Driven evolution of a constitutional dynamic library of molecular helices toward the selective generation of [2 × 2] gridlike arrays under the pressure of metal ion coordination

Article abstract of DOI:10.1021/ja0666452

Constitutional dynamics, self-assembly, and helical-folding control are brought together in the efficient Sc(OTf)₃/microwave-catalyzed transimination of helical oligohydrazone strands, yielding highly diverse dynamic libraries of interconvertin

Full text of DOI:10.1021/ja0666452

Published on Web 12/05/2006
Driven Evolution of a Constitutional Dynamic Library of
Molecular Helices Toward the Selective Generation of [2 × 2]
Gridlike Arrays under the Pressure of Metal Ion Coordination
Nicolas Giuseppone, Jean-Louis Schmitt, and Jean-Marie Lehn*
Contribution from the Laboratoire de Chimie Supramole´culaire, Institut de Science et
d’Inge´nierie Supramole´culaires, UniVersite´ Louis Pasteur, 8 Alle´e Gaspard Monge, BP 70028,
67083 Strasbourg Cedex, France
Received October 5, 2006; E-mail: lehn@isis.u-strasbg.fr
Abstract: Constitutional dynamics, self-assembly, and helical-folding control are brought together in the
efficient Sc(OTf)3/microwave-catalyzed transimination of helical oligohydrazone strands, yielding highly
diverse dynamic libraries of interconverting constituents through assembly, dissociation, and exchange of
components. The transimination-type mechanism of the ScIII-promoted exchange, as well as its regio-
selectivity, occurring only at the extremities of the helical strands, allow one to perform directional terminal
polymerization/depolymerization processes when starting with dissymmetric strands. A particular library is
subsequently brought to express quantitatively [2 × 2] gridlike metallosupramolecular arrays in the presence
of ZnII ions by component recombination generating the correct ligand from the dynamic set of interconverting
strands. This behavior represents a process of driven evolution of a constitutional dynamic chemical system
under the pressure (coordination interaction) of an external effector (metal ions).
strands,7,8 or on noncovalent interactions such as hydrogen
bonding9,10 or metal-ligand coordination.6a,11 In particular, the
Introduction
Molecular and supramolecular self-organization results from
programmed structure generation directed by conformational
properties and intermolecular noncovalent interactions.1-3 The
functions carried out by biological macromolecules, for example,
nucleic acids and proteins, are based on their ability to perform
processes such as molecular recognition and catalysis, via well-
defined three-dimensional (supra)-molecular interactions. In
particular, internal folding of molecular strands in biological
helical structures is induced by well-defined long-range inter-
actions.4,5 In view of its significance in biology, the precise
generation and control of folded entities capable of mimicking
the secondary structures of such biopolymers has been inten-
sively studied. Furthermore, artificial self-organized structures
can be implemented in catalysis, materials science, or nano-
technologies, and numerous investigations have recently been
directed toward these domains by various research groups.6
Typically, the generation of synthetic helical species may be
enforced through the implementation of “helicity codons”7 based
on nonbonded interactions within specific polyheterocyclic
construction of helical strands by condensation of suitably
designed hydrazino and carbonyl components into reversible
hydrazone type bonds gives access to dynamic libraries of
molecular helices.12,13
(8) (a) Hanan, G. S.; Lehn, J.-M.; Kyritsakas, N.; Fischer, J. J. Chem. Soc.,
Chem. Commun. 1995, 765. (b) Hanan, G. S.; Schubert, U. S.; Volkmer,
D.; Riviere, E.; Lehn, J.-M.; Kyritsakas, N.; Fischer, J. Can. J. Chem. 1997,
75, 169. (c) Bassani, D. M.; Lehn, J.-M.; Baum, G.; Fenske, D. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1845. (d) Bassani, D. M.; Lehn, J.-M. Bull.
Soc. Chim. Fr. 1997, 134, 897. (e) Cuccia, L. A.; Lehn, J.-M.; Homo, J.-
C.; Schmutz, M. Angew. Chem., Int. Ed. 2000, 39, 233. (f) Cuccia, L. A.;
Ruiz, E.; Lehn, J.-M.; Homo, J.-C.; Schmutz, M. Chem.-Eur. J. 2002, 8,
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P. I.; Frackenpohl, J. HelV. Chim. Acta 2001, 84, 271. (e) Gee, P. J.;
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J. AM. CHEM. SOC. 2006, 128, 16748-16763
10.1021/ja0666452 CCC: $33.50 © 2006 American Chemical Society

Selective Generation of [2
×
2] Gridlike Arrays
A R T I C L E S
Constitutional dynamic chemistry (CDC)3,14 encompasses the
study of the dynamic features presented by the constitution of
molecular15,16 as well as supramolecular17 entities linked through
reversible connections. The generation of constitutional diversity
by exchange and reshuffling of components is by essence
subjected to evolution under the pressure of molecular informa-
tion and recognition processes. This seminal concept has been
implemented in particular in the recently developed dynamic
combinatorial/covalent chemistry (DCC).16 Basically, in dy-
namic combinatorial/covalent libraries (DCLs), the thermody-
namic equilibrium may be shifted toward the amplification of
the substrate best-fitted for a given receptor through host-guest
recognition. Numerous investigations have been pursued on
DCC by different research groups over the past decade,
highlighting its potentialities in the field of drug discovery18 as
well as in the self-assembly of molecular receptors19,20a,b and
of metallosupramolecular architectures.20 In recent years, work
from our laboratory has shown that these basic principles can
be implemented in materials science and has extended the range
of suitable external triggers to pH,21,22b metal ions,22 tempera-
ture,21 the formation of a stable hydrogel23a or of a solid,23b
application of an electric field,24 and by tuning the physical
properties of dynamic polymers, dynamers,14b,25 upon controlling
their constitution with external stimuli.22
The key to the generation of dynamic constitutional diversity
for both biological and materials science purposes resides in
the availability of chemical connections displaying efficient
reversibility in a given set of (mild) conditions. The CdN unit,
present in imines, hydrazones, and oximes, offers in principle
highly attractive potentialities to CDC, provided fast reversibility
in organic solvents is achieved. We have recently described the
Lewis acid catalysis of self-sufficient transimination reactions
using Sc(OTf)3 in organic solvents with accelerations of over
105 as compared to the uncatalyzed pathway.26 This methodol-
ogy was applied to the generation of a constitutional dynamic
library of helical strands incorporating hydrazone bonds and
capable of assembling, dissociating, and exchanging compo-
nents. We also demonstrated that this library can undergo driven
evolution in the presence of suitable metal ions, that is, Zn(II)
salts, to express preferentially [2 × 2] grid-type metal complexes
from the mixture of helices. These combined processes are
illustrated schematically in Figure 1.27
We here present a detailed account of these preliminary
results. First, we show that the exchanges promoted by ScIII
ions can be highly accelerated upon microwave activation due
to a local heating of the catalyst. Second, we point out that the
mechanism of the constitutional exchange involves interesting
directionally polarized polymerization/depolymerization pro-
cesses. Finally, we highlight an optimized DCC system in which
a library of helices can be driven to full reorganization toward
the formation of [2 × 2] grid-type complexes.
(14) (a) Lehn, J.-M. Science 2002, 295, 2400. (b) Lehn, J.-M. Prog. Polym.
Sci. 2005, 30, 814.
(15) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart,
J. F. Angew. Chem. 2002, 114, 938; Angew. Chem., Int. Ed. 2002, 41, 898.
(16) (a) Lehn, J.-M. Chem.-Eur. J. 1999, 5, 2455. (b) Cousins, R. L.; Poulsen,
S. A.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2000, 4, 270. (c) Corbett,
P. T.; Leclaire, J.; Vial, J.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.;
Otto, S. Chem. ReV. 2006, 106, 3652.
(17) Lehn, J.-M. In Supramolecular Science: Where It Is and Where It Is Going;
Ungaro, R., Dalcanale, E., Eds.; Kluwer: Dordrecht, The Netherlands, 1999;
p 287.
(18) (a) Swann, P. G.; Casanova, R. A.; Desai, A.; Frauenhoff, M. M.; Urbanic,
M.; Slomezynska, U.; Hopfinger, A. J.; Le, Breton, G. C.; Venton, D. L.
Biopolymers 1996, 40, 617. (b) Huc, I.; Lehn, J.-M. Proc. Natl. Acad. Sci.
U.S.A. 1997, 94, 2106. (c) Eliseev, A.; Nelen, M. J. Am Chem. Soc. 1997,
119, 1147. (d) Ramstro¨m, O.; Lehn, J.-M. ChemBioChem 2000, 1, 41. (e)
Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Winssinger, N.; Smethurst, C.;
Labischinski, H.; Endermann, R. Angew. Chem. 2000, 112, 3981; Angew.
Chem., Int. Ed. 2000, 39, 3823. (f) Case, M. A.; McLendon, G. L. J. Am.
Chem. Soc. 2000, 122, 8089. (g) Bunyapaiboonsri, T.; Ramstro¨m, O.;
Lohmann, S.; Lehn, J.-M.; Peng, L.; Goeldner, M. ChemBioChem 2001,
2, 438. (h) Hochgu¨rtel, M.; Kroth, H.; Piecha, D.; Hofmann, M. W.;
Nicolau, C.; Krause, S.; Schaaf, O.; Sonnenmoser, G.; Eliseev, A. V. Proc.
Natl. Acad. Sci. U.S.A. 2002, 99, 3382. (i) Lins, R. J.; Flitsch, S. L.; Turner,
N. J.; Irving, E.; Brown, S. A. Angew. Chem. 2002, 114, 3555; Angew.
Chem., Int. Ed. 2002, 41, 3405. (j) Gerber-Lemaire, S.; Popowycz, F.;
Rodr´ıguez-Garc´ıa, E.; Carmona, Asenjo, A. T.; Robina, I.; Vogel, P.
ChemBioChem 2002, 5, 466. (k) Hochgu¨rtel, M.; Biesinger, R.; Kroth, H.;
Piercha, D.; Hofmann, M. W.; Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev,
A. V. J. Med. Chem. 2003, 46, 356. (l) Ramstro¨m, O.; Lohmann, S.;
Bunyapaiboonsri, T.; Lehn, J.-M. Chem.-Eur. J. 2004, 10, 1711. (m) Zameo,
S.; Vauzeilles, B.; Beau, J.-M. Angew. Chem. 2005, 117, 987; Angew.
Chem., Int. Ed. 2005, 44, 965.
Results and Discussion
I. Synthesis and Conformational Analysis of the Building
Blocks. Previous investigations in our laboratory have estab-
lished the helical structure of molecular strands based on
pyrimidine-pyridine-pyrimidine (pym-py-pym) sequences
(Scheme 1, A).7,8 In these units, the helicity is enforced by the
programmed intramolecular self-organization carried out by
three encoding features: (1) an alternating pym-py-pym
sequence, (2) linkages at specific positions, and (3) the strong
preference for the transoid conformation around the single bonds
between the R,R′-linked heterocyclic units. Nevertheless, syn-
(19) (a) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y.-F.; Redman, J. E.; Sanders,
J. K. M. Angew. Chem. 2001, 113, 437; Angew. Chem., Int. Ed. 2001, 40,
423. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. Curr. Opin. Chem.
Biol. 2002, 6, 321. (c) Furlan, R. L. E.; Ng, Y.-F.; Otto, S.; Sanders, J. K.
M. J. Am. Chem. Soc. 2001, 123, 8876. (d) Otto, S.; Furlan, R. L. E.;
Sanders, J. K. M. Science 2002, 297, 590. (e) Roberts, S. L.; Furlan, R. L.
