Di- and trinuclear Zn2+ complexes of calix[4]arene based ligands as catalysts of acyl and phosphoryl transfer reactions

Article abstract of DOI:10.1021/jo0487350

(Chemical Equation Presented) The calix[4]arene scaffold, blocked in the cone conformation by proper alkylation of the lower rim hydroxyls, was used as a convenient molecular platform for the design of bi- and trimetallic Zn ²⁺ catalysts. The catalytic activity of the Zn²⁺ complexes of calix[4]arenes decorated at the 1,2-, 1,3-, and 1,2,3-positions of the upper rim with 2,6-bis[(dimethylamino)methyl]pyridine units were investigated in the cleavage of ester 6 and of the RNA model compound HPNP. High rate enhancements, up to 4 orders of magnitude, were observed in a number of catalyst-substrate combinations. Interestingly the order of catalytic efficiency among regioisomeric dinuclear complexes in the cleavage of ester 6 is 1,2-vicinal ? 1,3-distal, but it is reversed in the reaction of HPNP. The higher efficiency of trinuclear compared to dinuclear complexes provides an indication of the cooperation of three Zn²⁺ ions in the catalytic mechanism.

Full text of DOI:10.1021/jo0487350

Di- and Trinuclear Zn2+ Complexes of Calix[4]arene Based Ligands
as Catalysts of Acyl and Phosphoryl Transfer Reactions
Roberta Cacciapaglia,† Alessandro Casnati,‡ Luigi Mandolini,*,† David N. Reinhoudt,*,§
Riccardo Salvio,† Andrea Sartori,§ and Rocco Ungaro*,‡
Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di Reazione, Universita` di Roma La
Sapienza, Box 34-Roma 62, 00185 Roma, Italy, Dipartimento di Chimica Organica e Industriale,
Universita` degli Studi di Parma, Parco Area delle Scienze 17/A, 43100 Parma, Italy, and Laboratory of
Supramolecular Chemistry and Technology, MESA-Research Institute, University of Twente,
P.O. Box 217, 7500 AE Enschede, The Netherlands
d.n.reinhoudt@ct.utwente.nl; luigi.mandolini@uniroma1.it; rocco.ungaro@unipr.it
Received July 23, 2004
The calix[4]arene scaffold, blocked in the cone conformation by proper alkylation of the lower rim
hydroxyls, was used as a convenient molecular platform for the design of bi- and trimetallic Zn2+
catalysts. The catalytic activity of the Zn2+ complexes of calix[4]arenes decorated at the 1,2-, 1,3-,
and 1,2,3-positions of the upper rim with 2,6-bis[(dimethylamino)methyl]pyridine units were
investigated in the cleavage of ester 6 and of the RNA model compound HPNP. High rate
enhancements, up to 4 orders of magnitude, were observed in a number of catalyst-substrate
combinations. Interestingly the order of catalytic efficiency among regioisomeric dinuclear complexes
in the cleavage of ester 6 is 1,2-vicinal . 1,3-distal, but it is reversed in the reaction of HPNP. The
higher efficiency of trinuclear compared to dinuclear complexes provides an indication of the
cooperation of three Zn2+ ions in the catalytic mechanism.
Many hydrolytic enzymes possess two or three metal
ions in their active sites.1 Common strategies in the
mimicry of such enzymes are based on synthetic catalysts
consisting of a number of ligated metal ions connected
by suitable spacers.2-4 To this purpose, the use of either
rim of calix[4]arenes as convenient platforms for the
introduction of metal ion binding sites is well prece-
dented.2b,4 Particularly successful has been the use of the
upper rim of calix[4]arenes blocked in the cone conforma-
tion by proper alkylation of the lower rim hydroxyls. The
dinuclear Zn2+ complex of a ditopic receptor (4) consisting
of two 2,6-bis[(dimethylamino)methyl]pyridine units at-
tached to the 1,3-positions of the calixarene upper rim
showed a high degree of catalytic cooperation of the two
metal centers in the cleavage of phosphodiester bonds.2b
More recently, we reported the synthesis of the two
regioisomeric ligands 1 and 2, and an extensive investi-
(3) For more recent contributions see, for example, the following
papers and references therein: (a) Fritsky, I. O.; Ott, R.; Pritzkow,
H.; Kra¨mer, R. Chem. Eur. J. 2001, 7, 1221-1231. (b) Worm, K.; Chu,
F.; Matsumoto, K.; Best, M. D.; Lynch, V.; Anslyn, E. V. Chem. Eur.
J. 2003, 9, 741-747. (c) Cacciapaglia, R.; Di Stefano, S.; Mandolini,
L. J. Am. Chem. Soc. 2003, 125, 2224-2227. (d) Mancin, F.; Rampazzo,
E.; Tecilla, P.; Tonellato, U. Eur. J. Org. Chem. 2004, 281-288. (e)
Iranzo, O.; Richard, J. P.; Morrow J. R. Inorg. Chem. 2004, 43, 1743-
1750.
(4) (a) Cacciapaglia, R.; Mandolini, L. Calixarene Based Catalytic
Systems. In Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.;
Imperial Collage Press: London, UK, 2000; pp 241-264. (b) Sansone,
F.; Segura, M.; Ungaro, R. Calixarenes in Bioorganic and Biomimetic
Chemistry. In Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield,
J., Vicens J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001; pp 496-
512. (c) Ozturk, G.; Akkaya, E. U. Org. Lett. 2004, 6, 241-243.
* To whom correspondence should be addressed. D.N.R.: fax +31
(0)534 894645. L.M.: fax +39 06 490421. R.U.: fax +39 0521 905472.
† Universita` di Roma.
‡ Universita` di Parma.
§ University of Twente.
(1) (a) Stra¨ter, N.; Lipscomb, W. N.; Klabunde T.; Krebs, B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2025-2055. (b) Wilcox, D. E. Chem.
