Generation of mono- and bis-dioxiranes from 2,3-butanedione

Article abstract of DOI:10.1021/jo060694f

Biacetyl reacts with oxone to give bis-dioxirane [3,3′-dimethyl-3, 3′-bidioxirane, 3B] and mono-dioxirane [1-(3-methyl-dioxiran-3-yl) ethanone, 3A)]. Bis-dioxirane 3B is formed when two oxygens are incorporated into biacetyl, while mono-dioxirane 3A incorporated only one. A greater stability is observed in 3B compared to 3A, which is attributed to an α-dioxiranyl (anomeric) effect in the former. In contrast, 3A suffers from a destabilizing π-electron withdrawing effect from the adjacent carbonyl group.

Full text of DOI:10.1021/jo060694f

SCHEME 1
SCHEME 2
Generation of Mono- and Bis-dioxiranes from
2,3-Butanedione
Nahed Sawwan and Alexander Greer*
Department of Chemistry, Graduate Center and The City
UniVersity of New York (CUNY), Brooklyn College,
Brooklyn, New York 11210
agreer@brooklyn.cuny.edu
ReceiVed March 31, 2006
dioxiranes). The juxtaposition of two dioxirane groups would
represent a new type of structure in dioxirane chemistry.
In the present work, we focus on the synthesis of a molecule
containing R-dioxirane groups, 3B, along with mono-dioxirane
3A. Rationale is presented to account for the greater stability
of 3B compared to 3A.
NMR Spectroscopy and Chemical Trapping. The oxidation
of biacetyl (1.23 M) in buffered aqueous solution at pH 7 was
conducted in the presence of oxone (0.48 M) at -17 °C.
Separation of the organic-soluble fraction at -17 °C led to the
detection of the mono-dioxirane 3A and the bis-dioxirane 3B
along with carbon dioxide, acetic acid, and other byproducts
(discussed later). The low-temperature separation method
permitted an NMR analysis at -17 °C of unstable 3A and 3B.
Two sets of peaks disappeared as a result of addition of sulfide
or on warming the sample to 25 °C according to NMR. An
HMBC experiment on 3A shows a long-range correlation of
H2 (1.59 ppm) with the dioxirane carbon (94.5 ppm) and
carbonyl carbon (208.0 ppm) (Figure 1). A directly attached
methyl carbon of H2 was identified at 24.4 ppm by a HSQC
experiment. However, the methyl R to the carbonyl group (2.41
ppm) is obscured by the biacetyl peak. With a HMBC
experiment on 3B, the correlation between H1 (1.41 ppm) and
dioxirane carbon (110.5 ppm) was identified, while a HSQC
experiment confirmed the directly attached methyl carbon at
21.6 ppm (Figure 2). The measured integral values indicate that
the relative ratio of 3A:3B is 5:1. Dioxiranes 3A and 3B are
stable at -17 °C but cannot be obtained in pure form to enable
their complete characterization.
Biacetyl reacts with oxone to give bis-dioxirane [3,3′-
dimethyl-3,3′-bidioxirane, 3B] and mono-dioxirane [1-(3-
methyl-dioxiran-3-yl)ethanone, 3A)]. Bis-dioxirane 3B is
formed when two oxygens are incorporated into biacetyl,
while mono-dioxirane 3A incorporated only one. A greater
stability is observed in 3B compared to 3A, which is
attributed to an R-dioxiranyl (anomeric) effect in the former.
In contrast, 3A suffers from a destabilizing π-electron
withdrawing effect from the adjacent carbonyl group.
Dimethyldioxirane (1) possesses low strain energy (11
kcal/mol) compared to oxirane (26 kcal/mol) and cyclopropane
(27 kcal/mol) based on ab initio calculations.1 The low strain
energy of 1 was rationalized assuming gem-dioxa anomeric
stabilization (Scheme 1).1 Vicinal gem-dioxa-containing mol-
ecules are known. Thus, structures bearing 1,2-bis-acetals would
be topologically similar to a hypothetical bis-dioxirane (3B,
Scheme 2). The comparison of 1 with butane-2,3-bisacetal (2),
such as the 1,1,2,2-oxygenation generated as a protecting group
for 1,2-diols, led us to raise the following question: Can more
than one dioxirane center occupy a molecule? Despite the
intense interest in the synthesis of dioxiranes,2 in studies gauging
dioxirane stability,3 and in oxone-mediated cleavage of 1,2-
dicarbonyl compounds,4 no studies have yet focused on
molecules containing adjacent R-dioxirane groups (1,2-bis-
Chemical trapping studies5 provided strong evidence for the
presence of the dioxirane intermediates 3A/3B. Oxygenation
(3) (a) Cassidei, L.; Fiorentino, M.; Mello, R.; Sciacovelli, O.; Curci, R.
