Distance between Metal Centres Affects Catalytic Efficiency of Dinuclear CoIII Complexes in the Hydrolysis of a Phosphate Diester

Article abstract of DOI:10.1002/ejoc.201800300

Dinuclear Co^III complex catalysed hydrolysis of bis-p-nitrophenylphosphate, a DNA model substrate, is reported. The catalysts were designed in such a way that the two Co^III ions cannot be contemporaneously involved in the complexation of the substrate or transition state. Experimental evidence of the involvement of such a remote metal centre in the catalysis of the hydrolysis of a phosphate diester is provided. This contribution amounts to a ca. 64-fold rate acceleration for the second-order rate constants of the best dinuclear complex over the mononuclear one, which is apparently due to general acid or H-bonding catalysis. Furthermore, there is significant distance dependence for this catalytic contribution and, in this case, it appears that the best distance (as estimated by DFT calculations) is ca. 7.7 ?. This may indicate that the presence of metal centres in close proximity, as required for mechanism proposals in which all metals are directly involved in transition-state coordination, is not the only option for rate acceleration in natural phosphate hydrolysis.

Full text of DOI:10.1002/ejoc.201800300

A Journal of
Accepted Article
Title: Distance Between Metal Centres Affects Catalytic Efficiency of
Dinuclear Co(III) Complexes in the Hydrolysis of a Phosphate
Diester
Authors: Paolo M Scrimin, Eva Suzanna Bencze, Cristiano Zonta,
Fabrizio Mancin, and Leonard Jan Prins
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800300
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800300
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10.1002/ejoc.201800300
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Distance Between Metal Centres Affects Catalytic Efficiency of
Dinuclear Co(III) Complexes in the Hydrolysis of a Phosphate
Diester
Eva Szusanna Bencze,[a] Cristiano Zonta,[a] Fabrizio Mancin,[a] Leonard J. Prins,[a] and Paolo
Scrimin*[a]
Abstract: The effect on the catalysis of the hydrolysis of bis-p-
nitrophenylphosphate, a DNA model substrate, by dinuclear Co(III)
complexes is reported. They were designed in such a way that the
two Co(III) ions cannot be contemporaneously involved in the
complexation of the substrate or transition state. Experimental
evidence of the involvement of such a remote metal centre in the
catalysis of the hydrolysis of a phosphate diester is provided. This
contribution amounts to ca. a 64-fold rate acceleration, comparing the
second order rate constants of the best dinuclear complex with the
mononuclear one, and is apparently due to general acid or H-bonding
catalysis. Furthermore, there is significant distance dependence for
this catalytic contribution and, in this particular case, it appears that
the best distance (as estimated by DFT calculations) is ca. 7.7 Å. This
may indicate that the presence of metal centres in close proximity, as
required for mechanism proposals in which all metals are directly
involved in transition state coordination, is not the only option for rate
acceleration in natural phosphate hydrolysis.
other[2b,8,9] groups had estimated a distance between the two
metal centres lower than 6.5 Å to take advantage of such close
interaction by studying model substrates. Many crystallographic
studies reveal that, compared to the metal ions considered critical
for catalysis, the “remote” (in most cases the third) metal ion is too
far away from the others to interact with the transition-state
complex.[6d] This appears to be the case of the DNA repair
enzyme endonuclease IV, T5 flap endonuclease and alkaline
phosphatase, to provide a few examples, for which three metals
are present and have been suggested as catalytically relevant,
although possibly to different extents.[6] One explanation
suggested in these cases is that that isolated metal ion moves
within the protein to follow the changes of the substrate towards
the transition state of the reaction.[6b] In this scenario the distance
between metal centres would change in reaching the transition
state. This, however, does not account for all possible
mechanistic options and the question of the catalytic relevance of
these “remote” metal ions even without a rearrangement of the
protein in the course of the catalytic process, is still open.
Interestingly, also artificial catalysts appear to be more effective
in diphosphate cleavage when based on a cluster of metal ions,[10]
although in these systems a relevant statistical contribution to
binding has been suggested.[11] In this paper we address the
possible role of a remote metal ion in the catalysis of the
hydrolysis of a phosphate diester with a good leaving group and
provide experimental evidence that such a metal ion can be
catalytically active without getting close enough to the catalytic
site to be involved in the coordination of the transition state.
Introduction
The nucleophilic cleavage of the P-O bond in phosphate diesters
is a very challenging reaction. With extraordinary efficiency
enzymes accelerate it by up to 17 order of magnitude.[1]
Experimental evidence indicates that most of these enzymes
present in their active site catalytically relevant divalent metal
ions.[2] The most plausible mechanisms for them require two of
these ions operating in a concerted fashion such as depicted in
Scheme 1A.[2-4] This conventional wisdom has been questioned
with the suggestion that only one metal ion is really catalytically
necessary.[5] To make this picture more complex, phosphate-
cleaving enzymes with more than two metal centres are also
known.[6] Not all metals in these systems are close enough to
interact directly with the substrate or the nucleophilic species
involved in the cleavage. Previous work from our[7] as well as
Scheme 1. A represents a putative transition state for the cleavage of a
phosphate diester catalysed by two transition metal ions. The extent of the
formation of the bonds between the nucleophile, the leaving group and the
phosphorus atom defines whether the mechanism is dissociative, associative or
concerted. B represents the accepted mechanism for mononuclear Co(III)
complexes-catalysed cleavage of a phosphate diester. C represents the
suggested mechanism for the best dinuclear catalysts discussed here. The
coordinating cyclen derivatives and the spacing units have been omitted for
clarity.
