Poly(ethylene glycol)-supported copper(II) triazacyclononane: An efficient, recoverable, and recyclable catalyst for the cleavage of a phosphodiester

Article abstract of DOI:10.1016/S0040-4039(02)02584-4

The triazacyclononane macrocycle has been linked to the soluble polymer monomethoxy poly(ethylene) glycol and its copper(II) complex efficiently catalyzes the hydrolysis of a model phosphodiester. The catalyst, easily recovered from the water solution, sh

Full text of DOI:10.1016/S0040-4039(02)02584-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 535–538
Poly(ethylene glycol)-supported copper(II) triazacyclononane:
an efficient, recoverable, and recyclable catalyst for the
cleavage of a phosphodiester
a,
a
a
b
b
Gian Maria Bonora, * Sara Drioli, Fulvia Felluga, Fabrizio Mancin, Paola Rossi,
b
a,
Paolo Scrimin and Paolo Tecilla *
a
Dipartimento di Scienze Chimiche, Universit a` di Trieste, Via Licio Giorgieri 1, I-34127 Trieste, Italy
b
Dipartimento di Chimica Organica e ITM-CNR, Sezione di Padova, Universit a` di Padova, Via Marzolo 1, I-35131 Padova,
Italy
Received 4 October 2002; revised 13 November 2002; accepted 14 November 2002
Abstract—1,3,5-Triazacyclononane macrocycle has been linked to the soluble polymer monomethoxy poly(ethyleneglycol) and its
copper(II) complex efficiently catalyzes the hydrolysis of a model phosphodiester. The catalyst, easily recovered from the water
solution, shows no appreciable loss of activity when recycled up to three times. © 2002 Elsevier Science Ltd. All rights reserved.
The hydrolytic cleavage of phosphoric esters is an
important reaction both in environmental and in bio-
logical chemistry. However, these substrates and in
Modified poly(ethylene glycol)s (PEGs) of Mw>2000
Da are readily functionalized polymers that feature
1
8
these convenient solubility properties. Recently, the
particular phosphodiesters are exceptionally stable
toward hydrolysis: at neutral pH and 25°C the half-life
for the cleavage of dimethyl phosphate is estimated to
mono methyl ether of PEG5000 (MPEG) has success-
fully been used for the immobilization of different
9
reactive systems used, for example, as phase transfer
2
be 130 000 years. As a consequence, much effort has
7
10
11
catalysts and in hydrogenation, epoxidation, and
been devoted to the development of efficient catalysts
for this reaction. It is well documented that a variety of
metal ions and metal complexes are able to dramati-
cally increase the rate of hydrolysis of phosphodiesters
12
carbon–carbon bond formation. To the best of our
knowledge, however, a copper(II) complex has never
been attached to PEG and used as a recoverable cata-
lyst for the hydrolytic cleavage of a phosphodiester.
3
in water solution. A drawback of these homogeneous
catalyses is the impossibility to recover and recycle the
catalyst. Immobilization of the catalysts on an insoluble4
matrix can provide a simple solution to this problem.
For example, copper(II) complexes have been incorpo-
For this reason, we argued that a triazacyclononane
(
TACN)-functionalized MPEG would be a particularly
interesting target because: (i) the reported complexation
constant for the binding of copper(II) by this macrocy-
5
rated into insoluble polymers or linked to silica parti-
13
6
cle is very high (log K=15.5) ; (ii) extensive work by
Burstyn and co-workers has highlighted the efficiency
of the copper(II) complex of this macrocycle in the
15
cles, obtaining heterogeneous catalysts active in the
cleavage of phosphoric esters. In this context, the ideal
polymer support should allow the complete solubility of
the catalysts in some solvents, in order to maintain the
advantages of homogeneous catalysis, and insolubility
in other solvents, so that the supported catalyst can
easily be isolated and recovered by precipitation and
14
hydrolysis of phosphate diesters and carboxamides
as well; and (iii) the conjugation of the catalyst to the
MPEG polymer would allow an easy recovery and
reuse of the catalyst.
