Highly efficient organic reactions "on water", "in water", and both

Article abstract of DOI:10.1002/anie.200705347

(Chemical Equation Presented) Wet, wet, wet: Hydrophobic aldehydes are cleanly oxidized upon stirring with water in air. Addition of hydrophobic isocyanides to aqueous suspensions of such aldehydes results in the formation of Passerini reaction products, with the aldehyde being the source of both carbonyl and ester functions. Partially watersoluble reagents reacted slower than water-insoluble ones. Isotope labeling studies show that water participates in these "on water" reactions.

Full text of DOI:10.1002/anie.200705347

Angewandte
Chemie
DOI: 10.1002/anie.200705347
Organic Synthesis
Highly Efficient Organic Reactions “on Water”, “in Water”, and
Both**
Nelly Shapiro and Arkadi Vigalok*
Water is the most abundant and environmentally friendly
solvent in nature. Yet, its application in organic synthesis is
currently limited.[1] As most organic compounds have low
solubility in water, much effort has been invested in the
development of organic microenvironments in the aqueous
phase, for example, in micellar catalysis.[2,3] Recently, reac-
tions of water-insoluble organic compounds that take place in
aqueous suspensions (“on water”) have received a great deal
of attention because of their high efficiency and straightfor-
ward synthetic protocols.[4] Nevertheless, such reactions are
still rare and lack generality. Herein we report a general
procedure toward a common aerobic oxidation of aldehydes
that takes place “on water” and its use in the consecutive
three-component Passerini reaction both “on water” and “in
water”.
(Scheme 1).[11] As both the starting materials and products are
insoluble in water, they can be easily separated from the
aqueous phase at the end of the reaction. The bubbling of gas
Scheme 1. Aldehyde oxidation “on water”.
through the liquid phase was not required, thus making the
use of a condenser or other reactant traps unnecessary. The
reactions proceeded smoothly both on a small scale (1 mmol)
and on a relatively large laboratory scale (50 mmol). Table 1
The oxidation of aldehydes by oxygen or oxygen/nitrogen
mixtures is a well-known reaction.[5] Organic chemistry
textbooks pay very little attention to the use of air in the
synthesis of carboxylic acids from aldehydes. Notably, air is
the ultimate “green” oxidant, more so than hydrogen
peroxide, which is considered “green” for synthetic oxidation
processes. In industry, aldehyde oxidation reactions are
usually performed in bulk liquid aldehyde or organic solvents,
with the stream of gas passing through the liquid phase.[6]
Various additives are often introduced into the system,[7] but
the role of these is still unclear.[8] As the solubility of nonpolar
gases, such as molecular oxygen, is generally low in any
solvent,[9] we hypothesized that the solvent is unnecessary or
even detrimental to the oxidation process. An aldehyde
oxidation taking place in thin layers of aldehyde, which
increases the surface of interaction between the reagents, has
also been reported, however, the yields were poor.[10] Alter-
natively, such an increase in surface interaction can be
achieved by mixing the aldehyde with water in the presence
of oxygen. Indeed, we found that hydrophobic aliphatic
(branched and linear) and aromatic aldehydes undergo facile
oxidation upon simply stirring their aqueous emulsions in air
to give the corresponding carboxylic acids in high yields
Table 1: Aldehyde oxidation “on water”.[a]
Entry
Aldehyde
Oxidation
conditions
Yield [%]
1
2
cyclo-C6H11CHO (1a)
1a
A
B
C
A
B
A
B
C
A
B
C
A
87
87
66
50
60
86
88
75[b]
83
81
53
11
3
1a
4
nC7H15CHO (1b)
5
1b
6
2-ethyl hexanal (1c)
7
1c
8
1c
9
benzaldehyde (1d)
10
11
12
1d
1d
nC4H9CHO (1e)
[a] See the Experimental Section for detailed reaction conditions. [b] 90%
yield after 2 h with O2.
shows typical results of the oxidation of liquid aldehydes “on
water”. The reaction was especially straightforward for the
preparation of solid carboxylic acids, such as benzoic acid,
which precipitated from the reaction mixture and could be
isolated by simple filtration. Importantly, very low amounts of
by-products (mainly the corresponding formate) were
observed in the “on water” reaction compared with the
same reaction performed in bulk aldehyde. No oxidation was
observed under the same conditions when the reaction was
carried out in methanol or dichloromethane instead of water.
