Nanoscale borromeates

Article abstract of DOI:10.1021/jo050969b

In addition to a parent zinc(II) Borromean ring (BR) complex, the preparation and characterization of two hexasubstituted BR complexes with either 4-acetoxymethylphenyl or 4-methylthiophenyl substituents associated in turn with all six pyridyl rings has b

Full text of DOI:10.1021/jo050969b

Nanoscale Borromeates
Kelly S. Chichak, Andrea J. Peters, Stuart J. Cantrill, and J. Fraser Stoddart*
The California NanoSystems Institute, and Department of Chemistry and Biochemistry,
University of California, Los Angeles, 405 Hilgard Avenue, Los Angeles, California 90095-1569
stoddart@chem.ucla.edu
Received May 14, 2005
In addition to a parent zinc(II) Borromean ring (BR) complex, the preparation and characterization
of two hexasubstituted BR complexes with either 4-acetoxymethylphenyl or 4-methylthiophenyl
substituents associated in turn with all six pyridyl rings has been achieved convergently in good
yields by appealing to the dynamic features of the reactions between primary amino groups in a
preformed acyclic ligand and 2,6-diformylpyridine. Two molecules of the acyclic ligands react with
two molecules of 2,6-diformylpyridine to form a cyclic [2 + 2] tetraimine in the presence of Zn(II)
ions as templates in 2-propanol at 70 °C. The successful preparation of the two derivatives by
convergent template-directed syntheses opens up opportunities to self-assemble, under equilibrium
control, numerous nanoscale metallo-organic particles with potentially useful properties.
Recently, we reported1 the near-quantitative self-
assembly of a nanoscale Borromean ring (BR) compound
from 18 components by the template-directed formation
of 30 dative bonds and 12 imine bonds. The highly
efficient synthesis involves the coordination of three
interlocked macrocycles, each tetranucleating overall, to
a total of six zinc(II) ions (Figure 1). The successful
construction of this topologically unique molecular struc-
ture2 is rooted in the cooperative interactions that exist
between coordinating metal-ligand bonds, consequent
upon imine bond formation, that are aided and abetted
by 12 π-π stacking interactions between π-donating and
FIGURE 1. Two representations of the Borromean rings as
π-accepting aromatic rings buried in the nether regions
observed (a) in the solid-state X-ray structure of the parent
of the shell of the molecule, which is 2.5 nm in diameter
zinc(II) Borromean ring complex where the arrows indicate
and has an inner cavity of 250 Å3 in volume. The
the 4-positions on the pyridine rings and (b) graphically,
fundamental principles that govern the molecular rec-
ognition associated with the self-assembly are to be found
deep within the realms of dynamic covalent chemistry3,4
with coordination5 and supramolecular6 chemistry help-
highlighting, with handles, the six positions for exohedral
synthetic modifications.
ing to provide the necessary stereoelectronic control
under equilibrating conditions where proof-reading and
error-checking are operative.
Since completing the template-directed synthesis7 of
our first metallo-BR complex1 or Borromeate,8,9 we have
probed the reversible nature associated with the 30
dative and the 12 imine bonds by conducting ligand-
exchange experiments8 in acidic methanolic solutions of
* To whom correspondence should be addressed. Tel: (+1)-310-206-
7078. Fax: (+1)-310-206-1843.
(1) Chichak, K. S.; Cantrill, S. J.; Pease, A. R.; Chiu, S.-H.; Cave,
G. W. V.; Atwood, J. L.; Stoddart, J. F. Science 2004, 304, 1308-1312.
(2) (a) Siegel, J. S. Science 2004, 304, 1256-1258. (b) Schalley, C.
A. Angew. Chem., Int. Ed. 2004, 43, 4399-4401. (c) Cantrill, S. J.;
Chichak, K. S.; Peters, A. J.; Stoddart, J. F. Acc. Chem. Res. 2005, 38,
1-9.
10.1021/jo050969b CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/08/2005
7956
J. Org. Chem. 2005, 70, 7956-7962

Nanoscale Borromeates
SCHEME 1. Synthesis of the Dibenzylammonium Bipyridine Trifluoroacetate Salt (DAB) and BR‚12TFA
the hexachloro-BR and hexabromo-BR derivatives where
the halogen atom labels are sited at the 4-positions of
the six pyridine rings that eventually become the six endo
tridentate bis-Schiff base ligands in the Borromeate
structure. These positions also afford by far the easiest
way to introduce functionality onto the surfaces of these
metallo-organic nanoparticles by carrying out their tem-
plate-directed synthesis7 with 4-substituted 2,6-diformylpy-
ridines in place of the 2,6-diformylpyridine (DFP) in a
reaction between DFP and a diamine (DAB) containing
the incipient six exo bidentate ligands. Here, we report
the synthesis of the parent zinc(II) metallo-BR complex
as well as two derivatives that illustrate the synthetic
potential of this Borromeate structure to serve as a
hexavalent metallo-organic core.
