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Research paper
Acid clay minerals as eco-friendly and cheap catalysts for the synthesis of - MARK
amino ketones by Mannich reaction
Fernando Gmez-Sanza, Mara Virtudes Morales-Vargasa, Beatriz Gonzlez-Rodrguezb,
Mara Luisa Rojas-Cervantesa, Elena Prez-Mayorala,
a
Departamento de Qumica Inorgnica y Qumica Tcnica, Facultad de Ciencias, UNED, Paseo Senda del Rey 9, E-28040 Madrid, Spain
b
Departamento de Qumica Inorgnica, Facultad de Ciencias Qumicas, Universidad de Salamanca, Plaza de la Merced s/n, E-37008 Salamanca, Spain
A B S T R A C T
The characterization and catalytic performance of dierent smectites, one raw saponite and some commercial
montmorillonites, exhibiting mesoporous and acid character are herein reported. The catalysts under study are
able to catalyze eciently via Mannich-type reactions the synthesis of -amino ketones, which are important
building blocks for the drugs synthesis and biologically active natural products. Montmorillonite K10 (Mt-K10)
was the most ecient catalyst for the Mannich reaction between the pre-formed imine, N-benzylideneaniline,
and cyclohexanone resulting in a recyclable catalyst for at least three catalytic cycles without activity loss.
Almost quantitative yield to the -amino carbonyl compound was obtained after 240 min when operating under
the most favorable conditions. The catalytic performance of the smectites seemed to be inuenced by their
porosity, but also by both Brnsted and Lewis acid site concentrations. In fact, the concentration of the Lewis
acid catalytic sites would be the key in the Michael addition of cyclohexanone to the imine, although the
Brnsted acid sites contribution cannot be neglected. The -amino carbonyl compound was also synthesized in
an excellent yield (86%) in only 15 min of reaction time through the one-pot three component reaction, by
reaction between benzaldehyde, aniline and cyclohexanone.
1. Introduction diversity allowing the fast, safe, highly selective and ecient synthesis
of structurally complex molecules (Zhu and Bienaym, 2005). Among
CeC and CeN bond forming reactions are widely investigated since the MCRs the Mannich reaction is important for CeC and CeN bond
they are involved in the most relevant bio-transformations. formation; it consists of the condensation of a non-enolizable aldehyde,
Methodologies implying the formation of CeC and CeN bonds through a primary or secondary amine and frequently an enolizable ketone
cascade reactions are the key in the synthesis of natural products, leading to the corresponding -amino ketone. This synthetic approach
pharmaceuticals or even in materials science. Our research group requires acid or basic conditions taking place through two processes in
possesses a wide experience in this type of reactions aimed at the cascade constituted by i) an initial imination reaction, often between
development of synthetic methodologies based on catalytic synthesis of benzaldehydes and aromatic amines, and ii) subsequent Michael
biologically heterocyclic compounds (Prez-Mayoral et al., 2015a,b). In addition of ketone, as its enol form, to the previously formed imine
this respect, the Friedlnder reaction is one of the most explored providing the corresponding -amino carbonyl compounds. Mannich
transformation by us (Marco-Contelles et al., 2009), involving CeC and bases are structural components of many biologically active natural
CeN bond forming cascade reactions, catalyzed by a great variety of products and synthetic drugs, such as peptides, hormones, vitamins,
dierent porous systems (Domnguez-Fernndez et al., 2009; Lpez- alkaloids, and antibiotics showing a broad range of biological activities
Sanz et al., 2010; Lpez-Sanz et al., 2012; Smuszkiewicz et al., 2013a,b; (Mller et al., 1999, Arend et al., 1998; Heravi et al., 2016).
Prez-Mayoral and Cejka, 2011; Prez-Mayoral et al., 2012; Polozij Dierent heterogeneous catalytic systems have been developed for
et al., 2013; Lpez-Sanz et al., 2013; Godino-Ojer et al., 2014). Mannich-type reactions such as Amberlyst-15 (Dasa et al., 2009),
Multicomponent reactions (MCRs) are considered as a powerful tool sulfated ceria-zirconia (Reddy et al., 2006), tungstated zirconia
in the drug discovery. The MCRs, one-pot processes requiring very (Reddy et al., 2008), Cu nanoparticles (Kidwai et al., 2009),
simple experimental procedures, are source of a great molecular SiO2eOAlCl2 (Li et al., 2007), and SiO2eH2SO4 (Wu et al., 2007).
Corresponding author.
