This work was supported by the UOIT start-up fund. We thank Mr. Matthew Baxter (UOIT) for his assistance in the laboratory.

1. Synthesis of Ynone
<ol>
	<li>Using an analytical balance, weigh 0.15 mmol of desired potassium alkynyltrifluoroborate salt (1.5 equivalents) and add to a clean vial fitted with a magnetic stir bar.</li>
	<li>Using a glass plunger syringe fitted with a needle, add 0.5 ml of anhydrous DCM to the vial to afford a 0.3 M solution of trifluoroborate. 
	NOTE: Since this is a new methodology, the reactions have been performed for proof of concept. In order to reduce waste they have been performed on a small scale. The reaction may be scaled to produce larger yields as required.</li>
	<li>Using a glass syringe, add 0.15 mmol of 1.0 M boron trichloride solution (1.5 equivalents, 150 &#181;l) dropwise to the reaction vessel at ambient temperature (20 &#176;C) with stirring. Replace cap. Hold or clamp the capped reaction vessel such that the reaction solution is below the water line in the sonicator. Sonicate the solution for 30 sec at 20 &#176;C and a frequency of 40 kHz.</li>
	<li>Stir the reaction solution at room temperature (20 &#176;C) for an additional 20 min. Depending on the nature of the alkynyltrifluoroborate starting material, observe a color change. A color change from white to tan or dark brown, red, or purple is common.</li>
	<li>Add 0.1 mmol of the desired acyl chloride (1.0 equivalent) to the vial at ambient temperature (20 &#176;C) with stirring. Alternatively, transfer the contents of the reaction vessel to a flask charged with a magnetic stir bar and 0.1 mmol of acyl chloride. Replace cap. Stir the reaction solution at ambient temperature (20 &#176;C) for 30 min. 
	NOTE: Generally, a change to a very dark color is an indication that the reaction is taking place.</li>
	<li>Using a thin layer chromatography (TLC)34 monitor the progress of the reaction by comparing with appropriate acyl chloride standard. 
	NOTE: Depending on the nature of the starting materials, the reaction may not go to completion. The acyl chloride starting material has been observed as a higher running spot than the final product for all of the ynones prepared to date using this method.
	<ol>
		<li>Prepare the acyl chloride standard by diluting approximately 10 mg of the acyl chloride starting material with 1 ml of ethyl acetate in a small vial.</li>
		<li>Using a TLC spotter, spot the reaction solution and the standard on the starting line of the TLC plate. A co-spot with both the reaction solution and standard may be useful to determine if there is still starting material present in the reaction solution.</li>
		<li>Determine a suitable TLC mobile phase by trial and error. For the preparation of product 1a, a mobile phase consisting of 1:30 ethyl acetate:hexanes results in Rf values of approximately 0.5 and 0.8 for the ynone product and benzoyl chloride starting material, respectively.</li>
		<li>Visualize the developed TLC plate under UV light. Use a pencil to mark any visible spots.</li>
	</ol>
	</li>
</ol>
2. Aqueous Workup
<ol>
	<li>Quench the reaction by adding a 1 ml of cold water (approximately 5 &#176;C) to the reaction vessel. Using a Pasteur pipette, transfer the solution to a clean separatory funnel. Further dilute the contents of the separatory funnel with 10 ml cold water and extract the product once into 15 ml ethyl acetate.</li>
	<li>Discard the bottom aqueous layer and wash the organic layer one additional time with 10 ml of water and one time with 10 ml of brine. Collect the organic layer into a clean Erlenmeyer flask and dry with magnesium sulfate. Filter the solution into a clean round bottom flask using gravity filtration.</li>
</ol>
3. Purification of Ynone
<ol>