Results and Discussion
The diamine DAB containing a bipyridyl ligand was
-
obtained (Scheme 1) as its nCF3CO2 salt, DAB-Hn‚
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S. L.; Naumann, C.; Jarrosson, T.; Otto, S.; Sanders, J. K. M. Science
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(4) Reversible imine bond formation and exchange has been em-
ployed successfully in the synthesis of rotaxanes. For stoppering
approaches to rotaxanes incorporating imine-containing dumbbells,
see: (a) Cantrill, S. J.; Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1,
1363-1366. (b) Rowan, S. J.; Stoddart, J. F. Org. Lett. 1999, 1, 1913-
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Chem. Eur. J. 2003, 9, 4046-4054. (e) Hogg, L.; Leigh, D. A.; Lusby,
P. J.; Morelli, A.; Parsons, S.; Wong, J. K. Y. Angew. Chem., Int. Ed.
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J. Org. Chem, Vol. 70, No. 20, 2005 7957

Chichak et al.
FIGURE 2. 1H NMR (600 MHz, CD3SOCD3, 25 °C) spectra of the (a) BR‚12TFA and Zn@BR‚14TFA, (b) BR(C6H4CH2OAc)‚
12TFA and Zn@BR(C6H4CH2OAc)‚14TFA, and (c) BR(C6H4SMe)‚12TFA and Zn@BR(C6H4SMe)‚14TFA complexes. The letters
a-l have been designated on structural formulas in Schemes 1 and 3.
nTFA, in five steps starting from 4-methoxybenzylamine.
Its demethylation in refluxing 48% HBr afforded (92%)
the hydrobromide10 1-H‚Br of 4-hydroxybenzylamine.
When this salt was treated with 1.1 equiv of (t-Boc)2O in
a methanolic suspension of NaHCO3, the tert-butyloxy-
carbonyl-protected amine 2 was isolated in 93% yield. In
the meantime, the bipyridyl N,N′-dioxide 3 had been
prepared by the treatment of 4,4′-dinitro-2,2′-bipyridyl
N,N′-dioxide with the potassium salt of 2 in anhydrous
DMF at 80 °C. Compound 4 was obtained in 92% yield
as a result of the catalytic transfer hydrogenolysis11 of 3
using 10% Pd/C with NaH2PO2 as the source of H2 in a
mixture of EtOH/AcOH under mild conditions. In the
final step, DAB-Hn‚nTFA was isolated in almost quan-
titative yield (95%) following t-Boc deprotection using
CF3CO2H.
The template-directed self-assembly of BR‚12TFA was
achieved almost quantitatively in i-PrOH by heating
equimolar amounts (0.10 mM) of DFP, freshly depro-
tected DAB-Hn‚nTFA, and Zn(OAc)2 at 70 °C for 24 h.
From the point of view of controlling stoichiometry, it
proved advantageous to avoid the use of isolated DAB-
Hn‚nTFA as it exists undoubtedly as a mixture of tris-
and tetrakis-TFA salts. By following this protocol, BR‚
12TFA was isolated as an off-white solid in 95% yield by
filtration of the reaction mixture. Close inspection of the
1H NMR spectrum revealed that the product is a mixture
of BR‚12TFA and a complex, Zn@BR‚14TFA, in which
an additional Zn(II) ion has been trapped within the
molecule, in a ratio of 86:14. The admixture is evidenced
by the additional signals observed in the 1H NMR
spectrum (Figure 2a) recorded12 in CD3SOCD3. The large
chemical shift difference for the proton (H-i/i′), which is
pointing into the cavity of the BR12+ dodecacation,
supports the hypothesis that a seventh Zn(II) ion is
(5) (a) Dietrich-Buchecker, C. O.; Sauvage, J.-P.; Kern, J.-M. J. Am.
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Chem. Commun. 2000, 847-848. (g) Gunter, M. J.; Bampos, N.;
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2678-2682. (j) Dietrich-Buchecker, C. O.; Colasson, B.; Fujita, M.; Hori,
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Chem. Soc. 2003, 125, 5717-5725. (k) Arico, F.; Mobian, P.; Kern, J.-
M.; Sauvage, J.-P. Org. Lett. 2003, 5, 1887-1890. (l) Tominaga, M.;
Suzuki, K.; Kawano, M.; Kusukawa, T.; Ozeki, T.; Sakamoto, S.;
Yamaguchi, K.; Fujita, M. Angew. Chem., Int. Ed. 2004, 43, 5621-
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401. (b) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278-286. (c) Lehn,
J.-M. Science 2002, 295, 2400-2403. (d) Reinhoudt, D. N.; Crego-
Calama, M. Science 2002, 295, 2403-2407.
(7) (a) Templated Organic Synthesis; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, Germany, 2000. (b) Breault, G. A.; Hunter,
C. A.; Mayers, P. C. Tetrahedron 1999, 55, 5265-5293. (c) Hubin, T.
J.; Busch, D. H. Coord. Chem. Rev. 2000, 200, 5-52. (d) Stoddart, J.
