molecules
Review
Porphyrins as Catalysts in Scalable Organic Reactions
Juan C. Barona-Castaño † , Christian C. Carmona-Vargas † , Timothy J. Brocksom
and Kleber T. de Oliveira *
Departamento de Química, Universidade Federal de São Carlos, São Carlos 13565-905, Brazil;
[email protected] (J.C.B.-C.); [email protected] (C.C.C.-V.); [email protected] (T.J.B.)
* Correspondence: [email protected]; Tel.: +55-16-3351-8083
† These authors contributed equally to this work.
Academic Editors: M. Graça P. M. S. Neves and M. Amparo F. Faustino
Received: 29 January 2016 ; Accepted: 1 March 2016 ; Published: 8 March 2016
Abstract: Catalysis is a topic of continuous interest since it was discovered in chemistry centuries
ago. Aiming at the advance of reactions for efficient processes, a number of approaches have been
developed over the last 180 years, and more recently, porphyrins occupy an important role in this
field. Porphyrins and metalloporphyrins are fascinating compounds which are involved in a number
of synthetic transformations of great interest for industry and academy. The aim of this review is
to cover the most recent progress in reactions catalysed by porphyrins in scalable procedures, thus
presenting the state of the art in reactions of epoxidation, sulfoxidation, oxidation of alcohols to
carbonyl compounds and C–H functionalization. In addition, the use of porphyrins as photocatalysts
in continuous flow processes is covered.
Keywords: porphyrins; catalysis; scalable reactions; sensitizers; continuous flow photocatalysis
1. A Brief History of Catalysis
Catalysis is a phenomenon observed since ancient times when Valerius Cordus (1514–1544)
converted ethanol to ethyl ether using sulfuric acid as catalyst [1]. Formally, this term was proposed in
1835 by Berzelius (1779–1848), who defined catalysis as the ability of substances “to awaken affinities,
which are asleep at a particular temperature, by their mere presence and not by their own affinity” [1,2].
Later, Ostwald (Nobel Prize in Chemistry in 1909) introduced a rational physical chemical definition
of a catalyst in 1895 as a “substance that can change the reaction rate (accelerate or inhibit) without
modification of the energy factors of the reaction” [2]. However, the complete molecular basis of the
catalytic processes was established just one century later, [3] and now is widely applied on a large
scale. One important and historical example in industry is the Haber–Bosch process for ammonia
synthesis [3].
In fact, acid-base and metal catalysis have been the most recurrent procedures in industry and
academy over the last centuries, allowing the growth of chemistry with many benefits for society.
However, very complex systems have been developed more recently, including mixed metallo-organic
materials and multiple catalysts [4].
Currently, almost all the chemical processes in industry are mediated by catalysts implying large
annual expenses, involving green and energy-saving processes. In 2009 Noyori [5] stated “I personally
consider that catalysis is the most important subject in chemistry and also technology—80 per cent of
all commercial products are made by catalysis and the total market of these commercial products is
$7 trillion [£4.3 trillion]”; in a very recent editorial Zhou affirms that it is now 90% [6].
Taking into account the challenges of the global economy and the needs for more sustainable
chemical processes, catalysed reactions represent an important role for the development of new
synthetic methods to generate target molecules in fewer steps and with less chemical waste.
Molecules 2016, 21, 310; doi:10.3390/molecules21030310
www.mdpi.com/journal/molecules
Molecules 2016, 21, 310
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Molecules 2016, 21, 310
Certainly,
the design,
Molecules 2016,
21, 310
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synthesis and applications of new catalysts are a hot research topic in the three
2 of 26
scientific
disciplines,
considered
essential
for
catalysis:
chemical
engineering,
inorganic
chemistry
and
synthesis and applications of new catalysts are a hot research topic in the three scientific disciplines,
synthesis
and applications
of new
catalysts
are a hot research
topic
in the three
scientific
disciplines,
organic
chemistry.
considered
essential
for catalysis:
chemical
engineering,
inorganic
chemistry
and organic
chemistry.
considered
essential
catalysis: chemical
engineering,
inorganic
chemistryare
andspecial
organic
chemistry.
In this context,
it for
is important
to highlight
that porphyrin
derivatives
molecular
In which
this context,
is important
to highlight
that porphyrin
derivatives are
special
molecular
scaffolds,
presentitrelevant
activities
and cost-competitive
transformations
in these
fields,
thus
scaffolds,
which
present
relevant
activities
and
cost-competitive
transformations
in
these
fields,
thus
attention. In
In this
this review, we intend
deserving attention.
intend to
to cover
cover the
the most
most relevant
relevant scalable
scalable porphyrin-catalysed
porphyrin-catalysed
deserving showing
attention.how
In this
review,
we intend
to cover
the most
relevantin
scalable
porphyrin-catalysed
procedures,
these
compounds
represent
broad
applications
chemistry.
these
compounds
represent
broad
applications
in
chemistry.
procedures, showing how these compounds represent broad applications in chemistry.
2. General
GeneralConcepts
Conceptsin
inPorphyrin
PorphyrinCatalysis
Catalysis
2.
2. General Concepts in Porphyrin Catalysis
Porphyrins and
and their
their derivatives
derivatives are
are aa class
class of
of naturally
naturally occurring
occurring macrocyclic
macrocyclic compounds
compounds with
with
Porphyrins
intense
colour,
that
have
been
extensively
studied
[7–9]
due
to
the
key
role
played
in
some
life
processes
Porphyrins
and
their
derivatives
are
a
class
of
naturally
occurring
macrocyclic
compounds
with
intense colour, that have been extensively studied [7–9] due to the key role played in some life
(Figures
2) and
involving
their
specialtheir
aromatic
structure
(18π
electrons).
A
suitable
example
thatlife
intense1 and
colour,
that
have
been
extensively
studied
[7–9] due
to
the key
role
played
in suitable
some
processes
(Figures
1 and
2) and
involving
special
aromatic
structure
(18π
electrons).
A
can
be
given
is
the
heme
group
which
contains
an
iron-porphyrin
complex
which
coordinates
oxygen
processes
(Figures
1
and
2)
and
involving
their
special
aromatic
structure
(18π
electrons).
A
suitable
example that can be given is the heme group which contains an iron-porphyrin complex which
and
carbon dioxide
[10],
for contains
cellular
respiration,
andcellular
contributing
towhich
the
example
that
canfor
becellular
given
isdioxide
the heme
group which
an iron-porphyrin
complex
coordinates
oxygen
and
carboncarriage
for responsible
cellular
carriage
[10], responsible
for
respiration,
catalytic
activities
many
enzymes
as cofactors
[11].
This
is as
onecofactors
of theresponsible
reasons
why
coordinates
oxygen
and
carbon
dioxide
cellular
carriage
[10],
for
cellular
and
contributing
toofthe
catalytic
activities
offor
many
enzymes
[11]. This
isporphyrin-derived
one
of therespiration,
reasons
pigments
are
called
“the
Pigments
of
Life”
(Figures
1
and
2)
[12,13].
and
contributing
to
the
catalytic
activities
of
many
enzymes
as
cofactors
[11].
This
is
one
of the reasons
why porphyrin-derived pigments are called “the Pigments of Life” (Figures 1 and 2) [12,13].
why porphyrin-derived pigments are called “the Pigments of Life” (Figures 1 and 2) [12,13].
Figure 1. Porphyrin-derived pigments that participate in life processes.
Figure
1. Porphyrin-derived
pigments
that
participate
in life
processes.
Figure
1. Porphyrin-derived
pigments
that
participate
in life
processes.
Cyanocobalamin
Cyanocobalamin
O
H 2N
O
H 2N
O
H 2N
O
H 2N
O
O
O
H2 N
H2 N
N
N
Co
N
N
N
H 2N
H 2N O
O
O
NH 2
NH 2
N
N
Co
O
N
O
NH
O
O
NH
O
N
N
O
NH2
NH2
N
N
P
OOH
HO O P
OH
HO O
O
HO
HO
Figure 2. Metalloporphyrin derivatives involved in life processes.
Figure 2. Metalloporphyrin derivatives involved in life processes.
Figure 2. Metalloporphyrin derivatives involved in life processes.
The history of the study of metalloporphyrins’ activities began in 1747 when Menghini
The history
thetime
study
of metalloporphyrins’
began
1747inwhen
Menghini
demonstrated
for theoffirst
the presence
of iron in bloodactivities
[14]. Hoppe
andinSeyler
1871 isolated
demonstrated
for
the
first
time
the
presence
of
iron
in
blood
[14].
Hoppe
and
Seyler
in
1871
isolated
porphyrins from blood, describing these compounds as pyrrole derivatives, and in 1940 the structure
porphyrins from blood, describing these compounds as pyrrole derivatives, and in 1940 the structure
Molecules 2016, 21, 310
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The history of the study of metalloporphyrins’ activities began in 1747 when Menghini
demonstrated
Molecules 2016, 21,for
310 the first time the presence of iron in blood [14]. Hoppe and Seyler in 1871 isolated
3 of 26
Molecules
2016,
21,
310blood, describing these compounds as pyrrole derivatives, and in 1940 the structure
3 of 26
porphyrins from
and biological functions of iron porphyrin complexes were well established [15]. Nowadays, this kind
and
biological functions
of iron
porphyrin
were well
established
[15]. Nowadays,
kind
of
metalloporphyrins
is well
known
since complexes
they are prosthetic
group
of an important
class ofthis
proteins
of metalloporphyrins
is well known since they are prosthetic group of an important class of proteins
and
enzymes called hemoproteins.
hemoproteins.
and enzymes
called
hemoproteins.
Metalloporphyrins
havealso
alsobeen
been
widely
studied
as bioinspired
models
of cytochrome
Metalloporphyrins have
widely
studied
as bioinspired
models
of cytochrome
P-450
Metalloporphyrins
have
also
been
widely
studied
as
bioinspired
models
of
cytochrome
P-450
P-450
(hemoproteins),
andexhibited
have exhibited
forselective
highly selective
monooxygenation
(hemoproteins),
and have
catalyticcatalytic
activity activity
for highly
monooxygenation
reactions
(hemoproteins),
and
have
exhibited
catalytic
activity
for
highly
selective
monooxygenation
reactions
reactions
[16],
whichvia
proceed
via of
formation
of a high
valence metal-oxygen
complex intermediate.
In
[16], which
proceed
formation
a high valence
metal-oxygen
complex intermediate.
In 1979, Groves
[16],
which
proceed
via
formation
of
a
high
valence
metal-oxygen
complex
intermediate.
In
1979,
Groves
1979,
Groves
and
co–workers
developed
the
first
oxidation
system
using
a
synthetic
metalloporphyrin
and co–workers developed the first oxidation system using a synthetic metalloporphyrin as a
and
co–workers
developed
as
a bioinspired
catalyst
bioinspired
catalyst
[17].[17]. the first oxidation system using a synthetic metalloporphyrin as a
bioinspired
catalyst
[17].
Since then,
and
study
of these
very robust
macrocycles
inspiredinspired
by biological
systems,
then,the
thesynthesis
synthesis
and
study
of these
very robust
macrocycles
by biological
Since
then,
the
synthesis
and
study
of
these
very
robust
macrocycles
inspired
by
biological
have
been
incorporated
into
the
development
of
sophisticated
bulky,
chiral,
and
surface
linked
catalysts,
systems, have been incorporated into the development of sophisticated bulky, chiral, and surface linked
systems,of
have
beenofincorporated
into
development
offor
sophisticated
bulky,synthesis
chiral,
and
linked
because
a variety
of
properties
thatthe
turn
them
useful
organic
(Scheme
1)surface
[18]. 1)
catalysts,
because
a variety
of properties
that
turn
them
useful
forsynthesis
organic
(Scheme
[18].
catalysts, because of a variety of properties that turn them useful for organic synthesis (Scheme 1) [18].
Scheme
oxidation of
of cyclohexane
cyclohexane by
by aa µ-oxo-iron
μ-oxo-iron porphyrin.
porphyrin.
Scheme 1.
