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 shake vigorously for approximately 30 s.</li>
	<li>Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.</li>
	<li>Separate the layers. Dry the organic layer with anhydrous magnesium sulfate. Filter the solution to remove magnesium sulfate and concentrate in vacuo using a rotary evaporator.</li>
</ol>
2. Separation of Aliphatic Aldehydes and Ketones from a&#160;Mixture. Example: Separation of Benzyl Butyrate from a&#160;1:1 Mixture with Benzylacetone.
<ol>
	<li>Dissolve 213 &#956;L of benzylacetone and 250 &#956;L of benzyl butyrate in 10 mL of dimethylformamide 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 25 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.</li>
	<li>Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.</li>
	<li>Separate the layers. Return the aqueous layer to the separatory funnel, add 25 mL of 10% ethyl acetate/hexanes and shake vigorously. Drain the aqueous layer, leaving the organic layer in the separatory funnel. Add the previous organic layer back to the separatory funnel.</li>
	<li>Wash the combined organic layers three times with deionized water (10 mL for each wash). Dry the organic layer with anhydrous magnesium sulfate. Filter the solution to remove magnesium sulfate and concentrate in vacuo using a rotary evaporator.</li>
</ol>
3. Separation of Aldehydes from a&#160;Mixture Containing an Alkene. Example: Separation of Benzyl Butyrate from a 1:1 Mixture with Citronellal.
<ol>
	<li>Dissolve 255 &#956;L of citronellal and 250 &#956;L of benzyl butyrate in 10 mL of dimethylformamide 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 25 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.</li>
	<li>Add 25 mL of deionized water and 25 mL of hexanes and shake vigorously.</li>
	<li>Separate the layers. Return the aqueous layer to the separatory funnel, add 25 mL hexanes and shake vigorously. Drain the aqueous layer, leaving the organic layer in the separatory funnel. Add the previous organic layer back to the separatory funnel.</li>
	<li>Wash the combined organic layers three times with deionized water (10 mL for each wash). Dry the organic layer with anhydrous magnesium sulfate. Filter the solution to remove magnesium sulfate and concentrate in vacuo using a rotary evaporator.</li>
</ol>
4. Re-isolation of Aldehydes from a Mixture. Example: Separation of Piperonal from a 1:1 Mixture with Benzyl Butyrate.
<ol>
	<li>Dissolve 217 mg of piperonal 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 shake vigorously for approximately 30 s.</li>
	<li>Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.</li>
	<li>Separate the layers. Return the aqueous layer back to the separatory funnel.
	<ol>
		<li>Optional: Wash aqueous layer once with 25 mL of 10% ethyl acetate/hexanes to remove the small amount of remaining benzyl butyrate.</li>
	</ol>
	</li>
	<li>Add 25 mL of ethyl acetate and then add 50% sodium hydroxide until a pH strip indicates that the pH is 12. Shake vigorously. 
	Caution: Gas evolution has been observed during this step and can cause pressure build-up. Make sure to properly vent the separatory funnel. Scaling up this procedure will make gas evolution more pronounced. Use caution.</li>
	<li>Separate the layers. Return the aqueous layer to the separatory funnel and add 25 mL of ethyl acetate. Shake vigorously.</li>
	<li>Separate the layers. Combine the organic layer with the organic layer from the previous step. Dry the combined organic layer with anhydrous magnesium sulfate. Filter the solution to remove magnesium sulfate and concentrate in vacuo using a rotary evaporator.</li>
</ol>

<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>

The authors have nothing to disclose.

