Alkali Metal Bases Research Articles

Functionalisation of Chromane by Deprotonative Metallation

Despite the biological interest in chromane derivatives, few studies dedicated to the functionalisation of this heterocycle have been reported. Herein, our objective is to demonstrate the potential of alkali metal bases for the introduction of substituents at its positions 4 and 8, and to explain the observed reactivity based on quantum chemical calculations. Guided by these theoretical results, preliminary optimisation was carried out on 2,3‐dihydrobenzofuran before applying the optimal conditions to chromane. Deprotolithiation at C8 was thus achieved using n‐butyllithium in hexane at room temperature, while functionalisation at C4 was promoted by a 1:1 mixture of lithium 2,2,6,6‐tetramethylpiperidide and potassium tert‐butoxide in tetrahydrofuran at ‐50 °C. Various electrophiles were used to intercept the lithiated intermediates, providing a convenient access to substituted chromane derivatives.

Lithium-Directed Transformation of Amorphous Iridium (Oxy)hydroxides To Produce Active Water Oxidation Catalysts

The oxygen evolution reaction (OER) is crucial to future energy systems based on water electrolysis. Iridium oxides are promising catalysts due to their resistance to corrosion under acidic and oxidizing conditions. Highly active iridium (oxy)hydroxides prepared using alkali metal bases transform into low activity rutile IrO2 at elevated temperatures (>350 °C) during catalyst/electrode preparation. Depending on the residual amount of alkali metals, we now show that this transformation can result in either rutile IrO2 or nano-crystalline Li-intercalated IrOx. While the transition to rutile results in poor activity, the Li-intercalated IrOx has comparative activity and improved stability when compared to the highly active amorphous material despite being treated at 500 °C. This highly active nanocrystalline form of lithium iridate could be more resistant to industrial procedures to produce PEM membranes and provide a route to stabilize the high populations of redox active sites of amorphous iridium (oxy)hydroxides.

Alkali-metal bases in catalytic hydrogen isotope exchange processes.

The preparation of compounds labelled with deuterium or tritium has become an essential tool in a range of research fields. Hydrogen isotope exchange (HIE) offers direct access to said compounds, introducing these isotopes in a late stage. Even though the field has rapidly advanced with the use of transition metal catalysis, alkali-metal bases, used as catalysts or under stoichiometric conditions, have also emerged as a viable alternative. In this minireview we describe the latest advances in the use of alkali-metal bases in HIE processes, showcasing their synthetic potential as well as current challenges in the field. It is divided in different sections based on the isotope source used, emphasizing their benefits, disadvantages and limitations. The influence on the choice of alkali-metal in these processes as well as their possible mechanistic pathways are also discussed.

In Situ Generated DBU⋅HF Acts as a Fluorinating Agent in a Hexafluoroisobutylation Tandem Reaction: An Effective Route to 5,5,5,5’,5’,5’‐Hexafluoroleucine

AbstractWe report the direct incorporation of the hexafluoroisobutyl group on a chiral glycine Schiff base complex mediated by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). The fluoroalkylation involves 2‐(bromomethyl)‐1,1,1,3,3,3‐hexafluoropropane reagent, which generates in situ hexafluoroisobutylene (HFIB), and reacts then with the enolate through a tandem allylic shift/hydrofluorination process. We showed that the use of neutral organic base DBU generates in situ an original DBU⋅HF salt, which preserves the fluoride nucleophilicity and acts as a fluorinating agent. This fluoride salt promotes the hydrofluorination of the pentafluorinated alkene overcoming the usual fluoride β‐elimination observed with α‐CF3‐vinyl reagents. With alkali metal bases, by contrast, the hydrofluorination is disfavored and the pentafluorinated alkene intermediate is obtained predominantly. This study highlights the critical role of the fluoride counter ion to preserve its nucleophilicity. The protocol is amenable to multidecagram scale synthesis of enantiopure (S)‐ and (R)‐5,5,5,5’,5’,5’‐hexafluoroleucine and their N‐Fmoc or N‐Boc derivatives in good overall yield.

Sigma/pi Bonding Preferences of Solvated Alkali-Metal Cations to Ditopic Arylmethyl Anions.

