PERSISTENT FREE RADICALS AS REACTIVE INTERMEDIATES . APPLICATIONS IN SYNTHETIC ORGANIC CHEMISTRY Ph. D. Student Under the guidance of Ahmed Juwad… [618465]

UNIVERSITY OF BUCHAREST
FACULTY OF CHEMISTRY
DOCTORAL SCHOOL IN CHEMISTRY

DOCTORAL THESIS
PERSISTENT FREE RADICALS AS REACTIVE INTERMEDIATES .
APPLICATIONS IN SYNTHETIC ORGANIC CHEMISTRY

Ph. D. Student: [anonimizat]

2017

To my parents

The science is the lamp of mind
Imam Ali

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Table of content

List of abbreviations ………………………….. ………………………….. ………………………….. …………………….. v
Acknowledgements ………………………….. ………………………….. ………………………….. …………………….. vii
Abstract ………………………….. ………………………….. ………………………….. ………………………….. ………….. 1
Objectives of the thesis ………………………….. ………………………….. ………………………….. ……………….. 3
Literature data
Chapter 1. Free radicals ………………………….. ………………………….. ………………………….. ……………… 5
1.1. Generalities ………………………….. ………………………….. ………………………….. ……………………….. 5
1.2. Classification of free radicals ………………………….. ………………………….. ………………………….. .. 8
1.2.1 Taking into consideration their stability ………………………….. ………………………….. ……….. 8
1.2.2 Taking into consideration the atom contai ning the unpaired electron ………………………. 11
1.2.3 Taking into consideration their chemical structure ………………………….. ……………………. 12
1.2.4 Taking into consideration the number of radicals center ………………………….. ……………. 13
1.3. Synthesis and generation of free radicals and their properties ………………………….. …………. 15
1.3.1 Generation of free ra dicals ………………………….. ………………………….. ………………………… 15
1.3.2 Synthesis of nitroxides ………………………….. ………………………….. ………………………….. …. 17
1.3.3 Synthesis of hydrazyls ………………………….. ………………………….. ………………………….. …. 20
1.4. Applications of free radicals ………………………….. ………………………….. ………………………….. . 21
1.4.1 Free radica ls in polymerization ………………………….. ………………………….. ………………….. 21
1.4.2 Free radicals in redox reactions ………………………….. ………………………….. …………………. 25
1.4.3 Nitroxide and hydrazyl free radicals as mediators in selective oxidation reaction ……… 26
1.4.3.1 TEMPO as mediator ………………………….. ………………………….. ………………………….. 26
1.4.3.2PINO as mediator ………………………….. ………………………….. ………………………….. …… 31
1.4.3.3 Hydrazyls as mediator ………………………….. ………………………….. ………………………… 36
1.4.3.4 TEMPO with transition metals as mediators in oxidation reactions …………………… 38
1.4.3.5 Oxidation with TEMPO and NOx ………………………….. ………………………….. ……….. 44
1.4.3.6 Oxidation with TEMPO and acids ………………………….. ………………………….. ……….. 50
1.4.3.7 TEMPO -mediated processes for ester synthesis ………………………….. …………………. 53
1.4.3.8 TEMPO on materials ………………………….. ………………………….. …………………………. 57
1.4.3.9 Nitroxide free radical as catalyst for the dehydrogenation of amines ………………… 64
1.4.3.10 Oxidation mechanism using nitroxide radicals ………………………….. …………………. 70
1.5. Conclusion ………………………….. ………………………….. ………………………….. ………………………. 77
1.6. References ………………………….. ………………………….. ………………………….. ……………………….. 79
Original Data
Chapter 2. Nitrox ide and hydrazyl radicals as mediators in selective alcohols oxidation …… 89
2.1. Introduction ………………………….. ………………………….. ………………………….. ……………………… 89
2.2. Synthesis of DN -DPPH ………………………….. ………………………….. ………………………….. ……… 91

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2.3. Characteristics and comparison of the employed free radicals ………………………….. …………. 99
2.4. Oxidation of alcohols ………………………….. ………………………….. ………………………….. ………. 101
2.5. Mechanisms of oxidation ………………………….. ………………………….. ………………………….. …. 103
2.6. Conclusion ………………………….. ………………………….. ………………………….. …………………….. 105
2.7. References ………………………….. ………………………….. ………………………….. ……………………… 105
Chapter 3. Stable organic polyradicals as mediators in oxidation reactions ……………………. 107
3.1. Introduction ………………………….. ………………………….. ………………………….. ……………………. 107
3.2. Synthesis and characterization of polyradicals ………………………….. ………………………….. … 108
3.3. Oxidation of alcohols mediated by polyradicals ………………………….. ………………………….. . 115
3.4. Mechanistic proposal ………………………….. ………………………….. ………………………….. ………. 117
3.5. Conclusion ………………………….. ………………………….. ………………………….. …………………….. 119
3.6. References ………………………….. ………………………….. ………………………….. ……………………… 119
Chapter 4. Sele ctive oxidation of alcohols by silica supported TEMPO ………………………….. 121
4.1. TEMPO versus silica supported TEMPO ………………………….. ………………………….. ……….. 121
4.2. Oxidation of alcohols ………………………….. ………………………….. ………………………….. ………. 121
4.3. Catalytic system robustness ………………………….. ………………………….. ………………………….. 124
4.4. Mechanistic proposal ………………………….. ………………………….. ………………………….. ………. 125
4.5. Conclusion ………………………….. ………………………….. ………………………….. …………………….. 127
4.6. References ………………………….. ………………………….. ………………………….. ……………………… 127
Chapter 5. TEMPO on nanosilica and the influence of supported gold clusters in aerobic
oxidations ………………………….. ………………………….. ………………………….. ………………………….. …… 129
5.1. Introduction ………………………….. ………………………….. ………………………….. ……………………. 129
5.2. Development of nanosilica -TEMPO materials ………………………….. ………………………….. … 130
5.3. Characterization of the nanomaterials ………………………….. ………………………….. ……………. 132
5.4. Oxidation of alcohols to aldehyde/ketone (route I) ………………………….. ………………………. 138
5.5. Oxidative coupling with methanol (route II and III) ………………………….. …………………….. 139
5.6. Mechanism of oxidation ………………………….. ………………………….. ………………………….. ….. 141
5.7. Conclusion ………………………….. ………………………….. ………………………….. …………………….. 142
5.8. References ………………………….. ………………………….. ………………………….. ……………………… 142
Chapter. 6. TEMPO on graphene oxide: material for selective oxidations of alcohols ……… 144
6.1. General ………………………….. ………………………….. ………………………….. ………………………….. 144
6.2. Synthesis and characterization of GO and iGO ………………………….. ………………………….. .. 148

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6.3. GO Functionalized with 4 -amino -TEMPO (GO -T and iGO -T) ………………………….. ……… 148
6.4. Oxidation of alcohols ………………………….. ………………………….. ………………………….. ………. 157
6.5. Mechanism of oxidation ………………………….. ………………………….. ………………………….. ….. 159
6.6. Conclusion ………………………….. ………………………….. ………………………….. …………………….. 162
6.7. References ………………………….. ………………………….. ………………………….. …………………….. 163
Chapter 7. Experimental part ………………………….. ………………………….. ………………………….. ….. 167
7.1. Chemicals, solvents and materials ………………………….. ………………………….. …………………. 167
7.2. Apparatus ………………………….. ………………………….. ………………………….. ………………………. 167
7.2.1 IR spectroscopy ………………………….. ………………………….. ………………………….. …………. 167
7.2.2 UV -Vis spectroscopy ………………………….. ………………………….. ………………………….. …. 167
7.2.3 HR -MS ………………………….. ………………………….. ………………………….. …………………….. 167
7.2.4 EPR spectroscopy ………………………….. ………………………….. ………………………….. ……… 167
7.2.5 NMR spectroscopy ………………………….. ………………………….. ………………………….. …….. 168
7.2.6 X -ray diffraction ………………………….. ………………………….. ………………………….. ……….. 168
7.2.7 Raman spectroscopy ………………………….. ………………………….. ………………………….. ….. 168
7.2.8 Thermal measurements ………………………….. ………………………….. ………………………….. . 168
7.2.9 Cyclic voltammetry ………………………….. ………………………….. ………………………….. ……. 169
7.2.10 GC analysis ………………………….. ………………………….. ………………………….. …………….. 169
7.2.11 Brunauer Emmette Teller (BET) and Barrett –Joyner– Halenda (BJH) methods …… 169
7.2.12 SEM and EDX spectroscopy ………………………….. ………………………….. …………………. 170
7.2.13 Elemental analysis ………………………….. ………………………….. ………………………….. …… 170
7.3. Synthesis of compounds ………………………….. ………………………….. ………………………….. ….. 170
7.3.1 Synthesis of DN -DPPH ………………………….. ………………………….. ………………………….. . 170
Synthesis of picryl chloride ………………………….. ………………………….. ………………………….. … 172
Synthesis of 2,2 -diphenyl -1-picrylhydrazine ………………………….. ………………………….. ……… 172
Synthesis of 2,2 -dinitrophenyl -1-picrilhydrazine ………………………….. ………………………….. .. 173
Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl ………………………….. ………………………….. … 174
7.3.2 Synthesis of PINO ………………………….. ………………………….. ………………………….. ……… 175
7.3.3 Synthesis of 4 -isocyanato -TEMPO ………………………….. ………………………….. …………… 175
7.3.4 Synthesis of DI -T radical ………………………….. ………………………….. ………………………… 176
7.3.5 Synthesis of TRI -P radical ………………………….. ………………………….. ………………………. 176
7.3.6 Synthesis of TE -T radical ………………………….. ………………………….. ………………………. 177
7.3.7 Synthesis of TE -P radical ………………………….. ………………………….. ………………………… 179
7.3.8 Synthesis of Cat. A ………………………….. ………………………….. ………………………….. ……. 180
7.3.9 Synthesis of Cat. B ………………………….. ………………………….. ………………………….. …….. 180
7.3.10 Synthesis of Cat. C ………………………….. ………………………….. ………………………….. …… 181
7.3.11 Synthesis of Cat. D ………………………….. ………………………….. ………………………….. ….. 182
7.4. Synthesis methods for GO and iGO ………………………….. ………………………….. ……………….. 182
7.5. Method for functionalization of graphene oxides with TEMPO ………………………….. …….. 183
7.6. Procedures for the oxidation of alcohols ………………………….. ………………………….. ………… 184

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7.6.1 General procedure for the oxidation of alcohols by TEMPO, PINO and DN -DPPH f ree
radicals ………………………….. ………………………….. ………………………….. ………………………….. … 184
7.6.2 General procedure for the oxidation of alcohols by polyradicals (DI -T, TRI -P, TE -T and
TE-P) ………………………….. ………………………….. ………………………….. ………………………….. …… 184
7.6.3 General procedure for the oxidation of alcohols using nitrogen dioxide or nitrosonium
tetrafluoroborate and silica -supported TEMPO ………………………….. ………………………….. ….. 185
7.6.4 Typical procedure for oxidation of benzylic alcohols using our silica -TEMPO materials
Cat. A, Cat. B, Cat. C and Cat. D) ………………………….. ………………………….. ……………………. 185
7.6.5 Procedure for oxidation of alcohols by GO/iGO ………………………….. …………………….. 186
Quantification of the oxidation yields ………………………….. ………………………….. ……………….. 186
7.7. References ………………………….. ………………………….. ………………………….. ……………………… 188
General conclusion ………………………….. ………………………….. ………………………….. ………………….. 189
List of contributions ………………………….. ………………………….. ………………………….. ………………… 193

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List of abbreviations
ABNO
ACOH
ACT
AIBN
APTMOS
AuNPs 9-azabicyclo[3.3.1]nonane -N-oxyl
acetic acid
4-acetamido -TEMPO
azoisobutyronitrile
(3- aminopropyl)trimethoxysilane
gold nanoparticle
AZADO 2-azaadamantane -N-oxyl
BAIB
BDE
BPO
CPGMA bis(acetoxy)iodobenzene
bond dissociation energy
benzoyl peroxide
poly(glycidyl methacrylate)
CPME
CRP cyclopentyl methyl ether
controlled radical polymerizations
DCE dichloroethane
DCM
DLS dichloromethane
dynamic light scattering
DPPH
DN-DPPH 2,2-diphenyl -1-picrylhydrazyl
2,2-dinitrophenyl -1-picrylhydrazine
EEDQ
FETs
GFET
Kd
Kc
KPF 4 N-ethoxycarbonyl -2-ethoxy -1,2-dihydroquinoline
field effect transistors
graphene based field effect transistor
dissociation rate constant
combination rate constant
potassium hexafluorophosphate
MCPBA m- chloroperbenzoic acid
MeTHF
NCS 2-methyltetrahydrofuran
N-chlorosuccinimide
NHPI N-hydroxyphthalimide
NMI N-methyl imidazole
NMP nitroxide -mediated radical polymerization
PINO
PTM phthalimide -N-oxyl
perchlorotriphenylmethyl
PTMA
PTMSS
PTSA
SEM
SGI 2,2,6,6 -tetramethylpiperidinyl – oxymethacrylate
PTM derivatives
p-toluenesulfonic acid
scanning electron microscop y
N-(2-methylpropyl) -N-(1,1-diethylphosphono -2,2-dimethylpropyl) -N-oxyl

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SFRP
SQUID
TBN stable free -radical p olymerization
superconducting quantum interference device
t-butyl nitrite
TCCA trichloro isocyanuric acid
TEMPO
TEMPO H
THF
TIPNO
TMOS
TPM 2,2,6,6 -tetramethylpiperidin -1-yl
1-hydroxy -2,2,6,6 -tetramethyl -piperidine
tetrahydrofuran
2,2,5 -trimethyl -4-phenyl -3-azahexane -3-nitroxide
tetramethoxysilane
triphenylmethyl

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Acknowledgements
First and for most, I would like to thank the Almighty God for bestowing me with the
strength, patience and perseverance to accomplish the present study.
It is impossible to acknowledge everyone who has been a part of this work and to give an
appropriate amount of thanks to those who have helped in this journey. I have been fortunate
enough to work with some of the best and most patient professors in chemis try, and it is essential
that I give thanks for their scholarly input and supervision on this research.
However, I feel entitled to write this section with the intent of being comprehensive rather
than succinct. It is the best opportunity I have to thank those people who extended their help to me
throughout my graduate career, and probably the last good opportunity to express my gratitude, in
writing, to the many individuals who have instructed and supported me throughout my formal
education.
I am greatly indebted to my supervisor Assoc. Prof. Habil . Petre Ionita , for his penetrating
remarks, valuable comments and constructive suggestions on every aspect of this work without
which this study would not have taken its present shape. The many references he pro vided me with
have proved extremely valuable to the work, and I am extremely grateful to him .
I gained a lot from his chemistry knowledge and scientist curiosity. I was fortunate to have
the chance to work with him, and he was an extremely reliable source of practical scientific
knowledge. During my tenure, he contributed to a rewarding graduate school experience by giving
me intellectual freedom in my work, supporting my attendance at various conferences, engaging
me with new ideas, and demanding a high q uality of work in all my endeavors.
Sincere thanks are also due to (prof. Dr. Simona Coman, conf. Dr. Ileana Farcasanu and
conf. Dr. Irina Zarafu ) for their interest in my work. They provided a friendly and cooperative
atmosphere at work and also useful fe edback and insightful comments on my work.
I would like to express my deep respect and gratitude to ( prof. Dr. Camelia Bala ). I am
very grateful to ( Cristina Stavarache and Anamaria Hanganu ) for help ing me. I would like to thank
the various members of the department of organic chemistry, biochemistry and catalysis with
whom I had the opportunity to work and have not alrea dy mentioned ( Conf. Dr. habil. Marcu Ioan
Cezar , Ș.l. Dr. Mihaela Matache and As. Dr . Bogdan Cojocaru ).

viii
Every result described in this thesis was accomplished with the help and support of fello w
lab- mates and collaborators and for reading the draft proposal of the study and making valuable
comments on it, as well as for providing me wit h useful references.
I am particularly indebted to (Mohammed Nasser Hassoon, Ahmad Kareem Salem and
Ahmed Hamod Shlaka) for their cheerful cooperation .
Finally, I would like to acknowledge friends and family who supported me during my time
here. First and foremost, I would like to thank Dad, Mom, my brothers (Haider and Mostafa) , my
sister and Anfal for their constant love and support.

Ahmed Juwad Shakir – Doctoral Thesis

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Abstract
Free radicals are chemical species that have at least one unpaired electron. This 'free'
electron give to the chemical species uncommon properties. The chemistry of free radicals started
more than 150 years ago and had an astonishing evolution in the last decades. Organic free
radicals are known since the beginning of the 20th century and nowadays are well known as
important reactives or intermediates in many physical, che mical or biological processes.
This thesis deals with the study of some free radicals and their possible use as mediators in
oxidation processes. The thesis is divided into two main parts, theoretical (literature data) and
practical (original experimental data).
In the first par t are explained and enumerated some definitions, classifications, synthesis,
properties and application of free radicals. This part high lighted most the nitroxide free
radicals. Their applications as effective mediators towards the oxidation of alcohols were taken
into account; in a similar way, informa tion about their use in polymerization or redox reactions
like dehydrogenation of amines are presented. For all these types of reactions, the oxidation
mechanism is showed according with literature data.
In the second part of the thesis, original experimental data are presented. Most of them refers
to the use of free radicals as intermediates in selective oxidation reactions of alcohols. The study
starts with commercially available free radicals of nitroxide or hydrazyl types and then moves
toward s several types of free mono -, di, tri – and tetra -radicals, as pure organic compounds. The
next step is their attachment to solid materials, like silica and graphene oxide. Usually, these free
radicals are unable to directly oxidize alcohols, therefore a c onvenient way to generate the
corresponding oxoamm onium derivative is necessary.
Besides the direct comparison of the properties of such free radicals, a study about the
different ways to generate the oxoammonium salts is shown. This was generated using
sodium nitrite and acetic acid, sodium hypochlorite, nitrosonium tetrafluoroborate and nitrogen
dioxide gas. As alcohols were used benzyl alcohol, 1 -phenylethanol, diphenylmethanol, 1-octanol,
furfurol and so on.
To improve the oxidation system (in terms or the recovery of the free radical and to easy
the work -up procedures) commercially available silica supported TEMPO has been used in a first

Ahmed Juwad Shakir – Doctoral Thesis

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instance, then it were synthesized silica nanoparticles to which TEMPO has been attached by
different linkers. The influence of gold nanoparticles in the oxidation system was also studied.
Finally , TEMPO was covalently grafted onto graphene oxide through an amide bond and
the thus obtained material was successfully used as easily recoverable solid catalyst for selective
oxidation of some alcohols, using under very mild conditions oxygen or air as final oxidant.
Compounds and materials synthesiz ed were characterized by appropriate m eans.

Ahmed Juwad Shakir – Doctoral Thesis

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Objectives of the thesis

►Use of persistent or stable (poly) free radicals as reactive intermediates in alcohol oxidations
using air or oxygen as final oxidant.
►Focus on nitroxide as well as on hydrazyl free radicals as oxidation mediators.
►Use a range of co -oxidant s (most of them NO x generating system).
►Start from commercially available of non -commercial available free radicals.
►Synthesis and characterization of some free radicals.
►A comparative study between nitroxide and hydazyls regarding their properties and oxidant
capabilities .
►Increase the effectiveness of free radicals through the preparation and use of polyradicals.
►Test silica -supported TEMPO as recoverable mediator.
►Prepare novel silica -supported TEMPO mediator s.
►Study the influence of gold nanop articles on such material.
►Make the free radicals recoverable by attaching them to graphe ne oxide .
►Use a wide range of alcohols as substrates .