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><tbody><tr><td>sodium bisulfite</td><td>Fisher</td><td>AC419440010&amp;nbsp;</td><td>1 kg</td></tr><tr><td>benzyl butyrate</td><td>Fisher</td><td>AAB2424130&amp;nbsp;</td><td>250 g</td></tr><tr><td>anisaldehyde</td><td>Fisher</td><td>AC104801000&amp;nbsp;</td><td>100 mL</td></tr><tr><td>magnesium sulfate</td><td>Fisher</td><td>M65-500&amp;nbsp;</td><td>500 g</td></tr><tr><td>ethyl acetate</td><td>Fisher</td><td>E195-4&amp;nbsp;</td><td>4 L</td></tr><tr><td>hexanes</td><td>Fisher</td><td>H292-4&amp;nbsp;</td><td>4 L</td></tr><tr><td>methanol&amp;nbsp;</td><td>Fisher</td><td>A456-1&amp;nbsp;</td><td>1 L</td></tr><tr><td>dimethylformamide</td><td>Fisher</td><td>D119-1&amp;nbsp;</td><td>1 L</td></tr><tr><td>citronellal</td><td>Fisher</td><td>AAL15753AE&amp;nbsp;</td><td>100 mL</td></tr><tr><td>benzylacetone&amp;nbsp;</td><td>Fisher</td><td>AC105832500&amp;nbsp;</td><td>250 mL</td></tr><tr><td>deionized water</td><td>Fisher</td><td>BP28194&amp;nbsp;</td><td>4 L</td></tr><tr><td>piperonal&amp;nbsp;</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&amp;nbsp;</td><td>1 kg</td></tr><tr><td>separatory funnel with cap</td><td>Fisher</td><td>10-437-5B&amp;nbsp;</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&amp;nbsp;</td><td>5 cm</td></tr><tr><td>cork ring</td><td>Fisher</td><td>07-835AA&amp;nbsp;</td><td>8 cm outer dimension</td></tr><tr><td>round bottom flask</td><td>Fisher</td><td>31-501-107&amp;nbsp;</td><td>100 mL</td></tr><tr><td>rotary evaporator with accessories</td><td>Fisher</td><td>05-000-461&amp;nbsp;</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&amp;nbsp;</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&amp;nbsp;</td><td>borosilicate 5.75&quot;</td></tr><tr><td>two 250 microliter syringes</td><td>Fisher</td><td>14-813-69&amp;nbsp;</td><td></td></tr><tr><td>4 erlenmeyer flasks</td><td>Fisher</td><td>10-040D&amp;nbsp;</td><td>125 mL</td></tr><tr><td>fume hood&amp;nbsp;</td><td>Fisher</td><td>13-118-370&amp;nbsp;</td><td></td></tr><tr><td>nitrile gloves</td><td>Fisher</td><td>19-149-863B&amp;nbsp;</td><td>medium</td></tr><tr><td>safety goggles</td><td>Fisher</td><td>17-377-403&amp;nbsp;</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&amp;nbsp;</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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33.8K Views.  Trinity College. 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.

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

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.

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 ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of ...

Reducing Agents

Source: Vy M. Dong and Daniel Kim, Department of Chemistry, University of California, Irvine, CA
Controlling the reactivity and selectivity during the synthesis of a molecule is very important criteria for chemists. This has led to the development of many reagents that allow chemists to pick and choose reagents suitable for a given task. Quite often, a balance between reactivity and selectivity needs to be achieved. This experiment will use IR spectroscopy to monitor the reaction and to understand the reactivity of carbonyl compounds as well as the reactivity of hydride-reducing reagents.

Reduction of Carbonyl Compounds

Source: Vy M. Dong and Daniel Kim, Department of Chemistry, University of California, Irvine, CA
Controlling the reactivity and selectivity during the ...

