The effect of iodine on the peroxidation of carbonyl compounds

Article abstract of DOI:10.1021/jo0708745

(Chemical Equation Presented) Peroxidation of ketones and aldehydes with iodine as a catalyst was studied. Ketones reacted with 30% aq hydrogen peroxide in the presence of 10 mol % of iodine to yield gem-dihydroperoxides in acetonitrile and hydroperoxyketals in methanol. The yield of hydroperoxidation of various cyclic ketones was 60-98%, including androstane-3,17-dione, while acyclic ketones were converted with a similar efficiency. Aromatic aldehydes were also converted to gem-dihydroperoxides with hydrogen peroxide and iodine as catalyst in acetonitrile and to hydroperoxyacetal in methanol, while the reactivity of aliphatic ones remained the same as in noncatalyzed reactions. tert-Butylhydroperoxide reacted in a similar manner, giving the corresponding perether derivatives. A study was also made of the relative kinetics of dihydroperoxidation from which the Hammet equation gave a reaction constant (ρ) of -2.76, indicating the strong positive charge development in the transition state and the important role of rehybridization in the conversion of hydroperoxyhemiketal to gem-dihydroperoxide. In acetonitrile, the iodine catalyst is apparently able to discriminate between the elimination of a hydroxy, methoxy, and hydroperoxy group and addition of water, methanol, and H₂O₂ to a carbonyl group.

Full text of DOI:10.1021/jo0708745

The Effect of Iodine on the Peroxidation of Carbonyl Compounds
†
†,‡
†
,†
Katja Zˇ mitek, Marko Zupan, Stojan Stavber, and Jernej Iskra*
Laboratory of Organic and Bioorganic Chemistry, “Jo zˇ ef Stefan” Institute, JamoVa 39, Ljubljana,
SloVenia, and Faculty of Chemistry and Chemical Technology, UniVersity of Ljubljana, A sˇ ker cˇ eVa 5,
Ljubljana, SloVenia
jernej.iskra@ijs.si
ReceiVed April 26, 2007
Peroxidation of ketones and aldehydes with iodine as a catalyst was studied. Ketones reacted with 30%
aq hydrogen peroxide in the presence of 10 mol % of iodine to yield gem-dihydroperoxides in acetonitrile
and hydroperoxyketals in methanol. The yield of hydroperoxidation of various cyclic ketones was 60-
98%, including androstane-3,17-dione, while acyclic ketones were converted with a similar efficiency.
Aromatic aldehydes were also converted to gem-dihydroperoxides with hydrogen peroxide and iodine as
catalyst in acetonitrile and to hydroperoxyacetal in methanol, while the reactivity of aliphatic ones remained
the same as in noncatalyzed reactions. tert-Butylhydroperoxide reacted in a similar manner, giving the
corresponding perether derivatives. A study was also made of the relative kinetics of dihydroperoxidation
from which the Hammet equation gave a reaction constant (F) of -2.76, indicating the strong positive
charge development in the transition state and the important role of rehybridization in the conversion of
hydroperoxyhemiketal to gem-dihydroperoxide. In acetonitrile, the iodine catalyst is apparently able to
discriminate between the elimination of a hydroxy, methoxy, and hydroperoxy group and addition of
2 2
water, methanol, and H O to a carbonyl group.
5
Introduction
eroxides, and acyclic analogues with a variety of functional
5
a
groups. Organic peroxides are also valuable radical initiators
and oxidants.
The increasing resistance of malaria parasites to commonly
used alkaloidal drugs and the discovery of the antimalarial
properties of artemisinin have boosted interest into organic
peroxides as potential antimalarials. Monoperoxyketals and
dihydroperoxides are key intermediates in the synthesis of many
6
1
2
(4) (a) Iskra, J.; Bonnet-Delpon, D.; Begue, J. P. Tetrahedron Lett. 2003,
4, 6309. (b) Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra,
J. Tetrahedron 2006, 62, 1479. (c) Terent’ev, A. O.; Kutkin, A. V.;
Starikova, Z. A.; Antipin, M. Y.; Ogibin, Y. N.; Nikishina, G. I. Synthesis
004, 2356. (d) Solaja, B. A.; Terzic, N.; Pocsfalvi, G.; Gerena, L.; Tinant,
4
3
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Y. X.; Vennerstrom, J. L. J. Org. Chem. 1998, 63, 8582. (f) Opsenica, I.;
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Nojima, M.; McCullough, K. J. J. Chem. Soc., Perkin Trans. 1 1999, 1867.
†
“
Jo zˇ ef Stefan” Institute.
‡
University of Ljubljana.
