Synthesis and structure of novel closo-dodecaborate-based glycerols

Article abstract of DOI:10.1016/j.jorganchem.2009.10.038

The reactions of oxonium derivatives of [B₁₂H₁₂]^2- with different glycerol-based nucleophiles were studied. A series of novel closo-dodecaborate-based glycerols with different net charges on the molecules were prepared. A structure of {2-[2-(4-(2, 3-dihydroxypropyl)-dipiperazinium-1-yl)-ethoxy]-ethoxy}-undecahydro-closo-dodecaborate was determined and the existence of different intermolecular H-bonds was shown.

Full text of DOI:10.1016/j.jorganchem.2009.10.038

Journal of Organometallic Chemistry 695 (2010) 370–374
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis and structure of novel closo-dodecaborate-based glycerols
a,*
a
a
a
a
Andrey Semioshkin , Julia Laskova , Olga Zhidkova , Ivan Godovikov , Zoya Starikova ,
a
b
Vladimir Bregadze , Detlef Gabel
a
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russia
Department of Chemistry, University of Bremen, Leobener Str. NW2 C3020, D-28357 Bremen, Germany
b
a r t i c l e i n f o
a b s t r a c t
The reactions of oxonium derivatives of [B12H12]2 with different glycerol-based nucleophiles were stud-
ied. A series of novel closo-dodecaborate-based glycerols with different net charges on the molecules
were prepared. A structure of {2-[2-(4-(2, 3-dihydroxypropyl)-dipiperazinium-1-yl)-ethoxy]-ethoxy}-
undecahydro-closo-dodecaborate was determined and the existence of different intermolecular H-bonds
was shown.
ꢀ
Article history:
Received 15 June 2009
Received in revised form 19 October 2009
Accepted 25 October 2009
Available online 30 October 2009
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Closo-dodecaborate
Oxonium derivatives
Glycerol
X-ray structure
1
. Introduction
Water-soluble functionalized derivatives of the dodecahydro-
lipids in the liposome bilayer. Both approaches, using different
types of boron compounds, have been described and some results
are summarized in reviews [3–5]. Boron-containing lipids consti-
tute very interesting building blocks for the construction of bor-
on-containing liposomes. A few approaches toward the synthesis
of such lipids intended for incorporation into liposomes have been
described in the literature. Synthesis of a nido-carborane lipid with
a one-tailed moiety has been described, and the liposomal boron
delivery using this compound and distearoylphosphatidylcholine
(DSPC) has been examined in mice [6,7]. Later, Nakamura et al. de-
signed a nido-carborane lipid with a double-tailed moiety for the
purposes of high boron accumulation into liposomes [8]. More re-
cently, Hawthorne et al. described a very similar lipid and investi-
gated the in vivo toxicity of liposomes formed from the
boron-containing lipid and helper lipids (DSPC, cholesterol
(CHO)). They found that the liposomes were very toxic already at
dosages of 6 mg boron per kg body weight [9]. Therefore, nido-car-
borane-based lipids might be problematic as agents for boron
delivery in BNCT. Synthesis of the first ether lipid based on the clos-
o-dodecaborate anion was reported by Sivaev et al. [10], some later
closo-dodecaborate anion are promising candidates for boron
neutron capture therapy (BNCT) [1]. Our continuing interest in
the chemistry of the dodecahydro-closo-dodecaborate anion [B12
2
ꢀ
H
12
]
aims toward facile, reliable and rational introduction of a
broad variety of substituents. One of these methods consists of
synthesis of its oxonium derivatives followed by their nucleophilic
cleavage. This approach permits us to synthesize a range of
2
-
12 12
[B H ] derivatives with different active groups and them to var-
ious molecules [2]. Synthesis of closo-dodecaborate derivatives of
glycerol is important because these compounds are standard start-
ing materials for the preparation of lipids, precursors of liposomes.
Liposomes are the smallest spherical lipid bilayers that can be pro-
duced from non-toxic phospholipids and cholesterol. These vesi-
cles can be used as drug carriers and can be loaded with variety
of molecules. The most commonly used lipids in preparation of lip-
osomes are phosphatidylcholine, phosphatidylinositol and choles-
terol which have limited intrinsic toxicity and are found
abundantly as the components of cell membranes. Drugs with
widely varying lipophilicities can be encapsulated in liposomes
either in the phospholipid bilayer or in the entrapped aqueous
core. Therefore, two approaches are possible when using liposomes
in boron delivery: encapsulation of boron compounds in the aque-
ous core of the liposome, and incorporation of boron-containing
2ꢀ
2ꢀ
10
ester lipids containing [B12
H
12
]
and [B10
H
]
anions were pre-
pared by Lisovskii et al. [11]. A series of closo-dodecaborate-con-
taining ester lipids was recently described by Nakamura and co-
workers [12]. Synthesis of the double-tailed boron cluster lipids
and, which have a [B12
was achieved by S-alkylation of [B12
H11S]-moiety as a hydrophilic function,
2
ꢀ
H11SH] (BSH) with bromo-
acetyl and chloroacetocarbamate derivatives of diacylglycerols. A
new class of lipids containing also BSH as hydrophilic lipid head
group was synthesized by Gabel and co-workers [13]. Two lipids
*
Corresponding author.
