Synthesis of bifunctional hydroxamic acids as novel ligands for the hydrophilic stabilization of iron oxide nanoparticles

Article abstract of DOI:10.1055/s-0029-1218654

A general method for synthesizing bifunctional hydroxamic acids containing carboxylic acid or amino functionalities is reported. Various products from simple alkyl to complex dendrimer-like structures are described. Such molecules have recently been used in ligand-exchange reactions for the hydrophilic stabilization of originally oleic acid protected iron oxide nanoparticles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218654

1150
PAPER
Synthesis of Bifunctional Hydroxamic Acids as Novel Ligands for the
Hydrophilic Stabilization of Iron Oxide Nanoparticles
Hydroxamic
Acid
n
B
ased
L
igan
d
ds for Stabilir4
z
ing Fe
e
O
Nanopa
a
3
Eckart Rühla
a
Physikalische Chemie, Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83852717; E-mail: ah79@chemie.fu-berlin.de; E-mail: cmgraf@chemie.fu-berlin.de
Department of Chemistry and Biochemistry, University of Arkansas, Dickson Street, Fayetteville, AR 72701, USA
b
Received 12 August 2009; revised 16 December 2009
group. The size of the ligands is an important parameter
for steric stabilization of nanoparticles, because bulky
ligands often exhibit a considerably higher stability of the
nanoparticle–ligand system.15,16 Therefore, it is necessary
Abstract: A general method for synthesizing bifunctional hydrox-
amic acids containing carboxylic acid or amino functionalities is re-
ported. Various products from simple alkyl to complex dendrimer-
like structures are described. Such molecules have recently been
used in ligand-exchange reactions for the hydrophilic stabilization to synthesize polar groups containing bulky hydroxamic
of originally oleic acid protected iron oxide nanoparticles.
acid ligands for the stabilization of nanoparticles as well
as model compounds of smaller size.6
Key words: protecting groups, hydroxamic acids, hydrogenation,
ethers, alkylations
We describe in this work a general synthetic route for the
preparation of alkanehydroxamic and arenecarbohydrox-
amic acids containing carboxylic 1, 2, and 3 or amino 4
end groups (Figure 1).
Hydroxamic acid derivatives possess a wide spectrum of
biological activity1 and are well known as chelating
ligands for metal ions.2 Extensive studies have shown that
the bond strength between Fe(II)/Fe(III) ions and hydrox-
amic acids greatly exceeds that between carboxylic acids
and iron ions because of the possibility of forming a five-
membered chelating ring, instead of the four-membered
rings or monodendate species formed in case of the car-
boxylic acid ligands.3,4 This enhanced bond strength could
also be observed with other isolated metal ions, such as
Co(II), Ni(II), Cu(II), and Zn(II) as well as on metal sur-
faces and self-assembled monolayers.2,3,5 As a conse-
quence, hydroxamic acid derivatives are particularly
suitable for functionalizing metal-containing complexes
as well as metal-containing nanoparticles.6 Moreover, the
use of hydroxamic acid ligands with additional functional
groups allows the introduction of new functional groups
into the ligand sphere of nanoparticles and permits alter-
ation of the solubility of nanoparticles in a controlled way.
This is especially interesting for the transfer of iron oxide
nanoparticles from nonpolar solvents into polar solvents.7
Most applications of iron oxide nanoparticles, such as
magnetic resonance tomography or hyperthermia treat-
ment, require water-dispersible systems.8–11 Such func-
tionalization involves the necessity of synthesizing
hydroxamic acid derivatives containing additional polar
functional groups, such as carboxylic acids or amines. In
spite of the potential applications of these compounds and
the well-known synthesis routes for normal hydroxamic
acids without additional functionalities,1,12–14 the synthe-
sis of bifunctional hydroxamic acids is often tedious be-
cause of the polarity and reactivity of the hydroxamic acid
(MEE)2N
O
N
O
O
R
8
OH
9
O
HO
O
O
N
H
O
NH
OH
O
N
R = CH2NH2⋅HCl 4
R = CO2H 2
N(MEE)2
O
N(MEE)2
O
O
HO
1
N
OH
H
10
OMe
MEE =
O
3
Figure 1 Bifunctional hydroxamic acid compounds as novel
ligands for iron oxide nanoparticles
The preparation of key intermediate compounds 6, 8, and
10 is shown in Scheme 1. Thus, 11-aminoundecanoic acid
(5) was reduced by lithium aluminum hydride and the re-
sulting primary alcohol was converted into the desired
alkyl bromide using concentrated hydrobromic acid, as
described by Niwa et al.17 After the introduction of the
Boc group, 6 was obtained in 5% overall yield. The ben-
zyl-protected carboxylic acid 8 was prepared from 11-
bromoundecanoic acid (7) in one step in 84% overall
yield.18
Compound 10 was prepared from benzylamine (9) in
three steps and in 49% overall yield. First, tosylated di-
ethylene glycol monomethyl ether19 was added to
SYNTHESIS 2010, No. 7, pp 1150–1158
Advanced online publication: 29.01.2010
DOI: 10.1055/s-0029-1218654; Art ID: T15909SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

PAPER
Hydroxamic Acid Based Ligands for Stabilizing Fe3O4 Nanoparticles
1151
benzylamine in a nucleophilic substitution reaction. Sub- ditions and no cleavage was observed. In the same way, an
sequently, the benzyl group was removed by palladium- ether linkage between 12 and 8 afforded product 15 in
catalyzed hydrogenolysis reaction at 1 bar.19 Finally, reac- 47% yield. Both protecting groups in compound 15,
tion of the resulting free amine and bromoacetyl bromide namely the benzyl group and the 4-methoxybenzyl group,
afforded 10, containing two amine-bound 2-(2-methoxy- could be removed in one step by hydrogenolysis at 1.5 bar
ethoxy)ethyl (MEE) groups.6
in tetrahydrofuran. Thus, the desired hydroxamic acid 2
was obtained in 22% overall yield starting from 11.
Br
O
The preparation of the more complex dendron-like struc-
1. LiAlH4, reflux
HO
tures 1 and 24 is shown in Scheme 3.
2. HBr 48%, reflux
3. Boc2O, THF
3,5-Dihydroxybenzoic acid (16) was esterified22 and alky-
lation with 1823 yielded monomer 19 (73%),6,24,25 from
which the methyl ester group was cleaved using sodium
hydroxide in methanol to give acid 20 (94%). The hydrox-
amic acid protecting benzyl group was introduced with O-
benzylhydroxylamine hydrochloride by using N-[3-(di-
methylamino)propyl]-N¢-ethylcarbodiimide hydrochloride
(EDCI) and 1-hydroxybenzotriazole (HOBt) as carboxyl-
ic acid activating agents. Optimization of this process led
to an improved procedure affording 21 in 86% yield by
using dichloromethane as solvent and N,N-diisopropyl-
ethylamine instead of triethylamine. The diamine hydro-
chloride salt 22 was obtained from Boc cleavage. Both
compounds 23 (14%) and 25 (27%) could be obtained in
one step by using 3.2 equivalents of 10. However, this
H
N
5%
H2N
Boc
5
6
OBn
O
O
BnOH, DMAP,
DCC, CH2Cl2
HO
Br
84%
Br
8
7
O
1. TsO-MEE (2 equiv)
BnNH2
Br
2. H2, Pd/C, MeOH
3. bromoacetyl bromide
N(MEE)2
9
10
49%
Scheme 1 Synthesis of the key intermediate compounds 6, 8, and 10
The long-chain carboxylic acid and amine containing ben- method required a tedious purification process. In con-
zenecarbohydroxamic acids 2 and 4 were prepared as trast, 23 could be synthesized from 22 in 56% yield, with-
shown in Scheme 2. Protection of 4-hydroxybenzoic acid out formation of 25, using excess 10 (5 equiv) and N,N-
(11)
using
O-(4-methoxybenzyl)hydroxylamine diisopropylethylamine instead of triethylamine. After
hydrochloride20 gave 12 in 58% yield. This product can be subsequent hydrogenolysis of 23 the final product 24 was
further functionalized in different ways. For the prepara- obtained in 91% yield. In order to obtain hydroxamic acid
tion of amine 4, an ether linkage between compound 12 1, compound 25 was treated with 26 in acetone under re-
and 6 was formed under highly basic conditions at pH fluxing conditions with sodium carbonate followed by
>12.21 After deprotecting of the amino group by hydro- palladium-catalyzed hydrogenolysis, which gave 1 in
chloric acid at room temperature, the 4-methoxybenzyl 67% yield. During the synthesis of 23 and 25, also a prod-
group was removed by hydrogenation to give 4 in 22% uct with two N,N-bis[2-(2-methoxyethoxy)ethyl]ethyl-
overall yield starting from 11. It should be pointed out that amide groups could be isolated. This compound can also
the 4-methoxybenzyl group was stable under acidic con- be used to prepare hydroxamic acid dendrons with two
O-(4-methoxy-
benzyl)hydroxyl-
amine hydro-
chloride
O
O
O
MeO
OH
OH
6, KOH
MeO
OR
DMSO
58%
O
NH
HO
O
NH
50%
O
12
11
13
R = H2C
N
H
O
8
HCl 37%
Et2O–
CH2Cl2
8, K2CO3
DMF
47%
HCl
NH2
O
85%
R =
14
H2C
8
O
OH
9
O
MeO
H2, Pd/C
THF
OR
H2, Pd/C, MeOH
91%
O
NH
81%
15
O
O
HCl
NH2
O
NH
OH
2
O
H2C
O
9
HO
NH
R =
8
4
Scheme 2 Synthesis of the carboxylic acid and amino containing arenecarbohydroxamic acids 2 and 4
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