7
filtration.
The preparation of the MPEG-linked catalyst is shown
in Scheme 1. 1,6-Aminohexanol was CBz-protected at
the amino nitrogen and the hydroxyl group was con-
verted into the corresponding bromide 3. Reaction of
*
Corresponding authors. Tel.: +39-040-5583927; fax: +39-040-
583903 (G.M.B.); tel.: +39-040-5583925; fax: +39-040-5583903
P.T.); e-mail: bonora@dsch.univ.trieste.it; tecilla@dsch.
univ.trieste.it
5
(
1
6
the bromide with the diprotected triazacyclonane, fol-
lowed by removal of the CBz group, led to compound
0
040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02584-4

5
36
G. M. Bonora et al. / Tetrahedron Letters 44 (2003) 535–538
5
ready to be connected to the MPEG polymer. On the
son purposes and using the same synthetic scheme we
17
basis of our experience we decided to use a carbamate
linkage for this connection. The terminal hydroxyl
group of MPEG (Mw=5000 Da) was reacted with
prepared compound 8 in which the PEG polymer has
1
8
been substituted with a shorter ethoxyethyl ether.
4
-nitrophenyl chloroformate obtaining the 4-nitro-
phenyl carbonate 6. Nucleophilic displacement of the
-nitrophenyl group with 5 followed by deprotection of
the amines led to the target compound 7. For compari-
In water at pH 7.8 the MPEG-conjugate triazacyclo-
nonane binds copper(II) as shown by the appearance of
an absorption band at 620 nm in the UV–vis spectrum.
Figure 1 shows the UV–vis titration of 7 and TACN
with copper(II): in both cases the absorbance increases
linearly up to 1 equiv. of metal ion and then levels off
though to a different final value. This is a clear indica-
tion of a strong binding with a 1:1 stoichiometry and
that the conjugation to the polymer does not alter
substantially the complexation properties of the aza-
macrocycle but for a slight increase in the molar extinc-
tion coefficient of the complex. Moreover, by using
compound 8 we checked the stability of the carbamate
linkage under the hydrolytic conditions used. After 1
week at acidic (pH 2), basic (pH 10) and almost neutral
pH (8), in the presence or absence of copper(II), no
evidence of hydrolytic degradation was observed using
4
1
H NMR after removal of the metal ion.
Kinetic studies were performed by using bis(4-nitro-
phenyl)phosphate (BNPP) which is considered a refer-
3
ence substrate for the cleavage of phosphodiesters.
Figure 2 reports the kinetic profiles for the cleavage of
BNPP (0.1 mM) at pH 7.8 and 40°C in the presence of
increasing concentrations of the copper(II) complexes
19
of compounds 7, 8, and TACN.
Analysis of the Fig. 2 shows that the order of reactivity
is 7>8>TACN: at 0.8 mM concentration 7 is about 25%
more reactive than 8 and more than threefold than
TACN. The maximum apparent rate constant observed
−
6
−1
for 7 is 4.5×10
s
which is considerably faster than
20
the uncatalyzed rate of cleavage of BNPP. However,
the three kinetic profiles are not linear and show a
downward curvature. This behavior has been already
14
observed for TACN
and for other polyamine
21
ligands and has been attributed to a monomer–dimer
equilibrium where the monomer is a more active cata-
lyst. Increasing the concentration of copper(II) complex
the dimer, probably a bis(m-hydroxide)-bridged species,
is increasingly formed and the reaction rate decreases.
Scheme 1. (a) CBzCl, MeOH, Et N, rt, 5 h; (b) CBr , Ph P,
3
4
3
CH Cl , rt 1.5 h; (c) DIPEA, CH CN, reflux 10 h; (d) H ,
2
2
3
2
Pd/C, MeOH, rt, 5 h; (e) 4-NO PhOCOCl, TEA, CH Cl , rt,
2
2
2
overnight; (f) 5, CH Cl , rt, 48 h; (g) TFA/CH Cl 1:1, rt, 4 h.