E-mail address: semi@ineos.ac.ru (A. Semioshkin).
0
022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.10.038

A. Semioshkin et al. / Journal of Organometallic Chemistry 695 (2010) 370–374
371
based on diethanolamine (S-(N,N-(2-dimyristoyloxyethyl)acetam-
ido)thioundecahydro-closo-dodecaborate (2-) and S-(N,N-(2-
dipalmitoyloxyethyl)acetamido)thioundecahydro-closo-dodecaborate
19.7 (NCH
cm ): 2478 (BH).
2
CH
2
CH
2
CH ); 13.8 (NCH CH
3 2 2
CH CH
2 3
). IR (m, nujol,
ꢀ
1
(
2-)) were described by them. One of these compounds was found
to form liposomal vesicles without the addition of helper lipids,
representing the first boron-containing lipid with this capability.
Recently two more diethanolanine B12-containig lipids were syn-
thesized from the corresponding oxonium derivatives and their
liposomal formation was studied as well by Gabel and co-workers
2.3. Synthesis of dicesium {2-[2-(2,3-dihydroxypropoxy)ethoxy]ethoxy}-
undecahydro-closo-dodecaborate 3
Compound 2 (0.985 g) (0.0016 mol) was dissolved in 10 ml of
MeOH and the solution of 0.65 g (0.00424 mol) of CsF in 10 ml of
MeOH was added. A white precipitate was formed. It was filtered,
washed with 10 ml of MeOH and vacuum dried. Then it was dis-
[
14]. In conclusion, till now B12-based lipids were prepared either
from BSH or from oxonium derivatives, but with a diethanolamine
fragment.
2
solved in 50 ml of H O, and 10 ml of HCl was added. After 4 h of
It is to be mentioned that B12-derivatives that contain the glyc-
erol fragment, especially with free –OH groups, have not yet been
described. However, preparation of such compounds is important
because they seem to be rather attractive synthons for the prepa-
ration of various lipids by simple acylation reactions. Thus, in this
paper we present easy and convenient methods of preparation of
dodecaborate derivatives of glycerol in which the net charge on
the products can be varied. The net charge of the corresponding
lipids may influence the zeta potential of the liposomes and thus
their biological properties, including the interaction with the neg-
atively charged cell membranes.
stirring water was removed in vacuum, the rest was suspended
in 20 ml of THF. The white precipitate was filtered, washed with
20 ml of THF and air dried. Yield: 0.870 g (0.0015 mol, 95%). M.p.
>250 °C. Anal. Calc. For C
7
H
26
B
12Cs
2
O
5
: C, 14.35; H, 4.47. Found:
1
C, 14.20; H, 4.45%. H NMR (D
3.7–3.4 (12H, broad m, CH O); 2.2–0.1 (11H, broad m, BH).
NMR (D
O, d, ppm): 4.64 (1B, s, B(1)); ꢀ17.0 (10B, m, B(2–11));
2
O, d, ppm): 3.85 (1H, m, HCO);
11
2
B
2
1
3
ꢀ21.2 (1B, d, B(12), J = 126 Hz). C NMR (DMSO-d
6
, d, ppm):
ꢀ1
71.7, 71.0, 70.3, 69.9, 69.3, 67.6, 62.6 (CH
2
O). IR (m, nujol, cm ):
3633, 3481 (OH), 2482 (BH).
2.4. Synthesis of tetrabutylammonium-{2-[2-(4-(2, 3-dihydroxypropyl)-
2
. Experimental
dimethylammonium)-ethoxy]-ethoxy}-undecahydro-closo-
dodecaborate 4
2.1. Materials and equipment
The mixture of 1 g (0.002 mol) of 1 and 0.266 g (0.002 mol) of
Chemicals were reagent grade and were used as received from
(2,3-dihydroxy)-propyl-dimethylamine was refluxed in 25 ml of
commercial vendors. Acetonitrile was distilled from P
from CaH . Oxonium derivative 1, and ethyl 4-[(2,2-dimethyl-1,3-
dioxolan-4-yl)methyl]piperazine-1-carboxylate were prepared
2
O
5
and then
CH
O was added to precipitate 4. It was filtered off and vacuum
dried. Yield: 0.787 g (0.0013 mol, 62%). M.p. = 117–118 °C. Anal.
