Synthesis and self-assembly of functionalized donor-σ-acceptor molecules

Article abstract of DOI:10.1021/ol047597y

(Chemical Equation Presented) 3,5,7-Tris(arylmethyl)-1-aza-adamantanetrione donor-σ-acceptor compounds have been synthesized in four steps. Computational and ¹H NMR analyses rationalize the solubility, gelation, and conformational properties of the C₃-symmetric molecules toward employing σ-coupled donor-acceptor interactions in molecular self-assembly.

Full text of DOI:10.1021/ol047597y

ORGANIC
LETTERS
2005
Vol. 7, No. 3
443-446
Synthesis and Self-Assembly of
Functionalized Donor−σ−Acceptor
Molecules
Hengfeng Li, Edwin A. Homan, Andrew J. Lampkins, Ion Ghiviriga, and
Ronald K. Castellano*
Department of Chemistry, UniVersity of Florida, P.O. Box 117200,
GainesVille, Florida 32611-7200
castellano@chem.ufl.edu
Received November 22, 2004
ABSTRACT
3,5,7-Tris(arylmethyl)-1-aza-adamantanetrione donor−σ−acceptor compounds have been synthesized in four steps. Computational and 1H NMR
analyses rationalize the solubility, gelation, and conformational properties of the C3-symmetric molecules toward employing
σ-coupled donor−
acceptor interactions in molecular self-assembly.
Donor-σ(spacer)-acceptor molecules1 are unique alterna-
tives to traditional π-conjugated chromophores in applica-
tions ranging from nonlinear optics2,3 to unimolecular
electrical rectification;4 a high transparency in the visible
region and significantly dipolar excited state5 underlie their
function. While well-studied at the molecular level, only
recently have these chromophores been considered as build-
common motif within the donor-σ-acceptor class features
a nitrogen donor atom and carbonyl π-acceptor at opposite
ends of a saturated three-carbon spacer;8 the resulting
through-bond interactions1b are apparent even in the ground
state where they can influence the stereoselectivity of
addition to the carbonyl group9 and bias conformation at
nitrogen.10 We have initiated a research study that employs
such donor-σ-acceptor chromophores in supramolecular
ing blocks for advanced materials and polymers.6,7
A
(1) (a) Cookson, R. C.; Henstock, J.; Hudec, J. J. Am. Chem. Soc. 1966,
88, 1060-1062. (b) Hoffmann, R.; Imamura, A.; Hehre, W. J. J. Am. Chem.
Soc. 1968, 90, 1499-1509.
(7) Kawashima, N.; Kameyama, A.; Nishikubo, T.; Nagai, T. J. Polym.
Sci., Part A: Polym. Chem. 2001, 39, 1764-1773.
(8) (a) Verhoeven, J. W.; Dirkx, I. P.; de Boer, T. J. Tetrahedron Lett.
1966, 7, 4399-4404. (b) Dekkers, A. W. J.; Verhoeven, J. W.; Speckamp,
W. N. Tetrahedron 1973, 29, 1691-1696. (c) Worrell, C.; Verhoeven, J.
W.; Speckamp, W. N. Tetrahedron 1974, 30, 3525-3531. (d) Pasman, P.;
Verhoeven, J. W.; de Boer, T. J. Tetrahedron 1976, 32, 2827-2830.
(9) (a) Hahn, J. M.; Le Noble, W. J. J. Am. Chem. Soc. 1992, 114, 1916-
1917. (b) Coxon, J. M.; Houk, K. N.; Luibrand, R. T. J. Org. Chem. 1995,
60, 418-427. (c) Gung, B. W.; Wolf, M. A. J. Org. Chem. 1996, 61, 232-
236. (d) Tomoda, S.; Senju, T. Tetrahedron 1999, 55, 5303-5318. (e)
Yadav, V. K.; Senthil, G.; Jeyaraj, D. A. Tetrahedron 1999, 55, 14211-
14218.
(2) (a) Verbiest, T.; Houbrechts, S.; Kauranen, M.; Clays, K.; Persoons,
A. J. Mater. Chem. 1997, 7, 2175-2189. (b) Rao, J. L.; Bhanuprakash, K.
Synth. Met. 2003, 132, 315-324.
(3) (a) Schuddeboom, W.; Krijnen, B.; Verhoeven, J. W.; Staring, E. G.
J.; Rikken, G.; Oevering, H.; Jonker, S. A. Abstr. Pap. Am. Chem. Soc.
1991, 202, 222-POLY. (b) Schuddeboom, W.; Krijnen, B.; Verhoeven, J.
