Tautomerization in naphthalenediimines: A keto-enamine Schiff base macrocycle

Article abstract of DOI:10.1021/ol051511z

(Chemical Equation Presented) A new [3 + 3] Schiff base macrocycle incorporating naphthalene groups has been prepared. By examination of its properties, X-ray crystallography of model compounds, and calculations, it has been determined that the macrocycle

Full text of DOI:10.1021/ol051511z

ORGANIC
LETTERS
2
005
Vol. 7, No. 22
827-4830
Tautomerization in
Naphthalenediimines: A Keto-Enamine
Schiff Base Macrocycle
4
Amanda J. Gallant, Michael Yun, Marc Sauer, Charles S. Yeung, and
Mark J. MacLachlan*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC, Canada V6T 1Z1
mmaclach@chem.ubc.ca
Received June 28, 2005
ABSTRACT
A new [3
+ 3] Schiff base macrocycle incorporating naphthalene groups has been prepared. By examination of its properties, X-ray crystallography
of model compounds, and calculations, it has been determined that the macrocycle exists predominantly as the keto-enamine tautomer. This
unexpected tautomerization presents an unusual hexaketo interior in the macrocycle.
Conjugated macrocycles, such as porphyrins and phthalo-
cyanines, may be extended using polyaromatic components
to modify their electronic and optical properties. Macro-
macrocycles may enhance the binding affinity or selectivity
of the macrocycle. For example, attaching a second row of
linked aromatic moeities to the upper rim of the resorcinarene
scaffold produces compounds with even deeper cavities.6
These macrocycles can be used as templates for the forma-
tion of large crown ethers, as well as enzyme mimics, and
have been shown to self-assemble into molecular cap-
1,2
3
4
cycles with free volume, such as cyclodextrins, calixarenes,
5
and resorcinarenes, have long been investigated as hosts for
supramolecular chemistry. The size, shape, and chemical
properties of the cavity within these molecules influences
the guests to which they bind. Extending the cavity of the
7
sules.
We have recently synthesized a conjugated Schiff base
macrocycle 1 (Figure 1) with a crown-ether-like interior.
(
1) (a) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
8,9
R., Eds; Academic Press: San Diego, 2000. (b) Sessler, J. L.; Weghorn, S.
J. Expanded, Contracted and Isomeric Porphyrins; Pergamon: New York,
1
997.
2) (a) Jasat, A.; Dolphin, D. Chem. ReV. 1997, 97, 2267. (b) Sessler, J.
(6) Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. J. Am. Chem. Soc. 2001,
123, 5849.
(
L.; Seidel, D. Angew. Chem., Int. Ed. 2003, 42, 5134. (c) Manley, J. M.;
Roper, T. J.; Lash, T. D. J. Org. Chem. 2005, 70, 874. (d) Kobayashi, N.;
Nakajima, S.-I.; Ogata, H.; Fukuda, T. Chem. Eur. J. 2004, 10, 6294. (e)
de la Torre, G.; V a´ zquez, P.; Agull o´ -L o´ pez, F.; Torres, T. J. Mater. Chem.
(7) (a) Li, X.; Upton, T. G.; Gibb, C. L. D.; Gibb, B. C. J. Am. Chem.
Soc. 2003, 125, 650. (b) Laughrey, Z. R.; Gibb, C. L. D.; Senechal, T.;
Gibb, B. C. Chem. Eur. J. 2003, 9, 130. (c) Gibb, C. L. D.; Gibb, B. C. J.
Am. Chem. Soc. 2004, 126, 11408.
(8) Gallant, A. J.; MacLachlan, M. J. Angew. Chem., Int. Ed. 2003, 42,
5307.
(9) For recent examples of conjugated Schiff base macrocycles, see: (a)
Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548. (b) Ma, C.; Lo, A.;
Abdolmaleki, A.; MacLachlan, M. J. Org. Lett. 2004, 6, 3841. (c) Akine,
S.; Hashimoto, D.; Saiki, T.; Nabeshima, T. Tetrahedron Lett. 2004, 45,
4225. (d) Sessler, J. L.; Tomat, E.; Mody, T. D.; Lynch, V. M.; Veauthier,
J. M.; Mirsaidov, U.; Markert, J. T. Inorg. Chem. 2005, 44, 2125.
1
998, 8, 1671. (f) Lash, T. D. J. Porphyrins Phthalocyanines 2001, 5, 267.
3) (a) Harada, A. Acc. Chem. Res. 2001, 34, 456. (b) Douhal, A. Chem.
ReV. 2004, 104, 1955.
4) (a) Ikeda, A.; Shinkai, S. Chem. ReV. 1997, 97, 1713. (b) Gutsche,
C. D. Acc. Chem. Res. 1983, 16, 161.
5) (a) Moran, J. R.; Karbach, S.; Cram, D. J. J. Am. Chem. Soc. 1982,
(
(
(
1
04, 5826. (b) Rudkevich, D. M.; Rebek, J., Jr. Eur. J. Org. Chem. 1999,
991. (c) MacGillivray, L. R.; Atwood, J. L. Nature 1997, 389, 469.
1
1
0.1021/ol051511z CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/29/2005

