– 0 – Persistent free radicals as reactive [600585]

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

Literature report ( I )

Ph D student: [anonimizat] 1 – Index
3 List of abbreviations
4 Introduction . Free Radicals 1
4 TEMPO 1.1
6 Triphenylmethyl 1.2
6 DPPH 1.3
8 Application of free radicals in orginc chemistry 2
10 Examples of literature procedures 3
10 Room temperature Fe(NO 3)3.9H 2O/TEMPO/NaCl – catalyzed aerobic
oxidation of homopropargylic alcohols 3.1
12 An aerobic nitroxide -catalyzed oxidation of alcohols using the NO+/NO·
redox pair 3.2
14 Aerobic oxidation of alcohols by using a completely metal -free catalytic
system 3.3
18 Simple copper/TEMPO catalyzed aerobic dehydrogenation of benzylic
amines and anilines 3.4
22 Facile oxidation of primary amines to nitriles using an oxoammonium salt 3.5
26 Copper(I) /keto ABNO catalysed aerobic alcohol oxidation 3.6
30 A facile and efficient synthesis of polystyrene/ gold –platinum composite
particles and their application for aerobic oxidation of alcohols in water 3.7
35 Recent advances in green catalytic oxidations of alcohols in aqueous
media 3.8
50 TEMPO radical polymer grafted silicas as solid state catalysts for the
oxidation of alcohols 3.9
59 Size-specific catalytic activity of polymer -stabilized gold nanoclusters for
aerobic alcohol oxidation in water 3.10
63
A selective and mild oxidation of primary amines to nitriles with
trichloroisocyanuric acid
3.11

– 2 – 66 Metal -free aerobic oxidations mediated bN – hydroxyphthalimide. a
concise review 3.12

78 Mechanism of copper/TEMPO -catalyzed aerobic oxidation of primary
alcohols 3.13
81 Conclusion 4
82 References 5

– 3 – 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-methyltetrahydrofuran
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 triphenylmeth yl

– 4 – 1. Introduction
Free radicals are often difficult to be unequivocally classified as organic radicals centered at
specific atoms. Clearly, a radical should be regarded as centered on a restricted number of C
or heteroatoms if the bulk of the spin population resides on the se atoms. However, how
should ‗‗bulk‘‘ be interpreted is still questionable.[1]
Often free radical compounds are unstable because they contain un unpaired electron, but
there are some of the them that compounds have a relative stability . Some of this
comp ounds, of free radical type, are well known as :
1. TEMPO (2,2,6,6 -tetramethylpiperidin -1-yl)
2. TPM (triphenylmeth yl)
3. DPPH ( 2,2-diphenyl -1-picrylhydrazyl)
1.1 TEMPO is a chemical compound with the chemical formula (CH 2)3(CMe 2)2NO shown in
Fig. 1.

Fig. 1 . Chemical structure of the free radical TEMPO
This heterocyclic compound is a red -orange, sublimable solid. As a stable radical , it has
applications in chemistry and biochemistry.[2] TEMPO was discovered by Lebedev and
Kazarnowskii in 1960.[3] It is prepared by oxidation of 2,2,6,6 -tetramethylpiperidine . TEMPO
is widely used as a radical marker, as a structural probe for biological syste ms in conjunction
with electron spin resonance spectroscopy, as a reagent in organic synthesis , and as a
mediator in controlled free radical polymerization .[4]
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 b etween either carbon adjacent to nitrogen.[5]

– 5 – 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.[6]
TEMPO can be prepared by treating the hindered secondary amine with m- chloroperbenzoic
acid (MCPBA) , with the intention of transforming it into the nitroxide. 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. 2.

Fig. 2. Synthesis of 4 -oxo-TEMPO
As peracids react very sluggishly with alcohols, it was apparent that the presence 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 t he
oxidation of alcohols mediated by catalytic 2,2,6,6 -tetramethylpiperidine -1-oxyl (TEMPO)
published almost simultaneously by Cella and Ganem .[7]
These authors presented two papers with remarkably similar contents, in which alcohols were
oxidiz ed 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
oxidize s 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 .

N
HOH
MCBPA MCBPA
NO
ONOH
O

– 6 – 1.2 Triphenylmethyl
Triphenylmethyl free radical is the hydrocarbon with the formula (C6H5)3C shown in Fig. 3.
This colorless solid is soluble in nonpolar o rganic solvents and not in water. Triphenylmeth yl
is the basic skeleton of many synthetic dyes called triarylmeth yl dyes, many of them are pH
indicators , and some display fluorescence . A trityl group in organic che mistry is a
triphenylmethyl group Ph 3C, e.g. triphenylmethyl chloride — trityl .

Fig. 3. Chemical structure of triphenylmeth yl free radical
Triphenylmeth yl can be synthesized by Friedel – Crafts reaction from benzene and
chlomroform with aluminium chloride as catalyst .
3 C 6H6 + CHCl 3 → Ph 3CH + 3 HCl
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 andphosphorus
pentachloride , is used as well .
1.3 DPPH
Is a common abbreviation 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 notab ly it is a
common antioxidant assay, and another is a standard of the position and intensity of electron
paramagnetic resonance signals .

– 7 –

Fig. 4. Chemical structure of DPPH free radical
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 -know n radical and a trap ("scavenger") 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 absorptio n 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-marker) and intensity of electron paramagnetic
resonance (EPR) signals – the number of radicals for a freshly prepared sample can be
determined by weighing 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 4 1 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 with a high -frequency
EPR setup (~200 GHz), where the slight g-anisotropy of DPPH becomes detectable.

– 8 – 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.
2. Application of free radicals in organic chemistry
TEMPO is employed in organic synthesis as a catalyst for the oxidation of
primary alcohols to aldehydes . 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. 5.
N
O+

Fig. 5. The oxoammonium salt of TEMPO
One typical reaction example is the oxidation of (S) -(-)-2-methyl -1-butanol to (S) -(+)-2-
methylbutanal.[8] 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 .[9] TEMPO oxidations also exhibit chemoselectivity , being inert towards
secondary alcohols, but the reagent wil l convert aldehydes to carboxylic acids.
In cases where secondary oxidizing agents cause side reactions, it is possible to
stoichiometrically convert TEMPO to the oxoammonium salt in a separate step. For example,
in the oxidation of geraniol to geranial , 4-acetamido -TEMPO is first oxidized to the
oxoammonium tetra fluoro borate.[10]
TEMPO can also be employed in nitroxide mediated radical polymerization (NMP), a
controlled free radical polymerization technique that allows better control over the final
molecular weight distribution. The T EMPO 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 polymerizatio n to continue. Thus, the chemist can
control the extent of polymerization and also synthesize narrowly distributed polymer chains.

– 9 – TEMPO itself is relatively inexpensive,[11] but there are TEMPO derivatives that are often
used such as 4-hydroxy -TEMPO (TEMPOL )[12] 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 availabl e.[13]
In 1987, Anelli published a landmark paper [14] 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 bi phasic 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 solvents more rarely
employed include THF[15] and PhMe -EtOAc mixtures.[16] 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. 6.
OH
O1mol 4-MeO-TEMPO, 1.25 eq. NaOCl
0.1 eq. KBr, NaHCO3,CH2Cl2,H2O,0o

Fig. 6. 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 Anelli‘s protocol are routinely perf ormed at a
slightly basic pH of 8.6 –9.8[17] 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 .[18]

– 10 – 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 .
On the other hand, it may be advisable to limit the reaction time [19] in order to minimize the
hydrolysis of acetates .In this artic les were used various alcohols primary as well as secondary
alcohols ; also extended reaction times were required for the immobilized catalyst.
3. Examples of literature procedures
3.1. Room temperature Fe(NO 3)3.9H 2O/TEMPO/NaCl – catalyzed aerobic oxidation of
homopropargylic alcohols .
Numerous oxidation methods towards alcohols have been reported in literature using at least
a stoichiometric amount of oxidants, such as MnO 2, chromium oxides, DMSO as well as
hypervalent i odine compounds. However, those conventional oxidants would produce almost
the same amount of oxidant -derived waste causing serious environmental problems.
As a mild and natural terminal oxidant, molecular oxygen would be the best alternative from
the view point of eco -friendly and economic advantages .[20] 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.[21] Therefore, developing
novel protocol for the oxidation of alcohols using molecular oxygen as terminal oxidant
under mild conditions is highly required.
As a literature example, it has been tried the aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol
(Fig. 7) . To the authors surprise, when 10 mol % Fe(NO 3)3.9H 2O, 10 mol % TEMPO, and 10
mol % NaCl (the role of Cl- in this reaction is not quite clear yet, it is probably working as a
ligand to Fe+3 to accelerate the oxidation ) were used, this reaction work smoothly at room
temperature under atmospheric pressure of molecular oxygen affording corresponding
homopropargylic ketone in 91% NMR yield.

– 11 –
Fig. 7. Oxidation of a propargyl alcohol
Based on this observation, it was tried t o optimize the reaction conditions based on solvent
effect, catalyst loading as well as different nitrate, the results being summarized in Table 1.
Compared to toluene, ethyl acetate, and THF, the full conversion and highest NMR yield
could be achieved whe n using DCE as solvent (Table 1). 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).
Interestingly, after chromatographic workup procedure the allelic ketone was isolated in
87% .
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.
they have initially tried this aerobic oxidation of 1 -phenyl -butyl -3-yl-1-ol. when 10 mol %
Fe(NO 3)3 9H2O, 10 mol % TEMPO, and 10 mol % NaCl (the role of Cl- in this reaction is not
quite clear yet, it is probably working as a ligand to Fe+3 to accelerate the oxidation) were
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

– 12 – used, this reaction could work smoothly at room temperature under atmospheric pressure of
molecular oxygen affording corresponding homopropargylic ketone.
3.2. 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 and
chiral alcohols to carbonyl compounds without epimerization and no formation of nonvolatile
byproducts.
Alkyl nitrites are a source o f the nitrosonium ion, a strong oxidizing agent with a redox
potential of 1.0 V vs ferrocene.[22] Some time ago, authors used the NO+ /NO· pair as
stoichiometric SET oxidants .[23] This triggered the author interest to apply it for TEMPO
reoxidation.[24] 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 comp romising resident
stereocenters. When i ncreasing 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 2).Using diethyl ether as the solvent gave only in 30% yield, probably due
to prec ipitation of the active oxidant, while s witching to CH 2Cl2 at a 10 mol % loading at
room temperature provided a very good 94% yield after 4 h (entry 2). Heating the reaction
mixture to reflux and reduction of the catalyst loading to 5 mol % led to similar yields
(entries 3, 4). However, when th e 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. 8. Oxidation of benzylic alcohol using butylnitrite

– 13 – Table 2. 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. 9). First TBN reacts with
the catalytic amount of BF 3 OEt 2 to generate nitrosonium tetra fluoro borate and the borate
ester .[25] The nitrosonium salt oxidizes to the N -oxopiperidinium salt. 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 c ycle.

Fig. 9. 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 th e catalyst with
stoichiometric oxidants such 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 r adicals has
been more recently used , the condition of this oxidation are shown in Fig. 10 and Table 3

– 14 –
Fig. 10. Oxidation of benzylic alcohol
Table 3. Results obtained for reaction showed in Fig. 10
Entry Solvent Time(h) Tempo(mole%) Yield
1 Et2O 5 10 30
2 CH 2Cl2 4 10 94
3 CH 2Cl2 0.75 10 65
4 CH 2Cl2 1.5 5 67
5 CH 2Cl2 5 1 82
6 CH 2Cl2 5.5 – 73

3.3. Aerobic oxidation of alcohols by using a completely metal-free catalytic system
A metal -free reaction system of air, NH 4NO 3, 2,2,6,6 -tetramethylpiperidine -1-oxyl
(TEMPO), and H+ is introduced as a simple, safe, inexpensive, efficient and chemo selective
mediator for aerobic oxidation of various primary , secondary benzyl and alkyl alcohols,
including those bearing oxidizable heteroatom s (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 redo x 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,
performed in an open -air system by using a renewable and reusable polymer -suppor ted form
of TEMPO ( OXYNITROX).
The reaction solvent was recovered by distillation under at mospheric pressure, and the pure
final product was isolated under reduced pressure; the acid activators (HCl or H 2SO 4) were
recovered as ammonium salts .

