Ahmed Juwad Shakir – Doctoral Thesis [618462]

Ahmed Juwad Shakir – Doctoral Thesis

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Chapter 1. Free radicals
l.1. General
A free radical can be defined as any molecular species capable of independent existence that
contains an unpaired electron in an atomic orbital. It exhibits a magnetic moment . [1] Many free
radicals are h ighly reactive and unstable (usually have a very short lifetime ). For example hydroxyl
radical is a molecule that has one unpaired electron on the oxygen atom .
Free radicals have been found to play a vital role in biological processes, with applications in
biology . A large number of these are fundamental forever, for example, the intracellular executing
of microbes by phagocytic cells, such as granulocytes and macrophages. Specialists have likewise
involved free radicals in certain cell signaling procedures . [2] They are useful in industry and
medicine (such as control of blood pressure and vascular tone and play a role in the intermediary
metabolism of various biological compounds).
Many of the molecules that make up the structure of human tissue are susceptible to
hemolysis in intense light, and the b ody makes use of 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 H from
the phenolic hydroxyl group of vitamin E (see Fig. 1) produces a relatively stable radical that does
no further damage).
O
MeMeMeMe
OHRO
vitamin EROH +OMe
O
Me
MeMe

Fig. 1. Abstraction of H atom from vitamin E.

Free radicals play a pivotal role in many chemical processes and biochemistry, they are used
as catalysts or in polymerization processes and also as the reporter molecules to get dynamic,
structural, or reactivity information.

Ahmed Juwad Shakir – Doctoral Thesis

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They can behave as reductants or oxidants because they can either accept or dona te an
electron from other molecules.
R R R+e_-e_
oxidation reduction

Fig. 2. Oxidation and reduction of free radicals
The first free radical was Frémy's salt (potassium nitrosodisulfonate), discovered in 1845
by Edmond Fremy. [3]

Fig. 3. Frémy's salt
It is generally believed that such structures are unstable and therefore highly reactive, the
stability of free radicals depends on the next reasons;
– Delocalization of unpaired electron by conjugation .
– Steric shielding of unpaired electron.
Molecular nitrogen monoxide and oxygen are especially stable radicals. However, in
common radicals are radical coupling reaction, and reactive species, polymerizat ion,
oligomerization, and so forth, occur rapidly, and their control is difficult. This is one of the
principal motives why most organic chemists do no longer like radical reactions in organic
synthesis. B ut, mild and tremendous radical reactions have recently been confirmed.
Truth be told, a few sorts of stable particles containing (at least one) unpaired electrons
have been known for quite a long time, and a few more broad classes of free radicals have been
produced as of late.

NO
O3SSO3K2

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1.2. Classification of free radicals

1.2.1 Taking into consideration their stability
1.2.1.1 Unstable free radicals
1.2.1.2 Persistent free radicals
1.2.1.3 Stable free radicals
1.2.1.1 Unstable free radicals
Unstable free radicals play roles as transient intermediates in many chemical reactions see
Fig. 4 .
2HCC
RCH3

Fig. 4. . Structure unstable compounds
1.2.1.2 Persistent free radicals
It is important to notice that there are long lived free radicals, and such radicals are known
as persistent radicals (radicals that have long lifetimes and are resistant to dimerization,
disproportionation).
Free radicals
Taking into
consideration their
stability
Taking into consideration
the atom contains
unpaired of electron
Taking into
consideration the
structure
Taking into
consideration the
number of radicals
center

Ahmed Juwad Shakir – Doctoral Thesis

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The theory of persistent free radicals had rise n to prominence, with the bold announcement
in 1900 by Moses Gomberg of the formation of triphenylmethyl free radical. [4] (Fig. 5), by
abstraction of chlorine from Ph 3CCl by Ag metal.

Fig. 5 . Synthesis of triphenylmethyl radical

The o riginal suggested structure of triphenylmethyl dimer (Fig. 6 ).

Fig. 6. Dimer structure of triphenylmethyl
1.2.1 .3 Stable free radicals
The stability of persistent radicals is caused by two reasons, steric hindrance and electronic
stabilization. The stability always refers to a stability difference with respect to a reference
compound.
Increasing the number of donating group s on the atom bearing the free radical led to
increase its stability. For example α,β-bisdiphenylene -β-phenylallyl radical (Fig. 7), is indefinitely
as stable solid, even in the presence of air.

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Fig. 7. Chemical structure α,β-bisdiphenylene -β-phenylallyl free radical
Recently reported stable free radicals as shown in Fig. 8.
NNNN
ON
SN
N NN
O

Fig. 8. Some of stable free radicals
1.2.2 Taking into consideration the atom contains unpaired of electron
1.2.2.1 C- center radicals
1.2.2.2 O- center radicals See Fig. 8.
1.2.2.3 N- center radicals
Fig. 8 . Some example free radicals

O
NHO
Ph
CH3 H3CNOO
ON

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1.2.3 Taking into consideration the structure
1.2.3.1 Nitroxide such as TEMPO (2,2,6,6 -tetramethylpiperidine 1 -oxyl).
1.2.3.2 Hydrazyl like DPPH (2,2-diphenyl -1-picrylhydrazyl ), Fig. 9.
N
O
DPPH TEMPONNO2N
NO2
O2N

Fig. 9 . Structure of DPPH and TEMPO radicals
1.2.4 Taking into consideration the number of radicals center
1.2.4.1 monoradicals
1.2.4.2 diradicals see Fig. 10
1.2.4.3 polyradicals
When we think about polyradicals we take into consideration their paramagnetic properties.
However, these are not their only properties. We have to also emphasize their potential probes and
sensors in many physi cal, chemical, or biological processes, or in materials labeling (like
nanoparticles, silica, polymers, etc). [5-8]
The first perchlorotriphenylmethyl (PTM) polyradicals reported were the diradical (1) and
triradical (2) in Fig. 10, both have high -spin ground states with low -spin excited states, which are
inacce ssible even at room temperature. [9]

Ahmed Juwad Shakir – Doctoral Thesis

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Cl
Cl
Cl
ClCl
Cl
Cl
ClClClClCl
ClClClClClCl
Cl
ClCl Cl
Cl
ClCl
Cl
Cl
ClCl
Cl
ClClClClCl
ClClClClClCl
Cl
ClCl Cl
Cl
ClCl
Cl
ClClCl
ClCl
Cl
Cl
1 2
Fig. 10. Structure of PTM polyradicals

Tetraphenyl -para-xylylene (Thiel radical) was prepared by Thiel and Balhorn in 1904 as an
isolable species [10] and has been characterized by X -ray, [11] (Fig. 11).

Ph
Ph PhPh
PhPh Ph
Ph
Fig. 11. Tetraphenyl -para -xylylene radical
In 2016, Gabriela Ionita et al. [12] synthesized new polyraicals (one kind of nitroxide) see
Fig. 12.
HN
NHC
CO
O
NONO

Fig. 12. Structure of polyradical

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1.3. Synthesis of free radicals
– There are several reactions to generate free radicals, some of these reactions used peroxides
as sources of radical intermediates, such as di -t-butyl peroxide, t-butyl peroxybenzoate and
benzoyl peroxide, because the bond between oxygen -oxygen in peroxides is weak (30 kcal/mol).
[13]
OOO
OOO
C
OO
O +Half-life 10 mins at 70oCO
acetone
+2 X 2 X
CH3

Fig. 13. Formation of radicals from peroxide
– The decomposition of azo compounds is considered as anot her source of free radicals
andth energy required for the decomposition is eith er thermal or photochemical. [14 ]

NN
CNNCheat
NNC
NC
N

Fig. 14. Decomposition of AIBN (azoisobutyronitrile )
– C-M bond in organometallic compound has low bond dissociation energy (BDE) and are
easily homolyzed into radicals.
Pb
CH3CH3
H3C CH3heatPb+4 CH3

Fig. 15 . Synthesis free radicals from organometallic compound

– Electron transfer processes , for example Kolbe reaction – electrochemical oxidation

Ahmed Juwad Shakir – Doctoral Thesis

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1 e – oxidationRCO
ORCO
OR + CO2
COO
2heatCOO
2+ CO2 2 2
NBrO
O+NO
O+Br

Fig. 16 . Synthesis free radicals
– Single Electron Transfer (SET) reactions .

NN
CH3CH3
BrNH3
Na Na+NNCH3
Br
CH3
NN
+ Br CH3
CH3
s- imidazyl radical

Fig. 17 . Synthesis of free radical
– Single electron oxidants like Fe+3, Mn+3 and Cu+2 abstract one electron from the substrates
to supply carbon -centered radicals . Fig. 18 .
–
H3C CH3O O
H3C CH3OHOMn(OAc)3
AcOH H3C CH3O O
+H+

Fig. 18 . Synthesis of free radicals

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1.4. D etection of free radicals
1.4.1 ESR technique
The distinguishing characteristic of free radicals is the presence of an unpaired electron.
Species with an unpaired electron are paramagnetic, therefore they have a nonzero electronic spin.
The most useful method for detecting and characterizing unstable radical intermediates is electron
spin resonance (ESR) spectroscopy. [15,16 ]
ESR spectroscopy is a highly specific tool for detecting radical species because only
molecules with unpaired electrons give rise to ESR spectra.
ESR spectroscopy can detect the transition of an electron between the energy levels
associated with the two possible orientations of electron spin in a magnetic field. ESR spectra have
been widely used in the study of reactions to detect free radical intermediates. ESR spectroscopy
affords the quality without problems available method for detecting free radicals in reacting
systems.
Free radicals may be detected at concentrations as little as 10−8 M with a commercially
available device. Currently, the ESR technique of detecting short -lived free radicals in solution has
been evolved which include a free radical addition to a nitroso group ( for example , phenyl N -t-
butyl nitrone ). [17 -20] There are a few methods in use to diagnostic free radicals, such as: Nuclear
magnetic resonanc e, chemical labeling and indirect method s.
1.4.2 IR technique
Infrared spectroscopy is an easy and dependable approach widely utilized in each organic
and inorganic chemistry. IR methods h ave been used to detect widely compounds such as free
radicals.
It is utilized as a part of control, dynamic estimat ion, and observing applications. Infrared
spectroscopy is likewise helpful in measuring the degree of polymerization in polymer fabricate.
Infrared spectroscopy achievement the way that particles absorb frequencies that are
distinctive for their structure, a valuable method for analyzin g solid specimens without the
requirement for cutting examples utilizes ATR .

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1.5. Applications of free radicals
In fact, there are fie lds of life depend on the effectivess of the free radicals, such as organic
and inorganic chemistry, medicine, industry, scientific research and so on. The last 60 years have
made the improvement of free radical chemistry in organic synthesis. The main hold -back is the
capability of free radicals to react with themselves .
+R RR R

Fig. 19 . React of free radicals with themselves
Free radical used as initiated emulsion polymerization reactions for making elastomers, like
acrylonitrile -butadiene, butadiene rubber, and styrene -butadiene rubber. (DEHA) N,N′ –
diethylhydroxylamine and (IPHA) N-Isopropylhydroxylamin e are used shortstopping agent.
Marian Valko et al. used free radicals in human d isease. [21 ]
In 2015, Yi Li et al. used TEMPONa and (NFSI)N -fluorobenzenesulfonimide to react with v arious
alkenes. [22 ] see Fig. 20 .

