Tautomeric switching and metal-cation sensing of ligand-equipped 4-hydroxy-/4-oxo-1,4-dihydroquinolines

Article abstract of DOI:10.1002/chem.201103868

Novel 4-hydroxyquinoline (4HQ) based tautomeric switches are reported. 4HQs equipped with coordinative side arms (8-arylimino and 3-piperidin-1-ylmethyl groups) were synthesized to access O- or N-selective chelation of Zn ²⁺ and Cd²⁺

Full text of DOI:10.1002/chem.201103868

FULL PAPER
DOI: 10.1002/chem.201103868
Tautomeric Switching and Metal-Cation Sensing of Ligand-Equipped
4-Hydroxy-/4-oxo-1,4-dihydroquinolines
Aleksandar R. Todorov,[a] Martin Nieger,[b] and Juho Helaja*[a]
Abstract: Novel 4-hydroxyquinoline
(4HQ) based tautomeric switches are
reported. 4HQs equipped with coordi-
native side arms (8-arylimino and 3-pi-
peridin-1-ylmethyl groups) were syn-
thesized to access O- or N-selective
chelation of Zn2+ and Cd2+ ions by
4HQ. In the case of the monodentate
arylimino group, O chelation of metal
ions induces concomitant switching of
phenol tautomer to the keto form in
nonpolar or aprotic media. This change
is accompanied by selective and highly
sensitive fluorometric sensing of Zn2+
ions. In the case of the bidentate 8-
(quinolin-8-ylimino)methyl side arm,
NMR studies in CD3OD indicated that
both Cd2+ and Zn2+ ions afford N che-
lation for 4HQ, coexisting with tauto-
meric switching from quinolin-4(1H)-
one to quinolin-4-olate. In corrobora-
tion, UV/Vis-monitored metal-ion ti-
trations in toluene and methanol im-
plied similar structural changes. Addi-
tionally, fluorescence measurements in-
dicated that the metal-triggered tauto-
meric switching is associated with
compound signaling properties. The re-
sults are supported by DFT calcula-
tions at the B3LYP 6-31G* level. Sev-
eral X-ray structures of metal-free and
metal-chelating 4HQ are presented to
support the solution studies.
Keywords: molecular devices
·
quinolines · sensors · tautomerism ·
zinc
Introduction
An obvious reason for the existence of only a few tauto-
meric switches is the difficulty of controlling the related in-
tramolecular proton transfer equilibria, while the processes
are susceptible to environmental conditions such as solvent
polarity and pH.[4] Optimally this sensitivity to media can be
exploited as an input signal in control of adjustable tauto-
mers. Recently, para azo phenol derivatives have been
shown to exhibit adjustable tautomerism with their hydra-
zone form. Farrera et al. have shown that para azo (benzoic
acid) phenol derivatives exist predominantly as aza or hy-
drazone tautomer in polar and nonpolar media, respectively,
and each tautomer exhibits a distinct bioaffinity.[5] Antonov
et al. have used similar compounds, namely, para azo
(phenyl) phenol ortho piperidines, to demonstrate the gener-
al concept that azo-hydrazone tautomerism can be con-
trolled by the proton or a metal equivalent which leads to
signaling effects.[6]
Our research interest lies in the generation of switch con-
trol for 4-hydroxyquinoline (4HQ, 1)–quinolin-4(1H)-one
(2) tautomerism (Scheme 1). Their tautomeric behavior is
analogous to the structurally parent compounds 4-hydroxy
pyridines (bold in Scheme 1), which are known to be in tau-
tomeric equilibrium with their oxo form, 4-pyridone, with
the former prevailing in polar media and in the crystal,
Keto-enol-type tautomeric switches are to date a rather rare
class of molecular switches, even though the proton shift oc-
curring in equilibrating tautomerism is a fairly general phe-
nomenon in organic chemistry that is relevant to a number
of organic compounds.[1] Important examples of tautomer-
ism include that of nucleic acids, which play a key role in
base pairing, and that found in several enzymatic processes
exploiting the phenomenon.[2] Accordingly, one could envi-
sion a class of less explored, conceptually novel, tautomeric
molecules with significant supramolecular and biomimetic
potential. The challenge is to introduce a “switch” into the
molecule, in order to control its tautomeric states by means
of some specific external input.[3] In practice this demands
intelligent molecular design enabling molecules to respond
to an input by energetically favoring one tautomeric state
over the other.