1152
A. Hofmann et al.
PAPER
HO
OH
R
R
Boc
Boc
O
O
O
O
Boc
N
H
N
H
N
N
H
NH
H
18
O-benzylhydroxyl-
amine hydrochloride
EDCI, HOBt, i-Pr2NEt
Br
O
OR
K2CO3, DMF
O
NH
O
OR
86%
73%
R = H 16
OBn
R = Boc 21
H2SO4, MeOH
reflux
R = Me 19
R = H 20
HCl
NaOH 1 M
MeOH, 60 °C
94%
92%
CH2Cl2–
Et2O
R = Me 17
R = H
22
86%
N(MEE)2
N(MEE)2
Br
O
O
10
HN
O
HO
N
O
(MEE)2N
9
O
THF–H2O, Et3N
HO
Br
O
O
O
9
O
O
26
NaI, acetone
Na2CO3, reflux
27%
O
N(MEE)2
(MEE)2N
O
N
BnO NH
RO
NH
O
O
O
N
O
O
N
O
N
O
(MEE)2N
(MEE)2N
N(MEE)2
O
NH
(MEE)2N
O
O
N(MEE)2
N(MEE)2
OR
25
R = Bn 27
R = H
H2, Pd/C
MeOH
R = Bn 23
R = H 24
H2, Pd/C
MeOH
91%
1
67%
Scheme 3 Synthesis of the dendritic hydroxamic acids 1 and 24
carboxylic acid groups. In principle, dendritic hydroxam- For comparing arenecarbohydroxamic and alkanehydrox-
ic acids with up to four carboxylic acid groups are con- amic acids and investigating the general accessibility of
ceivable starting from 22.
the described synthetic method for preparing carboxylic
acid containing hydroxamic acids, 3 was prepared from
dodecanedioic acid (28) in five steps (Scheme 4).
Alternatively, the preparation of the hydroxamic acids 1
and 24 without using a benzyl-protected hydroxamic acid
derivative was also attempted. In this case, after the intro- Compound 28 was first converted into the corresponding
duction of 10, we simply tried to convert the aryl methyl dimethyl ester under acidic conditions followed by partial
ester (in 19) into the acid and subsequently to the hydrox- cleavage of the resulted dimethyl ester under basic condi-
amic acid group.6 However, even under relatively mild tions. The free carboxylic acid group was activated by
basic ester cleavage conditions using dilute sodium or EDCI and coupled with O-(4-methoxybenzyl)hydroxyl-
lithium hydroxide, the ester cleavage could only be per- amine hydrochloride for the introduction of the protected
formed in 25% yield. Moreover, after deprotection of the hydroxamic acid group. Subsequently, the remaining es-
aryl ester, 24 could be synthesized only with 21% yield ter group was hydrolyzed under basic conditions at 60 °C
by using hydroxylamine directly. In addition, the poor sol- in 90% yield. During deprotection of the hydroxylamine
ubility of the product and the presence of inseparable im- group in the last step by a palladium-catalyzed hydro-
purities impeded its purification. In the case of 1, we were genolysis reaction, a methyl ester group was generated,
not able to prepare the final product without using the ben- which could be cleaved by lithium hydroxide to give com-
zyl-protected hydroxamic acid.
pound 3 in 40% yield. The formation of an ester can be
avoided by performing the hydrogenolysis in tetrahydro-
furan or dioxane.
O
O
1. MeOH, H2SO4, reflux, 100%
2. KOH 1 M, 15%
O
O
In summary, we conclude that the two protecting groups
O-benzylhydroxylamine and O-(4-methoxybenzyl)hy-
droxylamine can be used as suitable and easily removable
groups for the protection of hydroxamic acids during the
integration of new reactive functionalities into hydroxam-
ic acid containing molecules.
HO
HO
OH
10
N
OH
3. O-(4-methoxybenzyl)-
H
10
hydroxylamine hydrochloride, 84%
4. KOH 1 M, 90%
5. H2, Pd/C, MeOH; LiOH, 36%
28
3
Scheme 4 Synthesis of the alkyl chain hydroxamic acid compound
3
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

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Hydroxamic Acid Based Ligands for Stabilizing Fe3O4 Nanoparticles
1153
a soln of 11-bromoundecan-1-amine hydrobromide (0.33 g, 1.0
mmol) and Et3N (0.5 mL) in THF–H2O (1:2, 7.5 mL) at 0 °C. The
mixture was stirred at r.t. for 20 h, Et2O (50 mL) was added, and the
product was washed with 0.5 M HCl (2 × 25 mL), H2O (25 mL),
and brine (25 mL). The solvent was dried and evaporated and the
product was purified by column chromatography (silica gel, hex-
ane–EtOAc, 1:0.05 to 1:0.11) to afford 6 (0.3 g, 88%) as a colorless
solid; mp 59–60 °C.
1H NMR (400 MHz, CDCl3): d = 4.50 (br, 1 H), 3.39 (t, J = 6.8 Hz,
2 H), 3.31–3.04 (m, 2 H), 1.87–1.80 (m, 2 H), 1.45–1.36 (m, 13 H),
1.29–1.20 (m, 12 H).
In conclusion, various bifunctionalized arenecarbohy-
droxamic and alkanehydroxamic acids with free carboxy-
lic acids and amino groups were prepared. These
molecules are highly suitable to be used as ligands for the
polar functionalization of iron oxide nanoparticles, since
they are able to replace even strong binding long chain
carboxylic acid ligands. This ligand exchange approach
has already been used by Kim et al. for methylated trieth-
ylene glycol capped hydroxamic acid based dendron
ligands.6 However, the ligands used in ref. 6 do not con-
tain reactive groups besides the hydroxamic acid group.
Hence, their use for the electrostatic stabilization of nano-
particles is restricted. In contrast, the novel dendron
ligands exhibit, in principle, an adjustable number of up to
four carboxylic acid functionalities. In this way, even
more polar ligands become available. In addition, the ad-
justable size of the different types of ligands presented in
this work permits controlled steric stabilization of nano-
particles and clusters. We selected molecules from simple
systems up to dendrimer-like structures to establish a uni-
versal approach of surface stabilization of nanoparticles
as well as metal complexes. The graded electrostatic sta-
bilization of iron oxide nanocrystals with these novel type
of ligands and the characterization and properties of the
obtained highly water-dispersible and biocompatible par-
ticles will be described in detail elsewhere.11
13C NMR (100 MHz, CDCl3): d = 155.9 (s), 78.9 (s), 40.6 (t), 34.0
(t), 32.8 (t), 30.0 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.2 (t), 28.7 (t), 28.4
(q, 3 C), 28.1 (t), 26.8 (t).
