Persistent free radicals as reactive intermediates. [602415]

– 0 –
Persistent free radicals as reactive intermediates.
Applications in synthetic organic chemistry

Literature report (I)

Ph.D. student: [anonimizat] 1 –
Index
Entry Subject Page
No.
List of abbreviations 2
1 Introduction. Free radicals 3
A TEMPO 9
B Triphenylmethyl 10
C DPPH 11
2 Application of nitroxide free radicals as oxidant in organic chemistry 13
3 Nitroxide free radicals as mediators in selective oxidation reaction 18
A Nitroxide free radical as catalyst with metals for oxidation alcohols 19
B Nitroxide free radical as catalyst for oxidation or dehydrogenation of
amines 32
C Nitroxide free radical generation a polymer 45
D Metal -free aerobic oxidations mediated N – hydroxyphthalimide . 59
4 Mechanism of nitroxide free radical. 69
5 Conclusion 73
6 References 75

– 2 – List of abbreviations
ABNO azabicyclo[3.3.1]nonane
AZADO 2 -azaadamantane N -oxyl
BAIB bis(acetoxy)iodobenzene
CPME cyclopentyl methyl ether
DCE Dichloroethane
DCM Dichloromethane
DPPH 2,2-diphenyl -1-picrylhydrazyl
EEDQ N-Ethoxycarbonyl -2-ethoxy -1,2-dihydroquinoline
MCPBA m – chloroperbenzoic acid
MeTHF 2 -methyltetrahydrofura n
NHPI N -hydroxyphthalimide
NMI N -methyl imidazole
NMP Nitroxide -mediated radical polymerization
PINO phthalimide N -oxyl
PTMA 2,2,6,6 -tetramethylpiperidinyl – oxymethacrylate
TBN tert -butyl nitrite
TCCA Trichloro isocyanuric acid
TEMPO 2,2,6,6 -tetramethylpiperidin -1-yl
TEMPOH 1-hydroxy -2,2,6,6 -tetramethyl -piperidine
THF Tetrahydrofuran
TPM triphenylmethyl

– 3 –

(1)
Introduction

– 4 – Organic chemistry has become very important in our lives as well as in the industrial and
medical field.
So it became the focus through the use of new roads or the preparation of new compounds.
Free radicals usually have a very short lifetime
Chemists are more interested in radicals that are reactive, so it‘s interesting and useful things.
Free radicals may be created in a number of ways, including synthesis with very dilute or
rarefied reagents, reactions at very low temperatures, or breakup of larger mol ecules.
The latter can be affected by any process that puts enough energy into the parent molecule,
such as ionizing radiation , heat, electrical discharges, electrolysis , and chemical reactions.
Indeed, radicals are intermediate stages in many chemical reactions.
Free radicals reactive oxygen species and reactive nitrogen species are generated by our body
by various endogenous systems.
Free radicals play an important role in combustion , atmospheric
chemistry , polymerization , plasma chemistry, biochemistry , and many other chemical
processes.
In living organisms, the free radicals superoxide and nitric oxide and their reaction products
regulate many processes, such as control of vascular tone and thus blood pressure.
They also play a key role in the intermediary metabolism of various biological compounds.
Such radicals can even be messengers in a process dubbed redox signaling .
Many of the molecules that make up the structure of human tissue are susceptible to
homolysis in intense light, and the body makes use of sophisticated chemistry to protect itself
from the action of the reactive radical products.
Vitamin E plays an important role in the ‗taming‘ of these radicals: abstraction of H fro m the
phenolic hydroxyl group produces a relatively stable radical that does no further damage.
The most important industrial application of free -radical chemistry is in the production of
polymers.
The first organic free radical identified was triphenylmethyl radical . This species was
discovered by Moses Gomberg in 1900 at the University of Michigan USA few free radicals
in organic chemistry are unreactive ,
Such radicals are known as persistent radicals compounds (like TEMPO ) are th ose whose
longevity is due to steric crowding around the radical center, which makes it physically
difficult for the radical to react with another molecule.[1]
There are two reasons why some radicals are more persistent than others:

– 5 – (1) steric hindrance and
(2) electronic stabilization.
This persistent free radicals its useful in organic chemistry and have more application in
oxidation reaction , oxidation re action in an inorganic chemistry are extremely hazardous to
use or toxic but in organic chemistry which have low toxicity, more stability and high
efficiency.
– Free radicals
A free radical can be defined as any molecular species capable of independent existence that
contains an unpaired electron in an atomic orbital.
The presence of an unpaired electron results in certain common properties that are shared by
most radicals.
Many radicals are unstable and highly reactive. They can either donate an electron to or
accept an electron from other molecules, therefore behaving as oxidants or reductants.[2]
A notable example of a free radical is the hydroxyl radical (HO•), a molecule that has one
unpaired electron on the oxygen atom. Two other examples are triplet oxygen and
triplet carbine. Unpaired electrons are desperate to be paired.

This means that radicals usually have a very short lifetime but in free radicals in organic
chemistry special persistent radicals its more stable it‘s have single electron carried by an
oxygen or a nitrogen atom are known, the some important free radical as flowing :
– triphenylmethyl radical stable in solution in equilibrium with its dime fig. 1

Fig. 1. Chemical structure of triphenylmethyl free radical

– 6 – – TEMPO (2,2,6,6 -tetramethylpiperidin -1-yl) tetramethylpiperidine N -oxide fig. 2

Fig. 2. Chemical structure of the free radical TEMPO
– DPPH (2,2 -diphenyl -1-picrylhydrazyl) compound fig. 3

Fig. 3. Chemical structure of DPPH free radical
– 2,4,6 -tri-tert-Butylphenoxy radicals its dark blue solid m.p. 97 C fig. 4

Fig. 4. Chemical structure 2,4,6 -tri-tert-Butylphenoxy
– α,β-bisdiphenylene -β-phenylallyl radical fig. 5

Fig. 5. Chemical structure α,β -bisdiphenylene -β-phenylallyl

– 7 – There are different types of free radicals in organic chemistry we are focus on stable
have long-lived radicals These are categorized as follows:
Stable radicals
In Organic radicals can be long lived if they occur in a conjugated π system, such as the
radic al derived from α-tocopherol (vitamin E ) There are also hundreds of examples
of thiazyl radicals,which show low reactivity and remarkable thermodynamic stability with
only a very limited extent of π resonance stabilization .[a][3]
Persistent radicals
we are explain this for example TEMPO , azephenylenyls and TTM (tris(2,4,6 –
trichlorophenyl)methyl radical .
Persistent radicals are generated in great quantity during combustion, and "may be
responsible for the oxidative stress resulting in cardiopulmonary disease and probably cancer
that has been attributed to exposure to airborne fine particles.[4]
Diradicals
is a molecular species with two electrons occupying two degenerate molecular orbitals [5] and
its containing two radical center s.
Multiple radical centers can exist in a molecule Atmospheric oxygen naturally exists as a
diradical in its ground state as triplet oxygen .
To making radicals unpairing a pair of electrons by homolysismaking two new radicals.
Temperatures of over 200 °C will homolyse most bonds; on the other hand, some weak bonds
will undergo homolysis at temperatures little above room temperature. Light is a possible
energy source for the homolysis of bonds too.

First radical detected the very first radical to be detected, the triphenylmethyl radical, was
made in 1900 by abstraction of Cl• from Ph 3CCl by Ag metal. Fig. 6 shown the formation of
triphenylmethyl radical.

[a]Oakley, Richard T. "Progress in Inorganic Chemistry" (PDF). Progress in Inorganic
Chemistry. (1988).

– 8 –
Fig. 6. Formation triphenylmethyl radical
Also radicals formation by radical addition its occur when a single electron is added to
a spinpairedmolecule. This process is a reduction by giving up their odd s electron they form
a stable M+ ion.
They will donate this electron to several classes of molecules; for example ketones can react
with sodium to form ketyl radicals.
Radicals form by homolytic cleavage of weak bonds for example The radicals formed from
this homolysis are unstable and each breaks down by cleavag e of a C –C bond generating
CO 2 and a phenyl radical.
These homolytic bond cleavages are elimination reactions and are the reverse of radical
addition reactions. shown in fig. 7

Fig. 7 . Radicals form by homolytic cleavage of weak bonds
Can detection free radicals by using a spectroscopic technique known as electron spin
resonance, or ESR this technique not use to confirm that radicals do exist only but it can also
tell us quite a lot about their structure.

– 9 – – Nitroxide free radicals
There are some of the them that compounds have a relative stability . Some of this
compounds, of free radical type s, its nitrixide free radicals its very important in organic
reaction and useful in oxdation reaction in oganic chemistry such as :

a TEMPO (2,2,6,6 -tetramethylpiperidin -1-yl)
b. TPM (triphenylmethyl)
c. DPPH ( 2,2-diphenyl -1-picrylhydrazyl)
a) TEMPO
is a chemical compound with the chemical formula (CH 2)3(CMe 2)2NO shown in Fig. 2.
This heterocyclic compound is a red -orange, sublimable solid. a stable radical , it has
applications in chemistry and biochemistry.[6] TEMPO was discovered by Lebedev and
Kazarnowskii in 1960.[7]
It is prepared by oxidation of 2,2,6,6 -tetramethylpiperidine . TEMPO is wide ly used as a
radical marker, as a structural probe for biological systems in conjunction with electron spin
resonance spectroscopy, as a reagent in organic synthesis , and as a mediator in controlled
free radical polymerization .[8]
The stability of this radical is attributed to the resonance provided by non -bonding electrons
on the nitrogen atom, which form a half -bond between nitrogen and oxygen, and has hyper
conjugative ability.
Additional stability arises from the steric protection provided by the four methyl groups
adjacent to the nitroxyl group; however, the methyl groups prevent a double bond occurring
between either carbon adjacent to nitrogen.[9]
The stability of the radical is also indicated by the weakness of the O -H bond in the
hydrogenated derivative TEMPO -H. With an O -H bond dissociation energy of about 70
kcal/mol, this bond is about 30% weaker than a typical O -H bond.[10]
TEMPO can be prepared by treating the hin dered secondary amine with m- chloroperbenzoic
acid (MCPBA), with the intention of transforming it into the nitroxide.

– 10 – Unexpectedly, the oxidation of the amine functionality was accompanied by the
transformation of the alcohol moiety into a ketone, resulting in the formation of the
compound named 4 -oxo-TEMPO, Fig. 8.