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(
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10.1021/jo0708745 CCC: $37.00 © 2007 American Chemical Society
6
534
J. Org. Chem. 2007, 72, 6534-6540
Published on Web 07/28/2007

Effect of Iodine on the Peroxidation of Carbonyl Compounds
7
The major synthetic route to monoperoxyketals and gem-
SCHEME 1
dihydroperoxides5 is ozonolysis of ketone enol ethers or
R-olefins in the presence of hydrogen peroxide, which happens
to be the only general procedure for synthesis of primary gem-
dihydroperoxides. In addition, dihydroperoxides can be syn-
thesized from ketones or ketals with H2O2 under acidic
conditions (tungstic acid, BF3‚Et2O,9 HCl, or AcOH as
solvent),11 while methyltrioxorhenium (MeReO3) in trifluoro-
ethanol enables the synthesis of 4-tert-butylcyclohexyl-1,1-
dihydroperoxide under neutral conditions.4 Dihydroperoxides
can be further transformed into gem-bisperethers by alkylation
with olefins or alkyl iodides in the presence of silver oxide or
cesium hydroxide.5 Alternative methods for alkylation include
the acid-catalyzed reaction of the carbonyl compound with
d,e
8
10
a
Results
a,c
Dihydroperoxides from Ketones. First we studied the effect
of iodine (10 mol %) on the conversion of 4-tert-butylcyclo-
hexanone 1 with 30% aq H2O2 (3 equiv) in different solvents.
The reaction in acetonitrile (24 h at 22 °C) resulted in a 90%
yield of the gem-dihydroperoxide, DHP (4-tert-butylcyclohex-
ane-1,1-diyl dihydroperoxide 2), as determined by NMR
spectroscopy of the crude reaction mixture (Scheme 1). Trif-
luoroethanol also proved to be a good solvent, resulting in a
high yield (80%) of DHP 2, whereas reactions in water in N,N-
dimethylformamide and without a solvent had lower selectivity
and yielded lower amounts of 2 together with a mixture of
various hydroperoxides. Consequently, we deemed acetonitrile
to be the optimal solvent for the synthesis of DHPs, and so all
further optimization of the reaction was made in this solvent.
Interestingly, I2 is able to discriminate between hydroxy and
hydroperoxy as leaving groups and H2O2 versus H2O as
nucleophiles in addition to the ketone 1.
1
2
alkylhydroperoxides in the presence of desiccants and a
recently published method involving the condensation of acetals
and enol ethers with hydroperoxides catalyzed by protic or
Lewis acids.13 The drawbacks of these peroxidation reactions
are the need for the prior synthesis of the starting substrates,
the use of highly concentrated H2O2, the need for excess acid,
moderate yields, and a restricted substrate range. The selectivity
of ozonolysis is also poor and cannot be used for substrates
containing ozone-sensitive groups. Because of these limitations,
new, more efficient, and broad spectrum methods for synthesis
of monoperoxyketals, dihydroperoxides, and also gem-bispere-
thers are sought.
Since molecular iodine is a proven Lewis acid catalyst for
the activation of carbonyl compounds, including acetalization
1
4
reactions, we envisage that iodine could catalyze the peroxi-
dation reactions of such compounds. We present our research
on the use of iodine as a catalyst for conversion of ketones and
aldehydes into dihydroperoxides, peroxyketal derivatives, and
their perethers with 30% aq hydrogen peroxide or tert-
Since the synthesis of acyclic DHPs is more problematic than
cyclohexyl DHPs, we chose 3-decanone 3 as a test compound
for the optimization of the reaction conditions. The reaction
under above-mentioned conditions resulted in a low conversion
of the 3-decanone 3 to DHP 4 (22%). Optimum results were
obtained using 4 equiv of H2O2 at 22 °C, while the amount of
iodine and the concentration of the reaction mixture had a
marked effect (Figure 1); with 1 mol % of iodine, the conversion
was below 40% at each concentration studied. Increasing the
amount of iodine to 5 mol %, however, resulted in a significant
improvement in conversion in the 0.1 and 0.5 M solutions of
15
butylhydroperoxide under neutral reaction conditions. We also
describe the reaction mechanism and the effect of iodine on
the transformation of carbonyl compounds.
(
6) (a) Adam, W., Ed. Peroxide Chemistry: Mechanistic and PreparatiVe
Aspects of Oxygen Transfer; Wiley-VCH: Weinheim, Germany, 2000. (b)
Ando, W., Ed. Organic Peroxides; John Wiley & Sons: Chichester, UK,
1
992. (c) Berkessel, A.; Vogl, N. Synthetic Uses of Peroxides. In The
Chemistry of Peroxides; Rappoport, Z., Ed.; John Wiley & Sons: Chichester,
UK, 2006; Vol. 2, Part 1, pp 307-596. (d) Jakka, K.; Liu, J.; Zhao, C. G.
Tetrahedron Lett. 2007, 48, 1395. (e) Ganeshpure, P. A.; Adam, W.
Synthesis 1996, 179.
(
7) (a) Nakamura, N.; Nojima, M.; Kusabayashi, S. J. Am. Chem. Soc.
987, 109, 4969. (b) Dussault, P. H.; Lee, I. Q.; Lee, H. J.; Lee, R. J.; Niu,
Q. J.; Schultz, J. A.; Zope, U. R. J. Org. Chem. 2000, 65, 8407.
8) Jefford, C. W.; Li, W.; Jaber, A.; Boukouvalas, J. Synth. Commun.
990, 20, 2589.
9) Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.; Ogibin, Y. N.;
Nikishin, G. I. Tetrahedron Lett. 2003, 44, 7359.
10) (a) Opsenica, D.; Pocsfalvi, G.; Juranic, Z.; Tinant, B.; Declercq, J.
P.; Kyle, D. E.; Milhous, W. K.; Solaja, B. A. J. Med. Chem. 2000, 43,
274. (b) Todorovic, N. M.; Stefanovic, M.; Tinant, B.; Declercq, J. P.;
Makler, M. T.; Solaja, B. A. Steroids 1996, 61, 688.
11) (a) Ledaal, T. Acta Chem. Scand. 1967, 21, 1656. (b) Ramirez, A.;
Woerpel, K. A. Org. Lett. 2005, 7, 4617-4620.
12) (a) Dickey, F. H.; Rust, F. F.; Vaughn, W. E. J. Am. Chem. Soc.
1
(
1
(
(
3
(
(
1
949, 71, 1432. (b) Kharasch, M. S.; Sosnovsky, G. J. Org. Chem. 1958,
3, 1322.
2
(
13) Terent’ev, A. O.; Kutkin, A. V.; Troizky, N. A.; Ogibin, Y. N.;
Nikishin, G. I. Synthesis 2005, 2215.
14) (a) Basu, M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K. Synlett
002, 319. (b) Togo, H.; Iida, S. Synlett 2006, 2159. (c) Karimi, B.;
(
2
Golshani, B. Synthesis 2002, 784. (d) Banik, B. K.; Chapa, M.; Marquez,
J.; Cardona, M. Tetrahedron Lett. 2005, 46, 2341.
2
FIGURE 1. The effect of I and reactant concentration on the
conversion of 3-decanone 3 to DHP 4 using 30% H O (conversion
2 2
(15) Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. Org. Lett. 2006, 8,
2
491.
determined by NMR spectroscopy).
J. Org. Chem, Vol. 72, No. 17, 2007 6535

Zˇ mitek et al.
TABLE 1. Synthesis of Dihydroperoxides from Cycloalkanones
with I2/30% H2O2a
SCHEME 3
substrate
t (h)
yield (%)b
4
4
3
2
-tBu-cyclohexanone
-Me-cyclohexanone
-Me-cyclohexanone
-Me-cyclohexanone
1
5
7
5
5
5
5
24
24
24
2: 91
6: 98d
8: 93
10: 80
12: 70
14: 90
16: 60
18: 92
20: 89e
9
c
cyclopentanone
cycloheptanone
cyclododecanone
11
13
15
17
19
TABLE 2. Synthesis of Dihydroperoxides with I2/30% H2O2
c
2
-adamantanone
24
4
tetrahydro-4H-pyran-4-one
a
Conditions: 1 mmol of ketone, 4 mmol of 30% H2O2, 0.1 mmol of I2,
b
1
0 mL of MeCN, 22 °C. Yield after column chromatography. c 2 mL of
MeCN. DHP 6 was synthesized on a few gram scale without any apparent
complication. Determined from the NMR spectra of the crude product
d
e
and based on the starting compound.
SCHEME 2. Iodine-Catalyzed Hydroperoxidation of
Androstane-3,17-dione
a
Isolated yield after column chromatography. b Conditions: 1 mmol of
ketone, 4 mmol of 30% H2O2, 0.1 mmol of I2, 10 mL of MeCN, 22 °C, 24
h.
porates both structures in a more complex steric environment.
Reaction of 21 showed complete selectivity for the carbonyl
group on the six-membered ring over the five-membered one,
giving 3,3-dihydroperoxyandrostan-17-on 22 in a yield of 77%
after column chromatography (Scheme 2).
3
, although in the 0.05 and 2.0 M solutions, the effect was less
pronounced. With the exception of the 0.5 M mixture, using
0 mol % of I2 improved conversion still further with the best
1
conversion occurring in a 0.1 M concentration of 3. We observed
a similar pattern in reactions with 20 mol % of iodine, although
optimum conversion (0.1 M mixture) was lower than that in
the case of 10 mol % of I2.
Conversion of cholestan-3-one 23 into its dihydroperoxide
25 was noticeably lower (29%) as determined by H NMR of
1
the crude reaction mixture. Considering the similarity of the
reaction site to that in androstane-3,17-dione 21, it is likely that
this low conversion originated from cholestanone’s poor solubil-
ity in acetonitrile. We were able to improve conversion by
increasing the reaction time, by adding CH2Cl2 to improve
solubility (Scheme 3), or alternatively by using a more soluble
ketal derivative 24. The result was a similar conversion in a
shorter reaction time.
I2-catalyzed hydroperoxidation with 30% H2O2 was also
effective for acyclic ketones (Table 2), but again steric effects
are important as seen from the lower yield of DHP 31.
Furthermore, tert-butyl methyl ketone was unreactive and gave
only trace amount of its gem-dihydroperoxide. Acetophenone
32 was also converted to its DHP; to our knowledge, this is the
first report of the dihydroperoxidation of acetophenone deriva-
tives.
