Highly Stable Keto-Enamine Salicylideneanilines

Article abstract of DOI:10.1021/ol0352714

(Matrix presented) Highly stable NH salicylideneanilines have been prepared by reaction of 1,3,5-triformylphloroglucinol with aniline derivatives. The NH form was confirmed by X-ray crystallographic data, as well as by NMR studies. A convenient one-step synthesis of triformylphloroglucinol is also reported.

Full text of DOI:10.1021/ol0352714

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3823-3826
Highly Stable Keto-Enamine
Salicylideneanilines
Jonathan H. Chong, Marc Sauer, Brian O. Patrick, and Mark J. MacLachlan*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC, V6T 1Z1, Canada
mmaclach@chem.ubc.ca
Received July 9, 2003
ABSTRACT
Highly stable NH salicylideneanilines have been prepared by reaction of 1,3,5-triformylphloroglucinol with aniline derivatives. The NH form
was confirmed by X-ray crystallographic data, as well as by NMR studies. A convenient one-step synthesis of triformylphloroglucinol is also
reported.
Proton tautomerism is central to several fields of chemistry
and biochemistry and plays a role in pharmaceutical action,
enzyme activity, and the stabilization of base pairs in duplex
DNA.1,2 N-Salicylideneanilines (1) are an interesting class
of compounds possessing an OH‚‚‚N hydrogen bond. These
compounds are often thermo- and photochromic, undergoing
reversible proton transfers (tautomerism) in the solid state
(e.g., 1a h 1b).3
As proton transfer in these systems causes a change
in optical properties, these molecules are candidates for
optical switches and storage devices.4 There have been
many studies of proton transfer in the solid-state and in
solution.5
Generally, the enol-imine (OH) form (i.e., 1a) is the most
stable form at room temperature but is in equilibrium with
the keto-enamine (NH) form (i.e., 1b).6 As a result, the OH
form of N-salicylideneanilines has been well-characterized,
but, until recently, no NH form had been structurally
characterized.7,8 Ogawa has undertaken low-temperature
X-ray diffraction experiments of 2 and observed that at 15
K, the NH form (2b) is present.8,9 However, as the bond
lengths more strongly resemble those of 2a than those
calculated (DFT) for the quinoidal form 2b, the authors
conclude that 2c is the canonical structure that is dominating
(1) (a) Rodr´ıguez-Santiago, L.; Sodupe, M.; Oliva, A.; Bertran, J. J. Am.
Chem. Soc. 1999, 121, 8882. (b) Glaser, R.; Lewis, M. Org. Lett. 1999, 1,
273. (c) Phillips, R. S.; Sundararaju, B.; Faleev, N. G. J. Am. Chem. Soc.
2000, 122, 1008. (d) Heyes, D. J.; Hunter, C. N.; van Stokkum, I. H. M.;
van Grondelle, R.; Groot, M. L. Nature Struct. Biol. 2003, 10, 491. (e)
Gilli, P.; Bertolasi, V.; Pretto, L.; Lycˇka, A.; Gilli, G. J. Am. Chem. Soc.
2002, 124, 13554. (f) Thompson, M. J.; Bashford, D.; Noodleman, L.;
Getzoff, E. D. J. Am. Chem. Soc. 2003, 125, 8186. (g) Naumov, P.; Sekine,
A.; Uekusa, H.; Ohashi, Y. J. Am. Chem. Soc. 2002, 124, 8540. (h) Chou,
P.-T.; Chen, Y.-C.; Wei, C.-Y.; Chen, W.-S. J. Am. Chem. Soc. 2000, 122,
9322.
(2) (a) Abou-Zied, O. K.; Jimenez, R.; Romesberg, F. E. J. Am. Chem.
Soc. 2001, 123, 4613. (b) Duarte, H. A.; Carvalho, S.; Paniago, E. B.; Simas,
A. M. J. Pharm. Sci. 1999, 88, 111. (c) Susan-Resiga, D.; Nowak, T. J.
Biol. Chem. 2003, 278, 12660.
(3) (a) Inabe, T. New J. Chem. 1991, 15, 129. (b) Hadjoudis, E. Mol.
Eng. 1995, 5, 301. (c) Harada, J.; Uekusa, H.; Ohashi, Y. J. Am. Chem.
Soc. 1999, 121, 5809.
Figure 1. Tautomerization of compounds 1 and 2 showing the
two canonical structures contributing to the resonance structure of
the NH form. Atomic numbering is for use in Table 1.
10.1021/ol0352714 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/17/2003

