Reversible-irreversible approach to schiff base macrocycles: Access to isomeric macrocycles with multiple salphen pockets

Article abstract of DOI:10.1021/ol8001317

We have developed methodology for the formation of a new family of metal-free Schiff base macrocycles utilizing the differential exchange rates of aldimines and ketimines. The more robust ketimine bond Is kinetically Inert under the milder conditions used for aldimine bond formation. In particular, this route enables access to the first conjugated macrocycles with four unsymmetrical N₂O₂ salphen-like pockets.

Full text of DOI:10.1021/ol8001317

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1255-1258
Reversible−Irreversible Approach to
Schiff Base Macrocycles: Access to
Isomeric Macrocycles with Multiple
Salphen Pockets
Peter D. Frischmann, Jian Jiang, Joseph K.-H. Hui, Joseph J. Grzybowski,† and
Mark J. MacLachlan*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer BC V6T 1Z1, Canada
mmaclach@chem.ubc.ca
Received January 19, 2008
ABSTRACT
We have developed methodology for the formation of a new family of metal-free Schiff base macrocycles utilizing the differential exchange
rates of aldimines and ketimines. The more robust ketimine bond is kinetically inert under the milder conditions used for aldimine bond
formation. In particular, this route enables access to the first conjugated macrocycles with four unsymmetrical N2O2 salphen-like pockets.
Over the past 30 years, many Schiff base macrocycles have
been synthesized, often with the ultimate goal of metal
complexation.1,2 The polydentate nature of Schiff base
macrocycles makes them excellent scaffolds for the coordi-
nation of multiple metal ions. These multimetallic complexes
frequently exhibit intriguing magnetic,3 catalytic,4 or su-
pramolecular5 behavior.
We have been especially interested in conjugated macro-
cycles with multiple salphen-type N2O2 pockets. These
macrocycles have proven to be useful precursors to molecular
metal clusters5a,6 and nanotubular assemblies.7 The Schiff
base condensation of geometrically programmed dialdehydes
† On sabbatical leave at UBC from Gettysburg College 2006-07,
jgrzybow@gettysburg.edu.
(1) For reviews, see: (a) Borisova, N. E.; Reshetova, M. D.; Ustynyuk,
Y. A. Chem. ReV. 2007, 107, 46-79. (b) Vigato, P. A.; Tamburini, S.;
Bertolo, L. Coord. Chem. ReV. 2007, 251, 1311-1492.
(2) Recent examples: (a) Tomat, E.; Cuesta, L.; Lynch, V. M.; Sessler,
J. L. Inorg. Chem. 2007, 46, 6224-6226. (b) Croucher, P. D.; Klingele,
M. H.; Noble, A.; Brooker, S. Dalton Trans. 2007, 4000-4007. (c) Givaja,
G.; Volpe, M.; Leeland, J. W.; Edwards, M. A.; Young, T. K.; Darby, S.
B.; Reid, S. D.; Blake, A. J.; Wilson, C.; Wolowska, J.; McInnes, E. J. L.;
Schro¨der, M.; Love, J. B. Chem. Eur. J. 2007, 13, 3707-3723. (d) Kwit,
M.; Plutecka, A.; Rychlewska, U.; Gawron´ski, J.; Khlebnikov, A. F.;
Kozhushkov, S. I.; Rauch, K.; de Meijere, A. Chem. Eur. J. 2007, 13, 8688-
8695. (e) Sessler, J. L.; Tomat, E.; Lynch, V. M. Chem. Commun. 2006,
4486-4488. (f) Kuhnert, N.; Burzlaff, N.; Patel, C.; Lopez-Periago, A. Org.
Biomol. Chem. 2005, 3, 1911-1921. (g) Shimakoshi, H.; Takemoto, H.;
Aritome, I.; Hisaeda, Y. Tetrahedron Lett. 2002, 43, 4809-4812.
(3) (a) Tandon, S. S.; Bunge, S. D.; Thompson, L. K. Chem. Commun.
2007, 798-800. (b) Tandon, S. S.; Thompson, L. K.; Bridson, J. N.; Benelli,
C. Inorg. Chem. 1995, 34, 5507-5515.
(4) (a) Na, S. J.; Joe, D. J.; S, S.; Han, W.-S.; Kang, S. O.; Lee, B. Y.
J. Organomet. Chem. 2006, 691, 611-620. (b) Thirumavalavan, M.; Akilan,
P.; Kandaswamy, M.; Chinnakali, K.; Kumar, G. S.; Fun, H.-K. Inorg.
Chem. 2003, 42, 3308-3317.
(5) (a) Frischmann, P. D.; MacLachlan, M. J. Chem. Commun. 2007,
4480-4482. (b) MacLachlan, M. J. Pure Appl. Chem. 2006, 78, 873-888.
(c) Huang, W.; Gou, S.; Hu, D.; Chantrapromma, S.; Fun, H.-K.; Meng,
Q. Inorg. Chem. 2001, 40, 1712-1715.
10.1021/ol8001317 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

