Synthesis of phosphonic acids with the semicarbazide group for the functionalization of metal oxide mid zeolite nanoparticles

Article abstract of DOI:10.1055/s-2004-829565

The syntheses of two phosphonic acids possessing the Fmoc-protected semicarbazide group are described. The key step was the Curtius rearrangement, performed in the presence of dibenzyl phosphonate esters. Preliminary experiments showed that the phosphonic acid can be grafted at the surface of oxide nanoparticles and colloidal zeolite nanocrystals, without deprotection of the Fmoc group.

Full text of DOI:10.1055/s-2004-829565

LETTER
1735
Synthesis of Phosphonic Acids with the Semicarbazide Group for the
Functionalization of Metal Oxide and Zeolite Nanoparticles
S
ynthesis of Ph
r
osphonic
i
Acids
s
w
ith the
S
t
emica
a
G
ro
n
up Doussineau,*a Jean-Olivier Durand,a Michel Granier,a Monique Smaïhi,b Valentin Valtchevc
a
Chimie Moleculaire et Organisation du Solide, UMR 5637 cc 007 Université Montpellier, 2, Place Eugène Bataillon,
34095 Montpellier Cedex 05, France
Fax +33(4)67143852; E-mail: doussine@iemm.univ-montp2.fr
b
c
Institut Européen des Membranes, UMR 5635 cc 047 Université Montpellier, 2, Place Eugène Bataillon, 34095 Montpellier Cedex 05,
France
Laboratoire des Matériaux Minéraux, (LMM) UMR 7016, ENSCMu, 3 rue Alfred Werner, 68093 Mulhouse, France
Received 21 April 2004
O
O
Abstract: The syntheses of two phosphonic acids possessing the
Fmoc-protected semicarbazide group are described. The key step
was the Curtius rearrangement, performed in the presence of diben-
zyl phosphonate esters. Preliminary experiments showed that the
phosphonic acid can be grafted at the surface of oxide nanoparticles
and colloidal zeolite nanocrystals, without deprotection of the Fmoc
group.
(HO)2P(CH2)nNHCONHNHFmoc
(BnO)2P(CH2)nN=C=Om
O
Br(CH2)nCO2H
(BnO)2P(CH2)nCO2H
3a: n=4, 3b: n=10
Figure 1
Key words: nanoparticle, zeolite, Curtius’ rearrangement, phos-
phonic acid, grafting
The benzyl group, which is orthogonal to the Fmoc, was
chosen as the protective group of the phosphonic acid.
The phosphonate was first introduced by alkylation of
dibenzylphosphite. To generate the semicarbazide group,
we studied the formation of the isocyanate obtained from
carboxylic acid by Curtius’ rearrangement and subse-
quent addition of Fmoc hydrazine. Indeed, the efficiency
of Curtius’ reaction has been reported in the presence of
ethylphosphonates.4 The synthesis of acids 3 is described
in Scheme 1.
The synthesis and use of the semicarbazide functionality
has shown an important interest in solid-state chemistry,
due to its high reactivity with aldehydes and derivatives in
mild conditions.1 The first application, reported by Dev in
the eighties, described the isolation of aldehyde and ke-
tones from natural mixtures such as essential oils1a by re-
action with H2NNHCONHNH2 adsorbed on silica. Later,
solid supports covalently functionalized with the semi-
carbazide group have been used for various applications
such as resins1b for peptide synthesis, silica hybrid organ-
ic-inorganic materials,1c DNA1d and protein chips.1e An
extension of the application of the semicarbazide group to
metal oxide and zeolite nanoparticules is highly desired as
there is growing interest on such materials particularly in
life sciences.2 Covalent attachment of organic molecules
at the surface of metal oxide nanoparticles has been suc-
cessfully achieved using the phosphonic acid function,
with less drawbacks than alkoxysilanes (homocondensa-
tion of the silane and stability of the Si-O-M bond).3 Thus,
the availability of phosphonic acids bearing a semi-carba-
zide group is prefered for the functionalization of metal
oxide nanoparticles and their further use in life sciences.
We present here the synthesis of two original phosphonic
acids possessing the Fmoc-protected semicarbazide group
and their use for the modification of metal oxide and zeo-
lites nanoparticles.
O
a
b or c
Br(CH2)nCO2H
Br(CH2)nCO2Me
(PhCH2O)2P(CH2)nCO2Mem
1a: n=4, 1b: n=10
2a: n=4, 2b: n=10
O
d
(PhCH2O)2P(CH2)nCO2H
3a: n=4, 3b: n=10
Scheme 1 a) TMSCl cat, MeOH, 1a: 87%, 1b: 81%; b) Na-
PO(OBn)2, THF, 2b: 15%; c) KPO(OBn)2, DMF 2b: 74%., Na-
PO(OBn)2, DMF, 2a: 74%; d) 5 equiv KOH, dioxane, H2O, 3a: 83%,
3b: 92%.
