Ahmed Juwad Shakir – Doctoral Thesis [618464]
Ahmed Juwad Shakir – Doctoral Thesis
List of abbreviations
Chapter 1. Free radicals ………………………….. ………………………….. ………………………….. ………………… 1
l.1. Generalities ………………………….. ………………………….. ………………………….. ………………………… 1
1.2. Classif ication of free radicals ………………………….. ………………………….. ………………………….. .. 4
1.2.1 Taking into consideration their stability ………………………….. ………………………….. ……….. 4
1.2.2 Taking into consideration the atom containing the unpaired electron ………………………. 7
1.2.3 Taking into consideration their chemical structure ………………………….. ……………………. 7
1.2.4 Taking into consideration the n umber of radicals center ………………………….. …………….. 9
1.3. Synthesis and generation of free radicals and their proprteis ………………………….. …………… 11
1.3.1 Generation of free radicals ………………………….. ………………………….. ………………………… 11
1.3.2 Synthesis of nitroxides ………………………….. ………………………….. ………………………….. ….. 13
1.3.3 Synthesis of hydrazyls ………………………….. ………………………….. ………………………….. …… 17
1.4. Applications of free radicals ………………………….. ………………………….. ………………………….. . 17
1.4.1 Free radicals as initiator in polymerization ………………………….. ………………………….. …. 17
1.4.2 Free radicals in redox reactions ………………………….. ………………………….. ………………… 21
1.4.3 Nitroxide free radicals as mediators in selective oxidation reaction ………………………… 22
1.4.3.1 TEMPO as mediator ………………………….. ………………………….. ………………………….. . 22
1.4.3.2 PINO as mediator ………………………….. ………………………….. ………………………….. .. 26
1.4.3.3 Oxidation with TEMPO and transition metals ………………………….. …………………….. 31
1.4.3.4 Oxidation with TEMPO and NOx ……………………….. Error! Bookmark not defined.
1.4.3.5 Oxidation with TEMPO and acids ………………………….. ………………………….. ………… 47
1.4.3.6 TEMPO on materials ………………………….. ………………………….. ………………………….. 56
1.4.3.7 Nitroxide free radical as catalyst for dehydrogenation of am ines ………………………. 67
1.4.3.8 Oxidation mechanism using nitroxide radicals ………………………….. ……………………. 74
1.6. References ………………………….. ………………………….. ………………………….. ……………………….. 83
Chapter 2. A comparison between nitroxide and hydr azyl radicals as catalyst in selective alcohols
oxidation ………………………….. ………………………….. ………………………….. ………………….. 93
2.1. Oxidation reactions free radicals and issues …………………….. Error! Bookmark not defined.
2.2. Free radicals characteristics and comparison ………………………….. ………………………….. …….. 94
2.3. Mechanisms ………………………….. ………………………….. ………………………….. ……………………. 106
2.4. Conclusion ………………………….. ………………………….. ………………………….. ……………………… 107
Ahmed Juwad Shakir – Doctoral Thesis
2.5. References ………………………….. ………………………….. ………………………….. ……………………… 108
Chapter 3. Stable or ganic polyradicals as oxidants ………………………….. ………………………….. ……. 109
3.1. Introduction ………………………….. ………………………….. ………………………….. ……………………. 109
3.2. Synthesis and characterization of stable organic polyradicals …………. Error! Bookmark not
defined.
3.3. Synthesis and characterization of polyradicals ………………………….. ………………………….. … 111
3.4. Mechanistic proposal ………………………….. ………………………….. ………………………….. ……….. 118
3.5. Conclusion ………………………….. ………………………….. ………………………….. ……………………… 120
3.6. References ………………………….. ………………………….. ………………………….. ……………………… 121
Chapter 4. A convenient alternative for the selective oxidation of alcohols by silica supported
TEMPO using dioxygen as the final oxidant ………………………….. ……………………….. 123
4.1. Silica supported TEMPO ………………………….. ………………………….. ………………………….. …. 123
4.2. Silica supported TEMPO for oxidation of alcohols ………………………….. ……………………… 125
4.3. Catalytic system robustness ………………………….. ………………………….. ………………………….. 129
4.4. Mechanistic proposal ………………………….. ………………………….. ………………………….. ……….. 129
4.5. Conclusion ………………………….. ………………………….. ………………………….. ……………………… 131
4.6. References ………………………….. ………………………….. ………………………….. ……………………… 132
Chapter 5. Exploring porous nanosilica -TEMPO as heterogeneous aerobic oxidation catalyst: the
influence of supported gold clusters ………………………….. ………………………….. ……….. 134
5.1. Nanosilica -TEMPO as heterogeneous catalyst ………………………….. ………………………….. … 134
5.2. Development of the catalysts (Cat. A –D) ………………………….. ………………………….. ……….. 136
5.3. Characterization of the catalysts ………………………….. ………………………….. ……………………. 137
5.4. Oxidation of alcohols to aldehyde/ketone (route I) ………………………….. ……………………….. 144
5.5. Oxidative coupling with methanol (route II and III) ………………………….. ……………………… 145
5.6. Mechanism of oxidation ………………………….. ………………………….. ………………………….. …… 147
5.7. Conclusion ………………………….. ………………………….. ………………………….. ……………………… 149
5.8. References ………………………….. ………………………….. ………………………….. ……………………… 150
Chapter. 6. Covalently grafted TEMPO on graphene oxide: A composite material for selective
oxidations of alcohols ………………………….. ………………………….. ………………………….. . 152
6.1. General ………………………….. ………………………….. ………………………….. ………………………….. 152
6.2. Synthesis and characterization of GO and iGO ………………………….. ………………………….. .. 156
6.3. GO functionalized with 4 -amino -TEMPO (GO -T and iGO -T) ………………………….. ………. 156
Ahmed Juwad Shakir – Doctoral Thesis
6.4. Oxidation of alcohols ………………………….. ………………………….. ………………………….. ………. 166
6.5. Mechanism of oxidation ………………………….. ………………………….. ………………………….. …… 169
6.6. Conclusion ………………………….. ………………………….. ………………………….. ……………………… 172
6.7. References ………………………….. ………………………….. ………………………….. …………………….. 184
Chapter 7. Experimental part ………………………….. ………………………….. ………………………….. ……… 188
7.1. Chemicals and solvents ………………………….. ………………………….. ………………………….. ……. 188
7.2. IR spectroscopy ………………………….. ………………………….. ………………………….. ………………. 188
7.3. UV -Vis spectroscopy ………………………….. ………………………….. ………………………….. ………. 188
7.4. EPR spectroscopy ………………………….. ………………………….. ………………………….. ……………. 188
7.5. NMR spectroscopy ………………………….. ………………………….. ………………………….. ………….. 188
7.6. X -ray diffraction ………………………….. ………………………….. ………………………….. ……………… 188
7.7. Raman spectroscopy ………………………….. ………………………….. ………………………….. ………… 189
7.8. Thermal measurements ………………………….. ………………………….. ………………………….. ……. 189
7.9. Cyclic voltammetry ………………………….. ………………………….. ………………………….. …………. 189
7.10. GC analysis ………………………….. ………………………….. ………………………….. ………………….. 189
7.11. Br unauere Emmette Teller (BET) method ………………………….. ………………………….. …….. 189
7.12. Barrett –Joyner –Halenda (BJH) method ………………………….. ………………………….. ………… 190
7.13. Synthesis of compounds ………………………….. ………………………….. ………………………….. …. 190
7.13.1 Synthesis of DN -DPPH ………………………….. ………………………….. ………………………….. 190
7.13.2 Synthesis of N -Nitrosodiphenylamine ………………………….. ………………………….. ………. 191
7.13.3 Synthesis of N,N -diphenylhydrazine ………………………….. ………………………….. ………… 191
7.13.4 Synthesis of picryl chloride ………………………….. ………………………….. …………………….. 191
7.13.5 Synthesis of 2,2 -diphenyl -1-picrylhydrazine ………………………….. …………………………. 192
7.13.6 Synthesis of 2,2 -dinitrophenyl -1-picrulhydrazine ………………………….. ………………….. 192
7.13.7 Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl ………………………….. …………………….. 193
7.13.8 Synthesis of PINO ………………………….. ………………………….. ………………………….. …….. 194
7.13.9 Synthesis of 4 -isocyanato -TEMPO ………………………….. ………………………….. ………….. 194
7.13.10 Synthesis of DI -T radical ………………………….. ………………………….. ……………………… 195
7.13.11 Synthesis of TRI -P radical ………………………….. ………………………….. ……………………. 195
7.13.12 Synthesis of 2,2’ -succinic acid disulphide ………………………….. ………………………….. . 196
7.13.13 Synthesis of TE -T radical ………………………….. ………………………….. …………………….. 196
Ahmed Juwad Shakir – Doctoral Thesis
7.13.14 Synthesis of TE -P radical ………………………….. ………………………….. …………………….. 197
7.13.15 Synthesis of Cat. A ………………………….. ………………………….. ………………………….. ….. 198
7.13.16 Synthesis of Cat. B ………………………….. ………………………….. ………………………….. ….. 198
7.13.17 Synthesis of Cat. C ………………………….. ………………………….. ………………………….. ….. 199
7.13.18 Synthesis of Cat. D ………………………….. ………………………….. ………………………….. ….. 200
7.14. The procedure of oxidation of alcohols ………………………….. ………………………….. …………. 200
7.14.1 General procedure for the oxidation of alcohols by TEMPO, PINO and DN -DPPH free
radicals ………………………….. ………………………….. ………………………….. …………………… 200
7.14.2 General procedure for the oxidation of alcohols by polyradicals (DI -T, TRI -P, TE -T
and TE -P) ………………………….. ………………………….. ………………………….. ………………… 200
7.14.3 General procedure for the oxidation of alcohols using nitrogen dioxide as cocatalyst
………………………….. ………………………….. ………………………….. ………………………….. …… 201
7.14.4 General procedure for the oxidation of alcohols using nitrosonium tetrafluoroborate as
cocatalyst ………………………….. ………………………….. ………………………….. ………………… 201
7.14.5 Typic al procedure for oxidation of benzylic alcohols by (Cat. A, Cat. B, Cat. C and
Cat. D) ………………………….. ………………………….. ………………………….. …………………….. 201
7.14.6 Procedure for oxidation of alcohols by GO/iGO ………………………….. …………………… 202
7.15. Synthesis methods of GO/iGO ………………………….. ………………………….. …………………….. 202
7.16. Method for functionalization of graphene oxides with TEMPO ………………………….. ……. 203
7.17. References ………………………….. ………………………….. ………………………….. ……………………. 204
General co nclusion ………………………….. ………………………….. ………………………….. ……………………. 205
Ahmed Juwad Shakir – Doctoral Thesis
List of abbreviations
ABNO Azabicyclo[3.3.1]nonane
AZADO 2-azaadamantane -N-oxyl
BAIB
BPO bis(acetoxy)iodobenzene
benzoyl peroxide
CPME Cyclopentyl methyl ether
DCE dichloroethane
DCM dichloromethane
DPPH 2,2-diphenyl -1-picrylhydrazyl
EEDQ
Kd
Kc N-ethoxycarbonyl -2-ethoxy -1,2 dihydroquinoline
dissociation rate constant
combination rate constant
MCPBA m- chloroperbenzoic acid
MeTHF 2-methyltetrahydrofuran
NHPI N-hydroxyphthalimide
NMI N-methyl imidazole
NMP Nitroxide -mediated radical polymerization
PINO Phthalimide N -oxyl
PTMA 2,2,6,6 -tetramethylpiperidinyl – oxymethacrylate
SFRP
TBN Stable Free -Radical Polymerization
tert-butyl nitrite
TCCA trichloro isocyanuric acid
TEMPO 2,2,6,6 -tetramethylpiperidin -1-yl
TEMPOH 1-hydroxy -2,2,6,6 -tetramethyl -piperidine
THF Tetrahydrofuran
TPM triphenylmethyl
Ahmed Juwad Shakir – Doctoral Thesis
Ahmed Juwad Shakir – Doctoral Thesis
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Chapter 1. Free radicals
1.1. Generalities
A free radical can be defined as any molecular species capable of independent existence
that contains an unpaired electron in an atomic orbital. It exhibits a magnetic moment [1]. Many
free radicals are h ighly reactive and unstable (usually they have a very short lifetime ). For example
hydroxyl radical (.OH) is a molecule that has one unpaired electron on the oxygen atom . In a
similar way methyl radical has the unpaired electron of the carbon atom. Carbon -centered free
radic als are very often encoun tered in organic chemistry and hold focal places in present day
organic reactivity. The structure of methyl radical is shown in Fig. 1.1.
C
H HH
Fig. 1.1. Structure of methyl radical
Free radicals have been found to play a vital role in biological processes. Scientists have
likewise involved free radicals in certain cell signaling procedures [2]. Free radicals are
encountering in industry and medicine (such as halogention reactions or in the control of blood
pressure and vascular tone) and play an important in the intermediary metabolism of various
biological compounds.
Many of the molecules that make up the structure of human tissue are susceptible to
homolysis in intense light, and th e organism uses sophisticated chemistry to protect itself from the
action of reactive radical products. Vitamin E plays an important role in the ‘taming’ of these
radicals. Abstraction of one H atom from the phenolic hydroxyl group of vitamin E (Fig. 1.2)
produces a relatively stable radi cal that does no further damage .
Free radicals play a pivotal role in many chemical or biochemical processes and also in
industrial ones. They are used as catalysts or in polymerization processes and as reporter molecules
to get dynamic, structural, or reactivity information.
Free radicals can behave both as reductants or oxidants, because they can either accept or
donate an electron from other molecules (Fig. 1.3).
Ahmed Juwad Shakir – Doctoral Thesis
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O
MeMeMe
OHRO
vitamin E
ROH +OMe
O
Me
Me
Fig. 1.2. Abstraction of one H atom from vitamin E
RRR+e_ -e_
oxidation reduction free radicalcation anion
Fig. 1.3. Oxidation and reduction of free radicals
The first discovered free radical was potassium nitrosodisulfonate (Fig. 1.4) , obtained in
1845 by Edmond Fremy [3 -7].
It is a strong oxidant , and is generally used to observe the mechanism of oxidation and
hydroxylation [8], as a standard for g -value determination in an electronic spin resonance (ESR)
technique, due to its stability and water solubility. It is also used in oxidation reactions [9,10] and
specifically in oxidation of phenol and aromatic amine [8,11].
Ahmed Juwad Shakir – Doctoral Thesis
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NO
O3SSO3K+
K+
Fig. 1.4. Fremy's salt, an inorganic nitroxide
Fremy's salt was prepared by the reaction of sulfur dioxide, sodium bicarbonate and sodium
nitrite followed by electrolysis [12], under 5 oC (Fig. 1.5).
HNO2 + 2HSO3-HON(SO3)2-2 + H2O
3 HON(SO3)2-2 + MnO4- + H+ 3 ON(SO3)2-2 + MnO2 + 2 H2O
2 ON(SO3)2-2 + 4 K+ K4[ON(SO3)2]2
Fig. 1.5. Synthesis of Fremy's salt
It is generally believed that such structu res are unstable and therefore highly reactive. The
stability of free radicals depen ds on the next reasons, d elocalization of un paired electron by
conjugation and s teric shielding of unpaired electron.
The common radical coup ling reaction, is dimerization that occurs rapidly. This is one of
the principal motifs why most organic chemists avoid radical reactions in organic synthesis.
The di stinguishing characteristic of free radicals is the presence of an unpaired electron.
Species with an unpaired electron are paramagnetic, therefore they have a nonzero electronic spin.
The most useful method for detecting and characterizing unstable radica l intermediates is electron
spin resonance (ESR) spectroscopy [13,14].
ESR spectroscopy is a highly specific tool for detecting radical species because only
molecules with unpaired electrons give an ESR spectra.
ESR spectroscopy can detect the transition of an electron between the energy levels
associated with the two possible orientations of electron spin in a magnetic field. ESR spectra have
been widely used in the study of reactions to detect free radical intermediates.
Free radicals may be detected at concentrations as little as 10−8 M with a commercially
common available device. The ESR technique of detecting short -lived free radicals in solution has
been evolved to the spin -trapping technique [15-18].
Ahmed Juwad Shakir – Doctoral Thesis
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1.2. Classification of free radicals
Free radicals can be divided in several ways, considering their stability, structure, number
of radicals center and so on.
Fig. 1.6. General ways to classify free radicals
1.2.1 Taking into consideration their stability
We can classify free radicals as unstable, persistent or stable, depending on their lifetime .
Unstable free radicals
Unstable free radicals play important roles as transient intermediates in many c hemical
reactions. For example, phenyl, hydroxyl and methyl free radicals are unstable species. Free radicals Taking into
consideration their
stability Taking into consideration
the atom containing the
unpaired electron
Taking into
consideration the
number of radicals
center Taking into
consideration their
chemical structure
Ahmed Juwad Shakir – Doctoral Thesis
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CH3 OH
Fig. 1.7. Examples of some unstable free radicals
Persistent free radicals
The theory of persistent free radicals had risen to prominence with the bold announcement
in 1900, by Moses Gomberg, of the formation of trip henylmethyl free radical [19]. Fig. 1.8 . This
was obtained by abstraction of chlorine from Ph 3CCl by Ag metal.
ClAg
+ AgCl
Fig. 1.8. Synthesis of triphenylmethyl radical
The original suggested structure of the triphenylmethyl dimer (Fig. 1.9) has been proved to
be wrong, the dimerization being in fact a p -phenyl addition. It is important to mention that are
long lived free radicals, and such radicals are known as persistent radicals (radicals that usually
have l ong lifetimes and are resistant to dimerization and disproportionation).
Ahmed Juwad Shakir – Doctoral Thesis
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wrong correct
Fig. 1.9. Proposed dimer structure s of triphenylmethyl
Stable free radicals
The stability of free radicals is caused by two reasons, steric hindrance and electronic
stabilization. The stability sometimes refers to the difference with respect to a reference
compound.
Increasing the number of donating groups on the atom bearing the unpaired electron led to
increase its stability. For example α,β -bisdiphenylene -β-phenylallyl radical (Fig. 1.10) is
indefinitely a stable solid, even in the presence of air.
Fig. 1.10. Chemical structure α,β-bisdiphenylene -β-phenylallyl free radical
Some other reported stable free radicals are shown in Fig. 1.11.
Ahmed Juwad Shakir – Doctoral Thesis
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NNNN
ON
SN
N N
N
O
Fig. 1.11. Some stable free radicals
1.2.2 Taking into consideration the atom containing the unpaired electron
In this way can divide them as C -centered free radicals, O -centered free radicals, N –
centered free radicals and so on.
Fig. 1.12. Some examples of free radicals (unpaired electron on different types of atoms )
1.2.3 Taking into consideration their chemical structure
Nitroxide, such as TEMPO (2,2,6,6 -tetramethylpiperidin -1-yl).
Hydrazyl, like DPPH (2,2-diphenyl -1-picrylhydrazyl), Fig. 1.13.
O
NHO
Ph
CH3 H3CNOO
ON
Ahmed Juwad Shakir – Doctoral Thesis
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N
ONNO2N
NO2
O2NN
O
nitroxide TEMPONN
hydrazyl DPPH
Fig. 1.13. Structure of DPPH and TEMPO free radicals
Nitroxides are N,N -disubstituted NO radicals with an unpaired electron delocalized
between the nitrogen and the oxygen atom. Nitroxide free radicals have two resonance structures
(Fig. 1.14), due to the delocaliza tion of the electron. Spin density is divided between both atoms,
often with a slightly higher density at the oxygen atom [20].
1 e – oxidationRCO
ORCO
OR + CO2
Fig. 1.14 . Resonance structures of nitroxide radicals
The overall thermodynamic stability of different nitroxide radicals is influenced by the
substituents on the ca rbons attached to the nitrogen. Thus, for example, if all four groups attached
to the carbons attached to the nitroxide nitrogen are alkyl, the nitroxide is stable. Replacing one of
the alkyl groups with hydrogen or attaching a phenyl group directly to nitrogen renders the
nitroxide relatively unstable [21]. The stability of nitroxide radicals makes it possible to carry out
reactions selectively on functional groups not involving the u npaired electron.
In 1911 Wieland and Offenbacher [22] studied some diaryl nitroxides using different
chemical means prepare d by the reaction between N -nitroso -diphenylamine and phenylmagnesium
bromide.
NO
Aryl Aryl
Fig. 1.15. Structure of diaryl
Ahmed Juwad Shakir – Doctoral Thesis
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Nowadays, X-ray diffraction studies of some rep resentative cyclic nitroxides with five-,
six- and seven -membered rings s howed the values of geometrical paramet ers for nitroxide radicals
(Fig. 1.16 and Table 1) .
NO NO
ON
N
O
Fig. 1.16. Structure of nitroxide radicals confirmed by X -ray analysis
Table 1. Geometrical parameters of cyclic nitroxides
N-O (oA) C-N-C α (o)a
5-membered ring [23-27] 1.27 112-117 0-5
6-membered ring [28 -33] 1.27-1.31 123-126 15-20
7-membered ring [34] 1.29 130 21
aOut-of-plane angle
1.2.4 Taking into consideration the number of radicals center
Monoradicals,
diradicals and
polyradicals
are classified by the number of unpaired electron s.
When we think about polyradicals we take into consideration firstly the total number of
unpaired electrons and their special paramagnetic properties. However, these are not their only
properties. We have to also emphasize their potential as probes and sens ors in many physical,
chemical, or biological processes, or in materials labeling (like nanoparticles, silica, polymers,
etc.) [35 -38]. The first perchlorotriphenylmethyl (PTM) free radicals reported were the diradical
and triradical showed in Fig. 1.17, both having high -spin ground stat es [39].
Ahmed Juwad Shakir – Doctoral Thesis
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Cl
Cl
Cl
ClCl
Cl
Cl
ClClClClCl
ClClClClClCl
Cl
ClCl Cl
Cl
ClCl
Cl
Cl
ClCl
Cl
ClClClClCl
ClClClClClCl
Cl
ClCl Cl
Cl
ClCl
Cl
ClClCl
ClCl
Cl
Cl
Fig. 1.17. Structure of PTM polyradicals
Tetraphenyl -para-xylylene (Thiel radical) was prepared by Thiel and Balhorn in 1904 as an
isolable species [40] and has bee n characterized by X -ray [41], Fig. 1.18 .
Ph
Ph PhPh
PhPh Ph
Ph
Fig. 1.18. Tetraphenyl -para -xylylene radical
Literature data showed [42] some recently synthesized polyradicals, Fig. 1.19.
Ahmed Juwad Shakir – Doctoral Thesis
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H
NH
N
ONO NHNC NOO
HNC NO
ONH H
N
ONOHNN
HNO
O
Fig. 1.19. Structure of some polyradical s bosed on TEMPO moieties
Most organic radicals have been chemically anchored on the surfaces of metals, for
example the diradical PTMSS [43,44 ]. Fig. 1.20.
SSCl
Cl
Cl ClCl
ClCl
Cl
ClCl Cl
Cl Cl
ClClClClCl
Cl Cl
ClCl
ClClCl
ClCl
ClPTMSS
Fig. 1.20. Structure of PTMSS
1.3. Synthesis and generation of free radicals and their properties
1.3.1 Generation of free radicals
There are several ways to generate free radicals, some of these using peroxides as sources
of radical intermediates (di -t-butyl peroxide, t-butyl peroxybenzoate and ben zoyl peroxide) ,
because the bond between oxygen -oxygen in per oxides is weak (30 kcal/mol) [45 ].
Ahmed Juwad Shakir – Doctoral Thesis
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OOO
OOO
C
OO
O +Half-life 10 mins at 70 oC
O
acetone
+2 2
CH3
Fig. 1.21 . Formation of methyl radicals from a peroxide
The decomposition of azocompounds is considered as another source of free radicals, and
the energy required for the decomposition is eit her thermal or photochemical [46 ].
NN
CNNCheat
C
N- N2
Fig. 1.22 . Decomposition of AIBN (azoisobutyronitrile)
Carbon -metal bond in organometallic compounds have low bond dissociation energy
(BDE) and are easily homolyzed into radicals.
Pb
CH3CH3
H3C CH3heatPb+4 CH3
Fig. 1.23 . Synthesis of methyl free radicals from tetra methyl lead
Kolbe reaction can be used as well as any other electrochemical oxidation. Fig. 1.2 4.
Ahmed Juwad Shakir – Doctoral Thesis
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1 e – oxidationRCO
ORCO
OR + CO2
Fig. 1.24 . Synthesis of free radical s by Kolbe reaction
Single electron oxidants like Fe+3, Mn+3 and Cu+2 can abstract o ne electron from activated
substrates to supply carbon -centered radicals. Fig. 1.25.
H3C CH3O O
H3C CH3OHOMn(OAc)3
AcOH H3C CH3O O
+H+
Fig. 1.25 . Synthesis of free radicals by transition method oxidation
1.3.2 Synthesis of nitroxides
The synthesis of nitroxides R 1N(•O)R 2 is carried out through different synthetic routes that
depend on the nature of the targeted R 1 and R 2 groups, for example by oxidation of amines using
dimethyldioxirane [47] (oxone ), [20] and hydrogen peroxide [48]. Hydroxylamines can be easily
oxidized to nitroxides, [49], as showed in Fig. 1.26.
NHOH
EtEtO O
EtEt
NH4OAcNN
EtEt
EtEt
HOMnO2
CHCl3NN
EtEt
EtEt
O
Fig. 1.26. Synthesis of a nitroxide radical
Nitroxide can be prepare d by react ion of nitrones with organometallic compounds, in order
to get first the corresponding hydroxylamines, which can be oxidize d to nitroxides, [50] Fig. 1.27.
N
R1O
R2
R31) R4 Metal
2) OxidationN
R1O
R2
R3R4
Fig. 1.27. Synthesis of nitroxide radicals from nitrones
Different other methods, except these most usually used approaches, were suggested for the
synthesis of nitroxides, by the reaction between tertiary nitroalkanes and sodium metal to give the
Ahmed Juwad Shakir – Doctoral Thesis
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corresponding di -tert-alkyl nitroxides [51]. Furthermore, the reaction of nitroal kanes with Grignard
reagents and organolithium compounds can also result s in nitroxides [52]. Ultimately, nitroxides
can be prepared by the reaction between C -centered radicals with nitrous and nitrogen derivatives
[53].
The development of nitroxide chemis try came from Wieland et al. and Meyer et al. [54]
who prepared diarylnitroxides. Fig. 1.28.
MgBr+N
ON
OMgBrN
O1)H3O+
2)Ag2O
N
HOMe MeO
PhCO3HOMe MeO
N
O
Fig. 1.28. Synthesis of diarylnitroxides by Wieland and by Meyer
TEMPO the most known stable nitroxide free radical (Fig. 1.13) is a commercial product, a
stable free radical discovered by Lebedev and Kazarnowskii in 1960 [55].
TEMPO is a stable radical due to the steric influence of the methyl groups. It is prepared by
oxidation of the corresponding tetramethylpiperidi ne or tetramethylpiperidine hydroxide and it is
able to abstract hydrogen atoms only from weak hydrogen bonds, including thiols, phenols, allylic
positions, and metal hydrides [29].
Tamura et al. [56] developed a new synthesis of α-asymmetric bicyclic nitroxide radicals,
by the reduction with samarium diiodide (SmI 2) of homoallylic nitroenones and the subsequent
additi on of electrophiles, Fig. 1.29.
Ahmed Juwad Shakir – Doctoral Thesis
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O
NO21) SmI2 – 50 oC
2) ArCOCl
N
OOOR1R2 R3
R1 = R3 = NO2, R2 = H
R1 = R2 = NO2, R3 = H
R1 =R3 = H, R2 = NO2
R1 = R3 = CF3, R2 = H
Fig. 1.29. Preparation of chiral nitroxides
It is worth to remember that t he first organic nitroxide was porphyrexide prepared and
named by Piloty and Schwerin in 1901. [57] and 2,2,6,6 -tetramethyl -4-piperidone -1-oxyl (4-oxo-
TEMPO) (Fig. 1.30) was prepared by Lebedev et al. [58] in 1959 , Fig. 1.30.
NNH
NHHN
ONO
O
Fig. 1.30. Structure of 4 -oxo-TEMPO and porphyrexide
TEMPO was also synthesized fifty years ago [59]. Nitroxide radicals may found
applications in many supramolecular systems such as cyclodextrins, calix[4]arenes, curcubiturils
and micelles. The first study of the interaction between nitroxides and cyclodextrins was done by
Rassat et al. [60].
Many polyradicals were also prepared, and have been used in different applications . Fig.
1.31 shows such types of polynitroxi des. Organic di – and polyradicals are used as relevant sensors
to study weak interatomic/intermolecular interactions in large systems.
Their spectroscopi c and magnetic properties [68 -71] depend on the electron spin –spin
exchange coupling between unpaired electrons .
Ahmed Juwad Shakir – Doctoral Thesis
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H
N
H
NH
N
O OO N
NO
O
O
SO2O2S
HNNH
NN
OONNHH
N
NHOO
ONNN
OOOSSNH
NH
N
OO
ONO
HNO
ONHNO
NO
N
ORO OR
OR RONONO
N
ON
ONONO
[63-65] [66]N NO ONO
N
ON N
NOMe
MeO OMeO
O
O
[67][61]NN
OO
[61]
[71]
Fig. 1.31. Structure of some nitroxide polyradicals
Ahmed Juwad Shakir – Doctoral Thesis
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1.3.3 Synthesis of hydrazyls
There is an expanding benefit in antioxidants, especially in those expected to keep the
assumed harmful impacts of free radicals in the human body, one of these free radicals are 2,2 –
diphenyl -1-picrylhydrazyl (DPPH) hydra zyle free radical was discovered in the 1920, by
Goldschmidt and Renn, as a crystalline stable powder and has been used mainly as an electron spin
resonance (ESR) s tandard, a radical scavenger in polymer chemistry, and an indicator for
antioxidant chemistry. Example of type hydrazyl [72], Fig. 1.32 .