W.; Staring, E. G. J.; Rikken, G.; Oevering, H. Chem. Phys. Lett. 1991,
179, 73-78.
(4) (a) Aviram, A.; Ratner, M. A. Chem. Phys. Lett. 1974, 29, 277-
283. (b) Metzger, R. M. Chem. ReV. 2003, 103, 3803-3834.
(5) Wasielewski, M. R. Chem. ReV. 1992, 92, 435-461.
(6) (a) Oosterbaan, W. D.; van Gerven, P. C. M.; van Walree, C. A.;
Koeberg, M.; Piet, J. J.; Havenith, R. W. A.; Zwikker, J. W.; Jenneskens,
L. W.; Gleiter, R. Eur. J. Org. Chem. 2003, 3117-3130. (b) Oosterbaan,
W. D.; Kaats-Richters, V. E. M.; Jenneskens, L. W.; Van Walree, C. A. J.
Polym. Sci., Part A: Polym. Chem. 2004, 42, 4775-4784.
(10) (a) Krijnen, B.; Beverloo, H. B.; Verhoeven, J. W.; Reiss, C. A.;
Goubitz, K.; Heijdenrijk, D. J. Am. Chem. Soc. 1989, 111, 4433-4440. (b)
De Ridder, D. J. A.; Goubitz, K.; Schenk, H.; Krijnen, B.; Verhoeven, J.
W. HelV. Chim. Acta 2003, 86, 799-811. (c) De Ridder, D. J. A.; Goubitz,
K.; Schenk, H.; Krijnen, B.; Verhoeven, J. W. HelV. Chim. Acta 2003, 86,
812-826.
10.1021/ol047597y CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/13/2005

Scheme 1. Synthesis of Donor-σ-Acceptor
1-Aza-adamantanetriones from Substituted Phloroglucinol
Derivatives14
Table 1. Synthesis of
Tris(arylmethyl)-1-aza-adamantanetrionesa
architectures; for example, reversible assemblies wherein the
inherent dipole of the molecules should facilitate their one-
dimensional organization in solution, an important morphol-
ogy for gels,11 liquid crystals,12 and hydrogen-bonded
assemblies13 that display polar order.
% yield
of 5b
% yield
of 1b,c
entry
R1
R2
R3
R4
a
b
c
d
e
f
g
h
i
H
CH3
H
H
H
i-Pr
H
H
H
H
CH3
H
CH3
H
H
H
H
H
H
H
CH3
H
H
t-Bu
F
H
90
65
61
62
43
48
64
33
44
The shape, symmetry, and rapid entry into 1-aza-adaman-
tanetriones 1 made them an attractive scaffold to initiate our
studies. Elegant work by Nicholas Risch and co-workers
demonstrated the single-step conversion of 2,4,6-trialkyl-
phloroglucinol derivatives 2 (where R ) Me, Et, and i-Pr)
to 3,5,7-trisubstituted 1-aza-adamantanetriones 1 via a Man-
nich-type reaction effected by hexamethylenetetramine
(HMTA, Scheme 1).14 Three carbonyl groups and three “R”
groups converge on the concave underside of the adaman-
tanoid platform; the constrained orientation of the bridgehead
nitrogen lone pair with respect to the carbonyl π systems
via an intervening three σ-bonds defines the donor-σ-
acceptor framework. Enforced through-bond interactions are
then evident in the ground state through greatly diminished
nitrogen basicity15 and nucleophilicity.16 Reported here are
the syntheses and solution-phase properties of the tris-
(arylmethyl) derivatives of the 1-aza-adamantantriones (1a-
j, Table 1); once prepared and studied, we reasoned that a
variety of structures could be derived from appropriate
modifications to the aromatic periphery.
H
H
H
55
42
66
CH3 27
H
H
H
H
66
64
63
H
OR
63 (OMe) 58 (OH)
24 40
j
3-naphthalenyl
a See the Supporting Information for synthetic details. b Isolated yield.
c Yield for two steps where the conversion of 5 to 2 is quantitative (HMTA
) hexamethylenetetramine; Ar ) aryl).
and various analogues (Table 1) begins with the bromo-
methylation18 of commercially available 1,3,5-trimethoxy-
benzene 3 and subsequent 3-fold benzylic substitution with
an appropriate, freshly prepared aryl Grignard reagent. The
yields of 5a-j are generally good, representing a minimum
80-90% average conversion at each of three benzylic sites.