Few examples of nucleophilic substitution of bromoalkyl
derivatives with the sodium anion of dibenzylphosphite
have been reported in the literature. The methods usually
give poor to average isolated yields from 28–65% depend-
ing on the conditions and solvents.5 One example with 4-
bromobutanenitrile is briefly described in 80% yield.5d
Substitution of ethyl 4-bromobutanoate and ethyl 5-bro-
mopentanoate have been detailed in 28% and 51% yield,
respectively.5b We first tried standard experiments for the
nucleophilic substitution of bromo esters 1b with the so-
dium anion of dibenzylphosphite in THF. The anion was
classically generated at 0 °C by adding the phosphite to a
solution of 0.75 M NaH. After one hour, 1b was added
and the reaction was allowed to warm to room tempera-
The retrosynthetic scheme is described in Figure 1.
SYNLETT 2004, No. 10, pp 1735–1738
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829565; Art ID: G13504ST
© Georg Thieme Verlag Stuttgart · New York
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9
.0
8
.2
0
0
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1736
T. Doussineau et al.
LETTER
ture overnight. The reaction was not clean, the desired Treatment of 3a or 3b diphenylphosphorylazide led to the
product was isolated in very low yield (about 15%), ben- azide without damaging the benzylphosphonate group, no
zylalcohol and its side-reaction products were observed, substituent exchanges were observed with phosphorus
which is most probably due to the partial decomposition compounds. After rearrangement into isocyanate and ad-
of the dibenzylphosphite sodium anion under those condi- dition of Fmoc hydrazine, the Fmoc-protected semicarba-
tions. We turned to DMF as the solvent. We checked so- zide phosphonates 4a and 4b were obtained in average
dium and potassium counterions. Dibenzylphosphite was yield. Debenzylation was achieved in quantitative yield.
added dropwise to a solution of 0.15 M NaH in DMF at
We then performed preliminary experiments to analyze
0 °C. After ten minutes, 1a was added. The reaction was
the grafting reaction of compounds 5b9 at the surface of
allowed to warm to room temperature for 5 hours. No de-
different metal oxide nanoparticles and zeolites
composition products were observed in this case, the de-
(Scheme 4).
sired benzylphosphonate was cleanly synthesized in 74%
isolated yield. The same procedure with 1b, using KH as
O
the base, gave 74% yield as well.6 After saponification of
(HO)2P(CH2)10NHCONHNHFmoc
MxOySiz
MxOySiz
+
the esters, the Curtius’ reaction was then examined with
3b by first using the efficient conditions described with
ethyl phosphonates4 (Scheme 2).
DMSO
O
O
O
P(CH2)10NHCONHNHFmoc
O
a or b
O
c
d
3b
(BnO)2P(CH2)nCOCl
(BnO)2P(CH2)nCON3
O
O
MxOySiz : TiO2, Al2O3, [Na4Al4Si60O128][N(C2H5)4]6[H2O
e
(BnO)2P(CH2)nNHCONHNHFmoc
(BnO)2P(CH2)nN=C=O
Scheme 4
Scheme 2 a) 2 Equiv SOCl2, 1 equiv pyridine, r.t.; b) 2 equiv
(COCl)2, 1 equiv pyridine; c) 5 equiv NaN3, H2O, Et2O 0 °C; d) tolue-
ne, 80 °C; e) 1 equiv Fmoc NHNH2, EtOH–toluene 60 °C.
We used two types of oxides nanoparticles : TiO2 P25 De-
gussa (reported average particle size 21 nm, and specific
surface area 50 m2g–1 determined by N2 adsoprtion mea-
surements), Al2O3 C Degussa (reported average particle
size 13 nm, and specific surface area 90 m2g–1) and colloi-
dal zeolite b-crystals10 with Si/Al ratio of 18.5 (particle
size of 140 nm, specific surface area 220 m2g–1). The
amount of 1.1 mmol of 5b in DMSO per gram of TiO2 or
Al2O3 nanoparticles were reacted overnight at room tem-
perature. The suspension was filtered and washed with
DMSO, H2O, THF, and Et2O. The solids obtained were
analyzed by HPDECMAS 31P NMR, CPMAS 13C NMR,
FTIR and microanalysis. The 31P NMR spectrum showed
one signal centered at d = 21 ppm, enlarged to d = 15 ppm
at half maximum, which is characteristic of a covalent an-
choring of the phosphonic acid at the surface, with forma-
tion of P-O-M bonds in different coordination modes.
