Synthesis of unstable cyclic peroxides for chemiluminescence studies

Article abstract of DOI:10.1590/S0103-50532012001100018

Cyclic four-membered ring peroxides are important high-energy intermediates in a variety of chemi and bioluminescence transformations. Specifically, a-peroxylactones (1,2-dioxetanones) have been considered as model systems for efficient firefly bioluminescence. However, the preparation of such highly unstable compounds is extremely difficult and, therefore, only few research groups have been able to study the properties of these substances. In this study, the synthesis, purification and characterization of three 1,2-dioxetanones are reported and a detailed procedure for the known synthesis of diphenoyl peroxide, another important model compound for the chemical generation of electronically excited states, is provided. For most of these peroxides, the complete spectroscopic characterization is reported here for the first time.

Full text of DOI:10.1590/S0103-50532012001100018

J. Braz. Chem. Soc., Vol. 23, No. 11, 2093-2103, 2012.
Printed in Brazil - ©2012 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Article
A
Synthesis of Unstable Cyclic Peroxides for Chemiluminescence Studies
#
Fernando H. Bartoloni, Marcelo A. de Oliveira, Felipe A. Augusto,
#
Luiz Francisco M. L. Ciscato, Erick L. Bastos and Wilhelm J. Baader*
Departamento de Química Fundamental, Instituto de Química,
Universidade de São Paulo, 05508-000 São Paulo-SP, Brazil
Peróxidos cíclicos de quatro membros são intermediários de alta energia importantes
em diversas transformações quimi e bioluminescentes. Especificamente, a-peroxilactonas
(1,2-dioxetanonas) têm sido consideradas sistemas modelo para a eficiente bioluminescência do
vaga-lume. Contudo, a preparação deste tipo de compostos altamente instáveis é extremamente
difícil e, por isso, apenas alguns poucos grupos de pesquisa puderam estudar as propriedades
dessas substâncias. Neste trabalho, a síntese, purificação e caracterização de três 1,2-dioxetanonas
são relatadas e é apresentado um procedimento detalhado para a preparação do peróxido de
difenoíla, outro importante composto-modelo para a geração química de estados eletronicamente
excitados. Para a maioria destes peróxidos, a caracterização espectroscópica completa é relatada
pela primeira vez.
Cyclic four-membered ring peroxides are important high-energy intermediates in a variety of
chemi and bioluminescence transformations. Specifically, a-peroxylactones (1,2-dioxetanones)
have been considered as model systems for efficient firefly bioluminescence. However, the
preparation of such highly unstable compounds is extremely difficult and, therefore, only few
research groups have been able to study the properties of these substances. In this study, the
synthesis, purification and characterization of three 1,2-dioxetanones are reported and a detailed
procedure for the known synthesis of diphenoyl peroxide, another important model compound for
the chemical generation of electronically excited states, is provided. For most of these peroxides,
the complete spectroscopic characterization is reported here for the first time.
Keywords: organic peroxides, diphenoyl peroxide, 1,2-dioxetanones, a-peroxylactones,
chemiluminescence
Introduction
cyclic peroxides with high energy content have been
prepared, allowing the experimental mechanistic
8,18-20
The light emission resulting from a chemical
transformation is called chemiluminescence. Most
chemiluminescent reactions have four-membered cyclic
organic peroxides as high-energy intermediates. These
compounds are fundamental for the chemical generation of
electronic excited states and are assumed to take part also
in bioluminescence reactions, such as the firefly luciferin/
luciferase system.
investigation of chemiluminescent reactions
as well as
1
the development of several applications, including the uphill
2-5
21
22
energy conversion. In 1969, Kopecky and Mumford
synthesized 3,3,4-trimethyl-1,2-dioxetane (Scheme 1,
1: R = R = R = CH , R = H), the first 1,2-dioxetane (1)
1
2
3
3
4
1
derivative, a compound formerly assumed to be too unstable
23
to be isolated. Three years later, Adam and Liu reported
the synthesis of 3-tert-butyl-1,2-dioxetanone (Scheme 1,
2: R = tert-butyl, R = H), the first 1,2-dioxetanone (2)
6
,7
Many theoretical investigations have been performed,
including recent studies, to contribute to the mechanistic
elucidation of chemiluminescent and bioluminescent
1
2
derivative, using the corresponding a-hydroperoxy
carboxylic acid as precursor. These cyclic peroxides
decompose thermally and can generate one of the two
8
-17
transformations. Furthermore, some of these unstable
1
carbonyl fragments in its electronic excited state.
However, the chemiluminescence emission efficiency of
these unimolecular processes is low (FCL < 0.01%),
because triplet-excited carbonyl compounds are formed
*
e-mail: wjbaader@iq.usp.br
1
,24,25
#
Current address: Centro de Ciências Naturais e Humanas, Universidade
Federal do ABC, 09210-170 Santo André-SP, Brazil

2
094
Synthesis of Unstable Cyclic Peroxides for Chemiluminescence Studies
J. Braz. Chem. Soc.
−
4
−1
preferentially (i.e., F < 10 E mol vs. Φ up to
relationship between their structure and the chemiexcitation
efficiency. Only the research groups of W. Adam, G. B.
S
T
−
1
26
1,26
0
.3 E mol ).
Schuster and N. J. Turro have accomplished the synthesis
of 1,2-dioxetanone derivatives; however, no other research
group has ever reported the synthesis of any of these
derivatives, indicating the extreme difficulties in working
1
with this class of compounds.
