Name: synthesis of esters via a greener steglich esterification in acetonitrile
Uploaded: 2018-10-30T15:00:00
Description: Watch this Scientific Journal Video about Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile at JoVE.com

This research was supported by Siena College and the Center for Undergraduate Research and Creative Activity. We thank Dr. Thomas Hughes and Dr. Kristopher Kolonko for helpful conversations, Ms. Allycia Barbera for early stage work on this methodology, and the Siena College Stewart&#39;s Advanced Instrumentation and Technology (SAInT) Center for instrumentation resources.

Caution: Consult Safety Data Sheets (SDSs) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE) including splash goggles, lab coat, and nitrile or butyl gloves as many of the reagents and solvents are corrosive or flammable. Carry out all reactions in a fume hood. It is unnecessary to dry glassware or to use a nitrogen atmosphere for this protocol.
1. Carbodiimide Coupling Reaction for Primary Alcohols
<ol>
	<li>In a 50 mL round bottom flas...

<ol>
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E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Peptide+synthesis+beyond+DMF:+THF+and+ACN+as+excellent+and+friendlier+alternatives.">Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives.</a> Organic &amp; Biomolecular Chemistry. 13 (8), 2393-2398 (2015).</li><li>Williams, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+method+for+the+profiling+of+the+endocannabinoid+metabolome+by+LC-atmospheric+pressure+chemical+ionization-MS.">Quantitative method for the profiling of the endocannabinoid metabolome by LC-atmospheric pressure chemical ionization-MS.</a> Analytical Chemistry. 79 (15), 5582-5593 (2007).</li><li>Benmansour, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Discovery+of+novel+dengue+virus+NS5+methyltransferase+non-nucleoside+inhibitors+by+fragment-based+drug+design.">Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design.</a> European Journal of Medicinal Chemistry. 125, 865-880 (2017).</li><li>Maier, W., Corrie, J. E. T., Papageorgiou, G., Laube, B., Grewer, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparative+analysis+of+inhibitory+effects+of+caged+ligands+for+the+NMDA+receptor.">Comparative analysis of inhibitory effects of caged ligands for the NMDA receptor.</a> Journal of Neuroscience Methods. 142 (1), 1-9 (2005).</li><li>Schwartz, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Water+soluble+azido+polyisocyanopeptides+as+functional+&#946;-sheet+mimics.">Water soluble azido polyisocyanopeptides as functional &#946;-sheet mimics.</a> Journal of Polymer Science Part A: Polymer Chemistry. 47 (16), 4150-4164 (2009).</li><li>Hangauer, M. J., Bertozzi, C. 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The methodology presented here was developed to minimize the hazards from solvent associated with a traditional Steglich esterification by using a greener solvent system and by reducing the need for column chromatography8,9. Comparable reaction yields and rates can be achieved with the use of acetonitrile in place of dry chlorinated solvents or DMF22.
Several key steps enable the efficient purification of produc...