E-mail address: eperez@ccia.uned.es (E. Prez-Mayoral).
http://dx.doi.org/10.1016/j.clay.2017.03.033
Received 23 November 2016; Received in revised form 21 March 2017; Accepted 22 March 2017
0169-1317/ 2017 Elsevier B.V. All rights reserved.
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
Modied clays catalyzing the Mannich-type reactions have been also acidity of samples, according to the method reported in (del Rey-Perez-
reported. For instance, the phosphomolybdic acid supported on sulfate Caballero and Poncelet, 2000). The spectra were recorded with a
grafted Zr-Pillared clay (Samantaray et al., 2011) is active in the Perkin-Elmer Spectrum-One spectrometer. In a typical experiment,
synthesis of -amino carbonyl compounds, in aqueous media, while Ag 20 mg of samples were contacted with 1 mL of pyridine in a desiccator
(I)-exchanged K10 montmorillonite was used in one of the variants for and were evacuated for 1 h at room temperature. Afterwards, the
Mannich reaction yielding propargyl amines (Jeganathan et al., 2014a). samples were pressed into wafers with KBr (dilution ratio sample/KBr
The goal of this paper is aimed to study dierent clay minerals, of 10/600) and the IR spectra were recorded in the 4000450 cm 1
exhibiting acid character, able to eciently catalyze the synthesis of - range. Subsequent spectra were recorded after stepwise heating for 1 h
amino ketones via direct Mannich-type reactions, under mild condi- in a vacuum oven, at temperature intervals of 100 C, between 100 and
tions. With this purpose, a raw and some commercial smectites have 400 C and cooling down. The Brnsted and Lewis acid contents, qH and
been selected, all of them showing dierent composition, Lewis and qL (mol/g), respectively, were calculated with the Eq. 1 (Barzetti et al.,
Brnsted acid site concentrations, and porosity. The advantage of using 1996):
these catalysts regarding other clay minerals previously reported for
qH,L = (AI D2) (4w I)1 (1)
Mannich-type reactions is that in our case no modication of the
samples was required. In this work, the inuence of various parameters where D (cm) is the diameter of the wafer, and w (g) the sample weight.
such as the amount of the catalyst, the acid-base and textural proper- The integrated area AI (in arbitrary units) of the bands at 1545 (Py-B)
ties, and the eect of the temperature on the catalytic performance of and 1450 cm 1 (Py-L) were provided by the software of the instru-
clay minerals under study has been investigated. Both the reaction ment, after baseline optimization. The extinction coecients I with
between the pre-formed imine (N-bencylildenaniline) and cyclohexa- Brnsted and Lewis sites given by Emeis, 1993,
none and the one-pot three component reaction have been explored. 1.67 0.12 cm mol 1 and 2.22 0.21 cm mol 1, respectively,
The reactants selected in this study were benzaldehyde, aniline and were adopted. The qH and qL values were established from the
cyclohexanone because the Mannich-type reaction involving dierently recordings of samples outgassed at 100 C.
substituted both benzaldehyde and anilines gives the corresponding -
amino ketones biologically active by themselves as good antioxidants
2.3. Reaction procedure
inducing acute oxidative stress of cancer cell lines (Petrovic et al.,
2014).
The used reactants were N-benzylideneaniline (Alfa Caesar), cyclo-
hexanone (Sigma-Aldrich), benzaldehyde (Sigma-Aldrich) and aniline
2. Experimental (Sigma-Aldrich).
In a typical experiment, a solution of N-benzylideneaniline (2 mmol)
2.1. Catalysts and cyclohexanone (3 mmol) was heated under stirring at the appro-
priate reaction temperature and the catalyst was added. Aliquots of the
The catalysts under study are clay minerals belonging to the reaction crude were successively extracted at predetermined times and
smectites group: one raw saponite from Cabaas (Toledo, Spain) and diluted in ethyl acetate (0.5 mL), the catalyst was removed by ltration
four commercial montmorillonites. The nomenclature and the suppliers through 0.45 m Durapore membrane syringe lters and the solvent
of the catalysts used in this work are given in Table 1. was removed in vacuo. The reaction was qualitatively monitored by TLC
on silica gel (Merck F254) using a mixture of hexane/ethyl acetate (9:1)
as eluent. The reaction products were characterized by 1H RMN (Bruker
2.2. Characterization
DPX 300 MHz, CDCl3) and the results were analysed by MestRec, v.