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(8) Chichak, K. S.; Cantrill, S. J.; Stoddart, J. F. Chem. Commun.
2005, 3391-3393.
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386.
(12) A much better resolved 1H NMR spectrum (see the Supporting
Information) can be obtained by recording it in CD3OD solution. The
reason for using CD3SOCD3 as the solvent relates to the need to make
comparisons with two other hexasubstituted derivatives which are not
both easily soluble in CD3OD.
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Nanoscale Borromeates
SCHEME 2. Synthesis of the 4-Substituted
2,6-Diformylpyridinesa
up to 10 possible different products. Thus, it is much
easier to prepare hexasubstituted homo-BR complexes by
following the protocol of pre-assembly covalent modifica-
tions of the components, provided that the substituents
which are being introduced are stable to the conditions
of the self-assembly process. In this manner, all of the
kinetic penalties that accompany covalent bond-forming
reactions are paid before the assembly step that operates
under thermodynamic control. It is an approach that
makes it relatively easy to introduce (Figure 1) substit-
uents onto the 4-positions of the 2,6-diformylpyridine
component prior to the thermodynamically controlled
self-assembly step that will then lead to the formation
of the hexasubstituted homo-BR derivatives in high
yields.
The relative ease by which large quantities of 4-bromo-
2,6-diformylpyridine14 (5) can be synthesized singles it
out as an ideal candidate for introducing substituents
onto the periphery of the BR scaffold by employing the
efficient Suzuki-type palladium-catalyzed cross-coupling
reactions of aryl boronic acids. The synthesis of two
4-aryl-2,6-diformylpyridines shown in Scheme 2 follows
this protocol. 4-Acetoxymethylphenylboronic acid15 (6)
and 4-methylthiophenylboronic acid16 (7) were coupled
to 5 to afford the aryl-substituted dialdehydes 8 and 9
in good yields, respectively. In the case of 8, reactions
that were carried out in aqueous THF had a detrimental
effect on the yield, suggesting that significant amounts
of the ester group was hydrolyzed under increasingly
aqueous conditions. The hydrolysis of the ester group was
minimized by carrying out this coupling reaction in
PhMe/H2O (30:4) saturated with NaHCO3, conditions
which reduce the total water content in the organic
phase, affording 8 in excellent yields.
The formation of the corresponding BR complexes
incorporating these aryl substituents is outlined in
Scheme 3. They are assembled from equimolar mixtures
(0.07 mM) of either 8 or 9 with Zn(OAc)2 and the freshly
deprotected diaminobipyridyl ligand DAB-Hn‚nTFA in
alcoholic solutions which were heated at 70 °C for 24 h.
In both cases, the aryl-BR complexes BR(C6H4CH2OAc)6‚
12TFA and BR(C6H4SMe)6‚12TFA precipitated out from
a Key: (i) Pd(PPh3)4/NaHCO3/PhMe/H2O, 90 °C, 15 h; (ii)
Pd(PPh3)4/NaHCO3/H2O/THF, 85 °C, 15 h.
trapped therein. Other protons (H-a/a′, H-b/b′, H-c/c′, H-e/
e′, H-f/f′) on the periphery of the molecule are only ever
so slightly shifted, depending on whether the cavity is
occupied by a Zn(II) ion or not. The appearance13 of
additional peaks corresponding to Zn@BR‚14TFA in the
ESI mass spectrum were not observed. Only peaks at m/z
1465, 1070, and 834 corresponding to [M - 3TFA]3+, [M
- 4TFA]4+ and [M - 5TFA]5+, respectively, where M
represents the fully assembled BR‚12TFA complex, were
present in the spectrum.
In principle, it is conceivable to try to produce deriva-
tives of BR‚12TFA by carrying out either pre-assembly
or post-assembly covalent modifications. Although it does
depend on what type (kinetically or thermodynamically
controlled) of chemical reactions are employed, post-
assembly modifications will, more often than not, be done
under kinetic control, leading to a complex mixture of
SCHEME 3. Self-Assembly of the Hexasubstituted Borromeates
J. Org. Chem, Vol. 70, No. 20, 2005 7959

Chichak et al.
1
further purification. H NMR (500 MHz, D2O, 25 °C): δ 3.95
(s, 2H), 6.79 (d, J ) 8.6 Hz, 2H), 7.19 (d, J ) 8.6 Hz, 2H).
the reaction mixtures and were isolated by filtering the
solutions to afford air-stable solids in 97% and 89% yields,
respectively. The H NMR spectra of these products in
1
tert-Butyl (4-Hydroxybenzyl)carbamate (2). Di-tert-
butyl dicarbonate (18.5 g, 84.8 mmol) was added with stirring
under an atmosphere of argon to a solution of 1-H‚Br (16.0
g, 78.4 mmol) and NaHCO3 (26.3 g, 313 mmol) in MeOH (200
mL) at room temperature. After the reaction mixture was
stirred for 24 h, it was filtered to remove excess of NaHCO3.
