Trifluoromethylthiolation of Tryptophan and Tyrosine Derivatives: A Tool for Enhancing the Local Hydrophobicity of Peptides.

The incorporation of fluorinated groups into peptides significantly affects their biophysical properties. We report herein the synthesis of Fmoc-protected trifluoromethylthiolated tyrosine (CF3S-Tyr) and tryptophan (CF3S-Trp) analogues on a gram scale (77-93% yield) and demonstrate their use as highly hydrophobic fluorinated building blocks for peptide chemistry. The developed methodology was successfully applied to the late-stage regioselective trifluoromethylthiolation of Trp residues in short peptides (66-80% yield) and the synthesis of various CF3S-analogues of biologically active monoamines. To prove the concept, Fmoc-(CF3S)Tyr and -Trp were incorporated into the endomorphin-1 chain (EM-1) and into model tripeptides by solid-phase peptide synthesis. A remarkable enhancement of the local hydrophobicity of the trifluoromethylthiolated peptides was quantified by the chromatographic hydrophobicity index determination method, demonstrating the high potential of CF3S-containing amino acids for the rational design of bioactive peptides.

From cyclic (alkyl)(amino)carbene (CAAC) precursors to fluorinating reagents. Experimental and theoretical study.

Addition of anhydrous HF to the hydrochloride [MeCAACH][Cl(HCl)0.5] resulted in the formation of salts with high HF content. By stepwise removal of HF in vacuo, we selectively prepared [MeCAACH][F(HF)2] (3) and [MeCAACH][F(HF)3] (4). We also characterised a salt with [F(HF)4]- anions within the structure of [MeCAACH][F(HF)3.5] (5). Compounds with a lower content of HF were not accessible under vacuum conditions. MeCAAC(H)F (1) was selectively prepared by abstraction of HF from 3 with CsF or KF, while [MeCAACH][F(HF)] (2) was prepared by mixing 3 and 1 in a 1 : 1 ratio. Compound 2 proved to be quite unstable as it tends to disproportionate into 1 and 3. This observation triggered our computational study, in which the structural relationships between CAAC-based fluoropyrrolidines and dihydropyrrolium fluorides were investigated using different DFT methods. The study showed that the results were very sensitive to the computational method used. For a correct description, the quality of the triple-ζ basis set was crucial. Surprisingly, the isodesmic reaction of [MeCAACH][F] + [MeCAACH][F(HF)2] → [MeCAACH][F(HF)] + [MeCAACH][F(HF)] did not confirm the low thermodynamic stability of 2. Furthermore, the use of 3 as a nucleophilic fluorinating reagent was tested on a range of organic substrates, as it is the most stable compound in this series. It was found to have the potential to fluorinate benzyl bromides, 1- and 2-alkyl bromides, silanes and sulfonyls with good to excellent yields of the target fluorides.

Synthesis of imidazolium-based pentacoordinated organofluorosilicate and germanate salts.

The syntheses of a new triphenyldifluorogermanate and various pentacoordinated organofluorosilicates are presented. The fluorogermane and fluorosilane compounds were obtained from the corresponding chlorosilanes and chlorogermane by halogen substitution with KF. Subsequent reaction with the imidazolium-based fluoride reagent [IPrH][F] (1,3-bis(2,6-diisopropylphenyl)imidazolium fluoride) led to the formation of [IPrH][Ph3SiF2] (1), [IPrH][Ph2SiF3] (3), [IPrH][Et2SiF3] (4), [IPrH][PhSiF4] (5), [IPrH][EtSiF4] (6) and [IPrH][Ph3GeF2] (7). All the products obtained were characterised by NMR, Raman spectroscopy and X-ray diffraction. The results were supported by DFT calculations of the structurally optimised compounds.

New Insights into Amino-Functionalization of Magnetic Nanoplatelets with Silanes and Phosphonates.

