Formation Of Linkages Research Articles

Unprecedented Benzoquinone Motifs Reveal Post-Oligomerizational Modification of Proanthocyanidins.

Proanthocyanidins (PACs) are complex flavan-3-ol polymers with stunning chemical complexity due to oxygenation patterns, oxidative phenolic ring linkages, and intricate stereochemistry of their heterocycles and inter-flavan linkages. Being promising candidates for dental restorative biomaterials, trace analysis of dentin bioactive cinnamon PACs now yielded novel trimeric (1 and 2) and tetrameric (3) PACs with unprecedented o- and p-benzoquinone motifs (benzoquinonoid PACs). Challenges in structural characterization, especially their absolute configuration, prompted the development of a new synthetic-analytical approach involving comprehensive spectroscopy, including NMR with quantum mechanics-driven 1H iterative functionalized spin analysis (HifSA) plus experimental and computational electronic circular dichroism (ECD). Vital stereochemical information was garnered from synthesizing 4-(2,5-benzoquinone)flavan-3-ols and a truncated analogue of trimer 2 as ECD models. Discovery of the first natural benzoquinonoid PACs provides new evidence to the experimentally elusive PAC biosynthesis as their formation requires two oxidative post-oligomerizational modifications (POMs) that are distinct and occur downstream from both quinone-methide-driven oligomerization and A-type linkage formation. While Nature is known to achieve structural diversity of many major compound classes by POMs, this is the first indication of PACs also following this common theme.

Structure and property variations of mixed hardwood kraft lignins

Kraft lignin as an emerging renewable feedstock can be used to produce fuels, chemicals, and materials. Hardwood kraft lignin bears intrinsic variation due to wood species and the isolation process. The structure and property variation of hardwood kraft lignin could introduce new challenges and opportunities for its application. To better understand such variation, seven kraft lignin samples, originated from southern mixed hardwood (North America), northern mixed hardwood (North America), and Asian mixed hardwood, were isolated from commercial kraft pulping black liquor using both LignoBoost and LignoForce processes. Modern analytical techniques were used to elucidate the characteristics of mixed hardwood kraft lignins, including chemical composition, molecular weight, functional groups, and thermal properties. All lignin samples had a lignin content over 90% (92% to 96%) with one exception, which was northern mixed hardwood kraft lignin with 86% of lignin content and 6% polysaccharides. The elemental and methoxy analyses revealed the expected variation of hardwood kraft lignins with the methoxy content ranging from 0.85 to 1.20 per C9 unit. The weight average molecular weight exhibited a higher variation (from 4800 to 1895 Da) with a descending order of southern mixed hardwood kraft lignins, northern mixed hardwood lignins, and Asian mixed hardwood lignins. The aliphatic hydroxy groups ranged from 14 to 25 per 100 C9 units, and phenolic hydroxy groups ranged from 65 to 112 per 100 C9 units. The catecholic group content ranged from 12 to 34 per 100 C9 units, which is higher than softwood kraft lignin. The lignins isolated from the rapid displacement heating (RDH) pulping process were more condensed than from the regular kraft pulping process. 2D HSQC and quantitative 13C NMR revealed the drastic structure change upon kraft pulp with the low abundance of native lignin linkages and formation of new interunit linkages, such as stilbene, enol ethers, and 1-1’/5’. The S/G ratio was calculated using 2D HSQC spectra correcting for signal shift caused by the catecholic groups.

Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.

There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease Mpro plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of Mpro. By comparing the efficacy of a panel of warheads installed on a common scaffold against Mpro, we discovered that the terminal alkyne could covalently modify Mpro as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of Mpro. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.