	<li>Using thin layer chromatography, determine a suitable mobile phase for flash chromatography purification of the product. A retention factor (Rf) of approximately 0.5 is generally sufficient to separate the product from any remaining starting material and side products. 
	NOTE: In the case of poor separation, a less polar solvent system may be used such that the product has a lower Rf value. Depending on the polarity of the starting materials, a hexanes:ethyl acetate mixture in the range of 30:1 to 5:1 is generally suitable.</li>
	<li>Prepare a column containing silica wet with the appropriate mobile phase. Add a layer of sand to the top of the column in order to avoid disturbing silica upon addition of the product and eluent.</li>
	<li>Evaporate the workup solution using a rotary evaporator with the bath temperature at 40 &#176;C and the rotation set to 120 rpm. Dissolve the contents of the flask in a 2 ml of mobile phase and carefully load the solution evenly onto the column. Ensure that the silica is wet but the solvent line does not exceed the height of the silica. Allow some solvent to elute such that the product is on the silica. Add a small amount of mobile phase and repeat.</li>
	<li>Fill the column with the mobile phase determined in step 3.1; in the case of product 1a, a 30:1 hexanes:ethyl acetate mixture is appropriate. Collect the fractions in test tubes using flash chromatography to speed up the purification process. Simply connect an adaptor with tubing to an air outlet. Adjust the air pressure such that the eluent flows through the column at a suitable rate.</li>
	<li>Spot each of the column fractions on a TLC plate. Optionally, spot the acyl chloride standard as a reference. Develop the TLC using the mobile phase deemed appropriate in step 1.8. Mark any spots visible under UV light, noting that the product is expected to have a lower Rf than the acyl chloride standard.</li>
	<li>Collect all fractions containing visible spots into a large round bottom flask. If more than one spot with a lower Rf than the starting material is present, collect them in separate flasks. Evaporate the solvent using a rotary evaporator and dry the material collected under high vacuum for two hours.</li>
	<li>If required, perform a pentane wash on a small column in order to further purify an ynone product prepared from an electron poor acyl chloride starting material. On a small scale, this may be performed using a Pasteur pipette as the column.
	<ol>
		<li>Dissolve the product in a minimum of chloroform, DCM, or diethyl ether and load onto a silica column wet with pentane. Elute 1-2 column lengths of pentane through the column and collect into a waste beaker.</li>
		<li>Elute the pure ynone product from the pentane column using diethyl ether or ethyl acetate. Collect eluent in a separate flask, evaporate, and place under high vacuum for a minimum of two hours. Obtain approximately 10 mg of product for characterization by NMR spectroscopy.</li>
	</ol>
	</li>
</ol>
4. Characterization of Ynone
<ol>
	<li>Characterize and assess the purity of the final product using 1H and 13C NMR spectroscopy.34 Typically, the chemical shift of the carbonyl carbon appears near 177 ppm on the 13C NMR spectrum. The two SP carbons of the ynone functional group are represented by characteristic peaks near 87 and 93 ppm.</li>
	<li>Use infrared spectroscopy34 to identify the characteristic carbonyl peak of the ynone product. Electron delocalization from the adjacent triple bond usually causes the carbonyl peak to appear between 1,600 and 1,650 cm-1, depending on the electronic characteristics of the compound.</li>
	<li>Determine the molecular mass of the product and further validate the identity using high resolution mass spectrometry.34</li>
</ol>