– 15 – In this project based on previous reports dealing with aerobic oxidation of alcohols, supported
by eit her catalytic or equimolar amounts of a nitric oxide source, authors decided to further
investigate various inorganic nitrates as potential catalytic promoters of these processes.
In their initial experiments, they used benzyl alcohol as a model substrate . Promising
preliminary results were achieved and are presented in Table 3. Authors assumed 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 re dox 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 intermediates
[E°(TEMPO cation / TEMPO) = 0. 76[26] as well as nitric oxide sourcing compounds.
Accordingly, they chose TEMPO and HClO 4 as cocatalysts to establish an efficien t and
selective aerobic process.
They started their investigation with the most widespread and environmentally friendly
transition -metal catalyst, iron(III) nitrate, which appeared 20 mol-% acid was necessary to
achieve good conversion of alcohol into ben zaldehyde at room temperature (Table 4 Entry 1).
On the other hand, the use of copper (II) nitrate alternative was efficient even without the
presence of acid (Entries 2 and 3).
Sodium nitrate as an alkali metal candidate was found to be inefficient at ro om temperature
(Entry 5), but catalyzed the reaction to completion at 60 °C in the presence of 10 mol -% acid
(Entry 6). In an attempt to establish a fully metal -free catalytic system, ammonium nitrate
appeared to be the logical choice and, as it turned out , the right one.
Under neutral conditions, the catalyst was found to be unreactive (Entry 7), but when an
appropriate acidic activator was added at room temperature , moderate efficiency was
obtained (Entry 8). Encouraged with this result, the authors increased the temperature to 60
°C and achieved quantitative conversion into benzaldehyde (Entry 9). Therefore, the three –
component catalytic system NH 4NO 3/TEMPO/H+ was used in subsequent studies .

– 16 –
Fig. 11. Novel oxidation system

Table 4 . 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

They further evaluated the role of the acids in the oxidation process and found that acids
with p Ka values of at least –5 support the process quantitatively (Table 5), whereas weaker
acids gave worse or even negative results. For this reason, HCl (aq. 37%) or H 2SO 4 (aq. 98%)
Were used for further experiments as the most abundant acids.

Fig. 12. Novel oxidation system

– 17 – Table 5. The effect of acid on the aerobic oxidation of benzyl alcohol with NH 4NO 3 and
TEMPO.[a]

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[27] The most desirable are solvent -free transformations or
those performed in recyclable and reusable reaction media such as alcohols, ethyl acetate,
green ethers etc. Unfortunately, aerobic oxidation of benzyl alcohol by using their catalytic
system under so lvent -free reaction conditions was unsuccessful. Equally unsuccessful were
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 acetonitrile .
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 -MeOT EMPO)
(Fig. 13). Trial oxidations were carried out with benzyl alcohol ( 1a) in acetonitrile 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 considerably 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 .

– 18 –
Fig. 13. 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

It is worth mentioning that all control experiments highlighting the essential role of each
member of the described reaction system, i.e., air oxygen as reagent and NH 4NO 3, TEMPO
and HCl as catalysts, were performed; all the control systems gave negative results under
argon or under air. In the absence of any one of the three components of the catalytic system,
benzyl alcohol was not converted into benzaldehyde
3.4. Simple copper / TEMPO catalyzed aerobic dehydrogenation of benzylic 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 .[28] However, 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[29] and as far as they are aware this is the only example to date. Herein, they report a
simple CuBr 2-TEMPO catalytic system for aerobic oxidations of primary and secondary
benzyl amines. Also, they report CuBr -TEMPO catalyzed dehydrogenative coupling of
electron -rich anilines, which yield azo compounds. The oxidative self -coupling of benzyl
amine was chosen as a model reaction to optimize the reaction conditions (Table 6).
Copper salt and TEMPO are crucial for the oxidation of benzylamine (Table 6, entries 1 and
2). Different copper salts were tested for catalytic oxidation activity. Copper(II) bromide gave

– 19 – the best activity with 86% conversion of benzylamine to N -benzyliden e-benzylamine in 8 h
(Table 6, entry 3). Copper(II) chloride and copper(II) acetate led to only 58% and 62%
conversions, respectively, under the same reaction conditions (Table 6, entries 4 and 5).

Fig. 14. 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 be en broadly used as a solvent in
Cu(II) -catalyzed oxidation reactions.[30] 86% conversion was obtained in 8 h with a 2 : 1
(v/v) acetonitrile / water solvent mixture (Table 6, entry 3).
No conversion was achieved in neat CH 3CN due to the formation of a green precipitate
(Table 6, 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 solubilit y of the organic substrate (Table 6, entry 8).
Only 8% conversion was obtained when a biphasic solvent mixture was used (Table 6, entry
9). This may be explained by unsatisfactory mixing of the reactants, catalysts and co –
catalysts.
With the optimized rea ction conditions above in hand, they investigated CuBr 2-TEMPO
catalyzed oxidations for a range of primary and secondary benzylic amines (Table 7). The
electronic properties of substituents had no significant effect on the conversions and
selectivities.
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 corresponding im ines (Table
7, entries 1 –8).

– 20 – This also contrasts with a recently reported V 2O5-H2O2 catalytic system,[31] where
significantly different reaction conditions were needed for the two classes of substrate, with
benzyl amines bearing electron donating groups 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 7, 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 7, entry 9). This could be explained by the steric demands 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 secondary 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 reactio n 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 first 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 studi es 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% catalyst 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 system reported he re. Also, for the oxidation of electron –

– 21 – donating benzyl amines, the selectivities for the imine products were not notable. As shown
in Table 6, entry 4, only 78% selectivity was obtained due to the formation of p-methoxy
benzaldehyde as a by -product. 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 w ould be desirable if
TEMPO could be efficiently recycled and reused. Chung and Toy reported a recyclable PEG
modified Cu / TEMPO catalyst for selective aerobic alcohol oxidation.[32] The development
of a recyclable Cu / TEMPO catalyst system or another reu sable non -precious metal -based
catalyst system for aerobic oxidation reactions of amines is under way in their group .
Table 6. 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

– 22 – Table 7. CuBr 2-TEMPO catalyzed primary and secondary benzylic amines

3.5. Facile oxidation of primary amines to nitriles using an oxoammonium salt
Amines are acutely sensitive to oxidation, and a host of products may be generated depending
on the oxidant. A particularly challenging oxidat ion is the conversion of a primary amine to a
nitrile (RCH 2NH 2 → RCN). This transformation, which formally involves a double
dehydrogenation, has been accomplished in a variety of ways[33] including transition -metal
catalyzed dehydrogenation,[34] and aerobic oxidation catalyzed by transition metals.[35] More
recently, catalytic systems for aerobic oxidation of amines to nitriles have been developed
that involve catalytic quantities of a, a base, cuprous iodide, and an appropriate ligand for the
metal.[36] In this connection, they were intrigued by reports on the oxidation of amines to

– 23 – nitriles by the oxoammonium cation generated from TEMPO by electrochemical
oxidation.[37]
They report that the oxidation of a primary amine to corresponding nitrile may be
accomplished expediently, and in high yield using a stoichiometric quantity of a readily
available oxoammonium salt (1) As detailed below, the oxidation proceeds under mild
conditions using inexpensive reagents via a well -defined process. Moreover, the reduced
oxidant (2), 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 (1), is a stable, high ly crystalline,
yellow solid. The salt is commercially available. Alternatively, it is easily prepared in a few
simple steps from 4 -amino -2,2,6,6 -tetramethylpiperidine and inexpensive reagents in
multimole quantities.[38]

Fig. 15. Oxoammonium salt s

Oxidation of primary amines to nitriles using 1 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 chlor ide (150 ml
per 10 mmol of amine) containing 8 molar equiv of dry pyridine followed 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 8.

The stoichiometry of the overall process, depicted in Fig. 15, eq 1, requires explanation. For
the stepwise oxidation of the amine to an aldimine ( Fig. 15, eq 2) and then to the nitrile

– 24 – (Fig. 15, eq 3), 2 molar equiv of 1 are required. However, in the presence of base, 1 and the
hydroxylamine (3) synproportionate ( Fig. 16, eq 4) to give 2 molar equiv of nitroxide (2).[39]
Thus, a total of 4 molar equiv of 1 are required for the transformation and the product mixture
consists of nitrile (Table 8, pyridinium tetra fluoro borate, and nitroxide 2. 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 1. The results summarized in Table 8 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. Benzylic amin es bearing strongly electron –
withdrawing substituents are, however, oxidized rather slowly (Table 8, entries 7 and 9).
Sluggish oxidations may be accelerated, with little loss in yield, by simply heating the
reaction mixture at gentle reflux (Table 8, entr ies 9, 13, and 14).

Fig. 16. Oxidation of primary amines to nitriles

– 25 – Table 8. Oxidation of primary amines to nitriles (Fig . 14, eq 1a )

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

– 26 – 3.6. Copper(I) / keto ABNO catalysed aerobic alcohol oxidation
Cu(I)/9 -azabicyclo[3.3.1]nonan -3-one N -oxyl (keto ABNO) aerobic catalyst system is highly
effective for the oxidation of secondary alcohols, including unactivated aliphatic substrates.
The effects of pressure and gas composition on catalyst performance are examined. The
radical can be employed at low loadings and is also amenable to immobilisation on to solid
supports. The selective oxidation of alcohols is an important reaction in organic chemistry.
This fundamental reaction still poses problems when carri ed out on a larger scale, as
traditional methods often use toxic reagents and/or inefficient methods.[40] There has
therefore been considerable interest in developing catalytic methods for alcohol oxidation,[41]
and in their opinion one of the best aerobic catalytic systems available is the Cu/2,2,6,6 –
tetramethylpiperidinyloxy (TEMPO) system.[42] The most active version of this 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. This system has a number of
attractive features. It can oxidise a variety of alcohols including those possessing alkenes,
alkynes and heteroatoms that cause significant problems for noble metal catalyst systems.
The method is als o very accessible to researchers, as all catalytic components are
commercially available and on a small scale it is possible to employ an ―open flask‖
approach, using ambient air as the oxidant. One of the notable attributes of this system is the
very high selectivity for primary alcohols over secondary alcohols. However, this selectivity
means the catalyst is not suitable for the oxidation of secondary alcohols to ketones, a
synthetically useful transformation. The poor performance of Cu/TEMPO systems for
secondary alcohols is attributed to steric hindrance. The mechanism for alcohol oxidation
involves the Cu complex and radical working in unison.[43] In order to efficiently oxidise
secondary alcohols, replacing TEMPO with a radical that is less sterically hindered should
remove this limitation.
Fig. 17 shows the structures of TEMPO and some sterically unhindered stable nitroxyl
radicals. Such unhindered radicals have been known since the 1960s and in fact keto ABNO
was the first in this class to be reported[44] To date TEMPO has undoubtedly been the most
widely studied stable radical used in a number of alcohol oxidation systems,3 for example,
TEMPO/sodium hypochlorite type oxidations have been applied on an industrial scale.[45]
Although it was shown some time ago that such unhindered radicals are more reactive than
TEMPO,[46] it is only recently that they have been explored in oxidation catalysis.

– 27 –

Fig. 17. Comparison of TEMPO with unhindered nitroxyl radicals .

Early studies used electrochemical or chemical (primarily sodium hypochlorite) oxidants to
generate the oxoammonium salt, which in turn acts as the catalyst.[47] 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).[48] More recently, Cu / keto ABNO
and Cu/ABNO aerobic systems have been used for the oxidation of amines to imines[49] (and
subsequent deriviti sation) and the oxidation of amines to nitriles.[50] Given the fundamental
importance of alcohol oxidation they investigated the use of keto ABNO as a replacement for
TEMPO. The synthesis of most unhindered radicals involves lengthy synthetic procedures
and in some cases undesirable steps.[51] ABNO can be prepared in three [52] or four[53] steps
(depending on the route) and keto ABNO can be prepared in three steps. In this initial study
they have focused on three model substrates to test the ability of Cu / keto ABNO to oxidise
secondary alcohols that Cu/TEMPO struggles to or indeed cannot oxidise (Fig. 18). It is
known from previous studies that Cu/ TEMPO systems have excellent substrate scope
tolerance (e.g. heteroatom and olefin containing molecules), so they wanted to focus on this
limitation of secondary alcohols and examine the reactivity for such substrates. The substrate
1-phenylethanol was included as an example of an activated secondary alcohol that the Cu(I)
/ TEMPO system can oxidise.[54] The othe r model substrates are more challenging; 2 -octanol
is an aliphatic, unactivated alcohol and isoborneol is a sterically hindered, unactivated
alcohol.