Arylmethyl anions allow alkali‐metals to bind in a σ‐fashion to the lateral carbanionic centre or a π‐fashion to the aryl ring or in between these extremities, with the trend towards π bonding increasing on descending group 1. Here we review known alkali metal structures of diphenylmethane, fluorene, 2‐benzylpyridine and 4‐benzylpyridine. Next, we synthesise Li, Na, K monomers of these diarylmethyls using polydentate donors PMDETA or Me6TREN to remove competing oligomerizing interactions, studying the effect that two aromatic rings has on negative charge (de)localisation via NMR, X‐ray crystallographic and DFT studies. Diphenylmethyl and fluorenyl anions maintain C(H)−M interactions regardless of alkali‐metal, although the adjacent arene carbons engage in interactions with larger alkali‐metals. Introducing a nitrogen atom into the ring (at the 2‐ or 4‐position) encourages relocalisation of negative charge away from the deprotonated carbon and onto nitrogen. Phenyl(2‐pyridyl)methyl moves from an enamide formation at one extremity (lithium) to an aza‐allyl formation at the other extremity (potassium), while C‐ or N‐coordination modes become energetically viable for Na and K phenyl(4‐pyridyl)methyl complexes.

Hexafluoroisobutylation of enolates through a tandem elimination/allylic shift/hydrofluorination reaction.

The isobutyl side chain is a highly prevalent hydrophobic group in drugs, and it notably constitutes the side chain of leucine. Its replacement by a hexafluorinated version containing two CF3 groups may endow the target compound with new and advantageous properties, yet this modification remains overlooked due to the absence of a general and practical synthetic methodology. Herein, we report the first general method to introduce the hexafluoroisobutyl group into ketoesters, malonates, 1,3-diketones, Schiff base esters and malononitrile. We demonstrated that the reaction occurs through an elimination/allylic shift/hydrofluorination cascade process which efficiently overcomes the usual fluoride β-elimination observed with α-CF3-vinyl groups. We showed that with alkali metal bases, a pentafluorinated alkene is obtained predominantly, whereas the use of tetrabutylammonium fluoride (TBAF) allows hydrofluorination to occur. This tandem process represents a conceptually new pathway to synthesize bis-trifluoromethylated compounds. This methodology was applied to the multigram-scale synthesis of enantiopure (S)-5,5,5,5′,5′,5′-hexafluoroleucine.

Synthesis of a Tetraphenyl-Substituted Dihydropentalene and Its Alkali Metal Hydropentalenide and Pentalenide Complexes

We report a high-yielding solution phase synthesis of 1,3,4,6-tetraphenyl-dihydropentalene based on a simple annulation reaction of cyclopentadiene with a chalcone. Deprotonative metalation of 1,3,4,6-tetraphenyl-dihydropentalene with alkali metal bases (Li, Na, K) of moderate basicity (pKa > 15) cleanly yields the corresponding hydropentalenide complexes, which exist as solvent-separated ion pairs in coordinating solvents such as THF, pyridine, and DMSO. A second deprotonative metalation with stronger alkali metal bases (pKa > 25) yields the double-anionic, 10 π aromatic tetraphenyl-pentalenide complexes, which are of low solubility in the case of Li2, Na2, and K2. In the solid state the two metals are bound η5 to each anionic ring in anti configuration as in the unsubstituted pentalenide Li2[C8H6]. Mixed-metal tetraphenyl-pentalenide complexes of Li/Na/K display remarkably enhanced solubility, allowing for solution phase characterization via NMR and UV–vis spectroscopy and application in transmetalation reactions.

Alkali Metal Complexes of a Bis(diphenylphosphino)methane Functionalized Amidinate Ligand: Synthesis and Luminescence.

A novel bis(diphenylphosphino)methane (DPPM) functionalized amidine ligand (DPPM−C(N‐Dipp)2H) (Dipp=2,6‐diisopropylphenyl) was synthesized. Subsequent deprotonation with suitable alkali metal bases resulted in the corresponding complexes [M{DPPM−C(N‐Dipp)2}(Ln)] (M=Li, Na, K, Rb, Cs; L=thf, Et2O). The alkali metal complexes form monomeric species in the solid state, exhibiting intramolecular metal‐π‐interactions. In addition, a caesium derivative [Cs{PPh2CH2‐C(N‐Dipp)2}]6 was obtained by cleavage of a diphenylphosphino moiety, forming an unusual six‐membered ring structure in the solid state. All complexes were fully characterized by single crystal X‐ray diffraction, NMR spectroscopy, IR spectroscopy as well as elemental analysis. Furthermore, the photoluminescent properties of the complexes were thoroughly investigated, revealing differences in emission with regards to the respective alkali metal. Interestingly, the hexanuclear [Cs{PPh2CH2‐C(N‐Dipp)2}]6 metallocycle exhibits a blue emission in the solid state, which is significantly red‐shifted at low temperatures. The bifunctional design of the ligand, featuring orthogonal donor atoms (N vs. P) and a high steric demand, is highly promising for the construction of advanced metal and main group complexes.

