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

Summary

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.

Abstract

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.

Introduction

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 α-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, α,β-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 α-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.

Protocol

1. Standard Protocol for The Separation of Aromatic Aldehydes from a Mixture. Example: Separation of Benzyl Butyrate from a 1:1 Mixture with Anisaldehyde.

1. Dissolve 175 μL of anisaldehyde and 250 μL 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.
2. Add 1 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.
3. Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.
4. 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.

2. Separation of Aliphatic Aldehydes and Ketones from a Mixture. Example: Separation of Benzyl Butyrate from a 1:1 Mixture with Benzylacetone.

1. Dissolve 213 μL of benzylacetone and 250 μL 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.
2. Add 25 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.
3. Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.
4. 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.
5. 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.

3. Separation of Aldehydes from a Mixture Containing an Alkene. Example: Separation of Benzyl Butyrate from a 1:1 Mixture with Citronellal.

1. Dissolve 255 μL of citronellal and 250 μL 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.
2. Add 25 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.
3. Add 25 mL of deionized water and 25 mL of hexanes and shake vigorously.
4. 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.
5. 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.

4. Re-isolation of Aldehydes from a Mixture. Example: Separation of Piperonal from a 1:1 Mixture with Benzyl Butyrate.

1. Dissolve 217 mg of piperonal and 250 μL 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.
2. Add 1 mL of saturated aqueous sodium bisulfite and shake vigorously for approximately 30 s.
3. Add 25 mL of deionized water and 25 mL of 10% ethyl acetate/hexanes and shake vigorously.
4. Separate the layers. Return the aqueous layer back to the separatory funnel.
   1. Optional: Wash aqueous layer once with 25 mL of 10% ethyl acetate/hexanes to remove the small amount of remaining benzyl butyrate.
5. 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.
6. Separate the layers. Return the aqueous layer to the separatory funnel and add 25 mL of ethyl acetate. Shake vigorously.
7. 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.

Results

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...

Discussion

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...

Materials

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