Table 5 Parameters obtained from the hydrolysis of ester 3a in the presence and absence of caffeine (1) and TAA (2) for 1:2 complexation by fitting
eqn. (9)
Purine
KOH/10Ϫ3 Ϫ1 sϪ1
kS1/10Ϫ3 sϪ1
kS2/10Ϫ7 sϪ1
KS1/
KS2/10Ϫ7
1
2
4.05 0.01
3.95 0.01
1.90 0.30
1.46 0.50
Ϫ1.90 122
Ϫ4.00 0.120
0.166 0.03
0.143 0.03
4.82 2.38
2.95 9.08
ester, indicates that the selectivities are approximately equal,
KS1
kS1
S + Host
Product
HostS
+
Host
consistent with relatively similar rate constants (3a has kOH
=
820, kcaffeine = 340 and kTAA = 156 Ϫ1 sϪ1).
kun
The system may be compared with that of the cetyltrimethyl-
ammonium bromide catalysed alkaline hydrolysis of esters;
there is no substituent effect for the complexation of substi-
tuted phenyl laurates with the micelle.8 In that case it is sug-
gested that the ester function resides in a microenvironment
similar to that of the bulk solvent which is not substantially
involved in the binding process. Moreover the ester group in
that complex is in the Stern layer, to which hydroxide ion is
attracted. In the xanthine complexation the host provides a
microenvironment for the ester group, which is more electron
attracting than that of the bulk solvent.
It is paradoxical that a host which binds the ester by attrac-
tion of electrons reduces the reactivity of the ester in the com-
plex towards attack by hydroxide ion. The complexation almost
certainly involves a parallel planar arrangement of the two flat
molecules and charge polarization towards the host. It may be
that the π-electron cloud of the ester is attracted to the xanthine
acceptor host; little else could explain the relatively large
increase (ϩ0.2) in effective charge on the ether oxygen when the
ester is complexed. The carbonyl functions in the xanthine
hosts would effectively act to reduce electron density on the
aromatic ring, consistent with its acting as an electron acceptor
in molecular complexes with esters. The planar arrangement
would be disrupted in the transition state by the formation of a
tetrahedral structure and this fits the observation of a more
weakly bound transition state–host complex (Table 4). We sug-
gest that the reduced reactivity of the host–guest complex to
hydroxide ion attack is, in addition, due to repulsion of the
hydroxide ion from the relatively hydrophobic complex. The
electron attracting mechanism in the xanthine–ester interaction
is unlikely to complex the hydroxide ion; no such complexation
has been observed and if it were, it would compete with ester
binding.
KS2
Product
kS2
Host2S
Product
Scheme 2
the data because there are more disposable parameters than in
eqn. (1).
Theophylline-7-acetate anion (TAAϪ), which should not
aggregate due to electrostatic repulsion, also forms complexes
with 1:1 stoichiometry, eqn. (1). The reactivity difference
observed in the alkaline hydrolysis of benzoates complexed by
caffeine and TAAϪ may by ascribed to the negative charge of
the latter, which electrostatically repels hydroxide ion attack.
We conclude that stacking does not account for the inhib-
ition of ester hydrolysis by xanthine derivatives. Moreover, the
heterocyclic host molecules cannot form a cavity, into which a
substrate may penetrate and from which hydroxide ion may be
excluded.
Charge development
The negative Brønsted β values for the dissociation of the host–
ester complexes (KS) [eqns. (4) and (6)] indicate an increase in
positive effective charge on the leaving ester oxygen in the com-
plex compared with that in free aqueous solution. The intro-
duction of a carboxylate group to the host, as in TAAϪ, has no
observable effect on the effective charge development in the
complex.
Effective charges may be derived for the complexation reac-
tions from β values from Brønsted equations and Scheme 3
khost/KS
khost
TSH‡ost
±0.54
[EsterX]W
0.70
[EsterX:Host]
+0.90
Acknowledgements
KS
The University of Dicle is thanked (N. P.) for a studentship and
NATO for a travel grant (910922). We are grateful for helpful
discussion with Dr G. Cevasco of the University of Genoa and
Professor S. Thea of the University of Sassari.
βeq = +0.20
βhost = –0.36
TSW‡
0.30
kun
[EsterX]W
0.70
Products
References
β
W = –0.40
1 T. Higuchi and L. Lachman, J. Am. Pharm. Assoc., 1955, 44, 521.
2 F. M. Menger and M. L. Bender, J. Am. Chem. Soc., 1966, 88, 131.
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Org. Chem., 1994, 29, 1.
5 A. Williams, Adv. Phys. Org. Chem., 1992, 27, 1.
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Scheme 3 Effective charge map for alkaline hydrolysis of phenyl
benzoates in the absence and in the presence of caffeine. The numbers
represent effective charges in various states, which are relative to the
ionization of phenol in water.5 The β values are quoted with the conven-
tion that they are positive for increase in positive effective charge from
left to right.
illustrates the effective charge map for the reaction in the pres-
ence and absence of caffeine. The map for the interactions of
esters with TAAϪ ion has similar values. The change in effective
charge from free ester to complexed transition state (Ϫ0.16) is
less negative than from free ester to transition state in aqueous
solution (Ϫ0.40). The smaller selectivity for the complexation
reaction is not consistent with the reactivity–selectivity hypo-
thesis and this can be explained by the fact that the two rate
parameters (kOH and khost/KS) have different units, so that com-
parison is not possible. Comparison of khost and kOH, the rate
constants for attack of hydroxide ion on complexed and free
Paper 7/05499H
Received 29th July 1997
Accepted 15th September 1997
40
J. Chem. Soc., Perkin Trans. 2, 1998