Inthiswork,thesynthesis,purificationandcharacterization
of diphenoyl peroxide (3), 3,3-dimethyl-1,2-dioxetanone (4),
spiro-adamantyl-1,2-dioxetanone (5) and spiro-cyclopentyl-
1,2-dioxetanone (6) are reported (Scheme 2). Literature
data related to the synthesis and characterization for the
known compounds 3-5 are sparse and lack experimental
details, which are provided here (including details on the
preparation and characterization of the a-hydroperoxyacid
precursors 7-9). Furthermore, the complete NMR
spectroscopic characterization of compounds 3 and 4, as
well as the synthesis and characterization of the novel
a-peroxylactone derivative 6 are described here for the
first time. These synthesized compounds have been
used for chemiluminescence emission quantum yield
Scheme 1. General structures of 1,2-dioxetane (1) and 1,2-dioxetanone (2).
Several cyclic peroxide derivatives have been prepared
22
since the pioneering works of Kopecky and Mumford and
23
Adam and Liu , and it was found that fluorescent oxidizable
1
compounds were able to catalyze the decomposition
2
4,27,28
of some of them, e.g., diphenoyl peroxide (3),
2
9-35
3
,3-dimethyl-1,2-dioxetanone (4)
(Scheme 2). These
compounds have been used as simple chemical models in
order to rationalize the efficient excited state generation
−
1
36,37
in firefly bioluminescence (Φ ca. 0.4 E mol ).
BL
38
However, Catalani and Wilson found that compound 3 is
very inefficient in generating electronically excited states
upon catalyzed decomposition, an observation confirmed
more recently by our research group. Additionally, our
group found that compound 4, a much better model for the
a-peroxylactone derivative formed in the bioluminescent
transformation of firefly luciferin, is also highly inefficient
39
determinations and detailed mechanistic studies.
39
Experimental
Materials and methods
Chemicals
39
for excited state formation upon catalyzed decomposition.
Contrarily, there are other highly efficient chemiluminescent
reactions involving cyclic peroxides, like the intramolecular
decomposition of electron-rich 1,2-dioxetanes and the
peroxyoxalate reaction, where a cyclic four-membered
Pentane(Synth),hexane(Synth)andCH Cl (Synth)were
2
2
stirred overnight over EDTA (ethylenediaminetetraacetate),
filtered and distilled, thereafter distilled again from metallic
sodium (alkanes) or P O (CH Cl ). Dimethylsulfoxide
1,40-53
ring peroxide is believed to occur as an intermediate.
In contrast to the convenient preparation of
2
5
2
2
o
(DMSO, Synth) was heated to ca. 100 C, distilled under
5
4-56
sterically-hindered 1,2-dioxetanes,
the difficult
reduced pressure from CaH (Aldrich) and stored over
2
synthesis and purification of 1,2-dioxetanones and related
cyclic peroxides still limits the investigation of the
4 Å molecular sieves, under argon. MeOH (Synth) was
refluxed and distilled (1 L) from magnesium methoxide
Scheme 2. Cyclic organic peroxides 3-6 prepared in the present study as well as the a-hydroperoxyacid precursors 7-9.

Vol. 23, No. 11, 2012
Bartoloni et al.
2095
(
prepared from 50 mL of MeOH, 5 g of magnesium and 0.5 g
GC-MS Shimadzu 14B/QP5050A with a quadrupole
analyzer. A Zebron ZB-5 (30 m × 0.25 mm × 0.25 μm)
column with split, helium as carrier gas and 70 eV as
ionization energy were used. Injector temperature was at
250 °C, oven temperature at 60 °C (0 to 1 min) increasing
of iodine). Et O (Synth orVetec) was refluxed and distilled
from H SO conc. (Merck, 100 mL per 1 L Et O) and
2
2
4
2
then refluxed and distilled from sodium/benzophenone
Acros). THF (Sigma-Aldrich) was refluxed over
sodium and distilled from sodium/benzophenone. EtOAc
Sigma-Aldrich) was kept over CaCl (Sigma-Aldrich)
(
−
1
10 °C min until 280 °C and keeping this temperature
constant for 33 min.
(
2
during 24 h, filtered, mechanically stirred with NaOH pellets
Synth, 40 g per 1 L EtOAc), filtered again and then distilled
from P O under inert atmosphere. Diisopropylamine
(
Infrared spectroscopy
Spectra were obtained on a FTIR Bomem MB100
spectrometer, operating between 4000 and 350 cm .
2
5
−1
(
Aldrich) was refluxed over CaH (Aldrich) and distilled
2
-1
under an argon atmosphere. n-BuLi (1.6 mol L ) in hexanes
Acros) was titrated with t-butanol/1,10-phenanthroline
(
Elemental analysis
5
7
prior to use. Isobutyric acid and cyclopentanecarboxylic
The CHN composition of samples was obtained in a
Perkin-Elmer CHN 2400 analyzer. Benzoic acid was used
as a standard, resulting in measurements with a standard
deviation (sd) of 0.3%.
acid were refluxed and distilled from KMnO , then
4
refluxed and distilled from P O and stored under argon.
2
5
Trimethyl phosphite (Acros) was refluxed over sodium,
decanted and distilled under argon prior to use. Methyl
iodide (Acros) was distilled and stored at 4 °C in the
dark. 9,10-Phenanthrenequinone (Sigma-Aldrich) was
recrystallized from 1,4-dioxane (mp 206-207 °C, literature
TLC at low temperature
Despite the extreme instability of 1,2-dioxetanone
derivatives, it was possible to perform TLC (thin layer
chromatography) analysis for derivatives 5 and 6 using
a special methodology; this analysis was used to follow
reaction progression. The TLC plates (Merck, 2 × 5 cm
Kieselgel 60 F254 over aluminum foil) were eluted in a
closed glass chamber, which had been previously placed
in a thermally insulated box containing small chunks of
dry ice. Using this simple procedure, it was possible to
elute samples of 5 and 6 at low temperature and detect
the peroxidic spots by development with aqueous 10%
KI solution. However, 1,2-dioxetanone 4 proved to be too
unstable to be analyzed by TLC even with this methodology.
