Electrophilicity Scale of Activated Amides: 17O NMR and 15N NMR Chemical Shifts of Acyclic Twisted Amides in N−C(O) Cross-Coupling

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to n_N→π*_C=O conjugation. In this study, we report electrophilicity scale by exploiting ¹⁷O NMR and ¹⁵N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.     

Synthesis and conformational studies of 3,4-di-O-acylated furanoid sugar amino acid-containing analogs of the receptor binding inhibitor of vasoactive intestinal peptide

Structural analysis of the di-O-caprylated Gaa-containing analog of the receptor binding inhibitors of vasoactive intestinal peptide by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined β-turn structure in DMSO-d₆ with an intramolecular hydrogen bond between TyrNH → MetCO.     

Solution and Solid State Studies of Urea Derivatives of DITIPIRAM Acting as Powerful Anion Receptors

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4–7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2′,3′-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO₂, F, CF₃, and Me). Solution, X-ray, and DFT studies reveal that the presented host–guest system offers a convergent array of four urea NH hydrogen bond donors to anions allowing the formation of remarkably stable complexes with carboxylates (acetate, benzoate) and chloride anions in solution, even in competitive solvent mixtures such as DMSO-d₆/H₂O 99.5/0.5 (v/v) and DMSO-d₃/MeOH-d₃ 9:1 (v/v). The most effective derivatives among the series turned out to be receptors 5 and 6 containing electron-withdrawing F- and -CF₃ para-substituents, respectively.     

A novel anion receptor employing the pyrrole and amide moieties in the cooperative binding of anions

A novel anion receptor 1 based on pyrrole and amide moieties was designed, synthesized and characterized by X-ray crystallography, ¹H NMR, ESI-MS and so on. Its anions (such as AcO^?, F^?, Cl^? and H₂PO₄ ^?) binding properties was studied in detail by the ¹H NMR titrations in DMSO-d ₆ .     

The mechanism of α-γ transition of poly- (vinylidene fluoride) in the miscible blends

The simultaneous DSC-FTIR was used for the observation of crystallization and melting of poly(vinylidene fluoride) (PVDF) and its blends with poly(methyl methacrylate) (PMMA) and poly(ethyl methacrylate) (PEMA). The isothermal crystallization was carried out under the condition of both α-form and γ-form crystallized competitively. The crystal growth rate of α -form and γ -form were evaluated from the absorbance changes at 795 cm^-1 (α -form, CH₂ rocking) and 810 cm^-1 (γ -form, CH₂ rocking) obtained by the DSC-FTIR. The crystal growth rate of γ -form decreased at the same crystallization temperature in the order of PVDF/syn-PMMA, PVDF/PEMA and PVDF/at-PMMA, which was corresponding to the order of interaction parameter. The mechanism of α -g transition of PVDF in the miscible blends with at-PMMA, syn-PMMA and PEMA was evaluated from the relationship between the decrease of α -form and the increase of γ -form. The critical crystallization temperature, at which the transformation from α -form to γ -form proceeded only in the solid state, shifted to higher temperature side in the order of interaction parameter. This revised version was published online in August 2006 with corrections to the Cover Date.     

Isolation of the saddle and crown conformers of cyclotriveratrylene (CTV) oxime

The oxime of cyclotriveratrylene (CTV) has been prepared and the individual crown and saddle conformers were isolated and characterized. The equilibrium constant was measured in CDCl₃ and in DMSO-d₆ and was shown to favor the crown conformer by an order of magnitude in DMSO-d₆, relative to an approximately equal mixture at equilibrium in CDCl₃. The time course for interconversion of the saddle to the crown was measured by ¹H NMR and the t_1/2 of the saddle was determined to be 2.45 h in CDCl₃ at 25 °C, and 3.71 h in DMSO-d₆.     

Stéréochimie des échanges hydrogène-deuterium des protons benzyliques des arènetricarbonylchrome. Echange des protons en syn du métal

Tetralintricarbonylchromium exchanges anti and syn benzylic protons in a solution of potassium tert-butoxide DMSO-d₆. Under the same conditions the syn benzylic tertiary proton of trans-1-methyltetralintricarbonylchromium remains unchanged. The anti and syn benzylic protons of dihydroanthracenetricarbonylchromium and xanthenetricarbonylchromium undergo exchange and trans-9-methyl xanthenetricarbonylchromium undergoes exchange and epiinerisation.     