Figure 2. Structures of the tautomers of tris(N-salicylideneaniline) 3a.
in the crystalline state. The relative contributions of the
quinoidal (1b) and zwitterionic (1c) canonical structures to
the resonant structure of N-salicylideneanilines have been
an issue of investigation.10
Here, we report the first structural characterization of the
NH form of a N-salicylideneaniline that resembles the
quinoidal form predicted by DFT calculations in the gas
phase.
We identified tris(N-salicylideneaniline) 3a (Figure 2) as
an intriguing target since it might undergo multiple proton
transfers and serve as a multistep photochemical switch. In
the case of 3, there are four tautomers that could possibly
be addressed. To initiate this work, 1,3,5-triformylphloro-
glucinol (4) was required. Although this molecule was
previously prepared in seven steps from 1,3,5-trichloroben-
zene, with an overall yield of 21%, the product was not
characterized.11 We discovered that reaction of phloroglucinol
with hexamethylenetetramine (HMTA) in trifluoroacetic acid
(Duff formylation12) afforded compound 4 in one step
(Scheme 1). Although the yield is low (14%), the reaction
is simple, takes only 2 h, and affords a crude product with
ca. 99% purity. We have attempted to increase the yield by
varying the reaction conditions (time, temperature) but have
not found improved conditions. Moreover, drying of the
phloroglucinol does not significantly affect the yield.
Compound 4 is remarkably stable. It melts at 198-200
°C and can be sublimed at 120 °C under vacuum (∼10-3
Torr). Its 1H NMR spectrum shows only two singlets at 10.14
and 14.10 ppm (CDCl3), assigned to the aldehyde and phenol,
respectively. The large downfield shift of the phenolic proton
is consistent with strong intramolecular hydrogen-bonding
in the molecule. The IR spectrum of 4 shows an intense
absorption at 1641 cm-1, characteristic of an aldehyde.
Tris(N-salicylideneaniline) derivatives 6a-c were prepared
in 52-62% yield by the reaction of compound 4 with an
excess of aniline derivative 5a-c in refluxing ethanol
(Scheme 1). The IR spectra of the yellow-orange, fluorescent
compounds 6a-c all confirmed the disappearance of the
aldehyde.
1H NMR spectra of 6a-c were surprisingly complicated
(Figure 3). Whereas singlets were expected for the imine
and phenol in the OH form, the spectra showed multiple
peaks between 8.5-9.0 and 12.8-13.5 ppm. 1H-1H COSY
spectra elucidated coupling between doublets in these two
1
regions. The H NMR spectra for 6a-c show that only the
(4) (a) Feringa, B. L.; Jager, W. F.; de Lange, B. Tetrahedron 1993, 49,
8267. (b) Delaire, J. A.; Nakatani, K. Chem. ReV. 2000, 100, 1817. (c) Lo,
D. S. Appl. Optics 1974, 13, 861. (d) Nakatani, K.; Delaire, J. A. Chem.
Mater. 1997, 9, 2682.
Scheme 1. Synthesis of 4 and 6
(5) (a) Ogawa, K.; Fujiwara, T. Chem. Lett. 1999, 657. (b) Pizzala,
H.; Carles, M.; Stone, W. E. E.; Thevand, A. J. Chem. Soc., Perkin Trans.
2 2000, 935. (c) Alarco´n, S. H.; Pagani, D.; Bacigalupo, J.; Olivieri, A.
C. J. Mol. Struct. 1999, 475, 233. (d) Ogawa, K.; Harada, J.; Fujiwara,
T.; Yoshida, S. J. Phys. Chem. A. 2001, 105, 3425. (e) Vargas, V.; Amigo,
L. J. Chem. Soc., Perkin Trans. 2 2001, 1124. (f) Ogawa, K.; Harada,
J. J. Mol. Struct. 2003, 647, 211. (g) Amimoto, K.; Kanatomi, H.;
Nagakari, A.; Fukuda, H.; Koyama, H.; Kawato, T. Chem. Commun. 2003,
870.
(6) (a) Suzuki, T.; Arai, T. Chem. Lett. 2001, 124. (b) Charette, J. J.; De
Hoffmann, E. J. Org. Chem. 1979, 44, 2256. (c) Hansen, P. E.; Duus, F.;
Schmitt, P. Org. Magn. Reson. 1982, 18, 58.
(7) There are a few references where the NH form was claimed, but
reexamination suggests that there is more likely a mixture of the OH and
NH forms. See ref 8.
(8) Ogawa, K.; Harada, J.; Tamura, I.; Noda, Y. Chem. Lett. 2000, 528.
(9) Ogawa, K.; Kasahara, Y.; Ohtani, Y.; Harada, J. J. Am. Chem. Soc.
1998, 120, 7107.
(10) Krygowski, T. M.; Woz´niak, K.; Anulewicz, R.; Pawlak, D.;
Kolodziejski, W.; Grech, E.; Szady, A. J. Phys. Chem. A 1997, 101, 9399.
(11) Himmelman, W.; Roos, E.; Sobel, J. German Patent 2002063, 1971;
Chem. Abstr. 1971, 75, 373.
(12) Anderson, A. A.; Goetzen, T.; Shackelford, S. A.; Tsank, S. Synth.
Commun. 2000, 30, 3227.
3824
Org. Lett., Vol. 5, No. 21, 2003