[a] A. R. Todorov, Dr. J. Helaja
Laboratory of Organic Chemistry
Department of Chemistry, University of Helsinki
A.I.Virtasen aukio 1, P.O. Box. 55, University of Helsinki
00014 Helsinki (Finland)
Fax : (+358)919150466
E-mail: juho.helaja@helsinki.fi
[b] Dr. M. Nieger
Laboratory of Inorganic Chemistry
Department of Chemistry, University of Helsinki
A.I.Virtasen aukio 1, P.O. Box. 55, University of Helsinki
00014 Helsinki (Finland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103868.
Scheme 1.
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while the latter are detected in the gas phase and under
dilute conditions in nonpolar media.[7] Substituent effects
such as polarization of the aromatic ring by electron-with-
drawing atoms or groups have been shown to affect this
equilibrium.[7a] For 4HQ it was suggested that electron-with-
drawing groups at C-2 or hydrogen-bond acceptors at C-3
could favor the enol form in solution.[8]
In a similar way, tautomeric duality has been recognized
among natural product 4HQ derivatives; for example, ky-
nurenic acid (4-hydroxyquinoline-2-carboxylic acid) is gener-
ally considered to be in its phenol form and even crystal-
lized in such form,[9] but it has been shown to exist chiefly in
the keto form in polar medium (DMSO).[10] In contrast, acri-
done (acridin-9ACHTUNGTRENNUNG(10H)-one) was found solely in the oxo form
in both CDCl3 and DMSO.[11] The phenol form is assigned
to O-methylated 4HQ derivatives (e.g., dictamnine), where-
as the quinolone form is assigned to N-alkylated com-
pounds.[12] The activity of a number of synthetic N-alkylated
4-quinolone-based antibiotic drugs and antiviral agents can
be linked to the oxo form.[13] On the other hand, some
phenol forms assigned to 4HQ amide derivatives have
shown antiviral activity in DNA polymerase inhibition.[14]
Although in the above-mentioned cases the activity may
genuinely arise in large part from other structural proper-
ties, the distinct tautomers have different physical and chem-
ical properties that can be expected to correlate with, for ex-
ample, bioactivity. This raises the issue of whether external
control could regulate related activity in tautomerically
switchable 4HQ.
Figure 1. Tautomer switching and locking scenario for ligand-equipped
4HQ by site-selective metal chelation, where hn’ and hn’’ denote expect-
ed fluorescence signalling under light irradiation (hn). M=metal, AD=
hydrogen-bond acceptor/electron-pair donor, AD’=hydrogen-bond ac-
ceptor/electron-pair donor/electron donor.
Scheme 2.
From the photophysical point of view, 4HQ are attractive
because quantum chemical calculations have indicated that
each tautomer is clearly electronically divergent and leads
to visibly distinct luminescence properties.[15] Notably, O-al-
kylated 4HQ have been successfully used as platforms in
building fluorescent probes for Zn2+ and Cd2+ ions.[16]
In this study our approach is to functionalize 4HQ with
two ligand side arms that act either as hydrogen-bond ac-
ceptors or metal chelators in co-coordination with quinoline
O or N electron pairs (Figure 1). The metal chelation is sup-
posed to freeze the tautomer in which chelation is energeti-
cally favoured and thereby induce controlled tautomer
switching.