Ahmed Juwad Shakir – Doctoral Thesis

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Literature data

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 therefore 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 radi cal has the unpaired electron on the carbon atom. Carbon –
centered free radicals are very often encoun tered in organic chemistry and hold focal places in
present day o rganic reactivity. The structure of the methyl radical is shown in Fig. 1.1.
C
H HH

Fig. 1.1. Structure of methyl free radical
Free radicals have been found to play a vital role in biological processes. Scientists have
likewise studied free radicals in certain cell signaling procedures [2]. Free radicals are
encountering in industry and medicine (such as halogen ation reactions or in the control of blood
pressure and vascular tone) and play an important task 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, a nd the 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 .
As mentioned already, free radicals play a pivotal role in many chemical or biochemical
processes and also in industrial ones, for example they can be used as catalysts or in
polymerization processes and also as reporter molecules to get dynamic, structural, or reactivity
information.
Free radicals can behave both as reduc ing agents or as oxidants, because they can either
accept or donate an electron f rom other molecules (Fig. 1.3).

Ahmed Juwad Shakir – Doctoral Thesis

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O
MeMeMe
OHRO
vitamin E
ROH +OMe
O
Me
Mereactive free radical
less reactive free radical
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) , obtaine d in
1845 by Edmond Fremy [3 -5] as a yellow solid that dissolves in water generating a violet solution.
It is a strong oxidant , and is generally used to monitor the mechanism o f oxidation and
hydroxylation [6 ], and as a standard for g-value determination in an electronic
paramagnetic resonance (EP R) technique; it is also used in oxidation reacti ons [7,8 ] and
specifically in oxidation of phenol and aromatic amine [6,9 ].

Ahmed Juwad Shakir – Doctoral Thesis

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NO
O3SSO3K+
K+
Fig. 1.4. Fremy's salt, an inorganic stable nitroxide
Fremy's salt was prepared by the reaction of sulfur dioxide, sodium bicarbonate and sodium
nitrite , followed by oxidation [10].

HNO2 + 2HSO3-HON(SO3)2-2 + H2O (1)
3 HON(SO3)2-2 + MnO4- + H+ 3 ON(SO3)2-2 + MnO2 + 2 H2O (2)
2 ON(SO3)2-2 + 4 K+ K4[ON(SO3)2]2 (3)

It is generally believed that such structu res (free radical) 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 the unpaired electron.
The common radical coup ling reaction is their dimerization that occurs rapidly. This is one
of the principal motifs why most organic chemists avoid radical reactions in organic synthesis.
The most distinguishing characteristic of free radicals is the presence of an unpaired
electron. Species with an unpaired electron are paramagnetic, therefore they have a non -zero
electronic spin. The most useful method for detecting and characterizing free radical intermediates
is electron paramagnetic resonance (EP R) spectroscopy [11,12 ].
EPR spectroscopy is a highly specific tool for detecting radical species because only
molecules with unpair ed electrons give an EP R spectrum .
EPR spectroscopy can detect the transition of an electron between the energy levels
associated with the two possible orientations of elect ron spin in a magnetic field. EP R spectra have
been widely used in the s tudy of reactions to detect free radical intermediates.

Ahmed Juwad Shakir – Doctoral Thesis

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Free radicals may be detected at concentrations as little as 10−8 M with a commercially
common available device. The EP R technique of detecting short -lived free radicals in solution has
been evolved to the spin -trapping technique [13-16].

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. 1.5 . 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 very reactive and 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
centers
Taking into
consideration their
chemical structure

Ahmed Juwad Shakir – Doctoral Thesis

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CH3 OH
Fig. 1.6 . 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 radica l [17 ] (Fig. 1.7 ). This
was obtained by abstraction of the chlorine atom from triphenylchloromethane by silver metal.

ClAg
+ AgCl

Fig. 1.7 . Synthesis of triphenylmethyl radical
The original suggested structure of the triphenylmethyl dimer (Fig. 1.8 ) has been proved to
be wrong, the dimerization being in fact a p-phenyl addition. It is important to mention that such
radicals are known as persistent radicals (radicals that usually have long lifetimes and are resistant
to dimerization and disproportionation).

Ahmed Juwad Shakir – Doctoral Thesis

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wrong correct
Fig. 1.8 . Proposed dimer structure s for triphenylmethyl radical

Stable free radicals
In a common way , the stability of free radicals is caused by two reasons, steric hindran ce
and electronic stabilization ; however 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 of its stability. For example , α,β-bisdiphenylene -β-phenylallyl radical (Fig. 1.9 ) is
indefinitely a stable solid, even in the presence of air.

Fig. 1.9 . Chemical structure α,β -bisdiphenylene -β-phenylallyl , as a stable carbon -centred free
radical

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Some other reported stable free radicals are shown in Fig. 1.10 .
NNNN
ON
SN
N NN
O

Fig. 1.10 . Examples of some stable (or persistent) free radicals

1.2.2 Taking into consideration the atom containing the unpaired electron
In this way free radicals can be divide d as C-centred free radicals, O -centred free radicals,
N-centred free radicals and so on.

Fig. 1.1 1. Some examples of free radicals with the unpaired electron on different types of atoms

O
NHO
Ph
CH3 H3CNOO
ON

Ahmed Juwad Shakir – Doctoral Thesis

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1.2.3 Taking into consideration their chemical structure
Many free radicals are classified as nitroxide s, such is TEMPO (2,2,6,6 –
tetramethylpiperidin -1-yl), or as hydrazyl s, like DPPH (2,2-diphenyl -1-picrylhydrazyl), F ig. 1.12 .

NNO2N
NO2
O2NN
O
nitroxide TEMPONN
hydrazyl DPPHN
O

Fig. 1.12 . 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 r esonance structures
(Fig. 1.13 ), due to the delocalization of the e lectron. The s pin density is divided between both
atoms, often with a slightly higher d ensity at the oxygen atom [18 ].

N N
O O_
1 2

Fig. 1.13 . 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 g roups with hydrogen or attaching a phenyl group directly to nitrogen renders the
nitroxide relatively unstable [19 ]. The stability of nitroxide radicals makes it possible to carry out
reactions selectively on functional groups not involving the unpaired el ectron.
In 1911 , Wieland and Offenbacher [20 ] studied many diaryl nitroxides using different
chemical means , most of them prepare d by the reaction between N-nitroso -diphenylamine and
phenyl -magnesium bromide.

Ahmed Juwad Shakir – Doctoral Thesis

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Nowadays, X-ray diffraction is a total tool to study the chemical structure of some
representative cyclic nitroxides with five-, six- and seven -membered rings . Fig. 1.14 and Table 1
show the values of geometrical paramet ers for these nitroxide radicals .
NONO
ON
N
O

Fig. 1.14 . 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 [21-25] 1.27 112-117 0-5
6-membere d ring [26 -30] 1.27-1.31 123-126 15-20
7-membered ring [31] 1.29 130 21
aOut-of-plane angle

1.2.4 Taking into consideration the number of radicals center s
Monoradicals,
diradicals and
polyradicals
are classified by the number of their 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 only their
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.) [32 -35]. The first perchlorotriphenylmethyl (PTM) free radicals reported were the diradical
and tri -radical showed in Fig. 1.15 , both having high -spin ground stat es [36].

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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. 1.15 . Structure of PTM polyradicals
Tetraphenyl -p-xylylene (Thiel radical) was prepared by Thiel and Balhorn in 1904 as an
isolable species [37 ] and has bee n characteri zed by X -ray [38 ], Fig. 1.16 .

Ph
Ph PhPh
PhPh Ph
Ph

Fig. 1.16 . Tetraphenyl -p-xylylene radical
Literature data showed [39] some recently synthesized polyradicals (Fig. 1.17 ).
H
NH
N
ONO NHNC NOO
HNC NO
ONH H
N
ONOHNN
HNO
O

Fig. 1.17 . Structure of some polyradical s based on TEMPO moieties

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Most organic free radicals have been chemically anchored on the surfaces of metals, for
example the diradical PTMSS [40,41 ], Fig. 1.18 .

SSCl
Cl
Cl ClCl
ClCl
Cl
ClCl Cl
Cl Cl
ClClClClCl
Cl Cl
ClCl
ClClCl
ClCl
ClPTMSS

Fig. 1.18 . Structure of PTMSS diradical

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 peroxybenzoat e and benzoyl peroxide) ,
because the bond between oxygen -oxygen in per oxides is weak (30 kcal/mol) [42 ].

OOO
OOO
C
OO
O +Half-life 10 mins at 70 oC
O
acetone
+2 2
CH3

Fig. 1.19 . Formation of methyl free radicals from a peroxide

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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 [43 ].
NN
CNNCheat
C
N- N2

Fig. 1.20 . Decomposition of azoisobutyronitrile ( AIBN )
Carbon -metal bond in organometallic compounds have also low bond dissociation energy
(BDE) and are easily homolyzed into free radicals.

Pb
CH3CH3
H3C CH3heatPb+4 CH3

Fig. 1.21 . Synthesis of methyl free radicals from tetramethyl lead
Kolbe reaction can be used as well , as any other electrochemical oxidation (Fig. 1.2 2).

1 e – oxidationRCO
ORCO
OR + CO2

Fig. 1.22 . 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. 1.23.
H3C CH3O O
H3C CH3OHOMn(OAc)3
AcOH H3C CH3O O
+H+

Fig. 1.23 . Synthesis of free radicals by transition metal oxidation

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1.3.2 Synthesis of nitroxides
The synthesis of nitroxides R 1N(•O)R 2 are achieved through several synthetic routes that
depend on the nature of R 1 and R 2 groups, for example by oxidation of ami nes using
dimethyldioxirane [44 ,45] (oxone ) or hydrogen peroxide [46]. Hydroxylamines can b e easily
oxidized to nitroxides [47-49], as showed in Fig. 1.24 .
NHOH
EtEtO O
EtEt
NH4OAcNN
EtEt
EtEt
HOMnO2
CHCl3NN
EtEt
EtEt
O

Fig. 1.24. Synthesis of a nitroxide radical
Nitroxide s can be prepare d also by react ion of nitrones with organometallic compounds, in
order to get first the corresponding hydroxylamines, which can be easily oxidize d to nitroxides
[50], Fig. 1.25 .
N
R1O
R2
R31) R4 Metal
2) OxidationN
R1O
R2
R3R4

Fig. 1.25 . Synthesis of nitroxide radicals from nitrones
Different other methods, except these most usually used approaches, were suggested for the
synthesis of nitroxides, such is the reaction between tertiary nitroalkanes and sodium metal t o give
the corresponding di -t-alkyl nitroxides [51]. Furthermore, the reaction of nitroalkanes 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 nitrox ide chemistry came from Wieland and Meyer [54], who
extensivelly prepared diarylnitroxides (Fig. 1.26 ).

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MgBr+N
ON
OMgBrN
O1)H3O+
2)Ag2O
N
HOMe MeO
PhCO3HOMe MeO
N
O
Fig. 1.26 . Synthesis of diarylnitroxides by Wieland and 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] , which can also be
stored for long periods of time with out decomposition. TEMPO is a stable free radical due to the
steric influence of the four methyl groups. It is prepared by oxidation of the corresponding
tetramethylpiperidine 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]. 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 fr ee radical compounds such as
the prototypical 2,2,6,6 – tetramethylpi peridine -1-oxyl ( TEMPO ).
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. 1.27 ).

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. 1.27 . Preparation of chiral nitroxides

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It is worth to remember that t he first organic nitroxide was the so called porphyrexide ,
prepared and named by Piloty and Schwerin in 1901 [57]; 2,2,6,6 -tetramethyl -4-piperidone -1-oxyl
(4-oxo-TEMPO , Fig. 1.28 ) was prepared by Lebedev et al. [58] in 1959 (Fig. 1.28 ).

NNH
NHHN
ONO
O

Fig. 1.28 . Structure of porphyrexide and 4 -oxo-TEMPO
Although TEMPO was synthesized fifty years ago [59], nitroxide radicals may found today
interesting 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 along time , and have been used in different
applications . Fig. 1.29 shows such types of polynitroxides . 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 -70] depend on the electron spin –spin
exchange coupling between unpaired electrons .

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RO 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]
Fig. 1.29 . Structure of some nitroxide polyradicals

1.3.3 Synthesis of hydrazyls
2,2-Diphen yl-1-picrylhydrazyl free radical (DPPH ) was discovered in the 1922 by
Goldschmidt and Renn, as a crystalline stable powder , and has been used mainly a s an electron
spin resonance (EP R) standard, a radical scavenger in polymer chemistry, and an indicator for
antioxidant chemistry. There are also known stable poly hydrazyl s [71] (Fig. 1.30 ).
Synthesis of such radicals starts usua lly from the aromatic secondary amines, that are
converted into the N-nitroso derivatives, reduced to the corresponding hydrazines, coupled with
activated halogeno -polynitroaromatics and finally oxidized to the hydrazyls free radicals. More
details follow in the original data part.

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N N
N N NO2
O2N NO2NO2
NO2 O2NNNO2N
NO2
O2N
DPPH
Fig. 1.30 . Structure of hydrazyls free radical s

1.4. Applications of free radicals
1.4.1 Free radicals in polymerization
One of t he main hold -back in free radical chemistry is the capability of these to react with
themselves (dimerization).
+R RR R

Fig. 1.31 . Dimerization of free radicals
Free radicals are used as initiators in emulsion polymerization reactions for making
elastomers. In 2015, Yi et al. used TEMPO Na and N-fluorobenzenesulfonimide (NFSI) to react
with various a lkenes [72 ], Fig. 1.32 . Linyi et al. [73] developed the aminoxylation of hydrocarbons
under mild conditions by using [( Bpy)Cu(II)/TBHP] copper(II)/ t-butyl hyd roper oxide cataly tic
system, Fig. 1.33 .

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NPhO2S SO2Ph
F NFAS
NaFNONa
NO
NPhO2S SO2Ph
RR-R
R-N(SO2Ph)2NO
RN(SO2Ph)2
R-
Fig. 1.32 . 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. 1.33 . The copper -catalyzed aminoxylation reaction with TEMPO

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Xin et al. [74] used TEMPO with B(C 6F5)3 as Lewis acid to abstract a hydrogen atom from
different type of subst rates, and they had been found TEMPO able to split dihydroge n under
ambient conditions (Fig. 1.34 ).
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. 1.34 . 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 [75 -80], but
three dominate because of their simplicity and functional molecular tolerance: i) reversible
addition fragmentation chain tr ansfer polymerization (RAFT) [81 ], ii) atom switch r adical
polymerization (ATRP) [82 ,83], and iii) nitroxide -mediated polymerization (NMP) [84,85 ].
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 R AFT and ATRP techniques.
In 1985, Solomon and Moad described nitroxides as reversible radical trapping agents for
carbon -centred radicals [86,87 ]. TEMPO was applied as a trapping agent for acrylate and
methacrylate monomers polymerization initiated with azobisisobutyronitrile to generate
alkoxyamines adducts (Fig. 1.35 ).

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ON R
OH3CONC
R = H,CH3
Fig. 1.35 . An alkoxyamine adduct
TEMPO was initially shown to be an efficient mediator for the homopolymerization of
styrene and the copol ymerization 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 lo w molecular
weight oligomers [88 ].
A series of nitroxides were developed that formed alkoxyamines with styrene 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-nitroxide
(TIPNO , Fig. 1.36 ) have the dissociation rate constant value of 3.6 × 10−3 s−1 [89], while N-(2-
methylpropyl) -N-(1,1-diethylpho sphono -2,2-dimethylpropyl) -N-oxyl (SG1, Fig. 1.36 ) have the
dissociation rate constant value of 3.3 × 10−4 s−1 [90].
These radicals , show n in Fig. 1.36 , are very effective in mediating the polymerization of
acrylates and other non -styrenic monomers, specif ically acrylamides, 1, 3-dienes, and acrylonitriles
[91].
NP O EtOO
OEt
SG1NO
TIPNO

Fig. 1.36 . Structure of TIPNO and SG1
Initial polymerizations of styrene performed by stable free radical polymerization ( SFRP )
using TEMPO as the moderating nitroxide were quite slow, taking over 40 hours to reach
conversions of 76 % [92 ].

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The use of DMF as an additiv e for the polymerization of t-butyl acrylate initiated by 4 -oxo-
TEMPO -capped polystyrene macroinitiator ha s been shown to be e ffective [93 ].
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, lowe r kc), with very good effect [88 ].
It was subsequently shown that polymerizations of styrene can proceed quickly and
efficiently using a primary initiator, such as benzoyl peroxide ( BPO ), in the absence of an additive,
if the ratio of TEMPO to BPO is varied according to t he targeted molecul ar weight [94 ].

1.4.2 Free radicals in redox reactions
Nitroxides are redox compounds and they can be reduced to the corresponding
hydroxylamines or oxidized to the corresponding oxoammonium salt ; in most cases the reaction s
are reversible (Fig. 1.37 ).
N
O
N
OHN
O++ H++ 1e-
– 2 e– 1e-TEMPO
Hydroxylamine
TEMPOHTEMPO,
oxoammonium salt

Fig. 1.37 . Reversibl e redox properties of TEMPO
TEMPO is a weaker oxidant than the N-oxoammonium salt , but it can react s with an
organometallic compound to form in the first step carbon – centred radicals; that easily couple with
TEMPO to form al koxyamines (reaction requires two equivalents from TEMPO , one for oxidation

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of organometallic compound to the corresponding carbon -centered radical and another to provide
the alkoxyamine ).
For example, TEMPO reacts with organoboron species. Fig. 1.38 shows that the B-
alkylcatecholboranes reacts with TEMPO , which leads to the f ormation of boric acid ester [27 ].
This reaction it is supp osed to takes place by a radical intermediate (Fig. 1.38) [28 ].
OBO
R
OBO
O
NTEMPO
R
OBOO
RNTEMPO
N
OR

Fig. 1.38 . Reaction of B -alkylcatecholboranes with TEMPO

1.4.3 Nitroxide and hydrazyl 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 their study
is very important because of the ir particular properties . Various kinds of stable free radicals having
one or more unpaired electrons were devel oped for applications in medicine and materials science.
In chemistry , oxidation processes usually involve free radicals and require harsh
experimental conditions . For example , selective oxidation of alcohols to aldehyde and ketone are
performed in difficult conditions for the reactions and generate toxic waste.

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Several oxidants are available for use in the selective oxidation of alcohols , most of them
containing transition metal ions ( Jones reagent and Collins oxidation ) and requiring extensive
work-up is order to isolate the compound from the reaction mixture .
The treatment of oxoammonium salt (Fig. 1.39 ) with excess of ethanol caused the
formation of acetaldehyde. Cella et al. established in 1975 [95 ] that alcohols can be oxidized to
carboxylic ac ids by using a treatment with m-chloroperbenzoic acid (MCBPA) within the presence
of a catalytic quantity of 2,2,6,6 -tetramethylpiperidine, as a precursor of the free radical ( Fig.1.40).

CH3CH2OH CH3CHON
OCl-

Fig. 1.39. Oxidation of ethanol by the oxoammonium salt

Fig. 1.40. Oxidation of alcohol with a free radical precursor
In 1987, Anelli publi shed a landmark paper [96 ] on TEMPO -mediated oxidations, which
signaled the beginning of the routine employment of catalytic oxoammonium salts 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 [97,98 ]
and toluene -ethylacetate mixtures [99 ].
Under these conditions, primary alcohols are transformed in 3 min at 80oC into the
corresponding aldehydes, while secondary alcohols are transformed into ketones in 7–10 min, as
shown in Fig. 1.41 .
OH
N
HMCBPACOOH

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OHH
O1 % mol 4-MeO-TEMPO, 1.25 eq. NaOCl
0.1 eq. KBr, NaHCO3, CH2Cl2, H2O, 0 oC
Fig. 1.41 . Anelli's protocol for the TEMPO -mediated oxidation of alcohols
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 [96 ], obtained by beveling the blea ch solution with NaHCO 3,
sometimes, in order to avoid base induced side reactions, it is advisable to adjust the pH a t 6.5–7.5
by adding an acid [100 ].
In fact, the primary oxidant in such reactions is an oxoammonium salt. The classical
selective oxidation of alcohols using Anelli ‟s protocol contains a DCM -water mixture with
TEMPO as oxidation mediator ( catalyst ), and sodium hypochlorite (NaCl O) acting as a secondary
oxidant, giving high selectivity for oxidation of primary alcohols in the p resence of secondary
alcohols [101 -103]. This can be and is currently used in organic che mistry synthetic preparations
[104-107] (Fig. 1.42).
OMe
NS
MeHO
OMeO
Me
MeMeOH
O OH1.5 eq TEMPO, 1.1 eq NaOCl
KBr, DCM, 0.5 h, 0 oC
OMe
NS
MeHO
OMeO
Me
MeMeO
O OH

Fig. 1.42. Anelli selective oxidation of primary alcohols in the presence the secondary alcohols
(90% yield)
In 1997, Piancatelli et al. [108] used TEMPO with [bis(acetoxy)iodo]benzene ( BAIB)
acting as the secondary oxidant for the selective oxidation of primary alcohols in the presence of
secondary alcohols, Fig. 1.43 .

