Complexation-induced Chemical Shifts Research Articles

Supramolecular complexation of phenylephrine by cucurbit[7]uril in aqueous solution.

Cucurbiturils (CBn) are known to establish stable host-guest complexes with a variety of drug molecules. Herein, the supramolecular complexation between cucurbit[7]uril (CB7) and phenylephrine hydrochloride is reported in aqueous solution. Phenylephrine forms inclusion complex with CB7 with high binding affinity (Kaffinity = 4.0 × 106 M-1), which allows for the development of a fluorescence-based sensing assay applying the dye displacement strategy. The structure of the host-guest inclusion complex is investigated by 1H NMR spectroscopy, in which complexation-induced chemical shifts indicate the immersion of the aromatic ring inside the hydrophobic cavity of CB7. Density functional theory (DFT) calculations support the 1H NMR results, and reveal that the complex is stabilized through intermolecular interactions between the polar groups on the phenylephrine and the carbonyl rims of CB7, as well as the hydrophobic effect. Moreover, preferential binding of phenylephrine in its protonated over the neutral form results in a complexation-induced pKa shift.

Super Aryl-Extended Calix[4]pyrroles: Synthesis, Binding Studies, and Attempts To Gain Water Solubility.

We describe the synthesis of unprecedented calix[4]pyrrole receptors featuring "super aryl extended" (SAE) cavities. We elaborated the aromatic cavity provided by the αααα-isomer of para-tetraiodo-meso-phenyl calix[4]pyrrole by installing ethynyl-aryl substituents at its upper rim. We report the binding properties of the prepared SAE-calix[4]pyrrole tetraester towards pyridyl-N-oxides. The binding data revealed the formation of thermodynamically and kinetically highly stable 1:1 complexes. The complexation-induced chemical shifts indicated the formation of hydrogen bonds and aromatic interactions with the calix-core adopting the cone conformation. We quantified the additional interactions established between the four terminal aryl groups and the para-phenyl substituent of 4-phenyl pyridine N-oxide to be in the order of 1 kcal mol(-1) . The complex formation rate was found to be close to the diffusion control suggesting that the free host adopted a 1,3-alternate conformation. Finally, we attempted to gain water solubility of SAE-calix[4]pyrroles using derivatives that display four ionizable or charged groups at their upper rims.

Cucurbiturils as fluorophilic receptors

We report the formation of strong inclusion complexes between the macrocyclic host cucurbit[7]uril (CB7) and more than 20 perfluorinated compounds (PFCs) in aqueous solution. The binding constants and structures of the complexes were determined through a combination of dye displacement titrations, 19F as well as 1H NMR spectroscopy, and quantum chemical calculations. The high affinities, for example 1.2 × 107 M− 1 for perfluorohexane and 1.1 × 108 M− 1 for perfluoro(methylcylohexane), are driven, among others, by the low polarisability of the cucurbituril cavity, which favours the binding of non-polarisable guests such as PFCs. The complexation-induced chemical shifts of the 19F resonances are downfield in cases where a conformational flexibility allows the (partial) interconversion of gauche conformations (favoured in water) to anti conformations (favoured inside the cavity of CB7). Only for conformationally rigid substrates, for example SF6 and (CF3)3COH, upfield shifts prevail. These are attributed to the low polarisability of the inner cavity, similar to the upfield shifts observed for 19F resonances upon going from highly polarisable to less polarisable solvents. Cucurbituril homologues (CB5, CB6 and CB8) were also studied and, among those, evidence for the formation of inclusion complexes was observed for CB6 as host and CF4, SF6 and CF3CH2OH as guests. Besides contributing to the fundamental understanding of fluorophilic interactions, the results have implications for PFC separation and for the efficient removal of PFCs from and the sensing of PFCs in aqueous solution.

