11B NMR Probes of Copper(II): Finding and Implications of the Cu2+-Promoted Decomposition of ortho-Carborane Derivatives

Article abstract of DOI:10.1002/ejic.201600117

The development of noninvasive methodologies for the detection of d-block metal ions such as copper (Cu²⁺), zinc (Zn²⁺), and manganese (Mn²⁺) is important for understanding their biological roles and relationship with diseases. We have been interested in the use of ¹¹B NMR probes for the detection of d-block metal ions, because ¹¹B is an ultratrace element in living systems. o-Carboranes, which consist of ten boron and two carbon atoms, have been applied to numerous drugs and biological active agents. In this work, we found that the o-carborane-pendant cyclens (L³-L⁵) (cyclen = 1,4,7,10-tetraazacyclododecane) are decomposed in the presence of Mn²⁺ or Cu²⁺ in aqueous solution at neutral pH, accompanied by the release of 4-9 equiv. of B(OH)₃. Furthermore, it was found that o-carborane derivatives that contain hydroxyl groups instead of a cyclen unit also undergo decomposition in the presence of Cu²⁺ and the corresponding complexes such as Cu(bpy) to afford 10 equiv. of B(OH)₃, as confirmed by ¹¹B NMR spectroscopic analysis and an azomethine-H assay. These reactions are applied to ¹¹B MRI (magnetic resonance imaging) probes for Cu²⁺.

Full text of DOI:10.1002/ejic.201600117

DOI: 10.1002/ejic.201600117
Full Paper
Boron NMR Probes
1
1
B NMR Probes of Copper(II): Finding and Implications of the
2
+
Cu -Promoted Decomposition of ortho-Carborane Derivatives
Tomohiro Tanaka, Yukiko Nishiura, Rikita Araki, Takaomi Saido, Ryo Abe, and
Shin Aoki*
[a]
[a]
[b]
[c]
[d]
[
a,e]
Abstract: The development of noninvasive methodologies for cyclododecane) are decomposed in the presence of Mn2+ or
2
+
2+
the detection of d-block metal ions such as copper (Cu ), zinc Cu in aqueous solution at neutral pH, accompanied by the
2
+
2+
(
Zn ), and manganese (Mn ) is important for understanding release of 4–9 equiv. of B(OH) . Furthermore, it was found that
3
their biological roles and relationship with diseases. We have o-carborane derivatives that contain hydroxyl groups instead of
11
been interested in the use of B NMR probes for the detection a cyclen unit also undergo decomposition in the presence of
of d-block metal ions, because 11B is an ultratrace element in Cu and the corresponding complexes such as Cu(bpy) to af-
2+
1
1
living systems. o-Carboranes, which consist of ten boron and ford 10 equiv. of B(OH) , as confirmed by B NMR spectroscopic
3
two carbon atoms, have been applied to numerous drugs and analysis and an azomethine-H assay. These reactions are
1
1
biological active agents. In this work, we found that the o- applied to B MRI (magnetic resonance imaging) probes for
3
5
2+
carborane-pendant cyclens (L –L ) (cyclen = 1,4,7,10-tetraaza- Cu .
Introduction
in terms of understanding their metabolism and roles in dis-
eases and pathological events.
[
9]
+
Biologically relevant d-block metals, including copper (Cu and
+
[10]
2+ [11]
A number of fluorescence-based probes for Cu ,
Cu ,
2
+
2+
2+
Cu ), zinc (Zn ), and manganese (Mn ), play important roles
2
+ [12]
2+ [13]
2+[14]
[15]
Mn ,
Zn ,
and Fe
have been reported to date.
[
1]
in the physiological processes of living organisms. For exam-
ple, copper functions as a required cofactor for many enzymes
such as tyrosinase, cytochrome c oxidase, and superoxide dis-
However, the fluorescence detection of these metal ions has
limitations in term of the impermeability of emission through
biological tissue. In contrast, magnetic resonance imaging (MRI)
is considered to be a powerful technique for the detection of
molecules and in the diagnosis of various diseases, because it
is noninvasive and capable of producing three-dimensional im-
ages of opaque organisms with a high spatial and temporal
[
2]
mutase. Current research indicates that the level of copper in
the blood circulation, cells, and tissues are closely related to
[
3]
[4]
many diseases such as Menkes syndrome, Willson's disease,
amyotrophic lateral sclerosis, and Alzheimer's disease.[6] In ad-
[
5]
2+
dition, high levels of Cu in the blood may induce cancer pro-
[
16]
resolution.
of metal ions has been much slower than that of fluorescent
Nevertheless, progress in developing MRI probes
gression. It was also reported that Mn2+ is associated with the
[
7]
[
8]
development of Parkinson's disease and Willson's disease.
3
+
sensors and they have mostly been limited to Gd -based con-
trast agents that are used to observe changes in H NMR sig-
Zn is known to be a crucial cofactor for Zn2+ enzymes and
2
+
1
2
+
Zn -containing proteins, and also functions as an intracellular
second messenger, especially in neurons. Thus, the develop-
ment of imaging probes for these d-block metals is important
[
17–21]
nals.
In this context, we have been interested in the possible use
of 11B NMR probes for the detection of d-block metal ions, be-
1
1
[22]
cause B is an ultratrace element in living systems. We previ-
[
a] Faculty of Pharmaceutical Sciences, Tokyo University of Science,
641 Yamazaki, Noda, Chiba 278-8510, Japan
1
ously reported on phenylboronic acid-pendant cyclen 1 (L ) for
2
the detection of d-block metals (cyclen = 1,4,7,10-tetraazacyclo-
E-mail: shinaoki@rs.noda.tus.ac.jp
http://www.rs.noda.tus.ac.jp/aokilab/
b] Bruker Biospin K. K.,
[
23,24]
1
dodecane).
The C–B bond of L is cleaved upon the forma-
[
[
[
[
1
tion of metal complex 2 (ML ) with d-block metals to give 3
ML ) and B(OH) in aqueous solution at neutral pH (Scheme 1).
3
-9 Kanagawa-ku Moriya-cho, Yokohama, 221-0022, Japan
c] Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute,
-1 Hirosawa, Wako, Saitama 351-0198, Japan
d] Research Institute for Biomedical Sciences, Tokyo University of Science,
641 Yamazaki, Noda 278-8510, Japan
2
(
3
Mechanistic studies strongly indicate that the cyclen unit of 1
2
forms stable complexes 2 with metal ions such as Zn , Cu+/2+,
2
+
Ni , Mn , and Co and produce a metal-bound OH– ion,
2
+
2+
3+
2
e] Imaging Frontier Center, Research Institute for Science and Technology,
which then attacks the boron atom to promote C–B bond cleav-
Tokyo University of Science,
2
age, resulting in the formation of 3 (ML ) and 1 equiv. of B(OH) .
3
2
641 Yamazaki, Noda 278-8510, Japan
1
1
Moreover, we succeeded in the in-cell B NMR detection of
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejic.201600117.
2
+
Zn in cultured Jurkat cells.
Eur. J. Inorg. Chem. 2016, 1819–1834
1819
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
As an extension to the aforementioned work, we turned our
1
1
attention to B NMR (MRI) probes having the o-carborane (1,2-
closo-dicarbadodecaborane) unit 4, which is comprised of ten
[
25]
boron and two carbon atoms.
o-Carborane derivatives have
been utilized as a hydrophobic pharmacophore, carbonic anhy-
[
26]
drase (CA) inhibitors
and nuclear receptor ligands such as a
[
27]
vitamin D receptor (VDR), androgen (AR) and estrogen recep-
tor (ER), and a retinoid receptor,[29] because of their remarka-
[
28]
[
30]
ble chemical and thermal stability.
have been proposed as potent agents for boron neutron cap-
Carborane analogues
[
31]
ture therapy (BNCT).
It has been reported that 4 undergoes
decomposition when treated with a Brønsted or Lewis base
such as hydroxide, alkoxide, amine, fluoride and carbene to give
the corresponding anionic nido-form 5 and 1 equiv. of B(OH)3
Scheme 1. Mechanism for the deboronation reaction of phenylboronic acid-
pendant cyclen 1 by complexation with metal ions.
[32]
(Scheme 2).
Although degradation of 5 has been reported
[
33]
under harsh conditions (acidic and high temperature),
it is
generally believed that 5 undergoes very little further degrada-
tion under physiological conditions (in aqueous solution at neu-
[
34]
tral pH).
In this article, we report on the design and synthesis of o-
3
5
carborane-pendant cyclens 6a–c (L –L ), in which an o-carbor-
ane unit is connected to cyclen through different linkers (C1–
C3), as shown in Scheme 3. We expected that 6a–c would form
3
5
metal complexes 7 (ML –ML ) with d-block metals, in which the
metal-bound OH– functions as a nucleophile to decompose
their carborane units to afford the corresponding nido-form 8
1
1
or a further decomposed species, resulting in B NMR spectral
changes.
During the experiments, we observed that 6a–c decompose
to the corresponding nido-forms 8 (metal complex) and 9
2
+
Scheme 2. Decomposition reaction of o-carborane 4 in the presence of Brøn-
sted or Lewis base.
(metal-free form) in both the presence and the absence of Zn ,
2+
2+
2+
2+
2+
2+
Co , Fe , Ni , Mn , Pb , and Ca in aqueous solution at
Scheme 3. Decomposition reaction of o-carborane-pendant cyclen 6a–c.
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1820
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
neutral pH. Interestingly, it was discovered that Cu2+ and Mn2+
accelerate the decomposition of nido-8 to release 4–9 equiv. of
11
B(OH) , as confirmed by B NMR measurements and azome-
3
thine-H assays. Furthermore, we observed that o-carboranes
possessing no cyclen unit 10 undergo complete decomposition
2
+
and release ten B(OH) in the presence of Cu (Scheme 4). The
3
2+
results of the ligand screening of Cu -mediated decomposition
of 10 suggest that Cu2 complexes with 2,2′-bipyridyl (bpy) and
ethylenediamine (en) units accelerate this reaction at pH 5–10.
+
1
1
Finally, applications of these findings to the B MRI detection
2
+
of Cu are also reported.
Scheme 4. Decomposition reaction of o-carborane derivative 10.
Results and Discussion
Scheme 5. Synthesis of o-carborane-pendant cyclen 6a–c.
Synthesis of o-/m-Carborane Derivatives
The synthesis of o-carborane-pendant cyclen containing the
C1–C3 linkers 6a–c was carried out as shown in Scheme 5. The
[
35]
tri-Boc-1,4,7,10-tetraazacyclododecane (12)
was alkylated
with 1-bromo-3-propyne (13a), 1-bromo-4-butyne (13b) and 1-
bromo-5-hexyne (13c) to give 14a–c, respectively. The reaction
[
36]
of 14a–c with decaborane (B H ) complex followed by the
1
0 14
deprotection of the Boc group with 4
N
HCl in 1,4-dioxane gave
3
5
6
a–c (L –L ) in moderate chemical yields.
[
37]
15,[38] and 16 were syn-
The o-carborane analogues 10,
thesized according to a reported method using tetrabutylam-
[
37]
monium fluoride (TBAF) and an aldehyde (Scheme 6). Debor-
onation reaction of 10 was achieved by treatment with sodium
methoxide in MeOH to afford nido-form 10′.[32i] The m-carbor-
ane 17 was treated with BuLi and paraformaldehyde in Et O to
2
[
38]
obtain 18 and 19, as previously reported.
Deboronation of
1
7 was performed according to reported methods to afford the
[
32e]
nido-m-carborane tetrabutylammonium salt 20.
Decomposition Reaction of o-Carborane-Pendant Cyclen
The decomposition of 6a–c in the presence of various d-block
2
+
2+
2+
2+
2+
2+
2+
metals (Mn , Fe , Co , Ni , Cu , Zn , and Cd ) was moni-
1
1
1
1
[39]
tored by B{ H} NMR ( H decoupled)
and azomethin-H as-
[
40]
11
1
says.
Figure 1 displays changes in the B{ H} NMR spectra
2
+
(
128 MHz) of 6b (10 m
M
) in the absence and presence of Zn ,
Co , Cu , and Mn (20 m ) in 0.5 HEPES buffer (pH 7)/D O
4:1) at 50 °C. After incubation for 96 h in the absence of a
2
+
2+
2+
M
M
2
(
1
1
metal ion, new B NMR signals corresponding to B(OH) (δ =
Scheme 6. Structure and synthetic scheme of carborane analogues.