1. Bioinspired
Bioinspired aerobic
aerobic C–H
C–H oxidation
Scheme 1. Bioinspired aerobic C–H oxidation of cyclohexane by a μ-oxo-iron porphyrin.
The development of metalloporphyrin catalysts as synthetic tools has recently evolved significantly
The development
development of
metalloporphyrin
catalysts
as synthetic
hasevolved
recently
evolved
metalloporphyrin
catalysts
as synthetic
tools has tools
recently
significantly
[19]. The
For instance, in of
catalytic
C–H oxidation
reactions,
the simplest
metalloporphyrins
without
significantly
[19]. For
in catalytic
C–H oxidation
reactions,
the simplest
metalloporphyrins
[19]. For instance,
in instance,
catalytic
oxidation
reactions,
simplest
without
substituents
at the meso
positionsC–H
are not
useful because
theythe
undergo
fastmetalloporphyrins
oxidative degradation
[20].
without
substituents
at
the
meso
positions
are
not
useful
because
they
undergo
fast
oxidative
substituents
at
the
meso
positions
are
not
useful
because
they
undergo
fast
oxidative
degradation
[20].
The degradation process (the catalase reaction) leads to hydroxylation at the meso position, followed
degradation
[20].process
The degradation
process
(the
catalase
reaction) leads
tomeso
hydroxylation
at the
The
degradation
(the
catalase
reaction)
leads
to
hydroxylation
at
the
position,
followed
by other processes that occur in natural heme degradation, in order to form meso-hydroxyporphyrin
meso
position,
followed
by other
processes
that
occur in natural
heme
in order to form
by other
processes
that inactivate
occur
in natural
heme
degradation,
order
to degradation,
form
derivatives
which then
the catalytic
activity [20]. in
Therefore,
it
has meso-hydroxyporphyrin
been demonstrated that
meso-hydroxyporphyrin
derivatives
which
then
inactivate
the
catalytic
activity
[20].
Therefore, it that
has
derivatives
which
inactivate
thegroups
catalytic
Therefore,
it has
demonstrated
the
introduction
ofthen
phenyl
or related
atactivity
the meso[20].
positions
(Figure
3) isbeen
a good
strategy which
been
demonstrated
that theor
introduction
of phenyl
related
groups at the 3)
meso positions (Figure 3) is
the introduction
phenyl
related groups
at theor
meso
positions
provides
efficientofcatalytic
oxidations
by protecting
these
reactive(Figure
sites [19]. is a good strategy which
aprovides
good strategy
which
provides
efficient
oxidations
by protecting
these reactive sites [19].
efficient
catalytic
oxidations
bycatalytic
protecting
these reactive
sites [19].
Figure 3. Common synthetic β- and meso-substituted porphyrins.
Figure 3. Common synthetic β- and meso-substituted porphyrins.
Figure 3. Common synthetic β- and meso-substituted porphyrins.
In 1997, Dolphin and Traylor proposed a classification system for all the different
In 1997, Dolphin
Traylor
proposed
classification
system
for
all the different
metalloporphyrins
used inand
catalysis
based
on their aastructural
featuressystem
(Figure for
4) [21].
authors
In 1997, Dolphin
and
Traylor
proposed
classification
all These
the different
metalloporphyrins
used
in catalysis basedwithout
on theirsubstituents
structural features
(Figure
4)at[21].
These
authors
classified
the
synthetic
metalloporphyrins
in
the
aryl
moiety
the
meso
positions
metalloporphyrins used in catalysis based on their structural features (Figure 4) [21]. These authors
classified
the
synthetic
metalloporphyrins
without
substituents
in
the
aryl
moiety
at
the
meso
positions
as first generation
porphyrins,
and one example
the meso-tetraphenylporphyrin
iron(III)
chloride
classified
the synthetic
metalloporphyrins
without is
substituents
in the aryl moiety at the
meso positions
as
first
generation
porphyrins,
and
one
example
is
the
meso-tetraphenylporphyrin
iron(III)
chloride
([Fe(TPP)]Cl)
that Groves
et al. employed
in cytochrome
P-450 bioinspired catalysisiron(III)
(Figure 4a)
[17].
as
first generation
porphyrins,
and one example
is the meso-tetraphenylporphyrin
chloride
([Fe(TPP)]Cl) that Groves et al. employed in cytochrome P-450 bioinspired catalysis (Figure 4a) [17].
([Fe(TPP)]Cl) that Groves et al. employed in cytochrome P-450 bioinspired catalysis (Figure 4a) [17].
Molecules 2016, 21, 310
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Figure 4. Classification of metalloporphyrin catalysts. (a) First generation; (b) Second generation;
Figure 4. Classification of metalloporphyrin catalysts. (a) First generation; (b) Second generation;
(c) Third generation. R1–R5 represent EWG or bulky groups and R6 halogens.
(c) Third generation. R1 –R5 represent EWG or bulky groups and R6 halogens.
Nonetheless, meso–phenyl-substituted metalloporphyrins bearing electronegative and bulky
groups
were classified
as second-generation porphyrins
such as meso-tetrakis(pentafluorophenyl)
Nonetheless,
meso–phenyl-substituted
metalloporphyrins
bearing electronegative and bulky
porphyrin
iron(III) chloride
and meso-tetramesitylporphyrin
iron(III)
(TMPFeCl) (Figure 4b).
groups
were classified
as second-generation
porphyrins such
as chloride
meso-tetrakis(pentafluorophenyl)
The introduction of electron-withdrawing groups (such as halogens) in the β-pyrrole positions of
porphyrin iron(III) chloride and meso-tetramesitylporphyrin iron(III) chloride (TMPFeCl) (Figure 4b).
second-generation porphyrins yields the so-called third generation porphyrin derivatives (Figure 4c)
The introduction of electron-withdrawing groups (such as halogens) in the β-pyrrole positions
[22], which provide better catalytic activity over the other porphyrin generations, according to Haber
of second-generation
porphyrins yields the so-called third generation porphyrin derivatives
and co-workers [23].
(Figure 4c)Over
[22],the
which
provide
better
catalytic
overhave
the other
porphyrin
according
last few
decades,
a number
of activity
publications
covered
the manygenerations,
catalytic activities
to Haber
and
co-workers
[23].
of porphyrins; however, these studies were typically focused on methodology, converting only a few
Over
last few decades,
a number
publications
covered
the many
catalytic
activities
milli- the
or micrograms
of substrates
duringofthe
experiments.have
Herein,
we intend
to present
porphyrin
derivativeshowever,
which are these
able tostudies
performwere
scaled-up
transformations.
of porphyrins;
typically
focused on methodology, converting only a few
milli- or micrograms of substrates during the experiments. Herein, we intend to present porphyrin
3. Oxidation Reactions with Porphyrin and Metalloporphyrin–Based Catalysts
derivatives
which are able to perform scaled-up transformations.
Oxidation reactions are important synthetic tools, and a number of applications can be found in
3. Oxidation
Reactions
Porphyrin
andofMetalloporphyrin–Based
Catalysts
the chemical
industry with
[24]. The
manufacture
products obtained from oxidation
of organic substrates
and the production of pharmaceutical ingredients (APIs) are of major importance [25].
Oxidation reactions are important synthetic tools, and a number of applications can be found in
The inert nature of C–H bonds requires the use of highly reactive reagents and stoichiometric
the chemical industry [24]. The manufacture of products obtained from oxidation of organic substrates
amounts of oxidizing agents such as strong inorganic acids, peroxyacids, or highly toxic oxo–metal
and the
production
pharmaceutical
ingredients
(APIs)
are of majorand
importance
[25].amounts of
oxidants;
all yieldofproducts
with low chemo,
regio and
stereoselectivity,
generate large
The
of C–Hsince
bonds
requires of
the
use of highly
reactive
and stoichiometric
toxicinert
wastenature
[26]. However,
the discovery
cytochrome
P450, the
use of reagents
metalloporphyrin
catalysts
amounts
of oxidizing
such
strong inorganic
acids, peroxyacids,
highly
toxic5)oxo–metal
has emerged
as an agents
alternative
foras
controlled
oxidation reactions
in the above or
aspects
(Figure
[27].
cytochrome
family
enzymes
a key
in aerobic oxidation
reactions large
in biological
oxidants; This
all yield
products
withof
low
chemo,play
regio
androle
stereoselectivity,
and generate
amounts of
under However,
mild conditions,
highly selective
hydroxylation
of alkanes
(C–O
formation
toxic systems
waste [26].
sincesuch
theasdiscovery
of cytochrome
P450,
the use
of bond
metalloporphyrin
via
saturated
C–H
bond
functionalization)
(Scheme
2)
[28,29].
Metalloporphyrins
with
ruthenium,
catalysts has emerged as an alternative for controlled oxidation reactions in the above aspects
iron,
among other metals, constitute the family of catalysts which are efficient to mediate
(Figure
5) manganese,
[27].
C–H oxidations with high selectivity and good yields [30].
This cytochrome family of enzymes play a key role in aerobic oxidation reactions in biological
systems under mild conditions, such as highly selective hydroxylation of alkanes (C–O bond formation
via saturated C–H bond functionalization) (Scheme 2) [28,29]. Metalloporphyrins with ruthenium,
iron, manganese, among other metals, constitute the family of catalysts which are efficient to mediate
C–H oxidations with high selectivity and good yields [30].
Molecules 2016, 21, 310
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Figure 5. Some important transformations catalysed by porphyrins.
Figure 5. Some important transformations catalysed by porphyrins.
Figure 5. Some important transformations catalysed by porphyrins.
Figure 5. Some important transformations catalysed by porphyrins.
Scheme 2. First industrial-scale bioinspired oxidation of cyclohexane with CoTPP.
Scheme 2. First industrial-scale bioinspired oxidation of cyclohexane with CoTPP.
3.1. Epoxidation
Scheme 2. First industrial-scale bioinspired oxidation of cyclohexane with CoTPP.
The epoxidation
alkenes
is one ofbioinspired
the processes
of great
importance
the fine chemical
Scheme 2.of
First
industrial-scale
oxidation
of cyclohexane
within
CoTPP.
3.1. Epoxidation
industry from an economic point of view, because epoxides are useful intermediates in the production
3.1. Epoxidation
The epoxidation
of alkenes commercial
is one of thepolymers
processeslike
of polyurethane,
great importance
in the fine
chemical
andEpoxidation
manufacture
of high–value
polyamides,
resins,
and
3.1.
The
epoxidation
of alkenes
one
the processes
of
great
in
theproduction
fine[32]
chemical
industry
from
point
view,ofbecause
epoxides
useful
intermediates
in the
polyesters
[31].anIneconomic
addition,
thisisof
transformation
is
used toare
carry
outimportance
bioinspired oxidations
to
The
epoxidation
of
alkenes
is
one
of
the
processes
of
great
importance
in
the
fine
chemical
and
manufacture
of
high–value
commercial
polymers
like
polyurethane,
polyamides,
resins,
and
industry
fromdrug
an economic
of view, because
are useful intermediates in the production
produce
candidatespoint
or metabolites
(Scheme epoxides
3).
industry
from
anIneconomic
of
view, because is
epoxides
useful
in the production
polyesters
[31].
addition,point
this
transformation
used like
toare
carry
outintermediates
bioinspired
oxidations
[32] to and
and manufacture
of high–value
commercial
polymers
polyurethane,
polyamides,
resins,
and
manufacture
of high–value
commercial
polymers
like polyurethane, polyamides, resins, and
produce
drug
candidates
or
metabolites
(Scheme
3).
polyesters [31]. In addition, this transformation is used to carry out bioinspired oxidations [32] to
polyesters [31]. In addition, this transformation is used to carry out bioinspired oxidations [32] to
produce
drug candidates or metabolites (Scheme 3).
produce drug candidates or metabolites (Scheme 3).
Scheme 3. Metalloporphyrin catalysed bioinspired oxidation of 2-propylquinoline.
Scheme 3.are
Metalloporphyrin
catalysed
bioinspired oxidation
2-propylquinoline.