Sustainable polyurethane coatings based on functional Camelina oil-based polyols

Polyurethane (PU) coatings have garnered considerable attention across diverse applications and industries, owing to their versatile physiochemical attributes. Despite their widespread use, the environmental implications associated with their carbon footprint have raised concerns in recent years. To address this issue, we explored the potential of Camelina oil as a base chemical for synthesizing polyesteramide polyols as a viable alternative to petrochemical-based materials. Consequently, we formulated biocarbon-rich polyurethane coatings using the synthesized polyols. Initially, we synthesized a fatty amide intermediate through a transamidation reaction, involving the interaction of diethanolamine and triglyceride. Subsequently, we produced three distinct polyesteramide polyols using citric acid, itaconic acid, and phthalic acid. To confirm the formation of ester and amide linkages, we employed various structural analyses, including Nuclear Magnetic Resonance (NMR) and Fourier Transform Infrared (FTIR) spectroscopy, on the Camelina-oil-derived polyols. Furthermore, we utilized quantitative techniques such as titration to ascertain hydroxyl number, acid number, and amine value. Our structural analyses corroborated the establishment of ester linkage and the incorporation of OH functionality in Camelina oil, while titration results indicated a remarkable 1200 % surge in hydroxyl value. We subsequently employed the three polyesteramide polyols to fabricate polyurethane coatings, subjecting them to a battery of tests. The resultant biobased coatings were assessed using Dynamic Mechanical Analysis (DMA), Thermo-Gravimetric Analysis (TGA), and an array of surface characteristics such as gloss, hardness, impact resistance, water contact angle, and saline resistance. All tested samples exhibited satisfactory thermal stability, with the biocarbon content of the final PU coatings measuring at least 61.6 %. Moreover, our study demonstrates that the derived polyurethane coatings hold promise for non-wet applications, particularly in the realm of interior coatings.

Activation of Pyroptosis Using AIEgen-Based sp2 Carbon-Linked Covalent Organic Frameworks.

Covalent organic frameworks (COFs) have emerged as a promising class of crystalline porous materials for cancer phototherapy, due to their exceptional characteristics, including light absorption, biocompatibility, and photostability. However, the aggregation-caused quenching effect and apoptosis resistance often limit their therapeutic efficacy. Herein, we demonstrated for the first time that linking luminogens with aggregation-induced emission effect (AIEgens) into COF networks via vinyl linkages was an effective strategy to construct nonmetallic pyroptosis inducers for boosting antitumor immunity. Mechanistic investigations revealed that the formation of the vinyl linkage in the AIE COF endowed it with not only high brightness but also strong light absorption ability, long lifetime, and high quantum yield to favor the generation of reactive oxygen species for eliciting pyroptosis. In addition, the synergized system of the AIE COF and αPD-1 not only effectively eradicated primary and distant tumors but also inhibited tumor recurrence and metastasis in a bilateral 4T1 tumor model.

Electrochemical synthesis of biaryls by reductive extrusion from N,N’-diarylureas

The synthesis of biaryl compounds by the transition-metal free coupling of arenes is an important contemporary challenge, aiming to avoid the toxicity and cost profiles associated with the metal catalysts commonly used in the synthesis of these pharmaceutically relevant motifs. In this paper, we describe an electrochemical approach to the synthesis of biaryls in which aniline derivatives are coupled through the formation and reduction of a temporary urea linkage. The conformational alignment of the arenes in the N,N’-diaryl urea intermediates promotes C-C bond formation following single-electron reduction. Our optimized conditions are suitable for the synthesis of a variety of biaryls, including sterically hindered examples carrying ortho-substituents, representing complementary reactivity to most metal catalysed methods.

Drug delivery based on a supramolecular chemistry approach by using chitosan hydrogels

Microbial infections are a serious healthcare related problem, causing several complications and even death. That is why, the development of new drug delivery systems with prolonged effect represents an interesting research topic. This study presents the synthesis and characterization of new hydrogels based on chitosan and three halogenated monoaldehydes. Further, the hydrogels were used as excipients for the development of drug delivery systems (DDS) by the incorporation of fluconazole, an antifungal drug. The systems were structurally characterized by Fourier Transformed Infrared Spectroscopy and Nuclear Magnetic Resonance, both methods revealing the formation of the imine linkages between chitosan and the aldehydes. The samples presented a high degree of ordering at supramolecular level, as demonstrated by WXRD and POM and a good water-uptake, reaching a maximum of 1.6 g/g. The obtained systems were biodegradable, loosing between 38 and 49 % from their initial mass in the presence of lysozyme in 21 days. The ability to release the antifungal drug in a sustained manner for seven days, along with the high values of the inhibition zone diameter, reaching a maximum of 64 mm against Candida parapsilosis for the chlorine containing sample, recommend these systems as promising materials for bioapplications.

