Zinc(II) mediated imine-enamine tautomerization

Article abstract of DOI:10.1021/ol300874c

Reduction of imine-anthracenone compounds selectively produces secondary alcohols leaving the external imine group unreacted. Addition of the Zn(II) ion induces a metal-mediated imine-enamine tautomerization reaction that is selective for Zn(II), a new fluorescence detection method not previously observed for this important cation.

Full text of DOI:10.1021/ol300874c

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2698–2701
Zinc(II) Mediated ImineꢀEnamine
Tautomerization
Prem N. Basa, Arundhati Bhowmick, LaShawn Medicine Horn, and Andrew G. Sykes*
Department of Chemistry, University of South Dakota, Vermillion, South Dakota
57069, United States
asykes@usd.edu
Received April 5, 2012
ABSTRACT
Reduction of imineꢀanthracenone compounds selectively produces secondary alcohols leaving the external imine group unreacted. Addition of
the Zn(II) ion induces a metal-mediated imineꢀenamine tautomerization reaction that is selective for Zn(II), a new fluorescence detection method
not previously observed for this important cation.
Elevated levels of zinc are known to play a key role in
potential neurological disorders such as Alzheimer’s and
Parkinson’s disease;1 however a detailed understanding of
the role played by the Zn(II) ion in cell homeostasis, signal
transduction, and translocation still remains a challenge.
Within the pastdecade, pioneering researchin PET,2 ICT,3
FRET,4 and other5 based fluorescent chemosensors have
made significant progress in understanding the bioinor-
ganic chemistry and coordination properties of Zn(II), and
recentadvancesinCdN isomerizationof imine-containing
fluorescence sensors selective for Zn(II) have also proven
to be an attractive tool.6
Imines are typically more stable than their enamine
tautomers;7 however, the energy barrier for imineꢀenamine
interconversion is an order of magnitude smaller than that
for the isoelectronic ketoꢀenol tautomerization,8 which
allows preparative/catalytic procedures to be developed
involving enamine intermediates.9 We have recently reported
the site-selective imination of anthraquinone-containing
macrocycles (analogues similar to 2aꢀb in Scheme 1) and
have explored the host/guest chemistry of these new adducts
as fluorescence sensors.10 Herein we report the selective
reduction of the internal carbonyl group (3aꢀb) and the
resulting 1,5-prototopic shift involving metal-mediated
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Zhou, X.; Yu, B.; Guo, Y.; Tang, X.; Zhang, H.; Liu, W. Inorg. Chem.
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r
10.1021/ol300874c
Published on Web 05/14/2012
2012 American Chemical Society