Iron porphyrins
effective catalysts
for epoxidation
of olefinsofby
a number of oxidants, such
as iodosylbenzene (PhIO) and 2,6-dichloropyridine-N-oxide (2,6-Cl2pyNO) [15]. Due to the relevance
Scheme
3.
Metalloporphyrin
catalysed
bioinspired
oxidation
ofby
2-propylquinoline.
Iron porphyrins
are
effectivecatalytic
catalysts
for epoxidation
of olefins
a has
number
of great
oxidants,
such
of cytochrome
P-450
mechanism,
epoxidation
by iron
porphyrins
gained
attention
Scheme
3. Metalloporphyrin
catalysed
bioinspired
oxidation
of 2-propylquinoline.
as
iodosylbenzene
(PhIO)
2,6-dichloropyridine-N-oxide
2pyNO) [15]. Due to the relevance
[33].
Since the Groves
and and
co-workers’
first report in 1983 [34],(2,6-Cl
several
research groups have employed
Iron porphyrins
are effectivecatalytic
catalysts for epoxidation
of olefins
by a has
number
of oxidants,
such
of
cytochrome
P-450 mechanism,
iron
porphyrins
gained
chiral
metalloporphyrins
[35] to catalyse theepoxidation
oxidation ofby
various
organic substrates,
andgreat
new attention
synthetic
as
iodosylbenzene
(PhIO)
and
2,6-dichloropyridine-N-oxide
(2,6-Cl
2
pyNO)
[15].
Due
to
the
relevance
Iron
porphyrins
are
effective
catalysts
for
epoxidation
of
olefins
by
a
number
of
oxidants,
such as
[33].
Since
the
Groves
andto
co-workers’
first
report in
1983 [34], several
research
groupscomplexes.
have employed
routes
have
been
created
improve the
catalytic
performance
of these
heterocyclic
of
cytochrome
P-450
mechanism,
catalytic
epoxidation
by
iron
porphyrins
has
gained
great
attention
iodosylbenzene
(PhIO)
and
2,6-dichloropyridine-N-oxide
(2,6-Cl
pyNO)
[15].
Due
to
the
relevance
chiralThe
metalloporphyrins
[35] to and
catalyse
the oxidation
of 6)
various
organic
substrates,
and new synthetic
2
complexes FeTHAPP
FeTCBCPP
(Figure
are examples
of metalloporphyrins
which of
[33].
Since
the
Groves
and
co-workers’
first
report
in
1983
[34],
several
research
groups
have
employed
routes
have
been
created
to catalytic
improve
the
catalytic
thesePhIO
heterocyclic
complexes.
cytochrome
P-450
mechanism,
epoxidation
by iron porphyrins
hasor
gained
great attention
are able
to perform
asymmetric
induction
in theperformance
presence
of of
either
iodosylmesitylene
as [33].
metalloporphyrins
[35] to and
catalyse
the oxidation
various
organic
substrates,
and new
synthetic
complexes
FeTHAPP
FeTCBCPP
6)
areseveral
examples
of metalloporphyrins
which
Sincechiral
the The
Groves
and co-workers’
first
report
in(Figure
1983of[34],
research
groups
have
employed
routes
have
been created
to improve
the catalytic
thesePhIO
heterocyclic
complexes. as
able
to perform
asymmetric
induction
in theperformance
presence
of of
either
or iodosylmesitylene
chiralare
metalloporphyrins
[35] to catalyse
the oxidation
of various
organic
substrates,
and new synthetic
The complexes FeTHAPP and FeTCBCPP (Figure 6) are examples of metalloporphyrins which
routes have been created to improve the catalytic performance of these heterocyclic complexes.
are able to perform asymmetric induction in the presence of either PhIO or iodosylmesitylene as
Molecules 2016, 21, 310
6 of 27
The complexes FeTHAPP and FeTCBCPP (Figure 6) are examples of metalloporphyrins which are
Molecules 2016, 21, 310
6 of 26
able to
perform asymmetric induction in the presence of either PhIO or iodosylmesitylene as
oxygen
donors,
achieving
products
with
enantioselectivities
up to 50% up
andtoa 50%
turnover
near to
oxygen
donors,
achieving
products
with enantioselectivities
and anumber
turnover(TON)
number
Molecules 2016, 21, 310
6 of 26
100 [36].
(TON) near to 100 [36].
oxygen donors, achieving products with enantioselectivities up to 50% and a turnover number
(TON) near to 100 [36].
Figure 6. Chiral iron porphyrin catalysts for enantioselective epoxidation of olefins.
Figure 6. Chiral iron porphyrin catalysts for enantioselective epoxidation of olefins.
Optically
active
epoxides
obtained from
thefor
catalytic
enantioselective
epoxidation
Figure
6. Chiral
iron porphyrin
catalysts
enantioselective
epoxidation
of olefins. of alkenes
are important
intermediates
asymmetric
synthesis,
since these
compounds are
very useful for
Optically
active
epoxides in
obtained
from
the catalytic
enantioselective
epoxidation
of the
alkenes
synthesis
of
chirons
with
up
to
two
contiguous
stereogenic
centres
[37,38].
Chiral
epoxidation
of
allylic
Optically
active epoxides
obtained from
the catalytic
enantioselective
epoxidation
of alkenes
are important
intermediates
in asymmetric
synthesis,
since
these compounds
are very
useful for
alcohols
provides
interesting
blocks
for the
asymmetric
synthesis
of biologically
active
are
important
intermediates
inbuilding
asymmetric
synthesis,
since
these compounds
are
very
usefulepoxidation
for
the
the synthesis
of chirons
with up
to two contiguous
stereogenic
centres
[37,38].
Chiral
compounds,
and consequently,
epoxidation
of allylic
alcohols
has
been extensively
synthesis
of chirons
with up
to twoasymmetric
contiguous
stereogenic
centres
[37,38].
Chiralsynthesis
epoxidation
allylic
of allylic
alcohols
provides
interesting
building
blocks for
the asymmetric
ofofbiologically
developed
[39]. Chiral
non-racemic
iron
porphyrins
with binaphthyl
moieties
linked to
the
provides
building
blocks
forepoxidation
the asymmetric
synthesis
of biologically
active
activealcohols
compounds,
andinteresting
consequently,
asymmetric
of allylic
alcohols
has been extensively
macrocycle
allow
the
enantioselective
epoxidation
of
non-functionalized
terminal
olefins
with
good
compounds, and consequently, asymmetric epoxidation of allylic alcohols has been extensively
developed
[39]. Chiral
non-racemic
iron
porphyrins
with binaphthyl
moieties
linked to the
enantioselectivity
(>97%
for
styrene) and
high
turnover numbers
(>16,000) (Scheme
[35,40].
developed
[39]. Chiral
non-racemic
iron
porphyrins
with binaphthyl
moieties4) linked
to the
macrocycle allow the enantioselective epoxidation of non-functionalized terminal olefins with good
macrocycle allow the enantioselective epoxidation of non-functionalized terminal olefins with good
enantioselectivity
(>97%
forfor
styrene)
numbers(>16,000)
(>16,000)
(Scheme
4) [35,40].
enantioselectivity
(>97%
styrene)and
andhigh
high turnover
turnover numbers
(Scheme
4) [35,40].
Scheme 4. Enantioselective epoxidation of styrene derivatives.
In general, iron porphyrins
present good epoxidation
reactivity to
two primary reactions, namely
Scheme 4. Enantioselective
of catalyse
styrene derivatives.
of styrene
derivatives.
the enantioselectiveScheme
transfer4.ofEnantioselective
an oxygen atomepoxidation
from the hydrogen
peroxide
to the substrate, and the
decomposition
of
the
peroxide
in
water
and
oxygen
[41].
On
the
other
hand,
the use
of manganese
In general, iron porphyrins present good reactivity to catalyse two primary
reactions,
namely
porphyrins
as
catalysts
with
hydrogen
peroxide
as
oxidant,
yield
low
enantiomeric
excesses
for
thegeneral,
enantioselective
transfer of an
oxygengood
atomreactivity
from the hydrogen
peroxide
to the substrate,
and the
In
iron porphyrins
present
to catalyse
two primary
reactions,
namely
epoxidations
in
organic
solvents
or
biphasic
medium
[42].
decomposition oftransfer
the peroxide
water and
oxygen
On the other
hand, the
use substrate,
of manganese
the enantioselective
of anin
oxygen
atom
from [41].
the hydrogen
peroxide
to the
and the
However,
Simonneaux
co-workers
reported
in 2012yield
the enantioselective
epoxidation
of
porphyrins
as the
catalysts
withand
hydrogen
peroxide
as [41].
oxidant,
low enantiomeric
excesses
for
decomposition
of
peroxide
in
water and
oxygen
On the other
hand, the use
of manganese
styrene
derivatives
using
H
2
O
2
(ee
up
to
68%),
in
water-methanol
solutions
using
chiral
water-soluble
epoxidations in organic solvents or biphasic medium [42].
porphyrins
as catalysts with hydrogen peroxide as oxidant, yield low enantiomeric excesses for
manganese
andSimonneaux
iron porphyrins
catalysts reported
(Scheme 5)
They
also studied various
factors
However,
and as
co-workers
in [43,44].
2012 the
enantioselective
epoxidation
of
epoxidations in organic solvents or biphasic medium [42].
styrene derivatives using H2O2 (ee up to 68%), in water-methanol solutions using chiral water-soluble
manganese and iron porphyrins as catalysts (Scheme 5) [43,44]. They also studied various factors
Molecules 2016, 21, 310
7 of 27
However, Simonneaux and co-workers reported in 2012 the enantioselective epoxidation of
styrene derivatives using H2 O2 (ee up to 68%), in water-methanol solutions using chiral water-soluble
manganese
and 2016,
iron21,porphyrins
as catalysts (Scheme 5) [43,44]. They also studied various
factors
Molecules
310
7 of 26
which affect
the
catalytic
epoxidation
of
olefins
and
found
that
the
water
present
in
the
methanol
is
Molecules
2016,
21, 310
of 26
which
affect
the catalytic epoxidation of olefins and found that the water present in the methanol7is
quite useful
[44].
quite useful [44].
which affect the catalytic epoxidation of olefins and found that the water present in the methanol is
O
quite useful [44].
O
H2O2, Catalyst
X
Imidazole, H2O/ MeOH
H2O2, Catalyst
1 mmol
X
Imidazole, H2O/ MeOH
X = H, CH3, OCH3, Cl, CF3
1 mmol
X
O
H
+ X
O
H
Yield = 45%-100%
X
+ X
%ee = 43%-68%
Yield = 45%-100%
%ee = 43%-68%
SO3Na
X = H, CH3, OCH3, Cl, CF3
SO3Na
NaO3S
N Cl N
M
N
N
N
N Cl N
M
NaO3S
MHaltS(Cl)
N Cl N
M
SO3Na
N
SO3Na
N
N
N Cl N
M
N
MHalt(Cl)
N
SO3Na
MHaltS(Cl)
M = Fe3+ or Mn3+
MHalt(Cl) M = Fe3+ or Mn3+
Scheme 5. Epoxidation of styrenes using manganese porphyrins as catalyst and H2O2.
SO3Na
Scheme 5. Epoxidation of styrenes
using manganese porphyrins as catalyst and H2 O2 .
3+
3+
M=
3+
3+
Fe or Mn
M = Fe ordecomposition
Mn
Besides the hydrogen peroxide
[45] and other factors
like the structural features
of the porphyrin
catalyst
[46],
the
substrate
concentration
and
the
solvent
[47] and
affect 2strongly
the
Scheme 5. Epoxidation
styrenes using manganese
as catalyst
O2.
Besides the hydrogen
peroxide of
decomposition
[45] andporphyrins
other factors
like theHstructural
features of
activity and the selectivity of these catalysts.
the porphyrinScheme
catalystshows
[46], how
the substrate
concentration
andtotal
theconversion
solvent [47]
affectwhen
strongly
the reaction
conditions affect
of alkenes
anfeatures
ironthe activity
Besides the6 hydrogen
peroxide
decomposition
[45] the
and other
factors like
the structural
and theofselectivity
of
these
catalysts.
porphyrin
is
employed
as
catalyst
in
a
mixture
of
dichloromethane
and
methanol.
