Liquid-Liquid Extraction Protocol for the Removal of Aldehydes and Highly Reactive Ketones from Mixtures

Article abstract of DOI:10.1021/acs.oprd.7b00231

The reaction of the bisulfite ion with aldehydes to form charged bisulfite adducts is a well-established method for the purification of aldehydes. This reaction has been modified to create a convenient liquid-liquid extraction method for the removal of aldehydes from mixtures. The use of a water-miscible solvent allows the reaction to occur during a simple 30 s shaking protocol by increasing the contact between the bisulfite ion and the aldehyde. The introduction of an immiscible solvent allows for the extraction of the uncharged organic components away from the bisulfite adduct. The developed protocol is applicable to a wide range of aldehydes, including sterically hindered neopentyl aldehydes. Sterically unhindered cyclic and linear ketones, as well as highly electrophilic ketones, are also removed using this protocol. The mild conditions tolerate a wide range of functional groups, allowing for excellent aldehyde contaminant removal rates with high levels of recovery of the desired component.

Full text of DOI:10.1021/acs.oprd.7b00231

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Full Paper
Liquid-Liquid Extraction Protocol for the Removal of
Aldehydes and Highly Reactive Ketones from Mixtures
Maria Marsian Boucher, Maxwell Hyland Furigay, Phong Kim Quach, and Cheyenne S. Brindle
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00231 • Publication Date (Web): 12 Jul 2017
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Liquid-Liquid Extraction Protocol for the Removal of Aldehydes and Highly Reactive Ketones
from Mixtures
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Maria M. Boucher, Maxwell H. Furigay, Phong K. Quach, and Cheyenne S. Brindle*
Trinity College, 300 Summit Street, Hartford, CT 06106
cheyenne.brindle@trincoll.edu
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TOC graphic
remove aldehyde contaminants using a simple extraction protocol
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extract with
water-immiscible
organic solvent
add saturated
NaHSO3(aq)
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dissolve mixture in
water-miscible
organic solvent
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Abstract
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The reaction of bisulfite ion with aldehydes to form charged bisulfite adducts is a well-
established method for the purification of aldehydes. This reaction has been modified to create
a convenient liquid-liquid extraction method for the removal of aldehydes from mixtures. The
use of a water-miscible solvent allows the reaction to occur during a simple 30 second shaking
protocol by increasing the contact between the bisulfite ion and the aldehyde. Introduction of
an immiscible solvent allows for extraction of the uncharged organic components away from
the bisulfite adduct. The developed protocol is applicable to a wide range of aldehydes,
including sterically-hindered neopentyl aldehydes. Sterically unhindered cyclic and linear
ketones, as well as highly electrophilic ketones are also removed using this protocol. The mild
conditions tolerate a wide range of functional groups, allowing for excellent aldehyde
contaminant removal rates with high levels of recovery of the desired component.
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Keywords
extraction, bisulfite, aldehyde, purification
Introduction
The ability to separate chemical components from mixtures of compounds is critical to
the chemical field, including practicing organic chemists.1 Numerous techniques are available
for separation, yet difficulties in molecular separations remain an everyday issue. Recently, we
encountered a particularly difficult separation that involved excess aldehyde that was used as a
reagent in the synthesis of a desired product. This problem led us to investigate the use of an
extraction protocol based on the reactivity of aldehydes with sodium bisulfite (equation 1).
Extraction is a routine part of most chemical reactions, and a new protocol that could remove
unwanted aldehydes from mixtures would provide a convenient tool for purification. Aldehydes
are a particularly important functional group for synthesis due to their high reactivity, so this
protocol would have widespread applicability. The results of these efforts, described herein,
have produced a simple new protocol that we believe will be of great utility to synthetic
chemists.
Equation 1.
The reaction of sodium sulfite with aldehydes to form charged bisulfite adducts is a well-
known reaction,2,3 but its utility in the lab is mainly centered on its use in purifying aldehydes
from mixtures, rather than removing them.4,5 Outside of the lab, there are numerous
commercial uses of bisulfite removal of aldehydes in a variety of settings.6,7 In principle, using
this reaction to remove aldehydes rather than purify them is merely a matter of nomenclature.
In practice, however, this change required some manipulation to perform as a simple liquid-
liquid extraction (LLE) procedure to achieve separation as a work-up, rather than using a more
typical reaction setup. For an extraction to be successful with a simple shaking protocol, the
rate of the reaction must be very fast. In general, this limits the types of reactions that can be
achieved in extraction to reactions such as acid/base chemistry (e.g. sodium hydroxide), redox
reactions (e.g. sodium thiosulfate), or the complexation of metals and ligands (e.g. copper
sulfate), unless longer time periods are used for mixing (e.g. Rochelle’s salt). The mechanism of
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bisulfite addition is generally believed to occur through nucleophilic attack of the carbonyl by
the sulfur of the bisulfite ion,8 or of the sulfite dianion,9 although a pericyclic mechanism has
also been suggested to account for the high negative entropy measured for certain
aldehydes.10,11 If bisulfite addition to aldehydes is sufficiently rapid, a liquid-liquid extraction
would be possible.
