Name: separation of aldehydes and reactive ketones from mixtures using a bisulfite extraction protocol
Uploaded: 2018-04-02T15:00:00
Description: Watch this Scientific Journal Video about Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol at JoVE.com

Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research. We are grateful to the National Science Foundation (CHE-0619275 and CHE-0963165) for renovation and instrumentation grants that supported this research.

1. Standard Protocol for The Separation of Aromatic Aldehydes from a Mixture. Example: Separation of Benzyl Butyrate from a 1:1 Mixture with Anisaldehyde.
<ol>
	<li>Dissolve 175 &#956;L of anisaldehyde and 250 &#956;L of benzyl butyrate in 5 mL of methanol and transfer the solution to a separatory funnel. 
	Caution: Sodium bisulfite can generate sulfur dioxide gas, thus this protocol should be carried out with proper ventilation, such as in a fume hood.</li>
	<li>Add 1 mL of saturated aqueous sodium bisulfite and ...

<ol>
	<li>Boucher, M. M., Furigay, M. H., Quach, P. K., Brindle, C. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Liquid-Liquid+Extraction+Protocol+for+the+Removal+of+Aldehydes+and+Highly+Reactive+Ketones+from+Mixtures.">Liquid-Liquid Extraction Protocol for the Removal of Aldehydes and Highly Reactive Ketones from Mixtures.</a> Org. Process Res. Dev. 21 (9), 1394-1403 (2017).</li><li>Lauer, G. G., Pratt, R. S., Wilson, W. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Separation+of+Aldehydes+and+Ketones.">Separation of Aldehydes and Ketones.</a> , (1951).</li><li>Hsu, W. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Separation of Aldehydes from Ketones via Acid-Catalyzed Cyclotrimerization of the Aldehyde. , 4701561 (1987).</li><li>Schreiber, R. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Process+for+Separating+Aldehydes+and+Ketones.">Process for Separating Aldehydes and Ketones.</a> , (1942).</li><li>Bludworth, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Separation+of+Aldehyde-Ketone+Mixtures.">Separation of Aldehyde-Ketone Mixtures.</a> , (1944).</li><li>Masilamani, D., Manahan, E. H., Vitrone, J., Rogic, M. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Organic+Reactions+of+Sulfur+Dioxide.+Reactions+with+Nucleophilic+Double+Bonds+Leading+to+the+Isomerization,+Aromatization,+Selective+Hydrogen-Deuterium+Exchange,+and+Electron-Transfer+Proceses.">Organic Reactions of Sulfur Dioxide. Reactions with Nucleophilic Double Bonds Leading to the Isomerization, Aromatization, Selective Hydrogen-Deuterium Exchange, and Electron-Transfer Proceses.</a> J. Org. Chem. 48 (25), 4918-4931 (1983).</li><li>Masilamani, D., Rogic, M. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Organic+Reactions+of+Sulfur+Dioxide.+4.+A+Facile+Regiospecific+Hydrogen-Deuterium+Exchange+in+Olefins.+Consequence+of+the+Intermediacy+of+Allylic+Sulfinic+Acids+in+the+Ene+Reaction+of+Sulfur+Dioxide+with+Double+Bonds.">Organic Reactions of Sulfur Dioxide. 4. A Facile Regiospecific Hydrogen-Deuterium Exchange in Olefins. Consequence of the Intermediacy of Allylic Sulfinic Acids in the Ene Reaction of Sulfur Dioxide with Double Bonds.</a> J. Am. Chem. Soc. 100 (14), 4634-4635 (1978).</li><li>Makitra, R. G., Kal'muk, S. D., Bryk, D. V., Polyuzhin, I. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Factors+Controlling+Sulfur+Dioxide+Solubilities+in+Organic+Solvents.">Factors Controlling Sulfur Dioxide Solubilities in Organic Solvents.</a> Russ. J. Inorg. Chem. 55 (8), 1322-1329 (2010).</li><li>van Dam, M. H. H., Lamine, A. S., Roizard, D., Lochon, P., Roizard, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+Sulfur+Dioxide+Removal+Using+Organic+Solvents.">Selective Sulfur Dioxide Removal Using Organic Solvents.</a> Ind. Eng. Chem. Res. 36 (11), 4628-4637 (1997).</li><li>Li, H., Jiao, X., Chen, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Solubility+of+Sulphur+Dioxide+in+Polar+Organic+Solvents.">Solubility of Sulphur Dioxide in Polar Organic Solvents.</a> Phys. Chem. Liq. 52 (2), 349-353 (2014).</li><li>Trost, B. M., Brindle, C. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Direct+Catalytic+Asymmetric+Aldol+Reaction.">The Direct Catalytic Asymmetric Aldol Reaction.</a> Chem. Soc. Rev. 39 (5), 1600 (2010).</li></ol>

Initial attempts to use the bisulfite reaction as a method to remove aldehydes using a typical two-phase extraction led to very low levels of removal. We hypothesized that the reaction was not fast enough to occur during the very limited time that the two layers were in contact. To increase the contact between the reactants, we developed a two-stage extraction protocol in which a water-miscible solvent is used initially to allow sufficient mixing of the reactants prior to the introduction of an immiscible solvent. The in...

