Sodium Dispersion Research Articles

Sodium dispersion-mediated reductive dimerization of benzylic halides for symmetrical bibenzyls: Column-free applications to natural products

We report a method for the synthesis of symmetrical bibenzyls by the reductive dimerization of benzylic halides using sodium dispersion (SD). SD, a reagent consisting of sodium particles dispersed in mineral oil, has recently attracted attention as a safer but more reactive source of sodium than sodium lump. We have found that the reductive dimerization of benzylic halides proceeds within 1 h at room temperature in tetrahydrofuran (THF) solvent using SD as a reducing agent. This method is highly sustainable for the synthesis of symmetrical bibenzyls since it uses sodium, which is abundant on earth. As the SD-derived mineral oil in the crude product can be readily removed, three natural products were synthesized on a gram scale without the need for column chromatography. The utility of this reaction was also exemplified by a decagram-scale reaction using 2-methyltetrahydrofuran, known as a green alternative solvent to THF.

Sodium-Mediated Reductive anti-Dimagnesiation of Diarylacetyl­enes with Magnesium Bromide

AbstractDiarylacetylenes undergo anti-dimagnesiation using magnesium bromide and sodium dispersion to afford (E)-1,2-dimagnesioalkenes. This dimagnesiation utilizes simple magnesium bromide as a reduction-resistant electrophile, contrasting with the previously reported dimagnesiation using tricky organomagnesium halides. The resulting vicinal double Grignard reagents react with various electrophiles to yield multisubstituted alkenes stereoselectively.

Reductive anti-Dizincation of Arylacetylenes.

Arylacetylenes undergo anti-1,2-dizincation to afford trans-1,2-dizincioalkenes. The process employs sodium dispersion as a reducing agent and zinc chloride TMEDA complex as a reduction-resistant zinc electrophile. This reductive anti-dizincation contrasts with the conventional additive syn-dimetalation like silylzincation. The resulting dizincated alkenes undergo the cross-coupling to yield multi-substituted alkenes stereoselectively.

Single Electron Transfer Reductive Deuteration of Acyl Chlorides for the Synthesis of Deuterated Alcohols with a High Deuterium Atom Economy.

We present a highly deuterium atom economical approach for the synthesis of deuterated alcohols via the single electron transfer (SET) reductive deuteration of acyl chlorides. Cost-effective sodium dispersion and EtOD-d1 were used as the single electron donor and deuterium donor, respectively. Our approach achieved up to 49% deuterium atom economy, which represents the highest deuterium atom economy yet achieved in SET reductive deuteration reactions. With all 20 tested substrates, excellent regioselectivity and >92% deuterium incorporations were obtained. Furthermore, we demonstrated the potential of this methodology by synthesizing four deuterated analogues of pesticides.

Freshwater Salinization Syndrome Alters Nitrogen Transport in Urban Watersheds.

Anthropogenic salt inputs have impacted many streams in the U.S. for over a century. Urban stream salinity is often chronically elevated and punctuated by episodic salinization events, which can last hours to days after snowstorms and the application of road salt. Here, we investigated the impacts of freshwater salinization on total dissolved nitrogen (TDN) and concentrations and fluxes across time in urban watersheds in the Baltimore-Washington D.C. metropolitan area of the Chesapeake Bay region. Episodic salinization from road salt applications and snowmelt quickly mobilized TDN in streams likely through soil ion exchange, hydrologic flushing, and other biogeochemical processes. Previous experimental work from other studies has shown that salinization can mobilize nitrogen from sediments, but less work has investigated this phenomenon with high-frequency sensors and targeted monitoring during road salt events. We found that urban streams exhibited elevated concentrations and fluxes of TDN, , and specific conductance that rapidly peaked during and after winter road salt events, and then rapidly declined afterwards. We observed plateaus in TDN concentrations in the ranges of the highest specific conductance values (between 1000 and 2000 μS/cm) caused by road salt events. Plateaus in TDN concentrations beyond a certain threshold of specific conductance values suggested source limitation of TDN in watersheds (at the highest ranges in chloride concentrations and ranges); salts were likely extracting nitrogen from soils and streams through ion exchange in soils and sediments, ion pairing in soils and waters, and sodium dispersion of soils to a certain threshold level. When watershed transport was compared across land use, including a forested reference watershed, there was a positive relationship between Cl- loads and loads. This relationship occurred across all sites regardless of land use, which suggests that the mass transport of Cl- and are likely influenced by similar factors such as soil ion exchange, ion pairing, sodium dispersion of soils, hydrologic flushing, and biogeochemical processes. Freshwater salinization has the potential to alter the magnitude and timing of total dissolved nitrogen delivery to receiving waters during winter months following road salt applications, and further work should investigate the seasonal relationships of N transport with salinization in urban watersheds.