Ester compounds are widely used for the applications such as flavor compounds, pharmaceuticals, cosmetics, and materials. Commonly, the use of carbodiimide coupling reagents is used to facilitate an ester formation from a carboxylic acid and an alcohol1. For example, in the Steglich esterification, dicyclohexylcarbodiimide (DCC) is reacted with a carboxylic acid in the presence of 4-dimethylaminopyridine (DMAP) to form an activated acid derivative, generally in a chlorinated solvent system or dimethylformamide (DMF)2,3,4. The activated acid derivative then undergoes a nucleophilic acyl substitution with an alcohol to form the ester product, which is usually purified via chromatography. The Steglich esterification enables mild coupling of large, complex carboxylic acids and alcohols, including sterically hindered secondary and tertiary alcohols2,5,6. The goal of this work is to modify the standard Steglich esterification protocol to provide a greener synthetic option for this common esterification reaction.
One important aspect in the design of new synthetic methodology is to seek to minimize the use and formation of hazardous substances. The Twelve Principles of Green Chemistry7 can be used to provide a guideline for creating safer syntheses. Some of these include the prevention of waste generation (Principle 1) and the use of safer solvents (Principle 5). In particular, solvents account for 80-90% of the non-aqueous mass of the materials in pharmaceutical manufacturing8. Thus, modifying a protocol to use a less hazardous solvent can make a large impact on the greenness of an organic reaction.
Steglich esterification reactions often use anhydrous chlorinated solvent systems or DMF; however, these solvents are of concern for both the environment and human health. Dichloromethane (CH2Cl2) and chloroform (CHCl3) are probable human carcinogens, and DMF has reproductive toxicity concerns9. In addition, CH2Cl2 is ozone depleting10. Thus, a less hazardous solvent for the Steglich esterification would be of great utility. While there are not yet green replacements for polar aprotic solvents, acetonitrile is recommended as a greener replacement for CH2Cl2, CHCl3, and DMF9. Acetonitrile is currently produced as a byproduct in acrylonitrile manufacturing; however, a green synthesis of acetonitrile from biomass on an academic scale has been reported11, and potential options for the reuse and recovery from waste streams are being investigated12. Acetonitrile has previously been used as a greener solvent alternative for carbodiimide coupling reactions in solid-phase peptide synthesis to form amide linkages13. The use of acetonitrile as a solvent system for Steglich esterifications has been demonstrated14,15,16,17,18,19,20,21; however, these methods have not focused on the green aspect of the solvent and also employ additional purification via column chromatography.
Reducing the need for column chromatography as a purification step also minimizes hazardous solvent waste8. In addition to using a less hazardous reaction solvent, the methodology enables the isolation of highly pure product without the need for chromatography. The traditionally used dicyclohexylcarbodiimide (DCC) coupling reagent is substituted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The basic amine functional group on this reagent enables the reaction byproducts and any residual reagents to be removed via acidic and basic wash steps.
The protocol presented herein can be used with a variety of acid and alcohol partners (Figure 1). It was used to synthesize a small library of cinnamyl ester derivatives using primary, secondary, benzyl, and allyl alcohols and phenols22. Additionally, the rate of the esterification reaction in acetonitrile is comparable to that in the chlorinated and DMF solvent systems, without a need to dry or distill the acetonitrile prior to the reaction22. Esters synthesized from tertiary alcohols have not been isolated, which is currently a limitation of the methodology compared to the traditional Steglich esterification in chlorinated solvent23. In addition, other acid-labile groups could be affected by the acid wash steps, potentially necessitating column chromatography for purification after acetonitrile removal. Despite these limitations, the reaction is a facile and general method for the synthesis of esters in high yields using a range of both alcohol and carboxylic acid components. The use of a greener solvent system and high purity without the need for chromatography steps make this protocol an attractive alternative to a traditional Steglich esterification.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58803/58803fig1.jpg" /> 
Figure 1. General reaction scheme. The general scheme for the reaction involves the coupling of a carboxylic acid and an alcohol, which is facilitated using a carbodiimide coupling reagent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or EDC) and 4-dimethylaminopyridine (DMAP) in acetonitrile. To demonstrate the reaction breadth, esters were formed using various acids (1-5) with either a primary (6) or secondary (7) alcohol. <a href="https://www.jove.com/files/ftp_upload/58803/58803fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