From our results, we chose the best reaction conditions (a
0.1 M solution of ketone in acetonitrile, 4 equiv of 30% aq
H2O2 and 10 mol % of I2 at 22 °C) to synthesize DHPs from
cyclic ketones (Table 1). Cyclohexanone derivatives had the
highest reactivity, requiring only 5 h for an efficient conversion
to DHPs, while the reactivity of the carbonyl group was sensitive
to steric effects, as evidenced by a decrease in yield from 98%
for 4-Me-cyclohexyl DHP 5 to 93% for 3-Me 7 and to 80% for
2-Me 9. Cycloheptanone 13 and cyclododecanone 15 were also
converted to their corresponding DHPs in good yields, while
the formation of cyclopentyl 12 and 2-adamantyl dihydroper-
oxide 18 in sufficient amounts required a higher reaction
concentration. Tetrahydro-4-pyranone 19 was efficiently trans-
formed into DHP 20 as determined by the NMR spectroscopy
of the crude reaction mixture, albeit the DHP 20 gradually
decomposes during isolation into the starting ketone. To
investigate the selectivity of dihydroperoxidation of cyclic
ketones, we set up an experiment using typical reaction
conditions with equimolar amounts of cyclopentanone 11 and
Miscellaneous Peroxides from Ketones. Since iodine proved
to be a good catalyst for the reaction of ketones with hydrogen
peroxide and able to discriminate between the hydroxy and
hydroperoxy group and the two nucleophiles, H2O2 versus H2O,
we wanted to investigate its effect on peroxidation in a
t
4
-methylcyclohexanone 5. According to NMR analysis of
nucleophilic solvent and with alkylhydroperoxide ( BuOOH) as
reaction mixture, the six-membered ring was 3.3 times more
reactive (Scheme 2). To investigate how steric effects influence
selectivity, we chose androstane-3,17-dione 21 since it incor-
a source of the peroxide unit. When using methanol as a solvent
for iodine-catalyzed peroxidation of ketone with 30% aq H2O2,
the major reaction product was monoperoxyketal 34. Optimum
6536 J. Org. Chem., Vol. 72, No. 17, 2007

Effect of Iodine on the Peroxidation of Carbonyl Compounds
SCHEME 4
SCHEME 5
since isolation of its DHP 20 failed due to its high polarity and
instability. We did succeed in transforming 19 to its bisper-
oxyether 38 with 68% conversion and isolating it using column
chromatography with a yield of 51% (Scheme 4).
Peroxidation of Aldehydes. There are, to our knowledge,
also no reports concerning the direct dihydroperoxidation of
aldehydes with hydrogen peroxide. To address this, we tested
selectivity was obtained using a 0.5 M solution of ketone 1 in
methanol, 1 equiv of 30% aq H2O2, and 5 mol % of I2. After
iodine-catalyzed hydroperoxidation with 30% aq H O2 on
2
2
4
0 h at 22 °C, product 34 was isolated in 72% yield (Scheme
). Next, we performed reactions in ethanol, n-propanol, and
benzaldehyde 39a and found that it selectively converts 39a
into the gem-dihydroperoxide 40a in a yield of 66 and 55%
after column chromatography. The effect of the electron-
donating substituent on the phenyl ring on the conversion to
the DHP proved remarkable (Scheme 5) as DHP with a p-methyl
group was isolated with 70% yield and 76% with a p-methoxy
group. Iodine is clearly critical for good conversion of 39a since
i-propanol. Reaction of ketone 1 and H2O2 in ethanol resulted
in a 64% conversion, while selectivity decreased and dihydro-
peroxide 2 and monoperoxyketal 37 were formed in a ratio of
1
:1.6. Changing the amount of I2 to 10 mol % and the
concentration of 1 to 0.25 M solution in ethanol yielded the
monoperoxyketal 37 selectively in a yield of 80% based on
starting compound as determined from H NMR spectra of the
the absence of I resulted in only a 15% conversion under
2
1
equivalent reaction conditions.
crude reaction mixture (Scheme 4). However, 37 was unstable
and it decomposed to the starting ketone and dihydroperoxide
during isolation, but it was possible to determine its structure
from the crude reaction mixture by comparing spectroscopic
data with its stable analogue 34. In less nucleophilic n-propanol
and sterically hindered i-propanol, selectivity for the monop-
eroxyketal formation was lost.
Next, we performed the reaction of 39a with H2O2 in
methanol, and we isolated hydroperoxyketal 41a in 42% yield.
We observed a similar reactivity using BuOOH, where tert-
butylperoxyacetal 42a was formed in methanol, while the
reaction in acetonitrile yielded di-tert-butylperoxide 43a.
t
Simple, nonaromatic aldehydes, which easily undergo hydra-
tion,1 have different reactivities than ketones and benzalde-
hydes. Using the reaction conditions under which benzaldehyde
was transformed into DHP, both alkyl aldehydessdihydro-
cinnamaldehyde 44a and octanal 44bswere not converted into
their corresponding DHPs but instead into hydroxyhydroper-
oxides 45a and 45b (Scheme 6). In fact, the products are the
same as in the noncatalyzed reaction. In methanol, 44b yields
6
We also wanted to investigate whether or not iodine could
catalyze reactions of ketones with tert-butylhydroperoxide, as
this would open up a route to producing the gem-bisperethers.
