On the Conformation of Anionic Peptoids in the Gas Phase.

Although N-(S)-phenylethyl peptoids are known to adopt helical structures in solutions, the corresponding positively charged ions lose their helical structure during the transfer from the solution to the gas phase due to the so-called charge solvation effect. We, here, considered negatively charged peptoids to investigate by ion mobility spectrometry-mass spectrometry whether the structural changes described in the positive ionization mode can be circumvented in the negative mode by a fine-tuning of the peptoid sequence, that is, by positioning the negative charge at the positive side of the helical peptoid macrodipole. N-(S)-(1-carboxy-2-phenylethyl) (Nscp) and N-(S)-phenylethyl (Nspe) were selected as the negative charge carrier and as the helix inductor, respectively. We, here, report the results of a joint theoretical and experimental study demonstrating that the structures adopted by the NspenNscp anions remain compactly folded in the gas phase for chains containing up to 10 residues, whereas no evidence of the presence of a helical structure was obtained, even if, for selected sequences and lengths, different gas phase conformations are detected.

Controlled Oxyanionic Polymerization of Propylene Oxide: Unlocking the Molecular-Weight Limitation by a Soft Nucleophilic Catalysis.

The oxyanionic ring-opening polymerization of propylene oxide (PO) from an exogenous alcohol activated with benign (complexed) metal-alkali carboxylates is described. The equimolar mixture of potassium acetate (KOAc) and 18-crown-6 ether (18C6) is demonstrated to be the complex of choice for preparing poly(propylene oxide) (PPO) in a controlled manner. In the presence of 18C6/KOAc, hydrogen-bonded alcohols act as soft nucleophiles promoting the PO SN 2 process at room temperature and in solvent-free conditions while drastically limiting the occurrence of parasitic hydrogen abstraction generally observed during the anionic ROP of PO. The resulting PPO displays predictable and unprecedented molar masses (up to 20 kg mol-1 ) with low dispersities (DM < 1.1), rendering the 18C6/KOAc complex the most performing activator for the oxyanionic polymerization of PO reported to date. Preliminary studies on the preparation of block and statistical copolyethers are also reported.

Helical Peptoid Ions in the Gas Phase: Thwarting the Charge Solvation Effect by H-Bond Compensation.

Folding and unfolding processes are key aspects that should be mastered for the design of foldamer molecules for targeted applications. In contrast to the solution phase, in vacuo conditions represent a well-defined environment to analyze the intramolecular interactions that largely control the folding/unfolding dynamics. Ion mobility mass spectrometry coupled to theoretical modeling represents an efficient method to decipher the spatial structures of gaseous ions, including foldamers. However, charge solvation typically compacts the ion structure in the absence of strong stabilizing secondary interactions. This is the case in peptoids that are synthetic peptide regioisomers whose side chains are connected to the nitrogen atoms of the backbone instead of α-carbon as in peptides, thus implying the absence of H-bonds among the core units of the backbone. A recent work indeed reported that helical peptoids based on Nspe units formed in solution do not retain their secondary structure when transferred to the gas phase upon electrospray ionization (ESI). In this context, we demonstrate here that the helical structure of peptoids bearing (S)-N-(1-carboxy-2-phenylethyl) bulky side chains (Nscp) is largely preserved in the gas phase by the creation of a hydrogen bond network, induced by the presence of carboxylic moieties, that compensates for the charge solvation process.

Organocatalytic Synthesis of Alkyne-Functional Aliphatic Polycarbonates via Ring-Opening Polymerization of an Eight-Membered-N-Cyclic Carbonate.

The synthesis of well-defined propargyl-functional aliphatic polycarbonates is achieved via the organocatalytic ring-opening polymerization of prop-2-yn-1-yl 2-oxo-1,3,6-dioxazocane-6-carboxylate (P-8NC) using a wide variety of commercially available or readily made, shelf-stable organocatalysts. The resulting homopolymers show low dispersities and end-group fidelity, with the versatility of the system being demonstrated by the synthesis of telechelic copolymers and block copolymers with molar mass up to 40 kDa.

Limitations of ion mobility spectrometry-mass spectrometry for the relative quantification of architectural isomeric polymers: A case study.