imine-enamine tautomerization resulting in enhancement in
anthracene emission, selective for the Zn(II) ion (Scheme 1).
Compounds 2aꢀb have been synthesized and character-
ized by our previously reported procedure.10 Here the
carbonyl group has been selectively reduced to the corre-
sponding 2° alcohols, 3aꢀb, using sodium borohydride in
ethanol (Scheme 1), leaving the imine functionality intact.
Scheme 1. Synthesis and Reactivity of ImineꢀAnthracenone
Compounds
The reduction of the carbonyl group is confirmed by
FT-IR, 1HNMR, and13C NMR spectroscopic data (Figures
S1ꢀS14, Supporting Information). FT-IR analysis of
compounds 3aꢀb shows a new broad peak at 3400ꢀ3500
cmꢀ1 which is characteristic of the ꢀOH group that is not
seen in the unreduced compounds, 2aꢀb. In addition, the
strong resonance for the internal carbonyl CdO stretch
(∼1670 cmꢀ1) disappears after reduction; however an
imine stretching frequency (1660ꢀ1675 cmꢀ1) still remains.
13C NMR spectra reveal a new peak at (∼57 ppm) for the
reduced CH(OH) carbon, and the peak for the carbonyl
carbon (∼180 ppm) disappears. The peak for the CdN
carbon (∼158.4 ppm) remains upon reduction however.
Such spectroscopic data indicate that only the carbonyl
group (CdO) has been selectively reduced. In addition,
ESI-MS spectra of compounds 3aꢀbshow MHþ and MNaþ
peaks consistent with a single reduction (Figures S7 and S11).
Structural confirmation by X-ray crystallography of
compound 3a has also been determined (Figure 1). The
hydroxyl group O(1) is bound to an sp3 hybridized carbon,
while the imine carbon remains sp2 hybridized and exhibits
Figure 1. X-ray crystal structure (30%) of 3a CH3CN.C(10)ꢀN(2) =
3
˚
˚
1.285(3) A, C(7)ꢀO(1) = 1.439(3) A, and C(10)ꢀN(2)ꢀC(15) =
121.6(2)°. One intermolecular hydrogen bond exists in the structure
between the hydroxyl proton and a neighboring acetonitrile:
˚
O(1)ꢀH(99) N(1) = 2.835(4) A. The acetonitrile solvent mole-
3 3 3
cule has been removed from the thermal ellipsoid diagram for clarity.
carbonyl group occurs first, followed by imineꢀenamine
tautomerization preventing further imine reduction. Com-
pound 411 (the anthraquinone analogue without the imine
group) does not produce growth in anthracene fluores-
cence with added Zn(II) ion, since ketoꢀenol tautomeriza-
tion has a higher conversion barrier (Scheme S1). In
addition, the fluorescence properties of the fully reduced
anthracene analogue, compound 5,12 was compared and
the emission manifold is almost identical to that of com-
pounds 3aꢀb plus added Zn(II) (Figure S15).
˚
C(10)ꢀN(2) = 1.285(3) A, an interatomic distance typical
Titration of a 50:50 acetonitrile/water mixture of 3a with
Zn(II) produces a 1:1 ligandꢀmetal formation as evi-
denced by the saturation in the fluorescence data at
1.0 equiv of added zinc (Figure 2 and insert). Fitting the
data to an L þ Zn(II) f LZn(II) stoichiometry (solid line)
of CdN double bonds. The hydroxyl proton was also
observed from the difference map and is involved in a
hydrogen bond with the nitrogen atom of the neighboring
acetonitrile molecule.
results in a binding constant of ∼1.0 ꢁ 105 ((10%) Mꢀ1
.
Addition of Zn(II) to compounds 3aꢀb all show the
growth of new fluorescence peaks characteristic of an
anthracene emission manifold (Figures 2, 4 and Support-
ing Information) We propose that these new reduced
compounds undergo imineꢀenamine tautomerization to
form the fully conjugated, three-ring anthracene π-system
(Scheme 1). Imineꢀenamine tautomerization may also
explain why reduction of the imine does not take place as
usual with NaBH4. Reduction of the more electronegative
Additional evidence for 1:1 Zn(II) complex formation
comes from the ESI-MS data. Upon addition of 3.0 equiv
of the Zn(II) to 3b in acetonitrile, a new peak at 729 m/z
appears, which corresponds to the MZnþ parent ion as
shown in Figure S16. The 729 m/z MZnþ parent ion domi-
nates when 10.0 equiv of Zn(II) are added (Figure S17). The
hydroxyl proton is deprotonated in this case, and the anion
(12) (a) Lu, L.; Chen, Q.; Zhu, X.; Chen, C. Synthesis 2003, 2003,
2464. (b) Hua Jiang, H. X.; Xia, P.; Zhou, Q. Chin. Chem. Lett. 1999, 10,
1015.
(11) Kadarkaraisamy, M.; Caple, G.; Gorden, A. R.; Squire, M. A.;
Sykes, A. G. Inorg. Chem. 2008, 47, 11644.
Org. Lett., Vol. 14, No. 11, 2012
2699

