Organic Chemistry Research Articles

Electrochemically Generated Carbocations in Organic Synthesis

AbstractThis Minireview examines a selection of case studies that showcase distinctive and enabling electrochemical approaches that have allowed for the generation and reaction of carbocation intermediates under mild conditions. Particular emphasis is placed on the progress that has been made in this area of organic synthesis and polymer chemistry over the past decade.

John I. Brauman (1937–2024)

Groundbreaking physical organic chemist

“Marriage” of Inorganic to Organic Chemistry as Motivation for a Theoretical Study of Chloroform Hydrolysis Mechanisms

“Marriage” of Inorganic to Organic Chemistry as Motivation for a Theoretical Study of Chloroform Hydrolysis Mechanisms

Chemical Abundance Gradients of Organic Molecules within a Protostellar Disk

Observations of low-mass protostellar systems show evidence of rich, complex organic chemistry. Their low luminosity, however, makes determining abundance distributions of complex organic molecules within the water snowline challenging. However, the excitation conditions sampled by differing molecular distributions may produce substantive changes in the resulting emission. Thus, molecular excitation may recover spatial information from spatially unresolved data. By analyzing spatially unresolved NOrthern Extended Millimeter Array observations of CH3OH and CH3CN, we aim to determine if CH3OH and CH3CN are distributed differently in the protostellar disk around HOPS-370, a highly luminous intermediate-mass protostar. Rotational diagram analysis of CH3OH and CH3CN yields rotational temperatures of 198 ± 1.2 K and 448 ± 19 K, respectively, suggesting the two molecules have different spatial distributions. Source-specific 3D LTE radiative transfer models are used to constrain the spatial distribution of CH3OH and CH3CN within the disk. A uniform distribution with an abundance of 4 × 10−8 reproduces the CH3OH observations. In contrast, the spatial distribution of CH3CN needs to be either more compact (within ∼120 au versus ∼240 au for CH3OH) or exhibit a factor of ≳15 increase in abundance in the inner ∼55 au. A possible explanation for the difference in spatial abundance distributions of CH3OH and CH3CN is carbon-grain sublimation.

Reactivity Inside Molecular Flasks: Acceleration Modes and Types of Selectivity Obtainable

There is increasing interest in the discovery and application of molecular flasks ‐ supramolecular host structures capable of catalyzing organic reactions. Reminiscent of enzymes due to possessing a host cavity akin to an active site, molecular flasks can exhibit complex catalytic mechanisms and in many cases provide selectivity not achievable in bulk solvent. In this Review, we aim to organize the increasingly diverse examples through a two‐part structure. In part one, we provide an overview of the different acceleration modes that operate within molecular flasks, while in part two we showcase, through selected examples, the different types of selectivity that are obtainable through the use of molecular flasks. Particular attention is given to examples that are relevant to current challenges in synthetic organic chemistry. We believe that this structure makes the field more approachable and thus will stimulate the development of novel applications of molecular flasks.

Reactivity Inside Molecular Flasks: Acceleration Modes and Types of Selectivity Obtainable.

There is increasing interest in the discovery and application of molecular flasks - supramolecular host structures capable of catalyzing organic reactions. Reminiscent of enzymes due to possessing a host cavity akin to an active site, molecular flasks can exhibit complex catalytic mechanisms and in many cases provide selectivity not achievable in bulk solvent. In this Review, we aim to organize the increasingly diverse examples through a two-part structure. In part one, we provide an overview of the different acceleration modes that operate within molecular flasks, while in part two we showcase, through selected examples, the different types of selectivity that are obtainable through the use of molecular flasks. Particular attention is given to examples that are relevant to current challenges in synthetic organic chemistry. We believe that this structure makes the field more approachable and thus will stimulate the development of novel applications of molecular flasks.

Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry

Diesters of geminal diols (R-CH(O-CO-R′)2, RR′C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related “non-classical acylals”, as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

Strategies Employing Transition‐Metal Free Conditions for C−C Bond Formation in Indoles

AbstractIndole motifs are omnipresent in nature and can be found in many natural products as well as pharmaceuticals. It is for this reason synthetic transformations of indole have become a topic of interest for the organic and medicinal chemist community for decades. In this review, we have emphasized the functionalization of indoles via transition‐metal‐free approaches. This review touches on many aspects in different sub‐sections, which gives a proposition of the tactics employed for the functionalization of indoles and an overview of the road ahead.

How does using an AR learning environment affect student learning of a radical substitution mechanism?