4.8.6.0 Software. In the case of the one pot three-component reaction
The textural characterization of all samples was accomplished by
the reactants used were benzaldehyde (2 mmol), aniline (2 mmol) and
nitrogen adsorption. The adsorption isotherms for N2 at 196 C were
cyclohexanone (3 mmol) following the same experimental protocol as
measured using a Micromeritics ASAP 2010 equipment. Previously to
explained above.
the adsorption measurements, the samples were out-gassed at 40 C for
2 h and 150 C for 5 h up to 102 mm Hg. The specic surface areas and
the micropore size distribution were calculated by the BET method and 2.3.1. Recyclability of the catalyst
the Horvath-Kawazoe method, respectively (Gregg and Sing, 1991). The The reusability of the catalyst was investigated using, Mt-K10. The
mesopore size distribution as well as the mesopore volume and the rst cycle was carried out at 35 C using 100 mg as catalyst, by
average mesopore diameter were determined by the BJH method sampling only once at the longest reaction time, i.e., 240 min. Due to
(Gregg and Sing, 1991). The pore size distributions are in the micropore the slight loss of catalyst between two successive cycles, the reactant
and mesopore range and were calculated by applying the DFT method amounts were rescaled in order to keep constant the catalyst/reactants
(Lastoskie et al., 1993). ratio. After each reaction cycle, the used catalyst was washed with ethyl
The X-ray powder diraction patterns between 5 and 80 of 2 were acetate for several times, ltered and dried in an oven at 60 C for 16 h,
obtained using a X'Pert diractometer with ltered Cu-K radiation before being used in the following cycle.
operating at 40 kV and 30 mA and with 0.04 and 2 s step over non-
oriented powder samples. 3. Results and discussion
FTIR spectroscopy of adsorbed pyridine was used to investigate the
3.1. Catalyst characterization
Table 1
Nomenclature of the clay minerals used as catalysts. The diraction patterns of the catalysts together with the assigna-
tion of the corresponding basal and (hk0 + hkl) reections are shown
Catalyst Nomenclature Supplier
in Fig. 1. In some of the samples, additionally to the reection lines
Saponite Sap Tolsa typical from saponite or montmorillonite, others assigned to impurities
Montmorillonite K10 Mt-K10 Sigma-Aldrich of quartz and mica were detected. In the case of Mt-K10, Mt-K30 and
Montmorillonite K30 Mt-K30 Sigma-Aldrich
Mt-KSF catalysts, the presence of these impurities could be due to the
Montmorillonite KSF Mt-KSF Sigma-Aldrich
Montmorillonite pillared (Al) Mt-pil Sigma-Aldrich acid treatment applied during their preparation (Tabernero et al.,
2010).
251
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
Table 2
Textural properties of the clay minerals used as catalysts.
SBET = specic surface area; Smic = micropore surface area determined by t-plot;
VP = total pore volume at P/P0 = 0.99; Vmes = mesopore volume by BJH;
Vmic = micropore volume by Hortvath-Kawazoe method; dp = average pore diameter
(4V/A) by BJH.
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F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
Table 4
Concentration of Brnsted (B) and Lewis (L) acid centres (mol/g) of the catalysts
determined by pyridine adsorption.
Catalyst 25 C 100 C 45 Ca
a
Data at 45 C were calculated by extrapolation.
absence of reactivity when using Mt-KSF, the sample with the lowest
porosity, after 30 min of reaction time, could be due to the low SBET.
Fig. 3. Distributions of porosity of the catalysts determined by DFT.
The low porosity of the sample could be behind the low conversion of
compound 1 (8%), similarly to that obtained in the blank experiment.
This eect was almost insignicant if considering the conversion to 3,
after 300 min of reaction time, with the order of reactivity being Mt-
K10 Mt-K30 Sap > Mt-pil Mt-KSF. It is important to note that
although small dierences in the conversion of N-benzylideneaniline 1
to products 3 (7382%) were observed, Mt-KSF is the least ecient
catalyst.
Scheme 1. Mannich-type reaction between N-benzylideneaniline 1 and cyclohexanone 2. The investigated clay minerals exhibited acid character provided by
the presence of Brnsted and Lewis acid functions. In order to
45 C, under solvent-free conditions (Scheme 1). determine the concentration of both acid centres, at the edges/external
The conversion of N-benzylideneaniline 1 as well as the selectivity surfaces of particles and the interlayer space, experiments of pyridine
to 3-anti/3-syn diatereoisomers at two reaction times are given in adsorption at several temperatures were carried out (Table 4).
