Catalysts: Zeolites As Acid/Basic Solid Catalysts: Recent Synthetic Developments

catalysts
Review
Zeolites as Acid/Basic Solid Catalysts: Recent
Synthetic Developments
Valentina Verdoliva 1 , Michele Saviano 2 and Stefania De Luca 1, *
1 Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy;
valentina.verdoliva@gmail.com
2 Institute of Crystallography, National Research Council, 70126 Bari, Italy; msaviano@unina.it
* Correspondence: stefania.deluca@cnr.it; Tel.: +39-081-253-4514

Received: 13 February 2019; Accepted: 1 March 2019; Published: 8 March 2019
Abstract: The zeolites are porous solid structures characterized by a particular framework of
aluminosilicates, in which the incorporation of the Al+3 ions generates an excess of negative charge
compensated by cations (usually alkali or alkali earth) or protons. In the latter case, they are employed
as catalysts for a wide variety of reactions, such as dehydration, skeletal isomerization and cracking,
while the catalytic activity of basic zeolites has not found, up to now, any industrial or whatever
relevant application in chemical processes. In the present review, we firstly intend to give an overview
of the fundamental chemical composition, as well as the structural features of the zeolite framework.
The purpose of this paper is to analyze their key properties as acid, both Lewis and Brønsted, and basic
solid support. Their application as catalysts is discussed by reviewing the already published works
in that field, and a final remark of their still unexplored potential as green, mild, and selective catalyst
is also reported.
Keywords: zeolites; catalysis; solid acid; solid base; chemical modification; alkylation; glycosidation
1. Introduction
Zeolites, both naturally occurring or synthetic, are solids of aluminosilicates with crystalline
structure and pore size in the microporous range (<10 Å). They can be described as a framework of
SiO4 and AlO4 tetrahedrons cross-linked at their corners by a common oxygen ion. The isomorphic
substitution of Si+4 with a trivalent ion Al+3 generates a negative charge in the lattice, which needs
to be compensated. Inclusion in the crystal structure of cations, such as alkali or alkali earth metals,
compensates the electrovalence of the tetrahedrons containing aluminum. The spaces between the
tetrahedrons, which constitute their channels, are naturally occupied by water molecules, so that
hydrated zeolites can be generally represented by the formula [1–3]
M+2 x/n [(AlO2 )x (SiO2 )y ]·wH2 O
Dehydrated zeolites are able to act as molecular sieves, since the dimension of their pores is such as to
accept for absorption only molecules of a certain size, shape, and polarity. The available void volume
of the zeolites is directly connected to their sieving properties. There are a variety of ways in which
they are employed in order to take advantage of these properties. Indeed, alkali cationic zeolites are
largely employed as adsorbents for industrial gas purification, such as CO2 capture [4]. They have also
a high tendency to capture water and other polar molecules, such as NH3 and H2 S [5].
The charge-balancing cations can be partially or totally exchanged by other cations, since they are
bonded to the lattice through Coulombic interactions, or either by the ammonium ion, which can be
later decomposed, or by heat treatment in gaseous ammonia and a proton, thus generating a Brønsted
Catalysts 2019, 9, 248; doi:10.3390/catal9030248 www.mdpi.com/journal/catalysts

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employing templating agents, in fact their decomposition leads to having a residual proton, which
acid form of the zeolite [6]. Recently, protonated zeolites have also been synthesized by employing
neutralizes the net negative charge on the framework aluminum atoms (Figure 1). Brønsted acid sites
templating agents, in fact their decomposition leads to having a residual proton, which neutralizes the
in zeolites are the bridging hydroxyl groups between Al and Si tetrahedral, while the second source
net negative charge on the framework aluminum atoms (Figure 1). Brønsted acid sites in zeolites are
of acidity, Lewis acidity, is ascribed to both framework and extra-framework aluminum species
the bridging hydroxyl groups between Al and Si tetrahedral, while the second source of acidity, Lewis
(EFAL) [3].
acidity, is ascribed to both framework and extra-framework aluminum species (EFAL) [3].
(a) (b)
Figure 1. Representation of the basic (a) and acid (b) sites in Na- zeolites.
In the
In the last
last thirty
thirty years,
years, zeolites,
zeolites, as as solid
solid acids,
acids, have
have become
become extremely
extremely successful
successful as as catalysts
catalysts andand
have been employed for a wide variety of reactions, such as the cracking of carbon–carbon bonds,
have been employed for a wide variety of reactions, such as the cracking of carbon–carbon bonds,
skeletal isomerizations,
skeletal isomerizations, polymerization,
polymerization, aromatic aromatic alkylation
alkylation with with alkenes
alkenes or or alcohols,
alcohols, and and other
other acid
acid
catalyzed reactions [7]. The reason for their success in catalysis is related to several specific features.
catalyzed reactions [7]. The reason for their success in catalysis is related to several specific features.
First of
First of all,
all, zeolites,
zeolites, because
because of of their
their cage-like
cage-like porous porous structure,
structure, have have a a very
very high
high surface
surface area area and
and
adsorption capacity. In addition, the sizes of their channels and cavities are in the range typical for
adsorption capacity. In addition, the sizes of their channels and cavities are in the range typical for
many molecules of interest (5–12 Å) and offer at the same time, shape selectivity, which can be used
many molecules of interest (5–12 Å) and offer at the same time, shape selectivity, which can be used to
to direct a given catalytic reaction toward the desired product, avoiding undesired side reactions. is
direct a given catalytic reaction toward the desired product, avoiding undesired side reactions. It It
is also
also worth
worth mentioning
mentioning thatthatforforthethe hydrogenation/dehydrogenation,
hydrogenation/dehydrogenation, thethe activity
activity of of
thethe
acidacid zeolites
zeolites is
is implemented
implemented byby metals
metals like
like Pt,Pt,Pd,
Pd,NiNiand,
and,ininthisthiscase,
case,the thesolid
solidcatalyst
catalystacts acts as
as aa support
support providing
providing
its large surface as a deposit of the metals listed above [4].
its large surface as a deposit of the metals listed above [4].
The Brønsted
The Brønsted acidity acidity of of zeolites,
zeolites, whenwhen the the negative
negative chargecharge presentpresent on on the the Al-substituted
Al-substituted
framework is compensated by alkaline cations, can be generated by exchanging the synthesis cations
framework is compensated by alkaline cations, can be generated by exchanging the synthesis cations
with protons.
with protons. In In other
other words,
words, the the number
number of of thethe Brønsted
Brønsted acid acid sites
sites of of aa zeolite
zeolite depends
depends on on thethe
framework Si/Al ratio. On the other hand, it has been experimentally demonstrated that, while the
framework Si/Al ratio. On the other hand, it has been experimentally demonstrated that, while the
+3 content, a low strength of them is observed, which
density of
density of these
these acid
acid sites
sites increases
increases with with thethe AlAl+3 content, a low strength of them is observed, which
means the
means the Brønsted
Brønsted acidityacidityof ofzeolites
zeolitesisisalsoalsoinfluenced
influencedbybythe thepresence
presence ofof the
the Lewis
Lewis acidity.
acidity. More
More in
in general, several factors are involved with the catalytic performance of the zeolites, the ability of
general, several factors are involved with the catalytic performance of the zeolites, the ability of the
the substrate
substrate to sieve
to sieve through
through their
their pores,
pores, thethe topology
topology ofofthe thecrystal
crystalframework
frameworkand and extra-framework
extra-framework
and, also,
and, also, the
the electrostatic
electrostatic field field generated
generated by by the
the framework
framework Si/Al Si/Al ratioratio [8,9].
[8,9].
Among the
Among the solid
solid catalysts
catalysts employed
employed for for the
the Friedel–Craft
Friedel–Craft aromatic aromatic acylation,
acylation, the the zeolites
zeolites have
have
successfully replaced
successfully replaced the the Lewis
Lewis acids acids AlCl
AlCl33,, FeCl
FeCl33,, SnCl
SnCl44,, andand TiCl TiCl4 for academic and
for academic and industrial
industrial
applications, due
applications, due to to the
the shape
shapeselectivity
selectivityoffered
offeredby bythisthismaterial.
material.In In somesome cases
casesseveral
several metals,
metals, in
particular, metal triflates such as La(OTf)3, 3Ce(OTf)4, Y(OTf)
in particular, metal triflates such as La(OTf) , Ce(OTf) 4 , Y(OTf) 3, and
3 , andZn(OTf)2, were
Zn(OTf) 2 , wereincorporated in
incorporated
their
in framework
their framework andand moremore stable,
stable, efficient
efficientandand recyclable
recyclable catalysts
catalysts were wereobtained.
obtained. The Theresults in this
results in
field allowed advances toward the employment of more eco-compatible methodologies and are
this field allowed advances toward the employment of more eco-compatible methodologies and are
greatly reviewed
greatly reviewed by by Sartori
Sartori and and Maggi
Maggi [10].
[10]. TheThe samesame authors
authors also also provided
provided an an exhaustive
exhaustive overview
overview
about the
about the heterogeneous
heterogeneous catalysis catalysis applied
applied in in the
the field
field ofof the
the protection
protection and and deprotection
deprotection reactions
reactions of of
functional groups during the organic synthesis. Zeolites are also extensively employed in this field,
functional groups during the organic synthesis. Zeolites are also extensively employed in this field,
and have
and have thethe advantage
advantage of of providing
providing an an easier
easier reaction
reaction handling
handling and and finalfinal purification
purification step, step, together
together
with an improved selectivity obtained for the protective chemistry [11].
with an improved selectivity obtained for the protective chemistry [11].
After all,
After all, the
the application
application of zeolites as
of zeolites as acidacid catalysts
catalysts has has been been basically
basically linked
linked with with thethe
development of
development of refinery
refinery and and petrochemistry.
petrochemistry. In In oil
oil refinery,
refinery, they they play play aa key key role,
role, since
since theythey result
result
highly active,
highly active, selective,
selective, andand durable
durable catalysts,
catalysts, and, and, as as aa matter
matter of of fact,
fact, have
have replaced
replaced mineral
mineral acidsacids as as
the new environmentally friendly solid catalyst. Moreover, it has been proved that these materials
the new environmentally friendly solid catalyst. Moreover, it has been proved that these materials
would have a key role also for the biomass conversion [12,13]. In fact, zeolites, as solid catalysts, offer
Catalysts 2018, 8, x FOR PEER REVIEW 3 of 21
the advantage of being tunable and recyclable, and are easily separated from reaction mixtures.3 For
Catalysts 2019, 9, 248 of 21
all the listed reasons, they are particularly useful for clean and economical production processes of
fine chemicals, which is becoming an area of growing interest [14].
would In all
have thea cited
key role applications,
also for the thebiomass
zeolites conversion
are used for[12,13].their acid–base properties;
In fact, zeolites, however,
as solid the
catalysts,
chemical discussion for defying this key role is still an active debate [4]. Both acidic and basic zeolites
offer the advantage of being tunable and recyclable, and are easily separated from reaction mixtures.
are
Foravailable,
all the listed butreasons,
acidic zeolites
they arehave found broad
particularly usefulapplication
for clean and ineconomical
important industrial
productionprocesses
processesas of
well as in organic
fine chemicals, chemistry
which reactions.
is becoming In comparison,
an area of growing much interest less attention has been paid, in chemical
[14].
technology,
In all the to thecited application
applications, of thethezeolites
zeolitesasare “basic
usedcatalysts”
for their for academic
acid–base reactions, however,
properties; while it
results
the chemicaltotallydiscussion
absent forfor industrial
defying processes.
this key role Indeed,
is still the structure–activity
an active debate [4]. Both relationship
acidic and forbasic
the
microporous basic properties
zeolites are available, but acidicofzeolites
zeolites is still
have found an broad
open discussion.
application in What is clearindustrial
important is that the zeolite
processes
acid–base
as well as in pair is different
organic chemistryfromreactions.
that of the In homogeneous
comparison, much acid–base compounds,
less attention since
has been their
paid, in strength
chemical
is rather influenced
technology, by the type
to the application of exchangeable
of the zeolites as “basic cations, aluminum
catalysts” content,
for academic structural
reactions, dimension,
while it results
and porosity [4,15,16].
totally absent for industrial processes. Indeed, the structure–activity relationship for the microporous
basicHerein,
properties we do not intend
of zeolites to give
is still a comprehensive
an open discussion. What review, butisinstead
is clear that theanzeolite
overview of thepair
acid–base mostis
recent
different organic
from that reactions
of thethat have employed
homogeneous zeolites
acid–base as mild acid
compounds, sinceortheir
basicstrength
solid catalysts
is ratherfor efficient
influenced
and
by theselective
type ofchemical
exchangeable transformation of quite sensitive
cations, aluminum substrates.dimension,
content, structural In particular,andthe present
porosity paper
[4,15,16].
focuses on thewe
Herein, recent
do not results
intend dealing
to give with zeolites as basic/acid
a comprehensive review,solids for organic
but instead transformations
an overview of the most of
peptide and carbohydrate
recent organic reactions that have molecules,
employed since wideasapplications
zeolites mild acid or basic were solidfound on these
catalysts substrates.
for efficient and
Moreover, in recent
selective chemical studies of theof
transformation modulation
quite sensitive activity of zeolites,
substrates. for both purposes,
In particular, the presentacidpaper andfocuses
basic
catalysts
on the recent are reported,
results dealing in order withto zeolites
prove its asvaluable
basic/acid application
solids forin some transformations
organic of the very useful of organic
peptide
reactions. For all the
and carbohydrate reported since
molecules, organic wide process, the employment
applications were foundofon zeolites as solid catalysts
these substrates. Moreover, could in
avoid the formation
recent studies of by-products
of the modulation activityand waste, for
of zeolites, moreboth usually
purposes, associated with catalysts
acid and basic traditionalare
homogeneous
reported, in order catalysts,
to prove besides being easily
its valuable separated
application in somefrom ofthe
thefinal
veryproducts and also
useful organic regenerated,
reactions. For all
ifthe
it was necessary,
reported organicinprocess,
order tothe be employment
reused more of times in the
zeolites as same process. The
solid catalysts couldfinal aimthe
avoid is to exploit
formation
the potential andand
of by-products thewaste,
additional
moreadvantages of replacing
usually associated withthe currentlyhomogeneous
traditional used homogenous catalyst
catalysts, for
besides
standard
being easily organic reactions
separated from with
theheterogeneous
final products catalysts
and also such as the zeolites.
regenerated, if it was necessary, in order to
The structural
be reused more times andincomposition
the same process.description
The finalof the
aim several types of
is to exploit thezeolites,
potentialnatural
and theor additional
synthetic,
is not reported
advantages in this review,
of replacing it has been
the currently used extensively
homogenous reviewed
catalyst in for
a recently
standard published article [17].
organic reactions with
We deal in particular with the Zeolites A (Si/Al ratio usually 1) structurally denoted with the
heterogeneous catalysts such as the zeolites.
code The LTAstructural
(Linde Type andA), in particular
composition with Na-LTA,
description of thewhich
several contains
types ofsodium as natural
zeolites, cation (Figure 2), it
or synthetic,
counterbalances
is not reported inthe this negative
review, it charge
has beenofextensively
the oxygen atoms in
reviewed and has a published
a recently pore diameterarticleof[17].
4 Å:
Na12[(AlOWe deal2) (SiO 2)]12 27H2O with the Zeolites A (Si/Al ratio usually 1) structurally denoted with the
. in particular
.
codeWhen 75% of Type