Magnetic nanoplatelets (NPLs) based on barium hexaferrite (BaFe12O19) are suitable for many applications because of their uniaxial magneto-crystalline anisotropy. Novel materials, such as ferroic liquids, magneto-optic composites, and contrast agents for medical diagnostics, were developed by specific surface functionalization of the barium hexaferrite NPLs. Our aim was to amino-functionalize the NPLs' surfaces towards new materials and applications. The amino-functionalization of oxide surfaces is challenging and has not yet been reported for barium hexaferrite NPLs. We selected two amine ligands with two different anchoring groups: an amino-silane and an amino-phosphonate. We studied the effect of the anchoring group, backbone structure, and processing conditions on the formation of the respective surface coatings. The core and coated NPLs were examined with transmission electron microscopy, and their room-temperature magnetic properties were measured. The formation of coatings was followed by electrokinetic measurements, infrared and mass spectroscopies, and thermogravimetric analysis. The most efficient amino-functionalization was enabled by (i) amino-silanization of the NPLs precoated with amorphous silica with (3-aminopropyl)triethoxysilane and (ii) slow addition of amino-phosphonate (i.e., sodium alendronate) to the acidified NPL suspension at 80 °C.

Oxidation of Iodine to Dihaloiodate(I) Salts of Amines With Hydrogen Peroxides and Their Crystal Structures.

Herein we report a general preparation of dihaloiodate salts of heterocyclic amines (tertiary and quaternary) with sterically accessible and hindered nitrogen atom. A number of such compounds were prepared from preformed HICl2 or HIBr2 formed in situ by the reaction of corresponding hydrogen halide, iodine and H2O2. The salts of 1,4-diazabicyclo[2.2.2]octane (DABCO) and its methylated derivatives, 1,3,5,7-tetraazaadamantane (HMTA), diazabicycloundecene (DBU) and 2,4,6-tri-tert-butylpyridine (TBP) were obtained in excellent yields and their structure was determined by NMR and Raman spectroscopy and single crystal X-ray diffraction. Non-hindered bases such as DABCO, HMTA and DBU formed IX2 - salts, which further decomposed to complexes with interhalogen compounds due to formation of N…X halogen bonds. The dihaloiodiate(I) salts of sterically hindered 2,4,6-tri-tert-butylpyridine were stable. Its dichlorobromate(I) salt was also prepared via a different synthetic method using N-chlorosuccinimide as oxidant.

Reusable Pd-PolyHIPE for Suzuki-Miyaura Coupling.

Palladium was immobilized on a highly porous copolymer of 4-vinylpyridine and divinylbenzene (polyHIPE-poly(high internal phase emulsion)) using palladium(II) acetate to obtain PolyPy-Pd with 6.1 wt % or 0.57 mmol Pd/g. The immobilized catalyst was able to catalyze the coupling of iodobenzene and phenylboronic acid in ethylene glycol monomethyl ether/water (3:1) within 4 h at rt and complete conversion was observed when 2.5 mol % of Pd per PhI was used. The reaction tolerated a wide range of substituents on the aromatic ring. Iodobenzene derivatives with electron-withdrawing substituents showed higher reactivity, while the opposite was true for the phenylboronic acid series. The polyHIPE-supported Pd catalyst was also used for the direct conversion of phenylboronic acid to biphenyl through an iodination/coupling reaction sequence. The recyclability of the heterogeneous catalyst was also optimized, and by finding a suitable combination of solvents for the loading of Pd, the reaction, and the isolation of the product, the solid-supported catalyst was completely regenerated and used in the next reaction with the same activity.

Renewable Reagent for Nucleophilic Fluorination.