Calc. For C25 : C, 50.85; H, 11.61; N, 4.74. Found: C,
50.64; H, 11.48; N, 4.50%. H NMR (DMSO-d
m, HCO); 3.87 (2H, m, CH O); 3.67 (2H, m, CH
CH N); 3.57 (2H, m, CH O); 3.48 (1H, dd, HOHCHCH, J = 8.9 Hz,
3
CN for 24 h. Then the solvent was evaporated and 10 ml of
H
2
2
according to the described methods [15,16]. The 1H, C and
13
11
B
68 12 2 4
H B N O
1
NMR spectra were recorded at 400.13, 100.61 and 128.38 MHz,
respectively, on a BRUKER-Avance-400 spectrometer. Tetramethyl-
6
, d, ppm): 4.03 (1H,
O); 3.61 (2H, m,
2
2
13
silane and BF
3
/(C H
2 5
)
2
O were used as standards for 1H and
C
2
2
1
1
NMR, and B NMR, respectively. All chemical shifts are reported
in ppm (d) relative to external standards. IR spectra were recorded
on Infralum FT-801 FTIR spectrometer in nujol. Elemental analysis
was performed in the Microanalytical laboratory of the A.N. Nes-
meyanov Institute of Organoelement Compounds.
J = 6.4 Hz); 3.42 (1H, dd, N-HCHCH, J = 7.4 Hz, J = 3.4 Hz); 3.33
(1H, dd, OHCHCH, J = 9.0 Hz, J = 6.4 Hz); 3.30 (1H, dd, N-HCHCH,
J = 7.4 Hz, J = 3.4 Hz); 3.26 (6H, s, CH
3
); 3.17 (8H, m,
CH ); 1.31 (8H, m,
CH , J = 7.3 Hz); 1.9–
, d, ppm): 5.2 (1B, s,
B(1)); ꢀ16.9 (5B, d, B(2–6), J = 127 Hz); ꢀ17.6 (5B, d, B(7–11),
NCH
NCH
2
CH
CH
2
CH
CH
2
CH
CH
3
); 1.56 (8H, m, NCH
2
CH
2
CH
2
3
2
2
2
3
); 0.93 (12H, t, NCH CH
2
2
CH
2
3
1
1
0
.2 (11H, broad m, BH). B NMR (DMSO-d
6
1
3
2
1
.2. Synthesis of tetrabutylammonium sodium (2-{2-[(2,2-dimethyl-
,3-dioxolan-4-yl)methoxy]ethoxy}ethoxy)-undecahydro-closo-
J = 128 Hz); ꢀ21.8 (1B, d, B(12), J = 126 Hz); C NMR (DMSO-d
d, ppm): 70.2 (CHOH); 68.5, 67.9, 66.6, 64.6 (CH O); 64.2, 64.1
); 23.5 (NCH CH
CH CH CH ). IR (
6
,
2
dodecaborate 2
(CH
CH
2
N); 58.0 (NCH
CH ); 19.6 (NCH
2
CH
CH
2
CH
CH
2
CH
CH
3
); 52.5 (CH
); 13.7 (NCH
3
2
2
2
3
2
2
2
3
2
2
2
3
m
,
ꢀ1
To the solution of 2.8 g (0.02 mol) of (2,2-dimethyl-1,3-dioxo-
nujol, cm ): 3629, 3494 (OH), 2485 (BH).
3
lan-4-yl)methanol (solketal) in 25 ml of dry CH CN was added
0
,51 g (0.02 mol) of NaH and the mixture was stirred for 5 min un-
til the evolution of H
2
was completed. Then 1 g of 1 (0.002 mol)
2.5. Synthesis of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazine
was added and the mixture was refluxed for 10 h. Then the solid
was filtered off and washed with 10 ml of CH CN. The solvent
(5)
3
was evaporated and the rest was vacuum dried to afford pure 2
as colorless oil. Yield: 0.985 g (0.0016 mol, 74%). H NMR (DMSO-
Ethyl 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperazine-1-
carboxylate was refluxed in 50 ml of EtOH with 16.8 g (0.3 mol)
1
d
3
1
6
, d, ppm): 4.14 (1H, m, HCO); 3.95, 3.54 (2H, 2 ꢁ m, CH
.5–3.1 (10H, broad m, OCH ); 3.13 (8H, m, NCH CH CH
.54 (8H, m, NCH CH CH CH ); 1.31 (3H, s, CH ); 1.28 (3H, s,
); 1.27 (8H, m, NCH CH CH CH ); 0.90 (12H, t,
NCH CH CH CH , J = 7.3 Hz); 1.9–0.2 (11H, broad m, BH).
NMR (DMSO-d
, d, ppm): 6.4 (1B, s, B(1)); ꢀ16.8 (5B, d, B(2–6),
J = 128 Hz); ꢀ18.2 (5B, d, B(7–11), J = 127 Hz); ꢀ22.8 (1B, d,
2
OCH);
of KOH for 6 h, Then EtOH was evaporated, 50 ml of H
followed by extraction by Et
O (2 ꢁ 10 ml). The organic layers were
combined, dried over K CO , Et O was evaporated and the rest was
vacuum distilled to give 5. Yield: 7.4 g (0.037 mol, 73.8%).
2
O was added
2
2
2
2
CH );
3
2
2
2
2
3
3
2
3
2
CH
3
2
2
2
3
1
1
ꢀ2
1
2
2
2
3
B
B.p. = 75 °C, 5 ꢁ 10 Torr. H NMR (CDCl
CH–O); 4.10 (1H, m, O–HCH); 3.64 (1H, t, O–HCH, J = 10.7); 2.94
(4H, t, CH –N, J = 6.4); 2.50 (6H, m, CH –N); 1.64 (1H, s, NH);
1.46 (3H, s, CH
108.8 (OCHO); 73.6 (CH–O); 68.1 (CH
3
, d, ppm): 4.33 (1H, m,
6
2
2
1
3
13
B(12), J = 128 Hz); C NMR (DMSO-d
6.9 (CHO); 74.7, 72.1, 70.6, 69.9, 67.7, 66.5 (CH
NCH CH CH CH ); 27.1, 25.9 (CH ); 23.5 (NCH CH
6
, d, ppm): 109.0 (C(CH
O); 58.0
CH CH );
3
)
2
);
3
); 1.40 (3H, s, CH
3
). C NMR (CDCl
O); 55.0, 45.7 (CH
3
25.4 (CH ). IR (m, nujol, cm ): 3271 (NH).
3
, d, ppm):
7
(
2
2
2
N); 26.7,
ꢀ1
2
2
2
3
3
2
2
2
3

3
72
A. Semioshkin et al. / Journal of Organometallic Chemistry 695 (2010) 370–374
2.6. Synthesis of Cesium {2-[2-(methyl-(3-(2, 2,-dimethyl-1-3-
2
Cryostream (Oxford Cryosystems) open-flow N gas cryostat.
dioxalanyl))-piperazinium-1-yl)-ethoxy]-ethoxy}-undecahydro-closo-
dodecaborate 6
Reflection intensities were integrated using SAINT software (SMART
V5.051 and SAINT V5.00, area detector control and integration soft-
ware and semi-empirical method SADABS [17]).
The mixture of 1 g (0.002 mol) of 1 and 0.852 g (0.004 mol) of 5
in 50 ml of EtOH was refluxed for 4 h. Then the solvent was evap-
The colorless plate (0.45 ꢁ 0.35 ꢁ 0.20 mm)
ꢂ3(H O) is triclinic (M = 444.19), at 120 K a = 10.157(1) Å,
b = 11.206(1) Å, c = 13.1420(15) Å, = 102.949(3)°, b = 109.403(2)°,
11 36 12 2
C H B N
O
4
2
orated. The residue was washed with Et
recrystallized from 5 ml of EtOH. Compound 6 was filtered and
2
O (2 ꢁ 20 ml) and then
a
3
ꢀ
c
= 107.152(3)°, V = 1259.1(3) Å , space group P1, Z = 2,
3
vacuum dried. Yield: 1 g (0.0015 mol, 75%). M.p. = 170–172 °C.
Dcalc = 1.172 g/Å .