We chose 8-arylimino-3-(piperidin-1-ylmethyl)quinolinols
(3) as target structures (Scheme 2) to test this scenario
(Figure 1). The compounds were expected to be synthetical-
ly accessible from 8-bromoquinolin-4-ol (5) in a straightfor-
ward manner. The imino group at C-8 is p-conjugated with
the quinoline and therefore is expected to strengthen indi-
vidual signaling properties for each tautomer, which could
facilitate monitoring by NMR, absorption, and fluorescence
spectroscopy. On the contrary, the piperidin-1-ylmethyl
moiety is a non-p-conjugated electron-pair donor, which, in
addition to its coordination ability, is anticipated to also
quench quinoline fluorescence when free of proton or metal
coordination.[17]
Results and Discussion
Computational Studies: To theoretically assess the envi-
sioned switchability (Figure 1) and screen potential synthetic
targets, we geometry optimized several quinoline derivatives
equipped with 8-arylimino and 3-piperidin-1-ylmethyl
groups at the DFT level using ZnCl2 and CdCl2 salts as
models for trigger inputs (Table 1).
Inspection of the energetics of tautomers 6–10 in Table 1
shows a rather clear trend; electron-rich imines favour H-
bonding of the imine to amine NH, thus resulting in the oxo
form, whereas electron-poor substitution slightly promotes
the phenol form, in which the piperidine nitrogen atom acts
as a hydrogen-bond acceptor. In contrast, the bidentate 8-
iminoquinoline in compound 11 favors N-site chelation of
the metal and therefore the phenol form.
It has been observed for 4HQ that the large dipole
moment calculated in vacuum favours a specific tautomer in
polar media.[18] In this light the oxo form should be prefera-
ble for metal complexation of electron-rich imines 6–8,
while electron-poor imines should favour N-site chelation
and the phenol form (Table 1).
Ligand function test for solely 8-imino- and 3-piperdinyl-
functionalized 4HQ: First, we synthesized simple 8-phenyl-
3-(piperidin-1-ylmethyl)quinolin-4-ol (12) as reference com-
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Ligand-Equipped 4-Hydroxy-/4-oxo-1,4-dihydroquinolines
FULL PAPER
Table 1. DFT B3LYP/6-31G* geometry optimized 4HQ tautomer energies with and without metal salts
(lanl2dz basis set was applied for Zn and Cd).
case; the spectral changes were
similar and even more visible,
and saturation was reached
when one equivalent of metal
ions was added. Together these
titrations imply that for 12 both
an increase of solvent polarity
and metals ion are capable of
inducing switching from phenol
to keto tautomer.
With the aim of improving
the low solubility of 12 in non-
polar or aprotic solvents, com-
pound 13 was synthesized with
flexible dipicolylamine (Dpa)
moiety. In UV/Vis titration ex-
periment with ZnCl2 in toluene,
this compound showed similar
behaviour to compound 12
Compound
R
Metal salt M
Relative
Dipole
moment [D] tautomer
E [kcalmolÀ1
]
Relative
Dipole
moment [D]
tautomer
E [kcalmolÀ1
]
–
À1.4
À6.1
À7.7
À1.7
À6.3
À8.0
À2.3
À6.3
À8.1
0
5.02
17.32
16.75
6.55
19.13
18.51
8.67
21.82
21.25
1.43
11.16
10.53
1.62
0
0
0
0
0
0
0
0
6.6
10.9
10.9
6.7
10.7
10.9
4.7
6
7
8
9
ZnCl2
CdCl2
–
ZnCl2
CdCl2
–
ZnCl2
CdCl2
-
ZnCl2
CdCl2
–
8.2
8.5
0
À0.55
11.9
16.0
15.7
12.2
16.5
16.0
(Supporting
Information).
À5.5
À7.2
0
0
Compound 13 is sufficiently
0
À1.56
soluble in CD3CN to perform
ZnCl2
CdCl2
À5.1
10.85
10.18
0
0
1H NMR-monitored
titration
with ZnAHCTNUGTER(NNGNU ClO4)2 (Figure 4). Ad-
10
11
À8.1
–
À3.3
7.44
17.32
19.58
0
6.1
6.5
7.6
dition of metal ions induced
prominent spectral changes.
