Dielectric Response of Different Alcohols in Water-Rich Binary Mixtures from THz Ellipsometry.

We report a study on the hydrogen bonding mechanisms of three aliphatic alcohols (2-propanol, methanol, and ethanol) and one diol (ethylene glycol) in water solution using a time-domain ellipsometer in the THz region. The dielectric response of the pure liquids is nicely modeled by the generalized Debye-Lorentz equation. For binary mixtures, we analyze the data using a modified effective Debye model, which considers H-bond rupture and reformation dynamics and the motion of the alkyl chains and of the OH groups. We focus on the properties of the water-rich region, finding anomalous behavior in the absorption properties at very low solute molar concentrations. These results, first observed in the THz region, are in line with previous findings from different experiments and can be explained by taking into account the amphiphilic nature of the alcohol molecules.

Alcohol-Induced Denaturation of Hen Egg White Lysozyme Studied by Infrared, Circular Dichroism, and Small-Angle Neutron Scattering.

In aqueous binary solvents with fluorinated alcohols, 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), and aliphatic alcohols, ethanol (EtOH) and 2-propanol (2-PrOH), the denaturation of hen egg white lysozyme (HEWL) with increasing alcohol mole fraction xA has been investigated in a wide view from the molecular vibration to the secondary and ternary structures. Circular dichroism (CD) measurement showed that the secondary structure of α-helix content of HEWL increases on adding a small amount of the fluorinated alcohol to the aqueous solution, while the ß-sheet content decreases. On the contrary, the secondary structure does not significantly change by the addition of the aliphatic alcohols. Correspondingly, the infrared (IR) spectroscopic measurements revealed that the amide I band red-shifts on the addition of the fluorinated alcohol. However, the band remains unchanged in the aliphatic alcohol systems with increasing alcohol content. To observe the ternary structure of HEWL, small-angle neutron scattering (SANS) experiments with H/D substitution technique have been applied to the HEWL solutions. The SANS experiments were successful in revealing the details of how the geometry of the HEWL changes as a function of xA. The SANS profiles indicated the spherical structure of HEWL in all of the alcohol systems in the xA range examined. The mean radius of HEWL in the two fluorinated alcohol systems increases from ∼16 to ∼18 Å during the change in the secondary structure against the increase in the fluorinated alcohol content. On contrast, the radius does not significantly change in both aliphatic alcohol systems below xA = 0.3 but expands to ∼19 Å as the alcohol content is close to the limitation of the HEWL solubility. According to the present results, together with our knowledge of the alcohol cluster formation and the interaction of the trifluoromethyl (CF3) groups with the hydrophobic moieties of biomolecules, the effects of alcohols on the denaturation of the protein have been discussed on a molecular scale.

Combating Alcohol Adduct Impurity in Immunosuppressant Drug Product Manufacturing: A Scientific Investigation for Enhanced Process Control.

OBJECTIVE: This research aims to elucidate critical impurities in process validation batches of tacrolimus injection formulations, focusing on identification and characterization of previously unreported impurity at RRT 0.42, identified as the tacrolimus alcohol adduct. The potential root causes for the formation of new impurity was determined using structured risk assessment by cause and effect fishbone diagram. The primary objective was to propose mitigation plan and demonstrate the control of impurities with 6 month accelerated stability results in development batches. METHODS: The investigation utilizes method validation and characterization studies to affirm the accuracy of quantifying the tacrolimus alcohol adduct. The research methodology employed different characterization techniques like rotational rheometer, ICP‒MS, MALDI-MS, 1H NMR, 13C NMR, and DEPT-135 NMR for structural elucidation. Additionally, the exact mass of the impurity is validated using electrospray ionization mass spectra. RESULTS: Results indicate successful identification and characterization of the tacrolimus alcohol adduct. The study further explores the transformation of Tacrolimus monohydrate under various conditions, unveiling the formation of Tacrolimus hydroxy acid and proposing the existence of a novel degradation product, the Tacrolimus alcohol adduct. Six-month data from development lots utilizing Manufacturing Process II demonstrate significantly lower levels of alcohol adducts. CONCLUSIONS: Manufacturing Process II, selectively locates Tacrolimus within the micellar core of HCO-60, this prevent direct contact of ethanol with Tacrolimus which minimizes impurity alcohol adduct formation. This research contributes to the understanding of tacrolimus formulations, offering ways to safeguard product integrity and stability during manufacturing and storage.