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Organic Chemistry II

Alcohols from Carbonyl Compounds: Reduction

Reduction is a simple strategy to convert a carbonyl group to a hydroxyl group. The three major pathways to reduce carbonyls to alcohols are catalytic hydrogenation, hydride reduction, and borane reduction.
Catalytic hydrogenation is similar to the reduction of an alkene or alkyne by adding H2 across the pi bond in the presence of transition metal catalysts like Raney Ni, Pd&#8211;C, Pt, or Ru. Aldehydes and ketones can be reduced by this method, often under mild to moderate heat (25&#8211;100&#176;C) and pressure (1&#8211;5 atm H2), to yield 1&#176; and 2&#176; alcohols, respectively.
<img alt="Figure1" src="/files/ftp_upload/11925/11925_PT_Figure_1.svg" style="text-align: center; height: 90px;" />
Figure 1. Catalytic hydrogenation can be suitable for industrial applications when harsh conditions are not required, but unsaturated carbon&#8211;carbon bonds are also reduced.
Hydride reduction can be achieved by hydride transfer reagents, like sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4, or LAH), as nucleophilic attack by a free hydride ion, <img alt="Figure2" src="/files/ftp_upload/11925/11925_PT_Figure_2.svg" style="height: 18px;" />, is almost unknown for NaH salts due to its high charge density, making it a strong base. The hydrogen atoms of LAH and NaBH4, being covalently bonded to boron and aluminum atoms, have partial negative charges, thereby enhancing their nucleophilicity at the cost of basicity. The first step of nucleophilic addition leads to the formation of alkoxide ions. The byproduct alkoxyborohydride or alkoxyaluminate reduces three more carbonyl molecules, successively transferring all their hydrogen atoms. Since hydride is a poor leaving group, the hydride transfer steps are irreversible, and therefore the reaction proceeds to completion. Lastly, the reaction mixture is worked up with solvent (i.e., water or alcohol in the case of NaBH4 and dilute acid in the case of LAH).
<img alt="Figure3" src="/files/ftp_upload/11925/11925_PT_Figure_3.svg" style="text-align: center; height:55px;" />
Figure 2. Aldehydes and symmetrical esters produce one 1&#176; alcohol product. Unsymmetrical esters produce a mixture of 1&#176; alcohols.
LAH, NaBH4, and their derivatives are highly useful in the reduction of aldehydes and ketones. LAH, a powerful reducing agent, can also reduce carbonyl compounds like acids, esters, acyl chlorides, and amides. LAH reacts violently with water and other protic solvents, liberating hydrogen gas and forming metal hydroxides/alkoxides. Hence, LAH reductions are typically carried out in aprotic solvents like anhydrous diethyl ether and THF.
<img alt="Figure4" src="/files/ftp_upload/11925/11925_PT_Figure_4.svg" style="text-align: center; height: 45px;" />
Figure 3. An alcoholic solution of lithium borohydride is a non-hazardous alternative to LAH in selectively reducing esters over acids.
On the other hand, NaBH4 is of a milder nature and generally reduces only in protic solvents like ethanol or methanol. Therefore, NaBH4 can be used to reduce aldehydes and ketones in the presence of functional groups like alkyl halides, esters, alkyl tosylates, and nitro groups. Diisobutylaluminum hydride (DIBAL-H) can also convert carbonyls to alcohols at room temperature by two successive additions of hydride ions. However, when reacted with esters at low temperatures, this reaction can be stopped at the aldehyde stage by adding only one equivalent of hydride ion.
Borane reduction uses a borane (BH3) solution in diethyl ether, THF, or Me2S to selectively reduce electron-rich carbonyl groups like carboxylic acids in the presence of other reducible functional groups such as esters and even ketones.
<img alt="Figure5" src="/files/ftp_upload/11925/11925_PT_Figure_5.svg" style="text-align: center; height: 65px;" />
Figure 4. The formation of a reactive triacylborate intermediate with a more electrophilic carbonyl group than the starting ester molecule drives the reduction reaction forward.
For living organisms, reduced coenzyme NADH or its phosphoester NADPH is equivalent to laboratory hydride reagents in enzyme catalysis of similar biological reductions.

Reduction is a simple strategy to convert a carbonyl group to a hydroxyl group. The three major pathways to reduce carbonyls to alcohols are catalytic ...