Complexation of [2.2]paracyclophane with β- and γ-cyclodextrins studied by HPLC and NMR

AbstractThe NMR spectra of [2.2]paracyclophane with β- or γ-cyclodextrin in DMF-d7 at room temperature do not show significant complexation, while HPLC of the complexes in mixed H2O:alcohol solvents demonstrate complexation with different stoichiometries. At 243 K in DMF solution the H3 and H5 NMR signals of γ-cyclodextrin (but not β) exhibit complexation-induced chemical shifts denoting complex formation. According to HPLC, at room temperature the [2.2]paracyclophane complex with β-cyclodextrin in 20% H2O:EtOH exhibits 1:2 stoichiometry with K 1 = 1×102 ± 2, K 2 = 9.0×104 ± 2×103 (K = 9×106) while that with γ-cyclodextrin in 50% H2O:MeOH exhibits 1:1 stoichiometry with K 1 = 4×103 ± 150 M−1. Thermodynamic parameters for both complexes have been estimated from the retention time temperature dependence. For the β-cyclodextrin complexation at 25°C ΔG 0CD is −39.7 kJ mol−1 while ΔH 0CD and ΔS 0CD are −88.2 kJ mol−1 and −0.16 kJ mol−1 K−1. For γ-cyclodextrin, the corresponding values are ΔG 0CD = −20.5 kJ mol−1, ΔH 0CD = −33.5 kJ mol−1 and ΔS 0CD = −0.04 kJ mol−1 K−1.

Formation of Host-Guest Complexes of β-Cyclodextrin and Perfluorooctanoic Acid

Structural characterization and dynamic properties of solid-state inclusion complexes of β-cyclodextrin (β-CD) with perfluorooctanoic acid (PFOA) were investigated by (19)F/(13)C solid-state and (19)F/(1)H solution NMR spectroscopy. The complexes in the solid state were prepared using dissolution and slow cool methods, where thermal analyses (DSC and TGA), PXRD, and FT-IR results provided complementary support that inclusion complexes were formed between β-CD and PFOA with variable stoichiometry and inclusion geometry. (19)F DP (direct polarization) and (13)C CP (cross-polarization) with magic-angle spinning (MAS) solids NMR, along with (19)F/(1)H solution NMR were used to characterize the complexes in the solid and solution phases, respectively. The dynamics of the guest molecules in the inclusion complexes (ICs) were studied using variable temperature (VT) (19)F DP/MAS NMR experiments in the solid state. The guest molecules were observed to be in several different molecular environments, providing strong evidence of variable host-guest stoichiometry and inclusion geometry, in accordance with the preparation method of the complex and the conformational preference of PFOA. It was concluded from PXRD that β-CD and PFOA form inclusion complexes with "channel-type" structures. Variable spin rate (VSR) (19)F DP/MAS NMR was used to assess the phase purity of the complexes, and it was revealed that slow cooling resulted in relatively pure phases. In the solution state, (1)H and (19)F NMR complexation-induced chemical shifts (CISs) of β-CD and PFOA, respectively, provided strong support for the formation of 1:1 and 2:1 β-CD/PFOA inclusion complexes. The dynamics of the guest molecule in the β-CD/PFOA complexes in D(2)O solutions were probed using VT (19)F NMR and revealed some guest conformational and exchange dynamics as a function of temperature and the relative concentrations of the host and guest.

Effect of temperature on the enantioselectivity of basic analytes using CE with sulfated β‐cyclodextrins

Twelve basic analytes, including ephedrine and its structurally related compounds, were used to study the influence of capillary temperature on enantioselectivity in CE enantioseparations under reversed polarity mode using sulfated beta-CD (S-beta-CD) as chiral selectors. All of the effective mobility changes of (+)-enantiomers between 35 and 20 degrees C were higher than those of (-)-enantiomers whosoever enantioselectivity increased or decreased with an increase in temperature. However, the unusual temperature effect that enantioselectivity was increased with an increase of temperature was observed for the compounds with hydroxyl substitution on phenyl ring and had relationship with the molecular structures. With performing NMR studies on the selected selector-analyte complexes, the results led to a deeper understanding of the chiral discrimination process. Inspection of the complexation-induced chemical shifts (CICS) of the enantiomers showed that the phenyl ring sits deeply and slantways in the cavity of S-beta-CD and alkyl chain pointed out of the wider rim of S-beta-CD with ion-ion and hydrogen bond interactions between analytes and S-beta-CD.