NPhO2S SO2Ph
F NFAS
NaFNONa
NO
NPhO2S SO2Ph
RR-R
R-N(SO2Ph)2NO
RN(SO2Ph)2
R-

Fig. 20 . Radical alkene aminooxygenation

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Linyi Li et al. [23] development of the aminoxylation of hydrocarbons under mild
conditions by used [(Bpy)Cu(II)/TBHP] copper(II)/tert -butyl hydroperoxide catalyst system, see
Fig. 21 .
+ 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. 21 . The copper -catalyzed aminoxylation reaction with TEMPOa

While Xin Tao et al. [24] used TEMPO with B(C 6F5)3 boron Lewis acid to abstract a
hydrogen atom from different type of substrates , they had been found the TEMPO free radical able
to split dihydrogen under ambient conditions . See Fig. 22 .

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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. 22 . Reaction of the TEMPO/B(C 6F5)3 system with hydrogen sources
Numerous latest reviews show the excessive number of ongoing research on free radicals,
the discovery of free radicals became particularly of theoretical hobby and helped the foundation
for organic chemistry.
Regarding the magnetic properties of free radicals have been used in a large number of
research fields: organic synthesis, biology, medicine and so on. The present day field of radical
reactions in synthesis pr otrude. Now, radical reactions are considered in the lively synthetic
design, and energetic look into proceeds on better approaches to making and utilize radicals. As
the results of radic al–molecule reactions are again radicals, successive reaction s are a characteristic
fit. Similarly , in light of the fact that radicals can be oxidized or reduced, radical –ionic crossover
reactions can be executed.

1.6. Hydrazyl
Numerous radicals , which qualify as stable or persistent are in view of first radicals,
especial ly carbon, nitrogen, and oxygen, such as (NO, NO 2, O2) and an extensive variety of
organic radicals, for example, nitroxides, hydrazyls, phenalenyls, and numerous others .

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Some of hydrazo compounds are generally stable, the fact that hydrazobenzene and some
of its derivatives ca n endure both photolytic and thermal disproportionation with the arrangement
of the relating azo mixes and amines . [25-28]
There is an expanding benefit in antioxidants, especially in those expected to keep the
assumed harmful impacts of free radicals in the human body, one of these free radicals are 2,2-
diphenyl -1-picrylhydrazyl (DPPH) hydrazyl free radical (see Fig. 9) was discovered in the 1920s
by Goldschmidt and Renn, as a crystalline stable powder and has been used mainly as an electron
paramagnetic resonance (EPR) standard, a radical scavenger in polymer chemistry, and an
indicator for antioxidant chemistry.
DPPH has d iscovered nu merous applications due to its exceptional purple shading that
progressions at whatever point it react and high stability. [ 29-36] In 2016, DPPH·–luminol CL
method became suggested and the chemiluminescence (CL) mechanism mentioned in line with the
CL kinetic homes after collection injecting DPPH· into the DPPH· –luminol reaction combination .
[37] DPPH proved to be quite useful in a variety of investigations, such as polymerization
inhibition or radical chemistry. [38] The DPPH radical goes abou t as a scavenger for other odd –
electron species which manage the of para -substitution result at phenyl rings .
Recent work demonstrated the usefulness of DPPH and its derivatives in studying inter
phasic processes assisted by transport agents such as crown ethers (CEs) or kryptands. [39]
The species formed by these agents are supramolecular complexes and behave as
stoichiometric compounds. [40-42]
DPPH also was used f or oxidation of amino acids, [43 ] as well as catalysts for oxidation of
primary and seco ndary alcohols to the correspo nding aldehydes and ketones, [44 ] in the presence
of WO 3/Al 2O3 as a cocatalyst , under moderate conditions and the oxygen as the terminal oxidant
see Fig. 23 , they applied a wide range of substrate bearing different functional groups as
heterocycles and ester, the reaction method under neutral conditions (acid, base not required).
The approach is amenable to gram scale and not using a unique precauti ons to exclude air
or moisture, t his strategy gives a green and environmentall y benign approach for the synthesis of
aldehydes and ketones.

Ahmed Juwad Shakir – Doctoral Thesis

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O
10h, 83%OOCH3CHO
OCH3CHOCHO
OCH3 O
SCHO
CHO3h, 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.

Fig. 23 . Oxidation of alcohols by DPPH radical in the presence of WO 3
1.7. Nitroxide
1.7.1 General
Nitroxides are N,N -disubstituted NO radicals with an unpaired electron delocalized between
the nitrogen and the oxygen atom. Nitroxide free radical s have two resonance structures (1 , 2 in
Fig. 24), due to the delocalization of the electron. Spin density is distributed between both atoms,
often with a slightly higher density at the oxygen atom. [45]

N N
O O_
1 2

Fig. 24. Resonance structures of nitroxide radicals

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The overall thermodynamic stability of different nitroxide radicals is influenced by the
substituents on the carbons attached to the nitrogen. Thus, for example, if all four groups attached
to the carbons attached to the nitroxide nitrogen are alkyl, the nitroxide is stable. Replacing one of
the alkyl groups with hydrogen or attaching a phenyl group directly to nitrogen renders the
nitroxide relatively unstable. [46] The stability of nitroxide radicals makes it possible to carry out
reactions selectively on functional groups not involving the unpaired electron.
In 1911, Wieland and Offenbacher [47] studied dia ryl nitroxides (prepare by reaction
between n -nitroso -diphenylamine with phenylmagnesium bromide) see Fig. 25.

NO
Aryl Aryl

Fig. 25. Structure of diaryl
1.7.2 Synthesis of nitroxide and properties
The synthesis of nitroxides R 1N(•O)R 2 is carried out through different synthetic routes that
depend on the nature of the targeted R 1 and R 2 groups, for example by oxidation of amines using
dimethyldioxirane [48] oxone, [49] and hydrogen peroxide . [50] Hydroxylamines can be easily
oxidized to nitroxides, [51], see Fig. 26.
NHOH
EtEtO O
EtEt
NH4OAcNN
EtEt
EtEt
HOMnO2
CHCl3NN
EtEt
EtEt
O

Fig. 26. Synthesis of a nitroxide radical
Nitroxide can prepare by react of nitrones with organometallic compounds to prepare the
corresponding metalated hydroxylamines , which can oxidize to nitroxides , [52] see Fig. 27.
N
R1O
R2
R31) R4 Metal
2) OxidationN
R1O
R2
R3R4

Fig. 27. Synthesis of nitroxide radicale

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Different methods, except these most usually used approaches, were suggested for the
synthesis of nitroxides, by the reaction between tertiary nitroalkanes and sodium metal to give the
corresponding di -tert-alkyl nitroxides . [53]
Furthermore, the reaction of nitroalkanes with Grignard reagents and organolithium
compounds can also result in nitroxides , [54] ultimately, nitroxides can be prepared by the reaction
between C -centered radicals with nitrous and nitrogen derivatives. [55]
The development of nitroxide chemistry came from Wieland et al. [56] Fig. 28 (a), and
Meyer et al. [53] Fig. 28 (b), who prepared diarylnitroxides.

MgBr+N
ON
OMgBrN
O1)H3O+
2)Ag2O
a

N
HOMe MeO
PhCO3HOMe MeO
N
Ob

Fig. 28 . Synthesis of diarylnitroxides by Wieland et al (a) by Meyer et al (b)

Tamura et al. [58 ] developed a new synthesis of α-asymmetric bicyclic nitroxide radicals,
by the reduction with samarium diiodide (SmI 2) of homoallylic nitroenones and the subsequent
addition of electrophiles, Fig. 29 .
O
NO21) SmI2 – 50 C
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. 29. Preparation of chiral nitroxides

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The first organic nitroxide was porphyrexide prepared and named by Piloty and Schwerin
in 1901. [59] and 2,2,6,6 -tetramethyl -4-piperidone -1-oxyl (4-oxo-TEMPO) (Fig. 30 ) was prepared
by Lebedev et al. [60] in 1959 .
NNH
NHHN
ONO
O1 2

Fig. 30. Structure of 4-oxo-TEMPO (1) and porphyrexide (2)

The first stable di -tert-alkyl nitroxide of piperidine type (TEMPO) [61] was syn thesized
fifty years ago. Nitroxide radicals may interact with 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. [62]
Many nitroxide polyradicals were prepared, and have been used in different applications as
Fig. 31 shows different type polynitroxides .
RO OR
OR RONONO
N
ON
ONONO
a [65-67]b [68]
N NO ONO
N
ON N
NOMe
MeO OMeO
O
O
c [69]d [63]e NN
OO
f [63]

Fig. 31. Some structure of nitroxide polyradicals

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Organic di – and polyradicals are especially relevant sensors to study weak
interatomic/intermolecular interactions in large systems. Their spectroscopic and magnetic
properties [70-72] depend on the electron spin –spin exchange coupling between unpaired electrons
localized on different centers. Some of di, tri, and tetra -radicals are shown in Fig. 32.
S
SH
N
N
HO
ON
NN
NNO2
NO2
1H
N
H
NH
N
O OO N
NO
O
O
SO2O2S
HNNH
NN
OO3
NNHH
N
NHOO
ONNN
OOO4NO2NO2SSNH
NH
N
OO
ONO
HNO
ONHNO
NON
O
5O2
SO2
SH
N NH
N NO O
6
2

Fig. 32. Structure of some nitroxide polyradicals [73]

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Synthesis of some polyradicals
The polyradical (1 from Fig. 33) was prepare d by dissolv ing in DCM 1 mmol of
dibenzofuran -2,8-disulfonyl chloride than added 2.2 mmol of 4 -amino tempo and 5 mL of
pyridine, the mixture was left to stand until the following day and washed with aqueous
hydrochloric acid (1 N), aqueous sodium hydroxide (1 N), water, and dried over anhydrous sodium
sulphate. After that , the solvent was remove d under vacuum (at no more than 40o C).
The polyradical (2 from Fig. 33) was prepare d by dissolv ing in DCM 1 mmol of N –
(triaminoethyl)amine, add ing 4 mmol of 4 -carboxyproxyl free radical and 5 mmol of EEDQ,
This mixture was left to stand for 5 days, then washed with aque ous sodium hydroxide (1 N),
aqueous hydrochloric acid (1 N), water, and dried over anhydrous sodium sulphate, the solvent
was removed under vacuum (at no more than 40o C).
The polyradical (3 from Fig. 33) was prepare d by dissolv ing in DCM 1 mmol cystamine ,
adding 2.2 mmol DCC, 2.2 mmol 4 -(N,N -diphenylhydrazine) -3,5dinitrobenzoic acid, the mixture
was left to stand for 3 days. It was then w ashed with aqueous sodium hydroxide (1 N), aqueous
hydrochloric acid (1 N), water, and dried over anhydrous sodium sulp hate. The solvent was
removed under vacuum (at no more than 40 °C).
The polyradical (4 from Fig. 33) was prepare d by dissolv ing in DCM 1 mmol of benzene –
1,3,5 -tricarbonyl chloride, add ing 5 mL of pyridine, 3.3 mmol of 4 -aminotempo, the mixture was
left to stand for 1 day, washed with aqueous sodium hydroxide (1 N), aqueous hydrochloric acid (1
N), water, and dried over anhydrous sodium sulphate. The solvent was removed under vacuum (at
no more than 40 °C).
The polyradical (5 from Fig. 3) was prep ared by oxidation of 2 -mercaptosuccinic acid
resulting in the formation of the corresponding disulphide.
The polyradial (6 from Fig. 33) was prepare d by dissolv ing in DCM 1 mmol of biphenyl –
4,4’-disulfonyl chloride, add ing 2.2 mmol of 4 -aminotempo and 5 mL of pyridine, and the mixture
mixture was left to stand 1 day, washed with aqueous sodium hydroxide (1 N), with aqueous
hydrochloric acid (1 N), water, and dried over anhydrous sodium sulphate, Removal of the solvent
was carried out under vacuum (at no mo re than 40 °C).
Most organic radicals have been chemically anchored on the surfaces of metals , for
example the diradical PTMSS Fig. 33, synthesized by a disulfide binding group to be anchored on
gold. [74,75 ]

