Topics in Catalysis Vol. 27, Nos.

1–4, February 2004 (# 2004) 49

TEMPO-mediated oxidation of polysaccharides:

survey of methods and applications
P.L. Bragda, H. van Bekkumb, and A.C. Besemerc,

a
SCA Hygiene Products, Bäckstengatan 5, Gothenburg, S-405 03 Sweden
b
Delft University of Technology, Julianalaan 136, 2628 BL, Delft, The Netherlands
c
SCA Hygiene Products, Utrechtseweg 48, P.O. Box 360, 3700 AJ, Zeist, The Netherlands

This review deals with TEMPO as a catalyst in oxidation of alcohol functions in polysaccharides. Synthesis of TEMPO and
derivatives and the mechanism of the oxidative cycle in which TEMPO is involved in oxidation of alcohols are discussed. Results of
oxidation of various polysaccharides with respect to yield, and introduction of the functional groups (aldehyde and/or carboxylate)
are presented. Most of the primary oxidants are not ideal, as they produce large amounts of salts, e.g., sodium chloride from
sodium hypochlorite. Results and perspectives are given to change the salt-based oxidative systems for much cleaner oxygen or
hydrogen peroxide/enzyme-based TEMPO systems. Moreover, several immobilized TEMPO systems have been developed.
KEY WORDS: TEMPO as oxidation catalyst; TEMPO-enzyme systems; regioselectivity; starch oxidation; cellulose oxidation.

1. Introduction achieved using stoichiometric as well as catalytic

methods. Full oxidation of monosaccharides by nitric
Biopolymers such as polysaccharides constitute an
acid to aldaric acids has been an established technique
important group of compounds, which serve many for more than a century. Analogously, oxidation of
commercial applications in food, energy, wood, paper,
polysaccharides of cellulose or starch by nitrogen
textiles, fibers and oil drilling [1–2].
dioxide ðN2 O4 Þ yields 6-carboxy starch and 6-carboxy
Chemical or enzymatic derivatization is an important cellulose respectively [10,11]. Subsequent hydrolysis at
approach for improving the properties of polysacchar- rigorous conditions (0.5–2 M HCl at 150  C) of these
ides. For applications in aqueous media, methods for materials yields D-glucuronic acid.
introduction of anionic or cationic groups into poly- A drawback of the oxidation with nitrogen dioxide is
saccharides to afford the corresponding polyelectrolytes that depolymerization may be an important side
are firmly established. Polyelectrolytes made from reaction. An improvement of the process with respect
abundant polysaccharides such as starch and cellulose, to this aspect can be achieved by conducting the reaction
e.g., carboxymethyl cellulose (CMC) and cationic starch when the polysaccharide is dissolved in 85% phosphoric
are widely used as thickeners, water soluble adhesives, acid and with sodium nitrite as the oxidant [12]. Under
binders, additives in food, paint and cosmetics, as the acidic and anhydrous conditions described, the
antiredeposition agents, superabsorbents and as addi- active nitrogen oxide species ðNOþ Þ is formed in situ
tives in papermaking [3–6]. from nitrite. In a recent study, it was shown that nitrite
Direct oxidation of hydroxyl groups provides inter- could be replaced by nitrate in combination with a
esting routes for the introduction of carbonyl and catalytic amount of nitrite, while maintaining the high
carboxyl groups into polysaccharides. Oxidized carbo- yield and low degree of depolymerization [13,14]. In this
hydrate materials have been found to be interesting for respect, the latter system is advantageous as the
various applications e.g., as calcium-sequestering agents consumption of reactants is three times lower compared
[7]. With respect to modification of pyranosides, e.g., to the nitrite process.
starch and cellulose, the hydroxyls on positions C-2, C-3 Catalytic oxidation of primary alcohols by hetero-
and C-6 are available for oxidation. Oxidation of geneous noble-metal catalysts, such as supported
secondary hydroxyl groups (C-2 and C-3) has been platinum (Pt/C) has widely been applied for the
achieved by various oxidation agents, e.g., periodate and oxidation of monosaccharides [15]. From an environ-
hypochlorite, which results in oxidative scission of 1,2- mental point of view, it is a clean process that only
diols and the formation of dialdehyde and dicarboxylic consumes oxygen. However, with reducing sugars,
structures, respectively [8,9]. Turning to the more protection of the anomeric carbon is required in order
difficult primary alcohol, selective oxidation can be to attain a high selectivity in the oxidation.
Not unexpectedly, application of the Pt/C oxidant

To whom correspondence should be addressed. system in polysaccharide oxidation will become increas-
E-mail: arie.besemer@sca.com ingly difficult with increasing molecular mass due to