1-Fluoro-2-hydrostibatrane

1-Fluoro-2-hydrostibatrane was synthesized by the reaction of antimony trifluoride with triethanolamine. The molecular structure of the compound was studied by X-ray diffraction and multinuclear magnetic resonance. The coordination polyhedron of the Sb atom is intermediate between a distorted tetrahedron (AX₄E type of molecule) and a tetrahedral pyramid (AX₄DE type of molecule). Diastereotopism of the geminal protons of each methylene group in the half-rings of the heterocycle, observed in the NMR spectra, vanishes at 65°C because of reversible cleavage of the N → Sb coordination bond and inversion of the nitrogen atom. The chemical environment of the OCH₂ and NCH₂ protons of the heterocycle and 2-hydroxyethyl protons is averaged due to the fast prototropic tautomerism at 75–120°C (in DMSO-d ₆).     

Komplexkatalyse: XXV. 31P-NMR-spektroskopische charakterisierung der anti- und syn-struktur von C3-substituierten η3-allylbis(triarylphosphit)-nickel(II)-hexafluorophosphat-komplexen und der mechanismus der durch [C3H5Ni(P(OPh)3)2]PF6 katalysierten 1,4-trans-polymerisation des butadiens

The reaction of the η₃-allylbis(triarylphosphite)nickel(II) complexes with butadiene under chain propagation to give the polybutadienyl complex, [3-RC₃H₄Ni(P(OAr)₃)₂]PF₆, was monitored by ³¹P NMR spectroscopy. In the case of the triphenylphosphite complex both the anti- and the syn-configuration could be identified by means of their different AB spectra. The anti-syn isomerization, the higher reactivity of the thermodynamically more stable syn-form, and the formation of the anti-structure as a result of each individual butadiene insertion step was also proved. From these observations an experimentally well-grounded mechanism of the trans regulation with the anti-syn isomerization as the rate-determining step could be derived for the first time.     

Conformation of some ribofuranosyl imidazole and uracil nucleosides: a 1H and 13C nmr study

100 and 220 MHz ¹H NMR spectra, recorded in DMSO-d₆ solution and including some measurements at 343 K, of three anomeric pairs of novel 2', 3'-O-isopropylidene nucleosides (two ribofuranosyl imidazoles, 1 and 2, and one uridine 3, all related to intermediates in denovo nucleotide biosynthesis) have been analysed, mostly as overlapping ABX spin systems. Chemical shifts and couplings have enabled the α- and β-anomers to be identified; the sugar-ring vicinal H-H coupling constants indicate that the 2',3'-ketal blocking group locks the α and β anomers in predominantly S and approximately 1:1 N/S ribofuranoside conformations, respectively. Among the ¹³C shifts reported for 3 in DMSO-d₆, those of the 2', 3'-O-isopropylidene CH₃ in the α anomer (shift difference 1.4ppm) are around 1.6 ppm upfield of those for the β anomer (which have a shift difference of 1.8 ppm).     

A conformational study of [3.3](3,5)pyridinophane

A variable temperature ¹H NMR study of the [3.3](3,5)pyridinophane indicated that the syn(chair/chair) is more stable than syn(chair/boat) by 0.2 kcal/mol in solution, whereas the trimethylene bridges show disorder even at −150 °C in the solid state. A transition state search by ab initio MO calculations suggested two competitive conformational changes for syn(chair/chair)-syn(chair/boat) conversion via a bridge wobble or a ring inversion in the [3.3](3,5)pyridinophane.     

Unprecedented rearrangement during the formation of P-P homoatomic N-phosphino formamidine complexes

