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1. Iterative Exponential Growth of Oxygen-Linked Aromatic Polymers Driven by Nucleophilic Aromatic Substitution Reactions

   https://doi.org/10.3389/fchem.2021.620017  

   Jaynes, Tyler J.; Sharafi, Mona; Campbell, Joseph P.; Bocanegra, Jessica; McKay, Kyle T.; Little, Kassondra; Osadchey Brown, Reilly; Gray, Danielle L.; Woods, Toby J.; Li, Jianing; et al (April 2021, Frontiers in Chemistry)

   null (Ed.)

   This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (S N Ar) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) 1 H- 1 H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C–H bonds of the electron-poor pyrimidine functions. Our results not only introduce a transition metal-free synthetic methodology to access precision polymers but also demonstrate how interactions between relatively small, neutral aromatic units in the polymers can be utilized as new supramolecular interaction pairs to control the folding of precision macromolecules. 

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2. Incorporation of Azapeptoid Residues Into Collagen

   https://doi.org/10.1002/pep2.70008  

   Wright, Madison M; Rathman, Benjamin M; Del_Valle, Juan R (September 2025, Peptide Science)

   Collagen, the major structural protein in connective tissue, adopts a right‐handed triple helix composed of peptide chains featuring repeating Gly‐Xaa‐Yaa tripeptide motifs. While the cyclic residues proline (Pro) and hydroxyproline (Hyp) are prevalent in the Xaa and Yaa positions due to their PPII‐favoring conformational properties, diverse acyclic peptoid (N‐alkylated Gly) residues can also stabilize the collagen fold. Here, we investigated the effects of N‐aminoglycine (aGly) derivatives—so‐called “azapeptoid” residues—on the thermal stability of collagen mimetic peptides (CMPs). Substitution of Pro at the central Xaa11 position with aGly resulted in destabilization of the triple helix, yet the introduction of select N′‐alkyl groups (isopropyl, butyl) partially restored thermal stability. Moreover, the N‐amino group of azapeptoid residues enhanced thermal CMP stability relative to an unsubstituted Gly analog. Kinetic studies revealed that the introduction of the hydrazide bonds in aGly and (iPr)aGly CMPs did not significantly impact triple helix refolding rates. Their modular late‐stage derivatization and tunable properties highlight azapeptoid residues as potentially valuable tools for engineering CMPs and probing the structural determinants of collagen folding. 

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3. N -Hydroxy peptides: solid-phase synthesis and β-sheet propensity

   https://doi.org/10.1039/D0OB00664E  

   Sarnowski, Matthew P.; Del Valle, Juan R. (May 2020, Organic & Biomolecular Chemistry)

   Peptide backbone amide substitution can dramatically alter the conformational and physiochemical properties of native sequences. Although uncommon relative to N -alkyl substituents, peptides harboring main-chain N -hydroxy groups exhibit unique conformational preferences and biological activities. Here, we describe a versatile method to prepare N -hydroxy peptide on solid support and evaluate the impact of backbone N -hydroxylation on secondary structure stability. Based on previous work demonstrating the β-sheet-stabilizing effect of α-hydrazino acids, we carried out an analogous study with N -hydroxy-α-amino acids using a model β-hairpin fold. In contrast to N -methyl substituents, backbone N -hydroxy groups are accommodated in the β-strand region of the hairpin without energetic penalty. An enhancement in β-hairpin stability was observed for a di- N -hydroxylated variant. Our results facilitate access to this class of peptide derivatives and inform the use of backbone N -hydroxylation as a tool in the design of constrained peptidomimetics. 

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4. Remolding and Deconstruction of Industrial Thermosets via Carboxylic Acid-Catalyzed Bifunctional Silyl Ether Exchange

   https://doi.org/10.1021/jacs.2c11858  

   Husted, Keith E.; Brown, Christopher M.; Shieh, Peyton; Kevlishvili, Ilia; Kristufek, Samantha L.; Zafar, Hadiqa; Accardo, Joseph V.; Cooper, Julian C.; Klausen, Rebekka S.; Kulik, Heather J.; et al (January 2023, Journal of the American Chemical Society)

   Convenient strategies for the deconstruction and reprocessing of thermosets could improve the circularity of these materials, but most approaches developed to date do not involve established, high-performance engineering materials. Here, we show that bifunctional silyl ether, i.e., R′O–SiR2–OR′′, (BSE)-based comonomers generate covalent adaptable network analogues of the industrial thermoset polydicyclopentadiene (pDCPD) through a novel BSE exchange process facilitated by the low-cost food-safe catalyst octanoic acid. Experimental studies and density functional theory calculations suggest an exchange mechanism involving silyl ester intermediates with formation rates that strongly depend on the Si–R2 substituents. As a result, pDCPD thermosets manufactured with BSE comonomers display temperature- and time-dependent stress relaxation as a function of their substituents. Moreover, bulk remolding of pDCPD thermosets is enabled for the first time. Altogether, this work presents a new approach toward the installation of exchangeable bonds into commercial thermosets and establishes acid-catalyzed BSE exchange as a versatile addition to the toolbox of dynamic covalent chemistry. 

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5. Glycine in Water Favors the Polyproline II State

   https://doi.org/10.3390/biom10081121  

   Andrews, Brian; Zhang, Shuting; Schweitzer-Stenner, Reinhard; Urbanc, Brigita (August 2020, Biomolecules)

   null (Ed.)

   Conformational preferences of amino acid residues in water are determined by the backbone and side-chain properties. Alanine is known for its high polyproline II (pPII) propensity. The question of relative contributions of the backbone and side chain to the conformational preferences of alanine and other amino acid residues in water is not fully resolved. Because glycine lacks a heavy-atom side chain, glycine-based peptides can be used to examine to which extent the backbone properties affect the conformational space. Here, we use published spectroscopic data for the central glycine residue of cationic triglycine in water to demonstrate that its conformational space is dominated by the pPII state. We assess three commonly used molecular dynamics (MD) force fields with respect to their ability to capture the conformational preferences of the central glycine residue in triglycine. We show that pPII is the mesostate that enables the functional backbone groups of the central residue to form the most hydrogen bonds with water. Our results indicate that the pPII propensity of the central glycine in GGG is comparable to that of alanine in GAG, implying that the water-backbone hydrogen bonding is responsible for the high pPII content of these residues. 

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