tography. The structure of 5 was verified by single-crystal
X-ray diffraction (SCXRD). Notably, the molecules assemble
into a 1-D π-stacked assembly with a pitch of 1/3 and
an average separation between the molecules of 3.356 Å
(Figure 2).
Figure 1. Structures of macrocycles 1 and 2.
Upon addition of small cations (e.g., Na , NH
4
+), 1 as-
+
8
sembles into tubular structures. The crystal structure and
calculations of this rigid macrocycle reveal that it is
nonplanar, with the macrocycle adopting an open-cavity
structure similar to classical calixarenes.10 In an effort to
expand these macrocycles and to modify their properties,
we sought to simply replace the dihydroxybenzene rings in
Figure 2. (a) Crystal structure of 5. (b) 1-D π-stacked assembly
of 5 showing the 1/3 pitch.
Reaction of compound 5 with phenylenediamine 6 af-
forded macrocycle 2 in 46% yield as shown in Scheme 2.
1
2
with dihydroxynaphthalene rings to generate macrocycle
with increased aromatic exposure, retaining the hydroxy-
imine groups in the center. Reinhoudt et al. previously
investigated the incorporation of naphthalene rings into Schiff
Scheme 2. Synthesis of Macrocycle 2
11
base macrocycles related to 2. They required the use of
2+
Ba as a template, and the template was not removed.
Moreover, the structural aspects of the macrocycle were not
investigated.
We found it was necessary to improve the synthesis of
11
1
,4-diformyl-2,3-dihydroxynaphthalene 5. With the recent
report of 1,4-bis(hydroxymethyl)-2,3-dimethoxy-naphthalene
12
(
3), we developed a simple route to 5 that can be scaled to
multigram quantities (Scheme 1). Oxidation of 3 with
The reversibility of the Schiff base condensation allows the
reaction to achieve the thermodynamically stable [3 + 3]
macrocycle rather than expected kinetic intermediates of
oligomer and polymer. This macrocycle is unstrained and
maximizes intramolecular hydrogen bonding. Initially, we
tried to prepare macrocycle 2 with longer alkoxy chains (e.g.,
hexyloxy), but we found that the product was more soluble
than macrocycle 1 and difficult to crystallize. We had
anticipated that the additional aromatic rings of 2 would
Scheme 1. Synthesis of Diformyl Precursor 5
1
render the macrocycle less soluble than 1. The H NMR
pyridinium chlorochromate (PCC) yielded the diformylnaph-
thalene species 4 (85%), which afforded compound 5 in 80%
spectrum of 2 shows the expected resonances for the
extended macrocycle. However, the resonances assigned to
the hydroxyl (15.6 ppm) and imine (9.6 ppm) groups are
considerably shifted downfield relative to where they are
observed in the spectrum for 1 (13.3 and 8.5 ppm, respec-
tively). The naphthalene CO and imine C resonances
yield after deprotection with BBr
product that was ca. 99% pure ( H NMR) without chroma-
3
. These steps provided
1
(
10) (a) Gallant, A. J.; Patrick, B. O.; MacLachlan, M. J. J. Org. Chem.
004, 69, 8739. (b) Gallant, A. J.; Hui, J. K.-H.; Zahariev, F. E.; Wang, Y.
A.; MacLachlan, M. J. J. Org. Chem. 2005, 70, 7936.
11) Huck, W. T. S.; van Veggel, F. C. J. M.; Reinhoudt, D. N. Recl.
TraV. Chim. Pays-Bas, 1995, 114, 273.
12) Tran, A. H.; Miller, D. O.; Georghiou, P. E. J. Org. Chem. 2005,
0, 1115.
2
1
3
(
C NMR spectroscopy) are observed in 2 at 162.0 and
(
155.6 ppm, respectively. For comparison, the imine C is
1
3
observed at 161 ppm in the C NMR spectrum of macro-
(
7
cycle 1.
4828
Org. Lett., Vol. 7, No. 22, 2005