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Results and Discussion
To model a typical to relatively challenging separation scenario, a contaminant aldehyde
and model substrate were mixed in a 1:1 mole ratio, and several extraction protocols were
evaluated. This mixing ratio was convenient for accurate determination of the decontamination
1
factor using H NMR integration analysis. Anisaldehyde was chosen as a model substrate
because of its relatively low volatility, allowing for easy re-isolation and evaluation of different
protocols. We also wanted an electron-rich aromatic ring that would not overly bias the system
toward nucleophilic attack at the aldehyde. Benzyl butyrate was chosen as a non-volatile model
substrate for purification. This choice also highlights the known chemoselectivity of the bisulfite
reaction in terms of carbonyl reactivity toward aldehydes and cyclic ketones as compared to
other carbonyl-containing functional groups.
Our first effort at LLE separation illustrated the kinetic limitations of this separation
method (Table 1, entry 1). Using a typical extraction protocol, in which a 1:1 mixture of
anisaldehyde and benzyl butyrate were dissolved in ethyl ether and then washed three times
with saturated sodium bisulfite, negligible separation was achieved. Dissolving the 1:1 mixture
in dichloromethane and filtering through solid sodium bisulfite also had a negligible effect
(entry 2). However, when the more polar solvent methanol was used to elute through a column
of solid sodium bisulfite, the amount of aldehyde remaining dramatically decreased, likely due
to better solvation of the bisulfite ion (entry 3). Though the bisulfite adduct was not detected
by 1H NMR, the mass balance indicated that benzyl butyrate and remaining aldehyde were not
the only components present. This observation led us to conclude that deuterated chloroform-
insoluble bisulfite adducts were present after filtration, and therefore we needed to combine
the improved solubility of bisulfite in polar organic solvents with the removal of the charged
bisulfite adduct into an aqueous layer. Therefore, the 1:1 mixture was first dissolved in
methanol, then saturated sodium bisulfite solution was added, and the single phase was shaken
vigorously for approximately 30 seconds. At this point an immiscible solvent was introduced to
provide two layers, which were then separated. Several solvent systems were evaluated for this
extraction technique (entries 4-8), and all were found to remove 90% or more of the aldehyde
from the model substrate. The best result was found for the nonpolar solvent hexanes (entry
8). Since many substrates are not soluble in pure hexanes, however, 10% ethyl acetate/hexane
(entry 7) was chosen as a more general immiscible solvent for purification. It should be noted
that ethyl acetate and ether, though not as effective, are still useful solvents for separation,
allowing for the applicability of this protocol to more polar substrates that are not be soluble in
10% ethyl acetate/hexanes.
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Table 1. Separation of anisaldehyde from benzyl butyrate using sodium bisulfite. aA mixture of
benzyl butyrate (250 μL, 1.4 mmol) and anisaldehyde (175 μL, 1.4 mmol) were tested using the
listed conditions. bDecontamination factor. cDetermined by 1H NMR analysis. hex = hexanes.
With these promising results, we next began to examine the substrate scope of our
extraction protocol with respect to the removable aldehyde component (Scheme 1). Aromatic
aldehydes were easily removed. Electron-rich aldehydes, in addition to anisaldehyde 2, such as
p-dimethylaminobenzaldehyde 3 and piperonal 4 also were removed in high selectivity.
Electron-neutral benzaldehyde 5, and more electrophilic aldehydes, p-cyanobenzaldehyde 6
and p-nitrobenzaldehyde 7 were also removed effectively. The method was altered slightly for
p-nitrobenzaldehyde 7, due to insolubility of this substrate in methanol. Simply exchanging
dimethylformamide for methanol as the miscible solvent proved effective, though this
substitution required additional water washes to remove the less volatile solvent from the
model substrate, which was not necessary with the more aqueous-soluble methanol. More
sterically
hindered
ortho-substituted
substrates
2-tolylaldehyde
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and
2-
trifluoromethylbenzaldehyde 9 were also easily removed. 1-Naphthaldehyde 10 required
filtration through celite after treatment with saturated sodium bisulfite solution to effectively
separate the water- and organic-insoluble bisulfite adduct from the organic layer. 2,6-
Dimethylbenzaldehyde 11 was much less susceptible to the work-up protocol, giving only 64%
removal. This substrate also required celite filtration. In contrast, 2,6-dimethoxybenzaldehyde
12 was almost completely removed under the separation conditions. α,β–Unsaturated
aldehyde trans-cinnamaldehyde 13 was also effectively removed using this protocol.
Scheme 1. Removal of aromatic aldehydes from benzyl butyrate.
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aBenzyl butyrate (250 μL, 1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 5 mL MeOH, 25
mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and
extracted with 25 mL 10% EA/hexanes. bDMF instead of MeOH used. Organic layer washed two
times with 15 mL water. cRequired filtration to remove solid bisulfite adduct.
Non-aromatic aldehydes were found to be less effectively removed using this protocol,
prompting us to further examine the extraction parameters using 3-phenylpropionaldehyde 14
as the model aliphatic aldehyde (Table 2). The standard work-up protocol used for aromatic
aldehydes gave only 85% removal (entry 1). As expected from the results with anisaldehyde 2,
switching to the more non-polar extraction solvent hexane increased separation (entry 2).
Performing the work-up a second time on the mixture isolated after one round of extraction
gave 95% separation, but this is not ideal in terms of the ease and duration of the extraction
protocol (entry 3). Similarly, stirring the mixture for 30 minutes, rather than using a simple
shaking protocol, increased the separation to 98% (entry 4). In our initial protocol, we had
diluted the aqueous layer before extracting with an immiscible solvent to improve the bisulfite
adduct solubility in the aqueous layer and improve separation. This dilution could push the
equilibrium away from bisulfite adduct formation, therefore we attempted omitting the
dilution step (entry 5). This change resulted in only 75% removal of aldehyde 14. Increasing the
amount of the miscible solvent by a factor of two increased the separation to 93% (entry 6).