Ahmed Juwad Shakir – Doctoral Thesis

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SSCl
Cl
Cl ClCl
ClCl
Cl
ClCl Cl
Cl Cl
ClClClClCl
Cl Cl
ClCl
ClClCl
ClCl
ClPTMSS
Fig. 33. Structure of PTMSS

X-ray diffraction studies of some representative cyclic nitroxides, (five -, six- and seven –
membered rings). Showed the values of geometrical parameters for nitroxide radicals (see Fig. 34
and Table 1 ).
NO NO
ON
N
O

Fig. 34. Structure of nitroxide radicals

Table 1. Geometrical parameters of cyclic nitroxides

NO(A)
CNC Α
5-membered ring [76-80] 1.27 112-117 0-5
6-membered ring [81-86] 1.27-1.31 123-126 15-20
7-membered ring [87] 1.29 130 21

Nitroxides have often been used for the oxidation of primary and secondary alcohols as
well as sulfides to the corresponding aldehydes and ketone s, and sulfoxides respectively, nitroxide
free radicals have more applications in many important fields of chemical and biological research .

Ahmed Juwad Shakir – Doctoral Thesis

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TEMPO (Fig. 9) is a commercial product, a stable free radical discovered by Lebedev and
Kazarnowskii in 1960. [88] TEMPO is a stable radical due to the steric influence of the methyl
groups. It is prepared by oxidation of the corresponding tetramethylpiperidine or
tetramethylpiperidine hydroxide , it is able to abstract hydrogen atoms only from weak hydroge n
bonds, including thiols, phenols, allylic positions, and metal hydrides. [89] Nitroxides are redox
radicals like TEMPO and they can be reduced to the corresponding hydroxylamines and in some
cases the reaction is irreversible, Fig. 35.
N
O
N
OHN
O++ H++ 1e-
– 2 e– 1e-TEMPO
Hydroxylamine
TEMPOHTEMPO salt

Fig. 35. Reversible redox properties of nitroxides (TEMPO)

TEMPO is a weaker oxidant than N-oxoammonium salt , show in Fig. 36.

N
O

Fig. 36. The oxoammonium salt of TEMPO
TEMPO can react with an organometallic compound to form carbon – centered radicals, it
require s two equivalents from TEMPO, one for oxidation of organometallic to the corresponding
carbon -centered radical and anothe r to provide the alkoxyamine. For example, TEMPO reacts with

Ahmed Juwad Shakir – Doctoral Thesis

23
organoboron species. Fig. 38, show s that the B-alkylcatecholboranes react s with TEMPO , which
leads to the formation of boric acid ester ( 1 in Fig. 37 ). [86] This reacti on perhaps takes place by
radical intermediate ( 2 in Fig. 37 ). [91]

OBO
R
OBO
O
NTEMPO
R
OBOO
RNTEMPO
N
OR
12

Fig. 37. Reaction of B -alkylcatecholboranes with TEMPO

N- hydroxyphthalimide (PINO Fig. 38 ) is a free radical formed from NHPI ( N-
hydroxyphthalimide), it can be generated by treating NHPI with the inorganic oxidant Pb(OAc) 4
[92], and can also be formed by an electrochemical oxidation of NHPI.
NO
OO

Fig. 38 . Structure of PINO

1.7.3 Application of nitroxide free radicals in organic chemistry
1.7.3.1 Nitroxide free radicals as mediators in selective oxidation reaction of organic substrates
In 1965, Golubev, Rozantsev, and Neiman reported [93] that treatment of oxoammonium
salt (A in Fig. 39 ) with excess of ethanol led to the formation of acetaldehyde. In 1975, Cella et al.
demonstrated [94] that alcohols can be oxidized to carboxylic acids by treatment with m-
chloroper benzoic acid in the presence of a catalytic amount of 2,2,6,6 -tetramethylpiperidine (B in
Fig. 40 ).

Ahmed Juwad Shakir – Doctoral Thesis

24

Fig. 39. Oxidation of ethanol

Fig. 40. Oxidation of alcohol
The conversion of a primary alcohol to a carboxylic acid can occur in the presence of
protected phenols, protected and heteroaromatic nitrogens, and alkynes, [95] see Fig. 41.

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. 41. Oxidation of alcohol to carboxylic acid
In 1987, Anelli published a landmark paper [96] on TEMPO -mediated oxidations, which
signaled the beginning of the routine employment of catalytic oxoammonium salts in the oxidation

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25
of alcohols. In this paper, a protocol was established, whereby alcohols can be oxidized to
aldehydes and ketones in a bip hasic DCM – water medium, 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 PhMe -EtOAc mixtures. [99] Under these conditions, primary alcohols
are transformed in 3 min at 80o C into the corresponding aldehydes, while secondary alcohols are
transformed into ketones in 7–10 min, as shown in Fig. 42 .
OH O1 % mol 4-MeO-TEMPO, 1.25 eq. NaOCl
0.1 eq. KBr, NaHCO3, CH2Cl2, H2O, 0 oC

Fig. 42. 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 bas e-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 [95] 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 at 6.5 –7.5
by adding an acid. [100] TEMPO -mediated processes [101] are used for selective conversions of
sulfides into the corresponding sulf oxides, see Fig. 43. [102]

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. 43. Oxidation of sulfides to sulfoxides

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PINO is reactive as a hydrogen abstractor and can abstract inactivated hydrogen atoms
under ambient conditions, Fig. 44.
NO
OOHinitiation
NO
OO NO
OOH
NHPIC
HR3 R1R2
CR3 R1R2
C
OOR3 R1R2
C
OOHR3 R1R2KH

Fig. 44. Catalytic role of PINO in the selective oxidation of organic substrates
The first who observed the activation of PINO was Ishii et al. in 1997. [103] The reaction
took place by reacting adamantine in a mixed solvent of acetic acid and benzonitrile under an
atmosphere of NO and in the presence of catalytic amounts of NHPI. This lead to the formation of
1-N-adamantylbenzamide as a principal product (Fig. 45).

PhCNNOPINO NHPINO
NCPh
H2O
NCPh
OH2-H+ NCPh
OH HNCPh
O

Fig. 45. NHPI -catalyzed reaction of adamantane under NO atmosphere
PINO is used for selective oxidation of cellulose fibers promoted according to the proposed
mechanism (Fig. 46) by the NaClO/NaBr system. [104]

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NO
OOH
NHPIAQ
NO
OO NO
OO
O
HOOH
OHOO
HOO
OHOO
HOCOOH
OHOAQ
Fig. 46. NHPI/AQ -mediated oxidation of cellulose fibers by the NaClO/NaBr system
Nitroxide radical PINO is also used in aerobic oxidation, when us ing NHPI -catalyzed in
the presence of Co(OAc) 2 in acetic acid for the aerobic oxidation of various alkylbenzenes , Fig. 47 .
[105]
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. 47 . Aerobic oxidation of various alkylbenzenes at room temperaturea

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Using NHPI (10 mol), Co(OAc) 2 (0.5 mol %) in CH 3CN at 70 0 C for 20 h leads to the
oxidation of 2 -octanol with molecular oxygen . These result s are shown in Table 2 .

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 %)

The first reported use of a copper/nitroxide radical was in 1966, when Brackman and
Gaasbeek showed the use of di-tert-butylnitroxide for the oxidation of methanol with
phenanthroline/copper(II) complexes in basic methanol solutions. [106]
Copper/TEMPO employed lactonization of polyols in the synthesis of more complex
molecules. Nonappa and Maitra prepared the steroidal lactone by usi ng Cu/TEMPO TEMPO –
catalyzed in the presence of several unprotected secondary alcohols, [107] Fig. 48.

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

Fig. 48. Cu/TEMPO -catalyzed aerobic lactonization reactions

The oxidation of secondary amines that contain no α hydrogen atoms, such as 2,2,6,6 –
tetramethylpiperidine, leads to the formation of nitroxides, stable free radical compounds such as
the prototypical 2,2,6,6 – tetramethylpiperidine -1-oxyl (TEMPO).
TEMPO is stable organic radical, which exhibits high efficiency, low toxicity, can be easily
recycled after use in liquid phase oxidation reactions and can also be stored for long periods of
time without decomposition.

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The selective oxidation of alcohols is an important reaction in organic chemistry. TEMPO
has been used in catalytic oxidation reactions of pri mary and secondary alcohols. [108 ]
From the history of the development of aerobic oxidation of alcohols, the first catalytic aerobic
oxidatio n of alcohols using TEMPO with CuCl in DMF was in 1984, di scovered by Semmelhack
et al.[109 ]
In 2014 Yoshiharu I. et al. [110] used AZADO type nitroxide (see Fig. 49) as catalysts for
the aerobic oxidation of alcohols.
NR2
R1
ONX
O
R1 = R2 = H AZADO (1)
R1 = F, R2 = H 5-F-AZADO (2)
R1 = R2 = F 5,7-diF-AZADO (3)
R1 = OMe, R2 = H 5-MeO- AZADO (4)
R1 = R2 = OMe 5,7-diMeO-AZADO (5)X = O oxa-AZADO (6)
X =Ts-N TsN-AZADO (7)
X = O-N diAZADO (8)

Fig. 49. Structures of AZADO derivatives

Fig. 50, shows the comparison of the temporal profiles of 5 -F-AZADO (2 in Fig. 49 ),
AZADO (1 in Fig. 49 ), 5,7 -diF-AZADO (3 in Fig. 49 ) and TEMPO as reference [111] by using 1 –
menthol as the substrate under reaction condition (NaNO 2, 10 mol %, nitroxy radical 1 mol % and
AcOH solvent under air balloon). [112]

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

Fig. 50. Oxidation of 1 -menthol

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Fig. 51. Temporal profiles of AZADO (1), 5 -F-AZADO (2), 5,7 – diF-AZADO (3), and TEMPO,
substrate, l -menthol [110]
Under the same reaction conditions, the temporal profiles of 5 -MeO -AZADO (4 in Fig. 49)
and 5,7 -diMeO -AZADO (5 in Fig. 49 ) [110] were also investigated. In Fig. 52, 5-MeO -AZADO
can complete the reaction within 10 h without any marked slowdown, meaning that the inductive
effect of the heteroatoms plays an important role in preventing a marked slowdown of the reaction.