The separation of components of mixtures from one another is essential to the preparation of pure materials. The method described herein allows for the facile separation of aldehydes and sterically unhindered cyclic and methyl ketones from other organic molecules1. The technique relies on the reactivity of bisulfite with the carbonyl group to create a charged adduct that can be separated into an aqueous layer, while other components separate into an immiscible organic layer. The key to achieving reactivity between bisulfite and the carbonyl is the use of a miscible solvent, which allows the reaction to take place prior to the separation into separate phases. Without the addition of the miscible solvent minimal separation is obtained, presumably due to poor contact between the hydrophilic bisulfite and the hydrophobic organics.
The advantage of this separation method for purification is the ease of the protocol. Liquid-liquid extraction is a simple operation to perform, and can be carried out on large scale. Alternative purification techniques, such as column chromatography, are much more expensive, time-consuming, and challenging to perform on large scale and require sufficient differentiation of the components in terms of polarity. Purifying by recrystallization or distillation requires sufficient differentiation between the solubility or boiling points of the components of the mixture, respectively. Because bisulfite extraction relies on the difference in reactivity of the carbonyl group of aldehydes and ketones, compounds with similar solubility, boiling points, or polarities can be effectively separated. Other chemical separation methods exist for the selective separation of aldehydes and ketones from mixtures, for example, the selective formation of oximes2, cyclic acetals3, or mercaptal4 formation. These methods require an additional step to separate the formed species from the mixture, because the product is not water soluble and therefore cannot be separated by a simple extraction protocol. Aldehyde oxidation to form removable carboxylic acids is another reported technique5, but the required oxidation step is less chemoselective than the mild bisulfite conditions described herein, and requires the use of oxygen gas and a cobalt catalyst.
This method is applicable to the separation of aldehydes (Figure 1) and sterically-unhindered cyclic and methyl ketones (Figure 2) from molecules that do not contain these functional groups. Particularly reactive ketones, such as &#945;-keto esters are also removed using this process. Alkanes, alkenes, dienes, alkynes, esters, amides, carboxylic acids, alkyl halides, alcohols, phenols, nitriles, benzyl chlorides, epoxides, anilines, acetals, and slightly hindered, &#945;,&#946;-unsaturated, or aryl ketones are all unreactive under the conditions and can be separated from the aldehyde or reactive ketone component of the mixture (Figures 2 and Figure 3). Ethyl ketones or &#945;-substituted cyclic ketones, for example, are sufficiently hindered and are therefore separable from aldehydes and more reactive ketones. When using alkenes, hexane is recommended as the immiscible solvent to prevent unwanted decomposition due to sulfur dioxide present in the bisulfite solution. The functional group compatibility of the bisulfite extraction protocol is extremely broad, and is therefore applicable to an extremely wide range of separations, if the carbonyl contaminant to be separated from the mixture is either an aldehyde or an unhindered methyl or cyclic ketone. Less reactive ketones do not react with bisulfite under these conditions and are therefore not removed.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>sodium bisulfite</td>
			<td>Fisher</td>
			<td>AC419440010&#160;</td>
			<td>1 kg</td>
		</tr>
		<tr>
			<td>benzyl butyrate</td>
			<td>Fisher</td>
			<td>AAB2424130&#160;</td>
			<td>250 g</td>
		</tr>
		<tr>
			<td>anisaldehyde</td>
			<td>Fisher</td>
			<td>AC104801000&#160;</td>
			<td>100 mL</td>
		</tr>
		<tr>
			<td>magnesium sulfate</td>
			<td>Fisher</td>
			<td>M65-500&#160;</td>
			<td>500 g</td>
		</tr>
		<tr>
			<td>ethyl acetate</td>
			<td>Fisher</td>
			<td>E195-4&#160;</td>
			<td>4 L</td>
		</tr>
		<tr>
			<td>hexanes</td>
			<td>Fisher</td>
			<td>H292-4&#160;</td>
			<td>4 L</td>
		</tr>
		<tr>
			<td>methanol&#160;</td>
			<td>Fisher</td>
			<td>A456-1&#160;</td>
			<td>1 L</td>
		</tr>
		<tr>
			<td>dimethylformamide</td>
			<td>Fisher</td>
			<td>D119-1&#160;</td>
			<td>1 L</td>
		</tr>
		<tr>
			<td>citronellal</td>
			<td>Fisher</td>
			<td>AAL15753AE&#160;</td>
			<td>100 mL</td>
		</tr>
		<tr>
			<td>benzylacetone&#160;</td>
			<td>Fisher</td>
			<td>AC105832500&#160;</td>
			<td>250 mL</td>
		</tr>
		<tr>
			<td>deionized water</td>
			<td>Fisher</td>
			<td>BP28194&#160;</td>
			<td>4 L</td>
		</tr>
		<tr>
			<td>piperonal&#160;</td>
			<td>Sigma-Aldrich</td>
			<td>P49104-25G</td>
			<td>25 G</td>
		</tr>
		<tr>
			<td>sodium hydroxide</td>
			<td>Fisher</td>
			<td>S318-1&#160;</td>
			<td>1 kg</td>
		</tr>
		<tr>
			<td>separatory funnel with cap</td>
			<td>Fisher</td>
			<td>10-437-5B&#160;</td>
			<td>125 mL</td>
		</tr>
		<tr>
			<td>ring stand</td>
			<td>Fisher</td>
			<td>03-422-215</td>
			<td>3 aluminum rods</td>
		</tr>
		<tr>
			<td>ring clamp</td>
			<td>Fisher</td>
			<td>12-000-104&#160;</td>
			<td>5 cm</td>
		</tr>
		<tr>
			<td>cork ring</td>
			<td>Fisher</td>
			<td>07-835AA&#160;</td>
			<td>8 cm outer dimension</td>
		</tr>
		<tr>
			<td>round bottom flask</td>
			<td>Fisher</td>
			<td>31-501-107&#160;</td>
			<td>100 mL</td>
		</tr>
		<tr>
			<td>rotary evaporator with accessories</td>
			<td>Fisher</td>
			<td>05-000-461&#160;</td>
			<td>cold trap bondenser</td>
		</tr>
		<tr>
			<td>bump trap 14/20 joint</td>
			<td>Fisher</td>
			<td>CG132201</td>
			<td>14/20 joint</td>
		</tr>
		<tr>
			<td>funnel</td>
			<td>Fisher</td>
			<td>05-555-6&#160;</td>
			<td>organic solvent compatible</td>
		</tr>
		<tr>
			<td>cotton</td>
			<td>Fisher</td>
			<td>22-456-881</td>
			<td>non-sterile</td>
		</tr>
		<tr>
			<td>glass pipets</td>
			<td>Fisher</td>
			<td>13-678-20A&#160;</td>
			<td>borosilicate 5.75&#34;</td>
		</tr>
		<tr>
			<td>two 250 microliter syringes</td>
			<td>Fisher</td>
			<td>14-813-69&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>4 erlenmeyer flasks</td>
			<td>Fisher</td>
			<td>10-040D&#160;</td>
			<td>125 mL</td>
		</tr>
		<tr>
			<td>fume hood&#160;</td>
			<td>Fisher</td>
			<td>13-118-370&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>nitrile gloves</td>
			<td>Fisher</td>
			<td>19-149-863B&#160;</td>
			<td>medium</td>
		</tr>
		<tr>
			<td>safety goggles</td>
			<td>Fisher</td>
			<td>17-377-403&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>spatula</td>
			<td>Fisher</td>
			<td>14-357Q</td>
			<td></td>
		</tr>
		<tr>
			<td>balance</td>
			<td>Fisher</td>
			<td>01-912-403&#160;</td>
			<td>120 g capacity</td>
		</tr>
	</tbody>
</table>