Switching to potassium bisulfite gave poorer results when compared to the sodium salt (entry 6
vs. entry 7). Switching to the more nucleophilic sulfite dianion10 also gave poorer results (entry
8). Mechanistic evidence suggests that this aldehyde addition, though faster than bisulfite
addition, does not favor the dianionic adduct that is formed, making this pathway to the final
adduct a minor contributor to the overall mechanistic picture.10,11 This conclusion is supported
by our experimental observation. We decided to pursue increasing the miscible solvent volume
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by a factor of two (entry 6) for our extraction protocol with non-aromatic aldehydes as the
optimal balance of user ease and aldehyde removal, though it should be noted that increased
mixing time gives the highest removal rates if purity is the main concern of the user.
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Table 2. Removal of 3-phenylpropionaldehyde from benzyl butyrate. aStandard procedure: 3-
phenylpropionaldehyde (190 μL, 1.4 mmol) and benzyl butyrate (250 μL, 1.4 mmol) were
dissolved in 5 mL MeOH, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s,
diluted with 25 mL H2O, and extracted with 25 mL 10% EA/hexanes. Decontamination factor.
cDetermined by 1H NMR analysis.
b
To explore the scope of the workup protocol with respect to the identity of the miscible
solvent, we undertook a solvent screen using 3-phenylpropionaldehyde 14 as the model
impurity (Table 3). All miscible solvents tested gave useful separation (Entries 1-11). The
concentration of the components in these mixtures is approximately 0.3M, which is similar, in
terms of order of magnitude, to the concentrations used for many reactions. This indicates that
when a solvent that is miscible with water is employed for a reaction, the solvent need not be
removed before performing the bisulfite workup described herein. The reaction mixture can
simply be added to a separatory funnel and then saturated sodium bisulfite can be added,
shaken, and then an immiscible solvent can be added to extract the desired organic
components away from the bisulfite adduct and other water soluble materials, including the
solvent. The best result found in this screen was with acetone and dimethyl sulfoxide. The
success of acetone was initially surprising, as the solvent contains a carbonyl that can
competitively react with bisulfite ion. Indeed, a noticeable exotherm was observed, but despite
this apparent reaction between bisulfite and the solvent, the removal rates were excellent,
likely due to the higher rate of reaction caused by the exotherm. Interestingly, when the
amount of acetone was increased two-fold as before (Table 2, entries 6-8) the material
solidified upon addition of the bisulfite solution, presumably because the amount of heat
generated was sufficient to cause large amounts of acetone to form a solid bisulfite adduct
(entry 12). Thus, acetone was not used in subsequent workup protocols to avoid this unwanted
solvent reactivity. Dimethyl sulfoxide also gave good separation results, but was accompanied
by an unpleasant odor, presumably due to the formation of dimethyl sulfide under the mild
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reducing conditions (entry 5). Although methanol gave inferior separation in comparison to
other miscible solvents, its high water solubility and relatively low boiling point relative to the
other miscible solvents screened makes it easy to remove from the purified substrate. For ease
of use, this solvent is recommended, but if higher levels of aldehyde removal is required,
dimethylformamide gives higher removal rates, particularly when a two fold increase is used,
coupled with the use of hexanes as the immiscible solvent (entry 13). This is particularly useful
for highly hydrophobic substrates that do not mix well with the aqueous layer, as the less polar
dimethylformamide (relative to methanol) allows better mixing with the bisulfite-containing
aqueous layer. The drawback to using this solvent is that an additional aqueous extraction is
required to recover the substrate from the aqueous layer, and three additional water washes
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were required to deplete the dimethylformamide to undetectable levels by H NMR. This extra
washing was necessary due to dimethylformamide’s less favorable partition coefficient
between water and the immiscible organic solvent, and its lower volatility, relative to
methanol.
Table 3. Water-miscible solvent efficacy in the removal of 3-phenylpropionaldehyde from
benzyl butyrate. aStandard procedure: 3-phenylpropionaldehyde (190 μL, 1.4 mmol) and benzyl
butyrate (250 μL, 1.4 mmol) were dissolved in 5 mL solvent, 25 mL saturated NaHSO3(aq) added,
shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL 10%
b
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EA/hexanes. Decontamination factor. Determined by H NMR analysis. 10 mL solvent used.
eExtracted with hexanes rather than 10% EA/hexanes.
Implementing the two-fold increase in the amount of the miscible solvent employed in
the work-up protocol improved removal efficiency to above 95% for all aliphatic aldehydes
tested (Scheme 2). For non-polar aldehydes, the more hydrophobic solvent dimethylformamide
was used to give efficient separation. α-Unbranched aldehydes 3-phenylpropionaldehyde 14, 1-
octanal 15, and 3-oxopropyl isobutyrate 1612,13 were all removed effectively, though celite
filtration was necessary to remove the insoluble solid bisulfite adduct of 1-octanal 15.
Introducing branching adjacent to the aldehyde did not decrease efficiency of removal. 2-
Ethylhexanal 17, 2-phenylpropionaldehyde 18, and 2-methyl-3-oxopropyl acetate 1914 were all
removed with excellent efficiency. Increasing α-branching further was also well-tolerated.
