Ozonolysis in solvent/water mixtures: Direct conversion of alkenes to aldehydes and ketones

Article abstract of DOI:10.1021/jo800323x

(Chemical Equation Presented) Ozonolysis of alkenes in the presence of solubilized water results in the direct formation of aldehydes and/or ketones, avoiding the need to isolate or decompose ozonides.

Full text of DOI:10.1021/jo800323x

Ozonolysis in Solvent/Water Mixtures: Direct
Conversion of Alkenes to Aldehydes and Ketones
Charles E. Schiaffo and Patrick H. Dussault*
Department of Chemistry, UniVersity of Nebraska-Lincoln,
Lincoln Nebraska 68588-0304
pdussault1@unl.edu
ReceiVed February 19, 2008
FIGURE 1. Alkene ozonolysis: traditional vs one-step approach.
often the aldehyde or ketone coproduced during the scission of
the primary ozonide, forms ozonides (1,2,4-trioxolanes).4 Al-
ternatively, trapping by unhindered alcohols and other related
nucleophiles generates hydroperoxyacetals and similar addition
products.3,10 When the carbonyl oxides cannot undergo addition
or cycloaddition, dimerization or oligomerization yields 1,2,4,5-
tetraoxanes or polymeric peroxides.11
We became interested in practical methodology for prepara-
tive trapping of carbonyl oxides by water. Assuming the
intermediate hydroperoxy hemiacetals would decompose under
the reaction conditions, the net result would be the direct
formation of carbonyl groups during ozonolysis (Figure 1).
However, while the gas-phase trapping of carbonyl oxides by
water has been extensively investigated,12 there are only a
handful of corresponding solution-phase studies and little
indication of whether water trapping can provide a useful
preparative alternative to conventional ozonolyses.10,13 We now
report that the ozonolysis of alkenes in the presence of
solubilized water offers a means for the direct synthesis of
aldehydes and ketones.
Our research grew from investigations of “reductive ozo-
nolyses”.14 The mechanism proposed for this transformation,
involving fragmentation of the tetrahedral intermediate derived
from addition of amine oxides to carbonyl oxides, suggested a
similar reaction might occur in the presence of any reagent
containing a nucleophilic oxygen weakly bonded to a potential
leaving group. As a test of this hypothesis, we investigated
biphasic ozonolysis of a mixture of 9-decenyl acetate and
sodium periodate in CH2Cl2/H2O under phase-transfer conditions
(Table 1). While initial results were promising, a similar yield
of aldehyde was obtained from a control reaction omitting
periodiate. In contrast, a reaction including periodate but lacking
Ozonolysis of alkenes in the presence of solubilized water
results in the direct formation of aldehydes and/or ketones,
avoiding the need to isolate or decompose ozonides.
Ozonolysis is a powerful and popular method for the oxidative
cleavage of alkenes, with thousands of reported examples.1,2
However, under typical conditions, alkene ozonolysis initially
generates ozonides or hydroperoxyacetals, which must be
reduced in a separate step to obtain the desired aldehydes or
ketones.1,3,4 The formation of intermediates potentially capable
of spontaneous and exothermic decomposition can be problem-
atic, particularly for preparative reactions.5 The initial reaction
products from ozonolyses are therefore typically reduced to
carbonyl compounds in a separate postozonolysis step. However,
the use of mild reductants such as Me2S carries the risk of
incomplete removal of ozonides,5 while more powerful reduc-
tants (Pt/H2, BH3, Zn/HOAc, LiAlH4) may be incompatible with
other functional groups or may complicate product purification.6–8
In approaching this problem it is useful to overview the
pathways for peroxide formation (Figure 1).1,3,9 The highly
exothermic addition of ozone to alkenes generates primary
ozonides (1,2,3-trioxolanes), which fragment, even at -80 °C,
to form carbonyl oxides. The fate of these short-lived intermedi-
ates determines the distribution of the observed products.
Cycloaddition of carbonyl oxides with a reactive dipolarophile,
(10) Yamamoto, Y.; Niki, E.; Kamiya, Y. Bull. Chem. Soc. Jpn. 1982, 55,
2677.
(1) Bailey, P. S. Ozonation in Organic Chemistry; Academic: New York,
1978; Vol. 1.
(11) Barton, M.; Ebdon, J. R.; Foster, A. B.; Rimmer, S. Org. Biomol. Chem.
2005, 3, 1323.
(2) Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Chem. ReV. 2006, 106,
(12) Ryzhkov, A. B.; Ariya, P. A. Chem. Phys. Lett. 2002, 367, 423. Crehuet,
R.; Anglada, J. M.; Bofill, J. M. Chem. Eur. J. 2001, 7, 2227. Hasson, A. S.;
Chung, M. Y.; Kuwata, K. T.; Converse, A. D.; Krohn, D.; Paulson, S. E. J.
Phys. Chem. A 2003, 107, 6176. Tobias, H. J.; Ziemann, P. J. J. Phys. Chem. A
2001, 105, 6129. (d) Aplincourt, P.; Anglada, J. M. J. Phys. Chem. A 2003,
107, 5798.
2990.
(3) Bunnelle, W. H. Chem. ReV. 1991, 91, 335.
(4) Kuczkowski, R. L. Chem. Soc. ReV. 1992, 21, 79.
(5) Kula, J. Chem. Health Safety 1999, 6, 21.
(6) For an overview of methods for ozonide reduction, see: (a) Kropf, H. In
Houben-Weyl Methoden Der Organische Chemie; Kropf, H., Ed.; Georg Thieme:
Stuttgart, Germany, 1988; Vol. E13/2, p 1111.
(13) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558. Pryor,
W. A.; Church, D. F. Free Radical Biol. Med. 1991, 11, 41. Pryor, W. A.; Das,
B.; Church, D. F. Chem. Res. Toxicol. 1991, 4, 341. Dowideit, P.; Sonntag,
C. V. EnViron. Sci. Technol. 1998, 32, 1112. Lee, J. Y.; Lee, C. W.; Huh, T. S.
Bull. Korean Chem. Soc. 1998, 19, 1244.
(7) Basic decomposition of terminal ozonides has been employed as an
alternative to reduction:(a) Isobe, M.; Iio, H.; Kawai, T.; Goto, T. Tetrahedron
Lett. 1977, 703. (b) Hon, Y.; Lin, S.; Lu, L.; Chen, Y. Tetrahedron 1995, 51,
5019.
(14) Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Tetrahedron 2006,
62, 10747. Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Org. Lett. 2006,
8, 3199.
(8) Dai, P.; Dussault, P. H.; Trullinger, T. K. J. Org. Chem. 2004, 69, 2851.
(9) Criegee, R. Angew. Chem. 1975, 87, 765.
4688 J. Org. Chem. 2008, 73, 4688–4690
10.1021/jo800323x CCC: $40.75 2008 American Chemical Society
Published on Web 05/28/2008