Synthesis, Crystal and Electronic Structures of a Thiophosphinoyl- and Amino-Substituted Metallated Ylide.

α‐Metallated ylides have revealed themselves to be versatile reagents for the introduction of ylide groups. Herein, we report the synthesis of the thiophosphinoyl and piperidyl (Pip) substituted α‐metallated ylide [Ph2(Pip)P=C−P(S)Ph2]M (M=Li, Na, K) through a four‐step synthetic procedure starting from diphenylmethylphosphine sulfide. Metallation of the ylide intermediate was successfully accomplished with different alkali metal bases delivering the lithium, sodium and potassium salts, the latter isolable in high yields. Structure analyses of the lithium and potassium compounds in the solid state with and without crown ether revealed different aggregates (monomer, dimer and hexamer) with the metals coordinated by the thiophosphoryl moiety and ylidic carbon atom. Although the piperidyl group does not coordinate to the metal, it significantly contributes to the stability of the yldiide by charge delocalization through negative hyperconjugation.

Synthesis of N-Alkyl and N-H-Carbazoles through SN Ar-Based Aminations of Dibenzothiophene Dioxides.

Alkyl amines have become available for the synthesis of diverse N-alkyl carbazoles through twofold SN Ar aminations of dibenzothiophene dioxides by using alkali metal bases. Of particular importance is the choice of counter cations on alkali metal bases, that is, i) the use of Li base for the efficient intermolecular reaction and ii) the sequential addition of heavier alkali metal bases (Na, K, or Cs) to promote intramolecular cyclization in a one-pot manner. This protocol also enables the cascade synthesis of N-H-carbazoles by using 2-phenylethylamine by removal of the 2-phenethyl group from N-(2-phenethyl) carbazoles in a single operation.

Alkali Blues: Blue-Emissive Alkali Metal Pyrrolates.

2-Iminopyrroles [HtBu L, 4-tert-butyl phenyl(pyrrol-2-ylmethylene)amine] are non-fluorescent π systems. However, they display blue fluorescence after deprotonation with alkali metal bases in the solid state and in solution at room temperature. In the solid state, the alkali metal 2-imino pyrrolates, M(tBu L), aggregate to dimers, [M(tBu L)(NCR)]2 (M=Li, R=CH3 , CH(CH3 )CNH2 ), or polymers, [M(tBu L)]n (M=Na, K). In solution (solv=CH3 CN, DMSO, THF, and toluene), solvated, uncharged monomeric species M(tBu L)(solv)m with N,N'-chelated alkali metal ions are present. Due to the electron-rich pyrrolate and the electron-poor arylimino moiety, the M(tBu L) chromophore possesses a low-energy intraligand charge-transfer (ILCT) excited state. The chelated alkali cations rigidify the chromophore, restricting intramolecular motions (RIM) by the chelation-enhanced fluorescence (CHEF) effect in solution and, consequently, switch-on a blue fluorescence emission.

Selective monoalkylation of p-tert-butylcalix-[4]-arene in a methyl carbonate ionic liquid.

Methyl carbonate ionic liquids are shown to readily mono-deprotonate p-tert-butylcalix-[4]-arenes initiating the formation of an organic mono-anionic p-tert-butylcalix-[4]-arate salt, methanol and carbon dioxide. These calix-[4]-arate salts have been successfully used in alkylation reactions with dialkyl sulfates and alkyl halides to form a mono-alkylated single product with high yield. This method avoids the common use of alkali metal bases such as caesium fluoride hence providing a safer and more selective synthetic route.

Enhancing Skin Permeation of Biphenylacetic Acid (BPA) Using Salt Formation with Organic and Alkali Metal Bases.