LTA (Linde its sodium
A), in is replaced with
particular by potassium,
Na-LTA, which it is referred
contains to as a zeolite
sodium of 3 Å (Figure
as cation pore size, 2),
alternatively,
it counterbalances the replacement
the negative of sodium
charge by of calcium
the oxygen givesatoms
rise to andthe typehas of 5 Å, with
a pore an increased
diameter of 4 Å:
diameter.
Na12 [(AlO2 ). (SiO2) ]12 ·27H2 O.
Thestructure
Figure2.2.The
Figure structureof
ofzeolite
zeoliteNa-LTA.
Na-LTA.
When 75% of its sodium is replaced by potassium, it is referred to as a zeolite of 3 Å pore

Other zeolites taken under consideration in this review (for them catalytic properties) are Zeolite
size, alternatively, the replacement of sodium by calcium gives rise to the type of 5 Å, with an
X (FAU-type structure, Si/Al ratio usually 1.2), Zeolite Y (FAU-type structure, Si/Al ratio usually 2.4),
increased diameter.
Other zeolites taken under consideration in this review (for them catalytic properties) are Zeolite
X (FAU-type structure, Si/Al ratio usually 1.2), Zeolite Y (FAU-type structure, Si/Al ratio usually 2.4),
Zeolite ZSM-5 (MFI-type structure, Si/Al ratio usually 15), and Natrolite (Na2[Al2Si3O10]⸱2H2O) [9,18]
(Figure 3).
Moreover
Catalysts 2019, 9, 248 we also report on several examples of recently published works performed by tuning
4 of 21
the acid–base properties of the zeolite catalysts. They depend on the aluminum content in the zeolite
Zeolite ZSM-5 (MFI-type structure, Si/Al ratio usually 15), and Natrolite (Na2[Al2Si3O10]⸱2H2O) [9,18]
framework, as well as on the nonframework charge balancing constituents that can be adequately
(FigureZSM-5
Zeolite 3). (MFI-type structure, Si/Al ratio usually 15), and Natrolite (Na2 [Al2 Si3 O10 ]·2H2 O) [9,18]
replaced. Some other references are only cited [19–23].
Moreover
(Figure 3). we also report on several examples of recently published works performed by tuning
the acid–base properties of the zeolite catalysts. They depend on the aluminum content in the zeolite
replaced. Some other references are only cited [19–23].
Figure 3. Al atom concentration and SiO2 /Al2 O3 ratio for various zeolites (adaptation from [9],
Figure
Nature 3. Al atom concentration and SiO2/Al2O3 ratio for various zeolites (adaptation from [9], Nature
1984).
1984).
Moreover we also report on several examples of recently published works performed by tuning
the2.acid–base
Glycosidation Reactions
properties Promoted
of the zeolite by Molecular
catalysts. Sieveson the aluminum content in the zeolite
They depend
Figure 3. Al atom concentration and SiO2/Al2O3 ratio for various zeolites (adaptation from [9], Nature
1984).
2.1. Glycosidation
replaced. Some otherReaction via Activation
references of Glycosyl
are only cited [19–23].Trichloro- and N-Phenyltrifluoroacetimidates
Iadonisi and
2. Glycosidation coauthors
Reactions performed
Promoted the glycosidation
by Molecular Sieves of primary and secondary saccharides by
2. Glycosidation Reactions Promoted by Molecular Sieves
using acid-washed 4 Å molecular sieves as catalyst that successfully activated glycosyl imidates,
2.1.acting
2.1. Glycosidation
Glycosidation Reaction
at the same time
Reaction viaasActivation
via Activation
promoters of Glycosyl
of Glycosyl Trichloro-
and as drying andN-Phenyltrifluoroacetimidates
agents
Trichloro- and N-Phenyltrifluoroacetimidates
[24]. In major detail, a donor such as
trichloro- or trifluoroacetimidate, and an acceptor, employed in a slight stoichiometric excess, were
Iadonisi and
Iadonisi and coauthors
coauthors performed
performed the the glycosidation
glycosidation of of primary
primary and and secondary
secondary saccharides
saccharides by by
dissolved under an Ar atmosphere in toluene and in presence of activated (T = 200 °C overnight under
using acid-washed 4 Å molecular sieves as catalyst that successfully activated
using acid-washed 4 Å molecular sieves as catalyst that successfully activated glycosyl imidates, acting glycosyl imidates,
vacuum) 4 Å aw (acid washed) MS (Scheme 1). The reaction was heated to a temperature of 70 °C
acting
at at the
the same same
time time as promoters
as promoters and as
and as drying drying
agents agents
[24]. [24].detail,
In major In major detail,
a donor such a as
donor such or
trichloro- as
and then stirred for two hours. Although common acidic activators like lanthanide triflates avoid the
trichloro- or trifluoroacetimidate,
trifluoroacetimidate, and an acceptor, andemployed
an acceptor, employed
in a slight in a slightexcess,
stoichiometric stoichiometric excess,under
were dissolved were
high temperature, the obtained yields with molecular sieves as catalyst resulted quite competitive. In
dissolved under an Ar atmosphere in toluene and in presence of activated
◦ (T
an Ar atmosphere in toluene and in presence of activated (T = 200 C overnight under vacuum) 4 Å = 200 °C overnight under
order to exclude that residual acids of the acid washed zeolite could have catalyzed the glycosidation
vacuum)
aw 4 Å aw (acid
(acid washed) washed)1).MS
MS (Scheme The(Scheme
reaction1). The
was reaction
heated to awas heated toofa70
temperature temperature
◦ C and then ofstirred
70 °C
reaction, the 4 Å aw MS were washed several times with distillated water before their use and the
andtwo
for then stirred
hours. for two hours.
Although common Although commonlike
acidic activators acidic activators
lanthanide like lanthanide
triflates avoid the triflates avoid the
high temperature,
efficiency of the reaction was not affected.
high temperature, the obtained yields with molecular sieves as catalyst resulted
the obtained yields with molecular sieves as catalyst resulted quite competitive. In order to exclude quite competitive. In
order
that to exclude
residual acidsthat residual
of the acids of zeolite
acid washed the acidcould
washedhave zeolite couldthe
catalyzed have catalyzed the
glycosidation glycosidation
reaction, the 4 Å
reaction, the 4 Å aw MS were washed several times with distillated water
aw MS were washed several times with distillated water before their use and the efficiency of the before their use and the
efficiency of the reaction
reaction was not affected. was not affected.
Scheme 1. Activation of glycosyl imidates with activated 4 Å aw MS in a glycosidation reaction.
2.2. Carbinol Glycosidation Reaction of the 17-β-Estradiol

The same
Scheme
Scheme 1. authors, of
1. Activation
Activation byglycosyl
of only using
glycosyl thewith
imidates
imidates same
with commercially
activated
activated 44 Å
Å aw
aw MS
MSavailable 4 Å aw reaction.
in aa glycosidation
in glycosidation MS, performed a
reaction.
regioselective carbinol glycosidation of 17β-Estradiol [25]. The reaction proceeded overnight via a
2.2.
2.2. Carbinol
Carbinol Glycosidation
Glycosidation Reaction
Reaction of
of the
the 17-β-Estradiol
17-β-Estradiol
The
The same authors, by only using the same
same authors, by only using the same commercially
commercially available
available 44 Å Å aw
aw MS,
MS, performed
performed aa
regioselective
regioselectivecarbinol
carbinolglycosidation
glycosidation ofof
17β-Estradiol [25].
17β-Estradiol TheThe
[25]. reaction proceeded
reaction overnight
proceeded via a via
overnight milda
Scheme 2. Regioselective carbinol glycosidation of Estradiol in presence of activated 4 Å aw MS.
Catalysts 2018, 9,
2.3. Selective
Catalysts 2019, 8,α-Fucosylation
x FOR PEER REVIEW
248 for Preparing the Antigenic Trisaccharide Sequence of Lewis X 55 of 21
of 21
mild Since the α-anomer