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MeHO
Me
OTBSMeOTBSMeMe Me
OH0.2 eq. TEMPO, 1.5 eq. PhI(OAc)2
DCM, 1h, 25 oCMeO
Me
OTBSMeOTBSMeMe Me
OH

Fig. 1.43. TEMPO -PhI(OAc) 2 used for selective primary alcohols oxidation in the presence of
secondary alcohols [109]
In literature there are many examples of TEMPO -mediated oxidations of a primary alcohol
group in the presence of secondary alcohols, which include NaBrO 2 [110], CuCl 2/O2 [111], N-
chlorosuccinimide (NCS ) [112,113 ] and trichloroisocyanuric acid [114 ] as co-oxidants.
Nowadays, free radical TEMPO can be used as an oxidant in combination with transition
metals , such a re iron and copper. TEMPO has many applications, for example Liu et al. [115] used
TEMPO -containing polymer brushes, which were grafted onto cross -linked polystyrene
microspheres for the selective oxidation of alcohols. Ahn et al. [116] studied rocking disc
electrode of the TEMPO – mediated catalytic oxidation of primary alcohols , and Buxaderas et al.
[117] used a heterogeneous catalyst contain ing copper and palladium nanoparticles supported on
bio-silica that was prepared in the presence of TEMPO . These are just very few recent examples.
Very recently (2017), Gao, et al. [118] immobilized TEMPO on crosslinked polystyrene
(CPS) to get microspheres of the heterogeneous catalyst TEMPO /CPS. These microspheres were
used for the aerobi c oxidation of 1 -phenylethanol. TEMPO was used also for oxidation of
secondary alcohols to the corresponding ketones i n excellent yields. Ma et al. [119] used 9-
azabicyclo[3.3.1]nonane -N-oxyl ( ABNO )/t-butyl nitrite/ potassium hexafluorophosphate (KPF 6)
under mild reaction conditions for the oxidation of different kind of secondary benzylic alcohols
and secondary aliphatic alcohols to their corresponding ketones.
The conversion of a primary alcohol to a carboxylic acid can occur in the presence of
protected phenols and alkynes [120 ], as shown in Fig. 1.44 .

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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. 1.44 . Oxidation of alcohol s to carboxylic acid s, mediated by TEMPO
TEMPO -mediated processes [1 21] were also used for selective conversions of sulfides into
the corresponding sulfoxides, Fig. 1.45 [122].

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

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1.4.3.2 PINO as mediator
Phtalimide -N-oxyl (PINO , Fig. 1.46 ) is a free radical formed from N-hydroxyphthalimide
(NHPI) by treating it with the inorganic oxidant lead tetraacetate Pb(OAc) 4 [30], or can be formed
also by an electrochemical procedure.
NO
OO

Fig. 1.46 . Structure of PINO
PINO reacts as a hydrogen abstractor and generally can abstract even 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 in such processes was Ishii et al. in 1997 [31]. The
reaction took place by reacting adamanta ne 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 ).

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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 [123].

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

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Nitroxide radical PINO was also used in the presence of Co(OAc) 2 in acetic acid for the
aerobic oxidation of variou s alkylbenzenes [12 4], 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 [125]. These results are shown in Table 2.
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 way PINO was used as catalyst for aerobic oxidation of benzylic alcohol derivatives
[126], Table 3.
Table 3. NHPI -catalyzed aerobic oxidation 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) , NHPI (10 mol % ), PhCN (5 mL) under dioxygen atmosphere at 100 oC for 20 h. GLC
yields.

In latest years, NHPI has been identified as an efficient mediator for aerobic oxidation of
diverse organic substrates with co -catalysts [ 127]. A group of substituted N-hydroxyphthalimides
(NHPI) were used as mediators ( catalyst ) for aerobic oxi dation of alcohols of cumene [128 ]. Hu et
al. [129] used NHPI and t-butyl nitrite (TBN) with oxygen as the terminal oxidant for oxidation of
a different kind of aliphatic, aromatic, allylic, and heterocyclic alcohols, Fig. 1 .51.

Ahmed Juwad Shakir – Doctoral Thesis

35

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%

Fig. 1 .51. 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 azyls as me diator
DPPH has been proved to be quite useful in a variety of investigations, such as polymerization
inhibition or radical chemistry [130 ]. Literature data demonstrated also the usefulness of DPPH
and its derivatives in studying interphasic processes assisted by tra nsport agents such as cro wn
ethers (CEs) or kryptands [131 -134]. DPPH also was used for oxidation of amino acids [135 ].
However, up to date, there are very few paper s containing data about involving stable
hydrazyl free radicals as mediators in oxidation r eactions [136,137 ]. DPPH has been employed i n
the presence of WO 3/Al 2O3 as a co-catalyst, under moderate conditions and oxygen being used as
the terminal oxidant (Fig. 1.52 .), the authors applied a wide range of substrate bearing different
functional groups and the reaction method works under neutral conditions (acid, base not required)
[138].
This approach is amenable to gram scale and not require precautions , giving a green and
environmentally benign advance for the synthesis of aldehydes and ketones .

Ahmed Juwad Shakir – Doctoral Thesis

37

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. 1.52. Oxidation of alcohols by DPPH radical in the presence of WO 3

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1.4.3.4 TEMPO with transition metals as mediators in oxidation reactions
The first reported use of a copper/nitroxide radical was in 1 966, when Brackman and
Gaasbeek used di-t-butylnitroxide for the oxidation of methanol with phenanthroline/copper(II)
complexes in basic solutions [139 ].
The selective oxidation of alcohols is an important reaction in organic chemistry. Many
oxidation meth ods towards alcohols have been reported in literature using at least a stoichiometric
amount of oxidants such as DMSO, MnO 2, chromium oxides or hypervalent iodine compounds .
TEMPO has been used in catalytic oxidation reactions of primary and secondary alco hols
[140]. From the history of the 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. [111].
Copper/ TEMPO lactonization of polyols in the synthesis of more complex molecules has
been also reported . Nonappa and Maitra prepared a steroidal lactone using Cu/ TEMPO in the
presence of several unprotected sec ondary alcohols [141 ], Fig. 1.53 .

OHOH
OHOH
OHOHOH
O0.4 equiv
CuCl/TEMPO
DMF, O2
78%OHO

Fig. 1.53 . Cu/TEMPO -catalyzed aerobic lactonization
Liu and Ma [142 ] studied the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol (Fig. 1. 54)
employing 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 , they were able to form the corres ponding
homopropargylic ketone at room temperature. An optimization of the reaction based on the solvent
effect is shown in Table 4.

Ahmed Juwad Shakir – Doctoral Thesis

39

Ph
OHPh
O10 mol% Fe(NO3)3. 9H2O
10 mol % TEMPO
10 mol % NaCl
DCE, O2, (balloon), rt, 4 h

Fig. 1.54 . Oxidation of a propargyl alcohol by TEMPO /iron salt system

Table 4. Optimization of the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol
a5 mol % each of the three catalysts were used here. bCu(NO 3)2.3H 2O was used instead of Fe(NO 3)3.9H 2O

Table 4 shows that by u sing DCE as a solvent, the highest yield (91%, Table 4, entry 1) is
achieved , while by using 5 mole % from TEMPO , Fe(NO 3)3.9H 2O and NaCl , only 76% yield 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 ( 52%, Table
4, entry 6). The results obtained , in the same condition for aerobic oxidation react ion of many
other homopr opargylic alcohols are shown in Fig. 1.55 . 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

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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. 1.55 . Aerobic oxidation of the homopropargylic alcohol s
Rogan et al. [143] used a Cu(I)/9 -azabicyclo[3.3.1]nonan -3-one-N-oxyl (ketoABNO , Fig.
1.56) as the aerobic catalytic system for the oxidation of alcohols.
The drawback of this system is that it is not working well for the oxidation of secondary
alcohols due to steri c hindrance, therefore the authors have replaced TEMPO with a radical that is
less sterically hind ered. Fig . 1.56 shows the structure s of several nitroxide radicals employed for
this purpose (ketoABNO should remove this limitation ).

Ahmed Juwad Shakir – Doctoral Thesis

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N
ON
ON
ON
ON
ON
OO
TEMPO AZADO 1-Me-AZADO Nor-AZADO ABNO ketoABNO
Fig. 1.56 . Structures of several nitroxide radicals used in aerobic oxidation of alcohols
The reactivity of TEMPO , 4-oxoTEMPO and ketoABNO for three sample subs trates 1-
phenyleth anol, 2 -octanol and isoborneol , is shown in Fig. 1.57 and Fig. 1.58 . 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. 1.57 . Secondary alc ohols used as substrates

Fig. 1.58 . Comparison of 4-oxoTEMPO , TEMPO and ketoABNO for the
oxidation of some secondary alcohols (picture from ref. [143])

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The radicals 4 -oxo-TEMPO and TEMPO cannot oxidase two secondary alcohols , 2-octanol
and isoborneol, but oxidase 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 and 4-methoxy TEMPO ,
against ketoABNO [144 ] the same result was obtained. This established that all unhindered
radicals have the same reactivity under these conditions.
Nitroxide radicals are used today for the oxidation reaction of alcoh ols in organic chemistry
[145]. For this purpose TEMPO , ABNO and AZADO were tested as a catalyst with stoichiometric
oxidants like bleach, t-butyl hypochlorite, bis (acetoxy)iodobenzene (BAIB) [146]. Yoshiharu
[147] used also AZAD O type nit roxide as catalysts for th e aerobic oxidation of alcohols, Fig. 1.59.
The new catalysts [147 ] were prepared in f ive steps, as shown in Fig. 1.60 [148].
NO
ONTsN
ONN
OO
Oxa-AZADO (6) TsN-AZADO (7) diAZADO (8)

Fig. 1.59 . Structures of novel AZADO free radical 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. 1.60 . Synthesis of oxa -AZADO
sN-A ADO and diA ADO were synthesized using modified ofmann−L ffler− Freytag
reaction (Fig. 1.61 ).

Ahmed Juwad Shakir – Doctoral Thesis

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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. 1.61 . Syntheses of TsN -AZADO and diAZADO
For diAZADO there is a more efficient procedure for t he synthe sis, shown in Fig. 1.62 .
NTsTsN1. red Al
toluene, reflux, 18 h
2. UHP, Na2WO4.2H2O
MeCN, 3 h
44% for 2 stepsNN
OO

Fig. 1.62 . Procedure for the synthesis of diAZADO free radical
The synthesis of 5 -MeO-AZADO and 5,7-diMeO -AZADO [149 ] are shown in Fig. 1.63.
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. 1.63 . Synthesis of 5 -MeO -AZADO ( 4) and 5,7 -diMeO -AZADO ( 5) free radicals

Ahmed Juwad Shakir – Doctoral Thesis

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1.4.3.5 Oxidation with TEMPO and NOx
A recent approach in alcohol oxidation is the employment of nitrogen dioxide as TEMPO
activator; this is usually easily obtained from sodium nitrite or organic nitrites. Using 1 -menthol as
the substrate under new reaction conditions (10 mol % NaNO 2, 1 mol % nitroxy radical and AcOH
solvent under air balloon , Fig. 1.64 ) [150 ], very good yie lds of oxidation were obtained
Fig. 1.65 shows the comparison of the temporal profiles of 5-F-AZADO, AZADO, 5,7 -diF-
AZADO and TEMPO as reference [146].

OHnitroxyl radical (1 mol %)
NaNO2 (10 mol %)
AcOH(1 M), air ballon, rtO

Fig. 1.64 . Oxidation of 1 -menthol

Fig. 1.65 . Temporal profiles of AZADO, 5 -F-AZADO , 5,7- diF-AZADO , and TEMPO , for
conversion of 1-menthol (picture from ref. [147])
Under the same reaction conditions, the temporal profiles of 5 -MeO -AZADO and 5,7 –
diMeO -AZADO [147] were also investigated. In Fig. 1.66 , 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 prevent ing a slowdown of the reaction.

Ahmed Juwad Shakir – Doctoral Thesis

45

Fig. 1.66 . Temporal profiles of AZADO, 5 -MeO -AZADO , and 5,7-diMeO -AZADO (picture from
ref. [147 ])
The temporal profiles of oxa -AZADO, TsN -AZADO and diAZADO are shown in Fig.
1.67, and these oxidation mediators have a wide range of substrate applicability (Table 5).

Fig. 1.67 . Temporal profiles of oxa -AZADO, TsN -AZADO, and diAZADO for the oxidation of 1-
menthol (picture from ref. [147])

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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
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)

Holan and Ullrich [151 ] 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.

Ahmed Juwad Shakir – Doctoral Thesis

47

OHTEMPO cat.
BF3OEt2 (cat.) 2 eq
t-BuONO (2 eq)
solvent, temp.O
Fig. 1.68 . Oxidation of benzylic alcohol using TEMPO and TBN as mediators
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
4 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, [152] TEMPO /nitrite -based syste ms [153 ] and TEMPO /Br 2/NaNO 2 [154].
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. 1.69 . Oxidation of aromatic and allylic alcoholsa

Ahmed Juwad Shakir – Doctoral Thesis

48

OH OTEMPO
BF3OEt2
t-BuONO (3 equiv)
DCM, reflux

Fig. 1.70 . Oxidation of 1-dodecan ol
Table 7. Oxidation of dodecan -1-ol
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
DCM (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 TEMPO

Fig.1.71 . Oxidation of aliphatic alcoholsa

Ahmed Juwad Shakir – Doctoral Thesis

49
Organic solvents or ionic liquids can be used as the solvent in a combination with TEMPO
and several other mediators for the aer obic oxidation of alcohols [155]. For example , using
acetonitrile as solvent and TEMPO and Cu(II) –triethanolamine comp lexes , aerobic oxidation of
primary alcohols to the corresponding aldehydes can be performed [156].
Employing water as the solvent is more favorable sometimes [157 ] several catalytic
systems have been shown to be useful . Yan et al. [158] used the TEMPO–Ce(IV)–NaNO 2 system
for the aerobic oxidations of differ ent alcohols in water, Fig. 1.72 .

OH TEMPO, CAN, NaNO2
O2, H2OCHO

Fig. 1.72 . Oxidation of benzyl alcohol with TEMPO and CAN
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.

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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
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 is
nevertheless costly and has a highly undesirable environmental impact and toxicit y [159].
TEMPO is an available easy -to-handle catalyst, with high efficiency, low toxicity and good
stability. Prebil and Stavber [160 ] 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,
Fig. 1.73.

Ahmed Juwad Shakir – Doctoral Thesis

51

OH Oair, NH4NO3(cat.), TEMPO, acid
MeCN
Fig. 1.73 . A novel oxidation system
This kind of cataly tic system is inexpensive , uses air as the terminal oxidant, yields the
highest result and exhibits selectivity. Table 10 shows the role of acid in the oxidation reaction.

Table 10 . 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 [160] used the air/ TEMPO /NH 4NO 3/HCl catalytic system (Fig. 1.74 ) in
acetonitrile for the oxidation of substituted primary and secondary benzyl alcohols. The results are
shown in Table 11 .
ArOH
R1
RArO
R1
Rair, NH4NO3, TEMPO, HCl
MeCN, 60 oC

Fig. 1.74 . Oxidation of substituted primary and secondary benzyl alcohol s

Table 11 . 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
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 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)

Ahmed Juwad Shakir – Doctoral Thesis

52

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. 1.75 . 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. 1.76 , where 5 mol -% NH 4NO 3 and 5 mol -% HCl (aq. 37%)
were used for 24 h at a moderate temperature.

Fig. 1.76 . Efficiency of nitroxide radicals (picture from ref. [160])

Ahmed Juwad Shakir – Doctoral Thesis

53
1.4.3.7 TEMPO -mediated processes for ester synthesis
Esters are produced by the simple reaction between alcohols and carboxylic acid; they are
widely used in industry, such as acrylate esters. Oxidative esterification has been mentioned as a
convenient pathway to each symmetric ester, a s well as asymmetric esters [161 -166].
Perusqua -Hernndez et al. [167] synthesized aryldiazomethanes and their corresponding
arylmethyl esters, by using benzophen one hydrazine (Fig. 1.83), which reacted with an e xcess of
sodium hypochlor ite solution and TEMPO . In 5 min at 0 oC, diphenyldiazomethane (Fig. 1.77 )
was formed reddish color, due to the diazo group that shows the band C=N=N at 2050 cm-1. The
compound diph enyld iazomethane is unstable in air andreacts with acetic acid to yield the ester
[168]. Table 12 shows the role of temperature and time in this reaction.
Ph PhNNH2NaOCl
TEMPO
KBr, NaHCO3
temp.PhN2
PhAcOH
PhOAc
Ph
a b c

Fig. 1.77 . Synthesis of benzhydryl ester from diphenyldiazomethane and benzophenone hydrazone

Table 12 . 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

Table 13 shows the results using sodium or calcium hypochlorite as oxidizing agents.

Ahmed Juwad Shakir – Doctoral Thesis

54
Table 13 . 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
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)

Table 14 . 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

Using the same conditions of Table 12 , different types of benzhydryl esters were
synthetized from diazoalkanes, as shown in Table 15 .

R1 R2NNH2NaOCl
TEMPO
KBr, NaHCO3
-5 CR1N2
R2R3COOH
R1OCOR3
R2

Fig. 1.78 . Synthesis of benzhydryl ester s

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Table 15 . Benzhydryl esters prepared using TEMPO /NaOCl

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
12 Ph Ph 3-ClC 6H4 55
13 4-ClC 6H4 H CH 3 30
14 4-ClC 6H4 H Ph 38

In 2016, Hac kbusch and Franz [169 ] synthesized symmetric esters from primary alcohols
in a biphasic dichloromethane -water solvent mixture, using TEMPO /CaCl 2 oxone, a convenient
catalytic system, as shown in Table 16 .
OHTEMPO (0.01 mmole)
CaCl2 . 2H2O
Oxone
2 mL DCM, H2O
rtOO
1 mmole

Fig. 1.79 . Oxidation of 1 -hexanol to ester (oxidative coupling)
Under the same reaction conditions, the authors synthesized different type of esters from
alcohols as sho wed in Fig. 1.80 .

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Table 16 . Result s 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
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, NRba detected by DART-HRMS
bNR = no reactionROH
2TEMPO/CaCl2/Oxone
DCM, H2O, rt RO RO
1.0 mmole

Fig. 1.80 . Synthesis of esters from alcohols (oxidative coupling)

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1.4.3.8 TEMPO on materials
Materials containing free radicals, like s ilica-supported TEMPO , can be obtained as shown
in Fig. 1.81 , and can be used as a recyclable mediator ( catalyst ) in the oxidation of numerous
alcohol s. Table 17 shows a compilation of such alcohols found in literature [170].

siica NH2+
N
OO
NaBH3CN MeOH, rt
silica N
HNO

Fig. 1.81 . Synthesis of silica supported TEMPO
There are m any literature data show ing that silica supported TEMPO can be easily used in
the oxidation of alcohols. Zhu et al. [171] prepared and used a fibrous nanosized catalyst
containing supported TEMPO on silica nanospheres. Yujie et al. [172] prepared silica
nanoparticles functioned with various TEMPO and applied as well for the oxidation of alcohols.
Oliver et al. [173] reported a simple and efficient covalent functionalization of TEMPO
using a copper catalyst azide/alk yne cycloaddition as a selective method for the oxidation of
alcohol s. Fig. 1.82 illustrates the grafting of diazonium salts onto carb on coated cobalt pa rticles .
After formation, the azidomethyl phenyl derivative reacts wit h the alkyne resulting in a p-
nitro ester which is further functionalized with TEMPO .