[a]
E. V. Bencze, C. Zonta, F. Mancin, L. J. Prins, P. Scrimin
Department of Chemical Sciences
University of Padova
Via Marzolo, 1- 35131 Padova, Italy
E-mail: paolo.scrimin@unipd.it;
http://www.chimica.unipd.it/paolo.scrimin/pubblica/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
FULL PAPER
mechanistic information on the hydrolysis. Ligands 1-3 were
obtained by reacting the 1,7-benzyloxycarbonyl(Z)-diprotected
cyclen with the appropriate dibromomethyl derivative of the
aromatic system used as the spacer. Mononuclear ligand 4 was
also synthesized for comparison purposes. The structure of the
four ligands and the synthetic route followed for their synthesis is
reported in Scheme 2. Their Co(III) complexes were obtained
following procedures reported for similar complexes. [12,14]
Scheme 2. Synthesis of ligands 1-3 and their structure as well as that of 4.
Results and Discussion
To simplify our approach we have reduced the transition-state
coordinating site to a single ion choosing a Co(III) complex as a
model. The mechanism of action of Co(III) complexes in
phosphate cleavage is fairly well known[12] and requires (Scheme
1B) the coordination of the phosphate to the metal ion and
nucleophilic attack by a deprotonated water molecule bound to
the same metal in a pseudo-intramolecular process. This Co(III)
ion plays the double role of activating the phosphate (Lewis acid
catalysis) and delivering the nucleophilic species. In many
dinuclear phosphate-cleaving enzymes such a double role is
played typically by two different metal ions (like Zn(II), Mg(II) or
Ca(II)). Thus the behaviour of a single Co(III) ion is reasonably
similar to that of many dinuclear catalysts but for the assistance
in leaving group departure. In model studies this latter is usually
addressed by using a substrate with a very good leaving group.
Although Co(III) is not found in the catalytic site of phosphate-
cleaving enzymes, it has the advantage of a well-defined
coordination geometry thus allowing a better analysis of the
system than with other, biologically more relevant, metal ions (like
Zn(II) or Mg(II)).
Figure 1. Structure obtained from the DFT calculations for the anti (a) and syn
(b) isomers of complex 2-Co(III)2(H2O)4. Hydrogen atoms have been omitted for
clarity.
In order to assess the role of the second Co(III) ion (it would
be the third in a trinuclear catalyst in which two metals are directly
involved in the stabilization of the transition state[13]) we have
varied systematically its distance from the first one from 7.1 to 9.3
Å (based on DFT calculations), monitoring the effect on the
cleavage of the phosphate diester bis-p-nitrophenyl phosphate
Structure of the complexes
To better understand the structures of the complexes involved in
the reaction, in the absence of suitable crystals for
a
(BPNPP).
A
comparison
with neutral
p-nitrophenyl-
diffractometric analysis, we performed calculations using the
unrestricted DFT method, UB3LYP, with the 6-31+G(d,p) basis
set. This gave us the possibility to determine the Co-Co distances
for the tetrahydrated dinuclear Co(III) complexes of ligands 1-3.
The presence of the flexible methylene groups allows two stable
conformations for each dinuclear complex (syn and anti) but the
distance between the two ions in each of the two varies only
slightly: 7.07 and 7.15 for 1-Co(III)2(H2O)4, 7.64 and 7.75 Å for 2-
Co(III)2(H2O)4, and 9.55 and 9.17 Å for 3-Co(III)2(H2O)4, for the
syn and anti isomers, respectively. The minimized structures of
the syn and anti isomers 2-Co(III)2(H2O)2 are reported in Figure 1
while those of complexes 1-Co(III)2(H2O)2 and 3-Co(III)2(H2O)2
are reported in the Supporting Information. Although we have not
diphenylphosphate (PNPDPP), a phosphate triester was also
performed.
The catalysts
We have designed our catalysts by selecting relatively rigid
aromatic spacers and, as ligand subunits, we have chosen
1,4,7,10-tetraaza-cyclododecane (cyclen) for its symmetry and,
hence, ease of functionalization and for the relatively fast rate of
phosphate coordination (anation) of its Co(III) complexes
compared with that of other Co(III) complexes with tetraaza
ligands.[3b,d] If the phosphate binding process were the rate
determining step in the process it would be impossible to obtain
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
FULL PAPER
performed calculations for structures with the Co(III) ions pointing
outward with respect to the cavity, available crystal structures for
Co(III) complexes of cyclen[15] indicate that the substituents on the
nitrogens are oriented in the same direction of the metal ion (i.e.