N N
N N NO2
O2N NO2NO2
NO2 O2N
Fig. 1.32 . Structure of hydrazyle free radical
1.4. Applications of free radicals
1.4.1 Free radicals as initiator in polymerization
One of t he main hold -back in free radical chemistry is the capability of these to react with
themselves.
+R RR R
Fig. 1.33 . dimerization of free radicals
Free radicals used as initiate are in emulsion polymerization reactions for making
elastomers. In 2015, Yi Li et al. used TEMPONa and N -fluorobenzenesulfonimide (NFSI) to react
with various a lkenes [73], Fig. 1.34 . Linyi Li et al. [74] developed the aminoxylation of
hydrocarbons under mild conditions by using [(Bpy)Cu(II)/TBHP] copper(II)/tert -butyl
hydroperoxide catalyst system, Fig. 1.35 .
Ahmed Juwad Shakir – Doctoral Thesis
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NPhO2S SO2Ph
F NFAS
NaFNONa
NO
NPhO2S SO2Ph
RR-R
R-N(SO2Ph)2NO
RN(SO2Ph)2
R-
Fig. 1.34 . Radical alkene aminooxygenation
+ RHNO Cu(OAc)2/bby
(0.5 mole)
TBHP (2 eq.)
air, 60 oCNOR
NO
PhNO
CN PhNO Ph
O OPh
97% (2a, 50min)77%(2b, 4 min)98%(2c, 30 min)
NO
Ph PhNO
CO2MeNO
Ph
MeO2C
87%(2d, 50 min)
70%(2e, 3 min)54%(2f, 2 h)
Reaction conditions: aConditions: TEMPO (0.3 mmol), 1 (10 equiv.), Cu(OAc)2 (0.5 mol%), bpy
(0.5 mol%), TBHP ( aqueous 65%, 2 equiv.), air, 60 oC, 4 min- 42 h, isolated yield, bTBHP (aqueous
65%, 4 equiv.), c100 oC, d 80 oC, e100 oC 48 h, f150 oC 4h.1
2
Fig. 1.35 . The copper -catalyzed aminoxylation reaction with TEMPO
Ahmed Juwad Shakir – Doctoral Thesis
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While Xin Tao et al. [75] used TEMPO with B(C 6F5)3 as Lewis acid to abstract a hydrogen
atom from different type of subst rates, they had been found TEMPO free radical able to split
dihydroge n under ambient conditions. Fig. 1.36 .
NO
+B(C6F5)3NO(C6F5)3B
a b
+
(1 hour)HH(DD)
(10 minutes)
NOH(D)
B(C6F5)3O(C6F5)3B
(C6F5)3BH)N+
Fig. 1.36 . Reaction of the TEMPO/B(C 6F5)3 system with hydrogen sources
Controlled radical polymerizations (CRP) are of paramount importance to the field of
polymer chemistry. Their potential to get well -defined polymers with chemical functionality
makes them esse ntial. At the same time there are a large methods of CRP techniques [76 -81], but
three dominate because of t heir simplicity and functional molecular tolerance: i) reversible
addition fragmentation chain transfer polymerization (RAFT) [82], ii) atom switch radical
polymerization (ATRP) [83,84], and iii) nitroxide -mediated polymerization (NMP) [85,86].
Of those, NMP is particularly beneficial because of its inherent simplicity (needing only
monomer and unimolecular initiator) and its avoidance of sulfur and metal catalysts found inside
the RAFT and ATRP techniques.
In 1985, Solomon and Moad described nitroxides as reversible radical trapping agents for
carbon -centered radicals [87,88]. TEMPO was applied as a trapping agent for acrylate and
methacrylate monomers initiated with azobisisobutyronitrile to generate alkoxyamines adducts
(Fig. 1.37 ).
Ahmed Juwad Shakir – Doctoral Thesis
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ON R
OH3CONC
R = H,CH3
Fig. 1.37 . Alkoxyamine adduct
TEMPO was initially shown to be an efficient mediator for the homopolymerization of
styrene and the copolymerization of styrene and acrylates , in which the acrylate concentration was
50% or less on a molar basis. Attempts for the homopolymerization of acrylates and methacrylates
were uniformly unsuccessful , proceeding to about 5% conversions and producing low molecular
weight oligomers [89].
A series of nitroxides were developed that formed alkoxyamines with styren e and acrylate
monomers with relatively large dissociation rate constant values. Alkoxyamines, comprised of a
benzyl radical with the acyclic nitroxides 2,2,5 -trimethyl -4-phenyl – 3-azahexane -3-oxy (TIPNO ,
Fig. 1.38 ) have the dissociation rate constant value of 3.6 × 10−3 s−1 [90], SG1 (Fig. 1.38 ) have the
dissociation rate constant value of 3.3 × 10−4 s−1 [91].
These radicals show in Fig. 1.38 are very effective in mediating the polymerization of
acrylates and other non -styrenic monomers, specifically acrylamides, 1,3 -dienes, and acrylonitriles
[92].
NP O EtOO
OEt
SG1NO
TIPNO
Fig. 1.38 . Structure of TIPNO and SG1
Initial polymerizations of styrene performed by SFRP using TEMPO as the moderating
nitroxide were quite slow, taking over 40 hours to reach conversions of 76 % [93].
The use of DMF as an additiv e for the polymerization of t -butyl acrylate initiated by 4 -oxo-
TEMPO -capped polystyr ene macroinitiator has been shown to be effective [94].
Ahmed Juwad Shakir – Doctoral Thesis
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Studer et al. employed a combination of alkoxyamines to polymerize styrene, with one
alkoxyamine containing TEMPO (low kd) and the other containing a sterically bulky nitroxide
(higher kd, lower kc), with very good effect [89].
It was subsequently shown that polymeriza tions of styrene can proceed quickly and
efficiently using a primary initiator, such as BPO, in the absence of an additive, if the ratio of
TEMPO to BPO is varied according to the targeted molecular weight [95].
1.4.2 Free radicals in redox reactions
Nitroxides are redox compounds like and they can be reduced to the corresponding
hydroxylamines or oxidized to the oxoammonium salt in most cases the reaction s are reversible
(Fig. 1.39) .
N
O
N
OHN
O++ H++ 1e-
– 2 e– 1e-TEMPO
Hydroxylamine
TEMPOHTEMPO,
oxoammonium salt
Fig. 1.39 . Reversible redox proper ties of nitroxides (TEMPO)
TEMPO is a weaker oxidant than N-oxoammonium salt , but can react s with an
organometallic compound to form carbon – centered radicals. Reaction two equivalents from
TEMPO, one for oxidation of organometallic compound to the corresponding carbon -centered
radical and another to provide the alkoxyamine.
Ahmed Juwad Shakir – Doctoral Thesis
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For example, TEMPO reacts wit h organoboron species. Fig. 1.40 shows that the B –
alkylcatecholboran es reacts with TEMPO, which leads to the formation of boric acid ester . [30]
This reaction perhaps takes place by radical intermediate (Fig. 1.40 ). [31]
OBO
R
OBO
O
NTEMPO
R
OBOO
RNTEMPO
N
OR
Fig. 1.40 . Reaction of B -alkylcatecholboranes with TEMPO
1.4.3 Nitroxide free radicals as mediators in selective oxidation reaction
1.4.3.1 TEMPO as mediator
As mentioned before free radicals are often encountered in chemistry, therefore the study
of free radicals in organic chemistry is very important because of the features and effectiveness of
these chemicals. Many free radicals have been prepared during the previous decades. This area
was first started in 1900 by Gomberg, when he discovered triphenylmethyl [1].
Many others stable free radicals were prepared [2]. V arious kinds of stable free radicals
having one or more unpaired electrons are known, and recently, several classes of stable free
radicals were developed for applications in medicine and materials science.
In chemistry oxidation processes usually involve free radicals, the oxidation processes
require harsh experimental conditions . For examples selective oxidation of alcohols to aldehyde
and ketone required difficult conditions for the reactions, and include toxic waste.
Several oxidants are available for u se in the selective oxidation of alcohols, such as
Pyridinium Dichromate, the Jones reagent and Collins oxidation, and extensive work -up is
required to isolate the compound from these reactions.
Ahmed Juwad Shakir – Doctoral Thesis
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Nowadays, free radical TEMPO can be used as an oxidant in com bination with transition
metals such as iron and copper. TEMPO has many applications, for example, Liu, et al. [3] used
TEMPO -containing polymer brushes, which were grafted onto cross -linked polystyrene
microspheres for the selective oxidation of alcohols. Ahn, et al. [4] studied rocking disc electrode
of the TEMPO – mediated catalytic oxidation of primary alcohols and Meng. et al. [5] prepared a
silica TEMPO complex for oxidation of cinnamyl alcohol. These are just few v ery recent
examples.
In fact, the primary oxidant in such reactions is an oxoammonium salt. The classical
selective oxidation of alcohols using Anelli’s protocol contains a bypass DCM -water mixture with
TEMPO catalyst and NaOCl (sodium hypochlorite) acting as a secondary oxidant, giving high
selectivity for oxidation of primary alcohols in the presence of secondary alcohols [6 -8]. This can
be and is used in organic chemistry synthetic preparations [9 -12], see Fig. 2.1.
Fig. 2.1. Selective oxidation of primary alcohols in presence the secondary alcohols (90% yield)
In 1997, Piancatelli et al. [13] used TEMPO with BAIB ([bis(acetoxy)iodo] benzene)
acting as the secondary oxidant for the selective oxidation of primary alcohols in th e presence of
secondary alcohols.
Fig. 2.2. TEMPO -PhI(OAc) 2 used for selective primary alcohols oxidation in the presence of
secondary alcohols [14]
OOH
HO
MeMe
Me MeO
OMe
NS
Me
O OHOO
HO
MeMe
Me MeO
OMe
NS
Me
O OHH
1.5 eq TEMPO, 1.1eq NaOCl
KBr, DCM, 0.5 h, 0 Co
MeHO
Me
OTBSMeMeMeMe
OH OTBSMeO
Me
OTBSMeMeMeMe
OH OTBS0.2 eq. TEMPO, 1.5 eq. PhI(OAc)2
DCM, 1h, 25 CoH
Ahmed Juwad Shakir – Doctoral Thesis
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In literature there are many examples of TEMPO -mediated oxidations to select a primary
alcohol in the presence of secondary alcohols, which include NaBrO 2 [15], CuCl 2/O2 [16], NCS
[17,18] and trichloroisocyanuric acid [19] co -oxidants.
This year (2017), Gao, et al. [20] immobilized TEMPO on crosslinked polystyrene (CPS)
microspheres by using polymer reaction to get microspheres of the heterogeneous catalyst
TEMPO/CPS. These microspheres were used for the aerobic oxidation of 1 -phenylethanol.
TEMPO was used also for oxidation of secondary alcohols to the corresponding ketones in
excellent yields. Jiaqi Ma et al. [21] used ABNO/ tert-butyl nitrite/KPF under mild conditions
reaction for the oxidation of different kind of secondary benzylic alcohols and secondary aliphati c
alcohols to their corresponding ketones.
Golubev et al. notify in 1965 [96] that treatment of oxoammonium salt (Fig. 1.41 ) with
excess of ethanol cause d the formation of acetaldehyde. Cella et al. establish [97] that alcohols can
be oxidized to carboxylic acids by using treatment with m -chloroperbenzoic acid within the
presence of a catalytic quantity of 2,2,6,6 -tetramethylpiperidine ( Fig.1.42 ).
CH3CH2OH CH3CHO
N
OCl-
Fig. 1.41 . Oxidati on of ethanol
Fig. 1.42 . Oxidation of alcohol
OH
N
HMCBPACOOH
Ahmed Juwad Shakir – Doctoral Thesis
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The conversion of a primary alcohol to a carboxylic acid can occur in the presence of
protected phenols, protected or heteroaromatic nitrogens, and alkynes [98], as shown in Fig. 1.43.
N
OMeOHCO2H
BuOO
1. TEMPO (cat.)
NaOCl (cat.), NaClO2
2. NaOEt
N
OMeCO2NaCO2H
BuOO
85%
OH
OMeTEMPO, NaOCl, NaClO2
MeCN, phosphate buffer, pH 6.7, 45 oCCO2H
OMe
Fig. 1.43 . Oxidation of alcohol s to carboxylic acid s
In 1987, Anelli published a landmark paper [99] on TEMPO -mediated oxidations, which
signaled the beginning of the routine employment of catalytic oxoammonium salt s in the oxidation
of alcohols. In this paper, a protocol was established, whereby alcohols can be oxidized to
aldehydes and ketones in a biphasic DCM – water system, containing ca. 1% mol of a TEMPO
related stable nitroxide radical, excess of bleach (NaOCl ), KBr and NaHCO 3.
Usually, DCM is used in the biphasic system. Other organic solvents more rarely employed
include THF [100,101] and PhMe -EtOAc mixtures [102].
Under these conditions, primary alcohols are transformed in 3 min at 80 oC into the
correspondi ng aldehydes, while secondary alcohols are transformed into ketones in 7–10 min, as
shown in Fig. 1.44 .
OH O1 % mol 4-MeO-TEMPO, 1.25 eq. NaOCl
0.1 eq. KBr, NaHCO3, CH2Cl2, H2O, 0 oC
Fig. 1.44 . Anelli's protocol for the TEMPO -mediated oxidation of alcohols
Ahmed Juwad Shakir – Doctoral Thesis
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NaHCO 3 must be added in order to achieve a pH of ca. 8.6 –9.5, because commercial bleach
possesses a very basic pH (12.7) that greatly retards the reaction . TEMPO -mediated oxidations
can also be performed under almost neutral conditions. Therefore, acid – and base-sensitive
functionalities and protecting groups can remain unchanged during TEMPO -mediated oxidations .
Although TEMPO -mediated oxidations under Anelli’s protocol are routinely performed at a
slightly basic pH of 8.6 –9.8 [99] , obtained by beveling the bleach solution with NaHCO 3,
sometimes, in order to avoid base induced side reactions, it is advisable to adjust the pH at 6.5 –7.5
by adding an acid [103].
TEMPO -mediated processes [104] were also used for selective conversions of sulfides into
the corresp onding sulfoxides, Fig. 1.45 [105].
RSPhBocHN TEMPO (1.0 mol%)
NaOCl (1.2 equiv)
KBr (10 mol%)
aq NaHCO3
DCM, 0 oCRSPhBocHN
R =+O-
RSPhO-
18% 80%
10% 80%
30% 68%
Fig. 1.45 . Oxidation of sulfides to sulfoxides
1.4.3.2 PINO as mediator
N-hydroxyphthalimide (PINO , Fig. 1.46 ) is a free radical formed from N-
hydroxyphthalimide (NHPI) that can be generated by treating NHPI with the inorganic oxidant
Pb(OAc) 4 [32], or can be formed by an electrochemical procedure.
NO
OO
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 1.46 . Structure of PINO
PINO reacts as a hydrogen abstractor and generally can abstract inactivated hydrogen
atoms und er ambient conditions, Fig. 1.47 .
NO
OOHinitiation
NO
OO NO
OOH
NHPIC
HR3 R1R2
CR3 R1R2
C
OOR3 R1R2
C
OOHR3 R1R2
Fig. 1.47 . H-abstraction of PINO from hydrocarbon
The first who observed the use of PINO was Ishii et al. in 1997 [34]. The reaction took
place by reacting adamantine in a mixed solvent of acetic acid and benzonitrile under an
atmosphere of NO and in the presence of catalytic amounts of NHPI. This lead to the formation of
1-N-adamantylbenzamide a s a principal product (Fig. 1.48 ).
Ahmed Juwad Shakir – Doctoral Thesis
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PhCNNOPINO NHPINO
NCPh
H2O
NCPh
OH2-H+ NCPh
OH HNCPh
O
Fig. 1.48 . NHPI -catalyzed reaction of adamantane under NO atmosphere
PINO is used for selective oxidation of cellulose fibers promoted according to t he proposed
mechanism (Fig. 1.49 ) by the NaClO/NaBr system [106].
NO
OOH
NHPIAQ
NO
OO NO
OO
O
HOOH
OHO
O
HOO
OHO
O
HOCOOH
OHOAQAQ = 9,10-anthraquinone
Fig. 1.49 . NHPI/AQ -mediated oxidation of cellulose fibers by the NaClO/NaBr system
Nitroxide radical PINO was also used in the presence of Co(OAc) 2 in acetic acid for the
aerobic oxidation of variou s alkylbenzenes [107], Fig. 1.50 .
Using NHPI (10 mol) and Co(OAc) 2 (0.5 mol %) in CH 3CN at 70 oC for 20 h led to the
oxidation of 2 -octanol with molecular oxygen. These results are shown in Table 2.
Ahmed Juwad Shakir – Doctoral Thesis
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COOH COOHOH
OCOOH
But
COOH
MeOCOOH
Cl
COOH20h, 85% 20h, 83% 20h, 21%
20h, 37%20h, 91%
6h, 80%b20h, 67%
12h, 93%
aSubstrates (3mmol), NHPI (10 mol %) and Co(OAc)2 (0.5 mmol %) in
AcOH (5mL) under dioxygen (1 atm) at 25 oC. bCH3CN was used as the
solvent
Fig. 1.50 . Aerobic oxidation of various alkylbenzenes at room temperaturea
Table 2 . Oxidation of 2 -octanol to 2 -octanone with molecular oxygen catalyzed by NHPIa
Entry Solvent Additiveb Temp. C Time (h) Yield %c
1d CH 3CN – 70 20 9
2 CH 3CN – 70 20 93
3 ACOEt – 70 12 84
4 ACOEt MCBA 70 3 90
5 ACOEt MCBA 25 20 75
6 ACOEt – 25 20 21
7e ACOEt MCBA 25 20 60
a2-Octanol (3 mmol), molecular oxygen (1 atm), NHPI (10 mol %), Co(OAc) 2 (0.5 mol %), additive (5
mol %) in solvent (5 mL). bMCBA = m -chlorobenzoic acid, BA = benzoic acid, PMBA = p –
methoxybenzoic acid, PNBA = p -nitrobenzoic acid. cGC yield. dWithout Co(OAc) 2. eMCBA (1 mol %)
Ahmed Juwad Shakir – Doctoral Thesis
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In the same ways PINO was used as catalyst for aerobic oxidation of alcohols of benzylic
derivatives (Table 3 ).
Table 3. NHPI -Catalyzed aerobic axidation of benzylic derivatives
Entry Substrate Product Yield %
1
O
80
2
O
15
3
O
73
4
OH 30
5
O
37
6
O
42
7
O
OO
83
Substrate (2 mmol) was reacted in the presence of NHPI (10 mol % ) in PhCN (5 mL) under dioxygen
atmosphere at 100 oC for 20 h. GLC yields.
Ahmed Juwad Shakir – Doctoral Thesis
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In latest years, NHPI has been identified as an efficient catalyst for aerobic oxidation of
diverse organic substrates with co -catalysts [32].
A group of substituted N -hydroxyphthalimides (NHPI) were used as catalyst for aerobic
oxidation of alcohols of cumene [33]. Hu, et al. [34] used NHPI and t-butyl nitrite (TBN) with
oxygen as the thermal oxidant for oxidation of a different kind of aliphatic, aromatic, allylic, and
heterocyclic alcohols, see Fig. 2.5.
OH
R1 R2NHPI (5 mole%)
TBN (10 mole%)
DCM, O2- balloonOH
R1 R2
O
80%O
92%O
87%O
H3CO
99%
O
OCH3
95%O
Cl
94%O
Br
83%O
NO2
78%
Reaction conditions: 2 mmol of alcohol, 2 mL of
CH3CN, O2
(balloon, 1 atm), 80 oC, 3h.O
1.5h, 97%NO
OOH
NHPI
Fig. 2.5. Result of NHPI/TBN catalyzed oxidation of primary and secondary alcohols to ketones
Ahmed Juwad Shakir – Doctoral Thesis
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1.4.3.3 Hydr azyl as me diator
Very recently, some systems as DPPH -luminol chemiluminescence (CL) has been reported in
(2016) along with an attempt to discuss CL mechanism. This has been done according to the
properties of CL kinetic after a sequence of injecting DPPH. The observation that we could realize
is that the CL response of DPPH -luminos system could be inhibited by scutellarin [22].
DPPH has been proved to be quite useful in a variety of investigations, such as polymerization
inhibition or radical chemistry [23].
Literature data demonstrated the us efulness of DPPH and its derivatives in studying inter
phasic processes assisted by transport agents such as crown ethers (CEs) or kryptands [24]. The
species formed by these agents are supramolecular complexes and behave as stoichiometric
compounds [25 -27]. DPPH also was used for oxidation of amino acids [28].
However, up to date, there is a single paper containing data about involving stable hydrazyl
free radicals as catalyst in oxidation reactions [29,30], in the presence of WO 3/Al 2O3 as a
cocatalyst, un der moderate conditions and oxygen used as the terminal oxidant see Fig. 2.4.
authors applied a wide range of substrate bearing different functional groups and the reaction
method works under neutral conditions (acid, base not required) [31].
The approach is amenable to gram scale and not require precautions giving a green and
environmentally benign approach for the synthesis of aldehydes and ketones.
NNO2N
NO2
O2NO2N
O2N
Fig. 2.3. Structure of DN -DPPH free radical
Ahmed Juwad Shakir – Doctoral Thesis
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O
10h, 83%O
OCH3CHO
OCH3
CHOCHO
OCH3 O
SCHOCHO
3h, 73%3h, 74% 3h, 78%
4h, 73%4h, 69%O
2h, 88%O
12h, 81%O
CH2CH2CH3
12h, 95%
O
12h, 82%CHO
OCH3
3h, 74%10h, 93%
CHO
3h, 74%CHO
4h, 83%
O
12h, 94%O
6h, 96%OH DPPH
WO3/Al2O3O
Reaction conditions: alcohol (50 mmol), DPPH(0.25 mmol), WO3/Al2O3(W: 3 mmol) in solvent (30 mL), 80
°C. Determined by GC analysis using a normalization method.NN NO2O2N
O2N
DPPH
Fig. 2.4. Oxidation of alcohols by DPPH radical in the presence of WO 3
Ahmed Juwad Shakir – Doctoral Thesis
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1.4.3.4 Oxidation with TEMPO and transition metals
The oxidation of secondary amines that contain no α hydrogen atoms, such as 2,2,6,6 –
tetramethylpiperidine, leads to the formation of nitroxides, stable free radical compounds such as
the prototypical 2,2,6,6 – tetram ethylpiperidine -1-oxyl (TEMPO). TEMPO is stable organic radical,
which exhibits high efficiency, low toxicity, can be easily recycled after use in liquid phase
oxidation reactions and can also be stored for long periods of time without decomposition.
The first reported use of a copper/nitroxide radical was in 1966, when Brackman and
Gaasbeek showed the use of di -tert-butylnitroxide for the oxidation of methanol with
phenanthroline/copper(II) complexes in basic methanol solutions [108].
The selective oxidation of alcohols is an important reaction in organic chemistry. Many
oxidation methods towards alcohols have been repor ted in literature using at least a stoichiometric
amount of oxidants such as DMSO, MnO 2, chromium oxides also hypervalent iodine compounds .
TEMPO has been used in catalytic oxidation reactions of primary and secondary alcohols
[109] . From the history of t he development of aerobic oxidation of alcohols, the first catalytic
aerobic oxidation of alcohols using TEMPO with CuCl in DMF was in 1984, discovered by
Semmelhack et al. [110].
Copper/TEMPO lactonization of polyols in the synthesis of more complex mole cules has
been reported . Nonappa and Maitra prepared the steroidal lactone by using Cu/TEMPO in the
presence of several unprotected sec ondary alcohols [111], Fig. 1.51 .
OHOHOH
OHOH
OHOHOH
O
O0.4 equiv
CuCl/TEMPO
DMF, O2
78%
Fig. 1.51 . Cu/TEMPO -catalyzed aerobic lactonization
Ahmed Juwad Shakir – Doctoral Thesis
35
Jinxian Liu and Shengming Ma [112] studied the aerobic oxidation of 1 -phenyl -butyl -3-yl-
1-ol (Fig. 1. 52) using TEMPO as a catalyst . By using only 10 mol %from TEMPO,
Fe(NO 3)3.9H 2O and NaCl under atmospheric pressure of molecular oxygen to form corres ponding
homopropargylic ketone at room temperature. For an optimization of the reaction based on the
solvent effect, see Table 4.
Ph
OHPh
O10 mol% Fe(NO3)3. 9H2O
10 mol % TEMPO
10 mol % NaCl
DCE, O2, (balloon), rt, 4 h
Fig. 1.52 . Oxidation of a propargyl alcohol
Table 4. Optimization of the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol
Table 4 shows that by u sing DCE as a solvent, the highest yield (Table 4, entry 1) are
achieved, while by using 5 mol % from TEMPO, Fe(NO 3)3.9H 2O and NaCl only 76% was
observed (Table 4, entry 5).
When using Cu(NO 3)2 3H2O instead of Fe(NO 3)3.9H 2O, the result was lower (Table 4,
entry 6). The results obtained in the same condition react ion for aerobic oxidation of many other
homopropargylic alcohols are shown in Fig. 1.53 .
This experiential that t he selective oxidation of alcohols to the corresponding carbonyl
compounds is among the most important functional group transformations in organic synthesis on
laboratories as well as on an industrial scale [113]. Entry Time (h) Solvent Yield %
1 4 DCE 91
2 20 Toluene 89
3 20 Ethyl acetate 52
4 20 THF 25
5a 20 DCE 76
6b 20 DCE 52
Ahmed Juwad Shakir – Doctoral Thesis
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O O
O
OO
OO
OO
O
O
OBr
OOCl
OS
OOO
nC9H19
O4h, 87% 5h, 91% 24h, 51%
5h, 81% 6h, 89% 7h, 80%
24h, 77%
7.5h, 85%24h, 83%
3h, 91%
5h, 81%48h, 39%
48h, 51%OO
5h, 81%substrate 1 mmol, 10
mol% each of
Fe(NO3)3 9H2O,
TEMPO, NaCl in
DCM (4 ml)R
OH1) 10 mol% Fe(NO3)3 9H2O
10 mol% TEMPO
10 mol% NaCl
DCE, O2, rt
2) cromatographic workup
on silica gelR
O
Fig. 1.53 . Aerobic oxidation of the homopropargylic alcohol
Luke Rogan, et al. [114] used a Cu(I)/9 -azabicyclo[3.3.1]nonan -3-one N -oxyl (ketoABNO
Fig. 1.54 ) as the aerobic catalytic system for the oxidation of alcohols. The catalyst system that
consists of TEMPO, N -methylimidazole (NMI) and Cu(I) salt combined with 2,2′ -bipyridine ( bpy)
as a ligand, is highly effective for the oxidati on of secondary alcohols even containing unactivated
aliphatic substrates; moreover it can oxidize a variety of alcohols possessing heteroatoms, alkynes,
alkenes.
Ahmed Juwad Shakir – Doctoral Thesis
37
The drawback of this system is that it is not working well suitable for the oxidation of
secondary alcohols due to steri c hindrance, therefore the authors have replaced TEMPO with a
radical that is les s sterically hindered. Fig. 1.54 shows the structure s of several nitroxide radicals
(ketoABNO should remove this limitation ).
N
ON
ON
ON
ON
ON
OO
TEMPO AZADO 1-Me-AZADO Nor-AZADO ABNO ketoABNO
Fig. 1.54 . Structures of several nitroxide radicals used in aerobic oxidation of alcohols
The reactivity of TEMPO, 4 -oxoTEMPO and ketoABNO for three sample substrates (1 –
phenyleth anol, 2 -octanol and isoborneol Fig. 1.55, is shown in Fig. 1.56) . In this reaction the
conditions used were 1% mol of radical, 10.5% N -methylimidazole and 7.5% CuI and 2,2 ′-
bipyridine.
OHOHOH
Fig. 1.55 . Secondary alc ohols used as sample substrates
Fig. 1.56 . Comparison of 4-oxoTEMPO, TEMPO and ketoABNO for the
oxidation of some secondary alcohols, nitroxyl radical [114]
Ahmed Juwad Shakir – Doctoral Thesis
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The radicals 4 -oxo-TEMPO and TEMPO cannot oxidase two secondary alcohols 2 -octanol
and isoborneol, but oxidase only 1-phenylethanol. KetoABNO can oxidase all three alcohols
(isoborneol, 2 -octanol, 1 -phenylethanol) under the same reaction conditions.
When comparing the nitroxide radicals 4 -oxoTEMPO, TEMPO, 4 -methoxyTEMPO,
against ketoABNO [115 ] the same result was obtai ned. This established that all unhindered
radicals have the same reactivity under these conditions.
Nitroxide radicals are mostly used today for the oxidation reaction of alcoh ols in organic
chemistry [116]. For this purpose TEMPO , ABNO and AZADO were used as a catalyst with
stoichiometric oxidants like bleach, tert-butyl hypochlorite, BAIB (bis (acetoxy)iodobenzene)
[117], Fig. 1.57 . Yoshiharu I. et al. [118] used also AZAD O type nitroxide as catalysts for the
aerobic oxidation of alcohols.
The synthesized three new catalysts [118], Fig. 1.57 , Oxa-AZADO was prepared in f ive
steps, as shown in Fig. 1.58 [119].