3
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1821 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ca. 20 ppm) and the anionic nido-form 9 (δ = –10 to –40 ppm)
Figure 1) were observed (Figure 1, a and b). Similar spectral
(
2+
2+
changes were observed in the presence of Zn and Co , sug-
gesting that 1 equiv. of B(OH) and 8 was released (Figure 1, c
3
and d). Interestingly, stronger 1 B NMR signals for B(OH) were
1
3
observed in the presence of Cu2 and Mn (Figure 1, e and f),
albeit broad signals were observed in the case of with Mn .
+
2+
2
+
Figure 2. Results of azomethin-H assays of the decomposition reaction of 6b
2
+
(
10 mM) in the absence (cross) and presence of Zn (20 mM) (open squares),
2
+
2+
2+
Cu (20 m
closed squares) in 0.5
sorption spectra of azomethine-H in the presence of B(OH)
M) (closed circles), Co (20 m
M
) (open circles), and Mn (20 m
O (4:1) at 50 °C. UV/Vis ab-
and those meas-
M)
(
M
HEPES buffer (pH 7)/D
2
3
ured in the decomposition reaction of 6a are shown in Figure S2 and Fig-
ure S3 in the Supporting Information, respectively.
Figure 1. Change in 11B { H} NMR spectra (128 MHz) of 6b (10 m
1
M) in the
presence of d-block metals in 0.5
M HEPES buffer (pH 7)/D O (4:1) at 50 °C.
2
2+
2+
(
(
a) none, 0 h, (b) none, 96 h, (c) in the presence of Zn , 96 h, (d) Co , 96 h,
e) Cu2+, 180 h, and (f) Mn , 96 h ([metal ion] = 20 m
Et O in toluene was used as an external standard (see ref. and Figure S1
in the Supporting Information).
2+
M). A solution 10 %
[
39]
BF
3
2
The chemical yields of B(OH) released from 6b (10 m
M
) in
3
3
Figure 3. Chemical yields of B(OH) produced from 6b (10 mM) in the absence
HEPES (pH 7)/D O (4:1) at 50 °C in the absence and presence
2
or presence of CuSO , ZnSO , NiSO , MnSO , FeSO , Co(NO ) , CdSO ,
4
4
4
4
4
3 2
4
2
+
2+
2+
2+
of Cu , Mn , Co , and Zn (20 m
M
) were also determined
It was found that 8 and about
equiv. of B(OH) were released from one molecule of 6b after
Pb(NO
3
)
2
, and CaCl
2
(20 m
2
M) in 0.5 M HEPES buffer (pH 7)/D O (4:1) after
[
40]
incubation at 50 °C for 48 h (azomethine-H assay).
by azomethine-H assays.
4
3
incubation with CuSO or MnSO (20 m ) for 96 h (Figure 2). D O (4:1) at 50 °C are summarized in Figure 4. Although the
M
4
4
2
2
+
Furthermore, 9 equiv. of B(OH) was produced after incubation reactivity of 6c with Cu is somewhat lower than that of 6a
3
2
+
with Cu for 144 h. In contrast, only 1 equiv. of B(OH) was and 6b, all of the compounds decomposed to release 8–
released in the presence of Co and Zn . These results indi- 9 equiv. of B(OH) (Figure 4, a). On the other hand, the chemical
cate that Cu and Mn induce the decomposition of the o- yields of B(OH) released from 6a and 6b by Mn reached a
3
2+
2+
3
2
+
2+
2+
3
carborane unit of 6b to produce not only the corresponding plateau at 4–6 equiv. after a 96 h incubation. These results show
1
1
nido-form but also further decomposition products. As shown good agreement with the B NMR spectra as shown in Fig-
in Figure 3, the presence of Cu2 and Mn produces 4–9 equiv. ure S4 in the Supporting Information. Given that it was possible
+
2+
2+
2+
2+
of B(OH) , whereas other metals such as Zn and Co produce that Mn might be oxidized during the reaction, 10 equiv. of
3
less than 1 equiv.
DTT (dithiothreitol) and sodium ascorbate were added to the
The results of the reaction of 6a, 6b, and 6c (10 m
M
) with resulting mixture and the reaction was continued for 24 h. How-
2
+
2+
[41]
2
equiv. of Cu and Mn (20 m
M
) in 0.5
M
HEPES buffer (pH 7)/ ever, negligible acceleration was observed (data not shown).
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1822 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 4. Comparison of the decomposition reaction of 6a (open circles), 6b
open squares), and 6c (open triangles) with (a) Cu2+ and (b) Mn in 0.5
HEPES buffer (pH 7)/D O (4:1) at 50 °C (azomethine-H assay). [6] = 10 m
and [Cu2+ or Mn ] = 20 m
2+
M
(
2
M
2+
M.
Decomposition Reaction of o- and m-Carborane
Derivatives by Metal Ions
To examine the effect of the cyclen unit on the decomposition
reaction of 6a–c, o-carborane derivatives 10 and 11 (10 m
Figure 5. Change in 11B { H} NMR spectra (128 MHz) of 10 (10 mM) in 0.5
acetate buffer (pH 4)/DMSO/D O (3:5:2), 50 °C, after incubation for (a) 0 h
and (b) 96 h in the absence of Cu and after (c) 24 h, (d) 48 h, (e) 96 h, and
1
M
M
)
containing a hydroxymethyl group were treated with a selec-
tion of metals. Given that neutral pH (pH 7) was not appropriate
for following the reactions because of the formation of precipi-
tates, the reaction was carried out at pH 4. As shown in the
2
2
+
2
+
(
(
f) 108 h in the presence of Cu (20 mM), and after 96 h in the presence of
g) Pb , (h) Zn , (i) Co2+, and (j) Mn2+
2+
2+
.
1
1
B NMR spectra presented in Figure 5, the closo-form of 10
observed to occur in the presence of a catalytic amount of Cu2+
0.1 equiv.), although the reaction was slower than that in the
presence of 1–10 equiv. of Cu (Figure S5a in the Supporting
Information). The reaction rate at 37 °C was also slower than at
decomposes to give the nido-form 10′ and 1 equiv. of B(OH)3
(
after 96 h in the absence of metal (Figure 5, a and b). In con-
2
+
2
+
trast, Cu accelerates the decomposition of 10 to afford
1
1
1
0 equiv. of B(OH) (Figure 5, c–f). It should be noted that
B
3
signals of nido-form 10′ and B(OH) were observed in the
3
1
1
1
2+
B{ H} NMR spectra of the reaction mixture with Cu (Figure 5,
c–e).
The B NMR spectra recorded in the presence of Pb , Zn ,
Co , and Mn shown in Figure 5 (g–j) are almost identical to
that of nido-10′ (Figure 5, b). These data suggest that the o-
carborane unit in 10 initially decomposes to the corresponding
nido-form 10′ and that abstraction of the next boron atom may
trigger the complete decomposition of nido-10′.
1
1
2+
2+
2
+
2+
2
+
The effect of pH, the number of equivalents of Cu , and
reaction temperature was examined (the pH of each reaction
mixture was adjusted at 25 °C). As displayed in Figure 6, 9–
1
0 equiv. of B(OH) (900–1000 % yields based on 10) were re-
3
leased from 10 (10 m
for 48 h at pH 4–5, but only 4–6 equiv. of B(OH) were produced
at pH >6. Interestingly, the decomposition of 10 (10 m
M) after incubation with CuSO (10 mM)
4
Figure 6. The decomposition reaction of 10 (10 m
M) in the presence of CuSO
4
3
(closed circles) or Cu(bpy) (open circles) at 50 °C and various pH at 48 h
2
+
M
) was
([Cu or Cu(bpy)] = 10 m
M) (azomethine-H assay).
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1823
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5
0 °C, but ca. 10 equiv. of B(OH) were released after incubation previous hypothesis that the decomposition reaction of 10 pro-
3
for 96 h (Figure S5b in the Supporting Information). The results ceeds via the nido-form 10′.
using the Cu(bpy) complex (bpy = 2,2′-bipyridine) plotted with
The decomposition of various o-carborane derivatives (4, 10,
11, and 16) and m-carborane derivatives (17, 18, 19, and 20)
open circles are discussed below.
2+
2+
The effect of different Cu salts and other metal ions with Cu was also examined. As shown in Figure 8, more than
2
+
2+
2+
2+/3+
2+
2+
2+
(
10 m
M
) such as Zn , Ni , Mn , Fe
Pb on the decomposition of 10 (10 m
azomethin-H assay, is shown in Figure 7. The results imply that fered.
, Co , Cd , Ca , and 6 equiv. of B(OH) were released after incubation for 48 h from
M
3
2
+
), as followed by an each o-carborane derivative, although the reaction rates dif-
2
+
2+
2+
2+/3+
2+
2+
2+
Zn , Ni , Mn , Fe
, Co , Cd , and Ca do not cause
the decomposition of nido-10′, whereas Pb2 and Cu [CuSO4,
+
2+
Cu(NO ) , Cu(OAc) and Cu(ClO ) ] accelerate the decomposi-
3
2
2
4 2
tion of nido-10′ to release 4–10 equiv. of B(OH) . The decompo-
3
sition in the presence of CuI and CuI with sodium ascorbate
2
+
2+
was slower than with Cu . Interestingly, the addition of Cu
2+
2+
2+
to nido-10′, which had been produced by Zn , Ni , or Mn ,
permitted decomposition to restart. These data support our
Figure 8. Decomposition reaction of carborane derivatives. Each carborane
derivative (10 m ) was reacted in the presence of CuSO (10 m ) in 0.5
acetate buffer (pH 4)/DMSO (1:1 for 4, 10, 11, 19, and 20, 7:3 for 16 and 18,
M
4
M
M
6
:4 for 17) at 50 °C for 48 h (the reaction of decaborane was conducted for
2
4 h) (azomethine-H assay).
On the other hand, the decomposition of the m-carborane
derivatives (17, 18, 19, and 20) after 48 h was negligible. In
comparison, decaborane (B H ) (10 m ) in 0.5 acetate
M
M
1
0 14
buffer (pH 4)/dimethyl sulfoxide (DMSO) (1:1) completely de-
composed to give 10 equiv. of B(OH) after incubation with and
3
2
+
without Cu (10 mM) at 50 °C for 24 h (Figure 8 and Figure S6
in the Supporting Information), as previously reported.
[
42]
Effect of Ligands and Additives on Decomposition
Reactions of 10
2
+
The effect of chelators on the Cu -induced decomposition of
0 was examined. We used several copper ligands such as 2,2′-
1
6
bipyridine (bpy) 21 (L ), 6,6′-bis(hydroxymethyl)-2,2′-bipyridine
7
[43]
[6,6′-bis(hydroxymethyl)bpy] 22 (L ),
1,10-phenanthroline
8
9
Figure 7. Effect of metal cations on the decomposition reaction of 10 (10 m
with 2.0 equiv. of CuSO , Cu(NO , Cu(OAc) , Cu(ClO , CuI (with or without
a reducing agent), FeCl , CaCl , and Pb(NO (20 m ) in 0.5 acetate buffer
pH 4)/DMSO/D O (3:5:2), 2.0 equiv. of ZnSO , NiSO , MnSO , FeCl , Co(NO
and CdSO (20 m ) in 0.5 acetate buffer (pH 4)/DMSO (1:1) at 48 h (black
bar) ([metal salts] = 20 m ) then 1.0 equiv. of CuSO was added (white bar)
azomethine-H assay). NaAsc refers to sodium ascorbate.
M)
(phen) 23 (L ), N,N′-dimethylethylendiamine (DMEDA) 24 (L )
and N,N,N′,N′-tetramethylethylenediamine (TMEDA) 25 (L ),
N,N,N′,N′-tetramethylpropane-1,3-diamine (TMPDA) 26 (L ), 8-
quinolinol 27 (L ), histamine 28 (L ), iminodiacetic acid 29
10
4
3
)
2
2
4
)
2
3
2
3
)
2
M
M
11
(
2
4
4
4
2
3 2
) ,
1
2
13
4
M
M
1
4
15
2+
(L ), cyclen 30 (L ), bis(Zn -cyclen) containing a bpy linker
M
4
1
6
16
(
31 (Zn L ), and 4:4:4 supramolecular catalyst 32 {(Zn L ) -
2
2
4
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1824
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
–
12+
6
(
CA ) -[Cu (OH) ] } , which was previously reported to func- in Figure 9a, Cu(bpy) (CuL ), Cu[6,6′-bis(hydroxymethyl)bpy]
4
2
2 4
[
44]
7
8
9
10
tion as an artificial phosphatase
(Scheme 7). As summarized (CuL ), Cu(phen) (CuL ), Cu(DMEDA) (CuL ), Cu(TMEDA) (CuL ),
1
1
12
Cu(TMPDA) (CuL ), Cu[H (8-HQ)] (CuH L ), Cu(histamine)
CuL ), Cu(ZnL ), and 32 gave almost the same or better yields
than ligand-free Cu in 0.5
whereas the Cu(imino diacetic acid) [Cu(H L )] and Cu -cy-
clen complex (CuL ) showed lower activity. It should also be
reiterated that the decomposition of 10 proceeds at pH 5–10
in the presence of a Cu(bpy) complex (Figure 6, open circles).