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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 17 shows the results of oxidation of different alcohols to aldehydes by
using CoNP -TEMPO mediated oxidation s.
Table 17 . Oxidation of alcohols by CoNP -TEMPO mediated oxidation sa
Entry Alcohols Yields %
1 4-methylbenzyl alcohol 89
2 4-bromobenzyl alcohol 92
3 4-methoxybenzyl alcohol 96
4 Benzyl alcohol 85
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

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Babak and Elham [174] prepared also 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 finally the magnetic nanopartic le-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 18 show the types of alcohols that have both electron -withdrawing and electron –
donating groups, converted to the co rresponding 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 by supported -TEMPO
Table 18 . Results of aerobic oxidation 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 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

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Various free radical TEMPO functionalized solid catalysts were prepared by immobilising
individual TEMPO molecule s onto solid support materials [175].
TEMPO polymer grafted silicas are prepared by grafting poly 2,2,6,6 –
tetrameth ylpiperidinyl -oxymethacrylate (PTMA) [176] onto silica , by using reversible addition –
fragmentation chain transfer (RAFT) . RAFT polymerization and the so -formed precursor are used
to graft polymerized 2,2,6,6 -tetramethylpiperidine methacrylate (treated first with 3 –
chloroperoxybenzoic acid ), to yield the TEMP O polymer 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 . The molecular weights of these polymers were determined by gel permeation
chromatography (GPC).
The prepared compounds (Fig. 1.85 ) were then grafted onto synthesized amino –
functionalized silica (ca. 2.0 mmol g -1) with a 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 reaction since this reagent is readily available at low cost and allows the coupling in
high yield in a single operation [177].

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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

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
Scanning electron microscope (SEM) and dynamic light scattering (DLS) were used to
determine the morphology of synthetic material (Fig. 1.86 ).

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Fig. 1.86 . SEM image of TEMPO catalyst (picture from ref. [178])
Polymer grafted silica was used for oxida tion of several benzyl alcohol s (the oxidation
reaction of benzyl alcohol s was achieved in water or DCM/water bi -phasic system ).

Table 19 . Results of conversion (%) of alcohols to aldehydes with TEMPO catalyst a
Entry Substrate Product 4 TEMPO on silica
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/alcoho l, 0.5 mol%, solvent DCM/water

The results using TEMPO polymer grafted silica for the oxidation variou s alcohols are
shown in Table 19 . TEMPO has been also immobilized onto other solid supports, such as
polymeric resins, mole cular sieves and silica gel [179 -181]. TEMPO was linked to the
poly(glycidyl methacrylate) microspheres ( CPGMA ) between the epoxy groups of 4 -HO-TEMPO ,
forming heterogeneous catalys t microspheres TEMPO /CPGMA [182 ] by the ring opening
reaction. The polymer resin has the advantage that active groups can be easily inserted onto it via
chemical modification.

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Gao et al. [183] used the heterogeneous catalyst TEMPO /CPGMA combined with
Fe(NO 3)3 as co -catalyst for the aerobic oxidation of cyclohexanol under mild con ditions, in order
to obtain cyclohexanone with good yields .

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. 1.87 . Immobilization of TEMPO on CPGMA microspheres
There are also some reports using homogenous TEMPO combined with Fe(NO 3)3
[184,142 ]. The activity of th is oxidation system is shown in Fig. 1.88 The resulting product yield
of cyclohexanone was 44% in 36 h , when using the system consisting of CPGMA microspheres
and Fe(NO 3)3.

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Fig. 1.88. Curves of cyclohexanone yield with time using the combination of TEMPO /CPGMA and
Fe(NO 3)3 as co -catalyst or the single components as catalyst (picture from ref. [183 ])

1.4.3.9 Nitroxide free radical as catalyst for the dehydrogenation of amines
The oxidation of primary amines into the corresponding nitriles constitutes a very useful
functional group transformation in organic synthesis. Amines are acutely sensitive to oxi dation,
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 [185 ].
The c atalyst TEMPO , together with ano ther co-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 [186 ]. Oxidation of a pri mary amine to a nitrile includes a double
dehydrogenation that has been achieved in different way s [187], aerobic oxidation catalyzed by
transition metals [188 ], transition -metal catalyzed dehydrogenation, and so on.

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Some of the oxidizing agents used in the process of oxidation of primary amines into the
corresponding nitriles have a lot of drawbacks , such as harsh reaction conditions, low yields,
tedious work -up procedures and limitations.
Chen et al. [189] reported that by using trichloroisocyanuric acid (TCCA) with TEMPO
under mild reaction conditions , the oxidation of benzylamine to the benzonitrile was achieved,
(Table 20 ).

RCH2NH2TCCA, TEMPO (1mol%)
DCM, 10 oCRCN

Fig. 1.89 . Oxidation of primary amines to nitriles
Trichloroisocyanuric acid is an inexpensive, stable reagent used in organic synthesis such
as in the transformation of alcohols to halides alkenes or to β-chloroethers, or carboxy lic acids to
acid chlorides [114 ]; it is also used in the oxidation of alcoho ls to ca rbonyl compounds [190 ].

Table 20 . Oxidation of benzylamine to the benzonitrile
Yield % 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
72 3 1:0.8 5 DCM 9
90 2 1:1.3 5 DCM 10
90 2 1:1.5 5 DCM 11

These conditions (DCM as solvent) were also employed for the oxidation of other aliphatic,
aromatic and heterocyclic primary ami nes, and the results are shown in Table 21 .

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Table 21 . Oxidation of primary amines into n itriles
Entry R Time (h) Yield%
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

Kyle et al. [191] reported the oxidation of a primary amine into the corresponding nitrile by
using a 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 -tetramethylpiperidin e and is an inexpensive reage nt in multimole quantities [192 ].

Ahmed Juwad Shakir – Doctoral Thesis

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NNH
OO
BF4
Fig. 1.90 . Oxoammonium salt of 4 -acetamido -TEMPO
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, while 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 oxidation 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 . Overall reaction for converting primary amines into nitriles

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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
Largeron et al. reported on the oxidation of primary aliphatic amines into imines by using
the biomime tic electrocatalytic method [19 3].
In 2012 , Kerton applied a method for the oxidation of primary and secondary amines using
a Cu/ nitroxide –catalyzed syst em [194 ]. Nicolaou et al. used 2 -iodoxybenzoic acid to develop
stoichiometric oxidations of s econdary amines into imines [195,196 ].
In 2012 , Zhenzhong and Kerton [194 ] 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. 1.93 ). Table 22 shows the results of the oxidative
self-coupling of benzylamine using CuBr 2-TEMPO .

NH25 mol. % catalyst
solvent, air, 25 oC2N

Fig. 1.93 . Copper -catalyzed oxidative self -coupling of benzylamine

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Table 22 . Oxidative self -coupling of benzylamine
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
catalyst (0.05 mmol), benzylamine (2 mmol), solvent (9 m L), 1 atm and 8 h

Using CuBr 2/TEMPO as the catalyst, benzylamine converts into imines with high yield, so
it was employed for a range of primary and secondary benzylic amines with high conve rsion and
selectivity (Fig. 1.94 ).
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. 1.94 . Imines synthesis using TEMPO as mediator sa

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In 2016, Ashley L. Bartelson et al. developed nitroxide -cataly zed oxidation of amines
(prepar ation of imines an d nitriles) using the nitroxide 4-acetamido -TEMPO (ACT), pyridinium
bromide, and oxone [197 ].
Combining the approach of Bolm , it was predicted a stoichiometric protocol to develop a
catalytic procedure for the usage of ACT, because the nitroxyl catalyst can easily oxidize primary
amines to nitriles [198 ]. Fig. 1.95 shows the results of oxidation of such amines.
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. 1.95 . Oxidation of amines using oxone as co -oxidant

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, as shown in Fig. 1.96 .

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N
ON
O
Fig. 1.96 . Resonance structure of the oxoammonium cation
Generally, there are two different types of TEMPO mechanisms in the oxidation of alcohol,
one under acidic conditions, and another under basic conditions. Usually, the dominant mechanism
under acidic conditions is slower than the dominant mechanism under b asic conditions; oxidations
of alcohols in base include an alcoholate as the nucleophile. Fig. 1.97 shows the conceivable
mechanism of oxidation of alcohol under basic conditions, and Fig. 1.98 shows it under acidic
conditions.

R R
OH+ B
– BH+R R
ON
ON
OO R
RHN
OH+O
RR BH++ +

Fig. 1.97 . Mechanism of oxidation of alcohol under basic conditions
N
ONO HO
HRH
:BN
OH+RCHO RCH2OH +

Fig. 1.98 . Mechanism of oxidation of alcohol under acidic conditions

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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 [199 ], Fig. 1.99. In the first step, the aerobic oxidation of CuI produced CuII-OH. In the
second step, aerobic oxidation of TEMPO H produces TEMPO . Whe n 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. 1.99). After the second step, the base (L nCuII-OH)
is formed upon reduction of O2. Step 3 causes the oxidation of alcohol through the generation of a
pre-equilibrium of a CuII–alkoxide. The last step is the hydrogen transfer to TEMPO .

Tyr
OHLnCuI1/2O2
1/2[LnCu]2(O2)
TEMPOH
TEMPOLnCuII-OHLnCuIIOH RHTEMPOTEMPOH+RO
1
2 34
R HOH2OL=

Fig. 1.99 . Mechanism of Cu/ TEMPO -catalyzed alcohol oxidation
as shown by Stahl et al. [201]

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73
Mechanism for oxidation of alcohols using 5 -F-AZADO and NO 2
Yoshiharu I. et al. [147] suggested the mechanism for oxidation of alcohols using 5-F-
AZADO , Fig. 1.100. In the first step, a hydrate ( 2 in Fig. 1.100 ) is formed from the oxoammonium
cation with water in equilibrium, the oxoammonium oxidizes the alcohol to form alcohol adduct 3
in equilibri um with the intermediate 4. Then, formed hydroxylamine and the nitroxy free radical
lead to the regeneration of the oxoammonium cation in the final step.
N
OHOH F2
N
OF
1H2O H+,
NFO
OHR1
R2OH
R1 R2
N
OOFR1
R2
R2R1ONF
ONF
OHNO
NO21/2O2
H2O3
4

Fig. 1.100 . Mechanism of oxidation using 5 -F-AZADO and NO

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Mechanism for the oxi dation of alcohols using t -butyl nitrite
Martin and Ullrich proposed a mechanism for the oxidation of alcohols using t-butyl nitrit e
(TBN) [151 ]. In Fig. 1.101 , the first step in the reaction between TBN and the catalytic amount of
BF3·OEt 2 lead to the formation of nitrosonium tetrafluoroborate and the borate ester . Then ,
nitrosonium salt oxidizes the free radical TEMPO to the N-oxopiperidinium salt. Oxidation of
alcohols by salt 2 to the corresponding aldehydes or ketones 4 resulted in tetrafluoroboric acid and
hydroxylamine 5,which is in equilibrium with its salt 6. Final ly, the hydroxylamine 9 reoxidizes to
TEMPO 1 (Fig. 1.101) .

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. 1.101 . Proposed mechanism of alcohol oxidation with TBN /TEMPO

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Mechanism of TEMPO as mediator in esterification reactions
A mechanism of TEMPO as mediator in the esterification reactions of aryl diazomethanes
derived from hydrazine was proposed by Ramstrom [20 0] and Sheldon [20 1]. In the first step (Fig.
1.102) the free radical TEMPO reacts with chlorine (derived from sodium hypochlorite) to form
the oxoammonium ion , then the oxoammonium ion combines with hydrazine to form the
intermediate 5 from Fig. 1 .102.
Next, h ydrogen is transferred to form the intermediate 6 which disproportiona tes to
hydroxy HO-TEMPO and diazocompound 8. Fina lly, hydroxy HO-TEMPO is re -oxidized by
chlorine to form the intermediates 2 and 3 (Fig. 1.102) .
N
OCl2
N
OClN
OClB+NNH2
BH
NOH N
N N
OH
NNCl21 23
6
784
NO N
NH
5

Fig. 1.102 . Reaction mechanism of esterification reactions of aryl diazomethanes derived from
hydrazine using TEMPO as mediato

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Mechanism for the condensation of benzyl amines using CuII/TEMPO catalysts
Zhenzhong [194] suggested also a mechanism for the condensation o f 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. [202]. In Fig. 1.103 , first step entailed the CuII bonding with
the amine to form the intermediate co mplex. In the second step, the 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 due to the
hydrogen bonding between the oxygen atom of TEMPO 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 (Fig. 1.103) .Next, the ox idation of CuI complex and
TEMPO H 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. 1.103 . Proposed mechanism for CuBr 2-TEMPO catalyzed oxidation of benzyl amines

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1.5. Conclusion
The development of organic free radicals che mistry begun when Gomberg discovered the
triphenylmethyl radical in 1900. The exploration of the chemical synthesis and app lication of free
radicals plays a vital role in chemical reactions , biology and medicine.
In organic chemistry, the achievement of free radicals exhibiting different levels of stability
and reactivity leads to numerous advances in chemical theory and to some practical application .
Organic chemistry of these species offers many possibilities 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 s in biology . Cyclic nitroxides have been
used for years as biophysical probes and so on.
Researchers are studying nitroxides that display appropriate characteristics, such as redox
potential, fast rate of trapping of free radicals, biocompatibility, ferromagnetic intera ctions, etc.
The advantage of nitroxides compared to other stable free radicals is that the aminoxyl group can
resist the experimental 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 compa red to the use of cleaner organic oxidants.
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 ca talysts like supported -TEMPO ,which can be easily recycled after use in
liquid phase oxidation reactions, and which have low toxicity, good stability and high efficiency is
thus an essential improvement .
Free radical TEMPO has been useful in roles such as mediators in the selecti ve oxidation of
alcohols, as a catalyst for the oxidation or dehydrogenation of amines , to synthesize ester s and so
on, due to its ability to work under various reaction condition s.

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Through the survey of the chemical applications of the free radicals their importance is
emphasized; effective contributions in various chemical, medical and industrial preparations is
clearly a topic of high interest and has been highlighted .
Free radicals are generally easy to obtain and use, especially nitroxide free radicals. They
can be used as oxidation mediators or catalysts, which are very important in the preparation of
many useful chemical compounds in a safe and easy way, with accura te results.
Taking into consideration all of these, the literature data part showed general information
about organic free radicals, followed by several ways of their synthesis. The next step was to
compile their ma inly practical used as media tors in oxida tion reaction.
Finally, if can be conducted that organic free radicals are a strong subject in chemistry and
their properties and applications still present a high interest.

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Original Data

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Chapter 2. Nitroxide and hydrazyl radicals as
mediators in selective alcohols oxidation
2.1. Introduction
The classical procedure for the s elective oxidation of primary and secondary alcohols to the
corresponding aldehydes and ketones 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 management of the large quantities of transition metal ion by -products.
A better approach should avoid the environmental matter and diminish the work -up protocol, thus
making possible large -scale or e ven industrial applications.
Frequently, alcohol oxidation cannot be stopped at the carbonyl derivative, therefore
selective oxidation methods are highly desirable [1]. Many syntheses of medicines or other fine
chemicals require aldehydes and ketones as in termediates [2], 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.
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 [2]. Novel catalytic methods
that involve clean oxidants like air, hydrogen peroxide or sodium hypochlorite and non -metallic
catalysts [2,3] are currentl y under consideration . A promising and nowadays well documented
procedure makes use of stable or persistent free radicals as catalyst and of air as final oxidant [4],
as was shown in detail in the first part of this thesis .
In the last decade nitroxides st able free radicals were successfully 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.) [5-7]. Among nitroxides, TEMPO
and PINO free radicals are most known and employed in such reactions, due to their effectiveness
[8-10].
Bobbitt‟s salt (4 -acetamido -2,2,6,6 -tetramethylpiperidine -1-oxoammonium
tetrafluoroborate) [11], 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 [11].

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Other stable free radicals, which a lso have also oxidant capacities, are hydrazyl ones, l ike 2,2-
diphenyl -1-picrylhydrazyl (DPPH ), and its congener 2,2 -p-nitrophenyl -1-picrylhydrazyl (Fig. 2.1).
DPPH has numerous app lications due to its intense purplecolour and its stability [1 2-14].

NNO2N
NO2
O2NO2N
O2NN
ONO
OONNO2N
NO2
O2N
TEMPO DPPH PINO
DN-DPPH

Fig. 2.1. Structure of the free radicals used as mediators in oxidation reactions
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). Regarding
hydrazyl radicals, literature data are extremelly scarce about their use as oxidants, therefore we
introduced in this comparative study DPPH and DN -DPPH .
In an attempt to compare the catalytic properties of these free radicals, in our work we used
as substrates three activated alcohols (benzy l alcohol, 2 -phenylethanol and diphenylcarbinol, Table
25) and several co -oxidants (different NO x generating systems and sodium hypochlorite);
moreover , TEMPO itself doesn‟t have the ability to oxidize alcohols, a co -oxidant being required
[15-17].
The rol e of the co -oxidant is to extract one electron from TEMPO , yielding the
oxoammonium ion (Fig. 2.2), which is the real oxidant in such processes. As co -oxidant were
employed a wide range of chemicals, including nitrogen oxides, nitric acid, transition metal ions,
halogens, etc . [17-19].

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N
ON
ON
O+ e-
– e-+ e-
– e-
Fig. 2.2. Redox behavior of TEMPO
A breakthrough in such systems was the exploit of nitrogen oxides as mediator between
dioxygen and TEMPO [16-21]. Initially, NO x was obtained in situ from sodium nitrite and acetic
acid, but the drawbacks of removing the acetic acid from the reaction syste ms 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 inconvenient has been surpassed by absorbing gaseous NO x into silica
supported TEMPO , yielding thus a solid insoluble material that works as a heterogenous catalyst ,
which practically does not require either an additional co -oxidant or an acid [21].
Due to our previous experience in selec tive oxidations of alcohols , in this work we chosen
as co -oxidant s different NO x generating systems [22]; besides, we used also sodium hypochlorite,
as this system was one of the first used in literature in such mediated oxidation reactions.