activation of the trichloroacetimidate,
of a glycosyl L-fucose is widely present in active oligosaccharide
in 1,2-dichloroethane as solvent;sequences,
the final
Iadonisi and
glycosidated
activation coauthors
of aestradiol
glycosyl was have devotedinbig
obtained
trichloroacetimidate, attention
a satisfactory toyield
the development
(Scheme
in 1,2-dichloroethane of synthetic
2). The
as solvent; illustrated
the strategies
procedure
final glycosidated to
introduce
estradiol fucose,
was with
obtained its
in peculiar
a α-linkage,
satisfactory yield into oligosaccharide
(Scheme 2). The domains
illustrated [26]
conferred water solubility to a steroid derivative that has a wide interest for its pharmacokinetic
procedure (Scheme 3).
conferred water
In this
properties.
solubility to regard,
a steroidthe investigation
derivative must
that has take interest
a wide into account
for itstwo important aspects:
pharmacokinetic fucosyl donors
properties.
are rather reactive and so prone to decomposition and that the α-fucosylation reaction is efficiently
assisted by the presence of acetyl groups on the donor. A mild synthetic protocol for preparing the
antigenic trisaccharide sequence of Lewis X has proven that 4 Å aw MS are able to promote a highly
stereocontrolled α-fucosylation, having the advantage of long-range participation of the fucose acetyl
protective groups. In major detail, following a procedure previously illustrated, glucosamine 1 was
reacted with a galactosyl imidate 2 providing that disaccharide 3 was quickly deprotected alcohol 4
for the subsequent α-fucosylation reaction. In case of a perbenzylated donor such as the fucosyl N-
(phenyl)trifluoroacetoimidate, the reaction took place in a short time (1–3 h) in the presence of a
catalytic amount
Scheme
Scheme 2. of Yb(OTf)3. carbinol
2. Regioselective
Regioselective The final
carbinol yield and the
glycosidation
glycosidation of stereoselectivity
of Estradiol
Estradiol in presence
in presencewere totally 44satisfying
of activated
of activated ÅÅ aw MS.for the
aw MS.
trisaccharide 5. For a partially acetylated fucose derivative, only activated 4 Å aw MS (T = 200 °C
2.3. Selective α-Fucosylation for Preparing the Antigenic Trisaccharide Sequence of Lewis X
2.3. Selective
overnight α-Fucosylation
under vacuum) were for Preparing the Antigenic
used as catalyst and anTrisaccharide
excess of twoSequence of Lewis
equivalent X donor (6). The
of the
reaction
Sincetime
Since thewas prolonged
the α-anomer
α-anomer
of theto
of the24–36
L-fucose h,
L-fucosetheis yield
is widely waspresent
present
widely quite satisfying,
in active and
in active oligosaccharidecomplete stereocontrol
sequences,
oligosaccharide
Iadonisi
sequences,
Iadonisi and coauthors have devoted big attention to the development of synthetic strategiesthe
was achieved. The developed strategy disclosed a remarkable mildness that can characterize
and coauthors have devoted big attention to the development of synthetic strategies to introduce
to
synthetic
fucose, procedure
with for
its peculiar preparing
α-linkage, important biological
into oligosaccharide saccharidic
domains [26] targets.
(Scheme 3).
introduce fucose, with its peculiar α-linkage, into oligosaccharide domains [26] (Scheme 3).
In this regard, the investigation must take into account two important aspects: fucosyl donors
reacted with a galactosyl imidate 2 providing that disaccharide 3 was quickly deprotected alcohol 4
for the subsequent α-fucosylation reaction. In case of a perbenzylated donor such as the fucosyl N-
(phenyl)trifluoroacetoimidate, the reaction took place in a short time (1–3 h) in the presence of a
catalytic amount of Yb(OTf)3. The final yield and the stereoselectivity were totally satisfying for the
trisaccharide 5. For a partially acetylated fucose derivative, only activated 4 Å aw MS (T = 200 °C
overnight under vacuum) were used as catalyst and an excess of two equivalent of the donor (6). The
reaction time was prolonged to 24–36 h, the yield was quite satisfying, and complete stereocontrol
was achieved. The developed strategy disclosed a remarkable mildness that can characterize the
synthetic procedure for preparing important biological saccharidic targets.
Scheme 3.
Scheme 3. α-fucosylation
α-fucosylation reaction promoted by activated 4 Å aw MS
MS to
to synthesize
synthesize aa trisaccharide
trisaccharide
antigenic fragment.
antigenic fragment.
In this regard,
2.4. Synthesis the investigation
of a Tetrasaccharide must
Sequence of take
Globointo
H account two important aspects: fucosyl donors
reacted with a galactosyl imidate 2 providing that disaccharide 3 was quickly deprotected alcohol
4 for the subsequent α-fucosylation reaction. In case of a perbenzylated donor such as the fucosyl
N-(phenyl)trifluoroacetoimidate, the reaction took place in a short time (1–3 h) in the presence of a
catalytic amount of Yb(OTf)3 . The final yield and the stereoselectivity were totally satisfying for the
trisaccharide 5. For a partially acetylated fucose derivative, only activated 4 Å aw MS (T = 200 ◦ C
overnight under vacuum) were used as catalyst and an excess of two equivalent of the donor (6). The
reaction time was prolonged to 24–36 h, the yield was quite satisfying, and complete stereocontrol was
Scheme 3. α-fucosylation reaction promoted by activated 4 Å aw MS to synthesize a trisaccharide
achieved. The developed strategy disclosed a remarkable mildness that can characterize the synthetic
antigenic fragment.
procedure for preparing important biological saccharidic targets.
2.4. Synthesis of a Tetrasaccharide Sequence of Globo H
Catalysts 2019, 9, 248 6 of 21

2.4. Synthesis of a Tetrasaccharide Sequence of Globo H
Globo
Globo H H(Figure
(Figure4)4) is antigen
is an an antigen oligosaccharide
oligosaccharide widely widely employed
employed for the for the development
development of
of vaccines
Globo
vaccines
against some H cancers,
against(Figure
some4) isterminal
an antigen
cancers,
the oligosaccharide
the portion
terminal ofportion ofwidely employed for the
it, a tetrasaccharide
it, a tetrasaccharide that was thatdevelopment
was
proven toproven ofto be
be endowed
vaccines againstactivity,
some cancers, the terminal portionby of it, a tetrasaccharide that was proven
mildtoreaction
be
endowed
with with biological
biological activity,
was nimblywas nimbly
synthesizedsynthesized
Iadonisi byand
coauthors combiningcombining mild
endowed with biological activity, was nimbly synthesized by Iadonisi and coauthors combining mild
reaction
strategiesstrategies
[27]. [27].
reaction strategies [27].
Figure
Figure 4. Chemical structure
4. Chemical structure of
of Globo
Globo H.
H.
Figure 4. Chemical structure of Globo H.
As shown in Scheme 4, by coupling the azido-functionalized donor 1 with the acceptor 2 in
As
As shown
shown in in Scheme
Scheme 4,4,bybycoupling
couplingthe theazido-functionalized
azido-functionalized donor
donor 1 with
1 with the the acceptor
acceptor 2 in 2 in
acetonitrile as solvent and Yb(OTf)3 as catalyst, the β-linked disaccharide 3 was prepared thanks to
acetonitrile
acetonitrile as solvent
solvent and
andYb(OTf)
Yb(OTf)3 3asascatalyst,
catalyst,thethe β-linked
β-linked disaccharide
disaccharide 3 was
3 was prepared
prepared thanks
thanks to to
the β-directing solvent effect. After deacetylation and successive benzylidene formation, acceptor 4
the β-directing
the β-directing solvent
solvent effect.
effect.After
Afterdeacetylation
deacetylation and
andsuccessive
successive benzylidene
benzylidene formation,
formation,acceptor 4
acceptor 4
was coupled
wascoupled
with galactosedonor
coupled with galactose
donor 5. For this reaction only, activated 5 Å aw MS were used as catalyst,
was galactose donor5.5.For Forthis
thisreaction
reactiononly, activated
only, 5 Å5aw
activated MSMS
Å aw were usedused
were as catalyst,
as catalyst,
they gave
gave aa
they gave higher yield
a higher
higher yield ofthe
the finaltrisaccharide
trisaccharide product in a shorter reaction time if compared with
they yieldof
of thefinal
final trisaccharide product
product in in
a shorter
a shorterreaction timetime
reaction if compared
if compared withwith
the results
the results obtained
results obtained
obtained by by using the smaller pore size 4 Å aw MS. Basic deprotection performed with
the by using
usingthethesmaller
smallerporeporesize 4Å
size 4Å awaw MS. Basic
MS. deprotection
Basic deprotection performed
performed withwith
a a
asolution
solutionofofpotassium
potassium bicarbonate
bicarbonate in in methanol
methanol allowed
allowed the the preparation
preparation of of acceptor
the the acceptor7 7 that
that was was
solution of potassium bicarbonate in methanol allowed the preparation of the acceptor 7 that was
subsequently reacted,
subsequently
subsequently reacted, at
reacted, atlow
at lowtemperature,
temperature,with
low temperature,
withfucosyl
with fucosyl
fucosyldonor 8. The
donor
donor
8. reaction
8. The is performed
The reaction
reaction in aninα-an
is performed
is performed
in an
α-
directing system
α-directing
directing system solvent
system
solvent (DCM/diethyl
solvent
(DCM/diethylether/dioxane
(DCM/diethyl
ether/dioxane4:1:1)
ether/dioxane and
4:1:1)
4:1:1) with
and
and the the
with
with efficient
the activation
efficient
efficient of of
activation
activation
of
Yb(OTf) .. Then,
Yb(OTf) Then,by byaareduction
reductionprocedure,
procedure,protecting
protecting groups
groups such as benzyl
such as benzylandand
benzylidene
benzylidene werewere
Yb(OTf)33. Then, by a reduction procedure, protecting groups such as benzyl and benzylidene were
removed, and
removed, and the
the azido-group
azido-group waswas converted
converted in in an
an amino
amino group.
group. The
The obtained
obtained final
final product
product (10)(10) was
removed, and the azido-group was converted in an amino group. The obtained final product (10)
was considered
considered a suitable
a suitable precursor
precursor for developing
for developing novel
novel analogs
analogs of of
thethe originalbiological
original biologicaltarget.
target.
was considered a suitable precursor for developing novel analogs of the original biological target.
Scheme
Scheme4.4.Synthesis
Synthesisof of
thethe
tetrasaccharide.
tetrasaccharide.
Scheme 4. Synthesis of the tetrasaccharide.