FIGURE 2. Yield of 9-acetoxynonanal upon ozonolysis of decenyl
acetate in solvent/water mixtures: 9 ) acetone; [ ) acetonitrile.
TABLE 1. Ozonolyses of 9-Decenyl Acetatea
FIGURE 3. Relative proportions of alkene and aldehyde during
ozonolysis of 9-decenyl acetate in H2O/acetone: 9 ) 9-acetoxynonanal;
[ ) 9-decenyl acetate
PTC
additive
% H2O (v/v)
ozonide (%)
aldehyde (%)
Bu4NBr
Bu4NBr
none
NaIO4
none
none
none
5
5
5
0
9
9
13
72
42
51
29
13
none
FIGURE 4. Proposed reaction mechanism.
a See the Experimental Section.
TABLE 2. Direct Ozonolytic Preparation of Carbonyl Compounds
the phase-transfer catalyst (PTC) resulted in low yields for both
the aldehyde and ozonide; a similar outcome was obtained in
biphasic CH2Cl2/H2O in the absence of both periodate and the
PTC. These results suggested that solubilized water was an
effective nucleophile toward carbonyl oxides.
We therefore elected to investigate ozonolysis of alkenes in
miscible water/organic mixtures (Figure 2). As our initial
solvent, we selected acetone, an inexpensive, low-boiling, and
ozone-stable solvent. Ozonolysis of 9-decenyl acetate in solu-
tions of water and reagent grade acetone revealed formation of
aldehyde to be the dominant pathway over a range of added
water. Ozonide formation was almost completely suppressed
in 5% H2O/acetone (v/v) and this solvent was used for most
subsequent reactions. An analogous series of ozonolyses in H2O/
acetonitrile mixtures generated nearly identical results, suggest-
ing the role of the polar solvent is simply to solubilize water.
Monitoring the reactions (NMR, aliquots removed at 0.55 min
intervals) demonstrated that the carbonyl product is generated
immediately and with a stoichiometry proportional to the
disappearance of alkene (Figure 3); only traces of ozonide could
be detected at any point in the reaction.
At this point we set out to test the methodology on a series
of synthetically relevant substrates (Table 2). Ozonolysis was
performed until the alkene was consumed, based upon the end
point of a Sudan III indicator.15 Products were isolated after
extraction, with no separate reduction. The results vary with
the structure of the substrate. Ozonolyses of terminal alkenes
(products 1, 2, 5, and 6) generate aldehydes in yields of
72-100%. Ozonolysis of a 1,1-diaryl alkene (product 3)
proceeded in moderate yield. The corresponding cleavage of a
1,1-dialkyl-substituted alkene (product 4) provided a quantitative
yield of ketone on 3 mmol scale, with a slightly lower yield
obtained on a preparative scale (the Supporting Information
includes a description of a preparative reaction employing a
distillative purification).
a Addition of 2% O3/O2 into a 0.15 M solution of alkene (3 mmol).
b 20 mmol scale. c 30 mmol scale with distillation of product.
The addition of water to carbonyl oxides is believed to
generate a gem-hydroperoxy alcohol, which for most substrates
decomposes with liberation of the aldehyde or ketone and H2O2
(Figure 4).1,12,13 Monitoring of our reactions with a redox-active
TLC indicator invariably detected the build-up of a substantial
quantity of H2O2.16 A more quantitative postreaction assay,
conducted by testing the separated aqueous layer with peroxide
test strips, detected a stoichiometric amount of H2O2 relative
to the consumed alkene.17 In contrast, a control experiment
involving ozonolysis of a solution of 5% H2O/acetone in the
absence of alkene generated barely detectable quantities of H2O2.
(15) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807.
(16) Smith, L. L. Hill, F. L. J. Chromatogr. 1972, 66, 101.
J. Org. Chem. Vol. 73, No. 12, 2008 4689