Neopentyl substrate 2015,16 demonstrates the difference in the standard protocol for aromatic
versus aliphatic substrates in particularly dramatic fashion. When methanol is used, only 41%
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removal is obtained, but by simply switching the identity of the miscible solvent to
dimethylformamide, as well as doubling the volume of solvent used, 97% removal is achieved.
For more polar substrates, such as acetate-protected neopentyl aldehyde 21,17 methanol is a
suitable miscible solvent. This modification was also successful when applied to 2,6-
dimethylbenzaldehyde 11, resulting in an improvement from 64% removal to 96% removal
(Scheme 1). Steric hindrance does not appear to be an important a factor in aldehyde
separation under these conditions. Interestingly, the extraction protocol resulted in noticeable
impurities when applied to a mixture of citronellal 22 with benzyl butyrate 1. The mass balance
after the workup protocol indicated that 58% of the original aldehyde mass remained after
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separation, though no aldehyde was observable by H NMR. We suspected that the electron-
rich alkene may be involved in a reaction with dissolved sulfur dioxide, which is well-known to
isomerize alkenes.18,19 Thin layer chromatography indicated that many different impurities had
formed under these conditions. The solubility of sulfur dioxide in organic solvents is known to
be low in hydrophobic solvents such as hexanes,20–22 therefore the immiscible solvent used to
extract benzyl butyrate was changed to hexanes to limit the interaction of citronellal 22 with
sulfur dioxide. This small change eliminated the problem almost entirely, giving only a trace
amount of impurity after the workup protocol. Hexanes are not capable of solvating many
organic compounds, due to low polarity, so more polar alternatives to hexanes that would also
limit alkene reactivity were explored. Chloroform, which is also known to have low sulfur
dioxide solubility (though higher than hexane), may be a preferable solvent in many situations,
given its higher polarity and dielectric constant. When chloroform was used as the immiscible
extraction solvent, impurities were reduced as compared to the use of 10% ethyl
acetate/hexanes, but they were still observable: 16% of the original aldehyde mass was
retained after the protocol. Implementing the low sulfur dioxide extraction solvent hexane
allowed for excellent results with alkene-containing aldehyde 23, which was removed in 96%
1
from benzyl butyrate, with no discernable impurities from the aldehyde by H NMR or mass. In
all cases, benzyl butyrate was recovered in 93% or greater yield using the dimethylformamide
protocol.
Scheme 2. Removal of aliphatic aldehydes from benzyl butyrate.
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aAldehyde (1.4 mmol) and benzyl butyrate (250 μL, 1.4 mmol) were dissolved in 10 mL DMF, 25
mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and
extracted with 25 mL hexanes. The aqueous layer was extracted once with hexanes and the
combined organics were washed three times with water to remove DMF (25 mL, 10 mL, 5 mL).
c
d
bRequired filtration to remove solid bisulfite adduct. Pentane used in place of hexanes. 10%
e
f
EA/hexanes used in place of hexanes. MeOH used in place of DMF. CHCl3 used in place of
hexanes.
The substrate scope of this workup protocol was investigated, using anisaldehyde as a
model contaminant (Scheme 3). A wide range of functional groups were found to be
compatible with the protocol, including a variety of carbonyl compounds. Esters, carboxylic
acids, and amides all gave excellent results (1, 24-28). Aryl bromide 29 was also well-tolerated.
Primary, secondary, tertiary and benzylic alcohols (substrates 30-33), phenols (substrates 34
and 35), and nitriles (substrates 36-38) were all compatible with the work-up protocol as well.
The procedure was also compatible with electrophilic substrates, such as benzyl chloride 38 and
epoxides (substrates 3923 and 40). Anilines 41 and 42 were also compatible with the protocol,
though additional extraction of the aqueous layer was required to recover these more polar
substrates. The protocol is not appropriate for more basic amines, such as secondary amine 43,
due to unwanted acid-base chemistry with the weakly acidic bisulfite ion (pKa 7.2). The mild
work-up protocol is compatible with acid-sensitive functional groups such as acetal 44. The use
of electron-rich alkenes, such as α-terpineol 45 and α-pinene 46, resulted in the observation of
significant decomposition, in agreement with the results obtained for the removal of citronellal,
though the decomposition in the case of α-pinene 46 was greater, presumably due to the
presence of the reactive cyclobutane ring that is known to undergo ring-opening under a
variety of conditions. Using hexane as the immiscible solvent resolved this issue, allowing for
98% re-isolation of both α-terpineol 45 and α-pinene 46. The use of hexanes was not necessary
for the disubstituted double-bond-containing substrates 47-50, as these substrates did not
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undergo degradation under the standard work-up conditions. Camphene 50 was subjected to
the conditions as a 2:1 ratio together with tricyclene 51. Very little change was observed in the
ratio of the two isomers after the work-up protocol. Terminal alkyne 52,24 as well as internal
alkynes 5325 and 54 did not undergo isomerization, even without the use of hexane to limit the
solubility of sulfur dioxide. Diene 55 also did not undergo isomerization, however allo-ocimene
56 isomerized from a 4:1 mixture of trienes 56 and 57 to a 1:0.7 mixture after the bisulfite
work-up,26 even when hexanes was employed as the immiscible solvent. The substrate scope
was found to be extremely broad using the mild conditions of the bisulfite work-up, making this
method applicable for routine removal of aldehyde impurities from most organic reactions.