NO
ONTsN
ONN
OO
Oxa-AZADO (6) TsN-AZADO (7) diAZADO (8)
Fig. 1.57 . Structures of AZADO derivatives
COOH HOOCO
acetonedicarboxylic acid1. glutaraldehyde
28% NH3 aq., H2O
rt, 24 h
2. TsCl, Na2CO3
DCM-H2O (1:1)
36% for 2 stepsNTsOLiAlH4
THF
3 h
71%NTsHO
NTsOhv
PhI(OAc)2, I2
cyclohexane
0 oC, 1 h
70% 1. red Al
toluene, reflux, 1.5h
2. UHP, Na2WO4.H2O
MeCN, 2 h
50% for 2 stepsNO
O
Fig. 1.58 . Synthesis of oxa -AZADO
Ahmed Juwad Shakir – Doctoral Thesis
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TsN-AZADO and diAZADO were synthesized using modified Hofmann −Löffler−Freytag
reaction conditions, Fig. 1.59 .
NTsONH2OH.HCl
pyridine
EtOH,60 oC
10 h, 98%NTsHON
NaBH4, MoO3
TsCl
MeOH, 0 oC
2 h, 81%NTsTsHN
hv, I2
PhI(OAc)2
1,2-dichloroethane
0 oC, 3 min.
63%
NTsTsN1. red Al
toluene, reflux, 1h
2. UHP, Na2WO4.H2O
MeCN, 5.5 hN
ONO
diAZADO (8)
10 %NTsN
O
N-Ts-AZADO (7)
16%
Fig. 1.59 . Syntheses of TsN -AZADO and diAZADO
For diAZADO there is a more efficient procedure for t he synthesis, shown in Fig. 1.60 .
NTsTsN1. red Al
toluene, reflux, 18 h
2. UHP, Na2WO4.2H2O
MeCN, 3 h
44% for 2 stepsNN
OO
Fig. 1.60 . Procedure for the synthesis of diAZADO
The synthesis of 5 -MeO -AZADO and 5,7 -diMeO -AZADO [120] are shown in Fig. 1.61 .
Ahmed Juwad Shakir – Doctoral Thesis
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NTFARuCl3.nH2O
CCl4-MeCN-H2O
2:3:3
70 oC, 41 hNTFAHO +
NTFAHOOH
31% 28%
NTFAHONaH
Me2SO4
THF
rt, 5 hNTFAMeO1. 10% aq. NaOH
EtOH, rt, 2.5 h
2. UHP, Na2WO2.H2O
MeCN, rt, 4 h
59% for 3 stepsNMeO
O
5-MeO-AZADO (4)
NTFAHONaH
Me2SO4
THF
rt, 5 h
81%NTFAMeOOMe 1. 10% aq. NaOH
EtOH, rt, 1 h
2. UHP, Na2WO2.H2O
MeCN, rt, 5 h
67% for 2 stepsNMeO
OOMe
5,7-DiMeO-AZADO (5)
Fig. 1.61. Synthesis of 5 -MeO -AZADO (4) and 5,7 -diMeO -AZADO (5)
1.4.3.5 Oxidation with TEMPO and NO x
A recent approach in alcohol oxidation is the employment of nitrogen dioxide as TEMPO
activator this is easily obtained from sodium nitrate or other nitrites.
For example , Fig. 1.63 , shows the comparison of the temporal profiles of 5-F-AZADO,
AZADO, 5,7-diF-AZADO and TEMPO as reference [117] by using 1 -menthol as the substrate
under new reaction condition s (10 mol % NaNO 2, 1 mol % nitroxy radical and AcOH solvent
under air balloon) [121].
OHnitroxyl radical (1 mol %)
NaNO2 (10 mol %)
AcOH(1 M), air ballon, rtO
Fig. 1.62 . Oxidation of 1 -menthol
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 1.63 . Temporal profiles of AZADO (1), 5 -F-AZADO (2), 5,7- diF-AZADO (3), and TEMPO,
conversion of l-menthol [118]
Under the same reaction conditions, the temporal profiles of 5 -MeO -AZADO and 5,7 –
diMeO -AZADO [118] were also investigated. In Fig. 1.64 , 5-MeO -AZADO can complete the
reaction within 10 h without any marked slowdown, meaning that the inductive effect of the
heteroatoms plays an important role in preventing a marked slowdown of the reaction.
Fig. 1.64 . Temp oral profiles of AZADO, 5 -MeO -AZADO , and 5,7-diMeO -AZADO [118]
The temporal profiles of oxa -AZADO, TsN -AZADO and diAZADO are shown in Fig.
1.65, and these catalysts have a wide range of substrate applicability (Table 5).
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 1.65 . Temporal profiles of oxa -AZADO, TsN -AZADO, and diAZADO for the oxidation of l –
menthol [118]
Table 5. Scope of oxa -AZADO, TsN -AZADO and diAZADO for oxidation alcoholsa
Entry Alcohols 5-F-AZADO Oxa-AZADO TsN-AZADO DiAZADO
1
MeOOH
96% / 3h 93%/ 3h 86%/ 2h 100%/ 2h
2
OH
85%/ 9h 80% / 8h 80% / 6.5h 83% / 8.25h
3
Ph
OH
96% / 6h 98% / 6.5h 93% / 4.5h 93% / 7.5h
4
PhOH
95% / 7h 93% / 7.5h 97% / 6.5h 100% / 8h
5
n-C5H11OH
86% / 10hb 86% / 8hb 91% / 7hb 94% / 6hb
6
PhOH 72% / 5h 70% / 8h 67% / 6h 80% / 5h
Ahmed Juwad Shakir – Doctoral Thesis
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7
PhOH 93% / 3hb 95% / 1.5hb 90% /2.5 hb 100% / 1.5hb
8
OBz
OH
96% / 6.5h 95% / 5.5h 88% / 4h 92% / 4.5h
9
OH
CHbzN
86% / 6hc 96% / 2.5hb,c 98% / 2.5hb,c 92% / 4hc
10
O
OHO
OO
O
98% / 2h 95% / 1.5h 94% / 1.5h 92% / 1.5h
11
O
O
OTBSO
97% / 2h 90% / 2.5h 85% / 2h 98% / 2.5h
a nitroxyl radical (1 mol%), NaNO 2 (10 mol%), AcOH (1 M) and air ballon at rt. bnitroxy l radical (3 mol),
cAcOH (0.4 M), dnitroxyl radical (5 mol%), eAcOH (2 equiv), MeCN (1 M)
Martin Holan and Ullrich Jahn [122] reported that using tert-butyl nitrite (TBN) and
TEMPO or AZADO in the presence of BF 3·OEt 2 or LiBF 4, they achieved the oxidation of different
types of alcohols.
Fig. 1.66 . Oxidation of benzylic alcohol using TEMPO as catalyst
Table 6. Results obtained using TEMPOa
Entry Solvent Temp Time(h) TEMPO mol% Yield %
1 Et2O Rt 5 10 30
2 DCM Rt 4 10 94
3 DCM Reflux 0.75 10 95
Ahmed Juwad Shakir – Doctoral Thesis
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4 DCM Reflux 1.5 5 97
5 DCM Reflux 5 1 82
aalcohol (2 mmol), BF 3·OEt 2 (1.35 times the amount of TEMPO), solvent (10 m ol), TBN (4 mmol)
Several transition -metal -free aerobic oxidation processes have used the same versions of
the supported catalysts, [123] TEMPO/nitrite -based systems [124] and TEMPO/Br 2/NaNO 2 [125] .
R1R2OH
R1R2OTEMPO (5 mol%)
BF3OEt(6.75 mol%)
t-BuONO (3 equiv)
DCM, reflux
O
Ph
O2NO
MeOO
NCOPhO
O5h, 80%
4h, 87% 4h, 99%
3h, 87%3h, 88%
3h, 60%aalcohol (2 mmol),
BF3·OEt2 (6.75 mol %),
DCM (10 ml), TEMPO (5
mol %), TBN (6 mmol).
bLiBF4 (5 mol %), TBN (3
mmol), TEMPO (5 mol %),
alcohol (1 mmol), DCM
(5 ml)
Fig. 1.67 . Oxidation of aromatic and allylic alcoholsa
OH OTEMPO
BF3OEt2
t-BuONO (3 equiv)
DCM, reflux
Fig. 1.68 . Oxidation of dodecan -1-ol
Ahmed Juwad Shakir – Doctoral Thesis
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Table 7. Oxidation of dodecan -1-oa
Entry BF 4− source (mol %) Time TEMPO (mol %) Yield %
1 BF3·OEt 2 (6.75) 3 5 50
2 BF3·OEt 2 (6.75) 5.5 5 + 5 98
3 BF3·OEt 2 (5) 5 5 + 5 92
4 BF3·OEt 2 (5) 5 5 88
5 LiBF 4 (5) 5 5 92
aDCM (5 ml), TBN (3 mmol), alcohol (1 mmol)
R1R2OHTEMPO(5+5mol)
BF3OEt2(5mol%)
t-BuONO (3 equiv)
DCM, refluxO
R1R2
O
10Ph OPh OO
3O
5TESO
OO
OO TBDPSO
NO
BocPh O
NHBocPh O
BocNNO5.5h, 83% 9h, 87%b9h, 88%b7h, 69% 8h, 73%c
3h, 99% 9h, 75%14h, 95%d9h, 98%
12h, 40% 12h, 27%24h, 47%
a1-4,5-12 (2 mmol), DCM (10 mL), BF3·OEt2 (5mol %), TBN (6 mmol),
TEMPO (5 + 5 mol %), reflux. bTBN (8 mmol) used. cDCM (5 mL), LiBF4 (5
mol %), TBN (3 mmol), TEMPO (5 + 5 mol %), 5 (1 mmol), reflux. dAZADO
(5 +5 mol %) used instead of TEMP
Fig.1.69 . Oxidation of aliphatic alcoholsa
Organic solvents or ionic liquids can be used as the solvent in a combination of TEMPO
and several mediators for the aerobic oxidation of alcohols, [126] . For example , using acetonitrile
as solvent and TEMPO and Cu(II) –triethanolamine comp lexes aerobic oxidation of primary
alcohols to the corres ponding aldehydes can be performed [127] .
Employing water as the solvent is more favorable sometimes [128] s everal catalytic
systems have been shown to be useful in employing water. Y. Yan et al. [129] used the TEMPO –
Ce(IV) –NaNO 2 system for the aerobic oxidations of differ ent alcohols in water, Fig. 1.70 .
Ahmed Juwad Shakir – Doctoral Thesis
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OH TEMPO, CAN, NaNO2
O2, H2OCHO
Fig. 1.70 . Oxidation of benzyl alcohol with TEMPO – in water
The conversion of benzyl alcohol into corresponding aldehydes by using different catalytic
systems is shown in Table 8.
Table 8. Oxidation of benzyl alcohol with different catalytic systemsa.
Entry TEMPO CAN (Ceric ammonium nitrate ) NaNO 2 Yield %
1 N N N 34.8
2 U N N 36.1
3 N U N 13.8
4 N N U 31.9
5 U U N 50.3
6 N U U 18.5
7 U N U 89.5
8 U U U 94.5
a1.08 g benzyl alcohol in water (10 mL), 1.0 mol% TEMPO, 5.0 mol% CAN, 10.0 mol% NaNO 2, ETAB
(20 mol%) under 0.3 MPa of O 2, 80 oC, time 6 h. (U) represents “being added, (N) represents “not being
added
Table 9 shows the results of the oxidation of various alcohols by using the TEMPO –
Ce(IV) –NaNO 2 catalytic system in aqueous media.
Table 9. The aerobic oxidation of various alcohols in aqueous mediaa
Entry Substrate TEMPO (mol %) Time (h) Yield %
1
H3COH
1 1.5 91.3
Ahmed Juwad Shakir – Doctoral Thesis
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2
C2H5OOH
1 2 98
3
OH
H3CO
1 1.5 98
4
OH
3 4 98
5
OH
Cl
3 4 95.9
6
OH
3 6 55.6
7
OH
3 4 45.5
8
OH
2 3 58.2
9
O
O OH
2 3 12.4
a1.08 g benzyl alcohol, in 10 mL water, 5.0 mol% CAN and 10.0 mol% NaNO 2, in the presence of 20.0
mol% TEAB, under 0.3 MPa of O 2, temperature 80 oC.
1.4.3.6 Oxidation with TEMPO and acids
Using heterogeneous or homogeneous activation with transition -metal -based catalysis such
as Pd, V, W, Mo, Ru, Ag, Co and Au, led to the development of oxidation methodologies in a
closed vessel containing molecular ox ygen. This method is nevertheless costly and has a highly
undesirable environmental impact and toxicity [130].
Ahmed Juwad Shakir – Doctoral Thesis
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TEMPO is an available easy -to-handle catalyst, with high efficiency, low toxicity and good
stability. Rok Prebil, Gaj Stavber and Stojan Stavber [131] reported an efficient and selective
oxidation of primary and secondary alcohols to aldehydes or ketones by using a three -component,
completely metal -free and cost -beneficial catalytic system based on NH 4NO 3/ TEMPO/H+ under
mild, aerobic c onditions, F ig. 1.71 .
OH Oair, NH4NO3(cat.), TEMPO, acid
MeCN, Time
Fig. 1.71 . Novel oxidation system
This kind of catalyst system is inexpensive , uses air as the terminal oxidant, yields the
highest result and exhibits selectivity. The use of TEMPO / nitrate salt / HClO 4 in acetonitrile for
aerobic oxidation of benzyl alcohol is shown in Fig. 1. 72 and Table 10.
OH Oair, MnO3(cat.), TEMPO, acid
MeCN, Time
Fig. 1.72 . Novel oxidation system
Table 10. Oxidation of benzyl alcohola
Entry Nitrate cat. Acid mole % T (C) Time (h) Result %
1 Fe(NO 3)2 HClO 4 20 20 5 81
2 Cu(NO 3)2 – 20 6 86
3 Cu(NO 3)2 – 60 7 100
4 NaNO 3 – 60 6 0
5 NaNO 3 HClO 4 10 20 8 4
6 NaNO 3 HClO 4 10 60 5 100
aalcohol (1 mmol), TEMPO (0.05 mmol), nitrate salt (0.1 mmol), HClO 4 (0–0.2 mmol), MeCN (2 mL),
20–60 oC, 5–6 h under air balloon (1 L)
Ahmed Juwad Shakir – Doctoral Thesis
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Table 11 shows the role of acid in the oxidation reaction.
Table 11. The effect of acid on the oxidation of benzyl alcohol with TEMPO and NH 4NO 3a
Entry Acid pka Yield [%]
1 HCOOH 3.75 0
2 CF3COOH -0.6 0
3 PTSA -2.8 1
4 MeSO 3H -1.9 83
5 HClO 4 -5 100
6 HCl -6 100
aalcohol (1 mm ol), NH 4NO 3 (10 mol -%), TEMPO (5 mol -%), acid (aq., 10 mol -%), MeCN (2 mL), 60
oC,4 h, air balloon
The authors [131] used the air/TEMPO/NH 4NO 3/HCl catalytic system (Fig. 1.73) in
acetonitrile for the oxidation of substituted primary and secondary benzyl alcohols. The results are
shown in Table 12.
ArOH
R1
RArO
R1
Rair, NH4NO3, TEMPO, HCl
MeCN, 60 oC
Fig. 1.75 . Oxidation of substituted primary and secondary benzyl alcohol
Table 12. Aerobic oxidation of substituted primary and secondary benzyl alcohola
Entry R R1 Time [h] Result [%]
1 H H 6 90
2 4-MeO H 5 95
3 4-Me H 3 80
Ahmed Juwad Shakir – Doctoral Thesis
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4 4-Cl H 6 82
5 4-F3C H 8 73
6 4-O2N H 21 87
7 3-F H 6 95
8 H Me 6 95
9 4-MeO Me 5 89
10 4-Me Me 6 80
11 4-F Me 6 96
a Alcohol (1 mmol), NH 4NO 3 (5–25 mol -%), TEMPO (2.5– 12.5 mol -%), HCl (aq. 37% , 5–12.5 mol –
%), MeCN (2 mL), 60 oC, 5–7 h, air balloon (1 L)
OOOO
O
aTEMPO (2.5-5 mol-%), HCl
(aq. 37%, 5-10 mol-%),
NH4NO3 (5-10 mol-%), alcohol
(1 mmol), MeCN (2 mL), 60
oC, 5-6 h, air balloon7h, 90%9h, 92%6h, 92%6h, 90%9h, 82%
Fig. 1.76. Oxidation of aromatic alcohols by using the TEMPO/NH 4NO 3/HCl catalytic system in
acetonitrilea
The efficiency of nitroxide radicals (TEMPO, 4 -HO-TEMPO, 4 -HO-TEMPO benzoate and
4-MeO -TEMPO) is shown in Fig. 1.77, where 5 mol -% NH 4NO 3 and 5 mol -% HCl (aq. 37%)
were used for 24 h at a moderate temperature.
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 1.77. Efficiency of nitroxide radicals [131]
1.4.3.7 TEMPO -mediated processes for synthesizing the ester
Esters are produced by the simple reaction between alcohols and carboxylic acid; they are
widely used in industry, such as acrylate esters.
Oxid ative esterification has been mentioned as a convenient pathway to each symmetric
ester , as well as asymmetric esters [132 -137].
C. Perusqua -Hernndez et al. [138] synthesized aryldiazomethanes and their corresponding
arylmethyl esters, by using benzophenone hydrazine (Fig. 1.83), which reacted with an excess of
13% sodium hypochlor ite solution and TEMPO. In 5 min at 0 oC, diphenyldiazomethane (Fig.
1.78) was formed reddish color, due to the diazo group that shows a band C=N=N at 2050 cm-1.
The co mpound diphenyldiazomethane is unstable in air, reacting with acetic acid to the ester
yielding [139 ]. Table 13 shows the role of temperature and time in this reaction.
Ph PhNNH2NaOCl
TEMPO
KBr, NaHCO3
temp.PhN2
PhAcOH
PhOAc
Ph
a b c
Fig. 1.78 . Synthesis of benzhydryl ester from diphenyldiazomethane and benzophenone hydrazone
Ahmed Juwad Shakir – Doctoral Thesis
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Table 13 . Effect of temperature and reaction time
Entry Temp. C Time (min.) Yield %
1 0 15 32
2 0 30 53
3 0 45 60
4 0 60 83
5 0 90 10
6 5 60 22
7 0 60 83
8 -5 60 92
9 -10 60 89
catalyst ratio (3.8 mol %)
Table 14 shows the results sodium or calcium hypochlorite as oxidizing agents.
Table 14 . Effect of oxidizing agents
Entry Oxidizing agent
Oxidizing agent/
hydrazone (mmol) Yield %
1 Ca(ClO) 2 1 52
2 Ca(ClO) 2 2 57
3 Ca(ClO) 2 3 65
4 Ca(ClO) 2 4 58
Ahmed Juwad Shakir – Doctoral Thesis
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5 NaClO 1 80
6 NaClO 2 70
7 NaClO 3 92
8 NaClO 4 85
acatalyst ratio (3.8 mol %)Improving the yield of esters by using (TEMPO, NaHNO 3, KBr) is shown in
table 29.
Table 15 . Effect of catalyst, co -oxidizing agent, base, and KBr
Entry Catalyst ratio
(mol %) NaOCl
hydrazone
(mmol) NaHCO 3/
hydrazone
(mmol) KBr/
hydrazone
(mmol) Yield (%)
1 3.8 3 0.3 0.2 62
2 3.8 3 0.6 0.2 73
3 3.8 3 1 0.2 60
4 3.8 3 0.6 0.1 43
5 3.8 3 0.6 0.2 80
6 3.8 3 0.6 0.4 72
7 1 3 0.6 0.2 52
8 2 3 0.6 0.2 91
9 4 3 0.6 0.2 48
10 2 1 0.6 0.2 75
11 2 2 0.6 0.2 70
12 2 3.5 0.6 0.2 95
Ahmed Juwad Shakir – Doctoral Thesis
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Using the same conditions of Table 13 , different types of benzhydryl esters were
synthetized from diazoalkanes, Table 16 .
R1 R2NNH2NaOCl
TEMPO
KBr, NaHCO3
-5 CR1N2
R2R3COOH
R1OCOR3
R2
Fig. 1.79 . Synthesis of benzhydryl ester
Table 16 . Benzhydryl esters prepared
Entry R1 R2 R3 Yield %
1 Ph Ph CH 3 95
2 Ph Ph Ph 81
3 Ph Ph 4-NO 2C6H4 73
4 Ph Ph 3-NO 2C6H4 55
5 Ph Ph 4-NO 2C6H4 79
6 Ph CH 3 CH 3 74
7 CH 3 CH 3 Ph 62
8 Ph Ph
OCH2
63
9 Ph Ph 2-Naphthyl 50
10 Ph Ph 4-CH 3C6H4 75
11 Ph Ph 4-ClC 6H4 70
Ahmed Juwad Shakir – Doctoral Thesis
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12 Ph Ph 3-ClC 6H4 55
13 4-ClC 6H4 H CH 3 30
14 4-ClC 6H4 H Ph 38
In 2016, Sven Hac kbusch and Andreas H. Franz [140 ] synthesized symmetric esters from
primary alcohols in a biphasic dichloromethane -water solvent mixture, using TEMPO/CaCl 2
oxone, a convenient catalytic system, Table 17 .
OHTEMPO (0.01 mmole)
CaCl2 . 2H2O
Oxone
2 mL DCM, H2O
rtOO
1 mmole
Fig. 1.80 . Oxidation of 1 -hexanol to ester
Under the same reaction conditions, the authors synthesized different type of esters from
alcohols as sho wed in Fig. 1.81 .
Table 17 . Result of esterfication reaction
Entry H2O (mL) CaCl 2.2H 2O
(mmole) Oxone
(mmole) Time (h) Yield %
1 0.0 0.5 1.0 24 0
2 1.0 0.5 1.0 2.5 44
3 0.5 0.5b 1.0 2.5 65
4 0.1 0.5 1.0 2.5 82
5 0.05 0.5 1.0 2.5 80
6 0.1 0.5 1.5 2.5 87
7 0.1 0.5 1.5 5 99
8 0.1 0.5 2.0 2.5 90
Ahmed Juwad Shakir – Doctoral Thesis
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9 0.1 0.5 2.0 5 97
10 0.1 0.1 1.5 5 96
11 0.1 1.5 1.5 5 35
12 0.1 0.5 1.3 4 97
adetermined by GC/MS, ba control reaction with anhydrous CaCl 2 gave the same result
OO
OOONO2OO
ONO2
O O
OO
O
OO
O
4h, 72%
2.5h, 89% 24h, tracesa24h, tracesa
24h, 27%24h, NRb
a detected by DART-HRMS
bNR = no reactionROH
2TEMPO/CaCl2/Oxone
DCM, H2O, rt RO RO
1.0 mmole
Fig. 1.81 . Synthesis of esters from alcohols
1.4.3.8 TEMPO on materials
Silica -supported TEMPO Fig. 4.2, was used as a recyclable catalyst in the oxidation of
numerous alcohols [26], Table 32.
Ahmed Juwad Shakir – Doctoral Thesis
57
siica NH2+
N
OO
NaBH3CN MeOH, rt
silica N
HNO
Fig. 4.2. Structure silica supported TEMPO
Many literature data shown that of silica supported TEMPO can be used in the oxidation of
alcohols. Jie Zhu et al. [27] prepared and used a fibrous nanosized catalyst containing s upported
TEMPO on silica nanospheres.
Yujie Liu et al. [28] prepared silica also nanoparticles functioned with various TEMPO and
applied as well for the oxidation of alcohols.
The preparation of heterogeneous bifunctional catalysts has been described by a reliable
and simple methodology. The preparation of the component had a highly control over surface
composition. However, the standard of grafting of a mix of catalytic components from an
azidefunctionalized silica platform using the CuAAC reaction is the standard by which the strategy
of preparation relies on. Therefore, what we could get is that the engineered supported catalysts are
employed in the model Cu/TEMPO -catalyzed aerobic oxidation of benzylic alcohol. and hence
that leads to good resulting [29] .
Table 32. The result of oxidation alcohols by silica supported TEMPO
Ahmed Juwad Shakir – Doctoral Thesis
58
Entry Substrate Yields %
1 Benzyl alcohol 92
2 Heptan -1-ol 90
3 Octan -1-ol 88
4 Nonan -1-ol 90
5 Dodecan -1-ol 81
6 1-Phenylethanol 91
7 Benzyl alcohol/1 -phenylethanol 92
8 (S)-2-Methylbutan -1-ol 60
9 Nonan -2-ol 65
Zhang Y. C. et al. [30] prepared a pyridinecarboxaldimine grafted to silica -coated magnetic
nanoparticles the functionalized magnetic silica nanoparticles supported CuBr 2 and TEMPO as
catalyst for oxidation of primary alcohols to corresponding aldehydes Table 34.
Table 34. The result of oxidation of primary alcohols
Entry Product Time (h) Yields
Ahmed Juwad Shakir – Doctoral Thesis
59
1
O
33.0 95.0
2
O
8.0 99.0
3
O
Cl
5.0 99.0
4
ClO
16.0 99.0
5
O
6.5 99.0
6
O
OCH3
8.0 99.0
Reaction conditions: substrate (2 mmol), supported pyridinecarboxaldimine (3 mol %), TEMPO (4 mol %),
CuBr 2 (5 mol %), N-methyl imidazole (15 mol %), MeCN (3 mL), atmospheric pressure of O 2, temperature
50°C. Unless otherwise specified, the selectivity was 100% according to GC.
Organic nanoparticles are of interest in the mater ial and life sciences. Th ere are many
applications of nanoparticles in biotechnology and clinical research, and they are also recognize d
as supports for catalysts [141 ]. One example are carbon -cobalt nanoparticales, which exhibit
excellent magnetic properties with increased stabil ity [142 ].
Oliver R. et al. [143] reported that the simple and efficient covalent functionalization of
TEMPO using a copper catalyst azide/alkyne cycloaddition as a selection method for the oxidation
of alcohols, Fig. 1.82 shown illustrates the grafting of diazonium salts onto carb on coated cobalt
Ahmed Juwad Shakir – Doctoral Thesis
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particles . After formation, the (azidomethyl) phenyl derivative reacts with the alkyne resulting in a
para-nitroohenolester and propargyl ether TEMPO.
CoCo CoNaNO2/HCl
rt, H2O, 15 min.
H2NOH*OH
n
12rt, toluene
24 hHN3
PPh3
DEAD
*N3
n
3
CoCo
Co*N3
n
320 mol% CuI
rt, dioxane, 36 h
NO2O
O
4N
NN
5
Co*N3
n
320 mol% CuI, NEt3
rt, toluene, 36 h
N
OON NN
67ONO2
ONOO
Fig.1.82 . Functionalization of CoNPs with TEMPO
The final material CoNP -TEMPO exhibits high efficiency for oxidation of benzylic and
aliphatic alcohols. Table 18 shows the results of oxidation of different alcohols to aldehydes by
using CoNP -TEMPO mediated oxidation.
Table 18 . Oxidation of alcohols by CoNP -TEMPO mediated oxidationa
Entry Alcohols Yields %
1 4-methylbenzyl alcohol 89
2 4-bromobenzyl alcohol 92
3 4-methoxybenzyl alcohol 96
4 Benzyl alcohol 85
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5 2-phenylethanol 77
6b 1-octanol 87
7b 1-dodecanol 92
8c Cyclohexanol 96
aalcohol (3mmol), DCM (6 mL), KBr (1 mmol), CoNP -TEMPO (2.5 mol%), NaOCl (3.8 mmol), NaHCO 3
(0.6 mmol), 8 oC, 60 min. d5 mol% CoNP -TEMPO. c5 mol% CoNP -TEMPO, 2.7 mmol NaOCl, 3 h
Babak K. and Elham F. [144 ] prepared a new cat alyst (Fig. 1. 83) used for the aerobic
oxidation of a wide range of alcohols.
This was prepared by the reaction of silica -coated Fe 3O4 nanoparticl es with (3-
aminopropyl) triethoxysilane to form amino -functionalized silica -coated nanomagnets (Fe 3O4-
SiO 2PrNH 2) which underwent reductive amination wit h 4-oxo-2,2,6,6, -tetramethylpiperidine in the
presence of NaBH 3CN, to form magnetic nanoparticale -supported TEMPO ( Fig. 1. 83).
Fe3O4SiO2 O
O
OSi N
HNO
aFe3O4 Fe3O4SiO2
Fe3O4SiO2O
O
OSi
H2N
Fig. 1. 83. General synthesis of magnetic nanoparticle -supported TEMPO a
Table 19 show the types of alcohols that have both electron -withdrawing and electron –
donating groups, converted to the corresponding aldehyde or ketone.
R1 R2OHa (0.2-0.35 mol%)
TBN (4-5 mol%)
H2O (0.3 mL), 50 oC, O2 (1 atm)R1 R2O
Fig. 1. 84. Oxidation of alcohols
Ahmed Juwad Shakir – Doctoral Thesis
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Table 19 . The results of aerobic oxid ation of various alcohols
Entry R1 R2 Time (h) Yield %a
1 Ph H 4 100
2 2,4-Cl2C6H3 H 16 100
3 4-MeOC 6H4 H 2.5 100
4 1-Naphthyl H 15 99
5 C6H5 Me 9 100
6 C6H5 C6H5 24 80
7 4-ClC 6H4CO 4-ClC 6H4 25 86
8 C6H5(CH 2)2 H 29 100
9 Cyclohexanol 24 91
10 (CH 3)2C=CH H 13 100
11 C6H5-CH=CH – Me 48 61
12 Cyclohexanol C6H5 24 96
aprimary benzylic alcohols (1mmol), tBuONO (4mol%), catalyst a (0.2mol %) in H 2O (0.3 mL) at 50 oC.