Chemical synthesis of oligosaccharide derivatives with partial structure of β1-3/1-6 glucan, using monomeric units for the formation of β1-3 and β1-6 glucosidic linkages.

β1-3/1-6 Glucans, known for their diverse structures, comprise a β1-3-linked main chain and β1-6-linked short branches. Laminarin, a β1-3/1-6 glucan extracted from brown seaweed, for instance, includes β1-6 linkages even in the main chain. The diverse structures provide various beneficial functions for the glucan. To investigate the relationship between structure and functionality, and to enable the characterization of β1-3/1-6 glucan-metabolizing enzymes, oligosaccharides containing the exact structures of β1-3/1-6 glucans are required. We synthesized the monomeric units for the synthesis of β1-3/1-6 mixed-linked glucooligosaccharides. 2-(Trimethylsilyl)ethyl 2-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside served as an acceptor in the formation of β1-3 linkages. Phenyl 2-O-benzoyl-4,6-O-benzylidene-3-O-(tert-butyldiphenylsilyl)-1-thio-β-d-glucopyranoside and phenyl 2,3-di-O-benzoyl-4,6-di-O-levulinyl-1-thio-β-d-glucopyranoside acted as donors, synthesizing acceptors suitable for the formation of β1-3- and β1-6-linkages, respectively. These were used to synthesize a derivative of Glcβ1-6Glcβ1-3Glcβ1-3Glc, demonstrating that the proposed route can be applied to synthesize the main chain of β-glucan, with the inclusion of both β1-3 and β1-6 linkages.

A comparative study between two carboxymethylated polysaccharides/protein electrostatic and cross-linked nanogels constructed for caffeic acid and eugenol delivery

In response to the pressing demand for functional nanomaterials synthesis and applications, two polyelectrolyte complexes (PECs) [electrostatic and cross-linked nanogels (NGs)] loaded individually with caffeic acid (CafA) and eugenol (Eug) demonstrating multifunctionalities were proposed for the first time. Curdlan (Curd) and glucomannan (GM) were carboxymethylated (CMCurd and CMGM) successfully and polymeric ratios of 1:1 and 4:1 (v/v) for chitosan (Cs): CMCurd and lactoferrin (Lf): CMGM were selected for the synthesis of Cs/CMCurd and Lf/CMGM NGs. Due to the use of EDC/NHS, Cs/CMCurd/CafA and Lf/CMGM/Eug NGs possessed very uniform particles sizes of 177 ± 18 and 230 ± 17 nm with marked encapsulation efficiencies (EEs) of 76 ± 4 and 88 ± 3 %, respectively. The formation of a carbonyl-amide linkage in both cross-linked NGs was confirmed by FTIR. It should be noted, the self-assembly was not reliable in retaining enough of the encapsulated compounds. Owing to the excellent physicochemical characteristics of the loaded cross-linked NGs, they were prioritized over the electrostatic ones. Both Cs/CMCurd/CafA and Lf/CMGM/Eug NGs exhibited high colloidal stability over 12 weeks, elevated hemocompatibility, and in vitro serum stability. The generated NGs were also tailored to possess controlled release profiles for CafA and Eug over 72 h. Cs/CMCurd/CafA and Lf/CMGM/Eug NGs had promising antioxidant efficacies and could remarkably inhibit 4 bacterial pathogens at low 2–16 μg/mL concentration of encapsulated NGs compared to their unencapsulated counterparts. Interestingly, the respective NGs could significantly decline the IC50 against colorectal cancer HCT-116 than conventional drugs. Based on these data, it was conferred that the investigated NGs could be promising candidates for functional foods and pharmaceutics.

Selective Sensing of Epinephrine by Phenylboronic Acid Tethered Carbon Dot.