The solvents were removed under reduced pressure, and the
oily residue was purified by column chromatography [SiO2:
EtOAc/hexanes (1:4)] to afford 2 as a yellow oil. Yield: 16.2 g,
CD3SOCD3 revealed (Figure 2b,c) that they have been
isolated as mixtures of the empty BR compounds and
filledseach with a Zn(II) ionsBR complexes. A set of
duplicate signals (primed letters) of lower intensities,
corresponding to the Zn@BR complexes are evident in the
spectrum. Apart from these additional signals, singlets
at δ 9.02 and 9.00 ppm for the imine protons in
BR(C6H4CH2OAc)6‚12TFA and BR(C6H4SMe)6‚12TFA
are consistent with the successful formation of the
chelated bis-Schiff base tridentate ligands. In addition
to the presence of these diagnostic signals for the highly
symmetrical BR complexes, the two pairs of protons for
the aryl substituents on the DAB units are significantly
shifted upfield, a situation that is consistent with them
being π-stacked around matching bipyridyl ligands in the
orthogonally disposed macrocycle. All this molecular
recognition is evident in the solid-state structure (Figure
1) of BR‚12TFA. ESI mass spectrometric analysis of
these two products revealed three major peaks at m/z
values at 1760, 1292, and 1011 for BR(C6H4CH2OAc)6‚
12TFAandalsoat1709,1253,and980forBR(C6H4SMe)6‚
1
93%. H NMR (500 MHz, CD2Cl2, 25 °C): δ 1.46 (s, 9H), 4.19
(d, J ) 5.5 Hz, 2H), 5.09 (bs, 1H), 6.77 (d, J ) 8.5 Hz, 2H),
6.96 (bs, 1H), 7.09 (d, J ) 8.1 Hz, 2H). 13C NMR (125 MHz,
CD2Cl2, 25 °C): δ 28.5, 44.4, 115.8, 129.1, 130.8, 156.0. HRMS
(MALDI): m/z 246.1100 [M + Na]+.
4,4′-(tert-Butyl (4-hydroxybenzyloxy)carbamate)-2,2′-
bipyridyl N,N′-Dioxide (3). Solid K2CO3 (8.0 g, 58 mmol)
was added to a stirred solution of 2 (9.00 g, 40.3 mmol) and
4,4′-dinitro-2,2′-bipyridyl N,N′-dioxide (4.50 g, 16.2 mmol) in
anhydrous DMF (30 mL) under an argon atmosphere, and the
reaction mixture was heated at 80 °C for 15 h. Thereafter, the
solution was cooled to room temperature, and the solvents
were removed under reduced pressure, leaving a yellow-brown
solid residue. H2O (300 mL) was added to this residue, and
the resulting mixture was sonicated until a suspended solid
was produced. The suspension was removed by filtration,
washed with H2O, and dried to afford a light-yellow solid (10.1
g). The solid was then dissolved in CH2Cl2 (200 mL) and
diluted with EtOAc (300 mL). This solution was brought to a
boil and concentrated to 300 mL. The title compound 3
precipitates from the mixture upon cooling and is collected by
filtration and dried. Yield: 8.03 g, 78%. Mp: 217-218 °C
(EtOAc). 1H NMR (500 MHz, CD2Cl2, 25 °C): δ 1.44 (s, 18H),
4.08 (d, J ) 5.8 Hz, 4H), 5.12 (bs, 2H), 6.92 (dd, J ) 3.5, 7.3
Hz, 2H), 7.08 (d, J ) 8.5 Hz, 4H), 7.15 (d, J ) 3.5 Hz, 2H),
7.34 (d, J ) 8.5 Hz, 4H), 8.12 (d, J ) 7.3 Hz, 2H). 13C NMR
(125 MHz, CD2Cl2, 25 °C): δ 28.5, 44.1, 115.8, 116.6, 120.8,
129.6, 137.5, 141.1, 143.0, 153.7, 155.2. HRMS (MALDI): m/z
631.2762 [M + H]+.
4,4′-Bis(4-tert-butyl-N-phenoxycarbamate)-2,2′-bipyri-
dine (4). The following procedure is a modified one based on
that reported11 for the deoxygenation of 2,2′-bipyridyl N,N′-
dioxide. An excess of NaH2PO2 (5.00 g, 55.0 mmol) was added
in one portion to a three-necked flask equipped with a
condenser containing a stirred suspension of 3 (5.00 g, 7.93
mmol) and 10% Pd/C (1.00 g) in 75/15 EtOH/AcOH (90 mL).
