Hydrogen Bridges Research Articles

Highly Selective Ortho-Directed Dicarboxylation of Cyclopentadiene by Methylcarbonates and CO2 or COS - First Insight into Co-ordination Chemistry of New Ambident Ligands.

This research presents the highly regioselective syntheses of 1,2‐dicarboxylated cyclopentadienide salts [Cat]2[C5H3(CO2)2H] by reaction of a variety of organic cation methylcarbonate salts [Cat]OCO2Me (Cat=NR4 +, PR4 +, Im+) with cyclopentadiene (CpH) or by simply reacting organic cation cyclopentadienides Cat[Cp] (Cat=NR4 +, PR4 +, Im+) with CO2. One characteristic feature of these dianionic ligands is the acidic proton delocalized in an intramolecular hydrogen bridge (IHB) between the two carboxyl groups, as studied by 1H NMR spectroscopy and XRD analyses. The reaction cannot be stopped after the first carboxylation. Therefore, we propose a Kolbe‐Schmitt phenol‐carboxylation related mechanism where the acidic proton of the monocarboxylic acid intermediate plays an ortho‐directing and CO2 activating role for the second kinetically accelerated CO2 addition step exclusively in ortho position. The same and related thiocarboxylates [Cat]2[C5H3(COS)2H] are obtained by reaction of COS with Cat[Cp] (Cat=NR4 +, PR4 +, Im+). A preliminary study on [Cat]2[C5H3(CO2)2H] reveals, that its soft and hard coordination sites can selectively be addressed by soft Lewis acids (Mo0, Ru2+) and hard Lewis acids (Al3+, La3+).

Zinc- and Cadmium meso-Aryl-Isoporphyrins: Non-Aromatic NIR Dyes with Distinct Conformational Features.

A series of pyrrolyl and dipyrrinyl isoporphyrins carrying different phenyl and thienyl groups is reported. The compounds are obtained by a one‐pot approach in the presence of a template reagent. Thienyl derivatives gave better yields, and were the only subclass to form with steric hindrance. The structural analyses carried out on compounds 1 and 14 revealed distinct conformational differences which are likely to result from an intramolecular NH…Cl hydrogen bridge of the pyrrolyl subclass. In addition, this hydrogen bridge strongly favors one of the two possible atropisomers. Hindered rotation of the meso‐aryl groups is observed only in the cases of methylbenzothienyl derivatives 10 and 15 and leads to the observation of several diastereomers. NIR absorptions up to 923 nm are found throughout. Electrochemical investigations into the 1e− and 2e− reduced species unravel axial ligand exchange dynamics for the zinc isoporphyrin radical, and the probable formation of a zinc phlorinate.

Structure-Property Relationship in Selected Naphtho- and Anthra-Quinone Derivatives on the Basis of Density Functional Theory and Car–Parrinello Molecular Dynamics

Intra- and inter-molecular interactions were studied in 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone and 1,4-dihydroxy-anthraquinone to shed more light on the molecular assembly phenomena. The electronic ground and excited states features of the compounds were investigated to find structure-property dependencies. The theoretical study was carried out on the basis of Density Functional Theory (DFT), its Time-Dependent (TD-DFT) extension, and using Car–Parrinello Molecular Dynamics (CPMD). In order to show how the environmental effects modulate the physico-chemical properties, the simulations were performed in vacuo, with the solvent reaction field (Polarizable Continuum Model (PCM) and water as a solvent) and crystalline phase. The intramolecular hydrogen bonds and the bridged proton dynamics were analyzed in detail. The aromatic rings and electronic structure changes were estimated using the Harmonic Oscillator Model of Aromaticity (HOMA) and Atoms in Molecules (AIM) theory. The Symmetry-Adapted Perturbation Theory (SAPT) was employed for interaction energy decomposition in the studied dimers and trimers. It was found that the presence of a polar solvent decreased the energy barrier for the bridged proton transfer. However, it did not significantly affect the aromaticity and electronic structure. The SAPT results showed that the mutual polarization of the monomers in the dimer was weak and that the dispersion was responsible for most of the intermolecular attraction. The intermolecular hydrogen bonds seem to be much weaker than the intramolecular bridges. The TD-DFT results confirmed that the electronic excitations do not play any significant role in the intramolecular proton transfer. The CPMD results indicated that the protons are very labile in the hydrogen bridges. Short proton transfer and proton-sharing events were observed, and a correlation between them in the twin bridges was noticed, especially for the first investigated compound.