Figure 2. Fluorescence titration of 5.0 ꢁ 10ꢀ5 M of compound
3a in acetonitrile/water (50:50) mixture with increasing amounts
of Zn(II), λext = 367 nm. Inset, intensity vs equiv of Zn(II),
monitored at 434 nm.
Figure 4. (a) Photograph and (b) fluorescence emission spectra
of compound 3a (4.0 ꢁ 10ꢀ5 M) verses 1.2 ꢁ 10ꢀ2 M, 5.0 equiv of
Liþ, Mg2þ, Mn2þ, Naþ, Ni2þ, Pb2þ, Sr2þ, Zn2þ, and Cu2þ in
metal salts, NH4þ, Ba2þ, Ca2þ, Cd2þ, Co2þ, Fe2þ, Fe3þ, Hg2þ
,
acetonitrile at λext = 367 nm.
Figure 5. A 3D bar graph showing fluorescence enhancement of
compound 3a (front, gray) and 3b (back, black),with respect to
metal ions, monitored at 430 nm. λext = 367 nm was used for
compounds 3aꢀb.
The UV-vis titration of compound 3b with Zn(II) pro-
duces the characteristic absorbance manifold for anthra-
cene, essentially the mirror image of the emission manifold
(Figure 3). Also polar protic solvents show slight blue
shifts in emission and absorption maxima as compared to
nonpolar aprotic solvents (Figures S20ꢀS21).
Figure 3. UVꢀvis spectrum of compound 3b (4.0 ꢁ 10ꢀ5 M),
upon increasing addition of the Zn(II) in acetonitrile.
UVꢀvis and fluorescence responses were observed for
compounds 3aꢀb with the addition of 5.0 equiv of perchlo-
formed is stabilized by the Zn(II) trapped within the poly-
ether ring. The single negative charge of the host and the
double positive charge of the Zn(II) ion form the MZnþ
singly charged parent ion (Scheme 1). In addition, the MS/
MS spectrum of the 729 m/z parent ion peak was obtained
(Figure S18) which shows a main 462 m/z fragment ion
which corresponds exactly to the loss of the benzo-15-
crown-5 ring, necessitating that the Zn cation be located in
the larger polyether ring containing the intraannular oxy-
rate salts of NH4þ, Ba2þ, Ca2þ, Cd2þ, Co2þ, Cu2þ, Fe2þ
,
Fe3þ, Hg2þ, Liþ, Mg2þ, Mn2þ, Naþ, Ni2þ, Pb2þ, Sr2þ, Zn2
in acetonitrile, and the resulting spectra were recorded after
4 min (Figures 4, 5 and S20ꢀS22). Compounds 3a and 3b have
similar selectivity for Zn(II); however compound 3b shows
the greatest fluorescence enhancement for the Zn(II) ion
(∼100-fold) as compared to 3a (∼50-fold). Pb(II) is the only
other cation that showed spectral interference, where the
same high affinity for Pb(II) has previously been observed
1
gen. H NMR titrations of compound 3b with increasing
addition of Zn(II) in CD3CN also show a loss of the
anthrone hydroxyl proton and anthrone CꢀH proton at
5.7 and 6.8 ppm (Figure S19).
(13) Kadarkaraisamy, M.; Sykes, A. G. Inorg. Chem. 2005, 45, 779.
Org. Lett., Vol. 14, No. 11, 2012
2700

of pH on Zn(II) induced fluorescence was investigated by
taking a 1:1 mixture (acetonitrile/water) of compound 3b
(4.0 ꢁ 10ꢀ5 M) and buffered solutionsof pH 1.0ꢀ10.0. The
intensity remained unaffected at the pH range 6.0ꢀ8.0,
thus suggesting that the sensor is suitable for physiological
applications (Figure S26).
In summary, we have selectively reduced the internal
carbonyl of new imine compounds with NaBH4, leaving
the external imine intact as confirmed by FTIR, 1H NMR,
13C NMR, ESI-MS, elemental analyses and single-crystal
X-ray crystallography. The fluorescence emission pattern
upon addition of the Zn(II) ion is due to a cation-mediated
imineꢀenamine tautomerization reaction, a new detection
method not previously observed for this important cation
of clinical concern.
Figure 6. SelectivityꢀCompetition study of compound 3a with
added M(II) perchlorate salts (5.0 equiv) followed by 1.0 equiv
of added Zn(II). 4.0 ꢁ 10ꢀ5 M = [3a], λext = 367 nm.
Fluorescence intensity monitored at 434 nm: Gray = 3a þ 5.0
equiv of M(II); Black =3a þ 5.0 equiv of M(II) þ 1.0 equiv
of Zn(II).
Acknowledgment. The authors thank NSF-EPSCOR
(EPS-0554609) and the South Dakota Governor’s 2010
Initiative for the purchase of a Bruker SMART APEX II
CCD diffractometer. The elemental analyzer was provided
by funding from NSF-URC (CHE-0532242). P.N.B. also
thanks NSF-EPSCoR (EPS-0903804).
for the parent anthraquinone macrocycle.13 Interference
from Cd(II) and Hg(II), members of the same family, is
not observed in this case which is common with many other
fluorescence detection systems for Zn(II).
A competition experiment was carried out for com-
pound 3a (Figures 6, S25), showing good selectivity for
Zn(II) in the presence ofmost othercations. Pb(II) remains
competitive for the binding site, and the paramagnetic
cations Fe(II) /Cu(II) quench the emission. The influence
Supporting Information Available. Experimental pro-
cedures, crystallographic data, and full spectroscopic
data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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