning effective problem-solving strategies, (ii) students like the fact that they can both reproduce experimental procedures and explore various topics in ways they choose, (iii) students naturally divide themselves into two groups: creative learners, who excel in an open-ended learning environment, and structured learners, who struggle in this same environment, and (iv) students almost uniformly agree that these simulations help them learn chemistry. In this article, we will describe the Organic Synthesis and Organic Qualitative Analysis simulation; we will also share specific evaluation findings from using the organic simulation in a laboratory setting.