Lanthanide-EDTA complexes covalently bonded on Fe3O4@SiO2 magnetic nanoparticles promote the green, stereoselective synthesis of: N-Acylhydrazones

Article abstract of DOI:10.1039/c9nj02916h

In the last few years, many synthetic methods have been developed using magnetic nanomaterial-based catalysts with considerable advantages for the efficiency, selectivity and applicability of green procedures. In this work, lanthanide-EDTA complexes coval

Full text of DOI:10.1039/c9nj02916h

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Lanthanide–EDTA complexes covalently bonded
on Fe3O4@SiO2 magnetic nanoparticles promote
the green, stereoselective synthesis of
N-acylhydrazones†
Cite this:DOI: 10.1039/c9nj02916h
a
b
Joao Batista M. de Resende Filho,
Gilvan P. Pires,
Nathalia Kellyne S. M. Falcao,
´ ˜
˜
b
b
b
Luiz Fernando S. de Vasconcelos,
Savio M. Pinheiro,
´
c
d
Jose Maurıcio dos Santos Filho,
Marılia Imaculada Frazao Barbosa,
Ercules E. S. Teotonio
´
´
´
˜
d
b
b
Antonio Carlos Doriguetto,
and Juliana A. Vale
*
ˆ
In the last few years, many synthetic methods have been developed using magnetic nanomaterial-based
catalysts with considerable advantages for the efficiency, selectivity and applicability of green
procedures. In this work, lanthanide–EDTA complexes covalently bonded on Fe3O4@SiO2 magnetic
nanoparticles (Fe3O4@SiO2-xN-EDTA–Ln3+, with x = 1, 2, or 3 N spacer groups, and Ln3+ = La3+, Ce3+
,
Received 4th June 2019,
Accepted 1st August 2019
Sm3+, Eu3+, Gd3+, Tb3+, Er3+ or Yb3+) were prepared and investigated as a heterogeneous catalyst for
the synthesis of N-acylhydrazones. The target molecules were obtained in good to excellent yields,
exclusively as E-diastereomers after short reaction times under mild conditions and low concentration
of the easily recyclable catalyst.
DOI: 10.1039/c9nj02916h
rsc.li/njc
synthesis of N-acylhydrazones is mainly carried out by reacting
N-acylhydrazines with aryl/alkyl aldehydes or, less frequently,
1. Introduction
The N-acylhydrazone (NAH) framework has been recognized with ketones under refluxing in the presence of Brønsted–Lowry
as a privileged structure in Medicinal Chemistry, interacting acid catalysts in protic polar solvents for times varying from
with several distinct biological targets, which relates the NAH- a few minutes to several hours, depending upon the nature of
bearing derivatives to a plethora of biological activities. As a the reactants23–26 (Scheme 1). Under these conditions, the reaction
consequence, new compounds have been designed, bringing to is expected to lead to a mixture of E/Z diastereomers, predomi-
light bioactive molecules and potential drug candidates.1–4 In nantly forming the E-isomer.
the last few years, N-acylhydrazone derivatives have been stu-
Recently, dos Santos Filho reported the stereoselective
died as antiviral,5–7 analgesic and anti-inflammatory,8–10 synthesis of N-acylhydrazones under mild conditions via a
antitrypanosomal,11–13 and antimalarial agents,14,15 among reaction between hydrazides and aldehydes/ketones using
others.16–18 Due to these biological activities, many N-acylhydrazone CeCl3ꢀ7H2O as a Lewis acid catalyst in excellent reaction times
derivatives have been considered as potential market drugs, and isolated yields27 (Scheme 1). It was the first reported
which has increased the number of patent applications involving application of a lanthanide as a catalyst in the synthesis of
this kind of compound.19–22 Despite their importance, the NAH, opening the possibility of exploiting other transition
metals with the same purposes.
In the last few years, the use of magnetic nanoparticles
a
˜
ˆ
´
Instituto Federal de Educaçao, Ciencia e Tecnologia da Paraıba, Campus Sousa.
(MNP) as a support for heterogeneous catalysts has grown
considerably.28,29 These materials present many advantages
when compared with both homogeneous and conventional
heterogeneous catalysts such as: (1) more efficient catalyst
recovery by magnetic separation; (2) smaller loss of the catalyst;
(3) facility of purification; (4) increase of the surface area; (5)
implementation of greener methodologies, among others.30,31
A large number of catalytic systems bonded on MNP have been
developed, disclosing new and efficient synthetic methods
ˆ
Av. Presidente Tancredo Neves, s/n – Jardim Sorrilandia, 58800-970, Sousa (PB),
Brazil. E-mail: juliana@yahoo.com.br; Tel: +55-83-3522-2727
b
c
´
´
˜
Departamento de Quımica, Universidade Federal da Paraıba, 58051-970 Joao
Pessoa-PB, Brazil. Fax: +55-83-3216-7437; Tel: +55-83-3216-7591
´
´
`
´
Laboratorio de Planejamento e Sıntese Aplicados a Quımica Medicinal –
SintMeds, Universidade Federal de Pernambuco, 50740-521, Recife, PE, Brazil.
Tel: +55-81-2126-3008
d
´
Instituto de Quımica, Universidade Federal de Alfenas, CEP 37130-000,
Alfenas-MG, Brazil
† Electronic supplementary information (ESI) available. CCDC 1859291. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9nj02916h for oxidation32–34 and reduction reactions,35–37 carbon–carbon
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Scheme 1 General methodologies for the synthesis of N-acylhydrazones.
couplings,38–40 olefin metathesis,41,42 and asymmetric catalysis,43,44 literature50 by reaction between lanthanide oxides (Ln2O3) and
among others.45,46 In a recent work, our group investigated hydrochloric acid. Ethanol (p.a.) was obtained from Tedia. Pyr-
the catalytic activity of new magnetic nanocatalysts based on idine was stored over a 3 Å molecular sieve (Sigma Aldrich). Water
3-trimethoxysilylpropylamine derivatives chemically bonded on was deionized to 18 MO (Milli-Q, Millipore). All the chemicals
the Fe3O4@SiO2 surface, acting as a Lewis base for Knoevenagel were used without further purification.