These results could be explained by higher Lewis acidity of Cu
in these complexes than that of ligand-free Cu .
–1
–1
1
3
16
(
2
+
M HEPES (pH 7)/DMSO (1:1),
1
4
2+
–2
1
5
2+
2
+ [24a–24d]
Figure 9. Effect of metal ligands on the decomposition reaction of 10 (10 mM)
in the presence of (a) CuSO
10 m ) listed in Scheme 7 in 0.5
H assay). In (b), L was treated with CuSO
0.5 HEPES (pH 7)/D O (4:1) at 50 °C (after reaction for 48 h).
4
(10 m
M
) or (b) MnSO
HEPES (pH 7)/DMSO (1:1) (azomethine-
(20 m ) or MnSO (20 m ) in
4
(10 mM) with metal ligands
(
M
M
4
4
M
4
M
Scheme 7. Structures of various ligands and additives.
M
2
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1825
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
On the other hand, these ligands improved the reactivity of 6a–c were constructed from the corresponding alkyne in the
2
+
of Mn very little (Figure 9, b). These data indicate that the synthesis of intermediates 13a–c (Scheme 5). Based on this as-
decomposition of 6a–c proceeds only in an intramolecular sumption, it was assumed that 16 would not undergo complete
2+
manner (through complexation with Mn ) rather than by an decomposition and that the reaction would stop at some inter-
intermolecular mechanism. mediates, because these cyclic alkyne products would not be
The effect of the stoichiometry between Cu and ligands formed due to their highly strained structures. However, 16 un-
2+
6
7
10
12
including 21 (L ), 22 (L ), 25 (L ), and 27 (L ) on the decompo- derwent nearly complete decomposition, as shown in Figure 8,
sition of 10 was also assessed. As shown in Figure S7 in the suggesting that the intermediates or final products of the sub-
Supporting Information, the decomposition of 10 (10 m
M
) by strates are not alkynes such as 33. Based on these results, fur-
2
+
Cu (10 m
equiv. of 21 (L ), 22 (L ), and 27 (L ), whereas the addition ing.
of 2 equiv. of these ligands resulted in lower yields. On the Hawthorne and co-workers reported that the anionic nido-
other hand, the loss of activity was only slightly improved by carborane 5 is oxidized by FeCl and, when reacted with a Lewis
M
) was accelerated in the presence of 0.5 and ther characterization study of decomposition product is ongo-
6
7
12
1
3
7
7
2
2 (L ), which likely forms a 1:1 CuL complex, due to the steric base such as pyridine and tetrahydrofuran, gives the charge-
effect of the substituent at the 6- and 6′-positions. Additionally, compensated derivatives 35a and 35b (Scheme 9), respec-
1
0
2+
[46a]
2
2
5 (L ) had little effect on the reactivity of Cu , even when tively.
In addition, they reported that 5 reacts with FeCl in
3
[
33a]
equiv. was used. These data indicate that a 1:1 complex would water and completely decomposes
and that the oxidation
be more active for the decomposition of o-carborane than a of 5 by FeCl under acidic conditions gives the neutral nido-
3
[
46b]
2:1 complex.
carborane 36.
The results of a recent mechanistic study con-
The effect of oxidants and the reaction product [B(OH) ] on cluded that these reactions proceed via the unstable intermedi-
3
[
47]
the decomposition of 10 was also examined. As summarized in ate 34. On the other hand, Kudinov and co-workers reported
Figure S8 in the Supporting Information, the catalytic activity on the oxidative reaction of 5 with NMe
using CuSO
in a two-
3
4
6
of Cu(bpy) (10 m
M
, CuL ) was not inhibited in the presence of phase system of CH
2
Cl
2
and aqueous NH
3
solution to afford the
[
45]
2+
an excess amount (10 equiv.) of B(OH) and glycerol in trap- charge-compensated compound 37, suggesting that Cu is ca-
3
3+ [46c]
ping the B(OH) produced by the decomposition of 10, sug- pable of oxidizing 5 under basic conditions, unlike Fe .
3
gesting that inhibition by B(OH) is negligible. The addition of Plešek and co-workers reported that 5 is converted into the
3
the weak oxidant TBHP had no effect on decomposition rate, nido-carborane dimer 38a and 38b in the presence of a strong
[
46d]
despite the fact that the strong oxidant H O strongly inhibits oxidant such as chromic acid.
2
2
the decomposition of 10, suggesting that a redox reaction is
involved in the decomposition of o-carboranes.
Mechanistic Studies of the Decomposition Reaction of o-
Carborane Derivatives
We initially assumed that the products of the full decomposi-
tion of 10 would be alkyne derivatives, resulting from the loss
of 10 boron atoms (Scheme 8), because the o-carborane units
Scheme 9. Reported oxidation reaction of 5 with metal ions.
In our experiments described above, the formation of a
0
Scheme 8. Our initial assumption for the product of decomposition reaction.
brownish metal-like material, possibly Cu or an alloy, was ob-
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1826
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
served (ca. 70–80 % of the copper was recovered based on the Supporting Information). On the other hand, the oxidation po-
0
2+
2+
calculation as Cu , see Figure S9 in the Supporting Information). tentials of Mn (0.45 V) and Zn (–0.97 V) are more negative
2+
We therefore hypothesized that Cu likely functions as an oxi- than those for the nido-o-carborane derivatives (Figure S11 in
dant in the decomposition of o-carboranes (namely, Cu is re- the Supporting Information), suggesting that these metals are
duced to Cu or Cu ). To obtain evidence for this hypothesis, not capable of oxidizing the nido-form. The results shown in
the redox potentials of 4, 5, 10′, 20, and CuL were measured Figure 10f implies that the nido-m-carborane 20, which is not
2
+
+
0
6
2
+
by cyclic voltammetry. As shown in Figure 10b, 5 (nido-form) decomposed by Cu , has a more positive oxidation potential
exhibits two irreversible oxidation peaks at 0.57 and 0.87 V vs. (0.98 V) than that of 5, suggesting that a relationship exists
2
+
Ag/AgCl, corresponding to the two-electron oxidation of the between oxidation potential and the Cu -induced decomposi-
nido-anion, whereas 4 (closo-form) undergoes negligible levels tion reaction.
[
48a,48b]
of oxidation (Figure 10, a).
ation peaks correspond to an oxidative ring-closure reaction and nido-forms of o-carborane (Figure S12 in the Supporting
5→34 in Figure S10 in the Supporting Information) and further Information), a reaction mechanism is proposed, as shown in
oxidation reaction of the nido-anion, respectively. The C-mono- Scheme 10. Initially, the closo-form 39 is deboronated by a nu-
We assumed that these oxid-
Based on these results and on DFT calculations of the closo-
(
–
–
–
alkyl-substituted nido-carborane derivative 10′ shows two irre- cleophile such as OH (metal-bound OH or OH ) and OMe at
versible oxidation peaks at 0.51 and 0.83 V (Figure 10, c).
The oxidation potentials of (CuL ) (Figure 10, d, 0.67 V)
and Fe (Figure 10, e, 0.76 V) are more positive than the first and undergoes a ring-closure reaction to produce the closo-
oxidation peak of the nido-o-carborane derivatives (0.57 V for form 41,
and 0.51 V for 10′), suggesting that Cu is capable of oxidiz- product has yet to be studied. The B2 atom of 41 is attacked
2
[
48b]
the electron positive B3 or B6 to afford the nido-form 40. The
latter is then oxidized by Cu at the electronegative B10 of 40
6
2+
[48c]
2+
3
+
[
47]
although the isolation and characterization of this
2+
[49]
5
–
ing nido-C B H
to produce neutral closo-5,6-C B H (34), by H O to produce the transient state 42, which decomposes
2
9
12
2 8 12
2
3
+
–
similar to Fe . Given that the oxidation potential of 34 (0.87 V) in the presence of OH to generate 9 equiv. of B(OH) and other
3
is more positive than Cu2 (0.5–0.8 V), the next oxidation is products.
+
very slow and the further oxidation of 34 is negligible (see the
Scheme 10. Proposed mechanism for the decomposition reaction (arrows
indicate positively charged boron atoms, which are susceptible to attack by
–
H
2
O or OH ).
Detection of Cu with 11B MRI Based on Decomposition
II
Figure 10. Cyclic voltammograms of (a) 4 (closo-form) (10 m
form) (1 m ), (c) 10′ (nido-form) (1 m ), (e) FeCl
), (d) CuL6 (1 m
and (f) 20 (nido-m-carborane) (1 m ) recorded in DMF solutions of tetrabutyl-
ammonium hexafluorophosphate (0.1 ) on a glassy carbon electrode
0.1 mV s–1) starting on reduction (potentials vs. Ag/AgCl).
M
), (b) 5 (nido-
M
M
M
3
(1 m ),
M
Reactions of o-Carborane Derivatives
The aforementioned results allowed us to conduct 11B MRI ex-
periments. Sample solutions of B(OH) and o-carboranes were
M
M
(
3
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1827
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
prepared as shown in Figure 11, in which a smaller vial is nested tioned spin echo sequence and succeeded in the selective de-
1
1
in a larger vial. The solution in the inside vial (S ) contains a tection of the B signals of B(OH) , as shown in Figure 11 (a-
in
3
solution of the o-carborane derivative 10 (1 m
side vial (Sout) contains B(OH) (10 m
M
) and the out- ii).
M
) with Cu(bpy) (1 m
M
)
These results allowed us to monitor decomposition of 10 by
3
1
1
(
the ratio of two-dimensional area of S and Sout is ca. 1:1.6).
B MRI. As shown in Figure 12, the solution in the inside vial
in
1
1
The B atoms of B(OH) and o-carborane can be irradiated sep- contains a solution of 10 (1 m
M
) in 0.5
M
HEPES buffer
) and 21
) at 50 °C for 0, 48, and 96 h. As shown in Figure 12 (a–
the basic transmitter frequency) values for B(OH) and 10 are c), the brightness of the inside sample increased in proportion
3
arately because of their different chemical shifts, allowing these (pH 7)/DMSO (1:1) after incubation with CuSO (10 m
M
4
two different molecules to be detected separately. Namely, BF1 (10 m
M
(
3
ca. 128.392 and 128.387 MHz, respectively, as shown in Fig- to the progress of the decomposition reaction. After 96 h, the
ure 11 (a-i and b-i, irradiation range: 5 kHz). In our initial experi- inside sample could be detected as well as the outside refer-
ments using spin echo sequence with TE (echo time) of 3.4 ms ence, indicating that 10 had decomposed and nearly 10 equiv.
and TR (repetition time) of 200 ms, 11B MRI signals of o-car- of B(OH) had been released.
[51]
3
boranes (4 and 10) were clearly observed (Figure 11, b-ii, and
Figure S13 in the Supporting Information).[ However, B sig-
50]
11
nals of B(OH) were very weak, possibly due to shorter relaxa-
3
tion time of B atoms in B(OH) (< 1 ms) than that in 10 and
3
other o-carborane analogues (ca. 10 ms). Thus, we have used
an ultra-short echo time (UTE) sequence with shorter TE and TR
values (199 μs and 30 ms, respectively) than those of aforemen-
Figure 12. The decomposition of 10 was monitored by 11B MRI. Sin: 1 m
M
10
+
1 m
M
Cu(bpy) after incubation for (a) 0 h, (b) 48 h, and (c) 96 h. Sout: 10 mM
1
1
B(OH)
3
+ 1 mM Cu(bpy) (as a reference). Both B NMR images were acquired
by using a two-dimensional ultra-short echo time sequence (UTE2D) with
BF1 values of ca. 128.392 MHz, TE = 199 μs and TR = 30 ms.
Figure 11. 11B MRI images differentiating B(OH)
and 10. Curves (a-i) and (b-
3
We then observed change in 11B MRI at several concentra-
i) show typical 11B NMR spectra of solutions in two vials [inside vial contains
2
+
1
m
M
10 and outside contains 10 m
M
B(OH)
3
]. Images (a-ii) and (b-ii) show
10 and the outside vial (Sout
tions of Cu (10, 5, 2.5, and 1.25 m
(bpy) (10 m ) for 96 h in 0.5 HEPES buffer (pH 7)/DMSO (1:1).