5
8,59
206-207 °C).
N,N’-Dicyclohexylcarbodiimide (DCC,
Acros) was used as received.
UV-Vis spectrophotometry
UV-Vis spectra were obtained with a Varian Cary 50
spectrophotometer with a cell holder thermostatized at
25.0 ± 0.5 °C by a Varian Cary PCB 150 water-circulating
bath. Peroxide concentrations were determined by
−
4
−1
−1 60
iodometry (I absorption, ε = 2.55 × 10 L mol cm ),
3
353
−
1
using an absorption cuvette with 3.0 mL of a 0.05 mol L
potassium iodide solution in 0.1 mol L HOAc/OAc buffer
pH 3.8), containing 10 μL of a 1 mg mL aqueous solution
−1
−
−1
(
of HRP-VI (Sigma, hydrogen-peroxidase oxidoreductase,
EC 1.11.1.7, type VI-A, from horseradish) and 10 μL of a
diluted peroxide solution in MeOH, in order to obtain an
absorbance between 0.5 and 0.8 at 353 nm.
Synthesis of cyclic peroxides
Caution! Crystals of organic peroxides tend to explode
even with minor impacts and are extremely sensitive to
temperature increase! Careful handling is recommended
during the preparation and isolation of such compounds!
NMR spectroscopy
A Bruker AC200 (200 MHz) spectrometer was used
(
25 °C, CDCl ) to obtain the spectra of non-peroxidic
Diphenoyl peroxide (3)
3
compounds. Chemical shifts (d) are reported in parts per
million (ppm) relative to tetramethylsilane (TMS) as an
internal standard. For low temperature (< −10 °C) peroxide
characterization, NMR spectra were obtained on two
Bruker spectrometers, DPX300 (300 MHz) and DRX500
Trimethyl phosphite (0.75 mL, 6.4 mmol) was added
slowly under stirring to a pale yellow suspension of
9,10-phenanthrenequinone (1.2 g, 5.8 mmol) in 60 mL dry
toluene. After 30 min, the suspension became a slightly
orange clear solution, which was kept stirring at room
temperature for another 6 h under an argon atmosphere.
The solvent was removed at low pressure, yielding a
brownish oil, which was dissolved in 3.0 mL of dry hexane.
The mixture was cooled in an ice/water bath, affording
crystals of the desired phosphorane adduct. The solvent
(500 MHz), both equipped with low temperature probes.
Mass spectrometry
Low-resolution spectra (LR-MS) were obtained with
a gas chromatographer coupled to a mass spectrometer

2
096
Synthesis of Unstable Cyclic Peroxides for Chemiluminescence Studies
J. Braz. Chem. Soc.
was carefully removed with a pipette and the crystals dried
under an inert gas flow.
flask, equipped with septum, mechanical stirring (sealed
with vacuum grease) and a system of nitrogen flow, was
charged with 70 mL of dry THF and its temperature lowered
to < −70 °C using a liquid nitrogen/ethanol slush bath.
The solvent in this flask was saturated with dry oxygen
gas by bubbling with a needle for 10 min. The dianion
solution in the first flask was then slowly transferred to
the oxygen-saturated solution in the second flask using
a cannula, while keeping the oxygenation flask at low
temperature and under strong oxygen flow and mechanical
stirring. After the dianion addition was completed, the
mixture was left stirring for 2 h. Still under strong stirring and
with cooling, 5.0 mL of a 36% aqueous HCl solution were
added, and the mixture was left stirring for another 30 min,
allowed to warm up to −20 °C and transferred to a 500 mL
separatory funnel containing 100 mL of a cold saturated
NaCl solution. The aqueous layer was extracted with
5 × 25 mL Et O and 5 × 25 mL CH Cl , while keeping
For the ozonization, the obtained phosphorane
crystals were dissolved in dry CH Cl and transferred to
2
2
a round-bottomed flask fitted with a cannula. Using an
acetone/dry ice slush bath, the solution was cooled
to −78 °C, and ozone was gently bubbled through
the mixture for 6 h, using an Aqua Zone ozonisator
(
Red Sea Fish pHarm Ltd.) at maximum power, producing
−
1
ca. 0.1 mmol min of ozone. After this period, the solvent
was removed at low pressure and temperatures below 10 °C;
3
0 mL of MeOH were added and the mixture was cooled
to −70 °C for 40 min, allowing the crystallization of the
produced peroxide. The supernatant was removed with a
pipette under N atmosphere, 2.0 mL of CH Cl and 3.5 mL
2
2
2
of MeOH were then added, and the mixture allowed to rest
for 1 h in an ice/water bath. After complete crystallization,
the supernatant was removed carefully with a pipette and
under nitrogen flow. The solid was kept for 10 min under
high vacuum (< 1 mmHg) at 0 °C, affording 310 mg (22%)
of 3 as colorless needles, which were stored at −20 °C.
