Modified aryldifluorophenylsilicates with improved activity and selectivity in nucleophilic fluorination of secondary substrates.

Nucleophilic fluorination of secondary aliphatic substrates, especially of halides, still remains a challenge. Among the available reagents, TBAT belongs to one of the best choices due to its stability, affordable price and low toxicity. With the aim to improve its selectivity, we synthesized three analogues modified in the aryl part of the TBAT reagent with one or two electron donating methoxy groups or with one electron withdrawing trifluoromethyl group. All three reagents are air-stable compounds and their structure was confirmed by a single crystal X-ray analysis. In testing the reactivity and selectivity of the reagents with a library of secondary bromides, as well as of other selected primary and secondary substrates, we found that substitution with methoxy groups mostly improves both reactivity and selectivity compared to TBAT, while the substitution with trifluoromethyl group leads to inferior results. Difluorosilicates modified by more than two electron donating methoxy groups proved to be unstable and decomposed spontaneously to the HF2 - anion. DFT calculations of tetramethylammonium analogues of the studied reagents disclosed that the substitution of the phenyl group with the methoxy substituent lowers the transitions state energy of the decomposition to a fluorosilane-fluoride complex, while the substitution with the trifluoromethyl group has an opposite effect.

Quaternary ammonium fluorides and difluorosilicates as nucleophilic fluorination reagents.

TBAT (tetrabutylammonium difluorotriphenylsilicate) is an excellent homogeneous nucleophilic fluorination reagent, but a high excess of the reagent was reported to be essential. We hence optimized the reaction conditions and compared its nucleophilic fluorination reactivity with that of other common commercial nucleophilic fluorination reagents, such as anhydrous TBAF and TASF (tris(dimethylamino)sulfonium difluorotrimethylsilicate). As the substrates, we employed a standard set of primary and secondary octyl substrates under identical conditions. To eliminate the possibility of hydrogen fluoride elimination in the above reagents, we prepared four quaternary ammonium fluorides lacking ß-elimination possibility in the hydrocarbon chain, transformed them to the corresponding difluorotriphenylsilicates, and compared their reactivity with that of the commercial reagents. Furthermore, attempts to isolate analogous tetrabutylammonium difluoromethyldiphenylsilicate or difluorodimethylphenylsilicate failed, as was confirmed by comparison of the published experimental data with computed 19F NMR spectra. Finally, we studied the transition states of decomposition of various tetramethylammonium methylphenyldifluorosilicates by DFT methods and found that their relative energies increase with an increasing number of phenyl groups. The formation of difluorosilicates is a nearly barrierless process.

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.

Non-Symmetrical Tetrafluoroalkadienes Synthesized by ROCM of 3,3,4,4-Tetrafluorocyclobutene.

As the first known example of ring-opening cross metathesis (ROCM) of polyfluorinated strained cyclobutenes, ROCM of 3,3,4,4-tetrafluorocyclobutene with electronically rich alkenes, catalyzed by Grubbs or Hoveyda-Grubbs 2nd generation precatalysts, gave a small library of non-symmetrical isolated dienes bearing a tetrafluoroethylene spacer between the double bonds. 1-Butoxy-3,3,4,4-tetrafluorohexa-1,5-diene thus formed underwent subsequent regioselective cross metathesis (CM) with a series of styrenes, catalyzed by Hoveyda-Grubbs 2nd generation precatalyst, leading to non-symmetrically substituted dienes. 6,6-Dibutoxy-3,3,4,4-tetrafluorohex-1-ene, formed by regioselective butoxylation of 1-butoxy-3,3,4,4-tetrafluorohexa-1,5-diene, was dihydroxylated and cyclized to the corresponding 3,3,4,4-tetrafluorohexopyranose.

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.

Electrochemical investigation of structurally varied azinium scaffolds.

Inspired by the successful utilization of aziniums as anolytes in redox-flow batteries, we have designed and prepared a systematically extended series of (di)azinium compounds based on pyrazine, bipyridine, 1,5-naphthyridine, 3,8-phenanthroline, (E)-4,4'-diazastilbene and 1,2-bis(pyridin-4-yl)acetylene. It has been revealed that the fundamental electrochemical properties are affected mostly by the water-solubility and chemical stability of the particular redox forms. Based on the systematically evolved azinium structure and gathered electrochemical data, structure-property relationships were thoroughly elucidated. Further investigation on flow battery cells identified that the known 4,4'-bipyridinium decorated with two peripheral N-propyl-3-sulfonato pendants allows utilizing both redox steps with good cycling stability, while the naphthyridine scaffold turned out to be a new and promising scaffold for redox-flow batteries.

Mechanism of Alkyl Chloroformate-Mediated Esterification of Carboxylic Acids in Aqueous Media.

The protection of carboxyl groups by esterification has been the most common method in macroscale and microscale chemistries. The esterification is usually conducted under anhydrous conditions; however, in biological chemistry and related fields, the reaction is of major concern in aqueous environments. Immediate esterification of the carboxyl in aqueous alcoholic media driven by an alkyl chloroformate and pyridine has been such a method which has found widespread use in many research and industrial laboratories. Nevertheless, the reaction mechanism has not yet been investigated, to our knowledge, and is not well understood. Herein, we describe the reaction intermediates and demonstrate that the reaction proceeds via a continual formation of the N-acylpyridinium intermediate decomposed by several reaction channels to the final ester. The understanding of the mechanism could encourage novel laboratory applications of this important esterification method.

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans.