1022-5528/04/0200–0049/0 # 2004 Plenum Publishing Corporation

50 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

steric hindrance and adsorption phenomena. Despite chemistry. Also, other types of oxidation will be
long reaction times in polysaccharide oxidation, only considered.
limited conversions (<20%) have been reported [16].
Other reported examples of chemical oxidation of
primary OH groups in monosaccharide derivatives
include the use of ruthenium tetroxide in combination 2. Structure, properties and synthesis of TEMPO and its
with sodium periodate, potassium ferrate, chromic acid derivatives
and potassium permanganate in acetic acid [17]. 2.1. Chemical structures, properties and applications
Biocatalytic oxidations of mono- and disaccharides
using oxidative enzymes like glucose oxidase yield (TEMPO) 2,2,6,6-tetramethylpiperidine-1-oxyl and
aldonic acids. Also, the method to oxidize the primary its analogues belong to a class of compounds, which
alcohol group of galactose and galactose-containing usually are referred to as nitroxyl or nitroxide radicals.
polymers like gum guar to aldehyde groups is an These compounds are secondary amine nitrogen oxides
interesting application [18]. with the general chemical structure given below.
In the recent decade, catalytic oxidation of carbohy- R R
drates using the stable nitroxyl radical 2,2,6,6-tetra-
methylpiperidine-1-oxyl (TEMPO) has become one of R C N C R
the most promising procedures to convert polysacchar-
ides into the corresponding polyuronic acids. The R .
O R
method is very suitable for selective oxidation of
primary alcohol groups into aldehydes and/or car- The unpaired electron is delocalized between the
boxylic acid groups. Contrary to enzymatic or metal- nitrogen and the oxygen atom, and the NO-bond energy
catalyzed oxidation, the TEMPO-oxidation process is has been estimated to be 420 kJ/mol, which approxi-
highly effective in the conversion of high molecular mately corresponds to the energy of one and a half
weight polysaccharides. Other advantages to be men- bond. Aspects of the properties and chemistry of
tioned in connection to the TEMPO-oxidation process nitroxyl radicals have been the subject of several
are extensive reviews [19–21]. The most striking feature of
many of the nitroxyl radicals is their high, or even
– high reaction rate and yield,
extreme stability toward dimerization or decomposition
– high selectivity,
and inertness to typical organic molecules [22].
– catalytic process,
The nitroxyl radicals can generally be stored and
– just modest degradation of polysaccharides through-
handled without any special precautions taken to moist,
out the process.
temperature or atmosphere. However, the stability
Despite the promising results of the technique concern- largely depends on the structure of the radical com-
ing the oxidation of carbohydrate materials, the method pound and especially on the nature of the substituents
has some shortcomings with respect to the environ- attached next to the nitroxyl group. Hydrogens attached
mental impact and cost issues, which have to be on the (
-carbon are a source of instability, which often
addressed in order to meet the requirements of the causes the radical to disproportionate, producing a
chemical processes of today. The process was first nitrone and an N-hydroxylamine (scheme 1) [22]. The
utilized some 10 years ago, but to this day no rate of this decomposition reaction is largely dependent
commercial process is in operation. on the degree of substitution and the solvent.
The most serious concern regarding the current Apart from sterically unhindered nitroxyls e.g.,
process arises from the fact that halide-based reagents, Fremy’s salt, which exists as a dimer in the crystalline
e.g., sodium hypochlorite and sodium bromide have state [23], stable ditertiary nitroxyls do not dimerize
been used in the process. appreciably, although some exceptions from this rule
After the first publications on TEMPO-mediated have been shown [21].
oxidation of polysaccharides and other types of A vast variety of free radical nitroxyl compounds
alcohols, numerous papers have been published. This have been synthesized since they first appeared in
paper gives a survey of TEMPO-catalyzed oxidation of literature approximately one hundred years ago. Despite
polysaccharides and all aspects dealing with TEMPO the large number of studies on various classes of

R H R H R
R

R C N C R R C N C R + R C N C

R O R R OH R R O R
.

Scheme 1. Disproportionation of nitroxyls into hydroxylamine and nitrone.

 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 51

nitroxyls, it is not until the recent decades that this class Using the usually sharp and well-resolved ESR
of compounds has become highly interesting. This is due spectra of the introduced paramagnetic nitroxyl, much
to the discovery of cyclic hindered nitroxyls such as information about components in biological systems,
2,2,6,6-tetramethylpiperidine-N-oxyl (A) [20] 2,2,5,5- e.g., molecular structure, conformational change, polar-
tetramethylpyrrolidine-N-oxyl (B) [20] and 4,4-dimethy- ity, molecular orientation and molecular motion can be
loxazolidine-N-oxyl (C) [24]. These compounds, and acquired owing to the great sensitivity of the ESR
derivatives thereof, have proven to be useful in various technique. Spin label compounds generally possess
application areas, owing to their exceptional stability functional groups, which can be covalently linked to
and inertness. Apart from the recent development as specific sites on the target molecule without involvement
oxidants in organic synthesis, particularly in carbohy- of the unpaired radical. For this reason, many
drate oxidation, which is described in this survey, other derivatives of (A–C) have been synthesized in order to
applications where the nitroxyls have been used as spin label enzymes and other biological compounds. A few
labels, spin traps, antioxidants and as inhibitor systems examples are given in table 1.
in chain polymerization, have been developed since the In addition, noncovalently bonded nitroxyl spin label
early sixties. As a result, several derivatives of A, B and systems have been developed in which functional groups
C are commercially available as analytical reagents and attached to the nitroxyl radical are designed to interact
as industrial process chemicals. with components of the biological system [30].
R
Furthermore, the nitroxyl radicals are also utilized as
R
analytical reagents in so-called spin-trap reactions to
detect short-lived radicals, which otherwise would be
difficult to detect and quantify. In these procedures, the
N
O N O short-lived radical species are typically reacted with
N
highly reactive nitrones or nitroso compounds or other
R1 R2
.
O O suitable compounds to afford the persistent nitroxyl
A B C radicals, which can be detected by ESR [31]. Many
amido, aryl, alkyl, alkoxyl and thiyl radicals generated
A vast number of studies in which the various in a variety of ways in biological and other systems have
nitroxyl radicals have been used as spin labels acting been trapped using this technique [23].
as probes in biological systems have been published Apart from being used as analytical reagents, several
[25,26]. industrial applications have been developed. Most of

Table 1
Some biological systems using nitroxyl radicals as spin labeling agents

Entry Biological component Spin label References

1 Hemoglobin [27]
O O
N

O .
2 Ribonuclease A NHCOCH2CHBrCOOH [28]

.
O

3
-Chymotrypsin O [29]

C O NO2

O.
52 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

Scheme 2. Synthesis of triacetoneamine by aldol condensation of acetone and ammonia.

these concern the use of hindered nitroxyls or derivatives important as the best product characteristics often occur
thereof as radical scavenger (antioxidants) in polymeric between 50 and 75% conversion.
materials, polymeric melts, monomeric solutions and
pigments to inhibit aging effects or unwanted polymer-
ization induced by photo or thermal oxidation [32,33].
For many of these applications, compounds known as 2.2. Synthesis of cyclic nitroxyl radicals
HALS (hindered amines light stabilizers), derived from There are numerous routes described in literature for
the piperidine series, are utilized. The chemistry and the synthesis of nitroxyl radicals, including procedures
properties of these compounds have been extensively for oxidation of hydroxylamines, amines, nitrones and
studied [34–36]. The mechanism of functioning as nitrosoamines to the corresponding nitroxyls [21,40].
photostabilizer involves the formation of the corre- However, in the vast majority of the studies concerning
sponding nitroxyl radicals by the reaction of the the preparation of cyclic hindered nitroxyl derivatives
hindered amine derivatives with acylperoxy and alkyl- from the piperidine series, 4-oxo-2,2,6,6-tetramethylpi-
peroxy radicals. peridine (triacetoneamine) has served as the starting
Despite the inertness of the nitroxyl groups toward material.
most reagents, coupling of most alkyl radicals ðR
Þ to The latter compound can be made most conveniently
nitroxyl free radicals proceeds at high reaction rate. This by aldol condensation of acetone and ammonia in the
is utilized in chain polymerization processes when presence of a suitable catalyst [41] (scheme 2).
process control of the molecular weight distribution of The conversion of triacetoneamine, or derivatives
the polymer chains is desired. By addition of carefully thereof, to the corresponding nitroxyl derivatives has
considered amounts of suitable hindered nitroxyl been performed using a wide variety of reagents [20,42–
radicals prior to the initiation, polymerization reactions, 44]. The prevailing, most convenient preparative method
in which the propagating centers do not undergo either is the oxidation using hydrogen peroxide with sodium
transfer or termination, are achieved. In these so-called tungstate, which proceeds rapidly with high selectivity
living polymerization reactions [37], the resulting poly- and yield (98%) [45] (scheme 3). Recently, a process for
mer is characterized by a high degree of polymerization the oxidation of the amine with a system comprising
and a narrow molecular weight distribution [38]. hydrogen peroxide in the presence of titanium dioxide or
Further, nitroxyl radicals have found to be very titanium silicates was disclosed [46]. The titanium
useful as shortstop agents in free radical polymerization catalysts are claimed to be recyclable.
[39]. The term shortstop means a process in which a Once synthesized, the substituted stable nitroxyls, may
radical quencher agent is added to the polymerization undergo a wide variety of reactions without the involve-
mixture at defined times to terminate the growing alkyl ment of the odd electron (see reference [47] for a review).
radical reaction at desired conversions. The ability to Among the nitroxyls, 2,2,6,6-tetramethylpiperidine-N-
shortstop the free radical polymerization processes is oxyl (TEMPO) by far has been the most utilized in the

