Assessment of liquid-liquid partition for the assignment of descriptors for the solvation parameter model.

The solvation parameter model uses five system independent descriptors to characterize compound properties defined as excess molar refraction, E, dipolarity/polarizability, S, hydrogen-bond acidity, A, hydrogen-bond basicity, B, and McGowan's characteristic volume, V, to model transfer properties between condensed phases. The V descriptor is assigned from structure. For compounds liquid at 20 °C the E descriptor can be assigned from the characteristic volume and its refractive index. The E descriptor for compounds solid at 20 °C and the S, A, and B descriptors are experimental properties traditionally assigned from chromatographic, liquid-liquid partition, and solubility measurements. In this report liquid-liquid partition constants in totally organic and aqueous biphasic systems are evaluated as a standalone technique for descriptor assignments. Using six totally organic biphasic systems the S, A, and B descriptors were assigned with an average absolute deviation (AAD) of about 0.04, 0.03, and 0.04, respectively, compared with the best estimate of the true descriptor values for 65 compounds. The E descriptor for compounds solid at 20 °C can only be estimated with an AAD of approximately 0.1. For six aqueous biphasic systems the B descriptor is assigned with a lower AAD of 0.028 and higher AAD of 0.08 and 0.05 for the S and A descriptors, respectively, than for the totally organic biphasic systems for compounds with a reliable value for the E descriptor. The preferred system for descriptor assignments utilizes both totally organic biphasic systems (heptane-1,1,1-trifluoroethanol, isopentyl ether-propylene carbonate, isopentyl ether-ethanolamine, heptane-ethylene glycol, heptane-formamide, and 1,2-dichloroethane-ethylene glycol) and aqueous biphasic systems (octanol-water, cyclohexane-water) with the possible substitution of some systems with alternative systems of similar selectivity. For 55 varied compounds this combination of eight organic and aqueous biphasic systems resulted in an AAD of approximately 0.03, 0.02, and 0.02 for the S, A, and B descriptors compared to the best estimate of the true descriptor value. For 30 compounds solid at 20 °C the AAD for the E descriptor of 0.11 is poorly assigned. The relative average absolute deviation in percent (RAAD) corresponds to 9.7 %, 3.1 %. 4.0 % and 8.3 % for E, S, A, and B, respectively, for the eight biphasic systems. Liquid-liquid partition is compared to reversed-phase liquid and gas chromatography as a standalone technique for descriptor assignments.

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes.

The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.

Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

2-Oxa-5-azabicyclo[2.2.1]heptane as a Platform for Functional Diversity: Synthesis of Backbone-Constrained γ-Amino Acid Analogues.

We communicate a versatile synthetic approach to C-3 disubstituted 2-oxa-5-azabicyclo[2.2.1]heptanes as carbon-atom bridged morpholines, starting with 4R-hydroxy-l-proline as a chiron. Attaching an acetic acid moiety on the C-3 carbon of the 2-oxa-5-azabicyclo[2.2.1]heptane core reveals the framework of an embedded γ-amino butyric acid (GABA). Variations in the nature of the substituent on the tertiary C-3 atom with different alkyls or aryls led to backbone-constrained analogues of the U.S. Food and Drug Administration-approved drugs baclofen and pregabalin.

Migration of substances from food contact plastic materials into foodstuff and their implications for human exposure.

The safety of food contact plastic materials, including PP, PE, PET, PCT, PLA, PBT and cross-linked polyester, was assessed with regard to migrated substances. The migrated concentrations of overall migrants (OMs), terephthalic acid, acetaldehyde, 1,4-butanediol and lead, were determined according to the standards and specifications for utensils, containers and packages in Korea. Food simulants of 4% acetic acid, water and n-heptane were used for the analysis of the substances. The dietary exposures of terephthalic acid, acetaldehyde and 1,4-butanediol were assessed using the dietary concentrations and the food consumption data. As a result, the dietary exposures were considered to be safe comparing to the health-based guidance values. In the case of lead, the margin of exposure (MOE) approach was applied. The MOEs calculated using the UB concentration and mean consumption data were ranged from 3 to 1000, which indicated low concern for health risk. Moreover, in this study, the dietary exposures were estimated by the Korean MFDS and U.S. FDA methods, respectively. As a result, the assessed risks were considered to be low in both cases. Based on the results of current exposure assessments, it could be considered that the food contact plastic materials are properly controlled by the regulatory authorities.