The mass spectrum of macrocycle 2 shows the expected
mass for the [3 + 3] Schiff base macrocycle. However, the
IR and UV-vis spectra are substantially different for this
new extended macrocycle as compared to macrocycle 1,
suggesting a fundamental difference between these two
systems.
To improve our understanding of macrocycle 2, we
synthesized model compounds 7-9 (Scheme 3). The imine
Scheme 3. Synthesis of Model Compounds 7-9 and the
Tautomers of Compound 10 Used for Calculations
Figure 3. Structure of compound 8 as determined by SCXRD. (a)
View perpendicular to the naphthalene ring. (b) View parallel to
the naphthalene ring reveals OdC-C-CH torsions (dihedral angles
of 0.7° and 4.8°). H atoms removed for clarity in (b). Thermal
ellipsoids are shown at 50% probability.
rather than on the oxygen atoms. The structure of 9 (Figure
4
) is also in agreement with the keto-enamine form.
1
and hydroxyl resonances in the H NMR spectrum of 7 are
comparable to those of macrocycle 1. Both the macrocycle
and the model compound are unequivocally present as the
Figure 4. Structure of compound 9 as determined by SCXRD. (a)
View perpendicular to the naphthalene ring. (b) View parallel to
the naphthalene ring reveals OdC-C-CH torsions (dihedral angles
enol-imine tautomer. The COH resonance is observed at
50.7 and 150.3 ppm in the 1 C NMR spectra of 1 and 7,
3
1
t
of 5.9° and 7.3°). Boc groups and H atoms removed for clarity in
respectively.
(b). Thermal ellipsoids are shown at 50% probability.
The imine and hydroxyl resonances observed for com-
pounds 8 and 9 are similar to those observed for macrocycle
2
, suggesting that the naphthalene unit is responsible for the
To confirm that 8 and 9 were keto-enamine tautomers in
the solid state, ab initio DFT calculations were performed
using compound 10 as an analogue of 8 and 9. Energy-
13
structural differences. The C NMR spectrum of the model
compounds 8 and 9 revealed the naphthalene CO resonance
at 168.7 and 158.5 ppm, respectively. Although these
resonances are shifted downfield relative to the typical
position of a phenol (e.g., 154.9 ppm in 5), the assignment
of enol-imine vs keto-enamine tautomer was ambiguous. To
obtain more accurate structural information, SCXRD was
performed on both 8 and 9.
The single-crystal structure of 8 (Figure 3) revealed that
the model compound is in the keto-enamine form in the solid
state at -100 °C. The naphthalene C-O bond lengths
observed in the structure are characteristic of ketones rather
than phenols, and the C-N bond is elongated relative to that
of a typical imine. Moreover, the hydrogen atoms involved
in hydrogen bonding were located on the nitrogen atoms
minimized structures were determined using B3LYP with a
13
6
(
-31G(d,p) basis set. DFT calculations of compound 10
keto) predict the bond lengths and overall structure of the
model compounds very well. Table 1 compares key bond
lengths obtained from the crystal structures and calculations.
Most of the bonds affected by the tautomerization agree with
the calculated bond lengths for the keto isomer within error.
These data show that the model compounds 8 and 9, which
are structurally analogous to one side of the [3 + 3] Schiff
base macrocycle 2, are present mostly in the keto-enamine
14
tautomer at -100 °C. Moreover, the DFT calculations
(13) Spartan ’04; Wavefunction: Irvine, CA.
Org. Lett., Vol. 7, No. 22, 2005
4829