Scheme 3. Oxidation of triacetoneamine to 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl by sodium tungstate/hydrogen peroxide.

 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 53

NH2-NH2 H2O2
-
N OH N Na2WO4 N

H H .
O

Scheme 4. TEMPO synthesis.

numerous oxidation investigations that have appeared in Over the years, many other derivatives of the
the last decade. Other applications include stabilization piperidine series with a wide variety of substituents in
against light deterioration, crop protection and stabiliza- 2, 3 and 4 position have been prepared. Two compre-
tion of olefin polymerization processes [46,48]. hensive reviews concerning the synthesis and properties
Synthesis of TEMPO involves a reductive step of of nitroxyl derivatives have appeared [48,51]. The
triacetoneamine to 2,2,6,6-tetramethylpiperidine, which toxicity of TEMPO and derivatives is presently under
subsequently is oxidized to TEMPO. The reductive step investigation.
can be made using a Wolf–Kishner procedure [48–50] In scheme 5, some 4-substituted 2,2,6,6-tetrametylpi-
(scheme 4). For industrial manufacture, other reductive peridine-1-oxyls that can be synthesized from triaceto-
procedures may be used, e.g., hydrogenation, dehydra- neamine or the corresponding radicals are depicted. In
tion and another hydrogenation step. Direct one-step general, introduction of a functional group has a large
catalytic reduction is a challenge here. impact on the physical properties, such as melting point,
O

NH2
HN

N
N

.
O
.
O
OH

Ref. 55
Ref. 52

N
Ref. 56

N .
O

O
O
.
COOH

54
CHO Ref.
N
Ref. 53

H
N

N
Ref. 57 Ref. 58
.
O

.
O
OH

O P OH
+
(CH3)2NCH2CH2OH O

N N

.
O
.
O

Scheme 5. 4-substituted TEMPO derivatives prepared from triacetoneamine.

54 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

-2e- -e- -e-

+
N N N N
O
H H .
O O

IV II I III

Scheme 6. TEMPO (I) and the corresponding members of the redox series (amine) (IV), hydroxylamine (II), nitrosonium ion (III) and amine (IV).

polarity, solubility in various solvents and compatibility The stability of the pure nitrosonium salts is
with biological macromolecules. dependent on the structure of the anion. Less stable
salts can be converted to more stable ones by exchange
of the anion [60]. In general, nitrosonium salts in
solution are more stable than the pure compound.
2.3. Redox properties
Cyclic nitroxyl radicals of the piperidine and pyrro-
lidine series represent only one species in a series of 3. Application of TEMPO (derivatives) in alcohol
compounds interrelated by one-electron transfer oxida- oxidation
tion or reduction reactions. Reduction of the radical by
3.1. General
mild reducing agents, e.g., hydrazine, ascorbic acid and
thiols gives the hydroxylamine (II) (scheme 6) [47,52– Since the first successful attempts by Golubev more
59], whereas stronger reductants, e.g., Raney nickel and than three decades ago [63], oxidation of organic
hydrogen and sodium borohydride, yield the amine (IV) compounds by stable nitroxyl radicals has become an
[47,58]. Preparation and isolation of the nitrosonium important and versatile method in organic synthesis.
salts (III) by oxidation of the radical with an appro- Over the years, numerous studies and patents have
priate oxidant, e.g., chlorine or bromine, have been appeared describing procedures for oxidation of amines
described in several studies. The older literature has [64,65], triarylphosphines [64] and phenols [64]. Addi-
been reviewed by Bobbit et al. [60]. Another procedure tional work includes N-demethylation [66] and conver-
for the preparation of the nitrosonium salt involves sion of ketones to
-dicarbonyl compounds [67].
acid-catalyzed disproportionation of the radical to give However, the majority of the work concerns the
the nitrosonium ion (III) and the hydroxylamine (II) conversion of primary and secondary alcohols to the
[60]. The equilibrium is shifted to the right as (II) is corresponding carbonyl groups. The older literature has
protonated at low pH [61] (scheme 7). been reviewed by De Nooy et al. [68] and by Adam et al.

Scheme 7. TEMPO-radical disproportionation under acidic conditions to the nitrosonium ion (III) and the protonated hydroxylamine (V).
 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 55

- RCHO/
+ RCH2OH + OH +
RCOOH
+
N N

O OH

Scheme 8. Oxidation of alcohols by the nitrosonium salt under alkaline conditions.