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Scheme 3. Substrate scope of the sodium bisulfite work-up protocol.
aSubstrate (1.4 mmol) and anisaldehyde (175 ꢀL, 1.4 mmol) were dissolved in 5 mL MeOH, 25
mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and
b
extracted with 25 mL 10% EA/hexanes. DMF used in place of MeOH. EA used in place of 10%
EA/hex. The aqueous layer was extracted twice. The organic layer was washed three times with
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water. 50% EA/hex used in place of 10% EA/hex. The aqueous layer was extracted three
e
f
times. Pentane was used in place of 10% EA/hexanes. Hexanes was used in place of 10%
EA/hexanes.
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With the compatibility of a wide-range of functional groups now established, we turned
our attention to the reactivity of ketones, to see if these substrates would participate in the
reaction with bisulfite on the time scale of the work-up protocol. Cyclic ketones are well-known
to form bisulfite adducts,27 so we were curious about which ketones would react under the
work-up conditions, and which would remain unreacted. A variety of ketones were mixed with
benzyl butyrate and the extent of their removal from this mixture was evaluated after the
standard bisulfite work-up protocol using methanol as the miscible solvent. 3-nonanone 58 was
only slightly depleted after the work-up, despite the minimal level of steric hindrance present
for this linear ketone. The more sterically-hindered substrate camphor 59, was not measurably
removed from the mixture. Aromatic substrate 4’-ethylacetophenone 60 was largely retained in
the mixture, as was α-tetralone 61 and benzophenone 62. α,β-Unsaturated dihydrojasmone 63
and carvone 64 were also largely retained. This is notable, as 1,4-addition of bisulfite has been
observed for carvone and other α,β-unsaturated ketones previously.28 The rate of this
conjugate addition must be slow relative to the timescale of the extraction protocol. Cyclic
ketones with α-substituents 65-6729–33 were largely retained, although the six-membered ring
substrate was removed by 19% from the mixture. Interestingly, non-aromatic methyl ketones
benzyl acetone 68 and 2-octanone 69 were removed in 47% and 35%, respectively. The
decrease in steric size from ethyl to methyl appears to increase bisulfite reactivity, as seen in
the difference in removal rate (4% versus 35%) between ethyl ketone 58 and methyl ketone 69.
The rate of removal was enhanced to 92% and 93%, respectively, by using the DMF conditions
developed for hydrophobic substrates. Cyclic unhindered substrates were found to be reactive
under the conditions. β-tetralone 70, 2-indanone 71, 4-tert-butylcyclohexanone 72, 3-
phenylcyclopentanone 73,34,35 and 3-phenylcyclohexanone 7434,35 were all effectively removed.
Filtration was required for nonpolar substrates 72 and 74, which formed water and organic-
insoluble bisulfite adducts. As observed with other nonpolar substrates, the removal of 3-
phenylcyclohexanone 74 was greatly improved when dimethylformamide was employed as the
miscible solvent (97% removal). α-Keto esters are known to be highly electrophilic, and
therefore the complete removal of ethyl pyruvate 75 was unsurprising. In general, the ketones
tested fell into two distinct groups: unreactive ketones (conjugated or slightly sterically
hindered ketones: 58-67) and reactive ketones (unhindered cyclic ketones, methyl acyclic
ketones, and highly electrophilic ketones: 68-75). This sharp distinction will prove convenient
for routine separation of bisulfite-reactive carbonyl compounds from those carbonyl
compounds that are unreactive.
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Scheme 4. Ketone removal from a 1:1 mixture with benzyl butyrate.
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aKetone (1.4 mmol) and benzyl butyrate (250 μL, 1.4 mmol) were dissolved in 5 mL MeOH, 25
mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and
extracted with 25 mL 10% EA/hexanes. bDMF used in place of methanol. The aqueous layer was
extracted twice. The organic layer was washed three times with water. Required filtration to
remove solid bisulfite adduct. dPentane used in place of 10% EA/hexanes.
c
The high degree of differential reactivity between conjugated or slightly sterically-
hindered ketones and reactive carbonyl compounds allows for selective separation. To
demonstrate this selectivity, a variety of unreactive ketone substrates were mixed with
anisaldehyde 2 and subjected to the bisulfite work-up conditions to measure the selectivity of
the separation (Scheme 5). Aromatic methyl ketones 76 and 60 were recovered in 86% and 89%
yield, respectively. 4-aminoacetophenone 77 and 2-hydroxyacetophenone 78 were more
effectively recovered, likely due to the decreased electrophilicity of the carbonyls when
conjugated to electron rich aromatic rings. Slightly sterically-hindered ethyl ketones 79 and 58
were both recovered in high yield from the separation conditions. Benzophenone 62 was
recovered in 99% yield after the separation protocol. Sterically-hindered camphor 59 was also
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effectively separated. α,β-Unsaturated substrates carvone 64, dihydrojasmone 63, beta-ionone
80, and chalcone 81 were all separated effectively from the more reactive aldehyde
contaminant, with no observed conjugate addition products. Progesterone 82, containing an
α,β-unsaturated ketone and a sterically-hindered methyl ketone was recovered in 99% yield
from the mixture after the bisulfite protocol. In addition to ketones, hemi-acetal 83 was also
subjected to the work-up protocol to demonstrate the selectivity of the work-up. Though the
hemi-acetal pyranose 83 is in equilibrium with its open-chain aldehyde form, the rate of this
isomerization is slow relative to the timeframe of the work-up,36 allowing for selective removal
of anisaldehyde. These results demonstrate the discrimination possible among carbonyl
compounds of differing reactivities.