J. Org. Chem. 1987, 52, 699. (b) Murray, R. W.; Singh, M.; Jeyaraman, R.
J. Am. Chem. Soc. 1992, 114, 1346. (c) Tomioka, H.; Mizutani, K.;
Matsumoto, K.; Hirai, K. J. Org. Chem. 1993, 58, 7128. (d) Kirschfeld,
A.; Muthusamy, S.; Sander, W. Angew. Chem., Int. Ed. Engl. 1994, 33,
2212. (e) Sander, W.; Schroeder, K.; Muthusamy, S.; Kirschfeld, A.;
Kappert, W.; Boese, R.; Kraka, E.; Sosa, C.; Cremer, D. J. Am. Chem.
Soc. 1997, 119, 7265. (f) Block, K.; Kappert, W.; Kirschfeld, A.;
Muthusamy, S.; Schroeder, K.; Sander, W.; Kraka, E.; Sosa, C.; Cremer,
D. Peroxide Chem. 2000, 139. (g) Schroeder, K.; Sander, W. Eur. J. Org.
Chem. 2005, 3, 496.
(4) (a) Ashford, S. W.; Greta, K. C. J. Org. Chem. 2001, 66, 1523. (b)
Yang, D.; Chen, F.; Dong, Z.-M.; Zhang, D.-W. J. Org. Chem. 2004, 69,
2221. (c) Yan, J.; Travis, B. R.; Borhan, B. J. Org. Chem. 2004, 69, 9299.
(5) Sulfides have been used previously to assay dioxirane content: (a)
Murray, R. W.; Jeyaraman, R.; Pillay, M. K. J. Org. Chem. 1987, 52, 746.
(b) Gonzalez-Nunez, M. E.; Mello, R.; Royo, J.; Rios, J. V.; Asensio, G. J.
Am. Chem. Soc. 2002, 124, 9154.
(1) (a) Bach, R. D.; Dmitrenko, O. J. Org. Chem. 2002, 67, 3884. (b)
Bach, R. D.; Dmitrenko, O. J. Org. Chem. 2002, 67, 2588.
(2) A very abbreviated list of the literature includes: (a) Murray, R. W.
Chem. ReV. 1989, 89, 1187. (b) Adam, W.; Curci, R.; Edwards, J. O. Acc.
Chem. Res. 1989, 22, 205. (c) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem.
Soc. 2002, 124, 8792. (d) Sartori, G.; Armstrong, A.; Maggi, R.; Mazzacani,
A.; Sartorio, R.; Bigi, F.; Dominguez-Fernandez, B. J. Org. Chem. 2003,
68, 3232. (d) Yang, D. Acc. Chem. Res. 2004, 37, 497. (e) Curci, R.;
D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006, 39, 1. (f) Chan, T.-C.; Chan,
W.-Y.; Chan, W.-K.; Vrijmoed, L. L. P.; O’Toole, D. K.; Wong, M.-K.;
Che, C.-M. EnViron. Sci. Technol. 2006, 40, 625.
10.1021/jo060694f CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/23/2006
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J. Org. Chem. 2006, 71, 5796-5799

SCHEME 3
SCHEME 4
FIGURE 1. HMBC -17 °C spectra [600 MHz, CDCl3:CHCl3 (4:1
ratio)] of 3A and 3B taken from the CHCl3 extract of the biacetyl (1.23
M) oxone (0.48 M) buffer mixture. The extra cross-peaks are attributed
to solvents and hydrated compounds.
2,2,3,3-tetramethyloxirane (41.7% yield) and trans-2,3-diphen-
yloxirane (47.0% yield). These percent yields were determined
after 8 h of stirring at -17 °C.