In the present study, a series of organic and alkali metal salts of biphenylacetic acid (BPA) have been prepared and evaluated in vitro for percutaneous drug delivery. The physicochemical properties of BPA salts were determined using solubility measurements, DSC, and IR. The DSC thermogram and FTIR spectra confirmed the salt formation with organic and alkali metal bases. Among the series, salts with organic amines (ethanolamine, diethanolamine, triethanolamine, and diethylamine) had lowered melting points while the alkali metal salt (sodium) had a higher melting point than BPA. The in vitro study showed that salt formation improves the physicochemical properties of BPA, leading to improved permeability through the skin. Amongst all the prepared salts, ethanolamine salt (1b) showed 7.2- and 5.4-fold higher skin permeation than the parent drug at pH 7.4 and 5.0, respectively, using rat skin.

ChemInform Abstract: Rhodium‐Catalyzed Synthesis of Unsymmetrical Di(aryl/heteroaryl)methanes Using Aryl/heteroarylmethyl Ketones via CO—C Bond Cleavage.

AbstractUnsymmetrical diarylmethanes are prepared in the absence of alkali metal bases in moderate to good yields.

Enhanced skin permeation of 6-methoxy-2-naphthylacetic acid by salt formation

The aim of this work was to prepare salts of 6-methoxy-2-naphthylacetic acid (6-MNA) to improve its physicochemical properties for percutaneous application. 6-MNA, an active metabolite of non-steroidal anti-inflammatory drug nabumetone has long half life and has the tendency to penetrate well into synovial fluid. The physicochemical properties of 6-MNA salts were investigated by solubility measurements, differential scanning calorimetry (DSC) and infrared (IR). The DSC thermograms and Fourier transform infrared (FT-IR) spectra indicated that 6-MNA formed salts with organic and alkali metal bases. Among the series, salts formed with amine bases (ethanolamine, diethanolamine, triethanolamine and diethylamine) had lower melting points while alkali metal salt (sodium) had higher melting point than 6-MNA. The salts had higher solubilities than 6-MNA as determined in phosphate buffer at pH 5.0 and 7.4. There is no significant difference in partition coefficient (log P) values between salts and 6-MNA at pH 5.0 but, at pH 7.4, the log P values for the salts increased by 4–10 times as compared to 6-MNA. In vitro permeation studies showed that all the salts increased the flux in comparision to 6-MNA, and the ethanolamine salt (1b) was found to be having 7.7 and 9.4 times higher permeability as compared to 6-MNA at pH 5.0 and 7.4, respectively.

Copper-catalyzed C–N coupling of amides and nitrogen-containing heterocycles in the presence of cesium fluoride

The copper-catalyzed C–N coupling of amides to aryl halides usually requires the use of strong alkali metal bases, such as K 2CO 3, K 3PO 4, and Cs 2CO 3, at high temperature. We discovered that CsF is sufficiently basic to promote the cross-coupling of amides and carbamates with aryl halides. Most aryl iodides coupled in high yield at room temperature. This alternative base may be a suitable replacement for substrates that are incompatible with high temperature and strongly basic conditions and can further enhance the chemoselectivity of this reaction.

Synthesis, structures and full characterization of p-tert-butylcalix[5]arene mono-, di-, tri- and pentaanionic ligand precursors

Abstract The synthesis, complete characterization, and solid state conformation of a new series of p-tert-butylcalix[5]arene (ButC5) mono-, di-, tri- and pentaanions are reported. X-ray structures of the alkali metal salts illustrate the strong influence of the alkali metal ion on the structure of the calixanion. The strength of the alkali metal base and its reaction stoichiometry play an important role in the conformation and level of deprotonation of the resulting anion. Reaction of ButC5 in a 2:1 molar ratio with alkali metal bases M2CO3 (M = Rb, Cs), or in a 1:1 ratio with M2CO3 (M = Na, K), MOH (M = Na, K, Rb, Cs) or MH (M = Li, Na) produces ButC5 monoanions, but ButC5 reacts in a 1:1 molar ratio with M2CO3 (M = Rb, Cs) or a 1:2 molar ratio with MOC(CH3)3 (M = Na, K) to afford ButC5 dianions. Due to the steric bulkiness of the But group no polymeric structures are observed. Alkali metal salts of trianionic ButC5 were obtained in high yields from reactions of ButC5 with MOC(CH3)3 (M = Li, Na, K), BunLi, LiH and LiOH in a 1:3 molar ratio. Pentaanionic ButC5 salts were obtained by the reaction with MOC(CH3)3 (M = Li, Na, K) or BunLi in a 5:1 ratio. X-ray crystal structures of ButC5 · Na and ButC5 · Cs indicate that the size of the alkali metal influences the level of cation-π arene interactions and therefore the conformation of the ButC5 unit; for example, ButC5 · Na has a cone conformation while ButC5 · Cs shows a flattened cone conformation. Cation-π arene interactions are observed in most of the calixarene salts.