2
2
2
the temperature of the solution the lowest possible by the
addition of ice chunks. The combined organic layers were
dried with MgSO at 4 °C for 10 min, filtered at 0 °C and
4
-1
IR (KBr) ν/cm 1758, 1281, 1230, 1065, 1012, 771;
stored at −20 °C. The crude product was concentrated by
evaporation under reduced pressure, keeping the bath at
0 °C, to obtain a yellow peroxidic oil (positive peroxide
test with 10% aqueous KI solution). The oil was purified by
recrystallization at low temperature under inert atmosphere
anal. found (calc.) % for C H O C 69.45 (70.00), H 2.91
14
8
4
1
(
3.36), N 0.50 (0.00); H NMR (500 MHz, CDCl , −10 °C)
3
d 7.37 (ddd, 2H, Jorto 7.7 Hz, Jmeta 0.7 Hz, H3), 7.62 (dd,
H, Jorto 7.6 Hz, Jmeta 1.2 Hz, H2), 7.69 (ddd, 2H, Jorto 7.6
Hz, J 1.4 Hz, H4), 7.76 (dd, 2H, Jorto 7.5 Hz, Jmeta 1.1 Hz,
2
from Et O/pentane by dissolving it between 0 and −5 °C and
meta
2
1
3
H5); C NMR (125 MHz, CDCl , −10 °C) d 128.0 (C5),
crystallizing at −20 °C, obtaining colorless crystals. The
supernatant solvent was removed using a Pasteur pipette
with a special very narrow tip. The remaining traces of
solvent were removed under vacuum (< 1 mmHg) at −30 °C
to finally obtain 690 mg (46% yield) of 7.
3
1
28.3 (C3), 129.4 (C1), 130.6 (C2), 132.9 (C4), 136.0
(
C6), 171.3 (C=O).
2
-Hydroperoxy-2-methylpropanoic acid (7)
In a 250 mL vacuum-flame dried triple-necked
R = 0.2 (Hex/EtOAc 1:1), 0 (CH Cl ) and 0.3 (EtOAc);
f
2
2
-1
1
round-bottomed flask, 4.2 mL (30 mmol) of dry
diisopropylamine and 70 mL of dry THF were mixed under
inert atmosphere.An acetone/dry ice slush bath was used to
keep the temperature between −60 and −40 °C while, under
IR (CHCl ) ν/cm 3620, 3450, 1715; H NMR (500 MHz,
3
CDCl , 0 °C) d 1.51 (s, 6H, two CH ), 9.51 (bs, 2H,
3
3
13
–COOH and -OOH); C NMR (125 MHz, CDCl , 0 °C)
3
d 22.4 (–CH , C3), 83.5 (–C(CH ) , C2), 180.3 (C=O).
3
3 2
-1
vigorous stirring, 20 mL (31.5 mmol, 1.05 eq.) of 1.6 mol L
n-BuLi solution in hexanes were slowly added with a
syringe.After addition, the bath was removed, the flask was
allowed to warm up slowly to room temperature, and stirred
for additional 10 min; then the flask was cooled again to
2-Carboxy-2-hydroperoxyadamantane (8)
The overall procedure is similar to the one used
for 7. A 250 mL vacuum-flame dried triple-necked
round-bottomed flask was charged with 5.6 mL (40 mmol)
of dry diisopropylamine and 45 mL of dry THF, under a
strong argon flow. The system was then cooled with an
acetone/dry ice slush bath at −78 °C and 27 mL (42 mmol)
−78 °C and 1.2 mL (12.5 mmol) of anhydrous isobutyric
acid diluted in 5.0 mL of dry THF were added through a
syringe. The resulting mixture was allowed to reach room
temperature and then heated at 50 °C for 1 h, obtaining
a clear yellow solution, characteristic for the presence
of a dianion. The solvent and the diisopropylamine were
removed under vacuum (room temperature, 5 mm Hg) and
the obtained white solid dissolved in 60 mL of dry THF.
Additionally, a second triple-necked round-bottomed
-1
of a 1.54 mol L n-BuLi solution in hexanes were slowly
added through a syringe. The temperature was raised
to 0 °C, kept constant for 20 min, and then lowered
again to −20 °C. Using a syringe, 3.0 g (17 mmol) of
2-adamantanecarboxylic acid (see its preparation in the
Supplementary Information section) dissolved in 20 mL

Vol. 23, No. 11, 2012
Bartoloni et al.
2097
of dry THF were slowly added and the solution allowed
to reach room temperature under stirring. The solvent and
the amine were removed under vacuum (room temperature,
oxygen was bubbled vigorously in the reaction flask. After
complete reaction, 30 mL of a 10% aqueous solution of
HCl were added at −78 °C, the mixture stirred for more
30 min and the temperature allowed to rise to −20 °C. The
solution was then transferred to a 500 mL separatory funnel
containing 200 mL of a cold saturated NaCl solution and
5
mm Hg), the obtained white solid dissolved in 200 mL
of dry THF and slowly transferred during 3 h, through a
cannula, to another round-bottomed flask already charged
with 150 mL of dry THF saturated with oxygen gas and
stirred vigorously, placed in a dry ice/acetone slush bath
at −78 °C. After one additional hour of stirring at −78 °C,
the aqueous layer extracted with 5 × 50 mL Et O, keeping
2
the temperature low by adding ice chunks. The combined
organic layers were dried over MgSO at 4 °C for 10 min,
4
3
0 mL of a 10% aqueous solution of HCl were added still
filtered at 0 °C and concentrated by evaporation under
reduced pressure, keeping the bath temperature always
below 2 °C, obtaining a slightly yellow solid. This solid
was dissolved at 0 °C in pentane and allowed to crystallize
at −20 °C under an inert gas flow. The supernatant was
removed with a Pasteur pipette and the clear yellow cubic
crystals were dried under vacuum (< 1 mmHg) at −30 °C
to obtain 970 mg (53% yield) of 9.
under argon atmosphere. The temperature was allowed
to rise to −20 °C and the reaction mixture extracted with
Et O (3 × 50 mL). The combined organic layers were dried
with MgSO for 10 min at 4 °C, filtered and concentrated
under vacuum in a water/ice bath. The crude peroxidic
product was purified by column chromatography at −45 °C,
2
4
using petroleum ether (30-70 °C)/Et O 1:1 as eluent. The
peroxide 8 (710 mg, 20%) was obtained as a colorless solid.