In
this
case,
direct
the porphyrin catalyst [46], the substrate concentration and the solvent [47] affect strongly the
oxygen
transferhow
to obtain
epoxideconditions
is observed from
the the
high-valent
Fe(IV)-porphyrin
radical cation
Scheme
6and
shows
the the
reaction
affect
total conversion
of alkenes
when an iron
activity
the selectivity
of
these
catalysts.
complex (path A) [37]. On the other hand, when an aprotic solvent such as acetonitrile is used, the
6 shows
the reaction
conditions
affect the total conversion
of alkenes when
an iron
porphyrin isScheme
employed
as how
catalyst
in a mixture
of dichloromethane
and methanol.
In this
case, direct
reactive intermediate is more likely to be the iron hydroperoxide complex, leading to the generation of
is obtain
employed
asepoxide
catalyst in
aobserved
mixture offrom
dichloromethane
and methanol.
In this case,radical
direct cation
oxygen porphyrin
transfer
to
the
is
the
high-valent
Fe(IV)-porphyrin
competing radicals, thus promoting low selectivity and yield even though an imidazole is added to
oxygen transfer to obtain the epoxide is observed from the high-valent Fe(IV)-porphyrin radical cation
complex
(path
A)stabilization
[37]. On of
the
hand,(path
when
an aprotic solvent such as acetonitrile is used, the
help the
theother
intermediate
B) [37].
complex (path A) [37]. On the other hand, when an aprotic solvent such as acetonitrile is used, the
reactivereactive
intermediate
is more likely to be the iron hydroperoxide complex, leading to the generation of
intermediate is more likely to be the iron hydroperoxide complex, leading to the generation of
competing
radicals,
thus
promoting
low
andyield
yield
even
though
an imidazole
is to
added to
competing radicals, thus
promoting
lowselectivity
selectivity and
even
though
an imidazole
is added
help thehelp
stabilization
of the
the stabilization
of intermediate
the intermediate(path
(pathB)
B) [37].
[37].
Scheme 6. Different mechanisms in catalytic epoxidation depending on the conditions.
Scheme 6. Different mechanisms in catalytic epoxidation depending on the conditions.
Scheme 6. Different mechanisms in catalytic epoxidation depending on the conditions.
Molecules 2016, 21, 310
8 of 27
Molecules 2016, 21, 310
8 of 26
Despite
on the
epoxidation
of olefins,
substrate
Despite numerous
numerousstudies
studies
on metalloporphyrin–catalysed
the metalloporphyrin–catalysed
epoxidation
of the
olefins,
the
types
in
such
oxidation
systems
reported
in
the
literature
were
rather
limited
and
were
usually
substrate types in such oxidation systems reported in the literature were rather limited and
were
confined
to electron–rich
alkenes such
as styrenes,
norbornene,
cyclohexene
and cyclooctene.
However,
usually confined
to electron–rich
alkenes
such as styrenes,
norbornene,
cyclohexene
and cyclooctene.
employing
dendritic
ruthenium
porphyrins
[48]
as
catalysts,
and
2,6-Cl
pyNO,
t-BuOOH
or
O2 , some
However, employing dendritic ruthenium porphyrins [48] as catalysts, 2and 2,6-Cl2pyNO, t-BuOOH
or
authors
have
described
efficient
epoxidations
of
different
alkenes
in
high
yields
and
turnover
numbers
O2, some authors have described efficient epoxidations of different alkenes in high yields and turnover
(>700).
numbers (>700).
Che
Che and
and co-workers
co-workers investigated
investigated the
the catalytic
catalytic properties
properties of
of the
the catalyst
catalyst for
for the
the epoxidation
epoxidation of
of
unsaturated
cholesteryl
esters
with
2,6-Cl
pyNO
in
dichloromethane
using
just
0.1
mol
%
of
the
2
unsaturated cholesteryl esters with 2,6-Cl2pyNO in dichloromethane using just 0.1 mol % of the
dendritic
dendritic ruthenium
ruthenium porphyrin
porphyrin catalyst
catalyst (Scheme
(Scheme 7)
7) [48].
[48].
Scheme 7. Dendritic Ru-porphyrin catalysed epoxidation of cholesteryl esters
Scheme 7. Dendritic Ru-porphyrin catalysed epoxidation of cholesteryl esters.
3.2. Sulfides to Sulfoxides
3.2. Sulfides to Sulfoxides
Since the pioneering work of Oae and co-workers (Scheme 8) [49] on the bioinspired oxidation of
Since
pioneering
of Oae and has
co-workers
(Scheme
8) [49] on
the bioinspired
oxidation of
sulfides tothe
sulfoxides,
thiswork
transformation
gained much
attention.
Historically,
sulfur-containing
sulfides
to sulfoxides,
thisastransformation
gained much
Historically,
sulfur-containing
compounds
have figured
targets for theirhas
importance
to theattention.
pharmaceutical
industry
as antibacterial
compounds
have
figured
as
targets
for
their
importance
to
the
pharmaceutical
industry
as antibacterial
agents [25]. Therefore, the development of catalytic systems for the preparation of optically
active
agents
[25].
Therefore,
the
development
of
catalytic
systems
for
the
preparation
of
optically
sulfoxides is important, because they are chiral synthons [50] in the synthesis of bioactive
active
sulfoxides
compounds
[51]. is important, because they are chiral synthons [50] in the synthesis of bioactive
compounds [51].
Sulfoxidation is commonly presented as being a direct pathway for generating sulfoxides,
however, most of the reagents used for this reaction such as iodosylbenzene, peroxyacids, and
stoichiometric oxo-metal oxidants are unsatisfactory due to their high toxicity and low chemoselectivity
between sulfoxide and sulfone products [52]. One successful example of a green protocol was described
by Baciocchi and co-workers, who reported the oxidation of sulfides with an ethanolic solution of H2 O2
Scheme 8. First example of a bioinspired sulfoxidation.
Scheme 7. Dendritic Ru-porphyrin catalysed epoxidation of cholesteryl esters
3.2. Sulfides to Sulfoxides
Since the pioneering work of Oae and co-workers (Scheme 8) [49] on the bioinspired oxidation of
Molecules
2016, 21,
sulfides
to 310
sulfoxides, this transformation has gained much attention. Historically, sulfur-containing9 of 27
compounds have figured as targets for their importance to the pharmaceutical industry as antibacterial
agents [25]. Therefore, the development of catalytic systems for the preparation of optically active
and iron
tetrakis(pentafluorophenyl)porphyrin
as catalyst,
thus[50]
giving
the synthesis
corresponding
sulfoxides
sulfoxides
is important, because they are chiral
synthons
in the
of bioactive
on a gram-scale
(Scheme
9)
[53].
compounds [51].
Molecules 2016, 21, 310
9 of 26
Sulfoxidation
Molecules
2016, 21, 310 is commonly presented as being a direct pathway for generating sulfoxides, however,
9 of 26
most of the reagents used for this reaction such as iodosylbenzene, peroxyacids, and stoichiometric
oxo-metal
oxidantsisare
unsatisfactory
due
theira direct
high toxicity
chemoselectivity
between
Sulfoxidation
commonly
presented
asto
being
pathwayand
for low
generating
sulfoxides, however,
sulfoxide
and
sulfoneused
products
[52].
One successful
example of a green
protocol and
wasstoichiometric
described by
most of the
reagents
for this
reaction
such as iodosylbenzene,
peroxyacids,
Baciocchi
co-workers,
who reported
thetooxidation
of toxicity
sulfides
withlow
an ethanolic
solutionbetween
of H2O2
oxo-metaland
oxidants
are unsatisfactory
their
high
and
chemoselectivity
Scheme
8. Firstdue
example
of a bioinspired
sulfoxidation.
Scheme 8. First example of
bioinspired
and
iron tetrakis(pentafluorophenyl)porphyrin
as acatalyst,
thusofsulfoxidation.
giving
theprotocol
corresponding
sulfoxides
sulfoxide
and sulfone products [52]. One successful
example
a green
was described
by
on
a gram-scale
(Scheme 9)who
[53].reported the oxidation of sulfides with an ethanolic solution of H2O2
Baciocchi
and co-workers,
and iron tetrakis(pentafluorophenyl)porphyrin as catalyst, thus giving the corresponding sulfoxides
on a gram-scale (Scheme 9) [53].
Scheme 9. Synthesis of sulfoxides from sulfides.
Scheme 9. Synthesis of sulfoxides from sulfides.
Among the methods toScheme
obtain 9.
sulfoxides
[54],
the enantioselective
Synthesis of
sulfoxides
from sulfides. oxidation of sulfides with
small
amounts
of
metal-organic
catalysts
is
one
of
the
most
attractive
routes toofoptically
Among the methods to obtain sulfoxides [54], the enantioselective
oxidation
sulfides active
with small
sulfoxides
[55].
For
example,
Simonneaux
and
co-workers
reported
a
small
scale
enantioselective
Among
the
methods
to
obtain
sulfoxides
[54],
the
enantioselective
oxidation
of
sulfides
with [55].
amounts of metal-organic catalysts is one of the most attractive routes to optically active
sulfoxides
sulfide
oxidationofwith
35% aqueous
hydrogen
peroxide
and
a chiral
water-soluble
iron-porphyrin
as
small
amounts
metal-organic
catalysts
is
one
of
the
most
attractive
routes
to
optically
active
For example, Simonneaux and co-workers reported a small scale enantioselective sulfide oxidation
catalyst
[56],
thus
obtaining
sulfoxides
with
enantioselectivities
between
78%
and
90%
from
alkyl
sulfoxides [55]. For example, Simonneaux and co-workers reported a small scale enantioselective
with 35% aqueous hydrogen peroxide and a chiral water-soluble iron-porphyrin as catalyst [56], thus
aryl
sulfides,
bearing
groups
in the
phenyl
ring
(Scheme 10a).
sulfide
oxidation
withelectron-withdrawing
35% aqueous hydrogen
peroxide
and
a chiral
water-soluble
iron-porphyrin as
obtaining sulfoxides with enantioselectivities between 78% and 90% from alkyl aryl sulfides, bearing
catalyst [56], thus obtaining sulfoxides with enantioselectivities between 78% and 90% from alkyl
electron-withdrawing
groups
in the phenyl ring
(Scheme
aryl sulfides, bearing
electron-withdrawing
groups
in the 10a).
phenyl ring (Scheme 10a).
Scheme 10. (a) Enantioselective sulfoxidation of styrenes using iron porphyrins as catalyst and hydrogen
peroxide; (b) Metalloporphyrin-catalysed epoxidation for the enantioselective synthesis of Sulindac®.
Scheme 10. (a) Enantioselective sulfoxidation of styrenes using iron porphyrins as catalyst and hydrogen
Scheme
10.
(a) Enantioselective
of
using
porphyrins
as catalyst
and
The
advantages
of the processsulfoxidation
is supported
bystyrenes
the
of iron
excess
of
oxidant,
reaction
®.
peroxide;
(b) Metalloporphyrin-catalysed
epoxidation
forabsence
the enantioselective
synthesis
of small
Sulindac
hydrogen
peroxide;
(b)
Metalloporphyrin-catalysed
epoxidation
for
the
enantioselective
synthesis
time, reaction at room temperature, and protection against destruction of the macrocycle by the two
®.
of
Sulindac
bulky
norbornane
groups
to is
thesupported
central benzene
ring [56];ofhowever,
procedure
not
The
advantages
of thejoined
process
by the absence
excess of this
oxidant,
small was
reaction
scaled-up,
andatonly
a few
micrograms
ofprotection
sulfide were
converted.
time, reaction
room
temperature,
and
against
destruction of the macrocycle by the two
Another
example
of
an
enantioselective
oxidation
sulfides
scale)
by was
a chiral
bulky norbornane groups joined to the central benzeneofring
[56]; (small
however,
thiscatalysed
procedure
not
manganese
porphyrin
in
an
aqueous
methanol
solution
in
the
presence
of
H
2
O
2
furnished
the
scaled-up, and only a few micrograms of sulfide were converted.