Some decrease in yield is observed as the size of the aryl
group increases (e.g., 5e, 5j). Demethylation of 5a-j is
performed quantitatively by treatment with BBr3 and con-
densation of the phloroglucinol products 2a-j with HMTA
in the manner described by Risch (methanol, reflux)14
produces the tricyclic targets 1a-j. While the yields of the
desired 1-aza-adamantanetriones are modest, the products
precipitate from methanol in each case and only filtration
and washing are required for their isolation. Moreover, a
variety of substituents can be accommodated in this final
reaction, including fluorinated (1h) and bicyclic aromatics
(1j) and phenols (1i).
Upon designing the synthesis of 1a-j, only O-protected
tribenzyl precursor 5a could be found in the literature,17 the
product of a five-step sequence beginning from phloroglu-
cinol. Our alternative two-step sequence to this compound
(11) Mamiya, J.; Kanie, K.; Hiyama, T.; Ikeda, T.; Kato, T. Chem.
Commun. 2002, 1870-1871.
(12) (a) Serrette, A.; Carroll, P. J.; Swager, T. M. J. Am. Chem. Soc.
1992, 114, 1887-1889. (b) Xu, B.; Swager, T. M. J. Am. Chem. Soc. 1993,
115, 1159-1160.
(13) Bushey, M. L.; Nguyen, T.-Q.; Zhang, W.; Horoszewski, D.;
Nuckolls, C. Angew. Chem., Int. Ed. 2004, 43, 5446-5453 and references
therein.
(14) (a) Risch, N. J. Chem. Soc., Chem. Commun. 1983, 532-533. (b)
Risch, N. Chem. Ber. 1985, 118, 4073-4085. (c) Risch, N. Chem. Ber.
1985, 118, 4849-4856. (d) Risch, N.; Langhals, M.; Hohberg, T.
Tetrahedron Lett. 1991, 32, 4465-4468. (e) Risch, N.; Langhals, M.;
Mikosch, W.; Bo¨gge, H.; Mu¨ller, A. J. Am. Chem. Soc. 1991, 113, 9411-
9412. (f) Kardel, D.; Knoche, W.; Risch, N. J. Chem. Soc., Perkin Trans.
2 1993, 1455-1459.
(15) The pKa values for the protonated 3,5,7-trimethyl-1-aza-adaman-
tanetrione, -dione, and -one are 0.3 (3:1 water/dioxane), 3.5, and 7.14,
respectively (ref 14f).
The 1-aza-adamantanetrione cores have the expected
spectroscopic signatures.14 Using parent 1a as an example,
two intense carbonyl stretches (1735 and 1692 cm-1) appear
in the IR spectrum (Fermi resonance), and a weak UV
transition is observed that is attributable to the σ-coupled
transition (λCT ) 284 nm (n f π*), ꢀCT ) 2200 M-1 cm-1,
THF). The compounds show moderate solubility in haloge-
(16) For example, treatment of 3,5,7-tripropyl-1-aza-adamantanetrione
1l (vide infra) with methyl iodide, hydrogen peroxide, or m-CPBA gives
no reaction at the bridgehead nitrogen.
(17) Simaan, S.; Siegel, J. S.; Biali, S. E. J. Org. Chem. 2003, 68, 3699-
3701.
(18) Cho, B. R.; Chajara, K.; Oh, H. J.; Son, K. H.; Jeon, S. J. Org.
Lett. 2002, 4, 1703-1706.
444
Org. Lett., Vol. 7, No. 3, 2005

1
Table 2. Solvent-Dependent H NMR Chemical Shiftsa of the
N-R-CH2 Protons for Substituted 1-Aza-adamantantriones (300
MHz, 25 °C)b
compd
DMSO-d6
pyridine-d5
CDCl3
C6D6
1a
1k
1l
3.15
3.33
3.47
3.37
3.55
3.62
3.11
3.41
3.38
2.63
2.78
2.74
a Reported in ppm versus TMS. b The shifts were concentration inde-
pendent over the range permitted by solubility (2.5-50 mM).
nated solvents and DMSO, with excellent solubility in
pyridine. A corresponding dependence of the N-R-CH2 1H
NMR chemical shift on solvent polarity/polarizability19 is
observed (Table 2) that roughly follows the expected dipolar
properties of the core in solution. Namely, as the core dipole
is stabilized (through-bond effects) in more polar solvents,
the bridgehead nitrogen becomes more electron deficient;
the consequence is a deshielding of the N-R-CH2 protons.20
That these effects are unique to the core and do not arise
from chemical shift anisotropy (involving the aromatic
substituents) is shown through model compounds. Three-
fold O-allylation of phloroglucinol 6 followed by a Claisen
rearrangement offers new triallyl derivative 7 (Scheme 2).