The reaction flask was sealed with a balloon to prevent the
loss of the H2 gas which evolves from the decomposition of
NaH2PO2, and the mixture was heated at 70 °C for 15 h. The
reaction mixture was cooled to room temperature and filtered
through Celite. The filter cake was washed with CH2Cl2 (3 ×
100 mL). The filtrates were combined, and the volume was
concentrated to 50 mL under reduced pressure, giving a light
yellow solution. The AcOH was neutralized by adding solid
NaHCO3 (6 g) in H2O (50 mL). The solution was concentrated
to dryness, producing a beige product which was suspended
in H2O, collected by filtration, washed with H2O, and dried.
Yield: 4.32 g, 92%. The crude product was recrystallized from
EtOAc/hexanes, affording 4 as fine white needles. Yield: 3.72
g, 78%. Mp: 158-160 °C. 1H NMR (500 MHz, CD2Cl2, 25 °C)
δ 1.45 (s, 18H), 4.33 (d, J ) 7.1 Hz, 4H), 5.04 (bs, 2H), 6.86
(dd, J ) 3.5, 7.3 Hz, 2H), 7.11 (d, J ) 8.5 Hz, 4H), 7.37 (d, J
) 8.5 Hz, 4H), 7.92 (d, J ) 3.5 Hz, 2H), 8.44 (d, J ) 7.3 Hz,
2H). 13C NMR (125 MHz, CD2Cl2, 25 °C) δ 28.5, 44.2, 109.3,
112.9, 121.2, 129.5, 137.0, 151.0, 153.7, 158.1, 166.1. HRMS
(MALDI): m/z 621.2684 [M + Na]+.
12TFA, arising from the [M - 3TFA]3+, [M - 4TFA]4+
,
and [M - 5TFA]5+ ions, respectively, where M represents
the mass of the fully assembled BR complexes.
Thus, we have prepared and characterized, in addition
to the parent Borromeate BR‚12TFA, two new hexasub-
stituted BR complexes as a result of conducting template-
directed syntheses, starting from readily available com-
ponents. Suzuki cross-coupling reactions make it possible
to append substituents to the 4-position on DFP. The
synthetic approach, which has been developed success-
fully and reported here in detail, will surely aid future
synthetic modifications of these nanoscale metallo-
organic particles.
Experimental Section
4-Hydroxybenzylammonium Bromide (1-H‚Br). The
following procedure is a modified one based on that reported10
in the patent literature. When 4-methoxybenzylamine (11.6
g, 84.6 mmol) was added with stirring to 48% HBr (30 mL), a
precipitate was formed. Since an extremely exothermic reaction
ensues, the addition was done very slowly. The mixture was
then stirred under reflux for 6 h before being cooled to room
temperature and concentrated to dryness, giving a light pink
solid. MeCN (20 mL) was added to this residue, and the
product 1-H‚Br was collected by filtration and dried under
vacuum. Yield: 16.2 g, 92%. The product was identified by 1H
NMR spectroscopy and employed in the next step without
(13) Samples which contain upwards of 50% of the Zn@BR‚14TFA
complex do reveal peaks at m/z 1563 and 1143 corresponding to [M -
3TFA]3+ and [M - 4TFA]4+ ions, respectively, where M represents the
mass of the Zn@BR‚14TFA complex. See ref 1.
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DAB-Hn‚nTFA. The Boc protecting groups in 4 were
removed by the addition of CF3CO2H (4 mL) to solid 4 (1.00 g,
1.67 mmol) with stirring at room temperature for 10 min. The
reaction mixture was concentrated to dryness, leaving a sticky
residue. The excess of CF3CO2H was removed by three
7960 J. Org. Chem., Vol. 70, No. 20, 2005

Nanoscale Borromeates
repeated additions and removal of MeOH (20 mL) by rotary
evaporation under reduced pressure at 50 °C, leaving a pink
sticky residue. This residue was treated with CH2Cl2, and the
solvent was removed by rotary evaporation under reduced
pressure at 40 °C until a light pink amorphous solid remained
that is moisture sensitive. Yield of crude DAB-Hn‚nTFA: 1.32
g, 95%. 1H NMR (500 MHz, CD3OD, 25 °C): δ 4.20 (s, 4H),
7.18 (dd, J ) 3.5, 7.3 Hz, 2H), 7.33 (d, J ) 8.5 Hz, 4H), 7.64
(d, J ) 8.5 Hz, 4H), 8.06 (d, J ) 3.5 Hz, 2H), 8.66 (d, J ) 7.3
Hz, 2H). 13C NMR (125 MHz, CD3OD, 25 °C) δ 43.6, 112.8,
114.8, 117.9 (q, J ) 291 Hz, TFA), 122.6, 132.8, 133.0, 149.8,
152.2, 155.2, 162.3 (q, J ) 35.5 Hz, TFA) 170.0. HRMS (ESI):
m/z 399.1836 (100) [M - 4CF3CO2H + H]+, 819.3428 (62) [2M
- 8CF3CO2H + Na]+.