Harnessing alcohols as sustainable reagents for late-stage functionalisation: synthesis of drugs and bio-inspired compounds.

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C-X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources.

Excess Enthalpies Analysis of Biofuel Components: Sunflower Oil-Alcohols Systems.

This study addresses the pressing issues of energy production and consumption, in line with global sustainable development goals. Focusing on the potential of alcohols as "green" alternatives to traditional fossil fuels, especially in biofuel applications, we investigate the thermochemical properties of three alcohols (n-propanol, n-butanol, n-pentanol) blended with sunflower oil. The calorimetric analysis allows for the experimental determination of excess enthalpies in pseudo-binary mixtures at 303.15 K, revealing similarities in the trends of the curves (dependence on concentrations) but with different values for the excess enthalpies for each mixture. Despite the structural differences of the alcohols studied, the molar excess enthalpy values exhibit uniformity, suggesting consistent mixing behavior. The peak values of excess enthalpies for systems with sunflower oil and n-propanol, n-butanol and n-pentanol are, respectively, 3255.2 J/mole, 3297.4 J/mole and 3150.1 J/mole. Both the NRTL and Redlich-Kister equations show satisfactory agreement with the obtained values.

Alkene dialkylation by triple radical sorting.

The development of bimolecular homolytic substitution (SH2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism1-8. Biomimetic9,10 SH2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp3)-C(sp3) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp3)-C(sp3) bonds, greatly accelerating access to complex molecules and drug-like chemical space11. However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways12,13. Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp3)-rich molecules and defines a distinct mechanistic approach for alkene dialkylation.

Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation.

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)-CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

8-Iodoisoquinolinone, a Conformationally Rigid Highly Reactive 2-Iodobenzamide Catalyst for the Oxidation of Alcohols by Hypervalent Iodine.

The first lactam-type 2-iodobenzamide catalysts, 8-iodoisoquinolinones 8 (IB-lactam) and 9 (MeO-IB-lactam), were developed. These catalysts have a conformationally rigid 6/6 bicyclic lactam structure and are more reactive than the previously reported catalysts 2-iodobenzamides 4 (IBamide) and 5 (MeO-IBamide) for the oxidation of alcohols. The lactam structure could form an efficient intramolecular I---O interaction, depending on the size of the lactam ring.

Stored alcohol and fatty acid intermediates and the biosynthesis of sex pheromone aldehyde in the moth Chloridea virescens.

In most species of moths, the female produces and releases a volatile sex pheromone from a specific gland to attract a mate. Biosynthesis of the most common type of moth sex pheromone component (Type 1) involves de novo synthesis of hexadecanoate (16:Acyl), followed by modification to various fatty acyl intermediates, then reduction to a primary alcohol, which may be acetylated or oxidized to produce an acetate ester or aldehyde, respectively. Our previous work on the moth Chloridea virescens (Noctuidae) showed that females produce 90% of the major pheromone component, (Z)-11-hexadecenal (Z11-16:Ald), via a direct and rapid route of de novo biosynthesis with highly labile intermediates, and ca. 10% from an indirect route that likely mobilizes a pre-synthesized 16-carbon skeleton, possibly, (Z)-11-hexadecenoate (Z11-16:Acyl) or hexadecanoate (16:Acyl). In this paper, we use stable isotope tracer/tracee techniques to study the dynamics of the precursor alcohol (Z)-11-hexadecenol (Z11-16:OH) and stores of Z11-16:Acyl and 16:Acyl to determine their roles in biosynthesis of Z11-16:Ald. We found: (i) that intracellular Z11-16:OH is synthesized at roughly the same rate as Z11-16:Ald, indicating that translocation and oxidation of this moiety does not rate limit biosynthesis of Z11-16:Ald, (ii) intracellular Z11-16:OH consists of two pools, a highly labile one rapidly translocated out of the cell and converted to Z11-16:Ald, and a less labile one that mostly remains in gland cells, (iii) during pheromone biosynthesis, net stores of Z11-16:Acyl increase, suggesting it is not the source of Z11-16:Ald produced by the indirect route, and (iv) no evidence for the gland synthesizing stored 16:Acyl prior to (up to 2 days before eclosion), or after, synthesis of pheromone commenced, suggesting the bulk of this stored moiety is synthesized elsewhere and transported to the gland prior to gland maturation. Thus, the pheromone gland of C. virescens produces very little stored fat over its functional lifetime, being optimized to produce sex pheromone.

