Elucidating the Structure, Dynamics, and Interaction of a Choline Chloride and Citric Acid Based Eutectic System by Spectroscopic and Molecular Modeling Investigations.

Eutectic solvent systems are versatile solvents that have found widespread use in numerous applications. Traditional solvents are homogeneous, having only one component, and their chemistry is relatively simple, with some exceptions. On the other hand, deep eutectic solvents (DESs) comprise binary components, generally a donor and an acceptor in hydrogen bonding with varying ratios. The interaction chemistry among the donor and acceptor involved in hydrogen bonding in DESs is complicated. Although numerous research is focused on the synthesis and application of DESs, few studies are reported to elucidate the complex structure and dynamic and interaction behavior of DESs. In this study, we employed calorimetry, vibrational spectroscopy techniques including FTIR and Raman, and nuclear magnetic resonance to derive insight into the structural feature and noncovalent contact of choline chloride (ChCl) and citric acid (CA) while they formed DESs. The 1:1 ChCl/CA eutectic system showed phase transitions and melting peaks with the most pronounced peak at 156.22 °C, suggesting the DESs melting at a lower temperature than the melting temperatures of ChCl and CA. In addition to IR and Raman findings, 1H NMR investigations demonstrate hydrogen bonding intermolecular interactions between ChCl and CA, supporting the formation of 1:1 ChCl/CA DESs based on the deshielded chemical shifts of the proton for Ch. The interaction of the chloride anion with the methyl protons (H4) and methylene protons (H3) of ChCl as well as the strong hydrogen bonding interactions between the hydroxyl hydrogen (H1) of ChCl with one of CA's carbonyl oxygens both supported the formation of conformer E. In addition, molecular dynamics followed by the density functional theory (DFT) was employed to visualize the structure and interaction of DESs using the ωB97XD theory and 6-311++G (d,p) basis set. Both experimental and theoretical IR, Raman, and structural analyses provided evidence of the formation of DESs by possessing hydrogen bonds. These multifaceted experimental and computational investigations provide details of structural and intermolecular interactions of ChCl/CA DESs.

Solvatochromic and Aggregation-Induced Emission Active Nitrophenyl-Substituted Pyrrolidinone-Fused-1,2-Azaborine with a Pre-Twisted Molecular Geometry.

Boron-nitrogen-containing heterocycles with extended conjugated π-systems such as polycyclic aromatic 1,2-azaborines, hold the fascination of organic chemists due to their unique optoelectronic properties. However, the majority of polycyclic aromatic 1,2-azaborines aggregate at high concentrations or in the solid-state, resulting in aggregation-caused quenching (ACQ) of emission. This practical limitation poses significant challenges for polycyclic aromatic 1,2-azaborines' use in many applications. Additionally, only a few solvatochromic polycyclic aromatic 1,2-azaborines have been reported and they all display minimal solvatochromism. Therefore, the scope of available polycyclic 1,2-azaborines needs to be expanded to include those displaying fluorescence at high concentration and in the solid-state as well as those that exhibit significant changes in emission intensity in various solvents due to different polarities. To address the ACQ issue, we evaluate the effect of a pre-twisted molecular geometry on the optoelectronic properties of polycyclic aromatic 1,2-azaborines. Specifically, three phenyl-substituted pyrrolidinone-fused 1,2-azaborines (PFAs) with similar structures and functionalized with diverse electronic moieties (-H, -NO2, -CN, referred to as PFA 1, 2, and 3, respectively) were experimentally and computationally studied. Interestingly, PFA 2 displays two distinct emission properties: 1) solvatochromism, in which its emission and quantum yields are tunable with respect to solvent polarity, and 2) fluorescence that can be completely "turned off" and "turned on" via aggregation-induced emission (AIE). This report provides the first example of a polycyclic aromatic 1,2-azaborine that displays both AIE and solvatochromism properties in a single BN-substituted backbone. According to time-dependent density function theory (TD-DFT) calculations, the fluorescence properties of PFA 2 can be explained by the presence of a low-lying n-π* charge transfer state inaccessible to PFA 1 or PFA 3. These findings will help in the design of future polycyclic aromatic 1,2-azaborines that are solvatochromic and AIE-active as well as in understanding how molecular geometry affects these compounds' optoelectronic properties.

Photo-Electroswitchable Arylaminoazobenzenes.