E.; Cousins, G. R. L.; Sanders, J. K. M. Chem. Commun. 2002, 938. (f)
Otto, S.; Kubik, S. J. Am. Chem. Soc. 2003, 125, 7804.
(21) (a) Giuseppone, N.; Lehn, J.-M. Chem.-Eur. J. 2006, 12, 1715. (b) For the
influence of pH and temperature on dynamic covalently bonded rotaxanes,
see: Kawai, H.; Umehara, T.; Fujiwara, K.; Tsuji, T.; Suzuki, T. Angew.
Chem. 2006, 118, 4387; Angew. Chem., Int. Ed. 2006, 45, 4281.
(22) (a) Giuseppone, N.; Lehn, J.-M. J. Am. Chem. Soc. 2004, 126, 11448. (b)
Giuseppone, N.; Fuks, G.; Lehn, J.-M. Chem.-Eur. J. 2006, 12, 1723.
(23) (a) Nampally, S.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,
5938. (b) For an earlier example, concerning a constitutional reorganization
of equilibrating coordination compounds driven by crystallization, see:
Baxter, P. N. W.; Lehn, J.-M.; Rissanen, K. J. Chem. Soc., Chem. Commun.
1997, 1323. (c) By solvent composition, see: Baxter, P. N. W.; Khoury,
R. G.; Lehn, J.-M.; Baum, G.; Fenske, D. Chem.-Eur. J. 2000, 6, 4140.
(24) Giuseppone, N.; Lehn, J.-M. Angew. Chem. 2006, 118, 4735; Angew. Chem.,
Int. Ed. 2006, 45, 4616.
(25) The term “dynamers” designates dynamic polymers connected by either
reversible covalent or non-covalent bonds: (a) Lehn, J.-M. Polym. Int. 2002,
51, 825. (b) Polyacylhydrazones: Skene, W. G.; Lehn, J.-M. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 8270. (c) Supramolecular Polymers, 2nd ed.;
Ciferri, A., Ed.; Taylor Francis: New York, 2004.
(26) Giuseppone, N.; Schmitt, J.-L.; Schwartz, E.; Lehn, J.-M. J. Am. Chem.
Soc. 2005, 127, 5528 and references therein.
(27) Giuseppone, N.; Schmitt, J.-L.; Lehn, J.-M. Angew. Chem. 2004, 116, 5010;
Angew. Chem., Int. Ed. 2004, 43, 4902.
(20) For inorganic entities, see, for instance: (a) Hasenknopf, B.; Lehn, J.-M.;
Kneisel, B. O.; Baum, G.; Fenske, D. Angew. Chem. 1996, 108, 1987;
Angew. Chem., Int. Ed. Engl. 1996, 35, 1838. (b) Hasenknopf, B.; Lehn,
J.-M.; Boumediene, N.; Dupont-Gervais, A.; Van, Dorsselaer, A.; Kneisel,
B.; Fenske, D. J. Am. Chem. Soc. 1997, 119, 10956. (c) Fleming, J. S.;
Mann, K. L. V.; Carraz, C.-A.; Psillakis, E.; Jeffery, J. C.; McCleverty, J.
A.; Ward, M. D. Angew. Chem. 1998, 110, 1315; Angew. Chem., Int. Ed.
1998, 37, 1279. (d) Huc, I.; Krische, M. J.; Funeriu, D. P.; Lehn, J.-M.
Eur. J. Inorg. Chem. 1999, 1415. (e) Goral, V.; Nelen, M. I.; Eliseev, A.
V.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 1347. (f) Johnson,
D. W.; Raymond, K. N. Inorg. Chem. 2001, 40, 5157. (g) Grote, Z.;
Scopelliti, R.; Severin, K. Angew. Chem., Int. Ed. 2003, 42, 3821. (h) Mezei,
G.; Baran, P.; Raptis, R. G. Angew. Chem. 2004, 116, 584; Angew. Chem.,
Int. Ed. 2004, 43, 574. (i) Huang, X.-C.; Zhang, J.-P.; Chen, X.-M. J. Am.
Chem. Soc. 2004, 126, 13218. (j) Aoyagi, M.; Minamikawa, H.; Shimizu,
T. Chem. Lett. 2004, 33, 860. (k) Mahmoudkhani, A. H.; Coˆte´, A. P.;
Shimizu, G. K. H. J. Chem. Soc., Chem. Commun. 2004, 2678. (l)
Brumaghim, J. L.; Michels, M.; Raymond, K. N. Eur. J. Org. Chem. 2004,
4554. (m) Chi, K.-W.; Addicott, C.; Arif, A. M.; Stang, P. J. J. Am. Chem.
Soc. 2004, 126, 16569. (n) Saur, I.; Scopelliti, R.; Severin, K. Chem.-Eur.
J. 2006, 12, 1058. (o) Storm, O.; Lu¨ning, U. Chem.-Eur. J. 2002, 8, 793.
9
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A R T I C L E S
Giuseppone et al.
Figure 1. Schematic representation of the constitutional dynamic processes undergone by the present system: (left) Lewis acid-catalyzed generation of
dynamic constitutional diversity in helical molecular strands, involving compounds 1 and A, with 1 shown in its preferred helical folding; (right) evolution
of the dynamic library toward the formation of a [2 × 2] grid driven by the coordination of suitable metal ions.27
Scheme 1. Schematic Representation of the Isomorphic Correspondence between the Helicity Codons pym-py-pym (Sequence A), and
pym-hyz-pym (Sequence B), Represented in Their Transoid Forma
a One helical turn is constituted of three of the represented units A and B and enforced by (1) the electrostatic repulsion between the nitrogen dipoles, (2)
the steric repulsion between the CH’s in the cisoid conformation, and (3) the presence of weak CH‚‚‚N hydrogen bondings in the transoid form.12
Figure 2. Schematic representation of the conformational dynamic folding/unfolding of hyz-pym-based chains, triggered by metal ion binding.28
thetic access to such helicity codons necessitates extensive
synthetic efforts. The isomorphic correspondence between the
py group of the pym-py-pym sequence and a hydrazone (hyz)
group provides a powerful alternative approach and greatly
simplifies the connection of building blocks by making use of
the hydrazone condensation reaction (Scheme 1, right). Molec-
ular strands built on several hydrazone-pyrimidine (hyz-pym)
units indeed undergo self-organization into helices both in
solution and in the solid state, as has been shown by NMR
spectroscopy and X-ray crystallography.12
advanced intermediates that may be involved in the generation
of combinatorial diversity through dynamic reshuffling (Figure
3). The general synthetic pathways to access these monomeric
and oligomeric entities have been published elsewhere,12b,c and
the new compounds are described in the Experimental Section.
II. Generation of Dynamic Constitutional Diversity. He-
licity-encoded oligomeric and polymeric molecular strands based
on hydrazone connections have been found to resist many
attempts to perform component exchange,12b indicating a high
stability even at an elevated temperature and/or in the presence
of acid. As model systems for the exploration of potential
exchange catalysts, crossover experiments between the dihy-
drazone compound 5 and the dihydrazine A in chloroform at
60 °C were performed first (Figure 4). In these conditions and
without a catalyst, only 7% of 5 had been consumed after 48 h
and slow degradation of constituents of the mixture had taken
place. Under acid catalysis (20 mol % CF3CO2H), extensive
decomposition into unidentified compounds other than 2-4, B
occurred. In contrast, addition of 20 mol % of Zn(BF4)2‚H2O22b
led to complete exchange with a half-life time of 10 h without
observable degradation (Figure 4a). With Sc(OTf)3 as a catalyst,
the exchange is very efficient and the equilibrium is reached
with a half-life time of only 20 min (30 times faster) (Figure
4b). The statistical distribution of the products at equilibrium
indicates the nonspecific interaction of the metal ions with the
different compounds and the isoenergetic nature of the library.16a
As in the case of other CdN bonds under ScIII catalysis,26 the
reaction proceeds via a transimination process; indeed, in similar
conditions, the pyrimidine 4,6-biscarboxaldehyde analogue of
B and dihydrazone 5 did not yield any detectable amount of
exchange after 3 days. Moreover, for the lanthanide triflate series
In addition to their easy accessibility from simple condensa-
tion of the corresponding hydrazine and aldehyde moieties and
to their preferential helical folding, the hyz-pym sequences
present two types of dynamic features: motional dynamic
processes, conformational changes triggered by metal-ion bind-
ing and allowing contraction/extension motions, that is, revers-
ible folding/unfolding into helical/linear shapes (Figure 2);28 and
constitutional dynamic processes resulting from the well-
established reversibility of the hydrazone29 connection and
involving component exchange, reorganization, incorporation,
and decorporation as well as chain lengthening or shortening
(Figure 1).
To study the constitution of the dynamic libraries of helical
strands and to accurately identify their members, we first
synthesized a series of building blocks as well as some more
(28) Stadler, A.-M.; Kyritsakas, N.; Graff, R.; Lehn, J.-M. Chem.-Eur. J. 2006,
12, 4503.
(29) Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W. ComprehensiVe Organic
Functional Group Transformations; Pergamon: New York, 1995; Vol. 3,
p 404.
(30) In all structural formulas, the molecules are shown, for clarity, in a linear,
extended representation rather than in the correct helical form.
9
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Selective Generation of [2
×
2] Gridlike Arrays
A R T I C L E S
Figure 3. Structures of the compounds contained in the dynamic libraries investigated. Compounds 1-5, 12, 13, 20, 29-43, 49-57, as well as the two grid
structures [2 × 2]Zn454 and [2 × 2]Zn4434 were synthesized and characterized as described.12a,b,30,33
(Sc, Yb, Y, Sm, and La), the results indicated that the activity
was directly correlated with the ionic radius of the trivalent
metallic ions assayed, with scandium being the most powerful
Lewis acid catalyst for hydrazone scrambling, in agreement with
earlier results.26
To test the efficiency and generality of the process, we moved
to compound 1, a 1-turn helical strand containing four hydrazone
groups, which was expected to be much more reluctant to
undergo component exchange (Figure 5, equilibrium (a)) than
the shorter related structures (2-5, Figure 3), due to its folding
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A R T I C L E S
Giuseppone et al.
Figure 4. Evolution with time of the composition of the hydrazone/hydrazine mixture 5, A as model reaction for component exchange (top): followed by
1H NMR (a) under ZnII catalysis and (b) under ScIII catalysis; c(5) ) c(A) ) 50 mm.30
and the resulting lesser accessibility of its hydrazone sites (vide
infra). Compound 1 nevertheless underwent exchange of its two
bis-hydrazine components with bis-hydrazine A in 48 h when
mixed in a stoichiometric ratio in the presence of 20 mol %
(i.e., 5 mol % per hydrazone site of 1) of Sc(OTf)3 in chloroform
at 60 °C. The equilibrium was reached after about 48 h as
a catalyst, the microwave irradiation at 140 °C produces only
5% of conversion after 1 h (measured in 1H NMR by the
decrease of 36). The graphical representation of the systematic
comparison between classical heating (Figure 6, bottom right,
squares) and microwave heating (dots) for various temperatures
between 60 and 200 °C shows the linear dependence of both
processes on the temperature. Besides, the steep slope observed
under microwave irradiation could be indication for a very
efficient local heating of the metal center, leading to an
improvement of its efficiency as a catalyst.
Finally, microwave activation does not generate detectable
degradation products even in more complex systems, and the
equilibrium involving helices described in Figure 5 can be
reached in only 30 min at 140 °C in C2D2Cl4, as compared to
the 48 h necessary previously. It should also be pointed out
that the use of microwaves is compatible with grid-type metal
complexes, as it does not disrupt their coordination structures
(vide infra).