Anal. Calc. For C30
H
75
B
12
N
3
O
4
: C, 53.65; H, 11.25; N, 6.26. Found:
Intensities of 10962 reflections were measured and 4060 inde-
1
C, 53.60; H, 11.18; N, 6.18%. H NMR (DMSO-d
6
, d, ppm): 9.61
pendent reflections (Rint = 0.0388) were used in further calcula-
tions and refinement. The structures were solved by direct
method and refined by the full-matrix least-squares against F2 in
anisotropic (for no-hydrogen atoms) approximation. All carborane
hydrogen atoms and, the H(N) atoms were located from the differ-
ence Fourier syntheses, the H(C) and H(OH) atoms were placed in
geometrically calculated positions. All hydrogen atom positions
were refined in isotropic approximation in riding model with the
Uiso(H) parameters equal to 1.2 Ueq(Xi), where U(Xi) are the
equivalent thermal parameters of the atoms to which correspond-
+
(
1H, broad s, NH ); 4.21 (1H, m, HCO); 4.01 (1H, m, O–HCH);
+
3
.81 (2H, m, CH
2
–O); 3.53 (7H, m, 2 ꢁ CH
2
O, 2 ꢁ CH
2
N
CH
and
CH );
N);
); 1.31 (8H, m,
); 0.94 (12H, t, NCH CH CH CH
J = 4.9); 1.9–0.2 (11H, broad m, BH). B NMR (DMSO-d , d, ppm):
.1 (1B, s, B(1)); ꢀ16.8 (5B, d, B(2-6), J = 127 Hz); ꢀ18.0 (5B, d,
+
OHCH); 3.30 (2H, m, CH
2
N ); 3.17 (8H, m, NCH
2
CH
2
2
3
3
1
NCH
.05 (2H, m, CH
.58 (8H, m, NCH
CH CH CH ); 0.27 (3H, s, CH
2
N); 2.89 (2H, m, CH
2 2
N); 2.55 (2H, m, CH
2
CH CH CH ); 1.33 (3H, s, CH
2
2
3
3
2
2
2
3
3
2
2
2
3
,
11
6
6
13
B(7–11), J = 128 Hz); ꢀ22.6 (1B, d, B(12), J = 126 Hz); C NMR
(
(
5
(
DMSO-d
CH O); 71.5 (CH–O); 60.2, 54.3 (CH
1.6, 49.6 (CH N); 27.2, 26.0 (CH ); 23.6 (NCH
NCH CH CH CH ); 14.0 (NCH CH CH CH ); IR (
133 (NH ), 2485 (BH).
6
,
d, ppm): 108.9 (C(CH
3
)
2
); 74.1, 68.8, 67.9, 64.1
ing H atoms are bonded. The refinement converged to wR
and GOF = 1.013 for all 4860 independent reflections (R
2
= 0.1625
= 0.0716
+
2
2
N ); 58.0 (NCH
CH CH
, nujol, cm ):
2
CH
2
2 3
CH CH );
1
2
3
2
2
2
CH
3
); 19.7
was calculated against F for the 2096 independent reflections with
I > 2 (I)). The number of the refined parameters was 336.
ꢀ
1
2
2
+
2
3
2
2
2
3
m
r
3
All calculations were performed on an IBM PC/AT using the
SHELXTL software [17].
2.7. Synthesis of {2-[2-(4-(2, 3-dihydroxypropyl)-dipiperazinium-1-
yl)-ethoxy]-ethoxy}-undecahydro-closo-dodecaborate (7)
3
. Results and discussion
Since different glycerol derivatives with O– or N – single nucle-
One gram (0.0015 mol) of 6 was dissolved in 20 ml of 16% of
aqueous HCl. Then the solvent was evaporated and the rest was
0
ophilic center are either commercially available or can be easily
prepared, we have studied the reactions of some of these com-
pounds with dioxonium derivative of closo-dodecaborate (1) to
get its novel glycerol derivatives.
recrystallized from the 5 ml of H
6
2
2
O. Yield: 0.5 g (0.0013 mol,
4%). M.p. = 246 °C (dec). Anal. Calc. For C11 ꢂ3H O: C,
9.74; H, 9.53; N, 6.31. Found: C, 29.09; H, 9.34; N, 6.15%.
O, d, ppm): 9.91 (2H, broad s, NH (detected in DMSO-
H
36
B
12
N
2
O
4
2
1
H
NMR (D
2
Previously we have shown that oxonium derivatives of
d
5
6
)); 4.05 (1H, m, CH–O); 3.8–3.4 (18H, m, 4 ꢁ CH
2
O
and
2ꢀ
[
B
12
H
12
]
do react with alcohols [18] and phenols [19] leading
+
+
11
ꢁ CH
2
N ); 3.23 (2H, m, CH
2
N ); 1.9–0.2 (11H, broad m, BH).