2.2. Synthesis of DN -DPPH
All the free radicals used in this chapter are known in literatur e. TEMPO , DPPH 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 considered a
persistent free radical, as is decomposing slowly i n 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, nitrogen dioxide, etc.) [23].
Because DN -DPPH is not a commercially available product , our first step in our work was
to synthesize. Our synthesis started from diphenylamine, that was N-nitrosated to N-

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nitrosodiphenylamine. This is reduced to the corresponding unsimetrical diphenylhydrazine, which
reacts furth er with picryl chloride to yield 2,2 -diphenyl -1-picrylhydrazine. This is soluble in DCM
and easily reacts in a biphasic system with nitrogen dioxide generated by an aqueous mixture of
sodium nitrite and diluted hydrochloric acid [24]. DPPH is formed in th e first step and it is a good
scavenger of nitrogen dioxide, leading to the p,p-dinitrophenyl -1-picrylhydrazine, which is
oxidised to the desired product DN-DPPH free radical in about 90% yields (Fig. 2.3).
NNaNO2 NNO
NNH2
NO2 O2N
NO2OH
Reflux(2h)
SOCl2
DMFNO2 O2N
NO2Cl
NaNO2PbO2NNO2N
NO2
O2NO2N
O2Npicric aciddiphenylamine
NH
NO2N
NO2
O2NO2N
O2NNH
NO2N
NO2
O2NH
HCl CH3COOHZn
HCl1,1-diphenylhydrazine
2,2-diphenyl-1-picrylhydrazine
2,2-dinitrophenyl-1-picrylhydrazinepicryl chloride
DN-DPPHN-nitrosodiphenylamine

Fig. 2.3. Synthesis of DN -DPPH

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Synthesis of N-nitroso -diphenylamine was achieved at 0 oC in ethanol by nitrosation of the
starting material with sodium nitrite and hydrochloric acid. Instantly the nitroso -derivative
precipitated as a yellow solid; the yield of the reaction is practically quantitative. Just for structure
confirmation, 1H- and 13C-NMR was performed (see Experimental part).
N,N-diphenylhydrazine was obtained by the reduction of the previous nitroso -compound
with Zn dust and acetic acid. The reaction wa s perfo rmed in ethanol for 2 h, keeping the
temperature below 25 oC. Filtration of the mixture and removal of the solvent afforded the
hydrazine as a viscous liquid. Because it is easily oxidable, it is adviced to keep it a hydrochloride
derivate. For this , the hydrazine has been dissolved in DCM and gaseous hydrochloric acid is
bubbled. N,N-diphenylhydrazine hydrochloride precipitated as a gray solid. 1H- and 13C-NMR
were recorded to confirm the structure and purity. Yield was about 70%.
Picryl chloride wa s obtained from picric acid and excess thionyl chloride under reflux
condition in toluene. After one hour, the cooled mixture was poured into hexane, and the
precipitated picryl chloride filtered off and dried. This should be handled with care, due to its
explosive behavior. 1H- and 13C-NMR confirmed the structure. Yields is quantitative.
N,N-diphenylhydrazine hydrochloride reacts with picryl chloride in hot ethanol and in the
presence of sodium hydrogen carbonate, yielding 2,2, -diphenylpicrylhydrazine. Column
chromatography was employed to purify the compound, although crystallization from a mixture of
ethanol and chlorof orm can be done. The structure has been confirmed by 1H- and 13C-NMR . The
yield of the reac tion is over 90%.
2,2-Diphenylpicrylhydrazine dissolved in DCM reacted wit h nitrogen dioxide obtained
from sodium nitrite and aqueous hydrochloric acid. The biphasic system was stirred for at least one
day, yielding p,p-dinitrophenyl -1-picrylhydrazine , which was purified by column chromatography.
1H- and 13C-NMR spectra confirmed the structure. As this compound is not commercially
available, these spectra are showed below.

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Fig. 2.4 .1H-NMR spectra of p,p-dinitrophenyl -1-picryl hydrazine

Fig. 2. 5 .13C-NMR spectra of p,p-dinitrophenyl -1-picryl hydrazine
O2NO2N
NO2
O2NO2N
N
HN
O2NO2N
NO2
O2NO2N
N
HN

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Oxidation in DCM of p,p-dinitrophenyl -1-picryl hydrazine with lead dioxide affords finally
the DN -DPPH free radical. By chance, we obtained good quality crystals 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 crystallographically 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 that 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 2 3, while Fig. 2.6 shows the crystal structure of DN -DPPH .

Fig. 2 .6. Perspective view of one and two DN-DPPH molecule s

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Fig. 2.7. Packing diagram in crystal structure of DN-DPPH , view of the supramolecular dimers
formed by π-π interactions

Fig. 2.8 Packing diagram in crystal structure of DN-DPPH , view along the crystallographic
b axis (showing also DCM molecules)

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Table 23 .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 24.

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Table 24 . 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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2.3. Characteristics and comparison of the employed free radicals
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 (14N); 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 hyp erfine
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 sh own as Fig. 2.9 .

a b

c d

Fig. 2. 9. EPR spectra of TEMPO (a), PINO (b), DPPH (c) and DN -DPPH (d), recorded at room
temperature in acetonitril e (scale range 100 G).

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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. Delocalization of the unpaired electron in hydrazyl free radicals
led to their intense colour. The UV -Vis spectra are showed as Fig. 2.10 .
Because the employed free radicals will be used in oxidation reactions, it was worth to find
out their oxidation potential Eox, and this was achieved by employing cyclic voltammmetry (CV).
The values obtained were 0.54 V for TEMPO , 0.59 V for PINO, 0.08 V for DPPH and 0.39 V for
DN-DPPH (similar values are presented in literature [25 ]). The CVs of the mentioned free radic als
are showed as Fig. 2.11 .

a b

c d

Fig. 2.10 . UV-Vis spectra of TEMPO (a), PINO (b), DPPH (c), and DN -DPPH (d)

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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
-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. 2.11 . Cyclic voltammetry of TEMPO , PINO, DPPH , and DN -DPPH

2.4. Oxidation of alcohols
In an attempt to compare the oxidant properties of TEMPO , PINO and DN -DPPH , we used
as substrates three activated alcohols (benzyl alcohol, 2 -phenylethan ol and diphenylcarbinol, Table
25) and several co -oxidants (different NO x genera ting systems and sodium hypochlorite).

ROH10% free radical, 20% co-catalyst
rt, DCM, airRO

Fig. 2.12. Oxidation of benzyl alcohols using free radicals as mediators

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Table 2 5. Result of oxidation of alcohols
Entry Free radical Co-oxidant 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-
(B)
OH
100
11 PINO 4
12 DN-DPPH 30
13 TEMPO
OH
100
14 PINO 44
15 DN-DPPH 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
33 DN-DPPH 0
34 TEMPO
OH
100
35 PINO 0
36 DN-DPPH 25

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Typically, the oxidation reactions of the chosen alcohols (Table 2 5) were performed at
room temperature in air atmosphere, using a ratio of 10% mol free radical and 20% mol co –
oxidant . The yields of oxidations were quantified by 1H-NMR and the values obtained are
compiled in Table 2 5. As a general rule, the first thi ng that emerges from the Table 25 is that
TEMPO is a much better oxidant compared with PINO and DN -DPPH . For all alcohols used and
also for all used co -oxidant s, TEMPO performed better, reaching quantit ative oxidation yields for
nitrosonium tetrafluoroborate and sodium hypochlorite co -oxidants (Entries 10, 13, 16, 19, 22, 25);
moreover, in the case of nitrogen dioxide as co -oxidant the same yields (100%) were found for
benzyl alcohol and diphenylcarbinol (Entries 28 and 34, respectively).
However, PINO seems 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 l owest yields.
The high differences between the oxidation yields obtained by different free radicals might
be attributed to different oxidation capacity and also to different reaction mechanisms. As
mentioned before, the highest Eox has been recorded for TEMPO (0.54 V), therefore this can
explain its better performance.

2.5.Mechanisms of oxidation
Regarding the mechanisms, there are two ways of action, one for nitroxide type free
radicals and one for hydrazyl. Fig. 2.13 shows these p athways in a simplified manner. For the type
I mechanism, the now classical pathway involving oxoammonium salt is taking place [26,27 ].
Thus, the nitroxide radical ( TEMPO or PINO) is oxidized via one electron transfer to the more
powerful oxoammonium oxidant, and this oxidizes t he 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. Using NHPI instead of TEMPO , the same pathway is followed, as the
oxidant (nitrogen diox ide or sodium hypochlorite) generates in situ the PINO nitroxide free
radical.

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NONN
OHH
OOHH
O
NNHNOHoxoxII
INOox
Fig. 2.13 . The two proposed mechanisms of oxidation, involving a nitroxide (I) and a hydrazyl (II)
free radical
A simpler catalytic cycle (II) 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
[9,10,25,28,29 ].

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2.6. Conclusion
In conclusion, four free radicals (two nitroxides, TEMPO and PINO, and two hydrazyls,
DPPH and DN -DPPH ) were used for the oxidation of three benzylic alcohols ( benzyl alcohol, 2 –
phenylethan ol and diphenylcarbinol ), using as co -oxidant s NaNO 2/CH 3COOH, NO+BF4-, NaClO/
KBr and NO 2 gas.
In the first instance, DN -DPPH was synthesiz ed; its characteristics (UV -Vis, EPR,
oxidation potential) were compared with the other ones ( TEMPO , PINO, DPPH ). It was found that
between nitroxides and hydrazyls, nitroxides react better under the conditions used. Between
TEMPO and PINO nitroxides, we have found that TEMPO was more active as mediator towards
the oxidation of alcohols. Between the four co -oxidants employed (sodium ni trite/acetic acid,
nitrosonium tetrafluoroborate, sodium hypochloride/potassium bromide and nitrogen dioxide),
nitrosonium tetrafluoroborate led to the highest yields.
Two distinct mechanism of oxidation were found. In the first case, nitroxides are oxidis ed
by the co -oxidant to the oxoammonium salt; the oxoammonium salt oxidises the alcohol, while
generating the reduced nitroxide (the corresponding hydroxylamine); the hydroxylamine
regenerate the nitroxide free radical by simple oxidation with air. For the second case, hydrazyls
can abstract directly from the alcohol one hydrogen atom, yieldind finally the carbonyl group; the
reduced hydrazine is oxidised back to the starting hydrazyl by the co -oxidant.

2.7. References
[1] Backvall, J. E., Modern Oxidation Methods, Wiley, Weinheim, 2004.
[2] Tojo , G., Fernandez, M., Oxidation of Alcohols to Aldehydes and Ketones, Springer, 2006.
[3] Backvall, J. E., Modern Oxidation Methods, Wiley, Weinheim, 2004.
[4] Lenoir, D., Angew. Chem., Int. Ed. 2006, 45, 3206.
[5] Ciriminna, R., Blum, J., Avnir , D., Pagliaro, M., Chem. Commun. 2000, 15, 1441.
[6] Sheldon, R. A. , Arenas, I. W. C. E. , Adv. Synthesis & Catal. 2004, 356, 1051.
[7] Balterson, A. R. , Lambert, K. M. , Bobbitt, J. M. , Bailey,W. F. , ChemCatChem. 2016, 8, 3421.
[8] Holan, M., Jahn, U., Org. Lett . 2014, 16, 58.

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[9] Shakir, A. J. , Culita, D. C. , Moreno, J. C. , Musuc, A., Carp, O., Ionita, G ., Ionita, P., Carbon.
2016, 10, 607.
[10] Coseri, S., Catal. Rev. 2009, 51, 218.
[11] Mercadante, M. A., Kelly, C. B., Bobbitt, J. M., Tilley, L. J., Leadbeater, N. E. , Nat. Protoc.
2013, 8, 666.
[12] Recupero, F., Punta, C., Chem. Rev. 2007, 107, 3800.
[13] 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.
[14] Nanjo, F., Mori, M., Goto, K., Hara, Y., Bio sci. Biotechnol. Biochem. 1999, 63, 1621.
[15] Ryland, B. L., Stahl, S. S., Angew. Chem. Int. Ed. 2014, 53, 8824.
[16] Yang, G., Wang, W., Zhu, W., An, C., Gao, X., Song, M., Synlett. 2010, 3, 437.
[17] Shibuya, M., Osada, Y., Sasano, Y., Tomizawa, M., Iwabuchi, Y., J . Am. Chem . Soc.2011,
133, 6497.
[18] Wertz, S., Studer, A., Green Chem. 2013, 15, 3116.
[19] Yongtao, Y., Xinli T., Kaixuan, W., Xueqin, B., Catal. Commun. 2014, 43, 112.
[20] Sabbatini, A., Martins, L. M. D. R. S., Mahmudov, K. T., Kopylovich, M. N., Drewe, M. G.
B., P ettinari, C., Pombeiro, A. J., Catal. Commun. 2014, 48, 69.
[21] Ionita, P., RSC Adv. 2013, 3, 21218.
[22] Shakir, A., Madalan, A., Ionita, G., Lupu, S., Le te, C., Ionita, P., Chem. Phys. 2017, 490, 7.
[23] Fargere, T., Abdennadher, M., Delmas, M., Boutevin, B., Eur. Polym. J. 1995, 31, 489 .
[24] Melone, L., Punta, C. , Beilstein , J. Org. Chem. 2013, 9, 1296.
[25] Nanjo, F., Goto, K., Seto, R., Suzuki, M., Sakai, M., Hara, Y., Free Radicals Biol. Med. 1996,
21, 895.
[26] Suzuki, K. , Watanabe,T. , Murahashi, S. I ., J. Org. Chem. 2013, 78, 2301.
[27] Sawai, Y., Moon, J. H., Sakata, K., Watanabe, N., Mol.J . Sci. 2006, 7, 141 .
[28] Sawai, Y., Moon, J. H., Sakata, K., Watanabe, N., J. Agric. Food Chem. 2005, 53, 3598.
[29] Ionita, P., Gilbert, B. C., Whitwood, A. C., Org. Chem. Lett. 2004, 1, 70.

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Chapter 3. S table organic polyradicals as mediators in
oxida tion reactions
3.1. Introduction
After the demonstration of the notable emplyment of simple free radicals of nitroxide or
hydrazyl type as mediators in oxidation of the benzilyc alcohols, our aim moved towards the
possibility of employing polyradicals in the same type of reaction s. Polyradicals can bring out
some cooperative properties, as the unpaired electrons can interact with each other. Polyradicals
are also known in literature as high spin compounds, showing interesting magnetic properties ,
therefore such compounds are worth to be investigated. The polyradicals synthesized in our study
(Fig. 3.1.) are alrea dy known in literature [1-6] and they were obtained by similar experimental
procedures, as shown in the experimental part .

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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-TNNNN
NNH
N
OO
N
HNHO
O
HN OO
OO.
.
TE-P
Fig. 3 .1. Structure of the polyradicals used as mediators inalcohol oxidation reactions

3.2. Synthesis and characterization of polyradicals
The synthesis of these polyradicals consists in simple coupling reactions (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). DI-T radical was prepared by adding 4 -isocyanato -TEMPO to 4-amino –

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TEMPO in THF. 4-Isocyanato -TEMPO was obtained in a similar way as shown in literature data
[7], using 4-amino -TEMPO and diphosgene (Fig. 3.2). The y ield was around 50 %.
N
ONH2
diphosgen
N
ONCO
N
ONCO N
HN N
HOO
4-NH2-TEMPO
DI-T N
O

Fig. 3 .2. Synthesis of DI -T radical
The EP R spectra of the polyradicals may contain aditional features due to spin -spin
interaction, so the thus synthesized DI-T diradical showed the expected triplet with additional
features due to the spin -spin coupling , as mentioned before . The presence of two or more nitroxide
moieties in a molecular structure usually is accompa nied by the appearance in the EPR 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) [6].
As a consequence, it is expected for the polyradicals used in this study to show the
predictable triplet attributed to interaction of the unpaired electron with the 14N nucleus and , most
important, additional lines attributed 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 interactions, as well. HR -MS spectra confirmed
also the structure of the compound. The EP R spectrum of DI -T is shown in Fig. 3.3 (aN=16.21 G) .
A supplementary confirmation of the structure was coming from the HR-MS (Fig. 3.4) : (m/z)
calculated for C 19H36N4O3 [M+H+] 368.2807 ; found 368.2728 .

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Fig. 3.3. EPR spectr um of DI-T di-radical

Fig. 3 .4. HR-MS spectrum of DI -T di-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 after a couple of days by column chromatography using
silica as the stationary phase and ethyl acetate as the eluent. The y ield was around 30%.

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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 tri-radical
The EPR spectra of TRI-P radical is shown in Fig. 3 .6 (aN= 16.06 G) . The HR-MS
confirmed the structure : calculated for C 33H61N7O6 [M+H+] 651.4678; found to be 651.5704, Fig.
3.7..

Fig. 3.6. EPR spectr um of TRI-P tri-radical

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Fig. 3 .7. HR-MS spectrum of TRI-P tri-radical
In order to obtain the tetra -radical TE -T, firstly 2,2‟-succinic acid disulphide was obtained
by oxidation of 2 -mercapto -succcinic acid [1 ]. The y ield was quantitative ; secondly, TE-T
tetraradical was obtained by reacting the disulphide with 4 -amino -TEMPO in the presence of
EEDQ.

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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
HO4-aminoTEMPO
Fig. 3.8. Synthesis of TE-T tetra radical
The crude mixture was purified by column chromatography using silica as the stationary
phase and ethyl acetate as the eluent. The y ield was about 30%. The EP R spectra of TE-T
tetraradical is shown in Fig. 3.9 (aN= 16.13 G) . In Fig. 3.10 it is showed the HR-MS (m/z):
calculated for C 44H78N8O8S2 [M+] 910.5379 ; found 910.5458 ..

Fig. 3.9. EPR spectr um of TE -T tetra -radical

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Fig. 3 .10. HR-MS spectrum of TE-T tetra -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. The yield was around 20%.
NNNN
NNH
N
OO
N
HNHO
O
HN OO
OONNNH2
H2NNH2
NH2NO
OOH.
..
+
TE-PEEDQ

Fig. 3.11. Synthesis of TE -P tetra -radical

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The EPR spectra of TE -P radical is shown in Fig. 3.12 (aN= 16.01 G) . HR-MS (m/z):
calculated for C 52H97N10O8 [M+H+] 989.7485 ; found 989.7488, Fig. 3.13 .

Fig. 3.12. EPR spectr um of TE -P tetra -radical

Fig. 3 .13. HR-MS spectrum of TE-P tetra -radical

3.3. Oxidation of alcohols mediated by polyradicals
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 two or more paramagnetic groups in the
molecular structure.

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For testing as substrates in the oxidation pro cedure, we took into consideration five
alcohols [8], with different reactivity, namely benzyl alcohol, 1 -phenylethanol, diphenyl methanol,
1-octanol and furfurol alcohol (Table 26).
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
[9,10 ]. The results are compiled into Table 26.

Table 26 . Yields of oxidation (measured by NMR) of the employed alcohols to the corresponding
aldehydes or ketone using the synthesized polyradicals
Entry Alcohol Polyradical Yield %
1
DI-T 96
2 TRI-P 55
3 TE-T 100
4 TE-P 38
5
DI-T 56
6 TRI-P 25
7 TE-T 45
8 TE-P 21
9
DI-T 29
10 TRI-P 44
11 TE-T 34
12 TE-P 60
13
DI-T 20
14 TRI-P 18
15 TE-T 1
16 TE-P 8
17
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 furfuro l (Entries 1, 3 and 17, Table 26 ), while 1 -octanol
cannot overpass 20% (Entry 13). PROX YL 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).
OH
OH CH3
OH
OH
OOH

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Comparison of the yields obtained for alcohol oxidation in the presence of TEMPO
monoradicals with those obtained in the present study leads to conclusion that using of
polyradicals does not improve the oxidative p rocess, comparatively with the use of monoradicals
[10,11 ]; moreover, we were unable to recover it in order to recycle them (however, the un -reacted
alcohols can be recovered, as no other decomposition or oxidation products of them were noticed).
Another e xplanation of the different reactivities regarding the benzyl alcohol derivatives may
consist in the steric hindrance; also, the stability of the disulphide group towards NOx sh ould not
be disregarded.

3.4. Mechanistic proposal
Regarding the mechanism of reaction, Fig. 3.14 shows an overview of the reactions that
took place; this is well known in literature [12-16]. 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
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.

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R1
R2OH
H
OR1
R2NO
NOHNO
O2NO2NaNO2 + CH3COOH CH3COONa + HNO2
2 HNO2 H2O + NO + NO2
2NO + O2 2 NO2

Fig. 3.14. Proposed mechanism for selective o xidation of alcohols
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 oxidative process, probably due to the labile amido

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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 catalytic cycle. This pr ocedure will be used further in the following chapter.

3.5. Conclusion
The polyradicals used were a diradical contain ing two of TEMPO moieties , a triradical
containing three PROXYL groups , a tetraradical containing four TEMPO moieties and a
tetraradical contain ing four PROXYL groups . Those were prepared and characterized by EPR and
HR-MS spectra to confirm the structure of the compounds. They can act as oxidation mediators in
selective oxidation processes of alcohols . The alcohols used for this aim were benzyl alco hol, 1 –
phenylethanol, diphenyl methanol, 1 -octanol and furfurol alcohol .
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 a nd
furfurol. The main drawback is the difficulty to recycle the polyradicals .

