New Rebek imide-type receptors for adenine featuring acetylene-linked π-stacking platforms

Article abstract of DOI:10.1039/b404311a

Rebek imide-type molecular clefts with π-stacking plat-forms attached to the imide scaffold by an acetylene linker have been prepared by Sonogashira cross-coupling. In the solid state, a novel dimerisation mode for this class of imide receptors was found

Full text of DOI:10.1039/b404311a

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New Rebek imide-type receptors for adenine featuring
acetylene-linked ꢀ-stacking platforms†
Raffaella Faraoni,a Muriel Blanzat,a Stefan Kubicek,a Christophe Braun,a W. Bernd Schweizer,a
Volker Gramlichb and François Diederich*a
a Laboratorium für Organische Chemie, ETH-Hönggerberg, CH-8093 Zürich, Switzerland.
E-mail: diederich@org.chem.ethz.ch
b Laboratorium für Kristallographie, ETH-Zentrum, Sonneggstrasse 5, CH-8092 Zürich,
Switzerland
Received 23rd March 2004, Accepted 27th May 2004
First published as an Advance Article on the web 10th June 2004
Rebek imide-type molecular clefts with ꢀ-stacking plat-
forms attached to the imide scaffold by an acetylene linker
have been prepared by Sonogashira cross-coupling. In the
solid state, a novel dimerisation mode for this class of
imide receptors was found by crystal structure analysis,
whereas efficient 1 : 1 complexation with 9-ethyladenine
was observed in CDCl3 solution.
Fig. 1 Bifurcated H-bond proposed for the complex of Rebek imide
receptor 4 with 9-ethyladenine (5).
By modification of Kemp’s triacid, Rebek and co-workers
developed a variety of powerful achiral and chiral molecular
clefts for the recognition of small H-bonding molecules and
metal ions (e.g. 1).1 Some of these derivatives (e.g. 2a and 3a)
have been used as chiral auxiliaries to control the stereo-
chemical outcome of various reactions, such as radical
additions, allylations, annulations and enolate alkylations.2
Other applications include the catalytic enantioselective
protonation of prochiral enolates using the optically active
clefts as chiral proton sources3 and enantioselective intra-
molecular [2 ϩ 2]-photocycloadditions in supramolecular
complexes formed by 2b and 3b.4
Furthermore, the absence of H-bonding sites in the linker
would enable a more precise determination of the energetic
contributions of imide recognition and π-stacking.
The formation of the new receptors 6 and 7 required the
synthesis of the novel alkyne 8. After a variety of protocols for
the introduction of the ethynyl residue in the sterically
encumbered site close to the protected imide moiety failed, a
five-step synthesis starting from Kemp’s triacid was finally
successful (Scheme 1).‡ The imide–acid chloride 9, obtained
from the triacid by a known procedure,2a was selectively
reduced with LiAlH(tBuO)3 to the primary alcohol that
was subsequently oxidised to aldehyde 10 with PCC. The
direct conversion of 9 to aldehyde 10 by other methods failed.
Protection of the imide moiety by PMBCl afforded 11 in 85%
yield. Alkyne 8 was obtained from aldehyde 11 under
mild conditions in a Horner–Wadsworth–Emmons-type reac-
tion using dimethyl-1-diazo-2-oxopropylphosphonate (12).7
Attempts to perform this reaction with unprotected 10 failed,
likely due to unfavourable electronic effects caused by the
deprotonation of the neighboring imide N–H in the basic
solution. Sonogashira cross-couplings of 8 with 3-bromo-
quinoline or 8-iodo-9-propyladenine afforded compounds
13 (75%) and 14 (90%), respectively. Finally, removal of the
imide-protecting group with CAN provided the two targeted
receptors 6 (72%) and 7 (88%).
The majority of the known Rebek imide receptors5 feature
an aromatic, π-stacking platform attached by ester or amide
linkers to the imide scaffold. In a few cases, this platform is
directly linked to the imide by a heterocyclic ring formed by
condensation of the carboxyl group.2–4 Restricted rotation
about the ester and amide bonds may lead to different receptor
conformations and, ultimately, to host–guest complexes with
different interaction geometries and strengths. In addition,
amide linkers can directly contribute to the binding process as
shown in Fig. 1 for the complex of Rebek imide 4 with
9-ethyladenine (5), for which a bifurcated hydrogen bond
involving the basic amide carbonyl group was proposed.5
The crystal structure of 6, obtained by X-ray diffraction
analysis, contains two symmetry-independent molecules.§
Two conformationally equivalent molecules arrange in a local
pseudo-twofold symmetry, forming two H-bonds between the
cyclic imide N–H protons and the basic nitrogen atoms of the
quinoline rings (Fig. 2). The dimer is further stabilised by
As part of our investigations of the interaction preferences
of adenine in complexes formed by Rebek imide receptors,6 we
became interested in introducing an acetylenic linker between
the aromatic platform and imide scaffold. Such a spacer would
allow free rotation of the platform to adopt the best possible
geometry for interactions with bound adenine derivatives.