Catalysts 2018,
Catalysts 2018, 8,
8, xx FOR
FOR PEER
PEER REVIEW
REVIEW 77 of
of 21
21
Catalysts 2019, 9, 248 7 of 21
3. O-Protection
3. O-Protection of
of Sugars
Sugars Promoted
Promoted by
by Molecular
Molecular Sieves
Sieves
3. O-Protection of Sugars Promoted by Molecular Sieves
3.1. Protection
3.1. Protection Procedure
Procedure of
of Sugar
Sugar Alcoholic
Alcoholic Functions
Functions
Iadonisi Procedure
3.1. Protection
and coauthors
of Sugarachieved interesting results
Alcoholic Functions
achieved interesting results by by employing
employing the the acid-washed
acid-washed 44 Å Å
molecular
molecular
Iadonisi sieves
sieves (300 aw
(300 aw MS)
and coauthors MS) to install
to install
achieved protecting
protecting
interesting groups
resultsgroups on primary
on primary
by employing and secondary
and secondary
the acid-washed alcoholic
alcoholic
4 Å molecular
functions
functions
sieves ofaw
(300of saccharides
saccharides
MS) to install[28]. In
[28]. In particular,
particular,
protecting benzhydrylation
benzhydrylation
groups on primary and and tritylation
and tritylation
secondarywere were performed
performed
alcoholic under
under
functions of
the following
the following
saccharides conditions.
conditions.
[28]. To aa mixture
To
In particular, mixture of of aa model
benzhydrylation model andsaccharide
saccharide dissolved
tritylationdissolved in anhydrous
in
were performed anhydrous toluene
undertoluene and in
and
the following in
presence
presence of To
conditions. of activated
activated
a mixture 300
300 aw
of aw MS
MS (T
a model (T = 200
= 200 °C
saccharide °C overnight
overnight
dissolved under vacuum),
under vacuum),
in anhydrous several
tolueneseveral portions
and in portions
presence of of
of
diphenylmethanol
diphenylmethanol
activated 300 aw MSwere were added
(T =added during
200 ◦ Cduring
overnightaa time-lapse
time-lapse of several
of
under vacuum), several hours
hours
several at room
at roomof
portions temperature.
temperature.
diphenylmethanolConcerning
Concerning
were
the tritylation,
the
addedtritylation,
during ait ittime-lapse
was performed
was performed by aahours
by
of several singleataddition
single addition of aa slight
of
room temperature. slight stoichiometric
stoichiometric
Concerning the excess
excess of triphenyl
of triphenyl
tritylation, it was
methanol
performed (Scheme
methanol (Schemeby a single5). The
5). The procedure
procedure
addition followed
followed
of a slight a dehydration
a dehydration
stoichiometric mechanism
mechanism
excess of triphenyl avoiding
avoiding the employment
the employment
methanol (Scheme 5).
of strong
of
Thestrong proticfollowed
protic
procedure or Lewis
or Lewis acid, it
a acid, it also
also allowed
dehydration allowed
mechanism the avoiding
the protection
protection ofemployment
of
the the less
the less reactive
reactive secondary
secondary
of strong alcoholic
protic alcoholic
or Lewis
functionalities
functionalities
acid, under
underthe
it also allowed mild
mild conditions
conditions
protection that
of that
the lessresult
result compatible
compatible
reactive with both,
with alcoholic
secondary acid and base
both, acidfunctionalities labile
and base labileunder protecting
protecting
mild
groups. Molecular
groups.
conditions Molecular sieves
that resultsieves were with
were
compatible thoroughly
thoroughly
both, acid washed
washed
and base andlabile
and thenprotecting
then reused for
reused for another
another
groups. reaction.
reaction.
Molecular The
The
sieves
protection
protection
were procedure
procedure
thoroughly resulted
resulted
washed totally
totally
and then ineffective
ineffective
reused when performed
when
for another performedThe
reaction. in presence
in presence of
protection ofprocedure
standard, resulted
standard, not acid
not acid
washed,
washed,
totally 4 Å MS.
4 Å MS. when performed in presence of standard, not acid washed, 4 Å MS.
ineffective
Scheme 5.
Scheme
Scheme 5. Benzhydrylation
5. Benzhydrylation and
Benzhydrylation and tritylation
and tritylation of
tritylation of aaa saccharide
of saccharide in
saccharide in presence
in presence of
presence of activated
of activated 444 A
activated A aw
A aw MS.
aw MS.
MS.
3.2. O-Acetylation
3.2.
3.2. O-Acetylation and
O-Acetylation and De-O-Acetylation
and De-O-Acetylation of
De-O-Acetylation of Carbohydrates
of Carbohydrates Activated
Carbohydrates Activated by
Activated by Molecular
by Molecular Sieves
Molecular Sieves
Sieves
Iadonisi and
Iadonisi
and coauthors have
coauthors have also employed 44 Å
also employed
employed ÅÅ MS,MS, without
MS, without any
without any previous
any previous activation,
previous activation, for
activation, for
for
promoting the
promoting
promoting the selective
the selective acetylation
selective acetylation of primary
acetylation of primary and secondary carbohydrate alcoholic groups [29].
primary and secondary carbohydrate alcoholic groups [29].
◦ C and provided the final monoacetylated
The
The reaction was performed in neat acetic anhydride at
The reaction was performed in neat acetic anhydride
reaction was performed in neat acetic anhydride at 000 °C
at °C and
and provided
provided the
the final
final monoacetylated
monoacetylated
primary product
primary
primary product when
product when continued
when continued at room
continued at room temperature,
room temperature, while the heating
temperature, while the heating of the
heating of the reaction
the reaction mixture
reaction mixture
mixture
promoted
promoted a di-acetylated carbohydrate
promoted a di-acetylated carbohydrate synthesis (Scheme 6). In both cases, the final products were
a di-acetylated carbohydrate synthesis (Scheme 6). In both cases, the final products
products were
were
obtained
obtained in
in high
high yields
yields after
after few
few hours.
hours.
obtained in high yields after few hours.
Scheme 6.
Scheme
Scheme 6. Acetylation
6. Acetylation of
Acetylation of saccharide
of saccharide promoted
saccharide promoted by
promoted by 444 Å
by Å MS.
Å MS.
MS.
Ravindranathan
Ravindranathan Kartha Kartha and
Kartha and coauthors
coauthorsproved
provedthatthatactivated
activated 4ÅÅmolecular
molecular sieves areare able
Ravindranathan and coauthors proved that activated 44 Å sieves
molecular sieves are able
able to
to
to promote
promote the the selective
the selective deacetylation
selective deacetylation
deacetylation of of several
of several O-acetylated
several O-acetylated
O-acetylated and and O-benzylated
and O-benzylated carbohydrate
O-benzylated carbohydrate
carbohydrate
promote
derivatives
derivatives [30].
[30]. The procedure
The procedure consist
consist of
of using
using methanol
methanol as
as solvent
solvent over
over activated
activated 44 Å
Å molecular
molecular
derivatives [30]. The procedure consist of using methanol as solvent over activated 4 Å molecular
sieves,
sieves, thus
thus the methanolic
the sodium
methanolic methoxide
sodium methoxidewas hypothesized
was to
hypothesizedbe generated.
to be The reaction
generated. The allowed
reaction
sieves, thus the methanolic sodium methoxide was hypothesized to be generated. The reaction
the deprotection
allowed the almost
the deprotection quantitatively
deprotection almost after a variable
almost quantitatively
quantitatively after time, from
after aa variable minutes
variable time,
time, fromto several
from minutes hours
minutes to (Scheme
to several
several hours7).
hours
allowed
(Scheme 7).
(Scheme 7).
Catalysts 2019, 9, 248 8 of 21
Scheme7.7.De-O-acetylation
Scheme De-O-acetylation of
of saccharide
saccharide promoted by activated
activated4444Å
ÅÅMS.
Scheme
Scheme7.7.De-O-acetylation
De-O-acetylationof
of saccharide promotedby
promoted
saccharide promoted byactivated
by activated ÅMS.
MS.
MS.
4. Alkylation
4. Alkylation
4. Alkylation ReactionsPromoted
Reactions
Reactions Promotedby
byMolecular
Molecular Sieves
Sieves
4. Alkylation ReactionsPromoted
Promotedby
byMolecular Sieves
Molecular Sieves
4.1.4.1.
Side Chain
Side ChainMono-N-Alkylation
Mono-N-AlkylationofofFmoc-Amino
Fmoc-Amino Acids
Acids and Peptide Sequences
and Peptide Sequences
4.1.4.1.
Side Chain
Side Chain Mono-N-Alkylation
Mono-N-AlkylationofofFmoc-Amino
Fmoc-Amino Acids and and Peptide
PeptideSequences
Sequences
OurOur group
group reported
reported ononananN-alkylation
N-alkylationas as the
the first
first reaction
reactionpromoted
promotedby byactivated
activated4 Å
4Åmolecular
molecular
OurOur group
group
◦ reportedon
reported onananN-alkylation
N-alkylation asas the first
first reaction
reaction promoted
promoted bybyactivated
activated4Å4 molecular
Å molecular
sieves
sieves (280C,°C,
(280 TT= =4 4h hunder
undervacuum)
vacuum)[31].
[31]. The
The reaction waswas performed
performedon onortho-Ns-protected
ortho-Ns-protected basic
basic
sieves
sieves (280
(280 °C,°C,
T T= =4 4h hunder
undervacuum)
vacuum)[31].
[31]. The
The reaction
reaction was
was performed
performed on
on ortho-Ns-protected
ortho-Ns-protected basic
basic
Fmoc-amino
Fmoc-amino acids
acids (Fmoc-Lys(Ns)-OH;Fmoc-Orn(Ns)-OH;
(Fmoc-Lys(Ns)-OH; Fmoc-Orn(Ns)-OH; Fmoc-Dab(Ns)-OH;
Fmoc-Dab(Ns)-OH;Fmoc-Dap(Ns)-OH)
Fmoc-Dap(Ns)-OH)
Fmoc-amino
Fmoc-amino acids(Fmoc-Lys(Ns)-OH;
acids (Fmoc-Lys(Ns)-OH; Fmoc-Orn(Ns)-OH;
Fmoc-Orn(Ns)-OH; Fmoc-Dab(Ns)-OH;
Fmoc-Dab(Ns)-OH; Fmoc-Dap(Ns)-OH)
Fmoc-Dap(Ns)-OH)
by by using
using different
different alkylhalides
alkyl halides(Scheme
(Scheme8).
8).One
One ofof the
the obtained
obtained mono-N-alkylated
mono-N-alkylatedaminoamino acids was
acids was
by by using
using differentalkyl
different alkylhalides
halides(Scheme
(Scheme 8).
8). One
One ofof the
the obtained
obtained mono-N-alkylated
mono-N-alkylated amino
amino acids was
acids was
introduced
introduced as
as as a building
a building blockinto
block intoaapeptide
peptidesequence.
sequence.
introduced
introduced a buildingblock
as a building blockinto
intoaapeptide
peptide sequence.
sequence.
Scheme
Scheme 8. 8. N-alkylationofofnosyl-protected
N-alkylation nosyl-protected Fmoc-amino
Fmoc-amino acid
acidpromoted
promotedby
byactivated
activated4 4ÅÅ
MS.
MS.
Scheme 8. N-alkylation of nosyl-protected Fmoc-amino acid promoted by activated 4 Å MS.
Scheme 8. N-alkylation of nosyl-protected Fmoc-amino acid promoted by activated 4 Å MS.
The The success
success of of
thethe obtained
obtained results
results prompted
prompted us us to explore
to explore thethe
new new N-alkylation
N-alkylation strategy
strategy on on
fully
The success of the obtained results prompted us to explore the new N-alkylation strategy on
fully
deprotecteddeprotected
peptide
Thedeprotected peptide
sequences
success of peptide sequences
the obtained as as postsynthetic
postsynthetic
results modification
modification strategy
prompted us modification
to explore the strategy
[32]. The [32]. The
reaction
new N-alkylation reaction
was was
performed
strategy
fully sequences as postsynthetic strategy [32]. The reaction wason
in performed
DMF
fully under in
an
deprotected DMF
Ar under
atmosphere
peptide an Ar
sequencesand atmosphere
employed and
under
as postsynthetic employed
very mildunder
modification very
conditions,
strategy mild
only conditions,
activated
[32].conditions,
The reaction4only
Å was
MS
performed in DMF under an Ar atmosphere and employed under very mild only
as activated
basic 4 Å MS
catalyst andas the
basicappropriate
catalyst andalkylthe appropriate
halide. Thealkyl halide. The nosyl-protected
nosyl-protected amino group amino
of group
the amino
performed
activated 4inÅ DMF
MS as under an Arand
basic catalyst atmosphere and employed
the appropriate alkyl halide.under very mild conditions,
The nosyl-protected amino group only
of residue
acid the amino acid residue
performed the performed thesubstitution,
nucleophilic nucleophilicso substitution,
that a so that a mono-N-alkylation
mono-N-alkylation was performed wason
of the amino acid residue performed
activated 4 Å MS as basic catalyst and the nucleophilic substitution, so that a mono-N-alkylation
appropriate alkyl halide. The nosyl-protected amino group was
performed on the peptide side chain (Scheme 9). The strategy allowed theofintroduction of differenton
of performed
the peptide
the on
aminoside the
chain
acid peptide
(Scheme
residue side9).
performedchain (Scheme
Thethe strategy 9). The strategy
allowed
nucleophilic allowed
the introduction
substitution, the introduction
so that adifferent of different
substituents
mono-N-alkylation was
substituents on model peptides and provided high chemoselectivity and excellent conversion yields.
substituents
model
performed on on
peptides the model
andpeptide peptides
providedsidehighand
chain provided
(Scheme high
chemoselectivity chemoselectivity
9). Theand excellent
strategy and excellent
conversion
allowed conversion
yields.
the introduction of yields.
different
substituents on model peptides and provided high chemoselectivity and excellent conversion yields.
Scheme 9. Chemoselective N-alkylation of a peptide sequence promoted by activated 4 Å MS.

