Cation-promoted hierarchical formation of supramolecular assemblies of self-organized helical molecular components

Article abstract of DOI:10.1002/1521-3773(20020402)41:7<1195::AID-ANIE1195>3.0.CO;2-L

Alternating naphthyridine-pyrimidine strands self-organize into a helical conformation containing a strongly polar cavity. The binding of metal and ammonium cations promotes supramolecular self-assembly in a sort of effector-induced growth process to form

Full text of DOI:10.1002/1521-3773(20020402)41:7<1195::AID-ANIE1195>3.0.CO;2-L

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[6] a) E. Hey, F. Weller, Chem. Commun. 1988, 782; b) R. A. Bartlett,
M. M. Olmstead, P. P. Power, G. A. Sigel, Inorg. Chem. 1987, 26, 1941;
c) G. W. Rabe, G. P. A. Yap, A. L. Rheingold, Inorg. Chem. 1997, 36,
1990; d) G. W. Rabe, S. Kheradmandan, G. P. A. Yap, Inorg. Chem.
1998, 37, 6541; e) G. A. Koutsantonis, P. C. Andrews, C. L. Raston,
Chem. Commun. 1995, 47.
[7] The unique electronic and steric properties of the related 2,4,6-
tris(trifluoromethyl)phenyl substituent have been reviewed:
F. T. Edelman, Comments Inorg. Chem. 1992, 12, 259. See also
ref. [4a].
[8] Formallythis reaction represents a rare example of the nucleophilic
substitution of an organyl group in primary phosphanes. Similar
behavior was reported for Cp*PH2 (Cp* ˆ pentamethylcyclopenta-
dienyl): P. Jutzi, G. Reumann, J. Chem. Soc. Dalton Trans. 2000, 2237.
[9] Participation of such species in nucleophilic substitution reactions at
phosphorus(iii) centers is known. For a review on this topic, see K. B.
Dillon, Chem. Rev. 1994, 94, 1441.
J(F,C) ˆ 273 Hz, CF3), 127.6 and 128.1 (s, m-Carom), 170.3 (d, J(C,P) ˆ
87 Hz, i-Carom).
[17] G. N. Merill, S. R. Kass, J. Phys. Chem. 1996, 100, 17465.
[18] J. Escudie, C. Couret, H. Ranaivonjatovo, M. Lazraq, J. Satge,
Phosphorus Sulfur 1987, 31, 27.
[19] Gaussian98 (RevisionA.7), M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A.
Montgomery, R. E. Stratmann, J. C. Burant, S. Dapprich, J. M.
Millam, A. D. Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi,
V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo,
S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K.
Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B.
Foresman, J. Cioslowski, J. V. Ortiz, B. B. Stefanov, G. Liu, A.
Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin,
D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C.
Gonzalez, M. Challacombe, P. M. W. Gill, B. G. Johnson, W. Chen,
M. W. Wong, J. L. Andres, M. Head-Gordon, E. S. Replogle, J. A.
Pople, Gaussian, Inc., Pittsburgh, PA, 1998.
[20] W. J. Hehre, L. Radom, P. von R. Schleyer, J. A. Pople, Ab Initio
Molecular Orbital Theory, Wiley, New York, 1986.
[21] R. G. Parr, W. Yang in Functional Theory of Atoms and Molecules
(Eds.: R. Breslow, J. B. Goodenough), Oxford UniversityPress, New
York, 1989.
[22] a) A. D. Becke, Phys. Rev. A 1988, 38, 3098; b) A. D. Becke, J. Chem.
Phys. 1993, 98, 5648; c) C. Lee, W. Yang, R. G. Parr, Phys. Rev. 1988,
B37, 785.
[23] SADABS, Program for data correction, Bruker-AXS.
[24] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467.
[25] SHELXL-97, Program for Crystal Structure Refinement, Sheldrick,
G. M. Universityof Gˆttingen, 1997.
[10] Ab initio calculations were performed with the Gaussian 98 pro-
[21]
gram.[19, 20] The densityfunctional method
used was the hybrid
exchange functional B3LYP.[22] This functional includes a linear
combination of a small amount (20%) of exact exchange[22a] with
the Becke 88 gradient-corrected exchange and with the correlation
energyfunctional LYP. [22c] The basis set retained for all calculations is
the 6-31G ‡ (d,p) set, since the inclusion of polarization and diffuse
functions is necessaryfor the obtention of accurate energies. The
optimized structure were confirmed as minima on the potential energy
surface bysecond-derivative calculations. All energies were corrected
for zero-point energy(ZPE) and temperature using unscaled density
functional frequencies. Gas-phase acidities of HA (or proton affinities
of AÀ) were calculated by Eanion À Eneutral
.