[69]. Depending on the alcohol substrate and the such as CH2 Cl2 . 4-acetamido-TEMPO was preferred
reaction conditions, the oxidation proceeds to carbonyl over TEMPO as oxidant as it was easier to recover.
or carboxyl groups or a mixture thereof. Both primary In most of the work published in the recent decade,
and secondary alcohols have been converted, often at TEMPO and its analogues have been utilized as
high specificity. oxidation catalysts. In this process, the nitrosonium
In recent years, the technique has being extensively ion is continuously regenerated in situ by a primary
used for oxidation of many different carbohydrates, oxidant, e.g., sodium hypochlorite. The main advantage
which has proven to be an extremely important of such a process is that the radical species can be added
application area. in catalytic amounts (in most studies, 1% of the
In virtually all oxidation studies, TEMPO or the substrate).
corresponding 4-substituted analogues have been used, The amount of primary oxidant determines the yield
although nitroxyls from the pyrrolidine series might also of the oxidation reaction. The procedure for in situ
be utilized in oxidation applications. However, most generation of TEMPO was first described by Semmel-
other cyclic nitroxyls, e.g., oxazolidines, are precluded hack et al. [75].
because of the lack of stability in oxidation conditions Two distinct reaction paths have been postulated
[70]. depending upon the reaction conditions.
At alkaline pH, the nitrosonium ion is continuously
regenerated by the primary oxidant throughout the
3.2. Oxidation methodology and reaction mechanisms process. The nitrosonium ion reacts with one molecule
of the hydroxylamine to regenerate the TEMPO radical
Several principally different methods for transforma-
[68] (scheme 9).
tion of alcohols to carbonyl compounds or carboxylic
At acid pH, the hydroxylamine, which is formed after
acids using hindered nitroxyl radicals from the piper-
disproportionation or substrate oxidation, respectively
idine series as oxidants have been described. In virtually
(schemes 7 and 8), is converted into the radical by the
all the studies, the nitrosonium salts are assumed to be
primary oxidant [68]. Although the ‘‘acid process’’ has
the responsible oxidizing species. The oxidation poten-
been used to oxidize various organic compounds, it is of
tial of the TEMPO radical is not negligible, but in order
limited interest in the oxidation of carbohydrates and
to function as efficient oxidants of organic substrates the
virtually all the papers concerning the oxidation of
nitroxyl radical has to be converted into the more
carbohydrates rely on the alkaline process.
powerful nitrosonium salts.
The mechanism of the reaction between the nitro-
Firstly, the nitrosonium salts can be applied in
sonium ion and the substrate has been extensively
stoichiometric amounts with respect to the substrate
studied. At alkaline pH, primary alcohols are generally
(one equivalent of the nitrosonium ion for each
oxidized much faster than the more hindered secondary
equivalent of substrate, see scheme 8) [71,72].
alcohols, whereas at acidic pH the reaction rates are
Secondly, treatment of the substrate with two
comparable [76]. However, recently de Mico et al.
equivalents of nitroxyl radicals at low pH (pH <2)
presented an acid-catalyzed TEMPO process that
has been reported to give quantitative yields of
exhibited a high degree of selectivity for primary alcohol
aldehydes or ketones from primary or secondary
oxidation [77]. Two distinct pathways have been
alcohols [73]. In this process, the nitrosonium salt is
postulated depending on the reaction conditions:
formed in situ via acid-catalyzed disproportionation, in
accordance with scheme 7. The main disadvantage of – Under alkaline conditions, it has been proposed [78]
this process is that a relatively large amount of nitroxyl that the mechanism involves a sterically confined
radical is required. Also, the low pH precludes the use of cyclic elimination that may preclude more hindered
acid-sensitive substrates such as most carbohydrates. secondary alcohols as substrates (scheme 10, VI).
A procedure for the recovery of the nitroxyls was – At acidic pH (II) [74], the adduct VII is more likely to
demonstrated by Ma et al. [74]. The protonated be the reactive intermediate since this mechanism
hydroxylamine salt obtained after oxidation was pre- involves an acyclic less sterically demanding mecha-
cipitated and reused in appropriate organic solvents nism.
56 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

-H+
+ RCH2OH RCHO +
+
N N

O OH

+
N

-H+
N
Primary oxidant

.
O

Scheme 9. A simplified mechanism for the catalytic cycle in TEMPO-mediated oxidation of alcohol substrates under weakly alkaline conditions.
The TEMPO radical is continuously regenerated in situ by reaction of the nitrosonium ion and the hydroxylamine.

However, the exact mechanisms for the substrate and inorganic reagents and also for easier workup
oxidation have not been elucidated so far. procedures. In these systems, the product contains either
carbonyl or carboxyl groups. If a phase-transfer catalyst
was added to the mixture CH2 Cl2 =H2 O, hydrophobic
3.3. Oxidation of alcohols substrates were converted to the carboxylates at high
yield, whereas in the absence of the phase-transfer
3.3.1. Reaction conditions and product composition
catalyst only the corresponding aldehyde was formed.
By TEMPO-mediated oxidation a vast number of
These results suggest that the conversion of aldehydes
alcohols has been oxidized. Most notably is the effect on
to carboxyl groups predominantly takes place in the
the product composition of reaction conditions, e.g. pH,
water phase. Since the presence of water is essential for
primary oxidant and reaction medium [68,69].
the latter conversion, it is plausible that only the
It has been established that under homogeneous
hydrated form of the aldehyde intermediate (a gem-
conditions using organic solvents, the aldehyde or keto
diol) can be oxidized further (scheme 11)
groups are solely formed without any appreciable
However, recent reports show conflicting data. Bolm
subsequent oxidation to the carboxyl group [77,81–83].
et al. found that oxidation of organic substrates in a
Two-phase or mixed solvent systems have been
CH2 Cl2 =H2 O two-phase system yielded only the alde-
chosen because of the different solubilities of the organic
hyde compound despite the presence of a phase-transfer
agent [88]. Furthermore, Herrmann et al. [84] reported
on a water-based system (acetic acid–water) that only
gave the aldehyde groups (entry 5).
+ + An interesting approach to convert hydrophobic
N N
alcohols to the carboxylic acids was described by Zhao
_
O O HO O et al. [85] and Inukuchi et al. [86]: this is to conduct the
oxidation in homogeneous mixtures of, e.g., acetoni-
R H trile–water. Various alcohols were oxidized to the acids
H R :B without the presence of a phase-transfer agent. The
H R importance of the solvent was thus demonstrated, as the
same system applied in CH2 Cl2 =H2 O resulted only in
the formation of aldehydes.
VI VII In the oxidation of diols sometimes -lactones have
Scheme 10. Proposed mechanistic adducts in alkaline (VI) and acidic been reported to be the main product, but only relatively
conditions (VII). strain-free five-membered rings have been established
 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 57

H H
TEMPO H
R R
Primary oxidant
OH O

H OH
H2O OH TEMPO
R R
Primary oxidant
OH O

Scheme 11. TEMPO-mediated oxidation of primary alcohols to carboxyl via the hydrated (gem-diol) aldehyde intermediate.