condensations between carbonyl compounds (aldehydes and
ketones) and malononitrile. These catalysts promoted good N-acylhydrazones were purchased from Sigma Aldrich as well
isolated yields in considerable short reaction times.47
as the DMF (anhydrous, 99.8%) and acetonitrile (anhydrous,
The aldehydes and ketones used for syntheses of
Although it is well-known that trivalent lanthanide ions play 99.8%) solvents. The carboxylic acids and hydrazine hydrate
an important role in different types of organic reactions,48,49 were purchased from Sigma Aldrich, Merck, Fluka and Acros
few studies report their catalytic behavior on solid materials. To Chemicals, and were used without further purification. The
the best of our knowledge, until now, no work using a hetero- substituted benzohydrazide derivatives were synthesized from
geneous catalyst for N-acylhydrazone synthesis has been the corresponding carboxylic esters (previously prepared by
reported in the literature. Thus, the present work describes Fischer esterification of commercial carboxylic acids) by the
the synthesis of several N-acylhydrazones catalyzed by lantha- reaction with hydrazine hydrate, in accordance with the method
nide ions bonded with EDTA-tethered to Fe3O4@SiO2 magnetic reported by Stevens and co-authors.51 The benzohydrazide deri-
nanoparticles. The catalysts were prepared according to the vatives were purified by column chromatography, using silica
procedure reported in our previous work,50 in which an EDTA flash SiliaFlashs F60, 40–63 mm, as a stationary phase and ethyl
moiety was bonded to three different aminoalkoxysilane agents: acetate (ACS reagent) as an eluent, both purchased from Tedia.
3-(trimethoxysilyl)propylamine (1 N), N-[3(trimethoxysilyl)propyl]- The reaction progress was monitored by thin layer chromato-
ethylenediamine (2 N) and N-1-(3-trimethoxysilylpropyl)diethylene- graphy (TLC), performed on glass-backed plates of silica gel 60
triamine (3 N). These MNP ligands were bonded with lanthanide F254 with gypsum, and all compounds were detected by ultra-
ions, resulting in the title catalysts, which were evaluated for their violet light (254 nm) as well as by iodine vapor.
efficacy as catalysts in N-acylhydrazone synthesis, as well as in
the reaction mechanism elucidation.
Attenuated Total Reflectance Fourier-Transform Infrared
(ATR-FTIR) spectra were carried out in a Vertex 70 Brukers
spectrophotometer using the germanium crystals technique
with a measuring range of 400–4000 cmꢁ1. The Fourier-
transform infrared (FT-IR) spectra were recorded in a Shimadzu
FTIR spectrophotometer model IRPrestige-21 by using the
2. Experimental
2.1 Reagents and instruments
technique of KBr pellets in the interval of 400–4000 cmꢁ1
.
All reagents used for the catalyst synthesis were purchased The 1H NMR spectrum was recorded on a VARIAN Mercury
from Sigma-Aldrich: iron(III) chloride hexahydrate (FeCl3ꢀ6H2O, 200 MHz. The chromatograms were recorded on a GC-QP2010-
ACS reagent, 97%), iron(II) chloride tetrahydrate (FeCl2ꢀ4H2O, Shimadzu equipped with an FID detector and capillary Rtx-5
Puriss. p.a., Z99%), sodium hydroxide (NaOH, ACS reagent, column (30 m ꢂ 0.25 mm ꢂ 0.25 mm) and N2 as a carry gas.
Z97.0%), silver nitrate (AgNO3, ACS reagent, Z99.0%), poly- Heating gradient: 80–300 1C (35 1C minꢁ1). Crystallographic data
vinylpyrrolidone (PVP, average molecular weight 40 000), tetra- were collected on a Bruker-AXS Kappa Duo diffractometer with
ethoxysilane (TEOS, reagent grade, 98%), ammonium hydroxide an APEX II CCD detector. Melting points were determined with a
(NH4OH, ACS reagent, 28.0–30.0% NH3 basis), 3-(trimethoxysilyl)- capillary apparatus Fisatom Mod431 and are uncorrected. X-ray
propylamine (1 N, H2N(CH2)3Si(OCH3)3, 97%), N-[30-(trimethoxy- diffraction patterns of the magnetite and catalyst were recorded
silyl)propyl]ethylene-1,2-diamine (2 N, H2N(CH2)2NH(CH2)3- with a LAB-X XRD-6000 diffractometer (Shimadzu) using Cu-Ka
Si(OCH3)3, 97%), N1-(3-trimethoxysilylpropyl)diethylenetriamine radiation (l = 0.154056 nm). Magnetization curves were acquired
(3 N, H2N(CH2)2HN(CH2)2NH(CH2)3-Si(OCH3)3, technical grade), at 25 1C using a VersaLab Vibrating Sample Magnetometer
ethylenediaminetetraacetic acid (EDTA, ACS, 99.4%), acetic anhy- (Quantum Design). Transmission electron microscopy was carried
dride (Ac2O, ACS, Z98.0%), pyridine (ACS reagent, Z99.0%), out using a JEM-1200 (JEOL) operating at 120 kV.
lanthanides oxides (Ln2O3, 99.9%; Ln = La, Ce, Sm, Eu, Gd, Tb,
2.2 Preparation of the catalyst
Er, Yb), hydrochloric acid (HCl, ACS, 97%), and hydrogen per-
oxide (H2O2, 30%). Hexahydrated lanthanide chlorides, LnCl3ꢀ The catalysts used in this work were prepared in accordance
6H2O, were prepared according to procedures reported in the with the procedures described by Pires and coworkers.50
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Synthesis of core–shell magnetic nanoparticles, Fe3O4@SiO2. The product, Fe3O4@SiO2-xN-EDTA (x = 1, 2 or 3), was removed
A chemical co-precipitation method was used to obtain the by magnetic separation and washed with ethanol (six times,
magnetic nanoparticles of magnetite, Fe3O4. An aqueous 200 mL) and deionized water (twice, 100 mL). Lastly, the solid
solution of iron(II) and iron(III) chlorides (2.1 ꢂ 10ꢁ2 mol of was dried under reduced pressure at room temperature.