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Scheme 5. Separation of ketones and a cyclic hemi-acetal from anisaldehyde using the sodium
bisulfite work-up protocol.
aKetone (1.4 mmol) and anisaldehyde (175 μL, 1.4 mmol) were dissolved in 5 mL MeOH, 25 mL
saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and
extracted with 25 mL 10% EA/hexanes. bPyranose 83 (0.28 mmol) and anisaldehyde (35 μL, 0.29
mmol) were dissolved in 5 mL DMF, 25 mL saturated NaHSO3(aq) added, shaken for
approximately 30 s, diluted with 25 mL H2O, and extracted with 25 mL EA. The organic layer
was washed three times with 25 mL H2O.
Scheme 6. Aldehyde recovery by basification of aqueous layer.
O
Ph
O
Me
organic
1
O
O
NaHSO3
98% recovery
94% removal
BnO
Me
H
Ph
O
Me
Me
O
50% NaOH
aqueous
1
20
BnO
Me
H
Me
20
94% recovery
>99.9% pure
In some cases, recovery of the aldehyde is desirable, particularly when the aldehyde is not
commercially available. Bisulfite adduct formation is reversible, and is known to occur under
both acidic and basic conditions. We found that basification of the aqueous layer with 50%
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sodium hydroxide followed by extraction allowed for facile recovery of aldehyde 20 from a
mixture with benzyl butyrate in 94% recovery and in greater than 99.9% purity (Scheme 6).
Acidification with concentrated hydrochloric acid was not nearly as effective as basification;
aldehyde 20 was only recovered in 33% yield under these conditions. Basification of the
aqueous layer provides a convenient method for aldehyde re-isolation.
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The scale of the work-up protocol was selected for ease of use, precision of measurements, and
minimization of reagents. For large scale work-ups, however, it is increasingly important to use
minimal amounts of solvents to improve safety, cost, and convenience. To test the limits of the
protocol, we re-examined the separation of benzyl butyrate from anisaldehyde (Table 4).
Doubling the amount of substrate and contaminant aldehyde dramatically decreased the
decontamination factor from 110 to 5.8 (entry 2). Increasing the scale of the substrates by a
factor of five lowered the decontamination factor further to 2.6 (entry 3). Interestingly, when
the scale was increased tenfold, a precipitate was observed between the two layers. Water was
added until the precipitate dissolved to aid in separation. This improved the decontamination
factor to 3.7, presumably due to better solvation and removal of the bisulfite adduct (entry 3
vs. entry 4). Increasing the amount of miscible solvent improved the separation dramatically,
presumably due to increased contact between the aldehyde and aqueous layer created by the
miscible solvent (entry 2 vs entry 5). When these conditions were applied to a fivefold increase
in substrate, precipitate was observed and additional water was added until complete solvation
was achieved, resulting in an improved decontamination factor of 50 (entry 6). These
conditions were repeated for a tenfold increase in substrate, requiring an additional 50 mL of
water to dissolve the precipitate. Even at this high concentration, anisaldehyde was removed in
97% from the mixture. Decreasing the amount of saturated sodium bisulfite resulted in
complete solidification of the mixture, presumably due to insufficient water available to solvate
the bisulfite adduct. Although water was successfully added to dissolve the solid, solidification
in a separatory funnel is inconvenient and tedious to unclog, and thus should be avoided.
Interestingly, the removal rate was improved under these conditions, presumably due to the
slight exotherm observed upon solidification of the mixture. Clearly, the amount of bisulfite in
the saturated solution is sufficient even at these high aldehyde concentrations. The main
concern is solvation of the resultant bisulfite adduct and avoiding the formation of a solid
aqueous layer. We next re-examined the small-scale conditions by lowering the amount of
bisulfite, since the results at large scale showed that much less was required. Interestingly,
when the amount of bisulfite was lowered, even better results were obtained, as compared to
the standard conditions (entries 9-11). Anisaldehyde was not detected even when only 1 mL of
saturated sodium bisulfite was employed. This surprising observation is likely due to improved
solubility of the adduct in the aqueous layer at higher methanol concentrations and lower salt
concentrations.
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Table 4. Separation of anisaldehyde from benzyl butyrate using sodium bisulfite. Anisaldehyde
and benzyl butyrate were dissolved in methanol, saturated NaHSO3(aq) added, shaken for
approximately 30 s, diluted with H2O, and extracted with 25 mL 10% EA/hexanes.
c
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d
bDecontamination factor. Determined by H NMR analysis. Water added until precipitate
dissolved. eSolidified upon shaking.
Conclusion
In conclusion, the developed bisulfite protocol is an effective way to separate aromatic
and aliphatic aldehydes from substrates containing a wide variety of functional groups. In
addition, unhindered methyl ketones and unconjugated cyclic or highly electrophilic ketones
can also be removed from mixtures, while unreactive aromatic, conjugated, or slightly
sterically-hindered ketones are retained. Unwanted reactivity of electron-rich alkene-containing
substrates can be mitigated by employing hexanes as the immiscible solvent, by taking
advantage of the low sulfur dioxide solubility of nonpolar solvents. Highly nonpolar substrates
can also be successfully removed by using dimethylformamide as the miscible solvent to
improve mixing of the substrate with the bisulfite ion. The workup can be scaled up successfully
to minimize the amount of solvents employed for separation. The mildness of these conditions
and the ease of the protocol, together with the ubiquity of aldehydes in organic synthesis,
should make this work-up protocol widely applicable to the daily task of separation
encountered by many organic chemists.