Fig. 18. Secondary alcohols used as model substrates.

– 28 – In previous studies isoborneol has been shown as an excellent test of steric hindrance using
nitroxyl radicals under hypochlorite conditions.[55] In Fig. 19 they show a comparison in
reactivity of keto ABNO, TEMPO and 4 – oxo TEMPO for the three model substrates.

Fig. 19.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.

Although TEMPO is commonly used, they have included 4 -oxoTEMPO as perhaps this is
more analogous to keto ABNO. In these reactions they used 7.5 mol% CuI, bpy and 10.5
mol% NMI with 1 mol% of the radical. In the case of TEMPO systems, typically the copper
complex and radica l are used at 5 mol% loadings.[56] they had anticipated that keto ABNO
would be more reactive than TEMPO, allowing the use of lower catalyst loadings. However,
when the copper complex and base were reduced to 1 and 1.4 mol% respectively,
performance was poor. When the 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. The radical is
significantly mor e expensive than the copper complex, therefore, from an economical and

– 29 – indeed a green point of view, emphasis should perhaps be on the optimal use of the radical. In
Fig. 18 it can be seen that there is a dramatic difference in performance of keto ABNO
compared to TEMPO and 4 -oxoTEMPO. The radicals TEMPO and 4 -oxoTEMPO can only
oxidise 1 -phenylethanol and no oxidation products were obtained for the unactivated alcohols
2-octanol and isoborneol. As mentioned earlier, it is known that Cu(I) / TEMPO can oxidiz e
some activated secondary alcohols [57] and nearly 40% yield of acetophenone was obtained in
four hours with this system. The yield was significantly decreased when 4 -oxoTEMPO was
used. While this manuscript was in preparation, Steves and Stahl reported a study which
focused on the use of Cu(I) / 9-azabicyclo[3.3.1] nonane N -oxyl (ABNO) for aerobic alcohol
oxidation. 15 In their initial screening, TEMPO, 4 -methoxyTEMPO and 4 -oxoTEMPO were
compared against ABNO, keto ABNO and AZADO (2 -azaadamantane N -oxyl). They
observed similar behavior to that shown in Fig. 17; where the sterically less hindered radicals
delivered superior reactivity to TEMPO derivatives, particularly for secondary alcohols.
Unhindered radicals were compared for the oxidation of cyclo hexane methanol at loadings
of 5 mol% Cu complex and 5 mol% radical. It was found that all of the aforementioned
unhindered radicals delivered similar reactivity under these conditions. Their study primarily
focused on the use of ABNO and the catalyst syst em 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. This system was used to oxidise a wide range of primary and secondary
alcohols at room temperature and at these loadings, most su bstrates were fully converted in 1
h. This catalyst system was tolerant of a range of functionalities (e.g. heteroatoms, alkenes
and alkynes) similar to that previously observed for Cu(I) / TEMPO.[58] Substrates that could
bind tightly or chelate with the Cu catalyst were found to be unreactive, again similar to that
observed for Cu(I) / TEMPO.4a In their studies they have not focused on a wide range of
substrates. Rather, they wished to further examine the reactivity of their Cu(I) / keto ABNO
system for the three representative substrates shown in Fig. 16, as well as the development of
a solid supported ABNO derivative. In Fig. 16 it can be seen that under these reaction
conditions keto ABNO enabled the oxidation of all three secondary alc ohols at a very similar
rate. This is unusual, as normally activated alcohols react much faster than aliphatic alcohols.
This is arguably the case for all catalysts, including Cu / TEMPO, although aerobic Cu /
TEMPO studies have been limited to primary alc ohols. Given that the reactions shown in Fig.
17 are carried out in ―open flask‖ it was possible that, under these conditions, the reactions
with keto ABNO were mass transfer limited in O 2. To test their theory they examined the
influence of stir rate on t he reaction. they examined stirrer speed effects with 1 mol% and 0.1

– 30 – mol% loadings of keto ABNO for both 1 -phenylethanol and 2 -octanol. Different stirrer
speeds were tested using a standard round bottom flask set -up, open to the air. There is
arguably a li mit 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. This reactor meant they had t o
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 pha se. 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.
3.7. A facile and efficient synthesis of polystyrene/ gold –platinum composite particles
and their application for aerobic oxidation of alcohols in water
They develop a facile and effective method for the synthesis of composite particles composed
of polystyrene microspheres decorated with gold –platinum alloy nanoparticles, which
exhibited excellent catalytic activity and recyclability for 1 -phenylethanol oxidation under
mild conditions (without a base, air as an oxidant, in water, at 40 Co).
Aldehydes and ketones are important intermediates in the synthesis of fine chemicals and
they are often synthesized by aerobic oxidation of alcohols[59]
Traditionally, the alcohol oxidation is performed by using stoichiometric amounts of
expensive and toxic inorganic oxidants, such as chromate or permanganate, which usually
cause environmental problems due to the large amounts of by -products[60]. In order to
overcome this shortcoming, a lot of developments have been made towards the design and
preparation of new catalysts in the past few decades. Among them, metal nanoparticles have
shown high c atalytic activity and good selectivity for aerobic oxidation of alcohols. In this
respect, the pioneering work has been accomplished by Rossi et al. and Hutchings et al., but
their catalysts were usually used under solvent -free conditions or at high temper ature[61]
It is evident that this cannot be suitable for the aerobic oxidation of alcohols with a high
melting point or low stability at high temperature .[62]
There is thus still a substantial necessity for developing catalysts that can operate in water
under mild pressure Recently, bimetallic nanoparticles have been found to be more
advantageous in terms of activity and selectivity, compared to their monometallic
counterparts .[63]

– 31 – The improved catalytic performance of bimetallic nanoparticles can be ascr ibed to synergistic
effects, derived from electronic or geometrical interactions between the two
metals[64]Nevertheless, in order to prevent their aggregation owing to vander Waals
attractions and simultaneously to effectively recover them for reuse in a simple manner, the
formation of such bimetallic nanoparticles inevitably requires a certa in support .[65]However,
as far as they know, few papers have been reported on the preparation of polymer supported
bimetallic nanoparticles, although a number of efforts have been focused on the inorganic
supports. For example, Akashi et al. reported the in situ formation of polystyrene (PS)
supported gold –platinum (Au –Pt) bimetallic nanoparticles by dispersion copolymerization of
styrene and a poly(N -isopropyl acryl amide) (PNIPAAm) macromonomer in the presence of
HAuCl 4 and H 2PtCl 6. The coordination of metal ions to PNIPAAm played an important role
in the successful synthesis of these composite particles .[66] Ballauff and co -workers used
spherical polyelectrolyte brushes consisting of a PS core and cationic long chains to adsorb
metal salt precursors by electrostatic interaction for the generation of stable Au –Pt alloy
nanoparticles on the surface of PS particles. Here it is worth noting that the preparation
method s mentioned above generally include the surface pretreatments of polymer supports in
order to promote the deposition of bimetallic nanoparticles on them. In this communication,
they report a facile and effective route to coat the PS microspheres with Au –Pt alloy
nanoparticles based on a thermodynamic effect .[67] The advantage of their approach relies on
the fact that surface pretreatment is not required for the deposition of alloy nanoparticles on
support microspheres. More importantly, the resultant PS/Au –Pt composite particles can be
used as highly active and recyclable catalysts for aerobic oxidation of alcohols in an ideal
green process. Fig. 20 illustrates the synthetic method employed to produce the PS/Au –Pt
composite particles. they chose PS microspheres, which were synthesized by dispersion
polymerization, as support microspheres. They did not undergo any surface pretreatments and
just were transferred from isopropanol into water by centrifugation and redispersion. Note
that during this trans fer process, the amount of PVP adsorbed on the surface of PS
microspheres might be decreased, and as a result, the hydrophobic PS microspheres
shiftedinto meta stable microspheres in water owing to the insufficient protection of
stabilizers. On the other hand, the hydrophilic Au –Pt alloy nanoparticles were prepared by
the co -reduction of HAuCl 4 and H 2PtCl 6 with NaBH 4 in the presence of tri sodium citrate ,[68]

– 32 –

Fig. 20. Schematic representation of the proposed method for fabricating
the PS/Au -Pt composite particles .
The carboxyl groups derived from tri sodium citrate made the as -prepared alloy nanoparticles
hydrophilic, which was confirmed by the formation of a stable aqueous dispersion of them.
After mixing the PS microspheres with the Au –Pt alloy nanoparticles in water, the alloy
nanoparticles can be adsorbed and assembled spontaneously on the surface of PS
microspheres, as this was more energetically favourable based on colloid thermodynamics. In
other words, PS / Au–Pt composite particles w ere formed to reduce the Gibbs free energy of
the colloidal system Herein the Au –Pt alloy nanoparticles were first prepared by reducing an
equimolar amount of HAuCl 4 and H 2PtCl 6 together by NaBH 4 In addition, it can be seen from
Fig. 20 that these nanoparticles have well -defined morphology and their average size is
about 3.6 nm with a narrow size distribution. Noticeably, such nanoparticles indeed possess
an alloyed structure, which can be seen from the high -resolution

Fig. 21. TEM image of Au 1.25Pt1 alloy nanoparticles (a) and the corresponding histogram of
particle size distribution (b). The inset in panel (a) shows a HR -TEM image of an Au 1.25Pt1
alloy nanoparticle
TEM image (inset), exhibiting a uniform lattice spacing of 0.229 nm between the values of
0.235 and 0.223 nm for pure Au(111) and Pt(111) lattice planes, throughout the entire
nanoparticle TEM images of the Au 1.25Pt1 alloy nanoparticles coated on the PS microspheres

– 33 – are presented in .21. Obviously, dense dark spots can be observed, i ndicating that the
Au1.25Pt1 alloy nanoparticles are immobilized successfully on the surface of PS microspheres
by their proposed method. In addition, the composition of these composite particles was
acquired as the electron beam was converged to them based on energy -dispersive X -ray
(EDX) analysis

Fig. 22. TEM images of PS/Au 1.25Pt1 composite particles with low (a) and
high (b) magnification
Next, they turned to their catalytic performance for aerobic oxidation of alcohols. The
catalytic activity of Au –Pt alloy nanoparticles with different composition supported on PS
microspheres for aerobic oxidation of 1 -phenylethanol was first examined In Table 9, it is
clearly found that the PS / Au1.25Pt1 composite particles show the highest catalytic activit y
and the conversion of acetophenone can reach as high as 99%. This is a significant result
because the use of air and water rather than oxygen and organic solvents under atmospheric
pressure is an ideal green process. In contrast, the PS / Au or PS / Pt composite particles
prepared by the same method has low activity in the absence of base which is similar to that
in previously reported studies[59].Moreover, the physical mixture of PS / Au and PS / Pt
composite particles also gave a lower conversion than the PS / Au1.25Pt1 composite particles
These results are consistent with the recent report that the Au –Pt alloy nanoparticles
promoted the oxidation of 2 -octanol more effectively under the same conditions, as compared
to their monometallic counterparts .[70].
it is interesting to see that the non -activated cyclohexanol and 1 -octanol can also be
effectively converted into the corresponding carbonyl compounds in 80% and 84% yields,
respectively. This is comparable to the results obtained from the aerobic oxida tion of non –
activated alcohols, which has been originally reported by Uozumi et al.29

– 34 – Table 9. Aerobic oxidation of alcohols using PS / Au–Pt composite particles as catalystsa

aReaction conditions: substrate [10 mM], Au –Pt alloy catalyst [0.3 mM], H 2O, air, 24 h, 40 C0. bSize of
supported Au –Pt alloy nanoparticles. cEstimated from GC analysis .