Abstract As the use of augmented reality (AR) in educational settings grows, it becomes increasingly important to understand how to use AR in classrooms. Here, we present an AR learning environment that we designed for teaching an organic chemistry reaction mechanism in high school chemistry classes. This new environment was tested in six tenth-grade chemistry classes (upper secondary) taught by five different teachers in three different schools over the course of five months and evaluated for effectiveness. Students completed knowledge tests before and after they used the AR learning environment to test their learning gain, and surveys to measure their acceptance of the technology, the cognitive load they experienced, and their attitude toward the use of AR to learn the mechanism for radical substitution. Analysis shows that the knowledge posttest scores were significantly higher than the pretest scores (p < 0.001), with a large effect size (r = 0.8). Student responses showed acceptance of the technology, experience of low extraneous cognitive load, and a positive attitude toward the use of AR to learn this reaction mechanism. These findings indicate that this AR learning environment can be used to teach the mechanism of radical substitution to tenth-grade students in introductory high school chemistry courses.

Evaluation of the Use of a 360° Immersive Visit of the Organic Chemistry Practical Laboratory for Pharmacy Students

Evaluation of the Use of a 360° Immersive Visit of the Organic Chemistry Practical Laboratory for Pharmacy Students

Virtual Reality in an Eco-Niche Undergraduate Organic Chemistry Laboratory Course: New Practice in Chemistry Lab Teaching

Virtual Reality in an Eco-Niche Undergraduate Organic Chemistry Laboratory Course: New Practice in Chemistry Lab Teaching

The Progress of Reductive Coupling Reaction by Iron Catalysis.

The transition metal catalyzed coupling reaction has revolutionized the strategies for forging the carbon-carbon bonds. In contrast to traditional cross-coupling methods using pre-prepared nucleophilic organometallic reagents, reductive coupling reactions for the C-C bonds formation provide some advantages. Because both coupling partners are reduced in the final products using a stoichiometric amount of a reductant, this approach not only avoids the need to use sensitive organometallic species, but also provides an orthogonal and complementary access to classical coupling reaction. Notably, the reductive coupling reactions feature readily available fragments, promote good step economy, exhibit high functional group tolerance and unique chemoselectivity, which have propelled their increasingly popular in the organic synthesis. In recent years, due to the low price, minimal toxicity, and environmentally benign character, iron-catalyzed carbon-carbon coupling reactions have garnered significant attention from the organic synthetic chemists and pharmacologists, especially the iron-catalyzed reductive coupling. This review aims to provide an insightful overview of recent advances in iron-catalyzed reductive coupling reactions, and to illustrate their possible reaction mechanisms.

Recent Advances in Visible‐Light‐Mediated Synthesis of Phosphorylated Heterocycles

Organophosphorus compounds, especially phosphorylated heterocycles, are gaining increasing attention in the fields of materials science, pharmaceuticals, and agrochemistry due to their excellent biological activities. Consequently, the exploration of green and efficient methods for the synthesis of phosphorylated heterocycles has garnered significant interest from organic chemists. In recent years, visible light‐induced photoredox‐catalyzed organic synthesis has made substantial progress in the field of phosphorylation reaction since its eco‐friendly and mild conditions. This review summarizes the advance of the past five years in the visible‐light‐mediated synthesis of phosphorylated heterocycles using phosphine oxides as precursors through P‐centered radical addition, cross‐couping, and cyclization reactions.

Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion.

Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single-nitrogen-atom insertion reaction, and skeletal editing to construct N-heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen-atom into hydrocarbons to generate N-heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen-containing heterocycles, and the current mechanistic understanding of these processes.

A solventless carbonyl addition reaction as a guided inquiry laboratory activity for second-year undergraduate organic students

ABSTRACT A less hazardous, environmentally friendly, and energy-efficient Knoevenagel reaction performed using proline as a catalyst has been designed and implemented within a sophomore-level organic chemistry laboratory as a guided inquiry activity. The main learning objective is to enable students to identify and understand various green chemistry principles such as atom economy, use of safer chemicals, design for energy efficiency, and inherently safer chemistry for accident prevention. Students were successful in synthesizing α,β-unsaturated diesters using unknown substituted benzaldehydes (later identified by the students spectroscopically) and Meldrum’s acid at room temperature in the presence of proline as a catalyst without the need for an additional base. By analyzing 1H NMR spectroscopic data, infrared spectroscopy, and mass spectrometry to identify the synthesized product, the unknown benzaldehyde starting material, and the major reaction pathway, students have enhanced their spectroscopy skills and developed a deeper understanding of the mechanism of the reaction that may not be covered in the lecture course.

Cobalt-Catalyzed Asymmetric Hydrogenation of Ketones Enabled by the Synergism of an N-H Functionality and a Redox-Active Ligand.