IV. Mechanistic Aspects of the Exchange Process -
Toward Directionally Polarized Polymerization/Depolym-
erization Processes. The mechanism of catalyzed transimination
in organic solvents was investigated previously, and, in most
cases, rate accelerations were higher with ScIII ions as compared
to those with protons.26 It was, however, unexpected that for
the equilibration described in Figure 5 and under Bro¨nsted acid
catalysis (20 mol % CF3CO2H) after 48 h, only traces of 1 had
been converted solely into compounds 11 and 3 and degradation
of the dihydrazine A had set in (as shown by NMR and LC/
MS).31 Therefore, in the particular case of hyz-pym-based
1
indicated by the stabilized pattern of the complex H NMR
spectra (Figure 5, top right). Even with only 4% catalyst (i.e.,
1% per site), extensive exchange had taken place after 48 h,
although the reaction was much slower. The constituents of the
mixture could be separated and identified by HPLC/ESMS
(Figure 5, bottom). The data analysis demonstrated that full
recombination between 1 and A had taken place, with the
generation of the set of compounds 1-28, containing even
expanded helices of up to 10 hydrazone sites (more than 3
helical turns). Moreover, all of the possible cross-combinations
with components bearing phenyl and/or methoxyphenyl moieties
were statistically generated for each size of helical strand
(Gaussian distribution), highlighting the efficiency of the
reorganization process.
III. Activation by Microwave Heating. To further improve
the efficiency of the ScIII scrambling catalysis, we investigated
the potential effect of activation by microwave heating on the
equilibration rate of another model system involving hydrazone
36 and bis-hydrazinopyrimidine A in deuterated tetrachloro-
ethane (Figure 6, top). In this mixture, the application of
microwave heating at a constant temperature of 140 °C enables
one to reach the equilibrium after only 4 min, while it requires
12 min under oil bath heating (Figure 6, bottom left). Without
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Figure 5. Generation of a highly diverse recombination library of helicity-encoded molecular strands from the 1-turn/4-sites helical compound 1 (c ) 50
mm) and the dihydrazine A (c ) 50 mm) using Sc(OTf)3 (20%) as catalyst in CDCl3 at 60 °C; 1H NMR spectra show the evolution of the equilibrium with
time and its stabilization after 48 h (top right); 28 constituents have been identified by LC/MS (bottom left) and direct introduction ESI/TOF (bottom center)
mass spectrometry, as indicated (bottom right).30
helical strands, ScIII acts as an efficient promoter of the
exchange. Insight into this specific behavior can be gained from
the crystal structures of protonated and non-protonated hyz-
pym sequences of various lengths (Figure 7).
1, although the resolution of the structure was of low quality
(data not shown). On the other hand, it is known that ZnII and
PbII ions are able to fully unfold helical strands based on hyz-
pym sequences and produce racks of linear shape (see Figure
2).28 Therefore, it seems conceivable that catalytic amounts of
ScIII ions allow the partial opening/activation of the helical
strands and facilitate as well their subsequent exchange with
free hydrazines (Figure 8, top). To obtain information about
The solid-state molecular structure of compound 42, a 4
hydrazone sites/1-turn helical strand, shows that access to the
exchangeable CdN bonds is hindered by wrapping of the
molecule around them, thus leading to a low reactivity for the
transimination reaction (Figure 7). The activation of the hydra-
zone sites would require an unfolding via a change of the s-trans
to the s-cis conformation through, for example, chelation to a
cationic center. However, protonation does not lead to an
unfolding of such structures. Indeed, the crystal structure of the
diprotonated form of 43 (Figure 7) shows that the two protons
are located on the pyridine moieties and do not lead to the
desired s-cis linear strand. A similar observation was also made
for the crystal structure of the bis-protonated helical strand of
1
these mechanistic aspects, we performed the partial H NMR
titration of helix 1 with increasing amounts of Sc(OTf)3 between
0 and 0.5 equiv (Figure 8, bottom). The observed changes are
in agreement with a partial unfolding at the pyridine termini,
as indicated by the marked deshielding of the protons located
in this pym-hyz-pyr moiety (c-f), while the protons of the
central part of the strand are hardly affected (a and b). Moreover,
the fact that 11 and 3 are the first two products to be formed,
as a function of time, appearing during the equilibration
described in Figure 5, supports the hypothesis that, not
unexpectedly, the helical strands react first by their more
accessible extremities and not by their core hydrazone sites.
(31) In all our attempts involving crossover reactions, the use of the metallic
salts Zn(BF4)2‚8H2O or Sc(OTf)3 avoided the degradation of the library
constituents, whereas uncatalyzed and, to a larger extent, proton-catalyzed
reactions always underwent extensive side reactions.
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Figure 6. Generation of a model hydrazone/hydrazine equilibrium (top) under ScIII catalysis/microwave activation and followed by 1H NMR as a function
of time and depending on the heating conditions (bottom left); c(36) ) c(A) ) 5 mm in C2D2Cl4. Comparative catalytic activities of ScIII upon classical/oil
bath and microwave heating (bottom right) where t represents the time to reach the equilibrium.
strand, despite the presence of exchangeable sites inside the
strand. This loss of the exchange and reshuffling capabilities
can be directly related to the requirement to partially unfold
the strands to activate the first accessible hydrazone site,
depending on the nature of the extremities. The unfolding
energies have been calculated for the 2-turns helices 17, 30,
and 29, respectively (Figure 10), and it was confirmed that this
energy increases with the use of more “static” capping moieties.
Thus, these observations point to the regioselectivity of the
exchange, starting at the termini of the strands due to their
folding, and leading to a directional polymerization/depolym-
erization process. The feasibility of an oriented constitutional
elongation/shrinkage process using dissymmetric helices having
a single static ending was tested by first synthesizing compound
57, which can then react with A to produce, as a function of
time, the various structures described in Figure 11 by reaction
at one end only. The reaction was set up in relatively mild
Figure 7. X-ray structures of compounds 55, bis-protonated 43, and 1-turn
conditions (60 °C, [57] ) 5.7 mm) to keep a slow rate of
exchange, which allows the analysis of new crossover products
by LC/MS as a function of time. The first set of adducts (58
and 3) was observed after a reaction time of 100 min (t1), the
second one (34, 6, 7, and 4) after 28 h (t2), and finally 59 was
detected after 60 h (t3) together with longer strands such as 60
(and others up to 3 turns). These experimental facts, together
with the absence at any time of crossover products resulting
from the addition of a free hydrazine to an inner hydrazone,
agree with the occurrence of an oriented constitutional motional
process in this system (see Figure 11, top right).
helix 42 (sticks and space-filling representations).
To confirm that the crossover exchange starts at the ends of
the strands, nonexchangeable capping-agents were introduced
into the helices. To this end, we synthesized both 1-turn (4 sites)
and 2-turns (6 sites) helical strands incorporating a non-dynamic
terminal pyrimidine-pyridine moiety (single non-reversible
connection; “static” capping) at each extremity (type b helices
31 and 30, respectively, Figure 3), as well as their analogues
incorporating a pyrimidine-bipyridine moiety, containing two
terminal non-reversible connections (type c helices 32 (see X-ray
in Figure 9) and 29; “double static” capping). The results of
the attempts to perform transimination reactions on these
compounds in the presence of bis-hydrazinopyrimidine A in the
presence of 5 mol % of ScIII catalyst per chelating site are
summed in Table 1.
V. Driven Evolutions of Helical Libraries Toward Met-
allosupramolecular [2 × 2] Gridlike Arrays. The dynamic
library of helical structures under equilibrating conditions,
represented in Figure 5, was treated with Zn(OTf)2 (1 equiv
with respect to the initial amount of compound 1). ZnII ions
are known to self-assemble with two-site ligands such as 5,
yielding [2 × 2] grid-type complexes in acetonitrile (Figure 12,
It appears clearly that the presence of nonexchangeable
endings “freezes” the constitutional dynamics of the whole
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Figure 8. Schematic representation of the partial unfolding of a 1-turn/4-sites s-trans helicity-encoded molecular strand upon ScIII chelation and leading to
a terminal s-cis hydrazone bond, thus activated for transimination reactions (top); selected 1H NMR spectra of the titration of helical strand 1 (c ) 25 mm)
by increasing amounts of Sc(OTf)3, between 0 and 0.5 equiv in CDCl3.
Table 1. Effect of the Presence of Different Capping Agents for
the Constitutional Dynamics of the 1-Turn/4-Sites and 2-Turns/
6-Sites Helicity-Encoded Molecular Strands upon ScIII Catalysis
crossover reactions with
bis-hydrazinopyrimidine Aa
4 sites/1 turn
6 sites/2 turns
type a helices
1, exchange
17, exchange
(“dynamic” capping)
type b helices
(“static” capping)
type c helices
31, exchange
30, no exchange
29, no exchange
32, no exchange
(“double static” capping)
a Checked by 1H NMR and LC/MS after 24 h of heating at 60 °C in
CDCl3 in the presence of 5 mol % of Sc(OTf)3 per chelating site.
Figure 9. X-ray structure of the 1-turn helical strand 32 containing two
non-reversible connections, pyrimidine-pyridine-pyridine (top and side
views).
resulting from the dissociation of the complexes on the column)
and the ESMS data indicated a marked increase of the amount
of 5, which forms the [2 × 2] grid structure, accompanied by
a decrease of the larger helical species, as compared to the initial
equilibrium (a). Moreover, ZnII ions favored 5 over 4, which
contains a more bulky central group that hinders the formation
of the homoleptic grid complex Zn444. These observations
indicate that the addition of ZnII drives the evolution of the
dynamic set toward the expression of ligand 5 under the pressure
equilibrium (b)).32 The formation of Zn454 as a major tetra-
nuclear grid species, together with the Zn4534 and Zn45242
analogues, was observed by ESI/TOF mass spectroscopy using
direct injection. The HPLC trace (b) (displaying the ligands
(32) Ruben, M.; Lehn, J.-M.; Vaughan, G. J. Chem. Soc., Chem. Commun. 2003,
1338.
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Figure 10. MM2 calculations of the minimum relative energies necessary to allow the constitutional dynamics of the 2-turns/6-sites helicity-encoded
molecular strands upon partial unfolding (by a single s-cis f s-trans conversion) depending on their capping moieties.