Construction of Charring-Functional Polyheptanazine towards Improvements in Flame Retardants of Polyurethane.

Nitrogen-containing flame retardants have been extensively applied due to their low toxicity and smoke-suppression properties; however, their poor charring ability restricts their applications. Herein, a representative nitrogen-containing flame retardant, polyheptanazine, was investigated. Two novel, cost-effective phosphorus-doped polyheptazine (PCN) and cobalt-anchored PCN (Co@PCN) flame retardants were synthesized via a thermal condensation method. The X-ray photoelectron spectroscopy (XPS) results indicated effective doping of P into triazine. Then, flame-retardant particles were introduced into thermoplastic polyurethane (TPU) using a melt-blending approach. The introduction of 3 wt% PCN and Co@PCN could remarkably suppress peak heat release rate (pHRR) (48.5% and 40.0%), peak smoke production rate (pSPR) (25.5% and 21.8%), and increasing residues (10.18 wt%→17.04 wt% and 14.08 wt%). Improvements in charring stability and flame retardancy were ascribed to the formation of P-N bonds and P=N bonds in triazine rings, which promoted the retention of P in the condensed phase, which produced additional high-quality residues.

Effect of Cation Structure in Quinolinium-Based Ionic Liquids on the Solubility in Aromatic Sulfur Compounds or Heptane: Thermodynamic Study on Phase Diagrams.

Experimental and theoretical studies on thermodynamic properties of quinolinium-based ionic liquids (ILs) based on bis(trifluoromethylsulfonyl)imide anion (namely N-butyl-quinoloinium bis(trifluoromethylsulfonyl)imide, [BQuin][NTf2], N-hexylquinoloinium bis(trifluoromethyl-sulfonyl)imide, [HQuin][NTf2], and N-octylquinoloinium bis(trifluoromethyl-sulfonyl)imide, [OQuin][NTf2]) with aromatic sulfur compounds and heptane, as a model compound of fuel were examined in order to assess the applicability of the studied ionic liquids for desulfurization of fuels. With this aim, the temperature-composition phase diagrams of 13 binary mixtures composed of organic sulfur compounds (thiophene, benzothiophene, or 2-methylthiophene) or heptane and ionic liquid (IL) were investigated at ambient pressure. A dynamic method was used to determine the (solid-liquid) equilibrium phase diagrams in binary systems over a wide composition range and temperature range from T = 255.15 to 365.15 K up to the fusion temperature of ILs. The immiscibility gap with an upper critical solution temperature (UCST) was observed for each binary system under study. The influence of the alkane chain length of the substituent on the IL cation and of the sulfur compounds (the aromaticity of the solvent) was described. The experimental (solid + liquid) phase equilibrium dataset were successfully correlated using the well-known NRTL equation.

Influence of residual solvents on the physical properties of transdermal drug delivery systems.

The purpose of this investigation was to systematically assess the effect of residual solvents on the physical properties of a silicone adhesive-based transdermal system (TDS) containing n-heptane and o-xylene as residual solvents. The processing temperature was varied in this study to obtain various contents of residual solvents in the TDS. The adhesion performance was determined by evaluating the tack, shear, and peel of these TDS at week 0 and week 2. The adhesion measurements showed significant changes in tack values with a decrease in the contents of residual solvents, but the changes in peel and shear were insignificant. The rheological characteristics such as linear viscoelastic region, loss modulus and storage modulus were also measured. The outcome of the rheological measurements was found to be more sensitive to the changes in the contents of residual solvents in comparison to adhesion measurements. These results show that the residual solvent content may affect TDS performance and should be controlled from a product quality and performance perspective.

Solvents, CO2 and biopolymers: Structure formation in chitosan aerogel.

The functionality of biopolymer aerogels is inherently linked to its microstructure, which in turn depends on the synthesis protocol. Detailed investigations on the macroscopic size change and nanostructure formation during chitosan aerogel synthesis reveal a new aspect of biopolymer aerogels that increases process flexibility. Formaldehyde-cross-linked chitosan gels retain a significant fraction of their original volume after solvent exchange into methanol (50.3 %), ethanol (47.1 %) or isopropanol (26.7 %), but shrink dramatically during subsequent supercritical CO2 processing (down to 4.9 %, 3.5 % and 3.7 %, respectively). In contrast, chitosan gels shrink more strongly upon exchange into n-heptane (7.2 %), a low affinity solvent, and retain this volume during CO2 processing. Small-angle X-ray scattering confirms that the occurrence of the volumetric changes correlates with mesoporous network formation through physical coagulation in CO2 or n-heptane. The structure formation step can be controlled by solvent-polymer and polymer-drying interactions, which would be a new tool to tailor the aerogel structure.