Seventy percent aqueous and 60% decane solutions of tert-
butylhydroperoxide were tested as a substitute for hydrogen
peroxide under the same reaction conditions used for the
synthesis of DHPs. Our results revealed the conversion to gem-
bisperether with decane solution of oxidant to be greater than
that with the aqueous solution. The best result was obtained
using a 1.0 M solution of ketone 1 in acetonitrile, 2 equiv of
a mixture of peroxyacetal 46b and hydroxyhydroperoxide 45b
t
(
Scheme 6). The reaction with BuOOH was also tested, and as
anticipated, the tert-butylperoxy hemiacetal 47a was formed
Scheme 6).
(
t
BuOOH (60% in decane), and 10 mol % of I2, and after 24 h
reaction at 22 °C, 4-tert-butyl-1,1-bis-tert-butylperoxycyclo-
hexane 35 was isolated in a yield of 82% (Scheme 4).
By analogy to reactions with hydrogen peroxide, we expected
the formation of tert-butylperoxyketal when using BuOOH in
methanol. Starting from 4-tert-butylcyclohexanone 1 as a
substrate, we were able to isolate tert-butylperoxyketal 36 in a
Discussion
t
A major aim of ours was to achieve a better insight into the
mechanism of iodine-catalyzed dihydroperoxidation of carbonyl
compounds. The reaction follows the route of acid-catalyzed
addition to the carbon-oxygen multiple bond, where iodine acts
7
0% yield (Scheme 4).
Since bisperoxyethers are more stable than DHPs, we used
BuOOH for the peroxidation of tetrahydro-4H-pyran-4-one 19
t
(16) Mcclelland, R. A.; Coe, M. J. Am. Chem. Soc. 1983, 105, 2718.
J. Org. Chem, Vol. 72, No. 17, 2007 6537

Zˇ mitek et al.
SCHEME 6
SCHEME 7
FIGURE 2. Relative kinetics of iodine-catalyzed reaction of benzal-
dehydes with 30% H O .
2 2
as a catalyst for the elimination of the hydroxy group and leads
via the TS-B to form the intermediate peroxycarbenium ion I-B.
In the case of DHPs, it is trapped by another H2O2 molecule to
give the product.
It is evident that I2 plays an essential role in the reaction.
We found that the absence of I2 results in a loss of selectivity
in the formation of DHP in the case of the reaction of
cyclohexanones, while the reaction of 3-decanone 3 and other
less reactive substrates did not proceed at all. Similarly, the
reaction of tert-butylcyclohexanone 1 with hydrogen peroxide
in methanol without iodine did not lead to the selective
formation of hydroperoxyketal 34, instead conversion was low
and the reaction was nonselective. We also observed a marked
effect of the substituent on the aromatic ring of benzaldehyde
on the formation of DHP. To quantify this effect by linear free-
energy relationships (LFER), relative reactivities for I2-catalyzed
dihydroperoxidation of benzaldehydes with electron-donating
(4-MeO, 4-Me) and electron-accepting groups (3-Cl, 4-Cl) were
determined by comparison with unsubstituted benzaldehyde.
Thus we obtained the relative reaction rates with a Hammett
correlation with very good linearity (Figure 2). The negative
reaction constant suggests the electrophilic activation of the
carbonyl group, with iodine acting as a Lewis acid, while its
high value (F ) -2.76) suggests a transition state with a more
developed charge in the rate-determining step. This is similar
to the value obtained for the acid-catalyzed hydrolysis of
1
6
benzaldehyde hydrates.
as a Lewis acid (Scheme 7).17 Initially, a multicomponent system
exists, where each componentscarbonyl compound, iodine,
hydrogen peroxide, water, and acetonitrilesplays an important
role. The reaction begins with an interaction between iodine,
the oxygen atom of a carbonyl group, and a nucleophile (H2O2
or H2O) to produce a transition state TS-A (at present, we have
insufficient evidence to say whether or not it is open or cyclic).
We also wanted to determine whether or not the role of iodine
is crucial in the second reaction step. Dussault et al. have
proposed for the reaction of perketals with carbon nucleophiles
18
the formation of a peroxycarbenium ion as an intermediate.
3
We believe that the rehybridization of the sp C atom in I-A
2
into a sp one in I-B (Scheme 7) is important in the second
reaction step. The reactions involving aliphatic aldehydes stop
after the first step (yielding hydroxyhydroperoxides 45), in
contrast to benzaldehydes, where resonance stabilization of the
Proton migration in the first intermediate (not stated in Scheme
3
7
) leads to the sp intermediate I-A, which is transformed into
either the hydrate or the peroxyhydrate. Iodine once again acts
2
sp intermediate can occur and supposedly favors the formation
of DHP. To determine the role of iodine in this step, we chose
methoxyhydroperoxide 34 as our model for the intermediate
(
17) (a) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry,
5
th ed.; John Wiley & Sons: New York, 2001; pp 1172-1298. (b) Isaacs,
N. S. Physical Organic Chemistry, 2nd ed.; Longman Scientific &
Technical: Singapore, 1995; pp 507-543.