and diamines is a very convenient route to these macrocycles,
as the reversibility of the reaction enables the preparation
of macrocycles in high yield and purity without formation
of oligomer and polymer.
2-benzoyl-4-methylphenol,13 respectively. Solutions of 1 and
2 were prepared in CD3CN and combined with 2 equiv of
3,5-dimethylaniline, Scheme 1. At equilibrium a mixture of
Although the reversibility of Schiff base condensation is
convenient for preparing macrocycles, it leads to one
significant drawbacksthis route is usually limited to highly
symmetrical macrocycles. For example, we have reported
facile routes to conjugated [3 + 3] Schiff base macrocycles
with average D3h symmetry,8 but template-free routes to
larger cycles are virtually unknown.9 Schiff base condensa-
tion is not generally useful for obtaining fully conjugated
macrocycles with more than one type of imine. Attempts to
make macrocycles with chemically distinct imines often leads
to a mixture of products unless imines are reduced or
coordinated to metals to prevent exchange.
Scheme 1. Aldimine and Ketimine Exchange
Salphens and salens have been synthesized with two
different aldimines or one ketimine and one aldimine by
stepwise condensation.10 This low symmetry in a single N2O2
pocket is useful for developing chirality in metal complexes11
which might in turn influence the products of catalysis.
Despite the appeal of unsymmetric N2O2 pockets, methodol-
ogy to make Schiff base macrocycles possessing them is
lacking.
both aldimines or both ketimines should exist due to the
similar electron-donating properties of p-anisidine and 3,5-
dimethylaniline.14
At 20 °C, no exchange was observed by 1H NMR
spectroscopy for either 1 or 2. When a solution of 1 in CD3-
CN was heated to 57 °C (330 K), resonances assigned to
free p-anisidine appeared indicating formation of 3 through
imine exchange (measured rate of exchange: 1 × 10-6 mol
L-1 s-1). Conversely, when ketimine 2 was subjected to the
same conditions for 36 h, no exchange was observed.15 These
results show that in hot acetonitrile aldimine bonds are labile
but ketimines are kinetically inert.
Here we report a new route to Schiff base macrocycles
with multiple salphen pockets, each having two distinct
imines. The synthesis is achieved by taking advantage of
the differential exchange rates of aldimines and ketimines
with primary amines. This route has enabled us to prepare a
new family of [2 + 2] Schiff base macrocycles, each
possessing four unsymmetrical N2O2 pockets.
We applied this knowledge to the synthesis of Schiff base
macrocycles through a cascade of ketimine condensation
followed by aldimine condensation. Dihydroxydibenzoyl-
benzenes 616 and 717 were prepared as shown in Scheme 2.
The synthesis of ketimine macrocycles from the condensa-
tion of diketones and diamines results in a mixture of
products, each in low yield, due to the kinetic stability of
the ketimine bond.12 We expected that aldimines and
ketimines should exhibit very different rates of exchange
when reacted with another amine. To test our hypothesis,
model substrates, aldimine 1 and ketimine 2, were synthe-
sized by condensing p-anisidine with salicylaldehyde and
Scheme 2. Synthesis of Dihydroxydibenzoyl Compounds
(6) (a) Frischmann, P. D.; Gallant, A. J.; Chong, J. H.; MacLachlan, M.
J. Inorg. Chem. 2008, 47, 101-112. (b) Gallant, A. J.; Chong, J. H.;
MacLachlan, M. J. Inorg. Chem, 2006, 45, 5248-5250. (c) Nabeshima,
T.; Miyazaki, H.; Iwasaki, A.; Akine, S.; Saiki, T.; Ikeda, C.; Sato, S. Chem.
Lett. 2006, 35, 1070-1071.
(7) (a) Gallant, A. J.; MacLachlan, M. J. Angew. Chem., Int. Ed. 2003,
42, 5307-5310. (b) Ma, C. T.-Z.; MacLachlan, M. J. Angew. Chem., Int.
Ed. 2005, 44, 4178-4182.
(8) (a) Gallant, A. J.; Hui, J. K.-H.; Zahariev, F. E.; Wang, Y. A.;
MacLachlan, M. J. J. Org. Chem. 2005, 70, 7936-7946. (b) Gallant, A. J.;
Yun, M.; Sauer, M.; Yeung, C. S.; MacLachlan, M. J. Org. Lett. 2005, 7,
4827-4830. (c) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett.
2001, 42, 8861-8864. (d) Huck, W. T. S.; van Veggel, F. C. J. M.;
Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1995, 114, 273-276.
(9) Hui, J. K.-H.; MacLachlan, M. J. Chem. Commun. 2006, 2480-2482.
(10) (a) Curreli, S.; Escudero-Ada´n, E. C.; Benet-Buchholz, J.; Kleij,
A. W. J. Org. Chem. 2007, 72, 7018-7021. (b) Holbach, M.; Zheng, X.;
Burd, C.; Jones, C. W.; Weck, M. J. Org. Chem. 2006, 71, 2903-2906.
(c) Dalla Cort, A.; Gasparrini, F.; Lunazzi, L.; Mandolini, L.; Mazzanti,
A.; Pasquini, C.; Pierini, M.; Rompietti, R.; Schiaffino, L. J. Org. Chem.
2005, 70, 8877-8883.
Condensation of benzoin with catechol at 260 °C afforded
tetraphenyl-o-benzodifuran 5 in 25% yield. Oxidation with
CrO3 followed by hydrolysis of the benzoate ester gave 6.
(11) Dalla Cort, A.; Mandolini, L.; Palmieri, G.; Pasquini, C.; Schiaffino,
L. Chem. Commun. 2003, 2178-2179.
(13) Fries rearrangement of phenylbenzoate ester heavily favors acylation
of the para position so a methyl group is introduced to block para acylation.
(14) Schultz, D.; Nitschke, J. R. J. Am. Chem. Soc. 2006, 128, 9887-
9892.
(12) Higuchi, M.; Kanazawa, H.; Yamamoto, K. Org. Lett. 2003, 5, 345-
347.
1256
Org. Lett., Vol. 10, No. 6, 2008