Another example of an enantioselective oxidation of sulfides (small scale) catalysed by a chiral
manganese porphyrin in an aqueous methanol solution in the presence of H2O2 furnished the
Molecules 2016, 21, 310
10 of 27
The advantages of the process is supported by the absence of excess of oxidant, small reaction
time, reaction at room temperature, and protection against destruction of the macrocycle by the two
bulky norbornane groups joined to the central benzene ring [56]; however, this procedure was not
scaled-up, and only a few micrograms of sulfide were converted.
Another
example
of an enantioselective oxidation of sulfides (small scale) catalysed by a 10
chiral
Molecules
2016, 21,
310
of 26
manganese porphyrin in an aqueous methanol solution in the presence of H2 O2 furnished the
non-steroidal anti-inflammatory drug Sulindac®® (Banyu
(Banyu Pharmaceutical
Pharmaceutical Co.,
Co., Ltd.,
Ltd., Tokyo, Japan)
(Scheme
(Scheme 10b)
10b) [57].
[57].
Nonetheless, the formation of sulfoxides using metalloporphyrins as catalyst can be achieved
achieved
by other methodologies,
methodologies,but
butininthis
thiscase,
case,onon
a superior
scale.
of oxygen
asoxidant
the oxidant
a superior
scale.
TheThe
use use
of oxygen
as the
with
with
and
Me4[58]
NOH,
[58]
is an example
theproduct
oxidized
product of diarylsulfide
NaBHNaBH
4 and 4
Me
4NOH,
is an
example
to obtain to
theobtain
oxidized
of diarylsulfide
compounds
compounds
(Scheme 11).(Scheme 11).
S
Me4N.OH, C6H6/MeOH
20°C, 5 h
0.559 g, 3 mmol
O
S
MTPPCl, NaBH4, O2
Obtained:
M= Fe (0.182 g, 0.90 mmol)
Mn (0.194 g, 0.96 mmol)
Co (traces)
.OH system.
Scheme11.
11.Synthesis
Synthesisofofsulfoxides
sulfoxidesfrom
fromsulfides
sulfidesusing
usingthe
theMTPPCl/NaBH
MTPPCl/NaBH4/Me
/Me4N
.
Scheme
4
4 N OH system.
3.3. Hydroxylation
3.3.
Hydroxylation
Once the
the mechanism
mechanism by
by which
which the
the cytochrome
cytochrome P-450
P-450 acts
acts as
as catalyst
catalyst in
in C–H
C–Hfunctionalization
functionalization
Once
became known
known [59],
[59], with
with an
an iron
iron porphyrin
porphyrin core
core as
as the
the active
active site,
site, many
many synthetic
synthetic metalloporphyrins
metalloporphyrins
became
have
been
studied
as
catalyst
for
this
purpose
with
different
organic
substrates
[60,61].
In fact,
fact, this
this is
is
have been studied as catalyst for this purpose with different organic substrates [60,61]. In
one of
ofthe
themost
most
difficult
transformations
forpetrochemical
the petrochemical
industry,
one
of the
major
one
difficult
transformations
for the
industry,
and oneand
of the
major
challenge
challenge
to
convert
petroleum
derivatives
into
chemicals
of
higher
value
[62].
to convert petroleum derivatives into chemicals of higher value [62].
The first
first report
report of
of metalloporphyrin-catalysed
metalloporphyrin-catalysed hydroxylation
hydroxylation of
of saturated
saturated C–H
C–H bonds
bonds was
was
The
published by
by Groves
Groves and
and co-workers
co-workers in
in 1979
1979 [17],
[17], where
where they
they showed
showed the
the catalytic
catalytic activity
activity of
of
published
[Fe(TPP)Cl]
towards
oxidation
of
cyclohexane
and
adamantane
with
iodosylbenzene
to
give
the
[Fe(TPP)Cl] towards oxidation of cyclohexane and adamantane with iodosylbenzene to give the
corresponding alcohols.
alcohols. Approximately
corresponding
Approximately 10
10 years
years later,
later, Groves
Groves and
and Viski
Viski reported
reported for
for the
the first
first time,
time,
the
enantioselective
hydroxylation
of
ethylbenzenes
catalysed
by
a
chiral
iron
porphyrin
with
up
to
the enantioselective hydroxylation of ethylbenzenes catalysed by a chiral iron porphyrin with up to
77%
ee
using
PhIO
as
oxidant
(Scheme
12)
[63,64].
When
manganese
was
used,
higher
yields
were
77% ee using PhIO as oxidant (Scheme 12) [63,64]. When manganese was used, higher yields were
obtained, but
but the
the enantioselectivity
enantioselectivity decreased
decreased and
and ketones
ketones were
were also
also observed
observed as
as by-products
by-products in
in the
the
obtained,
catalytic
reactions.
catalytic reactions.
In 1999, Gross and Ini reported the first example of ruthenium-catalysed enantioselective (ee up
to 38%) hydroxylation of racemic tertiary alkanes, using a chiral porphyrin ligand and 2,6-Cl2 pyNO as
oxidant (Scheme 13) [65].
Che and co-workers [66] reported the Ru-catalysed enantioselective hydroxylation of aromatic
hydrocarbons with benzylic C–H bonds. Using 2,6-Cl2 pyNO as oxidant, the chiral ruthenium
porphyrin was shown to be an effective catalyst for hydroxylating a series of aromatic hydrocarbons to
form the corresponding secondary alcohols. Although the conversion of the substrates was incomplete,
the Ru-based hydroxylation gave yields up to 76% ee (Scheme 14).
In 2012 Simonneaux and co-workers reported examples of enantioselective hydroxylation of
alkanes, with a chiral iron porphyrin as catalyst and using hydrogen peroxide as oxidant in methanol
and water, to give optically active secondary alcohols (ee up to 63%) [43]. Nonetheless, one limitation
for this system is the requirement of an excess of alkane versus the oxidant, and consequently the
asymmetric hydroxylation of alkanes using these conditions is still difficult to proceed without
Scheme 12. Enantioselective hydroxylation of ethylbenzene by a chiral iron-porphyrin.
In 1999, Gross and Ini reported the first example of ruthenium-catalysed enantioselective (ee up
one of the most difficult transformations for the petrochemical industry, and one of the major
challenge to convert petroleum derivatives into chemicals of higher value [62].
The first report of metalloporphyrin-catalysed hydroxylation of saturated C–H bonds was
published by Groves and co-workers in 1979 [17], where they showed the catalytic activity of
[Fe(TPP)Cl] towards oxidation of cyclohexane and adamantane with iodosylbenzene to give the
Molecules 2016, 21, 310
11 of 27
corresponding alcohols. Approximately 10 years later, Groves and Viski reported for the first time,
the enantioselective hydroxylation of ethylbenzenes catalysed by a chiral iron porphyrin with up to
77%
ee using PhIOchiral
as oxidant
(Scheme 12) [63,64].
When
manganese
was used, higher
electron-deficient
metalloporphyrins
[44]. The
treatment
of ethylbenzene
withyields
H2 O2were
and
obtained,
butthe
thecomplex
enantioselectivity
ketones
were also observed
as by-products
in the
catalysis by
(Scheme 15)decreased
afforded aand
mixture
of 1–phenylethanol
(57%)
and acetophenone
catalytic
reactions.
(43%) with
88% of conversion [43].
Molecules 2016, 21, 310
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Scheme 12. Enantioselective hydroxylation of ethylbenzene by a chiral iron-porphyrin.
Scheme 12. Enantioselective hydroxylation of ethylbenzene by a chiral iron-porphyrin.
Molecules
2016, 21,
310 and Ini reported the first example of ruthenium-catalysed enantioselective (ee
11 ofup
26
In 1999,
Gross
to 38%) hydroxylation of racemic tertiary alkanes, using a chiral porphyrin ligand and 2,6-Cl2pyNO
as oxidant (Scheme 13) [65].
Scheme 13. Catalytic enantioselective hydroxylation of a tertiary alkane.
Che and co-workers [66] reported the Ru-catalysed enantioselective hydroxylation of aromatic
hydrocarbons with benzylic C–H bonds. Using 2,6-Cl2pyNO as oxidant, the chiral ruthenium
porphyrin was shown to be an effective catalyst for hydroxylating a series of aromatic hydrocarbons
Scheme
enantioselective
hydroxylation
of aa tertiary
tertiary alkane.
Scheme 13.
13. Catalytic
Catalytic
enantioselective
hydroxylation
to form the corresponding
secondary
alcohols. Although
the of
conversionalkane.
of the substrates was
incomplete,
the
Ru-based
hydroxylation
gave
yields
up
to
76%
ee
(Scheme
14).
Che and co-workers [66] reported the Ru-catalysed enantioselective hydroxylation of aromatic
hydrocarbons with benzylic C–H bonds. Using 2,6-Cl2pyNO as oxidant, the chiral ruthenium
porphyrin was shown to be an effective catalyst for hydroxylating a series of aromatic hydrocarbons
to form the corresponding secondary alcohols. Although the conversion of the substrates was
incomplete, the Ru-based hydroxylation gave yields up to 76% ee (Scheme 14).
Scheme 14. Ruthenium catalysed asymmetric alkane hydroxylation.
Scheme 14. Ruthenium catalysed asymmetric alkane hydroxylation.
In 2012 Simonneaux and co-workers reported examples of enantioselective hydroxylation of
alkanes, with a chiral iron porphyrin as catalyst and using hydrogen peroxide as oxidant in methanol
and water, to give optically active secondary alcohols (ee up to 63%) [43]. Nonetheless, one limitation
Scheme 14. Ruthenium catalysed asymmetric alkane hydroxylation.
for this system is the requirement of an excess of alkane versus the oxidant, and consequently the
asymmetric
of alkanes
using
these conditions
is enantioselective
still difficult to hydroxylation
proceed without
In 2012 hydroxylation
Simonneaux and
co-workers
reported
examples of
of
electron-deficient
chiral
metalloporphyrins
[44].
The
treatment
of
ethylbenzene
with
H
2O2 and
alkanes, with a chiral iron porphyrin as catalyst and using hydrogen peroxide as oxidant in methanol
catalysis
bytothe
complex
(Scheme
affordedalcohols
a mixture
(57%) and one
acetophenone
and
water,
give
optically
active 15)
secondary
(ee of
up1–phenylethanol
to 63%) [43]. Nonetheless,
limitation
and water, to give optically active secondary alcohols (ee up to 63%) [43]. Nonetheless, one limitation
for this system is the requirement of an excess of alkane versus the oxidant, and consequently the
asymmetric hydroxylation of alkanes using these conditions is still difficult to proceed without
electron-deficient chiral metalloporphyrins [44]. The treatment of ethylbenzene with H2O2 and
Molecules 2016,
21, 310
12 of 27
catalysis
by the
complex (Scheme 15) afforded a mixture of 1–phenylethanol (57%) and acetophenone
(43%) with 88% of conversion [43].
Scheme
15.15.
Hydroxylation
of ethylbenzene
derivatives
using a using
water-soluble
iron-porphyrin
as catalyst.
Scheme
Hydroxylation
of ethylbenzene
derivatives
a water-soluble
iron-porphyrin
as catalyst.
