International Journal of
Molecular Sciences
Review
Chlorine Dioxide: Friend or Foe for Cell Biomolecules?
A Chemical Approach
Celia María Curieses Andrés 1 , José Manuel Pérez de la Lastra 2, * , Celia Andrés Juan 3 , Francisco J. Plou 4
and Eduardo Pérez-Lebeña 5
Citation: Andrés, C.M.C.; Lastra,
J.M.P.d.l.; Andrés Juan, C.; Plou, F.J.;
Pérez-Lebeña, E. Chlorine Dioxide:
Friend or Foe for Cell Biomolecules?
A Chemical Approach. Int. J. Mol. Sci.
2022, 23, 15660. https://doi.org/
10.3390/ijms232415660
Academic Editor: James K. Bashkin
Received: 26 October 2022
Accepted: 8 December 2022
Published: 10 December 2022
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Attribution (CC BY) license (https://
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4.0/).
Int. J. Mol. Sci. 2022, 23, 15660. https://doi.org/10.3390/ijms232415660
1 Hospital Clínico Universitario, Avenida de Ramón y Cajal, 3, 47003 Valladolid, Spain
2 Institute of Natural Products and Agrobiology, CSIC-Spanish Research Council, Avda. Astrofísico Fco.
Sánchez, 3, 38206 La Laguna, Spain
3 Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University,
Paseo de Belén, 7, 47011 Valladolid, Spain
4 Institute of Catalysis and Petrochemistry, CSIC-Spanish Research Council, 28049 Madrid, Spain
5 Sistemas de Biotecnología y Recursos Naturales, 47625 Valladolid, Spain
* Correspondence: jm.perezdelalastra@csic.es
Abstract: This review examines the role of chlorine dioxide (ClO2 ) on inorganic compounds and
cell biomolecules. As a disinfectant also present in drinking water, ClO2 helps to destroy bacteria,
viruses, and some parasites. The Environmental Protection Agency EPA regulates the maximum
concentration of chlorine dioxide in drinking water to be no more than 0.8 ppm. In any case, human
consumption must be strictly regulated since, given its highly reactive nature, it can react with
and oxidize many of the inorganic compounds found in natural waters. Simultaneously, chlorine
dioxide reacts with natural organic matter in water, including humic and fulvic acids, forming
oxidized organic compounds such as aldehydes and carboxylic acids, and rapidly oxidizes phenolic
compounds, amines, amino acids, peptides, and proteins, as well as the nicotinamide adenine
dinucleotide NADH, responsible for electron and proton exchange and energy production in all
cells. The influence of ClO2 on biomolecules is derived from its interference with redox processes,
modifying the electrochemical balances in mitochondrial and cell membranes. This discourages its
use on an individual basis and without specialized monitoring by health professionals.
Keywords: chlorine dioxide; toxicity; “miracle mineral solution”; human consumption
1. Introduction
Regarding chlorine dioxide (ClO2 ), most of the reviews in the technical literature have
been carried out from a biological or medical point of view, and others have analyzed
its efficacy and safety as a disinfectant or in drinking water treatment. In this review,
we focus on the chemical study of the interaction of ClO2 with organic molecules or
inorganic cations present in cells, giving an overview of its reactivity, its potential toxicity
for biological molecules and hazardousness if not used correctly, and cases for which it has
been approved.
Chlorine dioxide was discovered in 1811 by Sir Humphry Davy and since the mid-20th
century, it has been widely used in the paper industry as a bleach and for the treatment
of drinking water. More recent developments extend its application to food processing,
disinfection of premises and vehicles, mold eradication, air disinfection and odor control,
swimming pool treatment, wound cleaning, and dental applications [1].
Chlorine dioxide (ClO2 ) is classified by the World Health Organization (WHO) as
a safe and effective fourth generation, broad-spectrum, class A1 disinfectant [2,3]. It is
used to purify drinking water without creating harmful concentrations of disinfection
by-products [4]. The properties of ClO2 result from one-electron transfer reactions, so
it is considered a strong oxidizing agent [5] and, unlike chlorine, does not tend to react
https://www.mdpi.com/journal/ijms
 materials to form chlorinated species or with ammonia to form chloramine. Chlorin
oxide is an important biocide and bleach and is used as an alternative to chlorine i
purification and disinfection of drinking water[6]. ClO2 is used in 8.1% of drinking w
treatment plants in the USA and 32.8% of those in China[7,8], and in some European c
Int. J. Mol. Sci. 2022, 23, 15660 2 of 27
tries[9], it is used in paper bleaching, sterilization of medical devices, and disinfecti
foodstuffs[10]. According to the EPA, ClO2 is used “in public water‐treatment faciliti
make water safe withfor
organic materials to
drinking.” form chlorinated
When chlorinespecies or with
dioxide is ammonia
added to to form chloramine.
drinking water, it
Chlorine dioxide is an important biocide and bleach and is used as an alternative to chlorine
to destroy bacteria, viruses,and
in the purification and some types
disinfection of water
of drinking parasites
[6]. ClOthat can make people sick,
2 is used in 8.1% of drinking
as Cryptosporidium parvumplants
water treatment andinGiardia
the USA andlamblia.
32.8% of those in China [7,8], and in some European
countries [9], it is used in paper bleaching, sterilization of medical devices, and disinfection
Its main advantage over chlorine is that it reduces the formation of harmful org
of foodstuffs [10]. According to the EPA, ClO2 is used “in public water-treatment facilities,
chlorine compounds[11–17].
to make water safe for ClO 2 is beneficial
drinking.” When chlorinein minimizing
dioxide is addedthe formation
to drinking water,ofit trihal
helps to destroy bacteria, viruses, and some types of parasites that can make people sick,
thanes; however, ClO2 is converted to ClO2 and ClO3 , which can cause hemolytic an
− −
such as Cryptosporidium parvum and Giardia lamblia.
and other health Its effects. The Environmental
main advantage over chlorine is that itProtection Agency
reduces the formation (EPA)
of harmful has set the m
organochlo-
rine compounds
mum concentration in drinking water [11–17]. ClO 2 is beneficial in minimizing the formation of trihalomethanes;
at 0.8 milligrams per liter (mg/L) for chlorine
however, ClO2 is converted to ClO2 − and ClO3 − , which can cause hemolytic anemia and
ide and 1.0 mg/L otherfor chlorite
health ions[18].
effects. The SomeProtection
Environmental of its industrial
Agency (EPA) applications are listed in
has set the maximum
ure 1. concentration in drinking water at 0.8 milligrams per liter (mg/L) for chlorine dioxide and
1.0 mg/L for chlorite ions [18]. Some of its industrial applications are listed in Figure 1.

Figure 1. Applications of chlorine

Figure 1. Applications dioxide.
of chlorine dioxide.

Chlorine dioxide is a compound that differs from elemental chlorine, both in its
Chlorine dioxide
chemical is a and
structure compound
in its behaviorthat differs
[19]. An from
important elemental
characteristic chlorine,
is its high solubility both
in water, especially in cold water. Chlorine dioxide is about 10 times more soluble in water
chemical structure and in its behavior[19]. An important characteristic is its high solu
than chlorine.
in water, especially in cold water. Chlorine dioxide is about 10 times more soluble in w
2. Physicochemical Properties of ClO2
than chlorine.
ClO2 is a yellowish-green gas and has a pungent odor, like Cl2 , with a boiling point of
11 ◦ C, a melting point of −59 ◦ C, a density of 1.64 g mL−1 (liquid) at 0 ◦ C, a water solubility
of 3 g L−Properties
2. Physicochemical 1 at 25 ◦ C, and a pKa = 3. ClO is very soluble in water and does not hydrolyze,
of ClO2 2
remaining in solution as a dissolved gas [20]. Solutions of ClO2 in water are stable when
ClO2 is a protected
yellowish‐green
from light and gas and
kept hastemperature
at room a pungent odor,well-sealed,
or below, like Cl2, and with a boiling
slightly
acidified
of 11 °C, a melting (pH = of
point 6). −59
The ultraviolet absorption
°C, a density of spectrum
1.64 g mLof ClO solutions at
−1 2(liquid) is broadband
0 °C, a water
bility of 3 g L−1 at 25 °C, and a pKa = 3. ClO2 is very soluble in water and does not h
lyze, remaining in solution as a dissolved gas[20]. Solutions of ClO2 in water are s
when protected from light and kept at room temperature or below, well‐sealed
 bond. Studies on the geometry of ClO2 established that the bond distance between th
atom and the O atom is smaller compared to the bond in chlorine monoxide (ClO). Th
results explain and justify the representation of the double bond between these two ato
Int. J. Mol.as
Sci. well
2022, 23,as showing that resonance structures satisfactorily explain the unpaired
15660 3 of 27 elect

of the chlorine atom. ClO2 has a molecular geometry with an oxygen‐chlorine‐oxy

bond angle of 117.6°, as shown in Figure 2. In its ground state, although the unpai
with a peak at 359 nm and a molar extinction coefficient of 1250 M−1 cm−1 . ClO2 has a
electron is shared between
relatively short the two
half-life andoxygen
is highly atoms andexplosive
volatile and the chlorine atom, most
at concentrations > 10% in of the e
air [21]. Chlorine dioxide
tron density resides mainly on either oxygen atom. may not be compressed, stored, or transported under pressure
and must be manufactured at the place of consumption.
It has an odd number of valence
ClO2 is a neutral monomeric electrons (itwith
free radical is aa dipole
paramagnetic radical),
moment of 1.792 and its e
Debye [22].
tronic structure has long puzzled chemists, because none of the possible Lewis structu
From the microwave spectra of gas-phase chlorine dioxide, the chlorine-oxygen distance
is found to be approximately 0.147 nm and electron diffraction indicates 0.149 nm. This
are satisfactory.chlorine-oxygen
In 1933, Brockway proposed
distance is approximately a anstructure
that of involving
average chlorine-oxygen a three‐elect
double bond.
bond[23]; LinusStudies Pauling on thelater developed
geometry this idea
of ClO2 established and
that the bondproposed two the
distance between possible
Cl atom reson
and the O atom is smaller compared to the bond in chlorine monoxide (ClO). These results
structures involving a double bond on the one hand and a single bond with a three‐e
explain and justify the representation of the double bond between these two atoms, as
tron bond on the other[24].
well as showing that resonance structures satisfactorily explain the unpaired electron of
the chlorine
The electronegativity atom.
of ClO has a molecular
the2 two oxygengeometry
atoms with an oxygen-chlorine-oxygen
is large enough to eliminate bond the e
◦
angle of 117.6 , as shown in Figure 2. In its ground state, although the unpaired electron is
tron density of the shared chlorine
between the atom and gives
two oxygen chlorine
atoms and a partial
the chlorine positive
atom, most charge,
of the electron Figure 2
density
resides mainly on either oxygen atom.

Figure 2. (a) The molecular structure of ClO2 . (b) The Lewis structure of ClO2 .
Figure 2. (a) The molecular structure of ClO2. (b) The Lewis structure of ClO2.
It has an odd number of valence electrons (it is a paramagnetic radical), and its
electronic
3. Generation of Chlorine structure has long puzzled chemists, because none of the possible Lewis struc-
Dioxide
tures are satisfactory. In 1933, Brockway proposed a structure involving a three-electron
Chlorine dioxide
bond [23];isLinus
a widely
Paulingused disinfectant
later developed asand
this idea anproposed
alternative to chlorine,
two possible resonant due to
structures involving a double bond on the one hand and a single bond with a three-electron
effectiveness inbond
pathogen inactivation and low production of halogenated organic
on the other [24].
products of disinfection. However,
The electronegativity during
of the the atoms
two oxygen generation of ClO
is large enough 2, chlorine
to eliminate is inevita
the electron
density of the chlorine atom and gives chlorine a partial positive
introduced into the ClO2 solution obtained as an impurity. The presence of chlorin charge, Figure 2.

chlorine dioxide3.may affect

Generation of the formation
Chlorine Dioxide and toxicity of disinfection by‐products as w
as the disinfection efficiency.
Chlorine dioxide is a widely used disinfectant as an alternative to chlorine, due to
its effectiveness in pathogen inactivation and low production of halogenated organic by-
There are different methods However,
products of disinfection. for the during
preparation of chlorine
the generation dioxide[16],
of ClO2 , chlorine depend
is inevitably
on the amount introduced
required,into thethenumber of obtained
ClO2 solution by‐products that can
as an impurity. be tolerated,
The presence of chlorineand
in whet
chlorine dioxide may affect the formation and toxicity of disinfection by-products as well
the gas is required in solution or in gaseous form, Figure 3.
as the disinfection efficiency.
There are different methods for the preparation of chlorine dioxide [16], depending on
the amount required, the number of by-products that can be tolerated, and whether the gas
is required in solution or in gaseous form, Figure 3.
Int. J. Mol. Sci. 2022, 23, 15660 4 of 28

Int.
Int. J.J. Mol.
Mol. Sci. 2022,
2022, 23,
23, 15660
15660 44 of
of 27
28

Figure 3. ClO2 preparation methods.

Figure 3. ClO
Figure 3. preparation methods.
ClO22 preparation methods.
3.1. From Chlorite Ions
3.1. From Chlorite Ions
3.1.ClO 2 isChlorite
From generated
Ionsfrom chlorite ions using chemicals, electrochemicals, and biocata‐
ClO is generated
lysts, and from the reaction
2 fromofchlorite
chloriteions
withusing chemicals,
chlorine gas Cl2electrochemicals, and biocatalysts,
or hydrochloric acid (HCl)[25–
and from is generated
ClO2the reaction offrom chlorite
chlorite with ions using
chlorine gaschemicals,
Cl or electrochemicals,
hydrochloric acid and
(HCl) biocata‐
[25–27], as
27], as shown in Figure 4. 2
lysts, and from
shown in Figure 4.the reaction of chlorite with chlorine gas Cl 2 or hydrochloric acid (HCl)[25–

27], as shown in Figure 4.

Figure
Figure4.4.Preparation
Preparationofofchlorine
chlorinedioxide
dioxidefrom
fromsodium
sodiumchlorite.
chlorite.
Figure 4. Preparation of chlorine dioxide from sodium chlorite.
Themethods
The methodsdescribed
describedin inFigure
Figure 44 have have major disadvantages
disadvantages due dueto tothe
theproduction
productionof
high amounts of chlorides, which can be avoided by
of high amounts of chlorides, which can be avoided by replacing hydrochloric withreplacing hydrochloric with sulfuric
sul‐
The methods described in Figure 4 have major disadvantages due to the production
acid, although in such cases, the processes become less
furic acid, although in such cases, the processes become less efficient. These methodsefficient. These methods involve
in‐
of high amounts of chlorides, which can be avoided by replacing hydrochloric − , and with sul‐
concentrated
volve concentratedacidsacids
and/or externally
and/or externally added oxidants
added oxidants suchsuchas Clas 2 , Cl
OCl 2, OCl H2 O
−, and H22.O2.
furic acid, although in such cases, the processes become less efficient. These methods in‐
Anotherway
Another waytotogenerate
generateClO ClO 2 from
2 from chloritebybyone‐electron
chlorite one-electrontransfer transferis isbybyelectro‐
electro-
volve concentrated acids and/or externally added oxidants such as Cl2, OCl−, and H2O2.
chemicalmeans[28],
chemical means [28], but
but this
this procedure
procedure requires
requires a considerable
a considerable input
input ofof electrical
electrical energy.
energy.
Another way to generate ClO2 from chlorite by one‐electron transfer is by electro‐
An electrochemical method using mixed metal oxide
An electrochemical method using mixed metal oxide MMO electrodes in the presence of MMO electrodes in the presence
chemical means[28], but this procedure requires a considerable input of electrical energy.
of chlorite
chlorite and and boron-doped
boron‐doped diamond
diamond BDDBDD anodes anodes to promote
to promote the evolution
the evolution of chlorine
of chlorine spe‐
An electrochemical
species was also method
studied using
[29,30]. mixed metal
Another oxideisMMO
possibility to start electrodes
from an in the presence
undoped solution of
cies was also studied[29,30]. Another possibility is to start from an undoped solution of
chlorite
of sodium and boron‐doped
chlorite diamond BDD anodes to promote the evolution of chlorine spe‐
sodium chlorite andand a mixture
a mixture of sodium
of sodium chloride
chloride in inanan undividedelectrochemical
undivided electrochemicalcell cell
cies was also
witha aconstant studied[29,30].
constantcurrent,
current,Ti/IrO2 Another
Ti/IrO2anode,
anode,and possibility
andTi/Pt
Ti/Pt is to start
cathode [31,32].from an undoped solution of
with cathode[31,32].
sodium chlorite
Tooxidize
oxidize and a
chlorite mixture
to ClO of sodium chloride in an undivided electrochemical cell
To chlorite to ClO 2 , catalysts
2, catalysts
are based
are based on manganese
on manganese or ironorporphyrin
iron porphyrincom‐
with a constant
complexes. In current,
these Ti/IrO2
systems, anode,dismutation
chlorite and Ti/Pt cathode[31,32].
is initiated through the oxidation
plexes. In these systems, chlorite dismutation is initiated through the oxidation of Mn(IIof
To oxidize chlorite bytochlorite
ClO2, catalysts are basedhypochlorite
on manganese or and
iron high-valent
porphyrin com‐
orMn(II
III) ororFe(III)
III) or byFe(III)
chlorite ions toions to produce
produce hypochlorite ions and ions high‐valent Mn and Mn
plexes.
and In
Fe(IV these
or V). systems,
Both chlorite
oxidation dismutation
states, IV and V,is initiated
oxidize through
chlorite the
directly oxidation
to ClO , of Mn(II
although
Fe(IV or V). Both oxidation states, IV and V, oxidize chlorite directly to ClO2, 2although
or III) or Fe(III)
complete conversion by chlorite ions to to ClO
produce hypochlorite ions and high‐valent Mn and
complete conversion ofof chlorite
chlorite to ClO 2 was
2 was
achieved
achieved in water
in water using using water-soluble
water‐soluble Fe orFe
Fe(IV or V). Both oxidation states, of IV these
and V, oxidizeand chlorite directly to ClO 2, although
Mn porphyrins. The synthesis of these ligands and catalysts is very expensive. A catalyticA
or Mn porphyrins. The synthesis ligands catalysts is very expensive.
completeprocess
catalytic conversion of chlorite
has also to ClO2 was
been developed usingachieved
a manganesein water using water‐soluble
porphyrin Fe or
catalyst, tetra-kis-
process has also been developed using a manganese porphyrin catalyst, tetra‐kis‐
Mn porphyrins. The synthesis of these ligands and catalysts
5,10,15,20-(N,N-dimethylimidazolium) porphyrinatomanganese(III), which is soluble in is very expensive. A catalytic
5,10,15,20‐(N,N‐dimethylimidazolium) porphyrinatomanganese(III), which is soluble in
process
water andhas also been
catalyzes developed
the formation using dioxide
of chlorine a manganese porphyrin
from chlorite at room catalyst,
temperaturetetra‐kis‐
and
water and catalyzes the formation of chlorine dioxide from chlorite at room temperature
5,10,15,20‐(N,N‐dimethylimidazolium)
pH = 5 [33–36]. porphyrinatomanganese(III), which is soluble in
and pH = 5[33–36].
water and catalyzes the formation of chlorine dioxide from chlorite at room temperature
3.2.
andFrom
pH =Sodium
5[33–36]. Chlorate
3.2. From Sodium Chlorate
Currently, the most widely used method to produce chlorine dioxide is the reduction
3.2.Currently,
Fromby
method, SodiumtheChlorate
reacting most widely
sodium used method
chlorate to produceacid
in a concentrated chlorine
solution dioxide
withisreducing
the reduction
agents
method, by reacting
such Currently,
as sulfur dioxide, sodium chlorate in a concentrated acid solution with reducing agents
the mostmethanol,
widely used oxalic
methodacid,tohydrogen peroxide,
produce chlorine hydrochloric
dioxide acid, or
is the reduction
method, by reacting sodium chlorate in a concentrated acid solution with reducing agents
Int. J. Mol. Sci. 2022, 23, 15660 5 of 28
Int. J. Mol. Sci. 2022, 23, 15660 5 of 28