Pectin Nanoporous Structures Prepared via Salt-Induced Phase Separation and Ambient Azeotropic Evaporation Processes.

Polysaccharide nanoporous structures are suitable for various applications, ranging from biomedical scaffolds to adsorption materials, owing to their biocompatibility and large surface areas. Pectin, in particular, can create 3D nanoporous structures in aqueous solutions by binding with calcium cations and creating nanopores by phase separation; this process involves forming hydrogen bonds between alcohols and pectin chains in water and alcohol mixtures and the resulting penetration of alcohols into calcium-bound pectin gels. However, owing to the dehydration and condensation of polysaccharide chains during drying, it has proven to be challenging to maintain the 3D nanoporous structure without using a freeze-drying process or supercritical fluid. Herein, we report a facile method for creating polysaccharide-based xerogels, involving the co-evaporation of water with a nonsolvent (e.g., a low-molecular-weight hydrophobic alcohol such as isopropyl or n-propyl alcohol) at ambient conditions. Experiments and coarse-grained molecular dynamics simulations confirmed that salt-induced phase separation and hydrogen bonding between hydrophobic alcohols and pectin chains were the dominant processes in mixtures of pectin, water, and hydrophobic alcohols. Furthermore, the azeotropic evaporation of water and alcohol mixed in approximately 1:1 molar ratios was maintained during the natural drying process under ambient conditions, preventing the hydration and aggregation of the hydrophilic pectin chains. These results introduce a simple and convenient process to produce 3D polysaccharide xerogels under ambient conditions.

Upgrading of the general AMBER force field 2 for fluorinated alcohol biosolvents: A validation for water solutions and melittin solvation.

The standard GAFF2 force field parameterization has been refined for the fluorinated alcohols 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 1,1,1,3,3,3-hexafluoropropan-2-one (HFA), which are commonly used to study proteins and peptides in biomimetic media. The structural and dynamic properties of both proteins and peptides are significantly influenced by the biomimetic environment created by the presence of these cosolvents in aqueous solutions. Quantum mechanical calculations on stable conformers were used to parameterize the atomic charges. Different systems, such as pure liquids, aqueous solutions, and systems formed by melittin protein and cosolvent/water solutions, have been used to validate the new models. The calculated macroscopic and structural properties are in agreement with experimental findings, supporting the validity of the newly proposed models.

Microbial alcohol dehydrogenases: recent developments and applications in asymmetric synthesis.

Alcohol dehydrogenases are a well-known group of enzymes in the class of oxidoreductases that use electron transfer cofactors such as NAD(P)+/NAD(P)H for oxidation or reduction reactions of alcohols or carbonyl compounds respectively. These enzymes are utilized mainly as purified enzymes and offer some advantages in terms of green chemistry. They are environmentally friendly and a sustainable alternative to traditional chemical synthesis of bulk and fine chemicals. Industry has implemented several whole-cell biocatalytic processes to synthesize pharmaceutically active ingredients by exploring the high selectivity of enzymes. Unlike the whole cell system where cofactor regeneration is well conserved within the cellular environment, purified enzymes require additional cofactors or a cofactor recycling system in the reaction, even though cleaner reactions can be carried out with fewer downstream work-up problems. The challenge of producing purified enzymes in large quantities has been solved in large part by the use of recombinant enzymes. Most importantly, recombinant enzymes find applications in many cascade biotransformations to produce several important chiral precursors. Inevitably, several dehydrogenases were engineered as mere recombinant enzymes could not meet the industrial requirements for substrate and stereoselectivity. In recent years, a significant number of engineered alcohol dehydrogenases have been employed in asymmetric synthesis in industry. In a parallel development, several enzymatic and non-enzymatic methods have been established for regenerating expensive cofactors (NAD+/NADP+) to make the overall enzymatic process more efficient and economically viable. In this review article, recent developments and applications of microbial alcohol dehydrogenases are summarized by emphasizing notable examples.

Exploring the catalytic diversity of two short-chain dehydrogenases/reductases from Stachybotrys chartarum.