Determination of toxic metal release from metallic kitchen utensils and their health risks.

The effect of simulants, repeated use, washing, and oiling on the release of toxic metals from metallic kitchen utensils was investigated. The release of As, Cd, Cr, Ni, and Pb from kitchen utensils composed of stainless steel, aluminum, copper alloy, and cast iron into food simulants was quantified using inductively coupled plasma-mass spectrometry. The results show that this release of toxic metals was highly dependent on pH. Generally, the release of toxic metals tended to decrease with repeated use, and the release of Cr and Ni from stainless steel samples was significantly higher in the first test, compared to the third test. The washing conditions affected the release of As and Cr, whose release levels were higher when washing only with water and with a steel wool pad, respectively. Furthermore, oiling cast iron cookware reduced the release of As, Cd, Cr, and Ni into acidic simulants by 66%, 83%, 71%, and 15%, respectively. The margin of exposure (MOE) was calculated for each toxic metal; the calculated MOE values indicated that it is improbable that the current level of exposure from metallic kitchen utensils would pose a health risk in Korea.

Optimal-robust selection of a fuel surrogate for homogeneous charge compression ignition modeling.

Homogeneous Charge Compression Ignition (HCCI) combustion is a potential candidate for dealing with the stringent regulations on vehicle emissions while still providing very good energy efficiency. Despite the promising results obtained in preliminary studies, the lack of autoignition control has delayed its launch in the engine industry. In the development of the HCCI concept, the availability of reliable computer models has proved extremely valuable, due to their flexibility and lower cost compared with experiments using real engines. In order to obtain the best formulation of a fuel surrogate formulated with n-heptane, toluene and cyclohexane that efficiently estimate the autoignition behaviour, regression adjustments are made to the Root-Mean-Square Errors (RMSE) of experimental Starts of Combustion (SOC) from the modeled SOC. The canonical form of the Scheffé polynomials is widely used to fit the data from mixture experiments, however the experimenter might have only partial knowledge. In this paper we present the adaptation of the robust methodology for possibly misspecified blending model and an algorithm to obtain tailor-made optimal designs for mixture experiments, instead of using standard designs which are indiscriminately employed, to make good estimations of the parameters blending model. We maximize the determinant of the mean squared error matrix of the least square estimator over a realistic neighbourhood of the fitted regression mixture model. The maximized determinant is then minimized over the class of possible designs, yielding an optimal design. Thus, the computed desings are robust to the exact form of the true blending model. Standard mixture designs, as the simplex lattice, are around 25% efficient for estimation purposes compared with the designs obtained in this work when deviances from the considered model occur during the experiments. Once an optimal-robust design was selected (based on the level of certainty about model adequacy), we computed the optimal mixture that best reproduces the combustion property to be imitated. Optimal mixtures obtained when the considered model is inadequate agree with the results achieved in empirical studies, which validates the methodology proposed in this work.

The Influence of Anionic, Cationic Surfactant and AOT/Water/Heptane Reverse Micelle on Photophysical Properties of Crocin: Compare with RPMI Effect.

Encapsulation of crocin (CN), having large nonlinear optical (NLO) properties, can be utilized in studies of photodynamic therapy (PDT). For this purpose, photo-physical and NLO properties of CN encapsulation with and without cell culture medium (CCM) were investigated. As well, nonlinear absorption (NLA) coefficient and nonlinear refractive (NLR) indices were found to be 10-7 (cm W-1) and 10-12 (cm2 W-1); respectively. The results revealed that NLO properties of CN had changed through its dipole moment. Reflecting on the theory of Bilot and Kawski, it was evidenced that the dipole moment of CN could change with a nano-droplet size. Furthermore, it was demonstrated that RPMI-1640 as a growth medium had failed to change NLO properties of CN encapsulated in nano-droplet. Accordingly, the encapsulated CN in nano-droplet in the form of a photosensitizer (PS) was suggested as a good candidate to examine PDT under in-vitro conditions.