Silanization of siliceous materials, part 3: Modification of surface energy and acid-base properties of silica nanoparticles determined by inverse gas chromatography (IGC)

Surface modified silica nanoparticles are well-established composite materials. To improve their embedding and application behavior, surface energy analysis has been performed before and after silanization with mercaptopropyltrimethoxysilane (MPTMS) using inverse gas chromatography technique (IGC). Experiments with two silica materials have been conducted at infinite dilution to determine the dispersive component of the surface energy (γsd) as well as the specific component (γssp) using the van Oss theory and a least-squares procedure evaluating the IGC data of 8 polar probe molecules collectively (instead of evaluating only the data of a pair of monopolar probes as is often the case in IGC studies). After surface silylation, the total surface energy (γst) of pyrogenic silica nanoparticles decreased from 225 mJ/m2 to 149 mJ/m2 referring to both a reduced wettability and an increased hydrophobicity of the MPTMS-modified sample. Moreover, the acidity/basicity parameters according to the van Oss and the Gutmann approach indicated that the acidity of the silica surface decreases by MPTMS grafting. In addition, IGC at finite concentration (using isopropanol as probe molecule) was applied to obtain the energetic heterogeneity of the silica surface. The results showed a bimodal energy distribution with maxima at about 18 and 25 kJ/mol and a reduction of the higher energetic sites from 65% to only 35% after MPTMS treatment. Overall, it can be seen that the dominance of specific interactions on silica surfaces is maintained even after extensive silanization. These findings are in agreement with the results of 29Si CP MAS NMR measurements which confirm the assignment of higher energetic sites to silanol groups. For the interpretation of the IGC results, quantum chemical calculations proved the preferred interaction of isopropanol onto silica surfaces via hydrogen bridging.

Molecular Dynamics Analysis of Stabilities of Transitional Hydrogen Bonds in Sulfate Aqueous Solution

Abstract Different mechanisms of H-bond formation between sulfate anion and water are presented using molecular dynamics simulations. Multi-centered hydrogen bonds were observed. Always the hydrogen bridge making/breaking goes according to the large angular jump mechanism. Moreover, classical, bifurcated and trifurcated hydrogen bonds between water and sulfate have transitional character. This is supported by free energies of binding of water to sulfate ion determined for particular types of hydrogen bridges. This phenomenon is similar to the one observed in the hydration shell of perchlorate anion. Nevertheless the amplitudes of angular jump as well as hydrogen bond lifetimes are different in both cases.

Triple-Decker Sandwich Complexes of Tungsten with Planar and Puckered Middle Decks.

A triple-decker complex of tungsten, [(Cp*W)2{μ-η6:η6-B4H4Co2(CO)5}(H)2] (1; Cp* = η5-C5Me5), with a planar middle deck has been isolated by thermolysis of an in situ formed intermediate from the reaction of Cp*WCl4 and LiBH4 with Co2(CO)8. In addition, we have also isolated another triple-decker complex, [(Cp*W)2{μ-η6:η6-B5H5Fe(CO)3}(H)2] (4), having a puckered central ring, from a similar reaction with Fe2(CO)9. Clusters 1 and 4 are unprecedented examples of a triple-decker complex having a 24-valence electron with bridging hydrogen atoms.

Raman spectroscopic quantification of tetrahedral boron in synthetic aluminum-rich tourmaline

Abstract The Raman spectra of five [4]B-bearing tourmalines of different composition synthesized at 700 °C/4.0 GPa (including first-time synthesis of Na-Li-[4]B-tourmaline, Ca-Li-[4]B-tourmaline, and Ca-bearing ☐-[4]B-tourmaline) reveal a strong correlation between the tetrahedral boron content and the summed relative intensity of all OH-stretching bands between 3300–3430 cm–1. The band shift to low wavenumbers is explained by strong O3-H···O5 hydrogen bridge bonding. Applying the regression equation to natural [4]B-bearing tourmaline from the Koralpe (Austria) reproduces the EMPA-derived value perfectly [EMPA: 0.67(12) [4]B pfu vs. Raman: 0.66(13) [4]B pfu]. This demonstrates that Raman spectroscopy provides a fast and easy-to-use tool for the quantification of tetrahedral boron in tourma-line. The knowledge of the amount of tetrahedral boron in tourmaline has important implications for the better understanding and modeling of B-isotope fractionation between tourmaline and fluid/melt, widely used as a tracer of mass transfer processes.