3.6. References
[1] Caproiu, M. T., Ionita, G., Drag hici, C., Ionita, P., Arkivoc. 2008, 14, 158.
[2] Yochai, B., Alfred, H., J. Org. Chem. 2000, 65, 6368.
[3] Ashok, J. M., Ni cholas, J. T., Anton, W. B., Jeroen, C., Meijer. E. W., J. Phys. Chem. A.
2003, 107, 8467.
[4] Bosman, A. V., Janssen, R. A. J., Meijer, E. W., Macromolecules. 1997, 30, 3606.
[5] 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.
[6] Kokorin, A. I., Tran, V. A., Rasmussen, K., Grampp, G., Appl . Magn . Reson.2006, 30, 35.
[7] Edwards, T. E., Okonogi, T. M., Robinson, B. H., Sigurdsson, S. T., J. Am. Chem. So c.
2001 , 123 ,1527.
[8] Shakir, A. J. , Ionita, G ., Ionita, P., Rev. Roum . Chim . Accepted. 2017.

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[9] Shibuya, M., Osada, Y., Sasano, Y., Tomizawa, M., Iwabuchi, Y., J . Am. Chem . Soc.2011,
133, 6497.
[10] Shakir, A., Florea, M., Culita, D. C., Ionita, G., Ghica, C., Stavarach e, C., Hanganu, A.,
Ionita, P., J . Porous Mat. 2016, 23, 247.
[11] Wertz, S., Studer, A., Green Chem. 2013, 15, 3116.
[12] Liu, R., Liang, X., Dong, C., Hu, X., J. Am. Chem . Soc. 2004, 126, 4112 .
[13] Xie, Y. , Mo,W. , Xu, D., Shen, Z., Sun, N. , Hu, B., Hu, X., J. Org. Chem . 2007, 72, 4288 .
[14] Karimi, B., Biglari, A., Clark, J., Budarin,V. , Angew . Chem . Int. Ed. Eng. 2007, 46, 7210 .
[15] Wang, X., Liu, R., Jin,Y. , Liang, X., Chem . Eur. J. 2008, 14, 2679 .
[16] Hoover, J. M. , Ryland, B. L. , Stahl, S. S., ACS Catal . 2013, 3, 2599 .

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Chapter 4 . Selective oxidation of alcohols by silica
supported TEMPO
4.1.TEMPO versus silica supported TEMPO
As mentioned before, n owadays literature data are rich in novel methods of using
transition -metal free aerobic oxidation, like those involving hypervalent iodine compounds (Dess –
Martin oxidation), oxalyl chloride/DMSO (Swern oxidation), sodium hypochlorite, nitric acid or
its salts and also nitroxide free radicals [1-10]. The oxoammonium salt of TEMPO is also well
known as a strong yet specific oxidant [11]. On the other hand, TEMPO is often used in
combination with transition metals and seldomly with metal -free co -oxidant s. For example,
copper, iron, manganese and silver have commonly been used as transition metal co -oxidant s [12-
15], while halogens and/or acids have been employed in the metal -free systems [16,17 ].
An interesting heterogenous system made of iron oxide nanoparticles together with
TEMPO (free or covalently attached) were employed as catalytic systems for the oxidation of
benzylic alcohols [18-20].
Heterogeneous catalysts are preferred in large scale or industrial applications. Therefore,
we continue d our research into conducting practical oxidations of different types of alcohols
employing new NOx and TEMPO based systems. The newly developed metal -free system
employ ed commercially available silica supported TEMPO as the catalyst and nitrosonium
tetrafluoroborate as co-oxidant , as is shown below.

4.2. Oxidation of alcohols
As part of our interest in organic reactions mediated by stablefree 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, an d cyclic) to the
corre sponding aldehydes and ketones [21].

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Table 27 .Oxidation of various alcohols using silica supported TEMPO as catalyst and nitrogen
dioxide or nitrosonium tetrafluoroborate as co -catalyst (yield by isolated compound)

Entry Product Co-oxidant Molar ratio substrate/ free
radical / co-oxidant Time
(h) Yields
(%)
1
2
3
4
5
6
O NO 2 1/ 0.2 /0.2 4
16 8
40
NO+BF 4- 1/ 0.1 /0.1
1/ 0.2 /0.1
1/ 0.1 /0.2
1/ 0.2 /0.2 4 8
18
18
97
7
O
NO 2 1/0.2/0.2 4 0
8
NO+BF 4- 1/0.2/0.2 4 0
9 16 50
10
OO
NO 2 1/0.2/0.2 16 9
11 NO+BF 4- 1/0.2/0.2 16 27
12
O
NO 2 1/0.2/0.2 4 0
13 1/0.2/0.2 16 1
14 NO+BF 4- 1/0.1/0.1 16 25
15 1/0.2/0.2 16 38
16
OO
H
H H
NO 2 1/0.2/0.2 16 40
17
NO+BF 4- 1/0.2/0.2 16 60
18 16 93
19
OO
H
H H
NO+BF 4- 1/0.2/0.2 4 99
20 16 90
21
O
NO+BF 4- 1/0.2/0.2 1 73
22 2 92
23
CO
CH3
NO+BF 4- 1/0.2/0.2 1 100
24 1/ 0.1 /0.1 2 100
25
O
NO+BF 4- 1/0.2/0.2 1 50
26 2 67
27
N N
O O
NO 2
1/0.2/0.2 72 99
28 NO+BF 4- 16 99

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We started this study with the previously described system (NO x and TEMPO ) [22], and
employing more complicated substrates, known for their lower reactivity and containing moieties
that were also suitable for oxidation, such as double bonds (Table 27 ). 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).
Instead of plain TEMPO it was used the commercially available TEMPO on silica, a
yellow solid containing about 0.7 mmol TEMPO per gram. The active oxoammonium salt was
obtained by passing gaseous nitrogen diox ide through the solid material.
As a result, p reviously used activated alc ohols (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 co-oxidant . Using nitrosonium tetrafluoroborate as a co -oxidant , similar results
were obtained in much shorter times: 92% for benzaldehyde ( Table 27 , entry 22, 2 h), 100% for
acetophenone(entry 24, 1 h), and 67% for diphenylketone (entry 26, 2 h).
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 co -oxidant . Different ratios
between substrate, catalyst and co -catalyst (co-oxidant) were st udied, as well different reaction
times. As a general rule, higher reaction time improves the yields of oxidation, as well as the
amount of free radicals or co -oxidants used (Table 27 ).
Interestingly, nitrosonium tetrafluoroborate seems to be a far better co-oxidant than
nitrogen dioxide. In the case of cyclohexanol, after 4 h, nitrogen dioxide is able to convert only 8%
into cyclohexanone (Entry 1), while with 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 for 1 -octanol an increased yield from 1% to 38% (Entries 13 and 15).
Using more complicated substrates (of steroids type), the same tendency ha s 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).

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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
efficiency decreases, requ iring longer time of reaction [21 ]. The efficiency of the recycled silica
supported TEMPO in the new system remains very simi lar with the first used one, requiring only
the addition of nitrosonium tetrafluoroborate.
As a model we reproduced the Entry 23 a nd recycled the catalyst. Fig. 4.1, 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 methanol.
This is due probably to the accumulation of solid residues on the silica (i.e. tetrafluoroborate sa lts)
than cannot be removed by DCM, but are easily soluble in water or methanol. The simple
separation of the solid heterocatalyst from the reaction process and its fully reuse is an economic
and green improvement.

Fig. 4.1. Efficiency of the recovered catalyst (for Entry 23; grey columns – after washing with
DCM; black col umn- after washing with water).

020406080100
1 2 3 4 5
Runs%

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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 [5,16 ] and ii) a complicated cooperative redox mechanism involving transition metals [20].
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 co -catalyst, but this fact
cannot be taken in an absolute way, as a metal ion can tune the reactivity of TEMPO free radical
[23].
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 co -oxidant 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 collection of diverse and seemingly contradictory experimental and
computational data rep orted previously in the literature [20].
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 anaerobic system [9]. Therefore, nitrosonium tetrafluoroborate oxidizes TEMPO
into the corresponding oxoammonium cation, yiel ding in the same time NO (Fig. 4.2).
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 TEMPO H 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. 4.2).
The solid TEMPO catalyst operates as a reservoir of NO x, and NO x are practically the
species that activate dioxygen [22,24 ]. Overall, the catalytic system involving NO x as an
unconventional oxidant is a very promising alternative for oxidation of a broad array of alcohols
with minimal workout.

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NO2NO2
NO
BF4
silica silica_silica
NO+BF4-OH2O
or NO2NOH
NOCO
R2R1
H
R2R1HO

Fig. 4.2. A proposed mechanism involving supported TEMPO and NO x species

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4.5. Conclusion
Silica immobilized TEMPO , commercially available , was used to selectively convert a
wide range of primary and secondary alcohols (including testosterone , furan and pyridine
derivatives ) into the cor responding aldehydes or ketones. No over-oxidation of aldehydes to acids,
nitration processes or oxidation of double bondswas observed.
The process minimizes the drawbacks of classical oxidation systems (acidic medi a,
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 can
be easil y recovered and reused directly, after four reactions, the silica supported TEMPO kept its
original activity.
This system, which is the first time that nitrosonium tetrafluoroborat e has been used in
literature as a co -oxidant, represents a good alternative f or selective alcohol oxidation (nitrosonium
tetrafluoro borate appeared to be a far better co -oxidant than nitrogen dioxide).

4.6. Refer ences
[1] Smith, M. B., March, J., Mar ch‟s Advanced Organic Chemistry, John Wiley: New Jersey. 2007
[2] Backvall, J. E. , Modern Oxi dation Methods, Wiley. Weinheim. 2004.
[3] Tojo, G., Fernandez, M., Oxidation of Al cohols 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.
[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.
[10] Saito, K., Hirose, K., Okayasu, T ., Nishide, H., Hearn, M. T. W., RSC Adv. 2013, 3, 9752.
[11] Lenoir, D., Angew. Chem. Int. Ed. 2006, 45, 3206.
[12] Hu, Z., Kertan, F. M., Org. Biomol. Chem. 2012, 10, 1618.

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[13] Liu, J., Ma, S., Tetrahedron. 2013, 69, 10161.
[14] Ryland, B. L., Stahl, S. S., Angew. Chem. Int. Ed. 2014, 53, 8824.
[15] Jeena, V., Robinson, R. S., Chem. Commun. 2012, 48, 299.
[16] Moriyama, K., Takemura, M., Togo, H., J. Org. Chem. 2014, 79, 6094.
[17] Obermayer, D., Balu, A. M., Romero, A. A., Goesller, W., Luque, R., Kappe, C. O., Green
Chem. 2013, 15, 1530.
[18] Karimi, B., Mirzael, H. M., Farhangi, E., ChemCatChem. 2014, 6, 758.
[19] Karimi, B., Farhangi, E., Chem. Eur. J. 2011, 17, 6056.
[20] Ryland , B. L., McCann, S. D., Brunold , T. C., Stahl, S. S., J. Am. Chem . Soc. 2014, 136,
12166.
[21] Shakir, A. J., Paraschivescu, C., Matache, M., Tudose, M., Mischie, A., Spafi u, F.,
Tetrahedron Lett. 2015, 56, 6878.
[22] Ionita, P. , RSC Adv. 2013, 3, 21218.
[23] Scepaniak, J. J., Wright, A. M., Lewis, R. A., Wu, G., Hayton, T. W. , J. Am. Chem. Soc.
2012, 134, 19350.
[24] Luts, T., Iglesia, E., Katz, A. , Mater . J. Chem . 2011 , 21, 982.

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Chapter 5. TEMPO on nanosilica and the influence of
supported gold clusters in aerobic oxidation s
5.1.Introduction
Heterogeneous catalysis is one of the most used chemical industrial processes, being
employ ed for the completion of a large variety of oxidation reactions, among others . The ch oice
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 a ldehydes and
ketones is one of the most required processes in the production of fine chemicals [4,5].
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 p owerful catalytic activity (i.e.
gold clusters can oxidize carbon monoxide) [6]. Literature data regarding novel approaches for
selective oxidation showed that gold nanoparticles (Au NPs) can also convert benzylic alcohols
into aldehydes or even esters (through an oxidative coupling). Such processes do not require an
additional co -catalyst, as is usual in the case of TEMPO [7-9].
Interestingly, recently it was reported that TEMPO can greatly extend the lifetime of the
gold (III) chloride catalyst (the tu rnovers 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 [10].
In 2008, Su et al. [11] used gold nanoparticles on polymorphs of gallia (α – β- ϫ- Ga2O3) for
the oxidation of benzyl alcohol. A gold nanocluster (PI-Au) polymer [12] 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 compoundsare obtained usually by the well -known esterification or trans -esterification
processes, always requiring the presence of a strong acid or base as a catalyst. Direct
transformation of the alcohols into esters via oxidative coupling between aldehyd es 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 ester s from alcohols under mild
conditions requires precious metals catalysts (palladium, gold, ruthenium, or iridium). Moreover,

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there are some serious technical drawbacks -high yields are obtained only using pure oxygen under
autoclave working conditions at el evated temperatures [13-15], therefore a more convenient and
trouble -free procedure is highly desirable.
Nanometric size catalysts have the advantage of extremely large surface area and attracted
a high interest owing to their unique characteristicsand potential. Supported metals are performing
usually better compared only with simple metal. Noble metals supported catalysts are nowadays
widely used in organicsynthesis, especially AuNPs prepared by the adsorption ordeposition –
precipitation method.
Inspire d by the literature data [ 9,16,17 ] and by our previous work in alcohols oxidation
mediated by TEMPO free radical and nitrogen dioxide [ 18] and by the dual behavior of gold
nanoparticle s, as generators and scavengers for short -lived free radicals [19], here in 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 heterogeneous material that works as a catalyst with
improved behavior.
As mentioned before, it w as also demonstrated that TEMPO highly extend the catalytic
activity of gold [ 10], therefore using a hybrid catalyst containing both gold a nd TEMPO can be a
step forward. As nitrogen dioxide source we used nitrosonium tetrafluoroborate, with the great
advantage of working with a solid instead a gas.

5.2.Development of nanosilica -TEMPO materials
TEMPO free radical can be covalently bonded to (nano)silica in various way s, employing
different methods, like sol–gel or surface modi fication reactions on prefor med 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) [ 20-22]. In our work we used the both types, for comparison reason [23].
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.Bis in fact the
previous one which contains supported go ld, obtained the reduction of a gold(III) salt with sodium
borohydride).

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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
used as silica precursor. The TEMPO 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 bysupporting 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. 5.1.
OH
O
OHNO
SiO2OH
ONO
SiO2
OH
OHSiO2H
N NOOH
SiO2H
N NOCatalyst A Catalyst B
Catalyst C Catalyst D
Au
AuAuAu

Fig. 5.1. Structure s representing Cat. A -D

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5.3.Characterization of the nanomaterials
All TEMPO containing catalysts were obtained as solid materials having a yellow or violet –
black colour ( Fig. 5.1); the yellow color is due to the TEMPO free radical, while the violet -black
colour is due to the supported gold nanoparticles.
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. 5.2. shows the TEM images of samples A –D.

Fig. 5.2. 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)

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IR spectra ( Fig. 5.3) 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 an d D, and those are attributed to the C –H groups; however, C –H
groups are also visible between 1350 and 1450 cm-1.

Fig. 5.3. IR spectra of the samples A -D
The nitrogen adsorption –desorption isotherms 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. 5.4).
This type of hysteresis is usually associated with the presence of interconnected pores of
not well -defined or irregular shape (ofte n referred to as „ink -bottle‟ pores). As can be seen in the
inset (Fig. 5.4 ), 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 1.001020304050
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)
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)
Fig. 5.4. 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 nanoparticles.
Sample C has a quite smaller specific surface are a (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 synthe sis.
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
of sample B, deposition of gold on the surface of sample C has as result a decrease of the surface
area an d total pore volume (Table 28 ).

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Table 28 . 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 EP R 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 via
a nitrogen atom). The content lost when heatin g 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 28 ).
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 present (Fig. 5.5).

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Fig. 5.5. 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 mo bility of the TEMPO moieties is quite restricted.
However, some differences are visible between dry and wet samples; furthermore, large
differences are obs erved between samples A –D. As EP R spectra are very sensitive to the
microenvironment 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 oxygen atom.
EPR technique can give important information about the environment in which the
TEMPO free ra dical is found [24 ]. Fig. 5.6 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 t his
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. 5.6. EPR 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 the TEMPO moieties is quite res tricted.
However, some differences are visible between dry and wet samples; furthermore, large
differences are observed between samples A –D. As E PR spectra are very sensitive to the
microenvironment in which TEMPO moiety is found, significant information c an 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.
For sample B, containing gold clusters, the EP R spectra, both in solid and suspended in
DCM, are very similar , and clearly showed the three l ines characteristics of a nitroxide free
radical, together with small outside humps. The interpretation of these features means the

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coexistence 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 explanation.
It is possible for s ome TEMPO units to leak, as Si –O–TEMPO bonds can break. Sample C
shows an EP R 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 sam ple 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
involvement of gold clusters, tha t 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 29). In this c ase all
samples A –D showed good oxidation abilities, the yiel ds in aldehyde or ketones bein gin 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 ability.
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 no t 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 [ 13,14 ].

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O O OHH3CO OH3CHO
O2 /catalyst CH3OH O2 /catalyst
– H2O
– H2O
Route IRoute II
Route III

Fig. 5.7. 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 29). Moreover, starting directly
from benzylic alcohol, none of the catalys t 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 [13,14]; 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 salt is conver ted into gold nanoparticles [13 ] ); 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 co -catalyst used in our experiments is acidic. Therefore, working
in different environments would explain these results.

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Table 29 .Yields (%) by isolation and NMR 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)
OH

O
OCH3

0 (0)a

0 (0)a

0 (0)a

0 (0)a
a After 24 h

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5.6. Mechanism of oxidation
The key point in this oxidation procedure is the generation of oxoammonium salt from
TEMPO and NO x [25,26 ]. 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. 5.8).
silica
silica
silicaN
NOOHOBF4-H
R2HO
R1
R1
R2O
NO2
NOO2NO+BF4-
NO+

Fig. 5.8. Plausible mechanism of oxidation involving nitrosonium tetrafluoroborate and TEMPO

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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.
Regardingthe formation of an ester via oxida tive coupling of alcohol with the aldehyde (see
Fig. 5.7), 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 oxidiz ed to the methyl benzoate ester [13,14 ]. In all reactions of such type oxygen is
the final oxidant and water the by -product of alcohols oxidations or oxidative coupling reactions
(not showed in Fig. 5.8 , for simplicity).

5.7. Conclusion
Four types of supp orted TEMPO (Cat. A, B, C, D) coupled with nitrosonium
tetrafluoroborate may represent a very good alternative for non -metal oxidation systems of
alcohols (benzyl alco hol, 1 -phenyl ethanol, diphenyl methanol ).
We used two types of linker between the silica surface and the TEMPO , an oxygen atom
and nitrogen , and characterized all the materials by IR, TEM, t hermal analysis and EPR .
The addition of gold nanoparticles in such systems doesn‟t represent an asset; however,
gold seems to be compu lsory for oxidative coupling with the aim of obtaining esters in a single pot
reaction; cat. B was capable of converting it to methyl benz oate, with a yield of 13 %; all other
catalysts were unable to get the desired product .

5.8. Refer ences
[1] Catala, L., Turek, P. J., Chim . Phys. 1999, 96, 1551.
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[23] Shakir, A., Florea, M., Culita, D. C., Ionita, G., Ghica, C., Stavarach e, C., Hanganu, A.,
Ionita, P., J . Porous Mat. 2016, 23, 247.
[24] Narayana, K. V., Raju, B. D., Masthan, S. K., Rao, V. V., Rao, P. K., Subrahmanian, R.,
Martin, A., Catal. Commun. 2004, 5, 487.
[25] Shibuya, M. , Nagasawa, S., Osada, Y., Iwabuchi, Y. , J. Org. Chem. 2014, 79, 10256.
[26] Sheldon, R. A., Catal. Today . 2015, 4, 247.