(18) Dussault, P. H.; Lee, I. Q. J. Am. Chem. Soc. 1993, 115, 6458.
6538 J. Org. Chem., Vol. 72, No. 17, 2007

Effect of Iodine on the Peroxidation of Carbonyl Compounds
SCHEME 8
2 4
and the solution dried over Na SO . The solvent was evaporated
and product 2 isolated by column chromatography (SiO
2 2 2
, CH Cl /
EtOAc ) 8:2).
(4-Methylphenyl)methylene Dihydroperoxide 40b: 40b was
made from aldehyde 39b according to the general procedure, with
1
reaction time of 24 h: white solid (70%); mp 55-56 °C; H NMR
(
CDCl ) δ 2.34 (s, 3H), 6.28 (s, 1H), 7.16 (d, J ) 8 Hz, 2H), 7.31
3
13
(d, J ) 8 Hz, 2H), 9.72 (s, 2H); C NMR (CDCl
3
) δ 21.2, 110.0,
1
7
5
26.9, 129.1, 129.5, 139.7; IR ν 3250, 1306, 1183, 1042, 983, 805,
-
1
77 cm . Anal. Calcd for C
6.60; H, 6.18.
8 10 4
H O : C, 56.47; H, 5.92. Found: C,
Synthesis of Hydroperoxyketals. Methoxy(phenyl)methyl Hy-
1
9
product I-A. From Scheme 8, the importance of iodine in this
reaction step is evidenced by the fact that methoxyhydroperoxide
droperoxide 41a: To a solution of 0.05 mmol of I
2
(12.7 mg)
and 1 mmol of 30% H (0.12 mL) in 2 mL of methanol was
2
O
2
added 1 mmol (120 mg) of 4-methylbenzaldehyde 39a, and the
solution was stirred at 22 °C for 24 h. The reaction mixture was
then concentrated under reduced pressure (ca. 20 mmHg), dichlo-
romethane (10 mL) added, and the solution dried over Na
The solvent was evaporated and the product isolated by column
chromatography (SiO , CH Cl /EtOAc ) 9:1), and 65 mg (42%)
of colorless oil was obtained: H NMR (CDCl
.73 (s, 1H), 7.30-7.68 (m, 5H), 8.82 (br s, 1H); C NMR (CDCl
δ 56.0, 107.6, 126.9, 128.3, 129.2, 135.3.
Synthesis of Bisperethers. 4-tert-Butyl-1,1-bis(tert-butylper-
oxy)cyclohexane 35: To a solution of 0.1 mmol of I (25.4 mg)
and 2 mmol of 60% BuOOH decane (0.72 mL) in 1 mL of
acetonitrile was added 1 mmol (154 mg) of 4-tert-butylcyclohex-
anone 1, and the solution was stirred at 22 °C for 24 h. The reaction
mixture was concentrated under reduced pressure (ca. 20 mmHg),
34 conversion to DHP 2 occurs only in the presence of iodine.
Further, we believe that iodine activates the substitution of the
OCH3 group with OOH, while it does not activate the reverse
reaction from DHP 2 to 34 (Scheme 8), which can be attributed
to iodine’s ability to interact with the methoxy O atom as a
Lewis acid and to facilitate its release. Therefore, I2 assists in
2 4
SO .
2
2
2
1
3
) δ 3.58 (s, 3H),
3
the rehybridization of the sp C atom in I-A by enabling the
13
5
3
)
addition of the second nucleophile. Also, iodine does not
facilitate rehybridization through interactions with the OOH
group, and this is possibly due to an interaction with the O atom
attached to the H and consequently does not enhance the leaving
group ability of the hydroperoxo substituent.
The solvent used also had a marked effect on the iodine-
catalyzed hydroperoxidation of carbonyl compounds. Acetoni-
trile is a good partner for iodine because it does not strongly
coordinate the catalyst. Conversely, methanol is known to
interact strongly with iodine, and the reaction in methanol does
not lead to the formation of DHP but instead to peroxyketals.
This points to the important role that solvation has on iodine
and on its strength since methanol deactivates iodine to the point
where it is incapable of catalyzing the second step of reaction.
2
t
and the product was isolated by column chromatography (SiO
2
,
petrolether/ether ) 95:5); 235 mg (82%), mp 49.5-50.5 °C, mp
20
1
(
1
(
lit) 48-49 °C; H NMR (CDCl
3
) δ 0.86 (s, 9H), 0.93-1.08 (m,
H), 1.23 (s, 9H), 1.27 (s, 9H), 1.20-1.46 (m, 4H), 1.55-1.69
13
m, 2H), 2.24-2.36 (m, 2H); C NMR (CDCl
27.6, 30.9, 32.4, 47.4, 78.9, 79.1, 106.8.
