Exploiting tautomerism for switching and signaling

Article abstract of DOI:10.1002/anie.200903301

Good form: Attaching a flexible piperidine unit to 4-(phenyldiazenyl) naphthalen-1-ol allows construction of a tautomeric switch, where directed shift of the tautomeric equilibrium can be achieved through protonation and deprotonation (see picture). The developed molecular switch shows acceptable complexation with small alkali- and alkaline-earth-metal ions and forms a promising base for further development of effective molecular sensors.

Full text of DOI:10.1002/anie.200903301

Angewandte
Chemie
DOI: 10.1002/anie.200903301
Tautomeric Switches
Exploiting Tautomerism for Switching and Signaling**
Liudmil Antonov,* Vera Deneva, Svilen Simeonov, Vanya Kurteva, Daniela Nedeltcheva, and
Jakob Wirz
Herein, we demonstrate a conceptual idea for a tautomeric
switch based on implementation of a flexible piperidine unit
in 4-(phenyldiazenyl)naphthalen-1-ol. The results show that a
directed shift in the position of the tautomeric equilibrium
can be achieved through protonation/deprotonation in a
number of solvents. The developed molecular switch, in spite
of the simple host–guest system, has shown acceptable
complexation ability towards small alkali- and alkaline-
earth-metal ions and can be a promising basis for further
development of effective molecular sensors through imple-
mentation of azacrown ethers.
Scheme 1. Molecular switch based on molecular recognition (left) and
Organic molecular materials are increasingly recognized
as suitable molecular-level elements (such as switching,
signaling, and memory elements[1]) for molecular devices,
because the wide range of molecular characteristics can be
combined with the versatility of synthetic chemistry to alter
and optimize molecular structure in the direction of desired
properties. Virtually every molecule changes its behavior
when acted upon by external fields or other stimuli. True
molecular switches undergo reversible structural changes,
caused by a number of influences, which give a variety of
possibilities for control. Several classes of photoresponsive
molecular switches are already known; these operate through
processes such as bond formation and bond breaking, cis–
trans isomerization, and photoinduced electron transfer upon
complexation.[2] A conceptual scheme of a molecular switch
based on molecular recognition is shown in Scheme 1. The
host–guest system represents, for instance, a crown ether that
can bind ions or a cyclodextrin that can bind other small
molecules. It is bound to a signal converter. The complexation
behavior is monitored by the state of the signal converter, and
in turn its optical or electronic properties are determined by
the complexation state of the host–guest system.
conceptual idea for a tautomerism-based molecular switch (right).
The main requirement in the design of new molecular
switches is to provide fast and clean interconversion between
structurally different molecular states (on and off). Tauto-
merism could be a possibility, because change in the
tautomeric state can be accomplished by a fast proton
transfer reaction between two or more structures, each of
them with clear and different molecular properties.[3] There-
fore, our aim herein is to show how tautomerism can be
exploited for signal conversion. The conceptual idea of such a
device is presented in Scheme 1. In this structure, a change in
tautomeric state, labeled A and B, is linked to changes in the
complexation abilities of the host–guest system by modulating
the propensity of the system to hydrogen bond to the antenna.
At the same time, engagement of this antenna causes a change
in the tautomeric state. The sensitivity of the electronic
ground and excited states of the tautomeric forms to environ-
ment stimuli (light, pH value, temperature, solvent) and to
the presence of a variety of substituents or to hydrogen
bonding can be exploited in the design of flexible tools for
control.
Obviously, such a device should be based on a tautomeric
structure with easy proton exchange between the tautomers,
which means that they must coexist in solution. At the same
time, a main feature of systems of tautomers coexisting in
solution is that the overall optical response is a mixture of the
optical responses of the individual tautomers. Consequently,
in the design of tautomeric switches, conditions for obtaining
pure end tautomer in the corresponding off and on states must
be provided.