<table>
	<tbody>
		<tr>
			<td>trans -cinnamic acid</td>
			<td>Acros Organics</td>
			<td>158571000</td>
			<td></td>
		</tr>
		<tr>
			<td>butyric acid</td>
			<td>Sigma-Aldrich</td>
			<td>B103500</td>
			<td>Caution: corrosive</td>
		</tr>
		<tr>
			<td>hexanoic acid</td>
			<td>Sigma-Aldrich</td>
			<td>153745-100G</td>
			<td>Caution: corrosive</td>
		</tr>
		<tr>
			<td>decanoic acid</td>
			<td>Sigma-Aldrich</td>
			<td>21409-5G</td>
			<td>Caution: corrosive</td>
		</tr>
		<tr>
			<td>phenylacetic acid</td>
			<td>Sigma-Aldrich</td>
			<td>P16621-5G</td>
			<td></td>
		</tr>
		<tr>
			<td>3-methoxybenzyl alcohol</td>
			<td>Sigma-Aldrich</td>
			<td>M11006-25G</td>
			<td></td>
		</tr>
		<tr>
			<td>diphenylmethanol</td>
			<td>Acros Organics</td>
			<td>105391000</td>
			<td>Benzhydrol</td>
		</tr>
		<tr>
			<td>chloroform-d</td>
			<td>Acros Organics</td>
			<td>166260250</td>
			<td>99.8% with 1% v/v tetramethylsilane, Caution: toxic</td>
		</tr>
		<tr>
			<td>hexane</td>
			<td>BDH Chemicals</td>
			<td>BDH1129-4LP</td>
			<td>Caution: flammable</td>
		</tr>
		<tr>
			<td>ethyl acetate</td>
			<td>Sigma-Aldrich</td>
			<td>650528</td>
			<td>Caution: flammable</td>
		</tr>
		<tr>
			<td>diethyl ether</td>
			<td>Fisher Scientific</td>
			<td>E138-500</td>
			<td>Caution: flammable</td>
		</tr>
		<tr>
			<td>acetonitrile</td>
			<td>Fisher Scientific</td>
			<td>A21-1</td>
			<td>ACS Certified, &#62;99.5%, Caution: flammable</td>
		</tr>
		<tr>
			<td>4-dimethylaminopyridine</td>
			<td>Acros Organics</td>
			<td>148270250</td>
			<td>Caution: toxic</td>
		</tr>
		<tr>
			<td>magnesium sulfate</td>
			<td>Fisher Scientific</td>
			<td>M65-3</td>
			<td></td>
		</tr>
		<tr>
			<td>hydrochloric acid, 1 M</td>
			<td>Fisher Scientific</td>
			<td>S848-4</td>
			<td>Caution: corrosive</td>
		</tr>
		<tr>
			<td>sodium chloride</td>
			<td>BDH Chemicals</td>
			<td>BDH8014</td>
			<td></td>
		</tr>
		<tr>
			<td>sodium bicarbonate</td>
			<td>Fisher Scientific</td>
			<td>S25533B</td>
			<td></td>
		</tr>
		<tr>
			<td>1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride</td>
			<td>Chem-Impex</td>
			<td>00050</td>
			<td>Caution: skin and eye irritant</td>
		</tr>
		<tr>
			<td>thin layer chromatography plates</td>
			<td>EMD Millipore</td>
			<td>1055540001</td>
			<td>aluminum backed sheets</td>
		</tr>
		<tr>
			<td>Note: All commercially available reagents and solvents were used as received without further purification.</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis of esters via a greener steglich esterification in acetonitrile

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1&#176; and 2&#176; aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

Using the modified Steglich esterification in acetonitrile followed by an acid-base extraction workup, 3-methoxybenzyl cinnamate (8) was obtained as a light-yellow oil (205 mg, 90% yield) without the need for column chromatography. 1H and 13C NMR spectra are presented in Figure 2 to confirm the structure and to indicate purity.
Compounds 9-<str...

Watch this Scientific Journal Video about Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile at JoVE.com

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...