Since their discovery, cyclic polymers have attracted great interest because of their unique properties. Today, the preparation of these macrocyclic structures still remains a challenge for polymer chemists, and most of the preparation pathways lead to an inescapable contamination by linear by-products. As the properties of the polymers are closely related to their structure, it is of prime importance to be able to assess the architectural purity of a sample. METHODS: In this work, the suitability of ion mobility spectrometry-mass spectrometry (IMS-MS) for the quantification of two isomers was investigated. A cyclic poly(L-lactide) was prepared through photodimerization of its linear homologue. Since IMS-MS can be used to differentiate cyclic polymer ions from their linear analogues because of their more compact three-dimensional conformation, the present work envisaged the use of IMS-MS for the quantification of residual linear polymers within the cyclic polymer sample. RESULTS: Using the standard addition method to plot calibration curves, the fraction of linear contaminants in the sample was determined. By doing so, unrealistically high values of contamination were measured. CONCLUSIONS: These results were explained by an ionization efficiency issue. This work underlines some intrinsic limitations when using IMS-MS in the context of the relative quantification of isomers having different ionization efficiencies. Nevertheless, the linear-to-cyclic ratio can be roughly estimated by this method.

Bulk Organocatalytic Synthetic Access to Statistical Copolyesters from l-Lactide and ε-Caprolactone Using Benzoic Acid.

The development of synthetic strategies to produce statistical copolymers based on l-lactide (l-LA) and ε-caprolactone (CL), denoted as P(LA- stat-CL), remains highly challenging in polymer chemistry. This is due to the differing reactivity of the two monomers during their ring-opening copolymerization (ROcP). Yet, P(LA- stat-CL) materials are highly sought after as they combine the properties of both polylactide (PLA) and poly(ε-caprolactone) (PCL). Here, benzoic acid (BA), a naturally occurring, cheap, readily recyclable, and thermally stable weak acid, is shown to trigger the organocatalyzed ring-opening copolymerization (OROcP) of l-LA and CL under solvent-free conditions at 155 °C, in presence of various alcohols as initiators, with good control over molar masses and dispersities (1.11 < D < 1.35) of the resulting copolyesters. Various compositions can be achieved, and the formation of statistical compounds is shown through characterization by 1H, 13C, and diffusion ordered spectroscopy NMR spectroscopies and by differential scanning calorimetry, as well as through the determination of reactivity ratios ( rLA = 0.86, rCL = 0.86), using the visualization of the sum of squared residuals space method. Furthermore, this BA-OROcP process can be exploited to access metal-free PLA- b-P(LA- stat-CL)- b-PLA triblock copolymers, using a diol as an initiator. Finally, residual traces of BA remaining in P(LA- stat-CL) copolymers (<0.125 mol %) do not show any cytotoxicity toward hepatocyte-like HepaRG cells, demonstrating the safety of this organic catalyst.

Photoactive Boron-Nitrogen-Carbon Hybrids: From Azo-borazines to Polymeric Materials.

In this paper, we describe synthetic routes for preparing a novel switchable BNC-based chromophore, composed of a borazine core peripherally functionalized with azobenzene moieties. Capitalizing on the Pd-catalyzed Suzuki cross-coupling reaction between a tris-triflate borazine and an organoboron azobenzene derivative, a photoswtichable azo-borazine derivative was successfully prepared. The molecule showed reversible E/Z photoisomerization upon irradiation at the maximum of the intense π-π* absorption feature (360 nm). X-ray crystallographic investigations revealed a nonplanar orientation of the three azobenzene moieties and the trans configuration of the -N═N- bonds. Building on the synthetic versatility of the borazine-azobenzene derivative, we used this photoactive scaffold to engineer soluble BN-doped polythiophene polymers. Photophysical characterization performed in solvents of different polarity suggested that the polymer undergoes intramolecular charge transfer (ICT).

Synthesis and Characterization of Double Crystalline Cyclic Diblock Copolymers of Poly(ε-caprolactone) and Poly(l(d)-lactide) (c(PCL-b- PL(D)LA)).

The synthesis of symmetric cyclo poly(ε-caprolactone)-block-poly(l(d)-lactide) (c(PCL-b-PL(D)LA)) by combining ring-opening polymerization of ε-caprolactone and lactides and subsequent click chemistry reaction of the linear precursors containing antagonist functionalities is presented. The two blocks can sequentially crystallize and self-assemble into double crystalline spherulitic superstructures. The cyclic chain topology significantly affects both the nucleation and the crystallization of each constituent, as gathered from a comparison of the behavior of linear precursors and cyclic block copolymers. The stereochemistry of the PLA block does not have a significant effect on the nonisothermal crystallization of both linear and cyclo PCL-b-PDLA and PCL-b-PLLA copolymers.

Cyclic Polymers by Ring-Closure Strategies.