As summarized in Figure 13, the brightness of the inside sample
M
) in the presence of 21
1
1
B MRI of the inside vial (Sin) containing 1 m
M
)
M
M
6
including 10 m
3 3
M B(OH) + 1 mM Cu(bpy) (CuL ). BF1 values for B(OH) and
1
0 are ca. 128.392 MHz (a-i) and ca. 128.387 MHz (b-i), respectively (irradia-
2
+
increased in a Cu concentration dependent manner. These
results were also supported by azomethine-H assays (Figure S15
in the Supporting Information).
11
tion range = 5 kHz). Both B NMR images are acquired by using a two-
dimensional ultra-short echo time sequence (UTE2D) with TE = 199 μs and
TR = 30 ms.
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1828
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
We believe that these results provide useful information re-
garding the fundamental chemistry of o-carboranes and boron-
containing drugs, and for the design and synthesis of 11B MRI
(NMR) probes and related materials.
Experimental Section
General Information: o-Carborane was purchased from Sigma–Al-
drich and Katchem Ltd and organic solvents for spectroscopic anal-
ysis were purchased from Wako Chemicals Co., Ltd. ZnSO ·7H O and
4
2
NiSO ·6H O were purchased from Yoneyama Chemical Industry Co.
4
2
Ltd. Zn(NO ) ·6H O and Cd(NO ) ·4H O, Co(NO ) ·6H O, Fe-
3
2
2
3 2
2
3 2
2
SO ·7H O were purchased from Kanto Chemical Co. Ltd. FeCl ·4H O,
4
2
2
2
Cu(NO ) ·3H O and CuBr was purchased from Wako Pure Chemical
3
2
2
Industries, Ltd. Anhydrous CaCl , Pb(NO ) , CuSO ·5H O and CuI
2
3 2
4
2
were obtained from Nacalai Tesque, Inc. and MnSO ·H O,
4
2
Cu(CH COO) ·H O and Cu(ClO ) ·6H O were purchased from
3
2
2
4 2
2
Sigma–Aldrich Co. Azomethine-H reagent was purchased from Do-
jindo. Acetonitrile (CH CN) was distilled from calcium hydride prior
3
to use. All aqueous solutions were prepared by using deionized and
distilled water. The Good's buffer reagents (Dojindo) were obtained
from commercial sources: MES (2-morpholinoethanesulfonic acid,
pK = 4.8), HEPES [N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic
a
acid, pK = 7.5], EPPS [N-(2-hydroxyethyl)piperazine-N′-3-propanes-
a
ulfonic acid, pKa = 8.0], CHES [2-(cyclohexylamino)ethanesulfonic
acid, pKa = 9.5], CAPS [3-(cyclohexylamino)propanesulfonic acid,
pK = 10.4]. Buffer solutions (KCl/HCl, pH 1 and pH 2; K-Cl/HCl, pH 3;
a
acetic acid/sodium acetate, pH 4 and pH 5; MES, pH 6; HEPES, pH 7;
EPPS, pH 8; CHES, pH 9; CAPS, pH 10) were used. All other reagents
and solvents were of the highest commercial quality available and
were used without further purification, unless otherwise noted.
Melting points were measured with a YANACO Micro Melting Point
Apparatus and are uncorrected. IR spectra were recorded with a
JASCO FTIR-410 and a PerkinElmer Spectrum100 spectrophotome-
ter at room temperature. 1H (400 MHz), C (100 MHz), and
13
11
B
Figure 13. Change in 11B MRI of 1 m
10 at [Cu2+] of (a) 1 m
M, (b) 0.5 mM,
M
2+
(
(
c) 0.25 m
bpy) in 0.5
0 °C. Sout: 10 m
M
, and (d) 0.125 m
M
. Sin: 1 m
M
10 + 0.125–1 m
M
Cu + 1 m
M
21
(128 MHz) NMR spectra were recorded with a JEOL Lambda 400
spectrometer. 1H (300 MHz) and C (75 MHz) NMR spectra were
recorded with a JEOL Always 300 spectrometer. Chemical shifts (δ)
13
M
HEPES buffer (pH 7)/DMSO (1:1) after incubation for 96 h at
2
+
5
M
3
B(OH) + 1 mM Cu + 1 mM 21(bpy) (as a reference). Both
1
1
B NMR images were acquired by using a two-dimensional ultra-short echo
in CDCl were determined relative to an internal reference of tetara-
3
time sequence (UTE2D) with BF1 values ca. 128.392 MHz, TE = 199 μs and
TR = 30 ms.
1
13
methylsilane (TMS) for H NMR and CDCl3 for C NMR spectro-
scopy. The sodium salt of 3-(trimethylsilyl)propionic-2,2,3,3-d acid
4
1
(
TSP) was used as an external reference for H NMR and 1,4-dioxane
for C NMR measurements in D O. B NMR spectra were measured
13
11
2
in a quartz NMR tube by using boron trifluoride diethyl ether com-
Conclusions
plex in CDCl as an external reference (δ = 0 ppm). Elemental analy-
3
ses were performed with a Perkin–Elmer CHN 2400 analyzer. Elec-
trospray ionization (ESI) mass spectra were recorded with a JEOL
JMS-SX102A and Varian 910-MS. Thin-layer chromatography (TLC)
was performed using Merck Silica 5554 (silica gel) TLC plates. Silica
gel column chromatography was performed using Fuji Silysia
Chemical FL-100D. Density functional theory (DFT) calculations
were also performed by using the Gaussian 09 program (B3LYP, the
6-31G basis set.) Compound 5, 10, 15, 18, 19, and 20 were prepared
We report on the degradation of o-carborane-pendant cyclens
(
6a, 6b, and 6c) to release ca. 4 equiv. of B(OH) in the presence
3
2
+
2+
of Mn and 8–9 equiv. of B(OH) in the presence of Cu . It
3
was also discovered that o-carborane derivatives 10 and 11,
2
+
having a hydroxyl group, are completely decomposed by Cu
2+
2+
in the presence of Cu or a Cu complex such as Cu(bpy)
CuL ) and Cu(phen) (CuL ) to release 10 equiv. of B(OH) . Mech-
6
8
(
3
anistic studies indicate that the closo-form of o-carborane deriv- according to the reported methods.[38,39,32e]
atives are converted into the corresponding nido-forms and
1
-(Prop-2-yn-1-yl)-4,7,10-tris(tert-butyloxycarbonyl)-1,4,7,10-
that further decomposition reactions are triggered by the sin-
[
36]
tetraazacyclododecane (13a): A mixture of 3-Boc-cyclen 11
2+
gle-electron oxidation by Cu . To our knowledge, this repre-
sents the first report dealing with the complete decomposition
(900 mg, 1.90 mmol), propargyl bromide 12a (272 mg, 2.29 mmol),
and Na CO (403 mg, 3.80 mmol) in CH CN (25 mL) was heated to
2
3
3
2+
of o-carborane derivatives by Cu under physiological condi-
reflux for 16 h. After filtration through a Celite pad, the filtrate was
tions. Finally, the B MRI detection of B(OH) released from 10 evaporated and purified by silica gel column chromatography (hex-
1
1
3
(
and 6a, 6b) in the presence of Cu2+ is reported.
ane/EtOAc, 1:1) to afford 13a (922 mg, 95 %) as a colorless amor-
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1829 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
1
phous solid. H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 3.20–3.60
H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 3.95 (br s, 1 H), 2.50–
3
3
(
m, 14 H), 2.77 (br. s, 4 H), 2.19 (s, 1 H), 1.47 (s, 9 H), 1.45 (s, 18
2.72 (br, 12 H), 2.31 (t, J = 8.1 Hz, 2 H), 1.46 (s, 9 H), 1.45 (s, 18
13
13
H) ppm. C NMR (75 MHz, CDCl , 25 °C, TMS): δ = 155.80, 155.50,
H) ppm. C NMR (75 MHz, CDCl , 25 °C, TMS): δ = 134.52, 133.41,
3
3
1
4
(
55.07, 79.49, 79.27, 79.07, 73.51, 54.68 (br), 54.11, 53.03, 49.63,
133.30, 131.94, 128.77–128.99 (m), 128.04–128.21 (m), 66.73–67.66
8.95 (br), 47.67, 47.48, 46.85, 46.33, 28.54, 28.33, 28.28 ppm. IR (m), 57.20–57.69 (m), 48.34–48.64 (m), 43.95–44.33 (m), 41.81–42.22
ATR): ν = 630, 757, 772, 1104, 1152, 1247, 1363, 1412, 1458, 1679, (m) ppm; 11B{ H} NMR (128 MHz, CDCl , 25 °C, BF ·Et O): δ = –1.8,
1
˜
3
3
2
–1
+
2
932, 2976 cm . HRMS (ESI): m/z calcd. for C H N O + H [M + –5.1, –9.1, –11.3 (br s) ppm. IR (ATR): ν˜ = 758, 772, 1110, 1152, 1247,
2
6 46 4 6
+
–
1
H ] 511.3490; found 511.3486.
-(1,2-Dicarbadodecaboranyl)methyl-4,7,10-tris(tert-butyloxy-
carbonyl)-1,4,7,10-tetraazacyclododecane (14a): To a solution of
1365, 1414, 1457, 1675, 2587, 2932, 2976 cm . HRMS (ESI): m/z
+
+
calcd. for C H B N O + H [M + H ] 643.5443; found 643.5432.
2
7 58 10 4 2
1
1-(1,2-Dicarbadodecaboranyl)ethyl-1,4,7,10-tetraazacyclodo-
B H (42.8 mg, 0.35 mmol) in toluene (2 mL) was added CH CN decane Hydrochloride Salt (6b): To a CHCl solution (1 mL) of 14b
10
14
3
3
(0.33 mL) and 13a (185 mg, 0.35 mmol) and the reaction mixture
(24 mg, 0.0382 mmol) was added 4 N HCl/dioxane (1 mL) at room
was heated at 80–90 °C for 11 h. After evaporation, the resulting
residue was purified by silica gel column chromatography (hexane/
temperature and the reaction mixture was stirred for 2 h. After
evaporation, the resulting residue was reprecipitated from hexane/
EtOAc, 5:1) to afford 14a (53.6 mg, 24 %) as a colorless amorphous
CHCl /MeOH to give 6b (8.9 mg, 52 %) as a colorless solid, which
3
1
solid. H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 4.51 (br. s, 1 H),
was determined to be the 3HCl salt by elemental analysis, m.p. 234–
3
13
1
3
.10–3.60 (m, 14 H), 2.70 (br. s, 1 H), 1.46 (s, 27 H) ppm. C NMR
240 °C (dec.). H NMR (300 MHz, D O, 25 °C, TSP): δ = 4.42 (br s, 1
2
(
75 MHz, CDCl , 25 °C, TMS): δ = 156.34, 155.80, 80.29, 80.08, 74.28,
9.53 (br), 53.98 (br), 50.04 (br), 49.45 (br), 46.20 (br), 28.51 ppm.
H), 3.65–3.90 (m, 2 H), 3.10–3.30 (m, 7 H), 2.75–3.05 (m, 9 H), 2.48–
3
5
2.60 (m, 2 H) ppm. 13C NMR [75 MHz, D O, 25 °C, 1,4-dioxane (exter-
2
1
1
1
B{ H} NMR (128 MHz, CDCl , 25 °C, BF ·Et O): δ = –2.2, –5.1, –10.0,
nal reference)]: δ = 73.91, 67.75, 63.59, 51.44, 47.50, 44.96, 42.57,
3
3
2
11.8 ppm. IR (ATR): ν˜ = 755, 773, 1248, 1365, 1414, 1457, 1680, 42.12, 30.83 ppm. 11B{ H} NMR (128 MHz, D O, 25 °C, BF ·Et O): δ =
1
–
2
2
3
2
–1
587, 2933, 2978 cm . HRMS (ESI): m/z calcd. for C H B N O + –2.8, –5.7, –9.4, –11.7 ppm. IR (KBr): ν˜ = 722, 960, 1017, 1072, 1448,
2
6 56 10 4 6
+
+
–1
H [M + H ] 629.5287; found 629.5288.
-(1,2-Dicarbadodecaboranyl)methyl-1,4,7,10-tetraazacyclodo-
decane Hydrochloride Salt (6a): To a MeOH solution (6 mL) of
4a (120 mg, 0.19 mmol) was added 4 HCl/dioxane (6 mL) at
1577, 1613, 2575, 2970, 3381 cm . HRMS (ESI): m/z calcd. for
+
+
C15H27B10N O + H [M + H ] 306.2339; found 306.2336.
