Synthesis of hydrophilic ultrafine nanoparticles coordinated with carbohydrate cluster

Article abstract of DOI:10.1081/CAR-120014905

A hydrophilic phosphine oxide (1) as a suitable ligand for semiconductor nanoparticles was synthesized. The hydrophilicity of the phosphine oxide was enhanced by introduction of three mannose moieties to the end of the molecule via amide linkages. The ligand 1 was able to coordinate to the CdSe/ZnS nanoparticle making the newly formed hydrophilic complex.

Full text of DOI:10.1081/CAR-120014905

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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 21, No. 5, pp. 445–449, 2002
COMMUNICATION
SYNTHESIS OF HYDROPHILIC ULTRAFINE
NANOPARTICLES COORDINATED WITH
CARBOHYDRATE CLUSTER
1
1,2
Jun-ichi Tamura,1,2, Masumi Fukuda, Junko Tanaka,
*
and Manabu Kawa3
1Department of Environmental Sciences, Faculty of Education and Regional
Sciences, Tottori University, Tottori 680-8551, Japan
2CREST, Japan Science and Technology Corporation (JST),
Kawaguchi 332-0012, Japan
3MCC-Group Science and Technology Research Center,
Mitsubishi Chemical Corporation, 1000 Kamoshida-cho,
Aoba-ku, Yokohama 227-8502, Japan
ABSTRACT
A hydrophilic phosphine oxide (1) as a suitable ligand for semiconductor
nanoparticles was synthesized. The hydrophilicity of the phosphine oxide was
enhanced by introduction of three mannose moieties to the end of the
molecule via amide linkages. The ligand 1 was able to coordinate to the
CdSe/ZnS nanoparticle making the newly formed hydrophilic complex.
Key Words: Nanoparticles; Carbohydrate cluster
Semiconductor nanocrystals and nanoparticles can exhibit unique photonic prop-
erties such as the absorption and emission of photons, properties which can be used for
medical and pharmaceutical purposes. It is necessary that the nanoparticles be soluble
in common solvents for practical applications, and efforts have been made to make
*
Corresponding author. E-mail: jtamura@fed.tottori-u.ac.jp
445
DOI: 10.1081/CAR-120014905
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446
TAMURA ET AL.
Figure 1. Targeted hydrophilic ligand for the nanoparticles.
these materials suitably soluble. Phosphine oxides can coordinate transition metals and
semiconductor nanocrystals. Katari[1] and Dabbousi[2] reported that transition metals
combine with trioctylphosphine oxide (TOPO) as a ligand to form semiconductor ul-
trafine nanoparticles. These nanoparticles are soluble in organic solvents such as chlo-
roform and toluene through coordination with the hydrophobic TOPO, but not soluble
in polar solvents such as water and ethanol. We are interested in applying such spec-
trometrically useful nanoparticles to luminescence diagnostic agents using a hydrophilic
or water-soluble ligand instead of TOPO. Bawendi and coworkers have addressed this
problem[3] by employing ionic functional groups such as carboxylate salts to solubilize
the nanoparticles. However, water solubility of the nanoparticle is significantly affected
by the pH and ionic strength of the aqueous solution, and the nanoparticles exhibit no
peculiar biological activity such as cell recognition. These facts prompted us to syn-
thesize hydrophilic and stable nanoparticles that can overcome these problems. Thus we
designed and synthesized molecule 1 (Figure 1) composed of these hydrophilic a-
Scheme 1. Synthesis of tris [(4-aminobenzyl) oxypropyl] phosphine oxide (4) from 2.

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HYDROPHILIC ULTRAFINE NANOPARTICLES
447
mannopyranosyl moieties linked to phosphine oxide, which can be examined in order
to determine the affinity of the mannose units to specific proteins such as Concanavalin
A. We demonstrated the increased hydrophilicity through coordination of 1 to the
semiconductor nanoparticles.
We selected a commercially available phosphine oxide [2, tris(3-hydroxypro-
pyl)phosphine oxide] as the ligand-core possessing a tris(3-hydroxypropyl) group, and
added a linker at the end of 2. As shown in Scheme 1, the 4-nitrobenzylation of 2 was
first examined. Although 2 showed a slight or no solubility in common solvents such as
CH2Cl2, THF, benzene and pyridine, a longer reaction time (10 days) using 4-nitro-
benzyl bromide and Ag2O in CH2Cl2 did produce the desired tris[(4-nitrobenzyl)oxy-
propyl]phosphine oxide (3)[4] in 96% yield. The use of benzene as the solvent produced
a similar result, but THF and pyridine did not provide the desired compound. AgOTf
was used in CH2Cl2 in place of Ag2O, although the yield of 3 was low. The AgOTf-
THF system,[5] which completely dissolved 2, did not afford 3 at all. The three nitro
groups of 3 were then reduced with zinc powder in aq AcOH to yield 4 in 75%.
2,3,4,6-Tetra-O-acetyl-a-D-mannopyranosyl trichloroacetimidate[6] was converted
to the corresponding allyl glycoside (5) using TMSOTf as a promoter in 54% yield
together with the corresponding b-isomer (23%). The allyl a-glycoside 5 was then
oxidized to give the carboxylic acid (6) with RuCl3-NaIO4 in CCl4-CH3CN-H2O[7] in
88% yield (Scheme 2). The coupling reaction of 4 and 6 was performed with O-
benzotriazol-1-yl-N, N, N’, N’-tetramethyluronium hexafluorophosphate (HBTU) and N-
Scheme 2. Conversion to the targeting compound 1.

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TAMURA ET AL.
Scheme 3. Schematic of the cross sections of the synthesized nanoparticles.
hydroxybenzotriazole (HOBt) in the presence of iPr2EtN in DMF at ꢀ 20°C, and the
desired triamide (7)[4] was obtained in 67% yield as the key intermediate. The sol-
volysis of 7 was carried out with Et3N in aq MeOH and the targeted compound 1[4] was
obtained in 85% yield after purification with HPLC (C18). We assigned the structures
1
of 3, 7 and 1 from their H NMR spectra which showed the high symmetries of these
tris-substituted phosphine oxides.
We selected the luminescing CdSe/ZnS core/shell type nanoparticle,[2] where the
cadmium selenide core crystal is covered with zinc sulfide shell crystals via epitaxial
crystal growth on the CdSe core. The CdSe/ZnS was then coordinated with TOPO to
give CdSe/ZnS-TOPO (8) as reported by Dabbousi et al.[2] Finally, we coordinated the
carbohydrate-derived phosphine oxide (1) to the nanoparticle (8). To the stirred dis-
persion of 8 in EtOH was added an excess amount of 1 and the mixture was refluxed.
A clear EtOH solution was produced indicating that we had obtained the hydrophilic
semiconductor nanoparticle (9) due to the replacement of TOPO with hydrophilic 1
(Scheme 3).
In summary, we have designed and synthesized a hydrophilic phosphine oxide (1)
as a suitable ligand for semiconductor nanoparticles. The hydrophilicity of the
phosphine oxide was enhanced by introduction of three mannose moieties to the end of
the molecule via amide linkages. These results indicate that the ligand 1 was able to
coordinate to the CdSe/ZnS nanoparticle making the newly formed complex signi-
ficantly more hydrophilic than CdSe/ZnS-TOPO.
REFERENCES
1. Katari, L.E.B.; Colvin, V.L.; Alivisatos, A.P. X-ray photoelectron spectroscopy of
CdSe nanocrystals with applications to studies of the nanocrystal surface. J. Phys.
Chem. 1994, 98, 4109–4117.
2. Dabbousi, B.O.; Rodriguez-Viejo, J.; Mikulec, F.V.; Heine, J.R.; Mattoussi, H.;
Ober, R.; Jensen, K.F.; Bawendi, M.G. (CdSe)ZnS core-shell quantum dots:
Synthesis and characterization of a size series of highly luminescent nanocrystal-
lites. J. Phys. Chem., B 1997, 101, 9463–9475.
3. Inventor: Bawendi, M.G.; Mikulec, F.V.; Sundar, V.C. Biological Applications of
Semiconductor Nanocrystals, USA, WO 2000017642 (A2), March 30, 2000.

