Magnetically Retrievable Nanocomposite Based on Thiosemicarbazide-Formaldehyde Resin as a Versatile Nucleophilic Scavenger

Article abstract of DOI:10.1021/acscombsci.6b00090

A magnetically retrievable nanocomposite was prepared by in situ polycondensation and entrapment of iron oxide nanoparticles. This material was found to be efficient in trapping excess electrophilic reagents such as carbonyl compounds, acid chlorides and

Full text of DOI:10.1021/acscombsci.6b00090

Technology Note
pubs.acs.org/acscombsci
Magnetically Retrievable Nanocomposite Based on
Thiosemicarbazide−Formaldehyde Resin as a Versatile Nucleophilic
Scavenger
Maomin Zhen, Danfeng Zhang, Zeyu Zhang, and Yanqing Peng*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, P. R. China
S
* Supporting Information
ABSTRACT: A magnetically retrievable nanocomposite was
prepared by in situ polycondensation and entrapment of iron
oxide nanoparticles. This material was found to be efficient in
trapping excess electrophilic reagents such as carbonyl com-
pounds, acid chlorides and isothiocyanates. Advantages of the
new scavenger include facile preparation, high loading capacity,
low cost, satisfactory swelling properties in polar solvents, and
convenient magnetic recovery.
KEYWORDS: purification, scavenger, nanocomposite, polycondensation, magnetic separation
ombinatorial synthetic techniques are widely applied in
pharmaceutical and agrochemical research for the syn-
metal cations such as Cu(II).9 However, no effort has been
made to use this material in synthetic chemistry. We reasoned
that such a polymer could be used as a scavenger due to the
reactivity of the hydrazino groups on thiosemicarbazide with a
range of reagents. Herein a new and convenient method for the
synthesis of a magnetic nanocomposite based on thiosemi-
carbazide−formaldehyde resin (denoted as TFR) was reported,
and its use as a hydrazide-type nucleophilic scavenger for
solution−phase parallel synthesis. The distinctive advantagess
of this novel scavenger include (1) facile preparation procedure,
polycondensation between thiosemicarbazide and formalde-
hyde is a very simple operation, needing no special apparatus or
manipulation; (2) high loading, hydrazino groups are brought
into the material as part of each monomer rather than by post-
synthetic functionalization; (3) low cost, the two monomers are
inexpensive and readily available (thiosemicarbazide = USD
$130/500 g, from Sigma-Aldrich); (4) satisfactory swelling in
polar solvents; (5) regenerable after scavenging; and (6) readily
recovered by laboratory magnets, making filtration and
extraction manipulations unnecessary. For these reasons, this
new resin is well suited for application in both small-scale
laboratory synthesis and scaled-up processes.
C
thesis and identification of new leads by screening and
optimization of drug candidates.1 Among the routine strategies
of combinatorial chemistry, solution-phase synthesis offers
many advantages over solid-phase ones, such as homogeneous
reaction conditions and easier analysis and manipulation.2 To
aid in the rapid purification or isolation of desired compounds
from homogeneous reaction mixtures, scavenger resins of
varying types have been employed to remove impurities,
byproducts, or desired products.3 While a number of scavenger
resins are available commercially, there is considerable scope
for improvement. For example, the use of functionalized ionic
liquids as novel scavengers has been reported by our group4
and others.5
Most commercially available polymeric scavengers are based
on cross-linked polystyrene gel-type resins sized on the
micrometer scale. As is well-known, when the size of a
heterogeneous reagent is decreased to the sub-micrometer or
nanometer scale, the reagent can be dispersed in reaction media
to form quasi-homogeneous systems with improved mass
transfer characteristics. However, the isolation of such nano-
reagents is also a problem because of their small dimensions. A
convenient solution to this problem is magnetic separation,
which has been applied most often to nanosized heterogeneous
catalysts6 but not commonly to scavengers. Recent examples
include magnetic aminomethylated polystyrene resin as a
scavenger of sulfonyl chlorides,7 and magnetically recyclable
reagents and scavengers based on Co/C or Fe/C nanoparticles
from Reiser and co-workers.8
Thiosemicarbazide−formaldehyde resin (TFR) was previ-
ously synthesized via polycondensation between thiosemicar-
bazide and formaldehyde at 40 °C for 24 h using DMF as a
solvent.9 Because both thiosemicarbazide and formaldehyde are
water-soluble reagents, we performed this condensation
reaction in water containing 10 mol % acetic acid and were
Thiosemicarbazide−formaldehyde resin has previously been
reported as a polymeric ligand (polychelate); showed
antibacterial activities after forming complexes with transition
Received: June 20, 2016
Revised: October 17, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acscombsci.6b00090
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ACS Combinatorial Science
Technology Note
delighted to find that it proceeded smoothly at 40 °C, affording
desired product in 82% yield after drying. While TFR has been
reported to be insoluble in water, methanol, ethanol and
nonpolar solvents but soluble in THF, DMF and DMSO at
room temperature, our material was insoluble in common
organic solvents including THF and DMF. We assume this is
due to more extensive cross-linking, perhaps occurring at the
sites of hydroxymethyl groups under the influence of acidic
catalyst as shown in Scheme 1.