2
2
2
2
Figure 1. UV–vis titration of 7 (ꢀ) and TACN (ꢁ) with
Cu(II). Conditions: [ligand]=5×10 M, HEPES buffer 50
mM, pH 7.8, 25°C.
Figure 2. Kinetic profiles for the cleavage of BNPP (0.1 mM)
in the presence of the copper(II) complexes of 7 ("), 8 (ꢀ),
and TACN (ꢁ) at 40°C and pH 7.8 (HEPES buffer, 50 mM).
−
4

G. M. Bonora et al. / Tetrahedron Letters 44 (2003) 535–538
537
1
4
By fitting the data it is possible to obtain the apparent
recovery yield was obtained by lyophilization of the
water solution and extraction of the solid residue with
methylene chloride followed by precipitation of the
MPEG derivative with ethyl ether. Using this procedure
more than 80% of the copper(II) complex of 7 was
recovered from the reaction medium in the conditions
of the kinetic experiments, where the maximum amount
of 7 used was limited to 10–15 mg to avoid excessive
absorbance of the samples. However, the recovery yield
increases substantially (up to 97%) when the reactions
are performed on larger scale, employing larger
amounts of PEG-conjugate.
dimerization constants which are 840, 1060, and 2800
for 7, 8, and TACN, respectively. Clearly, substitu-
tion at one macrocycle nitrogen reduces the dimeriza-
−
1
M
2
2
tion constant
reactivity.
and this is reflected in a higher
To verify if the MPEG-conjugate copper(II) complex is
a real catalyst we investigated its kinetic behavior under
conditions of excess substrate. Figure 3 shows a typical
kinetic experiment where BNPP is five times more
concentrated than the copper(II) complex of ligand 7.
The concentration of the hydrolyzed product increases
smoothly with time following first order kinetics. After
about 160 h of reaction more than 75% of the initial
BNPP is hydrolyzed in 3.7 turn-over cycles of the
catalyst. Moreover, the regular profile of Figure 3
shows that product inhibition is not significant, at least
under these experimental conditions.
The hydrolytic efficiency of the recovered catalyst was
tested in the following experiment: 11 mg of 7 was
dissolved in HEPES buffer (50 mM, pH 7.8) and 1
equiv. of copper(II) was added to form the metal ion
complex. The solution was placed in a cuvette and the
substrate was added. The final volume and concentra-
tions were: 1.0 mL, [7·Cu(II)]=2.1 mM, [BNPP]=2.0
mM. The reaction was followed at 40°C, monitoring
the increase in absorbance at 440 nm for 12 h until
about 10% of the substrate was hydrolyzed. The cop-
per(II) complex of 7 was then recovered from the water
solution as described above. The recovered catalyst was
dissolved in fresh buffer and its concentration was
determined using the typical absorbance band of the
metal ion complex at 620 nm. A new aliquot of BNPP
was then added in order to obtain an identical final
volume and substrate concentration as in cycle 1. The
reaction was monitored for about 12 h and then the
catalyst was again recovered and reused in a third cycle.
The kinetic data relative to this experiment are collected
in Table 1.
Finally, we investigated the possibility to recover and
reuse the MPEG-conjugate catalyst. Different condi-
tions for the extraction of the polymer from the reac-
tion medium were tested: acidic (pH 1), basic (pH 12)
in the presence of EDTA, and direct extraction from
the water solution buffered at pH 7.8. This last proce-
dure was found to be the most convenient also because
the copper(II) complex of 7, i.e. the whole catalytic
system, is directly obtained ready to be reused. How-
ever, the direct extraction of the water phase with
methylene chloride was not satisfactory especially when
using small amount of MPEG-conjugate. A higher
As said above, the use of a relatively small amount of
MPEG-conjugate hampers the full recovery of the cata-
lyst. In the recycling experiments the yield of recovery
was around 80% and, the total volume of the water
solution being the same, the concentration of catalyst
decreases in the subsequent cycles. As a consequence,
the apparent pseudo-first order rate constant (k% ) of
obs
the reaction decreases on going from the first to the last
cycle. However, if the decrease of concentration is
taken into account and the comparison is made using
the apparent second order rate constants (k%% =k% /
obs
obs
[
7·Cu(II)]), it is evident that the intrinsic reactivity of
the MPEG-conjugate is the same in the three cycles and
no activity has been lost.