Herein, we report a study on the reactivity of three 1,3-diarylimidazolium-based fluoride reagents, with a general formula of [IPrH][F(HF)n] (n = 0, 1, or 2), that tackle the challenges of limited solubility, hygroscopicity, instability, and laborious preparation procedures of nucleophilic fluoride reagents. Fluorination of 4-tert-butylbenzyl bromide reveals that trifluoride [IPrH][F(HF)2] is the most selective reagent. Microwave-assisted activation coupled with the addition of sterically hindered amine DIPEA or alkali metal fluorides increases the rate of fluorination with [IPrH][F(HF)2], making it an excellent reagent for the fluorination of various organic substrates. The scope of substrates includes benzyl bromides, iodides, chlorides, aliphatic halides, tosylates, mesylates, α-haloketones, a silyl chloride, acyl and sulfuryl chlorides, and a nitroarene. The exceptional stability of the air-stable and nonhygroscopic [IPrH][F(HF)2] reagent is illustrated by its convenient synthesis and detailed experimental regeneration protocol using hydrofluoric acid without organic solvents.

Antiviral Activities of Halogenated Emodin Derivatives against Human Coronavirus NL63.

The current COVID-19 outbreak has highlighted the need for the development of new vaccines and drugs to combat Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Recently, various drugs have been proposed as potentially effective against COVID-19, such as remdesivir, infliximab and imatinib. Natural plants have been used as an alternative source of drugs for thousands of years, and some of them are effective for the treatment of various viral diseases. Emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) is a biologically active anthraquinone with antiviral activity that is found in various plants. We studied the selectivity of electrophilic aromatic substitution reactions on an emodin core (halogenation, nitration and sulfonation), which resulted in a library of emodin derivatives. The main aim of this work was to carry out an initial evaluation of the potential to improve the activity of emodin against human coronavirus NL63 (HCoV-NL63) and also to generate a set of initial SAR guidelines. We have prepared emodin derivatives which displayed significant anti-HCoV-NL63 activity. We observed that halogenation of emodin can improve its antiviral activity. The most active compound in this study was the iodinated emodin analogue E_3I, whose anti-HCoV-NL63 activity was comparable to that of remdesivir. Evaluation of the emodin analogues also revealed some unwanted toxicity to Vero cells. Since new synthetic routes are now available that allow modification of the emodin structure, it is reasonable to expect that analogues with significantly improved anti-HCoV-NL63 activity and lowered toxicity may thus be generated.

One pot synthesis of trifluoromethyl aryl sulfoxides by trifluoromethylthiolation of arenes and subsequent oxidation with hydrogen peroxide.

Hydrogen peroxide was used for oxidation of various aryl trifluoromethyl sulfides. Trifluoroacetic acid was used as an activating solvent that enables non-catalyzed oxidation and increases selectivity for sulfoxide formation. As shown by oxidation of thianthrene TFA enhances electrophilic character of the oxidant and further oxidation of sulfoxide group is blocked. We have joined trifluoromethylthiolation of arenes using a modified Billard reagent (p-ClPhNHSCF3) with oxidation of aryl trifluoromethyl sulfides using 1.2 equiv. of 30% aqueous hydrogen peroxide and this one-pot process has superior yields than would have been obtained in a two step process.

Effect of Oxygen Plasma on Sprout and Root Growth, Surface Morphology and Yield of Garlic.

Depending on the climate, garlic can be planted either in the fall or spring for a harvest in the summer, but spring planting might require the strengthening of the plant by external techniques. We have used low pressure, inductively coupled, radio frequency oxygen plasma for the treatment of peeled garlic cloves of a spring-planted Slovenian autochthonous cultivar. The aim of the study was to assess the effects of plasma treatment on garlic clove shoot and root growth and, ultimately, the yield. The roles of surface chemistry, surface morphology, and water uptake in these effects were also evaluated. The plasma treatment of cloves induced increases in water uptake. The increases were explained by changes in surface morphology that were determined by using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Nanostructured epicuticular wax structures appeared at the cuticle surface. The optimal treatment parameters accelerated root growth, but not shoot growth, in a laboratory setting. After growth in the field, the trends indicated that plant height and dried bulb mass increase, but the improvements were not statistically significant.

Aerobic Oxidation of Secondary Alcohols with Nitric Acid and Iron(III) Chloride as Catalysts in Fluorinated Alcohol.