Fig. 8. Synthesis of 4 -oxo-TEMPO
As peracids react very sluggishly with alcohols, it was apparent that the prese nce of a
nitroxide was playing an important role in the oxidation of the alcohol into a ketone.
This seminal serendipitous observation led to the development of the first description of the
oxidation of alcohols mediated by catalytic 2,2,6,6 -tetramethylpi peridine -1-oxyl (TEMPO)
published almost simultaneously by Cella and Ganem.[11]
These authors presented two papers with remarkably similar contents, in which alcohols were
oxidized by treatment with MCPBA in DCM (CH 2Cl2) at room temperature in the presence of
a catalytic amount of TEMPO.
In both papers, a plausible mechanism is presented, where by m-chloroperbenzoic acid
oxidizes TEMPO to an oxoammonium salt.
This oxoammonium salt , as detailed in Ganem‘s paper, can react with the alcohol producing
an intermediate, which can deliver a carbonyl compound by a Cope -like elimination .
b) Triphenylmethyl
Triphenylmethyl free radical is the hydrocarbon with the formula (C6H5)3C shown in Fig. 1.
The stability of the triphenylmethyl radical due to mainly to steric , Triphenylmethyl is the
basic skeleton of many synthetic dyes called triarylmethyl dyes , many of them are pH
indicators , and some display fluorescence .
Triphenylmethyl can be synthesized by Friedel – Crafts reaction from benzene and
chlomroform with aluminium chloride as c atalyst.
3 C 6H6 + CHCl 3 → Ph 3CH + 3 HCl

– 11 – Alternatively, benzene may react with carbon tetrachloride using the same catalyst to obtain
the trityl chloride -aluminium chloride adduct, which is hydrolyzed with dilute acid:
3 C 6H6 + CCl 4 + AlCl 3 → Ph 3CCl·AlCl 3
Ph3CCl·AlCl 3 + HCl → Ph 3CH
Synthesis from benzylidene chloride , prepared from benzaldehyde and phosphorus
pentachloride , is used as well.
c) DPPH
Is a common a bbreviation for an organic chemical compound 2,2-diphenyl -1-picrylhydrazyl,
shown in fig. 4. It is a dark -colored crystalline powder composed of stable free-
radical molecules, undimerized.
DPPH has two major applications, both in laboratory research: one is a monitor of chemical
reactions involving radicals, most notably it is a comm on antioxidant assay, and another is a
standard of the position and intensity of electron paramagnetic resonance signals .
DPPH has several crystalline forms which differ by the lattice symmetry and melting
point (m.p.). The commercial powder is a mixture of phases which melts at ~130 °C. DPPH -I
(m.p. 106 °C) is orthorhombic , DPPH -II (m.p. 137 °C) is amorphous and DPPH -III
(m.p. 128–129 °C) is triclinic .
DPPH is a well -known radical and a trap ("sc avenger") for other radicals.
Therefore, rate reduction of a chemical reaction upon addition of DPPH is used as an
indicator of the radical nature of that reaction.
Because of a strong absorption band centered at about 520 nm, the DPPH radical has a deep
violet color in solution, and it becomes colorless or pale yellow when neutralized.
This property allows visual monitoring of the reaction, and the number of initial radicals can
be counted from the change in the optical absorption at 520 nm or in the EPR signal of the
DPPH.
As a stable and well -characterized solid radical source, DPPH is the traditional and perhaps
the most popular standard of the position ( g-marke r) and intensity of electron paramagnetic
resonance (EPR) signals the number of radicals for a freshly prepared sample can be

– 12 – determined by we ighing and the EPR splitting factor for DPPH is calibrated at g = 2.0036.
DPPH signal is convenient by that it is normally concentrated in a single line,
whose intensity increases linearly with the square root of microwave power in the wider
power range,
The dilute nature of the DPPH radicals (one unpaired spin per 41 atoms) results in a relatively
small line deprecated (1.5 –4.7 Gauss).
The line deprecated may however increase if solvent molecules remain in the crystal and if
measurements are performed w ith a high -frequency EPR setup (~200 GHz), where the slight
g-anisotropy of DPPH becomes detectable.
Whereas DPPH is normally a paramagnetic solid, it transforms into
an antiferromagnetic state upon cooling to very low temperatures of the order 0.3 K. This
phenomenon was first reported by Alexander Prokhorov in 1963.

– 13 –

(2)
Application of nitroxide free radicals as oxidant in organic
chemistry

– 14 – Free radical TEMPO is employed in organic synthesis as a catalyst for the oxidation of
primary and secondary alcohols to aldehydes and ketone , generation of polymer, oxidation of
sulfides and hydrogen abstractions, trapping regent, reaction with organometallic compounds ,
….. etc.
The actual oxidant is the N-oxoammonium salt . In a catalytic cycle with sodium
hypochlorite as the stoichiometric oxidant, hypochlorous acid generates the N-oxoammonium
salt from TEMPO, shown in fig. 9.

Fig. 9. The oxoammonium salt of TEMPO
One typical reaction example is the oxidation of (S )-(-)-2-methyl -1-butanol to (S) -(+)-2-
methylbutanal.[12]
4-Methoxyphenethyl alcohol is oxidized to the corresponding carboxylic acid in a system of
catalytic TEMPO and sodium hypochlorite and a stoichiometric amount of sodium
chlorite .[13]
TEMPO oxidations also exhibit chemoselectivity , being inert towards secondary alcohols,
but the reagent will convert aldehydes to carboxylic acids.
In cases where secondary oxidizing agents cause side reactions, it is possible to
stoichiometrically convert T EMPO to the oxoammonium salt in a separate step.
For example, in the oxidation of geraniol to geranial , 4-acetamido -TEM PO is first oxidized to
the oxoammonium tetra fluoro borate.[14]
TEMPO can also be employed in nitroxide mediated radical polymerization (NMP), a
controlled free radical polymerization tec hnique that allows better control over the final
molecular weight distribution.
The TEMPO free radical can be added to the end of a growing polymer chain, creating a
"dormant" chain that stops polymerizing.
However, the linkage between the polymer chain and TEMPO is weak, and can be broken
upon heating, which then allows the polymerization to continue.

– 15 – Thus, the chemist can control the extent of polymerization and also synthesize narrowly
distributed polymer chains.
TEMPO itself is relatively inexpensive ,[b] but there are TEMPO derivatives that are often
used such as 4-hydroxy -TEMPO (TEMPOL )[c] or 4-acetamido -TEMPO that have cheaper
precursors.
Examples of TEMPO use in chemical industry are bisnor alcohol (a steroid ) to bisnor
aldehyde conversion by Upjohn and retinol to retinal conversion by Novartis .
One industrial method employs H 5PV 2Mo 10O40 as co -oxidant, the reduced form of which can
be reoxidized by atmospheric oxygen. Polymer -supported TEMPO catalysts are also
commercially available.[15]
In 1965, Golubev, Rozantsev, and Neiman reported[16]
that treatment of oxoammonium salt (A) with excess of ethanol led to the formation of
acetaldehyde. See fig. 10.

Fig. 10. Oxidation of ethanol
In 1975, Cella et al. demonstrated[17] that alcohols can be oxidized to carboxylic acids by
treatment with m -chloroperbenzoic acid in the presence of a catalytic amount of 2,2,6,6 –
tetramethylpiperidine (B). see fig. 11.

Fig. 11. Oxidation of alcohol

[b] http://en.wikipedia.org/wiki/TEMPO .
[c] http://en.wikipedia.org/wiki/TEMPO ."4-Hydroxy -TEMPO" .

– 16 – In 1987, Anelli published a landmark paper [18] on TEMPO -mediated oxidations, which
signalled 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 CH 2Cl2 – water medium, containing ca. 1% mol of a TEMPO related
stable nitroxide radical, excess of bleach (NaOCl), KBr and NaHCO 3.
Usually, CH 2Cl2 is used in the biphasic system. Other organic solve nts more rarely employed
include THF[19] and PhMe -EtOAc mixtures.[20]
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. 12.

Fig. 12. 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 be performed also 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 Anel li‘s protocol are routinely performed at a
slightly basic pH of 8.6 –9.8[18] obtained by beveling the bleach solution with NaHCO 3,
sometimes, in order to avoid base induced side reactions, it is advisable to adjust the pH at
6.5–7.5 by adding an acid.[21]
A proper adjustment of the pH for example allows to obtain carbonyl compounds without –
epimerization in difficult substrates in which other common oxidants fail .
It is important to note that under the slightly basic conditions (pH 8.6 (employed under the
standard Anelli‘s protocol, many base -sensitive functional groups remain unelected,
including the ubiquitous ester groups .

– 17 – In 1999, Epp and Widlanski described[22] the oxidation of alcohols to carboxylic acids using
catalytic TEMPO, with bis(acetoxy)iodobenzene — PhI_OAc_2, commonly referred as
BAIB —as secondary oxidant in an acetonitrile –aqueous buffer mixture.
This procedure for the oxidation of primary alcohols p ossesses the distinctive advantage of
producing the rather benign iodobenzene and acetic acid as side compounds.
Furthermore, in contrast to other oxidation procedures, it is possible to perform the oxidation
of Epp and Widlanski in the absence of metalli c salts.

– 18 –

(3)
Nitroxide free radicals as mediators in selective
oxidation reaction

– 19 – There are a lot of oxidation reactions process in the field of organic chemistry this reaction
are very important in our lives and in industrial processes.
nitroxide free radical compound have so many applection in organic chemistry like
oxidation of primary or secondary alcohols, oxidation of amine by involvement with some
of catalysts .
2,2,6,6 -tetramethylpiperidin -1-yl TEMPO and its derivative free radical compound one of the
most important in oxidation reaction that enter into reactions as catalyst with interventions a
lot of catalysts to increase its effectiveness, selectivity, high re sult and low toxicity in this
oxidation reaction.
The oxidation reaction when using this kind of nitroxide free radical are easy , high results
of product and possible recycling of free radicals compounds while remaining a long time
without being deco mposed. Following so many reaction using nitroxide free radicals :

A- Nitroxide free radical as catalyst with metals for oxidation alcohols
Heterogeneous catalysts are favoured for many chemical reactions within industrial settings,
The ability to recycle the catalyst often remains a challenge after the chemical reaction is
completed, or when improvements to the overall economic efficiency of the process have to
be realized.
So many oxidation methods toward alcohols have been reported in literature using different
types of catalyst, We see some examples of TEMPO as catalyst to oxidation of alcohols with
a cocatalyst .
In this oxidation reaction there is a high result of product with selectivity, less effort, Easy
reaction and low toxicity is available.
– Room temperature Fe(NO 3)3.9H 2O/TEMPO/NaCl – catalyzed aerobic oxidation
of homopropargylic alcohols.
So many oxidation methods toward alcohols have been reported in literature using at least a
stoichiometric amount of oxidants such as DMSO, MnO 2, chromium o xides also hypervalent
iodine compounds. This article use TEMPO as catalyst to oxidation one type of alcohol with
a cocatalyst .

– 20 – As a mild and natural terminal oxidant, molecular oxygen would be the best alternative from
the viewpoint of eco -friendly and economic advantages.[23]
On the other hand, 2,2,6,6 -tetramethylpiperidine -N-oxyl (TEMPO) has been reported in
literature as the catalyst to oxidize alcohols with various oxidants including molecular
oxygen.[24]
Therefore, developing novel protocol for t he oxidation of alcohols using molecular oxygen as
terminal oxidant under mild conditions is highly required.
They tried the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol (Fig. 13). When use 10 mol
%from (Fe(NO 3)3.9H 2O, TEMPO, and NaCl) (the role of Cl- in this oxidation it is probably
working as a ligand to Fe+3 to accelerate the oxidation) this reaction work smoothly at room
temperature under atmospheric pressure of molecular oxygen affording corresponding
homopropargylic ketone in 91% NMR yield.

Fig. 13. Oxidation of a propargyl alcohol
They tried in this oxidation to optimize the reaction conditions based on solvent effect the
result showing in table 1.
Can see in this result when use toluene, ethyl acetate, and THF as solvent, but when use
DCE the full conversion and highest NMR yield, Lowering the catalyst to 5 mol % each of
Fe(NO 3)3 9H2O / TEMPO / NaCl, only 76% NMR yield and 14% recovery of
homopropargylic alcohol in 20 h was observed (Table 1 , entry 5). When Cu(NO 3)2 3H2O
was used instead of Fe(NO 3)3.9H 2O, the yield was obviously lower (Table 1, entry 6).