Figure 11. Various structures (and corresponding observed exact masses) obtained by addition of compound A on the dissymmetric helical strand 57 (ratio:
1/1) under ScIII catalysis (20 mol %) and as a function of increasing times of reaction (t0, ..., t3) : c57 ) 5.7 mm, T ) 60 °C, t0 ) 0, t1 ) 1 h 40 min, t2 )
28 h, t3 ) 60 h. Each period is the time necessary to generate a new set of compounds, and the drawn structures, until the fourth generation, are limited to
the one observed by LC/MS and resulting from the addition of a free hydrazino group to one exchangeable extremity of the library of strands (see dashed
and bold plain arrows). (Top right) Schematic directional polymerization/depolymerization process occurring from the reaction of 57 and A for the strands
bearing the terminal bipyridine unit.30
of the formation of the (least bulky) grid-type complex by
dissociation and recombination of the subunits of the helical
strands to form the corresponding ligand 5. The process was
also found to depend on the ZnII concentration (Figure 10,
equilibrium (c)). As shown by the HPLC trace as well as by
the direct introduction ESI/TOF mass spectroscopy, when 3
equiv of Zn(OTf)2 was added to the mixture, in addition to an
increase of 5 (and of 4 to a lesser extent), the main effect was
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Figure 12. Driven evolution of the dynamic library (a), produced initially from strand 1 (see Figure 5), toward the generation of the [2 × 2] grid complex
Zn454 (bottom left: HPLC traces) by addition of 1 (b) or 3 (c) equiv of Zn(OTf)2 (CD3CN; 60 °C; 24 h) to the library (a), pre-equilibrated as in Figure 4
(20% Sc(OTf)3; CDCl3; 60 °C; 48 h), and then evaporated and redissolved in CD3CN; the equilibrium was not significantly affected by the change in
solvent; (bottom right) comparison between the reference (no metal ion), Zn(OTf)2, and Co(BF4)2, for the generation of ligands 4 and 5 as induced by the
amplification of the grid-type complex after heating in CD3CN at 60 °C for 24 h (bottom right: expanded HPLC traces).30
the formation of mononuclear Zn22, Zn23, and Zn32 complexes,
leading to a large amplification of the single site ligands 2 and
3 in the library, as compared to the equilibria (a) and (b). This
observation may be accounted for as resulting from the
adaptation of the system to generate the ligands providing the
sites required for more complete zinc coordination.
the spectrum, before exchange (t ) 0), of ligand 43 mixed with
0.5 equiv of bis-hydrazinopyrimidine A (to allow generation
of a library of helical strands) in the presence of only 10 mol
% ScIII. The equilibrium was reached after 18 min upon
microwave heating at 140 °C in CDCl3 with the unambiguous
formation of a mixture of helical entities, as seen in spectrum
b (characteristic triplets below 6.9 ppm). The subsequent
treatment of this library with 1 equiv of Zn(OTf)2 in CD3CN
We also compared the effect of different metal salts [Zn-
(OTf)2, Co(BF4)2, Hg(OAc)2, Pb(OAc)2, and Fe(BF4)2] for the
amplification of short ligands through the formation of the
corresponding [2 × 2] grids.8 Whereas ZnII ions led to a light
yellow solution, the addition of 1 equiv of CoII, HgII, PbII, or
FeII yields light orange, dark red, dark red, and dark green
solutions, respectively. The analysis of the HPLC traces showed
that PbII, HgII, and FeII gave some supplementary unidentified
products, whereas CoII appeared to be the most efficient metal
ion for the amplification of 5 (increase by a factor 2 as compared
to ZnII, in line with the expected relative stabilities of the grids
formed with ZnII and CoII ions) (Figure 12, bottom right).
Next, to set up a system that would be capable of highly
selective amplification, we used as starting material the slightly
different helical library generated from the 2 sites ligand 43
(Figure 3), in which the positions of the hydrazone sites are
reversed as compared to ligand 5. This connection was chosen
as it may be expected to produce in situ, during the library
formation, the nucleophilic hydrazinopyridine capping entities
41, with the correct stoichiometry for converting the set of
helices into the ligand necessary for the quantitative formation
of the gridlike complex [2 × 2]Zn4434.
1
led to a dramatic evolution of the H NMR pattern toward
spectrum c, which is almost superimposable to that of the
independently prepared genuine grid complex [2 × 2]Zn4434
(d). Moreover, the opposite evolution from the grid (d) to the
library of helices (b) is also possible by adding 1 equiv of
hexamethylhexacyclene to trap ZnII ions and release free 43.
This spectacular evolution of the library is also confirmed
by ESMS spectroscopy (Figure 14). Direct injection of the
equilibrated mixture (b in Figure 13) before the addition of ZnII
indicates the presence of various helical entities of different
sizes, up to 2 turns/6 sites (Figure 14, spectrum a). An almost
quantitative shift in the composition of helices via the formation
of the grid array is observed in the presence of 1 equiv of Zn-
(OTf)2 after 3 h at 140 °C (Figure 14, trace c). In the latter
spectrum, the assignment of the grid fragments was given by
superimposition with the spectrum of the pure [2 × 2]Zn4434
[see also the HRMS extension of the doubly charged grid [2 ×
2+
2]Zn4434(OTf)6 (e) as well as its theoretical isotopic pattern
(f)]. Moreover, spectrum b shows that the grid is kinetically
formed from the corner intermediate Zn2432(OTf)3+, which was
the major component after 0.5 h (see extension of spectrum d
1
These assumptions were verified experimentally first by H
NMR studies, as described in Figure 13. Spectrum (a) shows
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Figure 13. Generation of a library of helicity-encoded molecular strands from the 2-sites compound 43 and bis-hydrazinopyrimidine A (0.5 equiv) upon
ScIII (10 mol %) catalysis (top left). Subsequent driven evolution of the dynamic library toward the formation of the [2 × 2] grid complex Zn4434 (top right).
Bottom right: 1H NMR spectra of the initial mixture 43 + A (a), of the equilibrated library of helices after 18 min (b), of the equilibrated library after 3
h in presence of Zn(II) ions (c), and of the separately prepared grid [2 × 2]Zn4434 as reference (d).
remove any trace of acid. Yields refer to purified spectroscopically
(1H NMR) homogeneous materials. Thin layer chromatographies were
showing the mono-charged corner together with some emerging
doubly charged grid).
performed with TLC silica plastic sheets (Polygram SIL G/UV254
,
Conclusion
Macherey-Nagel) or TLC alox plastic sheets (Polygram Alox N/UV254
,
Macherey-Nagel). In most cases, irradiation using a Bioblock VL-4C
UV-lamp (6 W, 254 nm and/or 365 nm) and p-anisaldehyde staining
were used for visualization. Preparative adsorption flash column
chromatographies were performed using silica gel (Geduran, silica gel
60 (230-400 mesh, 40-63 µm, Merck)) and aluminum oxide 90
(Merck; 70-230 mesh, standardized activity II). High-pressure liquid
chromatography (HPLC) was carried out on a Hewlett-Packard HP 1100
apparatus equipped with a diode array detector, using a reverse phase
column (Thermo, hypersil C8, 5 cm × 4.6 mm 5 µm). 1H NMR spectra
were recorded on a Bruker Avance 400 spectrometer at 400 MHz and
13C spectra at 100 MHz in CDCl3 unless stated otherwise. The spectra
were internally referenced to the residual proton solvent signal. In the
1H NMR assignments, the chemical shifts are given in ppm. The
coupling constants J are listed in Hz. The following notation is used
The data reported here provide a general and efficient
procedure for the generation of dynamic libraries of constituents,
discrete molecules of helical shapes, undergoing assembly,
dissociation, and exchange processes, induced by ScIII catalysis
and facilitated by microwave activation. The transimination-
type mechanism of the ScIII-promoted exchange, as well as its
regioselectivity, occurring at the extremities of the strands, allow
one to perform directional terminal polymerization/depolym-
erization processes. These libraries can subsequently be driven
by interaction with metal ions (such as ZnII and CoII) toward
the amplification of specific ligand constituents, under the
pressure of the formation of stable [2 × 2] gridlike coordination
architectures (Figure 1). Furthermore, suitable design of these
libraries in terms of chemical structures and stoichiometry
enables one to make this evolution from helices to grids
quantitative. In a broader perspective, the results illustrate the
ability of constitutional dynamic systems to respond to envi-
ronmental parameters and to perform internally (folding) and
externally (metal ions) driven evolution toward the fittest
constituent, an essential feature characterizing the adaptive and
evolutive nature of CDC under the pressure of environmental
factors.
1
for the H NMR spectral splitting patterns: singlet (s), doublet (d),
triplet (t), multiplet (m), large (l). The temperatures that are given for
the kinetic and thermodynamic data were directly measured and
regulated in the NMR probe using a thermocouple. Electrospray (ESI-
TOF) studies were performed on a Bruker MicroTOF mass spectrometer
(sample solutions were introduced into the mass spectrometer source
with a syringe pump with a flow rate of 40 µL min-1). Melting points
(Mp) were recorded on a Kofler Heizblock and on a Bu¨chi Melting
Point B-540 apparatus and are uncorrected. Microanalyses were
performed by the Service de Microanalyse, Institut de Chimie,
Universite´ Louis Pasteur. X-ray crystallography: The crystals were
placed in oil, and a single crystal was selected, mounted on a glass
fiber, and placed in a low-temperature N2 stream. The X-ray diffraction
data were collected on a Nonius-Kappa-CCD diffractometer with
graphite monochromatized Mo KR radiation (λ ) 0.71071 Å), φ scans,
using a “φ scan” type scan mode. The structures were solved using
Experimental Section
General Aspects. All reagents and solvents were purchased at the
highest commercial quality and used without further purification unless
otherwise noted. Deuterated chloroform used for the kinetic measure-
ments was flashed through basic alumina immediately prior to use, to
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Figure 14. Driven evolution of the dynamic library derived from 43 and A (Figure 13, top) toward the generation of the [2 × 2] grid complex Zn4434.
ESMS direct injection spectra: (a) of the library of the molecular strands after 20 min under microwave activation at 140 °C (some products are ionized with
protonated compound 41); (b) of the equilibrated library after 0.5 h at 140 °C in the presence of Zn(II) ions; (c) of the equilibrated library after 3 h at 140
°C in the presence of Zn(II) ions; (d) and (e) are the expansions of the corresponding sets of peaks in spectra b and c, respectively; spectrum f is the
calculated isotopic pattern of the grid [2 × 2] Zn4434(OTf)62+. Spectra a-c were obtained using the same spectroscopic/ionization conditions and are
directly comparable in terms of intensities.
direct methods and refined (based on F2 using all independent data)
by full-matrix least-squares methods (OpenMolen Package). CCDC
620827-620830 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Center via www.ccdc.ac.uk/
data_request/cif. All molecular representations (Stick, CPK) and 3D-
images in this Article were created using WebLabViewer Pro (ver. 5,
2002, Accelrys). Microwave heating was performed using a CEM
discover with closed vessels filled with 1-2 mL solutions. The
regulation of the heating was done by fixing the temperature and without
regulation of the power or the pressure. LC/MS was performed by
coupling a Hewlett-Packard HP 1100 chromatography apparatus and
either a Thermo Finnigan Surveyor MSQ mass spectrometer or a Bruker
MicroTOF mass spectrometer. The samples were prepared from an
aliquot of the mixtures under equilibration, diluted 1000 times in a
solution of CHCl3/MeOH (2/3:1/3).
General Procedure for Crossover Experiments and Determina-
tions of Kinetic Data. A typical protocol is realized by the preparation
of a fresh CDCl3 solution containing the compounds to exchange in a
NMR tube (0.6 mL, 22.6 mM in hydrazone) or a vial (2 mL, 22.6 mM
in hydrazone). The desired amounts of catalyst were immediately added
to this mixture from a CD3CN solution (5-50 µL, 45 mM, 0.2-8.0
vol % of CD3CN in CDCl3), prior to NMR measurements. The first
spectrum was usually recorded 30 s after addition without spinning in
the probe. The NMR tubes were topped with Teflon caps to keep a
constant concentration upon heating.
Figures 13 and 14). Compound 43 (21.15 mg, 5 × 10-3 mmol) and
bis-hydrazinopyrimidine A (8.3 mg, 2.5 × 10-3 mmol) were dissolved
in 2 mL of CDCl3. The catalyst (10%) was added via a microsyringe
(15 µL) from of a solution of Sc(OTf)3 in CD3CN (90 mg in 0.5 mL).
The yellow solution was heated in a closed vial adapted to the
microwave apparatus at 140 °C for 18 min. Next, the solvent was
evaporated to almost dryness under reduced pressure, and the residue
was dissolved using a solution of Zn(OTf)2 (18 mg, 5 × 10-3 mmol)
in 1 mL of CD3CN. After 3 h of heating under microwaves at 140 °C,
the solution turned dark red/brown, the characteristic color of grid [2
× 2]Zn4434.