Benzyl 11-Bromoundecanoate (8)18
11-Bromoundecanoic acid (7, 5.0 g, 19 mmol) was mixed with an-
hyd CH2Cl2 (50 mL) under an argon atmosphere. Subsequently,
BnOH (2.03 g, 1.74 mL, 19 mmol) and DMAP (0.59 g, 4.8 mmol)
were added under stirring. To the stirred mixture a soln of DCC
(4.65 g, 23 mmol) in a small amount of CH2Cl2 was added slowly.
The reaction was left overnight and the product was filtered to re-
move the urea. The solvent was removed under reduced pressure
and the product was purified by column chromatography (CH2Cl2)
to afford 8 (5.63 g, 84%) as a colorless oil.18
1H NMR (400 MHz, CDCl3): d = 7.38–7.29 (m, 5 H), 5.11 (s, 2 H),
3.39 (t, J = 6.8 Hz, 2 H), 2.34 (t, J = 7.5 Hz, 2 H), 1.87–1.80 (m, 2
H), 1.67–1.60 (m, 2 H), 1.45–1.36 (m, 2 H), 1.34–1.23 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 173.5 (s), 136.1 (s), 128.5 (d, 2
C), 128.1 (d, 3 C), 65.9 (t), 34.2 (t), 33.9 (t), 32.7 (t), 29.3 (t), 29.2
(t), 29.1 (t), 29.0 (t), 28.7 (t), 28.1 (t), 24.9 (t).
The chemicals were purchased from Sigma-Aldrich, Alfa Aesar,
and ABCR and were used without purification. All solvents were
purified by distillation before use and dried according to standard
procedures where necessary. All reactions were carried out in a dry
argon atmosphere unless otherwise mentioned. Melting points are
determined by a Büchi 510 apparatus. NMR spectra were recorded
on a Jeol ECX 400 (100.62 MHz for 13C, 400.13 MHz for 1H) spec-
trometer. Chemical shifts are referenced to the residual proton or
carbon resonance of the deuterated solvent [CHCl3 d = 7.26 (1H) or
d = 77.00 (proton decoupled 13C)]. The samples were characterized
by ESI-TOF using an Agilent 6210 ESI-TOF, Agilent Technolo-
gies. The solvent flow rate was adjusted to 4 mL/min and the spray
voltage was set to 4 kV. The drying gas flow rate was set to 15 psi
(≈1 bar). All other parameters were adjusted for a maximum abun-
dance of [M + H]+, where M is the parent cation. Flash chromatog-
raphy was carried out using silica gel (43–60 mesh) purchased from
Fluka.
2-Bromo-N,N-bis[2-(2-methoxyethoxy)ethyl]acetamide (10)
BnNH2 (9, 9.00 g, 89.0 mmol) and K2CO3 (35 g, 254 mmol) were
dispersed in MeCN (85 mL). To this suspension was added drop-
wise a soln of TsO-MEE (50.7 g, 185 mmol) in MeCN (165 mL) at
r.t. When the addition was complete, the mixture was refluxed at 90
°C for 48 h. The suspension was filtered and the residue was washed
with CHCl3. The solvent was evaporated, the crude product was dis-
solved in 5% HCl (100 mL), and the side products were extracted
with Et2O (3 × 100 mL). Sat. NaHCO3 soln was added to the acidic
phase to change the pH value to 7–8. The product was extracted
with Et2O (5 × 75 mL). The solvent was dried and removed at re-
duced pressure to yield N,N-bis[2-(2-methoxyethoxy)ethyl]benzyl-
amine (26.7 g, 98%) as a yellowish oil.19
1H NMR (250 MHz, CDCl3): d = 7.32–7.20 (m, 5 H), 3.69 (s, 2 H),
3.58–3.46 (m, 12 H), 3.35 (s, 6 H), 2.75 (t, J = 6.4 Hz, 4 H).
tert-Butyl N-(2-bromoacetyl)carbamate (18),23 2-(2-methoxy-
ethoxy)ethyl 4-methylbenzenesulfonate TsO-MEE,19 and O-(4-
methoxybenzyl)hydroxylamine20 were prepared according to
known literature procedures.
A
mixture of N,N-bis[2-(2-methoxyethoxy)ethyl]benzylamine
(39.8 g, 128 mmol), Pd/C (10%) (2.00 g), and MeOH (50 mL) was
hydrogenated at r.t. at 1.5 bar H2 pressure for 24 h. Subsequently,
the mixture was centrifuged and filtered and the solvent was re-
moved. The mixture was dissolved in sat. NaHCO3 soln and extract-
ed with CHCl3 (5 ×). The combined organic fractions were dried
and the solvent was removed. The product was purified by distilla-
tion to afford bis[2-(2-methoxyethoxy)ethyl]amine (22.5 g, 80%) as
a colorless oil.19
tert-Butyl N-(11-Bromoundecyl)carbamate (6)
11-Aminoundecanoic acid (5, 3.74 g, 18.6 mmol) was added in
small portions to a stirred suspension of LiAlH4 (1.06 g, 27.9 mmol)
in anhyd THF (50 mL). The mixture was refluxed for 20 h, CHCl3
was added, and the mixture was washed with sat. NaHCO3. The or-
ganic phase was dried (Na2SO4), the solvent was removed, and the
product was purified by column chromatography (silica gel,
CHCl3–MeOH, 1:0 to 15:1) to afford 11-aminoundecan-1-ol (0.95
g, 27%) as a slightly yellowish solid. 11-Aminoundecan-1-ol (0.95
g, 5.0 mmol) was refluxed with concd HBr (48%, 15 mL) for 24 h.
The mixture was cooled to 0 °C and the precipitate was filtered and
purified by recrystallization (acetone) to give 11-bromoundecan-1-
amine hydrobromide (0.33 g, 20%) as a brown solid.17 A mixture of
Boc2O (0.44 g, 2.0 mmol) in THF (2.5 mL) was added dropwise to
1H NMR (250 MHz, CDCl3): d = 3.55–3.40 (m, 12 H), 3.28 (s, 6 H),
2.72 (t, J = 5.4 Hz, 4 H), 1.68 (br s, 1 H).
Bromoacetyl bromide (41.4 g, 205 mmol) was added dropwise to a
cooled soln (0 °C) of bis[2-(2-methoxyethoxy)ethyl]amine (22.4 g,
101 mmol) and Et3N (10.2 g, 101 mmol) in EtOAc (300 mL) over
90 min. When the addition was complete, the mixture was stirred at
0 °C for an additional 3 h and then at r.t. for 24 h. The reaction was
quenched by the addition of sat. NaHCO3 soln and the product was
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

1154
A. Hofmann et al.
PAPER
washed with H2O (3 × 50 mL) and brine. The crude product was pu-
rified by column chromatography (silica gel, EtOAc–CHCl3 to
CHCl3–EtOH, 5:0.2 to CHCl3–EtOH, 5:0.6) to give 10 (21.6, 62%)
as a yellowish oil; bp 138–140 °C/0.1 mbar.
1H NMR (400 MHz, CDCl3): d = 4.00 (s, 2 H), 3.63–3.58 (m, 6 H),
3.56–3.52 (m, 6 H), 3.48–3.44 (m, 4 H), 3.33 (s, 3 H), 3.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.7 (s), 71.7 (t), 71.6 (t), 70.6
(t), 70.3 (t), 68.9 (t), 68.7 (t), 58.9 (q), 58.8 (q), 49.9 (t), 46.7 (t), 27.1
(t).
4-(11-Aminoundecyloxy)-N-(4-methoxybenzyloxy)benzamide
Hydrochloride (14)
Concd HCl (37%, 0.4 mL) was added with stirring to a soln of car-
bamate 13 (65 mg, 0.12 mmol) in Et2O–CH2Cl2 (1:1, 4 mL). The
mixture was stirred at r.t. for a further 3 h. The solvent was removed
at reduced pressure and the resulting solid was suspended in Et2O
and filtered to afford 14 (49 mg, 85%) as a colorless solid; mp 166
°C (dec).