FeCl2ꢀ4H2O and 4.2 ꢂ 10ꢁ2 mol of FeCl3ꢀ6H2O) in 280 mL of
Lanthanide ions bonded with EDTA-tethered to magnetic
deionized water was heated until 70 1C. After that, a 2.5 mol Lꢁ1 nanoparticles, Fe3O4@SiO2-xN-EDTA–Ln3+ (x = 1, 2, or 3; Ln3+
=
NaOH solution was added dropwise to the system until pH = 11, La3+, Ce3+, Sm3+, Eu3+, Gd3+, Tb3+, Er3+, or Yb3+). A suspension
resulting in a black solid. The reaction was mechanically stirred of Fe3O4@SiO2-xN-EDTA (1 g, x = 1, 2, or 3) in 30 mL of
for 2 h under a N2 atmosphere, and the solid material was deionized water was prepared and, then, 2.87 ꢂ 10ꢁ3 mol of
removed from the mixture by magnetic separation using a LnCl3ꢀ6H2O previously dissolved in 10 mL of deionized water was
magnet (Nd2Fe14B), and exhaustively washed with deionized added. The mixture was magnetically stirred for 24 h at room
water until a negative test for chloride ions was observed in temperature. The solid was removed by magnetic separation and
the washing water. The Fe3O4 nanoparticles were washed with washed with deionized water (four times, 200 mL) and ethanol
50 mL of ethanol and mixed with 200 mL of ethanol. To this (twice, 100 mL). Finally, the magnetic nanoparticles, Fe3O4@SiO2-
suspension, a mixture of 5 g of PVP and 33 mL of deionized xN-EDTA–Ln3+, were dried under reduced pressure at room
water was added, acting as a surface stabilizer.52 Then, the temperature. Scheme 2 shows a summary of the Fe3O4@SiO2-
system was heated until 60 1C, and 1.2 ꢂ 10ꢁ2 mol of TEOS xN-EDTA–Ln3+ catalyst preparation.
was added to the suspension, followed by the addition of 3.7 mL
The magnetic nanoparticles were characterized by X-ray
of NH4OH. The mixture was mechanically stirred at 60 1C for diffraction (XRD) patterns, measurements of magnetization
8 h. The silica-coated magnetite, Fe3O4@SiO2, was magnetically curves and transmission electron microscopy (TEM) images
decanted. The magnetic nanoparticles were washed with deionized (ESI†). The Fourier-transform infrared (FT-IR) spectra, thermo-
water (twice, 100 mL) and ethanol (six times, 200 mL), and dried gravimetric analysis (TGA), determination of zeta potentials,
under reduced pressure at room temperature.
and scanning electron microscopy (SEM) images of the catalyst
EDTA functionalization of core–shell magnetic nanoparticles, material can be found in ref. 50 Quantitative analysis of C, H, N,
Fe3O4@SiO2-xN-EDTA (x = 1, 2, or 3). The EDTA dianhydride and Ln ions was in agreement with previous results,50 while the
(EDTA-DA) was synthesized as described by Capretta and co- percentages of adsorbed lanthanides La3+ (17.6%), Ce3+ (16.3%),
authors.53 1.97 ꢂ 10ꢁ2 mol of EDTA-DA was dissolved in 60 mL Sm3+ (10.4%), Eu3+ (13.7%), Gd3+ (9.4%), Tb3+ (9.4%), Er3+
of anhydrous pyridine under a N2 atmosphere using a standard (16.3%), and Yb3+ (21.6%) in MNPs Fe3O4@SiO2-1N-EDTA were
Schlenk line technique. To the EDTA-DA solution, 3.94 ꢂ 10ꢁ2 determined by complexometric titration with EDTA in the result-
mol of the aminoalkylmethoxysilane containing one (1 N), two ing solution after an adsorption process.
(2 N) or three (3 N) amino groups was added. The reaction was
magnetically stirred for 24 h under a N2 atmosphere at room
2.3 General procedure for the synthesis of N-acylhydrazones
temperature. Then, 2.0 g of Fe3O4@SiO2 was added to the
mixture, followed by the addition of NH4OH (13.85 mL). The
reaction system was also stirred for 24 h at room temperature.
To a warm solution of the arylhydrazide (1 mmol in 0.2 mL of
ethanol) in a glass tube, the catalyst (8 mg, 5 mol% of Ln3+) and
a solution of the carbonyl compound (1 mmol in 0.3 mL of
Scheme 2 Synthesis of the magnetic nanoparticles, Fe3O4@SiO2-xN-EDTA–Ln3+ (x = 1, 2, or 3; Ln3+ = La3+, Ce3+, Sm3+, Eu3+, Gd3+, Tb3+, Er3+, or Yb3+).
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3
ethanol) were added and magnetically stirred. The temperature 7.02 (d, 2H, J = 8.8 Hz, ArH), 7.54 (m, 3H, ArH), 7.67 (d, 2H,
was adjusted to 75 1C. Once the reaction’s end was detected by 3J = 8.6 Hz, ArH), 7.89 (d, 2H, 3J = 6.4 Hz, ArH), 8.39 (s, 1H,
TLC, the catalyst was removed by magnetic separation. Then, cold NQCH), 11.7 (s, 1H, NH).
water was added into the reaction medium and a solid was
N0-Cyclohexylidenebenzohydrazide (9)27 m.p. 193–195 1C;IR
obtained. When a precipitate was not formed (compound 11), (KBr, nmax, cmꢁ1): 3246 (CONH), 3064, 3030 (ArH), 2949, 2933,
the solvent was removed under vacuum, producing a yellow oil. 2858 (CH), 1662 (CQO), 1641 (NH), 1523 (CQN); 1H NMR
Then, cold ethyl acetate was added until the medium became (200 MHz, DMSO-d6, dH ppm): d 1.59 (br s, 6H, 3xCH2), 2.31
cloudy. Afterwards, the solid material was filtered off and dried in (br s, 2H, CH2), 2.38 (d, 2H, 3J = 14.0 Hz, CH2), 7.51 (m, 5H, Ar),
a desiccator, resulting in a pale yellow solid. All products were 10.6 (s, 1H, NH).
recrystallized in warm ethanol and characterized by melting point,
IR, and 1H NMR analysis, which matched the literature data.