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HYDROPHILIC ULTRAFINE NANOPARTICLES
449
4. Physical data for key compounds are given below, values of dH were measured at
25°C. Chemical shifts are expressed in ppm downfield from the signal for internal
Me4Si for solutions in CDCl3, and for the solutions in D2O, in ppm downfield from
the signal for Me4Si, by reference to internal DHO (4.65). 3: dH (500 MHz, CDCl3)
8.12 (d, 2Hx3, J= 8.3Hz, Ph), 7.40 (d, 2Hx3, J =8.8Hz, Ph), 4.53 (s, 2Hx3, PhCH2),
3.52 (m, 2Hx3, OCH2), 1.92 ꢀ 1.74 (m, 4Hx3, PCH2CH2). Anal. Calcd for
C30H36N3PO10ꢁ0.5H2O (638.67): C, 56.41; H, 5.85; N, 6.58. Found: C, 56.51; H,
5.77; N, 6.62. 7: dH (500 MHz, CDCl3) 8.17 (s, 1Hx3, NH), 7.57 (m, 2Hx3, Ph),
7.29 (m, 2Hx3, Ph), 5.41 (m, 1Hx3, H-2), 5.40 (dd, 1Hx3, J2,3 = 3.2Hz, H-3), 5.32 (t,
1Hx3, J3,4 = J4,5 =9.7Hz, H-4), 4.97 (s, 1Hx3, H-1), 4.47 (s, 2Hx3, PhCH2), 4.31 (m,
2Hx3, H-6a, 1/2OCH2CO), 4.13 (m, 2Hx3, H-6b, 1/2OCH2CO), 4.03 (m, 1Hx3,
H-5), 3.51 (m, 2Hx3, OCH2), 2.18, 2.11, 2.17, 2.14 (each s, 3Hx4x3, CH3CO),
1.91 ꢀ 1.78 (m, 4Hx3, PCH2CH2), MALDI-MS: m/z = 1704.4 (calcd for
C78H103N3PO37 1704.60 [M + H] + ), 1726.4 (calcd for C78H102N3PO37Na
1726.58 [M + Na] + ), 1742.4 (calcd for C78H102N3PO37K 1742.55 [M +K] + ). 1:
dH (500 MHz, D2O) 7.27 (d, 2Hx3, J= 8.5Hz, Ph), 7.21 (d, 2Hx3, J=8.5Hz, Ph),
4.77 (d, 1Hx3, J1,2 =1.6Hz, H-1), 4.44 (s, 2Hx3, PhCH2), 4.28, 4.19 (ABq, 2Hx3,
J=15.4Hz, OCH2CO), 3.93 (dd, 1Hx3, J2,3 =3.4Hz, H-2), 3.74 (dd, 1Hx3,
J3,4 =8.9Hz, H-3), 4.70 (dd, 1Hx3, J5,6a = 2.1Hz, Jgem = 12.1Hz, H-6a), 4.59 (dd,
1Hx3, J5,6b =5.5Hz, H-6b), 3.52 (t, 1Hx3, J4,5 = J4,5 =8.9Hz, H-4), 3.48 (m, 1Hx3,
H-5), 3.42 (m, 2Hx3, OCH2), 1.65 ꢀ 1.54 (m, 4Hx3, PCH2CH2), MALDI-MS: m/
z=1222.5 (calcd for C54H78N3PO25Na 1222.45 [M +Na] + ), 1238.5 (calcd for
C54H78N3PO25K 1238.43 [M +K] + ).
5. Tamura, J.; Horito, S.; Yoshimura, J.; Hashimoto, H. Effect of complexation of
silver ion with the glycosyl donor and acceptor on the regio- and stereoselectivity in
the b-mannopyranosylation of 1,3-Di-N-benzyloxycarbonyl-2-deoxystreptamine
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a-D-Manp-(1 ! 3)-b-D-Manp-(1 ! 4)-b-D-Glcp-(1 !1)-cer and a-D-Manp-
(1 ! 3)-[b-D-Xylp-(1 ! 2)]-b-D-Manp-(1! 4)-b-D-Glcp-(1 !1)-cer. Carbohydr.
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Received January 24, 2002
Accepted June 27, 2002