Immobilized 1,2-bis(guanidinoalkyl)benzenes: Potentially useful for the purification of arsenic-polluted water

Article abstract of DOI:10.1055/s-0033-1338980

Guanidines can act as ligands for various organic and inorganic ions. We have previously synthesized polymer-supported aromatic bisguanidine derivatives and evaluated their potential for removing arsenic from polluted water. In this work, we designed and

Full text of DOI:10.1055/s-0033-1338980

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cIlmustemr obilized 1,2-Bis(guanidinoalkyl)benzenes: Potentially Useful for the Puri-
fication of Arsenic-Polluted Water
Immobilized 1,2-Bis(guanidinoalkyl)benzenes
Noriyuki Suzuki,*a Kaito Kishimoto,a Kohei Yamazaki,a Takuya Kumamoto,a Tsutomu Ishikawa,*a Davor Margetićb
a
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba
260-8675, Japan
Fax +81(43)2262919; E-mail: n-suzuki@chiba-u.jp; Fax +81(43)2262944; E-mail: benti@faculty.chiba-u.jp
b
Laboratory for Physical-Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruder Bošković Institute, Bijenicka c. 54,
10001 Zagreb, Croatia
Received: 11.09.2013; Accepted: 17.09.2013
ferent. Furthermore, the HypoGel resin-anchored BGBs 4
Abstract: Guanidines can act as ligands for various organic and in-
and 5 effectively coordinated metal salts (ZnCl2 and
organic ions. We have previously synthesized polymer-supported
CoCl2), as well as arsenic acid, in aqueous media. Thus,
immobilized bisguanidine base ligands might serve as
aromatic bisguanidine derivatives and evaluated their potential for
removing arsenic from polluted water. In this work, we designed
and synthesized the corresponding aliphatic bisguanidine deriva- useful recyclable scavengers for the removal of toxicants
tives, and we demonstrated that they show greater affinity for arse-
nic acid than do the previous aromatic ligands. The newly
synthesized HypoGel resin-anchored aliphatic bisguanidines might
7 containing a 1,2-bis(aminoalkyl)benzene core, the eval-
serve as useful recyclable scavengers for the removal of arsenic
from polluted water.
from polluted water. Here we describe the preparation of
the HypoGel resin-anchored aliphatic bisguanidines 6 and
uation of their relative affinities for arsenic acid, and their
comparison with the commercially available bicyclic gua-
nidine 8.
Key words: chelates, complexes, ligands, green chemistry, poly-
mers
We have previously reported that BGBs can serve as
Brønsted base ligands for arsenic acid. A Job plot ob-
tained from a 1H NMR spectroscopy experiment indicated
Contamination of drinking water by arsenic is a serious
that 1:1 complexes are formed in solution; however, X-
problem in Asia, particularly in Bangladesh. The source
ray crystallographic analysis and solid-state 13C NMR
of the arsenic is usually an inorganic acid, such as arsenic
acid (H3AsO4).1–4 Guanidines can act as powerful organo-
superbase catalysts in organic synthesis5,6 or as ligands ca-
pable of forming complexes with various cations or
anions.7 We are currently studying guanidine chemistry
with the aim of discovering practical applications,8 in-
cluding the decontamination of water containing toxic
substances.9–13 We previously examined the roles of 1,2-
diaminobenzene-based bisguanidinobenzenes (BGBs;
Figure 1), such as N,N′-bis(1,3-dimethylimidazolidin-2-
ylidene)benzene-1,2-diamine (1) and N′′,N′′′′′-1,2-
phenylenebis(N,N,N′,N′-tetramethylguanidine) (2) as aro-
matic bisguanidine-type Brønsted base ligands for arsenic
acid and phosphoric acid in solution and as solids.13 We
prepared the Merrifield resin-anchored BGB 3 and the
HypoGel resin-anchored BGBs 4 and 5 as polymer-sup-
ported host ligands and we investigated these immobi-
lized BGBs as potential solid scavengers for toxic metals
and for arsenic acid. The monomeric BGBs 1 and 2 acted
as Brønsted base ligands for arsenic acid, which has pKa
values of 2.25, 6.77, and 11.60 at 18 °C, and for phosphor-
ic acid, which has pKa values of 2.12, 7.21, and 12.67 at
25 °C,14 although the composition ratios of the base and
