Mohamed and Brown
JOCArticle
phosphodiesterases, considerable interest has devel-
oped in the design of small molecule mono- and dinuclear
metal complexes that catalyze the cleavage of phosphate
diesters.2
and leads us to conclude that the large rate enhancements
observed upon moving from aqueous solution9 into alcohols
of lower dielectric constant and polarity stem from an important
medium effect that has, until recently, been underappreciated.
The importance of nonpolar surroundings has been recently
demonstrated by Wolfenden,10 who reported that the sponta-
neous hydrolysis of a nonactivated phosphate diester mono-
anion is accelerated by nearly a million times by moving
from pure water to wet cyclohexane. In our hands, the alcohol
medium seems to simplify, in some respects, problems encoun-
tered in water where active dinuclear M(II)2 complexes
cannot be formed unless an auxiliary oxo-bridging group is
present, probably to insulate the charge repulsion between the
two metal centers, thus stabilizing the dinuclear core.11 The
lower polarities of methanol and ethanol seem to enhance
the metal binding to the ligands relative to water, probably
by decreasing the solvation of the metal ions This allows us
to make highly active dinuclear Zn(II) complexes operating
in alcohol without auxiliary bridging oxo groups that, when
present in comparison systems, are detrimental to catalytic
activity.12
The catalytic role of the metal ions in the enzymes is
thought to be enhanced by contributions from strategically
located amino acid residues in the active site. The micro-
environment surrounding a metal ion has been shown to
play a major role in biologically relevant metal-promoted
reactions.3 A recent trend in the design of metal complexes
that catalyze the cleavage of phosphate esters is the in-
corporation of ancillary hydrogen-bonding (H-bonding)
substituents that are postulated to enhance catalysis
through favorable interactions with the transforming sub-
strate in the transition state.4 A number of these catalysts
employ ligands based on the bis(2-amino-pyridinyl-6-
methyl)amine moiety that incorporates a primary amino
group at the 2-position of both pyridyl rings. The observa-
tion that complexes bearing H-bond donating groups are
generally more active than the corresponding unsubstituted
complexes is taken as evidence that catalyst activity can be
modulated by strategically incorporating the H-bonding
functionality.
Building on the large catalytic acceleration that results
from alcohol media rather than water, we wondered if the
addition of simple hydrophobic groups proximal to the
dinuclear core of the catalyst might create an extended
hydrophobic pocket and enhance activity through inter-
actions similar to the hydrophobic effects observed in
aqueous media.13 In order to test whether specifically posi-
tioned H-bonding groups might provide additional cata-
lytic benefits in methanol, we have also prepared, for
comparison with the complexes with hydrophobic substit-
uents and for results obtained in water, complexes with
a 2-NH2 and 2-acetamido (NH(CdO)CH3) group, both of
which have been suggested to exert positive H-bonding
effects on phosphate binding and cleavage in suitably
substituted Zn(II) complexes.4,14 Herein we report a
kinetic study of the cyclization of the simple RNA analogue
2-hydroxypropyl-p-nitrophenyl phosphate (2, HpNPP) in
methanol catalyzed by a series of Zn(II)2 complexes with
alkyl substituents 4:Zn(II)2, 5:Zn(II)2, and 9:Zn(II)2, com-
paring their activities with the nonfunctionalized parent
complexes substituted only with H, 3:Zn(II)2 and 8:Zn(II)2.
The studies show that the rate of the catalyzed cleavage of 2
can be enhanced by up to 3 orders of magnitude by mod-
ification of a Zn(II)2 catalyst with simple alkyl/alkenyl
substituents (CH3, (CH)4). We have also studied a pair
of dinuclear catalysts that are functionalized with H-bonding
groups, 6:Zn(II)2 and 7:Zn(II)2. The data indicate that
both H-bond donating substituents and alkyl substituents
enhance catalysis relative to the unsubstituted complex,
but surprisingly, the H-bond donating substituents are no
Recent work from this laboratory has focused on the
cleavage of simple RNA and DNA models catalyzed by
dinuclear Zn(II) complexes in the light alcohols methanol
and ethanol.5 We have demonstrated that the cleavage of
phosphate diesters as RNA and DNA models is accelerated
by 1011-17 relative to the background reactions in the pres-
ence of the a system comprising an alcohol medium and the
dinuclear complex 1:Zn(II)2.6-8 This system far outperforms
any reported synthetic nuclease models that operate in water
(2) For a representative list of references on various metal-containing com-
plexes, see: (a) Mancin, F.; Tecillia, P. New J. Chem. 2007, 31, 800. (b) Weston, J.