CPMAS 13C NMR performed with functionalized Al2O3
nanoparticles showed signals at d = 30.3 (CH2), 40.4
(CH2-NH), 48.5 (CH2-O), 118.3 and 126.3 (C Fmoc) ppm,
which confirm the presence of the carbon chain. Note that
the carbonyl groups were not detected in these conditions,
because of the very low content of the carbon part versus
mineral part. FTIR spectroscopy showed principal signals
at 3367 (n OH), 2923, 2851 (n CH2), 1729 (n C=O), 1664
(n C=O), 1560 cm–1 (d NH). Microanalysis showed a
phosphorus content of 0.69% and 0.88% for TiO2 and
Al2O3, respectively. Assuming that each molecule occu-
pies 24 Å2 based on the size of the phosphonic group,11 a
loading of about 0.30 mmol g–1 is expected for TiO2 and
0.60 mmol g–1 for Al2O3, respectively.11 We obtained a
loading of 0.22 mmol g–1 for TiO2 and 0.28 mmol g–1 for
Al2O3 based on the microanalysis, which shows that the
coverage is about 70% of the monolayer for TiO2 and
The acyl chloride was generated from 3b by reaction with
(COCl)2 or SOCl2. In the two cases we observed partial
cleavage of the dibenzylphosphonate ester, this side-reac-
tion could be partially limited by addition of 1 equivalent
of pyridine, but not totally avoided. After evaporation, the
residue was dissolved in Et2O at 0 °C and activated NaN3
in H2O was added. Acyl azide was isolated by extraction
with Et2O followed by a careful evaporation of volatiles.
7
Addition of FmocNHNH2 in EtOH to the reaction after
Curtius’ rearrangement in toluene at 80 °C led to 4b pos-
sessing the Fmoc-protected semicarbazide group. Com-
pound 4b was obtained in 20–40% yield. Carbamoyl
azide was also observed as a by-product due to over addi-
tion of azide to the isocyanate. To overcome the difficul-
ties and long procedures with this strategy, we decided to
avoid the generation of the azide through the acyl chlo-
ride. We turned to diphenylphosphorylazide, a reagent,
which directly convert carboxylic acids into azide and iso-
cyanates (Scheme 3).8
O
O
c
b
a
3a–b
(BnO)2P(CH2)nN=C=O
O
(BnO)2P(CH2)nCON3
O
d
(BnO)2P(CH2)nNHCONHNHFmoc
(HO)2P(CH2)nNHCONHNHFmocm
4a, 4b
5a, 5b
Scheme 3 a) 1.2 Equiv (PhO)2PON3, 1.1 equiv Et3N, toluene, r.t.;
b) reflux; c) 1 equiv FmocNHNH2, EtOH, toluene, 60 °C (52%); d)
Pd/C 10%, H2, MeOH (100%).
Synlett 2004, No. 10, 1735–1738 © Thieme Stuttgart · New York

LETTER
Synthesis of Phosphonic Acids with the Semicarbazide Group
1737
about 50% of the monolayer for Al2O3. The accessibility
of 5b seems to be in the same range at the surface of TiO2
and Al2O3 nanoparticles. Colloidal zeolite b-crystals were
reacted with 5b (0.32 mmol per gram of particles) in a
mixture of DMSO–H2O 50:50 overnight. The suspension
was purified using centrifugation (12000 t/min, 20 min)
removal of the liquid and redispersion in water under ul-
trasonic radiation. The procedure was repeated three
times. One sample was dried for analyses. 31P HPDEC-
MAS NMR showed two large signals at d = 25.1 and 17.9
ppm, which showed that the grafting reaction occurred at
different sites of the zeolite surface. Microanalysis
showed a phosphorus content of 0.12%, which correspond
to a loading of 38 mmol g–1, which is lower than that on the
metal oxide supports. This coverage variation could be at-
tributed to the lability of the P-O-Si bond12 at the zeolite
surface, versus P-O-M in the presence of water. The pres-
ence of the Fmoc group was then detected by fluorescence
spectroscopy13 (Figure 2). Grafted TiO2 presented no flu-
orescence because it was quenched by the photo-oxida-
tion properties of TiO2. The grafted Al2O3 nanoparticles
presented the characteristic emission of the Fmoc group at
322 nm and a broad band at 440 nm indicating the pres-
ence of excimers. This result suggests that some aggrega-
tion of molecules occurred during the grafting procedure,
with formation of face-to-face dimers. The grafted zeolite
nanocrystals showed a homogeneous dispersion of the
Fmoc group at the surface of the particles, as the fluores-
cence of the monomer was observed without the excimer
broad band.
Acknowledgment
We thank Dr Oleg Melnyk for kind and useful discussions. We
thank the Degussa society for a gift of TiO2 and Al2O3 nanopartic-
les.