Figure 1. Organogels from tribenzyl-1-aza-adamantanetrione 1a:
(a) 0.5 wt % of 1a in DMSO after heating and cooling; (b) TEM
and (c) SEM images of a xerogel formed from critical point drying
of an 0.5 wt % DMSO gel (inset: an ∼0.5 µm fiber that appears
as a tube); (d) SEM images of a xerogel formed from conventional
freeze-drying of an 0.5 wt % DMSO gel.
Scheme 2. Synthesis of Model Compounds 1k and 1l
wt %). The gels take nearly 1 h to form and then exhibit a
sol-gel transition (Tgel) at ∼45 °C (determined by the
inverted vial technique);21 importantly, the process is revers-
ible with no signs of decomposition or structural change to
the monomer by 1H NMR (DMSO-d6).22 Similarly, addition
of water to DMSO solutions of 1i results in gelation at the
solvent interface.
SEM and TEM techniques were used to explore the
morphologies of xerogels formed from 1a (Figure 1b-d).
The solvent was removed from DMSO gels (e.g., Figure 1a)
via both critical point drying and conventional freeze-
drying.23 TEM images reveal 0.5 µm fibers (Figure 1b) that
do not show any discernible higher-ordered structure,
although some do appear hollow (Figure 1b, inset). Extended
fibrillar structures are also detected by SEM from each of
the sample preparations; these show little entanglement,
consistent with more crystalline gelators.24,25 In all cases, the
This material, although challenging to purify, was reacted
with HMTA directly to provide triallyl 1-aza-adamantantri-
one 1k in 35% yield (isolated yield for two steps). Similar
chemical shift trends are observed for this compound and
saturated tris(propyl) 1l (Table 2), demonstrating that ground-
state electronic stabilization of the core is responsible for
the downfield shifts in more polar solvents.
Unexpected given the modest solubility of 1a-j in most
organic solvents, two derivatives, 1a and 1i, display gelation
behavior.21 Optically clear gels result from heating and
cooling DMSO (Figure 1a) and CHCl3 solutions of 1a (∼0.5
(21) (a) Terech, P.; Weiss, R. G. Chem. ReV. 1997, 97, 3133-3159. (b)
Gronwald, O.; Snip, E.; Shinkai, S. Curr. Opin. Colloid Interface Sci. 2002,
7, 148-156. (c) Estroff, L. A.; Hamilton, A. D. Chem. ReV. 2004, 104,
1201-1217.
(22) An important consideration as the tricyclic ring systems are not
strain-free. The bond angle at the carbonyl is calculated as 114.5°, smaller
than the optimum sp2 bond angle of 120°.
(23) For a discussion of gel morphology dependence on drying technique
see: Frey, M. W.; Cuculo, J. A.; Spontak, R. J. J. Polym. Sci., Part B:
Polym. Phys. 1996, 34, 2049-2058.
(19) Katritzky, A. R.; Fara, D. C.; Yang, H. F.; Tamm, K.; Tamm, T.;
Karelson, M. Chem. ReV. 2004, 104, 175-198.
(20) The same effect is found upon introducing carbonyl groups to the
1-aza-adamantane core. For 1,3,5-trimethyl-1-aza-adamantane, 1H NMR
(CDCl3) δ N-R-CH2 ) 2.60 ppm; this value increases through the
monoketone (2.88-3.03), diketone (2.75-3.45), and triketone (3.41)
indicative of enhanced through-bond effects (data taken from ref 14).
(24) Wang, G. J.; Hamilton, A. D. Chem. Eur. J. 2002, 8, 1954-1961.
(25) DSC analysis of the monomer reveals a sharp endothermic transition
upon first heating (297.1 °C) and sharp exotherm upon cooling (222.5 °C).
Likewise, preliminary powder X-ray diffraction studies show a series of
low angle diffraction peaks that are not readily indexed.
Org. Lett., Vol. 7, No. 3, 2005
445

Evidence for the lowest energy conformation in solution
comes through a NOESY experiment where NOEs are
observed between hydrogens Hc on the aromatic ring and
Ha on the core (Figure 2b; d ) 2.7 Å in the minimized
structure of 1a), a result only possible if the “all-arms-up”
conformer is present in solution. In any case, compounds
1a-j exist as equilibrium mixtures of conformers in solu-
tion,29 as indicated by the relatively large temperature
dependence of their chemical shifts. The temperature de-
pendence coefficient is 0.2 ppb/K for Ha and 1.1 ppb/K for
Hb in 1a; these coefficients increase in 1b to -2.6 and 2.3
ppb/K, respectively. The o-CH3 protons of 1b also display
a large temperature dependence (0.6 ppb/K) as does the
o-proton of the aromatic ring (4.1 ppb/K). The barriers to
conformational exchange become even higher for 1e; at -80
°C, Ha and Hb display a pattern of at least eight lines which
coalesce into two at 20 °C.