Moreover, the addition of THF (5%) also completely
inhibited the reaction.
[*] N. Shapiro, Dr. A. Vigalok
School of Chemistry, The Sackler Faculty of Exact Sciences
Tel Aviv University, Tel Aviv 69978 (Israel)
Fax: (+972)3-640-6205
E-mail: avigal@post.tau.ac.il
[**] This work was supported by the Israel Science Foundation and The
Porter School of Environmental Studies at Tel Aviv University. N.S. is
the recipient of Gutwirth Foundation and Rieger Foundation
Fellowships, as well as the Israel Ministry of Science, Culture, and
Sport Fellowship for the Advancement of Women in Science.
The highly efficient conversion of aldehydes into carbox-
ylic acids described above inspired us to explore the
possibility of coupling this reaction with a known “on
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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2849

Communications
water” accelerated process. Recently, Pirrung et al. reported
slight heating (408C) to give the Passerini reaction products.
On the other hand, more water soluble aldehydes gave
mixtures of the Passerini products with another product—the
a-hydroxyamide (Scheme 2). The ratio between the products
roughly followed the solubility properties of the aldehyde
(Table 2). Both propionic aldehyde and acetaldehyde, which
are fully miscible with water, formed gemi-
elegant multicomponent Passerini- and Ugi-type reactions
that were accelerated by using water as a solvent.[4a,12,13] This
finding led us to explore the possibility of using an aldehyde
as the source of both carbonyl and ester functions in the
Passerini reaction (Scheme 2).[14] In this three-component
nal diols in 100% yield in aqueous solu-
tions.[17] a-Hydroxyamides were the only
products obtained for these two aldehydes
(Table 2, entries 15 and 16, 17 and 18,
respectively). Although water-miscible
aldehydes do not readily oxidize under
these conditions, the lack of a carboxylic
acid moiety was not responsible for the
Scheme 2. Tandem aldehyde oxidation/Passerini reaction “on water”.
absence of the three-component Passerini
products with such aldehydes. The reaction
reaction, only two components would be added to the
reaction mixture, with the third one generated in situ from
one of the reagents. As many aldehydes and carboxylic acids
show considerable solubility in water, it was important to
establish to what extent the reactions proceed “in water”
rather than “on water”.[15] To this end, we studied the reaction
of various aldehydes with water-insoluble isocyanides, which
gave the Passerini products in the oxidation/three-component
reaction sequence, (Table 2). As isocyanides slowly hydrolyze
upon stirring with water, a slight excess of the aldehyde was
used.[16] Interestingly, the reactions between the highly hydro-
phobic aldehydes and the isocyanides “on water” and in air
were complete after 3–4 hours at room temperature or upon
between acetaldehyde, isocyanide, and acetic acid resulted in
the formation of the a-hydroxyamide as the only product,
which suggests that the reaction “in water” only gives this
compound. In contrast, the reaction between octanoic
aldehyde, isocyanide, and acetic acid gave only the Passerini
product. It is likely that the formation of a gem-diol
significantly decreases the concentration of the water-soluble
aldehyde in the reaction. In addition, water competes
favorably with the carboxylate in the nucleophilic addition
to the carbonyl carbon atom when the reaction takes place “in
water”.