Reaction Products. The biacetylsoxone reaction is an
effective reaction to generate 3A and 3B, but the reaction also
gives byproducts. Separation of the organic-soluble fraction at
-17 °C led to the detection of seven stable byproducts: acetic
anhydride (4), acetic acid (5), succinaldehyde (6), diacetyl
peroxide (7), acetone (8), methyl acetate (9), and CO2 (10)
(Scheme 3). Some compounds exist as hydrates and reside to a
greater extent in the aqueous layer, making quantification
difficult.6 The percent conversion of the biacetyl ranged from
30 to 40%. Carbon dioxide, acetic anhydride, and acetic acid
are the major components of this reaction in the organic layer,
where acetic acid presumably arises from the hydrolysis of acetic
anhydride. Evidence for the formation of 4, 5, and 7-9 was
FIGURE 2. HSQC -17 °C spectra [600 MHz, CDCl3:CHCl3 (4:1
ratio)] of 3A and 3B taken from the CHCl3 extract of the biacetyl (1.23
M) oxone (0.48 M) buffer mixture. The extra cross-peaks are attributed
to solvents and hydrated compounds.
1
provided by H NMR. Carbon dioxide was detected by 13C
NMR. The evidence for the existence of monomeric 6 was
provided using 1H and 13C NMR, although 6 may also exist as
the hydrate or in dimeric or trimeric forms.
The experimental evidence suggests that intermediates
3A/3B decompose to the final stable products 4-10. We believe
that acyloxy and alkyl radicals play a role in the decomposition
of 3A and 3B, which arises from homolysis of the O-O bond.7
Dioxirane 3A can react to give dialdehyde 6, and 3B can convert
to the stable diacetyl peroxide 7, by losing CO2 (Scheme 4). A
process involving methyl radical cleavage can give intermediates
CH3C(dO)CO2• and CH3C(O2)CO2•, subsequently yielding
CH3C•(dO) and CH3C•(O2), respectively, upon loss of CO2.
There is reason to believe that rearrangements via [•CH2CHO
T CH2dCHO•] precede tail-to-tail dimerization to 6, and
of added Ph2S or (p-CH3O-C6H4)2S proceeded at -17 °C in
the presence of the organic-soluble fraction of the biacetyls
oxone mixture and was monitored by GC/MS and H NMR,
1
respectively. (Control reactions demonstrate that oxone was not
present in the organic-soluble fraction after the extraction and
is not responsible for the sulfide oxidation reaction) The products
formed are the corresponding Ph2SO and (p-CH3O-C6H4)2SO.
The concentrations of sulfoxides were determined to be 0.06
M. Combining the data from the sulfide trapping studies, and
from NMR detection allowed us to calculate that the -17 °C
organic fraction contains 0.05 M 3A and 0.01 M 3B. The
observation that diacetyl peroxide 7 reacted slowly with Ph2S
and (p-CH3O-C6H4)2S leads us to suggest that the oxygen-
transfer chemistry is derived from 3A and 3B. A quantitative
study of biacetyl with oxone with added olefins also showed
the oxygen-transfer chemistry expected of 3A and 3B. 2,3-
Dimethyl-2-butene and trans-stilbene reacted in the presence
of the -17 °C CHCl3 fraction. GC/MS analyses of these
reactions revealed the formation of the corresponding epoxides,
(6) Hydrated ketones and aldehydes related to this study have been
reported: (a) Lin, T. F.; Christian, S. D.; Affsprung, H. E. J. Phys. Chem.
1967, 71, 968. (b) Lee, Y. J.; Burr, J. G. Chem. Phys. Lett. 1976, 43, 146.
(c) Buschmann, H. J.; Fueldner, H. H.; Knoche, W. Ber. Bunsen-Ges. 1980,
84, 41. (d) Burkey, T. J.; Fahey, R. C. J. Am. Chem. Soc. 1983, 105, 868.
(e) Segretario, J. P.; Sleszynski, N.; Partch, R. E.; Zuman, P.; Horak, V. J.
Org. Chem. 1986, 51, 5393.
(7) (a) Singh, M.; Murray, R. W. J. Org. Chem. 1992, 57, 4263. (b)
Cremer, D.; Kraka, E.; Szalay, P. G. Chem. Phys. Lett. 1998, 292, 97.
J. Org. Chem, Vol. 71, No. 15, 2006 5797

SCHEME 5
SCHEME 6
units in molecules can be doubled (or even possibly multiplied)
to produce new dioxirane structures. A new synthetic utility
for 3A and 3B has not yet been demonstrated.