Fluorinated alcohols as solvents strongly influence and direct chemical reaction through donation of strong hydrogen bonds while being weak acceptors. We used 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the activating solvent for a nitric acid and FeCl3-catalyzed aerobic oxidation of secondary alcohols to ketones. Reaction proceeded selectively with excellent yields with no reaction on the primary alcohol group. Oxidation of benzyl alcohols proceeds selectively to aldehydes with only HNO3 as the catalyst, while reaction on tertiary alcohols proceeds through dehydration and dimerization. A mechanistic study showed in situ formation of NOCl that converts alcohol into alkyl nitrite, which in the presence of Fe3+ ions and fluorinated alcohol decomposes into ketone. The study indicates that iron(III) acts also as the single-electron transfer catalyst in regeneration of NOCl reactive species.

Hydrothermal Degradation of Rutin: Identification of Degradation Products and Kinetics Study.

The model glycoside compound quercetin-3-O-rutinoside (rutin) was subjected to subcritical water within the temperature range of 120-220 °C, and the hydrothermal degradation products were analyzed. Two kinetic models describing the degradation of this compound in two different atmospheres (N2 and CO2), used for pressure establishment in the reactor, have been developed and compared. Reaction was considered a successive one with three irreversible steps. We confirmed that rutin degradation to quercetin follows first-order kinetics. At higher temperatures quercetin is further degraded in two degradation steps. Formations of 3,4-dihydroxybenzoic acid and catechol were described with the zero-order kinetic models. Reaction rate constants for hydrolysis of glycoside to aglycone in a CO2 atmosphere are higher compared to those in a N2 atmosphere, whereas at higher temperatures reaction rate constants for further two successive reactions of aglycone degradation are slightly lower in the presence of CO2. The difference in reaction activation energies is practically negligible for both gases. Furthermore, degradation products of sugar moieties, that is, 5-hydroxymethylfurfural and 5-methylfurfural, were also detected and analyzed.

Understanding malarial toxins.

Recognized since antiquity, malaria is one of the most infamous and widespread infectious diseases in humans and, although the death rate during the last century has been diminishing, it still accounts for more than a half million deaths annually. It is caused by the Plasmodium parasite and typical symptoms include fever, shivering, headache, diaphoresis and nausea, all resulting from an excessive inflammatory response induced by malarial toxins released into the victim's bloodstream. These toxins are hemozoin and glycosylphosphatidylinositols. The former is the final product of the parasite's detoxification of haeme, a by-product of haemoglobin catabolism, while the latter anchor proteins to the Plasmodium cell surface or occur as free molecules. Currently, only two groups of antimalarial toxin drugs exist on the market, quinolines and artemisinins. As we describe, they both target biosynthesis of hemozoin. Other substances, currently in various phases of clinical trials, are directed towards biosynthesis of glycosylphosphatidylinositol, formation of hemozoin, or attenuation of the inflammatory response of the patient. Among the innovative approaches to alleviating the effects of malarial toxins, is the development of antimalarial toxin vaccines. In this review the most important lessons learned from the use of treatments directed against the action of malarial toxins in antimalarial therapy are emphasized and the most relevant and promising directions for future research in obtaining novel antimalarial agents acting on malarial toxins are discussed.

The micro-scale synthesis of (117)Sn-enriched tributyltin chloride and its characterization by GC-ICP-MS and NMR techniques.