polystyrene-based scavengers are poorly swelled in these
solvents, the TFR material is a beneficial supplement to the
toolbox of combinatorial synthetic chemistry.
To allow for efficient manipulation in parallel purifications, a
magnetic TFR nanocomposite was prepared by the direct
incorporation of Fe3O4 particles into the resin matrix in a one-
pot process (Scheme 1). To a stirred suspension of Fe3O4
nanoparticles in aqueous solution of thiosemicarbazide
containing 10 mol % acetic acid was added dropwise 37%
formaldehyde under continuous stirring. After 24 h, the
resulting solid products were separated magnetically and
washed several times with distilled water, DMF and ethanol
to remove impurities. It was presumed that the formation of
this nanocomposite included not only physical entrapment but
also chemical anchoring. TFR is an efficient polymeric chelate
to transition metal cations; therefore the polymer might anchor
onto the magnetite through coordination interactions between
the chelating groups in polymer chain and the nanoparticle
surface.
Scheme 1. Synthesis of Magnetic TFR Nanocomposites and
Proposed Crosslinking Mechanism
The surface morphology of magnetic TFR was observed by
scanning electron microscopy (SEM) as shown in Figure 2A. It
Solvent-induced swelling is usually essential to the use of a
polymer scavenger in purification operations, since this
promotes diffusion of reagents or impurities through the
material. The swelling property of TFR was measured by a
standard method10 and reported in percentage terms in Figure
1. Substantial swelling was observed in polar solvents such as
alcohols, water, and DMF, with relatively poor swelling in water
and low-polarity solvents. Since many reactions in drug
synthesis are carried out in polar solvents, but many
Figure 2. SEM and TEM images of magnetic TFR.
shows that the resin particles present regular surface
morphology of aggregates. Microstructural features of the
magnetic TFR were characterized by transmission electron
microscopy (TEM, Figure 2B). In this representative image, the
dark points are magnetite nanoparticles (average size around 25
nm) and the light gray domain is the polymeric matrix of TFR
(Figure 2B). The sample shows a typical nanostructure of an
inorganic−organic hybrid nanocomposite.
Thermogravimetric analysis (TGA) of magnetic TFR under
air atmosphere showed the main weight loss in the range of
215−345 °C, indicating thermal decomposition of TFR in that
Figure 1. Swelling behavior of TFR prepared in this work.
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range (Figure 3). Weight loss below 150 °C is assigned to the
removal of physically adsorbed water. Magnetite was found to
represent approximately 63% of the mass of the material.
benzaldehyde in methanol, revealing there to be approximately
0.82 mmol of available hydrazines per gram of resin.
Benzaldehyde and acetophenone were taken up with similar
time-course profiles by magnetic TFR (molar ratio of
hydrazino:carbonyl groups = 3:1), with scavenging of the
ketone occurring somewhat more slowly as expected.
Figure 3. Thermogravimetric analysis curve of magnetic TFR.
Figure 5. Kinetic profiles in the capture of representative aldehyde and
ketone.