– 21 – Table 1. Optimization of the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-o

a5 mol % each of the three catalysts were used here bCu(NO 3)23H 2O was used instead of Fe(NO 3)39H 2O.
In this oxidation reaction could work smoothly at room temperature under atmospheric
pressure of molecular oxygen affording corresponding homopropargylic ketone.
– Aerobic oxidation of alcohols by using a completely metal -free catalytic system
This anther article use 2,2,6,6 -tetramethylpiperidine -1-oxyl (TEMPO) as cocatalyst.
They use NH 4NO 3, 2,2,6,6 -tetramethylp iperidine -1-oxyl (TEMPO) and H+ , oxidation in this
article simple, safe, inexpensive, efficient and chemo selective mediator for aerobic oxidation
of various primary, secondary benzyl and alkyl alcohols, including those bearing oxidizable
heteroatoms (N, S, O) to the corresponding aldehydes or ketones.
Air oxygen under slight overpressure plays the role of the terminal oxidant, which is
catalytically activated by redox cycles of nitrogen oxides released from a catalytic amount of
NH 4NO 3 and cocatalyzed by TEMPO (nitroxyl radical compound), under acidic conditions,
which are essential for an overall activation of the reaction system.
The synthetic value of this reaction system and its green chemical profile was illustrated by a
10 g scale -up experiment, pe rformed in an open -air system by using a renewable and reusable
polymer -supported form of TEMPO ( OXYNITROX).
In this project use aerobic oxidation of alcohols supported by either catalytic, they used
benzyl alcohol as substrate see table 2. Entry Time (h) Solvent Yield Recovery
1 4 DCE 91 –
2 20 Toluene 89 4
3 20 Ethyl
acetate 52 26
4 20 THF 25 73
5a 20 DCE 76 14
6b 20 DCE 52 36

– 22 – Authors assu med that nitrates as a potential source of nitric oxides would not be suitable for
the catalytically mediated direct oxidation, because NO / NO 2 has an insufficient redox
potential [E°(NO 2/ NO) = 1.03 V]. The presence of stable nitroxyl radicals as additional
electron -flow carriers could be beneficial for the efficiency of the overall process.
The increased reactivity of the nitroxyl radicals under ordinary acidic conditions causes
disproportion cation and formation of active oxoammonium cation inter mediates
[E°(TEMPO cation / TEMPO) = 0.76[25] as well as nitric oxide sourcing compounds.
Accordingly, they chose TEMPO and HClO 4 as cocatalysts to establish an efficient and
selective aerobic process.
They use the most widespread and environmentally frien dly transition -metal catalyst,
iron(III) nitrate (20 mol -%) acid use here to achieve good conversion of alcohol into
benzaldehyde at room temperature (Table 2 Entry 1). But they use of copper (II) nitrate
without the presence of acid (Entries 2 and 3).
Sodium nitrate as an alkali metal candidate was found to be inefficient at room temperature
(Entry 5), ), but catalyzed the reaction to completion at 60 °C in the presence of 10 mol -%
acid (Entry 6).
They found neutral medium the catalyst unreactive (Entry 7), when use acidic at room
temperature efficiency more obtained (Entry 8). But the authors when increase the
temperature to 60 °C (Entry 9).

Fig. 13. Novel oxidation system

– 23 – Table 2 . Results using ammonium nitrate as cocatalyst
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
7 NH 4NO 3 – 60 7 0
8 NH 4NO 3 HClO 4 10 20 7 27
9 NH 4NO 3 HClO 4 10 60 4 100

The role of the acids in the oxidation reaction they found that acids with p Ka values (Table
3), when use weaker acids gave worse or even negative results, but when use , H 2SO 4 (aq.
98%) or HCl (aq. 37%) give the most abundant acids.

Fig. 14. Novel oxidation system

– 24 – Table 3. The effect of acid on the aerobic oxidation of benzyl alcohol with NH 4NO 3 and
TEMPO.[a]
Entry Acid Pka Conv. 1a 2a [%]b
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
7 H2SO 4 -9 100
aReaction conditions: 1a (1 mmol), TEMPO (5 mol -%), NH 4NO 3 (10 mol -%), acid (aq., 10 mol -%), MeCN
(2 mL), 60 °C,4 h, air balloon. bConversion of 1a into 2a determined from 1H NMR spectra of crude
reaction mixtures.
The use of organic solvents in chemical processes is one of the most conflicting issues from
the green -chemistry point of view.[26] .
The most desirable are solvent -free transformations or those performed in recyclable and
reusable reaction media like alc ohols, ethyl acetate, green ethers.
In this oxidation aerobic oxidation of benzyl alcohol by using under solvent -free reaction
conditions was unsuccessful, also the same when use reactions in H 2O, MeOH, 2 –
methyltetrahydrofuran and Solkane (1,1,1,3,3 -pentafluorobutane, HFC 365) as preferred
environmentally benign reaction media.
Good conversion was observed by using cyclopentyl methyl ether (66%), and quantitative
conversion was achieved in aceto nitrile.
They also checked the efficiency of four chosen nitroxide radicals, including TEMPO and
three TEMPO derivatives (4 -HO-TEMPO, 4 -HO-TEMPO benzoate, and 4 -MeOTEMPO)
(Fig. 15).

– 25 – Trial oxidations were carried out with benzyl alcohol ( 1a) in acetonitri le with variations of
nitroxide catalyst loading and 5 mol -% HCl (aq. 37%) and 5 mol -% NH 4NO 3 at mild
temperature for 24 h.
Under identical conditions, 4 -substituted derivatives were somewhat more efficient than
TEMPO; however, because the latter is con siderably less expensive, its use seems to be more
reasonable. Of the tested nitroxide radicals, 4 -HO-TEMPO benzoate seemed to be the most
efficient under the same conditions.
Full conversion of benzyl alcohol into benzaldehyde was achieved by using only 0.075 mol –
% catalyst.

This image from Eur. J. Org. Chem. 2014, 395 –402
Fig. 15. Efficiency of TEMPO, 4 -HO-TEMPO, 4 -HO-TEMPO benzoate and 4 -MeO -TEMPO
cocatalysts in the aerobic oxidation of benzyl alcohol by using the NH 4NO 3/TEMPO/HCl

They says in this article all oxidation reaction in present of TEMPO , NH 4NO 3 and HCl as
catalyst under air or argon it‘s give negative result, and if any one of the three compounds
(catalyst) absence not give any result (no convert to benzaldehyde from benzyl alcohol).

– 26 – – Copper(I) / keto ABNO catalysed aerobic alcohol oxidation
In this article the authors confirm the compound Cu(I)/9 -azabicyclo[3.3.1]nonan -3-one N –
oxyl (keto ABNO) is highly effective for the oxidation of secondary alcohols in aerobic
catalyst system, and aliphatic substrates is unactivated .
The effect of gas and pressure composition on catalyst performance are examined. The
selective oxidation of alco hols is an important reaction in organic chemistry.
This fundamental reaction still poses problems when carried out on a larger scale, as
traditional methods often use toxic reagents and/or inefficient methods.[27] the catalyst system
is composed of a Cu (I) salt combined with 2,2 ′-bipyridine (bpy) as a ligand, N -methyl
imidazole (NMI) as a base and the stable radical TEMPO is most active version.
They use catalytic components are commercially available and employ a small scale on an
―open flask‖ approach , using an air as the oxidant.
In this oxidation very high selectivity for primary alcohols and secondary alcohols.
The poor of Cu/TEMPO systems for secondary alcohols due to steric hindrance. The
mechanism for alcohol oxidation involves the Cu complex a nd radical working in unison.[28]
For efficiently oxidise replacing TEMPO with a radical that is less sterically hindered should
remove this limitation.
In Fig. 16 the structures of TEMPO with some sterically unhindered stable nitroxyl radicals.
TEMPO h as the most widely studied stable radical used in a number of alcohol oxidation
systems, for example, TEMPO/sodium hypochlorite type oxidations have been applied on an
industrial scale.[29]

This image from Catal. Sci. Technol., 2014, 4, 1720 –1725

Fig. 16. Comparison of TEMPO with unhindered nitroxyl radicals .

– 27 – There have also been reports of these systems being used with O 2 as the terminal oxidant,
with initial reports using NOx type co -catalysts (e.g. sodium nitrite or nitric acid).[30]
More recently, Cu / keto ABNO and Cu/ABNO aerobic systems have been used for the
oxidation of amines to imines[31] (and subsequent derivitisation) and the oxidation of amines
to nitriles.[32] They use keto ABNO as a replacement for TEMPO.
ABNO can be prepa red in three [33] or four[34] steps, but in three steps
keto ABNO can be prepared. In first they have three model substrates shown in Fig. 17 for
test the ability of Cu / keto ABNO to oxidise secondary alcohols that Cu/TEMPO struggles to
or indeed cannot oxidase .
The Cu/ TEMPO systems have excellent substrate scope tolerance (for example heteroatom
and olefin containing molecules).
But they focus on this limitation of secondary alcohols and the reactivity of substrates. 1 –
phenylethanol is an example of secondary alcohol that the Cu(I) / TEMPO system can
oxidise.[35] ; 2-octanol is an aliphatic is unactivated alcohol and isoborneol is a sterically
hindered, unactivated alcohol.

Fig. 17. Secondary alcohols used as model substrates.
isoborneol has been s hown as an excellent test of steric hindrance using nitroxyl radicals
under hypochlorite conditions.[36] In Fig. 18 they show a comparison of reactivity between
keto ABNO, TEMPO and 4 – oxo TEMPO for the three model substrates.

– 28 –
This image from Catal. Sci. technol, 2004, 4, 1720 -1725.
Fig. 18. Comparison of ketoABNO, TEMPO and 4 -oxoTEMPO for the
oxidation of secondary alcohols. Reaction conditions: 1 mmol of substratein acetonitrile (5
mL), nitroxyl radical (1 mol%), CuI (7.5 mol%),bpy (7.5 mol%), NMI (10.5 mol%), 25 °C,
ambient air, stir rate = 340 RPM.
They have included 4 -oxoTEMPO as perhaps this is more analogous to keto ABNO.
In this oxidation used 7.5 mol% CuI, bpy and 10.5 mol% NMI with 1 mol% of the radical.
They had anticipated that keto ABNO w ould be more reactive than TEMPO.
In the case of TEMPO systems ,
Typically the copper complex and radical are used at 5 mol% loadings.[37] However, when the
copper complex and base were reduced to 1 and 1.4 mol% respectively, performance was
poor.
When th e copper complex and base were kept at higher loadings excellent catalyst
performance was observed with lower radical loadings.
These results are in -line with previous mechanistic studies of Cu / TEMPO systems. In fig.
17. Shown difference in performance of keto ABNO compared to TEMPO and 4 –
oxoTEMPO.

– 29 – The radicals TEMPO and 4 -oxoTEMPO can oxidise 1 -phenylethanol and no oxidation
obtained for the unactivated alcohols 2 -octanol and isoborneol.in this reaction Cu(I) /
TEMPO can oxidize some activated seconda ry alcohols [38] and nearly 40% yield of
acetophenone was obtained in four hours with this system. The yield was decreased when use
4-oxoTEMPO.
Steves and Stahl reported a study which focused on the use of Cu(I) / 9 -azabicyclo[3.3.1]
nonane N -oxyl (ABNO) f or aerobic alcohol oxidation.
They compared between TEMPO, 4 -methoxyTEMPO and 4 -oxoTEMPO against ABNO,
keto ABNO and AZADO (2 -azaadamantane N -oxyl),
The behavior its similar to that shown in fig. 16, the sterically less hindered radicals delivered
superi or reactivity to TEMPO derivatives and particularly for secondary alcohols. cyclo
hexane methanol when use unhindered radicals to compared for the oxidation at loadings of 5
mol% Cu complex and 5 mol% radical.
They found that all of the aforementioned un hindered radicals delivered similar reactivity
under these conditions.
Their study focused on the use of ABNO and the catalyst system was further optimised to: 5
mol% Cu(MeCN) 4OTf, 5 mol% 4,4 ′-dimethoxy -2,2′-bipyridine (MeObpy), 10 mol% NMI
and 1 mol% ABNO. They use this system to oxidise a wide range of primary and secondary
alcohols at room temperature and at these loadings, many oxidation converted in 1 h.
In this article focus on examine the reactivity o f their Cu(I) / keto ABNO system for the three
representative substrates shown in fig. 16, and also study the development of a solid
supported ABNO derivative.
In Fig. 18 it can see keto ABNO enabled the oxidation of all three secondary alcohols at a
very similar rate under these reaction conditions.
To test their theory they examined the influence of stir rate on the reaction. they examined
stirrer speed effects with 1 mol% and 0.1 mol% loadings of keto ABNO for both 1 –
phenylethanol and 2 -octanol. Differ ent stirrer speeds were tested using a standard round
bottom flask set -up, open to the air.
There is arguably a limit to how much you can improve the efficiency of the gas -to-liquid
mixing using such a set -up, therefore they also employed a mechanically stirred reactor/view
cell with a constant flow of air supplied to avoid O 2 depletion.