Hosting of the antibiotic Vancomycin by bentonite: Characterization and slow release study

Bentonite (Bent) is a highly promising material to be used in the pharmaceutical industry as drug delivery system due to its high drug loading capacity and controlled drug release properties. The adsorption and controlled release of vancomycin (VCM) ―a glycopeptide antibiotic of large molecular size and structural complexity― on/from an unmodified Bent is reported. The adsorption and release of this drug on/from the Bent―whose safety was demonstrated by in vivo studies―was monitored by ultraviolet (UV) spectroscopy. In order to enhance the VCM loading by the clay, different physical-chemical parameters (pH, drug initial concentration, temperature and interaction time) were evaluated. The Bent-VCM composite was characterized by X-ray diffraction (XRD), transmittance Fourier transform infrared spectroscopy (FT-IR) and thermal gravimetric analysis (TGA). The results showed that the Bent is able to efficiently adsorb VCM, achieving a higher load (qmax= 655 ± 5 mg/g) at 9 × 103 mg/L, when it is in its monovalent cationic form. The characterization studies indicated surface adsorption, as well as clay-drug interactions by hydrogen bridges and electrostatic forces. The Sips isotherm model exhibited a good correlation to the equilibrium experimental data, indicating heterogeneous adsorption of the adsorbate-adsorbent system under study. The ΔG0 calculation indicated the spontaneous and reversible nature of the adsorption process. The in vitro assays at pH values typical of the human gastrointestinal tract demonstrated that the VCM release profiles fulfill the pharmaceutical standards, suggesting the potential use of Bent as VCM carrier.

Investigation of Structural and Optoelectronic Properties of Organic Semiconductor Film Based on 8-Hydroxyquinoline Zinc

In this work, we investigated an organic semiconductor based on zinc 8-hydroxyquinoline (ZnQ2) and tetracyanoquinodimethane (TCNQ), which can be used as a photoactive layer in organic devices. The semiconductor was optimized by applying density-functional theory (DFT) methods, and four hydrogen bridges were formed between ZnQ2 and TCNQ. Later, thin films of ZnQ2-TCNQ were successfully deposited. The films were structurally and morphologically characterized, and the optical characteristics of the photoactive layer were investigated using ultraviolet–visible spectroscopy and time-dependent density-functional theory (TDDFT) calculations. The comparison and analysis of the experimental and theoretical absorption spectra indicate that the optical bandgap of the photoactive layer is 2.4 eV. Additionally, a flexible photo device was manufactured with the active layer ZnQ2-TCNQ, and its electrical behavior was evaluated under dark and light conditions. The results show a significant change in the behavior of the device when radiation is eliminated; the layer is light sensitive. The electrical resistance in the flexible photo device is associated with the optical behavior of the materials that constitute the active layer.

Anion-cation interactions in a series of salts with substituted Hphen, Hbpy and H2bpy cations and [W(CN)8]4- anion: polymer with "super-short" N-H⋯N hydrogen bridges containing exclusively anions and H.

The 10 ion-pairs of [W(CN)8]4- with substituted Hphen and Hnbpyn+ (where phen = 1,10-phenantroline, bpy = 2,2'-bipyridine, n = 1 or 2) were isolated and the spectroscopic properties of these salts are discussed. Three salts with dimethyl-substituted Hnbpyn+ cation were structurally characterized. In the structure of the salt with H2bpy, one of the cyanido ligands of the anion is in the CNH form. This situation is very unique, as well as the formation of two water double bridges by water molecules in [W(CN)8]4-. The formulas of other compounds were determined based on the IR spectra, thermogravimetry, and elemental analyses. The ion-pair formation was accompanied not only by anion-cation charge-transfer bands in the visible part of the electronic spectra, but also low-energy bands above 1000 nm were found and are related to the thermal electron transfer; the amount of the paramagnetic WV was determined by EPR measurement. The thermal excitation of electrons may indicate the possibility of using these compounds as semiconductors. Finally, the improved method of K4[W(CN)8]·2H2O synthesis is also described.