The overall goal of this experiment is to provide a greener methodology for a common esterification reaction, which could serve useful for estro-synthesis in academic and industrial applications. Our method can be used for efficient and mild synthesis of esters by coupling carboxylic acids with primary or secondary alcohols or phenols. The main advantage of this technique is that it eliminates the use of hazardous chlorinated or amide reaction solvents and it minimizes solvent waste during purification without sacrificing reaction rate or product purity.Demonstrating the procedure will be Andrew Lutjen and Mackenzie Quirk, undergraduate researchers from my laboratory. First, combine trans-Cinnamic acid, DMAP, and EDC in a 50-milliliter round-bottom flask. Add 15 milliliters of acetonitrile, and 98 microliters of 3-Methoxybenzyl alcohol to the mixture, along with a magnetic stir bar.Clamp the flask in a 40-degree Celsius water bath and stir the reaction. Monitor the reaction by TLC, using ethyl acetate and hexanes. Once the reaction is complete, remove the acetonitrile under reduced pressure using a rotary evaporator to obtain a crude solid.To the residue, add 20 milliliters each of diethyl ether and one molar of hydrochloric acid. Swirl the flask to dissolve the residue into the solvent layers. Next, pour the solution into a separatory funnel.Rinse the evaporating flask with five milliliters of diethyl ether, and add the rinse to the separatory funnel. Gently shake the separatory funnel to extract the product into the ether layer, venting periodically. Allow the layers to separate, and then remove the aqueous layer by draining it out the bottom of the funnel into an Erlenmeyer flask.To the organic layer remaining in the separatory funnel, add 20 milliliters of one molar hydrochloric acid and gently shake the separatory flask, venting periodically. Allow the layers to separate and then remove the aqueous layer by draining it out from the bottom of the funnel into an Erlenmeyer flask. Repeat the washing procedure with saturated sodium bicarbonate and saturated sodium chloride.After completing the washing steps, transfer the organic layer from the separatory funnel into a clean Erlenmeyer flask. Dry the layer with magnesium sulfate. Then gravity filter the solution through filter paper into a masked evaporation flask.Following this, remove the diethyl ether solvent under reduced pressure, using a rotary evaporator. Analyze a sample of the product by proton and carbon NMR Spectroscopy in deuterated chloroform, and by mass spectrometry. In a 50-milliliter round-bottom flask, combine trans-cinnamic acid, DMAP, and EDC.Add 15 milliliters of acetonitrile and 157 milligrams of Diphenylmethanol to the mixture, along with a magnetic stir bar. Clamp the flask and stir the reaction at room temperature for 24 hours. Insert an air condenser into the flask neck to minimize solvent evaporation.Once the reaction is complete, follow the extraction workup and washing procedure as previously described. In a 50-milliliter round-bottom flask, combine decanoic acid, DMAP, and EDC. Add 15 milliliters of acetonitrile and 157 milligrams of Dithenylmethanol to the mixture, along with a magnetic stir bar.Clamp the flask and stir the reaction at room temperature for 24 hours. Insert an air condenser into the flask neck to minimize solvent evaporation. Once the reaction is complete, follow the extraction workup and washing procedure as previously described.Using the modified Steglich esterification reaction, 3-Methoxybenzyl cinnamate was obtained in 90%yield without the need for column chromatography, as confirmed by proton and carbon NMR Spectroscopy. Compounds nine to 17 were synthesized using a similar protocol, with yields of 77 to 90%All compounds were analyzed by NMR Spectroscopy and high resolution mass spectrometry, and found to be of similar purity to 3-Methoxybenzyl cinnamate by NMR analysis. Slight changes to the protocol for primary alcohols were made to obtain optimal yields and purity for compounds 12 to 17.Secondary alcohol reactions were run for longer to allow the reaction to go to completion. In the decanoic acid reactions, for ester compounds 12 and 17, using 1.2 equivalents of carboxylic acid to one equivalent of alcohol for both primary and secondary alcohols, yielded esters with a decanoic acid impurity. The impurity issue was solved by using a one to one molar ratio of decanoic acid to alcohol with a slightly longer reaction time.These conditions yielded pure ester products, indicated by a loss of the impurity signal at 2.35 parts per million in the proton NMR spectrum. As with any organic synthesis method, safety data sheets for chemicals should be consulted and proper personal protective equipment and facilities should be used when performing this procedure.