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Chapter. 6. TEMP O on graphene oxide: a 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 -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, nanotube s, graphene)
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].
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 methods today; the graphite re acts 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
synthesis. 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

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which is exfoliated into sheets containing functionalities such as hydroxy, e poxide, carbonyl 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 functionaliz ation with 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 functi onalize GO, 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 ch emistry (i.e. with porphyrins [15], ferrocene [16], and
polymers ) [17]. In addition, another route is the use of aryl diazonium salts, which can also be
tailored by organic chemistry [18,19 ]. 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 appli cations, from electrochemical energy conversion and
storage to robust and highly selective carbocatalysts [20]. GO have so many applications , being
used as GFET device (graphene based field effect transistor) [21,22 ] or FETs (Field effect
transistors ); also is used as chemical sensors [23-25] and biosensors. MnO 2 has been used on a
surface of graphen e oxide for the selective aerobic oxidation of benzyl alcohols to corresponding
carbonyl compounds [26]. 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 [27]. GO is used as
a catalyst for the selective oxidation of alcohols to the corresponding aldehydes and ketones.
One of the most important organic chemistr y reactions is the selective oxidation of alcohols
to aldehydes or ketones. 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 t oxic waste is hard to process. Novel systems involve more gentle (air, oxygen, hydrogen
peroxide, etc.) or non -conventional (carbon -based materials, stable free radicals, etc.) oxidants,
with certain and large advantages: clean reactions, mild working cond itions, recovery and re -use of
the catalyst, less or no ntoxic by -products, and so on [28-34].
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. O rganic stable free radicals

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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
[35-37].
The stable free organic r adical 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 [38], ii) using a malonyl derivative of 4 -hydroxy -TEMPO (following the Bingele -Hirsch
reaction) [39] or iii) using the oxoammonium salt of TEMPO [40] (which in fact is not a free
radical). None of those have been used in the catalytic sel ective oxidation of alcohols.
In this work, we covalently bound 4 -amino -TEMPO to GO [41], using standard 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 chlo ride 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 [38] and by the higher stability of the
amide group. Am ides are much more stable than esters (which can easily hydrolyze under basic
conditions); moreover, 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 characteri zed by elemental analysis, infrared
(IR), electron spin resonance (EP R) 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 [42] because
different sources of natural graphite significantly affect the properties of the GO [43]. Literature
data [44] 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 [ 45] and improved Hummers [46]
methods, thus yieldingtwo 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. 6.1), 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 meth od afforded the best results. The thus , obtained materials were
further characteriz ed by elemental analysis, IR, EP R, 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 [47,48 ]. 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 th e graphite lattice,
while GO/iGO and GO/iGO functionalized with TEMPO showed two broad peaks, namely the G
(1580 cm-1) and D band (at about 1350 cm-1).

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Fig. 6.2. Raman spectra of the materials used in this study
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 ID/IG gives val ues higher than 1, which
correspond to the reduction of the crystallite domain size i n the hexagonal layers from 20 n m to
~40 Å, determined from the Tuinstra and Koenig equation [49].
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 [50], straining the sp2 bonds without openin g
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.

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Fig. 6.3. IR spectra of the materials used in this s tudy
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 showed that the intensities of the
bands at 1620 cm-1 and 1740 cm-1 are reduced [51], while new a band emerges at about 1570 cm-1,
corresponding to the C -N stretching vibrations [51]. This band is very intense and is also present in
the IR spectrum of 4 – amino -TEMPO , Fig. 6.4).

Fig. 6.4. 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 .
EPR spectroscopy is the most powerful tool to study free radicals, and provides additional
data on the samples used within this study. Unpaired 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 [53-55].
The EP R spectrum of the pristine graphite sh owed 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 material s a sharp line is noticed .

Fig. 6.5. EPR spectra of the materials used in this study
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 [56].
Because phenolic radic als are stabilized on GO [49], we do not exclude the presence of
semiquinone -type radicals, as they were identified for example in cigarette tar [57].
For TEMPO -functionalized samples (GO -T and iGO -T) additional data are noticed: the
EPR spectra showed a very broad line with a triplet feature, well known for grafted radicals
[58,59 ].

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These spectra represent a sum of two components: a single broad line determined by the
very short interspin distances and a second line showing the immobilized spectrum of TEM PO,
reflecting an increased distance between nitroxide spins.
Quantitative EP R analysis of the samples was also performed aiming to evaluate the degree
of functionalization of the graphe ne oxides with the 4-amino -TEMPO free radic al. Double
integration of t he EP R 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 30).

Table 30. Quantitative EP R analysis
Sample Mass (mg) EPR 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 si gnal to noise ratio and so on).

A rough evaluation of the content in the organic free radical l ed 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 content of 3.40% and 3.81%, respectively (see Table 31).

Table 31. 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

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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 differ ent ways of calculation, each of them with inherent experimental errors.
However, both methods showed without a doubt the presence of the TEMPO moiety in the
composite material.
An interesting feature was noticed in the thermo -gravimetric analysis. In gene ral, the
thermal degradation of GO materials occurs in several steps: up to about 300 oC 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 [24]. Several interesting outcomes may be revealed by
the thermal analysis (Fig. 6.6).
The first is the efficiency of the improved Hummers procedure in generating materials with
a greater c ontent 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 th ree- 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 content, the decay process of the samples occurs at
significantly lower tem peratures (dotted line marked zone, Fig. 6.6). A decomposition step
characteristic for the TEMPO samples is the one that occurs between ~300 and 500 oC (solid line
marked zone in Fig. 6.6), most likely caused by thermally induced decomposition of the TEMPO
moieties, in accordance with literature data [55,56 ].

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Fig. 6.6. 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 6.7). SEM micrographs of the samples are shown in Fig. 6.8.

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100 200 300024
GOT
IGOT
Temperature / oCDSC (mW/mg) TEMPO
melting of TEMPO

Fig. 6.7. DSC curves for 4 -amino -TEMPO , comparati ve with TEMPO functionalized GO
During heating in inert atmosphere, after a melting process (T DSC = 43.65 oC), 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 th e TEMPO melting process.

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Fig. 6.8. SEM micrographs and EDX spectroscopy of the samples G, GO, iGO, GO -T and
iGO-T (from top to bottom)

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In SEM, t here 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 E DX spectroscopy detects C and O, indicating that the morphological changes correspond to
the oxidation of the grapheme sheets.
The state of aggregation indicates that oxidation induces formation of intersheet bonds in
the GO sample. GO -T shows a similar mo rphology 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 microstructure 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 analys is detects the presence of N
and lower O content, confirming the incorporation 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 (seeTable 32).

Table 32. 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 [60-62]. GO itself has been found to be able to oxidize neat benzyl alcohol under harsh
reaction conditions (GO 200%, temperature 100 oC, 24 h [63]); in addition, GO in the presence of
TEMPO (80% GO and 100% TEMPO , autoclave) has been found to oxidize 5 –
hydroxymeth ylfurfural to 2,5 – diformylfuran [64].

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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 autocla ve and working at room temperature. Our test
experiments showed that G, GO, iGO, GO -T and iGO -T samples cannot oxidize benzyl alcohol 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 33, Entries 1 -4,7). This shows that the requirement
for getting the oxidation process to work is the simultaneous presence of a TEMPO moiety
(meaning samples GO -T and iGO -T) and the co -catalyst.
Some of our previous work [36,65,66 ] 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 ai r as the final oxidant.
Moreover, from this type of oxidation process, either aldehydes or ketones result and not
the carboxylic derivatives. All of our materials described above have been tested as catalysts for
alcohol oxidation; for this aim , we employe d five alcohols ( Table 33 ), namely benzyl alcohol, 1 –
phenylethanol, diphenylmethanol, furfuryl alcohol and 1 -octanol, thus covering a wide range
ofreactivities. As a general rule, our experiments showed that for activated alcohols iGO -T and
NO 2 are the bes t reactants ( Table 33 , Entries 6, 9, 11 and 13), reaching a 99% yield in the case of
benzyl alcohol (Entry 9); however, the less 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 oxidatio n of the iGO
starting material. There is also a possible synergistic effect of these, as the literature suggests [65].

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Table 33 . The result of oxidation of alcohols (yield s by NMR)
Entry Product Catalyst Co-oxidant Yield %
1

O
none
NaNO 2 trace
2 G < 1
3 GO < 1
4 iGO < 1
5 GO-T 42
6 iGO-T 46

G
iGO-T
iGO-T NO 2 trace
57
99 7
8
9

10
CH3O
iGO-T
iGO-T NaNO 2
NO 2
9
12
11

O
iGO-T
iGO-T NaNO 2
NO 2 9
25 12
13

OO
iGO-T
iGO-T NaNO 2
NO 2 5
11 14
15

O
iGO-T
iGO-T NaNO 2
NO 2 3
10 16
17
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

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 [36,63,64 ], which is generated by
NOx.
Regarding the mechanism, there are in fact two coupled cat alytic cycles ( Fig. 6.12), one in
which the oxoammonium salt is formed by NO 2 and the other one in which NO is converted into
NO 2.

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Further evidence of these catalytic cycleswas obtained by IR and EP R spectra of the used
catalyst. We have chosen as represen tative 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 the sample used as catalyst showed, as expected, the presence
of a band at 1384 cm-1(Fig. 6.9 ) due to NO 2/oxoammonium salt, meaning also that iGO -T can be
regarded as a reservoir for the NOx [36].
By EP R (Fig. 6.10), the spectrum of the used catalyst showed some differences compared
with the starting material: i) in the used catalyst, a decrease in the intens ity of the EP R spectrum of
about 15% has been noticed, and we assume this is due to the conversion of the nitroxide moiety
into the corresponding oxoammonium 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).

Fig. 6.9. Superimposed IR spectra of iGO -T before (black) and after it was used (red)

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Fig. 6.10. Superimposed EP R spectra of iGO -T before (black) and after it was used(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.
6.11), demonstrating thus the recyclability of the catal yst.

Fig. 6.11. SEM micrographs and EDX spectroscopy of the iGO -T sample, after it was used as a
catalyst in alcohols oxidations

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GO
GON
NOOHOH
R2R1
O
R2R1
H2ONO2NOO2
oxgyen activationactivation of TEMPO
Fig. 6.12. Proposed oxidation mechanism

6.6. Conclusion
The 4-amino -TEMPO free radical was covalently graf ted to G O through an amide bond
following two methods, the Hummers method yielding GO -T and the improved Hummers method
used to produce iGO -T; the composite materials were characterized by IR, Raman, EP R, thermal
analysis, SEM and EDX.
All these investigations demonstrating the co valent attachments of the TEMPO moieties to
the solid material. They were used as catalysts for selective oxidation of some alcohols (benzyl
alcohol, 1 -phenylethanol, diphenyl methan ol, 1 -octanol and furfurol alcohol ) in very mild
conditions, at room temperature and us ing oxygen as the final oxidant . As co-oxidant were used
sodium nitrite and nitrogen dioxide. The oxidation yield depends on the reactivity of the alcohols.
Benzyl alcohol can be oxidized selectively to benzaldehyde in an almost quantitative yield .

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The materials can be easily recovered by simple fi ltration or centrifugation and reused after
reacti vation with no or very little loss of activity .

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Chapter 7. Experimental part
7.1. Chemicals, solvents and materials
All chemicals and solvents were purchased from Sigma -Aldrich, Acros or Chimopar and
used as received. Flash column chromatography was performed on silica gel 60 from M erck (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. Apparatus
7.2.1IR spectroscopy
IR spectra were recorded on a Jasco FTIR 4100 apparatus using potassium bromide disks.

7.2.2UV-Vis spectroscopy
UV-Vis spectra were recorded on a UVD -3500 double beam spectrophotometer at room
temperature using 1 cm quartz cells and different solvents, as required.

7.2.3 HR -MS
HR-MS spectra were recorded on a ThermoScientific (LTQ XL Orbitrap) apparatus.

7.2.4EPR spectroscopy
EPR spectra were recorded in different solvents at room temperature on a Jeol JES FA 100
apparatus using the following typical settings: frequency 8.99 GHz, fi eld 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 plain glass tubes.

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7.2.5 NMR spectroscopy
1H and 13C-NMR spectra were recorded in deuterated solvents (CDCl 3, or DMSO -d6) on a
Bruker Fourier apparatus at 300 MHz or 500 MHz ( chemical shifts are reported in ppm, using
TMS or the solvent as standard).

7.2.6 X-ray diffraction
X-ray diffraction measurements 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 r efined with anisotropic displacement parameters. Calculations were performed
using SHELX -2014 crys tallographic software package.

7.2.7 Raman spectroscopy
Raman spectra were measured in a Horiba Jobin -Yvon LabRam spectrometer.
Measurements were carried out in the back scattering 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 ~20 mW . The laser
spot size was ~1 -2 µm.

7.2.8 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 analysis 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.

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7.2.9 Cyclic voltammetry
CVs were recorded in acetonitrile, using a potentiostat/galv anostat Autolab 302 N
connected to a PC running the softwar e GPES (Ecochemie, Utrecht, Netherlands), in an
electrochemi cal cell (Metrohm) with a three electrodes system, using platinum electrode as
working electrode, a glass y carbon rode wa s the auxiliary electrode, and a Ag/AgCl electrode was
used as reference electrode , at a concentration of 2 mmol in free radical . As support electrolyte
was used lithium percholate (0.1 M) at various potential scan rates ranging from 50 to 500 mV/s .
scan rate was 100 mV/s. Before the measurements, the surface of the working electrode was
polished with alumina powder (0.1 mm) a nd then sonicated for 10 min in deionized water and,
finally, throughly washed with acetone. Argon was bubbled through the solution before the
measurements .

7.2.10 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 measurement 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 f low 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).

7.2.11Brunauer Emmette Teller (BET) and Barrett –Joyner –Halenda (BJH)
method s
The samples (Cat. A, Cat. B, Cat. C and Cat. D) were outg assed at 90 oC for 7 h before
analysis. Specific surface areas (SBET) were calculated according to the Brunauer –Emmett–Teller
(BET) equation. The total pore volume (Vtotal) was estimated from the amount adsorbed at the
relative pressure of 0.99.

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The surfa ce area of covale ntly grafted TEMPO on graphene was calculated using the 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.
The average pore diameter and pore size distribut ion curves were obtained using Barrett–
Joyner–Halenda (BJH) met hod from the desorption branch.

7.2.12 SEM and EDX spectroscopy
Microstructural studies were carried out by Field Emission (FE) Scanning Electron
Microscopy (SE M) in a Dual Beam 3D FEG FEI. Secondary electron images were recorded at
accelerating voltages between 1.2 and 2 kV.
Elemental analysis measurements by Energy Dispersive X -ray (EDX) spectroscopy were
carried out in the same apparatus, operating at an accelerating voltage of 20 kV.

7.2.13 Elemental analysis
Elemental analysis was performed on a CHNPerkin Elmer 2400 apparatus.

7.3. Synthesis of compounds
7.3.1 Synthesis of DN -DPPH
The synthesis of DN -DPPH starts from dip henylamine and picric acid, as follows.
Synthesis of N-nitrosodiphenylamine [1]

H
NNaNO2 NNO
diphenylamineHCl
N-nitrosodiphenylamine

Fig. 7.1. Synthesis of N-nitrosodiphenylamine

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1 g of diphenyl amine was dissolved in 30 mL ethanol, then the solution was cooled on an
ice-bath to 0 oC. When the temperature of 0 oC was reached, 3 mL of 37% hydrochloric acid was
added, followed by 1 g of sodium nitrite previously dissolved in 4 mL of water. After few minutes
of stirring, the yellow precipitate was filtered off, washed with cold ethanol and let to dry. The
product has been checked by 1H-NMR and 13C-NMR. Yield over 90%.
1H-NMR (CDCl 3,  ppm): 7.31 -7.54 (6H, m, C H phenyl); 7.09 (4H, d, C H phenyl). 13C-
NMR (CDCl 3,  ppm): 142.51; 136.77; 128.78; 129.50; 129.31; 127.39; 126.99; 119.68.

Synthesis of N,N-diphenylhydrazine [1]
NNO
NNH2
CH3COOHZn
N-Nitrosodiphenylamine N,N-diphenylhydrazine

Fig. 7.2. Synthesis of N,N -diphenylhydrazine
N,N-diphenylhydrazine was prepared by the reduction of N-nitroso -diphenylamine (Fig.
7.2) with zinc powder. To 1 g of N-nitroso -diphenylamine dissolved in 20 mL cold ethanol was
added 6 g of zinc. External cooling was applied, as it is important not to exceed 25 oC. The mixture
was stirred continously, while 8 mL of acetic acid was added dropwise.
After 2h of stirring, the mixture was filtered off and the solid washed with ethanol. The
solvent was removed under vacuum and the residue dissolved in about 50 mL DCM. Gaseous
hydrochloric acid (obtained from sodium chloride, concentrated hydrochloric acid and sulfuric
acid) was passed through the solution. The white precipitate formed ( N,N-diphenylhydrazine
hydrochloride) was filtered off, washed with DCM and let to dry. The product has been checked
by 1H- and 13C-NMR . Yield about 70%.
1H-NMR (CDCl 3, ppm): 7.21 -7.25 (6H, m, C H phenyl); 7.40 -7.45 (4H, m, C H phenyl);
3.56 (2H, N H2). 13C-NMR (CDCl 3,  ppm): 149.49; 146.00; 125.37; 121.72.

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Synthesis of picryl chloride [1]

NO2 O2N
NO2OH
NO2 O2N
NO2Cl
picric acidDMFSOCl2
picryl chloride

Fig. 7.3. Synthesis of picryl chloride
Synthe sis of picryl chloride (Fig. 7.3) was done by reacting picric acid with thionyl
chloride (SOCl 2) under reflux in toluene. To 2 g picric acid suspended in 35 mL of toluene was
added 2 mL of thionyl chloride and 0.1 mL DMF and the mixture keep under reflux for one hour.
Then petroleum e ther was added to the mixture until picryl chloride precipitated and was filtered
off. The product has been checked by 1H- and 13C-NMR. Yiel d is almost quantitative .
1H-NMR (CDCl 3,  ppm): 8.86 (2H, s, C H picryl). 13C-NMR (CDCl 3,  ppm): 149.68;
145.77; 127.25; 122.57.

Synthesis of 2,2 -diphenyl -1-picrylhydrazine [1]

NO2 O2N
NO2Cl
NNH2
+ NH
NO2N
NO2
O2N
2,2-diphenyl-1-picrylhydrazine

Fig. 7.4. Synthesis of 2,2 -diphenyl -1-picrylhydrazine

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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 hydrochloride dissolved
in 50 mL ethanol together with 1 g of picryl chloride was added about 3 g of sodium hydrogen
carbonate and the mixture was refluxed for 1 h. After cooling down, 100 mL DCM was added and
the mixture was filtered off and the solvent removed. Slow evaporation of the solvend affords the
pure compound as crystals ; if the purity is n ot satisfactory, flash column chromatography or
recristalization can be employed. The product has been checked by 1H- and 13C-NMR. Yield is
about 90%.
1H-NMR (CDCl 3,  ppm): 10.13 (1H, s, N H); 9.21 (1H, s, C H picryl); 8.51 (1H, s, C H
picryl); 7.10 -7.38 (10H, m, C H phenyl). 13C-NMR (CDCl 3, ppm): 145.95; 149.97; 142.01;
136.44; 133.54; 129.57; 126.26; 125.01; 120.47.

Synthesis of 2,2 -dinitrophenyl -1-picrilhydrazine

NH
NO2N
NO2
O2NNH
NO2N
NO2
O2NO2N
O2NNaNO2HCl

Fig. 7.5. Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazine
To 1 g 2,2-diphenyl -1-picrylhydrazine dissolved into 50 mL DCM was added 50 mL of
diluted hydrochloric acid (1 M) and under vigorous stirring of the biphasic system was added from
time to time about 100 mg sodium nitrite (around 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 water solution, the pH was checked from time to time to be acidic – if not, this sho uld be
corrected by adding a small amount of acid).