Rev. 1996, 96, 2435-2458. (c) Perreault, D. M.; Anslyn, E. V. Angew.
Chem., Int. Ed. 1997, 36, 433-450. (d) Williams, R. J. P. Chem.
Commun. 2003, 1109-1113. (e) Parkin, G. Chem. Rev. 2004, 104, 699-
767.
(2) For review articles see: (a) Williams, N. H.; Takasaki, B.; Chin,
J. Acc. Chem. Res. 1999, 32, 485-493. (b) Molenveld, P.; Engbersen,
J. F. J.; Reinhoudt, D. N. Chem. Soc. Rev. 2000, 29, 75-86.
10.1021/jo0487350 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/18/2004
624
J. Org. Chem. 2005, 70, 624-630

Design of Bi- and Trimetallic Zn2+ Catalysts
SCHEME 1a
a Reagents and conditions: (i) SOCl2, CH2Cl2; (ii) CH3NH2, EtOH; (iii) 2-bromomethyl-6-hydroxymethylpyridine, CH3CN, K2CO3, 42%;
(iv) SOCl2, CH2Cl2; (v) (CH3)2NH, EtOH, 76%.
CHART 1
gation of the catalytic activity of their dinuclear Ba2+
complexes in the basic ethanolysis of a series of esters
endowed with a distal carboxylate anchoring group.5 We
found a high degree of cooperation of the two metal
centers in both cases and, most interestingly, a marked
superiority in catalysis of the 1,2-vicinal complex (1-Ba2)
compared with its 1,3-distal regioisomer (2-Ba2).
In view of our continuing investigations of metal
catalysts based on a calix[4]arene scaffold, we report here
on a quantitative investigation of the catalytic activity
of the upper rim regioisomeric 1,2- and 1,3-bimetallic
Zn2+ complexes (3-Zn2 and 4-Zn2, respectively) and of the
analogous trimetallic complex 5-Zn3 in the methanolysis
of ester 6, together with a comparison of the catalytic
activity of regioisomers 3-Zn2 and 4-Zn2 in the cleavage
of the RNA model compound 2-hydroxypropyl p-nitro-
phenyl phosphate (HPNP).
Results and Discussion
The recently developed6 synthetic procedure for the
preparation of 1,2-diformyl tetraalkoxycalix[4]arenes and
corresponding 1,2-dialcohols in synthetically useful
amounts has opened an easy way to hitherto elusive
upper-rim 1,2-difunctionalized receptors, as illustrated
by the procedure adopted for the synthesis of ligand 3
(Scheme 1). Other ligands were available from a previous
investigation.7
mental convenience substrate concentrations in the
kinetic runs were 0.10 mM (k > 1 × 10-3 s-1; time-course
experiments) or 0.50 mM (k < 1 × 10-3 s-1; initial-rate
technique).9
A number of control experiments were carried out to
evaluate the binding process involving the various species
in solution. UV-vis titration of the ligand 2,6-bis-
[(dimethylamino)methyl]pyridine (BAMP) with Zn(ClO4)2
at 268 nm revealed the existence of a fairly strong
complexation, K ) 6 × 104 M-1. Consistently, the absor-
bance variation observed upon addition of 3 molar equiv
of Zn(ClO4)2 to the tritopic ligand 5 amounted to 95% of
the saturation value, thus showing that under the
Cleavage of Ester 6. The esterase activity of metal
catalysts in the cleavage of esters 6 and 7 was studied
in methanol solution (eq 1), buffered at pH 10.4 by means
of a 10 mM 1:1 mixture of N,N-diisopropyl-N-(2-meth-
oxyethyl)amine and its perchlorate salt.8 Metal catalysts
were freshly prepared at 1.00 mM by mixing equivalent
amounts of the free ligand and Zn(ClO4)2. For experi-
(5) Cacciapaglia R.; Casnati, A.; Di Stefano, S.; Mandolini, L.;
Paolemili, D.; Sartori, A.; Reinhoudt, D. N.; Ungaro, R. Chem. Eur. J.
2004, 10, 4436-4442.
(8) The molar autoprotolysis constant of CH3OH, Kap ) 10-16.77
(Bosch E.; Bou P.; Allemann H.; Rose´s M. Anal. Chem. 1996; 68, 3651-
3657), implies that in this solvent the pH value corresponding to
neutrality is 8.39. At pH 10.4 the concentration (activity) of the
conjugate base of the solvent is 2 log units higher than under neutral
conditions.
(9) Excess catalyst minimizes product inhibition as well as complica-
tions arising from multiple binding of carboxylate to di- and trimetallic
complexes.
(6) Sartori, A.; Casnati, A.; Mandolini, L.; Sansone, F.; Reinhoudt,
D. N.; Ungaro, R. Tetrahedron 2003, 59, 5539-5544.
(7) (a) Molenveld, P.; Kapsabelis, S.; Engbersen, J. F. J.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1997, 119, 2948-2949. (b) Molenveld, P.;
Stikvoort, W. M. G.; Kooijman, H.; Spek, A. L.; Engbersen, J. F. J.;
Reinhoudt, D. N. J. Org. Chem. 1999, 64, 3896-3906.
J. Org. Chem, Vol. 70, No. 2, 2005 625

Cacciapaglia et al.
FIGURE 2. Proposed mechanism for the cleavage of ester 6
catalyzed by bimetallic complexes.
rather suggest that inhibition by carboxylate is due to
the formation of the pentacoordinate neutral species 15,12
in which the Zn2+-bound methoxide is less reactive than
that in 13.13
FIGURE 1. Effect of added tetramethylammonium benzoate
on kobs for the basic methanolysis of 0.1 mM p-nitrophenyl
acetate in the presence of 1 mM BAMP-Zn (MeOH, pH 10.4
buffer, 25 °C). The dashed line represents the background rate
constant (kbg ) 5.6 × 10-5 s-1).
conditions of the kinetic runs binding of Zn2+ to the ligand
units was nearly complete.