Synthesis of Peroxyketals. tert-Butyl 4-tert-Butyl-1-methoxy-
cyclohexyl Peroxide 36: To a solution of 0.05 mmol of I (12.7
3
) δ 23.4, 26.7, 26.9,
2
t
mg) and 2 mmol of 60% BuOOH (0.72 mL) in 1 mL of methanol
was added 1 mmol (154 mg) of 4-tert-butylcyclohexanone 1, and
the solution was stirred at 22 °C for 24 h. The reaction mixture
was then concentrated under reduced pressure (ca. 20 mmHg) and
Conclusion
Iodine-catalyzed hydroperoxidation of cyclic and acyclic
ketones as well as aromatic aldehydes with aqueous H2O2 in
acetonitrile is a straightforward and efficient method for the
synthesis of gem-dihydroperoxides. An analogous reaction in
methanol yields hydroperoxyacetals, while tert-butylhydroper-
oxide produces the corresponding perether derivatives.
product isolated by column chromatography (SiO
2
, petrolether/ether
)
95:5). Its structure was determined by comparing the NMR
spectroscopic data with its hydroperoxy analogue 34: 182 mg (70%,
mixture of diastereomers 1.7:1) of colorless oil; IR ν 1364, 1194,
103, 889 cm . Active oxygen content calcd 0.124, by iodometric
-1
1
titration 0.123.
I2-catalyzed reaction of ketones and H2O2 is a two-step
reaction, and iodine is essential in each step, possibly playing
a double role as a catalyst by enhancing the electrophilic
character of the carbonyl C atom (high negative value for the
Hammet reaction constant) and enhancing the nucleophilic
character of hydrogen peroxide. Iodine also assists in the
Major diastereomer: 1H NMR (CDCl
H), 0.95-1.55 (m, 5H), 1.55-1.70 (m, 2H), 2.20-2.35 (m, 2H),
3
.30 (s, 3H); C NMR (CDCl ) δ 23.6, 26.7, 27.5, 32.0, 32.3, 47.1,
3
) δ 0.86 (s, 9H), 1.29 (s,
9
3
13
48.1, 78.8, 103.0.
Minor diastereomer: 1H NMR (CDCl ) δ 0.86 (s, 9H), 1.24 (s,
3
9H), 0.95-1.40 (m, 5H), 1.55-1.70 (m, 2H), 2.06-2.17 (m, 2H),
3
2
13
rehybridization of the sp C atom into the sp one in the second
step, which enables the further addition of a nucleophile. Iodine
is able to discriminate between the hydroxy and hydroperoxy
group and between two nucleophiles (H2O2 vs H2O) in an
addition to the ketone.
3.26 (s, 3H); C NMR (CDCl
8.0, 78.75, 103.4.
3
) δ 23.4, 26.6, 27.6, 31.7, 32.3, 47.8,
4
Synthesis of Peroxyacetals. tert-Butyl Methoxy(phenyl)methyl
Peroxide 42a:2 To a solution of 0.05 mmol of I
1
(12.7 mg) and 1
2
t
mmol of 60% BuOOH decane solution (0.36 mL) in 2 mL of
methanol was added 1 mmol (120 mg) of benzaldehyde 39a, and
the solution was stirred at 22 °C for 24 h. The reaction mixture
was concentrated under reduced pressure (ca. 20 mmHg), and the
Experimental Section
Synthesis of gem-Dihydroperoxides. General Procedure for
the Synthesis of DHPs from Ketones and Aromatic Aldehydes:
(19) Griesbaum, K.; Kim, W. S.; Nakamura, N.; Mori, M.; Nojima, M.;
Kusabayashi, S. J. Org. Chem. 1990, 55, 6153.
To a solution of 0.1 mmol of I
2
(25.4 mg) and 4 mmol of 30%
(
20) Montecatini Edison S. P. A. GB1276758, 1972.
2 2
H O
(0.45 mL) in 10 mL of acetonitrile was added 1 mmol (154
(21) Dussault, P. H.; Trullinger, T. K.; Cho-Shultz, S. Tetrahedron 2000,
mg) of 4-tert-butylcyclohexanone 1, and the solution was stirred
at 22 °C for 5 h. The reaction mixture was concentrated under
reduced pressure (ca. 20 mmHg), dichloromethane (10 mL) added,
5
6, 9213.
(22) Mukaiyama, T.; Kato, J.; Miyoshi, N.; Iwasawa, N. Chem. Lett.
1985, 1255.
J. Org. Chem, Vol. 72, No. 17, 2007 6539

Zˇ mitek et al.
) 4.7 Hz, 1H); 13
product was isolated by column chromatography (SiO
ether ) 95:5). Obtained was 135 mg (64%) of colorless oil:
NMR (CDCl
2
, petrolether/
2H), 3.60 (br s, 1H), 5.17 (dd, J
1
) 5.4 Hz, J
2
C
1
H
NMR (CDCl ) δ 26.4, 30.6, 34.4, 99.4, 125.9, 128.2, 128.27,
3
3
) δ 1.28 (s, 9H), 3.59 (s, 3H), 5.76 (s, 1H), 7.25-
.55 (m, 5H); 13C NMR (CDCl
) δ 26.4, 56.2, 80.8, 106.86, 126.8,
28.1, 128.8, 136.2.
