Synthetic Organic Reactions Research Articles

200 Years of The Haloform Reaction: Methods and Applications.

Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive α-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavourings. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.

Metal‐Supported Heterogeneous Catalysts for the Synthesis of Nitrogen‐Containing Heterocycles: A Comprehensive Review

AbstractThe use of metals in the preparation of heterocycles has become increasingly popular due to several key advantages of metals as catalysts. These include recycling capability, eco‐friendliness, simplicity of catalyst preparation and separation, longer lifespan, abundance, and higher yields. As a result of their novel applications in organic, inorganic, medicinal, industrial, polymer chemistry, material sciences, nanotechnology, and biological processes, the utilization of nitrogen‐containing heterocycles has rapidly increased in recent years. Various nitrogen‐containing organic moieties are used in therapeutic processes to enhance effectiveness against several bacterial and viral diseases. This review covers the preparation of imidazoles, triazoles, tetrazoles, pyridine derivatives, azo compounds, pyrimidines, quinoxalines, and quinolines using metals as heterogeneous catalysts. It provides an overview of current methodologies for metal‐assisted heterogeneous catalytic reactions, including product yield, operating temperature, and solvents, among other factors. Heterogeneous catalyst‐mediated organic synthetic reactions offer several advantages, particularly in medicinal chemistry, pharmaceuticals, and industrial applications, by reducing time and energy consumption. This review emphasizes recent advancements in the fabrication of nitrogen heterocycles utilizing heterogeneous catalysts, taking into account various economic, eco‐friendly, and user‐friendly considerations. Additionally, it discusses the benefits, reaction conditions, and yields reported in the literature over the past six years.

A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols.

The haloform reaction from methyl ketones to carboxylic acids is one of the oldest known synthetic organic reactions, which has been used in myriad applications over the decades. The corresponding reaction to produce esters is, however, less developed, as the reaction is generally limited to simple, primary alcohols that are used in solvent-level quantities, thereby restricting the complexity of esters that can be directly formed. Herein, we detail the development of a general ester-forming haloform coupling reaction using one equivalent of alcohol. Mechanistic and kinetic modelling studies demonstrated that the key intermediates are formed under equilibrium, which facilitated the development of conditions that are amenable to secondary alcohols.

A Stoichiometric Haloform Coupling for Ester Synthesis with Secondary Alcohols

AbstractThe haloform reaction from methyl ketones to carboxylic acids is one of the oldest known synthetic organic reactions, which has been used in myriad applications over the decades. The corresponding reaction to produce esters is, however, less developed, as the reaction is generally limited to simple, primary alcohols that are used in solvent‐level quantities, thereby restricting the complexity of esters that can be directly formed. Herein, we detail the development of a general ester‐forming haloform coupling reaction using one equivalent of alcohol. Mechanistic and kinetic modelling studies demonstrated that the key intermediates are formed under equilibrium, which facilitated the development of conditions that are amenable to secondary alcohols.

Reaction Optimization of Strontium Perchlorate Catalyzed Novel Protocol for Stereoselective Synthesis of Dihydropyrimidinones.