Aliphatic and secondary benzylic alcohols (1mmol), tBuONO (5 mol%), catalyst a (0.3 mol%) in H 2O
(0.3 mL) at 50 oC. Allylic and hindered alcohols (1 mmol), tBuONO (5 mol%), catalyst a (0.35 mol%) in
H2O (0.3 mL) at 50 oC
One of the most important reactions in organic synthesis is the oxidation of alcohol [145].
Various free radical TEMPO functionalized solid catalysts were prepared by immobilising
individual TEMPO molecules onto solid support materials, and they have been use d in oxidation
reactions [146 ]. The synthesis of p oly (vinyl chloride) (PVC) via nitroxide -mediated
polymeriz ation using the SG1 – based BlocBuilder alkoxyamine at 30 oC and 42 oC was reported by
Carlos M. R. Abreu et al. [147] in 2016.
Also Simon Kwan and Milan Mari used (NMP) nitroxide mediated polymerization for the
heterogeneous grafting of chitosan with therm oresponsive (oligoethylene)glycol
methacrylate/diethyleneglycol me thacrylate/acrylonitrile [148 ]. Based on the assumption that
TEMPO polymer grafted solid state catalyst with high radical density can improve the efficiency
Ahmed Juwad Shakir – Doctoral Thesis
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and activity (due to the increase in the number of active sites of the catalyst to the substrate),
several methods were developed.
TEMPO polymer grafted silicas are prepared by grafting (PTMA) poly (2,2,6,6 –
tetramethylpiperidinyl -oxymethacrylate) [149] onto silica, by using the RAFT chain transfer agent
(Reversible addition -fragmentation chain transfer, used to make a chain transfer agent ), S-
methoxycarbonyl -phenyl -methyl S´ trimethoxysilylpropyltrithiocarbonate is inser ted onto the silica
surface [150 ] , after that, RAFT polymerization and the so -formed precursor are used to graft
polymerized 2,2,6,6 -tetramethylpiperidine methacrylate, treated with 3 -chloroperoxybenzoic acid ,
to yield the TEMPO p olymer grafted silica (Fig. 1.85 ).
The ratio of the polymer graft is 57 wt%, determined by using a superconducting quantum
interference device (SQUID) to estimate the number of radical groups in serted onto the silica
surface. 2,2,6,6 -Tetramethylpiperidine methacrylate was RAFT polymerized with the chain transfer
agent, treated with the chain transfer agent, (4 -cyano -4-[(phenyl -thioxomethyl)thio] -1-(2-
carboxyethyl) -1 cyanoethylbenzodithio -ate) [151 ] and with 3 -chloroperoxybenzoic acid to form
the poly (PTMA). The molecular weights of these polymers were determined by gel permeation
chromatography (GPC).
Si MeOOMe
OMeS SOCH3O
S OH
S SSOCH3O
1) toluene, 16h, 100 oC
2) 3h, 120 oC1
(1) +
N
HOO
RAFT polymnmCPBA
THFS SS
nOOCH3
OO
NO
2
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N
HOO
HOO
NCS
S+ RAFT polymnmCPBA
THFHOO
NCS
Sn
O
N
OO
3
NH2+ 3EEDQ
toluene, rtN
HO
NCS
S
O
N
On
4
Fig. 1.85 . Synthesis of the TEMPO polymer grafted silica
The prepared compounds (Fig. 1.85 ) were then grafted onto synthesized amino –
functionalized silica (ca. 2.0 mmol g -1) of particle size of ca. 10 nm using a condensation agent to
yield a series of different TEMPO polymer grafted silica . N-ethoxy -carbonyl -2-ethoxy -1,2-
dihydroquinoline (EEDQ) was used as the condensation agent. EEDQ was selected for this
condensation react ion since this reagent is readily available at low cost and allows the coupling in
high yield in a single operation [152 ], Table 20.
Table 20. TEMPO polymer grafted silica
radical conc.
(%) immobilized
TEMPOa
(mmol g-1) graft ratio
(wt%) 3 Entry
Mw/Mn Mn (x104)
92 1.56 54 1.2 1.0 1 (4-1)
91 1.71 64 1.2 1.7 2 (4-2)
90 1.76 66 1.1 3.0 3 (4-3)
99 2.11 91 1.2 7.4 4 (4-4)
Ahmed Juwad Shakir – Doctoral Thesis
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Scanning electron microscope (SEM) and dynamic light scattering (DLS) were used to
determine the morphology of synthetic material 4 -2 (Entry 2, Table 20) Fig. 1.86 .
Fig. 1.86 . SEM image of TEMPO c atalyst [153]
Polymer grafted silica was used for oxidation of benzyl alcohol (Table 21) and its
efficiency was compared with a commercially available mono -TEMPO Si. The oxidation reaction
of benzyl alcohol was achieved in water or DCM/water bi -phasic system. The results of 4 -2 in
Table 21 show the highest product conversion and high reaction rate constant compared with
mono -TEMPO Si.
Table 21. Conversion and reaction rate constant of the oxidation of benzyl alcohol to
benzaldehyde with TEMPO catalystsa
mono -TEMPO -Si 4-4 4-3 4-2 4-1 Catalyst
58 80 89 95 90 conversion (%)b
0.23 0.45 0.62 1.01 0.91 rate constant k 1 (x10-2 Lmol-1 s-1)
a10 min, reaction temp, 5 C, catalyst/alcohol, 0.5 mol%, solvent and DCM/water
The results usi ng TEMPO polymer grafted silica for the oxidation various alcohols are
shown in Table 22. TEMPO has been immobilized onto solid supports, such as polymeric resins,
mole cular sieves and silica gel [154 -156]. TEMPO was linked to the CPGMA microspheres
between the epoxy groups of 4 -OH-TEMPO , forming heterogeneous catalys t microspheres
TEMPO/CPGMA, [157 ] by the ring opening reaction. The polymer resin has the advantage that
active groups can be easily inserted onto it via chemical modification.
Ahmed Juwad Shakir – Doctoral Thesis
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Table 22. Results of conversion (%) of alcohols to aldehydes with TEMPO catalyst a
Entry Substrate Product 4b Mono -TEMPO -Si
1
OH
O 98 51
2
OH
O 99 34
3
HOOH
OH
OOH
OH 53 5
HOO
OH
0.1 0.3
a10 min, reaction temp, 5 oC, catalyst/alcohol, 0.5 mol%, solvent DCM/water. b4-3 for entry 1 and 2, 4 -2
for entry 3
Baojiao Gao et al. [158] used the heterogeneous catalyst TEMPO/CPGMA combined with
Fe(NO 3)3 as cocatalyst for the aerobic oxidation of cyclohexanol under mild conditions, in order to
obtain the product (cyclohexanone) with good activity. There are some reports using homogen ous
TEMPO combined with Fe(NO 3)3 [159,160 ]. The activity of th e catalyst is shown in Fig. 1.87 , and
the resulting product yield of cyclohexanone was 44% in 36 h when using the system consisting of
TEMPO/CPGMA microspheres and Fe(NO 3)3.
Fig. 1.87 . Curves of cyclohexanone yield with time using the combination of TEMPO/CPGMA and
Fe(NO 3)3 as cocatalyst or th e single components as catalyst [157]
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RH
CCH2
OCPGMA
CPGMA microshereC
CCH3
H2C
OO
CH2
CH
CH2O+C
CCH3
H2C
OO
CH2
CH2
O
CO
C H2C
CH3C
CCH3
OO
CH2
CH
CH2OCCH3
O
CH2
CH2
O
CO
C
CH3H2
CH2
C
COm n
H2
Csuspension
polymerization
RH
CCH2
OCPGMA +
N
OOH
ring opening
reaction
CPGMARH
CH2
C
OHO
N
OCPGMA
O
N
O4-OH-TEMPO
TEMPO/CPGMA
microsheres
Fig. 1.88 . Immobilization of TEMPO on CPGMA microspheres
1.4.3.9 Nitroxide free radical as catalyst for dehydrogenation of amines
The oxidation of primary amines into the corresponding nitriles constitutes a very useful
functional group transformation in organic sy nthesis. Amines are acutely sensitive to oxidation,
and products may depend on the oxidant. Catalytic systems for the aerobic oxidation of amines to
nitriles have been developed. They involve catalytic quantities of a base, cuprous iodide, and an
appro priate ligand for the metal [161 ].
The catalyst TEMPO, together with anether catalyst are used for the oxidation of different
types of amines, converting them to corresponding nitriles. This oxidation reaction is sensitive and
the products are depending on the TEMPO ratio, and has been used to a much lesser extent.
In 1983, Semmelhack and Schmid reported TEMPO assisted electro oxidation of amines to
nitriles and carbonyl com pounds using TEMPO catalyst [162 ]. Oxidation of a primary amine to a
nitrile included a double dehydrogenation that has been achieved in different ways [163 ], aerobic
Ahmed Juwad Shakir – Doctoral Thesis
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oxidation catalyzed by transition metals [164 ], transition -metal catalyzed dehydrogenation, and so
on.
Some of the oxidizing agents used in the process of oxidation of primary a mines into the
corresponding nitriles [165 ], have a lot of drawbacks such as harsh reaction conditions, low yields,
tedious work -up procedures and limitations.
F.-E. Chen et al. [166] reported that by using trichloroisocyanuric acid (TCCA) with
TEMPO a sta ble free radical under mild reaction conditions , the oxidation of benzylamine to the
benzonitrile was achieved, Table 23.
RCH2NH2TCCA, TEMPO (1mol%)
DCM, 10 oCRCN
Fig. 1.89 . Oxidation of primary amines
Trichloroisocyanuric acid is an inexpensive, stable reagent used in organic synthesis such
as in the transformation of alcohols to halides alkenes to β -chloroethers, carboxy lic acids to acid
chlorides [167 ], and also used in the oxidation of alcohols to ca rbonyl compounds [168 ].
Table 23. Oxidation of benzylamine to the benzonitrilea
Yield %b Time (h) TEMPO/TCCA (mol ratio) Temp. C Solvent Entry
70 4 1:1.2 5 Et2O 1
71 5 1:1.2 5 Dioxane 2
62 5 1:1.2 5 THF 3
85 3 1:1.2 5 DCM 4
49 6 1:1.2 0 DCM 5
88 3 1:1.2 10 DCM 6
69 1 1:1.2 10 DCM 7
45 5 1:0.5 5 DCM 8
Ahmed Juwad Shakir – Doctoral Thesis
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72 3 1:0.8 5 DCM 9
90 2 1:1.3 5 DCM 10
90 2 1:1.5 5 DCM 11
aall reactions were carried out according to the typical procedure.
byield of isolated pure product.
These conditions were also employed for the oxidation of other aliphatic, aromatic and
heterocyclic primary amines; the results are shown in Table 24.
Table 24. Oxidation of Primary Amines into Nitriles
Entry R Time (h) Yield%b
1 C3H7 4 80
2 C5H11 4 81
3 HO 2C(CH 2)5 4.5 80
4 Ph 2 90
5 4-MeC 6H4 2 91
6 4-MeOC 6H4 2 90
7 4-NO 2C6H4 2.5 90
8 4-Me 2NC 6H4 2 91
9 (E)-PhCH=CH 2 90
10 1-Naphthyl 1.5 90
11 3-(4-Methoxybenzyloxy)C 6H4 2 89
12 3,4-(HO) 2C6H3 2 91
13 2-ClC 6H4 2 90
14 3,4-(CH 2O2)C6H3 2 90
15 2-Furyl 2 89
16 3-Pyridyl 2 89
17 Piperonyl 2.5 89
aall products were identified by comparison with their spectral data (IR, 1H NMR and GC/MS) and physical
properties with those of the authentic samples, byields of isolated pure product.
Ahmed Juwad Shakir – Doctoral Thesis
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Kyle M. et al. [169] reported on the oxidation of a primary amine into the corresponding
nitrile by using a stable, solid and commercially available compound, namely 4 -acetamido -2,2,6,6 –
tetramethylpiperidine – 1-oxoammonium tetrafluorobor ate (Fig. 1.90 ).
This compound can be prepared using 4 -amino -2,2,6,6 -tetramethylpiperidine and
inexpensive reage nts in multimole quantities [170 ].
NNH
OO
BF4a
NNHO
O
bNNHO
OHc
Fig. 1.90 . Oxoammonium salts(a)
Aliphatic amines are oxidized more slowly than benzylic and allylic amines, be cause the
oxidation of aliphatic amines requires 24 -36 h at room temperature, but benzylic and allylic
oxidation requires just 12 h. A large number of reports have addressed the oxidation of primary
and secondary amines.
The results of the oxidat ion of primary amines into the corresponding nitrile are shown in
Fig. 1.91 .
RCH2NH2+ 4NNHO
OBF4-excess
pyridine
DCMRCN
N
ONHO
+ 4
N
HBF4-+ 4
ab
Fig. 1.91 . Oxidation of primary amines to nitriles
Ahmed Juwad Shakir – Doctoral Thesis
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CN CN CN
MeO CN CN
HO CN
F
CN
F3C
CN MeO CN F3C
CF3 CN
Cl CN S
CN
CN CN12h, 92%12h, 92% 12h, 86% 12, 90% 12h, 86% 12h, 73%
24h, 89%
12h, 87% 24h, 75%12h, 90% 14h, 91% 14h, 92%
36, 93% 24h, 95%aall reactions were
conducted on a 10 mmol
scale. bthe reaction
mixture was stirred at
room temperature or
reflux
Fig. 1.92 . Result of oxidation of primary amines to nitrilesa,b
The stoichiometry for the oxidation of primary amines into n itriles is shown in Fig. 1.93 .
Fig. 1.93 . Oxidation of primary amines to nitriles
Ahmed Juwad Shakir – Doctoral Thesis
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Largeron et al. reported on the oxidation of primary aliphatic amines into imines by using
the biomime tic electrocatalytic method [171 ].
In 2012 Kerton applied methods for the oxidation of primary and secondary amines by
using a Cu/ nitroxide –catalyzed system [172 ]. Nicolaou et al. used 2 -iodoxybenzoic acid to
develop stoichiometric oxidations of s econdary amines into imines [173,174 ].
In 2012 Zhenzhong Hu . and Francesca M. Kerton [175 ] reported on aerobic oxidations of
primary and secondary benzyl amines using the CuBr 2-TEMPO catalytic system (dehydrogenative
coupling of electron -rich anilin es to get azo compound Fig. 1.94 ). Table 25 shows the results of the
oxidative self -coupling of benzylamine using CuBr 2-TEMPO.
NH25 mol. % catalyst
solvent, air, 25 oC2N
Fig. 1.94 . Copper -catalyzed oxidative self -coupling of benzylamine
Table 25. Oxidative self -coupling of benzylamine a
Entry Catalyst Solvent mixture (v/v) Yield %
1 CuBr 2 CH 3CN/H 2O (2/1) Trace
2 TEMPO CH 3CN/H 2O (2/1) N.R.
3 CuBr 2 + TEMPO CH 3CN/H 2O (2/1) 86
4 CuCl 2 + TEMPO CH 3CN/H 2O (2/1) 58
5 Cu(CH 3COO) 2·H2O +
TEMPO CH 3CN/H 2O (2/1) 62
6 FeCl 3 + TEMPO CH 3CN/H 2O (2/1) N.R.
7 CuBr 2 + TEMPO CH 3CN N.R.
9 CuBr 2 + TEMPO Toluene/H 2O (2/1) 8
a catalyst (0.05m mol), benzylamine (2 mmol), solvent (9 ml), 1 atm and 8 (h)
Using CuBr 2/TEMPO as the catalyst, benzylamine converts into imines with high yield, so
it is employed for a range of primary and secondary benzylic amines with high conve rsion and
selectivity (Fig. 1.95 ).
Ahmed Juwad Shakir – Doctoral Thesis
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NOMe
NOMe
N
OMe OMe
N
OMe MeON N
NCl Cl
N
Cl ClNN
87% 94% 93%
94%93% 88%
82% 76% 92%b,c5%
acatalyst (0.10 mmol), solvent (9 ml), benzylamine (4 mmol),1 atm, 25 oC and 12 h, b7.5 mol%
catalyst loading. c45 °C reaction temperature
Fig. 1.95 . Oxidation primary and secondary benzylic aminesa
In 2016, Ashley L. Bartelson et al. developed nitroxide -catalyzed oxidation of amines
(prepare of imines an d nitriles) by using nitroxide 4-acetamido -TEMPO (ACT), pyridinium
bromide, and oxone [176 ].
Using oxone as a secondary oxidant for the nitroxyl system along with amine substrates as
it has been mentioned to react with amines underneath certain reaction conditions [177 ].
Combining the approach pronounced by Bolm they predicted a stoichiometric protocol to
develop a catalytic mannertor the usage of ACT, because the nitroxyl catalyst can oxidize primary
amines t o nitriles [178 ]. The Fig. 1.96 shows the results of oxidation of such amines.
Ahmed Juwad Shakir – Doctoral Thesis
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R NH25 mol % ACT
4.5 mol % pyrdinium bromide
4.4 eq. oxone
6 eq. pyridine
DCM, rt, 12hRCN
CNCN
F3C OCF3CN CN
H3CO
CN
ClCN O
OS
CN O
CN
92%86% 88%86%
98%90%
98%
86%
Fig. 1.96 . Oxidation of amines
1.4.3.10 Oxidation mechanism using nitroxide radicals
The oxidation of an alcohol to an aldehyde or ketone by TEMPO includes the abstraction
of two hydrogen atoms from the substrate. The oxoammonium cation, can be formulated in two
limiting resonance forms , Fig. 1.101.
N
ON
O
Fig. 1.101. Resonance of oxoammonium cation
Ahmed Juwad Shakir – Doctoral Thesis
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There are two different kinds of TEMPO mechanisms in the oxidation of alcohol, one
under acidic conditions, and another under basic conditions. Generally, the dominant mechanism
under acidic conditions is slower than the dominant mechanism under basic conditions; oxidations
of alcohols in base include an alcoholate as the nucleophile. Fig. 1.102 shows the conceivable
mechanism of oxidation of alcohol under basic conditions, and in Fig. 1.103 shows under acidic
conditions.
R R
OH+ B
– BH+R R
ON
ON
OO R
RHN
OH+O
RR BH++ +
Fig. 1.102. Mechanism of oxidation of alcohol under basic conditions
N
ONO HO
HHH
:BN
OH+RCHO RCH2OH +
Fig. 1.103. Mechanism of oxidation of alcohol under acidic conditions
– Mechanism for the aerobic oxidation of alcohol by using Cu/ TEMPO catalyst
Stahl et al. provides a mechanism for the aerobic oxidation of alcoh ol using Cu/ TEMPO
catalyst [179 ], see Fig. 1.104. In the first step, the aerobic oxidation of CuI produced CuII-OH.
In the second step, aer obic oxidation of TEMPOH produces TEMPO. When CuI salt is
used as the catalyst in the aerobic oxidation of alcohol, a strong base like 1,8-
diazabicyclo[5.4.0]undec -7-ene (DBU) is not required (see the first step in Fig. 1.104). After the
second step, the base (L nCuII-OH) is formed upon reduction of O 2. Step 3 in Fig. 1.104 causes the
oxidation of alcohol through the generation of a pre -equilibrium of a CuII–alkoxide. The last step is
hydrogen transfer to TEMPO .
Ahmed Juwad Shakir – Doctoral Thesis
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LnCuI1/2O2
1/2[LnCu]2(O2)
TEMPOH
TEMPOLnCuII-OHLnCuIIOH RHTEMPOTEMPOH+RO
1
2 34
R HOH2OL= ligand
Fig. 1.104. Mechanism of Cu/TEMPO -catalyzed alcohol oxidation
deduced by Stahl et al.
– Mechanism for NO x
One mechanism example for heteroatom in nitroxy radical was suggested by Yoshiharu I.
et al. [118] . It involved the use of 5 -F-AZADO (Fig. 1.105) catalyst for the aerobic oxidation of
alcohol. In the first step, a hydrate (2 in Fig. 1.105) is formed from t he oxoammonium cation with
H2O in equilibrium, the oxoammonium oxidizes the alcohol to form the intermediate 3 in Fig.
1.105 in equilibrium with the intermediate. Then, oxidation of alcohol, formed hydroxylamine and
the nitroxy free radical lead to the reg eneration of the oxoammonium cation in the final step.
Ahmed Juwad Shakir – Doctoral Thesis
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N
OHOH X2
N
OX
1H2O H+,
NXO
OHR1
R2OH
R1 R2
N
OOXR1
R2
R2R1ONX
ONX
OHNO
NO21/2O2
H2O3
4X= F
Fig. 1.105. Mechanism of 5 -F-AZADO catalyst for aerobic oxidation alcohol
– Mechanism for the oxidation of alcohols by using tert -butyl nitrite
Martin H. and Ullrich J. proposed a mechanism for the oxidation of alcohols by using tert -butyl
nitrite (TBN) [122].
In Fig. 1.106, the first step reaction between TBN and the catalytic amount of BF 3·OEt 2 lead to
the formation of nitrosonium tetrafluoroborate and the borate ester . Then nitrosonium salt oxidizes
the free radical TEMPO to the Noxopiperidinium salt. Oxidation of alcohols by salt 2 to the
Ahmed Juwad Shakir – Doctoral Thesis
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corresponding aldehydes or ketones 4 resulted in tetrafluoroboric acid and hydroxylamine 5 which
is in equilibrium with its salt 6. Finely hydroxylamine 9 reoxidizes to TEMPO 1.
t-BuONO + 4/3BF31/3(t-BuO)3B + [NO]+[BF4]-
t-BuONOt-BuOH
[NO]+[BF4]-
N
OBF4-N
OHNH
OHBF4-+ HBF3HBF3
N
ONOt-BuONOt-BuOH
NO
1
2
R1R2OH
R1R2O3
4567
Fig. 1.106. Proposed mechanism of alcohol oxidation with TBN
– Mechanism of TEMPO in esterification reactions
A mechanism of TEMPO in esterification reactions of aryl diazomethanes derived from
hydrazine was proposed by Ramstrom [180 ] and Sheldon [181 ]. In the first step, Fig. 1.107 the
free radical TEMPO reacts with chlorine (derived from sodium hypochlorite) to form
oxoammonium ion. Then oxoammonium ion combines with hydrazine to form the intermediate 5.
Ahmed Juwad Shakir – Doctoral Thesis
79
Next, h ydrogen is transferred to form the intermediate 6 which is disproportionate to
hydroxy TEMPO and diazocompound 8. Finaly hydroxy TEMPO is re -oxidized by c hlorine to
form the intermediates 2 and 3.
N
OCl2
N
OClN
OClB+NNH2
BH
NOH N
N N
OH
NNCl21 23
6
784
NO N
NH
5
Fig. 1.107. Reaction mechanism of esterification reactions of aryl diazomethanes derived from
hydrazine by using TEMPO as catalyst
– Mechanism for the condensation of benzyl amines using CuII/TEMPO catalysts
Zhenzhong H. and Francesca M. [175 ] suggested also a mechanism for the condensation of
benzyl amines using CuII/TEMPO catalysts. It is similar to the mechanism of Cu/TEMPO
catalyzed aerobic oxidation of alcohol reported by Sheldon et al. [182]. In Fig. 1.108, first step
entailed the CuII bonding with the amine to form the intermediate complex. In the second step, the
Ahmed Juwad Shakir – Doctoral Thesis
80
intermediate complex (II) combines with TEMPO to form type the next intermediate by the
abstraction of hydrogen from the amine (C -H bond) via the coordinated TEMPO molecule.
Intermediate 4 is stable because the hydrogen bonding between the oxygen atom of TEMPOH and
the second β -hydrogen atom of amine. Then, TEMPO -H and the intermediate imine is dissociated
from the radical species 4 via single proton transfer to form a CuI complex 5.
Next, the oxidation of CuI complex and TEMPOH with oxygen takes place to regenerate
the CuII complex and TEMPO.
LnCuIILn-1CuIIX
-X-
1R NH2
Ln-1CuIINH2R
2
N
O
N
OLn-2CuII
H2N
RH
H3N
OHLn-2CuII
H2N
RH4LnCuI
5
RHN
+
N
OHR NH2NH3N R RN
ON
OHO2
H2O
L = X-, H2O or CH3CN
Fig. 1.108. Proposed mechanism for CuBr 2-TEMPO catalyzed oxidation of benzyl amines
Ahmed Juwad Shakir – Doctoral Thesis
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1.5. Conclusion
The development of organic free radicals chemistry begun when the scientist Moses
Gomberg discovered the triphenylmethyl radical in 1900. The exploration of the chemical
synthesis and appication of free radicals plays a vital role in chemical reactions and medicine.
In organic chemistry, the achievement of free radicals exhibiting different levels of stability
leads to numerous advances in chemical theory and practical application . Organic chemistry offers
many advantages for all chemists interested in transient and persistent radicals.
Because of their paramagnetic properties, nitroxides have gained a lot of attention in
materials science . Nitroxides and polynitroxides continue to be of interest for different applications
and research topics ; organic synthesis, organic batteries, organic magnets, nitroxide mediated
polymerization (NMP) , supramolecular assemblies , antioxidants, magnetic resonance imaging
(MRI), dynamic nuclear p olarization (DNP), free radical biology and so on.
Researchers are studying nitroxides that display appropriate c haracteristics, such as redox
potential, relaxivity, rate of trapping of free radicals, biocompatibility, ferromagnetic interactions,
etc. The advantage of nitroxides compared to other stable free radicals is that the aminoxyl group
can resist the experime ntal conditions needed to perform various organic reactions.
The chemistry of nitroxides is very important, especially in the oxidation reaction and in
the chemical reactions taking place within industrial settings. Oxidation reactions have frequently
been performed with stoichiometric amounts of inorganic oxidants. Many of these are extremely
hazardous to use or toxic when compared to the use of organic oxidants.
Cyclic nitroxides have been used for years as biophysical probes . Heterogeneous catalysts
are favored for these reactions; the ability to recycle the catalyst often remains a challenge after the
chemical reaction is completed. The availability of easy -to-handle heterogeneous catalysts like
TEMPO as free radical which can be easily recycled after us e in liquid phase oxidation reactions,
and which have low toxicity, good stability and high efficiency is thus an essential requirement.
Free radical TEMPO has been useful in roles such as mediators in the selective oxidation
reaction of alcohols, as a cat alyst for the oxidation or dehydrogenation of amines , due to its ability
to moderate polymerizations , synthetize ester and so on, due to its high yield, mild conditions and
low toxicity.
Through our survey of the chemical applications of free radicals thei r important are and
effective contributions in various chemical; medical and industrial preparations is clearly a topic of
Ahmed Juwad Shakir – Doctoral Thesis
82
high interst. Free radicals are easy to obtain and use, especially nitroxide free radicals. They can
be used as catalysts, which are very important in the preparation of many useful chemical
compounds in a safe and easy way, with accurate results.
Ahmed Juwad Shakir – Doctoral Thesis
83
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ORIGINAL DATA
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Chapter 2. A comparison between nitroxide and
hydrazyl radicals as catalyst in selective alcohols
oxidation
2.1. Free radicals characteristics and comparison
2.1.1 Introduction
All the free radicals used in this study are known in literature. TEMPO and DN -DPPH are
indefinitely stable free radicals under usual conditions (meaning that they do not decompose in
time, dimerize nor react with atmospheric oxygen), while PINO is conside red a persistent free
radical, as is decomposing slowly in time (therefore it has to be prepared just before use; it is
simply obtained in situ by oxidation of N-hydroxyphtalimide (NHPI) with different reagents, like
lead dioxide, lead tetra -acetate, nitro gen dioxide, etc.) [23].
Because DN -DPPH is not a commercially available product , our first step in our work was
to synthesize it starting from DPPH. This reaction is easily performed in a biphasic system by
reacting DPPH (dissolved in dicloromethane, DCM) with nitrogen dioxide generated by an
aqueous mixture of sodium nitrite and diluted hydrochloric acid [36]. DPPH is a good scavenger of
nitrogen dioxide, leading finally to the desired product in about 90% yields .
By chance, we obtained good quality cryst als of DN -DPPH and therefore this compound
was also characterized also by X -Ray diffraction. DN-DPPH crystallizes in the P-1 triclinic space
group and the asymmetric unit contains two DN -DPPH molecules and two dichloromethane
solvent molecules. The two cry stallographically independent molecules of DN -DPPH have similar
conformations.
The nitro groups of the p-nitrophenyl moieties lie almost in the planes of the phenyl rings.
The dihedral angles formed by these groups with the mean planes of the corresponding phenyl
rings are: 3.41° (N6O7O8), 3.85° (N7O9O10), 3.25° (N13O17O18) and 16.68° (N14O19O20).
The dihedral angles formed by the ortho nitro groups with the mean planes of phenyl rings
in the picrylhydrazyl fragments are significant higher compared with tha t formed by the para
groups: 55.45° (N2O3O4), 35.47° (N3O5O6), 48.07° (N9O13O14), 32.20° (N10O15O16),
respectively 11.08° (N1O1O2) and 14.17° (N8O11O12). The bond lengths for the two DN -DPPH
molecules are gathered in Table 27 , Fig. 2.2 , shows the crystal s tructure of DN -DPPH.