[86]. The formation of lactones probably proceeds via made by Bragd et al. [96]. It was established that in the
a cyclic hemiacetal intermediate, which subsequently system TEMPO/NaOCl, the pH optimum rate of TEM-
is oxidized. However, recently, the highly selective PO, 4-hydroxy-TEMPO and 4-acetoxy TEMPO is found
oxidation of 1,5-diols to -lactones was also reported at pH 9, whereas that of 4-acetamido-TEMPO is distinctly
[87]. lower i.e., pH 8. Owing to the large diversity of these
Both primary and secondary alcohols are oxidized at oxidants, different process conditions e.g., different pH
high yields at both weakly alkaline and acidic pH. and solvents can be applied, depending on the substrate.
However, primary alcohols in general are oxidized much Since some of these reagents alone are known oxidants of
faster than secondary alcohols. Consequently, primary aldehyde groups, e.g., NaBrO2 , NaClO2 /NaOCl, NaOCl/
alcohols can be selectively oxidized in several types of NaBr, it must be taken into account that non-TEMPO-
diols without the protection of the secondary alcohols mediated oxidation to some extent is responsible for the
[79]. This rare chemoselectivity has also been reported in subsequent oxidation of aldehydes to carboxylates, which
oxidation mixtures of primary and secondary alcohols, has been reported in some studies. However, in compar-
i.e., only the primary substrate undergoes oxidation [77]. ison to the TEMPO-mediated oxidation, this additional
The high selectivity and mildness of the TEMPO- effect is probably insignificant for most oxidant systems
oxidation process has proven to be very useful in [76]. For the oxidation of carbohydrates, oxidative
organic synthesis [69]. Especially, this behavior is a very enzymes such as laccase have lately been used with oxygen
useful tool for the oxidation of mono-, oligo- and as a primary oxidant (see section 4.3).
polysaccharides.

4. Oxidation of carbohydrates
3.4. Primary oxidants 4.1. Mono- and disaccharides
As indicated in section 3.3, various oxidants have Oxidation of alcohol groups in carbohydrates by the
been utilized in the TEMPO process over the years for TEMPO process was first presented by Davis et al.;
in situ regeneration of TEMPO or the nitrosonium salt. partially protected carbohydrates were converted to
A distinction can be made between oxidants used in the uronic acids by TEMPO/hypochlorite/bromide under
acid-disproportionation process and under alkaline dichloromethane/water two-phase conditions [97]. Fol-
conditions. lowing this work, numerous other studies and patents
For the former process, acidic oxidants like m- have appeared utilizing the alkaline TEMPO process for
chloroperbenzoic and [bis(acetoxy)iodo]-benzene (BAIB) modifications of carbohydrates.
have been utilized [73,77]. For the alkaline TEMPO Virtually all studies concerning oxidation of carbo-
process, many oxidants have proven to be applicable, hydrates rely on the use of the hypochlorite process with
i.e., copper salts/O2 [89], ðK3 ½FeIII ðCNÞ6 Þ [90], NaBrO2 or without sodium bromide as the boosting cooxidant
[86], NaClO2 =NaOCl [85] and NaOCl/NaBr [80,92]. [68,76,80,92,96–100,107]. Lately, several works describ-
Recently, oxidants such as N-chlorosuccinimide [79], ing halide-free TEMPO processes, i.e., using manganese
silver catalysts/sodium peroxodisulfate [91], peracid/ dioxide or potassium permanganate [101], copper salt/
bromide and peroxomonosulfuric acid/bromide [93,94], bipyridine complex [102] and silver catalysts/sodium
H2 O2 /HBr/methyl trioxorhenium (MTO) [84] and peroxodisulfate [91] have been described. Additionally,
RuCl2 ðPPhÞ3 =O2 [81] have been successfully employed. oxidative enzymes have been employed for this purpose
Besemer and Bragd [95] found that monoperoxosulfuric (see section below).
acid also can be used without bromide. A comparison of TEMPO-mediated oxidation of monosaccharides has
the behavior of various TEMPO derivatives has been essentially been limited to cyclic aldohexoses and
58 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

CH2OH COO-Na+
O O
HO HO
TEMPO
HO HO
Primary oxidant OH
OH
O O

X X

Scheme 12. TEMPO oxidation of the primary hydroxyl group in anomeric-protected glucose.

ketopentoses and derivatives thereof. The oxidation of and sorbitol can be partially converted into the aldaric
glucopyranoside is depicted in scheme 12. acid analogue [104].
Generally, aqueous solutions of carbohydrates are An alternative route to glucuronic acid from
preferred because of the solubility of the substrate, less glucose was described by Heeres et al.; protected sugars,
toxicity and environmental impacts. As a consequence, e.g.,
- and -D-glucopyranoside-1-phosphate and
-D-
carboxyl groups are found as the reaction product in glucopyranoside-1-fluoride were selectively oxidized
virtually all carbohydrate works. by TEMPO/hypohalite to the corresponding uronic
Significant for TEMPO-mediated oxidation reactions acids. Subsequent enzymic or acidic hydrolysis afforded
of carbohydrates is the high chemoselectivity for the D-glucuronic acid as the main product [105].
primary alcohol groups, which probably is due to the Some additional examples of mono- and disaccharide
steric hindrance of the secondary alcohol groups. oxidation are given in table 2. Protected glucose,
Unfortunately, the hemiacetal functionality in pyrano- galactose and mannose derivatives were converted into
sides and furanosides has to be protected in order to their uronic counterparts. In virtually all studies con-
prevent oxidation to aldonic and aldaric acid cerning carbohydrate oxidation, the established hypo-
[76,103,104]. This precludes simple one-step conversion chlorite/bromide system has been utilized as regenerating
of, for example, glucose and fructose to glucuronic acid oxidants. In the classical method, bromide is added in
and fructuronic acid. On the other hand, unprotected a catalytic amount to accelerate the reaction rate and
mono- and disaccharide polyols, e.g., maltitol, mannitol to increase the conversion. Owing to environmental

Table 2
TEMPO-mediated oxidation of mono- and disaccharides using different hypohalites as primary oxidant systems

Entry Substrate Product Conditions Yield References

1 CH2OH COO Na - +
(a) NaOCl/NaBr >95 [100]
HO
O
HO
O
(b) NaOCl/ultrasound 82 [106]
HO HO (c) NaOCl >90 [107]
OH OH
O O
CH3 CH3

