Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 1
1.1 Catalysis
The term ‘catalysis’ originally coined by Berzelius in 1835 and since then the
concept of catalysis has evolved greatly. Catalysis can be defined as ‘the change of
the rate of chemical reactions under the action of certain substances’. A catalyst is
the substance that speeds up the rate of a reaction, by lowering the activation energy,
without being consumed in the reaction (Figure 1.1). They preserve their
composition throughout the chemical reaction and are not wasted in the course of the
catalysis. Furthermore, catalysts can speed up the reaction in a more selective
manner which allows chemical processes to work more efficiently and with less
waste. This makes catalysts of great importance in industrial applications.
Fig. 1.1 Progress of the reaction with catalyst and without catalyst
Apart from accelerating reactions, catalysts have another important property: they
can influence the selectivity of chemical reactions. This means that completely
different products can be obtained from a given starting material by using different
catalyst systems. Industrially, this targeted reaction control is often even more
important than the catalytic activity.
Catalysts can be gases, liquids, or solids. Most industrial catalysts are liquids
or solids, whereby the latter react only via their surface. The importance of catalysis
in the chemical industry is shown by the fact that 75 % of all chemicals are produced
with the aid of catalysts; in newly developed processes, the figure is over 90 %.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 2
Numerous organic intermediate products, required for the production of plastics,
synthetic fibers, pharmaceuticals, dyes, crop-protection agents, resins, and pigments,
can only be produced by catalytic processes. Most of the processes involved in
crude-oil processing and petrochemistry, such as purification stages, refining, and
chemical transformations, require catalysts. Environmental protection measures such
as automobile exhaust control and purification of off-gases from power stations and
industrial plant would be inconceivable without catalysts.
Catalysts have been successfully used in the chemical industry for more than
100 years, examples being the synthesis of sulfuric acid, the conversion of ammonia
to nitric acid, and catalytic hydrogenation. Later developments include new highly
selective multicomponent oxide and metallic catalysts, zeolites and the introduction
of homogeneous transition metal complexes in the chemical industry. This was
supplemented by new high-performance techniques for probing catalysts and
elucidating the mechanisms of heterogeneous and homogenous catalysis. The brief
historical survey given in Table 1.1 shows just how the closely the development of
catalysis is linked to the history of industrial chemistry.
Table 1.1 History of the catalysis of industrial processes
Catalytic reaction Catalyst Discoverer or company/year
Sulfuric acid (lead-chamber process)
NOx Désormes, Clement, 1806
Chlorine production by HCl oxidation
CuSO4 Deacon, 1867
Sulfuric acid (contact process)
Pt, V2O5 Winkler, 1875; Knietsch,
1888
Nitric acid by NH3 oxidation
Pt/Rh Ostwald, 1906
Fat hardening Ni Normann, 1907
Ammonia synthesis from N2, H2
Fe Mittasch, Haber, Bosch,
1908
Hydrogenation of coal to hydrocarbons
Fe, Mo, Sn Bergius, 1913; Pier, 1927
Oxidation of benzene V2O5 Weiss, Downs, 1920
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 3
Methanol synthesis from CO/H2
ZnO/Cr2O3 Mittasch, 1923
Hydrocarbons from CO/H2 Fe, Co, Ni Fischer, Tropsch, 1925
Oxidation of ethylene Ag Lefort, 1930
Cracking of hydrocarbons Al2O3/SiO2 Houdry, 1937
Olefin metathesis Re, W, Mo Banks, Bailey, 1964
Hydrogenation, isomerization,
hydroformylation Rh-, Ru- complexes Wilkinson, 1964
1.1.1 Classification of Catalyst
The numerous catalysts known today can be classified according to various criteria:
structure, composition, area of application, or state of aggregation. Here we shall
classify the catalysts according to the state of aggregation in which they act. There
are two large groups: heterogeneous catalysts (solid-state catalysts) and
homogeneous catalysts (Fig. 1.2)
Fig. 1.2 Classification of catalysts
Catalysts
Homogeneous
Catalysts
Heterogenized
homogeneous Catalysts
Biocatalysts (Enzymes)
Acid/Base Catalyst
Heterogeneous Catalysts
Bulk Catalysts
Transition
metal Catalyst
Supported catalysts
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 4
Catalytic processes that take place in a uniform gas or liquid phase are
classified as homogeneous catalysis. Homogeneous catalysts are generally well-
defined chemical compounds or coordination complexes, which, together with the
reactants, are molecularly dispersed in the reaction medium. Examples of
homogeneous catalysts include mineral acids and transition metal compounds (e. g.,
rhodium carbonyl complexes in oxo synthesis).
Heterogeneous catalysis takes place between several phases. Generally the
catalyst is a solid, and the reactants are gases or liquids. Examples of heterogeneous
catalysts are Pt/Rh nets for the oxidation of ammonia to nitrous gases (Ostwald
process), supported catalysts such as nickel on kieselguhr for fat hardening, and
amorphous or crystalline aluminosilicates for cracking petroleum fractions. Of
increasing importance are the so-called biocatalysts (enzymes).
Enzymes are protein molecules of colloidal size [e. g., poly(amino acids)].
Some of them act in dissolved form in cells, while others are chemically bound to
cell membranes or on surfaces. Enzymes can be classified somewhere between
molecular homogeneous catalysts and macroscopic heterogeneous catalysts.
Enzymes are the driving force for biological reactions. They exhibit
remarkable activities and selectivities. For example, the enzyme catalase decomposes
hydrogen peroxide 109 times faster than inorganic catalysts. The enzymes are
organic molecules that almost always have a metal as the active center. Often the
only difference to the industrial homogeneous catalysts is that the metal center is
ligated by one or more proteins, resulting in a relatively high molecular mass.
Apart from high selectivity, the major advantage of enzymes is that they
function under mild conditions, generally at room temperature in aqueous solution at
pH values near 7. Their disadvantage is that they are sensitive, unstable molecules
which are destroyed by extreme reaction conditions. They generally function well
only at physiological pH values in very dilute solutions of the substrate.
Table 1.2 shows distinguishing features of homogeneous and heterogeneous
catalysis.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 5
Table 1.2 Distinguishing features of homogeneous and heterogeneous catalysis
Homogeneous Heterogeneous
Form Soluble metal complexes,
usually mononuclear
Metals, usually supported,
or metal oxides
Active site Well-defined, discrete
molecules
Poorly defined
Phase Same as reactants Different from reactants
Temperature Low (<250˚C) High (250-500˚C)
Activity Moderate High
Selectivity High Low
Diffusion Facile Can be very important
Heat transfer Facile Can be problematic
Product separation Generally problematic Facile
Catalyst recycle Expensive Simple
Catalyst
modification Easy Difficult
Reaction
mechanisms Reasonably well understood Poorly understood
1.1.2 The importance of catalysis
The principal theme in catalysis is the desire to control chemical test reactions and
the secondary theme is to understand the mechanisms of the control. Catalysis is of
crucial importance for the environment and for chemical industry, the number of
catalysts applied in industry is very large and catalysts come in many different forms,
from heterogeneous catalysts in the form of porous solids over homogeneous
catalysts dissolved in the liquid reaction mixture to biological catalysts in the form of
enzymes.
� Environmental impact
Progress towards environmentally responsibility is marked by the reduced
dependence on hazardous chemicals and by-product generation. The key to both is
often provided by catalytic processes as alternatives to stoichiometric processes.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 6
Heterogeneous catalysis, long established in bulk–chemical processing, is
beginning to make inroads into the fine chemicals industry also. In the past, the need
to reduce costs was the driving power for improvements in process efficiency;
science wasteful processes are also uneconomic. However, recent public concern
about the environment, leading to regulatory activity by governments has accelerated
this tendency.
Two useful measures of the environmental impact of chemical process are the
E-factor defined by the mass of waste to desired product, and the atom utilization,
calculated by dividing the molecular weight of the desired product by the sum of
molecular weights all substances produced in the stoichiometric redox reagents,
represent the major sources of waste production in the form of salts and heavy metals
and high E-factors allow high atom utilization.
Reactions of this type, employed in the fine–chemicals industry particularly,
include Friedel-Crafts alkylation’s mediated by Lewis acids such as aluminium
chloride, reductions with metal hydrides or dissolving metals such as zinc or iron,
and stoichiometric oxidations with dichromate or permanganate, all of which
generate prohibitive amounts of metal–containing wastes.
The elimination of such wastes is the first goal of environmentally friendly
processing; the second is the reduction dependence on the use of hazardous
chemicals such as phosgene, dimethyl sulphate and peracids.
A good example of an environmental benefit occurring from the introduction
of heterogeneously catalysed process is provided by the petrochemical ethylene
(EO), in which the direct oxidation of ethene over silver catalyst replaced the old
chlorohydrins process. The direct process has an atom utilization of 100% and a E-
factor of zero (Zhang et al. 1988).
In petroleum refining, it is catalytic processes that allow refiners to produce
the broad mix of fuels and other products that drive today's economy and there is an
entire body of catalysis, outside the scope of this report, in environmental correction;
the most obvious examples are catalytic converters on automobiles that clean up auto
exhausts. Even our bodies are operated by catalysts, the biological catalysts called
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 7
enzymes, another important area of bio-catalysis that is outside our scope as well
(Thomas et al. 1999).
Catalysts have been used commercially for more than a century, dating from
the Deacon and contact processes, first used in the late 1800ies. Fritz Haber's
ammonia synthesis of 1908 can be considered the process that heralded the birth of
modern industrial catalysis. Catalysis thus has a strong impact on the global economy
and the economy of developing countries, since it is widely applied, in sectors
including polymer production, agricultural production, and the petrochemical,
pharmaceutical and fine chemicals industries. Within the industrialization
programmes of many developing countries, the transfer of the latest know-how and
technologies on catalytic systems and processes and their industrial application and
adoption is recognized as urgent.
In order to optimize an industrial process, special attention should be given to
recycling and reuse of specific fluids or semi-products into the mainstream of the
process line, introduction of innovative clean technologies into the process cycle, use
of new catalysts to give better kinetics of critical process reactions, thereby
improving process and product efficiency as well as environmental quality of the
waste byproduct, development and use of new catalysts in small and medium
enterprises.
Both homogeneous and heterogeneous catalysis may offer advanteges in
particular cases. Heterogeneous catalysts generally offer the advantage of simple
separation and recovery, are employed for both gas and liquid-phase operations, and
lend themselves for continuous reactor operations.
The advantages of heterogeneous catalysis were first appreciated in the
petroleum refining and bulk-chemical industries. However, fine chemicals
operations, although of smaller scale, are more numerous and on the average. Their
E-factors are of the order of 5-50 kg waste per kg product, compared with values of
<1-5 for bulk chemicals and about 0.1 for refinery operations.
The small-scale operations of the fine-chemicals industry make the costs of
developing catalysts, and possibly installing specialized equipment, for specific
reaction slow recoup.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 8
In general, acid and base are paired concepts; a number of chemical
interactions have been understood in terms of acid-base interaction. Among chemical
reactions which involve acid/base reactions are acid catalysed and base catalyzed
reactions which are initiated by acid-base interactions followed by catalytic cycles.
In contrast, relatively few studies solid basic catalysts. One of the reasons why the
studies of heterogeneous basic catalysts are not as extensive as those of
heterogeneous acidic catalysts seems to be the requirement for severe pretreatment
conditions for active basic catalysts.
Solid basic catalysts are becoming extensively studied in the past years and
the scientific literature on the subject is becoming more and more abundant because
of their necessity for the chemical industry. For more insight to the role of base
catalysis in chemical reaction, the next point presents some examples.
