Angewandte
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C H···p interactions and further arene–arene interactions to
to an energetically more favorable parallel-displaced orien-
tation. Therefore, we can conclude with confidence that
parallel-displaced p–p stacking is the dominant interaction in
solution.
neighboring receptors (see Section S4.4).[17]
The binding mode of system 3·2 in solution was first
1
investigated by H steady-state NOE experiments (Figure 5
In summary, we have reported the new Rebek imide type
receptor model system 3·2, which, together with the previ-
ously described host–guest system 1·2,[10] for the first time
enabled an experimental determination of the distance
dependence of substituent effects on parallel p–p stacking
interactions. In the host–guest system 1·2, the short ethyne-
1,2-diyl spacer generates partial overlap between the phenyl
platform substituent in the para position and the guest
di(isobutyramido)pyridine 2. As predicted by the Wheeler–
Houk model, the introduction of any substituent resulted in
stabilization by direct, through-space interactions. In the new
system 3·2, the elongated buta-1,3-diyne-1,4-diyl spacer shifts
the substituent away from the bound pyridine guest, which
prevents direct interactions between substituent and guest. A
linear correlation between logKa and the Hammett substitu-
ent constant spara was observed, with electron-withdrawing
substituents leading to a stabilization of the complex and
electron-donating substituents destabilizing the interaction.
This finding indicates an electrostatic influence of the
substituent on the aromatic platform of the receptor, as
predicted by the Hunter–Sanders model. The distance
between the substituent and the intermolecularly interacting
aromatic ring clearly matters when analyzing substituent
effects on aromatic p–p stacking interactions.
Figure 5. 500 MHz 1H NOE spectra of 3i·2 in (CDCl2)2 at 298 K;
[H]=38.2 mm, [G]=43.0 mm. A) Reference spectrum, B) irradiated
spectrum, C) difference spectrum.
and Section S3). Irradiation on the frequency of the aromatic
protons e in position 3 of the pyridine core shows a clear NOE
for the aromatic protons b and c, which are in meta and
ortho position to the substituent, respectively. Hence, it can
be assumed that pyridine guest 2 and the aromatic platform of Experimental Section
General procedures for the Cadiot–Chodkiewicz cross-coupling
receptor 3 are in close proximity owing to arene–arene
interactions. The 1:1 stoichiometry was additionally con-
firmed by Job plot analysis (Figure S21).[18]
and PMB deprotection are described here. Further synthetic details
and characterization can be found in the Supporting Information.
General procedure 1 (GP1): Cadiot–Chodkiewicz cross-cou-
In the solution analysis, however, no evidence for edge-to-
face interactions in our system was found. The p–p stacking
geometries of several systems in solution have been evi-
denced by using ring-current-induced changes in chemical
shifts.[3a–c,j,6c,19–21] In p–p stacking complexes, the protons at the
periphery of the stack usually encounter upfield shifts on the
order of À0.2 to À0.5 ppm, as we observed for both systems
1·2 and 3·2 (see above). No such upfield shifts are observed
for the face ring in an edge-to-face assembly. In a reverse-
titration study with di(isobutyramido)pyridine 2 at constant
concentration (4 mm), we measured a substantial complex-
ation-induced upfield shift that is due to the intermolecular
shielding of the aromatic pyridine protons (Section S2.1.4).
For example, the proton in position 4 moves upfield during
pling: Terminal alkyne
4 or 6 (1.0 equiv), the corresponding
(iodoethynyl)benzene derivative (1.5 equiv), CuI (0.1 equiv), and
[Pd(PPh3)2Cl2] (0.05 equiv) under an Ar atmosphere were suspended
in freshly distilled NEt3 and stirred for 16 h. The mixture was diluted
with Et2O and filtered over Celite. After evaporation of the filtrate
in vacuo, the residue was purified by column chromatography (SiO2).
General procedure 2 (GP2): CAN-mediated PMB deprotection:
PMB-protected imide 4 or 5 (1.0 equiv) was dissolved in MeCN/H2O
(10:1, 10 mm) at 08C. The solution was treated with CAN
(10.0 equiv), stirred for 15 min at 08C, warmed to 228C, and stirred
until completion (monitored by TLC). The mixture was carefully
treated with sat. aq. NaHCO3 solution, and the organic solvent was
removed in vacuo. The residual aqueous layer was extracted with
CH2Cl2 (3 ꢁ). The combined organic layers were dried over Na2SO4
and evaporated in vacuo. The residue was purified by column
chromatography (SiO2).
the reverse titration by Ddmax,obs = À0.32 ppm (Ddsat,calc
=
À0.35 ppm; Figure S19). Hence, regardless of the titration
mode, all involved aromatic protons show an upfield shift
upon complexation, indicating a parallel stacked geometry in
solution.[3b,c,j,6c,20] Indeed, if our system formed an intermo-
lecular edge-to-face interaction, as suggested by some of the
X-ray co-crystal structures (Section S4.4), a downfield change
in chemical shift for the pyridine protons would be expect-
ed.[3a,21] The parallel stacking geometry was further supported
by quantum-mechanical geometry optimizations (Sec-
tion S5), where all optimizations for system 3i·2 converged
Acknowledgements
This study was supported by the Swiss National Science
Foundation (SNF 200020_159802) and F. Hoffmann-La Ro-
che Ltd., Basel. We thank Michael Solar (ETH Zurich) for
recording X-ray crystal structures. We are grateful to the
NMR service of the LOC (ETH Zurich) for recording 1D
NOE spectra. We thank Dr. Michael Harder, Dr. Oliver
4
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
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