CONTENTS
ACKNOWLEDGEMENTS
VII
SUMMARY
VIII
CHAPTER 1
INTRODUCTION
1.1
GENERAL
1
1.2
USES OF COUPLED PHENOLICS
4
1.2.1 Antioxidants
4
1.2.2 Other Uses
6
METHODS OF PREPARATION OF COUPLED PHENOLICS
6
1.3.1 General Types of Coupling Reaction Mechanisms
8
1.3
1.3.2 Chemical and Electrochemical Methods for Oxidatively
Coupling Phenolics
1.3.2.1
Chemical oxidative coupling
15
1.3.2.1.1
Vanadium(IV) and vanadium(V)
16
1.3.2.1.2
A (nitrosonaphtholato)metal complex
18
1.3.2.1.3
Activated manganese dioxide
21
1.3.2.1.4
Cupric salts
23
1.3.2.2
1.4
15
Electrochemical oxidative coupling
25
1.3.2.2.1
Direct electroche mical oxidations
25
1.3.2.2.2
Indirect electrochemical oxidations
29
OBJECTIVES AND MOTIVATION FOR THIS STUDY
32
I
CHAPTER 2
2.1
2.2
EXPERIMENTAL
MATERIALS
34
2.1.1 Reagents for Synthesis and Analysis
34
SYNTHETIC PROCEDURES
36
2.2.1 Reagents for Analysis
36
2.2.1.1
Preparation of 3,3’-di-t-butyl-4,4’-dihydroxybiphenyl
36
2.2.1.2
Preparation of 3,3’,5,5’-tetra -t-butyldiphenoquinone
36
2.2.1.3
Preparation of 3,3’,5,5’-tetra -t-butyl-4,4’dihydroxybiphenyl
2.2.1.4
Preparation of 3,3’,5,5’-tetra -t-butyl-2,2’dihydroxybiphenyl
2.2.1.5
37
Preparation of 3,3’,5,5’-tetramethyl-2,2’Dihydroxybiphenyl
38
2.2.2 Preparation of Coupling Agents
38
2.2.2.1
Preparation of silver carbonate/celite
38
2.2.2.2
Preparation of barium manganate
39
2.2.2.3
Preparation of a (nitrosonaphtholato)metal complex
(MnII(1-nnap)2)
2.2.2.4
2.2.2.5
2.3
37
39
Electrochemical preparation of cerium(IV) from
cerium(III) using a divided cell
40
Preparation of silver oxide
42
EXPERIMENTAL PROCEDURES
43
2.3.1 Oxidative Coupling Reactions
43
2.3.1.1
Oxidation of alkylphenols using silver
II
carbonate/celite
2.3.1.2
43
Oxidation of alkylphenols using copper complexes
of dicarboxylic acids
2.3.1.3
45
Oxidation of alkylphenols using manganese(III)
acetate
44
2.3.1.4
Oxidation of alkylphenols using barium manganate
44
2.3.1.5
Oxidation of alkylphenols using a (nitrosonaphtholato)metal complex
2.3.1.6
45
Oxidation of alkylphenols using FeCl3 in an organic
solvent
2.3.1.7
45
Oxidation of alkylphenols using FeCl3 without
solvent
45
2.3.1.8
Oxidation of alkylphenols using Ag2O
46
2.3.1.9
Oxidation of alkylphenols using lead tetra -acetate
46
2.3.1.10
Oxidation of alkylphenols using Ce4+
46
2.3.1.11
Oxidation of alkylphenols using potassium
ferricyanide
47
2.3.2 Determination of Ce(III) Remaining After the Electrochemical
2.4
2.5
Oxidation of Ce(III) to Ce(IV)
47
2.3.3 Dealkylation of Dihydroxybiphenyls
48
ANALYTICAL TECHNIQUES
48
2.4.1 High Performance Liquid Chromatography (HPLC)
48
2.4.2 Nuclear Magnetic Resonance (NMR) Spectroscopy
50
2.4.3 Fourier Transform Infra Red (FTIR) Spectroscopy
50
2.4.4 Gas Liquid Chromatography-Mass Spectrometry (GC -MS)
51
2.4.5 Molecular Orbital Calculations
51
TERMS AND DEFINITIONS
52
III
CHAPTER 3
3.1
3.2
DISCUSSION
MODES OF PHENOLIC COUPLING
53
3.1.1 Molecular Orbital Calculations for the Coupling of Phenol