1H NMR (400 MHz, DMSO-d6): d = 11.67 (br s, 1 H), 8.07 (br s, 3
H), 7.76 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.01 (d,
J = 8.8 Hz, 2 H), 6.98 (d, J = 8.6 Hz, 2 H), 4.86 (s, 2 H), 4.03 (t,
J = 6.4 Hz, 2 H), 3.80 (s, 3 H), 2.81–2.70 (m, 2 H), 1.79–1.67 (m, 2
H), 1.63–1.53 (m, 2 H), 1.48–1.38 (m, 2 H), 1.38–1.23 (m, 12 H).
HRMS (+ESI): m/z [M + Na]+ calcd for C12H2479BrNNaO5:
364.0736; found: 364.0744; m/z [M
+
Na]+ calcd for
C12H2481BrNNaO5: 366.0715; found: 366.0723.
13C NMR (100 MHz, DMSO-d6): d = 164.5 (s), 161.8 (s), 159.8 (s),
131.2 (d, 2 C), 129.4 (d, 2 C), 128.5 (s), 124.8 (s), 114.6 (d, 2 C),
114.2 (d, 2 C), 77.1 (t), 68.2 (t), 55.6 (q), 39.2 (t), 29.5 (t), 29.4 (t),
29.36 (t), 29.28 (t), 29.1 (t, 2 C), 27.5 (t), 26.4 (t), 26.0 (t).
Anal. Calcd for C12H24BrNO5: C, 42.11; N, 4.09; H, 7.07. Found: C,
38.99; N, 3.78; H, 7.15.
4-Hydroxy-N-(4-methoxybenzyloxy)benzamide (12)
4-Hydroxybenzoic acid (11, 0.6 g, 4.34 mmol) was dissolved in an-
hyd DMF (10 mL) and the mixture was cooled to –10 °C. HOBt
(0.76 g, 5.64 mmol), EDCI (1.08 g, 5.64 mmol), O-(4-methoxyben-
zyl)hydroxylamine hydrochloride (0.99 g, 5.21 mmol), i-Pr2NEt
(3.75 mL, 21.7 mmol), and DMAP (0.01 g, 0.0868 mmol) were add-
ed at –10 °C with vigorous stirring and the mixture was stirred at r.t.
for 20 h. When the reaction was complete, the mixture was neutral-
ized with 1 M HCl, extracted with CH2Cl2, washed with brine, and
dried (Na2SO4). The crude product was purified by column chroma-
tography (CH2Cl2–MeOH, 50:1) to afford 12 (0.69 g, 58%) as a
white powder; mp 129–132 °C.
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.49 (d, J = 8.8 Hz, 2 H),
7.29 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.73 (d, J = 8.8
Hz, 2 H), 4.83 (s, 2 H), 3.73 (s, 3 H), 3.50 (br, 1 H).
13C NMR (100 MHz, CDCl3–CD3OD): d = 166.7 (s), 160.5 (s),
159.8 (s), 130.9 (d, 2 C), 128.9 (d, 2 C), 127.5 (s), 122.6 (s), 115.2
(d, 2 C), 113.7 (d, 2 C), 77.7 (t), 55.1 (q).
HRMS (+ESI): m/z [M – HCl + H]+ calcd for C26H39N2O4:
443.2910; found: 443.2911.
HRMS (–ESI): m/z [M – H]– calcd for C26H3835ClN2O4: 477.2520;
found: 477.2516.
Anal. Calcd for C26H39ClN2O4: C, 65.19; N, 5.85; H, 8.21. Found:
C, 64.26; N, 6.03; H, 8.29.
4-(11-Aminoundecyloxy)benzenecarbohydroxamic Acid Hy-
drochloride (4)
A mixture of benzamide hydrochloride 14 (40 mg, 83 mmol), MeOH
(6 mL), CHCl3 (3 mL), and Pd/C (20 mg) was hydrogenated for 3
h. When the reaction was complete, the catalyst was removed by
centrifugation and the organic phases were combined and evaporat-
ed to dryness. The solid was washed with CH2Cl2 to give 4 (27 mg,
91%) as a white solid.
IR (KBr): 3294 (m), 2921 (m), 2841 (m), 2730 (w), 1647 (s), 1608
(s), 1566 (m), 1506 (s), 1392 (m), 1306 (s), 1254 (s), 1165 (s), 1018
(s), 900 (m), 847 (s), 754 (m), 652 (m), 544 cm–1 (w).
1H NMR (400 MHz, DMSO-d6): d = 11.11 (br s, 1 H), 8.93 (br, 1
H), 7.76–7–94 (br, 3 H), 7.75 (d, J = 8.8 Hz, 2 H), 7.00 (d, J = 8.9
Hz, 2 H), 4.04 (t, J = 4.3 Hz, 2 H), 2.81–2.73 (m, 2 H), 1.76–1.71
(m, 2 H), 1.58–1.53 (m, 2 H), 1.45–1.25 (m, 14 H).
13C NMR (100 MHz, DMSO-d6): d = 164.9 (s), 161.8 (s), 129.5 (d,
2 C), 125.7 (d), 114.9 (d, 2 C), 68.5 (t), 39.7 (t), 29.9 (t), 29.8 (t),
29.73 (t), 29.66 (t), 29.47 (t), 29.44 (t), 27.9 (t), 26.7 (t), 26.4 (t).
HRMS (+ESI): m/z [M + Na]+ calcd for C15H15NNaO4: 296.0899;
found: 296.0891.
Anal. Calcd for C15H15NO4: C, 65.92; N, 5.13; H, 5.53. Found: C,
64.95; N, 6.07; H, 5.33.
tert-Butyl N-(11-{4-[(4-Methoxybenzyloxy)carbamoyl]phen-
oxy}undecyl)carbamate (13)
To a soln of KOH (0.23 g, 4.1 mmol) in DMSO (4 mL) was added
benzamide 12 (0.200 g, 0.732 mmol) and carbamate 6 (0.282 g,
0.805 mmol). The mixture was stirred for 2 h and quenched by ad-
dition of H2O (15 mL). The product was extracted with CH2Cl2
(3 × 25 mL) and EtOAc (2 × 25 mL). The combined organic frac-
tions were washed with brine (2 × 25 mL) and dried and the sol-
vents were removed at reduced pressure. Recrystallization (EtOAc)
gave 13 (0.20 g, 50%) as a colorless solid; mp 107–108 °C.
1H NMR (400 MHz, CDCl3): d = 9.12 (br s, 1 H), 7.65 (d, J = 8.8
Hz, 2 H), 7.32 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 6.7 Hz, 2 H), 6.83
(d, J = 6.9 Hz, 2 H), 4.91 (s, 2 H), 4.57 (br, 1 H), 3.93 (t, J = 6.5 Hz,
2 H), 3.77 (s, 3 H), 3.09–3.22 (m, 2 H), 1.78–1.71 (m, 2 H), 1.41 (s,
9 H), 1.48–1.20 (m, 16 H).
13C NMR (100 MHz, CDCl3): d = 166.0 (s), 162.0 (s), 159.8 (s),
156.0 (s), 130.9 (d, 2 C), 128.9 (d, 2 C), 127.5 (s), 123.9 (s), 114.2
(d, 2 C), 113.8 (d, 2 C), 78.9 (s), 77.7 (t), 68.1 (t), 55.2 (q), 40.5 (t),
30.0 (t), 29.4 (t, 2 C), 29.3 (t), 29.2 (t, 2 C), 29.0 (t), 28.3 (t, 3 C),
26.7 (t), 25.8 (t).
HRMS (+ESI): m/z [M + Na]+ calcd for C31H46N2NaO6: 565.3254;
found: 565.3234.
HRMS (+ESI): m/z [M – HCl + H]+ calcd for C18H31N2O3:
323.2335; found: 323.2352.