inward in the dinuclear complex). Such a binding mode appears,
accordingly, rather improbable. Furthermore, the Co-Co
distances rule out a possible mechanism involving a bridging of
the pseudo-intramolecular attack of the other one in its
deprotonated form as in Scheme 1B, the curve shows a bell-
shaped profile. In the low pH regime the phosphate replaces one
of the water molecules bound to Co(III) while the second one is
deprotonated and acts as a nucleophile; in the downward part of
the curve, at higher pH, the second water molecule is also
deprotonated thus favourably competing with the phosphate for
the coordination to the metal ion. It is well known that a Co(III)-
coordinated water molecule is easily replaced by the phosphate
contrary to an hydroxyl ion. At first glance the plots of Figure 2
suggest that also for both dinuclear catalysts 1-Co(III)2 and 2-
Co(III)2 a mechanism similar (or kinetically equivalent) to that
described above for mononuclear 4-Co(III) is operative. However,
a less superficial examination reveals that the downward part of
the bell-shaped plot at the higher pH regime, particularly for the
dinuclear catalyst 2-Co(III)2 is much steeper than that required for
such a mechanism. This hints for the loss, by increasing the pH,
the pentacoordinated[16] phosphorane transition state
or
intermediate among the two metal centres or the involvement of
an OH- bound to the second metal ion as the nucleophile.[17]
Experimentally, this is confirmed by the 31P-NMR spectra of
BPNPP with 2-Co(III)2 and 4-Co(III) revealing that very little
substrate is bound to the metal centres regardless the catalyst is
mono- or dinuclear, thus indicating that the second metal ion is
not involved in the binding as this would have resulted in larger
binding constants.[18]
Rate of phosphate hydrolysis
The observed rate constants for the cleavage of BPNPP for the
three dinuclear complexes and the mononuclear one at 40°C and
pH =6.6 are reported in Table 1. For correct comparison, kinetics
have been run at the same nominal concentration of Co(III)
(1.0×10-3 M, i.e. the concentration of the mononuclear catalyst is
double that of the dinuclear ones). At this concentration the
possibility for 4-Co(III) to dimerize to give a more reactive
dinuclear complex[19] should be minimized. On the contrary, the
conformation of the dinuclear complexes (see above) makes such
an event impossible. The very low binding constant of the
substrate for the complexes[18] and the concentration of catalysts
used ensure that, at 2×10-5 M substrate concentration, the kinetics
have been performed well below the saturation conditions.
Analysis of Table 1 reveals that the most active catalyst is 2-
Co(III)2 (31-fold better than the mononuclear one) while the worst
one is 3-Co(III)2. The activity of this latter is lower than that of
mononuclear 4-Co(III). This likely implies that each dinuclear
catalyst can interact with a single substrate molecule. It is
remarkable that by slightly changing the distance between the two
Co(III) ions in the dinuclear complexes, the observed rate
constants change so significantly. In fact just by increasing the
distance from ca. 7.1 Å (1-Co(III)2) to 7.7 Å (2-Co(III)2) kobs
becomes 11-fold faster while it drops 44 folds by increasing it to
ca. 9.3 Å (3-Co(III)2).
Table 1. Observed rate constants,a kobs (s-1) for the cleavage of BPNPP and
PNPDPP by catalysts 1-3-Co(III)2 and 4-Co(III) at 40°C.
Catalyst[b]
Substrate
106, kobs (s-1)
Substrate [e]
106, kobs (s-1)
(rel. rate)
(rel. rate)
1-Co(III)2
2-Co(III)2
2-Co(III)2
3-Co(III)2
4-Co(III)[c]
BPNPP
BPNPP
BPNPP
BPNPP
BPNPP
7.2 (2.9)
77.8 (31.1)
55.0[d] (22.0)
1.8 (0.7)
PNPDPP
PNPDPP
PNPDPP
PNPDPP
PNPDPP
6.0 (1.7)
9.9 (2.8)
n. d.[f]
n. d.[f]
2.5 (1)
3.5 (1)
[a] At pH 6.6 and [substrate]=210-5 M. [b] [Catalyst]=5.210-4 M. [c]
[Catalyst]=1.010-3 M. [d] In D2O. [e] Solutions contained 5% methanol (v/v)
to ensure solubility of the substrate. [f] Not determined.
-4
-4.5
-5
-5.5
-6
Figure 2 reports the activity of the dinuclear Co(III)
complexes of ligands 1 and 2 and that of mononuclear complex
with ligand 4 as a function of pH. All three complexes show a bell-
shaped profile with maximum activity in the 6.5-7 pH interval. By
fitting the kinetic data with equation (1):
-6.5
5.5
6.5
7.5
8.5
푘표푏푠 = 푘[퐶표]푡표푡/(1 + [퐻]/퐾푎11 + 퐾푎12/[퐻]) (1)
pH
(where Ka11, Ka12 represent the acidity constants of the two water
molecules bound to the metal ion) we obtain pKa 6.1 and 7.8
(Table 2) for the two H2O molecules bound to 4-Co(III) assuming
Figure 2. Dependence from pH of the observed rate of cleavage of BPNPP by
dinuclear complexes 1-Co(III)2 (red), 2-Co(III)2 (black) and mononuclear 4-
Co(III) (blue). The yellow points represent the observed rate constants for 2-
Co(III)2 in D2O. The solid lines represent the fitting of the experimental points by
using equations (1) for 4-Co(III) and 1-Co(III)2 or (2) for 2-Co(III)2.
the mechanism of Scheme 1B.