56
THE OXIDATIVE COUPLING OF 2-t-BUTYLPHENOL
58
3.2.1 The Range of Possible Products During the Oxidative
Coupling of 2 -t-Butylphenol
60
3.2.2 Oxidative Coupling Reactions of 2-t-Butylphenol
using Various Oxidants
3.2.2.1
Vanadium(V) oxytrichloride and vanadium(IV)
tetrachloride as coupling agents
3.2.2.2
65
Silver carbonate supported on celite as coupling
Agent
3.2.2.3
63
65
Copper acetate, in the presence of a dicarboxylic acid,
as coupling agent
70
3.2.2.4
Manganese(III) acetate as coupling agent
71
3.2.2.5
Barium manganate as coupling agent
72
3.2.2.6
Ferric chloride as coupling agent
73
3.2.2.7
Silver oxide as coupling agent
74
3.2.2.8
Potassium ferric cyanide, lead tetra-acetate,
a (nitrosonaphtholato)metal complex and
cerium(IV) sulphate as oxidants
75
3.2.3 Concluding Remarks on the Oxidative Coupling of 2-tButylphenol
3.3
75
THE OXIDATIVE COUPLING OF 2,6-DI-t-BUTYLPHENOL
IV
76
3.3.1 Molecular Orbital Calculations for the Oxidative Coupling of
2,6-Di-t-Butylphenol
77
3.3.2 Oxidative Coupling Reactions of 2,6-Di-t-Butylphenol
Using Various Oxidants
81
3.3.2.1
Silver oxide as coupling agent
83
3.3.2.2
Copper(II) acetate/oxalic acid as coupling agent
87
3.3.3 Concluding Remarks on the Oxidative Coupling of 2,6-Di-tButylphenol
3.4
88
THE OXIDATIVE COUPLING OF 2,4-DI-t-BUTYLPHENOL
88
3.4.1 Molecular Orbital Calculations for the Oxidative Coupling
of 2,4-Di-t-Butylphenol
90
3.4.2 Oxidative Coupling Reactions of 2,4-Di-t-Butylphenol Using
Various Oxidants
94
3.4.2.1
Ferric chloride as coupling agent
95
3.4.2.2
Silver oxide as coupling agent
97
3.4.2.3
Potassium ferric cyanide as coupling agent
100
3.4.2.4
Cerium as coupling agent
104
3.4.2.4.1
Identification of Ce(IV) as the preferred
oxidant
3.4.2.4.2
Oxidation in MeSO3 H mediated by
Ce(IV) ions
3.4.2.4.3
104
107
Reaction mechanism for the oxidative
coupling of 2,4-di-t-butylphenol using
Ce(IV)
119
3.4.3 Concluding Remarks on the Oxidative Coupling of 2,4-Di-tButylphenol
126
V
3.5
THE OXIDATIVE COUPLING OF 2,4-DIMETHYLPHENOL
127
3.5.1 Oxidative Coupling Reactions of 2,4-Dimethylphenol Using
Various Oxidants
131
3.5.1.1
Ferric chloride as coupling agent
132
3.5.1.2
Potassium ferric cyanide as coupling agent
136
3.5.1.3
Cerium(IV) as coupling agent
138
3.5.1.3.1
Reaction mechanism for the oxidative coupling
of 2,4-dimethylphenol using Ce(IV)
138
3.5.2 Concluding Remarks on the Oxidative Coupling of 2,4Dimethylphenol
3.6
148
BUTYLATED PHENOLIC COUPLINGS: COMPARISONS
149
3.6.1 Reactions of 2-t-Butylphenol and 2,6-Di-t-Butylphenol with Ag2O
and Cu(OAc)2 /Oxalic Acid
149
3.6.2 Reactions of 2,4-Di-t-Butylphenol and 2,6 -Di-t-Butylphenol with
Ce(IV) in MeSO3H
CHAPTER 4
151
CONCLUSION AND FINAL COMMENTS
REFERENCES
159
APPENDIX
169
VI
ACKNOWLEDGEMENTS
The author wishes to express his sincere appreciation to:
•
My promoters, Dr B. Barton and Prof B. Zeelie, for their assistance and
enthusiasm for this work.