Benzyl 11-{4-[(4-Methoxybenzyloxy)carbamoyl]phenoxy}un-
decanoate (15)
Benzamide 12 (0.150 g, 0.549 mmol) and K2CO3 (0.390 mg, 2.86
mmol) were added to anhyd DMF (50 mL) and the mixture was
heated to 80 °C under stirring for 1 h. Undecanoate 8 (0.298 g, 0.803
mmol) in anhyd DMF (5 mL) was added slowly and the mixture was
stirred at 80 °C for 24 h. The precipitate was removed by hot filtra-
tion, H2O was added to the filtrate, and the product was extracted
with EtOAc. Purification by column chromatography (hexane–
EtOAc, 7:3 to 0:1) gave 15 (0.14 g, 47%) as a colorless solid; mp
106–107 °C.
1H NMR (400 MHz, CDCl3): d = 8.79 (s, 1 H), 7.64 (d, J = 8.8 Hz,
2 H), 7.39–7.27 (m, 7 H), 6.90–6.82 (m, 4 H), 5.09 (s, 2 H), 4.92 (s,
2 H), 3.94 (t, J = 6.5 Hz, 2 H), 3.16 (s, 3 H), 2.33 (t, J = 7.5 Hz, 2
H), 1.80–1.71 (m, 2 H), 1.68–1.56 (m, 2 H), 1.50–1.37 (m, 2 H),
1.36–1.18 (m, 10 H).
Anal. Calcd for C31H46N2O6: C, 68.61; N, 5.16; H, 8.54. Found: C,
68.55; N, 5.16; H, 8.71.
13C NMR (100 MHz, CDCl3): d = 173.7 (s), 166.2 (s), 162.1 (s),
159.9 (s), 136.0 (s), 131.0 (d, 2 C), 128.8 (d, 2 C), 128.5 (d, 2 C),
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

PAPER
Hydroxamic Acid Based Ligands for Stabilizing Fe3O4 Nanoparticles
1155
128.1 (d, 3 C), 127.4 (s), 123.8 (s), 114.3 (d, 2 C), 113.8 (d, 2 C),
77.8 (t), 68.1 (t), 66.0 (t), 55.2 (q), 34.2 (t), 29.3 (t), 29.24 (t), 29.20
(t), 29.1 (t), 29.0 (t, 2 C), 25.9 (t), 24.8 (t).
HRMS (+ESI): m/z [M + Na]+ calcd for C33H41NNaO6: 570.2832;
3,5-Bis[2-(tert-butoxycarbonylamino)ethoxy]benzoic Acid (20)
A 1.0 M NaOH soln (18 mL) was added to a soln of benzoate 19
(3.00 g, 6.60 mmol) in MeOH (22 mL) and the resulting mixture
was stirred at r.t. for 24 h and at 70 °C for 3 h. The solvent was re-
moved and the product dissolved in H2O (10 mL) and washed with
Et2O. After acidification with concd HCl (37%) to pH 2, the product
was extracted with EtOAc (3 × 50 mL), and the combined organic
fractions were washed with brine. The organic phase was dried
(Na2SO4) and the solvent was removed to give 20 (2.7 g, 94%) as a
colorless solid; mp 125–127 °C.
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.08 (d, J = 2.3 Hz, 2 H),
6.54 (t, J = 2.1 Hz, 1 H), 3.93 (t, J = 5.1 Hz, 4 H), 3.41 (t, J = 6.4
Hz, 4 H), 1.35 (s, 18 H).
13C NMR (100 MHz, CDCl3–CD3OD): d = 168.8 (s), 159.3 (s, 2 C),
156.2 (s, 2 C), 133.0 (s), 108.0 (d, 2 C), 106.1 (d), 19.6 (s, 2 C), 67.1
(t, 2 C), 39.6 (t, 2 C), 18.1 (q, 6 C).
found: 570.2835.
Anal. Calcd for C33H41NO6: C, 72.37; N, 2.56; H, 7.55. Found: C,
71.93; N, 2.62; H, 7.05.
11-[4-(Hydroxycarbamoyl)phenoxy]undecanoic Acid (2)
Pd/C (10%, 0.06 g) was added to a stirred soln of undecanoate 15
(70 mg, 0.13 mmol) in THF (5 mL) and the system was flushed with
H2. The mixture was stirred in a H2 atmosphere for 72 h at 1.5 bar.
The Pd/C was removed by centrifugation and the product was dis-
solved in THF and filtered through a syringe filter (PTFE, 0.2 mm).
Removal of the solvent under reduced pressure gave 2 (35 mg, 81%)
as a colorless solid; mp 135–137 °C.
IR (KBr): 3087 (m), 2923 (s), 2852 (s), 2770 (w), 1770 (w), 1693
(s), 1606 (s), 1577 (w), 1511 (w), 1427 (m), 1280 (m), 1253 (s),
1172 (m), 1014 (m), 946 (w), 854 (w), 777 (m), 642 cm–1 (m).
HRMS (+ESI): m/z [M + Na]+ calcd for C21H32N2NaO8: 463.2056;
found: 463.2062; m/z [2 M + Na]+ calcd for C42H64N4NaO16:
903.4215; found: 903.4222.
1H NMR (500 MHz, DMSO-d6): d = 12.25 (br, 1 H), 8.90 (br, 1 H),
7.74 (d, J = 8.7 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 4.06 (t, J = 6.5
Hz, 2 H), 3.50 (br, 1 H), 2.22 (t, J = 7.3 Hz, 2 H), 1.78–1.71 (m, 2
H), 1.55–1.48 (m, 2 H), 1.47–1.41 (m, 2 H), 1.38–1.20 (m, 10 H).
Anal. Calcd for C21H32N2O8: C, 57.26; N, 6.36; H, 7.32. Found: C,
56.46; N, 6.28; H, 7.31.
N-(Benzyloxy)-3,5-bis[2-(tert-butoxycarbonylami-
no)ethoxy]benzamide (21)
13C NMR (100 MHz, DMSO-d6): d = 175.4 (s), 165.0 (s), 161.9 (s),
129.5 (d, 2 C), 125.7 (s), 115.0 (d, 2 C), 68.6 (t), 34.6 (t), 29.9 (t),
29.8 (t), 29.6 (t, 2 C), 29.5 (t, 2 C), 26.4 (t), 25.4 (t).
HRMS (+ESI): m/z [M + Na]+ calcd for C18H27NNaO5: 360.1787;
found: 360.1747.
HRMS (–ESI): m/z [M – H]– calcd for C18H26NO5: 336.1811; found:
336.1823; m/z [2 M – H]– calcd for C36H53N2O10: 673.3700; found:
673.3712.
Benzoic acid 20 (3.00 g, 6.81 mmol) was dissolved in anhyd CH2Cl2
(50 mL) and cooled to 0 °C. HOBt (1.12 g, 8.44 mmol), EDCI (1.58
g, 8.15 mmol), O-benzylhydroxylamine hydrochloride (1.11 g, 6.95
mmol), and i-Pr2NEt (4 mL) were added to this soln and the mixture
was stirred at r.t. for 24 h. CH2Cl2 (50 mL) was added and the mix-
ture was washed with 1 M HCl and brine, and dried (Na2SO4). The
crude product was purified by column chromatography (CHCl3–
MeOH, 5:0.5) to afford 21 (3.20 g, 86%) as a colorless foam.
1H NMR (400 MHz, CDCl3): d = 9.64 (br s, 1 H), 7.43–7.40 (m, 2
H), 7.36–7.31 (m, 3 H), 6.84–6.81 (m, 2 H), 6.47–6.44 (m, 1 H),
5.12 (br s, 2 H), 5.00 (s, 2 H), 3.91 (t, J = 5.1 Hz, 4 H), 3.45–3.41
(m, 4 H), 1.42 (s, 18 H).
Anal. Calcd for C18H27NO5: C, 64.07; N, 4.15; H, 8.07. Found: C,
64.39; N, 4.08; H, 7.60.
Methyl 3,5-Dihydroxybenzoate (17)22
13C NMR (100 MHz, CDCl3): d = 159.6 (s, 2 C), 155.9 (s, 2 C),
135.3 (s), 134.0 (s), 129.1 (d, 2 C), 128.6 (d), 128.5 (d, 2 C), 105.8
(d, 2 C), 104.9 (d), 79.6 (t), 78.2 (s, 2 C), 67.1 (t, 2 C), 39.7 (t, 2 C),
28.3 (q, 6 C). (The C=O from the hydroxamic acid group could not
be observed.)
