Unprecedented gas-phase chiroselective logic gates

Article abstract of DOI:10.1039/c0ob00664e

The gas-phase encounters between 2-aminobutane and proton-bound chiral resorcin[4]arene/nucleoside complexes behave in the gas phase as supramolecular "chiroselective logic gates" by releasing the nucleoside depending on the resorcin[4]arene and the 2-aminobutane configurations.

Full text of DOI:10.1039/c0ob00664e

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Unprecedented gas-phase chiroselective logic gates†
Bruno Botta,a Caterina Fraschetti,a Ilaria D’Acquarica,a Fabiola Sacco,a Jochen Mattay,b Matthias C. Letzelb
and Maurizio Speranza*a
Received 3rd September 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob00664e
The gas-phase encounters between 2-aminobutane and
proton-bound chiral resorcin[4]arene/nucleoside complexes
behave in the gas phase as supramolecular “chiroselective
logic gates” by releasing the nucleoside depending on the
resorcin[4]arene and the 2-aminobutane configurations.
Nucleosides are buildings blocks of RNA and DNA bio-
macromolecules, which may also act as neuromodulators or as
chemotherapeutic agents.1–3 Nucleoside analogues are widely used
for the treatment of human cancers. The study of the molecular
recognition of nucleobases and their derivatives by synthetic hosts
is aimed at a better understanding of the noncovalent interactions
that play a role in relevant biological processes and may also
contribute to the design of artificial receptors for therapeutic
purposes.
We recently found that the bis(diamido)-bridged basket
resorcin[4]arene enantiomers 1R and 1S (Scheme 1)4 are capable
of incorporating selectively chiral amino acids,5 amines,5 and
amphetamine6 in the gaseous phase, i.e. under conditions exclud-
ing solvation and ion pairing interference.7 Therefore, we believe it
is worth investigating the interactions between either 1R or 1S and
Scheme 1 Formulae of the cone resorcin[4]arene macrocycles 1R and 1S
some pyrimidine nucleosides (N), i.e. 2¢-deoxycytidine 4,8 cytidine,
and of the selected pyrimidine nucleosides N (2–5). The stereogenic centers
5,9 cytarabine 2,10 which is an epimer of cytidine, and gemcitabine
3,11 which is the gem-difluoro derivative of 2¢-deoxycytidine.
Aim of the investigation is to gain some information on the
sensitive molecular regions and functional groups which allow
their selective interaction with protonated 1R and 1S. In this
communication, it is reported that one of the systems investigated
behaves as a supramolecular device which, depending on its
chirality, is capable to keep the nucleoside firmly bound to it or to
release it slowly.
Proton-bound diastereomeric [M·H·N]+ complexes (M stands
for either 1R or 1S; N stands for one among the nucleosides
2–5 of Scheme 1) have been generated in the cell of a Fourier-
Transform Ion Cyclotron Resonance (FT-ICR) mass spectrometer
of 1R and 1S are denoted by the black dots.
by nano-electrospray ionization (nano-ESI) of M/N methanolic
mixtures. After collisional quenching with argon, the complexes
were isolated by broad-band ejection of the accompanying ions
and eventually allowed to react with a chiral amine B (either (R)-
(-)- (BR) or (S)-(+)-2-aminobutane (BS)), present in the FT-ICR
cell at defined concentrations.
Two products are exclusively formed: the addition [M·H·N·B]+
(B stands for either BR or BS) and the guest exchange [M·H·B]+
derivative. The time-dependent decay of the [M·H·N]+ reactant
was monitored by measuring its intensity (I) at any reaction time
t relative to that at t = 0 (I0), calculated as the sum of I and of the
intensities of the addition (Iadd ) and guest exchange (Iexc) products.
The dependence of ln[I/(I+Iadd +Iexc)] vs t is not linear, as expected
for simple parallel or consecutive reaction patterns, but invariably
exhibits a curvature towards an asymptotic limit, different for each
system (Figure S1 of the ESI†). This behavior is consistent with
the [M·H·N]+/[M·H·N·B]+ ratio converging towards a constant
value at long reaction times (Fig. 1).
aDipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Univer-
sita` di Roma, P.le Aldo Moro 5, 00185, Roma, Italy. E-mail: maur-
izio.speranza@uniroma1.it; Fax: +39 06 49913602; Tel: +39 06 49913497
bFakulta¨t fu¨r Chemie, Universita¨t Bielefeld, Postfach 100131, 33501,
Bielefeld, Germany. E-mail: oc1jm@uni-bielefeld.de; Fax: +49-(0)521-106-
6417; Tel: +49-(0)521-106-2072
† Electronic supplementary information (ESI) available: Experimental
Section. Kinetic results. Reaction mechanism. Kinetic equations. Table
of results. See DOI: 10.1039/c0ob00664e
Such a behaviour strongly supports the presence of a pseudo-
equilibrium step in their reaction sequence. Since the neutral
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Fig. 1 Time-dependent relative abundances of [M·H·N]+ (open circles), [M·H·N·B]+ (triangles), and [M·H·B]+ (full circles) for the reactions between
BS and [M·H·5]+ (M = 1R (a); 1S (b)). The continuous lines represent the relative abundance of reactants and products calculated from the exact rate
expressions for sequence (1) (see ESI†).
Table 1 Rate Constant Ratios (eqn (1))
1011k1/k-1 (cm3 molecule-1)
nucleoside N is completely absent in the FT-ICR reaction cell, the
pseudo-equilibrium step must necessarily concern the reversible
addition of B to [M·H·N]+ to yield [M·H·N·B]+. It is concluded
that all [M·H·N]+ complexes follow the reaction sequence
k-1/k2
Complexes
B = BR
B = BS
B = BR
B = BS
k
[1R·H·2]+
[1S·H·2]+
[1R·H·3]+
[1S·H·3]+
[1R·H·4]+
[1S·H·4]+
[1R·H·5]+
[1S·H·5]+
2.4
1.1
0.5
0.9
4.6
7.6
6.2
22.2
> 5 ¥ 103
25.1
43.1
1.3
21.5
12.7
5.3
k
1
+
+
+
2
⎯⎯⎯→
[M⋅H⋅ N⋅B] ⎯⎯→[M⋅H⋅B] + N
[M⋅H⋅ N] + B
(1)
←⎯⎯
k
−1
18.4
4.3
23.4
7.6
Best fit of the experimental results with the exact rate expressions
for each step of the reaction sequence (1) (see Figures S2–S15
and the kinetic equations in the ESI†) allows extraction of the
kinetic constants k1, k-1, and k2 (Table S1, ESI†). The second-
order k1 constants have been compared with the relevant collision
rate constants (kcoll), calculated using the trajectory calculation
method.12 From this comparison, it results that less than 3.5% of
the collisions between [M·H·N]+ and B leads to the formation of
the [M·H·N·B]+ addition complex (eqn (1).
4.1
< 2 ¥ 10-3
0.5
< 2 ¥ 10-3
0.5
> 5 ¥ 103
24.4
70.1
2.1
1.8
6.4
2.4
9.8
Once formed, the [M·H·N·B]+ addition complex can either
back dissociate to [M·H·N]+ and B (k-1) or rearrange to allow
interaction between B and the protonated amidocarbonyls of the
resorcin[4]arene host holding the leaving nucleoside N (k2). Even
though the first pathway invariably prevails over the latter one
(k-1/k2>1; Table 1), the relative efficiency of the two competing
steps still depends on the nature and the spatial orientation of the
substituents at the C2¢ centre of the nucleoside.
Previous experimental studies5,6 pointed out that the N guest
in [M·H·N]+ is proton bonded to one of the amidocarbonyls of
the resorcin[4]arene host and that its loss requires a prototropic
transfer from N to B. The appreciable effect of the configuration
of both the host and the amine B strongly support the view that
the nucleoside N resides inside the cavity of the host among its
chiral pendants and that the amine B must enter the same cavity
to displace the guest. Thus, the relatively inefficient addition of
B to [M·H·N]+ to yield [M·H·N·B]+ can be accounted for by the
establishment of preliminary electrostatic interactions between the
host pendants and B outside the host cavity. This view is supported
by the 1011k1/k-1 ratios of Table 1 which increase in the guest order:
4 < 2 ª 5 < 3, namely by increasing the electron withdrawing
character of the substituents at the C2¢ centre of the nucleoside
(H,H < H,OH < F,F). Since the basicity of the nucleoside is
expected to decrease in the order: 4 > 2 ª 5 > 3, it follows that the
fraction of positive charge on the host pendants and, therefore,
the strength of the electrostatic interactions between them and B
increase in the inverse guest order, as actually found.