Procedures for the Syntheses and Characterizations of the
Products. Products A, B, 1, 2, 4-6, 20, 41, 43 are described in ref
12b, products 39 and 40 are in ref 12a, and grids [2 × 2]Zn454 and [2
× 2]Zn4434 are described in ref 33.
Pyridine-2-carboxaldehyde Methyl[6-(1-methylhydrazino)-2-
(3,4,5-trimethoxyphenyl)pyrimidin-4-yl]hydrazone (3). To a solution
of 4,6-bis(N-methylhydrazino)-2-(3,4,5-trimethoxyphenyl)pyrimidine
A12b (250 mg, 74 × 10-2 mmol) in a mixture of absolute ethanol (20
mL) and CHCl3 (13 mL) was added a solution of pyridine-2-
carboxaldehyde (80 mg, 74 × 10-2 mmol) in 20 mL of absolute ethanol.
The solution was stirred at room temperature for 24 h under an
atmosphere of argon. All of the solvents were then removed under
reduced pressure, and the residue was purified by flash chromatography
(Al2O3, AcOEt/Hex, 1/1) to give 3 (170 mg, 51%) as a white solid.
(33) Barboiu, M.; Ruben, M.; Blasen, G.; Kyritsakas, N.; Chacko, E.; Dutta,
M.; Radekovich, O.; Lenton, K.; Brook, D. J. R.; Lehn, J.-M. Eur. J. Inorg.
Chem. 2006, 784.
Procedure for the Driven Evolutions of Helical Libraries Toward
Metallosupramolecular [2 × 2] Gridlike Arrays (Examples of
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3
3
Mp 162-165 °C. 1H NMR: 8.57 (d, 3J ) 4.8 Hz, 2H), 8.0 2 (d, 3J )
7.56 (s, 2H), 7.43 (s, 4H), 7.32 (t, J ) 6.8 Hz, 4H), 7.20 (t, J ) 6.8
Hz, 4H), 7.17-7.15 (m, 2H), 7.14 (s, 2H), 4.01 (s, 6H), 3.92 (s, 12H),
3.79 (s, 6H), 3.39 (s, 6H). 13C NMR: 164.25, 163.70, 162.10, 161.90,
161.85, 160.85, 154.35, 152.55, 149.00, 139.95, 138.10, 137.15, 136.25,
134.95, 133.10, 130.55, 130.20, 128.65, 128.15, 127.90, 127.80, 124.80,
120.95, 105.10, 88.20, 60.85, 55.95, 30.10, 29.25. HRMS (ESi-TOF-
MS) m/z (%): calcd for C74H67N20O6 1331.5547 [M + H]+; found
1331.5512 (100) [M + H]+.
3
5.4 Hz, 2H), 7.54 (s, 1H), 7.73 (m, 3H), 7.21 (t, J ) 5.4 Hz, 1H),
6.95 (s, 1H), 3.96 (s, 6H), 3.90 (s, 3H), 3.77 (s, 3H), 3.42 (s, 3H). 13
C
NMR: 163.1, 155.1, 153.0, 149.3, 140.3, 137.0, 136.6, 136.4, 136.1,
122.9, 119.9, 105.3, 86.8, 60.9, 56.1, 29.8, 29.7. HRMS (ESi-TOF-
MS) m/z (%): calcd for C21H25N7O3 446.1916 [M + H]+; found
446.1750 (100) [M + Na]+.
2-Phenylpyrimidine-4,6-dicarboxaldehyde 4,4-Bis{methyl{6-[1-
methyl-2-(pyridin-2-ylmethylene)hydrazino]-2-(3,4,5-trimethoxy-
phenyl)pyrimidin-4-yl}hydrazone} 6,6-{[2-(3,4,5-Trimethoxyphen-
yl)pyrimidine-4,6-diyl]bis(methylhydrazone)} (17). To a solution of
4,6-bis(N-methylhydrazino)-2-(3,4,5-trimethoxyphenyl)pyrimidine A12b
(5 mg, 1.49 × 10-2 mmol) in a CHCl3 solution (0.8 mL) was added 35
(18.5 mg, 2.99 × 10-2 mmol). The solution was stirred at 60 °C
overnight under an atmosphere of argon. All of the solvent was then
removed under reduced pressure, and the residue was purified by flash
chromatography (silica gel, gradient of solvents: CHCl3 to CHCl3/
MeOH (95/5)) to give 17 (22 mg, 96%) as a yellow powder. Mp >
6,6′-(6,6′-(1E,1′E)-(2,2′-(2-(3,4,5-Trimethoxyphenyl)pyrimidine-
4,6-diyl)bis(2-methylhydrazin-2-yl-1-ylidene))bis(methan-1-yl-1-
ylidene)bis(2-phenylpyrimidine-6,4-diyl))di-2,2′-pyridine (31). To a
solution of 2-phenyl-6-(pyridin-2-yl)pyrimidine-4-carbaldehyde 54 (94
mg, 2.77 × 10-1 mmol) in CHCl3 (2 mL) was added 4,6-bis(N-
methylhydrazino)-2-(3,4,5-trimethoxyphenyl)pyrimidine A12b (46.4 mg,
1.38 × 10-1 mmol). The solution was stirred at room temperature
overnight under an atmosphere of argon. All of the solvent was then
removed under reduced pressure, and the residue was purified by flash
chromatography (silica gel, CHCl3) to give a mixture of 31 (top spot,
62 mg, 55%, yellow powder) and of the corresponding monohydrazine
33 (bottom spot, 38 mg, yellow powder). 31, Mp > 250 °C
(decomposition). 1H NMR: 8.95 (s, 2H), 8.73-8.63 (m, 4H), 8.22 (s,
1
3
250 °C (decomposition). H NMR: 8.39 (s, 2H), 8.20 (dd, J ) 8.6
Hz, 3J ) 1.2 Hz, 4H), 8.03 (d, 3J ) 4.3 Hz, 2H), 7.69 (d, 3J ) 7.8 Hz,
2H), 7.64 (d, 3J ) 5.8 Hz, 4H), 7.60 (s, 2H), 7.57 (s, 2H), 7.45 (s, 4H),
7.42 (s, 2H), 7.35 (t, 3J ) 7.4 Hz, 2H), 7.22 (t, 3J ) 7.0 Hz, 4H), 7.22
(s, 1H), 6.98 (t, 3J ) 7.4 Hz, 2H), 6.64 (dd, 3J ) 6.2 Hz, 3J ) 1.2 Hz,
2H), 4.10 (s, 6H), 4.02 (s, 3H), 4.00 (s, 6H), 3.89 (s, 12H), 3.80 (s,
6H), 3.68 (s, 12H).13C NMR: 164.45, 162.45, 162.00, 161.45, 161.30,
161.20, 161.05, 160.75, 153.75, 153.05, 152.60, 140.30, 140.05, 137.05,
135.50, 135.25, 135.15, 133.50, 133.10, 130.30, 127.95, 127.90, 122.00,
119.30, 106.95, 105.40, 105.15, 89.00, 87.30, 61.00, 60.85, 56.30, 55.95,
30.15, 30.05, 29.80. HRMS (ESi-TOF-MS) m/z (%): calcd for
C81H81N24O9 1533.6618 [M + H]+; found 1533.6625 (100) [M + H]+.
3
1H), 8.14 (d, J ) 7.9 Hz, 2H), 8.00 (s, 2H), 7.85 (s, 2H), 7.60-7.50
(m, 8H), 7.55 (td, 3J ) 7.6 Hz, 3J ) 1.7 Hz, 2H), 6.96 (ddd, 3J ) 7.3
Hz, 3J ) 4.7 Hz, 3J ) 1.2 Hz, 2H), 4.06 (s, 6H), 3.99 (s, 3H), 3.94 (s,
6H). 13C NMR: 164.00, 163.25, 162.80, 161.95, 153.85, 153.10, 153.00,
148.50, 137.95, 136.05, 135.25, 133.40, 130.60, 128.55, 128.20, 124.55,
120.80, 110.25, 105.45, 101.95, 89.10, 61.00, 56.20, 30.15. HRMS (ESi-
TOF-MS) m/z (%): calcd for C47H41N12O3 [M + H]+ 821.3419; found
821.3453 (100) [M + H]+. 33, H NMR: 8.84 (s, 1H), 8.76 (d, J )
3.9 Hz, 1H), 8.70 (d, J ) 8.2 Hz, 1H), 8.64 (m, 2H), 7.92 (td, J )
7.8 Hz, J ) 1.6 Hz, 2H), 7.85 (s, 1H), 7.76 (s, 2H), 7.58-7.55 (m,
1
3
3
3
3
(1E,1′E)-(2,2′-(6,6′-(2E,2′E)-2,2′-(2-Phenylpyrimidine-4,6-diyl)bis-
(methan-1-yl-1-ylidene)bis(1-methylhydrazin-1-yl-2-ylidene)bis(2-
(3,4,5-trimethoxyphenyl)pyrimidine-6,4-diyl))bis(2-methylhydrazin-
2-yl-1-ylidene))bis(methan-1-yl-1-ylidene)bis(2-phenylpyrimidine-
6,4-diyl))di-2,2′-bipyridine (29). 6-(2,2′-Bipyridin-6-yl)-2-phenylpyrimi-
dine-4-carbaldehyde 53 (30 mg, 8.9 × 10-2 mmol) and 4,6-bis(1-
methylhydrazinyl)-2-(3,4,5-trimethoxyphenyl)pyrimidine (30 mg, 0.089
mmol) were stirred in 2 mL of chloroform at 40 °C for 2 h under an
atmosphere of argon. 4,6-Diformyl-2-phenyl-pyrimidine (9.5 mg, 0.045
mmol) was then added and stirred at 40 °C for 12 h. After the solvent
was removed under reduced pressure, the residue was purified by
chromatography (Al2O3, CHCl3) to give 29 (15 mg, 23%) as a yellow
solid. Mp > 250 °C (decomposition). 1H NMR: 8.88 (s, 1H), 8,57 (d,
3J ) 8.0 Hz, 2H), 8.40 (d, 3J ) 7.2 Hz, 2H), 8.31 (d, 3J ) 7.2 Hz, 4H),
3
3
3
2H), 7.44 (ddd, J ) 7.0 Hz, J ) 4.7 Hz, J ) 1.2 Hz, 1H), 7.11 (s,
1H), 4.00 (s, 6H), 3.95 (s, 3H), 3.82 (s, 3H), 3.48 (s, 3H). 13C NMR:
165.40, 164.35, 163.25, 162.70, 162.50, 161.75, 154.60, 152.95, 149.40,
140.20, 137.75, 137.10, 134.55, 133.85, 130.65, 128.50, 128.25, 125.20,
121.95, 109.90, 105.35, 83.35, 60.95, 56.15, 39.70, 30.10, 28.25. HRMS
(ESi-TOF-MS) m/z (%): calcd for C31H32N9O3 578.2623 [M + H]+;
found 578.2625 (100) [M + H]+.