Azobenzenes appended with a redox-active arylamino group (redox auxiliary, RA) are prepared and shown to undergo fast, complete, and catalytic Z→E azo isomerization upon electron loss from the RA unit of the azobenzene. The RA-azo structures can be reversibly (E→Z→E)n cycled by sequential photo- and electrostimulation. Due to the robust nature of the RA•+-azo radical cation chain carrying species, initiation of electron transfer (ET) catalysis occurs at low levels (1.0-0.04 mol %) of catalytic loading and is effective even at Z-RA-azo concentrations of 10-4-10-5 M, yielding TONs (turnover numbers) of 100-2300 under such dilute conditions. The RA-azo Z→E conversion is demonstrated using chemical oxidation (redox switching), electrochemical oxidation (electro switching), and photochemical oxidation (photoredox switching). The Z→E acceleration is shown to be at least 2 × 109-fold for RA-azo 5. DFT calculations on methyl yellow suggest that a N-centered radical cation of the RA group stabilizes the Z→E N-N twist transition state of the RA•+-azo, yielding a large reduction in the barrier for RA•+-azo compared to neutral RA-azo. The RA-azo structure class has nanomechanical features that can be toggled with photo- and electrostimulation, the latter offering a quick switch for complete Z→E conversion.

Synthesis, computational, and spectroscopic analysis of tunable highly fluorescent BN-1,2-azaborine derivatives containing the N-BOH moiety.

Nine new polycyclic aromatic BN-1,2-azaborine analogues containing the N-BOH moiety were synthesized using a convenient two-step, one-pot procedure. Characterization of the prepared compounds show the luminescence wavelength and the quantum yields of the azaborines were tunable by controlling the power and location of the donor and acceptor substituents on the chromophore. UV-visible spectroscopy and density functional theory (DFT) computations revealed that the addition of electron-donating moieties to the isoindolinone hemisphere raised the energy of the HOMO, resulting in the reduction of the HOMO-LUMO gap. The addition of an electron-accepting moiety to the isoindolinone hemisphere and an electron-donating group to the boronic acid hemisphere decreased the HOMO-LUMO gap considerably, leading to emission properties from partial intramolecular charge transfer (ICT) states. The combined effect of an acceptor on the isoindolinone side and a donor on the boronic acid side (strong acceptor-π-donor) gave the most red-shifted absorption. The polycyclic aromatic BN-1,2-azaborines emitted strong fluorescence in solution and in the solid-state with the largest red-shifted emission at 640 nm and a Stokes shift of Δλ = 218 nm, or Δν = 8070 cm-1.

The Synthesis and Characterization of Highly Fluorescent Polycyclic Azaborine Chromophores.

Six new heteroaromatic polycyclic azaborine chromophores were designed, synthesized, and investigated as easily tunable high-luminescent organic materials. The impact of the nitrogen-boron-hydroxy (N-BOH) unit in the azaborines was investigated by comparison with their N-carbonyl analogs. Insertion of the N-B(OH)-C unit into heteroaromatic polycyclic compounds resulted in strong visible absorption and sharp fluorescence with efficient quantum yields. The solid-state fluorescence of the heteroaromatic polycyclic compounds displayed a large Stokes shift compared to being in solution. The large Stokes shifts observed offset the self-quench effect in the solid state.

Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic.

High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' ß-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

Efficient parallel synthesis of macrocyclic peptidomimetics.

A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.

Potent macrocyclic antagonists to the motilin receptor presenting novel unnatural amino acids.

Novel, potent small molecule motilin receptor antagonists are described. These peptidomimetic macrocycles are composed of a tripeptide cyclized backbone-to-backbone with a nonpeptidic tether and bear new unnatural amino acids containing basic side chains.

Discovery of a new class of macrocyclic antagonists to the human motilin receptor.

A novel class of macrocyclic peptidomimetics was identified and optimized as potent antagonists to the human motilin receptor (hMOT-R). Well-defined structure-activity relationships allowed for rapid optimization of potency that eventually led to high affinity antagonists to hMOT-R. Potency and antagonist functional activity were confirmed both in functional and cell-based assays, as well as on isolated rabbit intestinal smooth muscle strips. Rapid access to this novel class of macrocyclic target structures was made possible through two efficient and complementary solid-phase parallel synthetic approaches, both of which are reported herein.