The preparation of cyclic macromolecules has always represented a challenging task for polymer science, mainly because of difficulties in connecting chain extremities together. Initiated by the pioneering studies of Jacobson and Stockmayer, preparative pathways to cyclic polymers have been considerably improved within the last two decades thanks to the advent of both controlled polymerizations and efficient coupling reactions in organic chemistry. This Review aims to provide a critical up-to-date overview and illustrate the considerable efforts that have been made in the past few years to improve the availability of macrocycles for industrial and academic investigations through the use of the ring-closure approach. Particular attention is paid to methods for the preparation of monocycles over more complex architectures, since the latter are usually derived from the former.

Organocatalysis paradigm revisited: are metal-free catalysts really harmless?

Catalysts are commonly used in polymer synthesis. Traditionally, catalysts used to be metallic compounds but some studies have pointed out their toxicity for human health and environment, and the removal of metal impurities from synthetic polymer is quite expensive. Organocatalysts have been intensively synthesized and are now widely used in ring-opening polymerization (ROP) reactions to address these issues. However, for most of them, there is not any evidence of their safety. The present study attempts to assess whether well-established organo-based ROP catalysts used for the preparation of FDA-approved polyesters may present a certain level of cytotoxicity. In vitro toxicity is evaluated using a methyl-thiazol-tetrazolium cytotoxicity assay on two cell models (FHs74Int and HepaRG). Among the investigated organocatalysts, only functionalized thiourea shows an important cytotoxicity on both cell models. 4-Dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and meta-(trimethylammonio)phenolate betaine (m-BE) show cytotoxicity against HepaRG cell line only at a high concentration.

Synthesis and post-polymerisation modifications of aliphatic poly(carbonate)s prepared by ring-opening polymerisation.

Owing to their low toxicity, biocompatibility and biodegradability, aliphatic poly(carbonate)s have been widely studied as materials for biomedical application. Furthermore, the synthetic versatility of the six-membered cyclic carbonates for the realization of functional degradable polymers by ring-opening polymerisation has driven wider interest in this area. In this review, the synthesis and ring-opening polymerisation of functional cyclic carbonates that have been reported in the literature in the past decade are discussed. Finally, the post-polymerisation modification methods that have been applied to the resulting homopolymers and copolymers and the application of the materials are also discussed.

Stereocomplexed Functional and Statistical Poly(lactide-carbonate)s via a Simple Organocatalytic System.

The stereocomplexation of polylactide (PLA) has been widely relied upon to develop degradable, sustainable materials with increased strength and improved material properties in comparison to stereopure PLA. However, forming functionalized copolymers of PLA while retaining high crystallinity remains elusive. Herein, the controlled ring-opening copolymerization (ROCOP) of lactide (LA) and functionalized cyclic carbonate monomers is undertaken. The produced polymers are shown to remain crystalline up to 25 mol % carbonate content and are efficiently stereocomplexed with homopolymer PLA and copolymers of opposite chirality. Polymers with alkene and alkyne pendent handles are shown to undergo efficient derivatization with thiol-ene click chemistry, which would allow both the covalent conjugation of therapeutic moieties and tuning of material properties.

RGD-tagging of star-shaped PLA-PEG micellar nanoassemblies enhances doxorubicin efficacy against osteosarcoma.

We developed cyclic RGD-tagged polymeric micellar nanoassemblies for sustained delivery of Doxorubicin (Dox) endowed with significant cytotoxic effect against MG63, SAOS-2, and U2-OS osteosarcoma cells without compromising the viability of healthy osteoblasts (hFOBs). Targeted polymeric micellar nanoassemblies (RGD-NanoStar@Dox) enabled Dox to reach the nucleus of MG63, SAOS-2, and U2-OS cells causing the same cytotoxic effect as free Dox, unlike untargeted micellar nanoassemblies (NanoStar@Dox) which failed to reach the nucleus and resulted ineffective, demonstrating the crucial role of cyclic RGD peptide in driving cellular uptake and accumulation mechanisms in osteosarcoma cells. Micellar nanoassemblies were obtained by nanoformulation of three-armed star PLA-PEG copolymers properly synthetized with and without decoration with the cyclic-RGDyK peptide (Arg-Gly-Asp-D-Tyr-Lys). The optimal RGD-NanoStar@Dox nanoformulation obtained by nanoprecipitation method (8 % drug loading; 35 % encapsulation efficiency) provided a prolonged and sustained drug release with a rate significantly lower than the free drug under the same experimental conditions. Moreover, the nanosystem preserved Dox from the natural degradation occurring under physiological conditions (i.e., dimerization and consequent precipitation) serving as a slow-release "drug reservoir" ensuring an extended biological activity over the time.