– 30 – This reactor meant they had to carry out reactions on a slightly larger scale; however, it is
specifically designed for efficient mixing.
It has a gas entrainment stirrer, which at high operating speeds (in this case 2400 RPM)
delivers excellent dispersion of gases into the liquid phase.
The reactor also has a viewing window that allows observation of the mixing, and they could
see that at the high stir rate the mixture was very well mixed and highly aerated.

– Anaerobic nitroxide -catalyzed oxidation of alcohols using the NO + NO· redox
pair
In this articles a new method for alcohol oxidation using TEMPO or AZADO conjunction
with BF 3 ·OEt 2 or LiBF 4 as precatalysts and tert-butyl nitrite as a stoichiometric oxidant has
been developed.
The system is based on a NO+ /NO· pair nitroxide reoxidation under anaerobic conditions.
This allows the simple, high -yielding conversion of various a chiral an d chiral alcohols to
carbonyl compounds without epimerization and no formation of nonvolatile byproducts.
Alkyl nitrites are a source of the nitrosonium ion, a strong oxidizing agent with a redox
potential of 1.0 V vs ferrocene.[39] Some time ago, authors used the NO+ /NO· pair as
stoichiometric SET oxidants .[40]
This triggered the author interest to apply it for TEMPO reoxidation.[41] They report here that
tert-butyl nitrite (TBN) as a convenient and cheap NO+ precursor efficiently mediates alcohol
oxidations catalyzed in the presence of BF 3 OEt 2 or LiBF 4 providing aldehydes and ketones
in high yield without compromising resident stereocenters.
When increasing the amount of BF 3 OEt 2 to 1.35 equiv improved the yield of 79% (Entry 2).
n-Butyl nitrite was similarly effective.
The oxidation in CH 2Cl2 also proceede in 70% yield (Entry 3). HBF 4 and LiBF 4 provided
good yields, although the reaction with LiBF 4 was considerably slower (entries 4, 5). Benzyl
alcohol served to optimize the catalytic oxidations (Table 4).
Using diethyl ether as the solvent gave only in 30% yield, probably due to precipitation of the
active oxidant, while switching to CH 2Cl2 at a 10 mol % loading at room temperature
provided a very good 94% yield after 4 h (entry 2).

– 31 – Heating the reaction mixture to reflux and reduction of the catalyst loading to 5 mol % led to
similar yields (entries 3, 4).
However, when the amount of catalyst was further decreased to 1 mol %, a drop in the yield
to 82 % was observed (entry 5).
A reaction in the absence of TEMPO under otherwise identical conditions also gave similar
result, however in a lower yield and after a considerably longer reaction time.

Fig. 19. Oxidation of benzylic alcohol using butylnitrite

Table 4. Results obtained using butylnitrite
Entry Solvent Temp Time(h) Yield %
1 Et2O Rt 5 30
2 CH 2Cl2 Rt 4 94
3 CH 2Cl2 Reflux 0.75 95
4 CH 2Cl2 Reflux 1.5 97
5 CH 2Cl2 Reflux 5 82
6 CH 2Cl2 Reflux 5.5 73

The mechanism of this oxidation can be proposed as follows (Fig. 20). First TBN reacts with
the catalytic amount of BF 3 OEt 2 to generate nitrosonium tetra fluoro borate and the borate
ester.[42] The nitrosonium salt oxidizes to the N -oxopiperidinium salt.

– 32 – The alcohols are subsequently oxidized by salt hydroxylamine and tetra fluoro boric acid,
which is in equilibrium with its salt. Another equivalent of TBN subsequently reoxidizes to
thus closing the catalytic cycle.

This image from American Chemical Society 2014, 16, 58 -61
Fig. 20. Proposed mechanism of alcohol oxidation with TBN
The oxidation of alcohols catalyzed by nitroxides is a widely used methodology in organic
synthesis. Usually 2,2,6,6 -tetramethylpiperidin -1-oxyl (TEMPO) is used as the catalyst with
stoichiometric oxidants suc h as bleach, tert-butyl hypochlorite, elemental halogens, bis
(acetoxy) iodobenzene BAIB, or tri chloro isocyanuric acid.
Catalysis based on azaadamantane – (AZADO) and azabicyclo [3.3.1] nonane -(ABNO) type
nitroxyl radicals has been more recently used , the condition of this oxidation are shown in
fig. 20 and Table 4.
B- Nitroxide free radical as catalyst for oxidation or dehydrogenation of amines
The oxidation of primary amines into the corresponding nitriles constitutes a very useful
functional group transformation in organic synthesis, and the plethora of oxidizing agents for
such a transfor mation documented in literature directly demonstrates the importance with
which the functional group transformation has been addressed.[43]
Amines are acutely sensitive to oxidation, and a host of products may be generated depending
on the oxidant. Catalyt ic systems for aerobic oxidation of amines to nitriles have been

– 33 – developed that involve catalytic quantities of a, a base, cuprous iodide, and an appropriate
ligand for the metal.[44]
TEMPO catalyst with anther catalyst use to oxidation different type of amines convert to
corresponding of nitriles, this oxidation are sensitive and the product depending on the the
TEMPO has been used to a much lesser extent in oxidation reactions of amines. Semmelhack
and Schmid reported TEMPO assisted electro oxidation of amines to nitriles and carbonyl
compounds in 1983.[45]
For example using simple CuBr 2-TEMPO catalytic system for aerobic oxidations of primary
and secondary benzyl amines and TEMPO with trichloroisocyanuric acid .

– Facile oxidation of primary amines to nitr iles using an oxoammonium salt
In the oxidation amines are acutely sensitive and the product depending on the the oxidant.
In this article the oxidation of a primary amine to conversion to a nitrile,
This transformation, which formally involves a double dehydrogenation, has been
accomplished in a variety of ways[46] including transition -metal catalyzed
dehydrogenation,[48] and aerobic oxidation catalyzed by transition metals.[47]
More recently, catalytic systems for aerobic oxidation of amines to nitri les have been
developed that involve catalytic quantities of a, a base, cuprous iodide, and an appropriate
ligand for the metal.[49]
They using oxoammonium salt (a) with stoichiometric quantity to oxidation of a primary
amine to corresponding nitrile,
In the oxidation using inexpensive reagents via a well -defined process under mild
conditions, the reduced oxidant (b), a stable nitroxide, may be recovered and recycled using
commercial bleach to regenerate the oxoammonium salt.
The oxoammonium salt, 4 -acetamido -2,2,6,6 -tetramethylpiperidine – 1-oxoammonium tetra
fluoro borate (a), is a stable, highly crystalline, yellow solid.

– 34 – The salt is commercially available. Alternatively, it is easily prepared in a few simple steps
from 4 -amino -2,2,6,6 -tetramethylpip eridine and inexpensive reagents in multimole
quantities.[50]

Fig. 21. Oxoammonium salts
In this oxidation of primary amines to nitriles using (a) is accomplished as follows:
slow addition (syringe pump; (15−20 mL/h) of an approximately 0.5 M solution of the amine
in dry methylene chloride to a stirred slurry of 4 molar equiv of 1 in dry methylene chloride
(150 ml per 10 mmol of amine) containing 8 molar equiv of dry pyridine f ollowed by stirring
the reaction mixture at room temperature or at gentle reflux under an atmosphere of nitrogen
for a period of time. A simple extractive workup affords essentially pure nitriles, without the
need for chromatographic purification, in good to excellent yield as evidenced by the results
presented in Table 5.
The stoichiometry of the overall process, depicted in fig. 22, eq 1, requires explanation. For
the stepwise oxidation of the amine to an aldimine (Fig. 22, eq 2) and then to the nitrile.
(Fig. 22, eq 3), 2 molar equiv of (a) are required.
However, in the presence of base, (a) and the hydroxylamine (c) synproportionate (Fig. 22, eq
4) to give 2 molar equiv of nitroxide (b).[51]
Thus, a total of 4 molar equiv of (a) are required for the t ransformation and the product
mixture consists of nitrile (Table 5, pyridinium tetra fluoro borate, and nitroxide (b).
Although only 4 molar equiv of pyridine would seem to be required for the transformation, an
excess of pyridine was used so as to avoid protonation of the amine substrate.
It is important to note, as detailed in the supporting information, that the nitroxide may be
recovered with 70−80% efficiency and recycled to give (a).
The results summarized in Table 5 demonstrate that the oxidation protocol is a robust one.
Benzylic and allylic amines are oxidized more quickly than aliphatic amines, typically 12 h at
room temperature for benzylic amines and 24−36 h at room temperature for aliphatic amines.

– 35 – Benzylic amines bearing strongly electron -withdrawing substituents are, however, oxidized
rather slowly (Table 5, entries 7 and 9).
Sluggish oxidations may be accelerated, with little loss in yield, by simply heating the
reaction mixture at gentle reflux (Table 5, entries 9, 13, and 14).

Fig. 2 2. Oxidation of primary amines to nitriles

– 36 – Table 5 . Oxidation of primary amines to nitriles (Fig. 14, eq 1a)
Yield c % Timeb , h Nitrile Entry
92 12
1
93 12
2
86 12
3
90 12
4
86 12
5
73 12
6
89 24
7
87 12
8
75d 24d
9
90 12
10
91 14
11
92 14
12
93, 88d 36 , 14d
13
95 , 92d 24, 12d
14
aAll reactions were conducted on a 10 mmol scale. bTime reaction mixture was stirred at room
temperature or reflux. cIsolated yield of chromatographically pure product. dReaction mixture was
heated at gentle reflux

– 37 – – A selective and mild oxidation of primary amines to nitriles with
trichloroisocyanuric acid
The oxidation of primary amines into the corresponding nitriles constitutes a very useful
functional group transformation in organic synthesis, and the plethora of ox idizing agents for
such a transformation documented in literature directly demonstrates the importance with
which the functional group transformation has been addressed.[52]
However, a lot of drawbacks may be encountered in using some of these reagents suc h as low
yields, harsh reaction conditions, tedious work -up procedures, and some limitations.
In addition, some of them are corrosive, toxic, expensive, or commercially unavailable.
Consequently, there is a need for the development of protocols using read ily available and
safe reagents, which lead to high yield of nitriles from primary amines.
Trichloro isocyanuric acid (TCCA) is a stable and inexpensive reagent frequently used for
swimming -pool disinfection. Some recent application of the utilization of T CCA in organic
synthesis include thioacetalization of carbonyl compound,[53] conversion of alcohols to
halides,3 carboxylic acids to acid chloridescarboxylic acids to acid chlorides,[54], alkenes to _
β-chloroethers[55] N-nitrosation of N,N-dialkylamines[56]selective mononitration of phenols[57]
and oxidation of alcohols to carbonyl compounds[58] aldehydes to methyl esters[59] thiols to
disulfides,[60] selenols to diselenides[61] and sulfides to sulfoxides[62] (To the best of their
knowledge, however, th ere is no indication in the literature on the utilization of TCCA as an
oxidant for the conversion of primary amines into nitriles. Herein, they wish to report a new,
simple and extremely efficient procedure for the preparation of nitriles from primary ami nes
utilizing TCCA in the presence of catalytic 2,2,6,6 -tetramethyl – 1-piperidinyloxy, free radical
(TEMPO) under mild reaction conditions as outlined in Fig. 23.