NMR characterization of the host–guest inclusion complex between β‐cyclodextrin and doxepin

The interaction between doxepin, a member of the tricyclic antidepressant (TCA) class of drugs, with beta-cyclodextrin (beta-CD) was investigated using NMR. Several TCAs have been reported to form a complex with beta-CD having 1:1 stoichiometry. Previous results from UV-visible spectroscopy, fluorescence measurements, and molecular modeling indicated that for imipramine, desipramine, and amitriptyline, the TCA aliphatic tail is included in the cyclodextrin cavity with apparently no interaction of the tricyclic ring. An alternative view of the doxepin-beta-CD complex is presented in this work using analysis of complexation-induced chemical shifts (CICSs), the method of continuous variation (Job's analysis), and analysis of ROESY spectra. The Job's plot derived from the NMR spectral data confirms that the complex formed has 1:1 stoichiometry. The largest changes in the CICS data were observed for the aromatic protons of one of the doxepin rings, with much smaller chemical shift changes observed for the protons of the other aromatic ring and the doxepin tail. Perhaps the most significant evidence for inclusion of the doxepin tricyclic ring is the strong ROESY cross peaks between the doxepin aromatic resonances and the protons located inside the beta-CD cavity. Changes in the doxepin (1)H NMR spectrum and the behavior of ROESY exchange cross peaks suggest that inclusion complex formation decreases the rate of internal motions of doxepin.

NMR Spectroscopic and Molecular Modelling Studies on Cyclodextrin–Dipeptide Inclusion Complexes

AbstractCyclodextrins (CDs) are often used to separate the enantiomers of chiral drugs by HPLC, GC, and capillary electrophoresis (CE). For dipeptides containing one aromatic amino acid, a reversal of the migration order is observed in CE upon increasing the pH value of the background electrolyte from 2.5 to 3.5. In order to understand the mechanism of chiral recognition of this phenomenon, NMR experiments, namely complexation‐induced chemical shifts (CICS) and ROESY, were performed. Comparing the CICSs obtained for the pairs Diac‐β‐CD/Ala‐Phe and HDAS‐β‐CD/Ala‐Phe and Diac‐β‐CD/Ala‐Tyr and HDAS‐β‐CD/Ala‐Tyr revealed very small changes, thereby indicating a rather weak interaction of the respective guest molecules with their host. The CICS for β‐CD and HS‐β‐CD confirmed an inclusion of the aromatic moiety into the CD cavity. It is shown that, at pH 2.5, the D,D‐enantiomer of Ala‐Tyr immerses deeper into the cavity of β‐cyclodextrin than the L,L‐enantiomer, and this was subsequently confirmed by molecular dynamics simulations. Furthermore, at pH 3.5 the immersion is shallower, as shown by the 1H and ROESY NMR findings and confirmed by the molecular dynamics simulations. The immersion depths of the dipeptides were calculated by defining a plane in the cavity to gain information about the different behaviour of the studied chemical species. The employed procedure is easily generalised to other host‐guest complexes and is expected to improve data evaluation in other cases, too. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Applicability of the 1H NMR chemical shifts computed by the ab initio/GIAO-HF methodology to the study of geometrical features of Zn-porphyrin dimers

Several porphyrin dimers have been newly designed and synthesized to construct assemblies with 1,4-diazabicyclo[2.2.2]octane (DABCO) as a bidentate binding ligand. Semi empirical (AM1) and ab initio calculations have been used to study the assemblies generated by the organization of dimers and DABCO, including the computation of 1H NMR complexation-induced chemical shifts using the ab initio/GIAO methodology. The diagnostic capacity of the theoretical method has been applied to explain experimental results and geometrical features of the complexes.

An NMR tool for cyclodextrin selection in enantiomeric resolution by high‐performance liquid chromatography

AbstractComplexation‐induced chemical shifts and diffusion coefficients (HR‐DOSY) of enantiomers with native and derivatized cyclodextrins were used for calculations of the apparent binding constants of three cyclohexanone inclusion complexes. Correlations between these data and high‐performance liquid chromatography were established, revealing that this approach can be applied as an alternative method to predict enantiomeric discrimination. Copyright © 2002 John Wiley & Sons, Ltd.

GIAO-DFT calculated and experimentally derived complexation-induced chemical shifts of calix[4]arene–solvent inclusion complexesElectronic supplementary information (ESI) available: calculated and observed NMR data and geometrical details for complexes 1–3, 1–4 and 1–5. See http://www.rsc.org/suppdata/p2/b1/b110078p/

Various possible geometries of host–guest complexes of p-tert-butylcalix[4]arene with guest molecules such as toluene or THF are modeled using fast force field optimisations. Based on minima structures obtained by this approach quantum chemical gauge-independent atomic orbital (GIAO)-DFT NMR calculations [B3LYP/3-21G and B3LYP/6-31G(d)] were performed. By a comparison of the theoretically derived chemical shifts for the guest molecule in the host–guest complex with the chemical shifts calculated for the free guest using the same theoretical approach, calculation of complexation-induced chemical shifts (CISs) is possible. Spatial arrangements for which the theoretically derived complexation-induced shifts are in accordance with data stemming from CP-MAS 13C NMR spectroscopy also show reasonable agreement with structures obtained by single crystal structure determinations. Thus, it is possible for calix[4]arene complexes using a combination of force field geometry optimisation and GIAO-DFT NMR shift calculations to screen various starting geometries against experimental data yielding good structural models for these complexes in the solid state.