Fig. 52. Temporal profiles of AZADO (1 in Fig. 49 ), 5-MeO -AZADO (4 in Fig. 49 ), and
5,7-diMeO -AZADO (5 in Fig. 49 ) [110]

Yoshiharu I. et al. also synthesized three new catalysts, [109] (Fig. 53).

NO
ONTsN
ONN
OO
Oxa-AZADO (6) TsN-AZADO (7) diAZADO (8)

Fig. 53. Structures of AZADO derivatives

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Oxa-AZADO (6 in Fig. 53) was prepared in five steps , as show n in Fig. 54. [114]

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. 54. Synthesis of oxa -AZADO (6 in Fig. 53)

TsN-AZADO (7 in Fig. 53) and diAZADO (8 in Fig. 53) were synthesized using modified
Hofmann−L ffler−Freytag reaction conditions, see Fig 55.

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. 55. Syntheses of TsN -AZADO (7 in Fig. 53) and diAZADO (8 in Fig. 53)

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For diAZADO (8 in Fig. 53), there is a more efficient procedure for the synthesis, shown in
Fig. 56.
NTsTsN1. red Al
toluene, reflux, 18 h
2. UHP, Na2WO4.2H2O
MeCN, 3 h
44% for 2 stepsNN
OO

Fig. 56. More efficient procedure for the synthesis of diAZADO (8 in Fig. 53)

The temporal profiles of oxa -AZADO (6 in Fig. 53), TsN -AZADO (7 in Fig. 53) and
diAZADO (8 in Fig. 53) are shown in Fig. 57, and these catalysts have a wide range of substrate
applicability (Table 3 ).

Fig. 57. Temporal profiles of oxa -AZADO (6 in Fig. 53), TsN -AZADO (7 in Fig. 53), and
diAZADO (8 in Fig. 53) for the oxidation of l -menthol [110]

Ahmed Juwad Shakir – Doctoral Thesis

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Table 3 . Scope of oxa -AZADO (6 in Fig. 53), TsN -AZADO (7 in Fig. 53) and diAZADO (8 in Fig.
53) for oxidation alcoholsa

Entry Alcohols Catalyst (2) Catalyst (6) Catalyst (7) Catalyst (8)
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 radical (3 mol),
cAcOH (0.4 M), dnitroxyl radical (5 mol%), eAcOH (2 equiv), MeCN (1 M)

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The synthesis of 5 -MeO -AZADO (4 in Fig. 49) and 5,7 -diMeO -AZADO (5 in Fig . 49),
[115] is shown in Fig. 58.

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. 58 . Synthesis of 5 -MeO -AZADO (4) and 5,7 -diMeO -AZADO (5)
Many oxidation methods toward s alcohols have been reported in literature using at least a
stoichiometric amount of oxidants such as DMSO, MnO 2, chromium oxides also hypervalent
iodine compounds .
Jinxian Liu and Shengming Ma [116] tried the aerobic oxidation of 1-phenyl -butyl -3-yl-1-
ol (Fig. 59 ). A worker reported that using TEMPO as a catalyst for oxidant one type of alcohol . By
using only 10 mol %from TEMPO, Fe(NO 3)3.9H 2O and NaCl under atmospheric pressure of
molecular oxygen to form corresponding homopropargylic ketone at room temperature.

Ahmed Juwad Shakir – Doctoral Thesis

35

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

Fig. 59. Oxidation of a propargyl alcohol

For an optimiz ation of the reaction based on the solvent effect, see Table 4 .
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)23H 2O was used instead of Fe(NO 3)39H 2O
Table 4 shows that by using DCE as a solvent, a large number of conversions and the
highest result (Table 4 , entry 1) are achieved, but by using 5 mol % from (TEMPO,
Fe(NO 3)3.9H 2O and NaCl ) only 76% was observ ed (Table 4 , entry 5).
When using Cu(NO 3)2 3H2O instead of Fe(NO 3)3.9H 2O, the result was lower (Table 4 ,
entry 6). The results when using the same condition reaction for aerobic oxidation of the
homopropargylic alcohols are shown in Fig. 60.
The selective oxidation of alcohols to the corresponding carbonyl compounds is among the
most important functional group transformations in organic synthesis on laboratories as well as on
an industrial scale. [117]

Entry Time (h) Solvent Result
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%asubstrate (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. 60. Aerobic oxidation of the homopropargylic alcohola
Using heterogeneous or homogeneous activation with transition -metal -based catalysis such
as Pd, V, W, Mo, Ru, Ag, Co and Au, leads to the development of oxidation methodologies in a
container containing molecular oxygen. This method is nevertheless costly and has a highly
undesirable environmental impact and toxicity. [118] TEMPO is an availability easy -to-handle
persistent catalyst, with high efficiency, low toxicity and good stability. Rok Pr ebil, Gaj Stavber

Ahmed Juwad Shakir – Doctoral Thesis

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and Stojan Stavber [119] 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 conditions, Fig. 62.

OH Oair, NH4NO2(cat.), TEMPO, acid
MeCN, Time

Fig. 62. Novel oxidation system
This kind of catalyst system is inexpensive , uses air as the terminal oxidant, yields the
highest result and exhibits selectivity. The use of TEMPO / nitrate salt / HClO 4 in acetonitrile for
aerobic oxidation of benzyl alcohol is shown in Fig. 63 and Table 5 .

OH Oair, MnO3(cat.), TEMPO, acid
MeCN, Time

Fig. 63. Novel oxidation system
Table 5 . Oxidation of benzyl alcohola
Entry Nitrate cat. Acid mole % T (C) Time (h) Result %
1 Fe(NO 3)2 HClO 4 20 20 5 81
2 Cu(NO 3)2 – 20 6 86
3 Cu(NO 3)2 – 60 7 100
4 NaNO 3 – 60 6 0
5 NaNO 3 HClO 4 10 20 8 4
6 NaNO 3 HClO 4 10 60 5 100
aalcohol (1 mmol), TEMPO (0.05 mmol), nitrate salt (0.1 mmol), HClO 4 (0–0.2 mmol), MeCN
(2 mL), 20 –60 oC, 5–6 h under air balloon (1 L)

Ahmed Juwad Shakir – Doctoral Thesis

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Table 6 shows the role of acid in the oxidation reaction (Fig. 63). With a pk a value, weaker
acid gave even negative results .

Table 6 . 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 mmol), NH 4NO 3 (10 mol -%), TEMPO (5 mol -%), acid (a q., 10 mol -%), MeCN (2 mL), 60 oC,4
h, air balloon

The authors , [119] used the air/TEMPO/NH 4NO 3/HCl catalytic system (Fig. 64) in
acetonitrile for the oxidation of substituted primary and secondary benzyl alcohols. The results are
shown in Table 7, and Fig. 65 , shows the results of the aerobic oxidation of aromatic alcohols.

ArOH
R1
RArO
R1
Rair, NH4NO3, TEMPO, HCl
MeCN, 60 oC

Fig. 64. Oxidation of substituted primary and secondary benzyl alcohol

Table 7 . 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 H Me 6 95
9 4-MeO Me 5 89
10 4-Me Me 6 80
11 4-F Me 6 96
a Alcohol (1 mmol), NH 4NO 3 (5–25 mol -%), TEMPO (2.5 – 12.5 mol -%), HCl (aq. 37% , 5 –12.5 mol – %),
MeCN (2 mL), 60 oC, 5–7 h, air balloon (1 L)

Ahmed Juwad Shakir – Doctoral Thesis

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OOO O
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 balloon 7h, 90%9h, 92%6h, 92%6h, 90%9h, 82%

Fig. 65 . 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. 66 , where 5 mol -% NH 4NO 3 and 5 mol -% HCl (aq. 37%) were
used for 24 h at a moderate temperature.

Fig. 66. Efficiency of nitroxide radicals [119]

Luke Rogan, N. et al. [120] used a Cu(I)/9 -azabicyclo[3.3.1]nonan -3-one N -oxyl
(ketoABNO) as the aerobic catalytic system for the oxidation of alcohols.
The catalyst system consist s of TEMPO, N -methylimidazole (NMI) and Cu(I) salt
combined with 2,2 ′-bipyridine (bpy) as a ligand, is highly effective for the oxidation of secondary
alcohols, contain s unactivated aliphatic substrates, it can oxid ize a variety of alcohols possessing
heteroatoms, alkynes, alkenes. The drawback of this system is that it is not suitable for the
oxidation of secondary alcohols due to steric hindrance. The authors have repla ced TEMPO with a
radical that is less sterically hindered . Fig. 67 show s the structures of several nitroxide radicals,
and using one type of nitroxide radical , ketoABNO , should remove th is limitation.

Ahmed Juwad Shakir – Doctoral Thesis

40

N
ON
ON
ON
ON
ON
OO
TEMPO AZADO 1-Me-AZADO Nor-AZADO ABNO ketoABNO
Fig. 67 . Structures of several nitroxide radicals
Fig. 69 shows the reactivity of TEMPO, 4 -oxoTEMPO and ketoABNO for three sample
substrates (1 -phenylethanol, 2 -octanol and isoborneol), in this reaction the conditions used were
1% mol of radical, 10.5% N -methylim idazole and 7.5% CuI and 2,2 ′-bipyridine, but when
TEMPO was used in the reaction, the radical and copp er complex decreased by 5 mol%.

OH
Fig. 68. Secondary alcohols used as sample substrates

Fig. 69. Comparison of TEMPO, ketoABNO and 4 -oxoTEMPO for the
oxidation of secondary alcohols, reaction conditions: nitroxyl radical (1 mol%) (5 mL), 1 mmol of
substrate in acetonitrile, CuI (7.5 mol%),bpy (7.5 mol%), NMI (10.5 mol%), at room temperature,
ambient air [120]

For a comparison of the three different catalysts (ketoABNO, TEMPO, 4 -oxoTEMPO) see
Fig. 69. The radicals 4 -oxo-TEMPO and TEMPO cannot oxidase two secondary alcohols 2 –

Ahmed Juwad Shakir – Doctoral Thesis

41
octanol and isoborneol, but oxidase only 1 -phenylethanol. KetoABNO can oxidase all three
alcohols (isoborneol, 2 -octanol, 1 -phenylethanol) under the same reaction conditions.
When comparing the four nitroxide radicals 4 -oxoTEMPO, TEMPO, 4 -methoxyTEMPO,
against ketoABNO and Cu(I)/9 -azabicyclo[3.3.1]nonane N -oxyl(ABNO) (study by Steves and
Stahl), [121] the same result was o btained.
When comparing oxidation of cyclohexanemethanol by using unhindered radicals with the
same compounds in the condition reaction it resulted in a 5 mol% decrease from radical and Cu
complex. This established that all unhindered radicals have the same reactiv ity under these
conditions. Nitroxide radicals are mostly used for the oxidation reaction of alcohols in organic
chemistry. [122]
For this purpose TEMPO is used as a catalyst with stoichiometric oxidants like bleach,
AZADO (catalysis based on azaadamanta ne), tert-butyl hypochlorite, BAIB
(bis(acetoxy)iodobenzene) and ABNO (zabicyclo[3.3.1]nonane), [123] see Fig. 49 .
Martin Holan and Ullrich Jahn [124] reported that by 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.