(E)-N0-(4-Hydroxy-3-methoxybenzylidene)benzohydrazide
(E)-N0-(Butan-2-ylidene)benzohydrazide (10)27 m.p. 118–
120 1C; IR (KBr, nmax, cmꢁ1): 3300, 3211 (CONH), 3051, 3022
(ArH), 2929, 2875 (CH), 1658 (CQO), 1614 (NH), 1562 (CQN);
(1)27 m.p. 140–143 1C; IR (KBr, nmax, cmꢁ1): 3483 (OH), 3238 1H NMR (200 MHz, DMSO-d6, dH ppm): 1.26 (s, 3H, CH3),
(CONH), 3078, 3062 (ArH), 1633 (CQO), 1608 (NH), 1562 2.12 (s, 3H, CH3), 2.48 (s, 2H, CH2), 7.80 (m, 5H, ArH),
(CQN); 1H NMR (200 MHz, DMSO-d6, dH ppm): 3.84 (s, 3H, 10.6 (s, 1H, NH).
OCH3), 6.83 (d, 2H, 3J = 7.0 Hz, ArH), 7.08 (d, 2H, 3J = 8.0 Hz, ArH),
(E)-N0-(1-Phenylethylidene)benzohydrazide (11)27 m.p. 166–
7.40 (s, 1H, ArH), 7.53 (m, 3H, ArH), 7.87 (d, 2H, 3J = 7.4 Hz, ArH), 169 1C; IR (KBr, nmax, cmꢁ1): 3302, 3194 (CONH), 3053,
8.30 (s, 1H, NQCH), 9.70 (s, 1H, OH), 11.8 (s, 1H, NH).
3001 (ArH), 2879 (CH), 1639 (CQO), 1610 (NH), 1543 (CQN);
(E)-N0-Benzylidenebenzohydrazide (2)27 m.p. 210–212 1C; IR 1H NMR (200 MHz, DMSO-d6, dH ppm): 2.35 (s, 3H, CH3),
(KBr, nmax, cmꢁ1): 3180, 3155 (CONH), 3062, 3032 (ArH), 1641 7.53 (m, 6H, ArH), 7.90 (m, 4H, ArH), 10.7 (s, 1H, NH).
(CQO), 1602 (NH), 1554 (CQN); 1H NMR (200 MHz, DMSO-d6,
N0-Cyclohexylidene-4-aminebenzohydrazide (12)27 m.p. 239–
dH ppm): 7.75 (m, 6H, ArH), 7.95 (d, 2H, 3J = 3.8 Hz, ArH), 241 1C; IR (KBr, nmax, cmꢁ1): 3302, 3222, 3180 (CONH, ArNH),
8.14 (d, 2H, 3J = 6.6 Hz, ArH), 8.68 (s, 1H, NQCH), 12.1 (s, 1H, NH). 3053, 2987, 2952 (ArH), 2885, 2837 (CH), 1662 (CQO), 1610
(E)-N0-Benzylidene-4-methoxybenzohydrazide (3)27 m.p. 230– (NH), 1568 (CQN); 1H NMR (200 MHz, DMSO-d6, dH ppm):
232 1C; IR (KBr, nmax, cmꢁ1): 3201 (CONH), 3068, 3028 (ArH), d 1.56 (br s, 6H, CH2); 2.26 (s, 2H, CH2), 2.33 (s, 2H, CH2),
2958, 2931, 2908, 2839 (CH), 1631 (CQO), 1604 (NH), 1547 5.63 (s, 2H, NH2), 6.54 (d, 2H,3J = 6.0 Hz, ArH), 7.57
(CQN), 1510 (NH); 1H NMR (200 MHz, DMSO-d6, dH ppm): (d, 2H,3J = 6.0 Hz, ArH), 10.1 (s, 1H, NH).
3.80 (s, 3H, OCH3), 7.03 (d, 2H, 3J = 8.8 Hz, ArH), 7.40 (m, 3H, ArH),
N’-Cyclohexylidene-4-nitrobenzohydrazide (13)27 m.p. 168–
7.68 (d, 2H, 3J = 3.8 Hz, ArH), 7.89 (d, 2H, 3J = 8.8 Hz, ArH), 169 1C; IR (KBr, nmax, cmꢁ1): 3303, 3190 (CONH), 3053,
8.42 (s, 1H, NQCH), 11.7 (s, 2H, NH).
3003 (ArH), 2945, 2883 (CH), 1637 (CQO), 1608 (NH), 1572
1
(E)-N0-Benzylidene-3,5-dinitroxybenzohydrazide (4)27 m.p. (CQN); H NMR (200 MHz, DMSO-d6, dH ppm): 1.05 (m, 3H),
295–297 1C; IR (KBr, nmax, cmꢁ1): 3217, 3190 (CONH), 3114, 1.64 (m, 5H), 2.34 (m, 2H), 8.05 (d, 2H, J = 4.0 Hz, ArH), 8.31
3
3068, 3032 (ArH), 1653 (CQO), 1602 (NH), 1552 (CQN); 1H NMR (d, 2H, J = 4.0 Hz, ArH), 10.96 (s, 1H, NH).
3
(200 MHz, DMSO-d6, dH ppm): 7.46 (t, 3H, 3J = 5.6 Hz, ArH),
3-(4-Tolyl)-N0-(E-ferrocenylmethylidene)-1,2,4-oxadiazol-5-
7.76 (m, 2H, ArH), 8.48 (s, 1H, NQCH), 8.97 (m, 1H, ArH), ylcarbohydrazide (14)14 m.p. 218–2201 (from dioxane/H2O); IR
3
9.10 (d, 2H, J = 1.0 Hz, ArH), 12.4 (s, 1H, NH).