1.1.3 Solid catalysts in chemical reactions
Solid base catalysts exhibit high activities and selectivities for many kinds of
reactions, including some condensation, alkylation, cyclization and isomerization
which are carried out using liquid bases as catalysts in industrial applications. Many
of these applications require stoichiometric amounts of the liquid base for conversion
to the desired product. Replacement of these liquid bases with solid base catalysts
would allow easier separation from the product as well as possible regeneration and
reuse of the catalyst (Prins, 1997).
Examples of commercially applied solid base catalysts are fewer than of solid
acids. However, in this area also, newer solids including basic zeolites and related
aluminosilicate, layered-structure materials such as hydrotalcite and immobilized
organic bases are enabling applications to be extended (Aramendia, 1999).
The next advance in the manufacture of the bulk chemical styrene may come
from processes in development for the side-chain alkylation of toluene with
methanol, employing solid basic catalysts such as Cs-X zeolites. The feed stock costs
are lower than for benzene alkylation, while the fact that methanol is preferentially
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 9
produced from natural gas and from renewable resources, gives this process an
environmental premium (Martin et al. 1994).
Additionally, the use of alkali-exchanged zeolites such as K-Y and Cs-X can
be used as effective base catalysts for the methylation of aniline and
phenylacetonitrile with methanol or dimethyl carbonate. For bulky substrates,
cesium-exchanged mesoporous MCM-41 prove and to be effective mild basic solid
catalyst for Knoevenagel condensation (Martin et al. 1994). Hydrotalcite clays are
built of positively charged brucite layers; upon calcinations they become active as
solid bases useful for reactions such as aldolizstion and Knoevenagel condensation,
exemplified by the reaction of benzaldehyde with ethylcyanoacetate (Figueras,
1998).
1.3.1 Generation of basic sites
At present, several classes of basic catalysts can be distinguished according how they
are synthesized. A first class would contain unmodified oxide solids, i.e. intrinsically
basic oxides, namely alkaline earth oxides like MgO or CaO and Al2O3 or ZrO2 that
have both acid and basic centers. The basic site of these solids is either oxygen or a
basic hydroxyl. A second group of basic solids could be modified oxides (Utiyama et
al. 1978).
γ-Alumina is widely used as catalyst and catalyst supports. Its catalytic
activity is closely related to certain “acid” sites developed when chemisorbed water
is removed from the surface. From the classical Lewis definition, the base strength of
a solid catalyst is determined by its ability to donate an electron pair to an adsorbed
molecule. These sites are believed to be aluminium ions (Lewis acids) exposed at the
surface in small amounts as a result of condensation of surface hydroxyl groups.
Ionic surfaces, unless highly dried, are usually covered with hydroxyl groups
formed by chemisorption of water. Removal of such groups from alumina leaves a
strained surface on which strained oxide linkages have been postulated as active
sites. The surface properties of heterogeneous basic catalysts have been studied by
various methods by which the existence of basic sites has been realized. Different
characterization methods give different information about the surface properties.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 10
Surfaces of solids are covered either with carbon dioxide, water or oxygen
and therefore show no activity for base catalyzed reactions. Generation of basic sites
requires high temperature pretreatment to remove the adsorbed species (Zechina et
al. 1957).
Figure 1.3 Ions in low coordination on the surface of MgO
Ion pairs of MgO of low coordination numbers exist at corners, edges. Ion pairs with
low coordination numbers are stronger sites than the pairs with high coordination
numbers, see Figure 1.3.
The appearance of basic sites depends on pretreatment temperature, higher
temperature generates stronger basic sites. Among the ion pairs of different
coordination numbers, the ion pair of Mg2+3c O2-
3c is most reactive and adsorbs
carbon dioxide most strongly. To reveal the ion pair Mg2+3c O
2-3c, the highest pre-
treatment temperature is required (Otake, 1995).
It was prepared Mg-Al oxides with Mg/Al molar ratios of 0.5-9.0 were
obtained by thermal decomposition of precipitated hydrotalcite precursors (Otake,
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 11
1995). The effect of composition on structure has been reported by different
characterizations methods like x-ray photo electron spectroscopy, temperature
program desorption of carbon dioxide, BET surface area and x-ray diffraction.
It was found that addition of small amounts of Al to MgO diminished
drastically the density of surface basic sites because of a significant Al surface
enrichment. Formation of surface amorphous alloy structures in samples with low Al
content (5>Mg/Al>1), the basic site density increased because the Al3+ cation within
the MgO lattice created a defect in order to compensate the positive charge generated
and the adjacent oxygen anions became coordinatively unsaturated. In samples
Mg/Al<1, segregation of bulk MgAl2O4 spinels occurred and caused the basic site
density to diminish.
The dehydrogenation of ethanol to acetaldehyde and the aldol condensation
to n-butanol both involved the initial surface ethoxide formation on a lewis acid-
strong base pair. Pure MgO exhibited poor activity because of the predominant
presence of isolated O2- basic centers hindered formation of the ethoxide
intermediate by ethanol dissociative adsorption (Otake, 1995).
1.3.2 Characterization of basic surfaces
There are many methods allowing determination of acidic and basic properties of
solids as described above. Apart from titration and spectroscopic techniques (FTIR,
XPS, NMR) (Choudary et al. 1999) temperature-programmed desorption is often used
(Yashima et al. 1972). The most widely applied molecular probes are ammonia (to
study acidic sites) and carbon dioxide (basic sites). Recently, the application of
catalytic test reactions for characterization of acidic and basic properties of solids has
been intensively developed (Bull et al. 1999).
1.3.2.1 Indicator methods
Typical measurements of basicity have been obtained by using titration of adsorbed
indicators having a wide range of pKa values. Acid–base indicators change their
colours according to the strength of the surface sites of the catalysts. The strengths of
the surface sites are expressed by an acidity function (H_). The H_ function is
defined by the following equation (Clark et al. 1983):
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 12
H_ = pKBH + log [B-]/[BH]
Where [BH] and [B–] are, respectively, the concentration of the indicator BH and its
conjugated base, and pKBH, is the logarithm of the dissociation constant of BH. The
reaction of the indicator BH with the basic site (B_) is:
BH + B_ B- + B_H+
One problem with using adsorbed indicators to evaluate basicity is the
interference of indicator reactions that are not due to acid-base chemistry. In
addition, evidence of reaction is often provided by a color change, which requires the
use of colorless catalyst.
1.3.2.2 Temperature programmed desorption (TPD)
This method is used to measure the number and base strengths of sites found on solid
base catalysts. Since strongly bound probe molecules have high binding energies,
increases temperatures are necessary to desorb these adsorbates. Experiments are
typically performed under identical experimental conditions (heating rates and
sample size) so that a qualitative comparison can be made between samples.
During a TPD experiment, the amount of desorbed molecules is often
monitored by mass spectrometry and the surface interactions are explored with
infrared spectroscopy. Numerous texts describe in detail the TPD method (Hattori,
1995; Prins, 1997).
� Temperature programmed desorption (TPD) of carbon dioxide
The desorption of carbon dioxide is often used in order to determine the strength and
amount of basic centers. The strength of the centers calculated then correlated with
the desorption temperature. At the same time it is found to be difficult because of the
large amount of the received area peaks, quantitative results. Often qualitative
measurements are carried out for different experiments under same conditions. TPD
of adsorbed carbon dioxide has been widely used to probe basic materials.
For example, rubidium–modified supports have been investigated using
stepwise TPD of CO2. The addition of Rb species to supports like MgO, Al2O3 TiO2
and SiO2, via the decomposition of supported rubidium acetate, increases the surface
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 13
density of adsorbed CO2 over that pure support. The high desorption temperatures
required to liberate CO2 from RbO/MgO indicated the formation of very strong basic
sites. Carbon dioxide temperature programmed desorption has also been used to
measure the base strengths of various alkali metals-containing (exchanged and
occluded) zeolites (Tsuji et al. 1992). TPD plots of carbon dioxide desorbed from
alkaline earth oxides are compared in Figure 1.4.
Figure 1.4 TPD plots of carbon dioxide desorbed from the alkaline earth oxide
� Temperature programmed desorption (TPD) of hydrogen
This method gives information about the coordination state of the surface ion pairs
when combined with other methods such as UV absorption and luminescence
spectroscopy. Hydrogen is heterolytically dissociated on the surface of MgO to form
H+ and H- which are adsorbed on the surface O²- and Mg²+ ions (Ito et al. 1983). The
adsorption sites on MgO are pretreated at different temperatures, a heterolytical
dissociation of hydrogen on the MgO surface can be verified by IR spectroscopies
(Ito et al. 1983).
� Temperature programmed desorption of Pyrrole
Pyrrole adsorption has been found to be useful for probing the basicity of zeolites.
An increase in solid base strength has been correlated to a shift in the NH vibration
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 14
frequency to lower wavenumbers in the IR spectrum for numerous alkali-exchanged
zeolites (Lavalley, 1996) and for various metal oxides (Murphy et al. 1996).
When the O2- species is highly basic, the surface OH species are unperturbed
and the H atom of the pyrrole molecule is localized near the basic oxygen,
undergoing dissociative chemisorption. When the O2- species are less basic, the
surface oxygen forms an NH-O bridge with pyrrole.
Complexities in the IR spectrum result from interaction with surface hydroxy
and pyrrole since hydroxy species are as both a basic surface species and as product
formed from pyrrole dissociation (Auroux et al. 1990).
1.3.2.3 Spectroscopic methods
� UV absorption and luminescence spectroscopies
UV absorption and luminescence spectroscopies give information about the
coordination states of the surface atoms. High surface area MgO absorbs UV light
and emits luminescence, which is not observed with MgO single crystal. Nelson and
Hale first observed the absorption at 5.7 eV, which is lower than the band gap (8.7
eV, 163 nm) for bulk MgO at 3 eV (Nelson et al. 1958).
Tench and Pott observed photoluminescence. The UV absorption corresponds
to the following electron transfer process involving surface ion pairs (Zechina et al.
1957).
Mg2++ O2- + hν Mg+O-
Absorption bands were observed at 230 nm and 274 nm, which are considerably
lower in energy than the band at 163 nm for bulk ion pair. The bands at 230 nm and
274 nm are assigned to be due to the surface O²- ion of coordination numbers 4 and 3
respectively.
Luminescence corresponds to the reverse process of UV absorption, and the
shape of the luminescence spectrum varies with the excitation light frequency and
with absorption of molecules. Emission sites and excitation sites are not necessarily
the same. Exactions move on the surface and emit at the ion pair of low coordination
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 15
numbers where emission of efficiency is high. Ion pairs of low coordination numbers
responsible for UV absorption and luminescence exist at corners edges.
The surface model for MgO shown in figure 1.1 was proposed on the basis of
UV absorption and luminescence spectrum excited by the 274 nm light and was it
much more severely influenced by hydrogen adsorption than that excited by the 230
nm light. Hydrogen molecules interact more strongly with the ion pairs of
coordination number 3 than with those of coordination number 4 are heterolytically
dissociated on these sites.
The UV absorption and luminescence spectroscopes give us useful information
about the coordination state, but it is difficult to quantify the sites of a certain
coordination state (Figueras et al. 1998).
� IR spectroscopy
CO2 interact strongly interaction with the basic centers of a surface. Three species of
adsorbed CO2 shown as Figure 1.5, correspond with three different types of surface
basic sites:
Figure 1.5 IR bands of adsorbed CO2 surface species
At the formation of the bidentate carbonates, also a metal ion is involved. Three
species of adsorbed CO2, which are shown in figure 3, were detected on samples of
MgO and Al2O3. Apparently reflecting three different types of surface basic sites.
Unidentate and bidentate carbonate formation requires surface oxygen atoms.