Figure 3. 1H NMR spectrum of 6b (top) and 1H-1H COSY NMR
spectrum (bottom; (CDCl2)2) showing coupling between vinylic and
NH protons. At the right are the two structures (with C3h and CS
symmetry) evident in the H NMR spectrum. (* ) CHCl2CDCl2;
** ) water in the NMR solvent).
Figure 5. Molecular structure of compound 6d shown with thermal
ellipsoids at 50% electron density. All hydrogen atoms, other than
those bonded to N1, N3, and N5, have been omitted. In the bottom
1
t
structure, the BOC groups have been removed for clarity.
all-keto-enamine (NH) form of 6a-c is present, in a mixture
of two geometric isomers (7 and 8), as shown in Figure 4.
In each compound, coupling is observed between the
enamine proton and the NH (3JHH ≈ 13.5 Hz).13
13C NMR spectra of 6a-c showed the carbonyl resonance
of the central ring at ca. 185 ppm, characteristic of the keto
isomer.5c,14 Moreover, the peaks assigned to the dCNH and
CdO groups of the two geometric isomers 7 and 8 could be
resolved.
The molecular structure of 6d is shown in Figure 5.16,17
Notably, the compound is the keto-enamine tautomer of 6d
(i.e., 7d), a cyclohexanetrione with approximately C3h
symmetry in the central ring.18 The central C6 ring is flat
(within error), with average C-C bond lengths of 1.45(1)
Å, considerably longer than the average C-C bond length
in benzene (1.38 Å). Moreover, the C-O bond lengths (avg
) 1.256(8) Å) are more characteristic of ketones than C-OH
bonds. As a virtue of the central cyclohexanetrione present
in compounds 7 and 8, these molecules may be viewed as
1,3,5-trisoxa[6]radialenes;19 this motif has been reported
previously in only a couple of cases with sulfur substituents.20
t
We also prepared the BOC-protected compound 6d by
reacting 4 with 5d.15 Compound 6d was purified by recrystal-
lization and characterized. To confirm the structure of 6d,
crystals suitable for single-crystal X-ray diffraction were
obtained from slow evaporation of 6d in 1:1 CH2Cl2/hexanes.
Unlike other N-salicylideneanilines that typically exist in
equilibrium between two tautomers in solution and as a
1
(13) Yields reported are of purified, isolated product. H NMR spectra
of the supernatant solution from the reaction of 4 with 5b appeared identical
to the isolated product plus excess 5b. There was no evidence for imine,
aldehyde, or other resonances that would be expected for the OH form 6b.
(14) Alarco´n, S. H.; Olivieri, A. C.; Gonza´lez-Sierra, M. J. Chem. Soc.,
Perkin Trans. 2 1994, 1067.
(15) Seto, C. T.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc.
1993, 115, 1321.
(16) Crystal data: FW ) 782.88, orthorhombic, Pccn; a ) 11.2522(5)
Å, b ) 22.989(1) Å, c ) 37.807(2) Å; V ) 9779.9(7) Å3, Z ) 8, T )
-100(1) °C, µ(Mo KR) ) 0.76 cm-1, 8537 observed reflections, 572
variables, R ) 0.156, Rw ) 0.292, GOF ) 0.92.
t
(17) X-ray structure shows positional disorder in the BOC groups and
one of the phenylenediamine rings. The central ring shows no disorder,
and its dimensions are reliable.
(18) Positions of the H atoms between O1, O2, O3 and N3, N5, N1
were refined isotropically and found to be localized on the N-atoms.
Figure 4. There are two possible geometric isomers of each
compound 6a-d in its keto-enamine (NH) form, 7 and 8, with
symmetry C3h and Cs, respectively.
Org. Lett., Vol. 5, No. 21, 2003
3825