Experimental
Reactants and reagents were purchased from commercial sources and used without further
purification, except for o-anisidine 42, α-terpineol 45, α-pinene 46, and alloocimene 57, which
were distilled prior to use. All reactions were carried out under a N2 atmosphere, except for the
extraction procedures, which were done under ambient atmospheric conditions.
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Aldehyde synthesis. The synthesis of 3-oxopropyl isobutyrate 16 is representative. 1,3-
Propanediol (1.8 mL, 25 mmol) was dissolved in THF (60 mL, 0.4M) and cooled to -78 ºC. n-BuLi
(1.6M hexanes, 16 mL, 25.6 mmol) was added slowly and the reaction was stirred for 5 minutes
and then isobutyrylchloride (2.7 mL, 26 mmol) was added and the reaction was stirred for 14
hours while slowly warming to ambient temperature. The reaction was quenched with
saturated aqueous NH4Cl and extracted with DCM. The organic layer was dried (MgSO4),
filtered, concentrated in vacuo, and chromatographed gradiently with 15-50% EA/hexanes to
give the known mono-acylated alcohol 3-hydroxypropyl isobutyrate37 (957.7 mg, 26% yield). 1H
NMR (400 MHz, CDCl3), δ 4.24 (t, J = 6.1 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.56 (septet, J = 7.0 Hz,
1H), 1.80-1.92 (m, 3H), 1.17 (d, J = 7.0 Hz, 6H) ppm.
3-hydroxypropyl isobutyrate (957.7 mg, 6.55 mmol) was dissolved in DCM (2.6 mL, 2.5M) and
(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) (11.7 mg, 0.075 mmol) was added. Potassium
bromide (93.0 mg, 0.78 mmol) dissolved in water (1.0 mL) was then added and the reaction was
cooled to 0 ºC. Sodium hypochlorite (15% available chlorine, 5.4 mL) with sodium bicarbonate
(221.1 mg, 2.6 mmol) suspended in the solution was added dropwise to give an orange-brown
color. After 15 minutes the reaction was warmed to ambient temperature and stirred for 15
minutes. The reaction was diluted with DCM, washed with water, and the aqueous layer was
extracted three times with DCM, dried (MgSO4) filtered, and concentrated in vacuo to give the
known title compound 1612,13 (397.0 mg, 42% yield) as a clear oil that was pure by 1H NMR.
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3-oxopropyl isobutyrate 16. 1H NMR (400 MHz, CDCl3), δ 9.79 (t, J = 1.6 Hz, 1H), 4.41 (t, J = 6.1
Hz, 2H), 2.76 (dt, J = 1.6, 6.1 Hz, 2H), 2.53 (septet, J = 7.0 Hz, 1H), 1.15 (d, J = 7.0 Hz, 6H) ppm.
3-Acetoxy-2-methylpropanal 19. The procedure was the same as for 3-oxopropyl isobutyrate
16, except 2-methyl-1,3-propanediol (0.44 mL, 5 mmol) and acetic anhydride (0.48 mL, 5.1
mmol) were used in the mono-acylation step. The known 3-acetoxy-2-methylpropanal 1914
(257.8 mg, 39% yield over 2 steps) was obtained as a clear oil. 1H NMR (400 MHz, CDCl3), δ 9.70
(d, J = 1.4 Hz, 1H), 4.30 (m, 2H), 2.69 (m, 1H), 2.05 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H) ppm.
3-Acetoxy-2,2-dimethylpropanal 21. The procedure was the same as for 3-oxopropyl
isobutyrate 16, except 2,2-dimethyl-1,3-propanediol (2.0039 g, 20 mmol) and acetic anhydride
(2.1 mL, 22 mmol) were used in the mono-acylation step. The known 3-acetoxy-2,2-
dimethylpropanal 2117 (705.4 mg, 25% yield over 2 steps) was obtained as a clear oil after
chromatography with 2-12% EA/hexane. 1H NMR (400 MHz, CDCl3), δ 9.53 (s, 1H), 4.11 (s, 2H),
2.04 (s, 3H), 1.11 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3), δ 203.5, 170.8, 67.9, 46.2, 20.7, 18.8
ppm.
Substrate synthesis.
4-Pentyn-1-yl benzoate 52. 4-pentyn-1-ol (0.46 mL, 5 mmol) was dissolved in THF (20 mL,
0.4M) and cooled to -78 ºC. n-BuLi (1.6M hexanes, 3.2 mL, 5.1 mmol) was added slowly and the
reaction was stirred for 5 minutes and then benzoyl chloride (0.58 mL, 5.0 mmol) was added
and the reaction was stirred for 14 hours while slowly warming to ambient temperature. The
reaction was quenched with saturated aqueous NH4Cl and extracted with DCM. The organic
layer was dried (MgSO4), filtered, concentrated in vacuo, and chromatographed gradiently with
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0-5% EA/hexanes to give the known title compound24 (883.0 mg, 94% yield). 1H NMR (400 MHz,
CDCl3), δ 8.05 (dd, J = 1.4, 8.5 Hz, 2H), 7.56 (tt, J = 1.4, 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 4.34
(t, J = 6.2 Hz, 2H), 2.39 (dt, J = 2.7, 7.1 Hz, 2H), 1.96-2.05 (m, 3H) ppm. 13C NMR (126 MHz,
CDCl3), δ 166.5, 132.9, 130.2, 129.5, 128.3, 83.0, 69.1, 63.4, 27.7, 15.3 ppm.