References
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(6) Experimental Procedure for 2b: KH 30% in mineral oil
(4.0 g, 30.0 mmol) was suspended in dry DMF (150 mL) at
0 °C. Dibenzylphosphite (8.0 g, 30.0 mmol) was added
dropwise. Methyl 11-bromo undecanoate (7.3 g, 26.1 mmol)
was then rapidly added. The reaction was allowed to warm
to r.t. after 15 min. After 6 h, the reaction was quenched at at
0 °C by careful addition of H2O (100 mL). The mixture was
extracted with EtOAc (3 × 100 mL) and the organic phase
washed with a minimum amount of H2O, dried over MgSO4,
the solvents were then evaporated. Flash chromatography
(Et2O) afforded 2b (8.94 g, 74%). 1H NMR (CDCl3): d =
1.26–1.85 (m, 18 H, CH2), 2.34 (t, 2 H, 3JH-H = 7.65 Hz),
3.70 (s, 3 H), 5.00 (m, 4 H), 7.38 (s, 10 H) ppm. 13C NMR
(CDCl3): d = 22.68 (td, 1 C, 2JC-P = 5.28 Hz), 25.35 (t, 1 C),
26.42 (td, 1 C, 1JC-P = 139.77 Hz), 29.39–29.74 (m, 5 C),
30.89 (td, 1 C, 3JC-P = 17.06 Hz), 34.51 (t, 1 C), 51.85 (q, 1
C), 67.41 (td, 2 C, 3JC-P = 6.46 Hz), 128.28 (d, 4 C), 128.73
(d, 2 C), 128.97 (d, 4 C), 136.97 (sd, 2 C, 3JC-P = 5.94 Hz),
174.73 (s, 1 C, C=O) ppm. IR (NaCl pellets): n (CHarom.) =
3090, 3064, 3033; n (CH2aliph) = 2928, 2854; n (C=Oester) =
1736 cm–1. MS (FAB+, NBA): m/z [MH+] = 461.
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(9) Data for 5b: IR (KBr): n (NH) = 3306; n (CH arom) = 3063,
3038; n (CH2) = 2922, 2850; n (POH) = 3500–2500, 2347; n
(C=O) = 1731; n (C=O) = 1661; d (NH) = 1556; n (P=O)
1264 and 1217, 1157, 1098, 898, 759, 738 cm–1. 1H NMR
(CDCl3, 1 drop of TFA: d = 1.30–1.60 (m, 16 H), 1.88–2.04
Figure 2
In conclusion, we have synthesized two phosphonic acids
possessing the Fmoc-protected semicarbazide group. The
key step was the Curtius’ rearrangement. It was per-
formed using diphenylphosphorylazide in the presence of
dibenzylphosphonate ester. After hydrogenolysis, prelim-
inary studies showed that the grafting reaction was effi-
cient at the surface of TiO2, Al2O3 and zeolite b-
nanoparticles. The conditions were smooth enough to pre-
serve the Fmoc group, whose fluorescence was studied.
Synlett 2004, No. 10, 1735–1738 © Thieme Stuttgart · New York

1738
T. Doussineau et al.
LETTER
(m, 2 H), 3.22 (t, 3J = 6.90 Hz, 2 H), 4.26 (t, 3J = 5.80 Hz, 1
H), 4.70 (d, 3J = 5.80 Hz, 2 H), 7,35–7.48 (m, 4 H), 7,55 (d,
(10) Smaihi, M.; Gavilan, E.; Durand, J. O.; Valtchev, V. P. J.
Mater. Chem. 2004, 14, 1347.
(11) Pawsey, S.; Kimberly, Y.; Reven, L. Langmuir 2002, 18,
5205.
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1994, 116, 1737.
(13) Blanchet, C.; Joly, P.; Granier, M.; Lanneau, G. F.; Cretin,
M.; Persin, M.; Melnyk, O.; Durand, J. O. Tetrahedron Lett.
2003, 44, 4191.
3J = 7.40 Hz, 2 H), 7.81 (d, 3J = 7.33 Hz, 2 H) ppm. 13
C
NMR (DMSO): d = 23.62 (td, 1 C, 2JC-P = 4.19 Hz), 28.82
(td,1 C, 1JC-P = 178.63 Hz), 29.58–29,90 (m, 7 C, CH2),
30.98 (td, 1 C, 3JC-P = 16.17 Hz), 47.42 (t, 1 C), 67.00 (d, 1
C), 120.97 (d, 2 C), 126.23 (d, 2 C), 127.98 (d, 2 C), 128.56
(d, 2 C), 141.57 (s, 2 C), 144.53 (s, 2 C), 157.71 (s, 1 C,
C=O), 159.10 (s, 1 C, C=O) ppm. 31P NMR (DMSO): d =
24.97 ppm. MS (ES+, Q-TOF): m/z [(M – H + Na) +
H+] = 540.3.
Synlett 2004, No. 10, 1735–1738 © Thieme Stuttgart · New York