Int. J. Mol. Sci. 2022, 23, 15660 5 of 27

such as sulfur dioxide, methanol, oxalic acid, hydrogen peroxide, hydrochloric acid, or
such as sulfur dioxide, methanol, oxalic acid, hydrogen peroxide, hydrochloric acid, or
sodium chloride. With hydrochloric acid, the chlorine content is high, the purity of the
sodium chloride. With hydrochloric acid, the chlorine content is high, the purity of the
chlorine
sodium dioxide
chloride.is With
low, and the contamination
hydrochloric acid, the is severe[37,38].
chlorine content is high, the purity of the
chlorine dioxide is low, and the contamination is severe[37,38].
The dioxide
chlorine sulfur dioxide
is low, method has the disadvantage
and the contamination is severeof[37,38].
SO2[38], with side reactions and
The sulfur dioxide method has the disadvantage of SO2[38], with side reactions and
The sulfurwhich
low efficiency, dioxide method
limits has the disadvantage
its application. The methanol of SOprocess
2 [38], with side reactions
is currently and
the most
low efficiency,
low efficiency, which
which limits
limits its
its application. The
The methanol
methanol process
process isis currently
currently the
the most
most
widely used method for chlorineapplication.
dioxide production in new‐build plants worldwide[37].
widely used
widely used method
method for for chlorine
chlorine dioxide
dioxide production
production in in new-build
new‐build plants
plants worldwide
worldwide[37].
[37].
The chlorine dioxide obtained is of high purity, but this method requires high acidity, and
The
The chlorine
chlorine dioxide
dioxide obtained
obtained is
is of
of high
high purity,
purity, but
but this
this method
method requires
requires high
high acidity,
acidity, and
and
the reactor needs materials with excellent corrosion resistance.
the reactor
the reactor needs materials
needs materials with
with excellent
excellent corrosion
corrosion resistance.
resistance.
In the chlorate reduction method, hydrogen peroxide advantageously replaces the
In the
the chlorate
chlorate reduction
reduction method,
method, hydrogen
hydrogen peroxide
peroxide advantageously
advantageously replaces the the
otherIn reagents, the process is more environmentally friendly, and the main replaces
by‐product
other reagents,
other reagents, the process
theFigure
process is more environmentally friendly, and the main by‐product
formed is oxygen, 5. is more environmentally friendly, and the main by-product
formed is
formed is oxygen,
oxygen, Figure
Figure 5. 5.

Figure 5. Preparation of chlorine dioxide from sodium chlorate.

sodium chlorate.
Figure 5. Preparation of chlorine dioxide from sodium chlorate.
The reaction between commercial solutions of chlorate and H2O2 results in the for‐
The reaction
reactionbetween
betweencommercial
commercialsolutions
solutionsofof
chlorate and
chlorate andH2HO22Oresults
2 resultsin in
thethe
forma-
for‐
mation of ClO2[38]. The reaction is very reproducible and stoichiometric. It is very im‐
tion of ClO
mation 2 [38].
of ClO TheThe
2[38]. reaction is very
reaction reproducible
is very and stoichiometric.
reproducible It is very
and stoichiometric. It isimportant
very im‐
portant that the reaction mixture is not depleted of chlorate to avoid further reduction of
that the that
portant reaction mixturemixture
the reaction is not depleted of chlorate
is not depleted to avoid
of chlorate to further reduction
avoid further of ClOof
reduction 2.
ClO
Once2. Once ClO2 is formed, the reduction of the chlorinated species continues, leading to
ClO is formed, the reduction of the chlorinated species continues, leading to the
ClO2. Once 2 ClO2 is formed, the reduction of the chlorinated species continues, leading to
the formation
formation of other
of other species,
species, such
such as chlorite,
as chlorite, Figure
Figure 6. 6.6.
the formation of other species, such as chlorite, Figure
(a)
(a)

2ClO2 + H2O2 2ClO2- - + O2 + 2H++

2ClO2 + H2O2 2ClO2 + O2 + 2H

(b) O O
(b) O O O
OOH O O
OOH O O O O
Cl Cl O O Cl O Cl O
O Cl O O ClOOHO O Cl O O Cl O
O O O OOH O O O O
OO H O O HH
O H O
Figure
Figure 6.
6. (a)
(a) Reduction
Reduction of
of chlorine
chlorine dioxide
dioxide with
with hydrogen
hydrogen peroxide.
peroxide. (b)
(b) Reduction
Reduction mechanism
mechanism of
of
Figure 6. (a) Reduction
chlorine of chlorine dioxide with hydrogen peroxide. (b) Reduction mechanism of
chlorinedioxide
dioxide with
with hydrogen
hydrogen peroxide.
peroxide.
chlorine dioxide with hydrogen peroxide.
When
When large
large quantities
quantities ofof chlorine
chlorine dioxide
dioxideareare needed,
needed, sodium
sodiumchlorate
chlorateisis used
used as
as aa
When large quantities of chlorine dioxide are needed, sodium chlorate is used as a
raw
raw material, this method
material, and this methodhas hastraditionally
traditionallybeen
beenused
usedinin
thethe pulp
pulp andand paper
paper indus‐
industries.
raw material, and this method has traditionally been used in the pulp and paper indus‐
tries. The conditions
The conditions for producing
for producing ClO2 from ClOsodium
2 from sodium chlorite
chlorite can can controlled
be better be better controlled
than those
tries. The conditions for producing ClO2 from sodium chlorite can be better controlled
for sodium
than chlorate,
those for sodiumbut chlorite
chlorate, butischlorite
more expensive and unstable,
is more expensive and therefore,
and unstable, from an
and therefore,
than thosepoint
industrial for sodium
of pointchlorate,
view, sodium but chlorite is is more suitable
expensive and unstable,
[39]. and therefore,
from an industrial of view, chlorate a more
sodium chlorate is a more feedstock
suitable feedstock[39].
from an industrial point of view, sodium chlorate is a more suitable feedstock[39].
4. Decomposition of ClO2
4.1. Disproportionation of Chlorine Dioxide with OH−
In solution at neutral pH, in the absence of light, and at room temperature or below,
chlorine dioxide is fairly stable [40], but its decomposition is accelerated in alkaline solution
to give ClO2 − and ClO3 − [41], Figure 7.
 4. Decomposition of ClO
chlorine 2
dioxide is fairly stable[40], but its decomposition is accelerated in alkaline solu‐
tion to give
4.1. Disproportionation ClO2− and
of Chlorine ClO3−[41],
Dioxide withFigure
OH−7.
4. Decomposition of ClO2
In solution 4.1.
at neutral pH, in the absence of light, and at room temperature or below,
Disproportionation of Chlorine Dioxide with OH−
chlorine
Int. J. Mol. Sci. dioxide is fairly
2022, 23, 15660 stable[40], but its decomposition is accelerated in alkaline solu‐ 6 of 27
In solution at neutral pH, in the absence of light, and at room temperature or below,
tion to give ClOchlorine
2 and ClO
− 3 [41],
−
dioxide Figure
is fairly 7.
stable[40], but its decomposition is accelerated in alkaline solu‐
tion to give ClO2− and ClO3−[41], Figure 7.

Figure 7. ClO2 as an oxidizing and reducing agent.

Ion chromatography shows that ClO2− and ClO3− are the only chlorine products
formed from the decomposition of ClO2 in a basic solution. However, the ratio of ClO2− to
ClO3− is not 1:1 as required for the disproportionation reaction. According to several au‐
thors, the percentage of ClO2− is higher than that of ClO3− as the ClO2 concentration de‐
Figure 7. ClO2 as an oxidizing and reducing agent.
creases.
Figure 7. At
ClOmicromolar
2 as an oxidizinglevels
andofreducing
ClO2 the yield of ClO2− is higher than that of ClO3−. The
agent.
Figure 7. ClO2 as an oxidizing
following
and reducing
additional reaction
agent.
could explain the change
Ion chromatography shows that ClO2− − and ClO3of molar stoichiometry
− are
− are the only chlorinefrom ClO2−
products
Ion chromatography
to ClO3 [42], Figure
− 8. shows that ClO 2 and ClO 3 the only chlorine products
formed
formed from the
the decomposition
from shows decomposition of
of ClO2 in aabasic solution. However, the
theratio ofofClO 2− to
−
Ion chromatography that ClO 2− ClO
and 2 in
ClO basic
3− aresolution.
the However,
only chlorine ratio
productsClO 2
ClO 3 is−
− not 1:1 as required for the disproportionation reaction.
to ClO3 is not 1:1 as required for the disproportionation reaction. According to several According to several au‐
formed from thethors,
decomposition
thethepercentage ofofClOClO 2 2in
− isahigher
− basic than solution.
that ofHowever,
ClO3− as−thethe ClOratio of ClO2− to
2 concentration de‐
authors, percentage of ClO 2 is higher than that of ClO3 as the ClO2 concentration
ClO3 is not 1:1 as
− required
creases.
decreases. At for
micromolarthe
At micromolar disproportionation
levels of ClO 2 the yieldreaction.
of ClO 2− isAccording
higher
− than to several
that of ClO 3−au‐
is higher than that of ClO3 − .. The
Figure 8. Molar stoichiometrylevels
from ClOof ClO 2 the
2 to ClO 2−.yield of ClO2
following
thors, the percentage
The following additional
− reaction
2 is higher
of ClOadditional could
thancould
reaction explain
that explainthe
of ClOthechange
3 as
− of molar
the ClO
change stoichiometry
2 concentration
of molar from ClO
stoichiometry de‐
from 2−

to
ClOClO
creases. At micromolar
−[42],
− 3to ClOFigure
levels of 8.ClO
− [42],
2 the
Figure 8. yield(Figures
of ClO29–11) − is higher thanthe that of ClO3−. The
2 The three3 possible mechanisms can explain stoichiometry of the
decomposition of ClO in alkaline solution, via assisted
following additional reaction could explain the change of molar stoichiometry from ClO2−
2 electron transfer[41].
to ClO3−[42], Figure 8. In the mechanism of ClO3− formation from ClO2 in basic media, the reaction of ClO2
with OH− generates species where OH− binds −. to the Cl atom of ClO2 to form the interme‐
Figure
Figure 8.8. Molar
Molar stoichiometry
stoichiometry fromfrom ClOClO22 to
to ClO
ClO2 − .
diate (HOCl(O)O)−. The formation of ClO3−2occurred from the reaction between HOClO2
and The
OH−.threeThis possible
pathwaymechanisms
shows first order (Figureskinetics
9–11) with respect the
can explain to the concentrations
stoichiometry of theof
ClO 2 and OH−, Figure 9.
decomposition of ClO 2 in alkaline solution, via assisted electron transfer[41]. transfer [41].
2
Figure 8. Molar stoichiometry from ClOof
In the mechanism 2 to ClO 2−.
ClO3− formation from ClO2 in basic media, the reaction of ClO2
with OH− generates species where OH− binds to the Cl atom of ClO2 to form the interme‐
The three possible mechanisms
diate (HOCl(O)O) (Figuresof9–11)
−. The formation ClO3− can explain
occurred from the stoichiometry
the reaction of the 2
between HOClO
and
decomposition of ClOOH2 in
−. This pathway
alkaline shows first
solution, viaorder kinetics
assisted with respect
electron to the concentrations of
transfer[41].
ClO2 andof
In the mechanism OH −, Figure 9.
ClO 3− formation from ClO2 in basic media, the reaction of ClO2
22, 23, 15660 7 of 28
with OH generates species where OH binds to the Cl atom of ClO2 to form the interme‐
− −

diate (HOCl(O)O) −. The

Figure formation
9. Mechanism
Mechanism of ClO3−ofoccurred
ofofformation
formation ofequimolar
equimolarfrom the
amounts reaction
ofof
amounts ClO − and
2− and
ClO between
ClO 3− from
ClO − from
HOClO
ClO in basic
2 ClO
Figure 2 3 2 2in
medium.
basic medium.
and OH . This pathway shows first order kinetics with respect to the concentrations of
−

ClO2 and OH−, Figure For9.the formation of ClO2− in basic media, it is proposed that OH‐ forms an adduct
with one of the oxygen atoms of ClO2 to give OClOOH−, and OCl is weakly bound to
OOH. This adduct can undergo rapid electron transfer with− a second −ClO2 to give ClO2−
Figure 9. Mechanism of formation of equimolar amounts of ClO 2 and ClO3 from ClO2 in basic
and OClOOH. The latter species reacts favorably with OH− to generate HOClO and HOO−.
medium.
The reaction between HOO− and ClO2 gives ClO2− and O2[43], Figure 10.
For the formation of ClO2− in basic media, it is proposed that OH‐ forms an adduct
with one of the oxygen atoms of ClO2 to give OClOOH−, and OCl is weakly bound to
OOH. This adduct can undergo rapid electron transfer with a second ClO2 to give ClO2−
and OClOOH. The latter species reacts favorably with OH− to generate HOClO and HOO−.
Figure 9. Mechanism of formation
The reaction ofHOO
between equimolar amounts
− and ClO of 2ClO
2 gives ClO and
2− O
− and ClO
2[43], 3− from
Figure 10. ClO2 in basic
medium.

For the formation of ClO2− in basic media, it is proposed that OH‐ forms an adduct
with one of the oxygen atoms of ClO2 to give OClOOH−, and OCl is weakly bound to
− from ClO in basic medium.
Figure This
OOH. 10. Mechanism
Figureof
adduct 10.formation
can Mechanismof
undergo of ClO 2− from
formation
rapid ClO
of ClO
electron 2 2 in basicwith
transfer 2medium.
a second ClO2 to give ClO2−
and OClOOH. The latter species reacts favorably with OH− to generate HOClO and HOO−.
A third possibility
The reaction between HOO involves
− and the
ClOformation of an intermediate dimer[44], Cl2O4, which
2 gives ClO2− and O2[43], Figure 10.
reacts with OH (an electron transfer step). This pathway is important at high ClO2 con‐
−

centrations, Figure 11.

 Figure 10. Mechanism of formation of ClO2− from ClO2 in basic medium.

A third possibility involves the formation of an intermediate dimer[44], Cl2O4, which

Int. J. Mol. Sci. 2022, 23, 15660 reacts with OH− (an electron transfer step). This pathway is important at high ClO27 con‐
of 27

centrations, Figure 11.

Figure 10. Mechanism of formation of ClO2− from ClO2 in basic medium.