More significantly, cinnamyl alcohol was oxidized selectively to afford the cinnamaldehyde
in a quantitative yield of as high as 99%. The considerable improvement of catalytic activity
of supported Au 1.25Pt1 alloyed nanoparticles can be ascribed to the interaction and synergistic
effect between Au and Pt atoms in the individual nanoparticle, which has been found
previously for many bimetallic systems .[71] The coexi stence of Au and Pt in alloy
nanoparticles leads to a modification of electronic and chemical properties of their parent
metals, and hence enhanced catalytic properties .[72]
In addition, the alloyed structure can also prevent the deactivation and leaching of parent
metals during the catalytic reactions .
In addition to catalytic activity, recyclability is another important criterion for heterogeneous
catalysts. In their work, the PS / Au–Pt composite particles can be recycled from the solution
easily and effectively by centrifugation or filtration owing to the large size of PS
microspheres. The recovered catalyst particles were then used in the next round of oxidation
reaction by adding them into the aqueous solution of substrate. As displayed in Table 10, the
high catalytic activity was maintained even after seven times, in which almost the same
conversion of acetophenone in each run was obtained.
In addition, it is also worth pointing out that no special treatment was required to reactivate
the catalyst in the successive oxidation reactions. This will simplify the operating procedure
clearly compared with previous work, in which Kobayashi et al. found that the activity of the

– 35 – polymer incarcerated Au –Pt bimetallic clusters was maintained by the treatment o f the
recovered catalyst with hydrogen under heating conditions .[73]
Table 10. Recovery and reuse of PS / Au1.25Pt1 composite particlesa

aReaction conditions: 1 -phenylethanol [10 mM], Au 1.25Pt1 alloy catalyst [0.3 mM], H 2O, air, 40 C0, 24 h

In summary, they have developed a facile and effective method surface of PS microspheres.
The complicated surface pretreatments of PS microspheres are not necessary in their designed
system and the key to the success is a thermodynamic effect. Illustrating their application, PS
/ Au1.25Pt1 composite particles exhibit high activity and excellent recyclability as
heterogeneous catalysts for aerobic oxidation of 1 -phenylethanol at 40 C0 without a base in
aqueous media and significantly, they show high selectivity for the oxidation of cinnamyl
alcohol to the cinnamaldehyde under the same conditions. In addition, these composite
particles can also catalyze the aerobic oxidation of non -activated cyclohexanol and 1 -octanol
efficiently. Hence, in combination with facile synthesis, excellent catalytic activity and
stability, and convenient recovery, the PS / Au–Pt composite particles will serve as promising
catalysts in other liquid phase catalytic reactions.
3.8. Recent advances in green catalytic oxidations of alcohols in aqueous media
Selective oxidations of primary and secondary alcohols to the corresponding aldehydes (or
carboxylic acids) and ketones, respectively, are pivotal reactions in organic synthesis.
Traditional methods involve stoichiometric inorganic or orga nic oxidants such as hexavalent
chromium, manganese dioxide or the Swern or Dess – Martin reagents,
respectively .[74]Although such methods have broad scope they are very atom inefficient,
involve the use of toxic and or hazardous reagents and generate copio us amounts of inorganic
or organic waste. Consequently, there is an on -going quest for sustainable catalytic
technologies, with broad substrate scope, using oxygen or hydrogen peroxide as the primary
oxidants .[75]However, hypochlorite is widely favored as an oxidant in the pharmaceutical and
fine chemical industries, rather than oxygen or hydrogen peroxide, because of the potential
explosion hazards associated with the use of the latter oxidants. they note, however, that the
use of water as an inert, non -inflammable solvent alleviates this problem. Nonetheless,
hypochlorite is inexpensive and the relatively low tonnages involved in pharma and fine

– 36 – chemicals mean that the generation of one or more equivalents of sodium chloride waste is
not really an issue. S imilarly, the use of environmentally unfriendly organic sol – vents as
reaction media should, where possible, be avoided. In this context, water has several
advantages: it is abundantly available, inexpensive, odorless, non -toxic and non -inflammable.
Indeed , a variety of commercially important catalytic processes, such as hydrogenation,
carbonylation, hydroformylation, olefin metathesis, polymerization and telomerization, is
already performed in an aqueous medium at industrial scale .[76]
The aerobic oxidation of water soluble alcohols, diols and carbohydrates, over heterogeneous
noble metal catalysts (Pt, Pd, Ru) in aqueous media has been extensively studied and dates
back to the introduction of the term catalysis by Berzelius in the early 19th century .[77]The
current drive toward the replacement of petroleum hydrocarbon feed stocks, derived from
fossil resources, by carbohydrates derived from renewable raw materials .[78]
is stimulating a renaissance in catalytic oxidations of carbohydrate feed stocks and water is
definitely the solvent of choice for these reactions. In the oxidation of alcohol substrates
which are sparingly soluble in water two strategies have been employed for catalyzing
oxidation in an aqueous/organic biphasic system. In the first category the substrate is
dissolved in, or forms itself, an organic phase while the oxidant, and possibly also the
catalyst, resides in the aqueous phase. A phase transfer agent is employed to transfer the
catalyst and/or oxidant to the organic p hase where the reaction takes place. Many catalytic
oxidations with water soluble oxidants, such as hydrogen peroxide, hypochlorite and
persulfate, fall into this category. In the second category the substrate is contained in a
separate organic phase and t he catalyst and oxidant are dissolved in the water phase where
the reaction takes place. The product is separated as the organic phase and the catalyst,
contained in the aqueous phase, is easily recovered and recycled .
In this review they shall focus on th e use of four types of catalyst: (a) water soluble metal
salts and complexes, (b) metal nanoparticles as hybrid species at the interface of
homogeneous and heterogeneous catalysis .[79]
(c) water soluble organo catalysts such as
stable N -oxy radicals .[80](and (d) enzymes [3g] in the oxidation of simple alcohols and, to a
lesser extent, diols and carbohydrates.
1. Water soluble ligands
A selection of water soluble ligands that have been used in catalytic oxidations with
oxygen or hydro gen peroxide is shown in Fig. 23 Early work generally involved
biomimetic oxidations employing water soluble derivatives of porphyrins 1 and the struc –
turally related phthalocyanines 2[81] A major issue associated with the use of porphyrins

– 37 – and, to a lesser extent, phthalocyanines is, in addition to their cost, their susceptibility
toward oxidative degradation. In vivo the ligand can be replenished by intracellular
synthesis by the host microorganism but this is not an option in vitro. Consequently, there
is a defini te need for oxidatively stable macrocyclic ligands. This led Collins and
coworkers .[82] to develop a seriesofiron(III) complexes of oxidatively and hydrolytically
stable tetraamido macrocyclic ligands (TAMLs) of general structure 3, which are efficient
activators of aqueous hydrogen per- oxide, over a broad pH range.

Fig. 23 . Examples of water soluble ligands in catalytic oxidations.
2. Tungsten and vanadium catalysts
DiFuria and Modena and coworkers[83]were the first to report the tungstate catalyzed
oxidation of alcohols with aqueous hydrogen peroxide, in a biphasic system composed of
water and 1,2 -dichloroethane using a tetraalkylammonium salt as a phase transfer agent.
Noyori and coworkers[84] optimized this methodology to afford an extremely effec tive,
chloride -and organic solvent -free system using 1.1 equiv . of 30% H2O2 at 90 ◦C and the

– 38 – lipophilic methyl trioctylammonium bisulfate, [CH 3(n- C8H17)3N]+HSO 4−, as a phase transfer
agent (Fig. 24)
Substrate catalyst ratios as high as 400.000 were used, affording turnover numbers up to
180.000. The active oxidant is a tetra alkyl ammonium pertungstate .A wide variety of
secondary alcohols , including unsaturated alcohols , afforded the corresponding ketones in
high yields . Primary alcohols gave the corresponding carboxylic acid in high yields via
further oxidation of the hydrate of the intermediate aldehyde. Subsequently, Shi and
Wei[85]reported the use of bis – quaternary phosphonium pertungstates or permolybdates for
the selective oxidation of cyclohexanol and benzyl alcohol, to cyclohexanone and
benzaldehyde or benzoic acid, respectively, under halide – and organic solvent -free conditions
with 30% aqueous hydrogen peroxide. Similarly, Neumann and coworkers[86]described the
use of a hydrolyticall y and oxidatively stable sandwich type tungsten polyoxometalate
(POM) catalyst , Na 12[WZn 3(H2O)2][(ZnW 9O34)2], in the oxidation of alcohols with hydrogen
peroxide in an aqueous biphasic medium without any added organic solvent . The catalyst
was prepared from a mixture of the POM , branched polyethyleneimine (MW 600) and an
octylamine -epichlorohydrin cross -linking reagent. in a further elaboration, Ikegami and
coworkers[87]reported the use of a recyclable , thermoresponsive tungsten catalyst for the
oxidation of alcohols with hydrogen peroxide in water. The catalyst consisted of a PNIPAM –
based copolymer containing pendant tetraalkylammonium cations and a heteropolytungstate ,
PW 12O403−, counter anion (see Fig. 24)

Fig. 24. Tungsten(VI) catalyzed oxidations of alcohols with H 2O2.

– 39 –
At room temperature the substrate and the aqueous hydrogen peroxide, containing the
catalyst in the form of micelles, formed distinct separate phases.
On heating the mixture to 90 ◦C a stable emulsion was formed, in which the reaction took
place with as little as 0.1mol% catalyst. Subsequent cooling of the reaction mixture to room
temperature resulted in precipitation of the catalyst as micelles which could be removed by
filtration and recycled . More recently, Wang and coworkers[88]employed a self -assembled,
mesoporous hybrid poly oxotungstate – guanidinium ionic liquid catalyst (see Fig. 24)
in the tri phasic oxidation of benzyl alcohol. During the reaction, the tri phase catalytic
system showed a special ―on water‖ effect which was ascribed to the mesoporous structure
and surface wettability of the catalyst. Ogawa and coworkers{89] recently reported the aerobic
oxidation of benzylic alcohols in water, at 90 ◦C and 0.1 MPaO 2, using 5 mol % of an
oxovanadium (IV) complex of 4,4/-di-tert-butyl bipyri – dine, 10, as the catalyst (Fig. 25).
Other bipyridine ligands were tested but the di-tert-butyl bipyridine gave the best results .

Fig. 25. Vanadium catalyzed aerobic oxidations of alcohols in water.

3. Palladium(II) catalysts
The palladium(II) catalyzed aerobic oxidation of alcohols has been extensively studied[90]A
general drawback of Pd catalysts is that slow reoxidation of Pd(0) to Pd(II) results in the
agglomeration of the Pd(0) particles to palladium black with accompanying catalyst
deactivation. In the well -known Wacker process for the oxidation of ethylene to acetaldehyde
this problem is circumvented by adding copper(II) as a cocatalyst[91]
The latter reoxidizes the Pd(0) to Pd(II) with concomitant formation of Cu(I) which, in turn,
is reoxidized by dioxygen to complete the catalytic cycle. In a continuation of studies[92]of
Pd(II) complexes of sulfonated phosphines as catalysts for carbonylations in aqueous
biphasic media, Pd(II) complexes of analogous water -soluble diamine ligands, such as the
commercially available sulfonated bathophenanthroline (4a), were shown to be active and
stable catalysts for aerobic oxidations of alcohols and olefins in aqueous biphasic media .[93]

– 40 – This and related ligands are able to stabilize transient Pd(0) species under oxidizing
conditions, thus suppressing the formation of palladium black. With water immiscible
alcohols the organic phase consists of the alcohol substrate and the carbonyl product (Fig. 26)
Reactions were generally complete in 5h at 100 at ◦C/3 MP a air with as little as 0.25 mol%
catalyst. No organic solvent is required (unless the substrate is a solid) and the prod uct is
easily recovered by phase separation. The catalyst is stable and remains in the aqueous phase,
facilitating recycling to the next batch.
A wide range of primary and secondary alcohols were oxidized with turnover frequencies
ranging from 10 to100 h−1. The alcohol must be at least sparingly s oluble in water as there
action occurs in the water phase. Secondary alcohols afforded thec orresponding ketones in
>99% selectivity in virtually all cases studied.
Primary alcohols afforded the corresponding carboxylic acids via further oxidation of the
initially formedaldehyde, e.g. 1 -hexanol afforded
1-hexanoic acid in 95% yield, and without the necessity to neutralize the carboxylic acid
product with one equivalent of base. Alternatively ,the aldehyde could be obtained in high
yield by conducting the reaction in the presence of 1 mol% of the stable free radical ,TEMPO
(2,2,6,6 -tetramethylpiperidinoxyl), which suppressed over -oxidation.
A plausible catalytic cycle[94]consistent with the observed half -order in palladium ,involves
initial dissociation of a hydroxyl bridged palladium(II) dimer to afford the monomer as the
active catalyst. Coordination of the alcohol substrateand _ -hydrogen elimination affords the
carbonyl product and palladium(0)which is reoxidized to palladium(II) by dioxygen. Further
evidence in support of this mechanism has been reported by Stahl and coworkers .[95]