A variety of homoatomic P-P donor-acceptor homoleptic (R = R′) and heteroleptic (R ≠ R′) N-phosphino formamidine complexes [iPr₂N-C(H)N-PR₂-PR′₂]Cl were synthesized from the addition of N-phosphino formamidine (phosfam) donor reagent iPr₂N-C(H)N-PR₂ on halogenophosphane compounds R′₂PCl which are synthetic sources for the corresponding phosphenium derivatives R₂P⁺. We have demonstrated that the dynamic equilibrium observed between the different species is shifted either completely to the side of the free species or to the side of the donor-acceptor adduct [iPr₂N-C(H)N-PPh₂-PPh₂]Cl by changing the solvent or by varying the temperature. Activation parameters of ΔS^≠ = (−130 ± 7.2) J mol⁻¹ K⁻¹, ΔH^≠ = (8.4 ± 0.6) kJ mol⁻¹ and ΔG^≠ (298.15 K) = (53.6 ± 2.3) kJ mol⁻¹ were determined by an Eyring analysis over the temperature range of 193-293 K. The negative entropy of activation is consistent with an associative pathway and the low value of ΔH^≠ suggests that the energy barrier for this reaction is entropically controlled. Phosphine-phosphenium adducts is the most appropriate term to describe the dynamic process observed at variable temperature for complexes [iPr₂N-C(H)N-PR₂ → PR′₂]⁺, but the ³¹P NMR chemical shift and the calculated electronic charges are more in favor of a phosphinophosphonium Lewis drawing [iPr₂N-C(H)N-PR₂-PR′₂]⁺. Formation of the homoatomic P-P heteroleptic formamidine complexes [iPr₂N-C(H)NPR′₂PR₂]Cl (R = Ph, R′ = Et, iPr) results in the formal insertion of the phosphino group of the corresponding alkyl chlorophosphanes R′₂PCl into the N-P bond of the starting phosfam ligand iPr₂N-C(H)N-PR₂. Computed data are in agreement with the transient formation of a heteroatomic N-P intermediate [iPr₂N-C(H)N(PR₂)PR′₂]Cl, which then rearranges to the more thermodynamically favored homoatomic P-P compound [iPr₂N-C(H)N-PR₂-PR′₂]Cl.     

Bimanes. 19. Characteristics of the molecular structures of 1,5-diazabicyclo[3.3.0]octadienediones (9,10-dioxabimanes) determined by x-ray crystallography

The molecular structures of a variety of 1, 5-diazabicyclo[3.3.0]octadienediones (9, 10-dioxabimanes), including three 9, 10-dioxa-syn-bimanes, three 4, 6-bridged 9, 10-dioxa-syn-bimanes, and three 9, 10-dioxa-anti-bimanes, as determined by x-ray crystallography, are analyzed and compared with respect to planarity, bond distances, bond angles and intermolecular packing. “Planarity” may be the resultant of two non-planar equilibrium forms, a conclusion based on the anisotropic thermal motion parameters of the central N-N bond. “Amide”-type conjugation (N-C=O) is important in all planar bimanes; peripheral conjugation (N-C=C-C = O) is more significant in planar syn-bimanes and decreased conjugation is evident in the bent bridged syn-bimanes. Weak C? H…O bonds contribute significantly to the crystal packing arrangements.     

Anti to syn isomerization of oxacalix[4]arene bearing two methyl groups at the intra-annular distal positions

The thermal isomerization of anti to syn stereoisomers of oxacalix[4]arene bearing two methyl groups at the intra-annular distal positions was investigated by temperature-dependent NMR spectroscopy. The conversion followed a first-order kinetics, and very slowly proceeded at 473 K in nitrobenzene-d₅ with a half-life of 7.2 h. The free energy of activation (ΔG^≠ 139 kJ mol⁻¹) is much higher than those for the ring inversion of related calix[4]arene derivatives.     

Solvation-dependent diastereofacial selectivity: addition of lithioacetonitrile to 2-phenyl propanal

Diastereofacial selectivity in the addition of lithioacetonitrile to 2-phenyl propanal is temperature and solvent-dependent. Each solvent studied (benzene, toluene, n-hexane, cyclohexane, methylcyclohexane, THF, and diethyl ether) shows a different Eyring plot of ln(anti/syn) versus 1/T with specific differential activation parameters ΔΔH^≠ and ΔΔS^≠, and discloses the presence of inversion temperatures (T_invs). We demonstrated that the opposite temperature behaviour of the diastereomeric ratio (dr) observed for n-hexane and methylcyclohexane does not depend on the base (n-BuLi, LDA and LiHMDS) used to generate the anion, but is exclusively due to the reaction solvent. A 5 mol% of an amine in n-hexane and methylcyclohexane deeply affects the anti/syn ratio, the differential activation parameters, and the T_inv values. For n-hexane we were able to connect the inversion temperature of the pure solvent and of the Bu₃N-mixture with dynamic solvation phenomena revealed by VT ¹³C NMR measurements.     