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Preparation and Use of Samarium Diiodide (SmI2) in Organic Synthesis: The Mechanistic Role of HMPA and Ni(II) Salts in the Samarium Barbier Reaction

Although initially considered an esoteric reagent, SmI2 has become a common tool for synthetic organic chemists. SmI2 is generated through the addition of molecular iodine to samarium metal in THF.1,2-3 It is a mild and selective single electron reductant and its versatility is a result of its ability to initiate a wide range of reductions including C-C bond-forming and cascade or sequential reactions. SmI2 can reduce a variety of functional groups including sulfoxides and sulfones, phosphine oxides, epoxides, alkyl and aryl halides, carbonyls, and conjugated double bonds.2-12 One of the fascinating features of SmI-2-mediated reactions is the ability to manipulate the outcome of reactions through the selective use of cosolvents or additives. In most instances, additives are essential in controlling the rate of reduction and the chemo- or stereoselectivity of reactions.13-14 Additives commonly utilized to fine tune the reactivity of SmI2 can be classified into three major groups: (1) Lewis bases (HMPA, other electron-donor ligands, chelating ethers, etc.), (2) proton sources (alcohols, water etc.), and (3) inorganic additives (Ni(acac)2, FeCl3, etc).3
Understanding the mechanism of SmI2 reactions and the role of the additives enables utilization of the full potential of the reagent in organic synthesis. The Sm-Barbier reaction is chosen to illustrate the synthetic importance and mechanistic role of two common additives: HMPA and Ni(II) in this reaction. The Sm-Barbier reaction is similar to the traditional Grignard reaction with the only difference being that the alkyl halide, carbonyl, and Sm reductant are mixed simultaneously in one pot.1,15 Examples of Sm-mediated Barbier reactions with a range of coupling partners have been reported,1,3,7,10,12 and have been utilized in key steps of the synthesis of large natural products.16,17 Previous studies on the effect of additives on SmI2 reactions have shown that HMPA enhances the reduction potential of SmI2 by coordinating to the samarium metal center, producing a more powerful,13-14,18 sterically encumbered reductant19-21 and in some cases playing an integral role in post electron-transfer steps facilitating subsequent bond-forming events.22 In the Sm-Barbier reaction, HMPA has been shown to additionally activate the alkyl halide by forming a complex in a pre-equilibrium step.23
Ni(II) salts are a catalytic additive used frequently in Sm-mediated transformations.24-27 Though critical for success, the mechanistic role of Ni(II) was not known in these reactions. Recently it has been shown that SmI2 reduces Ni(II) to Ni(0), and the reaction is then carried out through organometallic Ni(0) chemistry.28
These mechanistic studies highlight that although the same Barbier product is obtained, the use of different additives in the SmI2 reaction drastically alters the mechanistic pathway of the reaction. The protocol for running these SmI2-initiated reactions is described.

Preparation and Use of Samarium Diiodide SmI2 in Organic Synthesis: The Mechanistic Role of HMPA and NiII Salts in the Samarium Barbier Reaction

A straightforward procedure for the preparation of samarium diiodide (SmI2) in THF is described. The role of two main additives namely hexamethylphosphoramide (HMPA) and Ni(acac)2 in Sm mediated reactions is demonstrated in the Sm-Barbier reaction.

Although initially considered an esoteric reagent, SmI2 has become a common tool for synthetic organic chemists. SmI2 is generated through the addition of ...

Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and engineers. Growth of such anisotropic nanocrystals through a simple chemical method is a challenging task. In this study, we fabricate discotic nanodisks of zirconium phosphate [Zr(HPO4)2&#183;H2O] as a model material using hydrothermal, reflux and microwave-assisted methods. Growth of crystals is controlled by duration time, temperature, and concentration of reacting species. The novelty of the adopted methods is that discotic crystals of size ranging from hundred nanometers to few micrometers can be obtained while keeping the polydispersity well within control. The layered discotic crystals are converted to monolayers by exfoliation with tetra-(n)-butyl ammonium hydroxide [(C4H9)4NOH, TBAOH]. Exfoliated disks show isotropic and nematic liquid crystal phases. Size and polydispersity of disk suspensions is highly important in deciding their phase behavior.