First, development of an AB
system (H31) from the original
singlet on addition of metal
ZnCl2
CdCl2
0
0
À0.25
À0.97
pound. This compound was studied in order to probe wheth-
er a hydrogen-bonding acceptor alone at C-3 could favour
the phenol tautomer. Unfortunately, due to its poor solubili-
ty in nonpolar solvents, reliable tautomer characterization
by NMR methods was not feasible in toluene. However, an
adequate amount of compound was dissolved in toluene to
for monitoring by UV/Vis spectroscopy when titrated with
methanol (Figure 2). The observed changes in the spectra
can be explained by increase in polarity and hydrogen-bond-
ing interactions with methanol. Owing to the increasing po-
larity of the medium, the changes in the spectra may be in-
terpreted as arising from changes in electronic structure,
which in turn are caused by the isomerization of phenol to
keto form. In support of this hypothesis, the spectral shapes
are in good accordance with 4HQ tautomeric forms identi-
fied by photospectroscopic studies of inonization constant,[19]
which underpin the switch from phenol to keto form due to
the increase in solvent polarity.
ions indicates that the Dpa moiety chelates the Zn ion, as
expected. Second, a broadened proton signal at 9.5 ppm
Computational studies show that the phenol form of 12 is
À3.2 kcalmolÀ1 more stable than the keto form, and their
dipole moments are 4.84 and 5.79 D, respectively. This sug-
gests that the molecule would exists in phenol form in non-
polar media, whereas the more polar keto form could be
favoured in polar environments.
Compound 12 was additionally titrated with ZnCl2 in tolu-
ene and monitored by UV/Vis spectroscopy to probe wheth-
er similar switching could be induced by metal ions
(Figure 3). The titration indicated that this was indeed the
Figure 2. UV/Vis-monitored titration of 12 with MeOH (0–200 mL) in tol-
uene (0.1 mm in 2 mL).
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J. Helaja et al.
Figure 3. Titration of 12 with ZnCl2 (0–2 equiv) in toluene (0.1 mm in
3 mL).
Figure 5. UV/Vis-monitored titration of 14 with ZnCl2 (0–2 equiv) in tol-
uene (0.1 mm in 3 mL).
To examine whether the ary-
limine moiety can chelate metal
ions we synthesized O-benzyl-
protected 4HQ derivative 14.
As expected, this compound
chelated Zn ions, as reveled by
a clearly redshifted signal in
metal-ion titration (Figure 5).
The metal chelate structure was
also successfully characterized
by XRD (Figure 6). The com-
plex showed intense fluores-
cence response, but this could
be observed only in the solid
phase.[20]
Probing compounds 6, 7, 8, 10,
and 11 for metal-induced
switching: The NMR spectro-
scopic studies showed that for
all the bidentate compounds 6,
Figure 4. 1H NMR-monitored titration of 13 with Zn
ACTHUNRGTNEG(UN ClO4)2 (0–2 equiv) in CD3CN.
7, 8, 10 and 11, the keto form is
the prevailing tautomer in both
(H4) shifts 1.5 ppm to lower field (H1) on addition of one
equivalent of Zn. Third, proton resonance H2 is transformed
from a singlet into a doublet after addition of one equiva-
lent of metal ions to the system. The COSY spectrum con-
firmed that the doublet coupling is induced by NH proton
H4. Together these changes indicate switching from phenol
to keto tautomer on addition of metal ions (Figure 4).
CDCl3 and CD3OD solutions. In chloroform, this was indi-
cated by the doublet signal of the proton at C-2, resulting
from coupling to the vicinal amine proton; in methanol,
proton exchange with the solvent masked the phenomenon,
although chemical shifts were overall similar. Moreover, the
chemical shifts in CDCl3 in the range 12–14 ppm also indi-
cated that the amine proton was involved in hydrogen-bond-
ing with the imine, as predicted by the computational study.
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Ligand-Equipped 4-Hydroxy-/4-oxo-1,4-dihydroquinolines
FULL PAPER
Figure 6. Molecular structure of one of the crystallographically independ-
ent molecules of 14. Displacement parameters are drawn at 50% proba-
À
À
À
bility. Selected bond lengths [ꢁ]: N1 C2 1.333(4), C2 C3 1.389(4), C3
[21]
À
C4 1.380(4), C4 O19 1.329(3).