Herein we report the properties of two tautomeric
switches, namely 3 and 4 (Scheme 2), based on 4-(phenyl-
diazenyl)phenol (1) and 4-(phenyldiazenyl)naphthalen-1-ol
(2).
[*] Prof. Dr. L. Antonov, V. Deneva, S. Simeonov, Dr. V. Kurteva,
D. Nedeltcheva
Institute of Organic Chemistry with Centre of Phytochemistry
Bulgarian Academy of Sciences
Acad. G.Bonchev str., bl.9, 1113 Sofia (Bulgaria)
Fax: (+359)2-8700-225
E-mail: lantonov@orgchm.bas.bg
Homepage: http://www.orgchm.bas.bg/~lantonov
Prof. Dr. J. Wirz
Departement Chemie, University of Basel
Klingelbergstrasse 80, 4056 Basel (Switzerland)
[**] The work was supported by The Bulgarian Science Found (projects
TK-X-1716 and UNA-17/2005) and The Swiss National Science
Foundation (JRP IB7320-110961/1).
The parent compound 2 is the first dye that was shown to
tautomerize by Zincke and Bindewald in 1884.[4] It has been
the object of many spectral and theoretical studies[5] because
its tautomeric forms coexist in solution and the equilibrium
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903301.
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Communications
Scheme 2. Tautomeric equilibria in compounds 1–4.
can be markedly shifted by changing the solvent environment.
However, the pure individual tautomers have never been
observed at room temperature.
For the phenol analogue 1, the relatively unstable keto
form cannot be detected.[6] Relative stabilities[7] of the K and
E tautomers in 1–4 were calculated at the HF/6-31G** level
of theory, which was found to give acceptable results for this
class of compounds.[5] The energy difference between the
tautomeric forms in 1 is large, accounting for the absence of
the keto tautomer K in appreciable concentration (Figure S1
in the Supporting Information). In the case of 2, the moderate
energy gap allows both tautomeric forms to be observed
(Figure 1).[5] The piperidine moiety in compounds 3 and 4
stabilizes the enol forms E relative to the keto forms K.
The absorption spectra of 1–4 shown in Figure 2 and the
estimated tautomeric constants for 2 and 4 collected in
Table 1 fully support the theoretical expectations. In both 1
and 3 only the absorption maximum of the enol form around
350 nm is observed, irrespective of the solvent. The tauto-
meric equilibrium in 2 is strongly solvent-dependent. Polar
solvents favor the K tautomer, but specific solute–solvent
interactions can have the opposite effect.[8] For instance,
chloroform stabilizes the more polar K tautomer through
hydrogen bonding with the carbonyl oxygen atom, while the
more polar acetone shifts the equilibrium towards the less
polar enol form. However, the individual, pure tautomers
cannot be obtained under any conditions.
Figure 1. Change of the relative energy (HF/6-31G**) of the tautomers
of 2, 4, and 4H+. The values of DE, DE+ZPE, and DDG are given in
kJmolꢀ1
.
The addition of the piperidine fragment in 4 changes the
situation dramatically. Hydrogen bonding between the piper-
idine nitrogen atom and the enol OH group shifts the
equilibrium fully (within the detection limits, see Figure S2 in
the Supporting Information) to the
~
Figure 2. Absorption spectra of 1–4 in various solvents: 1 ( ) and 3
~
*
( ) in acetonitrile, 2 in acetonitrile (c) and chloroform ( ), 4 in
+
*
acetonitrile (b) and chloroform ( ), 4H in acetonitrile (a).
enol form in most solvents. The
Table 1: Tautomeric constants (KT =[K]/[E])[a] of 2 and 4 in selected solvents at room temperature.