MHz, CD3SOCD3, 25 °C): δ 4.75 (bs, 24H), 6.46 (bs, 12H), 6.55
(bs, 48H), 6.61 (bd, J ) 6.6 Hz, 24H), 6.70 (bd, 24H), 7.29 (bs,
12H), 7.95 (bs, 12H), 8.38 (d, J ) 7.2 Hz, 12H), 8.43 (d, J )
7.8 Hz, 12H), 8.66 (t, J ) 7.2 Hz, 6H), 8.70 (t, J ) 7.8 Hz, 6H),
9.03 (s, 12H), 9.05, (s, 12H). 13C NMR of BR‚12TFA (150 MHz,
CD3OD, 25 °C): δ 63.1, 112.6, 113.9, 117.9 (q, J ) 296 Hz,
TFA), 122.3, 130.8, 131.2, 135.1, 145.5, 148.2, 151.7, 153.3,
162.0, 162.5 (q, J ) 34.6 Hz, TFA) 169.8. 13C NMR data for
BR‚12TFA and Zn@BR‚14TFA (125 MHz, CD3SOCD3, 25
°C): δ 60.8, 109.7, 111.4, 114.3, 116.9 (q, J ) 298 Hz, TFA),
120.6, 129.6, 130.8, 133.6, 144.2, 146.2, 146.6, 148.9, 149.9,
151.1, 153.3,158.1 (q, J ) 31.6 Hz, TFA),160.7, 163.8, 167.3.
HRMS (ESI): m/z 1465.1902 (10) [M - 3CF3CO2]3+, 1070.1398
(100) [M - 4CF3CO2]4+, 833.7088 (50) [M - 5CF3CO2]5+
.
4-(4-Acetoxymethylphenyl)-2,6-diformylpyridine (8).
4-Bromo-2,6-diformylpyridine (5) (500 mg, 2.34 mmol), 4-ac-
etoxymethylphenyl boronic acid (6) (453 mg, 2.34 mmol), and
tetrakistriphenylphosphine palladium(0) (265 mg, 0.23 mmol)
were added to a degassed PhMe (30 mL) solution containing
NaHCO3 (2.0 g) and H2O (4 mL). The reaction mixture was
then heated under an inert atmosphere of argon at 90 °C for
15 h. The solvents were removed by rotary evaporation, and
the resulting residue was purified by column chromatography
[SiO2: CH2Cl2] to yield the title compound 8 as a white solid
(610 mg). Recrystallized from CH2Cl2/hexanes (524 mg).
Yield: 79%. Mp: 139-141 °C. 1H NMR (500 MHz, CD2Cl2, 25
°C): δ 2.13 (s, 3H), 5.17 (s, 2H), 7.54 (d, J ) 8.4 Hz, 2H), 7.79
(d, J ) 8.4 Hz, 2H), 8.39 (s, 2H), 10.20 (s, 2H). 13C NMR (150
MHz, CD2Cl2, 25 °C): δ 21.1, 65.7, 123.0, 127.7, 129.2, 136.0,
139.0, 150.9, 154.1, 170.9, 192.8. HRMS (EI): m/z 283.0850.
BR(C6H4CH2OAc)6‚12TFA and Zn@BR(C6H4CH2OAc)6‚
14TFA. Compound 4 (220 mg, 0.367 mmol) was dissolved in
TFA (2 mL) and stirred at room temperature for 10 min.
Excess TFA was removed by rotary evaporation under reduced
pressure followed by subsequent additions and removals of
MeOH (3 × 5 mL), leaving a pink tar. Zn(OAc)2 (67.0 mg, 0.367
mmol) was added to a stirred i-PrOH solution (5 mL) contain-
ing the freshly deprotected DAB-Hn‚nTFA, followed by 8 (104
mg, 0.367 mmol) dissolved in CH2Cl2 (1 mL). The reaction
mixture was first heated to remove CH2Cl2 solvents and then
at 70 °C for 24 h, producing an off-white colored precipitate
which was removed by filtration, washed with i-PrOH and
Et2O, and dried to afford the title compound as a mixture of
BR(C6H4CH2OAc)6‚12TFA and Zn@BR(C6H4CH2OAc)6‚
14TFA (86:14) as a light orange powder. Yield: 336 mg, 97%.
The product can be crystallized from a methanolic solution into
1
which Et2O was allowed to diffuse slowly. H NMR data for
4-(4-Methylthiophenyl)-2,6-diformylpyridine (9). 4-Bro-
mo-2,6-diformylpyridine (5) (500 mg, 2.34 mmol), 4-methyl-
thiophenyl boronic acid (7) (453 mg, 2.34 mmol), and tetraki-
striphenylphosphinepalladium(0) (265 mg, 0.23 mmol) were
added to a degassed 1:1 THF/H2O (20 mL) solution containing
NaHCO3 (2.0 g). The reaction mixture was then heated under
an inert atmosphere of argon at 85 °C for 15 h. The reaction
mixture was transferred to a separatory funnel containing H2O
(50 mL), and the aqueous solution was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were dried (MgSO4)
and filtered, and the solvents were removed by rotary evapora-
tion. The resulting residue was purified by column chroma-
tography [SiO2: CH2Cl2] to yield the title compound 9 as a
light yellow solid. Recrystallized from EtOAc/hexanes (502
mg). Yield: 83%. Mp: 168-170 °C. 1H NMR (500 MHz,
CD2Cl2, 25 °C): δ 2.13 (s, 3H), 5.17 (s, 2H), 7.54 (d, J ) 8.4
Hz, 2H), 7.79 (d, J ) 8.4 Hz, 2H), 8.39 (s, 2H), 10.20 (s, 2H).