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NNaNO2 NNO
NNH2
NO2 O2N
NO2OH
Reflux(2h)
SOCl2
DMFNO2 O2N
NO2Cl
NaNO2PbO2NNO2N
NO2
O2NO2N
O2Npicric acid 2-chloro-1,3,5-trinitrobenzenediphenylamine N-nitroso-N-phenylbenzenamine
NH
NO2N
NO2
O2NO2N
O2NNH
NO2N
NO2
O2NH
HCl CH3COOHZn
HCl
Fig. 2 .1. Synthesis of DN -DPPH
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Fig. 2 .2. Perspective view of one and two DN-DPPH molecule s
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Fig. 2.3. Packing diagram in crystal structure of DN-DPPH, view of the supramolecular dimers
formed by π-π interactions
Fig. 2.4 . Packing diagram in crystal structure of DN-DPPH, view along the crystallographic
b axis
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Table 27 . Selected bond distances (Å) for the DN -DPPH molecule
N1-O2 = 1.220(4) C1-C2 = 1.368(5) C19-C20 = 1.371(5)
N1-O1 = 1.228(4) C1-C6 = 1.381(5) C19-C24 = 1.376(5)
N2-O4 = 1.212(4) C1-N1 = 1.461(4) C19-N8 = 1.465(4)
N2-O3 = 1.213(4) C2-C3 = 1.372(4) C20-C21 = 1.370(4)
N3-O6 = 1.223(4) C3-C4 = 1.413(4) C21-C22 = 1.408(4)
N3-O5 = 1.225(4) C3-N2 = 1.458(4) C21-N9 = 1.463(4)
N4-N5 = 1.340(3) C4-N4 = 1.379(4) C22-N11 = 1.381(4)
N6-O8 = 1.219(4) C4-C5 = 1.411(4) C22-C23 = 1.410(4)
N6-O7 = 1.222(4) C5-C6 = 1.378(4) C23-C24 = 1.379(5)
N7-O10 = 1.214(4) C5-N3 = 1.467(4) C23-N10 = 1.470(4)
N7-O9 = 1.215(4) C7-C8 = 1.392(4) C25-C30 = 1.382(4)
N8-O12 = 1.218(4) C7-C12 = 1.393(4) C25-C26 = 1.393(4)
N8-O11 = 1.224(4) C7-N5 = 1.422(4) C25-N12 = 1.433(4)
N9-O13 = 1.216(3) C8-C9 = 1.375(5) C26-C27 = 1.371(5)
N9-O14 = 1.220(4) C9-C10 = 1.384(4) C27-C28 = 1.380(4)
N10-O16 = 1.219(4) C10-C11 = 1.383(4) C28-C29 = 1.381(4)
N10-O15 = 1.227(4) C10-N6 = 1.465(4) C28-N13 = 1.469(4)
N11-N12 = 1.349(3) C11-C12 = 1.379(4) C29-C30 = 1.382(4)
N13-O18 = 1.214(4) C13-C14 = 1.379(4) C31-C32 = 1.397(4)
N13-O17 = 1.217(4) C13-C18 = 1.396(4) C31-C36 = 1.404(4)
N14-O20 = 1.218(5) C13-N5 = 1.422(4) C31-N12 = 1.412(4)
N14-O19 = 1.223(5) C14-C15 = 1.379(4) C32-C33 = 1.371(5)
C15-C16 = 1.383(5) C33-C34 = 1.389(5)
C16-C17 = 1.375(5) C34-C35 = 1.369(5)
C16-N7 = 1.475(4) C34-N14 = 1.467(4)
C17-C18 = 1.382(4) C35-C36 = 1.378(5)
A summary of the crystallographic data and the structure refinement for crystal of DN –
DPPH are given in Table 28.
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Table 28 . Crystallographic data, details of data collection and structure refinement parameters for
compound DN-DPPH
Compound DN-DPPH
Chemical formula C19H12Cl2N7O10
M (g mol-1) 569.26
Temperature, (K) 2002
Wavelength, (Å) 0.71073
Crystal system Triclinic
Space group P-1
a(Å) 12.2010(13)
b(Å) 14.4162(15)
c(Å) 14.6132(15)
(°) 113.119(8)
(°) 93.134(8)
(°) 96.763(8)
V(Å3) 2333.1(4)
Z 4
Dc (g cm-3) 1.621
(mm-1) 0.350
F(000) 1156
Goodness -of-fit on F2 0.971
Final R1, wR 2 [I>2(I)] 0.0557, 0.1409
R1, wR 2 (all data) 0.0944, 0.1600
Largest diff. peak and hole (eÅ-3) 0.865, -0.740
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Usually, the best method to characterize free radicals is by electron paramagnetic resonance
(EPR). For TEMPO and PINO, the spectra showed the expected triplet, due to the interaction of
the unpaired electron with the nitrogen nucleus; the hyperfine coupling constants are a N = 15.7 G
for TEMPO, while for PINO a N 4.8= G. DPPH give five lines, as the two hyperfine coupling
constants are very close (a N1 = 9.0 G, a N2 = 8.9 G).
A very different spectrum is recorded for DN -DPPH, showing the interaction of the
unpaired electron with two different nitrogen nucleus (a N1 = 10.9 G, a N2 = 6.9 G). The EPR spectra
are shown as Fig. 2.5 .
a b
c d
Fig. 2. 5. EPR spectra of TEMPO (a), PINO (b), DPPH (c) and DN -DPPH (d), recorded at room
temperature in acetonitril (scale range 100 G).
Another interesting feature of these free radicals is their colour. UV -Vis spectra of TEMPO
showed an absorption band at max= 440 nm, PINO at max = 380 nm, DPPH at max = 515 nm,
and DN -DPPH at max = 475 nm. The UV -Vis spectra are showed as Fig. 2.6 .
Because the employed free radicals will be used in oxidation reactions, it was worth to find
out their oxidation potential E ox, and this was achieved by employing cyclic voltammmetry (CV).
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The values obt ained were 0.54 V fo r TEMPO, 0.5 9 V for PINO, 0.08 V for DPPH and 0.39 V for
DN-DPPH (similar values are presented in literature [37]) . The CVs of the mentioned free radic als
are showed as Fig. 2.7 .
a b
c d
Fig. 2.6 . UV-Vis spectra of TEMPO (a), PINO (b), DPPH (c), and DN -DPPH (d)
0.0 0.4 0.8-4.0×10-50.04.0×10-58.0×10-5
Ered=0.43VEOX=0.54V
TEMPOI / A
E / V
0.0 0.4 0.8 1.2-8.0×10-6-4.0×10-60.04.0×10-68.0×10-61.2×10-5EOX2=0.99V
EOX1=0.59V
Ered1=0.45VPINOI / A
E / V
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-0.4 0.0 0.4 0.8 1.2-6.0×10-5-3.0×10-50.03.0×10-56.0×10-5
Ered2=0.004VEred1=0.53VEOX2=0.62V
EOX1=0.088V
DPPHI / A
E / V
-0.4 0.0 0.4 0.8 1.2-4.0×10-5-2.0×10-50.02.0×10-54.0×10-56.0×10-5
Ered2=0.29VEred1=0.82VEOX2=0.91V
EOX1=0.39V
DNDPPHI / A
E / V
Fig. 2.7 . Cyclic voltammetry of TEMPO, PINO, DPPH, and DN -DPPH
Selective oxidation of primary and secondary alcohols to the corresponding aldehydes and
ketones is one of the most problematic reactions in organic chemistry [38]. A classical procedure
usually involves transition metal ions in at least stoichiometric quantities, which eventually leads
to the following two important issues: separation of the desired product and managem ent of the
large quantities of transition metal ion by -products.
As a consequence of these major difficulties, there is a continuous interest in the improvement
of such procedures or in the developing of new ones [39]. A better approach should avoid the
environmental matter and diminish the work -up protocol, thus making possible large -scale or even
industrial applications.
Currently, there are under consideration novel catalytic methods that involve clean oxidants
like air, hydrogen peroxide or sodium hypochlorite and non -metallic catalysts [40,41]. A
promising and nowadays well documented procedure makes use of stable or persistent free radicals
as catalyst and of air as final oxidant [42].
In the last decade nitroxides stable free radicals were succes sfully used as organ -catalyst for a
wide range of oxidations, including here those considered green (i.e. using air as oxidant, solvent
free reactions, high selectivity, mild conditions, etc.) [43-45]. Among nitroxides, TEMPO and
PINO free radicals are mos t known and employed in such reactions, due to their effectiveness [46-
48].
Other stable free radicals, which a lso have oxidant capacities, an expanding benefit in
antioxidants, especially in those expected to keep the assumed harmful impacts of free radic als in
the human body are hydrazyl ones, l ike DPPH, and its congener 2,2 -p-nitrophenyl -1-
picrylhydrazyl.
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DPPH has discovered numerous applications due to its exceptional purple shading that
progression at whatever point it reacts and high stability [31,4 9,50].
Although there is available large amount of quantitative data about the efficiency of
TEMPO or PINO in such catalytic oxidation reactions, no direct comparison between them is
available (in addition, many literature data reports on different reaction conditions).
In an attempt to compare the catalytic properties of TEMPO with PINO, in our work we
used as substrates three activated alcohols (benzyl alcohol, 2 -phenylethanol and diphenylcarbinol,
Table 2 7) and several co -catalyst (different NO x generating systems and sodium hypochlorite);
moreover, we introduced in this comparative study the use of a stable hydrazyl free radical , DN –
DPPH.
Due to our previous experience in selective oxidations of alcohols using TEMPO
derivatives as catalysts, in this work w e chosen as co -catalysts different NO x generating systems;
besides, we used also sodium hypochlorite, as this system was one of the first used in literature in
such catalytic oxidation reactions.
Typically, the oxidation reactions of the chosen alcohols (Table 2 9) were performed at
room temperature in air atmosphere, using a ratio of 10% mol free radical and 20% mol co –
catalyst. The yields of oxidations were quantified by 1H-NMR and the values obtained are
compiled in Table 2 9. As a general rule, the firs t thing that emerges from the Table 29 is that
TEMPO is a much better catalyst compared with PINO and DN -DPPH. For all alcohols used and
also for all used co -catalysts, TEMPO performed better, reaching quantitative oxidation yields for
nitrosonium tetraflu oroborate and sodium hypochlorite co -catalyst (Entries 10, 13, 16, 19, 22, 25);
moreover, in the case of nitrogen dioxide as co -catalyst the same yields were found for benzyl
alcohol and diphenylcarbinol (Entries 28 and 34, respectively).
However, PINO see ms to be particularly good for oxidation of diphenylcarbinol in the
presence of nitrosonium tetrafluoroborate (yield 95%, Entry 17). Compared wi th the other two free
radicals, DN-DPPH gave usually the lowest yields.
The high differences between the oxidati on yields obtained by different free radicals might
be attributed to different oxidation capacity and also to different reaction mechanisms. As
mentioned before, the highest E ox has been recorded for TEMPO (0.54 V), therefore this can
explain its better pe rformance.
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Table 2 9. Result of oxidation of alcohols
Entry Catalyst Co-catalyst Alcohol Yields
1 TEMPO
NaNO 2/CH 3COOH
(A)
OH
63
2 PINO 9
3 DN-DPPH 0
4 TEMPO
OH
39
5 PINO 10
6 DN-DPPH 0
7 TEMPO
OH
28
8 PINO 16
9 DN-DPPH 25
10 TEMPO
NO+BF4-
OH
100
11 PINO 4
12 DN-DPPH 30
13 TEMPO 100
14 PINO 44
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15 DN-DPPH (B)
OH
16
16 TEMPO
OH
100
17 PINO 95
18 DN-DPPH 25
19 TEMPO
NaClO/ KBr
(C)
OH
100
20 PINO 16
21 DN-DPPH 9
22 TEMPO
OH
100
23 PINO 38
24 DN-DPPH 7
25 TEMPO
OH
100
26 PINO 28
27 DN-DPPH 53
28 TEMPO NO 2
(D)
OH
100
29 PINO 0
30 DN-DPPH 1
31 TEMPO
OH
16
32 PINO 10
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33 DN-DPPH 0
34 TEMPO
OH
100
35 PINO 0
36 DN-DPPH 25
2.3. Mechanisms
Regarding the mechanisms, there are two ways of action, one for nitroxide type free
radicals and one for hydrazyl. Fig. 2.8 , shows these p athways in a simplified manner. For the type
I mechanism, the now classical pathway involving oxoammonium salt is taking place [29,51].
Thus, the nitroxide radical (TEMPO or PINO) is oxidized via one electron transfer to the more
powerful oxoammonium oxidant, and this oxidizes the alcohol to the corresponding aldehyde or
ketone. The hydroxylamine formed is easily oxidized even by air to the nitroxide radical, thus
closing the catalytic cycle. Usin g NHPI instead of TEMPO, the same pathway is followed, as the
oxidant (nitrogen dioxide or sodium hypochlorite) generates in situ the PINO nitroxide free
radical.
Ahmed Juwad Shakir – Doctoral Thesis
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NONN
OHH
OOHH
O
NNHNOHoxoxII
INOox
Fig. 2.8 . The two proposed mechanisms of oxidation, involving a nitroxide (I) and a hydrazyl (II)
free radical
A simpler catalytic cycle is taking place using DN -DPPH. This is able to directly extract
one hydrogen atom from the alcohol, leading finally to the desired product. DN -DPPH is reduced
to the corresponding hydrazine, and this is re -oxidized (i.e. by nitrogen dioxide) to the starting
hydrazyl free radical.
It is worth to mention that in both mechanisms the final oxidant is the oxygen from air,
nitrogen dioxide having its own catalytic cycle, as well it is documented in literature [47,48, 52,37].
2.4. Conclusion
In conclusion, the experiment has been done in order to compare the activity of different
free radi cals, nitroxides and hydrazyl. I n this experim ent, we have chosen the two kinds of
nitroxides, TEMPO and PINO. Along with one type of hydrazyl (DN -DPPH). However, we have
found that TMPO was more active as catalyst towards the oxidation of alcohols.
Ahmed Juwad Shakir – Doctoral Thesis
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2.5. References
[34] Li, J., Lv, G., Lu, B., Wang, Y., Deng, T., Hou, X., Yang, Y., Energy Technology. 2016.
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[37] Nanjo, F., Goto, K., Seto, R., Suzuki, M., Sakai, M., Hara, Y., Free Radicals Biol. Med. 1996,
21, 895.
[38] Yokozawa, T., Chen, C. P., Dong, E., Tanaka, T., Nonaka, G., Nishioka, I., Biochem.
Pharmacol. 1998, 56, 213.
[39] Ionita, P., Whitwood, A. C. , Gilbert, B. C. , J. Chem. Soc., Perkin Trans. 2000, 2, 2436.
[40] Tojo , G., Fernandez, M., Oxidation of Alcohols to Aldehydes and Ketones, Springer, 2006.
[41] Backvall, J. E., Modern Oxidation Methods, Wiley, Weinheim, 2004.
[42] Lenoir, D., Angew. Chem., Int. Ed. 2006, 45, 3206.
[43] Ciriminna, R., Blum, J., Avnir , D., Pagliaro, M., Chem. Commun. 2000, 1441.
[44] Sheldon, R. A. , Arenas, I. W. C. E. , Adv. Synthesis & Catal. 2004, 356, 1051.
[45] Balterson, A. R. , Lambert, K. M. , Bobbitt, J. M. , Bailey, W. F. , ChemCatChem. 2016, 8,
3421.
[46] Holan, M., Jahn, U., Organic Letters. 2014, 16, 58.
[47] Shakir, A. J. , Culita, D. C. , Moreno, J. C. , Musuc, A., Carp, O., Ionita, G ., Ionita, P., Carbon,
2016, 10, 607.
[48] Coseri, S., Catal. Rev. 2009, 51, 218.
[49] Popescu, D. O., Ionita, P., Zarna, N., Covaci, I., Stoica, A., Zarna, A., Nourescu, D., Spafiu,
F., Badea, F., Luca, C., Caproiu, M. T., Constantinescu, T., Balaban, A. T., Roum. Quart.
Rev. 1998, 6, 271.
[50] Nanjo, F., Mori, M., Goto, K., Hara, Y., Bio sci. Biotechnol. Biochem. 1999, 63, 1621.
[51] Sawai, Y., Moon, J. H., Sakata, K., Watanabe, N., Mol. J Sci. 2006, 7, 141 and J. Agric. Food
Chem. 2005, 53, 3598.
[52] Ionita, P., Gilbert, B. C., Whitwood, A. C., Org. Chem. Lett. 2004, 1, 70.
Ahmed Juwad Shakir – Doctoral Thesis
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Chapter 3. Stable organic polyradicals as oxidants
3.1. Introduction
The polyradicals synthesized in our research project are similar with those already known
[29-34] and they were obtained by similar experimental procedures, as shown in literature (see
Experimental part). Fig. 3.1 .
Summariz ing, the synthesis consists in simple coupling reaction s (such is an amide bond
formation), which were achieved by linking together an acid and an amine derivative
(commercially available) in the presence of the coupling agent N-ethoxycarbonyl -2-ethoxy -1,2-
dihydroquinoline (EEDQ).
Ahmed Juwad Shakir – Doctoral Thesis
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N
N NNHN
N
HN
HO O
O OOO
TRI-PN
N
OHN N
HOO
DI-T
NNN
NOH
N
SOHN
SO
O
O
NH
ON
HO
O
TE-T
NNNN
NNH
N
OO
N
HNHO
O
HN OO
OO.
.
TE-P
Fig. 3 .1. Structure of polyradicals
Ahmed Juwad Shakir – Doctoral Thesis
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3.3. Synthesis and characterization of polyradicals
DI-T radical was prepared by adding 4 -isocyanato -TEMPO to 4-amino -TEMPO in THF. 4-
Isocyanato -TEMPO was obtained in a similar way as literature data [35]. Using 4-amino -TEMPO
and diphosgene. (Fig. 3.2 ).
N
ONH2
diphosgen
N
ONCON
ONCO N
HN N
HOO
4-NH2-TEMPO
DI-T N
O
Fig. 3 .2. Synthesis of DI -T radical
The ESR spectra of the polyradicals thus synthesized showed the expected triplet with
additional features due to the spin -spin coupling. The presence of two or more nitroxide moieties
in a molecular structure usually is accompanied by the appearance in the ESR spectra of additional
lines attributed to spin -spin coupling. The intensity and number of lines depend on the ratio
between coupling constant ( J) and the hyperfine constant ( aN), and probability of collision with
solvent mo lecules (the solvent nature) [34 ].
As a consequence, the polyradicals used in this study show the expected triplet attributed to
interaction of the unpaired electron with the N nucleus and additional lines attri buted to spin -spin
interactions. The values of line -width of the central line increase in the case of polyradicals
compared with those observed for TEMPO and PROXYL monoradicals as an effect of spin -spin
Ahmed Juwad Shakir – Doctoral Thesis
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interactions, as well. HR -MS spectra confirmed also the structure of the compounds. The ESR
spectra of DI -T shown in Fig. 3.3 . The y ield was around 50 %. HR -MS: m/z calculated for
C19H36N4O3 [M+H+] 368.2807 ; it was found to be 368.2728 . Fig. 3.4.
Fig. 3.3. ESR spectra of DI-T radical
Fig. 3 .4. HR-MS spectrum of DI -T radical
TRI-P radical was prepared by adding tris(2 -aminoethyl)amine, EEDQ and 3 -carboxy –
PROXYL free radical to a mixture of DCM and THF (9/1 v/v) as solvent .
The crude mixture was purified by column chromatography using silica as the stationary
phase and ethyl acetate as the eluent.
Ahmed Juwad Shakir – Doctoral Thesis
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N
N NNHN
N
HN
HO O
O OOO
NO
OH
NNH2
H2N NH2+
TRI-PEEDQO
Fig. 3.5. Synthesis of TRI -P radical
The ESR spectra of TRI-P radical shown in Fig. 3 .6. The y ield was around 30%. HR -MS:
m/z calculated for C 33H61N7O6 [M+H+] 651.4678; it was found to be 651.5704. Fig. 3 .7.
Fig. 3.6. ESR spectra of TRP-P radical
Fig. 3 .7. HR-MS spectrum of TRP-P radical
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TE-T radical was obtained by reacting of the disulphide with 4 -amino -TEMPO in the
presence of EEDQ. The ESR spectra of TE -T radical. 2,2’-succinic acid disulphide was obtained
by oxidation of 2-mercapto -succcinic acid [ 29]. The y ield was quantitative. Fig. 3 .8.
OSH
O
OH
OHO
SOOH
S
O
OOHHO
OHI2
NNN
NOH
N
SOHN
SO
O
O
NH
ON
HOO
SOOH
S
OOHHO
TE-T
EEDQ
OO
HO
Fig. 3.8. Synthesis of TE-T radical
The crude mixture was purified by column chromatography using silica as the stationary
phase and ethyl acetate as the eluent. The ESR spectra of TE-T radical shown in Fig. 3 .9. The y ield
was 30%. HR -MS: m/z calculated for C 44H80N8O8S2 [M+2H+] 912.5535 was found to be 912.5584.
Fig. 3 .10.
Fig. 3.9. ESR spectra of TE -T radical
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 3 .10. HR-MS spectrum of TE-T radical
TE-P radical was obtained by dissolving DAB -Am-4 dendrimer (polypropylenimine
tetramine dendrimer, generation 1) with EEDQ and 3 -carboxy -PROXYL free radical into a
mixture made up of DCM and THF as the solvent.
NNNN
NNH
N
OO
N
HNHO
O
HN OO
OONNNH2
H2NNH2
NH2NO
OOH.
..
+
TE-PEEDQ
Fig. 3.11. Synthesis of TE -P radical
Ahmed Juwad Shakir – Doctoral Thesis
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The ESR spectra of TE -P radical shown in Fig. 3 .15. The yield was around 20%. HR -MS:
m/z calculated for C 52H97N10O8 [M+H+] 989.7485 was found to be 989.7488. Fig. 3.16.
Fig. 3.12. ESR spectra of TE -P radical
Fig. 3 .13. HR-MS spectrum of TE-P radical
The investigation on catalytic activity of these polyradicals in oxidation processes has been
performed aiming to evidence the influence of structural features of the paramagnetic moiety and
to find out if there is any synergic effect of the presence of tw o or more paramagnetic groups in the
molecular structure.
For testing as substrates in the oxidation procedure, we took into consideration five
alcohols, with different reactivity, namely benzyl alcohol, 1 -phenyl -ethanol, diphenyl -methanol, 1 –
octanol and f urfurol alcohol (Table 31).
The oxidation reactions were performed under air, using DCM as solvent; as nitrogen
oxides source has been used a mixture of sodium nitrite and acetic acid, as literature data showed
[36,37 ]. The results are compiled into Table 31.
Table 31 . Yields of oxidation (measured by NMR) of the employed alcohols to the corresponding
aldehydes or ketone using the synthesized polyradicals
Ahmed Juwad Shakir – Doctoral Thesis
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Entry Alcohol Polyradical Yield %
1
OH
DI-T 96
2 TRI-P 55
3 TE-T 100
4 TE-P 38
5
OH CH3
DI-T 56
6 TRI-P 25
7 TE-T 45
8 TE-P 21
9
OH
DI-T 29
10 TRI-P 44
11 TE-T 34
12 TE-P 60
13 DI-T 20
14 TRI-P 18
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15
OH
TE-T 1
16 TE-P 8
17
OOH
DI-T 100
18 TRI-P 66
19 TE-T 2
20 TE-P 10
As a general rule, it is noticed that activated alcohols gave higher yields of oxidation,
reaching 96 -100% for benzyl alcohol and furfurol (Entries 1, 3 and 17, Table 31), while 1 -octanol
cannot overpass 20% (Entry 13). PROXL derived poly -radicals (TRI -P and TE -P) generally gave
lower results than TEMPO derived poly-radicals (DI -T and TE -T); however, in the case of
diphenylmethanol the tendency is reversed (Entry 10 and 12 compared with Entry 9 and 11).
Comparison of the yields obtained for alcohol oxidation in the presence of TEMPO monoradicals
with those obtain ed in the present study leads to conclusion that using of polyradicals does not
improve the oxidative process, comparatively with the use of monoradicals;[37,38] moreover, we
were unable to recover it in order to recycle them (however, the un -reacted alcoh ols can be
recovered, as no other decomposition or oxidation products of them were noticed). Another
explanation of the different reactivities regarding the benzyl alcohol derivatives may consist in the
steric hindrance; also, the stability of the disulphi de group towards NOx sh ould not be disregarded.
3.4. Mechanistic proposal
Regarding the mechanism of reaction, Fig. 3.20, shows an overview of the reactions that
took place; this is well known in literature [39-43]. Nitrogen oxides are generated from the
reaction of sodium nitrite with acetic acid, which are mostly converted into nitrogen dioxide due to
the presence of air (oxygen). Nitrogen dioxide oxidizes the nitroxide moieties from TEMPO or
Ahmed Juwad Shakir – Doctoral Thesis
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PROXYL into the corr esponding oxoammonium salts, which oxidize further the alcohol. The
stable free radical is regenerated by the oxidation of the hydroxylamine, thus closing the catalytic
cycle.
R1
R2OH
H
OR1
R2NO
NOHNO
O2NO2NaNO2 + CH3COOH CH3COONa + HNO2
2 HNO2H2O + NO + NO2
2NO + O2 2 NO2
Fig. 3.20. Proposed mechanism for selective ox idation of alcohols
Ahmed Juwad Shakir – Doctoral Thesis
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Our attempts to collect the polyradical (for afterward reuse) by different means
(precipitation or even chromatographic separation) failed. A closer look by TLC analysis indicated
that a part of the polyradical is destroyed in the oxida tive process, probably due to the labile amido
or disulphide groups. No further experiments for improving the recyclability were made. In these
conditions, the grafting of polyradical to a solid support remains as a solution to assuring their re –
use in a c atalytic cycle. This procedure will be used in the following chapter.
3.5. Conclusion
The polyradicals used can act as catalysts in selective oxidation processes of alcohols.
Polyradicals containing TEMPO moieties gave better results than PROXYL ones. The yields
depend on the reactivity of the alcohol and can be quantitative for benzyl alcohol and furfurol. The
main drawback is the difficulty to recycle the catalyst.
Ahmed Juwad Shakir – Doctoral Thesis
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3.6. References
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[2] Tojo, G., Fernandez, M., Oxidation of alcohols to aldehydes and Ketones, Springer. 2006.
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[15] Forrester, A. R., Organic chemistry of stable free radicals. Academic Press, London. 1968.
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Chem. 2005, 2, 348.
[20] Ziessel, R., Stroh, C., Heise, H., Kohler, F. H., Turek, P., Claiser, N., Souhassou, M.,
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[21] Benaglia, M., Puglisi, A ., Holczknecht, O., Quici, S., Pozzi, G., Tetrahedron . 2005, 61, 12058 .
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[23] Ferreira, P., Phillips, E., Rippon, D., Tsang, S. C., The J. org. chem . 2004, 69(20), 6851 .
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[25] Ionita, P., Gilbert, B. C., Chechik, V. Angew. Chem. Int. Ed . 2005, 44, 3720.
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[26] Sahini, V. , Em., Ionita, G., Ionita, P., Acta Chim. Slovenica. 2000, 47, 111.
[27] Krinitskaya, L. A., Buchachenko, A. L., and Rozantsev, E. G., Zh. Org. Khim. 1966, 2,
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[28] Griffth, O. H., Keana, J. F. W., Rottschaefer, S., Warlick, T. A., J. Amer. Chem. Soc.
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[29] Caproiu, M. T., Ionita, G., Draghici, C., Ionita, P., Arkivoc. Xiv., 2008, 158.
[30] Yochai, B., Alfred, H., J. Org. Chem. 2000, 65, 6368.
[31] Ashok, J. M., Nicholas, J. T., Anton, W. B., Jeroen, C., Meijer. E. W., J. Phys. Chem. A.
2003, 107, 8467.
[32] Bosman, A. V., Janssen, R. A. J., Meijer, E. W., Macromolecules. 1997, 30, 3606.
[33] Yordanov, A. T., Yamada, K., Khrisna, M. C., Mitchell, J. B., Woller, E., Cloninger, M.,
Brechbiel, M. W., Angew. Chem. Int. Ed. 2001, 40, 2690.
[34] Kokorin, A. I., Tran, V. A., Rasmussen, K., Grampp, G., Appl Magn Reson. 2006, 30, 35.
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[36] Shibuya, M., Osada, Y., Sasano, Y., Tomizawa, M., Iwabuchi, Y., J Am Chem Soc. 2011,
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Ahmed Juwad Shakir – Doctoral Thesis
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Chapter 4 . A convenient alternative for the selective
oxidation of alcohols by silica supported TEMPO using
dioxygen as the final oxidant
4.1. Silica supported TEMPO
Oxidation processes often require harsh experimental conditions, involving transition
metals and str ong acids [1]. The oxidation of alcohols leads in the first step to the formation of the
corresponding aldehydes or ketones and , in the second step , aldehydes can be converted into
carboxylic acids by common oxidants, including air.
Frequently, alcohol oxi dation cannot be stopped at the carbonyl derivative, therefore
selective oxidation methods are highly desirable [2]. Many syntheses of medicines or other fine
chemicals require aldehydes and ketones as intermediates [3], and there is a high demand for
specific aldehydes and ketones: for example, menthone and octanal are used in the fragrance
industry, while cyclohexanone is a precursor in the plastic s industry.
The Jones reagent (CrO 3, aq H 2SO 4) and pyridinium dichromate (Cornforth reagent, PDC)
are some of the most used oxidants. Because a stoichiometric amount of reagents is needed to
convert primary alcohols into aldehydes [1-4], isolation of the desired compound from the reaction
mixture requires extensive work -up and generates a large amount of toxic ch emical waste.
Nowadays, literature data are rich in novel methods of using transition -metal free aerobic
oxidation, that is, those involving hypervalent iodine compounds (Dess –Martin oxidation), oxalyl
chloride/DMSO (Swern oxidation), sodium hypochlorite, nitric acid or its salts and nitroxide free
radicals [1-10].
One of the commonly used compounds for oxidation is the stable free radical TEMPO [11-
14]. Although it possesses an unpaired electron, this chemical is stable under normal conditions,
and does no t dimerize or react with dioxygen from the air.
This free radical can be involved in acid –base and redox type processes, as shown in Fig.