Synthesis of 2,2′-Bipyridines via Dehydrogenative Dimerization of Pyridines Using Sodium Dispersion

Abstract2,2′-Bipyridine derivatives were synthesized by dehydrogenative dimerization of nonactivated pyridines using sodium dispersion. The reaction features operational simplicity, mild conditions, and the use of earth abundant and nontoxic sodium as the sole metal source. Importantly, transition metals are not required, which is beneficial in the fields of materials science and drug synthesis, where the contamination of the transition metals may cause significant problems.

Formal Synthesis of Dictyodendrin B

A formal synthesis of dictyodendrin B is described. Regiocontrolled functionalization of the α,β-dibromopyrrole derivative provided the fully substituted pyrrole bearing an indole moiety. Subsequent reductive cyclization using a combination of sodium dispersion and triethylsilyl chloride enabled the formation of the benzene ring in the characteristic tetracyclic pyrrolo[2,3-c]carbazole skeleton, while the ethyl ester remained untouched. Further chemical transformation of the ester moiety and functional group manipulation completed the formal synthesis of dictyodendrin B.

Centrifugal Melt Spun Microfi brous Solid Dispersion of Diclofenac Sodium with Enhanced Solubility

A lower dissolution rate of poorly soluble drugs is the prime factor aff ecting their bioavailability. The centrifugal melt spinning method is a simple, aff ordable and scalable technique to prepare microfi bers with enhanced solubility and dissolution rate. This study aimed to enhance the solubility and dissolution rate of poorly soluble drug diclofenac sodium by centrifugal melt spinning technique. Microfi brous solid dispersion of diclofenac sodium 10% w/w with sucrose were prepared to utilize a cotton candy device. The dissolution studies revealed that the drug-loaded microfi bers released 98.10 ± 0.52% of drug within 5 minutes as compared with pure drug and physical mixture. The drug-loaded microfi bers were bead-free with uniform morphology and diameter of 13.25 ± 4.4 μm. The centrifugal melt-spinning process converted the drug and carrier to amorphous state, which was further confi rmed from the calorimetric and crystallographic study results. The results indicated that the centrifugal melt spinning process rapidly produced microfi bers with improved solubility and dissolution rate. The results of this study have shown that the centrifugal melt spinning technique may provide an easy, highly scalable, and adaptable fabrication technique to increase the solubility and rate of dissolution of poorly soluble drugs.

Synthesis of a Dibenzo-1,6,2,5-dioxadisilocine and Its Unexpected Reductive Coupling with Phenanthrene

A stable dibenzo-1,6,2,5-dioxadisilocine was synthesized as a difunctional electrophile for double-silylation reactions. Its molecular structure was fully characterized by spectroscopic means and single-crystal X-ray diffraction analysis. The reductive coupling with phenanthrene using a dispersion of sodium afforded an unexpected silylated polycyclic compound via a formal [3+3] dimerization of phenanthrene skeletons.

Synthesis of trans-1,2-dimetalloalkenes through reductive anti-dimagnesiation and dialumination of alkynes

Polar reactive organometallic species have been key reagents in synthesis for more than a century. Stereodefined 1,2-dimetallated alkenes offer promising synthetic utility; however, few methods are available for their preparation due to their relatively low stability. Here we report the reductive anti-1,2-dimetallation of alkynes to stereoselectively generate trans-1,2-dimagnesio- and 1,2-dialuminoalkenes, which are stable and have been demonstrated in organic synthesis. These stereodefined 1,2-dimetallated alkenes are prepared through the use of a sodium dispersion as a reducing agent, and organomagnesium and organoaluminium halides as reduction-resistant electrophiles. Highly nucleophilic 1,2-dimagnesioalkenes serve as dual Grignard reagents and have been demonstrated to react with various electrophiles to afford anti-difunctionalized alkenes. The 1,2-dialuminoalkenes react with paraformaldehyde with dearomatization of the aryl moieties to form the corresponding dearomatized 1,4-diols, with the overall reaction being regarded as alkynyl-directed dearomatization of arenes. X-ray crystallographic analysis further supports the formation of trans-1,2-dimagnesio- and 1,2-dialuminoalkenes, with computational studies providing insight into the mechanism of dearomative difunctionalization.