Figure 10. Mechanism of formation of ClO2− from ClO2 in basic medium.
A third possibility involves the formation of an intermediate dimer[44], Cl2O4, which
Figure
Figure
reactsA11.
third
11.
with possibility
Mechanism
OH − (an of
of involves
the
the theof
formation
formation
electron formation
of
transfer equimolar
equimolar
step). of
This an intermediate
amounts
amounts
pathwayofofClO
isClO 2 dimer[44],
− and
2− and ClO
important 3− from
ClO Cl
at3highCl22O
− from 4, in
O4Cl
ClO which
basic
22O 4 in
con‐
reacts
medium.
basic with OH − (an electron transfer step). This pathway is important at high ClO2 con‐
medium.Figure 11.
centrations,
centrations, Figure 11.
The
In thedistribution
mechanism of ClO −
chlorine dioxide from decomposition products in areaction
basic solution
3 formation ClO2 in basic media, the of ClO2
changes
with −
OH asgenerates
the ClO2 speciesconcentration
where OH −
decreases.
binds While
to the Cl disproportionation
atom of ClO2 to form reactions giving
the interme-
diate amounts of −
equal(HOCl(O)O) ClO. The formation
2− and of ClO3 −the
ClO3− dominate occurred from theatreaction
stoichiometry millimolarbetween HOClO
or higher ClO22
and OHthe − . This pathway shows
levels, ratio of ClO2− to ClO3first
− formedorderincreases
kinetics with respect to
significantly at the concentrations
micromolar levels of
of
ClO and OH− , Figure 9.
ClO22[42].
For −
Thethe formation
kinetic evidence of ClOshows2 in basicconcurrent
three media, it ispathways
proposedthat thatshow
OH- forms
a firstan adduct
order de‐
with one of the oxygen atoms of ClO to give OClOOH − , and OCl is weakly bound to OOH.
pendence on [OH ] but have a variable
− 2 order on [ClO2]. Pathway 1 is a disproportionation
This adduct
reaction thatcan undergo
is first order rapid
in [ClO electron
2], Figure transfer
12. with a second ClO2 to give ClO2 − and
OClOOH. The latter species reacts favorably with OH− to generate HOClO and HOO− .
The reaction between HOO− and ClO2 gives ClO2 − and O2 [43], Figure 10.
FigureA 11. Mechanism
third possibility of the formation
involves the of equimolarofamounts
formation of ClO2− and
an intermediate ClO3[44],
dimer − from Cl2O4 in basic
Cl2 O4 , which
Figure
medium. 11. Mechanism − of the formation of equimolar amounts of ClO2− and ClO3− from Cl2O4 in basic
reacts with OH (an electron transfer step). This pathway is important at high ClO2
Figure 12. First order disproportionation reaction in [ClO2].
medium.
concentrations, Figure 11.
The distribution
The distribution of of chlorine
chlorine dioxide
dioxide decomposition
decomposition productsproducts in in aa basic
basic solution
solution
changesPathway
The 2,ClO
distribution
as the a previously
of chlorine unknowndioxide reaction, is also first
decomposition order in
products
2 concentration decreases. While disproportionation reactions giving
in [ClO 2] but
a basic forms
solution
changes
ClO as the
− as the only ClO 2 concentration decreases.
chlorine‐containing product. While disproportionation
Pathway 2 is attributed to the reactions
attack of giv-−
OH
changes
equal2 as the of
amounts ClO2 concentration decreases. theWhile disproportionation reactions giving
ing equal amountsClO 2− and
of ClO − ClO
and
2 2 leading
3− dominate
ClO − dominate stoichiometry
the stoichiometry at millimolar
at or higher
millimolar or ClO
higher 2
on an amounts
equal
levels, oxygen
the ratioatom
ofofClOof 2ClO
ClO
− and
2− to −
ClO
ClO to3 −
3 formed
intermediate
3−−dominate
increases peroxide
the stoichiometry intermediates
significantlyat millimolar
at and producing
or higher
micromolar ClO
levels of2
ClO2 −levels, the ratio of ClO 2 to ClO3 formed increases significantly at micromolar levels
ClO22[42].
levels,
ClO and
the O 2 as products.
ratio of ClO2− to This
ClOpathway
3− formed is increases
importantsignificantly
at low levelsatofmicromolar
ClO2, Figurelevels13. of
of ClO2 [42].
ClO2[42].
The kinetic
kineticevidence
evidenceshows showsthree threeconcurrent
concurrentpathways
pathways that show a first order de‐
The that show a first order depen-
The kinetic
pendence on [OH
− evidence
−] but have shows
a three order
variable concurrent
on [ClO pathways
]. Pathway that1 is
show
a a first order de‐
disproportionation
dence on [OH ] but have a variable order on [ClO2 ]. Pathway 1 is a disproportionation
2
pendence
reaction that on [OH
that
−] but have a variable order on [ClO
is first
first order in in [ClO
[ClO22], ], Figure
Figure 12. 12. 2]. Pathway 1 is a disproportionation
reaction is order
reaction
Figure 13.that is first2 order
Pathway is alsoin [ClO
first 2], Figure
order in [ClO12.
2] but forms ClO2− as the only chlorine‐containing

product.

Figure 12.
Figure 12. First
First order
order disproportionation
disproportionation reaction
reaction in
in [ClO
[ClO2].
].
Figure 12. First order disproportionation reaction in [ClO22].
previously unknown
Pathway 2, a previously unknown reaction, is alsoalso first
first order
order in
in [ClO
[ClO22] but
but forms
forms
ClO22Pathway 2,
−−as the only a previously unknown
chlorine‐containing reaction,
product. is
Pathway also
2 first
is order
attributed into [ClO
the
as the only chlorine-containing product. Pathway 2 is attributed to the attack 2] but forms−
attack of OH
ClO 2− as
on OH − the
an oxygen only
atomchlorine‐containing
of ClO 2 leading
product. Pathway
to intermediate 2 is attributed to the attack of OH −
of on an oxygen atom of ClO 2 leading to peroxide intermediates
intermediate peroxide and producing
intermediates
on
ClOan
and − oxygen
2producing
atom
and O2 as ClO of−ClO
products. 2 leading to intermediate peroxide intermediates and producing
This
O2 pathway is important at low islevels of ClO2at , Figure 13. of
2 and as products. This pathway important low levels
ClO 2− and O2 as products. This pathway is important at low levels of ClO2, Figure 13.
ClO2 , Figure 13.

Figure 13. Pathway 2 is also first order in [ClO2] but forms ClO2− as the only chlorine‐containing
Figure
Figure 13.
product.13. Pathway 2 is2 also
Pathway first first
is also orderorder
in [ClO
in 2][ClO
but 2forms
] but ClO 2− as
forms the2 −
ClO only
as chlorine‐containing
the only chlorine-
product.
containing product.

Pathway 3 is second order in [ClO2 ] and generates equal amounts of ClO2 − and ClO3 − .
A Cl2 O4 intermediate is proposed for this pathway. At high ClO2 concentrations, pathway
3 brings the overall yield of ClO3 − close to the overall yield of ClO2 − , Figure 14.
 Int. J. Mol. Sci. 2022, 23, 15660 8 of 28
Int. J. Mol. Sci. 2022, 23, 15660 8 of 28
Pathway 3 is second order in [ClO2] and generates equal amounts of ClO2− and ClO3−.
A ClPathway 33isissecond
O4 intermediate
2Pathway order
orderin
is proposed
second in[ClO
for
[ClO 2]2]and
this generates
pathway.
and equal
At high
generates amounts
ClO
equal of
ofClO
ClO2 2−and
2 concentrations,
amounts
− ClO
ClO3 3.−.
pathway
and
−

A Pathway 3 is second order in [ClO 2] and generates equal amounts of ClO 2 − and ClO3−.
3AClCl2O
brings
2O 4 4intermediate
the overall
intermediate isisproposed
yield of
proposed 3−for
ClOin for this
close ] pathway.
2to
this At
thegenerates
overall
pathway. high
Atyield
high ClO
of
ClO 2 2concentrations,
ClO 2−, Figure pathway
14.2− and
concentrations, pathway
Int. J. Mol. Sci. 2022, 23, 15660 33AA ClPathway
brings the
3 is second
2O4 intermediate is proposed
overall yield
order
of ClO
[ClO
for this
− −close to
and
pathway.
the overallAt equal
high
yield of
amounts
ClO
ClO
of ClO
2 concentrations,
−,− Figure 14.
ClO3−.
pathway
8 of 27
brings the overall yield of ClO3 close to the overall yield of ClO 2 , Figure 14.
3 Cl 2O4 intermediate is proposed −for this pathway. At high ClO2 concentrations,
the overall yield of ClO3 close to the overall yield of ClO2−, Figure 14. pathway
3 2
brings
3 brings the overall yield of ClO3− close to the overall yield of ClO2−, Figure 14.

Figure 14. Pathway 3 is second order in [ClO2] and generates equal amounts of ClO2− and ClO3−.
Figure
Figure14.
14.Pathway
Pathway33isissecond
secondorder
orderinin[ClO
[ClO2]2]and
andgenerates
generatesequal
equalamounts
amountsofofClO
ClO2 2−and
−
andClO
ClO3 3.−.
−

Figure
4.2. 14. Pathway 3
Disproportionationis second order
of Chlorine in [ClO 2] and generates equal amounts of ClO2− and ClO3−.
Figure
Figure 14. Pathway
14. Pathway 33 is
is second
second orderDioxide
order in [ClO2with
in [ClO andNucleophile
2]] and generates equal
generates equal amounts
amounts of ClO22−−and
of ClO ClO3−3.− .
andClO
4.2.
4.2.Disproportionation
effect of OX−ofhypohalite
Disproportionation ofChlorine
ChlorineDioxide
Dioxide with
withNucleophile
Nucleophile
4.2. The
Disproportionation of Chlorine ion catalysis
Dioxide on the disproportionation of chlorine diox‐
with Nucleophile
4.2.
ide Disproportionation
4.2.inThe effect
basic of
solutionOX
Disproportionation −
to of
of Chlorine
hypohalite
Chlorine
give ClO − Dioxide
ion
Dioxide
and
The effect of OX −hypohalite ion catalysis on
− 2 ClO with
catalysis
with
3 − has Nucleophile
on the disproportionation
Nucleophile
been
thestudied. of
ofchlorine
In the first step
disproportionation diox‐
of hypohalite
chlorine diox‐
ide in The effect
basic solutionof OX
to −hypohalite
give ClO − −andionClO catalysis
− −has on the
been disproportionation
studied. In the first stepofof
chlorine diox‐
hypohalite
catalysis
ide inThe (the
effect
basic
The reaction
ofOX
solution
effect of OXto− between
give ClOClO
hypohalite
hypohalite2 2 and 2 and
ion ion
ClOOX
catalysis
3 3 has
catalysis
− involved
been
on the a transfer
onstudied.
the In of electrons
disproportionation
the first
disproportionation step
of to
of form
of ClO
chlorine
hypohalite
chlorine 2−
diox‐
ide in
catalysis
dioxide basic
(the
in(the solution
reaction
basic to
solution give
between ClO
toClO ClO
give 2− and ClO
ClO and − OX
and 3 − has been studied. In the first step of hypohalite
− −involved
ClO − a transfer of electrons to form ClO −
and
ide OX),
catalysis
in basicthis step
solution isto
reaction reversible[45–47],
between
give ClO
2− and
2 2 and Figure
2ClO OX3− has 15. 3 has
involved
been beenInstudied.
a transfer
studied. firstIn
of electrons
the theto
step offirst
formstep
ClOof2−
2
hypohalite
catalysis
and (the reaction between ClO 2 and OX− involved a−transfer of electrons to form ClO2−
andOX),
OX),this
hypohalite
catalysis this
(the step
stepisisreversible[45–47],
catalysis
reaction (the reaction
reversible[45–47],
between ClO between
2 and
Figure
Figure
OX ClO 15.
2 and OX
15.
− involved involved
a transfer a transfertoofform
of electrons electrons
ClO2−
and
to formOX),
ClO this− step
and is reversible[45–47],
OX), this step is Figure
reversible 15.
[45–47], Figure 15.
and OX), this step is reversible[45–47], Figure 15.
2

Figure 15. Effect of the OX− hypohalite ion on the disproportionation of ClO2 in basic solution.
Figure
Figure15.
15.Effect
Effectofofthe
theOXOX−−hypohalite
−
hypohaliteion
ionononthe
thedisproportionation
disproportionationofofClO
ClO2 2ininbasic
basicsolution.
solution.
Figure
FigureIn 15.
15.
the Effect
Effect of
second of the
the OX
OX
step,
− hypohalite ion on the disproportionation of ClO2
thehypohalite
reactions ion on the disproportionation
between ClO 2 and XO formof ClO
XOClO 2 in basic solution.
2, Figure 16.
Figure 15. Effect of the OX− hypohalite ion on the disproportionation of ClO2 in basic solution.
In
Inthe
thesecond
secondstep,
step,the
thereactions
reactionsbetween
betweenClO
ClO2 2and
andXO
XOform
formXOClO
XOClO2,2,,Figure
Figure16.
16.
In
Inthe
thesecond
secondstep,
step,the
thereactions
reactionsbetween
betweenClO2 2and
ClO andXO
XOform
formXOClO
XOClO2 2,Figure
Figure16.
16.
In the second step, the reactions between ClO2 and XO form XOClO2, Figure 16.

Figure 16. Formation of XOClO2.

Figure
Figure16.
16.Formation
Formationof
ofXOClO
XOClO2.2..
Figure
Figure16.
16.Formation
Formationof
ofXOClO
XOClO2 2.
In16.
Figure basic medium,
Formation hydrolysis
of XOClO 2.
of XOClO2 produces ClO3− and OX−, Figure 17.
In
Inbasic
In basicmedium,
medium,hydrolysis
hydrolysisof
ofXOClO
XOClO222produces
producesClO
ClO333−−and
−
andOX
and OX,−,−−
OX
− Figure 17.
Figure
Figure17.
Inbasic
basicmedium,
medium,hydrolysis
hydrolysisofofXOClO
XOClO2produces
producesClO
ClO3− and OX , ,Figure 17.
17.
In basic medium, hydrolysis of XOClO2 produces ClO3 and OX , Figure 17.
− −

Figure 17. Hydrolysis of XOClO2 in basic medium to produce ClO3− and OX−.
Figure −− −.− −
Figure17.
Figure 17.Hydrolysis
17. Hydrolysisof
Hydrolysis ofXOClO
of XOClO222in
XOClO inbasic
in basicmedium
basic mediumto
medium toproduce
to produceClO
produce ClO333−and
ClO OX
and
and OX
OX . .
Figure
4.3. 17. Hydrolysis
Photodissociation of
of XOClO
ClO 2
2 in basic medium to produce ClO3− and OX−.
Figure
4.3. 17. Hydrolysis of
Photodissociation of XOClO
ClO 2 in basic medium to produce ClO3 and OX .
− −
4.3.
4.3.Photodissociation
Photodissociation
The reactivity of ofofClO
ClO
ClO2222is modified by exposure to UV radiation in a process known
4.3. The
Photodissociation
reactivity of of
of ClO
ClO ClO 2is modified by exposure to UV radiation in a process known
as The
Thereactivity
4.3.UV/ClO
Photodissociation
2. ClO2 undergoes
reactivity ofofClO
ClO 2222isismodified
modifiedby byexposure
photodissociation to
toUV
leading
exposure to radiation
UV the in
formation
radiation inaaprocess known
of the primary
process known
as UV/ClO
as UV/ClO . ClO
The reactivity
2.22.ClO 2• undergoes photodissociation
of ClO2 isphotodissociation
2 2undergoes
modified by exposureleading
leading to totothe
UV theformation
formation
•radiation in aofof the primary
process
the primary
known
radical
as UV/ClOoxygen
The ClO
reactivity(O ), chlorine
undergoes (Cl
ClO2 is modified
• ),ofchlorine
•), and chlorine
photodissociation
• ), and by oxide
leading
exposure (ClO
to
to (ClO
UV the) by homolytic
formation
radiation of fission
the
in a process
• ) by homolytic of the
primary
known
radical
as
radical oxygen
UV/ClO
oxygen (O
2. ClO
(O • 2 undergoes(Cl
), chlorine (Cl •), •and
chlorine
photodissociation
chlorine oxide
leading
oxide (ClOto •)theby formation
homolytic offission
the
fission of the
the
primary
of
chlorine‐oxygen
radical
as UV/ClOoxygen
2. ClO bond• to
(O2 undergoes form ClO
(Cl •), •
• and
), chlorine photodissociation O •[48–50].
chlorine Illumination
oxide (ClO
leading
• [48–50].
•
to the ) byof a neutral
homolytic
formation aqueous
offission ofClO
the aqueousthe2
primary
chlorine-oxygen
radical oxygen
chlorine‐oxygen bond
(O
bond to to form
•), chlorine
form ClO
(Cl
ClO ), and
and
••and O•• O
chlorine
[48–50]. oxide Illumination
(ClO
Illumination
•) by
of a of a neutral
homolytic
neutral fission
aqueous of
ClO the
solution
radical gives a(O
chlorine‐oxygen
oxygen mixture
bond to of
form
•), chlorine chloric
ClO
(Cl •),acid
and and
O hydrochloric
[48–50].
chlorine acid,
Illumination
oxide (ClO •) byFigure 18. aqueous
ofhomolytic
a neutral fission ofClO22
the
ClO 2
solutionsolution
chlorine‐oxygen
gives gives
a mixture a
bond tomixture
ofform of
chloric chloric
ClOacid
• and acid
and and hydrochloric
O hydrochloric
• [48–50]. Illumination
acid, acid, Figure
of a neutral
Figure 18. 18.
aqueous ClO2
solution gives a mixture
chlorine‐oxygen to of chloric
ClO•acidandand hydrochloric acid, Figure 18. aqueous ClO2
solution gives a bond form O •[48–50]. Illumination of a neutral
mixture of chloric acid and hydrochloric acid, Figure 18.
solution gives a mixture of chloric acid and hydrochloric acid, Figure 18.