Fig. 23. oxidation of primary amines

Their preliminary studies were carried out with benzylamine ( 1d) as a model substrate in
order to establish the best reaction conditions. At the outset, the influence of solvent on this
oxidation was investigated. In Et 2O, dioxane, and THF, only low yield of benzonitrile ( 2d)
was obtained (Table 6, entries 1 –3); a dramatic increase in the yield, however, was obtained
in CH 2Cl2 (Table 6, entry 4), which was therefore used as the solvent in all further

– 38 – experiments. Next, the effect of temperature was examined. Enhancing the t emperature from
0 to 10 °C resulted in a considerable increase in the yield (49 to 88%, Table 6, entries 5,6). A
somewhat higher temperature (10 °C instead of 5 °C) led to shorter reaction time, but also
resulted in a significant decrease in the yield (Tab le 6, entry 7).
Table 6. Optimization of the Reaction Conditions for the TCCA Mediated Oxidation of
Benzylamine ( 1d) to the Benzonitrile ( 2d)
Yeildb
% Time
H 1d/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 CH 2Cl2 4
49 6 1:1.2 0 CH 2Cl2 5
88 3 1:1.2 10 CH 2Cl2 6
69 1 1:1.2 10 CH 2Cl2 7
45 5 1:0.5 5 CH 2Cl2 8
72 3 1:0.8 5 CH 2Cl2 9
90 2 1:1.3 5 CH 2Cl2 10
90 2 1:1.5 5 CH 2Cl2 11
aAll reactions were carried out according to the typical procedure. bYield of isolated pure product
The following experiments were therefore carried out at 5 °C. Finally, the oxidation was
carried out by varying the molar ratio of 1d to TCCA from 1:0.5 to 1:1.5.
It was observed that an increase in the 1d / TCCA molar ratio increased the yield of 2d, while
further increase in the amount of TCCA was not effective and gave only comparable yields.
When 1 equivalent of 1d was used with 1.3 equivalents of TCCA, 90% yield of 2d was
achieved (entry 10). Thus, a ratio of 1:1.3 was found to be the most suitable for this reaction.

– 39 – Guided by the above experiments with benzylamine ( 1d), a standard procedure was
employed for the oxi dation of other aliphatic, aromatic and heterocyclic primary amines with
TCCA, and the results are summarized in Table 7.

Table 7. Oxidation of Primary Amines 1a–q into Nitriles 2a–q with TCCA
Entry R Time (h) Producta yeildb
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

– 40 – The results illustrated in the Table 7 indicate that this oxidation is very successful for a
variety of primary amines.
Moreover, benzyloxy (entry 11), C,C -double bonds (entry 9), hydroxy (entry 12), N,N-
dimethlylamino (en try 8) groups present in the molecule were found to be resistant under the
reaction conditions employed, which were also described in the oxidation of alcohol to
carbonyl compounds.[63]
It is interesting to note that benzylic amines were oxidized more rea dily with a higher yield
than their aliphatic counterparts, just as reported in the dehydrogenation procedure of amines
to nitriles using NiSO 4 / K 2S2O8 system. at the same time, it is noteworthy that the presence
of catalytic TEMPO was essential for the d ehydrogenation of amines to nitriles.
No desirable nitriles were formed in its absence and the reaction did not go to completion
when lesser catalytic amounts of TEMPO was used in conclusion,
they have developed an efficient method for oxidative conversi on of the primary amines to
nitriles employing trichloroisocyanuric acid. Prominent advantages of this new method are its
mild reaction conditions, operational simplicity, and high yields.
Oxidation of Benzylamine (1d) to Benzonitrile (2d); Typical Procedure Tri chloroisocyanuric
acid (30.23 g, 130 mmol) was slowly added to a solution of benzylamine ( 1d; 10.7 g, 100
mmol) in CH 2Cl2 (200 mL), followed by addition of TEMPO (0.195 g, 1.3 mmol).
The reaction mixture was then stirred for 2 h at 10 °C and then quenched with H 2O (150 mL).
The organic layer was separated and the aqueous layer was extracted with CH 2Cl2 (3 × 10
mL).
The combined organic layers were washed successively with 0.5 N aq NaHSO 3 (2 × 10 mL),
aq 1 N HCl (2 × 5 mL) and H 2O (3 × 10 mL), and dried (Na 2SO 4). Evaporation of solvent
under reduced pressure gave the crude product, which was distilled to afford pure 2d (10.6 g,
90%) as a colorless oil; bp 189 –190 °C/ 760 Torr.

– Simple copper / TEMPO catalyzed aerobic dehydrogenation of benz ylic amines
and anilines.
As an efficient hydrogen extraction reagent, 2,2,6,6 -tetramethylpiperidinyl -1-oxy (TEMPO)
has been broadly used in catalytic oxidation reactions of alcohols.[64]
However, TEMPO has been used to a much lesser extent in oxidation r eactions of amines.
Semmelhack and Schmid reported TEMPO assisted electro oxidation of amines to nitriles

– 41 – and carbonyl compounds in 1983[65] and as far as they are aware this is the only example to
date.
They reported aerobic oxidations of primary and seco ndary benzyl amines by using simple
CuBr 2-TEMPO catalytic system for aerobic oxidations.
Also they report CuBr -TEMPO catalyzed dehydrogenative coupling of electron -rich
anilines, which yield azo compounds.
The oxidative self -coupling of benzyl amine wa s chosen as a model reaction to optimize the
reaction conditions (Table 8).
Copper salt and TEMPO are crucial for the oxidation of benzylamine (Table 8, entries 1 and
2). Different copper salts were tested for catalytic oxidation activity.
Copper(II) brom ide gave the best activity with 86% conversion of benzylamine to N –
benzylidene -benzylamine in 8 h (Table 8, entry 3).
Copper(II) chloride and copper(II) acetate led to only 58% and 62% conversions,
respectively, under the same reaction conditions (Table 8 , entries 4 and 5).

Fig. 24. Copper -catalyzed oxidative self -coupling of benzylamine
These differences are possibly associated with a ligand dissociation step in the reaction
mechanism, as the bromide anion would be weakly coordinated to the copper centre
compared with chloride and acetate anions.
This means that for the CuBr 2 system it is easier for the substrate to enter the coordination
sphere of the copper and become activated.
Good conversion was also achieved when copper (I) bromide was used.
No conversion was obtained when CuBr 2 was replaced with FeCl 3 Acetonitrile has been
broadly used as a solvent in Cu(II) -catalyzed oxidation reactions.[66] 86% conversion was
obtained in 8 h with a 2 : 1 (v/v) acetonitrile / water solvent mixture (Table 8, entry 3).

– 42 – No conversion was achieved in neat CH 3CN due to t he formation of a green precipitate
(Table 8, entry 7) that is presumably a coordination polymer of copper.
Conversion was decreased when the amount of CH 3CN was decreased in acetonitrile/water
solvent mixtures, probably because of a decrease in the solub ility of the organic substrate
(Table 8, entry 8). Only 8% conversion was obtained when a biphasic solvent mixture was
used (Table 8, entry 9).
This may be explained by unsatisfactory mixing of the reactants, catalysts and co -catalysts.
With the optimize d reaction conditions above in hand, they investigated CuBr 2-TEMPO
catalyzed oxidations for a range of primary and secondary benzylic amines (Table 9).
The electronic properties of substituents had no significant effect on the conversions and
selectivitie s.
This differs from a previously reported CuCl -catalyzed reaction where reaction selectivity
was affected by substituents all the benzylic amines studied whether containing electron –
withdrawing or -donating groups were smoothly oxidized to the correspond ing imines (Table
9, entries 1 –8).
This also contrasts with a recently reported V 2O5-H2O2 catalytic system,[68] where
significantly different reaction conditions were needed for the two classes of substrate, with
benzyl amines bearing electron donating gr oups being significantly less reactive than those
containing electron withdrawing groups.
Also, when using this Cu (II)/TEMPO catalytic system, the p -methoxy benzylamine
substrates achieved slightly faster reaction rates compared with p -chloro benzylamine (Table
9, entries 4 and 8). 80% GC -MS conversion was achieved in 8 h for the oxidation of p –
methoxy benzylamine, whereas 72% conversion was obtained for the oxidation of p -chloro
benzylamine in 8 h.
This is possibly due to a faster transamination for the phenyl methan imine intermediate when
a more basic (electron -donating) amine is used .
Unfortunately, the CuBr 2-TEMPO catalyst system was inactive for the oxidation of (R) -1-
phenylethanamine (Table 9, entry 9).

– 43 – This could be explained by the steric deman ds of the β -methyl group of the amine, which
would hinder the formation of the crucial species III in the proposed catalytic cycle.
For such a substrate, it would be challenging for Cα -H abstraction by the coordinated
TEMPO to occur.
However, some seconda ry amines could be converted to their corresponding imines in good
to excellent yields. However, the reaction conditions were more demanding than for the self –
condensation of benzylic amines.
In order to achieve high conversions, higher catalyst loadings and reaction temperatures were
essential.
If the catalyst loading was decreased to 5 mol % for the oxidation of dibenzyl amine, the
conversion dramatically dropped to 50%.
From this graph of catalyst loading and conversion, the reaction appears to be fir st order in
CuBr 2 -TEMPO, but more studies are needed to confirm this and to determine the relative
reaction orders for both catalyst and cocatalyst.
Also, it should be noted that dibenzyl amine could not be transformed to the imine at room
temperature.
Kinetic studies showed a first -order dependence for the reaction rate on the dibenzyl amine
concentration at 45 °C .
Very recently, Patil and Adimurthy reported CuCl -catalyzed aerobic oxidation of amines to
imines under neat conditions with 0.5 mol% catal yst loading.
The simple CuCl catalyst system could oxidize benzylic amines to imines efficiently and
moderately oxidize aliphatic and functional amines to the corresponding imines.
However, a higher reaction temperature was required compared with the sys tem reported
here. Also, for the oxidation of electron -donating benzyl amines, the selectivities for the
imine products were not notable.
As shown in Table 9, entry 4, only 78% selectivity was obtained due to the formation of p –
methoxy benzaldehyde as a b y-product.

– 44 – No benzaldehyde byproducts were observed in their reactions. However, their catalytic
system uses TEMPO as a co -catalyst.
This is a disadvantage, as TEMPO is the most expensive component in their catalytic system.
It would be desirable if TEMP O could be efficiently recycled and reused.
Chung and Toy reported a recyclable PEG modified Cu / TEMPO catalyst for selective
aerobic alcohol oxidation.[68]
The development of a recyclable Cu / TEMPO catalyst system or another reusable non –
precious metal -based catalyst system for aerobic oxidation reactions of amines is under way
in their group.
Table 8. Copper -catalyzed oxidative self -coupling of benzylamine
Entry Catalyst Solvent mix. Conv. %
1 CuBr 2 CH 3CN / H 2O(2/1) Trace
2 TEMPO CH 3CN / H 2O(2/1) n.r.
3 CuBr + 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 + TEMPO CH 3CN / H 2O(1/2) 53
9 CuBr 2+ TEMPO Toluene/ H 2O (2/1) 8

– 45 – Table 9. CuBr 2-TEMPO catalyzed primary and secondary benzylic amines
Entry Substrate Product Yriled %b
1 87(88)d
2
94
3
93
4
94(80c)(72d)
5
93
6 88
7
82
8
76(72c)
9
0
10 94ef(66d)
11 92ef
12 5c(50d, NMR yeild)
13
0(32d)
a Reaction conditions, unless otherwise stated: benzylamine (4 mmol), catalyst (0.10 mmol), solvent (9 ml),
air (1 atm), 25 °C, 12 h. b Isolated yield. c GC conversion, 8 h. d Under conditions reported in ref.
12d;entry 4, 78% selectivity (92% combined yield of imine and aldehyde). e 7.5 mol% catalyst loading. f
45 °C reaction temperature.

– 46 – C- Nitroxide free radical generation a polymer
Several free radical TEMPO functionalized s olid catalysts, prepared by immobilising
individual TEMPO molecules on to solid support materials as a covalently anchored
monomolecular layer .
So reaction TEMPO generation functionalized polymers this polymers have so many
advantage,
For example such polymers is TEMPO with NaBr and NaClO can produce oxidized starches
with different properties under good quality control, TEMPO -oxidized Konjac glucomannan
(OKGM) was developed as new material for preparing vegetarianhard capsules, a lacca se–
TEMPO system use to oxidation chitooligomer , ….etc.
There is same article show different type of polymers with TEMPO as following;

– TEMPO radical polymer grafted silicas as solid state catalysts for the oxidation
of alcohols
One of the most important desiderata in the field of green and sustainable technological
processes is improvement in catalyst performance.[d]
For many chemical reactions special in industrial heterogeneous catalysts are favored .
The ability to recycle the catalyst often remains a challenge after the chemical reaction is
completed, or when improvements to the overall economic efficiency of the process have to
be realized,[69] such oxidation reactions have frequently been performed with stoichiometric
amounts of inorganic oxidants, many of which are extremely hazardous to use or toxic. [70]
One of such compound use for this kind reaction its 2,2,6,6 tetramethylpiperidinyloxyl
(TEMPO) stable organic radical it's one of easy -to-handle heterogeneous catalysts, when use
in liquid phase oxidation reactions can easily recycled, have high efficiency and low toxicity.
A wide variety of derivatives and analogues of this type of stable free organic radical has
been reported[71 ]since TEMPO can work as a redox reagent, it has been used in oxidation
reactions under a variety of conditions.[72]

[d] Anastas, P. T., and Warner, J. C., Green Chemistry: Theoryand Practice, Oxford University
Press, London. (1998).