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S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conversion+of+alkyltrifluoroborates+into+alkyldichloroboranes+with+tetrachlorosilane+in+coordinating+solvents.">Conversion of alkyltrifluoroborates into alkyldichloroboranes with tetrachlorosilane in coordinating solvents.</a> Angew. Chem. 116, 3118-3120 (2004).</li><li>Thompson, L., Doraiswamy, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sonochemistry:+science+and+engineering.">Sonochemistry: science and engineering.</a> Ind. Eng. Chem. Res. 38, 1215-1249 (1999).</li></ol>

The authors declare that they have no competing financial interests.

Table 1 illustrates the steps taken to optimize the conditions for the reaction of phenylacetylene trifluoroborate with benzoyl chloride to form the corresponding ynone product. Initially, catalysts known to convert organotrifluoroborates to organodifluoroboranes were tested. Unfortunately Silica gel,35 silicon tetrachloride,36 and boron trifluoride31,32 did not promote the formation of the desired ynone (Table 1, entries 1-3). The use of chlorinated Lewis acid catalysts proved to be more successful. A low yield of the desired ynone 1a was obtained in the presence of an iron(III) chloride catalyst (Table 1, entry 4). Next, aluminum(III) chloride was investigated as a result of its well-established ability to promote oxocarbenium ion formation in Friedel-Crafts acylations.37-39 The desired product was obtained in 62% yield when an aluminum(III) chloride catalyst was employed.
Further optimization revealed that air and moisture have little effect on the yield of the reaction (Table 1, entries 5-7). As a result, subsequent reactions were performed in non-dried glassware in the presence of air. Attempts to optimize the solvent revealed that dichloromethane (DCM) is particularly well suited to the reaction (Table 1, entries 8-12). Inconsistencies in the results of reactions catalyzed by aluminum(III) chloride prompted the exploration of alternative catalysts. Commercially available aluminum(III) chloride hexahydrate was completely inactive under the reaction conditions (Table 1, entry 13). This is a good indicator that the formation of aluminum(III) chloride hydrate inhibits the reaction. Boron trichloride was found to produce similar yields with better consistency (Table 1, entry 14).
Upon interaction of the potassium alkynyltrifluoroborate with boron trichloride, a more reactive organodichloroborane species is formed.40 This initial step is critical for the reaction with the acyl chloride and formation of the ynone to proceed. Since organotrifluoroborate salts are not soluble in DCM, the reaction takes place as a heterogeneous mixture. After addition of boron trichloride, the solution is sonicated order to facilitate formation of the reactive dichloroborane species by increasing the surface area of the trifluoroborate salt available to react. Application of ultrasound waves to the reaction mixture causes mechanical effects through the generation of cavitation bubbles. During sonication, collapse of cavitation bubbles in the fluid results in localized areas of high temperatures and pressures.41 Shock waves are produced that create microscopic turbulence resulting in an increase in kinetic energy of the solid trifluoroborate salts. The increase in energy of the system during sonication promotes fragmentation of the trifluoroborate salt resulting increased surface area available to interact with boron trichloride. Sonication of the reaction mixture prior to addition of the acyl chloride starting material ensures the efficient formation of the reactive alkynyldichloroborane species without the need for more forcing conditions or longer reaction times.
Figure 2 illustrates the results obtained when phenylacetylene trifluoroborate was reacted with a variety of acyl chlorides under the optimized reaction conditions. Neutral aromatic (1b, 1c) and aliphatic (1j-l) acyl chlorides furnish the corresponding ynones in synthetically useful yields. Those acyl chlorides bearing electron donating groups (1d-g) provide excellent yields while electron withdrawing groups result in comparatively modest yields (1h, 1i, 1m). Interestingly, when the electron withdrawing group is located in the ortho position (1i, 59%), a significant yield increase is observed in comparison to the analogous para substituted acyl chloride (1h, 30%). The steric interaction of the substituent in the ortho- position may force the carbonyl functional group out of the plane, thereby offsetting the electron-withdrawing character of the aromatic ring. It is worth noting that 4-bromobutyryl chloride reacted to afford the desired product 1m in 39% yield. To our knowledge, this is the first protocol for the synthesis of ynones to tolerate an alkyl bromide functional group. Occasionally, when the acyl chloride starting material is neutral or electron deficient, aliphatic impurities appear on the proton NMR. This may necessitate a pentane wash in order to further purify the product. While possible, it is not economical to perform the pentane wash during the first purification stage since pentane is costly in comparison to hexanes. Completing the secondary purification separately on a smaller scale such as a Pasteur pipette column significantly reduces the amount of pentane required.
Figure 3 illustrates the effect of the identity of the alkynyltrifluoroborate salt on the yield of the reaction. In general, derivatives of the phenylacetylene trifluoroborate salt bearing electron-donating substituents on the aromatic ring reacted with aromatic and aliphatic acyl chlorides to produce the desired ynones in good to excellent yields (2a-c, 3a-c). Aliphatic alkynyltrifluoroborate salts proved to be less reactive substrates. Modest yields have been obtained when hexynyl- and cyclopentylethynyltrifluoroborate salts were reacted with electron-rich benzoyl chloride derivatives (4a, 5a).
In conclusion, a novel method for the preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts has been developed. The yields obtained for the synthesis of ynones by this method range from modest to excellent depending on the nature of the acyl chloride and trifluoroborate starting materials. In general those starting materials bearing electron donating substituents undergo the reaction more readily than starting materials bearing neutral and electron withdrawing functional groups. The value of this approach lies in the operational simplicity and functional group tolerance of the method. This straightforward, one-pot reaction proceeds rapidly at ambient temperature in the presence of boron trichloride without exclusion of air and moisture. This convenient method may be employed in the preparation of ynones in modest to excellent yields from a variety of acyl chlorides and alkynyltrifluoroborate salts.