6,6′-(6,6′-(1E,1′E)-(2,2′-(2-(3,4,5-Trimethoxyphenyl)pyrimidine-
4,6-diyl)bis(2-methylhydrazin-2-yl-1-ylidene))bis(methan-1-yl-1-
ylidene)bis(2-phenylpyrimidine-6,4-diyl))di-2,2′-bipyridine (32). 6-(2,2′-
Bipyridin-6-yl)-2-phenylpyrimidine-4-carbaldehyde 53 (30 mg, 8.9 ×
10-2 mmol) and 4,6-bis(1-methylhydrazinyl)-2-(3,4,5-trimethoxyphen-
yl)pyrimidine (14.5 mg, 4.5 × 10-2 mmol) were stirred in 2 mL of
chloroform at 40 °C for 12 h under an atmosphere of argon. The solvent
was then removed under reduced pressure, and the residue was purified
by chromatography (Al2O3, CHCl3) to give 32 (30 mg, 69%) as a yellow
solid. Mp > 250 °C (decomposition). 1H NMR: 8.82 (s, 2H), 8.40 (m,
3
3
8.08 (m, 5H), 7.97 (t, J ) 8.0 Hz, 2H), 7.74 (s, 2H), 7.54 (d, J ) 6
3
Hz, 4H), 7.50 (s, 2H), 7.45 (s, 4H), 7.26 (m, 4H), 7.23 (t, J ) 8 Hz,
2H), 7.05 (s, 2H), 6.85 (s, 2H), 6.71 (m, 2H), 4.01 (s, 6H), 3.93 (s,
12H), 3.82 (s, 6H), 3.42 (s, 6H). 13C NMR: 164.04, 162.62, 162.49,
162.33, 161.348, 160.75, 155.693, 154.86, 153.83, 152.96, 148.62,
140.50, 138.41, 137.60, 137.41, 135.96, 135.62, 133.44, 130.59, 128.91,
128.62, 128.29, 123.67, 122.47, 121.39, 120.91, 109.44, 105.57, 87.65,
61.20, 56.34, 34.24, 32.24. HRMS (ESi-TOF-MS) m/z (%): calcd for
C84H73N22O6 1485.6078 [M + H]+; found 1485.6279 (100) [M + H]+.
3
4H), 8.19 (m, 7H), 8.08 (d, J ) 8.2 Hz, 2H), 7.86 (s, 2H), 7.80 (s,
2H), 7.64 (t, 3J ) 8.0 Hz, 2H), 7.55 (m, 6H), 7.36 (td, 3J ) 8.2 Hz, 3J
3
) 1.2 Hz, 2H), 6.93 (t, J ) 5.4 Hz, 2H), 4.09 (s, 6H), 4.01 (s, 3H),
3.90 (s, 6H). 13C NMR: 163.78, 163.30, 162.29, 162.23, 154.72, 154.53,
153.13, 152.80, 148.33, 137.78, 137.21, 136.32, 135.68, 132.91, 132.13,
132.04, 131.95, 130.34, 128.54, 128.42, 128.33, 128.28, 123.42, 121.91,
121.27, 120.28, 109.53, 105.51, 87.22, 60.99, 56.24, 30.25. HRMS (ESi-
TOF-MS) m/z (%): calcd for C57H46N14Na1O3 997.3770 [M + Na]+;
found 997.3771 (100) [M + Na]+.
(1E,1′E)-(2,2′-(6,6′-(2E,2′E)-2,2′-(2-Phenylpyrimidine-4,6-diyl)bis-
(methan-1-yl-1-ylidene)bis(1-methylhydrazin-1-yl-2-ylidene)bis(2-
(3,4,5-trimethoxyphenyl)pyrimidine-6,4-diyl))bis(2-methylhydrazin-
2-yl-1-ylidene))bis(methan-1-yl-1-ylidene)bis(2-phenylpyrimidine-
6,4-diyl))di-2,2′-pyridine (30). A solution of 33 (30.8 mg, 4.7 × 10-2
mmol) and 2-phenylpyrimidine-4,6-dicarboxaldehyde12b (5 mg, 2.35
× 10-2 mmol) in 1.2 mL of CHCl3 was stirred at room temperature
for 12 h under an argon atmosphere. Chloroform was then removed
under reduced pressure, and the residue was purified by flash chro-
matography (silica gel, CHCl3) to afford 30 (30 mg, 96%) as a pale
yellow powder. Mp > 250 °C (decomposition). 1H NMR: 8.75 (l, 2H),
8.55 (d, 3J ) 7.8 Hz, 4H), 8.47 (s, 1H), 8.29 (d, 3J ) 7.4 Hz, 4H), 7.96
Crystal Structure of 32 (CCDC 620830). A suitable crystal of 32
was obtained by diffusion-recrystallization from CHCl3 (solvent).
Diffraction data were collected at 173 K. Formula: C60H49Cl9N14O3d
C57H46N14O3‚3CHCl3. Molecular weight: 1333.18. Yellow crystal;
crystal size (mm): 0.18 × 0.14 × 0.10. Unit cell parameters: a )
13.8400 (3) Å, b ) 15.0840(3) Å, c ) 16.3080(4) Å, R ) 82.84(5)°,
â ) 70.59°(5), γ ) 75.03(5)°; crystal system, triclinic; space group
P-1; V ) 3099.2(1) Å3; F(000) ) 1368; Z ) 2; calculated density )
1.43 g cm-3; linear absorption coefficient µ ) 0.464 mm-1. Of 21 844
3
(l, 2H), 7.86 (t, J ) 6.4 Hz, 2H), 7.65 (s, 2H), 7.64-7.50 (m, 3H),
9
16760 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006

Selective Generation of [2
×
2] Gridlike Arrays
A R T I C L E S
reflections measured, 14 155 reflections were unique (I > 3σ(I)); 877
refined variables. The θ range for data collection was 1.33-27.50°
with hkl limits: -19 to 19, -19 to 21, and -19 to 22. The final indices
were R ) 0.0866 and Rw ) 0.2108, with a goodness-of-fit (GOF) of
(6-(1-Methylhydrazino)-2-phenylpyrimidin-4-yl)methanol (38).
To a solution of (6-chloro-2-phenylpyrimidin-4-yl)methanol 4012a (3.6
g, 16.3 mmol) in ethanol (50 mL) was added methylhydrazine (3 mL,
56.4 mmol). The mixture was then heated to reflux for 48 h under an
argon atmosphere. Upon subsequent cooling to 0 °C, crystallization
occurred. The crystals were filtered, washed with ethanol, and air-dried
1.031. The largest peak in final difference was 0.831 e Å-3
.
(E)-6-(6-((2-Methyl-2-(6-(1-methylhydrazinyl)-2-(3,4,5-trimethoxy-
phenyl)pyrimidin-4-yl)hydrazono)methyl)-2-phenylpyrimidin-4-yl)-2,2′-bi-
pyridine (34). 6-(2,2′-Bipyridin-6-yl)-2-phenylpyrimidine-4-carbalde-
hyde 53 (30 mg, 8.9 × 10-2 mmol) and 4,6-bis(1-methylhydrazinyl)-
2-(3,4,5-trimethoxyphenyl)pyrimidine (29 mg, 9 × 10-2 mmol) were
stirred in 2 mL of chloroform at 40 °C for 12 h under an atmosphere
of argon. The solvent was then removed under reduced pressure, and
the residue was purified by chromatography (Al2O3, CHCl3) to give
1
to afford 38 as a white powder (2.8 g, 74%). Mp 137-138 °C. H
NMR (DMSO-d6): 8.34 (m, 2H), 7.45 (m, 3H), 5.38 (s, 1H), 4.83 (s,
2H), 4.45 (d, 2H), 3.39 (s, 3H). 13C NMR (DMSO-d6): 169.9, 165.3,
161.7, 138.7, 130.3, 128.6, 128.0, 97.75, 64.2, 39.4. Anal. Calcd for
C12H14N4O: C, 62.59; H, 6.13; N, 24.33. Found: C, 62.63; H, 5.89;
N, 24.44. ESI-TOF-MS m/z (%): 231.1 (100) [M + H]+.
2-Phenylpyrimidine-4,6-dicarboxaldehyde Mono{methyl{6-[1-
methyl-2-(pyridin-2-ylmethylene)hydrazino]-2-phenylpyrimidin-4-
yl}hydrazone} (42). A solution of 3 (10 mg, 2.6 × 10-2 mmol) and
4,6-diformyl-2-(3,4,5-trimethoxyphenyl)-pyrimidine12c (3.5 mg, 1.3 ×
10-2 mmol) in 0.7 mL of CDCl3 was stirred at 50 °C for 12 h. The
reaction mixture was then concentrated under reduced pressure and
purified by flash chromatography (Al2O3, CHCl3) to give 42 (9 mg,
60%). Mp > 250 °C (decomposition). 1H NMR: 8.64 (s, 1H), 8.10 (d,
3J ) 4.8 Hz, 2H), 7.97 (s, 2H), 7.91 (s, 2H), 7.85 (d, 3J ) 8.0 Hz, 2H),
1
34 (30 mg, 50%) as a yellow solid. H NMR: 8.99 (s, 1H), 8.78 (m,
3
3
2H), 8.68 (m, 3H), 8.60 (d, J ) 6.8 Hz, 1H), 8.08 (t, J ) 8.0 Hz,
3
1H), 7.96 (s, 1H), 7.88 (t, J ) 8.0 Hz, 1H), 7.79 (s, 2H), 7.57 (m,
3H), 7.36 (t, 3J ) 8.0 Hz, 1H), 7.15 (s, 1H), 4.03 (s, 6H), 3.96 (s, 3H),
3.91 (s, 3H). 13C NMR: 165.37, 164.20, 162.95, 162.41, 161.74, 157.04,
156.01, 155.63, 153.95, 152.96, 149.30, 137.90, 136.57, 135.17, 130.69,
128.51, 128.27, 123.84, 122.65, 122.03, 120.76, 105.40, 83.14, 79.17,
60.93, 56.17, 39.96, 39.85, 29.70. HRMS (ESi-TOF-MS) m/z (%):
calcd for C36H35N10O3 655.2888 [M + H]+; found 655.2977 (100) [M
+ H]+.
3
3
7.71 (s, 4H), 7.45 (s, 2H), 7.16 (t, J ) 8.0 Hz, 2H), 6.76 (t, J ) 4.8
Hz, 2H), 3.84 (s, 6H), 3.61 (s, 6H). 13C NMR: 162.5, 162.1, 161.3,
153.8, 153.1, 149.3, 140.6, 136.1, 135.6, 135.3, 133.4, 132.9, 122.9,
122.1, 119.5, 119.3, 105.5, 87.7, 60.95, 56.3, 55.9, 55.8, 30.2, 29.8.
ESI-TOF-MS m/z (%): 1113.5 (100) [M + H]+.
2-Phenylpyrimidine-4,6-dicarboxaldehyde Mono{methyl{6-[1-
methyl-2-(pyridin-2-ylmethylene)hydrazino]-2-(3,4,5-trimethoxy-
phenyl)pyrimidin-4-yl}hydrazone} (35). A solution of 3 (120 mg,
0.28 mmol) and 2-phenylpyrimidine-4,6-dicarboxaldehyde12c (56 mg,
0.28 mmol) in 25 mL of CH2Cl2 was stirred at room temperature for
2 h under an argon atmosphere. The reaction mixture was then cooled
to 0 °C and filtered to give 35 as a yellow powder (104 mg, 60%). Mp
Crystal Structure of 42 (CCDC 620827). A suitable crystal of 42
was obtained by diffusion-recrystallization from CHCl3 (solvent)/
MeOH (nonsolvent). Diffraction data were collected at 173 K.