B
to corresponding ethers with good yields. Thus, we have run the
reaction of oxoniun derivative 1 with solketal. We have found that
this reaction, as expected, resulted in a novel cleavage product 2 as
a mixed sodium and NBu salt with a good yield. The structure of 2
4
was elucidated by NMR and microanalysis (cf. experimental). For
NMR (D
2
O): 6.2 (1B, s, B(1)); ꢀ16.5 (5B, d, B(2–6), J = 129 Hz);
ꢀ
18.3 (5B, d, B(7–11), J = 129 Hz); ꢀ23.1 (1B, d, B(12),
1
3
J = 126 Hz). C NMR (D
2
O, d, ppm): 74.1 (CHOH); 71.5, 68.7,
+
6
6.0, 64.0 (CH O); 55.2, 54.3 53.9, 52.1, 51.5, 49.9 (CH N ). IR (m,
2
2
ꢀ1
+
nujol, cm ): 3623, 3495 (OH), 3128 (NH ), 2482 (BH).
11
example, in the B NMR of 2 the signal of the substituted boron
atom is shifted ca 2 ppm downfield compared to the starting mate-
+
2.8. X-ray diffraction data
rial 1 [15]. This is typical for the transformation of BO R
2
system to
B–OR. Compound 2 was transferred into its Cs-salt and then the ke-
tal protection was removed, leading to a novel B12-derivative with
glycerol fragment 3 (Scheme 1). In the IR spectrum of 3 the absorb-
Single-crystal X-ray diffraction experiment for 7ꢂ3(H
carried out with a Bruker SMART 1000 CCD area detector, using
graphite monochromated Mo K radiation (k = 0.71073 Å, -scans
and 10 s per frame exposure, 2h < 52 ) at
20 K. Low temperature of the crystals was maintained with a
2
O) were
ꢀ1
a
x
tion bands of OH-groups (3633 and 3481 sm ) were observed. The
o
o
11
1
with a 0.3 step in
1
x
B NMR of 3 was identical to 2. In H NMR, only signals of protons
2
CH–OH, CH –O and BH groups were observed and there were no
O
O
O
O
O
O
O
O
OH
O
O
O
O
HO
1. CsF/MeOH
OH
2. HCl/H2O
NaH/CH3CN
2
-
2-
2-
NBu4
(Na)NBu4
Cs2
=
BH èëè B -
1
2
3
Scheme 1.

A. Semioshkin et al. / Journal of Organometallic Chemistry 695 (2010) 370–374
373
signals of protons of methyl groups, detected in case of 2. In 13C
NMR of 3, seven signals of CH–OH, CH –OH and CH –O fragments
CH–OH, CH
–O and CH
N groups, the signals of two acidic protons
+
2
2
2
2
at 8.91 ppm were detected.
were observed between 72 and 62 ppm. Compound 3 is a novel
closo-dodecaborate cluster with glycerol fragment with (ꢀ2)
charge on the molecule.
In our previous work [20] we have found that oxonium deriva-
tives such as 1 react with various amines leading to corresponding
cleavage products with excellent yields. Thus we have studied the
reactions of 1 with amino derivatives of glycerol. We have found
that oxonium derivative 1 reacts with 3-dimethylamino-propane-
Compound 7 was also studied by single X-ray diffraction anal-
ysis. The molecular structure of (2-{2-[4-(2,3-dihydroxypropyl)
piperazinediium-1-yl]ethoxy}ethoxy)-undecahydro-closo-dode-
caborate (7) is presented in Fig. 1. The 2, 3-dihydroxypropyl frag-
ment is disordered over two positions with site occupancy factors
equal to 0.632 and 0.368, respectively. This disorder is probably
caused by incompactness of crystal packing that causes large
displacement of disordered atoms. The geometric parameters of
closo-dodecaborate cage are rather close to standard B–B bond
distances values. Some of the bond lengths are presented in Table
1. The same bond distances were observed previously [20] for
1
4
,2-diole to give the ammonium derivative 4, isolated as NBu -salt
(
Scheme 2). This (ꢀ1) charged closo-dodecaborate cluster with
glycerol fragment was characterized by NMR and IR spectroscopy.
In the IR spectrum of 4 the absorption band of OH-groups (3629
ꢀ
1
11
and 3494 sm ) were observed. In B NMR of 4, the signal of the
substituted boron atom is shifted ca 2 ppm downfield compared
to the starting material 1 as observed before for compound 2.
1
The H NMR spectrum of 4 was rather complicated, but we suc-
ceeded in assigning the signals using H- H COSY NMR (cf.
experimental).
1
1
To obtain closo-dodecaborate cluster derivatives with glycerol
fragment with no net charge of the molecule, we synthesized the
piperazine derivative 5. We found that 5 react with 1 to give the
corresponding novel ammonium salt 6 (Scheme 3). This precursor
was characterized by NMR spectroscopy. The signal of the acidic
1
NH proton was observed at 9.61 ppm in the H NMR spectrum.