In all cases, water-insoluble aldehydes gave the three-
component Passerini products in high yields, while partially
soluble aldehydes gave mixtures of both products, thus
indicating the competition between the “in water” and “on
water” reactions. Also, more hydrophobic pentyl isocyanide
(4) reacted significantly faster than ethyl isocyanoacetate (3)
and gave significant amounts of the Passerini product, even
with partially water soluble aldehydes (Table 2, entries 11 and
14,). In support of the heterogeneous nature of the reaction
mixture, the product distribution showed some dependence
on the stirring rates (Table 2, compare entries 11 and 12).[18]
Importantly, almost no reaction was observed when the
reactions were performed in methanol or dichloromethane
under the same conditions. Furthermore, the reaction “in
water” was significantly slower than the reaction “on water”
even when the reactants were partially water soluble.[19]
We further investigated the mechanism of the “on water”
oxidation–Passerini reaction sequence by using isotope label-
ing experiments. When 1-octanal (1b) was stirred with H218O
(2mL) under oxygen for 5 hours, about 60% of the 1-
octanoic acid (2b) obtained had one labeled oxygen atom
incorporated in the structure (Table 3, entry 1). As no 18O
incorporation was observed when nonlabeled 1-octanoic acid
was stirred with H218O, the incorporation of this isotope
occurs prior to the formation of the carboxylic acid. Two
possible pathways may account for this labeling: either rapid
aldehyde/gem-diol equilibration[20] on the water surface or an
exchange reaction in one of the peroxo or radical species that
are postulated in the oxidation of aldehydes by molecular
oxygen (Scheme 3).[5] Interestingly, when the Passerini reac-
tion (Scheme 2) was performed in H218O, the incorporation of
Table 2: Aldehyde oxidation/Passerini reaction “on water” and “in
water”.[a]
Entry Aldehyde
RCHO
Isonitrile
R1CH2NC
Product ratio [%]
5
7
6
8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1a
1a
1b
1b
1b
1d
1d
1e
3
4
3
3
4
3
4
3
4
3
4
4
3
4
3
4
80
–
0
–
0
0
–
0
–
–
–
0
–
–
0
–
0
–
81 (90)[b,d]
90
84[c]
–
–
–
90 (71)[d]
30[e]
–
–
57[e]
12
–
37
–
–
37
–
1e
11
–
R=iPr, 1 f
R=iPr, 1 f
R=iPr, 1 f
R=nPr, 1g
R=nPr, 1g
R=Et, 1h
R=Et, 1h
5[d] 74[d]
–
–
2
–
0
–
0
–
–
–
51
–
58
–
72
–
35 (30)[d]
42 (34)[d]
28[f]
60[f]
–
36
–
–
44
–
7(4)[d]
–
0
32 (30)[d]
R=Me, 1i 3[g]
R=Me, 1i 4[g]
–
59
[a] Conditions: The mixture of the aldehyde and isocyanide in a 3:1 ratio
was stirred at 1100 rpm for 3 h at 408C. The organic products were
extracted with CH2Cl2, the solvent was evaporated, and the mixture
analyzed by 1H NMR spectroscopy. [b] After 4 h. [c] The reaction was
performed at room temperature. [d] Yield of isolated product. [e] Benzoic
acid precipitates during the reaction, which results in lower yields. [f] The
reaction was stirred at 300 rpm. [g] An aldehyde/isocyanide ratio of 10:1
was used.
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Table 3: 18O Isotope distribution in aldehyde oxidation–Passerini reac-
purification system. The use of standard deionized water gave
tions “on H218O”.[a]
comparable results. The reagents were purchased from Sigma–
Aldrich and used as received. In several cases, the aldehydes were
purified by distillation, however, the reactivity of the distilled
compounds was found to be identical to that of the commercially
available chemicals. The reactions were performed in test tubes with
the Radleys Carousel Workstation. Alternatively, the reactions could
be performed in disposable 20 mL scintillation vials. Complete
product characterization is reported in the Supporting Information.