Synergetic enhancement of room-temperature phosphorescenceviawater molecules as a hydrogen bonding bridge

To improve the water and oxygen resistance of room-temperature phosphorescence based on copolymerization strategy, a facile secondary processing strategy using water as the hydrogen bridge was proposed, which extended the lifetime and quantum yield.

The structural state of Finnish Cr- and V-bearing clinozoisite: insights from Raman spectroscopy

Severe structural damage in Cr- and V-bearing clinozoisite (Czo) from the Outokumpu copper mine, Finland, was discovered by Nagashima et al. (Eur J Miner 23:731–743, 2011). Single-crystal X-ray and electron diffraction patterns indicated moderate-to-very-poor structural coherency, suggesting a high density of faults in the translational symmetry. However, the poor crystallinity cannot be attributed to self-radiation due to negligible concentrations of radioactive elements. Annealing of Cr- and V-bearing Czo up to 750 °C only slightly improved crystallinity. To solve this enigma, polarized Raman spectroscopy was applied to gain further insights into the structural state of the Cr + V-bearing Finnish Czo. According to the parallel-polarized Raman spectra of Cr + V-rich (Czo-ts3), Cr + V-bearing (Czo-ts2), and Cr + V-free (Czo-ts1) Czo, the peaks broaden with the Cr + V content, indicating increasing density of structural defects. Spectra from a euhedral Cr + V-bearing Czo single-crystal evidence intact structural domains by strong polarization and orientation dependence. Thus, the structural state of Finnish Czo should be described in terms of defect-rich segmented domains with common crystallographic orientation. The incorporation of V and Cr into the clinozoisite structure strongly affects the Raman-active O–H bond stretching modes near 3343 cm−1 [(OH)a] and 3435 cm−1 [(OH)b], assigned to O10-H···O4 and O10-H···O2 hydrogen bridges, respectively. The H···O2 hydrogen bonding is strongly promoted when M3 is partially occupied by Cr + V, and as a result, the linkages between the M2O6- and (M1, M3)O6-chains are disturbed, leading to periodicity faults and size reduction of coherent structural domains. In the case of M3Fe3+ substitution for M3Al, the local stress imposed by the larger M3-site cation is relaxed within the distorted M3O6 octahedron. In the case of M3V3+ or M3Cr3+ substitution for M3Al, M3O6 octahedra are less distorted and local stress fields propagate farther than only to the first coordination sphere, thus disturbing the transitional symmetry. New high-resolution transmission electron microscopy (HRTEM) images indeed display nanocrystals of ca. 10 nm with common crystallographic orientation surrounded by amorphous regions. It is suggested that the segmentation of large coherent crystalline areas in Cr + V-rich Czo to nanocrystals may be triggered by a potential miscibility gap in combination with the sluggish diffusion behavior of Cr3+. Moreover, this study implies that nanostructures as commonly observed for metamict materials may also be caused by strain effects and/or exsolution phenomena precluded by tardy diffusion.

CO2/N2-switchable sol–gel transition based on NaDC/NaCl solution: Experiments and molecular dynamics simulations