These values compare
reasonably well with those reported for cyclen-Co(III)[12] (5.6 and
8.0). Since this mechanism[12] requires the replacement of one of
the two water molecules bound to the metal by the phosphate and
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
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of a further proton providing an extra contribution to catalysis as
compared to 4-Co(III). Indeed, it is impossible to fit the data points
for 2-Co(III)2 with equation (1). The situation for 1-Co(III)2 appears
borderline (see below).
between the two ions discussed above suggests a catalytic
contribution with stringent geometrical requirements.
Table 2. Values of pKa obtained from the interpolation of kinetic data and
second order rate constants for the active catalyst obtained from the
interpolation of the kinetic data of Figure 2 using equations (1) for 4-Co(III)
and 1-Co(III)2 or (2) for 2-Co(III)2.
The role of the second, remote Co(III) ion
The most obvious way of thinking is to consider the involvement
of one of the water molecules bound to the second Co(III) ion.
Considering a third acid dissociation constant as kinetically
relevant for the hydrolytic process catalysed by 2-Co(III)2,
requires (see also Supporting Information) the data to be
interpolated by equation (2):
Catalyst
pKa11
pKa12
pKa21
k (M-1 s-1)
[a]
1-Co(III)2
2-Co(III)2
4-Co(III)[c]
6.15±0.15
6.05±0.05
6.1±0.15
7.2±0.1
7.6±0.05
7.8±0.15
2.2×10-2
2.05×10-1
3.2×10-3
8.3±0.1
--
[a] Fitting of the data with equation (2) gives an unreliable value for pKa21
(8.9), see discussion.
[
]
퐻
퐾
퐾
퐾
푎12
푎12
푎21 ) (2)
2
]
퐻
[
]
푘표푏푠 = 푘 퐶표 푡표푡/(1 +
+
+
[
]
[
퐾
푎11
퐻
When we use equation (2) to fit the kinetic data of complex
1-Co(III)2 we obtain the following values for pKa11, pKa12, and pKa21
respectively: 6.15, 7.35 and 8.9. In this case, however, the data
fit equally well just assuming the involvement of two acidic species
(equation (1), see Table 2). Indeed, the particularly high value of
pKa21 obtained from equation (2) suggests that the third
deprotonation does not provide any significant effect in the pH
range explored (in other worlds, pKa21 is a superfluous parameter
in the fit). Accordingly, we believe that in the case of 1-Co(III)2 the
contribution of one of the water molecules bound to the second
Co(III) ion should be much less relevant than in the case of
complex 2-Co(III)2. On the contrary the rate acceleration brought
about by the electrostatic stabilization of the transition state could
be more significant than that present with 2-Co(III)2 due to the
shorter distance between the two Co(III) ions in 1-Co(III)2.
Experimental support for the mechanism suggested above
for 2-Co(III)2 comes from the solvent kinetic isotope effect (skie)
obtained by carrying out the reaction in D2O (Figure 2). In this
solvent the maximum rate for 2-Co(III)2 is 1.4 fold slower while the
maximum of the curve shifts to an higher pH (from 6.6 to 7.0) as
expected. This relatively large skie is in striking contrast with the
0.8 value we have observed in catalysts with an ammonium group
in close proximity to the metal catalytic site.[20] This has likely to
do with the different pKa of the species involved: the pKa of the
ammonium group was 9.5 while those of the two water molecules
bound to the second Co(III) are significantly lower. The calculated
,
(where, again, Ka11, Ka12 represent the acidity constants of the two
water molecules bound to the first metal ion while Ka21 represents
the acidity constant of one of the water molecules bound to the
second metal ion). The best fit of the experimental points gives
the following values for pKa11, pKa12, and pKa21, respectively: 6.05,
7.6, and 8.3 (Table 2). The fitting obtained implies that only one
of the two water molecules bound to the second Co(III) ion plays
a significant role in the catalytic process.
A possible explanation for this behaviour is a strong H-bond
or general acid catalysis involving this water molecule that
stabilizes the negative charge developing on the phosphate
oxygen following the attack of the OH- bound to the first Co(III) ion
(Scheme 1C and Supporting Information). As a reviewer pointed
out, one might expect a general acid to have a catalytic effect, but
not effect on binding; a hydrogen bond would seem likely to be
able to form in both the ground state and transition state.
Accordingly, the fact that we don’t see substantial differences in
the binding of the substrate to the catalysts[18] might favour the
general acid catalysis hypothesis. It has to be considered,
however, that a new charge develops during the reaction and this
affects the interaction of the transition state with the water
molecule bound to the second Co(III) ion.
It is reasonable to assume that the pKa values of the two
water molecules bound to the second Co(III) ion do not differ
much from those of the first one. The pKa value we obtain from
the interpolation of the kinetic data for this molecule is ca. 0.5 units
higher than that of the least acidic H2O molecule bound to 4-
Co(III). However, it is expected that a proton, bridging between
the oxygens of water and of the phosphate (Scheme 1C and
Supporting information), to be less acidic than that not involved in
this process. Thus, this higher pKa appears reasonably in line with
the above mechanistic picture.
pKa for the second oxygen of
a putative phosphorane
intermediate (the first one is bound to the Co(III) ion) is 7.9, very
close to the pKa of the above water molecules but lower than that
of the ammonium. Accordingly, thermodynamics favour H-
bonding (or even proton transfer) to this phosphorane oxygen.