The transition metal-catalyzed asymmetric hydrogenation (AH) of ketones to produce enantioenriched alcohols is an important reaction in organic chemistry with applications in the pharmaceutical and agrochemical fields. Using earth-abundant, biorelevant cobalt as the central metal in the catalyst has a high potential to improve sustainability and achieve hydrogenation reactions that are scalable. However, due to the high d-electron count, designing cobalt catalysts that exhibit turnover numbers (TONs, ≥1000) and enantioselectivities (≥90%) sufficient for synthetic utility and practical scalability (≥1 kg scale) remains a challenge. In this work, an efficient catalyst design strategy utilizing an amino(imino)diphosphine Co(II) bromide precatalyst is presented to achieve this goal. The quantitative production of a wide range of secondary chiral alcohols with TONs of up to 150,000 and an enantiomeric excess (e.e.) of up to 99% at a scale of up to 1.35 kg was achieved, indicating that the proposed cobalt catalyst is highly promising for AH and scale-up reactions. A mechanistic study revealed that the synergism of an N-H functionality and a redox-active ligand endows the cobalt catalyst with a high productivity and excellent enantioselectivity.

Synthesis, Characterization, and Biological Evaluation of Novel [M(η6-arene)2]+ (M = Re, 99mTc) Hosted Terpyridines and Copper Complexes Thereof.

We report the synthesis, characterization, and in vitro biological activities of [Re(η6-arene)2]+-terpyridine conjugates and their CuII complexes. The terpyridine (terpy) chelators were attached to the [Re(η6-arene)2]+ scaffold via secondary amine linkers allowing for heteroleptic mono- and homoleptic bis-terpyridine-substituted chelators. Complexation with CuCl2 afforded the respective square pyramidal [Cu(terpy)Cl2] complexes hosted on the [Re(η6-arene)2]+ scaffold. The chelator conjugates and their respective complexes were found to be remarkably cytotoxic against malignant HT29 and A549 human cancer cell lines in vitro with IC50 values in the low micromolar range. Mitochondrial respiration disruption was identified as a possible mode of action of these novel drug candidates. Crucially, the [Re(η6-arene)2]+ hosts delivered water solubility of the otherwise insoluble [Cu(terpy)Cl2] motif. Importantly, the homoleptic [99mTc(η6-arene)2]+-terpyridine conjugate is available in a single step, which enables the presented system to be used as a theranostic approach to modern medicinal inorganic chemistry.

Photoinduced Deconstructive Alkylation Approach Enabled by Oxy-Radicals from Alcohols.

Alcohols are the most commercially abundant, synthetically versatile and operationally convenient functional groups in organic chemistry. Therefore, a strategy that utilizes hydroxy-containing compounds to develop novel bond disconnection and formation process would achieve molecular diversity. Herein, a deconstructive strategy for the generation of quinoxalin-2(1H)-one derivatives has been developed from alcohol precursors via oxy-radical-induced β-fragmentation. Additionally, 1,5-HAT and deoxygenation by P(III) along with oxy-radical were demonstrated as alternative pathways for this transformation. Furthermore, with the deep-seated reorganization of a few terpenes carbon framework, a unique activity with inhibition against the growth of pathogenic fungi was observed.

Recent Progress in Synthetic Applications of Hypervalent Iodine(III) Reagents.

Hypervalent iodine(III) compounds have found wide application in modern organic chemistry as environmentally friendly reagents and catalysts. Hypervalent iodine reagents are commonly used in synthetically important halogenations, oxidations, aminations, heterocyclizations, and various oxidative functionalizations of organic substrates. Iodonium salts are important arylating reagents, while iodonium ylides and imides are excellent carbene and nitrene precursors. Various derivatives of benziodoxoles, such as azidobenziodoxoles, trifluoromethylbenziodoxoles, alkynylbenziodoxoles, and alkenylbenziodoxoles have found wide application as group transfer reagents in the presence of transition metal catalysts, under metal-free conditions, or using photocatalysts under photoirradiation conditions. Development of hypervalent iodine catalytic systems and discovery of highly enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important recent achievement in the field of hypervalent iodine chemistry. Chemical transformations promoted by hypervalent iodine in many cases are unique and cannot be performed by using any other common, non-iodine-based reagent. This review covers literature published mainly in the last 7-8 years, between 2016 and 2024.

Hydroxylamine‐O‐Sulfonic Acid (HOSA): A Recent Synthetic Overview

AbstractHydroxylamine‐O‐sulfonic acid has been used as a versatile nitrogen source in synthetic organic chemistry. It has dual function and utilized both as a nucleophile and an electrophile during different synthetic transformations. This reagent is stable and easy to handle in both aqueous and organic solvents. It can be used with different functional groups under mild reaction conditions, making its widely applicable for constructing complex molecules. It has been utilized for various applications such as agrochemicals, pharmaceuticals, and polymer industries in the formation of S−N, C−N, O−N, and N−N bonds, as well as for efficient cyclization reactions under metal‐free conditions with excellent stereo– and regioselectivity. The present review provides a brief overview of all the advancements made in the past two decades using hydroxylamine‐O‐sulfonic acid as a nitrogen source.