Its acidic hydrolysis and quaternization of the second nitrogen
afforded the goal product 7, B12-derivative of glycerol with no
net charge. Compound 7 was characterized by IR and NMR spec-
troscopy and X-Ray diffraction (XRD) analysis. In the IR spectrum
of 7 the absobtion bands of OH groups and water (3623 (free),
ꢀ
1
+
ꢀ1
3
495 (bonded) cm ) and NH (bonded) (3128 cm ) were ob-
1
1
served. The B NMR of 7 consisted of 4 signals with intensity ratio
of 1:5:5:1 and their chemical shifts were typical for the mono-O-
substituted B12 cluster. In 1H NMR of 7, besides the signals of
O
Fig. 1. The molecular structure of 7 with disordered 2,3-dihydroxypropyl fragment.
OH
OH
OH
OH
N
O
N
Table 1
1
Some elected bond lengths in 7.
0
0
Bond
Bond
d ( AÅ )
d ( AÅ )
2-
B(1)–O(1)
O(1)–C(1)
C(1)–C(2)
C(4)–N(1)
C(10)–O(3)
1.449(4)
1.424(4)
1.500(4)
1.507(4)
1.448(6)
1.417(7)
C(2)–O(2)
O(2)–C(3)
C(3)–C(4)
O(1) ꢂꢂN(1)
C(11)–O(4)
1.421(4)
1.438(4)
1.499(4)
4.557
1.394(6)
1.502(7)
NBu4
4
0
0
0
C(10 )–O(3 )
C(11 )–O(4)
Scheme 2.
O
O
OH
OH
N
O
O
O
O
O
N
H
O
N
N
N
N
HCl
H
H
H
1
5
2-
2-
NBu4
6
7
Scheme 3.

3
74
A. Semioshkin et al. / Journal of Organometallic Chemistry 695 (2010) 370–374
Fig. 2. Dimeric associates formed in the structure of 7 (alkyl H-atoms not displayed). H-bond N2–H2NꢂꢂꢂO4 parameters: distances N2ꢂꢂꢂO4 and H2NꢂꢂꢂO4 are 2.843(4) Å and
.80 Å, respectively; angle at H2N is 158°.
1
In conclusion, we have succeeded in developing effective ap-
proaches to closo-dodecaborate-based glycerols with different net
charges on the molecules. The synthesis of lipids and liposomal
studies based on these novel compounds will be continued in
our laboratories.
Acknowledgements
Authors thank Russian Foundation for Basic Research (Grants
0
8-03-91951-NNIO-a and 09-03-00504-a), Scientific Schools Foun-
dation (Grant 3019.2008.3) and funding programs of Russian Acad-
emy of Sciences for financial support.
Appendix A. Supplementary data
CCDC 734889 contains the supplementary crystallographic data
for compound 7. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jorganchem.2009.10.038.
Fig. 3. The intermolecular hydrogen bonds formed in the structure 7. The distances
N(1)ꢂꢂ O1 W, O(1)ꢂꢂꢂO1 W, O(1) ꢂꢂO3 W, O(3) ꢂꢂO3 W, O(4) ꢂꢂO2 W and O1 W ꢂꢂO4 W
are 2.671(4), 2.804(3), 2.803(3), 2.703(5), 2.553(7) and 2.743(4) Å, respectively.
4
-morpholino-(ethoxy}ethoxy)-undecahydro-closo-dodecaborate.
In this molecule, the O(1)ꢂꢂꢂN(1) chain has twisted conformation
O(1)ꢂꢂꢂN(1) = 2.702 Å) due to the intermolecular hydrogen bond
References
(
N(1)–HꢂꢂꢂO(1). In case of 7, the conformation of this fragment is
stretched and the distance O(1)ꢂꢂꢂN(1) is much longer. An intra-
molecular hydrogen bond with the hydroxy group, N(1)–
H1NꢂꢂꢂO(4)–H, is formed, rather than an intermolecular one.
In the structure of 7, dimeric centeric symmetrical associates
are formed due to a strong hydrogen bonding N2–H2NꢂꢂꢂO4
[
1] I.B. Sivaev, V.I. Bregadze, S. Sjöberg, Collect. Czech. Chem. Commun. 67 (2002)
79.
[2] A.A. Semioshkin, I.B. Sivaev, V.I. Bregadze, Dalton Trans. (2008) 977.
3] M.F. Hawthorne, K. Shelly, J. Neurooncol. 33 (1997) 53.