Int. J. Mol. Sci. 2022, 23, 15660 9 of 28

Figure 18.
18. The
The homolysis
homolysis of
of ClO
ClO2 in neutral aqueous solution.
Figure 2 in neutral aqueous solution.
Figure
Figure 18. The homolysis of ClO2 in neutralaqueous
18. The homolysis of ClO 2 in neutral aqueoussolution.
solution.
The
Figure
The18.photochemical
The homolysis of
photochemical and
ClO
and thermal decomposition
2 in neutral
thermal ofofClO
aqueous solution.
decomposition 2 takes place by homolytic fis‐
ClO
Figure 18. The homolysis of ClO2 in neutral aqueous solution. 2 takes place by homolytic
sion ofof
fission the chlorine‐oxygen
the bond,
chlorine-oxygen Figure
bond, 19.19.
Figure

Figure 19.
19. Homolysis
Homolysis of
of ClO
ClO2 by thermal route or with irradiation.
Figure 2 by thermal route or with irradiation.

Once homolytic fission has occurred, further reactions will depend on the reaction
conditions. At room temperature, photolysis of dry, gaseous ClO2 gives Cl2, O2, and some
ClO3, which subsequently dimerizes to Cl2O6 or undergoes further photolysis to Cl2 and
 The photochemical and thermal decomposition of ClO2 takes place by homolytic fis‐
sion
sion of
of the
the chlorine‐oxygen
chlorine‐oxygen bond,
bond, Figure
Figure 19.
19.
Once homolytic fission has occurred, further reactions will depend on the reacti
conditions. At room temperature, photolysis of dry, gaseous ClO2 gives Cl2, O2, and som
ClO3, which subsequently dimerizes to Cl2O6 or undergoes further photolysis to Cl2 a
Int. J. Mol. Sci. 2022, 23, 15660 9 of 27
O2, Figure
Figure 20.Homolysis
Figure 19.
19. Homolysis of
of ClO
ClO22 by
by thermal
thermal route
route or
or with
with irradiation.
irradiation.

Once
Once homolytic
homolytic fission
fission has
has occurred,
occurred, further
further reactions
reactions will
will depend
depend onon the
the reaction
reaction
Once
conditions. homolytic
At room fission has
temperature, occurred,
photolysisfurther
of dry,reactions
gaseous will
ClO depend on the reaction
2 gives Cl2, O2, and some
conditions. At room temperature, photolysis of dry, gaseous ClO2 gives Cl2, O2, and some
conditions.
ClO At room temperature, photolysis of dry, gaseous ClO2 gives Cl2 , O2 , and some
ClO33,, which
which subsequently
subsequently dimerizes
dimerizes to
to Cl
Cl22O
O66 or
or undergoes
undergoes further
further photolysis
photolysis to to Cl
Cl22 and
and
ClO
O 3 , which
2, Figure 20.
subsequently dimerizes to Cl2 O 6 or undergoes further photolysis to Cl 2 and
O 2, Figure 20.
O2 , Figure 20.

Figure 20. The photolysis of dry, gaseous ClO2.

The degradation mechanisms and radical chemistry associated with UVC photoly
Figure
Figure 20.
20. The photolysis
The photolysis
photolysis of dry,
of dry, gaseous
dry,gaseous
gaseous ClO
ClO 2.
2.
of ClO 2 are20.
Figure quite
The complicated[51].
of TheClOphotolysis
2. of ClO2 by UVC light provides ClO− a
oxygen by Thecleavage of the
degradation Cl‐O[52]and
mechanisms and Cl•[53]
radical bond,associated
chemistry Figure 21.with UVC photolysis
The degradation
The degradation mechanisms
mechanisms andand radical
radical chemistry
chemistry associated
associated with
with UVC
UVC photolysis
photolysis
of
of ClO2 are quite complicated[51]. The photolysis of ClO2 by UVC light provides ClO−− and
of ClO22 are
are quite
quite complicated[51].
complicated [51].The
Thephotolysis
photolysis ofof
ClO 2 by
ClO UVC light provides ClOClO −
and
2 by UVC light provides
oxygen
oxygen
and by
oxygen cleavage
by cleavage of
by cleavagethe
of the Cl‐O[52]
of Cl‐O[52] and
the Cl-O and Cl
[52] Cl
•[53] •bond, Figure 21.
and[53]
• Cl bond, Figure
[53] bond, 21. 21.
Figure

Figure 21. The photochemistry and radical chemistry of photolysis of ClO2 by UVC light.
Figure
Figure 21. The
21. The
Figure 21. photochemistry
The photochemistry and
photochemistry and radical
and radical chemistry
radical chemistry of
chemistry of photolysis
of photolysis of
photolysis of ClO
ClO222 by
of ClO by UVC
UVC light.
light.
The above species can undergo chain reactions to generate secondary reactive sp
The
cies[54,55], above
above species
TheFigure
above speciescan
22.
species canundergo
can undergo
undergo chain
chain reactions
chain
reactions to
to generate
reactions secondary
to generate
generate reactive
secondary
secondary spe‐
reactive
reactive spe‐
species [54,55],
cies[54,55],
cies[54,55], Figure
Figure
Figure 22. 22.
22.

Figure
Figure 22.
22. The
The generated
generated ClO
ClO•,, O(3P),
•
O(3P), and
and Cl
Cl• undergo
•
undergo chain
chain reactions
reactions to
to generate
generate secondary
secondary reac‐
reac‐
tive species.
tive species.

Figure 22. The

Figure 22. generated ClO
The generated ClO • , O(3P),and
•, O(3P),
Cl••undergo
andCl chainreactions
undergo chain reactions to generate
to generate secondary re
secondary
tive species.
reactive species.

The degradation of ClO2 under UVC radiation accelerates the tendency of chlorite
and chlorate formation compared to ClO2 alone. In addition, chlorite and chlorate can also
be generated from radical-radical interactions [56–59], Figure 23.
022, 23, 15660
Int. J. Mol. Sci. 2022, 23, 15660 10 of 28 10 of 28

The degradation The degradation

of ClO of ClOradiation
2 under UVC 2 under UVC radiationthe
accelerates accelerates
tendency theoftendency
chlorite of chlorite
Int. J. Mol. Sci.
and and chlorate
23, 15660 formation
2022,chlorate formation
compared to ClOcompared to addition,
2 alone. In ClO2 alone.chlorite
In addition,
and chlorite
chlorateand
canchlorate
also can also
10 of 27

be generated fromberadical‐radical
generated frominteractions[56–59],
radical‐radical interactions[56–59],
Figure 23. Figure 23.

Figure 23. Chlorite and chlorate from the radical‐radical interactions.

Figure 23. Chlorite Figure

and chlorate fromand
23. Chlorite thechlorate
radical‐radical
from the interactions.
radical-radical interactions.
5. Reactivity of ClO2
5. Reactivity
The chemistryof ClO2of ClO2 is complex compared to that of other chlorine compounds,
5. Reactivity of ClO2
because The of its high of
chemistry reactivity.
ClO2 is complex Chlorine compared
dioxide is to a strong
that of oxidizing
other chlorine agentcompounds,
and, unlike
The chemistry of
chlorine, ClO 2 is not
does complex
tend to compared
react with to
organicthat of other
because of its high reactivity. Chlorine dioxide is a strong oxidizing agent and, or
materials tochlorine
form compounds,
chlorinated species, with
unlike
because of its high reactivity.
ammoniadoes
chlorine, to formChlorine
chloramine.
not tend dioxide
to react The is a
withoxidationstrong oxidizing
of ClO2 generally
organic materials agent and, unlike
begins withspecies,
to form chlorinated the removal or with of
chlorine, does notammonia
tend
an to react
electron tofrom
formwith organic
residual
chloramine. materials
organic Thecompounds to form
oxidation chlorinated
to ClO
of produce organic
2 generally species, or
radicals
begins withwith
andthe ClO 2−. Sub‐
removal
sequent oxidation fromof the organic −
ammonia to formof an electron
chloramine. The residual
oxidation of radicals
organicClOcompounds by ClO2 involves
2 generally to produce
begins oxygen
with thetransfer
organic with
radicals
removal the ClO
ofand release
2 .
of HOCl organic
Subsequent
an electron from residual or electron
oxidation transfer
of the with
compounds organic theradicals
releaseorganic
to produce of
byClO 2[46,50].
ClO2radicals
− involves and oxygen
ClO2−transfer
. Sub‐ with the
release of HOCl
Inorganic or electron
compounds transfer
are with
important the
in release
the body of andClO are −responsible
[46,50]. for many simple
sequent oxidation of the organic radicals by ClO2 involves oxygen transfer 2 with the release
Inorganic compounds
functions. The major inorganic compounds are important in the body and are responsible
are H2O, molecular oxygen O2, carbon for manydioxide
simple
of HOCl or electron transfer with the release of ClO2−[46,50].
functions.
CO2, and some The majoracids,inorganic
bases, and compounds
salts. Ironare is aHbiologically
2 O, molecular oxygencomponent
essential O2 , carbon of dioxide
every
Inorganic compounds
CO
are important in the body and are responsible for many simple of every
living2 , and some acids,
organism bases, and
and various salts.mechanisms
cellular Iron is a biologically
have evolved essential component
to capture iron from the
functions. The majorliving inorganic
environment organism compounds
in and variousare
biologically
H2O,mechanisms
cellular molecular
useful forms[60].
oxygen
It ishave
primarily
O2, involved
evolved carbon dioxide
to capture in theirontransfer
from the of
CO2, and some acids, bases,
environment
oxygen from the and salts.
in biologicallyIron
lungs to tissues. is a
useful biologically
forms [60].
However, essential
ironItalso
is primarily component
plays a role involved of every
in
in metabolism the transfer
as a com‐ of
living organism and oxygen
ponent variousfrom
of somecellular
theproteins
lungs mechanisms
toandtissues.
enzymes. have
However, evolved
Manganese to capture
iron also
(Mn) plays a iron
is a trace role from the is present
in metabolism
mineral that as a
component
environment in biologically of some
useful proteins
forms[60]. andIt enzymes.
is primarily Manganese
involved
in tiny amounts in the body. It is found mostly in bones, the liver, kidneys, and pancreas, (Mn)
in is
the a trace
transfer mineral
of that is
present
oxygen from the lungsand helps in tiny
to tissues. amounts
the body However, in the body. It
iron alsotissue,
form connective is found
plays abones, mostly
role in blood in bones,
metabolism the liver,
as a com‐
clotting factors, kidneys,
and sex hor‐ and
ponent of some proteins and enzymes. Manganese (Mn) is a trace mineral that is present and dis‐
pancreas,
mones. and
Manganese helps the
is a body
cofactor form for connective
many tissue,
enzymes, bones,
including blood clotting
manganese factors,
superoxide sex
hormones.
mutase, Manganese
arginase, and is a cofactor
pyruvate for many In
carboxylase. enzymes,
these including
enzymes, manganese
manganese is superoxide
involved in
in tiny amounts in the body. It is found mostly in bones, the liver, kidneys, and pancreas,
dismutase,
the form
metabolism arginase, and
of amino pyruvate
acids, carboxylase.
cholesterol, In these enzymes, manganese is involved
and helps the body in
connective tissue, bones, bloodglucose,
clottingand carbohydrates;
factors, and sex the the elimination
hor‐elimination
of the metabolism
reactive oxygenofspecies;
amino acids, cholesterol,reproduction;
bone formation; glucose, and carbohydrates;
immune response; and blood
mones. Manganese of is a cofactor
reactive oxygen forspecies;
many enzymes,bone including
formation; manganese
reproduction; superoxide
immune response;dis‐and blood
coagulation and hemostasis together with vitamin K[61–67].
mutase, arginase,coagulation
and pyruvate and carboxylase.
hemostasis In these
together withenzymes,
vitamin Kmanganese
[61–67]. is involved in
Some researchers have studied the reactivity of ClO2 with inorganic and organic com‐
the metabolism ofpoundsamino Some acids,
has beencholesterol,
researchers have studied
studied[68]. glucose, theand
In the human carbohydrates;
reactivity
body, of ClO
ClO 2 can
the with
with
2 react elimination
inorganic
I−, NOand organic
2−, O3, H2O2,
− , NO − ,
of reactive oxygenFe(II),
species;
compounds bone formation;
has
and Mn(II). been studied
The rate constantsreproduction;
[68]. In the immune
human
with tertiary body,
amines response;
ClOand can
2 phenols and were
react bloodalso high2 at
with I
O ,
coagulation and hemostasis
3 H 2 O 2 , Fe(II),
together and Mn(II).
with The
vitamin rate
pH ≥ 6. ClO2 does not react with ammonia, Br , carbohydrates, constants
K[61–67]. − with tertiary amines and phenols were
aromatic hydro‐carbides,
also high at pH ≥ 6. ClO does not react with ammonia, Br − , carbohydrates, aromatic
Some researchers have studied
and compounds the reactivity
containing 2 C=C double of ClO 2 with
bonds atinorganic
neutral pH and organic com‐
conditions.
hydro-carbides, and compounds containing C=C double bonds at neutral pH conditions.
pounds has been studied[68]. In the human body, ClO2 can react with I , NO2 , O3, H2O2, − −

5.1.
Fe(II), and Mn(II).5.1.
TheReactivity of ClO2 with
rate constants Inorganic
withInorganic Compounds
tertiaryCompounds
amines and phenols were also high at
Reactivity of ClO2 with
pH ≥ 6. ClO2 does notClO react
ClO with
2 can ammonia,
oxidize many Br −, carbohydrates,
inorganic compounds,aromatic hydro‐carbides,
being first reduced to chlorite by the
2 can oxidize many inorganic compounds, being first reduced to chlorite by the
transfer
and compounds containing of a
transfer of aC=C single
single electron.
double bonds
electron. In addition,
at neutral
In addition, chlorite can react
pH conditions.
chlorite with Fe(II)and
can react with Fe(II) andMn(II)
Mn(II)[69–72];
[69–72];
the reactions
the reactions[70,71]
[70,71] are
are summarized in Figure
summarized in Figure 24.
24.
5.1. Reactivity of ClO2 with Inorganic Compounds
ClO2 can oxidize many inorganic compounds, being first reduced to chlorite by the
transfer of a single electron. In addition, chlorite can react with Fe(II) and Mn(II)[69–72];
the reactions[70,71] are summarized in Figure 24.
Figure 24.
Figure 24. ClO
ClO2 oxidizes
oxidizes Fe(II)
Fe(II) and
and Mn(II)
Mn(II) via
via rapid
rapid one-electron
one‐electron transfer.
transfer.
2

The reaction rate constants of the ClO2 oxidation of Fe(II) and Mn(II) increase greatly
with alkaline pH. Iodide, unlike bromide, is readily oxidized in the presence of ClO2

Figure 24. ClO2 oxidizes Fe(II) and Mn(II) via rapid one‐electron transfer.
 Int. J. Mol. Sci. 2022, 23, 15660 11 of 2
Int. J. Mol. Sci. 2022, 23, 15660 11 of 2
Int. J. Mol. Sci. 2022, 23, 15660 11 of 2

The reaction rate constants of the ClO2 oxidation of Fe(II) and Mn(II) increase greatl
The reaction rate constants of the ClO2 oxidation of Fe(II) and Mn(II) increase greatl
with The
alkaline pH.rate
reaction Iodide, unlikeofbromide,
constants the ClO2 is readily oxidized
oxidation in the
of Fe(II) and presence
Mn(II) increase of ClO
greatl2 t
Int. J. Mol. Sci. 2022, 23, 15660 with alkaline pH. Iodide, unlike bromide, is readily oxidized in the presence of ClO
11 of 27 2 t
with The
iodine. reaction
During
alkaline pH. rate constants
oxidation
Iodide, of
unlikeof the
aqueous ClO
bromide, 2 oxidation
iodide,
is ClO
readily of
2 can Fe(II)
rapidly
oxidized and Mn(II)
oxidize
in the I−increase
to
presence I greatly
2[73].
of ClOChlo2 t
iodine. During oxidation of aqueous iodide, ClO2 can rapidly oxidize I− to I2[73]. Chlo −
with alkaline
rite[74,75]
iodine. pH.
produced
During Iodide,
by theunlike
oxidation bromide,
reduction of ClOis2 readily
can
ClOalso oxidized
react with in excess
the presence
I to form of ClO
I2 at 2pHto
rite[74,75] produced by theofreduction
aqueous iodide,
of ClO2 can 2 can rapidly oxidize I−− to I2[73]. Chlo
also react with excess I− to form I2 at pH
iodine. During
4–8[76–78]
rite[74,75] oxidation
(Figure
produced 25).
by theofreduction
aqueous iodide,
of ClO2ClOClO canreact
can2 2also rapidly
with oxidize
excess I− toto form
I2[73]. Chlo
4–8[76–78]
to (Figure
iodine. During 25).
oxidation of aqueous iodide, can rapidly oxidize I− Ito I [73]. I2 at pH
− to2form I2 at pH
rite[74,75]
4–8[76–78] produced
(Figure by the reduction of ClO 2 can also react with excess I
25). by the reduction of ClO2 can also react with excess I− to form I2
Chlorite [74,75] produced
4–8[76–78] (Figure 25).
at pH 4–8 [76–78] (Figure 25).