Benzyl alcohol Fig. 70 and Table 8

Fig. 70. Oxidation of benzylic alcohol using TEMPO as catalyst
Table 8 . 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 1.5 5 97
5 DCM Reflux 5 1 82
aalcohol (2 mmol), BF 3·OEt 2 (1.35 times the amount of TEMPO), solvent (10 mol), TBN (4 mmol)

Ahmed Juwad Shakir – Doctoral Thesis

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Several transition -metal -free aerobic oxidation processes have used the same versions of
the supported catalysts, [125] TEMPO/nitrite -based systems [126] and TEMPO/Br 2/NaNO 2 [127]
Aromatic and allylic alcohols Fig. 71.
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.71. Oxidation aromatic and allylic alcoholsa

Oxidation of dodecan -1-ol (Fig. 72) and Table 9.

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

Fig. 72. Oxidation of dodecan -1-ol

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Table 9. Oxidation of dodecan -1-oa
Entry BF 4− source (mol %) Time TEMPO (mol %) Yield %
1 BF3·OEt 2 (6.75) 3 5 50
2 BF3·OEt 2 (6.75) 5.5 5 + 5 98
3 BF3·OEt 2 (5) 5 5 + 5 92
4 BF3·OEt 2 (5) 5 5 88
5 LiBF 4 (5) 5 5 92
aDCM (5 ml), TBN (3 mmol), alcohol (1 mmol)

Oxidation of aliphatic alcohols (Fig. 73).
R1R2OHTEMPO(5+5mol)
BF3OEt2(5mol%)
t-BuONO (3 equiv)
DCM, refluxO
R1R2
O
10Ph OPh OO
3O
5TESO
OO
OO TBDPSO
NO
BocPh O
NHBocPh O
BocNNO5.5h, 83% 9h, 87%b9h, 88%b7h, 69% 8h, 73%c
3h, 99% 9h, 75%14h, 95%d9h, 98%
12h, 40% 12h, 27%24h, 47%
a1-4,5-12 (2 mmol), DCM (10 mL), BF3·OEt2 (5mol %), TBN (6 mmol),
TEMPO (5 + 5 mol %), reflux. bTBN (8 mmol) used. cDCM (5 mL), LiBF4
(5 mol %), TBN (3 mmol), TEMPO (5 + 5 mol %), 5 (1 mmol), reflux.
dAZADO (5 +5 mol %) used instead of TEMP

Fig.73 . Oxidation of aliphatic alcoholsa

Organic solvents or ionic liquids are typically used as the solvent in a combination of
TEMPO and several mediators for the aerobic oxidation of alcohols, [128] for example using
acetonitrile as solvent, with TEMPO and Cu(II) –triethanolamine complexes for aerobic oxidation
of primary alcohols to the corresponding aldehydes. [129]

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Employing water as the solvent is more favorable. [130] Several catalytic systems have
been shown to be useful in employing water.
Y. Yan et al. [131] used the TEMPO –Ce(IV)–NaNO 2 system for the aerobic oxidations of
different alcohols in water, Fig. 74.

OH TEMPO, CAN, NaNO2
O2, H2OCHO

Fig. 74. The oxidation of benzyl alcohol with TEMPO -containi ng catalytic systems

The conversion of benzyl alcohol into corresponding aldehydes by using different cataly tic
systems is shown in Table 10 .

Table 10 . Oxidation of benzyl alcohol with different catalytic systemsa.

Entry TEMPO CAN 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 11 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 11 . 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

Organic nanoparticles are of interest in the material and life sciences. There are more
applications of nanoparticles in biotechnology and clinical research, and they are also recognized
as supports for catalys ts. [132] One example are carbon -cobalt nanoparticales, which exhibit
excellent magnetic properties with increased stability. [133]
Oliver R. et al. [134] reported the simple and efficient covalent functionalization of
TEMPO using a copper catalyst [135] azide/alkyne cycloaddition [136] as a selection method for
the oxidation of alcohols, Fig. 75 illustrates the grafting of diazonium salts onto carbon coated
cobalt particles. [137]

Ahmed Juwad Shakir – Doctoral Thesis

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CoCo CoNaNO2/HCl
rt, H2O, 15 min.
H2NOH*OH
n
12rt, toluene
24 hHN3
PPh3
DEAD
*N3
n
3
Fig. 75. Grafting of diazonium salt
After formation, the (azidomethyl) phenyl derivative (3 in Fig. 76) reacts with the alkyne (4
in Fig. 75 ), resulting in a para -nitroohenolester [138] and propargyl ether TEMPO (6 in Fig. 76 ).
CoCo
Co*N3
n
320 mol% CuI
rt, dioxane, 36 h
NO2O
O
4N
NN
OO
O2N5
Co*N3
n
320 mol% CuI, NEt3
rt, toluene, 36 h
N
OON NN
O
N
O67

Fig. 76 . Copper(I) -catalyzed of azidomethyl benzene functionalized nanoparticles (3) with 1 –
(nitrophenyl) -2-propyn -1-one (4) and propargyl ether TEMPO (6)
The compound (7 in Fig. 76 ) is heterogeneous CoNP -TEMPO which exhibits high
efficiency for oxidation of benzy lic and aliphatic alcohols. Table 12 shows the results of oxidation
of different alcohols to aldehydes by using CoNP -TEMPO mediated oxidation.

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Table 12 . Oxidation of alcohols by CoNP -TEMPO mediated oxidationa
Entry Alcohols Yields %
1 4-methylbenzyl alcohol 89
2 4-bromobenzyl alcohol 92
3 4-methoxybenzyl alcohol 96
4 Benzyl alcohol 85
5 2-phenylethanol 77
6b 1-octanol 87
7b 1-dodecanol 92
8c Cyclohexanol 96
aalcohol (3mmol), DCM (6 mL), KBr (1 mmol), CoNP -TEMP O (2.5 mol%), NaOCl (3.8 mmol), NaHCO 3
(0.6 mmol), 8 oC, 60 min. d5 mol% CoNP -TEMPO. c5 mol% CoNP -TEMPO, 2.7 mmol NaOCl, 3 h

Babak K. and Elham F. [139] prepared a new catalyst (Fig. 77) used for the aerobic
oxidation of a wide range of alcohols. This catalyst is TEMPO which is anchored onto silica –
coated Fe 2O3 nanoparticales.
Fe3O4SiO2O
O
OSi N
HNO
a

Fig. 77. Structure of nanoparticles with TEMPO

Catalyst (a in Fig. 77 ) was prepared by the reaction of silica -coated Fe 3O4 nanoparticles
with a suitable concentration of (3 -aminopropyl) triethoxysilane to form amino -functionalized
silica -coated nanomagnets (Fe 3O4-SiO 2PrNH 2) which underwent reductive amination with 1 –
hydroxy -4-oxo-2,2,6,6, -tetramethylpiperidine in the presence of NaBH 3CN to form magnetic
nanoparticale -supported TEMPO ( a in Fig. 77 ) see Fig. 78.
Fe3O4SiO2 O
O
OSi N
HNO
aFe3O4 Fe3O4SiO2
Fe3O4SiO2O
O
OSi
H2N

Fig 78. General synthesis of magnetic nanoparticle -supported TEMPO a

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Table 13 and Fig. 79 show the types of alcohols that have both electron -withdrawing and
electron -donating groups, converted to the corresponding aldehyde or ketone.

R1 R2OHa (0.2-0.35 mol%)
TBN (4-5 mol%)
H2O (0.3 mL), 50 oC, O2 (1 atm)R1 R2O

Fig. 79. Oxidation of alcohols
Table 13 . The 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 C6H5-CH=CH – Me 48 61
12 Cyclohexanol C6H5 24 96
aprimary benzylic alcohols (1mmol), tBuONO (4mol%), catalyst a (0.2mol %) in H 2O (0.3 mL) at 50 oC.
Aliphatic and secondary benzylic alcohols (1mmol), tBuONO (5 mol%), catalyst a (0.3 mol%) in H 2O (0.3
mL) at 50 oC. Allylic and hindered alcohols (1 mmol), tBuONO (5 mol%), catalyst a (0.35 mol%) in H 2O
(0.3 mL) at 50 oC

– 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
esters, as well as asymmetric esters. [140-144] each metal lic containing in addition to metal -free
reagents and catalysts were advanced for this type of reactions . [140,145 -148]

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C. Perusqua -Hernndez et al. [149] synthesized aryldiazomethanes and their corresponding
arylmethyl esters, by using benz ophenone hydrazine ( a in Fig. 80 ), which reacted with an excess
of 13% sodium hypochlorite solution and TEMPO.
At 0 oC in 5 min. diphenyldiazomethane ( b in Fig. 80 ) of reddish color was formed,
because the diazo group shows a band C=N=N in 2050 cm-1. The compound
diphenyldiazomethane is unstable to air, reacting with acetic acid to determine the reaction yield.
[150] Table 14 shows the role of temper ature and time in the reaction.
Ph PhNNH2NaOCl
TEMPO
KBr, NaHCO3
temp.PhN2
PhAcOH
PhOAc
Ph
a b c

Fig. 80. Synthesis of benzhydryl ester c from diphenyldiazomethane b and benzophenone
hydrazone a

Table 14. Effect of temperature and reaction timea

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
acatalyst ratio (3.8 mol %)
Table 15, shows the results when us ing calcium and sodium hypochlorite as oxidizing agents .

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Table 15. 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) is shown in
table 29.

Table 16. 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 15, different types of benzhydryl esters were
synthetized from diazoalkanes. See Table 17, and Fig. 81.

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

Fig. 81. Synthesis of benzhydryl esters

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Table 17. Benzhydryl esters prepared via Fig. 81

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, Sven Hackbusch and Andreas H. Franz [151] synthesized symmetric esters from
primary alcohols in a biphasic dichlo romethane -water solvent mixture, by u sing
TEMPO/CaCl 2/Oxone a convenient catalytic system , see Fig. 82 and Table 18.

