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632
G. CEVASCO ET AL.
with its ‘simple’ encapsulation into RES3 cavity,
followed by slower reaction of the host-guest complex
with hydroxide ion. This result is in line with the
moderate reactivity of aryl sulfonates toward amines.6
The pH-dependences of kc for the acetate and benzoate
esters are consistent with the neutral dimethylamino
functions being involved in the catalysis. It is likely that
the dimethylamino function in RES3 and RES5 behaves
as a nucleophile to form a reactive acylammonium
species which subsequently decomposes and regenerates
the catalytic amine (Scheme 2).
Comparison of macrocycle reactivity with that
of a model nucleophile
Figure 2. pH-Dependence of the RES3-catalyzed (log kc)
and uncatalyzed (log kb) hydrolyses of esters 1, 2a, and 3.
Identification is as follows. Colors, lines and symbols: red, ester
1; black, ester 2a; blue, ester 3; solid lines refer to log kc
(circles); dashed lines refer to log kb (stars). Open symbols refer
to data from present work, closed ones to data from Ref. 3.
Line for the acetate/RES3 reaction is from Eqn (2) with kcmax
from Table 3 and pKa ¼ 8.49. kb values for all three esters
agree nicely with values for the hydroxide ion catalyzed fission
of the corresponding esters (ester 1: kOH ¼ 3.95 Mꢂ1 sꢂ1, this
work, see Table 1; ester 2a: kOH ¼ 9.5 Mꢂ1 sꢂ1, from Ref. 4;
ester 3: kOH ¼ 1.6 ꢀ 10ꢂ2 Mꢂ1 sꢂ1, from Ref. 5) [This figure is
available in colour online at www.interscience.wiley.com]
The catalytic activity of the hosts can be measured by the
ratio kc/KS which registers the difference in free energy
between the transition structure of the rate-limiting step
and the reactant state where host and ester substrate are
free.1 This ratio therefore could be compared with kNuc
,
the second order rate constant for the model catalyst
CH3CONH(CH2)3N(CH3)2 (1-acetylamino-3-dimethyla-
minopropane, compound 4), which also measures the free
energy difference between reactants (free ester and
catalyst) and the transition state. The reactivities kNuc of
the model 4 against esters 1 and 2a are shown in Table 2.
In a previous report,3 the reactivity of trimethylamine was
employed as a model, suggesting that in the hydrolysis of
ester 2a the reaction flux taken by the intramolecular,
RES3-catalyzed route (as compared to the intermolecular
one) is some 99% of the total. For the dimethylamino
group of 4, pKa was estimated to be 9.137 (a pKa value of
9.23 has been reported for N-(3-dimethylaminopropyl)-
acrylamide.8) A further refinement of the model was
carried out as follows: for the intermolecular reactions of
a hypothetical dimethylamino group with a pKa of 8.49
(the same as that of RES3) with ester 2a the bimolecular
rate constant of 6.5 ꢀ 10ꢂ3 can be calculated from that
of 4, assuming a bNuc of 0.9,9 and the respective pKa
values. Supposing that the same bNuc value holds also for
the aminolysis of aryl benzoates (Um et al.10 report a bNuc
of 0.85 for the reaction of 4-nitrophenyl benzoate and
work (shown in Table 1) indicate that in general fairly
strong binding takes place in ester complexes.
The pH-dependences of the kc term for the RES3-
catalysed fission of 4-nitrophenyl benzoate and acetate
should fit Eqn (2), corresponding to a simple ionization
taking place within the pH range explored (potentiometric
titration of RES3, and RES5 as well, gave good values of
the ionization constants Ka, suggesting that no significant
interaction occurred among the dimethylamino groups,
see Supplementary Material). The results for the 4-
nitrophenyl acetate and RES3 appear to fit Eqn (2) nicely,
but the kinetics of the benzoate seem to follow a flattened
sigmoid pH dependence with a relatively low slope (0.47)
over
secondary alicyclic amines),
a rate constant of
kcmax
10ꢂpH=Ka þ 1
1.1 ꢀ 10ꢂ3 Mꢂ1 sꢂ1 can be reckoned for ester 1 analo-
kc ¼
(2)
gously. Table 2 also shows the kNuc(calc) values
calculated for a dimethylamino nucleophile with
the entire range studied, at variance with 4-nitrophenyl
benzenesulfonate, whose dependence has unit slope. At
this stage, it is not possible to advance any simple
explanation about this fact; it seems reasonable, however,
that in the benzoate reaction specific host-guest inter-
action take place, most likely involving the dimethyla-
mino groups as nucleophiles. A tentative explanation
could be that, upon ionization, the RES3/benzoate
complex has a different behavior than the free RES3,
involving interaction between the ionizing functions. As
for 4-nitrophenyl benzenesulfonate, results are consistent
pKa ¼ 8.94, model for the intermolecular reaction of
RES5, as well as the kc(corr) values (kc(corr) ¼ kc/8, see
footnote e in Table 2). The comparison of model with host
reactivity is included in Table 2 and the ratio [(kc(corr)/
KS)/kNuc(calc)] shows that there are significant rate
enhancements in the ester hydrolysis catalyzed by RES3
and RES5 as compared with the model nucleophile (in the
less favorable case, i.e., the RES3 catalyzed hydrolysis of
4-nitrophenyl acetate 2a, the reaction flux taken by the
intramolecular route is some 97%).
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 630–636
Cevasco, Giorgio