A two dimensional model material of discotic zirconium phosphate was developed. The inorganic crystal with lamellar structure was synthesized by hydrothermal, reflux, and microwave-assisted methods. On exfoliation with organic molecules, layered crystals can be converted to monolayers, and nematic liquid crystal phase was formed at sufficient concentration of monolayers.

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

The Synthesis of [Sn10(Si(SiMe3)3)4]2- Using a Metastable Sn(I) Halide Solution Synthesized via a Co-condensation Technique

The number of well-characterized metalloid tin clusters, synthesized by applying the disproportionation of a metastable Sn(I) halide in the presence of a sterically demanding ligand, has increased in recent years. The metastable Sn(I) halide is synthesized at&#160;&#34;outer space conditions&#34; via the preparative co-condensation technique. Thereby, the subhalide is synthesized in an oven at high temperatures, around 1,300 &#176;C, and at reduced pressure by the reaction of elemental tin with hydrogen halide gas (e.g., HCl). The subhalide (e.g., SnCl) is trapped within a matrix of an inert solvent, like toluene at -196 &#176;C. Heating the solid matrix to -78 &#176;C gives a metastable solution of the subhalide. The metastable subhalide solution is highly reactive but can be stored at -78 &#176;C for several weeks. On heating the solution to room temperature, a disproportionation reaction occurs, leading to elemental tin and the corresponding dihalide. By applying bulky ligands like Si(SiMe3)3, the intermediate metalloid cluster compounds can be trapped before complete disproportionation to elemental tin. Hence, the reaction of a metastable Sn(I)Cl solution with Li-Si(SiMe3)3 gives [Sn10(Si(SiMe3)3)4]2- 1 as black crystals in high yield. 1 is formed via a complex reaction sequence including salt metathesis, disproportionation, and degradation of larger clusters. Further, 1 can be analyzed by various methods like NMR or single crystal X-ray structure analysis.

The Synthesis of [Sn10SiSiMe334]2- Using a Metastable SnI Halide Solution Synthesized via a Co-condensation Technique

The disproportionation reaction of a metastable Sn(I) chloride solution, obtained via the preparative co-condensation technique, is used for the synthesis of a metalloid tin cluster compound.

The number of well-characterized metalloid tin clusters, synthesized by applying the disproportionation of a metastable Sn(I) halide in the presence of a ...

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5&#39;-[CUA CGG AAU CAU]-3&#39; containing zero, one, or two modifications located at the C2&#39;-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2&#39;-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2&#039;-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2&#39;-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...

One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate glycosyl donor. Following azido-nitration of a glycal, the product 2-azido-1-nitrate ester can be hydrolyzed under microwave-assisted irradiation. This transformation is usually achieved using strongly nucleophilic reagents and extended reaction times. Microwave irradiation induces hydrolysis, in the absence of reagents, with short reaction times. Following denitration, the intermediate anomeric alcohol is converted, in the same pot, to the corresponding 2-azido-1-trichloroacetimidate.

A 2-azido-1-nitrate-ester can be converted to the corresponding 2-azido-1-trichloroacetimidate in a one-pot procedure. The goal of the manuscript is to demonstrate utility of the microwave reactor in carbohydrate synthesis.

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate ...

Synthesis of Substrate-Bound Au Nanowires Via an Active Surface Growth Mechanism

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a challenge, as it requires asymmetric growth of symmetric crystals. Here, we report a distinctive synthesis of substrate-bound Au nanowires. This template-free synthesis employs thiolated ligands and substrate adsorption to achieve the continuous asymmetric deposition of Au in solution at ambient conditions. The thiolated ligand prevented the Au deposition on the exposed surface of the seeds, so the Au deposition only occurs at the interface between the Au seeds and the substrate. The side of the newly deposited Au nanowires is immediately covered with the thiolated ligand, while the bottom facing the substrate remains ligand-free and active for the next round of Au deposition. We further demonstrate that this Au nanowire growth can be induced on various substrates, and different thiolated ligands can be used to regulate the surface chemistry of the nanowires. The diameter of the nanowires can also be controlled with mixed ligands, in which another &#34;bad&#34; ligand could turn on the lateral growth. With the understanding of the mechanism, Au nanowire-based nanostructures can be designed and synthesized.