Potentiomeric titration10 with tetramethylammonium
methoxide in MeOH showed that the complex of BAMP
with Zn(ClO4)2 behaves as a weak monoprotic acid with
pKa ) 9.5, which is easily interpreted as the pKa of a
metal-bound solvent molecule11 (eq 2). This implies that
at the pH of the kinetic solutions the Zn2+ complexes are
mostly in the methoxide-bound form 13.
In any case, independent of the precise nature of the
Zn2+-bound carboxylate species, the shape of the kinetic
titration plot in Figure 1 indicates that the binding of
carboxylate is strong enough (K g 104 M-1) to ensure a
complete or nearly complete anchoring of 6 to the metal
catalysts.
In conclusion, the results of the above control experi-
ments indicate that under the conditions of the catalytic
runs in the presence of the dinuclear catalysts 3-Zn2 and
4-Zn2, the concentration of the productive complex (Fig-
ure 2), in which one of the two Zn2+ ions is bound to
carboxylate and the other to methoxide, amounts to a
significant fraction, no less than 3/4, of the total substrate
concentration. Similar considerations apply to the tri-
metallic catalyst 5-Zn3, where only one metal ion is
involved in carboxylate binding.9
To provide an estimate of the binding constant between
the ligated Zn2+ ion and the carboxylate anchoring group
in 6, we carried out a series of experiments in which the
BAMP-Zn catalyzed methanolysis of p-nitrophenyl ac-
etate (PNPA) is inhibited by increasing amounts of added
tetramethylammonium benzoate (Figure 1). Methanoly-
sis of PNPA was chosen as the test reaction despite its
moderate sensitivity to the presence of the metal catalyst
because the liberated p-nitrophenol is easily monitored
by UV-vis spectroscopy (400 nm). Addition of a larger
than stoichiometric amount of benzoate caused the
reaction rate to reach a constant value that is nearly half
of the value measured in the absence of added benzoate,
but still slightly higher than the background rate ob-
served in the presence of buffer alone.
The kinetics of the catalyzed reactions were monitored
by HPLC. The chromatograms revealed the presence of
unreacted ester and phenol product (eq 1), and the
complete absence of undesired byproducts. Pseudo-first-
order rate constants for the faster reactions (k > 1 × 10-3
s-1) were obtained from time-course experiments, which
showed good adherence to first-order time-dependence in
all cases. An initial rate technique was applied to slower
reactions (k < 1 × 10-3 s-1). Methanolysis of esters 6 and
7 in the absence of metal catalysts was inconveniently
slow. We measured therefore the second-order rate
constant (k) for reaction with tetramethylammonium
methoxide, and calculated the rate constants for back-
ground methanolysis at the pH of the experiments kbg
This finding argues against the simple interpretation
that addition of benzoate transforms the catalytically
active species 13 into the unreactive complex 14. We
(12) The X-ray crystal structure of a neutral pentacoordinate species
analogous to 15 involving monodentate binding of two carboxylate ions
was reported in ref 7b.
(13) The widely accepted bifunctional mechanism for metal-
catalyzed hydrolysis (alcoholysis) involves combined nucleophile de-
livery to and Lewis acid activation of the ester carbonyl (see: Chin, J.
Acc. Chem. Res. 1991, 24, 145-152; for a recent example see ref 11).
When applied to complex 15 such a mechanism would require an
unlikely hexacoordination for a BAMP complexed Zn center.
(10) Neverov, A. A.; McDonald, T.; Gibson, G.; Brown, R. S. Can. J.
Chem. 2001, 79, 1704-1710.
(11) Cacciapaglia, R.; Di Stefano, S.; Fahrenkrug, F.; Lu¨ning, U.;
Mandolini L. J. Phys. Org. Chem. 2004, 17, 350-355.
626 J. Org. Chem., Vol. 70, No. 2, 2005

Design of Bi- and Trimetallic Zn2+ Catalysts
TABLE 1. Basic Methanolysis of Esters 6 and 7
Catalyzed by the Zn2+ Complexes of Ligands BAMP and
3-5a
Interestingly, the highest catalytic efficiency in the
cleavage of 6 is exhibited by the trimetallic complex
5-Zn3. In principle, the trimetallic complex could work
as a dinuclear complex, with the third metal ion acting
as a spectator. In 5-Zn3 there are one 1,3-distal and two
1,2-vicinal bimetallic arrangements. Since the efficiency
of the 1,3-distal dinuclear complex is very small, the
catalytic efficiency of 5-Zn3, thought as resulting from the
sum of contributions from the above dinuclear arrange-
ments, would be approximately twice as large as that of
3-Zn2. The finding that 5-Zn3 is about four times as
effective as 3-Zn2 provides an indication of the coopera-
tion of three Zn2+ ions in the catalytic mechanism.
Efficient cooperation of three metal ions (Zn, Cu) in the
catalytic cleavage of phosphodiesters was reported in a
few studies2b,15 but, to the best of our knowledge, trime-
tallic catalysis in ester cleavage is unprecedented.