Table 3. For purposes of comparison, the reaction was also carried out As far as we know both types of acid centres, Brnsted and Lewis
in the absence of any catalyst aording a mixture of the corresponding ones, are able to catalyze the direct Mannich-type reaction. In general,
isomers, 3-anti and 3-syn (isomers ratio, 1:1), in 40% of yield, after 5 h the concentration of Lewis acid sites into the samples was notably
of reaction time. higher than that of Brnsted ones, with the exception of Mt-KSF sample
Remarkably, a signicant enhancement of the conversion to pro- which did not contain Lewis centres (Table 4). Considering the
ducts 3 was observed when the reaction was carried out in the presence observed catalytic performance, it seems that the main contribution
of all investigated catalysts. In general, even at the shortest reaction to the activity is provided by the Lewis acid sites. In addition, analyzing
times, mixtures of the isomers 3 were obtained with increased yields the Brnsted (B), Lewis (L) and total (B + L) acid site concentrations of
and selectivities. The selectivity to 3-anti, the most stable isomer, was the samples at the reaction temperature, i.e., 45 C, the following
slightly higher ( 60%), and maintained during the process, when sequences were found:
operating in the presence of clay minerals, this feature being attributed
to the connement eects. B Mt-K10 > Mt-K30 Mt-pil > Mt-KSF Sap
According to data of Table 3, the order of the conversion at the L Sap Mt-K30 > Mt-K10 > Mt-pil > Mt-KSF
lowest reaction time was Mt-K10 Mt-pil > Sap Mt-K30 > Mt- B + L Mt-K30 > Sap Mt-K10 > Mt-pil > Mt-KSF
KSF. This order was in good agreement with those for SBET and
micropore volume values. This fact strongly suggests the importance The last sequence was in agreement with the order of catalytic
of the existence of micropores for the reactants connement and their activity at 300 min (M-K10 M-K30 Sap > M-pil > M-KSF).
diusion towards the catalytic active centres. Particularly, the almost Therefore, besides factors such as the porosity of the sample, the
concentration of the Lewis acid sites seems to be the key in the Michael
Table 3
addition of cyclohexanone 2 to the imine 1, although the participation
Conversion of N-benzylideneaniline and isomer anti/syn ratio. of Brnsted acid sites cannot be neglected. Because both acid sites are
located at the edges/external surfaces of particles and in the interlayer
Catalyst Time (min) Conversion (%) 3-Anti (%) 3-syn (%) space, the results reported herein seem to indicate that the addition
None 30 7 50 50
reaction of 2 to 1 could take place at both environments.
300 40 51 49
Mt-K10 30 49 59 41
300 81 60 40 3.2.2. Inuence of the amount of the catalyst
Mt-K30 30 32 60 40 Since the highest conversion ( 50%) was obtained in the presence
300 82 62 38
Mt-KSF 30 8
of Mt-K10, after the lowest reaction time, 30 min, this sample was the
300 73 63 37 catalyst of our choice to further studies. In this sense, dierent amounts
Mt-pil 30 45 59 41 of Mt-K10 (50, 100 and 200 mg) were tested in the reaction between N-
300 75 60 40 benzylideneaniline 1 and cyclohexanone 2, under solvent free-condi-
Sap 30 33 58 42
tions, at 45 C. The conversion of N-benzylideneaniline and the
300 80 56 44
distribution of diastereoisomers 3, after 30 min of reaction time, are
Reaction conditions: N-benzylideneaniline (2 mmol), cyclohexanone (3 mmol) and 50 mg depicted in Fig. 4.
of catalyst at 45 C. As can be seen, higher conversions of compound 1 (Fig. 4A) and also
253
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
100
A)
80
Conversion (%)
60
40
68
60
49
20
0
50 100 200
Catalyst amount (mg)
% Anti % Syn
100
B) Fig. 6. Inuence of the reaction temperature on the stereoselectivity using 100 mg of Mt-
Stereoisomer (%)
60
40
20
0
50 100 200
Catalyst amount (mg)
254
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
Fig. 9. Conversion of N-benzylideneaniline 1, at 35 C, after 240 min of reaction time, Fig. 11. Three-component Mannich reaction from benzaldehyde 4, aniline 5 and
using 100 mg of Mt-K10 as catalyst. cyclohexanone 2, at 35 C, under solvent-free conditions.
255
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
Table 5
Heterogeneous catalysts catalyzing Mannich reaction.
a
Reaction conditions: number of mmol of cyclohexanone: benzaldehyde: aniline, catalyst amount, solvent and reaction temperature.
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F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257
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