data given in Table 1 show that in
acetone, chloroform, and acetoni-
trile (ACN), where a substantial
amount of the keto form of 2 is
available, 4K is not presented. In
solvents with both proton donor
and acceptor properties (alcohols
I[b]
II
III
IV
V
VI
2
4
0.09 (5.94)[c]
<0.005 (>13)
1.34 (ꢀ0.71)
0.37 (2.42)
0.04 (7.95)
0.20 (3.97)
0.17 (4.35)
0.49 (1.75)
0.43 (2.09)
0.57 (1.38)
0.08 (6.23)
0.08 (6.23)
[a] See Ref. [10]. [b] Solvents (dielectric constants): I cyclohexane (2.02), II CHCl3 (4.90), III acetone
(20.7), IV absolute ethanol (24.5), V methanol (32.6), VI acetonitrile (36.6). [c] Calculated DG values
(kJmolꢀ1) are given in parentheses.
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Angewandte
Chemie
and water), the keto form is present in detectable amounts,
approximately the same as in 2. Moreover, the mass spectrum
of 4 shows fragmentation that is typical for the enol form (see
Supporting Information).[9]
As suggested from Figure 1, the protonation of the
piperidine nitrogen atom is a suitable tool to switch the
equilibrium from pure enol to pure keto form. The calculated
relative energies of K and E in compound 4 change from 17.5
to ꢀ8.3 kJmolꢀ1 upon protonation of the piperidine nitrogen
atom (pKa = 6.5 in ACN). The keto form is stabilized through
hydrogen bonding with the carbonyl oxygen atom
(Scheme 3). Indeed, the equilibrium switches from enol to
ketone, as is apparent from the spectra of 4 and 4H+ in
Figure 3. Spectrophotometric titration of 4 with Mg(ClO4)2 in dry
acetonitrile. Concentration of the salt: 0, 6.63ꢀ10ꢀ6, 6.63ꢀ10ꢀ5
1.32ꢀ10ꢀ4, 3.31ꢀ10ꢀ4, 3.98ꢀ10ꢀ4, 5.30ꢀ10ꢀ4 molLꢀ1
,
.
Scheme 3. Protonation of 4.
Table 2: Stability constants (logb) of the complexes of 4 with alkali- and
acetonitrile (Figure 2). The conjugate acid 4H+ exhibits a new
absorption band at 480 nm with twice the molar absorptivity
of the most intense band of 4. Further addition of acid (pH <
3) leads to protonation of the tautomeric fragment, resulting
in the appearance of a new band at approximately 540 nm
(Figure S3 in the Supporting Information). The same band is
observed in acidic solutions of 2 (Figure S4 in the Supporting
Information).
alkaline-earth-metal ions (as perchlorate salts) in dry ACN.[a]
Li+
Na+
K+
Be2+[b]
Mg2+
Ca2+
4
0.63ꢁ0.08 ca. ꢀ0.5
–
2.30ꢁ0.03 3.43ꢁ0.13[c] ca. 1.0
[a] Estimated using the spectra of 4 and 4H+ as references. [b] As sulfate
in ACN/H2O 1:1. [c] No complex detected in ACN/H2O 1:1.
Because the piperidine fragment is attached to the
azonaphthol moiety through a saturated spacer, the absorp-
tion spectra of 4 and 4H+ in acetonitrile are nearly identical to
those of the pure E and K tautomeric forms of 2, respectively,
which have been determined by an advance curve-fitting
procedure in ethanol.[11] This chemometric procedure esti-
mates the positions of 2E and 2K as 407 (e = 15500mꢀ1 cmꢀ1)
and 480 nm (e = 34400mꢀ1 cmꢀ1), in close agreement with the
spectral maxima of 4 (lmax = 413 nm, e = 15600mꢀ1 cmꢀ1) and
4H+ (lmax 486 nm, e = 31400mꢀ1 cmꢀ1) in acetonitrile. Thus, 4
is a tautomeric device, in which the tautomeric equilibrium
can be switched by the addition of acid or base. Hence, the
concept for a tautomerism-based molecular switch, described
in Scheme 1, works.
How does the addition of the piperidine fragment
influence the proton exchange rate? In previous flash
photolysis studies,[12] it has been found that the E form
undergoes light-induced trans–cis isomerization (Scheme 4),
whereas the keto tautomer does not show any detectable
transient signal. The cis enol tautomer does not undergo
direct cis–trans relaxation. Rather, it proceeds by tautomeri-
zation to the K form to restore the thermal-equilibrium
tautomeric ratio. The process of relaxation of Ecis to K is thus
governed by the rate constant k1 for the reaction Ecis!K, and
the restoration of the tautomeric equilibrium is defined by
kII = k2 + k3.
The complexation of 4 with alkali- and alkaline-earth-
metal perchlorates was investigated spectrophotometrically
(see Figure 3 as a typical representation of the process), and
the corresponding stability constants of the complexes are
listed in Table 2. As expected, the complexation ability
decreases sharply with increasing ion radius. From a spectral
point of view (Figure 3), complex formation is accompanied
by the appearance of a band at 486 nm, exactly where 4H+
absorbs, and by the disappearance of the enol band at 413 nm.
Owing to the very limited solubility of BeSO4 in dry ACN it
was not possible to measure the stability constant in ACN, but
we have detected complex formation in acetonitrile/water 1:1,
thus indicating a potentially large stability constant in ACN.
No complex was detected in the same solvent mixture with
Mg(ClO4)2 up to a pm value of 1.5.
Scheme 4. Kinetic scheme of the relaxation of excess Ecis generated by
flash photolysis.
A typical kinetic curve obtained with 4 in methanol is
shown in Figure 4. A fast process of accumulation of the keto
tautomer is followed by a slower process of returning to the
equilibrium state. The corresponding rate constants for 1–4
are collected in Table 3. Solutions of 4H+ do not show any
transients, a behavior that is typical for the keto tautomer.[12]
As seen, the implementation of the flexible piperidine
unit assists proton transfer, increasing the kII values substan-
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Communications
Scheme 5. Synthesis of azo compounds 3H+(4H+) and 3(4).
1) HCHO, piperidine, p-toluenesulfonic acid, benzene; 2) PhNH2,
conc. HCl, NaNO2, H2O, acetone.
Figure 4. Time dependence of the transient absorption of the solution
of 4 in methanol at 500 nm.
along with the details for the spectral measurements and data fitting
as well as for the quantum chemical calculations.
Table 3: Rate constants of 1–4 in methanol.
Received: June 18, 2009
Published online: September 15, 2009
Compound
k1 [sꢀ1
]
kII [sꢀ1
]
lobs [nm]
[a]
1
2
3
4
–
2.40ꢁ0.02ꢀ100
2.00ꢁ0.07ꢀ102
3.62ꢁ0.05ꢀ102
3.21ꢁ0.15ꢀ103
425
500
425
500
Keywords: alkali metals · alkaline earth metals ·
2.78ꢁ0.04ꢀ102
.
[a]
molecular switches · proton transfer · tautomerism
–
1.12ꢁ0.04ꢀ104
[a] Too fast to be measured with the available setup.
[1] Electron Transfer in Chemistry, Vol. 1 (Eds.: V. Balzani, P.
Piotrowiak, M. A. J. Rodgers, J. Mattay, D. Astruc, H. B. Gray, J.
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Gould), Wiley-VCH, Weinheim, 2001; Molecular Switches,
Vol. 1 (Ed. B. L. Feringa), Wiley-VCH, Weinheim, 2001.
[2] J. Andreasson, S. D. Straight, T. A. Moore, A. L. Moore, D. Gust,
J. Am. Chem. Soc. 2008, 130, 11122 – 11128.
[3] Hydrogen-Transfer Reactions, Vol. 1 (Eds.: J. T. Hynes, J. P.
Klinman, H. H. Limbach, R. L. Schowen), Wiley-VCH, Wein-
heim, 2007.
[4] T. Zincke, H. Bindewald, Ber. Dtsch. Chem. Ges. 1884, 17, 3026 –
3033.
[5] D. Nedeltcheva, L. Antonov, A. Lycka, B. Damyanova, S. Popov,
Curr. Org. Chem. 2009, 13, 217 – 240; I. Sheikhshoaie, W. M. F.
Fabian, Curr. Org. Chem. 2009, 13, 147 – 171.
tially. Probably, the piperidine nitrogen atom acts as a proton
crane, as has been described for 7-hydroxy-8-(N-morpholi-
nomethyl)quinoline.[l3] The fact that proton exchange is
facilitated could be supported by the change in the position
in the tautomeric equilibrium in 3 with addition of water
(Figure S5 in the Supporting Information), which cannot be
achieved in the parent compound 1.
By the attachment of a flexible piperidine fragment to 2,
we were able to demonstrate the concept of a tautomeric
switch, in which a directed shift in the position of the
tautomeric equilibrium is achieved either by protonation or
by complexation with small alkali- or alkaline-earth-metal
ions in a number of solvents. The system holds promise for the
development of effective molecular sensors through the
implementation of suitable host–guest systems.
[6] J. N. Ospenson, Acta Chem. Scand. 1951, 5, 491 – 509.
[7] The relative energies in the gas phase are defined as follows:
DE = EKꢀEE, DDG = DGKꢀDGE. Negative values correspond
to a more stable K form. ZPE is the abbreviation of zero-point
energy correction. See the Supporting Information for computa-
tional details.
[8] W. M. F. Fabian, L. Antonov, D. Nedeltcheva, F. S. Kamounah,
P. J. Taylor, J. Phys. Chem. 2004, 37A, 7603 – 7612.
[9] D. Nedeltcheva, V. Kurteva, B. Damyanova, S. Popov, Rapid
Commun. Mass Spectrom. 2009, 23, 1727 – 1734.
[10] The tautomeric constants for 2 and 4 have been estimated
according to the chemometric procedure described in refer-
ence [11]. In the case of 4, the tautomeric ratio has been
estimated additionally using the spectra of 4 and 4H+ in ACN as
spectra of the enol and keto tautomers, respectively.
[11] S. Stoyanov, L. Antonov, B. Soloveytchik, V. Petrova, Dyes
Pigm. 1994, 26, 149 – 158; L. Antonov, D. Nedeltcheva, Chem.
Soc. Rev. 2000, 29, 217 – 227; L. Antonov, S. Stoyanov, Anal.
Chim. Acta 1995, 314, 225 – 232.
[12] P. Jacques, Dyes Pigm. 1988, 9, 129 – 135, and references therein.
[13] C. J. Jalink, A. H. Huizer, C. A. G. O. Varma, J. Chem. Soc.
Faraday Trans. 1992, 88, 1643 – 1651; E. J. A. de Bekker, A.
Pugzlys, C. A. G. O. Varma, J. Phys. Chem. A 2001, 105, 399 –
409.
Experimental Section
The title compounds 3 and 4 were obtained by two independent
pathways (Mannich reaction then diazo coupling or the reverse
sequence) by the protocols summarized in Scheme 5. The position of
the absorption band in the spectra of the products showed that the
protonated forms were isolated from diazo coupling of intermediates
(pathway A), while Mannich reaction of 1 or 2 (pathway B) led
directly to the desired deprotonated products. To our knowledge,
there is no record of the synthesis of 3, while only one paper reports
on the preparation of 4 by pathway A,[14] where 4H+ was isolated, as
indicated by the surprising shift of the long-wavelength absorption
band. The deprotonation of 3H+ and 4H+ was achieved by treatment
of acetonitrile solutions with aqueous ammonia and subsequent
selective extraction with cyclohexane.
[14] W. E. Hahn, J. Weglewski, Acta Chim. 1966, 11, 67 – 74.
Experimental procedures, characterization data, and NMR
spectra for all compounds are provided in the Supporting Information
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