Formula: C60H66Cl6N16O10dC72H62N24‚2CHCl3‚CH3OH. Molecular
weight: 1384.01. Yellow crystal; crystal size (mm): 0.20 × 0.10 ×
0.10. Unit cell parameters: a ) 14.0332 (3) Å, b ) 15.6497(3) Å, c
) 16.0239(4) Å, R ) 87.837(5)°, â ) 74.861°(5), γ ) 75.625(5)°;
crystal system, triclinic; space group P-1; V ) 3289.2(1) Å3; F(000)
) 1440; Z ) 2; calculated density ) 1.40 g cm-3; linear absorption
coefficient µ ) 0.331 mm-1. Of 27 295 reflections measured, 10 961
reflections were unique (I > 3σ(I)); 829 refined variables. The θ range
for data collection was 2.5-30.05° with hkl limits: -19 to 19, -19 to
21, and -22 to 22. The final indices were R ) 0.093 and Rw ) 0.124,
with a goodness-of-fit (GOF) of 1.068. The largest peak in final
1
3
249 °C. H NMR: 10.22 (s, 1H), 8.66 (d, J ) 4.4 Hz, 2H), 8.61 (m,
2H), 8.39 (s, 1H), 8.34 (d, 3J ) 8.0 Hz, 1H), 8.20 (t, 3J ) 8.0 Hz, 1H),
3
8.01 (s, 1H), 7.92 (s, 1H), 7.80 (m, 4H), 7.58 (m, 4H), 7.32 (t, J )
8.0 Hz, 1H), 4.02 (s, 6H), 3.98 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H). 13
C
NMR: 193.4, 165.8, 164.2, 163.4, 162.7, 161.8, 158.3, 154.4, 153.2,
149.2, 138.9, 137.6, 136.7, 134.5, 133.26, 131.3, 128.6, 123.3, 119.8,
87.2, 60.8, 56.2, 30.4, 29.9. Anal. Calcd for C33H31N9O4: C, 64.17; H,
5.06; N, 20.41. Found: C, 63.54; H, 4.99; N, 19.98. ESI-TOF-MS m/z
(%): 618.2 (100) [M + H]+.
difference was 0.776 e Å-3
.
1-(6-(Methoxymethyl)-2-phenylpyrimidin-4-yl)-1-methyl-2-(py-
ridin-2-ylmethylene)hydrazine (36). A solution of 37 (0.3 mg, 1.23
mmol) and pyridine-2-carboxaldehyde (133 mg, 1.23 mmol) in 8 mL
of absolute ethanol was stirred at room temperature for 4 h under an
argon atmosphere. The solution was then concentrated under reduced
pressure and filtered to give 36 (333 mg, 81%) as a white solid. Mp
134-136 °C. 1H NMR: 8.55 (d, 3J ) 4.8 Hz, 1H), 8.44 (m, 2H), 8.10
Crystal Structure of 43(HOTf)2 (CCDC 620829). A suitable crystal
of 43 was obtained by diffusion-recrystallization from CHCl3/TfOH
95:5 (solvent)/MeOH (nonsolvent). Diffraction data were collected at
173 K. Formula: C26H24F6N8O6S2. Molecular weight: 722.65. Colorless
crystal; crystal size (mm): 0.20 × 0.20 × 0.20. Unit cell parameters:
a ) 9.05800 (10) Å, b ) 11.4700 (2) Å, c ) 29.730 (4) Å, R ) 90 °,
3
3
(d, J ) 8.0 Hz, 1H), 7.93 (s, 1H), 7.77 (t, J ) 8.0 Hz, 1H), 7.65 (s,
â ) 90°, γ ) 90°; crystal system, orthorhombic; space group P212121
;
3
V ) 3089.12 (8) Å3; F(000) ) 1480; Z ) 4; calculated density ) 1.554
g cm-3; linear absorption coefficient µ ) 0.264 mm-1. Of 8890
reflections measured, 6574 reflections were unique (I > 2σ(I)); 433
refined variables. The θ range for data collection was 2.35-30.04°
with hkl limits: -12 to 12, -16 to 16, and -41 to 41. The final indices
were R ) 0.0807 and Rw ) 0.1128, with a goodness-of-fit (GOF) of
1H), 7.47 (m, 3H), 7.26 (t, J ) 8.0 Hz, 1H), 4.60 (s, 2H), 3.83 (s,
3H), 3.57 (s, 3H). 13C NMR: 166.7, 163.1, 163.0, 154.5, 149.3, 138.3,
137.9, 136.5, 130.4, 128.3, 127.1, 123.27, 119.8, 100.6, 74.9, 59.0,
29.4. Anal. Calcd for C19H19N5O: C, 68.45; H, 5.74; N, 21.01. Found:
C, 68.41; H, 6.14; N, 20.60. ESI-TOF-MS m/z (%): 334.2 (100) [M
+ H]+.
1-(6-(Methoxymethyl)-2-phenylpyrimidin-4-yl)-1-methylhydra-
zine (37). Methylhydrazine (0.3 mL, 5.64 mmol) was added to a
solution of 4-chloro-6-methoxymethyl-2-phenylpyrimidine 3912a (0.5
g, 2.15 mmol) in ethanol (6 mL). The mixture was then heated to reflux
for 48 h under an atmosphere of argon. Upon subsequent cooling to 0
°C, crystallization occurred. The crystals were filtered, washed with
ethanol, and air-dried to afford 37 (0.42 g, 80%) as a white powder.
Mp 101-102 °C. 1H NMR: 8.39 (m, 2H), 7.43 (m, 3H), 6.87 (s, 1H),
4.52 (s, 2H), 3.52 (s, 3H), 3.42 (s, 3H). 13C NMR: 165.7, 163.2, 138.4,
130.1, 128.2, 128.1, 97.14, 93.4, 74.9, 58.9, 39.6. ESI-TOF-MS m/z
(%): 245.1 (100) [M + H]+. Anal. Calcd for C13H16N4O: C, 63.91;
H, 6.60; N, 22.93. Found: C, 63.58; H, 6.62; N, 23.13.
1.008. The largest peak in final difference was 0.316 e Å-3
.
4-(Methoxymethyl)-2-phenyl-6-(pyridin-2-yl)pyrimidine (49). A
mixture of 4-chloro-6-(methoxymethyl)-2-phenylpyrimidine 3912a (173
mg, 62.6 × 10-2 mmol), 2-(trimethylstannyl)pyridine (152 mg, 62.6
× 10-2 mmol), and Pd(PPh3)4 (36.2 mg, 5 mol %) was heated to reflux
for 12 h in 6 mL of degassed toluene. After cooling at room temperature,
the suspension was dissolved in CH2Cl2 and washed consecutively with
a saturated solution of potassium fluoride and water, and the organic
layers were dried over MgSO4 and purified by flash chromatography
(SiO2, CHCl3/MeOH: 95/5) to give 49 (120 mg, 70%) as a white solid.
Mp 94-96 °C. 1H NMR: 8.75 (d, 3J ) 4.0 Hz,1H), 8.70 (d, 3J ) 8.0
Hz, 1H), 8.58 (m, 2H), 8.40 (s, 1H), 7.91 (t, 3J ) 8 Hz, 1H), 7.51 (m,
9
J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16761

A R T I C L E S
Giuseppone et al.
3
3H), 7.41 (t, J ) 4.8 Hz 1H), 4.70 (s, 2H), 3.58 (s, 3H). 13C NMR:
nol 52 (55 mg, 16 × 10-2 mmol) in CH2Cl2 (20 mL) was added Dess-
Martin reagent (140 mg, 32 × 10-2 mmol). After 6 h of stirring, the
reaction mixture was quenched using 50 mL of a saturated solution of
NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated. The crude material was purified by flash chroma-
tography (SiO2, CHCl3/MeOH: 96/4) to give 53 (45 mg, 83%) as a
yellow solid. Mp 182-184 °C. 1H NMR: 10.23 (s, 1H), 8.87 (s, 1H),
8.68 (m, 5H), 8.61 (d, 3J ) 7.2 Hz, 1H), 8.04 (t, 3J ) 8 Hz, 1H), 7.91
(td, J ) 8 Hz, J ) 2 Hz, 1H), 7.56 (m, 3H), 7.37 (dd, J ) 7.6 Hz,
3J ) 1.2 Hz, 1H). 13C NMR: 193.46, 165.32, 165.14, 159.25, 155.87,
155.24, 152.54, 148.98, 137.92, 136.88, 136.65, 131.18, 128.53, 128.28,
123.95, 122.98, 121.66, 121.17, 110.70. HRMS (ESi-TOF-MS) m/z
(%): calcd for C21H14Li1N4O1 345.1322 [M + Li]+; found 345.1322
(100) [M + Li]+.
168.93, 163.88, 163.46, 154.55, 149.73, 137.73, 136.99, 130.62, 128.45,
128.30, 125.24, 121.89, 11.85, 74.82, 59.14. Anal. Calcd for C17H16N3O3‚
0.15CHCl3: C, 69.77; H, 5.17; N, 14.23. Found: C, 69.34; H, 5.07;
N, 14.97. HRMS (ESi-TOF-MS) m/z (%): calcd for C17H16N3O1
278.1288 [M + H]+; found 278.1282 (100) [M + H]+.
6-(6-(Methoxymethyl)-2-phenylpyrimidin-4-yl)-2,2′-bipyridine (50).
A mixture of 4-chloro-6-(methoxymethyl)-2-phenylpyrimidine 3912a
(220 mg, 62.6 × 10-2 mmol), 6-(trimethylstannyl)-2,2′-bipyridine34 (200
mg, 62.6 × 10-2 mmol), and Pd(PPh3)4 (36.2 mg, 5 mol %) was heated
to reflux for 12 h in 6 mL of degassed toluene. After cooling at room
temperature, the suspension was dissolved in CH2Cl2 and washed
consecutively with a saturated solution of potassium fluoride and water,
and the organic layers were dried over MgSO4 and purified by flash
chromatography (SiO2, CHCl3/MeOH: 95/5) to afford 50 (135 mg,
61%) as a white solid. Mp 102-104 °C. 1H NMR: 8.71 (m, 2H), 8.64
(d, 3J ) 8.8 Hz, 1H), 8.61 (d, 3J ) 2.4 Hz, 2H), 8.55 (d, 3J ) 8.8 Hz,
3
3
3
2-Phenyl-6-(pyridin-2-yl)pyrimidine-4-carbaldehyde (54). To a
solution of (2-phenyl-6-(pyridin-2-yl)pyrimidin-4-yl)methanol 51 (25
mg, 0.095 mmol) in CH2Cl2 (6 mL) was added Dess-Martin reagent
(80 mg, 1.9 mmol). After 6 h of stirring, the reaction mixture was
quenched using 50 mL of a saturated solution of NaHCO3 (50 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated.
The crude material was purified by flash chromatography (SiO2, CHCl3/
MeOH: 96/4) to give 54 (12 mg, 48%) as a white solid. Mp 129-131
1H), 8.52 (s, 1H), 8.00 (t, J ) 8.0 Hz, 1H), 7.87 (dt,3 J ) 7.6 Hz, J
) 1.6 Hz, 1H), 7.52 (m, 3H), 7.34 (dd, 3J ) 7.6 Hz, 3J ) 1.2 Hz, 1H),
4.73 (s, 2H), 3.60 (s, 3H). 13C NMR: 168.65, 163.79, 163,47, 155.73,
155.66, 153.69, 149.08, 137.88, 137.69, 136.88, 130.59, 128.45, 128.28,
122.51, 123.89, 122.50, 121.80, 121.25, 111.74, 74.91, 59.09. Anal.
Calcd for C17H16N3O3‚0.2CHCl3: C, 70.49; H, 4.85; N, 14.81. Found:
C, 70.56; H, 5.01; N, 14.81. HRMS (ESi-TOF-MS) m/z (%): calcd
for C12H19N4O1 355.1553 [M + H]+; found 355.1551 (100) [M + H]+.