OHTEMPO (0.01 mmole)
CaCl2 . 2H2O
Oxone
2 mL DCM, H2O
rtOO
1 mmole

Fig. 82. Oxidation of 1 -hexanol to ester

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Table 18. Result of esterfication reaction
Entry H2O (mL) CaCl 2.2H 2O
(mmole) Oxone
(mmole) Time (h) Yield %
1 0.0 0.5 1.0 24 0
2 1.0 0.5 1.0 2.5 44
3 0.5 0.5b 1.0 2.5 65
4 0.1 0.5 1.0 2.5 82
5 0.05 0.5 1.0 2.5 80
6 0.1 0.5 1.5 2.5 87
7 0.1 0.5 1.5 5 99
8 0.1 0.5 2.0 2.5 90
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
Under the same reaction conditions, the authors synthesized different type of esters from
alcohols see Fig. 83.
OO
OOONO2OO
ONO2
O O
OO O
OO
O
4h, 72%
2.5h, 89%24h, tracesa24h, tracesa24h, 27%24h, NRb
a detected by DART-HRMS
bNR = no reactionROH
2TEMPO/CaCl2/Oxone
DCM, H2O, rt RO RO
1.0 mmole

Fig. 83. Synthesis of esters from alcohols

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1.7.3.2 Nitroxide free radical as catalyst for dehydrogenation of amines
The oxidation of primary amines into the corresponding nitriles constitutes a very useful
functional group transformation in organic synthesis. Amines are acutely sensitive to oxidation,
and products may depend on the oxidant. Catalytic systems for the aerobic oxidation of amines to
nitriles have been developed. They involve catalytic quantities of a base, cuprous iodide, and an
appropriate ligand for the metal. [152]
The catalyst TEMPO, together with anther catalyst are used for the oxidation of different
types of amines converted to the corresponding nitriles. This oxidation is sensitive and the product
depending on the TEMPO has been used to a much lesser extent in the oxidation reactio ns of
amines.
Semmelhack and Schmid reported TEMPO assisted electro oxidation of amines to nitriles
and carbonyl compounds in 1983 using TEMPO catalyst . [153] Oxidation of a primary amine to a
nitrile included a double dehydrogenation, has been achieved i n different ways, [154] aerobic
oxidation catalyzed by transition metals, [155] transition -metal catalyzed dehydrogenation, and so
on.
Some of the oxidizing agents used in the process of oxidation of primary amines into the
corresponding nitriles, [15 6] have a lot of drawbacks such as harsh reaction conditions, low
yields, tedious work -up procedures and limitations.
F.-E. Chen et al. [157] reported that by using trichloroisocyanuric acid (TCCA) with
2,2,6,6 -tet-tetramethyl -1-piperidinyloxy (TEMPO), a sta ble free radical under mild reaction
conditions, to oxidation of benzylamine to the benzonitrile was achieved, see Table 19.

RCH2NH2TCCA, TEMPO (1mol%)
DCM, 10 oCRCN
1a-q 2a-q

Fig. 84 . Oxidation of primary amines

Trichloroisocyanuric acid is an inexpensive, stable reagent used in organic synthesis
such as in the transformation of alcohols to halides alkenes to β -chloroethers, carboxylic acids to
acid chlorides, [158] and also used in the oxidation of alcohols to carbonyl compounds. [159]

Ahmed Juwad Shakir – Doctoral Thesis

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Table 19. Oxidatio n of benzylamine to the benzonitrilea
Yield %b Time (h) TEMPO/TCCA (mol ratio) Temp. C Solvent Entry
70 4 1:1.2 5 Et2O 1
71 5 1:1.2 5 Dioxane 2
62 5 1:1.2 5 THF 3
85 3 1:1.2 5 DCM 4
49 6 1:1.2 0 DCM 5
88 3 1:1.2 10 DCM 6
69 1 1:1.2 10 DCM 7
45 5 1:0.5 5 DCM 8
72 3 1:0.8 5 DCM 9
90 2 1:1.3 5 DCM 10
90 2 1:1.5 5 DCM 11
aall reactions were carried out according to the typical procedure.
byield of isolated pure product.

These conditions were also employed for the oxidation of other aliphatic, aromatic and
heterocyclic primary amines; the results are shown in Table 20.

Table 20. Oxidation of Primary Amines 1a–q into Nitriles 2a–q
Entry R Time (h) Producta Yield%b
1 C3H7 4 2a 80
2 C5H11 4 2b 81
3 HO 2C(CH2) 5 4.5 2c 80
4 Ph 2 2d 90
5 4-MeC 6H4 2 2e 91
6 4-MeOC 6H4 2 2f 90
7 4-NO 2C6H4 2.5 2g 90
8 4-Me 2NC 6H4 2 2h 91
9 (E)-PhCH=CH 2 2i 90
10 1-Naphthyl 1.5 2j 90
11 3-(4-Methoxybenzyloxy)C 6H4 2 2k 89
12 3,4-(HO) 2C6H3 2 2l 91
13 2-ClC 6H4 2 2m 90
14 3,4-(CH 2O2)C6H3 2 2n 90
15 2-Furyl 2 2o 89
16 3-Pyridyl 2 2p 89
17 Piperonyl 2.5 2q 89
aall products were identified by comparison with their spectral data (IR, 1H NMR and GC/MS) and physical
properties with those of the authentic samples, byields of isolated pure product.

Ahmed Juwad Shakir – Doctoral Thesis

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Kyle M. et al. [160] reported on the oxidation of a primary amine into the corresponding
nitrile by using a stable, solid and commercially available compound, namely 4 -acetamido -2,2,6,6 –
tetramethylpiperidine – 1-oxoammonium tetrafluoroborate (a in Fig. 85 ).
This compound can be prepared using 4 -amino -2,2,6,6 -tetramethylpiperidine and
inexpensive reagents in multimole quantities. [161]
NNH
OO
BF4a
NNHO
O
bNNHO
OHc

Fig. 85. Oxoammonium salts (a)
Aliphatic amines are oxidized more slowly than benzylic and allylic amines, because the
oxidation of aliphatin amines requires 24 -36 h at room temperature, but benzylic and allylic
oxidation requires just 12 h. A large number of reports have addressed the oxidation of primary
and secondary amines.
The results of the oxidation of primary amines into t he corresponding nitrile (Fig. 8 7).

RCH2NH2+ 4NNHO
OBF4-excess
pyridine
DCMRCN
N
ONHO
+ 4
N
HBF4-+ 4
ab

Fig. 86. Oxidation of primary amines to nitriles

Ahmed Juwad Shakir – Doctoral Thesis

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CN CN CN
MeO CN CN
HO CN
F
CN
F3C
CN MeO CN F3C
CF3 CN
Cl CN S
CN
CN CN12h, 92%12h, 92% 12h, 86%12, 90% 12h, 86% 12h, 73%
24h, 89%
12h, 87% 24h, 75%12h, 90% 14h, 91% 14h, 92%
36, 93% 24h, 95%aallreactionswere
conductedona10
mmolscale.bthe
reactionmixturewas
stirred atroom
temperature or refluxFig. 87. Result of o xidation of primary amines to nitrilesa,b
The stoichiometry for the oxidation of primary amines into nitriles is shown in Fig. 88 .

Fig. 88. Oxidation of primary amines to nitriles

Ahmed Juwad Shakir – Doctoral Thesis

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Largeron et al. reported on the oxidation of primary aliphatic amines into imines by using
the biomimetic electrocatalytic method. [162]
In 2012 Kerton applied methods for the oxidation of primary and secondary amines by
using a Cu/nitroxide –catalyzed system. [163] Nicolaou et al. used 2 -iodoxybenzoic acid to
develop stoichiometric oxidations of secondary amines into imines. [164,165]
Zhenzhong Hu and Francesca M. Kerton in 2012 [163]reported on aerobic oxidations of
primary and secondary benzyl amines by using the CuBr 2-TEMPO catalytic system
(dehydrogenative coupling of electron -rich anil ines to get azo compound Fig, 89). Table 21 shows
the results of the oxidative self -coupling of benzylamine by using CuBr 2-TEMPO.

NH25 mol. % catalyst
solvent, air, 25 oC2N

Fig. 89. Copper -catalyzed oxidative self -coupling of benzylamine

Table 21 . Oxidative self -coupling of benzylaminea

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.
8 CuBr 2 + TEMPO CH 3CN/H 2O (1/2) 53
9 CuBr 2 + TEMPO Toluene/H 2O (2/1) 8
a catalyst (0.05m mol), benzylamine (2 mmol), solvent (9 ml), 1 atm and 8 (h)

Ahmed Juwad Shakir – Doctoral Thesis

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When using CuBr 2/TEMPO as the catalyst, benzylamine converts into imines with high
yield, so it is used for a range of primary and secondary benzylic amines with high conv ersion and
selectivity (Fig. 90).

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. 90 . Oxidation primary and secondary benzylic aminesa
In 2016, Ashley L. Bartelson et al. developed nitroxide -catalyzed for oxidation of amines
(prepare of imines and nitriles) by using nitroxide 4-Acetamido -TEMPO (ACT), pyridinium
bromide, and oxone . [167]
Using oxone as a secondary oxidant for the nitroxyl system along with amine substrates
isn't an apparent one as oxone has been mentioned to react with amines underneath certain reaction
conditi ons. [168]
They predicted combining the approach pronounced via Bolm and them stoichiometric
protocol to develop a catalytic manner the usage of ACT because the nitroxyl catalyst to oxidize
primary amines to nitriles. [169] The Fig. 91 , shown the results of oxidation of amines.

Ahmed Juwad Shakir – Doctoral Thesis

59

R NH25 mol % ACT
4.5 mol % pyrdinium bromide
4.4 eq. oxone
6 eq. pyridine
DCM, rt, 12hRCN
CNCN
F3COCF3CN
CN
H3CO
CN
ClCN O
OS
CNO
CN
92%86%88%
86%
98%90% 98%
86%
Fig. 91 . Oxidation of amines
1.7.3.3 Nitroxides and their ability to moderate polymerizations
Managed radical polymerizations (CRP) are of paramount importance to the field of
polymer chemistry. Their potential to get entry to well -defined polymers with wealthy chemical
functionality makes them essential to many state -of-the-art . At the same time as there are a diffuse
of CRP techniques, [170-175] three dominate because of th eir simplicity and functional molecular
tolerance, reversible addition fragmentation chain transfer polymerization (RAFT), [176] atom
switch radical polymerization (ATRP), [177,178] and nitroxide -mediated polymerization (NMP).
[179,180 ]
Of those, NMP is particularly beneficial because of each its inherent simplicity (needing
only monomer and unimolecular initiator) and its avoidance of sulfur and metal catalysts found
inside the RAFT and ATRP techniques .
In 1985, Solomon and Moad described nitroxides as reversible radical trapping agents for
carbon -centered radicals . [181,182] TEMPO was applied as a trapping agent for acrylate and
methacrylate monomers initiated with azobisisobutyronitrile to genera te alkoxyamines adducts
(Fig. 92 ).