Organotin compounds (OTCs) are among the most toxic substances ever introduced to the environment by man. They are common pollutants in marine ecosystems, but are also present in the terrestrial environment, accumulated mainly in sewage sludge and landfill leachates. In investigations of the degradation and methylation processes of OTC in environmental samples, the use of enriched isotopic tracers represents a powerful analytical tool. Sn-enriched OTC are also necessary in application of the isotope dilution mass spectrometry technique for their accurate quantification. Since Sn-enriched monobutyltin (MBT), dibutyltin (DBT) and tributyltin (TBT) are not commercially available as single species, "in house" synthesis of individual butyltin-enriched species is necessary. In the present work, the preparation of the most toxic butyltin, namely TBT, was performed via a simple synthetic path, starting with bromination of metallic Sn, followed by butylation with butyl lithium. The tetrabutyltin (TeBT) formed was transformed to tributyltin chloride (TBTCl) using concentrated hydrochloric acid (HCl). The purity of the synthesized TBT was verified by speciation analysis using the techniques of gas chromatography coupled to inductively coupled plasma mass spectrometry (GC-ICP-MS) and nuclear magnetic resonance (NMR). The results showed that TBT had a purity of more than 97%. The remaining 3% corresponded to DBT. TBT was quantified by reverse isotope dilution GC-ICP-MS. The synthesis yield was around 60%. The advantage of this procedure over those previously reported lies in its possibility to be applied on a micro-scale (starting with 10mg of metallic Sn). This feature is of crucial importance, since enriched metallic Sn is extremely expensive. The procedure is simple and repeatable, and was successfully applied for the preparation of (117)Sn-enriched TBTCl from (117)Sn-enriched metal.

The effect of fluorine atom on the synthesis and composition of gametocidal ethyl oxanilates.

Three derivatives of ethyl oxanilate were synthesized in order to test their application as gametocides on the hermaphrodite plants like common wheat (Triticum aestivum L.). A substituent at para position (F, Br, CN) of aniline defined its reactivity towards diethyl oxalate 2. Classical reaction in toluene was not selective and amidation occurred also at the second carbonyl groups of 2. Alternative synthesis under solvent-free conditions with application of low pressure for removal of EtOH provided selectively with ethyl oxanilate 3a and 3b. 4-Cyanoaniline did not react selectively and the corresponding ethyl oxanilate 3c was prepared from mono acid chloride of oxalic acid. Fluoro derivative 3a was found to be the only one that gives stable aqueous suspension for its application as chemical hybridizing agent for common wheat, while bromo- 3b and cyano- 3c analogues were not soluble enough and suspension was stable for less than 2 hours. Fluoro derivative had shown the best induction of male sterility, while in comparison with standard chemical hybridizing agent they were substantially less toxic for plant.

Conversion of aryl iodides into aryliodine(III) dichlorides by an oxidative halogenation strategy using 30% aqueous hydrogen peroxide in fluorinated alcohol.

Oxidative chlorination with HCl/H2O2 in 1,1,1-trifluoroethanol was used to transform aryl iodides into aryliodine(III) dihalides. In this instance 1,1,1-trifluoroethanol is not only the reaction medium, but is also an activator of hydrogen peroxide for the oxidation of hydrochloric acid to molecular chlorine. Aryliodine(III) dichlorides were formed in 72-91% isolated yields in the reaction of aryl iodides with 30% aqueous hydrogen peroxide and hydrochloric acid at ambient temperature. A study of the effect that substituents on the aromatic ring have on the formation and stability of aryliodine(III) dichlorides shows that the transformation is easier to achieve in the presence of the electron-donating groups (i.e. methoxy), but in this case the products rapidly decompose under the reported reaction conditions to form chlorinated arenes. The results suggest that oxidation of hydrogen chloride with hydrogen peroxide is the initial reaction step, while direct oxidation of aryl iodide with hydrogen peroxide is less likely to occur.

Oxidative halogenation with "green" oxidants: oxygen and hydrogen peroxide.

It is difficult to imagine organic chemistry without organo-halogen compounds and the molecular halogens needed for their preparation. The halogens have very different reactivity, with iodine usually requiring some form of activation, while others are reactive and hazardous chemicals. To avoid their use, various modified reagents have been discovered (N-bromo- and N-chlorosuccinimide, Selectfluor..), but halogens are used to prepare these reagents and when they are used the atom economy is poor. A better approach, which is based on biomimetric research on oxidative halogenation in nature, consists of generating the halogenating reagent in situ under acidic conditions from a halide salt. The result of such a reaction has been halogenation with 100 % halogen atom economy. Suitable oxidants for the oxidation of halides are hydrogen peroxide and oxygen.