Figure 25. ClO2 oxidizes to I−− to I2.

Figure 25. ClO2 oxidizes to I to I2.
Figure 25. ClO2 oxidizes to I− to I2.
FigureThe
Figure 25. nitrite
25.ClO
ClO ion is oxidized
2 oxidizes − I− to I2. to nitrate in the presence of ClO2. Like iodide, the oxidation
to
2 oxidizes to I to I2 .
The nitrite− ion is oxidized to nitrate in the presence of ClO2. Like iodide, the oxidatio
of nitrite
The (NO2 −)ion
nitrite by ClO 2 involves mainly electron transfer reactions (Figure 26).
is oxidized to nitrate in the presence of ClO2. Like iodide, the oxidatio
of nitrite
The (NOion
nitrite 2 ) by ClO2 involves mainly electron transfer reactions (Figure 26).
is oxidized to nitrate in the presence of ClOof
2 . Like 2iodide, the oxidation
of nitrite (NO−2 ) by ClO2 involvesnitrate
The nitrite − ion is oxidized to mainlyinelectron
the presence
transfer ClO . Like (Figure
reactions iodide, the
26).oxidation
of nitrite (NO
of nitrite (NO ) by ClO
2 2 ) by ClO
− involves mainly electron transfer reactions (Figure
2 2 involves mainly electron transfer reactions (Figure 26). 26).

Figure 26. Oxidation of nitrite NO2−− by ClO2.

Figure 26. Oxidation of nitrite NO2 by ClO2.
Figure26.26.Oxidation
Figure Oxidation of nitrite
of nitrite NO2NO by ClO
2− ClO
− by
2.
2.
FigureChlorite can beoffurther
26. Oxidation reduced
nitrite NO 2− by ClOto2.chloride through reactions with CN−− and NO2−−. In
Chlorite can be further reduced to chloride through reactions with CN and
− and NO −
NO2 . I
the following
Chlorite
Chlorite reaction
can bebe
can shown
further in Figure
reduced
further reduced to 27,
to chloride Hthrough
2O2 actsreactions
chloride as a reducing agent[8].
with CN 2 . NO2−. I
the following reaction shown in Figure 27, H2O2 through
acts as a reactions
reducing with CN− and
agent[8].
In
the Chlorite
followingcan
thefollowing be further
reaction
reaction shown
shownreduced
ininFigureto27,chloride
Figure H2H
27, O22O through
acts reactions
as a reducing with
agent [8]. CN− and NO2−. In
2 acts as a reducing agent[8].
the following reaction shown in Figure 27, H2O2 acts as a reducing agent[8].
Figure 27. Reaction of hydrogen peroxide with chlorine dioxide.
Figure27.27.
Figure Reaction
Reaction of hydrogen
of hydrogen peroxide
peroxide with chlorine
with chlorine dioxide.
dioxide.
Figure 27. Reaction of hydrogen peroxide with chlorine dioxide.
FigureIn27.
the reaction
Reaction of with O
hydrogen3, ClO 2 is the
peroxide reducing
with chlorineagent (Figure
dioxide. 28).
InInthe reaction
the with
reaction O3 , O
with ClO 2 is the
3, ClO 2 is reducing agentagent
the reducing (Figure 28). 28).
(Figure
In the reaction with O3, ClO2 is the reducing agent (Figure 28).
In the reaction with O3, ClO2 is the reducing agent (Figure 28).
Figure28.
Figure 28.Reaction
Reaction of ozone
of ozone withwith
ClO2ClO
. 2.
Figure 28. Reaction of ozone with ClO2.
Figure
5.2. 28. Reaction
Reactivity of ozone
with Organic with ClO2.
Compounds
5.2. Reactivity
Figure withofOrganic
28. Reaction ozone with Compounds
ClO2.
5.2. The
Reactivity
reactionswith
of Organic
ClO2 with Compounds
organic compounds have generally been investigated in
aqueousThesolutions
reactions
5.2. Reactivity with of ClO
Organic
with with organic
Compounds
low 22reagent compounds
concentrations, in whichhaveitgenerally
reacts withbeen humicinvestigated
and in
5.2. The reactions
Reactivity with of ClO
Organic with organic
Compounds compounds have generally been investigated i
aqueous
acidssolutions
The present inwith
reactions of ClOlow reagent
2 with organic
concentrations,
compounds inhave
which it reacts
generally with investigated
been humic
and and ful
fulvic
aqueous solutions water,
with lowforming
reagent oxidized organic compounds,
concentrations, in which such as aldehydes
it reacts with humic and fui
vic The reactions
acids
carboxylic
aqueous present
acids. inof
It does ClO
water,
not with
forming
2form organic
chlorinated compounds
oxidized organic
organic inhave generally
compounds,
by-products unless been
such
free as investigated
aldehydes
chlorine is and and in
vic acids solutions
present inwith low
water, reagent
forming concentrations,
oxidized organic which
compounds, it reactssuchwithas humic
aldehydes ful
an
aqueous
carboxylic
present
vic solutions
acids.
together
acids present It
with with
does low
inchlorine
water, reagent
notforming concentrations,
form chlorinated
dioxide. in which
organiccompounds,
oxidized organic it reacts
by‐products unless with humic
as free and
chlorine ful i
carboxylic acids. It does not form chlorinated organic by‐productssuch unless aldehydes
free chlorine and i
vic acids
ClO
present 2
carboxylic present
reacts
together
acids. in
with
with
It water,
phenolic
chlorine
does not forming
groups,
form oxidized
sulfur
dioxide.
chlorinated organic
compounds,
organic compounds,
and to a lesser
by‐products such
extent,
unlessas aldehydes
tertiary
free chlorineand i
present
amines andtogether
aromatic with chlorine
amines, while dioxide.
the reaction with hydrocarbons is practically
carboxylic
ClO
present acids. with
2 reacts
together It
withdoes not
phenolic
chlorine form chlorinated
groups,
dioxide. sulfur organic
compounds, by‐products
and lessernil.
to aunless freeThe
chlorine
extent, tertiari
ClO
reactivity 2
ofreacts
the with
phenoxide phenolic
ion andgroups,
the sulfur
neutral compounds,
form of the amineand is to a lesser
much extent,
greater (by tertiar
present
aminesClOtogether
and with amines,
aromatic chlorinewhile dioxide. the reaction with hydrocarbons is practically nil. Th
2 reacts with phenolic groups, sulfur compounds, and to a lesser extent, tertiar
aminesorders
several and aromatic
of magnitude) amines, thanwhile the reaction
the reactivity of the with
neutral hydrocarbons
form of the phenol is practically
and the nil. Th
aminesClOand
reactivity 2 reacts
the with
ofaromatic phenolic
phenoxide
amines, ion groups,
whileandthethesulfur compounds,
neutral
reaction andamine
formhydrocarbons
with of the to a lesser extent,
ispractically
is much tertiary
greater (b
nil. Th
reactivity of the phenoxide
protonated amine. ClO 2 tends toion and the neutral form of the amine is much greater
react with organic compounds as an electron acceptor (b
amines
several and
orders
reactivity aromatic
of theof amines,
magnitude)
phenoxide while
than
ion and the
the reaction
reactivity with
of the hydrocarbons
neutral form is
of practically
the phenol nil.
and The
th
and is reduced
several orders toof
chlorite. This makes
magnitude) than thethe
ClO neutralof
a selective
2reactivity form
oxidant ofwhose
the amine
the neutral ofisthe
reactivity
form much
generallygreater
phenol and (b th
reactivity
protonated
several
favors ofamine.
orders
organic theof phenoxide
ClOwith
magnitude)
molecules 2 tends
a ion toand
than
lone the
pair the
react
of neutral
with
reactivity
electrons. form
organic
of the of the amine
compounds
neutral formasof is much
antheelectrongreater
phenol accepto
and (by
th
protonated amine. ClO2 tends to react with organic compounds as an electron accepto
several
and
protonatedorders
is reduced oftomagnitude)
amine. chlorite.
ClO2 tendsThisthan makes
to the reactivity
react ClO
with of thecompounds
2 a selective
organic neutral
oxidantformwhoseasofanthe phenolgenerall
reactivity
electron and the
accepto
andReactivity
5.3. is reduced toPhenolic
chlorite.
withmolecules This makes ClO2 a selective oxidant whose reactivity generall
protonated
favors
and amine.
organic
is reduced ClO2 Compounds
tends
with atolone
to chlorite.with react with
pair
Thisamakes organic compounds as an electron accepto
of electrons.
ClOof 2 a selective oxidant whose reactivity generall
favors organic molecules lone pair electrons.
and is reduced
Chlorine
favors organic to
dioxidechlorite.
oxidizes
molecules This amakes
phenolic
with ClOof
lonecompounds
pair 2 a selective
and hasoxidant
electrons. whose
been used reactivity
to oxidize generally
chlori-
nated phenolic
5.3. Reactivity
favors compounds
organicwith Phenolic
molecules to reduce
Compounds
with their toxicity.
a lone pair of electrons. At neutral pH, phenols react with ClO 2
5.3. values
with Reactivity with 10
between Phenolic
3 –108 M Compounds
−1 s−1 . The reaction rate constants of phenols dissociated
Chlorine with
5.3. Reactivity dioxide oxidizes
Phenolic Compoundsphenolic compounds and has been used to oxidize chlo
with
5.3. Chlorine
ClO
Reactivity dioxide
2 are generally
with oxidizes
six
Phenolic orders
Compounds phenolic
of magnitude compounds
higher than and hasofbeen
those used to oxidize
undissociated phe- chlo
rinated
nols [79] phenolic
Chlorine
(Table 1). compounds
dioxide oxidizes
Therefore, tophenolic
at high reduce
pH, thetheir toxicity.
compounds
oxidation At neutral
and
of phenolshaswith
been pH,
ClO phenols
used react chlo
to oxidize
is favored. with
rinated phenolic compounds to reduce their toxicity. At neutral pH, 2phenols react wit
ClO
The 2Chlorine
rinatedwithphenolic
substituents dioxide
valuesof betweenoxidizes
compounds
phenols 10 3–10
greatly tophenolic
8 M−1 s−1compounds
reduce
affect their .
theirThe reaction
toxicity.
oxidation and
At
rates has
rate been
constants
neutral
with ClO . used
pH, of to
phenols oxidize
phenols react chlo
dissoci
wit
ClO2 with values between 10 –10 M s . The reaction rate constants of phenols dissoc
3 8 −1 −1 2
rinated
ated
ClO withphenolic
with ClO 2 are
values compounds
generally
between 3to
10six –10reduce
orders
8 M−1 s−1 their
of. The toxicity.
reactionAt
magnitude neutral
higher
rate thanpH,
constantsthosephenols
of of react with
undissociated
phenols dissoci
ated2 with ClO 2 are generally six orders of magnitude higher than those of undissociate
ClO 2 with values
phenols[79]
ated with ClO (Table between 10 –10atM
1). Therefore, 3 8
highs pH,
−1 −1 . The thereaction
oxidation rate
of constants
phenols with
2 are generally six orders of magnitude higher than those of undissociated
of phenols dissoci
ClO2 is favored
phenols[79] (Table 1). Therefore, at high pH, the oxidation of phenols with ClO2 is favored
ated
The with
phenols[79] ClO
substituents 2 are
(Table generally
of1).
phenols six
greatly
Therefore, orders
affect
at high of
pH, magnitude
their
theoxidation higher
oxidationrates than those
with ClO
of phenols with of
2. undissociated
ClO2 is favored
The substituents of phenols greatly affect their oxidation rates with ClO 2.
phenols[79]
The substituents of phenols greatly affect their oxidation rates with ClO2. ClO2 is favored
(Table 1). Therefore, at high pH, the oxidation of phenols with
The substituents of phenols greatly affect their oxidation rates with ClO2.
 Int. J. Mol. Sci. 2022, 23, 15660 12 of 28
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Table 1. Constants determined for ClO2 reactions with phenols.

Table1.1.Constants
Table Constantsdetermined
determinedfor
forClO
ClO2reactions
reactionswith
withphenols.
phenols.
2
Compound Solvent pH T ºC K (M−1 −1 s −1 )
−1
Compound
Compound SolventSolvent pH pH T ◦T
C ºC KK
(M(M
−1 s−s1 ))
Phenoxide ion H2O 23 4.9 × 10 7
7
Phenoxide ion H2O 23 4.9 × 10
Phenoxide ion
Phenol H2 O H2O 23 4.9 × 107
0.24
Phenol H2O 0.24
2‐Chlorophenoxide
Phenol ion H2 O H2O 2–5 23 3.5 x 107
0.24
2‐Chlorophenoxide ion H2O 2–5 23 3.5 x 107
2‐Chlorophenol
2-Chlorophenoxide ion H2 O H 2O 2–5 2–5 23 23 3.5 x1.5
107
2‐Chlorophenol H2O 2–5 23 1.5
2-Chlorophenol H2 O 2–5 23 1.5
The main products of the oxidation of phenols with chlorine dioxide are p‐benzoqui‐
The main products of the oxidation of phenols with chlorine dioxide are p‐benzoqui‐
noneThe
and various
main substituted
products chloro‐p‐benzoquinones[80].
of the oxidation of phenols with chlorineThe chlorophenols
dioxide are oxi‐
are p-benzoquinone
none and various substituted chloro‐p‐benzoquinones[80]. The chlorophenols are oxi‐
dized
and to the
various corresponding
substituted quinones. With
chloro-p-benzoquinones a large excess
[80]. The of ClO , the
chlorophenols
2 p‐quinone
are is oxi‐
oxidized to
dized to the corresponding quinones. With a large excess of ClO2, the p‐quinone is oxi‐
dized
the with ring cleavage,
corresponding quinones.forming
With a dicarboxylic
large excess acids.
of ClO Oxidation
, the of
p-quinonephenols
is and
oxidizedchloro‐
with
dized with ring cleavage, forming dicarboxylic acids. Oxidation
2 of phenols and chloro‐
phenols[81]
ring cleavage,is shown in Figure 29. acids. Oxidation of phenols and chloro-phenols [81] is
phenols[81] isforming
shown indicarboxylic
Figure 29.
shown in Figure 29.

Figure 29. Oxidation of phenols and chlorophenols by reacting with ClO2. In red, end products.
Figure29.
Figure 29. Oxidation
Oxidationof
ofphenols
phenolsand
andchlorophenols
chlorophenolsby
byreacting
reactingwith
withClO
ClO22.. In
In red,
red, end
end products.
products.

This is
is a two‐step mechanism:
mechanism: ClO2 reacts
reacts with aa phenoxide
phenoxide ion that
that is stabilized
stabilized to
This isaatwo-step
This two‐step mechanism: ClO ClO22 reacts with
with a phenoxide ionion that is
is stabilized toto
ClO2−
ClO
− and
andaaaphenoxy
phenoxy radical.
radical. This
This radical reacts rapidly with aa second
second equivalentof of ClO2
ClO22− and phenoxy radical. This radical reacts rapidly with
with a second equivalent
equivalent ofClO ClO22
to produce
to produce p‐benzoquinoneand and releaseHOCl.
HOCl. In thismechanism,
mechanism, itwaswas suggested that
to producep-benzoquinone
p‐benzoquinone andrelease
release HOCl.InInthisthis mechanism,it it wassuggested
suggested that a
that
a phenoxy
phenoxy radical
radical andand ClO
ClO 2 radical intermediate could be formed[82] (Figure 30).
radical intermediate could be formed [82] (Figure 30).
a phenoxy radical and ClO
2 2 radical intermediate could be formed[82] (Figure 30).

Figure 30.
30. Mechanism of
of oxidation of
of phenols with
with ClO22.
Figure 30. Mechanism
Figure Mechanism ofoxidation
oxidation ofphenols
phenols withClO
ClO2.