2
1
R = 0.4 (Hex/EtOAc 1:1) and 0.0 (CH Cl ); H NMR
f
2
2
-1
R = 0.3 (petroleum ether/Et O 1:1); IR (KBr) ν/cm
(300 MHz, CDCl , −40 °C) d 1.67-1.91 (m, 4H, H3),
f
2
3
3
1
600-2300, 3429, 2932, 2861, 1691, 1454, 1296, 1274,
1.98-2.21 (m, 4H, H2), 9.51 (bs, 2H, –COOH and –OOH);
13
104, 1065; anal. found (calc.) % for C H O C 63.13
C NMR (75 MHz, CDCl , −40 °C, Figure S11) d 25.1
11
16
4
3
1
(62.25), H 7.34 (7.60),; H NMR (500 MHz, acetone-d ,
(C3), 35.3 (C2), 93.4 (C1), 180.6 (C=O).
6
−
20 °C) d 1.45-2.16 (m, 12H, adamantyl-H), 2.39 (bs,
2
1
H, adamantyl-H, H2), 11.0 (bs, 1H, –OOH), 11.2 (bs,
3,3-Dimethyl-1,2-dioxetanone (4)
1
3
H, –COOH); C NMR (125 MHz, acetone-d , −20 °C)
A 250 mL triple-necked round-bottomed flask (flask
one), equipped with septum and magnetic stirring, was
connected to a 100 mL twin-necked round-bottomed
flask (flask two) through a U-shaped glass tube in order to
perform a bulb-to-bulb distillation. To avoid the transfer
of solid particles between flasks during distillation, a bit
of glass wool was placed inside the glass tube. The whole
set-up was vacuum-flame dried and then filled with argon.
Through a syringe, 0.75 g (6.3 mmol) of 7 dissolved
in 2.0 mL of dry CH Cl was added to flask one, the
6
d 27.4, 27.7, 32.1, 32.7, 35.2 (C2), 37.7 (C2), 88.0 (C1),
1
72.9 (C=O).
1
-Carboxy-1-hydroperoxycyclopentane (9)
The overall procedure is similar to the one used
for 7. A 250 mL vacuum-flame dried triple-necked
round-bottomed flask was charged with 4.2 mL (30 mmol)
of dry diisopropylamine and 70 mL of dry THF under
a strong argon flow. The system was then cooled with
an ethanol/dry ice slush bath at −45 °C, and 20 mL
2
2
temperature was lowered to −78 °C with an acetone/dry
ice slush bath and 6.5 mL (6.5 mmol) of a 1.0 mol L DCC
-
1
-1
(
32 mmol) of 1.6 mol L n-BuLi solution in hexanes
were slowly added through a syringe. After 15 min, the
reaction mixture was allowed to reach room temperature,
left stirring for 25 min, cooled to −78 °C, and 1.4 mL
solution in CH Cl were added. After 15 min of stirring,
2
2
additional 0.5 mL of the DCC solution was added and
the solution was left stirring for another 30 min. Flask
two was placed within a liquid nitrogen bath and the
a-peroxylactone 4, together with the solvent, was vacuum
distilled (1 mmHg) from reaction flask one to flask two.
Flask one was kept at −30 °C, under strong stirring, during
the distillation, which was continued until a dry white
paste was obtained in flask one, when 1.5 mL of CH Cl
(12.5 mmol) of freshly distilled cyclopentanecarboxylic
acid dissolved in 5.0 mL of dry THF were slowly added.
After 10 min, the temperature was allowed to rise to room
temperature and the reaction mixture left stirring for more
2
h. The solvent and the amine were removed under vacuum
(room temperature, 5 mmHg) and the obtained white solid
2
2
dissolved in 60 mL of dry THF and slowly transferred,
through a cannula, to another round-bottomed flask already
charged with 100 mL of dry THF saturated with oxygen
gas and vigorously stirred, placed in a dry ice/ethanol
slush bath at −78 °C. The transfer was performed within
were added and distillation was continued. Six successive
additions of CH Cl and distillations were realized during a
2
2
2 h period. The peroxidic solution of 4, with concentration
-2
-1
of (1.7 ± 0.5) × 10 mol L (5% yield), was stored in several
portions in separate vials, kept at −80 °C.
2
h and the reaction was carried on for another 2 h, while
For the NMR analysis, the synthesis of 4 was realized

2
098
Synthesis of Unstable Cyclic Peroxides for Chemiluminescence Studies
J. Braz. Chem. Soc.
directly in CDCl . The general procedure described above
was followed, with minor modifications. In this preparation,
isolated through bulb-to-bulb distillation (< 1 mmHg).After
distillation until dryness in flask one, additional 1.5 mL
of CH Cl were added and distillation was resumed. Five
3
2
60 mg (2.2 mmol) of 7 were dissolved in 1 mL of CDCl3
2
2
(
previously treated with K CO ) and added to the reaction
cycles of CH Cl addition and distillation were performed
2 2
2
3
flask at −40 °C, followed by 450 mg (2.2 mmol) of DCC
during a 2 h period. The peroxidic solution of 6, with a
concentration of (2.4 ± 0.1) × 10 mol L (1.2% yield),
was stored in several vials kept at −80 °C.