Organic Chemistry

Unit 1

Alcohols and Phenols

KEY TERMS AND CONCEPTS

Preparation of Aldehydes and Ketones from Alcohols, Alkenes, and Alkynes

Aldehydes and ketones are prepared from alcohols, alkenes, and alkynes via different reaction pathways. Alcohols are the most commonly used substrates for synthesizing aldehydes and ketones. The conversion of alcohol to aldehyde, which involves the oxidation process, depends on the class of the alcohol used and the strength of the oxidizing agent. For instance, primary alcohol will form an aldehyde when treated with a weak oxidizing agent; however, it gets over-oxidized to a carboxylic acid in the presence of a strong oxidizing agent. Hence, a mild oxidant like pyridinium chlorochromate is used to convert primary alcohols to aldehydes.
Similarly, Swern and Dess&#8211;Martin oxidations, which employ weaker oxidizing agents, convert primary alcohols to aldehydes. The strength of the oxidizing agent is irrelevant when converting secondary alcohol to a ketone. Both mild and strong oxidants give ketones from secondary alcohols.
Unsaturated hydrocarbons like alkenes undergo an ozonolysis reaction to give aldehydes and ketones. The product formed depends on the substitution present across the double bond in an alkene. A monosubstituted alkene forms formaldehyde and another aldehyde molecule. However, disubstitution gives rise to two cases. A 1,1-disubstituted alkene upon ozonolysis forms a mixture of formaldehyde and ketone, while a 1,2-disubstituted alkene yields a mixture of aldehydes. Both aldehydes and ketones are formed when trisubstituted alkenes undergo ozonolysis, while tetrasubstituted alkenes form ketones exclusively.
Alkynes&#160;also form aldehydes and ketones under hydroboration-oxidation and acid-catalyzed hydration reaction conditions. The hydroboration-oxidation reaction favors anti-Markovnikov&#8217;s addition. Hence terminal alkynes form aldehydes, and internal alkynes&#160;yield ketones. On the other hand, the acid-catalyzed hydration reaction follows Markonikov&#8217;s addition, and thus both terminal and internal alkynes generate&#160;ketones.

Aldehydes and ketones are prepared from alcohols, alkenes, and alkynes via different reaction pathways. Alcohols are the most commonly used substrates for ...

Aldehydes and Ketones

Preparation of Aldehydes and Ketones from Nitriles and Carboxylic Acids

Although it is possible to reduce a carboxylic acid to an aldehyde, strong reducing agents, like lithium aluminum hydride (LAH), prohibit a controlled reduction, instead causing the generated aldehyde to instantly over-reduce to a primary alcohol.
Reducing carboxylic acid derivatives like acyl chlorides (RCOCl), esters (RCO2R&prime;), and nitriles (RCN) using milder aluminum hydride agents like lithium tri-tert-butoxyaluminum hydride [LiAlH(O-t-Bu)3] and diisobutylaluminum hydride [DIBAL-H] allows the easy conversion of the derivative to the corresponding aldehyde. This is because alkylaluminum hydrides are less reactive than LAH, as the former is more sterically hindered.
According to recent studies, a reductant like diphenylsilane in combination with an air-stable Ni precatalyst and dimethyl dicarbonate as an activator converts most of the carboxylic acid to the aldehyde without causing any over-reduction.
In other studies, a hydrosilane through visible light photoredox catalysis efficiently reduces carboxylic acids to aldehydes.
Ketones, unlike aldehydes, can be directly prepared from carboxylic acids using organolithium reagents. The acid rapidly reacts with two equivalents of an organolithium reagent to form a dianion. This dianion gets protonated to form the corresponding hydrate, which loses a water molecule to give a ketone.
Both aldehydes and ketones can be prepared from nitriles using suitable reducing agents. Aldehydes are formed by the partial reduction of nitriles in the presence of DIBAL-H. The nitrile first forms an aluminum complex, which later, on hydrolysis, yields the corresponding aldehyde. Nitriles can be reduced to ketones via imine intermediates using Grignard or organolithium reagents.

Although it is possible to reduce a carboxylic acid to an aldehyde, strong reducing agents, like lithium aluminum hydride (LAH), prohibit a controlled ...

Preparation of Aldehydes and Ketones from Carboxylic Acid Derivatives

Aldehydes are more reactive than carboxylic acids and hence, can get over-reduced to alcohol in the presence of strong reducing agents. Therefore, carboxylic acids are&#160;inefficient in preparing aldehydes using LAH.
Carboxylic acid derivatives like acid chlorides and esters are more easily reducible than the corresponding acids. The derivatives reduce in the presence of mild reducing agents to give aldehydes. Aldehydes can also be prepared by Rosenmund reduction, that is, the reduction of acid chloride via hydrogenation over a poisoned catalyst. Catalytic poisoning inhibits the over-reduction of aldehydes. A Grignard reagent reduces an acid chloride to tertiary alcohol via a ketone intermediate. The reaction can be stopped at the ketone stage using a milder reducing agent like the Gilman reagent (R2CuLi). Aryl ketones can be prepared by Friedel&#8211;Crafts acylation&#160;in which acid chloride is treated with benzene and AlCl3.
Another carboxylic acid derivative, an ester, can be reduced to an aldehyde using DIBAL-H at dry ice temperature to give an aldehyde. Ketones cannot be prepared directly from esters because ketones are more reactive than esters and tend to over-reduce to tertiary alcohol.