The use of magnetic TFR as scavenger was first
demonstrated in the sequestration of aldehydes using 2-
hydroxy-5-phenylazo salicylaldehyde as a chromogenic reagent
(Figure 4). An orange solution of this reagent was decolorized
Regeneration12 of magnetic TFR was thought to be feasible
because thiosemicarbazides make less stable hydrazones than
do hydrazines. The trapping of 4-cyanobenzaldehyde by
magnetic TFR was followed by FTIR spectroscopy, monitoring
the characteristic CN absorption band around 2240 cm−1
(Figure 6A, B). The resin was then treated with 80% hydrazine
Figure 6. FTIR spectra of (A) fresh, (B) used, and (C) regenerated
scavengers.
Figure 4. Sequestration of 2-hydroxy-5-phenylazo salicylaldehyde (1
mmol in 15 mL solvents) by magnetic TFR (4.00 g) at 65 °C in
different stirred solvents.
monohydrate (5 equiv) in refluxed methanol for 8 h.
Quantitative removal of the aldehyde was shown by the
complete disappearance of the CN band (Figure 6C), and the
resulting resin was indistinguishable from freshly prepared
material in subsequent scavenging tests.
The use of magnetic TFR in the context of chemical
synthesis was illustrated with the three-component Petasis
borono−Mannich reaction involving a boronic acid, an amine,
and an aldehyde.13 Eight variations of the reaction were
performed; in each case, a 1.5-fold excess of salicylaldehyde was
used to ensure the consumption of the other substrates. Upon
completion of the reaction (as monitored by TLC), magnetic
TFR (3 equiv with respect to excess reagent) was added to
react with the excess salicylaldehyde, after which the resin was
magnetically separated and the resulting solution evaporated.
All of the reactions in this exercise were conducted on a scale of
with magnetic TFR in approximately 8 h in methanol. In
contrast, unsatisfactory results were obtained in toluene and
THF and intermediate scavenging rate was observed in
acetonitrile, reflecting the swelling properties of the resin.
Because no other semicarbazide-type scavenger has been
reported in the literatures, we compared this performance to
a known polymer-supported benzylhydrazine resin,11 which
required 24 h and a small amount of catalyst to remove the
same amount of aldehyde as sequestered by magnetic TFR
within 8 h in refluxing MeOH without any catalyst.
The loading capacity of accessible hydrazino groups in
magnetic TFR was determined by saturation with excess
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Technology Note
c
Table 1. Petasis Reaction among Salicylaldehyde, Secondary Amines,and Arylboronic Acids Using Magnetic TFR as Scavenger
a
b
c
Isolated yields. Purity was determined by HPLC. Reagents and conditions: amine (2 mmol), arylboronic acids (2 mmol), salicylaldehyde (3
mmol), magnetic TFR (3.65 g, 3 mmol), MeOH (5 mL), reflux.
2 mmol of substrates using 5 mL of solvent, and the results
obtained are summarized in Table 1. Yields were generally in
the 84−89% range, and the final products were found to be free
of aldehyde and essentially pure even in cases in which yields
were not so high. All of the products have been previously
such as carbonyl compounds, acid chloride and isothiocyanate,
and was illustrated with the Petasis reaction as a model. There
advantages of this new scavenger including facile preparation,
high loading capacity, low cost, and satisfactory swelling
properties in polar solvents.
1
reported and characterized by H and 13C NMR.
We also performed scavenging experiments using magnetic
TFR to sequester other representative electrophiles such as
benzoyl chloride and phenyl isothiocyanate from solution (1
mmol in 5 mL acetonitrile, respectively) monitored by GC
(Figure 7). At ambient temperature, when using three
EXPERIMENTAL PROCEDURES
■
Preparation of Magnetic TFR. To a stirred mechanically
suspension of Fe3O4 (50.00 g) in deionized water (500 mL)
was added thiosemicarbazide (27.30 g, 0.3 mol) and acetic acid
(1.80 g, 30 mmol). After the thiosemicarbazide was dissolved
completely, 37% aqueous solution of formaldehyde (72.98 g,
0.9 mol) was added dropwise under continuous stirring. The
mixture was then stirred at 40 °C for 24 h, while the black
precipitates were collected by a magnet, washed repeatedly with
deionized water (150 mL × 2) and ethanol (150 mL × 2),
successively, and dried in vacuo to give magnetic TFR (82.76
g).
Regeneration of Used Magnetic TFR with Hydrazine.