•
The NRF and Port Elizabeth Technikon for financial support.
•
My fellow students, Mteza, Nigel, Daniël, Melissa and Knowledge for their
moral support.
•
Dr S. Gouws, Dr G. Rubidge and Prof P. Loyson for their assistance.
•
The staff and students of the Department of Chemistry at the Port Elizabeth
Technikon for their assistance and moral support.
VII
SUMMARY
The oxidative coupling of 2,6-di-t-butylphenol under mild reaction conditions is well
documented and the subject of many patents. However, the coupling of other monoand di- substituted phenols is not as well documented and thus there is scope for
further investigation for providing a convenient, environmentally friendly and
economically viable method for the oxidative coupling of these phenols.
In this study, the oxidative coupling of a variety of alkylated phenolic substrates, 2-tbutylphenol, 2,6-di-t-butylphenol, 2,4 -di-t-butylphenol and 2,4-dimethylphenol, using a
range of different oxi dizing agents, were investigated by means of experimental
and/or theoretical means. The dibutylated aromatics provided the highest selectivities
to their respective coupled products, with results obtained with the dimethyl analogue
being only satisfactory, and that for 2 -t-butylphenol being totally inefficient.
PM3 Molecular orbital (MO) calculations were used to predict the possible modes of
coupling for the substrates 2,6 -di-t-butylphenol and 2,4-di-t-butylphenol, and these
results were then compared with those obtained experimentally in the laboratory.
Preliminarily, the coupling of unsubstituted phenolics was also assessed by means of
MO calculations.
Much emphasis was placed on Ce(IV) as the oxidant, and the reaction conditions
under which it was used and the results that were obtained have not been reported
before and are therefore novel. The oxidation of 2,4-di-t-butylphenol using Ce(IV) in
the presence of methanesulphonic acid was optimized to afford high yields and
selectivities to the desired ortho C-ortho C coupled product under mild reaction
conditions. Various reaction parameters were also investigated in this case, such as
varying the MeSO3 H concentration, the solvent, the reaction temperature, the reaction
time, the substrate loading, the rate of oxidant addition and the substrate to oxidant
ratio. Ce(IV) also gave a high selectivity to the para C-para C coupled product when
VIII
using 2,6-di-t-butylphenol as the substrate. However, it was not as effective with 2,4dimethylphenol, and even less so with 2-t-butylphenol.
The oxidation reactions of 2-t-butylphenol and 2,4-dimethylphenol with various
coupling agents were also investigated with the intention of obtaining high selectivities
to the respective desired coupled products. In these studies, 2-t-butylphenol afforded
a large number of products, irrespective of the oxidant used. The dimethyl analogue
was more selective, but results were not optimal. It was clear that the number of
substituents on the phenol ring, their nature and their position with regards to the
hydroxyl moiety was of great importance and made a significant impact on the
preferred coupling mode of the substrate. It was observed that steric effects also
played a major role in the outcome of these reactions:
2,6-di-t-butylphenol never
afforded any C-O coupled products whereas 2-t-butylphenol, 2,4-di-t-butylphenol and
2,4-dimethylphenol all appeared to undergo some C-O coupling.
Finally, reaction mechanisms were provided for both the K3Fe(CN)6 and Ce(IV) work,
these reacting in basic and acidic media, respectively. It was proposed that both of
these mechanisms operate through the initial formation of the phenoxyl radical.
IX
CHAPTER 1
INTRODUCTION
1.1
GENERAL
The chemical industry today is faced with major economic and environmental
challenges.
We as scientists have a responsibility towards the efficiency and
profitability of the industry. We thus have to look at developing sustainable processes
that have long -term economic and environmental viability. The chemical industry has
been continually driven by this need for better quality products and much more
effective and efficient production procedures, resulting in an industry that is currently
well established and one that continues to grow.1
From an initial slow start in the 1850’s, the chemical industry has made tremendous
strides in the field of organic synthesis, this being primarily due to enhanced
competition between the various chemical companies, leading to increased numbers
of products becoming commercially available.2 During the twentieth century, the
industry has experienced exponential growth and this has led to a major improvement
in both our living standards and life expectancy.