Unidenate carbonate exhibits symmetric O-C-O stretching at 1360–1400 cm-1
asymmetric O-C-O stretching at 1510-1560 cm-1. Bidentate carbonate shows
symmetric O–C-O stretching at 1320 – 1340 cm-1 and asymmetric O-C-O stretching
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 16
at 1610-1630 cm-1. Bicarbonate species formation involves surface hydroxyl groups
showing C-OH bending mode at 1220 cm-1 as well as symmetric and asymmetric O-
C-O stretching modes at 1480 cm-1 and 1650 cm-1, respectively (Prins, 1997).
The oxygen exchange between CO2 and MgO surface basic sites suggest an
important aspect of the nature of surface basic sites. The basic sites are not fixed on
the surface but are able to move over the surface when carbon dioxide is adsorbed
and desorbed. The position of the basic site (surface O atom) changes as CO2
migrates over the basic site. In addition, it became clear that not only O2- basic sites
but also adjacent Mg2+ sites participate in CO2 adsorption. Therefore, it is reasonable
to consider that the metal cations adjacent to the basic site participate in the base-
catalyzed reactions (Figueras et al. 1998; Utiyama et al. 1978).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 17
1.2 Multicomponent reactions
Multicomponent reactions (MCRs) are defined as reactions that occur in one reaction
vessel and involve more than two starting reagents that form a single product which
contains the essential parts of the starting materials (Domling, 2006; Hulme et al.
2003).
Organic-chemical synthesis performed through one-pot, or multicomponent
reactions (Fogg et al. 2004, Poli et al. 2002) have become a significant area of
research in organic chemistry (Malacria, 1996; Tietze, 1996; Climent et al. 2011) since
such processes improve atom economy. The one-pot transformations can be carried
out through multi-step sequential processes where the consecutive steps take place
under the same reaction conditions or, when this is not possible, they can be
performed in two or more stages under different reaction conditions, with the correct
addition sequence of reactants. There are cases however, in where the desired
product can be prepared in a one-pot mode throughout a multicomponent reaction.
An ideal multicomponent reaction involves the simultaneous addition of
reactants, reagents and catalyst at the beginning of the reaction and requires that all
reactants couple in an exclusive ordered mode under the same reaction conditions.
The success of multi-step sequential or multicomponent one-pot transformations
requires a balance of equilibria and a suitable sequence of reversible and irreversible
steps. Thus, in the case of MCRs three types of reactions are known:
(a) Type I MCRs in which there is an equilibrium between reactants, intermediates
and final products
(b) Type II MCRs in where an equilibrium exists between reactants and
intermediates with the final product being irreversibly formed
(c) Type III MCRs which involve a sequence of practically irreversible steps that
proceed from the reactants to the products. Type III MCRs are usual in biochemical
transformations, but rarely occur in preparative chemistry.
MCRs have been known for over 150 years and it is generally considered that
this chemistry began in 1850 when Strecker reported the general formation of a-
aminocyanides from ammonia, carbonyl compounds and hydrogen cyanide. Since
then, many multicomponent reactions have been developed. Some of the first
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 18
examples are the Hantzsch dihydropyridine synthesis and the Biginelli reaction
(Scheme 1.1). The first isocyanide-based 3CRs was introduced by Passerini in 1921,
while in 1959 Ugi introduced the four component reaction of the isocyanides (Ugi et
al. 1959) which involves the one-pot reaction of amines, carbonyl compounds, acid
and isocyanides. The Ugi reaction has been the most extensively studied and applied
MCR in the drug discovery process.
Scheme 1.1 (a) Biginelli reaction, (b) Hantzsch synthesis and (c) Ugi deBoc/cyclize
methodology
One key aspect of multicomponent reactions is that they are an important
source of molecular diversity (Eilbracht, 1999). For instance, a three component
coupling reaction will provide 1000 compounds when 10 variants of each component
are employed. This aspect together with its inherent simple experimental procedures
and its one-pot character, make MCRs highly suitable for automated synthesis. They
are powerful tools in modern drug discovery processes allowing rapid, automated
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 19
and high throughput generation of organic compounds (Weber, 2002). Additionally,
the one pot character delivers fewer by-products compared to classical stepwise
synthetic routes, with lower costs, time and energy.
1.2.1 Importance of heterogeneous catalysts in MCR
The simplest approximation to heterogeneous catalysis starting from
homogeneous mineral and organic acids has been to support them on porous solids.
For instance, perchloric, sulphuric and phosphoric acids are normally supported on
silica either by simple pore filling and/or by interacting with the surface of the solid.
In the case of the sulfonic acids a heterogenization procedure involves the
synthesis of organic polymers bearing sulphonic groups. In this case organic resins
can be excellent catalysts, especially when their pore structure is adapted to the
nature and dimensions of reactants (Guyot, 1998). Inorganic solid acids can be
prepared with acidity that ranges from weak to strong. One type of inorganic solid
acid is the family of silicates. In high surface area silica, the silicon atoms are
tetrahedrally coordinated and the system is charge neutral (Fig. 1.6 a).
However the silica nanoparticles terminate at the surface with silanol groups
(Fig. 1.6 b). In this silanol group the density of positive charge on the hydrogen of
the hydroxyl group is very small and it can be considered as a very weak Brønsted
acid site. Nevertheless they could be used for acid catalyzed reactions that require
weak acidity, provided that the silica has a relatively high surface area. With this
type of catalyst the reactants become activated by surface adsorption, being the heat
of adsorption the additive effect of the small van der Waals and hydrogen bridging
type of interactions.
Larger O–H polarizations are achieved when an isomorphic substitution of Al
by Si occurs. In this case, the tetrahedrally coordinated Al generates a negative
charge that is compensated by the positive charge associated with the hydrogen of
the bridging hydroxyl groups (Fig. 1.6 c).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 20
Fig. 1.6 Structure of silicates
These Brønsted acid sites are clearly stronger than the silanol groups and they exist
in well prepared amorphous and long range structured silica aluminas and in
crystalline aluminosilicates (Corma, 1995). When the T–O–T’ bond in
aluminosilicates is not constrained, as it occurs in amorphous silica alumina, the
tendency to release the proton and to relax the structure is lower and consequently
the Brønsted acidity is mild.
However, in the case of crystalline aluminosilicates such as zeolites the
bridging T–O–T’ bond is constrained and the Brønsted acidity of these materials is
higher than in amorphous silica alumina. If one takes into account that it is possible
to synthesize zeolites with different Al contents and with pores within a wide range
of diameters (Jiang et al. 2010), it is not surprising that zeolites have found and still
find a large number of applications as solid acid catalysts. Their applications can be
even enlarged through the synthesis of acid zeolites with pores of different
dimensions within the same structure.
If one takes into account that other metal atoms, such as Ti, Sn, Fe and Cr
with catalytic activity for oxidations, can be incorporated in the structure of the
crystalline microporous silicates or aluminosilicates (Boronat et al. 2007) enlarging
the reactivity of the zeolites and allowing the preparation of bifunctional acid-
oxidations catalysts. When metal nanoparticles are formed on the internal and/or
external surface of acid zeolites, bifunctional hydrogenation/ dehydrogenation solid
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 21
acid catalysts are obtained (Chupin et al. 2001; Silva et al. 2000) allowing zeolites to
catalyze multistep reactions (Iosif et al. 2004).
There are reactions that require sites with an acid strength stronger than that
of zeolites. Then, solid catalysts containing sulfonic groups can be used. For
instance, acidic resins with sulfonic acid groups are strong solid acid catalysts that
can be useful for acid catalysis, provided that the reaction temperature does not
surpass their thermal stability limit (Jermy et al. 2005). Along this line, Nafion is a
strong solid acid catalyst but its surface area is too low. To avoid this limitation,
Harmer et al. have shown that it is possible to partially depolymerize Nafion and to
disperse it in silica (Harmer et al. 1996; Harmer et al. 2000). The resultant high
surface solid catalysts can be used in a relatively larger number of acid catalyzed
reactions (Wabnitz et al. 2003; Beltrame et al. 2003).
Nevertheless, the acidity of this hybrid material is somewhat lower than
Nafion, owing to the interaction of sulfonic groups with the silanols of the silica
(Alvaro et al. 2005; Botella et al. 1999). In any case it should be considered that
polymer derived catalysts may be difficult to regenerate if poisoned by deposition of
organic compounds. Indeed, regeneration by calcination with air will be limited
because of thermal stability, and washing out the adsorbed products with solvents
cannot always restore the initial activity.
Looking for strong acid catalysts, heteropolyacids such as H3PW12O40
(H3PW) are able to catalyze at low temperatures a wide range of homogeneous
catalytic processes (Okuhara et al. 1996). Heteropolyacids can be heterogeneized by
either supporting them on a high surface area carrier such as silica or by forming
their cesium or potassium salts (Cs2.5H0.5PW or K2.5H0.5PW) that are solids with
micro and mesoporosity and are insoluble for organic reactions (Izumi et al. 1995).
Other solid acids such as metal organic frameworks bearing sulfonic groups
or metal Lewis acids (Corma et al. 2010), sulfonated zirconia (White et al. 1995) and
metal phosphates have also been used as catalysts (Campelo et al. 1986). With
respect to solid bases, basic resins, amines and alkyl ammonium hydroxides grafted
on silicas, or amines bearing part of MOF structures, KF on Al2O3, alkaline metal
oxides on alumina and zeolites, zeolites exchanged with alkaline cations, alkaline
earth oxides and anionic clays such as hydrotalcites and their corresponding mixed
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 22
oxides are useful catalysts and their basic properties and catalytic activity have been
very well described in a series of reviews (Ono et al. 1997; Gascon et al. 2009;
Weitkamp et al. 2001).
1.2.2 Multicomponent reactions catalyzed by solid catalysts
1) Synthesis of propargylamines
The Mannich reaction is a classic example of a three component condensation (A3
coupling). In general, an aldehyde, an amine and an active hydrogen compound such
as an enolizable ketone or terminal alkyne, react affording the corresponding β-
aminoketone or β-aminoalkyne (propargylamine) (Scheme 1.2).
Propargylamines are important synthetic intermediates for potential
therapeutic agents and polyfunctional amino derivatives (Matyus et al. 2004).
Traditionally these compounds have been synthesized by nucleophilic attack of
lithium acetylides or Grignard reagents to imines or their derivatives. However these
reagents must be used in stoichiometric amounts, are highly moisture sensitive, and
sensitive functionalities such as esters are not tolerated. Therefore, the most
convenient synthetic method for preparing propargylamines has been the Mannich
one-pot three component coupling reaction of an aldehyde, a secondary amine and a
terminal alkyne.
Scheme 1.2 Mannich type reactions
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 23
The reactions are usually performed in polar solvents (mostly dioxane) and in the
presence of a catalytic amount of a copper salt [CuCl, Cu(OAc)2] which increases the
nucleophilicity of the acetylenic substrate towards the Mannich reaction. Mechanistic
studies indicate that the reaction involves the formation of an iminium intermediate
from the starting aldehyde and amine. The C–H bond of the alkyne is activated by
the metal to form a metal acetylide intermediate which subsequently reacts with the
iminium ion leading to the corresponding propargylamine (Scheme 1.3).
Scheme 1.3 Plausible mechanism
A variety of transition metals such as AgI salts (Wei et al. 2003), AuI/AuIII
salts (Wei et al. 2004), AuIII salen complexes (Lo et al. 2006), CuI salts
(Gommermann et al. 2006), Ir complexes (Sakaguchi et al. 2004), InCl3 (Zhang et al.
2009), Hg2Cl2 (Li et al. 2005) and Cu/RuII bimetallic system (Li et al. 2002) have
been employed as catalysts under homogeneous conditions. In addition, alternative
energy sources like microwave (Shi et al. 2004) and ultrasonic (Sreedhar et al. 2005)
radiations have been used in the presence of CuI salts.