Table 1. Calculated and Measured Lengths (Å) of Selected
Bonds
bonda
8b
9b
10 (keto)c
10 (enol)c
C2-O1
C11-N1
C4-C11
C1-C2
C2-C4
1.275(3)
1.324(4)
1.399(3)
1.494(3)
1.427(3)
1.261(7)
1.33(1)
1.39(1)
1.510(6)
1.428(9)
1.247
1.341
1.392
1.519
1.401
1.328
1.298
1.449
1.438
1.450
a
Labeling as in Figures 3 and 4; averaged assuming mirror symmetry
b
c
through the naphthalene ring. SCXRD (-100 °C). Calculated at B3LYP/
-31G(d,p).
6
predicted that the keto tautomer 10 (keto) would be ca. 0.7
kcal/mol more stable than the enol tautomer 10 (enol) (0 K,
vacuum).
On the basis of these results, we can conclude that the
[3 + 3] Schiff base macrocycle 2 is a mixture of tautomers,
but predominantly the keto-enamine isomer, Figure 5. This
tautomerization breaks the conjugation in the macrocycle and
renders it more flexible and thus more soluble. The formation
of stable keto-enamines must be a sufficient driving force
to overcome the aromatic stabilization of the second ring in
1
5
naphthalene.
These compounds are the first naphthalene-based 1,4-
diimines to be structurally characterized. Studies of tau-
tomerization in these molecules are relevant to understanding
Figure 5. Tautomerization of macrocycle 2 between the enol-imine
and keto-enamine tautomers. The latter is more stable in the case
of this naphthalene-based macrocycle.
photochromism and thermochromism in N-salicylaldimines
and their naphthyl analogues.16
In conclusion, we have studied new naphthalenediimine
model compounds that tautomerize to the keto-enamine form.
We have used the reversible Schiff base condensation
reaction to prepare a new [3 + 3] macrocycle incorporating
naphthalene groups and established that it is present mostly
in the keto-enamine tautomer, thus exposing a hexaketo
Acknowledgment. We thank NSERC, CFI, and UBC for
funding, Jonathan Chong for solving the structures of 5, 8,
and 9, and Yu Zhang and Federico Zahariev for assistance
with calculations. A.J.G. and C.S.Y. thank NSERC for
postgraduate and USRA fellowships, respectively.
1
7
interior. Investigations are underway to study the host-
guest and coordination chemistry of these new extended
Schiff base macrocycles.
Supporting Information Available: Experimental pro-
1
13
cedures and spectroscopic data; H and C NMR spectra
for new compounds; CIF files for 5, 8, and 9; and coordinates
of calculated structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
14) In solution at room temperature, the model compounds exist as a
13
mixture of tautomers; on the basis of calculation and VT C NMR studies,
we estimate that the ratio of keto to enol is ca. 4:1 for 8. In the solid state
at -100 °C, we estimate that the model compounds are present as ∼99%
keto-enamine tautomer. Details are provided in Supporting Information.
OL051511Z
(15) (a) Fabian, W. M. F.; Antonov, L.; Nedeltcheva, D.; Kamounah, F.
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Momotake, A.; Arai, T. J. Photochem. Photobiol. A 2004, 162, 473.
(17) For examples of macrocycles with carbonyl groups, see: (a) Lagona,
J.; Fettinger, J. C.; Isaacs, L. Org. Lett. 2003, 5, 3745. (b) Okubo, H.;
Yamaguchi, M. J. Org. Chem. 2001, 66, 824. (c) Kobiro, K.; Takahashi,
M.; Nishikawa, N.; Kakiuchi, K.; Tobe, Y.; Odaira, Y. Tetrahedron Lett.
1987, 28, 3825.
(
16) (a) Hadjoudis, E. Mol. Eng. 1995, 5, 301. (b) Inabe, T. New J. Chem.
1
991, 15, 129. (c) Alarc o´ n, S. H.; Olivieri, A. C.; Nordon, A.; Harris, R.
K. J. Chem. Soc., Perkin Trans. 2 1996, 2293. (d) Harada, J.; Uekusa, H.;
Ohashi, Y. J. Am. Chem. Soc. 1999, 121, 5809.
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Org. Lett., Vol. 7, No. 22, 2005