† Electronic supplementary information (ESI) available: synthetic
protocols, binding studies and Job plot analysis. See http://www.rsc.org/
suppdata/ob/b4/b404311a/.
Fig. 2 Crystal structure of 6: a) the dimer viewed along the a axis;
b) π-stacking interaction between the quinoline rings viewed along the
c axis.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 6 2 – 1 9 6 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
1962

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Table 1 Association constants Ka and thermodynamic parameters describing the 1 : 1 binding of 4a and 6 to 5 in CDCl3 (295 K)b
Complex
Ka/MϪ1 b
Ϫ∆GЊ/kJ molϪ1
Ϫ∆HЊ/kJ molϪ1
Ϫ∆SЊ/e.u.
4ؒ5
6ؒ5
182
121
7
4
12.8
11.7
38.9
27.9
23.0
14.1
a Data for 4 taken from ref. 6b. b Uncertainty in Ka estimated from duplicate or triplicate runs; values corrected for imide dimerisation.
Scheme 1 Synthesis of compounds 6 and 13b. Reagents and conditions: i, LiAlH(tBuO)3, THF, 0 ЊC, 98%; ii, PCC, CH2Cl2, r.t., 84%; iii, PMBCl,
NaH, NaI (cat), DMF, 0 ЊC
r.t., 85%; iv, 12, K2CO3, MeOH, 0 ЊC
r.t., 68%; v, 3-Bromoquinoline, [Pd(PPh3)2Cl2], CuI, iPr2NH, THF, 50 ЊC,
75%; vi, CAN, CH3CN/H2O (10 : 1), r.t., 72%; vii, 8-Iodo-9-propyladenine, [Pd(PPh3)2Cl2], CuI, iPr2NH, THF, 50 ЊC, 90%; viii, CAN, CH3CN/H2O
(10 : 1), r.t., 88%. PCC = pyridinium chlorochromate; PMBCl = p-methoxybenzyl chloride; CAN = cerium ammonium nitrate.
π-stacking of the quinoline rings. This unusual geometry differs
from the solid-state structures of other known Rebek imide
dimers in which recognition is mediated by the complementary
hydrogen-bonding imides.6a On the other hand, this observation
confirms what Rebek and co-workers had predicted by analysis
of dimerisation data of 4 in CDCl3 solution.5b
In the solid state and in solution, Rebek imide 7 with an
adenine platform forms a dimer with a very high dimerisation
constant Kdim ≥ 104 measured in CDCl3 at 295 K. The X-ray
structure of 7 shows two independent pairs of molecules related
by a centre of symmetry forming Watson–Crick H-bonds
between the adenine rings and the imide moieties (Fig. 3),§
although the N–H ؒ ؒ ؒ O interaction (N ؒ ؒ ؒ O distances 3.02/
3.55 Å) is rather weak. One of the two dimers (shown in Fig. 3)
forms H-bonds to neighboring adenines via their Hoogsteen
faces, while the other dimer is anchored to heavily disordered
CHCl3 molecules.
results confirm the efficiency of the alkyne-linked quinoline in
π-stacking with the nucleobase. The difference in affinity can be
largely attributed to the lack of bifurcated H-bonds (Fig. 1) in
complex 6ؒ5. The substantial bonding contributions of H-bond
donor–acceptor centres in the linker are also illustrated by the
difference in the dimerisation constants: self-association of
receptor 6 (Kdim(6) = 36 4) is much less effective than that of 4
(Kdim(4) = 131 39). In the absence of H-bonding interactions
with the linker, the overall binding free enthalpy of 6ؒ5 (Ϫ∆GЊ
= 11.7 kJ molϪ1) can be easily separated into its component
terms. The imide–adenine H-bonding9 is worth 8.3 kJ molϪ1
while the aromatic stacking between the alkynated quinoline
and bound adenine provides 3.4 kJ molϪ1
.
In summary, Rebek imide receptors with acetylene-linked
π-stacking platforms eliminate undesirable H-bonding
contributions from previously used ester and amide linkers
to adenine complexation, thereby allowing a more accurate
separation of the energetics of imide H-bonding and
π-stacking. Alkyne 8 is a versatile partner for cross-coupling
reactions, and we will report on the properties of a larger family
of new Rebek imide receptors with different acetylene-linked
π-stacking platforms in due course.
We thank the ETH research council and F. Hoffmann-
La Roche, Basel for support of this work. We are grateful to
Prof. C. A. Hunter for providing us with his software for the
evaluation of the binding data.
Fig.
3
Crystal structure of 7: one of the two symmetrically
independent dimers is shown. Dimerisation occurs via Watson–Crick
H-bonding and adenine π-stacking; neighboring adenines in one plane
interact via Hoogsteen H-bonding.
Notes and references
‡ Selected experimental protocols (see also ESI): Preparation of 8. To a
solution of 12 (4.47 g, 23.2 mmol) in dry MeOH (47 ml) under N2 at
0 ЊC, oven-dried K2CO3 (3.86 g, 27.9 mmol) was added and the yellow
suspension stirred for 1 h. A solution of 11 (4.0 g, 11.6 mmol) in dry
THF (52 ml) was added dropwise and the resulting suspension stirred
for 2 h at 0 ЊC and for 12 h at r.t. The mixture was concentrated in
vacuo, the residue dissolved in Et2O and the solution washed with 5%
aq. NaHCO3, dried (Na2SO4) and concentrated. Flash chromatography
(FC, SiO2; CH2Cl2) afforded 8 (2.67 g, 68%) as a white solid, mp 118 ЊC;
νmax(neat)/cmϪ1 3276m, 2966w, 2935w, 2362w, 2336w, 1718m, 1671s,
The complexation between receptor 6 and 9-ethyladenine (5)
1
was studied by H-NMR binding titrations (CDCl3, 295 K),
which afforded the strength of the association (Ka [Ϫ1], Ϫ∆GЊ
[kJ molϪ1]).8 The thermodynamic parameters (∆HЊ, ∆SЊ) were
ascertained by van’t Hoff plots, while Job plot analysis con-
firmed the 1 : 1 binding stoichiometry (see ESI†). Although the
9-ethyladenine complex of 6 is less stable than the complex
of its amide analogue 4 (∆∆GЊ = 1.1 kJ molϪ1, Table 1), the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 6 2 – 1 9 6 4
1963

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1610m, 1600s, 1509s, 1468m, 1450m, 1432m, 1375s, 1292s; δH(300 MHz,
CDCl3) 7.34 (2 H, d, J 9.0), 6.8 (2 H, d, J 9.0), 4.74 (2 H, s), 3.77 (3 H,
s), 2.16 (2 H, d, J 14.1), 1.94 (1 H, d, J 13.2), 1.84 (1 H, s), 1.32–1.23 (12
H); δC(75 MHz, CDCl3) 176.56, 158.53, 130.55, 129.44, 113.53, 88.61,
69.43, 55.22, 48.07, 43.03, 42.86, 40.33, 33.17, 30.32, 26.1; HR-FT-
MALDI-MS (DHB) calcd for C21H25NO3Naϩ ([M ϩ Na]ϩ): 362.1727;
found: 326.1726; EA calcd for C21H25NO3 (339.43): C 74.31, H 7.42, N
4.13; found: C 74.34; H 7.62, N 4.04%. Preparation of 13: Alkyne 8
(0.63 g, 1.85 mmol) and 3-bromoquinoline (0.25 ml, 1.83 mmol) were
added to a pressure-resistant Schlenk flask, previously dried and evacu-
ated by N2-pump cycles. THF (15 ml) was added, the solution degassed
by three freeze–pump–thaw cycles and [Pd(PPh3)2Cl2] (64.4 mg,
c = 17.8082(7) Å, α = 88.088(3)Њ, β = 81.177(3)Њ, γ = 77.664(2)Њ, V =
2207.8(2) Å3, T = 100 K, Z = 2, µ = 0.170 mmϪ1, 6757 reflections
collected, R1 = 0.0843 based on F[I > 2σ(I )], wR(F 2) = 0.2353 (all data).
CCDC reference numbers 234432 and 234433. See http://www.rsc.org/
suppdata/ob/b4/b404311a/ for crystallographic data in .cif or other
electronic format.
1 (a) J. Rebek Jr., J. Mol. Recognit., 1988, 1, 1–8; (b) J. Rebek Jr.,
Angew. Chem., Int. Ed. Engl., 1990, 3, 245–255.
2 (a) G. S. Jeffrey, D. P. Curran, S. V. Geib, J. Rebek Jr. and P. Ballester,
J. Am. Chem. Soc., 1992, 114, 7007–7018; (b) K. S. Jeong, K. Parris,
P. Ballester and J. Rebek Jr., Angew. Chem., Int. Ed. Engl., 1990, 5,
555–556.
i
5 mol%), CuI (35 mg, 10 mol%) and Pr2NH (5 ml) were added under
N2. The mixture was degassed by four freeze–pump–thaw cycles and
stirred at 50 ЊC for 18 h. Upon cooling to r.t., Et2O was added and the
ammonium salt precipitated. The solution was filtered and concen-
trated to dryness. FC (SiO2; CH2Cl2/Et2O 10 : 0.1) afforded 13 (0.64 g,
75%) as a white solid, mp 146–147 ЊC; νmax(neat)/cmϪ1 2969w, 2933w,
1717w, 1667s, 1608w, 1513s, 1462w, 1378w, 1294m, 1250s, 1162s;
δH(300 MHz, CDCl3) 8.84 (1 H, d, J 1.8), 8.16 (1 H, d, J 1.8), 8.06 (1 H,
d, J 8.4), 7.74 (1 H, d, J 8.1), 7.66 (1 H, ddd, J 8.4, 7.8, 1.2), 7.51 (1 H,
td, J 8.1, 7.8), 7.14 (2 H, d, J 8.4), 6.72 (2 H, d, J 8.4), 4.64 (2 H, s), 3.70
(3 H, s), 2.31 (2 H, d, J 12.6), 1.92 (1 H, d, J 13.5), 1.40–1.24 (12 H, m);
δC(75 MHz, CDCl3) 177.04, 165.40, 158.85, 152.41, 146.91, 138.61,
130.31, 130.14, 130.00, 129.58, 127.78, 127.44, 117.37, 113.85, 97.78,
55.38, 48.24, 43.09, 42.96, 40.59, 33.37, 31.56, 26.30; HR-FT-MALDI-
3 A. Yanagisawa, T. Kikuchi, T. Watanabe, T. Kuribayashi and
H. Yamamoto, Synlett, 1995, 372–374.
4 (a) T. Bach, Synlett, 2000, 12, 1699–1707; (b) T. Bach, H. Bergmann
and K. Harms, Angew. Chem., Int. Ed., 2000, 13, 2302–2304.
5 (a) J. Rebek Jr., K. Williams, K. Parris, P. Ballester and K. S. Jeong,
Angew. Chem., Int. Ed. Engl., 1987, 26, 1244–1245; (b) K. Williams,
B. Askew, P. Ballester, C. Buhr, K. S. Jeong, S. Jones and J. Rebek Jr.,
J. Am. Chem. Soc., 1989, 111, 1090–1094.
6 (a) R. K. Castellano, V. Gramlich and F. Diederich, Chem. Eur. J.,
2002, 8, 118–129; (b) R. Faraoni, R. K. Castellano, V. Gramlich and
F. Diederich, Chem. Commun., 2004, 370–371.
7 (a) S. Müller, B. Liepold, G. J. Roth and H. J. Bestmann, Synlett,
1996, 521–522; (b) for the preparation of the diazophosphonate 12,
see P. Callant, L. D’Haenens and M. Vandewalle, Synth. Commun.,
1984, 14, 155–161.
8 A. P. Bisson, C. A. Hunter, J. C. Morales and K. Young, Chem. Eur.
J., 1998, 4, 845–851.
ϩ
MS (DHB) calcd for C30H31N2O3 (MHϩ): 467.2329; found: 467.2326;
EA calcd for C30H30N2O3 (466.58): C 77.23, H 6.48, N 6.00; found: C
76.94; H 6.65, N 5.99%.
§ Crystal data. Compound 6, C22H22N2O2, M = 346.43, monoclinic,
space group P21/a, a = 14.9171(2), b = 12.9531(2), c = 19.9159(3) Å, β =
107.7345(8)Њ, V = 3665.33(9) Å3, T = 172 K, Z = 8, µ = 0.081 mmϪ1
,
9 The imide–adenine H-bonding contribution has been extrapolated
from the complexation behaviour of dihydrouracil derivatives with
adenine in CDCl3, see: Y. Kyogoku, R. C. Lord and A. Rich, Nature,
1968, 218, 69–72.
9409 reflections collected, R1 = 0.0485 based on F [I > 2σ(I )], wR(F 2) =
0.1541 (all data). Compound 7, 2(C21H26N16O2)ؒ0.5(CHCl3), M =
¯
848.13, triclinic, space group P1, a = 7.6166(3), b = 16.8616(8),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 9 6 2 – 1 9 6 4
1964