Synthesis of 3,4-di-O-acylated glucose-derived furanoid sugar amino acids (Gaa): conformational analysis of a Leu-enkephalin analog containing di-O-myristoylated Gaa

3,4-Di-O-acylated derivatives 1-3 of a glucose-derived furanoid sugar amino acid (Gaa) were synthesized as novel peptide building blocks to study their effects on peptide conformation. Structural analysis of the di-O-myristoylated Gaa 3-containing Leu-enkephalin analog 4 by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined β-turn structure in DMSO-d₆ with an intramolecular hydrogen bond between PheNH → TyrCO.     

Asymmetric synthesis of the allocolchicinoid natural product N-acetylcolchinol methyl ether (suhailamine), solid state and solution phase conformational analysis

An asymmetric synthesis of the allocolchicinoid N-acetylcolchinol methyl ether (NCME) from 3-methoxybenzaldehyde is reported. Comparison of ¹H and ¹³C NMR spectroscopic data obtained for this sample of NCME provide further evidence for the assertion that this compound is congruous with the natural product that has been dubbed suhailamine, establishing NCME as a naturally-occurring allocolchicinoid. The single crystal X-ray diffraction structure of NCME is also reported for the first time, revealing a preference for adoption of the (7S,R_a,Z) form—i.e., describing the orientation of the biaryl axis and the amide N–CO bond as well as the configuration of the stereocenic centre—in the solid state. A preference for the same form in DMSO-d₆ solution is revealed upon analysis by a range of NMR spectroscopic techniques, whilst an interconverting 69:24:7 mixture of the (7S,R_a,Z), (7S,S_a,Z) and (7S,R_a,E) forms is observed in CDCl₃.     

Hydrogen bonding between carboxylic acids and amide-based macrocycles in their host–guest complexes

For 12- and 13-membered macrocycles in which two amide linkages are integrated in the macrocyclic ring systems, the formation of 1:1 host–guest complexes with acetic and benzoic acids has been confirmed by NMR titrations. The complex formation occurs with the formation constants of 8–27 M^? 1, under competition with the dimerisation of acid molecules. Benzoic acid tends to form more stable complexes than acetic acid. The binding force is due to a pair of hydrogen bonds, O_carboxyl–H…O = C_amide and C = O_carboxyl…H–N_amide, between the carboxyl group of a guest molecule and the amide group of a host molecule. The former bond is stronger than the latter, and defines the stability of the complexes. The formation of the pair of hydrogen bonds is accompanied by the conformational conversion of the amide group from the trans-form to the cis-form. The influence of such a conversion on the internal molecular motion is observed as a slight broadening of signal width.

For 12- and 13-membered macrocycles in which two amide linkages are integrated in the macrocyclic ring systems, the formation of 1:1 host–guest complexes with acetic and benzoic acids has been confirmed by NMR titrations. The binding force for the complex formation is due to a pair of hydrogen bonds, O_carboxyl–H…O = C_amide and C = O_carboxyl…H–N_amide. The former bond is stronger than the latter and dominates the hydrogen-bond formation. The formation of the pair of hydrogen bonds is accompanied by the conformational conversion of the amide group from the stable trans-form to the less stable cis-form.     

Spectroscopic and theoretical studies of N-trichlorophosphazotrifluoroacetyl,CF3C(O)NPCl3 and N-trichlorophosphazotrichloroacetyl,CCl3C(O)NPCl3

FTIR, Raman and NMR spectra of N-trichlorophosphazotrifluoroacetyl, CF₃C(O)NPCl₃ (1) and N-trichlorophosphazotrichloroacetyl, CCl₃C(O)NPCl₃ (2) were obtained. The experimental data are compared with results of ab initio and density functional theory (DFT) calculations. According the theoretical studies the main conformer for both molecules possesses C_s symmetry (CO bond syn respect to the NP bond). The preference of the syn conformation has been rationalized based on the natural bond orbital formalism. The vibrational spectra of 1 in the liquid phase and 2 in the solid phase are in good agreement with theoretical results.     

Conformational studies of some carbocyclic nucleoside analogues

Proton NMR spectra of some carbocyclic nucleoside analogs of tuberculin have been analyzed at 100 MHz in DMSO-d₆. The spectral characteristics and nuclear Overhauser effects indicate a preferential syn conformation about the glycosidic bond when a hydroxyl group, oriented toward the base, is available for intramolecular hydrogen bond formation.