-3
-1
dissolved in a minimal quantity of CDCl (< 1 mL). After
3
1
5 min stirring, the mixture was subjected to bulb-to-bulb
distillation as described before until all solvent was
removed from flask one. In order to obtain a maximum
For the NMR analysis, the synthesis of 6 was realized
directly in CDCl , as done for 4. The general procedure
3
concentration of 4 in CDCl solution, only one distillation
described above was followed, with minor modifications.
Addition of 290 mg (1.4 mmol) of DCC dissolved in a
3
was performed.
1
H NMR (500 MHz, CDCl , −20 °C) d 1.80 (s, 6H, two
minimal quantity of CDCl (< 1 mL) to 200 mg (1.4 mmol)
3
3
1
3
CH ); C NMR (125 MHz, CDCl , −20 °C) d 22.1 (–CH ,
of 9 at −30 °C in flask one was followed by 15 min
stirring and bulb-to-bulb distillation until dryness. Only one
distillation was performed to obtain a high concentration
3
3
3
C2), 99.0 (–C(CH ) , C1), 169.8 (C=O).
3
2
-
1
spiro-Adamantyl-1,2-dioxetanone (5)
of 6 (4.1 mmol L ) in CDCl .
3
1
A vacuum-flame dried twin-necked round-bottomed
flask was charged with 231 mg (1.09 mmol) of 8 dissolved
in 50 mL of CH Cl , while keeping the temperature at
H NMR (500 MHz, CDCl , −40 °C) d 1.89-1.94 (m,
3
4H, H3), 2.00-2.01 (m, 2H, H2), 2.12-2.15 (m, 2H, H2);
13
C NMR (125 MHz, CDCl , −40 °C) d 23.4 (C3), 38.7
2
2
3
−
40 °C using an acetone/dry ice slush bath, and 225 mg
(C2), both with low intensities. No signal at 220.6 ppm,
corresponding to the cyclopentanone carbonyl carbon, the
peroxide decomposition product, was observed.
(1.09 mmol) of DCC dissolved in 4.3 mL of CH Cl were
2
2
slowly added. The reaction mixture was strongly stirred
during 5 h at −40 °C, while being monitored byTLC analysis.
The insoluble urea derivative generated during the reaction
was removed by filtering the mixture on a column packed
with florisil (3 g) at −45 °C. The solvent was then evaporated
under reduced pressure at a temperature not higher than
Results and Discussion
Diphenoyl peroxide (3)
The first report on the synthesis of diphenoyl
peroxide (3) describes a two-step one-pot procedure
based on the preparation of the trimethylphosphite adduct
of 9,10-phenanthrenequinone followed by ozonization
−20 °C, yielding 120 mg (55%) of a slightly yellow solid.
For further purification, the product was recrystallized three
times from n-pentane between −25 °C (dissolution) and
6
1,62
−50 °C (crystallization) giving pure 8 as slightly yellow
(Scheme 3).
The first step is carried out in toluene,
cubic crystals, in a total yield of less than 10%.
followed by ozone bubbling for 30 min, and the peroxide 3
1
R = 0.7 (Hex/EtOAc 1:1); H NMR (500 MHz, CDCl ,
is recrystallized from MeOH/CH Cl 1:1.After reproducing
f
3
2
2
−
38 °C) d 1.71-1.97 (m, 10H, adamantane-H), 2.07-2.10
this method, the group concluded that its major drawback is
the presence of the starting material after recrystallization
of 3, as determined by TLC analysis.
(
m, 2H, adamantane-H), 2.61 (bs, 2H, adamantane-H,
1
3
H2); C NMR (125 MHz, CDCl , −38 °C) d 25.2, 25.3,
3
3
1
1.7, 33.0, 33.5 (C2), 35.3 (C2), 104.6 (–C-spiro-Ad, C1),
69.3 (C=O).
Consequently, it was used a slightly modified
procedure to obtain 3. It consists in the reaction of
9
,10-phenanthrenequinone and trimethylphosphite in
spiro-Cyclopentyl-1,2-dioxetanone (6)
toluene until complete consumption of the quinone (after
about 8 h, the reaction mixture becomes clear indicating
complete consumption of the quinone, insoluble in
toluene). The unstable adduct was then recrystallized from
hexane (yield not determined) and immediately submitted
to the ozonization reaction in toluene.
The overall procedure is similar to the one used for 4,
connecting two round-bottomed flasks through a U-shaped
glass tube. Flask one was charged with 413 mg (2.8 mmol)
of 9 dissolved in 3.0 mL of cold CH Cl , while keeping
62
2
2
the temperature at −30 °C with an ethanol/dry ice slush
bath, and 580 mg (2.8 mmol) of DCC, dissolved in 3.0 mL
of CH Cl , were slowly added. After 2 h, the reaction was
In a representative preparation, the ozonization product
afforded 310 mg (22%) of 3 as colorless needles, after
three recrystallizations from MeOH/CH Cl . High ozone
2
2
completed, as verified by TLC analysis at low temperature,
2
2
−
1
using CH Cl as eluent: R = 0.7 (6), 0 (9). While keeping
production rates (> 0.1 mmol min ) were needed to
increase the peroxide formation yield (> 10%) since in
low ozone concentrations the reaction between 3 and the
2
2
f
the temperature of flask one at −30 °C and flask two
immersed in liquid nitrogen, the a-peroxylactone 6 was

Vol. 23, No. 11, 2012
Bartoloni et al.
2099
Scheme 3. Preparation of diphenoyl peroxide (3), by ozonization of the 9,10-phenanthrenequinone trimethylphosphite adduct.