Considering that chiral propargylamines are widely present in many
important bioactive compounds, enantioselective synthesis of propargylamines
throughout this protocol have been recently developed using chiral Cu(I) complexes
(Bisai et al. 2006). However, operating under homogenous media two main
drawbacks must be considered: the difficulty to recover and reuse the catalyst and the
possible absorption of some of the metal catalyst on the final product (fine chemical).
In order to achieve the recyclability of transitionmetal catalysts, gold, silver
and copper salts in ionic liquids, [Bmim]PF6 (Li et al. 2004) as well as heterogeneous
catalysts have been used to obtain propargylamines. Thus, different metal exchanged
hydroxyapatites (metal–HAP) are able to catalyze the condensation of benzaldehyde,
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 24
piperidine and phenylacetylene in acetonitrile under reflux temperature (Choudary et
al. 2004). The results showed that the order of efficiency was Cu–HAP, Cu(OAc)2,
Ru–HAP, Fe–HAP achieving yields of the corresponding propargylamine of 85%,
80%, 60%, and 25% respectively.
A variety of structurally different aldehydes, amines and acetylenes in the
presence of Cu–HAP were converted into the corresponding propargylamines with
55–92% yield. Cu–HAP was reused several times showing consistent activity even
after the fourth cycle.
Silica gel anchored copper chloride has been described by Sreedhar and co-
workers as an efficient catalyst for the synthesis of propargylamines via C–H
activation (Sreedhar et al. 2007). Both aromatic and aliphatic aldehydes and amines
and phenylacetylene have been used to generate a diverse range of acetylenic amines
in good to moderate yields (52–98%) using water as a solvent and without any
organic solvent or co-catalyst. A stable and efficient catalyst for the three component
coupling Mannich reaction of aldehydes, amines and alkynes was prepared by Li et
al. by immobilizing Cu(I) on organic–inorganic hybrid materials (Li et al. 2007).
Thus, a silica-CHDA-CuI catalyst was prepared from benzylchloride
functionalized silica gel which was subsequently reacted with 1, 2-
diaminecyclohexane. This organic–inorganic hybrid material was reacted with
couprous iodide to generate a silica-CHDA-CuI catalyst with 1.6 wt% of Cu.
Reactions performed in the absence of solvent afforded the corresponding
propargylamines in excellent yields (82–96%). No catalyst leaching was observed in
the reaction media, and the catalyst remained active through at least 15 consecutive
runs. Others immobilized metals such as Ag(I) and Au(I) exhibited lower activity
than Cu catalysts while silica supported Pd(II) failed in this reaction.
Recently Wang et al. have reported a novel silica-immobilized N-heterocyclic
carbene metal complex (Si–NHC–CuI) as an efficient and reusable catalyst for the
synthesis of propargylamines (Wang et al. 2008). Different metal-supported zeolites
such as Cu-modified zeolites (H–USY, HY, H–Beta, Mordenite and ZSM-5), have
been successfully used for the synthesis of propargylamines (Patil et al. 2008).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 25
Very recently Namitharan et al. have reported that Ni exchanged Y zeolite
(Ni–Y) exhibits excellent activity for the A3 coupling of cyclohexanecarbaldehyde,
morpholine and phenylacetylene giving the corresponding propargylamine in 97%
yield under solvent free conditions at 80 oC (Namitharan et al. 2010). No leaching of
metal ions provides strong support for the heterogeneous nature of the catalyst.
While homogeneous gold complexes were reasonable active catalysts for the
three component reaction, it has now been shown that gold supported catalysts can
also catalyze the A3 coupling for preparation of propargylamines with excellent
success (Zhang et al. 2008). For instance, Zhang et al. reported the same reaction
using Au nanoparticles supported on nanocrystalline ZrO2 and CeO2 for the Mannich
reaction (Table 1.3).
Table 1.3 MCR of benzaldehyde, piperidine and phenyl acetylene with supported
gold catalyst[a]
Entry Catalyst Gold
conc. (mol %)
% Yield of
Propargylamine TON
1 Au/SiO2 0.013 - -
2 Au/C 0.081 Nd 161
3 Au/TiO2 0.075 Nd 464
4 Au/Fe2O3 0.247 Nd 162
5 Au/ZrO2 0.142 93 668
6 Au/CeO2 0.127 99 788
[a] Reactions were performed with benzaldehyde (1 mmol), piperidine (1.2
mmol) and phenyl acetylene (1.3 mmol) in 1 mL water, 6 h, 100 oC.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 26
Scheme 1.4 Plausible mechanism of gold supported on CeO2 or ZrO2
Table 1.4 A3 coupling of benzaldehyde, piperidine and phenyl acetylene with
reusable catalysts.
Catalyst Reaction conditions Yield (%) References
CuI–(bmim)PF6
(bmim)PF6, 120 oC, 2 h 85 Chem. Commun., 2005, 1315.
Cu-np CH3CN, 100 oC, 6 h 94 Synlett, 2007, 1581
Cu–HAP CH3CN, Reflux, 6 h 85 Tet. Lett., 2004, 45, 7319
Silica gel
CuCl H2O, 100 oC, 10 h 86 Tet. Lett., 2007, 48, 7882.
Si-NHC–Cu rt, 24 h 79 Eur J. Org. Chem, 2008, 2255
Si-CHDA–Cu
80 oC, 12 h 92 Eur. J. Org. Chem, 2008, 2255
USY–Cu 80 oC, 15 h 95 Eur. J. Org. Chem., 2008, 4440
Ag-TPA CH3CN, 80 oC, 6 h 92 Tet. Lett., 2006, 47, 7563
Au–np CH3CN, 80 oC, 5 h 94 Green Chem., 2007, 9, 742
Zn-dust CH3CN, Reflux, 9 h 90 Chem Rev, 2006, 106, 2875
Au/CeO2 H2O, 100 oC, 6 h 99 Angew Chem. Int. Ed. 2008, 47, 4358
LDH–AuCl4 THF, reflux, 5 h 92 Synlett, 2005, 2329
Fe3O4 np THF, 80 oC, 24 h 45 Journal of Catalysis, 2009, 265, 155
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 27
Table 1.4 summarizes the results obtained in the MCR of benzaldehyde, piperidine,
and phenylacetylene using different reusable catalysts.
2) Synthesis of indole derivatives
Functionalized indoles are biologically active compounds (Rivara et al. 2005)
that can be obtained using a variety of approaches (Humphrey et al. 2006). Recently,
following the Mannich approach functionalized indols have been obtained by three
component coupling and cyclization of N-tosyl protected ethynylaniline,
paraformaldehyde and piperidine in the presence of Au/ZrO2 (Zhang et al. 2008)
(Scheme 1.5). It was found that only a fraction of the total gold species i.e. only the
Au(III) are active for this reaction.
Scheme 1.5 Three component coupling and cyclization of an aldehyde, amine, and
N-protected ethynylaniline.
More recently the same authors (Zhang et al. 2009) have prepared metal
organic frameworks (MOF-Si–Au) containing a Au(III) Schiff base complex lining
the pore walls (Table 1.5). This material was obtained by reacting the NH2 groups of
MOF with salicylaldehyde to form the corresponding imine. The final step consists
of reacting a gold precursor (NaAuCl4) with the imine.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 28
Table 1.5 Three component coupling and cyclization of an aldehyde, amine and N-
protected ethynylaniline with gold supported catalysts.
Catalyst R1-CHO R2R3NH Yield (%)
Au/ZrO2
H piperidine 95
Heptyl Piperidine 97
Cyclohexyl piperidine 75
H pyrrolidine 87
H morpholine 70
H diethylamine 90
MOF-Si-Au
H piperidine 90
Heptyl piperidine 95
Cyclohexyl piperidine 80
3) Synthesis of Substituted benzo[b]furans
Benzo[b]furan derivatives are compounds of relevance because of their natural
occurrence associated with their biological properties (Chang et al. 2004).
Recently, following the Mannich protocol, Kabalka et al. have reported the
synthesis of a variety of propargylamines in good yields from different alkynes,
primary or secondary amines and paraformaldehyde using cuprous iodide doped
alumina as the catalyst under microwave irradiation (Kabalka et al. 2006). The
reaction was extended to the synthesis of 2-substituted benzo[b]furan derivatives
when ethynylphenol was condensed with secondary amines (such as piperidine,
morpholine, 1-phenylpiperazine etc.) and paraformaldehyde. In this case the
Mannich adduct resulting from the A3 coupling undergoes a subsequent cyclization
into the benzofuran ring (Scheme 1.6). The reaction is highly efficient and moderated
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 29
to good yields of 2-substituted benzo[b]furans (52–70%) were obtained in a short
reaction time, but high amounts of catalyst were required.
Scheme 1.6 Synthesis of substituted benzo[b]furans through a MC Mannich reaction
followed by cyclization
4) Synthesis of β -aminocarbonyl compounds
The MCR between an aldehyde, amine and ketones using Lewis (Prukala, 2004) or
Brønsted acids (Sahoo et al. 2006) and Lewis bases (Takahashi et al. 2004) as
catalysts produces β-aminocarbonyl compounds (Scheme 1.7). β-Aminocarbonyl
compounds are important building blocks for the synthesis of biologically active
nitrogencontaining compounds such as β-amino alcohols, β-amino acids and β-
lactams and pharmaceuticals (Kleinmann, 1991).
Mechanistically the reaction proceeds typically via imine formation through
the condensation of aldehyde and amine followed by the attack of the enol form of
ketone on imine to afford the desired product.
Scheme 1.7 Synthesis of β-aminocarbonyl compounds
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 30
Recently, the synthesis of β-amino ketones by a three component Mannich reaction
in liquid phase under solvent free and at room temperature, have been carried out
using tungstated zirconia (WOx-ZrO2) (Reddy et al. 2008). WOx from ammonium
metatungstate was incorporated into hydrous zirconia and calcined at 923 K to give a
solid, which exhibits strong acidity. Different aromatic aldehydes, anilines and
cyclohexanone give the corresponding β-amino ketones in good yields (66–90%) as a
mixture of syn and anti-stereoisomers (Scheme 1.8).
Also, the sulfated ceria-zirconia (SO42-/CexZr1-xO2) reported by Reddy et al.
was an efficient catalyst for the synthesis of β-amino ketones via a Mannich reaction
(Reddy et al. 2006). The reaction between benzaldehyde, aniline and cyclohexanone
proceeded smoothly to afford 82% of 2-[1-phenyl-1-N-phenylamino]
methylcyclohexanone, with an anti/syn ratio of 18:82. The catalyst could be recycled
and no appreciable change in activity was observed for 2–3 runs.
Scheme 1.8 Synthesis of β-aminocarbonyl compounds
Recyclable Cu nanoparticles for the one-pot reaction to obtain β-amino
ketones have been proposed by Kidwai and coworkers (Kidwai et al. 2009). The
authors found that Cu-np (particle diameter of about 20 nm), was the most active
catalyst.
5) Synthesis of dihydropyrimidinones
The synthesis of functionalized dihydropyrimidinones (DHPM) represents an
excellent example of the utility of one-pot multiple component condensation
reactions.
Aryl substituted 3,4-dihydropyrimidinones are important heterocyclic
compounds in organic synthesis and medicinal chemistry due to their therapeutic and
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 31
pharmacological properties. The DHPM and their derivatives exhibit a broad
spectrum of biological effects such as antitumor, antiviral, antibacterial and anti-
inflammatory activities and antioxidative properties (Ashok et al. 2007).
The simplest method for synthesising 3,4-dihydropyrimidin-2-(1H)-one was
reported first by Biginelli and involves a three component one-pot cyclocondensation
reaction of an aldehyde, an open chain β-ketoester and urea or thiourea in presence of
acid catalysts such as hydrochloric acid in ethanol at reflux temperature (Kappe,
1993) (Scheme 1.9).