Figure 3. Plot of concentration of 4-nitrophenol versus time
for the hydrolysis of BNPP (1.0 mM) catalyzed by 7 (0.2 mM)
at pH 7.8 (HEPES buffer, 50 mM) and 40°C. The reaction
was followed at 450 nm in order to keep the final absorbance
below 2.
In conclusion, the immobilization of the TACN macro-
cycle on a modified MPEG provides an efficient cata-
lyst for the copper(II) promoted cleavage of a model
a
Table 1. Kinetic parameters for the cleavage of BNPP by 7·Cu(II) in three subsequent reaction cycles
Cycle
% of recovering
[7·Cu(II)] (mM)
k%obs×106 (s−1
)
k%%obs×103 (s−1 M−1
)
1
2
3
–
85
81
2.1
1.7
1.4
9.6
8.6
6.0
4.6
5.0
4.3
a
[
BNPP]=2.0 mM, HEPES buffer 50 mM, pH 7.8, 40°C.

5
38
G. M. Bonora et al. / Tetrahedron Letters 44 (2003) 535–538
phosphate diester. The catalyst can be easily recovered
and reused without appreciable loss of activity. More-
over, the system presents all the advantages of an
homogeneous catalyst without the problems often con-
nected to a heterogeneous one. For instance, when
compared to an insoluble catalyst obtained by immobi-
10. (a) Fan, Q.-H.; Deng, G.-J.; Lin, C.-C.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 1241; (b) Guerreiro,
P.; Ratovelomanana-Vidal, V.; Gen eˆ t, J.-P.; Dellis, P.
Tetrahedron Lett. 2001, 42, 3423.
11. Reger, T. S.; Janda, K. D. J. Am. Chem. Soc. 2000, 122,
6929.
12. (a) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045; (b)
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Pitillo, M. J. Org. Chem. 2001, 66, 3160; (c) Bergbreiter,
D. E.; Osburn, P. L.; Wilson, A.; Sink, E. M. J. Am.
Chem. Soc. 2000, 122, 9058; (d) Yao, Q. Angew. Chem.,
Int. Ed. 2000, 39, 3896; (e) Benaglia, M.; Celentano, G.;
Cozzi, F. Adv. Synth. Catal. 2001, 343, 171.
6
lization of TACN on silica our system is about 40-fold
more reactive without the need of a high stirring rate or
large conditioning time to ensure accessibility of the
substrate to the catalytic site. These results open the
way to a new class of supported hydrolytic catalysts
and work is in progress to obtain more efficient systems
active toward phosphate esters and other relevant
substrates.
13. Smith, R. M.; Martell, A. E. Critical Stability Constant;
Plenum: New York, 1989; Vol. 6.
1
4. Deal, K. A.; Burstyn, J. N. Inorg. Chem. 1996, 35, 2792.
15. Hegg, E. L.; Burstyn, J. N. J. Am. Chem. Soc. 1995, 117,
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Acknowledgements
7
16. Rossi, P.; Felluga, F.; Scrimin, P. Tetrahedron Lett. 1998,
This work was supported by the Ministry of Education,
39, 7159.
University,
MM03194891) and by Regione Friuli Venezia Giulia
Fondo 2000’.
and
Research
(MIUR,
contract
17. (a) Bonora, G. M. In Seminars in Organic Synthesis;
Societ a` Chimica Italiana ed., 1998, pp. 117–142; (b)
Drioli, S.; Adamo, I.; Ballico, M.; Morvan, F.; Bonora,
‘
G. M. Eur. J. Org. Chem. 2002, 3473.
1
1
8. Selected analytical data for 7: H NMR l 5.15 (br, 1H,
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