The CO2/N2-triggered switchable sol–gel transition based on sodium deoxycholate (NaDC) and sodium chloride (NaCl) aqueous solutions has been investigated using both experiments and molecular dynamics (MD) simulations. The effects of CO2 on the phase behavior, viscosity, pH, electrical conductivity, and microstructure of the NaDC/NaCl mixed system were explored. The mixed system exhibits a recycled CO2/N2 response, and switching between solution state and gel state with six orders of magnitude variation in shear viscosity was achieved within a narrow pH range of 7.82–7.20. The FT-IR and 1H NMR spectra of the mixed system before and after CO2 bubbling were measured. The experimental results indicate that NaDC is not directly protonated to deoxycholic acid by the small amount of CO2 present; instead, an acid salt structure with a strong hydrogen bond, that is, [RCOOH⋯OOCR]−, is formed. MD simulation results reveal that, in the aqueous mixed NaDC/NaCl/CO2 system, three types of bridging hydrogen bonds between two deoxycholate (DC−) anions and one H3O+ or HCO3− ion are key factors for the formation of hydrogels. These bridging hydrogen bonds promote the formation of DC− pairs bridged by H3O+ or HCO3− ions (including the acid salt structure) and are beneficial to the growth of micelles and formation of hydrogels. It is worth noting that the bridging hydrogen bond connected by HCO3− ions is an aspect of CO2-induced hydrogels that distinguishes them from acid-induced hydrogels. In addition, the results indicate that CO2 and NaCl have a synergistic effect when inducing hydrogel formation. Based on experiments and MD simulations, a CO2/N2-switchable sol–gel transition mechanism for an aqueous mixed NaDC/NaCl system has been proposed.

Identification of Channel Hot Carrier Stress-Induced Oxide Traps Leading to Random Telegraph Signals in pMOSFETs

We investigated the effect of channel hot carrier (CHC) stressing on the creation of gate oxide defect centers causing random telegraph signals (RTSs) in pMOSFETs. To identify these stress-induced hole traps in the oxide and fully characterize their trapping properties, variable temperature RTS measurements were performed from room temperature down to 215 K and repeated after each stressing interval, up to 1200 s. The trapping properties of the stress-induced defect sites and those present before stress are quantified, including the hole capture and emission activation energies, structural relaxation in the oxide network due to trapping/detrapping, and entropy change as well as the energy level and position of the trap in the oxide. Based on this information, disassociated III-Si and hydrogen bridge defects are identified as the hole trapping centers in SiO2. Difference was observed between the process- and stress-induced traps in the entropy change upon hole emission from the oxide trap to Si channel (electron capture from the Si valence band), implying the possibility of stress-induced structural defects being different than the native ones.

Sunlight-induced dehydrogenation rearrangement of the dititanium complex [Ti(η5-C5HMe4)(μ-η1: η5-C5Me4)

Sunlight photolysis of the triplet state (S = 1) dititanium compound 1 induced its rearrangement to diamagnetic 2, which was a molecule containing two hydrogens less. The cage structure of 2 was determined by single crystal X-ray diffraction and was corroborated fully by 1H and 13C NMR spectra that identified three simple bridging moieties — a hydrogen atom, a methine carbon and a methylene carbon. Its extremely short Ti−Ti distance 2.7537(7) Å causes a strong distortion of the bridging fulvalene ligand, which becomes η5- bonded to one Ti(IV) and connected by two σ-bonds from nearest carbon atoms of its other ring to the other Ti(IV) of 2. Other photolytical byproducts in very minor amounts were also isolated, which differed from 2 by the absence of one bridging moiety: compound 4 lacked the methine group and compound 5 had no bridging hydrogen. In the latter cases, the Ti−Ti distance fell in the range 3.2077(8) – 3.5543(12) Å and the fulvalene ligand was coordinated in the common µ-η5: η5-mode to both titanium atoms. The octamethylfulvalene ligands in 4 and 5 had their ring planes rotated mutually by about 40° in order to relieve the steric hindrance between their methyl groups. The thermally robust µ-oxo complex 3 obtained from reacting 2 with water showed a very similar structure.

Symmetry/Asymmetry of the NHN Hydrogen Bond in Protonated 1,8-Bis(dimethylamino)naphthalene

Experimental and theoretical results are presented based on vibrational spectra and motional dynamics of 1,8-bis(dimethylamino)naphthalene (DMAN) and its protonated forms (DMANH+ and the DMANH+ HSO4− complex). The studies of these compounds have been performed in the gas phase and solid-state. Spectroscopic investigations were carried out by infrared spectroscopy (IR), Raman, and incoherent inelastic neutron scattering (IINS) experimental methods. Density functional theory (DFT) and Car–Parrinello molecular dynamics (CPMD) methods were applied to support our experimental findings. The fundamental investigations of hydrogen bridge vibrations were accomplished on the basis of isotopic substitutions (NH → ND). Special attention was paid to the bridged proton dynamics in the DMANH+ complex, which was found to be affected by interactions with the HSO4− anion.