Scheme 4. Reaction of diphenoyl peroxide (3) with the trimethylphosphite adduct leading to diphenic anhydride and 9,10-phenanthrenequinone, occurring
at low ozone production rates.
quinone-trimethylphosphite adduct becomes significant,
leading to the starting 9,10-phenanthrenequinone and
diphenic anhydride (dibenzo[c,e]oxepine-5,7-dione) as
62
side products (Scheme 4).
Dried crystals of 3 are extremely sensitive to even
minor impacts, and must be handled with care. Herein, it is
1
13
reported for the first time the H and C NMR spectra of 3,
Scheme 5. Thermal decomposition of diphenoyl peroxide (3) leading
obtained in CDCl at −10 °C on a 500 MHz spectrometer,
to CO and 6H-benzo[c]chromen-6-one, a benzocoumarin derivative.
3
2
completing its characterization together with the IR
absorption frequencies and elemental analysis (see the
Experimental section). Until now, the characterization of 3
had been performed solely based on elemental analysis and
with aqueous EDTA solutions and EDTA-purified CH Cl
prior to use. Additionally, a-hydroperoxyacids are highly
2
2
hygroscopic, thermallyunstable andtendto undergo acidand
62
68
other indirect evidences. The carbonyl group appeared
base-catalyzed decarboxylation via Grob fragmentation.
−
1
at 1758 cm in the IR spectrum and the carbonyl carbon
The preparation of 2-hydroperoxy-2-methylpropanoic
13
65
67
at 171.3 ppm in the C NMR spectra. No evidences were
found for the presence of starting materials, diphenic
anhydride or benzocoumarin, a possible product formed
acid (7) and 2-carboxy-2-hydroperoxyadamantane (8)
had already been reported before; however, 1-carboxy- 1
hydroperoxycyclopentane (9) is a novel derivative.
27
in the thermolysis of 3 (Scheme 5).
After formation of the enolate dianion from the
corresponding carboxylic acid derivative by addition
of two equivalents of LDA at low temperature, the
diisopropylamine formed from LDA was removed in
vacuum (room temperature, 5 mmHg) together with the
solvent THF. Removal of the amine before oxygenation
is essential for the success of the preparation, to avoid
electron transfer catalyzed decomposition of the peroxide
1
,2-Dioxetanones (4-6)
1
,2-Dioxetanones 4-6 were prepared according to
6
3-67
a general literature procedure,
introducing specific
modifications for each of the derivatives (see the
Experimental section for details). The methodology consists
in cyclization of an a-hydroperoxyacid derivative (7-9) with
N,N’-dicyclohexylcarbodiimide (DCC), in which 7-9 are
obtained by a-lithiation of the corresponding carboxylic
acids, followed by low-temperature autoxidation (Scheme 6).
The preparation of the a-hydroperoxyacids is extremely
difficult as it requires low temperatures, anhydrous
conditions (in order to produce the enolate dianion) and a
reaction medium free of transition metals (to avoid redox-
induced peroxide decomposition). To avoid transition
metal contamination, all glassware was thoroughly washed
2
6,38
by the electron rich amine.
Attempts to obtain 7-9
directly using n-BuLi as base instead of LDA were not
successful. Additionally, for an efficient preparation of
a-hydroperoxyacids, it is necessary to slowly add the
enolate dianion dissolved in THF to oxygen saturated THF
o
at about –70 C, not the contrary. Oxygen bubbling into a
solution of the dianion at low temperature does not lead
to a-hydroperoxyacid formation. The a-hydroperoxyacid
derivatives can be isolated by aqueous work-up at low

2
100
Synthesis of Unstable Cyclic Peroxides for Chemiluminescence Studies
J. Braz. Chem. Soc.
Scheme 6. General procedure for the preparation of 1,2-dioxetanones by DCC-induced cyclization of a-hydroperoxyacids obtained by autoxidation of
a-lithio carboxylic acids.
temperature and fast low-temperature extraction. For
derivatives 7 and 9, the crude products were purified
by low-temperature recrystallization from diethylether/
pentane mixtures to provide colorless or yellowish crystals,
in 46 and 53% yield, respectively. However, derivative 8
proved to be stable enough for column chromatographic
purification at –45 °C and it was obtained in pure form as
colorless solid in 20% yield. Interestingly, when more than
anion onto the derivatized carboxyl carbon followed by the
liberation of N,N’-dicyclohexylurea and 1,2-dioxetanone
formation. At the low temperatures at which this reaction
takes place, the resulting urea derivative is insoluble
in CH Cl , facilitating product isolation and inhibiting
2
2
peroxide decomposition (Scheme 7).
1,2-Dioxetanone 4 was synthesized by cyclization of
7 with DCC at −78 °C and a total reaction time of 45 min,
whereas 5 was similarly prepared from 8 at −40 °C in
5 h and the derivative 6 obtained from 9 at −30 °C with a 2 h
reaction time. Reaction progress was always accompanied
by TLC analysis (see Experimental section). The isolation
of 1,2-dioxetanones must occur immediately after their
preparation, given their susceptibility to decompose in the
reaction media. Derivatives 4 and 6 were isolated together
with the solvent by vacuum (1 mmHg) bulb-to-bulb
distillation with the reaction flask at –30 °C and the
recipient flask at −78 °C, resulting in peroxidic solutions
2
00 mg of crude 8 were applied to the chromatographic
column, much lower product yields were obtained. The
a-hydroperoxyacids were characterized by their low-
1
13
temperature H and C NMR spectra as well as their
infrared spectra (except 9), which are in agreement with
the proposed structures (see the Experimental section).