Chlorinated
Chlorinated derivatives
derivatives in
in the
the oxidations
oxidations of
of phenols
phenols with
with ClO
ClO2 can
can be
be explained
explained by
by
Chlorinated derivatives in the oxidations of phenols with ClO22 can be explained by
the
the hypochlorous
hypochlorousacid
acidformed
formedininthe
thereaction [83] (Figure 31).
reaction[83]
the hypochlorous acid formed in the reaction[83] (Figure 31).
 Int. J. Mol. Sci. 2022, 23, 15660 13 of 28
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28

Figure 31. Formation of chloroquinones in the oxidation of phenols with chlorine dioxide.
Figure31.
Figure 31.Formation
Formationofofchloroquinones
chloroquinonesininthe
theoxidation
oxidationofofphenols
phenolswith
withchlorine
chlorinedioxide.
dioxide.
5.4. Reactivity with Amines
5.4.
5.4.Reactivity
Reactivity with
with Amines
Amines
5.4.1. Reactivity with Aromatic Amines
5.4.1. Reactivity with Aromatic Amines
5.4.1.Aromatic
Reactivityamines
with Aromatic
are widely Amines
distributed in aqueous media, sometimes as degrada‐
Aromatic amines are widely distributed in aqueous media, sometimes as degradation
Aromaticofamines
tion products are widely
herbicides distributed
(in agriculture) in aqueous
or dyes media,
in industrial sometimes as degrada‐
wastewater[84].
products of herbicides (in agriculture) or dyes in industrial wastewater [84].
tion products of herbicides
The mechanism of ClO(in agriculture)
2 oxidation or dyesbegins
of aniline in industrial
with anwastewater[84].
electron transfer in the
The mechanism of ClO2 oxidation of aniline begins with an electron transfer in the first
The mechanism
first step. The amino groupof ClOis 2 oxidation of aniline
directly attached to begins withring
a benzene an electron
(and is atransfer in the
high electron
step. The amino group is directly attached to a benzene ring (and is a high electron density
first step. The amino group is directly attached to a benzene ring (and is a high
density center), so there is a change in the electron density of the nitrogen atom as it gives electron
center), so there is a change in the electron density of the nitrogen atom as it gives up charge
density
up center),
charge to the so there isring.
benzene a changereaction
in the electron density of the nitrogen atom as it gives
to the benzene ring. The reactionThepathways and pathways
products and products
obtained areobtained
differentare different
from those
up charge
from those toobserved
the benzenewith ring. The reaction
aliphatic amines. pathways
The main and products
product obtained
obtained is arequinone‐
the different
observed with aliphatic amines. The main product obtained is the quinone-azobenzene
from those observed
azobenzene derivative with aliphatic amines. The main product obtained is the quinone‐
derivative (Figure 32). (Figure 32).
azobenzene derivative (Figure 32).

Figure32.
Figure 32.Mechanism
Mechanismfor
forthe
theoxidation
oxidationof
ofaromatic
aromaticamines
amineswith
withClO
ClO22..
Figure 32. Mechanism for the oxidation of aromatic amines with ClO2.
Reaction × 10 5 5 −1−1s−−11
Reactionrates
ratesofofaniline (4.5
aniline (4.5 × 10M M s ) and and two
twosubstituted
substitutedanilines:
anilines:4-Aminoaniline
4‐Aminoan‐
(3.5 × 10 8 M−81 s−−11 ) −1
and N,N-dimethylaniline ( 4.4 × 10 6M −1−1s−−11 ) at pH 7 [75].
Reaction
iline (3.5 × 10 M ratess of) and
aniline (4.5 × 10 M s ) and
5 −1
N,N‐dimethylaniline −1
( 4.4two
× 10substituted
6 M s ) at pH anilines:
7[75].4‐Aminoan‐
iline (3.5 × 108 M−1 s−1) and N,N‐dimethylaniline ( 4.4 × 106 M−1 s−1) at pH 7[75].
5.4.2.
5.4.2.Reactivity
Reactivitywith
withAliphatic
AliphaticAmines
Amines
Aliphatic
5.4.2. Reactivityamines
with are widely
Aliphatic
Aliphatic amines are widely distributed
Amines
distributedin aqueous
in aqueousmedia, and they
media, react react
and they quickly with
quickly
ClO
with to form
2 Aliphatic freely
ClO2 to form aminesavailable
freelyare chlorine FAC
widely chlorine
available [85].
distributed Second-order
in aqueous
FAC[85]. rate
media, and
Second‐order constants for reactions
they reactfor
rate constants quickly
reac‐
ofwith
chlorine2 dioxide with aliphatic amines in FAC[85].
aqueous solutions are listedconstants
in Table 2.for reac‐
tions ClO to form
of chlorine freely
dioxide available chlorine
with aliphatic amines Second‐order
in aqueous solutionsrate are listed in Table 2.
tions of chlorine dioxide with aliphatic amines in aqueous solutions are
Table 2. Second-order rate constants for reactions of chlorine dioxide with aliphatic amines. listed in Table 2.
Table 2. Second‐order rate constants for reactions of chlorine dioxide with aliphatic amines.
Compound pH ◦C −1 s−1 )amines.
Table 2. Second‐order rate constants for reactions of chlorineTdioxide K (M
with aliphatic Refs
Compound pH T °C K (M−1 s−1−) 2 Refs
Benzylamine 8.96 25.0 4.1 × 10 [86]
Compound
Benzylamine pH
8, 96 T °C
25.0 K (M
4.1 × 10−1 s −1 )
−2 Refs
[86]
2
Benzyl-tert-butylamine
Benzylamine
Benzyl‐tert‐butylamine 8.496
8,8.4 25.0
25.0 2.92.9× ×
4.1 1010−2
2 [86]
[86]
2.9× × 4
N,N‐ Benzyl‐tert‐butylamine
N,N-dimethy‐3‐methoxybenzylamine
dimethy-3-methoxybenzylamine 8.4 25.0
27.0
27.0 2.9 1010
42 [86]
[87]
[87]
N,N‐ dimethy‐3‐methoxybenzylamine
Methylamine
Methylamine 7–10
7–10 27.0
25.0
25.0 2.9<1 ×<110 4 [87]
[85]
[85]
Methylamine
Dimethylamine
Dimethylamine 7–10
6.8–9.3
6.8–9.3 25.0
24.0
24.0 <1
5 5× ×1010
2 2 [85]
[88]
[88]
Dimethylamine
Trimethylamine 6.8–9.3 24.0
23.0 5 × 1042 4
6 [88]
[89]
Trimethylamine 23.0 6 × 10 [89]
Trimethylamine 23.0 6 × 104 [89]
Tertiaryamines
Tertiary aminesreact
reactwith
with ClO
ClO22 very
very quickly;
quickly;secondary
secondaryand and especially
especially primary
primary
aminesTertiary
react muchamines
morereact with
slowly, ClO
and very
ammoniaquickly;
does secondary
not react and
with especially
ClO
more slowly, and ammonia does not react with ClO2 at all [80,87].
2 2 at primary
all[80,87].
amines
ClO
ClO react muchmost
oxidizes
22 oxidizes morealiphatic
most slowly, and
aliphatic ammonia
tertiary
tertiary amines
amines does not react
rapidly
rapidly with ClOthem
andconverts
and converts 2 at all[80,87].
them tosecondary
to secondary
ClO
amines,also
amines, 2 oxidizes
alsoforming most aliphatic
formingaldehydes.
aldehydes. Thetertiary amines
The possible rapidly
possible mechanism
mechanism isand converts
is the
the formation them
formation of to
ofansecondary
an aminyl
aminyl
amines, also forming aldehydes. The possible mechanism is the formation of an aminyl
Int. J. Mol. Sci. 2022, 23, 15660 14 of 2

Int. J. Mol. Sci. 2022, 23, 15660 14 of 28

Int. J. Mol. Sci. 2022, 23, 15660 cation radical and chlorite followed by the elimination of a proton at alpha,
14 offorming
27 an
amine thatsubsequently hydrolyses to the aldehyde and secondary amine[8].
cation radical and chlorite followed by the elimination of a proton at alpha, forming an
5.5. Reactivity
cation with Aminofollowed
Acids, Peptides, and Proteins
amineradical and chlorite
thatsubsequently bythe
hydrolyses to thealdehyde
elimination
andofsecondary
a proton at alpha, forming an
amine[8].
amineReaction
thatsubsequently hydrolyses to the aldehyde and secondary amine
rates with amines decrease in the order tertiary amine [8].
> secondary amine >
5.5. Reactivity
primary withFor
amine. Amino Acids,amines,
tertiary Peptides,theandreaction
Proteins rate constants are in the range 103–106 M−
5.5. Reactivity with Amino Acids, Peptides, and Proteins
s−1 atReaction
neutral rates
pH andwithare between
amines 2–5inorders
decrease of magnitude
the order tertiary amine higher than for
> secondary secondary
amine > o
Reaction rates with amines decrease in the order tertiary amine > secondary
primary
primary amine.
amine
amines.ForClO 2 reacts
tertiary much
amines, thefaster with
reaction deprotonated
rate constants areamines in the range
> primary amine. For tertiary amines, the reaction rate constants are in the range
than 10with
3–106 M−1
neutral spe
s−13 atbecause
cies neutral pH and are between
deprotonated 2–5 orders of magnitude higher than for secondary or
10 –10 M−1 s−
6 1 at neutral pHamines and areare stronger
between 2–5 electron
orders of donors[90,91].
magnitude higher than for
primary amines.
The reactivityClO 2 reacts much faster with deprotonated amines than with neutral spe‐
secondary or primaryofamines.
ClO2 with ClO2biologically
reacts muchimportant
faster withmolecules
deprotonated (including
amines than amino acid
cies
with because
and neutral deprotonated
some peptides) has been
species because amines are stronger
well studied[92,93].
deprotonated electron donors[90,91].
ClO2 is an
amines are stronger effective
electron donorsand[90,91].
promising alter
Thereactivity
The reactivityofofClO
ClO2withwithbiologically
biologicallyimportant
important molecules(including (includingamino aminoacids acids
native to other chlorine‐containing
2 disinfectants, molecules
and a thorough understanding of the
and
and some
some peptides)
peptides) has
has been
been well
wellstudied[92,93].
studied ClO
[92,93]. 2 is an effective and promising alter‐
ClO is an effective and promising
chemistry of interactions with amino acids, proteins,2 and peptides is needed.
native to other
alternative chlorine‐containing disinfectants, and
andaand
athorough understanding of the
ClO2 to
chemistry of
other
reacts chlorine-containing
rapidly
interactions withwith
amino
disinfectants,
cysteine,
acids, tyrosine,
proteins, and
thorough
tryptophan
peptides is
understanding
needed. (104–107ofMthe −1 s−1), bu
chemistry of interactions with amino acids, proteins, and peptides is−2needed.
slowly ClOwith histidine, proline, alanine, and glycine (10 –10 4 M4–10
2 reacts rapidly with cysteine, tyrosine, and tryptophan (10
−5 −1
7 s7 M
−1)[93].
− 1−1s− Amino
s1−1),), but acid
ClO 2 reacts rapidly with cysteine, tyrosine, and tryptophan (10 –10 M but
have
slowly
a
slowlywith primary amine
withhistidine,
histidine, in their
proline,
proline,
structure;
alanine,
alanine, andand
this amino
glycine
glycine (10−(10
group
5 –10–10
−5 −2 M−−2 is not reactive
M1 s−s1 ))[93].
−1 −1 with
Amino acids
[93]. Amino
ClO
acids2. Amino
acids
haveaareactive
have primary with ClO
primaryamine
amine in 2 contain
intheir
their other
structure;
structure; thisreactive
this aminogroup
amino groups
group isisnotsuch
not as phenols
reactive
reactive withClO
with ClO or.2.Amino
sulfur
Amino groups
2
The
acids following
reactive order
with ClO of
2 reactivity
contain has
other been
reactive reported
groups (Figures
such as
acids reactive with ClO2 contain other reactive groups such as phenols or sulfur groups. 33
phenols andor 34).
sulfur groups.
Thefollowing
The followingorder
orderofofreactivity
reactivityhashasbeen
beenreported
reported(Figures
(Figures3333and and34).
34).

Figure 33.Reactivity
Figure33.
33. Reactivityofof cysteine,
cysteine, tyrosine,
tyrosine, tryptophan
tryptophan histidine,
histidine, and proline
andproline
proline withClOwith
ClO ClO2.
Figure Reactivity of cysteine, tyrosine, tryptophan histidine, and with 2 .2.
pH
pH= 8
=0
.
8.
0
0
6.
=
pH

0
6.
=
pH

Figure 34. Reaction rate constants of ClO2 with amino acids at 25 °C [7].

Figure 34.Reaction
Reaction rate ◦ at °C [7]. amino acid with
Figure 34.
Cysteine, duerate itsconstants
toconstants of 2ClO
of ClO
nucleophilic 2 with
with
‐SH aminoamino
is acids
acids
group, at C 25
the25most [7].
reactive
ClO2[94]. Oxidation of cysteine by ClO2 has been studied in detail, determining the stoi‐
Cysteine,
chiometry and due to its nucleophilic
reaction -SHThe
group, is the most reactive amino acid with ClO2 [94].
Cysteine, due to products[95].
its nucleophilic stoichiometry
‐SH group, isof the
the reaction
most ([ClO
reactive2]:[Cys])
amino was
acid with
Oxidation
found of cysteine
to be by ClO2 being
pH‐dependent, has been studied
1:0.9 in detail,
in 2acidic mediadetermining
and 1:3.7 the stoichiometry and
ClO 2[94]. Oxidation of cysteine by ClO has been studied in in basic
detail, media (Figure
determining the stoi
reaction
35). products [95]. The stoichiometry of the reaction ([ClO2 ]: [Cys]) was found to be
chiometry andbeing
pH-dependent, reaction products[95].
1:0.9 in The1:3.7
acidic media and stoichiometry of the
in basic media reaction
(Figure 35). ([ClO2]:[Cys]) wa
found to be pH‐dependent, being 1:0.9 in acidic media and 1:3.7 in basic media (Figur
35).
 Int. J. Mol. Sci. 2022, 23, 15660 15 of 28
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Int. J. Mol. Sci. 2022, 23, 15660 15 of 28

Figure 35. Reaction rate constants of ClO2 with amino acids at 25 °C.
Figure 35. Reaction rate constants of ClO2 with amino acids at 25 °C.
Figure 35. ReactionFigure
rate constants of ClO
35. Reaction with amino
rate 2constants acids
of ClO at 25 °C. ◦
2 with amino acids at 25 C.
At acidic pH, cysteine sulphonic acid was produced, while at alkaline pH, cystine
At acidic
acidicpH,
was obtained,
At pH,cysteine
cysteine
which sulphonic
are products acid
of acid
sulphonic the was produced,
oxidation
was while
of cysteine
produced, by at alkaline
ClO 2 (FigurepH,
36). cystine
At acidic pH, cysteine
was obtained,sulphonic
which areacid was of
products produced,
the while
oxidation of at while
cysteine
at alkaline
alkaline
by pH,
ClO
pH, cystine
cystine
2 (Figure 36).
was
obtained, which are products of the oxidation of cysteine by ClO (Figure 36).
2 36).
was obtained, which are products of the oxidation of cysteine by ClO2 (Figure

Figure 36. At acidic pH, cysteine sulfonic acid was produced. At alkaline pH, cystine was obtained.
Figure 36. At acidic pH, cysteine sulfonic acid was produced. At alkaline pH, cystine was obtained.
The reactive cysteine species is the thiolate ion, and it is proposed that the rate‐deter‐
pH,The
Figure 36. At acidicmining The reactive
reactive
step
cysteine cysteine
cysteine
involves
sulfonic species
acidspecies
electron
was is is
thethe
abstraction
produced. thiolate
thiolate
from
At ion,ion,
the
alkaline andand
thiolate
pH, it isbyproposed
it cystine
ision
proposed that that
the
ClOobtained.
was 2 to give
thecyste‐
rate-
rate‐deter‐
the
determining
mining
inyl radical. step radical
This involves
step involves electron
electron
reacts abstraction
abstraction
rapidly from
with from
the
another the
ClOthiolate
thiolate ion byion
2 molecule ClOby
to ClO
to 2atocysteinyl‐
give
2 form give
the the
cyste‐
cysteinyl
inyl radical.
radical. This This
radicalradical reacts
reacts rapidly
rapidly with
with another
another ClO
ClO molecule
molecule toto form
form aa cysteinyl-
cysteinyl‐
The reactive ClO 2 adduct,
cysteine which
species isisthedisproportionated
thiolate ion, and byittwo pH‐dependent
is proposed 2 2 pathways
that the to produce cys‐
rate‐deter‐
ClO
ClO
tine adduct,
adduct,
22and cysteicwhich
which
acid is isdisproportionated
disproportionated
(Figure 37). by by
twotwo pH-dependent
pH‐dependent pathways
pathways to produce
to produce cys‐
mining step involvescystine
electron
and
abstraction
cysteic acid
from37).
(Figure
the thiolate ion by ClO2 to give the cyste‐
tine and cysteic acid (Figure 37).
inyl radical. This radical reacts rapidly with another ClO2 molecule to form a cysteinyl‐
ClO2 adduct, which is disproportionated by two pH‐dependent pathways to produce cys‐
tine and cysteic acid (Figure 37).

Figure 37.
37. Proposed
Proposed mechanism
mechanism for
for the
the reactions
reactions between
between ClO
ClO2 and cysteine.
Figure 2 and cysteine.
Figure 37. Proposed mechanism for the reactions between ClO2 and cysteine.
The reactivity of glutathione is like that of cysteine, and similar steps in the reaction
with The
ClO2reactivity
ClO of glutathione
2 are proposed. A study is of like that of cysteine,
the oxidation of thiolsand similar
(Cys
(Cys andsteps
and GSH)in
GSH) bythe
by reaction
ClO
ClO 22 with
with ClO
varying
varying pH2 are
pH hasproposed.
has been A study
beenperformed.
performed. of rate
The
The the
rateoxidation
constant
constant foroffor
thiols
Cys and(Cys
Cys GSHGSH
and and GSH)
increased by ClO
with
increased with
pH2 from
with pH
3.2
fromto 3.2
varying5.9.pH
toThe pH-dependent
has
5.9. been
The performed.
pH‐dependentbehavior
The suggests
rate
behavior constantthatfor
suggests deprotonated
Cysdeprotonated
that and GSH thiols are the
increased
thiols reactive
with
are the pH
re‐
Figure 37. Proposed mechanism for the reactions between ClO2 and cysteine. −− )
species.
from 3.2 The
to rate
5.9. constants
The [94,95]
pH‐dependent for the
behavior reactions
suggests
active species. The rate constants[94,95] for the reactions of ClO of ClO
that with
deprotonated cysteinyl
thiolsanion
2 2 with cysteinyl anion (CSare (CS
the re‐
and glutathione
active species. The anion (GS−−) )are
rate (GS
anion 1.0× ×
are1.0
constants[94,95] 10
10for Ms−−1reactions
8 −1
8 Mthe
1 s−1 and 1.48× 10
and 1.4 of ClO
× 10
8
s−1M
M2 −1with
−1 s−1 , respectively.
, cysteinyl anion
respectively. (CS−)
Similar
The reactivity of glutathione
Similar rate constants
is like that of cysteine, and similar steps in the reaction
and glutathione anionsuggest
(GS ) are
− common
1.0 × 10oxidation
8 M s and
−1 −1 mechanisms
1.4 × 10 M8 for cysteine
−1 and glutathione
s , respectively.
−1 Similar
with ClO2 are proposed.
by ClO2 . A study of the oxidation of thiols (Cys and GSH) by ClO2 with
varying pH has been performed. The rate constant for Cys and GSH increased with pH
from 3.2 to 5.9. The pH‐dependent behavior suggests that deprotonated thiols are the re‐
active species. The rate constants[94,95] for the reactions of ClO2 with cysteinyl anion (CS−)
and glutathione anion (GS−) are 1.0 × 108 M−1 s−1 and 1.4 × 108 M−1 s−1, respectively. Similar
Int. J. Mol. Sci. 2022, 23, 15660 16 of 28

Int. J. Mol. Sci. 2022, 23, 15660 16 of 27

rate constants suggest common oxidation mechanisms for cysteine and glutathione by
ClO2.
In the reactions of histidine, tryptophan, and tyrosine with ClO2, different products
In the reactions of histidine, tryptophan, and tyrosine with ClO2 , different products
are obtained depending on the molar ratios of ClO2. The products also vary if the reaction
are obtained depending on the molar ratios of ClO2 . The products also vary if the reaction
is done in the presence or absence of oxygen. With an excess of ClO2, low molecular weight
is done in the presence or absence of oxygen. With an excess of ClO2 , low molecular weight
compounds are
compounds are obtained.
obtained.
ClO 2 oxidation of tyrosine occurs predominantly in its phenolic structure, resulting
ClO2 oxidation of tyrosine occurs predominantly in its phenolic structure, re-
in the formation
sulting of dopaquinone
in the formation and dopachrome
of dopaquinone at pH 6–7. Cyclisation
and dopachrome at pH 6–7. ofCyclisation
dopaquinone
of
occurred at pH > 4 to form cyclodopa, which was subsequently oxidized
dopaquinone occurred at pH > 4 to form cyclodopa, which was subsequently oxidized to do‐
pachrome[96]
to dopachrome(Figure 38). 38).
[96] (Figure

Figure 38.
Figure 38. Reaction
Reaction pathways
pathways proposed
proposed for
for ClO
ClO2 oxidation
oxidation of
of the
the amino
amino acid
acid tyrosine.
tyrosine.
2

The product
The product ofof tryptophan
tryptophanoxidation
oxidationbybyClO ClO2 was identified as N‐formyl alkyl‐nu‐
2 was identified as N-formyl alkyl-
renine [97].
nurenine The
[97]. initial
The reaction
initial reaction between
betweentryptophan
tryptophanand andClO
ClO22isisaaone‐electron
one-electron oxidation
oxidation
to form aa tryptophan
tryptophan radical
radical cation
cation and
and aa chlorite
chlorite ion.
ion. The radical cation deprotonates to
Int. J. Mol. Sci. 2022, 23, 15660 form a neutral
neutral tryptophilic
tryptophilic radical,
radical, which
which reacts
reacts rapidly
rapidly with
with aa second
second ClO
ClO22 molecule
molecule to
17 of to
28
give aa short-lived
short‐livedadduct
adduct(k (kobs = 48 ss−
obs = −11
))with formation of the C‐OClO
with formation of the C-OClO bond. This adduct
decomposes to
decomposes to give
give HOCl
HOCl [8][8] (Figure
(Figure 39).

Figure 39.
Figure 39. Proposed
Proposed reaction
reaction mechanism
mechanism for
for the
the attack
attack of
ofClO
ClO2 to
to tryptophane.
tryptophane.
2

The reaction consumes two ClO2 per Trp and forms chlorite and HOCl (Figure 40).
Int. J. Mol. Sci. 2022, 23, 15660 17 of 27
Figure 39. Proposed reaction mechanism for the attack of ClO2 to tryptophane.

The
The reaction
reaction consumes two ClO
consumes two ClO2 per Trp and forms chlorite and HOCl (Figure 40).
2 per Trp and forms chlorite and HOCl (Figure 40).

Figure 40. Stoichiometry of the reaction between tryptophan and ClO22..

5.6. Oxidation
5.6. Oxidation of of Peptides
Peptides and
and Proteins
Proteins by
by ClO
ClO22
ClO22 isisaaselective
ClO selectiveoxidant
oxidant that
that only
only reacts
reacts withwithfive five
aminoamino
acids:acids: cysteine,
cysteine, ty-
tyrosine,
rosine, tryptophan, histidine, and proline. Cysteine, tyrosine, and
tryptophan, histidine, and proline. Cysteine, tyrosine, and tryptophan have much fastertryptophan have
much faster
reaction rate reaction rate
constants. constants.
Mass Mass spectrometry
spectrometry and nuclear
and nuclear magnetic magnetic
resonance resonance
spectroscopy
spectroscopy show that tryptophan residues are converted to N-formyl
show that tryptophan residues are converted to N‐formyl alkyl‐nurenine and tyrosine alkyl-nurenine
and tyrosine residues are converted to 3,4-dihydroxyphenylalanine (DOPA) or 2,4,5-
residues are converted to 3,4‐dihydroxyphenylalanine (DOPA) or 2,4,5‐trihydroxy‐
trihydroxyphenylalanine (TOPA) in ClO2 -treated proteins. Tryptophan residues are critical
phenylalanine (TOPA) in ClO2‐treated proteins. Tryptophan residues are critical targets
targets in the reaction between ClO2 and proteins [98,99], causing protein fragmentation
in the reaction between ClO2 and proteins[98,99], causing protein fragmentation and de‐
and denaturation. Inactivation of influenza A virus when treated with ClO2 has been
naturation. Inactivation of influenza A virus when treated with ClO2 has been observed
observed due to oxidation of a tryptophan residue (W153 ) that was converted to NFK in
due to oxidation of a tryptophan residue (W153) that was converted to NFK in hemagglu‐
hemagglutinin, restricting its ability to bind to host cells [100].
tinin, restricting its ability to bind to host cells[100].
Using bovine serum albumin and glucose-6-phosphate dehydrogenase (G6PD) from
Using bovine serum albumin and glucose‐6‐phosphate dehydrogenase (G6PD) from
baker’s yeast (Saccharomyces cerevisiae) as model proteins, it was shown that the antimi-
baker’s yeast (Saccharomyces cerevisiae) as model proteins, it was shown that the antimicro‐
crobial activity of ClO2 is mainly attributed to its protein denaturing activity. Elemental
bial activity of ClO2 is mainly attributed to its protein denaturing activity. Elemental anal‐
analyses show that oxygen atoms, but not chlorine atoms, are incorporated into the ClO2 -
yses show
treated that providing
protein, oxygen atoms,
direct but not chlorine
evidence that ClOatoms, are incorporated into the ClO2‐
2 oxidizes the protein. For glutathione, a
Int. J. Mol. Sci. 2022, 23, 15660 treated protein, providing direct evidence that ClO 2 oxidizes the protein. For glutathione,
tripeptide consisting of glycine, cysteine, and glutamic acid, the ClO2 -reactive site18isofthe 28
athiol
tripeptide
group, consisting of glycine,
and the oxidation cysteine,
products areand
like glutamic acid, the(Table
those of cysteine ClO2‐reactive
3). site is the
thiol group, and the oxidation products are like those of cysteine (Table 3).
Table 3. Constants determined for ClO2 reactions with peptides and proteins.
Table 3. Constants determined for ClO2 reactions with peptides and proteins.
Compound pH T ◦C K (M−1 −1
s−1−1)
Compound pH T °C K (M s )
Peptides
Peptides
Glutathione 5.9 25.0 25.0 × 10
1.41.4 8
Glutathione 5.9 × 108
Proteins
Proteins
Bovine
Bovine serumserum albumin
albumin 7.0 7.0 25.0 25.0 6.46.4
Glucosa‐6‐fosfato deshidrogenasa
Glucosa-6-fosfato deshidrogenasa 7.0 7.0 25.0 25.0 9.79.7

5.7. Oxidation of NADH by Chlorine Dioxide

5.7. Oxidation of NADH by Chlorine Dioxide
The oxidation of dihydronicotinamide adenine dinucleotide (NADH) by chlorine di‐
The oxidation of dihydronicotinamide adenine dinucleotide (NADH) by chlorine
oxide in in
dioxide phosphate‐buffered
phosphate-buffered solutions (pH(pH
solutions 6–8)6–8)
is very fast,fast,
is very withwith
a second‐order rate con‐
a second-order rate
stant of 3.9 × 10 6 M−1 s−1 at 24.6 °C. The stoichiometry is shown in Figure 41.
constant of 3.9 × 106 M−1 s−1 at 24.6 ◦ C. The stoichiometry is shown in Figure 41.

Figure 41. Reaction of NADH with ClO22..

Unlike many oxidants in which NADH reacts by hydride transfer, the proposed
mechanism is a one-electron
one‐electron transfer from
from NADH
NADH to to ClO
ClO22. First, chlorine dioxide accepts
− and the radical cation NADH + . Then, the sub-
an electron from NADH to form ClO22− and the radical cation NADH+. Then, the subse‐
sequent sequence of very rapid deprotonation with the transfer of H+ to H O and the
quent sequence of very rapid deprotonation with the transfer of H to H2O and the
+ 2 transfer
transfer of an electron to a second equivalent of ClO gives as products 2ClO − , H O + , and
of an electron to a second equivalent of ClO2 gives 2 as products 2ClO22 , H3O , and
− +

NAD+ [101](Figure
NAD+[101] (Figure42).
42).
 Unlike many oxidants in which NADH reacts by hydride transfer, the proposed
mechanism is a one‐electron transfer from NADH to ClO2. First, chlorine dioxide accepts
an electron from NADH to form ClO2− and the radical cation NADH+. Then, the subse‐
quent sequence of very rapid deprotonation with the transfer of H+ to H2O and the transfer
Int. J. Mol. Sci. 2022, 23, 15660 18 of 27
of an electron to a second equivalent of ClO2 gives as products 2ClO2−, H3O+, and
NAD+[101] (Figure 42).

Figure42.
Figure 42. Proposed
Proposedmechanism
mechanismof
ofNADH
NADHoxidation
oxidationby
byClO
ClO22..

The
The mechanism which ClO
mechanism by which ClO22influences
influencesbiomolecules
biomoleculesisisbased
basedonon
thethe strong
strong in-
inter‐
terference with redox processes occurring in mitochondrial and cell membranes,
ference with redox processes occurring in mitochondrial and cell membranes, e.g., on thee.g., on
the NADH/NAD + system, which is responsible for cellular respiration and for mediating
NADH/NAD + system, which is responsible for cellular respiration and for mediating ATP
ATP synthesis [102].
synthesis[102].

Int. J. Mol. Sci. 2022, 23, 15660
6.
6. Oxidation
Oxidation of
of Hemoglobin
Hemoglobin by by ClO
ClO22
Chlorine
Chlorine dioxide is an oxidizing agent
dioxide is an oxidizing agentthat
thatconverts
convertshemoglobin
hemoglobin(oxygen-carrying
(oxygen‐carrying
protein)
protein) into methemoglobin, which cannot bind to other oxygen molecules
into methemoglobin, which cannot bind to other oxygen molecules and
and therefore
therefore
hinders oxygenation of the body. In these cases, as when ingested
hinders oxygenation of the body. In these cases, as when ingested in largein large quantities,
quantities, ClO2
ClO2 oxidizes ferrous iron2+(Fe2+ ) and transforms it into ferric iron 3+
(Fe3+ ), and hemoglobin
oxidizes ferrous iron (Fe ) and transforms it into ferric iron (Fe ), and hemoglobin be‐
becomes methemoglobin, which causes respiratory failure [33].
comes methemoglobin, which causes respiratory failure[33].
Methemoglobin is an oxidized form of hemoglobin that is unable to carry oxygen
Methemoglobin is an oxidized form of hemoglobin that is unable to carry oxygen in
in the blood and is therefore unable to release it effectively into the body’s tissues, thus
the blood and is therefore unable to release it effectively into the body’s tissues, thus pre‐
preventing oxygenation of the body. High levels of methemoglobin can have other risks.
venting oxygenation of the body. High levels of methemoglobin can have other risks. Me‐
Methemoglobin-forming chemicals can oxidate the ferrous nucleus of hemoglobin 2+(Fe2+ )
themoglobin‐forming3+chemicals can oxidate the ferrous nucleus of hemoglobin (Fe ) into
into trivalent iron3+(Fe ), transforming hemoglobin into methemoglobin. Its toxic 19 effects
trivalent iron (Fe ), transforming hemoglobin into methemoglobin. Its toxic effectsofare 28
are due to the reduced oxygen-carrying capacity of methemoglobin, resulting in cellular
due to the reduced oxygen‐carrying capacity of methemoglobin, resulting in cellular hy‐
hypoxia [103,104] (Figure 43).
poxia[103,104] (Figure 43).

pathology.
Figure 43. Methemoglobinemia pathology.

In 2015,
2015, the
the first
firstcase
caseofofaachild
childwith
withmethemoglobinemia
methemoglobinemia (high methemoglobin
(high methemoglobin levels)
lev‐
after accidentally
els) after ingesting
accidentally chlorine
ingesting dioxidedioxide
chlorine appeared in the literature.
appeared The authors
in the literature. Thereported
authors
that “the that
reported patient had
“the profound
patient hypoxia, hypoxia,
had profound did not respond
did not to oxygentotherapy,
respond oxygen and required
therapy, and
endotracheal intubation to maintain a normal oxygen level”
required endotracheal intubation to maintain a normal oxygen level” [105]. [105].
In another publication in 2013, a person who tried to commit commit suicide
suicide and ingested
ingested
less than 100 mL of a 28% sodium chlorite solution had 40% methemoglobin in his blood,
requiring
requiring aa kidney
kidney transplant
transplant andand transfusions
transfusions to
to save
save his
his life [106].
life[106].
For
For these
these reasons,
reasons, specialists
specialists conclude
conclude that
that chlorine
chlorine dioxide
dioxide notnot only
only deoxygenates
deoxygenates
the
the body, it can cause low tissue oxygenation capacity even in small doses, a situation
body, it can cause low tissue oxygenation capacity even in small doses, a situation that
that
can put people’s lives at
can put people’s lives at risk. risk.

7. Toxicity of ClO2
In December 2019, a new respiratory illness emerged in Wuhan, China. The source
of this infection was identified as a new coronavirus, related to other coronaviruses that
had previously caused outbreaks of SARS (Severe Acute Respiratory Syndrome) between
2002 and 2004 and MERS (Middle East Respiratory Syndrome) in 2012 (National Institutes
 Int. J. Mol. Sci. 2022, 23, 15660 19 of 27

Int. J. Mol. Sci. 2022, 23, 15660
of intoxication can be divided into three: inhalation, oral, and parenteral routes (Figure or
44).chlorine derivatives as preventive or therapeutic agents against COVID-19 [107–109].
7. Toxicity of ClO2
In December 2019, a new respiratory illness emerged in Wuhan, China. The source
of this infection was identified as a new coronavirus, related to other coronaviruses that
had previously caused outbreaks of SARS (Severe Acute Respiratory Syndrome) between
2002 and 2004 and MERS (Middle East Respiratory Syndrome) in 2012 (National Insti-
tutes of Health, 2020). This virus was named “severe acute respiratory syndrome coro-
navirus 2” (SARS-CoV-2) and the disease resulting from infection with this virus was
named “COVID-19”. On 11 March 2020, the World Health Organization WHO declared
COVID-19 a pandemic. Coronaviruses are a group of enveloped RNA viruses that can dam-
age multiple organ systems. Like other coronaviruses, SARS-CoV-2 is a spherical particle
with glycoprotein spikes on its surface. Coronaviruses enter host cells when a region of the
spike, known as the “receptor-binding domain”, binds to angiotensin-converting enzyme
2 (hACE2) in human cells. The viral membrane then fuses with the host cell membrane,
allowing the viral genome to enter the host cell.
During the COVID-19 pandemic, the consumption of chlorine dioxide solutions has
been promoted through different avenues (social networks, websites, mass media) for the
treatment or prevention of SARS-CoV-2 infection. Different regulatory agencies (such as
the European Medicines Agency and the US Food and Drug Administration) and scientific
societies have drafted and issued statements warning about the lack of scientific evidence
for their efficacy in COVID-19 disease and the associated risks to human health, and even
demanded the withdrawal of these products from the market. 20 of 28
The FDA (Food and Drug Administration) in the United States of America and
COFEPRIS (Comisión Federal para la Protección contra Riesgos Sanitarios) in Mexico
state thathave
Studies the consumption
described theoftoxic
ClOeffects
2 causes
ofkidney
chlorineand liver failure
dioxide andThe
ingestion. destroys red blood
main routes
cells. To date, there is no scientific evidence to support the use of chlorine dioxide
Studies have described the toxic effects of chlorine dioxide ingestion. The main routes
of intoxication can be divided into three: inhalation, oral, and parenteral routes (Figure 44).

Figure 44. The main routes of ClO2 poisoning.

Chlorine dioxide can be rapidly absorbed through the gastrointestinal tract. Peak
Figure 44. The
blood main routes of
concentration ClO2 can
levels poisoning.
be reached within 1 h after a single dose administered
orally. It can also be absorbed slowly through shaved skin with a median absorption time
ofChlorine
22 h. Intact dioxide can dioxide
chlorine be rapidly absorbedtothrough
is unlikely the gastrointestinal
be absorbed tract.its
by inhalation given Peak
highly
blood concentration levels can be reached within 1 h after a single dose
reactive nature; it is more likely that its derivatives can be absorbed. Chlorine dioxide is administered
orally. It can alsotobechlorite,
metabolized absorbed slowly and
chlorate, through
mainlyshaved skin with
chloride. Mostaofmedian absorption chlorine
the administered time
of 22 h. Intact chlorine dioxide is unlikely to be absorbed by inhalation
dioxide and its metabolites remain in the plasma, followed by the kidneys, lungs, stomach,given its highly
reactive nature;
intestine, it is
liver, andmore likely
spleen. that its
About 43%derivatives can be absorbed.
of orally administered Chlorine
chlorine dioxide
dioxide is
is excreted
metabolized
in the urine to chlorite,
and feceschlorate,
within 72and
h. mainly chloride. Most of the administered chlorine
dioxide and its metabolites remain
It is important to note that neither in the chlorine
plasma, dioxide
followed byitsthe
nor kidneys, lungs,
derivatives stom‐
have undergone
ach,any
intestine, liver, and spleen. About 43% of orally administered chlorine dioxide
evaluation or authorization by the competent authorities to ensure that the benefit/risk is ex‐
creted in the urine and feces
ratio is positive for the population.within 72 h.
It isThere
important is no to note thatscientific
published neither chlorine
evidencedioxide
that hasnor its derivatives
positively have under‐
considered the use of
gone any evaluation
chlorine dioxide or or its
authorization
derivatives by
as athe competent
preventive orauthorities
therapeutictoagent
ensure that the
against ben‐
COVID-19
efit/risk ratio is positive for the population.
There is no published scientific evidence that has positively considered the use of
chlorine dioxide or its derivatives as a preventive or therapeutic agent against COVID‐19
administered by inhalation, oral, or parenteral routes[109,110]. Some of the risks of con‐
suming ClO2 and its derivatives are listed in Figure 45.

Int. J. Mol. Sci. 2022, 23, 15660
ach, intestine, liver, and spleen. About 43% of orally administered chlorine dioxide is ex‐
creted in the urine and feces within 72 h.
It is important to note that neither chlorine dioxide nor its derivatives have under‐
gone any evaluation or authorization by the competent authorities to ensure that the ben‐
efit/risk ratio is positive for the population. 20 of 27
There is no published scientific evidence that has positively considered the use of
chlorine dioxide or its derivatives as a preventive or therapeutic agent against COVID‐19
administered by
administered by inhalation,
inhalation, oral,
oral,ororparenteral
parenteralroutes[109,110]. Some
routes [109,110]. of the
Some of risks of con‐
the risks of
suming ClO 2 and its derivatives are listed in Figure 45.
consuming ClO and its derivatives are listed in Figure 45.
2
Figure 45.
Figure 45. Serious adverse reactions
reactions after
after direct
direct consumption
consumption of
of chlorine
chlorine dioxide.
dioxide.
The median
median oral
oral lethal
lethal dose
dose (LD50)
(LD50) has
has been
beenestimated
estimatedto
tobebe9494mg/kg
mg/kg body weight
and it
it is
is therefore
therefore considered
considered aa moderately
moderately toxic
toxic and
and hazardous
hazardous substance.
substance. The
The Spanish
Spanish
Agency for Medicines and Health Products
Agency for Medicines and Health Products (AEMPS) (AEMPS) warns of serious health
serious health risks from
from
the consumption of chlorine dioxide
the consumption of chlorine dioxide[111].[111].
8. Antimicrobial Activity of ClO2
Chlorine dioxide acts as an oxidizing biocide and controls the growth of Gram-positive
and Gram-negative bacteria by inhibiting the transport of nutrients through the cell wall by
destroying it [112]. Its effectiveness is similar or even superior in some respects to that of
other known oxidants such as ozone or chlorine. It behaves as an oxidizing agent through
electronic exchange, which allows it to oxidize any type of organic compound, from viruses
and bacteria to proteins, hence its frequent use to purify water or certain surfaces. Pereira
et al., 2008, compared the efficacy of HOCl, ClO2 , and O3 in the inactivation of Cryptosporid-
ium oocyst in a public water supply from Brazilian South conditions. Experiments were
carried out in samples containing 2 × 104 oocysts/mL of C. parvum purified from feces
of experimentally contaminated calves. By using HOCl, the maximum inactivation rate
obtained was 49.04% after 120 min, at 2 ppm. ClO2 at 5 ppm inactivated 90.56% of oocysts
after 90 min of contact. O3 was the most effective product, rendering an inactivation of
100% at 24 ppm.
In the case of enveloped viruses, chlorine dioxide reacts directly with amino acid
residues of proteins located on the enveloped viral surface; in the case of non-enveloped
viruses, ClO2 acts on the viral genome, affecting the ribonucleic acid RNA in the cell.
By this mechanism, chlorine dioxide prevents the production of proteins and, therefore,
promotes the elimination of the virus. Chlorine dioxide is a strong oxidizing agent that
can be applied both in solution and in a gaseous state. It has bactericidal, fungicidal, and
virucidal properties. Several food-related microorganisms, including Gram-negative and
Gram-positive bacteria, yeasts and mold spores, and Bacillus cereus spores, were tested for
susceptibility to 0.08 mg/L gaseous ClO2 for 1 min at 90% relative humidity [17]. In this
screening, according to Vandekinderen et al., 2009, the resistance of the different groups of
microorganisms to gaseous ClO2 generally increased in the order of Gram-negative bacteria,
Gram-positive bacteria, yeast spores, molds, and Bacillus cereus spores. Factors influencing
the antimicrobial efficacy of gaseous ClO2 were its concentration, contact time, relative
humidity, and temperature. Yeasts were more resistant to ClO2 than Gram-negative and
Gram-positive bacteria. Significantly, ClO2 has been shown to be effective in inactivating
Bacillus anthracis spores [113–115] in government and commercial buildings; however,
Bacillus cereus was little affected by ClO2 [113–116].
Int. J. Mol. Sci. 2022, 23, 15660 21 of 27

The resistance of different groups of microorganisms to gaseous ClO2 generally in-

Int. J. Mol. Sci. 2022, 23, 15660
Int. J. Mol. Sci. 2022, 23, 15660
creased in the order of Gram-negative bacteria, Gram-positive bacteria, yeast and mold
spores, and Bacillus cereus spores. ClO2 arguably provides the complete solution for disin-
22 of 28
fection because it kills the widest variety of microbes in short contact times and has22fewer
of 28
corrosive effects on surfaces. In addition, the use of ClO2 avoids the threat of microbial
resistance (Figure 46).

Figure 46. ClO2 antimicrobial spectrum of activity.

Figure 46.
Figure 46. ClO
ClO22 antimicrobial spectrum of activity.
activity.
The oxidative capacity of chemicals denotes the number of electrons a molecule can
The
The oxidative capacity of
oxidative capacity ofchemicals
chemicalsdenotes
denotesthe the number
number of of electrons
electrons a molecule
a molecule can
accept
can
from
accept
surrounding
from surrounding
molecules. In the
molecules. In
case
the
of ClO₂,
case of
it can
ClO , it
gain
can
five electrons
gain five
from
electrons
accept from surrounding molecules. In the case of ClO₂, it can 2 gain five electrons from
microbial
from species
microbial per molecule,
species making
per molecule, it a superior
making biocide
it a superior to alternative
biocide oxidants,
to alternative which
oxidants,
microbial species per molecule, making it a superior biocide to alternative oxidants, which
can
which normally only
can normally gain two.
only gainThis enhanced
two. effect
This enhanced is attributed to its
effect is attributed two‐step reduction
to its reduction
two-step
can normally only gain two. This enhanced effect is attributed to its two‐step
(Figure 47).
reduction (Figure 47).
(Figure 47).

Figure 47.Reduction
Reduction ofchlorine
chlorine dioxide.
Figure 47. Reduction of
Figure 47. of chlorine dioxide.
dioxide.
Figure41
Figure 41shows
showsthe thereduction
reductionofofClO ClO₂. In the
2 . In thefirst
firststep,
step,ClOClO₂2 isisreduced
reducedto tochlorite
chlorite
Figure 41 shows the reduction of ClO₂. In the first step, ClO₂ is reduced to chlorite
afteraccepting
after acceptingoneoneelectron
electron and
and then
then further
further reduced
reduced by accepting
by accepting fourfour additional
additional elec‐
electrons
after accepting one electron and then further reduced by accepting four additional elec‐
trons
and andhydrogen
four four hydrogen
atomsatoms[117].
[117]. ThisThis two‐step
two-step process
process allows
allows it it
totosequester
sequesteraagreater
greater
trons and four hydrogen atoms[117]. This two‐step process allows it to sequester a greater
numberof
number ofelectrons
electronsfrom
frommicrobes
microbescompared
comparedto toother
otheroxidants.
oxidants.This Thismeans
meansthat thatchlorine
chlorine
number of electrons from microbes compared to other oxidants. This means that chlorine
dioxidewill
dioxide willhave
haveaareduced
reducedcorrosive
corrosiveeffect
effecton onthe
thesurfaces
surfacesto towhich
whichititisisapplied,
applied,while
while
dioxide will have a reduced corrosive effect on the surfaces to which it is applied, while
havingaagreater
having greaterability
abilityto
tokill.
kill.The
Thereason
reasonwhy whyoxidizing
oxidizingagents
agentssuchsuchas asClO
ClO₂ arepreferred
2 are preferred
having a greater ability to kill. The reason why oxidizing agents such as ClO₂ are preferred
tonon-oxidizing
to non‐oxidizingdisinfectants
disinfectantsisisdue
dueto totheir
theirproven
provenefficacy
efficacyagainst
againstbacterial
bacterialspores
sporesandand
to non‐oxidizing disinfectants is due to their proven efficacy against bacterial spores and
other
othermicroorganisms
microorganismsininshortshortcontact
contacttimes.
times.
otherChlorine
microorganismskills in short contactthrough
times.
Chlorinedioxide
dioxide killspathogens
pathogens throughelectron electronexchange,
exchange,sequestering
sequesteringelectrons
electrons
from Chlorine dioxide kills pathogens through electron exchange, organelles,
sequestering electrons
from the microorganism’s structures, such as cell walls, membranes, organelles, genetic
the microorganism’s structures, such as cell walls, membranes, and and ge‐
from the microorganism’s
materials, causing a molecular structures,
imbalance suchthatasleads
cell walls,
the membranes, organelles, and Mi- ge‐
netic materials, causing a molecular imbalance thattoleads death
to theofdeath
the microorganism.
of the microorgan‐
netic materials,
crobes causing a molecular
cannot develop imbalance thatreaction
leads to the death of theare
microorgan‐
ism. Microbes cannot resistance to ClO
develop resistance 2 due to the
to ClO₂ due to themechanism and
reaction mechanism destroyed.
and are
ism. Biocides,
Microbes such
cannot develop resistance to ClO₂ due to the reaction
as quaternary ammonium compounds and triamines, contribute mechanism and areto
destroyed.
destroyed.microbial resistance, and several resistant strains, such as E. coli and C. difficile
increased
Biocides, such as quaternary ammonium compounds and triamines, contribute to in‐
spores,Biocides,been
such as quaternary ammonium compounds and triamines, contribute ClOto in‐
creasedhave
microbial identified.
resistance, In andcontrast,
several microbial resistance
resistant strains, suchis not
as E.possible
coli andwithC. difficile
2
creased microbial resistance, and several resistant strains, such as E. coli and C. difficile
spores, have been identified. In contrast, microbial resistance is not possible with ClO₂
spores, have been identified. In contrast, microbial resistance is not possible with ClO₂
because of its mode of action, which is modifying microbial structures and targeting their
because of its mode of action, which is modifying microbial structures and targeting their
physiological molecular integrity. This induces membrane rupture, disrupting protein
physiological molecular integrity. This induces membrane rupture, disrupting protein
function, inhibiting RNA synthesis, and killing the microbes.
function, inhibiting RNA synthesis, and killing the microbes.
Int. J. Mol. Sci. 2022, 23, 15660 22 of 27

because of its mode of action, which is modifying microbial structures and targeting their
physiological molecular integrity. This induces membrane rupture, disrupting protein
function, inhibiting RNA synthesis, and killing the microbes.

9. Conclusions
In this study, the research has focused on two complementary aspects: (i) on analyzing
the reactivity of ClO2 and its possible reactions with organic and inorganic compounds;
and (ii) its potential uses and its toxicity if consumed out of specification.
ClO2 is added to drinking water to protect people from harmful bacteria and other
microorganisms. The Environmental Protection Agency (EPA) recognizes chlorine dioxide
use as a drinking water disinfectant, and it is included in WHO’s Guidelines for drinking-
water quality. When added to drinking water, it helps destroy bacteria, viruses, and
some types of parasites that can make people sick, such as Cryptosporidium parvum and
Giardia lamblia. EPA regulates the maximum concentration of chlorine dioxide in drinking
water to be no greater than 0.8 ppm. In medical settings, ClO2 can be used to help sterilize
equipment, surfaces, rooms, and tools. In hospitals and other healthcare environments,
ClO2 helps to sterilize medical and laboratory equipment, surfaces, rooms, and tools.
Researchers have found that at appropriate concentrations, ClO2 is both safe and effective
at helping to eliminate Legionella bacteria in hospital environments. Legionella pneumophila
bacteria can cause Legionnaires’ disease, a potentially deadly type of pneumonia [118,119].
ClO2 is highly reactive, reacting to oxidize inorganic and organic compounds found in
water, including humic and fulvic acids, forming oxidized organic compounds such as alde-
hydes and carboxylic acids. Inside cells, ClO2 oxidizes phenolic compounds, amines, amino
acids, peptides, and proteins, as well as NADH, whose key function is to regulate electron
and proton exchange and energy production in all cells. Their effect on biomolecules arises
from interference with redox processes, modifying the electronic exchanges that occur in
complexes I-IV of mitochondrial respiration and cell membranes.
Depending on concentration and frequency, it is toxic to human health, hence there are
limits to its exposure to ensure safe use. The mean oral lethal dose LD50 for rats is 94 mg
per kg body weight; it is therefore classified as a moderately toxic and hazardous substance.
According to the classification provided by companies to the European Chemical Agency
(ECHA) in the REACH registrations, this substance is fatal by inhalation, toxic by ingestion,
causes severe skin burns and eye damage, and is very toxic to the environment and aquatic
life, with long-lasting effects.
During the COVID-19 pandemic, the consumption of ClO2 solutions has been pro-
moted by non-scientists and non-medical people through different avenues (social net-
works, websites, mass media) for the treatment or prevention of SARS-CoV-2 infection. To
date, there is no scientific evidence to uphold the use of ClO2 or chlorine derivatives as
preventive or therapeutic agents against COVID-19. Its action is unproven, and deaths have
been reported, so health agencies such as the US Food and Drug Administration (FDA)
have officially stated that they do not recommend taking it. Some of the common symptoms
of intoxication include severe vomiting and diarrhea, anemia, severe liver failure, low blood
pressure, arrythmia, and methemoglobinemia [120].
Ingestion of ClO2 outside the regulations approved by health authorities can have
serious results, including intestinal perforation. It is important to emphasize the need to
follow communications and warnings from health authorities and governmental institu-
tions. There are documented cases, both in the scientific literature and in the popular media,
of severe side effects caused by ClO2 poisoning. According to court documents, in the
US alone, poison control centers have treated more than 16,000 cases of chlorine dioxide
poisoning from 2014 to the end of 2020 [121].

Author Contributions: Conceptualization, C.M.C.A. and C.A.J.; investigation, C.M.C.A. and C.A.J.;
writing—review and editing, C.M.C.A., C.A.J., J.M.P.d.l.L., E.P.-L. and F.J.P.; supervision, C.M.C.A.,
C.A.J. and J.M.P.d.l.L. All authors have read and agreed to the published version of the manuscript.
Int. J. Mol. Sci. 2022, 23, 15660 23 of 27

Funding: This research was funded by project APOGEO (Cooperation Program INTERREG-MAC
2014–2020, with European Funds for Regional Development-FEDER. “Agencia Canaria de Inves-
tigación, Innovación y Sociedad de la Información (ACIISI) del Gobierno de Canarias”, project
ProID2020010134, Caja Canarias, project 2019SP43 and Spanish Ministry of Economy and Competi-
tiveness (Grant PID2019-105838RB-C31).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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