4
2
1
C H B Cl N (451.91): calcd. C 31.89, H 8.25, N 12.40; found C
12
37 10
3 4
31.65, H 8.57, N 12.76.
1
N
room temperature and the reaction mixture was stirred for 2 h.
1-(3-Pentynyl)-4,7,10-tris(tert-butyloxycarbonyl)-1,4,7,10-tet-
raazacyclododecane (13c): A mixture of 11 (1 g, 2.11 mmol), 5-
chloro-1-propyne 12c (2.16 g, 21.1 mmol), NaI (3.80 g, 25.3 mmol)
and Cs CO (687 mg, 2.11 mmol) in CH CN (5 mL) was heated to
reflux for 4 d. After filtration through a Celite pad, the filtrate was
evaporated and the residue purified by silica gel column chroma-
After evaporation, the resulting residue was washed with CHCl to
3
give 6a (56.4 mg, 69 %) as a colorless solid; m.p. 239–243 °C (dec.).
1
H NMR (300 MHz, D O, 25 °C, TSP): δ = 4.50 (br. s, 1 H), 3.61 (s, 1
2
2
3
3
1
3
H), 3.15–3.30 (m, 12 H), 3.01 (m, 4 H) ppm. C NMR [75 MHz, D O,
2
2
4
2
1
2
5 °C, 1,4-dioxane (external reference)]: δ = 74.42, 63.23, 58.70,
1
1
1
8.79, 45.19, 43.92, 43.04, 42.01 ppm. B{ H} NMR (128 MHz, D O, tography (hexane/EtOAc, 3:1) to afford 13c (1.04 g, 91 %) as a color-
2
1
5 °C, BF ·Et O): δ = –0.4, –2.5, –6.9, –9.9 ppm. IR (KBr): ν = 718,
less amorphous solid. H NMR (300 MHz, CDCl , 25 °C, TMS): δ =
3
2
˜
3
075, 1083, 1098, 1377, 1442, 1450, 1584, 1651, 2351, 2428, 2559,
3.20–3.62 (br, 12 H), 2.68–2.74 (m, 6 H), 2.19 (td, J = 2.6, 7.0 Hz, 2
–
1
572, 2584, 2594, 2606, 2626, 2964, 3006, 3047, 3293, 3385 cm . H), 1.96 (t, J = 2.6 Hz, 1 H), 1.62–1.78 (m, 4 H), 1.47 (s, 9 H), 1.45 (s,
+
+
13
HRMS (ESI): m/z calcd. for C H N B + H [M + H ] 329.3705; 18 H) ppm. C NMR (75 MHz, CDCl , 25 °C, TMS): δ = 156.00, 155.58,
1
1
32
4
10
3
found 329.3707. C11H35B10Cl N ·2H O: calcd. C 27.88, H 8.30, N
155.28, 83.64, 79.36, 79.13, 68.71, 54.80, 53.60, 51.37, 49.86, 48.11
3
4
2
1
1.82; found C 28.28, H 8.29, N 11.87.
(br), 47.83 (br), 47.48 (br), 28.57, 28.39, 22.94, 16.55 ppm. IR (ATR):
ν = 772, 1104, 1151, 1248, 1363, 1413, 1459, 1681, 2933,
˜
1
-(3-Butynyl)-4,7,10-tris(tert-butyloxycarbonyl)-1,4,7,10-tet-
–
1
+
+
2
5
975 cm . HRMS (ESI): m/z calcd. for C H N O + H [M + H ]
39.3803; found 539.3798.
28 50 4 6
raazacyclododecane (13b): A mixture of 11 (1.0 g, 2.1 mmol), 4-
bromo-1-butyne 12b (1.4 g, 10.6 mmol), NaI (3.8 g, 25.3 mmol) and
Cs CO (825 mg, 2.5 mmol) in CH CN (33 mL) was heated to reflux
1-(1,2-Dicarbadodecaboranyl)propyl-4,7,10-tris(tert-butyloxy-
2
3
3
for 44 h. After filtration through a Celite pad, the filtrate was evapo- carbonyl)-1,4,7,10-tetraazacyclododecane (14c): To a solution of
rated and the residue was purified by silica gel column chromatog-
B H (227 mg, 1.86 mmol) in toluene (10 mL) was added CH CN
10 14 3
raphy (hexane/EtOAc, 1:1) to afford 13b (1.1 g, 90 %) as a colorless
(2 mL) and 13c (1.0 g, 1.86 mmol). The resulting solution was
1
amorphous solid. H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 3.20– heated at 80–90 °C for 14 h. After evaporation, the resulting residue
3
3
.60 (br, 12 H), 2.87 (t, J = 7.4 Hz, 2 H), 2.62–2.78 (br, 4 H), 2.34 (td,
was purified by silica gel column chromatography (hexane/EtOAc,
J = 2.5, 7.5 Hz, 2 H), 1.98 (t, J = 2.6 Hz, 1 H), 1.47 (s, 1 H), 1.45 (s, 18
5:1) to afford 14c (122 mg, 13 %) as a colorless amorphous solid.
H) ppm. 13C NMR (75 MHz, CDCl , 25 °C, TMS): δ = 157.39, 157.18,
1
H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 3.64 (br s, 1 H), 3.18–
3
3
1
1
2
1
+
57.00, 137.43, 137.05, 136.70, 134.59, 133.91, 133.29, 132.70,
28.38, 80.73, 57.91 (br), 56.56 (br), 50.76 (br), 48.50, 48.23, 29.09,
3.48 (br, 12 H), 2.38–2.62 (br, 8 H), 2.10–2.22 (br, 2 H), 1.45 (s, 9 H),
1.44 (s, 18 H) ppm. 13C NMR (75 MHz, CDCl , 25 °C, TMS): δ = 156.19,
3
8.86 ppm. IR (ATR): ν˜ = 630, 757, 772, 1104, 1152, 1247, 1363, 1412, 155.78, 155.42, 79.71, 79.56, 75.21, 61.38, 54.80 (br), 53.91 (br), 51.44
–
1
458, 1679, 2932, 2976 cm . HRMS (ESI): m/z calcd. for C H N O
7 48 4 6
(br), 49.87 (br), 48.37 (br), 47.79 (br), 35.90, 28.63, 28.51, 24.90 ppm.
2
+
+
11
1
H [M + H ] 525.3647; found 525.3645.
B{ H} NMR (128 MHz, CDCl /BF ·Et O): δ = –2.5, –5.9, –9.4,
3 3 2
–
2
6
11.7ppm.IR(ATR):ν˜=772,1153,1249,1365,1414,1458,1674,2589,2932,
1
-(1,2-Dicarbadodecaboranyl)ethyl-4,7,10-tris(tert-butyloxy-
–
1
+
+
976 cm . HRMS (ESI): m/z calcd. for C H B N O + H [M + H ]
2
8 60 10 4 2
carbonyl)-1,4,7,10-tetraazacyclododecane (14b): To a solution of
B H (229 mg, 1.87 mmol) in toluene (3 mL) was added CH CN
1
57.5600; found 657.5598.
0
14
3
(1.73 mL) and 13b (981 mg, 1.87 mmol). The resulting solution was
1-(1,2-Dicarbadodecaboranyl)propyl-1,4,7,10-tetraazacyclodo-
heated 80–90 °C for 24 h. After evaporation, the resulting residue
decane Hydrochloride Salt (6c): To a MeOH solution (3 mL) of 14c
was purified by silica gel column chromatography (hexane/EtOAc, (61.3 mg, 0.093 mmol) was added 4 N HCl/dioxane (3 mL) at room
5
:1) to afford 14b (122 mg, 10 %) as a colorless amorphous solid. temperature, and the reaction mixture was stirred for 3.5 h. After
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1830
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
evaporation, the resulting residue was washed with CHCl to give
(100 m
4; 4:3), and the solution was then added to a solution (0.2 mL) of
the metal salt in D O ([metal salt] = 100 m ). These resulting mix-
M) was mixed with 0.7 mL of DMSO/0.5 M acetate buffer (pH
3
6
c (37 mg, 85 %) as a colorless solid, which was determined to be
1
the 3HCl salt by elemental analysis, m.p. 239–243 °C (dec.). H NMR
M
2
(
300 MHz, D O, 25 °C, TSP): δ = 4.40 (br s, 1 H), 2.98–3.26 (br m, 16
tures were incubated in screw-top vials at the given temperature
2
H), 2.72 (t, J = 8.1 Hz, 2 H), 2.30 (t, J = 8.4 Hz, 2 H), 1.78–1.82 (m, 2
and for the given time. An aliquot of the reaction mixture (0.66 mL)
H) ppm. 13C NMR [75 MHz, D O, 25 °C, 1,4-dioxane(external refer- was placed into a quartz NMR tube and analyzed by B NMR spec-
11
2
ence)]: δ = 65.58, 52.79, 41.59, 38.00, 34.12, 32.20, 32.12, 24.58,
troscopy (128 MHz) with a sweep width of 38022 Hz, 4096 data
points, a 45° pulse width, a 0.16 second recycle time, and 2850
scans. Each spectrum was processed with 4.6 Hz line-broadening
3.19 ppm. 11B{ H} NMR (128 MHz, D O, 25 °C, BF ·Et O): δ = –3.2,
1
1
–
1
2 3 2
6.4, –9.8, –11.7 ppm. IR (KBr): ν = 722, 1021, 1381, 1445, 1458,
˜
–
1
473, 1575, 2568, 3231, 3400, 3473 cm . HRMS (ESI): m/z calcd. for using BF ·Et O in CDCl as an external reference (δ = 0 ppm) (see
3
2
3
+
+
C1 3 H3 6 B1 0 N4 + H [M + H ] 357.4018; found 357.4016.
Figure S1 in the Supporting Information).
C H B Cl N ·1/3,CHCl ·1/3CH OH: calcd. C 31.79, H 7.94, N 10.85;
found C 31.84, H 7.95, N 10.48.
13
39 10
3
4
3
3
Azomethin-H Assay for the Decomposition of Carborane Deriv-
[
40]
atives by Metal Ions: See Figures 2, 3, 4, 6, 7, 8, and 9.
Preparation of Reaction Samples (Solution A): For o-carborane-
pendant cyclen 6a–c, solutions (0.8 mL) of each compound in 0.5
HEPES buffer (pH 7) were prepared ([6a–c] = 12.5 m ) and mixed
with a solution (0.2 mL) of the metal salt (100 m ) in water. For o- or
m-carborane derivatives (4, 10, 11, 16, 17, 18, 19, and 20), solutions
0.9 mL) of each compound in DMSO/buffer (5:4 for 4, 10, 11, 17,
8, 19, and 20; 7:2 for 16) ([4, 10, 11, 16, 17, 18, 19, and 20] =
1.1 m ) were prepared, to which a solution (0.1 mL) of the metal
salt in water were added ([metal salt] = 1, 5, 10, 100 m ). These
–
8
-(Hydroxymethyl)-7,8-dicarbaundecaborate(2 ) Sodium Salt
(10′): To a MeOH solution (3 mL) of 10 (43.5 mg, 0.25 mmol) was
M
added NaOMe (27 mg, 2 equiv.) at room temperature and the reac-
tion mixture was stirred and heated to reflux for 18.5 h. After cool-
ing the reaction mixture, solvent was removed in vacuo and the
residue was dissolved in acetone and precipitation was removed by
filtration. After filtration, the filtrate was evaporated and the residue
M
M
(
1
was purified by silica gel column chromatography (CHCl /MeOH,
3
1
M
1
4
:1) to afford 10′ (41 mg, 88 %) as an amorphous mass. H NMR
M
(
1
400 MHz, CD OD, 25 °C, TMS): δ = 4.637 (s, 1 H), 3.72 (d, J = 11.2 Hz,
H), 2.53 to –0.36 (br. m, 9 H), –2.65 (br, 1 H) ppm. C NMR
3
mixtures were incubated at 37 or 50 °C in a screw-top vial for the
decomposition reaction. An aliquot (20 μL) of the reaction mixture
1
3
(
4
–
100 MHz, CD OD, 25 °C, TMS): δ = 70.61, 62.40–61.43 (m), 46.63–
5.55 (m) ppm. B{ H} NMR (128 MHz, CD OD, 25 °C, BF ·Et O): δ =
3 3 2
10.4, –11.4, –14.8, –17.3, –18.4, –22.1, –33.0, –37.4 ppm. IR (ATR):
3
(solution A) was taken at given reaction times (after 0, 12, 24, 48,
11
1
9
6 and 144 h), in which concentrations of B(OH) produced by the
3
decomposition reaction of carborane derivatives were determined
according to the following procedure.