In the case of compound 8, we succeeded in obtaining
single crystals for X-ray characterization (Figure 7). The
solid-state structure is in good agreement with the computa-
tional predictions and NMR results: as expected, the com-
pound is in the keto form and the imine nitrogen atom
shows strong hydrogen bonding to the NH proton
(N1H···N12 1.91(3) or 1.93(3) ꢁ, measured for the dimer in
the crystal unit cell).
Figure 8. UV/Vis-monitored ZnCl2 titration (0–2 equiv) of 8 in toluene
(0.1 mm in 3 mL).
Figure 7. Molecular structure of one of the crystallographically independ-
ent molecules of 8. Displacement parameters are drawn at 50% probabil-
Scheme 3.
À
À
À
ity. Selected bond lengths [ꢁ]: N1 C2 1.353(4), C2 C3 1.354(4), C3 C4
[21]
À
group strongly hydrogen-bonded to the amino group, while
on the right the metal ion is chelated by the O site as titra-
tion progresses. This implies that, under these conditions,
the tautomeric equilibrium is shifted towards the keto form,
which undergoes regioselective metal chelation.
1.445(4), C4 O4 1.251(4).
Monodendate aryl imines 6, 7, 8, and 10 were first titrated
with metal ions and monitored by UV/Vis absorbance. In
methanol, both the Zn2+ and Cd2+ ion titrations showed
only small changes overall (1–20 nm), of which the more
pronounced occurred for Zn2+ ions interacting with elec-
tron-rich aryl imines 7 and 8 (Supporting Information).
However, as shown in Figure 8, use of toluene led to drastic
spectral changes when these imines were titrated with
ZnCl2. Unfortunately, these data were not conclusive; there-
fore, we used computational approach to estimate the ener-
gies of the different tautomers (Table 1), and to explain the
observed spectral behaviour. Scheme 3 illustrates, on the
left, compound 8 in the keto form in toluene, with the imino
Unfortunately, the poor solubility of the Zn complexes in
1
both methanol and toluene did not allow for clear H NMR
spectra. Nevertheless, when titration was successfully per-
formed with CdACHTNUGTRNEG(UN OAc)2 in CD3OD, only minor changes in
the NMR spectra were observed on addition of metal ions,
as exemplified in Figure 9. Interestingly, the induced
changes appeared on the O site of the molecule: H-31 and
H-P1 and H-6 of the piperidine moiety experienced de-
shielding effects of 0.1–0.3 ppm, which are most likely in-
duced by metal chelation.
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J. Helaja et al.
In fluorescence studies, mon-
odentate aryl imines 6, 7, 8, and
10 showed selective emission
response
(Figure 10).
for
A
Zn2+
high quantum
ions
yield was measured for the
ZnCl2 complex of (FF =
6
0.205) in toluene and somewhat
lower in MeOH (FF =0.093).
The emission maxima of 6 were
only weakly dependent on sol-
vent or metal chelation; the
emission maximum was 517 nm
in toluene, while with ZnCl2
Figure 9. 1H NMR monitored titration of 8 with Cd
ACHTUNGTRENNUNG
Scheme 3.
and CdACHTUNGTRENNUNG(OAc)2 blue shifts to 514
and 511 nm, respectively, oc-
curred. When methanol was
employed, the metal-free emission maximum was at 522 nm,
and Zn and Cd ions caused blue shifts to 521 and 512 nm,
respectively. The hypsochromic shifts in the absorption max-
imum of 6 on changing from toluene to methanol and addi-
tion of metal ions were even more pronounced. For 7 the
trends for metal-ion additions were similar. However, over-
all inspection of absorption and emission maxima in Table 2
for compounds 6, 7, 8 and 10 does not fully confirm that
these values could provide information about tautomeric
equilibrium.
We could not obtain crystals of metal complexes 6–10
suitable for X-ray analysis, but we were able to isolate single
crystals of 6 from a reaction with ZnACHTNUTRGNE(UNG ClO4)2 in MeOH. The
X-ray structure shows formation of exceptional inclusion
complexes in the crystal unit cell: two molecules in the keto
form incorporate one perchlorate anion, with both piperi-
dine nitrogen atoms still protonated (Figure 11).