separation of aldehydes and reactive ketones from mixtures using a bisulfite extraction protocol

The purification of organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer by generating a charged structure provides an opportunity to use extraction as a simple purification technique. By combining the use of a miscible organic solvent with saturated sodium bisulfite, aldehydes and reactive ketones can be successfully transformed into charged bisulfite adducts that can then be separated from other organic components of a mixture by the introduction of an immiscible organic layer. Here, we describe a simple protocol for the removal of aldehydes, including sterically-hindered neopentyl aldehydes and some ketones, from chemical mixtures. Ketones can be separated if they are sterically unhindered cyclic or methyl ketones. For aliphatic aldehydes and ketones, dimethylformamide is used as the miscible solvent to improve removal rates. The bisulfite addition reaction can be reversed by basification of the aqueous layer, allowing for the re-isolation of the reactive carbonyl component of a mixture.

Procedure 1 for aldehyde removal is used for aromatic aldehydes. Procedure 2, in which dimethylformamide is used as the miscible solvent, should be used for aliphatic aldehydes and ketones. Procedure 2 should also be used for mixtures that are not fully soluble in methanol. The material obtained from each of the protocols is analyzed for purity using 1H NMR integration analysis and for recovery rate by mass. Typical purities an...

Watch this Scientific Journal Video about Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol at JoVE.com

Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol

Here, we present a protocol to remove aldehydes and reactive ketones from mixtures by a liquid-liquid extraction protocol directly with saturated sodium bisulfite in a miscible solvent. This combined protocol is rapid and facile to perform. The aldehyde or ketone can be re-isolated by the basification of the aqueous layer.

The purification of organic compounds is an essential component of routine synthetic operations. The ability to remove contaminants into an aqueous layer ...

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