We report a solution-based method to synthesize substrate-bound Au nanowires. By tuning the molecular ligands used during the synthesis, the Au nanowires can be grown from various substrates with different surface properties. Au nanowire-based nanostructures can also be synthesized by adjusting the reaction parameters.

Advancing synthetic capabilities is important for the development of nanoscience and nanotechnology. The synthesis of nanowires has always been a ...

A Rapid Synthesis Method for Au, Pd, and Pt Aerogels Via Direct Solution-Based Reduction

Here, a method to synthesize gold, palladium, and platinum aerogels via a rapid, direct solution-based reduction is presented. The combination of various precursor noble metal ions with reducing agents in a 1:1 (v/v) ratio results in the formation of metal gels within seconds to minutes compared to much longer synthesis times for other techniques such as sol-gel. Conducting the reduction step in a microcentrifuge tube or small volume conical tube facilitates a proposed nucleation, growth, densification, fusion, equilibration model for gel formation, with final gel geometry smaller than the initial reaction volume. This method takes advantage of the vigorous hydrogen gas evolution as a by-product of the reduction step, and as a consequence of reagent concentrations. The solvent accessible specific surface area is determined with both electrochemical impedance spectroscopy and cyclic voltammetry. After rinsing and freeze drying, the resulting aerogel structure is examined with scanning electron microscopy, X-ray diffractometry, and nitrogen gas adsorption. The synthesis method and characterization techniques result in a close correspondence of aerogel ligament sizes. This synthesis method for noble metal aerogels demonstrates that high specific surface area monoliths may be achieved with a rapid and direct reduction approach.

A rapid, direct solution-based reduction synthesis method to obtain Au, Pd, and Pt aerogels is presented.

Here, a method to synthesize gold, palladium, and platinum aerogels via a rapid, direct solution-based reduction is presented. The combination of various ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

Synthesis of Monodisperse Cylindrical Nanoparticles via Crystallization-driven Self-assembly of Biodegradable Block Copolymers

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock copolymers are produced by one of three techniques: thin film rehydration, solvent switching or polymerization-induced self-assembly, and produce only flexible, polydisperse cylinders. Crystallization-driven self-assembly (CDSA) is a method which can produce cylinders with these properties, by stabilizing structures of a lower curvature due to the formation of a crystalline core. However, the living polymerization techniques by which most core-forming blocks are formed are not trivial processes and the CDSA process may yield unsatisfactory results if carried out incorrectly. Here, the synthesis of cylindrical nanoparticles from simple reagents is shown. The drying and purification of reagents prior to a ring-opening polymerization of &#949;-caprolactone catalyzed by diphenyl phosphate is described. This polymer is then chain extended by methyl methacrylate (MMA) followed by N,N-dimethyl acrylamide (DMA) using reversible addition&#8722;fragmentation chain-transfer (RAFT) polymerization, affording a triblock copolymer that can undergo CDSA in ethanol. The living CDSA process is outlined, the results of which yield cylindrical nanoparticles up to 500 nm in length and a length dispersity as low as 1.05. It is anticipated that these protocols will allow others to produce cylindrical nanostructures and elevate the field of CDSA in the future.

Crystallization-driven self-assembly (CDSA) displays the unique ability to fabricate cylindrical nanostructures of narrow length distributions. The organocatalyzed ring-opening polymerization of &#949;-caprolactone and subsequent chain extensions of methyl methacrylate and N,N-dimethyl acrylamide are demonstrated. A living CDSA protocol that produces monodisperse cylinders up to 500 nm in length is outlined.

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock ...