Hydrogen bonded dimers of triurea derivatives of triphenylmethanes

Article abstract of DOI:10.1021/ol0476265

(Chemical Equation Presented) Tri-(2-alkoxy-5-ureido-phenyl)methanes represent a novel self-complementary motif forming hydrogen bonded homo- and heterodimers in nonpolar, aprotic solvents as evidenced by ¹H NMR and ESI-mass spectra and by the

Full text of DOI:10.1021/ol0476265

ORGANIC
LETTERS
2005
Vol. 7, No. 4
613-616
Hydrogen Bonded Dimers of Triurea
Derivatives of Triphenylmethanes
Yuliya Rudzevich,† Valentyn Rudzevich,†,‡ Dieter Schollmeyer,§
Iris Thondorf, and Volker Bo1
hmer*,†
Abteilung Lehramt Chemie, Fachbereich Chemie und Pharmazie, Johannes
Gutenberg-UniVersita¨t Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany, Institut
fu¨r Organische Chemie, Johannes Gutenberg-UniVersita¨t Mainz, Duesbergweg 10-14,
D-55099 Mainz, Germany, and Fachbereich Biochemie/Biotechnologie, Institut fu¨r
Biochemie, Martin-Luther-UniVersita¨t Halle-Wittenberg, Kurt-Mothes-Str. 3,
D-06099 Halle, Germany
Vboehmer@mail.uni-mainz.de
Received November 18, 2004
ABSTRACT
Tri-(2-alkoxy-5-ureido-phenyl)methanes represent a novel self-complementary motif forming hydrogen bonded homo- and heterodimers in
nonpolar, aprotic solvents as evidenced by 1H NMR and ESI-mass spectra and by the formation of heterodimers. MD simulations suggest the
formation of hydrogen bonds of different strength in agreement with NMR data. The dimerization does not interfere with that of tetraurea
calix[4]arenes. A combination of both motifs may be used therefore to build up larger structures via self-assembly processes.
Calix[4]arenes substituted at their wide rim by four urea
functions form dimeric capsules in nonpolar, aprotic solvents,
held together by a seam of hydrogen bonds formed alter-
natingly between urea groups of the two calix[4]arenes.1,2
Although attempts to form analogous dimers from calix[5]-
arenes failed so far, this hydrogen bonding motif3 seems to
possess some “general” importance, since dimers are formed
also between triurea derivatives of tribenzylamines4 and
calix[6]arenes.5 If, on the other hand, one of the four urea
functions in a tetraurea calix[4]arene is replaced by aceta-
mide, the molecules assemble to S4-symmetrical tetramers,
unless the dimerization is induced by a favorable guest such
as tetraethylammonium.6
(3) Analogous hydrogen bonds were found in numerous X-ray structures
of di-(aryl/alkyl)-ureas. For examples, see: Lortie, F.; Boileau, S.; Bouteiller,
L. Chem. Eur. J. 2003, 9, 3008-3014. Schwiebert, K. E.; Chin, D. N.;
MacDonald, J. C.; Whitesides, G. M. J. Am. Chem. Soc. 1996, 118, 4018-
4029. Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto,
T. W. J. Am. Chem. Soc. 1990, 112, 8415-8426.
(4) Alajar´ın, M.; Lo´pez-La´zaro, A.; Pastor, A.; Prince, P. D.; Steed, J.
W.; Arakawa, R. Chem. Commun. 2001, 169-170. Alajar´ın, M.; Pastor,
A.; Orenes, R.-AÄ .; Steed, J. W. J. Org. Chem. 2002, 67, 7091-7095.
Alajar´ın, M.; Pastor, A.; Orenes, R.-AÄ .; Steed, J. W.; Arakawa, R. Chem.
Eur. J. 2004, 10, 1383-1397.
† Abteilung Lehramt Chemie, J. G.-Universita¨t Mainz.
‡ Permanent address: Institute of Organic Chemistry, NAS of Ukraine,
Murmanska str. 5, Kyiv-94, 02094 Ukraine.
§ Institut fu¨r Organische Chemie, J. G.-Universita¨t Mainz.
Martin-Luther-Universita¨t Halle-Wittenberg.
(1) For a short review, see: Rebek, J., Jr. Chem. Commun. 2000, 637-
643.
(2) Mogck, O.; Paulus, E. F.; Bo¨hmer, V.; Thondorf, I.; Vogt, W. Chem.
Commun. 1996, 2533-2534. Thondorf, I.; Broda, F.; Rissanen, K.;
Vysotsky, M.; Bo¨hmer, V. J. Chem. Soc., Perkin. Trans. 2 2002, 1796-
1800. Vysotsky, M. O.; Bolte, M.; Thondorf, I.; Bo¨hmer, V. Chem. Eur. J.
2003, 9, 3375-3382.
(5) Gonza´lez, J. J.; Ferdani, R.; Albertini, E.; Blasco, J. M.; Arduini,
A.; Pochini, A.; Prados, P.; de Mendoza, J. Chem. Eur. J. 2000, 6, 73-80.
(6) Shivanyuk, A.; Saadioui, M.; Broda, F.; Thondorf, I.; Vysotsky, M.
O.; Rissanen, K.; Kolehmainen, E.; Bo¨hmer, V. Chem. Eur. J. 2004, 10,
2138-2148.
10.1021/ol0476265 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/27/2005

Figure 1. Molecular conformation of 4b seen from two different perspectives. Angles between least-squares planes through the aromatic
rings: 83.6, 88.3, and 89.7°. Intramolecular N‚‚‚N distances: 6.75, 7.29, and 6.41 Å.
Searching novel platforms for the “tripodal” arrangement
of ligating functions, we recently developed a simple syn-
thesis for tri-(2-alkoxy-5-aminophenyl)methanes, which is
indicated in Scheme 1.
ether 4a. A single-crystal X-ray analysis of 4b9 confirms its
structure and reveals an interesting conformation, resembling
a three-bladed propeller (Figure 1), in which all CH2COOEt
and all NH2 groups are found in a syn arrangement relative
to each other.
Triurea derivatives 5 are formed from 4 by reaction with
the respective isocyanates.10 Their 1H NMR spectra in
DMSO-d6 demonstrate the expected pattern of a molecule
with (dynamic) C3V symmetry (Figure 2a), showing for
Scheme 1. Synthesis of the Target Triureasa
a Key: (i) H2SO4, 155 °C; (ii) YBr, K2CO3, acetone; (iii) H2,
Raney-Ni, THF/EtOH; (iv) RNCO, CH2Cl2.
Acid-catalyzed condensation of 2-hydroxy-5-nitro-ben-
zaldehyde 1 with a 2-fold excess of p-nitrophenol leads to 2
(89%),7,8 which can be O-alkylated with reactive alkyl-
halogenides such as allylbromide or bromoethyl acetate. The
triethers 3 are reduced to the triamines 4 by catalytic hy-
drogenation, which in the case of 3a leads to the tripropyl
1
Figure 2. Sections of the H NMR spectra (400 MHz) of 5b in
DMSO-d6 (a) and in CDCl3 (b).
instance one singlet for the enantiotopic -O-CH2 protons
in 5b. In solvents such as CDCl3 or benzene, this signal splits
into a pair of doublets (∆δ ) 1.1 ppm) with geminal coupling
(2J ) 16 Hz) (Figure 2b), indicating that these CH2 protons
experience now a chiral environment, rendering them dia-
stereotopic. The strong splitting of the two NH singlets sug-
(7) Gru¨ttner, C.; Bo¨hmer, V.; Assmus, R.; Scherf, S. J. Chem. Soc.,
Perkin Trans. 1 1995, 93-94. Dinger, M. B.; Scott M. J. Eur. J. Org. Chem.
2000, 2467-2478.
(8) For the synthesis of similar triphenylcarbinol derivatives, see:
Kelderman, E.; Starmans, W. A. J.; van Duynhoven, J. P. M.; Verboom,
W.; Engbersen, J. F. J.; Reinhoudt, D. N. Chem. Mater. 1994, 6, 412-417.
614
Org. Lett., Vol. 7, No. 4, 2005

gests that one of the NH groups forms a hydrogen bond,
and the whole spectrum is in agreement with a C3-symmetri-
cal conformation, e.g., in a kinetically stable dimer with S3
symmetry.
Dimerization was unambiguously proved by the formation
of heterodimers in 1:1 mixtures of two triureas 5. While the
spectrum of such a mixture in DMSO-d6 consists of a super-
imposition of the two single spectra, in C2D2Cl4 an additional
double set of signals corresponds to the heterodimer, as
demonstrated in Figure 3. Simultaneously, the formation of
a larger assembly is excluded by this still simple spectrum.
Table 1. Geometric Parameters Obtained by MD Simulation
radius of gyration of the CdO groups (Å)
distance of the methine C atoms (Å)
intermolecular NR‚‚‚O distances (Å)a
intermolecular Nâ‚‚‚O distances (Å)b
intermolecular NR-H‚‚‚O distances (Å)
intermolecular Nâ-H‚‚‚O distances (Å)
intramolecular distances of the carbonyl
C atoms (Å)
4.02 ( 0.08
9.97 ( 0.23
2.99 ( 0.19
3.35 ( 0.29
2.46 ( 0.39
2.90 ( 0.43
4.28 ( 0.33
intramolecular NR‚‚‚NR distances (Å)
torsion angles around the Ar-C bonds (°)
interplanar angles between trityl phenyl
residues (°)
6.57 ( 0.23
83 ( 9/-84 ( 9
81.7 ( 8
a NR: nitrogen atom attached to R. b Nâ: nitrogen atom attached to the
trityl group.
such a “capsule” leads to a volume of ∼80-90 Å3, which
explains that an inclusion of guests is not observed.
As illustrated in Figure 4, only the NH groups attached to
the urea residues R seem to be involved in NH‚‚‚OdC
1
Figure 3. Sections of the H NMR spectra (400 MHz) of 5a (a),
5b (b), and of their stoichiometric mixture (c) in C2D2Cl4. The
signals for the heterodimer are shown in green.
In contrast to tetraureas 6 and 7, the dimerization could
be demonstrated also by ESI-MS. A mixture of 5b and 5d
shows the peak for the heterodimer with 100% abundance,
the two peaks for the homodimers with ∼30-35% abun-
dance, and the peaks for the single molecules with 25-100%
abundance (all peaks with one Na+). It is unclear if this is
due to a greater stability of dimers 5‚511 or to their lower
mass in comparison to 6‚6.
Figure 4. Minimized average structure obtained from molecular
dynamics simulation of 5 (R ) Tol, Y ) Et). Two stereoviews
from different directions are shown, the ether substituents have been
omitted for clarity.
hydrogen bonds; see also the distances in Table 1. Shorter
NH‚‚‚O distances by about 0.44 Å in comparison to the NH
Molecular dynamics simulations were used to obtain an
idea of the conformation of the dimers. Selected geometric
parameters derived from these calculations are collected in
Table 1.12 The average structure of the dimer can best be
described by two triangular pyramids whose vertexes are the
carbonyl and methine carbon atoms that are rotated by 60°
against each other.13 An estimation of the internal space of
(9) Crystal data for compound 4b at 193 K: C31H37N3O9, M ) 595.63,
space group P-1 (No.2), a ) 9.860(4), b ) 12.351(2), c ) 13.171(2) Å, R
) 100.79(1), â ) 103.51(2), γ ) 103.50(2)°, V ) 1466.1(7) Å3, dcalcd
)
1.349 g cm-3, Z ) 2. For the 5904 unique reflections collected (2 e θ e
2
2
74°) with Cu KR (λ ) 1.54178 Å), the 5249 with Fo > 2.0σ(Fo ) were
used in the final least-squares refinement to yield R1 ) 0.0757 and wR2 )
0.2050 for all reflections. CCDC reference number: 248 044.
Org. Lett., Vol. 7, No. 4, 2005
615

groups attached to the trityl skeleton are in agreement with
the NMR results.
The average geometry of the trityl groups obtained from
the MD simulation is very similar to those of the monomer
in the crystal (Figure 1), as indicated by the interplanar angles
(88.5 ( 3° vs 81.7 ( 8°), the intramolecular NR‚‚‚Nâ
distances (6.57 ( 0.23 Å), and the overall rms value of 0.27
Å for the aromatic and methane carbon atoms and the oxygen
and nitrogen atoms.
From tetraureas 6, it is known that in a stoichiometric
mixture of aryl (6a) and tosyl (6b) ureas heterodimers 6a‚
6b are formed exclusively.14 The analogous combination 5b
and 5c leads to the formation of all possible dimers. As
1
expected, H NMR spectra of the solutions of 5 and 6 in
CDCl3 show only the presence of both homodimers. Since
also 6a and the more rigid 7 do not form heterodimers,15
a
mixture of all three urea derivatives (5b, 6a, 7) contains only
the three possible homodimers (Figure 5).
1
A similar self-sorting process has been recently observed
for mixtures consisting of molecules with rather different
hydrogen bonding motifs,16 such as linear AADD mol-
ecules,17 “rosettes” formed by triazine triamides and barbi-
turates,18 and tetraurea calixarenes.19 It must be emphasized
that the hydrogen bonding systems involved in the present
case are much more similar, since they consist only of
diarylurea systems that are arranged in a (slightly) different
way or different number on different platforms. Self-sorting
Figure 5. Sections of the H NMR spectra (400 MHz) of 5b (a),
6a (b), and 7 (c) and of their stoichiometric mixture (c) in CDCl3.
selectivities such as these may be used to build up well
defined larger structures via self-assembly processes from
molecules containing two (or more) tri- and/or tetraurea units.
Acknowledgment. We gratefully acknowledge finan-
cial support from the Deutsche Forschungsgemeinschaft
(Bo¨ 523/14-2, SFB 625, Th 520/5-2).
(10) Anion binding by triureas 5 will be described elsewhere.
(11) Titration experiments show that dimers 5‚5 are present up to 9%
DMSO-d6 in a C2D2Cl4 solution, which is comparable to dimeric capsules
of calix[4]arenes 7 while dimers of 6a are less stable.
(12) MD simulations were performed for 60 ns in vacuo using the
AMBER force field, see: Case, D. A.; Pearlman, D. A.; Caldwell, J. W.;
Cheatham, T. E., III; Wang, J.; Ross, W. S.; Simmerling, C. L.; Darden, T.
A.; Merz, K. M.; Stanton, R. V.; Cheng, A. L.; Vincent, J. J.; Crowley,
M.; Tsui, V.; Gohlke, H.; Radmer, R. J.; Duan, Y.; Pitera, J.; Massova, I.;
Seibel, G. L.; Singh, U. C.; Weiner, P. K.; Kollman, P. A. AMBER 7;
University of California, San Francisco: San Francisco, CA 2002.
(13) Structure is in agreement with the preliminary results of an X-ray
structure that could not yet be sufficiently refined.
(14) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am. Chem Soc. 1997,
119, 12671-12672.
(15) Vysotsky, M. O.; Mogck, O.; Rudzevich, Y.; Shivanyuk, A.;
Bo¨hmer, V.; Brody, M. S.; Cho, Y. L.; Rudkevich, D. M.; Rebek, J., Jr. J.
Org. Chem. 2004, 69, 6115-6120.
(16) Wu, A.; Isaacs, L. J. Am. Chem. Soc. 2003, 125, 4831-4835.
Mukhopadhyay, P.; Wu, A.; Isaacs, L. J. Org. Chem. 2004, 69, 6157-
6164. See also: Wu, A.; Chakraborty, A.; Fettinger, J. C.; Flowers, R. A.,
II; Isaacs, L. Angew. Chem., Int. Ed. 2002, 41, 4028-4031.
1
Supporting Information Available: Selected H NMR
of triphenylmethane derivatives and crystallographic details
for 4b (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0476265
(17) A and D denote hydrogen bond acceptors and donors; see for
instance: Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer,
E. W. J. Am. Chem. Soc. 1998, 120, 6761-6769.
(18) For examples, see: Fe´lix, O.; Crego-Calama, M.; Luyten, I.;
Timmerman, P.; Reinhoudt, D. N. Eur. J. Org. Chem. 2003, 1463-1474.
Prins, L. J.; Neuteboom, E. E.; Paraschiv, V.; Crego-Calama, M.; Timmer-
man, P.; Reinhoudt, D. N. J. Org. Chem. 2002, 67, 4808-4820. Prins, L.
J.; Verhage, J. J.; de Jong, F.; Timmerman, P.; Reinhoudt, D. N. Chem.
Eur. J. 2002, 8, 2302-2313. Prins, L. J.; Hulst, R.; Timmerman, P.;
Reinhoudt, D. N. Chem. Eur. J. 2002, 8, 2288-2301.
(19) Rudzevich, Y.; Vysotsky, M. O.; Bo¨hmer, V.; Brody, M. S.; Rebek,
J., Jr.; Broda, F.; Thondorf, I. Org. Biomol. Chem. 2004, 2, 3080-3084.
616
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