An NMR study on the conformation of naphthalene–viologen linked compounds: effect of flexible spacer length

The conformational equilibria of naphthalene–viologen compounds linked with a flexible polymethylene bridge [–(CH2)n–; n = 3, 5, 7, 9, 12] were examined by NMR spectroscopy and molecular modeling. The chemical shift of the donor–acceptor dyad molecules depends on the linkage length and concentration. The equilibrium constants for the intramolecular and the intermolecular complexation were obtained from the chemical shift variation with concentration at high salt concentration. The complexation-induced chemical shifts (CISs) of the intra- and intermolecular complexes are obtained for molecules of n = 3 and 5. The molecules with longer linkages (n = 9 and 12) show aggregation behavior and the critical coagulation concentrations were obtained as 1.7 and 10 mM, respectively. Comparing the NMR results with molecular modeling calculations indicates that the naphthalene moiety can take various positions and orientations with respect to the bipyridinium moieties depending on the length of the linkage.

Characterisation of ‘sandwich’ charge-transfer complexes composed of bis-anthracene donors and aromatic acceptors

Properties of ‘sandwich’ charge-transfer (CT) complexes composed of bis-anthracene host compounds, in which two anthracences are connected by an anthraquinone spacer, and various aromatic acceptors have been systematically studied. Complexation stronger than that seen in monomer model compounds was observed in all cases. Thermodynamic analysis revealed that this enhanced binding to acceptors is due to larger enthalpic gain accompanied by a lower entropy loss effected by preorganization of the host. The major factor that determines the association constants is not the strength but the steric features of acceptor. Binding constants for fluorenones with nitro residues in the bay region are smaller because of the bulkiness of the substituents. It has been established that the CT complexes are of the weak bπ–aπ type from the analysis of the CT absorption energy. Complexation-induced chemical shifts in the 1H NMR spectra indicate highly oriented guest inclusion and have revealed some geometrical features of the complexes.

Molecular Recognition and Binding of a GC Site-Avoiding Thiazole-Lexitropsin to the Decadeoxyribonucleotide d-[CGCAATTGCG]2:1H-NMR Evidence for Thiazole Intercalation

The structural and dynamic aspects of the interaction of the thiazole containing lexitropsin (1) with an oligodeoxyribonucleotide were studied by high field 1H-NMR spectroscopy. Complete assignment of the 1H-NMR resonances of lexitropsin 1 was accomplished by 2D-NMR techniques. The complexation-induced chemical shifts and NOE cross peaks in the NOESY map of the 1:1 complex of lexitropsin (1) and d-[CGCAATTGCG]2 reveal that the thiazole ring of the lexitropsin (1) intercalates between dA4.A5 bases and the rest of the ligand resides in the minor groove of the AT rich core of decamer, thus occupying the 5'-AATT sequence on the DNA. Intercalation of the thiazole moiety of the drug has been detected by the presence of intermolecular NOEs both in the major and the minor groove of the decamer helix. The absence of intranucleotide NOEs between base protons and H1'/H2' protons suggested local unwinding of the binding site on the DNA. From COSY and NOESY methods of 2D-NMR, it was established that the N-formyl (amino) terminus of the thiazole lexitropsin (1) is projecting into the major groove towards A5H8 while the amidinium terminus lies in the minor groove towards the T7G8 base pairs of the opposite strand. The expected intranucleotide NOEs confirmed that the decadeoxyribonucleotide in the 1:1 complex exists in a right handed B-conformation. The presence of exchange signals along the binding site 5'-AATT indicated an exchange of the bound drug process wherein the rate of exchange between the two equivalent sites was estimated to be congruent to 130 s-1 at 30 degrees C and with delta G degrees of 62.4 kJ mol-1. Force field and Pi calculations permitted a rationalization of the experimentally observed binding mode in terms of preferred conformation of the ligand and repeat length in lexitropsins compared with the DNA receptor.