2 CH2OH 1. Tribenzoylation 74 [111]

HO
O
2. Methylation
HO 3. Debenzoylation
OH
O
4. NaOCl/NaBr/TEMPO
Me

3 CH2OH COOCH3 1. Ca(OCl)2/KBr 63 [110]

O O
HO AcO 2. Methylation
HO N3 AcO N3 3. Acetylation
NHAc NHAc

4 OH
CH2OH
AcO
COOCH3
1. Ca(OCl)2/KBr 64 [110]
O O 2. Methylation
HO N3 AcO N3
3. Acetylation
OH OAc

5 CH2OH COOH
NaOCl/NaBr 80 [106]
O O
HO HO Ultrasound (500 kHz)
HO HO

OH OH
CH2OH O COOH O
O O
OH OH

CH2OH COOH

OH OH
 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 59

COO-Na+
CH2OH
O
O
O
O CH2OH HO COO-Na+
HO
O O
TEMPO/NaOCl/NaBr OH
OH
O O
HO CH2OH HO COO-Na+

O OH O
OH
O O
HO HO

OH OH
O O

Scheme 13. TEMPO/NaOCl/NaBr oxidation of glucans (i.e., starch) to the corresponding polyuronic derivatives.

concerns, a bromide-free process, solely using hypo- interestingly leading to almost pure 1,4-linked poly-
chlorite, is desirable. By performing the reaction at glucuronic acid.
sonification conditions (500 kHz) [106] or at higher The potential of these analogues of expensive
temperatures ð20  CÞ [107], satisfactory conversions have polysaccharides as alginic acid and pectin is high in
been achieved with bromide-free conditions. With the several applications, e.g., as thickeners, stabilizers,
ultrasound technique, unprotected sucrose was oxidized hydrogels, superabsorbents, sequestering agents and
to its tricarboxylated analogue in good yields (entry 5). builders in detergent formulations [116–121]. Cyclo-
Subsequent work of Lemoine et al. [106] showed that also dextrins are a class of cyclic oligosaccharides, which are
in the absence of bromide as catalyst, the TEMPO- very interesting because of their inclusion properties,
NaOCl system efficiently converts sucrose to tricarboxy- i.e., the ability to form complexes with various
sucrose under ultrasound radiation. In a contribution to molecules in the hydrophobic cavity and thus enhancing
this special issue, Trombotto et al. [109] compare the the water solubility of various pharmaceuticals. The
TEMPO/hypochlorite oxidation of sucrose and its modification of primary hydroxyl groups to carboxylic
isomer isomaltulose. The open carbonyl group in groups utilizing the TEMPO process provides a material
isomaltulose gives rise to substantial degradation of the with increased solubility and a better association with
fructose unit with carboxymethyl-
-glucopyranoside as cationic substrates and special immobilization possibi-
end product. lities [122,123]. Also, the partial TEMPO oxidation of
Lately, the TEMPO process was applied for the cyclodextrins leading to products containing both
preparation of partially protected oxidized disacchar- aldehyde and carboxylate groups has been described
ides, which were intermediates in the synthesis of the [124].
antithrombotic pentasaccharide Arixtra of Organon and The TEMPO process has been extended to cellulose
Sanofi [112]. Regeneration of TEMPO was achieved by materials, but the oxidation of water-based suspensions
the use of 1,3-dibromo-5,5-dimethylhydantoin or 1,3- of insoluble native cellulose resulted only in little or
dichloro-5,5-dimethylhydantoin as the primary oxidant slight oxidation. Besemer et al. [125] reported that
at neutral to basic pH. cellulose without any pretreatment oxidized with TEM-
PO/NaOCl/NaBr could be oxidized only partially.
Glycolic oxidation by NaOCl/bromide seemed to be
4.2. Oxidation of oligo- and polysaccharides
an important side reaction in the later phase of the
In recent years, the TEMPO process has become a reaction. Only after mercerization in NaOH solution or
very important technique for the transformation of after regeneration from SO2 -diethylamine-dimethyl sulf-
primary alcohol groups in polysaccharides to the oxide or cupri-ethylenediamine solutions the cellulose
corresponding polyuronic analogues. Since the first materials could be oxidized to soluble polyuronic acids
report by de Nooy et al. [99] (scheme 13), several studies in quantitative yield [126,127]. Thus, the high degree of
describing procedures for oxidation of various poly- crystallinity of native cellulose has to be decreased to
saccharides have appeared. When applied to water- ensure sufficient accessibility of the primary alcohol
soluble aqueous systems of polysaccharides, e.g., cold- groups. Partly in conflict with these observations, Chang
water-soluble starch, inulin, amylodextrin and pullulan et al. in an earlier study reported that quantitative
[76,92,96,98–100,107,114], the corresponding polyuronic oxidation of cellulose may be obtained without any
acids generally were obtained at high reaction rate and pretreatment [113].
with high selectivity for the primary alcohol groups Moreover, it has been found by several groups [133–
(table 3). Moreover, cold-water-insoluble potato amy- 137] that the amount of intermediate carbonyl com-
lose (scheme 13) and potato amylopectin and various pounds upon TEMPO oxidation can be substantial and
other polysaccharides, e.g., chitin, chitosan, alternan that these carbonyl groups are mostly masked because
and dextran [113], were oxidized to the corresponding of hemiacetal formation. As a result, (i) the consecutive
polyuronates analogously. Kato et al. [115] reported oxidation to carboxylate is retarded and (ii) strength is
that especially 1,6-bonds were split—as a side reaction— introduced in the material as a result of acetal formation
in starch upon TEMPO-NaOCl-NaBr oxidation, between the glucose units.
60 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

Table 3
Oxidation of polysaccharides by the TEMPO/hypochlorite/bromide system

Entry Substrate Conditions Yield References

1 Potato starch (Cold-water soluble) NaOCl/NaBr >95 [92,98–100]

2 Wheat starch (Cold-water insoluble) NaOCl/NaBr 95 [113]
3 Potato amylose NaOCl/NaBr >95 [113]
4 Potato amylopectin NaOCl/NaBr 95 [113]
5 Inulin NaOCl/NaBr 87 [100,114]
6 Pullulan NaOCl/NaBr >95 [98,100]
7 Chitin (Crustacean) NaOCl/NaBr >90 [144]
8 Chitin (A. niger) NaOCl/NaBr 45 [143]
9 Chitosan NaOCl/NaBr 91 [113]
10 (
, , ) Cyclodextrin NaOCl/NaBr 90 [122–124]
11 Mercerized cellulosea NaOCl/NaBr >95 [126,127]
12 Dissolved and regenerated celluloseb,c NaOCl/NaBr >95 [126,138]
13 Mercerized cellulose (bacterial) NaOCl/NaBr >95 [127,128]
14 Mercerized cellulose (Microcrystalline) NaOCl/NaBr >95 [126,127]
15 Cellulosed NaOCl/NaBr 8 [128,129]
16 Hyaluronan NaOCl/NaBr 100 [145]
17 Galactomannan NaOCl/NaBr 66 [139]
18 Scleroglucan NaOCl/NaBr 100 [140,141]
a
Softwood-bleached kraft pulp.
b
Prepared from linter cellulose using 0.5 M cupri-ethylenediamine.
c
Prepared from wood cellulose pulp, using NMMO or phosphoric acid.
d
Hardwood kraft pulp.