[11] Crystal data for 3 and 4: 3: C20H28F6KO6P, Mr ˆ 548.49, monoclinic,
space group P21/n, a ˆ 10.44(6), b ˆ 17.38(8), c ˆ 14.53(13) ä, b ˆ
94.4(3)8, Vˆ 2629(30) ä3, Z ˆ 4, 1calcd ˆ 1.386 MgmÀ3, F(000) ˆ 1136,
l ˆ 0.71073 ä, Tˆ 193(2) K, m(MoKa) ˆ 0.337 mmÀ1, crystal size 0.1 Â
0.4 Â 0.7 mm3, 1.83 ꢀ q ꢀ 26.378, 15730 reflections (5367 independent,
Rint ˆ 0.0358), Tmin ˆ 0.825186, Tmax ˆ 1.0, 311 parameters, R1 [I >
2s(I)] ˆ 0.0424, wR2 (all data) ˆ 0.0985, max. residual electron
density: 0.423 eäÀ3. 4: C28H44F6KO10P, Mr ˆ 724.70, monoclinic, space
group P21/c, a ˆ 11.964(2), b ˆ 12.251(2), c ˆ 23.154(3) ä, b ˆ
Cation-Promoted Hierarchical Formation of
Supramolecular Assemblies of Self-Organized
Helical Molecular Components**
96.195(3)8, Vˆ 3374.0(8) ä3, Z ˆ 4, 1calcd ˆ 1.427 MgmÀ3
F(000) ˆ
,
1520, l ˆ 0.71073 ä, Tˆ 173(2) K, m(MoKa) ˆ 0.290 mmÀ1, crystal size
0.01 Â 0.5 Â 0.6 mm3, 1.71 ꢀ q ꢀ 21.978, 13038 reflections (4108 inde-
pendent, Rint ˆ 0.0798), Tmin ˆ 0.749166, Tmax ˆ 1.000000, 4108 param-
eters, 440 restraints, R1 [I > 2s(I)] ˆ 0.0599, wR2 (all data) ˆ 0.1424,
max. residual electron density: 0.529 eäÀ3. Data for both structures
were collected at low temperature using oil-coated shock-cooled
crystals on a Bruker-AXS CCD 1000 diffractometer. Semi-empirical
Anne Petitjean, Louis A. Cuccia, Jean-Marie Lehn,*
¬ ¡
Helene Nierengarten, and Marc Schmutz
Helical conformations of organic and inorganic entities
have received much attention as a result of their occurence in
many biological systems. Maintained by multiple hydrogen
bonds and electrostatic interactions, a-helices are involved in
absorption corrections were employed.[23] The structures were solved
[24]
bydirect methods (SHELXS-97)
and refined using the least-
squares method on F2.[25] CCDC-166948 (3) and -166949 (4) contains
the supplementarycrystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
ving.html (or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB21EZ, UK; fax: (‡44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
[*] Prof. Dr. J.-M. Lehn, A. Petitjean, Dr. L. A. Cuccia
¬
Laboratoire de Chimie Supramoleculaire, ISIS-ULP
4 rue Blaise Pascal, 67000 Strasbourg (France)
Fax : (‡33)390-24-11-17
E-mail: lehn@chimie.u-strasbg.fr
[12] The Lewis acid base interaction between K and F centers has already
been observed in potassium 2,4,6-tris(trifluoromethyl)phenoxide, see
S. Brooker, F. T. Edelmann, T. Kottke, H. W. Roesky, G. M. Sheldrick,
D. Stalke, K. H. Whitmire, Chem. Commun. 1991, 144.
[13] V. L. Rudzevich, H. Gornitzka, V. D. Romanenko, G. Bertrand, 2001,
unpublished results.
Dr. H. Nierengarten
¬
Laboratoire de Spectrometrie
de Masse Bio-Organique, ECPM
25 rue Becquerel, 67000 Strasbourg (France)
Dr. M. Schmutz
¬
¬
¬
Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/
INSERM/ULP
[14] S. Sasaki, F. Murakami, M. Yoshifuji, Angew. Chem. 1999, 111, 351;
Angew. Chem. Int. Ed. 1999, 38, 340.
BP 163, 67404 Illkirch (France)
[15] For comparaison, calculations have shown that the phosphorus atom
of the phenylphosphanide bears a charge of À0.43.