Ahmed Juwad Shakir – Doctoral Thesis

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ON R
OH3CONC
R = H,CH3
Fig. 92 . Alkoxyamines
TEMPO was initially shown to be an efficient mediator for the homopolymerization of
styrene and the copolymerization of styrene and acrylates in which the acrylate concentration was
50% or less on a m olar basis. Attempts for the homopolymerization of acrylates and methacrylates
were uniformly unsuccessful proceeding to about 5% conversions and producing low molecular
weight oligomers. [183]
A series of nitroxides were developed that formed alkoxyamines with styrene and acrylate
monomers with relatively large kd (dissociation rate constant ) values. Alkoxyamines, comprised of
a benzyl radical with the acyclic nitroxides 2,2,5 -trimethyl -4-phenyl – 3-azahexane -3-oxy (TIPNO
see Fig. 93 ) have kd values of 3.6 × 10−3 s−1 [184] or (SG1 see Fig. 93 ) have kd values of 3.3 ×
10−4 s−1. [185]
In (Fig. 93 ) these radicals are very effective in mediating the polymerization of acrylates
and other non -styrenic monomers, specifically acrylamides, 1,3 -dienes, and acrylonitri les. [186]

NP O EtOO
OEt
SG1NO
TIPNO

Fig. 93 . Structure of TIPNO and SG1
Initial polymerizations of styrene performed by SFRP using TEMPO as the moderating
nitroxide were quite slow, taking over 40 hours to reach conversions of 76 %. [187]
The use of DMF as an additive for the polymerization of tert-butyl acrylate initiated by 4 -oxo-
TEMPO -capped polystyrene macroinitiator has been shown to be effective. [188]

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Studer et al . employed a combination of alkoxyamines to polymerize styrene, with o ne
alkoxyamine containing TEMPO (low kd ) and the other containing a sterically bulky nitroxide
(higher kd, lower kc), to very good effect. [189]
It was subsequently shown that polymerizations of styrene can proceed quickly and
efficiently using a primary i nitiator, such as BPO, in the absence of an additive, if the ratio of
TEMPO to BPO is varied according to the targeted molecular weight. [190]
One of the most important reactions in organic synthesis is the oxidation of alcohol. [191]
Various free radical TEMPO functionalized solid catalysts were prepared by immobilising
individual TEMPO molecules onto solid support materials , and they have been used in oxidation
reactions. [192]
In 2013 W. Hearn and his assistant prepared TEMPO functionalized polyvinyl polymers as
materials for use in organic batteries , as this material can charge in a matter of seconds.
The synthesis of poly (vinyl chloride) (PVC) via nitroxide -mediated poly merization using the
SG1- based BlocBuilde r alkoxyamine at 30 oC and 42 oC, re ported by Carlos M. R. Abreu et al.
[193] in 2016. Also Simon Kwan and Milan Mari using (NMP) nitroxide mediated polymerization
for the heterogeneous grafting of chitosan with thermor esponsive (oligoethylene)glycol
methacrylate/di ethyleneglycol methacrylate/acrylonitrile. [194 ]
Based on the assumption that TEMPO polymer grafted solid state catalyst with high radical
density can improve the efficiency and activity due to the increase in the number of active sites of
the catalyst to the substrate.
TEMPO polymer grafted silicas are prepared by grafting (PTMA) poly (2,2,6,6 –
tetramethylpiperidinyl -oxymethacrylate) [195] onto silica, by using the RAFT chain transfer agent
(Reversible addition -fragmentation chain transfer, used to make a chain transfer agent ), S-
methoxycarbonyl -phenyl -methyl S´ trimethoxysilylpropyltrithiocarbonate is inserted onto the silica
surface [196] , Fig. 94 . (1), after that, RAFT polymerization and the so -formed precursor are used
to graft polymerized 2,2,6,6 -tetramethylpiperidine methacrylate , treated with 3 –
chloroperoxybenzoic acid, to yield the TEMPO poly mer grafted silica (2 in Fig. 94 ).
The ratio of the polyme r graft (Fig. 95 -2-) is 57 wt%, determined by using a
superconducting quantum interference device (SQUID) to estimate the number of radical groups
inserted onto the silica surface .

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2,2,6,6 -Tetramethylpiperidine methacrylate was RAFT polymerized with the chain transfer
agent, treated with the chain transfer agent, (4 -cyano -4-[(phenyl -thioxomethyl)thio] -1-(2-
carboxyethyl) -1 cyanoethylbenzodithio -ate) [197] and with 3 -chloroperoxybenzoic acid to form
the poly (PTMA) (Fig, 95 -3-).
The molecular weights of these pol ymers were determined by gel permeation
chromatography (GPC).
Si MeOOMe
OMeS SOCH3O
S OH
S SSOCH3O
1) toluene, 16h, 100 oC
2) 3h, 120 oC1

(a) +
N
HOO
RAFT polymnmCPBA
THFS SS
nOOCH3
OO
NO
2
Fig. 94. Synthesis of TEMPO polymer grafted silica using the grafting from method

N
HOO
HOO
NCS
S+ RAFT polymnmCPBA
THFHOO
NCS
Sn
O
N
OO
3

NH2+ cEEDQ
toluene, rtN
HO
NCS
S
O
N
On
4

Fig. 95. Synthesis of the TEMPO polymer grafted silica by the grafting to method

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The (Fig. 95 -3-) prepared compounds were then grafted onto synthesized amino –
functionalized silica (ca. 2.0 mmol g -1) of particle size of ca. 10 nm using a condensation agent to
yield a series of different TEMPO polymer grafted silicas, (Fig. 95-4-). N-ethoxy -carbonyl -2-
ethoxy -1,2-dihydroquinoline (EEDQ) was used as the condensation agent. EEDQ was selected for
this con densation reaction since this reagent is readily available at low cost and allows the
coupling in high yield in a single operation. [197] See Table 2 2.

Table 22. TEMPO polymer grafted silica (Fig. 95 -4-) synthesis by the grafting method

radical conc.
(%) immobilized
TEMPOa
(mmol g-1) graft ratio
(wt%)
Mw/Mn 3
Mn (x104) Entry
92 1.56 54 1.2 1.0 1 (4-1)
91 1.71 64 1.2 1.7 2 (4-2)
90 1.76 66 1.1 3.0 3 (4-3)
99 2.11 91 1.2 7.4 4 (4-4)

Scanning electron microscope (SEM) and dynamic light scattering (DLS) were used to
determine the synthetic material 4 -2 (Entry 2, Table 22 ) Fig. 96.

Fig. 96. SEM image of TEMPO Catalyst 4 -2 [197]

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Using polymer grafted silica for oxidation of benzyl alcohol (Table 2 3) and its efficiency
was compared with a commercially available mono -TEMPO Si, the oxidation reaction of benzyl
alcohol was achieved in water or DCM/water bi -phasic system.
The results of 4 -2 in Table 2 3 show the highest produc t conversion and high reaction rate
constant compared with mono -TEMPO Si.

Table 23. Product conversion and reaction rate constant of the oxidation of benzyl alcohol to
benzaldehyde with TEMPO catalystsa

mono -TEMPO -Si 4-4 4-3 4-2 4-1 Catalyst
58 80 89 95 90 conversion (%)b
0.23 0.45 0.62 1.01 0.91 rate constant k 1 (x10-2 Lmol-1 s-1)
a10 min, reaction temp, 5 C, catalyst/alcohol, 0.5 mol%, solvent and DCM/water

The results of using TEMPO polymer grafted silica (Fig. 95-4-) for the oxidation various
alcohols are shown in Table 2 4.

Table 2 4. Results of conversion (%) of alcohols to aldehydes with TEMPO catalyst a

Entry Substrate Product 4b Mono -TEMPO -Si
1
OH

O 98 51
2
OH

O 99 34
3
HOOH
OH

OOH
OH 53 5

HOO
OH
0.1 0.3
a10 min, reaction temp, 5 oC, catalyst/alcohol, 0.5 mol%, solvent DCM/water.b4-3 for entry 1 and 2, 4 -2 for
entry 3

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TEMPO has been immobilized onto solid supports, such as polymeric resins, molecular
sieves and silica gel. [198-200] TEMPO was linked to the CPGMA microspheres between the
epoxy groups of 4 -OH-TEMPO, forming heterogeneous catalyst microspheres TEMPO/CPGMA,
[201] by the ring opening reaction. The polymer resin has the advantage that active groups can be
easily inserted onto it via chemic al modification.
Baojiao Gao et al. [202] used the heterogeneous catalyst TEMPO/CPGMA combined with
Fe(NO 3)3 as cocatalyst for the aerobic oxidation of cyclohexanol under mild conditions, in order to
obtain the product (cycl ohexanone) with good activity. There are some reports using homogenous
TEMPO combined with Fe(NO 3)3. [203,204 ] The activity of the catalyst is shown in Fig. 97 , and
the result ing product yield of cyclohexanone was 44% in 36 h when using the system consisting of
TEMPO/CPGMA microspheres and Fe(NO 3)3.

Fig. 97. Curves of cyclohexanone yield with time using the combination of TEMPO/CPGMA and
Fe(NO 3)3 as cocatalyst or the single components as catalyst, reaction conditions: 55 °C, O 2
ordinary pressure, acetic acid as solvent [202]

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

Fig. 98. Preparation of cross -linked polymer microspheres CPGMA by suspension polymerization

Ahmed Juwad Shakir – Doctoral Thesis

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RH
CCH2
OCPGMA +
N
OOH
ring opening
reaction
CPGMARH
CH2
C
OHO
N
OCPGMA
O
N
O4-OH-TEMPO
TEMPO/CPGMA
microsheres
Fig. 99. Immobilization of TEMPO on CPGMA microspheres

1.7.3.4 Oxidation mechanism using nitroxide radicals
The oxidation of an alcohol to an aldehyde or ketone by 2,2,6,6 -Tetramethylpiperidin -1-
yl)oxyl (TEMPO) includes the abstraction of two hydrogen atoms from the substrate. The
oxoammonium cation, can be formulated in two limiting resona nce forms, a and b in Fig. 79.
N
ON
O

Fig. 79. Resonance of oxoammonium cation
There are two different kind s of TEMPO mechanism s in the oxidation of alcohol , one under
acidic conditions, and another under basic conditions. Generally the dominant mechanism under
acidic conditions is slower than the dominant mechanism under basic conditions; oxidations of
alcohols in base include an alcoholate as the nucleophile . Fig. 80 shows the conceivable
mechanism of oxidation of alcohol under basic conditions.

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

Fig. 8 0. Mechanism of oxidation of alcohol under basic condition s

Ahmed Juwad Shakir – Doctoral Thesis

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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 alcohol by using Cu/ TEMPO
catalyst, [205] see Fig. 81. In the first step, the aerobic oxidation of CuI produced CuII-OH.
In the second step, aerobic oxidation of TEMPOH produces TEMPO, when CuI salt is used as
the catalyst in the aerobic oxidation of alcohol, a strong base like 1,8-diazabicyclo[5.4.0]undec -7-
ene (DBU) is not required (see the first ste p in Fig. 81). After the second step, the base (L nCuII-
OH) is formed upon reduction of O 2. Step (3 in Fig, 81) causes the oxidation of alcohol through the
generation of a pre -equilibrium of a CuII–alkoxide. The last step (4 in Fig. 81) is hydrogen transfe r
to TEMPO.
LnCuI1/2O2
1/2[LnCu]2(O2)
TEMPOH
TEMPOLnCuII-OHLnCuIIOH RHTEMPOTEMPOH+RO
1
2 34
R HOH2OL= ligand

Fig. 8 1. Mechanism of Cu/TEMPO -catalyzed alcohol oxidation
deduced by Stahl et al.