The present work depicts development of phenylboronic acid (PBA) derived and appended carbon dots (CD1-PBAs) to detect epinephrine with high sensitivity and selectivity against structurally analogous biomolecules like norepinephrine, L-Dopa and glucose. Carbon dots were synthesized by hydrothermal method. Microscopic and spectroscopic studies ensured the suitability of CD1-PBAs for diol sensing. Catecholic-OH groups of epinephrine primarily form covalent adduct with CD1-PBAs via boronate-diol linkage that caused change in absorption intensity of CD1-PBAs. The limit of detection (LOD) for epinephrine was found to be 2.0 nM. For other analogous biomolecules, formation of boronate-diol linkage might have got retarded by the dominant participation of secondary interactions like hydrogen bonding owing to the presence of varying functional moieties. Subsequently, responsiveness in the change in absorbance intensity of CD1-PBAs was weaker compared to that for epinephrine. Hence, a selective and efficient carbon dot (CD1-PBAs) based epinephrine sensor was developed simply by utilizing boronate-diol linkage.

New Hydrogels Nanocomposites Based on Chitosan, 2-Formylphenylboronic Acid, and ZnO Nanoparticles as Promising Disinfectants for Duodenoscopes Reprocessing.

New hydrogels nanocomposites, based on iminoboronate hydrogels and ZnO nanoparticles (ZnO-NPs), were obtained and characterised in order to develop a new class of disinfectants able to fight the nosocomial infections produced by duodenoscopes investigation procedures. The formation of the imine linkages between chitosan and the aldehyde was demonstrated using NMR and FTIR spectroscopy, while the supramolecular architecture of the developed systems was evaluated via wide-angle X-ray diffraction and polarised optical microscopy. The morphological characterisation of the systems via scanning electron microscopy revealed the highly porous structure of the materials, in which no ZnO agglomeration could be observed, indicating the very fine and homogenous encapsulation of the nanoparticles into the hydrogels. The newly synthetised hydrogels nanocomposites was proven to have synergistic antimicrobial properties, being very efficient as disinfectants against reference strains as: Enterococcus faecalis, Klebsiella pneumoniae, and Candida albicans.

Ecotourism for transformative and youth development in sub-Saharan Africa: the role of corporate social responsibility in Nigeria’s oil host communities

ABSTRACT We examine the impact of multinational oil companies’ (MOCs) corporate social responsibility (CSR) initiatives on enabling youth participation in ecotourism development in the Niger Delta region of Nigeria. Results from the use of average treatment test of a combined propensity score matching and logit model indicate a significant difference between youths in MOCs’ CSR global memorandum of understanding (GMoU) households and non-GMoU households in the four parameters measured: availability of finance (3.76), access to adequate training (5.91), direct patronage (18.97), and economic capability of the youths (8.2). It shows that opportunities to supply products and services to the tourism sector can help ensure a sustainable market and increase incomes and other revenues in local communities driven from ecotourism-related activities, while minimizing economic leakages. This suggests that pro-youth GMoU ecotourism projects of MOCs have the potential to play in the formation of linkages to help promote local economic development through job creation and business opportunities. It implies that a younger generation can help to promote economic diversification and contribute to job creation and enterprise development, while helping to address underdevelopment in remoe areas and intractable environmental challenges of sub-Saharan Africa.

Kraft Lignin Periodate Oxidation for Biobased Wood Panel Resins

The development of biobased resins with high-bonding performance has gained considerable attention in the wood industry. In this study, we developed biobased novolacs phenol-formaldehyde (BNPF) resins by partially replacing petroleum-based phenol and formaldehyde with lignin derived from kraft biorefinery and modified kraft biorefinery-derived lignin, respectively. We first performed a mild and efficient chemical modification of the lignin through the periodate oxidation process. Sodium periodate was used to oxidize the hydroxyl functional groups present in the interunit linkages (β-O-4 bond) in the lignin structure and convert lignin partly to quinones. This was assessed by Fourier-transform infrared spectroscopy, elemental analysis, solid-state 1H–13C 2D HETCOR NMR, and aldehyde content analysis. We synthesized a series of BNPF resins by replacing phenol with lignin, then by replacing formaldehyde with oxidized lignin, and finally by replacing both phenol and formaldehyde with lignin and oxidized lignin. The structural characterization results of the NPF resins revealed the formation of methylene linkages in the phenolic rings. Before application as wood adhesives, we studied the curing behavior of the formulated adhesive via differential scanning calorimetry. The adhesion strength of the adhesive was determined using the tensile shear strength analysis. The bonding performance tests indicated that BNPF resin adhesives have high adhesion strengths (>0.7 MPa). The outcome of this research provides a promising perspective to utilize natural polymers such as lignin for the synthesis of biobased wood adhesives.