Phenol and other phenolics are currently some of the more versatile and important
industrial organic chemicals. Phenol itself was first isolated from coal tar by Runge.3
In 1843, C.F. Gerhardt prepared phenol by heating salicylic acid with lime; the
resulting product was given the name ‘phenol’.4
Until World War II, phenol was
essentially a coal tar extraction product, but due to an increased demand, synthetic
methods replaced extraction from natural resources. Currently, only small amounts of
phenol are obtained from coal tar (SASOL); larger quantities are being formed in
coking or by the low pressure carbonization of wood and brown coal, as well as from
oil cracking. The earlier methods of phenol synthesis via benzenesulphonic acid using
alkali fusion (Scheme 1) and via chlorobenzene (Scheme 2)5 have since been
replaced by more economically and environmentally friendly processes such as the
Hock process, which utilizes cumene as substrate.
1
SO3H
OH
1. NaOH, 300°C
2. H 3O+
Scheme 1: Preparation of phenol from benzenesulphonic acid (alkali fusion)
Cl
OH
1. aq. NaOH, 340°C, 2500 psi
2.
+
H 3O +
NaCl
Scheme 2: Preparation of phenol from chlorobenzene
The Mitsui group is the world’s second largest producer of phenol through the Hock
process. Acetone is produced as a byproduct in this process, but this is not deemed
a disadvantage of the Hock method since there is also a high demand for acetone
worldwide.
The Hock process involves the alkylation of benzene with propene to
afford isopropylbenzene (cumene); cumene is oxidized to the corresponding terthydroperoxide, which is then ultimately cleaved to yield phenol and acetone (Scheme
3).
2
OOH
OH
[O]
cumene
O
H3O+
+
acetone
cumene
hydroperoxide
Scheme 3: The Hock process for the production of phenol
Plants operating the cumene process are found in the USA, Canada, France, Italy,
Japan, Spain, Eastern Europe and Germany, with an overall capacity of 5 000 000
tons per annum.6
By noting the Japanese production output and usage of phenol and phenolic resins
(in tons) through the years 1996 to 2000, merely as an example, as contained in
Table 1.1, one can better comprehend the importance of these compounds in an
industrial capacity (Table 1.1).7
Table 1.1
Japanese production of phenol and phenolic resins (in tons)
Increase
Chemical/Year
1996
1997
1998
1999
2000
1999/2000
Phenol
768
833
851
888
916
3.2%
Phenol Resins
294
303
259
250
262
4.8%
Alkylphenols, such as xylenols, cresols, octylphenols and tert-butylphenols are
generally produced by the alkylation of phenol with methanol or the corresponding
olefins. Alkyphenols can the n be reacted further by oxidative coupling to form the
3
dihydroxybiphenyls, the focus of this investigation.
All of these products have
considerable economic importance because they are used to manufacture
thermosets, insulating foams, adhesives, laminates, impregnating resins, and serve
as raw materials for varnishes, herbicides and insecticides.
1.2
USES OF COUPLED PHENOLICS
1.2.1
Antioxidants
One of the more important uses of many phenolic materials is their ability to serve as
antioxidants. Antioxidants are merely compounds that are added to, or occur in,
various materials, both living organisms and synthetic organic materials –
antioxidants then readily react with free radicals that would otherwise damage the
materials prematurely. The free radicals are normally the result of autoxidation, a
process that occurs spontaneously all around us all the time due to the oxygen in the
air.
In human blood plasma, α-tocopherol, well known as a component of vitamin E, has
proved to be the most efficient phenol derivative to date to trap damaging phenoxyl
radicals (ROO •),8,9 caused by autoxidation, and therefore acts as an efficient
antioxidant. Uninhibited free radical peroxidation in vivo is implicated in a wide variety
of degenerate diseases such as cancer, heart disease, inflammation and even aging.
Thus, over the last two decades, there has been a tremendous increase in the
research of phenols as antioxidants.10,11
Phenols owe their efficient antioxidant activity to their ability to scavenge radicals by
hydrogen or electron transfer in processes that are much faster than radical attacks
on the substrate. The antioxidant property can be related to the readily abstractable
phenolic hydrogen as a consequence of the relatively low bond dissociation enthalpy
of the phenolic O-H group. Thus phenols and dihydroxybiphenyls are an extremely
important class of antioxidants.12,13
4
To understand the antioxidant strength of phenols and diols, we need to discuss the
reaction of molecular oxygen with organic molecules under mild conditions
(autoxidation). It may be represented by the following chemical reactions (1 – 5).