Synthesis of mono- and geminal dimetalated carbanions of bis(phenylsulfonyl)methane using alkali metal bases and structural comparisons with lithiated bis(phenylsulfonyl)imides

The alpha,alpha'-stabilized carbanion complexes [(PhSO2)2CHLi.THF]1, [(PhSO2)2CHNa.THF]2 and [(PhSO2)2CHK]3 were prepared by the direct deprotonation of bis(phenylsulfonyl)methane I in THF with one molar equivalent of MeLi, BuNa and BnK respectively. The geminal dianionic complexes [(PhSO2)2CLi2.THF]4, [(PhSO2)2CNa2.0.55THF]5 and [(PhSO2)2CK2]6 were similarly prepared by the reaction of I with two molar equivalents of MeLi, BuNa and BnK respectively in THF. NMR and MS solution studies of 1-3 are consistent with the formation of charge-separated species in DMSO media. Solutions studies of 4-6, in conjunction with trapping experiments, indicate that the dianions deprotonate DMSO and regenerate the monoanions 1-3. Crystallographic analysis of 1 revealed a 1D chain polymer in which the metal centers are chelated by the bis(sulfonyl) ligands and connect to neighboring units through Li-O(S) interactions. An unexpected feature of 1 is that the polymeric chains are homochiral, since the chelating ligands of the backbone adopt the same relative configuration. Also, the phenyl substituents of each chelate in 1 are oriented in a cisoid manner. The sodium derivative 2 adopts a related solid-state structure, where enantiomeric pairs of chains combine to give a 1D ribbon motif. The lithium bis(phenylsulfonyl)imides [(PhSO2)2NLi.THF]9 and [(PhSO2)2NLi.Pyr2]10 were also prepared and structurally characterized. In the solid state 9 has a similar connectivity to that found for 1 but with heterochiral chains. In comparison, the more highly solvated complex 10 forms a 1D polymeric arrangement without chelation of the ligands and with the phenyl substituents oriented in a transoid fashion.

Color change on deprotonation of 5-(8,8-dicyanoheptafulven-3-yl)-2-hydroxy-1,3-xylyl-18-crown-5

Compound 5-(8,8-dicyanoheptafulven-3-yl)-2-hydroxy-1,3-xylyl-18-crown-5 is a novel non-benzenoid crown ether dye derived from 8,8-dicyanoheptafulvene together with a crown ether having a phenolic hydroxide group in its cavity. The color change on deprotonation has been UV/Vis-spectroscopically investigated with special attention to the metal-selective coloration, using a variety of alkali metal bases. Deprotonation brought about a significant color change from red to blue ( λ max≈430→640 nm), but quite irrespective of the cation species of base added. In addition, the coloration is found to be very similar to that of the uncrowned 8,8-dicyanoheptafulvene-substituted phenol. Interestingly, geometry optimization by MO calculations revealed that the crown ether ring is heavily deformed due to lone pair repulsion of the oxygen atoms in the cavity, making the hydroxide group directly exposed to the surrounding environment. Thus, the electronic state of the title compound is almost equivalent to that of the uncrowned compound. This explains why no cation-dependent coloration takes place and why the bathochromic displacement is mainly due to π-electron delocalization of the phenoxide (O −) into the heptafulvene chromophore.

Low Temperature Electrochemical Synthesis and Dielectric Characterization of Barium Titanate Films Using Nonalkali Electrolytes

Polycrystalline thin films of approximately 1 μm thickness have been synthesized on Ti substrates by an electrochemical process using nonalkali electrolytes, at temperatures as low as 55°C. The effect of various processing parameters, such as solution chemistry, atmosphere, quality of substrate surface, applied voltage, temperature, and reaction time have been discussed. Film thickness and uniformity increase with reaction time up to 24 h. The quantity of total electric charge passed through the electrolytic cell is found to govern the film thickness and uniformity. Dielectric characteristics of the as‐prepared and heat‐treated films have also been reported. Use of tetraethylammonium hydroxide, a nonalkali base reagent to adjust solution pH, has resulted in films having improved dielectric properties as opposed to the films prepared with alkali metal bases such as . Heat‐treatment further improves the dielectric properties through a phase transition to the thermodynamically stable tetragonal phase from the as‐prepared pseudo‐cubic phase as confirmed by the x‐ray diffraction data.