(KBr, nmax cmꢁ1): 3182 (NH), 3100, 3029 (Ar CH), 1682 (CQO),
(E)-N0-Benzylidene-4-nitrobenzohydrazide (5)54 m.p. 221– 1598 (CQN, imine), 1547 (CQN, heterocyclic); 1H NMR
222 1C; IV (KBr, nmax, cmꢁ1): 3217, 3190 (CONH), 3114, 3068, (300 MHz, DMSO-d6, dH ppm): 2.40 (s, 3H, CH3), 4.26 (s, 5H,
3032 (ArH), 1654 (CQO), 1602 (NH), 1552 (CQN); 1H NMR Fc), 4.51 (s, 2H, CQNHFc-H), 4.70 (s, 2H, CQNHFc-H),
(200 MHz, DMSO-d6, dH ppm): 7.44 (t, 3H, J = 5.6 Hz, ArH), 7.43 (d, 2H, 3J = 7.8 Hz, ArH), 7.99 (d, 2H, 3J = 7.5 Hz, ArH),
3
3
7.73 (m, 2H, ArH), 8.12 (d, 2H, J = 8.8 Hz, ArH), 8.35 (d, 2H, 8.47 (s, 1H, NQCH), 12.47 (s, 1H, CONH).
3J = 8.8 Hz, ArH), 8.44 (s, 1H, NQCH), 12.1 (s, 1H, NH).
(E)-N0-(2-Nitrobenzylidene)benzohydrazide (6)27 m.p. 225–
2.4 X-ray crystallographic analysis
228 1C; IR (KBr, nmax, cmꢁ1): 3161 (CONH), 3049, 3016 (ArH), Orange crystals suitable for a single crystal X-ray diffraction
1647 (CQO), 1566 (CQN); 1H NMR (200 MHz, DMSO-d6, experiment were obtained for compound 14 by slow evaporation
dH ppm): 7.79 (m, 9H, ArH), 8.84 (s, 1H, NQCH), 12.2 (s, 1H, NH). from dichloromethane/tetrahydrofuran mixture. The compound
(E)-N0-(4-Nitrobenzylidene)benzohydrazide (7)55 m.p. 239– crystallized in an orthorhombic system (Pca21 space group) with
240 1C; IR (KBr, nmax, cmꢁ1): 3180 (CONH), 3066, 3012, 2848 four molecules per asymmetric unit. At room temperature
1
(Ar–H), 1647 (CQO), 1570 (CQN); H NMR (200 MHz, DMSO- (296(2) K) MoKa reflection data were collected on a Bruker-AXS
3
d6, dH ppm): 7.57 (m, 3H, ArH), 7.93 (d, 2H, J = 7.0 Hz, ArH), Kappa Duo diffractometer with an APEX II CCD detector. For
7.99 (d, 2H, 3J = 8.8 Hz, ArH), 8.30 (d, 2H, 3J = 8.8 Hz, ArH), data frame processing, the programs SAINT and SADABS were
8.55 (s, 1H, NQCH), d 12.2 (s, 1H, NH).
used. The structure was solved by direct methods of phase
(E)-N0-(4-Methoxybenzylidene)benzohydrazide (8)55 m.p. retrieval with SHELXS-2014,56 and the refinement was performed
144–146 1C; IR (KBr, nmax, cmꢁ1): 3199 (CONH), 3068, 3024 by full-matrix least squares on F2 with SHELXL-2014.56 All non-
(ArH), 2839(CH), 1641 (CQO), 1604 (N–H), 1550(CQN); hydrogen atoms were refined with free anisotropic displacement
1H NMR (200 MHz,DMSO-d6, dH ppm): 3.80 (s, 3H, OCH3), parameters while hydrogens had their displacement parameter
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fixed and set to isotropic. Their isotropic thermal parameters 60 minutes (Table 1, entry 3), but the catalyst couldn’t be
were 20% higher than the Ueq values of the parent atoms (except recycled since it acts in a homogeneous phase, and its isolation
in the case of a methyl group, wherein this value was 50%). The from the mother liquor is not easy to achieve. This result,
hydrogen positions were calculated according to both intra- however, has proven to be poorer than those arising from
molecular and intermolecular requirements and constrained the Fe3O4@SiO2-xN-EDTA–Ln3+complexes, as evidenced in the
following a riding model. The structure analysis and preparation further experiments.
of artwork were performed with ORTEP-3.57 Details of the single
Due to the large number of functionalized lanthanide-EDTA
crystal X-ray diffraction experiment can be found in the ESI,† as complexes covalently bonded on Fe3O4@SiO2 magnetic nano-
well as on the CCDC database (www.ccdc.cam.ac.uk/) free of particles that can be prepared, an experiment optimization was
charge under the deposit number 1859291,† while the molecular required. The MNP-EDTA ligands, Fe3O4@SiO2-xN-EDTA (x = 1,
structure of the compound is shown as an ORTEP representation 2 and 3), comprise only three examples, so that the evaluation
in Fig. 2.
of the amino spacer’s length was chosen as the first parameter
of analysis. On the other hand, there are eight lanthanide ions
(Ln3+), providing an excellent insight into the catalytic proper-
ties of the metals in the synthesis of N-acylhydrazones. Based
on the importance of the ionic radii of the Ln3+ ions for
their chemical and catalytic properties,59–61 the Fe3O4@SiO2-
xN-EDTA–Eu3+complexes were selected as reference catalysts,
placing the radius of the Eu3+ ion (1.09 Å) in a middle point of a
scale ranging from 1.01 Å to 1.17 Å for the whole group. Thus,
an experiment was performed in the presence of Fe3O4@SiO2-
1N-EDTA–Eu3+ (Table 1, entry 4), leading to the reaction’s
conclusion within 5 minutes and 91% yield. Changing the
catalyst for Fe3O4@SiO2-2N-EDTA–Eu3+, no difference in the
yield or reaction time was observed (Table 1, entry 5). However,
the introduction of another amino spacer, giving Fe3O4@SiO2-
3N-EDTA–Eu3+as a catalyst (Table 1, entry 6), causes a reduction
in the yield and decreases the reaction rate. According to Pires
et al., the longer the chain of the ligand, the higher the content
of Eu3+ in each material.50 However, in Fe3O4@SiO2-3N-EDTA–
Eu3+ the metallic ion coordinates not only with carboxylates,
but also with more nitrogen groups, making the access of
the reagents to the lanthanide sites difficult, and therefore,
affecting the catalytic efficiency. In light of these findings, the
3. Results and discussion
3.1 Catalyzed synthesis of N-acylhydrazones
The condensation reaction between benzohydrazide and vanillin,
leading to N0-(4-hydroxy-3-methoxybenzylidene)benzohydrazide 1
was selected as a reference synthesis, in order to evaluate ligand
features, and the lanthanide influence on the catalytic process.