The intention of this video is to demonstrate a straightforward approach for the preparation of compounds containing an ynone functional group from convenient starting materials. Ynones are valuable building blocks in organic chemistry that have been shown to have biomedical and material significance. Ynones are precursors to valuable organic functional groups including pyrimidines,1,2 quinolones,3 furans,4 pyrazoles,5,6 flavones,7 oximes,8 and chiral propargylic alcohols.9-11 A more convenient method for the preparation of ynones has been sought as a result of the drawbacks of traditional methods including poor functional group tolerance and tedious synthetic routes.
The reaction of metal12,13 and metalloid14 acetylides with acyl chlorides is one common route for the preparation of ynones. Alternatively, the synthesis of ynones from acyl chloride can be achieved via two-step procedures using Weinreb amides and organolithium or Grignard reagents.15 Another prevalent approach includes the addition of organolithium or Grignard reagents to an aldehyde, which is followed by the oxidation of a secondary alcohol to the corresponding ketone.16-19 Poor functional group tolerance of metal acetylides and the need to purify synthetic intermediates after each step are main deficiencies of the aforementioned methods. Transition-metal-catalyzed carbonylative couplings have recently emerged as an alternative approach for the preparation of ynones.20-22 Unfortunately, in addition to cost and toxicity associated with transition metals, metal-catalyzed carbonylative reactions often require elevated CO pressures and suffer from the presence of an undesired Sonogashira coupling byproduct. Given their utility in organic synthesis as well as the drawbacks associated with traditional synthetic methods, the development of a more straightforward method for the preparation of ynones is appealing.
Potassium organotrifluoroborate salts have recently emerged as versatile reagents in organic synthesis. Advantages including ease of preparation,23 inherent stability, low toxicity, and good functional group tolerance have made organotrifluoroborate salts attractive synthetic reagents.24-27 Organotrifluoroborate salts have been used primarily as a bench-stable equivalent of boronic acids for palladium-catalyzed Suzuki-Miyaura coupling.26 Recently, following a seminal work by Matteson and co-workers,28 Bode, Molander and others have highlighted the utility of organotrifluoroborates as reagents in non-metal catalyzed reactions.29-33 The field of transition-metal-free reactions of trifluoroborates is still in its infancy stage. Given the great potential for use of organotrifluoroborate salts in non-metal catalyzed organic synthesis, we sought to develop a novel method for the preparation of ynones from acyl chlorides and alkynyltrifluoroborate salts.

<table border="0" cellpadding="0" cellspacing="0" width="573">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Name of Material/ Equipment</td>
			<td style="width:71px;">Company</td>
			<td style="width:119px;">Catalog Number</td>
			<td style="width:167px;">Comments/Description</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Sonicator</td>
			<td style="width:71px;">VGT</td>
			<td style="width:119px;">1860QT</td>
			<td>Ultrasonic cleaner. Similar sonication devices may be used.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Dichloromethane</td>
			<td style="width:71px;">Sigma</td>
			<td style="width:119px;">270997</td>
			<td>Anhydrous</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Boron trichloride solution&#160;</td>
			<td style="width:71px;">Sigma</td>
			<td style="width:119px;">178934</td>
			<td>1M solution in DCM</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Acyl chloride</td>
			<td style="width:71px;">Sigma</td>
			<td style="width:119px;">Various</td>
			<td>Acyl chlorides from other suppliers such as Alfa Aesar may be used. Caution - refer to MSDS for safety information.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Potassium alkynyltrifluoroborate salt</td>
			<td style="width:71px;">N/A</td>
			<td style="width:119px;">N/A</td>
			<td>Synthesized23 from terminal alkyne</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Ethyl acetate</td>
			<td style="width:71px;">ACP</td>
			<td style="width:119px;">E-2000</td>
			<td>ACS grade</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Hexanes</td>
			<td style="width:71px;">ACP</td>
			<td style="width:119px;">H-3500</td>
			<td>ACS grade</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Pentane</td>
			<td style="width:71px;">Sigma</td>
			<td style="width:119px;">236705</td>
			<td>Anhydrous</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Magnesium sulfate</td>
			<td style="width:71px;">Sigma</td>
			<td style="width:119px;">M7506</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Filter paper</td>
			<td style="width:71px;">Whatman</td>
			<td style="width:119px;">1093 126</td>
			<td>Student grade. This speceific variety is not necessary.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Silica Gel 60</td>
			<td style="width:71px;">EMD</td>
			<td style="width:119px;">1.11567.9026</td>
			<td>Particle size 0.040-0.063</td>
		</tr>
	</tbody>
</table>