acid components in the solution and solid states were dif-
spectroscopy of the crystalline complexes indicated the
formation of 1:2 complexes between the BGBs and the ac-
id.13 Before attempting to prepare immobilized aliphatic
bisguanidines, such as the 1,2-bis(guanidinoalkyl)ben-
zenes (BGABs) 6 and 7, we assessed the basicity of the
monomeric model bisguanidine substrates. The absolute
proton affinities of aromatic BGB 1, aliphatic–aromatic
bisguanidine hybrid 9, and aliphatic BGAB 10 (Figure 2)
were calculated to be 254.3–262.8, 260.2–263.9, and
265.1–269.1 kcal/mol, respectively, suggesting that ali-
phatic BGAB 10 should be the strongest organosuper-
base.15 Immobilized BGABs 6 and 7 could therefore be
expected to act as effective basic ligands for acids, and
might be useful for purifying arsenic-polluted water.
Initially, we prepared the HypoGel resin-anchored
1,2-bis(aminomethyl)benzene-derived bisguanidine 6
(Scheme 1). Reduction of 4-bromophthalic anhydride
with diisobutylaluminum hydride (DIBAL-H) gave
the diol 11, which was smoothly converted into the
bromide 12 by treatment with phosphoryl tribromide.
Substitution with sodium azide, reduction with triphe-
nylphosphine, and refluxing with hydrochloric acid16
gave diamine 13, which was characterized as its hy-
drochloride after treatment with hydrogen chloride in
diethyl ether. Guanidinylation of diamine dihydro-
chloride 13 with 2-chloro-1,3-dimethylimidazolium
chloride (DMC)17 in the presence of triethylamine
gave the bromobisguanidine 14 in 86% yield. Re-
SYNLETT 2013, 24, 2510–2514
Advanced online publication: 14.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338980; Art ID: ST-2013-D0872-C
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Immobilized 1,2-Bis(guanidinoalkyl)benzenes
2511
O
Me
Me
Me
Me
Me
Me
N
N
R
R
N
N
N
N
R
R
N
N
N
N
N
N
N
N
N
Me
Me
1: R = (CH2)2
2: R = Me
3
8
O
O
5 O
5 O
Me
Me
Me
R
R
N
N
N
R
R
Me
Me
(CH2)n
(CH2)n
N
N
N
N
N
N
N
N
N
Me
Me
Me
4: R = (CH2)2
5: R = Me
6: n = 1
7: n = 2
Figure 1 Structures of guanidine base ligands 1–8
Me
Me
Me
N
N
N
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
1
9
10
Figure 2 Structures of bisguanidine substrates 1, 9, and 10 used for calculating the absolute proton affinities
placement of the bromine atom in 14 with acrylate un- reduction of the dicyanide 18. Although attempts at the di-
der Heck reaction conditions gave the 3,4- rect conversion of 18 into diamine 20 with lithium alumi-
bis(guanidinomethyl)cinnamate 15 as its dihexafluo- num hydride in the presence or absence of aluminum
rophosphate salt in 56% yield. We then attempted to chloride failed, treatment with a sodium borohydride–
prepare the alcohol 17 for use as a precursor of the im- nickel(II) chloride complex in the presence of di-tert-bu-
mobilized bisguanidine 6. Direct reduction of the cin- tyl dicarbonate19 gave the tert-butoxycarbonyl-protected
namate 15 with sodium borohydride in the presence of aminoethyl derivative 19 in 67% yield. The tert-butoxy-
poly(ethylene glycol) 30018 resulted in no reaction, carbonyl group was removed by stirring 19 with hydrogen
whereas the corresponding reaction with lithium alu- chloride in diethyl ether to give diamine 20, isolated as its
minum hydride gave a complex mixture. We therefore dihydrochloride salt in 93% yield. Other acids, such as tri-
adopted a stepwise approach in which hydrogenation fluoroacetic acid in dichloromethane, 10% sulfuric acid in
of cinnamate 15 over platinum oxide was followed by 1,4-dioxane, or 20% hydrochloric acid in 1,4-dioxane
hydride reduction with DIBAL-H to give the required gave unsatisfactory results. Diamine 20 was smoothly
alcohol 17. The HypoGel resin was introduced in N,N- converted into the 1,2-bis(guanidinoethyl)benzene deriv-
dimethylformamide for 90 hours with sonication to ative 21 by treatment with DMC; however, the product
give the immobilized BGAB 6. The loading was esti- was difficult to handle because of its high basicity. We
mated by elemental analysis to be 0.185 mmol/g.
therefore changed the synthetic route to introduce the gua-
nidinyl groups at a later stage.
Next, we attempted to prepare the 1,2-bis(guanidinoeth-
yl)benzene derivative 7, which contains a more flexible Treatment of the protected diamine 19 with methyl acry-
side chain, from the common dibromide precursor 12 by late under Heck conditions gave the cinnamate 22 in 92%
using the same synthetic procedure, with manipulation of yield. Cinnamate 22 underwent successive hydrogenation
the three-carbon tether for anchorage to the resin after the and hydride reduction with lithium aluminum hydride to
introduction of the guanidinyl functionality (Scheme 2). give the phenylpropanol derivative 24, which could also
The aminoethyl functionality was added to dibromide 12 be prepared directly from 22 by reduction with lithium
by substitution with sodium cyanide followed by hydride aluminum hydride. Treatment of phenylpropanol 24 with
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2510–2514

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N. Suzuki et al.
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hydrogen chloride in diethyl ether gave the deprotected prepared in this work showed the strongest complexation
bis(aminoethyl) phenylpropanol 25 as its crystalline hy- abilities, and BGAB 7, which contains a longer alkyl
drochloride salt. The guanidinyl functionality was intro- chain than 6, was the most efficient ligand for arsenic.
duced into alcohol 25 by treatment with DMC to give
diimine 26, which was immobilized on HypoGel resin by
treatment in N,N-dimethylformamide for 90 hours, with
sonication, to give the immobilized bisguanidine 7. The
loading of 7 was estimated by elemental analysis to be
0.185 mmol/g.
The affinities of HypoGel-anchored aliphatic BGABs 6
and 7 for arsenic acid were examined by means of our pre-
viously reported method.13 An aqueous mixture of the
BGAB and arsenic acid was stirred well with a glass rod
for 30 minutes. The insoluble polymer was collected by
centrifugation and washed successively with water and
methanol to give a pale-yellow powder, a small por-
tion(~2 mg) of which was treated with concentrated nitric
Figure 3 Comparison of the complexation abilities of PS-anchored
guanidine ligands for arsenic acid
acid to elute the bound arsenic. The concentration of arse-
nic liberated from each polymer was estimated by induc-
tively coupled plasma mass spectroscopy. The
In conclusion, aliphatic BGAB derivatives were designed
as more-effective ligands for arsenic acid, based on their
calculated basicities. HypoGel resin-anchored BABG de-
rivatives were prepared and their abilities to complex ar-
senic acid in aqueous medium were evaluated. Aliphatic
comparative complexation powers of PS-BGAB, Hypo-
Gel-anchored aromatic BGBs 4 and 5, and the Merrifield
resin-anchored bicyclic bisguanidine 8 are shown in Fig-