4.1. The oxoammonium salt of TEMPO is also well known as a strong yet specific oxidant [15].
On the other hand, TEMPO is often used in combination with transition metals and
seldomly with metal -free cocatalysts. For example, copper, iron, manganese and silver have
commonly been used as transition metal cocatalysts [16-19], while halogens and/or acids have
been employed in the metal -free systems [20,21 ]. Furthermore, iron oxide nanoparticles together
Ahmed Juwad Shakir – Doctoral Thesis
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with TEMPO (free or covalently attached) were employed as catalytic systems for the oxidation of
benzylic alcohols [22-24].
N
ON
OH
N
O
N
O+ H
– H- H+
+ H+
+ e-
– e-
– e-
+ e-
Fig. 4 .1. Acid–base and redox processes of TEMPO free radical (H- may stand also for H+ + e-)
A breakthrough in such systems was the exploit of nitrogen oxides as mediator between
dioxygen and TEMPO [6,11,13,20,30,31 ]. Initially, NO x was obtained in situ from sodium nitrite
and acetic acid, but the drawbacks of removing the acetic acid from the reaction systems pointed
out to the use of gaseous NO x. However, working with gaseous NO x represents a problematic issue
from a practical point of view. This incon venient has been surpassed by absorbing gaseous NO x
into silica supported TEMPO, yielding thus a solid catalyst which practically does not require
either an additional cocatalyst or an acid [30].
Bobbitt’s salt (4 -acetamido -2,2,6,6 -tetramethylpiperidine -1-oxoammonium
tetrafluoroborate) [25], an inexpensive TEMPO derivative, can be easily prepared in a green
manner, using water as the solvent and minimizing the use of environmentally unfriendly
materials. Such oxoammonium salts are metal -free, nontoxic and, after use, the spent oxidant can
be recovered and reused, thereby making the process recyclable [25].
Heterogeneous catalysts are preferred in large scale or industrial applications. Therefore, in
this work we continue o ur research into conducting practical oxidations of different types of
Ahmed Juwad Shakir – Doctoral Thesis
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alcohols employing new NOx and TEMPO bas ed systems. The newly developed metal -free system
employing commercially available silica supported TEMPO as the catalyst and a nitrosonium
tetrafluoroborate cocatalyst could be used unde r very mild reaction conditions to obtain a variety
of alde hydes or ketones in high yields, as is shown below.
4.2. Silica supported TEMPO for oxidation of alcohols
As part of our interest in organic reactions mediated by sta ble free radicals, we continued
our studies aimed at finding im proved and cost -effective strategies for the selective oxidation of a
range of different alcohols (primary, seco ndary, aliphatic, aromatic, and cyclic) to the
corre sponding aldehydes and ketone s.
We started this study with the previously described catalyst (NO 2 on TEMPO) [30 ], and
employing more complicated substrates, known for their lower reactivity and containing moieties
that were also suitable for oxidation such as double bonds (Table 33). Besides the previously
explored activated phenyl a lcohols the types of alcohols used was enlarged from simple ones (1-
octanol or cyclohexanol) to steroids (i.e., testosterone) or hetero -alcohols (furan and pyridine
derivatives).
Previously used activated alcohols (benzylic alcohol, 1-phenylethanol and
diphenylcarbi nol) afforded the corresponding aldehyde and ketones in over 90% yields after 24 h
using NO 2 as a cocatalyst.
Using nitrosonium tetrafluoroborate as a cocatalyst, similar results were obtained in much
shorter times: 92% for benzaldehyde ( Table 3 3, entry 22, 2 h), 100% for acetophenone (entry 24, 1
h), and 67% for diphenylketone (entry 26, 2 h).
Ahmed Juwad Shakir – Doctoral Thesis
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Table 33 . Oxidation of various alcohols using silica supported TEMPO as catalyst and nitrogen
dioxide or nitrosonium tetrafluoroborate as cocatalyst
Entry Product Cocatalyst Molar ratio
substrate/
catalyst/
cocatalyst Time (h) Yields (%)
1
2
O
NO 2 1/ 0.2 /0.2 4
16 8
40
3 NO+BF4- 1/ 0.1 /0.1 8
4 1/ 0.2 /0.1 4 18
5 1/ 0.1 /0.2 18
6 1/ 0.2 /0.2 97
7
O
NO 2 1/0.2/0.2 4 0
8 NO+BF4- 1/0.2/0.2 4 0
9 16 50
10
OO
NO 2 1/ 0.2 /0.2 16 9
11 NO+BF4- 1/ 0.2 /0.2 16 27
Ahmed Juwad Shakir – Doctoral Thesis
127
12
NO 2 1/ 0.2 /0.2 4 0
13
O
16 1
14 NO+BF4- 1/ 0.1 /0.1 16 25
15 1/ 0.2 /0.2 16 38
16
OO
NO 2 1/ 0.2 /0.2 4 40
17 16 60
18 NO+BF4- 1/ 0.2 /0.2 16 93
19
OO
NO+BF4- 1/ 0.2 /0.2 4 99
20 16 90
21
O
NO+BF4- 1/ 0.2 /0.2 1 73
22 2 92
23
CO
CH3
NO+BF4- 1/ 0.2 /0.2 1 100
24 1/ 0.1 /0.1 2 100
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25
O
NO+BF4- 1/ 0.2 /0.2 1 50
26 2 67
27
N N
O O
NO 2 1/0.1/0.1 72 99
28 NO+BF4- 1/ 0.2 /0.2 16 99
Encouraged by these results, we tried to extend the process to a wide range of alcohols. For
the start, a series of reactions were performed using cyclohexanol, menthol, furfuryl alcohol and 1 –
octanol, for both nitrogen dioxide and nitrosonium tetrafluoroborate as cocatalyst. Different ratios
between substrate, catalyst and cocatalyst were studied , as well different reaction times. As a
general rule, higher reaction time improves the yields of oxidation, as well as the amount of
catalyst or cocatalyst used (Table 3 3).
Interestingly, nitrosonium tetrafluoroborate seems to be a far better cocatalyst than nitrogen
dioxide. In the case of cyclohexanol, after 4 h, nitrogen dioxide is able to convert only 8% into
cyclohexanone (Entry 1), while nitrosonium tetrafluoroborate 97% (Entry 6). For menthol, no
oxidation has been observed in the case of nitrogen dioxide (Entry 7), even after 16 h (Entry 8),
while nitrosonium tetrafluoroborate converted 50% of menthol into menthone after 16 h (Entry 9).
Similar results were obtained for furfuryl alcohol, an increased yield from 9% (Entry 9) to 27%
(Entry 10), and f or 1-octanol an increased yield from 1% to 38% (Entries 13 and 15).
Using more complicated substrates (of steroids type), the same tendency has been noticed;
the yields in oxidation products are over 90% (Entry 18, 93%; Entry 19, 99%). Same result has
been obtained in the case of a dialcohol (yield 99%, Entry 27 and 28).
Ahmed Juwad Shakir – Doctoral Thesis
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4.3. Catalytic system robustness
Silica is a very good support for TEMPO, as it is stable over a wide range of pH and can be
easily modified using silica -coupling reagents; in addition, it is a solid that can be simply
recovered and used repeatedly.
It was shown previously that silica supported TEMPO/ NOx system can be used in a
second oxidation process without the need to be reactivated by passing through nitrogen dioxide,
but its efficien cy decreases, requ iring longer time of reaction [30 ]. The efficiency of the recycled
silica supported TEMPO in the new system remains very similar with the first used one, requiring
only the addition of nitrosonium tetrafluoroborate.
As a model we reproduc ed the Entry 23 a nd recycled the catalyst. Fig. 4.2, shows that even
after 4 runs silica supported TEMPO kept its original properties; however, after the 4th run the
yields were below 70% and the catalyst needs to be restored by washing with water or metha nol.
This is due probably to the accumulation of solid residues on the silica (i.e. tetrafluoroborate salts)
than cannot be removed by DCM, but are easily soluble in water or methanol. The simple
separation of the solid heterocatalyst from the reaction pro cess and its fully reuse is an economic
and green improvement.
Fig. 4.2. Efficiency of the recovered catalyst (for Entry 23; grey columns – after washing with
DCM; black col umn- after washing with water).
4.4. Mechanistic proposal
Literature data show generally two types of mechanisms for such selective oxidations
mediated by TEMPO, involving two different pathways: i) in situ gener ation of the oxoammonium
cation [5,20 ] and ii) a complicated cooperative redox mechanism involving transition metals [32].
020406080100
1 2 3 4 5
Runs%
Ahmed Juwad Shakir – Doctoral Thesis
130
A simple manner to assign the correct mechanism is to compare the redox potential of the
TEMPO+/TEMPO couple with the involved partner oxidant, used as cocatalyst, but this fact cannot
be taken in an absolute way, as a metal ion can tune the reactivity of TEMPO free radical [33].
For the first pathway, there is compulsory the presence of an oxidant able to convert the
nitroxide free radical into its oxoammonium cation, such are NO x and its related derivatives (i.e.
alkyl nitrites), peroxides, halogens, and other generally strong oxidants [9].
If the cocatalyst cannot directly oxidize TEMPO (i.e. copper salts), a complicated
concerted two -electron alcohol oxidation takes place. Very recently, this issue has been finally
well resolved, reconciling a collectio n of diverse and seemingly contradictory experimental and
computational data reported previously in the literature [32].
Nevertheless, in our case, the oxoammonium cation is the intermediate oxidant of the
alcohols, as NO+/NO redox pair in the presence of TEMPO has been proved to be able to oxidize
alcohols in an an aerobic system [9]. Therefore, nitrosonium tetrafluoroborate oxidizes TEMPO
into the corresponding oxoammonium cation, yiel ding in the same time NO (Fig. 4.8).
NO easily reacts with dioxygen yielding nitrogen dioxide (it is worth to mention that
dioxygen, nitrogen oxide and nitrogen dioxide are all stable free radicals, as they contain in their
molecule an unpaired electron). Nitrogen dioxide oxidises TEMPOH to TEMPO in a first step; of
course , it is also possible to oxidize TEMPO to TEMPO+ in a second step, thus reforming the
active oxidant species. The NO/NO 2 and TEMPO+/TEMPO cycles represents practically the two
active catalytic processes, acting as an electron transfer double bridge; on the other hand, dioxygen
is the final oxidant and water the by -product of alcohols oxidations ( Fig. 4.3).
The solid TEMPO catalyst operates as a reservoir of NO x, and NO x are practically the
species that activate dioxygen [30,34] . Overall, the catalytic syste m involving NO x as an
unconventional oxidant is a very promising alternative for oxidation of a broad array of alcohols
with minimal workout.
Ahmed Juwad Shakir – Doctoral Thesis
131
NO2NO2
NO
BF4
silica silica_silica
NO+BF4-OH2O
or NO2NOH
NOCO
R2R1
H
R2R1HO
Fig. 4.3. A proposed mechanism involving TEMPO and NO x species
4.5. Conclusion
Silica immobilized TEMPO as a catalyst in conjunction with nitrosonium tetrafluoroborate
as cocatalyst was used to selectively convert a wide range of alcohols into the corresponding
aldehydes or ketones. The process minimizes the drawbacks of classicaloxi dation systems (acidic
media, halogens, transition metals, orgaseous nitrogen oxides), proceeding at room temperature
under metal, acid and halogen free conditions.
Dioxygen is the final oxidant and water is obtained as a by -product. The solid catalyst ca n
be easily recovered and reused directly. This system, which is the first time that nitrosonium
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tetrafluoroborate has been used as a cocatalyst, represents a good alternative f or selective alcohol
oxidation.
4.6. Refer ences
[1] Smith, M. B., March, J., March’s Advanced Organic Chemistry; John Wiley: New Jersey. 2007
[2] Backvall, J. E. Modern Oxidation Methods; Wiley. Weinheim, 2004.
[3] Tojo, G., Fernandez, M., Oxidation of Alcohols to Aldehydes and Ketones; Springer. 2006.
[4] Burke, S. D., Danheiser, R. L., Oxidizing and Reducing Agents; John Wiley: NewYork. 1999.
[5] Aellig, C., Scholz, D., Conrad, S., Hermans, I., Green Chem. 2013, 15, 1975.
[6] Wertz, S., Studer, A., Green Chem. 2013, 15, 3116.
[7] Prebil, R., Stavber, G. Stavber, S., Eur. J. Org. Chem. 2014, 2, 395.
[8] Naimi -Jamal, M. R., Hamzeali, H., Mokhtari, J., Boy, J., Kaupp, G., ChemSusChem 2009, 2,
83.
[9] Holan, M., Jahn, U., Org. Lett. 2014, 16, 58.
Ahmed Juwad Shakir – Doctoral Thesis
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[10] Saito, K., Hirose, K., Okayasu, T., Nishide, H., Hearn, M. T. W., R SC Adv. 2013, 3, 9752.
[11] Sabbatini, A., Martins, L. M. D. R. S., Mahmudov, K. T., Kopylovich, M. N., Drewe, M. G.
B., Pettinari, C., Pombeiro, A. J. L. Catal. Commun. 2014, 48, 69.
[12] Kompanets, M. O., Kushcha, O. V., Litvinov, Yu. E., Pliekhova, O. L ., Novikova, K. V.,
Novokhatko, A. O., Shendrik, A. N., Vasilyev, A. V., Opeida, I. O. Catal. Commun. 2014, 57,
60.
[13] Yan, Y., Tong, X., Wang, K., Bai, X., Catal. Commun. 2014, 43, 112.
[14] Vogler, T., Studer, A., Synthesis. 2008, 13, 1979.
[15] Lenoir , D., Angew. Chem. Int. Ed. 2006, 45, 3206.
[16] Hu, Z., Kertan, F. M., Org. Biomol. Chem. 2012, 10, 1618.
[17] Liu, J., Ma, S., Tetrahedron. 2013, 69, 10161.
[18] Ryland, B. L., Stahl, S. S., Angew. Chem. Int. Ed. 2014, 53, 8824.
[19] Jeena, V., Robinson, R. S., Chem. Commun. 2012, 299.
[20] Shibuya, M., Osada, Y., Sasano, Y., Tomizawa, M., Iwabuchi, Y., J. Am. Chem. Soc. 2011,
133, 6497.
[21] Moriyama, K., Takemura, M., Togo, H., J. Org. Chem. 2014, 79, 6094.
[22] Obermayer, D., Balu, A. M., Romero, A. A., Goesller, W., Luque, R., Kappe, C. O., Green
Chem. 2013, 15, 1530.
[23] Karimi, B., Mirzael, H. M., Farhangi, E., ChemCatChem. 2014, 6, 758.
[24] Karimi, B., Farhangi, E., Chem. Eur. J. 2011, 17, 6056.
[25] Mercad ante, M. A., Kelly, C. B., Bobbitt, J. M., Tilley, L. J., Leadbeater, N. E. Nat. Protoc.
2013, 8, 666.
[31] Yang, G., Wang, W., Zhu, W., An, C., Gao, X., Song, M., Synlett. 2010, 3, 437.
[32] Ryland, B . L., McCann, S. D., Brunold , T. C., Stahl, S. S., J. Am. Chem . Soc. 2014, 136,
12166.
[33] Scepaniak, J. J., Wright, A. M., Lewis, R. A., Wu, G., Hayton, T. W. , J. Am. Chem. Soc.
2012, 134, 19350.
[34] Luts, T., Iglesia, E., Katz, A. Mater . J. Chem . 2011 , 21, 982.
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Chapter 5. Exploring porous nanosilica -TEMPO as
heterogeneous aerobic oxidation catalyst: the influence
of supported gold clusters
5.1. Nanosilica -TEMPO as heterogeneous catalyst
Heterogeneous catalysis is one of the most used industrial processes, being used for the
completion of a large variety of oxidation reactions, among others . The choice for such processes
is due first to the eas y recycling of the catalyst and the use of simpler procedures that allow a
greener and more environmental ly friendly approach [1-3].
Selective oxidation of primary and secondary alcohols to the corresponding aldehydes and
ketones is one of the most required processes in the production of fine chemicals [6,7].
Traditionally, such oxidations are made using excess of transition metal compounds (like
manganese or chromium derivatives), with their usual high drawbacks – large amount of toxic
waste, time consuming processes, expensive procedures [8,12,13 ].
A promising alternative for these methods is the use of stable free radicals, namely TEMPO
derivatives, as the catalyst in oxidation processes [14-16,2, 11,4-7,12, 8]. Such nitroxide free
radicals have quite interesting properties, showing redox behavior (Fig. 5.1); moreover, they are
indefinitely stable under ambient conditions, do not dimerize nor do they react with atmospheric
oxygen [12,13 ,9,10 ]. However, TEMPO its elf doesn’t have the ability to oxidize alcohols, a
cocatalyst being required [17-19].
The role of the cocatalyst is to extract one electron from TEMPO, yielding the
oxoammonium ion (Fig. 5.1), which is the real oxidant in such processes. As cocatalyst wer e
employed a wide range of chemicals, including nitrogen oxides, nitric acid, transition metal ions,
halogens, etc [77,20,21 ].
In the last decade’s gold catalyzed processes became a follow -up trend, starting mainly
after the discovery that the noble metal gold may have extremely powerful catalytic activity (i.e.
gold clusters can oxidize carbon monoxide) [22]. Literature data regarding novel approaches for
selective oxidation showed that gold nanoparticles (Au NPs) can also convert benzylic alcohols
into al dehydes or even esters (through an oxidative coupling). Such processes do not require an
additional cocatalyst, as is usual in the case of TEMPO [23-25].
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N
ON
O
N
O+ e-
– e-+ e-
– e-
Fig. 5.1. Redox behavior of TEMPO
Interestingly, recently it was reported that TEMPO can greatly extend the lifetime of the
gold (III) chloride catalyst (the turnovers of it being increased by 3300% and the catalytic activity
maintained for 33 cycles); this procedure can lower the cost of the gold catalyst in applied
synthesis [26].
Gold nanoparticles contain a diversity of conjugated and non -conjugated spherical gold
nanoparticles varying in size between 2 nm to 250 nm. Gold nanoclusters have applications in
catalysis [27].
In 2008, Su, FangZheng et al. [28] used gold nanoparticles on polymorphs of gallia (α – β-
ϫ- Ga2O3) for the oxidation of benzyl alcohol. A gold nanocluster (PI-Au) polymer [29] was used
in the aerobic oxidation of alcohols to methyl esters.
Ester groups are found in numerous pharmaceuticals, fragrances, agrochemicals and so on,
and these compounds are obtained usually by the well -known esterification or transesterification
processes, always requiring the presence of a strong acid or base as a catalyst. Di rect
transformation of the alcohols into esters via oxidative coupling between aldehydes and excess
alcohols is a very environmentally friendly process, performed in a single step; moreover, it can be
adapted to use as air as the final oxidant, yielding water as the byproduct .
Until now, literature data showed that direct synthesis of esters from alcohols under mild
conditions requires precious metals catalysts (palladium, gold, ruthenium, or iridium). Moreover,
there are some serious technical drawbacks -high yields are obtained only using pure oxygen under
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autoclave working conditions at elevated temperatures [31-33], therefore a more convenient and
trouble -free procedure is highly desirable.
Nanometric size catalysts have the advantage of extremely large s urface area and attracted
a high interest owing to their unique characteristics and potential. Supported metals are performing
usually better compared only with simple metal. Noble metals supported catalysts are nowadays
widely used in organic synthesis, e specially Au NPs prepared by the adsorption or deposition –
precipitation method.
Inspired by the literature data [ 17,20,25 ] and by our previous work in alcohols oxidation
mediated by TEMPO free radical and nitrogen dioxide [ 13] and by the dual behavior of gold
nanoparticle s, as generators and scavengers for short -lived free radicals [34 ], herein we tried to
pair the mediator properties of TEMPO with the ability of the gold nanoparticles to initiate free
radical oxidations, in order to achieve a new heteroge neous catalyst with improved behavior.
As mentioned before, it was also demonstrated that TE MPO highly extend the catalytic
activity of gold [ 26], therefore using a hybrid catalyst containing both gold a nd TEMPO can be a
step forward. As nitrogen dioxide s ource we used nitrosonium tetrafluoroborate, with the great
advantage of working with a solid instead a gas.
5.2. Development of the catalysts (Cat. A –D)
TEMPO free radical can be covalently bonded to (nano) silica in various way s, employing
different met hods, like sol –gel or surface modi fication reactions on preformed solid material.
Literature data showed that there are two types of linkers between t he silica surface and the
TEMPO moiety, either containing an oxygen atom (like in ethers or esters) or a nitrogen one (like
in amines) [ 35-37]. In our work we used the both types, for comparison reason.
Cat. A has been obtained by a sol –gel method, mixing together tetramethoxysil ane
(tetramethyl orthosilicate, TMOS) with 4 -hydroxy -TEMPO and gelling the combination by
addition of ammonia. Cat. B was obtained by precipitating gold on Cat.A (Cat.B is in fact the
previous one which contains supported go ld, obtained the reduction of a gold(III) salt with sodium
borohydride).
Cat. C employs a different way to covalent ly link the TEMPO moiety to the silica material;
for this r eason a mixture of TMOS and (3 – aminopropyl)trimethoxysilane (APTMOS) has been
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used as silica precursor. The T EMPO moiety has been covalently attached in two steps. In the first
one, 4 -oxo-TEMPO was reacted with the amino gro ups on the silica, yielding the corresponding
Schiff base, and in the second step the C=N bond was reduced by borohydride.
Cat. D was obtained by supporting gold on Cat. C, by reducing the gold salt with sodium
borohydride, in the same way like Cat. B. A cartoon showing a schematic drawing of catalyst
structure together with a picture of the actual solids , see Fig. 5.2.
OH
O
OHNO
SiO2OH
ONO
SiO2
OH
OHSiO2H
N NOOH
SiO2H
N NOCatalyst A Catalyst B
Catalyst C Catalyst D
Au
AuAuAu
Fig. 5.2. Structure representing Cat. A -D
5.3. Characterization of the catalysts
All catalysts were obtained as solid materials having a yellow or violet -black colour ( Fig.
5.2); the yellow color is due to the TEMPO free radical, while the violet -black colour is due to the
supported gold.
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TEM analysis showed for all samples A –D that the silica support is formed by the
agglomeration of regular nanoparticles with a size of about 20 nm; regarding the morphology of
the gold clusters deposited on silica, these are bigger in size ( 20–50 nm) and more asymmetrical in
shape. Fig. 5.3. shows the TEM images of samples A –D.
Fig. 5.3. TEM pictures of samples A –D (a silica/HO -TEMPO; b sample A on which Au NPs were
deposited; c silica/oxo -TEMPO; d sample C on which Au NPs were deposited)
IR spectra ( Fig. 5.4) do not provide a lot of information; however, there are large bands
visible between 3100 and 3500 cm-1, due to the OH and NH groups (Si –OH and C –NH moieties);
Si–O bonds are also noticed between 1200 and 1400 cm-1. Small peaks before 3000 cm-1 are
detected only for sample C and D, and those are attributed to the C –H groups; however, C –H
groups are also visible between 1350 and 1450 cm-1.
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Fig. 5.4. IR spectra of catalyst samples A -D
The nitrogen adsorption –desorption is otherms of the A – D samples showed that all are type
IV according to the IUPAC classification and the hysteresis loops are of H 2 type, typical for
mesoporous materials (Fig. 5.5).
This type of hysteresis is usually associated with the presence of interconnected pores of
not well -defined or irregular shape (often referred to as ‘ink -bottle’ pores). As can be seen in the
inset (Fig. 2.33), the pore size distribution for all samples is monomodal and relatively narrow. The
average pore diameters are in the range of about 4 –6 nm.
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0.0 0.2 0.4 0.6 0.8 1.0050100150200250300350400450
0 5 10 150.00.10.20.30.40.50.6
A
B
P/P0V (cm3g-1, STP )
D (nm)Pore volume (cm3 g-1 nm-1)
0.0 0.2 0.4 0.6 0.8 1.001020304050
0 5 10 15 200.0000.0020.0040.0060.0080.0100.0120.014
C
D
P/P0V (cm3g-1, STP )
D (nm)Pore volume (cm3 g-1 nm-1)
Fig. 5.5. N2 adsorption –desorption isotherms of A – D samples
The specific surface area for sample A is 323 m2/g. Upon deposition of gold, surface area
decreases to 257 m2/ g (sample B). As the gold clusters are bigger in size comparatively with the
pore size, therefore it is a common assumption that gold clusters are placed on the outer surface of
silica nanoparticles, a fraction of pores being blocked by the gold nanoparti cles.
Sample C has a quite smaller specific surface area (26 m2/g). This value may be explained
by taking into consideration the fact that these sample has been obtained using a mixture of TMOS
and APTMOS instead of plain TMOS, as in the case of samples A and B, and also to the low water
content used in synthesis.
The presence of the organic linkers of 3 -aminopropyl type (from APTMOS) makes the
material more compact and therefore it has a smaller surface and volume of pores. As in the case
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of sample B, depo sition of gold on the surface of sample C has as result a decrease of the surface
area an d total pore volume (Table 35 ).
Table 35 . Characterization of samples A –D
Catalyst Cat. A Cat. B Cat. C Cat. D
BET surface area (m2/g) 323 257 26 17
Average pores diameter (nm) 3.6 6.1 5.6 5.8
Total pore volume 0.41 0.50 0.05 0.03
Organic content lost (%)a 20 30 5 6
TEMPO content (mmol/g)b 0.11 0.10 0.23 0.22
Gold content (%)c 0 5 0 5
a Measured by TG –DTA, b Evaluated from ESR spectra, c Considering that all the gold has been deposited
on the silica by the thebprecipitation –deposition process
Thermal analysis performed on samples A –D showed a major difference between the
samples A –B (TEMPO linked to silica via an oxygen atom) and C –D (TEMPO linked to silica v ia
a nitrogen atom). The content lost when heating up to 300 oC for the first two samples is 20 and
30%, while for the last two samples it is only 5 and 6 %, respectively (Table 35 ).
This means firstly that TEMPO linked through the oxygen atom are more easily removed
by heating from the inorganic support comparatively with TEMPO linked through the nitrogen
atom, and secondly, the presence of gold clusters accelerates that decomposition.
Overall, these can be explained by the weak bonds Si –O–C against Si –C– N (that bound
TEMPO on silica) and by the ability of metals (in our case gold) to catalyze the decomposition of
organic materials. Moreover, in the cases of A and B samples an endothermic peak is noticed,
while for samples C and D an exothermic one is p resent (Fig. 5.6).
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Fig. 5.6. TG and DTA analysis of samples A –D
A second observation is extracted from the comparison of the spectra recorded for dry
samples and wet ones: addition of the solvent (DCM) doesn’t dramatically alter the shape of the
spectra, meaning that the mobility of the TEMPO moieties is quite restricted.
However, some differences are visible between dry and wet samples; furthermore, large
differences are observed between samples A –D. As ES R spectra are very sensitive tp the
micro environment in which TEMPO moiety is found, significant information can be extracted
from these. Sample A showed mainly a single broad line with small shoulders; in this case
TEMPO is attached very tight to the silica surface, the linker being one single o xygen atom.
ESR technique can give important information about the environment in which the
TEMPO free ra dical is found [38 ]. Fig. 5.7, shows the spectra for samples A –D as dry solids (red
line), as well as suspended solids in DCM (black line). Interesting features were noticed by this
technique: first of all, broad lines are present in all samples, and this characteristic is attributed to
immobilized TEMPO moieties on the surface of the nanoparticles.
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Fig. 5.7. ESR spectra of samples A –D (black -as solid; red -solid suspended in DCM)
A second observation is extracted from the comparison of the spectra recorded for dry
samples and wet ones: addition of the solvent (DCM) doesn’t dramatically alter the shape of the
spectra, meaning that the mobility of t he TEMPO moieties is quite restricted.
However, some differences are visible between dry and wet samples; furthermore, large
differences are observed between samples A –D. As ESR spectra are very sensitive tp the
microenvironment in which TEMPO moiety is fo und, significant information can be extracted
from these. Sample A showed mainly a single broad line with small shoulders; in this case
TEMPO is attached very tight to the silica surface, the linker being one single oxygen atom.
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For sample B, containing go ld clusters, the ESR spectra, both in solid and suspended in
DCM, are very similar, and clearly showed the three lines characteristics of a nitroxide free
radical, together with small outside humps. The interpretation of these features means the
coexistenc e of two types of TEMPO moieties, one in a rigid environment and one in a more
flexible one. This should be due to the presence of gold clusters, but at this moment, without
further investigation, it is inappropriate to elaborate an indisputable explanatio n.
It is possible for some TEMPO units to leak, as Si –O–TEMPO bonds can break. Sample C
shows an ESR spectrum consisting of a rigid and a flexible component superimposed upon
another; in this case, the linker between the TEMPO moiety and the silica surface is bigger than
for sample A, being formed from a chain with four atoms.
As expected, the addition of DCM to the dry sample increases the mobile component of the
spectrum. Sample D shows a more rigid component, and this can be explained from the
involvemen t of gold clusters, that may restrain the mobility of free radicals.
5.4. Oxidation of alcohols to aldehyde/ketone (route I)
Three benzyl alcohols have been chosen as test reactants (Table 34). In this c ase all
samples A –D showed good oxidation abilities, the yiel ds in aldehyde or ketones bein g in a range
of 53 –100 %. As a general rule, lower values were obtained for catalysts B an d D, and this can be
correlated with the presence of gold on th e silica supported TEMPO, which seems to lower the
oxidation abi lity.
Another fact that can be r eminded is that samples C and D contained twice th e amount of
TEMPO compared with samples A and B, and this aspect has no influence on the yields obtained.