Uranium Phthalocyanine-Anchored Acid-Functionalized Multiwalled Carbon Nanotubes for Water Electrolysis

One of the major challenges in the commercial production of hydrogen and oxygen from the electrochemical water splitting reaction is the nonavailability of potential and low-cost electrocatalysts for the enhancement of both the half-cell reactions. The bifunctional catalyst capable of demonstrating lower overpotentials for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) eliminates the usage of a membrane, simplifies the overall system design, reduces the cost, and enhances the electrochemical water splitting activity. Here, a bifunctional hybrid composite catalyst comprising an organic N4 macrocycle and acid-functionalized multiwalled carbon nanotubes (MWCNTs) is fabricated and tested for the water splitting reaction to produce H2 and O2. The uranium tetra[4-(2-{(E)-[(4-bromophenyl)imino]methyl}phenoxy)]phthalocyanine (UTBrImPc) is synthesized via a two-step process of imine and oxy-bridge linkage formation. The synthesized ligands and phthalocyanine macrocycle are characterized using various spectroscopic and analytical techniques. The glassy carbon electrode (GCE) and Ni foam are used as the conducting substrate for the fabrication of the UTBrImPc/MWCNT bifunctional electrode to generate H2 and O2. Surprisingly, the fabricated bifunctional hybrid catalyst on the GCE exhibited a lesser overpotential of 15 mV for the HER, which is close to that of the benchmark Pt/C catalyst. Furthermore, the Ni/UTBrImPc/MWCNT displayed a lower overpotential of 368 (±2) mV at a current density of 10 mA·cm–2 for the OER, which is close to the overpotential shown by the precious benchmark catalyst IrO2. In addition, the fabricated electrodes showed remarkable long-term stability for more than 20 h by a chronoamperometric method. The superior results for both the HER and OER at the composite organic hybrid catalyst may be due to the collusive effect of the acid-functionalized MWCNTs with UTBrImPc, which enhances the electronic conductivity and surface area. The developed state-of-the-art catalyst can be employed as a bifunctional catalyst in water electrolyzers.

Innentitelbild: Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity (Angew. Chem. 28/2023)

A scrambled but selective polycondensation reaction introduced the simplest route to generate porous poly(aryl thioether)s. Through a multi-para nucleophilic substitution of perfluoroaromatic compounds with sodium sulfide, temperature-dependent formation of thioether linkages leads to stepwise transition of the polymers into network structures with controllable porosity and bandgap, as reported by Jeehye Byun, Sheng Li, Cafer T. Yavuz et al. in their Research Article (e202304378).

Inside Cover: Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity (Angew. Chem. Int. Ed. 28/2023)

A scrambled but selective polycondensation reaction introduced the simplest route to generate porous poly(aryl thioether)s. Through a multi-para nucleophilic substitution of perfluoroaromatic compounds with sodium sulfide, temperature-dependent formation of thioether linkages leads to stepwise transition of the polymers into network structures with controllable porosity and bandgap, as reported by Jeehye Byun, Sheng Li, Cafer T. Yavuz et al. in their Research Article (e202304378).

Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SNAr for Tunable Bandgap and Porosity

AbstractPorous poly(aryl thioether)s offer stability and electronic tunability by robust sulfur‐aryl conjugated architecture, but synthetic access is hindered due to limited control over the nucleophilic nature of sulfides and the air sensitivity of aromatic thiols. Here, we report a simple, one‐pot, inexpensive, regioselective synthesis of highly porous poly(aryl thioether)s through polycondensation of perfluoroaromatic compounds with sodium sulfide. The unprecedented temperature‐dependent para‐directing formation of thioether linkages leads to a stepwise transition of the polymer extension into a network, thereby allowing fine control of the porosity and optical band gaps. The obtained porous organic polymers with ultra‐microporosity (<1 nm) and sulfur as the surface functional groups show size‐dependent separation of organic micropollutants and selective removal of mercury ions from water. Our findings offer easy access to poly(aryl thioether)s with accessible sulfur functionalities and higher complexity, which will help in realizing advanced synthetic designs in applications such as adsorption, (photo)catalysis, and (opto)electronics.