– 47 – several TEMPO functionalized solid catalysts, prepared by immobilising individual TEMPO
molecules on to solid support materials as a covalen tly anchored monomolecular layer, have
been previously studied for their potential in oxidation reactions.[73]
Same this reaction due to the low loading of TEMPO molecules onto the solid support
require more than stoichiometric amounts of these mono -molec ular layer solid state catalysts
to achieve acceptable product yields.
So in this reaction generation of TEMPO functionalized polymers, their group has reported
the preparation of TEMPO functionalized polyvinyl polymers, this polymer use as new
materials i n organic batteries, via the oxidation of the nitroxide radical and reduction of the
corresponding oxoammonium moiety of the TEMPO molecule.[74]
This polymeric TEMPO functionalized solid state catalysts based on multiply -displayed
TEMPO units introduced i nto a polymeric backbone, which has been concomitantly
immobilized onto a carrier surface.
a multiply -displayed TEMPO polymer grafted solid state catalyst of high radical density
would lead to recyclable heterogeneous catalysts with improved catalytic acti vity and
efficiency due to the increased number and accessibility of the active sites of the catalyst to
the substrate,
They describe herein methods to prepare a new type of TEMPO polymer grafted silica
materials and describe their application as novel s olid state catalysts for oxidation reactions. a
series of multiply -displayed TEMPO polymer grafted silicas has been synthesized by grafting
poly (2,2,6,6 -tetramethylpiperidinyl – oxymethacrylate) (PTMA)[75] onto silica.
They use a grafting from method its u sing the RAFT chain transfer agent,
S-methoxycarbonyl -phenyl -methyl S9 -trimethoxysilylpropyltrithiocarbonate, introduced
onto the silica surface to form a silica -supported chain transfer agent,[76]
Then, 2,2,6,6 -tetramethylpiperidine methacrylate was graf t polymerized using 1 by RAFT
polymerization and the so -formed precursor, poly (2,2,6,6 -tetra-methylpiperidine
methacrylate) grafted silica treated with 3 -chloroperoxybenzoic acid to yield the TEMPO
polymer grafted silica 2 (Fig. 25)

– 48 –
This image from RSC Adv., 2013, 3, 9752 –9756
Fig. 25 . TEMPO polymer grafted silica synthesis by ‘‘grafting from’’ method.

About the product 2 was characterized by IR, elemental analysis, and thermogravimetric
analysis (TGA).
TEMPO polymer grafted silicas with a radical densities approaching 100% of the theoretical
value The polymer graft ratio present for 2 was 57 wt% as calculated from the weight loss
observed by TGA from 200 uC to 600 uC due to the decomposition and removal of TEMPO
polymer from the surf ace of the silica.
Depending on the polymerization conditions, immobilized densities of the TEMPO units on
2, determined from the graft ratio, up to 1.6 mmolg-1 could be achieved .This density level is
considerably higher than that of commercially availab le silicas partially functionalized with a
mono -layer of TEMPO molecules (e.g. mono -TEMPO -Si, 0.6 mmol g-1).[77]
The molecular weight of the optimally grafted TEMPO polymer was determined by cleaving
the polymer from 2 using an aminolysis reaction.[78].
The molecular weight of the cleaved TEMPO polymer was measured by gel permeation
chromatography (GPC) and found to be Mn = 1.9 x104, Mw/Mn = 2.6.
This value is close to the theoretical value (Mn = 2.3 x 104) calculated from the monomer and
chain transfer agent concentration, indicating that the molecular weight of the grafted
polymer can be controlled by the RAFT polymerization conditions.
The most important value, the number of radical groups introduced onto the silica surface,
was estimated by supercon ducting quantum interference device (SQUID) measurements.

– 49 – The amount of radical groups on 2 was found to be only ca. 45% of the theoretical value.
This result suggests that under the ‗‗grafting to‘‘ conditions, treatment of the TEMPO
precursor molecule of 2 with 3 – chloroperoxy benzoic acid to form the radical grafted
polymer species was mainly associated with surface modification, with the intra -porous
regions of 2 not readily accessed due to steric restriction.
Based on these results, the synthesis of a series of TEMPO polymer grafted silicas with a
radical densities approaching 100% of the theoretical value, was undertaken using a
‗‗grafting to‘‘ method. 2,2,6,6 -Tetramethylpiperidine methacrylate was RAFT polymerized
with the chain transfer agent,( (4 -cyano -4-[(phenyl -thioxomethyl)thio] -1-(2-carboxyethyl) -1-
cyanoethylbenzodithio – ate),[79]and treated with 3 -chloroperoxybenzoic acid to form poly
(PTMA), 3.
By tuning the amount of the chain transfer agent present, different 39s of various molecular
weight s were synthesized.
The molecular weights of these polymers were again measured by GPC. The number of
radical groups introduced onto the poly (PTMA) was measured by SQUID, demonstrating
that all of these polymers had very high radical concentrations, typi cally above 90% of the
theoretical value.
The prepared 39s 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 sili cas, 49s (Fig. 26). 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 s ingle one operation.[80]

– 50 –
This image from RSC Adv., 2013, 3, 9752 –9756
Fig . 26. Synthesis of the TEMPO polymer grafted silica by the ‘‘grafting to’’ method.

The molecular weights of the poly (PMTA)s and the other characterization data of the
different 49s are summarised in Table 11. All samples showed a high level of TEMPO
immobilization (up to 2.1 mmol g-1) and a radical concentration greater than 90% of the
theoretical value the physical form and s ize of the derived TEMPO immobilization
particles was consistent with the presence of an extensively grafted layer.
Illustrative of these results, the morphology of the synthetic material 4 -2 (entry 2, in Table
11) was determined by scanning electron micr oscope (SEM) and dynamic light scattering
(DLS).
A SEM image of 4 -2 (Fig. 27) demonstrated the presence of largely spherical objects in the
size range of 80 –110 nm. The presence of a small percentage of particles of ca. 10 nm
average diameter can be attrib uted to the un -reacted fumed silica material.
The average size of 4 -2 was 108 nm from DLS which supported the result from SEM. The
size of 4 -2 was significantly higher than the size of the original amino functionalized silica
support, which had an average particle size of 9 nm.
As noted above, the size difference between the synthesized 4 -2 and amino functionalized
silica confirms the existence of an extensively grafted TMEPO polymer layer on the surface
of the silica.

– 51 – Table 10 . TEMPO polymer grafted s ilica 4 synthesis by grafting to method
radical
conc.b
(%) immobilized
TEMPOa
(mmol g-1) graft
ratioa
(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)
a Calculated by TGA. b Estimated by SQUID.

This image from RSC Adv., 2013, 3, 9752 –9756
Fig. 27 . SEM image of TEMPO Catalyst 4 -2.
As an initial evaluation of the catalytic performances of the TEMPO polymer grafted silicas
4-1, 4-2, 4-3, and 4 -4 (entry 1 –4 in Table 11, respectively), the oxidation of benzyl alcohol as
the substrate was examined (Table 12).
The efficiency of the TEMPO polymer grafted silica was also compared to a commercially
available mono -TEMPO Si. The reactions can be carried out in water or in a CH 2Cl2/water
bi-phasic system.
As evident from the results, 4 -2 showed the highest product conversion and reaction rate
constant compared to the other synthetic materials.
In addition, the conversion and the reaction rate constant of 4 -2 (> 95%, 1.01 x 10-2 L mol-1 s-
1) was much higher than that of the mono -TEMPO Si (58%, 0.23 x10-1L mol-1 s-1). No

– 52 – evidence for the oxidative modification of the aromatic ring was obtained as has previously
been noted[81] with other types of TEMPO -mediated oxidation reactions.
The need to use a co -catalyst, such as transition metal or nitric oxide derivatives,[82] or to
employ surface coating with an ionic liquid[83] is also circumvented with this new class of
immobilised poly TEMPO silica -based catalysts.
Moreover, the above results indicate that TEMPO polymer grafted silicas have a greatly
enhanced capability as oxi dation catalysts compared to monomer TEMPO functionalized
silicas due to the higher radical density that can be achieved by the grafted TEMPO
polymerisation procedure.
Interestingly, the oxidative capacity of the catalysts, 4, appeared to follow a parabol ic
dependency on the molecular weight of the grafted TEMPO polymer.
For example, the catalytic performance of 4 initially increased with polymer molecular
weight (4 -1–– 4-2).
This can be explained by the number of immobilized TEMPO units on the catal yst increasing
along with the molecular weight of the grafted TEMPO polymer.
However, above a certain value, the catalytic performance of 4 decreased with the molecular
weight of the grafted polymer (4 -2–– 4-4) with 4 -4, which corresponded to the high est
molecular weight grafted TEMPO polymer (Mn = 7.4 x 104), yielding the lowest conversion
and rate constant of the four different types of 4.
Although dispersion of the catalyst, and thus its efficiency, will be affected by the molecular
weight of the g rafted polymer, an alternative explanation for the decrease in catalytic
performance of the catalyst containing the highest molecular weight polymer species would
be steric crowding of the TEMPO moieties and lower solvation propensity of the larger
polymer ic chains.
In order to establish the reusability of the catalyst, the catalyst was recovered by filtration and
reutilised in subsequent cycles (Fig. 28). The catalyst was found to retain its activity for at
least five cycles of reuse.
The performance of the catalyst remained almost constant above 90% for all of these recycle
experiments.
These oxidation reactions with 4 were extended to various other alcohols. The oxidation of 1
octanol and 1 -decanol yielded the corresponding aldehydes in high yield (ca. 98–99%).

– 53 –

This image from RSC Adv., 2013, 3, 9752 –9756
Fig. 28. Recycling of the catalyst 4 -2 in the oxidation of benzyl alcohol (reaction time: 10
min, reaction temp: 5 0C, catalyst/alcohol: 0.5 mol%, solvent CHCl 3/ water).

Table 11 . Product conversion and reaction rate constant of the oxidation 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)

aReaction time: 10 min, reaction temp: 5 uC, catalyst/alcohol: 0.5 mol%, solvent CH 2Cl2/water.
bConversions were determined by NMR and GC.

– 54 – – TEMPO immobilized on polymer microspheres -catalyzed oxidation of
cyclohexanol by molecular oxygen

O2 are economic and environmental its green oxidant because O 2 is inexpensive and water is
the only byproduct.
because TEMPO is readily converted to a nitrogen carbonyl cation by a single electron
oxidation, and then the nitrogen carbonyl cation as a strong oxidant enables primary and sec –
ondary alcohols to be quickly oxidized to the corresponding aldehydes or ketones with a high
conversion rate and excellent selectivity.
Although these homogeneous TEMPO systems exhibit high catalytic activity for aerobic
alcohol oxidation, limitations still exist such as that the TEMPO chemical agent is
expensive, and as a homogeneous catalyst it is difficult to recover and recycle after the
reaction.
It is possible to overcome these limitations by immobilizing the TEMPO catalyst on a solid
support, and the heterogeneous TEMPO catalyst would have the advantages of easy
separation and efficient recycling. [84][85][86]
TEMPO has been immobilized on various solid supports, including silica gel, molecular
sieves and polymeric resins.[87][88][89]
Among these supports, the polymer resin is advantageous because active group can easily
introduced onto it by chemical modification, and these active groups can facilitate the
chemical bonding of TEMPO on the polymer resin.
The liter ature rarely has studied about heterogeneous TEMPO catalysts supported on polymer
resins.
In their previous study, crosslinked poly(glycidyl methacrylate) microspheres (CPGMA
microspheres) were prepared by suspension polymerization,
and TEMPO was bonded to the CPGMA microspheres by ring opening reactions between the
epoxy groups on the CPGMA microspheres and the hydroxyl groups of 4 -OH-TEMPO,
resulting in the heterogeneous catalyst microspheres TEMPO/CPGMA. [90].
In their present work, the heterogeneous catalyst TEMPO/ CPGMA was combined with a
cocatalyst Fe(NO 3)3 and was used in the aerobic oxidation of cyclohexanol as a secondary
alcohol under mild conditions.
The catalyst system constituted by the heterogeneous TEMPO/CPGMA and homogeneous
Fe(NO 3)3 effectively catalyzed the aerobic oxidation of cyclohexanol to cyclohexanone as the
sole product with good activity.