HRMS (+ESI): m/z [M + Na]+ calcd for C28H39N3NaO8: 568.2635;
found: 568.2653.
A soln of 3,5-dihydroxybenzoic acid (16, 30.0 g, 0.195 mol) and
concd H2SO4 (1.5 mL) in MeOH (150 mL) was refluxed at 68 °C
for 72 h. The solvent was removed under reduced pressure and the
crude product was dissolved in EtOAc (150 mL) and washed with
sat. NaHCO3 (2 × 50 mL), H2O (50 mL), and brine (3 × 50 mL).
The organic phase was dried (Na2SO4) and filtered. Removal of the
solvent at reduced pressure gave 17 (30.0 g, 92%) as a slightly yel-
lowish solid.
1H NMR (400 MHz, CDCl3): d = 6.91 (d, J = 2.3 Hz, 2 H), 6.46 (t,
J = 2.3 Hz, 1 H), 3.85 (s, 3 H).
3,5-Bis(2-aminoethoxy)-N-(benzyloxy)benzamide Dihydrochlo-
ride (22)
Concd HCl (37%, 4.5 mL) was added to a soln of carbamate 21
(3.20 g, 5.87 mmol) in Et2O–CH2Cl2 (1:1, 60 mL) and the mixture
was stirred at r.t. for 3 h. The solvent was removed at reduced pres-
sure and the product was washed with Et2O to give 22 (2.11 g, 86%)
as a colorless solid; mp 210 °C (dec).
1H NMR (400 MHz, D2O): d = 7.42–7.38 (m, 2 H), 7.37 (s, 1 H),
7.35–7.31 (m, 3 H), 4.89 (s, 2 H), 4.15 (t, J = 5.0 Hz, 4 H), 3.31 (t,
J = 4.8 Hz, 4 H).
13C NMR (100 MHz, D2O): d = 166.9 (s), 159.0 (s, 2 C), 134.6 (s),
133.1 (s), 130.1 (d, 2 C), 129.3 (d), 128.8 (d, 2 C), 106.5 (d, 2 C),
105.5 (d), 78.4 (d), 64.3 (t, 2 C), 38.9 (t, 2 C).
HRMS (+ESI): m/z [M – 2 HCl + H]+ calcd for C18H24N3O4:
346.1767; found: 346.1773.
Methyl 3,5-Bis[2-(tert-butoxycarbonylamino)ethoxy]benzoate
(19)25
A suspension of methyl 3,5-dihydroxybenzoate (17, 9.0 g, 54
mmol), tert-butyl N-(2-bromoacetyl)carbamate (18, 32.0 g, 143
mmol), and K2CO3 (40 g, 290 mmol) in anhyd DMF (100 mL) was
stirred at r.t. for 48 h. The precipitate was removed by filtration
through a glass filter frit and washed with EtOAc (3 × 80 mL). The
combined organic fractions were carefully washed with H2O
(5 × 75 mL) and brine (50 mL) and dried and the solvent was re-
moved under reduced pressure. Purification by column chromatog-
raphy (CHCl3–EtOAc, 5:0.3 to 5:1.5 to CHCl3–MeOH, 5:2) gave 19
(17.8 g, 73%) as a colorless solid.25
1H NMR (400 MHz, CDCl3): d = 7.17 (d, J = 2.3 Hz, 2 H), 6.61 (t,
J = 2.2 Hz, 1 H), 5.04 (br s, 2 H), 4.01 (t, J = 5.1 Hz, 4 H), 3.87 (s,
3 H), 3.54–3.48 (m, 4 H), 1.43 (s, 18 H).
Anal. Calcd for C18H25Cl2N3O4: C, 51.68; N, 10.05; H, 6.02. Found:
C, 53.39; N, 9.24; H, 6.01.
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

1156
A. Hofmann et al.
PAPER
N-(Benzyloxy)-3,5-bis{2-[bis(2-{bis[2-(2-methoxyethoxy)eth-
yl]amino}-2-oxoethyl)amino]ethoxy}benzamide (23) and N-
(Benzyloxy)-3-{2-[bis(2-{bis[2-(2-methoxyethoxy)ethyl]amino}-
2-oxoethyl)amino]ethoxy}-5-{2-[(2-{bis[2-(2-methoxy-
solved in CHCl3 (20 mL) and washed with NaHCO3 (1 × 10 mL)
and brine (1 × 10 mL). The solvent was removed to give 24 (0.59 g,
91%) as a slightly yellowish oil.
IR (film): 3246 (w), 2877 (s), 2821 (m), 2727 (w), 1651 (s), 1597
(m), 1456 (m), 1356 (m), 1304 (w), 1200 (m), 1115 (s), 1026 (m),
850 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 11.42 (br s, 1 H), 7.14 (d, J = 2.1
Hz, 2 H), 6.48 (t, J = 2.1 Hz, 1 H), 4.13 (t, J = 6.0 Hz, 4 H), 3.69 (s,
8 H), 3.60–3.50 (m, 48 H), 3.48–3.43 (m, 16 H), 3.31 (s, 12 H), 3.30
(s, 12 H), 3.06 (t, J = 6.0 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 171.1 (s, 4 C), 164.0 (s), 159.8 (s,
2 C), 132.6 (s), 106.2 (d), 105.1 (d, 2 C), 71.8 (t, 4 C), 71.7 (t, 4 C),
70.5 (t, 4 C), 70.1 (t, 4 C), 69.3 (t, 4 C), 69.2 (t, 4 C), 66.9 (t, 2 C),
58.9 (q, 8 C), 56.3 (t, 4 C), 52.7 (t, 2 C), 48.1 (t, 4 C), 46.2 (t, 4 C).
ethoxy)ethyl]amino}-2-oxoethyl)amino]ethoxy}benzamide (25)
Et3N (6.4 mL, 46 mmol) and acetamide 10 (5.09 g, 14.85 mmol, 3.2
equiv) were added slowly to a suspension of benzamide dihydro-
chloride 22 (1.94 g, 4.64 mmol, 1 equiv) in THF–H2O (40 mL:7
mL), and the resulting mixture was stirred at r.t. for 24 h. The sol-
vent was removed and the aqueous phase was extracted with CHCl3
(3 × 50 mL). The combined organic fractions were washed with
brine and dried (Na2SO4) and the solvent was removed at reduced
pressure. The crude product was separated by column chromatogra-
phy (silica gel, CHCl3–MeOH, 5:0.1 to 5:2) to afford the tetrasub-
stituted product 23 (0.91 g, 14%), the trisubstituted product 25 (1.40
g, 27%), the disubstituted product (0.32 g, 8%) and mixtures of dif-
ferent di-, tri- and tetrasubstituted products (2.18 g, 42%). The mix-
tures of the different substituted and the disubstituted products were
treated with excess acetamide 10 (4.5 equiv) using the same exper-
imental procedure described above. The crude product (2.5 g) was
purified by HPLC (CH2Cl2–MeOH, 91:9) to afford 23 (1.92 g, 37%)
as a colorless oil.
HRMS (+ESI): m/z [M + Na]+ calcd for C59H109N7NaO24:
1322.7422; found: 1322.7410; m/z [M
+
H]+ calcd for
C59H110N7O24: 1300.7602; found: 1300.7586; m/z [M + 2 Na]2+ cal-
cd for C59H109N7Na2O24: 672.8660; found: 672.8648.
Anal. Calcd for C59H109N7O24: C, 54.49; N, 7.54; H, 8.45. Found: C,
53.77; N, 7.20; H, 8.59.