Scheme
Scheme 9. 9. ChemoselectiveN-alkylation
Chemoselective N-alkylation of
of aa peptide
peptide sequence
sequencepromoted
promotedby
byactivated
activated4 Å
4ÅMS.
MS.
4.2.
4.2.4.2. S-Alkylation
S-Alkylation Reaction forIntroducing
Reaction IntroducingPeptide
Peptide Modification
Modification
S-Alkylation
Scheme 9. Reactionfor
for Introducing
Chemoselective Peptide
N-alkylation of aModification
peptide sequence promoted by activated 4 Å MS.
Considering
Considering the
thethe strong
strong nucleophilicity
nucleophilicity exhibited
exhibited by
by by the
the the cysteine
cysteine sulfhydryl
sulfhydryl group
group [33],
[33],[33], our
our group
Considering strong nucleophilicity exhibited cysteine sulfhydryl group our
4.2. S-Alkylation
group exploredReaction
and for
tuned Introducing
the Peptide
alkylation Modification
reaction conditions on peptide sequences containing a
group explored
explored and tuned andthetuned the alkylation
alkylation reaction reaction conditions
conditions on peptide
on peptide sequences
sequences containing
containing a
a cysteine
Considering the strong nucleophilicity exhibited by the cysteine sulfhydryl group [33], our
group explored and tuned the alkylation reaction conditions on peptide sequences containing a
Catalysts2019,
Catalysts 2018,9,8,248
x FOR PEER REVIEW 9 9ofof21
21
cysteine residue [34]. In analogy with the N-alkylation protocol, postsynthetic S-alkylation was
cysteine residue
promoted byIn [34]. InÅanalogy
activated with
acts the
as aN-alkylation protocol, postsynthetic
employedS-alkylation avoidwas
residue [34]. analogy 4with MS
thethat
N-alkylation base, the postsynthetic
protocol, mild conditions S-alkylation could
was promoted the
by
promoted
racemization by ofactivated
the 4
cysteine Å MS that
residue. acts
The as a base,
reactivity the
of mild
the conditions
thiol group employed
was explored could
by avoid
performingthe
activated
racemization4 Å MS
ofthethat
thesameacts as
cysteine a base,
residue. the mild
Thewith conditions
reactivity of the employed
thiol could
group was avoid the
explored racemization
by performing of
the
the reaction on model peptide different alkyl bromides, while the chemoselectivity
thecysteine
was reactionresidue.
assessed on adding
by
The reactivity
the same model
atwith
the
of thewith
peptide
N-extremity
thioldifferent
group was
of abromides,
peptide modelalkylexplored
bromides,
the amino
by performing
while
acid
the reaction on
the chemoselectivity
residues representative
the
wassame model
assessed by peptide
adding atgroups different
the N-extremity alkylof a peptide while
model the chemoselectivity
the amino acid residues was assessed by
representative
of the
adding range
at theof functional
N-extremity of a usually
peptide present
model the on the
amino side
acid chains
residuesof natural peptides
representative of (Scheme
the range 10).
of
of the range of functional groups usually present on the side chains of natural peptides (Scheme 10).
The reaction
functional time
groups was increased from 1 to 3 h, when less reactive alkyl bromides were employed;
The reaction timeusually presentfrom
was increased on the side
1 to 3 h, chains
whenofless natural peptides
reactive (Scheme 10).
alkyl bromides wereThe reaction
employed;
however,
time was in all casesfrom
increased a high1 yield
to 3 h, of the final
when less product alkyl
reactive was obtained.
bromides The
werereaction time was
employed; drastically
however, in all
however, in all cases a high yield of the final product was obtained. The reaction time was drastically
reduced when the protocol was further implemented by a microwave irradiation (40 °C for 5 min)
reduced
cases a highwhenyieldtheofprotocol
the finalwas further
product wasimplemented
obtained. The byreaction
a microwave
time was irradiation (40 reduced
drastically °C for 5 whenmin)
[35]. In addition, the methodology allowed the discrimination of the cysteine thiol [35].
◦ C for 5 min) group reactivity
[35].
the In addition,
protocol the methodology
was further implemented allowed the discrimination
by a microwave irradiationof the
(40 cysteine thiol group Inreactivity
addition,
upon that of other sensitive nucleophilic peptide functionalities. Even in the presence of a lysine
upon that of other sensitive nucleophilic peptide functionalities. Even in the presence of aoflysine
the methodology allowed the discrimination of the cysteine thiol group reactivity upon that other
residue a polyalkylated product was obtained in a low yield, which was farther reduced when MW-
residue anucleophilic
sensitive polyalkylated product
peptide was obtainedEven
functionalities. in a low
in theyield, whichofwas
presence farther
a lysine reduced
residue when MW-
a polyalkylated
activation was applied.in a low yield, which was farther reduced when MW-activation was applied.
activation was applied.
product was obtained
Scheme
Scheme10.
Scheme 10.Chemoselective
10. ChemoselectiveS-alkylation
Chemoselective S-alkylation of
S-alkylation of aaa peptide
of peptide sequence
peptide promoted
sequence promoted by
promoted by activated444Å
by activated
activated ÅMS.
Å MS.
MS.
We
We also
Wealsoalso succeeded
succeeded
succeeded in
in functionalizing
functionalizing
in functionalizing aa peptide
a peptide peptide with polyethylene
polyethylene
with polyethylene glycol, aa widespread
glycol,
glycol, a widespread widespread
substituent
substituent
substituentpresent
present on presenton
bioactive onbioactive
bioactivepeptides
peptides in peptides in
order to in order
order to increase their in vivo
increase their in vivo stability vivo stability
and stability and
solubility,andsolubility,
as solubility,
well as with asa
as
well
wellasaswith
fluorophore aafluorophore
withsuchfluorophore such
suchas
as5-(bromo-methyl)fluorescein
5-(bromo-methyl)fluorescein
as 5-(bromo-methyl)fluorescein (Figure 5). 5).
(Figure 5).
Figure5.
Figure
Figure 5.5.S-alkylation
S-alkylationpromoted
S-alkylation promoted by
promoted by activated
by activated 444 Å
activated Å MS
Å MS of
MS of peptide
of peptide
peptide with
with useful
with useful substituents.
useful substituents.
substituents.
Catalysts 2019, 9, 248 10 of 21
The
The most
mostinteresting
interestingresults were obtained by introducing lipidlipid
functionalities in several tailor-
The most interesting results were
results wereobtained by introducing
obtained lipid functionalities
by introducing in several
functionalities tailor-
in several
made peptides, such as farnesyl and hexadecyl groups (Figure 6), which represent the bioactive
made peptides, such as farnesyl and hexadecyl groups (Figure 6), which represent the bioactive
tailor-made peptides, such as farnesyl and hexadecyl groups (Figure 6), which represent the bioactive
portions of
of their Ras
Ras parent proteins
proteins [36].
portions of their
portions their Ras parent
parent proteins [36].
[36].
Figure
Figure 6.
6. Chemical
Chemical structure
structure of
of S-lipidated
S-lipidated peptides.
Figure 6. Chemical structure of S-lipidated peptides.
peptides.
4.3.
4.3. Solid-Phase
Solid-Phase S-Alkylation
S-Alkylation Reaction
Reaction for
for Introducing Peptide Modification
Introducing Peptide Modification
4.3. Solid-Phase S-Alkylation Reaction for Introducing Peptide Modification
Our
Our group
group hashas implemented
implemented the the developed
developed aa postsynthetic
postsynthetic S-alkylation
S-alkylation procedure
procedure promoted
promoted by by
Our group has implemented the developed a postsynthetic S-alkylation procedure promoted by
44 Å
Å MS
MS ininsolid
solidphase,
phase,with
withthe
theaim
aim ofof considering
considering it aitroutinely
a routinely solid-phase
solid-phase peptide
peptide synthetic
synthetic step step
[37].
4 Å MS in solid phase, with the aim of considering it a routinely solid-phase peptide synthetic step
[37].reaction
The The reaction is performed
is performed on a peptidyl
on a peptidyl resinresin andchemical
and the the chemical process
process can be can be considered
considered a solid-
a solid-state
[37]. The reaction is performed on a peptidyl resin and the chemical process can be considered a solid-
state procedure,
procedure, sincesince
both both the catalyst
the catalyst (molecular
(molecular sieves)
sieves) and and the substrate
the substrate (the (the peptide
peptide anchored
anchored on
on the
state procedure, since both the catalyst (molecular sieves) and the substrate (the peptide anchored on
the resin)
resin) are are provided
provided in solid-state.
in solid-state. After
After a completionofofthe
a completion thepeptide
peptidesequence,
sequence,the theN-terminus
N-terminus waswas
the resin) are provided in solid-state. After a completion of the peptide sequence, the N-terminus was
acetylated
acetylated andand then
then the
the cysteine
cysteine thiol
thiol group
group was
was freed
freed from the highly
from the highly acid
acid labile
labile protecting
protecting group
group
acetylated and then the cysteine thiol group was freed from the highly acid labile protecting group
(Mmt =
(Mmt = 4-methoxytrityl)
4-methoxytrityl) for for the
the subsequent
subsequent S-alkylation
S-alkylation reaction
reaction that
that was
was performed
performed in in DMF
DMF under
under
(Mmt = 4-methoxytrityl) for the subsequent S-alkylation reaction that was performed in DMF under
an
an Ar atmosphere,
atmosphere, in presence
presence of activated
activated molecular sieves.sieves. The
The alkyl
alkyl bromide
bromide was was employed
employed in a
an Ar
Ar atmosphere, in in presence of of activated molecular
molecular sieves. The alkyl bromide was employed in a
in a
stoichiometric
stoichiometric excess
excess and
and the
the reaction
reaction mixture
mixture was
was kept
kept under
under stirring
stirring for
for 15
15 hh at
at room
room temperature.
temperature.
stoichiometric excess and the reaction mixture was kept under stirring for 15 h at room temperature.
The efficiency
efficiency of thethe solid phase
phase S-alkylation was was investigated by reacting aa peptide
peptide model withwith
The
The efficiency of solid phase S-alkylation
of the solid S-alkylation was investigated
investigated by by reacting
reacting a peptide modelmodel with
different alkyl bromides
different alkyl bromides (Scheme
(Scheme 11).
11).
different alkyl bromides (Scheme 11).
Scheme 11. Solid-phase

Scheme 11. Solid-phase S-alkylation
S-alkylation of
of peptide
peptide sequences
sequences anchored
anchored on
on resin promoted by
resin promoted by activated
activated
Scheme 11. Solid-phase S-alkylation of peptide sequences anchored on resin promoted by activated
44 Å
Å MS.
MS.
4 Å MS.
By combining both protocols—the 4 Å MS solution and solid-phase strategy—it was possible to

prepare a multialkylated peptide, such as the C-terminal N-RAS decapeptide shown in Scheme 12. It
prepare a multialkylated peptide, such as the C-terminal N-RAS decapeptide shown in Scheme 12. It
Catalysts 2019, 9, 248 11 of 21

contains athe
prepare palmityl group
multialkylated introduced
peptide, in solid
such as the phaseN-RAS
C-terminal and the farnesyl that
decapeptide shown wasin necessarily
Scheme 12.
introduced
It contains on
thethe fully deprotected
palmityl functionalized
group introduced in solidpeptide 2. In the
phase and fact,farnesyl
the farnesyl couldnecessarily
that was avoid the
final acid treatment for the deprotection and the cleavage of the peptide, which can affect
introduced on the fully deprotected functionalized peptide 2. In fact, the farnesyl could avoid its
the final
stereochemistry.
acid treatment for the deprotection and the cleavage of the peptide, which can affect its stereochemistry.
Scheme 12. Solution

Solutionand
andsolid-phase
solid-phaseapproach
approachpromoted
promotedbybyactivated
activated4 4Å ÅMSMSto toperform a
perform
multialkylation.
a multialkylation.
4.4. Chemoselective Glycosylation of Peptides through S-Alkylation Reaction

4.4. Chemoselective Glycosylation of Peptides through S-Alkylation Reaction
The S-alkylation procedure promoted by activated 4 Å molecular sieves was also employed by
The S-alkylation procedure promoted by activated 4 Å molecular sieves was also employed by
our group to prepare S-linked glycopeptides [38]. The reaction was performed on peptide sequences
our group to prepare S-linked glycopeptides [38]. The reaction was performed on peptide sequences
containing the sensitive cysteine residue that could react with the chosen glycosyl halide, in DMF,
containing the sensitive cysteine residue that could react with the chosen glycosyl halide, in DMF,
under an Ar atmosphere, and in the presence of activated molecular sieves as the basic catalyst. A good
under an Ar atmosphere, and in the presence of activated molecular sieves as the basic catalyst. A
chemoselectivity for this site-directed functionalization of the cysteine thiol group was obtained,
good chemoselectivity for this site-directed functionalization of the cysteine thiol group was
even in presence of other nucleophiles. In addition, the reactivity of the sulfhydryl was explored
obtained, even in presence of other nucleophiles. In addition, the reactivity of the sulfhydryl was
toward a certain number of monosaccharides (acetobromo-α-D-glucose; acetobromo-α-D-galactose;
explored toward a certain number of monosaccharides (acetobromo-α-D-glucose; acetobromo-α-D-
1-chloro-N-acetyl-glucosamine) and also toward a disaccharide such as the acetobromo-maltose.
galactose; 1-chloro-N-acetyl-glucosamine) and also toward a disaccharide such as the acetobromo-
The reaction occurred through a SN 2 mechanism and allowed the formation of S-β-linked glycopeptide
maltose. The reaction occurred through a SN2 mechanism and allowed the formation of S-β-linked
(Scheme 13). The final compounds were prepared in moderate yields; however, they were obtained
glycopeptide (Scheme 13). The final compounds were prepared in moderate yields; however, they
without any manipulation of the sugar derivative that was in all cases commercially available, neither
were obtained without any manipulation of the sugar derivative that was in all cases commercially
a peculiar activation of the thiol group was necessary in order to achieve chemo and stereoselective
available, neither a peculiar activation of the thiol group was necessary in order to achieve chemo
cysteine functionalization.
and stereoselective cysteine functionalization.
Catalysts 2019, 9, 248 12 of 21
Catalysts
Catalysts 2018,
2018, 8,
8, xx FOR
FOR PEER
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REVIEW 12
12 of
of 21
21
Scheme
Scheme 13.
13. S-glycosylation
Scheme 13. S-glycosylation of
S-glycosylation of peptide
of peptide sequences
peptide sequences promoted
sequences promoted by
promoted by activated
by activated 444 Å
activated Å MS
Å MS using
MS using different
using different
different
carbohydrate
carbohydrate derivatives.
derivatives.
carbohydrate derivatives.
4.5.
4.5. Lanthionine-Containing
4.5. Lanthionine-Containing Peptide
Lanthionine-Containing Peptide Obtained
Peptide Obtained via
Obtained via Cysteine
via Cysteine S-Alkylation
Cysteine S-Alkylation
S-Alkylation on on Cyclic
on Cyclic Sulfamidates
Cyclic Sulfamidates
Sulfamidates
Our
Our group
Our group has
group has also
has also developed
developed aa
also developed a 444 Å
Å MS
Å MS promoted
MS promoted strategy
promoted strategy
strategy toto prepare
to prepare lantipeptides,
prepare lantipeptides, peptide
lantipeptides, peptide
peptide
molecules
molecules that contain the unusual amino acid lanthionine [39]. The reaction consists of the
molecules that
that contain
contain thethe unusual
unusual amino
amino acid acid lanthionine
lanthionine [39]. [39].
The The
reaction reaction
consists consists
of the of the S-
S-alkylation
S-
alkylation
of a of
cysteine, a cysteine,
already already
inserted ininserted
a peptide in a peptide
sequence, sequence,
on a cyclicon a cyclic
sulfamidate. sulfamidate.
alkylation of a cysteine, already inserted in a peptide sequence, on a cyclic sulfamidate. The obtainedThe The
obtained obtained
modified
modified
peptide peptide
peptide acontains
modifiedcontains aa stereochemically
stereochemically
contains pure
pure lanthionine
pure lanthionine
stereochemically residue
residue (Scheme
lanthionine (Scheme
residue 14).
(SchemeThe 14).
mildThe
14). mild
reaction
The mild
reaction
conditionsconditions
allowed allowed
for the for the
employment employment
of of
orthogonal orthogonal
and and peptide-compatible
peptide-compatible
reaction conditions allowed for the employment of orthogonal and peptide-compatible protecting protectingprotecting
groups
groups
on on
on the
the sulfamidate
the sulfamidate
groups derivatives,
derivatives,
sulfamidate which iswhich
derivatives, a keyis
which aa key
key objective
isobjective of
of the
the proposed
of the proposed
objective procedure,
procedure,
proposed since
since they
procedure, since they
can be
they
can
can be
be selectively
selectively removed
selectively removed removed in
in order in order
order to
to to perform
perform perform the
the the subsequent
subsequent cyclization
subsequent cyclization and
cyclization and and introduce
introduce the
introduce the the thioether
thioether ring,
thioether
ring,
ring, typical structural motif of the natural lantibiotics. The successful outcome of
typicaltypical
structuralstructural
motif motif
of the of
naturalthe natural
lantibiotics. lantibiotics.
The The
successful successful
outcome of outcome
the new of the
the new
methodology,
new
methodology,
methodology, both in terms of efficiency and chemoselectivity, was proved by the excellent yield
both in terms ofboth in terms
efficiency and of efficiency and
chemoselectivity, chemoselectivity,
was proved by was
the proved
excellent by the
yield excellent
values (80–95%)
yield
values
found (80–95%)
values for found
the obtained
(80–95%) for
for the
the obtained
found monoalkylated monoalkylated
monoalkylated peptides.
obtainedpeptides. peptides.
Scheme
Scheme 14.
Scheme 14. S-alkylation
14. S-alkylation of
S-alkylation of peptide
of peptide sequences
peptide sequences performed
sequences performed on
performed on cyclic
on cyclic sulfamidates
cyclic sulfamidates and
sulfamidates and promoted
and promoted by
by
promoted by
activated 4 Å MS.
activated 4 Å MS.
As
As an
As an application
an application of
application of the
of the new
the new methodology,
new methodology, thethe synthesis
synthesis of
methodology, the synthesis
of Halβ
Halβ ring
of Halβ
ring B
B was
ring B
was successful
successful carried
was successful carried
carried
out,
out, it
out,
it serves
it
serves as
serves
as aa template
as a
template for
template
for future
for
future preparation
future
preparation of
preparation
of lantibiotic
of
lantibiotic analogs
lantibiotic
analogs (Scheme
analogs
(Scheme 15).
(Scheme 15).
15).
Catalysts 2019, 9, 248 13 of 21
Scheme 15.15. S-alkylation of