Remarkably these protons are not hydrogen-
bonded to the keto group in close proximity. How-
Figure 10. Fluorescence responses of compound 6 to metal ions.
Table 2. Emission, absorption maxima and selected quantum yields measured in
ever, this situation is probably different in solution
in the absence of crystal packing forces. It could be
speculated that the proton on the O site of 4HQ
would then favour the keto form by hydrogen-
bonding interactions.
Overall, 8-aryl amine compounds 6, 7, 8, and 10
did not show tautomeric changes on metal-ion coor-
dination; the prevailing keto form is instead locked
by O-site metal-ion chelation. With the exception
of compound 10, this was predicted by computa-
tionally modelling (Table 1). Nevertheless, the emis-
sion studies show that the compounds are selective
fluorescence probes for Zn2+ ions: they are quan-
tum-efficient in non-polar media, but still operative
in protic polar media.
methanol and toluene for compounds 6–8, 10–12 and 14.
Compound+metal salt Toluene
labs [nm] lem [nm] FF
MeOH
labs [nm] lem [nm] FF
6
390
384
378
390
404
385
416
447
421
387
375
392
385
429
371
325
333
–
517
514
511
504
501
500
553
559
–
554
560
–
562
567
565
398
–
–
368
522
521
512
513
510
502
576
576
–
552
538
–
560
565
556
–
–
+ZnCl2
+Cd
7+ZnCl2 +Cd
0.205 369
–
–
0.043 378
–
–
0.061 432
–
–
0.108 373
–
–
0.093
–
–
0.024
–
–
0.001
–
–
0.002
–
–
(OAc)2
366
377
(OAc)2
377
413
8+ZnCl2 +Cd
A
416
380
10+ZnCl2 +Cd
11+ZnCl2 +Cd
12+ZnCl2 +Cd
14+ZnCl2 +Cd
A
377
373
A
0.114 415
0.017
–
–
–
–
–
–
–
413
–
–
–
–
–
–
–
–
–
AHCTUNGERTG(NNUN OAc)2
Study on compound 11: UV/Vis-monitored titration
of 11 with both Cd2+ and Zn2+ ions showed very
clear spectral changes in both methanol and tolu-
ene. Figure 12 depicts the titration with ZnCl2 (0–
2 equivalents) in methanol. Encouragingly, com-
–
–
–
–
–
–
–
–
–
(OAc)2
325
350
331
328
340
330
–
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FULL PAPER
Figure 11. Molecular structure of one of the crystallographically inde-
pendent molecules of the dimeric inclusion complex of 6 and HClO4 (the
À
disordered second ClO4 anion is omitted for clarity; displacement pa-
À
rameters are drawn at 50% probability). Selected bond lengths [ꢁ]: N1
[21]
À
À
À
C2 1.329(5), C2 C3 1.358(5), C3 C4 1.418(5), C4 O4 1.256(4).
plete spectral changes were reached after the addition of the
first equivalent of the zinc salt. Comparison of this titration
to that of 8 in toluene shows that the changes in spectral
line shape are more pronounced; individual additions of 0.1
ion equivalents have substantial effects, not only by red-
shifting the absorption maxima, but also by reshaping the
spectral profile.
Figure 12. UV/Vis-monitored ZnCl2 titration (0–2 equiv) of 11 in MeOH
(0.1 mm in 3 mL).
To find out whether the metal ion genuinely induces the
desired structural change, we repeated the titrations with
Zn2+ and Cd2+ ions, monitoring by 1H NMR in CD3OD
(Figure 13). For Zn2+ addition, the spectral changes were
partially indefinite (Supporting Information) and precipita-
tion of the metal complex was observed. However, when
Cd2+ was used, we could observe clear tautomer-related
spectral changes that occurred upon addition of the first ion
equivalent; at the start of titration a set of aromatic protons
disappeared and, on subsequent additions, appeared again,
but with different chemical shifts and coupling patterns.