A conclusio n that arises from here suggest that the TEMPO content is not necessarily to be high,
as it acts as catalyst; literature dat a showed that it can be used as low as 1 % mol in total
conversions [ 31,32 ].
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O O OHH3CO OH3CHO
O2 /catalyst CH3OH O2 /catalyst
– H2O
– H2O
Route IRoute II
Route III
Fig. 5.8. Oxidation and oxidative coupling of benzylic alcohol to benzaldehyde and methyl
benzoate ester
5.5. Oxidative coupling with methanol (route II and III)
In our attempts to obtain esters in a single pot reaction from oxidative coupling of alcohols
(via an aldehyde intermediate), we experienced very low yields; for example, starting from
benzaldehyde, only catalyst B was capable of converting it to methyl benzoate, with a yield of 13
%; all other catalysts were unable to get the desired product (Table 34). Moreover, starting directly
from benzylic alcohol, none of the catalyst A–D was able to convert it into methyl benzoate.
Literature data showed that gold was necessary in such processes involving oxid ative
coupling, and the working conditions were usuall y harsh: autoclave, pure oxygen atmosphere, 80
oC, 24 h reaction time [ 31,32 ]; however, simple gold salt can be used as catalyst for the direct
oxidative esterification reaction in the absence of any oxide or polymer supports (but during the
process gold s alt is conver ted into gold nanoparticles [31 ] ); these published reports showed as
well that gold catalytic systems act only in a presence of a base or a basic support, which is not the
case of our system; moreo ver, the cocatalyst used in our experiments i s acidic. Therefore, working
in different environments would explain these results.
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Table 36 . Yields (%) obtained using catalyst A –D
Reactant Product Cat. A Cat. B Cat. C Cat. D
Route I (solvent DCM)
OH
O
100
95
99
53
OH
CH3
CH3O 100 55 83 66
OH
O
70
85
87
69
Route II (solvent methanol)
O
O
OCH3
0 (0)a
13 (10)a
0 (2)a
0 (4)a
Route III (solvent methanol)
0 (0)a
0 (0)a
0 (0)a
0 (0)a
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OH
O
OCH3
a After 24 h
5.6. Mechanism of oxidation
The key point in this oxidation procedure is the generation of oxoammonium salt of
TEMPO and NO [ 39,40 ]. The oxoammonium salt oxidizes alcohols to the corresponding
aldehydes and ketones, while NO and NO 2 (NO is converted by air (oxygen) to NO 2) build a cycle
which activate oxygen in order to regenerate the TEMPO free radical (Fig. 5.12).
The catalytic s equence consists in fact, in two coupled cycles, (NO/NO 2 and
TEMPO+/TEMPO) representing practically the two active catalytic processes, operating as an
electron transfer double bridge involving two oxidants, the oxoammonium salt and NO 2.
Ahmed Juwad Shakir – Doctoral Thesis
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silica
silica
silicaN
NOOHOBF4-H
R2HO
R1
R1
R2O
NO2
NOO2NO+BF4-
NO+
Fig. 5.12. Plausible mechanism of oxidation involving nitrosonium tetrafluoroborate and TEMPO
Regarding the formation of an ester via oxidative coupling of alcohol with the aldehyde
(see Fig. 2.29), a classical mechanism takes place, the addition of the methanol to the
benzaldehyde is forming the hemiacetal (methanol being used as solvent), and the thus formed
hemiacetal is subsequently oxidized t o the methyl benzoate ester [31,32 ]. In all reactions of such
Ahmed Juwad Shakir – Doctoral Thesis
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type oxygen is the final oxidant and water the by -product of alcohols oxidations or oxidative
coupling reactions (not showed in Fig. 2.3 6, for simplicity).
5.7. Conclusion
Heterogeneous TEMPO coupled with nitrosonium tetrafluoroborate may represent a very
good alternative for non -metal oxidation systems of alcohols. Addition of gold nanoparticles in
such systems doesn’t represent an asset ; however, gold seems to be compulsory for oxidative
coupling with the aim of obtaining esters in a single pot reaction.
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M., Vital, J., Microporous Mesoporo us Mater. 2015, 203, 63.
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Chapter. 6. Covalently grafted TEMPO on graphene
oxide: A composite material for selective oxidations of
alcohols
6.1. General
Carbon is known since antiquity. It is a naturally occurring element found in large
quantities on Earth, being of tremendous importance for human society, due to its major role as a
fuel. Carbon, in addition to hydrogen, oxygen and helium is the most abundant element in the
universe and it s general all types of organic compounds. Carbon -based materials are cheap and
available in large quantities, and can be used in electronics and energy conversion and storage [1].
In addition, they can be easily functionalized to be employed in more specific applications.
Chemically modified carbon -based materials have the potential to be used on an industrial scale
[2,3].
Allotropes of carbon such as graphite , diamond , and amorphous carbon also have
significant technical applications; more unusual forms of carbon (fullerenes, nanotubes, grap hene)
have recently found astonishing use in state -of-the-art technologies [4-6].
Graphite is a mineral composed of many layers of graphene; it is inexpensive and readily
available . As a natural or artificial material, graphene is a single atomic layer of sp2 carbon atoms,
does not easily exfoliate to monolayer graphene sheets; in contrast, graphite oxide, is simply
obtained through oxidation of graphite (and therefore containing abu ndant oxygen -based groups).
When graphite exfoliates, it forms graphene oxide (GO), one of the nonconductive hydrophilic
carbon materials [7-10]. the graphene exfoliation can be done using different means, including
ultrasonic devices [11]. Graphene nanosh eets were first obtained by mechanical exfoliation [12].
Although the interest in studying GO began in 1859 with B. C. Brodie , who added a
portion of potassium chlorate to a slurry of graphite in fuming nitric acid [13]. This protocol is
improved by using sulfuric acid with fuming nitric acid and by the step by step addition of chlorate
over the reaction. The Hummers method [8] published in 1958 can be considered as a milestone in
obtaining GO and is one of the most used , widely methods today; the gra phite react s with KMnO 4
and NaNO 3 in the presence of concentrated H 2SO 4.
The improved method reported recently by J. M. Tour [14] has a simpler protocol, another
major advantages being the higher yield and the absence of any toxic gas evolution during
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synthesis. Such functionalized GO has new properties which can be some time difficult to be
linked to structure of GO. The contiguous aromatic lattice of grapheme which can link to alcohols ,
epoxide, carbonyls, ketone, and carboxylic groups [15-17].
GO is the practical precursor of graphene (reduced GO, rGO); both of them are known as
functional materials with many possible applications. GO is in fact highly oxidized graphite which
is exfoliated into sheets containing functionalities such as hydroxy, epoxide, c arbonyl and carboxyl
groups; these hydrophilic groups make GO dispersible in highly polar solvents (water, DMF).
Moreover, these oxygen -containing groups facilitate exfoliation, and more importantly, ensure the
possibility of covalent functionalization wit h organic molecules. Because the graphene layer can
also be regarded as a polyaromatic composition, a large number of physical interactions with
organic molecules, such as π – π stacking, are possible.
There are many reproducible methods to functionalize G O, and these can be mainly
divided into covalent and non -covalent functionalization. Covalent functionalization takes
advantages of the carbon surface chemistry; for example, carboxyl and hydroxyl groups can be
easily derivatized using standard chemistry ( i.e. with porphyrins [18], ferrocene [19], and
polymers ) [20]. In addition, another route is the use of aryl diazonium salts, which can also be
tailored by organic chemistry [21,22 ]. Non-covalent functionalization is based, as mentioned
before, on π – π stacking, ionic, cation -π or Van der Waals interactions [10].
Such functionalized GO has new properties (which can be chemically tuned) and has
therefore found new and interesting applications, from electrochemical energy conversion and
storage to robust and highly selective carbocatalysts [23]. GO have so many applications , being
used as GFET device (graphene based field effect transistor) [24,25 ], or FETs (Field effect
transistors ). Also is used as chemical sensors [26-28] and biosensors. MnO 2 has been used on a
surface of grapheme oxide for the selective aerobic oxidation of benzyl alcohols to corresponding
carbonyl compounds [29]. It is also used as catalyzes for the oxidation of various alkenes and
alcohols and the hydration of various alkynes into their aldehydes and ketones [30]. GO is used as
a catalyst for the selective oxidation of alcohols to the corresponding aldehydes and ketones.
One of the most important organic chemistry reactions is the selective oxidation of alcohols
to aldehydes or keto nes. Such a process usually requires a difficult management of the reaction
conditions, as transition metal species are involved in at least equimolecular quantities and the
resulting toxic waste is hard to process. Novel systems involve more gentle (air, oxygen, hydrogen
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peroxide, etc.) or non -conventional (carbon -based materials, stable free radicals, etc.) oxidants,
with certain and large advantages: clean reactions, mild working conditions, recovery and re -use of
the catalyst, less or no ntoxic by -produc ts, and so on [31-37].
Many catalytic processes involve metals or metal ions with high toxicity, therefore the
finding of a new benign catalyst represents an important goal in itself. Organic stable free radicals
of nitroxide type (or their functionalized materials) are nowadays a good practical choice for the
reliable, green and clean synthesis of carbonylic compounds obtained via oxidation of alcohols
[38-40].
The stable free organic radical TEMPO can be involved in redox processes as it can be
readily oxidized to the oxoammonium salt or reduced to the corresponding hydroxylamine.
TEMPO can be grafted onto inert materials in order to exploit its redox properties in catalytic
processes. In literature there are very few papers describing GO functionalized with TEMPO
moieties: i) coupling the HO group from 4 -hydroxy -TEMPO with the activated COOH group of
GO [41], ii) using a malonyl derivative of 4 -hydroxy -TEMPO (following the Bin gele Hirsch
reaction) [42] or iii) using the oxoammonium salt of TEMPO [43] (which in fact is not a free
radical). None of those have been used in the catalytic selective oxidation of alcohols.
In this work, we covalently bound 4 -amino -TEMPO to GO, using s tandard amide bond
formation in two steps. The first step refers to the activation of COOH groups from GO by
transforming them into the corresponding acid chloride COCl. The second step is represented by
the reaction of COCl with 4 -amino -TEMPO (Fig. 6.1). The choice of this method is justified by
the highest yield of coupling, as is also shown in literature [41] and by the higher stability of the
amide group. Amides are much more stable than esters (which can easily hydrolyze under basic
conditions); moreov er, epoxide groups from GO can also react with 4 -amino -TEMPO, resulting in
a highly functionalized GO.
All of the materials thus obtained were first characterized by elemental analysis, infrared
(IR), electron spin resonance (ESR) and Raman spectroscopy, thermo -gravimetric analysis (TGA)
and scanning electron microscopy (SEM), and further tested as heterogeneous catalysts in the
selective oxidation of alcohols.
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O
O
O
O
OH
O
OH
O HOOOHOOOHOHO
O
HO
O
OH
OHO
1] SOCl2
2]NO
NH2O
N
O
N
OH
O
HN
O N
HOOHOOOH
NHO
O
HO
O
OH
OHONONO
NO
NONOFig. 6.1. Representation of
TEMPO functionalization of GO.
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6.2. Synthesis and characterization of GO and iGO
We used synthetic graphite powder (<20 mm) as a reliable starting material [44] because
different sources of natural graphite significantly affect the properties of the GO [45]. Literature
data [46] report that smaller -size graphite oxidizes more under the same conditions, as shown by
X-ray diffraction and SEM results, thus demonstrating the importance of the precursor size to
obtain easily exfoliated sheets.
The synthesis of GO generally followed the Hummers [ 47] and improved Hummers [48]
methods, thus yielding two types of GO, named GO and iGO, respectively.
6.3. GO functionalized with 4 -amino -TEMPO (GO -T and iGO -T)
As GO contains COOH groups, the next step in our study was to functionalize these with 4 –
amino -TEMPO (see Fig. 6.6), using standard amide bond formation through coupling the NH 2
group with the COOH group. The COOH groups were activate d using thionyl chloride (Fig. 6.1).
As mentioned before, this method afforded the best results. The thus , the obtained materials were
further characterized by elemental analysis, IR, ESR, SEM, Raman and TGA; all these
investigations demonstra te the covalent attachments of the TEMPO moieties to the solid material.
Raman spectroscopy is one of the most powerful techniques to characterize carbonaceous
materials [49,50 ]. The Raman spectrum (Fig. 6.2) of the starting material (graphite) shows the
narrow G peak at ~1580 cm-1, corresponding to the vibrations of sp2 carbon in the graphite lattice,
while GO/iGO and GO/iGO functionalized with TEMPO showed two broad pea ks, namely the G
(1580 cm-1) and D band (at about 1350 cm-1).
Fig. 6.2. Raman spectra of the materials used in this study
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The D band is associated with the disruption of the sp2-bonded lattice of graphite by the
massive formation of C -O bonds in the GO samples, leading to the distortion and opening up of
aromatic rings.
The intensity ratios between both Raman bands I D/IG gives values higher than 1, which
correspond to the reduction of the crystallite domain size in the hexagonal layers from 20 mm to
~40 Å, determined from the Tuinstra and Koenig equation [51].
In addition, all of the oxidized samples also show a clear shift of the G band towards higher
Raman shift values, associated with the incorporation of oxygen -containing functionalities,
disrupting the graphitic bonds.
The TEMPO -functionalized samples show similar Raman features, except for a noticeable
splitting of the G band in the GO-T sample. G band splitting is caused by straining of the C -C
bridges in the sp2-bonded hexagonal layers, caused by pure mechanical strain or by chemical
doping with adatoms lying on the grapheme sheets [52], straining the sp2 bonds without opening
up the aromatic ring.
In our case, doping of the graphene hexagonal layers caused by TEMPO functionalization
seems to be the origin of the Raman G band splitting in the GO -T sample.
IR spectra of both samples of GO and iGO are quite different from the starting material G
(Fig. 6.3), demonstrating the presence of the new functional groups, such as carboxyl, hydroxyl
and carbonyl.
Fig. 6.3. IR spectra of the materials used in this study
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Specifically, the broad band at 3400 cm-1 belongs to the OH vibrations, while C=C double
bonds produce bands at about 1620 cm-1; bands due to carbonyl and carboxyl groups are also
noticed at around 1740 cm-1.
The IR spectra of the TEMPO -functionalized samples (Fig. 6.4) showed that the intensities
of the bands at 1620 cm-1 and 1740 cm-1 are reduced [53], while new a band emerges at about 1570
cm-1, corresponding to the C -N stretching vibrations [54]. This band is very intense and is also
present in the IR spectrum of 4 – amino -TEMPO Fig. 6.4 and 6.5).
Fig. 6.4. IR spectrum of 4 -amino -TEMPO
Fig. 6.5. Superimposed IR spectra of 4 -amino -TEMPO (black) and iGO -T (red)
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The possibility of physically adsorbed nitroxide being present on the GO is unlikely, as the
samples were extensively washed with methanol; in addition, the IR spectrum recorded for a
sample used in a catalytic cycle maintains the same shape (see Fig. 6.5).
ESR spectroscopy is the most powerful tool to study free radicals, and provides additional
data on the samples used within this study. Unpair ed electrons are easily detected by this
technique; moreover, shapes and intensities of the spectra provide information about the types,
number of radicals and their interactions with the microenvironment [55-57].
The ESR spectrum of the pristine graphite showed the well -known broad band due to the
free electrons that are present in a carbon -based material with extended p -electron systems
(carbon -centred radicals); also, in GO materials a sharp line is noticed (Fig. 6.7).
Fig. 6.6. ESR spectrum of 4 -amino -TEMPO
Fig. 6.7. ESR spectra of the materials used in this study
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However, the origin of the unpaired electron is still unclear and literature data showed that
different types of electrons exhibiting paramagnetic behavior are present at the edge and in the
bulk of such material [58].
Because phenolic radicals are stabilized on GO [51], we do not exclude the presence of
semiquinone -type radicals, as they were identified for example in cigarette tar [59].
For TEMPO -functionalized samples (GO -T and iGO -T) additional data are noticed: the
ESR spectra showed a very broad line with a triplet feature (Fig. 6.7), well known for grafted
radicals [60,61 ].
These spectra represent a sum of two components: a single broad line determined by t he
very short interspin distances and a second line showing the immobilized spectrum of TEMPO,
reflecting an increased distance between nitroxide spins.
Quantitative ESR analysis of the samples was also performed aiming to evaluate the degree
of functional ization of the grapheme oxides with the 4-amino -TEMPO free radical. Double
integration of the ESR spectra showed an increase in the number of spins contained by the
composite materials (GO -T and iGO -T) compared with the starting graphene oxides (GO and iGO )
of about two orders of magnitude (see Table 37 and Fig. 6.8).
Fig. 6.8. Superimposed ESR spectra of 4 -amino -TEMPO (black) and iGO -T (red)
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Table 37. Quantitative ESR analysis
Sample Mass (mg) ESR double integral Spins/mg
G 3.1 10626 7.17×1015
GO 6.5 3375 1.08 x1015
iGO 4.1 11666 5.95×1015
GO-T 2.8 902600 6.75×1017
iGO-T 3.5 612300 3.66×1017
For quantitative results all cautions were taken in order to get accurate
results (baseline corrections, integration on the whole spectrums,
acquiring a high signal to noise ratio and so on).
A rough evaluation of the content in the organic free radical led to a value of 0.6 mmol/g
for iGO -T and 1.1 mmol/g for GO -T. Elemental analysis showed for GO -T and iGO -T samples a
nitrogen con tent of 3.40% and 3.81%, respectively (see Table 38).
Table 38. Quantitative elemental CHN analysis
Sample Carbon (%) Hydrogen (%) Nitrogen (%)
GO 58.14 2.25 0.12
iGO 54.28 2.49 0.09
GO-T 72.16 2.96 3.40
iGO-T 60.32 4.19 3.81
As the starting free radical 4 -amino -TEMPO has two nitrogen atoms that are incorporated
into the final composite material, these values correspond to an average of 1.25 mmol/g. Although
there are some divergences between the values (provided by different methods), these can be
attributed to different ways of calculation, each of them with inherent experimental errors.
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However, both methods showed without a doubt the presence of the TEMPO moiety in the
composite material.
The presence of N atoms in the GO -T and iGO -T samples (see below). An interesting
feature was noticed in the thermo -gravimetric analysis. In general, the thermal degradation of GO
materials occurs in several steps: up to about 300oC water, carbon dioxide and carbon monoxide
derived from the adsorbed water and oxygenated groups are evolved, while at higher temperatures
(to approximately 900 -1000 oC) the more stable oxygen -containing functionalities are decomposed
[27]. Several interesting outcomes may be revealed by the thermal analysis (Fig. 6.9).
The first is the efficiency of the improved Hummers procedure in generating materials with
a greater content of oxygenated groups. The statement is supported by the higher mass loss of the
iGO samples compared with GO samples (e.g. 57.05% iGO > 51.15% GO). The second is the
capability of the graphene oxide to be functionalized with TEMPO. The lower mass loss recorded
for the samples containing TEMPO proved that the new amide groups formed during TEMPO
functionalization are more stable than COOH; in a temperature range characteristic for oxygenated
moieties decomposition (~100 -300 oC) a three – and two -fold smaller mass loss of the GO -T and
iGO-T samples is measured compared with the corresponding unfunctionalized TEMPO samples.
Moreover, because of a higher organic conte nt, the decay process of the TEMPO samples
occurs at significantly lower temperatures (dotted line marked zone, Fig. 9.6). A decomposition
step characteristic for the TEMPO samples is the one that occurs between ~300 and 500oC (solid
line marked zone in Fi g. 9.6), most likely caused by thermally induced decomposition of the
TEMPO moieties, in accordance with literature data [57,58 ].
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Fig. 6.9. TGA analysis of the materials used in this study
The covalent bonding of the TEMPO radical to GO induces a significant modification of its
thermo -chemistry, similar to those registered for the coordinatively linked ligands: the linkages
determine a sensibl y higher stability of the bonded moieties compared with the free ones.
Moreover, TEMPO’s characteristic melting point cannot be identified in the functionalized
samples (see Figs. 6.10 and 6.11). FE -SEM micrographs of the samples are shown in Fig. 6.12.
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100 200 300 400 500 6009080706050403020100
Temperature / oCMass loss / %4 amino TEMPO
-10.0-7.5-5.0-2.50.0DSC /
(mg/mW)DTG /
(%/min)
-10123
exo
Fig. 6.10. TG, DTG and DSC curves for 4 -amino -TEMPO
100 200 300024
GOT
IGOT
Temperature / oCDSC (mW/mg) TEMPO
melting of TEMPO
Fig. 6.11. DSC curves for 4 -amino -TEMPO comparati ve with TEMPO functionalized GO
During heating in inert atmosphere, after a melting process (T DSC = 43.65oC), bare 4 -amino
TEMPO undergoes a mass loss of 86.38% in the temperature range 70 -160 oC. As expected, the
decomposition is associated with an endothermic effect, determined by the splitting of the ring and
side chain bonds. Two proofs of the TEMPO radical covalent bonding to graphene oxide can be
brought by thermal investigations: i) the higher thermal stability of the functionalized GO, and ii)
the absence of the TEMPO melting process.
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Fig. 6.12. SEM micrographs and EDX spectroscopy of the samples G, GO, iGO, GO -T and
iGO-T (from top to bottom)
There are clear morphological changes : G morphology is that of flakes with straight edges
and is very easy to delaminate, typical of the grapheme sheets in graphite.
Elemental analysis by EDX spectroscopy detects only C. GO is formed of aggregates of
stacked sheets that are significantly corrugated, bent and with rounded edges. Elemental analysis
by EDX spectroscopy detects C and O, indicating that the morph ological changes correspond to
the oxidation of the grapheme sheets.
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The state of aggregation indicates that oxidation induces formation of intersheet bonds in
the GO sample. GO -T shows a similar morphology as GO, with cleaner, flatter surfaces than GO,
and EDX measurements detect C, O in lower content than GO, and N, indicating that in GO -T the
graphite oxide has been functionalized with TEMPO groups, which contain nitrogen. The iGO
sampl e is composed of flat flakes with fairly straight edges, a microstruc ture closer to the initial
one of G than GO; elemental analysis on the other hand determines an oxygen content similar to
GO. Sample iGO -T has a similar morphology to iGO; elemental analysis detects the presence of N
and lower O content, confirming the inc orporation of TEMPO groups in iGO -T. BET analysis
showed a surface of 4 and 8 m2/g, for iGO -T and GO -T samples, respectively (see Table 38).
Table 38. BET analysis of the samples
Sample SBET (m2/g)
G 10.4
GO 34.9
iGO 6.5
GO-T 8.2
iGO-T 3.9
6.4. Oxidation of alcohols
Literature data are abundant on new and versatile methods of selective oxidation of
alcohols [62-64]. GO itself has been found to be able to oxidize neat benzyl alcohol under harsh
reaction conditions (GO 200%, temperature 100 oC, 24 h [65]); in addition, GO in the presence of
TEMPO (80% GO and 100% TEMPO, autoclave) has been found to oxidize 5 –
hydroxymethylfurfural to 2,5 – diformylfuran [66].
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It was supposed that GO undergoes a partial reduction to form rGO which can be
reoxidized by air to GO. In our work, we used the GO -T and iGO -T samples as catalysts under
very mild conditions, without using an autoclave and working at room temperature. Our test
experiments showed that G, GO, iGO, GO -T and iGO -T samples cannot oxidize benzyl alcoh ol in
the absence of any co -catalyst; even in the presence of it, G, GO and iGO samples cannot afford
the oxidation product (yields below 1%, Table 38, Entries 1 -4,7). This shows that the requirement
for getting the oxidation process to work is the simulta neous presence of a TEMPO moiety
(meaning samples GO -T and iGO -T) and the co -catalyst.
Some of our previous work [39,67,68 ] showed that silica supported TEMPO coupled with a
NOx source (sodium nitrite/acetic acid, NO 2 or NOBF 4) acts as a bifunctional catalyst, being able
to oxidize with high yield activated alcohols in mild conditions and in a very clean way, using
oxygen or air as the final oxidant.
Moreover, from this type of oxidation process, either aldehydes or ketones result and not
the carboxyli c derivatives. All of our materials described above have been tested as catalysts for
alcohol oxidation; for this aim , we employed five alcohols ( Table 39 ), namely benzyl alcohol, 1 –
phenylethanol, diphenylmethanol, furfuryl alcohol and 1 -octanol, thus cove ring a wide range of
reactivities. As a general rule, our experiments showed that for activated alcohols iGO -T and NO 2
are the best reactants ( Table 39 , Entries 6, 9, 11 and 13), reaching a 99% yield in the case of
benzyl alcohol (Entry 9); however, the le ss reactive 1 -octanol was converted into the
corresponding aldehyde in only 10% yield (Entry 17).
The better catalytic activity of iGO -T compared with GO -T may reside in the higher
TEMPO content (as elemental analysis showed) and in a higher degree of oxid ation of the iGO
starting material. There is also a possible synergistic effect of these, as the literature suggests [67].
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Table 39 . The result of oxidation of alcohols
Entry Product Catalyst Cocatalyst Yield %
1
O
none NaNO 2 trace
2 G < 1
3 GO < 1
4 iGO < 1
5 GO-T 42
6 iGO-T 46
7 G NO 2 trace
8 iGO-T 57
9 iGO-T 99
10
CH3O
iGO-T
NaNO 2
9
11 iGO-T NO 2 12
12
O
iGO-T NaNO 2 9
13 iGO-T NO 2 25
14
OO
iGO-T NaNO 2 5
15 iGO-T NO 2 11
16
O
iGO-T NaNO 2 3
17 iGO-T NO 2 10
1 mmol alcohol, 20 mol% NaNO 2, 0.2 mL acetic acid, 25 mg catalyst, 10 mL DCM, room temperature,
oxygen (balloon), 20 h stirring
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6.5. Mechanism of oxidation
The catalyst employed can be easily recovered by simple filtration or centrifugation and
reused after reactivation (either after the addition of sodium nitrite/acetic acid or by bubbling NO 2)
with no or very little loss of activity (tests run at least twice). It is well known that such an
oxidation procedure involves the oxoammonium salt of TEMPO [39,65,66 ], which is generated by
NOx.
Regarding the mechanism, there are in fact two coupled catalytic cycles ( Fig. 6.19), one in
which the oxoammonium salt is formed by NO 2 and the other one in which NO is converted into
NO 2.
Further evidence of these catalytic cycleswas obtained by IR a nd ESR spectra of the used
catalyst. We have chosen as representative the iGO -T sample, which was first activated by NO 2
(more convenient than the sodium nitrite/acetic acid system, as no other impurities or by -products
are generated). The IR spectrum of t he sample used as catalyst showed, as expected, the presence
of a band at 1384 cm-1 (Fig. 6.16) due to NO 2/oxoammonium salt, meaning also that iGO -T can be
regarded as a reservoir for the NOx [39].
By ESR (Fig. 6.17), the spectrum of the used catalyst show ed some differences compared
with the starting material: i) in the used catalyst, a decrease in the intensity of the ESR spectrum of
about 15% has been noticed, and we assume this is due to the conversion of the nitroxide moiety
into the corresponding oxoa mmonium salt (thereby diminishing the total number of spins), and ii)
the shape of the spectrum changed, showing an increase in the interspin distance (for the same
reason).
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 6.16. Superimposed IR spectra of iGO -T before (black) and after it was used as a catalyst
(red)
Fig. 6.17. Superimposed ESR spectra of iGO -T before (black) and after it was used as a catalyst
(red)
In addition, SEM micrographs of the used iGO -T sample (as a catalyst) showed similar
morphology as the initial one; as well, EDX spectroscopy showed th e presence of nitrogen (Fig.
6.18), demonstrating thus the recyclability of the catal yst.
Ahmed Juwad Shakir – Doctoral Thesis
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Fig. 6.18. SEM micrographs and EDX spectroscopy of the iGO -T sample, after it was used as a
catalyst
GO
GON
NOOHOH
R2R1
O
R2R1
H2ONO2NOO2
oxgyen activationactivation of TEMPO
Fig. 6.19. Proposed oxidation mechanism
Ahmed Juwad Shakir – Doctoral Thesis
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6.6. Conclusion
The TEMPO free radical was covalently grafted to GO through an amide bond; the
composite materials were characterized by different means and used as catalysts for selective
oxidation of some alcohols in very mild conditions, at room temperature and using oxygen as the
final oxidant. The oxidation yield depends on the reactivity of the alcohols. Benzyl alcohol can be
oxidized selectively to benzaldehyde in an almost quantitative yield
Ahmed Juwad Shakir – Doctoral Thesis
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Chapter 7. Experimental part
7.1. Chemicals and solvents
All chemicals, solvents and materials were purchased from Sigma -Aldrich, Acros or
Chimopar and used as received. Flash column chromatography was achieved on silica gel 60 from
Merck (40 -63 M). Analytical TLC has been performed on Merck TLC plates (0.2 mm silica gel
60 on glass, with 254 nm fluorescent indicator).
7.2. IR spectroscopy
IR spectra were recorded on a Jasco FTIR 4100 apparatus using potassium bromide disks.
7.3. UV-Vis spectrosco py
UV-Vis spectra were recorded on a UVD -3500 double beam spectrophotometer at room
temperature using 1 cm quartz cells and methanol as solven t.
7.4. EPR spectroscopy
EPR spectra were recorded in different solvents (as required) at room temperature on a Je ol
JES FA 100 apparatus using the following typical settings: frequency 8.99 GHz, field 3330 G,
sweep width 100 -200 G, sweep time 60 -120 s, time constant 30 ms, gain 50 -500, modulation
frequency 100 kHz, modulation width 1 G, using 1 mm inn er diameter plai n glass tubes.
7.5. NMR spectroscopy
NMR spectra were recorded in deuterated chloroform or DMSO on a Bruker Fourier
apparatus at 300 MHz and 500 MHz ( chemical shifts are reported in ppm using TMS as standard).