Indeed, with N = 5 as the guest, the k-1/k2 ratio from [1R·H·5]+
exceeds that from [1S·H·5]+ by ca. 40 times. By simply inverting
the C2¢ configuration (N = 2), the k-1/k2 ratio does not depend
much on the host configuration, but rather on the B configuration
by increasing in passing from BR to BS. With N = 3 as guest, the
k-1/k2 ratio depends on both the host and the B configuration, thus
indicating that the presence of two electron-withdrawing fluorine
atoms in the 2¢ position appreciably affects the activation free
energies of the two competing pathways.
However, the more outstanding effect of the host configuration
is observed for the complexes with N = 4, as guest. Indeed, when
the host is 1R, no reaction products were observed even after 300 s
reaction time and at a [B] = 7.4 ¥ 109 molecule cm-3, whereas, under
the same conditions, the reaction involving 1S as host proceeded
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Table 2 Supramolecular chiroselective “logic gates”
Host
1R
1R
1S
1S
Input
Amine
Guest, N
BR
BS
BR
BS
Output
2
3
4
5
low
high
low
high
high
low
high
low
low
high
low
low
low
Fig. 2 “Logic gate” is a term borrowed from electronics where it
represents an elementary building block of a digital circuit. Most logic
gates have two inputs and one output. At any given moment, every terminal
is in one of the two binary conditions low (0) or high (1), represented by
different voltage levels. Extending the concept to the present systems, the
two inputs are the configuration of the macrocycle M and of the amine
B and the output is either the loss of B (relatively large k-1/k2; high state)
or the loss of nucleoside N (relatively small k-1/k2; low state) from the
[M·H·N·B]+ “logic gates”(Table 1).
low
high
high
to over 20%. Since the normal dynamic range of the FT-ICR is
ca. 103:1, it can be concluded that the pseudo-equilibrium step
involving [1R·H·4]+ (eqn (1)) is ca. 200 times more shifted towards
the reactants (k1/k-1 < 2 ¥ 10-14 cm3 molecule-1 and k-1/k2 >
5 ¥ 103) than that involving [1S·H·4]+ (k1/k-1 = 5 ¥ 10-12 cm3
molecule-1 and k-1/k2 ~ 25). This means that the [1R·H·4]+ complex
is inert towards B, whereas the same amine B can efficiently
add to the [1S·H·4]+ diastereoisomer and displace the nucleoside
from it.
Nazionale delle Ricerche (CNR). Research grant from Fondazione
Roma (Italy) to B.B. is gratefully acknowledged.
References
Thus, the diastereomeric complexes of Table 1 behave as
supramolecular devices which, depending upon the configuration
of both the macrocycle and the amine B, can or cannot release
the nucleoside. In particular, the [1R·H·4]+ and [1S·H·4]+ systems
can be regarded as the first example of gas-phase supramolecular
“logic gate” that, in the presence of a suitable reactant (B), can
selectively release one enantiomer of a chiral guest and keeping
bound the other enantiomer (Fig. 2 and Table 2). This view can be
somewhat extended to the other complexes investigated, although
in this case the adverb “selectively” must be replaced by “preferen-
tially”.
In conclusion, the present gas-phase results provide a first exam-
ple of selective release of biomolecules from chiral supramolecular
systems (bio-”logic gates”). Assessment of the factors governing
the process may be a starting point for understanding controlled
drug delivery from chiral molecular carriers.
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4 Enantiomerically pure basket-type resorcin[4]arenes, either in the all-R
configuration (1R) or in the all-S one (1S), in their cone conformations,
were synthesized and purified according to established procedures
(ref. 5).
5 B. Botta, I. D’Acquarica, L. Nevola, F. Sacco, Z. Valbuena Lopez,
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7 For a comprehensive survey on gas-phase chiral recognition see: “Chiral
Recognition in the Gas Phase”, Anne Zehnacker Ed., CRC Press, 2010.
8 2¢-Deoxycytidine: 4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymet-
hyl)-tetrahydro-furan -2-yl]-1H-pyrimidin-2-one.
9 Cytidine:
4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymet-
hyl)-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one.
10 Cytarabine: 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymet-
hyl)-tetrahydro-furan-2-yl]-1H-pyrimidin-2-one.
Acknowledgements
11 Gemcitabine:
4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy -5-
hydroxymethyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one.
12 (a) T. Su and W. J. Chesnavitch, J. Chem. Phys., 1982, 76, 5183–5185;
(b) T. Su, J. Chem. Phys., 1988, 88, 4102–41035355–5356.
Work supported by the Ministero dell’Istruzione dell’Universita`
e della Ricerca (MIUR-PRIN-2007H9S8SW) and the Consiglio
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