The label compound 4-cyano benzaldehyde (0.13 g, 1 mmol)
was captured onto magnetic TFR (3.65g, 3 equiv of hydrazino
groups to aldehyde) by refluxing in MeOH (5 mL) for 10 h,
followed by washing with ethanol (5 mL × 4). To regenerate
the used scavenger, the resin thus obtained was treated with
80% hydrazine hydrate (0.31 g, 5 mmol) in refluxed methanol
(5 mL) for 8 h. The resin was collected with magnet and
washed with ethanol until no species could be detected in the
washing. After dried in vacuo, the resin was characterized by
FTIR spectroscopy.
General Procedure for Scavenging Experiments:
Petasis Reaction. Various secondary amines (2 mmol) and
arylboronic acids (2 mmol) in methanol (5 mL) were
intentionally treated with an excess of salicylaldehyde (0.37 g,
3 mmol, 1.5 equiv). The mixture was stirred under refluxing for
13−20 h (Table 1) until the arylboronic acids were consumed
completely as monitored by TLC, after which magnetic TFR
(3.65 g, 3 mmol, at a molar ratio of hydrazino groups: excess
reagent 3:1) was added. The resulting suspension was stirred
for further 12 h. The scavenger was isolated using a magnet and
washed with methanol (5 mL × 2). The solvent in combined
filtrates was evaporated off under reduced pressure, and the
solid residue was washed with 1 mL of 30% aqueous EtOH to
Figure 7. Removal of acid chloride and isothiocyanate by magnetic
TFR.
equivalent of scavenger resin (hydrazino groups relative to
the excess electrophilic reagent), 99% of benzoyl chloride and
92% of phenyl isothiocyanate was sequestrated within 3 h. After
5 h, the isothiocyanate was no longer detectable in the mixture.
Magnetic TFR should also be a suitable scavenger for other
electrophiles such as sulfonyl halides and isocyanates. It should
be noted that, while the resin could be regenerated after
reaction with aldehydes and ketones, regeneration after loading
with acid chlorides or isocyanates gave unsatisfactory results.
In summary, we show here the synthesis and use of a
magnetically retrievable nanocomposite based on thiosemicar-
bazide−formaldehyde resin as nucleophilic scavenger for the
purification of solution-phase combinatorial libraries. Magnetic
TFR was found to be very efficient in trapping excess reagents
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Technology Note
(7) Rana, S.; White, P.; Bradley, M. Synthesis magnetic beads for
solid phase synthesis and reaction scavenging. Tetrahedron Lett. 1999,
40, 8137−8140.
(8) Kainz, Q. M.; Zeltner, M.; Rossier, M.; Stark, W. J.; Reiser, O.
Synthesis of Trisubstituted Ureas by a Multistep Sequence Utilizing
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polychelates: synthesis, characterization, and anti-bacterial activities
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remove possible impurities. After dried under vacuum, all of the
products were checked by HPLC and H NMR and were
essentially pure.
1
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00090.
(10) Kim, S. J.; Park, S. J.; Kim, S. I. Swelling behavior of
interpenetrating polymer network hydrogels composed of poly(vinyl
alcohol) and chitosan. React. Funct. Polym. 2003, 55, 53−59.
(11) Zhu, M.; Ruijter, E.; Wessjohann, L. A. New Scavenger Resin for
the Reversible Linking and Monoprotection of Functionalized
Aromatic Aldehydes. Org. Lett. 2004, 6, 3921−3924.
Detailed experimental procedures and analytical and
spectroscopic data for all compounds described (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +86-21-64252603. E-mail: yqpeng@ecust.edu.cn.
́ ́
(12) Guino, M.; Brule, E.; de Miguel, Y. R. Recycling and Reuse of a
Polymer-Supported Scavenger for Amine Sequestration. J. Comb.
Chem. 2003, 5, 161−165.
Notes
(13) (a) Petasis, N. A.; Akritopoulou, I. The boronic acid mannich
reaction: A new method for the synthesis of geometrically pure
allylamines. Tetrahedron Lett. 1993, 34, 583−586. (b) Candeias, N. R.;
Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Boronic Acids and
Esters in the Petasis−Borono Mannich Multicomponent Reaction.
Chem. Rev. 2010, 110, 6169−6193.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Key Project for Basic
Research (2010CB126101, The Ministry of Science and
Technology of China) is gratefully acknowledged.
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DOI: 10.1021/acscombsci.6b00090
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