Noteworthy, catalysts 1-Co(III)2 and 2-Co(III)2 perform quite
similarly to 4-Co(III) when the substrate is p-nitrophenyl-
diphenylphosphate, PNPDPP (see Table 1), a neutral phosphate
triester for which the single developing negative charge in the
transition state is stabilized by direct coordination to the first metal
ion and, hence, stabilization of other non-bridging oxygens is little
relevant. This also excludes assistance in leaving group
departure by the second Co(III), a quite unlikely event in view of
the very low pKa of p-nitrophenol.[21] Equations (1) and (2) allow
one to obtain second order rate constants for the processes
catalysed by mononuclear 4-Co(III) and dinuclear 1-Co(III)2 or 2-
Co(III)2. They are 3.2×10-3 M-1 s-1, 2.2×10-2 M-1 s-1 and 2.05×10-1
The alternative explanation of
a simple electrostatic
stabilization of the dianionic transition state by the additional
positive charge brought about by the second ion does not appear
so relevant, since this effect would favour the complex with the
smaller intermetallic distance, which is not the case. Electrostatic
contribution to binding has negligible geometrical dependence
and decreases with the inverse of the distance. On the contrary,
the peculiar dependence of the rate acceleration on the distance
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
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M-1 s-1, respectively (Table 2). Thus the kinetic advantage brought
about by this second, remote Co(III) ion amounts up to a 64-fold
rate acceleration with 2-Co(III)2. A quite significant contribution to
the catalytic process considering it is not involved in the
coordination of the substrate neither in the delivery of a
nucleophilic species.
by adding 20 µl of substrate in CH3CN to the cuvette containing 2 ml of
buffered solution with the proper amount of catalyst.
The buffer
components were used as supplied by the manufacturers: acetic acid
(Aldrich), 2-morpholinoethanesulfonic acid (MES, Fluka), 4-(2-
hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES, Sigma), 4-(2-
hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPES, Sigma), 2-[N-
cyclohexylamino]ethanesulfonic
acid
(CHES,
Sigma),
3-
[cyclohexylamino]1-propanesulfonic acid (CAPS, Sigma). The substrate
bis-p-nitrophenyl phosphate sodium salt (BPNPP) was an Aldrich product,
used as received. The substrate p-nitrophenyl diphenylphosphate
(PNPDPP) was synthesized following a reported procedure.[25] All kinetics
have been performed under pseudo-first-ordeer conditions with excess of
catalyst over substrate. Elemental analyses were performed by the
“Laboratorio di Microanalisi” of our Department.
Conclusions
In conclusion we have provided experimental evidence of the
involvement of a remote metal centre in the catalysis of the
hydrolysis of a phosphate diester without direct involvement of
this metal ion in transition state stabilization. In the case of a
Co(III)-based catalyst this contribution amount to 64-fold rate
acceleration and is apparently due to general acid or H-bonding
catalysis.[22] Furthermore, there is significant distance
dependence for this catalytic contribution and, in this particular
case, it appears that the best distance (as estimated by DFT
calculations) is ca. 7.7 Å. This indicates that three metal centres
in close proximity as required for mechanism proposals in which
all three metals are directly involved in transition state
coordination is not the only option for rate acceleration in natural
phosphate hydrolysis. Thus it appears, as it has been
suggested,[3a] that metal ions may have not unique roles and
several mechanisms are possible in phosphate cleaving
enzymes.[23,24] Our model system indicates that even a remotely
located metal ion, placed at the correct distance, can be kinetically
beneficial. The difference between the metal ions present in the
catalytic site of phosphate-cleaving enzymes (Zn(II) and Mg(II))
and Co(III) used in the present investigation is the presence of a
precise coordination geometry for the latter. It is thus not possible
to extend the conclusion we have obtained here as for the
optimum distance of a remotely-placed but catalytically relevant
metal ion when Zn(II) or Mg(II), devoid of a field effect, are the
metal ions. With this caveat in mind it is nevertheless undeniable
that a kinetic contribution of such remote metal centres is a
concrete possibility also in natural enzymes.
1,7-Bis(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane
was
synthesised according to the literature.[26] The product was purified using
rotating disk chromatography using as eluent CHCl3/MeOH (100:2) (yield:
72%). 1H NMR (250 MHz, CDCl3):  = 7.34 (10H, C6H5), 5.15 (s, 4H, OCH2),
3.42 (br, 8H, NCH2), 2.85 (br, m, 8H, NCH2). 13C NMR (62.860 MHz,
CDCl3):  = 155.99 (CO), 135.72, 128.55, 128.30, 127.89 (aromatic
carbons), 67.66 (OCH2), 50.43, 50.35, 50.8, 49.83, 49.48, 49.11, 48.88
(NCH2CH2N). ESI-MS (m/z): 441.1 (M + H+), 462.1 (M + Na+).
2,7-Bis(bromomethyl)naphthalene
was
prepared
following
the
literature[27,28] with little modifications. 2,7-Dimethyl naphthalene (1.14 g,
7.31 mmol) was dissolved in freshly distilled acetone (200 ml) and NBS
(2.2 eq, 16.08 mmol) was added to the solution. N2 was bubbled through
the solution for 1 h, maintaining a week stream of N2 during the reaction
time. When solids were completely dissolved a catalytic amount of benzoyl
peroxide was added to the reaction mixture. The solution was irradiated by
a water-cooled Hg lamp (120W) until the product formation was completed
(4-5 h, monitored by TLC). Then the solvent was evaporated, the solid
residue was taken up with CH2Cl2 (30 ml) and washed with NaOH 1N
solution (2×25 ml) and H2O (25 ml). The residue was purified by rotating
disk chromatography (petrol ether/ethyl acetate = 95:5) (yield: 50%). 1H
NMR (250 MHz, CDCl3):  = 7.84, 7.80, 7.53 (d), 7.50 (d) (6H, aromatic
protons), 4.65 (s, 4H, CH2). 13C NMR (62.860 MHz, CDCl3):  = 135.8,
132.94, 132.64, 128.57, 127.85, 127.48 (aromatic carbons), 33.72 (CH2).
Synthesis and characterization of compounds 1-4.
1,7-dibenzyl-1,4,7,10-tetraazacyclododecane (4), tetrahydrobromide
salt.
1,7-Bis(benzyloxycarbonyl)-4,10-bis(benzyl)-1,4,7,10-
tetraazacyclododecane was prepared following a procedure reported in
the literature[26] with some modifications. Thus, to a refluxing suspension
of 1,7-bis(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane (340 mg,
0.77 mmol) and Na2CO3 (410 mg, 3.86 mmol) in dry MeCN (6 ml) was
added dropwise benzylbromide (193 l, 1.62 mmol). After 1.5 h the
reaction mixture was cooled and filtered. The solvent was evaporated, the
residue was purified using rotating disk chromatography (eluent: 97:3 =
petrol ether/ethyl acetate) yielding 260 mg (55%) of pure compound. 1H
NMR (250 MHz, CDCl3):  = 7.15 (20H, C6H5, OC6H5), 4.92 (s, 4H, CH2),
3.60 (s, 4H, OCH2), 3.43 (br, 8H, NCH2), 2.68 (br, 8H, NCH2). 13C NMR
(62.860 MHz, CDCl3):  = 156.23 (CO), 136.64, 128.28, 128.13, 127,90,
127, 75 126,93 (aromatic carbons), 66.86 (OCH2), 54.5 (CH2), 47.20 (br,
NCH2CH2N). ESI-MS (m/z): 621.4 (M + H+), 643.4 (M + Na+).
Experimental Section
General. Solvents were purified by standard methods. All commercially
available reagents and substrates were used as received. TLC analyses
were performed using Merck 60 F254 precoated silica gel glass plates.
Column chromatography was carried out on Macherey-Nagel silica gel 60
(70-230 mesh). NMR spectra were recorded using a Bruker AC250F
spectrometer operating at 250 MHz for 1H and 62.9 MHz for 13C and a
Bruker AV300 operating at 300 MHz for 1H and 121.5 MHz for 31P.
Chemical shifts are reported relative to internal Me4Si. ESI-MS mass
spectra were obtained with an Agilent Technologies LC/MSD Trap SL
mass spectrometer. UV-Visible spectra and kinetic traces were recorded
on Perkin Elmer Lambda 16 and Lambda 45 spectrophotometers
equipped with thermostated multiple cell holders. Kinetics were followed
by monitoring the change of absorbance of formed p-nitrophenol at 317
nm (pH<6.2) or p-nitrophenolate at 400 nm (pH>6.2). They were started
The above compound was dissolved in a minimum volume of chloroform
and HBr in acetic acid (4M) was added in excess to the solution. The
solution was left stirring for 1 h at room temperature, while white precipitate
was formed. The white solid was filtered off, washed with Et2O and dried
1
in desiccator over P2O5 (yield: 84%). H NMR (250 MHz, D2O):  = 7.39,
7.36, 7.28, 7.26 (m, 10H, C6H5), 3.66 (s, 4H, CH2), 3.06 (br, 8H, NCH2),
2.78 (m, 8H, NCH2); 13C NMR (62.860 MHz, D2O):  = 136, 129.5, 128.9,
128.3, 58.15, 48.18, 42.53. ESI-MS (m/z): 353.4 (M
+
H+);
C22H32N4·4HBr.2H2O (712.19): calcd. C 37.10, H 5.66, N 7.87; found C
36.98, H 5.71, N 7.90.
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
FULL PAPER
Tetrabenzyloxycarbonyl derivatives of macrocycles 1-3, general
complexes, reported synthetic procedures were followed[12,14] and the
properties of the complexess were compared with literature data of similar
complexes.[28-30] The dinuclear Co(III) complexes of the trimacrocycles 1-
3 and the mononuclear one of compound 4 were obtained as NO3 salts
following a procedure in which they were first converted in the carbonates
and, subsequently, treated with concentrated HNO3 to yield the final
products. This two-step procedure was used previously also by other
authors.[15] The NO3 salts were used in all kinetic experiments.
procedure. To 1.07
g
of 1,7-bis(benzyloxycarbonyl)-1,4,7,10-
tetraazacyclododecane (2.4 mmol) dissolved in 500 ml of dry acetonitrile
was added 0.65 g of anhydrous Na2CO3. The solution was brought to reflux
and then
a
solution of the dibromoderivative (1,3-bis(bromo-
methyl)benzene for 1, 1,4-bis(bromomethyl)benzene for 2 and 2,7-
bis(bromomethyl)naphthalene for 3), 2.7 mmol, in 35 ml of dry acetonitrile
was added dropwise over a period of 2.5 h. The reaction mixture was kept
under reflux for further 40 h. The solution was cooled and filtered, the
residue was chromatographed on silica gel column (petrol ether/ethyl
acetate, 60:40 to 40:60 for 1; petrolether/ethylacetate/ethanol, 50:50:5, for
2; petrolethe/ethylacetate, 60:40 to 35:65 for 3) to give the final products
as oils.
.
Synthesis of (4)Co(NO3)3 2H20. Into a vial containing 4 (80 mg, 0.12
mmol) and H2O (10 ml) was added Na3Co(CO3)3 · 3H2O (57 mg, 0.14
mmol). The solution was placed in an oil bath (70ºC, ca. 2 h) until the
vigorous effervescence ceased. During the heating time the solution
turned to deep purple. MeOH (10 ml) was added and the solution was
filtered to remove unreacted sodium tris(carbonato)cobaltate(III).The
solution was concentrated to half its volume on a rotary evaporator and
some more precipitate was removed. Afterwards, acetone (30 ml) was
added removing the precipitate that formed immediately. Addition of
further acetone (10 ml) resulted in the formation, overnight, of a dark violet
precipitate. After filtration and vacuum drying the carbonate salt was
obtained (42 mg, 64%). C23H32BrCoN4O3 (551.36) calcd. C 50.10, H 5.85,
N 10.16; found C 49.96, H 5.89, N 10.09. This carbonate salt was
dissolved in a very small amount of cold water and stirred vigorously until
the complex had dissolved completely, then ca. 5 ml of HNO3 (6M) were
added. After a few hours a precipitate could be observed. This was let to
further sit at room temperature overnight. The solid was then filtered off,
washed with ice-cold HNO3 (0.3 M) and then with ethanol. The treatment
with HNO3 was repeated twice to ensure complete replacement of the
carbonate by the nitrate. The obtained reddish powder (44 mg, 78%) was
dried over P2O5. C22H36CoN7O11 (633.49) calcd. C 41.71, H 5.73, N 15.48;
found C 41.83, H 5.79, N 15.43.
Tetrabenzyloxycarbonyl derivatives of macrocycle 1: 455 mg, 35%. 1H
NMR (250 MHz, CDCl3):  = 7.52 – 7.15 (m, 28H, aromatic protons), 5.06
(d, 8H, OCH2), 3.53 (br, 16H, NCH2), 3.12 (d, 8H, CH2), 2.74 (br, 16H,
NCH2). ESI-MS (m/z): 1085.2 (M + H+), 1107.2 (M + Na+).
Tetrabenzyloxycarbonyl derivatives of macrocycle 2: 264 mg, 20%. 1H
NMR (250 MHz, CDCl3):  = 7.35, 7.29 (m, 28H, aromatic protons), 5.04
(br, 8H, OCH2), 3.50 – 3.26 (br, m, 24H, CH2, NCH2), 2.66 (br, 16H, NCH2).
13C NMR (62.860 MHz, CDCl3):  = 156.56 (CO), 138.29, 136.66, 128.99,
128.34, 127.81 (aromatic carbons), 66.93 (OCH2), 60.06 (CH2), 54.97,
47.83 (NCH2CH2N). ESI-MS (m/z): 1085.2 (M + H+), 1107.2 (M + Na+).
Tetrabenzyloxycarbonyl derivatives of macrocycle 3: 112 mg, 10%. 1H
NMR (250 MHz, CDCl3):  = 7.75 - 7.24 (m, 32H, aromatic protons), 5.08,
4.96 (br, d, 8H, OCH2), 3.80 (br), 3.47 (d), 3.18 (d), 2.86 (br) (40H, NCH2
+ CH2). 13C NMR (62.860 MHz, CDCl3):  = 156.36 (CO), 136.70, 136.31,
133.27, 131.85, 128.35, 127.85, 127.77, 127.48 (aromatic carbons), 66.89
(OCH2), 60.33 (CH2), 53.58, 47.36 (NCH2CH2N). ESI-MS (m/z): 1185.7 (M
+ H+), 1207.7 (M + Na+).
.
.
Synthesis of the HBr salts of macrocycles 1-3, general procedure.
The tetrabenzyloxycarbonyl derivatives of the corresponding macrocycle
was dissolved in a minimum volume of chloroform and HBr in acetic acid
(4M) was added in excess to the solution that was left stirring for 2 h at
room temperature. The white precipitate obtained was filtered off, washed
with Et2O and dried in desiccator over P2O5. Trimacrocycles 1 and 2 have
been already synthesised following a different route than the one we have
used here.[27] Our physical data are consistent with those already reported.
Trimacrocycle 1, heptahydrobromide: 59% yield. 1H NMR (250 MHz,):
 = 7.34 – 7.12 (m, 8H, aromatic protons), 3.88 (s, 8H, CH2), 2.80 (br), 2.64
(s) (32H, NCH2). 13C NMR (62.860 MHz, CDCl3):  = 140.06, 128.20,
128.12, 127.15 (aromatic carbons), 60.78 (CH2), 53.05, 47.01
Synthesis
(3)Co2(NO3)6 4H20.
of
(1)Co2(NO3)6 4H20,
(2)Co2(NO3)6 4H20,
and
a
.
These compounds were obtained following
procedure identical to that reported above for (4)Co(NO3)3 2H20 with
yields: 58.5%, 61%, 33%, respectively.
(1)Co2(NO3)6 4H20: Intermediate carbonate salt: IR: (Co(O-C=O)) = 1669,
1628 cm-1, (C=O) = 1455 cm-1; UV (max, H2O) 372 nm, 563 nm.
C34H52N8Br2Co2N8O6 (946.50) calcd. C 43.14, H 5.54, N 11.84, found C
43.07, H 5.59, N 11.79. Title compound: UV (max, H2O) 375 nm, 550 nm.
C32H60Co2N14O22 (1110.77) calcd. C 34.60, H 5.44, N 17.65; found C 34.66,
H 5.40; N 17.59.
.
.
.
(2)Co2(NO3)6 4H20: Intermediate carbonate salt: IR: (Co(O-C=O)) = 1675,
1635 cm-1, (C=O) = 1458 cm-1; UV (max, H2O) 370 nm, 568 nm.
C34H52N8Br2Co2N8O6 (946.50) calcd. C 43.14, H 5.54, N 11.84, found C
43.21, H 5.53, N 11.91. Title compound: UV (max, H2O) 375 nm, 550 nm.
C32H60Co2N14O22 (1110.77) calcd. C 34.60, H 5.44, N 17.65; found C 34.71,
H 5.51; N 17.56.
(NCH2CH2N). ESI-MS (m/z): 549.6 (M
+
H+). C32H52N8·7HBr.3H2O
(1169.24): calcd. C 32.87, H 5.60, N 9.58; found C 32.83, H 5.63, N 9.52.
Trimacrocycle 2, heptahydrobromide: 64% yield. 1H NMR (250 MHz,
CDCl3):  = 7.42 (s, 8H, aromatic protons), 3.53 (s, CH2), 2.71 – 2.48 (br,
1
.
m, 36H, NH, NCH2). H NMR (400 MHz, D2O):  = 7.57 (s, 8H, aromatic
(3)Co2(NO3)6 4H20: Intermediate carbonate salt: IR: (Co(O-C=O)) = 1660,
protons), 3.81 (s, 8H, CH2), 3.25 (t, 16H, NCH2), 3.13 – 2.89 (br, m, 16H,
HNCH2). 13C NMR (100.61 MHz, D2O/CH3OH):  = 137.61, 129.67
(aromatic carbons), 58.86 (CH2), 49.09, 42.78 (NCH2CH2N). ESI-MS
(m/z): 549.4 (M + H+), 571.4 (M + Na+). C32H52N8·7HBr.2 H2O (1151.22):
calcd. C 33.39, H 5.52, N 9.73; found C 33.44, H 5.48, N 9.69.
1615 cm-1, (C=O) = 1455 cm-1; UV (max, H2O) 357 nm, 574 nm.
C42H56N8Br2Co2N8O6 (1046.62) calcd. C 48.20, H 5.39, N 10.71, found C
48.31, H 5.30, N 10.77. Title compound: UV (max, H2O) 375 nm, 550 nm.
C40H64Co2N14O22 (1210.88) calcd. C 39.68, H 5.33, N 16.19; found C 39.66,
H 5.39; N 16.11.
Trimacrocycle 3, hexahydrobromide: 76% yield. 1H NMR (400 MHz,
D2O):  = 8.30 (s, 4H), 8.18 (d, 4H)), 7.65 (d, 4H), 3.93 (s, 8H, CH2), 3.26
–2.94 (m, br, 32H, NCH2). 13C NMR (100.61 MHz, CDCl3):  = 136.3, 133.3,
131.8, 128.4, 127.8, 127.7, 60.3, 56.4, 47.3. ESI-MS (m/z): 649.5 (M + H+),
671.5 (M + Na+). C40H56N8·6HBr (1134.4): calcd. C 42.35, H 5.51, N 9.88;
found C 42.27, H 5.55, N 9.84.
Computational Methods
Density functional theory (DFT) calculations were performed with
Gaussian 09 Revision B.01. Minima and transition structures were
optimized using the unrestricted DFT method, UB3LYP, with the 6-
31+G(d,p) basis set. Frequency analyses were carried out on stationary
points to verify that they are minima.
Preparation of the cobalt(III) complexes
Sodium tris(carbonato)cobaltate(III) trihydrate, Na3Co(CO3)3 · 3H2O was
synthesised using a literature method.[14a] In the preparation of the Co(III)
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10.1002/ejoc.201800300
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Acknowledgements
This work was supported by the EU under contract HPRN-
CT1999-00008, ENDEVAN (fellowship to ESB) and by the MIUR
of Italy (PRIN 2011).
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10.1002/ejoc.201800300
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
The effect on the catalysis of the
hydrolysis of bis-p-
Phosphate cleavage
E.S Bencze, C. Zonta, F. Mancin, L. J.
Prins, P. Scrimin*
nitrophenylphosphate by dinuclear
Co(III) complexes designed in such a
way that the two Co(III) ions cannot be
contemporaneously involved in the
complexation of the substrate, show a
remarkable dependence on their
distance.
Page No. – Page No.
Distance Between Metal Centres
Affects Catalytic Efficiency of
Dinuclear Co(III) Complexes in the
Hydrolysis of a Phosphate Diester
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