Synthesis of Hydroperoxyhemiacetals. To a solution of 0.1
mmol of I (25.4 mg) and 4 mmol of 30% H (0.45 mL) in 10
128.32, 141.2; IR ν 3429, 1364, 1244, 1194, 1095, 1030, 927, 878,
748, 700 cm . Active oxygen content calcd 0.143, by iodometric
-1
7
1
3
titration 0.143.
Hammet Correlation. The relative reactivities of benzaldehydes
were determined by competitive reactions, carried out as follows.
2
2 2
O
mL of acetonitrile was added 1 mmol (134 mg) of 3-phenylpro-
pionaldehyde 44a, and the solution stirred at 22 °C for 24 h. The
reaction mixture was concentrated under reduced pressure (ca. 20
mmHg), dichloromethane (10 mL) added, and the solution dried
To a solution of 0.05 mmol of I
2
(12.7 mg) and 2 mmol of 30%
2 2
H O
(0.22 mL) in 5 mL of acetonitrile were added 0.5 mmol (53
mg) of benzaldehyde and 0.5 mmol of substituted benzaldehyde,
and the solution was stirred at 22 °C for 15 h. The reaction mixture
was concentrated under reduced pressure (ca. 20 mmHg), dichlo-
over Na
of colorless oil 45a. Its structure was deduced by comparing NMR
2 4
SO . The solvent was evaporated to leave 153 mg (91%)
2 4
romethane (10 mL) added, dried over Na SO , and the solvent
22
spectroscopic data with its tert-butylperoxy methoxy analogue,
evaporated. The amounts of reacted benzaldehydes were determined
1
and active oxygen content was determined by iodometric titration
after isolation. Further characterization failed as it is not stable,
decomposing to the starting aldehyde although refrigerated.
from H NMR spectra of the crude reaction mixture using 1,1-
diphenylethylene as an internal standard. Applying this known
competitive technique, relative reactivities expressed by relative
rate factors (krel) were calculated from the equation2
3
k
1
-Hydroperoxy-3-phenylpropan-1-ol 45a: colorless oil, 153
A B
rel ) k /k
1
24
mg (91%); H NMR (CDCl
3
) δ 1.67-2.05 (m, 2H), 2.65 (t, J ) 8
) log((A - X)/A)/log((B - X)/B), derived from the Ingold-Shaw
relation where A and B are the amounts (in mmol) of starting
material and X and Y are the amounts of product derived from them.
Hz, 2H), 5.10 (br s, 1H), 5.10 (t, J ) 6 Hz, 1H), 7.00-7.30 (m,
5
3
1
H), 9.25 (br s, 0.5H), 9.98 (br s, 0.5H); 1 C NMR (CDCl
3
3
) δ 30.5,
4.2, 101.0, 126.1, 128.3, 128.4, 140.7; IR ν 3347, 1346, 1177,
098, 1031, 925, 746, 700 cm . Active oxygen content calcd 0.190,
-1
Acknowledgment. This research has been supported by the
Ministry of Higher Education, Science and Technology of the
Republic of Slovenia, the Young Researcher program (K. Zˇ .)
of the Republic of Slovenia. The authors are grateful to I. Pravst,
the staff of the National NMR Centre at the National Institute
of Chemistry in Ljubljana (A. Ga cˇ e sˇ a and J. Plavec), and the
staff of Mass Spectroscopy Centre at the JSI (B. Kralj, D.
Zˇ igon), to T. Stipanovi cˇ and Prof. B. Stanovnik for some
elemental combustion analysis.
by iodometric titration 0.187.
Synthesis of Peroxyhemiacetal. 1-(tert-Butylperoxy)-3-phe-
2
nylpropan-1-ol 47a: To a solution of 0.05 mmol of I (12.7 mg)
t
and 4 mmol of 60% BuOOH decane solution (1.44 mL) in 2 mL
of acetonitrile was added 1 mmol (134 mg) of 3-phenylpropional-
dehyde 44a, and the solution was stirred at 22 °C for 24 h. The
reaction mixture was concentrated under reduced pressure (ca. 20
2
mmHg) and the product isolated by column chromatography (SiO ,
petrolether/ether ) 95:5), and 199 mg (89%) of a colorless oil was
obtained. Its structure was deduced by comparing NMR spectro-
scopic data with its methoxy analogue,22 and active oxygen content
was determined by iodometric titration straight after isolation.
Further characterization failed as the product was unstable,
decomposing to starting aldehyde although refrigerated: 1H NMR
Supporting Information Available: General synthetic proce-
dures for DHP and characterization of substances are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3
(CDCl ) δ 1.25 (s, 9H), 1.87-2.00 (m, 2H), 2.76 (t, J ) 8 Hz,
JO0708745
(23) Pearson, R. E.; Martin, J. C. J. Am. Chem. Soc. 1963, 85, 3142.
(24) Ingold, C. K.; Shaw, F. R. J. Chem. Soc. 1927, 130, 2918.
6540 J. Org. Chem., Vol. 72, No. 17, 2007