Initially, all runs were carried out in ethanol at 75 1C as standard
conditions, as shown in Table 1. Refluxing both reactants with-
out any catalyst (entry 1) for 180 min resulted in the expected
product in 83% yield along with unreacted starting materials,
according to the TLC analysis. A similar outcome was ascer-
tained by repeating the reaction in the presence of the MNP
Fe3O4@SiO2-1N-EDTA, demonstrating that the magnetic ligand
does not act as a catalyst for the condensation reaction, since it
does not exhibit Lewis acid centers in its structure (Table 1, entry
2). The free complex Na[Eu(EDTA)(H2O)3], prepared according to
the literature methodology,58 has been used as a catalyst for the
N-acylhydrazone synthesis with better results than the previous
two experiments. Compound 1 was isolated in 77% yield after
Table 1 Effect of different lanthanide–EDTA complexes covalently bonded on Fe3O4@SiO2 on the N-acylhydrazone synthesisa
Entry
Catalyst
Timeb/min
Isolated yield/%
1
2
3
4
5
6
7
8
—
180
180
60
5
83
80
77
91
90
82
96
92
91
91
90
90
88
Fe3O4@SiO2-1N-EDTA
Na[Eu(EDTA)(H2O)3]
Fe3O4@SiO2-1N-EDTA–Eu3+
Fe3O4@SiO2-2N-EDTA–Eu3+
Fe3O4@SiO2-3N-EDTA–Eu3+
Fe3O4@SiO2-1N-EDTA–La3+
Fe3O4@SiO2-1N-EDTA–Ce3+
Fe3O4@SiO2-1N-EDTA–Sm3+
Fe3O4@SiO2-1N-EDTA–Gd3+
Fe3O4@SiO2-1N-EDTA–Tb3+
Fe3O4@SiO2-1N-EDTA–Er3+
Fe3O4@SiO2-1N-EDTA–Yb3+
5
10
10
8
5
6
5
8
10
9
10
11
12
13
a
Reaction conditions: vanillin (1 mmol), benzohydrazide (1 mmol), 0.5 mL of ethanol, 10 mol% of the Ln3+ (11–16 mg of the catalyst Fe3O4@SiO2-
xN-EDTA–Ln3+), 75 1C. The reaction times were determined by TLC, removing aliquots every minute for analysis.
b
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simplest MNP ligand, Fe3O4@SiO2-1N-EDTA, was picked out to quantities to assure the accomplishment of all further designed
conduct the further experiments with other lanthanide ions experiments in these studies, Fe3O4@SiO2-1N-EDTA–Tb3+ was
(Table 1, entries 7–13).
chosen as a standard catalyst for optimizing the catalyzed
The catalytic profile of lanthanides was fully determined by synthesis of N-acylhydrazones, as well as for evaluating electronic
using eight elements of the series. In all cases, isolated yields and steric effects on the catalytic process.
kept regular, while an interesting behavior in reactions’ time
A complete study under the reaction conditions using
was observed. The catalysts with Ln3+ that present frontier Fe3O4@SiO2-1N-EDTA–Tb3+as a catalyst was performed, varying
radii, i.e., La3+, Ce3+ (Table 1, entries 7 and 8), Er3+ and Yb3+ parameters such as temperature, solvent and amount of
(Table 1, entries 12 and 13) provided higher reaction times catalyst as described in Table 2. Keeping the catalyst amount
when compared with those catalysts complexed with Ln3+ ions as 10 mol%, the first experiment, carried out at room tempera-
with intermediate radii, namely Sm3+, Gd3+ and Tb3+ (Table 1, ture, led to the product in 93% yield in 30 minutes (Table 2,
entries 9 and 11). This general trend is clearly depicted in Fig. 1. entry 1), which is slower than the reaction under heating
We suggest that the Ln3+ ions with the shorter radii (Er3+and at 75 1C (Table 1, entry 10). The same behavior was observed
Yb3+) present a saturated coordination sphere by the oxygen when an experiment under ultrasound irradiation at the same
and nitrogen atoms from the EDTA moiety, making the activa- temperature was executed (Table 2, entry 2), establishing the
tion of the carbonyl group difficult. Whereas, the Ln3+ with the limitation of this kind of radiation on the catalyzed condensa-
larger radii (La3+ and Ce3+) can present coordinated molecules tion process. The investigation in polar protic medium
of water, which, in turn, makes access to the Ln3+ ion difficult included water as a solvent, with an increase in the reaction’s
for the carbonyl group. Once the entries 4 and 9–11 disclosed time, which is not meaningful, especially when the similar yield
similar outcomes, and the Tb2O3 was available in good is taken into account (Table 2, entry 3). This outcome evidences
Fig. 1 Effect of ionic radius of Ln3+ in the synthesis of N-acylhydrazones.