6-Carboxy-cellulose is a highly interesting material provides novel polymers with interesting properties that
for various commercial applications, e.g., as thickeners might be suitable in wound healing, cosmetics and drug
in aqueous solutions, as an alternative to cellulose ethers delivery applications. Scleroglucan, a neutral polysac-
such as carboxymethyl cellulose (CMC), methylcellulose charide that is produced by microorganisms and that
and hydroxypropyl methylcellulose. consists of a main chain of (1 ! 3)-linked -D-glucopyr-
In the paper industry, it is well established that anosyl units with a (1 ! 6)-glucopyranosyl unit on every
carbonyl and carboxyl functionalities play an important third group, was oxidized, and the product was studied
role in the pulping process and in the final paper with respect to its conformational behavior. Moreover,
properties. In this context, Kitaoka et al. recently the polyelectrolytes obtained were transformed into
utilized the TEMPO process for cellulose derivatization. hydrogels by various cross-linking reactions. Crescenzi
Sheets made from the partially oxidized fibers (<8% et al., oxidized various D-mannose-containing polysac-
conversion) experienced higher wet and dry tensile charides, e.g., konjac mannan and locust bean gum,
index, probably due to an increased opportunity of which subsequently were epimerized with C-5 recombi-
electrostatic interactions between anionic pulp and nant mannuronan C-5-epimerases in order to produce
cationic PAE (polyamideamine-epichlorohydrin), which alginate-like structures [142].
was added as a wet-strength agent [128]. Moreover, it Apart from polysaccharides, the TEMPO process
was shown that the sizing performance (upon treatment has recently been applied in the oxidation of oligo-
with aluminium sulfate and Rosin size) was improved saccharides, e.g., maltodextrins [103]. Contrary to poly-
when applied to oxidized fibers [129]. saccharides, these materials contain a significant
Van Brussel-Verraest and Besemer [138] established amount of terminal oxidizable hemiacetal functions.
that 6-carboxycellulose with a high molecular weight Upon oxidation in alkaline conditions (pH >11), the
could be obtained from ‘‘activated’’ cellulose. This was conversion of primary C6 -groups and hemiacetals
achieved by dissolving cellulose in an appropriate proceeded quantitatively with high selectivity (>98%)
solvent (phosphoric acid or NMMO), followed by (scheme 14). In the course of the oxidation, decarboxy-
precipitation in water or alcohol. The thus obtained lation of the dicarboxylic terminal unit yielded several
cellulose was oxidized with TEMPO/hypochlorite/bro- degradation products. At lower pH, non-TEMPO-
mide. The products had a high molecular weight and a mediated hypobromite/hypochlorite oxidation of C-2
high degree of oxidation. and C-3 functions was not negligible. This was indicated
Lately, the TEMPO-oxidation process has been by the formation of by-products such as oxalic acid
utilized for the oxidation of galactomannan, scleroglu- formed after diol cleavage.
can, mannan, chitin, chitosan and hyaluronan [139–144]. Finally, an application worth mentioning in connec-
The regiospecific oxidation of chitin and hyaluronan tion with sugar oxidation is the use of the oxidation
 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 61

CH2OH COONa+
O O
O
TEMPO/NaOCl/NaBr
CH2OH O COO-Na+
HO HO
O OH
OH OH
O O
HO HO
COO-Na+
n-1 n-1
OH OH
OH

Decarboxylation

COONa+

O COO-Na+
HO
OH
OH
O COO-Na+
HO
n-1

Scheme 14. Oxidation of maltodextrin to polyuronic acid by TEMPO/hypochlorite and sodium bromide. Terminal reducing units are
transformed into dicarboxylic functionalities, which subsequently are decarboxylated.

system for cleaning membrane filters that are used in nitrosonium salt is regenerated in situ; thus, only oxygen
water purification. The TEMPO system is particularly or hydrogen peroxide is consumed in the course of the
efficient to remove carbohydrates and humic acids reaction (scheme 15).
containing fouling [146], probably by oxidation of the Recently, this technology was first applied in the
primary OH-groups. oxidation of monosaccharides and polysaccharides.
Viikari et al. reported on the oxidation of starch and
cellulose suspensions by the TEMPO/laccase/oxygen-
system, which yielded mixtures of 6-aldehydes and 6-
4.3. Use of oxidative enzymes in TEMPO-mediated
carboxylates [130,147]. In spite of the fact that under the
oxidation of carbohydrates
conditions described (pH 5) only low conversions
The environmental awareness of today has prompted (<5%) were achieved, it was noticed that the modifica-
investigation of halide-free reagent systems to be used in tion affected several properties, e.g., gel properties,
connection with the TEMPO process. One interesting molecular weight, and viscosity of the material obtained.
approach for this purpose relies on the use of oxidative Jetten et al. [102,131,132] and Jaschinski et al. [133]
enzymes, e.g., oxidases and peroxidases together with independently used the same technique for partial
oxygen or hydrogen peroxide respectively as primary oxidation of various polysaccharides, e.g., pullulan,
oxidants. Similar to the hypochlorite process, the starch and cellulose. As enzymes, laccase and horse

O2/H2O2
Primary Aldehydes Carboxylates
alcohol groups Enzyme
TEMPO

2 +
O2/H2O2 Ox N
N
O HO
Enzyme

H2O Red
2
N
O
.