A biphasic system based on guanidinium ionic liquid: Preparative separation of eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester by countercurrent chromatography.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are high nutritional components. Evidence for unique effects of them is increasing. Further understanding of their independent biological functions urgently needs more efficient separation techniques. Nowadays, most of the commercially available fish oil products are the mixture of eicosapentaenoic acid ethyl ester (EPAEE) and docosahexaenoic acid ethyl ester (DHAEE). It will be convenient to directly separate esterified EPA and DHA without saponification pretreatment. However, it is of great challenge to separate EPAEE and DHAEE because of their extremely fat-soluble nature and the equivalent chain length rule. In this research, the suitability of green guanidinium ionic liquid (IL) in countercurrent chromatography (CCC) solvent system for the separation of them was evaluated for the first time. Compared with imidazolium IL and phosphonium IL, guanidinium IL based non-aqueous biphasic system showed more outstanding separation performance. The separation mechanism was elucidated in depth through quantum mechanical calculations. It was found that guanidinium IL acted a crucial role in the CCC separation, which resulted in difference of partition behavior of EPAEE and DHAEE via different hydrogen-bonding affinity. EPAEE and DHAEE were successfully separated by solvent system (n-heptane/methanol/propylguanidinium chloride ([C3Gun]Cl, 1:1:5%, v/v/m)) with high purity (>95%) in one step, which was not achieved beforehand. Moreover, an easy recycling procedure of IL had also been devised, which significantly reduced waste generated. It opens up a new way for reasonable design water-free two-phase solvent system for efficient separation of very non-polar lipid compounds.

On-chip integration of normal phase high-performance liquid chromatography and droplet microfluidics introducing ethylene glycol as polar continuous phase for the compartmentalization of n-heptane eluents.

We introduce an integrated chip-approach for a postcolumn segmentation of normal phase liquid chromatography. This is achieved by the seamless integration of a chiral NP-chip-HPLC column, a flow-focusing droplet generator, and a segmented flow channel in a single microfluidic glass chip. This allows a continuous segmentation of the eluent into droplets which are picked up and transported via an immiscible continuous phase. The combination of NP-chip-HPLC and droplet microfluidics enables to fractionate and conserve chromatographic runs for further downstream processes at picoliter scale. An essential aspect is the proper choice of the continuous phase concerning polarity, wetting properties and viscosity. For this purpose, ethylene glycol is introduced which facilitates this first combination of normal phase chromatography and droplet microfluidics. By adjusting the flow rates and varying the generator geometry, the size and frequency of the droplets could be precisely controlled.

Scalable Preparation of Enantioenriched (S)-5-methylhept-2-en-4-one. Synthesis and Aroma Properties of Achiral Analogues Thereof.

(S)-5-Methylhept-2-en-4-one is a key flavour compound in hazelnuts. We have performed its chiral-pool-based chemoenzymatic synthesis with 39% overall yield (73% ee). The four-step aldol-based sequence avoids the use of highly reactive and/or toxic reagents, does not require anhydrous conditions and uses only distillation as the purification method. Thus, such methodology represents a green and scalable alternative to only two stereoselective approaches towards this natural product known so far. In addition, we have designed and prepared a set of new (di)enones as achiral synthetic analogues of the title compound. The results of their sensory analyses clearly show that relatively minor structural changes of the natural molecule significantly alter its olfactory properties. Thus, simple (poly)methylation completely changes the original hazelnut aroma of (S)-5-methylhept-2-en-4-one and shifts the odour of its analogues to eucalyptus, menthol, camphor, and sweet aroma.

Synthesis and biological properties of tetranuclear ruthenium complexes containing the bis[4(4'-methyl-2,2'-bipyridyl)]-1,7-heptane ligand.