The Pd -bathophenanthroline system is an order of magnitude more reactive than hitherto
reported catalytic methods for the aerobic oxidation of alcohols. It requires no organic
solvent, involves simple product isolation and catalyst recycling by phase separation. The
reaction rate increases with electron -donating substituents in the alcohol substrate and
electron -withdrawing substituents in the ligand, in accordance with the putative
mechanism[96]. Buffin and coworkers[97]
observed similar electronic effects in a study of the
structurally related Pd(II) complexes of the biquinoline ligand (6) as catalysts for the aerobic
oxidation of alcohols in water .
The scope in organic synthesis of the Pd-bathophenanthroline system is limited by its low
tolerance for substrates containing heteroatom functional groups, e.g. N or S, which
coordinate strongly to palladium. Since the putative active catalyst is amonomeric species,
formed by dissociation of the hydroxyl -bridged dimer in solution, substitution at the 2 and 9

– 41 – positions in the phenanthro line ring should create steric crowding in the dimer and favor its
dissociation and, hence, increase the overa ll activity. Accord ingly, the bathophenanthroline
(4a) bathocuproin sulfonate (4b) and neocuproin complexes (5) of Pd(II) exhibited TOFs of
50,150 and 1800 h−1, respectively ,in the oxidation of 2-hexanol (Fig. 26), although the
reaction with the neocuproin complex was performed in 50/50(v/v) DMSO/ water while the
reactions with bathophenan throline and bathocuproin sulfonates were performed in water .[98]
)
The Pd ((II) neocuproin catalyzed oxidations were performed in 1:1 mixtures of water and
DMSO or ethylene carbonate at low catalyst loadings (0.1mol%) with TOFs of > 1500 h−1.
The system also tolerates a wide variety of O,N,and S-containing functional groups in the
alcohol substrate. More recently, Muldoon and coworkers[99]showed that Pd(II) complexes of
anionic N,O-chelating ligands such as 7 –9, were highly active catalysts for the aerobic
oxidation of 2 -octanol to 2-octanone at 100 ◦C and 4.5 MPa O2/N2 (8:92), with TOFs up to
1500h−1 using acatalyst loading of 0.1–0.2 mol%. The reactions were conducted with the neat
alcohol but the reaction could, presumably, be performed in an aqueous biphasic medium .

Fig. 26 . Palladium catalyzed aerobic oxidation of alcohols in water

– 42 – 4. Noble metal nanoparticles as quasi homogeneous catalysts
Amore detailed comparison of the Pd(II) bathophenthroline and Pd(II) neocuproin complexes
revealed a remarkable difference in the oxidation of the unsaturated alcohol substrate shown
in Fig. 27. With the former, Wacker -type oxidation of the olefinic double bond was primarily
observed while the latter underwent highly selec tive (>99%) oxidation of the alcohol
moiety[100] The latter result is consistent with the pioneering work of Moiseev and coworkers
who showed that giant Pd clusters (nowadays known as Pd n anoparticles) catalyze the
oxidation of alcohol moieties and selectively oxidize allylic C H bonds in olefins. Indeed,
further investigation[101] of the Pd(II) neocuproin complex revealed that it dissociates
completely, under the reaction conditions, to af ford Pd nanoparticles which are the actual
catalyst .

Fig 27 .Comparison of various palladium catalysts in 2 -hexanol oxidation

In aninteresting variant on this theme Pd nanoparticles were confined with in the protein core
of a highly stable ferritin from the hyper thermophilic bacterium, Pyrococcus furiosus.
Ferritin isan iron transport protein, one molecule of which can contain upto 4055 iron atoms
stored as [FeO(OH)] 8[FeO(H 2PO 4)]. Apo -ferritin, obtained by removing the iron salts, was
incubated with a Pd(II) salt, followed by size exclusion chromatographic purification and

– 43 – hydrogenation of the Pd (II) loaded ferritin to generate a novel nanopalladium -protein hybrid.
The latter proved to be an efficient and robust catalyst for the aerobic oxidation of alcohols in
water at 80 ◦C[102]
Following on from the pioneering studies of Rossi and coworkers[103] carbohydrate
oxidations, such as glucose to gluconic acid in aqueous media, various supported
nanoparticles, e.g. Au -on-CeO 2[104]

Au-on-Mg 2AlO 4[105] Au-on-hydrotalcite[106]
Pd-on-hydroxyapatite[107]and Pd –Au-on-TiO 2[108]

were shown to be excellent catalysts for alcohol oxidations .[109] The reactions were
performed successfully in organic solvents or solvent -free as well as in water .For example
,Christensen and coworkers reported the aerobic oxidation of aqueous (bio) ethanol to acetic
acid over Au-on-Mg 2AlO 4[110]When the oxidation was performed in methanol the methyl
ester of the corresponding carboxylic acid was obtained. Supported Au nanoparti cles have
also been used for the selective oxidation of renewable raw materials, such as glycerol,
furfural and hydroxyl methyl furfural[110] Mono – and bi -metallic nanoparticles are also
stabilized by immobilization in polymer matrices, affording ‗quasi ho mogeneous catalysts‘
for aerobic alcohol oxidations in water. Examples include Au and Pd nanoparticles embedded
in crosslinked N,N – dimethyl acryl amide -based microgels[111] Au dispersed in the stabilizing
hydrophilic poly (N-vinyl -2-pyrrolidone[112]Au incarcerated in a polystyrene matrix[113] and
Pd[114]or Pt[115]nanoparticles dispersed in an amphiphilic polystyrene -(poly) ethylene glycol (
resin. In a further elaboration pre -formed, poly vinyl pyrrolidone stabilized Au –Pd
nanoparticles were entrapped in a porous polyimide membrane[116]Palladium nanoparticles
confined in the nanocages of the mesoporous silica, SBA -16 catalyzed the aerobic oxidation
of alcohols at room temperature in water[117]Another interesting variation on this theme is the
use of Au nanoparticles, stabilized by the redox active, water soluble poly (aniline sulfonic
acid), as a catalyst for aerobic alcohol oxidation .[118]

5. Stable N -oxy radicals as organo catalysts
The stable free radical, TEMPO (2,2,6,6 – tetra methyl piperidinyloxyl) i s an example of an
organo catalyst that is effective in the oxidation of a broad range of alcohols[119]including
simple carbohydrates[120]
using hypochlorite (household bleach) as the terminal oxidant. The
method was first described in 1987 by Montanari an d coworkers[121]who used 4 -methoxy
TEMPO as the catalyst and has been widely applied in organic synthesis [9,55]. Typically,
1mol% TEMPO or a derivative thereof is used in combination with 10 mol% sodium bromide
as cocatalyst ,in dichloromethane /water at pH 9and 0 ◦C (Fig. 28). More recently,
environmentally acceptable ester solvents, notably methyl acetate and isopropy lacetate,were

– 44 – shown to give results[122] comparable to or better than dichloromethane. The active oxidant is
the oxoammonium cation, formed by oxidation of TEMPO by chlorine or bromine, which is
regenerated in the catalytic cycle by reaction of the reduced TEMPOH with the primary
oxidant t(hypochlorite). Although only 1mol% is used in the Montanari protocol, TEMPO is
rather expensive, a nd efficient recycling is, hence, an important consideration. It can be
replaced by a recyclable oligomeric TEMPO, referred to as PIPO (polymer -immobilized
piperidinyloxyl) which is derived from the commercially available antioxidant and light
stabilizer, chimassorb 944, an oligomeric sterically hindered amine (see Fig. 28). PIPO
proved to be a very effective and recyclable catalyst for the oxidation of alcohols, including a
wide variety of carbohydrates, with hypochlorite in a bromide – and chlorinated hydr ocarbon –
free system .[123]

Fig. 28. N-Oxy radical catalyze doxidation of alcohols with NaOCl

The reaction is performed with 1mol% of PIPO and 1.25 equivalents of NaOCl in water as
the sole solvent or in a water / methyl tert-butyl ether (MTBE) mixture. Other methods have

– 45 – also been described for the immobilization of TEMPO derivatives, e.g. by attachment to a
Merrifield poly stryrene resin[124]or functionalized silica, commercialized under the name
Fiber – cat TEMPO by Johnson Matthey[125]In another variation on this theme, as called ion-
supported TEMPO was synthesized by build ing a TEMPO moiety in to the side chain of a di
alkyl imidazolium salt (see Fig. 28). The resulting material catalyzed the oxidation of
alcohols with NaOCl or I2 in water or an ionic liquid / water mixture. [126] Alternatively,
immobilization on magnetite (Fe 3O4) nanoparticles provides the possibility of recovering the
TEMPO catalyst magnet ically .[127]
In the case of large volume products the industrial potential would be significantly enhanced
by replacing the hypochlorite by dioxygen or hydrogen peroxide. Copper complexes of
bipyridine ligands, in combination with TEMPO and a base, were shown to catalyze the
selective aerobic oxidation of primary alcohols, to the correspo nding aldehydes, in aqueous
acetonitrile[128]Based largely on kinetic studies, a mechanism (Fig. 29) was proposed[129]
which is analogous to that involved in the aerobic oxidation of primary alcohols catalyzed by
the copper -dependent oxidase, galactose ox idase. This copper centered dehydrogenation
mechanism, in which a copper coordinated TEMPO ligand plays the same role as a
coordinated tyrosine radical in the galactose oxidase mechanism, differs totally from the
oxoammonium type mecha – nism originally pro posed by Semmelhack[130] for the Cu/TEMPO
system.

– 46 –

Fig.29. The mechanism of aerobic oxidation of alcohols catalyzed by Cu / TEMPO .
The aerobic Cu/TEMPO system was further improved by using air -microbubble techniques
to facilitate gas absorption into the liquid phase[131]It was also shown[132] that Cu(I) salts give
better results than Cu(II) salts in a system using TEMPO and bipy in combination with N –
methylimidazole as a base. Furthermore, extensive mechanistic studies performed by Stahl
and coworkers[133] confirmed the copper -centered galactose oxidase -like mechanism for
these systems .
The absence of hydrogen atoms at the carbon atom in sterically hindered N-
reactions. More recently ,attention has been drawn to the use of sterically unhindered
nitroxyl radicals such as AZADO[134]and ABNO[135]
and derivatives there of (Fig. 30), which possess hydrogens but are nonetheless stable toward
elimination because the resulting double bond would be formed at a bridge head and, hence,
violate Bredt‘srule[136]

– 47 –
Fig. 30. Structures of unhindered stable nitroxyl radicals.
It was already known that such unhindered radicals react faster than TEMPO but, more
importantly, they are able to oxidize more sterically demanding alcohols that exhibit lower
activity toward TEMPO -based systems .As noted above, the Cu / TEMPO / bipy system is
very selective for primary alcohols. Secondary alcohols are much lesser active, which was
attributed to steric hindrance in the abstraction of an hydrogen atom from a coordinated
alkoxideby a coordinated TEMPO ligand. In contrast, it was recently shown[137] that an
analogous Cu(I) / ABNO can effectively oxidize a variety of secondary alcohols, including
sterically demanding ones such as menthol. Similarly, Iwabushi and coworkers[138] recently
showed that the Cu/AZADO system is active in the aerobic oxidation of a variety of
unprotected amino alcohols. Interestingly, Ji and coworkers[139] recently showed that a ligand –
and additive free system comprising Cu(OAc) 2 / TEMPO (1 mol%) was able to catalyze the
aerobic oxidation of a variety of primary and secondary alcohols to the corresponding
aldehydes and ketones ,respectively ,at ambient temperature in acetoni trile / water (1:2,v/v).
Although the copper / N-oxyradical systems are by far the most studied, other metals,
including iron, cobalt, manganese and vana dium, in combination with TEMPO, have also
been reported. The Fe / TEMPO system, for example ,has not yet been subjected to rigorous
mechanis tic investigation but, on the basis of the economic and environmental benefits of
using iron-based catalysts, it would seem to be worthy of further investigation. Many of the
iron /TEMPO systems studied have been with Fe(NO 3)3 or with added NaNO 2 or
NaNO 3[140]and such system scan involve reoxidation of the reduced TEMPO by NO 2 and O 2
as the terminal oxidant (Fig. 31). Similarly, Tong and coworkers[141] have reported highly
efficient and selective aerobic oxidation of alcohols using a catalyst comprising TEMPO (1–
3mol%), ceric bammonium nitrate (5mol%) and sodium nitrite (10 mol%), in water as
solvent. The cheapest source of NO 2 is nitric acid and systems have been described[142] which
utilize TEMPO / HNO 3 in the absence of added metals, i.e. transition metal -free systems.
Hypervalent iodine compounds, in stoichiometric amounts, are known to oxidize alcohols
and the use of iodosyl benzene or a polymer -supported iodine (III) reagent, in combination
with KBr as a cocatalyst, for the oxidation of alcohols in water has been