ν˜ = 1007, 1088, 1153, 1226, 1273, 1348, 1391, 1461, 1615, 1714,
–
1
2
505, 2850, 2889, 2925, 2950, 3557 cm . HRMS (ESI): m/z calcd. for
+
+
Preparation of Ammonium Acetate Buffer Solution (Solution B):
C H B ONa – Na [M – Na ] 165.1882; found 165.1883.
3
15 9
Ammonium acetate [(NH )OAc, 1.87 mol, 100 g] was dissolved in
4
Compound 16: To a solution of 5 (200 mg, 1.39 mmol) and phthal-
aldehyde (203 mg, 1.51 mmol) in THF (6.88 mL) was added tetrabu-
water (ca. 80 mL), to which EDTA (400 mg, 1.37 mmol) and anhy-
drous citric acid (366 mg, 1.9 mmol) had been added. Then, H PO
3
4
tylammonium fluoride (1.0
M in THF, 4.17 mL) under Ar atmosphere,
[
2 mL, 85 % (w/w), 38.6 mmol] and H SO4 [6 mL, 96 % (w/w),
2
and the mixture was stirred at room temperature for 30 min. The
1
13 mmol] were added dropwise to a solution of (NH )OAc, EDTA
4
reaction was quenched with saturated aqueous NH Cl, and the mix-
4
and citric acid with gentle stirring and warming at 50–70 °C to
dissolve the reagents, and the solution was then made up to
ture was extracted with diethyl ether, washed with brine, and dried
with anhydrous Na SO . After filtration, the filtrate was evaporated
2
4
100 mL with water to prepare solution B [containing 18.7
M
and the residue was purified by silica gel column chromatography
hexane/EtOAc, 3:1) to afford 16 (376 mg, 97 %) as a white solid.
For characterization of the diastereomer by NMR analysis, 16
50 mg) was purified by HPLC (H O/MeOH, 50:50 to 0:100 in 30 min,
(
NH )OAc, 13.7 m EDTA, 19 m citric acid, 386 m H PO , and
M
M
M
4
3
4
(
1
.13 M H SO ].
2 4
Preparation of Azomethine-H Stock Solution (Solution C).
Azomethine-H (1 g, 2.3 mmol) and ascorbic acid (3 g, 17 mmol)
were dissolved in water (100 mL). The resulting azomethine-H solu-
(
2
column: senshu pak PEGASIL ODS) to afford 16a (tR = 19 min,
2
2.1 mg) and 16b (t = 21 min, 18.1 mg) as a white solid.
R
tion (containing 23 m
M azomethine-H and 170 mM ascorbic acid)
1
Compound 16a: H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 7.50
3
was mixed with an equal volume of solution B (typically, 15 mL +
(
dd, J = 5.4 Hz, 2 H), 7.38 (dd, J = 5.8 Hz, 2 H), 5.24 (s, 1 H) ppm.
1
5 mL) to prepare solution C [containing 9.4
EDTA, 9.5 m citric acid, 193 m H PO , 551 m
ascorbic acid and 23 m azomethine-H].
M
(NH )OAc, 6.9 m
M
4
13
C NMR (100 MHz, CDCl , 25 °C, TMS): δ = 132.83 (2 C), 129.63 (2
3
M
M
M H SO , 170 m
M
3
4
2 4
1
1
1
C), 128.35 (2 C), 69.82 (2 C), 50.91 (2 C) ppm; B{ H} NMR (128 MHz,
M
CDCl , 25 °C, BF ·Et O): δ = –4.0, –10.0, –12.0 ppm.
3
3
2
Preparation of Standard Solution (Solution D): Standard solu-
1
Compound 16b: H NMR (300 MHz, CDCl , 25 °C, TMS): δ = 7.48
tions of B(OH) in water (4, 2, 1 mg/L) were prepared for preparing
3
3
(
dd, J = 5.8 Hz, 2 H), 7.37 (dd, J = 6.2 Hz, 2 H), 5.20 (s, 1 H) ppm.
a standard (working) curve (32, 16, 8.1 μM).
13
C NMR (100 MHz, CDCl , 25 °C, TMS): δ = 132.79 (2 C), 129.65 (2
3
Procedure of Azomethine-H Assay: For the measurement of the
blank solution, 2 mL of the azomethine-H solution (solution C) was
mixed with 8 mL of water (solution E, 10 mL in total). For the meas-
1
1
1
C), 128.36 (2 C), 69.83 (2 C), 58.12 (2 C) ppm; B{ H} NMR (128 MHz,
D O, 25 °C, BF ·Et O): δ = –3.9, –9.9, –12.0 ppm. IR (ATR): ν = 764,
1
2
3
2
˜
–
1
013, 2561, 2573, 2599, 2622, 3251, 3374 cm . HRMS (FAB): m/z
urement of the standard solution of B(OH) , 5 mL of standard solu-
+
+
3
calcd. for C H B O + H [M + H ] 280.2237; found 280.2246.
1
0 18 10 2
tion of B(OH) (solution D) were mixed with 3 mL of water and 2 mL
3
General Procedure for Detection of d-Block Metal Ions with 11B
of the azomethine-H solution (solution C) to obtain solution F
NMR Spectroscopy: (Figures 1 and 5). Sample solutions of o-car- (10 mL in total). For the measurement of the decomposition reac-
borane-pendant cyclens 6a–c (12.5 m
.8 mL) were prepared and each was mixed with a solution (0.2 mL)
of a metal salt in D O ([metal salt] = 100 m ). For o-carborane 10,
having a hydroxymethyl group, its solution (0.1 mL) in DMSO
M
) in 0.5
M
HEPES buffer (pH 7;
tion mixture of carborane derivatives, 10 μL of reaction mixture
(from 20 μL of solution A) was made up to 10 mL with water (solu-
tion G). From solution G, 2 mL was removed and 2 mL of the azome-
thine-H solution (solution C) was added to prepare sample solutions
0
M
2
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1831
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
for analysis (solution H, 10 mL in total). After standing for 1 h, the
absorbance at 412 nm of standard solution (solution F) and a sam-
ple solution (solution H) were measured by using absorbance of a
blank solution (solution E) as a baseline. It is strongly recommended
[1] a) J. J. R. Frausto da Silva, R. J. P. Williams, The Biological Chemistry of the
Elements: The Inorganic Chemistry of Life, Oxford University Press, Oxford,
UK, 1991; b) J. Osredkar, N. Sustar, J. Clinic. Toxicol. 2011, S3, 1.
[
[
[
2] a) B. Haliwell, J. M. C. Gutteridge, Biochem. J. 1984, 219, 1–14; b) M. C.
Linder, M. Hazegh-Azam, Am. J. Clin. Nutr. 1996, 63, 797S.
3] C. Vulpe, B. Levinson, S. Whitney, S. Packman, J. Gitschier, Nat. Genet.
to prepare standard solutions {solution F, in which [B(OH) ] = 8.1,
3
1
6 and 32 μM} and measure their UV/Vis spectra to make a working
1
993, 3, 7–13.
4] P. C. Bull, G. R. Thomas, J. M. Rommens, J. R. Forbes, D. W. Cox, Nat. Genet.
993, 5, 327–337.
curve, immediately before the measurement of the sample solu-
tions in all the experiments. Typical UV/Vis spectra of standard solu-
1
tion of B(OH) are shown in Figure S2a in the Supporting Informa-
3
[5] J. S. Valentine, P. J. Hart, Proc. Natl. Acad. Sci. USA 2003, 100, 3617–3622.
[6] Y. H. Hung, A. I. Bush, R. A. Cherny, J. Biol. Inorg. Chem. 2010, 15, 61–78.
[7] S. Ishida, P. Andreux, C. Poitry-Yamate, J. Auwerx, D. Hanahan, Proc. Natl.
Acad. Sci. USA 2013, 110, 19507–19512.
4
–1
–1
tion (ε415 = 1.01 × 10
M
cm ). Concentrations of B(OH) in sam-
3
ple solutions (solution H) were determined based on the standard
curve, which was obtained from standard B(OH)3 solutions (Fig-
ure S2b in the Supporting Information).
[
[
8] P. Dusek, P. M. Roos, T. Litwin, S. A. Schneider, T. P. Flaten, J. J. Aaseth, J.
Trace Elem. Med. Biol. 2015, 31, 193–203.
9] a) E. L. Que, D. W. Domaille, C. J. Chang, Chem. Rev. 2008, 108, 1517–
Cyclic Voltammetry of Carborane Derivatives and Metal Ions:
(
Figure 10) Cyclic voltammetry measurements were performed with
a BAS model 660A electrochemical analyzer at room temperature
in DMF containing 0.1 nBu N(PF ) as the supporting electrolyte
1
4
549; b) H. Zhu, F. Jiangli, B. Wang, X. Peng, Chem. Soc. Rev. 2015, 44,
337–4366.
M
4
6
[
[
10] a) M. Taki, S. Iyoshi, A. Ojida, I. Hamachi, Y. Yamamoto, J. Am. Chem. Soc.
010, 132, 5938–5939; b) P. Li, X. Duan, Z. Chen, Y. Liu, T. Xie, L. Fang, X.
in a standard one-component cell equipped with 3-mm outer diam-
eter glassy carbon working electrode, and a platinum wire counter
electrode, the Ag/AgCl-referenced electrode (Ag/AgCl in MeCN con-
2
Li, M. Yin, B. Tang, Chem. Commun. 2011, 47, 7755–7757; c) L. C. Yang,
R. McRae, M. M. Henary, R. Patel, B. Lai, S. Vogt, C. J. Fahrni, Proc. Natl.
Acad. Sci. USA 2005, 102, 11179–11184; d) L. Zeng, E. W. Miller, A. Pralle,
E. Y. Isacoff, C. J. Chang, J. Am. Chem. Soc. 2006, 128, 10–11; e) Z. Zhou,
C. J. Fahrni, J. Am. Chem. Soc. 2004, 126, 8862–8863; f) R. F. H. Viguier,
A. N. Hulme, J. Am. Chem. Soc. 2006, 128, 11370–11371.
taining 0.01
M AgNO and 0.1 M nBu NPF ). All solutions were deox-
3 4 6
ygenated by bubbling with argon for at least 10 min, immediately
before the measurement.
II
Magnetic Resonance Imaging of Probes in the Presence of Cu
11] a) A. Mokhir, A. Kiel, D. P. Herten, R. Kraemer, Inorg. Chem. 2005, 44,
II
and Mn : (Figure 11) A solution (1 mL) of 10 (10 mM), bpy (10 m
M)
5
661–5666; b) M. Royzen, Z. H. Dai, J. W. Canary, J. Am. Chem. Soc. 2005,
and CuSO ·5H O (10 m
was incubated at 50 °C in a screw-capped vial. After incubation for
a given time (24, 48 and 96 h), the solutions were diluted with 9 mL
M
) in DMSO/0.5
M
HEPES buffer (pH 7; 1:1)
127, 1612–1613; c) E. J. Jun, H. N. Won, J. S. Kim, K. H. Lee, J. Yoon,
Tetrahedron Lett. 2006, 47, 4577–4580; d) N. K. Singhal, B. Ramanujam,
V. Mariappanadar, C. P. Rao, Org. Lett. 2006, 8, 3525–3528; e) J. Liu, Y. Lu,
J. Am. Chem. Soc. 2007, 129, 9838–9839; f) M. X. Yu, M. Shi, Z. G. Chen,
F. Y. Li, X. X. Li, Y. H. Gao, J. Xu, H. Yang, Z. G. Zhou, T. Yi, C. H. Huang,
Chem. Eur. J. 2008, 14, 6892–6900.
4
2
of HEPES buffer (0.5
M
, pH 7) (10 mL in total). A solution of B(OH)3
), Cu2 (CuSO ·5H O) (1 m
M
+
(10 m
M
M) and 26 (1 m ) in DMSO/0.5
M
4
2
HEPES buffer (pH 7; 5:95) was prepared as reference solution. NMR
imaging experiments were performed with a 9.4 T Avance I Micro-
Imaging system (Bruker BioSpin, Rheinstetten, Germany) with a Mi-
[
[
12] a) K. Dutta, R. C. Deka, D. K. Das, J. Fluoresc. 2013, 23, 1173–1178; b) F.
Gruppi, J. Liang, B. B. Bartelle, M. Royzen, D. H. Turnbull, J. W. Canary,
Chem. Commun. 2012, 48, 10778–10780; c) J. Liang, J. W. Canary, Angew.
Chem. Int. Ed. 2010, 49, 7710–7713; Angew. Chem. 2010, 122, 7876.