Scheme 1.9 Synthesis of dihydropyrimidinones
Many synthetic methods for preparing DHPM based on the Biginelli reaction
have been reported which include classical conditions and microwave and ultrasound
irradiation in the presence of Brønsted and Lewis acids as catalysts (Lu et al. 2000).
In the last years, replacement of conventional toxic and polluting Brønsted
and Lewis acid catalysts by eco-friendly reusable solid acid heterogeneous catalysts,
has achieved considerable importance in the synthesis of 3,4-dihydropyrimidinones.
Thus, a wide variety of solid acid catalysts including supported Brønsted and Lewis
acids, heteropolyacids, zeolites and metal complexes have been reported in the
literature for performing the Biginelli reaction with variable success.
Table 1.6 summarizes results corresponding to the Biginelli reaction between
benzaldehyde, ethyl acetoacetate and urea to synthesize 5-(ethoxycarbonyl)-6-
methyl-4-phenyl-3,4-dihydropyridin-2(1H)-one over different heterogeneous
catalysts using both conventional heating or microwaves.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 32
Table 1.6 Comparison of different catalyst used in the Biginelli reaction for the
synthesis of 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(H)-one
Catalyst Reaction conditions Yield (%) References
I2–Al2O3 MW, 0.02 h 90 Tet. Lett., 2005, 46,1159
SiO2–NaHSO4 CH3CN, Reflux, 1.5 h 93 J. Mol. Catal.A: Chem., 2004,
221, 137
Alum–SiO2 80 oC, 4 h 92 Appl. Catal., A, 2006, 300, 85
Ferrihydrite in a silica
aerogel EtOH, Reflux, 84 h 65 Tetrahedron, 2003, 59, 1553.
SSA EtOH, Reflux, 6 h 91 Tet. Lett., 2003, 44, 2889
FeCl3–SiMCM MW, 0.08 h 89 Catal. Commun., 2003, 4, 449.
FeCl3–Nanopore Silica MW, 0.025 h 55 J. Ind. Eng. Chem., 2008, 14,
401
Montmorillonite 130 oC, 48 h 82 Tet. Lett., 1999, 40, 3465
ZrO2–pillared clay MW, 0.08 h 92 Catal. Commun., 2006, 7, 571
Nafion CH3CN, Reflux, 3 h 96 J. Mol. Catal. A: Chem.,
2006,247, 99
Amberlyst-15 CH3CN, Reflux, 5.5 h 85 J. Mol. Catal.A: Chem.,
2006,247, 99
Ag3PW12O40 H2O, 80 oC, 4 h 92 Eur. J. Org. Chem., 2004, 552
(PVP)-Cu complex MeOH, Reflux, 24 h 70 Catal. Commun., 2004, 5, 511
Scolecite CH3CN, Reflux, 0.5 h 83 Catal. Lett., 2008, 125, 57
ZrO2/SO42- MW, 0.5 h 98 Lett. Org. Chem., 2006, 3, 484
Heulandite AcOH, 100 oC, 5 h 75 J. Mol. Catal. A Chem, 2005,
236, 216
HY Toluene, Reflux, 12 h 21 Green Chem., 2001, 3, 305
HZSM-5 Toluene, Reflux, 12 h 80 Green Chem., 2001, 3, 305
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 33
Ersorb-4 EtOH, Reflux, 8 h 93 Synth. Comm., 2006, 129
Co(II) phthalocyanine CH3CN, Reflux, 1 h 98 J. Mol. Catal., 2007, 268, 134
TS-1 50 oC, 0.16 h 98 Beilstein JOC, 2009, 5.
HBF4–SiO2 EtOH, rt, 2 h 94 Chin. J. Chem., 2010, 28, 388
6) Synthesis of tetrahydroquinoline derivatives
Tetrahydroquinolines are an important class of natural product and exhibit diverse
biological properties such as antiallergic, antiinflammatory, estrogenic and
psychotropic activity (Yamada et al. 1992; Carling et al. 1993). The classical method
for the synthesis of tetrahydroquinolines involves the aza Diels–Alder reaction
between N-aryl-imines and nucleophilic olefins in the presence of Lewis acids, such
as FeCl3 in Et2O/t-BuOH, BF3.Et2O, AlCl3/Et3N (Loh et al. 1999).
Scheme 1.10 Synthesis of quinolone derivatives through a three component reaction
Sartori et al. have reported the synthesis of cyclopentatetrahydroquinoline
derivatives by one pot three component reactions from aromatic aldehydes, aromatic
amines, and cyclopentadiene in the presence of acid clays as catalysts (Scheme 1.10)
(Sartori et al. 2001). Reactions performed in aqueous or polar solvents at 40 oC
afforded the corresponding cyclopentatetrahydroquinoline derivatives in good yields
(85–98%) and selectivities (97–99%) independently of the electronic effect of
substituents.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 34
Scheme 1.11 MC synthesis of tetrahydroquinoline derivatives
Kobayashi et al. have prepared diverse tetrahydroquinoline derivatives
(Scheme 1.11) (Kobayashi et al. 1996) using a polymer supported scandium
[(polyallyl) scandium trifylamide ditriflate, (PA-Sc-TAD)] as a catalyst. The method
is especially useful for the construction of a quinoline library due to the efficiency
and simplicity of the process.
Scheme 1.12 Synthesis of quinoline derivatives
Quinoline derivatives having a spyrocyclopropyl ring can be synthesised by a
one-pot three component reaction using Montmorillonite KSF clay under mild
reaction conditions (Scheme 1.12) (Shao et al. 1996).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 35
Scheme 1.13 Multicomponent synthesis of pyran- and furandihydroquinolines
Recently, it has been reported that Brønstedand Lewis solid acids such as
antimony chloride doped on hydroxyapatite (SbCl3-HAP) (Mahajan, et al. 2006),
perchloric acid adsorbed on silica gel (HClO4–SiO2) (Kamble, et al. 2010), Fe3+–K10
Montmorillonite clay and HY zeolite (Srinivas, et al. 2004) are highly efficient and
diastereoselective solid acid catalysts for the one-pot synthesis of pyrano and
furoquinolines by coupling the three components, benzaldehydes, anilines and 3,4-
dihydro-2H-pyran or 3,4-dihydro-2H-furan (Scheme 1.13).
7) Synthesis of α-amino nitrile derivatives
α-Amino nitriles are a very useful intermediate compounds for the synthesis of
versatile α-amino acids, various nitrogencontaining heterocyclic compounds
(imidazoles, thiadiazoles etc.) and biologically useful molecules (such as Saframycin
A, a highly potent antitumor drug from Streptomyces lavendulae).
Scheme 1.14 Strecker reaction
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 36
The most important route for the synthesis of α-amino acids via the formation of a-
amino nitriles is the well-known Strecker reaction (1850). The classical Strecker
reaction involves a direct multi-component reaction of an aldehyde or a ketone, an
ammonium salt and alkaline cyanides in aqueous solution to form α-amino nitriles,
which can be subsequently converted to amino acids (Scheme 1.14).
Several modifications of the Strecker reaction have been reported using a
variety of cyanating agents in the presence of solid or supported acids as
heterogeneous catalysts.
Scheme 1.15 Strecker reaction of aldehyde, amine and TMSCN
Yadav and coworkers prepared 2-anilino-2-phenylacetonitrile in 90% yield
by treatment of benzaldehyde, aniline and trimethylsilyl cyanide (TMSCN) in
dichloromethane at room temperature with Montmorillonite KSF clay as the catalyst
(Scheme 1.15) (Yadav et al. 2004). The mechanism of the process involves the
formation of imines or iminium ions and the subsequent nucleophilic attack of the
cyanide ion of TMSCN to provide the final product.
Following the Strecker route, efficient synthesis of a-amino nitriles using
aldehydes, ketones and fluorinated ketones has been achieved with Nafion-H, Nafion
SAC-13 (10-20% Nafion-H polymer on amorphous silica porous nanocomposite)
silica gel and fumed silica (Prakash et al. 2008).
It is interesting to note that when ketones are involved in the reaction the
nature of the solvent plays an important role. Acetonitrile, THF, and toluene are not
suitable for the direct Strecker reaction of ketones, since they are more basic and
interact with the acidic sites, thus reducing the catalytic activity (Kawahara et al.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 37
2005). However, dichloromethane minimizes such interactions enhancing the
catalytic activity.
8) Synthesis of imidazole derivatives
Polysubstituted imidazole derivatives are an important class of compounds which
exhibit a wide spectrum of biological activities as for instance antiinflammatory and
antithrombotic activities. The well-known microtubule stabilizing agents such as
Eleutherobin and Sarcodictyn, among other marine and plant derived products
contain imidazole (Lindel et al. 1997). In addition 2,4,5-triarylimidazole have
received great attention for the development of fluorescence labelling agents for
biological imaging applications (Sun et al. 2009) or chromophores for non-linear
optics systems (Stahelin et al. 1992).
Numerous classical methods for the synthesis of polysubstituted imidazoles
have been developed. Among these methods a typical procedure is the
multicomponent reaction approach involving the cyclocondensation of a 1,2-diketone
(or α-hydroxy ketones), an aldehyde and ammonia or ammonium acetate (scheme
1.16) in the presence of a homogeneous strong protic acid catalysts (such as
phosphoric acid, sulphuric acid, acetic acid), (Liu et al. 2003), Lewis acids (Heravi et
al. 2007) or oxidant agents such as ceric ammonium nitrate.
Scheme 1.16 Synthesis of 2,4,5-trisubtituted and 1,2,4,5- tetra substituted imidazole
derivatives.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 38
Xu et al. have reported the condensation of a-hydroxy ketone (benzoin)
(instead of benzyl) with an aldehyde over silica gel or alumina impregnated with
ammonium acetate (Xu et al. 2004). Reactions performed under solvent free
conditions and microwave irradiation gave the corresponding trisubstituted
imidazoles in good yields.
Scheme 1.17 Synthesis of 2,4,5-triarylimidazoles
HY zeolite and silica gel (Balalaie et al. 2000) have also been used as
heterogeneous acid catalysts for the synthesis of triarylimidazoles by condensation of
benzyl, benzaldehyde derivatives and ammonium acetate under solvent free
conditions and microwave irradiation (Scheme 1.17).
Scheme 1.18 Synthesis of 2,4,5-triarylimidazol from benzil or benzoin or
benzylmonoxime, aldehyde and ammonium acetate in the presence of silica sulphuric
acid (SSA) catalyst.
Shaabani et al. have reported that silica supported sulphuric acid (SSA) is an
excellent and recyclable catalyst for the synthesis of trisubstituted imidazoles under
reflux of water or solvent free conditions (scheme 1.18) (Shaabani et al. 2000).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 39
Shelke et al. have been prepared cellulose sulphuric acid (CSA) as a bio-
supported and recyclable solid acid catalyst for the one-pot synthesis of 2,4,5-
triarylimidazoles (Shelke et al. 2010).
9) Synthesis of quinazolin-4-(3H)-one derivatives
Quinazolinone derivatives were reported to possess analgesical, antibacterial,
antifungical, antihelmentics, antiparkinson, anticancer, anti-HIV, MAO inhibitory,
central nervous system and antiaggregating activity.
Scheme 1.19 Some biological active quinazolinones
Recently, it has been reported that silica gel-supported ferric chloride
catalyzes efficiently the three component reaction of anthralinic acid, orthoesters and
amines to afford 4-(3H)-quinazolinones in one-pot reaction (Scheme 1.20) (Chari et
al. 2006).
Nafion has also been used as an efficient catalyst in this multicomponent
reaction to obtain 2,3-disubstituted 4-(3H)-quinazolinones under solvent free
microwave irradiation (Lingaiah et al. 2006).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 40
Scheme 1.20 Synthesis of 2,3-disusbtituted-4-(3H)-quinazolinones from anthranilic
acid or isatoic anhydride, orthoesters and amines.
A new multi-component synthesis of 4-arylaminoquinazolines has been
reported by Heravi and co-workers (Heravi et al. 2009). The protocol involves the
reaction of 2-aminobenzamide, orthoesters, and substituted anilines in the presence
of acid catalysts such as different Keggin-type heteropolyacids (Scheme 1.21).
Various anilines and orthoesters were reacted with 2-aminobenzamide in the
presence of different heteropolyacids H6[PMo9V3O40], H5[PMo10V2O40],
H4[PMo11VO40], H3[PMo12O40]) in acetonitrile under refluxing conditions.
Scheme 1.21 Multicomponent synthesis of 4-arylaminoquinazolines from reaction of
2-aminobenzamide, aniline derivative and orthoesters
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 41
10) Synthesis amidoalkyl naphthol derivatives
Generally, 1-amidoalkyl-2-naphthol derivatives can be prepared through MCR (via a
Ritter type reaction) of aryl aldehydes, 2-naphthol and acetonitrile or amides in the
presence of Lewis or Brønsted acid catalysts (Scheme 1.22).
Scheme 1.22 Multicomponent synthesis of 1-amidomethyl-2-naphthol derivatives
A variety of heterogeneous catalysts such as Montmorillonite K-10 clay,
Amberlyst-15, K5CoW12O40.3H2O, H3PW12O40, FeCl3–SiO2, Al2O3–SO3H, HClO4–
SiO2 and Al2O3–HClO4 have been reported in the literature to perform this MCR.
Recently Shaterian et al. have introduced the synthesis of 1-carbamate-alkyl-
2-naphthol in the presence of silica-supported sodium hydrogen sulphate (SiO2–
NaHSO4) as a catalyst (scheme 1.23) (Shaterian et al. 2008).
Scheme 1.23 Synthesis of 1-carbamato-alkyl-2-naphthol derivatives
Das et al. have found that perchloric acid supported on silica (HClO4–SiO2) is
an efficient catalyst for the synthesis of N- [(2-hydroxynaphthalen-1-yl)methyl]
amides through the condensation of 2-naphthol, aromatic aldehydes and urea (or an
amide) (Scheme 1.24) (Das et al. 2007).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 42
Scheme 1.24 Synthesis of N-[(2-hydroxynaphthalen-1- yl)methyl]amides
derivatives.
11) Synthesis of dihydropyridine derivatives
Dihydropyridines (DHPs) are an important class of compounds which cover a variety
of pharmaceutical and agrochemical activities such as insecticidal, herbicidal and
acaricidal (Kawase et al. 2002).
Scheme 1.25 1,4-Dihydropyridines of pharmaceutical interest
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 43
The classical method to obtain DHPs is the MC Hantzsch reaction involving the
condensation of and aldehyde, a β-ketoester and ammonia either in acetic acid or by
refluxing in alcohol for long reaction times (Scheme 1.26).
Scheme 1.26 Synthesis of DHPs through the Hantzsch reaction
Recently, heterogeneous acid–base catalysts have been used for the
preparation of DHPs. Gupta et al. have reported that sulfonic acid covalently
anchored onto the surface of silica gel (SiO2–SO3H) is an efficient and recyclable
catalyst to synthesize 1,4-dihydropyridines (1,4-DHPs) (Gupta et al. 2007). Various
aldehydes (aromatic, heterocyclic and unsaturated) and β-keto esters (ethyl and
methyl acetoacetate) in the presence of ammonium acetate at 60 oC under solvent
free conditions afforded the corresponding 1,4-DHPs in good yield (83–90%).
Scheme 1.27 Plausible mechanism for the synthesis of 1,4-DHP
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 44
Nikpassan et al. have developed the synthesis of fused 1,4-DHPs starting
from dimedone (5,5-dimethyl-1, 3-cyclohexadienone), different aldehydes and
ammonium acetate in the presence of HY zeolite (Nikpassan et al. 2009). The
reactions were carried out at reflux temperature of ethanol giving the corresponding
1,4-DHPs in good yields (70–90%) and in short reaction times (2.5–3.5 h) (Scheme
1.28). The catalyst was recovered and its activity was maintained after three
consecutive runs.
Scheme 1.28 Synthesis of fused 1,4-DHP
Various heterogeneous acid catalysts such as silica supported perchloric acid
(HClO4–SiO2) (Maheswara et al. 2006), Montmorillonite K10 (Song et al. 2005),
heteropolyacid (K7[PW11CoO40]) (Heravi et al. 2007), HY zeolite (Das et al. 2006)
and nickel nanoparticles (Sapkal et al. 2009) have been reported for the synthesis of
DHP.
Besides heterogeneous acid catalysts, solid base catalysts have also been
used to perform the MC synthesis of 1,4-DHP. Antonyraj et al. have reported the
coupling of benzaldehyde, ethyl acetoacetate and ammonium acetate using
hydrotalcites (HT) and hydrotalcite-like materials as solid base catalysts (Antonyraj
et al. 2008).
12) Synthesis of pyridine derivatives
Pyridines are interesting compounds because their saturated and partially saturated
derivatives are present in many biologically active and natural products such as for
instance pyridoxol (vitamin B6), NAD nucleotide (nicotin adenosin) and pyridine
alkaloids (Scheme 1.29).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 45
Scheme 1.29 Some examples of pyridine derivatives with pharmacological interest
As an alternative strategy to the homogeneous acid catalyzed Hantzsch reaction-
oxidation, De Paolis et al. developed a heterogeneous bifunctional noble metal–solid
acid catalyst system (Pd/C/K10 Montmorillonite) for the one-pot three component
reaction to obtain pyridines under microwave irradiation (Scheme 1.30) (Paolis et al.
2008).
Scheme 1.30 Synthesis of pyridine derivatives
Recently the synthesis of 2,4,6-triarylpyridines through one-pot condensation
of aldehydes, ketones and ammonium acetate have been carried out in the presence
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 46
of perchloric acid supported on silica gel (HClO4–SiO2) as heterogeneous catalyst
(Scheme 1.31) (Nagarapu et al. 2007).
Scheme 1.31 Synthesis of 2,4,6-trialkylpyridine derivatives
Heravi et al. have prepared a series of 3-cyanopyridine derivatives through
the MCR involving aldehydes, 3,4-dimethoxyacetophenone, malononitrile and
ammonium acetate using different heteropolyacids as heterogeneous and recyclable
acid catalysts (Scheme 1.32) (Heravi et al. 2009). The screening of different
heteropolyacids (H14[NaP5W30O110], H6[P2W18O62], H4[PMo11VO40], H3[PMo12O40]),
showed that the highest activity was achieved with H14[NaP5W30O110].
Scheme 1.32 Synthesis 3-cyanopyridine derivatives
13) Synthesis of 3-cyano-6-hydroxy-2(1H)-pyridinone
Balalaie et al. have performed the three component condensation of
alkylacetoacetates, primary amines and alkyl cyanoacetates catalyzed by solid acids
such as silica gel, Montmorillonite K-10, HY zeolite and acidic alumina under
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 47
microwave irradiation obtaining the corresponding 3-cyano-6-hydroxy-2(1H)-
pyridinones in good yields (Scheme 1.33). Using silica gel excellent yields of
different 3-cyano-6-hydroxy-2(1H)-pyridinones (87–94%) were obtained after two
minutes (Balalaie et al. 2003).
Scheme 1.33 One-pot three component synthesis of 3-cyano-6-hydroxy-2(1H)-
pyridinone derivatives
14) Synthesis β-acetamido ketone derivatives
The main route for the synthesis of these compounds is the Dakin–West reaction
which involves the condensation of α-aminoacid with acetic anhydride in the
presence of a base via an intermediate azalactone.
Recently Bathia et al. have proposed another general route for the synthesis
of β-acetamido ketones that involves the condensation of an aryl aldehyde, an
enolizable ketone or ketoester, acetyl chloride and acetonitrile in the presence of
Lewis acid catalysts such as CoCl2 (Scheme 1.34) (Bathia et al. 1994). The same
author performed this MCR using Montmorillonite K10 as the acid catalyst
(Bahulayan et al. 2003; Rao et al. 2003).
Scheme 1.34 One-pot synthesis of β-acetamido Ketones derivatives
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 48
Besides Montmorillonite K10, a variety of solid acid catalysts promoting this
MCR have been reported. HBeta zeolite has been used as an active and reusable
catalyst to perform this reaction at room temperature (Bhat et al. 2005). Also
heteropolyacids (Rafiee et al. 2006; Heravi et al. 2007; Nagarapu et al. 2007), acid
resins (Yakaiah et al. 2007; Das et al. 2006), sulfated zirconia (Krishnaiah et al.
2007), sulfuric acid supported on silica (Khodaei et al. 2005) or phosphomolybdic
acid supported on silica (PMA/SiO2) (Das et al. 2009) have been used to perform this
MCR using a wide variety of aromatic aldehydes and ketones or ketoesters.
14) Synthesis imidazo[1,2-a]pyridine derivatives
A variety of imidazo[1,2-a]pyridines were prepared starting from 2-
aminopyridine, aldehydes and isocyanides using Montmorillonite K10 clay as the
catalyst in a microwave reactor (scheme 1.35) (Rousseau et al. 2007).
Scheme 1.35 MC synthesis of imidazo-pyridine, -pyrazine and –pyrimidine using
Montmorillonite K10 as the catalyst
Sulfuric acid supported on silica has also been used recently as a reusable
acid catalyst to perform the synthesis of 3-aminoimidazo [1,2-a]pyridines and -
pyrazines by condensation of an aldehyde, 2-amino-5-substitutedpyridines or 2-
aminopyrazine and alkyl or aryl isocyanides (Shaabani et al. 2007).
14) 1,2,4,5-tetrazinan-3-one derivatives
The formation of N–N bonds is not easy and 1,2,4,5-tetrazines have generally
been prepared from hydrazine derivatives or from nitrilimines (Lamon et al. 1969).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 49
Recently Gopalakrishnan and co-workers have reported the synthesis of 6-aryl-
1,2,4,5-tetrazin-3-ones or thiones through a MC reaction involving urea, various
substituted benzaldehydes and ammonium acetate in the presence of NaHSO4
supported on silica gel (NaHSO4–SiO2) as an acid catalyst (Scheme 1.36)
(Kanagarajan at al. 2009). Reactions performed under microwave irradiation
afforded 6-aryl-1,2,4,5-tetrazin-3-ones in 68–75% yield within 2 or 3 min, while
under thermal conditions (heating at 75 oC) lower yield was achieved (30–38%) in
35–43 min.
Scheme 1.36 MC synthesis tetrazine derivatives
15) Synthesis of Tetrahydroisoquinolonic acid derivatives
Azizian et al. have reported the synthesis of cis-isoquinolonic acid derivatives
by coupling homophthalic anhydride, aldehydes and amines in the presence of
KAl(SO4)2.12H2O (Alum) and silica sulphuric acid as heterogeneous catalysts
(Scheme 1.37) (Azizian et al. 2006). When a mixture of equimolar amounts of
homophthalic anhydride, benzaldehyde and aniline in acetonitrile is allowed to react
in the presence of Alum catalyst at room temperature, 1-oxo-2,3-diphenyl-1,2,3,4-
tetrahydro-isoquinoline-4-carboxylic acid was obtained with yield of 88% after 7 h.
The reaction was extended to a range of different aldehydes and amines giving the
corresponding cis-isoquinolonic acid in good yields (81–91%).
Scheme 1.37 Synthesis of tetrahydroisoquinolonic acid derivatives
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 50
Karimi et al. have reported the use of sulfonic acid functionalized silica
(SAFS) as a recyclable heterogeneous catalyst for the synthesis of isoquinolonic
acids by a three component condensation of homophthalic anhydride, aldehydes and
amines (Karimi et al. 2010). The reaction was highly stereoselective and only the cis
isomer was obtained in all cases.