metal-free synthesis of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts

Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups and scaffolds. Traditional methods for the preparation of ynones are associated with drawbacks including harsh conditions, multiple purification steps, and the presence of unwanted byproducts. An alternative method for the straightforward preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts is described herein. The adoption of organotrifluoroborate salts as an alternative to organometallic reagents for the formation of new carbon-carbon bonds has a number of advantages. Potassium organotrifluoroborate salts are shelf stable, have good functional group tolerance, low toxicity, and a wide variety are straightforward to prepare. The title reaction proceeds rapidly at ambient temperature in the presence of a Lewis acid without the exclusion of air and moisture. Fair to excellent yields may be obtained via reaction of various aryl and alkyl acid chlorides with alkynyltrifluoroborate salts in the presence of boron trichloride.

Initial efforts were focused around the preparation of ynone 1a from phenylacetylene trifluoroborate S1 and benzoyl chloride (Figure 1). Table 1 illustrates the optimization steps performed including screening of various Lewis acids, solvents, as well as examination of the effect of water on the reaction. Next, the scope of the reaction has been explored by submitting phenylacetylene trifluoroborate to the optimized conditions in the presence of a variety of acyl chlorides (Figure 2). Modest to excellent yields may be obtained depending on the nature of the acyl chloride substrate. The scope of the reaction has further been evaluated through the preparation of several additional examples of alkynyltrifluoroborate salts. Figure 3 illustrates selected examples of other alkynyltrifluoroborate salts that can be employed in the preparation of ynones under the developed conditions. Derivatives of phenylacetylene trifluoroborate bearing electron donating substituents afforded the corresponding ynone products in good to excellent yields while aliphatic derivatives of alkynyltrifluoroborate salts proved to be slightly less reactive affording modest yields.
<img alt="Figure 1" src="/files/ftp_upload/52401/52401fig1highres.jpg" /> 
Figure 1: Preparation of Ynone 1a from phenylacetylene trifluoroborate S1 and benzoyl chloride. Scheme illustrating the conditions for the preparation of ynone 1a including formation of the reactive dichloroborane intermediate.
<img alt="Figure 2" src="/files/ftp_upload/52401/52401fig2highres.jpg" /> 
Figure 2: Representative 1H NMR spectrum of ynone 1a. Chemical shifts and relative integrations of characteristic protons are labeled.
<img alt="Figure 3" src="/files/ftp_upload/52401/52401fig3highres.jpg" /> 
Figure 3: Representative 13C NMR spectrum of ynone 1a. Chemical shifts of characteristic carbons are labeled.
<img alt="Figure 4" src="/files/ftp_upload/52401/52401fig4highres.jpg" /> 
Figure 4: Representative HRMS spectrum of ynone 1a obtained via atmospheric-pressure chemical ionization. The measured m/z value of the [M+H]+ ion is reported.
<img alt="Figure 5" src="/files/ftp_upload/52401/52401fig5highres.jpg" /> 
Figure 5: Reactions of phenylacetylenetrifluoroborate salt S1 with acyl chlorides. Structures and yields for products produced by varying the identity of the acyl chloride starting material are illustrated. Reactions were run with 1 equiv of acyl chloride, 1.5 equiv potassium phenylacetylenetrifluoroborate S1, and 1.5 equiv boron trichloride.
<img alt="Figure 6" src="/files/ftp_upload/52401/52401fig6highres.jpg" /> 
Figure 6: Reactions of various alkynyltrifluoroborates with acyl chlorides. Structures and yields for products produced by varying the identity of the alkynyltrifluoroborate starting material are illustrated. Reactions were run with 1 equiv of acyl chloride, 2.5 equiv potassium organotrifluoroborate salt and 2.5 equiv boron trichloride.
<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Entry</td>
			<td>Lewis acid</td>
			<td>Lewis acid (equiv)</td>
			<td>Conditions</td>
			<td>Yield (%)</td>
		</tr>
		<tr>
			<td>1b</td>
			<td>SiO2</td>
			<td>16.5</td>
			<td>CH2Cl2</td>
			<td>0</td>
		</tr>
		<tr>
			<td>2</td>
			<td>SiCl4</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>3</td>
			<td>BF3&#183;OEt2</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>4b</td>
			<td>FeCl3</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>24</td>
		</tr>
		<tr>
			<td>5c</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>62</td>
		</tr>
		<tr>
			<td>6d</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>66</td>
		</tr>
		<tr>
			<td>7e</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>60</td>
		</tr>
		<tr>
			<td>8</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>THF</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>9</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>toluene</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>10</td>
			<td>AlCl3</td>
			<td>2</td>
			<td>ClCH2CH2Cl</td>
			<td>33</td>
		</tr>
		<tr>
			<td>11</td>
			<td>AlCl3</td>
			<td>1</td>
			<td>DMSO</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>12</td>
			<td>AlCl3</td>
			<td>2</td>
			<td>acetonitrile</td>
			<td>trace</td>
		</tr>
		<tr>
			<td>13</td>
			<td>AlCl3&#183;6H2O</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>0</td>
		</tr>
		<tr>
			<td>14b</td>
			<td>BCl3</td>
			<td>1.5</td>
			<td>CH2Cl2</td>
			<td>67</td>
		</tr>
		<tr>
			<td>15</td>
			<td>BBr3</td>
			<td>1</td>
			<td>CH2Cl2</td>
			<td>20</td>
		</tr>
	</tbody>
</table>
Table 1: Optimization of conditions for the preparation of ynone 1aa. Yield of product 1a upon variation of reaction conditions and Lewis acid catalyst. aReactions were run with 1 equiv benzoyl chloride and 1 equiv potassium phenylacetylenetrifluoroborate S1. b1.5 equiv S1. cAnhydrous conditions. dThe reaction was done in non-dried glassware under air. eAnhydrous conditions + 1 &#181;l of water.