Compound 7 was obtained from the Friedel-Crafts acyla-
tion/demethylation of 1,3-dimethoxybenzene.
Scheme 4. Synthesis of 10 and 11a,b
To examine the reactivity of 6, we reacted 6 with 2 equiv
of p-anisidine in refluxing MeOH, Scheme 3. Compound 8
Scheme 3. Synthesis and Thermal Ellipsoid Plot of Model
Compound 8a
a Ellipsoids are at 50% probability (C ) gray, N ) blue, O )
red, H ) yellow).
was obtained in 82% yield and characterized by common
spectroscopic techniques. Notably, a 3.6 ppm downfield shift
1
is observed in the H NMR spectrum for the phenoxy
resonance after condensing 6 to 8, indicating strong intramo-
lecular H-bonding between the imine and the phenoxy
proton. A single-crystal X-ray diffraction study of 8 further
supports our structural assignment and confirms that both
ketimines are in the E configuration.
It is known that the condensation of a diphenyl ketone
with phenylenediamine stops after only one of the amines
has reacted unless harsh conditions are utilized.18 Thus,
condensation of 6 and 7 with dialkoxyphenylenediamines,
9a,b, afforded diketimine macrocycle precursors 10 and
11a,b, respectively (Scheme 4). These are air stable, bright
red, crystalline compounds that are easily handled.
This macrocycle contains four equivalent N2O2 pockets, each
incorporating one aldimine and one ketimine. Two downfield
phenoxy resonances and one imine resonance are observed
1
in the H NMR spectrum of macrocycle 12. The molecular
ion, found at m/z 1946.4, dominated the matrix assisted laser
desorption ionization time-of-flight (MALDI-TOF) mass
spectrum providing further support for the structural assign-
ment. Macrocycle 12 was isolated in 41% yield via the
Scheme 5. Synthesis of Macrocycle 12
To demonstrate the reversible-irreversible Schiff base
condensation approach to macrocycles with unsymmetrical
N2O2 pockets, diketimine 10 was reacted with 1 equiv of
4,6-diformylresorcinol in refluxing CH3CN/CHCl3, Scheme
5. We anticipated this reaction to give the rectangular [2 +
2] Schiff base macrocycle 12, and this was indeed obtained.
(15) To confirm that this was a kinetic effect and not a thermodynamic
equilibrium, a solution of ketimine 4 and 2 equiv of p-anisidine in CH3CN
was heated at 57 °C for 1.5 h. No exchange was observed under these
conditions.
(16) (a) Dischendorfer, O.; Limontschew, W. Monatsh. Chem. 1949, 80,
741-748. (b) Limontschew, W.; Wiesenberger, E. Monatsh. Chem. 1952,
83, 137-143.
(17) Abdul-Aziz, M.; Auping, J. V.; Meador, M. A. J. Org. Chem. 1995,
60, 1303-1308.
(18) Atkins, R.; Brewer, G.; Kokot, E.; Mockler, G. M.; Sinn, E. Inorg.
Chem. 1985, 24, 127-134.
Org. Lett., Vol. 10, No. 6, 2008
1257