Molecules 2016, 21, 310
12 of 26
Other
types of
of porphyrins
have been
been explored
explored for
for this
this hydroxylation
hydroxylation reaction,
reaction, and
and in
in 2007,
2007,
Other
porphyrins have
Molecules
2016,types
21, 310
12 of 26
Idemori
and
co–workers
studied
Mn(III)–tetrapyridylporphyrin
as
catalyst
in
the
hydroxylation
Idemori and co–workers studied Mn(III)–tetrapyridylporphyrin as catalyst in the hydroxylation of
of
cyclohexene
[67]. Iida
Iida
and co-workers
co-workers
have
shown
thatfor
thethis
combination
of tert-butyl
tert-butyl
hydroperoxide
cyclohexene
[67].
and
that
the
combination
of
hydroperoxide
Other types
of porphyrins
have have
been shown
explored
hydroxylation
reaction,
and in 2007,
(TBHP)
carbonyl
complex
of meso-tetramesitylporphyrin
[Os(TMP)(CO)]
as oxygen
(TBHP)
andthe
theosmium(II)
osmium(II)
carbonyl
complex
of meso-tetramesitylporphyrin
as
Idemoriand
co–workers
studied
Mn(III)–tetrapyridylporphyrin
as catalyst
in the[Os(TMP)(CO)]
hydroxylation
of
donor
and
catalyst
respectively
(Scheme
16),
is
an
efficient
and
versatile
oxidation
system
for
the
oxygen
donor[67].
andIida
catalyst
respectivelyhave
(Scheme
16),that
is an
efficient
and versatile
oxidation
system for
cyclohexene
and co-workers
shown
the
combination
of tert-butyl
hydroperoxide
functionalization
bioactive
molecules,
like like
bile bile
acids
[68] [68]
and and
terpenoids
[69].[69].
the
functionalization
of bioactive
molecules,
acids
terpenoids
(TBHP)
and the of
osmium(II)
carbonyl
complex
of meso-tetramesitylporphyrin
[Os(TMP)(CO)] as
oxygen donor and catalyst respectively (Scheme 16), is an efficient and versatile oxidation system for
the functionalization of bioactive molecules, like bile acids [68] and terpenoids [69].
Scheme 16. Representation of the oxidation process by the osmium-porphyrin [70].
Scheme 16. Representation of the oxidation process by the osmium-porphyrin [70].
The oxy-functionalization
system with
regioselectively
Scheme 16. Representation
of theosmium-porphyrins
oxidation process by as
thecatalyst
osmium-porphyrin
[70]. hydroxylates
The
system
osmium-porphyrins
one of
theoxy-functionalization
inactivated tertiary C–H
bondswith
in dihydrofaradiol
diacetateastocatalyst
form theregioselectively
corresponding
hydroxylates
one
of
the
inactivated
tertiary
C–H
bonds
in
dihydrofaradiol
diacetate
to form
the
alcohol
50% yield (Schemesystem
17). The
functionalization
of triterpenoids
with the oxidant
system
Theinoxy-functionalization
with
osmium-porphyrins
as catalyst regioselectively
hydroxylates
corresponding
alcohol
in
50%
yield
(Scheme
17).
The
functionalization
of
triterpenoids
with
the
afforded
a variety
of novel
oxygenated
derivatives
in one-step with
good to
isolated
yields
[69].
one of the
inactivated
tertiary
C–H bonds
in dihydrofaradiol
diacetate
form the
corresponding
oxidant
system
afforded
a variety
novel
oxygenated derivatives
in one-step
withoxidant
good isolated
alcohol in
50% yield
(Scheme
17). of
The
functionalization
of triterpenoids
with the
system
yields
[69].
afforded a variety of novel oxygenated derivatives in one-step with good isolated yields [69].
Scheme 17. Hydroxylation of dihydrofaradiol diacetate with the osmium porphyrin.
3.4. Oxidation
of Alcohols
to Carbonyl Compounds
Scheme
17. Hydroxylation
of dihydrofaradiol diacetate with the osmium porphyrin.
Scheme 17. Hydroxylation of dihydrofaradiol diacetate with the osmium porphyrin.
The transformation of primary alcohols to the corresponding aldehydes or carboxylic acids is
3.4. Oxidation of Alcohols to Carbonyl Compounds
important for organic synthesis, since these are versatile functional groups which are present in many
building
[71] (Scheme
18).
The blocks
transformation
of primary
alcohols to the corresponding aldehydes or carboxylic acids is
important for organic synthesis, since these are versatile functional groups which are present in many
building blocks [71] (Scheme 18).
Molecules 2016, 21, 310
13 of 27
Scheme 17. Hydroxylation of dihydrofaradiol diacetate with the osmium porphyrin.
3.4. Oxidation of Alcohols to Carbonyl Compounds
3.4. Oxidation of Alcohols to Carbonyl Compounds
The transformation of primary alcohols to the corresponding aldehydes or carboxylic acids is
The transformation of primary alcohols to the corresponding aldehydes or carboxylic acids is
important for organic synthesis, since these are versatile functional groups which are present in many
important for organic synthesis, since these are versatile functional groups which are present in many
building
blocks
[71][71]
(Scheme
18).
building
blocks
(Scheme
18).
Scheme 18. Oxidation of benzylic alcohols to carbonyl compounds with a Mn-porphyrin.
Scheme 18. Oxidation of benzylic alcohols to carbonyl compounds with a Mn-porphyrin.
Conventionally, stoichiometric or even over-stoichiometric amounts of metal oxides and metal
complexes are used for these oxidations [72], but the catalytic oxidation with O2 is of sustainability
interest [73].
Metalloporphyrins have been widely used as catalysts for various oxidations of alcohols
with PhIO [74], 2,6-Cl2 PyNO [75], m-chloroperbenzoic acid [76], Bu4 NHSO5 (tetrabutylammonium
peroxymonosulfate) [77] and oxygen as oxidants. Woo and co-workers reported the aerobic
Molecules 2016, 21, 310
13 of 26
homogeneous oxidation of benzyl alcohol with oxo-titanium porphyrin ((TPP)Ti=O), which gave
benzaldehyde
in 50% yield
[78]. It has been
found
that (TPP)Ti=Oamounts
reacts with
free oxides
diols to
yield
diolato
Conventionally,
stoichiometric
or even
over-stoichiometric
of metal
and
metal
complexes
[79],are
and
these
undergo
oxidative
cleavage
reactions
high
temperatures to
complexes
used
for complexes
these oxidations
[72], but
the catalytic
oxidation
with Oat2 is
of sustainability
interest
[73]. compounds.
release
carbonyl
Metalloporphyrins
have been
widely used
as catalysts
for various
oxidations compounds
of alcohols by
Ji and co-workers reported
a selective
oxidation
of alcohols
to carbonyl
with
PhIO
[74],
2,6-Cl
2PyNO [75], m-chloroperbenzoic acid [76], Bu4NHSO5 (tetrabutylammonium
molecular oxygen with isobutyraldehyde as oxygen acceptor in the presence of ruthenium (III)
peroxymonosulfate) [77] and oxygen as oxidants. Woo and co-workers reported the aerobic
meso-tetraphenylporphyrin
chloride (Ru(TPP)Cl) (Scheme 19) [80]. In addition, they found that
homogeneous oxidation of benzyl alcohol with oxo-titanium porphyrin ((TPP)Ti=O), which gave
the catalytic activity and selectivity of metalloporphyrins towards benzaldehydes appeared to be
benzaldehyde in 50% yield [78]. It has been found that (TPP)Ti=O reacts with free diols to yield diolato
dependent
on the nature of the central ion, and were influenced by the stability of different valences of
complexes [79], and these complexes undergo oxidative cleavage reactions at high temperatures to
the metal
atoms
andcompounds.
their respective electric potential.
release
carbonyl
Scheme 19. Gram-scale oxidation of benzylic alcohols with Ru(TPP)Cl.
Scheme
19. Gram-scale oxidation of benzylic alcohols with Ru(TPP)Cl.
Ji and co-workers reported a selective oxidation of alcohols to carbonyl compounds by
molecular oxygen with isobutyraldehyde as oxygen acceptor in the presence of ruthenium (III)
meso-tetraphenylporphyrin chloride (Ru(TPP)Cl) (Scheme 19) [80]. In addition, they found that the
catalytic activity and selectivity of metalloporphyrins towards benzaldehydes appeared to be
dependent on the nature of the central ion, and were influenced by the stability of different valences
Ji and co-workers reported a selective oxidation of alcohols to carbonyl compounds by
molecular oxygen with isobutyraldehyde as oxygen acceptor in the presence of ruthenium (III)
meso-tetraphenylporphyrin chloride (Ru(TPP)Cl) (Scheme 19) [80]. In addition, they found that the
catalytic activity and selectivity of metalloporphyrins towards benzaldehydes appeared to be
Molecules 2016, 21, 310
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dependent on the nature of the central ion, and were influenced by the stability of different valences
of the metal atoms and their respective electric potential.
Oxidation of aldehydes to the corresponding carboxylic acids is one of the ubiquitous
ubiquitous
transformation
the
preparation
of numerous
APIs,
vitamins
and and
fragrances
[73].
transformationin
inorganic
organicsynthesis,
synthesis,for
for
the
preparation
of numerous
APIs,
vitamins
fragrances
Rebelo
and co-authors
investigated
the oxidation
of benzaldehyde
with hydrogen
peroxideperoxide
using a
[73]. Rebelo
and co-authors
investigated
the oxidation
of benzaldehyde
with hydrogen
Mn(III)
acetate acetate
system system
to give benzoic
acid in 93%
[81].
using a porphyrin/ammonium
Mn(III) porphyrin/ammonium
to give benzoic
acid yield
in 93%
yield [81].
The oxidation of α,β-enones at the γ position is a relevant
relevant transformation,
transformation, with few known
methodologies. Che and co-workers reported the Ru-porphyrin catalysed oxidation of ketosteroids to
form diketosteroids
as catalyst
diketosteroids using
using meso-tetrakis(2,6-dichlorophenyl)porphyrin
meso-tetrakis(2,6-dichlorophenyl)porphyrin (Ru(TDClPP)Cl
(Ru(TDClPP)Cl22)) as
catalyst
and 2,6–Cl22pyNO as oxidant (Scheme 20) [82].
Scheme 20. Oxidation of ketosteroids catalysed by ruthenium 2,6-TDCPP dichloride.
Scheme 20. Oxidation of ketosteroids catalysed by ruthenium 2,6-TDCPP dichloride.
Molecules 2016, 21, 310
4. Porphyrin Derivatives Acting as Photocatalysts
14 of 26
4. Porphyrin
Derivatives
Acting
Photocatalysts
Since
1930, when
Kautsky
firstasexamined
the generation of singlet oxygen {O2 (1 ∆g )}, by energy
1Δgenvironmentally
transfer from
photoexcited
organic
moleculesthe
togeneration
molecularofoxygen,
this kind
)}, by energy
Sincea1930,
when Kautsky
first examined
singlet oxygen
{O2 (of
friendly
methodology
has been organic
of interest
[83]. The
importance
of singlet
oxygen
in many physical
transfer
from a photoexcited
molecules
to molecular
oxygen,
this kind
of environmentally
friendly methodology
hasbeen
been recognized,
of interest [83].
Therich
importance
of singlet oxygen
in many
physical
and biological
processes has
with
details concerning
the physics
and
chemistry
and
biological processes
been recognized,
with rich
detailsoxygen
concerning
andby
chemistry
of this
electronically
excitedhas
molecule
[84]. Generally,
singlet
canthe
be physics
generated
chemical or
of this electronically
excited
molecule
[84]. Generally,
singletis
oxygen
be generated by The
chemical
or
photosensitized
reactions,
but the
photochemical
approach
more can
cost-competitive.
mechanism
photosensitized reactions, but the photochemical approach is more cost-competitive. The mechanism
of the photochemical singlet oxygen generation includes the promotion of the photosensitizer to the
of the photochemical singlet oxygen generation includes the promotion of the photosensitizer to the
triplet state, passing through a singlet -excited state. At the triplet state many photosensitizers are
triplet state, passing through a singlet -excited state. At the triplet state many photosensitizers are
able to
transfer
energy
to molecular
oxygen
leading
to the
formation
of reactive
oxygen
species
able
to transfer
energy
to molecular
oxygen
leading
to the
formation
of reactive
oxygen
species(ROS)
(Figure
7)
[85].
(ROS) (Figure 7) [85].
Figure 7. Representation of the mechanism of porphyrin photosensitized reactions.