– 48 – described[143].Morerecently are lated catalytic system, consisting of PhIO 2 (2 mol%), Br2 (2
mol%) and NaNO 2 (1 mol%), for the aerobic oxidation of alcohols in water at 55 ◦C was
reported .[144]

Fig. 31. Reaction mechanism of TEMPO / nitritesystems .
6. Enzymatic oxidation of alcohols
Oxidoreductases are divided into four categories on the basis of reaction type.
Dehydrogenases and (mono) oxygenases are cofactor dependent, that is they consume a
stoichiometric amount of a nicotinamide cofactor (NAD or NADP) that has to be regenerated
in order to be catalytic in cofactor. Oxidases and peroxidases, in contrast, catalyze oxidations
with dioxyg en and hydrogen peroxide, respectively, without the need for a cofactor. In the
context of alcohol oxidations they shall be mainly concerned with oxidases[145]which catalyze
the oxidative dehydrogenation of alcohols by dioxygen, affording the corresponding carbonyl
compound and hydrogen peroxide or water. There are two major types: copper dependent
oxidases, exemplified by galactose oxidase and laccase, and flavin -dependent oxidases ,such
as glucoseoxidase . Alcohol dehydrogenases are widely applied in organic synthesis
butmostly as ketore ductases (KREDs) in the reversere action, i.e. the enantioselective
reduction of ketones . However ,recently they have been studied as possible catalysts ,in
conjunction with regeneration of the oxidized cofactor with dioxygen and a second enzyme
,for the oxidation of alcohols .[146]
Laccases (EC 1.10.3.2) are extracellular, copper -dependent oxidases that are secreted by
white rot fungi and play an important role in the delignification of lignocelluloses[147]. There
is currently considerable commercial interest in laccases for application in pulp bleaching (as
a replacement for chlorine) in paper manufacture and remediation of phenol -containing waste

– 49 – streams[148] Galli and coworkers[149] were the first to show that laccase, in combination with
TEMPO as a cocatalyst, catalyzed the selective aerobic oxidation of primary benzylic
alcohols to the corresponding benzaldehydes but 30 mol% of TEMPO was required. It was
subsequently shown[150] that these reactions involve one -electron oxidation of the TEMPO, or
a derivative thereof, by the oxidized form of the laccase to afford the oxoammonium cation,
followed by reoxidation of the reduced form of laccase by dioxygen (Fig. 32). 10 mol% of
TEMPO was sufficient to give good conversions and excellent selectivities[151] but further
reduction of the catalyst loading is necessary for large -scale use of this system.

Fig. 32 . Laccase /TEMPO -catalyzed aerobic oxidations of alcohols
More recently, the laccase / TEMPO system was shown[152] to catalyze the oxidation of 1,4
and1,5 -diols to the corresponding lactones (Fig. 33). The enzyme could be recycled by
immobi lizing it as cross -linked enzyme aggregates (CLEAs)[153]. The laccase /TEMPO
system also catalyzed the aerobic oxidation of the renewable diols, isosorbide and
isomannide ,affording the corre sponding diketones (Fig. 33) in > 99%yield[154]. The
corresponding diamines, produced by reductive amination of the diketones ,are of interest as
starting materials for the production of bio-based polymers, e.g. polyamides. Especially the
oxidation of isosorbide is surprising because of the low reactivity of the shielded endo OH
group in isosorbide .Similarly, laccase /TEMPO catalyzes the aerobic oxidation of the
primary alcohol moieties in starch,to give the corresponding carboxylic acid moieties[155].
The product, carboxy starch, has potentia l applications as a biodegradable water super
absorbent but the relatively high enzyme costs form an obsta cle to commercialization.
Inefficient laccase use is a direct result of its in stability toward the oxidizing reaction
conditions. Here again, the stability of the laccase under reaction conditions was improved by

– 50 – immobilization[156] as across -linked enzyme aggregate(CLEA)[157] thus removing reactive
amino groups from the surface of the enzyme.

Fig. 33. Laccase / TEMPO catalyzed oxidation of diols and polyols.

3.9. 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 .[158]although 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[159] One
of the most significant tasks in organic synthesis i s the oxidation of alcohols[160] However,
such oxidation reactions have frequently been performed with stoichiometric amounts of
inorganic oxidants, many of which are extremely hazardous to use or toxic[161]the availability
of easy -to-handle heterogeneous catalysts, which can easily recycled after use in liquid phase
oxidation reactions, and which have low toxicity, good stability and high efficiency is thus an

– 51 – essential requirement. the compound 2,2,6,6 -tetramethylpiperidinyloxyl (TEMPO) is known
to be a stable organic radical that can be stored for long periods of time without
decomposition. A wide variety of derivatives and analogues of this type of stable free organic
radical has been reported[162 ]since TEMPO can work as a redox reagent, it has been us ed in
oxidation reactions under a variety of conditions[163] several TEMPO functionalized solid
catalysts, prepared by immobilising individual TEMPO molecules on to solid support
materials as a covalently anchored monomolecular layer, have been previously studied for
their potential in oxidation reactions[164] however , these reactions usually require more than
stoichiometric amounts of these mono -molecular layer solid state catalysts to achieve
acceptable product yields due to the low loading of TEMPO molec ules onto the solid support.
To overcome this constraint, attention has turned to the generation of TEMPO functionalized
polymers allowing the introduction of higher densities of TEMPO.
For example, their group has reported the preparation of TEMPO functionalized polyvinyl
polymers for use as new materials in organic batteries, which can be charged in seconds via
the oxidation of the nitroxide radical and reduction of the corresponding oxoammonium
moiety of the TEMPO molecule[165] however , polymeric TEMPO functionalized solid state
catalysts based on multiply -displayed TEMPO units introduced into a polymeric backbone,
which has been concomitantly immobilized onto a carrier surface, have not been previously
reported for use in oxidation reactions. Base d on the hypothesis that a multiply -displayed
TEMPO polymer grafted solid state catalyst of high radical density would lead to recyclable
heterogeneous catalysts with improved catalytic activity 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 solid state catalysts for oxidation reactions.
The intent of this s tudy was to evaluate the catalytic performance of this new class of
oxidative heterogeneous catalyst when used in l oco multiple times, thus circumventing the
constraints found with single cycle heterogeneous catalysts to this end, a series of multiply –
displayed TEMPO polymer grafted silicas has been synthesized by grafting poly (2,2,6,6 –
tetramethylpiperidinyl – oxymethacrylate) (PTMA )[166] onto silica.
In initial experiments, a ‗‗grafting from‘‘ method was employed using t he RAFT chain
transfer agent, S -methoxycarbonyl -phenyl -methyl S9 -trimethoxysilylpropyltrithiocarbonate,
introduced onto the silica surface to form a silica -supported chain transfer agent,[167]
Then, 2,2,6,6 -tetramethylpiperidine methacrylate was graft polymerized using 1 by RAFT
polymerization and the so -formed precursor, poly (2,2,6,6 -tetra-methylpiperidine

– 52 – methacrylate) grafted silica treated with 3 -chloroperoxybenzoic acid to yield the TEMPO
polymer grafted silica 2 ( Fig. 34)

Fig. 34. TEMPO polymer grafted silica synthesis by ‘‘grafting from’’ method.
The product, 2, was characterized by IR, elemental analysis, and thermogravimetric analysis
(TGA).
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 surface 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 available silicas partially functionalized with a
mono -layer of TEMPO molecules (e.g. mono -TEMPO -Si, 0.6 mmol g-1).[168] (The molecular
weight of the optimally grafted TEMPO polymer was determined by cleaving the polymer
from 2 using an aminolysis reaction[169]. 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 condit ions. The
most important value, the number of radical groups introduced onto the silica surface, was
estimated by superconducting quantum interference device (SQUID) measurements. The
amount of radical groups on 2 was found to be only ca. 45% of the theore tical 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

– 53 – TEMPO polymer grafted silicas with a radical densities approaching 100% of the theoretical
value, was undertaken using a ‗‗gr afting 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),[170]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 weights 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, typically 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 silicas, 49s ( Fig. 35). N-ethoxy -carbonyl -2-ethoxy -1,2-
dihydroquinoline (EEDQ) was used as the condensation agent. EEDQ was selected for this
condensation reaction since this reagent is readily available at low cost and allows the
coupling in high yield in a single one operation.[171]

]
Fig . 35. 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 size of the derived TEMPO immobilization

– 54 – 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 determin ed by
scanning electron microscope (SEM) and dynamic light scattering (DLS).
A SEM image of 4 -2 (Fig. 36) 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 attributed 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.

Table 11. TEMPO polymer grafted silica 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.

Fig. 36 . 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

– 55 – 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 evidence for the oxidative modification of the aromatic ring was obtained as
has previously been noted[172] with other types of TEMPO -mediated oxidation reactions. The
need to use a co -catalyst, such as transition metal or nitric oxide derivatives ,[173] or to employ
surface coating with an ionic liquid[174] 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 oxidation catalysts
compared to monomer TEMPO functionalized silicas due to the higher radical density that
can be achieved by the grafted TEMPO polymerisation proced ure. Interestingly, the oxidative
capacity of the catalysts, 4, appeared to follow a parabolic 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 catalyst increasing along with the molecular
weight of the grafted TEMPO polymer. However, above a certain value, the catalytic
performance of 4 decreased with the molecul ar weight of the grafted polymer (4 -2–– 4-4)
with 4 -4, which corresponded to the highest 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 grafted polymer, an alternative explanation for the decrease in catalytic
performance of the catalyst containing the highest molecular weight pol ymer species would
be steric crowding of the TEMPO moieties and lower solvation propensity of the larger
polymeric chains. In order to establish the reusability of the catalyst, the catalyst was
recovered by filtration and reutilised in subsequent cycles ( Fig. 37). 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 ot her alcohols. The oxidation of 1 octanol and 1 -decanol
yielded the corresponding aldehydes in high yield (ca. 98 –99%).

– 56 – Table 12 . 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.

Fig. 37. 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).

– 57 –
Fig. 38 . Time vs. conversion of the oxidation of benzyl alcohol with 4 -2 (. = CH 2Cl2 /water,
o = ethyl acetate/water, = toluene/water, = N,Ndimethylformamide/ water, =
MeTHF / water, = CPME / water).
The reaction with 1 -undecanol, 1 -dodecanol, and 4 -hydroxy -methylbiphenyl also gave
similar results (ca. 99%, 97%, 84%, respectively). In contrast, the reaction with secondly
alcohols, e.g. 2 -octanol and 2 -decanol, only gave trace amounts of the correspondi ng
aldehydes (ca. 4% and 2%, respectively) which suggesting a high level of substrate
specificity of the catalyst. The catalyst was also evaluated for the oxidation of the diol. 2 –
methyl -1,3-hexanediol. The reaction yielded 54% (rate constant k1 = 1.1 x 10-2 Lmol-1 s-1) of
the corresponding 1 -hydroxy -2-methyl -3-ketohexane and a trace amount of the 2 -methyl -3-
hydroxyhexanaldehyde from the reaction (Table 13). Compared to conventional alternatives,
the conversion was much higher than that of, for example, mono -TEMPO Si (product
conversion = 5%, rate constant k1 = 0.45 x 10-2 L mol-1 s-1). The oxidation of another diol,
2,2,4 – trimethyl -1,3-pentanediol, did no t proceed with either 4 or the mono -TEMPO -Si and
this observation can be explained by the steric effect of access to the alcohol sites. Moreover,
The formation of carboxylic acids was not detected by 1H NMR or 13C NMR in the products
from these reactions. These results suggest that these new types of poly TEMPO grafted
catalysts have potential as effective and selective solid oxidation catalysts for both primary
and secondary alcohols. As noted above, these reactions can be carried out using a
CH 2Cl2/water solvent biphasic condition. In order to replace CH 2Cl2/water (Fig. 38) with a

– 58 – greener solvent for the reaction, ethyl acetate/water, 2-methyltetrahydrofuran
(MeTHF)/water, cyclopentyl methyl ether (CPME) / water were examined as alternatives for
the oxidation reaction of benzyl alcohols. As a result, ethyl acetate/water resulted in
comparable yields as CH 2Cl 2/ water, and would thus be a preferred option for these oxidative
reactions including those for the more hydrophobic alcohols.
Table 13 . Conversion (%) of alcohols to aldehydes with TEMPO catalysta

aReaction time: 10 min, reaction temp: 5 uC, catalyst/alcohol: 0.5 mol%, solvent CH 2Cl2/water. b 4-3 for
entry 1 and 2, 4 -2 for entry 3. cConversions were determined by NMR and GC .