7
6b
kobs (s-1
)
kobs/kbg
kobs (s-1
)
kobs/kbg
c
c
catalyst
BAMP-Zn
3-Zn2
5.3 × 10-6
9.7 × 10-6
4.1 × 10-6
1.2 × 10-5
5.6
10
4.4
13
2.1 × 10-5
3.4 × 10-3
1.3 × 10-4
1.3 × 10-2
38
6200
240
4-Zn2
5-Zn3
24000
a Runs carried out in MeOH, pH 10.4 buffer, 25 °C, on 0.10 mM
(k > 1 × 10-3 s-1; time-course experiments) or 0.50 mM (k < 1 ×
10-3 s-1; initial-rate technique) substrate in the presence of 1.00
mM metal catalyst. b Tetramethylammonium salt. c Rate con-
stants for background methanolysis (kbg) were calculated from eq
3, with k ) 1.3 M-1 s-1 (kbg ) 5.5 × 10-7 s-1) for ester 6 and k )
2.2 M-1 s-1 (kbg ) 9.4 × 10-7 s-1) for ester 7.
by means of eq 3, where pOMe ) 16.77-10.4.8
kbg ) k × 10-pOMe
(3)
The proposed mechanism depicted in Figure 3 empha-
sizes the three different functions performed by the metal
ions: (i) substrate recognition through binding to car-
boxylate, (ii) Lewis acid activation of the ester carbonyl,
and (iii) nucleophile delivery. The computer drawn model
of the complex of 5-Zn3 with the tetrahedral intermediate
illustrates the geometrical compatibility of the trimetallic
catalyst with the proposed mechanism.
Cleavage of HPNP. In previous papers7 the catalytic
activity of a number of calix[4]arene-based Zn2+ com-
plexes, including BAMP-Zn, 4-Zn2, and 5-Zn3, was thor-
oughly investigated in the intramolecular transesterifi-
cation of HPNP (eq 4) in CH3CN-H2O 1:1 (v/v) at pH
around neutrality.
The results of the kinetic measurements are sum-
marized in Table 1. We first note that solutions contain-
ing the metal complexes show in all cases enhanced rates
compared with those of background methanolysis. In the
reaction of 7 only moderate rate enhancements are
observed, and differences between the various metal
catalysts are small. Thus, nothing in the experimental
data suggests that the metals in the bimetallic and
trimetallic complexes act in a cooperative fashion. In
contrast, rate enhancements experienced by ester 6 are
not only much larger, but also strongly dependent on
catalyst structure. The markedly different behavior of the
two ester substrates illustrates well the important influ-
ence of the carboxylate function in 6. First, as noted in
previous instances,5,14 binding to a metal ion transforms
the moderately electron-releasing (rate-retarding) car-
boxylate substituent into an electron-withdrawing (rate-
enhancing) one, with the net result that the inherently
less reactive 6 (k6/k7 ) 1.3/2.2 or 0.59) becomes much
more reactive in the presence of BAMP-Zn (k6obs/k7
)
obs
2.1 × 10-5/5.3 × 10-6 or 4.0). Superimposed to this purely
electronic influence is the effect due to carboxylate as an
anchoring group. The higher efficiency of dinuclear
catalyst vs the mononuclear model clearly demonstrates
cooperation between metal centers, in accordance with
the mechanism depicted in Figure 2, in which one of the
metal ions binds to the distal carboxylate and the other
delivers a methoxide nucleophile to the ester carbonyl
in an intramolecular (intracomplex) reaction.
The very high catalytic efficiency of 4-Zn2 compared
with that of mononuclear counterparts demonstrates that
both metal centers in 4-Zn2 are involved in the binding
of the altered substrate in the transition state. A likely
mode of catalysis is a bifunctional mechanism in which
one of the Zn2+ ions binds and activates the phosphate
group, whereas the other has a role in the activation of
the neighboring â-hydroxyl nucleophile. The proposed
Catalyst 4-Zn2, in which the two metals are in distal
positions, shows but a moderate degree of cooperation
mononuclear
between metal ions, with a kobsdinuclear/kobs
ratio
of 240/38 or 6.3, whereas the corresponding ratio for the
vicinal regioisomer 3-Zn2 is as high as 6200/38 or 160.
Thus the vicinal dinuclear complex 3-Zn2 exhibits a much
higher catalytic activity in the cleavage of 6 than its distal
regioisomer 4-Zn2, as it was already observed with the
analogous bis-barium complexes 1-Ba2 and 2-Ba2. It
appears therefore that, in the light of available evidence,
the order of catalytic efficiency 1,2-vicinal . 1,3-distal
is a general feature of the upper rim dinuclear metallo-
catalysts for acyl transfer reactions that does not seem
to depend in a critical fashion on the nature of the metal
ion and of the corresponding ligating units.
(14) (a) Cacciapaglia, R.; Di Stefano, S.; Kelderman, E.; Mandolini,
L. Angew. Chem., Int. Ed. 1999, 38, 348-351. (b) Cacciapaglia, R.; Di
Stefano, S.; Mandolini, L. J. Org. Chem. 2001, 66, 5926-5928. (c)
Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. J. Org. Chem. 2002,
67, 521-525.
(15) (a) Komiyama, M.; Kina, S.; Matsumura, K.; Sumaoka, J.;
Tobey, S.; Lynch, V. M.; Anslyn, E. J. Am. Chem. Soc. 2002, 124,
13731-13736. (b) Scarso, A.; Scheffer, U.; Go¨bel, M.; Broxterman, Q.
B.; Kaptein, B.; Formaggio, F.; Toniolo, C.; Scrimin, P. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 5144-5149. (c) Bencini, A.; Berni, E.; Bianchi,
A.; Giorgi, C.; Valtancoli, B.; Chand D. K.; Schneider H.-J. Dalton
Trans. 2003, 793-800. (d) Kovbasyuk, L.; Pritzkow, H.; Kra¨mer, R.;
Fritsky, I. O. Chem. Commun. 2004, 880-881. (e) Takebayashi, S.;
Ikeda, M.; Takeuchi, M.; Shinkai, S. Chem. Commun. 2004, 420-421.
J. Org. Chem, Vol. 70, No. 2, 2005 627

Cacciapaglia et al.
FIGURE 3. Proposed mechanism of trimetallic catalysis in the methanolysis of 6 in the presence of 5-Zn3 (left) and the computer-
generated model of the tetrahedral intermediate/catalyst complex (right).