[**] Dr. R. P. Thummel is thanked for providing helpful advice for the
preparation of 4-aminopyrimidine-5-carboxaldehyde. We are indebt-
[16] Selected NMR data for 4 ([D8]THF, À508C): 1H NMR: d ˆ 3.02 (dqq,
1H, J(P,H) ˆ 161 Hz, J(H,F) ˆ 10 Hz and 4 Hz, PH), 5.69 (pseudo-t,
1H, J(H,H) ˆ 7.5 Hz, p-Harom), 6.80 and 6.81 (m, 1H, m-Harom); 19F
NMR: d ˆ 8.4 (dd, 3F, J(F,P) ˆ 72 Hz, J(F,H) ˆ 10 Hz, CF3), 10.2 (dd,
3F, J(F,P) ˆ 9 Hz, J(F,H) ˆ 4 Hz, CF3); 31P NMR: d ˆ À70 (dqq,
J(P,H) ˆ 161 Hz, J(P,F) ˆ 72, 9 Hz); 13C{1H} NMR: 105.9 (d, J(C,P) ˆ
6 Hz, p-Carom), 125.2 and 125.3 (m, o-Carom), 126.8 and 127.1 (q,
¬
ed to Dr. Andre Mathis (Institut Charles Sadron) for his kind help
with powder diffraction studies. This work was supported bythe
¡
French ™Ministere de la Recherche et de la Technologie∫. L.A.C.
¡
thanks the College de France and the CNRS for post-doctoral
fellowships. M.S. acknowledges the financial support of INSERM,
CNRS, and HUS.
Angew. Chem. Int. Ed. 2002, 41, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4107-1195 $ 20.00+.50/0
1195

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numerous natural architectures, such as ion
channels[1] and pumps,[2] which require high-
lyordered subunits. Likewise, in artificial
systems, self-organization into a helical spa-
tial arrangement maybe induced through
hydrogen bonding,[3] steric interactions,[4]
solvophobic effects,[5a,b] cation binding,[5c]
and/or local conformational preferences.[6]
In particular, helicitycodons based on spe-
ciallydesigned sequences of heteroccylic
units enforce the self-organization of linear
molecular strands into multiturn helical
entities.[7] As a consequence of the primary
helix encoding, the preferred conformer may
present further specific interactions and
undergo a second level, hierarchical self-
assembly[7c, 8, 9] to form polymolecular as-
semblies. This process maybe induced by
association with a substrate.[3d, 10]
Of particular interest is the potential
abilityof such helicallywrapped species to
present functional properties such as ion
binding and possiblychannel-like ion con-
duction. To this end, the central void must
have a diameter sufficient for the inclusion
of metallic or organic cations. Replacement
of the pyridine group in the previously
described pyridine pyrimidine (py pym)
helicitycodon [7] by1,8-naphthyridine (napy)
should provide such an increase in size.
Herein we describe a new type of oligomeric
strand composed of alternating pym and
napyheterocycles ( A, Scheme 1), where the
interheterocyclic transoid conformational
preference of 2,2'-bipyridine-like units may
be expected to enforce helix formation.[7] In
view of the large dipole moment of napy
(4.1 D in benzene, 258C),[11] the helical
entity A should present a verypolar interior
and be able to bind a varietyof cationic
species, which themselves could thereafter
promote helix aggregation. Acyclic and
macrocyclic structures containing rigidly
maintained napyunits have been described
and found to bind guanidinium ions.[12]
Scheme 1. Synthesis of the polyheterocyclic strands A. a) 1-tributylstannylethyl vinyl ether
(2.1 equiv), [Pd(PPh3)2Cl2] (0.05 equiv), DMF, 808C, 6 h; b) acetone, 2n HCl, room temp., 70%
(two steps); c) 4-aminopyrimidine-5-carboxaldehyde (2.2 equiv), KOH (cat.), EtOH, reflux,
0.5 h; d) 2n HCl in H2O, reflux, 65% (two steps). 1) 1-Tributylstannylethyl vinyl ether (1.1 equiv),
[Pd(PPh3)2Cl2] (0.03 equiv), DMF, 808C, 6 h; 2) acetone, 2n HCl, room temp., 89% (two steps);
3) 1-tributylstannylethyl vinyl ether (1.1 equiv), [Pd(PPh3)2Cl2] (0.03 equiv), DMF, 808C, 6 h,
92%; 4) 2-aminonicotinaldehyde (1.1 equiv), KOH (cat.), EtOH, reflux 4 h; 5) acetone, 2n HCl,
room temp., 84% (two steps); 6) pyridine, KOH (cat.), reflux, 3 h, 80%. Bz ˆ benzyl.