The residue obtained upon concentration was purified via flash
chromatography with ether/hexanes to afford the target aldehyde
or ketone. (B) The reaction solution was diluted with 25 mL of
water and the resulting mixture was extracted with CH2Cl2 (2 ×
25 mL), with the remaining workup identical with that described
above. An alternate workup employing distillation for product
purification is described in the Supporting Information.
Caution. The workup procedures described above may leave
the product aldehyde or ketone contaminated with a small amount
of residual H2O2. For large-scale reactions, an additional water or
brine wash will generally reduce the concentration of H2O2 to levels
below what can easily be detected with peroxide test strips.
Experimenters should be aware that concentrated solutions of H2O2
and carbonyl groups can undergo acid-promoted reaction to form
explosive dimers (1,2,4,5-tetraoxanes) and trimers (1,2,4,5,7,8-
hexaoxanes).18 Although we never detected the formation of cyclic
peroxides, experimenters should avoid strongly acidic conditions
during the ozonolysis or the workup, and should consider adding
a small amount of Ph3P or a smilar reductant to crude products
prior to preparative distillations.
Ozonolysis of alkenes in a mixture of water and a water-
miscible organic solvent achieves a fast, convenient, and efficient
one-pot synthesis of aldehydes and ketones without the need
for a separate reductive step. In contrast to the time required
for a traditional ozonolysis and workup,5–8 the new procedure
generates the carbonyl products at rates limited only by the
output of the ozonizer. While the trapping of carbonyl oxides
by water has been previously observed, this reaction has not to
our knowledge been studied as a preparative organic method.
We believe the procedures outlined in this paper will lead to
broader application of ozonolysis, a metal-free oxidation requir-
ing only electricity and oxygen.
Experimental Section
Standard Conditions for Ozonolysis. The alkene substrate (3
mmol) was placed in a round-bottomed flask and dissolved in 95:5
acetone/water (v/v) to a concentration of 0.15 M. Following addition
of a small amount of an acetone stock solution of Sudan Red III,15
the solution was cooled to 0 °C and a stream of O3/O2 (2%,
approximately 0.5 mmol/min O3) was bubbled into the reaction
solution through a disposable pipet. Once the color of the indicator
was discharged, the ozonizer voltage was set to zero, and the
reaction was sparged for 2 min with O2. The crude reaction mixture
was worked up by one of two procedures, either of which afforded
similar results: (A) The solution was diluted with 50 mL of pentane
and 3 mL of brine. The separated aqueous layer was extracted with
5 mL of pentane and the organic layers were dried over Na2SO4.
Acknowledgement. This work was funded, in part, by NSF
CHE 0749916. NMR spectra were acquired, in part, on
spectrometers purchased with NSF support (MRI 0079750 and
CHE 0091975). A portion of this research was conducted in
facilities remodeled with support from NIH (RR016544-01). We
thank Chris Schwartz for useful discussions.
Supporting Information Available: Experimental proce-
1
dures and H for 1 and 4; 13C spectra of 1-6. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) The concentration of liberated H2O2 corresponds to approximately 0.15
M in the reaction medium, and less than 1 M (approximately 2.5% v/v) in the
brine wash. The recovered H2O2 can be destroyed by treatment with bisulfite or
sulfite; however, many localities permit dilute aq H2O2 to be discarded into the
sanitary sewer. Storage or acidification of the aqueous layers should be avoided
(see the cautionary note in the Experimental Section).
JO800323X
(18) For example, see:Milas, N. A.; Golubovic, A. J. Am. Chem. Soc. 1959,
81, 3361.
4690 J. Org. Chem. Vol. 73, No. 12, 2008