– 55 – It was also found that both the Fe3+ and NO 3 species in Fe(NO 3)3 showed work together.
Although ther e have been some reports on the aerobic oxidation of secondary alcohols by a
homogeneous TEMPO analog combined with Fe(NO 3)3,[91][92] they report for the first time
that the heterogeneous TEMPO, i.e. TEMPO immobilized on polymer microspheres,
combined with Fe(NO 3)3 can be used for the aerobic oxidation of a secondary alcohol.
The catalytic oxidation mechanism was proposed.
The result is valuable for the green and effective oxidation transformation of secondary
alcohols in organic synthesis.
They preparation the heterogeneous catalyst TEMPO/CPGMA by using the procedure
described in (with some changes), the heterogeneous catalyst TEMPO /CPGMA was
prepared. (1) The crosslinked polymeric microspheres CPGMA were first prepared by
suspension polymerization.
The continuous phase was comprised by distilled water containing polyvinyl alcohol and
NaCl.
The monomer GMA was mixed with the crossl inker EGDMA as the oil phase, and this
mixture was used as the dispersed phase.
By adjusting the agitation speed to ensure good mixing of the two phases, a suspension
polymerization system was formed.
The initiator azoisobutyronitrile (AIBN) was then add ed, and the crosslinking
copolymerization of GMA and EGDMA was carried out at 55 °C for 5 h under N 2
atmosphere, obtaining translucent crosslinked polymeric microspheres GMA/EGDMA
(denoted by CPGMA microspheres because GMA was the main monomer).
The avera ge diameter of CPGMA microspheres was 100 μm measured by an optical
microscope. (2) TEMPO was bonded onto CPGMA microspheres by a polymer reaction.
CPGMA microspheres were first soaked and swelled in N,N-dimethylformamide (DMF), and
then 4 -OH-TEMPO was add ed into the mixture.
The ring opening reaction between the epoxy groups on the CPGMA microspheres and the
hydroxyl groups of 4 -OH-TEMPO was con – ducted at 85 °C for 12 h under N 2 atmosphere
with Na 2CO 3 as a catalyst.
The TEMPO -immobilized microsphere TEM PO/ CPGMA catalyst was obtained.
The TEMPO/CPGMA microspheres were characterized by FTIR, SEM and a chemical
analysis method.

– 56 – TEMPO/CPGMA microspheres in combination with Fe(NO 3)3 was used in the catalytic
oxidation of cyclohexanol with molecular O 2 as oxidant at normal pressure. A typical
procedure is as follows.
In a reactor equipped with a mechanical stirrer, reflux condenser, thermometer and O 2 inlet,
50 mL of glacial acetic acid and 10 mL of cyclohexanol were added, followed by adding the
combinatio n catalysts containing 1.10 g of TEMPO/CPGMA microspheres and 0.242 g of
Fe(NO 3)3·9H 2O as the cocatalyst.
Oxygen at normal pressure was introduced into the mixture (15 mL/min).
The oxidation reaction was performed at 55 °C with continuously stirring for 36 h. Samples
of the reaction mixture were taken at fixed time intervals, and then measured immediately by
a gas chromatograph (GC) with the internal standard method.
The GC anal ysis results showed that cyclohexanone was the only product, and so the
cyclohexanone yield was the conversion of cyclohexanol.
The cyclohexanone yield was calculated from the GC data. After the oxidation reaction, the
TEMPO/CPGMA microspheres were soaked , washed with acetic acid and ethanol in turn to
completely remove cyclohexanone physically attached on the microspheres, and dried under
vacuum.
The recovered TEMPO/CPGMA microspheres were reused in the oxidation reaction of
cyclohexanol under the same c onditions to examine their recycling performance.
In order to understand the catalytic mechanism of cyclohexanol oxidation by molecular
oxygen, the catalytic property of the combination catalyst, TEMPO/CPGMA microspheres
and FeCl 3+NaNO 3 was investigated.
The effects of ratio of TEMPO/ CPGMA to Fe(NO 3)3, combination catalyst amount and
reaction.
In this work, the nitroxide free radical was immobilized on the surface of the polymer
microspheres containing epoxy groups by an elaborate molecular design.
CPGMA microspheres were first prepared by suspension copolymerization of GMA and
EGDMA used as a crosslinker.
There were abundant active groups, namely, the epoxy groups, on the CPGMA microspheres.
Through the ring opening reaction between the epoxy group on t he CPGMA microspheres
and hydroxyl group of 4 -OH-TEMPO under alkaline condition, TEMPO was chemically
immobilized on the surface of the CPGMA microspheres, and TEMPO/CPGMA
microspheres were prepared.

– 57 – The process to prepare TEMPO/CPGMA microspheres and the ir chemical structures is
schematically depicted in fig. 29.

This image from Baojiao Gao et al. Chinese Journal of Catalysis (2015), 36, 1230 – 1236

Fig. 29. Chemical structure of CPGMA and TEMPO/CPGMA microspheres.

In the characterization of the TEMPO/CPGMA microspheres, the infrared spectrum
confirmed their chemical structure, and their morphology was observed by SEM.
The oxidation of cyclohexanol by molecular oxygen was catalyzed by the TEMPO/CPGMA
microspheres a nd Fe(NO 3)3
Combination catalyst, and was carried out under normal pressure of molecular oxygen.
Fig.30 gives the curve of cyclohexanone yield, i.e., conversion of cyclohexanol versus time.
For comparison, the oxidation reaction was also conducted in the presence of
TEMPO/CPGMA alone, Fe(NO 3)3 alone and with no catalyst, and it was found that there was
no reaction in the three systems.

– 58 –
This image from Baojiao Gao et al. Chinese Journal of Catalysis (2015), 36, 1230 – 1236

Fig. 30. 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,
O2 ordinary pressure, acetic acid as solvent

For the reaction system with TEMPO/CPGMA microspheres and Fe(NO 3)3 added, the
oxidation of cyclohexanol was obvious, and the cyclohexanone yield was 44% in 36 h.
This showed the immobilized TEMPO in combination with Fe(NO 3)3 effectively catalyzed
the oxidation of cyclohexanol by molecular oxygen.
The results showed only their combination had a catalytic role in the oxidation of
cyclohexanol by molecular oxygen.
As reviewed above, various combinations of TEMPO or immobilized TEMPO and a
cocatalyst can catalyze the aerobic oxidation of alcohols. In the present catalyst system, the
immobilized TEMPO was the main catalyst, and Fe(NO 3)3 was a cocatalyst.
In order to confirm that Fe3+ and NO3– in Fe(NO 3)3 should work together, a combination of
TEMPO/CPGMA, FeCl 3 and NaNO 3 (with a molar ratio of FeCl 3 to NaNO 3 of 1:3) was used
in the reaction.At the same time, the combination of TEMPO/CPGMA and FeCl 3 or NaNO 3
were also used, and the results are given in fig. 31. When TEMPO/CPGMA, FeCl 3 and
NaNO 3 was used as catalyst, the cyclohexanone yield reached nearly 40% in 36 h, close to
that of TEMPO/CPGMA and Fe(NO 3)3, suggesting that the combination of FeCl 3 and NaNO 3
can take place of Fe(NO 3)3 in the catalytic sys tem.

– 59 –
This image from Baojiao Gao et al. Chinese Journal of Catalysis (2015), 36, 1230 -1236 .

Fig. 31. Curves of cyclohexanone yield with time using combination of TEMPO/CPGMA,
FeCl 3 and NaNO 3 as catalyst as well as using other component combination as catalyst.
Reaction
However, no oxidation reaction was observed when using the combination of
TEMPO/CPGMA and FeCl 3 or NaNO 3.
The results demonstrated that only Fe3+ or NO3– did not play a co -catalyst role in the catalytic
system, and only their combination did.
The above results confirmed that in the combination of TEMPO/CPGMA microspheres and
Fe(NO 3)3, both of Fe3+ ion and NO3– ion must act together.
a catalytic oxidation mechanism is proposed in fig 32.

This image from Baojiao Gao et al. Chinese Journal of Catalysis (2015), 36, 1230 -1236

Fig. 32. Catalytic oxidation mechanism of the combination of TEMPO/CPGMA and
Fe(NO 3)3

– 60 – D- Metal -free aerobic oxidations mediated N – hydroxyphthalimide.

The development of efficient and cheap catalytic systems for the selective oxidation of
organic substrates under mild and environmentally benign conditions represents one of the
major challenges in organic synthesis.[93]
In this context, the replacement of traditional oxidants, often used in stoichiometric amounts,
with molecular oxygen is mandatory in order to improve the beneficial impact of selective
oxidation on industrial chemistry[94]Nevertheless, classical autoxidation is u sually very slow
at low temperatures, and catalysis is required to activate O 2.
Transition -metal salts are particularly effective for this scope[95] but their use is often
detrimental for the selectivity of the process and they would not meet the standard s of green
chemistry‖. An alternative catalytic route is based on the use of N-hydroxyphthalimide
(NHPI), which have found ample application as ideal catalysts for the aerobic oxidation of
organic substrates[96]
NHPI acts as a precursor of the phthalimide N-oxyl (PINO) radical, which is the effective
catalyst promoting hydrogen abstraction processes (Fig. 33). The reactivity of NHPI and
PINO is related to the bond dissociation energy (BDE) of the O –H group, which was
estimated at 88.1 kcal/mol,[97]
This value is similar to the BDE of O –H in hydroperoxides, suggesting that the faster
reactivity of PINO compared to peroxyl radicals should be attributed to an enhanced polar
effect involved in the hydrogen abstraction by this nitroxyl radical. [98]
Furthermo re, NHPI also behaves as a relatively good hydrogen donor even at low
temperatures ( kH = 7.2 × 103 M−1s−1)[97] trapping peroxyl radicals before they undergo
termination.
PINO generation represents the key step of the overall process. Many transition met al salts
and complexes have been successfully used as cocatalysts for NHPI activation.
However, once again their use should be avoided in order to improve the sustainability of the
process. For this reason, in the past decade several efforts have been dev oted to the
development of catalytic systems for the metal -free activation of NHIs under mild conditions.
With an overview on the results reported in the literature in the past decade, they aim to
describe herein the most significant examples related to th e selective oxidation of organic
molecules with molecular oxygen, catalyzed by NHIs in the presence of nonmetal
cocatalysts.

– 61 – After briefly describing the role of classical radical initiators obtained by thermal
decomposition, they focus on some intriguin g redox systems, including nitric oxides,
laccase, quinones and aldehydes, which allow operation under very mild conditions, offering
efficient alternative solutions to the classical autoxidation processes, especially in the field of
the selective oxygenat ion of hydrocarbons.

Fig. 33. Catalytic role of NHPI in the selective oxidation of organic substrates.