Sequential Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of Chlorobenzamides/Chemoselective Amide Reduction and Reductive Deuteration to Benzylic Alcohols

Benzylic alcohols are among the most important intermediates in organic synthesis. Recently, the use of abundant metals has attracted significant attention due to the issues with the scarcity of platinum group metals. Herein, we report a sequential method for the synthesis of benzylic alcohols by a merger of iron catalyzed cross-coupling and highly chemoselective reduction of benzamides promoted by sodium dispersion in the presence of alcoholic donors. The method has been further extended to the synthesis of deuterated benzylic alcohols. The iron-catalyzed Kumada cross-coupling exploits the high stability of benzamide bonds, enabling challenging C(sp2)-C(sp3) cross-coupling with alkyl Grignard reagents that are prone to dimerization and β-hydride elimination. The subsequent sodium dispersion promoted reduction of carboxamides proceeds with full chemoselectivity for the C-N bond cleavage of the carbinolamine intermediate. The method provides access to valuable benzylic alcohols, including deuterium-labelled benzylic alcohols, which are widely used as synthetic intermediates and pharmacokinetic probes in organic synthesis and medicinal chemistry. The combination of two benign metals by complementary reaction mechanisms enables to exploit underexplored avenues for organic synthesis.

Application of Central Composite Design for Formulation and Optimization of Solid Dispersion for Dissolution Rate Enhancement of BCS Class II Drug

The objective of this research work was to develop solid dispersion of Fluvastatin sodium (FLS-SD) by solvent evaporation technique for dissolution enhancement of Fluvastatin sodium (FLS). Furthermore, central composite design (CCD) was applied for studying the effect of drug: polymer (w/w) (X1) and surfactant concentration (% w/v) (X2) on dependent variables T50% (Minutes) (Y1), Q90(%) (Y2) and percentage drug content (Y3). Thirteen experimental runs were performed as per CCD design layout and analyzed. The model was exceptional fitted in quadratic model as indicated by lack of fit of p-value more than 0.05. An optimized FLS-SD composition having 0.998 desirability function was explored using Design-Expert software. The theoretical values of t50%, Q90 and % drug content for optimized FLS-SD given by software were 23 min, 94.289% and 88.515%, respectively. The percentage cumulative drug release from FLS, physical mixture and FLS-SD was found 25.43%, 27.54%, and 93.6% within 2 hour which demonstrated superior and significant dissolution enhancement of FLS (*p < 0.05). The r2 for the Zero-order, First-order, Korsmeyer-peppas (K-P), and Higuchi models for FLS-SD were 0.8336, 0.7594, 0.9539 and 0.9234, respectively. K-P model was found superior (y = 0.426x +1.1259, r2 = 0.9539) and ‘n’ value was 0.426(n <0.45) which revealed fickian drug release from FLS-SD. This research work concluded that solid dispersion formulation by solvent evaporation technique could be successfully utilized for dissolution enhancement of BCS class II drug.

Borylation of Alkenyl Carbamates by Means of Sodium Metal

AbstractTreatment of alkenyl carbamates with sodium dispersion and a co-existing boron electrophile affords alkenylboronates via the reductive cleavage of the vinylic C–O bond. The key to this borylation is an instant trapping of reactive organosodium species with the co-existing boron electrophile.

Formulation and Evaluation of Interpenetrating Polymer Network Microparticles of Diclofenac Sodium

Diclofenac sodium, a model anti-inflammatory drug, has adverse effects like gastric irritation and hepatic toxicity. To overcome these problems Interpenetrating Polymer Network microparticles can be used as a controlled drug delivery system. Preparation of Interpenetrating Polymer Network microparticles using two or more polymer is a novel approach as the polymers produce synergistic effect which could increase the mechanical strength and resilience of the microparticles. The aim of the study was to prepare Interpenetrating Polymer Network microparticles of Diclofenac Sodium using chitosan and Ghatti gum which were used to deliver Diclofenac Sodium to the intestine. Microparticles prepared by emulsion-cross-linking method using gluteraldehyde as a cross-linker were characterized by Fourier Transform Infrared Spectroscopy, Differential scanning calorimetry, Scanning electron microscopy and evaluated for in vitro dissolution rate. Fourier Transform Infrared Spectroscopy studies confirmed the absence of chemical interactions between drug, polymers and cross-linking agent. Differential scanning calorimetric results indicated amorphous dispersion of Diclofenac Sodium into Interpenetrating Polymer Network matrix. Scanning electron microscopy pictures showed that microparticles did not agglomerate and had a rough surface. Hydrated surface after swelling showed spongy porous surface which indicated the mechanism of drug release as diffusion. Particle size ranged between 294 to 366 µm. DS percentage encapsulation efficiency ranged from 84.09 to 96.81%. In vitro release studies indicated a dependence of drug release rates on both the amount of CS and GG used in preparation of microparticles. The release was extended up to 12 h and release rates indicated a non-Fickian and super case II mechanism.