The 1,2-dioxetanone derivatives 4-6 were obtained
by cyclization/dehydratation of the corresponding
a-hydroperoxyacids activated by DCC (Scheme 6). The
reaction sequence is initiated by proton transfer from the
carboxylic acid to DCC followed by nucleophilic attack of
−
1
with 17.0 and 2.4 mmol L concentration of 4 and 6,
corresponding to yields of 5 and 1.2%, respectively.
The lower peroxide concentration obtained for 6 might
be due to a somewhat lower volatility of this compound
when compared to 4. Stock solutions of these two
1,2-dioxetanones in CH Cl could be more conveniently
69
the carboxylate group onto the protonated DCC molecule.
Intramolecular proton transfer from the a-hydroperoxy
group to the DCC nitrogen atom transforms this moiety into
an excellent leaving group, allowing the cyclization reaction
by intramolecular nucleophilic addition of the peroxy
2
2
Scheme 7. Proposed mechanism for DCC-induced 1,2-dioxetanone (2) formation by dehydratation/cyclization of the corresponding a-hydroperoxyacids;
R = cyclohexyl.
3

Vol. 23, No. 11, 2012
Bartoloni et al.
2101
stored when maintained in several 1.5 mL glass vials kept
at −80 °C, which were defrosted and opened just before
Conclusion
39
use in kinetic experiments.
,2-Dioxetanone 5 could not be isolated through bulb-to-
In this study the synthesis, purification and
characterization of four cyclic organic peroxides, the
1,2-dioxetanone derivatives 4-6 and diphenoyl peroxide (3),
are reported. These peroxides are extremely unstable and it
was given herein a detailed description of the procedures
used for their synthesis and characterization, mainly by
1
bulb distillation due to its much lower volatility, therefore,
the reaction mixture was filtered over florisil at −45 °C to
remove the urea derivative and the solvent evaporated at
temperature less than −20 °C, leading to a slightly yellow
solid in 55% yield. This peroxide could be further purified
by low temperature recrystallization from n-pentane, being
obtained as slightly yellow cubic crystals (< 10% yields).
Peroxides 5 and 6 could be analyzed by TLC using
a specially developed low-temperature method (see the
Experimental section for details); however, derivative 4
proved to be too instable for analysis even using this
methodology. For the NMR analysis at low temperature,
the preparation of 4 and 6 was carried out in anhydrous
1
13
H and C NMR spectroscopy. The general preparation
procedure established for the synthesis of 1,2-dioxetanone
derivatives can be used for the synthesis of other derivatives
of this class of cyclic peroxides, which are of extreme
importance for mechanistic chemiluminescence research.
The compounds 3 to 6, whose synthesis is described
here in details, have already been used by our research
group to unequivocally demonstrate that the intermolecular
CIEEL (chemically initiated electron exchange
luminescence) decomposition of this kind of peroxides
occurs with low quantum yields, indicating that they do not
constitute adequate models for efficient bioluminescence
transformations and that better model systems have to be
CDCl (without TMS for 6) directly prior to spectra
3
acquisition, assuring the highest possible peroxide
concentration and low contamination by decomposition
1
products. The H NMR spectrum of 4 showed one
39
singlet at 1.80 ppm for the two methyl groups; after
heating the NMR tube at 25 °C for 1 h, a new strong
singlet at 2.22 ppm was observed, corresponding to the
decomposition product acetone. As expected, the two
designed, synthesized and studied in the future.
Supplementary Information
methylene groups appeared as multiplets at 2.00 and
Supplementary data for the preparation and
characterization of 2-adamantanecarboxylic acid (precursor
for 8), IR, H and C NMR spectra of compounds 3-9
(Figures S1 to S17) and pictures of critical steps in the
preparation of 1,2-dioxetanones (Figures S18 to S22) are
available free of charge at http://jbcs.sbq.org.br as a PDF file.
1
2
.12 ppm in the H NMR spectrum of 6.
1
3
1
13
The C NMR spectrum of 4 showed the expected
three signals: at 22.1 ppm for the two methyl groups, at
9.0 ppm for the saturated ring-carbon and at 169.8 ppm
9
13
for the C=O carbon. Similarly, the C NMR spectrum of
showed a signal at 104.6 ppm for the spiro carbon and
5
at 169.3 ppm for the carbonyl carbon, together with the
carbon signals corresponding to the adamantyl moiety.
The new 1,2-dioxetanone 6 could only be obtained in a
Acknowledgements
The authors thank the Fundação deAmparo à Pesquisa
do Estado de São Paulo (FAPESP, W. J. B. 2006/03420-7,
F. H. B. 2005/58320-4, L. F. M. L. C. 2012/02428-5,
E. L. B. 2007/00684-6 and 2011/23036-5), Conselho
Nacional de Desenvolvimento Científico e Tecnológico
(CNPq, E. L. B. 304887/2010-2) and Coordenadoria de
Aperfeiçoamento de Pessoal de Ensino Superior (CAPES)
for financial support.
−1
maximum concentration of 4.1 mmol L , therefore it was
not possible to observe the spiro carbon and the C=O carbon
13
in its C NMR spectrum. Unfortunately, attempts to obtain
CDCl stock solutions of 6 with higher concentrations failed.
3
The difficulties in detecting quaternary and carbonyl carbon
atoms of unstable compounds had already been observed
1
3
during the C NMR spectroscopic characterization of
7
0
peroxalic acids, even though these peroxides could be
obtained in much higher concentrations. Nonetheless, the
signal at 220.6 ppm relative to the decomposition product
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