Linear and non-linear tetranuclear ruthenium(ii) complexes containing the bridging ligand bis[4(4'-methyl-2,2'-bipyridyl)]-1,7-heptane have been synthesised and their biological properties examined. The minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) of the ruthenium(ii) complexes were determined against six strains of bacteria: Gram-positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA); and the Gram-negative Escherichia coli (E. coli) strains MG1655, APEC, UPEC and Pseudomonas aeruginosa (P. aeruginosa). The results showed that both tetranuclear complexes had significant antimicrobial activity, with the non-linear (branched) species (Rubb7-TNL) having slightly higher activity than the corresponding linear analogue (Rubb7-TL). The corresponding toxicity against three eukaryotic cell lines - BHK (baby hamster kidney), Caco-2 (heterogeneous human epithelial colorectal adenocarcinoma) and Hep-G2 (liver carcinoma) - have also been determined. Interestingly, both Rubb7-TNL and Rubb7-TL were as toxic to the eukaryotic cells as they were to the bacteria, a rarity for kinetically-inert cationic polypyridylruthenium(ii) complexes, and exhibited lower IC50 values than cisplatin over 24-, 48- or 72-hour incubation times. Fluorescence spectroscopy was used to study the binding of the ruthenium complexes with human serum albumin (HSA). Rubb7-TNL and Rubb7-TL exhibited strong HSA binding, with equilibrium binding constants in the order of 107 M-1. Confocal microscopy was used to examine the cellular localisation of Rubb7-TNL in BHK cells. The results indicated that the ruthenium complex localised in the nucleolus. Significant accumulation was also observed in the cytoplasm, but not in the mitochondria. Taken together, the results of this study suggest that Rubb7-TNL is an unlikely candidate as an antimicrobial agent, but may have potential as an anticancer drug.

New HSV-1 Anti-Viral 1'-Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Fragment as a Glycoside Moiety.

New 1'-homocarbanucleoside analogs with an optically active substituted bicyclo[2.2.1]heptane skeleton as sugar moiety were synthesized. The pyrimidine analogs with uracil, 5-fluorouracil, thymine and cytosine and key intermediate with 6-chloropurine (5) as nucleobases were synthesized by a selective Mitsunobu reaction on the primary hydroxymethyl group in the presence of 5-endo-hydroxyl group. Adenine and 6-substituted adenine homonucleosides were obtained by the substitution of the 6-chlorine atom of the key intermediate 5 with ammonia and selected amines, and 6-methoxy- and 6-ethoxy substituted purine homonucleosides by reaction with the corresponding alkoxides. No derivatives appeared active against entero, yellow fever, chikungunya, and adeno type 1viruses. Two compounds (6j and 6d) had lower IC50 (15 ± 2 and 21 ± 4 µM) and compound 6f had an identical value of IC50 (28 ± 4 µM) to that of acyclovir, suggesting that the bicyclo[2.2.1]heptane skeleton could be further studied to find a candidate for sugar moiety of the nucleosides.

HS-GC/MS method development and exposure assessment of volatile organic compounds from food packaging into food simulants.

A simultaneous headspace-gas chromatography/mass spectrometry (HS-GC/MS) method was developed and validated to determine the migration of 12 volatile organic compounds (methanol, acetone, methylethylketone, ethylacetate, isopropylalcohol, benzene, toluene, ethylbenzene, xylene, cumene, propylbenzene, and styrene) from food contact materials into food simulants (water, 4% acetic acid, 50% ethanol, and n-heptane). The limits of detection and quantification were 0.007-0.201 mg L-1 and 0.023-0.668 mg L-1, respectively. The method was applied to 205 samples of paper/paperboard, polyethylene, polypropylene, polystyrene, and polyethylene terephthalate. The estimated daily intake (EDI) was calculated using the migration results. Exposure assessments were carried out to compare the EDI to the tolerable daily intake (TDI); the results indicated that the EDI of styrene represented only a small percentage (8.0%) of the TDI. This analytical method will be a useful tool to examine levels of various volatile compounds migrating from food packaging to food simulants using HS-GC/MS method.

Modeling the competitive adsorption of sample solvent and solute in supercritical fluid chromatography.

Uncommon retention behavior of a series of n-alkylbenzene homologues as well as the effect of different sample solvents on chromatographic efficiency were studied in supercritical fluid chromatography. After testing various columns, an alkylamide stationary phase was selected for detailed studies. The results showed that even a small amount of methanol originating only from the sample, overloaded the column and competitive adsorption was induced between the analytes and the sample solvent for adsorption on the stationary phase. This was indicated by the changes in column efficiency, retention and peak widths. The concentration of the analytes in the sample was negligible compared to the amount of methanol - but their adsorption was influenced by the solvent - while the adsorption of methanol remained unaffected by the n-alkylbenzenes. First, the competition was described by determining the single-component adsorption isotherms for both the analytes and their solvent, then competitive isotherms were calculated. Based on the peak profiles, bi-Langmuir and competitive bi-Langmuir isotherms were assumed. The solvent effect was modeled by a numerical method created in-house where the differential mass balance equation given by the equilibrium-dispersive (ED) model was integrated using the Rouchon algorithm. The experimental observations were confirmed by in silico experiments and additional cases involving two hypothetical analytes were studied as well.