13] a) D. Y. Zhang, M. Azrad, W. D. Wahnefried, C. J. Frederickson, S. J. Lip-
pard, R. J. Radford, ACS Chem. Biol. 2015, 10, 385–389; b) D. Wang, J.
Guo, A. Ren, S. Huang, J. Feng, J. Phys. Chem. B 2014, 118, 10101–10110;
c) L. Prodi, F. Bolletta, M. Montalti, N. Zaccheroni, Coord. Chem. Rev. 2000,
205, 59–83; d) E. Kimura, S. Aoki, Biometals 2001, 14, 191–204; e) S. Aoki,
E. Kimura, in: Comprehensive Coordination Chemistry II (Eds.: L. Que Jr.,
W. B. Tolman); Elsevier, Amsterdam, The Amsterdam, 2004, vol. 8, p. 601–
1
11
11
cro2.5 gradient coil and H/ B dual tuned RF coil (dia. 25 mm).
B
NMR images were acquired by a two dimensional ultra-short echo
time sequence (UTE2D) with the following parameters: TE = 199 μs,
TR = 30 ms, flip angle: 60°, matrix size: 64 × 64, FOV = 60 × 60 mm,
slice thickness: 20 mm, number of projection: 202. The scan time
was 16 min.
6
40; f) P. Jiang, Z. Guo, Coord. Chem. Rev. 2004, 248, 205–229; g) K.
Acknowledgments
Kikuchi, K. Komatsu, T. Nagano, Curr. Opin. Chem. Biol. 2004, 8, 182–191;
h) N. C. Lim, H. C. Freake, C. Brückner, Chem. Eur. J. 2005, 11, 38–49; i) Z.
Dai, J. W. Canary, New J. Chem. 2007, 31, 1708–1718; j) P. Carol, S. Sreejith,
A. Ajayaghosh, Chem. Asian J. 2007, 2, 338–348; k) E. L. Que, D. W. Do-
maille, C. J. Chang, Chem. Rev. 2008, 108, 1517–1549; l) E. M. Nolan, S. J.
Lippard, Acc. Chem. Res. 2009, 42, 193–203; m) Z. Xu, J. Yoon, D. R. Spring,
Chem. Soc. Rev. 2010, 39, 1996–2006; n) R. Ohshima, M. Kitamura, A.
Morita, M. Shiro, Y. Yamada, M. Ikekita, E. Kimura, S. Aoki, Inorg. Chem.
This work is supported by grants-in-aid from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan (grant 25893259 to T. T. and grants 24659085 and
24640156 to S. A.). The authors appreciate the aid of Ms Fukiko
Hasegawa (Faculty of Pharmaceutical Sciences, Tokyo University
of Science) for the measurement of mass spectra data, Ms Nor-
iko Sawabe (Faculty of Pharmaceutical Science, Tokyo University
of Science) for the measurement of H NMR and B NMR spec-
tra and Ms Tomoko Matsuo (Tokyo University of Science) for
elemental analyses. The Research Resource Center of RIKEN
Brain Science Instituted supported the research by providing
the MRI facility. This work was carried out in part under the
visiting Researcher's Program of the Research Reactor Institute,
Kyoto University, Japan.
2
010, 49, 888–899; o) S. Aoki, K. Sakurama, R. Ohshima, N. Matsuo, Y.
Yamada, R. Takasawa, S. Tanuma, K. Takeda, E. Kimura, Inorg. Chem. 2008,
7, 2747–2754; p) T. Koike, T. Watanabe, S. Aoki, E. Kimura, M. Shiro, J.
1
11
4
Am. Chem. Soc. 1996, 118, 12696–12703; q) S. Aoki, D. Kagata, M. Shiro,
K. Takeda, E. Kimura, J. Am. Chem. Soc. 2004, 126, 13377–13390.
[
14] a) W. Luo, Y. M. Ma, P. J. Quinn, R. C. Hider, Z. D. Liu, J. Pharm. Pharmacol.
2
004, 56, 529–536; b) O. García-Beltrán, N. Mena, O. Yañez, J. Caballero,
V. Vargas, M. T. Nuñez, B. K. Cassels, Eur. J. Med. Chem. 2013, 67, 60–63;
c) T. Hirayama, K. Okuda, H. Nagasawa, Chem. Sci. 2013, 4, 1250–1256;
d) M. Niwa, T. Hirayama, K. Okuda, H. Nagasawa, Org. Biomol. Chem.
2014, 12, 6590–6597.
[
15] a) J. Chan, S. C. Dodani, C. J. Chang, Nat. Chem. 2012, 4, 973–984; b) J. F.
Zhang, Y. Zhou, J. Yoon, J. S. Kim, Chem. Soc. Rev. 2011, 40, 3416–3429;
c) M. Formica, V. Fusi, L. Giorgi, M. Michelon, Coord. Chem. Rev. 2012,
Keywords: Cluster compounds · Carboranes · Boron ·
Copper · MRI detection · Medicinal chemistry
2
56, 170–192.
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1832
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
[
16] a) L. M. D. Rodoriguez, A. J. M. Lubag, C. R. Malloy, G. V. Martinez, R. J.
Gillies, A. D. Sherry, Acc. Chem. Res. 2009, 42, 948–957; b) L. N. Goswami,
L. Ma, S. Chakravarty, Q. Cai, S. S. Jalisatgi, M. F. Hawthorne, Inorg. Chem.
Z. Xie, Coord. Chem. Rev. 2007, 251, 2452–2476; d) J. F. Valliant, K. J.
Guenther, A. S. King, P. Morel, P. Schaffer, O. O. Sogbein, K. A. Stephenson,
Coord. Chem. Rev. 2002, 232, 173–230; e) A. N. Alexandrova, A. I. Bold-
yrev, H.-J. Zhai, L.-S. Wang, Coord. Chem. Rev. 2006, 250, 2811–2866; f) F.
Issa, M. Kassiou, L. M. Rendina, Chem. Rev. 2011, 111, 5701–5722.
[26] J. Brynda, P. Mader, V. Šícha, M. Fábry, K. Poncová, M. Bakardiev, B. Grüner,
P. Cígler, P. Řezácová, Angew. Chem. Int. Ed. 2013, 52, 13760–13763;
Angew. Chem. 2013, 125, 14005.
2013, 52, 1694–1700.
17] For NMR/MRI probes for Zn2+, see: a) K. Hanaoka, K. Kikuchi, Y. Urano, T.
Nagano, J. Chem. Soc. Perkin Trans. 2 2001, 1840–1843; b) K. Hanaoka, K.
Kikuchi, Y. Urano, M. Narazaki, T. Yokawa, S. Sakamoto, K. Yamaguchi, T.
Nagano, Chem. Biol. 2001, 9, 1027–1032; c) R. Trokowski, J. Ren, F. K.
Kalman, A. D. Sherry, Angew. Chem. Int. Ed. 2005, 44, 6920–6923; Angew.
Chem. 2005, 117, 7080; d) X. Zhang, K. S. Lovejoy, A. Jasanoff, S. J. Lip-
pard, Proc. Natl. Acad. Sci. USA 2007, 104, 10780–10785; e) J. L. Major, G.
Parigi, C. Luchinat, T. J. Meade, Proc. Natl. Acad. Sci. USA 2007, 104,
[27] S. Fujii, H. Masuno, Y. Taoda, A. Kano, A. Wongmayura, M. Nakabayashi, N.
Ito, M. Shimizu, E. Kawachi, T. Hirano, Y. Endo, A. Tanatani, H. Kagechika,
J. Chem. Am. Soc. 2011, 133, 20933–20941.
[28] a) S. Fujii, A. Yamada, K. Tomita, M. Nagano, T. Goto, K. Ohta, T. Harayama,
Y. Endo, H. Kagechika, Med. Chem. Commun. 2011, 2, 877–880; b) T. Goto,
K. Ohta, S. Fujii, S. Ohta, Y. Endo, J. Med. Chem. 2010, 53, 4917–4926; c)
S. Fujii, T. Goto, K. Ohta, Y. Hashimoto, T. Suzuki, S. Ohta, Y. Endo, J. Med.
Chem. 2005, 48, 4654–4662; d) S. Fujii, Y. Hashimoto, T. Suzuki, S. Ohta,
Y. Endo, Bioorg. Med. Chem. Lett. 2005, 15, 227–230; e) Y. Endo, T. Iijima,
Y. Yamakoshi, M. Yamaguchi, H. Fukasawa, K. Shudo, J. Med. Chem. 1999,
42, 1501–1504; f) Y. Endo, T. Iijima, Y. Yamakoshi, H. Fukasawa, C. Miyaura,
M. Inada, A. Kubo, A. Itai, Chem. Biol. 2001, 8, 341–355; g) Y. Endo, T.
Yoshimi, K. Ohta, T. Suzuki, S. Ohta, J. Med. Chem. 2005, 48, 3941–3944.
[29] a) T. Iijima, Y. Endo, M. Tsuji, E. Kawachi, H. Kagechika, K. Shudo, Chem.
Pharm. Bull. 1999, 47, 398–404; b) K. Ohta, T. Iijima, E. Kawachi, H. Kage-
chika, Y. Endo, Bioorg. Med. Chem. Lett. 2004, 14, 5913–5918; c) R. N.
Grimes, Carboranes, 2nd ed.; Academic Press, New York, 2011.
13881–13886; f) J. L. Major, R. M. Boiteau, T. J. Meade, Inorg. Chem. 2008,
4
7, 10788–10795; g) A. C. Esqueda, J. A. Lopez, G. Andreu-de-Riquer, J. C.
Alvarado-Monzon, J. Ratnakar, A. J. M. Lubag, A. D. Sherry, L. M. D. Leon-
Rodríguez, J. Am. Chem. Soc. 2009, 131, 11387–11391; h) Y. You, E. To-
mad, K. Hwang, T. Atanasijevic, W. Nam, A. P. Jasanoff, S. J. Lippard, Chem.
Commun. 2010, 46, 4139–4141; i) R. Macrae, P. Bagchi, S. Sumalekshmy,
C. J. Fahrni, Chem. Rev. 2009, 109, 4780–4872.
[
18] NMR/MRI probes for Cu2+: a) E. L. Que, C. J. Chang, J. Am. Chem. Soc.
2006, 128, 15942–15943; b) E. L. Que, E. Gianolio, S. L. Baker, A. P. Wong,
S. Aime, C. J. Chang, J. Am. Chem. Soc. 2009, 131, 8527–8536.
19] NMR/MRI probes for Fe2+ and Mn : a) R. Ruloff, G. Van Koten, A. E.
Merbach, Chem. Commun. 2004, 842–843; b) J. B. Livramento, E. Toth, A.
Sour, A. Borel, A. E. Merbach, R. Ruloff, Angew. Chem. Int. Ed. 2005, 44,
2+
[
1
480–1484; Angew. Chem. 2005, 117, 1504; c) J. Paris, C. Gameiro, V.
Humblet, P. K. Mohapatra, V. Jacques, J. F. Desreux, Inorg. Chem. 2006,
5, 5092–5102.
[30] a) M. Scholz, E. Hey-Hawkins, Chem. Rev. 2011, 111, 7035–7062; b) V. I.
Bregradze, Chem. Rev. 1992, 92, 209–223.
4
[31] a) T. U. Probst, J. Fresenius, Anal. Chem. 1999, 364, 391–403; b) R. F. Barth,
J. A. Coderre, G. H. Vicente, T. E. Blue, Clin. Cancer Res. 2005, 11, 3987–
4002; c) R. F. Barth, M. G. H. Vincente, O. K. Harling, W. S. Kiger III, K. J.
Riley, P. J. Binns, F. M. Wagner, M. Suzuki, T. Aihara, I. Kato, S. Kawabata,
Radiat. Oncol. 2012, 7, 146; d) Z. Yinghuan, K. C. Yan, J. A. Maguire, N. S.
Hosmane, Curr. Chem. Biol. 2007, 1, 141–149; e) N. S. Hosmane, J. A.
Maguire, Y. Zhu, M. Takagaki, Boron and Gadolinium Neutron Capture
Therapy for Cancer Treatment, World Scientific, Singapore, 2012; f) M.
Takagaki, Y. Oda, S. Miyatake, H. Kikuchi, T. Kobayashi, Y. Sakurai, M.
Osawa, K. Mori, K. Ono, J. Neuro-Oncol. 1997, 35, 177–185.
[
20] For NMR/MRI probes for Ca2+, see: a) W. Li, S. E. Fraser, T. J. Meade, J.
Am. Chem. Soc. 1999, 121, 1413–1414; b) W. Li, G. Parigi, M. Fragai, C.