ure 3. As expected, the aliphatic BGABs 6 and 7 that were
Br
Br
Br
Br
2HCl
(b)
(a)
(c)
HO
OH
Br
Br
H2N
NH2
(d)
O
O
O
11
12
13
EtO2C
EtO2C
Br
2HPF6
(f)
(e)
Me
Me
Me
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
Me
16
(g)
15
14
O
HO
5
O
(b)
Me
Me
N
N
Me
Me
N
N
N
N
N
N
N
N
Me
Me
N
N
17
Me
Me
6
Scheme 1 Preparation of 1,2-bis(aminomethyl)benzene-derived bisguanidine 6. Reagents and conditions: (a) DIBAL-H, toluene, r.t., 1.5 h
(88%); (b) PBr3, Et2O, reflux, 7 h (95%); (c) (i) NaN3, 4:3:1 THF–EtOH–H2O, reflux, 1.5 h, (ii) PPh3, reflux, 0.5 h, (iii) concd aq HCl, reflux,
2 h, (iv) HCl, Et2O (88%), (d) DMC, Et3N, CH2Cl2, r.t., 8 h (86%); (e) (i) ethyl acrylate, PdCl2(PPh3)2, Et3N, DMF, 110 °C, 14 h, (ii) NH4PF6
(56%); (f) H2, 10% Pd/C, MeOH, r.t., 12 h (95%); (g) DIBAL-H, toluene–CH2Cl2, –40 °C, 12 h (65%); (h) NaH, HypoGel, DMF, r.t., 90 h,
sonication.
Synlett 2013, 24, 2510–2514
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Immobilized 1,2-Bis(guanidinoalkyl)benzenes
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Br
Br
Br
Br
(a)
(b)
(c)
2HCl
Br
Br
CN
CN
H2N
NH2
BocHN
NHBoc
12
18
19
20
(d)
(e)
MeO2C
BocHN
HO
CO2Me
Br
(f)
Me
Me
N
N
NHBoc
BocHN
NHBoc
N
N
23
22
N
N
Me
Me
21
(g)
(h)
HO
HO
2HCl
(j)
(i)
Me
N
Me
N
N
N
H2N
NH2
BocHN
NHBoc
24
25
N
N
Me
Me
26
O
(k)
5 O
Me
N
Me
N
N
N
N
N
Me
Me
7
Scheme 2 Preparation of the 1,2-bis(aminoethyl)benzene-derived bisguanidine 7. Reagents and conditions: (a) NaCN, EtOH, reflux, 0.5 h
(83%); (b) NaBH4, NiCl2·6H2O, Boc2O, MeOH, r.t., 8 h (95%); (c) HCl, Et2O, r.t., 8 h (93%); (d) DMC, Et3N, CH2Cl2, r.t., 1 d (85%); (e) methyl
acrylate, PdCl2(PPh3)2, Et3N, DMF, 110 °C, 39 h, sealed tube (92%); (f) H2, 10% Pd/C, MeOH, r.t., 1 d (96%); (g) LiAlH4, THF, r.t., 7 h (100%);
(h) LiAlH4, THF, r.t., 7 h (98%); (i) HCl, Et2O, r.t., 12 h (93%); (j) DMC, Et3N, CH2Cl2, r.t., 10 h (67%); (k) (i) NaH, DMF, r.t., 1 h: (ii)
HypoGel, r.t., 90 h, sonication.
BGABs might serve as useful recyclable scavengers for
removal of toxic arsenic from polluted water. However,
the effectiveness, selectivity, and recyclability of BGAB
derivatives for arsenic coordination, and their practical
applicability in decontamination of toxic water remain un-
clear. We are currently investigating these questions and
we expect to report our findings in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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Acknowledgment
The project was financially supported by JSPS Grants-in-Aid for
Scientific Research (C) (Grant No. 23590041). We thank Ms. M.
Fujinami for her experimental assistance.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2510–2514

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N. Suzuki et al.
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Synlett 2013, 24, 2510–2514
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