15) Synthesis of 4-amidotetrahydropyran derivatives
The most general method to obtain tetrahydropyran derivatives is via Prins
cyclization reaction using acid catalysts (Miranda et al. 2005). Recently 4-
amidotetrahydropyrans have been prepared by a three component coupling of
carbonyl compounds, homoallylic alcohols and nitriles using phosphomolybdic acid
(H3PMo12O40, PMA) as catalyst via Prins–Ritter reaction (Scheme 1.38) (Yadav et
al. 2008).
Scheme 1.38 Synthesis N-(2-cyclohexyltetrahydro-2H-4-pyranyl)-acetamide
For comparison purposes other solid acid catalysts such as Montmorillonite
KSF and Amberlyst-15 were tested, however the PMA catalyst was more efficient in
terms of conversion. Spirocyclic-4-amidotetrahydropyrans were also obtained in
good yields (84–88%) from cycloketones, homoallylic alcohols and nitriles (Scheme
1.39).
Scheme 1.39 Synthesis of pirocyclic-4-amidotetrahydropyrans
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 51
15) Synthesis of DL-5-(4-hydroxyphenyl) hydantoin
DL-5-(4-Hydroxyphenyl) hydantoin is an important intermediate for the enzymatic
production of (R)-2-(4-hydroxyphenyl)glycine, a compound widely used in the
preparation of semi-synthetic penicillins and cephalosporines (Long et al. 1971).
Scheme 1.40 Synthesis of DL-5-(4-Hydroxyphenyl)hydantoin
Cativiela et al. have reported the synthesis of DL-5-(4- hydroxyphenyl)
hydantoin following this approach using solid acids catalysts such as clays (KSF and
K10 Montmorillonite), beta zeolite, and sulfonic organic polymers (scheme 1.40).
The condensation reaction of phenol, urea and glyoxylic acid performed in water at
70 oC in the presence of clay or beta zeolite afforded the target product (Cativiela et
al. 2002).
16) Synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives
Among the large variety of nitrogen-containing heterocyclic compounds,
heterocycles containing the phthalazine moiety are of interest because they show
important pharmaceutical and biological activities (Jain et al. 2004).
Shaterian et al. have reported the use of silica supported sulfuric acid as an
efficient heterogeneous catalyst for the preparation of 2H-indazolo[2,1-b]
phthalazine-1,6,11(13H)-trione derivatives (Scheme 1.41). The catalyst could be
successfully recovered and recycled at least for five runs without significant loss in
activity (Shaterian et al. 2008).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 52
Scheme 1.41 Synthesis of 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo- [2,1-
b]phthalazine-1,6,11(13H)-trione
17) Synthesis of polyfunctionalized pyran, pyranodipirimidine and chromene
derivatives
4H-Pyrans rings can be also obtained through a A3 coupling reaction of an aldehyde,
malononitrile and an active methylenic diketo compound.
Recently, Babu et al. have synthesized this type of compound using a Mg/La
mixed oxide as the heterogeneous basic catalysts (Scheme 1.42) (Babu et al. 2008).
Compared to other solid basic catalysts such as MgO, KF/Alumina, Mg/Al
hydrotalcite, and Mg-Al-CO3, the Mg/La mixed oxide catalyst was the most active
promoting the coupling of benzaldehyde, ethyl acetoacetate and malononitrile in high
yield (92%).
Scheme 1.42 A3 coupling process for the synthesis of 4H-pyran derivatives
18) Synthesis of dihydropyran [3,2-c]chromene derivatives
Dihydropyran[3,2-c]chromene derivatives are important heterocyclic compounds
used in the treatment of neurodegenerative diseases including Alzheimer’s disease,
AIDS associated dementia, for the treatment of schizophrenia, Down’s syndrome and
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 53
Huntington’s disease. In addition, 2-amino-chromene derivatives exhibit
antihypertensive and antischemia activity.
Recently Heravi et al. have reported this 3CR using heterogeneous acid
catalysts such as H6P2W18O62.18H2O as a Wells–Dawson type heteropolyacid
catalyst (scheme 1.43) (Heravi et al 2008).
Scheme 1.43 MCR of 4-hydroxycoumarin, aldehydes and alkylnitriles
Seifi et al. presented a highly efficient method for the synthesis of a pyrano
annulated heterocyclic system via a three component reaction of an aldehyde,
malononitrile and a ahydroxy or an α-amino activated C–H acid in the presence of
MgO as the catalyst (scheme 1.44) (Seifi et al. 2008).
A variety of tetrahydrobenzo[b]pyran-, [2,3-d]pyrano- and pyrido[2,3-
d]pyrimidine derivatives were synthesized with this protocol in excellent yields in
the presence of MgO catalyst from aryl aldehyde, malononitrile and cyclic β-
diketones (A: 1,3-cyclohexanedione or dimedone, B: 4-hydroxy-6-methylpyrone, 4-
hydroxycoumarin,C: 1,3-dimethylbarbituric acid and D: 1,3-dimethyl-6-amino
uracil).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 54
Scheme 1.44 Synthesis of pyran annulated heterocyclic systems via three component
reaction
19) Synthesis of pyranodipyrimidine derivatives
The MCR involving benzaldehyde, malononitrile and barbituric acid or its thio
analogue was performed using neutral alumina as the catalyst under microwave
irradiation, and yields 7-amino-6-cyano-5-aryl-5H-pyrano[2,3-d]pyrimidine-2,
4(1H,3H)-diones, an intermediate in the synthesis of pyranodipyrimidines (Scheme
1.45) (Kidwai et al. 2007). This intermediate compound was allowed to react with
different aromatic carboxylic acids adsorbed on Montmorillonite under microwave
irradiation to give the desired product.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 55
Scheme 1.45 One-pot synthesis of pyranodipyrimidine derivatives
19) Synthesis of 2-amino-4H-benzo[h]chromene derivatives
The most straightforward synthesis for 2-aminobenzochromene derivatives involves
a three-component coupling of aromatic aldehyde, malononitrile and an activated
phenol in the presence of organic bases (such as piperidine), which is frequently used
in stoichiometric amounts using ethanol or acetonitrile as solvents (Scheme 1.46) )
(Bloxham et al. 1994).
Scheme 1.46 Synthesis of 2-aminochromene derivatives
Nevertheless, diverse heterogeneous catalysts have been employed for this
multicomponent reaction. Wang et al. synthesized a series of 2-aminochromene
derivatives from aryl aldehydes, malononitrile or ethyl cyanoacetate with 1-naphtol
or 1,5-naphthalenediol, in the presence of alumina coated with potassium fluoride
(KF-Alumina) (Wang et al. 2004).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 56
When aryl aldehydes, malononitrile or ethyl cyanoacetate and 1-naphthol
react in the presence of KF-Alumina in refluxing ethanol for 5–6 h, the 2-amino-4-
aryl-4H-benzo[h]chromene derivatives were obtained in slightly high yields (72–
90%). When 1,5-naphthalenediol was used instead of 1-naphthol, naphthol[1,2-b;6,5-
b’]dipyrans derivatives were isolated in good yields (83–94%) (Scheme 1.47).
Scheme 1.47 Synthesis of the naphthol[1,2-b;6,5-b’]dipyrans derivatives from aryl
aldehydes, malononitrile or ethyl cyanoacetate and 1, 5- naphthalenediol
Basic alumina was proposed by Maggi et al. as a catalyst in the synthesis of
substituted 2-amino-2-chromenes by coupling benzaldehyde, malononitrile and a-
naphthol using water as a solvent (Maggi et al.2004).
Nanosized magnesium oxide has been reported as an efficient catalyst for the
three component condensation of aldehyde, malononitrile and a-naphthol in
methanol, water or PEG-water as the reaction medium (Kumar et al. 2007).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 57
1.3 Hydrotalcites as green heterogeneous catalysts
1.3.1 Introduction
Hydrotalcite-like layered double hydroxides (LDHs), also known as anionic clays,
are natural or synthetic materials consisting of positively charged brucite-like sheets.
The structure of hydrotalcite can be visualized as the structure of brucite, Mg(OH)2,
in which some of the Mg2+ cations, coordinated octahedrally by hydroxyl groups, are
substituted by trivalent ions such as Al3+ (Fig. 1.7).
Fig 1.7 Structure of double layered hydrotalcites intercalated with CO32- anions.
The excess of positive charge in the LDHs’ layers is compensated by anions
located together with water in the interlayer space. The general formula of
hydrotalcite is:
[M1-x 2+Mx
3+(OH)2][An-]x/n · yH2O
where M2+ and M3+ represent divalent and trivalent cations in the octahedral sites
within the hydroxyl layers, x is equal to the ratio M3+/(M2+ + M3+) with a value
varying in the range of 0.17-0.50, and A is an exchangeable interlayer anion. It is
very important that M2+ and M3+ cations should have ionic radii not too different
from 0.65 Å (characteristic of Mg2+) to form a stable structure of hydrotalcite
(Yashima et al., 1972; Taylor et al., 1969).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 58
In naturally occurring hydrotalcite, carbonate is the interlayer anion.
However, the number of counterbalancing ions is essentially unlimited, and LDHs
intercalated by various simple inorganic (Cavani et al., 1991; Miyata, 1975),
polyoxometalate (Constantino et al., 1995; Narita et al., 1993; Evens, 1996), complex
(Dziembaj et al., 2002; Perez et al., 1991; Boclair, 2001) as well as organic anions
(Rives et al., 1999; Miyata et al., 1973; Meyn et al., 1990) have been synthesized.
Therefore, it seems to be possible to prepare tailor-made materials for
specific applications by changing the cationic and anionic compositions of
hydrotalcite. Unique basic properties of LDHs, which behave as solid bases, make
these materials very useful for catalytic purposes. The replacement of homogeneous
basic catalysts by solid bases would make separation and recovery of catalysts easier
and allow to avoid corrosion and environmental problems. Thus, LDHs as well as
mixed metal oxides formed by calcination of hydrotalcites have been studied as basic
catalysts in many chemical processes.
1.3.2 Catalytic applications of Hydrotalcites
In a time of growing need for green catalysts, hydrotalcites have been rediscovered
as a family of catalysts of great diversity and versatility for liquid phase organic
reactions. Recently hydrotalcites have been used as efficient catalysts for a liquid
phase organic reactions.
1.3.2.1 C-C and C-N bond formation reactions
Choudary, et al. have reported that the highly polarised basic fluoride ions in
developed LDHs, shown unprecedented catalytic activity both in Knoevenagel and
Michael reactions among the family of solid bases, in general, and known fluoride
catalysts, in particular, under very mild liquid phase conditions (Choudary et al.,
2001) (Scheme 1.48-1.49).
The other advantages of LDH-F include easy separation of the catalyst by
simple filtration, high atom economy to enable waste minimization, reduced
corrosion and reusability thus making the catalyst an attractive and potential
candidate for commercial realization in C–C coupling reactions.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 59
Ar-CHO
CN
CN
OH
140 0
CO NH2
CN
Ar
HT/MW
R1
O
H2CX
YR2
R1 CN
Y
LDH-F
MeCN, RT
R2
R1
LDH-FO H2C
CN
YR
2
R1 CN
Y
H2O
Scheme 1.48 Knoevenagel reaction on hydrotalcite
Scheme 1.49 Michael reaction over hydrotalcite
Surpur et al. have developed highly efficient methodology for the synthesis of
heterocyclic compounds via the multicomponent condensation of aromatic aldehyde,
malononitrile and 1-naphthol under microwave in the presence of Mg/Al hydrotalcite
(Surpur et al., 2009) (Scheme 1.50).