of peptide sequence promoted
promoted by activated 4
4 Å MS
MS to prepare
prepare bioactive
Scheme 15. S-alkylation
Scheme S-alkylation of peptide sequence promoted
peptide sequence by activated 4 Å
by activated Å MS to
to prepare bioactive
bioactive
lantibiotic fragment.
4.6. Benzylation
4.6. Benzylation of
of Arylcyanamides
Arylcyanamides Performed
Performed via
via Acid
Acid Catalysis
Catalysis ofof Zeolites
Zeolites
4.6. Benzylation of Arylcyanamides Performed via Acid Catalysis of Zeolites
Azarifar and
Azarifar and coauthors
coauthors performed
performed aa substitution
substitution reaction
reaction of of cyanamides
cyanamides by by employing
employing benzyl
benzyl
Azarifar and coauthors performed a substitution reaction of cyanamides by employing benzyl
bromide and
bromide andseveral
severalarylcyanamides
arylcyanamides in acetonitrile,
in acetonitrile, at 65at◦ C65and
°C inand in presence
presence of acid of acid as
zeolite zeolite as
catalyst.
bromide and several arylcyanamides in acetonitrile, at 65 °C and in presence of acid zeolite as
catalyst.
It is worthIt remembering
is worth remembering that substituted
that substituted cyanamidescyanamides
are usefulare and useful and widespread
widespread employedemployed
building
catalyst. It is worth remembering that substituted cyanamides are useful and widespread employed
building
blocks forblocks for the preparation
the preparation of biologically
of biologically active substrates,
active substrates, such as antiviral
such as antiviral and anticancer
and anticancer agents.
building blocks for the preparation of biologically active substrates, such as antiviral and anticancer
agents. Several
Several zeoliteszeolites haveemployed,
have been been employed, some naturally
some naturally occurringoccurring
in thein the Lewis
Lewis acid form
acid form (Na-Y (Na-Y
and
agents. Several zeolites have been employed, some naturally occurring in the Lewis acid form (Na-Y
and Na-ZSM-5)
Na-ZSM-5) and others
and others obtained
obtained by preparing
by preparing their Brønsted
their Brønsted H-form (H-Y H-form
and(H-Y and H-ZSM-5).
H-ZSM-5). The exchangeThe
and Na-ZSM-5) and others obtained by preparing their Brønsted H-form (H-Y and H-ZSM-5). The
exchange
of Na+ with ofthe
Naproton
+ with the
wasproton was
performed performed
by treatmentby treatment
of the zeolite of the
with zeolite
NH NOwith NH
followed
4NO by3 followed
a drying
exchange of Na+ with the proton was performed by treatment of the zeolite 4
with
3
NH4NO3 followed
by acalcination
and drying andprocess
calcination process
(Scheme 16) (Scheme
[40]. 16) [40].
by a drying and calcination process (Scheme 16) [40].
16. N-benzylation
Scheme 16.
Scheme N-benzylation of
of arylcyanamide
arylcyanamide promoted
promoted by
by acidic
acidic zeolites.
zeolites.
Scheme 16. N-benzylation of arylcyanamide promoted by acidic zeolites.
The
The zeolite
zeolite H-Y
H-Y exhibited
exhibited the
the best
best result
result in
in terms
terms of
of yield,
yield, probably
probably due
due to
to the
the high
high number
number of
of
The
acidic zeolite
sites and H-Y
the exhibited
dimension ofthe
thebest result
zeolite in
pores terms of
together yield,
with probably
the due
presence of to
the the high number
super-cages of
inside
acidic sites and the dimension of the zeolite pores together with the presence of the super-cages inside
acidic
the sites and the dimension of the zeolite pores together with the presence of the super-cages inside
the aluminosilicate
aluminosilicate solid.
solid.
the aluminosilicate
The solid.
The hypothesized reaction
hypothesized reactionpath
path is
is reported
reportedin inScheme
Scheme1717and
andsuggests
suggestsaaSSNN22 mechanism
mechanism into
into the
the
The
zeolite hypothesized
channels by reaction
acidic path
catalysis is reported in Scheme 17 and suggests a SN2 mechanism into the
assistance.
zeolite channels by acidic catalysis assistance.
zeolite channels by acidic catalysis assistance.
Scheme 17.
Scheme 17.Hypothesized
Hypothesizedmechanism
mechanismfor for N-benzylation
N-benzylation of arylcyanamides
of arylcyanamides promoted
promoted byzeolite.
by acidic acidic
Scheme 17. Hypothesized mechanism for N-benzylation of arylcyanamides promoted by acidic
zeolite.
zeolite.
Catalysts 2019,
Catalysts 2018, 9,
8, 248
x FOR PEER REVIEW 14
14 of 21
of 21
It is important to refer that the catalyst was recovered by filtration and reused, keeping the
original
It is activity.
important Moreover, thethe
to refer that reaction
catalyst was
was totally unsuccessful
recovered in absence
by filtration of the
and reused, zeolite.the original
keeping
activity. Moreover, the reaction was totally unsuccessful in absence of the zeolite.
4.7. Microwave Irradiation Promotes the N-Alkylation of Imidazole in Presence of a Basic Zeolite as Catalyst
4.7. Microwave Irradiation Promotes the N-Alkylation of Imidazole in Presence of a Basic Zeolite as Catalyst
The alkylation of heterocycles is an important synthetic step for the preparation of biological
activeThecompounds
alkylationsuch as fungicides
of heterocycles is and anticonvulsants.
an important Costarrosa
synthetic step for and coauthors reported
the preparation on an
of biological
alkylation reaction performed on imidazole by using different alkylating agents, alkaline-exchanged
active compounds such as fungicides and anticonvulsants. Costarrosa and coauthors reported on an
X-type zeolite
alkylation as catalyst,
reaction and microwave
performed on imidazole irradiation to promote
by using different the chemical
alkylating process
agents, [41].
alkaline-exchanged
X-typeThe sodium ions of 13X zeolites were exchanged with some other alkaline earth ions by
zeolite as catalyst, and microwave irradiation to promote the chemical process [41].
employing 2M solutions
The sodium ions of 13Xof zeolites
the corresponding
were exchanged salts,with
CaClsome
2, BaCl 2, and
other Sr(NOearth
alkaline 3)2. The
ionsprocedure was
by employing
performed
2M solutions asoffollows (Scheme 18).salts,
the corresponding The CaCl
imidazole
2 , BaCland theSr(NO
2 , and chosen 3 )2zeolite, previously
. The procedure wasdried at 353 K,
performed as
were blended in a Teflon vessel, then an excess of 9 equivalent of alkylating agent (1-Br-butane, 2-Br-
follows (Scheme 18). The imidazole and the chosen zeolite, previously dried at 353 K, were blended
butane,
in a Teflon and 1-Br-hexane)
vessel, was added.
then an excess The reactor
of 9 equivalent vessel was
of alkylating placed
agent in a microwave
(1-Br-butane, oven and
2-Br-butane,
irradiated at was
1-Br-hexane) 300 and 700 The
added. W during
reactordifferent
vessel was time-lapses
placed in(1, 3, and 5 min).
a microwave ovenThe reaction
and products
irradiated at 300were
and
extracted in acetone.
700 W during different time-lapses (1, 3, and 5 min). The reaction products were extracted in acetone.
Scheme
Scheme 18. presence of
18. N-Alkylation of imidazole with different alkylating agents in presence of basic
basic zeolites.
zeolites.
The
The obtained results indicated
obtained results indicated thethe following
followingtrendtrendofofbasicity
basicityNaXNaX>>CaXCaX> >BaX BaX> > SrX,
SrX, which
which is
is not related to the basic character of the alkaline earth ions exchanged zeolites
not related to the basic character of the alkaline earth ions exchanged zeolites (BaX > SrX > CaX). (BaX > SrX > CaX).
In
In general,
general, thethe comprehensive
comprehensive analysisofofthe
analysis theperformed
performedexperiments
experimentsassessed
assessedthat
thatthethe catalytic
catalytic activity
activity
depends on the basicity of the employed zeolite, the polarizing ability of the exchanged
depends on the basicity of the employed zeolite, the polarizing ability of the exchanged cation, and cation, and the
the power of the employed microwave irradiation. For 1-Br-butane and 2-Br-butane, the best catalyst
power of the employed microwave irradiation. For 1-Br-butane and 2-Br-butane, the best catalyst was
revealed to beto
was revealed NaX whenwhen
be NaX microwave irradiation
microwave was produced
irradiation was producedat 300atW.300
AnW.increase in thisin
An increase value
this
value would affect the activity only of the less basic catalysts. In the case of 1-Br-hexane, the found
would affect the activity only of the less basic catalysts. In the case of 1-Br-hexane, the found trend was
trend wasIn
different. different. In highest
fact, at the fact, at the highest
power of 700 power of best
W, the 700 W, the best
catalyst catalyst
resulted resulted
to be SrX with to be
theSrX with
shortest
the shortest time of irradiation, which is in agreement with the strongest basic character of SrX zeolite.
time of irradiation, which is in agreement with the strongest basic character of SrX zeolite.
5. Useful Examples of Broad Scope Reactions Promoted by Molecular Sieves

5. Useful Examples of Broad Scope Reactions Promoted by Molecular Sieves
5.1. Synthesis of α-Aminophosphonates by Using Natural Natrolite as Reusable and Efficient Catalyst
5.1. Synthesis of α-Aminophosphonates by Using Natural Natrolite as Reusable and Efficient Catalyst
Bahari and coauthors reported on a novel high yielding procedure for synthesizing
Bahari and coauthors reported on a novel high yielding procedure for synthesizing α-
α-aminophosphonates [42]. The one-pot reaction uses aromatic aldehydes or ketones, substituted
aminophosphonates [42]. The one-pot reaction uses aromatic aldehydes or ketones, substituted
anilines, and trialkyl phosphites under solvent-free conditions and Natrolite zeolite as catalyst.
anilines, and trialkyl phosphites under solvent-free conditions and Natrolite zeolite as catalyst. The
The optimized reaction conditions were found by employing 4-methylbenzaldehyde (1 mmol), aniline
optimized reaction conditions were found by employing 4-methylbenzaldehyde (1 mmol), aniline (1
(1 mmol), and triethyl phosphine (1 mmol); concerning the catalyst, the optimum amount of natural
mmol), and triethyl phosphine (1 mmol); concerning the catalyst, the optimum amount of natural
Iranian natrolite was found to be 0.05 g (Scheme 19). It is important to underline that the reaction does
Iranian natrolite was found to be 0.05 g (Scheme 19). It is important to underline that the reaction
not occur in absence of the catalyst and that it could be easily recovered by filtration after addition of
does not occur in absence of the catalyst and that it could be easily recovered by filtration after
ethylacetate to the mixture. As final step, the catalyst was washed of water and ethanol and dried in
addition of ethylacetate to the mixture. As final step, the catalyst was washed of water and ethanol
order to be reused without any loss of efficiency.
and dried in order to be reused without any loss of efficiency.
In conclusion, the developed procedure revealed to be efficient (high yield in a short reaction
time), environmentally friendly (little waste was produced), and economically convenient (a natural
and reusable zeolite was employed as catalyst).
Catalysts 2019, 9, 248 15 of 21

Scheme 19. α-aminophosphonate catalyzed by Natrolite zeolite.