Table 2 Optimization of the reaction conditions for N-acylhydrazone synthesisa
Entry
Amount of catalyst
Solvent
Temperature/1C
Timed/min
Isolated yield/%
1
2
3
4
5
6
7
8
10 mol% (16 mg)
10 mol% (16 mg)
10 mol% (16 mg)
10 mol% (16 mg)
10 mol% (16 mg)
10 mol% (16 mg)
5 mol% (8 mg)
Ethanol
Ethanol
Water
ACN
DMF
Toluene
Ethanol
Ethanol
rtb
30
30
8
120
30
180
8
93
90
91
79
97
0
rtc
75 1C
75 1C
75 1C
75 1C
75 1C
75 1C
99
95
1 mol% (1.6 mg)
35
a
b
Reaction conditions: vanillin (1 mmol), benzohydrazide (1 mmol), 0.5 mL of solvent, Fe3O4@SiO2-1N-EDTA–Tb3+ catalyst, 75 1C. Room
c
d
temperature (B30 1C). Under ultrasound conditions and room temperature (B30 1C). The reaction times were determined by TLC.
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the green nature of the methodology, which works well even Several hydrazides and carbonyl compounds (aldehydes and
under low reactant solubility in water. Carrying out the reac- ketones) were used for the synthesis of the N-acylhydrazones,
tion in aprotic polar solvents such as ACN and DMF (Table 2, exploiting the role played by the electronic effects of the
entries 4 and 5, respectively) led to a reduced performance in substituents (Table 3). At first, the reaction between benzalde-
comparison to polar protic solvents at 75 1C. As expected, the hyde and benzohydrazide, affording the corresponding
N-acylhydrazone synthesis did not successfully proceed in the N-acylhydrazone 2, occurred within 3 minutes’ time (Table 3,
apolar medium (Table 2, entry 6).
entry 1), evidencing that the catalyst works well, despite the lack
Since the catalysis occurs in heterogeneous conditions, the of substituents at both aromatic rings. The introduction of an
lack of result in toluene may be associated with the structural electron donating group (EDG) at the hydrazide ring (Table 3,
features of the reactants, as well as the mechanistic pathway of entry 2) enhanced the necessary time to the synthesis of
the reaction. As observed in Scheme 3, the proposed mecha- compound 3. Similarly, electron withdrawing groups (EWGs)
nism for the catalyzed formation of N-acylhydrazones involves linked at the aromatic ring of the hydrazide resulted in longer
the formation of ionic intermediates, whose charges can’t be reaction times (Table 3, entries 4 and 5). These differences are
stabilized by interactions with the apolar solvent. Lastly, differ- subtle and only could be identified due to the accurate reaction
ent amounts of Fe3O4@SiO2-1N-EDTA–Tb3+ were examined, control applied on these studies.
aiming to establish the effect of this parameter on the reaction.
An analysis of the electronic effects’ influence on the alde-
By reducing the amount of catalyst from 10 to 5 mol%, an hydes (Table 3, entries 5–7) led to similar conclusions.
excellent outcome was obtained, with the complete conversion The synthesis of compounds 7 and 8 (Table 3, entries 6 and 7)
of reactants in 8 minutes and excellent yield (Table 2, entry 7). didn’t disclose meaningful differences when compared with each
The reduction in the catalyst’s amount compensates the slight other. But the use of 2-nitrobenzaldehyde as a substrate (Table 3,
increment in the reaction’s time; thus, the process becomes entry 5) increased the reaction time to 10 minutes, the highest
greener. At this point, lowering the catalyst’s concentration to value observed for the synthesis of an aldo-N-acylhydrazone
one-tenth of the original experiment (Table 1, entry 10) was under the catalysis of Fe3O4@SiO2-1N-EDTA–Tb3+. In this case,
necessary to determine the limiting conditions of our investiga- it is reasonable to assume that the steric effect of the ortho-
tions. Although the use of 1 mol% of the catalyst burdened the substituent is more important than its electronic features.
reaction’s time, increasing it to 35 minutes, the reaction’s yield
As expected, reactions of hydrazides with ketones (Table 3,
remained excellent (Table 2, entry 8). By comparing these two entries 8–12) were considerably slower than that with aromatic
experiments with the one in Table 1 (entry 10), it became clear aldehydes, essentially due to the lower reactivity of the ketones.
that the ideal catalyst concentration can be set at 5 mol% The electronic effects of EDG and EWG groups attached to the
without any damage to the overall results.
hydrazides became more evident by studying compounds 12
With the optimal experimental conditions in hand, the (Table 3, entry 11) and 13 (Table 3, entry 12). Both reactions run
focus was put on the investigation of the methodology’s scope. very slow, regardless of the nature of the substituents, suggesting
Scheme 3 Proposed mechanism for the synthesis of N-acylhydrazones with Fe3O4@SiO2-1N-EDTA–Tb3+ as a catalyst.
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Table 3 Synthesis of several N-acylhydrazones with Fe3O4@SiO2-1N-EDTA–Tb3+ as a catalysta
Entry
1
Hydrazide
Carbonyl compounds
N-Acylhydrazones
Timeb/min
Isolated yield/%
82
3
2
3
5
8
85
95
4
5
6
7
6
80
90
86
91
10
4
6
8
15
78
9
60
60
82
84
10
11
120
89
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Table 3 (continued)
Entry
12
Hydrazide
Carbonyl compounds
N-Acylhydrazones
Timeb/min
180
Isolated yield/%
65
13
50
92
a
Reaction conditions: hydrazide (1 mmol), carbonyl compound (1 mmol), 0.5 mL of EtOH, 5 mol% of Tb3+ (8 mg of Fe3O4@SiO2-1N-EDTA–Tb3+
b
catalyst), 75 1C. The reaction times were determined by TLC.
that other factors may affect such processes. In fact, the
solubility of the substrates in ethanol is also an important
factor to consider, as demonstrated by dos Santos Filho, who
reported a detailed methodology for the N-acylhydrazone synth-
esis catalyzed by CeCl3ꢀ7H2O.27 Low solubility of the substrates
can affect the homogeneity of the reaction medium, complicat-
ing the reaction’s rate. Nevertheless, electronic effects also play
an important role in this case. Since the reaction’s mechanism
involves a nucleophilic attack of the NH2 group of the hydrazide
on the carbonyl group (Scheme 3), 4-aminobenzohydrazide,
a hydrazide bearing an EDG, is expected to react faster, leading
to the corresponding N-acylhydrazone 12 (Fig. 3, entry 11) in
120 minutes’ time. On the other hand, the nitro group attached
Fig. 2 ORTEP plot of the X-ray crystal structure for compound 14. Atomic
displacement parameters are shown at a 50% probability level.