Initiation:
production of RO •
Propagation:
R•
Termination:
+
→
O2
(1)
ROO•
(2)
ROO•
+
ROO•
+
RO•
→
products
(4)
ROO•
+
PhOH
→
ROOH + PhO•
(5)
→
RH
ROOH
+
R•
(3)
While reaction 1 is very fast, having a rate constant of approximately 109 M-1s-1,
reaction 4 is much slower at 10 1 M-1s-1. Oxidative degradation can therefore occur
readily, and the use of low concentrations of antioxidants is thus important for all
living organisms and for many commercial products in order to reduce the rate of
degradation.
Both phenols and dihydroxybiphenyls behave as antioxidants because of their ability
to undergo reactions such as that shown in reaction 5, thus trapping potentially
damaging peroxyl radicals. This is a much faster reaction than the attack of the
peroxyl radicals on the organic substrate (reaction 3) due to the low bond dissociation
energies for the oxygen-hydrogen bond in the hydroxyaromatic.
The substituents on the aromatic ring have a profound effect on the ability of the
phenol/diol to donate a hydrogen atom.
Only those phenols bearing electron-
donating substituents are active as antioxidants, particularly if these are at the ortho
and/or para positions relative to the hydroxyl moiety. This is not unexpected since
electron-donating groups are expected to lower the phenolic O-H bond dissociation
enthalpy and thus increase the reaction rates with peroxyl radicals, implying a more
efficient antioxidant.
5
1.2.2
Other Uses
Dihydroxybiphenyls are used in toner resins to increase surface additive adhesion
and to optimize cohesion between the toner particles.14 It also acts as a binder resin,
thus eliminating the need for gels to be present in the toner, and enabling the
magnetic brush development system to achieve consistent, high quality copy
images.15
They are also used as inexpensive and simple starting materials for producing
polycarbonate resins,16
which are used to
reinforce
rubber
vulcanizates.17
Dihydroxybiphenyls are extensively used in coating agents,18 glass moulding 19 and
infrared-reflecting colourants,20 and they are reacted with acid catalysts to form
polymers which are used as a polymer scale deposition preventative agent.21
1.3
METHODS OF PREPARATION OF COUPLED PHENOLICS
The diversity of phenol oxidation products offers interesting synthetic possibilities for
the preparation of simple and polymeric molecules containing phenolic and/or quinoid
structural elements; these can be formed from both like and unlike radical
species.13,22 The successful synthesis of various natural products from phenols has
been well documented from the 1950’s to the present.23-28
Biogenetic oxidative coupling routes were first investigated in 1957,29,30 and the
prevalence of the overall coupling process in the biosynthesis of natural products was
authenticated. Thus the oxidative coupling step has been found to be extremely
important in the natural formation of compounds as diverse as lignins,31 lignans,32
tannins,33 plant pigments,22 and an estimated 10% of all known alkaloids.23 (Lignin is
a complex biopolymer that accounts for 20-30% of the dry weight of wood. It is
formed by the free radical polymerization of substituted phenylpropane units to yield
polymers which have a number of functional groups such as aryl ethers, phenols and
benzyl alcohols.34)
6
The major difficulty with oxidative coupling reactions of phenols is that a large variety
of potential products are possible from a single substrate when carried out in the
presence of various chemical or biological oxidants. This is because the phenolic
molecules are able to undergo both carbon-carbon (Scheme 4 shows para-para
coupling, though ortho-para coupling may also occur) and carbon-oxygen (Scheme 5)
coupling reactions.
OH
+
OH
R
HO
OH
R
R
R
Scheme 4: Carbon-carbon oxidative coupling (showing para-para coupling)
OH
R
+
OH
R
HO
O
R
R
Scheme 5: Carbon-oxygen oxidative coupling
The type of coupled product (whether C-C or C-O coupled) is also dependent on
whether the ortho or para positions bear substituents or not. In addition to these two
potential reaction products, the oxidative coupling of phenols also often allows for the
formation of polymeric materials which, in general, are undesirable (though there are
a few industrial processes where these are of great importance35,36). It has been
reported that when carbon-oxygen coupling occurs, there is a tendency for further
coupling to occur on the resultant substrate, and this leads to the formation of
polymeric products.37
7
To understand the effect that both the nature of the reactant and oxidant has on the
type of products that are formed, one must have an understanding of the various
reaction pathways that are possible, from a mechanistic point of view. A summary of
literature reports dealing with the various mechanisms is now briefly discussed.