Porphyrins fused to N-heterocyclic carbenes (NHCs): modulation of the electronic and catalytic properties of NHCs by the central metal of the porphyrin.

We report herein a detailed study of the use of porphyrins fused to imidazolium salts as precursors of N-heterocyclic carbene ligands 1 M. Rhodium(I) complexes 6 M-9 M were prepared by using 1 M ligands with different metal cations in the inner core of the porphyrin (M=Ni(II) , Zn(II) , Mn(III) , Al(III) , 2H). The electronic properties of the corresponding N-heterocyclic carbene ligands were investigated by monitoring the spectroscopic changes occurring in the cod and CO ancillary ligands of [(1 M)Rh(cod)Cl] and [(1 M)Rh(CO)2 Cl] complexes (cod=1,5-cyclooctadiene). Porphyrin-NHC ligands 1 M with a trivalent metal cation such as Mn(III) and Al(III) are overall poorer electron donors than porphyrin-NHC ligands with no metal cation or incorporating a divalent metal cation such as Ni(II) and Zn(II) . Imidazolium salts 3 M (M=Ni, Zn, Mn, 2H) have also been used as NHC precursors to catalyze the ring-opening polymerization of L-lactide. The results clearly show that the inner metal of the porphyrin has an important effect on the reactivity of the outer carbene.

Quasi-alternating copolymerization of oxiranes driven by a benign acetate-based catalyst.

Alternating copolymers are distinctly unique in comparison with other copolymers. Herein, an in-depth investigation of the oxyanionic ring-opening copolymerization of propylene oxide (PO) and allyl glycidyl ether (AGE) from benzyl alcohol (BnOH) activated with potassium acetate (KOAc) complexed by 18-crown-6 ether (18C6) is described. We demonstrate that the 18C6/KOAc complex is an efficient and benign catalytic system to promote copolymerization of both oxirane monomers, leading to well-defined polyethers with varied comonomer content and low dispersity values (ƉM < 1.20). Kinetic analysis confirmed the controlled nature of the (co)polymerization process, and the determination of reactivity ratios revealed a quasi-alternating copolymerization profile, according to the Fineman-Ross method. The comparison between the quasi-alternating-type PO/AGE copolymerization and block or gradient copolymerization revealed significant differences, to confirm the different sequence incorporation in the different topological copolymers. These results highlight the great potential of 18C6/KOAc-mediated copolymerization process for the controlled sythesis of a series of copolymer topologies.

Controllable processes for generating large single crystals of poly(3-hexylthiophene).

Sowing the seeds: A simple strategy based on self-seeding allows large single crystals of long regioregular poly(3-hexylthiophene) chains to be grown from solution. When appropriately crystallized, materials differing in their degrees of regioregularity and molecular weights formed monoclinic form II crystals with interdigitated hexyl side groups (see picture).

Reaching High Stereoselectivity and Activity in Organocatalyzed Ring-Opening Polymerization of Racemic Lactide by the Combined Use of a Chiral (Thio)Urea and a N-Heterocyclic Carbene.

Stereochemical control during polymerization is a key strategy of polymer chemistry to achieve semicrystalline engineered plastics. The stereoselective ring-opening polymerization (ROP) of racemic lactide (rac-LA), which can lead to highly isotactic polylactide (PLA), is one of the emblematic examples in this area. Surprisingly, stereoselective ROP of rac-LA employing chiral organocatalysts has been under-leveraged. Here we show that a commercially available chiral thiourea (TU1), or its urea homologue (U1), can be used in conjunction with an appropriately selected N-heterocyclic carbene (NHC) to trigger the stereoselective ROP of rac-LA at room temperature in toluene. Both a high organic catalysis activity (>90% monomer conversion in 5-9 h) and a high stereoselectivity (probability of formation of meso dyads, Pm, in the range 0.82-0.93) can be achieved by thus pairing a NHC and a chiral amino(thio)urea. The less sterically hindered and the more basic NHC, that is, a NHC bearing tert-butyl substituents (NHCtBu), provides the highest stereoselectivity when employed in conjunction with the chiral TU1 or U1. This asymmetric organic catalysis strategy, as applied here in polymerization chemistry, further expands the field of possibilities to achieve bioplastics with adapted thermomechanical properties.

Three-armed RGD-decorated starPLA-PEG nanoshuttle for docetaxel delivery.