Characteristically, imine proton H-81 is deshielded (0.3 ppm)
by metal addition, which implies N-site chelation. Unexpect-
edly, the piperidine moiety N-
ZnACHTUNGRTNEUNG(ClO4)2 complex with 11 (Figure 14). The X-ray structure
confirms N-site chelation, with bond lengths of about 2 ꢁ
between the Zn centre and the three coordinating nitrogen
À
À
atoms. A comparison of the key bonds lengths (N1 C2, C2
À
C3, C3 C4) of crystalline 11 with similar values in both tau-
tomer-like phenol (14) and “neutral” keto (8) forms clearly
indicates a better correlation of bond lengths and similar
degree of electronic delocalization of 11 to phenol form 14.
The corresponding bond lengths in the keto form (8) can be
associated to p-bonding systems with a higher degree of
À
electronic localization. On the other hand, the C4 O4 bond
vicinal protons 31 and P1 were
both substantially deshielded,
shifted by 0.6 ppm to low field.
However, these large shifts
seem to imply N protonation
rather than metal chelation.
With the aid of 2D NMR ex-
periments (NOESY, HSQC and
HMBC) we were able to char-
acterize 11 with one equivalent
of CdACHTUNGTRENNUNG(OAc)2 as N-site-chelated
phenol tautomer.
To obtain final confirmation
for metal chelation of 11, we
Figure 13. 1H NMR-monitored titration of 11 with Cd
ACHTUNTRGENUNG(OAc)2 (0–2 equiv) in CD3OD. See proton numbering in
isolated single crystals of the Figure 12.
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shown in nonpolar media that O-site metal chelation caused
a switch from the tautomeric phenol form to the keto form.
Moreover, the 1H NMR-monitored titration of compound
13 with Zn salt showed spectral changes from phenol to
keto tautomer upon metal-ion addition. However, when the
piperidine-equipped compound is additionally armed with
a monodentate arylimino group at the C-8 position, it
seemed that the chelation will not take place at the N site,
and the prevailing oxo tautomer was rather locked by O
chelation. Bidentate aryl imino, 8-(quinolin-8-ylimino)meth-
yl quinoline derivative 11 evidenced that metal chelation
not only froze the tautomerism, but also induced unambigu-
ous switching from keto to phenolate tautomeric state.
Additionally, the metal-chelation experiments showed
that many of the synthesized 4HQ can be utilized in selec-
tive Zn2+ fluorescence sensing. A future challenge in this
area is to develop and study the 4HQ or analogues switches
in such a way that the free chelate site of moiety will partici-
pate in adjustable manner for supramolecular binding or
specific biological function.
Figure 14. Molecular structure of 11+ZnACTHNUTRGNEUNG(ClO4)2. Selected bond length-
À
À
À
À
s [ꢁ]: Zn1 N1 2.026(2), Zn1 N12 2.076(2), Zn1 N21 2.062(2), N1 C2
À
À
À
À
1.329(3), C2 C3 1.363(4), C3 C4 1.399(4), C4 O4 1.266(3), O4 H24
2.11(1).[21]
length (1.266(3) ꢁ) in 11 differ to the literature values typi-
cal for keto (1.210(8) ꢁ) and phenol (1.364(11) ꢁ) tauto-
Experimental Section
Synthesis of 6–11: Compounds 6–11 were synthesized by following the
retrosynthetic plan depicted in Scheme 2. The imine bond of compound 9
turned out to be unstable under ambient conditions, and hence this com-
pound was excluded from the experimental studies. The formal starting
compound 8-bromoquinolin-4-ol (5) was synthesized according to a litera-
ture procedure.[23] Compound 8 was functionalized with piperidine to
obtain 4 by modifying the existing Mannich reaction procedure[6a] to be
free from catalytic acid additives. For other compounds literature refer-
ences were followed strictly or with minor changes. The synthetic details
and characterization compounds are described in the Supporting Infor-
mation.