TABLE 2. Transesterification of HPNP Catalyzed by
Calix[4]arene Zn2+ Complexesa
kobs (s-1
)
kobs/kbg
kobsdinuclear/kobs
b
mononuclear
catalyst
BAMP-Zn
3-Zn2
3.4 × 10-6
2.0 × 10-4
1.3 × 10-3
180
11 000
68 000
61
380
4-Zn2
a Spectrophotometric rate measurements in 50% CH3CN/H2O,
20 mM HEPES, pH 7.0, T ) 25.0 °C. In all runs [cat.])1.00 mM,
[HPNP] ) 0.2 mM. kbg ) 1.9 × 10-8 s-1 (from initial-rate
b
measurements).
analogous mononuclear complexes are not rare,3b,d,4c,17
and show that two metal ions at a short distance do not
necessarily make a good catalyst. It is remarkable,
therefore, that the calix[4]arene-based di- and trinuclear
Zn2+ complexes described in this work show high levels
of cooperativity between metal ions both in the metha-
nolysis of 6 and in the intramolecular transesterification
of HPNP. Interestingly, and quite unpredictably, among
dinuclear complexes the order of catalytic efficiency 1,2-
vicinal > 1,3-distal is observed in the reaction of ester 6,
but the reverse order 1,3-distal > 1,2-vicinal holds for
the transesterification of HPNP. Clearly, our catalysts
possess degrees of conformational freedom arising from
rotations around the C-C and C-N bonds connecting
the ligand units to the calix[4]arene skeleton. If, on one
hand, such a high conformational mobility makes it
difficult to provide a rationale for the observed catalytic
orders even a posteriori, on the other hand it ensures a
large adaptability to transition states of different nature
and geometry.
FIGURE 4. Bifunctional catalytic mechanism of 4-Zn2 in
HPNP transesterification.
mechanism is depicted in Figure 4.16 Evidence for the
cooperative involvement of the three Zn2+ centers in 5-Zn3
was also obtained.
In light of the results obtained in the methanolysis of
ester 6, it seemed of interest to investigate the catalytic
activity in the cleavage of HPNP of the 1,2-vicinal
complex 3-Zn2, which was not available at the times of
previous investigations.7 In the context of the present
study, the relevant questions are whether and to what
an extent the two metal centers in 3-Zn2 work together
in a cooperative fashion, and how the catalytic activity
of 3-Zn2 compares to that of the 1,3-distal regioisomer
4-Zn2.
In conclusion, the data reported in this work, when
combined with analogous data from previous investiga-
tions,2b,5 show that calix[4]arenes are suitable building
blocks for the design of di- and trinuclear metallocatalysts
of acyl and phosphoryl transfer reactions. The calix[4]-
arenes scaffold provides quite a reasonable compromise
between proper preorganization of catalytic groups and
adaptability resulting from conformational flexibility.
The spectrophotometrically determined catalytic rate
constants listed in Table 2, obtained under conditions
very close to those of the previous investigations, clearly
reveal a high degree of synergism between metal centers
in 3-Zn2, with a 61-fold rate enhancement of dinuclear
over mononuclear catalyst. However, in contrast to what
was observed in the catalytic cleavage of ester 6, the 1,2-
vicinal dinuclear complex 3-Zn2 is significantly less
effective a catalyst than its 1,3-distal regioisomer 4-Zn2.
Experimental Section
Concluding Remarks
Instruments and General Methods. NMR spectra were
recorded on either a 300- or 400-MHz spectrometer. Chemical
shifts are reported as δ values in ppm from tetramethylsilane
added as an internal standard. Mass spectra by electrospray
ionization (ESI) and chemical ionization (CI) methods were
recoded on a Micromass ZMD and on a Finnigan Mat SSQ710
spectrometer, respectively. Spectrophotometric measurements
(kinetic runs involving pNPA, HPNP, and reaction of 0.1 mM
6 or 7 with 5 mM tetramethylammonium methoxide) were
Examples of dinuclear complexes whose catalytic activ-
ity is not much larger, or even lower, than that of
(16) A kinetic equivalent mechanism is one in which a Zn2+-bound
hydroxide acts as a general base. Another possibility is that both Zn2+
ions are involved in the binding of the phosphate moiety, whereas base
catalysis is provided by OH- bound to one of the Zn2+ centers in a
pentacoordinate geometry.
628 J. Org. Chem., Vol. 70, No. 2, 2005

Design of Bi- and Trimetallic Zn2+ Catalysts
carried out on either a double beam or on a diode array
spectrophotometer. HPLC analyses (methanolysis of esters 6
and 7 carried out in the presence of metal complexes) were
performed on a liquid chromatograph fitted with a UV-vis
detector operating at 220 nm. Kinetic runs monitored by HPLC
were carried out in the presence of 1,4-dimethoxybenzene as
an internal standard. Samples were analyzed on a Supelcosil
LC-18 DB column (25 cm × 4.6 mm i.d., particle size 5 µm).
At convenient time intervals 0.1 mL of the reaction mixture
was quenched with 0.1 mL of a 10 mM aqueous solution of
HBr, and subjected to HPLC analysis with CH3CN/MeOH/
H2O-0.03% trifluoroacetic acid 10/45/45 (v/v) as eluent, at a
flow rate of 0.6 mL/min.
Error limits of rate constants are in the order of (5% (time-
course kinetics) and (10% (initial-rate technique). Nonlinear
least-squares calculations of kinetic data were carried out with
the program SigmaPlot 2002 for Windows, Version 8.0 (SPSS,
Inc.).
Potentiometric titrations in methanol solution were carried
out as reported in the literature,10 by automatic titration under
an argon atmosphere.
Materials. THF was dried by distillation from sodium
benzophenoneketyl. 1,4-Dimethoxybenzene, phenyl acetate,
benzoic acid, and Zn(ClO)2‚6H2O were commercial samples
used without further purification. Acid 6‚H+,14 HPNP, and
nitrogen ligands BAMP, 4, and 5 were available from previous
investigations.7
Substrate 6 was generated in situ by addition of the parent
phenolic compound to the buffered reaction medium. The stock
solution of tetramethylammonium benzoate that was used in
the kinetic titration of BAMP-Zn was freshly prepared from
the parent carboxylic acid by addition of a stoichiometric
amount of tetramethylammonium methoxide. A solution of the
latter in methanol was prepared and handled as previously
described.18
Warning! Care was taken when handling N,N-diisopropyl-
N-(2-methoxyethyl)ammonium perchlorate because it is po-
tentially explosive.20 No accident occurred in the course of the
present work.
5,11-Bis(chloromethyl)-25,26,27,28-tetrakis(2-ethoxy-
ethoxy)calix[4]arene (9). Dialcohol calix[4]arene 8 (280
mg, 0.36 mmol) was dissolved in CH2Cl2 and SOCl2 (0.53 mL,
7.5 mmol) was added. The solution was stirred for 2 h at room
temperature and then the solvent was evaporated under
vacuum to give 9 as a colorless oil in quantitative yield (290
mg, 0.36 mmol). The crude was pure enough to be used in the
subsequent reaction. An analytically pure sample was obtained
by dissolving the crude prodouct in 10 mL of CH2Cl2 and by
washing with 10 mL of NaHCO3 saturated solution and water.
The organic phase was dried over Na2SO4 and filtered and the
solvent was evaporated under reduced pressure. 1H NMR (300
MHz; CDCl3) δ 6.62-6.56 (m, 10H), 4.49 (d, J ) 13.5 Hz, 4H),
4.29 (s, 4H), 4.11 (t, J ) 5.6 Hz, 4H), 4.10 (t, J ) 5.6 Hz, 4H),
3.82 (t, J ) 5.6 Hz, 8H), 3.54 (q, J ) 7.0 Hz, 8H), 3.14 (d, J )
13.5 Hz, 4H), 1.20 (t, J ) 7.0 Hz, 12H). 13C NMR (75 MHz;
CDCl3) δ 156.6, 156.3, 135.5, 135.2, 135.1, 134.7, 131.0, 128.6,
128.4, 128.2, 128.1, 122.0, 73.2, 73.1, 69.6, 66.3, 46.6, 30.8, 29.6,
15.2. MS (ES) m/z (%) 831.6 [M + Na]+ (100). Anal. Calcd for
C46H58Cl2O8 (809.87): C, 68.22; H, 7.22. Found: C, 68.31; H,
7.33.
5,11-Bis[(N-methyl)aminomethyl]-25,26,27,28-tetrakis-
(2-ethoxyethoxy)calix[4]arene (10). A 33% methylamine
solution in EtOH (10 mL) was added to a round-bottomed flask
containing the bischloromethyl calixarene 9 (260 mg, 0.32
mmol). The solution was stirred ca. 48 h at room temperature,
until completion was confirmed by TLC (Al2O3, CH2Cl2/MeOH
9/1). The solvent was evaporated under vacuum; the crude was
dissolved in CH2Cl2 (30 mL) and washed with a 10% NaHCO3
solution (30 mL). The organic phase was dried over Na2SO4,
filtered, and evaporated under vacuum to give 10 (252 mg,
0.32 mmol) as colorless oil. Yield 97%. 1H NMR (300 MHz;
CDCl3) δ 7.18 (d, J ) 1.6 Hz, 2H), 6.86 (dd, J ) 7.4 Hz, J )
1.2 Hz, 2H), 6.73 (d, J ) 1.6 Hz, 2H), 6.68 (d, J ) 7.4 Hz, 2H),
6.58 (t, J ) 7.4 Hz, 2H), 4.51 (d, J ) 13.1 Hz, 1H), 4.50 (d, J
) 13.1 Hz, 2H), 4.47 (d, J ) 13.1 Hz, 1H), 4.16-4.07 (m, 8H),
3.94 (d, J ) 13.4 Hz, 2H), 3.82 (t, J ) 5.5 Hz, 8H), 3.62 (d, J
) 13.4 Hz, 2H), 3.53 (q, J ) 7.0 Hz, 4H), 3.51 (q, J ) 7.0 Hz,
4H), 3.24 (d, J ) 13.1 Hz, 1H), 3.14 (d, J ) 13.1 Hz, 3H), 2.28
(s, 6H), 1.19 (t, J ) 7.0 Hz, 12H). 13C NMR (75 MHz; CDCl3)
δ 156.7, 155.9, 135.8, 135.6, 134.9, 134.3, 130.4, 129.6, 128.5,
128.3, 124.4, 122.6, 73.5, 73.2, 69.6, 69.5, 66.3, 51.6, 30.8, 30.7,
30.5, 15.2. MS (CI) m/z (%) 799.4 [M + H]+ (75), 767.5 [M -
NHCH3]+ (100). Anal. Calcd for C48H66N2O8 (799.06): C, 72.15;
H, 8.33; N, 3.51. Found: C, 72.32; H, 8.41; N, 3.44.
5,11-Bis[N-((6-hydroxymethyl)pyridin-2-ylmethyl)-N--
methylaminomethyl]-25,26,27,28-tetrakis(2-ethoxy-
ethoxy)calix[4]arene (11). K2CO3 (88 mg, 0.64 mmol) and
2-bromomethyl-6-hydroxymethylpyridine (130 mg, 0.64 mmol)
were added to a solution of diamine calix[4]arene 10 (250 mg,
0.315 mmol) in dry CH3CN (10 mL). The solution was stirred
under N2 atmosphere for 2 days. The solvent was removed
under reduced pressure and the residue dissolved again in
CH2Cl2 (70 mL). The organic layer was washed with a Na2-
CO3 saturated solution (70 mL) and the aqueous phase
extracted with CH2Cl2 (70 mL). The combined organic layers
were evaporated under vacuum and the product was obtained
as a colorless oil (138 mg, 0.132 mmol) after purification by
column chromatography (SiO2; CH2Cl2/MeOH, 9/1). Yield 42%.
1H NMR (400 MHz; CDCl3) δ 7.62 (t, J ) 7.4 Hz, 2H), 7.19 (d,
J ) 7.4 Hz, 2H), 7.13 (d, J ) 7.4 Hz, 2H), 6.68 (d, J ) 1.6 Hz,
2H), 6.63 (br s, 4H), 6.47 (d, J ) 7.4 Hz, 2H), 6.34 (t, J ) 7.4
Hz, 2H), 4.72 (s, 4H), 4.49 (d, J ) 12.9 Hz, 1H), 4.48 (d, J )
12.9 Hz, 2H), 4.46 (d, J ) 13.3 Hz, 1H), 4.12 (t, J ) 5.8 Hz,
4H), 4.10 (t, J ) 5.8 Hz, 4H), 3.86 (t, J ) 5.8 Hz, 4H), 3.85 (t,
Other materials, apparatus, and techniques for the trans-
esterification of HPNP in 50% (v/v) CH3CN-H2O were as
reported previously.7
N,N-Diisopropyl-N-(2-methoxyethyl)amine. N,N-Diiso-
propylethanolamine (14.5 g, 0.10 mol) was added at room
temperature to a stirred mixture of 6 g of 60% NaH dispersion
in mineral oil in 300 mL of THF. When addition of the reagent
was complete, the reaction mixture was heated at 40 °C for
30 min. After the mixture was cooled, a solution of methyl
iodide (12 mL, 0.14 mol) in THF (40 mL) was added dropwise.
The reaction mixture was allowed to stand for 16 h at room
temperature. The solvent and excess methyl iodide were
removed under vacuum. Fractional distillation afforded the
product (9.2 g, 58 mmol, 58% yield) as a volatile colorless oil
(bp 170.5-171.5 °C, 760 mmHg), pKa 10.4 in MeOH at 25 °C:
1H NMR (300 MHz; CDCl3) δ 3.34 (s, 3H), 3.33 (t, J ) 7.5 Hz,
2H), 2.99 (hept, J ) 6.5 Hz, 2H), 2.61 (t, J ) 7.5 Hz, 2H), 1.00
(d, J ) 6.5 Hz, 12H); 13C NMR (75 MHz; CDCl3) δ 67.5, 59.1,
56.7, 47.7, 18.9, 17.4.
N,N-Diisopropyl-N-(2-methoxyethyl)ammonium Per-
chlorate Salt. This salt was prepared according to a literature
procedure19 (56% yield of a white solid (needles) after recrys-
tallyzation from 2-propanol). 1H NMR (300 MHz; CDCl3) δ 3.82
(hept, J ) 6.5 Hz, 2H), 3.75 (t, J ) 5.5 Hz, 2H), 3.42 (s, 3H),
3.29 (t, J ) 5.5 Hz, 2H), 1.45 (br s, 12H); 13C NMR (75 MHz;
CDCl3) δ 67.5, 59.1, 56.7, 47.7, 18.9, 17.4. Anal. Calcd for C9H22-
ClNO5 (259.73): C, 41.62; H, 8.54; N, 5.39. Found: C, 41.71;
H, 9.04; N, 5.41.
(17) (a) Rossi, P.; Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Scrimin, P. J. Am. Chem. Soc. 1999, 121, 6948-6949. (b)
Iranzo, O.; Richard, J. P.; Morrow J. R. Inorg. Chem. 2003, 42, 7737-
7746.
(18) Cacciapaglia, R.; Lucente, S.; Mandolini, L.; van Doorn, A. R.;
Reinhoudt, D. N.; Verboom, W. Tetrahedron 1989, 45, 5293-5304.
(19) Wilcox, C. S.; Babston, R. E. J. Org. Chem. 1984, 49, 1451-
1453.
(20) Luxon, S. G., Ed. Hazards in the Chemical Laboratory, 5th ed.;
The Royal Society of Chemistry: Cambridge, UK, 1992; p 524.
J. Org. Chem, Vol. 70, No. 2, 2005 629

Cacciapaglia et al.
J ) 5.8 Hz, 4H), 3.55 (q, J ) 7.0 Hz, 4H), 3.53 (q, J ) 7.0 Hz,
4H), 3.35 (d, J ) 14.0 Hz, 2H), 3.28 (d, J ) 14.0 Hz, 2H), 3.25
(d, J ) 14.4 Hz, 2H), 3.12 (d, J ) 14.4 Hz, 2H), 3.12 (d, J )
12.9 Hz, 3H), 3.07 (d, J ) 13.3 Hz, 1H), 1.97 (s, 6H), 1.21 (t, J
) 7.0 Hz, 6H), 1.20 (t, J ) 7.0 Hz, 6H). 13C NMR (75 MHz;
CDCl3) δ 159.1, 159.0, 156.5, 155.8, 137.6, 135.4, 135.2, 135.0,
132.1, 129.5, 129.2, 128.5, 128.4, 122.5, 121.8, 119.2, 73.6, 73.5,
70.0, 66.8, 64.8, 62.2, 61.8, 42.8, 32.6, 31.2, 15.7. MS (CI) m/z
(%) 1041.6 [M + H]+ (100). Anal. Calcd for C62H80N4O10
(1041.34): C, 71.51; H, 7.74; N, 5.38. Found: C, 71.64; H, 7.84;
N, 5.46.
5,11-Bis[N-((6-chloromethyl)pyridin-2-ylmethyl)-N-me-
thylaminomethyl]-25,26,27,28-tetrakis(2-ethoxyethoxy)-
calix[4]arene (12). Thionyl chloride (0.14 mL, 1.9 mmol) was
added to a solution of calix[4]arene 11 (100 mg, 0.096 mmol)
in CH2Cl2 (15 mL) and the mixture was stirred for 3 h. The
solvent was removed under reduced pressure to give the bis-
(2-chloromethylpyridine) 12 (102 mg, 0.096 mmol) in quantita-
tive yield, and pure enough for further reactions. An analytical
sample of 12 was dissolved in CH2Cl2, washed with a saturated
NaHCO3 solution, and dried over Na2SO4. Dichloromethane
was removed in vacuo to give compound 12. 1H NMR (400
MHz; CDCl3) δ 7.67 (t, J ) 7.4 Hz, 2H), 7.33 (d, J ) 7.4 Hz,
2H), 7.25 (d, J ) 7.4 Hz, 2H), 6.67 (s, 2H), 6.65 (s, 2H), 6.62
(d, J ) 7.4 Hz, 2H), 6.47 (d, J ) 7.4 Hz, 2H), 6.39 (t, J ) 7.4
Hz, 2H), 4.65 (s, 4H), 4.47 (d, J ) 13.3 Hz, 3H), 4.45 (d, J )
13.3 Hz, 1H), 4.12 (t, J ) 5.8 Hz, 4H), 4.10 (t, J ) 5.5 Hz, 4H),
3.85 (t, J ) 5.5 Hz, 4H), 3.84 (t, J ) 5.8 Hz, 4H), 3.54 (q, J )
7.0 Hz, 4H), 3.53 (q, J ) 7.0 Hz, 4H), 3.39 (s, 4H), 3.27 (d, J )
12.9 Hz, 2H), 3.24 (d, J ) 12.9 Hz, 2H), 3.14 (d, J ) 12.9 Hz,
1H), 3.13 (d, J ) 12.9 Hz, 2H), 3.08 (d, J ) 13.3 Hz, 1H), 2.03
(s, 6H), 1.20 (t, J ) 7.0 Hz, 12H). 13C NMR (75 MHz; CDCl3)
δ 160.2, 156.5, 156.0, 155.8, 137.7, 135.3, 135.1, 135.0, 132.2,
129.2, 129.0, 128.5, 128.4, 122.8, 122.5, 121.2, 73.6, 70.1, 66.7,
62.9, 62.0, 47.2, 42.9, 31.2, 15.7. MS (CI) m/z (%) 1077.7 [M +
H]+ (100). Anal. Calcd for C62H78N4O8Cl2 (1079.23): C, 69.06;
H, 7.29; N, 5.20. Found: C, 69.21; H, 7.16; N, 5.29.
5,11-Bis[N-((6-N,N-dimethylaminomethyl)pyridin-2-yl-
methyl)-N-methylaminomethyl]-25,26,27,28-tetrakis(2-
ethoxyethoxy)calix[4]arene (3). A 33% dimethylamine
solution in EtOH (10 mL) was added to a round-bottomed flask
containing the calix[4]arene 12 (98 mg, 0.09 mmol). The
solution was stirred overnight and then evaporated. The
product was purified by column chromatography (neutral
Al2O3, CH2Cl2/MeOH 99/1) to give 3 as a pale yellow oil (75
mg, 0.068 mmol). Yield 76%. 1H NMR (400 MHz; CDCl3) δ 7.61
(t, J ) 7.4 Hz, 2H), 7.25 (d, J ) 7.4 Hz, 2H), 7.19 (d, J ) 7.4
Hz, 2H), 6.66 (s, 4H), 6.60 (d, J ) 7.4 Hz, 2H), 6.47 (d, J ) 7.4
Hz, 2H), 6.38 (t, J ) 7.4 Hz, 2H), 4.46 (d, J ) 12.9 Hz, 3H),
4.45 (d, J ) 13.3 Hz, 1H), 4.09 (t, J ) 5.8 Hz, 4H), 4.08 (t, J
) 5.4 Hz, 4H), 3.84 (t, J ) 5.4 Hz, 4H), 3.83 (t, J ) 5.8 Hz,
4H), 3.56 (s, 4H), 3.53 (q, J ) 7.0 Hz, 8H), 3.43 (s, 4H), 3.25
(d, J ) 12.9 Hz, 2H), 3.19 (d, J ) 12.9 Hz, 2H), 3.13 (d, J )
13.3 Hz, 1H), 3.12 (d, J ) 12.9 Hz, 2H), 3.07 (d, J ) 12.9 Hz,
1H), 2.27 (s, 12H), 2.02 (s, 6H), 1.194 (t, J ) 7.0 Hz, 6H), 1.192
(t, J ) 7.0 Hz, 6H). 13C NMR (75 MHz; CDCl3) δ 159.8, 158.5,
156.6, 155.7, 137.0, 135.4, 135.0, 132.7, 129.2, 129.0, 128.6,
128.5, 122.5, 121.6, 121.4, 73.5, 70.1, 66.7, 66.3, 63.5, 62.1, 46.1,
42.8, 31.2, 30.1, 15.7. MS (CI) m/z (%) 1095.6 [M + H]+ (100).
Anal. Calcd for C66H90N6O8 (1095.48): C, 72.36; H, 8.28; N,
7.67. Found: C, 72.48; H, 8.19; N, 7.78.
Acknowledgment. Financial contribution from
MIUR COFIN 2003 Progetto Dispositivi Supramoleco-
lari is acknowledged for the work carried out in Parma
and Roma. The Centro Interfacolta` di Misure (CIM) of
the University of Parma is also acknowledged for the
use of NMR and mass facilities.
JO0487350
630 J. Org. Chem., Vol. 70, No. 2, 2005