The PINO activation by means of nitric oxide was first reported by Ishii et al. in 1997[99]
By reacting adamantane in a mixed solvent of benzonitrile and acetic acid under an
atmosphere of NO and in the presence of catalytic amounts of NHPI he observed the
formation of 1 -N-adamantylbenzamide as a principal product (Fig. 34), while when operating
under the same conditions but in the presence of molecular oxygen, 1 -nitroadamantane was
achieved in good yields.
Moreover, by simply moving into acetonitrile, they observed the selective oxygenation of
phthalane to the corresponding phthalaldehyde in 80% yield[100] In both cases the
reactionproceed s via the formation of a carbocation intermediate (Fig. 35). The same research

– 62 – group also reported the efficient air -assisted nitration of alkanes and alkyl side -chain aromatic
compounds[101] by nitrogen dioxide and nitric acid, under NHPI catalysis (Fig. 45).

Fig. 34. NHPI -catalyzed reaction of adamantane under NO atmosphere.

Fig. 35. Nitration of alkanes and alkyl side -chains of aromatics.
Both HNO 3 and NO 2 are able to promote the formation of PINO according to path (a) and (b)
reported in Fig. 36. These initiation steps lead to the formation of HNO 2 which, in turn, is
converted into HNO 3, H2O, and NO. The latter is oxidized by molecular oxygen back to NO 2,
thus justifying the higher efficiency of the NO 2/air system if compared with anaerobic
conditions.
In this context, they reported in 2004 that the HNO 3/O2/I2 system could promote the nitric
aerobic oxidation of alkylbenzenes under NHPI -catalysis, leading to the selective formation
of benzyl alcohols through the corresponding acetates, if operating in acetic acid solution
(Fig. 37)[102]
According to the proposed mechanism, being that the concentrations of NO 2 and O 2 are much
lower than that of I 2, benzyl r adicals generated from hydrogen abstraction by PINO react
faster with the latter one, forming benzyl iodides selectively. Under the described reaction

– 63 – medium benzyl iodides undergo solvolysis, affording the corresponding benzyl acetates in
excellent yields .

Fig. 36. Radical mechanism for the nitration of alkanes catalyzed by NHPI.

Fig. 37. Benzyl alcohols from alkylbenzenes.
Quinones and analogous derivatives
As stressed before, the promotion of biological oxygenation is usually mediated by one –
electron transfers, which lead to the formation of radicals. On the basis of this consideration,
Xu and co -workers suggested that quinones, ubiquitous in nature and ofte n involved in ET
chains, could be employed to design biomimetic oxygenation models for the activation of
NHPI[103]
The catalytic redox cycle is reported in Fig. 38.

– 64 –
Fig. 38. DADCAQ/NHPI -mediated aerobic oxidation mechanism.
The one -electron -transfer interaction of antraquinone (AQ) with NHPI in zeolite HY,
followed by hydrogen -atom transfer, successfully led to the formation of the PINO radical,
which in turn was responsible for the propagation of the radical chain in the selective
oxidation of ethylb enzene to the corresponding acetophenone Among the different AQ
derivatives that were tested, 1,4 -diamino -2,3-dichloro -antraquinone (DADCAQ) was the
most effective in terms of both conversion and selectivity of the ketone product the potential
of this cata lytic system was proved by extending its application, in the absence of zeolite, for
the oxygenation of a wider range of hydrocarbons.[104]
Moreover, the electronic effect of substituents on quinones and on the aromatic ring of NHPI
was also investigated. Quinones bearing halogen groups were used in the selective oxidation
of alkylarenes, alkenes and alkanes[105]
Revealing how the moderate el ectron -withdrawing power of the substituents had a beneficial
effect on the ET process. The combined activity of tetrabromo -1,4-benzoquininone (TBBQ)
and NHPI afforded the best results. Aryl-tetrahalogenated NHPI derivatives were also
prepared and used in combination with DADCAQ for the oxidation of ethylbenzene[106] In
particular, aryl -tetrachloro -NHPI (TCNHPI) allowed significantly higher conversion and
selectivity with respect to the NHPI/DADCAQ classical system (Fig. 39).

– 65 –
Fig. 39. DADCAQ/TCNHPI medi ated aerobic oxidation of ethylbenzene.
More recently, analogous results were achieved by combining NHPI with 2,3 -dichloro -5,6-
dicyanobenzoquinone (DDQ).
Xu et al. also reported a similar one -electron -transfer activation of NHPI promoted by
nonmetal xantho ne and tetramethylammonium chloride (TMAC), for the selective oxidation
of hydrocarbons (Fig. 40)[107]
In the proposed mechanism, TMAC has the unique role of decomposing the hydroperoxide
intermediate, prolonging the free -radical chain[108]

Fig. 40. selective oxidation of hydrocarbons

The NHPI -activation by AQ has been also adopted by other research groups. Li and co –
workers applied the NHPI/AQ system to promote the metal and solvent -free oxidation of α –
isophorone to ketoisophorone, preventing the isomerization process of the substrate to β –
isophorone (Fig. 41)[109]

Fig. 41. NHPI/AQ -mediated aerobic oxidation of α -isophorone.

Very recently, Coseri et al. reported that NHPI[110] and other nonpersistent nitroxyl radical
precursors, such as VLA, H BT and N-hydroxy -3,4,5,6 -tetraphenylphthalimide (TPNHPI)[111]

– 66 – were suitable catalysts for the selective oxidation of cellulose fibers promoted by the
NaClO/NaBr system (Fig. 42).
According to the proposed mechanism PINO radical is oxidized to the corresponding N-
oxammonium cation, which in turn is responsible for the oxidation of the C 6 alcoholic
function .

Fig. 42. NHPI/AQ -mediated oxidation of cellulose fibers by NaClO/NaBr sy stem.
The surface modification of cellulose fibers by selectively converting primary hydroxyl
groups to the corresponding carboxylic functions, maintaining the original backbone of the
polysaccharide, is of major interest for different applications.[112]
]By comparing different activation approaches, including transition – metal complexes, Coseri
found that the NHPI/AQ catalytic system allowed higher conversion of hydroxyl groups. A
comparison study on the effect of TEMPO and PINO radicals on the oxidation efficiency
toward cellulose led to the conclusion that the NHPI/AQ oxidation mediator affords the

– 67 – highest content of carboxylic groups and better preserves the morphology and the molecular
weight of the starting material[113]
Moreover, this catalytic syst em could be employed with dioxygen in place of NaClO as the
ultimate oxidizing agent[114] In this case, the mechanism follows a radical chain via classical
HAT by PINO abstraction (Fig. 43).

Fig. 43. NHPI/AQ mediated aerobic oxidation of cellulose fiber s.
Aldehydes and the molecule -induced homolysis .
Sacrificial reductants have been widely reported in the literature as reactive agents able to
promote the autoxidation reaction of less -reactive hydrocarbons.
In this context, aldehydes have attracted increasing attention[115] In principle, the aerobic co –
oxidation promoted by aldehydes could be considered a nongreen and expensive process, due
to the need for sacrificial reagents.
However, this approach for oxy gen activation could become competitive for practical
application if the high efficiency in substrate conversion, the high selectivity in the final
product, and/or the field of application, together with the low cost and environmental impact
of the selecte d aldehyde, were significant enough to justify the reagent sacrifice.
Moreover, co -oxidation of aldehydes would become attractive also if the acyl derivatives
were not used as stoichiometric reagents, but just in catalytic amounts as initiators of free –
radical chains.
The use of aldehydes for the activation of NHPI in an aerobic co -oxidative process was first
reported by Einhorn and co -workers in 1997.[116

– 68 – The combination of stoichiometric amounts of acetaldehyde with catalytic quantities of NHPI
promote d the oxidation of a wide range of hydrocarbons, including cumene and
ethylbenzene, to the corresponding carbonyl groups.
Under these operative conditions, peracetic acid was directly responsible for the substrate
oxidation.
More recently they suggested t hat the NHPI/aldehyde system could promote the formation of
PINO radical following a molecule – induced homolysis mechanism .[117]
Mechanism for nitroxide free radicals
Mechanism of nitroxide free radical TEMPO with metal copper can show as example of role
of TEMPO in this article,

– 69 –

(4)
Mechanism of nitroxide free radical.

– 70 – Different mechanism is available of free radical TEMPO depend on kind of reaction and
cocatalyst with TEMPO can show following mechanism of TEMPO with metal copper.

– Mechanism of copper/TEMPO -catalyzed aerobic oxidation of primary alcohols
Koskinen[118] and Stahl[119] have carried out kinetic studies of their respective
(bpy)Cu/TEMPO -catalyzed alcohol oxidation reactions, and Stahl also reported an
independent comparative kinetic and mechanistic study of the catalytic reactions reported by
Semmelhack, Sheldon, Koskinen , and Stahl.
Several observations demonstrate clearly that the (bpy) Cu/TEMPO -catalyzed alcohol
oxidation does not involve an oxoammonium pathway:
1) different kinetic isotope effects (KIEs) are observed for (bpy)Cu/TEMPO – and TEMPO+ –
mediated alcohol oxi dation (similar to Sheldons observations with the Semmelhack system)
2) The CuII / CuI E1/2 is too low under the reaction conditions to oxidize TEMPOH or TEMPO
to the oxoammonium species, and
3) TEMPO+ -mediated alcohol oxidation was shown to be kineticall y incompetent to account
for the fast reaction rates observed with the (bpy) Cu/TEMPO catalysts
The mechanistic study of Stahl and co -workers provides the basis for the simplified catalytic
mechanism in Fig. 43 Aerobic oxidation of CuI and TEMPOH affords a CuII-OH species and
TEMPO (steps 1 and 2).
This sequence explains why a strong base, such as KO tBu or DBU, is not required when a
CuI salt is used as the catalyst source the base (LnCuII-OH) is generated upon reduction of
O2. As noted above, this feature has beneficial implications in the oxidation of base -sensitive
substrates.
The oxidation of the alcohol proceeds through the formation of a pre -equilibrium of a CuII–
alkoxide species (step 3) followed by hydrogenatom transfer to TEMPO (step 4). Details of
the H -atomtransfer step could not be discerned from these studies, but a first -order
dependence on [TEMPO] was observed in reactions of aliphatic alcohols and no evidence
was obtained for an interaction between TEMPO and CuII under the reaction conditio ns
These observations are consistent with a bimolecular H -atom transfer step, similar to that
proposed by Brackman and Gaasbeek however[120], mechanisms involving the rate -limiting

– 71 – coordination of TEMPO to Cu(II) followed by rapid H -atom transfer cannot be excluded on
the basis of available evidence.
The latter studies provide important insights into the origin of the reactivity difference
between activated and aliphatic alcohols.
Benzylic alcohols exhibit faster rates and no kinetic dependence on [alcohol ] or [TEMPO]. A
rate dependence on [Cu] and [O 2] suggests that the aerobic oxidation of the Cu catalyst (step ,
Fig. 43) is the turn over limiting step of the reaction. In contrast, aliphatic alcohols react more
slowly and the rate exhibits a saturation de pendence on [alcohol] and a first -order
dependence on [TEMPO].
These observations had a direct impact on the development of new Cu / nitroxyl catalyst
systems.

– 72 –

Fig. 43. Mechanism of (bpy)Cu/TEMPO -catalyzed alcohol oxidation deduced by Stahl and
co-workers

– 73 –

(5)
Conclusion

– 74 – Free radical in organic chemistry very important in organic reaction , special in oxidation
reaction.
Oxidation reactions have frequently been performed with stoichiometric amounts of
inorganic oxidants many of which are extremely hazardous to use or toxic compare when use
in organic chemistry.
The availability of easy -to-handle heterogeneous catalysts, w hich can easily recycled after
use in liquid phase oxidation reactions and more economic efficiency with low toxicity
remains a challenge in reaction of chemistry.
One of this heterogeneous catalyst is persistent nitroxidae free radical have paramagnetic
properties these nitroxide free radical not only use in oxidation reaction but use generation of
polymer, oxidation of sulfides and hydrogen abstractions, trapping regent, …etc
Nitroxide free radical like TEMPO is stable organic radical that can be stored for long
periods of time without decomposition, which have low toxicity, good stability and high
efficiency when use in oxidation reaction.

– 75 –

(6)
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