Watch this Scientific Journal Video about Metal-free Synthesis of Ynones from Acyl Chlorides and Potassium Alkynyltrifluoroborate Salts at JoVE.com

Metal-free Synthesis of Ynones from Acyl Chlorides and Potassium Alkynyltrifluoroborate Salts

The goal of this manuscript is to demonstrate a straightforward method for the preparation of ynones from acyl chloride and potassium alkynyltrifluoroborate salt starting materials. The one-pot reaction proceeds rapidly in the presence of boron trichloride without exclusion of air and moisture.

Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups ...

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11.1K Views.  University of Ontario Institute of Technology. The goal of this manuscript is to demonstrate a straightforward method for the preparation of ynones from acyl chloride and potassium alkynyltrifluoroborate salt starting materials. The one-pot reaction proceeds rapidly in the presence of boron trichloride without exclusion of air and moisture.

Video: Metal-free Synthesis of Ynones from Acyl Chlorides and Potassium Alkynyltrifluoroborate Salts

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 ...

Nucleoside Triphosphates - From Synthesis to Biochemical Characterization

The traditional strategy for the introduction of chemical functionalities is the use of solid-phase synthesis by appending suitably modified phosphoramidite precursors to the nascent chain. However, the conditions used during the synthesis and the restriction to rather short sequences hamper the applicability of this methodology. On the other hand, modified nucleoside triphosphates are activated building blocks that have been employed for the mild introduction of numerous functional groups into nucleic acids, a strategy that paves the way for the use of modified nucleic acids in a wide-ranging palette of practical applications such as functional tagging and generation of ribozymes and DNAzymes. One of the major challenges resides in the intricacy of the methodology leading to the isolation and characterization of these nucleoside analogues.
	
	In this video article, we present a detailed protocol for the synthesis of these modified analogues using phosphorous(III)-based reagents. In addition, the procedure for their biochemical characterization is divulged, with a special emphasis on primer extension reactions and TdT tailing polymerization. This detailed protocol will be of use for the crafting of modified dNTPs and their further use in chemical biology.

The protocol described herein aims to explain and abridge the numerous obstacles in the way of the intricate route leading to modified nucleoside triphosphates. Consequently, this protocol facilitates both the synthesis of these activated building-blocks and their availability for practical applications.