Scheme 19. α-aminophosphonate catalyzed by Natrolite zeolite.
Scheme 19.
Scheme 19. α-aminophosphonate
α-aminophosphonate catalyzed
catalyzed by
by Natrolite
Natrolite zeolite.
zeolite.
5.2. Metal-Catalyzed Enolization of Nucleophiles Precursors
5.2. Metal-Catalyzed
5.2. Metal-Catalyzed Enolization
Enolization ofof Nucleophiles
Nucleophiles Precursors
Precursors
Hasegawa and coauthors developed an efficient catalytic activation protocol for generating
time),Hasegawa and coauthors
environmentally coauthors developed
friendly developed an
(little wasteanwasefficient catalytic
produced), activation protocol
and economically protocol for generating
convenient generating
(a natural
metalHasegawa
enolate, byandemploying nitromethane efficient
as nucleophilecatalytic activation
and Lewis for
acid, such as chiral Ni(II) ions,
metal enolate,zeolite
and reusable
metal by employing
employing nitromethane
was employed as nucleophile
as catalyst). and Lewis acid, such as chiral Ni(II) ions,
in combination with 4 Å MS [43]. The reaction is performed in alcohol as solvent and providesions,
enolate, by nitromethane as nucleophile and Lewis acid, such as chiral Ni(II) the
in
in combination
combination with
with 4 Å MS [43]. The reaction is performed in alcohol as solvent and provides the
active enolate that can4 be
Å MS [43]. The reaction
subsequently involvedisinperformed in alcoholreaction
a Michael addition as solvent
withand provides the
α,β-unsaturated
5.2. Metal-Catalyzed
active
active enolate that
enolate Enolization
that can
can be of Nucleophiles
be subsequently
subsequently Precursors
involved
involved in aa Michael
in Michael addition
addition reaction
reaction with
with α,β-unsaturated
α,β-unsaturated
carbonyl electrophiles. Following the hypothesized mechanism, the catalytic activity of the molecular
carbonyl electrophiles.
Hasegawa
carbonyl and Following
coauthors the hypothesized
developed an mechanism,
efficient catalyticthe catalytic
activation activity
protocol offor
thegenerating
molecular
sieves, employed without any preactivation, consist of capturing a proton (Schemethe
electrophiles. Following the hypothesized mechanism, the catalytic activity of 20).molecular
In other
sieves, employed
metal enolate, without
bywithout
employing any preactivation,
nitromethane as consist of
nucleophile capturing a proton (Scheme 20). Inwords,
other
sieves,
words, employed
the molecular anybehaved
sieves preactivation, consist
an effective base, evenand
of capturing
withLewis acid,
a aproton
smaller suchsize
(Scheme
pore as chiral
20). Ni(II)
ofIn3 other
Å, whileions,
the
words, the molecular 4sieves behaved anreaction
effectiveisbase, even with a smalleras pore
of 3size of 3provides
Å, while the
5inÅcombination
the molecular
MS resulted with
sieves
much Å MS
behaved
less [43].
an The
effective
efficient base, even performed
with in alcohol
a smaller pore size solvent
Å, and
while the the
5 Å MS
5active
Å MSenolate
resulted resulted
muchthat much
less can lesssubsequently
be
efficient efficient involved in a Michael addition reaction with α,β-unsaturated
carbonyl electrophiles. Following the hypothesized mechanism, the catalytic activity of the molecular
sieves, employed without any preactivation, consist of capturing a proton (Scheme 20). In other
words, the molecular sieves behaved an effective base, even with a smaller pore size of 3 Å, while the
5 Å MS resulted much less efficient
Scheme 20. Ni(II)
Ni(II) nitronategenerated
generated by the catalyst activity of basic 4 Å MScaptures
that captures the α-
Scheme 20. Ni(II)nitronate
Scheme 20. nitronate generatedbyby
thethe
catalyst activity
catalyst of basic
activity 4 Å MS
of basic 4 Åthat the α-proton
MS that captures the α-
proton
of of a nucleophile
a nucleophile precursor.
precursor.
proton of a nucleophile precursor.
5.3. Different Base-Catalyzed Reactions
5.3. Reactions Promoted
Promoted byby Methylammonium-
Methylammonium- Faujasite
Faujasite
5.3. Different Base-Catalyzed Reactions Promoted by Methylammonium- Faujasite
It isiswell-known
It well-known thatthat the basicity
the basicity of theincreases
of the zeolites zeoliteswithincreases with ofthe
the decrease the decrease of the
electronegativity
It is well-known
Scheme 20. Ni(II) that the
nitronate basicity
generated by of catalyst
the the zeolites
activity increases
of basic 4 Åwith
MS thecaptures
that decreasethe of
α- the
electronegativity
of the compensating of the compensating
cations, cations, the
since it enhances since it enhances
electron densitytheon electron
the frameworkdensityoxygens.
on the
electronegativity
proton of abasic of the compensating
nucleophile precursor. cations, since it enhances the electron density
+ < Rb+on the
frameworkthe
Therefore, oxygens.strength
Therefore, the cationic
of the basic strength of follows
zeolites the cationic zeolites
the order Li+follows
< Na+ the <K order Li++<< Cs
Na+++.
framework oxygens. Therefore, the basic strength of the cationic zeolites follows the order Li < Na
< K++ <this
With Rb+ idea
< Cs++.inWith
mind,thisMartins
idea in mind, Martins and
and coauthors coauthors
prepared preparedCs-FAU
exchanged exchanged andCs-FAU and also
also exchanged
<5.3.
K Different
< Rb+ < Cs Base-Catalyzed
. With this idea Reactions
in mind, Promoted
Martinsbyand
Methylammonium-
coauthors prepared Faujasite
exchanged Cs-FAU and also
exchanged methylammonium-FAU,
methylammonium-FAU, which showed which
the showed the exchange
highest ion highest ion exchange degree.
degree.
exchanged
It methylammonium-FAU,
is well-known that the which showed
basicity of the the highest
zeolites ion exchange
increases degree.
(CH3)NH3+-FAU
(CH3)NH3+-FAU catalytic
catalytic power
power forfor several
several reactions,
reactions, such such as with the
anddecrease
Knoevenagel
as Knoevenagel of the
and Claisen-
Claisen-Shmidt
(CH3)NH3+-FAU
electronegativity of as catalytic
the power
compensating for several
cations, reactions,
since(Scheme such
it enhances as
theKnoevenagel
electron and
density Claisen-
onisand
the
Shmidt
condensation condensation
as well as alcoholysis
well as alcoholysis of propylene
of propylene oxide oxide (Scheme 21),the
21), gave gave
besttheresults,
best results,
and six
Shmidt
framework condensation
oxygens. as well as alcoholysis
Therefore, the basic of propylene oxide (Scheme 21), gave the best results, and
is six times
times more
more active active
than than Cs-FAU
Cs-FAU [44]. [44].strength of the cationic zeolites follows the order Li+ < Na+
is
<K six
+ <times
Rb+ < more active
Cs+. With than
this ideaCs-FAU
in mind, [44].
Martins and coauthors prepared exchanged Cs-FAU and also
exchanged methylammonium-FAU, which showed the highest ion exchange degree.
(CH3)NH3+-FAU catalytic power for several reactions, such as Knoevenagel and Claisen-
Shmidt condensation as well as alcoholysis of propylene oxide (Scheme 21), gave the best results, and
is six times more active than Cs-FAU [44].
Scheme
Scheme 21.
21. Three
Three different base-catalyzed reactions
different base-catalyzed reactions promoted
promoted by
by methylammonium
methylammonium FAU
FAUzeolites.
zeolites.
Scheme 21. Three different base-catalyzed reactions promoted by methylammonium FAU zeolites.
The experimental studies were performed on both modified FAU types, X (Si/Al = 1.4) and Y
(Si/Al = 2.5). The TPD-CO2 test (temperature-programmed desorption of CO2) found that the zeolites
Scheme 21. Three different base-catalyzed reactions promoted by methylammonium FAU zeolites.
The experimental studies were performed on both modified FAU types, X (Si/Al = 1.4) and Y
Catalysts 2019, 9, 248 16 of 21
(Si/Al = 2.5). The TPD-CO2 test (temperature-programmed desorption of CO2) found that the zeolites
containing the highest content of aluminum present also have a higher basicity character. On the
other hand the
containing the O1s-XPS measurements
highest content (X-raypresent
of aluminum photoelectron spectroscopy)
also have provedcharacter.
a higher basicity that the presence
On the
of thehand
other organic the cation
O1s-XPS methyl-ammonium
measurements (X-rayincreases the basic spectroscopy)
photoelectron character of the zeolite,
proved thatsince
the it exhibited
presence of
the highest ion exchange degree, so that the highest number of catalytic sites.
the organic cation methyl-ammonium increases the basic character of the zeolite, since it exhibited It was proved that the
acid–base
the highestpair ion of the alkyl-ammonium-FAU
exchange is morenumber
degree, so that the highest efficientofincatalytic
providingsites.basic catalysis
It was proved forthat
all the
the
performedpair
acid–base reactions, which confirm the greatispotential
of the alkyl-ammonium-FAU of the new
more efficient low-cost basic
in providing developed
catalysiscatalyst.
for all the
performed reactions, which confirm the great potential of the new low-cost developed catalyst.
5.4. Benzene Ethylation Performed with Ethanol in Presence of Modified Acidic Zeolite
5.4. Benzene Ethylation Performed with Ethanol in Presence of Modified Acidic Zeolite
Ethylbenzene is one of the most used chemical intermediate for several synthetic processes; in
fact, Ethylbenzene
it is the main feedstock formost
is one of the the production
used chemicalof styrene, whilefor
intermediate it isseveral
also utilized for processes;
synthetic the manufacture
in fact,
ofiscellulose
it the mainacetate, acetophenone,
feedstock diethylbenzene,
for the production of styrene,propylene oxide,
while it is and other
also utilized forsubstances.
the manufacture of
Emana
cellulose and acetophenone,
acetate, Chand reported on the ethylation
diethylbenzene, of benzene
propylene oxide, and by other
an electrophilic
substances. substitution
performed
Emanaupon and catalysis of an acidic
Chand reported zeolite
on the that activates
ethylation the alkene
of benzene by anobtained by dehydration
electrophilic substitution of
ethanol [45].upon
performed In details, all reagents
catalysis werezeolite
of an acidic placedthat
in aactivates
continuous the down
alkeneflow tubular
obtained byquartz reactor
dehydration
allocated
of ethanol in a controlled
[45]. furnace.
In details, all Two
reagents different
were placed kinds of zeolite,down
in a continuous previously activated
flow tubular for reactor
quartz 1 h in
nitrogen atmosphere,
allocated in a controlled were employed.
furnace. One of them
Two different kindswas the Brønsted
of zeolite, previouslyacidic H-ZSM-5
activated for zeolite,
1 h in
obtainedatmosphere,
nitrogen from the Na-ZSM-5 upon exchange
were employed. of the
One of them wascations with protons
the Brønsted acidic by using azeolite,
H-ZSM-5 1 M solution
obtained of
NH4NO
from the3.Na-ZSM-5
Subsequently, uponthe impregnation
exchange of H-ZSM-5
of the cations with magnesium
with protons by using aand 1 Mboron
solution wasofperformed
NH4 NO3 .
by using a solution
Subsequently, of boric acid of
the impregnation and magnesium
H-ZSM-5 withnitrate as source
magnesium andofboron
the desired elements.by
was performed The best
using
aresults,
solution in terms of both selective and high-yield production, of ethylbenzene were obtained by
of boric acid and magnesium nitrate as source of the desired elements. The best results,
employing
in terms of bothMg (5%)-B (4%)-HZSM-5
selective and high-yieldzeolite; in fact, of
production, other by-products
ethylbenzene were
were obtained
obtained in a negligible
by employing Mg
yield (Scheme
(5%)-B (4%)-HZSM-5 22). zeolite; in fact, other by-products were obtained in a negligible yield (Scheme 22).
Scheme 22.
Scheme 22. Reactions
Reactions occurring during the
occurring during the ethylation of benzene
ethylation of with ethanol
benzene with ethanol in
in presence of modified
presence of modified
acidic zeolite.
acidic zeolite.
5.5.
5.5. Basic
Basic Mesoporous
Mesoporous Zeolite
Zeolite Proved
Proved to
to Be
Be an
an Efficent
Efficent Catalyst
Catalyst for
for Several
Several Reactions:
Reactions: Condensation,
Condensation,
Hydroxylation, and Cycloaddition Reactions
Hydroxylation, and Cycloaddition Reactions
Mesoporous ZSM-5 zeolite was prepared under basic conditions and its calcined form was
Mesoporous ZSM-5 zeolite was prepared under basic conditions and its calcined form was
treated with NH4 OH. Sarmah and coauthors studied the catalytic activity of the obtained basic
treated with NH4OH. Sarmah and coauthors studied the catalytic activity of the obtained basic zeolite
zeolite by performing several base catalyzed reactions such as the synthesis of substituted
by performing several base catalyzed reactions such as the synthesis of substituted styrenes,
styrenes, carbinolamides, naphthopyrans, and cyclic carbonates via Knovenagal condensation, amide
carbinolamides, naphthopyrans, and cyclic carbonates via Knovenagal condensation, amide
hydroxylation, one-pot multicomponent reaction, and cycloaddition reactions (Scheme 23) [46].
hydroxylation, one-pot multicomponent reaction, and cycloaddition reactions (Scheme 23) [46].
Catalysts 2019, 9, 248 17 of 21
Catalysts 2018,
Catalysts 2018, 8,
8, xx FOR
FOR PEER
PEER REVIEW
REVIEW 17 of
17 of 21
21
Scheme 23.
Scheme
Scheme 23. Basic
23. Basic mesoporous
Basic mesoporous zeolite
mesoporous zeolite catalyzes
zeolite catalyzes the
catalyzes the synthesis
the synthesis of
synthesis of substituted
of substituted styrenes,
substituted styrenes, carbinolamides,
styrenes, carbinolamides,
carbinolamides,
naphthopyrans, and
naphthopyrans,
naphthopyrans, and cyclic
and cyclic carbonates.
cyclic carbonates.
carbonates.
5.6. Synthesis
5.6. Synthesis of
of Polysubstituted
Polysubstituted Cyclopropanes
Cyclopropanes Catalyzed
Catalyzed by
by Basic
Basic Zeolite
Zeolite
Rama and
Rama and coauthors reported on
coauthors reported on aa very
very convenient
convenient protocol
protocol toto promote
promote the
the one-pot
one-pot two-step
two-step
synthesis of
synthesis of substituted
substituted cyclopropane.
cyclopropane. The reaction utilizes
The reaction utilizes substituted
substituted benzyl
benzyl halides,
halides, aromatic
aromatic
aldehydes,
aldehydes, pyridine, acetonitrile derivatives, and potassium-exchanged Y zeolites as basic catalyst
pyridine, acetonitrile derivatives, and potassium-exchanged Y zeolites as basic catalyst
(Scheme24).
(Scheme 24).The
Thesame
same reaction
reaction performed
performed in absence
in absence of theofzeolite
the zeolite
gave nogave no product,
product, since thesince the
pyridine
basicity was insufficient for catalyzing the final addition that provides the cyclopropane, while
pyridine basicity was insufficient for catalyzing the final addition that provides the cyclopropane, it could
only
whilepromote
it could the
onlyKnoevenagel
promote thecondensation
Knoevenagel[47].condensation [47].
Scheme 24.
Scheme
Scheme 24. Synthesis
24. Synthesis of
Synthesis of polysubstituted
of polysubstituted cyclopropanes
polysubstituted cyclopropanes promoted
cyclopropanes promoted by
promoted by basic
by basic KY
basic KY zeolites.
KY zeolites.
zeolites.
The catalyst
The catalyst was
was prepared
prepared byby aa cation
cation substitution
substitution procedure
procedure performed
performed onon NaY
NaY with
with nitrate
nitrate
solution of potassium, lithium and cesium. The yield of the catalyzed reactions followed the basicity
solution of potassium, lithium and cesium. The yield of the catalyzed reactions followed the basicity
degree of
degree of the
the zeolites
zeolites (CsY
(CsY >> KY
KY >> NaY
NaY >>LiY).
LiY). Indeed,
Indeed, KY
KY was
was preferred
preferred to
to CsY
CsY for
for cost
cost effectiveness
effectiveness
and easy handling reasons. The exchanged cation increased the negative charges on the aluminum
center, which was transferred to the adjacent oxygen atom. It is believed that the basic cites are
Catalysts 2019, 9, 248 18 of 21
and easy
Catalysts handling
2018, reasons.
8, x FOR PEER The exchanged cation increased the negative charges on the aluminum
REVIEW 18 of 21
center, which was transferred to the adjacent oxygen atom. It is believed that the basic cites are
localized on
localized on the
the surface-bound
surface-bound metal oxides and
metal oxides and the
the plausible
plausible catalytic
catalytic mechanism
mechanism is reported in
is reported in
Scheme 25.
Scheme 25.
Scheme 25.
Scheme 25. Plausible
Plausible mechanism
mechanism for
for synthesis
synthesis of
of polysubstituted
polysubstituted cyclopropanes
cyclopropanes catalyzed
catalyzed by
by basic
basic
KY zeolites.
KY zeolites.
In conclusion,
In conclusion,thethedeveloped
developedprotocol
protocol requires
requires very
very mildmild conditions
conditions and and is characterized
is characterized by
by good
good yields,
yields, a simplea simple
work-up,work-up, and reusability
and reusability of the Itcatalyst.
of the catalyst. It was
was actually actually
used used
for three for three
consecutive
consecutive
reactions andreactions
retainedand retained
its full its full activity.
activity.
6. Final Remarks
6. Final Remarks
The acid–base sites of zeolites are related to the different charge of the two ions Al+3+3 and Si+4
The acid–base sites of zeolites are related to the different charge of the two ions Al and Si+4
present in the crystal structure, so (AlO4 ) tetrahedrons have a net negative charge that requires
present in the crystal structure, so (AlO4) tetrahedrons have a net negative charge that requires
balancing. As previously discussed, cations or protons can ensure the framework electroneutrality;
balancing. As previously discussed, cations or protons can ensure the framework electroneutrality;
in the latter case the zeolite is considered a solid acid that can give heterogeneous catalysis based on
in the latter case the zeolite is considered a solid acid that can give heterogeneous catalysis based on
Brønsted acidity of bridging Si-(OH)-Al sites [48,49]. On the other hand, in the cationic zeolite the
Brønsted acidity of bridging Si-(OH)-Al sites [48,49]. On the other hand, in the cationic zeolite the
oxygen atoms that possess a negative charge are characterized by a certain basicity/nucleophilicity,
oxygen atoms that possess a negative charge are characterized by a certain basicity/nucleophilicity,
also being the conjugate base of the corresponding acid form (Figure 1). After all, the basicity of the
also being the conjugate base of the corresponding acid form (Figure 1). After all, the basicity of the
zeolites
zeolites is
is aa documented
documented property,
property, considering
considering itsits deprotonating
deprotonating catalytic
catalytic activity
activity reported
reported in several
in several
publications, as well as all the spectroscopic studies performed to ensure this behavior [4].
publications, as well as all the spectroscopic studies performed to ensure this behavior [4].
We have already
We have alreadydiscussed
discussedintointo
thethe introduction
introduction the the influence
influence of theof framework
the framework and
and extra-
extra-framework chemical composition on the number and the strength of the acidic
framework chemical composition on the number and the strength of the acidic sites of protonated sites of protonated
zeolites
zeolites and
and so so of
of their
their catalytic
catalytic activity.
activity. Since
Since the
the reactions
reactions occur into the
occur into the zeolite
zeolite pores,
pores, itit must
must be
be
taken into account also of the zeolite geometry that causes the shape selectivity and the
taken into account also of the zeolite geometry that causes the shape selectivity and the confinement confinement
effect of the well-defined crystal pore sizes, where the catalytic active sites are located. This molecular
sieving property of the zeolites can select the desired reaction path, which gives rise to the so-called
“transition state shape selectivity”, that means only certain configurations of the transition state are
Catalysts 2019, 9, 248 19 of 21
effect of the well-defined crystal pore sizes, where the catalytic active sites are located. This molecular
sieving property of the zeolites can select the desired reaction path, which gives rise to the so-called
“transition state shape selectivity”, that means only certain configurations of the transition state are
allowed. In this regard, the modulation of the acid site strength has been considered a big challenge:
it seems fairly certain that the electric field present in zeolites is crucial in stabilizing ionic pairs of the
transition state [6]. On the other hand, nonuniformity of the zeolites in the proton transfer process
can affect the selectivity of the chemical process, thus generating unwanted by-products. However,
the attention for tuning the catalytic performance of the protonated acidic zeolites as well as the
cationic basic zeolites has been reported for several chemical transformations [50,51], some of them
illustrated in the present review.
Concerning the cationic zeolites, such as alkaline-LTA, it has been proven that they are naturally
endowed with mild basic properties, which is a great advantage compared to the basic strength of
the standardly employed organic bases. The exchange of Na+ ion with larger alkali metals (Cs+ for
example), which are weaker Lewis acids due to their larger size, increases to some extent the basicity
of the zeolite oxides, however the increase of the steric hindrance compensates this effect, since the
access to the basic sites or to the overall cavity is reduced. In any case, the basic catalytic activity is
regularly modulated and these materials result in not very strong solid bases. It likely represents the
main reason why cationic zeolites have been considered of less practical importance for industrial
applications. In our opinion, the moderate catalytic activity as basic solid should be considered a
strong point for the implementation in organic reactions of these cationic zeolites, since they are able to
provide great selectivity, due to the mild condition offered, together with ease handling of the reaction
mixture and a simple final work up.
In addition to these features, economic feasibility and reusability make zeolites in general
attractive heterogeneous benign catalysts, which can accomplish the need to develop new
environmentally friendly chemical processes and products, avoiding the use and generation of
hazardous substances.
Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.
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Catalysts: Zeolites As Acid/Basic Solid Catalysts: Recent Synthetic Developments