Stability of Human Serum Amyloid A Fibrils.

In systemic amyloidosis, serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure been resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a 2-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23-51) but is not affected by the presence of the disordered C-terminal tail.

Acid‐Base Interactions of Pyrazine, Ethyl Acetate, Di‐alcohols, and Lysine with the cyclic Alumosiloxane (Ph2SiO)8[Al(O)OH]4 in View of Mimicking Al2O3(H2O) Surface Reactions

The etherate of (Ph2SiO)8[Al(O)OH]4 can be transformed into the pyrazine adduct (Ph2SiO)8[Al(O)OH]4·3N(C2H2)2N (1), the ethyl acetate adduct (Ph2SiO)8[Al(O)OH]4·3H3C‐C(O)OC2H5 (2), the 1,6‐hexane diol adduct (Ph2SiO)8[Al(O)OH]4·2HO–CH2(CH2)4CH2–OH (3) and the 1,4‐cyclohexane diol adduct (Ph2SiO)8[Al(O)OH]4·4HO–CH(CH2CH2)2CH–OH (4). In all compounds the OH groups of the starting material bind to the bases through O–H···N (1) or O–H···O hydrogen bonds (2, 3, 4) as found from single‐crystal X‐ray diffraction analyses. Whereas in 1 only three of the central OH groups bind to the pyrazines, in 2 two of them bind to the same carbonyl oxygen atom of the ethyl acetate resulting in an unprecedented O–H···O···H–O double hydrogen bridge. The hexane diol adduct 3 in the crystal forms a one‐dimensional coordination polymer with an intramolecularly to two OH groups grafted hexane diol loop, while the second hexane diol is connecting intermolecularly. In the cyclohexane diol adduct 4 all OH groups of the central Al4(OH)4 ring bind to different diols, leaving one alcohol group per diol uncoordinated. These “free” OH groups form an (O‐H···)4 assembly creating a three‐dimensional overall structure. When reacting with (Ph2SiO)8[Al(O)OH]4 lysine loses water, turns into the cyclic 3‐amino‐2‐azepanone, and transforms through chelation of one of the aluminum atoms the starting material into a new polycycle. The isolated compound has the composition (Ph2SiO)12[Al(O)OH]4[Al2O3]2·4 C6H12N2O·6(CH2)4O (5).

Strong sequentially bridged MXene sheets

Titanium carbide (Ti3C2Tx) MXene has great potential for use in aerospace and flexible electronics due to its excellent electrical conductivity and mechanical properties. However, the assembly of MXene nanosheets into macroscopic high-performance nanocomposites is challenging, limiting MXene's practical applications. Here we describe our work fabricating strong and highly conductive MXene sheets through sequential bridging of hydrogen and ionic bonding. The ionic bonding agent decreases interplanar spacing and increases MXene nanosheet alignment, while the hydrogen bonding agent increases interplanar spacing and decreases MXene nanosheet alignment. Successive application of hydrogen and ionic bonding agents optimizes toughness, tensile strength, oxidation resistance in a humid environment, and resistance to sonication disintegration and mechanical abuse. The tensile strength of these MXene sheets reaches up to 436 MPa. The electrical conductivity and weight-normalized shielding efficiency are also as high as 2,988 S/cm and 58,929 dB∙cm2/g, respectively. The toughening and strengthening mechanisms are revealed by molecular-dynamics simulations. Our sequential bridging strategy opens an avenue for the assembly of other high-performance MXene nanocomposites.

Biosynthesis of lanthionine-constrained agonists of G protein-coupled receptors.

The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand–receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehydroamino acids to cysteines forming (methyl)lanthionines. The leader peptide also guides the export of the formed lanthionine-containing precursor peptide out of Gram-positive bacteria via a lanthipeptide transporter. An engineered cleavage site in the C-terminus of the leader peptide allows to cleave off the leader peptide yielding the modified peptide of interest. Lanthipeptide GPCR agonists are an emerging class of therapeutics of which a few examples have demonstrated high efficacy in animal models of a variety of diseases. One lanthipeptide GPCR agonist has successfully passed clinical Phase Ia.