11-({2-[3-(Benzyloxycarbamoyl)-5-{2-[bis(2-{bis[2-(2-methoxy-
ethoxy)ethyl]amino}-2-oxo-ethyl)amino]ethoxy}phenoxy]eth-
yl}(2-{bis[2-(2-methoxyethoxy)ethyl]amino}-2-
Tetrasubstituted product 23
1H NMR (400 MHz, CDCl3): d = 10.72 (br s, 1 H), 7.45–7.41 (m, 2
H), 7.34–7.27 (m, 3 H), 7.05 (d, J = 2.2 Hz, 2 H), 6.49 (t, J = 2.1 Hz,
1 H), 5.00 (s, 2 H), 4.11 (t, J = 5.8 Hz, 4 H), 3.68 (s, 8 H), 3.59–3.49
(m, 48 H), 3.45–3.42 (m, 16 H), 3.31 (s, 12 H), 3.28 (s, 12 H), 3.06
(t, J = 5.6 Hz, 4 H).
oxoethyl)amino)undecanoic Acid (27)
11-Bromoundecanoic acid (26, 0.56 g, 2.14 mmol), NaI (79.6 mg,
531 mmol), and Na2CO3 (225 mg, 2.14 mmol) were added to a soln
of benzamide 25 (0.600 g, 531 mmol) in acetone (10 mL) and the re-
sulting mixture was refluxed for 48 h. The solvent was removed and
the precipitate was dissolved in CHCl3 and washed with 1 M HCl
and brine. The solvent was removed and the product was purified
by column chromatography (CHCl3–MeOH, 5:0.3 to 5:2.5) to af-
ford 27 (185 mg, 27%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 10.69 (br, 1 H), 7.45–7.39 (m, 2
H), 7.36–7.24 (m, 3 H), 7.06 (m, 2 H), 6.48 (s, 1 H), 5.00 (s, 2 H),
4.11–3.99 (m, 4 H), 3.67 (s, 6 H), 3.57–3.40 (m, 48 H), 3.29 (s, 9
H), 3.26 (s, 9 H), 3.05–2.87 (m, 4 H), 2.59 (m, 2 H), 2.24 (t, J = 7.4
Hz, 2 H), 1.60–1.50 (m, 2 H), 1.48–1.39 (m, 2 H), 1.28–1.18 (m, 12
H).
13C NMR (100 MHz, CDCl3): d = 173.9 (s), 171.1 (s, 3 C), 165.1
(s), 159.7 (s, 2 C), 135.7 (s), 133.6 (s), 129.2 (d, 2 C), 128.4 (d),
128.3 (d, 2 C), 105.9 (d), 105.3 (d, 2 C), 77.9 (t), 71.8 (t, 3 C), 71.7
(t, 3 C), 70.4 (t, 3 C), 70.1 (t, 3 C), 69.2 (t, 6 C), 66.8 (t), 66.1 (t),
64.2 (t), 58.8 (q, 6 C), 56.3 (t, 3 C), 52.9 (t), 52.5 (t), 48.0 (t, 3 C),
46.1 (t, 3 C), 34.3 (t), 29.5 (t), 29.3 (t), 29.2 (t), 29.0 (t), 28.5 (t), 27.3
(t), 25.7 (t), 24.8 (t).
13C NMR (100 MHz, CDCl3): d = 171.0 (s, 4 C), 165.0 (s), 159.7 (s,
2 C), 135.7 (s), 133.7 (s), 129.2 (d, 2 C), 128.3 (d), 128.2 (d, 2 C),
105.8 (d), 105.4 (d, 2 C), 77.9 (t), 71.8 (t, 4 C), 71.7 (t, 4 C), 70.4 (t,
4 C), 70.1 (t, 4 C), 69.2 (t, 4 C), 69.1 (t, 4 C), 66.8 (t, 2 C), 58.8 (q,
8 C), 56.3 (t, 4 C), 52.9 (t, 2 C), 48.0 (t, 4 C), 46.1 (t, 4 C).
HRMS (+ESI): m/z [M + 2 H]2+ calcd for C66H117N7O24: 695.9075;
found: 695.9078; m/z [M + H + Na]2+ calcd for C66H116N7NaO24:
706.8985; found: 706.8987.
Anal. Calcd for C66H115N7O24: C, 57.00; N, 7.05; H, 8.34. Found: C,
55.88; N, 6.94; H, 8.40.
Trisubstituted product 25
1H NMR (400 MHz, CDCl3): d = 10.41 (br s, 1 H), 7.44–7.42 (m, 2
H), 7.36–7.30 (m, 3 H), 7.06–7.03 (m, 1 H), 6.99–6.97 (m, 1 H),
6.54 (t, J = 2.2 Hz, 1 H), 5.01 (s, 2 H), 4.12 (t, J = 5.9 Hz, 2 H), 4.05
(t, J = 5.2 Hz, 2 H), 3.68 (s, 4 H), 3.60–3.42 (m, 50 H), 3.35 (s, 3 H),
3.34 (s, 3 H), 3.32 (s, 6 H), 3.29 (s, 6 H), 3.05 (t, J = 5.9 Hz, 2 H),
2.95 (t, J = 5.2 Hz, 2 H), 2.38 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 171.3 (s), 171.2 (s), 171.0 (s),
165.2 (s), 160.0 (s), 159.8 (s), 135.8 (s), 133.8 (s), 129.4 (d, 2 C),
128.6 (d), 128.5 (d, 2 C), 106.3 (d), 106.2 (d), 105.3 (d), 78.0 (t),
71.8 (t, 3 C), 71.7 (t, 3 C), 70.5 (t), 70.4 (t, 2 C), 70.2 (t), 70.1 (t, 2
C), 69.2 (t, 2 C), 68.9 (t), 66.8 (t, 2 C), 58.9 (q, 6 C), 56.4 (t, 3 C),
56.3 (t), 55.5 (t, 2 C), 53.0 (t), 52.8 (t), 48.4 (t), 48.0 (t, 2 C), 46.3
(t), 46.1 (t, 2 C).
HRMS (+ESI): m/z [M + 2 H]2+ calcd for C65H114N6O21: 657.4018;
found: 657.4016.
3-{2-[Bis(2-{bis[2-(2-methoxyethoxy)ethyl]amino}-2-oxoeth-
yl)amino]ethoxy}-5-{2-[(2-{bis[2-(2-methoxyethoxy)ethyl]ami-
no}-2-oxoethyl)(11-hydroxy-11-oxo-undecyl)amino]eth-
oxy}benzenecarbohydroxamic Acid (1)
Undecanoic acid 27 (178 mg, 135 mmol) and Pd/C (25 mg) were dis-
persed in MeOH (6 mL) and hydrogenated for 72 h at 1.5 bar. The
solvent was removed by centrifugation to give 1 (110 mg, 67%) 1
as a slightly yellowish oil.
HRMS (+ESI): m/z [M + H]+ calcd for C54H93N6O19: 1129.6495;
found: 1129.6545.
Anal. Calcd for C54H92N6O19: C, 57.43; N, 7.44; H, 8.21. Found: C,
56.35; N, 6.78; H, 8.14.
IR (film): 3400 (w), 2931 (s), 2862 (m), 2725 (w), 1736 (w), 1654
(m), 1595 (m), 1456 (m), 1359 (w), 1105 (s), 849 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 11.56 (br s, 1 H), 9.13 (br s, 1 H),
7.19 (s, 2 H), 6.64 (s, 1 H), 5.04–4.63 (m, 4 H), 4.48 (s, 6 H), 3.92–
3.48 (m, 36 H), 3.48–3.40 (m, 14 H), 3.30 (s, 9 H), 3.27 (s, 3 H),
3,5-Bis{2-[bis(2-{bis[2-(2-methoxyethoxy)ethyl]amino}-2-oxo-
ethyl)amino]ethoxy}benzenecarbohydroxamic Acid (24)
Pd/C (10%, 0.1 g) was added to a stirred soln of benzamide 23 (0.70
g, 0.50 mmol) in MeOH (20 mL) and the system was flushed with
H2. The mixture was stirred in a H2 atmosphere for 48 h at 1.5 bar.