The prochiral 4-(allyloxy)hepta-1,6-diynes, optionally modified in the positions 1 and 7 with an alkyl or ester group, undergo a chemoselective ring-closing enyne metathesis yielding racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans. Among the catalysts tested, Grubbs 1st generation precatalyst in the presence of ethene (Mori conditions) gave superior results compared to the more stable Grubbs or Hoveyda-Grubbs 2nd generation precatalysts. This is probably caused by a suppression of the subsequent side-reactions of the enyne metathesis product with ethene. On the other hand, the 2nd generation precatalysts gave better yields in the absence of ethene. The metathesis products, containing both a triple bond and a conjugated system, can be successfully orthogonally modified. For example, the metathesis product of 5-(allyloxy)nona-2,7-diyne reacted chemo- and stereoselectively in a Diels-Alder reaction with N-phenylmaleimide affording the tricyclic products as a mixture of two separable diastereoisomers, the configuration of which was estimated by DFT computations. The reported enediyne metathesis paves the way to the enantioselective enyne metathesis yielding chiral building blocks for compounds with potential biological activity, e.g., norsalvinorin or cacospongionolide B.

Redox Property Tuning in Bipyridinium Salts.

Bipyridinium salts are currently very popular due to their perspective applications in redox flow batteries. Hence, we designed and prepared a series of bipyridiniums based on 2,2'-, 3,3'-, and 4,4'-bipyridine and 2,2'-bipyrimidine. The straightforward synthesis utilizes commercially or readily available starting compounds and their direct N-alkylation, mostly using 1,3-propanesultone. All eleven target derivatives with systematically evolved structure were investigated by cyclic voltammetry, which allowed elucidating thorough structure-property relationships. The electrochemical behavior depends primarily on the parent scaffold, type of N-alkylation, number of quaternized nitrogen atoms, planarity, counter ion as well as the used media. Two derivatives featuring quasi-reversible redox processes were further tested on rotating disc electrode and in a flow battery half-cell. 4,4'-Bipyridinium derivative bearing two sultone residues showed better performance and stability in the flow half-cell with small capacity decays of 0.09/0.15% per reduction-oxidation cycle, based on the number of the utilized redox processes (one/two).

Computational study of productive and non-productive cycles in fluoroalkene metathesis.

A detailed DFT study of the mechanism of metathesis of fluoroethene, 1-fluoroethene, 1,1-difluoroethene, cis- and trans-1,2-difluoroethene, tetrafluoroethene and chlorotrifluoroethene catalysed with the Hoveyda-Grubbs 2(nd) generation catalyst was performed. It revealed that a successful metathesis of hydrofluoroethenes is hampered by a high preference for a non-productive catalytic cycle proceeding through a ruthenacyclobutane intermediate bearing fluorines in positions 2 and 4. Moreover, the calculations showed that the cross-metathesis of perfluoro- or perhaloalkenes should be a feasible process and that the metathesis is not very sensitive to stereochemical issues.

Interaction of ionic liquids ions with natural cyclodextrins.

The interaction of natural α-, ß-, and γ-cyclodextrins (CDs) with 14 hydrophobic ionic moieties of ionic liquids (ILs) was systematically examined in dilute aqueous solutions using isothermal titration microcalorimetry (ITC) and NMR spectroscopy. The studied cationic and anionic moieties involved some recently developed heavily fluorinated structures, as well as some others of common use. To isolate the effect of a given ion, the measurements were performed on salts containing the hydrophobic IL ion in question and a complexation-inactive counterion. Additional ITC experiments on ILs whose both cation and anion can interact appreciably with the CD cavity demonstrated that to resolve the effect of individual ions from such data is generally a tricky task and confirmed the superiority of the isolation strategy adopted for the purpose throughout this work. The binding constant, enthalpy and entropy determined at 298.15 K for the 1:1 (ion:CD) inclusion complex formation range in broad limits, being 0 < K < 2 × 10(5), 0 < -Δ(r)H°/(kJ·mol(-1)) < 44, and -28 < TΔ(r)S°/(kJ·mol(-1)) < 14, respectively. The stabilities of complexes of perfluorohexyl bearing ions with ß-CD belong to the highest ever observed with natural CDs in water. The established binding affinity scales were discussed in both thermodynamic and molecular terms. The concepts of hydrophobic interaction and guest-host size matching supported by simple molecular modeling proved useful to rationalize the observed widely different binding affinities and suggest possible binding modes. Enthalpy and entropy contributions to the stability of the ion-CD complexes were found to compensate each other considerably obeying more or less the linear compensation relationship marked by existing literature data on binding other guests to natural CDs. As outliers to this pattern, the most stable complexes of -C(6)F(13) bearing ions with ß-CD were found to receive an enhanced inherent entropy stabilization due to extraordinarily high extent of desolvation occurring in the course of binding.

Trifluoromethylated (tetrahydropyrrolo) quinazolinones by a new three-component reaction and facile assignment of the regio- and stereoisomers formed by NMR spectroscopy.

A new three-component cyclisation reactions of methyl 3,3,3-trifluoropyruvate, 2-aminobenzylamine and oxo compounds afforded tetrahydropyrroloquinazolinones of the types 4 and 5 as mixtures of regio- and stereoisomers. Whereas standard 1D NMR spectroscopy was used for a facile assignment of the cyclization regioisomers, a combination of homo (proton-proton) and heteronuclear (proton-fluorine) NOE experiments allowed the determination of the relative configuration on stereogenic centres. The structure of some compounds was also confirmed by the X-ray diffraction. Adaptation of the 1D double-pulsed field-gradient spin-echo NOE for a heteronuclear case is presented.