A survey of the literature reveals that while low molecular
weight organogelators of diverse structure have been identi-
fied,21 few possess the structural and functional attributes
of 1a,i. While our studies have offered a glimpse of the
monomer structure and behavior of 1a in solution, our current
efforts seek to understand why this molecule is a gelator at
all. Certainly an appreciable ground-state dipole moment for
1a (∼4 D) is predicted by computation, and the dipole-driven
stacking of molecules is conceivable in solution12 where other
factorsscomplementary monomer shape, aryl substitution
(i.e., π-π interactions), weak intermolecular contacts (e.g.,
dispersion and C-H‚‚‚O), and solvationsalso play a role.30
Further studies are now conceivable to show how through-
bond interactions might both facilitate the organization of
donor-σ-acceptor molecules such as 1a in solution and
impart their assemblies with unique electronic properties.
Figure 2. Low-energy conformations of 1a identified from Monte
Carlo conformational searching:26 (a) energy-minimized lowest
energy “all-arms-up” conformation (one enantiomer is shown); (b)
NOE contacts identified by a NOESY experiment and labeling of
critical dihedral angles, φ and ψ; (c) energy-minimized lowest
energy “all-arms-down” conformation, approximately 5.8 kcal
mol-1 higher in energy.
manifestation of fibers is consistent with other gelators, the
assembly of which is generally understood to be one-
dimensional organization of the monomers.21
As ascertaining molecular ordering and conformation from
the gel phase remains an interminable challenge,21 both
solution-phase NMR experiments and computation were
undertaken to preliminarily probe the conformational prefer-
ences of 1a. Monte Carlo conformational searching26 identi-
fies the chiral (but racemic) C3-symmetric “all-arms-up”
arrangement as the lowest energy conformation (Figure 2a)
with values of φ ∼ 45° and ψ ∼ 90° (Figure 2b) for the two
relevant dihedral angles.27 Although appealing from a
molecular recognition standpoint, the “all-arms-down” con-
formations (Figure 2c) are predicted to be significantly higher
Acknowledgment. We are grateful to the University of
Florida for financial support. E.A.H. has been funded through
the NSF REU program (CHE-0139505) and the UF Uni-
versity Scholars Program. A.J.L. is a UF Alumni Graduate
Fellow. We thank Prof. Joanna Long for solid-state NMR
assistance, Dr. Kerry Siebein, Mr. Michael Tollon, and Mr.
Matt Olszta (UF MAIC) for the TEM and SEM measure-
ments, Dr. Kevin Powers (UF PERC) for help with the
critical point drying apparatus, and Mr. John Sworen for DSC
analysis.
in energy. The lowest energy of these is shown (∆∆Erel
)
5.75 kcal mol-1, HF/3-21G*)26 and reveals eclipsed interac-
tions between the N-R-CH2 hydrogens (Ha) and benzylic
hydrogens (Hb); additionally, the o-phenyl hydrogens are
poorly aligned to participate in favorable C-H‚‚‚O interac-
tions28 with the core carbonyl oxygens, and in fact, these
electrostatic interactions are likely repulsive.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-7, DSC
data, computational details, and relevant NMR data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) MacroModel V. 8.6 (Schro¨dinger, LLC), Amber* force field, CHCl3
GB/SA solvation model. The structures were further minimized at the ab
initio (HF/3-21G*) level using Gaussian 98 (Revision A.7, Gaussian, Inc.:
Wallingford, CT, 2004). Details and references are provided in the
Supporting Information.
(27) Close in energy are the Cs-symmetric “all-arms-up” conformers
bearing one disparate arm with φ ∼ -45° and ψ ∼ -90°.
(28) Castellano, R. K. Curr. Org. Chem. 2004, 8, 845-865.
OL047597Y
(29) Solid-state 13C CPMAS NMR (10 kHz) of a powdered sample of
1a reveals multiple resonances in the CdO, N-R-CH2, and CH2Ar regions.
(30) For comprehensive studies of dipolar aggregation phenomena in
solution see: Yao, S.; Beginn, U.; Gress, T.; Lysetska, M.; Wu¨rthner, F. J.
Am. Chem. Soc. 2004, 126, 8336-8348 and references therein.
446
Org. Lett., Vol. 7, No. 3, 2005