Short-chain dehydrogenase/reductases (SDRs) belong to the NAD(P)(H)-dependent oxidoreductase superfamily, which have various functions of catalyzing oxidation/reduction reactions and have been generally used as powerful biocatalysts in the production of pharmaceuticals. In this study, ScSDR1 and ScSDR2, two new SDRs have been identified and characterized from Stachybotrys chartarum 3.5365. Substrate scope investigation revealed that both of the enzymes possessed the ability to oxidize ß-OH to ketone specifically, and exhibited substrate promiscuity and high stereo-selectivity for efficiently catalyzing the structurally different prochiral ketones to chiral alcohols. These findings not only suggest that ScSDR1 and ScSDR2 might be potent synthetic tools in drug research and development, but also provide good examples for further engineered enzymes with higher efficiency and stereo-selectivity.

Designer phospholipid capping ligands for soft metal halide nanocrystals.

The success of colloidal semiconductor nanocrystals (NCs) in science and optoelectronics is inextricable from their surfaces. The functionalization of lead halide perovskite NCs1-5 poses a formidable challenge because of their structural lability, unlike the well-established covalent ligand capping of conventional semiconductor NCs6,7. We posited that the vast and facile molecular engineering of phospholipids as zwitterionic surfactants can deliver highly customized surface chemistries for metal halide NCs. Molecular dynamics simulations implied that ligand-NC surface affinity is primarily governed by the structure of the zwitterionic head group, particularly by the geometric fitness of the anionic and cationic moieties into the surface lattice sites, as corroborated by the nuclear magnetic resonance and Fourier-transform infrared spectroscopy data. Lattice-matched primary-ammonium phospholipids enhance the structural and colloidal integrity of hybrid organic-inorganic lead halide perovskites (FAPbBr3 and MAPbBr3 (FA, formamidinium; MA, methylammonium)) and lead-free metal halide NCs. The molecular structure of the organic ligand tail governs the long-term colloidal stability and compatibility with solvents of diverse polarity, from hydrocarbons to acetone and alcohols. These NCs exhibit photoluminescence quantum yield of more than 96% in solution and solids and minimal photoluminescence intermittency at the single particle level with an average ON fraction as high as 94%, as well as bright and high-purity (about 95%) single-photon emission.

Measurement of fluorotelomer alcohols based on solid phase microextraction followed by gas chromatography-mass spectrometry and its application in solid waste study.

This work developed a method based on solid phase microextraction followed by gas chromatography/mass spectrometry (SPME-GC/MS) for the measurement of fluorotelomer alcohols (FTOHs) in gas samples. The method quantification limit (MQL) is 6-7 ng/L for 6:2 fluorotelomer alcohols (6:2 FTOH) and 8:2 fluorotelomer alcohols (8:2 FTOH). In contrast to common methods such as thermal desorption combined with GC-MS, it needs neither pre-concentration equipment nor large sample volume. The extraction-evaporation-GC/MS is commonly used in literature for FTOHs measurement in solids samples. We developed a method to measure FTOHs in solid samples by adding solvent extraction prior to headspace SPME-GC/MS. The extraction-headspace SPME-GC/MS method has a quantification limit of 40-43 ng per gram for 6:2 FTOH and 8:2 FTOH in solid samples. This is comparable to the MQLs for the extraction-evaporation-GC/MS method. Removing the solvent evaporation step decreased the risk of contamination and loss of analytes. The developed methods were successfully used in three examples of solid waste study: 1) measuring 6:2 FTOH and 8:2 FTOH above the MQL in gas emissions from a closed landfill, 2) finding 6:2 FTOH above MQL in 9 of 31 solid consumer products, and 3) finding that the release of 6:2 FTOH in simulated landfills containing popcorn bags was linear at a rate of 3.15 ng/g popcorn bags-day and that partial 6:2 FTOH was from the hydrolysis of precursors.

Development of a novel magnetic metal-organic framework for the immobilization of short-chain dehydrogenase for the asymmetric reduction of pro-chiral ketone.