Chem. Rev. 2005, 105, 2151. (c) Molenveld, P.; Engbertsen, J. F. J.; Reinhoudt,
D. N. Chem. Soc. Rev. 2000, 29, 75. (d) Williams, N. H.; Takasaki, B.; Wall, M.;
Chin, J. Acc. Chem. Res. 1999, 32, 485. (e) Mancin, F.; Scrimin, P.; Tecilla, P.;
Tonellato, U. Chem. Commun. 2005, 2540. (f) Morrow, J. R.; Iranzo, O. Curr.
Opin. Chem.Biol. 2004, 8, 192.
(3) (a) Borovik, A. S. Acc. Chem. Res. 2005, 38, 54. (b) Marque Rivas,
J. C. Curr. Org. Chem. 2007, 11, 1434.
(4) For a representative example of studies on small molecule enzyme
mimics utilizing hydrogen bond donors, see: (a) Feng, G.; Natale, D.;
Prabaharan, R.; Marque-Rivas, J. C.; Williams, N. H. Angew. Chem., Int.
Ed. 2006, 45, 7056. (b) Feng, G.; Marque-Rivas, J. C.; Williams, N. H. Chem.
Commun. 2006, 1845. (c) Aıt-Haddou, H.; Sumaoka, J.; Wiskur, S. L.;
Folmer-Anderson, J. F.; Anslyn, E. V. Angew. Chem., Int. Ed. 2002, 41,
4014. (d) Livieri, M.; Mancin, F.; Tonellato, U.; Chin, J. Chem. Commun.
2004, 2862. (e) Feng, G.; Marque-Rivas, J. C.; Torres Martin de Rosales, R.;
Williams, N. H. J. Am. Chem. Soc. 2005, 127, 13470. (f) Lombardo, V.;
Bonomi, R.; Sissi, C.; Mancin, F. Tetrahedron 2010, 66, 2189. (g) Bonomi, R.;
Saielli, G.; Tonellato, U.; Scrimin, P.; Mancin, F. J. Am. Chem. Soc. 2009,
131, 11278. (h) Bonomi, R.; Selvestrel, F.; Lombardo, V.; Sissi, C.; Polizzi, S.;
Mancin, F.; Tonellato, U.; Scrimin, P. J. Am. Chem. Soc. 2008, 130, 15744.
(i) Livieri, M.; Mancin, F.; Saielli, G.; Chin, J.; Tonellato, U. Chem.-Eur. J. 2007,
13, 2246.
(5) Brown, R. S. Biomimetic and non-biological dinuclear Mxþ-complex
catalyzed alcoholysis reactions of phosphoryl transfer reactions. In Progress
in Inorganic Chemistry; Karlin, K. D., Ed.; John Wiley and Sons: Hoboken,
NJ, Vol. 57, in press.
(6) Neverov, A. A.; Lu, Z.-L.; Maxwell, C. I.; Mohamed, M. F.;
White, C. J.; Tsang, J. S. W.; Brown, R. S. J. Am. Chem. Soc. 2006, 128,
16398.
(10) (a) Stockbridge, R. B.; Wolfenden, R. Chem. Commun. 2010, 46,
4306. (b) See also: Stockbridge, R. B.; Wolfenden, R. J. Am. Chem. Soc.
2009, 131, 18248.
(7) Bunn, S. E.; Liu, C. T.; Lu, Z.-L.; Neverov, A. A.; Brown, R. S. J. Am.
Chem. Soc. 2007, 129, 16238.
(8) Liu, C. T.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc. 2008, 130,
16711.
(9) Kim and Lim ( Kim, J.; Lim, H. Bull. Korean Chem. Soc. 1999, 20, 491)
have reported that complex 1:Zn(II)2 is no more reactive in water than its
mononuclear analogue, the Zn(II) complex of 1,5,9-triazacyclododecane for
the cleavage of bis-p-nitrophenyl phosphate..
(11) Morrow, J. R. Comments Inorg. Chem. 2008, 29, 169.
(12) Mohamed, M. F.; Neverov, A. A.; Brown, R. S. Inorg. Chem. 2009,
48, 11425.
(13) (a) Blokzijl, W.; Engberts, J. B. F. N. Angew. Chem., Int. Ed. Engl.
1993, 32, 1545. (b) Otto, S.; Engberts, J. B. F. N. Org. Biomol. Chem. 2003, 1,
2809.
(14) Lee, J. H.; Park, J.; Lah, M. S.; Chin, J.; Hong, J.-I. Org. Lett. 2007,
9, 3729.
8472 J. Org. Chem. Vol. 75, No. 24, 2010