formation of four aldimine bonds with no evidence for
scrambling of the ketimines.
To further illustrate this approach, we synthesized mac-
rocycle 13 by condensing 11a with 3,6-diformylcatechol in
CH3CN/CHCl3 as shown in Scheme 6. The 1H NMR
not usually possible to make isomeric forms of Schiff base
macrocycles since the reversible condensation most often
yields the high-symmetry, thermodynamic product.
Based on our previous studies of [6 + 6] Schiff base
macrocycles made from the reaction of 4,6-diformylresor-
cinol with 1,2-dialkoxy-4,5-diaminobenzenes, the condensa-
tion of 4,6-diformylresorcinol with 11b was anticipated to
lead to a hexagon-shaped macrocycle, with the two reagents
reacting in a 3:3 ratio.9 Surprisingly, however, 4,6-diformyl-
resorcinol and 11b react to give exclusively a [2 + 2] Schiff
base macrocycle, 14, in 26% yield. MALDI-TOF mass
spectrometry clearly indicated the [2 + 2] macrocycle was
selectively formed, with no evidence of the anticipated [3
+ 3] macrocycle.19
Scheme 6. Synthesis of Macrocycles 13 and 14
Macrocycle 14 appears highly strained and must adopt a
nonplanar geometry. Semiempirical calculations indicate that
it will have a bowl shape, but we have not yet been able to
obtain single crystals of this macrocycle.
In conclusion, we have developed a strategy for making
Schiff base macrocycles that have two inequivalent CdN
bonds using a reversible-irreversible aldimine-ketimine
condensation approach. This method gives access to the first
conjugated Schiff base macrocycles containing eight imines
and multiple unsymmetrical N2O2 salphen-like pockets. We
are now exploring the scope of this versatile route and the
incorporation of metals into these new macrocycles. In
addition, we are studying the conformational dynamics of
these macrocycles, including the role of the peripheral phenyl
groups.
Acknowledgment. We thank UBC and NSERC (Dis-
covery Grant) for funding this research. J.J.G. thanks
Gettysburg College for a Research and Professional Devel-
opment Grant.
Supporting Information Available: Synthetic proce-
dures, full characterization, kinetic data, and crystallographic
information. This material is available free of charge via the
Internet at http://pubs.acs.org.
spectrum of 13 was very similar to that for 12 and the
structure was confirmed by mass spectrometry, elemental
analysis, and spectroscopy. Macrocycles 12 and 13 are
isomers, with the ketimine phenyl groups and imine protons
interchanged. Besides enantiomers and diastereomers, it is
OL8001317
(19) MALDI-TOF MS of the filtrate confirmed that no larger cyclization
products were present.
1258
Org. Lett., Vol. 10, No. 6, 2008