13C NMR (150 MHz, CD2Cl2, 25 °C): δ 21.1, 65.7, 123.0, 127.7,
129.2, 136.0, 139.0, 150.9, 154.1, 170.9, 192.8. HRMS (EI): m/z
257.0512.
BR(C6H4CH2OAc)6‚12TFA (600 MHz, CD3OD, 25 °C): δ 2.12
(s, 18H), 4.86 (s, 24H), 5.23 (s, 12H), 6.52 (bs, 12 H), 6.71 (d,
J ) 7.8 Hz, 24H), 6.76 (d, J ) 7.8 Hz, 24H), 7.65 (d, J ) 8.4
Hz, 12H), 8.00 (d, J ) 4.2 Hz, 12H), 8.03 (d, J ) 8.4 Hz, 12H),
8.63 (s, 12H), 8.93 (s, 12H). 1H NMR data for Zn@BR-
(C6H4CH2OAc)6‚14TFA (600 MHz, CD3OD, 25 °C): δ 2.14 (s,
18H), 4.76 (d, J ) 14 Hz, 12H), 4.81 (d, J ) 14 Hz, 12H), 5.25
(s, 12H), 6.58 (d, J ) 8.6 Hz, 24H), 6.63 (d, J ) 8.6 Hz, 24H),
7.31 (bs, 12H), 7.67 (d, J ) 8.6 Hz, 12H), 8.06 (d, J ) 8.6 Hz,
12H), 8.16 (bs, 12H), 8.23 (d, J ) 2.1 Hz, 12H), 8.65 (s, 12H),
8.94 (s, 12H). 1H NMR data for BR(C6H4CH2OAc)6‚12TFA
and Zn@BR(C6H4CH2OAc)6‚14TFA (600 MHz, CD3SOCD3,
25 °C): δ 2.12 (s, 12H), 2.14 (s, 12H), 4.78 (bs, 24H), 5.21 (s,
12H), 5.24 (s, 12H), 6.46 (bs, 12H), 6.56 (bs, 48H), 6.62 (bd, J
) 6.6 Hz, 24H), 6.73 (bd, J ) 6.6 Hz, 24H), 7.32 (bs, 12H),
7.67 (d, J ) 8.4 Hz, 12H), 7.70 (d, J ) 8.4 Hz, 12H), 8.07 (d,
J ) 8.4 Hz, 12H), 8.12 (d, J ) 8.4 Hz, 12H), 8.76 (s, 12H),
8.84(s,12H),9.02,(s,12H).13CNMRdataforBR(C6H4CH2OAc)6‚
12TFA and Zn@BR(C6H4CH2OAc)6‚14TFA (150 MHz, CD3-
SOCD3, 25 °C): δ 20.7, 61.0, 64.8, 109.8, 111.4, 115.5, 117.0
(q, J ) 298 Hz, TFA), 120.7, 126.6, 127.6, 128.9, 129.0, 129.6,
133.6, 134.5, 139.6, 146.9, 147.3, 149.0, 150.0, 151.2, 153.4,
153.9, 158.2 (q, J ) 32.6 Hz, TFA), 160.6, 163.8, 167.4 170.3.
HR-ESI-MS: m/z 1760.9303 (50) [M - 3CF3CO2]3+, 1292.4819
BR‚12TFA and Zn@BR‚14TFA. Compound 4 (600 mg,
1.00 mmol) was dissolved in TFA (5 mL) and stirred at room
temperature for 10 min. Excess TFA was removed by rotary
evaporation under reduced pressure followed by subsequent
additions and removals of MeOH (3 × 5 mL), leaving a pink
tar. Zn(OAc)2 (183.0 mg, 1.00 mmol) was added to a stirred
i-PrOH (10 mL) solution containing the freshly deprotected
DAB-Hn‚nTFA, followed by DFP (135 mg, 1.00 mmol), and
the reaction mixture was heated at 70 °C for 24 h, producing
an off-white precipitate which was removed by filtration,
washed with i-PrOH and Et2O, and dried to afford the title
compound as a mixture of BR‚12TFA and Zn@BR‚14TFA (86:
14) as an off-white powder. Yield: 754 mg, 95%. 1H NMR data
for BR‚12TFA (600 MHz, CD3OD, 25 °C): δ 4.84 (s, 24H), 6.50
(bs, 12H), 6.69 (d, J ) 8.5 Hz, 24H), 6.73 (d, J ) 8.5 Hz, 24H),
7.97 (d, J ) 2.4 Hz, 12H), 8.31 (d, J ) 7.8 Hz, 12H), 8.61 (t, J
) 7.8 Hz, 6H), 8.89 (s, 12H). 1H NMR data for Zn@BR‚14TFA
(600 MHz, CD3OD, 25 °C): δ 4.74 (d, J ) 14 Hz, 12H), 4.80
(d, J ) 14 Hz, 12H), 6.57 (d, J ) 8.4 Hz, 24H), 6.61 (d, J ) 8.4
Hz, 24H), 7.30 (d, J ) 5.4 Hz, 12H), 8.20 (d, J ) 2.4 Hz, 12H),
8.34 (d, J ) 7.8 Hz, 12H), 8.63 (t, J ) 7.8 Hz, 6H), 8.92 (s,
(100) [M - 4CF3CO2]4+, 1011.3981 (20) [M - 5CF3CO2]5+
.
BR(C6H4SMe)6‚12TFA and Zn@BR(C6H4SMe)6‚14TFA.
Compound 4 (209 mg, 0.350 mmol) was dissolved in TFA (2
mL) and stirred at room temperature for 10 min. Excess TFA
was removed by rotary evaporation under reduced pressure,
followed by subsequent additions and removals of MeOH (3 ×
5 mL), leaving a pink tar. Zn(OAc)2 (64.0 mg, 0.350 mmol) was
added to a stirred i-PrOH solution (5 mL) containing the
freshly deprotected DAB-Hn‚nTFA, followed by 9 (90 mg, 0.350
mmol) dissolved in CH2Cl2 (1 mL). The reaction mixture was
first heated to remove CH2Cl2 solvents and then at 70 °C for
24 h producing a yellow precipitate which was removed by
filtration, washed with washed with i-PrOH and Et2O, and
dried to afford the title compound as a mixture of BR-
(C6H4SMe)6‚12TFA and Zn@BR(C6H4SMe)6‚14TFA (74:26)
as a yellow solid. Yield: 282 mg, 89%. 1H NMR (600 MHz,
CD3OD, 25 °C): δ 2.59 (s, 18H), 4.86 (s, 24H), 5.23 (s, 12H),
1
12H). H NMR data for BR‚12TFA and Zn@BR‚14TFA (600
J. Org. Chem, Vol. 70, No. 20, 2005 7961

Chichak et al.
6.52 (bs, 12 H), 6.72 (d, J ) 7.8 Hz, 24H), 6.76 (d, J ) 7.8 Hz,
24H), 7.52 (d, J ) 8.4 Hz, 12H), 8.00 (m, 24H), 8.63 (s, 12H),
8.93 (s, 12H). H NMR data for BR(C6H4SMe)6‚12TFA and
160.6, 163.8, 167.4. HRMS (ESI): m/z 1709.3462 (20) [M -
3CF3CO2]3+, 1253.6640 (100) [M - 4CF3CO2]4+, 980.3720 (30)
[M - 5CF3CO2]5+
.
1
Zn@BR(C6H4SMe)6‚14TFA (600 MHz, CD3SOCD3, 25 °C): δ
2.59 (s, 12H), 2.61 (s, 12H), 4.78 (bs, 24H), 6.46 (bs, 12H), 6.56
(bs, 48H), 6.62 (bd, J ) 6.6 Hz, 24H), 6.73 (bd, J ) 6.6 Hz,
24H), 7.32 (bs, 12H), 7.54 (d, J ) 8.4 Hz, 12H), 7.57 (d, J )
8.4 Hz, 12H), 7.96 (bs, 12H), 7.99 (d, J ) 8.4 Hz, 12H), 8.08
(d, J ) 8.4 Hz, 12H), 8.75 (s, 12H), 8.83 (s, 12H), 9.00, (s, 12H).
13C NMR (150 MHz, CD3SOCD3, 25 °C): δ 14.1, 61.0, 109.8,
111.4, 115.3, 117.0 (q, J ) 299 Hz, TFA), 120.7, 125.9, 126.2,
127.7, 129.6, 130.7, 130.7, 133.6, 143.4, 143.4, 146.9, 147.3,
149.0, 150.0, 151.2, 153.4, 153.6, 158.2 (q, J ) 31.8 Hz, TFA),
Acknowledgment. This work was supported in
part by a National Science Foundation (NSF) grant
(CHE0317170) and two NSF equipment grants
(CHE9974928 and CHE0092036).
Supporting Information Available: 1H NMR spectra of
BR‚12TFA and Zn@BR‚14TFA and BR(C6H4CH2OAc)6‚
12TFA and Zn@BR(C6H4CH2OAc)6‚14TFA. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050969B
7962 J. Org. Chem., Vol. 70, No. 20, 2005