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Catalysts: Zeolites As Acid/Basic Solid Catalysts: Recent Synthetic Developments

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catalysts

M+2 x/n [(AlO2 )x (SiO2 )y ]·wH2 O

Catalysts 2019, 9, 248; doi:10.3390/catal9030248 www.mdpi.com/journal/catalysts

codeWhen 75% of Type

When 75% of its sodium is replaced by potassium, it is referred to as a zeolite of 3 Å pore

Scheme 1. Activation of glycosyl imidates with activated 4 Å aw MS in a glycosidation reaction.

2.2. Carbinol Glycosidation Reaction of the 17-β-Estradiol

mild Since the α-anomer

Catalysts 2018, 8, x FOR PEER REVIEW 6 of 21

Scheme 4. Synthesis of the tetrasaccharide.

Scheme 9. Chemoselective N-alkylation of a peptide sequence promoted by activated 4 Å MS.

Scheme 11. Solid-phase

By combining both protocols—the 4 Å MS solution and solid-phase strategy—it was possible to

Catalysts 2018, 8, x FOR PEER REVIEW 11 of 21

Scheme 12. Solution

4.4. Chemoselective Glycosylation of Peptides through S-Alkylation Reaction

Scheme 15.15. S-alkylation of

5. Useful Examples of Broad Scope Reactions Promoted by Molecular Sieves

Catalysts 2019, 9, 248 15 of 21

Scheme 19. α-aminophosphonate catalyzed by Natrolite zeolite.

Funding: This research received no external funding.

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