9
3-Pentyn-1-ol, benzoate 53. 3-pentyn-1-ol (0.46 mL, 5 mmol) was dissolved in THF (20 mL,
0.4M) and cooled to -78 ºC. n-BuLi (1.6M hexanes, 3.2 mL, 5.1 mmol) was added slowly and the
reaction was stirred for 5 minutes and then benzoyl chloride (0.58 mL, 5.0 mmol) was added
and the reaction was stirred for 14 hours while slowly warming to ambient temperature. The
reaction was quenched with saturated aqueous NH4Cl and extracted with DCM. The organic
layer was dried (MgSO4), filtered, concentrated in vacuo, and chromatographed gradiently with
0-3% EA/hexanes to give the known title compound25 (740.6 mg, 79% yield). 1H NMR (400 MHz,
CDCl3), δ 8.07 (dd, J = 1.2, 8.4 Hz, 2H), 7.56 (tt, J = 1.3, 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 4.38
(t, J = 7.0 Hz, 2H), 2.60 (m, 2H), 1.79 (t, J = 2.6 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3), δ 166.1,
132.8, 130.0, 129.5, 1282, 77.2, 74.5, 63.1, 19.2, 3.3 ppm.
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2-Benzylcycloheptanone 67. Diisopropylamine (0.46 mL, 3.3 mmol) was dissolved in THF (5 mL)
and cooled to -78 ºC. n-BuLi (1.6M hexanes, 2.1 mL, 3.4 mmol) was added slowly and the
reaction was stirred for 15 minutes and then cycloheptanone (0.35 mL, 3.0 mmol) was added.
After 15 minutes, benzyl bromide (0.71 mL, 6.0 mmol) was added and the reaction was stirred
for 14 hours while slowly warming to ambient temperature. The reaction was quenched with
saturated aqueous NH4Cl and extracted with DCM. The organic layer was dried (MgSO4),
filtered, concentrated in vacuo, and chromatographed gradiently with 0-4% EA/hexanes to give
the known title compound33 (470.6 mg, 78% yield). 1H NMR (400 MHz, CDCl3), δ 7.27 (t, J = 7.0
Hz, 2H), 7.14-7.25 (m, 3H), 3.08 (dd, J = 5.8, 13.7 Hz, 1H), 2.82 (m, 1H), 2.56 (dd, J = 8.5, 13.8 Hz,
2H), 2.43-2.50 (m, 2H), 1.77-1.86 (m, 4H), 1.56-1.65 (m, 1H), 1.25-1.36 (m, 3H) ppm. 13C NMR
(126 MHz, CDCl3), δ 215.6, 139.9, 129.1, 128.3, 126.0, 53.6, 43.1, 37.8, 30.3, 29.2, 28.6, 24.2
ppm.
Standard work-up procedure for aldehyde and ketone removal.
Substrate (1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 5 mL MeOH, 25 mL saturated
NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with
25 mL 10% EA/hexanes. The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo to yield the recovered substrate.
Work-up procedure for non-polar aldehyde and ketone removal.
Substrate (1.4 mmol) and aldehyde (1.4 mmol) were dissolved in 10 mL DMF, 25 mL saturated
NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL H2O, and extracted with
25 mL 10% EA/hexanes. The aqueous layer was extracted with 25 mL of 10% EA/hexanes. The
combined organic layers were washed three times with H2O (25 mL, 10 mL, 5 mL). The organic
layer was dried (MgSO4), filtered, and concentrated in vacuo to yield the recovered substrate.
Work-up procedure for isolation of both aldehyde and ketone.
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Benzyl butyrate (250 µL, 1.4 mmol) and aldehyde 20 (275.0 mg, 1.4 mmol) were dissolved in 10
mL DMF, 25 mL saturated NaHSO3(aq) added, shaken for approximately 30 s, diluted with 25 mL
H2O, and extracted with 25 mL 10% EA/hexanes. The aqueous layer was extracted with 25 mL
of 10% EA/hexanes three times. The organic layers were washed three times with H2O (25 mL,
10 mL, 5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to yield
recovered benzyl butyrate (261.3 mg, 98% recovery). The combined aqueous layers were
basified with 50% sodium hydroxide and extracted with 25 mL of 10% EA/hexanes three times.
The organic layers were washed three times with H2O (25 mL, 10 mL, 5 mL). The organic layer
was dried (MgSO4), filtered, and concentrated in vacuo to yield recovered aldehyde 20 (261.3
mg, 95% recovery).
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Acknowledgements
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.
Supporting Information. 1H NMR for aldehydes 16, 19 and 21, substrates 52, 53, and 67 and for
all separations is available.
References
(1) Wilson, I. D.; Adlard, E. R.; Cooke, M.; Poole, C. F. Encyclopedia of Separation Science;
Encyclopedia of Separation Science; Academic Press, 2000.
(2) Caron, S. In Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques;
Wiley, 2011; pp 75–76.
(3) Clayden, J.; Greeves, N.; Warren, S. In Organic Chemistry; Oxford University Press: New
York, 2001; pp 138–140.
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