The  traditional strategy for the introduction of chemical functionalities is the  use of solid-phase synthesis by appending suitably modified ...

Synthesis and Characterization of Supramolecular Colloids

Control over colloidal assembly is of utmost importance for the development of functional colloidal materials with tailored structural and mechanical properties for applications in photonics, drug delivery and coating technology. Here we present a new family of colloidal building blocks, coined supramolecular colloids, whose self-assembly is controlled through surface-functionalization with a benzene-1,3,5-tricarboxamide (BTA) derived supramolecular moiety. Such BTAs interact via directional, strong, yet reversible hydrogen-bonds with other identical BTAs. Herein, a protocol is presented that describes how to couple these BTAs to colloids and how to quantify the number of coupling sites, which determines the multivalency of the supramolecular colloids. Light scattering measurements show that the refractive index of the colloids is almost matched with that of the solvent, which strongly reduces the van der Waals forces between the colloids. Before photo-activation, the colloids remain well dispersed, as the BTAs are equipped with a photo-labile group that blocks the formation of hydrogen-bonds. Controlled deprotection with UV-light activates the short-range hydrogen-bonds between the BTAs, which triggers the colloidal self-assembly. The evolution from the dispersed state to the clustered state is monitored by confocal microscopy. These results are further quantified by image analysis with simple routines using ImageJ and Matlab. This merger of supramolecular chemistry and colloidal science offers a direct route towards light- and thermo-responsive colloidal assembly encoded in the surface-grafted monolayer.

A protocol for the synthesis and characterization of colloids coated with supramolecular moieties is described. These supramolecular colloids undergo self-assembly upon the activation of the hydrogen-bonds between the surface-anchored molecules by UV-light.

Control over colloidal assembly is of utmost importance for the development of functional colloidal materials with tailored structural and mechanical ...

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. The complexes were tested for catalytic activity in arylation and Suzuki-Miyaura reactions. For each reaction investigated, at least one of the four complexes successfully catalyzed the reaction.

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from ...

Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have been thought of as a type of molecular information storage. Mass spectrometry analysis has been considered the method of choice for sequencing peptoids. Peptoids can be synthesized via solid phase chemistry using a repeating two-step reaction cycle. Here we present a method to manually synthesize oligo-peptoids and to analyze the sequence of the peptoids using tandem mass spectrometry (MS/MS) techniques. The sample peptoid is a nonamer consisting of alternating N-(2-methyloxyethyl)glycine (Nme) and N-(2-phenylethyl)glycine (Npe), as well as an N-(2-aminoethyl)glycine (Nae) at the N-terminus. The sequence formula of the peptoid is Ac-Nae-(Npe-Nme)4-NH2, where Ac is the acetyl group. The synthesis takes place in a commercially available solid-phase reaction vessel. The rink amide resin is used as the solid support to yield the peptoid with an amide group at the C-terminus. The resulting peptoid product is subjected to sequence analysis using a triple-quadrupole mass spectrometer coupled to an electrospray ionization source. The MS/MS measurement produces a spectrum of fragment ions resulting from the dissociation of charged peptoid. The fragment ions are sorted out based on the values of their mass-to-charge ratio (m/z). The m/z values of the fragment ions are compared against the nominal masses of theoretically predicted fragment ions, according to the scheme of peptoid fragmentation. The analysis generates a fragmentation pattern of the charged peptoid. The fragmentation pattern is correlated to the monomer sequence of the neutral peptoid. In this regard, MS analysis reads out the sequence information of the peptoids.

A protocol is described for the manual synthesis of oligo-peptoids followed by sequence analysis by mass spectrometry.

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have ...

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to &#62;95%).

Chiral amino alcohols are versatile molecules for use as scaffolds in organic synthesis. Starting from L-lysine, we synthesize amino alcohols by an enzymatic cascade reaction combining diastereoselective C-H oxidation catalyzed by dioxygenase followed by cleavage of the carboxylic acid moiety of the corresponding hydroxyl amino acid by a decarboxylase.

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. ...

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 ...