Hydrated strontium perchlorate [Sr(ClO4)2.3H2O] acts as a very strong oxidizing and dehydrating agent. Until now, it could not be reported as a catalyst in dehydration mechanism-based organic synthetic reactions. Therefore, it is important to find whether it could be an effective catalyst for one-pot multicomponent reactions (MCRs). The main objective of the present work is the development of a novel process for the synthesis of 1,4-dihydropyrimidinones through the one-pot multicomponent strategy using hydrated Sr(ClO4)2 as a catalyst. Furthermore, it includes process optimization, stereoselectivity, and spectroscopic characterization of the synthesized compounds. Conventional and microwave-supported synthesis of 1,4-dihydropyrimidinones using 20 mol % of hydrated Sr(ClO4)2 catalyst via the one-pot solvent-free reaction was discovered as a new catalytic MCR methodology. The box-Behnken design approach and advanced analytical techniques were used for process optimization and reaction analysis. The results confirmed that hydrated Sr(ClO4)2; works as an efficient catalyst for one-pot multicomponent organic synthesis under both conventional and microwave heating. It is an effective catalyst for laboratory synthesis of 1,4-dihydropyrimidinones stereoselectively with moderate to excellent yield without any undesirable effect. Microwave heating provided the desired product within 1-4 minutes. Moreover, this method provides easy isolation of the pure products simply by recrystallization, and without the use of a chromatographic purification method. The simplicity and neutrality of reaction conditions, easy post-reaction workup, higher satisfactory to excellent yield, effectiveness, the diversity of substrates, etc. render the hydrated Sr(ClO4)2 catalyst-based protocol for the stereoselective synthesis of 1,4-dihydropyrimidinones as a highly efficient method. Furthermore, it has been found to be safe un-der laboratory reaction conditions and no undesirable issues have been faced during the process.

Light switching for product selectivity control in photocatalysis.

Artificial switchable catalysis is a new, rapidly expanding field that offers great potential advantages for both homogeneous and heterogeneous catalytic systems. Light irradiation is widely accepted as the best stimulus to artificial switchable chemical systems. In recent years, tremendous progress has been made in the synthesis and application of photo-switchable catalysts that can control when and where bond formation and dissociation take place in reactant molecules. Photo-switchable catalysis is a niche area in current catalysis, on which systematic analysis and reviews are still lacking in the scientific literature, yet it offers many intriguing and versatile applications, particularly in organic synthesis. This review aims to highlight the recent advances in photo-switchable catalyst systems that can result in two different chemical product outcomes and thus achieve a degree of control over organic synthetic reactions. Furthermore, this review evaluates different approaches that have been employed to achieve dynamic control over both the catalytic function and the selectivity of several different types of synthesis reactions, along with the remaining challenges and potential opportunities. Owing to the great diversity of the types of reactions and conditions adopted, a quantitative comparison of efficiencies between considered systems is not the focus of this review, instead the review showcases how insights from successful adopted strategies can help better harness and channel the power of photoswitchability in this new and promising area of catalysis research.

Contemporary Progress in the Applications of Iron-based Magnetic Nanoparticles in Multicomponent Synthesis: A Review

Abstract: In recent decades, organic synthetic reactions have advanced towards a greener and sustainable reactions by the usage of magnetic nanoparticles (MNPs). Such nanoparticles can be quickly recovered and reused in various organic syntheses. MNPs are a sustainable methodology while encountering environmental and profitable advantage. Due to their properties, MNPs have broad impacts on multiple fields. For instance, their size and magnetic properties have significant implications for various biomedicine, environmental remediation projects, and catalysis. MNPs are an alternative to conventional materials. These are smaller and have a high surface area that allows them to have copious catalytic sites. Amongst various MNPs, iron-based nanoparticles are being profoundly explored in different multicomponent reactions (MCRs). A convergent reaction, which retains most of the significant atoms of the starting components. This investigation targets to equip its readers a brief appertaining to nanoparticles, their processing, and characterization and summarize the evolution in applications of Iron-based MNPs in multicomponent synthetic procedures since 2010.

Synthesis and properties of biphenyl liquid crystal diluters terminated by 2,2-difluorovinyloxyl for high birefringence liquid crystals

ABSTRACT A series of liquid crystal (LC) diluters containing a rigid biphenyl core with a lateral fluorine substituent, a 2,2-difluorovinyloxyl terminal group and a flexible n-alkyl chain were designed and synthesised through classical organic synthetic reactions. Their chemical structures were characterised and confirmed by traditional methods. Meanwhile, the effects of alkyl-chain length, terminal group and lateral fluorine substituent on the melting point (T m), birefringence (Δn), dielectric anisotropy (Δε) and rotational viscosity (γ 1) of LC diluters were investigated. Density functional theory (DFT) calculations were employed to obtain the molecular polarisability, dipole moment, frontier orbitals, biphenyl dihedral angle and aspect ratio. Furthermore, their comprehensive properties in low-Δn LC mixture 002 and high-Δn LC mixture P01-F were further evaluated, and it was found that the 2,2-difluorovinyloxyl LC diluter 3FV have a significant advantage in reducing the T m and γ 1 of LC mixtures, and increasing the values of Δn and Δε. The research results provide technical support and theoretical guidance for the molecular design of new LC diluters and the development of fast response liquid crystals.

Synthesis and performance evaluation of fluorinated biphenyl diluters for high birefringence liquid crystals

ABSTRACT Liquid crystal (LC) mixtures with high birefringence (∆n) and low rotational viscosity play an essential role for fast-response LC devices. However, high birefringence and low rotational viscosity are a pair of contradictory performance parameters. In this work, two high-∆n LC diluters are proposed to achieve a fine balance between them. These two terminal olefin diluters containing a rigid biphenyl core with a lateral fluorine substituent, a buty-3-enyl terminal group and a flexible n-alkyl chain were designed and synthesised through classical organic synthetic reactions. Meanwhile, their comprehensive properties were further evaluated in a LC mixture P02-F containing fluoro-tolane and a LC mixture P12-ISO containing isothiocyano-tolane. The results show that the biphenyl diluters 2BBF2V and 3BFB2V could effectively decrease the T m of LC mixture P12-ISO to below −25°C, while maintain high ∆n and large Δε, which are suitable for the high-∆n LC mixtures containing isothiocyano-tolane. Furthermore, DFT calculations of molecular conformation and polarisability components were utilised to correlate the experimental findings.

The radical scavenging ability of phenylenediamine species: The role of electron and proton transfer processes in their oxidative transformation

A theoretical analysis of the thermodynamics of the oxidation–reduction reaction steps associated with proton-coupled electron transfer is presented for aniline and phenylenediamine isomers. In this context, the radical scavenging ability of the parent molecules and their ionic and/or radical species is compared. The acidity constants evaluated for heterolytic N–H bond decay in an aqueous environment and corresponding electrochemical oxidation potentials, as adapted to the standard hydrogen electrode, were used for the construction of a Pourbaix diagram (electrochemical potential vs. pH). Based on this diagram, the chemically relevant transformation routes for the corresponding radical cations were identified. Finally, the thermodynamics of model proton-coupled electron transfer reactions with hydrogen peroxide are considered. The theoretical data presented are compared and correlated with experimental results, published in the literature. The results obtained allow an estimation to be made of the oxidation mechanisms occurring in polymer matrices, including those containing phenylenediamine antioxidants, in synthetic organic reactions or in processes related to tertiary wastewater purification.

Fuelling the Digital Chemistry Revolution with Language Models.

The RXN for Chemistry project, initiated by IBM Research Europe - Zurich in 2017, aimed to develop a series of digital assets using machine learning techniques to promote the use of data-driven methodologies in synthetic organic chemistry. This research adopts an innovative concept by treating chemical reaction data as language records, treating the prediction of a synthetic organic chemistry reaction as a translation task between precursor and product languages. Over the years, the IBM Research team has successfully developed language models for various applications including forward reaction prediction, retrosynthesis, reaction classification, atom-mapping, procedure extraction from text, inference of experimental protocols and its use in programming commercial automation hardware to implement an autonomous chemical laboratory. Furthermore, the project has recently incorporated biochemical data in training models for greener and more sustainable chemical reactions. The remarkable ease of constructing prediction models and continually enhancing them through data augmentation with minimal human intervention has led to the widespread adoption of language model technologies, facilitating the digitalization of chemistry in diverse industrial sectors such as pharmaceuticals and chemical manufacturing. This manuscript provides a concise overview of the scientific components that contributed to the prestigious Sandmeyer Award in 2022.

Carbon Vacancies Steer the Activity in Dual Ni Carbon Nitride Photocatalysis.

The manipulation of carbon nitride (CN) structures is one main avenue to enhance the activity of CN-based photocatalysts. Increasing the efficiency of photocatalytic heterogeneous materials is a critical step toward the realistic implementation of sustainable schemes for organic synthesis. However, limited knowledge of the structure/activity relationship in relation to subtle structural variations prevents a fully rational design of new photocatalytic materials, limiting practical applications. Here, the CN structure is engineered by means of a microwave treatment, and the structure of the material is shaped around its suitable functionality for Ni dual photocatalysis, with a resulting boosting of the reaction efficiency toward many CX (X = N, S, O) couplings. The combination of advanced characterization techniques and first-principle simulations reveals that this enhanced reactivity is due to the formation of carbon vacancies that evolve into triazole and imine N species able to suitably bind Ni complexes and harness highly efficient dual catalysis. The cost-effective microwave treatment proposed here appears as a versatile and sustainable approach to the design of CN-based photocatalysts for a wide range of industrially relevant organic synthetic reactions.

マイクロ波特異効果はあるのか？ 有機合成反応における実験的検証

Highly polar compounds are generally heated by absorbing microwave energy. Since 1986, microwave irradiation has been applied to various organic syntheses as an efficient heating method. On the other hand, an additional effect called “microwave specific effect”, that cannot be explained by the simple heating effect, has been observed. In a solvent that absorbs less microwave, microwave energy can be directly provided to the reaction substrate, and microwave-specific effects can be expected. Some microwave-assisted asymmetric synthetic reactions have been observed to accelerate while maintaining enantioselectivity. Based on this working hypothesis, we experimentally confirmed the microwave-specific effect in several organic synthetic reactions.

Nanohybrids: A Burgeoning Need to Cater C−C and C−O Bonds Building in Organic Synthesis

AbstractNanohybrids (NHs) based on the conjugation of multiple carbonaceous nanomaterials and metal/metal oxides, are emerging as important photocatalysts of 21st century and have tremendous future scopes. Overcoating one material on top of another in NHs improves performance and multifunctionality growth for a wide range of catalytic applications in organic transformations. The catalytic activity of NHs brings a phenomenal change towards various organic synthetic reactions to improve their selectivity, productivity and yield. Thus, with the background of this context, the current review covers the state of art literature up to July 2022 and brings a comprehensive discussion on the entitled subject matter. As emphasized in this review, the application of heterogeneous NHs for common organic reactions has been confirmed to be a successful tactic for the growth of extremely resourceful conversions in terms of atom economy, atom efficiency E‐factor and selectivity. It also highlights the extensive and critical aspects to explore the catalytic prospects and challenges of NHs from obscurity to eminence.

Synthesis of N-(acyloxy)-N-alkynylamides via generation of "C2" from hypervalent alkynyliodane and a weak base.

The first synthesis of N-(acyloxy)ynamides was realized through the coupling of N-(acyloxy)amides and hypervalent alkynyliodane under mild conditions. This reaction probably involves biradical species ("C2") generation and radical processes. Furthermore, we also demonstrated that N-(acyloxy)ynamide could be transformed into a N-sulfonylimidate derivative by a copper catalyst. This study provides new building blocks for synthetic organic chemistry reactions and improves understanding of the chemical reactivity of "C2".