CH3CO2• precedes dimerization to 7. Subsequent methyl radical
recombination reactions give 8 and 9, and a H-abstraction
process gives 5. Previous work has been conducted on ther-
molytic dioxirane fragmentation; electron transfer and radical
formations have been suggested.7,8 The mono-dioxirane 3A can
also produce the stable anhydride 4 by a Baeyer-Villager type
rearrangement in an intramolecular process.
The data suggest that formation of 3B does not take place
efficiently due to a reduced reactivity of the hydrated form of
mono-dioxirane with oxone (11), which may predominant in
the aqueous buffered solution (Scheme 5). Similarly, a previous
study reported the equilibrium constant for the monohydration
of biacetyl to CH3C(OH)2C(O)CH3 to be 2.1.6c
The amount of 3A and 3B formed is a function of temper-
ature. After heating the -17 °C organic-soluble fraction of the
biacetylsoxone mixture to 25 °C, concentrations of 4-10
increased and 3A and 3B decreased. Biacetyl serves as the
cosolvent and reagent, and the yield of 3A and 3B depends on
the ratio of biacetyl to oxone used in the reaction. Using an
equivalent or excess of oxone to biacetyl (that is, 1:1 and 2:1)
resulted in lower concentrations of 3A and 3B, but increased
concentrations of 4-10. Past a certain point, decomposition of
both 3A and 3B is facilitated by higher oxone concentrations.
Under high oxone-to-biacetyl ratios (5:1 and 10:1) 3A and 3B
were not observed. The decomposition of 3A and 3B and
formation of stable products 4-10 also takes place rapidly when
chloroform, acetonitrile, or buffer is added as a cosolvent with
higher added oxone concentrations. It is known that dioxiranes
can react with oxone and decompose.
Origin of the Stability of Dioxiranes 3A/3B. The mono-
dioxirane 3A and the bis-dioxirane 3B differ in their relative
stability as revealed by NMR. For example, 3A decomposes
rapidly at 0 °C, while at the same temperature 3B is stable for
30 min. An explanation on dioxirane stability could follow
Bach’s lead.1 The decreased stability of 3A vs 3B can be viewed
from the greater role of the π-resonance contributor compared
to the R-dioxiranyl (anomeric) resonance contributor in terms
of R-electron withdrawing capacity (Scheme 6). In contrast to
bis-dioxirane 3B, the mono-dioxirane 3A will have a weaker
O-O bond, as anticipated from a π-electron withdrawing effect
from the adjacent carbonyl group. It has been previously shown
that substituting one of the methyl groups on 1 with an electron
withdrawing CF3 group increases the electrophilicity of the
oxidant.9
Experimental Section
Low-temperature and room-temperature NMR data were acquired
on 400 and 600 MHz NMR spectrometers. GC/MS data were also
collected. Reagents and solvents [chloroform, chloroform-d, 2,3-
butanedione, oxone (mono-persulfate triple salt, 2KHSO5, KHSO4,
and K2SO4), sodium phosphate monobasic, sodium phosphate
dibasic heptahydrate, sodium sulfite (anhydrous), m-chloroperoxy-
benzoic acid (MCPBA), diphenyl sulfide, diphenyl sulfoxide, 2,3-
dimethyl-2-butene, trans-stilbene, and triphenyl methane] were
obtained commercially and were used as received. The purity of
1
the reagents was checked by H NMR and GC/MS prior to use.
2,2,3,3-Tetramethyloxirane and trans-2,3-diphenyloxirane were
synthesized via MCPBA oxidation of their corresponding alkenes
and are known compounds previously described in the literature.10
Oxonesbiacetyl reactions were conducted with a salted ice bath
at -17 °C, where oxone (25 g, 0.0401 mol) in 25 mL of deionized
water was added to a solution containing sodium phosphate (pH
7.4, 10 mL), sodium bicarbonate (12 g, 0.14285 mol), chloroform
(10 mL), deionized water (10 mL), and 1 g of ice. A -5 °C solution
of biacetyl (8 mL, 0.0916 mol) and chloroform (5 mL) was added
to the mixture simultaneously with the oxone. Sodium bicarbonate
(12.6 g) was used to maintain the pH between 7.4 and 7.8. The
reaction mixture was then poured into a beaker cooled to -17 °C
containing anhydrous Na2SO4: NaH2PO4(H2O):NaH2PO4(7H2O) (4:
2:1). The organic layer was separated at low temperature (-17 °C)
and dried with magnesium sulfate. Chloroform-d was added to a 1
mL sample of the chloroform layer of the reaction mixture, which
was then analyzed by low-temperature and room-temperature NMR
spectroscopy, and GC/MS. The data used to generate Figures 1
and 2 were collected at -17 °C. Mono-dioxirane [1-(3-methyl-
1
dioxiran-3-yl)ethanone (3A)]: H NMR (CDCl3, ppm) δ 1.59 (s,
3H), 2.40 (s, 3H); 13C NMR (ppm) δ 208.0, 94.0. Bis-dioxirane
[(3,3′-dimethyl-[3,3′]bidioxirane (3B)]: 1H NMR (CDCl3, ppm) δ
1.407 (s, 3H); 13C NMR (ppm) 113.7. The data collected for 4-10
are consistent with literature values of NMR and/or GC mass
spectroscopy.