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– Mechanism for the condensation of benzyl amines using CuII/TEMPO catalysts

Zhenzhong H. and Francesca M. [206] suggested a mechanism for the condensation of
benzyl amines using CuII/TEMPO catalysts. It is similar to the mechanism of Cu/TEMPO
catalyzed aerobic oxidation of alcohol reported by Sheldon et al. [207] In Fig. 82, first step
entailed the CuII(1 in Fig. 82) bonding with the amine to form the intermediate complex (2 in Fig.
82), in the second step, the intermediate complex (II) combines with TEMPO to form type (3 in
Fig. 82) the next formed intermediate (4 in Fig. 82) by the abstraction of hydrogen from t he amine
(C-H bond) via the coordinated TEMPO molecule, intermediate (4 in Fig. 82) is stable because the
hydrogen bonding between the oxygen atom of TEMPOH and the second β -hydrogen atom of
amine. Then, TEMPO -H and the intermediate imine is dissociated fr om the radical species (4 in
Fig. 82), via single proton transfer to form a CuI complex (5 in Fig. 87). Next, the oxidation of CuI
complex (5 in Fig. 82) and TEMPOH with oxygen takes place to regenerate the CuII complex (1 in
Fig. 82) 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. 8 2. Proposed mechanism for CuBr 2-TEMPO catalyzed oxidation of benzyl amines

Ahmed Juwad Shakir – Doctoral Thesis

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– Mechanism of C -H arylation
Studer and Vogler proposed a mechanism of C -H arylation by using a rhodium -catalyzed
oxidative coupling of aryl – and alkenylboronic acids with arenes and hereroarenes with TEMPO as
an oxidant. [208] Fig. 83 shows the mechanism of the first step oxidation of an aryl rhodium(I)
complex to the corresponding aryl rhodium( III) complex.
The next step generated the rhodium (I) intermediate by ransmetallation of rhodium(I)
aminoalkoxide with an arylboronic acid, then two equivalents of TEMPO supposedly oxidized the
rhodium (I) intermediate to result in the rhodium (III) complex, after this step ligand of phosphine
is exchanged with arene (a in Fig. 83) lead to form b which finally afforded C -H arylation to
generate the rhodium (III) complex (c in Fig. 83) and hydroxylamine. In the final step, reductive
elimination and exchange of the liga nd provided the coupling product (d in Fig. 83) and
regenerated the rhodium (I) complex.

L2Rh(I)TEMPOArylB(OH)2
(TEMPO)B(OH)2
L2Rh(I)Aryl
2 TEMPO
(TEMPO)2Rh(III)ArylL
L
N
R
L(TEMPO)2Rh(III)ArylL
N(TEMPO)Rh(III)Aryl
N
RLLN
RAryl
RN
OHL =ligand of phosphine
bacd

Fig. 8 3. Proposed mechanism for the C –H arylation

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– Mechanism for heteroatom in nitroxy radical
One mechanism example for heteroatom in nitroxy radical was suggested by Yoshiharu I. et al.
[110] . It involved the use of 5 -F-AZADO (see Fig. 84) catalyst for the aerobic oxidation of
alcohol. In the first step, a hydrate (2 in Fig. 84) is formed from the oxoammonium cation with
H2O in equilibrium, the oxoammonium oxidizes alcohol to form the intermediate (3 in Fig. 84) in
equilibrium with the intermediate (4 in Fig. 84), then oxidation of alcohol, formed hydroxylamine
and the nitroxy free radical lead to the regeneration of the oxoammonium cation in the final step.
N
OHOH X2
N
OX
1H2O H+,
NXO
OHR1
R2OH
R1 R2
N
OOXR1
R2
R2R1ONX
ONX
OHNO
NO21/2O2
H2O3
4X= F

Fig. 8 4. Mechanism of 5 -F-AZADO catalyst for aerobic oxidation alcohol

Ahmed Juwad Shakir – Doctoral Thesis

71
– Mechanism for the oxidation of alcohols by using tert -butyl nitrite
Martin H. and Ullrich J. proposed a mechanism for the oxidation of alcohols by using tert -butyl
nitrite (TBN). [209]
In Fig. 85, the first step reaction between TBN and the catalytic amount of BF 3·OEt 2 lead to
the formation of nitrosonium tetrafluoroborate (7 in F ig. 85), and the borate ester. [209] Then
nitrosonium salt (7 in Fig. 85) oxidizes the free radical TEMPO (1 in Fig. 85) to the
Noxopiperidinium salt (2 in Fig. 85).
Oxidation of alcohols (3 in Fig. 85 ) by salt (2 in Fig. 85) to the corresponding aldehyde s or ketones
(4 in Fig 85 ) resulted in tetrafluoroboric acid and hydroxylamine (5 in Fig. 85), which is in
equilibrium with its salt (6 in Fig. 85 ). Finely hydroxylamine (9 in Fig. 85 ) reoxidizes to TEMPO
(1 in Fig. 85 ).

t-BuONO + 4/3BF31/3(t-BuO)3B + [NO]+[BF4]-
t-BuONOt-BuOH
[NO]+[BF4]-
N
OBF4-
N
OHNH
OHBF4-+ HBF3HBF3
N
ONO
t-BuONOt-BuOH
NO
1
2
R1R2OH
R1R2O3
4567

Fig. 85. Proposed mechanism of alcohol oxidation with TBN

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72
– Mechanism of TEMPO in esterification reactions
A mechanism of TEMPO in esterification reactions of aryl diazomethanes derived from
hydrazine was proposed by Ramstrom [206] and Sheldon. [211] In the first step, the free radical
TEMPO (1 in Fig. 86), reacts with chlorine (derived from sodium hypochlorite) to form
oxoammonium ion (3 in Fig. 86). Then oxoammonium ion combines with hydrazine (4 in Fig. 86)
to form the intermediate (5 in Fig. 86). Next, hydrogen is transferred to form the intermediate (6 in
Fig. 86) which is disproportionate to hydroxy TEMPO (7 in Fig. 86) and diazocompound (8 in Fig.
86). Finaly hydroxy TEMPO is re -oxidized by chlorine to form the intermediates (2 and 3 in Fig.
86).
N
OCl2
N
OClN
OClB+NNH2
BH
NOH N
N N
OH
NNCl21 23
6
784
NO N
NH
5

Fig. 86. Reaction mechanism of esterification reactions of aryl dizaomethanes derived from
hydrazine by using TEMPO as catalyst

Ahmed Juwad Shakir – Doctoral Thesis

73
1.8. Conclusion
The development of free radicals begun when the scientist Moses Gomberg discovered the
triphenylmethyl radical in 1900. The exploration of the chemical preparation of free radicals plays
a vital role in chemical reactions and medicine.
In organic chemistry, the achievement of free radicals exhibiting different levels of stability
leads to numerous advances in chemical theory and practical application . Organic chemistry offers
many advantages for all chemists interested in transient and persistent radicals.
Becau se 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 magn ets, Nitroxide Mediated
Polymerization (NMP) , supramolecular assemblies , antioxidants, Magnetic Resonance Imaging
(MRI), Dynamic Nuclear Polarization (DNP), free radical biology and so on.
These researches need to study nitroxides that display appropriat e characteristics, such as
redox potential, relaxivity, rate of trapping of free radicals, biocompatibility, ferromagnetic
interactions, etc. The advantage of nitroxides compared to other stable free radicals is that the
aminoxyl group can resist the exper imental conditions needed to perform various organic
reactions.
The chemistry of nitroxides is very important, especially in the oxidation reaction and in
the chemical reactions taking place within industrial settings. Oxidation reactions have frequently
been performed with stoichiometric amounts of inorganic oxidants. Many of these are extremely
hazardous to use or toxic when compared to the use of organic oxidants.
Cyclic nitroxides have been used for years as biophysical probes . Heterogeneous catalysts
are favored for these reactions; the ability to recycle the catalyst often remains a challenge after the
chemical reaction is completed. The availability of easy -to-handle heterogeneous catalysts like
TEMPO as free radical which can be easily recycled afte r use in liquid phase oxidation reactions,
and which have low toxicity, good stability and high efficiency is thus an essential requirement.
Free radical TEMPO has been useful in roles such as mediators in the selective oxidation
reaction of alcohols, as a catalyst for the oxidation or dehydrogenation of amines , due to its ability
to moderate polymerizations , synthetize ester and so on, due to its high yield, mild conditions and
low toxicity.

Ahmed Juwad Shakir – Doctoral Thesis

74
Through our survey of the chemical applications of free radicals that their important and
effective contributions in various chemical, medical and industrial preparations is clearly shown.
Free radicals are easy to obtain and use, especially nitroxide free radicals. Furthermore, for its
chemical effectiveness, we rec ommend that their preparation be continued. They can be used as
catalysts, which are very important in the preparation of many useful chemical compounds in a
safe and easy way, and with accurate results.

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Index

Chapter 1. Free radicals ………………………….. ………………………….. ………………………….. ………………… 1
l.1. General ………………………….. ………………………….. ………………………….. ………………………….. ….. 1
1.2. Classification of free radicals ………………………….. ………………………….. ………………………….. .. 3
1.2.1 Taking into consideration their stability ………………………….. ………………………….. ………… 3
1.2.1.1 Unstable free radicals ………………………….. ………………………….. ………………………….. …. 3
1.2.1.2 Persistent free radicals ………………………….. ………………………….. ………………………….. … 3
1.2.1.3 Stable free radicals ………………………….. ………………………….. ………………………….. ……… 4
1.2.2 Taking into consideration the atom contains unpaired of electron ………………………….. … 5
1.2.3 Taking into consideration the structure ………………………….. ………………………….. ………… 6
1.2.4 Taking into consideration the number of radicals center ………………………….. …………….. 6
1.3. Synthesis of free radicals ………………………….. ………………………….. ………………………….. ……… 8
1.4. Detection of free radicals ………………………….. ………………………….. ………………………….. …… 10
1.4.1 ESR technique ………………………….. ………………………….. ………………………….. …………….. 10
1.4.2 IR technique ………………………….. ………………………….. ………………………….. ………………… 10
1.5. Applications of free radicals ………………………….. ………………………….. ………………………….. . 11
1.6. Hydrazyl ………………………….. ………………………….. ………………………….. ………………………….. 13
1.7. Nitroxide ………………………….. ………………………….. ………………………….. ………………………….. 15
1.7.1 General ………………………….. ………………………….. ………………………….. ……………………….. 15

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1.7.2 Synthesis of nitroxide and properties ………………………….. ………………………….. ………….. 16
1.7.3 Application of nitroxide free radicals in organic chemistry ………………………….. ………… 23
1.7.3.1 Nitroxide free radicals as mediators in selective oxidation reaction of organic
substrates ………………………….. ………………………….. ………………………….. ………………………….. .. 23
1.7.3.2 Nitroxide free radical as catalyst for dehydrogenation of amines …………………………. 53
1.7.3.3 Nitroxides and their ability to moderate polymerizations ………………………….. ………… 59
1.7.3.4 Oxidation mechanism using nitroxide radicals ………………………….. ………………………. 66
1.8. Conclusion ………………………….. ………………………….. ………………………….. ……………………….. 73
1.9. Reference ………………………….. ………………………….. ………………………….. …………………………. 75