Synthesis and reactivity of fluorous and nonfluorous aryl and alkyl iodine(III) dichlorides: new chlorinating reagents that are easily recycled using biphasic protocols.

Fluorous aryl and alkyl iodine(III) dichlorides of the formulas (R(fn)(CH(2))(3))(2)C(6)H(3)ICl(2) (R(fn) = CF(3)(CF(2))(n-1); n = 8 for 3,5-disubstituted and n = 6, 8, 10 for 2,4-disubstituted) and R(fn)CH(2)ICl(2) (n = 8, 10) are prepared in 71-98% yields by reactions of Cl(2) and the corresponding fluorous iodides. These are effective reagents for the conversions of cyclooctene to trans-1,2-dichlorocyclooctene, anisole to 4-chloro- and 2-chloroanisole, 4-tert-butylphenol to 2-chloro-4-tert-butylphenol, PhCOCH(2)COPh to PhCOCHClCOPh, and PhCOCH(3) to PhCOCH(2)Cl and PhCOCHCl(2) (CH(3)CN, rt to 40 degrees C, 100-64% conversions). The chlorinated products and fluorous iodide coproducts are easily separated by organic/fluorous liquid/liquid biphase workups. The latter are obtained in 97-90% yields and reoxidized with Cl(2). Analogous chlorinations are conducted with 3-Cl(2)IC(6)H(4)COOH (16) and 4,4'-Cl(2)IC(6)H(4)C(6)H(4)ICl(2). With the former, the products and coproduct 3-IC(6)H(4)COOH (91-85% recoveries) are easily separated by organic/aqueous NaHCO(3) liquid/liquid biphase workups. The coproduct from the latter, 4,4'-IC(6)H(4)C(6)H(4)I, is insoluble in common organic solvents, allowing separation by liquid/solid phase workups (91-89% recoveries). The effect of the structure of the iodine(III) dichloride upon reactivity is analyzed in detail. The fluorous systems with R(f8) substituents are generally superior, but 16 is more reactive and gives higher selectivities.

Alpha-substituted organic peroxides: synthetic strategies for a biologically important class of gem-dihydroperoxide and perketal derivatives.

In this paper we review the recent developments in the synthesis of alpha-substituted hydroperoxides. Alpha-substituted hydroperoxides are interesting compounds due to their chemistry and bioactivity and as intermediates for the synthesis of other peroxides, of which cyclic peroxides are of major importance. Although the emphasis of this report will be on the derivatives of gem-dihydroperoxides, perketals, as well as the less studied nitrogen and sulfur derivatives, will also be covered.

The effect of iodine on the peroxidation of carbonyl compounds.

Peroxidation of ketones and aldehydes with iodine as a catalyst was studied. Ketones reacted with 30% aq hydrogen peroxide in the presence of 10 mol % of iodine to yield gem-dihydroperoxides in acetonitrile and hydroperoxyketals in methanol. The yield of hydroperoxidation of various cyclic ketones was 60-98%, including androstane-3,17-dione, while acyclic ketones were converted with a similar efficiency. Aromatic aldehydes were also converted to gem-dihydroperoxides with hydrogen peroxide and iodine as catalyst in acetonitrile and to hydroperoxyacetal in methanol, while the reactivity of aliphatic ones remained the same as in noncatalyzed reactions. tert-Butylhydroperoxide reacted in a similar manner, giving the corresponding perether derivatives. A study was also made of the relative kinetics of dihydroperoxidation from which the Hammet equation gave a reaction constant (rho) of -2.76, indicating the strong positive charge development in the transition state and the important role of rehybridization in the conversion of hydroperoxyhemiketal to gem-dihydroperoxide. In acetonitrile, the iodine catalyst is apparently able to discriminate between the elimination of a hydroxy, methoxy, and hydroperoxy group and addition of water, methanol, and H2O2 to a carbonyl group.