1.3.1
General Types of Coupling Reaction Mechanisms
The reaction pathway for the oxidative coupling of phenols has been extensively
investigated.38,39 There are two main modes of coupling that may be highlighted.
These are an external and an internal oxidation process. In the former, electrons are
transferred from the phenolic compound to an external oxidizing agent, whilst the
internal oxidation process involves an internal oxidation-reduction reaction in which
one substrate molecule is oxidized whilst another is simultaneously reduced. Since
there is no change in the net overall oxidation state, this process may be termed a
“non-oxidative coupling (NOC)” reaction.
In our investigations, only the external oxidative coupling process was studied. For
this reason, literature reports dealing only with this mode are summarized here.
External oxidative coupling reactions may be grouped into two separate classes,
those involving free radical intermediates, and those that are non-radical in nature.
These may further be subdivided into several general mechanistic types.
a)
Mechanisms involving free radical intermediates
i)
Direct coupling of two phenoxyl radicals (FR1)
ii)
Homolytic aromatic substitution (FR2)
iii)
Heterolytic coupling preceded by two successive one-electron oxidation
steps (FR3)
b)
Mechanisms which are non-radical in character
i)
Heterolytic coupling preceded by a single two-electron transfer (NR1)
ii)
Concerted coupling and electron transfer (NR2)
8
It has previously been widely accepted that, in the field of phenol oxidations, the FR1
mechanism is the most viable (without discounting the FR2 mechanism).
Most
reviewers have included the FR3 mechanism in their discussions but have attached
little importance to it.
Until recently, no one has considered the NR1 and NR2
mechanisms as significant enough to warrant a discussion of them in this context.
The para-para (C-C) coupling of a simple 2,6-disubstituted phenol is used to illustrate
the five general types of processes (FR1, FR2, FR3, NR1 and NR2) as listed above.
In all cases, the oxidized phenolic species is written as the neutral phenol molecule,
and only intermediates are shown as unprotonated. The following scheme (Scheme
6) highlights the FR1, FR2 and FR3 mechanisms.
9
OH
O
R
R
O
R
R
R
-e -, -H +
pathway (a)
R
phenoxy radical
(1)
FR1
coupling of two
phenoxy radicals
+ (1)
O
FR2
R
FR3
-e-
R
O
O
R
R
R
R
H
H
H
+
R
R
+ (1)
H
-e-
-H+
H
-H+
OH
R
R
O
disproportionation
(2)
tautomerization
OH
R
R
H
OH
R
R
R
R
H
H
-2e- , -2H+
R
R
OH
(4)
OH
(3)
Scheme 6: The FR1, FR2 and FR3 free radical mechanisms
10
The degree of protonation of the phenolic species in each of these mechanisms
depends on various factors, such as the acidity of the species, the nature of the
solvent and the pH of the solution.
The free radical processes are initiated by means of pathway (a) shown in Scheme 6.
The first one-electron transfer from the disubstituted phenol (1) to an oxidant results
in the formation of the phenoxyl radical which is stabilized by resonance, as shown in
the following scheme (Scheme 7).
O
R
O
R
R
O
R
R
O
R
R
R
Scheme 7: Resonance stabilization of the phenoxyl radical
The formation of the phenoxyl radical is well attested, for example by ESR.40,41,42 (It
has been shown9 that the subsequent dimerization thereof fits a diffusion-controlled
model.)
The phenoxyl radical is able to react in one of three ways, each leading to the same
product (Scheme 6).
• Firstly, it may homolytically combine with another phenoxyl radical by mechanism
FR1 to afford compound (2).
This dicyclohexadienone rapidly tautomerizes in
protic media to the more stable aromatic biphenol product (3).
• Secondly, the phenoxyl radical may react with the initial substrate (1) via
mechanism FR2 to generate a dimeric radical. Upon loss of an electron and a
proton from this new radical, (2) is formed once again.
However, the dimeric
radical may also disproportionate, leading to a dihydro product (4) as well as to (2).
As yet, compounds such as (4), although analogous to similar products produced
11
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