Synthesis and Characterization of Amphiphilic Gold Nanoparticles

Gold nanoparticles covered with a mixture of 1-octanethiol (OT) and 11-mercapto-1-undecane sulfonic acid (MUS) have been extensively studied because of their interactions with cell membranes, lipid bilayers, and viruses. The hydrophilic ligands make these particles colloidally stable in aqueous solutions and the combination with hydrophobic ligands creates an amphiphilic particle that can be loaded with hydrophobic drugs, fuse with the lipid membranes, and resist nonspecific protein adsorption. Many of these properties depend on nanoparticle size and the composition of the ligand shell. It is, therefore, crucial to have a reproducible synthetic method and reliable characterization techniques that allow the determination of nanoparticle properties and the ligand shell composition. Here, a one-phase chemical reduction, followed by a thorough purification to synthesize these nanoparticles with diameters below 5 nm, is presented. The ratio between the two ligands on the surface of the nanoparticle can be tuned through their stoichiometric ratio used during synthesis. We demonstrate how various routine techniques, such as transmission electron microscopy (TEM), nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), and ultraviolet-visible (UV-Vis) spectrometry, are combined to comprehensively characterize the physicochemical parameters of the nanoparticles.

Amphiphilic gold nanoparticles can be used in many biological applications. A protocol to synthesize gold nanoparticles coated by a binary mixture of ligands and a detailed characterization of these particles is presented.

Gold nanoparticles covered with a mixture of 1-octanethiol (OT) and 11-mercapto-1-undecane sulfonic acid (MUS) have been extensively studied because of ...

Hierarchical and Programmable One-Pot Oligosaccharide Synthesis

This article presents a general experimental protocol for programmable one-pot oligosaccharide synthesis and demonstrates how to use Auto-CHO software for generating potential synthetic solutions. The programmable one-pot oligosaccharide synthesis approach is designed to empower fast oligosaccharide synthesis of large amounts using thioglycoside building blocks (BBLs) with the appropriate sequential order of relative reactivity values (RRVs). Auto-CHO is a cross-platform software with a graphical user interface that provides possible synthetic solutions for programmable one-pot oligosaccharide synthesis by searching a BBL library (containing about 150 validated and &#62;50,000 virtual BBLs) with accurately predicted RRVs by support vector regression. The algorithm for hierarchical one-pot synthesis has been implemented in Auto-CHO and uses fragments generated by one-pot reactions as new BBLs. In addition, Auto-CHO allows users to give feedback for virtual BBLs to keep valuable ones for further use. One-pot synthesis of stage-specific embryonic antigen 4 (SSEA-4), which is a pluripotent human embryonic stem cell marker, is demonstrated in this work.

This protocol demonstrates how to use the Auto-CHO software for hierarchical and programmable one-pot synthesis of oligosaccharides. It also describes the general procedure for RRV determination&#160;experiments and one-pot glycosylation of SSEA-4.

This article presents a general experimental protocol for programmable one-pot oligosaccharide synthesis and demonstrates how to use Auto-CHO software for ...

A Femtoliter Droplet Array for Massively Parallel Protein Synthesis from Single DNA Molecules

Advances in spatial resolution and detection sensitivity of scientific instrumentation make it possible to apply small reactors for biological and chemical research. To meet the demand for high-performance microreactors, we developed a femtoliter droplet array (FemDA) device and exemplified its application in massively parallel cell-free protein synthesis (CFPS) reactions. Over one million uniform droplets were readily generated within a finger-sized area using a two-step oil-sealing protocol. Every droplet was anchored in a femtoliter microchamber composed of a hydrophilic bottom and a hydrophobic sidewall. The hybrid hydrophilic-in-hydrophobic structure and the dedicated sealing oils and surfactants are crucial for stably retaining the femtoliter aqueous solution in the femtoliter space without evaporation loss. The femtoliter configuration and the simple structure of the FemDA device allowed minimal reagent consumption. The uniform dimension of the droplet reactors made large-scale quantitative and time-course measurements convincing and reliable. The FemDA technology correlated the protein yield of the CFPS reaction with the number of DNA molecules in each droplet. We streamlined the procedures about the microfabrication of the device, the formation of the femtoliter droplets, and the acquisition and analysis of the microscopic image data. The detailed protocol with the optimized low running cost makes the FemDA technology accessible to everyone who has standard cleanroom facilities and a conventional fluorescence microscope in their own place.

The overall goal of the protocol is to prepare over one million ordered, uniform, stable, and biocompatible femtoliter droplets on a 1 cm2 planar substrate that can be used for cell-free protein synthesis.