to the 4-position of the benzohydrazide exerts a strong with-
drawing effect, so that the synthesis of compound 13 (Fig. 3,
entry 12) took longer to be accomplished, in agreement with
dos Santos Filho’s previous results.27
ascertained that all compounds were formed exclusively as
In order to investigate the efficiency of the catalyst in the the thermodynamically more stable E-isomers, along with the
presence of more complex hydrazides and sensitive carbonyl occurrence of rotamers for compounds 4 and 5 (Table 3, entries
compounds, the reaction between 3-(4-tolyl)-1,2,4-oxadiazol-5- 3 and 4, respectively), a consequence of the well-established
ylcarbohydrazide and ferrocenecarboxyaldehyde was performed, effects of the electron withdrawing groups, as described by
so that the previously reported N-acylhydrazone 1414 was isolated Lopes and coworkers.62 The catalytic effect of Fe3O4@SiO2-1N-
in excellent yield after 50 minutes (Table 3, entry 13), without any EDTA–Tb3+ on the N-acylhydrazone formation, reducing the
evidence of decomposition byproducts. This result is similar to reactions’ rates, prevents the formation of the Z-diastereomers,
that observed when CeCl3 was used as a catalyst, corroborating and assures a new and highly efficient stereoselective methodology
the importance of the lanthanide ions in the N-acylhydrazone’s accessing this important class of compounds. The crystal struc-
synthesis. Beside the physical and spectroscopic data for 14, the ture of 14 shows the E-configuration for this compound, rein-
crystallographic structure of the molecule was also acquired forcing the previous stereochemical analysis based exclusively
1
(Fig. 2), furnishing more details on the stereochemistry of the on H NMR studies.27
product after the catalysis performed by the Fe3O4@SiO2-1N-
EDTA–Tb3+.
A proposed mechanism for the synthesis of N-acylhydrazones
with Fe3O4@SiO2-1N-EDTA–Tb3+ as a catalyst was suggested in
The stereochemistry of the formed N-acylhydrazones was Scheme 3. The activation of the carbonyl compound (aldehyde
also of great concern, since all reactions were carried out at or ketone) through a Lewis acid–base interaction is fundamen-
75 1C. The 1H NMR spectra of the crude products were tal to the overwhelming results observed in this methodology.
accurately inspected to determine whether E/Z isomers were
The nucleophilic addition of the NH2 group of the hydrazide
present. Based on the work of dos Santos Filho,27 it was takes place, leading to the elimination step, which can be
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Fig. 3 Recycling performance of the Fe3O4@SiO2-1N-EDTA–Tb3+ in the synthesis of N0-(4-hydroxy-3-methoxybenzylidene)benzohydrazidea. a Reac-
tion conditions: benzohydrazide (1 mmol), vanillin (1 mmol), 0.5 mL of EtOH, 5 mol% of Tb3+ (8 mg of Fe3O4@SiO2-1N-EDTA–Tb3+ catalyst), 75 1C, 8 min.
favored by the interaction between the positively charged OH chemistry. The magnetic nanoparticle catalysts are highly effec-
group and the lanthanide ion, Tb3+, activating the leaving tive at low concentration as well as easily recovered from the
group. This mechanism is consistent with the results of this reaction medium and efficiently recyclable for at least six cycles
reaction in polar solvents. All intermediates formed in this without meaningful loss of activity. These characteristics intro-
process are ionic, so that their stability depends upon the polar duced a new green and advantageous methodology for the
force of the solvents, particularly, the hydrogen bond formation. preparation of N-acylhydrazones with synthetic and medicinal
Such assumptions are supported by the data disclosed in Table 2, applications. In addition, studies on the influence of several
in which the best results arise from the experiments in water and metals revealed that the lanthanides with intermediate ionic
ethanol.
radii (Tb3+, Gd3+, Eu3+, and Sm3+) exerted a better catalytic effect
than those with larger or short ionic radii (La3+, Ce3+, Er3+, and
Yb3+), suggesting that the coordination of carbonyl compounds
to the metal was possibly hampered by the saturated coordina-
tion sphere, leading to the catalysts’ optimization.
3.2 Recyclability studies
The Fe3O4@SiO2-1N-EDTA–Tb3+catalyst was recycled and reused
in the synthesis of the compound 1, N0-(4-hydroxy-3-methoxy-
benzylidene)benzohydrazide. After each run, the catalyst was
removed by magnetic separation, simply washed with water and
ethanol (both two times) and dried under vacuum. The recovered
catalyst was used in the next catalytic cycle, maintaining an
excellent activity until the 4th cycle. The catalyst’s exhaustion
was assigned from the 5th cycle on, however, it remained
effective (Fig. 3).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
CAPES (1651654) and CNPQ (304403/2017-2) for the financial
´
support, Unical (Unidade da Central Analıtica) of the IPeFarM-
4. Conclusions
´
UFPB (Instituto de Pesquisa em Farmacos e Medicamentos da
UFPB) for the assistance in the NMR analysis, and CETENE-
Herein we described a novel, highly efficient methodology for the
synthesis of N-acylhydrazones using a magnetic nanoparticle-
based catalyst with lanthanide ions. The lanthanide–EDTA com-
plexes covalently bonded on Fe3O4@SiO2 magnetic nanoparticles
(Fe3O4@SiO2-1N-EDTA–Ln3+) exhibited a remarkable performance
as a heterogeneous catalyst for the N-acylhydrazone synthesis,
giving access to structurally diverse products in good to excellent
isolated yields under mild conditions. Low reaction rates along
with the stereoselective formation of the E-diastereomer stress the
importance of the catalysts for both synthetic and medicinal
´
UFPE laboratory (Centro de Tecnologias Estrategicas do Nordeste
da Universidade Federal de Pernambuco) for the assistance in the
FTIR-ATR analysis.
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