Aldehydes are more reactive than carboxylic acids and hence, can get over-reduced to alcohol in the presence of strong reducing agents. Therefore, ...

Reactions of Aldehydes and Ketones: Baeyer&ndash;Villiger Oxidation

Baeyer&#8211;Villiger oxidation converts aldehydes to carboxylic acids and ketones to esters. The reaction uses peroxy acids or peracids and is often catalyzed by acid. The reaction is named after its pioneers, Adolf von Baeyer and Victor Villiger. The reaction is achieved by a wide range of peracids such as m-chloroperoxybenzoic acid (mCPBA), perbenzoic acid (C6H5COOOH), peracetic acid (CH3COOOH), hydrogen peroxide (H2O2), and tert-butyl hydroperoxide (t-BuOOH).
The carbonyl center is activated by protonating the carbonyl oxygen. The peracid then adds across the C=O bond to give a tetrahedral intermediate called the Criegee intermediate. During the concerted intramolecular rearrangement that follows, the carbonyl group is restored, a group migrates from carbon to oxygen, and the weak peroxide bond cleaves to give an acid (if the substrate is an aldehyde) or an ester (if the substrate is a ketone).
<img alt="Figure1" src="/files/ftp_upload/12341/12341_PT_Figure_1.svg" style="text-align: center; height: 275px;" />
The migratory aptitude of different groups follows the order of &#8211;H &#62; &#8211;CR3 &#62; &#8211;CHR2 &approx; &#8211;Ph &#62; &#8211;CRH2 &#62; &#8211;&NoBreak;CH3. This makes Baeyer&#8211;Villiger oxidation regioselective. Also, the reaction retains the stereochemistry at the migrating center for asymmetrical substrates. Reactions involving cyclic ketones produce lactones.

Reactions of Aldehydes and Ketones: Baeyer&amp;#8211;Villiger Oxidation

Baeyer&#8211;Villiger oxidation converts aldehydes to carboxylic acids and ketones to esters. The reaction uses peroxy acids or peracids and is often ...

&alpha;-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview

The pinacol and McMurry reactions involve the reductive coupling of ketones or aldehydes. Similarly, the bimolecular reductive coupling of two ester molecules in the presence of sodium metal in an aprotic solvent yields an &#945;-hydroxy ketone product. The &#945;-hydroxy ketone is also called acyloin, so the reaction is referred to as &#8216;acyloin condensation.&#8217;
<img alt="Figure1" src="/files/ftp_upload/12908/12908_PT_Figure_1.svg" style="text-align: center; height: 65px;" />
In the acyloin condensation reaction, esters are converted to ketyls, which undergo radical dimerization to form an unstable tetrahedral intermediate. Further, this intermediate collapses to give a 1,2-diketone intermediate. The 1,2-diketones are comparatively more reactive than ketones towards electrophiles and reducing agents because of lower &#960;* energy. Consequently, two electrons sequentially transfer to the 1,2-diketone to form an enediolate. Lastly, the enediolate intermediate is quenched with acid to yield an &#945;-hydroxy ketone with a good yield.
Often some by-products are obtained alongside the major product because of the reactivity of nucleophilic enediolate. To overcome the side reactions and improve the yield of an acyloin, trimethylsilyl chloride is used to silylate the enediolate. This results in a bis-silyl ether, further hydrolyzed with aqueous acid to give &#945;-hydroxy ketones.

&amp;#945;-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview

The pinacol and McMurry reactions involve the reductive coupling of ketones or aldehydes. Similarly, the bimolecular reductive coupling of two ester ...

Radical Chemistry

Alkylation of &beta;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide base that abstracts the acidic proton of the &beta;-keto esters. The step results in an enolate ion which is doubly stabilized. The enolate then reacts with an alkyl halide via the SN2 process to produce an alkylated ester intermediate with a new C&#8211;C bond. The hydrolysis of the intermediate, followed by acidification, results in an alkylated &beta;-keto acid. Under high-temperature conditions, the &beta;-keto acid undergoes decarboxylation to form a ketone. However, if the alkylation is repeated before hydrolysis and decarboxylation steps, a disubstituted ketone is obtained.

Alkylation of &amp;#946;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide ...

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

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