4] J. Carlsson, E.B. Kullberg, J. Capala, S. Sjöberg, K. Edwards, L. Gedda, J.
Neurooncol. 62 (2003) 47.
6
[
[
[5] G. Wu, R.F. Barth, W. Yang, R. Lee, W. Tjarks, M.V. Backer, J.M. Backer, Anti-
Cancer Agents Med. Chem. 6 (2006) 167.
[
(Fig. 3). The second N1–H1N group and water molecules O1w
6] D.A. Feakes, K. Shelly, M.F. Hawthorne, Proc. Natl. Acad. Sci. USA 92 (1995)
367.
and O3w form intramolecular H-bonds as well (Fig. 2).
Probably, the stretched conformation of 4-(2,3-dihydroxypro-
pyl)piperazinediium-1-yl]ethoxy}ethoxy fragment in 7 is caused
by crystal water that forms strong H-bond with the hydroxy
groups (Fig. 3).
It is to be noticed that compound 7 is one of the rare examples
of the neutral B12-based species and the first one which is structur-
ally characterized.
Thus, using facile cleavage reactions between the dioxanium
derivative of the dodecaborate and O-and N-glycerol based nucle-
ophiles, we have synthesized three novel compounds 3, 4 and 7 in
one or two steps with pretty good yields. These compounds con-
tain on the one hand, a glucerol fragment with two free OH-groups
and on the other hand, substituted closo-dodecaborate cluster unit.
The obtained compounds differ by the net charge of the molecule
1
[7] R.A. Watson-Clark, M.L. Banquerigo, K. Shelly, M.F. Hawthorne, E. Brahn, Proc.
Natl. Acad. Sci. USA 95 (1998) 2531.
[
8] H. Nakamura, Y. Miyajima, T. Takei, S. Kasaoka, K. Maruyama, Chem. Commun.
2004) 1910.
(
[9] T. Li, J. Hamdi, M.F. Hawthorne, Bioconjugate Chem. 17 (2006) 15.
10] I.B. Sivaev, S. Sj(berg, V.I. Bregadze, D. Gabel, Tetrahedron Lett. 40 (1999) 3451.
11] M.V. Lisovskii, N.V. Plyavnik, G.A. Serebrennikova, K.Yu. Zhizhin, E.A. Malinina,
N.T. Kuznetsov, Russ. J. Inorg. Chem. 50 (2005) 20.
[12] (a) J.-D. Lee, M. Ueno, Y. Miyajima, H. Nakamura, Org. Lett. 9 (2007) 323;
(b) H. Nakamura, J.-D. Lee, M. Ueno, Y. Miyajima, H.-S. Ban, Nanobiotechnol 3
[
[
(
2007) 135.
[
13] E. Justus, D. Awad, M. Hohnholt, T. Schaffran, K. Edwards, G. Karlsson, L.
Damian, D. Gabel, Bioconjugate Chem. 18 (2007) 1287.
[14] T. Schaffran, F. Lissel, B. Samatanga, G. Karlsson, A. Burghardt, K. Edwards, M.
Winterhalter, R. Peschka-Süss, R. Schubert, D. Gabel, J. Organomet. Chem. 694
(
2009) 1708.
[
15] I.B. Sivaev, N.Yu. Kulikova, E.A. Nizhnik, M.V. Vichuzhanin, Z.A. Starikova, A.A.
Semioshkin, V.I. Bregadze, J. Organomet. Chem. 693 (2008) 519.
16] M.E. Jung, T.J. Shaw, J. Am. Chem. Soc. 102 (1980) 6304.
17] G.M. Sheldrick, SADABS, Bruker AXS Inc., Madison, WI 53719, USA, 1997.
18] I.B. Sivaev, A.A. Semioshkin, B. Brellochs, S. Sjöberg, V.I. Bregadze, Polyhedron
19 (2000) 627.
19] A. Semioshkin, O. Tsaryova, O. Zhidkova, V. Bregadze, D. Wöhrle, J. Porphyrins
Phthalocyanines 10 (2006) 1293–1300.
20] A. Semioshkin, E. Nizhnik, I. Godovikov, Z. Starikova, V. Bregadze, J. Organomet.
Chem. 692 (2007) 4020.
[
[
[
(
ꢀ2(3), ꢀ1(4) and 0(7)). The free –OH groups of these compounds
can be easily acylated by fatty acids to give corresponding lipids.
Therefore, a different boronated lipids based on these compounds
can be prepared and the influence of the net charge of the lipids
on zeta potential of the liposomes and thus their biological proper-
ties can be studied.
[
[