Figure 7. Representation of the mechanism of porphyrin photosensitized reactions.
In this context, porphyrins are prominent photosensitizers because of their high light
absorption coefficient, exited state energy levels, and high photostability as compared to other dyes.
For example, meso-tetraphenylporphyrin (TPP) has been chosen as one of the most highly effective
photosensitizer [86] for singlet oxygen generation [87].
In 1999, methylene blue was used as photosensitizer in the photooxidation of 8-hydroxyquinoline
Molecules 2016, 21, 310
15 of 27
Figure 7. Representation of the mechanism of porphyrin photosensitized reactions.
In this context, porphyrins are prominent photosensitizers because of their high light absorption
In exited
this context,
porphyrins
are and
prominent
photosensitizersas because
of their
highdyes.
light For
coefficient,
state energy
levels,
high photostability
compared
to other
absorption
coefficient,
exited
state
energy
levels,
and
high
photostability
as
compared
to
other
dyes.
example, meso-tetraphenylporphyrin (TPP) has been chosen as one of the most highly effective
For example,[86]
meso-tetraphenylporphyrin
(TPP) has
been chosen as one of the most highly effective
photosensitizer
for singlet oxygen generation
[87].
photosensitizer [86] for singlet oxygen generation [87].
In 1999, methylene blue was used as photosensitizer in the photooxidation of 8-hydroxyquinoline
In 1999, methylene blue was used as photosensitizer in the photooxidation of 8-hydroxyquinoline
to afford quinoline-5,8-quinone in 64%–70% yields [88]. However, Cossy and Belotti showed in 2001 an
to afford quinoline-5,8-quinone in 64%–70% yields [88]. However, Cossy and Belotti showed in 2001
improved
method using TPP for the photooxygenation of substituted 8-hydroxyquinolines in 50%–89%
an improved method using TPP for the photooxygenation of substituted 8-hydroxyquinolines in
yield50%–89%
(Schemeyield
21) [85].
(Scheme 21) [85].
Scheme 21. Synthesis of substituted quinoline-5,8-quinones by photooxygenation.
Scheme 21. Synthesis of substituted quinoline-5,8-quinones by photooxygenation.
Spivey and co-workers reported in 2010 the synthesis of high-functionalized molecules using
two photooxygenation
reactions
with
visible
light and
TPP as photocatalyst,molecules
including ausing
Spivey
and co-workers
reported
inoxygen,
2010 the
synthesis
of high-functionalized
two photooxygenation reactions with oxygen, visible light and TPP as photocatalyst, including a
base-catalysed Kornblum DeLaMare rearrangement. Also, Co(II)TPP was used three times as the
oxidation catalyst (Scheme 22) showing its versatility in the entire synthetic approach [89].
By comparison, in 2011 Nicolaou presented the total synthesis of dithiodiketopiperazines
(epicoccin G and 8,8’-epi-ent-rostratin B) including two TPP-photocatalysed endoperoxide formations,
and base-catalysed Kornblum DeLaMare rearrangements (Scheme 23) [90]. Singlet oxygen generation
by porphyrins can take place in reactions with amines [91]. In the case of secondary amines, there is an
example with the dehydrogenation of N–neopentylallylic amine using TPP as photocatalyst to obtain
the
corresponding imine product [92]. Moreover, Che and co-workers [93] reported the highly efficient
Molecules 2016, 21, 310
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photooxidation of secondary benzylamines to imines in 90% yield using molecular oxygen and TPP as
photosensitizer.
They usedDeLaMare
directly therearrangement.
in situ formed imine
further
to
base-catalysed Kornblum
Also, products
Co(II)TPPforwas
usedfunctionalization
three times as the
develop
an
oxidative
Ugi–type
MCR
(Scheme
24).
oxidation catalyst (Scheme 22) showing its versatility in the entire synthetic approach [89].
Scheme
using porphyrins
porphyrins as
as catalysts.
catalysts.
Scheme 22.
22. Synthesis
Synthesis of
of decahydrodibenzofurans
decahydrodibenzofurans by
by using
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Scheme 22. Synthesis of decahydrodibenzofurans by using porphyrins as catalysts.
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Scheme
23. Synthesis of bisendoperoxide intermediates in the total synthesis of (a) epicoccin G and
Moreover, Che and co-workers [93] reported the highly efficient photooxidation of secondary benzylamines to
Scheme
23. Synthesis ofBbisendoperoxide
intermediates in the total synthesis of (a) epicoccin G and
(b)
8,8’-epi-ent-rostratin
using TPP
as photosensitizer.
imines in 90% yield using molecular
oxygen
and TPP as photosensitizer. They used directly the in situ formed
(b)
8,8’-epi-ent-rostratin
B
using
TPP
as
photosensitizer.
imine products for further functionalization to develop an oxidative Ugi–type MCR (Scheme 24).
By comparison, in 2011 Nicolaou presented the total synthesis of dithiodiketopiperazines (epicoccin G
and 8,8’-epi-ent-rostratin B) including two TPP-photocatalysed endoperoxide formations, and base-catalysed
Kornblum DeLaMare rearrangements (Scheme 23) [90]. Singlet oxygen generation by porphyrins can take place
in reactions with amines [91]. In the case of secondary amines, there is an example with the dehydrogenation of
N–neopentylallylic amine using TPP as photocatalyst to obtain the corresponding imine product [92].
Scheme 24. Photooxidation of secondary benzylamines to imines.
Scheme 24. Photooxidation of secondary benzylamines to imines.
Another photocatalytic application of porphyrins is their encapsulation in microemulsions of
Another
photocatalytic
application
of porphyrins
their
in microemulsions
ethyl acetate,
water and surfactants
to allow
the use ofisTPP
as encapsulation
photosensitizer for
singlet oxygen of
[94]. For
Oelgemöller
out the photooxygenation
of
ethylgeneration
acetate, water
andexample,
surfactants
to allowand
the co-workers
use of TPPcarried
as photosensitizer
for singlet oxygen
1,5-dihydroxynaphthalene
to Juglone
(5-hydroxy-1,4-naphthoquinone)
as aout
reaction
in a micellar of
generation
[94]. For example,
Oelgemöller
and co-workers carried
the model
photooxygenation
system, but only on a small-scale
25) [95].
1,5-dihydroxynaphthalene
to Juglone(Scheme
(5-hydroxy-1,4-naphthoquinone)
as a reaction model in a micellar
system, but only on a small-scale (Scheme 25) [95].
Scheme 24. Photooxidation of secondary benzylamines to imines.
Another photocatalytic application of porphyrins is their encapsulation in microemulsions of
ethyl acetate, water and surfactants to allow the use of TPP as photosensitizer for singlet oxygen
generation [94]. For example, Oelgemöller and co-workers carried out the photooxygenation of
Molecules 2016,
21, 310
1,5-dihydroxynaphthalene
to Juglone (5-hydroxy-1,4-naphthoquinone) as a reaction model in a micellar
system, but only on a small-scale (Scheme 25) [95].
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Scheme 25. Schematic representation of a “green” microemulsion Juglone synthesis.
Scheme 25. Schematic representation of a “green” microemulsion Juglone synthesis.
4.1. Immobilized Porphyrins as Photocatalysts
One
approach to
the usefulness of metalloporphyrin catalysis, involves recyclability
4.1. Immobilized
Porphyrins
asenhance
Photocatalysts
through heterogeneous catalytic systems [96] by using immobilized homogeneous catalysts [97].
In the case of
immobilization
can avoid the needcatalysis,
for chiral ligand
recovery.
One approach
toasymmetric
enhance oxidation,
the usefulness
of metalloporphyrin
involves
recyclability
One of the simplest
ways to prepare
a polymer-immobilized
catalyst is thehomogeneous
direct reaction of acatalysts
simple [97]. In
through heterogeneous
catalytic
systems
[96] by using immobilized
functionalized polymer, such as Merrifield`s resin with a derivative of the desired ligand and then
the case of asymmetric oxidation, immobilization can avoid the need for chiral ligand recovery. One
insertion of the metal [98].
of the simplest ways to prepare a polymer-immobilized catalyst is the direct reaction of a simple
functionalized polymer, such as Merrifield‘s resin with a derivative of the desired ligand and then
insertion of the metal [98].
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The covalent
immobilization of porphyrins on polymeric matrices is very versatile
to generate
singlet oxygenThe
[99].
Anchoring
the
photocatalyst
onto
a
poly(ethylene
glycol)
allows
the
easy
covalent immobilization of porphyrins on polymeric matrices is very versatile to generate recovery
singlet from
oxygenthe
[99].reaction
Anchoringmixture,
the photocatalyst
onto a poly(ethylene
glycol) allows
thereported
easy recovery
of the catalyst
as Benaglia
and co-workers
[100]
with a new
of theglycol)-supported
catalyst from the reaction
mixture,which
as Benaglia
and co-workers
[100] reported
with acomparable
new
poly(ethylene
porphyrin
exhibited
high activity
as catalyst,
to
poly(ethylene glycol)-supported porphyrin which exhibited high activity as catalyst, comparable to
that of a non-anchored
sensitizer
(Scheme
26).
that of a non-anchored sensitizer (Scheme 26).
Scheme 26. PEG-supported tetrahydroxyphenyl porphyrin for photooxidation reactions.
Scheme 26. PEG-supported tetrahydroxyphenyl porphyrin for photooxidation reactions.
Che and co-workers reported a covalently attached carbonylruthenium(II)meso-tetrakis
(pentafluorophenyl)porphyrin (Ru(TPFPP)(CO)) linked to hydrophilic PEG macromolecules [101].
The resulting PEG-supported Ru-porphyrin was shown to be an effective catalyst for oxidation of
both secondary and tertiary C–H bonds (Scheme 27) [101].
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Scheme 26. PEG-supported tetrahydroxyphenyl porphyrin for photooxidation reactions.
Che and
and co-workers
co-workers reported
reported aa covalently
covalently attached
attached carbonylruthenium(II)meso-tetrakis
carbonylruthenium(II)meso-tetrakis
(pentafluorophenyl)porphyrin
(Ru(TPFPP)(CO))
linked
to
hydrophilic
PEGPEG
macromolecules
[101].[101].
The
(pentafluorophenyl)porphyrin (Ru(TPFPP)(CO)) linked to hydrophilic
macromolecules
resulting
PEG-supported
Ru-porphyrin
was was
shown
to beto
anbe
effective
catalyst
for oxidation
of both
The resulting
PEG-supported
Ru-porphyrin
shown
an effective
catalyst
for oxidation
of
secondary
and
tertiary
C–H
bonds
(Scheme
27)
[101].
both secondary and tertiary C–H bonds (Scheme 27) [101].
Scheme 27.
27. PEG-supported
porphyrin for
for oxidation
oxidation reactions.
reactions.
Scheme
PEG-supported ruthenium
ruthenium porphyrin
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In
In 2004,
2004, Shiragami
Shiragami and
and co-workers
co-workers reported
reported aa scaled-up
scaled-up photocatalytic
photocatalytic oxidation
oxidation of
of cycloalkenes
cycloalkenes
with
O
under
visible-light
using
a
SbTPP(OH)
zSiO
catalyst
(Scheme
28)
[102].
with O22 under visible-light using a SbTPP(OH)22\SiO22 catalyst (Scheme 28) [102].
Scheme 28.
28. Different
photocatalytic properties
properties of
of antimony
antimony SbTPP(OH)
SbTPP(OH)2zSiO
\SiO2 supported
supported over
over silica.
silica.
Scheme
Different photocatalytic
2
2
Recently, Gonsalves and co-workers have synthesized supported materials with a non-symmetric
halogenated tetra-arylporphyrin linked to Merrifield polymers, thus showing high efficiency in the
scalable photooxygenations of different substrates using sunlight (Scheme 29) [103,104].
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Scheme 28. Different photocatalytic properties of antimony SbTPP(OH)2\SiO2 supported over silica.
Recently,
Recently, Gonsalves
Gonsalves and
and co-workers
co-workers have
have synthesized
synthesized supported
supported materials
materials with
with aa non-symmetric
non-symmetric
halogenated
tetra-arylporphyrin
linked
to
Merrifield
polymers,
thus
showing
high
efficiency
halogenated tetra-arylporphyrin linked to Merrifield polymers, thus showing high efficiency in
in the
the
scalable
scalable photooxygenations
photooxygenations of
of different
different substrates
substratesusing
usingsunlight
sunlight(Scheme
(Scheme29)
29)[103,104].
[103,104].
Scheme 29. Solar photooxygenation with supported porphyrins on Merrifield-modified polymers.
Scheme 29. Solar photooxygenation with supported porphyrins on Merrifield-modified polymers.
4.2. Continuous Flow Photocatalysis
Continuous flow reactors have recently emerged as a new technology in chemical synthesis with
a wide variety of efficient applications [105,106]. The small inner dimensions of these devices in
combination with their continuous flow operation make them especially attractive for photochemical
reactions [107]. A combination of a microreactor system as the reaction medium and visible light
offers a new and convenient approach towards green photochemistry, in which the production of
by-products is also reduced. As a result, not only enhanced selectivity is achieved, but also the
amount of environmentally problematic and expensive solvents are reduced, and the security is really
improved [108].
Reactions with singlet oxygen (1 O2 ) have not been used for large/industrial scale processes for
the following reasons: (I) decreased photochemical efficiency of photosensitizers in batch conditions
due to low light penetration in classic photochemical reactors); (II) the need for high substrate dilutions
due to the safety requested by procedures with peroxides and endoperoxides formation; (III) major
by-products formation; and (IV) difficulty to find suitable non-flammable and environmentally friendly
solvents, with no incompatibility with singlet oxygen generation [109].
However, the use of supercritical carbon dioxide as solvent brings a solution to some of these
issues, because it is neither flammable nor toxic, completely miscible with gases, and has a lower
viscosity and higher diffusivity [110]. For example, George and co-workers reported the production of
artemisinin (gram-scale) using liquid CO2 as solvent and an immobilized porphyrin as photocatalyst.
They developed a simple method to anchor TPP or TPFPP onto the sulfonated cross-linked polystyrene
ion-exchange resin (Amberlyst-15) [111]. This yielded a dual catalyst, with both the Bronsted acid
and photo-catalytic functions needed to convert dihydroartemisinic acid (DHAA) into artemisinin,
currently a very important drug for malaria treatment (Scheme 30). The reaction resulted in 98% of
conversion using toluene as co-solvent.
artemisinin (gram-scale) using liquid CO2 as solvent and an immobilized porphyrin as photocatalyst.
They developed a simple method to anchor TPP or TPFPP onto the sulfonated cross-linked polystyrene
ion-exchange resin (Amberlyst-15) [111]. This yielded a dual catalyst, with both the Bronsted acid
and photo-catalytic functions needed to convert dihydroartemisinic acid (DHAA) into artemisinin,
currently a very important drug for malaria treatment (Scheme 30). The reaction resulted in 98%
of
Molecules 2016, 21, 310
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conversion using toluene as co-solvent.
H
Ph
[CO2 + O2]
Ph
N
H
NH
HN
H
N
O Ph
O
O O S
O S
O
H
Amb(15)
O
Ph
O
O
H
O
O
2.4 g, 8.6 mmol
[CO2 + O2]
H
COOH
4 g, 17 mmol
Scheme
30. One-pot
artemisinin using
using immobilized
immobilized TPP
TPP on
on Amberlyst-15.
Amberlyst-15.
Scheme 30.
One-pot semi-synthesis
semi-synthesis of
of artemisinin
George and co-workers have been the pioneers in using this kind of green solvent approach, since
George and co-workers have been the pioneers in using this kind of green solvent approach, since
in 2011 they reported the use of supercritical carbon dioxide as solvent with different immobilized
in 2011 they reported the use of supercritical carbon dioxide as solvent with different immobilized
photosensitizers for the continuous flow synthesis of ascaridole from α-terpinene (Scheme 31) [112].
photosensitizers for the continuous flow synthesis of ascaridole from α-terpinene (Scheme 31) [112].
The authors coupled a porphyrin to amino functionalized PVC beads by covalent amide linkage, and
The authors coupled a porphyrin to amino functionalized PVC beads by covalent amide linkage,
achieved the continuous production of ascaridole and also citronellol hydroperoxide from citronellol
and achieved the continuous production of ascaridole and also citronellol hydroperoxide from
[112].
citronellol
[112].
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Lapkin
and
co-workers[113] have also carried out a gram-scale photooxygenation/rearrangement
of α-pinene using TPP as sensitizer in dichloromethane under continuous flow conditions, thus
obtaining pinocarvone quantitatively. This oxygenation reaction was efficiently performed in a
segmented gas-liquid flow condition in a very safe manner (Scheme 32) [113].
Scheme
PVC amino-functionalized
amino-functionalized covalently
covalently bonded
bondedporphyrin.
porphyrin.
Scheme 31.
31. Continuous
Continuous flow
flow reactions
reactions with
with PVC
Lapkin and co-workers[113] have also carried out a gram-scale photooxygenation/rearrangement
of α-pinene using TPP as sensitizer in dichloromethane under continuous flow conditions, thus
obtaining pinocarvone quantitatively. This oxygenation reaction was efficiently performed in a
segmented gas-liquid flow condition in a very safe manner (Scheme 32) [113].
Seeberger and co-workers have also established gram-scale photoinduced singlet-oxygen
generation under
continuous flow by using TPP as photocatalyst, and a very simple photoreactor
Scheme 32. Scalable photochemical conversion of α-pinene to pinocarvone.
(perfluoroalkoxy—PFA—tube coiled around a cooled glass tube and a lamp) [114]. In this apparatus,
Seeberger and co-workers have also established gram-scale photoinduced singlet-oxygen
generation under continuous flow by using TPP as photocatalyst, and a very simple photoreactor
(perfluoroalkoxy—PFA—tube coiled around a cooled glass tube and a lamp) [114]. In this apparatus,
the illumination of the entire solution is highly efficient because the tubing has a constant, narrow
diameter, and it is positioned very close to the light source. Thus, an increasing quantity (space-time
Molecules 2016, 21, 310
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the illumination of the entire solution is highly efficient because the tubing has a constant, narrow
diameter, and it is positioned very close to the light source. Thus, an increasing quantity (space-time
yield = 200g¨ day´1 ) of the product can be produced in long-term experiments (Scheme 33).
Scheme 31. Continuous flow reactions with PVC amino-functionalized covalently bonded porphyrin.
Scheme 31. Continuous flow reactions with PVC amino-functionalized covalently bonded porphyrin.
Scheme 32. Scalable photochemical conversion of α-pinene to pinocarvone.
Scheme 32. Scalable photochemical conversion of α-pinene to pinocarvone.
Seeberger and co-workers have also established gram-scale photoinduced singlet-oxygen
under continuous
using perspectives
TPP as photocatalyst,
verycrucial
simplestep
photoreactor
Thegeneration
above mentioned
methodflow
has by
opened
to carryand
outa the
in the synthesis
(perfluoroalkoxy—PFA—tube
coiled
around
a
cooled
glass
tube
and
a
lamp)
[114].
In
this
apparatus,
of artemisinin (Scheme 33) [115]. The great importance of TPP as photosensitizer for singlet oxygen
the illumination of the entire solution is highly efficient because the tubing has a constant, narrow
production can be highlighted by the green gram-scale synthesis of artemisinin recently established as
diameter, and it is positioned very close to the light source. Thus, an increasing quantity (space-time
an industrial
by
the
pharmaceutical
company
Sanofi [116].
-1) of
yield = process
200g·dayScheme
the32.
product
be produced
in long-term
experiments
(Scheme 33).
Scalablecan
photochemical
conversion
of α-pinene
to pinocarvone.
To finish this section, it is important to highlight the recent and cost competitive protocol for
photooxygenation
naphthols
under
flowgram-scale
conditions,
which wassinglet-oxygen
recently published
Seebergerofand
co-workers
havecontinuous
also established
photoinduced
generation
under
by using
TPP as
photocatalyst, and
a verywas
simple
photoreactor
by Oliveira,
Miller
andcontinuous
McQuadeflow
[117].
A careful
methodological
study
performed
using four
(perfluoroalkoxy—PFA—tube
coiled
around
a
cooled
glass
tube
and
a
lamp)
[114].
In
this
apparatus,
different porphyrins as photocatalysts. After optimisation of the reaction conditions, a number of
the illumination of the entire solution is highly efficient because the tubing has a constant, narrow
substituted naphthols were converted into the corresponding naphthoquinones in high yields, as well
diameter, and it is positioned very close to the light source. Thus, an increasing quantity (space-time
as in gram-scale
experiments
(up to can
1.4 be
g produced
in a 24 h(Scheme
experiment)
(Scheme 34).
-1) of the product
yield = 200g·day
produced incontinuously
long-term experiments
33).
Molecules 2016, 21, 310
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Schememethod
33. Synthetic
to artemisinin
fromtoartemisinic
The above mentioned
has route
opened
perspectives
carry outacid.
the crucial step in the
synthesis of artemisinin (Scheme 33) [115]. The great importance of TPP as photosensitizer for singlet
oxygen production can be highlighted by the green gram-scale synthesis of artemisinin recently
established as an industrial process by the pharmaceutical company Sanofi [116].
To finish this section, it is important to highlight the recent and cost competitive protocol for
photooxygenation of naphthols under continuous flow conditions, which was recently published by
Oliveira, Miller and McQuade [117]. A careful methodological study was performed using four
different porphyrins Scheme
as photocatalysts.
of the
reaction acid.
conditions, a number of
33. SyntheticAfter
route optimisation
to artemisinin from
artemisinic
Scheme 33. Synthetic route to artemisinin from artemisinic acid.
substituted naphthols were converted into the corresponding naphthoquinones in high yields, as well
as in gram-scale experiments (up to 1.4 g produced continuously in a 24 h experiment) (Scheme 34).
Scheme 34. Photo-oxidation of naphthols under continuous flow conditions.
Scheme 34. Photo-oxidation of naphthols under continuous flow conditions.
5. Perspectives
Over the last few decades, synthetic organic chemists have taken advantage of the catalytic
activity of porphyrin derivatives to develop novel laboratory procedures and to enhance existing
protocols, but normally on a small scale. Recently some scaled-up reactions have been described
showing that these macrocycles are very useful for increasing the scope of available multiple
catalysts. The challenge now is to explore the broad potential and applications of these catalysts for
Molecules 2016, 21, 310
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5. Perspectives
Over the last few decades, synthetic organic chemists have taken advantage of the catalytic activity
of porphyrin derivatives to develop novel laboratory procedures and to enhance existing protocols,
but normally on a small scale. Recently some scaled-up reactions have been described showing that
these macrocycles are very useful for increasing the scope of available multiple catalysts. The challenge
now is to explore the broad potential and applications of these catalysts for the synthesis of important
products from an economic point of view, for the industrial and pharmaceutical industries.
In addition, another challenge is to introduce simple and cost-competitive synthetic routes [118]
to access porphyrinods, since historically these compounds are considered rare due to low synthetic
yields and tedious purification protocols. Therefore, it is necessary to incorporate enabling techniques
for the optimisation of the production and utilization of these fascinating naturally inspired catalysts,
and chemists must now consider these robust compounds for many new purposes.
Acknowledgments: The authors would like to thank the São Paulo Research Foundation (FAPESP 2015/21110-4,
2013/07276-1 and 2011/13993-2) for the financial support and also CAPES and CNPq for fellowships.
Author Contributions: Juan C. Barona-Castaño and Christian C. Carmona-Vargas contributed equally to this
review. They accomplished the literature collection, designed the figures and schemes, and also wrote the first
draft of the manuscript. Timothy J. Brocksom and Kleber T. de Oliveira wrote the final version of the manuscript,
suggested modifications in schemes and figures, and checked the cited literature.
Conflicts of Interest: The authors declare no conflict of interest.
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