Development of Catalytic Synthetic Organic Reactions Utilizing Gaseous Molecule Surrogates

Development of Catalytic Synthetic Organic Reactions Utilizing Gaseous Molecule Surrogates

Photoelectrocatalytic biosynthesis fuelled by microplastics

Biocatalytic artificial photosynthesis integrates photocatalysis and redox biocatalysis to synthesize value-added chemicals using solar energy. However, this nature-inspired approach suffers from sluggish rates of reaction because of challenging water oxidation kinetics. Here we report photoelectrochemical biosynthetic reactions that use non-recyclable real-world poly(ethylene terephthalate) (PET) microplastics as an electron feedstock. A Zr-doped haematite photoanode extracts electrons from hydrolysed PET solutions obtained from post-consumer PET waste, such as drinks bottles, and transfers the electrons to the bioelectrocatalytic site. Carbon-based cathodes receive the electrons to activate redox enzymes (for example, unspecific peroxygenase, L-glutamate dehydrogenase and ene-reductase from the old yellow enzyme family) that drive various organic synthetic reactions. These reactions include oxyfunctionalization of C–H bonds, amination of C=O bonds and asymmetric hydrogenation of C=C bonds. These photoelectrocatalytic–biocatalytic hybrid reactions achieve total turnover numbers of 362,000 (unspecific peroxygenase), 144,000 (L-glutamate dehydrogenase) and 1,300 (old yellow enzyme). This work presents a photoelectrocatalytic approach for integrating environmental remediation and biocatalytic photosynthesis towards sustainable solar-to-chemical synthesis.

Recent Advances in the Catalytic Applications of Chiral Schiff‐Base Ligands and Metal Complexes in Asymmetric Organic Transformations

AbstractThe Schiff base and its metal complexes are extensively studied for their adaptable metal chelating properties. Their ability to alter the design and modify it for various organic and biological applications makes them versatile compounds. The chiral Schiff base and their metal complexes possess excellent stability in very high temperatures, making them a suitable candidate for organocatalysts in reactions involving harsh conditions. Besides, these chiral complexes of Schiff base can transform their chirality in the final product formed in different chemical reactions. This stereo‐induction by the chiral metal complexes of Schiff base is considerably valuable for synthesizing high optically active compounds in the field of medicinal and natural product synthesis. Thus, this review emphasizes the latest and relevant literature concerning the asymmetric catalysis of chiral Schiff base ligand‐metal complexes in various synthetic organic transformation reactions. The synthesis and the catalytic mechanisms of various reactions are discussed, including their enantioselectivities, diastereoselectivities, regioselectivities, and stereoselectivities of different complexes to organic transformation.

Transmetalation of boronic acids and their derivatives: mechanistic elucidation and relevance to catalysis.

The Suzuki-Miyaura reaction (the cross-coupling reaction of boronic acids with organic halides catalysed by Pd complexes) has been recognised as a useful synthetic organic reaction that forms a C(sp2)-C(sp2) bond. The catalytic cycle of the reaction involves the transmetalation of aryl- and alkenylboronic acids with Pd(II) complexes. It migrates the aryl and alkenyl groups of boronic acid to Pd and produces a Pd-C bond. Many studies have investigated the mechanism of transmetalation. They elucidated the mechanism of the organometallic reaction and its role as a fundamental step in catalytic reactions. This perspective reviews studies on the transmetalation of aryl- and alkenylboronic acids with Pd(II) complexes. Emphasis was laid on the structures and chemical properties of the intermediate Pd complexes and the effects of OH- on the pathways of the catalytic Suzuki-Miyaura reaction. The reactions of arylboronic acids with Rh(I)-OH complexes were investigated, which are relevant to the mechanism of Rh-catalysed addition of aryl boronic acids to enones and aldehydes. Recent studies on the transmetalation of boronic acids with other late transition metals such as Fe(II), Co(I), Pt(II), Au(III), and Au(I) are presented with the related catalytic reactions and their utilisation in the synthesis of aromatic molecules and π-conjugated materials.

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

In the presence of a suitable acid or base, α-hydroxyaldehydes, ketones, and imines can undergo isomerization that features the 1,2-shift of an alkyl or aryl group. In the process, the hydroxy group is converted to a carbonyl and the aldehyde/ketone or imine is converted to an alcohol or amine. Such α-ketol/α-iminol rearrangements are used in a wide variety of synthetic applications including asymmetric synthesis, tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades.