for the molecule to adopt conformations in which these two
groups are situated at distances as short as 2.9 Å,17 in
conformations readily accessible at 25 °C. An analogous
analysis can be applied to the motor system.
These geometric considerations are in agreement with rate
acceleration for hydrolysis via a mechanism in which a metal-
bound water (or hydroxide) molecule acts as an internal
nucleophile attacking the carbamate moiety.
For comparison, the catalyzed reaction was also studied
for two other divalent metals, namely, Zn2+ and Co2+. In
both cases the reaction was found to be slower than when
Cu2+ was used (Table 2) but still much faster than the
Figure 4. Rate vs [Cu2+]/[carbamate] ratio. Reaction carried out
at pH 7.5 and 25 °C under conditions described in the text and in
the Supporting Information section. kcalcs correspond to the values
calculated by linear regression.
Table 2. Comparison of Ionization and Hydrolysis Constants
of Metal2+ Complexes
copper
zinc
7.1
cobalt
7.0
of copper present in the solution (Figure 4). A linear plot
could be obtained for kobs vs [Cu2+]/[carbamate] for 0 <
[Cu2+]/[carbamate] e 1, and there is no additional rate
acceleration for values >1, at which point enough Cu2+ has
been added to complex all the ligand.
While other mechanisms involving intramolecular deliv-
ery15 of H2O/OH- are possible (such as ones involving
activation of the carbonyl by intramolecular coordination to
the metal ion), we believe that reaction is occurring via a
complex such as 15. It was expected that in solution tridentate
carbamate ligand 9 would form a stable monomeric complex
with divalent metals. In water, this dicationic complex could
adopt a square pyramidal shape such as 15, with two solvent
molecules bound to the metal center, one occupying the
vacant equatorial position and the second the apical posi-
tion.16 The equatorial water, being closer to the metal center,
was expected16 to be more acidic.
titr
a
pKa
pKa
5.4
7.4
0.56
0.78
app b
kobs (min-1) pH 7.5
kobs (min-1) pH 8.5
0.19
0.31
0.30
0.73
a Calculated by titration of a 0.01 M solution of the complex in 85:15
aqueous acetonitrile with a 0.1 M aqueous NaOH solution. Ionic strength
was not controlled. A combination glass electrode was used. b Derived by
calculating the regression curve for experimental data in Figure 3.
noncatalyzed reaction. At pH 7.5 the reaction catalyzed by
Zn2+ is 2.9 times slower than the reaction catalyzed by Cu2+.
Co2+ was found to be 1.9 times slower than copper. For both
cobalt and zinc, the values of the potentiometrically deter-
mined pKas for the metal-bound water molecule were found
to be higher than that obtained for the Cu2+ complex, and
these values are expected to be even higher in a 1:1
acetonitrile:buffer mixture.14 At pH 8.5 the reaction catalyzed
by Zn2+ is 2.5 times slower than the reaction catalyzed by
Cu2+, whereas the reaction catalyzed by Co2+ has ap-
proximately the same rate as the copper-promoted reaction.
However, for the reaction in the presence of Co2+, side
reactions seem to take place at this pH.
In conclusion, the results of this model study show that it
is possible to achieve substantial rate enhancements (2 ×
104) for the hydrolysis of a carbamate group by using a metal
salt as a catalyst. Incorporation of this system into a
molecular motor is currently under examination.
Acknowledgment. We thank the NIH (Grant GM56262)
for funding. We also wish to thank Prof. M. L. Snapper’s
research group for making their HPLC system available and
for help with its operation.
Molecular modeling calculations (Spartan, PM3) on 15
show that in the equilibrium geometry the equatorial water
and the carbamate carbonyl carbon are situated at a distance
of 3.4 Å. However, by rotating around bond a, it is possible
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds;
additional details of experimental procedures used during
kinetic studies. This material is available free of charge via
(15) In principle, one might also consider alternative structures for the
complex in which the carbonyl oxygen is coordinated to the metal. However,
for those complexes, intermolecular attack by water/hydroxide would display
a pH profile with increasing pkobs values for higher pHs instead of the
observed leveling off (Figure 2; see also ref 11 and Breslow, R.; Schepartz,
A. J. J. Am. Chem. Soc. 1987, 109, 1814). On the other hand, intramolecular
attack of metal-bound water/hydroxide onto the coordinated carbonyl would
be disfavored on the basis of geometric constraints.
OL016867Z
(16) For similar complexes and a detailed description of their structure,
see, for example: Young, M. J.; Wahnon, D.; Hynes, R. C.; Chin, J. J.
Am. Chem. Soc. 1995, 117, 9441.
(17) Menger has proposed an “optimal” distance for intramolecular
carbonyl addition to be a value close to 2.8 Å: Menger, F. M. Acc. Chem.
Res. 1985, 18, 128.
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Org. Lett., Vol. 3, No. 24, 2001