Covalent Scrambling in Porous Polyarylthioethers through a Stepwise SN Ar for Tunable Bandgap and Porosity.

Porous poly(aryl thioether)s offer stability and electronic tunability by robust sulfur-aryl conjugated architecture, but synthetic access is hindered due to limited control over the nucleophilic nature of sulfides and the air sensitivity of aromatic thiols. Here, we report a simple, one-pot, inexpensive, regioselective synthesis of highly porous poly(aryl thioether)s through polycondensation of perfluoroaromatic compounds with sodium sulfide. The unprecedented temperature-dependent para-directing formation of thioether linkages leads to a stepwise transition of the polymer extension into a network, thereby allowing fine control of the porosity and optical band gaps. The obtained porous organic polymers with ultra-microporosity (<1 nm) and sulfur as the surface functional groups show size-dependent separation of organic micropollutants and selective removal of mercury ions from water. Our findings offer easy access to poly(aryl thioether)s with accessible sulfur functionalities and higher complexity, which will help in realizing advanced synthetic designs in applications such as adsorption, (photo)catalysis, and (opto)electronics.

Waste Not, Want Not: Sustainable Use of Anti-Stripping-Treated Waste Ceramic in Superpave Asphalt Mixtures

This research studied the sustainable utilization of waste ceramic in asphalt mixtures by substituting fine aggregate with treated and untreated waste ceramic produced from construction and demolition activities. To improve its adhesion to the asphalt binder and lower the moisture susceptibility of Superpave asphalt mixes, the waste ceramic was treated with a silane anti-stripping agent. The Marshall quotient (MQ), Marshall stability (MS), indirect tensile strength (ITS), retained Marshall stability (RMS), and tensile strength ratio (TSR) were used to assess the mechanical performance and moisture susceptibility of all mixes. The changes in the chemical composition, synergy, physical state, and microstructure of the studied composites were also investigated using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results revealed that substituting fine aggregate with 50% silane-treated waste ceramics reduced permanent deformation by 46%. Moreover, integrating silane-treated ceramics reduced asphalt mixture moisture susceptibility, with an RMS value of 87.7% obtained for asphalt containing 75% treated ceramic particles. The application of a silane anti-stripping agent resulted in high adhesion between the ceramic particles and bitumen as well as the production of fewer air voids in the mixes due to the formation of strong CH aromatic linkages, as well as Si-O and Si-O-Si bonds. The possibility of employing waste ceramics in asphalt mixes as a sustainable alternative to virgin aggregates while decreasing environmental impacts and improving resource efficiency is highlighted in this paper.

Nanomole‐scale photochemical thiol‐ene chemistry for high‐throughput late‐stage diversification of peptide macrocycles

AbstractThe photochemical thiol‐ene reaction is an efficient method for rapid and chemoselective formation of thioether linkages under mild conditions. It has found widespread use in small‐molecule synthesis as well as peptide and protein chemistry. While high‐throughput experimentation provides an invaluable tool for drug discovery, the considerable potential of the thiol‐ene reaction remains unexplored in this context. Herein, we report the development of nanomole‐scale photochemical thiol‐ene chemistry, performed using an automated approach in 1536‐well plates in a cost‐efficient custom reactor. Through careful reaction design and selection of reactants, this chemistry is applied to the lateral diversification of peptidic macrocycles to yield high purity crude mixtures. Selection of the photoinitiator 2,2‐dimethoxy‐2‐phenylacetophenone yields volatile breakdown products, which facilitates removal in vacuo. We demonstrate the use of this approach in late‐stage diversification of peptidic macrocycles with 96 examples averaging 95% conversion to the desired product.