A series of molecular strands based on
napy pym sequences was synthesized by
using
the
Friedl‰nder
methodology
(Scheme 1). The 2-aryl-4,6-dichloropyrimi-
dines 1, which were obtained following published proce-
dures[13] from commerciallyavailable bromo-4-butylbenzenes
and 4-hydroxybenzonitrile, were used as starting compounds.
Stille coupling of the substituted dichloropyrimidines 1 with
1.1 or 2.1 equivalents of 1-tributylstannylethyl vinyl ether
gave respectivelythe mono- 2 or diacetyl 3 derivative after
acidic deprotection of the vinyl ether group. A second Stille
coupling on 2 yielded the unsymetrically protected ketone 4,
which was condensed with 2-aminonicotinaldehyde[14] and
deprotected to give the terminal end 6 of the strands. The
diketone 3 was subjected to base-catalyzed condensation with
2.2 equivalents of 4-aminopyrimidine-5-carboxaldehyde, fol-
lowed by acidic hydrolysis of the terminal pyrimidine to give
the compounds 5. Alkyl- and O-benzyl-substituted pyrimi-
dines 5 bearing bis(aminopyridylcarboxaldehyde) were there-
byprepared in reasonable yields. The final condensation of
5
and 6 was efficiently performed in pyridine using catalytic
amounts of potassium hydroxide and yielded sequences A
containing four napyand three pym groups. Longer strands
were also synthesized by using the same methodology.
1196
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1433-7851/02/4107-1196 $ 20.00+.50/0
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On the basis of ealier results involving (py-pym)n strands,[7]
(napy-pym)n sequences maybe expected to adopt a prede-
termined well-defined helical conformation. The presence of
Electrospraymass spectrometry(ES-MS) studies gave
results in line with the NMR spectroscopic data. Thus, when
a 1/1 mixture of AnBu and potassium picrate was investigated
in the same range of concentrations, mass signals correspond-
ing to assemblies containing xÀy ions for x ligands (y ꢀ x)
were detected (Figure 2). In addition to potassium ions,
1
such a shape in solution was supported by H NMR spectro-
scopic studies. The strong upfield shift of the terminal napy
protons (up to 0.5 ppm relative to a shorter non-overlapping
strand) in the well-resolved and sharp spectrum of AtBu is
consistent with overlapping aromatic rings and is diagnostic of
the helical folding[7] represented bystructure A, which defines
an internal cavitywith a diameter of about 3.5 ä. This helical
arrangement was confirmed byNOE crosspeaks in a ROESY
experiment which shows that protons 1 and 2 are close to
protons 6 and 5, respectively.
1
The H NMR spectra of the three helices bearing various
substituents in deuterated chloroform showed increased line
broadening when the substituent was less bulky(from tBu, to
OBz, and to nBu), which is suggestive of intermolecular
association at millimolar concentrations. Self-aggregation was
confirmed byother experiments: increasing the concentration
or the ionic strength of the medium (for example, byaddition
of NEt4I in CDCl3) led to signal shifts indicative of proton
shielding (especiallyfor the terminal napygroups). Marked
broadening was produced bythe addition of a polar solvent
such as acetonitrile–a solvophobic aggregation effect remi-
niscent of solvophobic folding.[5a,b]
Figure 2. ES-MS spectrum of a 1/1 mixture of AnBu and potassium picrate
‡
(2.7 mm in CHCl3/CH3CN (1.7/1.0)), 70 V. m/z: 1168.1 [A‡Na] , 1184.2
‡
[A‡K] , 1176.4 [2A‡K‡Na]2‡
,
1738.2 [3A‡K‡H]2‡
,
1749.0
[3A‡K‡Na]2‡
,
1757.0 [3A‡2K]2‡
,
1890.8 [3A‡3K‡Pic]2‡
,
2291.8
Most interestingly, self-association of helical monomers was
stronglyinfluenced bycationic additives. Titrations of the
nBu-substituted one-turn helix AnBu with alkali metal salts
(cesium and potassium picrates) showed a strong upfield shift
‡
‡
‡
‡
[2A‡H] , 2313.8 [2A‡Na] , 2329.7 [2A‡K] , 2597.4 [2A‡2K‡Pic] ,
2883.5 [5A‡K‡H]2‡. The stacked structures shown are speculative, but
agree with all the data obtained.
1
of all the H NMR signals (byapproximately2 ppm) and
broadened signals at millimolar concentrations (Figure 1).
the binding of cesium, sodium, guanidinium ions as well as
protons bythe supramolecular helix aggregates also occurred.