mers, but instead it matches rather well that of carboxylate
[22]
À
À
anion (C O 1.254(10)). Strikingly, also the C4 O4 bond
length of 1.251(4) ꢁ in keto form (8) may be attributed to
some ionic nature that probably arises from hydrogen-bond-
ing interaction between the imine and amine hydrogen
(Figure 7). On this basis, after examination of the crystal
structure of complex 11, we can establish that the ligand is
present in the neutral betaine structure, whereby the nega-
tive charge is localized over the phenolate oxygen (O4)
atom and is stabilized by the neighboring aminium cation
(N24). This clearly indicates that whilst the 4HQ ring struc-
ture in complex 11 can be identified as phenolic, the struc-
tures of neutral 8 and protonated 6 can described as keto-
type isomers. Indeed, this switterionic complex structure of
11 is also in agreement with the NMR studies regarding the
piperidine nitrogen atom, which turns out to be protonated.
All together, compound 11 acts as a metal ion adjustable
1
UV/Vis-, fluorescence- and H NMR-monitored titrations for compounds
6, 7, 8, 10, 11, 12 and 13 with Zn and Cd ions are presented in the Sup-
porting Information.
Computational studies: Performed with Gaussian 09 software[24] by the
B3LYP method at the 6-31G* level, except that the lanl2dz basis set was
applied for Zn and Cd atoms. The calculations presented in Table 1 were
run in the gas phase. The level of theory was shown be adequate for the
comparison of tautomers by performing test calculations on 4HQ with
more advanced basis sets or with implicit solvation models. In the former
case it was found that the keto form of 4HQ lies at 4.4 kcal lower energy,
while the IEFPCM implicit solvent model increases the energy difference
in favour of the keto tautomer to 5.5, 6.0 and 6.6 kcalmolÀ1 for toluene,
chloroform and water, respectively. For the latter case, calculations in the
gas phase with 6-31+Gd,p and 6-311+G2d,2b basis sets gave 3.25 and
3.28 kcalmolÀ1, respective, in favour of the keto tautomer.
tautomeric switch. Also,
a fluorescence measurement
(Table 2) showed strong emission for the Zn complex, which
makes the compound behave according to the right pathway
in Figure 1. The metal-ion titration experiments were carried
out with different counter-ions (chloride, acetate and per-
chlorate), and all displayed similar behaviour in the spectro-
scopic experiments.
Crystallographic data: The structures reported in this work have been de-
posited with the CCDC.[21] Crystallographic experimental data are pre-
sented in the Supporting Information.
Conclusion
Acknowledgements
Dr. Michele Melchionna is acknowledged for language corrections and
scientific criticism. We are grateful to Dr. Jorma Matikainen for the
HRMS measurements. This work was partially supported by Academy of
Finland (J.H., No. 118586 and 113317). The National Centre for Scientific
Computing (CSC) is acknowledged for computational resources.
We have demonstrated that 4HQ equipped with suitable
ligand side arms can co-chelate Zn2+ and Cd2+ ions with
4HQ keto or amino (pyridine-type) moieties, and adjust
thereby the associated tautomeric equilibria. For 4HQ 12
with C-3-attached piperidin-1-ylmethyl monoACTHNUTRGENNlUG iACHTUTGNRENgUNG and, it was
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Ligand-Equipped 4-Hydroxy-/4-oxo-1,4-dihydroquinolines
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Received: December 9, 2011
Revised: February 21, 2012
Published online: && &&, 2012
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J. Helaja et al.
Switching tautomers: Transformation
of 4-hydroxyquinolines (4HQ) into
novel tautomeric switches is described.
4HQ are equipped with ligand moiet-
ies at C-8 and C-3 positions to achieve
metal ion adjustable control of keto-
phenol tautomerism. In the case of the
8-(quinolin-8-ylimino)methyl side arm,
metal ion induced tautomeric switch-
ing from keto to phenolate form was
observed in nonpolar and polar media
(see figure). Both O- and N-site-
Molecular Switches
A. R. Todorov, M. Nieger,
J. Helaja* ...................... &&&& — &&&&
Tautomeric Switching and Metal-
Cation Sensing of Ligand-Equipped 4-
Hydroxy-/4-oxo-1,4-dihydroquinolines
directed chelation resulted in selective
Zn2+ fluorescence sensing.
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These are not the final page numbers!