The reactive intermediates known as acylketenes exhibit a rich chemistry and have been extensively utilized for many types of inter- and intramolecular bond-forming reactions within the field of organic synthesis. Characteristic reactions of acylketenes include cycloadditions, carbon–carbon bond-forming reactions, and nucleophilic capture with alcohols or amines to give β-keto acid derivatives. In particular, the intramolecular capture of acylketene intermediates with pendant nucleophiles represents a powerful method for forming both medium-sized rings and macrocycles, often in high yield. This tutorial review examines the history, generation, and reactivity of acylketenes with a special focus on their applications in the synthesis of natural products.

Aromatic polyamide thin-film composite membranes are widely used in reverse osmosis (RO) and nanofiltration (NF) due to their high water permeability and selectivity. However, these membranes undergo biofouling and can degrade and eventually fail during free chlorine exposure. To better understand this effect, the reactivity of the polyamide monomer (benzanilide (BA)) with free chlorine was tested under varying pH and chloride (Cl − ) conditions. The kinetic results indicated that the current existing mechanisms, especially the Orton rearrangement, were invalid. Revised reaction pathways were proposed where BA chlorination was driven by two independent pathways involving the anilide ring and amide nitrogen moieties. The ability for one moiety to be chosen over the other was highly dependent on the pH, Cl − concentration, and the resulting chlorinating agents (e.g., Cl 2 , HOCl, OCl − , and Cl 2 O) generated. Species-specific rate constants for BA with Cl 2 , OCl − , and HOCl equaled (7.6 ± 0.19) × 10 1 , (1.7 ± 1.5) × 10 1 , (2.1 ± 0.71) × 10 −2 M −1 s −1 , respectively. A similar value for Cl 2 O could not be accurately estimated under the tested conditions. The behavior of these chlorinating agents differed for each reactive site such that OCl − > HOCl for N-chlorination and Cl 2 > HOCl > OCl − for anilide ring chlorination. Experiments with modified monomers indicated that substituent placement largely affected which reactive site was kinetically favorable. Overall, such findings provide a predictive model of how the polyamide monomer degrades during chlorine exposure and guidance on how chlorine-resistant polyamide membranes should be designed.

Although Cl 2 and Cl 2 O have been recognized as highly reactive constituents of free available chlorine (FAC), robust rate constants for Cl 2 and Cl 2 O remain scarce in the environmental literature. In this work, we explored the chlorination kinetics of three structurally related alkenes (α-ionone, β-ionone, and dehydro-β-ionone), a class of compounds whose reactivities with Cl 2 and Cl 2 O have not been previously investigated. Second-order rate constants for Cl 2 , Cl 2 O, and HOCl were computed from experimental rate constants obtained at various pH values, [Cl − ], and [FAC]. Our results show that while HOCl is the predominant chlorinating agent for the most reactive alkene, Cl 2 and Cl 2 O can dominate the chlorination kinetics of the less reactive alkenes at high [Cl − ] and high [FAC], respectively. The tradeoff between overall reactivity with FAC and selectivity for Cl 2 and Cl 2 O previously observed for aromatic compounds also applies to the alkenes examined. In laboratory experiments in which high [FAC] may be used, omission of Cl 2 O in data modeling could yield second-order rate constants of dubious validity. In chlorinating real waters with elevated [Cl − ], formation of Cl 2 may enhance the formation kinetics of chlorinated disinfection byproducts (DBPs) and exacerbate the burden of DBP control for water utilities.

A tandem ketene-trapping/Diels–Alder cyclization sequence was the pivotal transformation in an efficient, asymmetric synthesis of a decahydrofluorene tricyclic structure possessing eight stereogenic centers and key features of the hirsutellone class of antitubercular natural products. The hirsutellone-like β-keto ester that was fashioned by this sequence (thirteen steps; 6% overall yield) demonstrated significant inhibitory activity against Mycobacterium tuberculosis. The mechanism of action of this antitubercular compound is not yet known.

1,3,5-Trimethoxybenzene can be used to quench residual chlorine and bromine without altering disinfection byproducts that are reactive toward traditional quenchers.

The first total syntheses of the natural products pyrophen and campyrones A-C, isolated from the fungus Aspergillus niger, have been achieved in six steps starting from commercially available N-Boc amino acids. Key steps in this sequence include a vinylogous Claisen condensation to achieve fragment coupling and a dioxinone thermolysis/cyclization cascade to form the α-pyrone ring. The route described herein afforded the natural products in 15-25% overall yield, furnishing sufficient material for testing in biological assays.

Electrophilic aromatic substitution reactions can initiate halogenated disinfection byproduct (DBP) formation. The rate-controlling step (RCS) of electrophilic aromatic halogenation is commonly assumed to be halogen addition (vs proton removal), although this assumption has not been previously assessed under water disinfection conditions. Herein, the herbicide dimethenamid (DM) was used as a model aromatic compound to examine the RCS of halogenation in water treated with free chlorine (chlorination), free chlorine and bromide (bromination), or monochloramine and iodide (iodination). Hydrogen–deuterium kinetic isotope effects (KIEs) were determined using DM (k H) and deuterated DM (k D) in separate reactors. DM chlorination and bromination exhibited no KIE (k H/k D ≈ 1), supporting halogen addition as the RCS. Iodination did, however, exhibit primary KIEs (k H/k D > 1.4), demonstrating some degree of proton removal in the RCS. Increasing the pH (5.2–8.9) and I– concentration (10–100 μM) suppressed iodination rates but did not significantly affect KIEs (1.47–2.06), suggesting that iodine addition is rate-controlling under these conditions ([Cl–] = 15 μM). In contrast, adding 25–100 mM Cl– increased the KIE in iodination (2.85–3.42), reflecting a shift in kinetic control toward proton removal. This study delineates how chloride can both enhance and inhibit electrophilic aromatic iodination, which has implications for I-DBP formation in halide-rich water.

This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring forming, nucleophilic capture of a transient acyl ketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B.