Divalent lead ions (introduced as the triflate salt) formed
multiligand assemblies with AnBu: the ES-MS spectrum of a
millimolar solution of the 1/1 complex in CH3CN/CHCl3 (1.7/
1.0) showed mainlythe [3 A‡2Pb]2‡ adduct. These spectro-
scopic results agree with the formation of an assemblyof
stacked helices of component A containing cations in the
internal void, as schematicallyrepresented in Figures 1
and 2.
The formation of a stack-type structure is supported by
X-raypowder diffraction patterns, which yield a characteristic
distance of 23 26 ä for the assemblies obtained with all the
cations, as well as for the ligand itself. This value corresponds
to the external diameter of the helix.[15]
The potassium-containing sample used for the ES-MS
studies was investigated bytransmission electron microscopy
(TEM). Long interdigitated fibers were found (Figure 3), thus
confirming bydirect observation, the self-association into
extended supramolecular assemblies. Single filaments could
not be observed under the conditions used for sample
preparation because of association. Similar observations were
made with cesium ions. No clear textures were observed by
TEM in the absence of added cations.
Figure 1. 1H NMR titration of AnBu (2.7 mm in CDCl3/CD3CN (1.7/1.0))
with cesium picrate (2.9 mm in the same mixture of solvents); right:
representation of the formation of a stack of helical AnBu components
‡
containing Cs ions.
Cations other than alkali ions appear to be even more
efficient aggregate inducers, as evident from the line broad-
ening of the NMR signals; indeed, hydronium and guanidi-
nium[10] ions show stronger effects than the alkali ions. Thus, in
a chloroform/ethanol/acetonitrile (3/6/2) mixture, the latter
yield birefringent gels, which will be further characterized.
The present results show that the self-organization features
resulting from the transoid conformational preference of the
[7]
py pym units can be generalized to strands composed of
sequences of alternating napy pym heterocycles as a novel
helicitycodon, which enforces the formation of a helical
Angew. Chem. Int. Ed. 2002, 41, No. 7
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4107-1197 $ 20.00+.50/0
1197

COMMUNICATIONS
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Figure 3. Transmission electron micrograph of a 1/1 mixture of AnBu and
potassium picrate (3 mm in CHCl3/CH3CN (1.7/1.0)). The white bar
(bottom right) represents 200 nm. The sample was prepared as described
in ref. [3d]).
foldamer[16] and generates a polar inner void towards the
center of which all the napyelectrical dipoles are directed.
This arrangement induces cation complexation, which in turn
promotes the multiple supramolecular association of ligands,
through effects such as ion dipole interaction and p stacking
between the aromatic rings.
The hierarchical self-organization observed amounts to a
sort of effector-induced growth process and is reminiscent of
the self-assemblyof the tobacco mosaic virus, where the
formation of the helical protein coat results from the induced
association of the peptide components bythe nucleic acid
strand occupying the central void of the polymolecular
architecture. The formation of cation-containing polymolec-
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up solelyif suitable ions are present, thus presenting a most
intriguing abilityto perform a cation-selective self-regulation
of ion flow.
√
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The Determination of the Absolute
Configurations of Diastereomers of (S)-
Camphanoyl 3-Hydroxy-5-oxohexanoic Acid
Derivatives by X-ray Crystallography**
Kwai-Ming Cheung, Simon J. Coles,
Michael B. Hursthouse, Neil I. Johnson, and
Peter M. Shoolingin Jordan*
Received: July2, 2001
Revised: January23, 2002 [Z17400]
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Polyketides form a major class of secondary metabolites,[1]
produced byfungi, lichens, and higher plants. 6-Methylsali-
cylic acid (6-MSA) is one of the simplest aromatic compounds
produced by a polyketide biosynthesis pathway. It is assem-
bled from one molecule of acetyl-coenzyme A (acetyl-CoA),
[*] Prof. P. M. Shoolingin Jordan, Dr. K.-M. Cheung, Dr. N. I. Johnson
Division of Biochemistryand Molecular Biology
School of Biological Sciences, Universityof Southampton
Biomedical Sciences Building, Bassett Crescent East
Southampton SO16 7PX (UK)
Fax : (‡44)23-80-594459
E-mail: pmsj@soton.ac.uk
Dr. S. J. Coles, Prof. M. B. Hursthouse
EPSRC National Crystallography Service
Department of Chemistry, University of Southampton
Highfield, Southampton SO17 1BJ (UK)
[**] This work was supported bythe EPSRC, the BBSRC, and bythe
Wellcome Trust. We also thank the Chemical Database Service
provided bythe EPSRC at Daresbury. We are grateful to Joan Street
for providing the NMR service and Dr. J. Langleyfor the high
resolution mass spectroscopy(HRMS) in the ChemistryDepartment
at Southampton.
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¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4107-1198 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 7