3.10. Size-specific catalytic activity of polymer -stabilized gold nanoclusters for
aerobic alcohol oxidation in water
Haruta‘s discovery of CO oxidation catalyzed by supported gold nanoclusters (NCs)[175] has
made a great impact on both the scientific and industrial communities. Following this
discovery, the literature has been inundated with reports on gold -catalyzed oxidation of
CO[176] and alcohols .[177]
Such great activity in this research field can be likened to a ―gold rush‖ in modern science.
As a consequence o f the exhaustive experimental and theoretical studies, it is now generally
accepted that adsorbed molecular oxygen, activated by electron donation from the gold
cluster, plays an important role in the CO oxidation[178]. In contrast, the fundamental aspect of
the gold catalyzed alcohol oxidation (e.g., cluster size effect) has not been well understood
mainly due to the poly disperse nature of the gold catalysts and the complex interactions with
the support Here, they report on the aerobic oxidation of benzy lic alcohols catalyzed by

– 59 – monodisperse gold NCs stabilized by the representative hydrophilic polymer, poly( N-vinyl -2-
pyrrolidone) (PVP; (C 6H9ON) n), with a focus on the cluster size effect in catalysis. The gold
NCs are known to be weakly stabilized through multiple coordination of the > NCdO sites of
PVP so that the reactants can access the NC surface.5 Kinetic measurements show that the
smaller Au:PVP NCs (1.3 nm) exhibit superior catalytic activities than the larger NCs (9.5
nm). A reaction mechanism is proposed on the basis of comparison with catalysis of Pd:PVP
NCs (1.5 and 2.2 nm).
The Au and Pd NCs stabilized by PVP (K -30, 40 kDa) were prepared as follows Rapid
injection of an aqueous solution of NaBH 4 into an aqueous solution of the AuCl 4 -/PVP
comp lexes at ca. 273 K yields the brownish Au:PVP (Au:PVP -1) NCs with an average
diameter, dav, of 1.3 ( 0.3 nm (Fig . 39a)[179]
The Au:PVP -1 NCs are allowed to grow in size by reducing AuCl 4 – with Na 2SO 3, leading to
the formation of reddish Au:PVP -2 with daV ) 9.5 ( 1.0 nm ( FIg. 39 1b). Reduction of PdCl 4
2-/PVP by NaBH 4 and ethanol[180] 1.5 ( 0.3 nm (Pd: PVP -1) and 2.2 ( 0.4 nm (Pd:PVP -2)
(Fig. 39, c and d), respectively. The molar ratios of the metal ions to PVP monomer units
were 1% for all the catalysts.
They first examined the catalytic activities of Au:PVP -1 toward aerobic oxidation of
benzylic alcohols ( 1a-1d) in water as a test reaction. Special care was taken to conduct a
batch of experiments under identical conditions an aqueous solution (15 mL) containing
Au:PVP -1and the alcohol was stirred in a test tube ( ᵩ ) 30 mm) at a rate of 1300 rpm while
the temperature was kept constant within an accuracy of (1 K. Table 14 lists the yields of
aldehydes and/or carboxylic acids formed in the reactio n of 1a-1d at 300 K. Benzoic acid and
benzyl benzoate were formed from 1a in 85% and 10% yields, respectively
In the oxidation of hydroxyl derivatives 1b-1d, the corresponding aldehydes were obtained;
hydroxyl benzaldehydes were selectively obtained in entries 2 and 4 Low conversion of 1b is
ascribed to steric hindrance by the quasi -two-dimensional NC surface7 and/or the chelate
effect by the OH group at the or the position. The TEM and optical measurements revealed
that Au: PVP -1 NCs do not grow in size in entries 2 and 4 but coagulate into larger particles
in entries 1 and 3 .
A fundamental question is how are the catalytic activities affected by the size and element of
the cores? To answer this, a comparison was made between the oxidation rates of 1d
catalyzed by Au:PVP – 1/2 and Pd:PVP -1/2 measured under the same conditions (2 at. %, 300
K); p-hydroxy benzaldehyde was selectively produced in all the systems. they monitored the

– 60 – conversion, C, from the measured yield of the product as a function of the r eaction time. As
shown in Fig. 40a, there is a linear relationship between –l n(1 – C) and the reaction time,
indicating that the reaction is first order with respect to 1d.

Fig. 39. Typical TEM images and size distributions of (a) Au:PVP -1,(b) Au:PVP -2, (c)
Pd:PVP -1, (d) Pd:PVP -2.
Table 14 . Alcohol Oxidation Catalyzed by Au:PVP -1

aEstimated from GC analysis. bBenzyl benzoate was additionally formed in 10% yield.c Oligomers of 2
were formed in aqueous phase

– 61 – The rate constant, k, is therefore obtained from the slope and is listed in Table 15. For the
sake of comparison, the k values are normalized by the surface areas of the corresponding
NCs by assuming spherical shapes with the diameters shown in Fig. 39. The k values listed in
Table 14 represent the relative rate constants thus normalized with respect to that of Au:PVP –
1.

Fig. 40. (a) Time course of conversion and (b) Arrhenius plots for oxidation of 1d
Table.15 . Catalytic activity toward oxidation of 1d

aAt 300 K. bRatio of the rate constant normalized by surface area of the clusters. cAt 330 K
The k value of Au:PVP -2 shows that the smaller (1.3 nm) Au NCs exhibit higher catalytic
activity than the larger (9.5 nm) NCs. The 1.3 -nm Au NCs are found to be catalytically more
active than the Pd NCs of similar size at 300 K, as recently observed in the glucose oxidation
catalyzed by their ―naked‖ clusters .
To explain these findings, the mechanistic aspects of the oxidation of 1d were studied in
more detail. Ki netic measurements have shown that Au:PVP -1 NCs cannot catalyze the
oxidation in the absence of either molecular oxygen or base.6 This result indicates that O 2
and the deprotonated form of 1d are intimately involved in the reaction. The oxidation under
air proceeds at a rate comparable to that under 1 atm of O 2, indicating that the reaction is not

– 62 – retarded by the concentration of O 2 dissolved in water.6 A large kinetic isotope effect (KIE)
was observed in the oxidation of R -deuterated 1d (p-HOC 6H4CD 2OH); kH/kD ) 74 ( 6 and 23
( 3 at 330 K for Au:PVP -1 and Pd:PVP -2, respectively (Table 15).
The primary KIE demonstrates that cleavage of the C -H bond at the benzylic position is the
rate-determining step. The apparent activation energy, Ea, associated with the C -H bond
cleavage is determined from the Arrhenius plots in the temperature range of 273 -345 K ( Fig.
40b). The least -squares fit analysis yields Ea values of 20, 25, and 33 kJ mol -1 for Au:PVP -1,
Au:PVP -2 and Pd:PVP -2, respectively (Table 15).
The marked difference in the KIE and Ea values between Au: PVP -1 and Pd:PVP -2 suggests
that different mechanisms are operating in their catalytic processes. It is accepted that the
alcohol oxidation catalyzed by Pd(0) NCs proceeds via the following mechanism[181]
First, the alcohol is dissociatively adsorbed on the Pd NC surface, affording the alkoxide and
hydride (oxidative addition). Then the H atom on the â-carbon of the adsorbed alkoxide is
transferred to the Pd NC surface to form the aldehyde and a Pd -hydride species in the rate –
determining step. Finally, the O 2 molecule removes the hydride species from the Pd surface
to reactivate it, as well as forming H 2O2. In contrast, the rate determining step of the Au:PVP –
1-catalyzed reaction may involve H-atom abstraction by a super oxo-like molecular oxygen
species, which is adsorbed on Au:PVP -1. Within the framework of this model, the size –
specific catalytic activity of Au:PVP -1 (Table 15) is reasonably explained in terms of the
efficient activation of O2 by small -sized gold NCs.4 Formation of similar complexes between
Au NCs and O 2 has also been postulated in the homocoupling of arylboronic acid catalyzed
by Au:PVP NCs[182] In summary, they report herein the first successful application of
colloidal Au NCs toward the aerobic oxidation of benzylic alcohols in water at ambient
temperatures. A size effect is clearly demonstrated, showing that O 2 adsorption onto the gold
NCs is the key factor for the size -specific catalytic activities. The results reported here will
contribute to the development of efficient and environmentally benign gold catalysts for
alcohol oxidations, that utilize ubiquitous air (viz. molecular oxygen) as an oxidant
3.11. 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 oxidizing agents for
such a transformation documented in literatu re directly demonstrates the importance with
which the functional group transformation has been addressed.[183] However, a lot of
drawbacks may be encountered in using some of these reagents such as low yields, harsh

– 63 – reaction conditions, tedious work -up pr ocedures, 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 readily available and safe reagents, which lead to
high yield of ni triles 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 TCCA in organic
synthesis include thioacetalization of carbonyl compound,[184] conversion of alcohols to
halides,3 carboxylic acids to acid chloridescarboxylic acids to acid chlorides,[185], alkenes to _
β-chloroethers[186] N-nitrosation of N,N-dialkylamines[187]selective mononitration of
phenols[188] and oxidation of alcohols to carbonyl compounds[189] aldehydes to methyl esters[190]
thiols to disulfides,[191] selenols to diselenides[192] and sulfides to sulfoxides[193] (To the best of
their knowledge, however, there 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
amines utilizing TCCA in the presence of catalyti c 2,2,6,6 -tetramethyl – 1-piperidinyloxy, free
radical (TEMPO) under mild reaction conditions as outlined in Fig. 41.

Fig. 41. 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 16, entries 1 –3); a dramatic increase in the yield, howev er, was obtained
in CH 2Cl2 (Table 1, entry 4), which was therefore used as the solvent in all further
experiments. Next, the effect of temperature was examined. Enhancing the temperature from
0 to 10 °C resulted in a considerable increase in the yield (49 to 88%, Table 16, 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 (Table 16, entry 7).
Table 16. Optimization of the Reaction Conditions for the TCCA Mediated Oxidation of
Benzylamine ( 1d) to the Benzonitrile ( 2d)a

– 64 –
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, whil e 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.
Guided by the above experiments with benzylamine ( 1d), a standard procedure was
employed for the oxidation of other aliphatic, aromatic and heterocyclic primary amines with
TCCA, and the results are summarized in Table 17.

– 65 – Table 17. Oxidation of Primary Amines 1a–q into Nitriles 2a–q with TCCA

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.

The results illustrated in the Table 17 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 (entry 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 .[194]
It is interesting to note that benzylic amines were oxidized more readily with a higher yield
than their aliphatic counterparts, just as reported in the dehydrogenation procedure of amines
to nitriles using NiSO 4 / K2S2O8 system.1e At the same time, it is noteworthy that the
presence of catalytic TEMPO was essential for the dehydrogenation 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, we have developed an efficient
method for oxidative conversion of the primary amines to nitriles employing
trichloroisocyanuric acid. Prominent advantages of this new method are its mild reaction
conditions, operat ional simplicity, and high yields..
Oxidation of Benzylamine (1d) to Benzonitrile (2d); Typical Procedure

– 66 – 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 combi ned 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 .
3.12. Metal -free aerobic oxidations mediated bN – hydroxyphthalimide. A concise review
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 .[195]
In this context, the replacement of traditional oxidants, often used in stoichiometric amounts,
with molecular oxygen is mandatory in order to improve t he beneficial impact of selective
oxidation on industrial chemistry[196]Nevertheless, classical autoxidation is usually very slow
at low temperatures, and catalysis is required to activate O 2. Transition -metal salts are
particularly effective for this scop e[197] but their use is often detrimental for the selectivity of
the process and they would not meet the standards 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[198]
NHPI acts as a precursor of the phthalimide N-oxyl (PINO) radical, which is the effective
catalyst promoting hydrogen abstraction processes ( Fig. 42). The reactivity of NHPI and
PINO i s related to the bond dissociation energy (BDE) of the O –H group, which was
estimated at 88.1 kcal/mol[199] 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 . [200] Furthermore, NHPI also behaves as a relatively good hydrogen donor even at low
temperatures ( kH = 7.2 × 103 M−1s−1)[201] trapping peroxyl radicals before they undergo
termination. PINO generation represents the key step of the overall process. Many transition
metal salts and complexes have been successfully used as co -catalysts 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 devoted 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

– 67 – describe herein the most significant examples related to the selective oxidation of organic
molecules with molecular oxygen, catalyzed by NHIs in the presence of nonmetal
cocatalysts. After briefly describing the role of classical radical initiators obtained by thermal
decomposition, they focus on some intriguing 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 oxygenation of hydrocarbons.