Concentrations of dioxiranes 3A/3B were measured by GC/MS
with the generation of Ph2SO from Ph2S with reference to a
calibration curve for Ph2SO and internal standard, triphenylmethane,
and are an average of four runs. Concentrations of dioxirane were
also measured by NMR by measuring the generation of (p-CH3O-
C6H4)2SO from (p-CH3O-C6H4)2S with reference to the internal
(9) (a) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem.
1988, 53, 3890. (b) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem.
1995, 60, 3887. (c) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (d) Frohn,
M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem. Soc. 1999,
121, 7718. (e) Armstrong, A.; Washington, I.; Houk, K. N. J. Am. Chem.
Soc. 2000, 122, 6297. (f) Li, W.; Fuchs, P. L. Org. Lett. 2003, 5, 2853. (g)
Bach, R. D.; Dmitrenko, O.; Adam, W.; Schambony, S. J. Am. Chem. Soc.
2003, 125, 924.
(10) (a) Pocker, Y.; Ronald, B. P. J. Am. Chem. Soc. 1980, 102, 5311.
(b) Neimann, K.; Neumann, R. Org. Lett. 2000, 2, 2861. (c) Jitsukawa, K.;
Shiozaki, H.; Masuda, H. Tetrahedron Lett. 2002, 43, 1491. (d) Denmark,
S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67, 3479.
In conclusion, the data taken together show that the biacetyls
oxone reaction provides the generation of the mono- and bis-
dioxiranes, 3A and 3B. This result demonstrates that dioxirane
(8) (a) Adam, W.; Asensio, G.; Curci, R.; Gonzalez-Nunez, M. E.; Mello,
R. J. Am. Chem. Soc. 1992, 114, 8345. (b) Houk, K. N.; Liu, J.; DeMello,
N. C.; Condroski, K. R. J. Am. Chem. Soc. 1997, 119, 10147. (c) Bravo,
A.; Fontana, F.; Fronza, G.; Minisci, F.; Zhao, L. J. Org. Chem. 1998, 63,
254. (d) Freccero, M.; Gandolfi, R.; Sarzi-Amade, M.; Rastelli, A. J. Org.
Chem. 2003, 68, 811.
5798 J. Org. Chem., Vol. 71, No. 15, 2006

standard triphenylmethane. The concentrations of 2,2,3,3-tetra-
methyloxirane and trans-2,3-diphenyloxirane were determined by
GC/MS, where triphenylmethane was used as an internal standard
along with prior-determined calibration curves from authentic
samples.
distributions of the epoxides are the average of four runs. A control
experiment demonstrated that oxone was absent in the organic layer,
where the solution was examined with added alkenes, which showed
that no epoxide was present by GC/MS.
Epoxidation and sulfoxidation reactions were conducted as
follows: biacetyl (0.008 mol) neat at -5 °C was added to the
mixture simultaneously with oxone (24.5 g, 0.04 mol). The organic
layer was extracted with CHCl3, washed 3 times with deionized
water, dried over anhydrous magnesium sulfate, and added to -10
°C solutions containing either 2,3-dimethyl-2-butene, trans-stilbene,
diphenyl sulfide, or p-methoxyphenyl sulfide (0.001 mol) in 50 mL
of acetonitrile. The solutions were stirred for 8 h at -10 °C. Product
Acknowledgment. We thank Hsin Wang and Ruth Stark
(College Staten Island) and Gopal Subramaniam (Queens
College) for assistance in collecting the NMR data, and the City
University of New York, PSC-CUNY, and the National
Institutes of Health (Grant S06 GM076168-01) for support.
JO060694F
J. Org. Chem, Vol. 71, No. 15, 2006 5799