Short-chain dehydrogenase/reductase (SDR) acts as a biocatalyst in the synthesis of chiral alcohols with high optical purity. Herein, we achieved immobilization via crosslinking on novel magnetic metal-organic framework nanoparticles with a three-layer shell structure (Fe3O4@PDA@Cu (PABA)). The results of scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and energy dispersive X-ray spectroscopy confirmed the morphology and cross-linking property of immobilized SDR, which was more durable, stable, and reusable and exhibited better kinetic performance than free enzyme. The SDR and glucose dehydrogenase (GDH) were co-immobilized and then used for the asymmetric reduction of COBE and ethyl 2-oxo-4-phenylbutanoate (OPBE). These finding suggest that enzymes immobilized on novel MOF nanoparticles can serve as promising biocatalysts for asymmetric reduction prochiral ketones into chiral alcohols.

DNA-Compatible Copper/TEMPO Oxidation for DNA-Encoded Libraries.

Aldehydes are important synthons for DNA-encoded library (DEL) construction, but the development of a DNA-compatible method for the oxidation of alcohols to aldehydes remains a significant challenge in the field of DEL chemistry. We report that a copper/TEMPO catalyst system enables the solution-phase DNA-compatible oxidation of DNA-linked primary activated alcohols to aldehydes. The semiaqueous, room-temperature reaction conditions afford oxidation of benzylic, heterobenzylic, and allylic alcohols in high yield, with DNA compatibility verified by mass spectrometry, qPCR, Sanger sequencing, and ligation assays. Subsequent transformations of the resulting aldehydes demonstrate the potential of this method for robust library diversification.

Systematic Development of Vanadium Catalysts for Sustainable Epoxidation of Small Alkenes and Allylic Alcohols.

The catalytic epoxidation of small alkenes and allylic alcohols includes a wide range of valuable chemical applications, with many works describing vanadium complexes as suitable catalysts towards sustainable process chemistry. But, given the complexity of these mechanisms, it is not always easy to sort out efficient examples for streamlining sustainable processes and tuning product optimization. In this review, we provide an update on major works of tunable vanadium-catalyzed epoxidations, with a focus on sustainable optimization routes. After presenting the current mechanistic view on vanadium catalysts for small alkenes and allylic alcohols' epoxidation, we argue the key challenges in green process development by highlighting the value of updated kinetic and mechanistic studies, along with essential computational studies.

Novel Strategies for Enantio- and Site-Selective Molecular Transformations.

A strategy for symmetric synthesis based on dynamic chirality of enolates (memory of chirality) has been developed. Asymmetric alkylation, conjugate addition, aldol reaction, and arylation via C-N axially chiral enolate intermediates are described. Asymmetric alkylation and conjugate addition via C-O axially chiral enolate intermediates with a half-life of racemization as short as approx. 1 s. at -78 °C have been accomplished. Organocatalysts for asymmetric acylation and site-selective acylation have been developed. Kinetic resolution of racemic alcohols via remote asymmetric induction by the catalyst is shown. Catalyst-controlled site-selective acylation of carbohydrates and its application to total synthesis of natural glycoside are described. Chemo-selective monoacylation of diols and selective acylation of secondary alcohols with reversal of inherent reactivity are also discussed. Geometry-selective acylation of tetrasubstituted alkene diols is achieved, where acylation takes place independent from the steric environments of the substrates.

Highly Efficient and Simultaneous Analysis of Three Common Fluorotelomer Alcohols in Vegetables and Soils.

Fluorotelomer alcohols (FTOHs), as precursors of perfluoroalkyl carboxylic acids, are difficult to analyze due to their high volatility and matrix interference. A method based on single-factor experiments and response surface methodology design was developed for simultaneous analysis of three common FTOHs in vegetables and soils, using single extraction, dispersive solid phase extraction cleanup, and gas chromatography-mass spectrometry in negative chemical ionization. The method improved the extraction efficiency up to ∼40 folds and showed a commendable linearity range (1-100 ng/mL, R2 > 0.991), low limit of detection (0.025-0.897 ng/g, dry weight (dw)), and high accuracy and precision (83 ± 7.2-117 ± 6.0% recoveries at 2-20 ng/g fortification levels). It was successfully applied to determine the FTOHs in real vegetables and soils, demonstrating its feasibility for routine analysis. Concentrations of the FTOHs ranged from 3.5 to 37.9 ng/g (dw) and from 6.5 to 141.0 ng/g (dw), respectively, in the vegetables and soils collected nearby fluorochemical factories, which warrants further investigations on FTOH pollution and food safety concerns for which the developed method will be useful.