The Pd/C was removed by centrifugation and the product was dis-
Synthesis 2010, No. 7, 1150–1158 © Thieme Stuttgart · New York

PAPER
Hydroxamic Acid Based Ligands for Stabilizing Fe3O4 Nanoparticles
1157
3.26 (s, 6 H), 3.22–3.01 (m, 4 H), 2.25 (t, J = 7.4 Hz, 2 H), 1.87–
1.71 (m, 2 H), 1.60–1.47 (m, 2 H), 1.36–1.11 (m, 12 H).
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.25 (d, J = 8.4 Hz, 2 H),
6.81 (d, J = 8.4 Hz, 2 H), 4.72 (s, 2 H), 3.74 (s, 3 H), 2.90 (br, 1 H),
2.21 (t, J = 7.4 Hz, 2 H), 1.95 (t, J = 7.2 Hz, 2 H), 1.54–1.50 (m, 4
H), 1.26–1.19 (m, 12 H).
13C NMR (100 MHz, CDCl3–CD3OD): d = 176.8 (s), 171.5 (s),
159.9 (s), 131.0 (d, 2 C), 127.6 (s), 113.8 (d, 2 C), 77.6 (t), 55.3 (q),
34.1 (t), 33.1 (t), 29.3 (t, 2 C), 29.1 (t, 3 C), 29.0 (t), 25.4 (t), 24.9 (t).
13C NMR (100 MHz, CDCl3): d = 176.3 (s), 173.9 (s), 165.3 (s, 3
C), 158.4 (s, 2 C), 133.3 (s), 106.1 (d), 106.6 (d, 2 C), 71.7 (t, 6 C),
70.2 + 70.0 (t, 6 C), 68.9 + 68.4 (t, 6 C), 64.2 (t), 63.5 (t), 58.9 + 58.8
+ 58.6 (q, 6 C), 56.9 (t, 3 C), 55.7 (t), 55.1 (t), 53.1 (t), 48.6 + 48.4
+ 46.5 + 46.2 (t, 6 C), 34.0 (t), 29.6 (t), 29.3 (t), 29.2 (t), 29.0 (t),
28.6 (t), 28.5 (t), 25.9 (t), 24.5 (t).
HRMS (+ESI): m/z [M + H]+ calcd for C58H107N6O21: 1223.7489;
found: 1223.7508; m/z [M + Na]+ calcd for C58H106N6NaO21:
1245.7309; found: 1245.7324.
11-[(4-Methoxybenzyloxy)carbamoyl]undecanoic acid (0.51 g,
1.40 mmol), anhyd MeOH (6 mL), CHCl3 (3 mL), and Pd/C (50 mg)
were hydrogenated for 1 h. When the reaction was complete, the
catalyst was removed by centrifugation and the organic phases were
combined and evaporated to dryness to give a white solid (0.34 g,
96%). The solid (0.25 g, 1.02 mmol) was dissolved in i-PrOH–H2O
(2:1, 44 mL) and LiOH (0.3 g, 4.1 mmol, 56%) was added. The mix-
ture was stirred for 20 h and then acidified with HCl soln to pH 3,
extracted with EtOAc and dried (Na2SO4). The resulting solid was
recrystallized (CHCl3–MeOH) to afford 3 (90 mg, 38%) as a color-
less solid; mp 102–105 °C.
11-(Hydroxycarbamoyl)undecanoic Acid (3)
Dodecanedioic acid (28, 25.00 g, 108.55 mmol), MeOH (85 mL),
and H2SO4 (2 mL) were refluxed for 24 h. The mixture was cooled
to r.t. and the solvent was removed to give a colorless solid that was
dissolved in Et2O and poured into ice H2O for extraction. The aque-
ous phase was washed with Et2O (3 ×). The organic phases were
combined and washed with 10% NaHCO3 soln and brine and dried
(Na2SO4). Evaporation at reduced pressure gave dimethyl dode-
canedioate (27.63 g, 100%) as a colorless powder.26
IR (KBr): 3265 (w), 3070 (w), 2914 (s), 2848 (s), 2737 (w), 1700
(s), 1662 (s), 1620 (m), 1470 (s), 1425 (m), 1294 (m), 1215 (m),
1117 (m), 1078 (m), 1047 (m), 970 (m), 899 (m), 720 (m), 647 (m),
555 (m), 474 cm–1 (m).
1H NMR (400 MHz, DMSO-d6): d = 11.22 (br, 1 H), 8.67 (br, 1 H),
3.39 (br, 1 H), 2.20 (t, J = 7.4 Hz, 2 H), 1.94 (t, J = 7.3 Hz, 2 H),
1.53–1.44 (m, 4 H), 1.30–1.20 (m, 12 H).
13C NMR (100 MHz, DMSO-d6): d = 175.5 (s), 170.1 (s), 34.6 (t),
33.2 (t), 29.8 (t, 2 C), 29.7 (t, 2 C), 29.52 (t), 29.50 (t), 26.1 (t), 25.4
(t).
1H NMR (400 MHz, CDCl3): d = 3.63 (s, 6 H), 2.26 (t, J = 7.5 Hz,
4 H), 1.62–1.51 (m, 4 H), 1.35–1.20 (m, 12 H).
KOH (6 g, 106.92 mmol) and MeOH (130 mL) were combined in a
bottom flask. When the soln became fully clear, dimethyl dode-
canedioate (27.63 g, 106.96 mmol) was added and the mixture was
stirred for 4 h. Subsequently, the solvent was removed at reduced
pressure at 40 °C. The resulting solid was dissolved in Et2O and the
product was extracted with H2O. The aqueous phase was acidified
with concd HCl. Then the aqueous phase was extracted with Et2O
(4 × 75 mL) and the combined organic phases were washed with
brine and dried (Na2SO4). The solvent was removed under reduced
pressure to give a solid that was washed extensively with hexane.
The washings were combined and evaporated to give dodecanedioic
acid monomethyl ester (4.01 g, 15%) as a colorless powder.26
HRMS (+ESI): m/z [M + Na]+ calcd for C12H23NNaO4: 268.1525;
found: 268.1522.
Anal. Calcd for C14H27NO4·HCl: C, 54.27; N, 4.52; H, 9.11. Found:
C, 54.55; N, 5.11; H, 8.89.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 10.64 (br, 1 H), 3.65 (s, 3 H), 2.32
(t, J = 7.5 Hz, 2 H), 2.28 (t, J = 7.5 Hz, 2 H), 1.64–1.54 (m, 4 H),
1.34–1.21 (m, 12 H).
We acknowledge Dr. R. Zimmer (Freie Universität Berlin) for
helpful discussions and critical reading of the manuscript and
W. Münch (Freie Universität Berlin) for HPLC purifications. A.H.
acknowledges financial support by Stipendienfons of Fonds der
Chemischen Industrie and DAAD. This work was supported by
Deutsche Forschungsgemeinschaft (SFB 765, projects A4 and C5)
and Freie Universität Berlin (Priority Area ‘Nanoscale Functional
Materials’).
Dodecanedioic acid monomethyl ester (0.20 g, 0.82 mmol) was dis-
solved in anhyd CH2Cl2 (6 mL) and cooled to –10 °C. HOBt (0.13
g, 0.98 mmol), EDCI (0.19 g, 0.98 mmol), O-(4-methoxybenzyl)hy-
droxylamine hydrochloride (0.19 g, 0.98 mmol), and i-Pr2NEt (0.47
mL) were added to this soln. The mixture was stirred at r.t. for 6 h
and then it was extracted with H2O, acidified with HCl to pH 2,
washed with brine and dried (Na2SO4). The crude product was pu-
rified by column chromatography (CH2Cl2) to afford methyl 11-[(4-
methoxybenzyloxy)carbamoyl]undecanoate (0.26 g, 84%) as a col-
orless powder; mp 70–72 °C.
1H NMR (400 MHz, CDCl3–CD3OD): d = 7.25 (d, J = 7.4 Hz, 2 H),
6.82 (d, J = 8.4 Hz, 2 H), 4.74 (s, 2 H), 3.74 (s, 3 H), 3.59 (s, 3 H),
2.97 (br, 1 H), 2.23 (t, J = 7.5 Hz, 2 H), 1.96 (t, J = 7.2 Hz, 2 H),
1.55–1.50 (m, 4 H), 1.31–1.19 (m, 12 H).
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