Reductive Ring Opening of Arylcyclopropanecarboxamides Accompanied by Borylation and Enolate Formation.

Treatment of arylcyclopropanecarboxamides with a sodium dispersion in the presence of methoxypinacolborane as a reduction-resistant electrophile leads to reductive cleavage of the cyclopropane ring followed by instant trapping with the boron electrophile to yield the enolates of γ-aryl-γ-borylalkanamides. The enolates react further with a different electrophile to yield the corresponding α-substituted amides with anti selectivity.

Evaluating a Dispersion of Sodium in Sodium Chloride for the Synthesis of Low‐Valent Nickel Complexes**

AbstractThe use of a sodium in sodium chloride dispersion is systematically evaluated for the synthesis of nickel(0) and nickel(I) complexes from readily‐prepared nickel(II) precursors. A variety of complexes with phosphine and bipyridine‐type ligands were accessed, although some reactions were found to produce mixtures of nickel(0) and nickel(I), and yields were highly variable. Several new nickel(I) complexes were obtained, and these were characterized using techniques including NMR spectroscopy, EPR spectroscopy, and single crystal X‐ray diffraction analysis.

Facile Multiple Alkylations of C60 Fullerene.

The reduction of fullerene (C60) with sodium dispersion in the presence of an excess amount of dipropyl sulfate was found to yield highly propylated fullerene, C60(nC3H7)n (max. n = 24), and C60(nC3H7)20 was predominantly generated as determined by mass spectroscopy.

Reductive Cleavage of Propargylic Ethers with Alkali Metal: Application to the Synthesis of Allenylboronates.

Treatment of propargylic ethers with sodium dispersion in the presence of lithium iodide results in the generation of the corresponding carbanion species via cleavage of the propargylic C-O bond. The anionic species react with trimethoxyborane to yield the allenylboronates including highly substituted ones that are difficult to synthesize.

Birch Reduction of Arenes Using Sodium Dispersion and DMI under Mild Conditions

Abstract An easy-to-handle sodium dispersion in paraffin oil (SD), in combination with inexpensive and environmentally benign 1,3-dimethyl-2-imidazolidinone (DMI) as an additive enables the Birch-type reduction of a variety of arenes with high yields, selectivity, and tolerance of functionality such as ether, alcohol, amine, amide, and carboxylic acid.

Dechlorination of short-chain chlorinated paraffins by the metal sodium dispersion method

Short-chain chlorinated paraffins (SCCPs) are listed in Annex A (elimination) of the Stockholm Convention on persistent organic pollutants, and products containing SCCPs require detoxification. In the present study, the metal sodium (Na) dispersion method was applied to a wax sample containing SCCPs (58%, C10–C13 and Cl5–Cl9) to assess the dechlorination effect. Effective dechlorination of SCCPs was confirmed using 2-L and 20-L reaction systems. The initial concentrations of the wax (5, 10, 20, 30%), reaction time (10, 30, 60, 120, 180 min), and the ratios of the amount of Na dispersion and the initial amount of the wax containing SCCPs (Na/wax ratios; 3.9, 4.4, 5.2) were tested. The destruction efficiency of SCCPs was over 99.999% after 10 min of reaction at 90 °C under several conditions. The initial concentrations of the wax and the Na/wax ratios did not affect the results. The ultralow SCCP contents in exhaust gas from the reaction tank demonstrated a destruction removal efficiency of over 99.999999%. Trace levels of polychlorinated dibenzo-p-dioxins and furans, dioxin-like polychlorinated biphenyls, hexachlorobenzene, and pentachlorobenzene in the wax sample and treated materials (oil, water, and gas) met various regulatory values or exhibited the same levels as the environmental background. After dechlorination of the SCCPs, the main reaction products in the reaction liquid and final oil phase were identified as aliphatic compounds. The metal Na dispersion method was found to be an effective and decontaminated destruction technique for application to SCCPs in liquid-like samples with no formation of hazardous organic byproducts.