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The organic layer was separated (it is possible that the compound to precipitate partially),
dried over anhydrous sodium sulphate and the solvent removed. The product has been puri fied by
column chromatog raphy and t he product has been checked by 1H- and 13C-NMR. Yield ~90%.
1H-NMR (DMSO -d6,  ppm): 11.45 (1H, s, N H); 8.99 (1H, s, C H picryl); 8.94 (1H, s, C H
picryl); 8.25 (4H, d (9 Hz) , CH nitrophenyl); 7.46 (4H, d (9Hz) , CH nitrophenyl). 13C-NMR
(DMSO -d6,  ppm): 149.07; 143.63; 124.86; 120.31.

Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl

NH
NO2N
NO2
O2NNNO2N
NO2
O2NO2N
O2NPbO2

Fig. 7.6. Synthesis of 2,2 -dinitrophenyl -1-picrylhydrazyl
Oxidation of 2,2 -dinitrophenyl -1-picrilhydrazine by lead dioxide yields 2,2 -dinitrophenyl –
1-picry lhydrazyl free radical (Fig. 7. 6). 1 g 2,2 -dinitrophenyl -1-picrilhydrazine together with 10 g
of lead dioxide and 10 g of anhydrous sodium sulphate were suspendeded in 100 mL of DCM. The
mixture was vigurously stirred for 2 hours, then filtered off. Slow evaporation afforded crystals of
DN-DPPH , which were characterized by X -ray diffraction.

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7.3.2 Synthesis of PINO

NO
OO NO
OOH

Fig. 7.7. Synthesis of PINO
N-hydroxyphthalimide ( PINO) can be generated from N-hydroxyphthalimide (NHPI) in
situ (Fig. 7.7), using as oxidant lead tetraacetate, lead dioxide or nitrogen dioxide.

7.3.3 Synthesis of 4 -isocyanato -TEMPO [2]

N
ONH2
diphosgen
N
ONCO

Fig. 7.8. Synthesis of 4-isocyanato -TEMPO
4-isocyanato -TEMPO was prepared by the reaction between 4 -amino -TEMPO and
diphosgene (Fig. 7.8). 4 -Isocyanato -TEMPO was obtained in a s imilar way as literature data [2 ]
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 0 oC with an external cooling (ice and salt); after few minutes, 70 mL DCM
were added, and the final solution was extracted twi ce 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 30 oC). The
compound was used directly in the next step. Yield 50%.

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7.3.4 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+] 368.2782; found 368.2807 . EPR (DCM); a N= 16.21 G.

N
ONCO N
HN N
HOO
4-NH2-TEMPO
N
O

Fig. 7.9. Synthesis of DI-T radical

7.3.5 Synthesis of TRI -P radical

N
N NNHN
N
HN
HO O
O OOO
NO
OH
NNH2
H2N NH2+
TRI-PEEDQO

Fig. 7.10. Synthesis of TRI -P radical

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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 of 50 mL DCM and THF (9/1 v/v) as
solvent. After five days, the solution was extracted with 50 mL aqueous hydrochloric acid (1 M)
and with 50 mL of sodium hydrogen carbonate (1 M); the organic layer was separat ed 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. EPR (DCM); a N= 16.06 G.

7.3.6 Synthesis of TE -T radical [3]

OSH
O
OH
OHO
SOOH
S
O
OOHHO
OHI2

Fig. 7.11. Synthesis of 2,2’-succinic acid disulphide

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NNN
NOH
N
SOHN
SO
O
O
NH
ON
HOO
SOOH
S
OOHHO
TE-T
EEDQ
OO
HO4-aminoTEMPO
Fig. 7.12. Synthesis of TE -T radical
2,2‟-succinic acid disulphide was obtained by oxidation of 2-mercapto -succcinic acid [3 ];
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 dr op-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 .
1H-NMR (DMSO -d6,  ppm): 3.85-3.80 (2H, m, C H); 3.01 -2.82 (4H, m, CH2). 13C-NMR
(DMSO -d6,  ppm): 171.23; 51.80; 47.44; 35.56.
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
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 magne sium 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 44H78N8O8S2 [M+] 910.5379; found 91 0.5458 . EPR (DCM); a N= 16.13 G.

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7.3.7 Synthesis of TE -P radical

NNNN
NNH
N
OO
N
HNHO
O
HN OO
OONNNH2
H2NNH2
NH2NO
OOH.
..
+
TE-PEEDQ

Fig. 7.13. 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 was extracted with 100 mL of sodium hydrogen carbonate (1
M); the organic lay er 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
stationary 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. EPR (DCM); a N= 16.01 G.

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7.3.8 Synthesis of Cat. A
OH
O
OHNO
SiO2
Catalyst A

Fig. 7.14. Schematic drawing 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 separated 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. 7.1 4). The ways of characterization (TEM, EPR, IR,
TG-TGA, etc.) were described in the Chapter 5.

7.3.9 Synthesis of Cat. B
OH
ONO
SiO2Au
Au
Catalsyst B

Fig. 7.15. Schematic drawing of Cat. B

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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
and 10 mg of sodium borohydride. After 2 h the solid material has been separated, washed with
methanol and dried. The final material i s a violet –black solid (Fig. 7.1 5). The ways of
characterization (TEM, EPR, IR , TG-TGA, etc.) were described in the Chapter 5.

7.3.10 Synthesis of Cat. C
OH
OHSiO2H
NNO
Catalyst C

Fig. 7.16. Schematic drawing 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 m ethanol and let to dry (Fig. 7.1 6). The ways of
characterization (TEM, EPR, IR, TG -TGA, etc.) were described in the Chapter 5.

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7.3.11 Synthesis of Cat. D
OH
SiO2H
N NO
Catalyst DAu
Au

Fig. 7. 17. Schematic drawing 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 w ith methanol and drie d (Fig. 7.1 7). The ways of
characterization (TEM, EPR, IR, TG -TGA, etc.) were described in the Chapter 5.

7.4. Synthesis methods for GO and iGO
Two methods for obtaining graphene oxides (GO) were followed [4,5] with slight
modifications, as follows:
i) Hummers methods (for 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 sulfuric acid (using
also an external cooling of the reaction mixture with ice), then 3 g of potassium permanganate was
added i n 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 lef t 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).

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The mixture was left overnight and then the supernatant w as removed. The resulting slurry
was centrifuged at 4000 rpm and the collected solid washed extensively with water, aqueous
hydrochloric 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; the characteristics of the material
were presented in the Chapter 6.
ii) improved Hummers method (iGO): to 150 mL of a mixture 9/1 (v/v) of concentrated
sulfuric acid and concentrated 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 at 50 oC, and then
the mixture was slowly poured into about 150 g of ice, adding 5 mL of hydrogen peroxide (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 atmosphere till the next day and then heated
at 60 oC under vacuum for one hour; the characteristics of the material were presented in the
Chapter 6.

7.5. Method for functionalization of graphene oxides with TEMPO
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 mixture was heated to reflux for
about 3 h, and then the solvent and excess 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
solvents. The TEMPO -functionalized samples thus obtained from GO and iGO were noted as GO –
T and iGO -T, respectively. T he characteristics of the material s were presented in the Chapter 6.

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7.6. Procedures for the oxidation of alcohols
7.6.1 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 ( benzyl alcohol, 2 -phenylethan ol and
diphenylcarbinol ), dissolved in 5 mL of DCM, was added 10% mol of the free radical as mediator
(TEMPO , DN -DPPH or NHPI – as precursor of PINO) and one of the co -oxidan ts A-D, and the
mixture was stirred at room temperature for 24h under air. As co -oxidant A was used a mixture of
20% mol sodium nitrite in 0.2 mL of acetic acid and 5 mL of water ; co-oxidant B was 20% mol of
nitrosonium tetrafluoroborate; co -oxidant C was used a mixture of 0.5 mL sodium hypochlorite
(5%) and 10 mg of potassium bromide dissolved in 5 mL of water; co -oxidant D was gaseous
nitrogen dioxide (5 mL) bubbled slowly into DCM solution. After completion of the reaction, the
solution was filtered of us ing a small cotton pad and the solvent was removed using a rotavap. The
residue was dissolved in 1 mL ofdeuterated chloroform and the NMR spectrum recorded. The
yieldsof the reactions were calculated using the integral values obtained from 1H-NMR spectra.

7.6.2 General procedure for the oxidation of alcohols by polyradicals (DI -T,
TRI-P, TE -T and TE -P)
Reactions for oxidation of the alcohols ( benzyl alco hol, 1 -phenylethanol,
diphenyl methanol, 1 -octanol and furfurol alcohol ) were done in the following cond itions: 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 the polyradical; the mixture was stirred for 24 hours and then 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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7.6.3 General procedure for the oxidation of alcohols using nitrogen dioxide or
nitrosonium tetrafluoroborate and silica -supported TEMPO
The active oxidation system ( TEMPO on silica gel – nitrogen dioxide) has been obtained
passing gaseous nitrogen dioxide (prepared by thermal decomposition of lead (II) nitrate) through
a pad of commercially available TEMPO on silica gel; the result is a dark b rown solid which
contain practically an equimolecular ratio of the oxommnium salt .
For the oxidation system made with nitrosonium tetrafluoroborate, a mixture of alcohol
substrate (usually between 0.1 -1 mmol, depending on molecular weight), silica support ed TEMPO
and nitrosonium tetrafluoroborate (exact molar ratio between alcohol -catalyst -co-catalyst are
shown in T able 27, 5-20% mol) were suspended into 5 mL DCM and magnetically stirred at room
temperature for a certain amount of time (see also Table 27) under dioxygen atmosphere (balloon).
The reactions were regularly monitored by TLC to 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 separa ted via filter ing through a small
cotton pad and washed with a small 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 , GC and NMR, and, if necessaril y, were purified by column or preparative chromatography
over silica gel using an appropriate eluent, the yield was ca lculated as isolated compound.

7.6.4 Typical procedure for oxidation of benzylic alcohols using our silica –
TEMPO materials Cat. A, Cat. B, Cat. C and Cat. D)
0.5 mmol alcohol ( benzyl alcohol, 2 -phenylethan ol and diphenylcarbinol ) was dissolved in
10 mL DCM, and under stirring were added 50 m g of the chosen catalyst and 20 % mol
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.
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.

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Measurement performed for r outes II and III have been done in the same working conditions,
using methanol as solvent (reactant as well) instead of DCM.

7.6.5 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 ( benzyl
alcohol, 1 -phenylethanol, diphenyl methanol, 1 -octanol and furfurol 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 solvent using a rotavap. The residue was dissolved in 1 mL of
deuterated chlorof orm 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 nitrogen 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.

Quantif ication of the oxidation yields
The measurements of the yields of oxidations was performed in the first instance b y
isolation of the compounds. To achieve this goal, column chromatography has been used. As one
of the major observation was that the reactions proceed in a very clean way (no over -oxidation to
carboxylic acids – checked by TLC and NMR) it became obvious th at direct GC or NMR of the
mixture can be used; h owever, an easy and fast work -up has been made, such is filtration.
As 1H-NMR became the most used method to quantify the oxidation yields, below is
shown, as an example, the superimposed spectra for the starting material benzilyc alcohol, pure
oxidation product benzaldehyde, and their mixture. Just by direct integration of th e H from

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C6H5CHO and C6H5CH2OH the yield is simple calculated ; additionally, overoxidation of the
aldehyde to the corresponding acid can be instantly spotted in 13C-NMR.

Fig. 7.1 8.1H-NMR spectra of benzyl alcohol ,benzaldehyde and their mixture

C
H2OH
C
HO
C
HO
C
H2OH

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Fig. 7.19.13C-NMR spectra of benzyl alcohol, benzaldehyde and their mixture

7.7. References
[1] Ionita, P., Caproiu, M. T., Balaban, A. T., Re. Rouma. Chimie . 2000, 45, 935 .
[2] Edwards, T. E., Okonogi, T. M., Robinson, B. H., Sigurdsson, S. T., J. Am. Chem. So c.
2001 , 123 ,1527.
[3] Caproiu, M. T., Ionita, G., Draghici , C., Ionita, P., Arkivoc. 2008, 14, 158.
[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. , ACS Nano.
2010, 4, 4806.
OH
O
OH
O+

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General conclusion
This thesis tried to emphasiz e the role of persistent free radicals as mediators in reactions of
oxidation with applications in organic chemistry. The idea started from the encounter in the
literature data of several protocols able to selective oxidize alcohols. A simple survey of the
literature showed that several groups of organic chemist s developed novel free radicals or novel
oxidant systems that gather together many advantages: simple procedure, easy work -up,
selectivity, benign (no transition metals, room temp erature, air as oxidant, etc.).
The thesis is structured into the two classical parts: literature and original data. Each part is
divided in sever al chapters, as appropriate; references follows after each chapter. The description
of the experimental procedures represent s the last chapter.
The first chapter is about free radicals. It shows a general description of what are free
radicals, h ow can be g enerated or synthesiz ed and how can be classified. It is worth to remind that
the first free radical of nitroxide type was the Fremy's salt, published in 1845, followed only after
about 50 years by the first organic nitroxide free radical; the well known TEMPO (stable nitroxide
free radical) was published after other 50 years. DPPH , as well the well known stable hydrazyl free
radical, was published in 1922. However, since 1960, the chemistry of free radicals gained wings.
After the introductory informatio n about free radicals, the following section is dedicated
and insists on their use as mediators in oxidation reactions, showing different systems that can be
applied by organic chemists. Thus, TEMPO (as representative free radical) is used as mediator in
selective oxidation of alcohols, either activated or with low reactivity. It can be considered a
catalyst in such processes, as it is used commonly in ratios between 1% to 10%.
TEMPO itself cannot oxidize alcohols, it has to be converted first to the corre sponding
oxoammonium salt, a much stronger oxidant. To achieve this, a co -oxidant is required, and in the
literature data are employed chlorine, bromine, sodium hypochlorite, nitrogen dioxide, cerium
sulphate, or transition metals, like copper, iron, manga nese and so on. The chapter shows that
immobilization of TEMPO on inert materials like silica or polymers affords a better working
system, as it is can be reused. All these details are presented in the literature data part.
The original data se ction is divided in other several chapters. In the first chapter from the
original data part TEMPO has been tested comparatively with PINO, DPPH and DN -DPPH free
radicals for the oxidation of alcohols. As DN -DPPH is not commercially available, it was

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synthesised as literature data showed, and by chance crystals were obtained and characterized for
the first time by X -ray difraction. As co -oxidant were used several systems that generates NOx or
sodium hypochlorite. For comparison of these free radicals, several methods were used. Thus, UV –
Vis and ESR spectroscopy together with cyclic voltammetry has been employed. It has been
shown that a nitroxide radical is a far better mediator in such aerobic oxidations comparati vely
with a hydrazyl one. The explanation of these results consists firstly in a different mechanism
involved in the oxidation procedures and secondly in the variation of the oxidation potentials of
nitroxides comparatively with hydrazyls.
In the second or iginal chapter we tried to see if there is any advantages in the use of
polyradicals as oxidation mediators. Polyradicals may have supplementary properties, as the spin
inter-interacts. To achieve this aim, four (poly)radicals have been synthesized: two
containing TEMPO moieties and the other two containing PROXYL moieties. These polyradicals,
named DI -T (containing two TEMPO ), TE -T (containing four TEMPO ), TRI -P (containing three
PROXYL) and TE -P (containing four PROXYL). It was found that those polyradicl s
containing TEMPO moieties are more active than PROXYL towards oxidation of several alcohols
(benzyl alcohol, 1 -phenylethanol, diphenylmethanol, 1 -octanol and furfuryl alcohol). As co –
oxidant was used a mixture of sodium nitrite and acetic acid. However, a major drawback is the
difficulty to recycle these polyradicals, as most of them are lost in the oxidation procedures. Of
course, a similar mechanism of oxidation takes place.
In the next chapter, the goal was shifted to materials functionelized with st able free
radicals, as these can be easily re -used. Thus, commercially available silica supported TEMPO has
been employed, together with NO 2 adsorbed on it or, even better, with nitrosonium
tetrafluoroborate as co -oxidant. Silica is a very good insoluble m aterial support for TEMPO , as it
is stable over a wide pH range and can be simply recovered and used repeatedly (i.e., after four
reactions the silica supported TEMPO kept its original activity). NO 2 adsorbed on silica
supported TEMPO does not require eith er an acid.
In this way, several primary and secondary alcohols ( including testosterone, furan and
pyridine derivatives) were selectively oxidized to the corresponding aldehydes and ketones. 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); furthermore, the reactions are

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very clean and the isolation of the desired compounds requires minimal work -up. The mechanism
of oxidation has been highlighted. This system represents a good alternative from a practical point
of view for selective alcohol oxidation; besides, it is first time when nitrosonium tetrafl uoroborate
is used as co -oxidant.
In the chapter five, we have synthesized our own silica -based materials containing
supported TEMPO . This, four types of silica were obtained: Cat. A has been obtained by a sol -gel
method; Cat. B was obtained by precipitating gold on Cat. A; Cat. C was obtained by reaction of 4 –
oxo-TEMPO with the group of amino on the silica surface; Cat. D was obtained by supporting gold
on Cat. C. All of them were characterized by IR, TEM, thermal analysis and EPR. Of course, th e
resulted materials have been tested as heterogeneous oxidation catalyst of three benzylic alcohols
(benzyl alcohol, 1 -phenylethanol, diphenylmethanol) to the corresponding aldehydes or ketones
under mild conditions (room temperature, air, metal and halo gen free condition), using air as final
oxidant and nitrosonium tetrafluoroborate as co -catalyst (as this was the best co -oxidant, as
previous results showed). Good to excellent yields were obtained. However, under these
conditions, supported TEMPO on sili ca nanoparticles containing gold clusters lowers the
efficiency. The presence of gold nanoparticles seems to be compulsory for oxidative coupling with
the aim of obtaining esters in a single step.
In the last chapter TEMPO has been covalently bound to grap hene oxide (this
carbonaceous material contai ns free caboxylic groups), a novel material with still unexploited
characteristics, in order to use its properties oxidation processes. Graphene oxide has been
synthesised using two methods, the Hummers method a nd the improved Hummer method. Further,
both materials were derivatized with 4 -amino -TEMPO . The characterization of all these materials
was done using scanning electron microscopy, thermal and elemental analysis, infrared, Raman
and electron spin resonanc e spectroscopy. It was found that these graphene oxide based materials
can be successfully used as easily recoverable solid catalysts for selective oxidation of alcohols
(benzyl alcohol, 1 -phenylethanol, diphenylmethanol, 1 -octanol and furfurol alcohol), u sing NOx as
co-oxidant and oxygen as final oxidant, under very mild conditions, with excellent yields
(i.e. benzyl alcohol was oxidized selectively to benzaldehyde in quantitative yield)

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The thesis ends with the presentation of all chemicals, materials an d appara tus used.
Synthetic details are showed for all organic compounds or materials employed, together with the
methods of analysis and calculus.
The original results compiled in this theses were published in five papers, showed on the
last page of the t hesis.

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List of contributions
1. Selective oxidation of alcohols w ith stable organic polyradicals. Shakir, A. J. , Ionita, G.,
Ionita, P., Rev. Roum . Chim . Accepted . 2017.
2. A comparison between nitroxide and hydrazyl free radicals in selective alcohols oxidation,
Shakir, A., Madalan, A. , Ionita, G., Lupu, S., Lete, C. , Ionita, P., Chem. Phys. 2017, 490, 7.
3. Covalently grafted TEMPO on graphene oxide: a composite material for selective
oxidations of alcohols, Shakir, A. J. , Culita, D. C ., Moreno, J. C ., Musuc, A., Carp, O.,
Ionita, G., Ionita, P., Carbon. 2016, 105, 607.
4. A convenient alternative for the selective oxidation of alcohols by silica supported TEMPO
using dioxygen as the final oxidant, Shakir, A. J., Paraschivescu, C., Matache, M., Tudose,
M., Mischie, A., Spafiu, F., Ionita, P ., Tetrahedron Lett. 2015, 56, 6878 .
5. Exploring porous nanosilica -TEMPO as heterogeneous aerobic oxidation catalyst: the
influence of supported gold clusters, Shakir, A., Florea, M., Culita, D. C., Ionita, G., Ghica,
C., Stavarache, C., Hanganu, A., Ionita, P., J. Porous Mat. 2016, 23, 247.