A novel star-shaped amphiphilic copolymer based on three poly(lactide)-block-poly(ethylene glycol) (PLA-PEG) terminal arms extending from a glycerol multifunctional core was newly synthesized and decorated with the tumor-targeting ligand cyclic-RGDyK peptide (Arg-Gly-Asp-D-Tyr-Lys) to be eventually formulated in polymeric micelles incorporating a suitable anticancer drug (i.e., Docetaxel, DTX; drug loading 16 %, encapsulation efficiency 69 %). The biological profile of unloaded micelles (RGD-NanoStar) was studied on Human Adipose-derived Mesenchymal Stem Cells (Ad-MSCs) as health control, pointing out the absence of toxicity. Surprisingly, an unprecedented effect on cell viability was exerted by RGD-NanoStar, comparable to that of the free DTX, on tumoral MDA-MB 468 Human Breast Adenocarcinoma cells, specifically starting from 48 h of culture (about 40 % and 60 % of dead cells at 48 and 72 h, respectively, at all tested concentrations). RGD-NanoStar reduced the cell viability also of tumoral U87 Human Glioblastoma cells, compared to cells only, at 72 h (about 25 % of dead cells) demonstrating a time-dependent effect exerted by the highest concentrations. The effects of DTX-loaded micelles (RGD-NanoStar/DTX) on U87 and MDA-MB 468 cell lines were evaluated by MTT, cell morphology analysis, and scratch test. A compromised cell morphology was observed without significant difference between DTX-treated and RGD-NanoStar/DTX - treated cells, especially in U87 cell line. Although no apparent benefit emerged from the drug incorporation into the nanosystem by MTT assay, the scratch test revealed a statistically significant inhibition of tumoral cell migration on both cell lines, confirming the well-known role of DTX in inhibiting cell movements even when loaded on polymeric micelles. Specifically, only 43 µm distance was covered by U87 cells after 30 h culture with RGD-NanoStar/DTX (30 µg/mL) compared to 73 µm in the presence of free DTX at the same concentration; more interestingly, a total absence of MDA-MB 468 cell movements was detected at 30 h compared to about 50 µm distance covered by cells in the presence of free DTX (10 µg/mL). The stronger inhibitory activity on cell migration of RGD-NanoStar/DTX compared to the free drug in both cell lines at 30 h attested for a good ability of the drug-loaded nanocarrier to reduce tumor propagation and invasiveness, enhancing the typical effect of DTX on metastatization.

Size dependence of the folding of multiply charged sodium cationized polylactides revealed by ion mobility mass spectrometry and molecular modelling.

Ion mobility spectrometry coupled with mass spectrometry was used to experimentally determine the three-dimensional structure of multiply charged sodium cationized polylactides (PLA). In particular, the experiments were conducted to evaluate the influence of the charge state and the size on the gas-phase conformation of cationized PLA. The measured collision cross sections were then compared to calculated values obtained by computational chemistry methods. The most striking feature was the experimental and theoretical observation of a breaking point in the quasilinear relationship between the average collision cross sections and the number of monomer units for the triply charged cations. This breaking point was theoretically demonstrated, for the doubly and triply charged cations, to be associated with a significant folding of the polymer chains around the cationizing agents. The occurrence of such breaking points could be exploited to correlate the charge state of the most intense ion series observed upon electrospray ionization with the number-average molecular mass of a polymer.

Stereoretention in the Bulk ROP of l-Lactide Guided by a Thermally Stable Organocatalyst.

Polylactide (PLA) has emerged as one of the most promising bio-based alternatives to petroleum-based plastics, mainly because it can be produced from the fermentation of naturally occurring sugars and because it can be industrially compostable. In spite of these benefits, the industrial ring-opening polymerization (ROP) of l-lactide (L-LA) still requires the use of highly active and thermally stable metal-based catalysts, which have raised some environmental concerns. While the excellent balance between activity and functional group compatibility of organic acid catalysts makes them some of the most suitable catalysts for the metal-free ROP of L-LA, the majority of these acids are highly volatile and subject to decomposition at high temperature, which limits their use under industrially relevant conditions. In this work we exploit the use of a nonstoichiometric acid-base organocatalyst to promote the solvent-free and metal-free ROP of L-LA at elevated temperatures in the absence of epimerization and transesterification. To do so, a stable acidic complex was prepared by mixing 4-(dimethylamino)pyridine (DMAP) with 2 equiv of methanesulfonic acid (MSA). Both experimental and computational results indicate that DMAP:MSA (1:2) not only is highly thermally stable but also promotes the retention of stereoregularity during the polymerization of L-LA, leading to PLLA with a molar mass of up to 40 kg mol-1 and a chiral purity in excess of 98%. This result provides a new feature to exploit in organocatalyzed polymerization and in the design of new catalysts to facilitate the path to market.