7.6. X-ray diffraction
X-ray diffraction measu rements were performed on a STOE IPDS II diffractometer,
operating with Mo -Kα ( = 0.71073 Å) X -ray tube with graphite monochromator. The structure
was solved by direct methods and refined by full -matrix least squares techniques based on F2. The
non-H atoms were refined with anisotropic displacement parameters. Calculations were performed
using SHELX -2014 crys tallographic software package.
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7.7. Raman spectroscopy
Raman spectra were measured in a Horiba Jobin -Yvon LabRam spectrometer.
Measurements were c arried out in the backscattering geometry, at room temperature, with a 50 x
microscope objective, in the range from 50 to 2000 cm-1, with acquisition times of 60 s; using as
excitation source the green line ( = 514.5 nm) of an Ar+ laser, with a power of ~2 0 mW, t he laser
spot size was ~1 -2 mm.
7.8. Thermal measurements
Thermal measurements were performed on a Netzsch STA 449 F1 Jupiter Simultaneous.
Thermal analyzer apparatus in dynamic argon atmosphere, with a heating rate of 5 oC min-1. Also
thermal anal ysis was performed with a TG –DTA Shimadzu DTA -60 apparatus under nitrogen
atmosphere, with a heating rate of 5 oC/min, from room temperature to 300 oC, using alumina as
reference.
7.9. Cyclic voltammetry
CVs were recorded in acetonitrile at a concentration of 2 mmol in free radical, using
platinum electrodes; as support electrolyte was used lithium percholate ( 0.1 M); scan rate was 100
mV/s.
7.10. GC analysis
A Carlo Erba Fractovap 2400, equipped with capillary split injection and flame ionization
detector, was used for GC analysis, following the area standardisation method. The sample volume
injected was 0.10 L, with a split ratio of 1/20.
For the dead time m easurement was used methane. Injector and detector temperature were
250 șC. A capillary column CW 20M, with a length of 14.8 m and the film thickness of 0.3 mm,
was used. The carrier gas was hydrogen, with a flow rate of 2.1 mL/min (operating conditions: 3
min isotherm at 40°C, followed by a heating rate of 5°C/min to 220 °C).
7.11. Brunauere Emmette Teller (BET) method
The samples (Cat. A, Cat. B, Cat. C and Cat. D) were outgassed at 90 oC for 7 h before
analysis. Specific surface areas (SBET) were calculated according to the Brunauer –Emmett –Teller
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(BET) equation. The total pore volume (Vtotal) was estimated from the amount adsorbed at the
relative pressure of 0.99.
The surface area of cov alently grafted TEMPO on graphene was calculated using the
Brunauere Emmette Teller (BET) method based on adsorption data in the partial pressure (P/Po)
range of 0.05 -0.3. Before analysis, the samples were degassed for 12 h at 100 oC under vacuum.
7.12. Barrett –Joyner –Halenda (BJH) method
The average pore diameter and pore size distribution curves were obtained using Barrett –
Joyner –Halenda (BJH) met hod from the desorption branch.
7.13. Synthesis of compounds
7.13.1 Synthesis of DN -DPPH
To 1 g of diphenyl amine was dissolved in 30 mL ethanol, then 3 mL of 37% hydrochloric
acid was added at 0 oC, 1 g of sodium nitri te was dissolved in 4 mL water and the mixture together
was added. Filtered and solvent removed, the yield was N -Nitrosodiphen ylamine. The N –
Nitrosodiphenylamine was reduced ( 1 g of N -nitroso -N-phenylbenzenamine was cooled (one
hour), then added 6 g of zinc was dissolved in 20 mL ethanol, the mixture was stirred and 8 mL of
acetic acid was added dropwise) and this one, by reacti on with 1 g of picryl chloride (synthesized
from picric acid and thyonyl chloride see Fig. 7.4) to form 2,2 -diphenyl -1-picrylhydrazine.
Then 1 g of 2,2 -diphenyl -1-picrylhydrazine was dissolved into 50 mL DCM was added 50
mL of diluted hydrochloric acid (1 M) and under vigorous stirring was added from time to time
100 mg sodium nitrite (about 20 times during 8 h) and the mixture left overnight.
Next day sodium nitrite was added and the stirring continued for 1 h. The solvent removed,
and the yield was 2,2 -dinitrophenyl -1-picrulhydrazine DN -DPPH. The DN -DPPH was dissolved in
100 mL DCM to which 10 g of lead dioxide together with 5 g of anhydrous sodium sulphate was
added; the mixture was stirred for 1 h, filtered off and the solvent removed.
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7.13.2 Synthesi s of N -Nitrosodiphenylamine
We started from diphenylamine that converted to N-Nitrosodiphenylamine Fig. 7.1 . To 4 g
of diphenyl amine was dissolved in 30 mL ethanol, then 3 mL of 37% hydrochloric acid was added
at 0 oC, finally added 2 g of sodium nitrite was dissolved in 4 mL.
H
NNaNO2
HClNNO
diphenylamine N-nitroso-N-phenylbenzenamine
Fig. 7.1 . Reduction of N -nitroso -N-phenylbenzenamine
7.13.3 Synthesis of N,N-diphenylhydrazine
N,N-diphenylhydrazine was prepared by reduction of N-nitroso-N-phenylbenzenamine
Fig. 7.2 . To 1 g of N-nitroso -N-phenylbenzenamine was cooled (one hour), then added 6 g of zinc
was dissolved in 20 mL ethanol, the mixture was stirred and 8 mL of acetic acid was added
dropwise.
NNO
NNH2
N-nitroso-N-phenylbenzenamineCH3COOHZn
Fig. 7.2 . Synthesis of DPPH -H
7.13.4 Synthesis of picryl chloride
In Fig. 7.3 , shows the synthesis of picryl chloride by reacted picric acid with SOCl 2 during
the reflux. To 2 g picric acid was added to the mixture of (2 ml of thionyl chloride and 0.1 mL
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DMF) were added under reflux for one h our. Then petroleum ether was added to the mixture until
picryl chloride was precipitated.
NO2 O2N
NO2OH
NO2 O2N
NO2Cl
picric acid 2-chloro-1,3,5-trinitrobenzeneDMFSOCl2
Fig. 7.3 . Synthesis of picryl chloride
7.13.5 Synthesis of 2,2 -diphenyl -1-picrylhydrazine
2,2-diphenyl -1-picrylhydrazine was prepared by coupling reaction between picryl chloride
and N,N -diphenylhydrazine Fig. 7.4 . To 1 g of N, N -diphenylhydrazine together with 1 g of picryl
chloride was added, the mixture was stirred for 1 hour, then sodium bicarbonate was added.
Filtered and t he solvent removed.
NO2 O2N
NO2Cl
2-chloro-1,3,5-trinitrobenzeneNNH2
+ NH
NO2N
NO2
O2N
Fig. 7.4 . Synthesis of 2,2 -diphenyl -1-picrylhydrazine
7.13.6 Synthesis of 2,2 -dinitrophenyl -1-picrulhydrazine
Attention: toxic nitrogen dioxide evolves during a reaction and a fume hood with good
ventilation is required. 2,2-diphenyl -1-picrylhydrazine was reacted with nitrogen dioxide to
prepare 2,2 -dinitrop henyl -1-picrulhydrazine Fig. 7.5 . To 1 g DPPH (this can be also easily
synthesized, dissolved into 50 mL DCM was added 50 mL of diluted hydroch loric acid (1 M) and
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under vigorous stirring was added from time to time 100 mg sodium nitrite (about 20 times during
8 h) and the mixture left overnight. Next day another portion of sodium nitrite was added and the
stirring continued for 1 h (for the wate r solution, the pH was checked from time to time to be
acidic – if not, this should be corrected by adding small amount of acid).
The organic layer was separated (it is possible that DN -DPPH to precipitate partially), dried
over anhydrous sodium sulphate an d the solvent removed. The residue was dissolved in DCM
(about 100 mL) to which 10 g of lead dioxide together with 5 g of anhydrous sodium sulphate was
added; the mixture was vigorously stirred for 1 h, filtered off and the solvent removed. DN -DPPH
is thus obtained as dark solid. Yield ~90%.
NH
NO2N
NO2
O2NNH
NO2N
NO2
O2NO2N
O2NNaNO2HCl
Fig. 7.5 . Synthesis of 2,2 -dinitrophenyl -1-picrulhydrazine
7.13.7 Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl
Oxidation of 2,2 -dinitrophenyl -1-picrulhydrazine by lead dioxide yielding 2,2 –
dinitro phenyl -1-picrylhydrazyl Fig. 7.6 . To 1 g of 2 -dinitrophenyl -1-picrulhydrazine together with
10 g of lead dioxide and 10 g of anhydrous sodium sulphate was dissolved in 100 mL of DCM.
The mixture was stirred for 2 hours .
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NH
NO2N
NO2
O2NNNO2N
NO2
O2NO2N
O2NPbO2
Fig. 7.6 . Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl
7.13.8 Synthesis of PINO
N- hydroxyphthalimide ( PINO) is generated from N-hydroxyphthalimide (NHPI) in situ
Fig. 7.7 .
NO
OO NO
OOH
Fig. 7.7 . Synthesis of PINO
7.13.9 Synthesis of 4 -isocyanato -TEMPO
4-isocyanato -TEMPO wa s prepared by reaction between 4-amino-TEMPO and diphosgene
Fig. 7.8 . 4-Isocyanato -TEMPO was obtained in a similar way as literature data [1] showed; 2 g of
4-amino -TEMPO were dissolved in 15 mL of cold DCM and 0.25 mL of diphosgen (also
dissolved in 15 mL of cold DCM) were added under vigorous stirring; the mixture was maintained
below 0o C with an external cooling (ice and salt); after few minutes, 70 mL DCM were added,
and t he final solution was extracted twice with 100 mL aqueous hydrochloric acid (1 M) and once
with 100 mL sodium hydroxide (1 M); the organic layer was dried over anhydrous magnesium
sulfate, filtered off and the solvent removed under vacuum (below 30o C). Yi eld 50%.
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N
ONH2
diphosgen
N
ONCO
Fig. 7.8 . Synthesis of 4-isocyanato -TEMPO
7.13.10 Synthesis of DI -T radical
DI-T radical was prepared by adding an equal amount of 4 -isocyanato -TEMPO and of 4 –
amino -TEMPO in THF and leaving the mixture at room temperature overnight; removal of the
solvent affords the pure material in almost quantitative yield. HR -MS: m/z calculated for
C19H36N4O3 [M+] 368.2 782; found 368.2807. Fig. 7.9 .
N
ONCO N
HN N
HOO
4-NH2-TEMPO
N
O
Fig. 7.9 . Synthesis of DI-T radical
7.13.11 Synthesis of TRI -P radical
TRI-P radical was prepared by adding 75 mg of tris(2 -aminoethyl)amine, 625 mg of EEDQ
and 372 mg of 3 -carboxy -PROXYL free radical to a mixture 50 mL DCM and THF (9/1 v/v) as
solvent. After five days, the solution was extracte d with 50 mL aqueous hydrochloric acid (1 M)
and with 50 mL of sodium hydrogen carbonate (1 M); the organic layer was separated and dried
over anhydrous magnesium sulfate, filtered off and the solvent removed under vacuum.
The crude mixture was purified by column chromatography using silica as stationary phase
and ethyl acetate as eluent. Yield 30%. HR -MS: m/z calculated for C 33H61N7O6 [M+H+] 651.4678;
found 651.5704.
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N
N NNHN
N
HN
HO O
O OOO
NO
OH
NNH2
H2N NH2+
TRI-PEEDQO
Fig. 7.10 . Synthesis of TRI -P radical
7.13.12 Synthesis of 2,2’ -succinic acid disulphide
2,2’-succinic acid disulphide was obtained by oxidation of 2 -mercapto -succcinic acid [2];
to 300 mg of the acid dissolved in 30 mL of methanol were added under stirring 300 mg of iodine;
after 2 hours, a solution of sodium thiosulfate was added drop -by-drop until the colour of iodine
disappear. To the mixture was added 150 mL of DCM and 100 mL of water, and the organic layer
was separated, dried over anhydrous magnesium sulfate, filtered off and the solvent removed. The
yield is quantitative. Fig. 7 . 11.
OSH
O
OH
OHO
SOOH
S
O
OOHHO
OHI2
Fig. 7.11 . Synthesis of 2,2’-succinic acid disulphide
7.13.13 Synthesis of TE -T radical
TE-T radical was obtained reacting 150 mg of the disulphide with 400 mg of 4 -amino –
TEMPO in the presence of 500 mg EEDQ dissolved in 100 mL DCM. After 3 days, the solution
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was extracted with 100 mL aqueous hydrochloric acid (1 M) and with 100 mL of sodium hydrogen
carbonate (1 M); the organic layer was separated and dried over anhydrous magnesium sulfate,
filtered off and the solvent removed under vacuum. The crude mixture was purified by column
chromatography using silica as stationary phase and ethyl acet ate as eluent. Yield 30%. HR -MS:
m/z calculated for C 44H80N8O8S2 [M+2H+] 912 .5535; found 912.5584. Fig. 7.12 .
NNN
NOH
N
SOHN
SO
O
O
NH
ON
HOO
SOOH
S
OOHHO
TE-T
EEDQ
OO
HO
Fig. 7.12 . Synthesis of TE -T radical
7.13.14 Synthesis of TE -P radical
TE-P radical was obtained dissolving 30 mg DAB -Am-4 dendrimer ( polypropylenimine
tetramine dendrimer, generation 1 ) with 1 g EEDQ and 750 mg of 3 -carboxy -PROXYL free
radical into a mixture formed by 80 mL DCM and 20 mL THF as solvent. After five days, 50 mL
of DCM were added and the solution wa s extracted with 100 mL of sodium hydrogen carbonate (1
M); the organic layer was separated and dried over anhydrous magnesium sulfate, filtered off and
the solvent removed under vacuum. Purification was performed by preparative TLC, using silica as
statio nary phase and a mixture of DCM and methanol 9/1 (v/v) as eluent. Yield 20%. HR -MS: m/z
calculated for C 52H97N10O8 [M+H+] 989.7485; found 989.7488. F ig. 7.13 .
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NNNN
NNH
N
OO
N
HNHO
O
HN OO
OONNNH2
H2NNH2
NH2NO
OOH.
..
+
TE-PEEDQ
Fig. 7.13 . Synthesis of TE-P radical
7.13.15 Synthesis of Cat. A
Cat. A was prepared by adding under stirring 0.1 g of 4 -hydroxy -TEMPO to a solution of 5
mL TMOS in 25 mL of methanol. After few minutes 0.5 mL of concentrated ammonia (25 %) has
been added, followed by 10 mL of water. Next day the resulting gel was separa ted and let to dry
under open air, yielding a pale yellow solid. The solid thus obtained has been washed several times
with methanol and let to dry in open air. Fig. 7.14 .
OH
O
OHNO
SiO2
Catalyst A
Fig. 7.14 . Schematic drawing of Cat. A
7.13.16 Synthesis of Cat. B
Cat. B was prepared in the same way like catalyst A, adding supplementary under stirring,
to the solid dry material obtained, 0.1 g of HAuCl 4 dissolved in 5 mL water, 20 mL of methanol
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and 10 mg of sodium borohydride. After 2 h the soli d material has been separated, washed with
methanol and dried. The final material is a violet –black solid. Fig. 7.15 .
OH
ONO
SiO2Au
Au
Catalsyst B
Fig. 7.15 . Schematic drawing of Cat. B
7.13.17 Synthesis of Cat. C
Cat. C was prepared by stirring a mixture of 2.5 mL of TMOS and 2.5 mL of APTMOS in
45 mL of methanol for 2 h, then adding 2 mL of concentrated ammonia. Next day 2.24 g of 4 -oxo-
TEMPO has been added, and the mixture stirred overnight. The following day 0.82 g of sodium
cyanoborohydride was added and the mixture stirred for another 2 days. At the end the excess of
borohydride was destroyed by adding diluted hydrochloric acid. The solid material has been
collected, washed several times with me thanol and let to dry. Fig. 7.16 .
OH
OHSiO2H
NNO
Catalyst C
Fig. 7.16 . Schematic drawing of Cat. C
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7.13.18 Synthesis of Cat. D
Cat. D was prepared by adding under stirring 1 g of catalyst C to 0.1 g of HAuCl 4 in 20 mL
of methanol, followed by 20 mg of sodium borohydride dissolved in 1 mL of water. After 2 h the
solid material has been separated, washed with methanol and dried. Fig. 7.17 .
OH
SiO2H
N NO
Catalyst DAu
Au
Fig. 7. 17 . Schematic drawing of Cat. D
7.14. The procedure of oxidation of alcohols
7.14.1 General procedure for the oxidation of alcohols by TEMPO, PINO and
DN-DPPH free radicals
To 0.5 mmole of one of the chosen alcohols, dissolved in 5 mL of DCM, was added 10%
mol of the free radical as catalyst (TEMPO, DN -DPPH or NHPI – as precursor of PINO) and one of
the co -catalysts A -D, and the mixture was stirred at room temperature for 24h under air.
7.14.2 General procedure for the oxidation of alcohols by polyradicals (DI -T,
TRI-P, TE -T and TE -P)
Reactions for oxidation of the alcohols were done in the following conditions: to 0.5 mmol
of alcohol dissolved into 5 mL DCM were added 7 mg NaNO 2 (20% mol), 0.2 mL of acetic acid
and 10% mol of free polyradical; the mixture was stirred for 24 hours and t hen the solution was
filtered off and the solvent removed under vacuum. The residue was dissolved into 1 mL of
deuterated chloroform and the yields of oxidation were measured by 1H-NMR.
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7.14.3 General procedure for the oxidation of alcohols using nitrogen dioxide as
cocatalyst
The first catalytic system (TEMPO on silica gel – nitrogen dioxide) has been obtained as
described previously [3] in short, through a pad of commercially available TEMPO on silica gel
was passed gaseous nitrogen dioxide (prepared by thermal decomposition of lead (II) nitrate); the
result is a dark brown solid which contain practically an equimolecular ratio of TEMPO and
nitrogen dioxide. The oxidation reactions were performed as it is shown below.
7.14.4 General procedure for the oxi dation of alcohols using nitrosonium
tetrafluoroborate as cocatalyst
A mixture of alcohol substrate (usually between 0.1 -1 mmol, depending on molecular
weight), silica supported TEMPO and nitrosonium tetrafluoroborate (exact molar ratio between
alcohol -catalyst -cocatalyst are shown in Table 1, 5 -20% mol) were suspended into 5 mL DCM and
magnetically stirred at room temperature for a certain amount of time (see also Table 1) under
dioxygen atmosphere (balloon). The reactions were regularly monitored by TLC t o find out the
best working conditions for a high conversion of alcohols into the corresponding aldehydes and
ketones.
After the reaction completion, the mixture was filtered through a small cotton pad to
separate the catalyst, which was washed with a smal l amount of DCM; the organic layers were
combined and the solvent was removed under vacuum using a rotavap. The reaction products were
firstly checked by TLC and NMR, and, if necessarily, were purified by column or preparative
chromatography over silica ge l using an appropriate eluent.
7.14.5 Typical procedure for oxidation of benzylic alcohols by (Cat. A, Cat. B,
Cat. C and Cat. D)
Oxidation 0.5 mmol alcohol was dissolved in 10 mL DCM, and under stirring were added
50 mg of the chosen catalyst and 20 % mo l cocatalyst (nitrosonium tetrafluoroborate). The
heterogeneous mixture was stirred under air for a total reaction time of 4 h, then the organic phase
was separated by simple filtration through a cotton pad (using a Pasteur pipette) and the solvent
removed under vacuum using a rotavap.
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The residue was dissolved into 1 mL of deuterated chloroform, loaded into an NMR tube
and the spectrum recorded; the signals integration affords the yields of transformation.
Measurement performed for routes II and III have b een done in the same working conditions,
using methanol as solvent (reactant as well) instead of DCM.
As co -catalyst A was used a mixture of 20% mol sodium nitrite in 5 mL of water and 0.2
mL of acetic acid; co -catalyst B consisted in 20% mol of nitrosoniu m tetrafluoroborate; co -catalyst
C was a mixture of 0.5 mL sodium hypochlorite (5%) and 10 mg of potassium bromide dissolved
in 5 mL of water; co -catalyst D was gaseous nitrogen dioxide (5 mL) bubbled into DCM solution.
After completion of the reaction, th e solution was filtered of using a small cotton pad and the
solvent was removed using a rotavap. The residue was dissolved in 1 mL of deuterated chloroform
and the NMR spectrum recorded. The yields of the reactions were calculated using the integral
values obtained from 1H-NMR spectra.
7.14.6 Procedure for oxidation of alcohols by GO/iGO
Two methods were employed, using either sodium nitrite/acetic acid or nitrogen dioxide as
co-catalyst under an oxygen atmosphere (balloon) . To 1 mmol of the chosen alcohol dissolved in
10 mL of DCM were added 25 mg of catalyst, 20 mol% sodium nitrite, 0.2 mL acetic acid and the
mixture stirred for 20 h.
The solution was worked up by simple filtration through a cotton pad to remove any solid,
followed by evaporation of the s olvent using a rotavap. The residue was dissolved in 1 mL of
deuterated chloroform and the 1H -NMR spectrum recorded. The ratio between the starting
materials and the oxidation product was evaluated by integration of the NMR signals. For the case
of nitroge n dioxide as co -catalyst, the catalyst was prepared by passing gaseous nitrogen dioxide
(prepared by thermal decomposition of lead(II) nitrate) through the catalyst. All experiments were
repeated at least twice.
7.15. Synthesis methods of GO/iGO
Two methods for obtaining graphene oxides were followed [4,5] with slight modifications,
as follows: i) Hummers methods (GO): to a mixture formed by 1 g of graphite and 0.5 g of sodium
nitrate was slowly added under stirring 25 mL of cold concentrated sulf uric acid, using also an
external cooling of the reaction mixture with ice, then 3 g of potassium permanganate was added in
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portions and the resulting mixture stirred for about half an hour, then the cooling system was
removed and the mixture stirred for another half an hour.
After addition of about 50 mL of water the temperature rose to almost 100 oC, and the
mixture was left for 15 min. Another portion of 100 mL of water was added, and the mixture
stirred again for half an hour, then hydrogen peroxide (30%) was added until the violet solution
decolorized (about 5 mL).
The mixture was left overnight and then the supernatant was removed. The resulting slurry
was centrifuged at 4000 rpm and the collected solid washed extensively with water, aqueous
hydrochlor ic acid and methanol, and after that was left to dry under an open atmosphere till the
next day, and then heated at 60 oC under vacuum for one hour; ii) improved Hummers method
(iGO): 150mL of a mixture 9/1 (v/v) of concentrated sulfuric acid and concentra ted phosphoric
acid were added to a mixture of 1 g of graphite and 6 g of potassium permanganate and the
resulting mixture was stirred for about 8 h under 50 oC, and then the mixture was slowly poured
into about 150 g of ice, adding 5 mL of hydrogen peroxi de (30%).
The resulting solution was left overnight to separate the solid, and the next day the slurry
was centrifuged at 4000 rpm and the collected solid washed extensively with water, aqueous
hydrochloric acid and methanol, left to dry under open atmosph ere till the next day and then heated
at 60 oC under vacuum for o ne hour.
7.16. Method for functionalization of graphene oxides with TEMPO
Very few literature data are available about TEMPO functionalized GO, preserving the
nitroxide spins [6,7] We used a faster and facile protocol, as follows. Graphene oxide 1 g (GO or
iGO) was suspended into 50 mL of dry dichloroethane and then 10 mL of thionyl chloride and 0.5
mL of DMF were added.
The mixturewas heated to reflux for about 3 h, and then the solvent and e xcess thionyl
chloride were removed under vacuum, yielding a black solid. To the solid was added 25 mL of
dichloromethane (DCM), 1 g of 4 -amino -TEMPO and 5 mL of triethylamine and the mixture kept
at room temperature and under stirring for three days.
The solid material recovered by centrifugation was extensively washed with methanol, left
to dry in the open air overnight and then heated under vacuum at 40 oC to remove any trace of
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solvents. The TEMPO -functionalized samples thus obtained from GO and iGO are noted herein a s
GO-T and iGO -T, respectively.
7.17. References
[1] Edwards, T. E., Okonogi, T. M., Robinson, B. H., Sigurdsson, S. T., J. Am. Chem. So c.
2001 , 123 , 1527.
[2] Caproiu, M. T., Ionita, G., Draghici, C., Ionita, P., Arkivoc. Xiv., 2008, 158.
[3] Ionita, P., RSC Adv. 2013, 3, 21218.
[4] Hummers, W. S., Offeman, R. E., J. Am. Chem. Soc. 1958, 80, 1339.
[5] Marcano, D. C., Kosynkin, D. V., Berlin, J. M., Sinitskii, A., Sun, Z., Slesarev, A. et al., ACS
Nano. 2010, 4, 4806.
[6] Du, Z., Ai, W., Xie , L., Huang, W., J. Mater. Chem. A. 2014, 2, 9164.
[7] Navarro, C. B., Busolo, F., Coronado, E., Duan, Y., Gastaldo, C. M., Garcia, H.P., J. Mater.
Chem. C. 2013, 1, 4590.
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General conclusio n
Many of the reactions in organic chemistry that appear without the presence of free
radicals. But in the last 50 years, there has been an enormous evolution of the number of diversity
of free radicals. The diversity of molecular structures found in the group of free radicals is
impressive. Given the importance of these compounds in all areas of medical, industrial and the
preparation in organic chemistry, as well as due to their activity its used as a catalyst in many of
the preparations for the important chemical compounds, such as preparations of polymer,
aldehydes and ketones and so on. For this reason we have in our research that shed light on the
effects of free radicals and preparation of such radicals and applied in the oxidation of primary and
secondary alcohols to the corresponding aldehydes and keto nes that have great significance.
We have focused on our research on the nitroxides free radicals beca use it is very effective
and had many applica tions in organic reactions. R ecent research on nitroxides free radicals have
many important applications. Nit roxides have several applications in organic chemistry such as
substitutions, polymerizations and biological processes.
Preparation of nitroxides free radicals and the interest in applications with different levels
of stability is one of the main reasons f or the development and practical application of chemical
theory.
The commercial availability of industrially produced TEMPO has a variety of applications,
especially in the oxidation of alcohols. In this p roject , we focused on the synthesis of several type s
of free radicals, including their characterization using different types of t echniques such as IR,
NMR, UV, Raman spectra and ESR (Electron Spin Resonance).
We have synthesized stable di -, tri- and tetra -radicals of TEMPO or PROXYL and one type
of hydraz yl as a prelude in their use for the selective oxidation of primary and secondary alcohols
with mild reaction conditions, and explored porous nanosilica -TEMPO as a heterogeneous catalyst
system and also supported TEMPO on silica nanoparticles containing go ld clusters. We also
prepared the TEMPO free radical covalent grafted to grapheme oxide GO through an amide bond.
In the first exper iment we are comparing between different types of free radicals, it was
niroxides and hydrazyl and we found that the nitroxi des are high more active than hydrazyl, we are
used TEMPO, PINO and DN -DPPH as catalyst for the oxidation of alcohols. According on this
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result, we used TEMPO for all our experiments. Following are the summary results of all
experiments:
Stable di -, tri- and tetra -radicals of TEMPO or PROXYL type were used as oxygen
activators in the selective oxidation of some alcohols, using air as final oxidant. The oxidation
process requires also the presence of nitrogen oxides, which convert the nitroxide moiety of the
free radicals into the corresponding oxoammonium salt, a strong oxidant able to oxidize selectively
the alcohols to aldehydes or ketones. Under these conditions, benzyl alcohol can be oxidized in
almost quantitative yields, while 1 -octanol cannot be conve rted into more than 20% 1 -octanal.
Various primary and secondary alcohols were selectively oxidized to the corresponding
aldehydes and ketones using silica supported TEMPO as heterogeneous catalyst and nitrosonium
tetrafluoroborate as cocatalyst. No over -oxidation of aldehydes to acids has been noticed and
neither nitration processes nor oxidation of double bonds has been noticed . The procedure is very
convenient, using mild experimental conditions (room temperature and dioxygen as terminal
oxidant); furthe rmore, the reactions are very clean and the isolation of the desired compounds
requires minimal work -up. A mechanistic pathway has been proposed, in which nitrogen oxides
and oxoammonium ions act as an electron transfer double bridge.The solid state cataly st can be
easily recovered and directly reused. This system represents a good alternative for selective
alcohol oxidation; besides, it is first time when nitrosonium tetrafluoroborate is used as cocatalyst.
TEMPO stable free radical has been supported on p orous silica nanoparticles in different
ways and the resulted materials have been tested as heterogeneous oxidation catalyst of three
benzylic alcohols using air as final oxidant and nitrosonium tetrafluoroborate as cocatalyst. Good
to excellent yields wer e obtained. The catalytic system consists in fact in two coupled cycles,
NO/NO 2 and TEMPO+/TEMPO, able to convert under mild conditions (room temperature, air,
metal and halogen free condition) alcohols into aldehydes or ketones. Under these conditions,
supported TEMPO on silica nanoparticles containing gold clusters lowers the efficiency of the
catalyst.
4-Amino -TEMPO, a stable nitroxide free radical, was covalently grafted onto graphene
oxides through an amide bond and the new composite solid materials th us obtained were
characterized using scanning electron microscopy, thermal and elemental analysis, infrared,
Raman and electron spin resonance spectroscopy. It was found that these materials can be
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successfully used as easily recoverable solid catalysts fo r selective oxidation of alcohols, using
NOx as co -catalyst and oxygen as final oxidant, under very mild conditions.
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