Conditions for aldehyde oxidation: Method A: A suspension of
aldehyde (100 mL, ca. 0.6–1 mmol) in pure water (3 mL) was added to
a 50 mL glass tube equipped with a magnetic stirrer bar and stirred at
room temperature at 1100 rpm for 12h in the presence of air. The
product was quantitatively extracted with CH2Cl2 and isolated after
solvent evaporation. When CDCl3 was used instead of CH2Cl2
without solvent evaporation, the 1H NMR analysis of the reaction
mixture showed a product distribution identical to that obtained
under standard work-up conditions, thus indicating that no
volatile organic compounds are formed. Method B: A suspen-
sion of aldehyde (100 mL, ca. 0.6–1 mmol) in pure water (3 mL)
was added to a 50 mL round-bottomed flask and stirred at room
temperature for 2h in pure molecular oxygen at 1 atm. The
product was quantitatively extracted with CH2Cl2 and isolated
after solvent evaporation. Method C: A suspension of aldehyde
(5 mL) in pure water (50 mL) was added to a 500 mL round-
bottomed flask and stirred at room temperature for 12h in the
presence of air. The product was quantitatively extracted with
CH2Cl2 and isolated after solvent evaporation. Generally, most
of the product could be collected by simple phase separation of
the reaction mixture. The organic solvents were used to ensure
quantitative mass balance of organic compounds.
Entry
1
Reaction on “H218O”
18O Isotope distribution in product
1b
O2, 5 h
1b (3 equiv) + 3
air, 3 h
1b (3 equiv) + 4
air, 3 h
1b + 2b + 3
air, 3 h
1b + 2b + 4
air, 3 h
2b
1 (2”16O): 3 (16O + 18O)
2
3
4
5
5b
1 (2”16O): 7 (16O + 18O): 20 (2”18O)
6b
1 (2”16O): 2 (16O + 18O): 3 (2”18O)
5b
1 (2”16O): 8 (16O + 18O)
6b
1 (2”16O): 6 (16O + 18O)
[a] All reactions were performed under standard conditions for the
aldehyde oxidation and Passerini reactions.
Scheme 3. General mechanism for aerobic oxidation of aldehydes (see
Ref. [5]).
Conditions for the Passerini reaction: Unless reported
otherwise, a suspension of aldehyde (0.51 mmol) and isocyanide
(0.17 mmol, 3:1 ratio) in water (3 mL) was stirred for 3 h at 408C
in the presence of air in a 50 mL glass reactor. Generally, 2equiv
of the aldehyde was sufficient to achieve high yields of the Passerini
product, however, small amounts of hydrolyzed isocyanide were
obtained in some cases. For 1i, 10 equiv of aldehyde was used. The
organic products were extracted with CH2Cl2, the solvent was
one (minor product) and two (major product) labeled oxygen
atoms into the final products was observed (Table 3, entries 2
and 3; 5b and 6b, respectively).
The reaction with nonlabeled 1-octanal (1b), 1-octanoic
acid (2b), and ethyl isocyanoacetate (3) or pentyl isocyanide
(4) in H218O, gave the Passerini product with one incorporated
18O as the major product (Table 3, entries 4 and 5; 5b and 6b,
respectively). For comparison, the Passerini reaction products
showed no incorporation of 18O upon stirring “on H218O” in
the presence of acid. The less reactive ethyl isocyanoacetate
(3) gave more 18O incorporation in the Passerini reaction
product compared to the reaction with pentyl isocyanide (4).
In conclusion, we have reported a general approach for
“on water” oxidation of aldehydes by using air or molecular
oxygen as the oxidant. This method can be extended to
perform consecutive organic reactions “on water” with
hydrophobic organic compounds, such as the multicomponent
Passerini reaction. The reported reactivity significantly
advances the use of water as a medium for organic reactions.
We are currently investigating the interaction modes between
water and organic substrates as well as the scope of the “on
water” oxidation of aldehydes in triggering other organic
transformations.
1
evaporated and the mixture analyzed by H NMR spectroscopy. No
by-products were observed in the reactions of aldehydes with
isocyanides. Small amounts of recovered starting materials and
hydrolysis of the isocyanide were also observed.
Received: November 21, 2007
Revised: January 20, 2008
Published online: March 3, 2008
Keywords: aldehydes · green chemistry · oxidation ·
.
Passerini reaction · water
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was obtained by using the Barnstead EASYpure II UF water
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Communications
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