Fig. 42. 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[202]
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-adamantylben zamide as a principal product ( Fig. 43), 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[203] In both cases the
reactionproceeds via the formation of a carbocation intermediate ( Fig. 44). The same research

– 68 – group also reported the efficient air -assisted nitration of alkan es and alkyl side -chain aromatic
compounds[204] by nitrogen dioxide and nitric acid, under NHPI catalysis ( Fig. 45).

Fig. 43 . NHPI -catalyzed reaction of adamantane under NO atmosphere.

Fig. 44. 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. 45. 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 ox ygen 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. 46)[205]
According to the propos ed mechanism, being that the concentrations of NO 2 and O 2 are much
lower than that of I 2, benzyl radicals generated from hydrogen abstraction by PINO react
faster with the latter one, forming benzyl iodides selectively. Under the described reaction

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

Fig. 45. Radical mechanism for the nitration of alkanes catalyzed by NHPI.

Fig. 46. 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 often involved in ET
chains, could be employed to design biomimetic oxygenation models for the activation of
NHPI[206]
The catalytic redox cycle is reported in Fig. 47.

– 70 –
Fig. 47. 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 selecti ve
oxidation of ethylbenzene 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 catalytic system was proved by extending its application, in the absence of zeolite, for
the oxygenation of a wider range of hydrocarbons.[207] Moreover, the electronic effect of
substituents on quinones and on the aromatic ring of NHPI w as also investigated. Quinones
bearing halogen groups were used in the selective oxidation of alkylarenes, alkenes and
alkanes[208]
Revealing how the moderate electron -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[209] In
particular, aryl -tetrachlo ro-NHPI (TCNHPI) allowed significantly higher conversion and
selectivity with respect to the NHPI/DADCAQ classical system ( Fig. 48).

– 71 –
Fig. 48. DADCAQ/TCNHPI mediated 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 xanthone and tetramethylammonium chloride (TMAC), for the selective oxidation
of hydrocarbons ( Fig. 49)[210]
In the proposed mechanism, TMAC has the unique role of decomposing the hydroperoxide
intermediate, prolonging the free -radical chain[211]

Fig. 49. 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. 50)[212]

Fig. 50. NHPI/AQ -mediated aerobic oxidation of α -isophorone.

Very recently, Coseri et al. reported that NHPI[213] and other nonpersistent nitroxyl radical
precursors, such as VLA, HBT and N-hydroxy -3,4,5,6 -tetraphenylphthalimide (TPNHPI)[214]

– 72 – were suitable catalysts for the selective oxidation of cellulose fibers promoted by the
NaClO/NaBr system ( Fig. 51). 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 C6 alcoholic function .

Fig. 51. NHPI/AQ -mediated oxidation of cellulose fibers by NaClO/NaBr system.
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[215] 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 highest content of carboxylic
groups and better p reserves the morphology and the molecular weight of the starting
material[216]
Moreover, this catalytic system could be employed with dioxygen in place of NaClO as the
ultimate oxidizing agent[217] In this case, the mechanism follows a radical chain via c lassical
HAT by PINO abstraction ( Fig. 52).

– 73 –
Fig. 52. NHPI/AQ mediated aerobic oxidation of cellulose fibers.

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[218] 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 oxygen 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, to gether with the low cost and environmental
impact of the selected 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 r eagents, 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 .[219]
The combination of stoichiometric am ounts of acetaldehyde with catalytic quantities of NHPI
promoted 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 responsib le for the substrate oxidation.
More recently they suggested that the NHPI/aldehyde system could promote the formation of
PINO radical following a molecule – induced homolysis mechanism[220]
Molecule -induced initiation is a process driven by a thermodynami c effect and consists of a
bimolecular reaction according to which an OH radical, generated from hydroperoxides or
peracids, undergoes hydrogen abstraction from a suitable molecule bearing relatively weak

– 74 – X–H bonds. The result is the formation of two radic al species and a molecule of water ( Fig.
53)[221]

Fig. 53. Molecule -induced homolysis by peracids .
They assumed that an analogous homolysis induced by peracids could occur for this NHPI,
leading to the formation of PINO radical under mild and metal -free conditions.
This hypothesis was supported by spectroscopic and analytical evidence. By simply adding
NHPI to a solution of acetonitrile containing m- chloroperbenzoic acid they could observe the
characteristic Electron Paramagnetic Resonance (EP R) spectrum of PINO radical, while m-
chlorobenzoic acid (90%) and Cl -benzene (10%) resulted as the unique reaction products
(Fig. 54, path a)[222] When the analogous experiment was conducted in benzene as solvent, m-
chlorobenzoate and m-chlorobiphenyl were also detected ( Fig. 54, path b).

Fig. 54. Molecule -induced homolysis of NHPI/m – chloroperbenzoic acid system.

On the basis of these experimental results, they suggested that the aerobic oxidation of
aldehydes could be performed for the in situ generation of the corresponding peracids in the
presence of NHPI, promoting co -oxidative processes catalyzed by PINO. In an early

– 75 – protocol, they reported the NHPI -catalyz ed selective aerobic epoxidation of α -olefins and
cyclic olefins in the presence of stoichiometric amounts of aldehydes .
The experimental results revealed an opposite selectivity with respect to classical epoxidation
by peracids, with internal olefins, whi ch were unreactive under their operating conditions.
They suggested a free -radical mechanism according to which the acyl peroxyl radical
generated in situ is the real epoxidizing agent ( Fig. 55). This protocol was successfully
applied on a larger scale (1 liter Büchi glass vessel) for the synthesis of propylene oxide from
the corresponding propene[223]

Fig. 55. Proposed mechanism for the NHPI/CH 3CHO/O 2-mediated epoxidation.

and more recently under continuous -flow conditions, by means of a new multi jet oscillating
disk (MJOD) reactor, designed and developed by Bjørsvik and co -workers[224] In this latter
case they succeeded in accelerating the overall process, shortening the residence time with
respect to the batch protocol. On the basis of this mecha nistic evidence, they also decided to
investigate the Einhorn‘s process for the oxidation of cumene and ethylbenzene more
thoroughly, as they were expected to find a high selectivity in the corresponding
hydroperoxides, which were not mentioned in the first report. Moreover, they also assumed
that high amounts of aldehyde were detrimental for the selectivity of the process, the
aldehyde having the unique role of initiating the radical chain by generating PINO radical by
molecule -induced homolysis.

– 76 – Indeed, their hypotheses were confirmed and they succeeded in increasing the selectivity in
hydroperoxides up to values higher than 80% by simply red ucing the amount of acetaldehyde
to 10% mol ratio with respect to the alkyl aromatic .[225]

Fig. 56. NHPI/CH 3CHO -mediated aerobic oxidation of alkylaromatics.

Thus, while the NHPI/AQ catalytic system was particularly effective in converting
alkylaromatics to the corresponding carbonyl derivatives, this approach represents a valuable
alternative when hydroperoxides are the desired products. Even if the presence of a polar
solvent is crucial to maintain the polar catalyst in solution, it was possible to conduct the
aerobic oxidation of cumene at 70 °C in the presence of 1% NHPI, 2% of acetaldehyde, and
with a volume ratio cumene/CH 3CN of 5/ 2, achieving the desired hydroperoxide in 28%
yield with 84% of selectivity. Similarly, ethylbenzene was oxidized to the corresponding
hydroperoxide with a lower yield (13%), but a higher selectivity (91%), by operating at the
same temperature with 2% NHPI, 2% acetaldehyde, and with a volume ratio ethylbenzene
/CH 3CN of 1/1. These results are objects of two patent applications[226]
Light -induced activation
The first example of light -induced in situ generation of PINO radical was reported in 2007 by
Lucarini and co -workers[227]
Irradiation of N-alkoxyphthalimides with filtered light (λ > 300 nm) from a mercury lamp
promoted the selective homolysis of the O –C bond, leading to the formation of the N-oxyl
radical, as documented by the strong characteristic EPR signal. The efficiency of the
initiation approach was documented by measuring the dioxygen consumption during the
aerobic oxidation of cumene. In the absence of light, cumene was completely inert, thus
proving the intervention of the catalysts in the oxidative cycle.

– 77 – This process was successfully employed in the selective oxidation of b enzyl alcohol at room
temperature, affording the corresponding aldehyde in 4 h, in accordance with the results
previously reported by their group operating under NHPI/ Co(OAc) 2 catalysis[228] (Fig. 57).
Even if this procedure seems to be particularly valua ble, as no further radical mediators or
initiators are required, it cannot be applied directly to NHPI. More recently, Antonietti and
co-workers have reported the photocatalytic oxidative activation of NHPI by graphitic carbon
nitride (g -C3N4) and visible light irradiation[229] g-C3N4, the most stable allotrope of carbon
nitride, is a two dimensional polymer with a tri -s-triazine ring unit and a π-conjugated layered
structure similar to graphene. It is a medium -band -gap semiconductor and has proved to be
an efficient photocatalyst for synthetic purposes .[230]
It has been demonstrated that the excited state of g -C3N4, obtained by irradiation with visible
light, is able to activate O 2 to the corresponding superoxide radical. The latter could undergo
hydrogen ab straction from NHPI, leading to the generation of PINO.

Fig. 57. Light -induced generation of PINO from N -alkoxyphthalimides.

This approach was successfully applied to promote the visiblelight – induced metal -free
oxidation of allylic substrates ( Fig. 58).

– 78 –
Fig. 58. Visible -light/g -C3N4 induced metal -free oxidation of allylic substrates.

3.13. Mechanism of copper/TEMPO -catalyzed aerobic oxidation of primary alcohols
Koskinen[231] and Stahl[232] 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

– 79 – 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. 48 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 o f
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 condition s
These observations are consistent with a bimolecular H -atom transfer step, similar to that
proposed by Brackman and Gaasbeek however[233], mechanisms involving the rate -limiting
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. 42) is the turn over limiting step of the reaction. In contrast, aliphatic alcohols react more
slowly and the rate exhibits a saturation dependence on [alcohol] and a first -order
dependence on [TEMPO] .
These observations had a direct impact on the development of new Cu / nitroxyl catalyst
systems .

– 80 –

When L= ligand such as

Fig. 42. Mechanism of (bpy)Cu/TEMPO -catalyzed alcohol oxidation deduced by Stahl and
co-workers

Tr
OH

– 81 – 4. Conclusion
Free radicals damage contributes to the etiology of many chronic health problems such as
cardiovascular and inflammatory disease, cataract, and cancer. Antioxidants prevent free
radical induced tissue damage by preventing the formation of radicals, scaveng ing them, or
by promoting their decomposition. Synthetic antioxidants are recently reported to be
dangerous to human health. Thus the search for effective, nontoxic natural compounds with
antioxidative activity has been intensified in recent years. In addi tion to endogenous
antioxidant defense systems, consumption of dietary and plant -derived antioxidants appears
to be a suitable alternative. Dietary and other components of plants form a major source of
antioxidants.
The traditional Indian diet, spices, an d medicinal plants are rich sources of natural
antioxidants; higher intake of foods with functional attributes including high level of
antioxidants in antioxidants in functional foods is one strat egy that is gaining importance.
Newer approaches utilizing collaborative research and modern technology in combination
with established traditional health principles will yield dividends in near future in improving
health, especially among people who do not have access to the use of costlier western
systems of med icine.
Various primary and secondary alcohols were oxidized to the corresponding aldehydes and
ketones using free radicals , used also to synthesis of esters and nitriles .
The procedure s are very convenient, using ussualy very mild experimental conditions (room
temperature and dioxygen as terminal oxidant).
No further over -oxidation of aldehydes to acids has been noticed ; also, the reactions are very
clean, isolation of the desired compounds requiring minimal work -up.

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