(2-Phenyl-6-(pyridin-2-yl)pyrimidin-4-yl)methanol (51). A solu-
tion of BBr3 (1 M, 5 mL, in CH2Cl2) was added dropwise to a solution
of 4-(methoxymethyl)-2-phenyl-6-(pyridin-2-yl)pyrimidine 49 (48 mg,
16.9 × 10-2 mmol) in CH2Cl2 (6 mL) at 25 °C. The solution was stirred
at the same temperature for 16 h, then cooled to 0 °C and quenched by
a slow addition of diethyl ether (1 mL), MeOH (1 mL), and H2O (1
mL). The mixture was stirred at room temperature for 1 more hour
and then extracted with CH2Cl2 (2 × 15 mL). The combined organic
layers were washed with H2O (10 mL) and brine (10 mL), dried over
Na2SO4, filtered, and concentrated to give 51 (40 mg, 90% of crude
product). The crude material was used without further purification for
the next step. Mp 141-143 °C. H NMR: 8.53 (d, J ) 4 Hz, 1H),
8.50 (d, 3J ) 7.6 Hz, 1H), 8.38 (m, 2H), 8.13 (s, 1H), 7.79 (t, 3J ) 7.6
Hz, 1H), 7.35 (m, 4H), 4.70 (s, 2H). 13C NMR: 168.90, 163.88, 163.46,
154.44, 149.47, 137.73, 136.99, 130.62, 128.48, 128.30, 125.24, 121.89,
111.85, 74.82. HRMS (ESi-TOF-MS) m/z (%): calcd for C16H13Li1N3O1
270.1213 [M + Li]+; found 270.1211 (100) [M + Li]+.
(6-(2,2′-Bipyridin-6-yl)-2-phenylpyrimidin-4-yl)methanol (52). A
solution of BBr3 (1 M, 5 mL, in CH2Cl2) was added by syringe to a
solution of 6-(6-(methoxymethyl)-2-phenylpyrimidin-4-yl)-2,2′-bipy-
ridine 50 (60 mg, 16.9 × 10-2 mmol) in CH2Cl2 (6 mL) at 25 °C. The
solution was stirred at 25 °C for 16 h, and was then cooled to 0 °C and
quenched by slow addition of diethyl ether (1 mL), MeOH (1 mL),
and H2O (1 mL). The mixture was stirred at room temperature for 1
more hour and then extracted with CH2Cl2 (2 × 15 mL). The combined
organic layers were washed with H2O (10 mL) and brine (10 mL),
dried over Na2SO4, filtered, and concentrated to give 52 (55 mg, 95%)
as a white solid. The crude material was used without further
3
3
1
3
°C. H NMR: 10.22 (s, 1H), 8.78 (d, J ) 4.8 Hz, 1H), 8.87 (s, 1H),
3
3
8.04 (d, J ) 7.2 Hz, 1H), 8.66 (m, 3H), 7.37 (t, J ) 7.6 Hz, 1H),
7.57 (m, 3H), 7.37 (t, J ) 7.2 Hz, 1H). 13C NMR: 193.28, 165.53,
3
15955, 149.76, 137.13, 136.81, 131.37, 128.73, 128.48, 125.86, 121.96,
111.18. HRMS (ESi-TOF-MS) m/z (%): calcd for C16H12N3O1 262.0975
[M + H]+; found 262.0968 (100) [M + H]+.
(1-Methyl-2-(pyridin-2-ylmethylene)hydrazinyl)-2-phenylpyrimi-
dine-4-methanol (55). A solution of 38 (50 mg, 0.22 mmol) and
pyridine-2-carboxaldehyde (23.3 mg, 0.22 mmol) was stirred in 5 mL
of absolute ethanol at room temperature for 4 h under an argon
atmosphere. The solution was then concentrated under reduced pressure
and filtered to give 40 (56 mg, 80%) as a white solid. 1H NMR (DMSO-
3
3
d6): 8.64 (d, J ) 4.4 Hz, 1H), 8.43 (m, 2H), 8.04 (d, J ) 8.0 Hz,
3
1H), 8.00 (s, 1H), 7.71 (s, 1H), 7.52 (m, 3H), 7.40 (t, J ) 8 Hz 1H),
1
3
7.71 (t, 3J ) 4.4 Hz,1H), 4.60 (d, 2H), 3.82 (s, 3H). 13C NMR (DMSO-
d6): 171.2, 163.12, 162.17, 154.4, 149.9, 139.4, 137.8, 137.2, 130.9,
128.8, 128.2, 124.0, 119.9, 100.1, 64.30, 29.89. Anal. Calcd for
C18H17N5O: C, 67.70; H, 5.37; N, 21.93. Found: C, 67.59; H, 5.15;
N, 22.15. ESI-TOF-MS m/z (%): 320.14(100) [M + H]+.
Crystal Structure of 55 (CCDC 620828). A suitable crystal of 55
was obtained by diffusion-recrystallization from CHCl3 (solvent).
Diffraction data were collected at 173 K. Formula: C18H17N5O.
Molecular weight: 319.37. Yellow crystal; crystal size (mm): 0.20 ×
0.10 × 0.10. Unit cell parameters: a ) 8.3996 (3) Å, b ) 13.3132 (3)
Å, c ) 14.1796 (4) Å, R ) 90(5)°, â ) 90(5)°, γ ) 90(5)°; crystal
system, orthorhombic; space group P212121; V ) 1585.64(1) Å3; F(000)
) 672; Z ) 4; calculated density ) 1.34 g cm-3; linear absorption
coefficient µ ) 0.088 mm-1. Of 4581 reflections measured, 2981
reflections were unique (I > 3σ(I)); 217 refined variables. The θ range
for data collection was 2.5-30.02° with hkl limits: -11 to 11, -18 to
18, and -19 to 19. The final indices were R ) 0.042 and Rw ) 0.055,
with a goodness-of-fit (GOF) of 1.037. The largest peak in final
1
purification for the next step. H NMR: 8.71 (m, 2H), 8.58 (m, 4H),
8.35 (s, 1H), 8.01 (t, 3J ) 8 Hz, 1H), 7.88 (td, 3J ) 7, 6 Hz, 3J ) 2 Hz,
difference was 0.831 e Å-3
.
3
3
1H), 7.53 (m, 3H), 7.35 (dd, J ) 8 Hz, J ) 1.2 Hz, 1H), 4.94 (s,
2H). 13C NMR: 169.02, 163.37, 162.89, 155.59, 155.53, 153.20, 149.08,
137.89, 137.18, 136.90, 130.82, 128.46, 128.24, 123.93, 122.64, 121.81,
121.20, 111.10, 63.98. Anal. Calcd for C21H16N4O‚0.2CHCl3: C, 69.90;
H, 4.48; N, 15.38. Found: C, 70.23; H, 4.74; N, 15.49. HRMS (ESi-
TOF-MS) m/z (%): calcd for C21H17N4O1 341.1397 [M + H]+; found
341.1391 (100) [M + H]+.
(1-Methyl-2-(pyridin-2-ylmethylene)hydrazinyl)-2-phenylpyrimi-
dine-4-carbaldehyde (56). A solution of Dess-Martin reagent (15%
in CH2Cl2, 7.1 g) was added to a solution of 55 (800 mg, 2.51 mmol)
in CH2Cl2 (60 mL), and the reaction was stirred for 6 h. Dichlo-
romethane (100 mL) and a saturated aqueous solution of NaHCO3 (50
mL) were added, and the aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under vacuum. The crude material was
purified by flash chromatography (SiO2, CHCl3/MeOH: 96/4) to give
56 (220 mg, 30%) as a yellow solid. 1H NMR: 10.14 (s, 1H), 8.66 (d,
6-(2,2′-Bipyridin-6-yl)-2-phenylpyrimidine-4-carbaldehyde (53).
To a solution of (6-(2,2′-bipyridin-6-yl)-2-phenylpyrimidin-4-yl)metha-
3
(34) Cardenas, D. J.; Sauvage, J.-P. Synlett 1996, 916.
3J ) 4.4 Hz, 1H), 8.55 (m, 2H), 8.19 (d, J ) 8.0 Hz, 1H), 8.06 (s,
9
16762 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006

Selective Generation of [2
×
2] Gridlike Arrays
A R T I C L E S
1H), 8.05 (s, 1H), 7.84 (t, 3J ) 8.0 Hz, 1H), 7.55 (m, 3H), 7.31 (dd, 3J
4.01 (s, 3H), 3.94 (s, 3H), 3.92 (s, 6H), 3.83 (s, 3H), 3.74 (s, 3H), 3.40
(s, 3H). 13C NMR: 161.40, 160.95, 160.90, 155.30, 154.80, 153.55,
153.15, 152.55, 148.50, 140.50, 140.00, 137.75, 137.35, 137.00, 136.55,
136.05, 135.75, 134.85, 133.35, 133.10, 130.40, 130.25, 128.50, 128.25,
127.90, 127.80, 123.50, 122.25, 122.05, 121.15, 120.65, 109.05, 107.05,
105.45, 105.05, 97.95, 88.05, 86.95, 61.00, 60.85, 56.30, 55.90, 30.30,
30.00, 29.40. HRMS (ESi-TOF-MS) m/z (%): calcd for C68H60N19O7
1254.5281 [M + H]+; found 1254.5079 (100) [M + H]+.
3
) 4.4 Hz, J ) 4.4 Hz, 1H), 2.89 (s, 3H). 13C NMR: 193.9, 164.6,
163.7, 158.3, 153.9, 149.2, 139.6, 136.9, 131.1, 128.5, 128.2, 123.7,
120.2, 112.6, 110.0, 101.3, 29.7. FAB-MS m/z (%): 318.1 (100) [M
+ H]+.
6-(6-((E)-(2-Methyl-2-(6-((E)-1-methyl-2-((6-((E)-(2-methyl-2-(6-
((E)-1-methyl-2-(pyridin-2-ylmethylene)hydrazinyl)-2-(3,4,5-tri-
methoxyphenyl)pyrimidin-4-yl)hydrazono)methyl)-2-phenylpyrimidin-
4-yl)methylene)hydrazinyl)-2-(3,4,5-trimethoxyphenyl)pyrimidin-4-
yl)hydrazono)methyl)-2-phenylpyrimidin-4-yl)-2,2′-bipyridine (57).
A solution of 34 (60 mg, 0.091 mmol) and 35 (56.6 mg, 0.091 mmol)
in 1.5 mL of CDCl3 was stirred at 30 °C for 1 h. The solution was
then concentrated under reduced pressure and purified by flash
chromatography (Al2O3, CHCl3) to give 55 (40 mg, 35%) as a yellow
Acknowledgment. We thank Dr. Patrick Wehrung for as-
sistance with mass spectroscopy and also Dr. Andre´ de Cian
and Dr. Augustin Madalan for help with X-ray diffraction
radiocrystallography.
1
powder. Mp > 250 °C (decomposition). H NMR: 8.96 (s, 1H), 8.64
(d, 3J ) 7.6 Hz, 2H), 8.50 (d, 3J ) 7.2 Hz, 2H), 8.37 (m, 2H), 8.30 (m,
Supporting Information Available: Crystallographic data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
3
3
3H), 8.24 (s, 1H), 8.18 (d, J ) 3.8 Hz, 1H), 8.12 (l, 1H), 8.05 (t, J
) 7.8 Hz, 1H), 7.90-7.50 (m, 5H), 7.66 (s, 1H), 7.63-7.58 (m, 3H),
3
7.41 (s, 2H), 7.39-7.25 (m, 4H), 7.20 (t, J ) 7.8 Hz, 2H), 7.07 (s,
1H), 6.93 (t, 3J ) 4.7 Hz, 1H), 6.73 (l, 1H), 4.11 (s, 6H), 4.02 (s, 3H),
JA0666452
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