Luchinat, T. J. Meade, Inorg. Chem. 2002, 41, 4018–4024; c) T. Atanasi-
jevic, M. Shusteff, P. Fam, A. Jasanoff, Proc. Natl. Acad. Sci. USA 2006, 103,
1
4707–14712; d) G. Angelovski, P. Fouskova, I. Mamedov, S. Canals, E.
Toth, N. K. Logothetis, ChemBioChem 2008, 9, 1729–1734; e) K. Dhingra,
M. E. Maier, M. Beyerlein, G. Angelovski, N. K. Logothetis, Chem. Commun.
2
N. K. Logothetis, E. Toth, J. Biol. Inorg. Chem. 2008, 13, 35–46; g) A.
Mishra, P. Fouskova, G. Angelovski, E. Balogh, A. K. Mishra, N. K. Logothe-
tis, E. Toth, Inorg. Chem. 2008, 47, 1370–1381; h) S. Khatua, S. H. Choi, J.
Lee, J. O. Huh, Y. Do, D. G. Churchill, Inorg. Chem. 2009, 48, 1799–1801;
i) T. Atanasijevic, X. Zhang, S. J. Lippard, A. Jasanoff, Inorg. Chem. 2010,
008, 3444–3446; f) K. Dhingra, P. Fouskova, G. Angelovski, M. E. Maier,
[32] a) R. A. Wiesboeck, M. F. Hawthorne, J. Am. Chem. Soc. 1964, 86, 1642–
1643; b) L. I. Zakharkin, V. N. Kalinin, Tetrahedron Lett. 1965, 6, 407–409;
c) M. F. Hawthorne, D. C. Young, P. M. Garrett, D. A. Owen, S. G. Schwerin,
F. N. Tebbe, J. A. Wegner, J. Am. Chem. Soc. 1968, 90, 862–868; d) T. D.
Getman, Inorg. Chem. 1998, 37, 3422–3423; e) M. A. Fox, W. R. Gill, P. L.
Herbertson, J. A. H. Macbride, K. Wade, Polyhedron 1996, 15, 565–571; f)
M. A. Fox, K. J. Wade, Organomet. Chem. 1999, 573, 279–291; g) J. Yoo,
J.-H. Hwang, Y. Do, Inorg. Chem. 2001, 40, 568–570; h) C. E. Willans, C. A.
Kilner, M. A. Fox, Chem. Eur. J. 2010, 16, 10644–10648; i) F. Tebbe, P. M.
Garrett, M. F. Hawthorne, J. Am. Chem. Soc. 1964, 86, 4222–4223.
[33] a) D. C. Young, D. V. Howe, M. F. Howthorne, J. Am. Chem. Soc. 1969, 91,
859–862; b) S. Heřmánek, T. Jelínek, J. Plešek, B. Štíbr, J. Fusek, Collect.
Czech. Chem. Commun. 1988, 53, 2742–2752; c) J. Plešek, T. Jelínek, F.
Mareš, S. Heřmánek, Collect. Czech., Chem. Commun. 1993, 58, 1534–
1547; d) V. I. Stanko, V. Brattsev, J. Gen. Chem. USSR (Engl. Transl) 1967,
37, 486; e) V. I. Stanko, V. Brattsev, J. Gen. Chem. USSR (Engl. Transl) 1968,
38, 636; f) V. I. Stanko, V. Brattsev, Dokl. Akad. Nauk SSSR 1967, 172, 1343.
[34] See: M. F. Hawthrone, D. C. Young, T. D. Andrews, D. V. Howe, R. L. Pilling,
A. D. Pitts, M. Reintjes, L. F. Warren Jr., P. A. Wegner, J. Am. Chem. Soc.
1968, 90, 879–896 [it is reported that nido-forms of o-carborane and
4
9, 2589–2591.
[
[
21] For MRI probes for Ca2+, K+ and Mg2+, see: H. Hifumi, A. Tanimoto, D.
Citterio, H. Komatsu, K. Suzuki, Analyst 2007, 132, 1153–1160.
22] a) G. W. Kabalka, C. Tang, P. Bendel, J. Neuro-Oncol. 1997, 33, 153–161;
b) P. Bendel, NMR Biomed. 2005, 18, 74–82; c) K. M. Bradshaw, M. P.
Schweizer, G. H. Glover, J. R. Hadley, R. Tippets, P. P. Tang, W. L. Davis,
M. P. Heilbrun, S. Johnson, T. Ghanem, Magn. Reson. Med. 1995, 34, 48–
5
2
6; d) G. W. Kabalka, M. Davis, P. Bendel, Magn. Reson. Med. 1998, 8,
31–237; e) S. Hermanek, Chem. Rev. 1992, 92, 325–362; f) Y. Zhu, N. S.
Hosmane, Future Med. Chem. 2013, 5, 705–714; g) D. V. Hingorani, A. S.
Bernstein, M. D. Pagel, Contrast. Media. Mol. Imaging 2014, 10, 245–265;
h) L. Ronconi, P. J. Sadler, Coord. Chem. Rev. 2008, 252, 2239–2277; i)
P. P. Z. Tang, M. P. Schweizer, K. M. Bradshaw, W. F. Bauer, Biochem. Phar-
macol. 1995, 49, 625–632.
[
[
23] M. Kitamura, T. Suzuki, R. Abe, T. Ueno, S. Aoki, Inorg. Chem. 2011, 50,
1
1568–11580.
2
+
24] For reviews of metal complexes of macrocyclic polyamines, see: a) E.
Kimura, T. Koike, Chem. Soc. Rev. 1998, 27, 179–184; b) S. Aoki, E. Kimura,
Chem. Rev. 2004, 104, 769–787; c) S. Itoh, S. Sonoike, M. Kitamura, S.
Aoki, Int. J. Mol. Sci. 2014, 15, 2087–2118; d) E. Kimura, Bull. Jpn. Coord.
Chem. 2012, 59, 26–47; e) S. Aoki, M. Zulkefeli, M. Kitamura, Y. Hisamatsu,
in: Synergy in Supramolecular Chemistry (Ed.: T. Nabeshima), CRC, Boca
Raton, FL, USA, 2015, p. 33–56; f) F. Liang, S. Wan, Z. Li, X. Xiong, L. Yang,
X. Zhou, C. Wu, Curr. Med. Chem. 2006, 13, 711–727; g) A. Bencini, V.
Lippolis, B. Valtancoli, Inorg. Chim. Acta 2014, 417, 38–58; h) A. E. Har-
grove, S. Nieto, T. Zhang, J. L. Sessler, E. V. Anslyn, Chem. Rev. 2011, 111,
2
Cu form a 2:1 complex (nido-5) Cu, which is unstable in the air, al-
though full decomposition products were not analyzed].
35] E. Kimura, S. Aoki, T. Koike, M. Shiro, J. Am. Chem. Soc. 1997, 119, 3068–
3076.
[
[36] a) R. J. Schaeffer, J. Am. Chem. Soc. 1957, 79, 1006–1007; b) T. L. Heying,
J. W. Ager Jr., S. L. Clark, D. J. Mangold, H. L. Goldstein, M. Hillman, R. J.
Polak, J. W. Szymanski, Inorg. Chem. 1963, 2, 1089–1092.
[37] H. Nakamura, K. Aoyagi, Y. Yamamoto, J. Am. Chem. Soc. 1998, 120, 1167–
1171.
[38] K. Ohta, S. Koohno, Y. Endo, Chem. Pharm. Bull. 2009, 57, 307–310.
1
1
6603–6782.
[39] As suggested by reviewers, B reference frequency can be calculated
1
[
25] a) M. F. Hawthorne, A. Mandera, Chem. Rev. 1999, 99, 3421–3434; b) P.
Kaszyuski, Collect Czech. Chem. Commun. 1999, 64, 895–926; c) L. Deng,
from H NMR signal of TMS. BF ·Et O was used as an external reference
3
2
in this work for the following two reasons. One is to measure accurate
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1833
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
chemical shifts of 11B NMR signals of B(OH)
derivatives accurately in all the decomposition reactions and the second
is to determine the concentrations of B(OH) produced by decomposi-
tion of o-carborane based on the amount (concentration) of BF ·Et
produced from o-carborane
senko, Z. A. Starikova, P. V. Petrovskii, Z. Janousek, M. Corsini, F. Laschi,
P. Zanello, A. R. Kudinov, J. Organomet. Chem. 2005, 690, 4745–4754; d)
Z. Janoušek, S. Heřmánek, J. Plešek, B. Štíbr, Collect. Czech. Chem. Com-
mun. 1974, 39, 2363–2373.
3
3
3
2
O
solution (the same reference sample was used throughout the decom-
position reactions of each substrate). An illustration of NMR samples
used in this work is shown in Figure S1 in the Supporting Information.
For the references of 11B NMR of boron-containing compounds in which
[47] B. Grüner, J. Holub, J. Plešek, B. Štíbr, M. Thornton-Pett, J. D. Kennedy,
Dalton Trans. 2007, 4859–4865.
[48] a) M. V. Yarosh, T. V. Baranova, V. L. Shirokii, A. A. Érdman, N. A. Maier,
Elektrokhimiya 1993, 29, 921–922; M. V. Yarosh, T. V. Baranova, V. L.
Shirokii, A. A. Érdman, N. A. Maier, Russ. J. Electrochem. 1993, 29, 789–
790; b) M. V. Yarosh, T. V. Baranova, V. L. Shirokii, A. A. Érdman, N. A.
Maier, Elektrokhimiya 1994, 30, 366–368; M. V. Yarosh, T. V. Baranova, V. L.
Shirokii, A. A. Érdman, N. A. Maier, Russ. J. Electrochem. 1994, 30, 366–
368; c) E. J. Ukpong, N. W. Akpanudo, J. Prasad, Afr. J. Pure Appl. Chem.
2010, 4, 38–43.
3 2
BF ·Et O was used as an external reference, see: a) R. Otero, S. Seoane,
R. Sigüeiro, A. Y. Belorusova, M. A. Maestro, R. Pérez-Fernández, N. Rochei,
A. Mourino, Chem. Sci. 2016, 7, 1033–1037; b) S. Krupski, G. Kehr, C. G.
Daniliuc, G. Erker, Dalton Trans. 2016, DOI: 10.1039/C5DT03879K.
40] R. A. Edwards, Analyst 1980, 105, 139–146.
[
[
41] Isolation of the products (or intermediates) from 6a–c after the release
2
+
of 4–5 B(OH)
3
was not successful.
4
[49] Reduction reaction of Cu by NaBH or other reducing agents has been
[
[
42] R. W. Atteberry, J. Phys. Chem. 1958, 62, 1457–1458.
43] C. D. Eisenbach, U. S. Schubert, G. R. Baker, G. R. Newkome, J. Chem. Soc.,
Chem. Commun. 1995, 69–70.
reported, see: a) L. F. Hohnstedt, B. O. Miniatas, S. M. C. Waller, Anal.
Chem. 1965, 37, 1163–1164; b) C. Gomez-Lahoz, F. Garcia-Herruzo, J. M.
Rodriguez-Maroto, J. J. Rodriguez, Sep. Sci. Technol. 1992, 27, 1449–1468.
[50] 11B MRI images differentiating B(OH)
and o-carborane 4 is shown in
Figure S13 in the Supporting Information. These B NMR images were
acquired by using spin echo sequence with TE = 3.4 ms and TR = 200 ms.
[
44] a) M. Zulkefeli, A. Suzuki, M. Shiro, Y. Hisamatsu, E. Kimura, S. Aoki, Inorg.
Chem. 2011, 50, 10113–10123; b) M. Zulkefeli, Y. Hisamatsu, A. Suzuki, Y.
Miyazawa, M. Shiro, S. Aoki, Chem. Asian J. 2014, 9, 2831–2841.
45] E. M. Shvarts, R. T. Ignash, R. G. Belouova, Russ. J. Gen. Chem. 2005, 75,
3
1
1
1
1
[
[
[51] Changes, in: the B MRI of 6a, 6b and 10 and a detailed explanation
1
687–1692.
46] a) H. C. Kang, S. S. Lee, C. B. Knobler, M. F. Hawthorne, Inorg. Chem. 1991,
0, 2024–2031; b) B. Štíbr, F. Teixidor, C. Vinas, J. Fusek, J. Organomet.
Chem. 1998, 550, 125–130; c) V. I. Meshcheryakov, P. S. Kitaev, K. A. Lys-
are presented in Figure S14 in the Supporting Information.
3
Received: February 5, 2016
Published Online: March 21, 2016
Eur. J. Inorg. Chem. 2016, 1819–1834
www.eurjic.org
1834
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim