Toward Fractioning of Isomers through Binding-Induced Acceleration of Azobenzene Switching

Article abstract of DOI:10.1021/jacs.7b09568

The E/Z isomerization process of a uracil-azobenzene derivative in which the nucleobase is conjugated to a phenyldiazene tail is studied in view of its ability to form triply H-bonded complexes with a suitably complementary 2,6-diacetylamino-4-pyridine ligand. UV-vis and ¹H NMR investigations of the photochemical and thermal isomerization kinetics show that the thermal Z E interconversion is 4-fold accelerated upon formation of the H-bonded complex. DFT calculations show that the formation of triple H-bonds triggers a significant elongation of the NN double bond, caused by an increase of its _g? antibonding character. This results in a reduction of the NN torsional barrier and thus in accelerated thermal Z E isomerization. Combined with light-controlled E Z isomerization, this enables controllable fractional tuning of the two configurational isomers.

Full text of DOI:10.1021/jacs.7b09568

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Article
Toward fractioning of isomers through binding-
induced acceleration of azobenzene switching
Rosaria Vulcano, Paolo Pengo, Simone Velari, Johan Wouters,
Alessandro De Vita, Paolo Tecilla, and Davide Bonifazi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09568 • Publication Date (Web): 24 Oct 2017
Downloaded from http://pubs.acs.org on October 24, 2017
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Toward fractioning of isomers through binding-induced
acceleration of azobenzene switching
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†
§
#
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#,‡
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Rosaria Vulcano, Paolo Pengo, Simone Velari, Johan Wouters, Alessandro De Vita, Paolo Tecilla,
¥,†,*
and Davide Bonifazi
†
§
Department of Chemistry, University of Namur (UNamur), Rue de Bruxelles 61, Namur, 5000 (Belgium);
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, Trieste, 34127
#
(
‡
Italy); Department of Engineering and Architecture, University of Trieste, Piazzale Europa 1, Trieste, 34127 (Italy);
¥
Department of Physics, King’s College London, Strand, London, WC2R 2LS (United Kingdom); School of
Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT (United Kingdom).
KEYWORDS: supramolecular chemistry, azobenzene, molecular switches, host-guest systems, H-bonding
interactions, nucleobases, triple H-bonding interactions.
ABSTRACT: The E/Z isomerization process of a uracil-azobenzene derivative in which the nucleobase is
conjugated to a phenyldiazene tail is studied in view of its ability to form triply-H-bonded complexes with a
suitably complementary 2,6-diacetylamino-4-pyridine ligand. UV-Vis and H-NMR investigations of the
photochemical and thermal isomerization kinetics show that the thermal Z→E interconversion is four-fold
accelerated upon formation of the H-bonded complex. DFT calculations show that the formation of triple H-
bonds triggers a significant elongation of the N=N double bond, caused by an increase of its π antibonding
character. This results in a reduction of the N=N torsional barrier and thus in accelerated thermal Z→E
isomerization. Combined with light controlled E→Z isomerization this enables controllable fractional tuning
of the two configurational isomers.
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Introduction
Isomerization is the process by which one molecule is transformed into another molecule that has exactly
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the same atoms, but with a different arrangement. In artificial systems, it is usually an external stimulus
e.g., light, electrochemical or thermal inputs, cf. path A, Scheme 1) that triggers such configuration
(
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interconversion. A typical example is the E/Z photoisomerization of the azobenzene scaffold, for which
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the single isomer can be selectively produced by the relevant light excitation
or electrochemical input.
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This is certainly one of the most studied functional groups allowing spatiotemporal control of the
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conformational and overall structural properties of molecular systems. Notable applications include the
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fabrication of photoresponsive architectures in materials science
and biology.
Isomerization also
For example, the
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plays a fundamental role in a number of naturally occurring biochemical processes.
cis-trans isomerization of amide bonds involving proline is an important step in the folding of proteins.
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Yet, being relatively slow, it is often rate-limiting.
To hasten it, Nature provides specific enzymes
referred as “peptidyl-prolyl isomerases” that through binding of the relevant amino acids trigger the
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switching at the N-terminal amide bond of proline (path B, Scheme 1).
G
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S mulus
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Z
Scheme 1. General scheme for a dual stimuli- and binding-triggered isomerization system. H and G indicate the host and
guest molecules, respectively, with the host adopting two different configurations (H and H
Z
E
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Systems that respond to both stimuli- and binding-induced mechanisms of isomerization or switching are,
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however, more difficult to find (Scheme 1). Hecht and co-workers developed a triply H-bonding motif
whose association strength could be modulated by the ring-closed switching state of a photochromic
bis(thiazol-4-yl)maleimides. Switchable H-bonded host-guest complexes containing an azobenzene were
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developed by the groups of Goswami, Rotello, Gadhiri, Hecht, and Ballester . The possibility to
further modulate the isomerization process through non-covalent bonding was not explored in these
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previous works and only examples describing the use of gold nanoparticles
have been described. This
would be appealing, as it could give access to responsive architectures that in the presence of a binder
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might enable a controlled structural selection protocol capable of achieving a well-defined target complex
structure in a desired concentration. This possibility is explored here, where our specific goal is to develop a
complete dual stimuli- and binding-triggered isomerization cycle.
The concept: toward fractioning of isomers. Namely, we wish to investigate the possibility of
controlling the relative molar fraction χ and (1-χ) of the two configuration isomers of a molecule, with the
goal of being able to tune these concentrations to arbitrary complementary values in the 0-1 range. We note
that a range of χ values consistent with thermodynamic equilibrium could be in principle obtained by
simply varying the temperature of the system and allowing the system equilibrate, provided that the two
isomers have different free energies. This however could be disruptive for the system if the temperatures
required for the desired concentration were too high, while this approach would in all cases never achieve a
higher concentration for the isomer of higher energy, which we wish to be able to do here. A second
possibility would be to use complexation of the isomers to tune the energy levels of the two complexes, so
to alter their equilibrium concentration without temperature adjustment. However, full tunability of χ in
the 0-1 range would be lost in this case, unless an “almost continuum” range of complexes could be devised
for this scope.
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Scheme 2. Schematic Gibbs free energy landscape illustrating the general principle of the E/Z isomer fractioning through
non-covalent complexation
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A different, simpler, and more interesting possibility is to achieve concentrations at “metastable” values
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outside thermodynamic equilibrium. A necessary condition for this route to be allowed is that the two
isomer states must correspond to local energy minima separated by energy barriers high enough to make
any equilibrating transition negligibly slow. In this respect, the E/Z isomerization of azobenzene is
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certainly one of the most accessible reactions . The (stable) E and the (metastable) Z isomers have
separated energies, so that at equilibrium for all temperatures of interest the E isomer is the only present
species. Furthermore, if some Z concentration is externally induced (e.g., by light), the thermal process
bringing the system back to equilibrium occurs on a slow (hour) time scale, i.e., meets a “slow kinetics”
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requirement. Under these circumstances, a shift of concentration out of the equilibrium value can be
achieved by suitably photoactivating the E→Z (after which, Z→E is also viable), using an appropriate light
frequency. Any Z concentration could in principle be achieved by this way by careful dosing the photon
flux and the irradiation time.
We can however conjecture that an alternative route to control the isomeric composition could be achieved
by photo-inducing a complete E→Z transition, and accelerating the Z→E back-transition process (Scheme
2, red arrow) only for a controllable fraction of the Z isomers. If the fast Z→E decaying isomers could be
those that form a non-covalent complex with appropriately designed guest molecules, their fraction would
be easily controlled by tuning the guest concentration. Once the fast, fractional Z to E back-conversion has
occurred, all that is needed to “pin” the system indefinitely at the remaining (target) Z isomer fraction, is to
correct for the slow drift towards thermodynamic equilibrium. This can be easily achieved by further, time-
sparse “refreshing” photoactivation steps.
Building on these hypotheses, here we report the first study of an azobenzene-like system whose
isomerization properties are responsive to both a luminous stimulus and a non-covalent H-bonded
recognition event. The idea is that a perturbation caused by the formation of a multiple H-bonded
interaction should trigger a change of the photoisomerisation behavior of the phenyldiazene moiety by
modifying the energy barriers associated with isomers interconversion.
Results and Discussion.
Molecular design and solid-state recognition investigations. To engineer such a system, one needs to
consider a structure in which the isomerizing unit is in direct conjugation with the recognition site. In this
way, any changes occurring at one of the two moieties, is then reflected to the other. Capitalizing on our
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earlier achievements on the H-bonded uracil•2,6-diamidopyridine complex,
we therefore designed and
synthesize a photoswitchable uracil-azobenzene derivative presenting direct anchoring of the
phenyldiazenyl group to the nucleobase either at the 5- or 6-position (5AUP and 6AUP, respectively Fig. 1).
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Figure 1. Molecular structures of the uracil-azobenzene derivatives
.
This bridging was selected to favor the establishment of an effective electronic communication between
the two moieties. As far as the synthesis is concerned, molecules 5AUP and 6AUP were prepared in a two-
steps pathway (see SI). To improve the solubility of the molecular scaffold in organic solvents, we equipped
the aryl and uracil rings with tert-butyl and N1-propyl substituents, respectively. N-dialkylated analogue
5AUPP (Fig. 1) was also prepared as a reference molecule. To probe the H-bonding recognition properties
of 5AUP and 6AUP we have used 2,6-diacetylamino-4-[(trimethylsilyl)ethynyl]pyridine (DAP) as
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complementary recognition unit (Fig. 1).
Figure 2. ORTEP representation of the X-ray structures of (a) E-6AUP, (b) E-5AUP, (c) E-6AUP∙DAP and (d) E-
AUP∙DAP. The space groups are P -1, P 2 /n, P -1, and P 2 /c for a), b), c) and d), respectively
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Suitable single crystals for X-ray diffraction analysis were grown by slow evaporation of a toluene solution
containing a 1:1 mixture of the relevant uracil-azobenzene derivative and DAP. As expected, the X-ray
structure (Fig. 2) reveals the presence of the H-bonded complex, in which the E isomer of 5AUP (E-5AUP)
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and 6AUP (E-6AUP) engages triple H-bonding interactions with DAP (relevant distances for E-
5AUP∙DAP: 2.911; 3.064 and 2.931 Ǻ for O1∙∙∙N9, N3∙∙∙N10 and O2∙∙∙N11, respectively). These values are
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comparable to those previously reported for similar H-bonded complexes.
Any attempts to obtained the
X-ray structure for the Z-5AUP∙DAP and Z-6AUP∙DAP complexes failed.
E/Z isomerization studies in solution for the uracil derivatives. The electronic absorption spectrum
of 5AUP in toluene is depicted in Figure 3a. The molecule exhibits two UV absorption bands at 360 nm and
442 nm, which are attributed to π-π∗ (of the E isomer) and n- π∗ (of the Z isomer) electronic transitions,
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respectively.
When irradiated at 360 nm, remarkable changes are observed in the absorption spectra of
5AUP (Fig. 3b), with an intense and fast increase of a new band centered at around 300 nm and a
substantial increase of the intensity of the n-π∗ band at 442 nm with a concomitant disappearance of the
π-π∗ absorption. Neat isosbestic points are maintained throughout the photoirradiation experiments,
showing the clean occurrence of the nearly quantitative E→Z isomerization. Thermal Z→E interconversion
producing the most thermodynamically-stable E isomer occurs very slowly as shown in Fig. 3c (see also
below). On the other hand, irradiation at 442 nm causes a fast Z→E isomerization, resulting in decreasing
of the n- π∗ absorption and a full restoring of the π-π∗ band (Fig. 4a). Repetitive photoinduced switching
cycles evidenced an excellent fatigue resistance and remarkable photostability of the system (Fig. 4b).
Taken all together, these data suggest that the substitution of the phenyl ring with the nucleobase has little
influence on the photochemical properties, with 5AUP showing the typical E/Z switching behavior of the
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archetypal azobenzene.
Figure 3. E/Z Isomerization equilibria for 5AUP (a) and 6AUP (d) in toluene. Photo E→Z (b and e) and thermal Z→E (c
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and f) isomerization of 5AUP (2.5 ∙10 M) and 6AUP (5.4∙10 M) in toluene at 25 °C. Inset: zoom in the n-  absorption
region. The thermal Z→E isomerization was followed over 120 and 20 min period for 5UAP and 6AUP, respectively.
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When looking at the photoisomerization of 6AUP, the characteristic azobenzene bands are no longer
distinguishable in the absorption spectrum of this regioisomer (Fig. 3e). Likely in 6AUP, the azobenzene
unit is involved in a 1,4-type conjugation with the carbonyl group of the uracil moiety. When irradiated at
360 nm, the absorption band in the 300-400 nm spectral region decreases, reaching saturation after 3 min
of irradiation. The weak features of the Z isomer seem to be substantially masked within the strong
absorption envelope of the conjugated molecule. When left into the dark, full recovery of the initial
absorption spectra is obtained after 20 min. Together with the possibility of reaching nearly quantitate
two-way isomerization, these data suggest that the slower reaction dynamics of 5AUP make this
regioisomer the best candidate to intercept both configurational isomers and study their binding
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properties with DAP in solution with classical spectroscopic techniques like H-NMR. For this reason, only
regioisomer 5AUP has been used to perform the binding studies.
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Figure 4. a) Z→E photoisomerization of 5AUP (2.5 ∙10 M); b) repetitive photoinduced switching cycles of 5AUP obtained
by alternating irradiation at 360 and 442 nm
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E/Z Isomerization and binding studies for the supramolecular complexes in solution. To shed
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further light on the recognition properties of 5AUP in solution, H-NMR titration and Job’s plot analysis
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were performed for both Z and E isomers to estimate the association constants (K ) and the binding
stoichiometry in solution. In both cases, increasing concentration of DAP caused a progressive downfield
shift of the uracil NH proton under a regime of fast equilibrium exchange (Fig. 5). As evidenced at the solid
state, the Job’s plots analysis confirmed the 1:1 binding stoichiometry in solution for the 5AUP∙DAP
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complex (see SI). The association constant (K , calculated through the data fitting with Dynafit software )
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for the E-5AUP∙DAP complex was found to be 6710 ± 800 M , which is half of that measured for the
reference Upr∙DAP complex under the same experimental conditions (see SI). This is in line with the
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literature findings obtained for other uracil-derived molecular scaffolds in toluene.
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Figure 5. Dark H-NMR titrations of E-5AUP (3.0 mM in toluene-d
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) upon addition of increasing amounts of DAP at 25 °C.
ΝΗ = 7.8 ppm) and in E-5AUP∙DAP
The red signal corresponds to the imide proton of the uracil unit in free E-5AUP (
δ
complex (
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Figure 6. Dark H-NMR titrations of Z-5AUP obtained after irradiation at 360 nm of the 5AUP sample (3.8 mM in toluene-
d
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uracil core in the Z-5AUP- and E-5AUP-containing species, respectively
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Regarding the Z-5AUP∙DAP complex, the titration experiments (Fig. 6) were performed in the dark at
constant temperature (T = 298 K) with a freshly, light-isomerized solution of 5AUP (δΝΗ = 7.5 ppm for the
imide proton in the absence of DAP, no presence of E-5AUP was detected at the beginning of the
titration). By adding increasing amounts of DAP, two different NH proton resonances started appearing,
reaching the saturation chemical shift values of 12.1 and 11.7 ppm after the addition of 3.4 equivalents of
DAP (Fig. 6). Considering the chemical shifts observed during the titration experiments performed for E-
5AUP∙DAP, the resonance at lower fields are attributed to E-5AUP, while that at higher fields to the Z
isomer. Upon increasing additions of DAP, the intensity of the imide proton signal for the E isomer
increases at the expenses of that pertaining to the Z isomer, which suggests Z→E interconversion (Fig. 6).
As one can notice, this gives rise to defined fractions of the two isomers depending on the DAP
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concentration. For instance at [DAP]/[5AUP] ratios of 0.2, 0.5, and 2 the molar fractions (χ ) of the E
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isomer (free and complexed) is 0.21, 0.34 and 0.66, respectively (Fig. 6). Because of this thermal Z→E
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interconversion, the estimation of the association constant (K ) for the Z-5AUP∙DAP complex revealed to
be not straightforward as its concentration is interconnected with the progressive increase of the other
complex, namely E-5AUP∙DAP. The fitting model (applied with Dynafit software) employed for estimating
the association constant need to use as independent variables the concentration of DAP and that of the
two isomers (measured from the integration of the imidic proton resonances). Using the K value
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estimated from the titration experiments of E-5AUP, we could estimate the K
Z
value for the Z-5AUP∙DAP
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complex to be 4040 ± 355 M . Notably, this is almost half of that measured for its isomer E-5AUP∙DAP.
Figure 7. a) UV-Vis measurements of the thermal Z→E-5AUP isomerization at 25 °C, after sample irradiation at 360 nm
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(3.0∙10 M toluene solution); b) Time-dependent variation of the concentration of the isomers estimated from the integrals
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of the NCH protons peaks area as measured by H-NMR after sample irradiation at 360 nm (3.0∙10 M toluene-d solution).
The rate constant of thermal Z→E isomerization for 5AUP was investigated in the dark by both UV-Vis
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and H-NMR measurements. The UV-Vis experiment shows an increasing of the absorbance at 360 nm
over the time, corresponding to the increasing of the concentration for the E isomer (Fig. 7a). The process
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-
5 -1
follows a first order kinetic equation with a rate constant (k ) value of 2.7 ± 0.01 ∙ 10 s (t = 7.1 h, see SI).
est
1/2
1
The H-NMR analysis was restricted to the first instants of the reaction according to the initial rate method
1
-5 -1
(
Fig. 7b). The kest value obtained from H-NMR measurements corresponds to 2.5 ± 0.2 ∙ 10 s , which is in
good agreement with the value obtained from the UV-Vis measurements. As a control experiment, we have
studied the thermal Z→E isomerization of the reference dialkylated uracil derivative (5AUPP), where also
the N(3) position bears a propyl chain. The kest value obtained from UV-Vis measurements corresponds to
0
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-5 -1
3.06 ± 0.03 ∙ 10 s (see SI), which is consistent with that calculated for the Z→E conversion of 5AUP in the
absence of DAP.
8
Figure 8. a) Kinetic profiles of the thermal Z→E isomerization of 5AUP in toluene-d in the absence and in the presence of
different DAP concentrations measured by H-NMR at 25 °C after sample irradiation at 360 nm; b) Kinetic profiles of the
1
1
thermal Z→E isomerization of 5AUP∙DAP complex in the presence of exceeding quantities of DAP measured by H-NMR at
-3
2
5 °C in toluene-d
8
after samples irradiation at 360 nm; initial sample concentrations: (ꢀ) [5AUP]
0
= 1.0∙10 M, [DAP]
0
=
-3
-3
-3
-3
-3
9
0 0 0 0
.4∙10 M ; (ꢁ) [5AUP] = 2.2∙10 M, [DAP] = 9.6∙10 M, and (ꢀ) [5AUP] = 3.2∙10 M, [DAP] = 10.2∙10 M.
To understand if the supramolecular interaction has an influence on the thermal Z→E isomerization rate,
1
further H-NMR investigations have been made using Z-5AUP solutions in the presence of variable DAP
concentrations (Fig. 8). In the presence of a large excess of DAP, the maximum concentration of complex
(about 96%) is achieved (Fig. 8b). This allows calculating the rate constant of the thermal Z→E
-
4
-1
isomerization process within the complex 5AUP∙DAP, which resulted to be 1.0 ± 0.3 ∙ 10 s (see SI). It is
now apparent that the Z→E isomerization process within the complex is about 4 times faster than that
-
5 -1
occurring for 5AUP alone (2.5 ± 0.2 ∙ 10 s ).
Scheme 3 summarizes the relevant equilibria and kinetic processes involving the Z-5AUP and E-5AUP
isomers along with their complexes with DAP. The isomer fractioning concept implies the
photogeneration of Z-5AUP in the presence of a given concentration of DAP. The fast isomerization within
the H-bonded complex will produce a Z/E mixture with an isomeric composition determined by the
amount of Z-5AUP∙DAP complex and subjected to a drift toward the thermodynamic equilibrium
composition due to the slower background thermal isomerization of free Z-5AUP. As a consequence, the
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possibility to produce a Z/E mixture with a defined isomeric composition and stable in time depends on
the kiso/kest ratio. On the other hand, being the equilibration of DAP between the two 5AUP isomers fast in
the isomerization time scale, this process should not influence the system which experiences a time
averaged composition ruled by the association constants. In our case the kiso/kest ratio is about 4. Although
this acceleration does not to allow a complete separation between the two kinetic processes, a simulation
shows that, for example, starting from a 1:1 mixture of Z-5AUP/DAP after about 10 hours the complex is
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fully isomerized but the χ (free and complexed) is 0.78 with the amount exceeding the 50% deriving from
E
the interconversion of the free Z-5AUP. However, the isomeric composition obtained is relatively stable in
E
time. For instance, after 5 hours the χ value has changed only by 0.09, going from 0.78 to 0.87.
Scheme 3. Summary of the relevant complexation equilibria and isomerization kinetics involving 5AUP and DAP
.
Theoretical rationale. To shed further light on the causes affecting the acceleration of the switching
process, we have performed density functional theory (DFT) calculations, using the PWSCF code of the
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65
Quantum ESPRESSO distribution, and the Perdew-Burke-Ernzehof (PBE) functional which was used
66,67
before in careful studies of similar systems.
First, we optimized the gas-phase structures of DAP, Z-
5AUP, E-5AUP molecules and those of their Z- and E-5AUP∙DAP complexes (see SI). The calculations
confirm the higher stability of the E isomers with respect to that of the Z both in both free and complex
species. In particular, the calculated energy of the metastable Z isomer is 0.65 and 0.61 eV higher than the
E level for 5AUP and 5AUP∙DAP, respectively. As expected, these energy differences between this
configurational isomers are comparable with the values previously computed for azobenzene by DFT
techniques (0.66 eV) as well as a broad range of techniques including highly sophisticated coupled-cluster
67
and diffusion Monte Carlo techniques (0.52-0.73 eV) . Analysis of our DFT results suggests a peculiar
redistribution of the electron density, which occurs around the N=N bond upon formation of the complex
of Z-5UAP molecule. This is visible in Figure 9, where the electron density difference ρtot - Σρmol is shown,
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portraying the electron density readjustment following the “switching on” of the interaction between the
two molecules in the complex (ρtot is the electron density of the complex and Σρmol is the sum of the
densities of the two isolated single molecules with same atomic position, in the gas phase). The alternated
lobes of opposite signs (Figure 9, inset) fingerprints the onset of hybridization of electronic states, mixing
∗
states with ꢀ antibonding orbital components with bonding molecular states that do not have a nodal
ꢁ
plane between the two N atoms of the C-N=N-C moiety. This is expected to lower the torsional barrier
associated with the C-N=N-C group upon formation of the Z-5UAP∙DAP complex, consistent with the
experimental observations.
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Figure 9. Side-view of the optimized structure of Z-5AUP∙DAP. The zoomed region displays the change of the calculated
electron density in the N=N bond region of Z-5AUP upon complexation with DAP (electron density accumulation is
depicted in red and depletion in blue)
.
Finally, in an effort to estimate the effect of complexation on the Z→E isomerization barrier, we
investigated the Z-5AUP∙DAP E-5AUP conversion, using the nudged elastic
to model the transition barrier. We note that solvent effects, as well as
→
E-5AUP∙DAP and the Z-5AUP→
68,69,70
band (NEB) technique
temperature effects should be fully included to properly account for the enthalpic and entropic
contributions that define the free energy barrier relevant to the experimental interconversion conditions.
While some techniques exist that could capture complex electron-phonon dynamics and level crossing
7
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occurring in system like the present ones during the isomerization transition , a simple estimate of the
barrier lowering upon DAP complexation relying on error cancellation can be simply obtained from our
DFT static potential energy results. These suggest that the Z to E barrier gets smaller upon Z-5AUP
complexation with DAP. Our computed 60 meV energy barrier reduction value (which would correspond
to a speed-up factor of about 10 at 300K) is furthermore comparable with the 34meV free energy barrier
reduction value (corresponding to the experimentally observed speedup of about 4) obtained from the
ratio of our experimental thermal conversion rates further assuming the same attempt rate for the Z→E
conversion in free Z-5AUP and H-bonded complex Z-5AUP∙DAP.
Conclusions
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In conclusion, in this work we have synthesized photoswitchable uracil-azobenzene conjugates
presenting direct anchoring of the phenyldiazenyl group to the uracil nucleobase, with the 5-
functionalized derivatives depicting a slow thermal switching process and a nearly quantitate two-way
isomerization. In the presence of a 2,6-diamidopyridine, triply H-bonded complexes were formed both in
1
solution and at the solid state. UV-Vis and H-NMR investigations of the photochemical and thermal
isomerization kinetics in toluene solutions showed that the thermal Z→E interconversion is four-fold
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accelerated upon formation of the H-bonded complex when compared to that of the uracil derivative
alone. DFT calculations suggest that the formation of the triply H-bonded complex trigger weakening and
*
g
elongation of the N=N double bond, through increase of its π
antibonding character. This is expected to
reduce the N=N torsional barrier and thus rationalize the acceleration of the thermal Z→E isomerization.
This binding-induced acceleration of the isomerization process revealed to give access to tailored isomers
fractioning (χ) with limited variation of the mixture over a few hours, although in our system the
acceleration factor is rather small to ensure a complete time separation of the two kinetic processes.
Structural modifications of the aza-derivative are currently under investigation to increase the gap
between the isomerization rates within and outside the complex. Such types of systems are indeed of
great appeal as they could give access to responsive architectures, which upon exposition to an external
72–75
stimulus undergo a structural perturbation (e.g., unfolding, unzipping and denaturation).
This
reactive state could eventually develop into a new minimum in the presence of the relevant binder (e.g.,
drugs, nucleic acid strand, enzyme active sites and metabolites), the concentration of which can control
both structure and its fraction. For instance, this modified system could be used to design
7
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photoresponsive nucleic acids that could undergo controlled unfolding and folding of DNA helixes,
possibly opening new horizons into light-triggered gene manipulation.
ASSOCIATED CONTENT
Supporting Information
Synthetic protocols and spectroscopic characterisations. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bonifazid@cardiff.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENT
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D.B. gratefully acknowledges the Science Policy Office of the Belgian Federal Government (BELSPO-IAP
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/05 project) and the EU through the ERC COLORLAND project. P.T. and D.B. thank the HORIZON2020
Marie Sklodowska Curie Actions through the INFUSION project. R.V. thanks UNamur for her doctoral
and teaching assistant position. The authors thank the physical chemistry and characterization (PC²) at the
UNamur and Bernadette Norberg for the Xꢀray measurements and data interpretation.
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