Scheme 15. TEMPO-mediated oxidation of primary alcohol groups in carbohydrates to C-6-aldehydes and carboxylates using oxidative enzymes
(e.g. laccase or peroxidase) in the presence of oxygen or hydrogen peroxide respectively as primary oxidant systems.
62 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides

radish peroxidase (HRP) were used. Similar to the study compounds [78]. Lately, Schnatbaum et al. oxidized
of Viikari et al., cellulose oxidation only resulted in low several pyranoside monosaccharide derivatives, which
conversions unless the cellulose fibers had been acti- were converted to their uronic analogues in high yield
vated by NaOH prior to the oxidative treatment. On the [152]. Other substrates included sucrose, cyclodextrins
other hand, oxidation of starch and pullulan by the and starch, which were converted in more moderate
systems led to a higher degree of conversion. Interest- yields. After the reaction, TEMPO could be recovered in
ingly, the authors found that the HRP/hydrogen high yield, which suggests sufficient stability of the
peroxide/TEMPO-system gave a significantly higher mediator for this kind of application.
amount of 6-aldehydes (ca. 30% of the primary alcohol Chemical immobilization of the mediator on elec-
groups) than the laccase/oxygen/TEMPO-system, which trodes is an alternative approach for the electrocatalytic
resulted in more uronic acid derivatives. alcohol oxidation. In most works, the grafting of
the nitroxide radical has been made by reacting 4-
amino-TEMPO to a graphite electrode precoated by
5. Electrochemical oxidation poly(acrylic acid) with subsequent cross-linking by
Much attention has been devoted to developing diamines. Nitroxide-coated electrodes have been applied
suitable electrochemical methods for oxidation of in the oxidation of various alcohol substrates, e.g.,
organic compounds. A characteristic of the electro- benzyl alcohol and nerol (3,7-dimethyl-2,6-octadien-1-
chemical systems is that the active species necessary for ol) [153,154].
the synthesis to proceed is generated at the electrode. By Electrocatalytic TEMPO-mediated systems have been
applying electrochemistry, reaction systems that only utilized for the synthesis of optically pure organic
consume electric energy and oxygen provided by water compounds. Thus, a TEMPO-modified graphite elec-
can be designed with obvious benefits [148]. Moreover, trode, (4-amino-TEMPO immobilized on poly(acrylic
the system has the advantage that the interference with acid)) in the presence of a chiral alkaloid such as
the electrode is low and that it is quite easy to work up sparteine was used as a simple and clean process for the
and scale up. optical resolution of racemic alcohols, e.g., octan-2-ol
However, organic compounds are generally difficult and cyclohex-2-en-1-ol [154,155]. The mechanism for the
to oxidize at the low potential used for common carbon reaction is not fully elucidated, but the crucial step is
electrodes. Therefore, an additional catalyst or mediator probably the deprotonation of the substrate with the
system is required as a prerequisite to overcome the chiral base, which proceeds with high selectivity for one
large potential needed for organic compounds. For this of the enantiomeric forms.
reason, TEMPO or analogues thereof, have been An alternative approach for attaining enantioselec-
applied as mediators. A simplified reaction system is tive oxidation is to use chiral TEMPO derivatives, e.g.,
depicted in scheme 16. 1-azaspiro[5.5]undecane-N-oxyl or (6S, 7R, 10R)-1-aza-
In this process, the mediator is continuously re- 4-acetylamino-2,2,7-trimethyl-10-isopropylspiro [5,5]un-
oxidized to the nitrosonium salt at the anode by decane-1-N-oxyl [156]. Using this system in the presence
applying a suitable potential over the electrical cell. of an achiral base, racemic alcohols were generally
The electrochemical properties of the nitroxides can be converted to their carbonyl analogues with high
investigated by cyclic voltammetry, which has been specificity for one of the enantiomeric forms.
demonstrated in several reports [149–151]. The last application to be mentioned in connection to
The electrochemical technique was first applied by electrocatalytic TEMPO oxidation are the promising
Semmelhack et al. for the oxidation of organic results obtained by Yamaguchi et al. with the use of the

Product
TEMPOred

-e-

TEMPOox Substrate

Scheme 16. Indirect electrode oxidation of organic substrates using TEMPO as mediator.
 P.L. Bragd et al./TEMPO-mediated oxidation of polysaccharides 63

TEMPO-grafted electrodes as electrochemical detectors. generally precluded because of diffusional limitations.

It was found that aqueous hydrophilic primary alcohols In fact, no successful work concerning polysaccharides
and carbohydrates can be detected and quantified at has been reported. Also, in the oxidation of small
constant potential mode at low potentials, using the alcohols and monosaccharides, the reaction rate is lower
amperometric response resulting from the reaction of in comparison to the homogeneous systems.
the substrate with TEMPO [157,158]. The technique was
claimed to be mild and sensitive and to have a high
selectivity toward primary alcohols, and therefore O O O O O O O O O
provides an option to more established techniques
relying on oxide-covered metal-based electrodes. Using Si

Si
Si
the technique, it might be possible to develop electro-
chemical detectors of carbohydrates suitable in connec-
tion to HPLC systems.

HN
O
O

CO
COOH

6. Oxidation using immobilized TEMPO derivatives

Use of immobilized TEMPO-related moieties as N
heterogeneous catalysts has become a widely recognized N
N
approach for the oxidation of primary alcohols and O
O

.
carbohydrates to the corresponding carbonyl and O

.
carboxyl functions. Heterogeneous catalysts offer sev-
eral benefits in comparison to homogeneous systems, VIII IX X

including easier product isolation and purification, the

possibility to reuse the catalyst and, generally, less
toxicity of the reagent-supported systems [159]. 7. Conclusion
For oxidation purposes, TEMPO species covalently The use of nitroxyl catalysts, e.g., TEMPO in alcohol
bound to polymers, or amorphous or ordered mesopor- oxidation was firmly established 10–15 years ago. Recent
ous silicas surfaces have been reported. Miyazawa et al. studies have confirmed the applicability of the technique
developed a system in which cross-linked polystyrene in a variety of carbohydrate oxidation. In particular, the
functioned as a polymeric carrier for the nitroxyl technique has been shown to be highly suitable for
radicals in the oxidation of benzyl alcohol to benzalde- modification of high molecular mass polysaccharides
hyde [160,161]. Lately, an oligomeric system with though, especially with respect to polysaccharide oxida-
immobilized nitroxyl radicals was derived from a tion development of halide-free systems is needed. A
sterically hindered amine monomer (Chimassorb 944). hypochlorite-free process using peracids such as peracetic
In combination with hypochlorite, this heterogeneous acid or persulfuric acid is described in some papers.
catalyst was used in the oxidation of methyl
-D- Moreover, oxidative enzymes together with oxygen or
glucopyranoside to the corresponding uronate in the hydrogen peroxide come to the fore.
absence of bromide as catalyst [162].
In the majority of the works, silicas have served as the
carrier of the nitroxyl groups. Functionalization of the
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