Scheme 1.50 Multicomponent reaction over Mg/Al hydrotalcite
Kantam et al. have developed a simple and efficient method for the preparation of 5-
substituted 1H-tetrazoles via (2 + 3) cycloaddition using Zn/Al hydrotalcite as a
heterogeneous catalyst (Kantam et al., 2006) (Scheme 1.51).
Scheme 1.51 Cycloaddition reaction of nitrile and azide over Zn-Al hydrotalcite
CN DMF, 120-130
0C
Zn/Al hydrotalcite
R
NaN3
RN
N
N
HN
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 60
Kantam et al. have described a simple and effective protocol for the 1,4-conjugate
addition of amines to α-β--unsaturated compounds using Cu-Al hydrotalcite catalyst
at room temperature in very good yields (Kantam et al., 2005) (Scheme 1.52).
Scheme 1.52 Coupling of alkyne compounds on Cu-Al hydrotalcite
1.3.2.1 Coupling reactions
Bing et al. have demonstrated a novel and efficient protocol for the synthesis
of conjugated diynes through oxidative dimerization of terminal alkynes that is
catalytic in CuAl–LDH at room temperature (Bing et al., 2007) (Scheme 1.53).
Scheme 1.53 Coupling of alkyne compounds on Cu-Al hydrotalcite
Namitharan et al. have reported for the first time, CuII as an active species in
the Huisgen [3+2] cycloaddition of azides with terminal alkynes in a nonaqueous
medium (Namitharan et al., 2009). Furthermore, CuII–HT serves as a novel
environmentally benign, highly reactive, recyclable and efficient heterogeneous
catalyst without any additives under aerobic conditions (Scheme 1.54).
Scheme 1.54 Cycloaddition reaction of alkyne and azide on Cu-Al hydrotalcite
ACN, RTR N
NN
CuII hydrotalciteN N N
R
R1 R1
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 61
HT/DMSOX
R
CHO
R
1.3.2.1 Transesterfication reactions
Choudary et al. have reported that β-ketoesters can be successfully transesterify with
primary, secondary, unsaturated, allylic, cyclic, hindered alcohols and amines by
Mg–Al–O–t-Bu hydrotalcite catalyst (Choudary et al., 2000) (Scheme 1.55).
Scheme 1.55 Transesterification reaction catalyzed be Mg/Al-tBuO hydrotalcite
1.3.2.1 Oxidation reactions
Kshirsagar et al. have reported Mg–Al hydrotalcites as the first heterogeneous basic
catalysts for the Kornblum oxidation of benzyl halides to benzaldehydes using
DMSO (Kshirsagar et al. 2008) (Scheme 1.56).
Scheme 1.56 Oxidation of benzyl halide on Mg-Al hydrotalcite
1.3.2.1 Reduction reactions
Qixun et al. have developed an exceedingly efficient and highly chemoselective
approach to prepare aromatic amines from the corresponding aromatic nitro
compounds using hydrazine hydrate over nickel-iron mixed oxide obtained by
calcinations of nickel-iron hydrotalcite-like precursor (Qixun et al., 2007) (Scheme
1.57).
The catalytic system described by Qixun et al. may be a promising alternative
to the sulphide reduction and Fe/HCl reduction which are widely used for preparing
sulphur-containing aromatic amines at present in industry.
Toluene, 90-100 0C
HT catalyst
R
O O
OR1R2- OH
R
O O
OR2
R1- OH
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 62
NO2
R
hydrazine hydrate, propan-2-ol
NH2
R
nickel-iron mixed oxide, reflux
Scheme 1.57 Reduction of aromatic nitro compounds on Ni-Fe hydrotalcite
Thus, in the present era of catalysis, looking at the growing interest in the
development of new and sustainable catalysts, hydrotalcites have immense scope as
robust heterogeneous catalysts for a wide variety of liquid phase organic reactions.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 63
1.4 Hydroxyapatites as heterogeneous catalysts
1.4.1 Introduction
Apatites have the general formula, Ca10(PO4)6X2 where X is typically F
(fluoroapatite, FAP), OH (hydroxyapatite, HAP), or Cl (chloroapatite, CAP). The
apatite lattice is very tolerant of substitutions, vacancies and solid solutions, for
example, X can be replaced by CO3, Ca by Sr, Cu, Ba, Pd and PO4 by HPO4, AsO4,
VO4, SiO4 or CO3 [Elliott, 1994].
Apatites are widely distributed as accessory minerals in igneous rocks and in
small quantities in most metamorphic rocks. This wide-spread occurrence is an
important factor in their extensive use in fission-track chronothermometry for the
study of geological thermal history. Rock phosphates (microcrystalline apatites),
mostly of biological origin, are the starting material for phosphate fertilizer
manufacture and a source of phosphorus for the chemical industry. The mineral of
bones and teeth is an impure form of HAP, the major departures in composition
being a variable Ca/P mol ratio (1.6 to 1.7, HAP is 1.66), and a few percent CO3 and
water. The mineral is microcrystalline. HAP is also used as a biomaterial, for
example, for bone replacement and augmentation, and for coating metal prostheses to
improve their biocompatibility.
The basic apatite structure was published nearly simultaneously by Elliott et
al. [Elliott et al. 1994]. The structure is hexagonal with space group P63/m and
approximate lattice parameters a = 9.37Å and c = 6.88Å. There are two
crystallographically different Ca atoms, and three O atoms [Elliott et al. 2002]. The
unit cell comprises Ca(1)4 Ca(2)6 (PO4)6 (OH)2.
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 64
Fig. 1.8 (a) Oxygen coordination of columnar Ca(1) ions in apatite, (b) linking of
columns via PO4 tetrahedra, (c) Arrangement of ions around the c-axis in
hydroxyapatite, the F--- ion is at the centre of the Ca(2) triangle.
C
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 65
1.4.2 Catalytic applications of Hydroxyapatites
1.4.2.1 Fixation of Carbon dioxide with epoxide
Mori et al. have developed ZnHAP as an extremely active and versatile catalyst
system for the coupling of epoxides and CO2 (Mori et al., 2005) (Scheme 1.58). The
present protocol can be considered as environmentally-benign due to the following
attractive features: (i) high activity and selectivity under mild reaction conditions, (ii)
additional organic solvents are unnecessary, and (iii) the simple work-up procedure
and ability to recycle the solid catalyst.
Scheme 1.58 Coupling of epoxides and CO2 catalyzed by the ZnHAP
1.4.2.2 C-C and C-N bond formation reaction
Kantam et al. have developed a simple and efficient method for N-arylation of
heterocycles using CuFAP as a heterogeneous catalyst (Kantam et al. 2006,
Subrahmanyam et al., 2010) (Scheme 1.59). Various bromo- and iodoarenes were
coupled with N-heterocyclic to yield the corresponding N-arylated products with
good to excellent yields (85–98%). The catalyst can be readily recovered and reused.
This methodology may find widespread use for the preparation of N-arylated
products.
Scheme 1.59 N-Arylation of N-heterocycles with bromo- or iodoarenes
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 66
Solhy et al. have demonstrated the use of hydroxyapatite–water system as an
efficient and clean catalyst for the preparation of chalcone derivatives via Claisen–
Schmidt condensation under microwave irradiation (Solhy et al., 2010) (Scheme
1.60). The high reactivity of HAP–water coupled with its ease of use and reduced
environmental problems makes it attractive as an alternative to homogeneous
reagents.
H2O, MW (700 watt)
HAP
O
O
R2
R1R1
O
R2
Scheme 1.60 Synthesis of chalcone using HAP
Sebti et al. have reported fluroapatite as a new solid catalyst of the
Knoevenagel reaction in heterogeneous media without solvent for the first time
(Sebti et al., 2000) (Scheme 1.61).
Scheme 1.61 Knoevenagel reaction catalyzed by FAP
1.4.2.3 Hydroxylation of phenol
The chlorobenzene hydrolysis to phenol over Cu-promoted hydroxyapatites at
different operational conditions was reported by Figoli et al. in flow equipment under
atmospheric pressure (Figoli et al., 1982) (Scheme 1.62).
Cl OH
H2O HCl K = 9.50 x 10-1
Scheme 1.62 Hydroxylation of chlorobenzene catalyzed by CAP
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 67
1.4.2.4 Coupling reactions
The coupling of three-components, namely an aldehyde, an alkyne and an amine to
prepare propargylamines was reported by Choudary et al. using copper exchanged
hydroxyapatite (Cu-HAP) as the catalyst under mild reaction conditions and in the
absence of any co-catalyst (Choudary et al., 2004) (Scheme 1.63).
A variety of aldehydes and amines were converted to the corresponding
propargylamines, demonstrating the versatility of the reaction.
Scheme 1.63 Three-component coupling reaction catalyzed by Cu-HAP
Ranu et al. reported a simple procedure for the synthesis of substituted (E)-2-
alkene-4-ynecarboxylic esters using hydroxyapatite-supported palladium as efficient
catalyst surface (Ranu et al., 2008) (Scheme 1.64).
.
Scheme 1.64 Coupling of diiodoalkenes and alkenes catalyzed by Pd-HAP
1.4.2.5 Allylation of Aldehyde
Sreedhar et al. reported a facile synthesis of homoallylic alcohols by the allylation of
aldehydes with allylic metal reagents or allyl halides using copper fluoroapatite
(CuFAP) as catalyst under mild reaction conditions (Sreedhar et al., 2008) (Scheme
1.65).
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 68
A variety of aldehydes were converted to the corresponding homoallylic
alchohols, demonstrating the versatility of the reaction.
Scheme 1.65 Allylation of aldehydes with allyltributylstannane and
allytrimethylsilane catalyzed by CuFAP
1.4.2.6 Oxidation of alcohol
Mori et al have demonstrated a novel approach to catalyst design using
hydroxyapatites and tested its catalytic performances for the oxidation of alcohols to
aldehydes or ketones (Scheme 1.66).
OH
CO H2OPd/HAP
1/2 O2
Scheme 1.66 Oxidation of alcohol to aldehydes catalyzed by PdHAP
Chapter 1
Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 69
1.5 Objectives of the research work
In the present era, the main objective in the field of catalysis is on placing
precincts to the use of conventional, corrosive, non recoverable and hazardous
catalytic materials and identifying robust, easy to handle, recoverable and
environmentally viable counter parts.
Multicomponent reactions using solid acid/base catalysts are particularly
important in synthetic chemistry. The heterogeneous catalysts can have more than
one type of active sites such as lewis and bronsted acidic/basic sites, which are
capable of catalyzing more than one type of reactions.
With this objective, several hydrotalcites and hydroxyapatites were prepared
by suitable methods. The catalysts were characterized by various analytical
techniques such as X-ay diffraction (XRD), FT-IR, DSC-TGA, SEM, TEM, BET
surface area, ICP-AES, elemental analysis (EDX), and basicity measurement by
phenol adsorption method.
Thus, the present work aims at
● Developing environmentally benign heterogeneous catalytic protocols with
better activity and selectivity for liquid phase organic reactions of industrial
importance.
● To correlate the activity / selectivity of these catalysts with their physico-
chemical properties, wherever possible.
● To check the reusability of the catalysts.
Depending upon the properties and possible active sites present, the catalytic
activity of these materials has been planned and will be explored for the following
important chemical transformations.
� Synthesis of 1,2,3-triazoles using copper apatite � Synthesis of 2-amino-4H-chromene using Mg/Al hydrotalcite � Synthesis of highly substituted pyridines using Mg/Al hydrotalcites � One pot reaction of aldehydes, amines, nitromethane and 1,3-dicarbonyl
compound to give functionalized pyrrole on γ-Fe2O3/HAP nanoparticles � Cycloaddition reaction of alkynes, halides and azides on γ-Fe2O3/HAP
nanoparticles in aqueous medium. � Synthesis of α-aminophosphonates using Palladium hydroxyapatite as a reusable
and heterogeneous catalyst.