mixture of the two tautomers in the solid state, 6a-d are
only observed in the NH form (7 and 8). We have not
observed the imine tautomers (OH form) of 6a-d in our
experiments. As the formation of the cyclohexanetrione core
in 7 or 8 is accompanied by loss of aromaticity in the central
benzene ring, it must be accompanied by a net stabilization
from other factors. This stabilization likely arises from the
relatively large basicity of the nitrogen vs the phenolic
oxygen.
Table 1. Experimental and Calculated Dimensions of
Enol-enamines 2 and 6
distance (Å)a
compound method T (K) tautomer O1-C2 C2-C3 C3-C4
2
2
2
6a c
6a
6d
XRDb
DFTb
DFTb
DFTd
DFTd
XRDd
15 NH
1.310(1) 1.433(2) 1.425(1)
0
0
0
0
OH
NH
OH
NH
1.341
1.263
1.330
1.256
1.423
1.469
1.421
1.461
1.452
1.400
1.443
1.386
Ab initio DFT calculations were performed on the OH
and NH forms of 6a. Calculations show that the keto form
(7a) is stabilized relative to the enol form (6a) by ∆Hf )
-75 kJ/mol.21 Moreover, the calculations indicate that the
planarity of the central core is maintained by hydrogen
bonding. With respect to the bond lengths and angles in the
core, the calculated dimensions of 7a are very similar to those
calculated for the quinoidal tautomers 1b and 2b (Table 1).
While the bond lengths for 2 at 15 K by Ogawa et al. are
best explained as a zwitterionic structure (2c), our X-ray
diffraction experiment (173 K) indicates that 6d is very
similar to that predicted for the quinoidal structure (2b).
With the exception of 6d, the two geometric isomers of
6a-c (i.e., 7a-c and 8a-c) were both present and could
not be separated by chromatography or recrystallization. They
do not interconvert on the NMR time scale even when heated
to 120 °C in aprotic solvent. This is surprising since a simple
proton transfer from NH to O would facilitate this isomer-
ization. From the 1H NMR spectrum for 6b, the ratio of the
C3h (7b) to CS (8b) isomers present is ca. 1:1.4 vs the 1:2
ratio expected in a statistical mixture. Calculations indicate
that the C3h isomer is more stable than the CS isomer, but
the difference is small. Due to the tremendous stability of
173 NH
1.256(8) 1.452(8) 1.38(1)
a Atom labels from Figure 1. b From ref 8. c Same as 3. d From this study.
the NH form in the tris(N-salicylideneaniline), these com-
pounds are not readily interconverted between their various
tautomeric forms in aprotic solvents. In methanol-d4, the ratio
of 7 to 8 changes, indicating that there is slow interconversion
between the geometric isomers, but still only the NH form
is observed by NMR spectroscopy.
In summary, we have obtained the first X-ray diffraction
evidence of a N-salicylideneaniline locked in the NH form
that is consistent with the gas-phase quinoidal structure. We
have also discovered a convenient route to triformylphloro-
glucinol, a molecule that leads to interesting conjugated
hetero[6]radialenes upon condensation with aromatic amines.
Acknowledgment. M.S. thanks NATO for a postdoctoral
fellowship. We also thank the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada and the
University of British Columbia for funding and Nick
Burlinson for helpful discussions.
(19) Hopf, H.; Maas, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 931.
(20) All known examples have ethylenedithiolate substituents. See: (a)
Gompper, R.; Kutter, E. Chem. Ber. 1965, 98, 1365. (b) Kimura, M.;
Watson, W. H.; Nakayama, J. J. Org. Chem. 1980, 45, 3719. (c) Coffin,
M. A.; Bryce, M. R.; Clegg, W. J. Chem. Soc. Chem. Commun. 1992, 401.
(d) Mono, S.; Pritzkow, H.; Sundermeyer, W. Chem. Ber. 1993, 126, 2111.
(21) Calculated with Spartan at the B3LYP/6-31G* level. Semiempirical
AM1 and PM3 calculations gave ∆HF ) -96.0 and -25.0 kJ/mol (keto
more stable), respectively. AM1 is known to give good estimates of energies
where strong hydrogen bonding is present, as in compounds 6. Geometries
predicted by all three methods were similar.
Supporting Information Available: Experimental details
for the synthesis of 4 and 6a-d and X-ray crystallographic
data for 6d. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0352714
3826
Org. Lett., Vol. 5, No. 21, 2003